This document summarizes findings from several studies related to cardiovascular protection in type 2 diabetes patients. It begins by noting that atherosclerosis and diabetes often have common antecedents. A framingham offspring study found that 2/3 of diabetes patients have subclinical cardiovascular disease, which increases their cardiovascular risk 4-fold. Another study found that 66-74% of asymptomatic South Asian type 2 diabetes patients have coronary artery disease. The document then notes that subclinical cardiovascular disease affects over 2/3 of diabetes patients, and that cardiovascular complications form a progressive continuum in type 2 diabetes, with heart failure developing early. It reviews findings on cardiovascular risk prior to diabetes diagnosis and the cardiovascular risk continuum in dysglycemia. The document discusses challenges with long

1. Cardiovascular
protection in T2DM
patients

2. Unlike classical microvascular complications,
large-vessel atherosclerosis can precede the development of diabetes,
suggesting that
atherosclerosis being a complication of diabetes, both conditions
have common genetic and environmental antecedents,
i.e., they spring from a "common soil."
Stern P. Diabetes . 1995;44:369-74

4. FRAMINGHAM OFFSPRING STUDY (N=1945)
INGELSSON E ET AL. DIABETES. 2007 JUN;56(6):1718-26
Inferences of Study Findings
2/3rd of patients of DM have Subclinical CVD
DM ↑ses the Risk of Subclinical CVD by 4.3-fold
(age and sex adjusted Odds Ratio: 4.33, p<0.0001)
Subclinical CVD ↑ses the Risk of CV event by ≈2-fold
Patients without
DM / Met-S
Patients with Diabetes
Prevalence of Subclinical
CVD
29.8% 70.4%
Prevalence and Prognostic Impact of Subclinical Cardiovascular
Disease in Individuals With the Metabolic Syndrome and
Diabetes

5. Asymptomatic CVD in
South Asian Patients of T2DM
≈2/3rd to 3/4th of Asymptomatic patients of T2D, may have CAD
Coronary Atherosclerosis South Asians Caucasians
Coronary Artery Calcium +ve 66% 53%
CAD (≥30% block in a coronary artery) 74% 59%
Significant CAD (≥50% block) 41% 28%
Study in Asymptomatic Patients of T2D
South Asians (n = 120) vs. Caucasians (n = 120)
Roos Cl et al. Am J Cardio2014
Jun 1;113(11):1782-7

6. Cardiovascular Complications
A Progressive Continuum in Type-2 Diabetes
In Patients of Diabetes1-4:
•Subclinical CVD affects >2/3rd of patients of Diabetes1
•2/3rd of deaths are attributable to CVD (As-CVD and HF)2
•As-CVD manifests nearly 15 years earlier2
Heart-failure develops early, is 2.5-5 fold more common2
CKD in DM increases CV mortality by 2.9-fold3

7. Elevated Risk of CV Events Prior to Clinical Diagnosis of T2DM
Frank B. Diabetes Care 2002 Jul; 25(7): 1129-1134.
Cardiovascular Risk Continuum in Dysglycemia
Nurses’ Health Study
RRs of MI or Stroke Event
according to DM Status

8. Maintaining glycaemic targets can be difficult to achieve
Glycaemic control tends to decline over time with
monotherapy
44
34
13
0
5
10
15
20
25
30
35
40
45
50
3 years 6 years 9 years
Percentageofpatientswith
HbA1c<7%(%)
Adequately controlled on metformin
JAMA 1999 Jun 2;281(21):2005-12.

