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

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

loss compared with liraglutide. However, dulaglutide and lixisenatide have shown promise in antidiabetic medication—naive patients by demonstrating A1C reductions that were statistically significant compared with placebo.³¹ In a phase 3 trial, lixisenatide, along with other oral antihyperglycemic drugs and/or insulin, was shown to have better outcomes versus placebo and to also be noninferior to exenatide.³² Semaglutide has also shown A1C reductions compared with placebo.³¹

SGLT2 (Sodium-Glucose Cotransporter 2) Inhibitors. Because the role of the kidneys in glucose regulation has been established, drug research has been recently focused toward SGLT2 inhibitors.³³ SGLT2 is a transporter that is exclusive to the kidneys and carries glucose from the proximal convoluted tubule back into the tubular epithelial cells. It is thought that by blocking SGLT2, more glucose will be excreted in the urine, which will impart added glycemic control, as well as possible weight loss from the glycosuric effect. ³³ SGLT2 inhibitors, such as the recently approved canagliflozin, ultimately work by causing glucose to be excreted in the urine by blocking the reabsorption of the filtered glucose in the kidneys.³³ Canagliflozin is given as a 100-mg capsule/tablet prior to the first meal of the day. The dose may be increased to 300 mg daily in patients with adequate renal function.

Several canagliflozin clinical trials have been completed.³³ The series of Canagliflozin Treatment and Trial Analysis (CANTATA) trials evaluated the 100-mg and 300-mg doses for safety and efficacy in inadequately controlled patients with T2DM, as well as the change in hemoglobin A1C.³³ CANTATA-SU was a 52-week study that compared canagliflozin 100 mg and 300 mg with glimepiride (titrated up to 6 mg or 8 mg daily) in patients who were not at goal on metformin therapy alone. The results of this trial showed that canagliflozin 100 mg was non-inferior to glimepiride, and canagliflozin 300 mg was superior to glimepiride, in providing A1C reductions. Compared with glimepiride, patients taking canagliflozin 100 mg and 300 mg had fewer documented hypoglycemic episodes, reduced body weight, reduced systolic and diastolic blood pressure, and increased HDL cholesterol and decreased triglycerides. However, patients taking canagliflozin also showed a doserelated increase in LDL cholesterol, increased number of genital mycotic infections, and higher rates of urinary tract infections.^33,34

The Canagliflozin Cardiovascular Assessment Study (CANVAS) is an ongoing trial with primary end points to assess major cardiovascular events, such as death, myocardial infarction, and stroke. This trial is a randomized, double-blind, placebo-controlled, parallel group, multicenter trial that was planned to have 2 consecutive phases. The second phase will not be completed, but the first phase will continue and follow 4330 participants that were enrolled to assess for safety and tolerability, as well as other secondary objectives.

The second phase was stopped because “a strategy that would ensure concealment of the hazard ratio for the primary outcome was not implemented, with the sponsor electing to un-blind the data to obtain better insight into the effects of the compound while preparing materials for submission to the regulators.”³⁵

Ipragliflozin and dapagliflozin are also SGLT2 inhibitors that are currently in the late stages of their clinical research.³⁶ Both of these drugs are structurally similar to canagliflozin and have been shown to have positive results on lowering A1C. Other SGLT2 inhibitors that are currently being evaluated are empagliflozin, tofogliflozin, and luseogliflozin.³⁶ As a class, SGLT2 inhibitors are advantageous antidiabetic drugs because they have been shown to lower A1C, reduce body weight, lower blood pressure, and also possibly improve beta-cell function, all of which may help prevent micro- and macrovascular complications in patient with T2DM.

GPR40 Agonist. Fasiglifam (TAK-785) is a novel drug that may be used for diabetes in the future. It is the first GPR40 (also known as FFAR1) agonist to reach phase III trials.^37,38 Fasiglifam works by activating free fatty acid receptor 1, which is a G protein-coupled receptor located primarily in pancreatic beta cells. This activation accelerates insulin secretion in a glucose-dependent manner.³⁷ In this 24-week multicenter, randomized, double-blind, placebo-controlled phase III comparative trial done in 192 Japanese subjects, fasiglifam 25 mg and 50 mg showed statistically significant reductions in A1C compared with placebo. The frequency of hypoglycemia was comparable to placebo, and the highest reported adverse events were nasopharyngitis and upper respiratory tract inflammation.³⁸

Novel Insulin Formulation. PEGylated insulin Lispro (LY2605541) is a new long-acting basal insulin that has showed promising effects in clinical trials. LY2605541 is composed of insulin lispro with a 20-kDa polyethylene glycol (PEG) moiety conjugated to it.^39,40 This PEG moiety prolongs the duration of action of the insulin by slowing the absorption and also reducing its clearance. ^39,40 Bergenstal et al performed a 12-week, randomized, open-label, 3-arm, multinational parallel group phase 2 study to compare the safety and efficacy of LY2605541 to insulin glargine.³⁹

The respective insulin was injected once daily in the morning in patients with T2DM. The primary objective was fasting blood glucose. At the end of the study, fasting blood glucose was similar between the LY2605541 group and the glargine group. The frequency of hypoglycemic events was also similar between the groups. There were no significant differences between either group with respect to A1C. LY2605541 demonstrated non-inferiority in this study.³⁹

When new agents come onto the market, it is essential to determine which patients will benefit from the drug, which patients will not, and which patients may be harmed by the drug. As a class, the GLP-1 receptor agonists offer low rates of hypoglycemia, blood pressure reduction, and weight loss benefits.³¹ Their mild side effects are usually brief and gastrointestinal in nature. Injection site reactions may occur and are more frequent with exenatide weekly than exenatide twice daily or liraglutide. More serious concerns of all of the incretin mimetics are pancreatitis pancreatic cancer, and thyroid cancer.

In March 2013 the US Food and Drug Administration (FDA) announced that it was investigating unpublished reports of pancreatic toxicity in all of the incretin mimetic drugs, including the GLP-1 receptor agonists. Many studies have not identified a common tie, and the FDA suggests following recommended drug labels at this time.^31,41

Despite these critical issues for incretin mimetics and the need for more information, the DPP-4 inhibitors and GLP-1 receptor agonists have proved that they deserve a place in the standard of treating T2DM. The family of incretin mimetics appears to be here to stay, at least for awhile. GLP-1 receptor agonists and DPP-4 inhibitors have shown clinical benefits. As with all products, some risks exist with these classes, and clinical judgment should be used when deciding which patients should receive these drugs. Many new drugs with novel mechanisms of action are on the horizon, and have many practitioners anxiously awaiting their review. With these new drugs come potential promises that one day soon the treatment of diabetes may offer more diverse choices with better patient outcomes.References

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