Low-Density Lipoprotein Cholesterol Lowering for the Primary Prevention of Cardiovascular Disease Among Men With Primary Elevations of Low-Density Lipoprotein Cholesterol Levels of 190 mg/dL or Above

Abstract

BACKGROUND:Patients with primary elevations of low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dL are at a higher risk of atherosclerotic cardiovascular disease as a result of long-term exposure to markedly elevated LDL-C levels. Therefore, initiation of statin therapy is recommended for these individuals. However, there is a lack of randomized trial evidence supporting these recommendations in primary prevention. In the present analysis, we provide hitherto unpublished data on the cardiovascular effects of LDL-C lowering among a primary prevention population with LDL-C ≥190 mg/dL. METHODS:We aimed to assess the benefits of LDL-C lowering on cardiovascular outcomes among individuals with primary elevations of LDL-C ≥190 mg/dL without preexisting vascular disease at baseline. We performed post hoc analyses from the WOSCOPS (West of Scotland Coronary Prevention Study) randomized, placebo-controlled trial, and observational posttrial long-term follow-up, after excluding individuals with evidence of vascular disease at baseline. WOSCOPS enrolled 6595 men aged 45 to 64 years, who were randomly assigned to pravastatin 40 mg/d or placebo. In the present analyses, 5529 participants without evidence of vascular disease were included, stratified by LDL-C levels into those with LDL-C <190 mg/dL (n=2969; mean LDL-C 178±6 mg/dL) and those with LDL-C ≥190 mg/dL (n=2560; mean LDL-C 206±12 mg/dL). The effect of pravastatin versus placebo on coronary heart disease and major adverse cardiovascular events were assessed over the 4.9-year randomized controlled trial phase and on mortality outcomes over a total of 20 years of follow-up. RESULTS:Among 5529 individuals without vascular disease, pravastatin reduced the risk of coronary heart disease by 27% (P=0.002) and major adverse cardiovascular events by 25% (P=0.004) consistently among those with and without LDL-C ≥190 mg/dL (P-interaction >0.9). Among individuals with LDL-C ≥190 mg/dL, pravastatin reduced the risk of coronary heart disease by 27% (P=0.033) and major adverse cardiovascular events by 25% (P=0.037) during the initial trial phase and the risk of coronary heart disease death, cardiovascular death, and all-cause mortality by 28% (P=0.020), 25% (P=0.009), and 18% (P=0.004), respectively, over a total of 20 years of follow-up. CONCLUSIONS:The present analyses provide robust novel evidence for the short-and long-term benefits of lowering LDL-C for the primary prevention of cardiovascular disease among individuals with primary elevations of LDL-C ≥190 mg/dL. ORIGINAL RESEARCH ARTICLE P atients with primary elevations of low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dL (to convert values for cholesterol to mmol/L, multiply by 0.02586) are at a higher risk of atherosclerotic cardiovascular disease (ASCVD) as a result of a longterm exposure to markedly elevated LDL-C levels, even in the absence of preexisting ASCVD (ie, primary prevention). Low-Density Lipoprotein Cholesterol Lowering for the Primary Prevention of Cardiovascular Disease Among Men With Primary Elevat...

Differential use of E2 ubiquitin conjugating enzymes for regulated degradation of the rate-limiting enzymes HMGCR and SQLE in cholesterol biosynthesis

“…syndrome [1,2]. Cells can acquire cholesterol by taking up low-density lipoprotein (LDL) via the LDL-receptor (LDLR) pathway, or alternatively via de novo cholesterol biosynthesis through the mevalonate pathway.…”

Response by Vallejo-Vaz et al to Letters Regarding Article, “Low-Density Lipoprotein Cholesterol Lowering for the Primary Prevention of Cardiovascular Disease Among Men With Primary Elevations of Low-Density Lipoprotein Cholesterol Levels of 190 mg/dL or Above: Analyses From the WOSCOPS (West of Scotland Coronary Prevention Study) 5-Year Randomized Trial and 20-Year Observational Follow-Up”

“…Given ethical concerns that would be posed by giving placebo to patients with LDL-C >190 mg/dL, the WOSCOPS data offers the only option to answer this question. 1 The authors cite that the unanswered question is "will providing statins to people at low risk of atherosclerosis cardiovascular disease (ASCVD) lower their risk even more?" This has been at least partly answered by the HOPE-3 trial 2 where the annual cardiovascular disease event rate was 0.7% per year in the placebo group and rosuvastatin reduced cardiovascular risk by about one quarter; however, the patients in that trial did not have elevated LDL-C as in WOSCOPS.…”

“…If treatment decisions were made on the basis of a risk prediction tool rather than LDL-C levels, then statin therapy would have been withheld in about 67% of our cohort with LDL-C >190 mg/dL, in whom the 10-year predicted risk was <7.5%, in contrast to the actual observed risk of approximately 15%. 1 Individuals with primary severe hypercholesterolemia are likely to have an underlying genetic component to their LDL-C elevation and, therefore, an integrated lifetime exposure to high LDL-C that is not reflected in a risk score algorithm; this aligns with the concept of cumulative LDL-C exposure over time as a determinant of the progression and risk of ASCVD ("LDL-C levels x years"), 7 which is inaccurately captured using a single LDL-C level measurement at one specific time-point. All this suggests that in cases of primary severe elevations of LDL-C conventional risk prediction tools may underestimate cardiovascular risk, and our findings suggest that risk prediction tools should not be routinely used when LDL-C is >190 mg/dL (primary elevations), as already stated in guidelines.…”

“…Statin therapy in the same population lowered the 10-year risk to <10%; 1 thus, among populations with primary LDL-C >190 mg/dL we believe that such individuals are at elevated lifetime risk and that early initiation of statins (small reductions maintained over time) would translate into meaningful benefits, as also suggested by our extended follow-up data. 1 While guidelines are recommendations and individual patients should be considered on an individual basis for prescription of therapy, including those with LDL-C >190 mg/dL, it must also be noted that using a risk scoring system to deny treatment to patients that may benefit of it would not be best practice. Our study provides a solid evidence-base for the clinician who decides on the basis of a full assessment including other risk factors, family history, querying familial hypercholesterolemia, or, in the future, a potential genetic score to decide on statin prescription.…”

Can LDL cholesterol ever be lowered too much?

“…This naturally aligns with the observation that subjects at highest absolute cardiovascular risk, and with the most severe disturbance in LDL cholesterol, have much to gain from LDL cholesterol-lowering intervention with statins. 13,32,33 Furthermore, such gains may not be limited to primary and secondary prevention, as apparently healthy individuals without known cardiovascular risk factors still appear to derive a cardiovascular benefit associated with LDL cholesterol lowering below normal values with statins in the setting of primordial prevention. 34 This may possibly also reflect the actions of statins to, for example, stabilise atherosclerotic plaques, improve vascular endothelial function and reduce inflammation and thrombosis.…”