GLP-1 agonists. Ian Gallen Consultant Community Diabetologist Royal Berkshire Hospital Reading UK

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1 GLP-1 agonists Ian Gallen Consultant Community Diabetologist Royal Berkshire Hospital Reading UK

2 What do GLP-1 agonists do?

3 Physiology of postprandial glucose regulation Meal ❶ ❷ Insulin Rising plasma glucose stimulates pancreatic β-cells to secrete insulin 1 Glucagon Insulin Glucagon Gastric emptying Plasma glucose inhibits glucagon secretion by pancreatic α-cells 1 PPG ❸ Gastric emptying Delaying and/or slowing gastric emptying is a major determinant postprandial glycaemic excursion 2 of Hepatic glucose output + Glucose uptake PPG = postprandial glucose 1 DeFronzo RA. Med Clin North Am 2004;88: Horowitz M et al. Diabet Med 2002;19:177-94

4 Glucagon-like peptide-1 and incretin effect β-cell α-cell Food intake GLP-1 Incretin effect Pancreatic islet GLP-1 is a major intestinal hormone mediating the incretin effect GLP-1 potentiates insulin release and reduces glucagon secretion in glucose-dependent manner Adapted from Drucker D. Diabetes Care. 2003;26: ; and Wang Q, et al. Diabetologia. 2004;47(3):

5 The incretin effect oral glucose load (50 g) iv glucose infusion 15 Plasma glucose Plasma insulin 10 mmol/l mg/dl mu/l Incretin effect Time (min) Time (min) Insulin response is greater following oral glucose than iv glucose, despite similar plasma glucose concentrations Nauck MA et al. Diabetologia 1986;29: Healthy volunteers n=8

6 GLP-1 restores insulin and glucagon responses in type 2 diabetes 17.5 GLP-1 Glucose (mmol/l) 3.0 Saline C-peptide (nmol/l) Glucagon (pmol/l) Infusion Infusion Infusion * * * * * * * * * * * * * * * * Time (min) Time (min) Time (min) GLP-1(7 36 amide) infused at 1.2 pmol/kg/min for 240 min. *p<0.05 Adapted from Nauck MA et al. Diabetologia 1993;36:741 4.

7 GLP-1 delays gastric emptying Subcutaneous injection of GLP-1 delays gastric emptying by about 30 min in type 2 diabetes GLP-1 or placebo Gastric volume (ml) Liquid meal 400 ml GLP-1 Placebo *p< GLP-1 (7-36 amide) 1.5 nmol/kg sc Adapted from Nauck MA et al. Diabetologia 1996;39: Time (min)

8 Incretin-based therapies GLP-1 receptor agonists and DPP-4 inhibitors GLP-1 receptor agonists Short-acting BD Exenatide (Byetta) OD Lixisenatide (Lyxumia) Long-acting OD Liraglutide* (Victoza) Longer-acting QW Exenatide (Bydureon) Dulaglutide (Trulicty) Subcutaneous injection DPP-4 inhibitors Sitagliptin OD Vildagliptin BD Saxagliptin OD Linagliptin OD Tablets Mimics endogenous GLP-1 Enhance endogenous GLP-1 *Human GLP-1 analogue, others are exendin-based DPP-4 = dipeptidyl peptidase-4; OD = once daily; BD = twice daily; QW = once weekly Drucker DJ, Nauck MA. Lancet 2006;368:

9 Actions of GLP-1 agonists Promote 1 st phase insulin secretion Reduce glucagon release Delay gastric emptying Weak satiety effect Thus lowering blood glucose with modest weight loss without hypoglycaemia

10 Choice of GLP-1 receptor agonist: short acting versus long acting The pharmacological profile and half-life of a GLP-1 receptor agonist influences its effects on postprandial and basal (fasting) glycaemia SHORT ACTING GLP-1 receptor agonists Lixisenatide OD, Exenatide BD or LONG ACTING GLP-1 receptor agonists Liraglutide OD, Exenatide/Dulaglutide QW Effect on FPG Effect on PPG Effect on FPG Effect on PPG FPG = fasting plasma glucose PPG = postprandial glucose Fineman MS et al. Diabetes Obes Metab 2012;14:675-88

11 HbA 1c (%) Short acting GLP-1 agonists: Lixisenatide Change in HbA 1c at endpoint* Change in body weight at endpoint* Placebo 20 mcg 10 mcg OD BD 0 0 n= n=53 n= p< p< HbA 1c (mmol/mol) Placebo (kg) 20 mcg OD n= n= mcg BD n= Adapted from Ratner RE. Diabet Med 2010:2; *LS mean

12 Differences with Short and Long acting GLP-1 agonists

13 Short and Long acting GLP-1 (other effects)

14 Short and Long acting GLP-1 Wysham C. et al. Diabetes Care 2014;37:

15 Long acting GLP-1

16 Long acting GLP-1

17 ABCD National GLP-1 agonist audits

18 ABCD National GLP-1 agonist audits

19 Adding GLP-1 to insulin therapy: Weight Jiten Vora Dia Care 2013;36:S226-S232

20 Adding GLP-1 to insulin therapy: Control and hypoglycaemia Jiten Vora, Dia Care 2013;36:S226-S232

21 IDegLira; Glycaemic Control

22 IDegLira; Side effects

23 Lixisenatide and Glargine

24 GLP1 agonists and HbA1c

25 GLP1 agonist and weight

26 GLP1 agonist and cost per month Lixisenatide 20mg od; Exenatide (10µg bd); Byduron; Liraglutide (1.2mg od); Liraglutide (1.8mg od); Dulaglutide (1.5mg) ; 73 pm IDegLira (50 dose daily);

27 When to use GLP1-agonists HbA1c>58 mmol/l +oral agents; Overweight. With metformin/pioglitizone/sglt2 inhibitors. Stop DPP4 and Sulphonylureas. Or with basal insulin; To avoid further weight gain. To reduce hypoglycaemia.

28 How to use GLP1-agonists With Oral Treatment; Use least expensive agent (lixisentatide). Continue with Metformin and/or Pioglitazone. Add SGLT2 inhibitor if post-prandial hyperglycaemia. Move from lixisenatide/exenatide to a Glutide; if nauseous or sub-optimal response. Transfer to biphasic insulin (Humulin M3); if no weight loss or improved glycaemic control. With OD human basal (Humulin I); with dose increasing by 10% alternate days to reduce FBG < 6mmol.

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