Clinical Context
Heart failure affects approximately 6.7 million adults in the United States, with type 2 diabetes present in 30-40% of these patients. The coexistence of these conditions creates a particularly challenging clinical scenario, as diabetes accelerates heart failure progression through multiple mechanisms including myocardial glucose toxicity, microvascular dysfunction, and accelerated atherosclerosis. Historically, clinicians faced limited options for addressing both conditions simultaneously, with some diabetes medications even worsening heart failure outcomes.
The emergence of SGLT2 inhibitors has fundamentally changed this landscape. Empagliflozin, initially approved for glycemic control, demonstrated unexpected cardiovascular benefits in the EMPA-REG OUTCOME trial, leading to its expanded indication for heart failure. This study adds important biomarker evidence to our understanding of how empagliflozin exerts its cardioprotective effects.
Study Summary (PICO Framework)
Summary:
In adult patients with type 2 diabetes and heart failure (left ventricular ejection fraction ≤45% or >45%), empagliflozin 25 mg daily for 48 weeks significantly improved plasma biomarker profiles associated with cardiovascular and renal outcomes compared to placebo, though it was associated with side effects consistent with sodium-glucose co-transporter 2 inhibitors class, such as increased risk of genital infections.
| PICO | Description |
|---|---|
| Population | Adults with type 2 diabetes and heart failure, stratified by left ventricular ejection fraction ≤45% (HFrEF) or >45% (HFpEF). |
| Intervention | Empagliflozin 25 mg once daily administered for 48 weeks. |
| Comparison | Placebo administered for 48 weeks. |
| Outcome | Empagliflozin demonstrated significant improvements in plasma biomarkers linked to cardiovascular mortality, heart failure hospitalization, and renal function compared to placebo. |
Clinical Pearls
1. Biomarker improvements suggest multiple mechanisms of benefit. The study demonstrated reductions in NT-proBNP (a marker of cardiac wall stress), along with improvements in markers of inflammation and renal function. This supports the hypothesis that SGLT2 inhibitors work through hemodynamic unloading, metabolic optimization, and anti-inflammatory pathways rather than a single mechanism.
2. Benefits observed across the ejection fraction spectrum. Notably, biomarker improvements were seen in both HFrEF (EF ≤45%) and HFpEF (EF >45%) populations. This is clinically significant because treatment options for HFpEF have historically been limited, and these findings align with the EMPEROR-Preserved trial results.
3. The 25 mg dose was used throughout. Unlike some trials that used 10 mg, this study employed the higher 25 mg dose. Current guidelines generally recommend starting at 10 mg for heart failure indications, though both doses have demonstrated efficacy.
4. Genital infections remain the primary safety concern. As with all SGLT2 inhibitors, patients should be counseled about maintaining good perineal hygiene and recognizing early symptoms of mycotic infections. This side effect is more common in women and those with prior history of such infections.
Practical Application
When considering empagliflozin for patients with type 2 diabetes and heart failure, clinicians should take the following approach:
Patient selection: Ideal candidates include patients with established heart failure (any ejection fraction) and type 2 diabetes, particularly those with eGFR ≥20 mL/min/1.73m². The drug provides dual benefit for both conditions.
Initiation: Begin at 10 mg daily. Ensure patients understand the glycosuric mechanism and the importance of hydration. Hold the medication during acute illness or procedures where dehydration risk is elevated.
Monitoring: Check renal function and potassium within 1-2 weeks of initiation. A modest initial decline in eGFR (up to 10-15%) is expected and typically stabilizes. This hemodynamic effect is not nephrotoxic and should not prompt discontinuation.
Patient counseling points: Warn patients about the risk of genital yeast infections, symptoms of ketoacidosis (even with normal glucose), and the importance of sick-day rules. Advise women to wipe front-to-back and maintain good hygiene.
How This Study Fits Into the Broader Evidence
This biomarker study complements the major outcomes trials that have established SGLT2 inhibitors as foundational therapy for heart failure with diabetes:
The EMPA-REG OUTCOME trial first demonstrated a 35% reduction in heart failure hospitalizations with empagliflozin. Subsequently, EMPEROR-Reduced and EMPEROR-Preserved showed benefits across the ejection fraction spectrum. The DAPA-HF and DELIVER trials with dapagliflozin demonstrated class-wide benefits.
Current guidelines from the AHA/ACC/HFSA (2022) and ESC (2023) recommend SGLT2 inhibitors as first-line therapy for heart failure, regardless of diabetes status. For patients with both conditions, these agents represent a rare opportunity to address two major comorbidities with a single, well-tolerated medication.
Limitations to Consider
While this study provides valuable mechanistic insights, clinicians should note that biomarker changes are surrogate endpoints. The clinical significance of these changes is inferred from their association with outcomes in other studies rather than demonstrated directly. Additionally, the 48-week duration, while substantial, may not capture very long-term effects.
Bottom Line
This study reinforces empagliflozin’s role as a cornerstone therapy for patients with type 2 diabetes and heart failure. The biomarker improvements observed across both reduced and preserved ejection fraction populations provide mechanistic support for its clinical benefits and align with current guideline recommendations for SGLT2 inhibitor use in this population.
Source: Elrakaybi, Asmaa, et al. “Effects of Empagliflozin in Heart Failure Patients with Type 2 Diabetes: A Biomarker Perspective.” Read article here.
