Metformin Use and Severe Dengue in Diabetic Adults

Htet Lin Htun,Junxiong Pang,Clarence C Tam,David C Lye,Yee Sin Leo,Tsin Wen Yeo

doi:10.1038/s41598-018-21612-6

Abstract

Diabetes mellitus is a risk factor for severe dengue in adults, but few studies have examined the association between metformin use and disease severity in dengue. In addition to its effect on glucose control, metformin has been associated with pleiotropic properties in preclinical studies. Using a cohort of laboratory-confirmed adult (≥21 years) dengue patients with diabetes mellitus admitted to Tan Tock Seng Hospital, we conducted a retrospective cohort study involving 131 (58.7%) metformin users and 92 (41.3%) non-users. Dengue severity was categorized as dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) in World Health Organization (WHO) 1997 criteria and severe dengue (SD) in WHO 2009 criteria. Multivariable Poisson regression with robust error variance was used to estimate risk ratio (RR). Compared with non-use, metformin use was associated with a decreased risk of developing severe dengue (adjusted risk ratio [aRR] = 0.60, 95% confidence interval [CI]: 0.37–0.98, P = 0.04). Additionally, there was an inverse dose-response relationship (aRR = 0.69, 95% CI: 0.49–0.98, P = 0.04) with dengue severity as classified by WHO 2009 criteria. Use of metformin, however, was not associated with dengue severity based on WHO 1997 criteria; and no dose-response relationship was noted. Our results suggest metformin use could attenuate disease severity in dengue-infected diabetes mellitus individuals.

Highlights

Dengue is the most common arthropod-borne viral infection, and the number of reported cases are increasing in the Western Pacific, the Americas and even Europe[1]
There were no significant differences between metformin users and non-users in terms of gender (P = 0.88), ethnicity (P = 0.09), proportion of overweight and obese patients (BMI ≥25–29.99 and ≥30 respectively, P = 0.57), proportion of current smokers (P = 0.48), median Charlson’s comorbidity index (CCI) (P = 0.47), median Diabetes complications severity index (DCSI) (P = 0.60), nephropathy (P = 0.39), HbA1c category (P = 0.27), serum creatinine >2.0 mg/dL (P = 0.20) or predominant circulating serotype (P = 0.07) (Table 1)
This retrospective cohort study of adult diabetic patients with acute dengue infection indicated that patients on metformin treatment had a 33–40% lower risk of developing severe dengue based on World Health Organization (WHO) 2009 dengue criteria

Summary

Introduction

Dengue is the most common arthropod-borne viral infection, and the number of reported cases are increasing in the Western Pacific, the Americas and even Europe[1]. It is caused by four antigenically distinct serotypes of dengue viruses (DENV-1, DENV-2, DENV-3 and DENV-4) belonging to the Flavivirus family, all of which are transmitted by the Aedes aegypti and Aedes albopictus mosquitoes[2]. The World Health Organization (WHO) 1997 and the more recent WHO 2009 dengue classification criteria are the two most common classification criteria used to define dengue severity Against this background of increasing dengue incidence worldwide, the non-communicable disease burden is growing. We performed a retrospective cohort study among adult DM patients with acute dengue infection to evaluate the association between metformin use and risk of severe dengue, using both WHO 1997 and WHO 2009 dengue classification criteria

Methods

Results

Conclusion