Future Clinical Impact to SGLT2i in the Treatment of Diabetes

Future Clinical Impact to SGLT2i in the Treatment of Diabetes Imam Subekti Division of Endocrinology and Metabolism, Department of Internal Medicine Ciptomangunkusumo Hospital / Faculty of Medicine, Universitas Indonesia Jakarta 1

Topics Cardiovascular disease and diabetes New approach in diabetes treatment: SGLT2 inhibitor EMPA-REG outcome trial How have the results of EMPA-REG OUTCOME influenced clinical practice What may explain the benefits of empagliflozin Take home messages 2

CV disease is the leading cause of death in patients with T2D CV, cardiovascular; T2D, type 2 diabetes Morrish NJ et al. Diabetologia 2001;44:S14 3

Life expectancy is significantly decreased in patients with T2D and established CV disease* 60 years End of life No diabetes Diabetes 6 years Diabetes + MI 12 years In this case, CV disease is represented by MI or stroke. *Male, 60 years of age with history of MI or stroke CV, cardiovascular; MI, myocardial infarction; T2D, type 2 diabetes The Emerging Risk Factors Collaboration. JAMA 2015;314:52 4

Diabetes doubles the risk of vascular disease Data from 528,877 participants (adjusted for age, gender, cohort, SBP, smoking, BMI) Coronary heart disease Cases (n) HR (95% CI) I 2, % (95% CI) 26,505 2.00 (1.83, 2.19) 64 (54, 71) Coronary death 11,556 2.31 (2.05, 2.60) 41 (24, 54) Non-fatal MI 14,741 1.82 (1.64, 2.03) 37 (19, 51) Cerebrovascular disease Ischaemic stroke 3799 2.27 (1.95, 2.65) 1 (0, 20) Haemorrhagic stroke 1183 1.56 (1.19, 2.05) 0 (0, 26) Unclassified stroke 4973 1.84 (1.59, 2.13) 33 (12, 48) Other vascular deaths 1 2 3 4 3826 1.73 (1.51, 1.98) 0 (0, 26) HR (diabetes vs no diabetes) BMI, body mass index; MI, myocardial infarction; SBP, systolic blood pressure Emerging Risk Factors Collaboration. Lancet 2010;375:2215

Age-adjusted incidence rate (per 1000 individuals) Heart failure affects 1 in 5 patients with diabetes 1 120 People with diabetes have a 2- to 5-fold higher risk of developing HF 2 100 80 60 40 Non-diabetes Diabetes 20 0 Men aged 45 74 years Women aged 45 74 years HF, heart failure 1. Hess K, et al. Eur Heart J Suppl. 2012;14(Suppl B):B4-B13; 2, Kannel WB et al. Am J Cardiol 1974;34:29 6

Patients with diabetes and HF have a worse prognosis than patients with HF alone Cumulative incidence (%) CV death or HHF in patients with or without diabetes 60 Diabetes No diabetes HFrEF 40 HFrEF: unadjusted HR 1.60 (95% CI 1.44, 1.77); p<0.0001 HFpEF: unadjusted HR 2.0 (95% CI 1.70, 2.36); p<0.0001 HFpEF HFrEF 20 HFpEF 0 0 0.5 1 1.5 2 2.5 3 3.5 Follow-up (years) *HRs refer to the risk of CV death or HHF in patients with diabetes versus those without diabetes CV, cardiovascular; EF, ejection fraction; HF, heart failure; HHF, hospitalisation for heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; pef, preserved ejection fraction; ref, reduced ejection fraction. MacDonald MR et al. Eur Heart J 2008;29:1377 7

Despite improved standard of care, patients with T2D remain at increased risk of CV mortality Standardised incidence rate (per 10,000) person -years Data from 457,473 patients with T2D from the Swedish National Diabetes Register Death from CV disease 250 200 150 T2D 100 No T2D 50 0 2000 1 2002 2 2004 3 2006 4 2008 5 2010 6 2012 7 8 1998 1999 2001 2003 2005 2007 2009 2011 2013 2014 CV, cardiovascular; T2D, type 2 diabetes Rawshani A et al. N Engl J Med 2017;376:1407 8

Pathophysiology of type 2 diabetes includes eleven main defects: Egregious eleven SGLT2i Schwartz SS, et al, Diabetes Care 2016;39:179 86.

