Cardiovascular safety of new drugs for the treatment of obesity and diabetes. Κyros Siomos MD PhD Internal Medicine- Diabetes

Cardiovascular safety of new drugs for the treatment of obesity and diabetes Κyros Siomos MD PhD Internal Medicine- Diabetes

Διαβητολογικο Κεντρο Ιπποκράτειο Νοσοκομειο UGDP 1970 DIABETES 19(SUPPL 2):789,1970

Rosiglitazone

Απαιτήσεις του FDA για μελέτες καρδιαγγειακών εκβάσεων για νέους αντιδιαβητικούς παράγοντες Οι κατευθυντήριες οδηγίες του FDA του 2008 ανέβασαν ουσιαστικά το κατώφλι έγκρισης των αντιδιαβητικών φαρμάκων από την τεκμηρίωση της μείωσης της γλυκόζης στην ισχυρή αξιολόγηση της καρδιαγγειακής ασφάλειας Εκτίμηση κινδύουν CV σε δεδομένα φάσης 2/3 για όλες τις αντιδιαβητικές θεραπείες που διατίθενται στην αγορά και που πρόκειται να διατεθούν: απαιτούμενο ανώτατο όριο του αμφίπλευρου 95% (CI) για τον εκτιμώμενο λόγο κινδύνου >1.8: τα δεδομένα δεν επαρκούν για την έγκριση; πρέπει να διεξαχθεί μία μεγάλη δοκιμή ασφαλείας 1.3 1.8: ενδέχεται να υπάρχει η πιθανότητα καρδιαγγειακής βλάβης. Είναι απαραίτητη μία μελέτη με επαρκή στατιστική ισχύ μετά τη διάθεση στην αγορά για να δείξει ένα ανώτατο όριο <1.3 <1.3: μία συνολική ανάλυση κινδύνου-οφέλους στηρίζει την εγκριση. Δεν είναι γενικά απαραίτητη η μελέτη μετά τη διάθεση στην αγορά Οδηγία του FDA για τη Βιομηχανία. Σακχαρώσης διαβήτης αξιολόγηση καρδιαγγειακού κινδύνου στις νέες αντιδιαβητικές θεραπείες του διαβήτη τύπου 2. Διαθέσιμο από: www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf [Accessed Jan 2014]

Timeline of Major Diabetes Outcomes Trials 1995 2000 2005 2010 2015 FDA CVOT Guidance 2008 Blue = Intensive vs standard control using same set of glucose-lowering agent(s) Purple = Intensive control with a specific agent vs standard care Red = Placebo- or active-controlled study * = FDA-mandated cardiovascular safety trial ACCORD, Action to Control Cardiovascular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation; CANVAS, Canagliflozin Cardiovascular Assessment Study; DCCT, Diabetes Control and Complications Trial; DEVOTE, Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; EMPA-REG, EMPA-REG OUTCOME trial; Exenatide Study of Cardiovascular Event Lowering; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; ORIGIN, Outcome Reduction with an Initial Glargine Intervention; PROActive, Prospective Pioglitazone Clinical Trial in Macrovascular Events; RECORD, Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes; SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus Thrombolysis in Myocardial Infarction; STOP-NIDDM, Study to Prevent Non-Insulin-Dependent Diabetes Mellitus; SUSTAIN, Trial to Evaluate Cardiovascular and Other Long-Term Outcomes with Semaglutide in Subjects with Type 2 Diabetes; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin; UKPDS, United Kingdom Prospective Diabetes Study; VADT, Veterans Affairs Diabetes Trial. 7

Αντικρουόμενη τεκμηρίωση ως προς τα οφέλη του γλυκαιμικού ελέγχου στην ελάττωση του μακροαγγειακού κινδύνου Μείωση κινδύνου (%) Μελέτη UKPDS 1 ACCORD 2 ADVANCE 3 VADT 4 Αρχική δοκιμή Μικροαγγειακό CVD Θνησιμότητα 10-ετη παρακολούθηση 5 0-5 -10-15 -20 Οι επιδράσεις της εντατικής μείωσης της γλυκόζης στις εκβάσεις CV και στη θνησιμότητα: μεταανάλυση των Τυχαιοποιημένων Κλινικών Μελετών Μη μοιραίο ΟΕΜ CHD Θνησιμότητα πάσης αιτιολογίας Εγκεφαλικό επεισόδιο 0,2% *UKPDS, PROactive, ADVANCE, VADT, ACCORD ACCORD = Δράση προς Ρύθμιση του Καρδιαγγειακού Κινδύνου στο Σακχαρώδη Διαβήτη; ADVANCE = Δράση στον Σακχαρώδη Διαβήτη και την Καρδιαγγειακή Νόσο: Ελεγχόμενη Αξιολόγηση Preterax και Diamicron MR, CHD = στεφανιαία νόσος, CI= διάστημα εμπιστοσύνης; CVD = καρδιαγγειακή νόσος; MI = έμφραγμα μυοκαρδίου; OR = ανάλυση λόγου πιθανοτήτων; PROactive = PROspective pioglitazone Κλινική Μελέτη σε μακρο-αγγειακά συμβάντα ; UKPDS = Προοπτική Μελέτη για τον διαβήτη του ΗΒ; VADT = Veterans Affairs Diabetes Trial -17% OR 0.83 (95% CI: 0.75 0.93) * (33,040 patients) 5-15% OR 0.85 (95% CI: 0,77-0,93-7% OR 0.93 (95% CI: 0.81 1.06) OR 1.02 (95% CI: 0.87 1.19) 1.Holman RR et al. N Engl J Med. 2008;359:1577 89. 2 ACCORD Study Group. N Engl J Med. 2008;358:2545 59. 3 ADVANCE Study Group. N Engl J Med. 2008;358:2560 72. 4.Duckworth W et al. N Engl J Med. 2009;360:129 39. 5 Ray KK et al. Lancet. 2009; 373:1765 72

Αριθμός καρδιαγγειακών συμβάντων που έχουν προληφθεί Απαιτούνται πολλαπλές παρεμβάσεις οι οποίες να περιλαμβάνουν τη διαχείριση της πίεσης του αίματος και των λιπιδίων για αποτελεσματική μείωση του καρδιοαγγειακού κινδύνου Οφέλη διαφορετικών παρεμβάσεων ανά 200 διαβητικούς ασθενείς σε θεραπεία για 5 χρόνια 0 Ανά 4mmHg χαμηλότερη ΣΑΠ Ανά 1mmol/L χαμηλότερη LDL- C Ανά 0.9% χαμηλότερη HbA1c -2-4 -2.9-6 -8-10 -8.2-12 -12.5-14 *Περιλαμβάνεται το μη μοιραίο έμφραγμα του μυοκαρδίου, η στεφανιαία νόσος, το εγκεφαλικό επεισόδιο και η θνησιμότητα πάσης αιτιολογίας Ray KK et al. Lancet. 2009;373:1765 1772

