Clinician Roundtable: Statins for CV Risk Reduction in Rheumatoid Arthritis

The risk for cardiovascular disease (CVD) is elevated significantly in patients with rheumatoid arthritis (RA).¹ CVD has been cited as the top cause of death in people with RA, contributing to nearly 40% of mortality in this population. In addition, study results have demonstrated that those with RA have twice the risk for myocardial infarction and stroke compared with the general population, and the risk is nearly 3-fold among those who have had RA for at least 10 years.¹

“It is well-established that accelerated atherosclerosis and vascular dysfunction in the setting of RA are the result of a complex interplay between traditional CVD risk factors, such as dyslipidemia, insulin resistance, hypertension, limited physical activity, and obesity, and RA-related characteristics including chronic high grade inflammation and autoimmune activation,” according to a recent review published in Frontiers in Medicine.² Such observations underscore the need for aggressive CVD risk management in these patients, taking into account both inflammation control and modification of previously validated traditional CVD risk factors.

Although findings on the topic are limited thus far, a growing body of research supports the benefits of statins in lowering CVD risk in RA. For people with RA treated at the Cleveland Clinic in Cleveland, Ohio, clinicians “aim to lower inflammation and lipids via statins if indicated,” Leslie Cho, MD, cardiologist and director of the Cleveland Clinic’s Women’s Cardiovascular Center told Rheumatology Advisor. “It goes without saying that we encourage aggressive dietary and lifestyle modification as well before we start statins.”

Results of selected relevant studies on the topic are highlighted below:

• Compared with placebo, patients with RA randomly assigned to simvastatin 40 mg/day showed significant improvement in flow-mediated dilatation, a measure of nitric oxide-dependent vascular endothelial function.³
• Arterial stiffness as measured by augmentation index decreased by 12% in patients with RA treated with atorvastatin 20 mg/day for 12 weeks.⁴ Patients with higher baseline disease activity scores demonstrated the greatest augmentation index reductions.
• In the Trial for Atorvastatin in Rheumatoid Arthritis, patients were randomly assigned to receive 40 mg atorvastatin or placebo along with their current disease-modifying therapy.⁵ Following 6 months of treatment, the intervention group showed significant improvement in levels of intercellular adhesion molecule 1 and fibrinogen.
• Statin treatment was found to be 92.1% successful in helping patients with RA achieve lipid goals.⁶
• In patients with comorbid RA and dyslipidemia, a combination of atorvastatin 5 or 10 mg/day along with adequate control of inflammation and disease activity led to significant reductions in lipid levels.⁷
• Compared with placebo, rosuvastatin 10 mg for 12 months led to significant reductions in total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B levels.⁸

The results of these studies suggest that statins may have a favorable effect on vascular function in RA, although more research is needed to inform clinical recommendations. Despite their lipid-lowering effects and potential angioprotective, antioxidative, and anti-inflammatory benefits, as well as their favorable safety profile, the “blanket use of statins on all [patients with] RA cannot be supported by evidence, thus appropriate CVD risk assessment tools for this population are necessary, which in addition to established risk factors could include noninvasive vascular assessments, particularly carotid intima media thickness,” the authors of the European League Against Rheumatism recommendations for CVD risk management in rheumatoid arthritis concluded.⁹

Dr Cho notes that all patients with RA who are seen at the Cleveland Clinic are also referred to a preventive cardiologist.

To further explore the topic from the clinician perspective, Rheumatology Advisor spoke with Seth S. Martin, MD, MHS, FACC, FAHA, assistant professor of medicine and cardiology, and co-director of the Johns Hopkins Lipid Center at the Ciccarone Center for the Prevention of Heart Disease; and Jane E. Salmon, MD, a rheumatologist and Collette Kean Research Professor at the Hospital for Special Surgery, New York, and professor of medicine at Weill Cornell College of Medicine, New York.  

Rheumatology Advisor: What is known about the effects of statins on CV risk in RA, and what are the proposed underlying mechanisms?

Dr Martin: The Cholesterol Treatment Trialists’ Collaboration has shown that statins lower CVD risk in a wide variety of patients at risk through low-density lipoprotein cholesterol lowering.¹⁰ These are far and away the best data we have for treating CVD risk in RA. Although these data do not include specific clinical trials of RA, we have every reason to believe the same benefits apply [for people with] RA. The main mechanism therefore is lipid lowering, but other mechanisms may also be at play. RA is an autoimmune, inflammatory condition and some data indicate that immunomodulatory and anti-inflammatory effects could contribute to the benefits of statins.

Dr Salmon: Statins have pleiotropic effects — lipid lowering and anti-inflammatory. Evidence from multiple studies indicates that statins are efficacious in lowering CV risk in patients with RA.

Rheumatology Advisor: What are the top treatment implications for clinicians?

Dr Martin: 

• Traditional risk calculators can be used in people with RA but may underestimate risk.
• Subclinical atherosclerosis imaging, such as coronary artery calcium scoring, can be used to clarify risk in people with RA.
• RA is an inflammatory condition that can contribute to CV risk, and these patients warrant extra attention with respect to reducing risk through lifestyle modification and pharmacotherapy.
• Because of the totality of efficacy and safety data, and their cost, statins are first-line pharmacotherapy for lipid lowering in people with RA to reduce CV risk.

Dr Salmon:

• Assess and manage traditional CV risk factors.
• Interpreting lipid levels in people with RA while disease is active is difficult. Systemic inflammation may lower total cholesterol, but this is paradoxically associated with increased CV risk. Ideally, lipids should be checked when RA disease activity is low or absent.
• RA disease activity contributes to CV risk, and its management reduces risk.

Rheumatology Advisor: What should be the focus of future research in this area?

Dr Martin: A top priority for future research is to refine methods for assessing CV risk in [people with] RA. This will set the foundation for treating patients with statins who are most likely to benefit. Whether immunomodulatory and anti-inflammatory effects truly contribute in a clinically significant way to the benefits of statins remains uncertain, so further high-quality clinical research in this area warrants consideration.

Dr Salmon: Further studies are needed to determine whether specific treatments for RA have differential capacities to decrease CV risk.

Rheumatology Advisor: Are there any additional points you would like to mention about the topic?

Dr Salmon: Although the risk for CVD in [people with RA] is elevated, similar to patients with diabetes, CV risk management is generally not implemented. Attention to comorbidities such as hypertension, hyperlipidemia, and smoking is essential [for people with] RA. Control of RA disease activity is also likely to attenuate or decrease CVD risk in RA.

References

1. Dhawan SS, Quyyumi AA. Rheumatoid arthritis and cardiovascular disease. Curr Atheroscler Rep. 2008;10(2):128-133.
2. Soulaidopoulos S, Nikiphorou E, Dimitroulas T, Kitas GD. The role of statins in disease modification and cardiovascular risk in rheumatoid arthritis. Front Med (Lausanne). 2018;5:24.
3. Hermann F, Forster A, Chenevard R, et al. Simvastatin improves endothelial function in patients with rheumatoid arthritis. J Am Coll Cardiol. 2005;45(3):461-464.
4. Van Doornum S, McColl G, Wicks IP. Atorvastatin reduces arterial stiffness in patients with rheumatoid arthritis. Ann Rheum Dis. 2004;63(12):1571-1575.
5. McCarey DW, McInnes IB, Madhok R, et al. Trial of atorvastatin in rheumatoid arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet. 2004;363(9426):2015-2021.
6. Rollefstad S, Kvien TK, Holme I, Eirheim AS, Pedersen TR, Semb AGP. Treatment to lipid targets in patients with inflammatory joint diseases in a preventive cardio-rheuma clinic. Ann Rheum Dis. 2013;72(12):1968-1974.
7. Akiyama M, Mawatari T, Nakashima Y, et al. Prevalence of dyslipidemia in Japanese patients with rheumatoid arthritis and effects of atorvastatin treatment. Clin Rheumatol. 2015;34(11):1867-1875.
8. Tam L-S, Li EK, Shang Q, et al. Effects of rosuvastatin on subclinical atherosclerosis and arterial stiffness in rheumatoid arthritis: a randomized controlled pilot trial. Scand J Rheumatol. 2011;40(6):411-421.
9. Agca R, Heslinga SC, Rollefstad S, et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis. 2017;76(1):17-28.
10. Cholesterol Treatment Trialists’ (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380(9841):581-590.