Day-long Subcutaneous Infusion of Exenatide Lowers Glycemia in Patients with Type 2 Diabetes

Abstract

Exenatide (exendin-4) is an incretin mimetic with potential antidiabetic activity. This study examined the effects of a continuous subcutaneous (SC) infusion of exenatide (0.2, 0.4, 0.6, or 0.8 μg/kg/day) or placebo (PBO) on glycemic control over 23 h intervals. Twelve subjects with type 2 diabetes treated with metformin and/or diet received 10 infusions (4 exenatide, 6 PBO) on consecutive days. Exenatide was given in a dose-increasing design with at least one placebo infusion between each exenatide infusion, and with meals and a snack provided during the first 14 h of infusion. Plasma exenatide concentrations were dose-proportional. Plasma glucose (4 - 23 h) was lower in all exenatide arms compared to placebo (p < 0.0001). The change in insulin/glucagon ratio and amylin concentrations from pre-infusion to post-infusion was increased (p < 0.005, p < 0.05, respectively) in the combined exenatide arms, but remained unchanged in the placebo groups. Nausea and vomiting were the most common treatment emergent adverse events. Exenatide infusion also appeared to have positive effects on β-cell and α-cell function as measured by proinsulin/insulin ratios and mean glucagon concentrations. In summary, exenatide lowered plasma glucose during both prandial and fasting states when delivered as a continuous SC infusion over twenty-three hours, suggesting that exenatide can provide day-long glycemic control in patients with type 2 diabetes.

