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
Incretin-based glucose lowering Two options DPP-4 inhibition GLP-1 receptor agonists GLP-1 receptor agonism Requires injection Effects Mimics the effect of GLP-1 Insulin secretion Reduces HbA 1c by ≥1% Glucagon secretion Causes weight loss of 2 – 3 kg Beta-cell mass Low risk of hypoglycaemia Insulin sensitivity when used with metformin Gastric emptying Reduced risk of hypoglycaemia Satiety if combined with insulin Baggio LL & Drucker DJ. Gastroenterology 2007;132:2131 – 2157
GLP-1 receptor agonists Broad approach Exendin-4 based Shortacting Exenatide BID Lixisenatide OD GLP-1 Human analogues receptor Liraglutide QD agonists Semaglutide QW Dulaglutide QW Longacting Exendin-4 based Exenatide LARQW ITCA 650 Meier JJ. Nat Rev Endocrinol 2012;8:728 – 742 Drucker DJ. Cell Metab 2016;24:15 – 30 Madsbad S et al. Diabetes Obes Metab 2011;13:394 – 407
GLP-1 receptor agonists in type 2 diabetes Results from available outcome trials Exendin-4 based Shortacting Exenatide BID Lixisenatide Lixisenatide OD GLP-1 Human analogues receptor Liraglutide QD agonists Semaglutide QW Dulaglutide QW Longacting Exendin-4 based Exenatide Exenatide LARQW ITCA 650 ITCA 650 ITCA 650 is an investigational product and not currently approved
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;373:2247 – 2257
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;377:1228 – 1239
GLP-1 receptor agonists in type 2 diabetes Results from available outcome trials Exendin-4 based Shortacting Exenatide BID Lixisenatide Lixisenatide OD GLP-1 Human analogues receptor Liraglutide QD Liraglutide agonists Semaglutide QW Semaglutide Dulaglutide QW Longacting Exendin-4 based Exenatide LARQW ITCA 650 Semaglutide is an investigational product and not currently approved
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 ~ 7.7% Liraglutide Placebo ~ 8.0% Marso SP et al. N Engl J Med 2016;375:311 – 322
SUSTAIN 6 Semaglutide 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 ~ 7.3% Liraglutide Placebo ~ 8.3% Marso SP et al. N Engl J Med 2016;375:1834 – 1844 Semaglutide is an investigational product and not currently approved
Liraglutide and semaglutide SUSTAIN 6 Semaglutide sc once-weekly Let us go into some details... Semaglutide is an investigational product and not currently approved
Liraglutide Placebo Patient characteristics at study start Variable 100 Male sex (%) 64 Percentage of patients 80 Age (years) 64 Diabetes duration (years) 13 60 HbA 1c 8.7 40 BMI (kg/m 2 ) 32.5 20 Blood pressure (mmHg) 136/77 0 Heart failure (%) 18 With previous CVD With CVD risk factors ( age ≥ 5 0 ) ( age ≥ 6 0 ) Marso SP et al. N Engl J Med 2016;375:311 – 322
Liraglutide Placebo Background therapy at study start Liraglutide Placebo 100 Proportion of patients ( % ) 77.1 75.8 80 60 50.8 50.6 45.6 43.7 40 20 6.3 6.0 3.8 3.7 3.0 2.6 0 M e t f ormin Su lphony lure a s Alpha - glucosida se inhibit ors TZ Ds Glinide s I n sulin Metform in SUs Alpha-glucosidase TZDs Glinides I nsulin Metformin SU AGI TZD Glinides Insulin inhibitors 100 92.7 92.1 Proportion of patients ( % ) 76.3 75.2 80 68.7 66.8 60 41.8 41.8 40 20 6.7 7.0 0 Antihypertensive therapy Diuretics Lipid-lowering drugs Platelet aggregation inhibitors Other Antihypertensive Diuretics Lipid-lowering Other anti-throm botic anti-thrombotic medication Platelet BP-lowering Diuretics Lipid-lowering ASA Plat stab therapy drugs aggregation m edication inhibitors Marso SP et al. N Engl J Med 2016;375:311 – 322
Treatment recommendations Treatment/guideline • HbA 1c ≤7.0% (individualised) Blood glucose • Blood pressure Target: 130/80 mmHg • Target LDL <100 mg/dL (<70 mg/dL [1.8 mmol/L] if CV events) Lipids • 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;375:311 – 322
