Background:  Metabolic abnormalities including insulin resistance, dyslipidemia, and hypertension occur commonly in HIV-infected patients.  These abnormalities are associated with increased coronary artery calcification (CAC), and contribute to increased cardiovascular disease (CVD) in this population. As shown by the MESA study, increased CAC is a strong predictor of CVD. We hypothesized that lifestyle modification (LSM) and metformin would improve CVD indices in HIV-infected patients with NCEP defined metabolic syndrome.

Methods:  A 12 month, randomized, placebo controlled trial to investigate LSM and metformin, alone and in combination was conducted among HIV-infected patients with metabolic syndrome.  The primary endpoint was change in CAC score.  We assessed CAC scores and calcified plaque volume using a 64-slice CT scanner.  Fasting lipids, insulin and measures of cardiorespiratory fitness were assessed.  50 subjects (age 47 ± 1 yr) were randomized, 76% were male, 48% White, 30% African American, and 18% Hispanic.    

Results:  Metformin-treated subjects demonstrated significantly less progression of CAC over 12 months  (-1 ± 2 vs. 33 ± 17, P=0.004) (Figure 1a), less progression in calcified plaque volume (-0.4 ± 1.9 vs. 27.6 ± 13.8 mm³, P=0.008), improved HOMA-IR (-0.1 ± 0.4 vs. 1.1 ± 0.4, P=0.05) and RANKL/OPG ratio          (-0.0002 ± 0.0002 vs. 0.0003 ± 0.0002, P=0.02) compared to placebo.  Subjects randomized to LSM vs. no LSM showed significant improvement in HDL (3 ± 1 vs. -1 ± 1 mg/dl, P=0.03), CRP (-1.57 ± 0.70 vs. 0.08 ± 0.45 mg/L, P=0.05), and cardiorespiratory fitness (2.9 ± 1.1 vs. -1.0 ± 0.9 VO_2max, P=0.009).  The effects of LSM on CAC were not significant (Figure 1b). For CAC, the net effect of metformin (vs. placebo) controlling for LSM randomization was -42 and the net effect of LSM (vs. no LSM) controlling for metformin randomization was -24.  Changes in CAC among the 4 groups: 1) no LSM, placebo (43 ± 30); 2) LSM, placebo (19 ± 7); 3) no LSM, metformin (1 ± 1); and 4) LSM, metformin (-4 ± 6) were different (P=0.03 for ANOVA and linear trend across groups) (Figure 1c), the majority of this effect was mediated by metformin.

Conclusions: HIV-infected patients with the metabolic syndrome demonstrate significant plaque progression over time. Treatment with metformin over one year prevents plaque progression in this population.  One potential mechanism of this benefit on CAC may be via modulation of the RANKL/OPG system.