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Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in Type 1 diabetes mellitus: a 1-year, randomized controlled trial

Background: Amylin (which is secreted by the pancreatic b-cells) is a regulatory hormone that is deficient in patients with Type 1 diabetes mellitus. Supplementation with a synthetic amylin analog (pramlintide) may aid patients in achieving their glycemic goals.

Objective: The purpose of this study was to assess the long-term efficacy and safety of varying doses of pramlintide as an adjunct to insulin therapy in patients with Type 1 diabetes mellitus.

Methods: This was a multicenter, double-blind, randomized, placebo-controlled, parallel-group study. Patients were enrolled from102 centers in the United States and Canada. Inclusion criteria for the study were: type 1 diabetes, between ages 16 and 76, requiring insulin for a minimum of 1 year, HbA1c level > 8%, stable body weight, stable daily insulin use for at least 2 months, and no severe hypo- or hyperglycemic symptoms for at least 2 weeks. Exclusion criteria included clinically significant disorders of the cardiovascular, pulmonary, central nervous, gastrointestinal, renal, or hematological systems, as well as eating disorders, acute febrile illness, alcohol/drug abuse, or use of medications that affect GI motility or glucose/insulin metabolism. Six hundred and fifty one patients were randomized to receive either placebo QID (154 patients), pramlintide 60mg TID (164 patients), pramlintide 60mg QID (161 patients) or pramlintide 90mg TID (172 patients) in addition to insulin therapy for 52 weeks. The primary endpoint for the study was the absolute change from baseline in HbA1c at week 26. Secondary endpoints were the absolute change in HbA1c at other time points, absolute change in body weight from baseline to weeks 26 and 52, and the percentage of patients who achieved the ADA recommended HbA1c target < 7% at any time throughout the study. Routine safety and laboratory measures including fasting lipids, vital signs, electrocardiograms, body weight and HbA1c were assessed throughout the study. Power was reported as being 90%. Investigators used the two-way ANOVA test and the Fisher’s LSD method for statistical analysis. Efficacy analyses were performed in the intent-to-treat population, evaluable population, and completer population.

Results: The 90mg treatment group was excluded from the efficacy analysis, but included in the safety analysis. This occurred because of results from another study, which indicated that this dose of pramlintide had an adverse tolerability profile compared with the lower doses. Overall, three hundred and ninety patients completed the study. Mean reductions in HbA1c from baseline to week 26 in the pramlintide groups (60mg TID and 60mg QID) were 0.41% (P=0.012) and 0.39% (P=0.013), respectively, compared to a 0.18% reduction in the placebo group. At week 52, the mean reductions in HbA1c from baseline in the pramlintide groups (60mg TID and 60mg QID) were 0.29% (P=0.011) and 0.34% (P=0.001), respectively, compared to a 0.04% reduction in the placebo group. A 3-fold greater number of patients achieved an HbA1c < 7% in the pramlintide groups compared to the placebo group. Mean reductions in weight from baseline to week 26 for the pramlintide groups (60mg TID and 60mg QID) were 1.3kg (P=0.0000) and 0.8kg (P=0.0000), respectively, compared with a 0.7kg weight gain in the placebo group. Safety analysis revealed that the only adverse effects that were more common in the pramlintide-treated patients (and occurred with an incidence > 10%) were anorexia, nausea, and vomiting. The authors concluded that mealtime amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with Type 1 diabetes.

Strengths: This study design was appropriate for the objective being studied. Additionally, investigators attempted to maintain blinding by ensuring that all patients received 4 injections daily (placebo was given to those with a dosing schedule of TID).

Weaknesses: Six of the eight authors of the study were affiliated with Amylin Pharmaceuticals, which is the company that manufactures pramlintide. This could have influenced the reporting of results in order to make the drug look more beneficial. Unblinding could have occurred in this study due to the adverse effects of the pramlintide and the ability of the investigators to transiently change doses of the study medications if those adverse effects occurred. As a result, investigators and/or patients may have known which groups were receiving the study drug and results could have been biased. The exclusion criteria were fairly specific and may limit the applicability of the results to the general population of Type 1 diabetic patients. The 90mg TID group was excluded from the statistical analysis. Investigators also failed to optimize insulin therapy in the study patients prior to initiating pramlintide. Finally, diet and changes in insulin doses were not controlled, all of which could have had an effect on the overall outcomes being studied.

Conclusion: Although pramlintide treated patients had statistically significant reductions in weight loss and HbA1c, the clinical significance of those results is lacking. The incidence of adverse effects (primarily nausea, vomiting and anorexia) could also affect the clinical utility of this medication. Another disadvantage would be the addition of four more injections to a patient’s insulin dosing schedule, which could lead to greater noncompliance in the diabetic population. Pramlintide would be appropriate as an adjunct treatment for patients who have optimized insulin therapy without achieving adequate glucose control. However, more studies are needed to determine the exact place of pramlintide in therapy.

Ratner RE, Dickey R, Fineman M, Maggs DG, Shen L, Strobel A, et al. Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic control in Type 1 diabetes mellitus: a 1-year, randomized controlled trial. Diabet Med. 2004 Nov;21(11): 1204-12.

Michelle Kovach, PharmD candidate