Αντικρουόμενη τεκμηρίωση ως προς τα οφέλη του γλυκαιμικού ελέγχου στην ελάττωση του μακροαγγειακού κινδύνου Αθροιστική επίπτωση (%) Αθροιστική επίπτωση (%) UKPDS 1 : Οφέλη από τη μείωση της HbA1c κατά 1% Μικρο-αγγειακή νόσος 36% Έμφραγμα του μυοκαρδίου 14% Μείζονα καρδιαγγειακά συμβάντα Αρθ. σε Εντατικός κίνδυνο Τυπικός ADVANCE 2 : Εντατικός γλυκαιμικός έλεγχος σε ασθενείς με προχωρημένο διαβήτη τύπου 2 25 20 15 10 5 P=0,32 Τυπικός έλεγχος Εντατικός έλεγχος 0 0 6 12 18 24 30 36 42 48 54 60 66 Μήνες παρακολούθησης 5570 5569 5494 5428 5338 5256 5176 5097 5486 5413 5330 5237 5163 5084 5005 4927 4396 2071 486 4995 4922 4385 2108 509 P<0,001 Μείζονα μικροαγγειακά συμβάντα Αρθ. σε Εντατικός κίνδυνο Τυπικός 25 20 15 10 5 P=0,01 Τυπικός έλεγχος Εντατικός έλεγχος 0 0 6 12 18 24 30 36 42 48 54 60 66 Μήνες παρακολούθησης 5571 5569 5495 5430 5358 5233 5120 5055 5498 5431 5353 5207 5069 4995 4968 4824 4258 1992 473 4911 4764 4204 2024 494 1 Stratton IM et al. BMJ. 2000;321:405 12. 2. ADVANCE Study Group. N Engl J Med. 2008;358:2560 72.

Metformin και καρδιαγγειακές εκβάσεις: Οι RCTs Μελέτες UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854 865 Kooy A et al Arch Intern Med 2009;169:616 625 Hong J et al Diabetes Care 2013;36:1304 1311

Proportion of patients with events (%) HR (95% CI) UKPDS 34 provides some evidence for beneficial CV effects of metformin in overweight patients Risk of MI is 39% lower with metformin vs conventional therapy in obese patients 1,2 Significant reduction in MI maintained over 10 years follow-up 3 30 20 10 Myocardial infarction Conventional (n = 411; events = 73) Intensive (n = 951; events = 139) Metformin (n = 342; events = 39) Metformin vs conventional p = 0.01 Overall values at study end in 1997 Annual values during 10-year post-trial monitoring period 1.4 1.2 1.0 0.8 0.6 RR 0.61 1 p = 0.01 RR 0.67 p = 0.005 0.0 0 3 6 9 12 15 Time from randomisation (years) 0.4 1997 1999 2001 2003 2005 2007 No. of events: Conventional therapy 73 83 92 106 118 126 Metformin 39 45 55 64 68 81 1. UKPDS 34. Lancet 1998;352:854 65. 2. http://www.medicines.org.uk/emc/medicine/23244/spc. 3. Holman et al. N Engl J Med 2008;359:1577 89. 13

UKPDS 34: CV effects of metformin added to SU Metformin added to SU vs SU alone was associated with increased risk of diabetes-related death and all-cause mortality *Interpret with caution in view of small event numbers. UKPDS 34. Lancet 1998;352:854 65. Median follow up 6.6 years RR p-value Any diabetes related endpoint 1.04 0.78 Diabetes-related deaths* 1.96 0.039 All-cause mortality* 1.60 0.041 Myocardial infarction* 1.09 0.73 Stroke* 1.21 0.61 Microvascular* 0.84 0.62 Relative risk (95% CI) 0.5 1.0 5 Favours added metformin Favours SU alone 14

Μελέτες νοσηρότητας θνησιμότητας σε διαβητικούς υψηλού κινδύνου Μελέτη ACCORD n=10 251 VADT n=1 791 ADVANCE n=11 140 Στόχοι HbA1c (εντατική έναντι τυπικής ρύθμισης) 6,4% vs 7,5% 6,9% vs 8,4% 6,5% vs 7,3% Αγωγές ομάδας εντατικής ρύθμισης Γλιμεπιρίδη Μετφορμίνη TZD Ινσουλίνη 78% 95% 91% 77% Γλιμεπιρίδη Μετφορμίνη TZD Ινσουλίνη 53% 60% 37% 67% Γλικλαζίδη MR Μετφορμίνη TZD Ινσουλίνη 91% 74% 17% 40% Πρωτεύον τελικό σημείο (σύνθετο κ/α) -10% P=0,16-13% P=0,12-6% P=0,12 κ/α θνησιμότητα +39% P=0,02 +25% P=NS -12% P=0,12 Θνησιμότητα κάθε αιτιολογίας +22% P=0,04 +6.5% P=NS -7% P=0,28 Νεφρική Ανεπάρκεια Τελικού Σταδίου -9% P=NS -36% P=NS -65% P=0,017 ACCORD Study Group. N Engl J Med. 2008;358:2545-2559. VADT Investigators. N Engl J Med. 2009;360:129-139 ADVANCE Collaborative group. N Engl J Med. 2008;358(24):2560-2572

Patients with MI (%) No deleterious CV effect of SUs vs insulin or conventional therapy observed in UKPDS 33 1 0.4 0.3 Conventional (896) Chlorpropamide (619) Glibenclamide (615) Insulin (911) 0.2 0.1 0.0 Conventional vs glibenclamide vs insulin p = 0.66 0 3 6 9 12 15 Years from randomisation In addition, in the ADVANCE study, intensive glucose control involving gliclazide was not associated with deleterious CV effects 2 1. UKPDS33. Lancet 1998;352:837 53. 2. Patel et al. N Engl J Med 2008;358:2560 72. 16

Meta-analysis of SU CV safety trials ( 6 months) found no consistent association with MACE risk 1 First author (year) Birkeland 1996 Chou 2008 Perriello 2006 Gerstein 2010 UKPDS 33 1998 Hanefeld 2007 Seino 2010 Charbonnel 2005 Matthews 2005 Rubin 2008 Home 2009 Arechavaleta 2011 va der Laar 2004 Mazzone 2006 Riddle 1998 Giles 2010 Tolman 2009 Kahn 2006 Goke 2010 Garber 2009 Nissen 2008 Ristic 2007 Ferrannini 2009 Bakris 2006 Gallwitz 2012 Jain 2006 Johnston 1998 Nauck 2011 Seck 2010 Overall 1. Monami et al. Diabetes Obes Metab 2013;15:938 53. 0.01 0.1 1 10 100 Favours SUs MH-OR (95% CI) Favours comparators Total # patients* Total # events* 36 1 452 3 283 9 672 55 3041 610 587 4 400 4 630 14 1250 15 1805 46 2222 312 1035 4 96 2 458 4 145 2 300 26 2097 61 4351 72 858 13 495 13 543 24 262 5 2789 34 374 11 1551 38 502 11 272 4 801 3 1172 4 29,783 1495 Overall MACE risk estimate: MH-OR 1.08 (95% CI: 0.86 1.36); p = 0.52 1 Mortality was significantly increased with sulphonylureas (MH-OR: 1.22 [1.01 1.49], p=0.047) 17 *SU + comparator groups combined.

