EDUCATIONAL SLIDE MODULES Module D: Evaluating CV safety and potential for CV risk reduction with newer T2D agents.

EDUCATIONAL SLIDE MODULES Module D: Evaluating CV safety and potential for CV risk reduction with newer T2D agents

ACROSS T2D educational slide modules
Module A CV disease and T2D Module B Approaches to managing CV risk in patients with T2D Module C Evidence for effects of older glucose-lowering agents on CV risk Module D Evaluating CV safety and potential for CV risk reduction with newer T2D agents Module E EMPA-REG OUTCOME® results Abbreviations CV, cardiovascular; EMPA-REG OUTCOME®, cardiovascular outcomes trial of empagliflozin; T2D, Type 2 Diabetes.

Completed and ongoing CVOTs
DPP4 inhibitors Completed and ongoing CVOTs Ongoing CVOTs SGLT2 inhibitors GLP1 receptor agonists Notes This slide provides a visual summary of this module. Abbreviations CVOT, cardiovascular outcomes trial; DPP4, dipeptidyl peptidase 4; GLP1R, glucagon-like peptide 1; SGLT2, sodium glucose cotransporter 2.

A closer look at CV effects of 21st century T2D agents
DPP4 inhibitors SGLT2 inhibitors  Older T2D agents Newer T2D agents  1950 1960 1970 1980 1990 2000 2010 2012 2013 GLP1 receptor agonists Lente class of insulins produced Recombinant human insulin produced Glimepiride: 3rd generation SU Insulin degludec SUs first used 2nd generation SUs available Insulin glargine available2 Notes In Module C we looked at the CV effects of older T2D agents (pre-2000 – note that metformin wasn’t licensed in the USA until 1995). In this module, the CV effects of the newer GLP1 agonists, DPP4 inhibitors and SGLT2 inhibitors will be examined. Abbreviations CV, cardiovascular; DPP4, dipeptidyl peptidase 4; GLP1, glucagon-like peptide 1; SGLT2, sodium glucose cotransporter 2; SU, sulphonylurea; T2D, Type 2 Diabetes; TZD, thiazolidinedione. Copyright Kirby. Br J Diabetes Vasc Dis 2012;12:315–20. Figure 1 Metformin introduced in the UK Three new classes introduced: -glucosidase inhibitors, meglitinides and TZDs Adapted from 1. Kirby. Br J Diabetes Vasc Dis 2012;12:315– Lantus® SPC. FDA 2015.

CV safety trials are being conducted for each compound within the newer classes
CANVAS-R8 (n = 5700) Albuminuria 2013 2014 2015 2016 2017 2018 2019 SAVOR-TIMI 531 (n = 16,492) 1,222 3P-MACE EXAMINE2 (n = 5380) 621 3P-MACE TECOS4 (n = 14,724) ≥ P-MACE LEADER6 (n = 9340) ≥ 611 3P-MACE SUSTAIN-67 (n = 3297) 3P-MACE DECLARE-TIMI 5815 (n = 17,150) ≥ P-MACE EMPA-REG OUTCOME®5 (n = 7034) ≥ 691 3P-MACE CANVAS10 (n = 4365) ≥ 420 3P-MACE CREDENCE17 (n = 3700) Renal + 5P-MACE CAROLINA®11 (n = 6000) ≥ 631 4P-MACE ITCA CVOT9 (n = 4000) 4P-MACE EXSCEL14 (n = 14,000) ≥ P-MACE DPP4 inhibitor CVOTs SGLT2 inhibitor CVOTs GLP1 CVOTs Ertugliflozin CVOT18 (n = 3900) OMNEON13 CARMELINA12 (n = 8300) 4P-MACE + renal REWIND16 (n = 9622) ≥ P-MACE 2021 ELIXA3 (n = 6068) ≥ 844 4P-MACE Notes This overview indicates all of the ongoing (and two completed – SAVOR-TIMI 53 and EXAMINE) CVOTs for the newer T2D agents. The trial name, the estimated recruitment and the primary outcome are indicated The timings indicate the estimated completion dates of the trial Planned or actual event rates are indicated in some cases (e.g. EXAMINE, ELIXA etc) Abbreviations CANVAS, Canagliflozin Cardiovascular Assessment Study CANVAS-R, Study of the Effects of Canagliflozin on Renal Endpoints in Adult Subjects with T2DM CARMELINA®, Cardiovascular Safety & Renal Microvascular Outcome Study with Linagliptin CAROLINA®, Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes CREDENCE, Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy CVOT, cardiovascular outcomes trial DPP4, dipeptidyl peptidase 4 DECLARE-TIMI, Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome EMPA-REG OUTCOME® [cardiovascular outcomes trial of empagliflozin] EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care EXSCEL, The EXenatide Study of Cardiovascular Event Lowering GLP1, glucagon-like peptide 1 LEADER®, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results OMNEON™ [randomised, double-blind, placebo-controlled, multicenter study to assess cardiovascular outcomes following treatment] REWIND, Researching Cardiovascular Events With a Weekly Incretin in Diabetes SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus - Thrombolysis in Myocardial Infarction SGLT2, sodium glucose cotransporter 2 SUSTAIN, Trial to Evaluate Cardiovascular and Other Longterm Outcomes With Semaglutide in Subjects With Type 2 Diabetes T2D, Type 2 diabetes TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin 3P-MACE, 3-point major adverse cardiovascular events (CV death, non-fatal myocardial infarction or non-fatal stroke) 4P-MACE, 4-point major adverse cardiovascular events (CV death, non-fatal myocardial infarction, non-fatal stroke or unstable angina requiring hospitalisation) References 1. Scirica et al. N Engl J Med 2013;369:1317–26. 2. White et al. N Engl J Med 2013;369:1327–35 3. Bentley-Lewis et al. Am Heart J 2015;0:1–8.e7. 4. Bethel et al. Diabetes Obes Metab 2015;17:1395–402 5. Zinman et al. Cardiovasc Diabetol 2014;13:102 6. NCT 7. NCT 8. NCT 9. NCT 10. NCT 11. NCT 12. NCT 13. NCT 14. NCT 15. NCT 16. NCT 17. NCT 18. NCT 19. NCT Copyright Johansen. World J Diabetes 2015; 6:1092–96 HARMONY Outcomes19 (n = 9400) 3P-MACE Timings represent estimated completion dates as per ClinicalTrials.gov. Adapted from Johansen. World J Diabetes 2015;6:1092–96. (references 1–19 expanded in slide notes)

DPP4 inhibitors GLP1 receptor agonists SGLT2 inhibitors Notes This slide provides a visual summary of this module. Abbreviations CVOT, cardiovascular outcomes trial; DPP4, dipeptidyl peptidase 4; GLP1, glucagon-like peptide 1; SGLT2, sodium glucose cotransporter 2.

DPP4 inhibitors: Mechanism of action
Glucose-dependent insulin secretion β-cells Food intake Increases glucose utilisation by muscle and adipose tissue Pancreas α-cells Glucose-dependent glucagon suppression Decreases hepatic glucose release improving overall glucose control Intestine Inactive GLP1 (9-36) amide Active GLP1 (7-36) DPP4 Abbreviations DPP4, dipeptidyl peptidase 4; GLP1, glucagon-like peptide 1. DPP, dipeptidyl-peptidase; GLP, glucagon-like peptide. 2 amino acids cleaved from amino terminus DPP4 inhibitors Adapted from Drucker. Expert Opin Invest Drugs 2003;12:87–100 and Ahrén Curr Diab Rep. 2003;3:365–372.

Selected mechanistic trials indicate potential CV effects of the DPP4 inhibitor class
Myocardial infarct size1,2 Endothelial function3 Triglycerides8 Inflammation and oxidative stress4 Left ventricular function6,7 Atherosclerotic plaque volume5 Notes Several mechanistic studies have indicated potential CV effects of the DPP4 inhibitor class: Ye et al. was a study in mice, which showed that the myocardial infarct size-limiting effect of sitagliptin was PKA-dependent. Hocher et al. showed that linagliptin reduced infarct size after myocardial ischaemia/reperfusion in rats. Van Poppel: vildagliptin for 4 weeks improved endothelium-dependent vasodilatation in 16 subjects with T2D. Kröller-Schön: in vivo (rat) and cell culture studies revealed antioxidant and anti-inflammatory properties of linagliptin, independent of glucose-lowering properties. Ta: alogliptin treatment reduced atherosclerotic lesions in diabetic mice. Sauvé and Read: improvement in LV performance is after MI (mice, ex vivo) and stress (humans). Matikainen: vildagliptin for 4 weeks improved postprandial plasma triglyceride in 15 T2D patients vs placebo (n = 16). Abbreviations CV, cardiovascular; DPP4, dipeptidyl peptidase 4; LV, left ventricular; MI, myocardial infarction; PKA, protein kinase A; T2D, Type 2 Diabetes. 1. Ye et al. Am J Physiol Heart Circ Physiol 2010;298:H1454– Hocher et al. Int J Cardiol 2013;167:87– van Poppel et al. Diabetes Care 2011;34:2072– Kröller-Schön et al. Cardiovasc Res 2012;96:140– Ta et al. J Cardiovasc Pharmacol 2011;58:157– Sauvé et al. Diabetes 2010;59:1063– Read et al. Circ Cardiovasc Imaging 2010;3:195– Matikainen et al. Diabetologia 2006;49:2049–57.

Summary of CV outcomes trials with DPP4 inhibitors
Link to study design + data Link to study design + baseline data SAVOR-TIMI 531 EXAMINE2 TECOS3 CAROLINA®4 CARMELINA®5 Intervention Saxagliptin/ placebo Alogliptin/ placebo Sitagliptin/ placebo Linagliptin/ glimepiride Linagliptin/ placebo Main inclusion criteria History of or multiple risk factors for CVD ACS within 15–90 days before randomisation CVD ≥ 2 specified traditional CV risk factors or manifest CVD High risk of CV events (e.g. albuminuria, prior CVD) No. of patients 16,492 5380 14,671 6041 8300 Primary outcome 3P-MACE 4P-MACE Key secondary outcome Expanded MACE 3P-MACE; renal composite Target no. of events 10406 650 1300 631 6257 Median follow-up (y) 2.1 1.5 3.0 6–7* 4*7 Estimated completion Completed 20188 2018 Notes This table provides a summary of the key features of the ongoing CVOTs of DPP4 inhibitors, and of those already completed (SAVOR-TIMI 53 and EXAMINE). Links to study design slides (in backup) are provided for ease of reference. SAVOR-TIMI 53: major secondary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina, coronary revascularisation or heart failure. CARMELINA®: Inclusion: high risk of CV events is defined by: 1) albuminuria (micro or macro) and previous macrovascular disease and/or 2) impaired renal function with predefined UACR. Secondary: composite renal endpoint is renal death, end stage renal disease and a sustained decrease of 50% or more in estimated glomerular filtration rate. Abbreviations ACS, acute coronary syndrome; CARMELINA®, Cardiovascular Safety & Renal Microvascular Outcome Study with Linagliptin; CAROLINA®, Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes; CV, cardiovascular; CVD, cardiovascular disease; CVOT, cardiovascular outcomes trial; DPP4, dipeptidyl peptidase 4; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin Versus usual care; HbA1c, glycosylated haemoglobin; HF, heart failure; MACE, major cardiovascular events; 3P-MACE, 3-point major adverse CV events (CV death, non-fatal myocardial infarction or non-fatal stroke); 4P-MACE, 4-point major adverse cardiovascular events (CV death, non-fatal myocardial infarction, non-fatal stroke or unstable angina requiring hospitalisation); MI, myocardial infarction; SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction 53; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin; UACR, urine albumin-to-creatinine ratio. *Ongoing. 1. Scirica et al. N Engl J Med 2013;369:1317– White et al. N Engl J Med 2013;369:1327– Green et al. N Engl J Med 2015; DOI: /NEJMoa Marx et al. Diabetes Vasc Dis Res 2015;12:164– NCT Scirica et al. Am Heart J 2011;162:818–25.e Data on file (BI trial no trial protocol). 8. NCT

DPP4 inhibitor CVOTs: baseline characteristics
SAVOR-TIMI 531 EXAMINE2 TECOS3 CAROLINA®4 CARMELINA®5 Mean age, years 65.1 61.0* 65.4 64.0 – % with prior MI 38.0 87.5 42.7 13.8 % with prior HF 12.8 27.8 17.8 % with prior CVD 78.4 73.6 34.5 Diabetes duration, y 10.3* 7.3* 11.6 6.2* HbA1c,% 8.0 7.2 Statin use, % 78.3 90.6 79.8 64.1 T2D therapy, % Naive Metformin SU TZD Insulin 4.1 69.9 40.5 6.2 41.6 Naive Metformin 1.1 65.0 46.9 2.5 29.4 Mono Dual 47.7 51.4 23.5 9.2 66.0 23.8 Ex. Notes Baseline characteristics are already published for most of the DPP4 inhibitor CVOTs, with the exception of CARMELINA®. The use of insulin was an exclusion criteria for the CAROLINA® trial. Data are given as published (e.g., not rounded up to a standard number of decimal places). The use of background anti-diabetes therapies is not reported in a standard manner across the trials. Abbreviations CARMELINA®, Cardiovascular Safety & Renal Microvascular Outcome Study with Linagliptin; CAROLINA®, Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes; CVD, cardiovascular disease; CVOT, cardiovascular outcomes trial; DPP4, dipeptidyl peptidase 4; Dual, dual therapy; Ex, excluded; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin Versus usual care; HbA1c, glycosylated haemoglobin; HF, heart failure; MI, myocardial infarction; Mono, monotherapy; SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction 53; SU, sulphonylurea; T2D, Type 2 Diabetes; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin; TZD, thiazolidinedione. References Data are provided for the DPP4 inhibitor treatment arm. Mean values show unless otherwise indicated. – indicates that the data are not reported. *Median. 1. Scirica et al. N Engl J Med 2013;369:1317– White et al. N Engl J Med 2013;369:1327– Green et al. N Engl J Med 2015; DOI: /NEJMoa Marx et al. Diabetes Vasc Dis Res 2015;12:164– NCT

Summary of completed DPP4 inhibitor CVOTS
SAVOR-TIMI Primary endpoint Hazard ratio CVD or CRFs HbA1c 6.5–12.0% n = 16,492 Saxagliptin Placebo 3P-MACE 1.00 (95% CI 0.89–1.12) p = 0.99 (superiority) 2.1 year median follow-up EXAMINE2 ACS HbA1c 6.5–11.0% n = 5380 Alogliptin Placebo 3P-MACE 0.96 (upper CI* 1.16) p = 0.32 (superiority) 1.5 year median follow-up TECOS3 CVD HbA1c 6.5–8.0% n = 14,735 Sitagliptin Placebo 4P-MACE 0.98 (95% CI 0.89–1.08) p = 0.65 (superiority) 3.0 year median follow-up Abbreviations ACS, acute coronary syndrome; CI, confidence interval; CRF, chronic renal failure; CVD, cardiovascular disease; CVOT, cardiovascular outcomes trial; DPP4, dipeptidyl peptidase 4; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin Versus usual care; HbA1C, glycosylated haemoglobin; 3P-MACE, 3-point major adverse CV events (CV death, non-fatal myocardial infarction or non-fatal stroke); 4P-MACE, 4-point major adverse cardiovascular events (CV death, non-fatal myocardial infarction, non-fatal stroke or unstable angina requiring hospitalisation); SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction 53; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin. Randomisation 1 2 3 years of median follow-up *Upper boundary of 1-sided repeated CI. 1. Scirica et al. N Engl J Med 2013;369:1317– White et al. N Engl J Med 2013;369:1327– Green et al. N Engl J Med 2015; DOI: /NEJMoa

DPP4 inhibitor GLP1 receptor agonists SGLT2 inhibitors Notes This slide provides a visual summary of this module. Abbreviations CVOT, cardiovascular outcomes trial; DPP4, dipeptidyl peptidase 4; GLP1, glucagon-like peptide 1; SGLT2, sodium glucose cotransporter 2.

