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Incretin Mimetics: Pros and Cons, and Emerging Agents in Diabetes Treatment
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Incretin Mimetics: Pros and Cons, and Emerging Agents in Diabetes Treatment

Jamie M. Terrell, PharmD, and Tibb F. Jacobs, PharmD, BCPS
Drug Pipeline
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.

Incretin Effect

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.)

GLP-1 analogues

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 Inhibitors

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

Adverse Effects. DPP-4 inhibitors appear to be well tolerated. There is typically no weight gain when these medications are used, and there is no risk of hypoglycemia, unless they are used in conjunction with sulfonylureas.18 The most common side effects reported are headache, nasopharyngitis, and upper respiratory tract infection.18-20

Safety Concerns With Incretin-Based Therapies

At this time, major safety concerns with incretin-based therapies (GLP-1 receptor agonists and DPP-4 inhibitors) include: pancreatitis, pancreatic cancer, and thyroid carcinoma. In animal studies there is evidence of damage to the pancreas with exenatide and sitagliptin.24,25 However, another study with liraglutide did not show this damage.24

Pancreatitis/Pancreatic Cancer. There are also reports of spontaneous acute pancreatitis in humans.25 There are GLP-1 receptors in the pancreatic ducts as well as the pancreatic islets. This could potentially be part of the reason why GLP-1 based therapies can cause increased risk of pancreatitis and/or pancreatic cancer. There are some observational studies however, that suggest that acute pancreatitis is just more common than expected in the diabetic population—the increased risk of pancreatitis is not worse with exenatide relative to other therapies.25,26

Obese T2DM patients are more likely to develop pancreatitis than patients in the general population.24 However, case control and retrospective studies have shown an increased risk for pancreatitis in patients taking GLP-1 based therapy.25,27 Increased risk of subclinical pancreatic inflammation, pancreatic cancer, and neuroendocrine tumors have been reported in patients taking sitagliptin.27,28

Because of the conflicting data and the increased prevalence of pancreatitis in the diabetic population, there is still some uncertainty about whether the association between the GLP-1 agonists and DPP-4 inhibitors and adverse pancreatic outcomes is causal. But, pancreatitis is the biggest risk factor for patients to develop pancreatic cancer.26,29

Earlier this fall, the FDA and the European Union reviewed all available data and both agreed there is not enough evidence to confirm concerns over increased risk of pancreatic side effects with GLP-1 or DPP-4 therapies.30 Presently, many patients continue to use medications impacting the incretin system. In these patients, pancreatitis should be considered if patients present with severe abdominal pain. The GLP-1 agonist or DPP-4 inhibitor should be discontinued in those patients. If pancreatitis is confirmed, the medication should not be restarted.6,12,18-20

Longterm studies, preferably prospective, are needed to examine this outcome as well as chronic pancreatitis and pancreatic cancer.25

Thyroid Cancer. Another risk for patients taking medications impacting the incretin system is thyroid cancer. Rodent studies with some of the GLP-1 agonists have shown that there is a potential increased response of thyroid C cells in patients on these medications. There are GLP-1 receptors that are expressed in most medullary thyroid cancer, C-cell hyperplasia, and some of papillary thyroid cancer.29 This could cause hyperplasia, adenomas, and eventually medullary thyroid carcinomas.24 Liraglutide has been shown to increase changes in rodent thyroid C cells. In animal studies, liraglutide increased the cases of C-cell hyperplasia, adenomas, and medullary thyroid carcinoma.24 Until more research is conducted, it is recommended to avoid liraglutide in patients with personal or family history of thyroid cancer.27

On the Horizon

There are new therapies being developed for diabetes, and some of these may be approved for use in the near future. Some novel mechanisms of action have been discovered recently, and drugs with these mechanisms are being tested. With these advancements and more treatment options available, the successful management of diabetes may become easier.

New GLP-1 Receptor Agonists. While there are currently 2 GLP-1 receptor agonists on the market, there are several that are on the road to future approval. Amylin Pharmaceuticals has studied a new formulation of exenatide that would allow for a single injection a month, compared with the twice-daily or once-weekly formulations that are currently available.31 Albiglutide is another GLP-1 receptor agonist that has been tested recently. In a noninferiority study against liraglutide, it missed the mark by providing a smaller decrease in A1C and lower total weight

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