Cardio Diabetes_2017 book

428 Glycemic Control- How Tight It Should Be?

HYPERGLYCEMIA AND DIABETIC HYPERGLYCEMIA AND DIABETIC
NEPHROPATHY NEUROPATHY

Diabetes mellitus is the major cause of end stage Diabetic neuropathy complicates both type 1 and
renal disease (ESRD) throughout the world. Diabet- type 2 diabetes. Diabetic peripheral and autonomic
ic nephropathy does not develop in all patients with neuropathies are common complications of diabe-
diabetes and it is believed to be progressive disease tes with a broad spectrum of clinical manifestations
from microalbuminuria to macroalbuminuria and and high morbidity. Among peripheral neuropathies
ESRD. The diagnosis of diabetic nephropathy can in diabetes, the most studied in clinical trials is dis-
be made by the persistent presence of albumin in tal symmetrical sensory motor polyneuropathy (DSP),
the urine, or continuous rise in serum creatinine, or and among autonomic neuropathies, the most stud-
a reduction in GFR. A target of HbA1c ≤ 7% is appro- ied is cardiovascular autonomic neuropathy (CAN).
priate for majority of patients with nephropathy. A The lack of standardized, validated measures for
lower target will increase the risk of hypoglycaemia DSP and CAN in most large trials limits the interpre-
and might increase their risk of mortality, whereas a tations of the data. DCTT/ EDIC and other smaller
higher target might accelerate the rate at which renal trials strongly demonstrated that intensive control
failure and other complications develop. designed to achieve near normoglycemia is essential
to delaying the progression of DSP and CAN in T1D.
Stage Description GFR (mL/min/ 1.73 m2) Target The effect of glycemic control on DSP and CAN are
1 Normal or ↑ GFR for ≥3 months HbA1c less conclusive for T2D.
2 Mild ↓ GFR >90 ≤7%
3 Moderate ↓ GFR 60–89 ≤7% CONCLUSIONS
4 Severe ↓ GFR 30–59 ≤7%
5 Kidney failure 15–29 ≤7% • In spite of the advent of newer therapeutic modal-
<15 or dialysis >7% (?) ities for diabetes, glycemic control remains chal-
lenging.
GFR - Glomerular Filtration Rate; HbA1c,
glycated hemoglobin. • By keeping glycemia under control, several compli-
cations can be prevented or at the least, delayed.

• Glycemic control can be achieved not only by tak-
ing drugs, but also through proper life style man-
agement.

• Tight glycemic control early on in the natural his-
tory of diabetes has far-reaching benefits for the
individual over his lifespan with respect to risk of
long-term vascular complications.

• Glycemic targets should be individualised, with
less stringent targets advocated for elderly pa-
tients, those with longer duration of diabetes and
multiple comorbidities.

REFERENCES

1. Rajalakshmi R, Prathiba V, Mohan V. Does tight control of systemic factors
help in the management of diabetic retinopathy? Indian J Ophthalmol
2016;64:62-68.Department of Ophthalmology, Dr. Mohan’s Diabetes Spe-
cialities Centre, Chennai, Tamil Nadu, India1Department of Diabetology,
Dr. Mohan’s Diabetes Specialties Centre and Madras Diabetes Research
Foundation, Chennai, Tamil Nadu, India

2. Chandalia HB, Thadani PM. Glycemic targets in diabetes. Int J Diabetes
Dev Ctries DOI 10.1007/s13410-016-0467-8

3. Newman D. Tight Glycemic Control for Type 2 Diabetes Mellitus (Over
Five Years). Medicine by the Numbers- A Collaboration of TheNNT.com
and AFP

4. Marik PE. Tight glycemic control in acutely ill patients: low evidence of
benefit, high evidence of harm! Intensive Care Med 2016;42:1475-1479.

GCDC 2017

Cardio Diabetes Medicine 2017 429

5. Buse JB. Glycemic Targets in Diabetes Care: Emerging Clarity after Accord.
Trans Am Clin Climatol Assoc.126:62-76.

6. Park TS. How much glycemic control is needed to prevent progression of
diabetic nephropathy? J Diabetes Investig 2012;3(5);411-412.

7. Ang L, Jaiswal M, Martin C, Pop-Busui R. Glucose Control and Diabetic
Neuropathy: Lessons from Recent Large Clinical Trials. Curr Diab Rep
2014;14:528.

8. Stephanie A. Amiel. The role of glycemia in diabetic complications. In: De-
Fronzo RA, Ferrannini E, Keen H, Zimmet P (eds) International Textbooks
of Diabetes Mellitus. Third edition. John Wiley & Sons, Ltd, Chichester,
West Sussex, John Wiley & Sons, Ltd. Chapter 63, 2004, pp 1161-74.

9. Adbulaziz R.Al-Harthi and William H.Herman. Effect of intensive
glycemic control on macrovascular events in patients with diabetes
mellitus. In: DeFronzo RA, Ferrannini E, Keen H, Zimmet P (eds)
International Textbooks of Diabetes Mellitus, Third edition. John Wiley
& Sons, Ltd, Chichester, West Sussex, John Wiley & Sons, Ltd. Chapter
76, 2004, pp 1371- 78.

Cardio Diabetes Medicine

430 Cardio Diabetes Medicine 2017

New Armamentarium In Combined Dyslipidemia
Management - Current Evidences

Dr. Sudhir Mehta, MD., MNAMS., FACP., FICP

Senior Professor, Department of Medicine,
SMS Medical College, Jaipur

ABSTRACT EZETIMIBE

Hypercholesterolemia, and in particular, an elevated Ezetimibe is a non-statin drug that decreases cho-
level of serum low density lipoprotein cholesterol lesterol level by inhibiting its absorption in the in-
(LDL-C), is associated with an increased risk of ad- testine. Ezetimibe was approved in 2003 for use in
verse cardiovascular events. Lipid lowering drug ther- management of dyslipidemia and prevention of CVD
apy, particularly with statins, is indicated to decrease as monotherapy in patients intolerant of statins or
the risk of cardiovascular events in most individu- as add on therapy to statins in high risk or refracto-
als with established atherosclerotic cardiovascular ry patients. Ezetimibe when added to statin therapy
disease and in many who are at high risk. Statins reduced LDL by 24% and CVD by 6%.1,2
are the preferred therapy for most patients requir-
ing treatment of dyslipidemia and in particular those Proprotein convertase subtilisin/kexin type
with an elevated LDL-C. If after treatment with the 9 (PCSK9) inhibitors [PCSK9 inhibitors]:
maximal tolerated dose of statin the patient has not
achieved the LDL-C goal, a number of other agents Proprotein convertase subtilisin/kexin type 9 (PCSK9)
are available with varying levels of evidence for clini- is a serine protease which binds to the LDL receptors
cal benefits. These individuals remain at high risk for on the hepatocyte surface and take it into lysosomes
cardiovascular events. This topic will discuss newer for degradation, thereby reducing the hepatic uptake
therapies beyond statins and their status in current of LDL.3 Inhibition of PCSK9 results in decreased LDL
clinical practice. receptor degradation, increased hepatic LDL uptake
and subsequently reduction in serum LDL.3 PCSK9
INTRODUCTION also enhances inflammation and endothelial dys-
function thus accelerate atherosclerosis.3
Dyslipidemia including hypercholesterolemia and
raised low density lipoprotein (LDL) is one of the The genetic studies document that loss-of-function
common risk factors for cardiovascular morbidity mutations of PCSK9 are associated with lower serum
and mortality. Many factors influence individual’s LDL and a reduction in cardiovascular risk while a
lipid levels including life style, endocrine/ metabolic gain of function mutation (as occurs in autosomal
status, genetic predisposition and drugs. With life- dominant familial hypercholesterolemia) is associat-
style modification, up to 37% reduction in LDL can ed with increased serum LDL.5
be achieved.Though statins (HMG CoA reductase in-
hibitors) are the most commonly used drug in man- Several PCSK9 inhibitors have been developed in-
agement of dyslipidemia, some patients are unable cluding evolocumab, alirocumab, LY3015014 and in-
to tolerate them and some fail to respond up to the clisiran. Evolocumab and alirocumab are fully human
desired level. To overcome these challenges, newer monoclonal antibodies. LY3015014 is a humanized
therapies are being developed for management of immunoglobulin G4 monoclonal antibody. Bococi-
dyslipidemia. This review will focus on the drugs be- zumab is a humanized antibody that inhibits PCSK9
yond statins. and was discontinued because of higher incidence
of antidrug antibodies formation that decreased its
efficacy in reduction of LDL.6 Inclisiran is a small in-

GCDC 2017

New Armamentarium In Combined Dyslipidemia 431
Management - Current Evidences

terfering RNA that silences target RNA and prevents bilized on a statin dose for 4 weeks with LDL ≥80 mg/
the synthesis of PCSK9 protein in the liver.7 dl or individuals with 1 major or 3 minor cardiovascu-
lar risk factors who had an LDL 60-80mg/dl. Individ-
A large pooled analysis of 24 randomized phase 2 uals had at least one epicardial coronary stenosis of
and 3 trials comprising 10,159 patients concluded ≥20% on clinically indicated coronary angiogram with
49% LDL reduction by PCSK9 inhibitors and relative a target vessel suitable for imaging. There was –0.95%
risk reductions (RRR) of 55% in all-cause mortality, change in atheroma volume at 78 weeks in the evolo-
50% in cardiovascular mortality and 51% in myocardial cumab group.13 This study documented effectiveness
infarction.8 of evolocumab in reducing LDL and atheroma plaque
in coronaries.
Two PCSK9 inhibitors alirocumab and evolucumab
are approved for use in familial hypercholesterolemia In March 2017, the results of FOURIER trial were
and in patients of CVD on maximum statin therapy published.14 This was a randomized, double-blind pla-
who needed an additional lipid lowering drug. cebo controlled multinational clinical trial recruiting
27,564 individuals with atherosclerotic CVD and LDL
ALIROCUMAB ≥70 mg/dl who were receiving statin therapy. Patients
were randomly assigned to receive evolocumab (ei-
Alirocumab is approved in dosage of 75 mg subcu- ther 140 mg every 2 weeks or 420 mg monthly) or
taneously every 2 week which can be titrated up to matching placebo as subcutaneous injections. After
150mg every 2 weeks. a median follow-up of 2.2 years, LDL decreased by
59% with median LDL of 30 mg/dl. LDL was <25mg/
Alirocumab significantly reduces serum LDL by 62 dl in 42% subjects on evolocumab. The primary effi-
% and major CVD by 48 % in a 78 week randamized cacy end point was the composite of cardiovascular
placebo controlled safety trial, the ODYSSEY-LONG death, myocardial infarction, stroke, hospitalization
TERM.9 The adverse effects were nasopharyngitis, in- for unstable angina, or coronary revascularization.
jection site reactions, myalgia, neurocognitive events, The key secondary efficacy end point was the com-
urinary tract infection and diarrhea. posite of cardiovascular death, myocardial infarction,
or stroke. Eevolocumab treatment significantly re-
Results of the ODYSSEY OUTCOMES are awaited duced the risk of the primary end point (9.8% vs. 11.3%
which is a randomized controlled trial recruiting ap- patients; hazard ratio, 0.85; 95% confidence interval
proximately 18000 individuals, to detect a 15% hazard [CI], 0.79 to 0.92; P<0.001) and the key secondary
reduction in MACE in individuals with a recent acute end point (5.9% vs. 7.4%; hazard ratio, 0.80; 95% CI,
coronary syndrome (<1 year) and LDL ≥70mg/dl.10 0.73 to 0.88; P<0.001). The adverse events occurred
were diabetes and neurocognitive events which were
EVOLOCUMAB similar in both groups while injection-site reactions
were more common with evolocumab. The FOURIER
Evolocumab decreases LDL by approximately 60% trial showed a median 30 mg/dl reduction in LDL and
when added to statin therapy.11 It is approved in significant reduction in CVD by evolocumab along
dosage of 140mg subcutaneously every 2 weeks or with statin therapy in patients with established ath-
420mg every 4 weeks. erosclerotic CVD.14

The OSLER 1 and 2 trials evaluated the safety and tol- Heterozygous Familial
erability of evolocumab therapy and found no severe Hypercholesterolaemia (HeFH)
or life-threatening adverse reactions. The most side
effects reported with equal frequency in both groups • Statins lower both LDL cholesterol and cardiovas-
were injection site reactions, nasopharyngitis, upper cular disease burden in heterozygous FH and even
respiratory tract infection, back pain, headache and normalise coronary mortality if started before the
arthralgia. Neurocognitive changes were more com- onset of cardio vascular disease (CVD). Individuals
mon with evolocumab. Evolocumab reduced LDL with established CVD remain at about 4 times in-
by 61%, from a median of 120 mg/dl to 48 mg/dl at creased risk of death from coronary heart disease
12 weeks. At 1 year the CV events were reduced to despite statin therapy and up to 40% of patients
0.95% in the evolocumab group compared to 2.18% with heterozygous FH fail to achieve acceptable
in placebo group (hazard ratio 0.47; 95% confidence LDL level despite statin therapy. Both alirocumab
interval, 0.28 to 0.78; P=0.003).12 and evolocumab are effective in reduction of LDL
in these patients.15
The GLAGOV trial used intravascular ultrasound to
monitor atheroma volume in individuals on evolo-
cumab. The GLAGOV trial recruited 968 individuals
with or at high risk for atherosclerosis who were sta-

Cardio Diabetes Medicine

432 Cardio Diabetes Medicine 2017

• In two studies (ODYSSEY FH I, n = 486; FH II, n = and in those without an identified LDLR mutation.24
249), patients were randomized 2 : 1 to alirocumab Thus, both alirocumab and evolocumab are highly eff
75 mg or placebo every 2 weeks. Alirocumab dose ective in further reducing LDL cholesterol in patients
was increased at Week 12 to 150 mg if Week 8 with heterozygous familial hypercholesterolaemia
LDL was ≥70 mg/dL. Mean LDL decreased from when added to high-intensity statin therapy.15
144.7 mg/dL to 71.3 mg/dL ( -57.9% vs. placebo) at
Week 24 in patients randomized to alirocumab in Homozygous Familial
FH I and from 134.6 mg/dL to 67.7 mg/dL ( -51.4% Hypercholesterolaemia (HoFH)
vs. placebo) in FH II (P < 0.0001). These reductions
were maintained through Week 78. LDL-C <71.3 HoFH is characterised by very high LDL and result-
mg/dL was achieved at Week 24 by 59.8 and ing atherosclerotic CVD early in life. It occurs due
68.2% of alirocumab-treated patients in FH I and to loss-of-function mutations in both alleles of the
FH II, respectively. In patients with HeFH and inad- LDLR gene (in most cases) or in other genes encod-
equate LDL control at baseline despite maximally ing proteins in the LDL-receptor pathway. Because
tolerated statin therapy, alirocumab treatment re- of very low or absent residual LDL-receptor activity,
sulted in significant LDL reduction and was well standard lipid-lowering therapies that work through
tolerated. Alirocumab also significantly reduced the common pathway of LDL-receptor upregulation
apolipoprotein B concentration by about 40% and (statins, ezetimibe, bile acid sequestrants) are much
non-HDL cholesterol concentration by about 50% less effective or completely ineffective in patients
compared with placebo (both p<0·0001).15 with HoFH. Even with optimised therapy including
high-intensity statin with or without ezetimibe, plus
Alirocumab (150 mg every 2 weeks) was also as- LDL apheresis, LDL remain raised and the mean age
sessed in a cohort of patients with severe hetero- of death is 33 years.
zygous familial hypercholesterolaemia (mean LDL
cholesterol 5 mmol/L) in ODYSSEY-HIGH, a phase In an open-label, single-arm study (TESLA part A),
3, 78-week study, in which treatment with alirocumab evolocumab (420 mg monthly) reduced LDL by a
led to a 40% placebo-corrected reduction in LDL cho- mean of 16·5% in HoFH.15 In a subsequent 12-week,
lesterol from baseline (p<0·0001), which was main- placebo-controlled RCT with 49 participants (TESLA
tained for 52 weeks.15 part B), evolocumab treatment significantly reduced
mean LDL cholesterol by 31%.16 Evolocumab is ap-
In a 12-week phase 2 trial (RUTHERFORD), more than proved for use in patients with homozygous famil-
160 patients with heterozygous familial hypercholes- ial hyper cholesterolaemia who are at least 13 years
tero laemia and an LDL cholesterol concentration of old, in addition to optimised standard therapy, and
2·6 mmol/L or more despite optimum lipid-lowering for most of these patients represents a reasonable
therapy were randomly assigned to evolocumab (350 next step beyond standard therapy.
mg or 420 mg monthly) or placebo.62 By week 12,
compared with placebo, evolocumab at both doses INCLISIRAN
signifi cantly reduced LDL cholesterol (44% reduction
with 350 mg dose; 56% reduction with 420 mg dose; Inclisiran is a small interfering RNA that binds to
p<0·001); non-HDL cholesterol and apolipoprotein B RNA-induced silencing complex (RISK), leading to
were also signifi cantly reduced in the evolocumab degradation of the mRNA of PCSK9, reducing its
groups versus placebo (p<0·001). In the phase 3 tri- translation, and subsequently decreasing the degra-
al of this series (RUTHERFORD-2), more than 300 dation of LDL receptors.
patients with heterozygous familial hypercholestero-
laemia and similar lipid profi les at baseline were Inclisiran (ALN-PCSSC) has been evaluated in phase
randomly assigned to evolocumab (140 mg every II trials and found to be well tolerated. Inclisiran re-
2 weeks or 420 mg monthly) and followed up for sults in dose-dependent reductions in PCSK9 and
12 weeks, with similar results to the phase 2 trial: LDL levels. At day 180, the least-squares mean re-
compared with placebo, evolocumab significantly ductions in LDL levels were 27.9 to 41.9% after a
reduced mean LDL cholesterol by 60% (p<0·0001), single dose of inclisiran and 35.5 to 52.6% after two
non- HDL cholesterol by 55% (p<0·0001), and apo- doses. Maximum reduction in LDL was seen after 2
lipoprotein B by 50% (p<0·0001).24 Roughly 80% of doses of 300 mg (at day 1 and 90), approximately
the participants in this study were reported to have 48% of the patients had LDL <50 mg/dl at day 180.
an LDLR mutation. The effects of evolocumab were At day 240, PCSK9 and LDL levels remained signifi-
similar across the different LDLR mutation classes cantly lower than at baseline. Serious adverse events
occurred in 11% of the patients in inclisiran arm (8% in

GCDC 2017

New Armamentarium In Combined Dyslipidemia 433
Management - Current Evidences

placebo arm). Injection-site reactions occurred in 5% LOMITAPIDE
of the patients receiving inclisiran.7
Lomitapide is an MTP inhibitor. MTP is crucial for
ANGPTL3 Antagonistic Agents: VLDL synthesis in the liver. MTP facilitates the trans-
fer of lipids to Apo B-100, playing an important role
An association was found between loss-of-function in assembling and synthesis of VLDL, and ultimately
genetic variants in the gene encoding angiopoie- LDL. MTP also participates in the association of TG
tin-like 3 (ANGPTL3) and low levels of LDL, HDL, and with Apo B-48 in chylomicrons. Lomitapide binds to
triglycerides.16 MTP and inhibits its function, therefore reducing both
chylomicrons and VLDL, and consequently decreas-
In a study loss-of-function variants in ANGPTL3 were ing plasma levels of LDL, TG, and Lp(a). Lomitapide
associated with decreased plasma triglycerides, LDL, lowers plasma LDL levels by up to 51%.3
HDL and reduced risk of CVD. In this study, ANGPTL3
monoclonal antibody injection resulted in a lipopro- There are no clinical outcome trials published yet.
tein profile similar to that found in people who have However since preventing VLDL formation is highly
loss of function variants.16 cytotoxic for the liver, the FDA has mandated that
patients should be monitored for liver toxicity.
Similarly in another study targeting ANGPTL3 in the
liver with the use of antisense oligonucleotides also Cholesterylester Transfer Protein (CETP): Cholestery-
leads to reduction in triglycerides and other plasma lester transfer protein (CETP) normally works to
lipoproteins.16 facilitate the transfer of cholesteryl esters and tri-
glycerides from HDL to lipoproteins. CETP inhibition
A meta-analysis of all five studies showed an odds increases HDL and decreases LDL and lipoprotein(a)
ratio for coronary artery disease of 0.61 (95% con- levels.3 Early studies of CETP inhibitors have failed
fidence interval, 0.45 to 0.81) among patients with to show any clinical benefit, while one study of the
loss-of-function variants in ANGPTL3. Progressive CETP inhibitor anacetrapib is currently ongoing.3
reductions in ANGPTL3 levels achieved with the use
of either single ascending doses of a monoclonal ANTISENSE TARGETING PCSK9: Several PCSK9
antibody targeting ANGPTL32 or multiple ascend- orally effective antibodies are also in development
ing doses of an antisense oligonucleotide targeting i.e. Adnectin (BMS-962476).
ANGPTL33 led to similar maximum reductions in lev-
els of triglyceride (76% and 63%, respectively), LDL CONCLUSION:
cholesterol (23% and 33%), and HDL cholesterol (18%
and 27%).16 Although statins are used for dyslipidemia manage-
ment since more than 30 years, they fail to achive
Antagonism of ANGPTL3 was associated with de- target lipid levels in some patients. Recently new
creased levels of LDL, HDL, TGs and decreased risk drugs are coming including PCSK9 inhibitors (aliro-
of atherosclerotic CVD. cumab and evolocumab) for patients who fail to re-
spond to conventional lipid lowering therapies. These
Orphan Drugs: These lipid lowering drugs are used drugs also have shown promising results in familial
to treat HoFH in combination with a low-fat diet and hypercholesterolemia. Mipomersen and Lomitapide
other lipid- lowering therapies. Currently, two drugs are also approved for familial hypercholesterolemia.
are approved- mipomersen and lomitapide.
Inclisiran, ANGPTL3 antagonistic agents and anti-
MIPOMERSEN sense targeting PCSK9 are under development.

