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EASD: SGLT-2/GLP-1 Combo Better Than Monotherapy

Trial finds improvement in control and weight loss.

Deciding which drugs to use in the treatment of type 2 diabetes, including the choice of glucose-lowering drugs in the treatment of patients with type 2 diabetes, should follow clinical science. Combined use of the most recently approved glucose-lowering drug classes—the injectable glucagon-like peptide-1 (GLP-1) receptor agonists and the oral sodium-glucose cotransporter-2 (SGLT2) inhibitors—has not previously been substantiated by clinical trials. Now, in The Lancet Diabetes & Endocrinology, Juan Frías and colleagues present results of DURATION-8, a 28-week randomized controlled trial comparing the combination of the GLP-1 receptor agonist (2 mg once weekly) and the SGLT2 inhibitor dapagliflozin (10 mg once daily) with either drug alone in patients with type 2 diabetes and inadequate glycemic control (mean baseline HbA1c 9·3% ) despite use of metformin.

According the results of the DURATION-8 trial, 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.

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).

Cristian Guja, MD, PhD, of the National Institute of Diabetes in Bucharest, Romania, reported at the European Association for the Study of Diabetes (EASD) meeting and also online in Lancet Diabetes and Endocrinology.  Exenatide plus dapagliflozin was also significantly better than either drug alone for all secondary efficacy endpoints.

The combination therapy provided 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.

Dr. Bernard Zinman, who was chair of the presentation, added that, “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 in treatment, which will provide visible benefits for the patient, which will motivate them to better care.”

However, the HbA1c reduction was far less than additive, perhaps in part because glucose-lowering efficacy decreases at lower glucose levels.

The truly added value of this combination is that they reduce cardiovascular death. But, it was 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 (i.e., 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.

It will have to be future trials that 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.

Practice Pearls:

  • The combination therapy provided 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.
  • Fasting plasma and postprandial glucose, HbA1c and systolic blood pressure were all reduced.
  • The most important aspect of this trial is that it reduced the risk of death.

References:

Frias JP, et al “Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial” Lancet Diabetes Endocrinol 2106; DOI: 10.1016/ S2213-8587(16)30267-4.

Nauck MA, et al “GLP-1 receptor agonists and SGLT2 inhibitors: a couple at last?” Lancet Diabetes Endocrinol 2016; DOI: 10.1016/ S2213-8587(16)30263-7.