GLP-1 agonists Ian Gallen Consultant Community Diabetologist Royal Berkshire Hospital Reading UK
What do GLP-1 agonists do?
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;88:787-835 2 Horowitz M et al. Diabet Med 2002;19:177-94
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;26:2929-2940; and Wang Q, et al. Diabetologia. 2004;47(3):478-487.
The incretin effect oral glucose load (50 g) iv glucose infusion 15 Plasma glucose 270 80 Plasma insulin 10 mmol/l 5 180 mg/dl 90 60 mu/l 40 20 Incretin effect 0 10 5 60 120 180 Time (min) 0 0 10 5 60 120 180 Time (min) Insulin response is greater following oral glucose than iv glucose, despite similar plasma glucose concentrations Nauck MA et al. Diabetologia 1986;29:46 52. Healthy volunteers n=8
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 30 15.0 2.5 25 12.5 10.0 7.5 5.0 2.5 * * * * * 2.0 1.5 1.0 0.5 * * * * * * * 20 15 10 5 * * * * 0.0 0.0 0 Time (min) Time (min) Time (min) 30 0 30 60 90 120 150 180 210 240 30 0 30 60 90 120 150 180 210 240 30 0 30 60 90 120 150 180 210 240 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.
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<0.0001 GLP-1 (7-36 amide) 1.5 nmol/kg sc Adapted from Nauck MA et al. Diabetologia 1996;39:1546 53 Time (min)
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;368:1696 1705
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
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
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=107-0.1 n=53 n=54-1 -0.2-2 -0.18-0.3-3 -0.4-4 -5-0.5-6 -0.6-7 -0.7-0.69-8 -0.8 p<0.0001-0.78-9 -0.9 p<0.0001-10 -1.0-11 HbA 1c (mmol/mol) 0-0.5-1.0-1.5-2.0-2.5-3.0-3.5 Placebo -1.94 (kg) 20 mcg OD n=53-3.01 n=108 10 mcg BD n=54-2.21 Adapted from Ratner RE. Diabet Med 2010:2;1024 32 *LS mean
Differences with Short and Long acting GLP-1 agonists
Short and Long acting GLP-1 (other effects)
Short and Long acting GLP-1 Wysham C. et al. Diabetes Care 2014;37:2159-2167
Long acting GLP-1
Long acting GLP-1
ABCD National GLP-1 agonist audits
ABCD National GLP-1 agonist audits
Adding GLP-1 to insulin therapy: Weight Jiten Vora Dia Care 2013;36:S226-S232
Adding GLP-1 to insulin therapy: Control and hypoglycaemia Jiten Vora, Dia Care 2013;36:S226-S232
IDegLira; Glycaemic Control
IDegLira; Side effects
Lixisenatide and Glargine
GLP1 agonists and HbA1c
GLP1 agonist and weight
GLP1 agonist and cost per month Lixisenatide 20mg od; 54.14 Exenatide (10µg bd); 68.24 Byduron; 73.76 Liraglutide (1.2mg od); 78.48. Liraglutide (1.8mg od); 117.72 Dulaglutide (1.5mg) ; 73 pm IDegLira (50 dose daily); 159.22
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.
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.