Cardio Diabetes_2017 book

528 Cardio Diabetes Medicine 2017

in the developing and mature retina. Neurotrophins tration of stem cells, whether targeted or peripheral,
are initially synthesized in a pro-form and undergo should be identified. In the targeted approach, de-
proteolytic cleavage to produce the mature form that termining the optimal administration method is also
activates two distinctive receptors, the tyrosine ki- important.
nase tropomycin receptor (Trk) and, to lesser extent,
the common low affinity p75 neurotrophin receptor References:
(p75NTR). Diabetes induces imbalance in neurotro-
phins by increasing its proform, which is associated 1. International Diabetic Federation, 2016
with upregulation of the p75NTR receptor in the reti-
na. ProNGF/NGF imbalance is an important biomark- 2. Zang Li et al, Mesenchymal stem cell therapy in type 2 diabetes mellitus,
er for Diabetic Retinopathy (DR) due to the reduction Diabetology & Metabolic Syndrome 2017 9:36
in expression and activity of MMP-7, the enzyme that
cleaves proNGF to form mature NGF resulting in ac- 3. Dor et al, Recovery from diabetes in mice by beta cell regeneration, J Clin
cumulation of proNGF and decreases in NGF levels in Invest. 2007 Sep;117(9):2553-61.
the retina. NGF has been shown to stimulate vascular
endothelial growh factor (VEGF) production which is 4. Seaberg et al, Clonal identification of multipotent precursors from adult
known regulator of vascular permeability and angio- mouse pancreas that generate neural and pancreatic lineages, Nat Bio-
genesis in ocular diseases including DR. Diabetes-in- technol. 2004 Sep;22(9):1115-24
duced breakdown of the blood retina barrier was as-
sociated with increases in proNGF and decreases in 5. Charles A. Goldthwaite, Jr., Ph.D. Are Stem Cells the Next Frontier for
NGF. diabetes treatment?

Diabetes-induced imbalance of proNGF/NGF result- 6. Estrada et al, Combined treatment of intrapancreatic autologous bone
ed in upregulation of proNGF/ p75NTR  axis and marrow stem cells and hyperbaric oxygen in type 2 diabetes mellitus, Cell
downregulation of NGF/TrkA axis. This imbalance Transplant. 2008;17(12):1295-304.
appears to play critical role in early pathogenesis
of DR such as retinal neurodegeneration, inflamma- 7. Juventas Clinic Germany, between February 2010- June 2010
tion and vascular dysfunction that eventually leads
to blindness. Restoring balance between proneuro- 8. Pittenger G. et al, Nerve Growth Factor and Diabetic Neuropathy, Exper-
trophin/mature neurotrophin represents a potential imental Diab. Res., 4:271–285, 2003
promising therapeutic strategy to overcome retinal
degenerative diseases including DR. (8)

3.Side Effects:

A low incidence of punctural hemorrhage, posttrau-
matic pain, and subcutaneous hematoma at the
injection site following intrapancreatic MSC trans-
plantation was reported. Mild and moderate fever
with spontaneous remission after transvenous MSC
transplantation was reported in 13.6–22.2% of patients.
Transient self-limiting nausea, vomiting, headache,
abdominal pain, and upper respiratory tract infection
occasionally occurred after the MSC transplantation.
(2)

4.Conclusion:

Longer disease duration, older age, poor islet func-
tion and other complications of T2DM were asso-
ciated with a less conducive microenvironment for
transplanted cells. Duration of DM, residual beta-cell
function, and the severity of complications will affect
treatment efficacy. Thus, the method of selection of
appropriate patients for this treatment needs to be
determined. In addition, the ideal route of adminis-

GCDC 2017

Cardio Diabetes Medicine 2017 529

Initiation & Intensification of
Insulin Therapy in T2DM

Dr. Palaniappen M.D., FICP.,

Sri Sakthi Vinayakar Multispecialitity Hospital &
Dr. V.Palaniyappen’s Diabetes Specialities Centre Guziliamparai-624703. Dindigul (DT)

UKPDS: FIRST 5 YRS INTENSIVE GLYCEMIC CONTROL reduces Micro & Macro vascular Complications in
Future– Metabolic Memory & Legacy Effect

UKPDS: FIRST 5 YRS INTENSIVE GLYCEMIC CONTROL reduces Micro &
Macro vascular Complications in Future–
Metabolic Memory & Legacy Effect

9
Conventional

Median HbA1C (%)
Relative risk reduction (%)
8 0
Intensive
6%
7 –10 12% P = 0.44

6.2% = upper limit of normal range P = 0.029 16%

6 5 10 15 –20 P = 0.052
0 25%

0 P = 0.0099
–30
UKPDS randomized years

Reproduced from UKPDS Study Group. Lancet 1998; 352:837–853.

Cardio Diabetes Medicine

530 Initiation & Intensification of Insulin Therapy in T2DM

GCDC 2017

Cardio Diabetes Medicine 2017 531

Standard Approaches to Therapy Result in
Prolonged Exposure to Elevated Glucose

10% Diet/Exercise Sulfonylurea or Combination Insulin
Metformin Therapy 9.6%
Monotherapy
9%
Mean A1C at Last 9.0%
Visit 8.6%
8%

7% ADA
Goal
6% <7%
Diagnosis 2 3 4 5 6 7 8 9 10
Years

At insulin initiation, the average patient had:
■ 5 years with A1C >8%
■ 10 years with A1C >7%

Brown JB, et al. Diabetes Care.
2004;27:1535-1540.

Cardio Diabetes Medicine

532 Initiation & Intensification of Insulin Therapy in T2DM

BURDEN OF UNTREATED HYPERGLCEMIA

By the time insulin is begun, the average patient accumulates 5 years of HbA1c > 8% and 10 years of HbA1c
>7%

OUTPATIENT GLUCOSE TARGETS FOR NONPREGNANT ADULTS

Parameter Treatment Goal
A1C, %
Individualize on the basis of age, comorbidities, du-
ration of disease, and hypoglycemia risk:

• In general, ≤6.5 for most*

• Closer to normal for healthy

FPG, mg/dL • Less stringent for “less healthy”
2-Hour PPG, mg/dL < 110
< 140

*Provided target can be safely achieved

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Cardio Diabetes Medicine 2017 533

Insulin Therapy Should Mimic 15
Endogenous Insulin Secretion

Plasma glucose profiles Endogenous insulin secretion

0.08 Glucose homeostasis

Insulin (U/l) 0.04 8 Plasma glucose (mmol/L)
6
0 4
2
0

08.00 13.00 16.00 19.00

Time (hours)

Owens DR, et al. Lancet 2001;358:739−46.

THE ADVENT OF THE ANALOGUES

• Discovery of insulin’s chemical structure,1–3 and elucidation of its 3D structure using X-ray crystallography,4
revealed the relationship between pro-insulin and insulin

• As a result, new forms of protracted insulin therapy based on alterations to the structure of the molecule
(i.e. insulin analogues) were developed

Rapid-acting Insulin Analogues Long-acting Insulin Analogues

Developed for more rapid absorption by engineering Developed to fulfil basal insulin requirements by pro-
insulin variants with amino- acid changes that reduce viding a constant low level of plasma insulin in fast-
the tendency of insulin molecules to self-associate ing and inter- prandial periods either by increasing

the isoelectric point or by covalent acylation

Currently available rapid-acting insulin analogues Currently available long-acting insulin analogues

• LISPRO • GLARGINE

• ASPART • DETEMIR

• GLULISINE • DEGLUDEC

Cardio Diabetes Medicine

534 Initiation & Intensification of Insulin Therapy in T2DM

O.P. HYPERGLYCEMIA

INDIAN INSULIN GUIDELINES –
INITIATING INSULIN

Start insulin

At diagnosis OAD failure
If: If:
• FPG >250 mg/dL • FPG >150 mg/dL
• PPG >300 mg/dL • PPG/RBG >200 mg/dL

• HbA1c >9% • HbA1c >8.5%

Or if patient has: Despite receiving optimal dose of
• Systemic infection two or three OADs
• Sepsis
• Acute myocardial Other indications if there is systemic infection,
sepsis, acute MI, unstable angina, DKA/HONK,
infarction
• Unstable angina pregnancy, diabetic kidney disease
• Diabetic ketoacidosis
• Pregnancy DKA, diabetic ketoacidosis; FPG, fasting plasma glucose; HONK, hyperosmolar nonketotic
• Perioperative care coma; MI, myocardial infarction; OAD, oral antidiabetic drug; PPG, postprandial plasma
glucose; RBS, random blood sugar

INCG. National guidelines on initiation and intensification of insulin 19
therapy with premixed insulin analogues. 2013. INCG. J Assoc
Physicians India 2009:57(Suppl. 1):42–6

Indian Insulin Guidelines – Initiating and
Optimising Insulin Analogues

First line Metformin

HbA1c >7.0 Metformin + HbA1c >7.0 Metformin + premix
to ≤7.5 OAD/GLP-1 after 3
months insulin (30) once/
HbA1c >7.5 agonist twice daily
to ≤8.5
HbA1c >8.5 Metformin + premix insulin (30) once daily
Metformin + premix insulin (30) twice daily

HbA1c >7.0 Titrate premix insulin (30) once/twice daily to
FPG >100 achieve <100 mg/dL
mg/dL
INCG. National guidelines on initiation
and intensification of insulin therapy 20
with premixed insulin analogues. 2013.

INCG. J Assoc Physicians India

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Cardio Diabetes Medicine 2017 535

BASAL INSULINS

APPROXIMATELY 8 MILLION PATIENTS
WORLDWIDE WITH T2DM RECEIVE BASAL INSULIN

T2DM Patients Treated
with Basal Insulin1 (worldwide)

On basal insulin On basal insulin
but HbA1C >7%

4 million 4 million

on Lantus®

4 million

on other
basal insulins2

1. Adapted from IMS data; 2. Includes all types of basal insulins

Hypothesis: the large hydrodynamic size of BASAL INSULIN may
allow slow absorption of monomers predominantly via the
lymphatic system

1. Kaminskas LM et al. J Controlled Release 2013;168:200-8; 2. Kaminskas LM, Porter CJ. Adv Drug Del Rev 2011;63:890-900;
3. Kaminskas LM et al. J Control Release 2009;140:108-16; 4. Charman SA et al. Pharm Res 2001;18:1620-6

Cardio Diabetes Medicine

536 Initiation & Intensification of Insulin Therapy in T2DM

Highlights

FIX FASTING FIRST1 CONSISTENT EFFICACY2

22.2 Lantus® with or without Metformin
Baseline Week 12 Week 24

16.6 ⊗ (12 wk): –1.5 –1.1 –1.6 –2.0 –1.1 –1.5
⊗ (24 wk): –1.7 –1.3 –1.9 –2.4 –1.5 –1.7
Glucose (mmol/L) 9.4
10 8.5 8.6 9.2 8.7
8.5 7.4 7.2 7.4 7 8.1 7.7
7 6.7 7.2 7
11.1 7.5 7 6.8
Type 2 diabetes Mean A1C (%)

5

5.5

2.5

0 1000 1400 1800 2200 0200 Normal 0 L2T3 INSIGHT 4020 4022 Pooled
0600 Time of day 0600 EASIE

SAFETY – HYPOGLYCAEMIA2 LONG-TERM SAFETY

Episodes per patient-year 4 Unadjusted pooled event rates of overall, Lantus® had a neutral effect on CV
33 nocturnal, and severe hypoglycaemia at outcomes and cancer incidence3

3 Week 12 and Week 24 with Lantus® with or

without Metformin

Week 12
2 Week 24

1 0.9 0.9 0.7 0.7 Epidemiology Lantus® is not associated with
Programme an increased risk of breast cancer in
0.2 0.3 0.1 0.1 women, prostate cancer in man, and
Severe Northern European, colorectal cancer in men and women4–
0 < 2.0 US Databases & ISICA
7

PG cut-off Overall Nocturnal
(mmol/L) < 3.9 < 3.1 < 3.9 < 3.1

1. Courtesy of Dr Jay Skyler, adapted from Polonsky KS, et al, N Engl J Med 1988;318:
1231–9; 2. Owens DR, et al. Diabetes Technol Ther 2013;15(suppl 1):A-88 [Abstract P-170]; 3.
ORIGIN Trial Investigators, et al. N Engl J Med 2012;367:319–28; 4. Boyle P. Oral presentation

at ADA 2012, Philadelphia, PA, USA. June 11, 2012; 5. Habel LA, et al. Diabetes Care
2013;36:3953–60; 6. Stürmer T, et al. Diabetes Care 2013;36:3517–25; 7. Grimaldi-Bensouda L,

et al. Diabetes Care 2014;37:134–43.