9. Khunti K et al. Primary Care Diabetes. 2017; 11:3–12.
Dysglycemic Legacy
Poor A1c Control in 1st Year of Diagnosis: ↑sed Long-term CV Risk

10. Early intervention with combination therapy allows proactive management
of glycemia
Same sequence of interventions but each stage of treatment is brought forward to provide
better and more rapid glycaemic control
Adapted from: Campbell IW. Br J Cardiol 2000;7:625 and Del Prato S et al. Int J Clin Pract 2005;59:1345

11. Hypo-
glycemia
Weight
Change
CV Effects Renal Effects
ASCVD CHF Progression of
DKD
Dosing /
Use
Metformin No Neutral
(potential for
modest loss)
Potential
benefit
Neutral Neutral Contra-
indicated in
eGFR <30#
SGLT2
inhibitors
No Loss Benefit*
(Empagliflozin)
Benefit
(Empagliflozin)
Benefit
(Empagliflozin)
Contra-
indicated in
eGFR <45#
SUs
(2nd
generation)
Yes Gain Neutral Neutral Neutral Glipizide,
glimepiride
initiate
conservatively
to avoid hypo-
glycemia#
DPP4
inhibitors
No Neutral Neutral Potential Risk
Saxagliptin
Alogliptin
Neutral Require
renal dose-
adjustment#
Clinical Considerations for Antidiabetic Agents
*Empagliflozin: Only OAD approved for CV Mortality benefit in T2DM with CVD
Adapted from: ADA Standards of Medical Care in Diabetes. Diabetes Care. 2018; 41(Suppl 1):s1 – s153.
# Refer to locally approved prescribing information of individual agents

15. ACC/ADA 2018 Consensus on CV Benefits
27th Nov’2018

16. AMERICAN DIABETES ASSOCIATION (ADA) STANDARDS OF MEDICAL CARE IN DIABETES - 2018
AMERICAN DIABETES ASSOCIATION (ADA)
STANDARDS OF MEDICAL CARE IN DIABETES - 2018

17. ADA Standards of Medical Care in Diabetes - 2019
Evidence DOES NOT Support Class-Effect for CV Outcomes Between Agents1-7
Recommendation for Patients with T2DM and Established
Atherosclerotic CVD*
Agent
MACE Reduction
CV Mortality
Reduction
Empagliflozin
+
(Level A)
+
(Level A)
Canagliflozin
+
(Level C)
Not Recommended
Dapagliflozin Not Recommended Not Recommended
Liraglutide
+
(Level A)
+
(Level A)
Semaglutide Not Recommended Not Recommended
*Consider Drug-specific and Patient factors before use
Lifestyle + Metformin
Levels of Evidence (ADA - 2018):
Level A: Clear / Supportive
evidence from well-conducted,
generalizable RCTs that are
adequately powered; Compelling
nonexperimental evidence
Level B: Supportive evidence
from well-conducted cohort /
case-control studies
Level C: Supportive evidence
from poorly controlled /
uncontrolled studies; Conflicting
evidence with weight of evidence
supporting recommendation
Level E: Expert consensus or
clinical experience

18. Which is a Safer Target for inhibition?
• The first SGLT2i discovered was phlorizin, derived from apple tree bark.
• Because of non-selective nature,
• Caused severe gastrointestinal symptoms
• Due to this and its poor bioavailability, its development was stopped
• Thus, drugs with specifically inhibit SGLT2 compared to SGLT1 were then developed.
Kalra S. Diabetes Ther (2014) 5:355–366
Canagliflozin Dapagliflozin Empagliflozin
SGLT2
Selectivity
over SGLT1
1 : 160 1 : 1400 1 : 5000
Data from http://www.ema.europa.eu/ (Jardiance SPC, Forxiga SPC , Invokana PI, Invokana SPC, all accessed June 2015);

19. SGLT family

20. Mechanisms involved in hyperglycemia in T2D and site of
action of metformin and empagliflozin
ForInternaluseonly

21. FDA approved SGLT2 inhibitors

22. ADA 2019

23. Empagliflozin versus dapagliflozin in patients with
type 2 diabetes inadequately controlled with
metformin, glimepiride and dipeptidyl peptide 4
inhibitors: A 52-week prospective observational
study

