Incretin-based therapies have been in use for nearly a decade now, as add-on agents to conventional therapy and as initial treatment for some patients. Here, a quick brush-up on GLP-1 agonists and DPP-4 inhibitors.
As a result of the progressive loss of beta cell function in type 2 diabetes, over time many patients will require combination therapy.1 Although conventional antidiabetic agents can effectively control hyperglycemia, side effects such as hypoglycemia and weight gain may limit their use. In addition, traditional agents do not address one of the major pathophysiological processes underlying type 2 diabetes: dysfunction in the incretin system.
Incretin-based therapies address the beta cell dysfunction and abnormal glucagon secretion found in type 2 diabetes.1 Often used in combination therapy, they can effectively control hyperglycemia while avoiding the adverse effects common to conventional antidiabetic agents. Incretin-based therapies are not without controversy, though. In March 2013, the FDA began reviewing unpublished research linking incretin mimetics to precancerous cellular changes of the pancreas. They have also been linked to acute pancreatitis, along with a range of other side effects in other physiological systems.
Incretins are peptide hormones, which include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), both of which are released from the small intestine after a meal. GIP promotes insulin secretion. GLP-1 stimulates insulin release from pancreatic beta cells, inhibits glucagon release, delays gastric emptying, and inhibits appetite, decreasing food intake and ultimately promoting weigh loss.2
GLP-1 agonists activate GLP-1 receptors, which enhances the effects of GLP-1 in the body. They are available as injection only. The 2 FDA-approved GLP-1 agonists are:
The enzyme dipeptidyl peptidase-4 (DPP-4) rapidly degrades GLP-1 in the gut; DPP-4 inhibitors competitively inhibit the enzyme, preventing degradation and enhancing the effects of GLP-1.2 The DPP-4 inhibitors are available as once-daily, oral formulations. The FDA-approved DPP-4 inhibitors are:
The GLP-1 agonists and DPP-4 inhibitors offer several advantages over conventional therapy.
Potential risks associated with incretin-based therapy stem from their mechanism of action on their hormone receptor targets, which are not confined to the GI system.
Since GLP-1 receptors are found in meninges, thyroid, pancreas, renal tubules, and bone, their activation may have off-target effects. GLP-1 agonists may have the potential to increase risk for:
The DPP-4 enzyme is found in the cell membranes of numerous tissues throughout the body, including immune cells, which has raised some concerns about their long-term safety. DPP-4 inhibitors carry potential increased risk for:
Aside from potential benefits and risks, whether or not to initiate incretin-based therapies can be influenced by a number of other factors, which could include: