SEATTLE – Treatment with the antidiabetic drug metformin halted the progression of coronary artery calcification in HIV-positive patients who had metabolic syndrome in a randomized clinical trial.
Lifestyle modification had a smaller, nonsignificant benefit, slowing down the progression of coronary artery calcification (CAC), according to the results of the 1-year trial, which enrolled 50 adult patients, Kathleen Fitch reported at the Conference on Retroviruses and Opportunistic Infections.
After 1 year of treatment, CAC scores had increased by 43 points with placebo, by 19 points with lifestyle modification alone, and by 1 point with metformin alone, and had decreased by 4 points with the combination of metformin and lifestyle modification (P = .03 for trend across groups).
Kathleen Fitch
Both interventions were well tolerated, and each had some additional benefits, said Ms. Fitch of the Program in Nutritional Metabolism at Massachusetts General Hospital, Boston. For example, metformin reduced insulin resistance, and lifestyle modification improved high-density lipoprotein cholesterol levels, fat content of muscle, C-reactive protein levels, and measures of physical fitness.
"Modification of risk factors for CVD [cardiovascular disease] is important in the management of HIV infection, including strategies for insulin resistance. Metformin may be a useful drug to modify CVD risk," she commented. "A larger study may be required to show lifestyle modification’s effect on CAC."
The study not only showed that metformin had a preventive effect on CAC progression, but also provided a window on the natural history of CAC progression over 1 year in these HIV-infected patients with metabolic syndrome, she said. In fact, the rate of progression seen in the placebo group was about twice the rate that has been reported for the general population.
To put the findings into clinical context, the investigators calculated adjusted Framingham risk scores for a hypothetical patient representative of their study population. At baseline, he had a 10-year risk of CVD events (12%) putting him at intermediate risk, but after a year with no intervention and the expected increase in CAC score, his risk more than doubled (25%), now putting him at high risk. "Importantly, this change would be preventable by metformin since we observed no progression of CAC among those taking metformin," Ms. Fitch said.
Dr. Jens Lundgren of the University of Copenhagen noted that the study may have been limited by the fact that only about half of patients had detectable CAC at baseline, reducing the population that could benefit. "So if you screened for CAC at baseline, would that optimize your power?" he asked.
"Initially, we weren’t sure if every patient would have detectable CAC. We also would hope that metformin would prevent development of CAC in these subjects," Ms. Fitch replied; however, it is possible that subsequent studies might include only patients having detectable CAC.
Dr. James Stein of the University of Wisconsin, Madison, said it was a "great study," but he questioned the possible impact of an imbalance in patients having detectable CAC at baseline, noting that "the single biggest predictor of CAC progression is the presence of CAC to begin with." He recommended repeating the analysis, taking that factor into account. "In the context of many other things that have been looked at for calcium progression, it’s a surprise to see such a change in such a small study," he added.
HIV-positive patients were eligible for the trial if they were 18-65 years old, had been on a stable treatment regimen for more than 6 months, and met criteria for metabolic syndrome but did not have diabetes. "Very few established treatment options exist for this population," Ms. Fitch said.
They were randomized nearly equally to four groups treated on a double-blind basis: placebo with and without lifestyle modification, and metformin with and without lifestyle modification.
Lifestyle modification consisted of 60 minutes three times weekly of cardiovascular and strength training, plus weekly nutrition counseling. Metformin (Glucophage and others) was given at a dose of 500 mg twice daily for 3 months, and then 850 mg twice daily thereafter. CAC was assessed with computed tomography.
The patients’ average age was about 47 years, and 76% were men. The majority were already taking antihypertensive and lipid-lowering medications. Overall, 44% had detectable CAC at baseline.
The four groups had similar rates of treatment discontinuation and similarly high rates of treatment compliance, Ms. Fitch reported. Both interventions were well tolerated: There were six cases of gastrointestinal adverse effects with metformin and two cases of muscle strain with the lifestyle modification.
"Further studies are clearly needed to understand the mechanisms of metformin to prevent CAC progression," she concluded. "And larger, longer-term studies using metformin in HIV-infected patients with metabolic syndrome and insulin resistance will be useful to determine whether this strategy will prevent CVD events."