24. Empa vs
Dapa
• Significantly (p=0.021) more patients on Empa (18.8%) reached the target HbA1c of <6.5% than with Dapa
(9.8%)
• Significantly (p=0.036) more patients on Empa (35.2%) reached the target HbA1c of <7% than with Dapa
(24.7%)
• Empa reduced greater HbA1c reduction (-1.6%) than Dapa (-1.2%) … which was very significant (p<0.001)
• Empa also caused a significantly greater (p=0.011) reduction (-65 mg%) in FPG than Dapa (-53 mg%)
Ku EJ1, Lee DH1, Jeon HJ1, Oh TK2. Empagliflozin versus dapagliflozin in patients with type 2 diabetes inadequately controlled with metformin, glimepiride and dipeptidyl peptide 4
inhibitors: A 52-week prospective observational study. Diabetes Res Clin Pract. 2019 Apr 4;151:65-73. doi: 10.1016/j.diabres.2019.04.008. [Epub ahead of print]

25. Empa vs
Dapa
Ku EJ1, Lee DH1, Jeon HJ1, Oh TK2. Empagliflozin versus dapagliflozin in patients with type 2 diabetes inadequately controlled with metformin, glimepiride
and dipeptidyl peptide 4 inhibitors: A 52-week prospective observational study. Diabetes Res Clin Pract. 2019 Apr 4;151:65-73. doi:
10.1016/j.diabres.2019.04.008. [Epub ahead of print]

26. CI, confidence interval; EMPA, empagliflozin; HbA1c, glycosylated haemoglobin; QD, once daily; SITA, sitagliptin.
ANCOVA, FAS (LOCF).
Roden M, et al. Lancet Diabetes Endocrinol. 2013;1:208–219.
24-week empagliflozin monotherapy versus placebo and sitagliptin
Change in HbA1c at Week 24
EMPA-REGMONO:study1245.20
-0.73
(95% CI:
-0.88, -0.59)
p < 0.0001
Placebo EMPA 10 mg EMPA 25 mg SITA 100 mg
Mean baseline HbA1c (%) 7.91 7.87 7.86 7.85
Mean baseline HbA1c (mmol/mol) 63.0 62.5 62.4 62.3
End HbA1c (%) 7.98 7.21 7.09 7.20
End HbA1c (mmol/mol) 63.7 55.3 54.0 55.2
-0.74
(95% CI:
-0.88, -0.59)
p < 0.0001
-0.85
(95% CI:
-0.99, -0.71)
p < 0.0001
Empagliflozin
Comparison with placebo
0.08
-0.66
-0.78
-0.66
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
Placebo
(n = 228)
10 mg QD
(n = 224)
25 mg QD
(n = 224)
Sitagliptin
100 mg QD
(n = 223)
Adjustedmean(95%CI)changefrom
baselineinHbA1c(%)

27. Efficacy of Empagliflozin in T2D and established CVD.
EMPA-REG-OUTCOME trial

28. Beneficial effects of SGLT2 inhibitors
Empagliflozin or Glimepiride as Add-on to Metformin
Good Glycemia Control Sustained Over 4 years
*MMRM analysis in the FAS using observed cases (excluding values observed after initiation of rescue therapy and off-
treatment values). †ANCOVA in the FAS using a LOCF approach to impute values missing at week 208 or measured after
the use of rescue therapy.
6.5
6.7
6.9
7.1
7.3
7.5
7.7
7.9
8.1
8.3
8.5
0 208
Glimepiride 1–4 mg Empagliflozin 25 mg
15665
738
734
609
645
522
589
457
545
329
433
297
413
268
391
243
365
761
759
660
672
561
621
493
564
338
453
314
427
284
403
259
384
78 104 130 18291 117 143 169 1954 12 4028 52
758
751
699
702
Glimepiride
Empagliflozin
Empagliflozin vs glimepiride change
from baseline at week 208:* -0.18%
(95% CI -0.33 to -0.03)
p=0.0172
Week
Adjustedmean(SE)HbA1c(%)*
Salsali A et al. American Diabetes Association 76th Scientific Sessions; 10-14 June 2016, New Orleans, Louisiana, USA
HbA1c Reduction

