July 9th, 2013
Low Rate of Problems with Statins in Study of Quarter Million Patients
Larry Husten, PHD
A very large analysis of previously published studies finds that statins are generally safe and well tolerated, but helps confirm previous links to a small increased risk for diabetes and elevation of liver enzymes. Some statins were better tolerated than others, and lower-dose statins were better tolerated than high doses.
In a paper published in Circulation: Cardiovascular Quality and Outcomes, Huseyin Naci and colleagues report their findings from a systematic review of clinical trials with statins for both primary and secondary prevention. The data from 135 trials included nearly 250,000 subjects, comparing statins with placebo or with other statins. Previous analyses have generally confirmed the overall benign profile of statins but have not explored in depth the differences between individual statins and the effect of different doses of individual statins.
The new study found no differences between statins and placebo in the rate of discontinuations due to myalgia, CK elevation, and cancer, but statins were associated with a higher risk for diabetes (OR 1.09, CI 1.02-1.16) and transaminase elevations (OR 1.51, CI 1.24-1.84).
“I am concerned that patients may misunderstand this small increase in risk and stop adhering to their medications,” said Naci in an AHA press release, concerning the diabetes finding.
Simvastatin and pravastatin were better tolerated than other statins, while atorvastatin and rosuvastatin were associated with more discontinuations. People taking high doses of atorvastatin, fluvastatin, lovastatin, and simvastatin were more likely to have transaminase elevations. People taking high-dose simvastatin had an increased risk for CK elevations.
In recent years, the value of statins for primary prevention has been the subject of intense controversy. The authors write that recent studies have confirmed “that all- cause mortality benefits of statins in the primary prevention setting are clinically and statistically significant.” The new study, they say, gives “supporting evidence for initiating statin therapy in individuals who are at an increased risk of developing cardiovascular disease.” However, they acknowledge that “expanding the limits of statin therapy to a wider population of individuals may have important safety implications. Although rare, adverse events associated with statin therapy range from mild to moderate, and appear to increase with treatment intensity.”
The authors also acknowledge that although their “review did not find statistical evidence of myopathy, this may be due to an under-detection of muscle toxicity in clinical trials.” They conclude:
Our findings have important clinical implications. First, there is strong evidence that statins as a class are generally safe with uncommon side effects. According to the findings of this comprehensive analysis, there is consistently strong evidence on the comparatively favorable side effect profile of simvastatin and pravastatin – particularly at low to moderate doses – which should be favored in clinical practice. This meta-analysis sheds new light on the discussion on the relation between statins and diabetes incidence and confirms that statin use is not associated with cancer incidence. Finally, we acknowledge the complex nature of making prescribing decisions and urge prescribers to consider the findings of this analysis in light of the comparative benefit profiles of individual statins in preventing all-cause mortality in addition to cardiovascular and cerebrovascular events.
The authors state that the average trial follow-up was 68 weeks(1.3 years). I doubt wheter cancer incidence is therefore representative. Furthermore, high drop-out was due to side effects with high doses.
There are several biases in this analysis. In many trials the participants are given a small dose of the statin drug before the start, and if they do not tolerate it, they are excluded from the trial. Furthermore, most trials have recorded muscular problems only if CK was ten times higher than the normal upper limit at two successive determinations. Independent researchers have reported that about 25 % of statin-treated patients who do regular exercise have muscular problems (1). This is a serious problem considering that the best, the cheapest and the least risky way to prevent heart disease is regular exercise.
Also questionable is that liver damage is only reported if the liver enzymes are more than three times higher than the normal upper limit at two successive determinations.
Most serious is the risk of cancer. It was increased significantly in the CARE, PROSPER and SEAS trials. In the two first simvastatin trials 4S and HPS non-melanoma skin cancer was seen more often in the treatment group, and the increase becomes statistically significant if the figures are added (p<0.02). Since then almost all trials have excluded non-melanoma skin cancer from their reports. But if statin treatment is carcinogenic, the first type we should expect to see is, of course, skin cancer, simply because it is easily detected.
That meta-analyses of the statin trials haven´t shown an increase of cancer is also that many patients stop taking the drug. A better way to measure side effects is to relate them to the cholesterol level achieved during treatment. In a Japanese cohort study of more than 40,000 patients treated with 5-10 mg simvastatin per day during 6 years, cancer mortality was three times higher in those whose cholesterol was the lowest at follow-up compared with the others (2).
And there is more evidence that statin treatment, or rather low cholesterol, is associated with cancer (3).
1. Sinzinger H et al. J Cardiovasc Pharm 2002;40:163-71
2. Matsuzaki M et al. Circ J 2002;66:1087–95.
3. Ravnskov U et al. QJM. 2012;105:383-8
I could not disagree more with the comment of Uffe Ravnskov.
Statins do not cause cancer, this is amply demonstrated (1,2).
Is more, statins have been shown to be effective in treating some types of cancers (3).
Statins have been and are currently the drugs that have changed the natural course of the more devastating disease, such as cardiovascular disease.
No doubt after vaccines, statins have been more effective drugs that have saved more lives in the history of medicine.
1-Curr Atheroscler Rep. 2013 Feb;15(2):297. Does the benefit from statin therapy extend beyond 5 years?
2-J Am Coll Cardiol. 2012 Sep 4;60(10):875-81. The controversies of statin therapy: weighing the evidence.
3-N Engl J Med. 2012 Nov 8;367(19):1792-802. Statin use and reduced cancer-related mortality.
Americans want the perfect drug – guaranteed success, no risk of side effects. We don’t have that yet. But statins are close enough for me.