How did SGLT2 become a therapeutic target for T2DM? 180 g glucose filtered each day Glomerulus Proximal tubule Distal tubule Collecting duct S1 S2 Glucose filtration SGLT2 90% SGLT1 10% S3 Glucose reabsorption Up to ~90% of glucose is reabsorbed from the S1/S2 segments ~10% of glucose is reabsorbed from the S3 segment Loop of Henle Minimal glucose excretion Special glucose transporters (SGLT) are responsible for this reabsorption in the kidneys Wright EM. Am J Physiol Renal Physiol 2001;280:F10 8; Lee YJ, et al. Kidney Int Suppl 2007;106:S27 35; Brown GK. J Inherit Metab Dis 2000;23:237 246.

SGLT2 inhibition reduces renal glucose reabsorption and increases glucose elimination 180 g glucose filtered each day Glomerulus Proximal tubule Distal tubule Collecting duct S1 S2 Glucose filtration SGLT2 90% SGLT1 10% S3 Reduced Glucose glucose reabsorption Up to ~90% of glucose is reabsorbed from the S1/S2 segments SGLT2 inhibitor ~10% of glucose is reabsorbed from the S3 segment Loop of Henle Increased Minimal glucose excretion Special glucose transporters (SGLT) are responsible for this reabsorption in the kidneys Wright EM. Am J Physiol Renal Physiol 2001;280:F10 8; Lee YJ, et al. Kidney Int Suppl 2007;106:S27 35; Brown GK. J Inherit Metab Dis 2000;23:237 246.

Metformin atau obat lini pertama yang lain + Metformin atau obat lini pertama yang lain + Obat lini kedua + Diabetes management consensus PERKENI 2015 Lifestyle modification HbA1c < 7.5% HbA1c 7.5% HbA1c 9.0% Monoterapi* dengan salah satu obat di bawah ini Metformin Agonis GLP-1 Penghambat DPP-4 Penghambat Glukosidase Alfa Penghambat SGLT-2 Tiazolidindion Sulfonilurea Glinid Jika HbAc1 > 6.4% dalam 3 bulan tambahan obat ke 2 (kombinasi 2 obat) Kombinasi 2 obat* dengan mekanisme kerja yang berbeda Agonis GLP-1 Penghambat DPP-4 Tiazolidindion Penghambat SGLT- 2 Insulin Basal SU/Glinid Kolsevelam** Bromokriptin-QR Penghambat Glukosidase Alfa Jika belum memenuhi sasaran dalam 3 bulan, masuk ke kombinasi 3 obat Kombinasi 3 obat Agonis GLP-1 Penghambat DPP-4 Tiazolidindion Penghambat SGLT-2 Insulin Basal Kolsevelam** Bromokriptin-QR Penghambat Glukosidase Alfa Jika belum memenuhi sasaran dalam 3 bulan, mulai terapi insulin atau intensifikasi terapi insulin Gejala (-) Gejala (+) Kombinasi 2 obat Kombinasi 3 obat Keterangan Insulin ± obat jenis lain Mulai atau intensifikasi Insulin *Obat yang terdaftar, pemilihan dan penggunaannya disarankan mempertimbangkan faktor keuntungan, kerugian biaya, dan ketersediaan sesuai tabel 11 ** Kolsevelam belum tersedia di Indonesia Bromokriptin QR umumnya digunakan pada terapi tumor hipofisis Konsensus Pengelolaan dan Pencegahan Diabetes Melitus Tipe 2 di Indonesia. 2015.

Pharmacological properties of available SGLT2 inhibitors Therapeutic dose (mg/day) Starting dose Administration Peak plasma concentration (hours post-dose) Absorption (mean oral bioavailability) Empagliflozin Dapagliflozin Canagliflozin 10 25 10 qd With or without food 5 10 10 qd With or without food 100 300 100 qd Before first meal 1.5 Within 2 1 2 60% ~78% ~65% Metabolism Primarily glucuronidation no active metabolite Elimination (half-life, hours) Hepatic:renal 43:57 [12.4] Hepatic:renal 22:78 [12.9] Hepatic:renal 67:33 [13.1]* Selectivity over SGLT1 1:5000 >1:1400 >1:160 1 Glucose excretion with higher dose (g/day) 78 ~70 119 *For the 300 mg dose Data from www.ema.europa.eu (Jardiance SmPC, Forxiga SmPC, Invokana PI, Invokana SmPC, all accessed 20 Feb 2016); Sha et al. Diab Obes Metab 2015;17:188

