Carmelina

linagliptin in renal perspectives

1. MYTH BUSTERS- Linagliptin in renal perspective DR LALIT KUMAR AGARWAL NEPHROLOGIST

2. Diabetes is the most common reason for progression to ESRD in many parts of the world 1−3 CKD is the one of the strongest predictor of mortality in patients with diabetes 4−6 CKD occurs as a consequence of multiple pathogenic pathways in the diabetic kidney 1 – Hyperglycaemia (glucotoxicity) plays a major, but not exclusive role CKD, chronic kidney disease; ESRD, end-stage renal disease; T2D, type 2 diabetes 1. Toth-Manikowski S & Atta MG. J Diabetes Res 2015;2015:697010; 2. Stewart JH et al. Nephrology 2007;12:520; 3. Thomas MC et al. Nat Rev Nephrol 2016;12:73; 4. Reidy K et al. J Clin Invest 2014;124:2333; 5. United States Renal Data System. Am J Kidney Dis 2003;42:1; 6. Afkarian M et al. J Am Soc Nephrol 2013;24:302; 7. National Kidney Foundation. Diabetes . 2015. www.kidney.org/atoz/content/diabetes (Accessed Sep 2017) Diabetes leads to micro and macrovascular complications Approximately 50% of those with T2D will eventually suffer from CKD 3,7 ~5 0%

3. 3 Kidney disease is a stronger risk factor for mortality than a prior CV event CKD, chronic kidney disease; eGFR , estimated glomerular filtration rate; MI, myocardial infarction Tonelli M et al. Lancet 2012;380:807-814 Previous MI Diabetes + CKD CKD ( eGFR <60) Diabetes 2x

4. T2D, type 2 diabetes; GFR, glomerular filtration rate Percentages indicate excess mortality above the reference group (individuals with no diabetes or kidney disease) Afkarian M et al . J Am Soc Nephrol 2013;24:302 Patients with T2D and kidney disease have higher mortality rates than those without kidney disease 10 20 30 40 60 50 70 No kidney disease Albuminuria Impaired GFR Albuminuria & impaired GFR Reference group Standardised 10-year cumulative incidence of mortality (%) 4.1 17 .8 23 .9 47 .0 Excess mortality Increased mortality

5. T2D –CKD-CVD : The connecting link 5

6. CKD, chronic kidney disease Moen MF et al . Clin J Am Soc Nephrol 2009;4:1121 Risk of hypoglycaemia is increased in CKD 8.4 4.1 1 .6 1.0 1 2 4 3 5 8 7 6 9 +CKD/ +diabe t es –CKD/ +diabetes +CKD/ –d i abetes –CKD/ –d i abetes Risk of severe hypoglycaemia (incidence rate ratio) With declining renal function, there is decreased clearance of insulin .

7. Challenges in optimising glycaemic control in CKD The management of glucose levels is particularly challenging in these patients, with the concomitant need to avoid hypoglycaemic events while managing renal comorbidities, often accompanied by CVD and/or other significant comorbidities 2 Dose adjustment or cessation may be required for oral antidiabetic agents excreted by the kidney 1 With declining renal function, there is decreased clearance of insulin 1 Need to avoid hypoglycemia Reduced renal gluconeogenesis with declining renal mass 1 CKD, chronic kidney disease; CVD cardiovascular disease. 1. KDOQI. Am J Kidney Dis 2012;60: 850–86. 2. Sherwin et al. J Clin Invest 1976;57: 722–31. 3. Defronzo et al. J Clin Invest 1978;62: 425–35 .

8. Concern regarding the long term CV and renal safety of anti- hyperglcemic agents have been raised in several studies following publication of meta-analysis in 2007 that ROSIGLITAZONE increased the risk of MI and in 2009, RECORD trial showed that adding ROSIGLITAZONE increased the risk of heart failure DDP4 Inhibitor – the net effect is a reduction in glucagon level and increased INSULIN secretion. Most of the DPP4 inhibitors have neutral effects on CV events(proved by many CVOT trials). LINAGLIPTIN is safe for CV and RENAL side effects.(CARMELINA TRIAL in subjects with high cardio-renal risks) ANTI HYPERGLYCEMIC AGENTS CHOICE: Concern on long term CV and renal safety - 8