Mipomersen is an apo B-100 antisense, a synthetic These newer agents in our armamentarium would
strand of nucleic acid that enters hepatocyte nuclei hopefully reduce dyslipidemia and cardiovascular
to form an antisense-Apo B-100 mRNA complex. This burden.
complex can be recognized and cleaved by RNase
H or interfere with translation to reduce synthesis of TAKE HOME MASSAGE:
Apo B-100. Since Apo B- 100 is the major apolipopro-
tein of LDL and VLDL, a reduction of Apo B-100 ex- New approaches that increase lipoprotein lipase ac-
pression decreases the synthesis of both VLDL and tivity, including PCSK9 inhibitors, ANGPTL3 inhibi-
LDL, and subsequently total plasma cholesterol and tors, mipomersen and lomitapide represent a fresh
LDL. Weekly subcutaneous injections of mipomersen frontier in the treatment of dyslipidemia not ade-
200 mg for 26 weeks reduce LDL by up to 36%. No quately managed with conventional drugs.
changes were observed in HDL-cholesterol.3

Cardio Diabetes Medicine

434 Cardio Diabetes Medicine 2017

REFERENCES :

1. Stone NJ et al.: 2013 ACC/AHA guideline on the treatment of blood
cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report
of the American College of Cardiology/ American Heart Association task
force on practice guidelines. Circulation 2014, 129(25 Suppl. 2):S1-S45.

2. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin ther-
apy after acute coronary syndromes. N Engl J Med 2015;372: 2387–97

3. Yingzi Chang, Jacques Robidoux. Dyslipidemia management update. Cur-
rent Opinion in Pharmacology 2017; 33:47–55

4. Edward T Carreras, Donna M Polk. Dyslipidemia: Current Therapies And
Guidelines For Treatment. US Cardiology Review 2017;11(1):10–5

5. Allard D, Amsellem S, Abifadel M, et al. Novel mutations of the PCSK9
gene cause variable phenotype of autosomal dominant hypercholesterol-
emia. Hum Mutat 2005; 26:497

6. Ridker PM. SPIRE 1 and SPIRE 2: safety and CV event efficacy of boco-
cizumab in high risk patients. American College of Cardiology Confer-
ence,2017. Washington, DC.

GCDC 2017

Cardio Diabetes Medicine 2017 435

Cardiovascular Outcomes with Antihyperglycemic
Therapy : Past, Present and Future Impact on Practice

Dr.V.Balachandran,

MD,MNAMS, FRCP, FACC, FCSI, FISC, Dip. Diab,

Chief Physician-Cardio-Diabetology,
Dr.Nair’s Hospital, Kollam ,Kerala,

Abstract years to develop evidence based treatment strate-
gies for type 2 diabetes that will not only reduce the
There is a wealth of epidemiological data which disease progression but will also reduce the CV dis-
shows that type 2 diabetes significantly increase the ease burden and will prolong life. Nissen and Wolski
risk of cardiovascular events. The evidence from ear- published a meta-analysis in 2007 suggesting that
lier trials have demonstrated that improvement in gly- Rosiglitazone was associated with significant risk
cated hemoglobin will reduce the risk of micro vas- of myocardial infarction (MI) and with increase risk
cular disease but there is lack of robust evidence to of death from CV causes. Their finding initiated an
suggest whether improvement in glycogenic control intense debate about the CV safety of the antidia-
will have similar beneficial outcomes on macro vas- betic drugs and led to a remarkable change in the
cular disease. In the last few years there have been a landscape of subsequent diabetic trials that have
paradigm shift by which cardiovascular trials relating been conducted over the last few years. The US FDA
to therapy in type 2 diabetes are being conducted revised their approval process for newer antidiabet-
as every new drug needs to demonstrate cardiovas- ic agents recommending that apart from lowering
cular safety as per the requirements set by several HbA1c which remains an acceptable primary effica-
health regulatory authorities. This article provides a cy endpoint sponsors should demonstrate that the
comparison between past and present cardiovascu- therapy does not increase CV risk to an unacceptable
lar outcome trials focusing on all anti hyperglycemic extent (1). The guidance also suggested that if the
agents used in type 2 diabetes and also explores the premarketing application contains clinical data that
challenges encountered in conducting such trials. showed that the upper bound of the two-sided 95%
confidence interval (CI) for the estimated increased
Keywords: Type 2 diabetes, glycated hemoglobin, risk (i.e., risk ratio) is between 1.3 and 1.8, and the
cardiovascular, trial overall risk benefit analysis supports approval, a post
marketing trial will be needed to definitely show that
Introduction upper bound of the two-sided 95% CI for the estimat-
ed risk ratio is less than 1.3. This essentially meant
The risk of cardiovascular disease (CVD) is twice in that the trials needed to be adequately powered and
people with type 2 diabetes when compared to peo- should include patients who are at higher risk of CV
ple without diabetes after events, such as patients with relatively advanced
disease, elderly and patients with some degree of
adjustment for established cardiovascular (CV) risk renal impairment (1). This has led to a plethora of CV
factors. Prospective epidemiological and experimen- outcome trials with glucose lowering agents in type 2
tal studies have reported an association between diabetes which are mostly and typically event-driven
suboptimal glycemic control [measured by an ele- and are conducted to satisfy regulatory requirements
vated glycated hemoglobin (HbA1c)] and both micro in the shortest possible time. Majority of these trials
and macro vascular complications. It was found that are simple placebo controlled non-inferiority study
the relative risk for coronary heart disease (CHD) or designs which aims to show an absence of cardio-
stroke has been estimated at 1.18% (95% CI: 1.10-1.26) vascular toxicity based on end point events. As per
for every 1% increase in HbA1c . In recognition of the
graded relationship between glycaemic control and
CV events a major shift has taken place in the recent

Cardio Diabetes Medicine

436 Cardiovascular Outcomes With Antihyperglycemic Therapy:
Past , Present , and Future Impact on Practice

guidance, in majority of the studies major adverse debate whether the response would have been dif-
CV events (MACE) has been selected as a primary ferent in a newly diagnosed diabetes population but
end point which include CV mortality, MI and stroke it reliably proved the principle that glycemic control
and also includes hospitalization for acute coronary alone is not a reliable surrogate marker for reduction
syndrome, urgent revascularization procedures and of CV events. However, a meta-analysis by Turnbull
heart failure (HF) (2) et al of these three trials together with first 5 years
of follow up data from UKPDS showed a significant
Cardiovascular outcome trials from the past reduction of MACE and particularly a risk reduction
on intense glycemic control in MI with intensive glucose lowering (3). There were
other trials which looked into CV events and mortality
In the past large scale landmark trials like United endpoints and did not solely concentrate on glucose
Kingdom Prospective Diabetes Study (UKPDS) have lowering strategies like the Record trial and Proactive
tried to address the effects of HbA1c lowering on CV trial which will be discussed later.
outcomes. In this trial, the effect of intensive glucose
lowering on micro vascular effects were undisputed Metformin
(25% relative risk reduction, p=0.0099) after a follow
up of 10 years compared to the conventional therapy Metformin acts by reducing insulin resistance, par-
but the relative risk reduction for MI reached border- ticularly in the liver and skeletal muscle, suppressing
line significance only (16%, p=0.052) and there was hepatic gluconeogenesis and increasing insulin sen-
no significant reduction in all cause death, stroke or sitivity and peripheral glucose utilization. This drug
composite of any diabetes related end point It was has beneficial effects on lipid decrease in the pro-
only with a further 10 years of post interventional trial portion of small dense LDL particles, associated with
follow up, significant risk reductions were noted for weight loss , have a moderate blood pressure (BP)
MI (15%, p=0.01) and all cause mortality (13%, p=0.007) lowering effect, protect against diabetes-induced
in the former intensive group with greater results in vascular disease, decrease inflammation preserve
the metformin subgroup . Further large scale stud- the endothelium, exhibits anti-thrombotic effects
ies have tried to evaluate the efficacy of intensive
versus standard glucose lowering strategies on CV The UK Prospective Diabetes Study (UKPDS) was
outcomes. The Action to Control Cardiovascular Risk a landmark study of the CV benefits of metformin,
in Diabetes (ACCORD) trial with a median follow up which demonstrated that, compared to the conven-
of 3.7 years showed a significant decrease rate of tional-treatment group, metformin was able to reduce
non-fatal MI but was stopped prematurely because any diabetes-related endpoint, diabetes-related death
of an unexpected 22% increased relative risk of all and all-cause mortality. When compared to chlorpro-
cause mortality from CV deaths in the intensive pamide, glibenclamide or insulin, metformin showed
treatment group . The Action in Diabetes and Vas- a more pronounced effect for any diabetes related
cular disease: Preterax and Dimicron MR Controlled endpoint, all-cause mortality and stroke. Moreover,
Evaluation (ADVANCE) trial had a median follow up the metformin treated group displayed a sustained
of 5 years and reported a statistically significant 10% risk reduction, lower all-cause mortality reduce the
reduction in the primary endpoint of major macro risk of macrovascular disease. Systematic reviews
vascular and micro vascular events in the inten- have revealed that treatment with metformin is as-
sive glycemic group (HR: 0.90, 95% CI: 0.82-0.98) sociated with a decreased risk of CV mortality and
but when analyzed separately the effect on macro with a significant reduction of CV events, especially
vascular outcomes were not significant (HR: 0.94, in younger patients. However, in the A Diabetes Out-
95% CI: 0.84-1.06) . The Veterans Affairs Diabetes come Progression Trial (ADOPT) metformin did not
trial (VADT) included a similar standard treatment demonstrate any advantage in terms of risk of death
and an intensive therapy arm with a median follow or CV events over glibenclamide or rosiglitazone.
up of 5.6 years There was no significant difference Moreover, the CV safety of metformin has been ques-
between the two groups in any component of the tioned since there is evidence of greater CV mortality
primary outcome or in the rate from death from any when it is added to sulfonylurea. More specifically, a
cause (HR: 1.07; 95% CI, 0.81-1.42; p=0.62). The con- study found that patients treated with SU in combina-
clusion from this trial was very similar to other trials tion with metformin were at higher risk of adverse CV
like ADVANCE, ACCORD which didn’t show any as- outcomes than those treated with metformin alone.
sociation between intensive glycemic control and risk A number of studies have pointed to beneficial ef-
reduction of CV events . These trials enrolled patients fects of metformin in heart failure (HF), namely lower
with long standing diabetes and it remains a topic of rates of mortality, mainly CV mortality, and a lower

GCDC 2017

Cardio Diabetes Medicine 2017 437

risk of death and readmission for HF. Among T2DM metformin. Most recently, a robust meta-analysis of
patients with documented coronary artery disease 115 trials was conducted in which patients with T2D
(CAD), metformin appears to be associated with low- who were treated with sulfonylureas for at least 24
er mortality and CV risk than secretagogues. Several weeks were compared with patients treated with a
studies are in progress evaluating the potential CV nonsulfonylurea agent for the incidence of major car-
benefits of metformin. The METformin in DIastolic diovascular events. (7). The investigators concluded
Dysfunction of MEtabolic syndrome (METDIME) trial that the use of sulfonylureas in patients with T2D
aims to evaluate if metformin added to the standard was associated with increased mortality and a higher
treatment of patients with metabolic syndrome (MS) risk for stroke, whereas the overall incidence of major
is able to improve diastolic dysfunction.(4) The Gly- cardiovascular events was unaffected; the difference
cometabolic Intervention as an adjunct to Primary was not statistically significant. Another review of 15
percutaneous intervention in ST elevation myocardi- randomized trials with at least 72 weeks of treatment
al infarction (GIPS)-III trial aims to provide confirma- with sulfonylureas compared sulfonylureas with ac-
tion that metformin is able to decrease infarct size, tive comparators and did not see a statistical differ-
prevent adverse remodeling and ultimately improve ence in cardiovascular outcomes. (8) Sulfonylureas
systolic function (5). The Glucose Lowering In Non are very inexpensive, and they are not going to dis-
diabetic hyperglycemia Trial (GLINT) was designed to appear. Many people need them. If one does not
establish the effectiveness and cost-effectiveness of want to use sulfonylureas because of hypoglycemia
metformin in preventing CV events in non-diabetic or weight gain that is okay; but the reason should not
individuals with high glucose levels (6) be the stigma of adverse cardiovascular effects asso-
ciated with these drugs.  As the DPP-4 inhibitors are
Cardiovascular safety of SU: Evidence from often considered to be the second line agents, the
studies Cardiovascular outcome study of Linagliptin versus
Glimiperide in patients with type 2 diabetes (CARO-
Sulfonylureas (SU) act by stimulating insulin release LINA) will stand out which compares linagliptin with
from pancreatic β-cells. SU also have a number of an active SU comparator, glimiperide for CV safety.
extra-pancreatic effects, although their clinical signif- The results will help to address the inconsistencies
icance needs to be clarified. These drugs can reduce regarding CV safety of SU’s and will also aid in fu-
hepatic glucose production and hepatic insulin up- ture decision making process regarding the choice
take and increase glucagon secretion by pancreatic of second line agents as an add on to metformin if
α-cells. They increase insulin sensitivity in peripheral linagliptin is found to be superior to glimiperide [9].
tissues as well as stimulate glucose utilization by As CAROLINA has no placebo group to calibrate any
these tissues. No consistent evidence exists as to findings to the population being studied a second
the association between SU use and risk of CVD in study called Cardiovascular safety and Clinical Out-
patients with T2DM. A meta-analysis revealed an in- come with Linagliptin (CARMELINA) is being carried
creased risk of stroke and a significant increase in out by the same sponsors who will compare the CV
mortality, without affecting the overall incidence of and renal safety of linagliptin vs placebo when added
major adverse cardiac events (MACE) with SU treat- to standard care in type 2 diabetes. (10)
ment. Another study has shown an increase in CV
risk and mortality with all SU, except for gliclazide Cardiovascular safety of insulin: Evidence
which was associated with a lower risk. In addition, from studies
in diabetic patients with documented CAD, glipizide
and glyburide were associated with increased mortal- Several studies have reported an increase in CV risk
ity, the latter probably because of its ability to impair and higher mortality, whereas others have demon-
ischemic preconditioning. SU have also been report- strated a reduction in CV events, apart of their raise
ed to reduce resting myocardial blood flow, to in- in the incidence of hypoglycemia. An observational
crease infarct size and to elicit proarrhythmic effects. study of patients on insulin plus metformin reported
Glimepiride however may be safer in patients with a higher risk of a composite effect of nonfatal CV
CVD, since it has no detrimental effects on ischemic and all-cause mortality among insulin therapy users
preconditioning. SU seem to increase mortality when compared to those administered sulfonylureas (SU)
patients are submitted to elective or emergency cor- as an add-on therapy. A recently published post
onary angioplasty for acute MI. Globally, several ret- hoc analysis of the action to control cardiovascular
rospective studies have demonstrated that all-cause risk in diabetes (ACCORD) trial suggests that insulin
mortality. and CV events and death are significantly dose did not play a role in the greater CV mortality
increased in patients treated with SU compared with in patients randomized to intensive glycemic control.

Cardio Diabetes Medicine

438 Cardiovascular Outcomes With Antihyperglycemic Therapy:
Past , Present , and Future Impact on Practice

In the sulfonylurea/insulin arm of the United King- and found an increased risk for MI, albeit less than
dom Prospective Diabetes Study (UKPDS), there before, and found no increased risk for CV mortality.
was no association between the use of insulin and Other meta-analysis have suggested that rosiglita-
CVD incidents, even after 10 years of follow-up. The zone is associated with a significantly increased risk
Outcome Reduction with Initial Glargine Intervention of MI and HF, without a significantly increased risk
(ORIGIN) trial with the long-acting insulin glargine in- of CV mortality. The bypass angioplasty revascular-
volved more than 12,000 patients with new-onset or ization investigation 2 diabetes (BARI 2D) trial in 2013
early T2DM, impaired glucose tolerance or impaired reported that among patients with T2DM and CAD,
fasting glucose, with a prior CV event or at high risk rosiglitazone is not associated with an increase in
for CVD, who were randomized either to glargine or major ischemic CV events. The PROspective piogli-
to standard care. The results demonstrated no as- tAzone clinical trial in macroVascular events (PRO-
sociation with macrovascular events in both groups. active) study has shown that in T2DM patients at
However, there was a positive link to both weight high risk for macrovascular events, pioglitazone sig-
gain and hypoglycemia. (11). The ORIGIN trial and the nificantly reduced a prespecified secondary endpoint
recently published legacy effects (ORIGINALE) study composed of death, non-fatal MI and stroke. In a sub-
followed up these patients for more 2.5 years and group analysis of the PROactive study, pioglitazone
confirmed that insulin glargine had neutral effects significantly decreased the risk of recurrent stroke
on CV health.(12). The hyperglycemia and its effect and of fatal and nonfatal MI and acute coronary syn-
after acute myocardial infarction on cardiovascular drome in high-risk patients with T2DM. Corroborating
outcomes in patients with type 2 diabetes mellitus this, a meta-analysis has revealed that pioglitazone
(HEART2D) trial No differences in respect of CV is associated with a significantly lower risk of death,
events between prandial versus basal strategies were MI or stroke in patients with T2DM. HF is increased
found.(13). Insulin degludec is a novel basal insulin by pioglitazone, although there is no increase in the
with a longer duration of action. The DEVOTE trial associated mortality.(15) However, a recent study re-
was designed to test its safety and efficiency in sub- ported that pioglitazone treatment did not produce
jects with T2DM at high risk of CV events. Published any significant reductions in the rate of primary CV
in the last ADA June 2017 Degludec vs glargine was events. (16) Both pioglitazone and rosiglitazone seem
associated with a statistically significant 40% reduc- to increase the risk of HF; nonetheless, the risk of
tion in severe hypoglycemia, as well as a statistically CV death is not increased. 17) Additionally, in a re-
significant 53% reduction in nocturnal severe hypo- cent Cochrane meta-analysis, PPAR-γ agonists were
glycemia and MACE shown to reduce recurrent stroke and total events
of CV death, as well as improving insulin sensitivity
Cardiovascular safety of TZD: Evidence from studies and carotid plaques stabilization.18) Despite these
TZD have the potential to modulate several CV risk impressive cardiovascular benefits with pioglitazone
factors, including lipids, BP, inflammatory bio mark- therapy, its use has also declined markedly, poten-
ers, endothelial function and fibrinolytic status. Both tially due to ‘guilt by association’ with rosiglitazone
pioglitazone and rosiglitazone can cause an increase and the description of new risks for fractures and
in HDL-c. LDL-c levels seem to remain unchanged bladder cancer.
with pioglitazone but to increase with rosiglitazone.
The Diabetes REduction Assessment with ramipril Meglitinides
and rosiglitazone Medication (DREAM) trial found
no increase in CV event rates with rosiglitazone, Meglitinides are insulin secretagogues that act on a
although the rosiglitazone group developed signifi- different receptor but have a similar mode of action
cantly more HF events. The Rosiglitazone Evaluated to sulfonylureas and exert similar but milder effects.
for CV Outcomes in Oral Agent Combination Therapy Repaglinide and nateglinide are the 2 agents in this
for T2DM (RECORD) trial showed that rosiglitazone class that are currently available. These agents low-
does not increase the risk of overall CV morbidity or er both glucose and hemoglobin A1c (HgA1c) levels
mortality; nevertheless, it confirmed an increased risk without a significant effect on lipids. The CV safety
of HF. In spite of this, issues related to trial design profile of meglitinides is largely unknown repaglinide
and data integrity led FDA to call for an independent controlled postprandial glucose excursion better than
reevaluation of the RECORD data, which reported glimepiride and was associated with a significant
similar results. A 2007 meta-analysis demonstrated decline in other surrogate CV markers, including
that rosiglitazone was associated with a significant markers of inflammation, platelet activation, and lip-
increase in the risk of MI and death from CV causes. id parameters, suggesting a beneficial role in lower-
In 2010, the same authors repeated the meta-analysis ing CVD risk. On the other hand, when compared to

GCDC 2017

Cardio Diabetes Medicine 2017 439

metformin, repaglinide was less effective in reducing but not diastolic BP (DBP); Monotherapy with GLP-
similar CVD biomarkers of inflammation and endo- 1 RA does not increase the risk of hypoglycemia, It
thelial dysfunction in nonobese patients with type has also been reported that β-cell function was im-
2 diabetes mellitus despite similar glycemic control, proved with GLP-1 RA (HOMA-B, proinsulin-to-insulin
The Nateglinide and Valsartan in Impaired Glucose ratio). The cardioprotective effects of GLP-1 agonists
Tolerance Outcomes Research (NAVIGATOR) trial have been well documented in pre-clinical studies.
did not find nateglinide to improve CV outcomes in Indeed, experimental models of ischemia and reper-
patients with impaired glucose tolerance and CVD fusion have shown improved post-ischemic myocar-
or CV risk factors compared to placebo or valsartan dial contractile dysfunction and reduced infarct size
treatment. While valsartan at least decreased the in- with constant infusions of GLP-1demonstrated car-
cidence of type 2 diabetes mellitus by 14% in these diovascular benefits including reduced arrhythmias,
patients, nateglinide had no effect on delaying the improved left ventricle function, and improved endo-
development of diabetes. thelial function, in patients with or without diabetes
and with coronary artery disease and chronic heart
Alpha –Glucosidase Inhibitors failure. Ongoing randomized large-scale trials will
be important to consolidate the results obtained so
Alpha Glucosiase inhibitors is a group of rugs which far. Indeed, several GLP-1 RA are undergoing long-
can delay release of glucose from complex carbohy- term randomized trials to assess their CV safety –
drate and thus leads to a reduction of post prandial ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN
blood glucose levels.. Three drugs in this class are 6 (semaglutide), REWIND (dulaglutide), and EXSCEL
Acarbose, Voglibose and Miglitol. STOP-NIDDM tri- (exenatide extended release). The Evaluation of Lix-
al has already revealed its efficacy in delaying the isenatide in Acute Coronary Syndrome (ELIXA) trial
development of type 2 diabetes in patients with IGT, randomized 6068 patients with T2DM and an acute
It reduces HbA1c and improves Post prandial insulin coronary event within the last 180 days to receive
levels and insulin sensitivity. STOP-NIDDM trial was lixisenatide or placebo on top of standard of care.(19)
the first study to report a significant reduction in After a median follow-up of 25 months, there was no
post prandial blood glucose and development of CV difference in the primary composite endpoint of car-
events of any type MI and new cases of hyperten- diovascular death, non-fatal MI, non-fatal stroke, or
sion. Meta-analysis of seven long term studies shows hospitalization for unstable angina between groups
highly significant relative risk reduction of 64% for and no difference in heart failure hospitalizations. In
CAD in Acarbose group more in the IGT group. the Liraglutide Effect And Action In Diabetes: Evalu-
ation Of Cardiovascular Outcome Results (LEADER)
Glucagon-Like Peptide 1 Agonists trial, (20) which randomized 9340 T2DM patients
with high cardiovascular risk, liraglutide reduced the
Incretins are enteroendocrine peptides that augment primary composite endpoint of cardiovascular death,
insulin response in a glucose-dependent manner, non-fatal MI or non-fatal stroke compared to place-
regulate postprandial glucagon secretion, slow gas- bo after a median follow-up of 3.8 years Although
tric emptying, and increase satiety by central mech- not currently FDA-approved, semaglutide, (21) a
anisms. Glucagon-like peptide 1 (GLP-1) and glu- once-weekly GLP-1 agonist, was non-inferior to pla-
cose-dependent insulinotropic polypeptide (GIP) are cebo after 26 months follow-up among 3297 patients
2 of these incretins whose secretions are known to with T2DM in the Trial to Evaluate Cardiovascular and
be impaired in type 2 diabetes mellitus; GLP-1–based Other Long-term Outcomes with Semaglutide in Sub-
therapy is meant to address this deficiency. Current- jects with Type 2 Diabetes (SUSTAIN-6) with regards
ly, the GLP-1R agonists (GLP-1 RA) approved for the to the primary composite endpoint of cardiovascular
treatment of T2DM are Albuglutide, Dulaglutide, Ex- death, nonfatal MI and non-fatal stroke
enatide and extended release Exenatide, Liraglutide ,
Lixisenatide and Semeglutide they have been shown Dipeptidyl Peptidase 4 Inhibitors
to provide effective HgA1c reduction of 1%-1.6%
Dipeptidyl peptidase 4 (DPP-4) is a ubiquitous en-
GLP-1 RA treatment seems to be associated with a zyme that degrades many targets such as GLP-1;
favorable impact on several CV risk factors, name- the pharmacologic inhibition of DPP-4 prolongs the
ly BP, lipid profile and weight. In fact, several meta bioavailability of endogenous GLP-1. Currently, 4
analyses have demonstrated that GLP-1 RA treatment DPP-4 inhibitors––sitagliptin, saxagliptin,Vildagliptin,
is associated with significant weight loss and bene- linagliptin, alogliptin and Teneligliptin. In addition
ficial effects on lipid profile, decreasing LDL-c and to their glucose-lowering effects, DPP-4 inhibitors
TG. These drugs are able to reduce systolic BP (SBP),