ORIGIN: a landmark Lantus® trial

First ORIGIN data presented at ADA ‘12: Label update in 2013

2012 The world’s longest and largest randomized Includes CV safety & efficacy
Lantus® cardiovascular (CV) outcomes trial in data from ORIGIN
pre- and early diabetes1*
Lantus® does not alter the risk
2013 ADA ’13: Assessing cognitive function, cancer for CV outcome vs
standard of care
safety, relationship of grip strength to CV risk
and also renal function No association with overall
incidence and increased risk
ESC ’13: CV risk and hypoglycemia
of any cancer
ORIGIN sub-studies continue, e.g.: Rates of severe hypoglycemia
• Hypoglycemia predictors
•2014 Microvascular are very low
• Biomarkers
Provides long-term
ORIGINALE observational follow-up: glycemic control

To assess effects of Lantus® and/or Results in a modest mean increase
n-3 PUFA on CV events / other outcomes in body weight

*12,500 patients with new or recently diagnosed diabetes with a high CV risk;
Treatment with Lantus® or omega-3 FA; Over 6 or 7 years of follow-up

1. ORIGIN Trial Investigators, Gerstein HC, et al. N Engl J Med 2012;367(4):
319–28

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Cardio Diabetes Medicine 2017 537

Reductions in HbA1c were significantly greater or
similar with BIL compared with insulin glargine

1. Rosenstock J et al. Diabetes Care 2013;36:522-8; 2. Bergenstal RM et al. Diabetes Care 2012;35:2140-7

FPG (laboratory) was significantly lower with BIL
compared with insulin glargine in T1DM patients

Rosenstock J et al. Diabetes Care 2013;36:522-8

Cardio Diabetes Medicine

538 Initiation & Intensification of Insulin Therapy in T2DM

BIL treatment resulted in significantly lower rates of nocturnal
hypoglycemia compared with insulin glargine in T1DM and T2DM

aData were adjusted for baseline hypoglycemia characteristics; bSignificant difference at endpoint after
adjusting for baseline; Note: a hypoglycemic event was defined as a blood glucose level of ≤70 mg/dL
(3.9 mmol/L) or, where blood glucose was not determined, as signs or symptoms of hypoglycemia1
1. Rosenstock J et al. Diabetes Care 2013;36:522-8; 2. Bergenstal RM et al. Diabetes Care 2012;35:2140-7

BIL was associated with weight loss in
T1DM and T2DM patients

Weight change from baseline

Mean weight change in T1DMa Mean weight change in T2DM
1.0 1.0

0.5 0.5

0.0 Δ 1.9 kg, 0.0 Δ 0.8 kg,
P<.001 P<.001

-0.5 -0.5

-1.0 -1.0

-1.5 -1.5
Insulin glargine Insulin glargine
BIL
BIL

aCrossover design of T1DM study required analysis by least squares means

Jacober SJ et al. Diabetes Obes Metab 2014;16:351-6

GCDC 2017

Cardio Diabetes Medicine 2017 539

BASAL PLUS INSULINS

BASAL PLUS- CLINICAL EVIDENCE

Trial Duration of Trial arms Population HbA1c Target Propor tion Severe Hypo- Weight
OPAL Study(20) randomized size change % HbAic achieving glycemia rate change,
treatment -0.36 {mmol/ target (events / pa- Kg
period Insulin glargine+ 162 mol} HbA1c % tient – year ) +1.0
OADs+ Insulin -0.31 0.01±0.15
24 weeks glulisine at break- 154 ≤48 (6.5) 27.8 +0.9
fast, -0.11 0.04±0.30
51 -0.37 ≤48(6.5) 33.8 -0.4
Insulin 45 0.2±1.1 +0.7
Proof of concept 3 months glargine+OADs+- ≤53 (<7) 8.8 0.0±0.0
study (33) Insulin glulisine at ≤53 (<7) 22.4
main meal time

Insulin
glargine+OADs

Insulin
glargine+OADs+-
Insulin glulisine at
main meal time

Basal-plus Therapy: Clinical Evidences

OPAL Study: A multicentre, randomized, study of 393 pati

Cardio Diabetes Medicine

540 Initiation & Intensification of Insulin Therapy in T2DM

A single bolus insulin, added to insulin glargine and OADs, resulted in significantly improved HbA1c levels

Proof of Concept (POC) Study: comparing Basal Plus
therapy with insulin glargine alone

• Subjects:

– Insulin treated (135 included, 106 randomized) with type 2 diabetes (HbA1c 7.5–
9.5% )

– Received basal insulin and metformin for ≥3 months, (OHAs continued during
study)

Mean study entry values: Insulin glargine (n=57)

• HbA1c (%): 8.5

• BMI (kg/m2): 33.1
• Diabetes duration (years): 11.5

Insulin glargine (n=135)

3 months

Randomization Insulin glargine + once-daily insulin glulisine (n=49)
(subjects with HbA1c ≥7.0%)
3 months

POC Study: adding glulisine to glargine further
improves glycemic control

Randomization
Endpoint

40 9 p=0.029*

% achieving HbA1c <7.030 p=0.0499 8
HbA1c (%) 8.0
20 22.4 7.8 7.8
7.5
10 Glargine 7
8.8 + glulisine Glargine
6 + glulisine
0
Control
Control group
group

Additionally, Basal Plus approach is safe & associated with only minor weight
*for dgifafeinrence in change in HbA 1c

Sanofi-aventis data on file. Basal Plus (POC) study

GCDC 2017

Cardio Diabetes Medicine 2017 541

BASAL BOLUS INSULINS

Top line conclusions from all guidelines on
intensification

A number of different options exist1-2:

Basal Premix /Basal plus
Premix OD Basal-bolus

Premix BD/basal
bolus /premix TID

Premix BID Basal-bolus/Premix
tid

NICE 2008 Clinical Guidelines
AACE 2007 Medical Guidelines

Basal insulin initiation provides an excellent treatment platform from which further insulin intensification can
be applied when patients fail to meet/maintain glycemic targets

Cardio Diabetes Medicine

542 Initiation & Intensification of Insulin Therapy in T2DM

Factors determining the choice of insulin intensification regimen

Factor Premixed insulin Basal-bolus therapy

Patient preference for injection frequency Preference for fewer injections No problem with more injections

Frequency of self- monitoring blood glucose Unwilling to self monitor Willing to self monitor

Variability of lifestyle, including meal timing and Fixed daily routine Variable daily routine
carbohydrate content of meals

Presence of postprandial hyperglycaemia Less significant postprandial Significant postprandial hypergly-

hyperglycaemia caemia

Patient’s ability to follow prescribed regimen Limited cognitive function Motivated and good cognitive
function

Educational and emotional support Limited support Support available

Miami 4/12 rule

GCDC 2017

Cardio Diabetes Medicine 2017 543

Effective Control of BG Elevations After
Mid-day Meals

Premixed insulin:
Elevation of
blood glucose
with mid-day
meal

Relative Blood glucose level Premixed
Insulin Premixed insulin
Levels
insulin

Breakf Lunch Dinner Bedti
ast me

Tim 42
eRizvi AA, et al Insulin. 2007;2(2):68-79

Effective Control of BG Elevations After
Mid-day Meals

Basal plus or basal-
bolus regimen:
Adequate control

Relative Blood glucose level
Insulin
Levels

Breakf Lunch Dinner Insulin glargine
ast
Bedti
Tim me
eAmpudia-Blasco FJ, et al. Diabetes
43
Technol Ther. 2011;13(Suppl 1):S75-83

Cardio Diabetes Medicine

544 Initiation & Intensification of Insulin Therapy in T2DM

1.2.3 study: Insulin glargine with addition of 1, 2 or 3
daily doses of glulisine

• Subjects:
• Insulin naïve (785 entered study, 343 randomized) with type 2 diabetes

(HbA1c ≥8.0%)
• Receiving 2 or 3 OHAs for ≥3 months (OHAs continued except sulfonylurea)

Mean study entry values: Additional insulin glulisine once daily (n=115)
Additional insulin glulisine twice daily (n=113)
• HbA1c (%): 9.8

• BMI (kg/m2): 35.0

Insulin glargine
(n=785)

14 weeks

Randomization (subjects Additional insulin glulisine three times daily (n=115)
with HbA1c >7.0%, n=434)
24 weeks

(1.2.3 study)

1.2.3 Study: Glargine Plus 1, 2 or 3
Doses of Glulisine

Responders in the whole Evolution of A1C in the randomized
population (n=785) population (n=343)

80 Additional 10.0 Glargine Glargine plus glulisine
(alone) (patients with A1C >7%)
% achieving HbA1C <7.0All subjects subjects who
HbA1c (%)(n=785) 10.19 Glulisine 1x
achieved 10.19 Glulisine 2x
60 23% A1C <7.0% 10.16 Glulisine 3x

40 with glulisine 9.0

added to
glargine

37% Subjects who 8.0 7.44
20 achieved A1C 7.40
7.0 7.29
0 <7.0% with Randomization Wk 8 Wk 16 Wk 24
glargine during Run in

run-in

A1C in all subjects (n=785) = 9.8 at run-in and 7.3 at randomization

Adapted from Raccah D. http://www.fesemi.org/grupos/obesidad/noticias/ponencias_iv_reunion/Prof.%20Denis%20Raccah.pdf.
Accessed April 9, 2010. Cited as sanofi aventis, data on file.

GCDC 2017

Cardio Diabetes Medicine 2017 545

4T Study : Three Way Randomisation

Glycemic target: A1C ≤6.5%

Add once (or twice) daily Add prandial insulin
basal insulin* if glycaemic target not met†

700 T2DM R Add twice daily biphasic Add midday prandial insulin if
on OAD glycaemic target not met†
insulin*

Add thrice daily prandial Add basal insulin
insulin* if glycaemic target not met†

Randomisation One Two Three
visit year years years

* progress to more intensive insulin regimen only if clinically necessary
† stop sulphonylurea if taken

4T Study : Mean One-year Changes

20 p= 0.04 25
Hypoglycemia 20
10 p<0.001 p<0.001 p<0.001 p<0.001 grade 2 or 3 15
(events/pts/yr)
Mean percentage change 0 10
5
-10 0

-20

-30

-40 FPG PPG Weight Biphasic
HbA1C 9.6 mmol/l 12.6 mmol/l 85.8 kg Prandial
8.5 (188 lbs) Basal
(%) (173 mg/dl) (227 mg/dl)

N Engl J Med 2007;357:1716-30.

Cardio Diabetes Medicine

546 Initiation & Intensification of Insulin Therapy in T2DM

4T Study : Relative Changes over 3
Years
Mean± 1SD

Mean relative change (%) 20 No. of Events/Patient/Yr 8
6
Biphasic insulin ± prandial

10 Prandial insulin ± basal

Basal insulin ± prandial

0

-10 4

-20
2

-30

-40 Fasting Postprandial Body 0
Plasma Glucose Weight
Glycated Glucose Hypoglycaemia
Haemoglobin 12.6 mmol/l 85.8 kg Grade 2 or 3
9.6 mmol/l 227 mg/dl 188 lbs
Baseline 8.5% 173 mg/dl <0.001
value 0.28 <0.001 0.20
0.83
p value

Basal-bolus regimen with insulin glargine is more
effective than twice-daily premixed insulin lispro

HbA1c

Basal-bolus Premixed insulin ▪ Hypoglycaemia rates and
lispro 50/50 weight gain were similar in
0 the two groups

Change from baseline (%) –0.5 ▪ 55% of patients in the
premixed insulin group
–1.0 switched from premixed

–1.5 insulin lispro 50/50 to 25/75
at dinner to achieve the FBG
-2.0 –1.9
-2.5 –2.1 target

p<0.021 for 0.2% difference

Basal-bolus insulin therapy provided a better efficacy
profile

Rosenstock J, et al. Diabetes andCare 2008;31:20–5. a similar safety profile
Rosenstock J, et al. Diabetes Care 2007;31:20–5.

GCDC 2017

Cardio Diabetes Medicine 2017 547

GINGER: Basal Bolus provides superior glycemic
control vs. intensified premixed insulin therapy

Subjects:
• 310 with inadequately controlled type 2 diabetes (HbA1c 8–11%)
• Pretreated with premixed insulin (mean of 5 years),

with some receiving metformin (continued during study)

Mean baseline values: Insulin glargine + three daily doses of insulin
glulisine +/- metformin (n=153)
• HbA1c (%): 8.5

• BMI (kg/m2): 30.1
• Diabetes duration (years): 13.0

Randomization Twice-daily premixed insulin +/- metformin (n=157)

52 weeks

Fritsche A, et al. Diabetologia 2008;51 Suppl. 1:S83

GINGER: Basal Bolus provides superior glycemic
control vs. intensified premixed insulin therapy

Subjects:
• 310 with inadequately controlled type 2 diabetes (HbA1c 8–11%)
• Pretreated with premixed insulin (mean of 5 years),

with some receiving metformin (continued during study)

Mean baseline values: Insulin glargine + three daily doses of insulin
glulisine +/- metformin (n=153)
• HbA1c (%): 8.5

• BMI (kg/m2): 30.1
• Diabetes duration (years): 13.0

Randomization Twice-daily premixed insulin +/- metformin (n=157)

52 weeks

Fritsche A, et al. Diabetologia 2008;51 Suppl. 1:S83

Cardio Diabetes Medicine

548 Initiation & Intensification of Insulin Therapy in T2DM

I.P. HYPERGLYCEMIA

INPATIENT GLUCOSE TARGETS FOR NONPREGNANT ADULTS

Hospital Unit Treatment Goal

Intensive/critical care. Glucose range, mg/dL 140 – 180
General medicine and surgery, non-ICU

Premeal glucose, mg/dL < 140

Random glucose, mg/dL < 180

54

INSULIN INFUSION STARTING DOSE(I.I.T.)

1. Starting dose for unstressed Normoglycemic adult with average BMI 1-2u/hr
2. (OR) 50% of previous Day’s TDD/24 Hours (Eg: TDD = 90u ! 50 % TDD = 45u ! 45/24 = 2u/Hr)
3. DKA, Steroid induced hyperglycemia may require higher infusion rates(5-7u/hr)

TITRATION OF INSULIN INFUSION RATE

1. Insulin action lasts approximately 1 hour
2. Meticulous Hourly Monitoring & Titration of BG
3. IF BG 400 mg% Starting dose 2u / Hr
4. Increase dose rate if BG does not reduce 30 – 50 mg/dL after 1 hour
5. Reduce the rate if BG drops > 30-50mg/dL after 1 hour
6. Continue insulin infusion till oral intake or improvement in general health condition

GCDC 2017

Cardio Diabetes Medicine 2017 549

7. Maintain the same correct infusion rate when the BG is 140 to 180 mg/Dl

INSULIN INFUSION SC INSULIN 6 hours prior to SC Insulin transition

1. RBG should be maintained in 140 – 180 mg/ dL for at least

2. Insulin requirement for the past 6 hours x 4 = TDD -80% New TDD for SC Insulin !

3. 50-80 % Basal (Higher for fasting pts)

4. 20-50 % divided Bolus

5. Give Rapid insulin 1 – 2 hrs BEFORE stopping the infusion

6. Give Long acting insulin 2 – 3 hrs BEFORE stopping the infusion

CARRY HOME MESSAGE

1. EAT RIGHT DIABETIC DIET WITH LSM
2. STRESS MANAGEMENT & ADEQUATE SLEEP REDUCES 25% OF HYPERGLYCEMIA
3. A1c TARGET <6.5 -8.5%-PATIENT CENTERED APPROACH
4. USE METFORMIN MAX. DOSE EVEN 2.850 gm / DAY UNLESS CONTRAINDICATED
5. USE MAXIMUM PHYSIOLOGICAL INSULIN BEFORE STARTING PARENTRAL INSULIN
6. USE ANALOG OR HUMAN INSULIN EARLY IF NOT ACHIEVED GLYCEMIC TARGETS
7. PREMIXED INSULINS AND PREFILLED INSULIN PENS SHOULD BE USED INSTEAD OF MIXING INSU-

LINS IN ELDERLY DIABETICS

8. HYPOGLYCEMIA & HYPOTENSION ARE MORE DANGEROUS THAN HYPERGLYCEMIA & HYPERTENSION

RESOURCES

1. AACE GUIDELINES 2017
2. STANDARDS OF MEDICAL CARE IN DIABETES - 2017, ADA
3. ADA GUIDELINES 2017
4. CANADIAN GUIDELINES 2017
5. BREMER JP ET AL. DIABETES CARE. 2009; 32 (8):1513-17

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550 Cardio Diabetes Medicine 2017

Cardio Diabetic Therapeutics
When to Use? When Not to Use –OHA

Dr. A. J. Asirvatham MD, D.Diab,

Senior Consultant Diabetologist,
Arthur Asirvatham Hospital, Madurai.

Introduction: The Algorithm:

In the spectrum of treatment of diabetes, when Most of the guidelines recommend Metformin as the
OHAs were born, there was an anticipation that insu- first line of medication following failure of life style
lin would vanish, which never happened. At the time modifications. Subsequently, knowledge about the
of discovery, there were only few molecules making benefits of metformin have improved tremendously
the selection of a drug easy. But now, there are quite making the authorities and guidelines, to promote its
a lot of drugs available which makes it more difficult use as an add on drug along with life style measures
to choose. With more pressure to use newer drugs, (Figure:1). Hence the first anti-diabetic drug is started
the indications and more importantly contraindica- at diagnosis of diabetes.(Fig 1)
tions should be very clearly known. This would help
not only the patient but also the treating physician It is customary to wait for an adequate period to al-
in achieving good glycemic as well as extra glycemic low this combination to work. As metformin has to
benefits. improve insulin sensitivity, it takes at least two to

Figure:1 showing American Diabetes Association 2017
recommendations emphasizing Metformin use along with life style modification.

GCDC 2017

Cardio Diabetic Therapeutics – 551
When to Use? When Not to Use –OHA

three weeks. Hence adding another drug two days This is the time when OHA should not be used just
later may not be a prudent move. This is when no forthe sake of a mere attempt. This is the indication
other drug should be added with a masterly inaction. for insulin and definitely not OHAs over and over
again.
When target glycemic control has not been achieved
with the above mentioned combination, a second Indications:
drug has to be selected to add on. The choice of
second drug should be based on the need, concern • Failure of life style modification
and indication of the treated individual. Though many
recommendations like AACE guidelines do not spec- • Addition of SGLT2i to existing LSM in high CV risk
ify the drug (Figure:2), ADA has recently suggested individuals
SGLT2i specificallyforthose with high CV risk. Hence
a preferred second add on would be SGLT2i for this • Addition of DPP4i or SU to insulin regimen to re-
particular group of diabetic population. (Fig 2) duce insulin requirement, cost and achieve control

All the other drugs have to be chosen depending on • When patient refuses insulin injection
many factors like age, duration of diabetes, prone-
ness to hypoglycaemia, affordability, family support Contraindications :
and other co-morbid conditions as per the recom-
mendations of AACE. • Chronic liver diseaseis not an ideal choice

One more addition alone may not be adequate es- • ESRD needs cautious use depending oneGFR.
peciallyin those with longer duration of diabetes and Though only few newer drugs could be safely pre-
hence in these situations few more drugs may be scribed in such situations, it is advisable to start
requiredin order to achieve target. Addressing every insulin rather than OHA.
component of ominous octet and adding more and
more drugs may not achieve and maintain euglycae- • In patients with cardiac failure, renal failure, pe-
mia in certain instances. ripheral circulatory failure, hepatic failure, respira-
tory failure and brain cell failure.

• During any surgicalprocedure

Figure:2 showing American Association of Clinical endocrinologists
2017 algorithm for glycemic control.

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552 Cardio Diabetes Medicine 2017

• During any infection
• Duringany acute medical problems
• During any acute complications of Diabetes
• When there is an evidence of allergy to OHA

Conclusion:

Thus the right group of drugs have to be used in the
right patient at the right time which may not be very
easy.But once this art is mastered, it is a child’s play
for the prescribing physician. May we try to master
this art by increasing the knowledge and learning
from the experience of our teachers, leaders and
patients and offer a safe and an effective therapy
for diabetes.

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Cardio Diabetes Medicine 2017 553

Novel Oral Anti Coagulants in
Chronic Kidney Disease

Georgi Abraham. MD, FRCP
Priya Haridas A. MBBS

Madras Medical Mission Hospital, Chennai

Abstract tion on warfarin therapy. Coumadin derivatives re-
quire monitoring by prothrombin time and INR which
Chronic kidney disease (CKD) is an emerging cause may vary widely in CKD patients on dialysis giving
of cardiovascular morbidity and mortality. As it pre- rise to bleeding episodes which could be devastating
dominantly affects the older population with comor- at times. However the availability of reversal agents
bidities such as coronary artery disease, hyperten- like vitamin K, fresh frozen plasma in case of drug
sion and diabetes mellitus, patients requiring oral over dose or life threatening bleeding make warfarin
anti coagulation are on the rise. Traditionally Cou- suitable for use in CKD patients.[1]
madin derivatives were used for this purpose. Novel
oral anti coagulants such as dabigatran, apixaban, Novel oral anti coagulants are of two classes: Direct
edoxaban, and rivaroxaban are increasingly being thrombin inhibitors and factor Xa inhibitor. All NO-
used for anti coagulation. There is limited data on ACs have a significantly lower risk of intracranial and
their use in various stages of CKD. intracerebral bleeding than w\arfarin. Since that is
the most feared bleeding risk and may be sufficient
Introduction reason to consider switching patients from warfarin
to a NOAC, even if they seem to be doing well on
CKD patients have complex issues with regards to warfarin therapy [3]
hemostasis . There are diverse group of patients
who are at various stages of CKD in India. The di- Dabigatran was the first NOACs approved for clini-
alysis group comprising both maintenance hemodi- cal use. It is a direct thrombin factor II inhibitor. The
alysis and chronic peritoneal dialysis have many co FDA approved dose for patients with Creatinine
morbidities such as diabetes mellitus, Hypertension, clearance(CrCl) more than 50ml/min and between
coronary artery disease with associated cardiac ar- 30 and 50ml/min is 150mg and 110mg twice a day.
rhythmias predominantly atrial fibrillation. The immi- In the RE-LY(Randomized Evaluation of Long –Term
nent threat of peripheral embolization mandates anti Anticoagulation Therapy)trial, as compared with war-
coagulation in this subset of patients. Warfarin and farin, the 110-mg dose of dabigatran was associated
other oral anti coagulants have many limitations for with similar rates of stroke and systemic embolism
use in dialysis patients. Novel oral anti coagulants are and lower rates of major hemorrhage; the 150-mg
being used increasingly for anti coagulation in non dose of dabigatran was associated with lower rates
CKD patients. There is limited data on their efficacy of stroke and systemic embolism but with a similar
and safety in CKD patients. rate of major hemorrhage.[4] About 80% of dab-
igatran is cleared by the kidneys, hence caution is
Long term warfarin use has been associated with a needed when used in patients with CrCl between 30
condition called warfarin nephropathy and develop- to 50ml/min and is contraindicated in advanced CKD
ment of both acute kidney injury and CKD[1].Warfarin stages [5] U.S SmPC prohibits the co-administration
is not removed by dialysis because 99 % is bound to of dabigatran with drugs that inhibit P-glycoprotien
plasma proteins.It is cleared by hepatic metabolism. due to the potential for drug accumulation.
[2] Patients with estimated GFR less than 30ml/min/
m2 have a 4.9 fold increase in the risk of bleeding Apixaban is a direct factor Xa inhibitor with 27%renal
when compared to patients with normal renal func- elimination[2]. It is 87% protein bound. Only 6.7% is

Cardio Diabetes Medicine

554 Novel Oral Anti Coagulants In Chronic Kidney Disease

cleared by standard 4 hour hemodialysis (dialysate The 2015 updated European Heart Rhythm Associ-
flow rate 500ml/min, blood flow rate 350 to 500 ml/ ation practical guidelines on the use of non-vitamin
min, no heparin)[2]. Hence in patients on apixaban K antagonist anticoagulant agents in patients with
with life threatening bleeding or drug overdose, dial- nonvalvular AF recommend refraining from NOACs
ysis is not effective to remove apixaban from circu- use in dialysis patients and those with CrCl <30ml/
lation. Although 4- factor prothrombin complex con- min[2,5] (Table 1 & 2)
centrate may reverse the effect of apixaban.
Bullets:
Edoxaban , a newer factor Xa inhibitor approved for
anticoagulation use in the United States of America • Warfarin can be used in all stages of CKD includ-
although it’s not marketed in the US at present.[2] ing those patients on dialysis
Renal clearance is about 50% of the un-metabolized
drug. Because of an increased risk of ischemic stroke • Concomintent use with anti platelet therapy exer-
compared to warfarin observed in the registered tri- cise extreme caution while using warfarin.
als, the FDA has now contraindicated the use edox-
aban in individuals with super normal renal function. • Persistent use of warfarin may produce a contition
called warfarin nephropathy with decrease in GFR.
The American College of Cardiology and the Ameri-
can Heart Association(AHA-ACC ) and Heart Rhythm • NOACs such as dabigatran, apixaban, edoxaban
Society (HRS) guildelines indicate warfarin as gold and rivaroxaban require dose adjustment in vari-
standard therapy in stage 4(eGFR between 15 and 30 ous stages of CKD and requires long term study
ml/min/m2), stage 5CKD(eGFR <15ml/min/1.73m2) for their safety in CKD.
and patients on dialysis due to various degree of re-
nal clearance of all NOACs [2]. • Apixaban has been approved by FDA for use in
Hemodialysis patients

Parameters Warfarin Apixaban Rivaroxaban Edoxaban Dabigatran
Renal clearance <1% 27% 35% 50% 80%
Dosing recommen- Varying dosage Serum creatinine≥1.5mg/dL,- CrCl≥50mL/min, Crcl≥50mL/min, CrCl≥50mL/min, no
dation no adjustment(i.e 5mg BID)a* no adjustment no adjustment adjustments (i.e 150
(i.e 60mg OD)b* mg BID)*
(i.e 20 mg OD)*

Dosing if CKD 20% lower CrCl 15-29mL/min: 2.5 mg 15mg OD when 30mg OD when CrCl<50ml/min/m2
dosage? BID CrCl CrCl 15-49 mL/ 110mg twice daily *
Not recommended if min*
Reversal agent If two-out-of-three: age≥- 15-49mL/min* 30mL/min
80years,weight ≤60kg, Idarucizumab
serum creatinine≥1.5mg/dL*

Can be used in <15mL/min** <15mL/min <15mL/min
ESRD and on 4F-PCC 4F-PCC 4F-PCC
RRT
Vitamin K,FFP,
4F-PCC

Table 1 NOACs dosage and recommendations in CKD

*ESC recommendations

a) The SmPc specifies dose reduction from 5 to 2.5mg BID if two of the three criteria are fulfilled :age≥80years,weight ≤60kg, serum creatinine>1.5mg/dL.

b) FDA provided a boxed warning that ‘edoxaban should not be used in patients with CrCl>95mL/min’. EMA advised that ‘edoxaban should only be used in patients with high CrCl
after a careful evaluation of the individual thrombo-embolic and bleeding risk’because of a trend towards reduced benefit compared to Vitamin K antagonists.

c) **A 5mg twice daily dose of apixaban is suggested for patients with CrCl<15ml/min/m2 based on a small single dose pharmacokinetic and pharmacodynamic (anti-Xa activity)
study. However due to lack of sufficient clinical studies regarding long term safety , apixaban should be used with caution in patients with ESRD

d) ESRD= end stage renal disease, RRT= Renal replacement therapy

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Cardio Diabetes Medicine 2017 555

First choice Subjects with non valvualr atrial fibrillation and CKD stage 3 and 4
Second choice Apixaban 2.5mg BID in the presence of one or more additional criteria: age≥80years, body weight
≤60kg
First choice Dabigatran 110mg twice daily
Not recommended
Subjects with nonvalvular atrial fibrillation on maintenance dialysis
First choice No anti coagulation or VKA is appropriate
Dabigatran,rivaroxaban, apixaban*,or edoxaban

Subjects with nonvalvular atrial fibrillation and stage 1 CKD
Dabigatran 150 mg BID, rivaroxaban 20 mg OD or apixaban 5mg BID

Table 2: European Society of Cardiology (ESC) recommendations for NOAC’s use in CKD subjects[1]

VKA= Vitamin K anticoagulants | *FDA approved apixaban in hemodialysis patients

References

1. Sergey V. Brodsky Anticoagulants and acute kidney injury: clinical and pa-
thology considerations. Kidney Res Clin Pract. 2014 Dec; 33(4): 174–180.

2. Di Lullo L, Barbera V, Bellasi A, Cozzolino M, Russo D, Otranto G, et al.
Non vitamin-K dependent oral anticoagulants (NOACs) in chronic kidney
disease patients with non-valvular atrial fibrillation. G Ital Nefrol.  2017
Apr;34(2):58-73.

3. Reiffel JA1. Novel oral anticoagulants. Am J Med. 2014 Apr;127(4):e16-7. 

4. Stuart J. Connolly, Michael D. Ezekowitz, M.B., Ch.B., D.Phil., Salim Yusuf,
D.Phil., John Eikelboom, M.D., Jonas Oldgren et al and *the RE-LY Steering
Committee and Investigators. Dabigatran versus Warfarin in Patients with
Atrial Fibrillation. N Engl J Med 2009; September 2009, 361:1139-1151

5. Heidbuchel H, Verhamme P, Alings M, Antz M, Diener HC, et al. Up-
dat ed European Heart Rhythm Association Practical Guide on the use
of non-vitamin K antagonist anticoagulants in patients with non-valvular
atrial fibrillation. Europace.  2015 Oct;17(10):1467-507.

6. Sakaan SA1, Hudson JQ, Oliphant CS, Tolley EA, Cummings C, Alabdan
NA, Self TH. Evaluation of warfarin dose requirements in patients with
chronic kidney disease and end-stage renal disease. Pharmacothera-
py. 2014 Jul;34(7):695-702.

