R3i Editorials

April 2021
Metabolic syndrome and COVID-19
Prof. Jean-Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco

Since report of the first cases of SARS-CoV-2 infection associated with the severe respiratory disease COVID-19 in Wuhan, China, the world has been enduring uniquely uncertain times. The rapid emergence of this pandemic has driven intensive investigation of major risk factors, management strategies, and innovative therapeutics for severe COVID-19. 

A key focus of studies has been the risk posed by metabolic factors, supported by evidence that individuals who are obese and/or have diabetes are at greater risk of adverse outcome associated with COVID-19 1,2. Both obesity and diabetes confer an increased risk of COVID-19-related mortality 3,4, which is further accentuated by age 4,5. As underlying metabolic dysfunction – typified by the metabolic syndrome – is common among obese and/or diabetes patients, identifying which of these factors are linked with adverse outcome is a priority.

Dyslipidemia has attracted attention, given evidence that decreases in total cholesterol, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), together with variable effects on triglycerides, have been reported in patients with severe COVID 19 6,7. To investigate this further, Hilser and colleagues studied whether pre-infection levels of HDL-C and triglycerides play a causal role in influencing COVID-19 outcomes, using data from the UK Biobank 8. As discussed in this month’s Focus article, higher preinfection HDL-C levels seemed to have a protective effect on risk for severe infection, with a 10 mg/dL increase in HDL-C levels (from the median) associated with ~10% reduced risk of SARS-CoV-2 infection. The mortality risk from COVID-19 was also higher with lower pre-infection HDL-C levels. There was, however, no association between pre-infection triglyceride levels and risk for severe COVID-19 8, in contrast with other reports 9.

Is the protective effect of higher HDL-C concentration causal? Using a Mendelian randomization design, Hisler and colleagues failed to demonstrate any association between genetically higher HDL C levels and risk of SARS-CoV-2 infection 8. However, there is strong support from other studies involving much larger samples showing a causal relationship between HDL-C and infection (10,11). Indeed, these findings align with current knowledge of the immuno-inflammatory functionality of HDL 12, and its role in modulating innate and adaptive immunity to increase resistance to viral infection and antiviral effects, including against SARS-CoV-2 (12-14).

Whether triglycerides are linked with risk for severe COVID-19 merits further study.

As this pandemic progresses, it has become evident that features of the metabolic syndrome, including obesity and dysglycemia, predispose to an increased risk of severe COVID-19 complications. The pandemics of obesity and diabetes are therefore drivers of adverse COVID-19 outcome, with devastating consequences for individuals, healthcare systems and societies. Given what is already known about ethnicity, economic deprivation and susceptibility to cardiometabolic disease, it is not surprising that the risk from SARS-CoV-2 infection and severe COVID-19 is higher among ethnic minority and lower socioeconomic groups. With this ‘perfect storm’ magnified by the public health crisis brought on by COVID-19, urgent action to address existing disparities in type 2 diabetes, obesity and metabolic syndrome prevalence and outcomes is a priority.

References

  1. Apicella M, Campopiano MC, Mantuano M, et al. COVID-19 in people with diabetes: understanding the reasons for worse outcomes. Lancet Diabetes Endocrinol 2020;8:782–92.
    2. Centers for Disease Control and Prevention. COVID-19: People with Certain Medical Conditions https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html. (19 March, 2021)
    3. Tartof SY, Qian L, Hong V, et al. Obesity and mortality among patients diagnosed with COVID-19: results from an integrated health care organization. Ann Intern Med 2020;173:773–81.
    4. Barron E, Bakhai C, Kar P, et al. Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study. Lancet Diabetes Endocrinol 2020;8:813–22.
    5. Holman N, Knighton P, Kar P, et al. Risk factors for COVID-19-related mortality in people with type 1 and type 2 diabetes in England: a population-based cohort study. Lancet Diabetes Endocrinol 2020;8:823–833.
    6. Tanaka S, De Tymowski C, Assadi M, et al. Lipoprotein concentrations over time in the intensive care unit COVID-19 patients: Results from the ApoCOVID study. PLoS One 2020;15:e0239573.
    7. Wei X, Zeng W, Su J, et al. Hypolipidemia is associated with the severity of COVID-19 2020. J Clin Lipidol 14: 297-304.
    8. Hilser JR, Han Y, Biswas S et al. Association of serum HDL cholesterol and apolipoprotein A1 levels with risk of severe SARS-CoV-2 infection. J Lipid Res 2021; doi: 10.1016/j.jlr.2021.100061.
    9. Zhang Y, Yang H, Li S, et al. Association analysis framework of genetic and exposure risks for COVID-19 in middle-aged and elderly adults. Mech Ageing Dev 2021;194: 111433.
    10. Madsen CM, Varbo A, Tybjaerg-Hansen A, et al. U-shaped relationship of HDL and risk of infectious disease: two prospective population-based cohort studies. Eur Heart J 2018;9:1181-90.
    11. Trinder M, Walley KR, Boyd JH, Brunham LR. Causal inference for genetically determined levels of high-density lipoprotein cholesterol and risk of infectious disease. Arterioscler Thromb Vasc Biol 2020;40: 267-78.
    12. Catapano AL, Pirillo A, Bonacina F, et al. HDL in innate and adaptive immunity. Cardiovascular Res 2014;103: 372–83.
    13. Singh IP, Chopra AK, Coppenhaver DH, Ananatharamaiah GM, Baron S. Lipoproteins account for part of the broad non-specific antiviral activity of human serum. Antiviral Res 1999;42:211-8.
    14. Cho KH, Kim JR, Lee IC, Kwon HJ. Native high-density lipoproteins (HDL) with higher paraoxonase exerts a potent antiviral effect against SARS-CoV-2 (COVID-19), while glycated HDL lost the antiviral activity. Antioxidants (Basel) 2021;102:209.