Cardio Diabetes_2017 book

28 Cardio Diabetes Medicine 2017

ity. Importantly recent data suggest that other renal suggests that these cardo-renal protective effects
pathologies often coexist or drive CKD in patients could be related to a SGLT2 inhibitors’ class effect.
with T2DM.
The precise mechanism/s by which SGLT2 inhibitors
Further we should be aware that any treatment could exert their cardio-renal protective effects are current-
have a different efficacy when utilized in different ly unknown.
stages of chronic kidney disease; many of the tri-
als conducted today have been considering patients Different theories/possibilities have been postulat-
solely in the advanced stages of kidney disease often ed and research is ongoing to better define the car-
with macro-proteinuria. This approach could result in dio-renal protective effects of SGLT2 inhibitors.
us missing potential drug-related beneficial effects in
earlier stages of CKD (e.g. microalbuminuria); these In line with the rapid (6-12 months) observed car-
studies are clearly longer, more expensive, and pos- dio-renal vascular protective effects of SGLT2 inhibi-
sibly not affordable today. tors, two major theories have been postulated:

Future better phenotypic patients’ characterization 1. Intrarenal theory: this theory postulates that the
with novel biomarker, possibly derived from proteom- SGLT2-mediated renoprotective effect is second-
ics and metabolomics analysis, might help our un- ary to activation of tubuloglomerular feedback with
derstanding of novel treatments studied at different secondary reduction in glomerular capillary pres-
stages of kidney disease. sure, and a parallel inhibition of enhanced tubuli
sodium-coupled glucose transport that would re-
Recent novel advances in the mechanisms involved sult in reduction of tubulointerstitial injury. Further
in diabetic kidney disease have recently opened the use of SGLT2 inhibitors in combination with
some hopes in the fight for the treatment of diabetic inhibitors of the renin-angiotensin-aldosterone
kidney disease. Indeed, within the class of oral hy- system could also result in upregulation of angio-
poglycaemic agents, recent studies have suggested tensin 1-7/1-9 known to retain a vasodilatory, an-
a potential renoprotective effects for SGLT2 antag- ti-inflammatory and anti-oxidative stress protective
onists(3) and incretin-mimetic drugs such as gluca- effects.
gon-like peptide (GLP)-1 analogues.
2. Systemic theory: the systemic theory suggests that
Of the multiple factors contributing to the develop- plasma volume contraction (driven by SGLT2 medi-
ment of T2DM (e.g. insulin resistance at the tissue ated glycosuria and possibly natriuresis) and blood
level, beta cell failure, increased glucagon secretion, pressure reduction observed with SGLT2 therapy
and decrease incretin effect), the increased renal could be at the basis of the cardio-renal protective
proximal tubular glucose reabsorption, secondary to mechanisms of this new class of drugs.
an upregulation of the SGLT2 transporters, has been
implicated in the pathophysiology of diabetes. The Studies are ongoing to understand the role of these
glucose proximal tubule reabsorption is mediated compounds in reducing the burden of diabetic chron-
by an energy-dependent sodium-coupled glucose ic cardiovascular-renal complications.
transporter called SGLT2 which has recently been
proposed as a target for treatment of hyperglycae- Recent clinical trials on GLP-1 analogues have demon-
mia in diabetes. strated a cardiovascular protective role for this new
class of drugs with suggestion of parallel renoprotec-
By blocking the action of SGLT2 in patients with tive effects(6, 7). Like for SGLT2 inhibitors the cardio-
T2DM studies have shown an improvement in gly- vascular protective role of these drugs occurs within
caemic control paralleled by weight loss and by a 6-12 months from their initiation and it appears to be
modest, but clinically significant, fall in systolic and beyond the improvement in glucose control.
diastolic blood pressure. The SGLT2 inhibitors mode
of action is insulin independent and rarely results in Studies have suggested direct effects of GLP-1 recep-
hypoglycaemia unless the SGLT2 inhibitor is utilized tor agonists on endothelial function, renal sodium ex-
in conjunction with insulin or beta cell secretagogues cretion and improvement in systolic blood pressure
(e.g. sulphonylurea). but more work is needed to dissect the mechanisms
for cardio-renal protection of these agents. Experi-
Recent clinical trials have demonstrated an important mental research has suggested GLP-1-mediated re-
cardiovascular(4) and possibly a renoprotective effect duction in glomerular filtration rate (GFR) in models
(5)of the SGLT2 inhibitor empaglifozin; importantly characterized by glomerular hyperfiltration, and an
more recent clinical trials and observational studies increase in GFR in models with normal glomerular
filtration.

GCDC 2017

Glucose is Not Always Sweet Diabetic Kidney Disease: 29
Can we Make it “SWEET” Again?

The understanding of the putative renoprotective role
of SGLT2 and GLP-1 will help towards the understand-
ing their cardiovascular and (putative) reno-protective
effect and possibly offer new target for treatment in
the future.

Highlights

• Diabetic kidney disease is the major cause of end
stage renal failure.

• Diabetic nephropathy is an irreversible progres-
sive disease though some evidence suggests its
reversibility.

• As diabetic renal diseases progress hypoglycae-
mic and blood pressure treatment needs to be
personalized to preserve patient safety.

• Preliminary studies strongly suggest a renoprotec-
tive role of SGLT2 antagonist and GLP-1 analogues.

• The cardiovascular protective role of SGLT2 antag-
onist and GLP-1 analogues is likely to be mediated
by haemodynamic effects affecting the cardiovas-
cular renal system.

References:

3. Gnudi L, Gentile, G., Ruggenenti, P. The patient with diabetes mellitus.
In: Turner N, Lamiere, N., Goldsmith, D.J.,Wineearls, C.G., Himmelfarb,
J., Remuzzi, G., editor. Oxford Textbook of Clinical Nephrology. 2. Oxford,
UK: Oxford University Press; 2016. p. 1199-247.

4. Fioretto P, Steffes MW, Sutherland DE, Goetz FC, Mauer, M. Reversal of
lesions of diabetic nephropathy after pancreas transplantation [see com-
ments]. New England Journal of Medicine. 1998;339(2):69-75.

5. DeFronzo RA, Norton L, Abdul-Ghani M. Renal, metabolic and cardiovas-
cular considerations of SGLT2 inhibition. Nat Rev Nephrol. 2017;13(1):11-
26.

6. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al.
Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes.
N Engl J Med. 2015;373(22):2117-28.

7. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mat-
theus M, et al. Empagliflozin and Progression of Kidney Disease in Type
2 Diabetes. N Engl J Med. 2016.

8. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck
MA, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes.
N Engl J Med. 2016;375(4):311-22.

9. Okerson T, Chilton RJ. The cardiovascular effects of GLP-1 receptor ago-
nists. Cardiovasc Ther. 2012;30(3):e146-55.

Cardio Diabetes Medicine

30 Cardio Diabetes Medicine 2017

The New Brave World of Dyslipidemia :
Ready to Target ASCVD after Statins

Dr. P. C. Manoria,

MD., DM., FSACC., FESC.,
Director menoria Heart and critical care Hospital,
Former Prof and H.O.D Cardiology GMC,Bhopal.

Abstract is therefore poised to improve compliance greatly
compared to PCSK9 MoAbs. It is obviously emerg-
With kicking off of second revolution of PCSK9 in- ing as a very important competitor to PCSK9 MoAbs.
hibition by fully humanized MoAbs after the statin The future ongoing trials will tell us more about this
revolution, we are amidst a new brave world of dyslip- molecule.
idemia which is ready to target atherosclerotic cardio-
vascular disease (ASCVD) beyond statins and eziti- Dyslipidemia is a major modifiable risk factor for ath-
mibe. Dyslipidemia related atherogenic CV events erosclerotic cardiovascular disease (ASCVD). As per
account for 50% of cases. The high intensity statins WHO 50% of cardiovascular events are attributed to
decrease LDL-C on an average of 1 mmol and this dyslipidemia (Figure 1) and the rest 50% is related to
transformed in 20-25% reduction in the CVE which non-lipid atherogenic risk factors.
means 50 % of the lipid related atherogenic risk,
PCSK9 inhibitors MoAbs decease LDL-C by another What are the validated lipid targets?
1 mmol on top of statins and they decrease CVE by
another 20%. Therefore the era has come when we Figure 2 shows the evolution of lipid guidelines
are able to minimize the dyslipidemia related athero- during the last 29 years ever since ATP-1 came into
genic risk to a very great extent. The PCSK9 MoAbs existence in 1987 (fig 2)
require 12-26 injection per year. Inclisiran which is a
small interfering RNA has shown to decrease LDL-C
consistently for 6 months after a single injection and

Figure 1: Relation of lipid to coronary heart disease

GCDC 2017

The New Brave World of Dyslipidemia : 31
Ready to Target ASCVD After Statins

Goals for Lipid targets:

For several years LDL-C goals < 70 has been rec-
ommended for the very high risk group. The lipid
association of India has slashed down this goal to
<501 and the AACE guidelines 20172 to < 55 ml/dl
(Table 1 & 2). The goals for Non HDL-C are 30mg /
dL more than the LDL-C goal

Figure 2: Evolution of lipid guidelines during last 29 Triglycerides
years after ATP1
Triglycerides (TG) may be playing an important role in
Amongst lipids, LDL-C and NonHDL-C are the prin- Indian dyslipidemia but this has not been properly in-
cipal targets. ApoB is also a target but usually it is vestigated in the Indian context.The Indian diabetolo-
not utilized because lack of facilities for estimating gists should conduct a large RCT to find an evidence
it and an idea about its level is obtained from Non based target and clarify its role. We have data that
HDL-C. All trials of HDL-C elevation on top of statins low TG levels with loss function mutation APOC33
have been flop trials and there is no evidence based and ANGPTL44 are associated with decreased cor-
target for it. In fact HDL-C is fallen angel. onary heart disease and so also increased TG levels
are associated with increase cardiovascular and all
cause mortality. But we do not have any RCT which
has shown benefit of lowering TG on top of stains.
The ACCORD trial which tested efficacy of fibrates on
top of statins in diabetic patients failed to show any
benefit. The diabetologists often use fibrates on ba-
sis of subgroup analysis of the ACCORD trial5 and
meta-analysis of fibrate trials but the problem with

Table 1: Treatment goals for LDL-C and Non LDL-C as per Lipid association of India

Table 2: AACE Guidelines 2017

Cardio Diabetes Medicine

32 Cardio Diabetes Medicine 2017

this data is that sub-group analysis of ACCORD trial reduction of CV events by 20-25% approximately ir-
in patients with raised TG>204 mg/dL and low HDL-C respective of baseline LDL-C. This means that statins
<34 mg/dL did show a benefit but sub-group analysis are powered to decrease 50 % of dyslipidemia related
are only hypothesis generating and the finding needs atherogenic risk.
to be confirmed in large randomized trial which is
non-existent at the present state of time. Likewise We have already witnessed the revolutionary era
in the meta-analysis of fibrate trials6, fibrates were of statins for last 30 years and indeed statins have
not used on top of statins in all trials. It is important emerged as uncontested king for lipid management.
to realize that it is apoB particles which enters the We have voluminous data on statins and they are
vessel wall and not TG per se. The risk of atheroscle- class IA recommendation for primary as well as sec-
rosis is related to the number of atherogenic particles ondary prevention of coronary artery disease. They
and each atherogenic lipoprotein particle contains a are highly effective drugs and have minimal side
single molecule of apoB. Therefore the concentration effects. 2015 came with breaking news when two
of apoB provides a direct measure of the number of PCSK9 inhibitors, evolocumab and alirocumab were
circulating atherogenic lipoprotein. In most hypertrigl- approved for clinical use by EMA and ACC/AHA.
ceridemic (HyperTG) patients including diabetics, LDL With this a new revolutionary era of PCSK9 has
particles make up 85-90% of total apoB particles and erupted and this kicked off the second revolution in
the contribution of VLDL is only 10-15%. Fibrates only dyslipidemia after the Statins. PCSK9 inhibitors de-
lower LDL particle by only about 10% and therefore crease LDL-C by another 1 mmol and this is expected
fibrates at most may only play a minor role. The Que- to decrease CVE by another 20-25%. Therefore with
bec cardiovascular study also showed that if there combination of both drugs the dyslipidemia related
is HyperTG with normal apoB levels, there is no in- atherogenecity can be minimized to a great extent.
crease in Odds ration of IHD but if there is HyperTG The effect of reduction in LDL-C on cardiovascular
with increased apoB levels, the Odds ratio of IHD are events is shown in Table 4.
significantly increased.
Atherogenic Risk Reduction Drug Decrease
What are the drugs for dyslipidemia Non Lipid Lipid in Utilized in CV
related related LDL-C events
The drugs utilized for modulating dyslipidemia are
outlined in 50% 50% 1 mmol High 25%
2 mmol intensity
LDL-C Non- TG HDL statins 45%
HDL-C
Statins +
Statins Intensify Fibrate No drug PCSK9
Ezetimibe statin recom- inhibitors
PCSK9 inhibitors OM3 fatty mended
a. Evolocumab Fibrates acid Table 4: Effect of LDL-C reduction on atherogenic cardio-
b. Aliorocumab vascular events
Colesevelam OM3 fatty Saroglita-
Lomipatide (For acid zar# Non Statin drugs:
FH*)
Mipomersen (For In selected high-risk patients, such as those with
FH*) existing ASCVD or LDL-C ≥190 mg/dl, use of non-
siRNA Inclisiran+ statins may be considered if maximally tolerated
statin therapy has not achieved >50% reduction in
Table 3: Drugs for treatment of dyslipidemia LDL-C from baseline.

*Familial Hypercholesterolemia , Ezetimibe is the first non-statin medication that
#Available only in India, no approved by FDA., should be considered in most of the patient scenar-
ios, given its safety and tolerability, though modest
+Under evaluation. efficacy, when added to moderate-dose statin in the
IMPROVE IT Trial7.
Statins are the first line agents for targeting dyslip-
idemia. CTT meta-analysis Collaboration (Figure 7) Bile acid sequestrants (BAS) may be considered as
has shown that high intensity statins on an average second-line therapy for patients in whom ezetimibe is
decrease LDL-C by 1 mmol and this reduction is seen not tolerated, but they should be avoided in patients
across the range of LDL-C and this translates into with triglycerides >300 mg/dl.

GCDC 2017

The New Brave World of Dyslipidemia : 33
Ready to Target ASCVD After Statins

Familial hypercholestolemia Evolocumab

For patients with homozygous hypercholesterolemia This has already been approved for clinical use and
(HoFH) the goals are difficult to achieve. Statins, is available commercially as 1ml pen containing 140
and non-statins drugs including ezetimibe, BAS are mg. It is given in doses of 140 mg. biweekly / 420
utilized with consideration for use of lomitapide8 mg. monthly sc. It was tested in the PROFICIO Global
, mipomersen9, and LDL apheresis as necessary. Programme which had 14 trials and roughly 30,000
LDL-apheresis is also approved for heterozygous FH. patients Most of the trials have been completed and
the results of FOURIER were presented in 2017. Most
PCSK9 inhibitors like evolocumab and alirocumab of these trials have shown significant reduction in
may be considered if the goals of therapy have not LDL-C by 40-60% on top of statins. There is also con-
been achieved on maximally tolerated statin and eze- sistent and robust reduction in other lipoproteins. The
timibe in familial hypercholesterolemia.PCSK9 inibi- Lp(a) is reduced by approximately 25%, triglyceride
tors are also used in higher-risk patients with clinical and non HDL-C are also decreased. The HDL-C and
ASCVD. apo-A1 are increased.

What is PCSK9 ? Interestingly when both statins and PCSK9 MoAbs
are combined together they decrease LDL to super
Serum proprotein convertase subtilisin/kexin 9 low levels as low as 25 mg/dl in substantial number
(PCSK9) is a protein that regulates LDL-C levels in of cases. Two questions automatically erupts out of
the blood by regulating LDL receptors (LDL-R). It is this, first is super low LDL-C safe and is it powered
secreted from the liver, goes into the blood, circulates to produce incremental benefits on top of statins.
back to liver and directly binds to LDL receptors in- The answer to both questions is yes because the
creasing their degradation and thereby reducing the FOURIER trial has proved both safety and efficacy
rate at which LDL-C is removed from circulation10 and of evolucumab. We had safety data first from the
thus increasing LDL-C levels in blood. Thus PCSK9 OSLER, ODDYSEY long term trials and recently from
is an important regulator of LDL metabolism.PCSK9 the FOURIER trial14, the first CV outcome trial for sec-
is also affected by genetic mutation. There are two ondary prevention of ASCVD. In this study LDL-C de-
types of mutation, loss of function mutation which creased from median base line value 92 mg/dl to 30
results in decrease in LDL-C and provides athero- mg/dl, i.e., approximately by 60% (P<0.001), 42% had
protection. The gain of function mutation11 causes LDL-C <25 mg / dL. (Figure 9).Despite such low levels
familial hypercholesterolemia (FH) and predisposes of LDL-C there was no evidence of muscle or liver
to ASCVD. toxicity, diabetogenecity, neurocognitive decline. The
dedicated sub-study, EBBINGHAUS also confirmed
Both statins and ezetimibe12 increase secretion of lack of neurocognitive decline with its use. The only
PCSK9, which could attenuate their efficacy by re- side effect which was more common with evolocum-
ducing the amount of cholesterol cleared from cir- ab was injection site reactions, 2.1% (evolocumab) vs
culation. This explains the limitation of statin ther- 1.6 % (Placebo).The study also demonstrated incredi-
apy and may be the best explanation regarding the ble safety on top of statins.
classic rule of 6 observed with statin therapy. This
rule refers to the fact that every time the statin dose We had the initial efficacy data from the OSLER and
is doubled, there is only an approximately 6% com- ODDYSEY long term and recently from the FOURIER
plementary decrease in LDL-C levels.Therefore the trial. The OSLER trial showed 53% RRR in the com-
combination of PCSK9 inhibition with a statin would posite endpoint of death, MI, unstable angina hos-
be a sensible and logical approach and will cause a pitalization, coronary revascularization, stroke, TIA
dramatic decrease in LDL-C levels. or CHF hospitalization (HR 0.47 95% CI 0.28-0.78
P=0.003) and the Post-Hoc analysis of ODYSSEY
PCSK9 inhibition LONG TERM showed a 48% RRR reduction in MACE
(HR=0.52 CI 0.31,0.90, P=0.02).This year the FOURIER
PCSK9 inhibition is now a validated therapeutic op- trial showed a statistically significant 15% risk reduc-
tion for modulating LDL cholesterol after the results tion in the primary endpoint of CV death, MI, stroke,
of the FOURIER trial in 2017. Its inhibition can be hospitalization for unstable angina and revasularisa-
achieved by gene silencing, small peptides or mono- tion, HR 0.85 (95% CI, 0.79-0.92 P<0.001).In the sec-
clonal antibodies (MoAbs). PCSK9 MoAbs13 is com- ondary end point of CV death <MI, stroke there was
monly used to inhibit PCSK9. Both evolocumab and a statistically significant reduction of 20% reduction,
alirocumab have been approved for clinical use in HR 0.80 (95% CI, 0.73-0.88 P<0.001). (Figure 3 a,b)
2015 by EMA and US FDA.

Cardio Diabetes Medicine

34 Cardio Diabetes Medicine 2017

nary revascularization by 22 %,P=<0.001. There was
no significant decrease in all cause or CV mortality.

