Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors and Lipid Modulation in Heart Failure: A Narrative Review

Area of Science:

• Cardiology
• Metabolic Diseases
• Pharmacology

Background:

• Atherogenic dyslipidemia and lipotoxicity are key drivers of adverse cardiac remodeling in heart failure (HF).
• Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated significant benefits in HF outcomes, but their precise effects on lipid profiles are not fully understood.

Purpose of the Study:

• To review and synthesize quantitative and qualitative changes in lipid parameters associated with SGLT2i use in HF patients.
• To explore the potential mechanisms by which SGLT2i influence lipoprotein metabolism in the context of HF.

Main Methods:

• Systematic review of clinical trials and HF-specific cohorts examining lipid profiles in patients treated with SGLT2i.
• Analysis of emerging data on qualitative lipoprotein remodeling, including LDL particle size and HDL subclasses.
• Exploration of proposed mechanistic pathways involving adipose tissue lipolysis, hepatic metabolism, and ketone body utilization.

Main Results:

• SGLT2i are associated with minor increases in LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C), and slight decreases in triglycerides.
• Emerging evidence suggests SGLT2i may promote a shift towards less atherogenic LDL phenotypes (e.g., decreased small-dense LDL) and increased HDL2 levels.
• Proposed mechanisms include enhanced lipolysis, increased hepatic beta-oxidation and ketogenesis, potentially providing a "thrifty substrate" for the myocardium.

Conclusions:

• SGLT2i induce modest quantitative lipid alterations but may confer significant qualitative lipoprotein remodeling in HF, contributing to improved metabolic flexibility and HF outcomes.
• These lipid effects appear independent of diabetes status and suggest benefits beyond traditional lipid-lowering.
• Further HF-specific trials are needed to definitively assess ApoB, sd-LDL, LDL-P, HDL function, and lipidomics to fully elucidate SGLT2i's role in HF lipid management.