GLP 1 agonists Winning the Losing Battle. Dr Bernard SAMIA. KCS Congress: Impact through collaboration

Transcription

1 GLP 1 agonists Winning the Losing Battle Dr Bernard SAMIA KCS Congress: Impact through collaboration CONTACT: Tel kcardiacs@gmail.com Web:

2 Disclosures I have no conflicts of interest for this talk I have no relationships to disclose

3 Outline Role of GLP-1 in human physiology Treatment options for diabetes Role of GLP-1 RA in managing T2DM CV Benefits of GLP1 RA Clinical trials on GLP1 RA and relevance in practice Conclusion CV, cardiovascular; GLP-1, glucagon-like peptide-1; GLP-1RA, glucagon-like peptide-1 receptor agonist; MACE, major adverse cardiovascular event

4 Pathophysiology of type 2 diabetes Increased hepatic glucose production Intake of carbohydrates amount and timing Neurotransmitter dysfunction Decreased insulin secretion Impaired gut incretin function Hyperglycaemia Islet cell: Increased glucagon secretion Increased glucose reabsorption Increased lipolysis Decreased glucose uptake Adapted from DeFronzo RA. Diabetes 2009;58:

5 Change in weight (kg) Patients with hypoglycaemia (%) Most therapies result in hypogly and weight gain over time UKPDS: up to 8 kg in 12 years Conventional (n=411) Glibenclamide (n=277) Metformin (n=342) Insulin (=409) Years from randomisation p<0.05 glibenclamide vs. rosiglitazone Rosiglitazone Metformin Glibenclamide UKPDS 34. Lancet 1998:352:854 65; Kahn et al. (ADOPT). N Engl J Med 2006;355:

6 Choosing a treatment for type 2 diabetes Clinicians must balance potential side effects with glycaemic benefits Glycaemic control HbA 1c Side effects Hypoglycaemia Weight gain Inzucchi et al. Diabetologia 2012;55:

7 Diabetes and Incretins: GLP1

8 The role of GLP-1 in human physiology Fat cells Glucose uptake Lipolysis Liver Glycogen storage GI tract Motility Brain Neuroprotection Neurogenesis Memory Glu Phe His Ala Glu Gly Thr Phe Thr Ser Asp Val Lys Ala DPP-4 Ala GLP-1 Gln Gly Glu Leu Tyr Ile Ala Trp Leu Val Lys Gly Arg Gly Ser Ser Heart Myocardial contractility Heart rate Myocardial glucose uptake Ischaemia-induced myocardial damage Pancreas New β-cell formation β-cell apoptosis Insulin biosynthesis Kidney Natriuresis Blood vessel Endothelium-dependent vasodilation Skeletal muscle Glucose uptake DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1 Adapted from Meier JJ et al. Nat Rev Endocrinol 2012;8:728 42

9 Plasma glucose (mmol/l) Insulin (mu/l) Role of incretin effect in healthy insulin response 15 Plasma glucose 80 Insulin response Incretin effect Time (min) Oral glucose load (50 g) Time (min) 180 IV glucose infusion Insulin response is greater following oral glucose than IV glucose, despite similar plasma glucose concentration IV, intravenous Nauck M et al. Diabetologia 1986;29:46 52

10 Insulin (mu/l) Insulin (mu/l) The incretin effect is diminished in patients with type 2 diabetes 80 Healthy controls 80 Type 2 diabetes Incretin effect Time (min) Oral glucose Time (min) IV glucose p<0.05, healthy volunteers (n=8) Nauck M et al. Diabetologia 1986;29:46 52

11 Plasma glucagon (pmol/l) Glucagon levels are elevated in patients with type 2 diabetes Fasting glucagon Postprandial glucagon 25 p< Normal subjects T2DM patients 10 5 n: T2DM patients=54; Normal subjects=33 T2DM, type 2 diabetes mellitus Toft-Nielson MB et al. J Clin Endocrinol Metab 2001;86: Minutes

12 Effect of GLP-1 is glucose-dependent 15 Glucose (mmol/l) 300 Insulin (pmol/l) 20 Glucagon (pmol/l) Time (min) Time (min) Time (min) Placebo Native human GLP-1 Effects of 4-hour GLP-1 infusion (1.2 pmol/kg/min) in 10 patients with type 2 diabetes Mean (SE); n=10 p<0.05 GLP-1, glucagon-like peptide-1; SE, standard error Nauck M et al. Diabetologia 1993;36:

13 Insulin (pmol/l) Insulin (pmol/l) GLP-1 restores insulin secretion in T2DM Physiological levels of GLP-1 1 (15 mm hyperglycaemic clamp) Pharmacological levels of GLP-1 2 (15 mm hyperglycaemic clamp) GLP-1 infusion period (0.5 pmol/kg/min) Plasma GLP-1: 46 pmol/l Healthy GLP-1 infusion period (1.0 pmol/kg/min) Plasma GLP-1: 126 pmol/l T2DM Plasma GLP-1: 41 pmol/l T2DM Time (min) Time (min) GLP-1, glucagon-like peptide 1; T2DM, type 2 diabetes mellitus 1. Højberg PV et al. Diabetologia 2009;52: ; 2. Vilsbøll T et al. Diabetologia 2002;45:

14 How does that translate with GLP1 RA

15 GLP-1RA addresses 6 of the 8 pathophysiological defects contributing to hyperglycaemia Impaired insulin secretion Islet β-cell Decreased incretin effect Increased glucagon secretion Islet α-cell Hyperglycaemia Increased hepatic glucose production Neurotransmitter dysfunction Decreased glucose uptake Created from: DeFronzo RA. Diabetes 2009;58: Wolters Kluwer Health.

