Repurposing New Use for Old Drug Chloroquine against Metabolic Syndrome: A Review on Animal and Human Evidence

Sok Kuan Wong, Sok Kuan Wong

Abstract

Chloroquine (CQ) and hydroxychloroquine (HCQ) are traditional anti-malarial drugs that have been repurposed for new therapeutic uses in many diseases due to their simple usage and cost-effectiveness. The pleiotropic effects of CQ and HCQ in regulating blood pressure, glucose homeostasis, lipid, and carbohydrate metabolism have been previously described in vivo and in humans, thus suggesting their role in metabolic syndrome (MetS) prevention. The anti-hyperglycaemic, anti-hyperlipidaemic, cardioprotective, anti-hypertensive, and anti-obesity effects of CQ and HCQ might be elicited through reduction of inflammatory response and oxidative stress, improvement of endothelial function, activation of insulin signalling pathway, inhibition of lipogenesis and autophagy, as well as regulation of adipokines and apoptosis. In conclusion, the current state of knowledge supported the repurposing of CQ and HCQ usage in the management of MetS.

Keywords: diabetes; dyslipidaemia; hypertension; immunomodulation; inflammation; obesity.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

© The author(s).

Figures

Figure 1
Figure 1
The mechanism of action of CQ and HCQ in improving MetS conditions.

References

    1. Sullivan DJ, Gluzman IY, Russell DG. et al. On the molecular mechanism of chloroquine's antimalarial action. Proc. Natl. Acad. Sci. USA. 1996;93:11865.
    1. Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat. Rev. Rheumatol. 2020;16:155–166.
    1. Tsiang H, Superti F. Ammonium chloride and chloroquine inhibit rabies virus infection in neuroblastoma cells. Arch. Virol. 1984;81:377–382.
    1. Kronenberger P, Vrijsen R, Boeyé A. Chloroquine induces empty capsid formation during poliovirus eclipse. J. Virol. 1991;65:7008–11.
    1. Khan M, Santhosh SR, Tiwari M. et al. Assessment of in vitro prophylactic and therapeutic efficacy of chloroquine against Chikungunya virus in vero cells. J. Med. Virol. 2010;82:817–24.
    1. Farias KJS, Machado PRL, de Almeida Junior RF. et al. Chloroquine interferes with dengue-2 virus replication in U937 cells. Microbiol. Immunol. 2014;58:318–326.
    1. Tricou V, Minh NN, Van TP. et al. A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults. PLoS Negl. Trop. Dis. 2010;4:e785.
    1. Shiryaev SA, Mesci P, Pinto A. et al. Repurposing of the anti-malaria drug chloroquine for Zika Virus treatment and prophylaxis. Sci. Rep. 2017;7:15771.
    1. Lima TLC, Feitosa RdC, Dos Santos-Silva E. et al. Improving Encapsulation of Hydrophilic Chloroquine Diphosphate into Biodegradable Nanoparticles: A Promising Approach against Herpes Virus Simplex-1 Infection. Pharmaceutics. 2018;10:255.
    1. Savarino A, Gennero L, Chen HC. et al. Anti-HIV effects of chloroquine: mechanisms of inhibition and spectrum of activity. Aids. 2001;15:2221–9.
    1. Mizui T, Yamashina S, Tanida I. et al. Inhibition of hepatitis C virus replication by chloroquine targeting virus-associated autophagy. J. Gastroenterol. 2010;45:195–203.
    1. Yan Y, Zou Z, Sun Y. et al. Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model. Cell Res. 2013;23:300–302.
    1. Cortegiani A, Ingoglia G, Ippolito M. et al. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J. Crit. Care. 2020;57:279–283.
    1. Haładyj E, Sikora M, Felis-Giemza A. et al. Antimalarials - are they effective and safe in rheumatic diseases? Reumatologia. 2018;56:164–173.
    1. Wu K, Zhang Q, Wu X. et al. Chloroquine is a potent pulmonary vasodilator that attenuates hypoxia-induced pulmonary hypertension. Br. J. Pharmacol. 2017;174:4155–4172.