Cardio Diabetes Medicine

440 Cardiovascular Outcomes With Antihyperglycemic Therapy:
Past , Present , and Future Impact on Practice

may have beneficial pleiotropic effects on the CV Trial Evaluating Cardiovascular Outcomes with Sita-
system. Some of these beneficial effects may be gliptin (TECOS) where patients had a median follow
through GLP-1–dependent mechanisms, while others up of three years and showed that sitagliptin was
are postulated to occur through other DPP-4 targets considered to be non-inferior to placebo for primary
independent of their effect on GLP-1. These targets composite CV outcomes (HR: 0.98; 95% CI, 0.88 to
include stromal-derived factor-1a whose prolongation 1.09; p<0.001) and the total number of primary out-
leads to stimulation of endothelial progenitor cells come that occurred were 11.4% (4.06 per 100 person
involved in endothelial homeostasis and vascular re- years) in sitagliptin group in comparison to 11.6% (4.17
pair. Animal studies also show a reduction in infarct per 100 person years) in the placebo group. Moreover
size and the activation of cardioprotective molecular the rate of hospitalization for heart failure did not
pathways with DPP-4 inhibitor use. These drugs are differ between the two groups (HR: 1.00; 95% CI, 0.83
shown to prevent atherosclerosis and myocardial in- to 1.20; p=0.98). The population that were studied in
jury, improve endothelial dysfunction and lipid pro- these three trials were very similar and the patients
file, lower blood pressure, and decrease arrhythmia had well managed cardiovascular and glycemic risk
after CABG surgery, There have been 3 large CV out- factors at baseline. These trials also suggested that
come trials that have been completed for the dipep- the catalytic inhibition of DPP-4 is basically safe for
tidyl peptidase 4 (DPP-4) inhibitors- SAVOR-TIMI on the CV standpoint but such inhibition alone is insuf-
Saxagliptin (22), EXAMINE on Alogliptin (23), TECOS ficient to improve CV outcomes in such short term
on Sitagliptin (24). In the Examination of Cardiovas- and longer follow up is necessary. Most of the CV
cular Outcomes with Alogliptin versus Standard of outcome trials with the DPP-4 inhibitors were con-
Care (EXAMINE) trial with a median follow up of 1.8 ducted in a placebo controlled setting with no active
years; Alogliptin was studied as an addition to exist- comparator. This leads to a limitation in clinical in-
ing anti-hyperglycaemic treatment in comparison to terpretation and does not allow an assessment of
a placebo in patients with type 2 diabetes who had comparative effectiveness. Currently there are other
an acute coronary event in the last 15-90 days prior ongoing randomized clinical trials comparing DPP-
to randomization. The study showed that a primary 4i versus placebo added to conventional therapy in
end point (composite death from CV disease, non-fa- patients with T2DM. The CArdiovascular safety and
tal MI, non-fatal stroke) was 11.3% in the Alogliptin renal microvascular outcome study with LINAgliptin
group compared to 11.8% in the placebo group (HR: in patients with T2DM (CARMELINA), lasting till 2018,
0.96, upper boundary of one sided repeated CI, 1.16: has been designed to assess the long-term impact
p<0.001 for non- inferiority) suggesting that the rates on CV morbidity, mortality and renal function of treat-
of major CV events were not raised with Alogliptin ment with linagliptin. The CARdiovascular outcome
in comparison to a placebo . This was followed by trial of LINAgliptin versus glimepiride in patients with
the results from the Saxagliptin Assessment of Vas- T2DM (CAROLINA) is a trial ongoing since 2010 com-
cular Outcomes recorded in Patients with Diabetes prising a comparison of a sulfonylurea with a DPP-4i.
Mellitus- Thrombolysis in Myocardial Infarction 53 This trial is expected to provide considerable insight
(SAVOR-TIMI 53) trial with a median follow up of 2.1 as it is unique in comparing head-to-head add-on
years which evaluated saxagliptin against a placebo therapy
showing similar results for a cardiovascular primary
endpoint (7.3% and 7.2% respectively, HR: 1.00; 95% Sodium-glucose transporter-2 inhibitor s
CI 0.89 to 1.12, p=0.99 for superiority and p<0.001
for non-inferiority). This suggested that saxagliptin The sodium-glucose transporter-2 (SGLT-2) inhibitors
did not increase or decrease rate of ischemic events (SGLT-2i) are a new class of antidiabetic agents that
but an unexpected outcome showed patient in the inhibit glucose reabsorption from the kidney increas-
saxagliptin group with an increased admission with ing urinary glucose excretion. The FDA and EMA have
heart failure compared to the placebo (3.5% Vs 2.8%, approved three inhibitors, canagliflozin, dapagliflozin
HR: 1.27; 95% CI 1.07-1.51, p<0.007) The possible ex- and empagliflozin, with several others being under
planation for this was shown in a later sub-analysis late-stage clinical development. Ipragliflozin, tofogli-
which concluded that subjects who had greater risk flozin and luseogliflozin have been approved for the
of hospitalization with HF were those who had an treatment of T2DM in Japan. Other compounds re-
eGFR <60 mls/min, had previous history of heart fail- main in development, as well as Lx4211, a dual so-
ure and with elevated baseline levels of N terminal dium-glucose transporter 1 and 2 inhibitor and ISIS
pro B type natriuretic peptide (NT-proBNP) . The latest – 388626, an antisense oligonucleotide (ASO) de-
published data reflecting a similar trend was in the signed to block the expression of the SGLT2 gene
in vivo. SGLT-2i protect the proximal tubular cells,

GCDC 2017

Cardio Diabetes Medicine 2017 441

most likely by blocking glucose entry into the cell, ergy with the metabolic substrate shift achieve the
and indirectly reduce insulin secretion, improve in- degree of cardioprotection revealed in the EMPA-REG
sulin sensitivity and increase the peripheral glucose OUTCOME and CANVAS trial
uptake. This drug acts independently of the severity
of insulin resistance and β-cell failure; Conclusion

The recently published EMPA-REG OUTCOME (25) Due to a high prevalence of cardiovascular morbid-
study presented exciting CV results with empagli- ity and mortality in T2DM, the optimal approach to
flozin. In fact, empagliflozin was shown to signifi- the reduction of cardiovascular risk should focus
cantly reduce deaths among patients with T2DM on aggressive management of the standard cardio-
and established CVD when compared with placebo. vascular risk factors rather than purely on intensive
These patients exhibited a 14% reduction in the three- glycemic control. As can be seen from the various
point MACE primary endpoint. This effect was mainly trials reviewed here, favorable glycemic efficacy does
due to the benefits related to CV death, since em- not necessarily translate to favorable cardiovascular
pagliflozin did not reduce the rate of nonfatal MI or outcomes. Clinicians must therefore make careful in-
nonfatal strokes. Overall, this drug displayed a 38% formed decisions based on the cardiovascular effects
reduction in CV death and a 32% reduction in all- of the various anti-diabetic drugs when prescribing.
cause mortality. A significant reduction in the key Based on current evidence, metformin should re-
secondary endpoint, which was the primary compos- main the first-line drug of choice in T2DM, being the
ite endpoint plus hospitalization for unstable angina, most extensively studied and demonstrating excel-
was also apparent, as well as a 35% reduction in HF lent cardiovascular safety even with long term use.
hospitalization (26). The CANVAS trial (29,30) looked Although evidence for the cardiovascular safety of
at canagliflozin versus placebo in patients at high sulfonylureas are inconsistent, the first-generation
risk for cardiovascular (CV) disease and in patients agents are probably associated with net harm and
with established CV disease. The primary endpoint should be avoided. Newer generation sulfonylureas
of three-point major adverse CV events (MACE)— have a comparatively more favorable cardiovascular
nonfatal myocardial infarction, nonfatal stroke, and profile, but weight gain remains a concern. The meg-
CV death—was statistically significantly lowered with litinides and AGIs lack cardiovascular safety data in
canagliflozin compared with placebo, demonstrating T2DM and should therefore be reserved in favor of
about a 14% reduction in risk Specifically, there was other second-line agents. Among the TZDs, rosigli-
no statistically significant reduction in CV death, but tazone may be associated with an increased risk of
there was a very significant reduction in congestive MI, while pioglitazone may have beneficial cardio-
heart failure, a secondary endpoint, with a 39% reduc- vascular effects. Both are however contraindicated in
tion in hospitalization for heart failure. The Multicenter heart failure. The incretin-based drugs have been at
Trial to Evaluate the Effect of Dapagliflozin on the In- the forefront of this era of cardiovascular safety trials
cidence of Cardiovascular Events (DECLARE-TIMI58), and have been extensively studied. Current evidence
(27,28) expected to be finished in 2019, was de- suggests that the gliptins have neutral overall cardio-
signed to evaluate the effect of dapagliflozin on the vascular effect, but may increase risk of heart failure,
incidence of CV events Inhibitor of sodium–glucose particularly saxagliptin. Among the GLP-1 agonists,
cotransporter 2 (SGLT2) in patients with type 2 diabe- liraglutide may have beneficial effects on cardiovas-
tes and high CV risk the reduction in MACE is due cular outcomes, but this requires further validation.
to multiple mechanisms like modest improvement in Similarly, the SGLT-2 inhibitors have shown promising
glycemic control, small decrease in body weight, and results with both empagliflozin and Canaglifozin may
persistent reductions in blood pressure and uric acid potentially confer cardiovascular benefits, the results
level, enhanced diuresis and reduced blood pressure) of ongoing clinical trials will provide further evidence
may be at play. Under conditions of mild, persistent about the cardiovascular safety and perhaps efficacy
hyperketonemia, such as those that prevail during of diabetes drugs. These trials will certainly help to
treatment with SGLT2 inhibitors, b-hydroxybutyrate is further refine therapeutic guidelines in the future.
freely taken up by the heart (among other organs)
and oxidized in preference to fatty acids. This fuel References
selection improves the transduction of oxygen con-
sumption into work efficiency at the mitochondrial 1. Spring S. US Food and Drug Administration. Guidance for industry- Dia-
level. In addition, the hemoconcentration that typical- betes Mellitus-Evaluating cardiovascular risk in new antidiabetic therapies
ly follows SGLT2 inhibition enhances oxygen release to treat type 2 diabetes. 2008. | 
to the tissues, thereby establishing a powerful syn-
2. Hirshberg B and Katz A. Cardiovascular outcome studies with novel
antidiabetes agents: scientific and operational considerations.  Diabetes

Cardio Diabetes Medicine

442 Cardiovascular Outcomes With Antihyperglycemic Therapy:
Past , Present , and Future Impact on Practice

Care. 2013; 36 Suppl 2:S253-8. | Article | PubMed Abstract | PubMed 19. Pfeffer MA, Clagget B, Diaz R, et al. Lixisenatide in patients with type 2
Full Text diabetes and acute coronary syndrome. N Engl J Med. 2015;373:2247-
2257.  Abstract
3. Turnbull FM, Abraira C, Anderson RJ, Byington RP, Chalmers JP, Duckworth
WC, Evans GW, Gerstein HC, Holman RR, Moritz TE, Neal BC, Ninomi- 20. Marso SP, Daniles DH, Brown-Frandsen K, et al. Liraglutide and cardio-
ya T, Patel AA, Paul SK, Travert F and Woodward M. Intensive glucose vascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311-
control and macrovascular outcomes in type 2 diabetes. Diabetologia. 322.  Abstract
2009; 52:2288-9
21. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular out-
4. Ladeiras-Lopes R, Fontes-Carvalho R, Bettencourt N, Sampaio F, Gama V, comes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834-
Leite-Moreira AF, 2014 METformin in DIastolic Dysfunction of MEtabolic 1844.  Abstract
syndrome (MET-DIME) trial: rationale and study design: METDIME trial.
Cardiovasc Drugs Ther 28: 191-196 22. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascu-
lar outcomes in patients with type 2 diabetes mellitus. N Engl J Med.
5. Lexis CP, van der Horst IC, Lipsic E, et al, 2012 Metformin in non-diabetic 2013;369:1317-1326.  Abstract
patients presenting with ST elevation myocardial infarction: rationale and
design of the glycometabolic intervention as adjunct to primary percuta- 23. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary
neous intervention in ST elevation myocardial infarction (GIPS)-III trial. syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327-
Cardiovasc Drugs Ther 26:417-426 1335.  Abstract

6. Medical Research Council (MRC) (UK). The Glucose Lowering In Non-di- 24. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on car-
abetic hyperglycaemia Trial (GLINT) - Glucose lowering in those at risk diovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232.
of diabetes. ISRCTN34875079. http://www.isrctn.com/ISRCTN34875079.
https://njl-admin.nihr.ac.uk/document/download/2006787 25. Zinman B, Wanner C, Lachin JM, et al, 2015 Empagliflozin, cardiovas-
cular outcomes, and mortality in type 2 diabetes. N Engl J Med 373:
7. Hemmingsen B, et al. Sulphonylurea monotherapy for patients with type 2117-2128.
2 diabetes mellitus. Cochrane Database Syst Rev. 2013;4:9008.
26. CV Protection in the EMPA-REG OUTCOME Trial: A“Thrifty Substrate” Hy-
8. Monami M, Genovese S, Mannucci E. Cardiovascular safety of sulfony- pothesis Diabetes Care 2016;39:1108–1114 | DOI: 10.2337/dc16-0330
lureas: a meta-analysis of randomized clinical trials. Diabetes Obes Metab.
2013;15(10):938–53. 27. Dziuba J, Alperin P, Racketa J, et al, 2014 Modeling effects of SGLT-2 in-
hibitor dapagliflozin treatment versus standard diabetes therapy on cardio-
9. Rosenstock J, Marx N, Kahn SE, Zinman B, Kastelein JJ, Lachin JM, Bluhm- vascular and microvascular outcomes. Diabetes Obes Metab 16: 628-635
ki E, Patel S, Johansen OE and Woerle HJ. Cardiovascular outcome
trials in type 2 diabetes and the sulphonylurea controversy: 28. clinicalTrials.gov, Multicenter Trial to Evaluate the Effect of Dapagli-
rationale for the active-comparator CAROLINA trial. Diab Vasc flozin on the Incidence of Cardiovascular Events (DECLARE-TIMI58)
Dis Res. 2013; 10:289-301. |  NCT01730534 https:// clinicaltrials.gov/ct2/show/NCT01730534 (Ac-
cessed: 9 June 2015)
10. Cardiovascular and Renal Microvascular Outcome Study With
Linagliptin in Patients With Type 2 Diabetes Mellitus (CARME- 29. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular
LINA). 2013-2018. and renal events in type 2 diabetes. N Engl J Med. 2017 Jun 12.

11. Gerstein HC, Bosch J, Dagenais GR, et al, 2012 Basal insulin and car- 30. Neal B, Perkovic V, de Zeeuw D, et al. Rationale, design, and base-
diovascular and other outcomes in dysglycemia.N Engl J Med 367: 319- line characteristics of the Canagliflozin Cardiovascular Assessment
328. 2016, Study (CANVAS) — a randomized placebo-controlled trial. Am Heart J.
2013;166:217-223.e11
12. Cardiovascular and other outcomes postintervention with insulin glargine
and omega-3 fatty acids (ORIGINALE). Diabetes Care 39: 709-716. .

13. Raz I, Wilson PW, Strojek K, et al, 2009 Effects of prandial versus fasting
glycemia on cardiovascular outcomes in type 2 diabetes: the HEART2D
trial. Diabetes Care 32: 381-386.

14. Marso SP, McGuire DK, Zinman B, et al. Efficacy and safety of degludec
versus glargine in type 2 diabetes. N Engl J Med. 2017. doi:10.1056/
NEJMoa1615692 [Epub ahead of print]

15. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE, 2007 Pioglitazone and risk
of cardiovascular events in patients with type 2 diabetes mellitus: a me-
ta-analysis of randomized trials. JAMA - J Am Med Assoc 298 : 1180-1188.

16. Yoshii H, Onuma T, Yamazaki T, et al, 2014 Effects of pioglitazone on
macrovascular events in patients with type 2 diabetes mellitus at high
risk of stroke: the PROFIT-J study. J Atheroscler Thromb 21: 563-573.

17. Lago RM, Singh PP, Nesto RW, 2007 Congestive heart failure and car-
diovascular death in patients with prediabetes and type 2 diabetes given
thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet
370: 1129-1136.

18. Liu J, Wang LN, 2014 Peroxisome proliferator-activated receptor gamma
agonists for preventing recurrent stroke and other vascular events in pa-
tients with stroke or transient ischaemic attack. Cochrane Db Syst Rev
1: CD010693.

GCDC 2017

Cardio Diabetes Medicine 2017 443

Obesity- Pharmacotherapy

Dr. Rakesh Kumar Sahay, MD, DM (Endo), FACE, FICP, FRSSDI

Professor & Head of Department of Endocrinology, Osmania Medical College, Hyderabad

Dr. Shravan Ankathi, MD (Medicine)

Department of Endocrinology, Osmania Medical College, Hyderabad

Abstract can reduce life expectancy [1]. Worldwide obesity has
more than doubled since 1980.In 2014, more than 1.9
Recent advances in the understanding of energy billion adults, 18 years and older, were overweight.
balance control have draw special attention to a Of these over 600 million were obese.39% of adults
number of new biological targets for the treatment of aged 18 years and over were overweight in 2014, and
obesity. Some of these pharmacological approaches 13% were obese [2]. Most of the world’s population
for weight loss have yielded promising results in live in countries where overweight and obesity kills
clinical trials. Lorcaserin, Phentermine-topiramate more people than underweight.
combination (phen-top), Liraglutide Bupropion-
Naltrexone and Orlistat are the currently approved Pathophysiology of obesity is complex, and new
drugs by US FDA. Lorcaserin, a 5HT2C agonist has information regarding neuronal circuits that control
moderate efficacy with an acceptable safety profile, food intake and their hormonal regulation has
Phenteramine blocks of norepinephrine reuptake, enlarged our understanding of energy homoeostasis
Phen-top combination in clinical trials have shown a [3]. These new signaling pathways discovered in the
reasonable efficacy but at the risks of teratogenicity hypothalamus are potential targets for development
and psychiatric disturbances. in the

Liraglutide, a glucagon-like peptide 1 (GLP-1) analog treatment of obesity. Some pharmacotherapies have
has a good efficact with relatively few side effects ultimately failed due to unexpected side effects that
compared with centrally acting drugs. Bupropion- may only identify during clinical trials and sometimes
naltrexone act on the monoaminergic and opioid many years following drug approval. Yet despite many
systems previous setbacks in the obesity drug development
process, several clinical trials in the last two decades
However, finding the precise balance between lead to develop new, safer and more tolerable anti-
efficacy and safety has proven challenging. In this obesity medications. In the last 10 years, several
article, we provide an overview of currently available therapies have emerged as potentially effective and
anti-obesity agents, and discuss future strategies for safe new long-term weight-loss pharmacotherapies.
pharmacological interventions. Given the high unmet
need and our growing understanding pathophysiology Diagnosis and Classifcation of Obesity
of bodyweight homeostasis, novel, more efficacious
and better tolerated treatments for obesity are clearly The diagnosis and classification of obesity is usually
required. based on the BMI. This simple anthropometric index
can be calculated from body weight and height,
Introduction is independent of body height and correlates
reasonably well with body fat mass (r = 0.4–0.7). The
Obesity is defined as a common chronic disorder current classification of body weight is according to
of excessive body fat and has become a global the World Health Organization (WHO) [3]
epidemic, which is present not only in the
industrialized world but also in many developing and BMI should be used to confirm an excessive degree
even in underdeveloped countries. Obesity impairs of adiposity and to classify individuals as having
the subjective quality of life in affected people and overweight (BMI 25-29.9 kg/m2 ) or obesity (BMI

Cardio Diabetes Medicine

444 Obesity- Pharmacotherapy

≥30 kg/m2 ), after taking into account age, gender, complications that can be ameliorated by weight loss.
ethnicity, fluid status, and muscularity; therefore, Pharmacotherapy should be offered to patients with
clinical evaluation and judgment must be used when obesity, when potentialbenefits outweigh the risks.
BMI is employed as the anthropometric indicator of
excess adiposity, particularly in athletes and those Short-term treatment (3-6 months) using weight-loss
with sarcopenia. medications has not been demonstrated to produce
long term health benefits and cannot be generally
At a defined BMI, the pattern of fat distribution can recommended based on scientific evidence.
vary substantially. This has been most impressively
shown using computed tomography (CT) or magnetic Clinicians should consider differences in efficacy, side
resonance imaging (MRI) scans which are the only effects, cautions, and that characterize medications
imaging techniques to provide a direct assessment approved for chronic management of obesity, as well
of the size of the intra-abdominal visceral adipose as the presence of weight-related complications and
tissue. medical history.

