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21st March 2023
Levels of the inflammatory marker, high-sensitivity C-reactive protein (CRP) serve as a better predictor for the risk of future cardiovascular events and death in comparison to LDL cholesterol (LDLC), according to an analysis of data from three, large, cardiovascular trials by US researchers.
It has been recognised for many years that high-sensitivity CRP predicts the risk of future myocardial infarction and stroke in healthy men and this relationship also holds true for women. In addition, while hyperlipidaemia is a risk factor for cardiovascular disease, it is also known that addition of drugs with an anti-inflammatory effect, such as colchicine to statin therapy, also significantly reduces the risk of cardiovascular events in patients with chronic cardiac disease.
Given how both inflammation and elevated LDL cholesterol are important cardiovascular risk factors, because patients prescribed statins can still experience an adverse cardiovascular event, an important question is how to deal with this residual risk. In other words, should clinicians treat with additional lipid lowering therapy (to minimise the residual cholesterol risk) or use an anti-inflammatory agent (to lower the residual inflammatory risk)?
Using data from three large statin trials (PROMINENT, REDUCE-IT and STRENGTH) the US researchers compared the highest and lowest quartiles of high-sensitivity CRP and LDLC , to determine the best predictors of future major adverse cardiovascular events, cardiovascular death, and all-cause death.
High-sensitivity CRP and cardiovascular outcomes
A total of 31,245 patients were included and participants aged between 64 and 65 with the proportion of females ranging from 28 to 35%.
Combining data from the three trials showed that the presence of residual inflammatory risk was significantly associated with incident major adverse cardiovascular events (adjusted Hazard Ratio, aHR = 1.31, 95% CI 1.20 – 1.43, p < 0.0001) for the highest vs the lowest high-sensitivity CRP quartiles. This relationship was also true for cardiovascular mortality (aHR = 2.68, p < 0.0001) and all-cause mortality (aHR = 2.42, p < 0.0001).
However, when comparing the highest to lowest quartiles of LDL cholesterol, the relationship was non-significant for major adverse cardiovascular events (aHR = 1.07, p = 0.11) but was significant, albeit smaller, compared to high-sensitivity CRP, for cardiovascular death (aHR = 1.27, p = 0.0086) and all-cause mortality (aHR = 1.16, p = 0.025).
The authors concluded that in those already prescribed a statin, high-sensitivity CRP proved to be a stronger marker for the prediction of future cardiovascular events and death compared to LDL cholesterol levels. They added that their findings suggested that both aggressive lipid-lowering and inflammation-inhibiting therapies might be needed to further reduce atherosclerotic risk.
Ridker PM et al. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials. Lancet 2023
24th March 2022
Statin therapy is associated with only a modest absolute risk reduction in cardiovascular disease outcomes including all-cause mortality and myocardial infarction (MI). This was the important main finding from a meta-analysis of randomised trials by researchers from the HRB Centre for Primary Care Research, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
It widely thought that the key initiating event in atherogenesis is the retention of low-density lipoprotein (LDL) cholesterol and other cholesterol-rich lipoproteins within the arterial wall. As a result, a great deal of effect has been directed at reducing LDL cholesterol levels so that the treatment with a statin drug has become a well-recognised approach for lowering LDL cholesterol. While there are clearly benefits from the use of statins, in much of the published work, authors report relative rather than absolute risk reductions. This represents an important weakness for the interpretation of the data since readers tend to overestimate the effect of an intervention when the results are expressed in relative terms. In contrast, the absolute risk gives a better representation of the actual situation and also from the patient’s point of view, absolute risks often give more relevant information.
For the present meta-analysis, the Irish team analysed both the relative and absolute risks associated with the use of statin therapy for outcomes such as all-cause mortality, MI and stroke. They included trials which examined the efficacy of a statin on cardiovascular outcomes with a duration of at least 2 years, which enrolled more than 1,000 participants and where the comparator was either placebo or usual care.
Statin use and cardiovascular disease outcomes
A total of 21 trials with 1,255 to 20,536 participants, of which 33% were for primary prevention, were included in the analysis. The average trial follow-up period was 4.4 years and ranged from 1.9 to 6.1 years.
