Empagliflozin Useful Second-Line for Diabetes vs Glimepiride

Marlene Busko

September 17, 2014

VIENNA — Two-year results of a head-to-head trial comparing the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim) with the sulfonylurea glimepiride as second-line therapy after metformin in patients with type 2 diabetes show that the SGLT2 inhibitor was better than its comparator.

From baseline to 104 weeks, mean HbA1c levels dropped by 0.66% in the empagliflozin-treated patients vs 0.55% in the glimepiride-treated patients, showing a small but nevertheless significantly superior difference, and empagliflozin also had fewer adverse effects.

"Empagliflozin, as an add-on to metformin, provided a sustained reduction in HbA1c compared with glimepiride…with a lower risk of hypoglycemia…[and greater] sustained body weight and blood-pressure reductions…[and it] was well tolerated," Martin Ridderstråle, MD, from the Steno Diabetes Center, in Copenhagen, Denmark, summarized.

The results, he said, "are fairly impressive."

He reported the findings in an oral presentation here at the European Association for the Study of Diabetes 2014 Meeting; they were also recently published in Lancet Diabetes and Endocrinology (Lancet Diabetes Endocrinol. 2014;2: 691-700).

Writing in an accompanying editorial (Lancet Diabetes Endocrinol. 2014;2:678–/679), Dr. Abd A. Tahrani, from the University of Birmingham, United Kingdom, says: "Although the difference in HbA1c in favor of the SGLT2 inhibitors is small in Ridderstråle and colleagues' study, it occurred in the context of less hypoglycemia…than in the glimepiride group" as well as weight loss. And the study was fairly long, suggesting that the glycemic benefits of empagliflozin are more long-lasting than with glimepiride, he added.

Other studies have shown similar reductions in HbA1c with empagliflozin and another SGLT2 inhibitor, canagliflozin (Invokana, Janssen Pharmaceuticals), vs the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin (Januvia, Merck) as an add-on to metformin monotherapy. Thus, as a class, "SGLT2 inhibitors seem to be a useful alternative to sulfonylureas because of greater and sustainable HbA1c reductions, a low risk of hypoglycemia, increased weight loss, and a favorable effect on cardiovascular risk factors," Dr. Tahrani writes.

Consistent Effect of SGLT2 Inhibitor Over Time

As reported by Medscape Medical News, empagliflozin was approved by the Food and Drug Administration in August. It is the third oral SGLT2 inhibitor to receive approval in the United States, after canagliflozin and dapagliflozin (Farxiga, AstraZeneca/Bristol-Myers Squibb). Drugs in this class prevent glucose uptake by the kidney and therefore increase the amount of glucose excreted in urine.

The current phase 3 trial enrolled adult patients with type 2 diabetes and HbA1c levels between 7% and 10%. The patients were required to be on a stable dose of metformin for at least 3 months prior to study entry and have an estimated glomerular filtration rate (eGFR) of 60 mL/min or higher.

The researchers randomized 1549 patients to receive 25-mg/day empagliflozin or 1- to 4-mg/day glimepiride on top of their metformin. A total of 40% of the patients in the glimepiride group were titrated up to the maximum dose, and the mean dose was 2.7 mg, which corresponds well to the dose generally used in clinical practice, according to Dr. Ridderstråle.

The patients had a mean age of 57, and 55% were men. Two-thirds were white, and a third were Asian. They had a mean body mass index (BMI) of 30 and were not hypertensive.

Interestingly, as expected, most patients [43%] had been taking metformin for 1 to 5 years before it failed, "but there were also 18% of patients with a duration above 10 years, and 10% with a duration below 1 year," Dr. Ridderstråle noted

A graph of the change in HbA1c over time showed "the familiar, more dominant effect of a sulfonylurea [glimepiride] when you initiate treatment" followed by treatment failure, Dr. Ridderstråle noted. In contrast, there was a more consistent effect of empagliflozin over time.

Drug-related adverse events were more common in the glimepiride arm vs the empagliflozin arm (32% vs 25%), driven primarily by hypoglycemia events.

The risk of hypoglycemia was 10-fold higher with glimepiride (24.2% vs 2.5%).

At 2 years, the mean body weight increased by 1.3 kg for patients in the sulfonylurea arm and dropped by 3.1 kg for patients in the empagliflozin arm.

There was no difference in the number of urinary-tract infections in the two groups (about 14% in each arm).

However, 9% of men and 15% of women in the empagliflozin arm vs only 1% of men and 3% of women in the glimepiride arm had genital fungal infections.

In reply to a question about genital infections, a well-known side effect of SGLT2 inhibitors, Dr. Ridderstråle said: "Genital infections are seen in patients, [but] when they are treated, [patients] respond."

There has been no signal so far for any kind of cancer, although there are no data yet beyond 2 years, he added. He noted that the study will continue out to 4 years.

Editorial: Tailor Second-Line Therapy to the Individual Patient

Despite the encouraging results reported by Dr Ridderstråle and colleagues, Dr. Tahrani points out in his editorial that "sulfonylureas are cheaper, have long-term safety data, and have a positive effect on microvascular complications."

Thus, clinicians need to choose the second-line glucose-lowering treatment based on the individual patient's "age, hypoglycemia risk, renal function, weight, cardiovascular disease, and the use of concomitant treatments," he advises.

"The results from ongoing longer head-to-head trials of the sustainability of HbA1c reductions and the safety profile of SGLT2 inhibitors — specifically cardiovascular safety — will aid the choice of a second-line treatment," he concludes.

The study was funded by Boehringer Ingelheim and Eli Lilly. Ridderstråle has received honoraria for lectures during scientific meetings sponsored or arranged by Boehringer Ingelheim, Novo Nordisk, Sanofi, Novartis, Eli Lilly, Roche, Johnson & Johnson, Merck, Medtronic, and GlaxoSmithKline.

European Association for the Study of Diabetes 2014; September 16, 2014; Vienna, Austria. Abstract 02

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