Dapagliflozin

Dapagliflozin

1. Dapagliflozin

2. Preamble Diabetes is a major health issue that has reached alarming levels - nearly half a billion people are living with diabetes worldwide 1 Burden of diabetes has steadily increased over the past quarter century in India and across the globe, with India contributing a major part of the global burden 2 The National Health Policy (2017) of India aims to increase screening and treatment of 80% of people with diabetes and reduce premature deaths from diabetes by 25% by 2025 2 IDF DIABETES ATLAS Ninth edition 2019 Tandon N et al. Lancet Glob Health. 2018 Dec;6(12):e1352-e1362 India State-Level Disease Burden Initiative Diabetes Collaborators

3. Global Burden of DM IDF Diabetes Atlas Ninth edition 2019 South-East Asia has a staggering 74% increase in diabetes cases DM - Diabetes Mellitus

4. SGLT2 inhibitors Type 2 diabetes mellitus (T2DM) is a family of metabolic disorders characterized by hyperglycemia as a consequence of abnormalities in insulin secretion and insulin sensitivity 1 SGLT2 (sodium glucose co‑transporter 2) inhibitors, a new class of oral anti-diabetic drugs, have garnered considerable attention in the recent past and are considered potential first‑line candidates for the management of T2DM 1 Recent published data has highlighted benefits of SGLT2 inhibitor like dapagliflozin in heart failure and chronic kidney disease, irrespective of diabetes status – and has emerged as a “game-changer” 1. Baruah MP et al. Indian J Endocr Metab 2019;23:140-9 T2DM – Type 2 Diabetes Mellitus SGLT2 - Sodium Glucose Co‑transporter 2

5. Normal Physiology

6. Mechanism of action of Dapagliflozin

7. Addressing unmet needs – SGLT2 inhibitors Common side effects - hypoglycemia , weight gain, edema and CV adverse effects – SGLT2 inhibitors cause minimal hypoglycaemia, cause weight loss without an increase in cardiac events Need for extra- glycemic benefits – blood pressure, weight loss, lipid parameters - SGLT2 inhibitors have beneficial effects on blood pressure and lipid parameters Beta cell dysfunction progressively increases and treatment effect ( glycemic durability) declines with time/ineffective in long term – action of SGLT2 inhibitors does not depend on beta cells

8. Glycemic variability and complications in DM Khunti K et al. Diabetes Care 2019;42:349–351 Failure of sustained glycemic variability leads to the dysglycemic legacy of diabetes complications DM – Diabetes Mellitus HbA 1c - Glycosylated Haemoglobin

9. Dapagliflozin and Glycemic Durability Patients with T2DM inadequately controlled with metformin (≥1500 mg/day) A low CoF (co-efficient of failure) value indicated greater durability CoF was lower for dapagliflozin versus saxagliptin over 18–24 weeks (−1.38%/year; p =0.009) and 20–102 weeks (−0.37%/year; p =0.04). Patients received either dapagliflozin (10 mg/day) or saxagliptin (5 mg/day) Fewer dapagliflozin -treated patients vs. saxagliptin -treated patients required rescue medication or discontinued the study because of failure to achieve glycaemic control at 24 weeks (3.4% vs 9.4%; p =0.0191). In patients with T2DM who were inadequately controlled with metformin, dapagliflozin was associated with greater durability of glycaemic control than saxagliptin over 18–24 and 20–102 weeks Bailey CJ et al. Diabetes Obes Metab . 2019;21:2564–2569 T2DM – Type 2 Diabetes Mellitus SGLT2 - Sodium Glucose Co‑transporter 2

10. T2DM – a complex metabolic disease Patients with T2DM are often overweight/obese Common associated co-morbidities include - arterial hypertension and dyslipidemia T2DM patients have a higher risk of developing cardiovascular or renal complications - leading causes of morbidity and mortality Beneficial effects of SGLT2 inhibition extend beyond glycaemic control and include improvement in blood pressure, body weight and lipid levels Banora BM et al. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2020;13:161–174 T2DM – Type 2 Diabetes Mellitus SGLT2 - Sodium Glucose Co‑transporter 2

11. Extra- glycemic benefits – body weight/SBP 3 kg Patients with T2DM ( n = 546) on metformin at least 1500 mg/day Body weight Blood Pressure 5.3 mm Hg SBP 2020 May Updated Dapagliflozin US FDA approved PI T2DM – Type 2 Diabetes Mellitus SBP – Systolic Blood Pressure Patients with inadequate glycemic control (HbA1c ≥7% and ≤10%) were randomized to dapagliflozin 5 mg or 10 mg as an add-on therapy 2.9 kg Body weight Blood Pressure 4.5 mm Hg SBP 5 mg 10 mg