9. 9 CARMELINA ® was specifically designed and statistically powered to evaluate both CV and Kidney Outcomes CARMELINA: Pre-specified adjudicated composite renal endpoints Sustained ESRD Sustained reduction in eGFR >40% Renal Death 1. Scirica BM et al. N Engl J Med 2013;369:1317; 2. White WB et al. N Engl J Med 2013;369:1327; 3. Green JB et al. N Engl J Med 2015;373:232; 4. Rosenstock J et al. Cardiovasc Diabetol 2018;17:39 Renal safety and potential benefits of Linagliptin has been proven with CARMELINA. Perception : All DPP-4i are kidney safe, it is not exclusive to Linagliptin What could be the clinical impact of a prespecified renal endpoint safety evidence as recorded from the CARMELINA trial? EXPERT OPINION

10. Linagliptin has proven Safety and Effectiveness Across the Spectrum of Chronic Kidney Disease -0.7% -0.7% -0.7% -1% -0.6% Baseline 8.0% Baseline 8.3% Baseline 8.2% Baseline 7.8% Baseline 8.2% 1. Cooper M, et al. ADA 2011, Poster 1068-P. 2. McGill JB, et al. Diabetes Care. 2013;36:237–244. 3. Kono T et al. 58 th Ann Mtg of the Japanese Society for Dialysis Therapy (JSDT), Fukuoka, J Jpn Soc Dial Ther 2013. 46 ( Suppl 1):670. 4. Sanyal, et al Indian J Endocr Metab 2013;17:S203-5. 5. Bae J et al. Endocrinol Metab (Seoul). 2016 Jan 6. PMID: 26754588 HbA1c Reductions with Linagliptin Across CKD Spectrum -1.4% Baseline 8.11% Diabetes in Renal Transplant 5 Preserved eGFR over 1-year 2

11. CV safety of DPP-4i in patients with kidney disease has been appropriately studied in CARMELINA 11 Schernthaner , Guntram et al.Diabetes Research and Clinical Practice, Volume 153, 30 - 4 The safety of linagliptin in patients with kidney disease , has been appropriately studied only in CARMELINA: 74% of trial population were having ‘prevalent kidney disease‘* *Defined as eGFR <60 ml/min/1.73 m 2 or macroalbuminuria (UACR ≥300 mg/g

12. CARMELINA demonstrated long-term kidney safety with Linagliptin CV, cardiovascular; CVOT, cardiovascular outcomes trial; eGFR , estimated glomerular filtration rate; ESKD, end-stage kidney disease; VEGF, vascular endothelial growth factor †ESKD, renal death, ≥50% decrease in eGFR, albuminuria progression, use of retinal photocoagulation or intravitreal injections of an anti-VEGF therapy for diabetic retinopathy, or vitreous haemorrhage or diabetes-related-blindness 1. Scirica BM et al. N Engl J Med 2013;369:1317; 2. White WB et al. N Engl J Med 2013;369:1327; 3. Green JB et al. N Engl J Med 2015;373:232; 4. Boehringer Ingelheim. Data on file. 2018 12 HR (95% CI) HR (95% CI) p -value Prespecified adjudicated kidney composite outcome Other DPP-4i CVOTs 1-3 Not studied ESKD, renal death or ≥40% eGFR decrease 4 1.04 (0.89, 1.22) 0.6164 ESKD or renal death 0.87 ( 0.69 , 1.10) 0.2371 Prespecified microvascular composite outcome † 0.86 ( 0.78 , 0.95) 0.0032 Albuminuria progression 0.86 (0.78, 0.95) 0.0034 Favours linagliptin Favours placebo ?

13. 13 UACR reduction ≥50% 14% Lower Risk of Progression of Albuminuria 14% RRR 15% Greater Likelihood of Significant Regression in UACR 15% Learnings from CARMELINA Trial: Risk Reduction for Albuminuria with Linagliptin Julio Rosenstock , Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk The CARMELINA Randomized Clinical Trial, JAMA, nov 2018

14. Participants: Type 2 DM Plus CVD or Renal disease Interventions: 5mg Linagliptin vs Placebo Outcomes: 3P-MACE, Kidney outcome Conclusion: Individuals with T2D and NRP having a high disease burden, Linagliptin reduces their albuminuria burden and HbA1c, without affecting CV or kidney risk. 14