29. Mechanisms of action of SGLT2i and their effect on the
physiological system in the human body

30. Empagliflozin vs. Glimepiride as Add-on to Metformin
Systolic BP Reduction Maintained Over 4 years
MMRM analysis in the FAS using observed cases (excluding values observed after initiation of rescue therapy and/or after
changes in antihypertensive therapy and off-treatment values). *Number with data at visit; number of patients at 4 and 8
weeks, n=737 and n=705, respectively; †Number with data at visit; number of patients at 4 and 8 weeks, n=732 and n=696,
respectively. SBP, systolic blood pressure.
-6
-5
-4
-3
-2
-1
0
1
2
3
4
0 208
Glimepiride 1–4 mg Empagliflozin 25 mg
490
537
394
475
327
427
224
336
191
314
165
289
146
266
739
735
554
579
438
510
358
446
238
361
207
331
177
302
161
284
612
618
4 15665 78 104 130 18291 117 143 169 19512 4028 528 16
650
649
677
669
Glimepiride*
Empagliflozin†
Difference: -6.2 mmHg
(95% CI -8.5 to -4.0)
p<0.0001
Week
Adjustedmean(SE)changefrom
baselineinSBP(mmHg)
Salsali A et al. American Diabetes Association 76th Scientific Sessions; 10-14 June 2016, New Orleans, Louisiana, USA

31. Empagliflozin vs. Glimepiride as Add-on to Metformin
Weight-loss Maintained Over 4 years
MMRM analysis in the FAS using observed cases (excluding values observed after initiation of rescue therapy and
off-treatment values).
-5
-4
-3
-2
-1
0
1
2
3
0 208
Glimepiride 1–4 mg Empagliflozin 25 mg
743
737
610
642
524
590
458
551
331
443
301
420
269
395
248
368
745
739
15678 104 130 18212 28 52
703
706
Glimepiride
Empagliflozin
Difference: -4.9 kg
(95% CI -5.5 to -4.3)
p<0.0001
Week
Adjustedmean(SE)changefrom
baselineinweight(kg)
Salsali A et al. American Diabetes Association 76th Scientific Sessions; 10-14 June 2016, New Orleans, Louisiana, USA

32. Wanner and Marx (2018) Diabetologia DOI 10.1007/s00125-018-4678-z
© Springer-Verlag GmbH Germany, part of Springer Nature 2018
Consequences of inhibition of SGLT2 on glucose, salt and water excretion, as
well as its potential metabolic impact on kidney, liver and heart function

