Incretin-Based Therapy: More Treatment Options for Diabetes

Waldrop G, Zhong J, Peters M, Rajagopalan S.
Incretin-Based Therapy for Diabetes: What a Cardiologist Needs to Know. J Am Coll Cardiol 2016;67:1488-1496.

The following are key points to remember from a review on incretin-based therapy for diabetes:

  1. Incretins are gut-derived members of the glucagon superfamily, released in response to nutrient ingestion. These peptides amplify the insulin secretory response to nutrients. Glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP), the major physiological incretins, account for 50-70% of total insulin secreted following an oral glucose load.
  2. The incretin effect is markedly diminished in type 2 diabetes mellitus (T2DM), due to resistance at the level of the pancreatic beta cell.
  3. Both GLP-1 and GIP have short half-lives in vivo and are rapidly degraded to their inactive forms by the peptide dipeptidyl-aminopeptidase-4 (DPP-4).
  4. Exenatide and liraglutide are GLP-1 analogs. Albiglutide and dulaglutide are synthetic fusion proteins composed of dimers of degradation-resistant GLP-1 with a linker protein that prolongs half-life. There are currently four DPP-4 inhibitors (“gliptans”) approved by the FDA; all are orally available.
  5. The American Diabetes Association/European Association for Study of Diabetes recommends that GLP-1a or DPP-4i be considered as alternatives to metformin or as combination therapy with metformin when glycemic targets are not reached.
  6. As the authors write, an “excellent indication for [GLPa or DPP-4i] is when either metformin, sulfonylurea, or pioglitazone is contraindicated, not indicated, or when avoidance of hypoglycemia and/or weight gain is a priority.” A GLP-1Ra may be recommended over a DPP-4i, when weight loss is a priority and if greater reductions in glycated hemoglobin are desired.
  7. An improvement in cardiovascular outcomes has not been seen with the incretinergic agents based on the duration (2-4 years) of currently designed studies.
  8. Regarding the risk of heart failure (HF) with incretinergic agents, the authors write, “It is safe to conclude that the HF risk is small, and mainly with saxagliptin. The risk of HF with other GLP-1Ra remains to be determined.”
  9. The authors conclude, “At the current time, the clinician should focus the treatment approach around the patient, with individual preferences, patient disease variables, and other factors (i.e., cost) also being considered, once glucose management targets are set.”

Clinical Topics: Anticoagulation Management, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure

Keywords: Aminopeptidases, Diabetes Mellitus, Diabetes Mellitus, Type 2, Dipeptides, Glucagon, Glucagon-Like Peptides, Glucose, Heart Failure, Hemoglobin A, Glycosylated, Hypoglycemia, Incretins, Insulin, Metabolic Syndrome X, Metformin, Peptide Fragments, Secondary Prevention, Thiazolidinediones, Weight Gain, Weight Loss

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