SGLT2 Inhibitor Added to GDMT in Functional MR May Obviate Need for TEER

Adding ertugliflozin (Steglatro; Merck Sharp & Dohme), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, to other therapies significantly reduces functional mitral regurgitation (MR) secondary to heart failure (HF) in patients with mildly or moderately reduced ejection fraction, according to the small, randomized EFFORT trial.

Researchers say their results, which also showed that ertugliflozin improved left ventricular global longitudinal strain, left atrial remodeling, and NYHA functional class, emphasize the importance of optimizing guideline-directed medical therapy (GDMT) before resorting to more-invasive, expensive procedures, such as mitral transcatheter edge-to-edge repair (M-TEER).

Lead investigator Duk-Hyun Kang, MD, PhD (Asan Medical Center, Seoul, Republic of Korea), said the need for GDMT applies to all patients with HF, regardless of the presence of functional MR, but that these treatments often fail to improve regurgitation. This led to the landmark COAPT trial that showed TEER reduced MR more effectively and improved clinical outcomes when compared with GDMT in patients severe functional MR. Kang pointed out, however, that two-thirds of patients in COAPT either died or were hospitalized for HF within 5 years.

“Thus, optimization of GDMT for timely reduction of functional MR is important, because the persistence of severe functional MR despite GDMT contributes to a vicious cycle of deterioration and leads to irreversible LV dysfunction and a poorer prognosis,” he told TCTMD in an email.

Stephen Greene, MD (Duke University School of Medicine, Durham, NC), who wasn’t involved in the study, said there is a lot of enthusiasm in the HF community for percutaneous approaches to mitral valve repair, specifically M-TEER, after the COAPT trial showed that in appropriately selected patients there were substantial benefits, including mortality benefits, over GDMT alone. 

“The key thing to remember is that before we consider M-TEER decisions, we need to really have a diligent focus on upstream optimal GDMT,” he told TCTMD. “If we do our due diligence with that upstream optimal GDMT, some patients will have significant improvement in their mitral regurgitation to the point that M-TEER would be unnecessary or inappropriate. We cannot forget that in the COAPT trial, there was a strong upstream focus on truly optimal GDMT in order for patients to be eligible for randomization.”

For Greene, the take-home message of the new study, which was published last week in Circulation, is that even though patients were already on some level of background therapy for HF at baseline, “if their GDMT was upgraded by adding ertugliflozin, they had an incremental benefit in terms of reducing their MR. This reiterates the message that there can be a major difference between any or some GDMT and truly optimal GDMT that includes delivery of all proven disease-modifying therapies.” 

Kang reached a similar conclusion, stating that the optimization of GDMT with an SGLT2 inhibitor, as well as an angiotensin receptor-neprilysin inhibitor (ARNI), “can preclude the need for TEER in patients with improvement of functional MR, and might reduce the residual risk after performance of TEER.”

Improvement in EROA

SGLT2 inhibitors have been shown to reduce the risk of major cardiovascular events, including mortality and hospitalizations, in patients with HF across a range of ejection fractions. Despite current recommendations, however, SGLT2 inhibitors aren’t used very often in patients with HF with functional MR because “their effects on cardiac remodeling and functional MR are uncertain,” said Kang.

For the EFFORT trial, researchers randomized 128 patients (mean age 66.4 years; 61% women) with NYHA functional class II or III heart failure and mildly or moderately reduced EF (mean LVEF 42%) to GDMT plus ertugliflozin or placebo. Kang said they excluded patients with LVEF < 35% because the current guidelines recommend SGLT2 inhibitors as a class 1 indication for HF with reduced ejection fraction (HFrEF). Additionally, because those scheduled for a mitral intervention also were excluded, the mean effective regurgitant orifice area (EROA) was smaller than reported in previous TEER trials, with only 10 patients having an EROA ≥ 0.40 cm².

Approximately 43% of patients were treated with an ARNI, 84% with a beta-blocker, and 53% with a mineralocorticoid receptor antagonist (MRA). During follow-up, concomitant use of GDMT did not change except for one patient who had an ACE inhibitor replaced with ARNI in the placebo group.

The primary endpoint, change in the EROA of functional MR from baseline to 12 months, was significantly different between the ertugliflozin- and placebo-treated patients (-0.05 vs 0.03 cm²; P < 0.001). In a prespecified subgroup analysis, there was no interaction between treatment group and change in EROA by cause and mechanism of functional MR, cardiac rhythm, EF, presence of diabetes, or use of ARNI. Regurgitant volume, as well as left atrial volume index and global longitudinal strain, were also significantly improved with ertugliflozin.

Overall, 44.8% of patients in the ertugliflozin group had an improvement in NYHA functional class compared with 14.3% in the placebo group (P < 0.001).

Solid Background Therapy

In the United States, M-TEER has a class 2a (level of evidence B) recommendation for patients with severe secondary MR and persistent symptoms despite treatment with optimal GDMT. Regardless of MR, Greene said, SGLT2 inhibitors are a foundational therapy for HF patients across the EF spectrum. 

Last year, however, an analysis of the Society of Thoracic Surgeons/American College of Cardiology TVT Registry showed that most patients are undergoing M-TEER without first being optimized on medications. In that study, just one in five patients with MR secondary to HF received triple therapy with a renin-angiotensin-aldosterone system (RAAS) inhibitor or ARNI, beta-blocker, and MRA before undergoing M-TEER with MitraClip (Abbott). There was wide variation among hospitals, with some centers doing a good job getting patients optimized on GDMT and others faring worse.

“That TVT Registry study was focused on use of ACE inhibitors/ARBs/ARNI, MRAs, and beta-blockers, and now we have the SGLT2 inhibitor as a focus with this current randomized trial,” said Greene. “It again suggests that it’s not just about checking the box with any or minimal GDMT before we proceed with these invasive, expensive procedures. Barring absolute contraindications, we need to be first and foremost truly optimizing GDMT with all proven medical therapies. That TVT Registry study suggested that in real-world US practice, there are large gaps in use of triple-therapy GDMT before proceeding to M-TEER. Unfortunately, we would guess that the use of quadruple therapy for HFrEF before M-TEER is even lower.”

Greene noted that other studies have shown similar results. PROVE-HF, for example, showed that the use of an ARNI reduced MR severity in HF patients with reduced EF, with the prevalence of severe MR decreasing by nearly half.

Even with implantable cardioverter-defibrillator (ICD) therapy, real-world evidence suggests that optimization of GDMT before pulling the trigger with the device is often very poor, said Greene. In PROVE-HF, he said, about one-third of patients who initially met criteria for a primary-prevention ICD at baseline were no longer ICD-eligible 6 months after being initiated on sacubitril/valsartan (Entresto; Novartis). The results from PROVE-HF are even more impressive because approximately three-quarters of the patients were already on an ACE inhibitor or ARB at baseline, he added.