👤 Allan D Sniderman

Apolipoprotein B (apoB) is a superior marker of residual atherosclerotic cardiovascular disease risk in patients treated with lipid-lowering therapy (LLT) compared with low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C). The cost-effectiveness of LDL-C, non-HDL-C, and apoB goals has not been established. To determine the relative cost-effectiveness of intensifying LLT for primary prevention based on LDL-C, non-HDL-C, and apoB goals. This economic evaluation used a computer simulation model to evaluate the cost-effectiveness of intensifying LLT with high-intensity statins or ezetimibe according to LDL-C, non-HDL-C, or apoB goals. A cohort of 250 000 statin-eligible and atherosclerotic cardiovascular disease-free US adults was constructed from 2005 to 2016 National Health and Nutrition Examination Survey participants (N = 4149). Individuals commenced the simulation after lipid screening and received statin therapy based on 2018 American Heart Association/American College of Cardiology guidelines. Model inputs were derived from national survey data, pooled longitudinal cohort studies, and published literature. Uncertainty was explored with traditional and probabilistic sensitivity analysis. Lipid-lowering therapy was intensified if individuals did not achieve treated LDL-C level less than 100 mg/dL, non-HDL-C level less than 118 mg/dL, or apoB level less than 78.7 mg/dL. Lifetime quality-adjusted life-years (QALYs) and costs (in 2025 US dollars), discounted 3.0% annually. The primary outcome was the incremental cost-effectiveness ratio. Strategies were considered cost-effective if they cost less than $120 000 per QALY gained. Compared with an LDL-C goal, 965 QALYs (95% uncertainty interval [UI], -3551 to 5341 QALYs) would be gained with a non-HDL-C goal, alongside a $2.1 million (95% UI, -$94.2 million to $92.0 million) reduction in costs. Compared with a non-HDL-C goal, 1324 QALYs (95% UI, -2602 to 5669 QALYs) would be gained with an apoB goal, alongside a $40.2 million (95% UI, -$43.6 million to $134 million) increase in costs, yielding an incremental cost-effectiveness ratio of $30 300 per QALY gained. At a willingness-to-pay threshold of $120 000 per QALY gained, an apoB goal was optimal in 65% of probabilistic analyses and a non-HDL-C goal was optimal in 25%. The cost of apoB testing was marginal; higher costs reflected longer life expectancy and prolonged preventive treatment. The results of this computer simulation study suggest that apoB can be used as a cost-effective marker to guide primary prevention LLT and improve population health. Show less

Familial dysbetalipoproteinemia (FDB) is a genetic lipoprotein disorder that can develop in patients homozygous for the APOE2 genotype (ε2/ε2). It is associated with decreased clearance of remnant lipoproteins and increased atherosclerotic cardiovascular disease (ASCVD) risk disproportionate to their level of LDL-C. A goal of this study was to develop a screening test for the ε2/ε2 genotype based on routinely available lipid tests and to determine those at most risk for ASCVD. After assembly of a primary prevention cohort from the UK Biobank (n= 269,895), gene array and exome data was utilized to classify patients as being ε2/ε2 genotype positive or negative. Lipid profiles and APOB levels were extracted and the number of ASCVD events was tabulated during a 15-year follow-up period. Using a newly developed equation for estimating APOB (eAPOB) with lipid panel test results, the ratio of measured APOB to eAPOB was better than any other individual lipid test or ratio for identifying patients with the ε2/ε2 genotype (AUC: APOB/eAPOB: 0.990 (0.986-0.994), nonHDL-C/APOB: 0.961 (0.952-0.970), APOB: 0.955 (0.949-0.961), VLDL/TG: 0.788 (0.771-0.804)). The majority of ε2/ε2 patients could be identified with the APOB/eAPOB ratio even before they expressed the FDB phenotype with elevated TG and nonHDL-C. The PCE or PREVENT risk equations were the most accurate method for identifying higher risk patients (AUC: PREVENT: 0.690 (0.637-0.742), PCE: 0.697 (0.645-0.749)). The APOB/eAPOB ratio can be used to accurately identify the ε2/ε2 genotype and conventional risk equations are the best method for determining those at risk for ASCVD. Show less

