A Pilot Study of Metformin to Reduce Cerebrovascular Dysfunction in Participants With HIV and Metabolic Syndrome.

NCT ID: NCT05571319

Last Updated: 2025-10-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-08-11
• Study Completion Date: 2025-03-28

Brief Summary

Metabolic syndrome is a constellation of risk factors for cardiovascular disease and type 2 diabetes mellitus which frequently occur together. Data is emerging suggesting metabolic syndrome causes brain disease by contributing to blood vessel damage and inflammation. People living with HIV (PLWH) are at high risk and the investigators will perform a pilot study of the well-known type 2 diabetes drug metformin to treat this blood vessel damage and inflammation in PLWH.

Detailed Description

Background: Metabolic syndrome (MetS) is a constellation of risk factors for cardiovascular disease and type 2 diabetes mellitus (T2D) 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 sub-Saharan Africa with the prevalence similar to that of high-income countries. Older antiretroviral regimens are 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.

The investigtors hypothesise that metformin is effective in treating endothelial dysfunction and thus ameliorating cerebrovascular function in HIV-positive patients with metabolic syndrome. 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 T2D. Metformin is widely available in public service settings and is considered to have a clinical effect beyond glucose lowering. Based on the rationale above, the investigators 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.

Objective: The investigators propose to address the Specific Aims listed below in HIV-positive participants with metabolic syndrome virologically suppressed on standard of care cART receiving open-label metformin 12 weeks. Aim 1: To obtain preliminary data on the effect of metformin on cerebral vascular reactivity and cerebral blood flow in HIV positive participants with metabolic syndrome. Aim 2: To assess whether metformin associated changes in cerebral vascular reactivity and cerebral blood flow (CBF) are mediated via improvements in endothelial function.

Methods: The investigators will enroll 30 participants in an open-label study of metformin treatment for 12 weeks with a 4-week washout period and a final evaluation. Comprehensive metabolic, laboratory and neuroimaging evaluation will be performed at screening and 12 weeks with selected procedures repeat after the 4 weeks washout period at week 16. Whole body dual-energy X-ray absorptiometry (DEXA) at study entry will be used to assess adipose tissue location.

Outcome: 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, the investigators 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.

Conditions

Metabolic Syndrome; HIV Seropositivity

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Open-label arm

All participants to receive metformin extended-release 1000mg to 2000mg daily for 12 weeks.

Group Type: EXPERIMENTAL

Metformin Extended Release Oral Tablet

Intervention Type: DRUG

Glucophage XR 500 mg

Interventions

Metformin Extended Release Oral Tablet

Glucophage XR 500 mg

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Adult (>18 years);
• HIV+ on antiretroviral therapy for at least 12 months prior to study entry;
• Viral load ≤50 copies/mL;
• Able to provide informed consent;
• Metabolic syndrome as per the harmonized criteria;
• Women of child-bearing potential willing to use adequate contraception (defined as either an intra-uterine contraceptive device or hormonal contraceptive);

Exclusion Criteria

• Treated with metformin as part of care;
• History of drug or alcohol abuse within 3 months before screening;
• Known neurosyphilis;
• Known vitamin B12 deficiency;
• Known neuropsychiatric disorders or serious psychiatric symptoms;
• Significant head trauma with imaging structural abnormalities;
• Renal impairment (estimated glomerular filtration < 60 mL/min/1.73m2);
• Type I or type II diabetes (fasting plasma glucose >7mmol/L and/or HbA1c >6.5%);
• Hypersensitivity to metformin;
• Any contraindication or special precaution in the metformin package insert which may put the participant at a safety risk;
• Cationic drugs (as listed in the metformin package insert) that may increase metformin concentrations significantly;
• Claustrophobia, metal implants or any other condition that prevents performing MR scan;
• Pregnant / breastfeeding;

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Rochester

OTHER

Sponsor Role: collaborator

Fogarty International Center of the National Institute of Health

NIH

Sponsor Role: collaborator

University of Stellenbosch

OTHER

Sponsor Role: lead

Responsible Party

Eric Decloedt

Associate Professor & Head of Clinical Pharmacology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Eric Decloedt, MBChB, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Stellenbosch

Locations

Desmond Tutu Health Foundation: Gugulethu Research Site

Cape Town, Western Cape, South Africa

Countries

South Africa

Other Identifiers

R21TW012185-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

M21/10/024

Identifier Type: -

Identifier Source: org_study_id