The development and clinical application of statins has been one of the most significant advances in health care over the past quarter of a century. Statins have been shown to prevent heart failure (HF), reduce the risk of myocardial infarction and stroke, as well as reduce mortality in patients with and without coronary artery disease, independent of serum cholesterol.1 Their role in patients with established HF is, however, controversial. Although their use in patients with HF is supported by observational studies and meta-analyses,2,3 their use has not been supported by the results of the pivotal large-scale prospective randomized trials in patients with HF and a reduced ejection fraction (HFrEF), GISSI-HF (Gruppo Italiano per la Sperimentazione della Streptochinasi nell'Infarto Miocardico—Heart Failure), and Controlled Rosuvastatin Multinational Trial in HF (CORONA).4,5 There is, however, a suggestion from the CORONA trial and other studies that patients with mild HF as evidenced by a relatively low level of NT-pro BNP may benefit.6 Current guidelines do not therefore recommend the use of a statin in patients with established HF without other indications such as hypercholesterolemia, diabetes, or atherosclerotic cardiovascular disease.7 The trial data suggest that statins can be continued in patients with established HF who are already on treatment.7 Given the relatively large number of patients with hypercholesterolemia, the proven benefit of statins in patients without HF as well as the suggestion that they may be of benefit in patients with mild HF an increasing number of patients with established HF, both those with HFrEF and HF with a preserved ejection fraction are currently being treated with a statin. Thus, it is important to understand whether these patients will benefit or be at increased risk from the use of a statin. The explanation as to why statins have been shown to have a clear beneficial effect in patients with hypercholesterolemia and/or coronary artery disease without established HF, although their use in patients with established HF has not been clearly proven, remains uncertain.

In this issue of the journal, Ahmad et al8 compared the physical performance of 172 patients diagnosed with chronic HF, both HFrEF and HF with a preserved ejection fraction (50 treated with and 122 without a statin) to 59 control patients. They measured handgrip strength, gait speed, and a short physical performance battery as well as plasma biomarkers including the sarcopenia marker C-terminal agrin fragment −22 (CAF22), the intestinal barrier integrity marker zonulin, and C-reactive protein (CRP) and correlated these biomarkers with the markers of physical performance. Not surprisingly, they found that the patients with HF had a reduction in physical performance as compared to their control patients without HF. Of interest was their finding that patients with HF, irrespective of etiology, had a significant elevation in CAF22 and zonulin and that there was a strong inverse correlation between CAF22 and markers of physical performance. They also found that CAF22, zonulin, and CRP were correlated with each other. However, the most important finding was that patients with HF treated with a statin had a significant increase in CAF22, zonulin, and CRP compared with patients with HF not receiving a statin and that the patients with HF on a statin had a worse physical performance than those not on a statin. They suggest that statins may adversely affect physical performance in patients with HF by an effect on the neuromuscular junction and increase intestinal permeability with a resultant increase in systemic inflammation. The finding that statins increase intestinal permeability is supported by some but not all previous studies in animals.9,10Thus, there is reason to consider the clinical implications of these findings but not to apply them clinically yet.