15. R eno -protective effects of linagliptin 1,2 Inhibition of podocyte injury and apoptosis Inhibition of myofibroblast transformation Increased GLP-1 receptor expression 1. Mima A et al. Linagliptin affects IRS1/ Akt signaling and prevents high glucose-induced apoptosis in podocytes . Sci Rep. 2020; 10: 5775.79-7 2. Sharkovska Y. J Hypertens. 2014 Nov;32(11):2211-23 Possible Mechanisms for Kidney Protection in Pre-c linical Studies Linagliptin can inhibit endothelial to mesenchymal transition ( EndMT ) , thus ameliorates diabetic kidney fibrosis and progressive CKD Such effects of Linagliptin were drug-specific , but not class effects

16. Linagliptin did not affect glomerular filtration rate (GFR), effective renal plasma flow (ERPF) or any intrarenal hemodynamic functions, compared to Glimepiride Linagliptin was associated with modest natriuresis , possibly mediated by SDF-1 α, with increase in fractional excretion of sodium ( FE Na ) and potassium (FE K ) The RENALIS Study: E ffect of Linagliptin on Fasting Renal Hemodynamics 16 After 8 weeks of treatment in overweight T2D patients without renal impairment: Muskiet MHA, et al. Diabetes Care 2020;dc200902 [DOI: 10.2337/dc20-0902]

17. With its unique mode of elimination, Linagliptin is the only available DPP-4 inhibitor that does not require dose adjustment for any stage of renal impairment Perception : Linagliptin is useful only in T2D with CKD Patients Any opinion regarding the same?

18. Baseline Characteristics of DPP-4i CVOTs 18 Renal Risk Cardiovascular Risk Low CV & Kidney Risk High CV Risk High CV & Kidney Risk Complementary Patient Profile With CARMELINA & CAROLINA, linagliptin has been studied in Patients across Cardio-Renal Risk Continuum Median T2D duration 6.3 years Median T2D duration 14.75 years Jennifer B. Green, Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes, n engl j med 373;3 nejm.org july 16, 2015. Benjamin M. Scirica,, Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus, n engl j med 369;14 nejm.org october 3, 2013. William B. White, Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes, n engl j med 369;14 nejm.org october 3, 2013. Julio Rosenstock, Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk The CARMELINA Randomized Clinical Trial, JAMA. doi:10.1001/jama.2018.18269 Published online November 9, 2018. Julio Rosenstock, Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes The CAROLINA Randomized Clinical Trial, JAMA. 2019;322(12):1155-1166. doi:10.1001/jama.2019.13772 Published online September 19, 2019 .

19. CAROLINA ® and CARMELINA ® provide evidence across a broad spectrum of T2D disease duration, CV and kidney risk CV, cardiovascular; T2D, type 2 diabetes 1. Rosenstock J et al. ADA 2019 ; 2. Rosenstock J et al. JAMA 2019; 321:69 19 Atherosclerosis Chronic kidney disease Target-organ damage Risk 42 % Median T2D duration 6.3 years Had established CV disease Displayed ≥2 defined CV risk factors Had T2D for ≤5 years Active-comparator Treatment naïve On insulin On metformin 37 % 40 % 9 % % 83 % 74 % Mean T2D duration 14.75 years Prevalent kidney disease Had established CV disease Had established CV disease and prevalent kidney disease Placebo- controlled Treatment naïve On metformin On insulin 57 % 33% <3 % 55 % 58 % Early disease Advanced disease CAROLINA ®1 CARMELINA ®2 Asymptomatic Symptomatic

20. CAROLINA ® Linagliptin, n/N (%) Glimepiride, n/N (%) HR (95% CI) p -value 3P-MACE 356/3023 (11.8) 362/3010 (12.0) 0.98 (0.84, 1.14)* 0.7625 HHF or CV death 236/3023 (7.8) 234/3010 (7.8) 1.00 (0.84, 1.20) 0.9671 All-cause mortality 308/3023 (10.2) 336/3010 (11.2) 0.91 (0.78, 1.06) 0.2263 Together CARMELINA and CAROLINA Demonstrate Long-term Safety of Linagliptin in Patients Across Cardio-renal Risk Continuum CARMELINA ® Linagliptin, n/N (%) Placebo, n/N (%) HR (95% CI) p -value 3P-MACE 434 /3494 ( 12.4) 420/3485 (12.1) 1.02 (0.89, 1.17) 0.7398 HHF or CV death 406/3494 (11.6) 422/3485 (12.1) 0.94 (0.82, 1.08) 0.3881 All-cause mortality 367/3494 (10.5) 373/3485 (10.7) 0.98 (0.84, 1.13) 0.7402 *95.47 CI. 3P-MACE, 3-point MACE; 4P-MACE, 4-point MACE; CV, cardiovascular; HF, heart failure; HHF, hospitalisation for HF; MACE, major adverse CV events; MI, myocardial infarction Rosenstock J et al. JAMA 2019; 321:69; Rosenstock J et al. ADA 2019