    1. Alberti KG, Eckel RH, Grundy SM. et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120:1640–5.
    1. Thatoi PK. Diabetes and Severe Malaria—Clinical Profile and Outcome. Diabetes. 2018;67:2388–PUB.
    1. Theengh DP, Yadav P, Jain AK. et al. Assessment of metabolic syndrome in HIV-infected individuals. Indian J. Sex. Transm. Dis. AIDS. 2017;38:152–156.
    1. Bellomio V, Spindler A, Lucero E. et al. Metabolic syndrome in Argentinean patients with systemic lupus erythematosus. Lupus. 2009;18:1019–1025.
    1. Graham ML, Janecek JL, Kittredge JA. et al. The streptozotocin-induced diabetic nude mouse model: differences between animals from different sources. Comp. Med. 2011;61:356–360.
    1. Asamoah KA, Furman BL, Robb DA. Attenuation of streptozotocin-induced diabetes in rats by pretreatment with chloroquine. Clin. Sci. 1989;76:137–41.
    1. Emami J, Gerstein HC, Pasutto FM. et al. Insulin-sparing effect of hydroxychloroquine in diabetic rats is concentration dependent. Can. J. Physiol. Pharmacol. 1999;77:118–23.
    1. Abdel-Hamid AAM, El-Firgany AEL. Hydroxychloroquine hindering of diabetic isletopathy carries its signature on the inflammatory cytokines. J. Mol. Histol. 2016;47:183–93.
    1. Yuan X, Xiao YC, Zhang GP. et al. Chloroquine improves left ventricle diastolic function in streptozotocin-induced diabetic mice. Drug Des. Devel. Ther. 2016;10:2729–37.
    1. Ighodaro OM, Adeosun AM, Akinloye OA. Alloxan-induced diabetes, a common model for evaluating the glycemic-control potential of therapeutic compounds and plants extracts in experimental studies. Medicina. 2017;53:365–374.
    1. Pareek A, Yeole PG, Tenpe CR. et al. Effect of atorvastatin and hydroxychloroquine combination on blood glucose in alloxan-induced diabetic rats. Indian J. Pharmacol. 2009;41:125–8.
    1. Halaby MJ, Kastein BK, Yang DQ. Chloroquine stimulates glucose uptake and glycogen synthase in muscle cells through activation of Akt. Biochem. Biophys. Res. Commun. 2013;435:708–713.
    1. Abdel-Hamid AAM, Firgany AEL. Favorable outcomes of hydroxychloroquine in insulin resistance may be accomplished by adjustment of the endothelial dysfunction as well as the skewed balance of adipokines. Acta Histochem. 2016;118:560–573.
    1. Qiao X, Zhou ZC, Niu R. et al. Hydroxychloroquine Improves Obesity-Associated Insulin Resistance and Hepatic Steatosis by Regulating Lipid Metabolism. Front. Pharmacol. 2019;10:855.
    1. Wang R, Xi L, Kukreja RC. PDE5 Inhibitor Tadalafil and Hydroxychloroquine Cotreatment Provides Synergistic Protection against Type 2 Diabetes and Myocardial Infarction in Mice. J. Pharmacol. Exp. Ther. 2017;361:29–38.
    1. Wang B, Chandrasekera PC, Pippin JJ. Leptin- and leptin receptor-deficient rodent models: relevance for human type 2 diabetes. Curr Diabetes Rev. 2014;10:131–45.
    1. Wong SK, Chin KY, Soelaiman I-N. Leptin, adiponectin and insulin as regulators for energy metabolism in a rat model of metabolic syndrome. Sains Malaysiana. 2019;48:2701–2707.
    1. Bili A, Sartorius JA, Kirchner HL. et al. Hydroxychloroquine use and decreased risk of diabetes in rheumatoid arthritis patients. J. Clin. Rheumatol. 2011;17:115–20.
    1. Chen YM, Lin CH, Lan TH. et al. Hydroxychloroquine reduces risk of incident diabetes mellitus in lupus patients in a dose-dependent manner: a population-based cohort study. Rheumatology. 2015;54:1244–9.
    1. Sheikhbahaie F, Amini M, Gharipour M. et al. The effect of hydroxychloroquine on glucose control and insulin resistance in the prediabetes condition. Adv. Biomed. Res. 2016;5:145.
