(Incretin) ( glucagon-like peptide-1 GLP-1 ) GLP-1. GLP-1 ( dipeptidyl peptidase IV DPP IV ) GLP-1 DPP IV GLP-1 exenatide liraglutide FDA 2 2 2

Transcription

1 (Incretin) Incretin ( ) -1 ( glucagon-like peptide-1 ) ( dipeptidyl peptidase IV ) liraglutide FDA ( Type diabetes mellitus ) -1 ( Glucagon-like peptide-1, ) ( Incretin ) ( Dipeptidyl peptidase IV ) ( United Kingdom Prospective Diabetes Study UKPDS ) ( 1 ) 1

2 190 thiazolidinediones ( TZDs ) alpha-glucosidase inhibitors meglitinides ( ) TZDs 1 3,4 8,9 ( 4 ) ( 1 ) ( ) ( 3 ) ( ischemia/ reperfusion ) ( enteroinsular axis ) ( incretin ) 50% ( 1 ) ( glucose dependent insulinotropic polypeptide ) ( gastric inhibitory polypeptide ) GIP ( ) -1 ( Glucagon-like peptide-1 ) ( Extrapancreatic effect ) ( 1 ) ( ) B ( apoptosis ) 7 ( 3 ) GIP ( endovascular serine protease ) dipeptidyl peptidase IV ( ) N N ( 9-36 amide ) Exenatide peptide ( fatty acid chain ) peptide vildagliptin ( LAF-37 ) sitagliptin ( MK-0431 ) Exenatide ( Byetta ) FDA 005 Exenatide ( Byetta ) 17

3 ( Sulfonylureas ) metformin HbA1c 7.0% ( ) 5 g twice daily 10 g twice daily Exenatide 30 HbA1c 10 g 5 g % % % HbA1c 7% 41% ( 10 g ) 33% ( 5 g ) 9% ( ) ( P ) 10 g kg ( P <0.05 vs. ) 17 metformin Exenatide 30 HbA1c 10 g 5 g % % % ( p 0.00 ) HbA1c 7% 46% ( 10 g ) 3% ( 5 g ) 13% ( ) ( P 0.01 vs. ) 10 g 5 g kg kg( P 30 HbA1c 10 g 5 g % % % ( ) ( P vs. ) HbA1c 7% 34% 7% 9% ( P ) kg kg ( P 0.01 ) g twice daily 10 g twice daily HbA1c 7% 51% [10 g ] 49% [5 g ] 47% [ ] 4.5 kg 0.5 kg 146 HbA1c 1.% 0.1% kg HbA1c 1.% 0.1% 4.6 kg 0.3kg triglyceride mg/dl ( 95% CI to ) Total cholesterol.5 mg/dl( 95%CI 6.43 to 1.39 ) HDL C 4.46 mg/dl ( 95% CI 3.64 to 5.7 ) 1.48mmHg ( 95% CI 3.46 to 0.51 ) 3.4 mmhg ( 95% CI 4.37 to.10 ) insulin glargine g twice daily 68 insulin glargine once daily 6 insulin glargine A1C 7% ( 48% vs.46% ) A1C 6.5% ( 3% vs.5% ).3 kg 0. kg insulin glargine kg ( p ) Liraglutide ( NN11 ) FDA 3 Liraglutide

4 mg metformin 1000 mg bid Liraglutide metformin mg 0.5 mg HbA1c 1.8% 0.86% 0.% 0.16% 0.30% and 0.09% [metformin ] ( inhibitors ) Sitagliptin ( Januvia ) FDA Merck Sitagliptin ( n=473 ) 18 ( n=96 ) ( HbA1c 7.0% to 10.0% ( 8.0% ) Sitagliptin HbA1c ( HbA1c 8.0%, n=441 ) ( HbA1c 8.0% 9.0%, n= 39 ) ( HbA1c 9.0%, n=119 ) % 0.7% 1.4% ( p ) 1 4 Sitagliptin 100 mg once daily ( add-on therapy ) metformin pioglitazone Sitagliptin metformin HbA1c 0.7% ( p ) pioglitazone HbA1c 0.7% ( p 0.01 ) HbA 1c 7% metformin Sitagliptin 47% 9% ( P ) pioglitazone Sitagliptin 45% 3% ( P ) 4 metformin Sitagliptin 100 mg qd 5 mg/dl 51 mg/dl ( p ) 4 Sitagliptin 0. kg ( vs. 1.1 kg in ) metformin add-on therapy 0.7 kg ( vs. 0.6 kg in ) Sitagliptin Vildagliptin ( Galvus ) Vildagliptin NDA FDA mg twice daily 5mg 50mg 100 mg once daily vildagliptin HbA1c vildagliptin 50 mg qd and 100 mg qd HbA1c vildagliptin 50 mg qd 4 vildagliptin 100 mg qd 4 B HOMA-B vildagliptin 100 mg qd vildagliptin 100 mg qd 1 1 Vildagliptin 5 mg bid ( n=70 ) Vildagliptin ( HbA1c 8.0 % ) HbA1c ( 0.6% ) HbA1c % HbA1c 1. % Vildagliptin 0 7 mg/dl ( p= ) 34 9 mg/dl ( p ) Vildagliptin 7