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556 Cardio Diabetes Medicine 2017

Sulfonylureas and Cardiovascular Mortality?

Dr. Vimala Paul, MD

Physician, Tuticorin

Abstract for the management of diabetes, there is a continued
controversy about their cardiovascular safety.4New-
Prevalence of diabetes mellitus has shown a steep er sulfonylureas have been developed over the
increase worldwide. Sulfonylureas are recommended years. Sulfonylureas are classified as first-genera-
by major guidelines for the management of diabetes. tion (chlorpropamide, tolazamide, and tolbutamide),
However, there is a controversy about cardiovascular second-generation (glipizide and glyburide), and
safety of sulfonylureas. Sulfonylureas may cause car- third-generation agent (glimepiride).5Fourth genera-
diovascular adverse effects by inhibiting extra-pan- tion photo-switchable sulfonylurea JB253 has been
creatic K ATP channels and sulphonylurea receptors developed recently.First-generation Sulfonylureas
present in cardiac myocytesand smooth muscle cells. have longer half-lives and are associated with in-
Impaired ischaemic preconditioning may be responsi- creased incidence of hypoglycaemia, and drug in-
ble for the excess cardiovascular mortality observed. teractions. The second- and third-generation agents
However, different sulfonylureas have different lev- have more rapid onset of action, shorter half-lives,
els of affinity towards sulphonylurea receptors. Large and lower incidence of hypoglycaemia. Different the
number of studies have evaluated the cardiovascu- generations differ in their pharmacokinetic, efficacy,
lar safety of sulfonylureas. Results of meta-analysis and safety profiles.5, 6
of RCTs(randomised controlled trial) suggest no in-
creased risk of cardiovascular adverse effects with How do Sulfonylureas compromise
sulfonylureas whereas results of meta-analysis of cardiovascular safety?
observational studies indicate increased risk of car-
diovascular adverse effects.Gliclazide and glimepiride Sulfonylureas act by binding to the subunit of ade-
were associated with a lower risk of all-cause mor- nosine triphosphate (ATP)–sensitive potassium chan-
tality and cardiovascular-related mortality compared nels in the pancreatic β cells to keep the channels
with glibenclamide. closed. This leads to an influx of calcium ions into the
cell that results in an increased release of insulin via
Key words: Sulfonylureas, cardiovascular mortality, exocytosis of insulin-containing granules. The cause
cardiovascular adverse effects,KATPchannels, ish- of increase in cardiovascular involvement may be di-
emic preconditioning rectly related to the mechanism of action. The first
two generation of sulfonylurea drugs do not act only
Introduction on pancreatic β cells. They also bind to ATP-sensitive
potassium channels in cardiomyocytes and vascular
Diabetes mellitus is a metabolic disorder that is an smooth-muscle cells.4 This binding of sulfonylureas
epidemic in the world today. India has more than 62 to potassium channel in cardiac tissues prevents 3
million diabetics today.1Several groups of drugs tar- otherwise beneficial mechanisms:
geting glucose metabolism and regulation are being
developed. • Vascular smooth-muscle cell relaxation that im-
proves coronary blood flow;
Sulfonylureas are recommended by the guidelines
issued by American Diabetes Association, Europe- • Limitation of myocardial damage during ischemia
an Association for the Study of Diabetes and Inter-
national Diabetes Federation.2,3The University Group • Protection of energy-generating mitochondria in
Diabetes Program (UGDP) trial results published in cardiomyocytes.4
1970 questioned the cardiovascular safety of sulfo-
nylureas. Even after 50 years of using sulfonylureas

GCDC 2017

Sulfonylureas and Cardiovascular Mortality? 557

Figure 1: Mechanism of action of sulfonylureas on pancreatic β-cells and cardiomyocytes (SUR: Sulfonylurea receptor)

Impaired ischaemic preconditioning (IPC) by Sul- Nonvascular SUR2B / Kir6.2 Glibenclamide
fonylureas is presumed to be the most important smooth muscle
mechanism for the excess cardiovascular mortality
observed.6 (Fig 1) SUR, Sulphonylurea receptor; Kir, Potassium inward rectifier

However, not all Sulfonylureas have same affinity Table 1. Affinity of different Sulfonylureas on
in these K ATP channels on different tissues (Table K ATP channels indifferent tissues
1). 7In addition, tolbutamide and gliclazide produce
a reversible inhibition of Kir6.2/SUR1 (potassium in- What is the evidence?
ward rectifier) and Kir6.2/SUR2 channels, whereas
glibenclamide has a reversible effect on cardiac, but After UGDP study results, tolbutamide was discon-
not on β-cell, K ATP channels.7According to a study,g- tinued. However, The UK Prospective Diabetes Study
libenclamideinhibits mitochondrial K ATP channels, (UKPDS) demonstrated that treatment with Sulfony-
impairs IPC and increased experimental infarct size, lureasshowed a trend toward protection against MI
whereas glimepiride does not inhibit beneficial ef- rather than augmentationof cardiovascular mortality.
fects of mitochondrial K ATP channel and showed Large number of studies have examined theassocia-
no adverse effect on IPC or infarct size.  In addition, tion between sulfonylureas and adverse cardiovascu-
glimepiride was found to maintain myocardial pre- laroutcomes with conflicting results.4Nine meta-anal-
conditioning with fewer cardiovascular side effects ysis have pooled the data of randomized controlled
as compared to glibenclamide. Unlike glibenclamide, trials and observational studies to assess the effect
glimepiride appears to preserve myocardial precondi- of Sulfonylureas on cardiovascular events (Table 2).4
tioning. These differences between the Sulfonylure-
assuggest that the effect on cardiac events is not a In the first meta-analysis, Selvin et al. included 40
group effect and depends on the molecule.6 RCTs reporting cardiovascular outcomes in type 2
diabetes patients treated with antidiabetic drugs. Re-
Tissue SUR type Blocked by sults indicated that sulfonylureashad a neutral effect
Pancreatic β-cell SUR1 / Kir6.2 on cardiovascular mortality [pooled odds ratio (OR)
Tolbutamide and 0.92; 95% CI 0.68–1.26] when compared with placebo
Cardiac and skele- SUR2A / Kir6.2 gliclazide or any other antidiabetic drug.4
tal muscle
Vascular smooth SUR2B / Kir6.1 Glibenclamide, Meta-analysis by Monami et al. included 67 RCTswhich
muscle glimepiride compared sulfonylureas with placebo or other anti-
diabetic drugs and reported cardiovascular events
Glibenclamide, as either the main study outcome or adverse drug
glimepiride effects. Sulphonylurea use wasassociated with a
significant 22% increased risk of all-cause mortality

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558 Cardio Diabetes Medicine 2017

Meta-analysis, Type of studies Sulphonylurea vs Outcome Pooled point e
authors & year included (n) comparator stimates (95% CI)

RCT (5) SU vs no SU Cardiovascular morbidity 0.89 (0.71–1.11)

Selvin et al., 2008 RCT (5) SU vs no SU Cardiovascular mortality 0.92 (0.68–1.26)

RCT (6) SU vs no SU All-cause mortality 0.90 (0.70–1.15)

Observational (5) SU + MET vs diet, MET Cardiovascular mortality 1.43 (1.10–1.85)
monotherapy, SU monotherapy or hospitalization

Rao et al., 2008 Observational (4) SU + MET vs diet, MET Cardiovascular mortality 1.29 (0.73–2.27)
monotherapy, SU monotherapy

Observational (7) SU + MET vs diet, MET All-cause mortality 1.19 (0.88–1.62)
monotherapy, SU monotherapy

Phung et al., 2013 Observational (9) SU vs no SU Cardiovascular mortality 1.27 (1.18–1.34)
RCT (7) SU vs no SU Cardiovascular mortality 1.22 (0.63–2.39)

Monami et al., 2013 RCT (30) SU vs no SU MACE 1.08 (0.86–1.36)
RCT (37) SU vs no SU All-cause mortality 1.22 (1.01–1.49)

RCT (3) SU monotherapy vs MET Cardiovascular morbidity 0.67 (0.48–0.93)

Hemmingsen et al., 2013* RCT (6) SU monotherapy vs MET Cardiovascular mortality 1.47 (0.54–4.01)

RCT (6) SU monotherapy vs MET All-cause mortality 0.98 (0.61–1.58)

Forst et al., 2013 Observational (4) SU vs no SU Cardiovascular mortality 2.72 (1.95–3.79)
Observational (12) SU vs no SU All-cause mortality 1.92 (1.48–2.49)

Zhang et al., 2014 RCT (4) DPP-4 inhibitors vs SU Cardiovascular events 0.53 (0.32–0.87)

Chlorpropamide vs glyburide 1.34 (0.98–1.86)

Simpson et al., 2015 RCT (7), Tolbutamide vs glyburide All-cause mortality 1.13 (0.90–1.42)
observational (17) Glipizide vs glyburide 0.98 (0.80–1.19)
Glimepiride vs glyburide 0.83 (0.68–1.00)

Gliclazide vs glyburide 0.65 (0.53–0.79)

VarvakiRados D et al., RCT (47) SU vs active control All-cause mortality Car- 1.12 (0.96- 1.30)
2016 diovascular mortality 1.12 (0.87 -1.42)

* AD, antidiabetic drug; CI, confidence interval; DPP-4, dipeptidyl peptidase-4; MACE, major adverse cardiovascular event; MET, metformin; RCT, randomized
controlled trial; SU, sulphonylurea. *Only results comparing second generation sulfonylureas against metformin are shown.

Table 2. Summary of meta-analysis of sulfonylureas on cardiovascular outcomes4

when compared with placebo or other antidiabetic sociated with DPP-4 inhibitors (pooled RR 0.53; 95%
drugs (pooled OR 1.22; 95% CI 1.01–1.49). However, CI 0.32–0.87).4
there was no significant difference between sulpho-
nylurea use and placebo or other antidiabetic drugs Results of meta-analyses of observational studies-
(pooled OR 1.08; 95% CI 0.86–1.36) when composite showed an increased cardiovascular mortality with
outcome of cardiovascular morbidity or mortality was sulfonylureas.4
considered.4
The most recent meta-analysis included RCTs of at
According to a Cochrane review which analysed RCTs least 52 weeks in duration evaluating second- or
of sulfonylureas as monotherapy, there was no sig- third-generation sulfonylureas in the treatment of
nificant association between sulphonylurea use and adults with type 2 diabetes. Primary outcomes were
mortality compared with metformin monotherapy all-cause mortality and cardiovascular mortality. Addi-
(pooled RR 1.47; 95% CI 0.54–4.01).4 tionally, myocardial infarction and stroke events were
evaluated. The meta-analysis included 47 RCTs with
In the meta-analysis by Zhang et al., RCTs comparing 37,650 patients and 890 deaths. Sulfonylureaswere
the effect of sulfonylureas with those of dipeptidyl not associated with all-cause (OR 1.12 [95%CI 0.96 to
peptidase-4 inhibitors were analysed. There was a 1.30]) or cardiovascular mortality (OR 1.12 [95%CI 0.87
significantly lower risk of cardiovascular events as- to 1.42]). Sulfonylureas were also not associated with-

GCDC 2017

Sulfonylureas and Cardiovascular Mortality? 559

increased risk ofmyocardial infarction (OR 0.92 [95% 4. Abdelmoneim AS, Eurich DT, Light PE, Senior PA, Seubert JM, Makowsky
CI 0.76 to 1.12]) or stroke (OR 1.16[95% CI 0.81 to 1.66]).7 MJ, Simpson SH. Cardiovascular safety of sulfonylureas: over 40 years of
continuous controversy without an answer. Diabetes ObesMetab. 2015
Summary Jun;17(6):523-32.

Diabetes is a worldwide epidemic metabolic disorder 5. Kumar R, Kerins DM, Walther T. Cardiovascular safety of anti-diabetic
and many Indians are diabetic or at risk of diabetes. drugs. Eur Heart J Cardiovasc Pharmacother. 2016 Jan;2(1):32-43.
Although, newer drugs are being introduced as better
drugs for glycemic control, sulfonylureas have long 6. Kalra S, Aamir AH, Raza A, Das AK, Azad Khan AK, Shrestha D, et al.
proven to be effective and safe for over 50 years. Place of sulfonylureas in the management of type 2 diabetes mellitus
There is a causal relationship between sulfonylureas in South Asia: A consensus statement. Indian J Endocrinol Metab. 2015
and adverse cardiovascular events based on the bio- Sep-Oct;19(5):577-96.
logically plausible mechanisms; however, the majori-
ty of this is based on animal studies. Evidence from 7. VarvakiRados D, Catani Pinto L, ReckRemonti L, BauermannLeitão C,
RCTs suggest a neutral effect between sulfonylureas Gross JL. The Association between Sulfonylurea Use and All-Cause and
and adverse cardiovascular outcomes, whereas evi- Cardiovascular Mortality: A Meta-Analysis with Trial Sequential Analysis
dence from observational studies suggests increased of Randomized Clinical Trials. PLoS Med. 2016 Apr 12;13(4):e1001992.
cardiovascular risk with sulfonylureas.Furthermore, it
may not be a group effect as it is not observed with 8. Highlighting points
second and third generation Sulfonylureas.Clinicians
should consider possible differences in risk of mor- 9. Sulfonylureasare considered to be one of the leading oral hypoglycaemic
tality when selecting a sulfonylurea. agents over the past half century.

Highlighting points 10. There is a controversy about cardiovascular safety of sulfonylureas.

• Sulfonylureasare considered to be one of the 11. Sulfonylureas may cause cardiovascular adverse effects by inhibiting ex-
leading oral hypoglycaemic agents over the past tra-pancreatic KATP channelsand sulphonylurea receptors present in abun-
half century. dance in cardiacmyocytesand smooth muscle cells.

• There is a controversy about cardiovascular safety 12. Results of meta-analysis of RCTs suggest no increased risk of cardiovascular
of sulfonylureas. adverse effects with newer sulfonylureas.

• Sulfonylureas may cause cardiovascular adverse 13. Results of meta-analysis of observational studies indicate increased risk of
effects by inhibiting extra-pancreatic KATP chan- cardiovascular adverse effectswith the older sulfonylureas.
nelsand sulphonylurea receptors present in abun-
dance in cardiacmyocytesand smooth muscle 14. Differences between different generation of sulfonylureas indicate that
cells. adverseeffect on cardiovascular system may not be a group effect.

