By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved the fifth oral sodium-glucose co-transporter 2 (SGLT2) inhibitor to treat type 2 diabetes mellitus (T2DM). Bexagliflozin joins a crowded field that includes canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. It is distributed as Brenzavvy.
INDICATION
Bexagliflozin can be prescribed as an adjunct to diet and exercise to improve glycemic control in adults with T2DM.1
DOSAGE
Take one dose per day in the morning (20 mg), with or without food.1 Patients with an estimated glomerular filtration rate (eGFR) < 30 mL/ min/1.73 m2 should not take this drug. Bexagliflozin is available as 20 mg tablets.
POTENTIAL ADVANTAGES
Bexagliflozin provides another option for SGLT2 inhibition. It is highly selective for SGLT2 over SGLT1, similar to empagliflozin, and greater than canagliflozin and dapagliflozin.2 Like other SGLT2 inhibitors, bexagliflozin is associated with modest reductions in blood pressure and body weight. No clear advantage has been established for bexagliflozin compared to other members of the class.
POTENTIAL DISADVANTAGES
There were more lower limb amputations among patients taking bexagliflozin compared to placebo-treated subjects (8.3 vs. 5.1 events per 1,000 patient-years).1 Canagliflozin and ertugliflozin also share this warning; this warning is absent from dapagliflozin and empagliflozin. Bexagliflozin shares the class warning for ketoacidosis, volume depletion, urosepsis/pyelonephritis, necrotizing fasciitis of the perineum, and genital mycotic infections.
COMMENTS
The efficacy of bexagliflozin in T2DM was evaluated in six clinical trials: one as monotherapy, one in combination with metformin, two vs. active controls (sitagliptin or glimepiride) in subjects inadequately controlled with metformin, one in subjects with moderate renal impairment, and one in subjects with established cardiovascular disease (CVD) or who were at increased risk for CVD.1,3,4,5 The primary outcome was change in percent hemoglobin A1c (HbA1c) from baseline. In subjects with a baseline mean HbA1c of 8, bexagliflozin treatment produced a placebo mean-adjusted difference of -0.4% (95% CI, -0.6% to -0.1%), with 31% achieving HbA1c < 7% vs. 20% in placebo-treated subjects at week 24.1 In subjects with a baseline HbA1c of 8.5-8.6, adding bexagliflozin to metformin ≥ 1,000 mg/day or ≥ 1,500 mg/day showed a placebo mean-adjusted difference of -0.5% (95% CI, -0.7% to -0.3%).1 Bexagliflozin was noninferior to glimepiride (up to 6 mg/day) and sitagliptin (100 mg/day).1,3,4 In those subjects with renal impairment (i.e., a eGFR level of 30 mL/min/1.73 m2 to 60 mL/min/1.73 m2), bexagliflozin showed a placebo mean-adjusted difference of -0.3% to -0.4% (95% CI, -0.4% to -0.1%).1,5 In subjects at higher risk for developing CVD, bexagliflozin showed a placebo mean-adjusted difference of -0.4% (95% CI, -0.5% to -0.4%) compared to placebo from a mean baseline of 8.3%.1
There was no statistical difference in major adverse CV events (MACE) after a median follow-up of 2.4 years (10.1% for placebo and 7.9% for bexagliflozin; HR, 0.77; 95% CI, 0.56-1.08). It did not reach statistical superiority over placebo for reducing MACE rates. Body weight and systolic blood pressure were lower compared to those who were taking placebo (difference of 2.7 kg and -2.7 mmHg, respectively).
CLINICAL IMPLICATIONS
SGLT2 inhibitors have become foundational therapy, not only for T2DM for glycemic control but also for lowering the risk of MACE and progression of kidney disease.6,7 In addition, non-T2DM patients with chronic kidney disease and those with heart failure can benefit from SGLT2 inhibitor therapy. For example, canagliflozin and empagliflozin can reduce the risk of MACE or CV death in adults with T2DM and established CVD.8,9
Dapagliflozin and empagliflozin can be prescribed to reduce the risk of death and hospitalization in adults with heart failure.9,10 Dapagliflozin can be prescribed to reduce the risk of eGFR decline, end-stage kidney disease, CV death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression.10 Bexagliflozin is the latest to join a crowded market. Its ultimate role will be determined based on more clinical experience and (possibly) cost estimates. The cost for bexagliflozin is unavailable at this time.
REFERENCES
1. TheracosBio. Brenzavvy prescribing information. January 2023.
2. Azzam O, Carnagarin R, Lugo-Gavidia LM, et al. Bexagliflozin for type 2 diabetes: An overview of the data. Expert Opin Pharmacother 2021;22:16:2095-2103.
3. Halvorsen YD, Lock JP, Zhou W, et al. A 24-week, randomized, double-blind, active-controlled clinical trial comparing bexagliflozin with sitagliptin as an adjunct to metformin for the treatment of type 2 diabetes in adults. Diabetes Obes Metab 2019;21:2248-2256.
4. Halvorsen YD, Lock JP, Frias JP, et al. A 96-week, double-blind, randomized controlled trial comparing bexagliflozin to glimepiride as an adjunct to metformin for the treatment of type 2 diabetes in adults. Diabetes Obes Metab 2023;25:293-301.
5. Allegretti AS, Zhang W, Zhou W, et al. Safety and effectiveness of bexagliflozin in patients with type 2 diabetes mellitus and stage 3a/3b CKD. Am J Kidney Dis 2019;74:328-337.
6. Xu B, Li S, Kang B, Zhou J. The current role of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes mellitus management. Cardiovasc Diabetol 2022;21:83.
7. The Nuffeld Department of Population Health Renal Study Group. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: Collaborative meta-analysis of large placebo-controlled trials. Lancet 2022;400:1788-1801.
8. Janssen Pharmaceuticals. Invokana prescribing information. October 2022.
9. Boehringer Ingelheim. Jardiance prescribing information. February 2022.
10. AstraZeneca Pharmaceuticals LP. Farxiga prescribing information. January 2023.
Bexagliflozin can be prescribed as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
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