Alirocumab

This is approved for clinical use in USA and is com-
mercially available as 1 ml pen containing 75 or 150
mg. It is given in doses in 150 mg. biweekly sc. It was
evaluated in ODYSSEY Global Programme which in-
cluded 11 trials and roughly has 22,000 patients

Figure 3 a,b: Primary and secondary efficacy end Bococizumab
point in the FOURIER trial
The SPIRE 1 and 2 with Bococizumab was premature-
The curves were divergent so that the risk reduction ly terminated because of presence of neutralizing
at 2 years translated to NNT of 74 to prevent CVD, antibody in 29% and antidrug antibodies in 48% of
MI, stroke but at three years it decreased to 50. It patients taking the drug. This is perhaps because Bo-
seems that the future is brighter than the present cocizumab is partially murine monoclonal antibody
and long term follow up may lead to more fruitful unlike Evolocumab and Alirocumab which are fully
results. The target of <70 for the high risk patients humanized monoclonal antibodies. The incidence of
has been scrapped by the FOURIER trial. The benefit antidrug antibody and neutralizing antibody to vari-
was seen across the range of LDL upto 20-25 mg/ ous PCSK9 inhibitors are mentioned in Table 5.
dl. All quartiles benefitted highest as well as lowest.
There was no J curve so lower is better is also validat- 1 Failure to achieve LDL-C goals despite optimal
ed for super low LDL. The reduction in primary & key doses of statins in patients with ASCVD
secondary end point were consistent across all key
subgroup including age, sex, different types of CVD 2 Statin intolerance
intensity of statin therapy, dosing regimen of evolo-
cumab and base line LDL levels including those with 3 Familial hypercholesterolemia
the lowest quartile of LDL cholesterol-starting at 74
mg/dL-in whom evolocumab reduced LDL down to Table 5: Indications of PCSK9
22 mg /dL .The FOURIER trial showed reduced MI
by 27% p=<0.001, stroke by 21%, p=0.01 and coro- Given the lack of long-term safety and efficacy data
on these agents, they are not recommended for use
for primary prevention except in patients with familial
hypercholesterolemia. The data of PCSK9 for primary
prevention like high risk diabetics is yet to evolve out

Future developments in PCSK9 inhibition

Despite several results of FOURIER trials, the trial-
ists realized two problems with PCSK9 monoclonal
antibodies i.e. the drug requires 12-26 injections per
year and adherence data with PCSK9 MoAb show no
substantial improvement over statins. Due to this, at-
tempts were made to explore other ways of inhibiting
PCSK9. Inhibiting the synthesis of PCSK9 by small
interfering RNA, siRNA targeted to PCSK9 showed
exciting results in the ORION-1 trial15. The side effects
are seen only in minority of patients and includes
cough musculo skeletal pain, nasopharyngitis, head-
ache, backache, diarrhea. The ORION-1 trial (figure
11) showed sustained reduction of LDL when two
dose starting regimen at 0 and 90 days followed by
six monthly injection of inclisiran showed sustained
reduction with mean LDL reduction of 52.6% at 180
days and 48% of patients had LDL-C below 50 mg/
dL. After the exciting results the FDA has cleared
phase II trials for inclisiran. Three trials are ongoing,

GCDC 2017

The New Brave World of Dyslipidemia : 35
Ready to Target ASCVD After Statins

the ORION-2 in HoFH, ORION-3 comparing incli- 12. Ason B, Tep S, Davis HR Jr, et al. Improved efficacy for ezetimbie and rosu-
siran vs. evolocumab and ORION-4 evaluating CV vastatin by attenuating the induction of PCSK9. J Lipid Res. 2011;52:679-
outcomes. It seems that inclisiran may emerge as a 87. 12
strong competitor for evolocumab and alirocumab in
future. 13. Marais DA, Blom DJ, Petrides F, Goueffic Y, Lambert G. Proprotein con-
vertase subtilisin/ kexin type 9 inhibition. Curr Opin Lipidol, 2012;23:511-
Conclusion 17. 13

Dyslipidemia is a major modifiable risk factor for ath- 14. Marc S. Sabatine M C,Giugliano,Keech A C,et al .for the FOURIER Steer-
erosclerotic CVD. Statins trials have validated LDL-C, ing Committee and Investigators. Evolocumab and clinical outcomes in
lower is better and they decrease lipid related cardio- patients with cardiovascular disease. N Engl J Med 2017:376:1713-1722
vascular events by 20-25%. The new wonder mole- 14
cule PCSK9 MoAbs have validated that super low
LDL-C as low as 25 mg/dl is still better and lower- 15. Ray K K, Landmesser Ulf, Leiter A L, et al. Inclisiran in patients at
ing LDL-C to this level produces incremental benefit high cardiovascular risk with elevated LDL cholesterol.N Engl J med
with incredible safety as shown in the FOURIER. It 2017;376:1430-1440. 15
therefore seems lowering LDL-C to levels at which
we are born is fruitful and this has kicked of a new
revolution in dyslipidemia after the statin era.

Reference

1. SS Iyengar, Raman Puri, et al. Special issue on LAI Expert Consensus
Statement on Management of Dyslipidemia in Indians 2016. JAPI Special
issue 2016; 64:7-52.

2. Garber Alan J, Abrahamson Martin J, Barzilay Joshua I, et al. Consensus
statement by the American association of clinical endocrinologists and
American college of endocrinology of the comprehensive type 2 diabe-
tes management algorithm -2017 executive summary. Endocrine practice
2017;23(2):207-227.

3. The Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary
Disease TG and HDL. Working Group of the Exome Sequencing Project,
National Heart, Lung, and Blood Institute N Engl J Med 2014; 371:22-31.

4. Folsom AR, Peacock JM, Demerath E, Boerwinkle E. Variation in ANGPTL4
and risk of coronary heart disease: the Atherosclerosis Risk in commu-
nities study.

5. The ACCORD Study Group. Effects of combination lipid therapy in type 2
diabetes mellitus. N Engl J Med 2010; vol. 362(17):1563-1574

6. Lee M, Saver JL, Towfighi A, Chow J, Ovbiagele B, et al. Efficacy of fibrates
for cardiovascular risk reduction in persons with atherogenic dyslipidemia:
a meta-analysis. Atherosclerosis 2011 Aug;217(2):492-8.

7. Christopher P. Cannon, Michael A. Blazing, Rober P. Giugliano, et al for the
IMPROVE-IT Investigators. Ezetimibe Added to Statin Therapy after Acute
Coronary Syndromes. N Engl J Med 2015;372:2387-97.

8. Neef D, Berthold HK, Gouni-Berthold, et al. Lomitapide for use in patients
with homozygous familial hypercholesterolemia: a narrative review. Expert
Rev Clin Pharmacol. 2016;9(5):655-63.

9. Stein EA, Dufour R, Gagne C, et al. Apolipoprotein B synthesis inhibition
with mipomersen in heterozygous familial hypercholesterolemia: results
of a randomized, double-blind, placebo-controlled trial to assess efficacy
and safety as add-on therapy in patients with coronary artery disease.
Circulation 2012 Nov. 6;126:2283-2292.

10. Yamamoto T, Lu C, Ryan RO, A two-step binding mode of PCSK9 interaction
with the low density lipoprotein receptor. J Biol Chem. 2011;286:5464-70.

11. Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 cause autosomal
dominant hypercholesterolemia. Nat Genet. 2003;34:154-156. Abstract
11

Cardio Diabetes Medicine

36 Cardio Diabetes Medicine 2017

Diabetes And Hypertension -
Common Soil Hypothesis

Dr. A. Muruganathan,

MD., FRCP (Glasg, London & Ireland)., FACP (USA)., FPCP (Philippines)., FICP.,
President –Hypertension Society of India: (HSI) 2015 – 2016
Dean Elect – Indian College of Physicians (ICP): 2016-2017

Past President – Association of Physicians of India (API): 2013-2014

Fighting against the deadly duo mean systolic blood pressure was associated with
relative risk reduction of 12% for any complication
Introduction of diabetes, 15% for deaths related to diabetes, 11%
for myocardial infarction and 13% for microvascular
Diabetes mellitus is a heterogeneous chronic met- complications
abolic disease where both microvascular and mac-
rovascular complications contribute to morbidity and • The HOT (Hypertension Optimal Treatment study)
mortality. Cardiovascular diseases are the costliest showed that diabetics with high BP,will need 2-3
complications of diabetes andare rapidly increasing drugs to control their BP.
in prevalence in recent decades in developing coun-
tries like India and have emerged as leading causes • The Systolic Hypertension in the Elderly Program
of death.1,2. Hypertension is a major risk factor for (SHEP) and other studies like Hypertension De-
cardiovascular and renal disease. Hypertension and tection and Follow-up Program(HDFP), Systolic
diabetes mellitus (DM) frequently coexist. When hy- Hypertension in Europe (Syst-Euro),HOT, normo-
pertension occurs in diabetes,it accelerates the pro- tensive Appropriate Blood pressure Control in Di-
gression of both microvascular and macrovascular abetes(ABCD), and Heart Outcomes Prevention
complications and the mortality increases by more Evaluation(HOPE) provide firm evidence that even
than sevenf­ old. small BP reductions translate to significant de-
crease in both micro and macrovascular compli-
Hypertension is twice as prevalent in diabetics as in cations in persons with type 2 diabetes.
non-diabetic individuals. In patients with type 1 diabe-
tes mellitus, hypertension develops at the onset of • The ADVANCE (Action in Diabetes and Vascular
diabetic nephropathy while in type 2 diabetes melli- Disease; Preterax and Diamicron MR Controlled
tus, more than 50% patients are hypertensive at the Evaluation) study showed that intensive control
time of diagnosis. of BP resulted in reduction in composite micro
and macrovascular complications by 9%, coronary
The estimated number of people with hypertension events by 14% and renal events by 21%.
is increasing worldwide, andis expected to increase
from 972million in2000, to 1.56 billion by 2025. In • The Advance Collaborative Group study demon-
diabetes, estimated number of people worldwide is strating the benefit of an angiotensin - converting
expected to increase from 382 million in 2012 to 592 enzyme (ACE) inhibitor and indapamide in a fixed
billion in 20302. Forty-eight percent of the anticipated combination, strongly suggesting that the blood
absolute global increase of 186 million people with di- pressure goal (<130/80 mmHg) was beneficial
abetes is projected to occur in India and China alone.
• The ACCORD (Action to Control Cardiovascular
EVIDENCE Risk in Diabetes) trial was unable to find a signifi-
cant reduction in incidence of major CV events in
Studies related to hypertension and diabetic patients patients with diabetes whose SBP was lowered to
worldwide 2,3 an average of 119mmHg compared with patients
whose SBP remained at an average of 133mmHg.
In the UKPDS study, each 10 mmHg decrease in

GCDC 2017

Diabetes And Hypertension-Common Soil Hypothesis 37

How are Diabetes and Hypertension coined to point out that the two diseases originate
Related? from the same soil rooting from insulin resistance.

Diabetes and hypertension are considered to be “co- The insulin resistance and the resultant hyperinsu-
morbidities” which tend to occur together because linemia,affectnitric oxide pathway, activates sympa-
they share certain physiological traits. thetic drive, increases in vascular smooth muscle
cell (VSMC) cytosolic calcium, induction of endo-
These two diseases sharethe important risk factors thelin secretion, and enhancement of vascular lipid
like deposition, sodium fluid retention, all contributing to
the pathogenesis of hypertension. Effect of insulin
• Aging on the blood vessel cells stimulates the proliferation
of VSMCs by increasing insulin like growth factor 1
• Body Mass – overweight and obesity (IGF1­) expression and also stimulates endogenous
angiotensinogen and angiotensin II expression and
• Diet – High fat diets, rich in salt and processed upregulation of angiotensin­1 receptors.The smooth
sugars muscle cell migration and proliferation occurred
bypotentiation of mitogenesis through Epidermal
• Low physical activity Growth Factor/Platelet Derived Growth Factor recep-
tor (EGF/PDGF).Hyperinsulinemia stimulates the ex-
• Dyslipidemia pression of endothelin­1, a potent mitogen for VSMCs.
Insulin resistance prevents intracellular magnesium
• Atherosclerosis transport into VSMCs and diminishes Na/KA­ TPase
activity resulting in elevated cytosolic calcium and
Types of Hypertension in Diabetes Mellitus increased vascular tone.

1. Hypertension associated with type 2 DM (Syn- Hyperglycemia also has a direct effect onthe Renin­
drome X) Angiotensin­Aldosterone System (RAAS).

2. Hypertension associated with nephropathy in Activation of the RAAS results in unregulated an-
type 1 DM giotensinogen II activity through its angiotensin1­ re-
ceptor leading to the formation of Reactive Oxygen
3. Coincidental hypertension in diabetic patients Species (ROS). RAAS activation also leads to uninhib-
- Essential hypertension ited production of aldosterone, which in turn induces
- Isolated systolic hypertension salt retention, enhanced sympathetic and decreased
- Renal scarring from recurrent pyelonephritis parasympathetic activity and increased extracellular
matrix deposition.
4. Diabetogenic anti-hypertensive drugs
- Potassium-losing diuretics (chlorthali- Hyperglycemia has mitogenic and antiapoptotic ef-
done,high dose thiazides) fects on VSMCs. It has the direct suppressive effect
- High dose beta blockers on nitric oxide release and inturn reduces vasodila-
- Combination ofdiureticsand beta blockers tion effect. Glucose activates the nuclear transcrip-
tion factor (NFκB) through a Protein Kinase C (PKC)
5. Drugs causing hypertension and glucose intol- dependent pathway and upregulates Plasminogen
erance Activator Inhibitor (PAI1­) expression and angiotensin
- Corticosteroids II mediated action.Increased oxidative stress and re-
- Combined oral contraceptive pills duced prostacyclin synthase activity compromises
vasodilatation. The Advanced Glycation Endproducts
6. Endocrine disorders causing hypertension and (AGEs) in circulation and vessel wall are associated
glucose intolerance with impaired endothelial­dependent vasodilatation
- Acromegaly and increased vessel wall stiffness.
- Cushing’s syndrome
- Conn’s syndrome Increased sympathetic activity has been observed in
- Pheochromocytoma people with insulin resistance and obesity.

The Pathophysiology2,4 High serum leptin levels (hyperleptinemia)from the
increased fat mass or secondary to leptin receptor re-
Thecommon pathophysiological mechanism contrib- sistance are further potentiated by hyperinsulinemia.
utes to both occurrences as well as exacerbation of
these two conditions.

The insulin resistance hypothesis is gaining more
acceptance as a common etiological factor for both
diseases; “the common soil hypothesis” is a term

Cardio Diabetes Medicine

38 Cardio Diabetes Medicine 2017

Thisincreases sympathetic drive via central and pe- Fig no 1, 2- Common pathophysiological mechanism
ripheral mechanisms, thus contributing to increased of Diabetes and Hypertension
BP and heart rate.
Diabetic Nephropathy and Hypertension
Adiponectin, (an adipocyte­derived peptide has anti­
inflammatory, insulin­sensitizing and endothelium­ • In type 1 diabetes, hypertension begins with the on-
protective properties) is lower in obese subjects and set of nephropathy (microalbuminuria stage).A his-
inversely related to systolic and diastolic pressure . tory of hypertension in the parents and increased
erythrocyte sodium -lithiumcounter transport and
Sodium and water retention -Insulin promotes renal DD iso form of the ACE gene, which is linked to
tubular reabsorption of sodium via Na/H antiport increased ACE generation are markers of genetic
system or the Na/KA­ TPase in the renal tubule. susceptibility to hypertension and nephropathy.

The ACE -D(Angiotensin­Converting Enzyme-D) iso- • In type 2 diabetes, about 50% already have obesity
form is associated with an increase in the circulat- and age related essential hypertension. Hyperten-
ing ACE activity and has recently been shown to be sion is present in more than 90% of diabetics with
a significant predictor of weight gain and abdominal impaired renal function. Increased systolic BP is
adiposity in men. a significant risk factor for micro albuminuria and
rapid progression of nephropathy.
Erythrocyte sodium­lithium counter transport, which
represent sodium reabsorption in the proximal tu- Strategy for management of Hypertensive
bule, has been found to be overactive in persons Diabetic patients
with diabetes and hypertension.
• Proper blood sugar control
Genetic variants in the gene encoding angiotensino-
gen, adrenomedullin, apolipoprotein, and α-adducin • Achieve target level of BP control for diabetic pa-
have been associated with common conditions such tients
as diabetes, hypertension, dysglycemia, or metabolic
syndrome. • Early detection of both diabetes and hypertension
complications, manage them, as well as delay their
A missense mutation of the β3a­ drenergic receptor progression and improve patient’s quality of life.
gene (ADRB3) is associated with low resting meta-
bolic rate, weight gain, early onset of type 2 diabetes
and hypertension.

Polymorphisms of the glucocorticoid receptor gene,
particularly those which alter the receptor’s sensi-
tivity to cortisol, have been associated with central
obesity and hypertension.

Enhanced activity of enzyme 11β­hydroxysteroid de-
hydrogenase type 1 leading to increased fat tissue­
specific cortisol production, and reduced inactivation
of cortisol by altered 11β­hydroxysteroid dehydroge-
nase type 2 in fat cells has been demonstrated in
insulin resistant obese subjects.

Non-Drug Therapy

The multifactorial approach, based on the following
nonpharmaco-therapeutic interventions are

NUTRITION

Blood pressure of diabetic patients more sensitive to
salt intake and this sodium sensitivity is found even
in absence of nephropathy.A decreased salt intake
is important for diabetic patients with hypertension.

GCDC 2017

Diabetes And Hypertension-Common Soil Hypothesis 39

Reducing Salt (Sodium) intake Dietary Approaches to Stop Hypertension (DASH)
diet is an eating plan, rich in fruits, vegetables,
Aim for less than 3-5 grams per day. However, the whole grains, fish, poultry, nuts, legumes, and low-
daily average salt consumption in Indian scenario is fat dairy. These foods are high in key nutrients such
8-9 grams per day. as potassium, magnesium, calcium, fibre and pro-
tein. The DASH diet can lower blood pressure be-
Ways to reduce sodium intake cause it has less salt and sugar.

• Food items without added salts 4-5 servings of fruits and vegetables / 6-8 servings
of whole grain / saturated fat 6% of total calories /
• Unsalted nuts, seeds, beans total cholesterol of <150 mg/day

• Avoid adding salt and canned vegetables to home- WEIGHT REDUCTION The prevention and correction
made dishes of overweight /obesity (BMI > 25) is a prudent way
of reducing the risk of hypertension and indirectly
• Unsalted and sodium free, fat-free broths and coronary artery disease; it goes with dietary changes.
soups Loss of weight by 1kg decreases BP by approximately
1mm Hg.
• Use fresh poultry, lean meat and fish.
EXERCISE PROMOTION
• Rinse canned foods to reduce sodium.
Physical activity
• Low sodium, low fat cheeses
F : Frequency - atleast Five days per week
• Add spices and herbs to enhance taste
I : Intensity- Moderate
• Add fresh lemon juice instead of salt to fresh veg-
etable salad T : Time - 30-45 minutes

Additional Benefits of Moderate Sodium T : Type - Cardiorespiratory Activity Walking, jog
Reduction ging- Cycling

• Improvement in large artery compliance (Gates Non-competitive swimming
et al., 2004)
Exercise should be prescribed as an adjunctive to
• Enhancement of efficacy of antihypertensive pharmacological therapy
drugs (Slagman et al., 2011; Aziza et al., 2013
BEHAVIOURAL CHANGES
• Reduction of diuretic -induced potassium loss
(Ram et al., 1981) Reduction of stress, cessation of smoking, moder-
ation of alcohol drinking, modification of personal
• Regression of left ventricular hypertrophy (Rodri- life-style, yoga and transcendental meditation could
guez et al., 2011) be beneficial.

• Reduction in proteinuria (Agarwal, 2012) SELF-CARE
• Reduction in urine calcium excretion (Carbone et
In order to overcome the limitations of the office
al., 2003) blood pressure (OBP) measurement, two methods
• Decrease in osteoporosis (Martini et al., 2000) are widely used in clinical practice
• Decreased prevalence of stomach cancer (Fock
1. Home Blood Pressure Monitoring (HBPM)
et al., 2008)
• Decreased prevalence of stroke (Joos- 2. 24 hours Ambulatory Blood Pressure Monitoring
(ABPM)
sens&Kesteloot, 2008)
• Decreased prevalence of cataract (Cumming et The patient is taught about self-care, i.e., Home Blood
Pressure Monitoring and keep a log-book of his BP
al., 2000) readings. 24 hours ABP monitoring is a precise meth-
• Protection against onset of hypertension (Whell- od to quantify blood pressure levels and to diagnose
hypertension and also it is used as a marker of CV
ton PK, 2014) morbidity and mortality.

Table:1

Know what to eat

Cardio Diabetes Medicine

40 Cardio Diabetes Medicine 2017

ROLE OF ABPM IN DIABETIC PATIENTS5,6 Fig no:2 ABPM in Diabetes

-- ABPM is advisable in all diabetic patients with TARGET BP IN DM
high-normal BP
-- Patients with no proteinuria or proteinuria of less
-- Diabetic patients are more likely to have than 1gmBP should be less than 130/80

-- White-coat hypertension -- Patients with proteinuria of more than 1gmBP
should be less than 125/75
-- Masked hypertension
-- The aim is to maintain low BP which patient can
-- Nondipping tolerate without postural hypotension and without
compromise on critical vascular beds as well as
-- Reverse dipping quality of life.

-- Morning BP surge Effects of Drugs on Both Diseases Ideal anti-
hypertensive drug in DM
-- High prevalence of masked hypertension in dia-
betic patients are associated with higher risk of -- Must decrease blood pressure to ≤ 130/80
brain and kidney damage and possible cardiac
damage, which further increase cardiovascular -- Must reduce the RAAS activity, improve endothe-
complications. lial dysfunction

-- White-coat hypertension in diabetic patients ap- -- Must prevent, improve or arrest proteinuria
pears to be associated with a lower risk than sus-
tained hypertension. -- Must prevent and protect from CAD, CKD, CHF

-- Nondipping and reverse dipping may reflect au- -- Must be favorable on glycemic control
tonomic dysfunction and it might be used as a
clinical marker of diabetic autonomic neuropathy. -- Must improve the dyslipidemia – not worsen it

-- ABPM provides information on heart rate at the -- Must not worsen peripheral arterial disease
time of BP measurements all over the 24 hours,
and a rough estimate of heart rate variability. The -- Must not cause impotence
reduced heart rate variability is the index of dia-
betic neuropathy. -- Must not decrease eGFR and increase serum cre-
atinine
-- ABPM also provides information on Pulse pres-
sure (difference between systolic and diastolic -- Must not increase uric acid, serum potassium
BP), when increased is considered as a surrogate
marker of stiffening of arterial walls -- Can be easily combined with other drugs

-- An ideal agent should not increase insulin resis-
tance

-- Well tolerated, cost effective

Effects of anti-hypertensives on diabetes

-- ACEIs and ARBsare suitable first line antihyperten-

GCDC 2017

Diabetes And Hypertension-Common Soil Hypothesis 41

sive in diabetics. It has renal protective effect in in- CONCLUSION
cipient nephropathy, reduce insulin resistance and
may improve glycemia in diabetics and patients Diabetes mellitus and hypertension are comorbid ill-
with the metabolic syndrome. nesses,in both developing and developed countries.
The presence of one increases the risk of having the
-- Why ACEI is Preferred in DM ? other. Both increase the risk of cardiovascular and
- Improves insulin sensitivity renal disease. Every diabetes patient need measuring
- Reverse vascular and ventricular remodeling of blood pressure in every visit. Hypertensive patients
- Reverse LVH need to be screened for diabetes regularly. HBPM
- Cardio protection could be an ideal way in monitoring BP in hyperten-
- Renal protection sive patients in general and diabetic patients in par-
- Favorable glucose lipid metabolism ticular to ensure that the patient does not progress
to develop cardiovascular and renal complications.
-- Thiazide diuretics and beta-blockers have meta-
bolic side-effects such as increasing insulin resis- REFERENCE
tance or direct diabetogenesis, which make them
less appropriate as first line agents 1. Reddy KS, Yusuf S. Emerging epidemic of cardiovascular disease in de-
veloping countries. Circulation. 1998;97: 5966­ 01.
-- The use of CCBs was not significantly associated
with incident diabetes compared to other antihy- 2. Nabil K Elnaggar,Diabetes and Hypertension: J Hypertens 2014,Volume
pertensive agents: the association with diabetes 3 • Issue 6 :page no 3:6
was lowest for ACEIs and ARBs, followed by CCBs,
β blockers, and diuretics. 3. Michael J. Cryer, MD; Tariq Horani, MD; Donald J. DiPette, MD:Dia-
betes and Hypertension: A Comparative Review of Current Guidelines:
Effects of anti-diabetics on blood pressure J ClinHypertens (Greenwich). 2016;18:page no;95–100.

