Benefits of statins ‘outweigh’ increased diabetes risk in rheumatoid arthritis
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The benefits of statins in reducing cardiovascular disease and mortality “outweigh” the associated increased risk for type 2 diabetes in patients with rheumatoid arthritis, according to data published in Arthritis Care & Research.
“Statins, the most employed intervention to improve [cardiovascular disease (CVD)] outcomes in the general population, have been repeatedly shown to reduce CVD- and all-cause mortality both in primary and secondary prevention through lipid lowering and pleiotropic effects,” Gulsen Ozen, MD, of the University of Nebraska Medical Center, in Omaha, and colleagues wrote.
“Yet, some unexpected adverse effects were also noted with the widespread use of statins, one of which is an increase in [type 2 diabetes mellitus (T2DM)] risk with different magnitudes in randomized controlled trials (RCTs), meta-analyses, and observational studies,” they added. “ Given that RA patients are already at high risk for CVD, mortality, and T2DM, it is important to determine the risk/benefit ratio of statins in RA.”
To examine the impact of statins on cardiovascular disease, all-cause mortality and type-2 diabetes in patients with RA, Ozen and colleagues conducted a prevalent new-user cohort study within the U.K. Clinical Practice Research Datalink (CPRD), linked to the Hospital Episode Statistics and Office of National Statistics databases. According to the researchers, the CPRD is a U.K. government nonprofit research service containing electronic health records from general practitioners on more than 11 million patients, from 1987 to present.
Using these linked data, the Ozen and colleagues identified adults with RA between 1989 and 2018. Each patient initiating statins was then matched to two concurrent nonusers based on time-conditional propensity score (TCPS). The researchers followed patients until the occurrence of the study’s composite endpoint — myocardial infarction, stroke, hospitalized heart failure or mortality due to cardiovascular disease, all-cause mortality and type 2 diabetes.
The analysis included a Cox proportional hazards model to estimate HRs for each outcome associated with as-treated statin use, adjusting for TCPS deciles and imbalanced covariables.
In all, the researchers included 1,768 patients who initiated statins, and 3,538 nonusers, for cardiovascular disease and all-cause mortality outcomes, as well as 3,608 statin initiators and 7,208 nonusers for the diabetes outcome.
According to the Ozen and colleagues, there were 63 cardiovascular disease events among statin initiators (three per 100 person-years), compared with 340 among nonusers (2.7 per 100 person-years). There were 62 deaths among the statin-initiators (2.8 per 100 person-years), compared with 525 deaths among non-users (4.1 per 100 person-years). Meanwhile, incident type 2 diabetes occurred in 128 statin-initiators (3 per 100 person-years) and in 518 nonusers (2 per 100 person-years).
Statin use was associated with a 32% reduction in cardiovascular disease risk (HR = 0.68; 95% CI, 0.51-0.9) and a 54% reduction in all-cause mortality risk (HR = 0.46; 95% CI, 0.35-0.6). Meanwhile, the risk for type 2 diabetes increased 33% with statin use (HR = 1.33; 95% CI, 1.09-1.63).
The numbers required to prevent cardiovascular disease or all-cause mortality, or cause type 2 diabetes, in 1 year was 102, 42 and 127, respectively, the researchers wrote.
“We found that statins are associated with important reductions in CVD and all-cause mortality in both primary and secondary CVD prevention which outweigh the modest T2DM risk increase in RA patients,” Ozen and colleagues wrote. “Given that RA patients are less frequently assessed for CVD risk factors and even less frequently treated with statins than the general population, our findings emphasize the importance of statin initiation in eligible RA patients with close monitoring for T2DM.
“Statins have several pleiotropic effects beyond their lipid-lowering properties which may be a reason for higher all-cause mortality reduction than CVD mortality reduction,” they added. “Further research would be helpful to identify other cause-specific mortality benefits of statins in RA.”
Perspective
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The association between chronic inflammatory diseases, including rheumatoid arthritis and cardiovascular disease, is well recognized. The retrospective cohort study from Ozen et al. examines and successfully demonstrates the cardiovascular (32% reduction) and mortality (54% reduction) benefits of statin therapy in patients with RA. Additionally, the study identified an acceptable risk for new onset type 2 diabetes mellitus in the treated population (33% increased risk). In contrast to other investigators’ efforts in this area, the present study employed a larger cohort population and longer follow-up duration, which may have accounted for their detection of bigger differences in the statin and comparator groups’ outcomes.
A major limitation of the study is the sparse data available regarding patients who were receiving biologic therapy. In fact, the recorded biologic users included only nine statin initiators and 29 comparators. The authors suggest that the RA population in the study may have been on biologic therapy at a similar rate to the general RA population in the United Kingdom, but there is no definitive way to determine this. They also acknowledge that due to the United Kingdom’s reimbursement system for biologic therapy, there would be an overall lower percentage of patients on a biologic compared with traditional synthetic DMARDs. This has important implications for the relevance and generalizability of the study to other RA populations, including in the United States where a larger percentage of patients with RA will be treated with a biologic. Given the data supporting the favorable impact of biologic therapy on RA patients’ cardiovascular risk and outcomes, it would be very helpful to see this study replicated in a country where biologics are used more widely to see if the impact is as significant.
Previous research efforts have failed to demonstrate significant mortality benefits regarding statin use for patients with RA without traditional cardiovascular risk factors. Future investigations to better identify the specific cohort of patients with RA most likely to benefit from statin therapy would be invaluable.
As many patients with RA view their rheumatologist’s office as their de facto medical home, the article also helps direct our attention to the need to focus beyond the traditional RA treatment endpoints of joint pain and damage, and highlights the need for more effective coordination with primary care physicians and other medical specialists.
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