SGLT2 inhibitors could better protect against major adverse cardiovascular events (MACE) in highest-risk patients with type 2 diabetes (T2D) than currently-favoured GLP-1 receptor agonists, Australian research suggests.

A review of the SAVOR, DECLARE and EMPA-REG trials saw SGLT2 inhibitors prevent an estimated five and six more MACE and hospitalisation for heart failure (HHF) incidents per year than GLP-1 receptor agonists currently available in Australia (per 1,000 treated, 95% CI: -2 to 13 and -1 to 13), respectively.

The drugs appear “worthy of endorsement” over GLP-1 receptor agonists in patients at highest cardiovascular risk, “where there is an apparent advantage derived from their efficacy for multiple outcomes”, the Baker Heart and Diabetes Institute and Monash University-based authors wrote in Diabetes Care.

Their advice comes from a two-pronged study aimed at identifying and separating MACE and HHF risks in patients with T2D, and determining which ones would benefit most from SGLT2 inhibitors versus GLP-1 receptor agonists.

A meta-analysis of the cardiovascular outcomes trials revealed HHF incidence was lower than MACE at all risk levels, yet increased with growing MACE rates.

Using aggregate baseline Thrombolysis Myocardial Infarction (TIMI) Risk Score for Secondary Prevention, the authors saw HHF rate increase from 18% of the MACE rate at low-intermediate HHF risk to 61% at highest HHF risk.

“Similarly, with increasing MACE risk, the incidence of HHF increased from 19% of the MACE incidence in those at low MACE risk to 51% in those with the highest MACE risk,” the authors wrote, based on the TIMI Risk Score for Heart Failure in Diabetes.

The findings confound an already confusing drug selection process, where contemporary guidelines recognise GLP-1 receptor agonists and SGLT2 inhibitors’ efficacy for MACE, and stronger evidence supporting risk reduction for the former, but also recommend clinicians consider HHF and chronic kidney disease progression risk, where the latter have known superiority.

“Our findings raise the question about the inherent feasibility of differentiating MACE from HHF risk in T2D,” the authors wrote, citing considerable overlap between risk factors, including renal impairment, history of heart failure and coronary artery disease, and cardiovascular outcomes.

“Heart failure may act as both a component (cardiovascular death) or consequence (nonfatal myocardial infarction) of MACE, which is obviously a composite outcome enriched with atherosclerotic events, but nonetheless includes any fatal [cardiovascular] disease.”

In this review, “estimated GLP-1RA- and SGLT2i-mediated reductions in cardiovascular events were similar in those at low-intermediate MACE or HHF risk but tended to favour SGLT2 inhibitors at higher risk levels of both scores”, the authors wrote.

They noted several limitations, however, including a reliance on two of many validated cardiovascular risk scores, which could give different results, as well as three “relatively short” trials (two to four years), which excluded long-term shifts in HHF and MACE risk, and the consequences of prioritising SGLT2 inhibitors versus GLP-1 receptor agonists.

Despite the shortfalls, their findings “warrant scrutiny of current management guidelines in T2D, which mandate a clear preference for SGLT2 inhibitors only when there is established heart failure or chronic kidney disease”, the authors wrote.

The drugs appeared to have “a more immediate protective effect (as observed from cumulative incidence curves)”, as well as greater benefit in highest-risk patients, they said.

“Thus, future guidelines pertaining to GLP-1 receptor agonists versus SGLT2 inhibitor add-on therapy may consider recommending an assessment of overall cardiovascular risk to drive this decision, rather than an estimation of risks of MACE and HHF relative to each other.”

Where therapy choice isn’t clear, clinicians may “instead focus on drug safety profiles, non-cardiovascular effects (e.g., weight loss), preference for oral (SGLT2 inhibitors) or injectable (most GLP-1 receptor agonists), and other factors when selecting between GLP-1 receptor agonist and SGLT2 inhibitor initiation”, the authors wrote.

The study was supported by funding from the NHMRC and the Victorian government.