GLP1 has various potential effects on the CV system: Data derived from non-clinical and mechanistic proof-of-concept studies ↑ Endothelial function ↑ Nitric oxide production ↑ ↓ Myocardial contractility (data conflict) ↑ Systolic function in myocardial infarction ↑ Systolic function in cardiomyopathy ↓ Infarct size ↑ Ischaemic pre-conditioning ↑ Post-ischaemic recovery ↑ Myocardial glucose uptake Heart ↑ Insulin secretion ↓ Glucagon secretion ↑ Insulin biosynthesis ↑ β-cell proliferation ↓ β -cell apoptosis Pancreas ↓ Appetite ↑ Neuroprotection Brain Incretin hormone1,2 ↓ Glucose output Liver ↑ Insulin sensitivity (direct or indirect?) Muscle and adipose tissue Clinical trial data show that GLP1 receptor agonists are associated with small increases in heart rate and modest reductions in body weight and blood pressure3 Notes This slide summarises the known clinical effects of the GLP1 receptor agonists, focusing on their effects on the CV system. Abbreviations CV, cardiovascular; GLP1, glucagon-like peptide 1. Copyright Grieve. Br J Pharmacol 2009;157:1340–51 (modified). Figure 3, page 1343 1. Jax. Clin Res Cardiol 2009;98:75– Grieve. Br J Pharmacol 2009;157:1340–51 (modified) Robinson et al. BMJ Open 2013;3:pii e

Summary of CV outcomes trials with GLP1 receptor agonists
Intervention Main inclusion criteria No. of patients Primary outcome Key 2° outcome Target no. of events Estimated follow-up Estimated completion ELIXA1,2 Lixisenatide/ placebo History of ACS 6068 4P-MACE Expanded MACE 844 2.1 years median Completed LEADER®3 Liraglutide/ placebo Vascular disease, or risk factors, or CRF, or CHF 9340 3P-MACE > 611 Up to ~5 years Nov-15 SUSTAIN-6™4 Semaglutide/ placebo Evidence of CV disease 3297 Not specified Up to ~3 years Jan-16 EXSCEL5 Exenatide ER*/ placebo No CV criteria specified 14,000 All-cause mortality; HHF Up to ~7.5 years Apr-18 REWIND6 Dulaglutide/ placebo Pre-existing vascular disease or ≥2 CV risk factors 9622 Microvascular composite Up to ~6.5 years Apr-19 HARMONY OUTCOMES7 Albiglutide/ placebo Established CVD 9400 3–5 years May-19 Link to study design + data Link to study + baseline data Notes This table provides a summary of the key features of the ongoing CVOTs of GLP1 agonists. ELIXA: expanded MACE secondary endpoints examined are 4P-MACE + HHF and 4P-MACE + HHF + coronary revascularisation procedure. LEADER: expanded MACE secondary endpoint examined is 3P-MACE + revascularisation + hospitalisation for unstable angina + hospitalisation for chronic heart failure. SUSTAIN: the details of the expanded MACE to be performed as a secondary endpoint are not provided. REWIND: a key secondary endpoint was a composite of diabetic retinopathy requiring laser therapy, vitrectomy or anti-vascular endothelial growth factor therapy (VEGF), clinical proteinuria, a 30% decline in estimated glomerular filtration rate, or need for chronic renal replacement therapy. HARMONY OUTCOMES: expanded MACE secondary endpoint examined is 3P-MACE + urgent revascularisation for unstable angina Abbreviations ACS, acute coronary syndrome; CHF, chronic heart failure; CRF, chronic renal failure; CV, cardiovascular; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; ER, extended release; EXSCEL, The EXenatide Study of Cardiovascular Event Lowering; GLP1, glucagon-like peptide 1; HHF, hospitalisation for heart failure; LEADER®, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results – A Long Term Evaluation; MACE, major cardiovascular events; 3P-MACE, 3-point major adverse CV events (CV death, non-fatal myocardial infarction or non-fatal stroke); 4P-MACE, 4-point major adverse cardiovascular events (CV death, non-fatal myocardial infarction, non-fatal stroke or unstable angina requiring hospitalisation); MI, myocardial infarction; RECORD, Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes; REWIND, Researching Cardiovascular Events With a Weekly Incretin in Diabetes; SUSTAIN, Study of Ranibizumab in Patients With Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration. References 1. Accessed March 2015. 2. Bentley-Lewis et al. Am Heart J 2015;0:1-8.e7. Accessed June 2015. 3. Marso SP et al. Am Heart J 2013;166:823–30.e5. Accessed March 2015. 4. Accessed March Accessed March 2015. 6. Accessed March 2015. 7. *Once weekly. 1. NCT Bentley-Lewis et al. Am Heart J 2015;0:1-8.e7. 3. Marso et al. Am Heart J 2013;166:823–30.e NCT 5. NCT NCT NCT

Summary of ELIXA findings
ACS HbA1c 5.5–11% n = 6068 Placebo 4P-MACE 1.02 (95% CI 0.89–1.17) Lixisenatide 2.1 year median follow-up Randomisation 1 2 3 years of median follow-up No difference in 4P-MACE with lixisenatide vs placebo HR 1.02 (95% CI 0.89–1.17) No difference in HHF with lixisenatide vs placebo HR 0.96 (95% CI 0.75–1.23) No difference in CV death + HHF with lixisenatide vs placebo HR 0.97 (95% CI 0.82–1.16) Abbreviations ACS, acute coronary syndrome; CI, confidence interval; CV, cardiovascular; CVOT, cardiovascular outcomes trial; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin Versus usual care; HbA1c, glycosylated haemoglobin; HHF, hospitalisation for heart failure; HR, hazard ratio; 4P-MACE, 4-point major adverse cardiovascular events (CV death, non-fatal myocardial infarction, non-fatal stroke or unstable angina requiring hospitalisation); SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction 53; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin. 1. Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation).

Summary of completed T2D CVOTS for newer T2D agents
SAVOR-TIMI 531 CVD or CRFs HbA1c 6.5–12.0% n = 16,492 Saxagliptin Placebo 3P-MACE 1.00 (95% CI 0.89–1.12) p = 0.99 2.1 year median follow-up Primary endpoint Hazard ratio EXAMINE2 ACS HbA1c 6.5–11.0% n = 5380 Alogliptin Placebo 3P-MACE 0.96 (upper CI* 1.16) p = 0.315 1.5 year median follow-up TECOS3 CVD HbA1c 6.5–8.0% n = 14,735 Sitagliptin Placebo 4P-MACE 0.98 (95% CI 0.88–1.09) p = (superiority) 3.0 year median follow-up ELIXA4 ACS HbA1c 5.5–11% n = 6068 Placebo 4P-MACE 1.02 (95% CI 0.89–1.17) 2.1 year median follow-up Lixisenatide Abbreviations ACS, acute coronary syndrome; CI, confidence interval; CRF, chronic renal failure; CVD, cardiovascular disease; CVOT, cardiovascular outcomes trial; DPP4, dipeptidyl peptidase 4; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin Versus usual care; HbA1C, glycosylated haemoglobin; 3P-MACE, 3-point major adverse CV events (CV death, non-fatal myocardial infarction or non-fatal stroke); 4P-MACE, 4-point major adverse cardiovascular events (CV death, non-fatal myocardial infarction, non-fatal stroke or unstable angina requiring hospitalisation); SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction 53; T2D, Type 2 Diabetes; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin. Randomisation 1 2 3 years of median follow-up *Upper boundary of 1-sided repeated CI. 1. Scirica et al. N Engl J Med 2013;369:1317– White et al. N Engl J Med 2013;369:1327– Green et al. N Engl J Med 2015; DOI: /NEJMoa Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation).

Number of events (event rate, % per 100 person-years)
For the primary outcome, all completed CVOTs fall within the FDA mandated upper 95% CI limit of 1.3 Number of events (event rate, % per 100 person-years) Placebo + usual care Comparator DPP4 inhibitor trials SAVOR-TIMI 531 609 (3.7%) 613 (3.7%) FDA mandated upper 95% CI for CV safety HR (95% CI) EXAMINE2 316 (11.8%†) 305 (11.3%†) * TECOS3 851 (4.17%) 839 (4.06%) GLP1 agonist trials ELIXA4 406 (13.4†%) 399 (13.2†%) Notes SAVOR-TIMI 53 – hazard ratio 1.00 (95% CI: 0.89, 1.12). EXAMINE – HR 0.96 (upper boundary of 1-sided repeated CI: 1.16). TECOS – HR 0.98 (95% CI: 0.89, 1.17). ELIXA – HR 1.02 (95% CI: 0.89, 1.17). Abbreviations CI, confidence interval; CV, cardiovascular; CVOT, cardiovascular outcomes trial; DPP4, dipeptidyl peptidase 4; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin Versus usual care; FDA, US Food and Drug Administration; GLP1, glucagon-like peptide 1; HR, hazard ratio; SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction 53; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin. 0.6 0.8 1.0 1.3 2.0 Favours comparator Favours placebo *Upper boundary of 1-sided repeated CI. †Total event rate, %. 1. Scirica et al. N Engl J Med 2013;369:1317– White et al. N Engl J Med 2013;369:1327– Green et al. N Engl J Med 2015; DOI: /NEJMoa Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation).

Hospitalisation for heart failure (HHF) data for all completed CVOTs
Number of events (%) Placebo + usual care Comparator HR (95% CI) SAVOR-TIMI 53 (HHF)1 EXAMINE (HHF analysis 1)2 EXAMINE (HHF analysis 2)2 TECOS (HHF)3 TECOS (HHF + CV death)3 ELIXA (HHF)4 ELIXA (HHF + CV death)4 228 (2.8) 79 (2.9) 89 (3.3) 229 (3.1) 525 (7.2) 127 (4.2) 253 (8.3) 289 (3.5) 85 (3.1) 106 (3.9) 228 (3.1) 538 (7.3) 122 (4.0) 248 (8.2) Notes SAVOR-TIMI 53 – hazard ratio for HHF 1.27 (1.07, 1.51). EXAMINE – Analysis 1 = Risk of HHF occurring as the first event in pre-specified exploratory extended MACE endpoint: HR 1.07 (0.79, 1.46). EXAMINE – Analysis 2 = Risk of events assessed as component of post-hoc composite endpoint of CV death and HHF: HR 1.19 (0.90, 1.58). TECOS – HHF: HR 1.00 (0.83, 1.20). TECOS – HHF + CV death: HR 1.02 (0.90, 1.15). ELIXA – HHF: HR 0.96 (0.75, 1.23). ELIXA – HHF + CV death: HR 0.97 (0.82, 1.16). Abbreviations CI, confidence interval; CV, cardiovascular; CVOT, cardiovascular outcomes trial; DPP4, dipeptidyl peptidase 4; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin Versus usual care; FDA, US Food and Drug Administration; GLP1, glucagon-like peptide 1; HHF, hospitalisation for heart failure; HR, hazard ratio; MACE, major cardiovascular events; SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction 53; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin. 0.6 0.8 1.0 2.0 Favours comparator Favours placebo Analysis 1 = as component of expanded MACE. Analysis 2 = as component of post-hoc composite of CV death and HHF. 1. Scirica et al. N Engl J Med 2013;369:1317– White et al. N Engl J Med 2013;369:1327– Green et al. N Engl J Med 2015; DOI: /NEJMoa Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation).

DPP4 inhibitors GLP1 receptor agonists SGLT2 inhibitors Notes This slide provides a visual summary of this module. Abbreviations CVOT, cardiovascular outcomes trial; DPP4, dipeptidyl peptidase 4; GLP1, glucagon-like peptide 1; SGLT2, sodium glucose cotransporter 2.

Urinary glucose excretion via SGLT2 inhibition1
Filtered glucose load > 180 g/day SGLT2 inhibitors reduce glucose reabsorption in the proximal tubule, leading to urinary glucose excretion* and osmotic diuresis SGLT2 inhibitor SGLT2 SGLT1 Notes *A loss of approximately 80 g of glucose per day equates to between 240 and 320 calories per day (calorific rates for sugars quoted vary between 3 and 4 calories per gram). Abbreviations SGLT1, sodium glucose cotransporter 1; SGLT2, sodium glucose cotransporter 2. 1. Bakris et al. Kidney Int 2009;75;1272–7.

