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Exenatide and pramlintide: new therapies for diabetes

For many years diabetes mellitus was believed to be characterised by insulin deficiency. Not surprisingly, diabetes therapies were directed towards replacing or stimulating insulin secretion, or enhancing the action of the body’s endogenously secreted insulin. In recent years, our understanding of the pathophysiology of diabetes has expanded to incorporate a multi-hormonal approach, and directed the development of new diabetes therapies. Current standards of care recommend intensive diabetes management and lowering A1c to as close to normal without unacceptable hypoglycaemia. A1c measurements provide an important index of diabetes management, but do not fully reflect diabetes control. Controlling postprandial glucose excursions has become both a means of achieving a lower A1c, as well as a potential mechanism by which microand macrovascular complications may occur because of an increased oxidative stress (1). The many insulins and oral agents available have improved diabetes control, but postprandial glucose management remains challenging. As doses are pushed in an attempt to normalise glucose following meals, weight gain and hypoglycaemia follow (2). Two new, first in class therapies improve postprandial glycaemia by addressing metabolic abnormalities of diabetes other than simply insulin deficiency. Pramlintide, the synthetic amylin analogue and exenatide, an incretin mimetic with properties similar to glucagon-like peptide-1 (GLP-1), were approved by the Food and Drug Administration for use in the United States in the spring of 2005. Exenatide has received a positive opinion recommending approval by the European Medicines Evaluation Agency and may be available in Europe by 2007. The close timing of their approval in the US and their similarity of therapeutic actions has created some confusion about their clinical use. As outlined by Edelman et al. in this issue (3), pramlintide is indicated as an adjunct to insulin therapy (4). It is injected subcutaneously prior to meals and regulates mealtime glucose appearance in conjunction with exogenous insulin by suppressing inappropriate postprandial glucagon secretion, regulating gastric emptying and increasing satiety (5). It reduces postprandial glycaemic excursions without the weight gain commonly seen with intensive insulin therapy (6). As described by Gallwitz in this issue (7), exenatide is an incretin mimetic, requiring functional islets for maximal efficacy. It regulates both hepatic glucose appearance and peripheral glucose disposal by stimulating glucose-dependent beta cell insulin and amylin secretion, in addition to suppressing inappropriate glucagon secretion (8). It is given by subcutaneous injection twice daily and is indicated for use as an adjunctive therapy in type 2 diabetes patients taking metformin and/or a sulfonylurea (9). Because exenatide stimulates glucose-mediated beta cell insulin secretion and therefore, amylin secretion, exenatide and pramlintide share some similar actions and effects. While only exenatide stimulates insulin secretion, both the drugs suppress inappropriate postprandial glucagon secretion, regulate gastric emptying and promote satiety. Exenatide more closely approximates normal beta cell function in those type 2 diabetic individuals with residual beta cell mass. Pramlintide, on the contrary, replaces the amylin deficiency seen in type 1 diabetes and in those type 2 diabetic individuals with sufficiently depleted beta cell reserve as to require exogenous insulin therapy. Thus, exenatide and the incretin mimetics and enhancers are likely to be most effective early in the natural history of type 2 diabetes, while pramlintide provides replacement therapy even after complete beta cell failure. And, unlike other diabetes therapies which are associated with weight gain, pramlintide and exenatide promote weight loss. The most common side effects of both the drugs are gastrointestinal. Nausea and vomiting, generally mild to moderate, are most often seen during drug initiation, and diminish with time. The titration schemes recommended for both the drugs reduce the intensity of gastrointestinal effects (4,9). Both the drugs are associated with an indirect risk of hypoglycaemia. Pramlintide is associated with insulininduced hypoglycaemia when insulin doses are not adequately reduced, particularly during the initiation of the drug (4). Similarly, an increased risk of hypoglycaemia is seen when exenatide is given with insulin secretagogues, such as sulfonylureas (9). The wide variety of off-label uses for both the drugs further contributes to the confusion about appropriate use of pramlintide and exenatide. Some clinicians may use exenatide in type 2 patients who take basal insulin to augment the prandial beta cell response. Clinical trials of such a protocol are currently underway, but no data are available at the present time. Exenatide may be preferred by patients for the convenience of twice daily dosing and its availability in a pen as pramlintide is currently only available in vials. Both exenatide and pramlintide are also being used for weight loss in patients without diabetes. Clinical trial data indicates pramlintide reduces food intake and promotes weight loss in individuals with and without diabetes (10). Animal and in vitro studies show exenatide may increase beta cell