FDA approves bexagliflozin for adults with type 2 diabetes

Ildiko Lingvay, MD

Competition is good for everyone. The SGLT2 inhibitor class has undergone a tremendous transformation since 2013 when the first SGLT2 inhibitor, canagliflozin, was approved in the U.S. Interestingly, SGLT2 inhibitors were initially regarded as a rather modest glucose-lowering intervention. However, over the next few years, following results from large cardiovascular outcome studies and, later, subsequent studies focused on heart failure and chronic kidney disease, the class has seen a major change in direction.

SGLT2 inhibitors are now recommended as one of the four pillars of care for patients with heart failure with reduced ejection fraction, regardless of the presence of diabetes. They are recommended as foundational therapy to prevent and reduce the progression of chronic kidney disease, regardless of the cause of the kidney disease. And at least one of the agents in the class – empagliflozin – showed positive outcomes in a study dedicated to heart failure with preserved ejection fraction. Several of the agents in this class also have an indication to prevent CV events in people with type 2 diabetes with preexistent CVD.

Given their myriad proven benefits beyond glycemic control, SGLT2 inhibitors are one of the key therapeutic interventions recommended by the current American Diabetes Association Standards of Care. With over 37 million Americans having type 2 diabetes, many of whom are at high risk for cardiorenal complications, there is a tremendous demand for these drugs. The hope is that having more options within the class will increase competition and ultimately drive down the price, which has been an important barrier to their use.

The key question is whether the medical community and patients are ready to assume that the beneficial effects demonstrated in the CV and renal outcome studies can be extrapolated to the class. The new agent, bexagliflozin, while it has been demonstrated to be safe in the intended population, has not been subject to any outcome study and carries a formal label indication only for glucose lowering. Time will tell!

Richard E. Pratley, MD

The FDA recently approved bexagliflozin, an SGLT-2 inhibitor, for the treatment of type 2 diabetes. According to the Prescribing Information, bexagliflozin 20 mg once daily is “indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.”

Bexagliflozin is the fifth SGLT-2 inhibitor approved for the treatment of type 2 diabetes in the U.S. According to TheracosBio, approval was based on 23 studies in over 5,000 patients with type 2 diabetes. Data from some of the trials have been presented previously at the ADA Scientific Sessions and in peer-reviewed journals. The phase 3 studies included monotherapy, add-on to metformin and insulin.

Collectively, these results indicate that the efficacy of bexagliflozin is typical of the class, with decreases in HbA1c of 0.5% to 0.8%, decreases in body weight of 3 kg and decreases in systolic blood pressure of almost 3 mm Hg on average. In head-to-head studies bexagliflozin was noninferior to sitagliptin and glimepiride with respect to HbA1c reductions. In patients with chronic kidney disease, bexagliflozin was safe and well tolerated, but decreases in HbA1c were somewhat less than in those with a normal eGFR, as expected. In 1,700 patients with pre-existing CVD or multiple risk factors who were treated with bexagliflozin or placebo for a median of 2.4 years, fewer patients experience a MACE event with bexagliflozin compared to usual care (3.3 vs. 4.2 MACE events per 100 person-years for placebo; HR = 0.77; 95% CI, 0.56, 1.08).

Bexagliflozin is not recommended if the eGFR less than 30 mL/min/1.73 m² and is contraindicated for those on dialysis. An increased, although not statistically significant, incidence of lower limb amputations was observed among patients treated with bexagliflozin (8.3 vs. 5.1 events per 1,000 patient-years; HR = 1.64, 95% CI, 0.70, 3.82), and therefore, the label has a warning similar to that for canagliflozin and ertugliflozin. Other warnings in the label include DKA, volume depletion, genital mycotic infections, urinary tract infections and urosepsis, similar to other SGLT-2 inhibitors. Finally, while the phase 3 data do not indicate any apparent CVD risk, a robust CVD outcomes trial has not been done.

Although new treatments for type 2 diabetes are always welcome, the approval of bexagliflozin raises several questions. First, the other four members of the class are all quite good and all have robust outcome trials supporting CVD, heart failure and kidney benefits. Bexagliflozin does not seem differentiated with respect to HbA1c lowering, weight, blood pressure effects, safety or tolerability, and while the CVD safety seems good, it is not supported by a robust CVOT.

How will bexagliflozin find space in the crowded type 2 diabetes oral medication market? Further, will providers assume that the CVD and kidney benefits demonstrated with other SGLT2 inhibitors represent a class effect? And why would providers choose bexagliflozin over a tried-and-true alternative?

One reason might be cost, of course. While the mission of TheracosBio is “to expand access to new medications for patients with common diseases,” it is not clear whether bexagliflozin will be a cheaper alternative to other branded SGLT2 inhibitors. If indeed bexagliflozin is significantly cheaper, that would be a benefit for many patients who are unable to access this class of medications because of cost and high deductible insurance plans. However, generic versions of dapagliflozin and empagliflozin will be available in a couple of years, and this might erase any economic differentiation. Finally, bexagliflozin was also recently approved as the first oral treatment for feline diabetes. As a former friend of a feline with diabetes, I can tell you that an oral alternative to daily insulin injections would have been welcome! The remaining question then is, will TheracosBio make more money on human or feline diabetes?