Pioglitazone: PROactive trial design Aim Drug-specific trial to determine the impact of pioglitazone on macrovascular morbidity and mortality in high-risk patients with T2D Main inclusion criteria 1. Patients with T2D and evidence of macrovascular disease 2. Age 35 75 years 3. HbA 1c > 6.5% With or without background therapy Pioglitazone versus Placebo N = 5238; average follow-up 34.5 months Primary endpoint: time to first occurrence of all-cause mortality, non-fatal MI, stroke, ACS, endovascular/surgical intervention in coronary/leg arteries, amputation above ankle Secondary endpoint: time to first occurrence of all-cause mortality, non-fatal MI, stroke Statistical analysis 760 patients with 1 endpoint event Last patient recruited followed up for 30 months Dormandy et al. Lancet 2005;366:1279 89. 18

Proportion of events (%) Proportion of events (%) PROactive: Pioglitazone was superior to placebo for main secondary endpoint, but not for primary endpoint Time to primary endpoint* Time to all-cause mortality, non-fatal MI, stroke 25 20 Pioglitazone (514 events) Placebo (572 events) 25 20 Pioglitazone (301 events) Placebo (358 events) 15 15 10 10 5 5 0 0 6 12 18 24 30 36 Time from randomisation (months) HR 0.90 (95% CI: 0.80 1.02) p = 0.095 0 0 6 12 18 24 30 36 Time from randomisation (months) HR 0.84 (95% CI: 0.72 0.98) p = 0.027 Hospitalisation for Heart Failure: 6% (149 of 2605) in pioglitazone vs 4% (108 of 2633) in placebo; p = 0.007 *Death from any cause, non-fatal MI (including silent MI), stroke, acute coronary syndrome, leg amputation, coronary revascularisation or revascularisation of the leg. Dormandy et al. Lancet 2005;366:1279 89. 19

Numerous Studies Assessing CV Outcomes in T2DM Drugs Are Either Recently Completed or Ongoing Trial Name Drug Target Enrollment Timing* DPP-4 Inhibitors SAVOR Saxagliptin N=16,492 Began 2010; Complete EXAMINE Alogliptin N=5384 Began 2009; Complete TECOS Sitagliptin N=14,000 Began 2008; Ending 2014 CAROLINA Linagliptin N=6000 Began 2010; Ending 2018 CARMELINA Linagliptin N=8300 Began 2013; Ending 2018 GLP-1 Agonists ELIXA Lixisenatide N=6000 Began 2010; Ending 2014 EXSCEL Exenatide N=9500 Began 2010; Ending 2017 LEADER Liraglutide N=9340 Began 2010; Ending 2016 REWIND Dulaglutide N=9622 Began 2011; Ending 2019 SUSTAIN 6 Semaglutide N=3260 Began 2013; Ending 2016 SGLT-2 Inhibitors CANVAS C-SCADE 8 DECLARE Canagliflozin Empagliflozin Dapagliflozin N=4410 N=7000 N=17,150 Began 2009; Ending 2018 Began 2010; Ending 2018 Began 2013; Ending 2019 *Trial ending dates are anticipated based on publicly available information. Clinicaltrials.gov; Accessed on Aug 12,2013. 2 0

Clinical Outcomes with Antihyperglycemic Agents TECOS (TRIAL EVALUATING CARDIOVASCULAR OUTCOMES WITH SITAGLIPTIN) 21

Clinical Outcomes with Sitagliptin TECOS Study Design N=14,671 patients with T2D and CVD Randomization Sitagliptin: n=7332 (6972 completed) Placebo: n=7339 (6905 completed) Noninferiority study: 1.3 marginal upper boundary of 2-sided 95% CI Primary composite outcome: cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina Secondary composite outcome: cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Key Results Median follow-up: 3.0 years Least squares mean difference in A1C: - 0.29% (95% CI -0.32 to -0.27) for sitagliptin vs placebo Noninferior to placebo for cardiovascular outcomes Primary HR: 0.98 (0.88-1.09); P<0.001 Secondary HR: 0.99 (0.89-1.11); P<0.001 No difference between sitagliptin and placebo in incidence of infections, cancer, renal failure, hypoglycemia, or noncardiovascular death CI, confidence interval; HR, hazard ratio; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin. Green JB, et al. N Engl J Med. 2015;373:232-242. 22

Primary and Secondary Outcomes with Sitagliptin TECOS Per Protocol Analysis (n=14,523) Median follow-up: 3.0 years Hazard ratio (95% CI) P value Primary composite endpoint* 0.98 (0.88-1.09) <0.001 (NF) Secondary composite endpoint 0.99 (0.89-1.11) <0.001 (NF) Acute pancreatitis 1.80 (0.86-3.76) 0.12 Any cancer (except nonmelanoma skin cancer) 0.93 (0.89-1.44) 0.38 Pancreatic cancer 0.91 (0.37-2.25) 0.85 Severe hypoglycemia 1.13 (0.89-1.44) 0.31 0.00 1.00 2.00 3.00 4.00 Favors sitagliptin *Cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. Secondary composite: cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. NF, noninferiority; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin. Green JB, et al. N Engl J Med. 2015;373:232-242. 23

Individual Secondary Outcomes with Sitagliptin TECOS Intent to Treat Analysis (n=14,671) Median follow-up: 3.0 years Hazard ratio (95% CI) P value CV death 1.03 (0.89-1.19) 0.71 Hospitalization for unstable angina 0.90 (0.70-1.16) 0.42 Fatal or nonfatal MI 0.95 (0.81-1.11) 0.49 Fatal or nonfatal stroke 0.97 (0.79-1.19) 0.76 Death from any cause 1.01 (0.90-1.14) 0.88 Hospitalization for heart failure 1.09 (0.83-1.20) 0.98 Hospitalization for heart failure or CV death 1.02 (0.90-1.15) 0.74 0.50 1.00 1.50 CV, cardiovascular; MI, myocardial infarction; NF, noninferiority; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin. Green JB, et al. N Engl J Med. 2015;373:232-242. Favors sitagliptin 24

Clinical Outcomes with Sitagliptin TECOS (n=14,671) TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin. Green JB, et al. N Engl J Med. 2015;373:232-242. 25

Clinical Outcomes with Antihyperglycemic Agents EXAMINE (EXAMINATION OF CARDIOVASCULAR OUTCOMES WITH ALOGLIPTIN VERSUS STANDARD OF CARE) 26

Clinical Outcomes with Alogliptin EXAMINE Study Design N=5380 patients with T2D and ACS Randomization Alogliptin: n=2701 Placebo: n=2679 Noninferiority study: prespecified HR margin = 1.3 for primary endpoint Primary composite endpoint: CV death, nonfatal MI, or nonfatal stroke Secondary: CV death, nonfatal MI, nonfatal stroke, urgent revascularization for unstable angina Key Results Median follow-up: 18 months Least squares mean difference in A1C: - 0.36% (95% CI -0.43 to -0.28; P<0.001) for alogliptin vs placebo CV outcomes Primary HR: 0.96 ( 1.16); P=0.32 Secondary HR: 0.95 ( 1.14*); P=0.26 No difference between alogliptin and placebo in incidence of acute and chronic pancreatitis, cancer, renal impairment, angioedema, or severe hypoglycemia *Upper boundary of 1-sided repeated CI, alpha level 0.01. CI, confidence interval; CV, cardiovascular; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care; HR, hazard ratio; MI, myocardial infarction. White W, et al. N Engl J Med. 2013;369:1327-1335. 27