5 193 DPP IV 1.UKPDS Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 35: UK Prospective Diabetes Study (UKPDS) Group. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA 1999; 81: Dormandy JA, Charbonnel B, Eckland DJ, et al. PROactive investigators. Secondary prevention of macrovascular events in patients with type diabetes in the PROactive Study (PROspective pioglitazone Clinical Trial In macrovascular Events): a randomised controlled trial. Lancet 005; 366: Kahn SE, Haffner SM, Heise MA, et al. Glycemic Durability of Rosiglitazone, Metformin, or Glyburide Monotherapy. N Engl J Med 006; 355: Vahl T, D'Alessio D.Enteroinsular signaling: perspectives on the role of the gastrointestinal hormones glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide in normal and abnormal glucose metabolism. Curr Opin Clin Nutr Metab Care 003; 6: Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab 004; 87: E Daniel J, Drucker. Glucagon-like peptide-1 and islet bcell: augmentation of cell proliferation and inhibition of apoptosis. Endocrinology 003; 144: Xu G, Stoffers DA, Habener -F, Bonner-Weir S. Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes 1999; 48: Tourrel C, Bailbe D, MeileM-J, Kergoat M, Portha B. Glucagonlike peptide-1 or exendin-4 enhances regeneration of s-cell mass in streptozotocin-treated newborn rats (Abstract). Diabetes 000; 49(Suppl 1): A Creutzfeldt WO, Kleine N, Willms B, et al. Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I (7-36) amide in type I diabetic patients. Diabetes Care 1996; 19: Vella A, Rizza RA. Extrapancreatic effects of GIP and. Horm Metab Res 004; 36: Gutzwiller JP, Tschopp S, Bock A, et al. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J Clin Endocrinol Metab 004; 89: Yu M, Moreno C, Hoagland KM, et al. Antihypertensive effect of glucagon-like peptide 1 in Dahl salt-sensitive rats. J Hypertens 003; 1: Nikolaidis LA, Elahi D, Hentosz T, et al. Recombinant glucagonlike peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy. Circulation 004; 110: Bose AK, Mocanu MM, Carr RD, Brand CL, Yellon DM. Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. Diabetes 005; 54: Nystrom T, Gutniak MK, Zhang Q, Zhang F, Holst JJ, Ahren B, Sjoholm A.Effects of glucagon-like peptide-1 on endothelial function in type diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab 004; 87: E Meier JJ. Glucagon-like peptide 1 and gastric inhibitory polypeptide: potential applications in type diabetes mellitus. Biodrugs 003; 17: Buse JB, Henry RR, Han J, et al. Effects of (exendin- 4) on glycemic control and weight over 30 weeks in sulfonylurea-treated patients with type diabetes. Diabetes Care 004; 7: DeFronzo RA, Ratner RE, Han J, et al. Effects of (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type diabetes. Diabetes Care 005; 8: Kendall DM, Riddle MC, Rosenstock J, et al. Effects of (exendin-4) on glycemic control and weight over 30 weeks in patients with type diabetes treated with metformin and a sulfonylurea. Diabetes Care 005; 8: Program and abstracts of the 65th Scientific Sessions of the American Diabetes Association; June 10-14, 005; San Diego, California. Poster 477, Poster 485, and Abstract 16-OR..Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG; GWAA Study Group. Exenatide versus insulin glargine in patients with suboptimally controlled type diabetes: a randomized trial. Ann Intern Med 005; 143: Degn KB, Juhl CB, Sturis J, et al. One week's treatment with the long-acting glucagon-like peptide 1 derivative liraglutide (NN11) markedly improves 4-h glycemia and alpha- and beta-cell function and reduces endogenous glucose release in patients with type diabetes. Diabetes 004; 53: Madsbad S, Schmitz O, Ranstam J, Jakobsen G, Matthews DR; NN International Study Group. Improved glycemic control with no weight increase in patients with type diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN11): a 1-week, double-blind, randomized, controlled trial. Diabetes Care 004; 7:

6 194 5.FDA Approves Once-Daily JANUVIA(TM), the First and Only DPP-4 Inhibitor Available in the United States for Type Diabetes. Press Release. Source: Merck & Co., Inc. 6.Ristic S, Byiers S, Foley J, Holmes D. Improved glycaemic control with dipeptidyl peptidase-4 inhibition in patients with type diabetes: vildagliptin (LAF37) dose response. Diabetes Obes Metab 005; 7: Pratley RE, Jauffret-Kamel S, Galbreath E, Holmes D. Twelveweek monotherapy with the DPP-4 inhibitor vildagliptin improves glycemic control in subjects with type diabetes. Horm Metab Res 006; 38: Clinical Evidence of Receptor Agonists and DPP VI Inhibitors in the Treatment of Type Diabetes Shu-Hwa Hsiao, Horng-Yih Ou 1, and Ta-Jen Wu 1 Department of Pharmacy, 1 Division of Endocrinology and Metabolism, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan Incretin plays an import role in postprandial insulin secretion. Glucagon-like peptide-1 () and gastric inhibitory polypeptide have well been known to have properties of incretin effect. Patients with type diabetes are noted to be with lost or severely impaired incretin effect. Therefore, the patients also have decresed postprandial insulin secretion. The major cause of impaired incretin effect in patients with type diabetes is decrease in secretion. also has some effects on promotion of cell growth and differentiation, decreasing cell apoptosis, and glucagon suppression effect. In addition, some beneficial extrapancreatic effects, such as decreasing food intake by acting on central nervous system and direct action on cardiovascular system are also noted. Due to its glucose-dependent insulin secretion effect, the risk of hypoglycemia is low. The incretins are rapidly inactivated by dipeptidyl peptidase IV (DPP VI). Recently, two different approaches are developed to retard DPP VI action. One is to use receptor agonists that are resistant to degradation by DPP VI. These mimetics include and liraglutide. Another approach is to inhibit the activity of DPP VI so that half-life of endogenously released can be prolonged. These DPP VI inhibitors include sitagliptin and vildagliptin. The beneficial effects of these preparations on clinical parameters in patients with type diabetes mellitus have recently been reported in some evidence-based studies. ( J Intern Med Taiwan 007; 18: )