Most adverse effects listed in statin product labels are not supported by evidence from randomized controlled trials, according to a large individual participant data meta-analysis published in The Lancet.
The Cholesterol Treatment Trialists' Collaboration analyzed data from 23 double-blind trials involving 154,664 participants to assess whether conditions listed as potential undesirable effects in statin Summaries of Product Characteristics are causally related to statin therapy.
Beyond previously reported excess risks of muscle symptoms and new-onset diabetes, only 4 of 66 additional prespecified adverse outcomes showed statistically significant excess risk after controlling for multiple testing using a false discovery rate method. These were abnormal liver transaminases, other liver function test abnormalities, urinary composition alteration, and edema.
Absolute annual excess risks were small — less than 0.1% per year for each outcome. When liver function abnormalities were combined, the absolute annual excess was 0.13%.
No significant excess risk was found for 62 of the 66 outcomes assessed, including cognitive impairment, depression, sleep disturbance, sexual dysfunction, peripheral neuropathy, acute kidney injury, or interstitial lung disease — all of which appear in at least one statin product label.
Study Design and Population
The analysis included 19 trials comparing statin vs placebo (123,940 participants; median follow-up, 4.5 years) and 4 trials comparing more intensive vs less intensive statin regimens (30,724 participants; median follow-up, 5 years). Mean participant age was 63 years; 72% were men, 48% had prior vascular disease, and 18% had a medical history of diabetes.
Trials were required to enroll at least 1,000 participants, include a scheduled treatment period of at least 2 years, and maintain a double-blind design. Adverse events were mapped to the Medical Dictionary for Regulatory Activities, with coding performed blind to treatment allocation.
Dose-Response Findings
Elevations in liver enzymes were the most consistent signal. More intensive statin regimens showed a greater excess of abnormal liver transaminases and other liver function test abnormalities, supporting a dose-dependent relationship.
The signal was largely driven by atorvastatin 80 mg daily in high-intensity trials. Importantly, no increase was observed in clinical hepatobiliary outcomes such as hepatitis, hepatic failure, cholestasis, or hepatic steatosis.
Although liver enzyme abnormalities were more frequent, their clinical relevance remains uncertain given the small absolute excess and lack of serious liver events.
No dose-response relationship was observed for urinary composition alteration or edema, raising uncertainty about whether these represent true causal effects.
Renal and General Outcomes
Post hoc analyses indicated that the urinary composition alteration signal was driven by a composite of proteinuria, albuminuria, or microalbuminuria, with no effect on white or red blood cells in urine. No significant impact was found on other renal outcomes, including acute kidney injury.
The researchers noted that statin therapy prevents or delays heart failure by reducing coronary heart disease, making it unlikely that the small excess in edema relates to cardiac dysfunction.
Limitations
All outcomes were derived from adverse event reports rather than systematic biochemical monitoring, potentially underestimating liver function test abnormalities.
The trials also may not capture very rare adverse effects or events emerging beyond follow-up durations. Variation in data collection methods across trials may have limited assessment of some outcomes.
Public Health Context
The researchers cited previous research showing that publication of misleading claims about statin side effects was followed by increased discontinuation rates in the United Kingdom, potentially resulting in 2,000 to 6,000 avoidable cardiovascular events over the subsequent decade.
“These findings indicate that some of the information provided in statin product labels is unreliable and misleading,” the researchers wrote. “Consequently, there is a pressing need for regulatory authorities to require revision of statin labels and for other official sources of health information to be updated, so that clinicians, patients, and the public can make informed decisions regarding the balance of the benefits and risks of statin therapy.”
Multiple researchers reported institutional grants and consulting relationships with pharmaceutical companies. Full disclosures are available in the published article.
Source: The Lancet