Clinical Outcomes with Alogliptin Hazard ratio (95% CI) P value Primary composite 0.96 ( 1.16)* 0.32 Primary endpoint components EXAMINE Safety Endpoints (n=5380) Median follow-up: 18 months CV death 0.79 (0.6-1.04) 0.10 Nonfatal MI 1.08 (0.88-1.33) 0.47 Nonfatal stroke 0.91 (0.55-1.50) 0.71 Primary secondary endpoint 0.95 ( 1.14)* 0.26 Death from any cause 0.85 (0.66-1.10) 0.21 0.00 0.50 1.00 1.50 2.00 Favors alogliptin *Upper boundary of 1-sided repeated CI, alpha level 0.01. CV death, nonfatal MI, nonfatal stroke, urgent revascularization for unstable angina. CI, confidence interval; CV, cardiovascular; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care; MI, myocardial infarction. White W, et al. N Engl J Med. 2013;369:1327-1335. 28

Alogliptin CV Outcomes and Mortality EXAMINE CV Death, Nonfatal MI, or Nonfatal Stroke CV Death All-Cause Death EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care. White W, et al. N Engl J Med. 2013;369:1327-1335. 29

Clinical Outcomes with Antihyperglycemic Agents SAVOR-TIMI (SAXAGLIPTIN ASSESSMENT OF VASCULAR OUTCOMES RECORDED IN PATIENTS WITH DIABETES MELLITUS THROMBOLYSIS IN MYOCARDIAL INFARCTION) 30

Clinical Outcomes with Saxagliptin SAVOR-TIMI Study Design N=16,492 patients with T2D and CVD or CVD risk Randomization Saxagliptin: n=8280 Placebo: n=8212 Superiority study with provision to test for noninferiority Primary composite endpoint: CV death, nonfatal MI, or nonfatal ischemic stroke Secondary: CV death, nonfatal MI, nonfatal ischemic stroke, hospitalization for HF, coronary revascularization, or unstable angina Key Results Median follow-up: 2.1 years Endpoint A1C Saxagliptin: 7.7% ± 1.4% (P<0.001 vs placebo) Placebo: 7.9% ± 1.5% CV outcomes Primary HR: 1.00 (0.89-1.27); P=0.99 Secondary HR: 1.02 (0.94-1.11); P=0.66 Higher incidence of HF hospitalization in saxagliptin group No difference between groups in incidence of acute or chronic pancreatitis; fewer cases of pancreatic cancer in saxagliptin group; more cases of nonfatal angioedema in saxagliptin group (8 vs 1) CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction; SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus Thrombolysis in Myocardial Infarction. Scirica BM, et al. N Engl J Med. 2013;369,1317-1326. 31

Clinical Outcomes with Saxagliptin SAVOR-TIMI Prespecified Composite Endpoints and Mortality (n=16,492) Median follow-up: 2.1 years Hazard ratio (95% CI) P value Primary composite endpoint* 1.00 (0.89-1.27) 0.99 Secondary composite endpoint 1.02 (0.94-1.11) 0.66 Death from any cause 1.11 (0.96-1.27) 0.15 CV death 1.03 (0.87-1.22) 0.52 0.50 1.00 1.50 Favors saxagliptin *CV death, nonfatal MI, or nonfatal ischemic stroke; CV death, nonfatal MI, nonfatal ischemic stroke, hospitalization for HF, coronary revascularization, or unstable angina. CI, confidence interval; CV, cardiovascular; HF, heart failure; MI, myocardial infarction; SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus Thrombolysis in Myocardial Infarction. Scirica BM, et al. N Engl J Med. 2013;369,1317-1326. 32

Individual Secondary Outcomes with Saxagliptin SAVOR-TIMI Prespecified Individual Endpoints (n=16,492) Median follow-up: 2.1 years Hazard ratio (95% CI) P value Myocardial infarction 0.95 (0.80-1.12) 0.52 Ischemic stroke 1.11 (0.80-1.12) 0.38 Hospitalization for unstable angina 1.19 (0.89-1.60) 0.24 Hospitalization for heart failure 1.27 (1.07-1.51) 0.007 Hospitalization for coronary revascularization 0.91 (0.80-1.04) 0.18 Renal endpoint* 1.08 (0.88-1.32) 0.46 Hospitalization for hypoglycemia 1.22 (0.82-1.83) 0.33 0.00 0.50 1.00 1.50 2.00 Favors saxagliptin *Doubling of creatinine, initiation of dialysis, renal transplantation, or creatinine >6.0 mg/dl CI, confidence interval; CV, cardiovascular; SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus Thrombolysis in Myocardial Infarction. Scirica BM, et al. N Engl J Med. 2013;369,1317-1326. 33

Baseline Characteristics and Risk of HF Hospitalization With Saxagliptin SAVOR-TIMI Post-hoc Analysis (n=16,492) Hazard ratio (95% CI) P value egfr 60 ml/min 1.36 (1.07-1.71) 0.03 egfr >60 ml/min 1.16 (0.89-1.51) 0.27 No prior heart failure 1.30 (1.03-1.65) 0.03 Prior heart failure 1.23 (0.94-1.59) 0.13 No risk factors* 1.15 (0.81-1.63) 0.03 1 risk factor 1.35 (1.06-1.72) 0.02 2 risk factors 1.22 (0.86-1.73) 0.27 Q4 NT-proBNP (333-46,627 pg/ml) 1.31 (1.04-1.66) 0.02 *egfr 60 ml/min or history of previous HF. 0.00 1.00 2.00 3.00 HF, heart failure; NT-proBNP, N-terminal pro B-type natriuretic peptide; Q, quartile; SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus Thrombolysis in Myocardial Infarction. Scirica BM, et al. Circulation. 2014;130:1579-1588. Favors saxagliptin 34

Absolute risk difference* No. excess HHF events in patients treated with saxagliptin vs placebo per 1000 pt-y 2.5 2 1.5 1 0.5 0 Risk of HF Hospitalization with 0.3 Saxagliptin vs Placebo 1.5 egfr (ml/min) SAVOR-TIMI Post-hoc Analysis (n=16,492) 0.6 1.5 0.3 HF history No. HF risk factors NT-proBNP quartiles (pg/ml) (5-64) (65-141) (142-333) (334-46,647) n = 11637 4855 14387 2105 10418 5188 866 3076 3076 3076 3073 1.4 >60 60 No Yes 0 1 2 Q1 Q2 Q3 Q4 1 5 1 6 0 4 9 0 1 0 7 1.7 0.0 0.7 0.2 2.1 *Saxagliptin vs placebo. egfr 60 ml/min or history of previous HF. HF, heart failure; HHF, hospitalizations for heart failure. Scirica BM, et al. Circulation. 2014;130:1579-1588. 35

CAROLINA & CARMELINA: Linagliptin CV Safety studies CAROLINA (CArdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 diabetes) CARMELINA (CArdiovascular Safety & Renal Microvascular outcome study with LINAgliptin)

