How to apply novel outcome data. to clinical practice. Preventing Cardiovascular Disease in Patients with T2DM

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1 Preventing Cardiovascular Disease in Patients with T2DM How to apply novel outcome data with GLP-1 RA to clinical practice Lars Rydén Department of Medicine K2 Karolinska Institutet Stockholm, Sweden Ljubljana April 19, 2018 For internal Medical Affairs training only

2 Incretin-based glucose lowering Two options DPP-4 inhibition GLP-1 receptor agonism Effects Insulin secretion Glucagon secretion Beta-cell mass Insulin sensitivity Gastric emptying Satiety GLP-1 receptor agonists Requires injection Mimics the effect of GLP-1 Reduces HbA 1c by 1% Causes weight loss of 2 3 kg Low risk of hypoglycaemia when used with metformin Reduced risk of hypoglycaemia if combined with insulin Baggio LL & Drucker DJ. Gastroenterology 2007;132:

3 GLP-1 receptor agonists Broad approach GLP-1 receptor agonists Shortacting Longacting Exendin-4 based Exenatide BID Lixisenatide OD Human analogues Liraglutide QD Semaglutide QW Dulaglutide QW Exendin-4 based Exenatide LARQW ITCA 650 Drucker DJ. Cell Metab 2016;24:15 30 Meier JJ. Nat Rev Endocrinol 2012;8: Madsbad S et al. Diabetes Obes Metab 2011;13:

4 GLP-1 receptor agonists in type 2 diabetes Results from available outcome trials GLP-1 receptor agonists Shortacting Exendin-4 based Exenatide BID Lixisenatide Lixisenatide OD Human analogues Liraglutide QD Semaglutide QW Dulaglutide QW Longacting Exendin-4 based Exenatide Exenatide LARQW ITCA 650 ITCA 650 is an investigational product and not currently approved

5 Lixisenatide Type 2 diabetes and recent ACS n=6,068 Treatment Lixisenatide Placebo Follow-up: 25 months (median) Impact on CV death or non-fatal MI, stroke or unstable angina HbA 1c at the end of study Lixisenatide 7.4% Placebo 7.6% Pfeffer MA et al. N Engl J Med 2015;373:

6 Exenatide Type 2 diabetes with (74%) or without CVD n=14,752 Treatment Exenatide (2 mg once weekly) Placebo Follow-up: 3.2 years (median) Impact on CV death or non-fatal MI or stroke HbA 1c at the end of study Exenatide 7.7% Placebo 7.9% Holman RR et al. N Engl J Med 2017;377:

7 GLP-1 receptor agonists in type 2 diabetes Results from available outcome trials GLP-1 receptor agonists Shortacting Exendin-4 based Exenatide BID Lixisenatide Lixisenatide OD Human analogues Liraglutide QD Liraglutide Semaglutide QW Semaglutide Dulaglutide QW Longacting Exendin-4 based Exenatide LARQW ITCA 650 Semaglutide is an investigational product and not currently approved

8 Liraglutide Type 2 diabetes at high risk for CVD n=9,340 Treatment Liraglutide (1.8 mg once daily) Placebo Follow-up: 3.8 years (median) Impact on CV death or non-fatal MI or stroke HbA 1c at the end of study Liraglutide ~7.7% Placebo ~8.0% Marso SP et al. N Engl J Med 2016;375:

9 Semaglutide SUSTAIN 6 Semaglutide sc once-weekly Type 2 diabetes at high risk for CVD n=3,297 Treatment Semaglutide (0.5 or 1.0 mg once daily) Placebo Follow-up: 3.8 years (median) Impact on CV death or non-fatal MI or stroke HbA 1c at the end of study Liraglutide ~7.3% Placebo ~8.3% Marso SP et al. N Engl J Med 2016;375: Semaglutide is an investigational product and not currently approved

10 Liraglutide and semaglutide SUSTAIN 6 Semaglutide sc once-weekly Let us go into some details... Semaglutide is an investigational product and not currently approved

