Commentary by Dr. Marco Alings, MD PhD, Amphia Ziekenhuis, Breda; WCN, Utrecht; Scientific Officer at Julius Clinical

There is a strong association between age, obesity, liver fibrosis and cardiovascular (CV) disease, particularly in the context of MAFLD.

Both obesity and age are associated with CV disease and chronic liver conditions.

Liver fibrosis is a significant predictor of cardiovascular outcomes. It is linked to increased liver stiffness, which correlates with various cardiovascular conditions such as heart failure, atrial fibrillation, and coronary artery disease. Liver fibrosis not only exacerbates cardiovascular risk factors like obesity, diabetes, and hypertension but also serves as a strong independent predictor of cardiovascular events, irrespective of traditional risk factors.

Although the impact of BMI and liver fibrosis on CV complications are well known, their role on CV risks in elderly patients is less well known.

Theel et al. describe the risk of cardiovascular disease in elderly subjects with obesity and liver fibrosis, and the potential benefit of statin treatment (Eur J Clin Invest. 2024;00:e14368).

The authors used the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial to analyse the association between CV outcomes across different BMI and FIB-4 categories.

The Fibrosis-4 index (Fib-4) is an easy tool to identify at high risk for advanced liver cirrhosis.

Statins are known to lower CV risks, and they may also reduce inflammation and the development of liver fibrosis.

PROSPER evaluated the effect of 40 mg pravastatin treatment in 5804 individuals (aged 70–82) at risk of CV disease in Scotland, Ireland and the Netherlands. Subjects were categorized by BMI: lean (<25 kg/m2), overweight (25–29.9 kg/m2) and obese (≥30 kg/m2), and by FIB-4 index: low risk (<2.0), intermediate risk (2.0–2.66) and high risk (≥2.67). Using hazard ratios of the cohort lean/low with lean BMI and low Fib-4 as reference (HR 1.0), comparisons were made between the 9 BMI/Fib-4 combinations: from [lean-low] to [obese-high] and adjusted for gender, alcohol use, LDL cholesterol, and antihypertensive and antidiabetic drugs.

The combined primary endpoint, which consisted of death from coronary heart disease, non-fatal myocardial infarction (MI) and fatal and non-fatal stroke, was not significantly different across each of the BMI and Fib-4 groups, nor across the nine BMI/Fib-4 combinations.

Participants with obesity were mostly female (61.9%), and they had more often diabetes and hypertension. Overall, the FIB-4 was negatively associated with BMI.

When stratified for the use of placebo or pravastatin, the [placebo]obese/high cohort had a significantly higher hazard ratio for (non-) fatal stroke when compared to the [placebo]lean/low cohort (HR 2.74; 95% CI 1.19–6.29). This difference was not observed when comparing [pravastatin]obese/high versus [pravastatin]lean/low (HR .93; 95% CI .22–3.91).

All-cause mortality was significantly higher in [placebo]lean/high subjects (HR 1.88; 95% CI 1.14–3.11), but not in [pravastatin]lean/high (HR .58; 95% CI .28–1.20).

Pravastatin did not affect other cardiovascular endpoints.

The authors conclude that elderly individuals with obesity and liver fibrosis (obese-high) are at higher risk for (non-)fatal stroke, which is mitigated with pravastatin.

There are several notable findings in this substudy. First, contrary to my expectations, FIB-4 was negatively associated with BMI. Obesity is known to influence the development and progression of liver fibrosis. While the FIB-4 score is effective in excluding advanced fibrosis in obese individuals,studies indicate that FIB-4 may fail to reliably predict advanced fibrosis in individuals at BMI extremes. (Eren at al., Eur J Gastroenterol Hepatol. 2022 Jan 1;34(1):98-103). As pointed out by the authors, survivorship bias may further explain this finding, underscoring the importance of prospective longterm studies in patients with obesity.

Second, MACE did not significantly differ across each of the BMI and Fib-4 groups, nor across the nine BMI/Fib-4 combinations. Although BMI is an independent predictor of MACE, the relation between BMI and CV outcome is sometimes complex. Known as the “obesity paradox”, in some populations higher BMI may be associated with better, and lower BMI (<18.5) with higher CV risk (Lamelas et al., Am J Cardiol. 2017;120(9):1453-1459), whereas in other populations BMI ≥30 was associated with an increased risk for MI (Mathew et al., Am J Med. 2024;137(2):163-171).

Third, pravastatin mitigated the risk of (non-)fatal stroke in the elderly obese patients with high Fib-4 score. The authors are to be commended to address the association of age, obesity and liver fibrosis on cardiovascular outcome and the investigate the protective effect of a statin in respective subgroups. Whether more potent statins or other LDL-lowering strategies, such as PCSK9 inhibitors, achieve a greater reduction across a broader range of BMI/FIB-4 subgroups remains to be proven.

While the Fib-4 score is recognized for its predictive value, unfortunately its integration into clinical guidelines and clinical practice for cardiovascular risk assessment lags behind. This PROSPER substudy highlights the need for further prospective studies that address hepatic and cardiovascular health in at-risk populations.

 

Original article: 

Theel, W. B., de Jong, V. D., Castro Cabezas, M., Grobbee, D. E., Jukema, J. W., & Trompet, S. (2023). Risk of Cardiovascular disease in elderly subjects with obesity and liver fibrosis and the potential benefit of statin treatment. Wiley