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The DPP-4 inhibitor linagliptin (Tradjenta) may control type 2 diabetes with less hypoglycemia or weight gain than glimepiride (Amaryl) when used as second-line treatment with metformin, a trial showed.

Hemoglobin A1c came down modestly when either drug was added to metformin, with noninferiority between the gliptin and the sulfonylurea, Baptist Gallwitz, MD, of Eberhard-Karls University of Tubingen in Germany, and colleagues found.

Hypoglycemia rates were substantially lower with linagliptin (7% versus 36% with glimepiride, P<0.0001), and patients lost weight, on average, with linagliptin compared with gaining weight with glimepiride, the group reported online in The Lancet.

Cardiovascular event risk appeared 54% lower with linagliptin than with glimepiride; however, the study was not powered or designed to assess cardiovascular outcomes.

"Although glycemic control remains the central feature of type 2 diabetes management for all oral anti-diabetic drugs, their side-effect profiles (including cardiovascular safety) are increasingly important to consider," the investigators wrote.

Their randomized trial findings matched the initial report out of the American Diabetes Association meeting last year.

The association and its European counterpart recommend the gliptin drugs as options for second-line treatment once metformin no longer adequately controls diabetes alone, though noting they lower glycosylated hemoglobin levels somewhat less than sulfonylureas.

In the trial, hemoglobin A1c levels -- starting at a baseline 7.69% average -- fell by 0.16 percentage points with linagliptin versus 0.36 percentage points with glimepiride.

The difference, though falling within the noninferiority threshold of 0.35 percentage points, supported the interpretation of slightly lower efficacy for the gliptin versus sulfonylurea, André J. Scheen, MD, PhD, and Nicolas Paquot, MD, PhD, both of the University of Liège, Belgium, noted in an accompanying commentary.

"However, several advantages are recognized for DPP-4 inhibitors such as no weight gain, a low risk of hypoglycemia, and no need for titration, but at higher cost," they wrote.

The much lower hypoglycemia risk and almost no severe hypoglycemia with linagliptin in the trial (one case versus 12, less than 1% versus 2%) might be a major advantage for some patient groups "and could affect the choice of drug to be added as second-line treatment to metformin," the editorial added.

Another advantage was that weight dropped by 3.1 lbs. (1.4 kg) with linagliptin, whereas it rose by 2.9 lbs. (1.3 kg) with glimepiride over the 2-year trial (P<0.0001).

"Most patients with type 2 diabetes are overweight or obese and so weight management is also an integral part of treatment," the researchers noted.

The study randomized 1,552 patients with type 2 diabetes to double-blind treatment with linagliptin (5 mg) or glimepiride (1 to 4 mg) orally once daily, primarily looking for efficacy but also prospectively assessing cardiovascular safety.

It showed fewer adjudicated major cardiovascular events with the gliptin drug -- 2% versus 3% with glimepiride -- for a relative risk of 0.46 (95% CI 0.23 to 0.91, P=0.0213).

The difference was mainly attributable to fewer nonfatal strokes on linagliptin (RR 0.27, 95% CI 0.08 to 0.97, P=0.0315), not related to hypoglycemic events.

While a cardiovascular risk reduction would be important if confirmed in further study, the finding was based on events in just 12 patients versus 26 with glimepiride over 2 years in a trial underpowered to detect a difference, the editorialists cautioned.

An ongoing large prospective trial known as CAROLINA, looking specifically at cardiovascular outcomes with linagliptin versus glimepiride, should provide the answer.