-- The anti-diabetic agents involve their antidiabetic 4. Deepak Bharati, Savita Tauro:Diabetes with Hypertension: Etiology,
actions which can be related to side actions where Pathogenesis and Management:Int. J. Integrative Science. Inn. Tech.
changes of blood pressure subsequently occurs. Vol. IV, Issue4 pg 7 – 14

-- Insulin causes salt and water retention, increases 5. Ehud grossman, MD- Ambulatory Blood Pressure Monitoring in the Di-
body weight and it causes growth of tissues as an agnosis and Management of Hypertension diabetes care, volume 36,
anabolic hormone supplement 2, AUGUST 2013

-- SGLT-2 inhibitors cause osmotic diuresis leading 6. Cristiane BauermannLeitão, Luís Henrique Canani, Sandra PinhoSilveiro,
to blood pressure reduction Jorge Luiz Gros: Ambulatory Blood Pressure Monitoring and Type 2 Di-
abetes Mellitus: Arq Bras Cardiol 2007; 88(2): 315-321
-- GLP-1 agonists and DPP-4 inhibitors have been
demonstrated to exert their effects directly through
the activation of their receptors on the cardiac and
vascular tissues or centrally positioned receptors
to reduce the blood pressure.

Effects of the different anti-diabetic drugs on
blood pressure

Drug Class Effect on Blood Pressure
Insulins Small increases
GLP-1 agonists Reduce blood pressure
SGLT-2 inhibitors Reduce blood pressure
DPP-4 inhibitors Small reductions
Biguanides (metformin) No effect
Sulphonylureas and No effect
Glinides
Amylin mimetics No effect

Table:2

Cardio Diabetes Medicine

42 Cardio Diabetes Medicine 2017

The Sugary Mind and the
Burdened Heart: A View Point

Avinash De Sousa,

Research Associate, Department of Psychiatry, Lokmanya Tilak Municipal Medical College,
Mumbai. Founder Trustee and Consultant Psychiatrist Desousa Foundation, Mumbai.

INTRODUCTION : Women are affected more adversely by the factors
mentioned above and are also more prone to diabe-
Diabetes and heart disease are two of the silent tes and heart disease due to the interplay of multiple
killers of the modern era. While there are multiple hormonal factors.
physiological reasons suggested for the causation of
these disorders and the pathophysiology is well un- Broken hearts and distraught marriages are common
derstood, there are a number of psychosocial factors causes of medical illness. The stress of a disturbed
that contribute to the genesis of these conditions. It relationship often takes a toll on both individuals in
is very important that the treating physician is aware the relationship especially the one who suffers in a
of these factors which affect the patient and also disturbed relationship. There is enough research ev-
vitally important that a psychological evaluation be idence to suggest that heart attacks and diabetes
done when such factors are elucidated. The current are common in the first few months after divorce
paper shall posit the various psychological factors or break ups. The chronic stress of a disturbed re-
that contribute to the development of diabetes and lationship raises the level of cytokines that are pro
heart disease and shall suggest methods for the ho- inflammatory and lead to triggering of a cascade
listic management of these conditions. of pathways that lead to the development of heart
disease and diabetes. Disturbed relationships cause
A variety of psychosocial factors have been implicat- hormonal abnormalities in the individual involved and
ed in these disorder. These range from personal to may affect mood and lead to further anxiety and
interpersonal and family as well as marital factors. stress that causes medical disease. The trauma of a
Loneliness is a major risk factor that has been shown troubled relationship can be huge and psychological
to cause both these disorders. Migration to a new help sought early in the problem can avert the de-
city and the adjustment that follows along lack of velopment of medical problems. Relationship coun-
social support and work environments that may be sellors that work on healing the problem relationship
unfriendly and hostile all build further to the burden may help prevent lifestyle related medical morbidity
of loneliness. Lonely individuals are twice as more in these subjects.
prone to a heart attack and a poor lifestyle that ac-
companies Loneliness increases the risk for one to Marital dissatisfaction is another cause of death due
develop diabetes. Work place issues and poor job to medical disease and many couples in disturbed
satisfaction and workplace harassment are other marriages suffer for years before help is sought.
factors that contribute to the genesis of these con- There is also an element of one person cheating
ditions. Unfriendly coworkers and a tyrannical boss on the other that can cause immense psychological
is often a cause of silent heart attacks. Job change trauma to the partner that has been truthful and may
is often advised as a lifestyle modification for heart be a silent factor in the genesis of medical problems.
disease and diabetes. A positive workplace environ- There is also a need for couples to address the bur-
ment reduces the risk of developing diabetes and den of sexual dissatisfaction in marriage. In a country
heart disease by 25%. Sexual harassment at work is a like India where one third of marriages are said to
risk factor for the development of medical problems get sex less,there is a direct need to look at sexual
in women. This is more common when the issue is unhappiness in marriage as a direct risk factor for
handled in an unjust manner by the management. the medical morbidity that shall ensue.

GCDC 2017

The Sugary Mind and the Burdened Heart : A View Point 43

Economic recession and financial stress is another shall in turn undo the effects of negative emotional
risk factor that has been implicated in the genesis factors and unhygienic lifestyle. Yoga and various
of these conditions. It is ironic that while economic types of relaxation training as well as mindfulness
recession may cause these disorders it also reduces is being incorporated into cardiac and diabetic recov-
healthcare utilisation due to financial costs involved ery programmes which ensure better recovery and
and causes a speedy rise in death due to reduction improvement in blood parameters that are raised due
in healthcare seeking for these conditions. Very often to these medical conditions.
months may pass during an economic downturn and
the medical illness may remain undetected. Depres- The time has come for medical specialties to not shy
sion and suicide that has been noted in economic away from psychiatry but rather embrace it whole
recession along with an increase in alcohol and nico- heartedly as psychiatry and psychiatrists always
tine consumption may compound the clinical picture. have a different perspective to offer and more so a
perspective that is very different from that held by
The relationship between psychiatric illness and heart physicians and medical doctors.
disease and diabetes is bidirectional. Both aggravate
one another and a combined management of both The cardiology field as a career is stressful and may
conditions is essential for complete control of any need the help of psychological sciences to help them
one. Genetic factors play a key in the genesis of these maintain their mental health and wellbeing as well
conditions and psychological disorders may trigger as the well being of their patients. There is a need
genetic pathways that shall cause an early onset of for integration of the knowledge we possess to help
the medical disease thereby increasing the overall medical care blossom in this era of holistic health
disease burden at a young age. Many medications care. Corporate hospitals and heart institutes must
that are used in the management of diabetes and integrate psychiatry and psychology into mainstream
heart disease cause depression and sleep problems care and help remove the stigma that already de-
as a side effect while many psychiatric drugs have prives so many of mental health care.
weight gain and hyperlipidemia along with raised
sugar as a side effect.

There is today a psychologist that forms an integral
part of cardiac and diabetes rehabilitation teams.
There are emerging fields like behavioral cardiology
and diabetology are taking over medical rehabilitation
and thus these specialties are realising the impor-
tance of the psychological sciences in the manage-
ment of their patients. Counseling and psychothera-
py for psychosocial factors involved are emerging as
vital tools in lifestyle modification programmes and
thus creates room for the holistic management of
patients with medical disease. The mind heart con-
nection is now being elucidated in many ways and
there is also an emerging role of psychoneuroendo-
crine factors in the genesis, maintenance and recov-
ery from diabetes.

One of the factors endemic in medicine is that med-
ical specialties do not speak often to each other
and know very little about the interplay of multiple
pathways that converge to lead to the development
of medical problems. It is important that treatment
teams complete themselves by equipping their ar-
mamentarium with psychological resources that
shall serve to improve the quality of life of the pa-
tient. Positive mental health which inculcates positive
values like optimism, generosity, gratitude and for-
giveness are vital for mental health promotion and
the release of positive chemicals in one’s body that

Cardio Diabetes Medicine

44 Cardio Diabetes Medicine 2017

Diabetes and Ethical Issue

Professor. Dr. Russell Dsouza, MD., DSc.,

Chair Asia Pacific Division, UNESCO Chair in
Bioethics Haifa, Melbourne Australia

INTRODUCTION “Ethics” stands for a set of philosophical beliefs and
practices concerned with the distinction between
The worldwide prevalence of diabetes is estimated right and wrong or system of moral values or code
to increase from 4% in 1995 to 5.4% by 2025. The of conduct relating to morals in human beings. Eth-
increase will be sharpest in developing countries, ical principles are intellectually derived by a particu-
where the number of diabetics will almost triple from lar profession for its specific needs and may / can
84 million to 228 million. The developing world will be be changed or modified as per needs of the society
responsible for more than 75% of diabetics in 2025, or community. Medical ethics refers chiefly to the
up from 62% in 1995. Among developing countries, rules of etiquette adopted by the medical profession
the highest increase in prevalence will be in China to regulate professional conduct with each other,
followed by India. However, the greatest increase in with individual patients, with society, including con-
numbers will be seen in India, where the number of siderations of the motives behind that conduct. In
diabetics will rise from 19 million in 1995 to 57 million modern era, traditional medical ethics changed into
in 2025, heading the list of countries with the great- an interdisciplinary field involving theologians, law-
est numbers of diabetics. yers, philosophers, social scientists and historians,
as well as physicians and other health professionals
The World Bank estimates that diabetes will account because of increasing impact of science and tech-
for 1,870,000 Disability Adjusted Life Years in India, nology, public expectations from new medicines and
with a per capita health expenditure of $21. Already, surgical techniques, changes in the financing and de-
some two-three per cent of the health-care budget livery of health care.
is spent on diabetes-related problems. An increase
in the number of diabetics is likely to have a serious Ethical Issues with managing Diabetes: An increase
impact on our country’s in the number of diabetics is likely to have a seri-
ous impact on a country’s health-care system raising
health-care system(3). This scenario raises many eth- many ethical and social issues related to diabetes.
ical and social issues related to diabetes. Long term Performing research and preventing, diagnosing,
care for chronic diseases like diabetes goes beyond and treating diabetes will raise ethical, legal, social
the traditional boundaries of medicine and single and policy issues. The Issues raised by diabetes
sector responsibility. One of the main characteristics can surround the understanding and addressing of
of chronic diseases is the involvement of caregivers identified barriers to research, such as analyzing the
and other professionals from many disciplines. At the impact of patents on genes related to diabetes; as-
same time, there are medicosocial implications in the sessing the challenges of bringing new diabetes-re-
need for long-term care for chronic diseases. One lated technologies through the regulatory approval
major goal of diabetes care is to achieve a condi- process; conflicts of interest in research and medi-
tion of wellbeing in the presence of chronic disease cine; and understanding and protecting the rights of
and disability. In this context, the harmful effects of human subjects in diabetes research, including ge-
medicalizing chronic care need to be recognized(2). netics based research on collected or stored tissue
In most developed countries, such medicalization samples. Further ethical issues arise with regards to
increases health-care costs without meeting the re- distributive justice related to assuring population’s
cipient’s non-medical psychosocial needs. India must access to appropriate services and healthcare; pre-
avoid this.

GCDC 2017

Diabetes and Ethical Issue 45

venting discrimination and stigma against people people’s needs. Traditional medicines can contribute
who have diabetes, a predisposition to diabetes, or significantly towards the development of cost effec-
family members with diabetes; and analyzing the ef- tive treatment modalities, guided by evidence based
fects of direct marketing to patients on diagnosis, research. Currently, compartmentalization within
prevention, and treatment. medical education and in the medical profession
prevents scientific research in traditional medicines.
Ethical issues with Primary prevention Such issues of market influences generate ethical
interventions deliberations relating market influences of diabetes
care.
The burden of diabetes in the next 25 years is likely
to sharpen the ethical dilemma of access to prima- Research for new modalities for the prevention or
ry care as opposed to technologically-intensive care treatment of complications must consider the fact
for complications. There is an urgent need to consid- that certain research such as for diabetic peripheral
er public health interventions to reduce the burden neuropathy and diabetic ulcer, cannot be done on
of diabetes and to contain its economic and social animals. Therefore, research in various treatment
costs. Without primary prevention strategies at the modalities for these problems must have stricter eth-
public health level, the number of undiagnosed and ical controls and independent reviews. Market-driven
uncared-for diabetics will increase, as will the number research can deprive patients of effective treatment
of complications be requiring a higher technological modalities. In the worldwide economic liberalization,
services. This in turn will limit access to health care the interests of the private sector are likely to take
for large numbers of patients impacting on the ethi- precedence over the needs of the healthcare system.
cal issues around access and distributive justice. Sci- This must be countered by vigilant patient interest/
entific evidence of treatment efficacy must also be consumer groups and the medical profession. An-
considered before the allocation of limited healthcare other area is in regard to traditional medicines, which
resources available. Primary prevention with popula- can contribute significantly towards the develop-
tion health initiates that limit or delay the onset of di- ment of effective treatment modalities, guided by
abetes are the direction that will be effective and cost evidence-based research. Currently, compartmental-
effective. The question of dividing funds between pri- ization within medical education and in the medical
mary prevention and pure research will cause intense profession prevents scientific research in traditional
political, social and ethical debates. The appetite medicines. This is also seen as an ethical issue that
for technologically-intensive, hospital based care in needs to be contended in the management of dia-
some regions will ensure that these interventions will betes. An open debate about various ethical, social,
take precedence over more cost-effective measures. economic aspects of diabetes, with the involvement
At present, bureaucratic regulation, corruption and a of all sectors of society.
lack of motivation are reported factors, responsible
for the poor quality of primary health care in India. Ethical Issues related to Diabetic Clinical
Thus, compromising the primary prevention strate- Trails
gies for diabetes, which leads to several ethical is-
sues that this will bring up. The Helsinki Declaration 2013 updated version, eth-
ical principles to be used in clinical investigations,
Ethical Issues in Market-driven research in states that “In any medical study, every patient, in-
Diabetes cluding those of a control group, if any, should be
assured of the best proven diagnostic and thera-
As the number of diabetic patients’ increases, the peutic method”. But many of the placebo-controlled
private health sector will find new and lucrative mar- trials currently being performed to assess new oral
ket opportunities. Market-driven research can deprive diabetic therapies do not meet this ethical standard.
patients of cost effective treatment modalities. For Comparing an experimental drug with a placebo is
example, companies have stopped production of perfectly ethical when no proven effective therapy
cheaper forms of insulin (Bovine and Pork) arguing exists and when the risk-to-benefit ratio needs to
that human insulin is more physiological. Now there be assessed. However, when effective therapy ex-
is promotion of analogs as compared to human in- ists, the use of placebo control subjects does not
sulin. However, the cost difference is phenomenal. meet the ethical standard because efficacy and safe-
There is ample evidence that health related strate- ty of the experimental medication should be tested
gies, including those in the development of newer by blindly randomizing to an existing drug that has
drugs, tend to be driven by the market rather than by been shown as effective and safe and not to placebo.

Cardio Diabetes Medicine

46 Cardio Diabetes Medicine 2017

Ethical issue that should be considered is, how long of the population, including low-risk subgroups. Low-
can hyperglycemia be permitted to continue in dia- risk individuals may ignore these recommendations
betic subjects undergoing trial? Prolonged hypergly- and consequently put their health conditions at risk.
cemia or more than 6 months hyperglycemia has the In presence limited or moderate clinical validity bur-
potential to exacerbate macrovascular complications densome or too strong preventive measures will raise
and will have an adverse effect on the quality of life ethical issues, such as psychological harms: at-risk
creating an ethical dilemma children who do not adhere to lifestyle recommenda-
tions and when they develop the disease later in life,
Ethical Issues in Genetic susceptibility blame may be attributed to themselves or be blamed
testing services for Type 2 Diabetes by others. Such ‘victim-blaming’ or feelings of guilt
will not always be justified in the context of a multi-
Meletus is available but experts are not convinced factorial disease for which susceptibility testing is of
of its current clinical validity and utility generating an moderate predictive ability: some at-risk individuals
ethical issue. With the rising number of individuals may develop the disease even if they take appropri-
affected with diabetes and the significant health care ate measures, whereas other at-risk individuals may
costs of treatment, the emphasis on prevention is not fall ill despite their failing to take preventive ac-
key to controlling the health burden of this disease. tion.
Several genetic and genomic studies have identified
genetic variants associated with increased risk to di- Ethical Issues with costly therapy and
abetes. As a result, commercial testing is available diabetic complications
to predict an individual’s genetic risk. Although the
clinical benefits of testing have not yet been demon- Various scientific trials have shown the enhanced
strated, it is worth considering some of the ethical im- benefits of aggressive insulin therapy to control and
plications of testing for this common chronic disease. delay the onset of complications in sever diabetes,
From an ethical perspective, several issues should but intensive therapy with insulin is costly. So, the
be considered during the translation of predictive ethical dilemma faced by many doctors is whether to
testing for diabetes, including familial implications, start costly, intensive therapy with expensive human
improvement of risk communication, implications for insulin to prevent future complications or to continue
behavioral change and health outcomes, the Genet- traditional therapy which could lead to early compli-
ic Information Nondiscrimination Act, direct-to-con- cations. Medical practitioners are often faced with
sumer testing, and appropriate age of testing. an ethical dilemma rooted in economics. An example
would be, foot gangrene a dreaded complication of
The variability of the severity of Type 2 Diabetes diabetes. It is often possible to salvage the foot, but
Meletus poses difficulties for the ethical evaluation at great expense. The family must incur heavy debts
of susceptibility testing for the disease. From a pre- for this high-technology treatment. The alternative
cautionary perspective, it could be argued that Type to taking on this economic burden may be ampu-
2 Diabetes Meletus should be viewed as a severe tation. In young diabetics, the loss of a limb can be
disease and require high levels of genetic counsel- crippling, affecting one’s employment. The difficult
ing and psychological support or hardly causes any decision to amputate is often based on social and
psychological harm or emotional impact at all. There economic factors. The similar can be considered in a
may be discrepancies between the severity of a dis- case of end stage renal disease, where renal trans-
ease as perceived by medical professionals and the plant is not feasible and the patient has multisystem
severity of the same disease as perceived by oth- failure. The issue might well be as to how long hemo-
er publics. There are both therapeutic options and dialysis should be continued given the costs and an
well-established preventive strategies available for almost certain unfavorable outcome. Such dilemmas
diabetes for children as well as for adults, at the lev- are likely to increase as the number of diabetics with
el of lifestyle improvements. Existence of preventive complications increases and the resource availability
options for Type 2 Diabetes Meletus implies a poten- becomes scarce leading to a wider debate on ethical,
tial for medical benefits to be obtained from suscep- social and economic issues related to management
tibility testing. Therefore, if false reassurance occurs, of diabetic complications.
it may lead to harm. Individuals who are found to
be at decreased risk may wrongly feel assured that Ethical issues with Embryonic stem cells: Stem cell
they will remain free from disease, regardless of their research could provide a means of replacing dam-
lifestyles. They may fail to understand that general aged tissue in patients with diabetes and embryos
health recommendations are relevant to the whole are a potentially rich source of viable stem cells.

GCDC 2017

Diabetes and Ethical Issue 47

Mesenchymal stem cells (MSCs) are multipotent, Health Policy. Ann Intern Med 2004; 140:951-957.
self-renewing cells that can be found in almost all
postnatal organs and tissues. The main functional 4. The economics of diabetes, Diabetes Care 1998 21(suppl.3); c7-c10.
characteristics of MSCs are their immunomodulatory
ability, capacity for self-renewal, and differentiation 5. Redman BK. Responsibility for control; ethics of patient preparation for
into mesodermal tissues. The ability of MSCs to dif- self-management of chronic disease. Bioethics 2007; 21:243-50.
ferentiate into several cell types, including muscle,
brain, vascular, skin, cartilage, and bone cells, makes 6. Daniel J. Cox, Harsimran Singh, Daniel Lorber. Diabetes and Driving Safety:
them attractive as therapeutic agents for several dis- Science, Ethics, Legality & Practice. Am J Med Sci 2013; 345:263–265.
eases including complications of diabetes mellitus.
Thus, MSCs has the potential as new therapeutic 7. Street RL, Voigt B: Patient participation in decision making and subsequent
agents in the treatment of diabetic cardiomyopathy, quality of life. Medical Decision Making 1997;17; 298-306
diabetic nephropathy, diabetic polyneuropathy, dia-
betic retinopathy, and diabetic wounds. 8. Volarevic V, Arsenjevic N, Lukic ML, Stojkovic M, Concise Review: Mesen-
chymal Stem Cell Treatment of the Complications of Diabetes Mellitus,
Cloned embryos may one day allow the customized Stem Cells 2011 Vol.29 1 5-10
replacement of damaged tissues and organs. The
ethical aspects of such a research are varied and 9. David S. H. Bell. Ethics in Diabetic Clinical Trials. Diabetes Care 2001;
debatable. A philosophically coherent approach to 24:606-606.
embryo research would acknowledge the intrinsic
value accorded by people to all human life. Society 10. Susanne B. Hagan. Ethical Issues of Predictive Genetic Testing for Diabe-
must find a way to reconcile these intuitive concerns tes. J Diabetes Sci Technol 2009; 3:781–788.
with the utilitarian desire to maximize the benefits of
stem cell research. 11. Eline M Bunnia, Maatjes HN Schermer, A Cecile JW Janssens. The role of
disease characteristics in the ethical debate on personal genome testing.
BMC Medical Genomics 2012

12. Bjorn Hofmann, Joran Hjelmeaeth Torgeir Thorson Sovik. Moral challenges
with surgical treatment of type 2 diabetes. 2013; 27:597–603.