33. SGLT2 inhibitor improves clinical outcome in T2D patients
with history of CABG
. Verma Diabetol 2018

34. Potential mechanism leading to reduced arterial stiffness
(AS) after empagliflozin

35. Prospective cardiovascular safety trials for SGLT2 inhibitors
Name of Trial Intervention Primary Endpoint No. of
Patients
Duration of
Trial (y)
Projected Year
of Completion
Cardiovascular Outcome Event Trial in Type 2
Diabetes Mellitus Patients (EMPA-REG
OUTCOME)
Empagliflozin 10 or 25
mg daily
Time to the first occurrence of any of the
following adjudicated components of the
primary composite endpoint: CV death
(including fatal stroke and fatal MI), nonfatal
MI, and nonfatal stroke
7000 5 2015
published
Canagliflozin cardiovascular Assessment Study
(CANVAS)
Canagliflozin 100 or
300 mg daily
Major adverse cardiovascular events, including
CV death, nonfatal MI, and nonfatal stroke
4330 ≥ 4 2017
published
Evaluation of the Effects of Canagliflozin on Renal
and Cardiovascular Outcomes in Participants
With Diabetic Nephropathy (CREDENCE)
Canagliflozin 100 mg
daily
Time to the first occurrence of an event in the
primary composite endpoint: ESRD, doubling
of serum creatinine, renal or CV death
3627 5.5 2019
published
Multicenter Trial to Evaluate the Effect of
Dapagliflozin on the Incidence of Cardiovascular
Events (DECLARE-TIMI58)
1
Dapagliflozin 10 mg
daily
Time to first event included in the composite
end point of CV death, MI or ischemic stroke
17150 6 2019
Completed
recruitment.
Due on Sep 19
Cardiovascular Outcomes Following Treatment
With Ertugliflozin in Participants With Type 2
Diabetes Mellitus and Established Vascular
Disease [VERTIS-CV]
Ertugliflozin 5 or 15
mg daily
Time to first occurrence of any component of
the composite endpoint of CV death, nonfatal
MI, or nonfatal stroke
3900 6.3 2020
1. Am Heart J. 2018 Dec;206:11-23

36. Place of SGLT2i in therapy by various guidelines 2019
American College of Physicians
(ACP) 2017
Recommends addition of either SU/TZD/SGLT2i/DPP4i to metformin to improve glycaemic control when
a second oral therapy is considered Combinations of metformin and SGLT2i reduce weight more than
metformin monotherapy SGLT2i, as monotherapy or with metformin, reduce SBP more than metformin
monotherapy
National Institute for Health and
Care Excellence (NICE) 2017
As a first line agent, SGLT-2i instead of DPP4i should be preferred if an SU/TZD is not appropriate If A1C
[7.5%, DPP4i/SU/TZD/SGLT2i can be used as a second-line or third-line agent
International Diabetes Federation
(IDF) 2017
The preferred combinations may be metformin ? SU, DPP4i or SGLT2i Recently SGLT2i have been
considered as an option to add to metformin ? SU or metformin ? DPP4i combination
American Diabetes Association
(ADA) 2018
If A1C > 9%, consider dual therapy If A1C target not achieved in 3 months, proceed to triple therapy
SGLT2i along with other antidiabetic drugs can be used as dual or triple therapy
AACE 2017 If entryA1C <7.5%, consider monotherapy If entry A1C > 7.5%, consider dual and triple therapies SGLT2i
placed before DPP4i, SU, and TZD in mono, dual, and triple therapies
Diabetes Canada Clinical Practice
Guidelines 2018
If A1C [ 1.5% above target, incretins and/or SGLT2i should be considered if lower risk of hypoglycaemia
and/or weight gain are priorities In adults with T2DM, on insulin, with inadequate glycaemic control,
SGLT2i should be considered as an add-on therapy to improve glycaemic control with weight loss and
lower hypoglycaemic risk compared to additional insulin
Research Society for the Study of
Diabetes in India (RSSDI) 2017
SGLT2i can be considered as a second-line agent when glucose targets are not being achieved SGLT2i
can be considered as a third-line agent along with AGIs, DPP4i, or TZD

37. EMPRISE STUDY
• Empagliflozin comparative effectiveness and Safety
• Assess empagliflozin’s effectiveness, safety, and healthcare utilization in
routine care from 08/2014 through 09/2019.
• First interim analysis, risk of Hospitalization for heart failure(HHF) was
investigated among T2D patients initiating empagliflozin vs. sitagliptin, a
dipeptidyl peptidase-4 inhibitor
• Conclusion:
compared with sitagliptin, the initiation of empagliflozin was associated
with a decreased risk of HHF among patients with T2D as treated in
routine care, with and without a history of cardiovascular disease
Patorno et al 10.1161/CIRCULATIONAHA.118.039177
http://ahajournals. April 8, 2019

38. Postulated tubuloglomerular feedback (TGF) mechanism in normal
physiology. Early stages of diabetic nephropathy and after SGLT2i

39. Place of Empagliflozin in the Management of T2D
• Effective OD agent with a low inherent risk of hypoglycaemia that can be used as
monotherapy or as an add-on therapy to other ADAs
• Both approved dosages (10 and 25 mg/day) achieve near-maximal
antihyperglycaemic efficacy
• Empagliflozin exerts a favourable effect modest reductions in bodyweight and BP
that may be the result of caloric loss and volumetric loss
• In (EMPA-REG OUTCOME), empagliflozin demonstrated cardioprotective and
Reno protective effects when added to standard care, with no apparent
differences between the two dosages.

