Best: Bexagliflozin Led to Significant Reductions in HBA1C and Cardiovascular Risk Factors in Patients with Type 2 Diabetes
Presenter: John J.V. McMurray, MD
The SGLT2 inhibitor bexagliflozin reduced HbA1c in patients at high risk of cardiovascular (CV) events and had beneficial effects on weight and blood pressure in the placebo-controlled multinational BEST trial. Bexagliflozin also proved to be noninferior to placebo in a prespecified analysis of CV safety, said John J.V. McMurray, MD, professor of medical cardiology and deputy director, BHF Cardiovascular Research Center, University of Glasgow, Scotland, UK.
In BEST, the efficacy and safety of bexagliflozin in controlling hyperglycemia, weight, and blood pressure was examined in patients with type 2 diabetes mellitus (T2DM) and established CV disease or multiple CV risk factors.
A total of 1,700 men and women > 40 years old with T2DM and a baseline HbA1c of 7.0% to 11.0% on stable medications were enrolled into BEST. Patients were enrolled into one of three groups: (1) history of atherosclerotic cardiovascular disease (n = 1,065), (2) history of New York Heart Association class II/III heart failure (HF; n = 246), or (3) age ≥ 55 years and ≥ 2 cardiovascular risk factors (n = 389). They were randomized 2:1 to bexagliflozin, 20 mg once daily, or placebo. Some 96% of the patients completed 24 weeks, at which time the primary endpoint of change in HbA1c was assessed. The median follow-up for assessment of CV safety was 123 weeks.
Approximately 30% of the overall cohort were women and 77% were white. Mean age of the study population was 64.4 years, mean body mass index (BMI) was 32.6 kg/m2, the mean systolic blood pressure (SBP) was 134 mm Hg, 19.6% had an estimated glomerular filtration rate < 60 mL/min/1.73 m2, 26.7% had a history of heart failure, and 69.2% had a history of coronary heart disease.
The mean HbA1c at baseline was 8.32% and the mean duration of diabetes at entry was 8.9 years. Neuropathy was present in 30.4%. The most common types of glucose-lowering medications were biguanides (76.6%), sulfonylureas (40.1%), and dipeptidyl peptidase-4 inhibitors (13.4%), and 53.1% of patients were taking insulin at baseline.
The placebo-corrected change in HbA1c at 24 weeks in patients randomized to bexagliflozin was –0.48% (P < .0001), despite nearly three times as many patients in the placebo group requiring rescue glucose-lowering therapy compared with the bexagliflozin group (19.6% vs. 7.1%). In the 834 patients on insulin at baseline, the placebo-corrected change in HbA1c at 24 weeks was 0.52% (P < .0001) in the bexagliflozin group.
The placebo-corrected decrease in body weight at 48 weeks in patients with baseline BMI ≥ 25 kg/m2 was 2.65 kg (P < .0001) in the bexagliflozin recipients.
The placebo-corrected decline in SBP at week 24 in participants with a baseline SBP ≥ 140 mm Hg was 2.96 mm Hg (P = .012) in those randomized to bexagliflozin. A reduction in SBP over the entire follow-up was also observed in the overall study population assigned to bexagliflozin versus placebo (P < .0001).
The hazard ratio (HR) for time to first hospitalization with worsening heart failure, an exploratory endpoint, was 0.63 in favor of bexagliflozin but did not achieve significance (95% CI, 0.34-1.18) because of the small number of events. Likewise, the HR for the time to the composite of CV death or HF hospitalization was 0.73 in favor of bexagliflozin, which was not significant because of the small number of events (95% CI, 0.46-1.15).
The proportion of patients with adverse events that led to treatment discontinuation was nearly identical in the two arms—8.4% in those randomized to bexagliflozin versus 8.5% in patients randomized to placebo. The only adverse event that occurred significantly more often in the bexagliflozin group versus the placebo group was genital mycotic infection (9.5% vs. 3.0%; P < .0001), “but the proportion of patients who had to stop study because of a genital mycotic infection was small; it was only 1.2% in the patients randomized to bexagliflozin,” said McMurray. No excess of urinary tract infection was observed in the bexagliflozin group, and only 0.9% of the bexagliflozin group versus 1.4% of the placebo group experienced serious hypoglycemia.
The composite CV outcome of CV death, myocardial infarction (MI), stroke, or unstable angina was assessed once 134 events occurred. This composite was numerically less in the bexagliflozin group (HR 0.77; 95% CI, 0.57-1.08), which met the criterion for noninferiority (P < .0001). Noninferiority was also established for a composite CV outcome that included CV death, MI, or stroke (P < .0001 using a 95% upper CI margin of 1.8; P = .0021 using a 95% CI margin of 1.3).
Link to abstract: 32-OR: The Bexagliflozin Efficacy and Safety Trial (BEST): A Randomized, Double-Blind, Placebo-Controlled, Phase IIII, Clinical Trial
John J.V. McMurray, MD, disclosed financial relationships with AbbVie Inc., Alnylam Pharmaceuticals, Amgen, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Bristol-Myers Squibb, Cardurion, GlaxoSmithKline plc., Novartis Pharmaceuticals Corporation, and Theracos, Inc.