• Results of meta-analysis of RCTs suggest no in-
creased risk of cardiovascular adverse effects with
newer sulfonylureas.

• Results of meta-analysis of observational studies
indicate increased risk of cardiovascular adverse
effectswith the older sulfonylureas.

• Differences between different generation of sulfo-
nylureas indicate that adverseeffect on cardiovas-
cular system may not be a group effect.

Reference

1. Kaveeshwar SA, Cornwall J. The current state of diabetes mellitus in India.
Australas Med J. 2014;7(1):45-8.

2. IDF. Treatment algorithm for people with type 2 diabetes. Available at
http://www.idf.org/treatment-algorithm-people-type-2-diabetes. Accessed
on 20August 2017

3. Standards of Medical Care in Diabetes—2016, Diabetes Care.
2016;39(Suppl 1): S1-112.

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560 Cardio Diabetes Medicine 2017

Glucose Lowering Strategies and
Cardiovascular Outcomes

Dr. Rakesh Sahay

Prof. & Head Department of Endocrinology
Osmania Medical College and Hospital, Hyderabad

Dr. Ella Reddy Chintala

Senior Resident, Department of Endocrinology

Introduction come studies, including the seminalDiabetes Control
and ComplicationsTrial (DCCT) and UK Prospective
Cardiovascular disease is the leading cause of mor- DiabetesStudy (UKPDS), HbA1c was establishedas a
bidityand death in people with diabetes mellitus. surrogate biomarker of glycaemiccontrol and thera-
While worseninghyperglycemia is directly associat- peutic goals were set accordingly (6).
ed with pooreroutcomes, studies aiming at euglyce-
mia have failed toshow an advantage over modest Cv Outcome Studies And Antidiabetic Drugs
glucose lowering strategies. Several diabetes drugs
that were approved solely onthe basis of their glu- CV safety trials of all new antihyperglycemic thera-
cose-lowering potential were latershown to increase pies have been mandated by the USFood and Drug
cardiovascular risk. Administration (FDA) since 2008. However, at least
three CV outcomestudies predated that mandate.
Background The UGDP trial [7] suggested that treatment with
theshort-acting sulfonylurea tolbutamide was associ-
Since the 2008 FDA Guidance for industry “Diabetes ated with an increase in CV death.However, concern
Mellitus Evaluating Cardiovascular Risk in New Anti- about methodology limited the impact of this study.
diabeticTherapies in Type 2 Diabetes” [1] sponsors of Although not designed to test the CV safety of met-
allnew antihyperglycemic drugs should demonstrate formin, a secondary analysis of overweight patientsin
that the therapy will not result in an unacceptable the UKPDS sub study showed that treatment with
increase in CV risk. Among the evaluated endpoints metformin was associated with a 39%reduction in MI,
stand cardiovascular mortality, myocardial infarction compared with diet and exercise [8]. The PRO-AC-
and stroke, but also can include hospitalization for TIVE study failed to showbenefit of pioglitazone
acute coronary syndrome, urgent revascularization in the primary endpoint (a composite of death, MI,
procedures, and possibly other endpoints. Moreover, stroke, acute coronary syndrome, leg revasculariza-
the FDA favours the enrolment of high-risk patients, tion or amputation, percutaneous coronaryinterven-
such as those with relatively advanced disease, el- tion, or coronary artery bypass graft) [9], but did show
derly patients, or under some degree of renal im- a significant 16% reductionin the 3-point major ad-
pairment. Along the lines of the FDA, the European verse CV event (MACE) endpoint (CV death, non fatal
Medicines Agency (EMA) [2] also requires an overall MI and non fatal stroke), which has been a more typ-
assessment of safety to exclude that a new drug ical endpoint for CV trials [10]. The ORIGIN study was
increases the risk of macro vascular complications designed to test the hypothesis that treatment with
such as CVD. glargine insulin might reducesecondary CVD events
in patients with CVD and prediabetes or recent onset
The goals of antidiabetic treatment are to avert the diabetes. Theresults showed no difference between
untoward metabolic effects of high glucose concen- glargine and placebo in the occurrence of the 3-point
trations and prevent microvascular and macrovascu- MACE endpoint [11].
lar complications. Compelling data in type 2diabetic
patients support the conclusionthat improved long-
term glycaemic controlreduces the risk of microvas-
cular complications (3-5). Based on several largeout-

GCDC 2017

Glucose Lowering Strategies and 561
Cardiovascular Outcomes

Cv Safety Studies of New Antihyperglycemic Sitagliptin
Agents
Sitagliptin is a dipeptidyl peptidase 4 (DPP-4) inhibitor
CV safety studies have been completed for three which increases the level of glucagon-like peptide1
dipeptidyl peptidase-4 (DPP-4) inhibitors, three glu- and glucose-dependent insulinotropic polypeptide.
cagon-like peptide 1 (GLP-1) receptor agonists, two The Trial Evaluating Cardiovascular Outcomes with
sodium/glucose cotransporter 2 (SGLT-2) inhibitors Sitagliptin (TECOS) randomized 14,671 patients with
and one long acting insulin analogue. All three of the type 2 diabetes (T2DM) and cardiovascular (CV) dis-
DPP-4 inhibitors demonstrated CV safety, but did not ease to receive either sitagliptin or placebo added to
show any CV benefit over placebo [12-14]. their existing therapy [14].The primary outcome of the
trial is the composite of CV mortality, nonfatal MI,
Saxagliptin nonfatal stroke, or hospitalization for unstable an-
gina. The primary outcome occurred in 11.4% of pa-
Saxagliptin is a selective dipeptidyl peptidase 4 tients in the sitagliptin group as compared to 11.6% in
(DPP-4) inhibitor that lowers glucose.  Saxagliptin placebo (HR 0.98; 95% CI 0.89-1.08). Sitagliptin was
therapy did not increase the risk of the composite non-inferior to placebo for the primary outcome (HR
Major Cardiovascular Event (MACE) endpoint of CV 0.98; 95% CI 0.88-1.09). Additionally, sitagliptin did
death, non-fatal myocardial infarction (MI), or nonfa- not increase the rate of hospitalization due to heart
tal ischemic stroke, meeting the primary safety ob- failure, or other adverse outcomes including pancre-
jective of SAVOR-TIMI 53 (The Saxagliptin Assess- atitis and pancreatic cancer.
ment of Vascular Outcomes Recorded in Patients
with Diabetes Mellitus–Thrombolysis in Myocardial Lixisenatide
Infarction 53) study [12]. Additionally, saxagliptin did
not increase the risk of an expanded CV composite Lixisenatide is an injectable glucagonlike peptide
endpoint, which also included hospitalization for HF, (GLP-1) agonist used for the treatment of type 2 di-
hospitalization for unstable angina, or hospitalization abetes. The first of the GLP-1 CV safety studies to
for coronary revascularization. An increased risk for report was ELIXA, which demonstrated that in com-
hospitalization for HF, a component of the balanced parison to placebo, treatment with lixisenatide did
secondary endpoint, was observed with saxagliptin not show a benefit on cardiovascular outcomes in
treatment. This finding was most relevant for patients the 6000 high-risk patients with diabetes in the Eval-
at increased risk for heart failure (HF), such as those uation of Lixisenatide in Acute Coronary Syndrome
with a history of HF or renal impairment. trial [15]. But the agent did not cause any harm in
these patients, who had recently suffered a coronary
Alogliptin event and there was no increased incidence of heart
failure or hospitalization for heart failure.
Alogliptin is a potent and highly selective DPP-4 in-
hibitor. In EXAMINE (The Examination of Cardiovas- Liraglutide
cular Outcomes With Alogliptin Versus Standard of
Care in patients with type 2 diabetes mellitus and Liraglutide is an FDA-approved, injectable, long-act-
acute coronary syndrome) study,[13]  alogliptin once ing GLP-1 receptor agonist that lowers blood sugar,
daily was compared with placebo once daily in com- reduces BP, and promotes weight loss. LEADER (The
bination with standard of care among individuals Liraglutide Effect and Action in Diabetes: Evaluation
with type 2 diabetes mellitus and acute coronary of Cardiovascular Outcome Results) trial randomized
syndrome (ACS). It randomized 5380 patients with 9,340 patients with type 2 diabetes and high CV risk
T2DM who had either a MI or unstable angina requir- to receive liraglutide or placebo [16]. With a median
ing hospitalization in the previous 15 to 90 days. The follow-up of 3.8 years, liraglutide was associated with
purpose was to address concern regarding elevated a significant reduction in CV mortality, nonfatal MI,
cardiovascular risk related to new antihyperglycemic or nonfatal stroke (13.0% vs. 14.9%, P<0.001) as well
drugs used to treat T2DM. The primary outcome end as a reduction in all-cause mortality (8.2% vs. 9.6%,
point was a composite of death from cardiovascular P=0.02). There was no reduction in hospitalizations
causes, non‐fatal myocardial infarction, or non‐fatal for CHF with liraglutide versus placebo. The mecha-
stroke, in which alogliptin proved to be non‐inferior nism leading to improved CV outcomes with liraglu-
vs. placebo (11.8% vs. 11.3%) with a median trial duration tide is uncertain.
of 18 months. There were no statistically significant
findings on other safety or outcome endpoints. Semaglutide

The Trial to Evaluate Cardiovascular and Other Long-

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562 Cardio Diabetes Medicine 2017

term Outcomes With Semaglutide in Subjects With overall risk of cardiovascular disease by 14 percent
Type 2 Diabetes (SUSTAIN-6) examines the long- and reduced the risk of heart failure hospitalization
term cardiovascular and other safety outcomes of by 33 percent. The drug also demonstrated potential
0.5-mg and 1.0-mg semaglutide, which was admin- renal protective effects [20].
istered subcutaneously once weekly and compared
with placebo, both in addition to standard of care, Degludec
in approximately 3300 people with type 2 diabetes
treated for 104 weeks. The primary outcome was the Insulin degludec is a new-generation injectable basal
composite of CV mortality, nonfatal MI, or nonfatal insulin that is administered once daily and provides
stroke. The outcome was observed in 6.6% and 8.9% a duration of action lasting at least 24 hours. The
of the semaglutide and placebo groups, respectively goal of the DEVOTE trial (A Trial Comparing Cardio-
(hazard ratio 0.74). The trial also noted that the sema- vascular Safety of Insulin Degludec Versus Insulin
glutide group had a higher incidence of diabetic reti- Glargine in Subjects With Type 2 Diabetes at High
nonpathy as compared to placebo (3 vs. 1.8%, hazard Risk of Cardiovascular Events) was to assess the car-
ratio 1.76) [17]. diovascular safety of insulin degludec compared with
insulin glargine in patients with type 2 diabetes at
Empagliflozin high risk of cardiovascular events. In DEVOTE, 7637
patients with T2D who were at high risk of major ad-
Empagliflozin is an inhibitor of the sodium glucose verse cardiovascular events (MACE) were evaluated
co-transporter-2(SGLT-2), which is found almost ex- for approximately 2 years at 436 sites in 20 countries.
clusively in the proximal tubules of nephronic com- Out of the total population, 6506 patients had prior
ponents in the kidneys. SGLT-2 accounts for about cardiovascular disease or chronic kidney disease,
90 percent of glucose reabsorption into the blood. and the remaining patients had multiple cardiovas-
Blocking SGLT-2 reduces blood glucose by block- cular risk factors. The results of this trial indicate that
ing glucose reabsorption in the kidney and thereby degludec is similar to insulin glargine in improving
excreting glucose via the urine. glycemic control and noninferior for reducing cardio-
vascular events in patients with type 2 diabetes and
The EMPA-REG OUTCOME trial was the first of the high cardiovascular risk. The risk of severe hypogly-
modern CV trials to show treatment benefit, in which cemia was lower with degludec. The upper limit of
empagliflozin met the primary endpoint of CV safety, the 95% CI for the HR had to be <1.8 for premarketing
but also showed benefit in the key secondary end- studies and <1.3 for postmarketing studies. This trial
point of 3-point MACE. A 38% reduction in CV death thus establishes the cardiovascular safety profile of
was the primary driver of the outcome. There was no degludec for use in patients with type 2 diabetes,
significant benefit for either MI or stroke. Empagli- compared with insulin glargine [21].
flozin was also associated with a 35% reduction in
hospitalization for CHF, another key secondary end- Discussion
point of this study [18]. Recently, despite the fact that
the mechanism for the improvement in CV outcomes CVOT trials completed after 2008 showed that new
is unknown, the FDA approved the indication of em- glucose lowering agents like the DPP-4 inhibitors
pagliflozin for reduction of CV death in patients with saxagliptin, alogliptin, and sitagliptin and the GLP-
type 2 diabetes and CVD [19]. 1 receptor agonist lixisenatide are safe with respect
to CV outcomes in high CV risk patient populations
Canagliflozin with long T2D duration under standard care for both
CVD and diabetes. In addition, the LEADER study has
Canagliflozin is a sodium–glucose cotransporter 2 in- shown that liraglutide, a GLP-1 receptor agonist, is
hibitor that reduces glycemia as well as blood pres- not only safe but that is also capable of reducing
sure, body weight, and albuminuria in people with CV risk and the incidence of cardiovascular-related
diabetes. The CANVAS Program assessed the effica- death [16]. Furthermore, recently published results
cy, safety, and durability of canagliflozin in more than from SUSTAIN-6 have proven another GLP-1 receptor
10,000 patients with type 2 diabetes, who had either agonist, semaglutide, superior to placebo in reducing
a prior history of CV disease, or at least two CV risk the risk of a cardiovascular composite primary end-
factors. It is composed of two, nearly-identical large point, driven by a significant reduction of stroke risk
outcomes studies: CANVAS (CANagliflozin Cardio- [17]. Moreover, treatment with the SGLT-2 inhibitors
Vascular Assessment Study) and CANVAS-R (Study empagliflozin and canagliflozin were not only non-in-
of the Effects of Canagliflozin on Renal Endpoints). ferior to placebo but also significantly reduced CV
The results showed that canagliflozin reduced the

