- Clinical trial data showed that some side effects attributed to statins on product labels rose above the level of likely false discovery due to multiple comparisons.
- Statins contributed less than 0.1% absolute risk per year for each of these outcomes, an analysis showed.
- Researchers and outside experts called for product labels to be revised.
Many adverse events listed on statin product labels don't have good evidence that they are actually caused by the drug, a pooled analysis of the clinical trial evidence showed.
In individual participant-level data from double-blind randomized controlled trials, only four of 66 assessed side effects attributed to statins on product labels rose above the level of likely false discovery due to multiple comparisons, the Cholesterol Treatment Trialists' (CTT) Collaboration reported in The Lancet.
Aside from known risk of muscle symptoms and diabetes, adverse events included abnormal liver transaminases, other liver function test abnormalities, urinary composition alteration, and edema. Statins contributed less than 0.1% absolute risk per year for each of these outcomes.
No significant excess risk emerged for cognitive impairment, depression, sleep disturbance, erectile and sexual dysfunction, peripheral neuropathy, acute kidney injury, and interstitial lung disease.
"Consequently, the undesirable effect sections of statin product labels might overstate risks and mislead clinicians and patients, and should be revised to better support informed, evidence-based decision making," the researchers concluded.
Multiple large-scale clinical trials corroborating all-cause mortality benefits of statins in persons with coronary disease and increasingly sophisticated real-world data tempering concerns of their harms haven't silenced claims of many risks, noted an accompanying commentary by Timo Strandberg, MD, PhD, of the University of Helsinki in Finland, and Raul D. Santos, MD, PhD, of the University of Sao Paulo Medical School Hospital in Brazil.
"[I]n patients' minds, the safety of statins has been undermined by long lists of potential adverse effects in drug labels, leading to possible nocebo-drucebo reactions," they wrote. "In addition, physicians might, perhaps inadvertently, emphasize potential harms more than expected benefits."
The new findings, though, show no reason for such caution in the clinic.
"The effects on liver tests are of little clinical significance, because overwhelming data show that statins have no specific liver toxicity," Strandberg and Santos wrote. "Reasons for slight changes in urinary composition and risk of oedema are obscure but apparently of uncertain clinical significance."
They agreed on the need for wide publicity and "profound revision of drug labelling of statins to be more evidence based."
The meta-analysis spanned 23 double-blind trials of statin therapy with at least 1,000 participants each and a planned duration of at least 2 years (median 4.7 years) as a source of "systematic and unbiased event reporting." The 19 trials comparing placebo with statins of various intensity included a total of 123,940 participants (mean age 63; 28% women) with 48% in the secondary setting with previous vascular disease, and 18% with diabetes. The remaining four double-blind trials focused on patients with known vascular disease (n=30,724) and compared more versus less intensive statin regimens. These participants averaged age 62.
Intention-to-treat data on adverse events were analyzed using a double false discovery rate (FDR) multiple-testing method to control for the number of health outcomes investigated. "For each outcome, the difference in event rates between treatment groups was deemed to be statistically significant if it was FDR significant at the 5% level (two-sided)," the researchers explained.
The researchers didn't look at muscle-related or diabetes adverse events, which they evaluated previously from the same dataset. Of the 66 adverse events they did look for based on label cautions, the four with FDR significance for those allocated to statin versus placebo were:
- Abnormal liver transaminases: 0.30% vs 0.22% per year, RR 1.41 (95% CI 1.26-1.57)
- Other liver function test abnormalities: 0.25% vs 0.20%, RR 1.26 (95% CI 1.12-1.41)
- Urinary composition alteration: 0.21% vs 0.18%, RR 1.18 (95% CI 1.04-1.33)
- Edema: 1.38% vs 1.31%, RR 1.07 (95% CI 1.02-1.12)
"Trials comparing different statin intensities also found significant excesses for abnormal liver transaminases and other liver function test abnormalities, supporting a dose-dependent effect," the researchers noted.
Study limitations included the relatively short duration of the trials for what is considered a lifelong therapy. "However, post-marketing experience of statins, now extending almost 40 years, and large cohort studies with modern epidemiological methods reducing possibilities for reverse causality, support the conclusions from masked trials," the CTT group noted.
Also, the oldest and most frail patients have been "marginally" enrolled in such trials, although the researchers noted that "special risks have not been noted even in nursing home residents, and ongoing large randomized primary prevention trials in individuals older than 70 years will shed more light on this issue."
Disclosures
The analysis was funded by the British Heart Foundation, U.K. Medical Research Council, and Australian National Health and Medical Research Council.
Researchers reported numerous relationships with drug companies, nonprofit group, and other organizations.
Strandberg disclosed relationships with Orion Pharma, Nutricia, Valio, Amgen, Novartis, Amarin, Sankyo, GSK, MSD, Finnish Medical Journal, Duodecim, Nutricia, CoroPrevention, the Päivikki and Sakari Sohlberg Foundation, and Helsinki University Hospital, as well as being National Dyslipidemia Guideline Group chair.
Santos disclosed relationships with Amgen, Aché, Boehringer Ingelheim, Daiichi-Sankyo, Esperion, Eli-Lilly, Ionis, Libbs, MSD, Novo-Nordisk, Novartis, PTC Therapeutics, Torrent, Sanofi-Regeneron, Ultragenyx, and Conselho Nacional de Pesquisa e Desenvolvimento Tecnológico.
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