Pharmacological properties of available SGLT2 inhibitors
Link to SGLT2 clinical data Empagliflozin Dapagliflozin Canagliflozin Therapeutic dose (mg/day) Starting dose 10–25 10 5–10 100–300 100 Administration QD With or without food Before first meal Peak plasma concentration (hours post-dose) 1.5 Within 2 1–2 Absorption (mean oral bioavailability) ≥ 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 > 1:1601 Glucose excretion with higher dose (g/day) 78 ~ 70 119 Notes Pharmacological differences exist between different members of the same drug class. This table indicates some of the pharmacokinetic distinctions between empagliflozin, dapagliflozin and canagliflozin. Given pharmacological and clinical differences between individual drugs within a class, effects on CV outcomes should be conducted for each drug within a class. Abbreviations CV, cardiovascular; CVOT, cardiovascular outcomes trial; QD, once daily; SGLT1, sodium glucose cotransporter 1; SGLT2, sodium glucose cotransporter 2. *For the 300 mg dose. Data from (Jardiance SPC, Forxiga SPC , Invokana PI, Invokana SPC, all accessed June 2015); 1. Sha et al. Diab Obes Metab 2015;17:188–97.

Link to SGLT2 clinical data
SGLT2 inhibitors modulate a range of factors related to CV risk Based on clinical and mechanistic studies Link to SGLT2 clinical data  Weight  Visceral adiposity  Blood pressure  Arterial stiffness  Glucose  Insulin  Albuminuria  Uric Acid Novel Pathways (?)  LDL-C  HDL-C  Triglycerides  Oxidative stress  SNS activity (?)  SNS activity (?) Notes CV risk factors beyond glucose that can potentially be modulated with SGLT2 inhibitors include blood pressure, weight, visceral adiposity, hyperinsulinaemia, arterial stiffness, albuminuria, circulating uric acid levels, oxidative stress and lipids. Abbreviations CV, cardiovascular; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SGLT2, sodium glucose cotransporter 2; SNS, sympathetic nervous system. Copyright Inzucchi et al. Diab Vasc Dis Res 2015;12:90‒100. Figure 1. Page 3 Inzucchi et al. Diab Vasc Dis Res 2015;12:90‒100.

Summary of CV outcome trials with SGLT2 inhibitors
Link to study design EMPA-REG OUTCOME®1 CANVAS2 CANVAS-R3 CREDENCE4 DECLARE- TIMI 585 Ertugliflozin CVOT6 Interventions Empagliflozin/ placebo Canagliflozin/ placebo Dapagliflozin/ placebo Ertugliflozin/ placebo Main inclusion criteria Est. vascular complications Est. vascular complications or ≥ 2 CV risk factors Stage 2 or 3 CKD + macroalbuminuria High risk for CV events No. of patients 7034 4339 5700 3627 17,150 3900 Primary outcome 3P-MACE Progression of albuminuria ESKD, S-creatinine doubling, renal/CV death Key secondary outcome 4P-MACE Fasting insulin secretion, progression of albuminuria Regression of albuminuria, change in eGFR 4P-MACE + HHF 4P-MACE + HHF + revascularisation Target no. of events 691 ≥ 420 TBD 1390 Estimated median FU ~3 years 6–7 years 3 years ~4 years 4–5 years 5–7 years Estimated completion 2015 Apr 2017 2017 2019 2021 Notes This table provides an overview of the ongoing CVOTs in SGLT2 inhibitors, including EMPA-REG OUTCOME® with empagliflozin; CANVAS, CANVAS-R and CREDENCE with canagliflozin; DECLARE-TIMI 58 with dapagliflozin; and a CVOT on ertugliflozin. All of these CVOTs take place in patients with established CVD or CV risk, and 3P-MACE is the primary outcome for most. Abbreviations BMI, body mass index; CANVAS, CANagliflozin cardioVascular Assessment Study; CANVAS-R, study of the Effects of Canagliflozin on Renal Endpoints in Adult Subjects with T2DM, NCT ; CHF, congestive heart failure; CKD, chronic kidney disease; CREDENCE, Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; CV, cardiovascular; CVD, cardiovascular disease; CVOT, cardiovascular outcomes trial; DECLARE-TIMI 58, Dapagliflozin Effect on CardiovascuLAR Events; EASD, European Association for the Study of Diabetes; eGFR, estimated glomerular filtration rate; EMPA-REG OUTCOME®, cardiovascular outcomes trial of empagliflozin; ESKD, end-stage kidney disease; Est., established; FPI, first patient in; FU, follow-up; HbA1C, glycosylated haemoglobin; HHF, hospitalisation for heart failure; 3P-MACE, 3-point major adverse CV events (CV death, non-fatal myocardial infarction or non-fatal stroke); 4P-MACE, 4-point major adverse cardiovascular events (CV death, non-fatal myocardial infarction, non-fatal stroke or unstable angina requiring hospitalisation); MI, myocardial infarction; RRR, relative risk ratio; SGLT2, sodium glucose cotransporter; TBD, to be determined. References 1. Zinman et al. Cardiovasc Diabetol 2014;13:102. 2. Accessed March 2015. 3. Accessed March 2015. 4. Accessed March 2015. 5. Accessed May 2015. 6. Accessed May 2015. Copyright Inzucchi et al. Diabetes Vasc Dis Res 2015;12:90‒100. Table 4.Page 8 Will report EASD 2015 Adapted from Inzucchi et al. Diabetes Vasc Dis Res 2015;12:90‒ Zinman et al. Cardiovasc Diabetol 2014;13: NCT NCT NCT NCT NCT

Long-term CV safety of empagliflozin is being evaluated in a large, multicentre Phase IV trial (EMPA-REG OUTCOME®) Countries with study centres involved in the EMPA-REG OUTCOME® trial 41% 19% Asia Europe North America / Western Pacific 20% 15% Latin America 4% Africa * Patients 7034 Countries 42 Notes EMPA-REG OUTCOME® is an ongoing multinational study taking place across the Americas, Europe, Asia, Australasia and South Africa. Abbreviations CV, cardiovascular; EMPA-REG OUTCOME®, cardiovascular outcomes trial of empagliflozin. Reference Copyright Zinman et al. Cardiovasc Diabetol 2014;13:102. Figure 1. Page 3 592 Clinical sites *Cumulative percentage for North America, Australia and New Zealand. 1. Zinman et al. Cardiovasc Diabetol 2014;13: NCT

EMPA-REG OUTCOME®: Study design
Aim Compound-specific To determine CV safety of empagliflozin vs placebo + usual care for glycaemic control and CV risk in patients with T2D and high CV risk 12 weeks of stable background glucose-lowering therapy Background therapy adjustment allowed after Week 12 Placebo run-in 2 weeks Placebo + usual care Screening (n = 11,507) Empagliflozin 10 mg QD + usual care R Follow-up Empagliflozin 25 mg QD + usual care End of study visit Visit 1 Visit 2 Visit 3 Visits 4–7 every 4 weeks Visits 8–10 every 12 weeks Visits every 14 weeks Notes EMPA-REG OUTCOME® aims to determine the effect of empagliflozin on CV safety in patients with T2D and at high CV risk. Patients were treated with empagliflozin 10 mg or 25 mg, or placebo (double-blind, double-dummy) superimposed upon usual care. The dose of background glucose-lowering therapy was required to be unchanged for ≥ 12 weeks prior to randomisation or, in the case of insulin, unchanged by > 10% from the dose at randomisation in the previous 12 weeks. After this period, therapy could be adjusted to achieve desired glycaemic control at the investigators’ discretion to achieve best usual care according to local guidelines. Abbreviations CV, cardiovascular; EMPA-REG OUTCOME®, cardiovascular outcomes trial of empagliflozin; QD, once daily; T2D, Type 2 Diabetes. -3 -2 4 8 12 16 28 40 52 +30 days Zinman et al. Cardiovasc Diabetol 2014;13:102. Week

EMPA-REG OUTCOME®: Inclusion criteria
Adults with insufficient glycaemic control High risk of CV events (≥1 of the following) Age ≥ 18 years HbA1c ≥ 7% and ≤ 10% if on background glucose-lowering therapy, or ≥ 7% and ≤ 9% if drug-naïve BMI ≤ 45 kg/m2 History of MI (> 2 months prior to enrolment) Evidence of single/multi-vessel CAD Unstable angina > 2 months prior to consent with evidence of single- or multi-vessel CAD History of stroke (ischaemic or haemorrhagic) > 2 months prior to consent Occlusive peripheral artery disease Notes Patients had T2D and were drug naïve or on background glucose-lowering drugs. All patients were at high risk for CV events. Age criteria were ≥ 20 years in Japan and ≤ 65 years in India. History of MI (> 2 months prior to enrolment). Evidence of multi-vessel CAD in ≥ 2 major vessels or left main coronary artery. Evidence of single-vessel CAD with no scheduled revascularisation/previously unsuccessful revascularisation and: Positive non-invasive, functional stress test for ischaemia (ECG, echo or nuclear); or Hospital discharge due to unstable angina pectoris ≤ 12 months before enrolment. Unstable angina > 2 months prior to consent with evidence of single- or multi-vessel CAD. History of stroke (ischaemic or haemorrhagic) > 2 months prior to consent. Occlusive peripheral artery disease documented by: Limb angioplasty, stenting or bypass surgery; limb or foot amputation due to circulatory insufficiency; evidence of significant peripheral artery stenosis in 1 limb; ankle brachial index < 0.9 in ≥ 1 ankle. Abbreviations BMI, body mass index; CAD, coronary artery disease; CV, cardiovascular; ECG, electrocardiogram; echo, echocardiogram; EMPA-REG OUTCOME®, cardiovascular outcomes trial of empagliflozin; HbA1c, glycosylated haemoglobin; MI, myocardial infarction; T2D, Type 2 Diabetes. Zinman et al. Cardiovasc Diabetol 2014;13:102.

EMPA-REG OUTCOME®: Primary endpoint
Primary endpoint: time to 1st occurrence of any of the following adjudicated components of the primary composite endpoint (3P-MACE) 1. CV death (including fatal stroke and fatal MI) 2. Non-fatal MI (excluding silent MI) 3. Non-fatal stroke Target number of events: ≥ 691 Non-inferiority and superiority of empagliflozin vs placebo will be assessed (hierarchical testing) 90% power to demonstrate non-inferiority for the primary (3P-MACE) and key secondary (4P-MACE) outcome ≥ 80% power to detect hazard ratio of for primary (3P-MACE) outcome Notes: A 4-step hierarchical testing strategy for the non-inferiority test of the primary endpoint and then the key secondary endpoint, each at a margin of 1.3, followed by a test of superiority of the primary and key secondary endpoints, respectively. Abbreviations CI, confidence interval; CV, cardiovascular; EMPA-REG OUTCOME®, cardiovascular outcomes trial of empagliflozin; 3P-MACE, 3-point major adverse CV events (CV death, non-fatal myocardial infarction or non-fatal stroke); 4P-MACE, 4-point major adverse cardiovascular events (CV death, non-fatal myocardial infarction, non-fatal stroke or unstable angina requiring hospitalisation); MI, myocardial infarction. Zinman et al. Cardiovasc Diabetol 2014;13:102.

EMPA-REG OUTCOME®: Secondary endpoints
Key secondary outcome Additional secondary outcomes Expanded primary outcome (4P-MACE) 3P-MACE + hospitalisation for unstable angina Occurrence of and time to new onset of: Albuminuria (UACR ≥ 30 mg/g) Macroalbuminuria (UACR ≥ 300 mg/g) Occurrence of and time to a composite microvascular outcome, comprising: Initiation of laser therapy for retinopathy, vitreous haemorrhage, diabetes-related blindness and new or worsening nephropathy as defined by: New-onset macroalbuminuria Doubling of serum creatinine accompanied by eGFR ≤ 45 mL/min/1.73 m2 Initiation of renal replacement therapy Death due to renal disease Individual components of this composite Further CV outcomes Individual components of the 4P-MACE Individual occurrence of and time to: Silent MI Heart failure requiring hospitalisation All-cause mortality Transient ischaemic attack Coronary revascularisation procedures Notes All CV outcomes events and deaths are being prospectively adjudicated by the Clinical Events Committee (1 for cardiac events and 1 for neurological events), as recommended in FDA guidelines. Abbreviations CV, cardiovascular; eGFR, estimated glomerular filtration rate; EMPA-REG OUTCOME®, cardiovascular outcomes trial of empagliflozin; FDA, US Food and Drug Administration; 3P-MACE, 3-point major adverse CV events (CV death, non-fatal myocardial infarction or non-fatal stroke); 4P-MACE, 4-point major adverse cardiovascular events (CV death, non-fatal myocardial infarction, non-fatal stroke or unstable angina requiring hospitalisation); MI, myocardial infarction; UACR, urinary albumin:creatinine ratio. Zinman et al. Cardiovasc Diabetol 2014;13:102.

EMPA-REG OUTCOME®: Other outcomes of interest
Efficacy Change from baseline in: HbA1c, fasting plasma glucose, weight, waist circumference and blood pressure Proportion of patients that obtain the composite endpoint of: HbA1c reduction ≥ 0.5%, systolic blood pressure reduction > 3 mmHg and body weight reduction > 2% Sub-studies Impact on renal and CV biomarkers (cystatin C, hs-CRP and hs-troponin T) Pharmacogenomics (potential genetic variations associated with drug responses) Safety AEs, clinical laboratory tests, vital signs, 12-lead ECG, physical examination, use of rescue medication, confirmed hypoglycaemia*, volume depletion, bone fracture, hepatic events, malignancies, UTI and GIs Notes Change from baseline in HbA1c, fasting plasma glucose, weight, waist circumference and blood pressure assessed in the short- (12 weeks), medium- (52 weeks) and long-term (annually, at end of study and at follow-up). Abbreviations AE, adverse event; CRP, C-reactive protein; CV, cardiovascular; ECG, electrocardiogram; EMPA-REG OUTCOME®, cardiovascular outcomes trial of empagliflozin; GI, genital infection; HbA1c, glycosylated haemoglobin; hs, high sensitivity; UTI, urinary tract infection. *Plasma glucose ≤ 70mg/dL (3.9 mmol/L) and/or requiring assistance. Zinman et al. Cardiovasc Diabetol 2014;13:102.

EMPA-REG OUTCOME®: Demographics
Treated set (n = 7034) Age, years, mean (SD) 63.1 (8.6) ≥ 75 y, n (%) 652 (9) Male, n (%) 5026 (72) Race, n (%) White Asian Black/African American Other 5089 (72) 1518 (22) 357 (5) 70 (1) Ethnicity, n (%) Hispanic or Latino 1268 (18) Smoking history, n (%) Current Ex-smoker 930 (13) 3216 (46) Time since T2D diagnosis, n (%) ≤ 5 years > 5–10 years > 10 years 1265 (18) 1754 (25) 4015 (57) Notes ‘Other’ includes American Indian/Native Alaskan/Native Hawaiian/Pacific Islander/missing. Abbreviations EMPA-REG OUTCOME®, cardiovascular outcomes trial of empagliflozin; SD, standard deviation; T2D, Type 2 Diabetes. Zinman et al. Cardiovasc Diabetol 2014;13:102.