GCDC 2017

Glucose Lowering Strategies and 563
Cardiovascular Outcomes

risk -as shown by the composite primary and sec- from the introduction of new strategies to improve
ondary outcomes- and a composite outcome of HF the applicability of trial results to daily clinical prac-
hospitalization and CV death [18,20]. tice, as was agreed by the members of the first CVOT
Summit of the Diabetes and CVD (D&CVD) EASD
Regardless of the CV safety of all anti-hyperglyce- Study Group [32].
mic agents tested, one trial on DPP-4 inhibitors, SA-
VOR-TIMI, found a significantly higher risk for HF in Most CVOTs started after the 2008 FDA/EMA guide-
the treatment group and another, EXAMINE a trend line analyze drugs of the SGLT-2 inhibitor, DPP-4-in-
towards such outcome [12, 13]. In contrast, there were hibitor, or GLP-1 receptor agonist class. Even when
no such concerns in the TECOS trial [14]. Differenc- the ORIGIN trial already focused on the evaluation
es to baseline patient characteristics, as well as to of insulin gargline versus standard care [11], since the
trial design make it difficult to compare results from FDA mandate only one CVOT study investigated CV
these trials. Moreover, the molecular structure differs risks of insulin treatment, the DEVOTE trial on insu-
among DPP-4 inhibitors and so does their safety lin glargine versus insulin degludec. To date there is
profile. As a result, the FDA recently issued a safe- not a single CVO trial on metformin or sulphonylurea
ty warning on saxagliptin and alogliptin increasing alone. Considering that metformin is a first line treat-
the risk of heart failure, particularly in patients who ment for T2D [33] and that sulphonylurea and insulin
already have heart or kidney disease [22]. Despite are also very common therapeutic tools in diabetes
recent meta analyses of randomized clinical trials [34], more CVOTs on these drugs are essential.
including results of SAVOR-TIMI and EXAMINE sug-
gested an increased risk of hospitalization due to Conclusion
HF in T2D patients [23–26], others have found no
difference in hospitalization rates for HF between Since the 2008 FDA/EMA regulations demanded an
treatment with saxagliptin compared with sitagliptin investigation of CV outcomes for newly developed
or with DPP-4 inhibitors compared with other classes glucose-lowering agents, a number of CVOTs have
of anti-diabetes agents [27, 28]. been completed and their results published. These
trials, in general, have shown that glucose-lowering
The analyses of results of the aforementioned drugs do not increase CV risks over placebo levels,
CVOTs have been very useful for treatment deci- and even that some drugs, as empagliflozin, cana-
sion-making and patient safety in diabetes [29]. Not gliflozin, semaglutide or liraglutide, can actually lead
only were these trials capable of proving CV safety, to cardiovascular protection. However, despite satis-
but four of them, EMPA-REG OUTCOME, LEADER, fying the requirements of regulatory agencies when
SUSTAIN-6 and CANVAS showed cardiovascular it comes to demonstrating not incrementing CV risk
benefits even when they were primarily designed for beyond a certain safety level, current CVOTs suffer
non-inferiority. However, it is important to note that still from certain design flaws that hinder their po-
these results are so far only valid for the particular tential. Head to head comparisons, broader patient
patient groups enrolled in the studies, and that it is population groups, long-term analysis and an expan-
not clear how translatable they are to the general pa- sion of safety end-points, etc. would serve to improve
tient population. Furthermore, a comparison among CVOT design and expand its applicability spectrum.
results from CVOT is overall difficult, among other Several future CVOT trials are being conducted with
reasons because the definition of CVD risk and/or linagliptin (CARMELINA, CAROLINA), dapagliflozin
CVD is different for each trial, and with it the degree (DECLARE-TIMI), ertugliflozin (VERTIS-CV), exenati-
of severity of prior disease of enrolled patients highly de once weekly (EXCEL), dulaglutide (REWIND) and
variable. Other reasons limiting comparability among albiglutide (HARMONY) which will further enlighten
CVOTs, especially in terms of event rates, apart from us in future.
the aforementioned differences in baseline patient
characteristics, are the variable trial duration and the References
diverse definitions of the primary end-point. In ad-
dition, another obstacle for compared evaluation of 1. Federal Drug Administration (FDA). Guidance for industry diabetes melli-
trials evaluating cardiovascular outcomes before and tus—evaluating cardiovascular risk in new antidiabetic therapies to treat
after FDA 2008 regulation is that the routine care type 2 diabetes. 2008. Compliance Regulatory Information Guidances/
background from those trials is somehow dissimilar. ucm071627.pdf.
In general, despite the great advance for the clinical
practice meant by new CVOTs, there is still room for 2. European Medicines Agency (EMA). Guideline on clinical investigation of
improvement [30, 31]. Trial design could still benefit medicinal products in the treatment or prevention of diabetes mellitus.
Verfügbar unter. http://www.ema.europa.eu/docs/en_GB/document_library/
Scientific_guideline/2012/06/WC500129256.pdf (2012).

3. The Diabetes Control and Complications Trial Research Group. The effect

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of intensive treatment of diabetes on the development and progression of ty communication—risk of heart failure. 2016. http://www.fda.gov/Safety/
long-term complications in insulin-dependent diabetes mellitus. N Engl J MedWatch/Safety Information /SafetyAlerts for Human Medical Products/
Med 1993;329: 977–986 ucm494252.htm.

4. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose 24. Monami M, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors
control with sulphonylureas or insulin compared with conventional treat- and heart failure: a meta-analysis of randomized clinical trials. Nutr Metab
ment and risk of complications in patients with type 2 diabetes (UKPDS Cardiovasc Dis. 2014;24(7):689–97.
33). Lancet 1998;352: 837–853
25. Udell JA, et al. Glucose-lowering drugs or strategies and cardiovascular
5. Chew EY, Ambrosius WT, Davis MD, et al.; ACCORD Study Group; AC- outcomes in patients with or at risk for type 2 diabetes: a metaanalysis of
CORD randomised controlled trials. Lancet Diabetes Endocrinol. 2015;3(5):356–
66.
6. Eye Study Group. Effects of medical therapies on retinopathy progression
in type 2 diabetes. N Engl J Med 2010;363: 233–244 26. Wu S, et al. Dipeptidyl peptidase-4 inhibitors and cardiovascular out-
comes: meta-analysis of randomized clinical trials with 55,141 partici-
7. American Diabetes Association. Standards of medical care in diabe- pants. Cardiovasc Ther. 2014;32(4):147–58.
tesd2010. Diabetes Care 2010; 33(Suppl. 1):S11–S61.
27. Li L, et al. Dipeptidyl peptidase-4 inhibitors and risk of heart failure in
8. Meinert C, Knatterud G, Prout T, Klimt CR. A study of the effects of hy- type 2 diabetes: systematic review and meta-analysis of randomised and
poglycemic agents on vascular complications in patients with adult-onset observational studies. BMJ. 2016;352:i610.
diabetes. II. Mortality results. Diabetes. 1970;19:789–830.
28. Fu AZ, Johnston S, Sheehan J, Ghannam A, Tsai K, Cappell K. Risk of
9. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive hospitalization for heart failure with dipeptidyl peptidase-4 inhibitors vs
blood-glucose control with metformin on complications in overweight pa- sulfonylureas and with saxagliptin vs sitagliptin in a US claims database.
tients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854–865. Diabetes. 2015;64(Suppl 1A):42.

10. Dormandy J, Charbonnel B, Eckland D et al. Secondary prevention of 29. Giorda CB, et al. Hospitalisation for heart failure and mortality associ-
macrovascular events in patients with type 2 diabetes in the PROactive ated with dipeptidyl peptidase 4 (DPP-4) inhibitor use in an unselected
Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a population of subjects with type 2 diabetes: a nested case–control study.
randomised controlled trial. Lancet 2005;366:1279–1289. BMJ Open. 2015;5(6):e007959.

11. Wilcox R, Kupfer S, Erdmann E et al. Effects of pioglitazone on major 30. Ryden L, Shahim B, Mellbin L. Clinical implications of cardiovascular out-
adverse cardiovascular events in high-risk patients with type 2 diabetes: come trials in type 2 diabetes: from DCCT to EMPA-REG. Clin Ther.
results from PROspective pioglitAzone Clinical Trial In macro Vascular 2016;38(6):1279–87.
Events (PROactive 10). Am Heart J 2008;155:712–717.
31. Smith RJ, Goldfine AB, Hiatt WR. Evaluating the cardiovascular safety of
12. ORIGIN Trial Investigators. Basal insulin and cardiovascular and other new medications for type 2 diabetes: time to reassess? Diabetes Care.
outcomes in dysglycemia. N Engl J Med 2012;367:319–328. 2016;39(5):738–42.

13. Scirica B, Bhatt D, Braunwald E et al. Saxagliptin and cardiovascular 32. Zannad F, et al. Assessment of cardiovascular risk of new drugs for the
outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013 treatment of diabetes mellitus: risk assessment vs. risk aversion. EurHeart
;369:1317–1326. J Cardiovasc Pharmacother. 2016;2(3):200–5.

14. White W, Cannon C, Heller S et al. Alogliptin after acute coronary syn- 33. Schnell O, et al. Report from the 1st cardiovascular outcome trial (CVOT)
drome in patients with type 2 diabetes. N Engl J Med 2013;369:1327– summit of the diabetes & cardiovascular disease (D&CVD) EASD study
1335. group. Cardiovasc Diabetol. 2016;15(1):33.

15. Green J, Bethel M, Armstrong P et al. Effect of Sitagliptin on Cardiovas- 34. An H, He L. Current understanding of metformin effect on the control of
cular Outcomes in Type 2 Diabetes. N Engl J Med 2015;373:232–242. hyperglycemia in diabetes. J Endocrinol. 2016;228(3):R97–106.

16. Pfeffer M, Claggett B, Diaz R et al. Lixisenatide in Patients with Type 2 35. Inzucchi SE, et al. Management of hyperglycemia in type 2 diabetes,
Diabetes and Acute Coronary Syndrome. N Engl J Med 2015;373:2247– 2015: a patient-centered approach: update to a position statement of
2257. the American Diabetes Association and the European Association for the
Study of Diabetes. Diabetes Care. 2015;38(1):1409.
17. Marso S, Daniels G, Brown-Frandsen K et al. Liraglutide and Cardiovas-
cular Outcomes in Type 2 Diabetes. N Engl J Med 2016;375:311–322.

18. Marso S, Bain S, Consoli A et al. Semaglutide and Cardiovascular Outcomes
in Patients with Type 2 Diabetes. N Engl J Med 2016;375:1834–1844.

19. Zinman B, Wanner C, Lachin J et al. Empagliflozin, Cardiovascular Out-
comes, and Mortality in Type 2 Diabetes. N Engl J Med 2015;373:2117–
2128.

20. FDA approves Jardiance to reduce cardiovascular death in adults with
type 2 diabetes. Available at www.fda.gov/NewsEvents/Newsroom/Pres-
sAnnouncements/ucm531517.htm.

21. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular
and renal events in type 2 diabetes. N Engl J Med. 2017.

22. Marso SP, McGuire DK, Zinman B, Poulter NR, Emerson SS, Pieber TR,
Pratley RE, Haahr PM, Lange M, Brown-Frandsen K, et al. Efficacy and
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23. FDA. Diabetes medications containing saxagliptin and alogliptin: drug safe-

GCDC 2017

Cardio Diabetes Medicine 2017 565

07. Prevention

1. Tight Glycemic Control Decreases Cardio Vascular Mortality
2. Diabetes and Exercise
3. Exercise and Physical Activity in Diabetes Mellitus
4. Medical Nutrition Therepy in Cardiodiabetes
5. Prevention of Non-Communicable Diseases - Whom to Focus?
6. Medical Nutritional Therapy in Gestational Diabetes
7. Medical Nutrition Therapy in Heart Failure
8. Primary Prevention of Type 2 Diabetes – Make in India
9. Medical Nutrition Therapy in Chronic Kidney Disease
10. The Role of Lifestyle Modification in the Prevention of Diabetes and Cardiovascular Disease
11. Lifestyle &Noncommunicable Diseases: My ‘Formula of 80’ to Live Up to 80 Years Without

a Lifestyle Disease

Cardio Diabetes Medicine

566 Tight Glycemic Control Decreases Cardio Vascular Mortality
(Proponent)

GCDC 2017

Cardio Diabetes Medicine 2017 567

Tight Glycemic Control Decreases Cardio Vascular Mortality

(Proponent)

DR. M. SHUNMUGAVELU M.D.,

Specialist in Internal Medicine / Diabetologist / Chairman
Trichy Diabetes Speciality Centre (P) Ltd.,
Trichy-620017, Tamil Nadu, India

Introduction As another recent example, after 15 years of fol-
low-up in a population-based study of nearly 10,000
Diabetes and Cardiovascular events are known to be individuals in Mauritius, Cardiovascular risk was
closely associated. In the presence of Diabetes, Car- greater in persons with Impaired Glucose Tolerance
diovascular risk is increased by two-to-five-fold, de- (IGT), newly diagnosed Diabetes or previously known
pending on the population considered and the nature Diabetes than in a group without glycemic abnormal-
of the event. Given this association, management of ities at baseline [1].
patients with or at risk for Diabetes to improve Car-
diovascular outcomes has received much attention. Inflammatory Cascade, Diabetes and
However, the role of glycemic control continues to Atherosclerosis
be debated [1].
Atherosclerosis is a complex multifactorial disease,
Epidemiologic association between and the acceleration of atherosclerosis in Diabetes
Hyperglycemia and Cardiovascular Events may be explained by several conditions including hy-
perglycemia, increased oxidative stress, AGE, dyslip-
Studies have shown that among persons with Dia- idemia, autonomic imbalance, hyper-insulinemia, in-
betes, a higher HbA1c predicts worse outcomes. Re- flammatory markers excess and genetic variables [3].
cent Studies show that persons with slightly elevat-
ed glucose, which does not meet the definition of Adiponectin, has many protective actions in the
Diabetes also, have increased Cardiovascular risk. atherosclerosis process, is markedly reduced with
In an epidemiologic study of a population of more increased obesity and in Diabetes and hypo-adi-
than 6,50,000 Korean men, men with FPG above ponectinemia is associated with an increase in CVD
100 mg/dl had significantly higher risk of both Myo- rates [3].
cardial Infarction and Ischemic Stroke [1]. For each
18 mg/dl higher FPG, risk increased 11% for MI and Epigenetic reactions could be an important mediator
21% for Stroke. A Meta-Analysis including nearly between Diabetes, CVD and chronic inflammatory re-
7,00,000 individuals yielded similar results. Persons sponse. Besides, some comorbidities associated with
with known diabetes whose FPG was less than 126 Diabetes have also been associated with epigenetics
mg/dl had 61% higher risk than those without Dia- like hypertension and Obesity. The Epigenetic modi-
betes and FPG 70–100 mg/dl, whereas those with fications associated with hypertension are related to
known Diabetes and FPG higher than 126 mg/dl had intrauterine environmental factors which can limit the
136% increased risk[1]. development of the nephrons and to other factors
that are related to autonomic responsiveness, vessel
Similar findings are reported for HbA1c (A1c) as an remodeling, salt sensitivity and to the Renin-Angio-
indicator of Glycemic status [1]. A recent report from tensin System[3].
continued long-term follow-up of a cross-section-
al US population of about 20,000 persons in the Recent studies have shown that dysregulation of the
NHANES confirms a much higher unadjusted car- Autonomic Nervous System (ANS) with increased
diovascular death rate among persons with diabetes sympathetic activity is associated with elevated in-
compared with those without diabetes [2]. flammatory markers such as IL-6 and CRP, demon-

Cardio Diabetes Medicine

568 Tight Glycemic Control Decreases Cardio Vascular Mortality
(Proponent)

strating a link between autonomic imbalance, inflam- Endpoints.Total and Cardiovascular mortality were
mation and CVD [3]. unchanged withthe intensive regimens in ADVANCE.