For practical means, waist circumference provides Treatment is individualized based weight-loss
a simple anthropometric measure to assess the fat pharmacotherapy; a generalizable algorithm for
distribution pattern. This variable has been used in medication preferences that would be applicable to
many cross-sectional and longitudinal studies; the all patients cannot currently be scientifically justified.
waist circumference is closely correlated with BMI
but cannot discriminate between subcutaneous and Combinations of FDA-approved weight-loss
intra-abdominal fat depots. Due to this limitation, medications should only be used in a manner
there is growing clinical interest for more precise approved by the FDA.
imaging methods to obtain a better insight into
intra-abdominal and ectopic fat deposition (visceral There is lack of clinical trials with head to head direct
fat, hepatic fat) in order to improve individual risk comparing the drugs approved for weight loss.
assessment.
Current /Fda Approved Anti-Obesity Drugs
Table 1 Obesity classification based on BMI [data
from WHO] The approval criteria for antiobesity drugs as set out
by the US FDA were revised in 2007[4] necessitating
Weight BM Disease Risk a 5% or more mean placebo-subtracted weight loss
after 1 year of therapy or a minimum of 35% of
Under weight <18.5 Normal participants achieving more than 5% weight loss.
Increase The European Medicines Agency (EMA) guidelines
Normal 18.5 – 24.9 similarly require a 10% or more weight loss over 1 year,
Heigh which should be more than 5% above that achieved
Over Weight 25.0 – 29.9 Very heigh by placebo [5] Of note, both agencies also call for
Extremely heigh evidence of improvements in metabolic comorbidities
Obesity as these are known to affect the cardiovascular risk
more than weight loss alone.
Class I 30.0 – 34.9
Medications for weight loss approved by the Food
Class II 35.0 – 39.9 and Drug Administration (FDA) since 2012

Class III > 40 Table 2.

Pharmacotherapy For Overweight And Current US FDA approved drugs for Obesity
Obesity
• Phentermine–topiramate ER (extended release),
Pharmacotherapy should be used only as an adjunct
to lifestyle therapy and not alone. • Lorcaserin,

Addition of pharmacotherapy produces greater • Naltrexone–Bupropion  
weight loss and weight loss maintenance compared
with lifestyle therapy alone. • Liraglutide.

Lifestyle therapy and pharmacotherapy should • Orlistat, an intestinal lipase inhibitor that was ap-
be considered in patients with weight-related proved in 1999

The efficacy and side-effect profiles of these
medications, when used as adjuncts to lifestyle

GCDC 2017

Cardio Diabetes Medicine 2017 445

modification, have been established through Lorcaserin for Obesity and Overweight Management
prospective randomized, controlled trials. Response in Diabetes Mellitus (BLOOM-DM) study was a
rates vary among the studies, participants assigned randomized, double-blind, placebo-controlled trial
to the medication groups achieved significantly that evaluated the efficacy and safety of lorcaserin
greater weight loss than compared to placebo, as (administered in conjunction with a lifestyle
well as improvements in cardio metabolic risk factors modification program) for weight loss among those
and quality of life. The average weight loss ranged with type 2 diabetes showed almost similar results
from 7.0 to 12.4% among participants who completed
1 year of treatment, who received one of the four Rates of adverse events (AEs) and discontinuations
newer medications groups, as compared to 1.6 to due to AEs in both trials were generally low (6–7%),
3.5% among those who received placebo. with the most common side effect being headaches
(6,8); however, around a third of patients in total
Lorcaserin withdrew from one trial, and in the other trial
the proportion of withdrawals rose to over 40%.
Lorcaserin, was first of these, approved in 2012, Lor- Echocardiogram studies were performed on all phase
caserin is selective 5-hydroxytryptamine 2C (5-HT2C) III trial participants, leading to the final assessment
receptor agonist to cause the release of serotonin (5- that lorcaserin did not cause cardiac valve tissue
HT) and inhibit the subsequent uptake of serotonin fibrosis.
(6). Anorectic POMC neurons expressing 5-HT2CR
depolarize on receptor activation and release MSH, Phentermine/Extended-Release Topiramate
which activate MC4R expressing neurons, principally
within the Paraventricular nucleus [PVH] of hypothal- Combination of phentermine and extended-release
amus. (ER) topiramate has been developed, approved by
the FDA for weight loss in 2012. Exact mechanism
It has low specificity for the 5-HT2B receptor (~100 of action remains unknown, phentermine is believed
times lower than that of the 5-HT2C receptor) (6), to mediate the release of catecholamines (including
lorcaserin carries a low risk of causing heart-valve noradrenaline and dopamine) in the hypothalamus,
abnormalities with long-term use. Side effects of which blunts appetite, while topiramate strengthens
lorcaserin are neuroleptic malignant syndrome-like the activity of the neurotransmitter gamma-
reactions: headache, dizziness, fatigue, nausea; dry aminobutyrate, [GABA] modulates voltage-gated
mouth; constipation and in diabetic patients cause ion channels, and inhibits AMPA/kainite excitatory
hypo glycaemia, and fatigue. glutamate receptors and carbonic anhydrase, which
prolongs satiety.
The first study investigating lorcaserin, the Behavioral
Modification and Lorcaserin for Overweight and Obe- Although originally declined for approval due to
sity Management (BLOOM) study, enrolled people 18 concerns over the increased risk of depression and
to 65 years of age [mean baseline weight of ~100 kg, cognitive-related disorders, as well as cardiovascular
] with a baseline BMI of 30 to 45 kg/m2 or a BMI of events, the drug was reconsidered and approved
27 to 45 kg/m2 with at least 1 concomitant weight-re- by the FDA for weight loss in 2012. Side effects
lated comorbidity. A total of 3182 participants were reported by the FDA include tingling of hands and
randomized to receive lorcaserin 10 mg twice a day feet (paraesthesia), dizziness, altered taste sensation,
(n =1595) or placebo (n =1587) for 52 weeks. insomnia, constipation and dry mouth.

Patients in the lorcaserin group lost an average of Clinical trials which played key role in is approval
5.81±0.16% of the baseline body weight, as compared include EQUATE, CONQUER, EQUIP and SEQUEL.
with 2.16±0.14% in the placebo group (P<0.001)
More patients lost 10% or more of their baseline The EQUATE trial, a 28-week, RCT, phase III study,
body weight in the lorcaserin group (22.6%) than compared the combination treatment of phentermine/
in the placebo group (7.7%,P<0.001). patients who topiramate (high and low dose) with the individual
achieved 5% weight loss of baseline weight after components alone (both high- and low-dose
52weeks, seen in 47.5% of those receiving lorcaserin phentermine and high- and low-dose topiramate).
compared with 20.3% receiving placebo and the loss Weight loss was significantly greater in patients
was maintained in a greater proportion of patients receiving the high-dose combination treatment
who continued to receive lorcaserin in year 2 than in compared with high doses of both compounds alone.
those who were reassigned to receive placebo (67.9%
vs. 50.3%,P<0.001). The Behavioral Modification and CONQUER was a 56-week, RCT double-blind, placebo-
controlled, phase III trial in which two phentermine/

Cardio Diabetes Medicine

446 Obesity- Pharmacotherapy

ER topiramate treatment arms (15 mg and 7.5 mg) −1.2%). More NB32-treated participants (P < 0.001)
and one placebo arm were initiated in conjunction experienced ≥5% weight loss versus placebo at week
with a 500 kcal/day dietary deficit (74). After 1 year 28 (55.6% vs. 17.5%) and week 56 (50.5% vs. 17.1%).
of treatment, a reduction in body weight of 12.4% with
phentermine 15.0 mg plus topiramate 92.0 mg and The most frequent adverse effect reported include
9.6% with phentermine 7.5 mg plus topiramate 46.0 nausea, headache, constipation, dizziness,
mg, compared with 1.6% in the placebo group was vomiting, insomnia and dry mouth, and the drug
reported. Cardiovascular improvements were also is contraindicated in patients with seizure history.
observed. A Multicentre, Randomized, Double-Blind, Placebo-
Controlled Study Assessing the Occurrence of
EQUIP trial similarly designed comprised two Major Adverse Cardiovascular Events (MACE) in
phentermine/ER topiramate treatment arms (15 mg Overweight and Obese Subjects With Cardiovascular
and 3.75 mg) and a placebo arm (14). From a mean Risk Factors Receiving Naltrexone SR/Bupropion SR
baseline body weight of 115.2–118.5 kg, the majority [LIGHT study] to address long term cardiovascular
of subjects (67%) in the 15 mg group lost at least 5% risk, which was due to reach completion in 2017.
of baseline body weight and 47% lost at least 10% of An interim analysis of 25% of the enrolled patients
body weight from baseline. In the 3.75 mg group, the showing a reduction in the number of cardiovascular
corresponding proportions of patients achieving 5% events in the naltrexone/bupropion arm. Based on
and 10% body weight loss from baseline were 45% this the FDA approved naltrexone/bupropion in
and 19%, respectively. Minimal improvements were September 2014, with the requirement for ongoing
reported in cardiovascular markers such as blood post-marketing studies.
pressure and lipid profiles.
Liraglutide
SEQUEL study, a 2-year extension trial of CONQUER,
has been performed, which confirmed the consistency Liraglutide, an analogue of human glucagon-like
and durability of the CONQUER findings. Moreover, peptide (GLP)-1, has a half- life of 13 h, which greatly
a 76% reduction in new-onset T2D in the maximum extends its activation of the GLP-1 receptor (the half-
dose group was observed. life of native GLP-1 is ~1.5 min), thereby increasing
stimulation of glucose-dependent insulin secretion
Pregnancy is a contraindication due to the topiramate- and glucagon suppression. Liraglutide Effect and
related increased risk of orofacial clefts; It is also Action in Diabetes (LEAD) trial demonstrated
contraindicated in hyperthyroidism glaucoma, most consistent efficacy in reducing HbA1c and fasting
common adverse effect to phentermine/topiramate in plasma glucose, leading to its approval (at doses up
these trials were paraesthesia dizziness, dysgeusia, to 1.8 mg daily) for management of glycaemic control
insomnia, constipation and dry mouth, with no in adults with T2D FDA in 2010.
increased risk of severe cardiovascular events.
Native GLP-1 has regulates appetite and feeding
Naltrexone/Bupropion centers in the brain; and it has, potential to impact
upon energy intake, most likely mediated by reducing
Bupropion is a relative weak inhibitor of norepinephrine appetite and decreasing food intake, as measured by
and dopamine uptake, it stimulates hypothalamic appetite scores and post-prandial satiety and fullness
proopiomelanocortin (POMC) neurons, leading ratings, and did not increase energy expenditure.
to melanocortin receptor activation [MCR4] and
induction of weight loss via appetite suppression and Liraglutide (3.0 mg daily), in higher doses was tested
increased energy expenditure. Naltrexone is opioid in phase III clinical trials (the SCALE programme) to
receptor antagonist that would normally induce a investigate the safety and efficacy of liraglutide 3.0
negative feedback-mediated repression of POMC mg in weight management in obese patients both
activation, and thus acts synergistically to prolong with and without T2D.
the action of bupropion on metabolism. Phase III trials
have been completed in diabetic and nondiabetic SCALE study, the Obesity and Prediabetes trial,
patients (Contrave Obesity Research [COR]-I, COR-II,
COR-Intensive Behaviour Modification [BMOD] and investigated the BeMffeI c≥ ts30ofkglir/amg2lutoidre237.0kmg/gmin2 3731
COR-Diabetes trials). In COR-II Significant (P < 0.001) individuals with with
greater weight loss was observed with NB32 (32 mg
naltrexone and 360 mg bupropion) versus placebo additional comorbidities, with or without prediabetes,
at week 28 (−6.5% vs. −1.9%) and week 56 (−6.4% vs.
over 56 weeks (97). At week 56, individuals on

liraglutide 3.0 mg had lost 8.0% (8.4 kg) of body weight

compared with 2.6% (2.8 kg) on placebo [estimated

treatment difference 5.4%, (5.6 kg), p < 0.001]. A

GCDC 2017

Cardio Diabetes Medicine 2017 447

total of 63.2% of the patients in the liraglutide group pancreatic lipase by cetilistat reduces the conversion
as compared with 27.1% in the placebo group lost of TGs into free fatty acids, and thus the TGs are
at least 5% of their body weight (P<0.001), Other excreted unchanged in the urine. In a 12-week study,
benefits in addition to weight loss are improvements weight loss of 3.3–4.1 kg (placebo not available) was
in glycaemic control, blood pressure and lipids. demonstrated.
Liraglutide 3.0 mg was generally well tolerated, with
the most common adverse effect being nausea and Most common side effects reported as
diarrhea during the first few weeks of treatment. gastrointestinal-related (38,39). As a result of phase
Incidences of pancreatitis were low, although events III data, cetilistat has been approved in Japan since
were reported more frequently with liraglutide 3.0 September 2013; however, it has not yet been filed
mg [3.1 events/100 patient-years of expo- sure (PYE) for approval in the USA and Europe.
and 0.4 events per 100 patient-years at risk (PYR),
respectively] than with placebo (1.4 events/100 PYE Belonarib
and < 0.1 events/100 PYR, respectively).
Belonarib is administered subcutaneously and that
Based on the results of phase III SCALE clinical trial acts via inhibition of methionine amino peptidase 2
(MetAP2) (41).
programme, the FDA approved liraglutide 3.0 mg in
In a 12-week, phase II study, participants receiving
December 2014 as an adjunct to a reduced-calorie belonarib 0.6 mg, 1.2 mg or 2.4 mg lost 5.5 kg, 6.9
kg or 10.9 kg, respectively, compared to 0.4 kg
diet oanf d≥ 3i0nckrega/sme2d, eoxr e≥ r2c7isekgi/nma2duinlt patients with a in the placebo group (p < 0.001) (108). Belonarib
BMI the presence of was generally well tolerated, although more sleep
disturbances and gastrointestinal AEs were reported
at least one weight-related comorbid condition (98).). in the belonarib group compared to the placebo
groups. These events were generally dose related;
Liraglutide is the first once daily GLP-1 analogue mild-to moderate in severity, transient Phase III trials
are ongoing.
to be licensed for treatment of obesity in the USA
Bupropion/Zonisamide
and Europe; post-marketing surveillance studies are
Bupropion/zonisamide (a mitochondrial carbonic
ongoing to assess long-term safety. anhydrase inhibitor) is another combination
pharmacotherapy for obesity (43). Currently phase II,
Orlistat preliminary findings in 18 patients have demonstrated
a 7.2kg weight loss with bupropion/zonisamide vs.
Orlistat was the only FDA approved anti-obesity 2.9 kg with zonisamide alone over 12 weeks (44),
drug until 2012. It acts locally to potently inhibit with the most frequent adverse effect as headache,
pancreatic and gastric lipase and thus the hydrolysis nausea and insomnia.
of triglycerides. This results in lower rate of fat
absorption by almost 30 percent. Clinical trials with Tesofensine
orlistat demonstrated significantly greater weight loss
compared with placebo [5.8 kg vs. 3.0 kg; p < 0.001 Tesofensine is a triple monoamine reuptake inhibitor
(34]; however, a meta-analysis of up to 15 trials with inhibits reuptake of serotonin, noradrenaline, and
orlistat revealed an overall mean placebo-adjusted dopamine and thereby suppresses appetite and
weight loss of only around 2.9 kg (2.9%) with up to increases thermogenesis. The clinical Phase 2b trial
4 years’ treatment. Major safety concern has arisen (TIPO-1), reported in The Lancet, showed levels of
with orlistat is its potential link with liver toxicity. weight loss over a six-month period that were of high
However, a recent meta analysis of its use in the clinical relevance, Patients lost an average of 12.8 kg
UK demonstrated no increased risk of liver toxicity. on a 1 mg dose, 11.3 kg on a 0.5 mg dose and 6.7 kg
Gastrointestinal side effects such as flatulence on a 0.25 mg dose compared with a 2.2 kg loss in
steatorrhea abdominal pain and discomfort, oily or the placebo group.
liquid stool and faecal urgency are very common;
Long-term tolerability remains problematic, overall The drug was fairly tolerated, adeverse effects are dry
median discontinuation rate in most studies for mouth, dizziness, constipation, abdominal pain, and
orlistat was 30%. Other Drugs in Clinical Development nausea being the common side effects. It received
approval to initiate a Phase 3 study for tesofensine
Cetilistat in obese Mexican patients. received in April 2017.

Cetilistat, It is a pancreatic lipase inhibitor that is
undergoing phase III clinical trials, works in a manner
similar to orlistat, Pancreatic lipase is a key enzyme
that causes breakdown of TGs into free fatty acids
that are absorbed in the intestine. Inhibition of

Cardio Diabetes Medicine

448 Obesity- Pharmacotherapy

GSK1521498 effects compared with centrally acting drugs. Given
the high unmet need and our growing understanding
GSK1521498 is a µ-opioid receptor inverse agonist that of the complexity of pathogenesis of obesity, novel,
is being investigated for the treatment of overeating more efficacious and better tolerated treatments for
behavior in obesity, it have been shown to reduce obesity are clearly required
short-term food intake and affective or subjective
pleasantness of palatable foods in healthy participants References
A study in healthy volunteers showed that GSK1521498
seletively reduced food craving for high-sugar and 1. Prospective Studies Collaboration. Lancet 2009; 373:1083–1096.

high fat dairy products and caloric intake of high-
fat snack foods. phase 1 study showed the drug to 2. WHO Obesity and overweight www.who.int/mediacentre/factsheets/fs311/
have an acceptable safety profile when the drug was en/index.html
administered for 10 days in multiple doses. It remains
to be seen whether the decreased food craving would 3. Richard D. Cognitive and autonomic determinants of energy homeostasis
translate into significant weight reduction when the in obesity. Nat Rev Endocrinal 2015; 11: 489–501.
drug is given for long period.
4. Public Citizen Comments on FDA Obesity Trial Guidelines www.citizen.
Table 3. Anti obesity drugs in pipeline org/page.aspx?pid=742

AgRP, agouti-related protein;, GLP-1, glucagon-like 5. European Medicines Agency. Committee for Medicinal Products for Human
peptide 1; GCGR, glucagon receptor; MetAP2, methi- Use. Guideline on clinical evaluation of medicinal products used in weight
onine aminopeptidase 2; MTP, microsomal triglycer- control (CPMP/EWP/281/96 Rev. 1). London, UK, 15 November 2007.
ide transfer protein; Doc. Ref. EMEA/CHMP/EWP/517497/2007 (2007).

6. Smith SR, Weissman NJ, Anderson CM et al.; Behavioral modification
and lorcaserin for over- weight and obesity management (BLOOM) Study
Group. Multicenter, placebo-controlled trial of lorcaserin for weight
management. N Engl J Med 2010; 363: 245–56.

Drug Mechanism of Action Clinical Development Phase
Phase 2 completed
Velneperit
Neuropeptide Y5 receptor antagonist
Phase 3 initiated
Phase 2 completed
Tesofensine
Triple monoamine reuptake inhibitor Phase 2 completed
Phase 2 completed
JNJ-16269110 MTP inhibitor
Phase 2 ongoing
Phase 1 completed
Beloranib
MetAP-2 inhibitor

Phase 1 completed
TTP-435 AgRP Inhibitors


Oxyntomodulin
DualGLP1R and GCGR agonist

PF-04971729

Selective inhibitor of the sodium-
dependent glucose cotransporter 2

GSK1521498 -Opioid inverse agonist

Conclusions 7. Weissman NJ, Sanchez M, Koch GG, Smith SR, Shanahan WR, Anderson
CM. Echocardiographic assessment of cardiac valvular regurgitation with
Obesity has changed from being a rare, and perhaps lorcaserin from analysis of 3 phase 3 clinical trials. Circ Cardiovasc Imaging
even revered, occurrence to a condition that is 2013; 6: 560–7.
common in a large proportion of the population in the
developed world. Pharmacotherapy even with all the 8. Fidler MC, Sanchez M, Raether B et al. ; BLOS- SOM Clinical Trial Group.
limitations plays an important role in the treatment A one-year random- ized trial of lorcaserin for weight loss in obese and
of obesity, by modestly improving the weight loss overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab 2011;
obtained with diet and exercise and thus helps in 96: 3067–77.
reducing the impact of comorbidities associated with
obesity. . Recent advances in the understanding of
energy balance control have highlighted a number
potential novel targets for therapeutic intervention. Gut
hormones may be especially promising candidates
for future exploration due to relatively few side

GCDC 2017

Cardio Diabetes Medicine 2017 449

Bariatric Surgery In Diabesity :
What Is Endocrinologist’s Perspective?

Dr. S. Murthy, MD, DM, Director

Endocrine Diagnostic and Research Centre,
Diabetes Care Centre, Chennai.