EMPA-REG OUTCOME®: Baseline metabolic characteristics
Treated set (n = 7034) HbA1c, % 8.1 (0.8) HbA1c < 8.5%, n (%) 4811 (68) FPG, mmol/L 8.5 (2.4) BMI, kg/m2 30.6 (5.3) ≥ 35, n (%) 1426 (20) Weight, kg 86.4 (18.9) Waist circumference, cm 105 (14) eGFR, mL/min/1.73 m2 (MDRD) 74 (21) ≥ 90, n (%) 1534 (22) 60 to < 90, n (%) 3671 (52) 30 to < 60, n (%) 1796 (26) Median (Q1, Q3) ACR albumin ratio, mg/g 17.7 (7.1, 72.5) Abbreviations ACR, albumin-to-creatinine ratio; BMI, body mass index; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; EMPA-REG OUTCOME®, cardiovascular outcomes trial of empagliflozin; FPG, fasting plasma glucose; HbA1c, glycosylated haemoglobin; MDRD, modification of diet in renal disease; Q, quartile; SD, standard deviation. Data are mean (SD) unless otherwise stated. Zinman et al. Cardiovasc Diabetol 2014;13:102.

EMPA-REG OUTCOME®: Baseline CV characteristics
Treated set (n = 7034) History of CVD (any of the below), n (%) 6978 (99) History of stroke 1631 (23) History of MI 3275 (47) Peripheral occlusive arterial disease 1449 (21) CABG 1738 (25) Single-vessel CAD 743 (11) Multi-vessel CAD 3285 (47) SBP/DBP, mmHg 135 (17) / 77 (10) Lipids (mmol/L) Total cholesterol 4.2 (1.1) LDL-cholesterol 2.2 (0.9) HDL-cholesterol 1.2 (0.3) Triglycerides 1.9 (1.4) Abbreviations CABG, coronary artery bypass graft; CAD, coronary artery disease; CV, cardiovascular; DBP, diastolic blood pressure; EMPA-REG OUTCOME®, cardiovascular outcomes trial of empagliflozin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MI, myocardial infarction; SBP, systolic blood pressure; T2D, Type 2 Diabetes. Data are mean (SD) unless otherwise stated. Zinman et al. Cardiovasc Diabetol 2014;13:102.

EMPA-REG OUTCOME®: Background therapies
Treated set (n = 7034) Glucose-lowering therapy, n (%) No therapy 128 (1.8) Monotherapy 2055 (29.2) Metformin (% of monotherapy) 745 (36.3) Insulin (% of monotherapy) 954 (46.4) Dual combination therapy 3188 (45.3) Metformin + sulphonylurea (% of dual combination therapy) 1383 (43.4) Metformin + insulin (% of dual combination therapy) 1420 (44.5) Total metformin 5205 (74.0)* Total insulin 3446 (48.2)* Anti-hypertensive therapy, n (%) 6641 (94.4) Blockers of the renin–angiotensin system 5651 (80.3) β-blockers 4537 (64.5) Any diuretic 3015 (42.9)* Calcium channel blockers 2114 (30.1) Other therapies, n (%) Acetylsalicylic acid 5990 (85.2) Statins 5387 (76.6) Fibrates 630 (9.0) Notes Data for total metformin and total insulin are based on the final dataset (data on file) and patient numbers deviate slightly from n = 7034 detailed in Zinman et al. Therefore, the percentages given are not calculated from 5205/7034 and 3446/7034. Abbreviations EMPA-REG OUTCOME®, cardiovascular outcomes trial of empagliflozin. *Data on file. Zinman et al. Cardiovasc Diabetol 2014;13:102.

Module D: Summary FDA guidance from 2008 requests CV outcome trials (CVOTs) to demonstrate CV safety of all new glucose-lowering compounds1 CVOTs designed to assess impact of drugs on CV outcomes (MACE) vs placebo on top of usual care for glucose and CV risk factor management Not designed to assess impact of differences between treatment arms in, for example, HbA1c on CV outcomes Completed CVOTs in DPP4 inhibitor and GLP1 class report neutral effects on CV outcomes confirming CV safety as defined by FDA2-6 Ongoing CVOTs will provide further clarity on the CV safety of individual glucose-lowering agents Abbreviations CV, cardiovascular; CVOT, cardiovascular outcomes trial; DPP4, dipeptidyl peptidase 4; FDA, US Food and Drug Administration; GLP1, glucagon-like peptide 1; HbA1C, glycosylated haemoglobin; MACE, major cardiovascular events; T2D, Type 2 Diabetes. 1. FDA Guidance for Industry Scirica et al. N Engl J Med 2013;369:1317– White et al. N Engl J Med 2013;369:1327– Zannad et al. Lancet 2015;385:2067– Green et al. N Engl J Med 2015; DOI: /NEJMoa Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation).

APPENDIX

ELIXA: Study design Next Back Aim Compound-specific
To assess CV morbidity and mortality associated with lixisenatide vs placebo Main inclusion criteria 1. Age ≥ 30 years old 2. Type 2 Diabetes 3. History of acute coronary syndrome + Usual care for Type 2 Diabetes Lixisenatide 10 g (0.1 mL injection) vs Placebo N = 6068; duration of follow-up 2.1 years Primary endpoint: time to first occurrence of: CV-related death Unstable angina requiring hospitalisation Non-fatal stroke Non-fatal MI CV, cardiovascular; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; MI, myocardial infarction. References Accessed March 2015. 1. NCT Katz P. Diabetes Vasc Dis Res 2014;11:395– Bentley-Lewis et al. Am Heart J 2015;0:1-8.e7. 4. Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation). Back

ELIXA: Baseline characteristics
Next Randomised population (N = 6068) Age, years (mean ± SD) 60.3 ± 9.7 Male, n (%) 4207 (69.3) Race, n (%) Asian Black White Other 768 (12.7) 221 (3.6) 4563 (75.2) 516 (8.5) Ethnicity, n (%) Hispanic 1768 (29.1) BMI, kg/m2 n (%) Mean ± SD 18.5–24.9 25.0‒29.9 ≥ 30 30.2 ± 5.7 1017 (16.8) 2297 (37.9) 2734 (45.1) Cholesterol, mg/dL (mean ± SD) Total Triglycerides HDL-C LDL-C 153 ± 44 164 ± 113 43 ± 11 78 ± 35 Fasting plasma glucose, mg/dL (mean ± SD) 148 ± 52 HbA1c, %, (mean ± SD) 7.7 ± 1.3 Qualifying ACS event STEMI Non-STEMI UA 2667 (44.0) 2346 (38.7) 1042 (17.2) Notes The ELIXA trial will assess the effect of lixisenatide treatment on CV outcomes of patients with T2D and a recent ACS event. Baseline characteristics of the population are indicated here. Abbreviations ACS, acute coronary syndrome; BMI, body mass index; CV, cardiovascular; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; HbA1c, glycosylated haemoglobin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SD, standard deviation; STEMI, ST-segment elevation myocardial infarction; T2D, Type 2 Diabetes; UA, unstable angina. Bentley-Lewis et al. Am Heart J 2015;0:1-8.e7. Back

ELIXA: Lixisenatide was non-inferior to placebo on primary 4P-MACE endpoint
Next Outcome Placebo (n = 3034) Lixisenatide (n = 3034) HR (95% CI) 4-P MACE 399 (13.2%) 406 (13.4%) 1.02 (0.89–1.17) Individual components CV mortality 158 (5.2%) 2.4/100 pt-y 156 (5.1%) 2.3/100 pt-y 0.98 (0.78–1.22) MI (fatal/non-fatal) 261 (8.6%) 4.1/100 pt-y 270 (8.9%) 4.2/100 pt-y 1.03 (0.87–1.22) Stroke (fatal/non-fatal 60 (2.0%) 0.9/100 pt-y 67 (2.2%) 1.0/100 pt-y 1.12 (0.79–1.58) Unstable angina 10 (0.3%) 0.1/100 pt-y 11 (0.4%) 0.2/100 pt-y 1.11 (0.47–2.62) Abbreviations CI, confidence interval; CV, cardiovascular; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; HR, hazard ratio; 4P-MACE, 4-point major adverse cardiovascular events (CV death, non-fatal myocardial infarction, non-fatal stroke or unstable angina requiring hospitalisation); MI, myocardial infarction; pt-y, patient-years. Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation). Back

ELIXA: HHF was not significantly increased with lixisenatide vs placebo
Outcome Placebo (n = 3034) Lixisenatide (n = 3034) HR (95% CI) MACE + HHF 469 (15.5%) 7.6/100 pt-y 456 (15.0%) 7.3/100 pt-y 0.97 (0.85–1.10) MACE + HHF + Coronary Revascularisation 659 (21.7%) 11.2/100 pt-y 661 (21.8%) 11.1/100 pt-y 1.00 (0.90–1.11) HHF 127 (4.2%) 1.9/100 pt-y 122 (4.0%) 1.8/100 pt-y 0.96 (0.75–1.23) CV death + HHF 253 (8.3%) 3.9/100 pt-y 248 (8.2%) 3.8/100 pt-y 0.97 (0.82–1.16) Notes There was no difference in HHF with lixisenatide vs placebo arms (HR 0.96; 95% CI: 0.75, 1.23). There was no difference in the composite endpoint of CV death + HHF with lixisenatide vs placebo (HR 0.97; 95% CI: 0.82, 1.16). Abbreviations CI, confidence interval; CV, cardiovascular; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; HHF, hospitalisation for heart failure; HR, hazard ratio; MACE, major cardiovascular events; pt-y, patient-years. Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation). Back

LEADER: Study design Next Back Aim Compound-specific
To assess the CV safety of liraglutide relative to current usual care Main inclusion criteria 1. Type 2 Diabetes 2. Patients with prior CVD (e.g., MI, stroke, CHF, CRF) and age ≥ 50 years, or patients without prior CVD and ≥ 60 years old at screening with ≥ 1 CV risk factors + Usual care for T2D Liraglutide 0.6–1.8 mg daily SC vs Placebo N = 9340; expected duration of follow-up 3.5–5 years Primary endpoint: time to first occurrence of primary major adverse cardiac events CV-related death CV death Non-fatal MI Non-fatal stroke Non-fatal MI Non-fatal stroke Notes CV risk factors leading to inclusion in patients without prior CVD were microalbuminuria or proteinuria, hypertension and left ventricular hypertrophy by ECG or imaging, left ventricular systolic or diastolic dysfunction by imaging, or ankle-brachial index < 0.9. Abbreviations CV, cardiovascular; CVD, cardiovascular disease; CHF, congestive heart failure; CRF, chronic renal failure; ECG, electrocardiogram; LEADER, liraglutide effect and action in diabetes: evaluation of cardiovascular outcomes results; MI, myocardial ischaemia; SC, subcutaneously; T2D, Type 2 Diabetes. Reference Results anticipated 2016 1. Marso et al. Am Heart J 2013;166:823–30.e5. 2. NCT Back

LEADER: Baseline characteristics
Total population (N = 9340) Age, years (mean ± SD) 64.3 ± 7.2 Male, n (%) 6003 (64.3) Race, n (%) White Asian Black Other 7237 (77.5) 922 (9.9) 775 (8.3) 406 (4.3) Ethnicity, n (%) Hispanic or Latino 1135 (12.2) BMI, kg/m2 (mean ± SD) 32.5 ± 6.3 Cholesterol, mg/dL (mean ± SD) Total Triglycerides HDL-C LDL-C 170.4 ± 45.3 182.5 ± 140.0 45.5 ± 12.3 89.5 ± 35.5 HbA1c, %, (mean ± SD) 8.7 ± 1.5 Previous CVD, n (%) 7592 (81.3) No previous CVD, n (%) 1748 (18.7) Hypertension, n (%) 8408 (90.0) Hyperlipidaemia, n (%) 7191 (77.0) Coronary artery disease, n (%) 5303 (56.8) Congestive heart failure, n (%) 1599 (17.1) Peripheral artery disease, n (%) 1644 (17.6) Diabetes duration, years 12.7 ± 8.0 Inclusion criteria ● Type 2 diabetes ● Anti-diabetic drug naïve or treated with one or more oral anti-diabetic drugs or treated with human NPH insulin or long-acting insulin analogue or premixed insulin, alone or in combination with OAD(s) ● HbA1c ≥7.0% ● Prior CVD cohort: age ≥50 and ≥1 of the following criteria. ○ Prior MI ○ Prior stroke or TIA ○ Prior coronary, carotid or peripheral arterial revascularization ○ >50% stenosis of coronary, carotid, or lower extremity arteries ○ History of symptomatic CHD documented by Positive exercise stress test or any cardiac imaging or Unstable angina with ECG changes ○ Asymptomatic cardiac ischemia ○ Chronic heart failure NYHA class II-III ○ Chronic renal failure: eGFR <60 mL/min per 1.73m2 MDRD; eGFR <60 mL/min per Cockcroft-Gault formula ● No Prior CVD group: Age ≥60 y and ≥1 of the following criteria. ○ Microalbuminuria or proteinuria ○ Hypertension and left ventricular hypertrophy by ECG or imaging ○ Left ventricular systolic or diastolic dysfunction by imaging ○ Ankle-brachial index <0.9 Abbreviations BMI, body mass index; HbA1c, glycosylated haemoglobin; HDL-C, high-density lipoprotein cholesterol; LEADER, liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results; LDL-C, low-density lipoprotein cholesterol; SD, standard deviation. Marso et al. Am Heart J 2013;166:823–30.e5. Back

SAVOR-TIMI 53: Study design
Next Aim Compound-specific To determine whether saxagliptin reduces risk of CV events when used alone or added to other diabetes medications Main inclusion criteria 1. Patients with T2D 2. HbA1c > 6.5%, < 12.0% 3. High-risk for CV events – established CVD and/or multiple risk factors + Usual care for T2D Saxagliptin 2.5 or 5 mg vs Placebo N = 16,492; median follow-up, 2.1 years (maximum, 2.9 years) Primary endpoint: time to first occurrence of primary composite endpoint: CV death Non-fatal MI Non-fatal stroke Abbreviations CV, cardiovascular; CVD, cardiovascular disease; HbA1c, glycosylated haemoglobin; MI, myocardial infarction; SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction 53; T2D, Type 2 Diabetes. 1. Mosenzon et al. Diabetes Metab Res Rev 2013;29:417– Scirica et al. N Engl J Med 2013;369:1317–26. Back