11 Percentage of patients Liraglutide Placebo Patient characteristics at study start Variable Male sex (%) Age (years) Diabetes duration (years) HbA 1c 8.7 BMI (kg/m 2 ) Blood pressure (mmhg) 136/77 20 Heart failure (%) 18 0 Wit h previous CVD (age 5 0 ) Wit h CVD risk f actors (age 6 0 ) Marso SP et al. N Engl J Med 2016;375:

12 Proport ion of patients ( % ) Proport ion of patients ( % ) Liraglutide Placebo 100 Liraglutide Background Placebo therapy at study start Metformin Sulphonylureas Alpha - glucosidase inhibitors TZDs Glinides Insulin Metform in SUs Alpha-glucosidase inhibitors TZDs Glinides Insulin Metformin SU AGI TZD Glinides Insulin Marso SP et al. N Engl J Med 2016;375: Antihypertensive therapy Diuretics Lipid-lowering drugs Platelet aggregation inhibitors Other anti-thrombotic medication Antihypertensive Platelet Other botic BP-lowering therapy Diuretics Lipid-lowering drugs aggregation ASA Plat medication stab inhibitors

13 Treatment recommendations Blood glucose HbA 1c 7.0% (individualised) Blood pressure Target: 130/80 mmhg Treatment/guideline Lipids Target LDL <100 mg/dl (<70 mg/dl [1.8 mmol/l] if CV events) Statins: Recommended for all patients Antiplatelet therapy Aspirin or clopidogrel (if aspirin intolerant) if CV events Marso SP et al. N Engl J Med 2016;375:

14 Subgroup Hazard rat io ( 9 5 % CI ) Favou rs lirag lut ide Marso SP et al. N Engl J Med 2016;375: Favou rs placebo Consistency Hazard ratio p-value for (95% CI ) Subgroup interaction No. of patients Hazard ratio (95% CI ) Prim ary analysis 0.87 ( 0.78 ; 0.97) Prim ary analysis ( 0.78 ; 0.97) Sex HbA 1c 0.84 Female 0.88 (0.72 ; 1.08) 8.3% (0.76 ; 1.05) Male 0.86 (0.75 ; 0.98) >8.3% (0.72 ; 0.98) Age Duration 0.27 of diabetes <60 years 0.78 (0.62 ; 0.97) 11 years (0.70 ; 0.97) 60 years 0.90 (0.79 ; 1.02) >11 years (0.78 ; 1.04) Geographic region Risk of 0.20 CVD p=0.04 Age 50 years and established CVD Europe 0.82 (0.68 ; 0.98) (0.74 ; 0.93) North America 1.01 (0.84 ; 1.22) Age 60 years and 2847 risk factors for CVD 1.20 (0.86 ; 1.67) Asia 0.62 (0.37 ; 1.04) Chronic heart failure 711 Yes 0.94 (0.72 ; 1.21) Rest of the world 0.83 (0.68 ; 1.03) 2486 No 0.85 (0.76 ; 0.96) Race 0.32 Antidiabet ic therapy White 0.90 (0.80 ; 1.02) OAD 0.75 (0.58 ; 0.98) Black or African 0.87 (0.59 ; 1.27) 777 >1 OAD 0.95 (0.78 ; 1.16) American Insulin with OAD(s) 0.89 (0.74 ; 1.06) Asian 0.70 (0.46 ; 1.04) Insulin without OAD (0.63 ; 1.17) Other 0.61 (0.37 ; 1.00) None (0.42 ; 1.25) Ethnic group Renal f0.30 unction p=0.01 Hispanic or Latino 0.74 (0.54 ; 1.02) <60 ml/min/ m (0.57 ; 0.85) Not Hispanic or 0.89 (0.79 ; 1.00) 60 ml/min/ m (0.83 ; 1.07) Latino Hazard rat io ( 9 5 % CI ) Favou rs lirag lut ide Favou rs placebo

15 Primary endpoint Cardiovascular death All-cause mortality Non-fatal myocardial infarction Non-fatal stroke Heart failure hospitalisation Marso SP et al. N Engl J Med 2016;375:

16 Primary outcome by insulin use at baseline Primary outcome in patients never treated with insulin during the trial Hazard ratio (95% CI) Liraglutide Placebo N % N % Hazard ratio (95% CI) Liraglutide Placebo N R N R Total number of patients Total number of patients Primary outcome 0.87 (0.78 ; 0.97) Primary outcome 0.87 (0.78 ; 0.97) Insulin use at baseline (Y/N) Patients not on insulin at baseline Yes 0.88 (0.75 ; 1.03) Primary outcome 0.82 (0.68 ; 0.98) No 0.86 (0.74 ; 1.01) ,5 0,75 1 1,25 Hazard ratio (95% CI) 0,5 0,75 1 1,25 Hazard ratio (95% CI) Favours liraglutide Favours placebo Favours liraglutide Favours placebo Presented at the American Diabetes Association 77th Scientific Sessions, Session 1-AC-SY June 2017, San Diego, CA, USA

17 Patien ts w ith an even t ( % ) Microvascular events Event type Definition one or m ore of the below Microvascu lar events Ren al Eye New onset of persistent macroalbuminuria Persistent doubling of serum creatinine * Need for continuous renal replacement therapy Death due to renal disease Need for retinal photocoagulation or treatment with intravitreal agents Vitreous haemorrhage Diabetes-related blindness 10 Time to first microvascular event Placebo 8 6 Liraglutide 4 2 HR (95% CI 0.73 ; 0.97) p=0.02 *and egfr 45 ml/min/1.73 m 2 per MDRD Marso SP et al. N Engl J Med 2016;375: No. at risk Liraglutide Placebo Tim e from random isation (months)

18 Number of patients Mean HbA 1c (%) Mean HbA 1c (mmol/mol) Liraglutide Liraglutide Placebo HbA 1c 9,0 Glycaemic control 75 Baseline ,0 8,5 70 8, ,5 55 7,0 50 6,5 45 6,0 40 5,5 35 5, EOT63 Time since randomisation (months) -1,0-2,0 GLOD added ,16-0,77 ETD 0.40 (95% CI: 0.45 ; 0.34) p<0.001 Liraglutide Placebo 2,019 0 Metformin Sulphonylureas Alpha-glucosidase inhibitors Metformin SUs Alpha-glucosidase inhibitors TZDs Glinides Insulin TZDs Glinides Insulin Additional classes added Liraglutide Placebo DPP-4 inhibitors *EOT may be any time from Month 42 to Month 60 Marso SP et al. N Engl J Med 2016;375: GLP-1RAs SGLT-2 inhibitors

19 Impact on HbA 1c, weight, blood pressure and lipids HbA 1c Body Weight SBP Lipids Treatment diff 0.4% 95% CI ( 0.45 ; 0.34) p<0.001 Treatment diff 2.3 kg 95% CI ( 2.54 ; 1.99) p<0.001 Treatment diff 1.2 mmhg 95% CI ( 1.9 ; 0.5) p<0.001 Small decrease TC LDL-C and TGs Small increase HDL-C Marso SP et al. N Engl J Med 2016;375:

20 Mean number of episodes per 1000 patients Severe hypoglycaemia Placebo Liraglutide Rate ratio: % CI: (0.51 ; 0.93) p= Time since randomisation (months) Liraglutide Placebo Number of patients with severe hypoglycaemia (%) 114 (2.4) 153 (3.4) Presented at the American Diabetes Association 77 th Scientific Sessions, Session 1-AC-SY June 2017, San Diego, CA, USA Marso SP et al. N Engl J Med 2016;375:

21 In summary 3P MACE ARR 1.9% RRR 13% p=0.01 CV death All death Microvasc Renal 22% p= % p= % p= % p=0.003 Marso SP et al. N Engl J Med 2016;375:

22 SUSTAIN 6 Semaglutide sc once-weekly SUSTAIN 6 Semaglutide sc once-weekly Patient characteristics at study start Male sex (%) 61 Age (years) 65 Diabetes duration (years) 14 HbA 1c 8.7 BMI (kg/m 2 ) 32.8 Blood pressure (mmhg) 136/77 Heart failure (%) 24 Male sex (%) 64 Age (years) 64 Diabetes duration (years) 13 HbA 1c 8.7 BMI (kg/m 2 ) 32.5 Blood pressure (mmhg) 136/77 Heart failure (%) 18 Marso SP et al. N Engl J Med 2016;375: Semaglutide is an investigational product and not currently approved

23 SUSTAIN 6 Semaglutide sc once-weekly Primary endpoint Non-fatal myocardial infarction Non-fatal stroke Cardiovascular death Marso SP et al. N Engl J Med 2016;375: Semaglutide is an investigational product and not currently approved

24 SUSTAIN 6 Semaglutide sc once-weekly Marso SP et al. N Engl J Med 2016;375: Favours semaglutide Favours placebo Semaglutide is an investigational product and not currently approved

25 SUSTAIN 6 Semaglutide sc once-weekly HbA 1c Glycaemic control and Body weight Weight *p< Marso SP et al. N Engl J Med 2016;375: Semaglutide is an investigational product and not currently approved

26 Subjects with an event (%) SUSTAIN 6 Semaglutide sc once-weekly Retinopathy HR 1.76 ( ) p= Time since randomisation (weeks) Semaglutide Placebo HR 1.15 ( ) p= vs 0.5/100 patient-years Marso SP et al. N Engl J Med 2016;375: Semaglutide is an investigational product and not currently approved

27 SUSTAIN 6 Semaglutide sc once-weekly In summary 3P MACE ARR 2.3% RRR 26% p=0.001 CV death All death Stroke Renal 2% n.s. +5% n.s. 39% p= % p=0.05 Marso SP et al. N Engl J Med 2016;375: Semaglutide is an investigational product and not currently approved

28 GLP-1 receptor agonists in type 2 diabetes SUSTAIN 6 Semaglutide sc once-weekly Why differences between GLP-1RA trials? Semaglutide is an investigational product and not currently approved

29 GLP-1 receptor agonists in type 2 diabetes Why different outcomes? Differences in study populations ELIXA in patients with T2DM and a recent ACS

30 GLP-1 receptor agonists in type 2 diabetes Why different outcomes? Patient populations in different GLP-1RA trials REWIND 1 (N=9,901) ELIXA 2 (N=6,068) EXSCEL 3 (N=14,752) SUSTAIN 6 4 (N=3,297) LEADER 5 (N=9,340) Drug tested Dulaglutide Lixisenatide Exenatide Semaglutide Liraglutide Dosage 1.5 mg/week 20 μg*/day 2.0 mg/week 0.5 or 1 mg /week 1.2 or 1.8 mg /day Mean age (yrs) Gender (% female) Diabetes duration (yrs) Prior CVD (%) Mean BMI (kg/m 2 ) Mean HbA 1c (%) *Initial dose of 10 μg with down- or up-titration permitted to maximum of 20 μg/day 1. Gerstein HC et al. Diabetes Obes Metab 2017 doi: /dom [Epub ahead of print]; 2. Pfeffer MA et al. N Engl J Med 2015;373: ; 3. Mentz RJ et al. Am Heart J 2017;187:1 9; 4. Marso SP et al. N Engl J Med 2016;375: ; 5. Marso SP et al. N Engl J Med 2016;375:

31 GLP-1 receptor agonists in type 2 diabetes Why different outcomes? Differences in study populations ELIXA in patients with T2DM and a recent ACS Differences in the use of non-study medications Differences in glycaemic control

32 GLP-1 receptor agonists in type 2 diabetes Why different outcomes? Differences in study populations ELIXA in patients with T2DM and a recent ACS Differences in the use of non-study medications Differences in glycaemic control GLP-1RA backbone Exendin-4 vs. Human analogue GLP-1 Duration of the GLP-1RA

