Safety and Tolerability of Glucagon-Like Peptide-1 Receptor Agonists Utilizing Data from the Exenatide Clinical Trial Development Program.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated benefits for patients with type 2 diabetes including A1C reduction and weight loss with minimal risk of hypoglycemia. This article provides an evidence-based update of safety and tolerability considerations for the clinical use of GLP-1RAs as a class, with a specific detailed review of data from the exenatide clinical trial development program, which has the longest history and availability of safety and tolerability data as the first-approved GLP-1RA. Specific areas covered include comparative risk of hypoglycemia, as well as pancreatic, thyroid, and cardiovascular safety data; clinical guidance regarding current safety and tolerability data is also reviewed.

Optimizing treatment success with an amylin analogue.

Diabetes affects approximately 18 million adults in the United States. Diabetes increases the risk of microvascular and macrovascular complications, such as nerve neuropathy, retinopathy, nephropathy, and cardiovascular disease. Intensive diabetes management reduces the risk of complications but presents numerous challenges in clinical practice. In the natural course of type 2 diabetes beta cell function declines over time and may necessitate frequent medication adjustment. Oral antihyperglycemic medications may lose efficacy over time and may induce intolerable adverse events. Some medications for diabetes can cause weight gain, even if patients exercise and watch their food intake. Furthermore, patients with type 1 diabetes may experience frequent blood glucose fluctuations despite optimizing their use of insulin. Hypoglycemia is a common adverse effect of intensive diabetes management. Pramlintide as an adjunct to insulin therapy is useful for treating both type 1 and type 2 diabetes to improve control of postprandial glucose. To ensure maximal efficacy of pramlintide with minimal adverse events, it is extremely important that diabetes educators thoroughly understand pramlintide's mode of action, indications, appropriate patient selection, required insulin dose adjustments, and provide careful patient instruction.

Pramlintide: A new tool in diabetes management.

The amylin analogue pramlintide acts in concert with insulin to regulate glucose metabolism. It reduces postprandial hyperglycemia by suppressing postprandial glucagon secretion, regulating gastric emptying, and reducing food intake. In clinical use, pramlintide reduces postprandial glycemic excursions and improves A(1c) without the weight gain and increased risk of hypoglycemia typically seen with intensification of diabetes therapy.

Overview of diabetes.

The number of people with diabetes is growing to epidemic proportions in the United States. There is a great deal of research on the evolving understanding of the pathogenesis of diabetes as compared to normoglycemia. The diagnostic criteria for diabetes have become streamlined to more appropriately and accurately diagnose the disease. There are millions of people who have diabetes, but do not know it. It is essential that appropriate screening be performed to make a diagnosis in order to delay or prevent the complications from occurring. The complications of diabetes have implications for the increasing number of people with the diagnosis who are hospitalized and how they are treated. There are specific methods for recognition and treatment of both acute and chronic complications in the hospitalized patent with diabetes. Managing blood glucose control is essential for favorable outcomes.

Impact of pramlintide on glucose fluctuations and postprandial glucose, glucagon, and triglyceride excursions among patients with type 1 diabetes intensively treated with insulin pumps.

OBJECTIVE: To assess the effects of adjunctive treatment with pramlintide, an analog of the beta-cell hormone amylin, on 24-h glucose fluctuations and postprandial glucose, glucagon, and triglyceride excursions in patients with type 1 diabetes intensively treated with continuous subcutaneous insulin infusion (CSII). RESEARCH DESIGN AND METHODS: In this study, 18 patients (16 of whom could be evaluated) with type 1 diabetes (age 44 +/- 11 years, HbA(1c) 8.2 +/- 1.3% [mean +/- SD]) were given mealtime injections of 30 micro g pramlintide t.i.d. for 4 weeks in addition to their preexisting CSII regimen (16 lispro, 2 regular insulin). Mealtime insulin boluses were reduced by a minimum of 10% during the first 3 days, and re-adjusted thereafter based on clinical judgment. At weeks 0 (baseline), 4 (on treatment), and 6 (2 weeks off treatment), 24-h interstitial glucose concentrations were measured using a continuous glucose monitoring system (CGMS), and postprandial plasma glucose, glucagon, and triglyceride concentrations were measured in response to a standardized test meal. RESULTS: At baseline, patients had excessive 24-h glucose fluctuations, with 59% of the CGMS measurements >140 mg/dl, 13% <80 mg/dl, and only 28% in the euglycemic range (80-140 mg/dl). After 4 weeks on pramlintide, measurements in the hyperglycemic range declined to 48% and measurements within the euglycemic range increased to 37%. This shift from the hyperglycemic to the euglycemic range occurred with a concomitant 17% reduction in mealtime insulin dosages and without relevant increases in measurements below the euglycemic range (15%) or any severe hypoglycemic events. After 4 weeks on pramlintide, postprandial glucose, glucagon, and triglyceride excursions were reduced by approximately 86, approximately 87, and approximately 72%, respectively (incremental areas under the curve, all P < 0.05 vs. baseline). At week 6 (off treatment), the 24-h glucose profile and postprandial glucose, glucagon, and triglyceride excursions approached pretreatment values. CONCLUSIONS: In this study, the addition of pramlintide to insulin therapy reduced excessive 24-h glucose fluctuations as well as postprandial glucose, glucagon, and triglyceride excursions in patients with type 1 diabetes intensively treated with insulin pumps.

Adjunctive therapy with the amylin analogue pramlintide leads to a combined improvement in glycemic and weight control in insulin-treated subjects with type 2 diabetes.

The objective of this study was to assess the effect of mealtime amylin replacement with pramlintide on long-term glycemic and weight control in subjects with type 2 diabetes. This 52-week, randomized, placebo-controlled, multicenter, double-blind, dose-ranging study in 538 insulin-treated subjects with type 2 diabetes compared the efficacy and safety of 30-, 75-, or 150-microg doses of pramlintide, a synthetic analogue of the beta-cell hormone amylin, to placebo when injected subcutaneously three times daily (TID) with major meals. Pramlintide therapy led to a mean reduction in HbA1c of 0.9% and 1.0% from baseline to week 13 in the 75- and 150-microg dose groups, which was significant compared to placebo (p = 0.0004 and p = 0.0002, respectively). In the 150-microg dose group, there was a mean reduction in HbA1c of 0.6% from baseline to week 52 (p = 0.0068 compared to placebo). The greater reduction in HbA1c with pramlintide was achieved without increases in insulin use or severe hypoglycemia, and was accompanied by a significant (p < 0.05) reduction in body weight in all dose groups compared to placebo. Three times the proportion of subjects in the 150-microg pramlintide group compared to the placebo group achieved a concomitant reduction in both HbA1c and body weight from baseline to week 52 (48% versus 16%). The most common adverse event reported with pramlintide treatment was nausea, which was mild to moderate and dissipated early in treatment. The results from this study support the safety and efficacy of pramlintide administered three times a day with major meals, in conjunction with insulin therapy, for improving long-term glycemic and weight control in subjects with type 2 diabetes.