SGLT2 Inhibition in the Management of T2DM: Potential Impact on CVD Risk

Managing Diabetes & CVD: Expling New Evidence & Opptunities ESC Congress, London, UK 30 August, 2015 SGLT2 Inhibition in the Management of T2DM: Potential Impact on CVD Risk Silvio E. Inzucchi MD Yale University New Haven, Connecticut, USA

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

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

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

Renal Glucose Handling* 600 Reabsption/Excretion (mg/min) Filtered Excreted Rate of Glucose Filtration/ 400 200 Tmax Threshold Reabsbed T m Threshold (Tm Glu ) = maximal resptive capacity of the proximal tubule 0 0 200 400 600 800 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; 1992:2017-2038. *Filters & reabsbs 140-180 g glucose / day

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

Nmal Physiology of Renal Glucose Homeostasis Glucose filtration Glomerulus Proximal tubule S1 SGLT2 SGLT1 S3 Distal tubule Collecting duct Glucose reabsption 90% 10% Minimal glucose excretion Loop of Henle 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 Inhibition Reduces Renal Glucose Reabsption Glucose filtration 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 Dapagliflozin Canagliflozin Empagliflozin Ipragliflozin Luseogliflozin Inverse-variance weighted random effects meta-analysis -1,25 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 est, 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.

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 Overall Monotherapy Add-on treatment -0,50-1,00-1,50-2,00 Inverse-variance weighted random effects meta-analysis -2,50 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 est, 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.

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). 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

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 Overall Monotherapy Add-on treatment -1,00-2,00-3,00-4,00-5,00 Inverse-variance weighted random effects meta-analysis -6,00 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 est, 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.

Adjusted mean (95% CI) difference versus placebo in change from baseline in DBP (mm Hg) Courtesy, A. Tsapas MD, Aristotle Univ, Thessaloniki, Greece Vasilakou D, et al. Ann Intern Med. 2013;159:262-74. Placebo-crected change from baseline in diastolic blood pressure (DBP) 0,00 Overall Monotherapy Add-on treatment -0,50-1,00-1,50-2,00-2,50 Inverse-variance weighted random effects meta-analysis -3,00 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 est, most common dose across studies. SGLT2: sodium glucose cotranspter 2, CI: confidence interval.

Additional Potential Benefit: Blood Pressure Reduction Well-documented, consistent reduction of systolic blood pressure in clinical trials Irrespective of background anti-htn therapy Appears to occur even in those with decreased GFR, where glycemic efficacy is reduced Probably triggered by osmotic diuresis Role of tubulo-glomerular feedback (?) Clinical value Improved BP control Reduction in use/dose of anti-hypertensives? Cardiovascular risk reduction?

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

Will They Hurt the Kidney? Small, reversible decreases in GFR. Decreases albuminuria Loss of glucose reabsption appears to be safe in non-diabetic patients with nmal egfr (i.e. FRG.) Unclear what long-term effect of persistent glucosuria will be in people with diabetes Less effective when kidney function is reduced. Don t use when egfr <60 (dapa) <45 (cana, empa) Scheen AJ. Clin Pharmacokinet 2015, PMID: 25805666

FRG : An Experiment of Nature Familial renal glucosuria Due to SGLT2 gene mutations Rare kidney disder Benign No cresponding kidney complications Absence of glucose reabsption indicated by er urinary glucose excretion Urinary glucose excretion up to 170 g/d Appear protected vs. obesity, T2DM Wright EM. J Intern Med. 2007;261:32-43.

SGLT2 Inhibits: Risks & Benefits BENEFITS Insulin-independent glucose lowering effect (irrespective of DM 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 Hgb/Hct Small LDL-C Urinary Ca losses (?) Kim Y et al. Diabetes Metab Syndr Obes. 2012;5:313-327. Inzucchi SE et al. Diabetes Care 2015;38:140-159

Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy Triple therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education Metfmin 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): Metfmin Sulfonylurea moderate risk gain hypoglycemia low Metfmin Sulfonylurea TZD Metfmin low risk gain edema, HF, fxs low Metfmin Thiazolidinedione Thiazolidinedione SU Metfmin DPP-4 inhibit intermediate low risk neutral rare Metfmin Metfmin SGLT2 inhibit intermediate low risk loss GU, dehydration Metfmin GLP-1 recept agonist low risk loss GI 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): DPP-4 Inhibit SU Metfmin SGLT-2 Inhibit SU Metfmin GLP-1 recept agonist SU Metfmin Insulin (basal) est risk gain hypoglycemia variable Metfmin Insulin (basal) TZD DPP-4-i DPP-4-i TZD TZD TZD DPP-4-i 2015 ADA-EASD Position Statement on Management of Hyperglycemia in T2DM Combination injectable therapy SGLT2-i GLP-1-RA Insulin SGLT2-i GLP-1-RA Insulin Basal Insulin SGLT2-i Insulin DPP-4-i Insulin Insulin SGLT2-i GLP-1-RA 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 SGLT2-i: Metfmin Mealtime Insulin GLP-1-RA Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy Triple therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education Metfmin 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): Metfmin Sulfonylurea moderate risk gain hypoglycemia low Metfmin Sulfonylurea TZD Metfmin low risk gain edema, HF, fxs low Metfmin Thiazolidinedione Thiazolidinedione SU Metfmin DPP-4 inhibit intermediate low risk neutral rare Metfmin Metfmin SGLT2 inhibit intermediate low risk loss GU, dehydration Metfmin GLP-1 recept agonist low risk loss GI 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): DPP-4 Inhibit SU Metfmin SGLT-2 Inhibit SU Metfmin GLP-1 recept agonist SU Metfmin Insulin (basal) est risk gain hypoglycemia variable Metfmin Insulin (basal) TZD DPP-4-i DPP-4-i TZD TZD 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 SGLT2-i: Metfmin Basal Insulin Mealtime Insulin GLP-1-RA Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

SGLT2 Inhibition, T2DM Management & CVD Impact SUMMARY The SGLT 2 inhibits are the latest categy of drugs used f type 2 diabetes; they lower glucose by increasing urinary glucose excretion. They are effective at any stage of disease, so long as there is sufficient renal function. No hypoglycemia. Additional advantages include modest reductions in body weight & BP. There are small beneficial changes in TGs & HDL. Long-term CVD effects are under study. Side effects stem directly from their mechanism of action increased urination, possible dehydration, and increase in GU infections. LDL-C is increased by 5%. Interesting recent repts of DKA - predominately in T1DM (offlabel use) and in some (presumably ly insulin-deficient) patients with T2DM.