Can glycemic intervention reduce Another Meta-Analysis, also using weighted data
cardiovascular risks? from each study rather than patient level data, added
the main UKPDS and the UKPDS obese sub-study to
Five large studies seeking lower glycemic targets the results of ADVANCE, VADT and ACCORD [1]. It
have been completed . showed a significant 10% reduction in a Cardiovas-
cular composite endpoint driven mainly by 16% lower
risk of nonfatal MI and also no significant changes in
all cause or Cardiovascular mortality. Heterogeneity
between the studies was apparent for all cause and
Cardiovascularmortality, with ACCORD being the out-
lier withunfavorable outcomes [1].

The earlier randomized Studies the DCCT in Type 1 Temporal relationships: the Legacy effect in
Diabetes and the UKPDS in Type 2 Diabetes both the DCCT and UKPDS
showed that intensive glycemic control can reduce
Microvascular complications more than a conven- In the DCCT/EDIC follow-up, a broad composite Car-
tional regimen. However, both failed to verify Car- diovascular endpoint was reduced 42% (P¼0.02) and
diovascular benefits. Specifically, the DCCT showed the composite of Cardiovascular death, nonfatal MI
a non-statistically significant 41% reduction of a broad or nonfatal Stroke was reduced 57% (P¼0.02). In the
Cardiovascular composite endpoint accompanying UKPDS follow-up, relative risk reductions after inten-
6.5 years of randomized treatment achieving a 2% sive treatment with Insulin or a Sulfonylurea were 13%
between-group A1c differential [1]. (P¼0.007) for all-cause mortality and 15% (P¼0.01) for
fatal or nonfatal MI. These findings support intensive
The main UKPDS found 16% fewer (P¼0.052) fatal or management of hyperglycemia early in Diabetes and
nonfatal MI events and 21% less nonfatal MI (P¼0.057), predict that studies may require up to 10 or more
accompanying 0.9% lower A1c during a 10-year period. years of follow-up to demonstrate benefits [1]. Alter-
Potential explanations for these inconclusive results natively, the beneficial effect of intensive therapy on
include low Cardiovascular event rates in the rela- the risk of Cardiovascular disease may be a result of
tively healthy populations studied and the failure of the reduction in the incidence of micro-vascular dis-
intensive treatment to obtain nearly normal glucose ease. Both Renal disease and Autonomic Neuropathy
levels. In both studies, the participants were relative- have been proposed as risk factors for Cardiovascu-
ly young and had recently diagnosed Diabetes and lar disease. To the extent that intensive therapy re-
in neither study were participants required to have duces these risk factors, Cardiovascular disease may
Cardiovascular risk factors other than Diabetes. Both also be reduced[2].
studies achieved A1c levels averaging close to 7.0%
with intensive treatment, although glycemic control The legacy concept is relevant to the ADVANCE,
deteriorated over time in the UKPDS [1]. VADT and ACCORD Studies, in which participants
with well-established Cardiovascular Disease were
In the more recent studies high-risk patients wereen- intentionally selected for Study. For such persons
rolled and thus event rates were high. These studies- with long-term hyperglycemia and established tissue
confirmed that Microvascular events can be reduced injury, glucose lowering may have little effect on es-
insuch patients, but also failed to show benefit of tablished Cardiovascular risk due to a legacy effect in
intensivetreatment on their primary Cardiovascular reverse. That is, just as the structural and functional
changes of advanced Diabetic Retinopathy and Ne-
phropathy are not reversed by late glycemic interven-
tion, structurally advanced Cardiovascular Disease
may not respond well to Glycemic Control [1].

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Cardio Diabetes Medicine 2017 569

seemsunlikely that hyperglycemia does not increase
Cardiovascular risk. The recent studies included
participants with low potential for reversing estab-
lished Cardiovascular disease and high risk of treat-
ment-associated side-effects. Fig. 3 shows a grid with
four subgroups arranged by duration of Diabetes and
evidence for Cardiovascular disease [1].

Off-target effects of treatment: Is Glucose Control Important for Prevention
Cardiovascularmortality in the ACCORD. of Cardiovascular Disease in Diabetes?

A multivariable analysis of baselinepredictors of the There is convincing evidence from epidemiological
excess mortality with intensive versusstandard gly- and pathophysiological studies that hyperglycemia
cemic strategies showed only three independent- has a detrimental effect on Cardiovascular risk profile
predictors. They were baseline A1chigher than 8.5%, in its own right. It is well known that among patients
symptomatic Neuropathy reported bythe participants with Type 2 Diabetes, those with higher levels of
and a history of daily Aspirin therapy [1]. High A1c at blood glucose and HbA1c are at greater risk for CVD
Baseline suggests, alone or in combination, greater [5]. Glycemic fluctuations and chronic hyperglycemia
prior hyperglycemic exposure, greater severity of un- are triggers for inflammatory responses via increased
derlying pathophysiologic defects and/or behavioral endoplasmic reticulum stress and mitochondrial su-
factors interfering with management. In the whole peroxide production.Several risk factors for CVD,
ACCORD population, each 1% higher average A1c was including Insulin resistance/ hyperinsulinemia, hy-
associated with 22% higher risk of death. One is that perglycemia, overweight/ obesity, haemorheological
the risk of severe hypoglycemia was greater at higher abnormalities, dyslipidemia and hypertension, are of-
rather than lower average [1]. ten present in varying combinations in patients with
Type 2 Diabetes [5].
The ACCORD trial also recently showed a signifi-
cant reduction in the rate of nonfatal Cardiovascular It should also be considered that the impact of hy-
events in a follow-up of its Study population, but that perglycemia on Cardiovascular risk could be different
benefit was offset by an increase in mortality in the in Type 1 and Type 2 Diabetes. Patients with Type 2
original trial [4]. In contrast, no reduction in the rate Diabetes are heterogeneous for age, duration of dis-
of Cardiovascular events or in mortality was found in ease, comorbidity and genetic background. Glucose
a follow up of the ADVANCE trial [4]. lowering therapy should be adapted to this complexi-
ty, with an attempt at improving, or at least avoidance
The extended follow-up study of the VADT showed of worsening, associated Cardiovascular risk factors.
that a current multidrug glycemic treatment regimen
can be associated with a significant reduction in ma-
jor Cardiovascular events among older patients who
have had Diabetes for many years [4].

One size does not fit all

With the strong and consistent epidemiologic data
andthe long-term results of the DCCT and UKPDS, it

Cardio Diabetes Medicine

570 Tight Glycemic Control Decreases Cardio Vascular Mortality
(Proponent)

Conclusion

Evidence that hyperglycemia leads to Cardiovascu-
larevents at a rate dependent on both severity and
durationof exposure continues to accumulate. Two
Interventional Studies with 17 and 20 years of fol-
low-up after initiationof treatment early in the natural
history of Diabetessupport the view that treating hy-
perglycemia can reduce Cardiovascular risk [1]. Ag-
gressive treatment ofpatients with long-duration dia-
betes and high Cardiovascularrisk has proved disap-
pointingly ineffective, andthe ACCORD trial showed
increased Cardiovascularmortality, for which neither
Clinical predictors of risknor a probable mechanism
has been well defined [1].

Reference:

1. Endocrinology, Diabetes & Obesity 2011,18:104–109. DOI:10.1097/
MED.0b013e3283446b7e

2. N Engl J Med 2005; 353:2643-2653; December 22, 2005.DOI: 10.1056/
NEJMoa052187

3. Int J Hypertens (2013) 2013:653789. DOI:10.1155/2013/653789.
4. N Engl J Med 2015;372:2197-206. DOI: 10.1056/NEJMoa1414266
5. Diabetes Care, Volume 36, Supplement 2, August 2013.DOI: 10.2337/

dcS13-2018

GCDC 2017

Cardio Diabetes Medicine 2017 571

Diabetes and Exercise

(Prevention In Special Population)

Dr.S.Rajan M.D

Retired Prof. and HOD of Medicine,TKMCH,
Tuticorin

Why people with diabetes need exercise? Types of physical activity recommended:

* Exercise improves general health * Aerobic exercises

* Exercise generally lowers blood glucose resulting * Anaerobic exercises
in decreased insulin/OHA requirements.
* Flexibility exercises
* It prevents/delays the progression of diabetes re-
lated complications. * Endurance exercises.

* Exercise lowers the blood pressure levels and low- Aerobic exercise moves large muscle groups and
ers blood cholesterol. causes you to breath more deeply & your heart to

* Lowers risk of heart disease and stroke. work harder to pump blood, improves health of heart
and lungs.
* Relives stress and improves mental health.
Anaerobic exercises helps build strong muscles,
How to prepare for doing exercise sessions: lowers blood glucose levels and makes the action
of insulin more sensitive and effective.
Proper warm up consisting of 5-10mins of aerobic
activity is mandatory. Low blood glucose can occur during/or long after
physical activity:
Benefits of warm up:
It is more likely to occur if:
* It cause gradual increases circulation in legs and
reduces risk for injury. * If pt has taken insulin before exercise.

* Warm up can-include: * Eat nothing within 30 minutes of exercise.

* Light walking ,light cycling, balance exercise, move- * Eat nothing 2 hour after workout.
ment &light stretching for 5-10 minutes.
* Exercise for a long time.
* Activity session for a period of atleast 15-30 min-
utes is preferred. * Exercise extra strenuously.

* Cool down should be structured similarly to warm * Injecting insulin in exercising limb/so one should
up and should least for 5-10minutes. always avoid it, abdomen site is preferred.

Goal is to avoid hypoglycemia for people during I should stop my exercise when?
exercise. If your values are either high or low, it is
recommended to check your blood glucose in the * get symptoms of hypoglycemia.
middle of doing exercise to avoid episodes of hypo/
hyperglycemia. * Blurred vision

* Weak/tired

* Hungry/Sweaty

* Shaky/Dizzy

Cardio Diabetes Medicine

572 Diabetes and Exercise
(Prevention in Special Population)

One should stop exercise when he/she has faint * Headache/chest pain
pain/feel shortness of breath.
* Sudden calf pain/swelling
Be prepared to treat hypoglycemia:
* Pre term labour
* If you experience hypoglycemia:
* Decreased fetal movement
* Have 15-20 gms of fast acting carbs9glucose tab-
lets, a piece of fruit, soft drinks, regular soda) * Amniotic fluid leakage

* Avoid exercising alone/in remote areas. During your 2nd and 3rd trimesters , don’t expect to
be able to achieve the same level of exercise per-
* Wait for 15-20 minutes and check your blood glu- formance as you did before pregnancy. During later
cose again. mages of pregnancy, a brisk walk is n sufficient to
reach a moderate level of intensity in doing exercise
* After you feel better, eat regular meals &snacks to .During exercise, it is best to avoid sudden change
keep blood glucose level up. of direction, bouncing ,and high impact. Women may
become less stable and susceptible to falls, so one
Remember: should play safe in terms of balance in later stages
of pregnancy.
Patient should always carry a source of carbohydrate
with him carry a source of carbohydrate with him After delivery:
during exercise (an apple, orange juice, a piece of
fruit)./always wear a diabetes identification bracelet * Regular exercises are recommended to strengthen
while exercising. the muscles of pelvic floor.

Exercising during pregnancy with diabetes: * Exercise patterns in diabetic patients:

Of course, no woman wants to do anything might * Aim is to do the following types of activity :
be harmful to her baby, so safety is the first option.
* Aerobic activity at relative moderate intensity for
Women are recommended to engage in 30 minutes atleast 150 minutes(2 hours and 30 minutes) a week.
of moderate –intensively, low impact aerobic exer-
cises 3 times per week. They include brisk walking, * Muscle strengthening activity on two or more days
swimming, water exercises, armchair exercises 7 use a week which work all major muscles groups ( legs
of stationary equipment such as treadmills, bicycles& , hips ,back ,abdomen ,chest, shoulder and arms).
ELLIPTICAL TRAINERS.
* Flexibility exercises on daily basis.
Activities to be avoided:
What type of activity is a diabetic patient adviced to
* High altitude activities (skydiving, mountain climb- do?
ing, scuba diving, weight lifting) exercises are usually
not recommended during pregnancy. Choose exercises , that you can enjoy, such as walk-
ing, cycling, or group fitness classes
* Few reasons to avoid exercise entirely
How long (duration)?
* Incompetent cervix
Once should do atleast 30 minutes /day to meet the
* Cerclage recommendations. You can split your sessions to a
minimum of 30 minutes /day.
* Expecting twins/triplets
How often(frequency)?
* Persistent 2nd &3rd trimester vaginal bleeding.
If you aim to do 30 minutes /day then do this atleast
* Placenta previa 5 times per week so that you can reach a total of 150
minutes a week. Distributes sessions over the week
* Premature labour and aim to have no more than 2 consecutive days
without physical activity.
* Ruptured membranes
Diabetic with peripheral neuropathy :
* Pregnancy induced hypertension Exercise should
be stopped and physician should be controlled im- - Repetitive exercises on insensitive feet can lead to
mediately when if anyone of the following occurs: ulceration and fractures.