From the meta-analysis, the overall absolute risk reduction (ARR) for all-cause mortality was 0.8%, 1.3% for MI and 0.4% for stroke for individuals randomised to receive a statin compared to either placebo or usual care. The corresponding relative risk reductions (RRRs) were 9% (all-cause mortality), 29% (MI) and 14% (stroke). As an example, the authors calculated that with an ARR of 1.3% for MI, 77 patients (i.e., 1/0.013) would need to be treated for an average of 4.4 years to prevent one myocardial infarction.
In subgroup analysis (primary vs secondary prevention), the ARR was 0.6%, 0.7% and 0.3% for all-cause mortality, MI and stroke respectively, in primary prevention trials. The corresponding RRRs were 13%, 38% and 24%.
For secondary prevention, the ARRs were 0.9% (all-cause mortality), 2.2% (MI) and 0.7% (stroke) with the corresponding RRRs of 14%, 27% and 13%.
The researchers also examined the the potential mediating effect of LDL cholesterol reduction with the absolute and relative treatment effects but these findings were inconclusive. In other words, it was not possible to either prove or disprove an association between the magnitude of LDL cholesterol reduction and the size of a treatment effect.
An important finding from the analysis was the high level of statistically heterogeneity in the studies, ranging from 27% to 82%, which suggested that pooling of results could make the findings unreliable.
The authors concluded that the absolute risk reductions associated with the use of a statin drug are modest in comparison to the often quoted relative risk reductions. However, they added that given the high level of heterogeneity, these results should be interpreted with caution. Despite this limitation, they suggested that clinicians should communicate both ARRs and RRRs to patients to enable informed decision-making about the benefits of statin treatment.
Byrne P et al. Evaluating the Association Between Low-Density Lipoprotein Cholesterol Reduction and Relative and Absolute Effects of Statin Treatment: A Systematic Review and Meta-analysis Ann Intern Med 2022
1st March 2022
Caffeine affects two regulators of low-density lipoprotein (LDL) cholesterol, reducing levels of the lipoprotein and thereby lowering cardiovascular disease risk (CVD) according to a study by researchers from the Department of Medicine, McMaster University, Hamilton, Canada.
Consumption of caffeine containing beverages has been found to have a nonlinear association with CVD risk, such that the lowest risk is achieved through drinking 3 to 5 cups per day. In addition, there is evidence from cohort studies that coffee consumption reduces the risk of ischaemic and haemorrhagic stroke. However, the mechanism underlying these potentially protective cardiovascular effects remains unclear but could be related to a reduction in risk factors such as LDL cholesterol, which when elevated, is known to be associated with a higher risk of myocardial infarction and atherosclerotic cardiovascular disease.
An important regulator of LDL cholesterol is the membrane-bound transcription factor, SREBP2, that is activated when intracellular cholesterol levels are reduced leading to the production of proprotein convertase subtilisin/kexin type 9 (PCSK9) which reduces the ability of tissues to remove excess LDL from the blood. But how caffeine might affect these two regulators is currently uncertain and was the focus of the study by the Canadian team who examined the impact of caffeine on SREBP2 transcriptional activation.
Caffeine intake and LDL cholesterol levels
Initially using a mouse model, the Canadian team found that caffeine was able to block SREBP2 activation which in turned reduced PCSK9 levels. PCSK9 inhibitors have recently become available for the treatment of high cholesterol and so this was a potentially important observation. Furthermore, the team were also able to show that caffeine increased hepatic cell uptake of LDL, which supported the notion that PCSK9 was attenuated.
In order to study whether this effect could also be seen in humans, the researchers recruited 12 healthy volunteers (4 males) between the ages of 22 and 45. The volunteers were asked to fast for 12 hours and given 400 mg of caffeine, which is roughly four cups of brewed coffee. Blood samples were taken prior to administration of the caffeine and after 2 and 4 hours. The results showed that caffeine reduced plasma levels of PCSK9 by 25% after 2 hours and by 21% after 4 hours and this change was not observed among a group of fasted individuals who were not given caffeine over the same time period.
In discussing their findings, the authors described how their data support the notion that small molecules such as caffeine, by blocking the activation of SREBP2, had a downstream effect of attenuating PCSK9 expression in humans. Furthermore, the overall effect of this action was increased expression of LDL receptors on the surface of hepatocytes (which is blocked by PCSK9) enabling increased cellular uptake of LDL cholesterol and therefore lowering plasma levels.
They concluded that the study offers compelling evidence for the development of caffeine-related compounds that might be able to mitigate the risk of cardiovascular disease.
Lebeau PF et al. Caffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance Nat Commun 2022