Conclusion

Non-communicative diseases are the challenge of
the current and foreseeable time. To face this chal-
lenge, we need an optimally trained, aware and
motivated medical profession, de-medicalization of
chronic disease health care and a proportional allo-
cation of health-care resources geared to the needs
of the poor.

With more stakeholders, such as medical devices
companies, pharmaceutical companies, diagnostic
clinics, insurance companies, clinical trial organiza-
tions and other service providers entering the field,
there was a need to expand the scope of the defini-
tion of ethics within the field of medicine. Now the
terms “bio-medical ethics”, “bio-pharmaceutical eth-
ics”, and “health care ethics” are gaining importance.

From the varied ethical and social issues that are to
be contended, we require an open deliberation on
the various ethical, social, economic aspects of dia-
betes, and with the involvement of all stake holder
and sectors of society.

REFERENCES

1. King H: Global burden of diabetes. Diabetes Care 1998; 21:1414-1431.

2. Arun Bal. Diabetes: ethical, social and economic aspects. The Indian Jour-
nal of Medical Ethics 2000; 8:3.

3. David F. Williamson, Frank Vinicor, Barbara A. Bowman. Primary Preven-
tion of Type 2 Diabetes Mellitus by Lifestyle Intervention: Implications for

Cardio Diabetes Medicine

48 Cardio Diabetes Medicine 2017

Gender And Outcomes in Type 2 Diabetes
Mellitus and Cardiovascular Disease

Dr Prema Tirou,

MRCP (UK), MRCGP (UK), D. Diabetes (UK)

Abstract distinction between sex and gender differences may
be difficult.(2)
There is increasing evidence of major clinically im-
portant differences in outcome between the genders In this article, the following topics are discussed
in Type 2 Diabetes Mellitus (T2DM). Diabetes seems namely biological and psychosocial risk factors and
to undermine the protective effect of the female sex cardiovascular complications in both genders.
in the development of cardiovascular disease (CVD).
A review of the literature shows that women with Biological Risk Factors
T2DM often have worse CVD risk profiles and out-
comes compared with men. Women with diabetes 1) Body Mass index (BMI) related risk
have a three- to fivefold higher risk of developing
CVD, and men have a two to threefold higher risk Diabetes in men is diagnosed 3–4 years earlier and
compared with their respective counterparts with- at a BMI 1–3 kg/m2 lower. This trend was partly ex-
out diabetes. There exist other differences including: plained by an increase of automation and decrease
T2DM is diagnosed at lower age and body mass in- of physical work particularly in men. Diabetic women,
dex in men; Obesity, as a risk factor, is more com- on the other hand, are more obese than diabetic men
mon in women. The disparities could be due to both in most studies and show a stronger association be-
biological and psychosocial factors. However, the tween increase of BMI and diabetes risk. (3)
cause for the various gender disparities in T2DM out-
comes remains unclear and future research should 2) Body fat distribution
provide us with more insight into this. Future treat-
ment of T2DM should be with gender based targets In an Asian population, women with normal waist
to achieve better outcomes. circumference (WCR) and BMI were diagnosed with
visceral obesity by computer tomography. This even
Introduction showed greater cardio metabolic risk in women, in
terms of glucose and lipid abnormalities compared
The disparities in T2DM outcomes between men and with males and the visceral obesity increases the risk
women could be attributed to sex differences and of diabetes more in women.
gender differences.
3) Brown adipose tissue (BAT)
Sex differences describe differences between wom-
en and men which are caused by biological aspects Sex differences are described regarding mass and
such as differences in sex chromosomes, sex-spe- activity of BAT in adults which will impact whole-body
cific gene expression of autosomes, sex hormones, energy metabolism, insulin resistance, and obesi-
and their effects on organ systems.(1) ty-related T2DM. Women have much higher preva-
lence and activity of BAT, which protects them from
Gender differences arise from sociocultural process- diabetes and cardiovascular risk.BAT transplantation
es, such as different behaviors of women and men, reversed obesity, increased adiponectin, and reduced
exposure to specific environmental influences, differ- insulin resistance and liver steatosis in leptin-defi-
ences in nutrition, life styles or stress, or attitudes cient animals.
towards treatments and prevention. In reality, the
4) Metabolic syndrome

GCDC 2017

Gender And Outcomes in Type 2 Diabetes Mellitus 49
and Cardiovascular Disease

Based on the guidelines from the National Heart, op impaired fasting glucose (IFG), whereas women
Lung, and Blood Institute (NHLBI) and the American more often show Impaired Glucose Tolerance (IGT).
Heart Association (AHA), any three of the following IFG is characterized by increased hepatic glucose
traits in the same individual meet the criteria for the output and impaired early insulin secretion, whereas
metabolic syndrome: IGT is primarily due to peripheral insulin resistance. It
further highlights the importance of performing oral
• Abdominal obesity: a waist circumference of Asian, glucose tolerance tests to screen for IGT, especially
the cutoff values are ≥90 cm (35 in) in men or ≥80 in women.
cm (32 in) in women
Psychosocial Risk Factors
• Serum triglycerides 150 mg/dl or above.
Social factors, like low educational level, occupation,
• HDL cholesterol 40mg/dl or lower in men and and income with low socioeconomic status (SES),
50mg/dl or lower in women. largely contribute to unhealthy lifestyle behavior and
social disparities and thus are related to higher risk of
• Blood pressure of 130/85 or more. obesity and T2DM particularly in women. Females ap-
pear to be more vulnerable to the so-called “allostatic
• Fasting blood glucose of 100 mg/dl load,” the imbalance between the ability to adapt to
environmental demands and overexposure to envi-
MetS, a term used for clustering of metabolic risk ronmental stress. Women at all ages were shown to
factors with insulin resistance disregard risk factors be at a 40% higher risk for suffering from insomnia,
like age, sex, family history, SES, and lifestyle. Di- which in turn was associated with insulin resistance
abetes appears to diminish the favorable cluster of and obesity.
risk factors of females compared with males and in-
creases the chances of cardiovascular complications. Cardiovascular Complications

5) Adipokines (Leptins and Adiponectins) The Global Burden of Cardiovascular Disease in
Women
These are important in the regulation of satiety, food
intake, and energy expenditure. They also influence • Cardiovascular disease is the leading cause of
the insulin glucose axis as well as peripheral insu- death for women worldwide.
lin resistance. Women show an up-regulation of ex-
pression of adiponectin and its receptor in abdominal • One-third of deaths in women are due to cardio-
adipose tissue, possibly contributing to their lower vascular disease.
cardiometabolic risk. Adiponectin and waist circum-
ference (WCR) are important predictors of insulin-re- • Each year, 8.6 million women around the globe
sistance even in healthy non-diabetic women, they die from heart disease and stroke.
may open a new opportunity to improve current risk
estimation. Sex-Specific Differences in Complications and Co-
morbidities of Diabetes is illustrated in the attached
6) New biomarkers Figure 1.

The following new biomarkers show promise in fu- Coronary heart disease
ture for prediction of diabetes in women.
Coronary artery disease in women tends to affect the
1) Hepatokine fetuin A smaller blood vessels, producing less-severe symp-
2) copeptin toms. The plaque burden in women also tends to be
3) Proneurotensin lower than in men but differs in that it often builds
up along the entire artery rather than within a con-
7) Imbalance of sex hormones centrated area. This means that it is not uncommon
for women to have chest pain without evident ob-
The polycystic ovary syndrome (PCOS) describes a structive coronary artery disease.
female-specific state of androgen excess and hyper-
insulinemia related to obesity, T2DM, and higher car- In newly diagnosed diabetic subjects without clini-
dio metabolic risk. Testosterone replacement therapy cal CVD, increased atherosclerosis and higher inti-
can improve insulin sensitivity and hyperglycemia in ma media thickness was found in carotid arteries.
hypogonadal diabetic males. Subgroup analysis revealed that as opposed to male
groups, carotid atherosclerosis was more prevalent in
8) Prediabetes newly diagnosed diabetic women than in nondiabet-

Prediabetic categories differ between sexes giving
rise to clinical implications: men more often devel-

Cardio Diabetes Medicine

50 Cardio Diabetes Medicine 2017

ic female controls. This data confirms that diabetes, diabetic female patients. The INTERHEART study of
even at an early stage, attenuates the protective ef- risk factors for CVD identified diabetes mellitus as
fect of female sex and increases the risk for CVD in one of the greatest risk factor for women, as diabetic
females to a greater extent than in males. women had a threefold to fourfold increased risk of
developing CVD compared to men. (4)

Fig-1 Sex differences in symptoms of IHD

Pathophysiology *) women report more angina despite lower rate of
obstructive CAD.
Hyperglycemia inhibits antiproliferative effects of
estrogen on vascular smooth muscle cells. These *) Meta analysis of 74 reports from 13,311 women and
are mediated through selective ERα activation under 11511 men, prevalence of angina is 11% to 27% greater
normoglycemic conditions. Hence, beneficial effects for women less than 65yrs.
are counterbalanced by simultaneous ERβ activation,
leading to loss of protective estrogen effects. This *) women have lesser obstructive CAD regardless of
causes a proinflammatory environment accelerating symptoms and continue to have signs and symptoms
atherosclerotic processes and CVD particularly in di- of ischemia, repeat hospitalization, consumption of
abetic women. health care resources.

Studies demonstrate under-treatment of women with
medication compared with men. Both studies also
show gender differences in use of procedures. While
increasing knowledge exists regarding pathophysio-
logical mechanistic pathways for “female-pattern”
ischemic HD, translational studies aimed at devel-
oping practical diagnosis and therapeutics with both
traditional and novel treatments are needed.

Coagulation

Diabetic women had a higher prothrombotic fibrin
profile, with denser fibrin clots and prolonged fibri-
nolysis.  In men only, worse glycemic control was
related to an increased atherothrombotic risk. An in-
dividualized therapy strategy might be needed with
more aggressive antithrombotic therapy in diabetic
women and other higher risk groups.

Cardiomyopathy

 Males tend to suffer more often of heart failure at
younger age due to CVD. They are also more likely to
develop myocardial dilatation, whereas women tend
to develop hypertrophic cardiomyopathy with diastol-
ic heart failure and preserved ejection fraction more
often. Diabetic females feature greater susceptibility
to diabetic cardiopathology besides CHD. They show
greater wall thickness and left ventricular (LV) mass
in relation to glycemic control and diastolic dysfunc-
tion. This more closely relates to IGT, which is more
relevant in women.

Fig-2 Stroke

The Nurses’ Health Study found CVD mortality in The excess risk of stroke associated with diabetes is
women with DM to be 8.7 times higher than in non- significantly higher in women than men, independent
of sex differences in other major cardiovascular risk

GCDC 2017

Gender And Outcomes in Type 2 Diabetes Mellitus 51
and Cardiovascular Disease

factors (5). These data add to the existing evidence 4. Anand SS, Islam S, Rosengren A, Franzosi MG, Steyn K, Yusufali AH, Kel-
that men and women experience diabetes-related tai M, Diaz R, Rangarajan S, Yusuf S; INTERHEART Investigators. Risk
diseases differently and suggest the need for further factors for myocardial infarction in women and men: insights from the
work to clarify the biological, behavioral, or social INTERHEART study. Eur Heart J. 2008 Apr;29(7):932-40.
mechanisms involved.
5. Peters SA, Huxley RR, Woodward M. Diabetes as a risk factor for stroke in
Mortality women compared with men: a systematic review and meta-analysis of 64
cohorts, including 775,385 individuals and 12,539 strokes. Lancet. 2014
Presence of MetS was associated with a 2-fold high- Jun 7;383(9933):1973-80.
er risk of CVD and 1.5-fold increase of mortality, with
consistently higher risk for women than men, includ-
ing all-cause mortality. Diabetes is associated with an
almost 2-fold increased risk of death. The sex ratio
of risk of fatal CHD or stroke showed a greater risk
in women, which did not improve over time.

Future Perspective

Increased awareness of health professionals regard-
ing sex and gender differences in development and
management of T2DM and its complications is need-
ed. At present, there are some interesting studies to
show the risk factors, pathophysiology and complica-
tions of diabetes for both men and women and they
differ from each other in all categories. Randomized
controlled trials proving sex-specific effects by ad-
equately designed interventions are widely missing.
Another problem is the lack of a defined methodol-
ogy for sex- or gender-specific analysis.

Highlights

• Morbidity and mortality of women with diabetes
is much higher when compared to men

• Men are diagnosed with diabetes at a younger
age but obese women are prone to diabetes even
at younger age.

• Women with T2DM are generally under treated
for cardiovascular risk than men

• Future studies need to focus on gender based
management of T2DM and CVD

• Physicians need to have better understanding of
gender differences and CVD risks in T2DM

References

1. Kautzky-Willer A, Harreiter J, Pacini G. Sex and gender differences in risk,
pathophysiology and complications of type 2 diabetes mellitus. Endocrine
reviews. 2016 May 9;37(3):278-316.

2. The EUGenMed, Cardiovascular Clinical Study Group. Gender in cardio-
vascular diseases: impact on clinical manifestations, management, and
outcomes Eur Heart J. 2016 Jan 1;37(1):24-34.

3. Garawi F, Devries K, Thorogood N, Uauy R Eur J Clin Nutr. , Global dif-
ferences between women and men in the prevalence of obesity: is there
an association with gender inequality? Eur.Journal of Clinical Nutrition
68, 1101-1106

Cardio Diabetes Medicine

52 Cardio Diabetes Medicine 2017

Cardiogenic Shock: Etiopathogenesis
and Clinical Recognition

Deep Chandh Raja, MD., DM., DNB., CARDIOLOGY

Associate Consultant
The Madras Medical Mission, Chennai

Shock is a pathophysiological state wherein there is to intra-cardiac causes of myocardial pump failure.
significant reduction in tissue oxygen delivery due
to decreased tissue perfusion. Tissue oxygen deliv- Intra-cardiac causes of cardiogenic shock: Causes of
ery is maintained in an individual by adequate blood pump failure are diverse, but can be classified into
volume and hemoglobin content, cardiac contractility 3 categories- Cardiomyopathic, Arrythmic and Me-
and tissue metabolic demand. Derangement in any chanical. (3)
of these parameters is usually compensated by one
or more of the following mechanisms: increase in Cardiomyopathy: Myocardial infarction is one of
heart rate, increase in cardiac contractility and diver- leading causes of acute cardiogenic shock. Incidence
sion of peripheral blood to vital organs by peripheral of cardiogenic shock ranges from 5-10% of patients
vasoconstriction and increased peripheral oxygen with myocardial infarction. (4) MI involving more than
extraction. 40% of the left ventricular myocardium, severe ex-
tensive ischemia due to multi-vessel coronary artery
Shock can be- Hypovolemic, Distributive, Cardiogenic disease, severe right ventricular infarction can lead
or Obstructive. (1) The underlying mechanism of shock to acute pump failure.
varies according to the type of shock and is more of-
ten an overlap of mechanisms. This is best explained 1. Acute decompensation of chronic heart failure:
in a patient of sepsis with distributive type of shock Majority of chronic heart failure patients are
with decreased peripheral vascular resistance who those with etiologies ranging from ischemic car-
later on develops cardiogenic pump failure due to diomyopathy, idiopathic dilated cardiomyopathy,
myocardial depression by circulating inflammatory end-stage hypertrophic cardiomyopathy or end-
mediators. stage restrictive cardiomyopathy. Such patients
remain in a compensated state with medications
Definition of Cardiogenic Shock: as well as their body’s own homeostatic mech-
anisms. Any deterioration in the pump function
Cardiogenic shock is defined by hypotension (sys- due to progressive heart failure or arrhythmias or
tolic blood pressure < 90mmhg for at least 30 min- an extraneous influence like sepsis or acidosis
utes) due to a low cardiac index (<2.2 L/mt/sq.mt or renal failure (Reno-cardiac) can lead to acute
with support and <1.8 L/mt/sq.mt without support) decompensation and cardiogenic shock.
and elevated filling pressures of the left, right or both
ventricles (>18mmhg) and decreased mixed venous 2. Acute stunning of myocardium can occur sec-
oxygen saturation. The systemic vascular resistance ondary to cardiac arrest, myocarditis, prolonged
is usually high by means of a compensatory periph- cardiopulmonary bypass, sepsis or insult to the
eral vascular constriction.(2) central nervous system. This can also result in
cardiogenic shock.
Etiology of Cardiogenic Shock:
3. Severe right ventricular infarction secondary to
Cardiogenic shock is due to intra-cardiac or ex- MI can lead to forward failure in the absence of
tra-cardiac causes of myocardial pump failure. In congestive features in the lungs.
the true sense the term cardiogenic shock applies

GCDC 2017

Cardiogenic Shock: 53
Etiopathogenesis & Clinical Recognition

Arrythmias: Cardiac output can be severely compro- rupture and 8% had shock due to other causes. In this
mised in instances of atrial tachyarrythmias (atrial registry, 75% developed cardiogenic shock within 24
flutter/ fibrillation with fast venticular rate), ventricu- hours of presentation. (5)
lar tachyarrythmias (ventricular tachycardia, ventric-
ular fibrillation) and extreme bradyarrythmias (com- Stages Of Shock: Shock is a continuum of physio-
plete heart blocks with slow escape rhythms). logical stages beginning with the triggering event
followed by the compensatory mechanisms and the
Mechanical: Acute severe mitral regurgitation due to effects of decreased perfusion and culminating in
papillary muscle rupture (secondary to MI), acute aor- death. (6)
tic regurgitation due to aortic dissection or acute val-
vular rupture (infective endocarditis) can lead to car- Compensated Shock: Systolic blood pressure is
diogenic shock. Ventricular septal rupture or ruptured maintained within the normal range. However tissue
left ventricular free wall can occur as consequence oxygen delivery is maintained by tachycardia and
to myocardial infarction and can lead to cardiogenic peripheral tissue vasoconstriction. Cardiac contrac-
shock. tility cannot improve in cardiogenic shock. Patients
in chronic heart failure remain in the compensated
Obstructive form of cardiogenic shock: Intracardiac stage. These patients are compensated by means of
obstruction like severe mitral stenosis or aortic ste- their own body’s homeostatic mechanisms in addi-
nosis leading to cardiogenic shock is usually due to tion to the anti heart failure drug treatment.
underlying hypovolemia or arrhythmias rather than
the critical obstruction per se. Decompensated shock: This stage is reached rapidly
in cardiogenic shock as the inciting stimulus primarily
Extra-cardiac causes of cardiogenic shock affects the myocardium. The patient develops symp-
are usually due to: toms related to increased filling pressures in the
heart. Later the signs and symptoms of decreased
1. Pulmonary vascular: Hemodynamically signifi- organ perfusion set in.
cant pulmonary embolism, severe pulmonary hy-
pertension lead to acute rise in right ventricular Irreversible shock: Progressive end-organ dysfunc-
pressures which eventually fails to accommodate tion leads irreversible organ damage, death and is
to the high pressures and thus leads to acute termed ‘multi-organ failure’.
right myocardial failure. Acute right ventricular
failure leads to interventricular interdependence Pathogenesis Of Cardiogenic Shock: (Fig 1)
and impaired filling of the left heart.
Acute cardiogenic pump failure is responsible for
2. Mechanical: The primary abnormality is de- acute heart failure. Whereas, in patients with chronic
creased preload to the left heart due to severe heart failure there is either deterioration in myocardi-
volume loss, tension pneumothorax, pericardial al functions or failure of compensatory mechanisms
tamponade, constrictive pericarditis or abdominal that leads directly to the stage of decompensation.
compartment syndrome. Cardiogenic shock is unique because signs and
symptoms are due to both backward and forward
Combined etiologies in shock: Few scenarios like the failure of the myocardial pump. Unlike in the other
following involve more than one mechanism contrib- types of shock wherein the improvement in cardiac
uting to shock other than the cardiac component: contractility and increase in stroke volume serves as
a primary compensatory response to maintain tissue
1. Septic shock with myocardial depression and perfusion, cardiogenic shock results in rapid fall of
stunning hypotension due to loss of functional myocardium.
Peripheral tissue perfusion is maintained initially by
2. Neurogenic shock with myocardial stunning peripheral vasoconstriction and increase in heart rate.
Failure of these compensatory mechanisms leads
3. Hypovolemia contributing to shock along with rapidly to the stage of hypotension and a vicious
the cardiac pump failure cycle sets in. (7) This is compounded by hypoxemia
caused by the pulmonary alveolar congestion.
4. Cardiac tamponade causing obstruction in addi-
tion to primary pump failure Backward failure of the myocardial pump leads to
increase in the left ventricular diastolic pressures.
In the SHOCK trial registry of 1160 patients with car- This increases the left atrial pressures. The increase
diogenic shock, 74.5% of patients had predominant in the pressures within the chambers of the heart is
left ventricular failure, 8.3% had acute mitral regur-
gitation, 4.6% had ventricular rupture, 3.4% had right
ventricular failure, 1.7% had tamponade or myocardial

Cardio Diabetes Medicine

54 Cardio Diabetes Medicine 2017

(Figure 1)FIGURE 1: THE MECHANISMS AND EFFECT OF CARDIOGENIC SHOCK

termed as ‘elevated filling pressures’. This in turn in- Cellular Effects Of Shock:
creases the pulmonary pressures causing pulmonary
congestion. Vascular redistribution occurs within the The effects of inadequate tissue perfusion are revers-
lung zones. Once the hydrostatic pressures within the ible initially. It results in cell membrane ion pump dys-
lung capillaries exceed the alveolar pressures, fluid function, intracellular edema, leakage of intracellular
exudation into the alveoli occurs. This increases the contents into extracellular space and decrease in in-
alveolar to arteriolar oxygen gradient leading to hy- tracellular pH. As the tissue hypoperfusion persists,
poxemia. Backward failure also affects the right heart cellular death results as a consequence to mitochon-
leading to congestion in the veins emptying into the drial disintegrity, membrane damage and apoptosis.
right heart. Thus neck veins get congested as well as Multiple cellular deaths lead to tissue and eventually
the hepatic veins. organ dysfunction. (8)

Forward failure leads to hypotension and decreased Clinical Recognition Of Shock: Symptoms
tissue perfusion. Splanchnic circulation is diverted And Signs
to the vital organs like the brain and myocardium .
Prolonged hypoperfusion of the kidneys causes hy- Cardiogenic shock is a syndrome comprising of con-
poxic tissue damage and renal injury. Likewise all stellation of findings involving multiple organs. The
end organs deteriorate with persisting hypotension clinical effects of cardiogenic shock are best ex-
culminating in death. plained by each of the organs involved in the process.