12. Dapagliflozin – Guideline Watch

13. 2020 ADA/2018 ADA-EASD guidelines for T2DM Diabetes Care 2020;43(Suppl. 1):S98–S110 Davies MJ et al. Diabetes Care 2018 Dec;41(12):2669-2701. doi: 10.2337/dci18-0033 * Borgharkar SS et al. TIGHT study. BMJ Open Diab Res Care 2019;7:e000654. doi:10.1136/bmjdrc-2019-000654 Now – cost too is no longer a limitation for use of SGLT2 inhibitors In Indian population with T2DM and a high burden of poor glycemic control* SGLT2 inhibitors form an vital value addition to the armamentarium of glucose lowering agents in addition to the already available popular DPP-4 inhibitors

14. 2019 Update to 2018 ADA-EASD guidelines for T2DM Buse JB et al. Diabetes Care 2019 Dec; dci190066.https://doi.org/10.2337/dci19-0066

15. 2020 AACE/ACE guidelines for T2DM *CKD 3: canagliflozin ; HFrEF : dapagliflozin Diabetes Management Algorithm, Endocr Pract. 2020;26(1):107-139 SGLT2 inhibitors can also be used as monotherapy

16. 2019 ACC/AHA guidelines on the Primary Prevention of CVD Arnett DK et al. Circulation. 2019;140:e596–e646

17. SGLT2 inhibitors and Cardiovascular Outcomes

18. CV Outcome Trials – SGLT2 inhibitors DAPAGLIFLOZIN DECLARE-TIMI DAPA-HF DAPA-CKD DM and non-DM EMPAGLIFLOZIN EMPAREG OUTCOME EMPEROR REDUCED CANAGLIFLOZIN CANVAS CREDENCE (only in DM) CV SAFETY HEART FAILURE CKD DAPA-MI (ONGOING) Dapagliflozin is the only SGLT2i which has shown benefits on sugar levels, heart and kidney in specific patient populations (heart failure, CKD) – that too in non-diabetics also - - - - AMI without DM

19. Dapagliflozin and Cardiovascular Safety

20. DECLARE-TIMI study Wiviott SD et al. N Engl J Med 2019;380:347-57 DECLARE-TIMI - Dapagliflozin Effect on CardiovascuLAR Events–Thrombolysis In Myocardial Infarction 58 MACE (defined as cardiovascular death, myocardial infarction, or ischemic stroke) Sample size - 17,160 patients with T2DM with or at risk for atherosclerotic cardiovascular disease ( Approx 40% had prior h/o ASCVD) Median duration of follow-up - 4.2 years Patients randomised to 10 mg of dapagliflozin daily or placebo Primary Safety Endpoint No increase in MACE events Primary Efficacy Endpoints CV death or hospitalization from Heart Failure ( hHF ) 17% Hospitalization from Heart Failure ( hHF ) 27% p =0.005 2,303 (13.42%) – Asians HR 0.83; 95% CI, 0.73 to 0.95 HR 0.73; 95% CI, 0.61 to 0.88

21. DECLARE-TIMI study – Important points 1. Wiviott SD et al. N Engl J Med 2019;380:347-57 2. Packer M et al. N Engl J Med 2020 Aug 29. doi : 10.1056/NEJMoa2022190 3. Neal B et al. N Engl J Med 2017;377:644-57 DECLARE-TIMI - Dapagliflozin Effect on CardiovascuLAR Events–Thrombolysis In Myocardial Infarction 58 EMPA-REG OUTCOME: EMPAgliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose CANVAS: CANagliflozin CardioVAScular Assessment Study/CANVAS-R (Renal) DECLARE-TIMI 1 EMPAREG OUTCOME 2 CANVAS 3 Sample Size 17,160 7,020 10,142 Asian patients (%/n) (13.4%/2303 pts) (21.6%/1517 pts) (12.7%/1284 pts) Duration of follow-up (years) 4.2 3.1 2.4

22. Dapagliflozin vs. empagliflozin – comparing CV events in T2DM Analysis of a multi-institutional electronic medical records database in Taiwan 12,681 new SGLT2 inhibitor users (from 2016 to 2017) with a mean age of 58.9 years, of whom 43.9% were female and 45.8% were new dapagliflozin users New users of dapagliflozin were found to have similar risks for primary composite outcome, cardiovascular death, myocardial infarction, and ischemic stroke, but a lower risk of heart failure than empagliflozin Primary Composite Outcome - cardiovascular death, myocardial infarction, ischemic stroke and heart failure Cardiovasc Diabetol 2019: 18:120 Risk of cardiovascular events was similar between dapagliflozin and empagliflozin new users, but dapagliflozin may have a better outcome in the reduction of heart failure in T2DM