40. Caution!!!
• Avoid in:
• complicated UTIs(pyelonephritis/urosepsis, indwelling urinary catheter, recurrent genital mycotic
infections.
• Men(prostatic hypertrophy) and women (urinary incontinence)
• Caution in hypovolaemia, borderline kidney function or potent diuretics or NSAIDs.
• In hypovolaemic or hypotensive individuals, SGLT2 inhibitor should be delayed until the fluid
status and BP are corrected.
• necrotizing fasciitis of the perineum, is also referred to as Fournier’s gangrene(USFDA BLACK BOX
WARNING)

41. Use of SGLT2 inhibitors in type 2 diabetes: weighing the
risks and benefits
Recognised major risks and benefits of
SGLT2 inhibitors.
To date, only empagliflozin and canagliflozin
have demonstrated CV and renal benefits,
and increased risk of amputations and
fractures only been observed with
canagliflozin in large, randomised,
controlled clinical trials.

42. Ketoacidosis and SGLT2 Inhibitors…
• FDA decided to add specific warnings to the labels of all SGLT2 I indicating the risk of ketoacidosis and serious
urinary tract infections.
• Review of the FAERS database identified 73 cases of ketoacidosis in T1 and T2 treated with SGLT2 I
• (canagliflozin [n=48], dapagliflozin [n=21], and empagliflozin [n=4]).
• The range of time from initiation of an SGLT2 inhibitor or an increase in dose to the onset of the reported
ketoacidosis was 1 day to 1 year (median 43 days).
• In the 73 cases of ketoacidosis, potential risk factors for developing ketoacidosis with an SGLT2 inhibitor included:
• Infection,
• Low carbohydrate diet or an overall reduction of caloric intake,
• Reduction in dose of exogenous insulin or
• Discontinuation of exogenous insulin, discontinuation of an oral insulin secretagogue,
• Alcohol use.

43. RENAL DOSING OF SGLT2 INHIBITOR
eGFR(ml/min) CANAGLIFLOZIN DAPAGLIFLOZIN EMPAGLIFLOZIN
>60 No adjustment
(100-300 mg OD)
No adjustment(5-
10 mg OD)
No adjustment (10-
25 mg OD)
45-60 Max 100 mg. daily - -
30-45 Not recommended
in therapy
initiation when
GFR <45
Not recommended
in therapy
initiation when
GFR 30-<60
Not recommended
in therapy
initiation when
GFR <45
<30 contraindicated contraindicated contraindicated
eGFR: estimated glomerular filtration Rate.
Source: References 3,19,20

45. Summary Points
• SGLT2i appear to be generally well tolerated and can be safely used as monotherapy or in
combination with other OADs and insulin in the management of T2DM. SGLT2i improve all
glycaemic parameters (A1C, FPG, and PPG), and have additional benefits like body weight and BP
reduction, and lipid level regulation.
• They are also associated with a reduction in CV and renal risk.
• However, GTIs, DKA and to a lesser extent UTIs are some of the concerns with SGLT2i which can
be managed with appropriate patient counselling and treatment individualisation.
• Taken together, SGLT2i are an attractive option for the management of T2DM patients in the
Indian scenario after initial metformin monotherapy failure.
• Moreover, they can be specifically preferred if body weight and BP reduction and improving
insulin sensitivity are the part of the primary treatment concern.