Metabolic syndrome (MetS) is a constellation of risk factors for cardiovascular disease and type 2 diabetes
mellitus which frequently occur together. The consequences of MetS extend beyond the increased risk of
vascular-metabolic disease. Data is emerging suggesting causality between MetS and cerebral small vessel
disease. MetS is associated with an increased incidence of vascular dementia and progression from mild
cognitive impairment to dementia. MetS cause endothelial dysfunction and low-level inflammation of adipose
tissue. MetS-associated endothelial dysfunction is independent of obesity status with an increased number of
MetS abnormalities correlating with more endothelial dysfunction. Middle cerebral artery stiffening with impaired
blood flow is associated with a higher MetS score.
Enhanced access to effective combination antiretroviral therapy (cART) improved the life expectancy of
people living with HIV (PLWH) substantially. Longevity, however, presents unique health challenges, one being
the development of non-communicable diseases including MetS. Emerging data from sub-Saharan Africa
indicate a higher prevalence of MetS among PLWH compared with their HIV-negative counterparts. The
incidence of MetS in PLWH is predicted to increase. Abdominal obesity is reaching alarming proportions in PLWH
in sub-Saharan Africa on cART with the prevalence similar to that of high-income countries. Antiretroviral
regimens were associated with higher treatment-emergent MetS. Given the growing HIV-positive population with
MetS, and that both MetS and HIV are chronic inflammatory conditions, there is an urgent need to identify
effective and affordable pharmacotherapy that addresses modifiable aspects of vascular disease.
Metformin has been shown to affect endothelial cells by inhibiting several inflammatory molecules. Pilot
clinical trial data support that metformin significantly improves endothelial function, even in short-term treatment.
Metformin is a low-cost and well-known drug used for the management of abnormal glucose homeostasis in
people with type 2 diabetes. Metformin is widely available in public service settings and is considered to have a
clinical effect beyond glucose lowering. Based on the rationale above, we propose to study metformin in HIV-
positive participants with MetS who are virologically suppressed by standard of care cART to receive open-label
metformin to assess its effect on cerebrovascular function.
The purpose of this pilot study in PLWH with MetS is to obtain preliminary data on the effect of metformin on
cerebrovascular function using non-invasive neuroimaging biomarkers. Furthermore, we will test the hypothesis
that metformin mediates the cerebrovascular changes in part via endothelial regulation by using a
comprehensive panel of endothelial functional and soluble markers which will be correlated with the imaging
metrics. The results of the study will form the basis for a future clinical trial that will assess the beneficial effect
of metformin in reducing the burden of cerebral small vessel disease in PLWH.