Clinical Outcomes with Antihyperglycemic Agents EMPA-REG OUTCOME (EMPAGLIFLOZIN CARDIOVASCULAR OUTCOME EVENT TRIAL IN TYPE 2 DIABETES MELLITUS PATIENTS) 37

Clinical Outcomes with Empagliflozin EMPA-REG OUTCOME Study Design N=7020 patients with T2D and CVD Randomization Empagliflozin: n=4687 Placebo: n=2333 Noninferiority study: prespecified HR margin = 1.3 for primary endpoint Primary endpoint: composite of CV death, nonfatal MI (excluding silent MI), or nonfatal stroke Secondary endpoint: composite of CV death, nonfatal MI (excluding silent MI), nonfatal stroke, and hospitalization for unstable angina Key Results Median follow-up: 3.1 years Week 206 A1C, difference from placebo Empagliflozin 10 mg: -0.24% (95% CI, -0.40% to - 0.08%) Empagliflozin 25 mg: -0.36% (95% CI, -0.51% to - 0.20%) CV outcomes (pooled analysis) Primary: HR 0.86 (95% CI 0.74 to 0.99); P=0.04 for superiority Secondary HR: 0.89 (95% CI 0.78 to 1.01); P<0.001 for noninferiority and P=0.08 for superiority Significantly lower rates of all-cause death, CV death, and HF hospitalization with empagliflozin Increased rates of genital infections in empagliflozin-treated patients CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction. Zinman B, et al. N Engl J Med. 2015;373:2117-2128. 38

Clinical Outcomes with Empagliflozin EMPA-REG OUTCOME Pooled Analysis (N=7020) Median follow-up: 3.1 years Hazard ratio (95% CI) P value Primary composite endpoint* 0.86 (0.74-0.99) 0.04 Secondary composite endpoint 0.89 (0.78-1.01) 0.08 Death from any cause 0.68 (0.57-0.82) <0.001 CV death 0.62 (0.49-0.77) <0.001 Fatal or nonfatal MI 0.87 (0.70-1.09) 0.23 Hospitalization for HF 0.65 (0.50-0.85) 0.002 Hospitalization for HF or CV death 0.66 (0.55-0.79) <0.001 0.00 0.50 1.00 1.50 Favors empagliflozin *CV death, nonfatal MI (excluding silent MI), or nonfatal stroke; CV death, nonfatal MI (excluding silent MI), nonfatal stroke, and hospitalization for unstable angina. CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction. Zinman B, et al. N Engl J Med. 2015;373:2117-2128. 39

Clinical Outcomes with Empagliflozin EMPA-REG OUTCOME Pooled Analysis (N=7020) *CV death, nonfatal MI (excluding silent MI), or nonfatal stroke; CV death, nonfatal MI (excluding silent MI), nonfatal stroke, and hospitalization for unstable angina. CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction. Zinman B, et al. N Engl J Med. 2015;373:2117-2128. 40

Microvascular and Renal Outcomes *In patients with normal albuminuria at baseline. with Empagliflozin EMPA-REG RENAL (N=7020) CI, confidence interval; CV, cardiovascular; egfr, estimated glomerular filtration rate in ml/min/1.73 m 2 ; HR, hazard ratio; SCr, serum creatinine. Wanner C, et al. N Engl J Med. 2016;375:323-334. Favors empagliflozin Hazard ratio (95% CI) P value Composite microvascular endpoint* 0.62 (0.54-0.70) <0.001 Incident or worsening nephropathy or CV death 0.61 (0.55-0.69) <0.001 Incident or worsening nephropathy 0.61 (0.53-0.70) <0.001 Progression to microalbuminuria 0.62 (0.54-0.72) <0.001 Doubling of SCr plus egfr 45 ml/min/1.73 m 2 0.56 (0.39-0.79) <0.001 Initiation of renal replacement therapy 0.45 (0.21-0.97) 0.04 Severe renal outcomes 0.54 (0.40-0.75) <0.001 Incident albuminuria in patients with normal albumin at baseline Median follow-up: 3.1 years 0.00 0.50 1.00 1.50 0.95 (0.87-1.04) 0.25 41

Clinical Outcomes with Antihyperglycemic Agents CANVAS (CANAGLFLOZIN CARDIOVASCULAR ASSESSMENT STUDY) 45

Clinical Outcomes with Canagliflozin CANVAS Program Study Design N=10,142 patients with T2D and high CV risk CANVAS: n=4330 CANVAS-R: n=5812 Randomization (across both studies) Canagliflozin: n=5795 Placebo: n=4347 Noninferiority/superiority criteria Noninferiority = upper bound of 95% CI of the HR <1.3 Superiority = upper bound of 95% CI of the HR <1.0 Endpoints Primary endpoint: composite of CV death, nonfatal MI, or nonfatal stroke Secondary endpoints: All-cause death CV death Albuminuria progression Composite of CV death and HF hospitalization CANVAS, Canaglflozin Cardiovascular Assessment Study; CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction. Neal B, et al. N Engl J Med. 2017;377:644-657. 46

Clinical Outcomes with Canagliflozin CANVAS Program (N=10,142) Median follow-up: 2.4 years Hazard ratio (95% CI) P value Primary composite endpoint* 0.86 (0.75-0.97) 0.02 CV death 0.87 (0.72-1.06) Nonfatal MI 0.85 (0.69-1.05) Nonfatal stroke 0.90 (0.71-1.15) Fatal or nonfatal MI 0.89 (0.73-1.09) Fatal or nonfatal stroke 0.87 (0.69-1.09) HF hospitalization 0.67 (0.52-0.87) CV death or HF hospitalization 0.78 (0.67-0.91) All-cause death 0.87 (0.74-1.01) Progression of albuminuria 0.73 (0.67-0.79) 40% reduction in egfr, renal replacement 0.60 (0.47-0.77) therapy, or renal death 0.00 0.50 1.00 1.50 *CV death, nonfatal MI, or nonfatal stroke. Superiority. Favors canagliflozin CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction. Neal B, et al. N Engl J Med. 2017 Jun 12 [epub ahead of print]. 47

Adverse Events with Canagliflozin CANVAS Program* Safety Results Event Canagliflozin Placebo P value Events per 1000-patient years All serious adverse events 104.3 120.0 0.04 Adverse events leading to discontinuation 35.5 32.8 0.07 Diabetic ketoacidosis (adjudicated) 0.6 0.3 0.14 Events of interest occurring in significantly more canagliflozin-treated patients Amputation 6.3 3.4 <0.001 Bone fracture (adjudicated) All 15.4 11.9 0.02 Low trauma 11.6 9.2 0.06 Infection of male genitalia 34.9 10.8 <0.001 Osmotic diuresis 34.5 13.3 <0.001 Volume depletion 26.0 18.5 0.009 Mycotic genital infection in women 68.8 17.5 <0.001 *Includes patients from CANVAS and CANVAS-R (N=10,142). CANVAS-only population (n=4330). Neal B, et al. N Engl J Med. 2017 Jun 12 [epub ahead of print]. 48