EMPA-REG OUTCOME is the first CV outcome trial with an SGLT2 inhibitor to report data EMPA-REG OUTCOME 1 CANVAS 2 CANVAS-R 3 CREDENCE 4 DECLARE- TIMI 58 5 Ertugliflozi n CVOT 6 Interventions Empagliflozin /placebo Canagliflozin /placebo Canagliflozin /placebo Canagliflozin / placebo Dapagliflozin / placebo Ertugliflozin /placebo Main inclusion criteria Est. CVD Est. CVD or 2 CV risk factors Est. CVD or 2 CV risk factors Stage 2 or 3 CKD + macroalbuminuria Est. CVD or 2 CV risk factors Est. vascular complication s No. of patients 7028 4339 5700 3627 17,150 3900 Primary outcome 3P-MACE 3P-MACE Progression of albuminuria ESRD, S-creatinine doubling, renal/cv death 3P-MACE 3P-MACE Estimated completion Completed Completed Completed 2019 2019 2021 Adapted from: Inzucchi SE et al. Diabetes Vasc Dis Res 2015;12:90; 1. Zinman B et al. N Engl J Med 2015;373:2117; 2. NCT01032629; 3. NCT01989754; 4. NCT02065791; 5. NCT01730534; 6. NCT01986881

In EMPA-REG OUTCOME, patients received empagliflozin or placebo, on top of current standard of care therapy All patients received standard of care for glucose control and CV risk reduction, including RAAS inhibition and lipid-lowering agents Stable background glucose-lowering therapy (first 12 weeks) Background glucose-lowering medication adjustment allowed to achieve glycaemic control Multifactorial CV risk reduction Randomised and treated (N=7020) Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) Pooled CV, cardiovascular; RAAS, renin angiotensin aldosterone system; T2D, type 2 diabetes Zinman B et al. N Engl J Med 2015;373:2117; Zinman B et al. Cardiovasc Diabetol 2014;13:102 21

CV benefit with empagliflozin was driven by a significant 38% reduction in CV death Patients with event/patients analysed (%) Empagliflozin Placebo HR (95% CI) HR (95% CI) p-value 3P-MACE 490/4687 (10.5) 282/2333 (12.1) 0.86 (0.74, 0.99)* 0.04* CV death 172/4687 (3.7) 137/2333 (5.9) Non-fatal MI 213/4687 (4.5) 121/2333 (5.2) 0.62 (0.49, 0.77) 0.87 (0.70, 1.09) <0.001 0.22 Non-fatal stroke 150/4687 (3.2) 60/2333 (2.6) 1.24 (0.92, 1.67) 0,25 0,5 1 2 0.16 Favours empagliflozin Favours placebo Empagliflozin is not indicated in all countries for CV risk reduction RRR for 3-point MACE: 14%; ARR for 3-point MACE: 1.6%; ARR difference for 3P-MACE: -6.5; RRR for CV death: 38%; ARR for CV death: 2.2%; ARR difference in CV death: -7.7%. Cox regression analysis. *95.02% CI and twosided p-value; Nominal p-value. 3P-MACE, 3-point major adverse cardiovascular events; 4P-MACE, 4-point major adverse cardiovascular event; ARR, absolute risk reduction; CV, cardiovascular; MI, myocardial infarction; RRR, relative risk reduction. Zinman B et al. N Engl J Med 2015;373:2117 22

Primary outcome 3P-MACE: 14% relative risk reduction CV death, non-fatal MI or non-fatal stroke HR 0.86 (95.02% CI, 0.74-0.99) p=0.04* for superiority Empagliflozin is not indicated in all countries for CV risk reduction Relative risk reduction (RRR) for 3P-MACE is 14%; absolute risk reduction (ARR) 1.6% rates of 3P-MACE: 10.5% (empagliflozin) vs. 12.1% (placebo). Cumulative incidence function. *Two-sided tests for superiority were conducted (statistical significance was indicated if p 0.0498) CI, confidence interval; HR, hazard ratio Zinman B et al. N Engl J Med 2015;373:2117 23

Patients with event (%) Reduction in risk of CV death occurred early and was sustained throughout the trial HR 0.62 (95% CI 0.49, 0.77) p<0.001* Months Empagliflozin is not indicated in all countries for CV risk reduction RRR for CV death: 38%; ARR for CV death: 2.2%; rates of CV death: 3.7% (empagliflozin) versus 5.9% (placebo). Cumulative incidence function. *Nominal p-value. ARR, absolute risk reduction; RRR, relative risk reduction Zinman B et al. N Engl J Med 2015;373:2117 24

Patients with event (%) Empagliflozin reduced hospitalisation for HF by 35% HR 0.65 (95% CI HR 0.50, 0.65 0.85) p=0.0017 (95% CI 0.50, 0.85) p=0.002* Months Empagliflozin is not indicated for the treatment of heart failure Cumulative incidence function. RRR for HHF is 35%; ARR for HHF is 1.4%, rates of HHF: 2.7% (empagliflozin) versus 4.1% (placebo) *Nominal p-value. ARR, absolute risk reduction; HF, heart failure; RRR, relative risk reduction Zinman B et al. N Engl J Med 2015;373:2117 25

Incident or worsening nephropathy Kaplan-Meier estimate in patients treated with 1 dose of study drug. Hazard ratios are based on Cox regression analyses. HR, hazard ratio; CI, confidence interval. Pre-specified analyses.

