Building Competency in Diabetes Education THE ESSENTIALS

TREATMENT MODALITIES: PHARMACOLOGICAL THERAPIES | 6-24

Incretin mimetics Incretin hormones are released from L-cells in the lining of the gastrointestinal tract in response to carbohydrate intake; they stimulate insulin production in the pancreas as well as a multitude of other factors (refer to Table 2 below). Incretin hormones account for up to 50-70% of the total insulin production post-intake in healthy subjects (46). Studies have shown the incretin effect is significantly decreased in people with type 2 diabetes (39,47,48). The primary incretin hormones released in response to carbohydrate intake include the following: • Glucagon-like peptide-1 (GLP-1): Promotes insulin secretion, reduces glucagon production, delays gastric emptying, increases satiety. Half-life 2 minutes. • Glucose-dependent insulinotropic polypeptide (GIP): Augments insulin secretion; inhibits hepatic glucose production. Half-life seven minutes. • Dipeptidyl peptidase-4 (DPP-4): Enzyme that rapidly breaks down GLP-1. Half-life one to two minutes. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) and Dipeptidyl peptidase-4 (DPP-4) inhibitors are incretin mimetics that do not cause hypoglycemia. DPP-4 inhibitors block the break down (inactivation) of endogenous GLP-1. The efficacy of DPP-4 inhibitors is therefore limited by the body’s ablity to produce GLP-1. Exogenous GLP-1 RA, on the other hand, is essentially “hormone replacement therapy”; similar to injecting insulin and giving the body the hormone that is not being produced in sufficient quantity. DPP-4 inhibitors therefore exert a physiological effect, whereas GLP-1 RA have a 5-fold incretin effect producing a supra-physiological (pharmacological) effect. As shown in table 2, this supra-physiological effect of GLP-1 RA produces more robust A1C lowering in comparison to DPP-4i therapy. While DPP-4i therapies are weight neutral, GLP-1 RA therapies promote weight loss. Given 80-90% of people with type 2 diabetes also have overweight/obesity, these classes that do not cause weight gain are a preferred option. Because of the significant benefit of GLP-1 RA and the fact that DPP-4 inhibitors do not have any effect on exogenous GLP-1 RA (i.e. do not have an additive effect on exogenous GLP-1 RA), it is not recommended to use GLP-1RA therapy in combination with DPP-4i. When a person is started on GLP-1 RA therapy, DPP-4i is stopped (if the person was previously on a DPP-4i).

Table 2 illustrates the differences between the two classes of incretin mimetics.