In early rheumatoid arthritis (RA), treatment with the antimalarial hydroxychloroquine may reduce the risk of hyperlipidemia, when compared with methotrexate (MTX), according to a large retrospective study from Brigham and Women’s Hospital, Boston.
The study of disease-modifying antirheumatic drug (DMARD) use also noted a possible increase in hyperlipidemia risk in some initiating treatment with tumor necrosis factor alpha (TNF alpha inhibitors). The investigation was led by Rishi J. Desai, PhD, a postdoctoral research fellow in the hospital’s Division of Pharmacoepidemiology and Pharmacoeconomics.
Although RA patients have a generally higher risk of cardiovascular disease (CVD), several studies have suggested that RA patients may have lower total and low-density lipoprotein (LDL) cholesterol than persons without RA. “Reports of inverse association between inflammatory markers and lipid parameters may explain this phenomenon,” Desai and associates wrote.
The study examined two large commercial insurance organizations’ claims data from 2001 to 2012 and was reported in the April 2015 issue of Arthritis Care and Research. The primary outcome was incident hyperlipidemia, defined by a diagnosis and a prescription for a lipid-lowering agent.
For the subgroup of patients with available pre-study laboratory results, changes in lipid levels were also assessed.
Excluding those diagnosed with a range of CVDs, or hyperlipidemia, or prescribed lipid-lowering drugs, the investigators identified 17,145 eligible new RA patients from a larger cohort of 30,831.
Patients — more than 70% female and on average in their mid to late 40s — were categorized into one of four mutually exclusive groups based on their DMARD of initiation on the index date: TNF alpha inhibitors, with or without other nonbiologic DMARDs; MTX without hydroxychloroquine or TNF alpha inhibitors; hydroxychloroquine without MTX or TNF alpha inhibitors; and other nonbiologic agents without MTX, hydroxychloroquine, or TNF alpha inhibitors.
The largest proportion (46.32%) initiated treatment with MTX (the reference treatment), followed by hydroxychloroquine (35.75%), other nonbiologic agents (12.04%), and TNF alpha inhibitors (5.89%). In the other-nonbiologics group, the majority of the patients initiated treatment with sulfasalazine (75.6%), leflunomide (15.4%), or azathioprine (6.8%).
The four exposure groups had similar distributions of age, hypertension, and diabetes mellitus. The frequency of obesity, smoking, CVD drug, and analgesic use was lower in TNF alpha inhibitor initiators, while hydroxychloroquine initiators had the highest proportion of females (84.06%). In a subgroup with available pre-index outpatient C-reactive protein (CRP) results, hydroxychloroquine initiators had a lower proportion of patients with high CRP levels (defined as >3 mg/dL). The distribution of CRP levels was similar in the remaining three subgroups.
Of the 17,145 early-RA patients, 364 developed hyperlipidemia. Compared with MTX, in the full cohort the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for hyperlipidemia were 1.41 (95% CI 0.99-2.00) for TNF alpha inhibitors; 0.81 (95% CI 0.63-1.04) for hydroxychloroquine; and 1.33 (95% CI 0.95-1.84) for other nonbiologic DMARDs. HRs for the propensity score-trimmed cohort were 1.18 (95% CI 0.80-1.73), 0.75 (95% CI 0.58-0.98), and 1.41 (95% CI 1.01-1.98), respectively.
In the subgroup analysis, hydroxychloroquine use showed significant reductions in lipids from baseline compared with MTX. For LDL cholesterol the decrease was -8.9 mg/dL (95% CI -15.8 to -2.0); for total cholesterol it was -12.3 mg/dL (95% CI -19.8 to -4.8); and for triglycerides it was -19.5 mg/dL (95% CI -38.7 to -0.3).
Based on its possible role in cholesterol metabolism, the lipid-lowering potential of hydroxychloroquine has been evaluated in several studies of RA and systemic lupus erythematosus patients that also reported reductions in LDL and total cholesterol. Although the effect of inflammation has garnered the most attention over the past decade, traditional factors continue to play a crucial role in the development of CVD in RA patients. “Therefore, understanding RA treatments associated with favorable changes in traditional cardiovascular risk factors can inform cardiovascular risk management in RA,” the authors wrote.
Primary analysis noted increased hyperlipidemia risk in patients starting treatment with anti-TNF alpha versus MTX, but the association was attenuated in the analysis stratifying by propensity score (PS), so that ultimately TNF alpha inhibition was not associated with risk elevation. “The discrepancy in the effect of TNF alpha inhibitors on the risk of hyperlipidemia between the full cohort and the PS trimmed cohort deserves discussion,” the authors wrote.
According to Desai and associates, previous meta-analyses have observed increased total cholesterol levels after anti-TNF alpha. The thinking is that higher levels of inflammation may reduce total cholesterol, whereas inflammation control via anti-TNF alpha may “normalize” lipid levels, while conferring other important CV benefits such as improved endothelial function.
Addressing the study’s limitations, the authors noted its retrospective observational nature and the potential for confounding by indication as well as by variables not captured in insurance-claims data such as weight, physical activity, and/or dietary habits.
They called for more research on the effect of TNF alpha inhibition on hyperlipidemia.
Several of the authors reported industry support in the form of research funding, contributions to academic programs, and/or royalties or stock ownership.