Review of prandial glucose regulation with repaglinide: a solution to the problem of hypoglycaemia in the treatment of Type 2 diabetes?

Abstract

Type 2 diabetes mellitus is characterised by abnormal beta-cell function (present at the time of diagnosis) that is often associated with insulin resistance. An important and consistent pathophysiological ®nding is the failure to produce adequate increments in insulin secretion in response to carbohydrate intake. Therefore, insulin secretagogue therapy, particularly when focused on prandial glucose regulation, is a logical approach to treatment because it addresses one of the most fundamental pathophysiological aspects of the disease. However, the traditional secretagogues Ð the sulphonylureas Ð have long been associated with the unwanted effect of hypoglycaemia. This is particularly likely to occur when drugs with lengthy plasma half-lives, prolonged drug ± receptor interactions, active metabolites or a reliance on renal clearance are used. The problem is most prevalent in elderly patients, where sulphonylurea-induced hypoglycaemia may be related to failure to comply with strict mealtimes or the need for supplementary food intake, often in the context of compromised renal function. Data from large-scale outcome studies demonstrate that when tight glycaemic control is achieved through aggressive antidiabetic therapy, late diabetic complications can be signi®cantly reduced. However, the pursuit of stricter HbA lc targets with more aggressive interventions may increase the risk of hypoglycaemia. This is an irony because the clinical need to avoid hypoglycaemia and patients' apprehension of it present barriers to the achievement of bene®cial glycaemic targets. However, an increased risk of hypoglycaemia may not be inevitable with insulin secretagogue therapy. The recently introduced carbamoylmethyl benzoic acid derivative, repaglinide, has pharmacological properties that are well suited to its intended role as a prandial glucose regulator. When taken prior to main meals, the rapid onset and relatively short duration of action of repaglinide aid disposal of the mealtime glucose load, without continued stimulation of pancreatic beta-cells in the postprandial fasting period. Repaglinide is also characterised by hepatic metabolism and elimination, which is an advantage in the context of impaired renal function. Prandial glucose regulation with repaglinide selectively increases insulin secretion, and hence limits glucose excursions, in the prandial phase. If a meal is omitted, so too is the corresponding dose. This more¯exible approach to the management of Type 2 diabetes has a number of advantages when compared with the ®xed daily dosing regimens of sulphonylureas, among them a reduced risk of hypoglycaemia Ð a bene®t that is particularly marked in the context of missed or irregular meals.

Oral antihyperglycemic therapy for type 2 diabetes mellitus

“…However, the risk of hypoglycemia is lower than that with sulfonylureas. 51 This difference is due in part to the shorter duration of action and in part to the glucose-dependent insulinotropic effects of nateglinide. 48 Similarly, the amount of weight gain appears to be less than that seen with sulfonylureas, 18 perhaps because of the limited duration of elevated insulin secretion.…”

Association of Depression With Increased Risk of Severe Hypoglycemic Episodes in Patients With Diabetes

“…behavioral factors include poor adherence to self-care activities, such as lack of regular meals, inconsistent blood glucose monitoring, erratic use of glucoselowering medications, use of alcohol, or increases in exercise. [6][7][8] Therapeutic and physiologic factors include older age, longer duration of treatment, medical comorbidities, diabetic complications (especially nephropathy), loss of residual insulin secretion, loss of awareness of hypoglycemia, and defects in glucagon responses to hypoglycemia. 2,[9][10][11] Although behavioral, physiologic, and therapeutic factors have been examined as causes of hypoglycemia, the authors are aware of only one study that examined the association of depression with severe hypoglycemic episodes in a population of adults with diabetes.…”

True

“…Although the mean follow-up period was 46 days, this incidence appears to be lower than has been reported in some comparative trials with sulphonylureas (as discussed by Nattrass and Lauritzen 34 in this publication) and may imply that the empirical, prandial use of repaglinide incurs a lower risk of hypoglycaemia than has been previously suggested by ®xed-regimen comparative studies.…”