Metformin as adjunctive therapy for dengue in overweight and obese patients: a protocol for an open-label clinical trial (MeDO)

Nguyet Minh Nguyen, Ho Quang Chanh, Dong Thi Hoai Tam, Nguyen Lam Vuong, Nguyen Thi Xuan Chau, Nguyen Van Vinh Chau, Nguyen Thanh Phong, Huynh Trung Trieu, Tai Luong Thi Hue, Tam Cao Thi, Trung Dinh The, Huynh Thi Le Duyen, Ninh Thi Thanh Van, Quyen Nguyen Than Ha, Laura Rivino, Peter Gallagher, Nick K Jones, Ronald B Geskus, Evelyne Kestelyn, Sophie Yacoub, Nguyet Minh Nguyen, Ho Quang Chanh, Dong Thi Hoai Tam, Nguyen Lam Vuong, Nguyen Thi Xuan Chau, Nguyen Van Vinh Chau, Nguyen Thanh Phong, Huynh Trung Trieu, Tai Luong Thi Hue, Tam Cao Thi, Trung Dinh The, Huynh Thi Le Duyen, Ninh Thi Thanh Van, Quyen Nguyen Than Ha, Laura Rivino, Peter Gallagher, Nick K Jones, Ronald B Geskus, Evelyne Kestelyn, Sophie Yacoub

Abstract

Background: Dengue is a disease of major global importance. While most symptomatic infections are mild, a small proportion of patients progress to severe disease with risk of hypovolaemic shock, organ dysfunction and death. In the absence of effective antiviral or disease modifying drugs, clinical management is solely reliant on supportive measures. Obesity is a growing problem among young people in Vietnam and is increasingly recognised as an important risk factor for severe dengue, likely due to alterations in host immune and inflammatory pathways. Metformin, a widely used anti-hyperglycaemic agent with excellent safety profile, has demonstrated potential as a dengue therapeutic in vitro and in a retrospective observational study of adult dengue patients with type 2 diabetes. This study aims to assess the safety and tolerability of metformin treatment in overweight and obese dengue patients, and investigate its effects on several clinical, immunological and virological markers of disease severity. Methods: This open label trial of 120 obese/overweight dengue patients will be performed in two phases, with a metformin dose escalation if no safety concerns arise in phase one. The primary endpoint is identification of clinical and laboratory adverse events. Sixty overweight and obese dengue patients aged 10-30 years will be enrolled at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam. Participants will complete a 5-day course of metformin therapy and be compared to a non-treated group of 60 age-matched overweight and obese dengue patients. Discussion: Previously observed antiviral and immunomodulatory effects of metformin make it a promising dengue therapeutic candidate in appropriately selected patients. This study will assess the safety and tolerability of adjunctive metformin in the management of overweight and obese young dengue patients, as well as its effects on markers of viral replication, endothelial dysfunction and host immune responses. Trial registration: ClinicalTrials.gov: NCT04377451 (May 6 th 2020).

Keywords: Vietnam; clinical trial; dengue; metformin; obesity; therapeutic.

Conflict of interest statement

No competing interests were disclosed.

Copyright: © 2021 Nguyen NM et al.

Figures

Figure 1.. Trial flow chart.
Figure 1.. Trial flow chart.

