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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 doi:10.1001/jamainternmed.2020.6084