16 What do the Guidelines recommend?

17 ADA/EASD position statement 2015 Healthy eating, weight control, increased physical activity Monotherapy Metformin Not at target HbA 1c after ~3 months Dual therapy Not at target HbA 1c after ~3 months Triple therapy Not at target HbA 1c after 3 months: combination therapy with insulin SU TZD DPP-4i GLP-1RA Insulin TZD SU DPP-4i GLP-1RA Insulin DPP-4i SU TZD Insulin SGLT-2i SU TZD DPP-4i Insulin GLP-1 RA SU TZD Insulin Insulin TZD DPP-4i GLP-1RA Disease progression Combination injectable therapy Metformin + basal insulin + mealtime insulin or GLP-1RA DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; SGLT-2i, sodium-glucose co-transporter-2 inhibitor; SU, sulphonylurea; TZD, thiazolidinedione American Diabetes Association. Approaches to glycemic treatment. Sec. 7. In Standards of Medical Care in Diabetes Diabetes Care 2016;39(Suppl. 1):S52 S59

18 Choice of therapy after metformin: What we know SU TZD DPP-4i GLP-1RA Insulin (basal) SGLT-2i Efficacy ( HbA 1c ) Hypoglycaemi a risk High High Intermediate High Highest Intermediate Moderate Low Low Low High Low Weight effect Major side effects Hypoglycaemi a Oedema Heart failure Bone fractures Rare GI Hypoglycaemi a GU infections Dehydration Limited comparative data are available DPP-4i, dipeptidyl peptidase-4 inhibitor; GI, gastrointestinal; GLP-1RA, glucagon-like peptide-1 receptor agonist; GU, genitourinary; HbA 1c, glycosylated haemoglobin; SU, sulphonylurea; TZD, thiazolidinedione;, increase;, decrease;, neutral American Diabetes Association. Approaches to glycemic treatment. Sec. 7. In Standards of Medical Care in Diabetes Diabetes Care 2016;39(Suppl. 1):S52 S59

19 Approved GLP-1 agonists exenatide liraglutide lixisenatide albiglutide dulaglutide Under investigation taspoglutide semaglutide

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21 Patient selection Patients who have had episodes of hypoglycemia on large insulin doses Obese patients who could benefit from the modest weight loss Patients who are failing to achieve adequate glycemic control on one or more oral medications.

22 Cardiovascular outcomes in Guidelines for GLP-1 RA Diabetes Care, January 2017, Volume 40, Supplement 1

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24 CV benefits The LEADER study

25 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 Jun 13. [Epub ahead of print] 25

26 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 Jun 13. [Epub ahead of print]. 26

27 Patients with an event (%) Primary outcome CV death, non-fatal myocardial infarction, or non-fatal stroke % P la c e b o L ir a g lu t id e Patients at risk Liraglutide Placebo HR= % CI (0.78 ; 0.97) p<0.001 for non-inferiority p=0.01 for superiority Time from randomisation (months) The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke. The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox-proportional hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI, confidence interval; CV, cardiovascular; HR, hazard ratio. Marso SP et al. N Engl J Med 2016; 375:

28 Individual components of the primary outcome 22% 12% 11% The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox-proportional hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI, confidence interval; CV, cardiovascular; HR, hazard ratio. Marso SP et al. N Engl J Med 2016; 375:

29 Expanded MACE, All-cause death, Hospitalisation for HF 22% 15% 13% The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox-proportional hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI, confidence interval; HR, hazard ratio; MACE, major adverse cardiovascular event; MI, myocardial infarction. Marso SP et al. N Engl J Med 2016; 375:

30 Microvascular events 16% 15% 22% The cumulative incidences were estimated with the use of the Kaplan Meier method, and the HRs with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; HR: hazard ratio

31 Clinical and metabolic outcomes Data are estimated mean values from randomisation to EOT. CI, confidence interval; EOT, end of trial; ETD, estimated treatment difference; HbA 1c, glycosylated haemoglobin. Marso SP et al. N Engl J Med 2016; 375:

32 Other CV outcome trials

33 Other clinical trials Monotherapy studies Comparison trials between GLP-1 RA Add-on to metformin studies Add-on to metformin + sulfonylurea studies Add-on to metformin + thiazolidinedione studies Comparisons with basal insulin Add-on to background insulin therapy

34 Conclusions GLP-1RAs and GLP-1 have a range of actions across the body GLP-1RAs have positive effects on numerous cardiovascular risk markers The positive effects of GLP-1RAs on different organs may be beneficial in the treatment of complex patients with type 2 diabetes Research into GLP-1RAs is ongoing, with novel indications, combination partners and delivery mechanisms expected over the coming years GLP-1, glucagon-like peptide-1; GLP-1RAs, glucagon-like peptide-1 receptor agonists

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