dpp4 And Diabetes

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Dpp4 … From pathophysiology to clinical practice :

Dpp4 … From pathophysiology to clinical practice Mohamed ELOKL, MD, MRCP (UK) Consultant Internist and Geriatrician Assistant Professor Geriatrics Ain Shams University , Egypt [email protected]

Roadmap :

Roadmap Development and Progression of Type 2 Diabetes Dpp4 inhibitors as New therapies for type 2 diabetes Efficacy and safety of Dpp4 inhibitors Place of Dpp4 in guidelines

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Development and Progression of Type 2 Diabetes

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a Conceptual representation. 1. Reproduced with permission of Elsevier from Ramlo-Halsted et al. Primary Care. 1999; 26(4):771–789. Development and Progression of Type 2 Diabetes Insulin level Insulin resistance Hepatic glucose production Postprandial glucose Fasting plasma glucose B eta -cell function Progression of Type 2 Diabetes Mellitus Impaired Glucose Tolerance Diabetes Diagnosis Frank Diabetes 4–7 years Development of Macrovascular Complications Development of Microvascular Complications

Pathophysiology of Type 2 Diabetes Other Factors:

Pathophysiology of Type 2 Diabetes Other Factors Two other factors: - Glucagon. - Gastric emptying. Oral glucose load increased insulin more than iv glucose !!!??

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GLP-1 Modes of Action in Man GLP-1 is secreted from the L-cells in the jejunum and ileum Stimulates insulin secretion Suppresses glucagon secretion Suppress hepatic glucose production Slows gastric emptying decelerates gastric emptying Long term effects demonstrated in animals… Increases beta-cell cell mass and maintains beta-cell efficiency Reduces food intake Upon ingestion of food… Drucker DJ. Curr Pharm Des 2001; 7:1399-1412 , Drucker DJ. Mol Endocrinol 2003; 17:161-171 Glucose dependent effect

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Adapted from Deacon CF, et al. Diabetes . 1995;44:1126-1131 . GLP-1 Secretion and Inactivation Intestinal GLP-1 release GLP-1 (7-36) active Mixed meal GLP-1 (9-36) inactive (>80% of pool) DPP-4 T 1/2 = 1 to 2 min GLP1 very short half life Changed into inactive form by DPP4

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The hormone exendin-4 occurs naturally in the saliva of the Gila monster , a large venomous lizard native to the southwestern United States and northwestern Mexico Incretin mimetics are glucagon-like peptide-1 (GLP-1) agonists. Exenatide Liraglutide

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Adapted from Deacon CF, et al. Diabetes . 1995;44:1126-1131 . GLP-1 Secretion and Inactivation Intestinal GLP-1 release GLP-1 (7-36) active Mixed meal GLP-1 (9-36) inactive (>80% of pool) DPP-4 T 1/2 = 1 to 2 min

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Inhibition of DPP- 4 Increases Active GLP-1 GLP-1 (9-36) inactive Intestinal GLP-1 release Mixed meal GLP-1 (7-36) active DPP-4 Adapted from Rothenberg P, et al. Diabe tes . 2000;49(suppl 1):A39. DPP-4 inhibitor GLP-1 (7-36) active Dipeptidyl peptidase-IV antagonists inhibit the breakdown of GLP-1.

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DPP 4 Inhibitors

↓ HbA1c :

↓ HbA1c Multiple trials lasting 12–52 weeks. Sitagliptin : ↓ HbA1c levels ↓ 0.65% after 12 weeks ↓ 0.84% after 18 weeks. ↓ 0.85% after 24 weeks. ↓ 1.0% after 30 weeks. ↓ 0.67% after 52 weeks. Saxagliptin: 0.43–1.17%. Vildagliptin ↓ HbA1c levels of 1.4% after 24 weeks as monotherapy in a subgroup of patients with no prior oral treatment and after a short period of time from the diagnosis of diabetes. In a meta-analysis sitagliptin and vildagliptin for ≥12 weeks compared with placebo and other oral antidiabetic drugs,showed a reduction of 0.74% in HbA1c levels. Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA 2007; 298(2): 194-206.

Dpp-4 inhibitors and weight:

Dpp-4 inhibitors and weight Variable effect on weight but generally considered to be neutral . Sitagliptin : 1.5 kg of weight loss to 1.8 kg of weight gain. Vildagliptin : 1.8 kg of weight loss to 1.3 kg of weight gain . Saxagliptin : 1.8 kg of weight loss to 0.7 kg of weight gain . In a metaanalysis of 13 studies regarding the treatment of all three DPP-4 inhibitors, the effect of this group of drugs on weight was neutral

Postprandial lipid levels:

Postprandial lipid levels DPP-4 inhibition augments postprandial lipid mobilization and oxidation by activation of the sympathetic system Animal studies : DPP4 reduces intestinal secretion of triacylglycerol, cholesterol, and apolipoprotein B-48. Vildagliptin For 4 weeks improves postprandial plasma triglyceride and apolipoprotein B-48 in drug-naive patients with type 2 diabetes. Matikainen N, Mänttäri S, Schweizer A, et al. Vildagliptin therapy reduces postprandial intestinal triglyceride-rich lipoprotein particles in patients with type 2 diabetes.Diabetologia 2006;49:2049–2057

