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1st September 2022
Statins cause only a small excess of the muscle pain symptoms experienced by patients according to the findings of a meta-analysis of 19 randomised controlled trials by researchers from the Cholesterol Treatment Trialists’ Collaboration, University of Oxford, UK.
Cardiovascular diseases (CVD) such as ischaemic heart disease and stroke, are the leading cause of global mortality and a major contributor to disability and cases of CVD nearly doubled from 271 million in 1990 to 523 million in 2019. Furthermore, large-scale evidence from randomised trials shows that statins reduce the risk of major vascular events by about one-quarter for each mmol/L reduction in LDL cholesterol during each year (after the first) that it continues to be taken. In terms of adverse effects, statins are known to cause myopathy, which is defined as muscle pain or weakness combined with large increases in blood concentrations of creatine kinase, though this is rare. In fact, it has been reported that treatment of 10,000 patients for 5 years with an effective regimen (eg, atorvastatin 40 mg daily) would cause about 5 cases of myopathy. However, less serious musculoskeletal pain has been observed with statins and in a population-based study of 5170 participants without arthritis, after controlling for confounders, statin use was associated with a significantly higher prevalence of musculoskeletal pain in any region, the lower back, and the lower extremities.
In an effort to provide a better understanding of the extent, severity and timing of adverse effects due to statins, the Oxford group examined individual level patient data from long-term, randomised, double-blind trials, to evaluate the effects of statin therapy on muscle events. The researchers looked at all adverse events including the timing of such events, the reasons for stopping statins, use of other medication and co-morbidities.
Statins and muscle events
A total of 19 placebo-controlled trials that included a total of 123,940 participants with a mean age of 63 years (28% women) were analysed.
Among the whole cohort, 27.1% of patients assigned to statins and 26.6% taking placebo, reported at least one episode of muscle pain or weakness during a median of 4.3 years. This represented a 3% relative increase (relative risk, RR = 1.03, 95% CI 1.01 – 1.06). In addition, the increased risk was similar for the different muscular symptoms, e.g., cramp or spasm (RR = 1.09), muscle fatigue or weakness (RR = 1.10) and myalgia (RR = 1.03).
When considering more intensive statin regimes (e.g., 40 – 80 mg atorvastatin) vs less intensive/moderate intensity regimes (e.g., atorvastatin 10 – 20 mg), the risk was slightly higher (RR = 1.08 vs 1.03) compared to placebo. During the first year of therapy, statins produced a 7% relative increase in muscle pain or weakness although there was no significant increase thereafter. The authors calculated that only 1 in 15 of the muscle-related effects reported by participants were due to the drug, adding that > 90% of all reports of muscle symptoms in patients allocated to statins were no due to the drug.
They concluded that while statins were responsible for a small proportional increase in reports of muscle pain, for patients prescribed the drugs and who report mild muscle symptoms, it is most likely that these symptoms were not due to the drug.
Cholesterol Treatment Trialists’ Collaboration. Effect of statin therapy on muscle symptoms: an individual participant data meta-analysis of large-scale, randomised, double-blind trials Lancet 2022
20th May 2022
Adding PCSK9 inhibitors and ezetimibe to maximally tolerated statin therapy in patients at a high risk of a cardiovascular event reduces the risk of a non-fatal myocardial infarction (MI) and non-fatal stroke but does not significantly reduce either all-cause mortality or cardiovascular mortality. This was the main finding from a network meta-analysis of trials by a group of US and Chinese researchers.
The 2021 European Society of Cardiology guidelines on cardiovascular disease prevention in clinical practice recommend that a high-intensity statin is prescribed up to the highest dose that can be tolerated in order to reach the LDL target for a specific risk group. Furthermore, the joint American College of Cardiology/American Heart Association Task Force has suggested that in patients at very high cardiovascular risk and whose LDL-C level remains ≥70mg/dl (≥1.8mmol/l) on maximally tolerated statin and ezetimibe therapy, adding a PCSK9 inhibitor is a reasonable option. Previously published data has already shown that when added to statin therapy, ezetimibe produces an incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Similarly, addition of alirocumab (a PCSK9 inhibitor) to patients receiving high-intensity statin therapy, reduced the risk of recurrent ischaemic cardiovascular events.
Whilst the benefits of both treatments cholesterol lowering agents are clear, the benefits to an individual patient depends upon their baseline risk. Moreover, the absolute incremental benefit derived from combining PCSK9 inhibitors and ezetimibe either separately or in combination, among individuals taking a maximally tolerated dose of statin or for those who are statin-intolerant and with different levels of baseline cardiovascular risk, remains to be determined.
For the present study, the authors performed a network meta-analysis of randomised controlled trials in which patients had a median baseline LDL cholesterol value > 1.8mmol/l and where they were randomised to receive PCSK9 inhibitors vs control, ezetimibe vs control, or PCSK9 inhibitors vs ezetimibe. The researchers assessed the relative and absolute risks (per 1000 patients treated for 5 years) in terms of non-fatal MI, non-fatal stroke, all-cause mortality and cardiovascular mortality. Patients were also categorised as being at low to very high cardiovascular risk. The authors set the minimal important difference as 12 per 1000 reductions for non-fatal MI, 10 per 10,000 for a non-fatal stroke and 8 per 1000 for all-cause or cardiovascular mortality.
PCSK9 inhibitors and ezetimibe and cardiovascular outcomes
A total of 16 trials with 111,098 patients (median age 61 years) and a median LDL cholesterol concentration of 2.71mmol/l, were followed-up for a median of 2 years and included in the analysis.
Among patients prescribed statins, addition of a PCSK9 inhibitor reduced the risk of a non-fatal MI by 19% (relative risk, RR = 0.81, 95% CI 0.76 – 0.87), non-fatal stroke by 26% (RR = 0.74) but not all-cause mortality (RR = 0.95, 95% CI 0.87 – 1.03) or cardiovascular mortality (RR = 0.95, 95% CI 0.87 – 1.03).
Similarly, the addition of ezetimibe reduced non-fatal MI and non-fatal stroke by 13% and 18% respectively but, again, there was no significant effect on all-cause or cardiovascular mortality.
Among adults with a very high cardiovascular risk, the authors calculated that adding a PCSK9 inhibitor to statins would lead to 16 fewer non-fatal MIs and 21 non-fatal strokes. Adding ezetimibe to a similar or equivalent statin patient, would lead to 14 fewer non-fatal strokes and 11 fewer MIs. Finally, adding PCSK9 inhibitors and ezetimibe to a statin would reduce non fatal strokes by 14 per 1000 and stroke by 17 per 1000, although there was no impact on all-cause or cardiovascular mortality.
The authors also found that among patients with low to moderate risk of cardiovascular disease, adding either a PCSK9 inhibitor provided no additional benefit over statin therapy alone. In other words, it was only patients with the highest cardiovascular risk who benefited from adding either ezetimibe or a PCSK9 inhibitor to their statin. Similar reductions, again only among high or very high risk individuals and a lack of mortality benefit, were observed in patients intolerant of statins.
The authors concluded that the benefits of adding PCSK9 inhibitors and ezetimibe were limited largely to patients only with a high or very high cardiovascular risk.
Khan SU et al. PCSK9 inhibitors and ezetimibe with or without statin therapy for cardiovascular risk reduction: a systematic review and network meta-analysis BMJ 2022
24th February 2022
The incidence of statin side-effects appears to be less than 10% according to the results of an analysis from both randomised and observational studies according to researchers from the Department of Public Health and Clinical Medicine, Umeå University, Sweden.
Hydroxymethyl glutaryl coenzyme A reductase inhibitors, or statins, have revolutionised the management of patients with coronary heart disease with a 2016 systematic review finding that in adults at an increased risk of cardiovascular disease, statin therapy was associated with reduced risk of all-cause and cardiovascular mortality and cardiovascular disease events. Despite these proven benefits other data has revealed that between 40 and 75% of patients discontinue their statin within one year after initiation. Reported statin side-effects have included myalgia, myopathy, rhabdomyolysis and diabetes with patients frequently discontinuing therapy without medical advice because of perceived side effects.
