Incretin Therapy: A Short Review

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 In March 2013, the FDA began reviewing unpublished research linking incretin mimetics to precancerous cellular changes of the pancreas.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. 

Brief Background

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:

• Exenatide: Twice-daily and once-weekly formulations
• Liraglutide: Once-daily formulation

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:

• Sitagliptin
• Saxagliptin
• Linagliptin
• Alogliptin

Advantages

The GLP-1 agonists and DPP-4 inhibitors offer several advantages over conventional therapy.

GLP-1 agonists

• Weight loss: Generally about 2 to 4 kg in most patients²
• HbA1C decrease: Exenatide usually lowers A1C by by 0.5% to 1.0% from baseline; liraglutide lowers A1C up to 1.6%¹
• Postprandial glucose lowering: Similar to insulin treatment²
• Blood pressure reduction: Approximately 2 to 5 mm Hg²

DPP-4 inhibitors

• Weight neutral³
• HbA1C decrease: Generally lowered by  0.5% to 0.8%¹
• Postprandial glucose lowering: Similar to sulfonylurea treatment²
• Blood pressure reduction: Generally occurs only in patients with established arterial hypertension²

Disadvantages  

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.

GLP-1 agonists

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:

• Acute pancreatitis: Especially exenatide, whose prescribing information comes with a precaution for pancreatitis¹
• Thyroid cancer: Contraindicated in patients with multiple endocrine neoplasia type 2; avoid in patients with genetic predisposition to thyroid cancer, or personal or family history of medullary thyroid carcinoma⁴; liraglutide, especially, is linked to increased risk of thyroid tumors
• Renal failure: Not indicated for those with stage 4 or 5 chronic kidney disease (CKD); use exenatide with care in patients with CKD⁵
• Nausea, GI discomfort: Common, tends to decrease over time; risk is lower with liraglutide⁶
• Cardiovascular: Increased heart rate by 2 to 5 beats per minute with long-acting GLP-1 receptor agonists²

DPP-4 inhibitors

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:

• Immune response: Serious allergic and hypersensitivity reactions have been linked to sitagliptin, and are noted in its prescribing information¹
• Acute pancreatitis: Especially for sitagliptin⁴
• All-cause mortality: Concerns have been raised, but currently little is known about the effects of DPP-4 inhibitors on this⁷

 Other Considerations

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:

• How far the patient is from the HbA1c goal, their initial response to metformin, or need for combination therapy
• Contraindication to metformin as initial therapy
• Patient preference and lifestyle (eg, patient tolerance for injectable therapy [GLP-1 agonists])
• Adherence issues, since available formulations can simplify treatment regimens
• Patient tolerance for GI side effects (ie, nausea, vomiting) with GLP-1 agonists; patient education (eg, on eating slowly, awareness of feelings of satiety) may help 
• High cost of treatment (none of the incretin agents are available as generics)

References:

• Freeman JS, Unger J.  Why and when to implement incretin therapy. J Fam Pract. 2008;57:S19-S25.
• Nauck, M.  A critical analysis of the clinical use of incretin-based therapies:  the benefits outweigh the risks.  Diabetes Care. 2013;36:2126-2132.
• Ross SA, Ekoe JM. Clinical Review:  Incretin agents in type 2 diabetes. Can Fam Physician. 2010;56:639-648.
• Butler PC, Elashoff M, Elashoff R, Gale EAM. A critical analysis of the incretin-based therapies:  Are the GLP-1 therapies safe? Diabetes Care. 2013;36:2118-2125.
• Linnebjerg H, Kothare PA, Parks S, et al.  Effect of renal impairment on the pharmacokinetics of exenatide.  Br J Pharmacol. 2007;64:317-327.
• Buse, JB, Rosenheck J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomized, parallel-group, multinational trial (LEAD-6).  Lancet. 2009;374:39-47.
• Erlich DR, Slawson DC, Shaughnessy A. Diabetes update: new drugs to manage type 2 diabetes. FP Essent. 2013 May;408:20-24.