Effectively addressing cardiovascular risk in people with metabolic-dysfunction associated fatty liver disease: not yet ready for prime time!

KEYWORDS:

• MAFLD
• cardiovascular risk
• MACE
• pharmacotherapy

“If you always do what you always did, you will

always get what you always got”

Sir Liam Donaldson

1. Introduction

Metabolic-dysfunction associated fatty liver disease (MAFLD) is an umbrella term used to describe the hepatic manifestation of metabolic syndrome. MAFLD encompasses a wide spectrum of disorders of varying severity, ranging from steatosis to nonalcoholic steatohepatitis (NASH) and its catastrophic advanced stages, such as cirrhosis and hepatocellular carcinoma (HCC) [1]. MAFLD is defined as the presence of hepatic steatosis in addition to one of the following three criteria: overweight/obesity, presence of type 2 diabetes (T2D) or evidence of metabolic dysregulation [2]. It has recently emerged as an alternative to the previously widely used term ‘nonalcoholic fatty liver disease’ (NAFLD), suggested as more appropriate, as it provides a positive definition of a clinical entity with complex pathophysiological background and heterogenous clinical presentation, course, and outcomes. In addition, it has been suggested that the change in name and criteria can contribute to better identification of people at high risk of cardiovascular (CV) and liver complications, but also increase disease awareness among physicians and the general population [3,4].

Today, MAFLD represents a growing threat to modern societies, as it is estimated to affect almost a quarter of the adult population worldwide, being a major driver of economic healthcare costs [5]. From a pathophysiological perspective, MAFLD is closely associated and coexists very often with a cascade of other disorders that negatively impact CV health, including T2D, obesity, chronic kidney disease, sleep apnea, thyroid dysfunction, and polycystic ovary syndrome, among others. Interestingly, a pooled analysis involving more than three million people suggested that the prevalence of MAFLD among lean and non-obese individuals is 5.37% and 29.87%, respectively [6]. Although the association between MAFLD and obesity is definitely strong, a considerable proportion of the affected people are of normal weight, highlighting the need for a high degree of clinical suspicion of the disorder, regardless of body mass index (BMI) [7]. It should be noted that mortality among individuals with MAFLD is significantly higher than expected in the general population, and despite the high risk of adverse liver outcomes, cardiovascular disease (CVD) continues to be the leading cause of death in this group of people, reflecting the high burden of CVD risk factors but probably also their inadequate management [8].

The purpose of this article is to highlight the mechanisms linking MAFLD with CVD, to discuss the bidirectional relationship between the two entities, and to increase physicians’ awareness of an underrated, yet very important, risk factor for the development of CV complications.

2. Mechanisms linking MAFLD with cardiovascular disease

Some of the key pathophysiological mechanisms that associate MAFLD with CVD are increased systemic and adipose tissue inflammation, endothelial dysfunction, atherogenic dyslipidemia, up-regulation of prothrombotic factors, and structural cardiac changes [9]. Insulin resistance, low adiponectin concentrations, and elevated de novo lipogenesis lead to hypertriglyceridemia, increased small dense low-density lipoprotein (LDL) particles, and decreased high-density lipoprotein cholesterol levels, a lipid profile that is correlated with the development of atherosclerosis [10].

Fricker et al. have shown that individuals with hepatic steatosis have high mean serum concentrations of inflammation markers, specifically high-sensitivity C-reactive protein (hs-CRP), urinary isoprostanes, interleukin 6, intercellular adhesion molecule 1 and P-selectin [11]. Interestingly, these associations remained significant after adjustment for BMI and visceral fat, suggesting the existence of inflammation drivers in MAFLD that act independently of adiposity. Hs-CRP, which is a strong predictor of future CV events, is higher in people with NASH compared to those with simple steatosis, while its levels are positively correlated with the degree of fibrosis [12].

VanWagner et al. demonstrated that MAFLD is associated with abnormalities in left ventricular (LV) structure and function, including LV hypertrophy, abnormal LV geometry, impaired LV relaxation, and worse longitudinal strain compared to controls without MAFLD [13]. In a well-designed study that included 65 bariatric surgery patients subjected to perioperative liver biopsy, NASH was correlated with alterations in myocardial structure, suggestive of subclinical heart failure [14]. In a recently published large meta-analysis that included data from more than 7,000,000 participants, MAFLD was independently associated with a higher risk of atrial fibrillation (Odds ratio 1.71, 95% confidence interval 1.14–2.57) [15]. However, the observational nature of the studies included in this systematic review makes it impossible to establish causal associations.

3. Is hepatic steatosis itself an independent cardiovascular risk factor?

Given that approximately 82% of people with MAFLD live with obesity, 44% with T2D, 72% have dyslipidemia, and 68% have hypertension [16], the high burden of CVD in this population is not surprising. However, whether hepatic steatosis independently contributes to CVD development or simply represents another piece of the puzzle of the metabolic syndrome remains a matter of debate.

A meta-analysis of 16 prospective and retrospective observational studies incorporating data from 34,033 individuals (almost a third had MAFLD diagnosed with imaging or histology), showed that people with MAFLD had a 64% higher risk of fatal and/or non-fatal CV events [17]. Although the findings were adjusted for the presence of other common CVD risk factors such as T2D, hypertension, and coronary artery disease (CAD), and the large number of events provides robust statistical power in this meta-analysis, the observational nature of the included trials makes the interpretation of the findings challenging. For example, in a large number of relevant published studies, the adjustment for possible confounders is incomplete, while the lack of adjudication of CVD outcomes is common.

In a sub-study of the PROMISE trial, Meyersohn et al. demonstrated a 69% higher risk of major adverse CV events among subjects with steatosis than among individuals without MAFLD [18]. The association remained significant after adjustment for atherosclerotic CVD risk scores, significant coronary artery stenosis, and metabolic syndrome or obesity. Interestingly, this study showed that MAFLD subjects had higher event rates even when only non-obstructive CAD was present and that liver steatosis was positively associated with plaque extent, as evaluated with coronary computed tomography (CT) angiography. However, in this study, the diagnosis of MAFLD was based on CT imaging, preventing the evaluation of the relationship between different histological stages and CV risk.

An interesting question is whether CV risk increases proportionally to the severity of the underlying hepatic disease. In a retrospective cohort study that included 428 MAFLD patients, magnetic resonance elastography was used to stratify participants into three groups according to liver stiffness: minimal fibrosis, moderate advanced fibrosis, and cirrhosis [19]. CVD risk was shown to increase with moderate advanced fibrosis, but decreased with cirrhosis. In contrast, liver-related adverse outcomes were more frequent in the cirrhosis group, suggesting the need to focus on different risk management strategies to reduce mortality between the various subgroups of the MAFLD population.

4. Expert opinion

Among the various drugs tested in MAFLD, current evidence suggests an important role for the newer categories of glucose lowering agents, namely glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and tirzepatide, in the management of the disorder [20]. Semaglutide therapy has been shown to result in a higher percentage of NASH resolution compared to placebo, however, without a significant effect on the degree of fibrosis [21]. In patients with T2D, tirzepatide, particularly when administered at high doses, improved NASH-related biomarkers and circulating adiponectin concentrations [22]. SGLT2i have been reported to alleviate key pathophysiological disturbances that lead to hepatic steatosis, fibrosis, and carcinogenesis [23]. Pioglitazone, an older drug, is known to improve liver biochemistry and lobular inflammation, however, at the cost of weight gain [24]. The benefits of these drugs are driven not only by their metabolic actions but also by their pleiotropic effects, including their antioxidant and anti-inflammatory properties [25]. It is worth mentioning that several agents targeting different pathogenetic pathways, including oxidative stress, inflammation, and apoptosis, are currently in the drug development pipeline and are being tested in clinical trials.

However, there are still important barriers to overcome before a universal implementation of effective CV risk reduction policies in daily practice. To date, there has been no approved pharmacotherapy for MAFLD, making physicians and patients treat it as a minor lifestyle-associated disorder, often considering it as the simple presence of ‘some fat in the liver’ and not as a clinical entity with potentially severe consequences. Relevant data highlight that 96% of people with MAFLD in the United States were unaware that they had liver disease [26], while only 18 and 30% of primary care physicians and endocrinologists, respectively, use standard diagnostic algorithms, such as the Fibrosis-4 score, to detect NASH in their routine practice [27]. Daily use of aspirin in individuals with MAFLD has been associated with a lower risk of progression to advanced fibrosis, with greater benefits with a longer duration of use (>4 years) [28]. However, bleeding risk should be carefully evaluated, while data on the effects of aspirin specifically on CV outcomes in the MAFLD population are limited.

There is robust evidence that statins can attenuate steatosis, inflammation, fibrosis, and even prevent the development of HCC, while their safety in MAFLD is well established [29]; however, these lifesaving drugs are underused even in very high-risk subjects with MAFLD, such as those with a history of a CV event [30]. 38.1% of people with MAFLD who are on statin therapy receive a clinically significant dose reduction or discontinuation at the time of detection of liver steatosis [31]. These data highlight the need to address misconceptions about the proper management of CVD risk among physicians treating these patients. A recent international multidisciplinary consensus statement on MAFLD and CVD strongly recommends the use of statins in people with MAFLD, even in the presence of modestly elevated serum liver enzyme levels [32]. Furthermore, the presence of MAFLD has not yet been incorporated into most CVD risk assessment tools, as is the case with other traditional CVD risk factors, and the ideal levels of LDL to be targeted remain vague. There is a paucity of well-designed and dedicated studies investigating CV outcomes in individuals with MAFLD, as competing the risk of liver-related death in high-risk patients would markedly increase the number of participants required to achieve adequate statistical power. Finally, liver biopsy surrogates, such as imaging methods, cannot always reflect the severity and progression of the disease.

In conclusion, there is no doubt that MAFLD is strongly associated with CVD and there is an unmet need to effectively address CV risk among people with liver steatosis. Innovative trial design and close collaboration and partnerships between stakeholders are essential factors to improve the care of people with MAFLD and reduce the risk of relevant adverse outcomes [33]. A multimodal approach, which incorporates intensive lifestyle modifications, aggressive treatment of additional risk factors such as hyperlipidemia, diabetes, and hypertension, weight reduction management, and behavioral or pharmacological interventions to prevent tobacco use, is undoubtedly the right and only way to travel.

Declaration of interest

T Koufakis has received honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Pharmaserve Lilly, and Novo Nordisk, for advisory boards from Novo Nordisk and Boehringer Ingelheim, and has participated in sponsored studies by Eli-Lilly and Novo Nordisk.

D S Popovic declares associations to: Abbott, Alkaloid, AstraZeneca, Boehringer-Ingelheim, Berlin-Chemie, Eli Lilly, Galenika, Krka, Merck, Novo Nordisk, PharmaSwiss, Sanofi-Aventis, Servier, Viatris, and Worwag Pharma.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Authors’ contributions

T Koufakis reviewed the literature and wrote the first version of the manuscript. D S Popovic, C Papadopoulos, O Giouleme, and M Doumas reviewed the literature and edited the manuscript. All authors have read and approved the final version of the manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.