However, patients who are taking statins should not stop taking them based on this study, senior author Dr Ishak A Mansi (University of Texas Southwestern, Dallas) stressed in an interview with heartwire from Medscape. "Our study did not examine whether the benefits outweigh the risk (it was not designed for that)," he noted. Moreover, there is strong evidence for overall benefit of statins for secondary prevention.
Still, this study shows that "despite the use of statins for more than a quarter of a century, there are aspects about its long-term effects in noncardiac diseases that we do not know very well," according to Mansi. "We are missing more extensive, real-world data of the effectiveness of statins on total morbidity and all-cause mortality, and we need further studies specifically focusing on long-term outcomes in primary prevention." Moreover, "the new [ACC] guidelines . . . are projected to increase statin use to many more hundreds of millions of healthy people, and before we do that we better make sure that we are not causing harm," he cautioned.
"Our paper says to scientists, physicians, funding agencies, [and] policy makers: 'Watch out, [it] seems that we still do not know enough about the long-term effects of these drugs on [the] overall well-being of patients.'"
Although the current study "has unique findings . . . it shouldn't be used as a final say in the controversy," he said. "Clinicians should tell their patients that there may be statin side effects we are not aware of, but there are also benefits that we are aware of." Clinicians also need to carefully monitor creatinine levels in patients taking statins.
A Cohort of 43,000 Strong
The researchers analyzed healthcare data from 2003 to 2012 from 30- to 85-year-olds who lived in the San Antonio, TX area and were members of Tricare Prime or Tricare Plus insurance plan for members of the military and their families. All patients were continuously enrolled in the healthcare plan during the study, and there were no missing data.
The overall cohort comprised 43,438 individuals: 13,626 statin users and 29,812 nonusers. The most commonly prescribed statin was simvastatin (73.5%), followed by atorvastatin (17.4%), pravastatin (7%), and rosuvastatin (Crestor, AstraZeneca) (1.7%); 38% of the statin users received high-intensity doses. The statin users took the drugs for a mean of 4.65 years.
The researchers matched 6342 statin users in the overall cohort with 6342 nonusers, according to baseline demographics, comorbidities, presence of renal disease, healthcare utilization, and medication use. In this matched cohort, patients had a mean age of 56, and 45% were women.
The researchers also identified a "healthy cohort" of 3982 statin users and 21,988 nonusers, and they matched 3351 statin users with 3351 nonusers. These individuals were all free of diabetes, chronic kidney disease, cardiovascular disease, and conditions that might limit life expectancy or physical activity.
In the overall cohort, statin use was associated with a significantly increased risk of different types of kidney disease.
Risk of Kidney Disease in Overall Cohort, Statin Users vs Nonusers*
|Kidney disease||Odds ratio (95% CI)||P|
|Acute and unspecified renal failure||1.30 (1.14–1.48)||<0.001|
|Chronic kidney disease||1.36 (1.22–1.52)||<0.001|
|Nephritis, nephrosis, renal sclerosis||1.35 (1.05–1.73)||0.02|
In the healthy cohort, patients who received statins had a significantly higher risk of chronic kidney disease (odds ratio 1.53; 95% CI 1.27–1.85, P<0.001), but after adjustment for diseases (such as hypertension) that developed during follow-up, this association weakened, suggesting that these factors are implicated in the development of kidney disease.
Long-term Primary-Prevention Statin Trials "Urgently Needed"
"The findings of this study, though cautionary, suggest that short-term [randomized controlled trial] may not fully describe long-term adverse effects of statins," Acharya and colleagues conclude. Statins lower the risk of cardiovascular disease and cardiovascular death, but "on the other hand, statins increase the risk of incident diabetes and possibly kidney diseases, both of which paradoxically increase long-term morbidity and mortality," they continue.
Randomized controlled trials for primary prevention with statins were sometimes prematurely terminated once the efficacy of reducing major acute cardiovascular events was achieved, and these trials rarely had total mortality as a primary outcome, according to the researchers. "Therefore, further studies, specifically primary-prevention studies, are urgently needed in which the long-term effects of statins on total mortality and total comorbidity indices (not only cardiovascular morbidity) are set as the primary outcomes."