The presentation describes use of SGLT2 Inhibitors for better cardiovascular Outcome in patients with or without diabetes

1. Getting to the Heart
of Diabetes
Dr Syed Raza, MD, MRCP, FRCP, CCT(UK), FESC, FACC
Consultant Cardiologist & Physician
Awali Hospital , Bahrain

2. What aspect of anti-diabetic agent attracts
you the most ?
• 1. Reduce blood glucose
• 2. Reduce HbA1C
• 3. Less hypoglycemia
• 4. Weight loss
• 5. Improve metabolic parameters
• 6. Reduce cardiovascular death
2

3. Objectives
1. Which anti-
diabetic to choose?
2. What is the
evidence to support
our decision and
choice of agent?
3. How do the
guidelines help us
reach that decision?

4. Meet Mustafa
54 years , banker . No symptoms
Type 2 DM for 5 years
Ex-smoker
Father had MI @ 59
Metformin 1000 mg BID , Atorvastatin 10 mg
P 86 BP- 138/86 Wt- 88 kgs waist = 40”
Diet – fairly controlled . No time for exercise
FBG- 8.4 HbA1C – 9.2 % LDL – 3.6 e-GFR = 86 ml/mt

5. Review by GP
• Commenced on Gliclazide 60 mg BID
• Atorvastatin dose increased to 20 mg HS
• Aspirin was proposed but he refused
• Advised to lose weight

6. Repeat lab in 3 months- Consulted an Internist
• Gets little short of breath on exertion . Wt = 86 kgs
FBG - 6.9 HbA1C= 7.6% LDL = 2.6
BP – 130/84
ECG – Normal
Metformin combined with Vildagliptin 50/1000 mg BID . Continued
Gliclazide and Statin same dose.

7. 6 months later admitted to hospital
Severe sudden onset chest pain and SOB
ECG - Anterior STEMI
PCI and stent x 1 to proximal LAD
Echo - Mid and basal anterior wall akinesia . LVEF = 35%
HBA1C – 7 % LDL – 2.2
Meds : Aspirin , Ticagrelor, Rosuvastatin , Bisoprolol , Entresto

8. How will you adjust his anti Diabetic
medications ?
• 1. Start on Insulin
• 2. Increase dose of Gliclazide
• 3. Start on GLP1 agonist
• 4. Start SGLT2 Inhibitor
• 5. Change Vildagliptin to Linagliptin

10. GLP-1 Agonist versus SGLT2 Inhibitor

12. Number needed to treat (NNT) to prevent one death across
landmark trials in patients with high CV risk
1 4S investigator. Lancet 1994; 344: 1383-89,
2 HOPE investigator N Engl J Med 2000;342:145-53,
3 Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med Sep 17, 2015. doi:10.1056/NEJMoa1504720;
4 Marso S et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes N Engl J Med June 2016 doi: 10.1056/NEJMoa1603827.
1994 2000 2016
Pre-statin era
Pre-ACEi/ARB era
<29% statin
>80% ACEi/ARB
>75% statin
30
Simvastatin1
for 5.4 years
High CV risk
5% diabetes, 26%
hypertension
98
Liraglutide4
for 3 years
T2DM with high CV risk
93% hypertension
Empagliflozin3
for 5 years
T2DM with high CV risk
92% hypertension
25
Ramipril2
for 5 years
High CV risk
38% diabetes, 46%
hypertension
56
2015
>80% ACEi/ARB
>70% statin

14. Which one to choose ?
SGLT2 Inhibitor
• 1. Established ischemic heart
disease
• 2. Heart Failure
• 3.CKD
GLP1 Agonist
1. Established ischemic heart
disease
2. Obesity
3. Stroke

15. CV disease occurs early and is the leading
cause of mortality in patients with T2D
15
CV, cardiovascular; T2D, type 2 diabetes
1. Booth GL et al. Lancet 2006;368:29; 2. Morrish NJ et al. Diabetologia 2001;44(Suppl 2):S14
CV disease can occur
10−15 years earlier
in patients with diabetes compared
with those without diabetes1
Despite advances in standard
of care, most patients with T2D
die from CV disease2

