An Oral Revolution in Treating Adults Diagnosed with Type II Diabetes Mellitus

By: Samia Rahman Adity, PharmD Candidate c/o 2025

Diabetes Facts and Statistics

Type II diabetes (T2D) has been a consequential public health concern in the United States (US). It is a condition where patients have elevated blood glucose levels. Escalation in plasma glucose can lead to detrimental health effects, which include cardiovascular complications like coronary heart disease or heart failure, any cerebrovascular accident, hypertension, microalbuminuria, or diabetic nephropathy.¹ According to the American Diabetes Association (ADA),  11.6% of the US population have diabetes.² Those who are aged 65 years or older have a higher prevalence of being diagnosed with the disease. Additionally, the incidence of having the health condition is more common in men [12.6%; 95% confidence interval (CI) 11.1 to 14.3] in comparison to women (10.2%; 95% CI 8.8 to 11.7).³

From an economic perspective, patients diagnosed with T2D have two times higher healthcare expenditure in comparison to healthy patients on average. According to the ADA, healthcare disbursement has increased to $327 billion in 2017 from $245 billion in 2012, with an approximate increment of 26% in a five-year period.⁴

There exists a number of significant factors leading to the disease. One of such representatives includes the increase in activity of the sodium-glucose cotransporter-2 (SGLT2).¹ The SGLT2 is present in the proximal convoluted tubule that is responsible for reabsorbing the filtered glucose back into the blood plasma and excreting sodium ions in urine during the process of glomerular filtration in the kidneys. The glucose level in the blood plasma further increases, leading to hyperglycemia.

Common Oral Hypoglycemic Agents for Diabetes Management

The consumption of sulfonylureas with metformin has been the “norm” for a long time. While this class of medications is widely known for their action of prolonged depolarization of the pancreatic beta cells and promotion of insulin release, they also result in weight gain and increased risk of hypoglycemia.⁵ In order to mitigate the side effects of sulfonylureas, insulin-independent mechanisms are preferred, which can primarily be attained by the consumption of SGLT2 inhibitors.⁶ One example of an SGLT2 inhibitor is bexagliflozin, which was newly approved by the Food and Drug Administration (FDA). This medication is an oral tablet with a strength of 20 mg. Bexagliflozin is also marketed with the brand name Brenzavvy. This drug is primarily classified as a benzyl benzene C-glycoside, which is known to be a potent inhibitor of the SGLT2.⁷

Analysis of Bexagliflozin vs. Glimepiride

In a double-blind, double-dummy, randomized controlled trial conducted by Dr. Yuan-Di Halvorsen et al., bexagliflozin 20 mg tablets were compared to a titrated dose of glimepiride.⁸ Bexagliflozin was proven to be better in terms of side effects such as weight loss and reduction in systolic blood pressure. The study consisted of a diversified cohort and was selected randomly through an interactive web-response system. The inclusion criteria of the study included participants with a hemoglobin (Hb) A1c between 7.0% and 10.5%, aged 18 years or older, with a BMI of at most 45 kg/m², and prescribed a daily dose of metformin 1500 mg for at least 8 weeks prior to the screening.⁸ The subjects were randomized to take the active dose and corresponding placebo once daily for 96 weeks. Dose titration for glimepiride was done by 2 mg at weeks 2, 4, and 6 if the fasting blood glucose measurement was reported to be greater than 110 mg/dl.⁸

The study consisted of 172 subjects on both treatment arms with 90% power and a p-value set to 0.025.⁸ The null hypothesis for this study was that bexagliflozin is inferior to glimepiride in lowering HbA1c in patients with type 2 diabetes. The experiment was conducted with an intention-to-treat analysis. The delineated results had a change in HbA1c from baseline to week 60 of -0.70% (95% CI -0.82 to -0.59) at the bexagliflozin arm and -0.66% (95% CI -0.77 to -0.54) in the glime-piride arm. This showed that use of bexagliflozin resulted in a greater decrease in HbA1c in comparison to use of glimepiride. Additionally, the intergroup difference between bexagliflozin and glimepiride was found to be -0.05% (95% CI -0.21 to 0.11). The prespecified margin was set at 0.35, and the upper boundary of the CI was less than 0.35, which indicated that bexagliflozin is noninferior to glimepiride.⁸