Tachycardia: Though a non-specific finding, increase

GCDC 2017

Cardiogenic Shock: 55
Etiopathogenesis & Clinical Recognition

in heart rate remains one of the first compensatory Unless the mesenteric arteries have a pre-existing
mechanisms to maintain tissue perfusion and hence stenosis which may lead to mesenteric ischemia,
is an important clue to the onset of decompensation. ischemic necrosis of the intestines usually occurs
late in the stages of irreversible shock.
Hypotension: Primary pump failure leads to earlier
onset of hypotension in cardiogenic shock compared Brain: Impaired perfusion to brain occurs as an end
to the other forms of shock. This is only one of the result of prolonged or severe shock. This leads to
manifestations of cardiogenic shock and other fea- cell death in the brain, cerebral edema, agitation, sei-
tures have to be sought for before making a diagno- zures, obtundation and finally brain death. Hepatitis
sis of cardiogenic shock. Hypotension could be due can also result in direct transmission of ammonia and
to hypovolemia or peripheral vasodilation (sepsis) or other toxins to the brain resulting in hepatic coma.
drug induced. It is defined in adults by systolic blood
pressure < 90mmhg, mean arterial blood pressure Lactic acidosis: Tissue hypoperfusion throughout
<65mmhg or relative drop in systolic BP>40mmhg. the body leads to intracellular accumulation of lactic
acid and eventually results in lactic acidosis. The det-
Skin: Peripheral vasoconstriction is an important rimental effects of acidosis include endothelial cell
compensatory mechanism for cardiogenic shock. death and failure of peripheral vasoconstriction and
Cold, clammy extremities are a result of this mech- fall in peripheral vascular resistance, further depres-
anism. Prolonged vasoconstriction, compounded by sion of myocardial contractility, elevation of pulmo-
intravenous vasopressors, has known to result in dig- nary arterial pressures and impaired responsiveness
ital gangrene. Backward failure of right heart leads to to the parenteral medications.
congested veins and elevated jugular venous pulse
and pressure in the neck which serve as an important History and clinical examination can result in a rea-
diagnostic clue to raised right heart pressures. sonable recognition of cardiogenic shock.

Lungs: Backward failure of the left heart leads to Symptoms and Signs of Heart Failure and
direct transmission of heart pressures to the pul- Cardiogenic Shock
monary circulation resulting in pulmonary alveolar
edema. Initially there is compensation in form of in- TYPICAL SPECIFIC
creased respiratory rate (tachypnoea) and pulmonary Breathlessness Elevated jugular venous
vascular redistribution. Type 1 respiratory failure sets pressure
in after the compensatory mechanisms fail to main- Orthopnoea Hepatojugular reflux
tain normal arterial oxygen saturation. Paroxysmal nocturnal Third heart sound (gallop
dyspnoea rhythm)
The combination of findings in the skin and lungs Reduced exercise toler- Laterally displaced apical
provide quick and vital clues to the stage of heart ance impulse
failure. Forrester et al (9) state that the ‘cold-wet’ va- Fatigue, tiredness, in-
riety of heart failure represents those in cardiogen- creased time to recover LESS SPECIFIC
ic shock. This bed-side assessment of cardiogenic after exercise Weight gain (>2 kg/week)
shock corresponds to low cardiac index (cold periph- Ankle swelling Weight loss (in advanced
eries) and pulmonary congestion (wet lungs). LESS TYPICAL HF)
Nocturnal cough Tissue wasting (cachexia)
Kidneys: Prolonged tissue hypoxia leads to acute re- Wheezing Cardiac murmur
nal injury. This is termed as ‘Cardio-renal syndrome’ Peripheral oedema (ankle,
because of the detrimental effects of cardiogenic Bloated feeling sacral, scrotal)
shock on the kidneys. Decreased glomerular filtration Loss of appetite Pulmonary crepitations
rate leads to decreased intraglomerular pressures Confusion (especially in Reduced air entry and dull-
and oliguria. Tissue acidosis, necrosis and death may the elderly) ness to percussion at lung
result in post glomerular obstruction. Depression bases (pleural effusion)
Palpitations Tachycardia
Liver: Intrahepatic pressures tend to be high as a
direct result of backward failure of the right heart. Dizziness
This results in hepatomegaly. Tissue hypoxia leads
to ischemic hepatic necrosis and hepatitis.

Gastro-intestinal system: Intestinal venous conges-
tion due to backward cardiac failure leads to de-
creased bowel movements and decreased appetite.

Cardio Diabetes Medicine

56 Cardio Diabetes Medicine 2017

Syncope Irregular pulse tion (9) according to the state of extremities and lungs
Trepopnoea Tachypnoea helps in understanding the severity of heart failure
Cheyne Stokes respiration and need for immediate action. Framingham devised
Hepatomegaly criteria (10) for recognising heart failure which includes
Ascites distended neck veins, cold extremities, gallop rhythm
Cold extremities or new onset murmur on cardiovascular system ex-
Oliguria amination, bilateral rales in the lungs, altered mental
Narrow pulse pressure status, hepatomegaly, pedal edema and/or oliguria.
Other positive findings are tachycardia, narrow pulse
(Table 1) Symptoms And Signs of Cardiogenic Shock pressure, S3 and S4 gallops and murmurs of mitral
and/or tricuspid regurgitation.
The suddenness of onset of shock may help in look-
ing for new onset causes of cardiogenic shock like Critically ill patients have to be stabilized with respect
myocardial infarction or myocarditis. History of cor- to securing airway, breathing and circulation. Early
onary artery disease or acute coronary syndrome or investigations should be directed to rule out obstruc-
pre-existing cardiomyopathy is useful in delineating tive forms of cardiogenic shock like tension pneumo-
the probable etiology of cardiogenic shock. thorax, cardiac tamponade or pulmonary embolism.
Initial blood investigations include arterial blood gas-
Forrester’s triage of patients es, hemoglobin, cardiac troponins, brain natriuretic
peptides and kidney and liver function tests and
Figure 2: Forrester’s Stages Of Heart Failure Based serum electrolytes. Chest X-ray aids in diagnosing
On Clinical Assessment And Hemodynamic Correla- pulmonary venous congestion, cardiomegaly as well

Figure 2: Forrester’s Stages of Heart Failure Based on
Clinical Assessment and Hemodynamic Correlation

GCDC 2017

Cardiogenic Shock: 57
Etiopathogenesis & Clinical Recognition

as in ruling out pneumothorax. An electrocardiogram III COLD- <2.2/<18 23 % 17 %
(ECG) reveals sinus tachycardia or underlying arrhyth-
mias if any. Also it helps in detecting a coronary eti- DRY
ology by revealing exaggerated ST-T changes. Non-
specific findings in an ECG usually seen in cardiomy- IV COLD- <2.2/>18 51 % 40 %
opathy are the diffuse low voltage complexes, mild
ST-T changes and conduction system abnormalities. WET

Evidence of primary cardiac failure has to be made (Table 2) : Forrester’s and Fonarow’s Prognostication
by 2D-echocardiography. Once an echocardiographic of Heart Failure Based on Clinical Assessment
documentation of myocardial pump failure is made,
investigations should be directed to rule out acute Conclusion:
coronary syndromes with aid of an electrocardio-
gram. Acute MI presenting as cardiogenic shock Cardiogenic shock is a clinical syndrome caused
should be offered early revascularization preferably primarily by myocardial pump failure due to diverse
by percutaneous coronary interventions. Mechanical etiologies. The diagnosis of cardiogenic shock in a
circulatory support devices like Intra-Aortic Balloon patient suggests poor short term as well as long
Pump or Extra-Corporeal Membrane Oxygenation term prognosis. Hence lays the importance of ear-
may be offered to the sick patients in cardiogenic ly recognition and instituting appropriate therapy. In
shock. Similarly acute mechanical causes of cardio- spite of developments in management of cardiogenic
genic shock like acute mitral or aortic regurgitation shock, the mortality as well as rehospitalisation rates
or ventricular septal rupture or free wall rupture need continue to be very high. Future research should be
to ruled out by echocardiography so that timely sur- directed towards unmet needs in the management
gical interventions may be offered. One should have of cardiogenic shock.
a high clinical suspicion of pulmonary embolism or
aortic dissection as etiologies of unexplained cardio- References
genic shock. CT should be offered to such patients to
expedite the diagnosis of these conditions. 1. Vincent JL, De Backer D. Circulatory shock. N Engl J Med 2013;
369:1726.
Prognosis of Cardiogenic Shock:
2. Rodgers KG. Cardiovascular shock. Emerg Med Clin North Am 1995;
Hospital mortality rates range from 50-80% depend- 13:793.
ing on the etiology of cardiogenic shock and other
prognosticators like age, gender, comorbidities and 3. Califf RM, Bengtson JR. Cardiogenic shock. N Engl J Med. 1994;330:1724-
multi-organ involvement.(11) Cardiogenic shock is the 30.
leading cause of death in patients with acute MI
wherein the hospital mortality rates approach 50% in- 4. Holmes DR Jr, Berger PB, Hochman JS, et al. Cardiogenic shock in
spite of offering the best-of-care available. The 5 year patients with acute ischemic syndromes with and without ST-segment
mortality is approximately 60%. (4) The ESC-HF pilot elevation. Circulation 1999;100:2067–73.
study(12) studied reveals that the 12 month all-cause
mortality and hospitalization rates for hospitalized 5. Hochman JS, Boland J, Sleeper LA, Porway M, Brinker J, Col J, et al.
heart failure patients were 17% and 44% respectively. Current spectrum of cardiogenic shock and effect of early revasculariza-
Forrester’s and Fonarow’s sub grouping (13) of cardio- tion on mortality. Results of an International Registry. SHOCK Registry
genic shock based on hemodynamic characteristics Investigators. Circulation. 1995;91:873-81.
also helps in assessing the in-hospital mortality out-
comes 6. Handler CE. Cardiogenic shock. Postgrad Med J. 1985;61:705–12

Stage Clinical Cardiac In-hos- 6 month 7. Knobel E. Cardiogenic shock. Arq Bras Cardiol volume 72, (nº 4), 1999
of Heart Recogni- Index pital hospital
Failure tion / PCW mortality mortality 8. Barber AE, Shires GT. Cell damage after shock. New Horiz 1996; 4:161.
Pressure
I WARM- >2.2/<18 3% 11 % 9. Forrester  JS, Diamond GA, Swan HJC. Correlative classification of clin-
DRY ical and hemodynamic function after acute myocardial infarction. Am
II WARM- >2.2/>18 9% 22 % J Cardiol 1977 Feb;39(2):137-45
WET
10. Ho KK, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart fail-
ure: the Framingham Study. J Am Coll Cardiol. 1993 Oct. 22 (4 Suppl
A):6A-13A

11. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the
diagnosis and treatment of acute and chronic heart failure: The Task
Force for the diagnosis and treatment of acute and chronic heart failure
of the European Society of Cardiology (ESC) developed with the special
contribution of the Heart Failure Association (HFA) of the ESC. Eur
Heart J2016;37:2129-2200

12. Maggioni A.P, Dahlstrom U,  Filippatos G, et al. EURO observational
Research Programme: the Heart Failure Pilot Survey (ESC-HF Pilot) Eur
J Heart Fail, 12 (2010), pp. 1076-1084

13. Fonarow G.C, Weber J.E. Assessment and treatment of acute heart
failure Clin. Cardiol. Vol. 27 (Suppl. V) September 2004

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58 Cardio Diabetes Medicine 2017

Progressive Heart Failure –Etiopathogenesis,
Invasive and Noninvasive Evaluation

Dr. G. Justinpaul, Professor Cardiology,

Madras Medical College

Dr. J. Cecilymarymajella, Assistant Professor Cardiology

Madras Medical College

ABSTRACT of progressive and declining ventricular function,
following an initial cardiac insult with or without an
The term‘progressive heart failure [PHF]’ is used intervening period of stable heart failure. Data and
to describe patients with increasing severity of evidence show that autonomic and neuro-humoral
symptoms, frequent decompensation and pro- mechanisms play a crucial role in this progressive
gressive cardiacdysfunction. The aetio-pathogen- decline in cardiac function. Drugs which specifically
esis of heart failure is varied and diverse among inhibit neurohumoral mechanisms have been shown
various parts of the world. Early and prompt iden- to prolong survival by slowing disease progression.
tification of these diverse pathologies is an im- Variables that help in reflecting the magnitude of
portant part of the diagnostic armamentarium, as neurohumoral dysfunction, will be useful to identify
they would offer better therapeutic opportunities. patients with chronic compensated heart failure who
are at an increasedpropensity in entering a decom-
Over the last 3 decades, advancements in treatment pensated spiral of declining ventricular function, de-
protocols have improved survival rates and de- clininghemodynamics, and mortality due to progres-
creased the rate of hospitalization and reduced the siveheartfailure.
rate of progression in heart failure patients. Accurate
evaluation and estimation of prognosis for morbidity DEFINITION OF HEART FAILURE
and mortality helps patients, their family members
and treatingphysicians to plan the appropriate ther- HF is a clinical syndrome characterized by typical
apies. Numerous prognostic markers of progressive symptoms (e.g. breathlessness, ankle swelling and
heart failure have been recognized and validated. fatigue) that may be accompanied by signs (e.g. el-
But their clinical utility and application is limited and evated jugular venous pressure, pulmonary crackles
precise risk stratification in progressive heart failure and peripheral edema) caused by a structural and/
remains a great challenge. Cardiac imaging plays a or functional cardiac abnormality, resulting in a re-
pivotal role in the diagnosis of heart failure and aids duced cardiac output and/or elevated intracardiac
in guiding and planning treatment protocols. pressures at rest or during stress.

INTRODUCTION: The current definition of HF restricts itself to stag-
es at which clinical symptoms are apparent. Before
Heart failure is a syndrome where tremendous ad- clinical symptoms become apparent, patients can
vancementin understanding the etiopathogenetic, present with asymptomatic structural or functional
pathophysiology, diagnosis and treatment modali- cardiac abnormalities [systolic or diastolic left ven-
ties have taken place in the last few decades. Yet tricular (LV) dysfunction], which are precursors of HF.
mortality rates in ambulatory HFpatientscontinue Recognition of these precursors is important because
to hover around10% per year. A major proportion they can guide the therapy, starting therapy early can
of these deaths are primarily due to a progressive improve prognosis and left untreated they lead to
and rapid decline in left ventricular function. It is not poor outcome.
yet clear why some individuals enter into a phase
Classification of Heart failure: Patients with HF are
often classified with respect to the LVEF, as this has

GCDC 2017

Progressive Heart Failure –Etiopathogenesis, Invasive and 59
Noninvasive Evaluation

a lot of therapeutic and prognostic implications. nephrine and angiotensin II play pivotal roles in pro-
moting progressive heart failure Tailored heart fail-
• HF with reduced EF [HFrEF] : HF patients with uretherapy requires the identification and treatment
LVEF < 40% of the detrimental pathophysiological factors in each
individual patient.
• HF with preserved EF [HFpEF] : HF patients with
LVEF ≥50% Heart failure patients suffer from recurrent hospi-
talization. With each hospitalization, there is likely
• HF with midrange EF [HFmrEF]: HF patients myocardial and renal damage which contributes to
withLVEF40–49% progressive LV or renal dysfunction, leading to an in-
evitable downward spiral. Comprehensive strategies
Stages of Heart failure is often looked at 4 stages. should focus on factors during hospitalization and
They include also during the early recovery period soon after dis-
charge to target stressors that probably contribute to
• Stage A : High risk of developing heart failure the vulnerability of patients.

• Stage B : Asymptomatic LV dysfunction PREDICTORS OF PROGRESSIVE HEART
FAILURE:
• Stage C : Past or current symptoms of HF
Heart rate variability and progressive heart failure:
• Stage D : Refractory of end stage heart failure A reduced value of SDNN, is a very important and
independent predictor of progressive heart failure
If chronic stable HF deteriorates, suddenly or slowly, and mortality. SDNN is the standard deviation of all
often leading to hospital admission, the condition is normal-to-normal RR intervals in the ECG. Patients
described as ‘decompensated’ HF with progressive heart failure have increased sym-
pathetic nerve activation,increased cardiac norepi-
The term progressive heart failure is used to de- nephrine spillover, elevated plasma catecholamine &
scribe patients with progressive increase in severity renin levels, decreased vagally mediated heart rate
of symptoms, recurrent decompensation and severe fluctuations. All these factors contribute or reduction
cardiac dysfunction of SDNN observed in progressive heart failure.

AETIOPATHOGENESIS OF PROGRESSIVE SDNN is a potential marker for changes in myocardi-
HEART FAILURE al size and geometry, both of which may be involved
with heart failure progression. This also could be a
An intricate interplay of underlying pathophysiolog- reason for reduction of SDNN observed in progres-
ical mechanisms determines the progression and sive heart failure. A recent study shows that chronic
clinicalpresentation of heart failure. The process ofre- sinoatrial node stretch reduces HRV, suggesting that
modelling and neurohumoral activation, through cen- SDNN may be a marker for adverse changes of car-
tral and peripheral mechanisms, increases suscepti- diac structure.
bility toarrhythmias and exacerbates the progression
of ischaemic disease and heart failure. Ischaemia in- Hyponatremia and progressive heart failure: Serum
duces arrhythmias and myocardialinfarction, which in sodium correlates closely with plasma renin activity.
turn may cause increased neurohumoral activation Hyponatremia in patients with chronic heart failure
and cardiac remodelling. has been shown tobe a predictor of progression and
mortality from pump failure. Lee and Packer reported
Patients with progressive heart failure have increased that patients with severe chronic HF (with mean EF
sympathetic nerve activation(8), cardiac norepineph- ∼17%) and serum sodium levels <137 mmol/l) have a
rine spillover (an index of sympathetic nerve traffic to life expectancy half that of patients with serum so-
the heart, and elevated plasma catecholamine, and dium levels >137 mmol/l. In another study Lee and
renin levels. Packer, showed that patients whose serum sodium
levels increased in response to ACE inhibition had
The decrease in vagally mediated heart rate fluctu- a better prognosis. The mechanism by which hypo-
ations in patients with heart failure is directly pro- natremia predicts HF progression may involve neu-
portional to the level of muscle sympathetic nerve rohumoral activity, including particularly that of the
activity and plasma norepinephrine levels. renin-angiotensin-aldosterone system.

