SGLT2 Inhibition in T2DM Management: Current Position and Future Promise

SGLT2 Inhibition, Diabetes and CVD: Where Does This Fit in CV Risk Management? ESC Congress, Rome, Italy 28 August, 2016 SGLT2 Inhibition in T2DM Management: Current Position and Future Promise Silvio E. Inzucchi MD Yale School of Medicine Yale-New Haven Hospital New Haven, Connecticut, USA

Silvio E. Inzucchi MD Profess of Medicine (Endocrinology) Disclosure of potential conflicts of interest Research contracts: Boehringer Ingelheim Stra Zeneca Janssen (TIMI Group) Daiichi Sankyo Takeda (study supplies) Eisai (TIMI Group) Consulting: Merck Sanofi/Lexicon Poxel VTV Therapeutics Employment in industry: None Stockholder of healthcare company: Owner of healthcare company: None None Other: Novo Ndisk (Trial DMC member) Intarcia (Trial DMC member)

One Half- Century of Marketed Drugs f Hypertension and Type 2 Diabetes in the United States Adapted from: Inzucchi SE. Comparing and Choosing Oral Agents, in Clinical Diabetes, Fonseca VA, WB Saunders, 2006.

Multiple Complex Pathophysiological Abnmalities in T2DM incretin effect gut carbohydrate delivery & absption - HYPERGLYCEMIA pancreatic insulin secretion pancreatic glucagon secretion? hepatic glucose production Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011 renal glucose excretion - peripheral glucose uptake

Multiple Pathophysiologically-Based Therapies f T2DM GLP-1R Insulin agonists incretin Glinides S U s effect DPP-4 Amylin inhibits mimetics guta G I s carbohydrate delivery & absption Bile acid sequestrants hepatic glucose production Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011 - pancreatic insulin secretion pancreatic glucagon secretion HYPERGLYCEMIA SGLT-2 inhibits - DA agonists T Z D s? peripheral glucose uptake

The 7 Maj Glucose-Lowering Drug Classes in Use in Patients with T2DM in US & Europe GLP-1R agonists incretin effect DPP-4 inhibits gut carbohydrate delivery & absption - Insulin pancreatic S U s insulin secretion pancreatic glucagon secretion HYPERGLYCEMIA - T Z D s? hepatic glucose production Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011 SGLT-2 inhibits peripheral glucose uptake

2 2 2 1 = 7 GLP-1R agonists DPP-4 inhibits incretin enhancers Insulin S U s insulin providers insulin sensitizers T Z D s SGLT-2 inhibits glucose excreter

Renal Glucose Handling* Rate of Glucose Filtration/ Reabsption/Excretion (mg/min) 600 400 200 Tmax Threshold Filtered Excreted 0 0 200 400 600 800 Reabsbed T m Threshold (Tm Glu ) = maximal resptive capacity of the proximal tubule Plasma Glucose (mg/dl) Schematic representation of the typical titration curve f renal glucose reabsption in man. Adapted from Silverman M, Turner RJ. Handbook of Physiology, Oxfd University Press; 1992:2017-38. *Filters & reabsbs 140-180 g glucose/day

Active (SGLT2) & Passive (GLUT2) Glucose Transpt in Renal Proximal Tubular Cell Nair S, et al. J Clin Endocrinol Metab. 2010;95:34-42. Tubular lumen Interstitium Na Glucose SGLT2 K Na ATPase Glucose Na -K Pump Na GLUT2 Glucose

Glucose filtration Nmal Physiology of Renal Glucose Homeostasis Glomerulus Proximal tubule S1 SGLT2 SGLT1 S3 Distal tubule Collecting duct Glucose reabsption 90% 10% Loop of Henle Minimal glucose excretion Wright EM. Am J Physiol Renal Physiol. 2001;280:F10-F18; Lee YJ et al. Kidney Int Suppl. 2007;106:S27-S35; Han S. Diabetes. 2008;57:1723-1729.

Glucose filtration SGLT2 Inhibition Reduces Renal Glucose Reabsption Glomerulus Proximal tubule S1 SGLT2 SGLT1 S3 Distal tubule Collecting duct Glucose reabsption 90% SGLT2 inhibit 10% Loop of Henle Increased glucose excretion - 70-80 g/day ( - 280-320 Kcal/day) Wright EM. Am J Physiol Renal Physiol. 2001;280:F10-F18; Lee YJ et al. Kidney Int Suppl. 2007;106:S27-S35; Han S. Diabetes. 2008;57:1723-1729.