Doubling of serum creatinine*, initiation of renal replacement therapy, or death due to renal disease Kaplan-Meier estimate in patients treated with 1 dose of study drug. Hazard ratios are based on Cox regression analyses. *Accompanied by egfr [MDRD] 45 ml/min/1.73m 2. HR, hazard ratio; CI, confidence interval. Post-hoc analyses.

Renal outcomes Incident or worsening nephropathy or CV death Empagliflozin no. with event /analyzed (%) 675/4170 (16.2) Incident or worsening nephropathy 525/4124 (12.7) Progression to macroalbuminuria 459/4091 (11.2) Doubling of serum creatinine* 70/4645 (1.5) Initiation of renal replacement therapy Doubling of serum creatinine*, initiation of renal replacement therapy, or death due to renal disease 13/4687 (0.3) 81/4645 (1.7) rate/ 1000 pt-yr Placebo no. with event/ analyzed (%) 60.7 497/2102 (23.6) 47.8 388/2061 (18.8) 41.8 330/2033 (16.2) 5.5 60/2323 (2.6) 1.0 14/2333 (0.6) 6.3 71/2323 (3.1) rate/ 1000 pt-yr Hazard Ratio (95% CI) Hazard ratio (95% CI) p-value 95.9 0.61 (0.55 0.69) <0.001 76.0 0.61 (0.53 0.70) <0.001 64.9 0.62 (0.54 0.72) <0.001 9.7 0.56 (0.39 0.79) <0.001 2.1 0.45 (0.21 0.97) 0.04 11.5 0.54 (0.40 0.75) <0.001 Incident albuminuria in patients with normoalbuminuria at baseline 1430/2779 (51.5) 252.5 703/1374 (51.2) 266.0 0.95 (0.87 1.04) 0.25 0,125 0,25 0,5 1,0 2,0 4,0 Favors empagliflozin Favors placebo Cox regression analyses in patients treated with 1 dose of study drug. Analyses were prespecified except for the composite of doubling of serum creatinine, initiation of renal replacement therapy, or death due to renal disease. *Accompanied by egfr [MDRD] 45 ml/min/1.73m 2.

Empagliflozin reduced micro- and macrovascular risk in patients with T2D and established CV disease, compared with placebo Relative risk reduction: 3P-MACE CV death All-cause mortality HHF Incident or worsening nephropathy 14% 38% 32% 35% 39% Empagliflozin is not indicated in all countries for CV risk reduction, and is not indicated for the treatment of HF or kidney disease 3P-MACE, 3-point major adverse cardiovascular events; CV, cardiovascular; HF, heart failure; HHF, hospitalisation for heart failure; T2D, type 2 diabetes 1. Zinman B et al. N Engl J Med 2015;373:2117; 2. Wanner C et al. N Engl J Med 2016;375:323 29

Incidence of AEs of particular relevance was comparable across groups, except for increased frequency of genital infections with empagliflozin 1,2 Incidence of AEs, % 0 20 40 60 80 100 Any AE* Severe AE Serious AE Death AE leading to discontinuation Confirmed hypoglycaemia Hypoglycaemia requiring assistance UTI Complicated UTI Genital infection** Volume depletion Acute renal failure Diabetic ketoacidosis Bone fractures Thromboembolic event Lower limb amputations Placebo Pooled empagliflozin *p<0.001; p<0.05; p<0.01; Glucose level of <70 mg/dl (3.9 mmol/l); Based on 79 MedDRA terms; **Based on 88 MedDRA terms; Based on 8 MedDRA terms; Based on 1 MedDRA term; Based on 4 MedDRA terms; Based on 62 MedDRA terms Patients treated with 1 dose of study drug. UTI, urinary tract infection 1. Zinman B et al. N Engl J Med 2015;373:2117; 2. Kohler S et al. Adv Ther 2017;34:12 30