Increasing evidence suggests an important role of intestinal permeability in patients with HF (gut–heart and gut–brain axis).11,12 An increase in intestinal permeability as suggested by the increase in zonulin, a diagnostic marker of intestinal barrier dysfunction, has been associated with an increase in lipoprotein polysaccharide, and trimethylamine-N-oxide as well as a decrease in short-chain fatty acids including butyrate.11,12 An increase in lipoprotein polysaccharide and trimethylamine-N-oxide and a decrease in short-chain fatty acid have been suggested to have important adverse effects in patients with HF including an increase in systemic inflammation; an increase in myocardial and renal fibrosis; an increase in platelet activation and thrombosis; an increase in major depression; and an increase in cognitive dysfunction including Alzheimer's disease.11,12 Although the suggestion from the study by Ahmad et al8 that statins increase intestinal permeability has important clinical implications, it should be pointed out that the study was observational, and the number of patients with HF relatively small (n = 172), the number on a statin even smaller (n = 50), and that patients were not on a sodium glucose transport inhibitor or mineralocorticoid receptor antagonist, both of which can alter the intestinal microbiome and are part of the recommended “4-pillar” therapy of patients with HF. Thus, there is need for further prospective adequately powered, placebo-controlled randomized trials to confirm these findings. It should also be pointed out that there is considerable variation in intestinal dysfunction by ethnicity, gender, age, and diet. Animal and clinical studies have shown that HF is associated with intestinal dysfunction and an increase in intestinal permeability independent of the use of a statin.11,12 Although statins may or may not increase intestinal dysfunction in patients without HF, as suggested by the results of preclinical studies,9,10 the evidence that they have a significant benefit on cardiovascular outcomes in patients without HF1 suggests that the benefits outweigh the risks. However, in patients with HF, especially advanced HF, who have an increase in intestinal dysfunction and inflammation independent of the use of a statin,11,12 it is possible that the risks outweigh the benefits. Thus, the findings from this study by Ahmad et al8 need to be confirmed by a prospective, placebo-controlled trial and, if confirmed, suggest the need for further studies evaluating other means of lowering serum cholesterol that bypass the gut such as PCSK9 inhibitors13 to determine whether or not a similar reduction in serum cholesterol in patients with HF is associated with an increase in intestinal permeability and decrease in physical performance. The use of statins may adversely affect physical performance by other mechanisms such as inducing in skeletal muscle mitochondrial dysfunction.

Statins have been shown to be effective and relatively well tolerated in large numbers of patients and are relatively inexpensive. Before advocating for a change in the use of statins in patients with HF, we will need evidence not only that they affect biomarkers such as CAF22 and zonulin, but that they are associated with the risks implied by the biomarker findings, such as an increase in the risk of HF, thrombosis, and cognitive dysfunction. Statins affect several important beneficial signaling pathways. Future research will be required to determine whether there are differences in lipophilic versus hydrophilic statins on intestinal dysfunction. Thus, it will be important to determine their effect on clinical outcomes, rather than biomarkers before advocating for a change in clinical practice.

1. Cholesterol Treatment Trialists' CTT Collaboration, Fulcher J, O'Connell R, et al. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet. 2015;385:1397–1405. 2. Alehagen U, Benson L, Edner M, et al. Association between use of statins and outcomes in heart failure with reduced ejection fraction: prospective propensity score matched cohort study of 21864 patients in the Swedish Heart Failure Registry. Circ Heart Fail. 2015;8:252–260. 3. Bielecka-Dabrowa A, Bytyçi I, Von Haehling S, et al. Association of statin use and clinical outcomes in heart failure patients: a systematic review and meta-analysis. Lipids Health Dis. 2019;18:188. 4. Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:1231–1239. 5. Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007;357:2248–2261. 6. Cleland JG, McMurray JJ, Kjekshus J, et al. Plasma concentration of amino-terminal pro-brain natriuretic peptide in chronic heart failure: prediction of cardiovascular events and interaction with the effects of rosuvastatin. J Am Coll Cardiol. 2009;54:1850–1859. 7. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidemias: lipid modification to reduce cardiovascular risk: the Task Force for the management of dyslipidemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J. 2019;41:111–188. 8. Ahmad F, Karim A, Khan J, et al. Statin therapy induces gut leakage and neuromuscular disjunction in patients with chronic heart failure. J Cardiovasc Pharmacol. 2023;82:189–195. 9. Kim J, Lee H, An J, et al. Alterations in Gut microbiota by Statin therapy and possible intermediate effects on hyperglycemia and hyperlipidemia. Front Microbiol. 2019;10:1947. 10. Cheng T, Li C, Shen L, et al. The intestinal effect of atorvastatin: Akkermansia muciniphila and barrier function. Front Microbiol. 2021;12:797062. 11. Mamic P, Snyder M, Tang W. Gut Microbiome-Based Management of patients with heart failure. J Am Coll Cardiol. 2023;81:1729–1739. 12. Lupu VV, Trandafir LM, Raileanu AA, et al. The implications of the gut microbiota in heart failure. Nutrients. 2023;15:2499. 13. Rosenson RS, Hegele RA, Fazio S, et al. The evolving future of PCSK9 inhibitors. J Am Coll Cardiol. 2018;72:314–329.