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Improved HIP Bone Density But Worse Insulin Resistance With Rosuvastatin
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CROI 2014, March 3-6, 2014, Boston
Mark Mascolini
Rosuvastatin for 48 weeks significantly improved total hip (but not spine) bone mineral density (BMD) in a double-blind placebo-controlled single-center study [1]. But insulin resistance worsened in people taking the statin.
Statins boost expression of the bone morphogenetic protein 2, which enhances bone formation, noted principal investigator Grace McComsey (Case Western University Cleveland), and recent studies found modest BMD gains with statins. But the impact of statins on BMD had not been studied in HIV-positive people until this trial. Studies in people with HIV--and in the general population--have yielded conflicting results on whether and how statins affect glucose, insulin, and diabetes risk.
The investigators enrolled adults taking antiretroviral therapy for more than 6 months with a viral load below 1000 copies, fasting low-density lipoprotein cholesterol at or below 130 mg/dL, and heightened immune activation indicated by high levels of CD8+CD38+DR+ cells and high-sensitivity C-reactive protein (hcCRP). No one had cardiovascular disease, diabetes, or a history of fragility fractures. And no one was taking immunomodulatory drugs, drugs toxic to bone (except antiretrovirals), or hypolipemics. The investigators randomized 72 people to rosuvastatin and 75 to placebo.
The statin and placebo groups did not differ in median age (46 and 47), median body mass index (27 and 27), or proportion of men (81% and 76%), whites (28% and 31%), or smokers (60% and 72%). Three quarters of participants in both arms had a viral load below 50 copies, and median CD4 counts were in the 600s. About half of participants in both groups were taking protease inhibitors, and almost 90% in each group were taking tenofovir. The statin and placebo groups did not differ in median baseline glucose (79 and 79), insulin (8 and 11), or HOMA-IR (1.7 and 1.0).
At week 48 average total hip BMD rose 0.6% with rosuvastatin (P = 0.061 from baseline) and fell 0.6% with placebo, a significant between-group difference (P = 0.017). Average trochanter BMD rose 0.9% with the statin (P = 0.042 from baseline) and fell 0.7% with placebo (P = 0.042 between groups). (The trochanter is the top of the thigh bone.) Lumbar spine BMD changed hardly at all with rosuvastatin or placebo.
Bigger increases in hip BMD were associated with lower baseline TNF-R1 and greater increases in body mass index and sTNF-RI, but not with favorable changes in monocyte or lymphocyte activation markers.
Meta-analysis of five case-control studies, six cohort studies, and four randomized trials in the general population determined that statins may "improve and maintain" BMD in the hip and femoral neck--as well as the lumbar spine--especially in Caucasians and Asians [2].
Rosuvastatin for 48 weeks significantly increased fasting glucose 8% (P = 0.0017 versus baseline, P = 0.217 versus 3.3% rise with placebo), fasting insulin 52% (P = 0.0006 versus baseline, P = 0.0055 versus 5.5% rise with placebo), and insulin resistance as measured by HOMA-IR 72% (P = 0.0015 versus baseline, P = 0.0068 versus 14.5% rise with placebo). Diabetes developed in only 1 study participant, who was taking placebo.
Higher baseline sCD14 (an activation signal) and hsCRP were associated with bigger gains in HOMA-IR. But HOMA-IR was not linked to changes in inflammation or activation of lymphocytes or monocytes. Protease inhibitor use did not affect changes in insulin and HOMA-IR in this study.
A study like this cannot discern whether the changes seen are particular to rosuvastatin or apply to other statins as well. McComsey noted that larger and longer studies are needed to see whether statins prevent fractures. Follow-up will continue through 96 weeks. These 48-week findings indicate a need for close glucose and insulin monitoring in HIV-positive people taking statins.
References
1. McComsey GA, Jiang Y, Erlandson KM, Debanne SM. Rosuvastatin improves hip bone mineral density but worsens insulin resistance. CROI 2014. Conference on Retroviruses and Opportunistic Infections. March 3-6, 2014. Boston. Abstract 134.
2. Liu J1, Zhu LP, Yang XL, Huang HL, Ye DQ. HMG-CoA reductase inhibitors (statins) and bone mineral density: a meta-analysis. Bone. 2013;54:151-156.
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