Conference Coverage

Newcomer canagliflozin improves beta-cell function in type 2 diabetes


 

AT THE AACE ANNUAL MEETING

PHOENIX – The recently approved diabetes drug canagliflozin improved beta-cell function in patients with advanced type 2 diabetes inadequately controlled with metformin plus sulfonylurea, according to a phase III study.

Although some of the changes did not reach statistical significance, the mean value of all calculated measures of beta-cell function increased with two different canagliflozin doses, compared with placebo, the randomized, double-blind placebo-controlled study showed.

The finding is promising, said David Polidori, Ph.D., an employee of Janssen Research and Development, who presented the abstract at the annual meeting of the American Association of Clinical Endocrinologists.

Canagliflozin is a sodium glucose cotransporter 2 (SGLT2) inhibitor, which lowers plasma glucose by a renal mechanism. It also reduces the fasting and postprandial glucose hemoglobin A1c levels.

Dr. Alan J. Garber

Several animal studies have shown beneficial effects of SGLT2 inhibition on beta-cell mass or function. Other clinical studies have shown improvements in measures of beta-cell function with canagliflozin, including a 26-week phase III study with the drug as monotherapy, said Dr. Polidori. But it is not clear exactly how canagliflozin improves beta-cell function. "It may be due to the glucose toxicity. Or it may also be due to reducing the load on beta cells, the so-called unloading," he said.

The improvement in beta-cell function is worthwhile, said Dr. Alan Garber, outgoing AACE president, and professor of medicine, biochemistry, and molecular biology and molecular and cellular biology at Baylor College, Houston. "But it’s not unique to this drug."

Although both canagliflozin doses were generally well tolerated, patients in treatment groups reported higher rates of genital mycotic infections, urinary tract infections, and adverse events related to osmotic diuresis, compared with placebo. The adverse events led to few study discontinuations, said Dr. Polidori.

The SGLT2 class of drugs has been included in the recently updated AACE diabetes management algorithm, but with a note to use with caution. Dr. Garber, chair of the algorithm task force, said that the 10% risk of vulvovaginitis in women and 1% balanitis in men are not minor concerns to some patients, especially those at risk of recurrence. For men, balanitis means a trip to the emergency department, he said, "So a 1% risk requires a little bit of forethought on the part of the clinician before prescribing in at-risk patients for recurrence."

To assess the effect of canagliflozin on beta-cell function as an add-on therapy in patients with type 2 diabetes on metformin plus sulfonylurea, researchers conducted a 26-week study comparing patients on 100 mg and 300 mg of daily canaglifozin with placebo.

The study included 469 patients. A subset of them (168 patients) was given a meal tolerance test on day 1 and week 26. Their liquid meal contained 700 kcal and 100 g of glucose. Patients had a mean age of 57 years, an average HbA1c level of 8%, a body mass index of 33 kg/m2, and type 2 diabetes for an average of 10 years.

Their plasma glucose and serum C-peptide levels were measured at seven time points over a period of 3 hours.

Results showed that the mean ratio of C-peptide area under the curve (AUCc) to glucose (AUCg) increased by a mean of roughly 20% from a baseline of 132 with the 100-mg dosage and 123 with the 300-mg dosage to 160 and 152, respectively, at week 26. There was a small decrease of 3.4% in the placebo group. There was a roughly 27% difference between the canagliflozin and placebo groups that did not reach statistical significance (100 mg, P = .051; 300 mg, P = .056)

The mean insulin secretion rate at 9 mM glucose at week 26 increased significantly in the treatment groups, compared with a 12.2% decrease in the placebo group. There was a 55% difference from placebo in the 100-mg canagliflozin group (P = .02) and a 70% difference in the 300-mg (P = .007) canagliflozin group.

The mean beta-cell glucose sensitivity increased by roughly 20% from baseline in both treatment groups, but the increases were not statistically significant.

"This is 26-week data. It will be interesting to see longer-term data, and to see if this type of treatment can better prolong beta-cell function and hopefully slow the rate of progression of type 2 diabetes," said Dr. Polidori.

Dr. Polidori is an employee of Janssen Research and Development, which funded and supported the study. Dr. Garber is a consultant/advisory board member and/or is on the speakers bureaus for Novo Nordisk, Daiichi Sankyo, Merck, Takeda, LipoScience, Boehringer Ingelheim, Sekris, and Lexicon.

nmiller@frontlinemedcom.com

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