SGLT2 Inhibits Currently Available Canagliflozin (100, 300 mg) Dapagliflozin (5, 10 mg) Empagliflozin (10, 20 mg) Ipragliflozin, Luseogliflozin, Tofogliflozin (Japan) Ertugliflozin (investigational)

Adjusted mean (95% CI) difference versus placebo in change from baseline in HbA 1c (%) Placebo-crected change from baseline in HbA1c 0,00-0,25-0,50-0,75-1,00-1,25 Dapagliflozin Canagliflozin Empagliflozin Ipragliflozin Luseogliflozin Dapagliflozin (~ 6000 patients) 0.56 ( 0.64 to 0.48) Canagliflozin (~ 3500 patients) 0.81 ( 0.93 to 0.69) Empagliflozin (~ 4000 patients) 0.65 ( 0.74 to 0.56) Ipragliflozin (~ 1000 patients) 0.97 ( 1.23 to 0.70) Luseogliflozin (~ 500 patients) 0.70 ( 0.85 to 0.55) Pooled results f 22 dapagliflozin, 11 empagliflozin, 9 canagliflozin, 7 ipragliflozin and 3 luseogliflozin studies with 12 weeks duration from published and gray literature sources through June 30, 2014 [search strategy adapted from Vasilakou et al. Ann Intern Med. 2013;159(4):262-274]. Results are presented f the group allocated to the highest, most common dose across studies. SGLT2: sodium glucose cotranspter 2, CI: confidence interval, HbA 1c : haemoglobin A 1c. Courtesy, A. Tsapas MD, Aristotle Univ, Thessaloniki, Greece Vasilakou D, et al. Ann Intern Med. 2013;159:262-74. Inverse-variance weighted random effects meta-analysis

Adjusted mean (95% CI) difference versus placebo in change from baseline in body weight (kg) Placebo-crected change from baseline in body weight 0,00-0,50-1,00-1,50-2,00-2,50 Overall Monotherapy Add-on treatment Overall Monotherapy Add-on treatment 1.87 ( 2.05 to 1.70) 1.72 ( 1.92 to 1.52) 2.02 ( 2.28 to 1.75) Pooled results f 18 studies of SGLT2 inhibits as monotherapy and 28 studies as add-on treatment with 12 weeks duration from published and gray literature sources through June 30, 2014 [search strategy adapted from Vasilakou et al. Ann Intern Med. 2013;159(4):262-274]. Results are presented f the group allocated to the highest, most common dose across studies. SGLT2: sodium glucose cotranspter 2, CI: confidence interval. Courtesy, A. Tsapas MD, Aristotle Univ, Thessaloniki, Greece Vasilakou D, et al. Ann Intern Med. 2013;159:262-74. Inverse-variance weighted random effects meta-analysis

Adjusted mean (95% CI) difference versus placebo in change from baseline in SBP (mm Hg) Placebo-crected change from baseline in systolic blood pressure (SBP) 0,00-1,00-2,00-3,00-4,00-5,00-6,00 Overall Monotherapy Add-on treatment Overall Monotherapy Add-on treatment 4.19 ( 4.77 to 3.61) 4.74 ( 5.52 to 3.95) 3.91 ( 4.68 to 3.14) Pooled results f 16 studies of SGLT2 inhibits as monotherapy and 29 studies as add-on treatment with 12 weeks duration from published and gray literature sources through June 30, 2014 [search strategy adapted from Vasilakou et al. Ann Intern Med. 2013;159(4):262-274]. Results are presented f the group allocated to the highest, most common dose across studies. SGLT2: sodium glucose cotranspter 2, CI: confidence interval. Courtesy, A. Tsapas MD, Aristotle Univ, Thessaloniki, Greece Vasilakou D, et al. Ann Intern Med. 2013;159:262-74. Inverse-variance weighted random effects meta-analysis

Adjusted mean (95% CI) difference versus placebo in change from baseline in DBP (mm Hg) Placebo-crected change from baseline in diastolic blood pressure (DBP) 0,00-0,50-1,00-1,50-2,00-2,50-3,00 Overall Monotherapy Add-on treatment Overall Monotherapy Add-on treatment 2.02 ( 2.30 to 1.74) 2.03 ( 2.56 to 1.50) 2.03 ( 2.38 to 1.68) Pooled results f 14 studies of SGLT2 inhibits as monotherapy and 27 studies as add-on treatment with 12 weeks duration from published and gray literature sources through June 30, 2014 [search strategy adapted from Vasilakou et al. Ann Intern Med. 2013;159(4):262-274]. Results are presented f the group allocated to the highest, most common dose across studies. SGLT2: sodium glucose cotranspter 2, CI: confidence interval. Courtesy, A. Tsapas MD, Aristotle Univ, Thessaloniki, Greece Vasilakou D, et al. Ann Intern Med. 2013;159:262-74. Inverse-variance weighted random effects meta-analysis

