Canagliflozin Lowers HbA1c in Elderly With Type 2 Diabetes

Daniel M. Keller, PhD

October 05, 2012

October 5, 2012 (Berlin, Germany) — In older adults with type 2 diabetes taking a variety of antihyperglycemic agents, canagliflozin lowered glycated hemoglobin (HbA1c) at 26 weeks, according to a new study.

Researchers reported the results here at the European Association for the Study of Diabetes 48th Annual Meeting.

In the randomized double-blind placebo-controlled phase 3 trial, canagliflozin was also associated with reductions in fasting plasma glucose and body weight, said coauthor Keith Usiskin, MD, from Janssen Research and Development in Raritan, New Jersey.

Canagliflozin was generally well tolerated in the trial. However, as with other sodium glucose cotransporter 2 (SGLT2) inhibitors, patients in the canagliflozin group experienced more genital mycotic and urinary tract infections than those in the placebo group. The drug acts by inducing urinary glucose excretion, resulting in decreased plasma glucose, a mild osmotic diuresis, and a net caloric loss.

The trial involved patients 55 to 80 years of age with type 2 diabetes that was not adequately controlled. Eligible patients were not taking any other antihyperglycemic therapy, had been taking a stable regimen of a variety of agents (including insulin) for at least 12 weeks, or had been taking pioglitazone for at least 6 months.

Patients were excluded if they had type 1 diabetes, a fasting plasma glucose level of 15 mmol/L or greater during the pretreatment period, or a decreased estimated glomerular filtration rate (eGFR).

Researchers randomly assigned patients to canagliflozin 100 mg (n = 241), canagliflozin 300 mg (n = 236), or placebo (n = 237). Of the 714 patients enrolled in the 26-week trial, 88.5% completed the treatment period. More subjects in the placebo group than in either of the canagliflozin groups required glycemic rescue therapy.

Baseline HbA1c was similar in all 3 groups; it was 7.8% in the placebo group, 7.8% in the 100 mg group, and 7.7% in the 300 mg group.

Canagliflozin reduced HbA1c from baseline by 0.60% in the 100 mg group and by 0.73% in the 300 mg group (P < .001 for both); in the placebo group, the reduction from baseline was 0.03%.

Fewer patients in the placebo group achieved an HbA1c of 7.0% or lower at 26 weeks (28.0%) than in the 100 mg and 300 mg groups (47.7% vs 58.5%; P < .001 for both). The decrease in fasting plasma glucose was smaller in the placebo group than it was in the 100 mg and 300 mg groups (1.0 vs 1.1 mmol/L; P < .001 for both).

Patients in the placebo group lost an average of 0.1% of their body weight at 26 weeks, compared with 2.4% (2.2 kg) in the 100 mg group and 3.1% (2.8 kg) in the 300 mg group (P < .001 for both). Patients in the canagliflozin groups had small increases in low-density-lipoprotein cholesterol and significant increases in high-density-lipoprotein cholesterol, compared with placebo (P < .001).

Canagliflozin Generally Well Tolerated

The rate of adverse events leading to the discontinuation of canagliflozin was higher in the 300 mg group (7.2%) than in the 100 mg group (2.1%) or the placebo group (4.2%). Rates of serious adverse events were low, and similar in the 100 mg, 300 mg, and placebo groups (4.1% vs 3.4% vs 5.1%).

In the canagliflozin groups, "genital mycotic infections increased in a nondose-dependent fashion in both men and women, and a small increase was seen in urinary tract infections," Dr. Usiskin reported during a poster presentation. Similar outcomes have been seen in studies of this drug and of other SGLT2 inhibitors.

Women experienced the highest rates of genital mycotic infections in the 100 mg, 300 mg, and placebo groups (15.4% vs 11.2% vs 2.1%). The rates of urinary tract infections for men and women combined were 5.8%, 8.1%, and 5.1%, respectively. Rates of postural dizziness or orthostatic hypotension were 1.3% or less for all groups.

Decreases in eGFR from baseline were small in the 100 mg, 300 mg, and placebo groups (2.8% vs 4.5% vs 1.2%). There were small increases in hemoglobin in the canagliflozin groups, which Dr. Usiskin suspects were related to hemoconcentration from the osmotic diuretic effect of the drug.

Patients in the canagliflozin groups who were taking antihyperglycemic agents associated with an increased risk for hypoglycemia, such as insulin and insulin secretagogues, experienced a slightly higher incidence of hypoglycemia than patients in the placebo group.

"In older adults (mean age of about 64 years), we have efficacy for both canagliflozin 100 mg and 300 mg and a safety profile that's consistent with the other age groups that have been studied," Dr. Usiskin said. He cannot explain the changes in blood lipid values, but noted that they might have resulted from a decrease in blood volume.

Session moderator Stefano Del Prato, MD, professor of endocrinology at the University of Pisa in Italy, told Medscape Medical News that canagliflozin "tends to be very much the same across the different populations in the different kinds of diabetic people and the different treatments they are on. It looks like it's a very nice achieve better glycemic control in a great variety of patients."

The SGLT2 inhibitors, as a class, have some advantages, according to Baptist Gallwitz, MD, professor of medicine, vice chair of the Department of Endocrinology, and head of the Outpatient Department for Diabetes and Endocrinology at the University of Tübingen in Germany. "The biggest advantage is that the mode of action is insulin-independent; therefore, it is sort of complementary to the drug classes we have so far," he told Medscape Medical News. "You will be able to give SGLT2 inhibitors over a broad spectrum of the disease duration, from early on to very late, and can combine it with any other class [of drugs]."

He added that the SGLT2 inhibitors have an antihyperglycemic efficacy comparable to other antidiabetic agents, and they have a very low hypoglycemia risk and lead to weight loss, "which is important in obese patients, especially in those with a high cardiovascular [risk] profile," he said.

Dr. Usiskin noted that the dropout rate resulting from genital mycotic infections is low. "There are data suggesting that most of these infections tend to occur early on with the start of the treatment.... I think that we really need to see this in the real world [to see] how the people are going to respond" when they are on the drug for a longer time. He added that the data so far suggest that these infections typically do not recur.

Dr. Gallwitz postulated that the tendency of infections not to recur when people are taking SGLT2 inhibitors "has to do with the better glycemic control and, therefore, the improvement in immune functions locally."

Dr. Del Prato said that, to resolve the blood lipid profile issues, data are needed to see the effect of statins when they are already on board or when they are added.

Dr. Usiskin is an employee of Janssen Pharmaceuticals. Dr. Del Prato reports receiving research funding and being a speaker for Boehringer Ingelheim and Janssen Pharmaceutica. Dr. Gallwitz reports having speaker relationships and/or receiving research funding from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Novo Nordisk, Novartis, Merck, Takeda, Sanofi, and Roche.

European Association for the Study of Diabetes (EASD) 48th Annual Meeting: Abstract 765. Presented October 3, 2012.