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Study of Metformin to reduce Cerebrovascular Dysfunction in South African patients with HIV and Metabolic Syndrome: A Phase II Pilot Trial. SMART

Award Number: R21TW012185
ORGANIZATION: FOGARTY INTERNATIONAL CENTER
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/11/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Study of Metformin to reduce Cerebrovascular Dysfunction in South African patients with HIV and Metabolic Syndrome: A Phase II Pilot Trial. SMART - Project Summary 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2022	STELLENBOSCH UNIVERSITY	ADMINISTRATION BUILDING B, VICTORIA ST	STELLENBOSCH				ZAF	International Research and Research Training	000	2	4/21/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2022	STELLENBOSCH UNIVERSITY	ADMINISTRATION BUILDING B, VICTORIA ST	STELLENBOSCH				ZAF	International Research and Research Training	000	2	10/28/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $145,800 )
2022	2022	UNIVERSITEIT STELLENBOSCH	ADMINISTRATION BUILDING B, VICTORIA STREET	STELLENBOSCH				ZAF	International Research and Research Training	002	2	6/8/2022	NON-COMPETING CONTINUATION	$145,800
2022	2021	UNIVERSITEIT STELLENBOSCH	ADMINISTRATION BUILDING B, VICTORIA STREET	STELLENBOSCH				ZAF	International Research and Research Training	000	1	10/22/2021	NEW	$0
2022	2021	UNIVERSITEIT STELLENBOSCH	ADMINISTRATION BUILDING B, VICTORIA STREET	STELLENBOSCH				ZAF	International Research and Research Training	001	1	2/18/2022	NEW	$0
														Subtotal = $145,800

Issue Date FY: 2021 ( Subtotal = $156,536 )
2021	2021	UNIVERSITEIT STELLENBOSCH	ADMINISTRATION BUILDING B, VICTORIA STREET	STELLENBOSCH				ZAF	International Research and Research Training	000	1	8/6/2021	NEW	$156,536
														Subtotal = $156,536

Grand Total All Awards = $302,336

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Study of Metformin to reduce Cerebrovascular Dysfunction in South African patients with HIV and Metabolic Syndrome: A Phase II Pilot Trial. SMART

Award Number: R21TW012185

ORGANIZATION: FOGARTY INTERNATIONAL CENTER

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/11/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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