    1. Rekedal LR, Massarotti E, Garg R. et al. Changes in glycosylated hemoglobin after initiation of hydroxychloroquine or methotrexate treatment in diabetes patients with rheumatic diseases. Arthritis Rheum. 2010;62:3569–73.
    1. Powrie JK, Shojaee-Moradie F, Watts GF. et al. Effects of chloroquine on the dyslipidemia of non-insulin-dependent diabetes mellitus. Metabolism. 1993;42:415–9.
    1. Powrie JK, Smith GD, Shojaee-Moradie F. et al. Mode of action of chloroquine in patients with non-insulin-dependent diabetes mellitus. Am. J. Physiol. 1991;260:E897–904.
    1. Pareek A, Chandurkar N, Thomas N. et al. Efficacy and safety of hydroxychloroquine in the treatment of type 2 diabetes mellitus: a double blind, randomized comparison with pioglitazone. Curr. Med. Res. Opin. 2014;30:1257–66.
    1. Gerstein HC, Thorpe KE, Taylor DW. et al. The effectiveness of hydroxychloroquine in patients with type 2 diabetes mellitus who are refractory to sulfonylureas-a randomized trial. Diabetes Res. Clin. Pract. 2002;55:209–19.
    1. Hsia SH, Duran P, Lee ML. et al. Randomized controlled trial comparing hydroxychloroquine with pioglitazone as third-line agents in type 2 diabetic patients failing metformin plus a sulfonylurea: A pilot study. J. Diabetes. 2020;12:91–94.
    1. Mercer E, Rekedal L, Garg R. et al. Hydroxychloroquine improves insulin sensitivity in obese non-diabetic individuals. Arthritis Res. Ther. 2012;14:R135.
    1. Wasko MC, McClure CK, Kelsey SF. et al. Antidiabetogenic effects of hydroxychloroquine on insulin sensitivity and beta cell function: a randomised trial. Diabetologia. 2015;58:2336–43.
    1. Pareek A, Chandurkar N, Thulaseedharan NK. et al. Efficacy and safety of fixed dose combination of atorvastatin and hydroxychloroquine: a randomized, double-blind comparison with atorvastatin alone among Indian patients with dyslipidemia. Curr. Med. Res. Opin. 2015;31:2105–17.
    1. McGill JB, Johnson M, Hurst S. et al. Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness. Diabetol. Metab. Syndr. 2019;11:61.
    1. Penn SK, Kao AH, Schott LL. et al. Hydroxychloroquine and glycemia in women with rheumatoid arthritis and systemic lupus erythematosus. J. Rheumatol. 2010;37:1136–42.
    1. Masui Y, Yanai H, Hiraga K. et al. Effects of anti-malarial drug, hydroxychloroquine, on glucose and lipid metabolism in Japanese population. J. Clin. Endocrinol. Metab. 2019;9:159–164.
    1. Solomon DH, Garg R, Lu B. et al. Effect of hydroxychloroquine on insulin sensitivity and lipid parameters in rheumatoid arthritis patients without diabetes mellitus: a randomized, blinded crossover trial. Arthritis Care Res. 2014;66:1246–51.
    1. Nwoha PU, Aire TA. Reduced level of serum cholesterol in low protein-fed Wistar rats administered gossypol and chloroquine. Contraception. 1995;52:261–5.
    1. Yuan J, Li LI, Wang Z. et al. Dyslipidemia in patients with systemic lupus erythematosus: Association with disease activity and B-type natriuretic peptide levels. Biomed. Rep. 2016;4:68–72.
    1. Erum U, Ahsan T, Khowaja D. Lipid abnormalities in patients with Rheumatoid Arthritis. Pak. J. Med. Sci. 2017;33:227–230.
    1. Ramos-Casals M, Brito-Zerón P, Sisó A. et al. High prevalence of serum metabolic alterations in primary Sjögren's syndrome: influence on clinical and immunological expression. J. Rheumatol. 2007;34:754–61.
    1. Batún Garrido JADJ, Radillo Alba HA, Hernández Núñez É. et al. Dyslipidaemia and atherogenic risk in patients with systemic lupus erythematosus. Med. Clin. 2016;147:63–66.