Safety profile of DPP-4 inhibitors:

Safety profile of DPP-4 inhibitors Sitagliptin: In controlled clinical studies the overall incidence of adverse reactions was similar to placebo. Discontinuation of therapy because of adverse reactions was also similar to placebo. Commonly reported adverse reactions : Nasopharyngitis Upper respiratory tract infection Headache. Acute Pancreatitis reported During postmarketing surveillance Reported in 88 patients between October 2006 and February 2009. In 19 cases (21%), occurred within 30 days of starting therapy. Hospitalization required in 58 (66%) cases. Upon discontinuation of sitagliptin , 47 of the 88 cases (53%) resolved. A causative relationship between sitagliptin and pancreatitis has not been established . Diabetes itself is a risk factor for pancreatitis Hypercholesterolemia, Hypertriglyceridemia , and obesity were also present in 51% of the U.S. cases. Postmarketing surveillance Acute Pancreatitis Serious allergic reactions, including anaphylactoid reactions, angioedema , and exfoliate dermatologic occurred within 3 months of sitagliptin initiation, with some occurring after the first dose.

Safety profile of DPP-4 inhibitors:

Safety profile of DPP-4 inhibitors saxagliptin hypersensitivity related event such as urticaria and facial edema. 1.5% compared with 0.4 % in the placebo . Lymphopenia Lymphocyte count of ≤750 cells/ mL 0.5 % with 2.4mg 1.5% with 5 mg 0.4 % of placebo recipients. Vildagliptin Cough peripheral edema . elevations in liver enzymes (ALT/ AST) to > 3 times 0.86%: 100 mg vildagliptin 0.21%: 50 mg vildagliptin OD 0.34%: 50 mg vildagliptin BID 0.4%: with placebo.

Effects of DPP-4 Inhibition:

Effects of DPP-4 Inhibition ß-cell function Glucagon secretion Insulin sensitivity ß -cell mass

PowerPoint Presentation:

Adapted from Ahrén B, et al. J Clin Endocrinol Metab . 2004;89:2078–2084 . Glycemic, Incretin, and Islet Cell Response to a Meal After 4 Weeks of Treatment With Vildagliptin Glucagon Glucose 0 25 50 75 –30 0 30 60 90 120 150 180 210 240 Time (min) 0 5 10 15 20 25 –30 0 30 60 90 120 Time (min) 5.0 8.0 11.0 14.0 50 75 100 125 GLP-1 [7-36amide] (pmol/L) Glucagon (ng/L) Active GLP-1 Insulin Glucose (mmol/L) IRI (µU/mL) Placebo Vildagliptin (100 mg qd) GLP-1 = glucagon-like peptide–1

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Vildagliptin and  -Cell Preservation and Regeneration (neonatal rat model) Vehicle Vildagliptin BrdU-positive cells (%) Apotag-positive cells (%) Vehicle Vildagliptin Vehicle Vildagliptin P<.001 P<.05 P<.05 b -cell mass (mg) Replication ß- cell mass Vildagliptin 60 mg/kg, po x 21 days Day 7 Day 21 Vehicle Vildagliptin Insulin Adapted from Duttaroy A, et al. Diabetes 2005 . 54 (suppl 1): A141.Abstract 572-P. Apoptosis 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0.14 0.0 0.5 1.0 1.5 2.0 2.5 0 20 40 60 80 100 120

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6.8 7.2 7.6 8.0 8.4 –4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Weeks Vildagliptin/Metformin (extension, n = 42) Placebo/Metformin (extension, n = 29) Placebo/Metformin (initial study, n = 51) HbA 1c (%) Vildagliptin/Metformin (initial study, n = 56) Ahrén et al, Diabetes Care 27:2874-2880 (2004) Combination of Vildagliptin and Metformin P < .0001  –1.1 ± 0.2%

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Vildagliptin provided glucose control (A1c -1.1%) Overall adverse events were not different between vildagliptin and comparator Under "real-life" conditions more patients responded in the vildagliptin as compared with comparator

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Summary of DPP-4 Inhibition Increases fasting and postprandial GLP-1 levels Reduces fasting and postprandial glycemia Improves ß -cell function Increases insulin secretion Increases beta-cell mass Inhibits glucagon secretion Reduces hepatic glucose production Reduces postprandial lipemia body weight neutral with less hypoglycemia Reduces HbA1c by ~1%

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Dpp4 inhibitors and the Guidelines

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Antihyperglycemic Therapy in Type 2 Diabetes ADA. V. Diabetes Care. Diabetes Care 2014;37(suppl 1): S27 . Figure 2;Inzucchi SE, et al. Diabetes Care 2012;35:1364 – 1369

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Blood glucose treatment algorithm for older people with diabetes

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Epilogue DPP4 inhibitors From clinical trials into guidelines :

Epilogue DPP4 inhibitors From clinical trials into guidelines DPP 4 Inhibitors are considered one of the basic and central treatment tools for diabetes . This treatment is efficient and safe Moved forward on the guidelines

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Thank you

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