This article discusses a new study by researchers revealing the link between ‘bad’ cholesterol (LDL-C) and poor health outcomes, such as heart attack and stroke, which may not be as strong as it has been considered.

---

Analysis

Treating cardiovascular disease is a complex issue; we need more robust results from evidence-based medicine to complement, modify or contradict the existing evidence.

1. A paper published online on 14 March 2022 in JAMA Internal Medicine, questions the efficacy of statins when prescribed to lower LDL-C and thereby reduce the risk of cardiovascular disease (CVD).
2. Previous research has suggested that using statins to lower LDL-C positively affects health outcomes, and this is reflected in the various iterations of expert guidelines for the prevention of CVD. Doctors commonly prescribe statins. For instance, the researchers noted the previous studies which show that one-third of Irish adults over the age of 50 are taking statins,
3. A more recent paper titled "Statin Safety and Associated Adverse Events: A Scientific Statement From the American Heart Association" in Arteriosclerosis, Thrombosis and Vascular Biology (2019) stated that  "one in 4 Americans, >40 years of age takes a statin to reduce the risk of myocardial infarction, ischaemic stroke, and other complications of atherosclerotic disease."
4. The new findings show that the relationship between statin consumption and CVD outcomes is not as strong as previously thought. Instead, the research demonstrates that lowering LDL-C using statins had an inconsistent and inconclusive impact on CVD outcomes such as myocardial infarction (MI), stroke, and all-cause mortality. The new research indicated that the overall benefit of taking statins may be small and will vary depending on an individual’s personal risk factors.

The lead author, Dr Paula Byrne from the HRB Centre for Primary Care Research based in RCSI’s Department of General Practice said:

“The message has long been that lowering your cholesterol will reduce your risk of heart disease and that statins help to achieve this. However, our research indicates that, in reality, the benefits of taking statins are varied and can be quite modest.”

The researchers suggested that this updated information should be communicated to patients through informed clinical decision-making and updated clinical guidelines and policy.

---

The study

In a new study by researchers at the University of Medicine and Health Sciences, Royal College of Surgeons in Ireland (RCSI), the researchers' effort was to get the answer to the following question: 

What is the association between statin-induced reductions in low-density lipoprotein cholesterol (LDL-C) levels and the absolute and relative reductions in individual clinical outcomes, such as all-cause mortality, myocardial infarction, or stroke?

They hoped that the results of such studies will facilitate shared decision-making between clinicians and patients and inform clinical guidelines and policy.

1. They carried out the review according to the methods of the Cochrane Handbook for Systematic Reviews of Interventions and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline statement.
2. They searched data sources PubMed and Embase to identify eligible trials from January 1987 to June 2021. They reviewed any randomised clinical trial (RCT) that examined the efficacy of statins on total mortality and cardiovascular outcomes and stroke in adults, had a planned duration of 2 years or longer, had an enrollment of more than 1000 participants (to ensure reasonable statistical power), whose comparator was placebo or usual care, and reported absolute changes in LDL-C levels.
3. They chose only RCTs written in English and included human participants. Interventions were treatment with statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) vs placebo or usual care.
4. Participants were men and women older than 18 years.

---

Results

1. Researchers included twenty-one trials in the analysis. This meta-analysis showed the following reductions:

• Absolute risk- 0.8%
• Myocardial infarction- 1.3%
• Stroke in those randomised to treatment with statins-0.4%
• with associated relative risk reductions of 9%, 29%, and 14% respectively

However, a meta-regression exploring the potential mediating association of the magnitude of statin-induced LDL-C reduction with outcomes was inconclusive.

2. Wikipedia defines meta-regression as a meta-analysis that uses regression analysis to combine, compare, and synthesise research findings from multiple studies while adjusting for the effects of available covariates on a response variable.

3. The recent meta-analysis suggests that the absolute risk reductions of treatment with statins in terms of all-cause mortality, myocardial infarction, and stroke are modest compared with the relative risk reductions, and the presence of significant heterogeneity reduces the certainty of the evidence.

4. The researchers found that they could not establish a conclusive association between absolute reductions in LDL-C levels and individual clinical outcomes. They added that their findings highlight the importance of discussing absolute risk reductions when making informed clinical decisions with individual patients.

5. Various iterations of expert guidelines for preventing cardiovascular disease (CVD) reflect the aggressive lowering of LDL-C levels with statin treatment. The researchers contended that this gave rise to the popular theory that the lower the LDL-C level, the better.

6. They noted that the Cholesterol Treatment Trialists’ (CTT) collaboration, which published a series of meta-analyses that suggested that a reduction of 38.7 mg/dL in LDL-C levels with statins yields about a 21% relative risk reduction (RRR) of major vascular events and a 10% RRR in all-cause mortality.

---

Limitations of the CTT study

1. The researchers argued that the CTT analyses were based on individual patient data (IPD) which are inaccessible to independent researchers and not replicable. In addition, the use of composite outcomes in such analyses is a point of concern. For instance, the outcomes reported in one such study comprised various composites as defined by the included trials rather than a universally defined composite.

2. The authors cautioned that reporting the reduction in cardiovascular outcomes as RRR without reporting the corresponding absolute risk reduction (ARR) has the potential to inflate the clinical importance of an intervention and may exaggerate trivial associations. Therefore, to enable better decision-making between clinicians and patients, the researchers assessed ARRs and RRRs from treatment with statins in hard outcomes, such as all-cause mortality, MI, and stroke, as well as explored the association between LDL-C reduction and statin treatment effects.

3. The study suggests that the absolute benefits of statins are modest, may not be strongly mediated through the degree of LDL-C reduction, and should be communicated to patients as part of informed clinical decision-making as well as to inform clinical guidelines and policy.

4. The researchers noted that cardiovascular benefits of treatment with statins are sometimes reported as RRR. Based on relevant references, they argued that reporting RRR without the corresponding ARR or number-needed-to-treat of treatment can be misleading.

5. "For example, in our analysis, the RRR for MI was 29%, whereas the ARR was 1.3%. In other words, 77 participants would need to be treated with a statin for roughly 4.4 years on average to prevent 1 MI.", they clarified

---

Potential harms from statin therapy

Besides considering the absolute benefit, patients and clinicians need to examine the potential for harm from treatment with statin therapy, an area of considerable controversy. The researchers cautioned that the exact incidence and definition of statin harms have been debated.

1. Collins et al reported that treating 10,000 patients with statins for 5 years could result in 5 cases of myopathy, 50 to 100 new cases of diabetes, and 5 to 10 cases of haemorrhagic stroke. The authors asserted that these harms are outweighed by the benefits of statins.
2. "This argument has merit if a patient’s baseline risk of serious CVD events is greater than their risk of harm from taking the medicine. However, the definition of myopathy used by Collins et al may be a high bar for diagnosing muscle symptoms among patients who may simply define myopathy as any muscle symptom.", they argued
3. Observational data suggest that the frequency of statin myopathy may be higher. Buettner et al reported that 22.0% of those taking statins in their study reported musculoskeletal pain in at least 1 anatomical region during the previous 30 days compared with 16.7% of those who did not use a statin.
4. Fernandez et al reported that the observational studies included in their review suggest that the frequency of statin myopathy is 9% to 20%.
5. The researchers revealed that their systematic review and meta-analysis found that the ARR of statins appears to be modest compared with the RRR, but these calculated benefits must be interpreted with caution because of the presence of significant heterogeneity.

The researchers concluded:

"Our findings were inconsistent and inconclusive regarding the association between the magnitude of LDL-C reduction because of treatment with statins and all-cause mortality, MI, or stroke. The transparent communication of RRR and ARR by clinicians, as well as the potential for harm, to their patients, may lead to more informed decision-making about the true benefits and risks of statins. In addition, our findings have implications for future clinical guideline development and for policymakers and payers considering the opportunity cost of statin therapy."

The press coverage of the new study was surprisingly mute. The British Medical Journal The BMJ headline for the news story is "For most healthy people, benefits of statins “may be marginal at best”. The American Heart Association and the British Heart Foundation did not react; not thus far.

Disclaimer- The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of M3 India.

Dr K S Parthasarathy is a former Secretary of the Atomic Energy Regulatory Board and a former Raja Ramanna Fellow, Department of Atomic Energy. A Ph. D. from the University of Leeds, UK, he is a medical physicist with a specialisation in radiation safety and regulatory matters. He was a Research Associate at the University of Virginia Medical Centre, Charlottesville, USA. He served the International Atomic Energy Agency as an expert and member of some of its Technical and Advisory Committees.