Introduction as liver andβ-cells thereby impairing function, survival
and regeneration.
The intrinsic association between obesity and Type
2 diabetes (T2DM) is well recognized, to the extent (3) The “adipokine hypothesis” refers to the
that the term Diabesity was coined by Dr Ethan principal feature of white adipose cells to function
Sims [1]. The word ‘diabesity’ highlights the etiologic as an endocrine organ, and to secrete a variety of
effect of obesity on type 2 diabetes, with or without hormones with auto- and paracrine function. It has
associated risk factors such as dyslipidaemia and been proposed that expanding fat stores in obesity
hypertension. Thus diabesity forms a subset of cause dysfunctional secretion of such endocrine
metabolic syndrome. factors, thereby resulting in metabolic impairment of
insulin target tissues and eventually failure of insulin
In India, standard international criteria are followed producing β-cells.
for the diagnosis of diabetes. For obesity, however,
ethnic-specific diagnostic criteria should be used. As Drug class & potential Reduction Side Effects
Asians have a higher risk of cardiovascular disease, Medication Effect on in A1c
low cut offs are taken for obesity. weight

While the World Health Organization suggests an Biguanides 2-3kg 1.5-2% Lactic acidosis,
upper limit of 25.0km/m2 for normal body mass (Metformin) weight loss Gastrointestinal
index (BMI), South Asians should ideally have a BMI
less than 23kg/m2. Similarly, overweight is defined Sodium- 2-3kg 0.6-0.9% Urinary tract
as a BMI of 23.0kg/m2 to 24.9kg/m2 in Indians. glucose co weight loss 0.9-1% infection, Genital
Obesity is diagnosed above BMI 25.0kg/m2 in South transporter Mycotic infection,
Asians. 2 inhibitors 2.87-3.84kg increase in
(SGLT2) weight loss potassium,
Pathophysiology (Empaglifozin, Creatinine and Low
canagliflozin, density lipoproteins
Three main hypotheses have been developed [2]: Dapagliflozin) cholesterol

(1) The “inflammation hypothesis” asserts that obesity Glucagon- Medullary Thyroid
represents a state of chronic inflammation in which like peptide cancer, acute
inflammatory molecules produced by infiltrating 1 agonists pancreatitis,
macrophages in adipose tissue exert pathological (Exenatide, Gastrointestinal
changes in insulin-sensitive tissues and β-cells. Liraglutide,
Dulaglutide)
(2) The “lipid overflow hypothesis”, also known as
“Adipose Tissue Expandability Hypothesis (ATEH)” Amylin 2.57kg 0.3-0.4% Gastrointestinal
predicts that obesity may result in increased ectopic analogues weight loss
lipid stores due to the limited capacity of adipose (Pramlinitide)
tissue to properly store fat in obese subjects.
Potentially harmful lipid components and metabolites
may exert cytotoxic effects on peripheral cells, such

Cardio Diabetes Medicine

vv

450 Bariatric Surgery In Diabesity

Pharmacological Management Of Obesity In Compared with previous guidelines for bariatric
T2dm surgery, which used only BMI as sole parameter
to select surgical candidates, the DSS-II
Pharmacological management of hyperglycaemia in recommendations introduce the use of diabetes-
T2DM is of paramount importance yet consideration related parameters to help identify clinical paradigms
should be given to those medications that are weight where surgical treatment of T2D should be one of
neutral or have potential to augment weight loss, see the preferred options. DSS-II also elucidated the
Table below for classes of anti-diabetic drugs in these preoperative workup and postoperative follow-up of
categories and associated benefits and side effects [ patients undergoing metabolic surgery for T2D.

3]. The ideal anti-diabetic drug should produce Statements and recommendations of DSS –II – Salient
sustained weight loss with minimal side effects. points [5]
Such a drug is still elusive in the market today. Drugs
that target pathways in metabolic tissues, such as Generalities
adipocytes, liver and skeletal muscle, have shown
potential in preclinical studies but none has yet - Given its role in metabolic regulation, the GI tract
reached clinical development. constitutes a clinically and biologically meaningful
target for the management of T2D. 
Numerous randomized clinical trials (RCTs) have
demonstrated that bariatric/metabolic surgery - There is now sufficient clinical and mechanistic
achieves superior glycemic control and reduction of evidence to support inclusion of GI surgery among
cardiovascular risk factors in obese patients with T2D antidiabetes interventions for people with T2D and
compared with various medical/lifestyle interventions. obesity. 
Despite existing growing evidence diabetes treatment
algorithms do not include surgical options. - Algorithms for treating T2D should include specific
scenarios in which metabolic surgery is considered
The 2nd Diabetes Surgery Summit (DSS-II), an to be a treatment option in addition to lifestyle,
international consensus conference, was convened nutritional, and/or pharmacological approaches. 
in collaboration with leading diabetes organizations
to develop global guidelines to inform clinicians Metabolic Surgery Versus Traditional
and policymakers about benefits and limitations of Bariatric Surgery
metabolic surgery for T2D.
- Metabolic surgery—defined here as the use of GI
Bariatric Surgery surgery with the intent to treat T2D and obesity—
requires the development of a diabetes-based model
The most common bariatric surgery is gastric bypass of clinical practice consistent with international
(also called Roux-en-Y gastric bypass, RYGB): standards of diabetes care. 
causing durable remission in majority of patients with
T2D. Favored is Rou-en-Y, Biliopancreatic duodenal - Complementary criteria to the sole use of BMI, need
diversion (duodenal switch) and to lesser extent to be developed to achieve a better patient selection
vertical sleeve gastrectomy for better and sustained algorithm for metabolic surgery. 
weight reduction and metabolic control [4].
- RYGB, VSG, LAGB, and BPD classic or duodenal
Gastric bypass patients lost an average of 25% of switch variant (BPD-DS), are common metabolic
their body weight (and nearly 11% of their body fat), operations, each with its own risk-to-benefit ratio.
gastric band dropped 15% of their weight (and 5.6% of
their body fat) and lifestyle group members lost 5.7% - Metabolic surgery should be performed in high-
of their weight and 3% of their body fat. volume centers with multidisciplinary teams.

Bariatric operations can directly improve glycemic Defining Goals And Success Of Metabolic
control and not merely weight reduction. In 90% it Surgery
causes lowering blood sugar, reducing the dosage and
type of medication required and improving diabetes- - The aim of metabolic surgery in people with T2D
related biochemical abnormalities, e.g. lipedema and and obesity is to improve their hyperglycemia and
blood pressure control. It can induce remission in other metabolic derangements, while reducing their
78% of patients by bringing blood glucose to normal complications of diabetes, in order to improve their
ranges and eliminating the need for medications. long-term health. 

GCDC 2017

Cardio Diabetes Medicine 2017 451

Patient Selection excellent weight loss and major improvement of T2D,
at least in the short to medium term (1–3 years).
- Patients’ eligibility for metabolic surgery should
be assessed by a multidisciplinary team including - LAGB is effective in improving glycemia in patients
surgeon(s), internist(s) or diabetologist(s)/ with obesity and T2D, but is associated with greater
endocrinologist(s), and dietitian(s) with specific risk for reoperation/revision compared with RYGB.
expertise in diabetes care.
Postoperative Follow-Up
- Contraindications for metabolic surgery include
diagnosis of T1D (unless surgery is indicated for other - After surgery, patients should continue to be
reasons, such as severe obesity); current drug or
alcohol abuse; uncontrolled psychiatric illness; lack managed by multidisciplinary teams including
of comprehension of the risks/benefits, expected
outcomes, or alternatives; and lack of commitment diabetologists/endocrinologists, surgeons,
to nutritional supplementation and long-term follow-
up required with surgery.  nutritionists, and nurses with specific diabetes

- Metabolic surgery is recommended as an option expertise. 
to treat T2D in patients with the following conditions:
- Postoperative follow-up should include surgical
Class III obesity (BMI ≥40 kg/m2), regardless of the and nutritional evaluations at least every 6 months,
level of glycemic control or and more often if necessary, during the first 2
postoperative years and at least annually thereafter. 
Complexity of glucose-lowering regimens.
- Within the first 6 months after surgery, patients
Class II obesity (BMI 35.0–39.9 kg/m2) with should be carefully evaluated for glycemic control and
inadequately controlled antidiabetes medication(s) tapered.. Further medical
treatment of T2D after this initial 6-month period
hyperglycemia despite lifestyle and optimum medical should be dosed accordingly. Stable nondiabetic
therapy. glycemia should be documented for at least two
3-month HbA1c cycles before considering complete
- Metabolic surgery should also be  considered withdrawal of glucose-lowering drugs,.
to be an option to treat T2D in patients with class
I obesity (BMI 30.0–34.9 kg/m2) and inadequately - In the event of plasma glucose levels rapidly
controlled hyperglycemia despite optimal medical approaching the normal range early postoperatively,
treatment by either oral or injectable medications appropriate adjustments to medical therapy should
(including insulin). be implemented. Metformin, thiazolidinediones, GLP-
1 analogs, DPP-4 inhibitors, α-glucosidase inhibitors,
- All BMI thresholds used in these recommendations
should be reconsidered depending on the ancestry
of the patient. For example, for patients of Asian
descent, the BMI values above should be reduced
by 2.5 kg/m2.

Preoperative Workup and SGLT2 inhibitors are suitable drugs for early
postoperative diabetes management due to their low
- Preoperative patient evaluation should include risk of inducing hypoglycemia. 
assessment of endocrine, metabolic, physical,
nutritional, and psychological health.  Algorithm for the treatment of T2D, as recommended
by DSS-II. Meds = medications. [5]
- In order to reduce the risk for postoperative
infection, improve glycemic control before surgery.  Fig: Algorithm for the treatment of T2DM, as
recommended by DSS-II. The indications above are
Choice Of Procedure intended for patients who are appropriate candidates.

- RYGB is a well-standardized surgical procedure, and
among the four accepted operations for metabolic
surgery, it appears to have a more favorable risk-
benefit profile in most patients with T2D. 

- VSG is an effective procedure that results in

Cardio Diabetes Medicine

vv

452 Bariatric Surgery In Diabesity

Endocrine And Metabolic Complications development of hypoglycemia.
After Bariatric Surgery
Service et al. and Patti et al. described cases of
Bariatric surgery is the most effective therapeutic noninsulinoma pancreatogenous hypoglycemia
option for obese patients; however, it carries syndrome (NIPHS) that presented with symptoms
substantial risks, including procedure-related of postprandial neuroglycopenia secondary to
complications, malabsorption, and hormonal hyperinsulinemic hypoglycemia. Diagnosis of NIPHS
disturbance [6]. was confirmed pathologically by the presence of
diffused islet hypertrophy or nesidioblastosis in
Short-term complicationsThe overall 30-day mortality pancreas.
postoperatively is shown to be less than 1% in general.
Wound infection, bleeding, deep venous thrombosis, The modality of treating hypoglycemia postbariatric
and pulmonary embolism are the early complications surgery depends on the severity of the symptoms
of the surgery, whereas pulmonary embolism and and the response of the patient to the initial dietary
surgical leak are the most common causes of death. recommendations. Patients with early postoperative
mild adrenergic post-postprandial symptoms can
Late complications be managed initially with dietary advises including
frequent, small meals and low-carbohydrate diet.
Late complications related to the surgical For resistant cases, or presenting later postoperative
procedure include stomal stenosis, marginal ulcers, and those with severe hypoglycemia require further
cholelithiasis, internal and incisional hernias, short evaluation and therapy. In patients who do not respond
bowel syndrome, nutritional deficiencies, and well to the dietary modification pharmacological
dumping syndrome. therapy can be initiated with acarbose, diazoxide,
verapamil, and somatostatin.
Metabolic complications
Metabolic bone disease
Metabolic complications of bariatric surgeries include
metabolic acidosis, and/or alkalosis, electrolyte Another complication of increasing concern arising
abnormalities including low calcium, potassium, as a consequence of bariatric surgery is metabolic
magnesium, sodium, and phosphorus that may bone disease that leads up to osteoporosis and
cause arrhythmias and/or myopathies. Nutritional osteoporotic fracture.
abnormalities in the form of fat-soluble vitamin
deficiencies involving A, D, E, and K, iron and folic acid The impact of major weight loss on bone metabolism
deficiency, negative calcium balance, and vitamin D after bariatric surgery was until recently considered
deficiency causing secondary hyperparathyroidism, to be the sole result of a combination of mechanical
oxalosis, kidney stones, thiamine deficiency, vitamin and nutritional effects. The notion changed with
B12 deficiency, increased bacterial overgrowth causing recent insights, which showed an intricate and
nocturnal diarrhea and abdominal distension, have complex interplay between the signaling factors
been documented. of gut, bone, and fat tissue, utilizing a third
neurohormonal mechanism regulating bone turnover
Hypoglycemia through adipokines; leptin and adiponectin, gonadal
steroids,] and gut-derived hormones. GIP’s receptor,
Hypoglycemia is increasingly being recognized as glucose-dependent insulinotropic polypeptide
a complication of gastric bypass surgeries. Relative receptor (GIPR), is expressed in bone tissue and its
risk of hypoglycemia increases sevenfold in the deficiency in animals reportedly led to increased
postgastric bypass population, and the frequency of bone resorption with a pronounced reduction in the
asymptomatic documented hypoglycemia after oral degree of mineralization of bone matrix.
glucose tolerance test reached 30% among postgastric
bypass patients. A median time from surgery to The degree of bone loss or disease varies with the
development of symptoms was observed to be 2.7 type of surgery undertaken. Surgeries employing
years. The pathophysiology of hypoglycemia remains malabsorptive techniques such as RYGB, bypass the
controversial; dumping syndrome, an increase in beta primary absorption sites for vitamins and minerals,
cell mass, alteration of beta cell function, and other that is, the duodenum and proximal jejunum resulting
factors not related to beta cell were all suggested in deficiencies of key osteogenic factors such as
as possible mechanisms. In addition, increased calcium that is actively absorbed from the proximal
weight loss following surgery along with an increase foregut, and vitamin D that requires bile acids and
in insulin sensitivity may additionally contribute to pancreatic secretions for optimal absorption.

GCDC 2017

Cardio Diabetes Medicine 2017 453

Restrictive techniques, such as sleeve gastrectomy, Society, and American Society for Metabolic and
on the other hand reduce the total amount of Bariatric Surgery AACE/TOS/ASMBS guidelines [7]
gastric acid required for lowering the pH for optimal recommends performing certain laboratory tests
absorption of other essential vitamins and minerals. every three months in the first year after surgery,
RYGB and biliopancreatic diversion can thus cause and every 3–12 months thereafter, depending on
malabsorption of calcium (25%–50%) and vitamin D symptoms.
(>50%). Numerous reported cases clearly show the
risk of metabolic bone disease occurring from as early Postoperatively, many bariatric patients require
as 8 weeks until 32 years after bariatric surgery. A chewable or liquid supplements to facilitate adequate
recent study found that losing 0.7 kg/week was more absorption.
detrimental to bone than a slower loss of 0.3 kg/
week due to the activation of the calcium–PTH axis. References:
After bariatric surgery, many patients rapidly lose 50–
100 kg of their weight; this weight loss combined with 1. Ribaric G, Buchwald JN, McGlennon TW, Diabetes and Weight in Com-
severely restricted oral intake of all the nutrients that parative Studies of Bariatric Surgery vs Conventional Medical Thera-
includes proteins, calcium, and vitamins predisposes py: A Systematic Review and Meta-Analysis, Obes Surg Volume 2014,
them to furthering the development of metabolic 24(3):437-455.
bone disease.
2. Alexander Chadt, PhD, Stephan Scherneck, PhD, et al, Molecular Links
In addition to gut hormones, locally synthesized between obesity and Diabetes: “Diabesity”, 2014
hormones such as the estrogens, known to impact
bone health were also altered post operatively. As 3. Emmeline de Gruchy and Vinay S Eligar, Review of the Pharmacological
weight decreases and adipose stores are depleted, Interventions and Bariatric Surgery for Diabesity, MoJ Drug Des Develop
the levels of estrogen decrease in both men and The 2017, 1(1):00005.
women resulting in decreased impact of estrogen on
bone. Estrogen may also affect bone metabolism by 4. Saadi J.S. Aljadir, bariatric/Metabolic Surgery for Diabesity..!, Endocrinol
Metab int J 2016, 3(2):00043.

5. Metabolic Surgery in the Treatment Algorithm for Type 2 Diabetes: A
Joint Statement by International Diabetes Organizations, Diabetes Care
2016;39:861-877.

6. Anwar A Jammah, Endocrine and Metabolic Complications after Bariatric
Surgery, Saudi J Gastroenterol 2015, Sept-Oct; 21(5): 269-277.

7. Mechanick JI, Kushner RF, et al. ; American Association of Clinical Endo-
crinologists; Obesity Society; American Society for Metabolic and Bariatric
Surgery. American Association of Clinical Endocrinologists, The Obesity
Society, and American Society for Metabolic and Bariatric Surgery medical
guidelines for clinical practice for the perioperative nutritional, metabolic,
and nonsurgical support of the bariatric surgery patient. (v).Obesity (Silver
Spring) 2009;17(Suppl 1):S1–70.

direct effects on vitamin D and calcium metabolism.

The investigations generally should include serum
and urine calcium, 25-hydroxyvitamin D, alkaline

phosphatase, and serum intact PTH levels.
Complications may be seen as early as 8 weeks
after bariatric surgery in the form of secondary
hyperparathyroidism and osteomalacia. The American
Association of Clinical Endocrinologists, The Obesity

Cardio Diabetes Medicine

454 Cardio Diabetes Medicine 2017

Idnetifying The Right Patients Who Benefits
From AICD Implantation

Dr.Raja Selvaraj

Additional Professor, Department of Cardiology,
JIPMER, Puducherry

Abstract: critical to optimal utilisation of an AICD. This is based
on identification of subgroups of patients who are at
Sudden cardiac death is a major cause of mortality all high risk for sudden death in whom the risk of device
over the world and in India. It is all the more significant implantation will be less than the benefit offered
because many of these patients are young and have by the device. This article discusses the important
otherwise good quality of life. indications and major subgroups who benefit from
AICD implant. This is not a comprehensive list of all
Ventricular arrhythmias have been established as the indications.
the leading cause of sudden cardiac death. After
various anti-arrhythmic drugs were found to provide Secondary prevention:
no protection against sudden death, the automatic
implantable cardioverter defibrillator (AICD) has Patients who have survived a prior cardiac arrest
emerged as an effective method to prevent sudden are among the highest risk groups for having a
death in patients at high risk. In this article, the key recurrent cardiac arrest. Pivotal studies in patients
indications for implantation of an AICD are discussed with aborted sudden cardiac death – AVID (2), CIDS
with the accompanying evidence based on which and CASH proved the survival benefit with AICD
these indications have been made. implantation in this subgroup of patients. Therefore
this remains one of the most important indications
Introduction: for AICD implantation. Apart from patients with
cardiac arrest due to ventricular fibrillation, those with
Sudden Cardiac Death is an unexpected natural death sustained ventricular tachycardia in the presence of
of cardiac causes occurring within a short period of structural heart disease are also considered for AICD
onset of symptoms. It is a major contributor to all implantation for secondary prevention.
death and in India, has been estimated to account
for about 10% of all deaths (1). When documented, the Thus secondary prevention is a class I indication
rhythm is found to be ventricular fibrillation in these for AICD implant except for one important caveat.
patients. Defibrillation is an effective Most important is to exclude a reversible cause for
the cardiac arrest in which case AICD implantation
treatment for this rhythm, but most events occur is not required. This may occur, for example, in the
outside a hospital setting and immediate access to following settings -
defibrillation is not available.
1. Ventricular fibrillation within 48 hours of acute
The Automatic Implantable myocardial infarction (primary VF).

Cardioverter Defibrillator (AICD) is a miniaturised 2. Ventricular fibrillation in setting of hypokalemia
defibrillator which can be implanted in a patient, can or other electrolyte disturbances.
sense fibrillation and provide immediate cardioversion.
It represents an important technical advance in the 3. Ventricular arrhythmias in the setting of acute
management of these patients. However, the device myocarditis that resolves with treatment.
is costly, implantation is an invasive procedure and
complications can occur during implantation and
follow up. Therefore, identifying the right patient is

GCDC 2017

Idnetifying The Right Patients 455
Who Benefits From AICD Implantation

Primary prevention: of 35% or less and are in heart failure (NYHA class II
or III) are recommended AICD implantation.
Patients with a prior cardiac arrest, although at very
high risk of a recurrent event, form only a small Nonischemic Cardiomyopathy:
proportion of patients who die suddenly. Often
sudden death happens as the first event in patients In patients with left ventricular dysfunction, but
without prior warning. In order to prevent these without a previous MI, recommendation to implant
deaths, the concept of primary prevention evolved. an AICD for primary prevention is based on the
SCDHeFT trial referred to above and the DEFINITE
This involves identifying patients who are at risk of trial (5) which both showed survival benefit in this
experiencing a lethal arrhythmia, but who have not subgroup of patients. However, the benefit from AICD
yet experienced a cardiac arrest. Structural heart implantation in patients with ventricular dysfunction
disease is one of the most important markers of and heart failure in the absence of coronary artery
risk and primary prevention is most often applied to disease has always been less robust than that in
patients with structural heart disease. patients with coronary

However, since not all these patients would require artery disease. The more recent DANISH trial (6) which
device implantation, other markers have to be used to specifically studied this in a large group of patients
identify those most at risk. Despite various markers found no survival benefit from AICD implantation.
like frequent premature ventricular complexes,
non-sustained VT, signal averaged ECG, Heart rate Hypertrophic Cardiomyopathy:
variability, T wave alternans, etc having been studied,
ejection fraction remains the one robust measurement Another form of cardiomyopathy that is relatively
that has been repeatedly shown in various studies common and carries a risk of sudden death in some
to predict future risk of sudden death. Therefore, patients is hypertrophic cardiomyopathy (HCM).
despite its known various limitations, it remains the With a population prevalence of about 1 in 500, it
most clinically useful marker of risk. The important is benign in most patients, but is also one of the
group of heart diseases where primary prevention is most important causes of sudden death in the young
considered are discussed below. and in athletes. Current guidelines suggest that all
patients with HCM should be evaluated for their risk
Ischemic Cardiomyopathy: of sudden death at initial presentation. Presence of
one of the established risk markers
Coronary artery disease is the most important
underlying substrate for lethal ventricular arrhythmias. unexplained syncope, maximal left ventricular wall
Patients with significant left ventricular dysfunction thickness more than 30 mm, non sustained ventricular
following an acute myocardial infarction (MI) are at tachycardia, abnormal blood pressure response to
risk. exercise and a history of sudden death in a first
degree relative should prompt AICD implantation.
The pivotal study was MADIT II (3) in which patients
with a previous MI and left ventricular dysfunction When not to implant an AICD:
with ejection fraction (EF) of 30 or less were
randomized to conventional medical therapy alone or As important as, or maybe more important than
implantation of a defibrillator in addition. Implantation knowing when to implant an AICD is knowing
of defibrillators was found to provide a survival benefit when not to implant an AICD. Idiopathic ventricular
with a mortality of 14.2% compared to 19.8% in the tachycardia is always amenable to ablation and
conventional medical treatment group over a follow does not warrant AICD implantation. Patients with
up of 20 months. Based on this study, patients with incessant or recurrent ventricular tachycardia are
EF of less than or equal to 30% at least 40 days after often advised emergency AICD implantation. The
an acute MI are recommended AICD implantation. emphasis should be on control of the arrhythmias
with drugs or ablation in these patients. Only after
Another major study was the SCDHeFT trial (4), where control of the arrhythmia should AICD implantation
patients with ischemic and non-ischemic causes of be considered. The overall clinical status of the patient
cardiomyopathy with EF less than 35% and heart should be taken into consideration when deciding on
failure were randomized to placebo, Amiodarone the need for device implant. Any coexistent condition
or AICD implantation. Over a follow up period of that results in an expected longevity of less than a
45 months, mortality was 29%, 28% and 22% in the year should be a contraindication for AICD implant.
placebo, amiodarone and AICD implantation groups. Significant comorbidities like renal dysfunction
Based on this patients with prior MI who have an EF

Cardio Diabetes Medicine

456 Cardio Diabetes Medicine 2017

or refractory class IV heart failure also reduce the References:
benefit from AICD implant and should be taken into
account. 1. Rao B.H., Sastry B.K., Chugh S.S. Contribution of sudden cardiac death
to total mortality in India - a population based study. Int J Cardiol.
Conclusion: 2012;154:163–167

The Automatic Implantable Cardioverter Defibrillator 2. The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators.
represents an important advance in the management A Comparison of Antiarrhythmic-Drug Therapy with Implantable
of patients at risk of dying suddenly. With Defibrillators in Patients Resuscitated from Near-Fatal Ventricular
advancements in technology over the last few Arrhythmias. N Engl J Med 1997; 337:1576-1584
decades, the device has become smaller and easier
to implant and more reliable and effective. The 3. Arthur J. Moss, Wojciech Zareba, W. Jackson Hall, Helmut Klein, David J.
challenge has been in identifying the right patients Wilber, David S. Cannom et al. Prophylactic Implantation of a Defibrillator
who will achieve maximum benefit from an AICD. in Patients with Myocardial Infarction and Reduced Ejection Fraction. N
Multiple studies have been done regarding this and Engl J Med 2002; 346:877-883.
guidelines have been formulated. It is important for
treating physicians to be familiar with these guidelines 4. Gust H. Bardy, Kerry L. Lee, Daniel B. Mark, Jeanne E. Poole, Douglas L.
and choose patients appropriately Packer, Robin Boineau et al. Amiodarone or an Implantable Cardioverter–
Defibrillator for Congestive Heart Failure. N Engl J Med 2005; 352:225-
Highlights: 237

• AICD is currently the only effective method to 5. Alan Kadish, Alan Dyer, James P. Daubert, Rebecca Quigg, N.A. Mark Estes,
reduce the risk of sudden death in patients at Kelley P. Anderson. Prophylactic Defibrillator Implantation in Patients with
high risk. Nonischemic Dilated Cardiomyopathy. N Engl J Med 2004;350:2151-8.