    1. Cairoli E, Rebella M, Danese N. et al. Hydroxychloroquine reduces low-density lipoprotein cholesterol levels in systemic lupus erythematosus: a longitudinal evaluation of the lipid-lowering effect. Lupus. 2012;21:1178–82.
    1. Kavanaugh A, Adams-Huet B, Jain R. et al. Hydroxychloroquine effects on lipoprotein profiles (the HELP trial): A double-blind, randomized, placebo-controlled, pilot study in patients with systemic lupus erythematosus. J. Clin. Rheumatol. 1997;3:3–8.
    1. Rossoni C, Bisi MC, Keiserman MW. et al. Antimalarials and cholesterol profile of patients with systemic lupus erythematosus. Rev. Bras. Reumatol. 2011;51:383–4. 386-7.
    1. Tam LS, Li EK, Lam CW. et al. Hydroxychloroquine has no significant effect on lipids and apolipoproteins in Chinese systemic lupus erythematosus patients with mild or inactive disease. Lupus. 2000;9:413–6.
    1. Kerr G, Aujero M, Richards J. et al. Associations of hydroxychloroquine use with lipid profiles in rheumatoid arthritis: pharmacologic implications. Arthritis Care Res. 2014;66:1619–26.
    1. Morris SJ, Wasko MC, Antohe JL. et al. Hydroxychloroquine use associated with improvement in lipid profiles in rheumatoid arthritis patients. Arthritis Care Res. 2011;63:530–4.
    1. Restrepo JF, Del Rincon I, Molina E. et al. Use of Hydroxychloroquine Is Associated With Improved Lipid Profile in Rheumatoid Arthritis Patients. J. Clin. Rheumatol. 2017;23:144–148.
    1. Desai RJ, Eddings W, Liao KP. et al. Disease-modifying antirheumatic drug use and the risk of incident hyperlipidemia in patients with early rheumatoid arthritis: A retrospective cohort study. Arthritis Care Res. 2015;67:457–466.
    1. Charles-Schoeman C, Wang X, Lee YY. et al. Association of Triple Therapy with Improvement in Cholesterol Profiles over Two-Year Followup in the Treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheumatol. 2016;68:577–586.
    1. Seideman P, Albertioni F, Beck O. et al. Chloroquine reduces the bioavailability of methotrexate in patients with rheumatoid arthritis. A possible mechanism of reduced hepatotoxicity. Arthritis Rheum. 1994;37:830–3.
    1. Migkos MP, Markatseli TE, Iliou C. et al. Effect of hydroxychloroquine on the lipid profile of patients with Sjögren syndrome. J. Rheumatol. 2014;41:902–8.
    1. Long L, Yang X, Southwood M. et al. Chloroquine prevents progression of experimental pulmonary hypertension via inhibition of autophagy and lysosomal bone morphogenetic protein type II receptor degradation. Circ. Res. 2013;112:1159–70.
    1. McCarthy CG, Wenceslau CF, Goulopoulou S. et al. Chloroquine Suppresses the Development of Hypertension in Spontaneously Hypertensive Rats. Am. J. Hypertens. 2017;30:173–181.
    1. McCarthy CG, Wenceslau CF, Goulopoulou S. et al. Autoimmune therapeutic chloroquine lowers blood pressure and improves endothelial function in spontaneously hypertensive rats. Pharmacol. Res. 2016;113:384–394.
    1. Baker JF, Sauer B, Teng CC. et al. Initiation of Disease-Modifying Therapies in Rheumatoid Arthritis Is Associated With Changes in Blood Pressure. J. Clin. Rheumatol. 2018;24:203–209.
    1. Angelakis E, Million M, Kankoe S. et al. Abnormal weight gain and gut microbiota modifications are side effects of long-term doxycycline and hydroxychloroquine treatment. Antimicrob. Agents Chemother. 2014;58:3342–3347.
    1. Wong SK, Chin KY, Ima-Nirwana S. Toll-like Receptor as a Molecular Link between Metabolic Syndrome and Inflammation: A Review. Curr. Drug Targets. 2019;20:1264–1280.
    1. González FEM, Ponce-RuÍz N, Rojas-GarcÍa AE. et al. PON1 concentration and high-density lipoprotein characteristics as cardiovascular biomarkers. Arch. Med. Sci, Atheroscler. Dis. 2019;4:e47–e54.
