The current meta-analysis totalled 70
388 participants without established cardiovascular disease but with cardiovascular risk factors who were randomised to statin therapy or control. Statin therapy was associated with a significant risk reduction in all cause mortality of 12%, in major coronary events of 30%, and in major cerebrovascular events of 19%. Moreover, statin use was not associated with an increased risk of cancer. These results are in line with those previously published on the effects of statins in secondary prevention.5 6
Our meta-analysis differs from earlier analyses in several ways.13 14
We were able to include several recently published studies targeted at primary prevention that enrolled a large number of women and people with diabetes.w1-w3
For example, the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese trial (MEGA)w2
comprised a large number of women (68%, 5356/7832), and we were able to obtain subgroup data. Additionally, the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus study (ASPEN)w3
was carried out in a large group of people with type 2 diabetes (n=1905) who did not have established cardiovascular disease. We also included data from the recently published JUPITER trial,w1
802 participants with no apparent vascular disease, low density lipoprotein cholesterol levels less than 3.4 mmol/l, and increased levels of high sensitivity C reactive protein (>2.0 mg/l).w1
As our study is based on such large numbers, this meta-analysis, including the subgroups, has significant statistical power. Previously, only the JUPITER trial showed improved survival associated with statin use in high risk participants, but it is clear from the current analysis that a mortality benefit is a shared characteristic of long term statin use in people without previous cardiovascular disease. The currently observed benefit, a 12% risk reduction in mortality, may even be an underestimation of the true effect because subsequent death after a morbid cardiovascular event was not always considered in individual trials.
The numbers and duration of follow-up of our study allow for relatively strong inferences on risk of cancer with long term statin use. We found no evidence for an increased risk of cancer, fatal or non-fatal. One of the trials (Prospective Study of Pravastatin in the Elderly at Risk; PROSPER)w6
did report an increased risk of cancer with use of statins among men and women older than 70. Although our results show that statins do not seem to increase the risk of cancer, longer follow-up would be helpful to determine whether new cancer events could occur with time. This is especially critical when statins are used in primary prevention. Follow-up of patients in WOSCOPS for 10 years did not show higher rates of malignancies.34 35
Concerns might remain about the higher risk of cancer in elderly patients (70-82 years) as in PROSPER,w6
and further follow-up studies in such patients are required. Although this meta-analysis cannot fully remove that uncertainty, it confirms that the risk of cancer is not increased in middle aged patients. Tolerance to statins is also important to tackle in primary prevention. Side effects such as an increase in creatine kinase levels and myopathy have been reported relatively frequently, but rhabdomyolysis and hepatotoxicity are rare.5
Lastly, by contacting principal investigators of each trial we were able to obtain data on clinically defined subgroups. This allowed us to draw meaningful inferences on treatment effects in large numbers of women, older people, and people with diabetes. Although there is little reason to suspect different treatment effects between such groups from a pathophysiological standpoint, it is reassuring that no significant treatment heterogeneity was found between the sexes, in elderly and young people, and between people with and without diabetes.
Limitations of the study
Some limitations of our study need to be mentioned. Firstly, we included three trials in the analyses that had recruited a small proportion of patients (about 6%) with clinical cardiovascular disease.30 w7 w9
Exclusion of these trials did not affect the outcome of our analyses. Secondly, the dose and type of statin differed between included trials. Depending on the statin and the dose, some treatment regimens may be more effective in lowering lipid levels. However, according to guidelines from the Adult Treatment Panel III, the statins included in our meta-analysis at their respective doses have similar clinical efficacy.8
Thirdly, the included trials represented participants with a clinically heterogeneous level of risk (although statistical heterogeneity was low). The benefit observed in the pooled estimate of treatment effect could be of different magnitude depending on the level of risk. However, exclusion of the studies with a small proportion of patients at higher risk did not influence the outcome of the analysis because our subgroup analysis indicated no heterogeneity in clinically defined groups such as elderly participants or those with diabetes mellitus who are at relatively higher risk. Such a risk dependent effect seems unlikely.
Our meta-analysis shows that the relative risk reduction from long term statin use in a primary care setting is comparable to that observed in secondary prevention. Our findings confirm the results of JUPITERw1
regarding the beneficial effect of statins on survival across a broader range of patients (n=70
388) at different levels of risk, and show that there is no significant difference in treatment benefit across a range of clinically defined groups (men and women, elderly people, and those with diabetes). Although our study population comprised participants without established cardiovascular disease, the pooled risk was high. The overall annual mortality was in the range of 1.4%, and fatal as well as non-fatal cardiac and cerebrovascular events occurred at an annual rate of about 1.1% and 0.6%, respectively. This is not too different from the event rates reported in trials of patients at relatively low risk in secondary prevention—for example, the European trial on reduction of cardiac events with perindopril in stable coronary artery disease and the Prevention of Events with Angiotensin-Converting Enzyme inhibition trial (PEACE).36 37
Statin based secondary prevention is considered mandatory in participants in PEACE. Still, the absolute overall treatment benefit observed in the current study population would certainly be less than 1%, and significant numbers of participants would need to be treated to prevent one event. From the currently pooled data it is not possible to exactly define one group of people who would benefit most from long term statin use. From current risk scoring systems, as well from current data, it is obvious that older men (>65 years) with risk factors, or older women with diabetes and risk factors, constitute the highest risk group. In view of the large treatment effects described here, it is likely that a considerable number of such people would benefit from long term statin use at reasonable costs. The correct identification of such people remains a challenge and, in addition to the assessment on the future cardiovascular risk based on standard cardiovascular risk factors, auxiliary diagnostic or prognostic assessments to improve risk prediction could be useful to identify these men and women more accurately. Given the favourable effects of long term statin treatment it would be wrong to deny these benefits to people at increased risk for cardiovascular disease.
What is already known on this topic
- Statins are effective in patients with established cardiovascular disease (secondary prevention) but whether the benefits apply to primary prevention is unknown
- Research has provided ambiguous answers on statin use in people at relatively lower risk
- Furthermore, the efficacy of statins in subgroups of people aged more than 65, women, and those with diabetes mellitus is debated
What this study adds
- Statins improve survival and reduce the risk of major cardiovascular and cerebrovascular events in people without established cardiovascular disease
- No significant differences in treatment effect of statins were observed in clinically defined groups for age, sex, and diabetes status
- People at increased risk for cardiovascular disease should not be denied the relative benefits of long term statin use