A double-blind, placebo-controlled trial assessing pramlintide treatment in the setting of intensive insulin therapy in type 1 diabetes.

Objective: To assess safety, efficacy, and tolerability of pramlintide dose escalation with proactive mealtime insulin reduction, followed by insulin optimization, in patients with type 1 diabetes.

Methods: This 29-week, double-blind, placebo-controlled study randomized 296 patients to pramlintide or placebo as an adjunct to insulin. During initiation, pramlintide was escalated from 15 to 60 microg/meal (15-microg increments) with recommended reductions (30-50%) in mealtime insulin. Insulin was subsequently adjusted to optimize glycemic control. End points included safety and change in HbA1c (A1C), postprandial glucose, insulin, weight, and tolerability.

Results: Baseline A1C was 8.1% for both groups and at week 29 had decreased comparably (pramlintide -0.5% [95% CI -0.61 to -0.33]; placebo -0.5% [-0.63 to -0.35]). Pramlintide treatment significantly reduced postprandial glucose excursions (incremental area under the curve [AUC](0-3h): pramlintide -175 +/- 40, placebo -64 +/- 38 mg x h(-1) x dl(-1); P < 0.0005) and weight (pramlintide -1.3 +/- 0.30, placebo +1.2 +/- 0.30 kg; P < 0.0001). At week 29, insulin dose decreased by 28 and 4% in pramlintide- and placebo-treated groups, respectively. Nausea, reported by 63 and 36% of patients in pramlintide and placebo groups (P < 0.01), respectively, was predominately mild to moderate in intensity. Severe hypoglycemia rates were low in both groups (pramlintide 0.57 +/- 0.09, placebo 0.30 +/- 0.06 event rate/patient-year; P < 0.05), with increased rates observed in patients remaining at 30 microg pramlintide.

Conclusions: Pramlintide dose escalation with reduced mealtime insulin was effective during therapy initiation in patients with type 1 diabetes. While both groups experienced equivalent A1C reductions relative to placebo, pramlintide-treated patients experienced reductions in postprandial glucose excursions and weight, not achievable with insulin therapy alone.