16. Which of the following does not improve CV
mortality ?
1. ACE Inhibitor
2. ARNI
3. MRA
4. B- Blocker
5. SGLT2 Inhibitors
6. Ivabradine
7. Vericiguat

17. As per new ESC-HF guideline , what does
HFmrEF mean to you ?
1.HF with moderately reduced EF
2. HF with mildly reduced EF
3. HF with mid range EF
4. HF with massively reduced EF
5. HF with mainly reduced EF

19. Empagliflozin significantly reduced the relative risk of CV death by 38% on
top of standard of care*†
19
CV death
HR 0.62
(95% CI 0.49, 0.77)
p<0.001
Placebo Empagliflozin
Patients
with
event
(%)
Months
Early separation of
curves for
CV death events
↓38% RRR
Cumulative incidence function. RRR for CV death: 38%; ARR for CV death: 2.2%; rates of CV death: 3.7% (empagliflozin) vs 5.9% (placebo)
*Exploratory endpoint; †Standard of care included CV medications and glucose-lowering agents given at the discretion of physicians
ARR, absolute risk reduction; RRR, relative risk reduction
Zinman B et al. N Engl J Med 2015;373:2117

20. 38% relative risk reduction of CV death was achieved on
top of standard of care*1–3
20
Data suggest reduced risk was largely independent of
baseline HbA1c†1,7
Reduced risk was consistent regardless of prior CV event at
baseline8
Empagliflozin had an early impact on risk reduction1,4–6
Results were consistent between 10 mg and 25 mg doses1
Standard of care included CV medications and glucose-lowering agents given at the discretion of physicians †EMPA-REG OUTCOME® was not powered to show differences between subgroups
HbAc1, glycated haemoglobin; MI, myocardial infarction
1. Zinman B et al. N Engl J Med 2015;373:2117; 2. Boehringer Ingelheim Pharmaceuticals, Inc. Jardiance® (empagliflozin) Prescribing Information. 2017; 3. Fitchett D et al. ESC-HF 2017; poster 301; 4. Fitchett D et al. J Am Coll
Cardiol 2018;71:364; 5. Van de Borne P et al. EASD 2016; poster 1119; 6. Boehringer Ingelheim Pharmaceuticals, Inc. Data on file; 7. Inzucchi S et al. ADA 2017; poster 1174-P; 8. Fitchett D. ACC 2018; oral presentation

21. CV death outcomes from SGLT2i CVOTs
21
Study
n event/N analysed (%)
HR (95% CI) p-value
SGLT2i Placebo
EMPA-REG OUTCOME®1
eCVD
172/4687 (3.7) 137/2333 (5.9) 0.62 (0.49, 0.77) <0.001
DECLARE-TIMI 582
Total population
245/8582 (2.9) 249/8578 (2.9) 0.98 (0.82, 1.17) -
MRF 92/5108 (1.8) 86/5078 (1.7) 1.06 (0.79, 1.42)
0.53*
eCVD 153/3474 (4.4) 163/3500 (4.7) 0.94 (0.76, 1.18)
CANVAS Program3,4
Total population
268/5795 (4.6) 185/4347 (4.3) 0.87 (0.72, 1.06) -
MRF - - 0.93 (0.60, 1.43)
0.44*
eCVD - - 0.86 (0.70, 1.06)
Direct comparison of studies should be interpreted with caution due to differences in
study design, populations and methodology. Arrow indicates where lower or upper bound
of 95% CI goes beyond axis
*p-value for interaction.
1. Zinman B et al. N Engl J Med 2015;373:2117 (supplemental appendix); 2. Wiviott S et al. N
Engl J Med 2018;DOI: 10.1056/NEJMoa1812389; 3. Neal B et al. N Engl J Med 2017;377:644
0.5 1 2
Favours SGLT2i Favours placebo