DECLARE TIMI 58

Trial Design 17,160 with Type 2 DM Established CV Disease (6974) or Multiple Risk Factors (10186) DAPAGLIFLOZIN 10 mg DAILY RANDOMIZE 1:1 DOUBLE BLIND All other DM Rx per treating MD PLACEBO Follow-up visits In Person Q 6 mo/ telephone Q 3 mo DURATION EVENT DRIVEN 1390 MACE Primary EPs Safety: MACE (CVD/MI/Ischemic Stroke) Dual Efficacy: CVD/HHF, MACE Median follow up 4.2 years Wiviott SD, Raz I Sabatine MA, AHJ 2018

Primary Endpoints CVD/HHF 4.9% vs 5.8% HR 0.83 (0.73-0.95) P(Superiority) 0.005 MACE 8.8% vs 9.4% HR 0.93 (0.84-1.03) P(Noninferiority) <0.001 P(Superiority) 0.17

Secondary Endpoints 1 st Renal Composite EP 40% egfr, ESRD, Renal or CV death 4.3% vs. 5.6% HR 0.76 (0.67-0.87) P<0.001 All-Cause Mortality 6.2% vs 6.6% HR 0.93 (0.82-1.04) P=0.20

Endpoints and Components Dapagliflozin Placebo *P for superiority, **P for non-inferiority

Clinical Outcomes with Antihyperglycemic Agents ELIXA (EVALUATION OF LIXISENATIDE IN ACUTE CORONARY SYNDROME) 54

Clinical Outcomes with Lixisenatide Study Design N=6068 patients with T2D and MI or unstable angina within 180 days prior to enrollment Randomization Lixisenatide: n=3034 Placebo: n=3034 Noninferiority criteria: upper bound of 95% CI of the HR for the primary endpoint <1.3 Primary endpoint: composite of CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina Key secondary endpoints Composite of composite of CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina or HF Composite of composite of CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina or HF, or coronary revascularization ELIXA Study Design Key Results Median follow-up: 25 months Difference from placebo at 25 weeks A1C: 0.27% (95% CI 0.31 to 0.22; P<0.001) Weight: 0.7 kg (95% CI, 0.9 to 0.5 kg; P<0.001) SBP: 0.8 mm Hg (95% CI, 1.3 to 0.3 mm Hg) CV outcomes Primary: HR 1.02 (95% CI 0.89 to 1.17); P<0.001 for noninferiority; P=0.81 for superiority Increased rates of gastrointestinal events in lixisenatide-treated patients Rates of serious adverse events, severe hypoglycemia, pancreatitis, pancreatic neoplasms similar to placebo CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction. Pfeffer MA, et al. N Engl J Med. 2015;373:2247-2257. 55

Clinical Outcomes with Lixisenatide ELIXA (Patients with T2D and CVD; N=6068) Hazard ratio (95% CI) P value Primary composite endpoint* 1.02 (0.89-1.17) 0.81 Secondary composite endpoint 0.97 (0.85-1.10) 0.63 CV death 0.98 (0.78-1.22) 0.85 Fatal or nonfatal MI 1.03 (0.87-1.22) 0.71 Stroke 1.12 (0.79-1.58) 0.54 Unstable angina 1.11 (0.47-2.62) 0.81 Hospitalization for heart failure 0.96 (0.75-1.23) 0.75 Death from any cause 0.94 (0.78-1.13) 0.50 0.00 1.00 2.00 3.00 Favors lixisenatide *CV death, nonfatal MI, or nonfatal stroke, and hospitalization for unstable angina; CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina, hospitalization for HF, and coronary revascularization. CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction. Pfeffer MA, et al. N Engl J Med. 2015;373:2247-2257. 56

Clinical Outcomes with Lixisenatide ELIXA Adverse Events Event Lixisenatide (%) (n=3031) Placebo (%) (n=3032) Hypoglycemia 16.6 15.2 Serious adverse event 20.6 22.1 Hypoglycemia requiring assistance from another person 0.4 0.8 Gastrointestinal event 2.2 2.7 Acute pancreatitis 0.16 0.26 Pancreatic cancer 0.09 0.3 Systemic allergic reactions 0.9 0.8 Adverse events leading to treatment discontinuation 11.4 7.2 Gastrointestinal 4.9 1.2 Pfeffer MA, et al. N Engl J Med. 2015;373:2247-2257. 57

Clinical Outcomes with Antihyperglycemic Agents LEADER (LIRAGLUTIDE EFFECT AND ACTION IN DIABETES: EVALUATION OF CARDIOVASCULAR OUTCOME RESULTS) 58

Clinical Outcomes with Liraglutide LEADER Study Design N=9340 patients with T2D and high CV risk Randomization Liraglutide: n=4672 Placebo: n=4668 Noninferiority study: prespecified margin <1.3 for upper bound of 95% CI of the HR for the primary endpoint Primary endpoint: composite of CV death, nonfatal MI (including silent MI), or nonfatal stroke Secondary endpoint: composite of CV death, nonfatal MI (including silent MI), nonfatal stroke, coronary revascularization, and hospitalization for unstable angina or HF Key Results Median follow-up: 3.5 years Difference from placebo at 36 months A1C: 0.40% (95% CI, 0.45% to 0.34%) Weight: 2.3 kg (95% CI, 2.0 to 2.5 kg) SBP: 1.2 mm Hg (95% CI, 0.5 to 1.9 mm Hg) CV outcomes Primary: HR 0.87 (95% CI 0.78 to 0.97); P=0.01 for superiority Secondary HR: 0.88 (95% CI 0.81 to 0.96); P=0.005 for superiority Significantly lower rates of all-cause death and CV death with liraglutide Increased rates of gastrointestinal events in liraglutide-treated patients Lower numerical incidence of pancreatitis in liraglutide group (not statistically significant) CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction. Marso SP, et al. N Engl J Med. 2016:375:311-322. 59

Clinical Outcomes with Liraglutide LEADER (N=9340) Median follow-up: 3.5 years Hazard ratio (95% CI) P value Primary composite endpoint* 0.87 (0.78-0.97) 0.01 Expanded composite endpoint 0.88 (0.81-0.96) 0.005 Death from any cause 0.85 (0.74-0.97) 0.02 CV death 0.78 (0.66-0.93) 0.007 Fatal or nonfatal MI 0.86 (0.73-1.00) 0.046 Nephropathy 0.78 (0.67-0.92) 0.003 0.00 0.50 1.00 1.50 Favors liraglutide *CV death, nonfatal MI (including silent MI), or nonfatal stroke; CV death, nonfatal MI (including silent MI), nonfatal stroke, coronary revascularization, and hospitalization for unstable angina or HF. CI, confidence interval; CV, cardiovascular; MI, myocardial infarction. Marso SP, et al. N Engl J Med. 2016:375:311-322. 60

Clinical Outcomes with Liraglutide LEADER (N=9340) *CV death, nonfatal MI (including silent MI), or nonfatal stroke. CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction. Marso SP, et al. N Engl J Med. 2016:375:311-322. 61

