Non-alcoholic fatty liver disease is a risk factor for cardiovascular and cardiac diseases: further evidence that a holistic approach to treatment is needed

Many,1 but not all,2 previous studies investigating the association between non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD) have shown that NAFLD is a risk factor for CVD morbidity and mortality. The debate over the last 5 years as to whether NAFLD is an independent CVD risk factor has focused on the suggestion that the association between NAFLD and increased CVD risk occurs because of residual confounding by metabolic syndrome-associated cardiovascular risk factors. With the burgeoning 21st problem of obesity, NAFLD has become a common disease that is often present but remains often undiagnosed in the adult population. Thus, in large registry studies investigating associations between NAFLD and outcomes such as CVD,2 it is not possible to prove that subjects in the control (reference) group do not have NAFLD. When undiagnosed NAFLD occurs in subjects in the reference group, this causes misclassification bias, and misclassification bias always attenuates the strength of any association between the exposure variable (ie, NAFLD) and the outcome (CVD), towards the null. Moreover, among the few published NAFLD histology cohorts, to date, that have investigated the association between NAFLD and risk of incident CVD, all have been limited by small sample sizes (previous largest study, n=603) with few recorded outcomes and imprecise estimates of risk across NAFLD histological categories. Thus, in previous cohort studies where histological data were available to gauge liver disease severity, studies were too small with too few CVD events to gauge the strength of any association between the different stages of liver disease severity and CVD events.3 In GUT, Simon et al present important data from a nationwide cohort of Swedish adults with histologically confirmed NAFLD and without pre-existing CVD at baseline (1966–2016; n=10 422).4 In this well-conducted cohort study, the authors investigated the incidence of major adverse cardiovascular events (MACEs) (defined as non-fatal ischaemic heart disease, stroke, congestive heart failure or CVD mortality), according to the presence and histological severity of NAFLD. NAFLD was defined from prospectively recorded histopathology, and categorised as simple steatosis (68.5% of the cohort), non-fibrotic steatohepatitis (NASH, 11.4%), non-cirrhotic fibrosis (14.9%) and cirrhosis (5.2%), respectively. Patients with NAFLD (n=10 422) were matched to ≤5 population controls without NAFLD or CVD, by age, sex, calendar year and country (n=46 517). Over a median of 13.6 years of follow-up, incident MACE was confirmed in 2850 patients with NAFLD (27.3%) and in 10 648 matched controls (22.9%). After adjustment for common cardiometabolic risk factors and potential confounders, NAFLD was significantly associated with a nearly 65% increased risk of incident MACE. Furthermore, risk of incident MACE increased monotonically with worsening NAFLD severity (Ptrend=0.02). Specifically, compared with matched controls, the absolute rate differences and corresponding fully-adjusted HR (aHR) were significantly increased in patients with both simple steatosis (7.0/1000 person year (PY); aHR=1.58, 95% CI 1.50 to 1.67) and NASH without fibrosis (8.1/1000PY; aHR=1.52, 95% CI 1.32 to 1.75), and they were further amplified in patients with non-cirrhotic fibrosis (11.1/1000PY; aHR=1.67, 95% CI 1.47 to 1.89) or in those with cirrhosis (27.2/1000PY; aHR=2.15, 95% CI 1.77 to 2.61). Interestingly, and worthy of further study, in stratified analyses, the significant association between NAFLD and incident MACE outcomes appeared stronger among women compared with men, among patients diagnosed with NAFLD at younger ages, and also among those with a positive family history of premature CVD. To address the issue of whether it is plausible that any association between NAFLD and risk of MACE outcomes could have occurred because of confounding, Simon et al comment that this is highly unlikely in their study; specifically because, ‘a confounder would need to have both an aHR ≥3.5 for incident MACE and simultaneously have a≥60% difference in prevalence between patients with NAFLD and controls, to fully attenuate the results’. Additionally, to address potential residual confounding related to shared genetic and intra-familial factors, including a family history of premature CVD, the authors rematched 4763 patients with NAFLD to 9128 full-sibling comparators, who were alive at the index date and without a recorded diagnosis of NAFLD or CVD. Consistent with their primary analyses, rates of incident MACE outcomes were significantly increased across all NAFLD histological categories, with the highest rates found in patients with cirrhosis. Thus, Simon et al show convincingly that NAFLD is associated with significant excess risk of individual MACE outcomes, including nonfatal ischaemic heart disease, stroke, congestive heart failure or CVD mortality. Although this work confirms the results of a previous meta-analysis showing that imaging-defined or biopsy-proven NAFLD was independently associated with a nearly 65% increased risk of fatal and nonfatal CVD events,1 Simon et al also provide substantive evidence that NAFLD may be a risk factor for congestive heart failure; an association with NAFLD that was recently discussed in a review on the subject.5 The authors also provide further evidence that increased liver disease severity in NAFLD is an independent risk factor for cardiovascular and cardiac diseases. During the last decade, evidence has accumulated to show that NAFLD is a ‘multisystem’ disease6 that not only increases risk of liver-related complications, but also increases risk of developing type 2 diabetes mellitus (T2DM),7 chronic kidney disease,8 and certain extrahepatic cancers.9 Overall, therefore, these data provide important evidence supporting a holistic approach to the treatment of NAFLD,10 where not only is the management and treatment of liver disease considered, but also the increased risk of CVD and other extrahepatic complications. Although there are presently no licensed treatments for liver disease in NAFLD, it is important to bear in mind that NAFLD occurs very frequently with T2DM; and where T2DM is present, clinicians should be aware that both pioglitazone and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are licensed treatments for T2DM that also have proven cardiovascular benefits in people with T2DM. Since GLP-1RAs (mostly subcutaneous liraglutide and semaglutide) and also pioglitazone have also been shown to be of benefit for liver disease in patients with NASH, we reason that healthcare professionals should have a low threshold for prescribing these medications (assuming there are no clinical contraindications) in patients with NAFLD who also have T2DM, in order to potentially decrease their risk of CVD.5