Cardiovascular risks reduced for patients with HIV by therapy with metformin and changes to diet and exercise

Treatment with the anti-diabetes drug metformin helps prevent the progression of sub-clinical cardiovascular disease in patients with HIV, according to the results of a randomised, placebo-controlled study published in the online edition of AIDS.

The study also showed that dietary changes and a thrice-weekly exercise regimen improved lipid profiles and overall cardiovascular fitness.

“We saw an effect of metformin to prevent significant increase in coronary artery calcification and calcified plaque volume over one year of follow up,” write the investigators. “Compliance with the medication was good…Safety and tolerance were good.”

It is now recognised that HIV-positive patients have an increased risk of cardiovascular disease. Sub-clinical cardiovascular disease is also seen with increased frequency in patients with HIV, who generally have a high prevalence of diabetes, dyslipidemia, high blood pressure and abdominal obesity. Such a collection of disorders is often referred to as metabolic syndrome and has been associated with increased calcification of the coronary artery.

HIV care guidelines stress the importance of diet and exercise for the management of metabolic syndrome.

Treatment with the anti-diabetes drug metformin may also have a role. Research in HIV-negative, over-weight patients with diabetes showed that the therapy significantly reduced rates of cardiovascular events. However, data are currently lacking on the drug’s safety and effectiveness in patients with HIV.

Therefore, investigators from the Massachusetts General Hospital designed a study to assess the impact of metformin treatment and lifestyle modification on calcification of the coronary artery and other established cardiovascular risk factors in patients with HIV.

A total of 50 patients, all of whom had metabolic syndrome, were recruited to the study between 2006 and 2010.

The patients were randomised into four arms:

• No lifestyle modification and placebo.

• Lifestyle modification and placebo.

• No lifestyle modification and metformin.

• Lifestyle modification and metformin.

The impact of these interventions on calcification of the coronary artery, diet and fitness, metabolic, biochemical and immunological parameters was assessed. Follow-up was for twelve months.

Patients had been infected with HIV for a median of 14 years and had been taking antiretroviral therapy for a median of six years. There were no significant differences between the four study arms in the characteristics of the patients.

Individuals treated with metformin demonstrated significantly less progression of coronary artery calcification than those who received the placebo (p = 0.004).

In contrast, there were no differences in coronary artery calcification scores between patients who changed their diet and exercise habits and those who did not have any lifestyle modification.

Therefore, metformin had a significantly greater effect on calcification of the coronary artery than lifestyle modification (p = 0.01).

In addition, individuals who were treated with metformin also demonstrated less progression of calcified plaque volume than the patients who received the placebo (p = 0.008).

Overall, plaque progression was greatest among the patients randomised to the no lifestyle modification and placebo arm. The median increase in coronary artery calcification among these patients was 56%. In contrast, the smallest increase was among patients in the lifestyle modification and metformin arm (p = 0.03). Significantly less coronary artery calcification was also seen in the group of patients who did not modify their diet and exercise habits, but who were treated with metformin (p = 0.01).

Unsurprisingly, lifestyle modification improved exercise capacity and strength (p < 0.01). However, metformin therapy had no impact on these parameters.

Changes to diet and exercise were also shown to have benefits for HDL-cholesterol levels (p = 0.03). Furthermore, lifestyle modification reduced levels of C-reactive protein (CRP), an important marker of inflammation (p = 0.05).

Treatment with metformin also had some metabolic benefits. Patients who received the drug had significantly better HOMA-IR scores (a marker of insulin resistance) than individuals randomised to receive the placebo (p = 0.05).

Neither of the interventions was associated with serious adverse events. However, lifestyle modification was associated with a small but significant reduction in CD4 cell count (p = 0.04). Two of the metformin-treated patients experienced mild elevations in creatinine levels. These returned to normal after the dose of the drug was modified. Several patients taking the drug also reported mild gastrointestinal side-effects.

“Our data demonstrate that metformin had a robust effect to prevent progression of coronary artery calcification and calcified plaque volume while improving HOMA-IR over one year in HIV patients with metabolic syndrome,” comment the authors. “Lifestyle modification had a lesser effect to prevent plaque progression than metformin.”

They conclude: “Further studies are now needed to understand the mechanisms of metformin to prevent calcified plaque progression and to determine whether metformin, alone or in combination with other strategies, might reduce or prevent cardiovascular disease events in [patients with HIV].”