Clinical Outcomes with Liraglutide LEADER Adverse Events Leading to Discontinuation Event Liraglutide (%) (n=4668) Placebo (%) (n=4672) P value Any adverse event 9.5 7.3 <0.001 Serious adverse event 4.1 5.2 0.01 Nausea 1.6 0.4 <0.001 Vomiting 0.7 <0.1 <0.001 Diarrhea 0.6 0.1 <0.001 Increased lipase level 0.3 0.2 0.43 Decreased appetite 0.2 <0.1 0.01 Abdominal discomfort 0.2 0 0.002 Marso SP, et al. N Engl J Med. 2016:375:311-322. 62

Clinical Outcomes with Antihyperglycemic Agents EXSCEL (EXENATIDE STUDY OF CARDIOVASCULAR EVENT LOWERING) 63

Clinical Outcomes with Exenatide EXSCEL Study Design N=14,752 patients with T2D with or without CVD By design, 70% had CVD (n=10,782; 73.1%) Randomization Exenatide: n=7356 Placebo: n=7396 Noninferiority study: prespecified margin <1.3 for upper bound of 95% CI of the primary endpoint HR Primary endpoint: composite of CV death, nonfatal MI, or nonfatal stroke Secondary endpoints: all-cause death, CV death, nonfatal or fatal MI, nonfatal or fatal stroke, and hospitalization for acute coronary syndrome or HF Key Results Median follow-up: 3.2 years Difference from placebo at trial end A1C: 0.53% (95% CI, 0.57% to 0.50%; P<0.001) Weight: 1.3 kg (95% CI, 1.4 to 1.1 kg; P<0.001) SBP: 1.6 mm Hg (95% CI, 1.9 to 1.2 mm Hg; P<0.001) CV outcomes Primary endpoint: HR 0.91 (95% CI 0.83 to 1.00); P<0.001 for noninferiority, P=0.06 for superiority No difference between treatment groups in confirmed cases of pancreatitis, pancreatic cancer, or medullary thyroid carcinoma More cases of thyroid papillary carcinoma in exenatide (n=10) than placebo group (n=4) CI, confidence interval; CV, cardiovascular; EXSCEL, Exenatide Study of Cardiovascular Event Lowering; HF, heart failure; HR, hazard ratio; MI, myocardial infarction. Holman RR, et al. N Engl J Med. 2017 Sept 14 [Epub before print]. 64

Clinical Outcomes with Exenatide EXSCEL (N=14,752) Median follow-up: 3.2 years Hazard ratio (95% CI) P value Primary composite endpoint* 0.91 (0.83-1.00) 0.06 Death from any cause 0.86 (0.77-0.97) NS CV death 0.88 (0.76-1.02) Fatal or nonfatal MI 0.97 (0.85-1.10) Fatal MI 1.29 (0.63-2.66) Fatal or nonfatal stroke 0.85 (0.70-1.03) Fatal stroke 0.71 (0.39-1.30) Hospitalization for HF 0.94 (0.78-1.13) Hospitalization for ACS 1.05 (0.94-1.18) *CV death, nonfatal MI, or nonfatal stroke. For superiority. 0.00 1.00 2.00 3.00 Favors exenatide ACS, acute coronary syndrome; CI, confidence interval; CV, cardiovascular; EXSCEL, Exenatide Study of Cardiovascular Event Lowering; HF, heart failure; MI, myocardial infarction; NS, not statistically significant based on hierarchical testing plan. Holman RR, et al. N Engl J Med. 2017 Sept 14 [Epub before print]. 65

Clinical Outcomes with Exenatide EXSCEL (N=14,752) Holman RR, et al. N Engl J Med. 2017 Sept 14 [Epub before print]. 66

Clinical Outcomes with Exenatide EXSCEL Serious Adverse Events and Events of Special Interest Event Exenatide (%) (n=7344) Placebo (%) (n=7372) Any serious AE 16.8 16.6 Serious adverse treatment-related event 0.8 0.5 Serious AE leading to study withdrawal 1.5 1.4 Events of Clinical Interest Adjudicated pancreatitis 0.4 0.3 Severe pancreatitis <0.1 <0.1 Adjudicated cancer (any) 4.8 4.9 Adjudicated medullary thyroid carcinoma <0.1 <0.1 Adjudicated pancreatic cancer 0.2 0.2 Severe hypoglycemia 3.4 3.0 Event rate 1.6 per 100 pt-years 1.8 per 100 pt-years AE, adverse event. Holman RR, et al. N Engl J Med. 2017 Sept 14 [Epub before print]. 67

Clinical Outcomes with Antihyperglycemic Agents SUSTAIN 6 (TRIAL TO EVALUATE CARDIOVASCULAR AND OTHER LONG-TERM OUTCOMES WITH SEMAGLUTIDE IN SUBJECTS WITH TYPE 2 DIABETES) 68

Clinical Outcomes with Semaglutide SUSTAIN 6 Study Design N=3297 patients with T2D with CVD, CHF, CKD, or age 60 with 1 CV risk factor Randomization Semaglutide: n=1648 Placebo: n=1649 Noninferiority study: prespecified margin <1.8 for upper bound of 95% CI of the HR for the primary endpoint Primary endpoint: composite of CV death, nonfatal MI (including silent MI), or nonfatal stroke Key secondary endpoints Composite of CV death, nonfatal MI, nonfatal stroke, coronary or peripheral revascularization, and hospitalization for unstable angina or HF Composite of all-cause death, nonfatal MI, nonfatal stroke Retinopathy complications New or worsening nephropathy CI, confidence interval; CHF, congestive heart failure; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; HF, heart failure; HR, hazard ratio; MI, myocardial infarction; SUSTAIN, Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes. Marso SP, et al. N Engl J Med. 2016:375:1834-1844. 69

Clinical Outcomes with Semaglutide SUSTAIN 6 Results (N=3297) Median follow-up: 2.1 years Hazard ratio (95% CI) P value Primary composite endpoint* 0.74 (0.58-0.95) 0.02 Expanded composite endpoint 0.88 (0.81-0.96) 0.002 All-cause death, nonfatal MI, nonfatal stroke 0.77 (0.61-0.97) 0.03 Death from any cause 1.05 (0.74-1.50) 0.79 CV death 0.98 (0.65-1.48) 0.92 Nonfatal MI 0.74 (0.51-1.08) 0.12 Nonfatal stroke 0.61 (0.38-0.99) 0.04 Revascularization 0.65 (0.50-0.86) 0.003 Retinopathy complications 1.76 (1.11-2.78) 0.02 New or worsening nephropathy 0.64 (0.46-0.88) 0.005 *CV death, nonfatal MI (including silent MI), or nonfatal stroke; CV death, nonfatal MI, nonfatal stroke, coronary or peripheral revascularization, and hospitalization for unstable angina or HF. CI, confidence interval; CV, cardiovascular; HF, heart failure; MI, myocardial infarction. Marso SP, et al. N Engl J Med. 2016:375:1834-1844. 0.00 1.00 2.00 3.00 Favors semaglutide 70

Clinical Outcomes with Semaglutide SUSTAIN 6 Selected Adverse Events Event Semaglutide 1 mg (%) (n=822) Placebo 1 mg (%) (n=825) Any adverse event 89.1 89.2 Serious adverse event 33.6 36.1 Gastrointestinal disorder 52.3 35.2 Diarrhea 18.4 10.5 Nausea 21.9 8.1 Vomiting 14.8 4.1 Acute pancreatitis 0.4 1.1 Gallbladder disorder 3.2 2.8 Cholelithiasis 2.1 1.5 Acute cholecystitis 0 0.2 Severe or symptomatic hypoglycemia 21.7 21.0 Injection site reaction 0.7 0.3 Neoplasm (any) 10.8 8.4 Any malignant 4.9 4.2 Malignant pancreatic 0.1 0.2 Marso SP, et al. N Engl J Med. 2016:375:1834-1844.. 71

