The investigational sodium glucose transporter 2 (SGLT2) inhibitor bexagliflozin (Theracos) met its efficacy and safety objectives in the phase 3 Bexagliflozin Efficacy and Safety Trial (BEST) cardiovascular outcomes trial.
John J.V. McMurray, MB ChB, MD, University of Glasgow, UK, delivered the top-line findings from BEST in an oral presentation at the virtual American Diabetes Association (ADA) 80th Scientific Sessions.
In patients with type 2 diabetes at high cardiovascular risk, bexagliflozin was well tolerated and improved A1c, systolic blood pressure, and weight compared with placebo.
In addition, noninferiority was demonstrated for MACE+ (cardiovascular death, myocardial infarction, stroke, or unstable angina), the authors summarize.
"BEST provides more evidence about the metabolic efficacy and overall safety of this remarkable new class of drugs [SGLT2 inhibitors] for patients with type 2 diabetes," McMurray told Medscape Medical News in an email.
"This was a particularly high-risk population, with a high proportion of patients with established cardiovascular disease (some with a history of heart failure), and bexagliflozin exerted many beneficial effects and was well tolerated and safe," he continued.
"Hopefully, bexagliflozin will receive regulatory approval and become available to physicians and patients," he added.
Albert Collinson, PhD, president and CEO of Massachusetts-based Theracos, which is developing bexagliflozin, told Medscape Medical News: "BEST is one of six phase 3 trials that make up the new drug application package that the company anticipates filing to the US Food and Drug Administration in the coming months."
One of the phase 3 trials evaluated the drug in patients with diabetes and kidney disease and has been published (Am J Kidney Dis. 2019;74:328-37). The other trials assessed the drug as monotherapy and as an add-on to metformin compared with placebo, glimepiride, or sitagliptin.
Findings "Consistent" With Those of Other SGLT2 Inhibitors
"The results seemed consistent with what we have been seeing with the SGLT2 inhibitor class: modest glucose lowering, with blood pressure and weight loss, and a consistent safety profile with increase in genital mycotic infection," Vanita R. Aroda, MD, Brigham and Women's Hospital, Boston, Massachusetts, told Medscape Medical News when asked to comment.
"What did strike me is how early the effects were seen," she said, "and I think this is something we are starting to see" in "newer analyses that are coming from this class."
Aroda was a site investigator 3 years ago in a trial of this drug when she worked for another company.
Even though there were few cardiovascular events (and thus the difference between bexagliflozin and placebo was not statistically significant), the risk reductions were similar to what has been seen for other drugs in this class, she added.
"Long-term data are always helpful, and it was nice to see the continued effects on weight and blood pressure, and it would be nice to see how these factors contribute to long-term health effects," she added.
Trial Design and Efficacy Findings
BEST aimed to evaluate the efficacy and safety of bexagliflozin 20 mg once daily compared with placebo in controlling hyperglycemia, weight, and blood pressure in patients with type 2 diabetes and established cardiovascular disease or multiple cardiovascular risk factors.
The trial enrolled 1700 patients in 10 countries between November 2015 and November 2019 and followed them for a median of 30 months.
Patients were age 40 or older with type 2 diabetes, an A1c of 7% to 11% on stable medication, and an estimated glomerular filtration rate (eGFR) > 45 mL/min/1.73m2.
Patients were classified into three groups based on cardiovascular disease history:
Established atherosclerotic cardiovascular disease (myocardial infarction, stroke, or revascularization (63%).
History of heart failure (14%).
≥ 55 years old with ≥ 2 cardiovascular risk factors (23%).
Patients were randomized 2:1 to drug (1133 patients) or placebo (567 patients) in addition to standard diabetes therapy.
Participants in each group were a mean age of 64 years, 77% were white, and 31% were female. Mean body mass index (BMI) was 33 kg/m2 and mean body weight was about 97 kg (214 lbs).
About 20% had kidney disease (mean eGFR < 60 mL/min/1.73m2), and almost all (94%) had hypertension (systolic blood pressure > 140 mm Hg).
On average, patients had had diabetes for 15 years and had an A1c of 8.3%. Just over three quarters were receiving metformin and just over half were receiving insulin.
The primary efficacy endpoint, drop in A1c at week 24 versus baseline, was 0.48% lower in the bexagliflozin group than the placebo group (P < .0001).
Within 6 weeks of therapy, there was a significant reduction in A1c, which persisted over time, McMurray pointed out.
From baseline to 48 weeks, on average, overweight or obese patients lost 3 kg in the bexagliflozin group versus 0.38 kg in the placebo group (a difference of 2.65 kg; P < 0001).
"There was a surprisingly early reduction in weight, and interestingly weight continued to decline during the almost 3 years of follow-up," McMurray commented.
From baseline to 24 weeks, mean systolic blood pressure dropped 2.96 mmHg more in the bexagliflozin group than in the placebo group (P = .012).
The trial continued until all patients had completed at least 52 weeks of treatment and at least 134 patients had had a MACE+ event.
This was a noninferiority trial, with a moderate size and few MACE+ events in the bexagliflozin and placebo groups (7.9% vs 10.1%).
Noninferiority for MACE+ was clearly established (hazard ratio [HR], 0.77; 95% CI, 0.57 - 1.08; P for noninferiority < .0001).
The rate of adverse events leading to discontinuation was the same in both groups, at 8.4%.
Adverse events were uncommon and rates were similar in both the bexagliflozin and placebo groups, except for genital mycotic infection (9.5% vs 3%), but this only led to discontinuation of bexagliflozin in 1.2% of patients.
The rate of any hypoglycemia was similar in the bexagliflozin and placebo groups (both 43%), and serious hypoglycemia was uncommon (0.9% and 1.4%).
BEST was sponsored by Theracos. McMurray was supported through funding from Theracos to the University of Glasgow for his work on this study. Aroda was previously a site investigator for a trial of bexagliflozin when she worked at MedStar Health Research Institute before leaving in 2017 to work at Brigham and Women's Hospital (which was not a study site).
ADA 2020 Scientific Sessions. June 12, 2020. 32-OR.
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Cite this: BEST: Bexagliflozin CV Outcomes Trial Meets Objectives - Medscape - Jun 24, 2020.