Conventional statistical approaches are not designed to compare highly correlated variables such as low-density lipoprotein cholesterol (LDL-C), non-high density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B (apoB). Discordance analysis was designed to overcome this limitation by creating groups in which the predictions of 2 markers differ. This systematic review compiled all discordance studies that compare the predictive powers of LDL-C and non-HDL-C vs LDL particle number (LDL P) or apoB as markers of atherosclerotic disease risk to determine which is the most accurate marker of cardiovascular risk. A PubMed search completed September 30, 2024, identified 15 studies involving 593,354 participants. These studies encompassed diverse populations, and included patients with and without statin therapy. Several variations of discordance analysis were used including median-based, percentile-based, residual-based, and variance-based approaches. ApoB outperformed LDL-C in 9 of 9 studies whereas LDL P was superior to LDL-C in 2 of 3 comparisons. In 1 study, non-HDL-C was superior to apoB, in 1 study apoB and non-HDL-C were equivalent, whereas in 7 studies, apoB, overall, was a significantly more accurate marker of atherosclerotic cardiovascular disease risk than non-HDL-C. Discordance analysis provides robust evidence that apoB is a more accurate marker of cardiovascular risk than either LDL-C or non-HDL-C, notwithstanding these variables are highly intercorrelated. Thus, neither LDL-C nor non-HDL-C are adequate clinical surrogates for apoB. Accordingly, apoB should be the primary measure in clinical care to estimate the cardiovascular risk attributable to the apoB lipoproteins and the adequacy of lipid-lowering therapy to reduce this risk. Show less

Atherogenic lipoprotein exposure during young adulthood increases the risk of atherosclerotic cardiovascular disease (ASCVD) later in life. The relationships between cumulative and usual yearly apolipoprotein B (apoB), low-density lipoprotein particle (LDL-P), and triglyceride-rich lipoprotein particle (TRL-P) exposure in early adult life and incident ASCVD was quantified. Follow-up data of young adults aged 18 to <40 years from the longitudinal population-based Coronary Artery Risk Development in Young Adults (CARDIA) cohort were used. Cumulative early adult exposure of apoB, LDL-P, and TRL-P were defined over a 22-year exposure period (18 to <40 years). 'Usual' exposure to atherogenic lipid particles was calculated by dividing the cumulative exposure to apoB, LDL-P, and TRL-P by 22 years, and the hazard ratio was calculated between a 1 SD higher cumulative lipoprotein exposure with incident ASCVD after age 40 using adjusted Cox regression models. Among 4366 CARDIA participants, there were 241 ASCVD events after age 40 (mean follow-up of 19.3 years). A 1 SD higher cumulative exposure to apoB, LDL-P, and TRL-P was associated with unadjusted HRs of 1.53 [95% confidence interval (CI) 1.36-1.72], 1.54 (95% CI 1.36-1.75), and 1.48 (95% CI 1.30-1.68) for incident ASCVD after age 40, respectively. Adjustment for covariates yielded HRs for each measure of approximately 1.30. The hazard ratio for ASCVD increased after a usual apoB exposure of approximately 75 mg/dL/year from age 18 to <40. Cumulative exposure to atherogenic lipid particles in young adulthood increases the risk for incident ASCVD later in life. Apolipoprotein B concentration <75 mg/dL may represent a goal to maintain low risk in young adults. Show less

The importance of any enhanced atherogenicity of triglyceride (TG)-rich lipoproteins (TRLs) will depend on the relative abundance of these particles compared with low-density lipoprotein (LDL) or total apolipoprotein (apo)B. Accordingly, we determined the contribution that TRLs make to total apoB as TG or apoB concentrations increase. We also describe compositional changes in TRLs as TG or apoB increases to assess whether very low-density lipoprotein (VLDL-[C]) is a valid proxy for VLDL-apoB. We used sequential ultracentrifugation to separate lipoprotein fractions in plasma samples from 1940 dyslipidemic patients not on lipid-lowering medication, and measured apoB, cholesterol and TG in the plasma and in each subfraction. We analyzed these data in quartiles of TG or apoB. There was wide variance in all parameters in all quartiles of both TG and apoB. Although VLDL-apoB accounted for almost all the increase in total apoB across TG quartiles, LDL-apoB still accounted for 80% of the total in TG quartile 4. In contrast, LDL-apoB accounted for 90% of the increase in apoB across apoB quartiles. As TG increases, the increase in VLDL-C is explained more by increased VLDL-C/apoB when TG is moderately elevated, and more by increased VLDL-apoB when TG is very high. In conclusion, VLDL-apoB only becomes a substantial component of total apoB with extreme hypertriglyceridemia and VLDL-C is not an appropriate proxy for VLDL-apoB. Show less