Additionally, a systemic review and meta-analysis proved bexagliflozin to be efficacious in patients with T2D.⁹ The results of multiple small randomized clinical controlled trials were totaled and ultimately showed that bexagliflozin is associated with a significant reduction in HbA1c. The experiment included six studies and 3111 patients where the SGLT2 inhibitor was compared with placebo in patients with type 2 diabetes mellitus. The overall result suggested a decrease in HbA1c in the bexagliflozin arm with a weighted mean difference of -0.53% (95% CI -0.75 to -0.31, p-value < 0.001, I² of 84%). I² values greater than 25% proved heterogeneity in the study.

Patients diagnosed with T2D also have an increased risk of atherosclerotic cardiovascular disease and heart failure. In the trial conducted by Halvorsen et al., the SGLT2 inhibitor has proven to be efficacious in reducing any adverse cardiovascular outcomes in patients.⁸ Conversely, in the review conducted by Pasqualotto et al., there was no significant difference in major adverse cardiovascular events (MACE) when comparing bexagliflozin with placebo.⁹ Thus, it is unclear bexagliflozin’s role in preventing cardiovascular events as of yet.

Adverse Effects of Bexagliflozin

Some of the reported adverse effects of the SGLT2 inhibitor include hypoglycemia, genital and urinary tract infection, allergic skin reaction, genital myotic infection, and diabetic ketoacidosis.⁵ The study also stated that the risk of hypoglycemia has been observed more often with Bexagliflozin in comparison to traditional SGLT2 inhibitors, like empagliflozin and dapagliflozin.⁵

Conclusion

It can be concluded that bexagliflozin is efficacious in terms of improved glycemic control, reduction in blood pressure, and weight loss in patients with type 2 diabetes. Still, the meta-analysis of different studies proved the efficacy of bexagliflozin; the data for concomitant use of insulin or glucagon-like peptide-1 (GLP-1) receptor agonists have not been recorded for the participants.⁹ In addition to this, the inconclusive results of bexagliflozin on the effects on cardiovascular outcomes warrant additional testing of the medication. In recent years, SGLT2 inhibitors have played an increasingly prominent role in the management of heart failure.¹⁰ It is worth exploring this indication for bexagliflozin now that it has proven its efficacy for T2D management.

References

1. Al-Lawati JA. Diabetes Mellitus: A Local and Global Public Health Emergency! Oman Medical Journal. 2017;32(3):177-179. doi:10.5001/omj.2017.34
2. Statistics about diabetes. American Diabetes Association. Updated November 2, 2023. https://diabetes.org/about-diabetes/statistics/about-diabetes
3. National diabetes statistics report. Centers for Disease Control and Prevention. Updated November 29, 2023. https://www.cdc.gov/diabetes/data/statistics-report/index.html
4. New American Diabetes Association report finds annual costs of diabetes to be $412.9 billion. News release. American Diabetes Association. Published November 1, 2023. https://diabetes.org/newsroom/press-releases/new-american-diabetes-association-report-finds-annual-costs-diabetes-be
5. Wexler DJ. Sulfonylureas and Cardiovascular Safety: The Final Verdict?. JAMA. 2019;322(12):1147-1149. doi:10.1001/jama.2019.14533
6. Xie Y, Bowe B, Gibson AK, McGill JB, Maddukuri G, Al-Aly Z. Comparative Effectiveness of Sodium-Glucose Cotransporter 2 Inhibitors vs Sulfonylureas in Patients With Type 2 Diabetes. JAMA Intern Med. 2021;181(8):1043-1053. doi:10.1001/jamainternmed.2021.2488
7. FDA Approves bexagliflozin for adults with type 2 diabetes. Pharmacy Times. Published January 24, 2023. https://www.pharmacytimes.com/view/fda-approves-bexagliflozin-for-adults-with-type-2-diabetes
8. 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(1):293-301. doi:10.1111/dom.14875
9. Pasqualotto E, Figueiredo Watanabe JM, Gewehr DM, et al. Efficacy and safety of bexagliflozin in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Obes Metab. 2023;25(7):1794-1802. doi:10.1111/dom.15051
10. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895-e1032. doi:10.1161/CIR.0000000000001063