21. Linagliptin has Proven CV and Renal Safety Across the Spectrum of CKD in T2DM *P value of subgroup-by-treatment interaction test. Adapted: Perkovic V et al. Diabetes Care. 2020 May 22;dc200279 CARMELINA Study: Patients of T2DM with CVD and/or CKD

22. Linagliptin Placebo HR (95% CI) HR (95% CI) p -value for treatment by age interaction n with event / N analysed (%) 3P-MACE 434/3494 (12.4) 420/3485 (12.1) 1.02 (0.89, 1.17) 0.0937 <65 years 154/1467 (10.5) 140/1501 (9.3) 1.11 (0.89, 1.40) 65 to <75 years 197/1405 (14.0) 182/1395 (13.0) 1.09 (0.89, 1.33) ≥75 years 83/622 (13.3) 98/589 (16.6) 0.76 (0.57, 1.02) HHF 209/3494 (6.0) 226/3485 (6.5) 0.90 (0.74, 1.08) 0.9788 <65 years 67/1467 (4.6) 77/1501 (5.1) 0.87 (0.63, 1.21) 65 to <75 years 89/1405 (6.3) 99/1395 (7.1) 0.89 (0.67, 1.18) ≥75 years 53/622 (8.5) 50/589 (8.5) 0.92 (0.63, 1.35) Kidney outcome* 327/3494 (9.4) 306/3485 (8.8) 1.04 (0.89, 1.22) 0.9968 <65 years 180/1467 (12.3) 173/1501 (11.5) 1.05 (0.85, 1.29) 65 to <75 years 113/1405 (8.0) 105/1395 (7.5) 1.06 (0.81, 1.38) ≥75 years 34/622 (5.5) 28/589 (4.8) 1.06 (0.64, 1.75) Albuminuria progression 763/2162 (35.3) 819/2129 (38.5) 0.86 (0.78, 0.95) 0.4318 <65 years 289/816 (35.4) 308/829 (37.2) 0.93 (0.79, 1.09) 65 to <75 years 320/903 (35.4) 339/877 (38.7) 0.84 (0.72, 0.98) ≥75 years 154/443 (34.8) 172/423 (40.7) 0.78 (0.63, 0.97) CARMELINA: No increased risk of cardio-renal events in older patients Favours linagliptin Favours placebo *Death due to kidney disease, progression to end-stage kidney disease, or sustained decrease in estimated glomerular filtration rate from baseline of ≥40% Cooper M et al. Diabetes Obes Metab 2020; Feb 9. doi : 10.1111/dom.13995 [ Epub ahead of print]

23. Summary: Linagliptin has Broadest Clinical Evidence in DPP-4i class 23 Uncertain Proven safety High CV risk Heart failure High kidney risk Proven safety Proven safety Safety Signal Proven safety Proven safety Uncertain Proven safety Uncertain Uncertain Safety signal Uncertain ‡ Uncertain Uncertain Sitagliptin 4, 5, 6 Teneligliptin 3, 8 Linagliptin 7 Saxagliptin 2 Vildagliptin 1 1. Novartis Europharm Ltd. Galvus ® ( vildagliptin ) summary of product characteristics; 2. Scirica B et al. N Engl J Med 2013;369:1317; 3. Indian J Endocrinol Metab . 2017 Jan-Feb;21(1):11-17; 4. Green J et al. N Engl J Med 2015;373:232; 5. Engel SE  et al. Diabetes  Obes   Metab 2017;19:1587; 6. Merck Sharp & Dohme Ltd. Januvia ® ( sitagliptin ) summary of product characteristics; 7. Trajenta PI 9 April 2020. Boehringer Ingelheim. 8 . Singh AK. Efficacy and safety of teneligliptin. Indian J Endocr Metab 2017;21:11-7 . + convenience of OD dosing without the need of dose adjustment

24. Summary : Simplifying T2DM Care with Linagliptin 24 5mg one dose, once daily independent of: CV Risk Trajenta PI Boehringer Ingelheim  Pvt. Ltd.  09 Apr 2020

25. Thank You !