Update on GLP-1 p Past Present Future
Effects of GLP-1: Glucose Metabolism and Nutritional Balance L-Cells: Glp-1 release Betacellfollowing ingestion Stress Increases satiety reduces appetite Betacell- response Betacells: Boost of glucose dependent insulin release Alpha cells: postprandiale Glucagonsecretion liver: Inhibits glucagon mediated gluconeogenesis Stomach: Reduces stomach mortality Modifiied according to Flint A, et al. J Clin Invest. 1998;101:515-5.; Modified acording to Larsson H, et al. Acta Physiol Scand. 1997;1:413-422.; Modified according to Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Modified according to Drucker DJ. Diabetes. 1998;47:159-169.
GLP-1 RA : Change in Proinsulin/Insulin-Ratio Placebo 5 µg Exendine 10 µg Exendine 0.1 ange in in Ratio Mean (± SE) Ch Proins sulin/insuli 0.0-0.1-0.2 0.0-0.03-0.17 * -0.3 ITT Population, N=336 (Plazebo, n=113; 5 µg Exenatide, n=110; 10 µg Exenatide, n=113); *P <0.001 DeFronzo RA, et al. Diabetes Care 05; 27:1092-1.
Effects on postprandial proinsulin release from the beta cell during treatment with a DPP-IV inhibitor compared dto glimepiride iid Individual process of postprandial proinsulin secretion under OAD therapy (pmol/l) intact Proinsulin i 40 0 1A 1B 1C Baseline Glimepiride 0 0 300 40 12 weeks Glimepiride 24 weeks Glimepiride 0 0 0 300 0 40 0 0 300 (pmol/l) ntact Proinsulin i 1D Baseline Vildagliptin 1E 12 weeks Vildagliptin 1F 24 weeks Vildagliptin 0 40 0 0 300 Forst T. et al.; DOM; 13 (15) 302-314 0 40 0 0 300 0 40 0 0 300
GLP1- RA reduces postprandial Glucagon Secretion (pg/ml) 140 1 Placebo (n=13) GLP1-RA (n=13) 24-h Glucagon AUC after 5 days (ng/l/h, Mean ± SE) 2371 ± 135 Plasmag glukacon 0 0 4 8 12 16 24 Time after injection (hours) Injection (08.00) 2179 ± 118 (p = 0.04) According to: Degn et al. Diabetes 04;53:1187-1194. Mean ± SEM
GLP 1 improves alpha cell function during Hypoglycemia y Hypoglycaemic Glucose Clamp Steps Range 300 (mmol/l): 5.0 4.0 3.2 2.7 Remission Plasm ma Glukagon (ng/l) 250 0 150 Placebo (n=11) GLP-1 (n=11) 50 0 30 0 30 90 1 150 1 210 240 270 300 330 3 Time (min) Exenatide infused at.066 pmol/kg/min for 270 minutes. Adapted from Degn KB, et al. Diabetes. 04; 54: 2397 2403.
Pancreatic Safety of Incretin-Based Therapy FDA and EMA-Assessment Re-evaluated evaluated more than 250 toxicology studies conducted in healthy animals (15.4 rodents and 2.475 non-rodents No finding of overt pancreatic toxic effects or pancreatitis Absence of drug induced pancreatic tumors in rats and mice Re-examined 1 pancreatic histopathology slides from one of the 3 sponsor conducted, 3 3-months pancreatic toxicity studie in rodent model of diabetes. No treatment related adverse effects FDA performed own pancreatic toxicology studies with exenatide in both disease and non-disease rodent models Egan AG et al., Pancreatic Safety of Incretin based Drugs FDA and EMA Assessment; N. Engl.. J. Med.; 14 (370) 794-797
Pancreatic Safety of Incretin-Based Therapy FDA and EMA-Assessment Assessment of clinical safety databases including data from more than 0 ti trials Involving 41.000 participants with more than 28.000 exposed to incretin based treatments 15.000 with exposure for 24 weeks or more 8.500 with exposure for 52 weeks or more Reviewed results from the outcome trials with DPP-IV Inhibitors Conclusion FDA /EMA: Both agencies agree that assertions concerning a causal association between incretin based drugs and pancreatitis or pancreatic cancer, as expressed recently in the scientific literature and in the media, are inconsistent i t with the current data. The FDA and the EMA believe, that the current knowledge is adequately reflected in the product information of the labeling Egan AG et al., Pancreatic Safety of Incretin based Drugs FDA and EMA Assessment; N. Engl.. J. Med.; 14 (370) 794-797
Conclusions I : T2DM is a complex disease driven by increasing insulin resistance (obesity) complemented by a progressing mismatch in alpha- and beta cell function of the Langerhans islet. Incretin based treatments address the pathophysiology of T2DM by: improving blood glucose control without increasing the risk of hypoglycemia reducing glucotoxic effects restoring alpha and beta cell function, reducing body weight and visceral body fat mass (GLP-1 RA) improving the cardiovascular risk profile (pleiotropic effects)
Conclusions II : Incretin based therapies appear to be highly complementary partners for pharmacological intervention in T2DM GLP1-RA and DPP-IV inhibitors are overall well tolerated with temporary mild to moderate gastrointestinal side effects (GLP1 RA) with proven cardiovascular safety (Safety-Endpoints in DPP-IV inhibitor studies) without indication of a serious association between incretin based treatments and drug induced and pancreatitis or cancer