22. * Reduction in CO-Primary end point was significant vs, placebo 0.86 HR (0.75, 0.97) and mainly driven by HHF
CV: cardiovascular; NS: not significant; MI: myocardial infarction
1 Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in
Type 2 Diabetes. N Engl J Med Sep 17, 2015. 10.1056/NEJMoa1504720; 2 Neal B., Perkovic V,
Mahaffey KW et al, Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes, N Engl J
Med Jun 12, 2017. doi: 10.1056/NEJMoa1611925 3. Wiviott S et al. N Engl J Med 2018;DOI:
10.1056/NEJMoa1812389 4.Davies MJ, D’Alessio DA, Fradkin J, et al. Management of
hyperglycaemia in type 2 diabetes, 2018
EMPAGLIFLOZIN is the only oral antidiabetic agent succeeded significantly to reduce CV death
for T2DM patients in a dedicated randomized CVOT.
Summary of SGLT2i CV outcomes Studies
3P MACE: CV Death, Nonfatal MI & Nonfatal Stroke N.S non significant
NEW: The ADA-EASD Consensus 2018 Report recognizes JARDIANCE as the SGLT2 inhibitor with
the strongest evidence of CV benefits4
Primary end point : 3P
MACE
CV Death All cause of mortality
Hospitalization for Heart
Failure
EMPA-REG OUTCOME1 14% RRR 38% RRR 32% RRR 35% RRR
CANVAS program2 14% RRR N.S N.S 33% RRR
DECLARE-TIMI58 3 N.S* N.S N.S 27% RRR

23. Despite Therapies With Established Efficacy, Morbidity
and Mortality Among Patients With HFrEF Is High
• Primary care data in the United Kingdom for n = 55,959 patients aged ≥ 45 yrs with new diagnosis of HF and n = 278,679 age- and sex-matched controls[1]
3
1. Taylor. BMJ. 2019;364:l223. 2. Yancy. J Am Coll Cardiol. 2018;71:201. Slide credit: clinicaloptions.com
Survival Rates for People With HF by Yr of Diagnosis*[1]
Yr of Diagnosis
Survival
(%)
100
2000
80
60
40
20
0
2005 2010 2015 2020
1-yr survival (Ptrend < .001)
5-yr survival (Ptrend < .001)
10-yr survival (Ptrend = .002)

24. Does our patient Mustafa have Heart Failure?

27. Primary endpoint: First adjudicated CV death or
hospitalisation for heart failure
Placebo
Empagliflozin
Days after randomisation
Estimated
cumulative
incidence
function
(%)
HR 0.75
(95% CI 0.65, 0.86)
p<0.001
Empagliflozin:
361 patients with event
Rate: 15.8/100 patient-years
Placebo:
462 patients with event
Rate: 21.0/100 patient-years
40
30
20
10
0
90 180 270 360 450 540 630 720 810
0
Patients at risk
Placebo
Empagliflozin
1867 1715 1612 1345 1108 854 611 410 224 109
1863 1763 1677 1424 1172 909 645 423 231 101
NNT = 19
RRR
25%
ARR
5.2%
Cox regression model including covariates age, baseline eGFR, geographic region, baseline diabetes status, sex, LVEF and treatment
ARR, absolute risk reduction; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HR, hazard ratio; LVEF, left ventricular ejection fraction; NNT: Number needed to treat; RRR, relative risk reduction
Packer M, et al. N Engl J Med. DOI: 10.1056/NEJMoa2022190

29. Study
n event/N analysed (%)
HR (95% CI) p-value
SGLT2i Placebo
EMPA-REG OUTCOME®1
eCVD
126/4687 (2.7) 95/2333 (4.1) 0.65 (0.50, 0.85) 0.002
DECLARE-TIMI 582
Total population
212/8582 (2.5) 286/8578 (3.3) 0.73 (0.61, 0.88) -
MRF 61/5108 (1.2) 94/5078 (1.9) 0.64 (0.46, 0.88)
0.30*
eCVD 151/3474 (4.3) 192/3500 (5.5) 0.78 (0.63, 0.97)
CANVAS Program3,4
Total population
123/5795 (2.1) 120/4347 (2.8) 0.67 (0.52, 0.87) 0.002
MRF - - 0.64 (0.35, 1.15)
0.91*
eCVD - - 0.68 (0.51, 0.90)
0.5 1 2
Direct comparison of studies should be interpreted with caution due to differences in study design, populations and methodology. Arrow indicates where lower or upper bound of 95% CI goes beyond axis
*p-value for interaction.
1. Zinman B et al. N Engl J Med 2015;373:2117 (supplemental appendix); 2. Wiviott S et al. N Engl J Med 2018;DOI: 10.1056/NEJMoa1812389; 3. Neal B et al. N Engl J Med 2017;377:644 (supplementary appendix);
4. Mahaffey KW et al. Circulation 2017;137:323
HHF outcomes from SGLT2i CVOTs
29
Favours SGLT2i Favours placebo

