Unwanted drug effects of antidiabetic drugs

Gallwitz, Baptist. Eberhard-Karls-University Tübingen Dept. Medicine IV, Otfried-Müller-Str. 10, 72076 Tübingen, Germany.

Intervention trials proved that diabetes therapy with treatment goals aiming at normoglycemia reduce microvascular and macrovascular risk. A definite glycemic threshold for reducing complications has not been found, therefore treatment should achieve near-normoglycemia as safely as possible.

Metformin is the drug for first line therapy, but it is contraindicated in patients with impaired renal function due to accumulation. Sulfonylureas, glinides and insulin therapy are associated with an increased risk for hypoglycemia and weight gain. Sulfonylureas and glinides are insulin secretagogues acting glucose-independently. The incretin based therapies are advantageous and save regarding hypoglycemia by a glucose-dependent mode of action, are weight neutral (DPP-4 inhibitors) or allow weight loss (GLP-1 receptor agonists).

Acarbose specifically acts on postmeal hyperglycemia, is weight neutral and has lowered cardiovascular events in a trial in subjects with IGT. Gastrointestinal side effects are a barrier to use of this compound. Glitazones act on insulin resistance but are associated with weight gain. In a trial on cardiovascular outcomes, pioglitazone failed to show a significant improvement of cardiovascular events defined in the primary endpoint. Recently, concerns on the long-term cardiovascular safety of rosiglitazone resulted that it is not recommended in the novel ADA/EASD guidelines.

In a recent trial a vigorous reduction of the HbA1c to <6.5% lowered nonfatal cardiovascular events but increased mortality most likely associated with hypoglycemia, weight gain and unfavourable multiple combinations of antidiabetic agents in combination with insulin. In this respect, a safe antihyperglycemic treatment not leading to hypoglycaemia and weight gain may be favourable, especially in patients with HbA1c values <7.5%. Here, the incretin based therapies may become an attractive and effective treatment option especially for overweight patients with type 2 diabetes. DPP-4 inhibitors demonstrated a sustained durability of efficacy in combination with metformin over 2 years; exenatide also showed a durable HbA1c reduction for 3 years in patients with a baseline therapy of metformin and/or sulfonylureas.

However, long-term intervention studies to investigate the durability of the effect of the incretin based drugs and their effect on vascular outcomes and hard endpoints are needed.