SAVOR-TIMI 53: Saxagliptin was non-inferior to placebo on primary 3P-MACE endpoint
Next 180 360 540 720 900 14 12 10 2 4 6 8 Saxagliptin Placebo HR 1.00 (95% CI 0.89–1.12) p < for non-inferiority p = 0.99 for superiority Patients with primary endpoint (%) Days No. at risk Placebo 8212 7983 7761 7267 4855 851 Saxagliptin 8280 8071 7836 7313 4920 847 Notes Saxagliptin neither reduced nor increased the risk of the primary composite endpoint when added to usual care in patients at high risk for CV events, despite reducing HbA1c: The 2-year Kaplan-Meier rate was 7.3% for saxagliptin and 7.2% for placebo. There were small differences in HbA1c between arms at study end (7.7% saxagliptin vs 7.9% placebo; p < 0.001). Abbreviations CV, cardiovascular; CI, confidence interval; HbA1c, glycosylated haemoglobin; HHF, hospitalisation for heart failure; HR, hazard ratio; 3P-MACE, 3-point major adverse CV events (CV death, non-fatal myocardial infarction or non-fatal stroke); MI, myocardial infarction; SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction 53. Copyright Scirica et al. N Engl J Med 2013;369:1317–26. Figure 1A. Page 1323 Scirica et al. N Engl J Med 2013;369:1317–26. Back

Hospitalisation for heart failure (%)
SAVOR-TIMI 53: Increased risk of hospitalisation for heart failure in saxagliptin arm HR 1.27 (05% CI 1.07–1.51); p = 0.007 8212 8280 180 8036 8064 Days 1 2 3 Hospitalisation for heart failure (%) 4 360 7856 7867 720 4959 4978 540 7389 7375 Placebo Saxagliptin 2.8% 3.5% Saxagliptin Placebo Notes However, the rate of hospitalisation for heart failure was increased in the saxagliptin arm. An increased relative risk (27%) of hospitalisation for heart failure (0.7% absolute risk over 2 years) was observed in patients assigned to saxagliptin. Abbreviations HR, hazard ratio; SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction 53. Copyright Scirica et al. Circulation 2014;130:1579–88. Figure 1 page 1584 Scirica et al. Circulation 2014;130:1579–88. Back

N = 5380; median follow-up = 18 months (maximum 40 months)
EXAMINE: Study design Next Aim Compound-specific To demonstrate non-inferiority of alogliptin vs placebo with respect to CV events in patients at high CV risk Main inclusion criteria 1. Patients with T2D 2. HbA1c ≥ 6.5%, ≤ 11.0% (if on oral or combination); HbA1c ≥ 7.0%, ≤ 11.0% (if treatment includes insulin) 3. History of acute coronary syndrome within 15–90 days pre-randomisation + Usual care for T2D Alogliptin 6.25–25 mg daily* vs Placebo N = 5380; median follow-up = 18 months (maximum 40 months) Primary endpoint: time to first occurrence of primary major adverse cardiac events Abbreviations CV, cardiovascular; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin Versus Standard of Care; HbA1c, glycosylated haemoglobin; MI, myocardial infarction; T2D, Type 2 Diabetes. CV death Non-fatal MI Non-fatal stroke *Depending on renal function. 1. White et al. Am Heart J 2011;162:620–26.e White et al. N Engl J Med 2013;369:1327–35. Back

EXAMINE: HHF was not significantly increased with alogliptin vs placebo
Next Risk of HHF occurring as the first event in pre-specified exploratory extended MACE endpoint did not differ significantly between groups Risk of events assessed as component of post-hoc composite endpoint of CV death and HHF was not significantly different between groups Alogliptin (n = 2701) Placebo (n = 2679) HR (95% CI) p value Hospital admission for heart failure 85 (3.1%) 79 (2.9%) 1.07 (0.79–1.46) 0.657 Alogliptin (n = 2701) Placebo (n = 2679) HR (95% CI) p value Hospital admission for heart failure 106 (3.9%) 89 (3.3%) 1.19 (0.90–1.58) 0.220 Notes HHF was not significantly increased with alogliptin vs placebo, regardless of the analysis used, although there were higher event rates in patients with a history of heart failure (8.2% alogliptin; 8.5% placebo). Abbreviations CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin Versus Standard of Care; HbA1C, glycosylated haemoglobin; HHF, hospitalisation for heart failure; HR, hazard ratio; MACE, major cardiovascular events. Zannad et al. Lancet 2015;385:2067–76. Back

Cumulative incidence of primary endpoint events (%)
EXAMINE: Alogliptin was non-inferior to placebo on primary 3P-MACE endpoint HR 0.96 (upper boundary of the 1-sided repeated CI 1.16) p < for non-inferiority; p = 0.32 for superiority 100 24 18 Placebo 80 12 Alogliptin 60 Cumulative incidence of primary endpoint events (%) 6 40 6 12 18 24 30 20 6 12 18 24 30 Notes The EXAMINE study also showed non-inferiority of alogliptin on the primary 3P-MACE endpoint, despite reducing HbA1c: Alogliptin 11.3% vs placebo 11.8%. There were small differences in HbA1c between study arms (-0.33% alogliptin vs 0.03% placebo, p < 0.001). Abbreviations CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin Versus Standard of Care; HbA1C, glycosylated haemoglobin; HHF, hospitalisation for heart failure; HR, hazard ratio; MACE, major cardiovascular events; 3P-MACE, 3-point major adverse CV events (CV death, non-fatal myocardial infarction or non-fatal stroke). Copyright White et al. N Engl J Med 2013;369:1327–35 Figure 2A. page 1334 Months No. at risk Placebo 2679 2299 1891 1375 805 286 Alogliptin 2701 2316 1899 1394 821 296 1. White et al. N Engl J Med 2013;369:1327–35, Back

N = 14,671; median follow-up 3.0 years
TECOS: Study design Next Aim Compound-specific To determine CV outcomes associated with long-term sitagliptin Main inclusion criteria Patients aged ≥ 50 years with T2D HbA1c 6.5–8.0% receiving stable oral glucose-lowering therapy and/or insulin* 3. Pre-existing vascular disease + Usual care for T2D Sitagliptin 100 mg daily* vs Placebo N = 14,671; median follow-up 3.0 years Primary endpoint: time to first occurrence of: CV-related death Unstable angina requiring hospitalisation Non-fatal stroke Non-fatal MI Notes 14,735 patients were randomised and 14,671 were included in the ITT analysis. The study was closed in March 2015 as the requisite 1300 patients had had the primary composite outcome. *Monotherapy or dual combination therapy with metformin, pioglitazone or a sulphonylurea; or insulin monotherapy or in combination with metformin for  3 months prior to enrolment. Regulatory requirement for recruitment of ≥ 2000 patients receiving metformin monotherapy at baseline. Abbreviations CV, cardiovascular; eGFR, estimated glomerular filtration rate; HbA1c, glycosylated haemoglobin; ITT, intention-to-treat; MI, myocardial infarction; T2D, Type 2 Diabetes; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin. *50 mg daily if the baseline eGFR was ≥ 30 and < 50 mL per minute per 1.73 m2. Green et al. N Engl J Med 2015; DOI /NEJMoa Back

TECOS: Baseline characteristics
Next Characteristic Sitagliptin n = 7332 Placebo n = 7339 Age, years 65.4 ± 7.9 65.5 ± 8.0 Women, n (%) 2134 (29.1) 2163 (29.5) Race, n (%) White Black Asian Other 4955 (67.6) 206 (2.8) 1654 (22.6) 517 (7.1) 5002 (68.2) 241 (3.3) 1611 (22.0) 485 (6.6) Hispanic or Latino 886 (12.1) 912 (12.4) BMI (kg/m2) (mean ± SD) 30.2 ± 5.6 30.2 ± 5.7 eGFR (mL/min/1.73 m2) 74.9 ± 21.3 74.9 ± 20.9 HbA1c 7.2 ± 0.5 7.2± 0.5 CV risk management Systolic blood pressure (mmHg) 135 ± 16.9 135 ± 17.1 Diastolic blood pressure (mmHg) 77.1 ± 10.3 77.2 ± 10.6 Total cholesterol (mg/dL) 166.1 ± 44.8 165.4 ± 45.9 LDL-C (mg/dL) 91.2 ± 63.8 90.7 ± 51.2 HDL-C (mg/dL) 43.5 ± 12.0 43.4 ± 13.0 Triglycerides (mg/dL) 166.0 ± 101.0 164.8 ± 98.8 Aspirin use, n (%) 5764 (78.6) 5754 (78.4) Statin use, n (%) 5851 (79.8) 5868 (80.0) Abbreviations BMI, body mass index; CV, cardiovascular; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HbA1c, glycosylated haemoglobin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SD, standard deviation; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin. Values mean ± SD if not specified n (%). Green et al. N Engl J Med 2015; DOI /NEJMoa Back

TECOS: Baseline CV risk factors
Next Characteristic, n (%) Sitagliptin n = 7332 Placebo n = 7339 Prior CV disease* 5397 (73.6) 5466 (74.5) Myocardial infarction 3133 (42.7) 3122 (42.5) PCI 2814 (38.9) 2900 (40.1) CABG 1845 (25.2) 1819 (24.8) ≥ 50% stenosis in a coronary artery 3804 (51.9) 3883 (52.9) Prior cerebrovascular disease 1806 (24.6) 1782 (24.3) Stroke 1297 (17.7) 1258 (17.1) TIA 280 (3.8) 286 (3.9) ≥ 50% stenosis in a carotid artery 431 (5.9) 429 (5.8) Peripheral arterial disease 1217 (16.6) 1216 (16.6) History of heart failure 1303 (17.8) 1340 (18.3) Abbreviations CABG, coronary artery bypass graft; CV, cardiovascular; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin; TIA, transient ischaemic attack. *Enrolled participants could have one or more prior CV event. Green et al. N Engl J Med 2015; DOI /NEJMoa Back

TECOS: Diabetes characteristics at baseline
Next Characteristic Sitagliptin n = 7332 Placebo n = 7339 Duration of diabetes, years 11.6 ± 8.1 HbA1c, % 7.2 ± 0.5 Medication taken alone or in combination Metformin 5936 (81.0) 6030 (82.2) Sulphonylurea 3346 (45.6) 3299 (45.0) Thiazolidinedione 196 (2.7) 200 (2.7) Insulin 1724 (23.5) 1684 (22.9) Median daily dose (units) 50 (33, 80) 50 (32, 80) Monotherapy 3496 (47.7) 3498 (47.7) Dual combination therapy 3766 (51.4) 3768 (51.3) Abbreviations HbA1c, glycosylated haemoglobin; IQR, interquartile range; SD, standard deviation; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin. Values are mean ±SD or median (IQR) for continuous variables or n (%) for categorical variables. Green et al. N Engl J Med 2015; DOI /NEJMoa Back

TECOS: Sitagliptin was non-inferior to placebo on primary 4P-MACE endpoint
Next 4 8 12 18 24 30 36 42 48 5 10 15 Sitagliptin Placebo 100 80 60 40 20 4 8 12 18 24 30 36 42 48 Months in the trial Patients with an event (%) Patients at risk: HR (95% CI): 0.98 (0.88–1.09) p < 0.001 Notes Sitagliptin was non-inferior to placebo on the primary outcome: CV death, non-fatal MI, non-fatal stroke, hospitalisation for unstable angina (per protocol analysis for non-inferiority). Overall in the intention-to-treat population, the primary composite cardiovascular outcome occurred in 839 patients in the sitagliptin group (11.4%, 4.06 per 100 person-years) and 851 in the placebo group (11.6%, 4.17 per 100 person-years). There was no significant between-group difference in the primary composite cardiovascular outcome (hazard ratio in the per-protocol analysis, 0.98; 95% CI: 0.88–1.09; p < for non-inferiority; hazard ratio in the intention-to treat analysis, 0.98; 95% CI: 0.89–1.08; p = 0.65 for superiority). At 4 months, mean HbA1c values were 0.4 percentage points lower in the sitagliptin group than in the placebo group. This difference narrowed during the study period, with an overall least-squares mean difference of % in the sitagliptin group (95% CI: -0.32– -0.27), p < Abbreviations CI, confidence interval; CV, cardiovascular; HbA1C, glycosylated haemoglobin; HR, hazard ratio; 4P-MACE, 4-point major adverse cardiovascular events (CV death, non-fatal myocardial infarction, non-fatal stroke or unstable angina requiring hospitalisation); MI, myocardial infarction; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin. Copyright Green et al. N Engl J Med 2015; DOI: /NEJMoa Figure 3A Sitagliptin 7257 6857 6519 6275 5931 5616 3919 2896 1748 1028 Placebo 7266 6846 6449 6165 5803 5421 3780 2743 1690 1005 *CV death, non-fatal MI, non-fatal stroke, hospitalisation for unstable angina. Green et al. N Engl J Med 2015; DOI: /NEJMoa Back

TECOS: No significant difference in rate of hospitalisation for heart failure (ITT analysis)
Outcome Placebo Sitagliptin HR (95% CI) HHF* 228 (3.1%) 1.07/100 pt-y 1.09/100 pt-y 1.00 (0.83–1.20) p = 0.98 CV Death + HHF* 525 (7.2%) 2.50/100 pt-y 538 (7.3%) 2.54/100 pt-y 1.02 (0.90–1.15) p = 0.74 Notes There was no significant difference in the rate of hospitalisation for heart failure, which was reported in 228 patients in the sitagliptin group (3.1%; 1.07 per 100 person-years) and 229 in the placebo group (3.1%; 1.09 per 100 person-years) (HR in the intention-to-treat analysis, 1.00; 95% CI: 0.83–1.20; p = 0.98). The composite outcome of hospitalisation for heart failure or cardiovascular death occurred in 538 patients in the sitagliptin group (7.3%; 2.54 per 100 person-years) and 525 in the placebo group (7.2%; 2.50 per 100 person-years) (HR in the intention-to-treat analysis, 1.02; 95% CI: 0.90–1.15; p = 0.74). Abbreviations CI, confidence interval; CV, cardiovascular; HHF, hospitalisation for heart failure; HR, hazard ratio; ITT, intention-to-treat; pt-y, patient-year; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin. ITT population. Adjusted for history of heart failure at baseline *Pre-specified analyses Green et al. N Engl J Med 2015; DOI: /NEJMoa Back