Recent observational and Mendelian randomization analyses have reported significant effects of VLDL-C (very-low density lipoprotein cholesterol) on risk that is independent of ApoB (apolipoprotein B). We aim to determine the independent association of VLDL-C and ApoB with the risk of new onset cardiovascular events in the UK Biobank and Framingham Heart Study cohorts. We included 294 289 UK Biobank participants with a median age of 56 years, 42% men, and 2865 Framingham Heart Study participants (median age, 53 years; 47% men). The residual resulting from regressing VLDL-C on ApoB expresses the portion of VLDL-C not explained by ApoB, while the residual from regressing ApoB on VLDL-C expresses the portion of ApoB not explained by VLDL-C. Cox proportional hazards models for atherosclerotic cardiovascular disease incidence were created for residual VLDL-C and residual ApoB. Models were analyzed with and without high-density lipoprotein cholesterol (HDL-C). Furthermore, we investigated the independent effects of VLDL-C after accounting for ApoB and HDL-C and of HDL-C after accounting for ApoB and VLDL-C. In the UK Biobank, ApoB was highly correlated with VLDL-C (r=0.70; When adjusted for HDL-C, the association of VLDL-C with cardiovascular risk was no longer clinically meaningful. Our residual discordance analysis suggests that adjustment for HDL-C cannot be ignored. Show less

Selecting individuals for preventive lipid-lowering therapy is presently governed by the 10-year risk model. Once a prespecified level of cardiovascular disease risk is equaled or exceeded, individuals become eligible for preventive lipid-lowering therapy. A key limitation of this model is that only a small minority of individuals below the age of 65 years are eligible for therapy. However, just under one-half of all cardiovascular disease events occur below this age. Additionally, in many, the disease that caused their events after 65 years of age developed and progressed before 65 years of age. The causal-benefit model of prevention identifies individuals based both on their risk and the estimated benefit from lowering atherogenic apoB lipoprotein levels. Adopting the causal-benefit model would increase the number of younger subjects eligible for preventive treatment, would increase the total number of cardiovascular disease events prevented at virtually the same number to treat, and would be cost-effective. Show less

Cholesteryl ester transfer protein (CETP) facilitates the exchange of cholesteryl esters and triglycerides (TG) between high-density lipoprotein (HDL) particles and TG-rich, apolipoprotein (apo) B-containing particles. Initially, these compounds were developed to raise plasma HDL cholesterol (HDL-C) levels, a mechanism that was previously thought to lower the risk of atherosclerotic cardiovascular disease (ASCVD). More recently, the focus changed and the use of pharmacologic CETP inhibitors to reduce low-density lipoprotein cholesterol (LDL-C), non-HDL-C and apoB concentrations became supported by several lines of evidence from animal models, observational investigations, randomized controlled trials and Mendelian randomization studies. Furthermore, a cardiovascular outcome trial of anacetrapib demonstrated that CETP inhibition significantly reduced the risk of major coronary events in patients with ASCVD in a manner directly proportional to the substantial reduction in LDL-C and apoB. These data have dramatically shifted the attention on CETP away from raising HDL-C instead to lowering apoB-containing lipoproteins, which is relevant since the newest CETP inhibitor, obicetrapib, reduces LDL-C by up to 51% and apoB by up to 30% when taken in combination with a high-intensity statin. An ongoing cardiovascular outcome trial of obicetrapib in patients with ASCVD is expected to provide further evidence of the ability of CETP inhibitors to reduce major adverse cardiovascular events by lowering apoB. The purpose of the present review is to provide an up-to-date understanding of CETP inhibition and its relationship to ASCVD risk reduction. Show less

In clinical lipidology, we have focused our major efforts in defining risk status and specifying the targets of therapy by using the cholesterol content of the lipoproteins. However, we now know that these measures are variable and that they may not reveal all the valuable information that can be used to treat our patients. The amount of cholesterol in each lipoprotein can be quite different in different patients. The number of particles containing apolipoprotein B (apoB) can be abnormally high with a value for low-density lipoprotein cholesterol, which is within our guidelines. Furthermore, the content of apoC3 in apoB-containing lipoproteins can predict risk without a close association with triglycerides or cholesterol. The genome-wide association studies and studies in special families with known genetic polymorphisms have been particularly revealing relationships between these vascular risk. Show less