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Combination GLP-1, SGLT2 inhibitor therapy ‘effective option’ in poorly controlled type 2 diabetes

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February 28, 2018

Patients with poorly controlled type 2 diabetes randomly assigned the GLP-1 receptor agonist dulaglutide as an add-on to SGLT2 inhibitor therapy experienced greater reductions in HbA1c, body weight and systolic blood pressure vs. those assigned a placebo, according to findings from the AWARD-10 trial.

“Because of their relatively recent regulatory approvals, combination use of GLP-1 receptor agonists with SGLT2 inhibitors is still not common practice, despite potential advantages over other combinations commonly used to treat patients with type 2 diabetes,” Bernhard Ludvik, MD, of the Karl Landsteiner Institute for Obesity and Metabolic Disorders in Vienna, and colleagues wrote. “In the AWARD-10 Trial, addition of once-weekly dulaglutide to ongoing treatment with an SGLT2 inhibitor (with or without metformin) resulted in significant and clinically relevant improvement in HbA1 concentration as compared with placebo. This regimen also resulted in greater reduction of body weight with dulaglutide 1.5 mg.”

Ludvik and colleagues analyzed data from 424 patients with type 2 diabetes and HbA1c between 7% and 9.5% prescribed SGLT2 inhibitor therapy with or without metformin for at least 3 months, participating in AWARD-10, a randomized, double-blind, parallel-arm superiority study conducted at 40 sites in eight countries. Between December 2015 and February 2017, researchers randomly assigned patients to 1.5 mg or 0.75 mg subcutaneous dulaglutide (Trulicity, Eli Lilly; n = 142 for both) or placebo (n = 140), all once-weekly, while continuing with SGLT2 inhibitor therapy with or without metformin as prescribed. Primary outcome was superiority of dulaglutide vs. placebo for change in HbA1c from baseline to 24 weeks. Secondary outcomes included percentage of patients achieving HbA1c of 7% or less, change in body weight and change in fasting serum glucose from baseline to 24 weeks.

Compared with patients assigned placebo, those assigned dulaglutide experienced a greater reduction in HbA1c from baseline to 24 weeks with both 1.5-mg and 0.75-mg doses (least squares mean difference, –0.54% vs. –1.34% and –1.21%, respectively). The proportion of patients achieving HbA1c of 7% or less at 24 weeks was also greater in both dulaglutide arms vs. placebo (71% and 60% vs. 32%; P < .0001), according to researchers. Patients in both dulaglutide arms experienced greater weight loss vs. placebo (mean, –3.1 kg and –2.6 kg vs. –2.1 kg, respectively); however, weight loss for the 0.75-mg arm did not reach statistical significance. Changes in fasting serum glucose from baseline to 24 weeks were also greater for the two dulaglutide arms (mean, –31.6 mg/dL and –26.5 mg/dL) compared with placebo (mean, –6.9 mg/dL).

Treatment-related adverse events were more common in the dulaglutide arms and were typically gastrointestinal in nature. Two patients in the dulaglutide 1.5-mg arm died, but the deaths were not considered related to the drug, according to researchers.

The results follow similar findings on combination therapy published in The Lancet Diabetes & Endocrinology this month. In an analysis of the SUSTAIN 7 findings , researchers found that adults with type 2 diabetes assigned semaglutide (Ozempic, Novo Nordisk) 0.5 mg or 1 mg had greater reductions in HbA1c and body weight compared with those assigned to dulaglutide 0.75 mg or 1.5 mg, and were more likely to achieve HbA1c less than 7% or HbA1c 6.5% or less at week 40 (P < .0001 for the low-dose comparison; P = .0021 for the high-dose comparison).

“This combination might be an effective option for the treatment of type 2 diabetes in patients with inadequate glycemic control,” the researchers wrote. – by Regina Schaffer

Disclosures: Eli Lilly funded this study. Ludvik reports he serves on advisory boards and receives speaking fees and research support from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Novo Nordisk and Sanofi.

itj+ Perspective

Kevin Pantalone
Perspective

The combination of GLP-1 receptor agonists with SGLT-2 inhibitors offers many advantages: They work by separate but synergistic mechanisms, they both have an extremely low (to no) risk for hypoglycemia (unless used in combination with insulin or an insulin secretagogue), and the agents are often associated with weight loss, or at least help to mitigate further weight gain. It is because of these properties, in part, that the American Association of Clinical Endocrinologists recommends their use directly after metformin therapy and lifestyle modification (Garber AJ, et al. Endocr Pract. 2016;doi:10.4158/EP151126.CS.). Clearly, when the addition of one of these agents is not enough, using them in combination is not only effective, but safe. Use of these medication classes, which offer many advantages over older type 2 diabetes therapies, remain underutilized, both as combination therapy, but also as monotherapy. Physicians need to become more comfortable prescribing these therapies, alone and in combination, so that patients may reap the potential benefits. Some GLP-1 receptor agonists and SGLT-2 inhibitors have also demonstrated additional benefits on kidney function and cardiovascular outcomes, additional reasons to strongly consider their use in patients with type 2 diabetes and established CV disease.

Kevin M. Pantalone, DO, ECNU, FACE

Director of Clinical Research, Department of Endocrinology
Cleveland Clinic

Disclosure: Pantalone reports he received consulting fees from Merck, Novo Nordisk, and Sanofi; research support from Merck and Novo Nordisk; and speaker honoraria from AstraZeneca, Merck and Novo Nordisk.

Editor's note: Perspective disclosure was updated on May 1, 2018.