SGLT-2 Inhibitors: Discrepancy Between MACE Reduction and Incident MI and Stroke

Since 2008, the US Food and Drug Administration has mandated inclusion of 3-point (3-P) major adverse cardiovascular events (MACE) as primary composite endpoints (cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke) to establish cardiovascular safety in novel therapeutic trials investigating antihyperglycemic agents (1). This shift in focus eventually led to the joint consensus report from the American Diabetes Association and European Association for the Study of Diabetes 2022 suggesting that sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are a preferred agent in patients with type 2 diabetes who are at high risk for atherosclerotic cardiovascular disease (ASCVD) (2). Further, in people with heart failure, chronic kidney disease, established cardiovascular disease, or multiple risk factors for cardiovascular disease, the decision to use SGLT-2i (or GLP-1 RA) with proven benefit has been determined to be independent of the background use of metformin and independent of baseline hemoglobulin A1c (2, 3). With the recent recommendations for use of SGLT-2i, there have been studies that investigate the mechanisms by which SGLT-2i reduce MACE. More specifically, in examining 4 major clinical trials investigating SGLT-2i in MACE, a recent meta-analysis has suggested that the effect of SGLT-2i reduce the risk of MACE independent of their ability to reduce incident myocardial infarction (MI) and stroke (4). In this commentary, we will discuss this recent met-analysis and its clinical impact on the use of SGLT-2i as an antihyperglycemic agent for the reduction of MACE.

Mukhopadhyay et al performed a meta-analysis using pooled data from 4 eligible trials (EMPA-REG (5), VERTIS CV (6), CANVAS (7), and the DECLARE TIMI 58 (8)), which resulted in 42 568 subjects. The 3-P MACE factors analyzed in this meta-analysis were 4176 subjects for total MACE, 2157 for MI, and 1288 for stroke. In the results, it was reported that SGLT-2i did not reduce either MI or stroke individually, or in totality (Mantel Haenszel risk ratio: fatal and nonfatal MI 0.93 [95% CI, 0.85-1.01], stroke 1.00 [95% CI, 0.98-1.11], total ASCVD events 0.95 [95% CI, 0.89-1.02], nonfatal ASCVD [combined nonfatal MI and nonfatal stroke] 0.94 [95% CI, 0.88-1.02]). Based on these results, the authors concluded that SGLT-2i seems to reduce MACE without any discernible significant reduction in incident MI or stroke (both fatal and nonfatal); therefore, the authors concluded that the mechanism for SGLT-2i efficacy may be unrelated to antiatherogenic effects. Mukhopadhyay et al highlighted that heart failure was later included as part of the 5-P MACE primary outcome parameters (nonfatal MI, nonfatal stroke, cardiovascular death, coronary revascularization, or unstable angina requiring hospitalization) for antihyperglycemic clinical trials, in which SGLT-2i was found to be effective in heart failure–related outcomes.

The meta-analysis reported by Mukhupadhyay et al (4) is compelling in the sense that it is important that researchers and clinicians meet results with an appropriate amount of skepticism and determine the primary driver of the composite endpoint (such as 3-P and 5-P MACE, respectively). SGLT-2i was able to reduce the composite 3-P MACE, but not to reduce individual endpoints of incident MI and stroke. Importantly, the trials that later examined SGLT-2i and the ability to reduce 5-P MACE were able to identify what potentially may be the cause for reduced MACE with SGLT-2i: reduced risk for heart failure exacerbation and/or heart failure progression.

Most recently, SGLT-2i has been demonstrated to reduce the risk for cardiovascular mortality, progression of heart failure, and reduce the risk for heart failure exacerbation. Therefore, it seems like a plausible explanation that the primary driver for SGLT-2i reducing MACE, maybe because of optimization of heart failure and volume status. The explanation is intuitive given that SGLT-2i reduce renal tubular glucose reabsorption, which then lead to volume reduction via osmotic diuresis and natriuresis. The highlighted findings by Mukhopadhyay et al (4) represent an opportunity for the Food and Drug Administration to reconsider the stratification of cardiovascular mortality analyses in clinical trials, as suggested by the authors, and in future mandates consider separating cardiovascular mortality events associated with ischemic events from those associated with heart failure.

Abbreviations

ASCVD

atherosclerotic cardiovascular disease

MACE

major adverse cardiovascular event

MI

myocardial infarction

SGLT-2i

sodium-glucose cotransporter-2 inhibitor

Funding

This work did not receive funding from any government or commercial entity. D.T.B. acknowledges the following grant support from the National Institutes of Health: U54DK118612-04. D.T.B. is a research investigator for Novo Nordisk, Rhythm Pharmaceuticals, Inc., and Fractyl Health Laboratories, Inc.