Steve V. Edelman, MD
Robert R. Henry, MD
Mechanisms of Action: Gastric Emptying
In healthy individuals, amylin modulates the rate of gastric emptying, most likely via the vagus nerve, to regulate the inflow of nutrients into the small intestine and thereby reduce the postprandial rise in glucose.
It is interesting that the rate of gastric emptying is frequently accelerated in people with diabetes with early increases in PPG directly proportional to the rate of gastric emptying. This may be due to amylin deficiency, and when pramlintide is administered, there is a slowing in the rate of gastric emptying. In one study, diabetic rats treated with insulin alone were observed to have a markedly accelerated rate of gastric emptying compared with nondiabetic rats, but when rat amylin was administered to both diabetic and nondiabetic rats, a slowing of gastric emptying took place in both groups. Furthermore, comparison of the rates of gastric emptying in rodents showed that three key peptides — amylin, GLP-1, and CCK-8 — dose dependently retarded gastric emptying, although the effect of amylin was 15-fold more potent than that of GLP-1 and 20-fold more potent than CCK-8. Studies in patients with Type 1 diabetes utilizing both solid and liquid meals showed that pramlintide prolonged the half-gastric emptying time by 60 to 90 minutes, and did not influence gastric emptying rates of subsequent meals.
- Postprandial Glucagon Suppression
Glucagon, secreted from pancreatic alpha-cells, is a key catabolic hormone that stimulates the release of hepatic glucose reserves during fasting and protects against hypoglycemia. Inappropriate hypersecretion of glucagon, leading to inadequate suppression of hepatic glucose release at mealtime, contributes to postprandial hyperglycemia in patients with Type 2 and Type 1 diabetes. Pramlintide helps inhibit glucose appearance in the circulation by suppressing inappropriate glucagon secretion, most likely via the parasympathetic nervous system.
- Regulation of Food Intake
A study specifically designed to assess the effects of pramlintide on satiety has shown that pramlintide administered as a single preprandial injection increased levels of satiety leading to reduced food intake, with no macronutrient preferences noted and without affecting mean meal duration. In addition, the satiety effect appears to be independent of the nausea that can accompany pramlintide treatment. This information is consistent with the anorexigenic effect of amylin in rodents and suggests that increased satiety, and thus reduced food intake, is a mechanism for the weight loss observed in long-term pramlintide clinical trials.
- Postprandial Glucose
The effect of pramlintide on PPG excursions was assessed in a five-way crossover study in patients with type 2 diabetes using the rapid-acting insulin analog, insulin lispro. Following four separate standardized meals, each subject received pramlintide at different times relative to the meal (–15, 0, +15, and +30 minutes) and, on one occasion, they received placebo 15 minutes before the meal. Insulin lispro was administered immediately before meals. Administration of pramlintide either at or just prior to a meal caused a greater reduction in PPG than either placebo or postmeal pramlintide. Results from this study confirmed that pramlintide, as an adjunct to mealtime insulin therapy, significantly reduced PPG excursions compared with insulin therapy alone (Figure 11.3). Pramlintide achieved its effects with an average reduction in mealtime insulin dose of approximately 30%.
- Long-Term Glycemic Control With Pramlintide
Several long-term clinical trials have shown the benefit of adding pramlintide to an existing regimen of insulin therapy to improve glycemic control in insulin-using patients with type 2 diabetes. A 52-week, randomized, placebo-controlled, double-blind, dose-ranging study in 538 insulin-treated patients compared the efficacy and safety of 30-, 75-, or 150-mcg subcutaneous (SC) doses of pramlintide tid with placebo. Compared with placebo, at week 13 there were significant reductions in A1C in patients receiving the 75-mcg and 150-mcg pramlintide doses. (The 30-mcg dose was subtherapeutic.) The mean A1C reduction from baseline to week 52 of 0.6% in the 150-mcg–dose group was also significantly greater than in the placebo group (P = 0.0068). The greater reduction in A1C with pramlintide was achieved without increases in insulin use or severe hypoglycemia. Moreover, the proportion of patients who were able to achieve reductions in both A1C and body weight was 3-fold greater with the 150-mcg dose compared with placebo (48% vs 16%). In addition, there was a significant reduction in body weight in all pramlintide-dose groups compared with placebo. It is important to note that due to pH differences between formulations, the 75- and 150-mcg pramlintide doses used in this study were bioequivalent to the 60- and 120-mcg doses used in other studies.
Another 52-week, randomized, placebo-controlled, double-blind, dose-ranging study in 656 insulin-treated patients with type 2 diabetes compared the efficacy and safety of 60-, 90-, or 120-mcg doses of SC pramlintide tid to placebo. Treatment with pramlintide 120 mcg resulted in a sustained reduction from baseline in A1C (–0.68% and –0.62% at weeks 26 and 52, respectively), which was significantly greater than seen with placebo. The proportion of patients who achieved an A1C <8% was approximately 2-fold greater in patients receiving the 120-mcg dose compared with those receiving placebo (48% vs. 28%). Once again, the glycemic improvement with pramlintide 120 mcg was accompanied by a reduction in body weight (–1.4 kg) while the placebo group experienced weight gain (+0.7 kg).
© Copyright 2010. Steven V. Edelman, MD, Robert R. Henry, MD, Professional Communications, Inc. All rights reserved.
Next Week, Part 3: Clinical Practice Study – Tolerability – Dosing