* Vaginal bleeding

GCDC 2017

Cardio Diabetes Medicine 2017 573

-wear proper shoes. always monitor feet.

Recommended Contraindicated

Non –weight bearing Tread mill
exercises

Swimming Prolonged walking

Bicycling Jogging

Chair and aim exercis- Step Excercises
es

Patients with autonomic neuropathy:

-Should avoid exercise in hot, cold environment ,as
they have difficulty in thermo regulation

-They should be encouraged to have adequate hy-
dration.

Patients with diabetic retinopathy :

Recommended Contraindicated

Low impact cardiovas- Sternous activities,

cular conditioning, Such pounding jarning , weight

as Swimming, Walking, lifting high impact aero-

Stationary cycling endur- bics ,racquet sports.

ance e Exercise

Cardio Diabetes Medicine

574 Exercise and Physical Activity in Diabetes Mellitus

Exercise and Physical Activity in
Diabetes Mellitus

Dr. N. VETRIVEL

Abstract glyeridemia and ultimately increased cardiovascular
risk. On the other hand, regular moderate to vigorous
The global burden of diabetes, and associated meta- leisure time physical activity, structured aerobic exer-
bolic disorders increasing immensely. Sedentary life cise or both can often reverse these adverse sequlae.
style and blunder bus food habits are shown to pre- An appreciable increase in physical activity and daily
dispose to cardio diabetic disease burden in modern energy expenditure also improves insulin action in
world. Regular physical activity, structured aerobic obesity with or without a concommitant reduction in
exercise or both can offer reversal of this adversi- body weight and fat stores. This is an important and
ty. Since ancient times, regular exercise activity has frequently overlooked salutary effect suggesting that
been recognized as an important tool in the man- physical activity is as effective in preventing insulin
agement of the diabetes. Cardiovascular risk reduc- resistance as loosing body weight.
tion benefits of physical activity are manifold. They
out-weigh the risk associated with exercise program. Since ancient times of Sushrutha and Charaka reg-
Prudent screening to be done to avert hypoglycemia ular physical exercise was recognized as an import-
in T1DM. Exercise guidelines and prescription to be ant part of treatment of diabetes and frequently
in line with the recommendation of ADA and ACSM. prescribed during the pre- insulin era for those with
Physical activity is much useful in the prevention of diabetes. Allen et al(1919), demonstrated that exer-
T2DM. cise lowers the blood glucose concentration and
transiently improves glucose tolerance in DM and in
Introduction: 1926 Lawrence observed that exercise potentiates
the hypoglycemic effect of injected insulin. In spite
The global burden of diabetes, pre-diabetes of the salutary effects of achieving optimal blood glu-
and associated metabolic disorders is exponentially cose control, slightly more than half of individuals
increasing. Currently 382 million people are affected only with diabetes currently are reaching recognized
and this number is estimated to rise to 592 million treatment goals. Although, physical activity has long
by 2035. There is a pathophysiologic cascade by been considered a cornerstone of diabetes manage-
which physical inactivity predisposes to a cluster of ment, prescribing specific exercise for individuals
cardio metabolic diseases including type 2 diabetes with various types of diabetes including pre-diabetes
mellitus (T2DM). With an increasingly sedentary life can be a daunting task for the time pressured health
style, skeletal muscle down regulates its capacity to care provider or the diabetes naive fitness profes-
convert nutritional substances to ATP. Inactive skele- sionals. A fundamental need in facilitation such of
tal muscles inability to oxidize glucose and fatty ac- exercise prescription is an enhanced understanding
ids is presumably mediated by several mechanisms of the types of diabetes and how physical activity
including a) decreased mitochondrial concentration requirements and abilities may differ among them.
and oxidative enzymes b) a reduced ability to remove
glucose from blood because of fewer capillaries and Basics of Terminologies :
diminished glucose transporters and c) an attenuated
capacity to hydrolyze blood triglycerides (TGL) to free Before discussion moves to main topic, it is import-
fatty acids (FFA) due to decreased lipoprotein lapse ant to understand vividly some terminologies used
activity. These metabolic disturbances collectively in exercise medicine. By definition, physical activity
reduce the somatic capacity to burn fuel resulting is any bodily movement produced by the contraction
in Hyperinsulinemia, Insulin resistance and Hypertri-

GCDC 2017

Cardio Diabetes Medicine 2017 575

of skeletal muscle that substantially increases ener- It is appropriate to know one’s maximal heart rate
gy expenditure above resting expenditure. Exercise (MHR) while discussing on intensity of the program.
is the subset of planned structured and repetitive The more accurate equation of Garber (2011) for es-
bodily movements done with the intention of de- timating MHR, especially in older population utilizing
veloping and maintaining physical fitness which in- 70% of age rather than full age can be utilized.
cludes cardiovascular strength and flexibility training
options. Physical fitness has been defined as a set MHR = 208-(0.7 x Age)
of attributes that people have or achieve relating to
their ability to perform physical activity. It includes Benefits Of Exercise:
cardio respiratory fitness, muscle strength body com-
pensation and flexibility. Aerobic exercise means that Regular physical exercise is recognized to have sev-
uses primarily aerobic energy producing system and eral benefits to health, not only for those with DM
involves repeated and continuous movement of the but for everyone. Moderate intensity, sustained ex-
same large muscle groups for extended periods of ercise in patients with either type 1 or type 2 diabe-
time at last 10min at a time. If performed with suf- tes may be used to help day to day basic regulation
ficient intensity and frequency, aerobic exercise in- of glucose may be the mechanism by which regular
creases cardio respiratory fitness. This type includes physical exercise assists in achieving improved long
walking, cycling, jagging, swimming, calisthenics, etc. term metabolic control. The benefits of exercise for
Anaerobic exercise is short, high intensity exercise patients with diabetes are listed in Table 1. Regular
involving anaerobic energy producing systems. This physical exercise lowers blood glucose concentra-
type if, performed with sufficient intensity and fre- tions during and after exercise and also results in
quency can increase the body ability to with stand lower fasting and post meal insulin concentrations
acid-base imbalance during high intensity exercise. and increased insulin sensitivity. In T1DM, increased
insulin sensitivity results in lowered insulin require-
Resistance exercise ments. In T2DM, the improved insulin sensitivity is the
major importance in improving long term glycemic
means as strength training or weight training which control. Several studies have shown that both aero-
involves the use of muscular strength to work against bic and resistance exercise programs improve insulin
a resistance load or move a weight. This includes lift- sensitivity and glycemic control as evidenced by im-
ing free weights or using weight machines. Regular provement in HbA1c levels.
resistance exercise at sufficient intensity increases
muscular fitness. Dose in exercise physiology means Another major benefit of regular physical exercise is
the total amount of energy expended in physical ac- reduction in cardiovascular risk factors which is dis-
tivity. Intensity refers to the rate of energy expendi- cussed in detail. Physical exercise is effective adjunct
ture during such activity which classified as absolute to diet for weight reduction and weight maintenance.
or relative.
Regular and sustained physical exercise, because
Absolute intensity of increased energy expenditure, increased fat loss
occurs with preservation of lean body mass. Several
reflects the rate of energy expenditure during exer- studies have shown that regular physical exercise is
cise and in usually expressed in metabolic equiva- an important part of the life style modification pro-
lents or METS gram and especially important for achieving weight
maintenance after weight loss goal, have been
Relative intensity achieved besides cardiovascular conditioning, exer-
cise improves physical working capacity in terms of
refers to the percent of aerobic power utilized during increased strength and flexibility. Finally, psycholog-
exercise and is expressed as percent of maximal ical benefits of exercise such as an improved sense
heart rate or percent of Vo2 max. of well being, improved self esteem and an enhanced
quality of life are also important for persons with di-
Moderate physical activity or exercise is those per- abetes, who have to cope with the anxieties and lim-
formed at a relative intensity of 40% to 60% of Vo2 itation of living with a chronic disease.
max, whereas vigorous ones are there performed at a
relative intensity of > 60% of Vo2 max. Flexibility exer- TABLE 1.
cises improve range of motion around joints. Balance
exercises benefit gait and prevent falls. Activities like BENEFITS OF EXERCISE FOR PATIENTS
tai chi and yoga combine flexibility balance and re-
sistance activities.

Cardio Diabetes Medicine

576 Exercise and Physical Activity in Diabetes Mellitus

WITH DIABETES specific reference to change in body weight and fat
stores. Compared with the control group, supervised
 Lower blood glucose  Improvement in mild exercise produced significant improvements in cardio
respiratory fitness, upper and lower body strength,
concentrationsDuring to moderate hyperten- HbA1C, systolic and diastolic blood pressure, total
serum cholesterol, HDL-C and LDL-C, body mass
and after exercise sion index (BMI), waist circumference, insulin resistance,
inflammation (C reactive protein), leptin and CHD risk
 Lower basal and post  Increased energy ex- scores, independent of body weight loss. It is also
said that aerobic training increased mitochondrial
prandial insulin concen- penditure density, oxidative enzymes, pulmonary function, im-
mune function and cardiac output.
trations  Adjunct to diet for
Two meta analysis have shown that regular exercise
weight reduction undertaken, can decrease the overall risk of cardio-
vascular events up to 50%, from various mechanisms
 Increased fat loss including anti atherosclerotic, antiishemic, antiar-
rhythmic, antithrombotic and psychological effects.
 Preservation of lean As already noted, aerobic exercise with or without
body mass resistance training, has favorable effects on the di-
abetic patients cardio vascular risk factors profile as
 Improved insulin  Cardiovascular condi- well as on coagulability, fibrinolysis and coronary en-
dothelial function. It is also said that 40% of the risk
sensitivity tioning reduction presumably not explained by changes in
conventional risk factors, a cardio protective vascular
 Lower HbA1C levels  Increased strength condition effect of the exercise including enhanced
and flexibilit nitric oxide vasodilator function, improved vascular
reactivity, altered vascular structure or combination
 Improved lipid profile  Improved sense of thereof has been proposed. Increased threshold to
life threatening arrhythmias and increased resistance
 Increased triglycerides well being and quality to ventricular fibrillation have also been postulated,
of life reflect exercise-related autonomic system adapta-
tion. Endurance training produces reduction in rest-
 Slightly decreased ing sympathetic drive. Vagal tone and heart rate vari-
ability are increased (fig 1)
LDL cholesterol

 Increased HDL2 cho-
lesterol

Cardio Vascular Benefits of Regular Exercise:

Several recent randomized controlled trails in pa-
tients with T2DM have investigated the effects of
moderate to vigorous aerobic exercise and resistance
training on cardio respiratory fitness, modifiable car-
dio vascular risk factors and arterial stiffness, with

Fig 1: Cardio Protective Effects of Regular Exercise

ANTIATHERO- ANTITHROMBOTIC ANTIISHEMIC AUTIARHYTHMIC PSYCHOLOGIC
SCLEROTIC

Improved lipid Decreased platelet Decreased Myocardial Increased Vagal tone Decreased Depres-

profile aggregability O2 demand sion

Lower blood Increased Fibrino- Increased coronary Decreased adrenergic Decreased Stress

pressure lysis blood flow activity

Reduced adi- Decreased Fibrino- Decreased Endothelial Increased heart rate Increased social fit-

posity gen dysfunction variability ness

Increased insu- Decreased blood Increased endo- thelial
lin sensitivity viscosity progenitor cells & cul-
tured angiogenic cells

Decreased in- Increased Nitric oxide
flammation



GCDC 2017

Cardio Diabetes Medicine 2017 577

A structured endurance exercise program, increased unusual intensity for them may precipitate angina
physical activity or both sufficient to maintain and pectoris, myocardial infarction, cardiac arrhythmias
enhance cardio respiratory fitness and multiple ma- or sudden death if there is underlying coronary artery
chineries involved. dieses. Degenerative joint disease in obese people
may be exacerbated by weight bearing exercise and
Risks of Exercise in Diabetes : also patients with sensory neuropathy may experi-
ence joint and soft tissue injuries while participating
There are various risks associated with exercise in exercise.
for patients with diabetes and these risks must be
weighed against the potential benefits. In type1diabe- A number of other complications of diabetes may be
tes either hypoglycemia or hyperglycemia can occur aggravated by exercise. The most important compli-
during exercise, depending on its intensity and dura- cation is proliferative retinopathy in which exercise
tion, the amount and timing of injection insulin and may result in retinal or vitreous hemorrhage. Ex-
the carbohydrate intake of the individual. Moreover, tremely strenuous exercise or exercise associated
after strenuous and prolonged, onset post-exercise Valsalva like maneuvers is particularly dangerous in
hypoglycemia can occur 6 – 15 hr after completion of patients with proliferative retinopathy. Also exercise
the exercise which may persist up to 24hrs. Further resulting in jarring or rapid head motion may precip-
when exercise is superimposed on the insulin defi- itate hemorrhage or retinal detachment. Physical ex-
cient state a rapid increase in good glucose concen- ercise is also associated with increased proteinuria in
tration and the development of ketosis may occur. patients with diabetic nephropathy due to changes in
Even with well controlled T1DM, brief periods of high renal hemodynamics. In diabetic autonomic neurop-
intensity may cause hyperglycemia. athy , the capacity for high intensity exercise may
be impaired because of decreased maximum heart
Prudent screening for underlying cardiac disease rate and aerobic capacity. In addition, there may be
is mandatory for all diabetes, especially those with an impaired response to dehydration and problems
T2DM. In adults a vigorous exercise program with with postural hypotension.

TABLE 2. RISK O F EXERCISE FOR PATIENTS WITH DIABETES

1. Hypoglycemia if treated with Insulin or oral agents. 10. Worsening of long term complications of diabetes

2. Exercise induced hypoglycemia 11. Proliferative retinopathy

Vitreous hemorrhage

3. Late- onset post exercise Hypoglycemia Retinal detachment
12. Nephropathy

4. Hypoglycemia after very sternous exercise Increased Proteinuria
13. Peripheral Neuropathy

Decreased cardiovascular response to exercise

5. Hyperglycemia and ketosis in T1DM patients Decreased maximum aerobic capacity
6. Precipitation or exacerbation of CVD 14. Impaired response to dehydration
7. Angina pectoris 15. Postural hypotension
8. Myocardial Infarction
9. Arrhythmias

With proper screening of the patients and selection of the type, intensity and duration of exercise most of
these complications can be averted.

Cardio Diabetes Medicine