Incretin Mimetics: Pros and Cons, and Emerging Agents in Diabetes Treatment
Published Online: December 14, 2013
Jamie M. Terrell, PharmD, and Tibb F. Jacobs, PharmD, BCPS
Type 2 diabetes mellitus (T2DM) is a huge health problem globally. It affects nearly 25.8 million people in the United States.1 Over 35% of US adults 20 years or older (or 79 million Americans) are currently classified as having prediabetes, which places them at greater risk for developing diabetes. Patients diagnosed with diabetes have a much higher risk of developing heart disease, hypertension, stroke, and kidney disease.1
No optimal medication exists currently for the treatment of T2DM. The American Diabetes Association (ADA) recommends metformin as the preferred initial pharmacologic agent for the treatment of this disease. However, if high doses of noninsulin monotherapy are not successful at achieving a patient’s goal glycated hemoglobin (A1C), then a second oral agent, a glucagonlike peptide-1 (GLP-1) receptor agonist or insulin should be added. Many patients will eventually need to have insulin added to their medication regimen.2 Numerous side effects exist with all medications used for the treatment of T2DM, including hypoglycemia and weight gain, as well as difficulty tolerating therapy.2
Some of the more recent classes of medications for the treatment of T2DM focus on the incretin or GLP-1 system. GLP-1 based therapies have not been studied in patients with type 1 diabetes (T1DM) and therefore should not be used in those patients at this time. The goal in the treatment of patients with T2DM is to restore normoglycemia both fasting and postprandially.
To understand how the medications affecting the incretin system work, it is necessary to first understand the incretin effect. When nondiabetic patients are given oral glucose, their insulin levels increase as much as 3 times greater than when the same patients are given IV glucose to match the plasma glucose levels seen with the oral dose. This is what is referred to as the incretin effect.
It’s defined as the difference in insulin response to oral versus IV glucose dosing.3 Eating provokes the secretion of multiple GI hormones, including GLP-1, involving the regulation of gut motility and stimulation of insulin secretion.3 GLP-1 is produced in the L-cells of the small intestine and secreted in response to nutrients. It exerts its main effect by stimulating glucose-dependent insulin release from the pancreatic islet cells. It can slow gastric emptying and inhibit inappropriate post meal glucagon release and therefore decrease food intake.4,5 Because of its slowed gastric emptying and side effects of nausea and vomiting, GLP-1 therapy can be associated with weight loss.6 Dipeptidyl peptidase 4 (DPP-4) is an enzyme that can inactivate GLP-1. A second group of medications, DPP-4 inhibitors, exert their effects here. By inactivating GLP-1, these medications can potentially impact glucose regulation. DPP-4 inhibitors, unlike the GLP-1 analogues, can be administered orally.7 (Table.)
At this time there are no long term studies with GLP-1 analogues to assess weight loss over long periods of time, cardiovascular outcomes, or safety. The first product, exenatide, was not FDA-approved until 2005. For these reasons, they are not considered first-line therapy. Currently, there are two GLP-1 analogues on the market, exenatide and liraglutide.
Exenatide. This therapy works by slowing gastric emptying and suppressing inappropriately elevated glucagon levels. These affects can cause weight loss in many patients.6,8 Weight loss can average 5.4 kg at 2 years. Weight loss can also be associated with improvements in blood pressure and lipids.Exenatide is available in 5 or 10 mcg, and is dosed twice daily subcutaneously.
Exenatide is also available as an extended release product that is dosed 2 mg once weekly.6 A recent meta-analysis showed a reduction of 1.01% in patients taking exenatide versus patients on placebo.10 Once-weekly exenatide showed A1C decreases of 1.5% compared with insulin glargine.11
Nausea is a common side effect with exenatide therapy. It can be reduced with dose titration and does generally decrease over duration of therapy. Nausea is less common in the once weekly exenatide formulation than the twice daily formulation.6
Liraglutide. This is a once daily injectable GLP-1 analogue. It is available in 18 mg prefilled pens. It is typically dosed 1.2 mg or 1.8 mg daily.12 A 52-week study comparing liraglutide and glimepiride showed reductions in hemoglobin A1c of 1.14% in patients taking liraglutide.13 Similar to exenatide, the most common adverse effects seen with liraglutide are nausea, vomiting, and diarrhea.12
Comparisons of GLP-1 analogues. In 2 studies of exenatide once weekly versus exenatide twice daily, exenatide once weekly had greater A1C reductions (1.9 vs 1.5 and 1.6 vs 0.9) with similar reductions in body weight.14,15 In another study, liraglutide was compared with exenatide once weekly in patients already on other oral antihyperglycemic medications. There was no significant difference in mean A1C reductions (1.48 vs 1.28). However, there were slightly more side effects (nausea, diarrhea, vomiting) in the liraglutide group. There was also more weight loss in the liraglutide group.16
DPP- 4 acts in the body to inactivate GLP-1. By inhibiting this, DPP-4 inhibitors can increase the half-life of endogenous GLP-1. This inhibition can affect glucose regulation by augmenting glucose-stimulated insulin release and inhibited glucagon secretion. DPP-4 inhibitors can be administered orally. Possibly because they increase endogenous GLP-1 rather than augment it, they tend to be weight neutral.17 Currently sitagliptin, saxagliptin, linagliptin, and alogliptin are available as DPP-4 inhibitors in the United States. Vildagliptin is available in other countries, but not the United States at this time.
Efficacy. DPP-4 inhibitors provide average A1C reductions of –0.5 to –0.7%.18-20 These medications can be used as monotherapy in patients not tolerating other oral therapies. They can also be used as add-on therapy with metformin or sulfonylureas.18 Some of the products are marketed as combination products with metformin.21,22 There are still little data on long-term safety or mortality with these agents.
The DPP-4 inhibitors appear to have similar efficacy at reducing A1C. In a study comparing saxagliptin with sitagliptin, there was no significant reductions in A1C (0.52 vs 0.62).23 In a metaanalysis, sitagliptin versus placebo and vildagliptin versus placebo had similar efficacy as well.10
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