The overall prevalence of adverse effects from statins is uncertain, reportedly ranging from 7% in clinical trials to 30% in observational studies. Given this wide variation, for the present study, the Swedish team undertook a meta-analysis to try and provide an estimate of the overall prevalence of statin side-effects. They included both randomised trials and cohort studies which specifically reported on the incidence of adverse effects. The primary endpoint was set as the overall prevalence of adverse effects based on international diagnostic criteria. These criteria included the definition of an adverse effect as one affecting quality of life leading to treatment discontinuation, an inability to tolerate a dose of statin required to reduce an individual’s cardiovascular risk or in relation to adverse muscle-related pain and elevation of creatinine kinase levels.
Statin side-effects overall incidence
A total of 176 studies with 4,143,517 patients with a mean age of 60.5 years (40.9% female) and who were followed-up of 19 months were included in the analysis. The 176 studies comprised 112 randomised trials (195,575 patients) and the remainder cohort studies and White or Caucasian individuals accounted for the majority (81.1%) of participants.
The pooled estimate of statin side-effects was 9.1% (95% CI 8 – 10%) and this was similar for the different diagnostic criteria used. Interestingly, the prevalence of adverse effects was significantly lower in randomised trials compared to cohort studies (4.9% vs 17%). When comparing the different types of statins, the researchers found that for both lipophilic (e.g., atorvastatin, simvastatin, lovastatin) and hydrophilic (e.g., pravastatin, rosuvastatin) agents, the pooled prevalence was very similar (4% vs 5%, lipophilic vs hydrophilic).
Commenting on their findings, the authors suggested that the higher prevalence among cohort studies could have been over-estimated and that in randomised trials, there was a possibility for under-estimation especially because patients who were either older or with co-morbidities and who might therefore be more likely to experience adverse effects, would have been excluded from the trials.
They concluded that the prevalence of statin side-effects is low, highlighting the need for a careful assessment of patients who report adverse effects to reduce unnecessary discontinuation of therapy.
Bytyci I et al. Prevalence of statin intolerance: a meta-analysis Eur Heart J 20222
19th October 2021
Statin use appears to be associated with a lower mortality in those infected with COVID-19 according to the results of a large, Swedish cohort study. Previous studies in this area have been ambiguous. For example, a Danish observational study concluded that “recent statin exposure in patients with COVID-19 infection was not associated with an increased or decreased risk of all-cause mortality or severe infection.” In contrast, a US study observed a greater than 50% reduction in the risk of developing severe COVID-19 after controlling for co-morbidities and other treatments. Although a meta-analysis of studies on the use of statins and outcomes for COVID-19, concluded that the drug class was not associated with an improvement in a composite of poor outcomes, there was substantial heterogeneity with the included studies. While on-going trials examining the adjunctive value of statins will ultimately provide some much needed clarity of the possible benefit of this class of medicine, a team from the Department of Global Public Health, Karolinska Institute, Stockholm, Sweden, have published data from a large, population-based observational study, examining the relationship between statin use and COVID-19 mortality.
Using a prescribed drug registry, the team included individuals aged 45 years and older prescribed any type of statin between March 2019 and the end of February 2020. These individuals were followed-up until death from either COVID-19 or any other cause. For their study, the primary outcome of interest was death from COVID-19 and the analysis was presented as adjusted hazard ratios. Adjustments were made for numerous factors including age, gender, income, household crowding and wide range of co-morbidities.
A total of 963,876 individuals were included in the analysis. The cohort comprised, 169, 642 statin users with a median age of 71 years (43.4% female) with hypertension being the most common co-morbidity (74.3%). Overall, 2,545 individuals died from COVID-19 during the period of follow-up; 756 (0.5%) who were statin users, giving an adjusted hazard ratio for mortality of 0.88 (95% CI 0.79 – 0.97, p = 0.01) compared to non-statin users. This association did not differ by gender (p = 0.65), across age groups (p = 0.82) or COVID-19 risk groups (p = 0.72).
Although of course these data do not prove that statin use reduces death in those with COVID-19, it offers some tentative clues that individuals using these drugs appear less likely to die from infection with the virus. The authors concluded that the results provide some support for the continued use of statins during the COVID-19 pandemic.
