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SGLT-2 inhibitors were the favored diabetes treatment for heart failure risk reduction in a systematic review and meta-analysis, researchers said.

"Gliflozin" drugs showed the largest reduction for heart failure risk (RR 0.56, 95% CI 0.43-0.72) versus other medications for type 2 diabetes when compared with placebo, reported Ravi Retnakaran, MD, of Mount Sinai Hospital in Toronto, and colleagues in .

A pooled analysis restricted to the trials only assessing SGLT-2 inhibitors showed a similar significant reduction in the risk of hospitalization for heart failure when compared with placebo (RR 0.56, 95% CI 0.41-0.77, P=0.067, I²=70.2%).

In two other pooled analyses restricted to only GLP-1 agonists and DPP-4 inhibitors, neither treatment classes were tied to a significant heart failure risk reduction:

• GLP-1 agonists: RR 0.94 (95% CI 0.84-1.04, P=0.74, I²=0.0%)
• DPP-4 inhibitors: RR 1.11 (95% CI 0.95-1.30, P=0.177, I²=42.4%)

In a class ranking, Retnakaran's group concluded that, with 99.6% probability, SGLT-2 inhibitors were the best treatment specifically for heart failure risk reduction.

The researchers also found no significant association between heart failure risk in these trial participants with a lowering of HbA1c over time, measured with a meta-regression analysis.

"These findings suggest that specific drug classes, rather than glycemic targets, should be the focus of [heart failure] prevention efforts," commented Adam DeVore, MD, and Jennifer Green, MD, both of Duke University School of Medicine, who praised Retnakaran et al's study in an accompanying editorial calling it a "well-done analysis."

Although some prior studies have seen a heart failure risk reduction with a lowering in HbA1c, DeVore and Green noted that this relationship varies from patient to patient and is unlikely to be seen in those with a more advanced or complicated disease progression. "In such patients, the selection of particular antihyperglycemic drug classes may be more important to reducing [heart failure] risk," they suggested.

The meta-analysis included data on 87,162 participants with type 2 diabetes from trials conducted between 2013-2017, which included CANVAS, EXSCEL, SUSTAIN-6, LEADER, TECOS, EMPA-REG Outcome, ELIXA, SAVOR-TIMI 53, and EXAMINE.

Trials looking at GLP-1 agonists included lixisenatide (Adlyxin), liraglutide (Victoza), semaglutide (Ozempic), and once-weekly exenatide (Bydureon); DDP-4 inhibitors analyzed were alogliptin (Nesina), saxagliptin (Onglyza), and sitagliptin (Januvia). Empagliflozin (Jardiance) and canagliflozin (Invokana) were the specific SGLT-2 inhibitors tested in the analysis.

Hospitalizations for heart failure were defined as a new hospitalization or presentation to an acute care facility for congestive heart failure.

"Although the evidence base will change in the coming years owing to ongoing cardiovascular outcome/safety trials of other members of these classes, it is nevertheless encouraging that the current evidence from 9 trials involving >80,000 participants decisively differentiates the heart failure implications of SGLT-2 inhibitors (favoured), GLP-1 agonists (neutral), and DPP-4 inhibitors (neutral) at this time," the researchers ultimately concluded.

However, it is also important to note that this heart failure benefit doesn't come without added risks, as drugs containing canagliflozin carry a boxed warning for leg and foot amputation risk, as well as a FDA warning on acute kidney injury risk, and most recently a warning for Fournier's gangrene with SGLT-2 inhibitors.