Cardiology guidelines recommend empagliflozin to reduce CV death in patients with T2D and established CV disease ESC 2016 guidelines on cardiovascular disease prevention in clinical practice 1 ESC 2016 guidelines for diagnosis and treatment of acute and chronic heart failure 2 In DM patients with existing CV disease, the use of a SGLT2 inhibitor substantially lessened CV disease and total mortality and HF hospitalisation without major adverse effects. SGLT2 inhibitors should be considered early in the course of DM management in such patients. Recently, empagliflozin has been shown to improve outcomes (including the reduction of mortality and HF hospitalizations) in patients with T2D. CV, cardiovascular; DM, diabetes mellitus; HF, heart failure; SGLT2, sodium-glucose transporter 2; T2D, type 2 diabetes 1. Piepoli MF et al. Eur Heart J 2016;37:2315; 2. Ponikowski P et al. Eur Heart J 2016;37:2129 50

Diabetes guidelines recommend empagliflozin to reduce CV death in patients with T2D and established CV disease Diabetes Canada: pharmacologic management of T2D 2016 interim update 1 American Diabetes Association: standards of medical care in diabetes 2017 2 antihyperglycemic agent with demonstrated CV outcome benefits, such as empagliflozin or liraglutide, should be added if glycaemic targets are not met in patients with clinical cardiovascular disease. In patients with long-standing suboptimally controlled T2D and established atherosclerotic CV disease, empagliflozin or liraglutide should be considered as they have been shown to reduce CV and all-cause mortality when added to standard care. CV, cardiovascular; T2D, type 2 diabetes 1. Canadian Diabetes Association. Can J Diabetes 2016;40:484; 2. American Diabetes Association. Diabetes Care 2017;40:S1 51

Empagliflozin is the only glucose-lowering agent to be approved by the FDA for reducing CV mortality risk Empagliflozin is not indicated in all countries for CV risk reduction CV, cardiovascular Boehringer Ingelheim. JARDIANCE (empagliflozin) Prescribing Information. 2016 52

Haemodynamic renal mechanisms may have an important role in the effects of empagliflozin SGLT2i Glycosuria Natriuresis Negative caloric balance HbA1c Uricosuria Blood pressure Plasma volume Tubuloglomerular feedback Total body fat mass Inflammation Glucose toxicity Plasma uric acid Arterial stiffness Myocardial stretch Afferent arteriole constriction Epicardial fat Atherosclerosis Ventricular arrhythmias Activation of ACE2 Ang1/7 Inflammation Fibrosis Cardiac contractility Intraglomerular hypertension Hyperfiltration Vascular effects Solid lines represent pathways supported by existing data; dashed lines represent possible areas for future research ACE2, angiotensin-converting enzyme-2; Ang 1/7, angiotensin 1/7 Rajasekeran H et al. Kidney Int 2016;89:522 54

30-day follow-up 30-day follow-up Two dedicated HF trials are now investigating the HF benefit of empagliflozin in patients with and without T2D Phase III, randomised, double-blind, placebo-controlled studies Aim: To investigate the safety and efficacy of empagliflozin versus placebo on top of guideline-directed medical therapy in patients with HF with reduced 1 and preserved 2 ejection fraction Population: T2D and non-t2d, age 18 years, chronic HF (NYHA II IV) Screening EMPEROR-reduced 1 LVEF 40% Planned recruitment: 2850 patients Empagliflozin 10 mg qd + standard of care* Placebo qd + standard of care* Screening EMPEROR-preserved 2 LVEF >40% Planned recruitment: 4126 patients Empagliflozin 10 mg qd + standard of care* Placebo qd + standard of care* Estimated follow-up on treatment: ~38 months *Guideline-directed medical therapy HF, heart failure; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; T2D, type 2 diabetes. 1. ClinicalTrials.gov NCT03057977; 2. ClinicalTrials.gov NCT03057951 55

Take home messages Despite improved standard of care, CV disease is the leading cause of death in patient with type 2 diabetes mellitus We are learning more about CV risk in T2DM, recent CV trial reveals new hope in the management of cv risk in T2DM SGLT2 inhibition blocks glucose re-uptake in the proximal renal tubule, leading to urinary glucose excretion and glucose removal EMPA REG OUTCOME is the first CVOT with SGLT2i to report data 57

Take home messages Result of EMPA-REG OUTCOME show beyond glycemic control effect of Empagliflozin 3P-MACE CV death All-cause mortality HHF Incident or worsening nephropathy 14% 38% 32% 35% 39% Result of EMPA REG OUTCOME has influenced clinical practice as seen in the latest guidelines updates both endocrinology and cardiology 58