A review of the effects of antihyperglycaemic agents on body weight: the potential of incretin targeted therapies

BACKGROUND: Current American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) treatment guidelines recommend metformin (which does not promote weight gain) as the first-line antihyperglycaemic drug for patients with type 2 diabetes. However, when metformin fails, the recommended add-on treatment options (sulphonylureas, glitazones and basal insulin) can lead to significant weight gain. This article reviews the effect on body weight of current treatments for type 2 diabetes and discusses the potential impact of weight gain in this patient group. SCOPE: MEDLINE searches were performed to evaluate the prevalence and impact of changes in body weight in type 2 diabetes (articles published between January 1966 and August 2006) and the effects of sulphonylureas, glitazones, insulin, dipeptidyl peptidase-4 (DPP-4) inhibitors and incretin analogs on body weight in these patients (search between January 2004 and September 2006). FINDINGS: Weight gain in general affects not only the physiological capability of patients with diabetes to achieve glycaemic control, but also their psychological well-being, quality of life and persistence with antihyperglycaemic treatment. Excess body weight and obesity in patients with diabetes are also associated with increased healthcare resource utilisation. Development of obesity is also associated with increased cardiovascular risk, although a link between drug-induced weight gain per se and increased cardiovascular risk has not been established. Initial clinical trial experience with the new oral DPP-4 inhibitors such as sitagliptin and vildagliptin suggests that these agents are weight-neutral, while providing improved glycaemic control when added to metformin. CONCLUSIONS: Because currently available add-on treatments can cause weight gain, physicians initiating add-on therapy in patients who can no longer achieve glycaemic control with metformin are faced with the problem of improving glycaemic control while causing weight gain. Initial clinical trial experience with oral DPP-4 inhibitors such as sitagliptin and vildagliptin suggest that these agents may represent an important oral treatment option for weight-neutral, glycaemic control when added to metformin. The new oral DPP-4 inhibitors, therefore, represent a potentially important addition to the oral treatment options currently available for the management of type 2 diabetes mellitus. Long-term clinical trials are now required to evaluate the relative risk/benefit profile of these drugs compared with the established antihyperglycaemic drug classes.