Bergqvist R et al. HMG-CoA reductase inhibitors and COVID-19 mortality in Stockholm, Sweden: A registry- based cohort study. PLoS Med 2021
1st September 2021
The presence of an elevated cholesterol level increases the risk of several cardiovascular diseases including stroke, type 2 diabetes and peripheral arterial disease. Hence cholesterol lowering has become an important therapeutic goal in the prevention of cardiovascular disease although much focus has been placed on the levels of low-density lipoprotein (LDL), cholesterol. Patients with high cholesterol are normally prescribed statins, which block the rate limiting step of cholesterol biosynthesis, however, studies have shown that adherence to treatment reduces over time and in patients who experienced an acute myocardial infarction, over a third with hyperlipidaemia, did not achieve the low-density lipoprotein target level after 6 months of therapy. A further problem with statins is the development of side-effects, especially muscle-related effects, and in one study, these were reported by 60% of former statin users and a quarter of current users. The discovery of pro-protein convertase subtilisin-kexin type 9 (PCSK9), which is a protein that binds to LDL receptors, has been an important breakthrough in the management of hyperlipidaemia. PCSK9 reduces the number of LDL receptors on cell surfaces and prevents it from recycling, hence LDL cholesterol cannot be removed and levels remain high.
Inclisiran is a new class of molecule, termed a small, interfering RNA (siRNA) and these agents are able to regulate the expression of genes. Inclisiran targets the hepatic production of PCSK9 and inhibition of its action, effectively increases the number of available LDL receptors and results in an LDL cholesterol lowering effect. The efficacy of the drug, which is given via subcutaneous injection, at reducing LDL cholesterol levels was shown in a paper that combined the results of two randomised, double-blind controlled, phase 3 trials in patients with LDL cholesterol levels of 1.8 mmol/L or higher. Use of inclisiran reduced LDL cholesterol levels after 510 days by 52.3% and 49.9% in the second trial. However, much more importantly, the trials suggested that inclisiran could be given once every 6 months.
In its final appraisal document, NICE has recommended that inclisiran is used in patients with a history of any cardiovascular events (e.g., acute coronary syndrome, coronary or other arterial revascularisation procedures) and where LDL cholesterol levels remain persistently above 2.6 mmol/L, despite maximum tolerated lipid-lowering therapy. Inclisiran has been previously approved in the EU for the management of adults with primary hypercholesterolaemia or mixed dyslipidaemia as an adjunct to diet in combination with a statin or other lipid-lowering treatment in patients unable to reach their LDL cholesterol targets. Alternatively, it can be used alone or in combination with any lipid-lowering therapy for patients intolerant of statins. Despite this licensed use, NICE did not recommend the use of inclisiran as a preventative treatment (i.e., in those with familial hypercholesterolaemia.)
While the drug appears to be very effective at LDL cholesterol lowering, NICE accepted the lack of long-term data although on-going trials should provide this information in the future.
24th November 2020
Guidance on the use of statins as a means of reducing this risk recommends that any decisions are made jointly by patients and clinicians, especially given the wide range of cardiovascular risk factors, comorbidity burden and life expectancy of patients within this age range. While the benefits of statin therapy are well established, what remains unclear is the time-frame over which these benefits occur. In other words, how long is the “time to benefit” (TTB) from statins.
In an analysis, researchers from the Division of Geriatrics and Gerontology, University of California, US, conducted a meta-analysis of the major randomised clinical trials to determine the TTB, which served as the primary outcome and which they defined as the time from starting a statin to the first MACE. The team only included trials which had more than 1000 participants, aged at least 55 years and older. Given that the focus was primary prevention, researchers also limited the search to those trials in which less than 15% of participants had pre-existing cardiovascular disease.
A search of all the major databases, identified 8 randomised trials including 65,383 patients (66.3% male) and with less than 10% of participants having existing cardiovascular disease. The analysis showed how the benefit of statin therapy increased with the duration of the study so that, for example, after 1 year, 0.3 MACEs were prevented for every 100 people treated with statins and this increased to 2.5 MACEs after 5 years. They calculated that 2.5 years were required to prevent 1 MACE for every 100 patients given statins. Thus statin treatment was only likely to benefit patients aged 50 to 75 years where they had a life expectancy of at least 2.5 years. Interestingly, only one statin trial found that therapy reduced overall mortality.
The authors concluded that their results reinforce the importance of individualised statin treatment-related decision making.
Yourman LC et al. Evaluation of time to benefit of statins for primary prevention of cardiovascular events in adults aged 50 to 75 years. A Meta-analysis. JAMA Intern Med 2020