    1. Mangaraj M, Nanda R, Panda S. Apolipoprotein A-I: A Molecule of Diverse Function. Indian J. Clin. Biochem. 2016;31:253–259.
    1. Charles-Schoeman C, Yin Lee Y, Shahbazian A. et al. Improvement of High-Density Lipoprotein Function in Patients With Early Rheumatoid Arthritis Treated With Methotrexate Monotherapy or Combination Therapies in a Randomized Controlled Trial. Arthritis Rheumatol. 2017;69:46–57.
    1. Virdis A, Colucci R, Fornai M. et al. Cyclooxygenase-1 is involved in endothelial dysfunction of mesenteric small arteries from angiotensin II-infused mice. Hypertension. 2007;49:679–86.
    1. Ponce-Balbuena D, Rodríguez-Menchaca AA, López-Izquierdo A. et al. Molecular mechanisms of chloroquine inhibition of heterologously expressed Kir6.2/SUR2A channels. Molecular pharmacology. 2012;82:803–813.
    1. Girard CA, Shimomura K, Proks P. et al. Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes. Pflugers Arch. 2006;453:323–32.
    1. Hong M, Bao L, Kefaloyianni E. et al. Heterogeneity of ATP-sensitive K+ channels in cardiac myocytes: enrichment at the intercalated disk. The Journal of biological chemistry. 2012;287:41258–41267.
    1. Macfarlane WM, O'Brien RE, Barnes PD. et al. Sulfonylurea receptor 1 and Kir6.2 expression in the novel human insulin-secreting cell line NES2Y. Diabetes. 2000;49:953–60.
    1. Thomzig A, Laube G, Prüss H. et al. Pore-forming subunits of K-ATP channels, Kir6.1 and Kir6.2, display prominent differences in regional and cellular distribution in the rat brain. J Comp Neurol. 2005;484:313–30.
    1. Chen F, Zheng D, Xu Y. et al. Down-regulation of Kir6.2 affects calcium influx and insulin secretion in HIT-T15 cells. J Pediatr Endocrinol Metab. 2010;23:709–17.
    1. Boucher J, Kleinridders A, Kahn CR. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb. Perspect. Biol. 2014;6:a009191.
    1. Yu JH, Lee YJ, Kim HJ. et al. Monoacylglycerol O-acyltransferase 1 is regulated by peroxisome proliferator-activated receptor γ in human hepatocytes and increases lipid accumulation. Biochem. Biophys. Res. Commun. 2015;460:715–20.
    1. Valenzuela R, Videla LA. The importance of the long-chain polyunsaturated fatty acid n-6/n-3 ratio in development of non-alcoholic fatty liver associated with obesity. Food Funct. 2011;2:644–8.
    1. Wang L-H, Liu Y-C, Wang J-H. et al. Serum leptin level positively correlates with metabolic syndrome among elderly Taiwanese. Ci Ji Yi Xue Za Zhi. 2017;29:159–164.
    1. Makni E, Moalla W, Benezzeddine-Boussaidi L. et al. Correlation of resistin with inflammatory and cardiometabolic markers in obese adolescents with and without metabolic syndrome. Obes. Facts. 2013;6:393–404.
    1. Abushahla HS, Bulatova N, Kasabri V. et al. Correlates of ghrelin and visfatin in metabolic syndrome patients with and without prediabetes. Int. J. of Diabetes Dev. Ctries. 2019;39:82–93.
    1. Sparrenberger K, Sbaraini M, Cureau FV. et al. Higher adiponectin concentrations are associated with reduced metabolic syndrome risk independently of weight status in Brazilian adolescents. Diabetol. Metab. Syndr. 2019;11:40.
    1. Bhusal A, Rahman MH, Lee WH. et al. Paradoxical role of lipocalin-2 in metabolic disorders and neurological complications. Biochem. Pharmacol. 2019;169:113626.
    1. Ntaios G, Gatselis NK, Makaritsis K. et al. Adipokines as mediators of endothelial function and atherosclerosis. Atherosclerosis. 2013;227:216–21.
    1. Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. J. Pathol. 2010;221:3–12.