Key words

Exenatide - Exendin-4 - Type 2 diabetes - Glycemic control

References

• 1 Kahn S E, Porte D. Pathophysiology of type II diabetes mellitus. In: Porte D, Sherwin RS (eds) Diabetes Mellitus. 5th ed. Stamford, CT; Appleton and Lange 1997: 487-512
• 2 Weyer C, Bogardus C, Mott D M, Pratley R E. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus.  J Clin Invest. 1999;  104 787-794
• 3 UK Prospective Diabetes Study (UKPDS) Group . Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in subjects with type 2 diabetes.  Lancet. 1998;  352 837-853
• 4 UK Prospective Diabetes Study Group . Overview of 6 years' therapy of type II diabetes: a progressive disease.  Diabetes. 1995;  44 1249-1258
• 5 Mudaliar S, Edelman S V. Insulin therapy in type 2 diabetes.  Endocrinol Metabol Clinics N Amer. 2001;  30 935-982
• 6 Wright A, Burden A CF, Paisey R B, Cull C A, Holman R R. UKPDS Study Group: Sulfonylurea inadequacy. Efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U. K. Prospective Diabetes Study (UKPDS 57).  Diabetes Care. 2002;  25 330-336
• 7 Inzucchi S E. Oral antihyperglycemic therapy for type 2 diabetes.  JAMA. 2002;  287 360-372
• 8 DeFronzo R A. Pharmacologic therapy for type 2 diabetes mellitus.  Ann Intern Med. 1999;  131 281-303
• 9 Harris M I, Eastman R C, Cowie C C, Flegal K M, Eberhardt M S. Racial and ethnic differences in glycemic control of adults with type 2 diabetes.  Diabetes Care. 1999;  22 403-408
• 10 Parkes D G, Pittner R, Jodka C, Smith P, Young A. Insulinotropic actions of exendin-4 and glucagon-like peptide-1 in vivo and in vitro.  Metabol. 2001;  50 583-589
• 11 Bhavsar S, Watkins J, Young A. Comparison of central and peripheral effects of exendin-4 and GLP-1 on food intake in rats (Abstract).  In Program and Abstracts: 80th Annual Meeting Endocr Soc. 1998;. Bethesda, MD; Abs 433
• 12 Szayna M, Doyle M E, Betkey J A, Holloway H W, Spencer R GS, Greig N H, Egan J M. Exendin-4 decelerates food intake, weight gain, and fat deposition in Zucker rats.  Endocrinol. 2000;  141 1936-1941
• 13 Young A A, Gedulin B R, Bhavsar S, Bodkin N, Jodka C, Hansen B, Denaro M. Glucoselowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta).  Diabetes. 1999;  48 1026-1034
• 14 Jodka C, Gedulin B, Young A. Exendin-4 potently regulates gastric emptying in rats (Abstract).  Diabetes. 1998;  47 A403
• 15 Xu G, Stoffers D A, Habener J F, Bonner-Weir S. Exendin-4 stimulates both β-cell replication and neogenesis, resulting in increased β-cell mass and improved glucose tolerance in diabetic rats.  Diabetes. 1999;  48 2270-2276
• 16 Tourrel C, Bailbé D, Lacorne M, Meile M J, Kergoat M, Portha B. Persistent improvement of type 2 diabetes in the Goto-Kakizaki rat model by expansion of the β -cell mass during the prediabetic period with glucagon-like peptide-1 or exendin-4.  Diabetes. 2002;  51 1443- 1452
• 17 Tourrel C, Bailbé D, Meile M-J, Kergoat M, Portha B. Glucagon-like peptide-1 and exendin-4 stimulate β-cell neogenesis in streptozotocin-treated newborn rats resulting in persistently improved glucose homeostasis at adult age.  Diabetes. 2001;  50 1562-1570
• 18 Fineman M S, Bicsak T A, Shen L Z, Taylor K, Gaines E, Varns A, Kim D, Baron A D. Effect on glycaemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes.  Diabetes Care. 2003;  26 2370-2377
• 19 Nielsen L L, Baron A D. Pharmacology of exenatide (synthetic exendin-4) for the treatment of type 2 diabetes.  Curr Opinion Invest Drugs. 2003;  4 401-405
• 20 Buse J, Henry R, Han J, Kim D D, Fineman M, Baron A. Effect of Exenatide (Exendin-4) on Glycemic Control and Safety Over 30 Weeks in Sulfonylurea-Treated Patients with Type 2 Diabetes.  American Diabetes Association. 2004;  A82 abstract 352-OR
• 21 Goke R, Fehmann H C, Linn T, Schmidt H, Krause M, Eng J, Goke B. Exendin-4 is a high potency agonist and truncated exendin-(9 - 39)-amide an antagonist at the glucagon-like peptide 1-(7 - 36)-amide receptor of insulin-secreting β-cells.  J Biol Chem. 1993;  268 19 650- 19 655
• 22 Zander M, Madsbad S, Madsen J L, Holst J J. Effect of 6-week course of glucagon-like peptide 1 on glycemic control, insulin sensitivitiy, and β-cell function in type 2 diabetes: a parallel-group study.  Lancet. 2002;  359 824-830
• 23 Nauck M A, Sauerwald A, Ritzel R, Holst J J, Schmiegel W. Influence of glucagon-like peptide 1 on fasting glycemia in type 2 diabetic patients treated with insulin after sulfonylurea secondary failure.  Diabetes Care. 1998;  21 1925-1931
• 24 Kolterman O G, Buse J B, Fineman M S, Gaines E, Heintz S, Bicsak T A, Taylor K, Kim D, Aisporna M, Wang Y, Baron A D. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes.  J Clin Endocrinol Metab. 2003;  88 3082-3089
• 25 Drucker D J. Glucagon-like peptides.  Diabetes. 1998;  47 159-169
• 26 Morgan C R, Lazarow A. Immunoassay of insulin: two antibody system. Plasma insulin levels in normal, subdiabetic and diabetic rats.  Diabetes. 1963;  12 115-126
• 27 Percy A J, Trainor D A, Rittenhouse J, Phelps J, Koda J E. Development of sensitive immunoassays to detect amylin and amylin-like peptides in unextracted plasma.  Clin Chem. 1996;  42 576-585
• 28 Baron A D, Kim D, Weyer C. Novel peptides under development for the treatment of type 1 and type 2 diabetes mellitus.  Curr Drug Targets. 2002;  2 63-82