30. Renal Outcome Trials with SGLT2 Inhibitors

32. Empagliflozin significantly slowed eGFR decline
32
After an initial short-term reduction, eGFR was stabilised with empagliflozin and declined
steadily with placebo
66
68
70
72
74
76
78
Placebo Empagliflozin
12
Baseline
4 28 52 94 108
80 122
66 136 150 164 178 192
Adjusted
mean
(SE)
eGFR
(ml/min/1.73
m
2
)
Week
Adjusted mean difference
versus placebo at follow-up:*
4.7 ml/min/1.73 m2
p<0.001
Empagliflozin is not indicated for the treatment of chronic kidney disease
eGFR calculated according to the CKD-EPI formula
*Median follow-up: 3.1 years
CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate
Wanner C et al. N Engl J Med 2016;375:323

33. Empagliflozin significantly reduced the relative risk of incident or
worsening nephropathy*† by 39% on top of standard of care‡
0
5
10
15
20
25
30
0 6 12 18 24 30 36 42 48
Early separation of curves
for kidney events
Patients
with
event
(%)
HR 0.61
(95% CI 0.53, 0.70)
p<0.001
Placebo Empagliflozin
Months
Worsening
nephropathy
33
↓39% RRR
Empagliflozin is not indicated for the treatment of chronic kidney disease
*Exploratory endpoint; †Defined as progression to macroalbuminuria, doubling of serum creatinine (accompanied by eGFR [MDRD] ≤45 ml/min/1.73 m2), initiation of renal replacement therapy or death from kidney disease; ‡Standard of care included CV
medications and glucose-lowering agents given at the discretion of physicians; Kaplan–Meier estimate
eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease
Wanner C et al. N Engl J Med 2016;375:323

34. *New or worsening nephropathy, a composite of: progression to macroalbuminuria, doubling of serum creatinine, initiation of RRT, or renal death †≥40% decline in eGFR,
RRT, or renal death
3P-MACE, 3-point major adverse CV event; CV, cardiovascular; CVOT, CV outcomes trial; eGFR, estimated glomerular filtration rate; HHF, hospitalisation for heart failure;
RRT, renal replacement therapy; T2D, type 2 diabetes.
EMPA-REG OUTCOME® was the first CVOT so show cardiorenal protection with an
antidiabetic agent — raising new possibilities in the management of T2D
HHF1
6
4
2
0
0 6 12 18 24 30 36 42
Months
%
Patients
with
event
(cumulative)
Placebo
Empagliflozin
HR 0.65
95% CI 0.50–0.85
35%*
*P<0.05
*P<0.05
CV death1
8
6
4
2
0
0 6 12 18 24 30 36 42
Months
%
Patients
with
event
(cumulative)
Placebo
Empagliflozin
HR 0.62
95% CI 0.49–0.77
38%*
*P<0.05
14%*
*P<0.05
3P-MACE1 Death by any cause1
32%*
*P<0.05
Nephropathy*2
39%*
*P<0.05
Renal composite†2
46%*
*P<0.05

