Bexagliflozin

Bexagliflozin gained U.S. Food and Drug Administration (FDA) approval for the treatment of type 2 diabetes on 20 January 2023. Specifically, bexagliflozin should be considered as an adjunct agent to diet and exercise to improve glycemic control. Additionally, bexagliflozin can be used as monotherapy in patients whose glycemia is uncontrolled on metformin or who cannot take metformin. Bexagliflozin is approved to be taken as a standardized dose of 20 mg once daily in the morning with or without food (4).

SGLT2 is responsible for the reabsorption of ∼90% of filtered glucose by the proximal renal tubular cells. People with type 2 diabetes have been found to have increased reabsorption of glucose secondary to SGLT2 receptor overexpression. SGLT2 inhibitors such as bexagliflozin act by lowering the renal tubular threshold for glucose reabsorption, therefore decreasing renal glucose reabsorption and increasing urinary glucose excretion without requiring insulin secretion (5).

In concordance with previous literature on other SGLT2 inhibitors, bexagliflozin has been shown to effectively lower A1C in adults with type 2 diabetes. In recent studies that looked at the A1C-lowering ability of bexagliflozin compared with placebo, the bexagliflozin groups had a significant A1C reductions, and the drug lowered A1C by 0.56–0.85% (6–9). These findings show that the A1C-lowering efficacy of bexagliflozin is comparable to or better than that of other SGLT2 inhibitors; the agents in this class are known to reduce A1C by ∼0.5%.

In addition to its A1C-lowering effect, these studies also looked at bexagliflozin’s ability to aid in weight loss and systolic blood pressure reduction and found significant reductions in both outcomes (6–9). The Bexagliflozin Efficacy and Safety Trial (BEST), which is the largest study to date, showed a significant reduction in systolic blood pressure at 24 weeks by 9.83 mmHg in the bexagliflozin group compared with 6.87 mmHg in the placebo group (mean difference −2.96 mmHg, 95% CI −5.51 to −0.42, P = 0.0112) (8). The same trial looked at change in body weight from baseline to week 48 in patients with a baseline BMI ≥25 kg/m² and found that patients in the bexagliflozin group lost on average 3.03 kg compared with 0.38 kg in the placebo group (mean difference −2.65 kg, 95% CI −3.07 to −2.24, P <0.0001) (8). Another trial that looked at the effects of bexagliflozin for 96 weeks compared with placebo found that the treatment group reduced body weight by 2.63 kg within 24 weeks and maintained that weight loss through the end of the trial period (P <0.0001) (6).

Because of the mechanism of increasing urinary glucose excretion, bexagliflozin has been found to cause pollakiuria (frequent urination), dysuria, and polyuria, which can lead to volume depletion and in turn may result in acute kidney injury (AKI) (4,9). One study that looked at the A1C-lowering effect of bexagliflozin in patients with stage 3 CKD found a slightly higher incidence of stage I AKI in the bexagliflozin group (8 of 157 vs. 6 of 155 patients) (7). It would be advantageous to assess risk before starting bexagliflozin in combination with other medications that could contribute to volume depletion.

Although it is FDA approved, bexagliflozin is currently unavailable. Anticipate pricing to be similar to that of other SGLT2 inhibitors on the market (e.g., dapagliflozin, empagliflozin, and canagliflozin), with average wholesale pricing ranging from $678 to $717 for a month’s supply (10). It is important to note that these monthly prices do not take into account discounts, insurance coverage, rebates, or other price adjustments.

Bexagliflozin is the fifth agent in its class to receive FDA approval. Studies have found that bexagliflozin has been as efficacious as other SGLT2 inhibitors. When studied at a dose of 20 mg daily, bexagliflozin was found to lower the A1C by 0.56–0.85% over the course of 12–96 weeks (6–9). This lowering of A1C has been observed up to 168 weeks, with an average A1C reduction of 0.56% in 218 patients (8). When comparing completion rates, the percentage of patients who completed trials in the placebo groups and the bexagliflozin groups have been similar (6,7). Additionally, when comparing commonly encountered adverse reactions, it was found that the incidence of hypoglycemia was similar to placebo; however, genitourinary infections were higher in the bexagliflozin groups, although these findings were not statistically significant (6–9).

Regarding the rate of all-cause mortality, bexagliflozin was found to be noninferior to placebo (3.45% in the bexagliflozin group vs. 4.59% in the placebo group) (8).

Some SGLT2 inhibitors such as empagliflozin and dapagliflozin have been found to lower the risk of worsening heart failure, hospitalizations, and cardiovascular death in patients with heart failure with preserved or reduced ejection fraction, regardless of whether patients have a history of diabetes.

At this time, bexagliflozin has been found to be noninferior to placebo; however, it has not been studied in a large number of patients (8). Similar to other medications in its class, bexagliflozin shows promise in demonstrating renoprotective properties in patients with type 2 diabetes. In one study, an initial reduction in estimated glomerular filtration rate (eGFR) was found at 24 weeks; however, at 26 weeks, there was an increase in eGFR (7). Thus, more studies are needed to evaluate whether bexagliflozin has renoprotective properties.

Bexagliflozin is a reasonable glucose-lowering medication option for the treatment of type 2 diabetes. In patients with CKD and an eGFR <60 mL/min/1.73 m², bexagliflozin could be considered as a first-line agent independent of metformin use. However, at this time, there are no head-to-head comparisons of bexagliflozin with other SGLT2 inhibitors. Therefore, the choice of a particular agent from this class should be made in a circumspect manner and with consideration of glycemic as well as vascular and renal effects. Still, for patients looking to achieve and maintain glycemic goals, bexagliflozin is a plausible second- or third-line option to treat type 2 diabetes. Before starting patients on bexagliflozin, their medical history, financial status, and risk/benefit factors should be thoroughly considered.