Active comparator trial
CAROLINA® will evaluate CV safety of linagliptin compared with glimepiride in patients with T2D Next Active comparator trial Inclusion if ≥ 1 of the following is fulfilled: Previous vascular complications Evidence of end-organ damage, e.g., albuminuria Age ≥ 70 years ≥ 2 specified traditional CV risk factors With or without metformin background therapy (including patients with contraindication to metformin use in renal impairment) Linagliptin 5 mg vs Glimepiride 1–4 mg N = 6041; approximate 6–7 year follow-up Primary endpoint: time to first occurrence of primary composite endpoint: CV death (including fatal stroke and fatal MI) Non-fatal MI Non-fatal stroke Hospitalisation for UA Abbreviations CAROLINA®, Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes; CV, cardiovascular; MI, myocardial infarction; T2D, Type 2 Diabetes; UA, unstable angina. 1. Rosenstock et al. Diab Vasc Dis Res 2013;10:289– Marx et al. Diabetes Vasc Dis Res 2015;12:164–74. Back

CAROLINA®: Baseline characteristics
Total (n = 6041*) Group A: Previous CV events† (n = 2084, 34.5% of total) Group B: Retinopathy/ albuminuria (n = 513, 8.5% of total) Group C: Age > 70 years (n = 1163, 19.3% of total) Group D: ≥ 2 CV risk factors (n = 2252, 37.3% of total) Age, years (mean ± SD) 64.0 ± 9.5 64.6 ± 8.9 65.6 ± 9.7 74.0 ± 3.4 58.0 ± 7.2 ≥ 75 y, % 14.0 14.3 21.2 37.9 0.0 Sex, male, n (%) 3622 (60.0) 1511 (72.5) 284 (55.4) 593 (51.0) 1219 (54.1) Race, n (%) White 4408 (73.0) 1489 (71.4) 367 (71.5) 911 (78.3) 1634 (72.6) Asian 1061 (17.6) 427 (20.5) 85 (16.6) 145 (12.5) 402 (17.9) Black/African American 331 (5.5) 101 (4.8) 32 (6.2) 40 (3.4) 157 (7.0) Other‡ 241 (4.0) 67 (3.2) 29 (5.7) 67 (5.8) 59 (2.6) Ethnicity, n (%) Hispanic or Latino 1033 (17.1) 309 (14.8) 96 (18.7) 260 (22.4) 368 (16.3) Smoking: Current/ ex-smoker, % 19.5/33.7 16.3/46.2 14.4/30.2 6.6/32.8 30.7/23.6 Time since T2D diagnosis, years (median, IQR) 6.2 (2.9, 11.0) 5.8 (2.7, 10.4) 6.6 (3.6, 11.3) 7.7 (4.3, 12.0) (2.6, 10.7) Time since T2D diagnosis, % ≤ 5 years 40.6 43.7 36.1 30.5 44.2 > 5–10 years 28.2 29.1 30.4 25.9 > 10 years 30.9 27.2 33.5 39.0 29.9 Abbreviations CAROLINA®, Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes; CV, cardiovascular; IQR, interquartile range; SD, standard deviation; T2D, Type 2 Diabetes. Back *A few patients had no reliable CV risk categorisation. †Myocardial infarction 13.8%, coronary artery disease 17.1%, stroke 7.8%, peripheral arterial occlusive disease 5.5%. ‡American Indian/Native, Alaskan/Native, Hawaiian/Pacific Islander. Marx et al. Diabetes Vasc Dis Res 2015;12:164–74.

CARMELINA® will evaluate CV and renal safety of linagliptin in patients with T2D at high CV and renal risk Inclusion criteria T2D with HbA1c ≥ 6.5% and ≤ 10.0% Stable background anti-diabetes medication, excluding GLP1, DPP4 inhibitors, SGLT2 inhibitors High risk of CV, defined by: 1) albuminuria (micro or macro) and previous macrovascular disease ) and/or impaired renal function with predefined UACR Linagliptin 5 mg vs Placebo N = 8300; ~ 4-year follow-up Primary CV endpoint: time to first occurrence of primary composite endpoint: CV death (including fatal stroke and fatal MI) Non-fatal MI Non-fatal stroke Hospitalisation for UA Renal endpoint: time to first occurrence of the composite endpoint: Renal death, ESRD, and sustained decrease of ≥ 50% eGFR Abbreviations CARMELINA®, Cardiovascular Safety & Renal Microvascular Outcome Study with Linagliptin; CV, cardiovascular; DPP4, dipeptidyl peptidase 4; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; FDA, US Food and Drug Administration; GLP1, glucagon-like peptide 1; HbA1c, glycosylated haemoglobin; MI, myocardial infarction; SGLT2, sodium glucose cotransporter 2; T2D, Type 2 Diabetes; UA, unstable angina; UACR, urinary albumin:creatinine ratio. table angina pectoris; UACR, urine albumin-to-creatinine ratio. Reference Accessed March 2015. This study addresses the CV safety requirements from the FDA, as well as investigates the potential renal effects of the drug NCT Back

CANVAS: Study design Back Aim Compound-specific
To determine CV risk associated with canagliflozin Main inclusion criteria1 1. Patients with T2D 2. Age ≥ 30 years with history of symptomatic atherosclerotic vascular disease or ≥ 50 years with 2 or more risk factors for CVD Stable dose of background antihyperglycaemic agents administered for 8 weeks prior to screening In addition to usual care for T2D, patients randomised 1:1:1 to Canagliflozin (100 mg) Canagliflozin (300 mg) Placebo N = 43652; expected duration of follow-up 6-7 years Primary endpoint: time to first occurrence of1: Abbreviations CANVAS, Canagliflozin Cardiovascular Assessment Study; CV, cardiovascular; CVD, cardiovascular disease; MI, myocardial infarction; T2D; Type 2 Diabetes. Reference Accessed March 2015. CV-related death Non-fatal stroke Non-fatal MI 1. Neal et al. Am Heart J 2013;166:217–223.e NCT Back

CANVAS-R: Study design
Aim Compound-specific Effects of canagliflozin on renal endpoints in adults with T2D and at high CV risk Main inclusion criteria Established CV disease or multiple risk factors Age ≥ 30 years T2D + Usual care for T2D Canagliflozin (100 or 300 mg) vs Placebo N = 5700; expected duration of follow-up 3 years Primary endpoint: Although primarily a renal study, CANVAS-R will prospectively collect adjudicated CV outcomes, as required by the FDA mandate Number of participants with progression of albuminuria Notes Progression of albuminuria is defined as the development of microalbuminuria or macroalbuminuria in a participant with baseline normoalbuminuria or the development of macroalbuminuria in a participant with baseline microalbuminuria, accompanied by a urinary albumin/creatinine ratio (ACR) value increase of ≥ 30% from baseline. Abbreviations CANVAS-R, Study of the Effects of Canagliflozin on Renal Endpoints in Adult Subjects with T2D; CV, cardiovascular; 3P-MACE, 3-point major adverse CV events (CV death, non-fatal myocardial infarction or non-fatal stroke); FDA, US Food and Drug Administration; T2D, Type 2 Diabetes. Reference Accessed March 2015. Other endpoints: CV safety data will be evaluated as 3P-MACE NCT Back

CREDENCE: Study design
Aim Compound-specific To determine whether canagliflozin has a renal/vascular protective effect vs placebo Main inclusion criteria Stage 2 or 3 CKD and macroalbuminuria On ACE inhibitor or ARB Age ≥ 30 years + Usual care for T2D Canagliflozin (100 mg) vs Placebo N = 3700; expected duration of follow-up ~4 years Primary endpoint: time to first occurrence of: Although primarily a renal study, CREDENCE will prospectively collect adjudicated CV outcomes, as required by the FDA mandate End-stage kidney disease Serum creatinine doubling Renal or CV death Abbreviations ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; CREDENCE, Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; CV, cardiovascular; MI, myocardial infarction; T2D, Type 2 Diabetes. Reference Accessed March 2015. Other endpoints: Composite CV safety endpoint* *CV death, non-fatal MI, non-fatal stroke, hospitalised congestive heart failure and hospitalised unstable angina. NCT Back

DECLARE-TIMI 58: Study design
Aim Compound-specific To determine whether dapagliflozin reduces CV events vs placebo Main inclusion criteria High risk for CV events Age ≥ 40 years T2D + Usual care for T2D Dapagliflozin (10 mg) vs Placebo N = 17,150; expected duration of follow-up ~4.5 years Primary endpoint: time to first occurrence of: CV death Myocardial infarction Ischaemic stroke Abbreviations CV, cardiovascular; DECLARE-TIMI 58, Dapagliflozin Effect on CardiovascuLAR Events; T2D, Type 2 Diabetes. Reference Accessed March 2015. 1. Accessed March NCT Back

Ertugliflozin CVOT: Study design
Aim Compound-specific To determine whether ertugliflozin reduces CV events vs placebo Main inclusion criteria Evidence or a history of atherosclerosis (coronary, cerebral or peripheral) Age ≥ 40 years T2D + Background therapy for T2D Ertugliflozin (5 or 15 mg) vs Placebo N = 3900; expected duration of follow-up up to 6.3 years Primary endpoint: time to first occurrence of: CV death Non-fatal MI Non-fatal stroke Abbreviations CV, cardiovascular; CVOT, cardiovascular outcomes trial; MI, myocardial infarction; T2D, Type 2 Diabetes. Reference Accessed March 2015. NCT Back

Clinical profile of SGLT2 inhibitors
Back

Empagliflozin pooled Phase III placebo-corrected change from baseline in HbA1c*
Empagliflozin 10 mg QD Empagliflozin 25 mg QD Pooled data Pooled1 Monotherapy2 MET3 PIO4 MET + SU5 Insulin 78-week6 Mild RI7 Adjusted mean (SE) difference vs placebo in change from baseline in HbA1c (%) † † † † † † Notes This and the following slides provide some of the clinical data available for empagliflozin, before looking into the EMPA-REG OUTCOME® trial (which reports later this year) in more detail. Empagliflozin has been studied as monotherapy and in combination with metformin, pioglitazone and metformin + sulphonylurea; it has also been studied in patients with mild renal impairment: The pooled data in the first bar are derived from the 4 randomised controlled trials displayed in the following four bars within the light grey box. In all cases, empagliflozin at both the 10 mg and 25 mg once-daily doses provides significant reductions from baseline (vs placebo) in HbA1c in patients with T2D. Abbreviations BL, baseline; CI, confidence interval; CV, cardiovascular; EMPA-REG OUTCOME®, cardiovascular outcomes trial of empagliflozin; HbA1c, glycosylated haemoglobin; MET, metformin; PIO, pioglitazone; QD, once daily; RI, renal impairment; SE, standard error; SU, sulphonylurea; T2D, Type 2 Diabetes. Patients, n 831 821 224 217 213 165 168 225 216 169 155 98 97 BL HbA1c (%) 7.98 7.96 7.87 7.86 7.94 8.07 8.06 8.10 8.27 8.02 *All statistically significant. †Error bar represents 95% CI. 1. Hach et al. Diabetes 2013;62(suppl 1A):A21(P69-LB). 2. Roden et al. Lancet Diabetes Endocrinol 2013;1:208‒ Häring et al. Diabetes Care 2014;37:1650– Kovacs et al. Diabetes Obes Met 2014;16:147‒ Häring et al. Diabetes Care 2013;36:3396‒ Rosenstock et al. Diabetes 2013;(suppl 1):(1102-P) Barnett et al. Lancet Diabetes Endocrinol 2014;2:369‒84 Back

Empagliflozin pooled Phase III placebo-corrected change from baseline in body weight*
Pooled data Empagliflozin 10 mg QD Empagliflozin 25 mg QD Pooled1 Monotherapy2 MET3 PIO4 MET + SU5 Insulin 78-week Mild RI6 N/A N/A Adjusted mean (SE) difference vs placebo in change from baseline in body weight (kg) † † † † † † Notes Available clinical data on empagliflozin shows a consistent decrease from baseline in bodyweight (vs placebo) in patients with T2D. Abbreviations BL, baseline; BW, body weight; CI, confidence interval; CV, cardiovascular; MET, metformin; PIO, pioglitazone; QD, once daily; RI, renal impairment; SE, standard error; SU, sulphonylurea; T2D, Type 2 Diabetes. Patients, n 831 821 224 217 213 165 168 225 216 N/A 98 97 BL BW (kg) 78.8 79.1 78.4 77.8 81.6 82.2 78.0 78.9 77.1 77.5 91.6 94.7 92.1 88.1 *All statistically significant. †Error bar represents 95% CI. N/A, published data not available. 1. Hach et al. Diabetes 2013;62(suppl 1A):A21(P69-LB). 2. Roden et al. Lancet Diabetes Endocrinol 2013;1:208‒ Häring et al. Diabetes Care 2014;37:1650– Kovacs et al. Diabetes Obes Met 2014;16:147‒ Häring et al. Diabetes Care 2013;36:3396‒ Barnett et al. Lancet Diabetes Endocrinol 2014;2:369‒84. Back Empagliflozin is not indicated for weight loss. Weight change was a secondary endpoint in clinical trials

Empagliflozin pooled Phase III placebo-corrected change from baseline in SBP*
Pooled data Empagliflozin 10 mg QD Empagliflozin 25 mg QD Pooled1 Monotherapy2 MET3 PIO4 MET + SU5 Insulin 78-week Mild RI6 N/A N/A Adjusted mean (SE) difference vs placebo in change from baseline in SBP (mmHg) † † † † † † Notes Empagliflozin treatment was also associated with significantly greater reductions from baseline in systolic blood pressure than placebo treatment. Abbreviations BL, baseline; CI, confidence interval; CV, cardiovascular; MET, metformin; PIO, pioglitazone; QD, once daily; RI, renal impairment; SBP, systolic blood pressure; SE, standard error; SU, sulphonylurea. Patients, n 831 821 224 217 213 165 168 225 216 N/A 98 97 BL SBP (mmHg) 129.6 129.0 133.0 129.9 130.0 126.5 125.9 128.7 129.3 132.4 132.8 137.4 133.7 *All statistically significant. †Error bar represents 95% CI. N/A, published data not available. 1. Hach et al. Diabetes 2013;62(suppl 1A):A21(P69-LB). 2. Roden et al. Lancet Diabetes Endocrinol 2013;1:208‒ Häring et al. Diabetes Care 2014;37:1650– Kovacs et al. Diabetes Obes Met 2014;16:147‒ Häring et al. Diabetes Care 2013;36:3396‒ Barnett et al. Lancet Diabetes Endocrinol 2014;2:369‒84. . Back Empagliflozin is not indicated for blood pressure reduction. Change in blood pressure was a secondary endpoint in clinical trials

