Can hepatic steatosis and liver insulin resistance raise cardiovascular risk even with normal HbA1c?

Hepatic steatosis and selective liver insulin resistance are critical drivers of cardiovascular disease. While clinical assessments often rely on HbA1c to screen for metabolic risk, normal blood glucose levels can mask significant underlying vascular and lipid-related pathology.

Clinical and effectiveness evidence

• Elevated Cardiovascular Events: Research in large clinical cohorts indicates that patients with metabolic dysfunction-associated steatotic liver disease (MASLD/NAFLD) face a significantly higher risk of major adverse cardiovascular events (MACE) and cardiovascular mortality.
• Vascular Pathology: Imaging studies show that hepatic steatosis is strongly and independently linked to subclinical atherosclerosis, characterized by elevated coronary artery calcium (CAC) scores, rapid CAC progression, and increased carotid intima-media thickness (cIMT).
• Independence from Glycemia: Longitudinal data demonstrate that this heightened cardiovascular risk persists after controlling for glycemic status, meaning that a normal HbA1c does not mitigate or negate the cardiovascular hazards of hepatic steatosis.

Mechanistic explanations

• Atherogenic Dyslipidemia: Hepatic insulin resistance impairs insulin-mediated apolipoprotein B (ApoB) degradation. Concurrently, hyperinsulinemia drives de novo lipogenesis via the mTORC1-SREBP-1c pathway. This dual defect leads to the overproduction and secretion of large, triglyceride-rich VLDL particles, driving a highly atherogenic triad of hypertriglyceridemia, elevated ApoB, and a predominance of small dense LDL (sdLDL) particles.
• Systemic Inflammation: The accumulation of lipotoxic intermediates within hepatocytes triggers endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and oxidative stress. This activates hepatic inflammatory cascades (such as the NF-κB pathway), promoting the release of pro-inflammatory cytokines and pro-coagulant factors into systemic circulation, which directly destabilizes the vascular endothelium.

Bottom line

• Hepatic steatosis and liver insulin resistance significantly increase cardiovascular risk independently of blood glucose levels. Practitioners and patients should look beyond a normal HbA1c, as subclinical atherosclerosis, atherogenic dyslipidemia (elevated ApoB and sdLDL), and chronic systemic inflammation can actively progress even in euglycemic individuals.