35. After EMPA-REG OUTCOME®, some other diabetes CVOTs also suggested some CV and
renal benefits with other antidiabetic agents
3P-MACE, 3-point majore adverse CV event; CV, cardiovascular; CV, CV outcomes trial; HHF, hospitalisation for heart failure.
1. Zinman et al. N Engl J Med 2015;373:2117–28. 2. Wanner et al. N Engl J Med 2016;375:323–4. 3. Neal et al. N Engl J Med 2017;377:644–57.
4. Perkovic et al. N Engl J Med 2019;380:2295–2306. 5. Wiviott et al. New Engl J Med 2019;380:347–57. 6. Marso et al. N Engl J Med
2016;375:311–22. 7. Marso et al. N Engl J Med 2016;375:1834–44. 8. Holman et al. N Engl J Med 2017;377:1228–39. 9. Gerstein et al. Lancet
3P-MACE
CV death
HHF
Renal
function
Death by
any cause
Empagliflozin1,2 Canagliflozin3,4 Dapagliflozin5 Liraglutide6 Semaglutide7 Exenatide8 Dulaglutide9,10
Exploratory Exploratory
Exploratory
Exploratory
Exploratory
Difference only seen in
some renal function
outcomes
EMPA-REG
OUTCOME®
CANVAS/-R
CREDENCE
DECLARE-TIMI 58 LEADER® SUSTAINTM-6 EXSCEL REWIND

36. ESC–EASD guidelines on diabetes, pre-diabetes and CVD —
updated treatment pathway for patients with T2D and CV risk1
SGLT2 inhibitors and GLP-1 receptor agonists are not indicated as a monotherapy in the EU, except for patients who cannot tolerate metformin or for
whom metformin is contraindicated. Please always consult local prescribing information.
CV, cardiovascular; CVD, CV disease; HF, heart failure; RA, receptor agonist; SU, sulfonylurea; T2D, type 2 diabetes; TZD, thiazolidinedione.

41. Recommendations consider cardiorenal disease when choosing a first
add-on to metformin in patients with T2D
CKD, chronic kidney disease; CV, cardiovascular; CVD, CV disease; RA, receptor agonist; T2D, type 2 diabetes.
1. Davies et al. Diabetes Care 2018;41:2669–701. 2. American Diabetes Association. Diabetes Care 2019;42(Suppl 1):S1–S181. 3. Das et al. J Am Coll Cardiol
2018;72:3200–23. 4. Arnett et al. J Am Coll Cardiol 2019;74:e177–232
Patients with
T2D and…
Atherosclerotic
CVD
CV
risk factors
Heart
failure
CKD
EASD–ADA
(ACC endorsed)1,2
ACC CV risk reduction
in T2D3
ACC–AHA primary
prevention of CVD4
SGLT2 inhibitor or
GLP-1 RA
First add-on to metformin
Empagliflozin or liraglutide preferred
SGLT2 inhibitor
SGLT2 inhibitor

42. ESC–EASD guidelines on diabetes, pre-diabetes and CVD —
levels of CV risk in patients with T2D1
CV, cardiovascular; CVD, CV disease; eGFR, estimated
glomerular filtration rate; T2D, type 2 diabetes; UACR, urinary
albumin-to-creatinine ratio.
1. Cosentino et al. Eur Heart J
The choice of drug to reduce CV events
in patients with T2D should be
prioritised based on the presence of
CVD and CV risk
Factors determining the level of CV risk

43. Back to Mustafa. Will you
change your thoughts now?
54 years , banker . No symptoms
Type 2 DM for 5 years
Ex-smoker
Father had MI @ 59
Metformin 1000 mg BID , Atorvastatin 10 mg
P 86 BP- 138/86 Wt- 87 kgs waist = 40”
Diet – fairly controlled . No time for exercise
FBG- 8.4 HbA1C – 9.2 % LDL – 3.1 e-GFR = 86

44. x
Summary
• Multiple international guidelines now incorporate CVOTs with anti diabetic medications
• The updated guidelines prioritise CV protection across a spectrum of CV risk
 CV protection is the foremost consideration when a glucose-lowering treatment in the majority of
patients — including patients with high or very high CV risk, or with CVD
 Where CV protection is the priority, an agent with proven CV benefit is recommended as first-line
monotherapy in treatment-naïve patients, or as an add-on in patients on metformin
• Empagliflozin and liraglutide are recommended as preferred agents to reduce CV death
 While SGLT2 inhibitor and GLP-1 RA classes are recommended to reduce CV events, empagliflozin
(patients with CVD only) and liraglutide are preferred to reduce death
 SGLT2 inhibitors are also recommended to reduce hospitalisations for HF and to slow the
progression of CKD, if not contraindicated due to inadequate eGFR