Statins and Long-Term Safety: An Essential Review for the Primary Care Physician

The reduction of low-density lipoprotein cholesterol (LDL-C) with statins has been one of the most important advances in cardiovascular medicine in the past decade. This class of drugs works by inhibiting HMG-CoA reductase, which plays a central role in production of cholesterol in the liver.  By lowering LDL-C and exerting a beneficial effect on triglyceride (TG) and high-density lipoprotein (HDL-C) levels, statins effectively modify cardiovascular risk in patients with and without a previous history of established coronary artery disease.

Here, we review safety and efficacy data from studies of prolonged statin use. Despite some concerns, the evidence shows these medications to be well tolerated, effective, and safe.

Efficacy of Statins
The efficacy of lowering LDL-C with statins has been repeatedly demonstrated. A large meta-analysis involving approximately 90,000 patients—the Cholesterol Treatment Trialists (CTT) Collaboration—reported a 20% relative risk reduction in major vascular events (coronary death, non-fatal myocardial infarction [MI], coronary revascularization or stroke) per 40 mg/dL reduction in LDL-C.¹ There appears to be a dose-response relationship between endpoint LDL-C levels and a reduction in untoward cardiovascular outcomes.² Several additional randomized controlled trials, including PROVE-IT TIMI 22 (Pravastatin or Atorvastatin(Drug information on atorvastatin) Evaluation and Infection Therapy) and TNT (Treating to New Targets), demonstrate the additional benefit of intensive, high-dose statins compared with standard-dose statin therapy for first and recurrent cardiovascular events.^3-8

Concerns about Statins
Despite the proven efficacy of statins and the wide availability of clinical guidelines that recommend lipid targets to help prevent cardiovascular disease, the widespread use of the drugs remains limited and some patients are either not at target LDL-C or remain undertreated following acute coronary syndromes (ACS).^9,10 One of the major barriers to compliance with statins stems from historical concerns raised by both physicians and patients regarding the safety of long-term treatment. These concerns may be particularly relevant to the geriatric population.

A possible association between lower total cholesterol and increased cancer risk emerged decades ago when the results of cohort studies suggested that low cholesterol was a marker for cancer 10 to 30 years later.^11-16 However, none of these studies adjusted for use of cholesterol-lowering treatment and were all observational studies; that is, not randomized and thus subject to confounding, where factors other than cholesterol level would account for the higher observed risk. Indeed, more recent studies have reached opposite conclusions: one showed lower rates of prostate cancer associated with statin use.¹⁷ A proposed mechanism for this risk relationship—the direct carcinogenicity of statins—has not been reproducible in animal studies.¹⁸ Thus, these possible associations appear to be invalid.

Additional concerns have arisen from conflicting data reporting higher rates of side effects in persons taking intensive doses of statins and an increase in non-vascular mortality and morbidity in persons with very low LDL-C concentrations.^19-21 Most of these results also are from observational, non-randomized trials. Because these observational data are unreliable, we mostly depend on outcomes from randomized trials to provide higher quality evidence regarding the safety of statins.

A recent meta-analysis of 26 randomized controlled trials with more than 160,000 participants and a median follow-up of  5 years showed a 10% reduction in all-cause mortality and a 22% reduction in major vascular events per 40 mg/dL LDL-C reduction.7 Although many patients achieved very low LDL-C concentrations in these trials, there was no difference in overall cancer incidence or in deaths related to cancer or non-vascular causes.7 These data, however, only had a 5-year follow-up, and since some cancers take longer than 5 years to emerge clinically, concern among some physicians persisted.^18,22,23

Long-term Safety
This ongoing apprehension prompted analysis of several other studies with longer follow-up periods. The West of Scotland Coronary Prevention Study (WOSCOPS),²⁴ a primary prevention study of 6,595 men with hypercholesterolemia receiving either 40 mg pravastatin(Drug information on pravastatin) or placebo, was a 5-year study but participants were followed for approximately 10 additional years after the end of the trial, resulting in a cumulative follow-up period of 15 years. Those in the statin arm experienced a significant decrease in risk of cardiovascular events during the parent trial and during the 10-year follow-up, without an increase in the risk of noncardiovascular deaths or fatal or incident cancers.²⁴  

Another study with an extended total follow up of 11 years (3 years in-trial; 8 years post-trial) was the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA),²⁵ which randomized patients with hypertension to atorvastatin 10 mg vs placebo for primary prevention. There was no increased risk of incident cancer, infections, or respiratory illness observed in association with prolonged statin use.²⁵  Most recently, efficacy outcomes in the Heart Protection Study (HPS), which randomized 20,536 study participants to 40 mg simvastatin(Drug information on simvastatin) daily vs. placebo and followed them for a mean total follow-up period of 11 years (5 years in-trial; 6 years post-trial), were consistent. The benefit of statins was seen early and was maintained during follow-up. Despite a very large number of cancers observed during the full follow-up period (n=3493), no difference in incident cancer, cancer mortality, or non-vascular mortality emerged with simvastatin therapy compared with placebo. This was consistent for elderly patients (aged 70 years or older) and those with low baseline cholesterol concentrations.

To address the safety of achieving very low LDL-C concentrations as well as the tolerability of high-dose statins, Wiviott and colleagues²⁶ undertook an analysis from the randomized PROVE-IT TIMI 22 study. Their results provided definitive evidence that achieving very low LDL-C concentrations with high-dose statins was well tolerated and did not cause statistically significant increases in safety parameters such as muscle, liver, or retinal abnormalities, intracranial hemorrhage, or death.²⁶ 

Taken together, these findings firmly establish that long-term use of statins does not increase cancer risk or non-vascular mortality. Furthermore, achieving low LDL-C levels, even if intensive statin therapy is needed to achieve these goals, dramatically improves outcomes without causing any demonstrable increase in adverse safety events. The original concerns regarding statin safety were a result of cohort observational studies, which were probably heavily confounded and have not been reproduced in animal studies or in data from randomized controlled trials.19 Multiple studies with prolonged statin use and extended follow-up have established the efficacy and safety of this important medication, with persistence of benefit even after discontinuation.

Practice Message
For the primary care physician, concerns regarding long-term statin safety can be laid to rest and physicians can feel confident in prescribing this life-saving treatment for primary and secondary prevention in patients who are at risk for acute coronary syndromes. There is a wealth of data to help reassure patients that statins do not increase their risk for cancer or non-vascular mortality, regardless of age or duration of treatment. With this increased awareness, widespread adoption of guideline-based therapy and higher patient compliance is much more likely. Ultimately, many more patients will reach their optimal LDL-C targets and have better outcomes.
 
Figure. Low magnification micrograph of the distal right coronary artery with complex atherosclerosis and luminal narrowing; source: Nephron, Wikimedia Commons.