Empagliflozin vs. glimepiride as add-on to metfmin After 2 years (n = 1,549): Me durable reduction in HbA 1c ( 0.11 %; 95% CI 0.19, 0.02). Significant body weight reduction of 4.5 kg (95% CI 4.8, 4.1). Lowering effect on SBP was 5.6 mm Hg (95% CI 6.8, 4.4). 6-fold fewer hypoglycemic events with empagliflozin (4%) than with glimepiride (25%). Similar rates of urinary tract infections but increased incidence of genital mycotic infections f empagliflozin (12%) compared with glimepiride (2%). Ridderstra le M et al. Lancet Diabetes Endocrinol. 2014;2(9):691-700

SGLT2 Inhibits: Risks vs. Benefit Assessment Befe Results of CVOTs BENEFITS Insulin-independent BGlowering effect (irrespective of disease duration) Low hypoglycemia rates Modest weight, BMI, WC Modest BP Albumin:Cr Ratio Modest TGs Small HDL-C RISKS Genital mycotic infections? UTIs DKA Polyuria/ dehydration Reversible GFR Small LDL-C Fracture risk (?) Kim Y et al. Diabetes Metab Syndr Obes. 2012;5:313-327; Inzucchi SE et al. Diabetes Care 2015;38:140-159

Potential pathways to CV benefits of SGLT2-inhibits based on clinical and mechanistic studies BP Arterial stiffness Novel Pathways (?) Albuminuria SNS activity(?) Weight Visceral adiposity Glucose Insulin Oxidative stress Uric Acid LDL-C HDL-C TGs Inzucchi SE et al. Diab Vasc Dis Res 2015;12:90-100

EMPA-REG OUTCOME Trial design Placebo (n=2333) Screening (n=11531) Randomized and treated (n=7020) Empagliflozin 10 mg (n=2345) Study medication was given in addition to standard of care. Primary outcome: 3-point MACE Analysis: Placebo vs. pooled empagliflozin groups Key inclusion criteria: Adults with type 2 diabetes established CVD Empagliflozin 25 mg (n=2342) BMI 45 kg/m 2 ; HbA1c 7 10%; egfr 30 ml/min/1.73m 2 (MDRD) Zinman B et al. N Engl J Med 2015;373:2117

EMPA-REG OUTCOME Trial design Placebo (n=2333) Screening (n=11531) Randomized and treated (n=7020) Empagliflozin 10 mg (n=2345) BASELINE FEATURES Age 63 years, BMI 31 kg/m2, 72% male A1c 8.1%, LDL 86 mg/dl, egfr 74 ml/min/1.73m 2 (26% CKD-3) DM meds: 74%, 43% Sulfonylurea, 48% Insulin CVD: 76% CAD, 46% MI, 10% HF, 23% stroke, 21% PAD Empagliflozin 25 mg (n=2342) CV meds: 77% statin, 81% ACEI/ARB, 65% BB, 43% diuretic, 83% ASA Zinman B et al. N Engl J Med 2015;373:2117

Primary outcome: 3-point MACE HR 0.86 (95.02% CI 0.74, 0.99) p=0.0382* 14% N=7020 Cumulative incidence function. MACE, Maj Adverse Cardiovascular Event; HR, hazard ratio. * Two-sided tests f superiity were conducted (statistical significance was indicated if p 0.0498) Zinman B et al. N Engl J Med 2015;373:2117

CV death HR 0.62 (95% CI 0.49, 0.77) p<0.0001 38% N=7020 Cumulative incidence function. HR, hazard ratio Zinman B et al. N Engl J Med 2015;373:2117

Categies of CV death Patients with event (%) Empagliflozin Placebo (n=4687) (n=2333) HR (95% CI) CV death* 172 (3.7%) 137 (5.9%) 0.62 (0.49, 0.77) Sudden death 53 (1.1%) 38 (1.6%) 0.69 (0.45, 1.04) Wsening of heart failure 11 (0.2%) 19 (0.8%) 0.29 (0.14, 0.61) Acute MI 15 (0.3%) 11 (0.5%) 0.68 (0.31, 1.48) Stroke 16 (0.3%) 11 (0.5%) 0.72 (0.33, 1.55) Cardiogenic shock 3 (0.1%) 3 (0.1%) Other 74 (1.6%) 55 (2.4%) 0.66 (0.47, 0.94) Not assessable 71 (1.5%) 53 (2.3%) Cox regression analysis. *Based on adjudication. Insufficient data f the adjudication committee to categize cause of death. HR, hazard ratio; CI, confidence interval; CV, cardiovascular; MI, myocardial infarction. Cardiogenic shock: HR and 95% CI not calculated as <14 patients with events. 0,13 0,25 0,50 1,00 2,00 Favs empagliflozin Favs placebo Fitchett D et al. ACC.16, Chicago, IL