References

    1. Bhatt S, Gething PW, Brady OJ, et al. : The global distribution and burden of dengue. Nature. 2013;496(7446):504–7. 10.1038/nature12060
    1. Organization WH: Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control: New Edition. WHO Guidelines Approved by the Guidelines Review Committee. Geneva2009.
    1. Whitehorn J, Yacoub S, Anders KL, et al. : Dengue therapeutics, chemoprophylaxis, and allied tools: state of the art and future directions. PLoS Negl Trop Dis. 2014;8(8):e3025. 10.1371/journal.pntd.0003025
    1. Yacoub S, Wills B: Predicting outcome from dengue. BMC Med. 2014;12: 147. 10.1186/s12916-014-0147-9
    1. Do LM, Tran TK, Eriksson B, et al. : Preschool overweight and obesity in urban and rural Vietnam: differences in prevalence and associated factors. Glob Health Action. 2015;8:28615. 10.3402/gha.v8.28615
    1. Kalayanarooj S, Nimmannitya S: Is dengue severity related to nutritional status? Southeast Asian J Trop Med Public Health. 2005;36(2):378–84.
    1. Libraty DH, Zhang L, Woda M, et al. : Low adiposity during early infancy is associated with a low risk for developing dengue hemorrhagic fever: a preliminary model. PLoS One. 2014;9(2):e88944. 10.1371/journal.pone.0088944
    1. Pichainarong N, Mongkalangoon N, Kalayanarooj S, et al. : Relationship between body size and severity of dengue hemorrhagic fever among children aged 0-14 years. Southeast Asian J Trop Med Public Health. 2006;37(2):283–8.
    1. Zulkipli MS, Dahlui M, Jamil N, et al. : The association between obesity and dengue severity among pediatric patients: A systematic review and meta-analysis. PLoS Negl Trop Dis. 2018;12(2):e0006263. 10.1371/journal.pntd.0006263
    1. Trang NTH, Long NP, Hue TTM, et al. : Association between nutritional status and dengue infection: a systematic review and meta-analysis. BMC Infect Dis. 2016;16: 172. 10.1186/s12879-016-1498-y
    1. Ellulu MS, Patimah I, Khaza'ai H, et al. : Obesity and inflammation: the linking mechanism and the complications. Arch Med Sci. 2017;13(4):851–63. 10.5114/aoms.2016.58928
    1. Gallagher P, Chan KR, Rivino L, et al. : The association of obesity and severe dengue: possible pathophysiological mechanisms. J Infect. 2020;81(1):10–16. 10.1016/j.jinf.2020.04.039
    1. Jamaluddin MS, Weakley SM, Yao Q, et al. : Resistin: functional roles and therapeutic considerations for cardiovascular disease. Br J Pharmacol. 2012;165(3):622–32. 10.1111/j.1476-5381.2011.01369.x
    1. Martin SS, Qasim A, Reilly MP: Leptin resistance: a possible interface of inflammation and metabolism in obesity-related cardiovascular disease. J Am Coll Cardiol. 2008;52(15):1201–10. 10.1016/j.jacc.2008.05.060
    1. Morioka T, Emoto M, Yamazaki Y, et al. : Leptin is associated with vascular endothelial function in overweight patients with type 2 diabetes. Cardiovasc Diabetol. 2014;13: 10. 10.1186/1475-2840-13-10
    1. Yacoub S, Lam PK, Huynh TT, et al. : Endothelial Nitric Oxide Pathways in the Pathophysiology of Dengue: A Prospective Observational Study. Clin Infect Dis. 2017;65(9):1453–61. 10.1093/cid/cix567
    1. Chen C, Jiang J, Lu JM, et al. : Resistin decreases expression of endothelial nitric oxide synthase through oxidative stress in human coronary artery endothelial cells. Am J Physiol Heart Circ Physiol. 2010;299(1):H193–201. 10.1152/ajpheart.00431.2009
    1. Jamaluddin MS, Yan S, Lu J, et al. : Resistin increases monolayer permeability of human coronary artery endothelial cells. PLoS One. 2013;8(12):e84576. 10.1371/journal.pone.0084576
    1. Yacoub S, Lam PK, Vu LHM, et al. : Association of Microvascular Function and Endothelial Biomarkers With Clinical Outcome in Dengue: An Observational Study. J Infect Dis. 2016;214(5):697–706. 10.1093/infdis/jiw220
    1. Andersen CJ, Murphy KE, Fernandez ML: Impact of obesity and metabolic syndrome on immunity. Adv Nutr. 2016;7(1):66–75. 10.3945/an.115.010207
    1. Nave H, Mueller G, Siegmund B, et al. : Resistance of Janus kinase-2 dependent leptin signaling in natural killer (NK) cells: a novel mechanism of NK cell dysfunction in diet-induced obesity. Endocrinology. 2008;149(7):3370–8. 10.1210/en.2007-1516
    1. Jeon SM: Regulation and function of AMPK in physiology and diseases. Exp Mol Med. 2016;48(7):e245. 10.1038/emm.2016.81
    1. Steinberg GR, Michell BJ, van Denderen BJ, et al. : Tumor necrosis factor alpha-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling. Cell Metab. 2006;4(6):465–74. 10.1016/j.cmet.2006.11.005
    1. de Oya NJ, Blázquez AB, Casas J, et al. : Direct activation of adenosine monophosphate-activated protein kinase (AMPK) by PF-06409577 inhibits flavivirus infection through modification of host cell lipid metabolism. Antimicrob Agents Chemother. 2018;62(7):e00360–18. 10.1128/AAC.00360-18