The intimate relationship between the sympathetic Serum creatinine and progressive heart failure: Alter-
and renin-angiotensin-aldosterone systems, is that
stimulation of one increases activity of the other.
Both norepinephrine and angiotensin II are strong
promoters of cardiac myocyte hypertrophy and ne-
crosis/ There is compelling evidence that norepi-

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60 Cardio Diabetes Medicine 2017

ations of fluid and electrolyte homeostasis are very 5. Left ventricular end-systolic diameter
important in the pathophysiology of chronic HF. Re-
cent data highlight the value of impaired renal func- 6. Left ventricular hypertrophy by ECG
tion as a marker for increased risk of progression and
death in chronic heart failure. Hillege et al., in a ret- 7. Increased age.
rospective analysis showed that creatinine clearance
derived from serum creatinine, body weight, and age 8. Calculated eGFR
is the most powerful predictor of all-cause mortality
in patients LVEF< 49$ and NYHA functional class In multivariate analysis, reduced SDNN and serum
III to IV symptoms.Dries et al. (1), in a retrospective sodium and creatinine remained independent and
analysis of the Studies of Left Ventricular Dysfunc- specific predictors of progressive HF irrespective of
tion (SOLVD) database, demonstrated that moderate the EF and etiology of Chronic HF. They could iden-
renal insufficiency is an independent predictor of all- tify patients with relatively mild disease who are at
cause mortality and progressive heart failure.Each high risk of death specifically due to progressive
10 μmol/l increment of creatinine level increases the HF over a five-year period. 24-h frequency-domain
risk of a progressive HF death by ∼14%.Thus, it ap- measurements of HRV did not provide additional
pears that renal dysfunction per se may contribute prognostic information over the simple time-domain
to HF progression. The mechanisms underlying this measurement SDNN.
detrimental cardiorenal interaction warrant further in-
vestigation. DIAGNOSTIC WORKUP FOR PROGRESSIVE HEART
FAILURE
INDEPENDENT PREDICTORS OF DEATH
SPECIFIC TO PROGRESSIVE HF 1. Symptoms and signs of heart failure: A detailed
history symptoms and signs of HF need to be
In ambulant outpatients with chronic HF, low serum assessed, every visit, with particular attention to
sodium and low SDNN (Standard deviation of all nor- evidence of congestion to monitor a patient’s re-
mal-to-normal RR intervals) and high serum creati- sponse to treatment and stability over time. Per-
nine identify patients at increased risk of death due sistence of symptoms despite treatment usually
to progressive HF. Identifying patients at risk of death indicates the need for additional therapy. Wors-
specifically from progressive HF may help to tailor ening of symptoms suggests progressive heart
further investigation or therapy to prevent death and failure, and merits prompt medical attention.
hospitalization from progressive heart failure.
2. Natriuretic peptides: Elevated natriuretic peptides
The United Kingdom Heart Failure Evaluation and (NPs) help establish an initial working diagnosis,
Assessment of Risk Trial (UK-HEART) was prospec- identifying those who require further cardiac
tively designed to assess the variables that specifi- investigation. The upper limit of normal in the
cally identify patients at increased risk of death due non-acute setting for B-type natriuretic peptide
to progressive HF. The following parameters were (BNP) is 35 pg/mL and for N-terminal pro-BNP
considered; Time-domain analyses of HRV, Fre- (NT-proBNP) is 125 pg/mL. In the acute setting,
quency-domain HRV analyses, Multifrequency bio- higher values should be used [BNP < 100 pg/
electrical impedance analysis [noninvasive estimate mL, NT-proBNP< 300 pg/mL and mid-regional
overload of extracellular water/ total body water], pro A-type natriuretic peptide (MR-proANP) < 120
ECG variables, Echo parameters, Chest X ray, clin- pmol/L] as upper limits of normal. Diagnostic val-
ical variables etc. ues apply similarly to HFrEF and HFpEF; on aver-
age, values are lower for HFpEF than for HFrEF.
of all the parameters assessed, eight variables pro- With these exclusionary cut-points, the negative
vided independent prognostic information that iden- predictive values are high (0.94–0.98) but the
tified patients at increased risk of death from any positive predictive values are lower both in the
cause non-acute and acute setting (0.44–0.67). NPs are
thus recommended more for ruling-out HF, than
1. SDNN to establish the diagnosis.

2. Reduced Serum sodium and creatinine, 3. Electrocardiogram. An abnormal (ECG) increases
the likelihood of the diagnosis of HF, but has low
3. Increased Cardiothoracic ratio specificity. HF is unlikely in patients presenting
with a completely normal ECG (sensitivity 89%).
4. Non-sustained ventricular tachycardia Some abnormalities on the ECG provide informa-

GCDC 2017

Progressive Heart Failure –Etiopathogenesis, Invasive and 61
Noninvasive Evaluation

tion on etiology (e.g. myocardial infarction), and workup in case of initial evidence of HFpEF/
findings on the ECG might provide indications HFmrEF and consists of objective demon-
for therapy (e.g. anticoagulation for AF, pacing stration of structural and/or functional alter-
for bradycardia, CRT if broadened QRS complex) ations of the heart as the underlying cause
Therefore, the routine use of an ECG is mainly for the clinical presentation. Key structural
recommended to rule out HF. alterations are a left atrial volume index
(LAVI) >34 mL/m2 or a left ventricular mass
4. Chest x-ray: A chest X-ray is probably most use- index (LVMI) ≥115 g/m² for males and ≥95 g/m²
ful in identifying an alternative, pulmonary expla- for females.Key functional alterations are an
nation for a patient’s symptoms and signs. The E/e′≥13 and a mean e’ septal and lateral wall
chest X-ray may show pulmonary venous con- <9 cm/s. Other echocardiographically de-
gestion in a patient with HF, and is more helpful rived measurements are longitudinal strain
in the acute setting than in the non-acute setting. or tricuspid regurgitation velocity (TRV).
It is important to note that significant LV dysfunc-
tion may be present without cardiomegaly on the b) A diastolic stress test can be performed
chest X-ray. non-invasively with echocardiography, us-
ing a semi-supine bicycle ergometer with
5. Echocardiography: assessment of rest and exercise-induced
increases in E/e′, pulmonary artery pres-
a) Assessment of left ventricular systolic func- sures (TRV), systolic dysfunction (longitudi-
tion:For measurement of LVEF, the modified nal strain), stroke volume and cardiac output
biplane Simpson’s rule is the recommended etc.
method. Three-dimensional echocardiogra-
phy improves the quantification of LV vol- c) Alternatively, cardiac catheterization can be
umes and LVEF and has the best accura- done to assesshemodynamics at rest and
cy compared with values obtained through exercise to assess filling pressures [pulmo-
CMR.Doppler techniques allow the calcula- nary capillary wedge pressure (PCWP) ≥15
tion of haemodynamic variables, such as mmHg, left ventricular end diastolic pres-
stroke volume index and cardiac output, sure (LVEDP) ≥16 mmHg] pulmonary artery
based on the velocity time integral at the LV systolic pressure, stroke volume and cardiac
outflow tract area. Tissue Doppler parame- output.
ters, speckle tracking, 3D echo, stress Echo,
and deformation imaging techniques (strain d) Stress imaging (CMR, stress echo, SPECT,
and strain rate) have been shown to be of PET) in the assessment of myocardial isch-
more use, in detecting subtle abnormalities emia and viability in HF + CHD is given a
in systolic function in the preclinical stage. class IIb recommendation

b) Assessment of left ventricular diastolic func- f) Cardiac CT can be considered to rule-out
tion: LV diastolic dysfunction is thought to coronary arteries stenosis (class IIb)
be the underlying pathophysiological abnor-
mality in patients with HFpEF and perhaps e) CMR plays a role in identifying the structural
HFmrEF, and thus its assessment plays an and functional status of the myocardium. It
important role in diagnosis. The doppler flow can identify the myocardial edema fibrosis,
patterns of the AV valves, pulmonary, hepat- viability and ischemia.
ic and the venacavae, combined with tissue
doppler imaging of the AV valve annular mo- Diagnosis of HFpEF in patients with AF is difficult. AF
tion and AV valve flows, go a long way not by itself is associated with higher levels of NT-proB-
only in assessing but also grading diastolic NP or BNP. LAVI is also increased by AF A higher cut
dysfunction. Assessment of right ventricular off values may be needed which however have not
function and pulmonary arterial pressure is been established. Other functional parameters of dia-
important in identifying and prognosticating stolic dysfunction are less well established in AF. On
progressive heart failure the other hand, AF might be a sign of the presence of
HFpEF and patients with HFpEF and AF might have
6. Advanced Work up in Progressive heart failure: more advanced HF compared with patients with HF-
pEF and sinus rhythm.
a) Once progressive heart failure is suspect-
ed the next step comprises an advanced Cardiac imaging thus plays a central role in the di-
agnosis of HF and in guiding treatment. Of several

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62 Cardio Diabetes Medicine 2017

imaging modalities available, echocardiography is
the method of choice in patients with suspected HF,
for reasons of accuracy, availability, safety and cost.

CONCLUSION:

This article provides insights into the pathophysiolo-
gy and diagnosis of progressive HF. Simple analysis
of 24-h ambulatory electrocardiograms and measure-
ment of serum sodium and creatinine levels identify
patients at increased risk for progressive heart failure.
SDNN a time domain variable of heart rate variability
and eGFR, remain strong independent predictors of
death due to progressive HF.These predictors refine
risk stratification of patients who may progress to ad-
vanced heart failure and identify patients who merit
aggressive medical treatment or complex therapeutic
regimes

REFERENCES

1. The SOLVD Investigators (1992) Effect of enalapril on survival in patients
with reduced left ventricular ejection fractions and congestive heart
failure. N Engl J Med 327:685–691.

2. Singh S.N., Fisher S.G., Carson P.E., et al. (1998) Prevalence and signif-
icance of nonsustained ventricular tachycardia in patients with prema-
ture ventricular contractions and heart failure treated with vasodilator
therapy. J Am Coll Cardiol 32:942–947.

3. Teerlink J.R., Jalaluddin M., Anderson S., et al. (2000) Ambulatory ventric-
ular arrhythmias in patients with heart failure do not specifically predict
an increased risk of sudden death. Circulation 101:40–46.

4. Nolan J., Batin P.D., Andrews R., et al. (1998) Prospective study of heart
rate variability and mortality in chronic heart failure. Results of the
United Kingdom Heart Failure Evaluation and Assessment of Risk Trial
(UK-Heart). Circulation 98:1510–1516.

5. Saul J.P., Arai Y., Berger R.D., et al. (1988) Assessment of autonomic
regulation in chronic congestive heart failure by spectral heart rate
analysis. Am J Cardiol 61:1292–1299.

6. Pomeranz B., Macaulay R.J.B., Caudill M.A., et al. (1985) Assessment
of autonomic function in humans by heart rate spectral analysis. Am J
Physiol 248:H151–153.

7. Coresh J., Astor B.C., McQuillan G., et al. (2002) Calibration and ran-
dom variation of the serum creatinine assay as critical elements of
using equations to estimate glomerular filtration rate. Am J Kidney Dis
39:920–929.

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Cardio Diabetes Medicine 2017 63

CVD in India

Dr. Ramasami Nandakumar

Singapore.

INTRODUCTION : Partially hydrogenated vegetable oils with high trans
fat content contribute to a significant proportion of
Cardiovascular diseases (CVDs) have now become total fat intake in Indians.
the leading cause of mortality in India. A quarter of
all mortality is attributable to CVD. Ischemic heart Also in India, the average blood pressure has in-
disease and stroke are the predominant causes creased in the past 2 decades, whereas in most
and are responsible for >80% of CVD deaths. CVD Western nations it has declined.
has emerged as the leading cause of death in all
parts of India, including poorer states and rural ar- In the urban areas of India, the prevalence of diabe-
eas. The Global Burden of Disease study estimate of tes mellitus has almost doubled in the past 20 years,
age-standardized CVD death rate of 272per 100 000 from 9% to 17%, and in rural areas it has nearly qua-
population in India is higher than the global average drupled, from 2% to 9%.47. In 2013, the International
of 235 per 100 000 population. Diabetes Federation estimated that 65.1 million peo-
ple in India had diabetes mellitus, a high proportion
Currently, in India, life expectancy has increased of whom were adults of working age. Diabetes melli-
from 58.3 to 65.2 years, resulting in the ageing of tus continues to have a positive social gradient (with
the population during the same period. Consequent- a higher burden among the rich and well educated).
ly, the NCD burden has increased rapidly in India. In
comparison with the people of European ancestry, Differences in CVD between Asians and
CVD affects Indians at least a decade earlier and in European populations:
their most productive midlife years. (23 vs 52%).
Studies among Indian migrants in various parts of
The progression of the epidemic is characterized by the world have documented an increased suscep-
the reversal of socioeconomic tibility to CHD in comparison to the native popula-
tion studied. In Britain, comparisons of age adjusted
gradients; tobacco use and low fruit and vegetable mortality statistics have shown a 40–60 per cent ex-
intake have become more prevalent among those cess in South Asian migrants (comprising Indian) in
from lower socioeconomic backgrounds. In addition, comparison to the population of England and Wales.
individuals from lower socioeconomic backgrounds Danaraj et al, in their seminal article in 1959, report-
frequently do not receive optimal therapy, leading to ed higher age-standardized mortality among Indians
poorer outcome. living in Singapore (even among individuals between
30 and 49 years of age) in comparison with other
Multiple factors contribute to the rise of the populations.
CVD epidemic in India.
In the United Kingdom, the prevalence of diabetes in
Tobacco use is increasing rapidly among young indi- South Asians approaches 15% to 20% and suggests
viduals (20–35 years) in India with a steeper rate of an interaction between genetic predisposition and
increase among those with lower education environmental influences, the so-called “thrifty gene”
hypothesis. In a contemporary, community-based
The rate of consumption of fruit and vegetables is study of Asian Indian immigrants in the Atlanta, Ga,
low in India.

Cardio Diabetes Medicine

64 CVD in India

area, the prevalence of diabetes was 18.3%, a rate higher fasting serum leptin and lower insulin sen-
markedly higher than reported for other populations sitivities, and stepwise regression analysis showed
in the United States, including whites, blacks, and that ethnicity was the only significant independent
Hispanics determinant variable for the differences in insulin
sensitivity index.
Diabetes may well serve as a link between potential
genetic predisposition and premature CAD in South CRP is the key inflammatory molecule associated
Asians- as levels of glucose intolerance, central with the metabolic syndrome in Caucasians, while C3
obesity (as measured by waist to hip ratio), fasting is the central inflammatory molecule in South Asians.
triglyceride, and insulin are uniformly elevated com- The mechanism for the increased C3 plasma levels in
pared to Europeans and these factors are key fea- South Asians with the metabolic syndrome is unclear
tures of the insulin resistance syndrome. but may be related to the close association between
insulin resistance and C3 in this population.
C reactive protein (CRP) concentrations are elevated
in South Asians, caused at least in part by a great- These changes in the south Asian population is mir-
er degree of central adiposity which promotes CRP rored in the East Asian population as Type 2 diabetes
expression. CRP is highly correlated with fasting and develops in East Asian patients at a lower mean body
post-load insulin, and independently predicts the risk mass index (BMI) and at any given BMI, East Asians
of IHD. PAI-1 and homocysteine concentrations are have a greater amount of body fat and a tendency
also raised in South Asians, and endothelial func- to visceral adiposity. DM develops at a younger age
tion is impaired; these may also contribute to the and is characterized by early B cell dysfunction in
elevation in IHD risk, either related to or separately the setting of insulin resistance, with many requiring
from their associations with insulin resistance. Poor early insulin treatment. The increasing proportion of
in utero development, resulting in low birth weight, in young-onset and childhood type 2 diabetes is pos-
particular coupled with catch up growth in early child- ing a particular threat, with these patients being at
hood, has been associated with a greater prevalence increased risk of developing diabetic complications.
of insulin resistance in South Asians. East Asian patients with type 2 diabetes have a
higher risk of developing renal complications than
Compared with European populations, South Asians European and with regard to cardiovascular compli-
have increased abdominal visceral fat and greater cations, a predisposition for developing strokes.
insulin resistance at similar levels of BMI. insulin re-
sistance is commonly noted in South Asians at BMI Cardiovascular disease in DM.
levels that are traditionally considered “ideal” (25 kg/
m2). This body type, often termed “thin-fat pheno- DM is an established risk factor for CVD in both
type” (muscle thin but body fat) is associated with men and women. Women with DM especially, seem
an increased risk of developing diabetes. to lose their inherent protection against developing
CVD.
Lipoprotein(a), homocysteine, and plasminogen ac-
tivator inhibitor- 1 levels tend to be higher in South CVD accounts for the cause of death in 65% of those
Asians than in white populations. Numerous studies with DM and acts as an independent risk factor for
have suggested that altered adipokine production or CVD. Once CVD develops prognosis is far worse in
action may play a role in the heightened vascular risk DM patients. Both type 1 and type 2 are independent
observed in South Asian patients. risk factors for CVD. Also with diabetic neuropathy
symptoms can be absent even with the presence of
Raji et al, found adiponectin levels were to be lower myocardial ischemia and multivessel atherosclerosis
in Asian Indians than in whites, which corresponded is often present by the time symptoms develop. Also
to increased whole-body insulin resistance, impaired the development of myocardial dysfunction due to
fibrinolysis, and altered endothelial function in this DM leads to accelerated heart failure due to a com-
population. Low adiponectin levels in nondiabetic bination of atherosclerosis, hypertension, chronic hy-
South Asians may not only confer increased vascu- perglycemia, microvascular disease, glycosylation of
lar risk but also may be linked to the development myocardial proteins and autonomic neuropathy.
of diabetes in Asian Indians.
DM also increase the mortality from stroke 3 fold and
In a study by Liew et al, 44 healthy, nondiabetic usually causes occlusion of small paramedical pen-
Asian Indians were compared with white and Chinese etrating arteries and increases likelihood of carotid
subjects living in Singapore with respect to insulin atherosclerosis. 13% of those with DM >65 years have
sensitivity and leptin levels. Indians had significantly had a stroke and are more likely to develop irrevers-

GCDC 2017

Cardio Diabetes Medicine 2017 65

ible brain damage with carotid emboli. subjects. In conclusion, asymptomatic South Asian
patients with type 2 DM have a higher prevalence
Difference in CVD between Diabetics and and extent of CAD compared with matched Cauca-
non diabetics. sian patients.

Patients with diabetes had a significantly higher cal- Approaches to diagnosis and treatment:
cium score compared to non-diabetics. Coronary ath-
erosclerosis was observed in 80% of diabetics and There is need to have a multi Pronged strategy to
almost half showed obstructive CAD. address the growing epidemic of DM and CVD.

A large autopsy cohort of 293 diabetic decedents A strategy of promotion of smoking/tobacco ces-
showed coronary atherosclerosis in almost 75% of in- sation, physical activity, and healthy dietary habits
dividuals, with 50% having diffuse multi-vessel CAD. should prevent risk factors from occurring in the first
place by providing information and an enabling en-
Since calcium deposition is related to the presence vironment for increasing awareness and adoption of
of atherosclerosis, coronary calcifications serve as a health living habits by the community
direct marker for CAD, and more severe plaques tend
to have a greater amount of calcium. Primary prevention should focus on early detection of
persons with risk factors and cost-effective interven-
The type of coronary atherosclerosis may also differ tions for reducing risk by early screening and better
by ethnicity. A reappraisal of angiography studies in- control of risk factors (hypertension, hypercholester-
dicates that, compared to Europeans, South Asians olemia, and diabetes) to prevent incidence of overt
in the UK are more likely to have triple vessel dis- CHD.
ease, several lesions on angiography and non-dis-
crete. Compared with Caucasian patients, South Early detection of persons with clinical disease and
Asian patients had a significantly higher coronary cost-effective secondary prevention measures to pre-
artery calcium score and higher prevalence of sig- vent complications to prevent premature mortality
nificant CAD (41% vs 28%, respectively, p = 0.008), and morbidity.
involving more coronary vessels and segments. Sig-
nificant CAD was especially more frequent in the left
anterior descending coronary artery.

Observations of smaller proximal LAD luminal diame-
ters and higher mean percent stenosis among South
Asians compared with Caucasians could reflect more
diffuse atherosclerosis in the South Asian group.
South Asians have smaller coronary artery luminal
diameters compared to Caucasians and reiterates a
possible role of coronary artery size in affecting in-
creased CAD risk and mortality among South Asians.

Differences between Asians and other
ethnic groups(West), in diabetics:

Increased LAD stenosis, despite equivalent levels of
calcified disease, in South Asians is attributable to
narrower arteries. Reduced LAD diameter is asso-
ciated with advanced disease in Europeans but not
in South Asians, indicative of ethnic differences in
vascular remodelling. Prevalence of obstructive CAD
is less influenced by symptomatic status in diabet-
ics with respect to non-diabetics. Extensive Coronary
calcium score (>400) is more prevalent in diabetic pa-
tients than nondiabetic pts but absence of coronary
calcium does not reliably exclude atherosclerosis or
even obstructive CAD in patients at high cardiovas-
cular risk and this may be especially true for diabetic

Cardio Diabetes Medicine

66 Cardio Diabetes Medicine 2017

Childhood and Youth Onset Diabetes in
India: Profile, Changes, Progress & Future ?

Dr. Anju Virmani, MD, DNB (Endocrinology) (AIIMS)

Senior Consultant Endocrinologist,
Max, Pentamed & SL Jain Hospitals, Delhi

Abstract Childhood and youth onset diabetes in India:
Profile, challenges, progress and future? 
Pediatric diabetes poses high medical, psychosocial
and financial burden, especially in resource con- Diabetes is the second commonest chronic disorder
strained and remote environments where supplies of childhood, but is extremely demanding in terms
and specialized team members may not be avail- of medical, social and financial burden on the family
able. T1D remains the commonest diagnosis, but and the health care team. In recent years, however,
T2D and other types are increasing. Challenges are awareness of the disorder and management options
many. Correct diabetes education, which is crucial, have improved dramatically, making it easier for a
may not be imparted if medical and para-medical per- child with diabetes to become a healthy, productive
sonnel are themselves not aware. Insulin may not be adult.
available where needed, with storage and transport
at 2-8°C. Multidose regimens based on daily self glu- The complexity of management means that ideally
cose monitoring, most appropriate for age, finances, the team looking after these children should consist
intelligence and motivation of patient/ family, may of a pediatric diabetologist, nurse – educator, psy-
not be advised. Safe disposal of sharps may not be chologist, dietician, with several supporting special-
advised. Unnecessary dietary and other restrictions ties, with access not just to insulin, but the necessary
can interfere with compliance, growth, and physical technology for administering insulin (syringes, pens,
and emotional development. Adequate monitoring of pumps), tracking glycemia (glucostrips, continuous
A1C, growth and puberty, and for co-morbidities (eg glucose monitoring systems i.e. CGMS), and for mon-
hypothyroidism, celiac) and chronic complications, itoring for acute as well as chronic complications. In
and timely treatment, may not be done. Adequate the absence of a nation-wide registry, exact figures
financial and psychological support may be unavail- of incidence and prevalence cannot be given, but it
able. Poverty, illiteracy, and discrimination, in socializ- is estimated that presently India has about 70,000
ing, education, jobs and marriage, can further worsen children with diabetes [1]. These numbers and their im-
health and quality of life. pact are set to rise for a number of reasons. Till a few
decades ago, even pediatricians would not suspect
The challenges can be met by patients, families, diabetes in a drowsy or comatose child, breathing
HCP, charitable organizations, and society at large, rapidly, or dehydrated yet passing urine, or with pain
working together, using awareness, support, and abdomen, etc. Death before diagnosis or soon after
technology. Significant progress has been made: im- diagnosis will decrease as awareness and medical
proved insulin delivery (syringes, pens, pumps) and facilities increase. All forms of diabetes are becoming
monitoring (glucometers, CGMS) devices; range of in- more common as obesity increases (and the signifi-
sulins and drugs; better lab support; freely available cant overlap between type 1 diabetes (T1D) and type
information on the internet; multiple self-help groups. 2 (T2D) can cause confusion). As survival improves,
Extensive research of different aspects is ongoing: the burden of chronic complications will rise, as will
T1D prevention, oral insulins, better devices, and islet social issues, including education, employment, mar-
cell and pancreatic transplantation. riage, discrimination, etc. Poverty, often associated
with illiteracy, poor nutrition, and poor access to

GCDC 2017

Childhood and Youth Onset Diabetes in India: 67
Profile, Changes, Progress and Future ?

health facilities, has a major impact on all aspects a day, causing patients to suffer hypo-and hypergly-
of diabetes care: survival, glycemic control, rate of cemia daily. Both low and high BG interfere with ac-
acute and chronic complications, social problems, ademics and activity - the child cannot study or play
and quality of life. properly. They prescribe U-40 insulins even to ado-
lescents and adults, causing needless pain because
The absolute numbers as well as the proportions of of the greater volume. Very few patients are taught
different types of diabetes vary widely in different premeal BG testing to adjust insulin doses: instead,
regions and socio-economic strata. Thus, since the they are “prescribed” the insulin doses, regardless of
mid-1960s, north India has reported that over 90% BG level/ food/ activity levels. Often, the only aim is
of children and youth have T1D, the south has found to get “good” A1C levels, which is quite possible if
that as many as a third may have T2D, and eastern low and high sugars average out, leaving the patient
India a higher proportion of pancreatic diabetes. Mal- miserable, but the doctor happy!
nutrition related diabetes (MRDM) seems to occur far
less, while gestational diabetes occurs far more. As Insulin requires storage at proper temperatures. This
genetic tests become more accessible, more patients means ensuring proper storage and transport - an
with confusing clinical presentation or course will be effective cold chain, and precautions at home - till the
diagnosed with specific types of diabetes. last drop is used. Making insulin available in remote
areas, and with erratic electricity i.e. refrigeration in
The challenges posed by pediatric diabetes in our a country with extremes of climate, and educating
country and elsewhere are enormous. Let us start not only patients but also everyone in the distribution
with diagnosis. A 5 year old presenting in diabetic ke- network of the importance of this aspect is a daunt-
toacidosis (DKA), with a history of recent weight loss ing challenge. [3] Technology to detect whether a vial
and bedwetting, is easily diagnosed as having T1D, has been exposed to high temperatures does exist
and getting GAD-65 or other antibodies, or C-peptide and is used routinely and widely for oral polio vac-
levels done may be unnecessary. Parents can safely cine, but unfortunately the insulin companies have
be told that the child will need multiple daily doses of not seen fit to apply this to insulin vials. Injection
insulin life-long. The obese 15 year old with acantho- technique is also vital for proper action. [4]
sis and hirsutism, found to have high blood glucose
(BG) during work up for polycystic ovarian syndrome Good glycemic control needs frequent self BG mon-
(PCOS), may also not pose any diagnostic dilemma – itoring (SBGM). [2] If the family is taught how to
she has T2D and needs metformin, with weight loss. utilize BG tests for dose adjustments, they can en-
However, what if an obese 12 year old with acantho- sure glycemic control while maintaining flexibility of
sis and skin tags, presents in DKA, with history of lifestyle. Unless taught how to balance food, activity
losing 3 kg in the past month? She is more likely to and insulin doses using BG testing, they soon stop
have T2D - here antibody or C-peptide testing may testing, since this does add to the pain, cost and in-
be helpful. Or a lean 16 year old has surprisingly well convenience of diabetes care. The physician is then
controlled diabetes, and father has a similar history? given excuses (“I forgot the diary at home”), or blank
Here testing for MODY may help. diaries, or diaries neatly filled with fabricated values
(“Doctor scolds me if the diary is blank”)! It is cru-
Next is treatment. Standard of care today [2] is mul- cial to make sure that patients use only glucome-
tiple doses of insulin, whether by injection (multiple ters with memory, and bring the glucometers with
daily doses of insulin or MDI), or continuous subcu- them at each clinic visit. This ensures that if the BG
taneous insulin injection (CSII using insulin pumps), have not been recorded, they can be retrieved from
on a basal bolus regimen, the doses being modu- the meter so that some assessment can be made of
lated by pre-meal BG testing, and if possible, taking glucose patterns. Conversely, if the BG values have
carb count into account. Reasonable glycemic control been fudged, then the physician or educator will not
is possible with syringes and conventional insulins, be misled into giving wrong advice.
with regular insulin given before each meal, and a
longer acting insulin to cover the night. Designer A basic dictum is there is no special “diabetic diet”:
insulins can be advised to people who can afford the person with diabetes should have a sensible,
them, only if necessary. Unfortunately, many physi- balanced diet, as should everyone else. However,
cians prescribe these insulins, which cost 3-10 times misguided health care personnel (HCP) may advise
the conventional insulins, even to poor families, thus several dietary restrictions, only for the child, making
needlessly increasing the financial burden and com- normal life difficult, and school treats, festivals, func-
promising care. On the other extreme, many physi- tions, and parties huge obstacles. This can force the
cians continue to prescribe premixed insulins, twice child and family to become social recluses, and/ or

Cardio Diabetes Medicine

68 Cardio Diabetes Medicine 2017

tell the health care team lies. An over-restricted diet cian/ psychologist not well versed in T1D care can
can result in poor nutrition, interfering with the child’s result in poor glycemic control, complications, and
growth and development. The entire family must be poor quality of life.
taught how to “eat healthy, yet tasty”, and adjust on
special occasions. Therefore, the challenges faced by patients, families,
HCP, and society at large, are varied and may seem
Equally, the child with diabetes should have daily insurmountable. Fortunately, there have been many
play and activity, as should everyone else. However, changes and advances since the discovery of insulin
activity levels are decreasing steadily in our country, made it possible for children with diabetes to even
especially in urban areas. With diabetes, the situa- survive.
tion is worse if the child is considered “sick”, and
therefore discouraged from play and sports; or con- Awareness among HCP has meant diabetes is di-
versely forced into long hours of activity as a way of agnosed earlier, often before severe DKA develops.
decreasing or avoiding insulin doses. This means better survival, lesser costs, especially
since treatment and education can be initiated on an
Regular SBGM must be supplemented by 3-monthly outpatient basis. A few centers in India are now pro-
testing of A1C, testing for autoimmune disorders and viding gene testing for better diagnosis of neonatal
chronic complications, as well as growth and puberty. diabetes as well as MODY.
[5] Short stature and/or delayed puberty worsen body
image and self-esteem. Hypothyroidism or celiac dis- There is a greater willingness among doctors to
ease may cause few/ no symptoms, and be missed refer to teams with expertise in pediatric diabetes,
for long periods, further compromising health. These and among of patients to seek such teams. Families
tests also add to pain, cost and inconvenience, so willing and able to travel to a city for care every 3-4
patients may avoid or delay clinic visits, again com- months, can benefit not only from better advice, but
promising care. Early detection and treatment of also access insulin and other supplies at lower cost
these disorders, of hypertension, and of micro- or and better quality. Families can also access peer sup-
macro-angiopathic complications can prevent wors- port and information about facilities through social
ening. media.

Insulin use and BG monitoring generate sharps at the Availability of better devices to administer insulin
home level. In a country where even hospitals and has improved diabetes care: insulin syringes with
laboratories discard sharps carelessly, educating pa- near-painless 31G needles; insulin pens with 0.5 unit
tients to dispose them off safely may seem pointless. insulin increments, 31G and 4 mm pen needles; and
It is nonetheless important we teach our patients to feature-rich insulin pumps. Carefully reusing syringes
be careful at home, and also vigilant outside, de- or pen needles (and BG lancets) 2-10 times reduces
manding safety from health care institutions. [6] costs. Pumps provide insulin in the most physiologi-
cal way, but need money and intelligence. A range of
The complexity of diabetes care and its impact on insulin analogs, from ultra-short acting to ultra-long
daily life of the entire family means marked psycho- acting, have made MDI easier, with glycemic control
logical stress, leading to poor self-care, marital dis- close to what CSII can achieve. Over the past few
cord, even harming behaviors. The problems affect all decades, conventional insulins have become less
aspects of diabetes care, and are particularly severe expensive, poverty has come down, mobiles have
during adolescence. [7] They may lead to risk taking become ubiquitous, self-help groups and charita-
behavior like inducing hypoglycemia with surrepti- ble agencies (international and local) are providing
tious high doses of insulin, smoking, drugs and sex. support, so the possibility of a child dying for lack
The issues have to be recognized, and handled with of insulin is gradually decreasing. Similarly, as glu-
care, expertise and patience. In addition, issues such costrips become cheaper, and SBGM awareness in-
as discrimination, in education, jobs and marriage, creases, more children are using SBGM. Continuous
need to be flagged and tackled, at social and legal glucose monitoring systems (CGMS) of varying pric-
levels. es and accuracy becoming available to those who
can afford them, has improved glycemic control and
All this involves long hours of diabetes education, quality of life. These provide more information, and
without which diabetes care is considered substan- better memory, so reducing the stress of monitoring
dard. [8] This is possible only if the patient has access and the need or likelihood of falsifying information.
to well-trained diabetes educators, dieticians and Closed loop pumps (“artificial pancreas”) combine
psychologists familiar with T1D. [8] Care by a general CGMS with CSII, and may provide solutions which
physician/ pediatrician/ “adult” diabetologist/ dieti-

GCDC 2017

Childhood and Youth Onset Diabetes in India: 69
Profile, Changes, Progress and Future ?

biological options like pancreatic or islet cell trans- 6. Societal, emotional, financial, and other support
plants cannot. More accurate testing for A1C, lipid is needed periodically.
levels, microalbuminuria, etc., including point of care
(POC) testing, and widespread availability of tests 7. Regular monitoring of A1C, growth and puberty,
such as TSH and transglutaminase, have made long co-morbidities and chronic complications is es-
term monitoring easier. sential.

Teams and individuals providing focused care to chil- 8. Technology and awareness are improving: the
dren and youth with diabetes are gradually increasing challenges can be met by patients, families, HCP,
in number, particularly in urban areas. The greater charitable organizations, and society at large,
availability of pediatric endocrinologists, diabetolo- working together.
gists with special interest in pediatric diabetes, and a
few diabetes educators, dieticians and psychologists REFERENCES
trained in pediatric diabetes, is changing the lives
of those who can reach them. Self-help groups are 1. IDF Diabetes Atlas, seventh edition, 2015. Page 14.
playing an increasing role in providing psychological,
social and financial support to each other, in person 2. Danne T, Bangstad H-J, Deeb L, Jarosz-Chobot P, Mungaie L, Saboo B,
or through social media; and reducing costs by bulk Urakami T, Battelino T, Hanas R. Insulin treatment in children and
purchases or charity. Information is more freely avail- adolescents with diabetes. Pediatric Diabetes 2014: 15 (Suppl. 20):
able in the most remote of areas, on the internet – to 115–134
HCP, and to patients and families, especially Guide-
lines from respected organizations like the Interna- 3. Ranabir S. Managing type 1 diabetes in remote and challenging locations
tional Society for Pediatric and Adolescent Diabetes in India. Indian J Endocr Metab 2015; 19, Suppl S1: 29-30.
(ISPAD), Indian Society for Pediatric and Adolescent
Endocrinology (ISPAE) and the American Diabetes 4. Tandon N, Kalra S, Balhara YPS, Baruah MP, Chadha C, Chandalia HP, et
Association (ADA). al. Forum for Injection Technique and Therapy Expert Recommendations,
India: The Indian Recommendations for Best Practice in Insulin Injection
Extensive research by different agencies is exploring Technique, 2017. Indian J Endocr Metab 2017; 21 (4): 600-617.
a wide variety of aspects, including prevention of T1D,
better insulins (including oral or inhaled insulin) and 5. Virmani A. Growth disorders in type 1 diabetes: an Indian experience.
other drugs, better devices (including pumps with in- Indian J Endocr Metab 2015; 19, Suppl S1: 64-67.
sulin and glucagon or insulin and pramlintide), islet
cell and pancreatic transplantation. 6. Virmani A. Safe disposal of used sharp objects. Indian Pediatr 2009;
46: 539.
In summary, the scenario faced by a child with T1D
is daunting, but improving. 7. Puri S, Vedwal AK, Virmani A. A study of health seeking behavior in
families of children with type 1 diabetes. Indian J Endocr Metab 2016;
Abstracts, 21: 75.

8. Standards of Medical Care in Diabetes 2017. Diabetes Care 2017;40(Sup-
pl. 1): S105–S113.

HIGHLIGHTS

1. Pediatric diabetes poses several challenges and
high medical, psychosocial and financial burden,
especially in resource constrained and remote
environments where supplies and specialized
team members may not be available.

2. Health care personnel should be well versed in
pediatric diabetes care, and provide correct dia-
betes education.

3. Appropriate multidose insulin regimens must be
advised, based on self blood glucose monitoring.

4. Insulin availability, correct storage and transport,
and availability of adequate glucostrips is crucial.

5. Unnecessary dietary and other restrictions can
cause harm and must be avoided.

Cardio Diabetes Medicine

70 Cardio Diabetes Medicine 2017

The Applied Biochemical and Metabolic
Aspects of Diabetes and Heart

Dr. Siva Somana Rajasekar, MD., (Biochemistry),

Affiliation Laboratory Consultant, SAH Hospitals, Thoothukudi.

Abstract defects may occur includingresistance to exogenous
insulin. The mechanism for this includes the develop-
Diabetes mellitus is a chronic metabolic disease- mentof anti-insulin antibodies andinsulin resistance
causing hyperglycemia resulting in microvascular because of genetic and morphological factors(4).
and macrovascular complications contributing to the
increased morbidity and mortality and thereby to Type 2 Diabetes mellitus: Hyperglycaemia is due to
the disease burden in India. β-Cell destruction and elevated hepatic glucoseoutput and, to a lesser ex-
Insulin resistance results in hyperglycemia. In Insulin tent, failure of skeletal muscle totake up glucose and
resistance, Insulin fails to produce an increased store it as glycogen due to defective Insulin action.
peripheral glucose utilisation and to inhibit lipolysis Although manyfactors are believed to contribute to
resulting in dyslipidaemia characterised by elevated these two defects,they can broadly be categorized
triglycerides, reduced high-density lipoprotein (HDL), into three groups: β-Celldeficiency/dysfunction, insu-
and increased small dense low-density lipoprotein lin resistance and abnormalitiesof non-insulin-medi-
(LDL) particles. Insulin’s inhibition of platelet aggre- ated glucose disposal(4).
gation and fibrinolytic action due to modulation of
plasminogen activator inhibitor-1 (PAI-1) levels is de- Insulin resistance: Insulin resistance is ‘a state in
fective in Insulin resistance. New therapeutic targets which greater than normal amounts of insulin are
from the pathogenetic mechanisms of diabetes and required to elicit a quantitatively normal [glucose] re-
atherosclerosis may help to further improve their sponse’ (4)ie.an impaired biologic response to insulin
prognosis. (either exogenous or endogenous). It is manifested
by decreased insulin-stimulated glucose transport
The applied biochemical and metabolic and metabolism in adipocytes and skeletal muscle
aspects of Diabetes and Heart Background: and by impaired suppression of hepatic glucose
output. Insulin sensitivity is influenced by a number
Diabetes mellitus is a chronic disease which occurs of factors including age, weight, ethnicity, body fat
when the pancreas is not able to produce enough (especially abdominal), physical activity, and medica-
Insulin (Type1) or when the body cannot utilise Insulin tions. There is also a strong influence of environmen-
effectively(Type2). Raised blood sugar levels in diabe- tal factors on the genetic predisposition to insulin
tes over time results in serious damage to nerves and resistance and therefore to diabetes (5)
blood vessels contributing to the increased morbidity
and mortality and thereby to the disease burden in
India. Among the 422million diabetics in the world,
60million people belong to India as per data till 2015
and this is projected to rise to 109 million diabetics
in India by 2035(1,2).The epidemic of diabetes is at-
tributed to the changes in dietary patterns, decreased
physical activity, population aging, and urbanization(3)

Biochemical Basis of Diabetes Mellitus

Type 1 Diabetes mellitus: β-Cell destruction is the
cause of type 1 diabetesmellitus, secondary metabolic

GCDC 2017

The Applied Biochemical and 71
Metabolic Aspects of Diabetes and Heart

Figure 1 : Insulin suppresses hepatic glucose production ofHDL particles by the liver and loss of apolipoprotein (Apo)
by direct and indirect mechanisms. In insulin resistance, A, resulting in low HDLconcentrations. The triglyceride-rich
the ability of insulin to suppress lipolysis in adipose tissue LDL particle is stripped of its triglycerides, resultingin the
and glucagon secretion by alpha cells in the islet results in accumulation of atherogenic small, dense LDL particles.(5)
increased gluconeogenesis. In addition, insulin inhibition
of glycogenolysis is impaired. Therefore, both hepatic and The probable mechanisms are:
peripheral insulin resistance result in abnormal glucose pro-
duction by the liver(5). 1. Non-enzymatic glycation of apolipoproteins im-
Highcirculating concentrations of alternative fuels pairs lipoprotein clearance.
such as triglycerides, NEFA, lactate and ketone
bodies compete with glucose for uptake and in their 2. Insulin inhibits lipolysis through inhibition of hor-
presence, glucose clearance is reduced. Insulin re- mone-sensitive lipase, which breaks down adi-
sistance is a consequence of ‘cellularsatiety’, seen pose tissue triglyceride and consequently mobi-
whenever intracellular sensors such as uridinedi- lizes fat stores for subsequent utilization. In dia-
phosphate (UDP)-glucosamine detect excess energy- betes, insulinmediated inhibition is attenuated or
supply(4).To maintain metabolic homeostasis, nutrient lost, so breakdown of fat stores carries on even if
intake exceeding expenditure whether carbohydrate, food is available. The uncontrolledrelease of free
protein, or lipid, are ultimately stored as triglyceride fatty acids is followed by their uptake by the liv-
in adipose tissue . If this storage capacity of adipose er in a simple concentration-dependent manner.
tissue is exceeded, lipids and other Free fatty acids are metabolized by β-oxidation,
Nutrients enter nonstorage tissues, such as myo- but once their concentration exceeds capacity
cytes, hepatocytes, vascular cells, and beta cells, for oxidationthey are re-esterified with glycerol
and trigger a variety of cellular responses that lead to formtriacylglycerol (triglyceride) which leads to
to insulin resistance and cellular dysfunction. increasedrate of synthesis (and thereby release)
Dyslipidaemia: Dyslipidaemia is said to be charac- of triglyceriderichvery low density lipoprotein
terised by elevated triglycerides, reduced high-den- (VLDL).
sity lipoprotein (HDL), and increased small dense
low-density lipoprotein (LDL) particles.(6) Diabetes is 3. PeripheralVLDL-triglyceride clearance may be
strongly associated with abnormalities of lipid me- impaired becauselipoproteinlipase, the principal
tabolism (fig.2). enzyme responsible for clearingVLDL-triglycer-
ide, is synthesis and secretion is induced by In-
Figure 2 Insulin resistance and dyslipidemia. The suppres- sulin(4).
sion of lipoprotein lipase and very low density lipoprotein
(VLDL) production by insulin is defective in insulin resis- 4. High density lipoprotein(HDL) acts as an anti-
tance, leading to increased flux of free fatty acids (FFAs) oxidant and thereby limitsthe lipid peroxidation,
to the liver and increased VLDL production, which results which is responsiblefor atheroma formation. The
in increased circulating triglyceride concentrations. The tri- overproduction of VLDL triglyceride in Diabetes
glycerides are transferred to low-density lipoprotein (LDL) mellitus results in increased transfer of VLDL
and highdensitylipoprotein (HDL), and the VLDL particles triglyceride to HDL particles in exchange for
gain cholesterol esters by the actionof the cholesterol ester HDL-cholesterol esters mediated by the choles-
transfer protein (CETP). This leads to increased catabolism terol ester transfer protein. The triglyceride-rich
HDL is hydrolyzed by hepatic lipase leading to
the generation of small HDL, which is degrad-
ed more readily by the kidneys, resulting in low
serum HDL levels contributing to the increased
cardiovascular risk in diabetes(9). Total plasma
cholesterolconcentration is often normal in type
2 diabetes, but theHDL: LDL and HDL:total cho-
lesterol ratios are usually low(4).

