PHILADELPHIA ADA — The GLP-1 receptor agonist exenatide (Byetta) was superior to glimepiride (Amaryl) as an add-on therapy once patients with type 2 diabetes had failed on metformin, researchers found.

Patients on the twice-daily exenatide were significantly less likely to experience treatment failure than those on the sulfonylurea glimepiride (41% versus 54%, HR 0.75, 95% CI 0.62 to 0.90,P=0.002), Baptist Gallwitz, MD, of Universitatsklinikum Tubingen in Tubingen, Germany, and colleagues reported online in The Lancet and at the American Diabetes Association meeting here.

”Exenatide twice daily as add-on to metformin reduced worsening of glycemic control and rate of hypoglycemia compared with add-on glimepiride in patients with type 2 diabetes inadequately controlled by metformin alone,” they wrote.

Metformin is the first-line treatment for type 2 diabetes, but it’s unclear which agents to add when patients are no longer sufficiently controlled on metformin alone.

A usual choice is a sulfonylurea such as glimepiride, but the researchers said glycemic control quickly deteriorates after initiation, and they carry a higher risk of hypoglycemia.

So Gallwitz and colleagues compared exenatide with glimepiride as add-on therapy in patients not controlled on metformin in the open-label, randomized controlled EUREXA trial at 128 centers in 14 countries between Sept. 5, 2006 and March 29, 2011.

A total of 515 patients were randomized to exenatide twice daily, 514 were put on glimepiride; the intent-to-treat analysis included 490 and 487 patients, respectively.

The primary outcome was the time to inadequate glycemic control and the need for alternative treatment, defined as an HbA1c of more than 9% after 3 months, or an HbA1c higher than 7% at two consecutive visits 3 months apart.

The median time to inadequate HbA1c control was 180 weeks (about 3.5 years) for those on exenatide compared with 142 weeks (a little over 2.5 years) with glimepiride. The difference was significant at P=0.032.

Significantly more patients on exenatide achieved an HbA1c lower than 7% (45% versus 31%, P<0.0001) and 6.5% or less (29% versus 18%, P=0.0001).

Exenatide patients also had a significantly greater decrease in body weight — losing 3.32 kg (7.32 lbs) compared with a gain of 1.15 kg (2.54 lbs) for those on glimepiride (P<0.0001) -- and significantly less hypoglycemia (P<0.0001).

However, more patients on exenatide had adverse events, predominantly gastrointestinal effects such as nausea and diarrhea, and discontinued therapy. But the researchers noted that most adverse events occurred within the first 6 months of treatment (P=0.0005).

Five patients in each group died from causes that were determined to be unrelated to treatment.

The researchers noted that the study may be limited in its generalizability, given that most patients were white.

In an accompanying editorial, Sten Madsbad, MD, of Hvidovre Hospital and University of Copenhagen in Denmark, wrote that strengths of the study included its long-term follow-up and its comparison between frequently used agents.

Madsbad noted that few studies have compared anti-diabetic drugs for the durability of their effectiveness on glycemic control, cost, quality of life, and their effects on late diabetic complications.

He concluded that GLP-1 receptor agonists have thus far displayed cardioprotective effects and reduced markers of inflammation, although regulators are watching closely for upcoming results on cardiovascular risks with these agents in the near future.

The study was supported by Eli Lilly and Amylin.

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