Reductions in BP were not associated with increases in pulse rate
12-week ABPM study with empagliflozin in patients with T2D and hypertension: hourly mean SBP (mmHg) Baseline Mean (SE) SBP (mmHg) Week 12 Notes This 12 week study investigated the efficacy, safety and tolerability of empagliflozin 10 mg and 25 mg vs placebo in patients with type 2 diabetes (baseline HbA1c 7.9%) and hypertension (baseline 24-hour (ABPM) SBP/DBP: 131.4/75.0 mmHg; baseline office measured SBP/DBP: 142.1/83.9 mmHg). At week 12, adjusted mean difference vs placebo in change from baseline in mean 24-hour SBP (ambulatory blood pressure monitoring) was mmHg (95% CI -4.78, -2.09) with 10mg empagliflozin and mmHg (95% CI -5.50, -2.83) with 25mg empagliflozin (both P<0.001) Reductions in BP were not associated with increase in pulse rate. At week 12, mean (SD) changes from baseline in mean 24-hour pulse rate (ABPM) (6.10) bpm, (7.70) bpm and (6.16) bpm with placebo, 10 mg empagliflozin and 25 mg empagliflozin, respectively, in the treated set. Abbreviations ABPM, ambulatory blood pressure monitoring; DBP, diastolic blood pressure; LOCF-H, last observation carried forward, after a change in antihypertensive medication; FAS, full analysis set; QD, once daily; SBP, systolic blood pressure; SE, standard error. Copyright Tikkanen et al. Diabetes Care 2015;38:420–8. Figure 1 A . Page 422 1 2 3 4 5 Hour Back Reductions in BP were not associated with increases in pulse rate FAS (LOCF-H). 1. Tikkanen et al. Diabetes Care 2015;38:420–8. Empagliflozin is not indicated for blood pressure reduction. Change in blood pressure was a secondary endpoint in clinical trials

Reductions in BP were not associated with increases in pulse rate
12-week ABPM study with empagliflozin in patients with T2D and hypertension: hourly mean DBP at Week 12 Mean (SE) DBP (mmHg) Notes This 12 week study investigated the efficacy, safety and tolerability of empagliflozin 10 mg and 25 mg vs placebo in patients with type 2 diabetes (baseline HbA1c 7.9%) and hypertension (baseline 24-hour (ABPM) SBP/DBP: 131.4/75.0 mmHg; baseline office measured SBP/DBP: 142.1/83.9 mmHg). At week 12, adjusted mean difference vs placebo in change from baseline in mean 24-hour DBP (ambulatory blood pressure monitoring) was -1.4 mmHg (95% CI -2.2, -0.6) with 10mg empagliflozin and -1.7 mmHg (95% CI -2.5, -0.9) with 25mg empagliflozin (both P<0.001) Reductions in BP were not associated with increase in pulse rate. At week 12, mean (SD) changes from baseline in mean 24-hour pulse rate (ABPM) (6.10) bpm, (7.70) bpm and (6.16) bpm with placebo, 10 mg empagliflozin and 25 mg empagliflozin, respectively, in the treated set. Abbreviations ABPM, ambulatory blood pressure monitoring; QD, once daily; SBP, systolic blood pressure; DBP, diastolic blood pressure; SE, standard error. Copyright Tikkanen et al. Diabetes Care 2015;38:420–8. Figure 1B. Page 422 1 2 3 4 5 Hour Back Reductions in BP were not associated with increases in pulse rate Tikkanen et al. Diabetes Care 2015;38:420–8. Empagliflozin is not indicated for blood pressure reduction. Change in blood pressure was a secondary endpoint in clinical trials

Empagliflozin pooled Phase III data: Change in lipids (mg/dL) from baseline at Week 24
** *** ** ** * Notes In comparison to placebo, small increases in cholesterol (total, HDL and LDL) were observed with empagliflozin. However, triglyceride levels were decreased from baseline with empagliflozin compared to placebo (significantly with 10 mg but not 25 mg dose). For HDL-C analyses, n = 816 for placebo, n = 816 for empagliflozin 10 mg and n = 818 for empagliflozin 25 mg ANCOVA (treated set). Percentage change in lipids from baseline at Week 24 Adjusted mean % change from baseline in LDL-C: PBO 4.0, Empa 10mg 7.4, Empa 25mg 8.5 Adjusted mean % change from baseline in HDL-C: PBO 1.1, Empa 10mg 6.6, Empa 25mg 6.2 Adjusted mean % change from baseline in LDL/HDL-C ratio: PBO 3.9, Empa 10mg 2.2, Empa 25mg 3.3 Adjusted mean % change from baseline in Triglycerides: PBO 9.2, Empa 10mg 2.3, Empa 25mg 5.7 Abbreviations ANCOVA, analysis of covariance; HDL, high-density lipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; QD, once daily; SE, standard error. Copyright Hach et al. Diabetes 2013;62(Suppl 1A):A21 (P69-LB).graph LDL-C HDL-C Triglycerides LDL/HDL-C ratio Total cholesterol Mean baseline 101.2 99.2 48.6 49.0 164.7 172.7 173.6 2.18 2.11 181.7 180.6 *p < 0.05; **p < 0.001; ***p = vs placebo Hach et al. Diabetes 2013;62(Suppl 1A):A21 (P69-LB). Back

Rate per 100 patient-years
Empagliflozin pooled safety and tolerability data: Summary of adverse events n (%) Placebo (n = 3695) Empagliflozin 10 mg QD (n = 3806) 25 mg QD (n = 4782) Patients with any AE 2621 (70.9) 2686 (70.6) 3499 (73.2) Patients with AE(s) leading to discontinuation of trial drug 208 (5.6) 191 (5.0) 255 (5.3) Patients with serious AE(s) 494 (13.4) 393 (10.3) 573 (12.0) One or more severe AE(s) 324 (8.8) 258 (6.8) 373 (7.8) Deaths 29 (0.8) 19 (0.5) 26 (0.5) Back Rate per 100 patient-years Notes Safety data were analyzed from >12,000 patients with type 2 diabetes treated with 10 mg empagliflozin, 25 mg empagliflozin or placebo in 17 randomized phase I-III clinical trials plus 6 extension studies. • Assessment of safety and tolerability was based on AEs and clinical laboratory tests. • AEs of special interest (prospectively defined search of investigator-reported AEs) included: - confirmed hypoglycemic AEs (plasma glucose ≤70 mg/dL and/or requiring assistance) - events consistent with urinary tract infection (UTI; based on 77 MedDRA preferred terms) - events consistent with genital infection (based on 89 MedDRA preferred terms) - events consistent with volume depletion (based on 8 MedDRA preferred terms, including hypotension, syncope and hypovolemia) - bone fracture (based on 60 MedDRA preferred terms) - malignancies (based on 2 standardized MedDRA queries) - decreased renal function (based on 1 standardized MedDRA query) - hepatic injury (based on 4 standardized MedDRA queries). • Diabetic ketoacidosis AEs were identified from a post-hoc search of 3 MedDRA preferred terms (ketoacidosis, diabetic ketoacidosis and acetonemia). • Analyses were descriptive and performed in data from all patients who received ≥1 dose of study drug, including patients re-randomized from a different empagliflozin dose to empagliflozin 10 mg or 25 mg in an extension study, except for analysis of laboratory values, for which patients who switched to empagliflozin 10 mg or 25 mg in an extension study were excluded. AE frequencies were calculated (n [%]) and exposure-adjusted incidence rates were calculated per 100 patient-years = 100 × n/T, where n was the number of patients with the specified event and T was the total patient-years. Patient-years were defined as the time from the first dose to the onset of the first event (for patients with an event) or to the last dose (for patients without an event). Abbreviations ADA, American Diabetes Association; AE, adverse event; QD, once daily. Copyright Kohler et al. ADA 2015 (poster 1173-P). Adverse events table Kohler et al. ADA 2015 (poster 1173-P).

Pooled empagliflozin data: Important identified safety topics
Placebo (n = 3695) Empagliflozin 10 mg QD (n = 3806) 25 mg QD (n = 4782) Urinary tract infection2 344 (9.3) 374 (9.8) 497 (10.4) Female2 Male2 269 (19.3) 75 (3.3) 281 (20.2) 93 (3.8) 360 (20.1) 137 (4.6) Pyelonephritis2 4 (0.1) 1 (< 0.1) 3 (0.1) Pyelonephritis acute2 2 (< 0.1) Urosepsis2 2 (0.1) Genital infection2 41 (1.1) 177 (4.7) 268 (5.6) 23 (1.6) 18 (0.8) 94 (6.8) 83 (3.4) 156 (8.7) 112 (3.7) Volume depletion2 51 (1.4) 57 (1.5) 74 (1.5) No. of patients with confirmed hypoglycaemic AEs1 567 (15.3) 562 (14.8) 627 (13.1) Episode requiring assistance (‘severe hypoglycaemic episode’)1 19 (0.5) 18 (0.5) 18 (0.4) Notes Safety data were analyzed from >12,000 patients with type 2 diabetes treated with 10 mg empagliflozin, 25 mg empagliflozin or placebo in 17 randomized phase I-III clinical trials plus 6 extension studies. • Assessment of safety and tolerability was based on AEs and clinical laboratory tests. • AEs of special interest (prospectively defined search of investigator-reported AEs) included: - confirmed hypoglycemic AEs (plasma glucose ≤70 mg/dL and/or requiring assistance) - events consistent with urinary tract infection (UTI; based on 77 MedDRA preferred terms) - events consistent with genital infection (based on 89 MedDRA preferred terms) - events consistent with volume depletion (based on 8 MedDRA preferred terms, including hypotension, syncope and hypovolemia) - bone fracture (based on 60 MedDRA preferred terms) - malignancies (based on 2 standardized MedDRA queries) - decreased renal function (based on 1 standardized MedDRA query) - hepatic injury (based on 4 standardized MedDRA queries). • Diabetic ketoacidosis AEs were identified from a post-hoc search of 3 MedDRA preferred terms (ketoacidosis, diabetic ketoacidosis and acetonemia). • Analyses were descriptive and performed in data from all patients who received ≥1 dose of study drug, including patients re-randomized from a different empagliflozin dose to empagliflozin 10 mg or 25 mg in an extension study, except for analysis of laboratory values, for which patients who switched to empagliflozin 10 mg or 25 mg in an extension study were excluded. AE frequencies were calculated (n [%]) and exposure-adjusted incidence rates were calculated per 100 patient-years = 100 × n/T, where n was the number of patients with the specified event and T was the total patient-years. Patient-years were defined as the time from the first dose to the onset of the first event (for patients with an event) or to the last dose (for patients without an event). Abbreviations ADA, American Diabetes Association; AE, adverse event; BL, baseline; MedDRA, medical dictionary for regulatory activities; QD, once daily; RMP, risk management plan; ULN, upper limit of normal. 1. Kohler et al. ADA 2015 (poster 1173-P). 2. Data on file. Back

Pooled empagliflozin data: Important potential safety topics
Placebo (n = 3695) Empagliflozin 10 mg QD (n = 3806) 25 mg QD (n = 4782) Events consistent with malignancies*1 36 (1.0) 46 (1.2) 67 (1.4) Events consistent with malignancies with an onset after 6 months of therapy or later1 22 (0.9) 30 (1.0) 39 (1.0) Patients with renal or bladder cancer with an onset after 6 months of therapy or later2 2 (<0.1) 1 (<0.1) Decreased renal function†1 64 (1.3) Serum creatinine increase ≥ 2x BL and ≥ ULN2 10 (0.3) 11 (0.3) 14 (0.3) Hepatic injury‡1 66 (1.8) 52 (1.4) 82 (1.7) Events consistent with bone fracture§1 67 (1.8) 66 (1.7) 63 (1.3) Events consistent with DKA1 5 (0.1) 2 (0.1) 1 (< 0.1) Diabetic ketoacidosis2 4 (0.1) Ketoacidosis2 Acetoanaemia2 Notes Safety data were analyzed from >12,000 patients with type 2 diabetes treated with 10 mg empagliflozin, 25 mg empagliflozin or placebo in 17 randomized phase I-III clinical trials plus 6 extension studies. • Assessment of safety and tolerability was based on AEs and clinical laboratory tests. • AEs of special interest (prospectively defined search of investigator-reported AEs) included: - confirmed hypoglycemic AEs (plasma glucose ≤70 mg/dL and/or requiring assistance) - events consistent with urinary tract infection (UTI; based on 77 MedDRA preferred terms) - events consistent with genital infection (based on 89 MedDRA preferred terms) - events consistent with volume depletion (based on 8 MedDRA preferred terms, including hypotension, syncope and hypovolemia) - bone fracture (based on 60 MedDRA preferred terms) - malignancies (based on 2 standardized MedDRA queries) - decreased renal function (based on 1 standardized MedDRA query) - hepatic injury (based on 4 standardized MedDRA queries). • Diabetic ketoacidosis AEs were identified from a post-hoc search of 3 MedDRA preferred terms (ketoacidosis, diabetic ketoacidosis and acetonemia). • Analyses were descriptive and performed in data from all patients who received ≥1 dose of study drug, including patients re-randomized from a different empagliflozin dose to empagliflozin 10 mg or 25 mg in an extension study, except for analysis of laboratory values, for which patients who switched to empagliflozin 10 mg or 25 mg in an extension study were excluded. AE frequencies were calculated (n [%]) and exposure-adjusted incidence rates were calculated per 100 patient-years = 100 × n/T, where n was the number of patients with the specified event and T was the total patient-years. Patient-years were defined as the time from the first dose to the onset of the first event (for patients with an event) or to the last dose (for patients without an event). Abbreviations ADA, American Diabetes Association; AE, adverse event; BL, baseline; MedDRA, medical dictionary for regulatory activities; QD, once daily; RMP, risk management plan; ULN, upper limit of normal. *Based on 2 MedDRA preferred terms. †Based on 1 standardized MedDRA query. ‡Based on 4 standardized MedDRA queries. §Based on 60 MedDRA preferred terms. 1. Kohler et al. ADA 2015 (poster 1173-P). 2. Data on file. Back

