Metformin, a drug used in the treatment of type 2 diabetes, may have a role in reversing weight gain in people with HIV on antiretroviral treatment, a small preliminary study suggests.
The drug’s impact on weight gain in people with HIV needs to be tested in larger studies, especially in women with HIV of African descent, say Canadian investigators reporting in the journal Open Forum Infectious Diseases.
People with HIV with low CD4 cell counts, women and black people tend to gain more weight after starting treatment than other people. Weight gain after starting treatment has varied widely; although studies show that people gain a median of 2kg in the first two years on treatment, a minority gain much more.
Substantial weight gain on HIV treatment may place people at risk of cardiovascular disease and other conditions associated with obesity, such as cancers. Why people gain weight is unclear. Identifying treatment options that can restrict or reverse weight gain may require a better understanding of what causes weight gain, but equally, existing medications shown to regulate weight in people without HIV may have a role in weight management.
Metformin is one agent that has been suggested as a potential treatment option.
Metformin is an insulin-sensitising drug. It works to correct blood sugar levels by increasing the amount of sugar taken up by tissues and reducing the amount released by the liver. In type 2 diabetes, the body fails to respond to signals from the hormone insulin to move glucose from the blood into tissues. Sugar builds up in the blood and can damage small blood vessels, eventually leading to kidney damage, nerve damage and heart disease if type 2 diabetes is left untreated.
Metformin also increases the variety of bacteria in the gut – the microbiota – and has been shown to reduce levels of inflammatory cytokines. These effects of metformin led Dr Stéphane Isnard of McGill University and colleagues to ask whether metformin might improve gut defects in people with HIV and reduce systemic inflammation, as well as reducing weight.
HIV causes damage to the gut, leading to leakage of microbes through the gut wall. This leads to systemic inflammation that contributes to the development of fatty liver disease, cardiovascular disease and cancers. Damage to the integrity of the gut also upsets the microbial balance in the gut (dysbiosis). Gut dysbiosis has been associated with poor CD4 recovery and immune activation in several studies of people taking antiretroviral treatment.
To investigate the effects of metformin in non-diabetic people with HIV, the researchers recruited 23 people with HIV who had viral load suppressed below 50 copies/ml on antiretroviral treatment for at least three years and a CD4/CD8 ratio < 0.7.
The study population was predominantly male (21) and white (15) with a median age of 56 years. Participants had been taking antiretroviral treatment for a median of ten years, had a median CD4 count of 435 and a median CD4/CD8 ratio of 0.6. Eighteen of 23 participants were taking a regimen containing an integrase inhibitor; the remainder were taking regimens containing a boosted protease inhibitor or efavirenz.
Participants received 850mg of oral metformin twice daily for 12 weeks and were followed for 12 weeks after discontinuation of treatment.
Study participants had fasting glucose levels within the normal range at baseline and fasting glucose levels did not change significantly during the study.
Although waist circumference did not change during the study, median weight fell by 1.6kg over 12 weeks of treatment (range -8kg to +2.3kg; p = 0.021) but returned to baseline 12 weeks after discontinuation of metformin. Median baseline weight was not stated by the authors but participant baseline weights ranged from approximately 50kg to 120kg.
Greater weight loss was associated with higher levels of GDF-15, a cytokine associated with appetite loss. Metformin has been shown to increase GDF-15 levels and correlate with weight loss in obese people and in this study plasma GDF-15 levels rose significantly during metformin treatment (p = 0.0003), returning to baseline after treatment discontinuation. Weight loss associated with GDF-15 was independent of integrase inhibitor treatment, age and sex.
Weight loss was also associated with changes in gut bacteria composition. Metformin treatment resulted in increased abundance of several types of bacteria that may be involved in the regulation of weight and inflammation. The investigators say that more research is needed into the roles of gut bacteria species in regulating weight in people with HIV.
A larger randomised trial is needed, they say, to investigate how metformin can regulate weight in people with HIV. Recruitment of women of African descent will be important, the investigators say, to gain a comprehensive view of metformin’s effects on weight in people with HIV.
Isnard S et al. Repurposing metformin in nondiabetic people with HIV: influence on weight and gut microbiota. Open Forum Infectious Diseases, 7: ofaa338, 2020.