GLP-1RA and insulin: friends or foes?

Transcription

1 Tresiba Expert Panel Meeting 28/06/2014 GLP-1RA and insulin: friends or foes? Matteo Monami Careggi Teaching Hospital. Florence. Italy

2 Dr Monami has received consultancy and/or speaking fees from: Merck Sharp & Dohme AstraZeneca Bristol-Myers Squibb Eli Lilly Novo Nordisk Sanofi Takeda Disclosures In addition, the Diabetes Section directed by Dr Monami received research grants from AstraZeneca and BMS.

3 Initial drug monotherapy Two drug combinations Position statement ADA/EASD 2012 DPP-4-i GLP-1-RA Healthy Eating, Weight Control, Increased Physical Activity Metformin Sulfonylurea Thiazolidinedione DPP-4 inhibitor DPP-4-i GLP-1-RA SU GLP-1 receptor agonist SU Adapted from: Inzucchi et al. Diabetes Care 2012;35: (usually basal) DPP-4-i GLP-1-RA

4 Initial drug monotherapy Two drug combinations Position statement ADA/EASD 2012 DPP-4-i GLP-1-RA Healthy Eating, Weight Control, Increased Physical Activity Metformin Sulfonylurea Thiazolidinedione DPP-4 inhibitor DPP-4-i GLP-1-RA SU GLP-1 receptor agonist SU Adapted from: Inzucchi et al. Diabetes Care 2012;35: (usually basal) DPP-4-i GLP-1-RA

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7 Initial drug monotherapy Two drug combinations Position statement ADA/EASD 2012 Healthy Eating, Weight Control, Increased Physical Activity Metformin Sulfonylurea Thiazolidinedione DPP-4 inhibitor GLP-1 receptor agonist (usually basal) DPP-4-i DPP-4-i SU SU DPP-4-i And when failing to dual terapy? GLP-1-RA GLP-1-RA Adapted from: Inzucchi et al. Diabetes Care 2012;35: GLP-1-RA

8 Position statement ADA/EASD 2012 Initial drug monotherapy Two drug combinations Three drug combinations DPP-4-i GLP-1-RA Healthy Eating, Weight Control, Increased Physical Activity Metformin Sulfonylurea Thiazolidinedione DPP-4 inhibitor DPP-4-i GLP-1-RA SU GLP-1 receptor agonist SU Adapted from: Inzucchi et al. Diabetes Care 2012;35:

9 Position statement ADA/EASD 2012 Initial drug monotherapy Two drug combinations Three drug combinations DPP-4-i GLP-1-RA Healthy Eating, Weight Control, Increased Physical Activity Metformin Sulfonylurea Thiazolidinedione DPP-4 inhibitor DPP-4-i GLP-1-RA SU GLP-1 receptor agonist SU Adapted from: Inzucchi et al. Diabetes Care 2012;35:

10 Position statement ADA/EASD 2012 Initial drug monotherapy Two drug combinations Three drug combinations Healthy Eating, Weight Control, Increased Physical Activity Metformin Sulfonylurea Thiazolidinedione DPP-4 inhibitor DPP-4-i GLP-1-RA SU GLP-1 receptor agonist SU Adapted from: Inzucchi et al. Diabetes Care 2012;35:

11 Adding insulin to SU: efficacy Hirst JA, et al. Diabetologia 2013; 56:

12 Adding insulin to SU: low doses Hirst JA, et al. Diabetologia 2013; 56:

13 Adding insulin to SU: weight Hirst JA, et al. Diabetologia 2013; 56:

14 Adding insulin to SU: hypos Hirst JA, et al. Diabetologia 2013; 56:

15 Bone fracture and hypoglycemic treatments in type 2 diabetic patients Exposure for at least 36 months A case-control study Exposure at index date Monami M., et al. Diabetes Care 31: , 2008

16 Cardiovascular mortality Prevention of cardiovascular disease through glycemic control in type 2 diabetes UKPDS 7.0 vs 7.9 ADVANCE 6.5 vs 7.3 A meta-analysis of randomized clinical trials PROACTIVE 7.0 vs 7.6 VADT 6.9 vs 8.4 ACCORD 6.4 vs 7.5 In trials in which the reduction of HbA1c was obtained with a higher incidence of hypoglycaemia, CV MORTALITY is increased Mannucci E., Monami M., et al., NMCD 2009

17 Vascular disease and diabetes: is hypoglycemia an aggravator factor? Adrenercic activation could have a negative impact on the prognosis of MYOCARDIAL ISCHEMIA Wright RJ, et al., DMRR 2008; 24:

18 SU+Met Adding insulin to SU SU+Met+Ins Low insulin doses Risk of hypoglycemia Weight gain Questionable CV safety

19 Position statement ADA/EASD 2012 Initial drug monotherapy Two drug combinations Three drug combinations Healthy Eating, Weight Control, Increased Physical Activity Metformin Sulfonylurea Thiazolidinedione DPP-4 inhibitor DPP-4-i GLP-1-RA SU GLP-1 receptor agonist SU Adapted from: Inzucchi et al. Diabetes Care 2012;35:

20 Risk of heart failure Diabetes Trial GSK 0,01 Comparators Pbo/None Add-on to Overall / and chronic heart failure Yes No No Yes Metformin Sulfonylureas Monotherapy Metformin Sulfonylureas ,01 Chronic Heart Failure ,1 0,1 Better rosiglitazone 1 1 Worse rosiglitazone [ ] 2.61[ ] 2.44[ ] 1.12[ ] 1.45[ ] 1.00[ ] 2.10[ ] 1.67[ ] 2.20[ ] 0.30[ ] 1.00[ ] 1.69[ ] Mannucci E, Monami M, Di Bari M, Lamanna C, Gori F, Gensini GF, Marchionni N. International Journal of Cardiology 2010; 143: ;