• Most important group of patients at risk are 6. Lars Køber, Jens J. Thune, Jens C. Nielsen, Jens Haarbo, Lars Videbæk,
those who have survived a cardiac arrest. Eva Korup, Gunnar Jensen et al. Defibrillator Implantation in Patients with
Nonischemic Systolic Heart Failure. N Engl J Med 2016; 375:1221-1230
• Patients with ischemic or non-ischemic
cardiomyopathy with reduced ejection fraction
are eligible for AICD implantation for primary
prevention of sudden death, although the
evidence is stronger for patients with coronary
artery disease

• Patients with hypertrophic cardiomyopathy
who have one of the established risk factors
should be considered for AICD implantation.

GCDC 2017

Cardio Diabetes Medicine 2017 457

Heart Failure: Drug Thaerapies and
Revascularization Strategies

Dr. Abraham Oomman

M D, DM (Cardiology), DNB (Cardiology),
MNAMS, FACC, FESC, FSCAI,

Senior Consultant Interventional Cardiologist
Apollo Hospitals, Chennai

Introduction tolic dysfunction - IIa A

Heart failure is the modern day plague with a 5 year BB in asymptomatic LVD and h/o MI - I B
mortality over 50% , deadlier than most cancers ex-
cept possibly lung cancer. It is common , costly and ICD in asymptomatic LVD (EF < 30%), ischaemic 40
deadly. Its prevalence is 2-3% and is the number one days after MI - I B
cause of hospitalizations in patients over 65 years.
Heart failure expenses in USA annually is nearly 40 ICD in asymptomatic non- ischaemic DCM (EF < 30%)
billion dollars annually. Prevention, diagnosis, risk on OMT - I B
stratification, monitoring and managing heart failure
is challenging. Acute Heart Failure

There is a rising prevalence of heart failure in India ESC 2016 mang ement algorithm is given below (pic
due rising incidence of hypertension(HT), diabetes 1, 2,)
mellitus (DM), obesity and coronary artery disease
i(CAD). The AFAR study on the epidemiology of Main messages in AHF
acute decompensated heart failure (ADHF) in India
noted that there is a significant difference from the In AHF with no shock ,decongestion with vasodilators
Western data( OPTIMIZE registry). Mean age was 2 to be initiated. Low CO with myocardial ischaemia
decades earlier (53.5 vs 73.1),the in-hospital mortality tackle myocardial ischaemia urgently. Time is muscle.
was 30.8% vs 3.8%, post discharge 6 month mortality Combine inotropes with norepinephrine if needed.
was 26.3% vs 8.6% and 6 month combined mortalty Avoid epinephrine as much as possible.
and rehospitalizatiion was 39.5%.
Main messages in AHF
Recommendations to prevent or delay the
onset of HF(ESC 2016) In AHF with no shock ,decongestion with vasodilators
to be initiated. Low CO with myocardial ischaemia
Treat Hypertension - I A tackle myocardial ischaemia urgently. Time is muscle.
Combine inotropes with norepinephrine if needed.
Statins for those with or high risk of CAD I A Avoid epinephrine as much as possible.

Counselling and treatment for smoking cessation Management algorithm is given below of Symptomatic
and alcohol reduction - IC chronic heart failure (ESC2016)

Treat other RF (obesity, dysglycemia) - IIa C Pharmacotherapy in HFrEF

Empagliflozin in T2DM - IIa B The objectives in the management of HFREF are
reduction in mortality, improve clinical status,
ACEI in asymptomatic LV dysfunction with h/o MI I A functional capacity, quality of life and reduce re-
admissions. There has been a steady improvement
ACEI in asymptomatic LV dysfunction without h/o in mortality reduction in CHF management.
MI I B

ACEI in stable CAD even if they do not have LV sys-

Cardio Diabetes Medicine

Heart Failure: Drug Thaerapies &
458 Revascularization Strategies

Pic 1 : ESC 2016 mangement algorithm

GCDC 2017

Cardio Diabetes Medicine 2017 459

Pic 2 : ESC 2016 mangement algorithm

Cardio Diabetes Medicine

Heart Failure: Drug Thaerapies &
460 Revascularization Strategies

Management of Acute RV Failure

Step 1 assess Severity : Hemo Dynamic monitoring and
• Clinical Evaluation ( Arterial Pressure, Mental status, Diuresis support (ICU or Inter mediate
• Biochemical evaluation (Lactate, Liver markers , renal function , BNB , troponins) Care unit)
• Imaging ( Echocadiography , CT Scan )
• Invasive Evaluation (central venous or pulmonary artery Catheter

Step 2 Identify and treat triggering Factor(s) :
• Sepsis ,Arrhythmias , Drug Withdrawl Ensure cause – specific management
• PCI for RV infarction ,Reperfusion for acute PE

Step 3 Optimize Fluid status
• Iv Diuretics if Volume Over load
• RRT if situation insufficiently managed with diuretics
• Cautious fluid Filling If low CVP ,Avoid over filling

Step 4 maintain arterial Pressure

• Nor Epinephrine

Step 5 Consider inotropes reducing cardiac Filling Pressure

• Levosimendan Consider transfer to hospital
with possibility for ECMO / Me-
• Dobutamine chanical Circulatory support

• Phospo diestarase III Inhibitor

Step 6 Further measures for after load reduction
Inhaled NO
Inhaled prosta cycline

Consider transfer to hospital with possibility for ECMO / Mechanical Circulatory support

ACEIs , MRAs , BB and currently ARNIs have been ACE inhibitors should be started at low doses and
shown to improve survival and is recommended for titrated upward to doses shown to reduce the risk of
treatment of every patient.The use of diuretics has to cardiovascular events in clinical trials.
be modulated according to the patient clinical status.
BB and ACIs are complementary and can bee started ARBs: Patients intolerant to ACE inhibitors because
as soosn as the diagnosis of HFrEF is made. of cough or angioedema should be started on ARBs;
patients already tolerating ARBs for other indications
In patients with chronic symptomatic HFrEF NYHA may be continued on ARBs if they subsequently
class II or III who tolerate an ACE inhibitor or ARB, develop HF.
replacement by an ARNI is recommended to further
reduce morbidity and mortality (ACC/AHA 2017 In ARNI, ARB is combined with an inhibitor of
classI). neprilysin, an enzyme that degrades natriuretic
peptides, bradykinin, adrenomedullin, and other
However ESC 2016 guidelines reserves it for patients vasoactive peptides. In an RCT that compared the first
who are still symptomaticon ACE/ARB and EF < 35%. approved ARNI, valsartan/sacubitril, with enalapril
in symptomatic patients with HFrEF tolerating an
ACE inhibitors have been shown in large RCTs to adequate dose of either ACE inhibitor or ARB, the ARNI
reduce morbidity and mortality in patients with HFrEF reduced the composite endpoint of cardiovascular
with mild, moderate, or severe symptoms of HF, with death or HF hospitalization significantly, by 20%. The
or without coronary artery disease . Data suggest benefit was seen to a similar extent for both death
that there are no differences among available ACE and HF hospitalization and was consistent across
inhibitors in their effects on symptoms or survival . subgroups. The use of ARNI is associated with the

GCDC 2017

Cardio Diabetes Medicine 2017 461

risk of hypotension and renal insufficiency and may symptomatic patients with HFrEF, despite treatment
lead to angioedema, as well. Ivabradine can be with an ACEI and, in most cases, a diuretic, but have
beneficial to reduce HF hospitalization for patients not been tested in congested or decompensated
with symptomatic (NYHA class II-III) stable chronic patients. There is consensus
HFrEF (LVEF ≤35%) who are receiving GDEM, including
a beta blocker at maximum tolerated dose, and who that beta-blockers and ACEIs are complementary,
are in sinus rhythm with a heart rate of 70 bpm or and can be started together as soon as the diagnosis
greater at rest.( ACC/AHA class IIa). of HFrEF is made. There is no evidence favouring
the initiation of treatment with a beta-blocker before
Beta-blockers an ACEI has been started. Betablockers should be
initiated in clinically stable patients at a low dose and
Beta-blockers reduce mortality and morbidity in

Cardio Diabetes Medicine

Heart Failure: Drug Thaerapies &
462 Revascularization Strategies

gradually up-titrated to the maximum tolerated dose. and concomitant HF, most of whom had HFrEF.
In patients admitted due to acute HF (AHF) beta-
blockers should be cautiously initiated in hospital, Coronary angiography
once the patient is stabilized. An individual patient
data meta-analysis of all the major betablocker trials Coronary angiography is recommended in patients
in HFrEF has shown no benefit on hospital admissions with HF who suffer from angina pectoris recalcitrant
and mortality in the subgroup of patients with HFrEF to medical therapy, provided the patient is otherwise
who are in AF. However, since this is a retrospective suitable for coronary revascularization. Coronary
subgroup analysis, and because beta-blockers angiography is also recommended in patients with
did not increase the risk, the guideline committee a history of symptomatic ventricular arrhythmia or
decided not to make a separate recommendation aborted cardiac arrest. Coronary angiography should
according to heart rhythm. Beta-blockers should be be considered in patients with HF and intermediate
considered for rate control in patients with HFrEF to high pre-test probability of CAD and the presence
and AF, especially in those with high heart rate. of ischaemia in non-invasive stress tests in order to
Beta-blockers are recommended in patients with a establish the ischaemic aetiology and CAD severity.
history of myocardial infarction and asymptomatic
LV systolic dysfunction to reduce the risk of death. Myocardial revascularization

Combination of hydralazine and isosorbide Percutaneous and surgical revascularization are
dinitrate complementary approaches for symptomatic relief
of angina in HFpEF, but whether these interventions
There is no clear evidence to suggest the use of improve outcomes is not entirely clear. Recent
this fixed-dose combination therapy in all patients ESC guidelines on myocardial revascularization
with HFrEF. Evidence on the clinical utility of this recommended coronary artery bypass grafting (CABG)
combination is scanty and comes from one relatively for patients with significant left main stenosis and
small RCT conducted exclusively in men and before left main equivalent (proximal stenosis of both the
ACEIs or beta-blockers were used to treat HF. A left anterior descending and left circumflex arteries)
combination of hydralazine and isosorbide dinitrate to improve prognosis. However, one needs to be
may be considered in symptomatic patients with aware of a lack of studies including patients who
HFrEF who can tolerate neither ACEI nor ARB (or they have well-defined HF, therefore this recommendation
are contraindicated) to reduce mortality. However, is solely based on expert opinion. On the basis of the
this recommendation is based on the results of the results of the STICH trial [which excluded patients
Veterans Administration Cooperative Study, which with left main disease and Canadian Cardiovascular
recruited symptomatic HFrEF patients who received Society (CCS) angina classes III–IV], CABG is also
only digoxin and diuretics. recommended in patients with HFrEF, significant
CAD (left anterior descending artery or multivessel
In patients with NYHA class II and III HF and iron disease) and LVEF ≤35% to reduce death and
deficiency (ferritin <100 ng/mL or 100 to 300 ng/ hospitalization for cardiovascular causes. Patients
Ml if transferrin saturation is <20%), intravenous with >10% dysfunctional but viable LV myocardium
iron replacement might be reasonable to improve may be more likely to benefit from myocardial
functional status and QoL(ACC/AHA 2017 class II b). revascularization (and those with ≤10% are less likely
to benefit), although this approach to patient selection
Digoxin and other digitalis glycosides for revascularization is unproven. In the STICH trial,
neither the presence of viability nor the severity of
Digoxin may be considered in patients in sinus LV remodelling identified those who benefited from
rhythm with symptomatic HFrEF to reduce the CABG in terms of a reduction in mortality. Post hoc
risk of hospitalization (both all-cause and HF analyses from the STICH trial revealed that the
hospitalizations), although its effect on top of presence of inducible myocardial ischaemia (either
betablockers has never been tested. The effects on radionuclide stress test or dobutamine stress
of digoxin in patients with HFrEF and AF have echocardiogram) or angina does not identify those
not been studied in RCTs, and recent studies have with worse prognosis and greater benefit from CABG
suggested potentially higher risk of events n patients over OMT.However, CABG does improve angina to a
with AF receiving digoxin. However, this remains greater extent than medical therapy alone. The choice
controversial, as another recent meta-analysis between CABG and PCI should be made by the Heart
concluded on the basis of non-RCTs that digoxin has Team after careful evaluation of the patient’s clinical
no deleterious effect on mortality in patients with AF

GCDC 2017

Cardio Diabetes Medicine 2017 463

status and coronary anatomy, expected completeness severe, secondary mitral regurgitation who are judged
of revascularization, coexisting valvular disease and inoperable or at high surgical risk, percutaneous
co-morbidities. mitral valve intervention (percutaneous edge-to-
edge repair) may be considered in order to improve
Primary (organic) mitral regurgitation symptoms and quality of life, although no RCT
evidence of improvement has been published, only
Surgery is indicated in symptomatic patients with registry studies.
severe organic mitral regurgitation with no contra-
indications to surgery. The decision of whether to Aortic stenosis
replace or repair depends mostly on valve anatomy,
surgical expertise available, and the patient’s In symptomatic patients with reduced LVEF and
condition. When the LVEF is < 30%, a durable surgical low flow low gradient AS( valve area< 1cm2,LVEF
repair may improve symptoms, although its effect on <40% mean pressure gradient <40 mmHg), low-
survival is unknown. In this situation, the decision to dose dobutamine stress echocardiography should
operate should take account of response to medical be considered to identify those with severe aortic
therapy, co-morbidities, and the likelihood that the stenosis suitable for valve replacement. IIa C TAVI is
valve can be repaired (rather than replaced). recommended in patients with severe aortic stenosis
who are not suitable for surgery as assessed by a
Secondary mitral regurgitation ‘heart team’ and have predicted post-TAVI survival
>1 year. I B
This occurs because LV enlargement and remodelling
lead to reduced leaflet closing. Effective medical TAVI should be considered in high-risk patients with
therapy (including CRT in suitable patients) leading to severe aortic stenosis who may still be suitable for
reverse remodelling of the LV may reduce functional surgery, but in whom TAVI is IIa
mitral regurgitation, and every effort should be made
to optimize medical treatment in these patients. In patients with severe aortic regurgitation, aortic
Combined valve and coronary surgery should be valve repair or replacement is recommended in all
considered in symptomatic patients with LV systolic symptomatic patients and in asymptomatic patients
dysfunction (LVEF < 30%), coronary arteries suitable
for revascularization, and evidence of viability. with resting LVEF who are otherwise fit for surgery.

Surgery is also recommended in patients with severe Conclusions;
mitral regurgitation undergoing CABG with LVEF <
30%. Heart failure is the emerging epidemic of the
twenty first century with a projected 25% increase
However, a recent study in patients with moderate, in prevalence by 2030.In spite of multiple advances
secondary ischaemic mitral regurgitation did not prove in therapy , the mortality and re- hospitalizations
that the addition of mitral valve repair to CABG would remain unacceptably high.However this serious
lead to a higher degree of LV reverse remodelling. threat is underrecognized by the public and health
care professionals.A team approach is mandatory to
Also, there is no evidence favouring mitral valve repair tackle this serious malady.
over replacement in the context of better outcomes
and magnitude of LV remodelling.In the presence of Suggested reading
AF, atrial ablation and LA appendage closure may
be considered at the time of mitral valve surgery. The 1. McMurray . Eur Heart J 2001 Jun 3 (3) 315-22.
role of isolated mitral valve surgery in patients with
severe functional mitral regurgitation and severe LV 2. Journal of practice of cardiovascular sciences 2015 : Volume 1; Issue
systolic dysfunction (LVEF < 30%) who cannot be : 1 : Page : 35-38 Epidemiology of acute decompensated heart failure
revascularized or have non-ischaemic in India : The AFAR study (Acute failure registry study) Sandeep Seth,
Suraj Khanal, Sivasubramanian Ramakrishnan, Namit Gupta, Vinay K Bahl
cardiomyopathy is questionable, and in most
patients conventional medical and device therapy are 3. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic
preferred. In selected cases, repair may be considered
in order to avoid or postpone transplantation. heart failure. European Heart Journal (2016) 37, 2129–2200.
The decision should be based on comprehensive
evaluation (including strain echocardiography or 4. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline
magnetic resonance imaging and discussed within for the Management of Heart Failure. Journal of the American College
the ‘heart team’. In patients with HF with moderate- of Cardiology April 2017

Cardio Diabetes Medicine

vv Cardio Diabetes Medicine 2017

464

When To Use ? When Not To Use ?
-Antiplatelets.

Prof.A.S.Mohan, M.D.,F.I.C.P.,

Professor & HOD, Medicine
Tirunelveli Medical College, Tirunelveli, Tamilnadu, India

The platelet is integral to the initiation of thrombosis. • Adenosine reuptake inhibitors
Drugs that affect platelet function are a fundamental
part of primary and secondary management of • Dipyridamole
atherosclerotic thrombotic disease. As reviewed in
various guideline documents, authoritative reviews, • Thromboxane inhibitors
and meta-analyses, the indications for the use of
antiplatelet drugs in the management of thrombotic • Thromboxane synthase inhibitors
diseases include stroke, acute myocardial infarction
(AMI),acute coronary syndrome (ACS),angina, • Thromboxane receptor antagonists
percutaneous coronary intervention (PCI), cardiac
surgery, primary and secondary cardiovascular • Terutroban
disease prevention, peripheral vascular disease, and
thrombotic disorders such as atrial fibrillation. Uses Of Antiplatelet Agents :

There are several anti platelet drugs available for use Prevention and treatment of arterial
in clinical practice and several under trial . thrombosis

Classification of antiplatelet drugs Prevention and treatment of arterial thrombosis is
essential in patients with certain medical conditions
• Irreversible cyclooxygenase inhibitors whereby the risk of thrombosis or thromboembolism
may result in disastrous consequences such as heart
• Aspirin, Triflusal attack, pulmonary embolism or stroke. Patients who
require the use of antiplatelet drugs are: stroke with or
• Adenosine diphosphate (ADP) receptor without atrial fibrillation, any heart surgery (especially
inhibitors prosthetic replacement heart valve), Coronary Heart
Disease such as stable angina, unstable angina and
• Clopidogrel , Prasugrel , Ticagrelor , Ticlopidine heart attack, patients with coronary stent, Peripheral
Vascular Disease/Peripheral Arterial Disease and
• Phosphodiesterase inhibitors apical/ventricular/mural thrombus.

• Cilostazol Treatment of established arterial thrombosis includes
the use of antiplatelet drugs and thrombolytic therapy.
• Protease-activated receptor-1 (PAR-1) Antiplatelet drugs alter the platelet activation at the
antagonists site of vascular damage crucial to the development
of arterial thrombosis.
• Vorapaxar
Asprin:
• Glycoprotein IIB/IIIA inhibitors (intravenous use
only) Irreversibly inhibits the enzyme COX, resulting in
reduced platelet production of TXA2 (thromboxane -
• Abciximab , Eptifibatide, Tirofiban powerful vasoconstrictor that lowers cyclic AMP and
initiates the platelet release reaction).

GCDC 2017

When to Use ? When Not to Use ? -Antiplatelets. 465

Disorders for Which Aspirin Has Been Shown tablets):
to Be Effective and the Lowest Effective
Daily Dose(mgm) Respiratory alkalosis combined with a severe
metabolic acidosis
Hypertension 75
Seizures, coma, pulmonary edema & cardiovascular
Chronic stable angina 75 collapse can occur.

Polycythemia vera 100 Clopidogrel:

Unstable angina 75 Clopidogrel is a prodrug that must be metabolized by
CYP 2C19 to be effective
Acute myocardial infarction 160
Its active metabolite irreversibly blocks the ADP
Transient ischemic attack and ischemic stroke 50 receptor on platelets, thereby reducing platalet
aggregation
Severe carotid artery stenosis 75
It has no effect on prostaglandin metabolism (unlike
Acute ischemic stroke 160 aspirin)

Atrial fibrillation 325 75 mgm OD

Men at high cardiovascular risk 75 Indications:

Immediate postcardiac surgery graft preservation Recent MI, acute coronary syndrome, stroke or
?325 established peripheral artery disease, after coronary
stenting (to reduce the risk of restenosis)
Contraindications:
Secondary prevention after an MI for those who are
Hypersensitivity to NSAIDs or history of bleeding allergic to aspirin
disorders, such as GI bleeding or hemophilia
Contraindications:
Not recommended during pregnancy, but may be
valuable in treating preeclampsia-eclampsia. Patients with intracranial hemorrhage, peptic ulcers
or other active bleeding disorders
Children and teenagers should not use this medicine
for chicken pox or flu symptoms before a doctor is Use with caution in patients with recent trauma or
consulted about Reye’s syndrome, a rare but serious surgery due to risk of bleeding. Caution is needed
illness reported to be associated with aspirin. in patients with liver impairment.

