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
“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
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].”