No Clear Winner in SGLT2 Showdown for Cardiovascular Disease

Individual SGLT2 inhibitors showed roughly comparable cardiovascular effectiveness and safety in an observational study of real-world claims data.

Compared with people who had type 2 diabetes treated with empagliflozin (Jardiance), peers on canagliflozin (Invokana; HR 0.98, 95% CI 0.91-1.05) or dapagliflozin (Farxiga; HR 0.95, 95% CI 0.89-1.03) had about the same risk of hospitalization for acute myocardial infarction or ischemic stroke at just under 12 months of follow-up.

Findings were similar for heart failure hospitalization, the exception being a reduced benefit detected for low-dose dapagliflozin (HR 1.30, 95% CI 1.12-1.50) relative to empagliflozin. High-dose dapagliflozin had no such difference regarding heart failure hospitalization risk relative to empagliflozin (HR 1.06, 95% CI 0.88-1.27), according to Elisabetta Patorno, MD, DrPH, of Brigham and Women’s Hospital and Harvard Medical School, and colleagues.

“These findings reinforce the use of dapagliflozin, 10 mg, or other SGLT2 inhibitors when the therapeutic goal is to reduce the risk of heart failure,” the authors noted in JAMA Internal Medicine.

No surprises here in general, commented Marvin Konstam, MD, of Tufts Medical Center in Boston.

Taken at face value, the results would suggest that the three SGLT2 inhibitors are “virtually identical,” according to Konstam, who told MedPage Today that he personally prescribes either dapagliflozin or empagliflozin to his heart failure patients. The choice comes down to accessibility: as these can be expensive drugs, “I’m handing it to pharmacists and saying ‘Give the patient the best deal on one of these,'” he said.

The present comparative effectiveness study included adults with type 2 diabetes who initiated SGLT2 inhibitors from 2014 to 2020, covering a period from when all three diabetes drugs were made available stateside to shortly after the label expansion of dapagliflozin to individuals with heart failure regardless of type 2 diabetes.

Both empagliflozin and dapagliflozin are now indicated to prevent cardiorenal events, whether people have type 2 diabetes or not. In the case of dapagliflozin, the 5-mg dose is recommended for glycemic control and the 10-mg for cardiovascular risk reduction — the latter being what had been studied in the drug’s cardiovascular outcomes trial DELIVER. A dual SGLT1 and SGLT2 inhibitor, sotagliflozin (Inpefa) has also gotten FDA approval for heart failure.

“Given that there are extremely robust randomized trial data suggesting very comparable benefits with the three SGLT2 inhibitors for prevention of cardiovascular events in patients with diabetes and in kidney disease, and extremely robust randomized data in heart failure with empagliflozin and dapagliflozin which strongly suggest nearly identical treatment effects, the totality of the evidence suggests that the similarity of these drugs far outweigh the differences,” commented Scott Solomon, MD, also of Brigham and Women’s Hospital and Harvard, who was not involved with the report.

Patorno and colleagues reported that safety outcomes were comparable among the three SGLT2 inhibitors in their study.

“Although there were differences in the risk of specific safety outcomes — such as a lower risk of genital infection for canagliflozin and dapagliflozin initiators compared with empagliflozin, a higher risk of severe UTI with canagliflozin, and a lower risk of [diabetic ketoacidosis] with dapagliflozin — the overall risk for safety events, including bone fracture and lower-limb amputation, was similar across the three SGLT2 inhibitors,” Patorno’s group wrote.

Konstam cautioned against making definitive statements based on this type of study but said that a randomized trial, pitting the SGLT2 inhibitors against each other, would be unlikely; it would have to be a very large trial and someone would have to pay for it.

For the present observational study, Patorno’s group had pooled data from Optum’s Clinformatics Data Mart Database, MarketScan Research, and fee-for-service Medicare.

New initiators of canagliflozin (n=232,890), dapagliflozin (n=129,881), and empagliflozin (n=295,043) during the study period were included. SGLT2 inhibitor users were only included in the study if they had no prior use of any SGLT2 inhibitor within the preceding 365 days, and no concurrent exposure to multiple SGLT2 inhibitors.

Participants were in their early 60s on average, with over 55% men. Compared with empagliflozin initiators, those receiving canagliflozin or dapagliflozin were less likely to have baseline diabetes-related conditions or a history of cardiovascular disease.

After weighting, baseline characteristics appeared well-balanced across comparisons.

As with any observational study, the potential for residual confounding was a major limitation of this study. Also possible was a misclassification of dose, since the databases only capture the initial dose prescribed, according to Patorno and colleagues.