    1. Mankouri J, Tedbury PR, Gretton S, et al. : Enhanced hepatitis C virus genome replication and lipid accumulation mediated by inhibition of AMP-activated protein kinase. Proc Natl Acad Sci U S A. 2010;107(25):11549–54. 10.1073/pnas.0912426107
    1. Vuong NL, Le Duyen HT, Lam PK, et al. : C-reactive protein as a potential biomarker for disease progression in dengue: a multi-country observational study. BMC Med. 2020;18(1): 35. 10.1186/s12916-020-1496-1
    1. Rena G, Hardie DG, Pearson ER: The mechanisms of action of metformin. Diabetologia. 2017;60(9):1577–85. 10.1007/s00125-017-4342-z
    1. Eskens BJ, Zuurbier CJ, van Haare J, et al. : Effects of two weeks of metformin treatment on whole-body glycocalyx barrier properties in db/db mice. Cardiovasc Diabetol. 2013;12: 175. 10.1186/1475-2840-12-175
    1. Forouzandeh F, Salazar G, Patrushev N, et al. : Metformin beyond diabetes: pleiotropic benefits of metformin in attenuation of atherosclerosis. J Am Heart Assoc. 2014;3(6):e001202. 10.1161/JAHA.114.001202
    1. Pernicova I, Korbonits M: Metformin--mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol. 2014;10(3):143–56. 10.1038/nrendo.2013.256
    1. Ersoy C, Kiyici S, Budak F, et al. : The effect of metformin treatment on VEGF and PAI-1 levels in obese type 2 diabetic patients. Diabetes Res Clin Pract. 2008;81(1):56–60. 10.1016/j.diabres.2008.02.006
    1. Golay A: Metformin and body weight. Int J Obes (Lond). 2008;32(1):61–72. 10.1038/sj.ijo.0803695
    1. Pastor-Villaescusa B, Canete MD, Caballero-Villarraso J, et al. : Metformin for Obesity in Prepubertal and Pubertal Children: A Randomized Controlled Trial. Pediatrics. 2017;140(1):e20164285. 10.1542/peds.2016-4285
    1. Degner NR, Wang JY, Golub JE, et al. : Metformin Use Reverses the Increased Mortality Associated With Diabetes Mellitus During Tuberculosis Treatment. Clin Infect Dis. 2018;66(2):198–205. 10.1093/cid/cix819
    1. Doyle MA, Singer J, Lee T, et al. : Improving treatment and liver fibrosis outcomes with metformin in HCV-HIV co-infected and HCV mono-infected patients with insulin resistance: study protocol for a randomized controlled trial. Trials. 2016;17(1):331. 10.1186/s13063-016-1454-6
    1. Harris K, Smith L: Safety and efficacy of metformin in patients with type 2 diabetes mellitus and chronic hepatitis C. Ann Pharmacother. 2013;47(10):1348–52. 10.1177/1060028013503108
    1. Htun HL, Yeo TW, Tam CC, et al. : Metformin use and severe dengue in diabetic adults. Sci Rep. 2018;8(1):3344. 10.1038/s41598-018-21612-6
    1. Oglesby W, Kara AM, Granados H, et al. : Metformin in tuberculosis: beyond control of hyperglycemia. Infection. 2019;47(5):697–702. 10.1007/s15010-019-01322-5
    1. Eikawa S, Nishida M, Mizukami S, et al. : Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proc Natl Acad Sci U S A. 2015;112(6):1809–14. 10.1073/pnas.1417636112
    1. Yu JW, Sun LJ, Zhao YH, et al. : The effect of metformin on the efficacy of antiviral therapy in patients with genotype 1 chronic hepatitis C and insulin resistance. Int J Infect Dis. 2012;16(6):e436–e41. 10.1016/j.ijid.2012.02.004
    1. Soto-Acosta R, Bautista-Carbajal P, Cervantes-Salazar M, et al. : DENV up-regulates the HMG-CoA reductase activity through the impairment of AMPK phosphorylation: A potential antiviral target. PLoS Pathog. 2017;13(4):e1006257. 10.1371/journal.ppat.1006257
    1. Webb TJ, Carey GB, East JE, et al. : Alterations in cellular metabolism modulate CD1d-mediated NKT-cell responses. Pathog Dis. 2016;74(6):ftw055. 10.1093/femspd/ftw055
    1. van Rongen A, van der Aa MP, Matic M, et al. : Increased Metformin Clearance in Overweight and Obese Adolescents: A Pharmacokinetic Substudy of a Randomized Controlled Trial. Paediatr Drugs. 2018;20(4):365–74. 10.1007/s40272-018-0293-1
    1. Xie W, Wang L, Dai Q, et al. : Activation of AMPK restricts coxsackievirus B3 replication by inhibiting lipid accumulation. J Mol Cell Cardiol. 2015;85:155–67. 10.1016/j.yjmcc.2015.05.021
    1. Gomez-Diaz RA, Talavera JO, Pool EC, et al. : Metformin decreases plasma resistin concentrations in pediatric patients with impaired glucose tolerance: a placebo-controlled randomized clinical trial. Metabolism. 2012;61(9):1247–55. 10.1016/j.metabol.2012.02.003
    1. Kestelyn E, Yacoub S: Oxford University Clinical Research Unit Metformin Trial Supporting Documents. University of Oxford. 10.5287/bodleian:5Rk2p9EVK
    1. Yacoub S, Kotit S, Yacoub MH: Disease appearance and evolution against a background of climate change and reduced resources. Philos Trans A Math Phys Eng Sci. 2011;369(1942):1719–29. 10.1098/rsta.2011.0013

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner