AACE 2011: New Agents for the Treatment of Diabetes

Research shows promising results for PPAR modulators, long-acting GLP-1 receptor agonists, SGLT2 inhibitors, and other new classes of diabetes treatments.

Three new classes of agents, dual PPAR (peroxisome proliferator-activated receptor) modulators, long-acting GLP-1 (glucagon-like peptide 1) receptor agonists/analogs, and SGLT2 (sodium-dependent glucose cotransporters) inhibitors, show promise for improving outcomes for patients with diabetes. The exciting findings were presented by Robert R. Henry, MD, professor of medicine at UCSD and director of the Center for Metabolic Research at the VA Medical Center in San Diego, at the 20th Annual Meeting and Clinical Congress of the American Association of Clinical Endocrinologists. Henry was also the recipient of this year’s AACE Frontiers in Science Award.

Henry began his presentation describing the phase II and III clinical trial findings involving aleglitazar, a dual PPAR modulator acting on both PPAR-alpha and PPAR-gamma. The SYNCHRONY study was a phase 2 dose-finding study in patients with type 2 diabetes mellitus (T2DM). The primary endpoint in the placebo-controlled study was change in HbA1c from baseline. Findings revealed significant dose-dependent reductions in HbA1c and fasting plasma glucose (FPG) compared to placebo. “Perhaps the most intriguing aspect of treatment with dual PPARs is their ability to lower lipid profiles through activation of PPAR alpha,” he explained. The relative efficacy and high tolerability of aleglitazar resulted in continuation onto a phase III study, ALECARDIO. Currently underway, the study evaluates cardiovascular outcomes in patients with type 2 diabetes mellitus who experienced a recent acute coronary syndrome event. Started in February 2010, the international study’s goal is to obtain 950 events in 2.5 years. Patients are randomized to aleglitazar or placebo, and receive standard care for their conditions. “This is a very pivotal study, explained Henry. “If it turns out to be positive, there will be an indication for acute coronary syndrome and other conditions. We will know in the next few years.”

The second class of drugs he focused on was the long-acting GLP-1 receptor agonists/analogs. Results from a 16-week phase II trial of albiglutide revealed significant (p<.004) and dose-dependent reductions in HbA1c for patients receiving 30-mg weekly, 50-mg biweekly, and 100-mg monthly, compared to those receiving placebo or open-label exenatide. FPG levels were also significantly lower for patients on albiglutide compared to placebo. Gastrointestinal (GI) side effects were observed with higher doses of albiglutide and exenatide. Reductions in HbA1c were observed with dulaglutide in a study of patients with diabetes for 8 years. Dose-dependent weight reduction was also noted, but higher doses of the drug did result in more frequent side effects. Phase III studies with taspoglutide were halted in September 2010 due to hypersensitivity reactions and gastrointestinal side effects.

Finally, Henry discussed findings from two studies of exenatide, which employs biodegradable polymeric microspheres that entrap the medication, allowing gradual delivery of drug at controlled rates. The Exenatide Once Weekly (EQW) study found larger decreases of HbA1c and FPG in patients receiving the drug once weekly compared to those receiving the drug twice daily. At the end of 30 weeks, patients in each group had lost approximately 4 kg, but the weekly dose had lower incidences of nausea and vomiting. The DURATION 3 study compared exenatide weekly with insulin glargine and found similar reductions in HbA1c over time. However, achievements in HbA1c targets were significantly greater with exenatide, as well as reductions in weight and waist/hip circumference. Henry summarized that the clinical implications of the longer-acting GLP-1 studies showed “greater efficacy at lowering HbA1c, greater reductions at FPG, effects on body weight appear to be preserved, and variability and incidence of GI side effects appear to be less.”

Henry concluded his talk by describing the third class of drugs, the SGLT2 inhibitors. “Under normal circumstances, virtually all glucose is filtered through the glomerulus, therefore SGLT1 and SGLT2 are often targets of drug development,” he said. In a study evaluating dapagliflozin as an add-on to treatment in patients with T2DM after metformin failure, results found reductions in FPG, HbA1c, and body weight compared to placebo. There were some increases in UTIs, but no significant incidences of hypoglycemia. Similar findings were observed in a study with canagliflozin, which is currently in phase III trials.

Overall advantages to the SGLT2 inhibitors, according to Henry, are “weight loss, low risk of hypoglycemia, and blood pressure lowering, and the effects are independent of insulin.” He said that concerns include “polyuria, electrolyte disturbances, bacterial UTI, fungal genital infections, and other effects not yet known.”