ApoB and non-HDL-c are better markers of residual risk than LDL-c in statin-treated patients
Apolipoprotein B and Non-HDL Cholesterol Better Reflect Residual Risk Than LDL Cholesterol in Statin-Treated Patients
Introduction and methods
LDL-c is the primary target in major guidelines on hypercholesterolemia, while apoB and non-HDL-c are secondary targets [1-3]. ApoB, non-HDL-c and LDL-c are highly correlated, but apoB and non-HDL-c include triglyceride-rich lipoproteins in addition to LDL [4-6]. Residual risk of ASCVD remains a challenge during statin therapy. Previous studies have shown that apoB and non-HDL-c are more strongly associated with ASCVD than LDL-c [7-9]. However, discordance analyses on ASCVD risk in statin-treated patients have not been performed to date. In addition, the relative importance of apoB, non-HDL-c and LDL-c on risk of all-cause mortality in patients on statin therapy remains unknown. This study evaluated whether elevated apoB and/or non-HDL-c better reflect residual risk of all-cause mortality and MI than LDL-c in statin-treated patients.
The study included 13,015 individuals from the Copenhagen General Population study. The Copenhagen General Population study was initiated in 2003 to 2015 and reflects the white Danish general population. Participants were aged 20-100 years at baseline. Individuals included in this study were treated with statins and had measurements of apoB, non-HDL-c and LDL-c at baseline. Median follow-up was 8 years. Analyses were adjusted for age, sex, smoking status, pack-years, SBP, and any diagnosis of ASCVD, cancer, or chronic obstructive pulmonary disease at baseline. Hazard ratios of all-cause mortality and MI were estimated by Cox proportional hazards regressions on categories of discordant vs. concordant categories of 1) apoB vs LDL-c; 2) non-HDL-c vs LDL-c; 3) apoB vs non-HDL-c; and 4) apoB vs non-HDL-c vs LDL-c.
Multivariable-adjusted risk of all-cause mortality
- A J-shaped association was seen between apoB and all-cause mortality, with lowest risk at 73 mg/dl and increased risk at lower and higher values.
- Non-HDL-c concentrations ≥3.1 mmol/l (120 mg/dl) were associated with increased risk of all-cause mortality.
- For LDL-c, risk of all-cause mortality was lowest at concentrations of 2.1 mmol/l (82 mg/dl). Concentrations below this level were associated with increased risk of all-cause mortality, whereas higher levels were not significantly associated with increased risk of all-cause mortality.
- Discordant apoB above the median (of 92 mg/dl) with LDL-c below the median (of 2.3 mmol/l [89 mg/dl]) was associated with increased risk of all-cause mortality, compared with concordant apoB and LDL-c below the medians (HR 1.21, 95%CI 1.07-1.36). Similarly, discordant non-HDL-c above the median (of 3.1 mmol/l [120 mg/dl]) with LDL-c below the median (of 2.3 mmol/l) was associated with increased risk of all-cause mortality (HR 1.18, 95%CI 1.02-1.36). Discordant LDL-c above the median with apoB or non-HDL-c below the median were not associated with increased risk of all-cause mortality, compared with concordant values below medians.
- Discordant apoB above the median with non-HDL-c below the median was associated with higher risk of all-cause mortality (HR 1.21, 95%CI 1.03-1.41), while discordant apoB below the median with non-HDL-c above the median was associated with lower risk of all-cause mortality (HR 0.75, 95%CI 0.62-0.92).
- Dual discordant apoB and non-HDL-c above the medians with LDL-c below the median had a HR of 1.23 (95%CI 1.07-1.43) for all-cause mortality. Discordant apoB below the median with non-HDL-c and LDL-c above the median was associated with decreased risk of all-cause mortality (HR 0.75, 95%CI 0.61-0.92).
Multivariable-adjusted risk of MI
- Any higher level of apoB or non-HDL-c was associated with increased risk of MI. There was no association between any higher LDL-c level and risk of MI.
- Discordant apoB above the median with LDL-c below the median was associated with increased risk of MI, compared with concordant values below the medians (HR 1.49, 95%CI 1.15-1.92). Discordant non-HDL-c above the median with LDL-c below the median was also associated with increased risk of MI (HR 1.78, 95%CI 1.35-2.34). There was no clear trend for discordance between apoB and non-HDL-c. Risk for MI was only higher if both markers were above the median.
- Dual discordant apoB and non-HDL-c above the medians with LDL-c below the median was associated with increased risk for MI, compared with concordant values of all 3 markers below the medians (HR 1.82, 95%CI 1.37-2.42). Concordant values above the medians for all 3 lipid markers presented a HR of 1.25 (95%CI 1.02-1.54).
Elevated apoB and non-HDL-c were associated with increased risk of all-cause mortality and MI in statin-treated patients. No association was found between elevated LDL-c and all-cause mortality or MI. Thus, the results of this study suggest that elevated apoB and non-HDL-c better reflect residual risk in patients on statins than elevated LDL-c. Discordant analyses showed that apoB is a more accurate marker of all-cause mortality risk than LDL-c or non-HDL-c in statin-treated patients.
In their editorial comment , Neil J. Stone, MD and Donald Lloyd-Jones, MD dive into the question which patients with low statin-treated levels still have elevated non-HDL-c or apoB. And, how can/should these patients be treated? Stone and Lloyd-Jones suggest that these patients will in general be those with metabolic disorders, such as obesity, insulin resistance and/or diabetes, with concomitant risk related to elevated triglycerides, hypercoagulability, inflammation, and elevated Lp(a). Non-HDL-c and apoB markers could be used to motivate and monitor the success of lifestyle changes, as elevations in non-HDL-c and apoB often respond well to improvements in diet, weight loss and increased physical activity. Another potential treatment option to reduce residual risk in statin-treated patients is use of high-dose icosapent ethyl in high risk patients who are well treated with statins.
Stone and Lloyd-Jones further discuss a sequential approach in the treatment of patients with hypercholesterolemia; first achieve as much risk reduction as possible through statins (and adjunctive ezetimibe or PCSK9 inhibition), and then assess the non-HDL-c and apoB level. A possible strategy to efficiently identify those with residual risk while being on optimal statin therapy could be to start with selected groups where the subsequent benefit of additional therapy is likely to be highest; those with hypertriglyceridemia, obesity, metabolic syndrome, or diabetes.
Current American and European guidelines acknowledge the usefulness of apoB and non-HDL-c in risk calculations. However, they do not strongly recommend measurement of apoB for assessing residual risk. Stone and Lloyd-Jones argue that guideline panels should consider whether apoB and non-HDL-c should be routinely or selectively measured and how these measurements could influence guideline-directed care.
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