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DURATION-8 Trial: Combining a GLP-1 Receptor Agonist Plus an SGLT-2 Inhibitor

Jun 30, 2018
 

With over 6 million possible combinations, it is difficult to come up with the best treatment for each patient. The phase III DURATION-8 trial may help you to decide.

The study showed that the combination treatment with a GLP-1 receptor agonist plus an SGLT-2 inhibitor was effective as long-term treatment for type 2 diabetes, researchers reported in Orlando in a late-breaker presentation at the American Diabetes Association’s annual scientific meeting. The 104-week results of the phase III DURATION-8 trial showed HbA1c reduction from once-weekly exenatide (Bydureon) plus once-daily dapagliflozin (Farxiga) was maintained throughout the trial. Compared to exenatide alone or dapagliflozin alone, combination treatment showed a significantly lower mean reduction in A1c percentage from baseline after 104 weeks of treatment (P<0.01):

  • Exenatide plus dapagliflozin: -1.7 percentage points
  • Exenatide alone: -1.29 percentage points
  • Dapagliflozin alone: -1.06 percentage points

Several other clinical markers of efficacy for glucose management were also maintained over the 104-week study, with combination treatment showing significantly improved fasting plasma glucose levels (-49 mg/dL versus -29.8 mg/dL for exenatide only and versus -21.9 for dapagliflozin only), as well as 2-hour postprandial glucose (-86.2 mg/dL versus -79.0 mg/dL versus -64.0 mg/dL, respectively).

Dr. S. Jabbour, lead researcher, explained, “The maintenance of effect observed in this analysis was not unexpected given the profile of the individual drugs. Long-term studies of exenatide QW have demonstrated sustained glycemic improvement, weight reduction, and improved markers of cardiovascular risk, even up to seven years of treatment. Similar durability has been observed in long-term studies of dapagliflozin in patients with type 2 diabetes.”

Jabbour said the combination treatment is ideal for patients whose diabetes is not managed and who have an A1c of 9% or higher while already on a maximum tolerated dose of metformin.

“Combining both agents would provide the needed A1c reduction to get patients to or close to goal based on ADA guidelines,” he recommended. “Alternatively, these agents could be added sequentially if providers are not comfortable adding them at the same time or because of patient resistance.”

These findings build upon the previously reported 28-week findings and are reflective of related long-term observational studies of these drugs. The latest extension of the trial included 431 patients who completed 104 weeks of treatment. At baseline, all participants had an A1c of 8% or higher and were on at least 1,500 mg/day of metformin.

The combination treatment group received 2 mg of subcutaneous injectable exenatide weekly and a 10-mg oral tablet of dapagliflozin daily added to their metformin. Doses in the exenatide- and dapagliflozin-only were the same. Basal insulin was also allowed as rescue therapy if needed.

As expected, patients receiving dapagliflozin also experienced weight loss that was maintained long-term; patients in the exenatide-only group did not.

Similarly, patients on combination treatment saw improvement in systolic blood pressure over 104 weeks (-3.1 mm Hg), greater than with either monotherapy.

Overall, the combination treatment was well-tolerated with no unexpected safety findings. Across the treatment groups, rates of adverse events were similar. Although no patients in any treatment groups experienced any major episodes of hypoglycemia during the course of the trial, there was a slightly higher percentage of minor events occurring with the combination treatment (1.7% versus 0% with exenatide alone and 0.4% with dapagliflozin alone); the differences were not statistically significant.

Practice Pearls:

  • The combination treatment is ideal for patients whose A1c is 9% or higher.
  • The combination dropped the A1c by 1.7%.
  • Blood pressure and weight loss was maintained over the 104 weeks.

References:
American Diabetes Association.
Jabbour S, et al “DURATION-8 randomized controlled trial 104-week results — once-weekly exenatide (ExQW) plus once-daily dapagliflozin (DAPA) vs. ExQW or DAPA alone.” https://plan.core-apps.com/tristar_ada18/abstract/5188446740e191fd289345d56a7dc3a8. ADA 2018; Abstract 104-LB.