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MUNICH -- The combination of once-weekly exenatide (Bydureon) and dapagliflozin (Farxiga) as the next step after metformin improved type 2 diabetes control and weight loss better than either drug alone, according to the DURATION-8 trial.

The primary endpoint of hemoglobin A1c improved by 2.0 percentage points from baseline to week 28 with the combination, a 0.4 percentage point greater effect than seen with exenatide alone and 0.6 percentage points greater than with dapagliflozin alone (P=0.004 and P<0.001).

Exenatide plus dapagliflozin was also significantly better than either drug alone for all secondary efficacy endpoints, , of the National Institute of Diabetes in Bucharest, Romania, reported at the European Association for the Study of Diabetes meeting and simultaneously online in the.

Combination therapy yielded a 3.41 kg (7.52 lbs) weight loss over baseline, compared with 1.54 kg (3.40 lbs) on exenatide alone and 2.19 kg (4.83 lbs) on dapagliflozin alone, both significant differences.

Other secondary endpoints favored the combination as well: fasting plasma and postprandial glucose, proportion at HbA1c target of 7.0%, and reduction in systolic blood pressure (all P≤0.025).

"I think we are entering the era of combination therapy and the combinations that we should be using are combinations that don't cause hypoglycemia and weight gain, and we should be using them early because clinical inertia is a big problem," commented session chair , of the University of Toronto.

However, the , perhaps in part because glucose-lowering efficacy decreases at lower glucose levels, , and , both of St. Josef Hospital in Bochum, Germany, wrote in an accompanying commentary.

Zinman, calling himself an optimist, noted that the two classes "have added value -- the added value is they reduce cardiovascular death!," adding "Who ever thought we'd have a diabetes therapy that reduces cardiovascular death?"

But, the editorialists pointed out, "the GLP-1 receptor agonist and the SGLT2 inhibitor used in Frias and colleagues' study are not the ones that have shown significant cardiovascular benefits (ie, liraglutide and empagliflozin); the results of the cardiovascular outcome trials for exenatide (EXSCEL) and dapagliflozin (DECLARE-TIMI 58) are not expected until 2018 and 2019, respectively."

Both agreed that future trials will have to answer whether the combination of GLP-1 receptor agonists and SGLT2 inhibitors might increase cardiovascular risk reduction beyond what the individual drugs can do.

While Zinman suggested that, for now, agents with demonstrated cardiovascular benefit "should be given priority in the algorithm of drugs we would use to treat diabetes," he still acknowledged the cost and convenience factors: "I would start with metformin, an SGLT2, and a DPP-4 inhibitor; and then I would ratchet up to an injectable combination -- and GLP-1 receptor agonist is the best. Weekly GLP-1 would be a great idea in that kind of patient, and stop the DPP-4."

The DURATION-8 phase 3 trial included 695 adults in six countries who had type 2 diabetes and inadequate glycemic control, defined as an HbA1c of 8% to 12%, while on stable metformin monotherapy of at least 1,500 mg per day.

Participants were randomly assigned to once-weekly exenatide (2 mg) by subcutaneous injection plus once-daily dapagliflozin (10 mg) oral tablets, to exenatide with dapagliflozin-matched oral placebo, or to dapagliflozin with exenatide-matched placebo injections.

The researchers called the combination well-tolerated, "with the expected safety profile for this combination." Adverse events occurred in 57% of the combination therapy group, 54% on exenatide alone, and 52% on dapagliflozin alone. None of the groups had episodes of major hypoglycemia or minor hypoglycemia.

"I'm surprised no one asked about the comparison between dapagliflozin and exenatide," Zinman noted. "Dapa is pretty good, and it's a pill. Exenatide is an injection. When you look at the weight loss, the glucose lowering, the blood pressure lowering -- it was just as good as exenatide. But that wasn't the design."