Aspirin may trigger asthmatic symptoms in some Abciximab:
patients .
A humanized monoclonal antibody directed against
Other expected side effects are dose-dependent the IIb/IIIa complex

With therapeutic doses: It binds to the receptor complex on platelets and
thereby prevents platelet aggregation
gastric upset, gastric and duodenal ulcers are the
most common side effects The IIb/IIIa complex functions as a receptor for
fibrinogen and other proteins involved in the final
With higher doses: common pathway for platelet aggregation. Blocking
this receptor therefore inhibits platelet aggregation..
“salicylism” can occur - vomiting, tinnitus, decreased There are roughly 50,000 copies of this complex on
hearing, vertigo (reversible) the surface of each platelet.

With very large doses: Indications:

Hyperpnea (increased depth & rate of respiration) Adjunct antiplatelet therapy for percutaneous
through a direct effect on the medulla resulting in coronary intervention (PCI) (e.g. angioplasty, placement
arespiratory alkalosis of coronary stints) & in acute coronary syndromes

Body temperature may be elevated due to uncoupling Commonly used concomittantly with aspirin & heparin
of oxidative phosphorylation, potentially resulting
insevere hyperthermia (Olson, 2009).

At progressively higher and potentially fatal doses
(300 to 500 mg/kg)(or 20-35 full strength 325 mg

Cardio Diabetes Medicine

vv Cardio Diabetes Medicine 2017

466

Ticlopidine • Increased platelet activation/aggregation in
diabetic patient contributes to their increased
• Thioenopyridine platelet inhibitor rate of ischemic events. Clear role for aspirin in
secondary prevention, ? “primary” prevention.
• Prodrug. Requires activation by cytochrome Dual antiplatelet therapy indicated for at least
P450 in liver 1 year after ACS or PCI. More potent P2Y12
receptor antagonists likely of greater benefit
• Irreversibly modifies platelet ADP receptor in diabetics, if bleeding risk not too high.
and thus blocks pro-aggregatory effects of ADP
. Dual antiplatelet therapy with aspirin and
Clinical uses clopidogrel has been the mainstay of
secondary prevention of atherothrombotic
Unclear. Appears to be more effective than aspirin in events in patients with ACS or those
preventing stroke in patients who have already had undergoing PCI. However, despite the benefit
a stroke or a TIA. However aspirin remain treatment of this combination, atherothrombotic events
of choice because of ticlopidine’s bone marrow continue to occur.
suppressant effects.
Conclusion:
Ticlopidine plus aspirin is more effective than aspirin
alone or aspirin plus anticoagulants in preventing In practice, a favourable balance between the
thromboembolic complications related to coronary beneficial and harmful effects of antiplatelet therapy
stenting, but it is not licensed for this use. is achieved by treating patients whose thrombotic risk
clearly outweighs their risk of bleeding complications.
Adverse effects
References
• Neutropaenia in 2.4%, severe in 0.8%
1. Jennings LK. Role of platelets in atherothrombosis. Am J
• TTP in 0.02% Cardiol 2009;103:4A–10A

• Nausea, diarrhoea. 2. Bhatt DL. Role of antiplatelet therapy across the spectrum of
patients with coronary artery disease. Am J Cardiol 2009;103:11A–9A
• Rashes
3. Hirsh J, Guyatt G, Albers GW, Harrington R, Schunemann HJ.
• Abnormal liver function tests rarely. Executive summary: American College of Chest Physicians Evidence-Based
Cholestatic jaundice has been reported Clinical Practice Guidelines (8th Edition). Chest 2008;133:71S–109S

• Rashes and diarrhoea are more common than 4. Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P. Antithrombotic
with aspirin but other GI effects, including and thrombolytic therapy for ischemic stroke: American College of Chest
peptic ulceration are less common. Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest
2008;133:630S–9S
Contraindications
5. Hankey GJ, Sudlow CL, Dunbabin DW. Thienopyridine derivatives
• history of leucopaenia, thrombocytopaenia (ticlopidine, clopidogrel) versus aspirin for preventing stroke and other
or agranulocytosis serious vascular events in high vascular risk patients. Cochrane Database
• blood diseases that prolong bleeding time Syst Rev 2000;2:CD001246

• lesions likely to bleed (eg active peptic ulcer,
acute haemorrhagic stroke)

• caution in patients with impaired liver function.
Should be discontinued if hepatitis or jaundice
develops. There is little experience of its use in
patients with renal impairment.

Dual Antiplatelet Therapy:

• Often a combination of aspirin plus an ADP/
P2Y inhibitor (such as clopidogrel, prasugrel,
ticagrelor, or another) is used in order to obtain
greater effectiveness than with either agent
alone.

GCDC 2017

Cardio Diabetes Medicine 2017 467

Nutrient Manipulation for Obesity
Metabolic Syndrome and Diabetes

Dr.Sethuramashankaran A, PGDD

Physician and Diabetologist, Chennai

Abstract: genetic and environmental factors contribute to the
development of obesity, metabolic syndrome and di-
Nutrition is essential to maintain optimal health. abetes Their alarming rise in prevalence necessitates
When nutrition becomes inappropriate it causes over the need to study the modifiable factors and novel
weight and obesity leading to metabolic syndrome, treatment options(11). At an individual level causes
diabetes and associated metabolic conditions like of obesity are physical inactivity, and increased in-
hypertension, dyslipidemia, etc. This article enumer- takes of foods high in saturated fats and sugars. At
ates the various factors that causes obesity, meta- a societal level, non-supportive policies in the health,
bolic syndrome and diabetes with focus on energy agriculture, transport, urban planning, environment,
imbalance and weight gain. The alarming increase food processing, distribution, marketing, and educa-
in prevalence with 13% of the adult population being tion sectors can all have influence. Obesity has been
obese and 39% over weight. Their association with shown to increase the risks of chronic disease, such
more deaths worldwide than underweight necessi- as metabolic syndrome, type 2 diabetes, cardiovas-
tates the need to address the obesogenic environ- cular disease, hypertension, stroke and certain types
ment that causes it. Diet rich in carbohydrates, re- of cancer(1). To promote weight loss, changes in life
fined sugars and fats along with sedentary life style style affecting the dietary habits and physical activi-
contribute to the obesogenic environment. Dietary ties are to be implemented.
strategies that help in weight loss and weight man-
agement were reviewed. Certain type of diets were Facts:
found to be superior when compared to others as
they showed beneficial effects on Obesity is one of the most common, but most ne-
glected public health problem in the developed and
cardiovascular and diabetes risk profiles. developing countries. In 2014,an estimated 1.9 billion
adults aged 18 years and older were overweight, with
Key words: one third of these classified as obese. The worldwide
prevalence of obesity more than doubled between
Obesity, metabolic syndrome, type 2 diabetes, carbo- 1980 and 2014. An estimated 41 million children under
hydrates, proteins, fats, dietary strategy, weight loss, the age of 5 years were overweight or obese. Near-
weight maintenance, ad libitum. ly half of the children under 5 who were overweight
or obese in 2014 lived in Asia. Overweight and obe-
Introduction: sity are linked to more deaths worldwide than un-
derweight. Globally there are more people who are
Body weight is an intricate balance between calories obese than underweight except sub-Saharan Africa
consumed (energy intake) and calories burned (ener- and parts of Asia. United Nations General Assembly
gy expenditure). Body weight is gained when energy on Prevention and Control of Non Communicable
intake (nutrition) exceeds energy expenditure over an Diseases of 2011 recognizes the importance of reduc-
extended period of time leading to overweight and ing unhealthy diet and physical inactivity(1). Increase
obesity. The exact cause whether it is the increased in obesity, abdominal obesity, metabolic syndrome
energy intake (nutrition) or the reduced energy ex- in Asian Indians leads to diabetes and atherogen-
penditure is not clearly known; it is a combination of
both in varying proportions in each individual. Both

Cardio Diabetes Medicine

468 Nutrient Manipulation for Obesity
Metabolic Syndrome and Diabetes

ic dyslipidemia at lower body mass index and waist 500-1000 gram/week. To sustain weight loss energy
circumference(2,3). deficit should be maintained(12). Dietary fat restric-
tion and carbohydrate (CHO) restriction have been
Nutrition & Causes: tried and studied in different populations across the
world. The conventional weight reduction diet had
Obese people have higher energy requirements when 15% proteins, <30% fats and 50-55% carbohydrates;
compared to normal weight individuals for a given with lesser fat and increased fiber. This was effective
physical activity(12). Reducing energy intake in obese in short term weight loss due to low satiety and poor
individuals will eventually cause weight loss. Symonds adherence over long period of time. Low CHO diet
et al review have suggested that nutritional fluctua- were useful in short term weight loss and their long
tions in pregnancy may act via changes in maternal term benefit not established well(7).
body composition and hormonal insulin sensitivity
to determine feto-placental adaptations and these The satiating ability of the various dietary compo-
determine the offspring’s relative risk for developing nents are used to cause a spontaneous reduction
obesity and metabolic syndrome(4). The current obe- in energy intake; this is the principle of ad libitum
sity epidemic is due to the obesogenic environment diet(12). Different nutritional treatments with varying
- calorie dense foods and a very sedentary life style. nutritional composition have been used like incorpo-
But not all become obese and the variability is due rating fiber or flavonoids, manipulating the glycemic
to the inheritance of the obesity susceptibility genes index, Omega 3 Fatty Acids and of minerals like
and its interaction with the obesogenic environment calcim and selenium(7). Low GI diets have shown
leading to positive energy balance and weight gain. to cause rapid weight loss, better management of
Sedentary behaviour and reduced physical activity glucose, insulin levels and decrease in triglycerides
together promotes over consumption of fats and re- and blood pressure. Recent evidence suggests that
fined carbohydrates (dietary macronutrients). Dietary diet moderately high in protein and modestly restrict-
pattern, food frequency, breakfast consumption all ed in carbohydrates and fat show benefits on body
have an impact on body weight. Role of gut microbi- homeostasis and metabolic parameters. Diet rich in
ota, energy homeostasis and inflammation also con- omega 3 fatty acids(FA) positively affects weight loss
tribute to obesity and related disorders(5). and weight maintenance by affecting satiety regula-
tion. Diet with moderately high proteins (30-35%), low
Weight Loss Advantages: GI carbohydrates (40%) and specific omega 3 fatty
acids (30%) creates satiety and contributes to weight
Weight loss has significant role in treating obesi- loss and weight control(7).
ty, metabolic syndrome, dyslipidemia, hyperten-
sion, insulin resistance and hyperglycemia. Modest Options for weight loss diets:
weight loss can reduce the prevalence of obesity
and metabolic syndrome. 5-10% weight loss reduc- Several regimens of therapeutic weight loss diet ex-
es triglycerides and increases HDL-C and for every ists. Low-energy diets (LED) provides 800-1500 Kcal/
kilogram of weight loss the risk of diabetes mellitus day uses food with reduced fat and carbohydrate.
development reduces by 16%. Studies have shown Very-low-energy diets (VLED) are modified fasts pro-
that low calorie diet along with physical activity is the viding 200-800 Kcal/day and replace normal food.
most effective strategy to improve insulin resistance Ad libitum low fat diets restricts fat intake by 20-
and obesity(6). 30% of total energy intake, increased protein intake
because of the satiating power and modest carbo-
Nutritional Modifications in Obesity, hydrate intake leading to a modest weight loss(12).
Metabolic Syndrome & Diabetes Mellitus:
Very-low-energy diets (VLED):
Different strategies were used in nutritional therapy.
Reducing the energy intake of a obese individual to Earlier starvation was the ultimate treatment for obe-
that of a normal weight individual inevitably causes sity, but it is no longer used due to the associated
weight loss, about 75% fat and 25% lean tissue(12). complications. This has been replaced by VLED (200-
Diet composition doesn’t affect energy absorption 800 Kcal/day) which provides very less energy but all
and energy expenditure but it reduces hunger, cre- essential nutrients, This diet should have increased
ates satiety and reduces energy intake. Larger the nutrient density and it is difficult to get this from nat-
energy deficit the more rapid the weight loss. A defi- ural foods leading to commercial production of VLED
cit of 300-500 Kcal/day reduces 300-500 gram/ supplemented with all nutrients in RDA quantities.
week and a deficit of 500-1000 Kcal/day reduces VLED providing 800Kcal/day is safe and effective.

GCDC 2017

Cardio Diabetes Medicine 2017 469

Studies showed VLED providing lesser calories did eg; Atkin’s, Dunkan, The Zone, South Beach, I-diet,
not provide greater weight loss and were less accept- Paleolithic diet, etc. Energy restriction is not there and
ed. VLED contains proteins, minerals, trace elements, they work by suppression of hunger and enhanced
and are vitamin enriched. they cause rapid weight satiety(12). Higher protein content with restricted car-
loss in 2-3 months should be used for weight loss bohydrates; no simple sugars, low GI carbohydrates,
induction and should be followed by weight main- high fiber and/or whole grain content. common
tenance program(8). Similar attrition for VLED and definition for low carbohydrate diet is ≤ 45% carbohy-
Low-energy diets (LED). Increased risk of gall stones drates, low fat diets have ≤ 30% fats and high protein
and concern about cardiac safety is there(12) diet have > 20% protein (but it can vary from 20-50%)
(12).
Low-energy diets (LED):
Many RCTs have been done comparing HPCLDs
It provides 800-1500 Kcal/day and usually made with low fat diets and it has been found that HP-
of natural foods - low fat, protein rich. Earlier diets CLDs score in weight loss, body composition, resting
had restricted total energy level but no importance metabolic rate and cardiovascular risk factors than
for macronutrient composition; they were known as low fat diets . Meta analysis of 23 RCTs by Santos
Conventional diets/Calorie-counting diets. For short et al involving 1141 obese non diabetics showed that
term weight reduction macronutrient composition is HPCLDs produced greater weight loss 7 kg over 6-12
not important but it has positive effects on cardiovas- months and difference maintained for 2 years. great-
cular risk factors, Insulin resistance, prevent cancers er reduction in waist circumference, systolic BP, dia-
and also supports long term weight maintenance. stolic BP, plasma triglycerides, fasting blood glucose,
LED for women is 800-1200 Kcal/day and for men glycated hemoglobin, plasma insulin, plasma hs-CRP
it is 1000-1500 Kcal/day. LED should be supplement- and in HDL cholesterol. No change in LDL-cholester-
ed with daily vitamins and minerals. Weight loss rate ol and serum creatinine(9).
is lower than VLED but t randomized control trials
(RCTs) show that the long term (>1year) weight loss In a meta-regression analysis of RCTs of 87 studies
is no different from VLED(9). 34 RCTs confirmed that with 165 groups done by Kreiger et al. to determine
LED causes weight loss regardless of the duration of the effects of changes in dietary protein and carbo-
treatment(12). hydrate contents during energy restriction conclud-
ed that HPCLDS positively influence body mass and
Ad libitum lower fat diets: composition independent of energy intake(10).

In the past dietary strategies were energy restricted Safety:
but the current strategy is to be ad libitum. Ad libitum
diet has a variety of macronutrients options which In healthier high fat diets, replacement of saturated
decreases the feeling of being restricted to a diet and transfats with unsaturated oils instead of carbo-
and so adherence and weight loss are improved(8). hydrates have shown positive benefits on cardiovas-
Studies have shown that high dietary fat leads to cular and diabetes profile; but there is risk of weight
development of obesity. Passive over consumption gain due to higher energy density food. DASH diet
of high energy dense fatty foods and a decreased with reduced fat or non fat dairy, fruits and vegeta-
fat oxidation capacity is the mechanism involved. bles, whole grains and lean meat has shown reduc-
Usually obese individuals consume high fat diet (35- tion in blood pressure (BP) and cardiovascular risk
50% of energy) so a lower fat diet (25-30% of energy) factors(12).
helps them along with increased protein, low-glyce-
mic index (GI) carbohydrates, high fiber foods and High protein intake can lead to decreased intake of
whole grain; this ensures lowest cardiovascular risk fiber, vitamins and minerals (i.e. potassium, calcium,
profiles(12). Ad libitum programs have demonstrat- magnesium) which can have negative influence on
ed weight loss and weight maintenance(8). A meta cardiovascular, bone and kidney functions(9). Stud-
-analysis of 34 ad libitum diet, lasting > 2 months ies have shown that there is positive influence on
and 35 groups found statistically significant weight inflammation, risk factors for T2DM, bone health
loss difference of 3.3kg(12). and renal function(12). Again high protein diet have
not been found to be detrimental for kidneys as all
Low-carbohydrate, high protein diets risk factors like diabetes, hypertension and obesity
(HPLCDs): for impaired kidney function improve. Bone health is
maintained as they get the required protein, calcium
These are diets that are similar to ad libitum diets, and vitamin D(12).

Cardio Diabetes Medicine

470 Nutrient Manipulation for Obesity
Metabolic Syndrome and Diabetes

Conclusion: Index and Waist Circumferece cutpoints in multi ethnic populations from
the UK and India: the ADDITION-Leicester, Jaipur heartwatch and New
Nutritional research on specific foods in the pre- Delhi cross sectional studies. PLoS One 2014: 9: e90813.
vention and treatment of obesity is ongoing. Food
composition has changed with variations in macro- 4. Symonds, M.E. et al. Nat. Rev. Endocrinol. 5, 604-610 (2009); published
nutrients, fiber content, bioactive food ingredients on line September 2009; doi:10.1038/nrendo.2009.195.
with the change in dietary strategy to decrease the
fat mass; there is intense debate on dietary regime 5. Koletzko B, Shamir R, Turck D, Philips M(eds): Nutrition and Growth Year
which provides weight loss and long term weight book 2014. World Rev Nutr Diet. Basel, Karger, 2014 Vol 109, pp 1-22
maintenance. Crux of obesity treatment is to control (DOI:10.1159/000356352)
the food intake due to its direct association with en-
ergy balance. Adherence to weight loss program is 6. Ebrahimof. S, Mirmiran. P, Nutritional Approches for Prevention and Treat-
influenced by appetite regulation, feeling of hunger ment of Metabolic Syndrome in Adults. JPS. Spring 2013. Vol. 4, No. 2,
and satiety. Weight loss and beneficial health ef- ISSN 2008-4978.
fects were always consistently produced by energy
restricted diets. In spite of the health benefits like 7. Abete I et al. Obesity and the Metabolic Syndrome: Role of different
weight loss, greater reduction in waist circumference, dietary macronutient distribution patterns and specific nutritional com-
systolic BP, diastolic BP, plasma triglycerides, fasting ponenets on weight loss and maintenance. Nut Rev April 2010. Vol.
blood glucose, glycated hemoglobin, plasma insulin, 68(4);214-231(DOI:10.1111/J.1753-4887.2010,00280.x)
plasma hs-CRP and in HDL cholesterol(9); many in-
dividuals were unable to sustain on energy restricted 8. Casazza K, Fontaine KR, Astrup A, et al. Myths presumptions and facts
diets due to increased hunger and energy expendi- about obesity. New England Journal of Medicine 2013; 368(5):446-454.
ture adaptations. HPLCDs is superior to low fat diet
in decreasing weight and improving metabolic risk 9. Santos FL, Esteves SS, da Costa Pereira A, et al, Systematics review and
factors(12).Dietary monotony and lack of variability meta-analysis of clinical trials of the effects of low carbohydrate diets on
makes compliance difficult(7). The greatest challenge cardiovascular risk factors. Obesity Reviews 2012;13:1048-1066.
is to incorporate the appropriate diet into a food cul-
ture to achieve long term adherence. 10. Krieger JW, Sitren HS, Daniels MJ, Langham -Henken B: Effects of vari-
ations in protein and carbohydrate intake on body mass and composition
Key Messages: during energy restriction: a meta-regression. American Journal of Clinical
Nutrition 2006;83:260-274.
Body weight is an intricate balance between calories
consumed and calories burned. Books:

Overweight and obesity are linked to more deaths `Tan CS, Ravussin E, The role of energy metabolism in
worldwide than underweight.  the regulation of energy balance, Defronzo RA, Fer-
rannini E, ZImmet P, Alberti K, International Textbook
Excess food intake with sedentary life style is one of Diabetes Mellitus, Haryana, Wiley India Pvt Ltd ,
of the reason for obesity, metabolic syndrome and Vol. I/Fourth Edition 2015: 479.
diabetes.
Tan CS, Ravussin E, Treatment of obesity: life style
Diet is the crux in obesity management and compli- and pharmacotherapy, Defronzo RA, Ferrannini E,
ance is a challenge. ZImmet P, Alberti K, International Textbook of Dia-
betes Mellitus, Haryana, Wiley India Pvt Ltd , Vol. I/
High protein, low carbohydrate diets are the most Fourth Edition 2015: 489-494.
efficient and produces beneficial effects on all the
cardiometabolic risk factors.

In type diabetics, weight loss can be induced by diet
and exercise this usually leads to optimal glycemic
control with reduced dose and use of antidiabetics

References:

1. http://www.who.int/mediacentre/factsheets/fs311/en/ 4th August 2017

2. Gupta R, Agarwal A, Misra A, Gupta S, VIkram NK. Metabolic Cardiovas-
cular Risk Factors Worsen Continuously Across the Spectrum of Body Mass
Index in Asian Indians. Indian Heart J 2012:66: 236-244.

3. Bodicat DH, Gray LJ, Henson J, Webb D, Guru A, Misra A et al.Body Mass

GCDC 2017

Cardio Diabetes Medicine 2017 471

Cardio Vascular Safety of Antidiabetic
Drugs Do We Know Enough?

Dr.S.Saravanan, MD (Gen.MED)

Senior Assistant Professor / Registrar, Department of General Medicine
Govt. Thoothukudi Medical College, Thoothukudi.

