DPP-4 Inhibitors and Combined Treatment in Type 2 Diabetes: Re-evaluation of Clinical Success and Safety

Abstract

The incretin system has proven to be a new source of glucose-lowering drugs. Glucon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are the incretins which are degraded by dipeptidyl peptidase-4 (DPP-4). GLP-1 is the major relevant incretin in type 2 diabetes, GIP has little stimulatory capacity. Oral inhibitors of DPP-4 increase GLP-1 levels and this leads to lower glucose levels caused by increased insulin secretion and decreased glucagon levels. There are currently two oral drugs registered with the European Medicinal Evaluation Agency: sitagliptin and vidagliptin. Both compounds have shown similar effects to date. A main issue is to establish the value of this new class of drugs in the treatment of patients with type 2 diabetes. In this article, results from randomized studies on the efficacy of the new drugs are discussed: 1. comparison with placebo to establish long-term efficacy, 2. comparison with placebo when added to the regimen in patients failing on another oral glucose-lowering drug and 3. comparison in a head-to-head trial with other conventional drugs. Also, the combination with insulin is a promising new avenue. Both efficacy and safety (regarding hypoglycemia, body weight changes and changes in lipid levels) are major components in the decision of the optimal pharmacological treatment, which is discussed in this article. Finally, the advantages, disadvantages and risks of the new anti-diabetic compounds are highlighted, which are applicable to other classes of diabetes drugs.

Figure 1

Conceptual model on advantages, disadvantages and risks of the new glucose-lowering drugs based on DPP-4 inhibition. However, it needs to be noted that positive and negative effects are detected in study sample populations. It is questionable if the model can be extrapolated to all type 2 diabetes patients. The optimal therapies for patients need to be verified in individual cases with innate clinical characteristics.