Pramlintide in the treatment of type 1 and type 2 diabetes mellitus

Background: Amylin is a 37-amino acid peptide 1026 neurohormone that is cosecreted with insulin from the pancreatic β cells in response to meals. It lowers serum glucose by decreasing glucagon release, slowing gastric emptying, and decreasing food intake. Pramlintide, a synthetic amylin analogue, is approved by the US Food and Drug Administration for use with mealtime insulin in patients with type 1 diabetes and patients with type 2 diabetes who are using mealtime insulin only or the combination of insulin and metformin and/or a sulfonylurea. Objective: This article reviews the available literature102 on pramlintide with respect to its mechanism of action, pharmacokinetics and pharmacodynamics, clinical efficacy in type 1 and type 2 diabetes, safety and tolerability, dosing, contraindications, and drug interactions. Methods: MEDLINE (1966-April 2005), Iowa Drug 1026 Information Service (1966-April 2005), and International Pharmaceutical Abstracts (1970-April 2005) were searched for clinical trials and therapeutic reviews published in the English language. The search terms were pramlintide and amylin. The bibliographies of identified articles were reviewed for additional references. All relevant studies were included in the review. Results: Six studies, ranging in duration from 4 to 1026 52 weeks, examined the effect of administering pramlintide with premeal insulin in patients with type 1 diabetes. In these trials, pramlintide 120 to 270 μg/d reduced glycosylated hemoglobin (HbA_1c) by 0.1 % to 0.67%, 1-hour postprandial glucose (PPG) by 4.4 to 7 mmol/L, and 2-hour PPG by 3.6 to 4.8 mmol/L. Five studies, also ranging from 4 to 52 weeks' duration, examined the effect of administering premeal pramlintide in patients with type 2 diabetes. In these trials, pramlintide 90 to 450 μg/d reduced HbA _1c by 0.3% to 0.62%, 1-hour PPG by 4.8 mmol/L, and 2-hour PPG by 3.4 mmol/L. The principal adverse events reported in clinical trials were nausea and hypoglycemia. The incidence of hypoglycemia in the first 4 weeks of therapy was 2 to 4 times greater with pramlintide compared with placebo; thus, the manufacturer recommends reducing the dose of premeal insulin by 50% when starting pramlintide. Close monitoring of blood glucose levels is recommended when initiating pramlintide therapy. Conclusions: Use of pramlintide in addition to insulin1026 in patients with type 1 and type 2 diabetes was associated with modest reductions in HbA_1c. The primary adverse effects of pramlintide therapy were nausea and hypoglycemia.