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Metformin Prevented CAC Progression But Lifestyle Modification Did Not
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Reported by Jules Levin
CROI 2012 Seattle March 5-8
The study was relatively small. Perhaps a larger study might find a beneficial effect by lifestyle modification on CAC, the study author presenter Fitch said. In Q&A from the audience it was noted that only half of the patients in this study 5/13 or 15 had CAC at baseline, see baseline characteristics in webcast. Jim Stein questioned the large improvement seen in such a small study, see webcast. Graeme Moyle raised a question that seemed to imply to me that effect of Metformin may be related to the fact that patients had insulin resistance, see webcast.
Of course Metformin also prevented insulin resistance. Exercise/lifestyle modification improved HDL, fat in the muscle and in the inflammatory marker hsCRP.
Of particular note I think was the author reporting CAC progression over 12 months only in the groups that did not receive Metformin was 56% progression which is double the rate seen in the general population.
Fitch summarized:
Metformin had a significant effect to prevent progression of CAC & calcified plaque volume.
Metformin also had a significant effect to improve HOMA-IR.
LSM significantly improved HDL, hsCRP, IMCL(fat in muscle), and measures of physical fitness.
The potential mechanism of the effects of Metformin are "at this time unkown", potential mechanism: effects on insulin resistance, anti-inflammatory effects, activation of AMP kinase.
More studies are needed to understand the effect of Metformin, mechanisms of Metformin in preventing CAC progression in this study.
Patients were excluded for history of angina or aortic stenosis, uncontrolled hypertension, current insulin or diabetic medications, fasting blood sugar >126 mg/dL, creatinine >1.5 mg/dL(males, 1.3 mg/dL (females), lactate >2x ULN, and ALT>2.5 x ULN.
Inclusion criteria included NCEP defined metabolic syndrome, 3 of the following:
HDL <40 mg/dL men, <50 mg/dL women
waist circumfrance >102 cm men, >88cm women
triglycerides >149 mg/dL or current lipid lowering therapy, blood pressure >/= 130/85 mmHg or current antihyperintensive use
fasting glucose >/= 100 mg/dL
Lifestyle modification included
60 minutes, 3x weekly cardiovascular and strengt training
weekly nutrition counseling
Baseline and 12 month visits:
fasting bloods
cardiac CT for CAC & CA+ plaque volume
MRI/MRS for body comp
Link to webcast:
http://app2.capitalreach.com/esp1204/servlet/tc?c=10164&cn=retro&s=20481&&dp=player.jsp&e=16637&mediaType=podiumVideo
Abstract
Effects of Life-style Modification and Metformin on Coronary Calcium in HIV<+>/supersc> Patients with the Metabolic Syndrome
Kathleen Fitch*, S Abbara, H Lee, E Stavrou, R Sacks, T Michel, L Hemphill, M Torriani, and S Grinspoon
Massachusetts Gen Hosp, Boston, US
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 VO2max, 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.
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