HbA1c mean change from baseline (%)†
Dapagliflozin: Short-term (Week 24) HbA1c change from baseline in Phase III trials Study Add-on INS1 Mono- therapy1 Add-on MET1 Add-on MET vs GLP1 Add-on GLM1 Add-on PIO2 Add-on SU + MET1 Add-on SITA ± MET1 PBO+ SITA ± MET PBO PBO + MET GLP + MET PBO + GLM PBO + PIO PBO + INS PBO+ SU + MET Comparator HbA1c mean change from baseline (%)† * (Week 52 data) * * * * * * Abbreviations BL, baseline; GLM, glimepiride; GLP, glipizide; HbA1c, glycosylated haemoglobin; INS, insulin; MET, metformin; PBO, placebo; PIO, pioglitazone; SITA, sitagliptin; SU, sulphonylurea. Reference Forxiga 5 mg and 10 mg film-coated tablets [SPC]. Bristol-Myers Squibb/AstraZeneca EEIG, 18 December Accessed: February 2014. n BL HbA1c (%) 75 70 137 135 401 400 145 151 108 224 223 139 140 193 194 7.79 8.01 8.11 7.92 7.74 7.69 8.15 8.07 8.24 8.08 7.97 7.90 8.34 8.37 8.46 8.58 *p ≤ vs placebo. †Least-squares mean adjusted for baseline value. 1. Forxiga 5-mg and 10-mg film-coated tablets [SPC]. Bristol-Myers Squibb/AstraZeneca EEIG, 18 December Rosenstock et al. Diabetes Care 2012;35:1473–8. Back

Body weight mean change from baseline (kg)†
Dapagliflozin: Short-term (Week 24) body weight change from baseline in Phase III trials Study PBO + SITA ± MET PBO PBO + MET GLP + MET PBO + GLM PBO + PIO PBO + INS PBO + SU + MET Add-on INS1,2 Mono- therapy1,2 Add-on MET1,2 Add-on MET vs GLP1 Add-on GLM1,2 Add-on PIO3 Add-on SU + MET1 Add-on SITA ± MET1 Comparator Body weight mean change from baseline (kg)† * * * * * * * (Week 52 data) Abbreviations BL, baseline; BW, body weight; GLM, glimepiride; GLP, glipizide; INS, insulin; MET, metformin; PBO, placebo; PIO, pioglitazone; SITA, sitagliptin; SU, sulphonylurea. Reference Forxiga 5 mg and 10 mg film-coated tablets [SmPC]. Bristol-Myers Squibb/AstraZeneca EEIG, 18 December Accessed: February 2014. n BL BW (kg) 75 70 137 135 401 400 145 151 108 224 223 139 140 193 194 88.8 94.2 87.7 86.3 87.6 88.4 80.9 80.6 90.1 88.6 89.2 91.0 86.4 84.8 94.5 *p < vs placebo. †Least-squares mean adjusted for baseline value. 1. Forxiga 5-mg and 10-mg film-coated tablets [SPC]. Bristol-Myers Squibb/AstraZeneca EEIG, 18 December Whaley et al. Diabetes Metab Syndr Obes 2012;5:135– Rosenstock et al. Diabetes Care 2012;35:1473–8 . Back

Dapagliflozin: Short-term (Week 24) SBP change from baseline in Phase III trials
Study PBO + SITA ± MET PBO PBO + MET GLP + MET PBO + GLM PBO + PIO PBO + INS PBO + SU + MET Add-on INS7 Mono- therapy1 Add-on MET2 Add-on MET vs GLP3 Add-on GLM4 Add-on PIO6 Add-on SU + MET Add-on SITA ± MET5 Comparator NA NA n Week 8 in patients with SBP ≥ 130 mmHg at baseline SBP mean change from baseline (mmHg)* Abbreviations BL, baseline; GLM, glimepiride; GLP, glipizide; INS, insulin; MET, metformin; NA, data not available; PBO, placebo; PIO, pioglitazone; SBP, systolic blood pressure; SITA, sitagliptin; SU, sulphonylurea. n BL SBP (mmHg) 75 70 119 122 401 400 145 151 108 111 101 139 140 193 194 NA 128 126 134 133 132 141 136 *Least-squares mean adjusted for baseline value. 1. Ferrannini et al. Diabetes Care 2010;33:2217– Bailey et al. Lancet 2010;375:2223– Nauck et al. Diabetes Care 2011;34:2015– Strojek et al. Diabetes Obes Metab 2011;13:928– Jabbour et al. Diabetes Care 2014;37:740– Rosenstock et al. Diabetes Care 2012;35:1473–8. 7. Wilding et al. Ann Intern Med 2012;156:405–15. Back

Dapagliflozin lipid profile (24-week data, SPC)
Abbreviations HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SPC, Summary of Product Characteristics. Reference Forxiga® 10 mg film-coated tablets [SPC]. AstraZeneca UK Limited. Accessed June 2015. LDL-C HDL-C Triglycerides Total cholesterol Forxiga® 10-mg film-coated tablets [SPC]. AstraZeneca UK Limited Back

Dapagliflozin: Pooled safety analysis from 12 placebo-controlled trials (12–24 weeks)1,2
Overall incidence of AEs with dapagliflozin 10 mg was similar to placebo Few AEs led to treatment discontinuation and were balanced across groups Most commonly reported events leading to discontinuation with dapagliflozin 10 mg: increased blood creatinine (0.4%), UTIs (0.3%), nausea (0.2%), dizziness (0.2%) and rash (0.2%)1 Common AEs2 Placebo (n = 1393) Dapagliflozin 5 mg (n = 1145) Dapagliflozin 10 mg (n = 1193) Genital mycotic infections Female* 1.5 8.4 6.9 Male† 0.3 2.8 2.7 Nasopharyngitis 6.2 6.6 6.3 UTI‡ 3.7 5.7 4.3 Back pain 3.2 3.1 4.2 Increased urination§ 1.7 2.9 3.8 Nausea 2.4 2.5 Influenza 2.3 Dyslipidaemia 2.1 Constipation 2.2 1.9 Discomfort with urination 0.7 1.6 Pain in extremity 1.4 2.0 Volume depletion¶ 0.4 0.6 0.8 Footnotes *Female genital mycotic infections include vulvovaginal mycotic infection, vaginal infection, vulvovaginal candidiasis, vulvovaginitis, genital infection, genital candidiasis, fungal genital infection, vulvitis, genitourinary tract infection, vulval abscess and vaginitis bacterial. (Females: Placebo, n = 677; Dapa 5 mg, n = 581; Dapa 10 mg, n = 598). †Male genital mycotic infections include balanitis, fungal genital infection, balanitis candida, genital candidiasis, genital infection male, penile infection, balanoposthitis, balanoposthitis infective, genital infection and posthitis. (Males: Placebo, n = 716; Dapa 5 mg, n = 564; Dapa 10 mg, n = 595). ‡UTIs include cystitis, Escherichia UTI, genitourinary tract infection, pyelonephritis, trigonitis, urethritis, kidney infection and prostatitis. §Increased urination includes pollakiuria, polyuria and urine output increased. ¶Volume depletion includes reports of dehydration, hypovolaemia, orthostatic hypotension or hypotension. Abbreviations AE, adverse event; Dapa, dapagliflozin; UTI, urinary tract infection. See notes for Footnotes. 1. Forxiga 5-mg and 10-mg film-coated tablets [SPC]. Bristol-Myers Squibb/AstraZeneca EEIG, 18 December Accessed: February Forxiga (dapagliflozin) tablets. US Prescribing Information; BMS/AstraZeneca, January 2014. Back

Canagliflozin: HbA1c change from baseline in Phase III trials
Weeks Add-on MET + SU vs SITA 52 Mono- therapy 26 Add-on MET Add-on SU 18 Add-on MET + SU Add-on MET vs GLM Add-on MET + PIO 26 Add-on INS1 Placebo-controlled PBO + INS PBO PBO + MET PBO + SU PBO + SU + MET GLM + MET SITA + MET + SU PBO + MET + PIO Comparator Active-controlled HbA1c mean change from baseline (%)† * * * * * * * * * * Abbreviations BL, baseline; GLM, glimepiride; HbA1c, glycosylated haemoglobin; INS, insulin; MET, metformin; PBO, placebo; PIO, pioglitazone; SITA, sitagliptin; SU, sulphonylurea. * * * * n BL HbA1c (%) 192 195 197 183 368 367 45 42 40 156 157 156 115 113 114 565 566 587 482 483 485 378 377 7.97 8.06 8.01 7.96 7.94 7.95 8.49 8.29 8.28 8.12 8.13 8.13 8.00 7.99 7.84 8.20 8.33 8.27 7.83 7.78 7.79 8.13 8.12 *p < vs comparator. †Least-squares mean adjusted for baseline value. Invokana (canagliflozin) tablets Prescribing Information. Janssen Pharmaceuticals, Inc., March 2013. Back

Canagliflozin: Body weight change from baseline in Phase III trials
Weeks Placebo-controlled Add-on INS 18 PBO + INS Mono- therapy 26 PBO Add-on MET PBO +MET Add-on MET + SU PBO + SU + MET Add-on MET + PIO PBO + MET + PIO Add-on MET vs GLM 52 GLM + MET Add-on MET + SU vs SITA SITA + MET + SU Comparator Active-controlled Body weight mean change from baseline (kg)† * * * * * * * * * * Abbreviations BL, baseline; BW, body weight; GLM, glimepiride; INS, insulin; MET, metformin; PBO, placebo; PIO, pioglitazone; SITA, sitagliptin; SU, sulphonylurea. * * * n BL BW (kg) 192 195 197 183 368 367 156 157 115 113 114 565 566 587 482 483 485 378 377 87.5 85.9 86.9 86.7 88.7 85.4 90.8 93.5 94.0 94.2 94.4 97.7 96.9 96.7 86.6 86.8 89.6 87.6 Back *p < vs comparator. †Least-squares mean adjusted for baseline value. Invokana (canagliflozin) tablets Prescribing Information. Janssen Pharmaceuticals, Inc., March 2013.

SBP mean difference from comparator (mmHg)†
Canagliflozin: SBP change from baseline vs comparator in Phase III trials Weeks Placebo-controlled Add-on INS2 18 PBO + INS Mono- therapy1 26 PBO Add-on MET2 PBO +MET Add-on MET + SU PBO + SU + MET Add-on MET + PIO2 PBO + MET + PIO Add-on MET vs GLM 52 GLM + MET Add-on MET + SU vs SITA3 SITA + MET + SU Comparator Active-controlled NA NA ** SBP mean difference from comparator (mmHg)† * ** * ** ** ** ** Abbreviations BL, baseline; GLM, glimepiride; INS, insulin; MET, metformin; NA, data not available; PBO, placebo; PIO, pioglitazone; SBP, systolic blood pressure; SITA, sitagliptin; SU, sulphonylurea. ** n BL SBP (mmHg) 192 195 368 367 113 114 566 587 375 127 129 NA 131 *p < 0.05, **p < vs comparator. †Least-squares mean adjusted for baseline value. 1. Stenlof et al. Diabetes Obes Metab 2013;15:372– Invokana (canagliflozin) tablets Prescribing Information. Janssen Pharmaceuticals, Inc., March Schernthaner et al. Diabetes Care 2013;36:2508–15. Back

Canagliflozin lipid profile (pivotal studies, SPC)
Abbreviations HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SPC, Summary of Product Characteristics. Reference Invokana® 100 mg and 300 mg film-coated tablets [SmPC]. Janssen-Cilag Ltd. Accessed June 2015. LDL-C HDL-C Triglycerides Total cholesterol Invokana® 100-mg and 300-mg film-coated tablets [SPC]. Janssen-Cilag Ltd Back

Canagliflozin: General safety profile Pooled analysis from 4 placebo-controlled trials* at 26 weeks
Adverse reactions occurring in ≥ 2% of canagliflozin-treated patients (%) Placebo (n = 646) Canagliflozin 100 mg (n = 833) Canagliflozin 300 mg (n = 834) Genital infections Male† 0.6 4.2 3.7 Female‡ 3.2 10.4 11.4 Urinary tract infection§ 4.0 5.9 4.3 Volume depletion¶ 1.5 2.3 3.4 Thirst# 0.2 2.8 Constipation 0.9 1.8 Vulvovaginal pruritis 0.0 1.6 3.0 Increased urination** 0.8 5.3 4.6 Abdominal pain also more commonly reported in patients taking canagliflozin 100 mg (1.8%) and mg (1.7%) than in patients taking placebo (0.8%) Footnotes *One monotherapy trial and 3 add-on combination trials with metformin, metformin + sulphonylurea or metformin + pioglitazone. †Male genital mycotic infections include the following adverse reactions: balanitis or balanoposthitis, balanitis candida and genital infection fungal. Percentages calculated with the number of male subjects in each group as denominator: placebo (n = 334), canagliflozin 100 mg (n = 408) and canagliflozin 300 mg (n = 404). ‡Female genital mycotic infections include vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis, vaginal infection, vulvitis and genital infection fungal. Percentages calculated with the number of female subjects in each group as denominator: placebo (n = 312), canagliflozin 100 mg (n = 425) and canagliflozin 300 mg (n = 430). §UTIs include urinary tract infection, cystitis, kidney infection and urosepsis. ¶Pooled results from 8 clinical trials: comparators, n = 3262; 100 mg dose, n = 3092; 300 mg dose, n = 3085; includes hypotension, postural dizziness, orthostatic hypotension, syncope and dehydration. #Thirst includes the following adverse reactions: thirst, dry mouth and polydipsia. **Increased urination includes polyuria, pollakiuria, urine output increased, micturition urgency and nocturia. Back See notes for Footnotes. Invokana (canagliflozin) tablets Prescribing Information. Janssen Pharmaceuticals, Inc. , March 2013.

EDUCATIONAL SLIDE MODULES Module D: Evaluating CV safety and potential for CV risk reduction with newer T2D agents.

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EDUCATIONAL SLIDE MODULES Module D: Evaluating CV safety and potential for CV risk reduction with newer T2D agents.

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