Benefits of SGLT2 Inhibitors for HF Affirmed in Large, Real-world Study

When used in everyday practice, sodium-glucose cotransporter 2 (SGLT2) inhibitors provide rapid and sustained benefits to patients with a recent heart failure (HF) hospitalization, a nationwide analysis out of France indicates.

Consistent with randomized trials, patients who did versus did not initiate SGLT2 inhibitors shortly after discharge had a significantly lower risk of all-cause death or HF hospitalization over the next several months (HR 0.71; 95% CI 0.67-0.75), lead author Paul Gautier, MD (Toulouse University Hospital, France), and colleagues report in a research letter published in the May 2025 issue of JACC: Heart Failure.

The findings were similar across subgroups defined by age, sex, diabetes, LVEF, and type of SGLT2 inhibitor.

“It’s important to corroborate results of clinical trials regarding SGLT2 inhibitors’ efficacy in particular, because the pharmacological effects are not well understood to this day,” Gautier told TCTMD, noting that the patients in their study were older, had more comorbidities, and were taking more medications than those enrolled in RCTs.

“Even in this context and within these patients, we saw the same effects of the drugs, so it’s reassuring because we now can say that these drugs have benefits in heart failure, even in everyday practice,” he said.

Senior author François Montastruc, MD, PhD (Toulouse University Hospital), added that this analysis is “the largest cohort study ever done in the context of heart failure to demonstrate real-world efficacy.”

Further, this study’s importance stands out because of oft-raised concerns that findings of clinical trials—which have specific inclusion/exclusion criteria—may not apply to the types of patients seen in routine practice, Stephen Greene, MD (Duke Clinical Research Institute, Durham, NC), told TCTMD.

Based on the findings, clinicians can be more confident applying these therapies to patients they see in clinic and expect “both mortality benefits and heart failure hospitalization benefits,” said Greene, who was not involved in the new research.

SGLT2 Inhibitor Use Up Over Time

For the study, the investigators turned to the French National Health Data System, which covers more than 99% of the population of France. They included 191,357 adults with an incident HF hospitalization from 2021 to 2023 after excluding those with prior exposure to SGLT2 inhibitors or who died or were readmitted in the 30 days after discharge.

Overall, 20.2% of patients started taking an SGLT2 inhibitor within 30 days of discharge, with that proportion increasing from just 5.1% in 2021 to 35.0% in 2023 (P < 0.001 for trend). Compared with those who didn’t initiate treatment with one of these drugs, those who did were younger (median 76 vs 84 years), more likely to be men (61.5% vs 45.7%), and more likely to have diabetes and an LVEF below 40%.

We need to convey both to patients and clinicians what’s on the line when we don’t initiate . . . or we delay therapy in eligible patients. Stephen Greene

To account for differences between groups, Gautier et al used calendar-time-specific propensity-score matching, resulting in 26,419 matched pairs of patients who did or did not start taking an SGLT2 inhibitor.

Through follow-up lasting up to 2 years (mean 9 months), patients treated with an SGLT2 inhibitor had a lower risk of all-cause mortality or HF hospitalization (14.2 vs 19.8 events per 100 patient-years), with gap between groups becoming statistically significant after just 18 days. SGLT2 inhibitor treatment was associated with lower risks of both all-cause death (HR 0.70; 95% CI 0.65-0.74) and HF hospitalization (HR 0.71; 95% CI 0.64-0.78).

The researchers note that “safety criteria were not included in our study, and this question will need to be addressed by other observational studies with a specific design.”

‘Sense of Urgency’

Gautier told TCTMD that the benefits of SGLT2 inhibitors seen early after initiation—which is consistent with what has been observed in the RCTs—could be due to the diuretic effect of the agents, noting that the “rest of the pharmacological mechanisms are not completely understood.”

Greene highlighted the importance of getting eligible patients on guideline-directed medical therapy (GDMT) for HF, including SGLT2 inhibitors. Though use of this class of agents increased over time, most patients were still not receiving treatment.

A prior study from Greene’s group affirmed that clinical inertia is the leading cause of underuse of GDMT, including SGLT2 inhibitors. As for how to increase uptake of these medications, “a lot of it just comes with continued educational initiatives on what’s at stake for heart failure,” he said. “Even if you delay a therapy a couple weeks, you are needlessly exposing your patient to excess clinical risk.”

A “sense of urgency” is a must, Greene said.

“This is a prognosis comparable to many forms of cancer, and we need to recognize that disease-modifying, quadruple medical therapy for [heart failure with reduced ejection fraction] and SGLT2 inhibitors for [heart failure with preserved ejection fraction] are really like the chemotherapy to take care of this condition,” he said.

“We would never tolerate, in the cancer world, delays in therapy and patients just going without therapy,” said Greene. “Yet in the heart failure world, this is unfortunately the status quo. And I just think we need to convey both to patients and clinicians what’s on the line when we don’t initiate . . . or we delay therapy in eligible patients.”