23. Prevalence of HF in India Burden of Heart Failure is rapidly increasing globally and it is projected that by 2030, the number of HF patients would rise by 25% Mortality rate is ≈ 50% at 5 years from the initial diagnosis of HF Recent estimates about incidence of HF in India vary widely from 1.3 to 23 million Trivandrum Heart Failure Registry (THFR) reported that HFpEF accounted for 25% of the total HF burden, indicating that in Indian clinical practice, HFrEF is predominantly observed Mishra S et al. Indian Heart Journal 2018;70:105–127

24. SGLT2 inhibitors in Heart Failure Large clinical trials involving patients with T2DM have shown that SGLT2 inhibitors reduce the risk of hospitalization for heart failure 1 SGLT2 inhibitors may slow the progression of cardiac and renal disease, regardless of cause and independent of the presence or absence of diabetes 2 Investigators of DAPA-HF trial aimed to prospectively evaluate the efficacy and safety of dapagliflozin in patients with heart failure and a reduced ejection fraction, regardless of the presence or absence of diabetes 1 1. McMurray JJV et al. N Engl J Med 2019;381:1995-2008 2. Packer M et al. N Engl J Med . 2020 Aug 29. doi : 10.1056/NEJMoa2022190 T2DM – Type 2 Diabetes Mellitus SGLT2 - Sodium Glucose Co‑transporter 2 DAPA-HF study - D apagliflozin A nd P revention of A dverse Outcomes in H eart F ailure

25. Dapagliflozin – DEFINE-HF trial Investigator-initiated, multi- center , randomized controlled trial 263 patients were randomized to dapagliflozin 10 mg daily or placebo for 12 weeks Patient profile: Left ventricular ejection fraction ≤40%, New York Heart Association (NYHA) class II-III, e-GFR ≥30 mL/min/1.73m 2 and elevated natriuretic peptides Dual-primary outcome: meaningful improvement in Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score or NT- proBNP , 61.5% of dapagliflozin -treated patients met this end point versus 50.4% with placebo ( p =0.039) Dapagliflozin was beneficial in HFrEF patients with/without T2DM DEFINE-HF - D apagliflozin EF ects on Biomarkers, Symptoms and Functional Status IN Pati E nts with HF with Reduced Ejection Fraction) Circulation. 2019;140:1463–1476

26. DAPA-HF trial - study design McMurray JJV et al. N Engl J Med 2019;381:1995-2008 *≥400 pg /ml if HF hospitalization within ≤12 months; ≥900 pg /ml if atrial fibrillation/flutter NYHA - New York Heart Association 1,116 (23.5%) – Asians Median duration of follow-up - 18.2 months # Worsening HF - hospitalization or an urgent visit resulting in intravenous therapy for heart failure Only 45% ( n = 1869) had T2DM at baseline DAPA-HF study - D apagliflozin A nd P revention of A dverse Outcomes in H eart F ailure * # #

27. DAPA-HF trial – Results McMurray JJV et al. N Engl J Med 2019;381:1995-2008 26% p <0.001 NNT = 21 17% PRIMARY COMPOSITE OUTCOME Composite of worsening heart failure* or cardiovascular death All Cause Mortality *Worsening HF - hospitalization or an urgent visit resulting in intravenous therapy for heart failure

28. DAPA-HF trial – Results McMurray JJV et al. N Engl J Med 2019;381:1995-2008 18% NNT = 21 30% Hospitalization from Heart Failure ( hHF ) or cardiovascular death 25% SECONDARY COMPOSITE OUTCOME HR 0.75; 95% CI, 0.65 to 0.85, p <0.001

29. Comparison of DAPA-HF Trial with EMPEROR-REDUCED trial Zannad F et al. Lancet. 2020;396(10254):819-829. 17% 18% 26% 30% 8% NS 8% NS 25% 31% EMPEROR-Reduced - Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction DAPA HF - Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure Meta-analysis published in Lancet (Aug 2020) No mortality benefit in EMPEROR-REDUCED trial

30. DAPA-HF trial – Strengths Benefits observed were on top of excellent background therapy – 94% of patients were taking ACEI or ARB, or ARNI, 96% were on beta blockers, and 71% MRAs Curves separated rapidly, indicating that patients can derive a benefit soon after treatment initiation Number needed to treat (over 18 months) was only 21, supporting a large absolute risk reduction Bhatt DL et al. Cell Metab 2019;30(5):847-849

31. DAPA-HF trial – Strengths Results were internally consistent, with a persuasive p value (<0.001) in addition to evidence of mortality reduction Post-hoc analyses - benefits seemed to be consistent in those who were users of ARNI therapy, the last reported class of medications that reduced heart failure mortality Efficacy was independent of glycemic status, extending the use of dapagliflozin beyond diabetes to patients with heart failure with reduced ejection fraction even without diabetes Bhatt DL et al. Cell Metab 2019;30(5):847-849

