Two-Year Data Show Combined Efficacy of GLP-1 RAs, SGLT2s for T2D

New data show a combination treatment of the glucagon-like peptide-1 receptor agonist (GLP-1 RA) exenatide plus the sodium–glucose cotransporter-2 (SGLT2) inhibitor dapagliflozin remains effective after 2 years in those with type 2 diabetes (T2D) uncontrolled with metformin. Findings of the DURATION-8 trial extension were published in Diabetes Care.

GLP-1 RAs and SGLT-2 inhibitors have beneficial effects on glycemic control and cardiovascular (CV) risk factors in this population. However, the mechanisms by which the drugs impact glucose metabolism differ, and no studies have been conducted on a potential combined long-term effect added to metformin therapy.

“GLP-1 receptor stimulation increases insulin secretion and decreases glucagon secretion, which slows gastric emptying and increases satiety; SGLT-2 inhibition increases urinary glucose excretion,” the authors wrote. “To produce sustained weight loss, GLP-1 RAs decrease food intake through a reduction in appetite, and SGLT2 inhibitors increase calorie excretion.”

To determine the efficacy of GLP-1 RA (exenatide once weekly [QW]) and an SGLT-2 inhibitor (dapagliflozin administered orally once daily) added to stable metformin monotherapy, the researchers conducted the first multicenter, double-blind, randomized trial of its kind. The phase 3 trial, DURATION-8, included 695 patients with T2D and poor glycemic control (glycated hemoglobin [A1C], 8.0%-12.0% [64-108 mmol/mol]).

The investigators assessed combined medication response in patients and compared it with that of each drug alone after 104 weeks. All participants were randomized (1:1:1) “to receive exenatide 2 mg QW by subcutaneous injection plus dapagliflozin 10-mg oral tablets daily, exenatide 2 mg QW plus dapagliflozin-matched oral placebo daily, or dapagliflozin 10 mg daily plus exenatide QW–matched placebo injection.”

The study’s end points included change in glycemic parameters from baseline to week 104 and changes in CV risk factors, including body weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), and waist circumference, among others.

At week 104, 431 patients (62%) continued treatment. Analyses revealed:

• Adjusted least squares mean change (SE) from baseline to week 104 in A1C was greater with exenatide QW plus dapagliflozin (-1.70% [0.11]) vs exenatide QW plus placebo (-1.29% [0.12]; P = .007) and dapagliflozin plus placebo (-1.06% [0.12]; P < .001)
• Mean change in fasting plasma glucose, 2-hour postprandial glucose, body weight, and SBP showed persistent clinically relevant efficacy over 104 weeks in the exenatide QW plus dapagliflozin group
• No unexpected safety findings over the 2 years of treatment
• The safety and tolerability profile of exenatide QW plus dapagliflozin was not different than expected based on the established safety profiles of the individual drugs

During the 104 weeks, no episodes of major hypoglycemia were reported. The most common adverse events were upper respiratory tract infections, urinary tract infections, nausea, injection-site nodules, diarrhea, headaches, nasopharyngitis, and vomiting. However, due to the variability in SBP observed in all treatment groups over the 104 weeks of treatment, results should be interpreted with caution, authors said.

Further investigation is warranted to determine how the 2 drug classes work together from a volume and renal perspective. Currently, DECADE (NTR6839) is investigating the albuminuria-lowering effect of QW plus dapagliflozin in patients with T2D and microalbuminuria or macroalbuminuria.

In addition, the low number of patients included in the 104-week analysis limits the data’s interpretability.

"Many therapies in diabetes management are short-lived, which is why it's useful to test for long-term effect," said lead study author Serge Jabbour, MD. “These 2 classes work synergistically to help control a T2D patient's glucose levels, and other measures associated with diabetes. We can now feel more confident about prescribing these medications long term."

Reference:

Jabbour SA, Frías JP, Ahmed A, et al. Efficacy and safety over 2 years of exenatide plus dapagliflozin in the DURATION-8 study: a multicenter, double-blind, phase 3, randomized controlled trial. Diabetes Care. 2020;43(10):2528-2536. doi:10.2337/dc19-1350