Differentiating among incretin therapies: a multiple-target approach to type 2 diabetes

What is known and Objective: Incretin-based glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitor therapies provide glycaemic control with reduced risks associated with weight gain or hypoglycaemia. Incretin therapies are compared with their mechanisms of action, effects on haemoglobin A1C (HbA1C), fasting plasma glucose (FPG), post-prandial glucose (PPG), body weight, beta-cell function, cardiovascular biomarkers and in their safety profiles to aid clinicians in the selection of individualized pharmacotherapy for patients with type 2 diabetes. Methods: Relevant articles for a systematic review were identified through PubMed. Randomized, head-to-head comparison studies among incretin therapies were identified and included in the review. Additionally, randomized, controlled monotherapy and combination therapy studies examining glycaemic and extraglycaemic effects of individual incretin therapies from 2007 to 2011 were reviewed. Results and Discussion: Glucagon-like peptide-1 receptor agonists are generally preferred over DPP-4 inhibitors because of their greater effectiveness in reducing HbA1C, FPG and PPG excursions, and greater weight loss potentiation. As a monotherapy option, longer-acting GLP-1 RAs, including liraglutide and exenatide once-weekly, may be preferred at higher HbA1C because of their more pronounced effects on FPG. At lower/near normal HbA1C, a short-acting GLP-1 RA, such as exenatide twice-daily, may be a better choice as its effects are more pronounced with PPG. Ideal patients or patient situations for DPP-4 inhibitors include patients who need minimal reduction in HbA1C, elderly patients, patients who are unwilling or unable to take an injectable agent, when GLP-1 RAs are contraindicated or when the patient will not benefit from weight loss. Treatment benefits common to all incretin-based therapies include minimal hypoglycaemia risk, potential preservation of beta-cell function and effective targeting of multiple organs underlying type 2 diabetes and of comorbidities commonly associated with type 2 diabetes, such as obesity and hypertension. What is new and Conclusion: Key differences in mechanisms of action and in glycaemic and extra-glycaemic treatment outcomes exist among incretin therapies, both within the GLP-1 RA class, and between GLP-1 RAs and DPP-4 inhibitors. Clinical judgment acknowledging important differences among incretin therapies and treatment-related patient characteristics will aid in the selection of the appropriate incretin agent for individualized pharmacotherapy.