21 and bone fractures

22 and bone fractures

23 +Met Adding insulin to s +Met+Ins Reduced insulin doses Weight gain-edema Heart failure Bone fractures

24 Position statement ADA/EASD 2012 Initial drug monotherapy Two drug combinations Three drug combinations Sulfonylurea DPP-4-i GLP-1-RA Healthy Eating, Weight Control, Increased Physical Activity Thiazolidinedione DPP-4-i GLP-1-RA Metformin DPP-4 inhibitor GLP-1 receptor agonist Adapted from: Inzucchi et al. Diabetes Care 2012;35: SU

25 DPP-4i and insulin: efficacy and safety Weight gain Diabetes, Obesity and Metabolism 12: , Hypoglycemic risk -0.6%

26 DPP-4i and insulin: heart failure The EXAMINE trial

27 Adding insulin to DPP4i DPP-4i+Met DPP4i+Met+Ins Modest increased in hypoglycemic risk Questionable CV safety Modest/No weight gain Low insulin doses Some advantages on HbA1c

28 Position statement ADA/EASD 2012 Initial drug monotherapy Two drug combinations Three drug combinations Sulfonylurea DPP-4-i GLP-1-RA Healthy Eating, Weight Control, Increased Physical Activity Thiazolidinedione DPP-4-i GLP-1-RA Metformin DPP-4 inhibitor SU GLP-1 receptor agonist Adapted from: Inzucchi et al. Diabetes Care 2012;35:

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31 Open-label study with two randomized and one non-randomized treatment arm Conducted in seven European countries, Canada and the USA Combining liraglutide with detemir Run-in phase: 12 weeks Liraglutide 1.2 mg 1 week Liraglutide 0.6 mg 1 week Liraglutide 1.8 mg Metformin 1500 mg/day SU discontinued Randomization Main treatment phase: 26 weeks 61% 39% HbA 1c <7.0% Non-randomized patients Liraglutide 1.8 mg (n=498) HbA 1c 7.0% 1:1 randomization Idet + liraglutide 1.8 mg (n=162) Liraglutide 1.8 mg (n=161) DeVries et al. Diabetes Care 2012;35: Extension phase: 26 weeks

32 Change in HbA1c (%) 0,4 0,2 0,0-0,2-0,4-0,6-0,8-1,0-1,2-1,4-1,6 Combining liraglutide with detemir Run-in phase (weeks 12 to 0) HbA 1c at week 12 (%) ,02 Main treatment phase (weeks 0 to 26) HbA1c at randomization (%) ,22-0,66-0,60-1,34-0,51-0,76-1,13 p< Total study duration (weeks 12 to 26) HbA1c at week 26 (%) ,12 Liraglutide 1.8 mg IDet + Liraglutide 1.8 mg Non-randomized liraglutide 1.8 mg DeVries et al. Diabetes Care 2012;35:

33 and GLP-RA: efficacy and safety

34 Adding insulin to GLP-1RA GLP-1RA+Met Very good effect on HbA1c Nice reduction of body weight No hypoglycemic risk Very good CV safety Some cases of pancreatitis Transient Nausea/vomiting GLP-1RA+Met+Ins Very good effect on HbA1c Neutral on body weight Reduction of insulin doses Relatively low hypoglycemic risk unknown CV safety Some cases of pancreatitis Transient nausea/vomiting

35 DUAL I: Study design Patients with type 2 diabetes (n= 1663) Inclusion criteria Type 2 diabetes naïve treated with metformin ± pioglitazone HbA 1c % BMI 40 kg/m 2 Age 18 years * Randomised 2:1:1 Open label IdegLira: the future IDegLira + met ± pio (n=834) IDeg + met ± pio (n=414) Liraglutide 1.8 mg + met ± pio (n=415) 0 26 weeks Titration algorithm: IDegLira and IDeg Mean fasting PG mmol/l Dose change dose steps or U < > Buse et al. ADA 2013: 65-OR; Gough et al. EASD 2013: 219-OR Titrate to target FPG 4 5 mmol/l Starting dose: 10 dose steps/units Dose adjustments (2-0-2) twice weekly

36 DUAL I: HbA1c over time HbA 1c (%) 8,5 8,0 7,5 7,0 6,5 6,0 IdegLira: the future 0.0 5, Time (weeks) Buse et al. ADA 2013: 65-OR; Gough et al. EASD 2013: 219-OR HbA 1C Liraglutide (n=414) IDeg (n=413) IDegLira (n=833) EOT -1.28% 7.0% -1.44% 6.9% -1.91%* 6.4% *p< vs. IDeg and vs. liraglutide

37 DUAL I: Benefits DUAL TM I HbA 1c (%) * IdegLira: the future Liraglutide FPG (mmol/l) IDeg -3.0 IDegLira Weight (kg) -0.5 * 1.6 Confirmed hypoglycaemia -32% Buse et al. ADA 2013: 65-OR; Gough et al. EASD 2013: 219-OR Nocturnal confirmed hypoglycaemia +661% +732% vs. Lira vs. IDeg -13%

38 Conclusions 1. The addition of insulin to GLP-1RA+Met is an effective choice in terms of A1c reduction and seems to be superior to other possible combinations with OAD and insulin. 2. The reduction of A1c is obtained with no weight gain and a relatively low hypoglycemic risk. 3. The future of this strategy seems to be IdegLira which appears to be superior in reducing A1c with a lower hypoglycemic risk and weight gain.

39 Conclusions (2) If it was possible.(glp1 RA add-on to pre-existing insulin therapy) Significant A1C lowering Alternative to intensification with prandial / premixed insulin Weight gain expected with insulin may be reversed with GLP1RA It should be considered an insulin dose reduction to prevent hypoglycemia