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, reports Aidsmap.
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.
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.
Abstract
Background
People with HIV (PWH) taking antiretroviral therapy (ART) may experience weight gain, dyslipidemia, increased risk of non-AIDS comorbidities, and long-term alteration of the gut microbiota. Both low CD4/CD8 ratio and chronic inflammation have been associated with changes in the gut microbiota of PWH. The antidiabetic drug metformin has been shown to improve gut microbiota composition while decreasing weight and inflammation in diabetes and polycystic ovary syndrome. Nevertheless, it remains unknown whether metformin may benefit PWH receiving ART, especially those with a low CD4/CD8 ratio.
Methods
In the Lilac pilot trial, we recruited 23 nondiabetic PWH receiving ART for more than 2 years with a low CD4/CD8 ratio (<0.7). Blood and stool samples were collected during study visits at baseline, after a 12-week metformin treatment, and 12 weeks after discontinuation. Microbiota composition was analyzed by 16S rDNA gene sequencing, and markers of inflammation were assessed in plasma.
Results
Metformin decreased weight in PWH, and weight loss was inversely correlated with plasma levels of the satiety factor GDF-15. Furthermore, metformin changed the gut microbiota composition by increasing the abundance of anti-inflammatory bacteria such as butyrate-producing species and the protective Akkermansia muciniphila.
Conclusions
Our study provides the first evidence that a 12-week metformin treatment decreased weight and favored anti-inflammatory bacteria abundance in the microbiota of nondiabetic ART-treated PWH. Larger randomized placebo-controlled clinical trials with longer metformin treatment will be needed to further investigate the role of metformin in reducing inflammation and the risk of non-AIDS comorbidities in ART-treated PWH.
[link url="https://academic.oup.com/ofid/article/7/9/ofaa338/5889914"]Full Open Forum Infectious Diseases study[/link]