    1. Loreto C, La Rocca G, Anzalone R. et al. The Role of Intrinsic Pathway in Apoptosis Activation and Progression in Peyronie's Disease. BioMed Res. Int. 2014;2014:616149.
    1. World Health Organization, Guidelines for the treatment of malaria. 2015: World Health Organization.
    1. Mota LM, Cruz BA, Brenol CV. et al. Guidelines for the drug treatment of rheumatoid arthritis. Rev Bras Reumatol. 2013;53:158–83.
    1. Karalis V, Ismailos G, Karatza E. Chloroquine dosage regimens in patients with COVID-19: Safety risks and optimization using simulations. Saf Sci. 2020;129:104842.
    1. Smit C, Peeters MYM, van den Anker JN. et al. Chloroquine for SARS-CoV-2: Implications of Its Unique Pharmacokinetic and Safety Properties. Clin Pharmacokinet. 2020;59:659–669.
    1. Arnaout A, Robertson SJ, Pond GR. et al. A randomized, double-blind, window of opportunity trial evaluating the effects of chloroquine in breast cancer patients. Breast Cancer Res. Treat. 2019;178:327–335.
    1. Srinivasa A, Tosounidou S, Gordon C. Increased Incidence of Gastrointestinal Side Effects in Patients Taking Hydroxychloroquine: A Brand-related Issue? J. Rheumatol. 2017;44:398.
    1. Jorge A, Ung C, Young LH. et al. Hydroxychloroquine retinopathy - implications of research advances for rheumatology care. Nat. Rev. Rheumatol. 2018;14:693–703.
    1. Wiwanitkit V. Antimalarial drug and renal toxicity. J. Nephropharmacol. 2015;5:11–12.
    1. Chen Y, Shen T, Zhong L, Research Progress of Chloroquine and Hydroxychloroquine on the COVID-19 and Their Potential Risks in Clinic Use. Front. Pharmacol. 2020. 11.
    1. Zhang X-l, Li Z-m, Ye J-t, Pharmacological and cardiovascular perspectives on the treatment of COVID-19 with chloroquine derivatives. Acta Pharmacologica Sinica. 2020. pp. 1–10.
    1. Ursing J, Rombo L, Eksborg S, High-Dose Chloroquine for Uncomplicated Plasmodium falciparum Malaria Is Well Tolerated and Causes Similar QT Interval Prolongation as Standard-Dose Chloroquine in Children. Antimicrob Agents Chemother. 2020. 64.
    1. Blignaut M, Espach Y, van Vuuren M. et al. Revisiting the Cardiotoxic Effect of Chloroquine. Cardiovasc Drugs Ther. 2019;33:1–11.
    1. de Sena LWP, Mello AGNC, Ferreira MVD. et al. Doses of chloroquine in the treatment of malaria by Plasmodium vivax in patients between 2 and 14 years of age from the Brazilian Amazon basin. Malar. J. 2019;18:439.
    1. Dos Reis Neto ET, Kakehasi AM, de Medeiros Pinheiro M. et al. Revisiting hydroxychloroquine and chloroquine for patients with chronic immunity-mediated inflammatory rheumatic diseases. Adv. Rheumatol. 2020;60:32–32.
    1. Devaux CA, Rolain J-M, Colson P. et al. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int. J. Antimicrob. Agents. 2020;55:105938–105938.
    1. Wyss K, Wångdahl A, Vesterlund M. et al. Obesity and Diabetes as Risk Factors for Severe Plasmodium falciparum Malaria: Results From a Swedish Nationwide Study. Clin. Infect. Dis. 2017;65:949–958.
    1. Hallajzadeh J, Khoramdad M, Izadi N. et al. The association between metabolic syndrome and its components with systemic lupus erythematosus: a comprehensive systematic review and meta-analysis of observational studies. Lupus. 2018;27:899–912.
    1. Chung CP, Oeser A, Solus JF. et al. Prevalence of the metabolic syndrome is increased in rheumatoid arthritis and is associated with coronary atherosclerosis. Atherosclerosis. 2008;196:756–63.
    1. Costa FF, Rosário WR, Ribeiro Farias AC. et al. Metabolic syndrome and COVID-19: An update on the associated comorbidities and proposed therapies. Diabetes Metab. Syndr. 2020;14:809–814.

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