32. Impact of DAPA-HF trial SGLT2 inhibition with dapagliflozin now represents a new foundational therapy Bhatt DL et al. Cell Metab 2019;30(5):847-849

33. Prevalence of CKD in India Reported prevalence of CKD in different regions in India ranges from < 1% to 13% Recent data from the International Society of Nephrology’s Kidney Disease Data Center Study reported a prevalence of 17% Etiology of CKD varies considerably throughout India Parts of the states of Andhra Pradesh, Odisha, and Goa have high levels of CKD of unknown etiology ( CKDu ), which is a chronic interstitial nephropathy with insidious onset and slow progression Varughese S et al. Clin J Am Soc Nephrol 2018;13:802–804

34. SGLT2i - DM and CKD Patients with chronic kidney disease (CKD) have a high risk of adverse kidney and cardiovascular outcomes CKD is an important contributor to illness and is associated with a diminished quality of life and reduced life expectancy SGLT2 inhibitors decrease glycated hemoglobin levels and have shown favorable effects on kidney and cardiovascular outcomes in large clinical trials involving patients with T2DM Heerspink HJL et al. N Engl J Med. 2020 Sep 24. doi : 10.1056/NEJMoa2024816 T2DM – Type 2 Diabetes Mellitus SGLT2 - Sodium Glucose Co‑transporter 2 CKD – Chronic Kidney Disease

35. DAPA-CKD trial - study design Heerspink HJL. et.al. Nephrol Dial Transplant. 2020 ;35(2):274-282 1,467 (34%) – Asians 201* (4.67%) - Indians DAPA-CKD: Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease *As presented at 2020 ESC GFR – Glomerular Filtration Rate Median duration of follow-up 2.4 years Presented at 2020 ESC 67.5% ( n = 2906) had T2DM at baseline 21 countries 386 sites n = 2152 n = 2152 n = 4304 Trial stopped early in March 2020 because of because of clear efficacy

36. DAPA-CKD trial – Results Heerspink HJL et al. N Engl J Med. 2020 Sep 24. doi : 10.1056/NEJMoa2024816. Primary Composite Endpoint Sustained decline in e-GFR ≥ 50% End-stage kidney disease Death from renal or cardiovascular causes 39% 44% Secondary Composite Endpoint Sustained decline in e-GFR ≥ 50% End-stage kidney disease Death from renal causes NNT = 19

37. DAPA-CKD trial – Results 29% 31% NNT = 19 Heerspink HJL et al. N Engl J Med. 2020 Sep 24. doi : 10.1056/NEJMoa2024816.

38. DAPA CKD trial – Additional endpoint Heerspink HJL et al. N Engl J Med. 2020 Sep 24. doi : 10.1056/NEJMoa2024816. Heerspink HJL. et.al. Presented at ESC 2020 34%

39. DAPA-HF trial – Safety McMurray JJV et al. N Engl J Med 2019;381:1995-2008 No notable excess of any event in the dapagliflozin group

40. DAPA-CKD trial – Safety Heerspink HJL et al. N Engl J Med. 2020 Sep 24. doi : 10.1056/NEJMoa2024816 Diabetic Ketoacidosis was not reported in any participants who received dapagliflozin Neither diabetic ketoacidosis nor severe hypoglycemia was observed in participants without type 2 diabetes No evidence of Fournier’s gangrene seen with dapagliflozin Amputation, fracture risk comparable to placebo

41. Dapagliflozin – Upcoming trials DAPA-MI trial DELIVER ( HFpEF ) – CV outcome study* DETERMINE-REDUCED ( HFrEF ) – effects to be studied on exercise* DETERMINE-PRESERVED ( HFpEF ) – effects to be studied on exercise* PRESERVED-HF ( HFpEF ) – effects to be studied on symptoms/biomarkers* DARE-19 - Dapagliflozin in Respiratory Failure in Patients With COVID-19 *Seferovic PM et al. European Journal of Heart Failure 2020;22:196–213

42. Conclusions Dapagliflozin belongs of the most recently developed category of oral anti-diabetic class of drugs, known as SGLT2 inhibitors In addition to improving blood sugar levels, recent promising data presented at international conferences and also published in reputed journals has confirmed beneficial effects of Dapagliflozin on the heart and kidney also Dapagliflozin also exhibits extra- glycemic benefits viz. reduction of blood pressure, improvement in lipid parameters

43. Conclusions Dapagliflozin exhibits lower incidence of side effect viz. hypoglycemia which is experienced with the use of some of the currently available anti-diabetic drugs Dapagliflozin has also shown to cause some amount of weight loss, which is also beneficial in patients with diabetes Dapagliflozin strengthens current armamentarium of oral drugs used to treat type 2 diabetes and has emerged as a “cardio-renal game-changer”