CV death, MI and stroke Patients with event/analysed Empagliflozin Placebo HR (95% CI) p-value 3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382 CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001 Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189 Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638 Cox regression analysis. MACE, Maj Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction *95.02% CI 0,25 0,50 1,00 2,00 Favours empagliflozin Favours placebo Zinman B et al. N Engl J Med 2015;373:2117

Ongoing Diabetes CV Outcomes Trials Involving SGLT2 Inhibits CANVAS DECLARE NCT01986881* Study CANVAS 1 Study DECLARE 2 Study NCT01986881 3 SGLT2 inhibit Canagliflozin SGLT2 inhibit Dapagliflozin SGLT2 inhibit Ertugliflozin Comparat Placebo N 4300 Results 2017 Comparat Placebo N 22,200 Results 2019 Comparat Placebo N 3900 Results 2020 CANVAS-R Renal outcomes in T2D patients at high CV risk CREDENCE Renal & CV outcomes in T2D patients with nephropathy (GFR 30-<90 with UACR 300-<5000 mg/g Cr) *Not approved by FDA EMA 1. Neal B, et al. Am Heart J. 2013;166:217-223; 2. Clinicaltrials.gov. NCT01730534; 3. Clinicaltrials.gov. NCT01986881.

Will They Wear Out the Kidney? Small, reversible decreases in GFR. Less effective when kidney function is reduced. (Not indicated when egfr <60 (dapa) <45 (cana, empa) Decreases in albuminuria Loss of glucose reabsption appears to be safe in non-diabetic patients with nmal egfr (i.e., Familial Renal Glucosuria) Unclear what long-term effect of persistent glucosuria will be in people with diabetes

Incident wsening nephropathy* 41% *Defined as: Progression to macroalbuminuria (UACR >300), N=7020 doubling of SCr (with egfr 45), dialysis/transplant, renal death Kaplan-Meier estimate. Hazard ratio based on Cox regression analyses. Wanner C, et al. N Engl J Med 2016;DOI: 10.1056/NEJMoa1515920

Incident wsening nephropathy (& components) Empagliflozin Placebo n with event/ N analyzed Hazard ratio (95% CI) p-value Incident wsening nephropathy New onset macroalbuminuria 525/4124 388/2061 0.61 (0.53, 0.70) <0.0001 459/4091 330/2033 0.62 (0.54, 0.72) <0.0001 Doubling of serumcreatinine * 70/4645 60/2323 0.56 (0.39, 0.79) 0.0009 Initiation of renal replacement therapy *Accompanied by egfr (MDRD) 45 ml/min/1.73m 2. Cox regression analyses. 0,13 0,25 0,50 1,00 2,00 13/4687 14/2333 0.45 (0.21, 0.97) 0.0409 Favours empagliflozin Favours placebo Wanner C, et al. N Engl J Med 2016;DOI: 10.1056/NEJMoa1515920

ADA-EASD Position Statement on the Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education high low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Sulfonylurea high moderate risk gain hypoglycemia low Thiazolidinedione high low risk gain edema, HF, fxs low DPP-4 inhibit intermediate low risk neutral rare high SGLT2 inhibit intermediate low risk loss GU, dehydration high GLP-1 recept agonist high low risk loss GI high Insulin (basal) highest high risk gain hypoglycemia variable Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR. Diabetes Care 2015;38:140-9; Diabetologia 2015;58:429-42 Triple therapy Sulfonylurea If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): TZD DPP-4-i Thiazolidinedione SU DPP-4-i DPP-4 Inhibit SU TZD SGLT-2 Inhibit SU TZD GLP-1 recept agonist SU TZD Insulin (basal) TZD DPP-4-i SGLT2-i SGLT2-i SGLT2-i DPP-4-i Insulin SGLT2-i GLP-1-RA GLP-1-RA Insulin Insulin GLP-1-RA Insulin Insulin Combination injectable therapy If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add GLP-1-RA mealtime insulin. In refracty patients consider adding TZD SGL T2-i: Basal Insulin Mealtime Insulin GLP-1-RA 30

Side effects stem directly from their mechanism of action increased urination, possible dehydration, and increase in GU infections. DKA is an emerging concern, mainly in T1DM (not indicated) but potentially in (presumably) insulin deficient T2DMs. SGLT2 Inhibition in T2DM : Current Position, Future Promise SUMMARY The SGLT 2-i s are the newest categy of T2DM drugs. They wk by augmenting urinary glucose excretion and are effective at any stage of disease, so long as there is sufficient renal function. They are not associated with hypoglycemia when used as monotherapy other non-hypoglycemic agents. SGLT 2-i s result in modest improvements in some CV risk facts (weight, BP.) The first SGLT2-i CVOT to rept, EMPA-REG OUTCOME, showed a surprising effect of empagliflozin to decrease 3-point MACE, primarily through a 38% relative risk reduction in CV death (ARR = 2.2%).