Miriam E. Tucker

May 07, 2013

PHOENIX — An investigational sodium glucose cotransporter-2 (SGLT2) inhibitor, empagliflozin (Boehringer Ingelheim), lowered glucose to a similar degree as metformin and also produced sustained weight loss for up to 90 weeks in an open-label extension study in patients with type 2 diabetes.

The data were presented during a late-breaking clinical-trial session on May 5 at the American Association of Clinical Endocrinologists (AACE) 2013 Scientific & Clinical Congress by Thomas Hach, MD, senior medical director, Boehringer Ingelheim, Germany.

Empagliflozin is one of a new class of glucose-lowering drugs, the oral SGLT2 inhibitors, which produce increased urinary glucose excretion, with a consequent lowering of plasma glucose levels, as well as weight loss.

Canagliflozin was the first of these agents to be approved in the US at the end of March; another, dapagliflozin, was rejected by the Food and Drug Administration (FDA) but is approved for marketing in Europe.

A new drug application (NDA) has been submitted to the US FDA for empagliflozin, and a decision is expected in the first quarter of 2014, Dr. Hach told Medscape Medical News. An application for marketing in the European Union has also been filed.

"Most important, clinicians should understand that glucose in the urine isn't bad. We were all trained in medical school that glucose in the urine is bad and is a sign of diabetes… But in fact, it actually makes sense," he noted.

Indeed, Alan Garber, MD, president of AACE and professor of medicine, biochemistry, molecular biology, and molecular and cellular biology at Baylor College of Medicine, Houston, Texas, said of the SGLT2 inhibitors in general, "They're very effective drugs. The only question really is the adverse-event profile and the eligible patient population." For example, certain patients with impaired renal function may not be good candidates, he told Medscape Medical News.

As for how empagliflozin might stack up against canagliflozin with regard to safety and efficacy, "I think they're substantially very similar. Until you get head-to-head trials, no one will really know," said Dr. Garber.

Empagliflozin as Monotherapy and Add-On to Metformin

Dr. Hach presented data from a randomized, 78-week extension study that followed 2 separate 12-week randomized controlled trials. In 1 trial, patients were randomized to 10-mg or 25-mg empagliflozin or to metformin, as monotherapy, in 81, 82, and 80 patients, respectively. The second study randomized 71, 70, and 71 patients, respectively, to empagliflozin 10 mg or 25 mg or to sitagliptin as an add-on to metformin.

The patients had a mean age of about 50 years, mean baseline body mass index of about 30 kg/m2 and glycated hemoglobin (HbA1c) of approximately 8%. Individuals with estimated glomerular filtration (eGFR) rates below 60 mL/min/1.73 m2 were excluded.

At 90 weeks, adjusted mean percentage-point reductions from baseline in HbA1c were 0.51 for empagliflozin 10 mg and 0.60 for 25 mg, compared with 0.64 for metformin as monotherapy.

When added to metformin as background, percentage-point reductions were 0.61 for empagliflozin 10 mg and 0.74 for 25 mg vs just 0.45 with sitagliptin.

As monotherapy, adjusted mean reductions in fasting plasma glucose were 32.4 mg/dL and 28.1 mg/dL with empagliflozin 10 mg and 25 mg, respectively, compared with 25.9 mg/dL with metformin.

As add-ons to metformin, mean reductions in fasting plasma glucose were 23.3 and 31.8 mg/dL for the 2 empagliflozin doses vs 11.7 mg/dL with sitagliptin.

Adjusted mean reductions in body weight were 2.1 kg and 1.9 kg for empagliflozin monotherapy 10 mg and 25 mg, respectively, vs a drop of 0.9 kg with metformin monotherapy. As add-ons, the 2 empagliflozin doses produced mean weight falls of 2.9 and 3.8 kg, respectively, compared with a negligible change in weight (-0.6 kg) with sitagliptin.

The loss in body weight is primarily due to loss of calories in the urine, with roughly 70 to 80 g of glucose excreted daily, which translates to about 250 to 300 calories per day, Dr. Hach noted.

Genital Infections an Unpleasant Side Effect

The proportion of patients reporting any adverse events ranged from 58% with empagliflozin 10 mg to 67.5% with metformin in the monotherapy trial and from 69% with sitagliptin to 80% with empagliflozin 25 mg as a metformin add-on.

Overall, serious adverse events occurred slightly more often in the metformin monotherapy (7.5%) and sitagliptin add-on group (12.7%) than in the respective empagliflozin groups (range, 5.7% – 7.0%). Hypoglycemia rates were less than 4% overall and also more common with the active comparators than with empagliflozin.

Urinary-tract infections were also not increased with empagliflozin, 5.0% for metformin compared with 3.7% to 4.9% for empagliflozin in the monotherapy trial and 12.7% with sitagliptin vs 9.9% to 11.4% with empagliflozin as add-ons.

"As you would expect, there was a higher number of urinary-tract infections in females... Also, keep in mind that patients with diabetes have a higher frequency of urinary-tract infections than the general population," Dr. Hach noted.

However, as has been seen with other SGLT2 inhibitors, rates of genital infection were increased with empagliflozin, 2.5% and 3.7% for the 10-mg and 25-mg doses, respectively, compared with 1.3% with metformin monotherapy and 8.5% and 4.3% vs 1.4% with sitagliptin add-on therapy.

Genital infections were seen predominantly in women, and none were severe, he noted.

"This is something we see consistently across our trials and have further investigated," Dr. Hach said, adding that the company will present more data on genital infections from over 2000 patients at the upcoming American Diabetes Association Scientific Sessions meeting in June.

According to Dr. Garber, these data suggest that "for women with a prior history of vulvovaginitis or men with balanitis, this is not a good drug."

The genital infections, which seem to be an issue in a small percentage of patients taking SGLT2 inhibitors, has been raised as a possible deterrent to their use by some physicians asked about prospects for canagliflozin.

Patients With Renal Impairment Not Good Candidates

There was a slight decrease in eGFR over the 90 weeks with empagliflozin, of approximately 1.8 mL/min/1.73 m2 from baseline. This effect was not significant, and the eGFR returned to normal when the drug was stopped. "So, there is no detrimental effect on kidney function," Dr. Hach said.

Dr. Garber told Medscape Medical News, "Patients who have impaired renal function with eGFRs less than 45 are not candidates for this drug, because it's not likely to be effective. Elderly folk who have any degree of renal impairment show diminished responsiveness, so other drugs might be a better choice."

Dr. Hach did not report cardiovascular data, but he told Medscape Medical News that no CV incidents occurred during the trial. He also said that Boehringer Ingelheim has just completed recruitment of approximately 7000 patients for a cardiovascular safety outcome trial that is likely to be the first to finish among those in the SGLT2-inhibitor class.

Dr. Hach is an employee of B oehringer Ingelheim. Dr. Garber is a consultant, advisory board member, and/or a paid speaker for Daiichi-Sankyo, Merck, Santarus, Novo-Nordisk, Janssen, Takeda, LipoScience, Tethys, Halozyme, Vivus, Boehringer Ingelheim and Viking Therapeutics.

American Association of Clinical Endocrinologists 2013 Scientific & Clinical Congress. Abstract 1102, presented May 5, 2013.