ΜΕΛΕΤΗ ΩRIGIN: Η χορήγηση ινσουλίνης glargine σε πρώιμο στάδιο ΣΔΤ2 παρέχει μακροχρόνια και σχεδόν φυσιολογική ρύθμιση των επιπέδων της γλυκόζης Μελέτη ORIGIN Διαταραγμένη ανοχή γλυκόζης (IGT), διαταραγμένη γλυκόζη νηστείας (IFG) ή πρώιμος ΣΔΤ2 με υψηλό καρδιαγγειακό κίνδυνο N=12.537 Τυχαιοποιήθηκαν στην ινσουλίνη glargine (με στοχευμένη FPG 95 mg/dl έναντι της τυπικής θεραπείας Μέση περίοδος παρακολούθησης 6,2 έτη HbA 1C, % 7,0 6,5 6,0 6,4 6,4 6,2 5,9 6,3 6,0 6,4 6,4 6,0 6,1 6,5 6,5 6,5 Ινσουλίνη glargine Τυπική θεραπεία 5,5 0 7 6,2 6,3 6,2 Ο στόχος αποκατάστασης της νορμογλυκαιμίας με την ινσουλίνη glargine είχε ουδέτερη επίδραση στα καρδιαγγειακά συμβάματα* Η μελέτη ΩRIGIN κατέδειξε την καρδιαγγειακή ασφάλεια της ινσουλίνης glargine Τα επεισόδια σοβαρής υπογλυκαιμίας ήταν 1,00 (ινσουλίνη glargine) έναντι 0,31 ανά 100 ανθρωπο-έτη Το μέσο σωματικό βάρος αυξήθηκε κατά 1,6 kg με την ινσουλίνη glargine και μειώθηκε κατά 0,5 kg με την τυπική θεραπεία 1 2 3 Έτη 4 5 6 IFG, διαταραγμένη γλυκόζη νηστείας, IGT, διαταραγμένη ανοχή στη γλυκόζη; ORIGIN, Outcome Reduction with an Initial Glargine Intervention *Οι δεύτερες κύριες εκβάσεις ήταν μη θανατηφόρο ΕΜ μη θανατηφόρο εγκεφαλικό επεισόδιο ή θάνατος καρδιαγγειακής αιτιολογίας και αυτά τα συμβάντα συν επαναγγείωση για καρδιακή ανεπάρκεια Ο πληθυσμός των ασθενών που εντάχθηκαν στην ORIGIN είναι ευρύτερος εκείνου που πληροί τις ενδείξεις της ινσουλίνης glargine ORIGIN. N Engl J Med. 2012;367:319-28 72

Clinical Outcomes with Antihyperglycemic Agents DEVOTE (TRIAL COMPARING CARDIOVASCULAR SAFETY OF INSULIN DEGLUDEC WITH INSULIN GLARGINE IN PATIENTS WITH TYPE 2 DIABETES AT HIGH RISK OF CARDIOVASCULAR EVENTS) 73

Clinical Outcomes with Insulin Degludec DEVOTE Study Design N=7637 patients with T2D at high risk of CV events Age 50 years with with CVD or renal disease Age 60 years with 1 CV risk factor Randomization Degludec: n=3818 Glargine: n=3819 Noninferiority study: prespecified margin <1.3 for upper bound of 95% CI of the HR for the primary endpoint; superiority tested if noninferiority criterion met Primary endpoint: composite of CV death, nonfatal MI, or nonfatal stroke Key secondary endpoints Adjudicated severe hypoglycemia Composite of CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina All-cause death CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; DEVOTE, Trial Comparing Cardiovascular Safety of Insulin Degludec With Insulin Glargine in Patients With Type 2 Diabetes at High Risk of Cardiovascular Events; HR, hazard ratio; MI, myocardial infarction. Marso SP, et al. N Engl J Med. 2017;377:723-732. 74

Clinical Outcomes with Insulin Degludec and Glargine DEVOTE CV Outcomes (N=7637) Median follow-up: 1.99 years Hazard ratio (95% CI) P value Primary composite endpoint* 0.91 (0.78-1.06) <0.001 (NI) Expanded composite endpoint 0.92 (0.80-1.05) 0.22 All-cause death 0.91 (0.76-1.11) 0.35 Noncardiovascular death 0.84 (0.60-1.16) 0.28 CV death 0.96 (0.76-1.21) 0.71 CV death excluding undetermined cause of death 0.91 (0.69-1.20) 0.52 Nonfatal MI 0.85 (0.68-1.06) 0.15 Nonfatal stroke 0.90 (0.65-1.23) 0.50 Unstable angina hospitalization 0.95 (0.68-1.31) 0.74 *CV death, nonfatal MI, or nonfatal stroke; Confirmed noninferiority; superiority, P=0.21. CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina. CI, confidence interval; CV, cardiovascular; MI, myocardial infarction; NI, noninferiority. Marso SP, et al. N Engl J Med. 2017;377:723-732. 0.50 1.00 1.50 Favors degludec Favors glargine 75

Clinical Outcomes with Insulin Degludec and Glargine DEVOTE Safety Outcomes (N=7637) Median follow-up: 1.99 years Hazard ratio (95% CI) P value Severe hypoglycemia* 0.60 (0.48-0.76) <0.001 Unconsciousness or coma 0.81 (0.55-1.19) 0.28 Seizure 1.02 (0.38-2.73) 0.97 Nocturnal severe hypoglycemia 0.47 (0.31-0.73) <0.001 1 severe hypoglycemia event 0.73 (0.60-0.89) <0.001 0.00 1.00 2.00 3.00 Favors degludec Favors glargine *Episode requiring assistance from another person to actively administer carbohydrate or glucagon or take other corrective actions. CI, confidence interval. Marso SP, et al. N Engl J Med. 2017;377:723-732. 76

Clinical Outcomes with Insulin Degludec and Glargine DEVOTE Selected Adverse Events Event Degludec (%) (n=3818) Glargine (%) (n=3819) Any adverse event 39.0 40.0 Any serious adverse event 38.6 39.7 Any serious adverse event except severe hypoglycemia 38.0 39.0 Events leading to permanent discontinuation 5.2 5.8 Externally classified neoplasms 3.2 3.0 Malignant 2.4 2.6 Benign 0.7 0.5 Unclassifiable 0.1 0.5 Marso SP, et al. N Engl J Med. 2017;377:723-732. 77

Glucose-lowering medication in type 2 diabetes: overall approach. Melanie J. Davies et al. Dia Care 2018;41:2669-2701 2018 by American Diabetes Association

Diabetes Metab J. 2012 Feb;36(1):13-25

Diabetes Metab J. 2012 Feb;36(1):13-25

Diabetes Metab J. 2012 Feb;36(1):13-25

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