Empagliflozin Enhances Cardiovascular Protection in HFrEF Patients with Low Serum Magnesium: Evidence from EMPEROR-Reduced

Introduction: The Silent Role of Magnesium in Heart Failure

Magnesium is the second most abundant intracellular cation and serves as a critical cofactor for over 300 enzymatic reactions, including those involved in ATP metabolism, DNA synthesis, and transmembrane ion transport. In the context of clinical cardiology, magnesium is indispensable for maintaining cardiac electrical stability and contractility. Despite its importance, magnesium derangements are frequently overlooked in patients with heart failure with reduced ejection fraction (HFrEF). These patients are particularly susceptible to hypomagnesemia due to the chronic use of loop diuretics, activation of the renin-angiotensin-aldosterone system (RAAS), and comorbid conditions like diabetes mellitus.

The emergence of sodium-glucose cotransporter 2 (SGLT2) inhibitors has revolutionized the management of HFrEF. While their benefits on heart failure hospitalizations and renal preservation are well-documented, their impact on mineral homeostasis—specifically magnesium—has remained less clear. A new analysis of the EMPEROR-Reduced trial provides critical insights into how serum magnesium levels influence patient outcomes and how empagliflozin may act as a stabilizer of this vital electrolyte.

Highlights of the EMPEROR-Reduced Magnesium Sub-analysis

• Empagliflozin significantly increased serum magnesium levels by an average of 0.05 mmol/L shortly after treatment initiation.
• The clinical benefit of empagliflozin on the primary composite endpoint (CV death or heart failure hospitalization) was significantly more pronounced in patients with the lowest baseline magnesium levels.
• Low serum magnesium was identified as a modest predictor of poor heart failure and kidney outcomes, though this association was partially confounded by other clinical factors.
• Empagliflozin reduced the relative odds of experiencing hypomagnesemia during the follow-up period.

Study Design and Methodology

The EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction) was a phase 3, double-blind, randomized controlled trial. The study enrolled 3,730 patients with NYHA class II–IV heart failure and an ejection fraction of 40% or less. Participants were randomized to receive either 10 mg of empagliflozin daily or a placebo, in addition to standard of care.

For this specific sub-analysis, researchers evaluated serum magnesium levels at baseline and at multiple follow-up intervals (weeks 4, 12, 32, 52, and every 24 weeks thereafter). The median follow-up was 16 months. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure. Secondary outcomes included total heart failure hospitalizations and the rate of decline in estimated glomerular filtration rate (eGFR).

Baseline Characteristics: The Magnesium Gradient

At baseline, the mean serum magnesium level across the cohort was 0.83 ± 0.11 mmol/L. To analyze the data, patients were divided into quintiles (Q1 to Q5). The study revealed distinct clinical profiles based on magnesium status:

Lower Magnesium (Q1: Mean 0.68 mmol/L)

Patients in the lowest quintile were more likely to have diabetes mellitus. This is consistent with the known pathophysiology of glycosuria-induced magnesium wasting in the renal tubules.

Higher Magnesium (Q5: Mean 0.97 mmol/L)

Conversely, patients with higher magnesium levels tended to be older and had lower eGFR. This suggests that as renal function declines, the kidney’s ability to excrete magnesium is impaired, leading to higher systemic levels.

Key Findings: Outcomes and Interactions

The study yielded several high-impact findings regarding the prognostic value of magnesium and the therapeutic response to empagliflozin.

1. Prognostic Significance of Magnesium

Lower magnesium levels were modestly associated with an increased risk of heart failure hospitalizations and adverse kidney events. However, when the researchers performed a full covariate adjustment (accounting for age, diabetes, and renal function), these associations were attenuated. This suggests that while low magnesium is a marker of higher risk, it may be partially reflective of the underlying disease severity rather than an independent driver of all outcomes.

2. Enhanced Benefit of Empagliflozin in Low-Magnesium Patients

Perhaps the most striking finding was the interaction between baseline magnesium and the efficacy of empagliflozin. The reduction in the primary composite outcome was most significant in patients with the lowest magnesium levels:

• Q1 (Lowest Mg): Hazard Ratio (HR) 0.54 (95% CI: 0.41-0.71)
• Q2: HR 0.69 (95% CI: 0.50-0.96)
• Q3: HR 0.82 (95% CI: 0.58-1.15)
• Q4: HR 0.99 (95% CI: 0.72-1.37)
• Q5 (Highest Mg): HR 0.87 (95% CI: 0.65-1.17)

The P-interaction was 0.043, indicating that the drug’s protective effect on cardiovascular death and heart failure hospitalization was significantly modified by the patient’s magnesium status at the start of treatment.

3. Correction of Hypomagnesemia

Empagliflozin led to a rapid and sustained increase in serum magnesium levels, averaging an increase of 0.05 mmol/L compared to placebo. Furthermore, the odds of patients experiencing new-onset low magnesium levels during the trial were significantly reduced in the empagliflozin group.

Expert Commentary and Mechanistic Insights

The mechanism by which SGLT2 inhibitors increase serum magnesium is of significant interest to the scientific community. Unlike many diuretics that cause electrolyte wasting, SGLT2 inhibitors appear to have a magnesium-sparing effect. Several hypotheses exist:

Renal Handling and TRPM6/7

SGLT2 inhibition may influence the electrochemical gradient in the proximal tubule or affect the expression of magnesium transporters like TRPM6 and TRPM7 in the distal convoluted tubule. By altering sodium and glucose reabsorption, these drugs may indirectly promote the reabsorption of magnesium.

Potential for Arrhythmia Reduction

Hypomagnesemia is a known trigger for ventricular arrhythmias and sudden cardiac death. The fact that empagliflozin provides the greatest benefit to those with the lowest magnesium suggests that part of its cardioprotective effect may be mediated through the stabilization of cardiac electrophysiology. This aligns with other studies suggesting that SGLT2 inhibitors reduce the risk of atrial fibrillation and sudden death.

Clinical Implications and Conclusion

The EMPEROR-Reduced findings suggest that serum magnesium is not only a prognostic marker but also a predictor of therapeutic response to SGLT2 inhibitors. For clinicians, this emphasizes the importance of monitoring electrolytes in HFrEF patients. In patients presenting with low magnesium—often those with comorbid diabetes—the initiation of empagliflozin may offer a dual benefit: improving heart failure outcomes and correcting a potentially dangerous electrolyte deficiency.

While the study has limitations, including the observational nature of the sub-analysis and the modest association with outcomes after adjustment, the data strongly support the role of empagliflozin as an essential component of the “four pillars” of HFrEF therapy, regardless of baseline electrolyte status, but especially in those at higher risk due to hypomagnesemia.

Funding and Clinical Trial Registration

The EMPEROR-Reduced trial was funded by Boehringer Ingelheim and Eli Lilly and Company. ClinicalTrials.gov Identifier: NCT03057977.

References

1. Ferreira JP, Anker SD, Butler J, et al. Serum Magnesium and the Effect of Empagliflozin in Heart Failure With Reduced Ejection Fraction: Findings From EMPEROR-Reduced. JACC Heart Fail. 2025;10.1016/j.jchf.2025.102751.
2. Packer M, Anker SD, Butler J, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020;383(15):1413-1424.
3. Tang WH, Kitai T. Magnesium and Heart Failure: A Forgotten Connection? JACC Heart Fail. 2016;4(8):667-669.