Consistency H azard ratio p- value for N o. of H azard Subgroup Subgroup ( 95% CI ) interaction patients ( 95% 0.87 ( 0.78 ; 0.97) Prim ary analysis Prim ary analysis 9340 0.87 ( 0.78 0.84 Sex H bA 1c ≤ 8.3% 0.89 (0.76 ; Female 0.88 (0.72 ; 1.08) 3337 >8.3% 0.84 (0.72 ; Male 0.86 (0.75 ; 0.98) 6003 Duration of diabetes 0.27 Age ≤ 11 years 0.82 (0.70 ; <60 years 0.78 (0.62 ; 0.97) 2321 >11 years 0.90 (0.78 ; ≥ 60 years 0.90 (0.79 ; 1.02) 7019 Risk of CVD 0.20 p=0.04 Geographic region Age ≥ 50 years and established CVD 0.83 (0.74 ; Europe 0.82 (0.68 ; 0.98) 3296 Age ≥ 60 years and risk factors for CVD 1.20 (0.86 ; North America 1.01 (0.84 ; 1.22) 2847 Chronic heart failure Asia 0.62 (0.37 ; 1.04) 711 Yes 0.94 (0.72 ; Rest of the world 0.83 (0.68 ; 1.03) 2486 No 0.85 (0.76 ; 0.32 Race Antidiabetic therapy White 0.90 (0.80 ; 1.02) 7238 1 OAD 0.75 (0.58 ; Black or African 0.87 (0.59 ; 1.27) 777 >1 OAD 0.95 (0.78 ; American Insulin with OAD(s) 0.89 (0.74 ; Asian 0.70 (0.46 ; 1.04) 936 Insulin without OAD 0.86 (0.63 ; Other 0.61 (0.37 ; 1.00) 389 None 0.73 (0.42 ; 0.30 Ethnic group p=0.01 Renal function Hispanic or Latino 0.74 (0.54 ; 1.02) 1134 <60 mL/min/1.73 m 2 0.69 (0.57 ; Not Hispanic or 0.89 (0.79 ; 1.00) 8206 ≥ 60 mL/min/1.73 m 2 0.94 (0.83 ; Latino 0 .2 2 1 0 . 2 1 2 Hazard rat io ( 9 5 % CI ) H azard rat io ( 9 5 % CI ) Favours liraglut ide Favours placebo Favours liraglu t id e Favours placebo Marso SP et al. N Engl J Med 2016;375:311 – 322
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;375:311 – 322
Primary outcome by insulin use at baseline Primary outcome in patients never treated with insulin during the trial Liraglutide Placebo Liraglutide Placebo Hazard ratio Hazard ratio (95% CI) (95% CI) N % N % N R N R Total number of patients 4668 4672 Total number of patients 4668 4672 Primary outcome 0.87 (0.78 ; 0.97) 608 13.0 694 14.9 Primary outcome 0.87 (0.78 ; 0.97) 608 3.4 694 3.9 Patients not on insulin at baseline 2630 2541 Insulin use at baseline (Y/N) Primary outcome 0.82 (0.68 ; 0.98) 229 2.9 217 3.5 Yes 0.88 (0.75 ; 1.03) 295 14.5 347 16.3 No 0.86 (0.74 ; 1.01) 313 11.9 347 13.7 0,5 0,75 1 1,25 Hazard ratio (95% CI) 0,5 0,75 1 1,25 Favours liraglutide Favours placebo Hazard ratio (95% CI) Favours liraglutide Favours placebo Presented at the American Diabetes Association 77th Scientific Sessions, Session 1-AC-SY13. 11 June 2017, San Diego, CA, USA
Microvascular events Definition – one or m ore of the below Event type New onset of persistent macroalbuminuria • Persistent doubling of serum creatinine * • Renal Need for continuous renal replacement therapy • Microvascular even ts Death due to renal disease • Need for retinal photocoagulation or treatment • with intravitreal agents Eye Vitreous haemorrhage • • Diabetes-related blindness Time to first microvascular event Placebo 10 8 Patients w ith an event ( % ) Liraglutide 6 4 HR 0 .8 4 (95% CI 0.73 ; 0.97) 2 p =0.02 0 0 6 12 18 24 30 36 42 48 54 *and eGFR ≤45 mL/min/1.73 m 2 per MDRD Tim e from random isation ( m onths) Marso SP et al. N Engl J Med 2016;375:311 – 322
Liraglutide Liraglutide Placebo Glycaemic control HbA 1c Baseline 8.7 8.7 9,0 75 0,0 70 8,5 -0,77 Mean HbA 1c (mmol/mol) -1,16 65 8,0 -1,0 Mean HbA 1c (%) 60 7,5 55 ETD – 0.40 (95% CI: – 0.45 ; 0.34) 7,0 50 p <0.001 -2,0 6,5 45 GLOD added 6,0 40 2500 Liraglutide Placebo Number of patients 2,019 5,5 2000 35 1500 5,0 30 -3 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 EOT63 EOT * 1000 Time since randomisation (months) 500 0 Metformin Sulphonylureas Alpha-glucosidase TZDs Glinides Insulin inhibitors Alpha-glucosidase Metformin SUs TZDs Glinides Insulin inhibitors Additional classes added Liraglutide Placebo DPP-4 inhibitors 149 170 GLP-1RAs 87 139 *EOT may be any time from Month 42 to Month 60 SGLT-2 inhibitors 100 130 Marso SP et al. N Engl J Med 2016;375:311 – 322
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