33 1. Byetta. Summary of Product Characteristics; 2. Lyxumia. Summary of Product Characteristics; 3. Victoza. Summary of Product Characteristics; 4. Barrington P et al. Diabetes Obes Metab 2011;13: ; 5. Tanzeum. Prescribing information; 6. Marbury T et al. Diabetes 2014;63(Suppl. 1):A260(1010-P); 7. Kapitza C et al. J Clin Pharm 2015;55: ; 8. Fineman M et al. Clin Pharmacokinet 2011;50:65 74 GLP-1 receptor agonists Similarities and dissimilarities Semaglutide is an investigational product and not currently approved Exenatide Liraglutide His Gly GluGly Thr Phe ThrSer Asp Leu Ser ArgVal AlaGluGluGluMetGlnLys Leu Phe Ile Glu TrpLeu Lys AspGly Gly Pro SerSerGly AlaPro ProPro Ser Exenatide 2005 Liraglutide 2010 Lixisenatide 2013 Albiglutide 2014 Lixisenatide Dulaglutide 2014 Semaglutide Under investigation Agent Half-life T max Exenatide BID hours 2 hours Lixisenatide OD hours hours Semaglutide Phe His Aib Thr Thr Ser Glu Gly As p Val GLP-1 1 Figur 3.3: Liraglutide OD 3 13 hours 8 12 hours Dulaglutide 90 hours (3.75 OW 4 days) hours (1 2 days) C-18 fatty acid spacer Glu Phe Lys Ala Ala Gln Gly Glu Leu Tyr Ser Ser Albiglutide OW days 3 5 days Arg Val Gly Arg Ile Ala Trp Leu Gly Semaglutide hours (~7 OW 6,7 days) hours (1 1.5 days) Exenatide OW days 6 7 weeks

34 GLP-1 receptor agonists in type 2 diabetes Gaps in knowledge In less ill patients REWIND of great interest Orally available PIONEER 6 will provide insights In people with IGT Of interest to study In obese people Of interest to study

35 GLP-1 receptor agonists in type 2 diabetes Impact on guidelines (January 2018) France Italy Sw itzerland Canada Brazil Sw eden Position Paper Position Paper Spain Catalonia, Andalucía Norway Germ any Bulgar ia USA Denm ark Cardio Slovenia Greece Poland Korea Turkey Hungary Slovakia Czech Republic CVOT, cardiovascular outcomes trial Latvia Bosnia and Herzegovina Scotland

36 GLP-1 receptor agonists in type 2 diabetes Impact on guidelines (January 2018) In patients with type 2 diabetes and established atherosclerotic cardiovascular disease begin with lifestyle management and metformin then choose an agent proven to reduce major adverse cardiovascular events and cardiovascular mortality (currently empagliflozin and liraglutide) after considering drug-specific and patient factors Evidence level A: Supportive evidence from well conducted trials ADA, American Diabetes Association; CVOT, cardiovascular outcomes trial American Diabetes Association. Diabetes Care 2018;41(Suppl 1):S73 S85

37 Outcome trials of glucose-lowering drugs in type 2 diabetes Completed and ongoing ELIXA (Lixisenatide, GLP-1RA) n=6068; follow-up ~2 yrs Q RESULTS More to follow SUSTAIN 6 (Semaglutide, QW GLP-1RA) n=3297; duration ~2.8 yrs Q RESULTS GLP-1RA REWIND (Dulaglutide, QW GLP-1RA) n=9622; duration ~6.5 yrs Completion Q LEADER (Liraglutide, GLP-1RA) n=9340; duration yrs Q RESULTS FREEDOM (ITCA 650, GLP-1RA in DUROS) n=4000; duration ~2 yrs Q RESULTS EXSCEL (Exenatide ER, QW GLP-1RA) n=14,752; follow-up ~3 yrs Q RESULTS HARMONY OUTCOMES (Albiglutide, QW GLP-1RA) n~9400; duration ~4 yrs Completion Q PIONEER 6 (Oral semaglutide, GLP-1RA) n=3176; duration ~1.5 yrs Completion Q Rydén L et al. Clin Ther 2016;38: ; ClinicalTrials.gov (accessed 15/3 2018)