Statin Use in HIV-Positive People
In contrast to this study, the final poster presented by Kenneth Lichtenstein reported an increased risk of DM with statin use in 4962 patients at 9 U.S. clinic sites in the HIV Out Patients Study (the HOPS cohort) who were prospectively followed from 2002-2011.10
Of these patients, 590 received statins during follow-up of a mean 49.4 months (IQR 21.7-78.1). New DM was diagnosed in 355 patients (crude incidence of 3.06 per 100 person-year while prescribed statins vs. 1.16 otherwise). In multivariate analysis, per year of statin use was associated with a 10% increased risk of incident DM (HR 1.10; 95%CI 1.01, 1.30), p=0.038. Other significant factors included older age, Hispanic race, BMI > 30 kg/m2 but not with individual ARVs or protease inhibitor use.
The conclusion from this study was that this showed the importance of routinely monitoring glucose in HIV positive patients and that these findings would be unlikely to reduce appropriate statin use for hyperlipidaemia and statin use should not be avoided when clinically warranted.
Questions relating to the methodology of this study included whether patients on statins would routinely be monitored more frequently for glucose tests, that higher diagnosis might relate to use of single elevated glucose results and that the U.S. background population risks, including BMI might be higher compared to Italians.
The full panel discussion emphasised the importance of separating use when clinically indicated from use when not clinically indicated (in the belief there are other benefits). While there are no data to support not using statins when indicated, the data are currently unknown for non-indicated use and this was not answered by any of the retrospective studies discussed in the session. It also included a comment that the assumption that inflammation is on the causal pathway for cardiovascular disease may be incorrect as there is little data supporting this in the general population.
In summary, Priscilla Hsue emphasised the strong associated between even modest LDL reductions in the general populations reducing major coronary events and mortality, with the impact on risk correlating to the degree of LDL reductions.11,12
HIV studies are largely small and observational compared to large randomised studies in the general population. In general population studies, statins are largely beneficial even in patients with diabetes, with similar benefits irrespective of DM status.13 However, the 9% increase risk of incident diabetes reported has a low absolute risk: requiring 255 patients (95%CI 150-852) to be treated for four years to produce on new case of DM.14
Finally, there were two late breaker oral presentations to the main conference.
In the first, Grace McComsey from Case Western Reserve University and colleagues reported early 24-week results on impact of rosuvastatin on cellular activation markers in treatment experienced patient on ART (~ median 6 years; IQR 3-10), but with normal LDL cholesterol (<130 mg/dL).15
This is a 96-week study looking at the impact of rosuvastatin on cardiovascular and bone health in 147 adults randomised to rosuvastatin 10 mg or matching placebo. Entry criteria included evidence of immune activation and/or inflammation (defined as CD8+CD38+HLA-DR+ >19% and/or hsCRP >2 mg/L, respectively).
At 24-weeks, rosuvastatin only significantly reduced one out of five inflammation markers (Lp-PLA2, with no impact on IL-6 or hsCRP) and two out of six markers of monocyte activation (sCD14 and CD14dimCD16+TF+ monocytes). Rosuvastatin had no impact on a panel of markers of lymphocyte activation or coagulation.
Further results from this study are needed in this mixed population. Although LDL was normal, median BMI was 26 and >30 kg/m2 in 25% of participants, >60% are current smokers, ART experience is extensive with 50% of current PI-based treatment.
The second late-breaker presented results from a randomised phase 4 study, designed to show superiority of the more recently approved pitavastatin (approved 2010 in the UK) compared to pravastatin (available as generic for at least five years) based on the primary endpoint of greater reductions in LDL cholesterol at 12 weeks.16
Although pitavastatin has reduced potential for CYP-mediated drug-drug interactions, metabolism is glucuronidation via UGT1A3 and UGT2B7. Pitavastatin is only marginally metabolized by CYP2C9 and to a lesser extent by CYP2C8
The study was sponsored by Kowa Pharmaceuticals, manufacturers of pitavastatin, and enrollment criteria included dyslipidaemia defined as LDL-C between 130-220 mg/dL and triglycerides ≤400 mg/dL.
Mean (SD) percentage changes in LDL at week 12 were -31.5 mg/dL (15.3) vs -20.9 mg/dL (15.2), mean difference -9%, p<0.001. Similarly significant differences were seen in reductions in Apo B and total cholesterol, but no difference were seen for HDL or triglyceride levels. No results were given in terms of the percentages of patients achieving target lipid levels. Tolerability results were similar for both drugs.
Taken together, the posters in this session did not addto what is already a confusing field, due to problems in the study designs.
The first study (Rasmussen) found no effect for primary prevention, but did find an effect in those with a prior co-morbidity. This would be slightly at odds with the general population where there is a (albeit relatively small) benefit of statin use in thegeneral population.
The second study (Drechsler) didn't find any association with CVD -- but did adjust for LDL as a time-updated covariate. This is on the causal pathway between statin use and MI development, so adjusting for this as a time-updated covariate is likely to remove the very effect you're looking for (like adjusting for time-updated CD4 count when assessing the effect of ART on mortality). This makes interpretation difficult. For example, they report that statins were protective of mortality in the univariate analysis which would not normally be expected as people who receive statins generally have multiple risk factors for CVD, many of which are also risk factors for mortality (high BMI, smoking, family history of CVD,older age, male gender). A study that doesn't find a negative association of mortality with statins in unadjusted analysis is unusual.
Most studies also have too limited data to be able to remove confounding in multivariate analyses. The same issue is relevant for the Spagnuolo study (as well as the issues about under-ascertainment).
The final study (Lichtenstein) is most convincing, although whether statins had causal relationship to the increased DM risk, or were just a consequence of unmeasured confounding), remains unclear.
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