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Practice guidelines include incretin-based therapies as alternative monotherapy agents when metformin is contraindicated or as a component of combination therapy.
Metformin is the drug of choice for treating type 2 diabetes (T2D), when lifestyle changes alone fail to control blood glucose, and is especially useful for overweight patients.1-3 Metformin may prevent the cardiovascular complications of diabetes and has emerging use in treating cancers (diabetes-related and others).4 In T2D, the treatment goal is tight glycemic control, but as beta cell function declines progressively, many patients need treatment intensification with a second glucose-lowering agent.5
Patients with T2D may have abnormalities that affect the release, or action, of incretin hormones, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These hormones control almost all postprandial insulin release. Since 2005, incretin- based therapies have been available. Practice guidelines include incretin-based therapies as alternative monotherapy agents when metformin is contraindicated or as a component of combination therapy.1-3
GLP IN THE GUT
GLP originates in the small intestine and colon and is released after eating. GLP-1 stimulates insulin secretion, but glucose must be present in the bloodstream for it to activate. GLP-1 delays stomach emptying, slows carbohydrate absorption, prevents the subsequent rise in the blood glucose level after meals, and suppresses appetite. Animal studies and in vitro work indicate GLP-1 may promote pancreatic beta cell regeneration and slow apoptosis (programmed cell death), lengthening existing beta cells’ lives.6,7
GIP is released when glucose comes into contact with cells in the upper small intestine. GIP stimulates insulin secretion from pancreatic beta cells to promote beta cell proliferation and improve beta cell survival.6,8
The dipeptidyl peptidase-4 (DPP4) enzyme regulates GLP-1 and GIP, leading to incretin breakdown.6,8 Table 19-17 lists drugs that affect GLP-1 and GIP, their indications, and key treatment points.
Incretin-based therapies are associated with the following:
GUIDELINE RECOMMENDATIONS
Clinicians primarily use 2 guidelines: the American Diabetes Association/European Association for the Study of Diabetes (ADA/ EASD) and the American Association of Clinical Endocrinologists (AACE). The ADA/EASD position statement for medical management of T2D indicates that incretin-based therapies are appropriate as the following1-2:
The AACE acknowledges that incretin-based therapies are appropriate as the following3:
COMBINATION THERAPY: WHAT IS SAFE?
Each incretin-based therapy’s prescribing information outlines its safe, effective, evidence-based use as monotherapy and its role in combination therapy. Online Table 29-17 summarizes the studies conducted as part of each product’s labeling.
Table 2. Incretin-Based Pivotal Trials
Alogliptin17 Nesina
Linagliptin16 Tradgenta
Saxagliptin10 Onglyza
Sitagliptin6 Januvia
Albiglutide11 Tanzeum
Exentide10 Byetta
Exentide ER9 Bydureon
Iraglutide12 Victoza
Dulaglutide13 Trulicity
Monotherapy
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Add-on combination therapy with metformin
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Initial combination therapy with metformin
Yes
Yes
Yes
Add-on to a thiazolidinedione
Yes
Yes
Yes
Yes
Yes
Yes
Initial combination therapy with a thiazolidinedione
Yes
Yes
Yes
Yes
Add-on to a thiazolidinedione and metformin
Yes
Yes
Yes
Add-on to a sulfonylurea
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Add-on to metformin and a sulfonylurea
Yes
Yes
Yes
Yes
Yes
Add-on to glimepiride (with or without metformin)
Yes
Add-on to insulin (with or without metformin)
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Adapted from references 9-17.
CONCLUSION
In the future, pharmacists can expect to see these drug classes used for other indications. Researchers suspect a link between neurodegenerative diseases and T2D and are investigating incretin’s effects in several diseases. GLP-1 receptor agonists have shown promise in neurodegenerative diseases in preclinical studies and are being studied in humans with Alzheimer disease and Parkinson disease. DPP4 inhibitors are also being studied.19
Ms. Wick is a visiting professor at the University of Connecticut School of Pharmacy.
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