5. The composition of VLDL changes such thatit
contains more triglyceride and cholesteroyl es-
ters relativeto the apoprotein content. Cholester-
ol ester transfer protein–mediated exchange of
VLDL triglyceride for LDL-cholesterol esters and
subsequent triglyceride hydrolysis by hepatic li-
pase probably result in generation of the small,
dense LDLparticles (6). Theseabnormalities are

Cardio Diabetes Medicine

72 Cardio Diabetes Medicine 2017

particularly atherogenic and underlinethe need to compared with thosefrom healthy subjects.Moreover,
consider the whole lipid profile ratherthan just to- platelet reactivity and excretionof thromboxane me-
tal or LDL-cholesterol in the dyslipidaemiaof type tabolites are increased in obese patients withinsu-
2 diabetes(4). lin resistance and this phenomenon is reversed by
weight loss or 3-week treatment with pioglitazone(9).
Mechanism that links cardiovascular
disease and insulin resistance -The Body weight as well asimpaired insulin sensitivity
metabolic syndrome: may also account for the faster recoveryof cycloox-
ygenase activity despite aspirin treatment. Hypergly-
A constellation of metabolic derangements often cemia and insulin resistance alone may not explain
seen in patients with insulin resistance and T2DM the persistent cardiovascular risk burden associated
with an increased risk of cardiovascular disease have with type 2 diabetes. In this regard, adipose tissue
been designated as syndrome X. The profile includes dysfunction, inflammation, and release of aberrant
mainly dyslipidaemia comprising of hypertriglyceri- adipokines like leptin, adipocyte fatty acid-binding
demia, low plasma HDL, and small, dense LDL parti- protein, interleukins, may be particularly relevant(10).
cle concentrations. The normal vasodilative response These molecules may drive vascular dysfunction via
of insulin is disrupted in obese, insulin-resistant, and increased proliferation/migration of smooth muscle
diabetic persons and also through insulin’s inability cells, eNOS inhibition, and activation of NFkB signal-
to increase the production of the potent vasodilator ling with subsequent expression of adhesion mole-
nitric oxide by endothelial cells(7).An intrinsic defect cules and atherosclerosis(11).
invasodilation in Hypertensive patients might con-
tribute to insulin resistance by decreasingthe surface Hyperglcemia per se causing diabetic tissue
area of the vasculature perfusing skeletalmuscle, damage:
decreasing the efficiency of glucose uptake.Several
factors involved in clotting and fibrinolysis, including- Postulated mechanisms are:
fibrinogen, factor VII, and PAI-1, have been shownto
be increased in persons with insulin resistance (5). 1. Increased activation of the polyol pathway,where
aldosereductase involved in the reduction of tox-
Atherogenesis in Insulin resistance: ic aldehydes to their respective alcohols, is divert-
ed to reducing excess glucose to sorbitol, which
The atherogenic effects of insulin resistance are is later oxidized to fructose under conditions of
also due to changes in lipid profile such as high tri- intracellular hyperglycaemia. T his process con-
glycerides, low HDL cholesterol, increased remnant sumes the cofactor NADPH, which is then not
lipoproteins, elevated apolipoproteins B (ApoB) as available for the regeneration of reduced glutathi-
well as small and dense LDL. Atherogenic dyslip- one, thus rendering cells vulnerable to the effects
idemia is a reliable predictor of cardiovascular risk of oxidative stress(12).
and its pharmacological modulation reduces vascular
events in subjects with type 2 diabetes and metabolic 2. Slow accumulation over time of advanced gly-
syndrome(8). cation endproducts (AGEs), Glucose and amino
acids combine with matrix, cellular and plasma
Coronary events are triggered because of a pro- proteins to form unstable Schiffbase adducts,
thrombotic state in patients with insulin resistance. which undergo chemical rearrangement overtime
Under physiological conditions,insulin inhibits plate- to form Amadori products and, eventually, AGEs
let aggregation and thrombosis via tissue factor (TF) by nonenzymatic glycation. Advanced glycation
inhibition and enhanced fibrinolytic action due to endproducts are thought to cause tissue damage
modulationof plasminogen activator inhibitor-1 (PAI- by alterationsin the structure and function of the
1) levels. In contrast, insulin resistance facilitates ath- extracellular matrix and these changes maycon-
erothrombosis through increased cellular synthesis tribute to the endothelial dysfunction, basement
of PAI-1 and fibrinogen and reduced production of membranethickening and increased vascular
tissue plasminogen activator. permeability(7).

In platelets, lack of insulinleads to a down-regulation 3. Intracellular hyperglycaemia, by causing in-
of the IRS-1/Akt pathway resulting incalcium accu- creased diacylglycerol (DAG) concentration, may
mulation upon basal conditions. This lattermecha- cause further activation of theNFκB pathway via
nism explains why platelets from diabetic patients activation of protein kinase C (PKC).The end re-
show faster response and increased aggregation sult is vasoconstriction and hypercoagulabilityvia
increased endothelin-1, TGF-β and plasminogen-

GCDC 2017

The Applied Biochemical and 73
Metabolic Aspects of Diabetes and Heart

activator inhibitor 1 (PAI-1) generation and reduced explains interindividual variability in responsiveness to low-dose aspirin in
endothelialnitric oxide synthase production(6). patients with and without diabetes. J Thromb Haemost 2012;10:1220–
1230.
4. Shunting of excessiveintracellular glucose via
fructose 6-phosphate to glucosamine6-phos- 11. Li ZY,Wang P, Miao CY. Adipokines in inflammation, insulin resistance and
phate, a reaction catalysed by the amidotrans- cardiovascular disease. Clin Exp Pharmacol Physiol 2011;38:888–896.
ferases. Glucosamine 6-phosphate undergoes
furtherconversion to UDP N-acetyl glucosamine,
which, bybinding to serine and threonine resi-
dues on transcriptionfactors, leads to increased
proinflammatory cytokine activity(TGF-β, PAI-1
and others)(12).

CONCLUSION

The overlap of pathogenetic mechanisms of diabe-
tes and atherosclerosis seems promising to identi-
fytherapeutic targets shared by both diseases. Many
of the pro-atherogenic mechanisms of diabetes may
be related to hyperglycemia and thereby promote
macrovascular complications. Also aggressive thera-
py of cardiovascular risk factors other than diabetes,
i.e. hyperlipidemia or hypertension, canimprove the
long-term prognosis of diabetic patients with cardio-
vascular disease. Identifying and approaching new
therapeutic targets may help to further improve their
prognosis.

References:

1. International Diabetes Federation (IDF). IDF Diabetes Atlas. 7th ed.
2015.diabetesatlas‑seventh‑edition. [Last accessed on 2016 May 11].

2. World Health Organization. Global Report on Diabetes. 2016. Available
from: http://www.who.int/diabetes/global‑report/en/.

3. Mohan V, Sandeep S, Deepa R, Shah B, Varghese C. Epidemiology of
type 2 diabetes: Indian scenario. Indian J Med Res 2007;125:217‑30.

4. William J. Marshall, Marta Lapsley, Andrew P. Day. Clinical Biochemistry
- Metabolic and clinical aspects 3rd Edition, 2014, pages 273 -304.

5. Shlomo Melmed, Kenneth S. Polonsky, MD, P. Reed Larsen, MD,Henry
M. Kronenberg, MD. Williams Textbook of Endocrinology, 13th Edition,
2016, pages1410 -1412.

6. Dan L. Longo, Dennis L.Kasper, J. Larry Jameson,Anthony S. Fauci,Stephen
L. Hauser, Joseph Loscalzo. Harrison’s Textbook of internal medicine
18thedition (2012); vol 2: page numbers2973-2975

7. Carl A. Burtis, Edward R. Ashwood, David E. Bruns.Tietz Textbook of
Clinical Chemistry and Molecular diagnostics, 5th Edition,2012 pages
854-865.

8. Lee M, Saver JL, Towfighi A, Chow J, Ovbiagele B. Efficacy of fibrates for
cardiovascular risk reduction in persons with atherogenic dyslipidemia:
a meta-analysis. Atherosclerosis 2011;217:492–498.

9. Taube A, Schlich R, Sell H, Eckardt K, Eckel J. Inflammation and met-
abolic dysfunction: links to cardiovascular diseases. Am J Physiol Heart
Circ Physiol 2012;302: H2148–H2165.

10. Rocca B, Santilli F, Pitocco D, Mucci L, Petrucci G, Vitacolonna E, Lat-
tanzio S, Mattoscio D, Zaccardi F, Liani R, Vazzana N, Del Ponte A,
Ferrante E, Martini F, Cardillo C, Morosetti R, Mirabella M, Ghirlanda
G, Davi G, Patrono C. The recovery of platelet cyclooxygenase activity

Cardio Diabetes Medicine

74 Cardio Diabetes Medicine 2017

Diabetes and Heart Are Inseparable Partners
- How & Why

Prof. Dr. Elango, MD.,
&

Dr. Sam Paul Wesley

Diabetic people have an increased prevalence as fuse atherosclerotic lesions . Cardiac catheterizations
well as morbidity & mortality of cardiovascular dis- in diabetic patients have shown significantly more
eases —most commonly in the form of coronary heart severe proximal and distal CHD. In addition, plaque
disease (CHD).There exists a need for the under- ulceration and thrombosis have been found to be
standing of the pathophysiological processes behind significantly higher in diabetic patients. The protec-
these states and also the need for mitigating them, tion that premenopausal women have against CHD
leading onto improved management of diabetes re- is not seen if they suffer from diabetes. The degree
lated heart diseases. Their association not only lies and duration of hyperglycemia are strong risk factors
in the evolution of disease state but also in medical for the development of microvascular and macro-
& interventional management of those morbidities af- vascular complications. The first detectable sign of a
fecting the success rate in treatment. Eighty percent problem in people genetically prone to develop type 2
of all deaths among diabetic patients are a result of diabetes is insulin resistance, which can be seen for
atherosclerosis, compared with approximately 30% as long as 15 to 25 years before the onset of diabe-
among nondiabetic persons.Among all hospitaliza- tes. Several atherogenic factors are associated with
tions for diabetic complications, >75% are a conse- insulin resistance, which can start the atherosclerotic
quence of atherosclerosis. Despite overall improve- process years before clinical hyperglycemia ensues.
ments in outcomes during the past several decades It is unclear whether the compensatory hyperinsu-
for patients with , the gradient of risk associated with linemia plays a role in atherosclerosis generation in
diabetes has persisted.This partnership of diabetes insulin-resistant patients. A number of prospective
with cardiac morbidity should be broken completely studies have shown an association between fast-
so as to reduce the impact on health,social and eco- ing or postprandial hyperinsulinemia and the future
nomical burden on the world and becomes a public development of CHD. Hyperglycemia itself plays an
health imperative. important role in enhancing the progression of ath-
erosclerosis in type 2 diabetes. The threshold above
TEXT: which hyperglycemia becomes atherogenic is not
known but may be in the range defined as impaired
Diabetes mellitus has an extensive negative effect glucose tolerance (ie, fasting plasma glucose level
on the heart and the circulatory system mainly due <126 mg/dL with 30-, 60-, or 90-minute plasma glu-
the “high glucose” levels and the actions of the the cose concentrations >200 mg/L and a 2-hour plas-
advanced end glycation products produced due to it. ma glucose level of 140-200 mg/dL during an oral
The primary disease states of heart associated with glucose tolerance test).
diabetes include , accelerated atherosclerosis, coro-
nary heart disease (CAD), acute coronary syndromes The mechanism implicated with the development of
, heart failure and cardiomyopathy. coronary vasculature affliction in diabetic patients
include :
Atherosclerosis & CAD:
Endothelium
Diabetes accelerates the natural course of athero-
sclerosis in all groups of patients and involves a ↑ NF-κB(Nuclear factor-kappa beta) activation
greater number of coronary vessels with more dif-

GCDC 2017

Diabetes and Heart Are Inseparable Partners - How & Why 75

↓ Nitric oxide production ↑ Activity of protein kinase C
↓ Prostacyclin bioavailability
↑ Endothelin 1 activity ↑ AGEs and AGE-RAGE interactions
↑ Angiotensin II activity
↑ Cyclooxygenase type 2 (COX-2) activity Even then the pernicious effects of hypoglycemic
↑ Thromboxane A2 activity episodes which occur as a risk of diabetic manage-
↑ Reactive oxygen species ment, the sympathovagal imbalance due to diabetic
↑ Lipid peroxidation products autonomic neuropathy, and the vascular effects of
↓ Endothelium-dependent relaxation constitutive exposure to excess insulin may further
↑ Receptor for advanced end glycation products contribute to atherosclerotic risk. Perturbations in the
(RAGE) expression coagulation and fibrinolytic pathways and in platelet
Vascular smooth muscle cells and vascular matrix biology add to the vascular risk of diabetes, yield-
↑ Proliferation and migration into intima ing a constitutive prothrombotic milieu. In addition,
↑ Increased matrix degradation disturbances of platelet activation, aggregation, mor-
Inflammation phology, and lifespan further contribute to increased
↑ IL-1β, IL-6, CD36, Monocyte Chemoattractant pro- thrombotic potential, as well as to the acceleration of
tein (MCP-1) atherosclerosis.
↑ Adhesion molecules and selectins
Prevention of atherosclerotic coronary
vascular disease:

Therapeutic lifestyle interventions remain the cor-
nerstone of prevention of the atherosclerotic com-
plications associated with diabetes like smoking ab-
stinence, at least 150 minutes of moderate-intensity
aerobic activity weekly, and nutrition recommenda-
tions for weight control with dietary composition and

Cardio Diabetes Medicine

76 Cardio Diabetes Medicine 2017

such intervention reduces risk factors for vascular beta blockers for patients with diabetes in the chronic
disease and yields many health benefits (1). ambulatory setting and in the post-ACS population.
With non cardioselective beta blockers that also have
The pharmacological interventions include that of alpha receptor–blocking properties, metabolic mark-
assiduous blood pressure and lipid management for ers may improve, although the clinical relevance of
all patients, and for patients at highest risk, angioten- these differential effects remains unproved. Random-
sin-converting enzyme (ACE) inhibitors independent ized trials of thiazide diuretics that included substan-
of blood pressure and also daily aspirin. tial numbers of patients with diabetes have consis-
tently demonstrated CVD benefits.
Each component of the diabetic dyslipidemia profile
is independently associated with CVD risk, including In a subanalysis of the Antihypertensive and
increased small, dense LDL particles, increased apo- Lipid-Lowering Treatment to Prevent
lipoprotein B concentration, increased triglycerides,
and decreased HDL cholesterol. The most recent Heart Attack Trial (ALLHAT), the CVD effects of
guidelines from the AHA and the American College chlorthalidone compared with both lisinopril and
of Cardiology (ACC) endorse the prescription of statin amlodipine were similar in patients with diabetes or
drug and intensity predicated on estimated 10-year impaired fasting glucose, despite modest but statis-
risk for atherosclerotic vascular disease, indepen- tically significant increases in incident diabetes as-
dent of LDL cholesterol concentrations or specified sociated with chlorthalidone use. A meta-analysis of
LDL cholesterol or non-HDL cholesterol therapeutic randomized trials further supported the benefits of
targets. For patients with type 2 diabetes, at least thiazide diuretics in the treatment of patients with di-
moderate-intensity statin therapy is endorsed for abetes. In the Anglo-Scandinavian Cardiac Outcomes
all patients with diabetes exceeding 7.5% estimated Trial–Blood Pressure Lowering Arm (ASCOT-BPLA),44
10-year risk for atherosclerotic cardiovascular com- which randomly assigned patients to treatment to
plications. Intensive-dose versus moderate-dose sta- amlodipine, with perindopril added as needed, or
tin therapy reduces cardiovascular risk further, but atenolol with bendroflumethiazide added as needed,
a large meta-analysis and analyses of data from the amlodipine-perindopril combination yielded a sig-
several randomized clinical trials have identified an nificant 13% relative risk reduction in major cardiac
increased risk of new-onset diabetes associated morbidity outcomes in the 923 patients with diabe-
with intensive-dose statin therapies compared with tes, compared with atenolol-bendroflumethiazide.
placebo or standard care. Other drugs like fibrates,
omega 3 fatty acids, niacin have controversial ben- The patients with diabetes have aberrations of plate-
efits in reducing the cardiac morbidity and mortality let structure, function, and activity, yielding in aggre-
of the patients. gate a prothrombotic milieu. In addition, absolute or
relative aspirin resistance may occur in up to 40% of
Hypertension affects approximately 70% of diabetic patients with diabetes. At present. the ADA and AHA
patients (twice the rate observed in nondiabetic sub- recommend daily aspirin (75 to 162 mg/day) for all
jects), with a steep graded association between blood patients with diabetes who have established CVD, or
pressure and adverse cardiovascular outcomes. Fur- for primary prevention in patients with diabetes older
thermore, blood pressure targets for patients with di- than 50 years of age for men or 60 years of age for
abetes are more aggressive than for theoverall pop- women. Two randomized clinical trials currently are
ulation, with a goal of less than 130/80 mm Hg for under way to explore further the role of aspirin in
patients with diabetes who can tolerate such aggres- the setting of primary CVD risk prevention in type 2
sive management without undue clinical burden, and diabetes. A Study of Cardiovascular Events In Diabe-
a target of below 140/80 for all others. For example, tes (ASCEND) &The Aspirin and Simvastatin Combi-
the Heart Outcomes Prevention Evaluation (HOPE) 2, nation for Cardiovascular Events Prevention Trial in
which compared ramipril (10 mg daily) with placebo in Diabetes (ACCEPT-D).Diabetes is associated with an
patients at increased risk for cardiac morbidity, rami- increased prevalence of resistance to clopidogrel, a
pril was superior to placebo in the diabetes subset of prodrug requiring metabolic conversion that tends to
3577 patients. Early in the course of clinical use, beta be impaired in diabetes, resulting in decreased circu-
blockers were judged to be relatively contraindicated lating active metabolite.
in the setting of diabetes because of concerns about
masking hypoglycemia symptoms and adverse ef- Oral hypoglycemic drugs that are used in diabetes
fects on glucose and lipid metabolism. The results as to have effect on the coronary vasculature as
of cardiovascular disease (CVD)outcomes trials have well as the cardiac musculature. Hence this discus-
allayed these concerns and support the benefit of sion becomes more imperative to discuss these drug

GCDC 2017

Diabetes and Heart Are Inseparable Partners - How & Why 77

effects on heart. The contraindication to use in HF of relative increases in mortality hazard ranging from
was removed from all U.S. metformin product la- 30% to 60% .Pathophysiologic Abnormalities Asso-
bels in 2006, on the basis of demonstrated clinical ciated with Cardiac Dysfunction, Congestive Heart
safety and observational associations of improved Failure, and Adverse Outcomes in Diabetes are Sym-
cardiovascular outcomes in the HF cohort among pathetic nervous system activation, Renin-angioten-
metformin-treated patients,thus making metformin sin-aldosterone system activation, Increased sodium
the first line of diabetic drug therapy unless contra and free water retention, Decreased vascular compli-
indicated. Concerns persist, however, about the use ance, Elevated endothelin levels, Loss of “dipping”
of sulfonylureas in CVD cohorts, driven by the weight nocturnal blood pressure pattern , Increased free
gain associated with the drugs, the increased risk for fatty acid levels ,Dysregulated myocardial glucose
hypoglycemia and commensurate stimulation of the and fatty acid metabolism,Increased left ventricular
adrenergic stress-response system with potential ad- hypertrophy or mass via myocyte hypertrophy, Depo-
verse CVD effects, and the potential of these drugs sition of advanced glycation end products in extra-
to inhibit so-called ischemic preconditioning through cellular matrix, Increased cardiac fibrosis,Increased
blockade of myocardial KATP channels. In animal cardiac steatosis.
models of MI, activation of myocardial KATP chan-
nels reduces infarct size—an effect termed ischemic Treatment of a diabetic patient’s heart failure re-
preconditioning that is blocked by sulfonylureas. semble those in nondiabetic patients: preservation of
Saxagliptin like DPP 4 inhibitors and Thiazolidine- myocardial function, relief of pulmonary congestion,
diones were associated with increase risk of heart slowing of the progression of the disease. effect of
failure. As expected, insulin use was associated with ACE inhibitors for primary prevention of HF in high-
more hypoglycemia and weight gain.Dopaminne ag- risk cohorts of patients with diabetes demonstrates
onist were used in trials which showed decrease in an 18% relative risk reduction. use of ARBs was as-
cardiac morbidity but the data was sparse to extrap- sociated with significant reduction for incident HF
olate to general population. After decades of inves- commensurate with the treatment effect observed
tigation, this combination of glucose, insulin, and
potassium has become known as GIK therapy, and
the focus of attention has shifted from the polarizing
effects to the direct effects of insulin, including pro-
motion of myocardial glucose oxidation, reduction
of circulating nonesterified free fatty acids that may
contribute to myocardial injury through an increased
oxygen demand associated with free fatty acid me-
tabolism and resultant accumulation of toxic free
fatty acid metabolites, improved coagulation param-
eters, and anti-inflammatory effects. The group with
diabetes has derived much greater absolute benefit
from thrombolytic therapy than non diabetic patients.
Although initial success rates in diabetic and nondi-
abetic patients are similar, diabetic patients exhibit
higher restenosis rates after PCI and worse long-term
outcomes. The GP IIb/IIIa antagonists have demon-
strated similar or increased efficacy in the setting of
PCI in patients with diabetes compared with nondia-
betic patients, both in stable and unstable coronary
disease.

HEART FAILURE:

Diabetes mellitus and insulin resistance before the
development of diabetes also are strong and inde-
pendent risk factors for HF, with an associated two-
to fivefold increased risk. once HF is present, dia-
betes portends an especially adverse prognosis for
subsequent morbidity and mortality, with estimates

Cardio Diabetes Medicine