ADA: First-in-Class Novel Drug Lowers Blood Glucose and Weight

Julio Rosenstock, MD, of the Dallas Diabetes and Endocrine Center, reported at the American Diabetes Association meeting that, after 12 weeks, patients taking canagliflozin had reductions in HbA1c similar to those among patients on sitagliptin, and both groups fared significantly better than placebo. Those on the SGLT2 inhibitor saw an added benefit -- weight loss -- compared with those on sitagliptin, they added. 

In a release, Rosenstock said the findings suggest that the drug can potentially offer a good alternative for Type 2 diabetes patients "who are not reaching their goals with metformin alone."

Results from a trial of dapagliflozin, another SGLT2 inhibitor -- a much-anticipated class of diabetes medications that works by dumping excess blood glucose into the urine -- were also reported at the meeting. The researchers conducted a 12-week, double-blind, randomized, placebo-controlled, phase IIb trial in 451 patients already taking metformin. Canagliflozin was given in once-daily doses of 50, 100, 200, or 300 mg, or 300 mg twice a day. Patients were randomized to one of those doses, or to sitagliptin or placebo.

The researchers found that by the end of the study, changes from baseline in HbA1c were statistically significant for all of the canagliflozin arms and sitagliptin, compared with placebo (P<0.001).

The greatest average decreases among the canagliflozin arms came in the 300-mg once or twice daily groups (0.9 percentage points); those on sitagliptin had mean reduction of 0.7 percentage points. Those in the placebo group saw only a 0.2 percentage-point average reduction.

For the secondary endpoint of weight loss, the researchers saw significant, dose-related weight reductions for all doses of canagliflozin but not for sitagliptin, compared with placebo. Weight reductions ranged from 2.3% to 3.4%, compared with a 1.1% drop for those on placebo. They noted, however, that the trial was not powered to directly compare canagliflozin and sitagliptin.

There were also decreases in fasting plasma glucose that were greatest at the 200-mg and 300-mg once daily groups as well as the 300-mg twice daily group, the researchers said.

As with other SGLT2 inhibitors, genital infections were more common in the canagliflozin groups than the others. Those on the drug had an incidence of 3% to 8% for vulvovaginal candida infections, compared with 2% in the sitagliptin and placebo groups, respectively.

Kirk Ways, MD, PhD, vice president and leader of development of canagliflozin for Johnson & Johnson's pharmaceuticals research and development division, stated that no patients "dropped out of the study due to a genital infections, and these infections were generally mild and self-limiting in nature, and appeared to respond to standard topical or antifungal therapy."

Hypoglycemia was reported at a rate of 0% to 6% in the canagliflozin arms, without dose-dependency, and in 5% of those on sitagliptin. Only 2% of those on placebo reported hypoglycemia.

Other adverse events were mild to moderate, and the overall incidence was the same across all arms of the study, the researchers said. There were similar incidences of serious adverse events and discontinuations as well.

Still, they concluded that the data are promising and need to be assessed in long-term trials.

A phase III trial to test the safety and efficacy of canagliflozin at 100 or 300 mg as monotherapy and in combination with other diabetes medications is currently enrolling more than 10,000 patients, and Ways says the company estimates filing a new drug application in 2012.

• Explain that in early trials, a novel SGLT2 inhibitor appears to be safe and effective, and leads to weight loss in diabetic patients.
• Caution that canagliflozin use does appear to be associated with an increased risk of genital infections, which is a known class effect with SGLT2 inhibitors.
• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Rosenstock J, et al "Canagliflozin, an inhibitor of sodium glucose co-transporter 2, improves glycemic control and lowers body weight in subjects with Type 2 diabetes on metformin" ADA 2010; Abstract 77-OR.