Metformin: a cheap and well‐tolerated drug that provides benefits for viral infections

Abstract

ObjectivesInsulin resistance in viral infections is common. We have explored the effectiveness of metformin for alleviating insulin resistance in HIV-infected patients and assessed the relevance of the ataxia-telangiectasia mutated (ATM) rs11212617 variant in the clinical response with the rationale that metformin modulates cellular bioenergetics in an ATM-dependent process. MethodsHIV-infected patients (n = 385) were compared with controls recruited from the general population (n = 300) with respect to the genotype distribution of the ATM rs11212617 variant and its influence on selected metabolic and inflammatory variables. We also followed up a subset of male patients with HIV and hepatitis C virus (HCV) coinfection (n = 47) who were not receiving antiviral treatment and for whom metformin was prescribed for insulin resistance, which tends to have a higher incidence and severity in coinfected patients. ResultsAmong the HIV-infected patients, human cytomegalovirus (91.9%) and HCV (62.3%) coinfections were frequent. Selected metabolic and/or inflammatory variables were significantly altered in infected patients. Treatment with metformin in HIV and HCV coinfected patients was well tolerated and significantly increased the sensitivity of peripheral tissues to insulin. The minor allele (C) of the rs11212617 variant was associated with treatment success and may affect the course of insulin resistance in response to metformin (odds ratio 1.21; 95% confidence interval 1.07-1.39; P = 0.005). There were no differences between treated and untreated patients in viral loads or variables measuring immune defence, indicating that toxicity is unlikely. ConclusionsWe provide novel data suggesting that identification of the ATM rs11212617 variant may be important in assessing the glycaemic response to metformin treatment for insulin resistance in HIV-infected patients. [3,6,7].In a previous study, we showed the benefits of metformin treatment in terms of visceral fat accumulation, the fasting lipid profile and endothelial function in HIV-infected patients with lipodystrophy [8,9]. The response to the drug varied widely, an effect initially attributed to the influence of antiretroviral therapy [10]. A recent pharmacogenomic study suggested that the genetic variant rs11212617 at the locus containing the ATM gene is robustly associated with metformin response in diabetic patients and established a link between glucose homeostasis and the DDR. Further, ATM acts upstream of AMPK and is required for a full response to metformin [11]. Hence, genetic variations affecting the function of ATM may contribute to the varying success of metformin treatment via AMPK activation or inhibition. We reasoned that this may also be applicable to patients with viral infections and insulin resistance and that understanding ATM-related associations may help to establish metformin as a useful coadjuvant in HIV-infected patients. Clinically, insulin resistance is a relatively common condition in HIV-infected patients. It is even more frequent, for poorl...

Cohort study of diabetes in HIV-infected adult patients: Evaluating the effect of diabetes mellitus on immune reconstitution

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Mitochondrial Dysfunction: A Basic Mechanism in Inflammation-Related Non-Communicable Diseases and Therapeutic Opportunities

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“…More important, an observational study from the UK in more than 78,000 subjects reported that type 2 diabetes patients treated with metformin had improved survival, as compared to those not receiving metformin, as well as matched, non-diabetic patients (Bannister and others 2014). Consistent with these putative effects on survival, accumulating observational and pre-clinical data have revealed benefits of metformin use that extend far beyond type 2 diabetes, and include protection against cardiovascular disease (Forouzandeh and others 2014), dyslipidemias in mice (Geerling and others 2014), certain cancers (Morales and Morris 2015; Sehdev and others 2015) infections (Joven and others 2013) and frailty syndrome (Sumantri and others 2014). Further, while metformin was shown to have no effect on bone mass and fracture healing time in young rodents (Jeyabalan and others 2013) or surgical stress in humans (Duncan and others 2007), it was found to reduce prolonged tracheal intubation and overall morbidities following surgery (Duncan and others 2007).…”