The heterogeneity of metabolic syndrome presentation and challenges this causes in its pharmacological management: a narrative review focusing on principal risk modifiers

ABSTRACT

Introduction

Metabolic syndrome (MetS), i.e. the cluster of cardiometabolic risk factors comprising visceral obesity, impaired glucose metabolism, arterial hypertension and atherogenic dyslipidemia, is prevalent globally and exacts a heavy toll on health care expenditures.

Areas covered

The pathophenotypes of individual traits of the MetS in adults are discussed first, with strong emphasis on nonalcoholic fatty liver disease (NAFLD) and sex differences. Next, I discuss recent studies on phenotypic and outcome heterogeneity of the MetS, highlighting the role of NAFLD, sex, reproductive status, and depressive disorders. In the second half of the article, the therapeutic implications of the variable MetS types and features are analyzed, focusing on the most recent developments, and guidelines.

Expert opinion

I have identified physiological, pathological, social and medical sources of phenotypical heterogeneity in the MetS and its constitutive traits. Improved understanding of these variables may be utilized in the setting of future precision medicine approaches in the field of metabolic disorders and target organ damage.

KEYWORDS:

• Cancer
• cardiovascular risk
• depressive disorders
• management
• MASLD
• menopause
• NAFLD
• sex differences

Article highlights

• Heterogeneity of metabolic syndrome presentation

• The pooled prevalence of the metabolic syndrome (MetS) in adults ranges from 17.1% to 41.0% according to the diagnostic criteria adopted, sex, age, ethnicity, lifestyle habits, and education achievement. Sources of heterogeneity in MetS and its individual traits comprise physiological, pathological, social, and medical determinants.

• The MetS has sexually dimorphic features with HTN being the most prominent feature among men, and low HDL-C among women. Moreover, it is influenced by female reproductive status, early menarche, and polycystic ovary syndrome (PCOS), which is a risk factor for fibrosing nonalcoholic steatohepatitis (NASH) and MetS.

• Data-driven cluster analysis supports a novel classification of adult-onset diabetes which promises identification of patients at high risk of complications that may inform management options.

• The two acknowledged obesity patophenotypes, metabolically healthy (MHO) and metabolically unhealthy obesity (MUO) differ owing to metabolomic signature; metaflammation, adipositis, intestinal dysbiosis, endotoxemia, dysregulated tone of the endocannabinoid system, increased activation of the NLPR3 inflammasome, lipotoxicity, age, and sex.

• Adding nonalcoholic fatty liver disease (NAFLD) to the definition of MetS would better identify oxidative stress, endothelial dysfunction, and individuals exposed to cardiometabolic risk. Based on 2-stage cluster analysis, NAFLD has been categorized into three different phenotypes with variable disease outcomes.

• Early onset MetS identifies individuals with higher cardiovascular and cancer risk and therefore necessitating more intensive medical approaches. NAFLD is a strong risk factor for youth-onset incident hypertension, particularly among women, and incident chronic kidney disease (CKD).

• Challenges this causes in its pharmacological management.

• First-line treatment of diabetes varies according to patient features, with empagliflozin, canagliflozin, or dapagliflozin. Liraglutide, semaglutide, or dulaglutide being the preferred options among those at high cardiovascular risk; while sodium glucose co-transporter 2 inhibitors.

• (SGLT2i) and glucagone-like peptide 1-receptor agonists (GLP1-RAs) are indicated in CKD.

• Two different sex-specific hypertension subsets, a ‘cardiac phenotype’ in men, and a ‘vascular phenotype,’ dominant among women, should be treated differently, e.g. peripheral vasodilators as opposed to either diuretics or β1 antagonists. High blood pressure affects disease outcomes differently among patients with and without heart failure.

• Tirzepatide, a dual glucose-dependent insulinotropic-peptide (GIP) and GLP-1 RA, exerts significant weight loss effects. GLP1-RA and SGLT2i are associated with variable weight loss ranging, whereas insulin and insulin secretagogues are associated with weight gain.

• The recent approval of a novel lipid-lowering agent, Bempedoic Acid is a substantial advancement for handling statin intolerance.

• SGLT2i and thiazolidinediones improve liver enzymes, steatosis, and fibrosis. However, SGLT2i induce a significant decrease in visceral fat and body weight, which are major determinants of steato-fibrosis in NAFLD.

• Socioeconomic status, MetS and depression are strongly associated. Genetically predicted depression is positively associated with the risk of MetS mediated by inflammation, MUO, sedentary lifestyle, unhealthy eating habits and by some antidepressant drugs.

Declaration of interest

The author has no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.