For a study, it was determined that people with non-alcoholic steatohepatitis or high liver enzymes had a higher risk of cardiovascular disease, although they were frequently excluded from preventative research. The impact of fixed-dose combination therapy for preventing major cardiovascular events (MCVE) in people with and without presumed non-alcoholic steatohepatitis (pNASH) was studied. A total of 2,400 people over the age of 50 were randomly assigned to one of 2 groups: intervention or control. Consent was sought after the randomization process. In the intervention group, consenting participants were given a tablet comprising aspirin, atorvastatin, hydrochlorothiazide, and valsartan (polypill). The participants were tracked for 5 years. Ultrasonography and increased liver enzymes were used to detect presumed non-alcoholic steatohepatitis. MCVE was the major result. During the 5-year follow-up, 138 of 1,249 in the intervention group (11.0%) and 137 of 1,017 controls (13.5%) in the initial randomised sample had MCVE [unadjusted risk ratio (RR) 0.83, 95% CI 0.66–1.03]. MCVE was found in 63 of 787 (8.0%) intervention group participants and 86 of 721 (11.9%) controls (adjusted RR 0.61, 95% CI 0.44–0.83) of the 1,508 participants who agreed to additional assessments and therapy. Although the adjusted relative risk of MCVE in people with pNASH was lower (0.35, 95% CI 0.17–0.74) than in people without pNASH (0.73, 95% CI 0.49–1.00), the difference was not statistically significant. After 60 months of follow-up, participants taking polypill had no change in liver enzymes, while those with pNASH had a substantial drop (intragroup −12.0 IU/L, 95% CI −14.2 to −9.6). Polypill was secure and effective for preventing MCVE in patients who agreed to receive fixed-dose combination medication, even in the ones with fatty liver and elevated liver enzymes.