Abstract : 5. SGLT -2 : Sodium Glucose co-transporter – 2

Type 2 Diabetes Mellitus (Type 2 DM) , cardiovascular 6. CVD : Cardiovascular death
disease (CVD) and the cardiovascular effect of
anti diabetic drugs are today critical medical 7. CVOT : Cardiovascular outcome trials
issues. Better control of Diabetes Mellitus reduces
Microvascular complications, but has limited effect Introduction:
on macrovascular complications including cardio
vascular mortality.Given the cardiovascular adverse Cardio vascular disease is the leading cause of
events associated with rosiglitazone, both the Food Morbidity and Mortality among patients with diabetes,
and Drug Admistration and the European Medicines underscoring the importance of choosing anti diabetic
Agency currently require the demonstrations of drugs that do not increase cardiovascular risk but
cardiovascular safety of new antidiabetic drugs. might reduce the risk of cardiovascular events.
Consequently, clinical trials to guarantee their
cardiovascular safety are now obligatory. This Prompted by the adverse effects of rosiglitazone
article aims to summarize the available evidence on in the RECORD study and subsequent meta
the cardiovascular effects and safety of the major analysis the US FDA since 2008 and European
drugs used in type 2 Diabetes Mellitus treatment medicines agency [EMA)since 2012 require besides
and also to provide an overview of clinical trials. Our beneficial hypoglycemic action, appropriate clinical
belief is review will be of substantial assistance to all cardiovascular outcome trials (CVOT) and safety
medical doctors who are treating Diabetic patients evidence of all anti diabetic drugs.
namely primary care physicians, internal medical
doctors, endocrinologists, diabetologists and less This article examines the current issues and evidence
well experienced personnel such as young doctors related to cardiovascular safety for each class of
in training. oral anti diabetic drugs understanding the potential
cardiovascular risk associated with these drugs will
Key words : Antidiabetic Drugs, Cardiovascular side help clinicians and patients with treatment decisions
effects and safety, Diabetes Mellitus, Treatment for TYPE 2DM.
outcome.
Generally, there is strong clinical trial evidence
Obbreviations: demonstrating that oral anti diabetic drugs reduce
hyperglycemia to a similar degree and significantly
1. UKPDS : United Kingdom Prospective Diabetes decrease the risk of micro vascular complications.
Study However the strategy used to reduce blood glucose
may affect a patient’s cardiovascular risk. For
2. ACCORD :Action to control cardiovascular risk example in the ACCORD study. (Action to control
in diabetes cardiovascular risk in Diabetes) patients with a
median 10 yrs history of type 2 Diabetes and mean
3. MACE : Major adverse cardiovascular events HBA1c of 8.3 were treated to rapidly achieve glycemic
targets of 60% (intervention group) or maintain their
4. DPP - 4 : Dipeptidyl Peptidase 4 current glycemic control. Although the ACCORD study

Cardio Diabetes Medicine

vv Cardio Vascular Safety of Antidiabetic
Drugs Do We Know Enough?
472

did not find a difference in the primary outcome of Thiazolidinediones:
cardiovascular death, non fatal myocardial infarction,
and non fatal stroke, there was a significantly higher Early clinical trials requested possible reductions in
rate of all - cause mortality in the intervention group cardiovascular events . In 2007, however evidence
compared with controls. Other studies examining emerged linking rosiglitazone to an increased risk of
intensive glycemic control strategies did not find a myocardial infarction and death. This observation was
significant effect on cardiovascular risk. However, soon replicated by others and extended to include an
extended follow- up of these trials suggest, that association with heart failure risk.
intensive treatment may have a legacy effect which is
associated with a lower risk of major cardiovascular As these retrospective analyses were hypothesis
events. generating, a cardiovascular outcome trial was
conducted to compare addition of rosiglitazone
Metformin with metformin or sulfonylurea monotherapy with
combination of metformin and sulfonylurea. This
Two clinical trials have randomly allocated patients to study demonstrated that the risk of cardiovascular
Metformin or a comparator and evaluated the risk of death or hospitalization for myocardial infarction
cardiovascular outcomes. In both studies, patients or stroke was similar between treatment groups.
allocated to Metformin use experienced significantly However hospitalization or death attributable to heart
lower rates of cardiovascular events. Metformin has failure was significantly higher in patients allocated
also been shown significantly reduce lipid levels. to rosiglitazone use.3

More recenlty, interest in Metformin has Although Pioglitazone doesn’t appear to have the
shifted to on examination of its safety in patients same level of cardiovascular risk as rosiglitazone,
with heart failure. Renal dysfunction and heart there appear to be a higher risk of fractures and
failure have been longstanding contraindications cancer.
for metformin use because of the perceived risk
of lactic acidosis moreover observational studies Alpha-Glucosidase Inhibitors
have demonstrated that metformin use in patients
with heart failure in associated with a lower risk of Initial reviews of the placebo controlled studies
cardiovascular morbidity and mortality. None of the suggested that acarbose use was associated with
patients allocated to metformin use in the UKPDS a significantly lower risk of myocardial infarction
study developed Lactic acidosis. These observations and other cardiovascular events. This reduction
may be influencing requests to regulatory agencies in cardiovascular risk was thought to be linked
to revisit previous restrictions on metformin use in to reduction in blood pressure, post prandial
patients with heart failure & reduced renal function.1 hyperglycemia and lipid levels as well as a neutral
effect on weight. However, as more comprehensive
Sulfonyl Ureas: reviews of the literature was unable to find a
difference in cardiovascular risk associated with any
Interestingly, sulfonylureas are frequently used even alpha-glucosidase inhibitors, including acarbose.
though question of cardiovascular safety were raised
over 40 yrs ago concern began when the university Dpp4 - Inhibitors : Evidence From Studies :
group Diabetes program (UGDP) investigators
reported a significantly higher rate of cardiovascular SAVOR-TIMI study showed that the use of saxagliptin
deaths in patients using tolbutamide compared with did not alter the rate of ischemic events. However the
placebo. rate of hospitalization for heart failure was increased.
4
When information from both direct and indirect
comparisons among sulfonylureas is combined, The TECOS trial showed that adding sitagliptin to
gliclazide appears to have the lowest risk of therapy did not
cardiovascular morbidity and mortality, followed by
glymepride, glipizide, and glyburide.2 Based on these increase the risk of MACE hospitalization for heart
observation, it is important to consider sulfonylureas failure or other adverse events. 5
as individual agents when examining the adverse
cardiovascular effects of these drugs. Linagliptin is not associated with increased
cardiovascular risk. In April 2016 the FDA warned
that the DPP-4 inhibitor saxagliptin, alogliptin may
increase the risk of heart failure, especially in patients
with pre existing heart failure or renal impairment.

GCDC 2017

Cardio Diabetes Medicine 2017 473

GLP-1RA: Conclusion :

At present, only the Evaluation of Lixisenatide Due to a high prevalence of cardiovascular
in Acute coronary syndrome [ELIXA] study is complete. morbidity and mortality in T2DM, the optimal
The cardiovascular safety is non inferior although approach to the reduction of cardiovascular risk
not superior to placebo. Placebo controlled trials, should focus on aggressive management of the
have demonstrated that patients treated with GLP-1 standard cardiovascular risk factors rather than
RA have a lower incidence of MACE, cardiovasculor purely on intensive glycemic control. As can be seen
mortality and all cause morality.6 from the various trials reviewed here, favourable
glycemic efficacy does not necessarily translate to
Several ongoing randomized large scale trials will be favourable cardiovascular outcomes. Clinicians must
important to consolidate the results obtained so far. therefore make careful informed decisions based
on the cardiovascular effects of the various anti-
SGLT -2I : diabetic drugs when prescribing . Based on current
evidence, metformin should remain the first-line
The recently published EMPA-REG outcome study drug of choice in T2DM, being the most extensively
presented exciting cardiovascular results, with studied and demonstrating excellent cardiovascular
empagliflozin. Overall this drug displayed on 38% safety even with long term use. Although evidence
reduction in cardiovascular death and a 32% reduction for the cardiovascular safety of sulfonylureas are
in all cause Morality.7 inconsistent, the first-generation agents are probably
associated with net harm and should be avoided.
DECLARE TIMI 58 study the effect of Dapagliflozin Newer generation sulfonylureas have a comparatively
on cardiovascular outcome expected to be finished more favourable cardiovascular profile, but weight
in 2019.(CANVAS) The Canagliflozin cardiovascular gain remains a concern. The meglitinides and AGIs
assessment study expected to complete data lack cardiovascular safety data in T2DM and should
collection in 2017. therefore be reserved in favour of other second-
line agents. Among the TZDs, rosiglitazone may
Study on Ertugliflozion to assess cardiovascular be associated with an increased risk of MI, while
safety is expected to be completed in 2021. pioglitazone may have beneficial cardiovascular
effects. Both are however contraindicated in heart
Insulin : Evidence From Studies: failure. The incretin-based drugs have been at the
forefront of this era of cardiovascular safety trials
Several studies have reported an increase in and have been extensively studied. Current evidence
cardiovascular risk and higher mortality, whereas suggests that the gliptins have neutral overall
others have demonstrated a reduction in cardiovascular effect, but may increase risk of heart
cardiovascular events, apart of their raise in the failure, particularly saxagliptin. Among the GLP-1
incidence of hypoglycaemia. An observational study agonists, liraglutide may have beneficial effects on
of patients on insulin plus metformin reported a higher cardiovascular outcomes, but this requires further
risk of composite effect of non fatal cardiovascular validation. Similarly, the SGLT-2 inhibitors have
and all cause mortality among insulin therapy users shown promising results with empagliflozin and may
compared to those administered sulfonylureas as potentially confer cardiovascular benefits, although
an add on therapy. A recently published ACCORD additional data is needed to substantiate this.
trial suggests that insulin dose did not play a role With results of several large ongoing randomized
in the greater cardiovascular mortality in patients trials expected in the coming years, the body of
randomized to intensive glycemic control.8 In the SU/ evidence will continue to expand and help guide
insulin arm of the UKPDS, There was no association clinicians in making the best decision in reducing the
between the use of insulin and CVD incidents, even cardiovascular risk of their diabetic patients.
after 10 yrs of follow up. The ORIGIN trial and the
legacy effects (ORIGINALE) study continued that High Lights :
glargine had neutral effects on cardiovascular health.
HEART 2D trial found no differences in respect of 1.Overall, Metformin appears to have the best benefit
cardiovascular events between prandial vs basal to risk profile, which is consistant with its place
strategies.9 as First line therapy in clinical practice guideline
recommendations.
Insulin Degludec DEVOTE trial was designed to
test its safety and efficiency in subjects with T2DM 2.Agarbose doesn’t appear to increase the risk of
at high risk of cardiovascular events. Due to the
satisfactory preliminary results, this trial has recently
been approved by the FDA.

Cardio Diabetes Medicine

vv Cardio Vascular Safety of Antidiabetic
Drugs Do We Know Enough?
474

Cardiovascular events.

3.Sulfonylurea use is associated with an increased
risk of adverse cardiovascular events. However, this
risk varies among individual drugs with lowest risk
with gliclazide.

4.TZD especially Roziglitozone increase the risk of
Heart failure, Myocardial infarction and stroke.

5.Saxagliptin and Alogliptin may increase the risk of
heart failure especially in patient with pre-existing
heart failure or renal impairment.

6.Empagliflozin and Liraglutide reduced composite
outcomes for myocardial infarction, stroke and CVD
in populations in which most, if not all, patients had
established atherosclerotic cardiovascular disease.

References:

1. Pawlyk AC, Giacomini KM, Mckean C, Shuldiner AR, Florez JC. Metformin
pharmaco genomics: Current status and future directions diabetes 2014 :
63 : 2590- 2599.

2. Simpson SH, Lee J, Choi S, Vandermeer B, Abdalmonein AS, Featherstone
TR. Mortality risk among sulfonyl ureas: a systematic review and network
metananlysis . Lancet Diabetes Endocrinol 2015 : 3: 43-51.

3. Nissen SE, Wolski K, 2007. Effect of Rosiglitozone on the risk of Myo-
cardial infarction And Death from Cardiovascular causes. N Eng J Med
356 : 2457 – 2471.

4. Scirica BM, bhatt DC, Braunwald E, et al, 2013 Saxagliptin and cardio-
vascular outcomes in patients with type 2 Diabetes Mellitus. N Eng J
Med 369: 1317 -1326.

5. Green JB Bethel MA, Armstrong Pw, et al, 2015 Effects of Sitagliptin on
cardiovascular outcomes in Type 2 Diabetes. N Eng J Med 373: 232- 42.

6. Monami M, Dicembrini I , Nardini C, Fiordelli I, Manucci E, 2014 Effects
of GLP -1 RA on cardiovascular risk : a metaanalysis of randomised clinical
trials. Diabetes obes metab 16 : 38 -47.

7. Zinman B, Wanner C, Lachin JM, et al, 2015 Empagliflozin, cardiovascular
outcomes and mortality in type 2 Diabetes. N Eng J Med 373 : 2117
– 2128.

8. Siraj ES, Rubin DJ, Riddle MC, Miller ME ,et al, 2015 insulin dose and
cardiovascular mortality in the ACCORD trial. Diabetes care 38: 2000-
2008

9. Raz I, Wilson PW, Strojek K, et al. 2009 Effects of Prandial vs Fasting
Glycemia on cardio vascular outcomes in Type 2 Diabetes : the HEART
2D trial. Diabetes care 32: 381-386.vw

GCDC 2017

Cardio Diabetes Medicine 2017 475

NAFLD and CVD - Importance and Therapies

Dr. R. Ramasubramanian. DNB, DM (Gastro)

Professor of Medical Gastroenterology,
Government Thoothukudi Medical College, Thoothukudi.

Introduction: achieved in 6-8 months.

Non-alcoholic fatty liver disease (NAFLD) is often b.Treatment of Dyslipidemia:
associated with insulin resistance and is strongly
associated with type 2 diabetes mellitus and Guidelines set forth by the NCEP Adult Treatment
obesity. In addition to being at risk for nonalcoholic Panel III provide guidance on which groups should
steatohepatitis, cirrhosis and its complications, be targeted for lipid-lowering therapy and outlines
NAFLD patients are also at higher risk of treatment goals. Most attractive group of lipid-
cardiovascular diseases (CVD), including coronary lowering agents for cardiovascular protection are
heart disease and stroke. NAFLD confers increased the statins. In addition to a major effect in lowering
cardiovascular disease risk independent of traditional LDL, they have modest effects on increasing HDL
cardiovascular risk factors and metabolic syndrome. and lowering serum triglycerides, as well as non-
Close followup of patients with NAFLD may be cholesterol-lowering effects on vascular endothelium
indicated to prevent major vascular events. by inducing endothelial nitric oxide synthase.

Mechanism: Statin hepatotoxicity has not been shown to be of
increased risk in NAFLD. Statins can be safely used
Several mechanisms have been postulated for in NAFLD and NASH, and routine liver enzyme
development of accelerated atherosclerosis monitoring need not be done. Statins can be safely
in patients with NAFLD, including genetic used in patients with decompensated liver disease.
predisposition, insulin resistance and atherogenic There is always concern for using high dose statins
dyslipidemia, oxidative stress, chronic inflammation, in patients with elevated liver enzymes; in such
reduced levels of the adiponectin and altered circumstances adding ezetimibe has a synergistic
production of pro and anticoagulant factors. effect with statins.

Management of cardiovascular disease risk Triglyceride elevations are also a risk factor
in NAFLD: for cardiovascular disease. Attempts to reduce
raised serum triglyceride levels center around
a. Lifestyle Modification: weight reduction, improving insulin resistance
(physical activity) and diabetic control, with use of
All patients with NAFLD, irrespective of their body polyunsaturated fatty acids (fish oil) as the first-line
weight, should be advised lifestyle modifications pharmacologic approach.
in the form of regular exercise. Those who are
overweight or obese are advised weight reduction. NAFLD and Diabetes Mellitus
An exercise regimen should aim to achieve a target
heart rate of 60%-70% of maximal heart rate through DM is associated with an increased risk of CVD.
exercises such as brisk walking, jogging, or other Because DM is highly prevalent among individuals with
aerobic exercises for at least 30 min, 5 d per week. NAFLD, comprehensive management is essential for
Initial weight reduction in patients who are overweight CVD risk reduction. Primary and secondary prevention
or obese should be 10% of the body weight to be of CVD events in individuals with DM should focus
on multifactorial risk reduction, including treatment

Cardio Diabetes Medicine

vv

476 NAFLD and CVD - Importance and Therapies

of hypertension and dyslipidemia. ll.Treatment of risk factors for cardiovascular
disease
Why treat NASH in patients with type 2
diabetes? Patients with NAFLD are at increased risk for
cardiovascular disease and often have multiple
Non-alcoholic fatty liver disease (NAFLD) is a cardiovascular disease risk factors.
frequent comorbidity in both paediatric and adult
populations, in particular in the setting of obesity Management of patients with NAFLD includes
and type 2 diabetes. Patients with type 2 diabetes optimization of blood glucose control in patients with
who also have NASH appear to be at a significantly diabetes and treatment of hyperlipidemia.
higher risk of death from cirrhosis, HCC and/or
cardiovascular disease. A. Pharmacologic therapies

Current treatment strategies: a.Vitamin E

I.General approach to the patient Vitamin E decreases oxidative stress, and initial
observational studies suggested improvement in
(i).Weight loss for patients who are overweight or aminotransferase levels in patients with NASH who
obese: received vitamin E. Not proved to be of benefit in
patients with NASH and Diabetes Mellitus.
Weight loss for all patients with NAFLD who are
overweight or obese and increased physical activity b.Insulin-sensitizing agents
can lead to sustained improvement in liver enzymes,
histology, serum insulin levels, and quality of life. The use of insulin-sensitizing agents in the treatment
of NAFLD is based upon the role insulin resistance
Options to promote weight loss include plays in the development of NAFLD.

1. Lifestyle modifications (i)Thiazolidinediones

2. For patients who are candidates, bariatric surgery. Thiazolidinediones, including pioglitazone and
rosiglitazone, are insulin-sensitizing agents that
Pharmacologic therapy can be used to aid with weight improve liver biochemical and histologic parameters in
loss in patients who fail to achieve weight loss goals patients with NASH. However, their use is associated
through diet and exercise alone. with adverse events, including weight gain, painful
swollen legs, and heart failure. Thiazolidinediones is
A reasonable goal for many patients is to lose 0.5 to 1 used for the treatment of NASH only in patients with
kg/week (1 to 2 lb/week). More rapid weight reduction type 2 diabetes.
may be associated with worsening of liver disease.
(ii)Metformin
Histologic improvement has also been observed after
bariatric surgery. Metformin lowers blood glucose by decreasing
hepatic gluconeogenesis, stimulating glucose uptake
(ii).Vaccinations by muscle, and increasing fatty acid oxidation in
adipose tissue. However, it does not appear to be
Hepatitis A and B vaccinations should be given to effective for the treatment of NASH.
patients without serologic evidence of immunity.
Additional vaccines recommended for patients (iii)Liraglutide
with chronic liver disease include pneumococcal
vaccination and standard immunizations It is a glucagon-like peptide-1 (GLP-1)-based
recommended for the population in general (eg, therapy that affects glucose control through
influenza, diphtheria, tetanus boosters). several mechanisms, including enhancement of
glucose-dependent insulin secretion, slowed gastric
(iii).Alcohol emptying, and reduction of postprandial glucagon
and of food intake. Liraglutide may be an option for
Patients with NAFLD should avoid all alcohol treating patients with NASH, but additional studies
consumption. Heavy alcohol use is associated with are needed.
disease progression among patients with NAFLD. It
is possible that light or moderate alcohol use may (iv)Dipeptidyl peptidase 4 inhibitors
have beneficial effects on the liver, and there are
potential cardiovascular benefits as well.

GCDC 2017

Cardio Diabetes Medicine 2017 477

Sitagliptin has been reported to be neutral [62] or to on blood markers of hepatic fibrosis and serum
decrease plasma aminotransferases, although their aminotransferase levels.
overall impact on liver histology is unknown.
(viii)Atorvastatin
(v)Sodium–glucose cotransporter 2 (SGLT2) inhibitors
Pilot studies found a benefit from atorvastatin on
A reduction in intrahepatic triacylglycerol aminotransferase levels in patients with NAFLD.
accumulation would be expected from a decrease
in substrate supply to the liver by the combined (ix)Pentoxifylline
effects of normoglycaemia plus modest weight loss
and enhanced insulin sensitivity. In animal models Pentoxifylline inhibits production of tumor necrosis
of NASH, sodium–glucose cotransporter 2 (SGLT2) factor-alpha, which has been hypothesized to
inhibitors like canagliflozin, have unique antifibrotic contribute to the progression of NASH. Pentoxifylline
properties. was associated with improvements in steatosis,
lobular inflammation, and liver fibrosis scores.
b.Other pharmacologic therapies
(x)Omega-3 fatty acids
(i)Orlistat
Studies have suggested a benefit of omega-3 fatty
Orlistat is a gastrointestinal lipase inhibitor used in acids in animals and humans with NAFLD or NASH.
the treatment of obesity and type 2 diabetes mellitus.
Orlistat is used when needed as an adjunct for weight c.Future treatments for patients with NASH
loss, but not as a primary treatment for NASH.
Therapeutic agent Proposed mode of action
(ii)Ursodeoxycholic acid
BMS986036 Improvement of hepatic lipid
Ursodeoxycholic acid (UDCA) may have antiapoptotic and glucose metabolism; anti-
and antiinflammatory effects in the liver. inflammatory

(iii)Obeticholic acid Cenicriviroc Inhibition of CCR2- and
CCR5-mediated monocyte/
Obeticholic acid is a synthetic variant of the bile acid macrophage infiltration and
chenodeoxycholic acid and is a potent activate of inflammation
the farnesoid X nuclear receptor. It promotes insulin
sensitivity and decreases hepatic gluconeogenesis Elafibranor Stimulation of NEFA
and circulating triglycerides. oxidation; improvement of
lipid and glucose metabolism;
(iv)Aramchol prevention of inflammation

Aramchol is a fatty acid (arachidic acid)-bile acid Emricasan Inhibition of fibrosis by blocking
(cholic acid) conjugate. It acts by inhibiting stearoyl- caspase protease activation
coenzyme A desaturase, an enzyme that modulates and apoptosis pathways
fatty acid metabolism in the liver.
GR-MD-02 Prevention of inflammation
(v)Probucol and fibrosis

Probucol is a lipid-lowering agent with antioxidant Px-104 Regulation of hepatic glucose
properties. Studies show a larger change in alanine and lipid metabolism
aminotransferase level than patients in the control
group. (vi)Betaine Simtuzumab Inhibition of fibrosis by a
LOXL2 monoclonal antibody
Betaine is a normal component of the metabolic cycle
of methionine and has a protective effect against Summary And Recommendations
steatosis in animal models. Showed favorable results
in a pilot study. 1.Weight loss is the only therapy with sufficient
evidence suggesting it is beneficial and safe. In
(vii)Losartan addition to its other health benefits, weight loss, either
through lifestyle modifications or bariatric surgery,
A pilot study of the angiotensin II receptor antagonist has been associated with histologic improvement in
losartan in patients with NASH suggested a benefit patients with NAFLD. A reasonable goal for many
patients is to lose 0.5 to 1 kg/week (1 to 2 lb/week).

2.Patients with NAFLD, require vaccinations for

Cardio Diabetes Medicine