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What to Do If Metformin Fails To Get Patients To Target

Oct 8, 2016

Combination therapy resulting in superior glycemic control, weight loss versus either agent alone

DURATION-8 is the first to put a GLP-1 and an SGLT-2 together and it showed that, when metformin is no longer enough in type 2 diabetes, going straight to combination therapy with once-weekly exenatide (Bydureon) and dapagliflozin (Farxiga) provided better control and weight loss than either monotherapy.

When using the  combination, it improved the primary endpoint hemoglobin A1c by 2.0 percentage points from baseline to week 28, a 0.4 percentage point greater effect than seen with exenatide alone and 0.6 percentage points greater than with dapagliflozin alone.

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 simultaneously online in the Lancet Diabetes and Endocrinology. That exenatide plus dapagliflozin was also significantly better than either drug alone for all secondary efficacy endpoints.

A 7.52-lb (3.41 kg) weight loss over baseline was reported with the combination, 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).

Session chair Bernard Zinman, MD, of the University of Toronto added in a press conference 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 because clinical inertia is a big problem.”

The HbA1c reduction was less than additive, but the added value is they reduce cardiovascular death. Who would have thought that a drug for diabetes can reduce the risk for which most people with diabetes die from?

But, the editorialists pointed out, “the GLP-1 receptor agonist and the SGLT2 inhibitor used in J.P. 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.” 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.
You can expect to see more examples of using this combo from other companies.

Practice Pearls:

  • Exenatide (a GLP-1 receptor agonist) injected once weekly plus dapagliflozin (an SGLT2 inhibitor) orally once daily was more effective than either drug alone when added to metformin monotherapy in patients with type 2 diabetes.
  • 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.
  • Liraglutide (another GLP-1 agonist) and empagliflozin (another SGLT2 inhibitor) have shown cardiovascular benefits in diabetes, but CV outcome data for exenatide and dapagliflozin are not expected until 2018 – 2019.


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.