Per cent reduction in LDL cholesterol following high-intensity statin therapy: potential implications for guidelines and for the prescription of emerging lipid-lowering agents

Ridker PM, Mora S and Rose L
Eur Heart J 2016; published online ahead of print

Background

It has recently been shown that the percentage reduction of low-density lipoprotein cholesterol (LDL-C) following statin therapy is highly variable between individuals [1]. This observation may impact future statin therapy guidelines. Currently, statin guidelines differ between Europe and Canada, and the US. Whereas Europe and Canada accept to achieve a fixed low-density LDL-C level or to decrease LDL-C levels with at least 50% [2,3], US guidelines allow a reduction of less than 50% when moderate intensity statin therapy is administered or ≥50% when high intensity statin therapy is given [4]. The variability in per cent LDL-C reduction may have impact on clinical outcome as well as on the effectiveness of PCSK9 inhibitors, since enrolment criteria for PCSK9 inhibitors typically include the attainments of fixed LDL-C levels on statin therapy.

To address the effect of the LDL-C reduction variability on clinical outcome, a secondary data analysis was performed using data derived from the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial [5]. LDL-C reduction as well as non-HDL-C and apolipoprotein B (apoB) reduction levels were assessed and related to cardiovascular events.
The JUPITER randomized trial of rosuvastatin 20 mg (high-intensity) versus placebo enrolled 17802 asymptomatic woman ≥60 years and men ≥50 years who had LDL-C levels <130 mg/dL, hsCRP >2.0 mg/L and triglycerides <500 mg/dL with 5 years follow-up [5]. Individuals with prior history of cardiovascular disease, diabetes or lipid-lowering therapy were excluded. The interquartile range of lipid levels at baseline was relatively narrow (LDL-C 94-119, non-HDL-C 118-147, apoB 95-122 mg/dL and median 108, 134, 109 mg/dL respectively).

Main results

The magnitude of per cent reductions in lipids was directly related to the incidence rates of first cardiovascular events:

• LDL-C:

- Overall median LDL-C reduction was 50% and ranged from modest increase to 80% decrease

Groups assigned: reduction ≥50%, 0-50%, none or increase
- Per cent individuals (within those allocated to rosuvastatin): 46.3%, 42.8%, 10,8% respectively
- Incidence rates: Respectively 9.2, 6.7, 4.8 per 1000 individuals. Placebo 11.2
- On-treatment reduction HR: 0.91; CI 95%: 0.54-1.53, HR: 0.61; CI 95%: 0.44-0.83, HR: 0.42; CI 95%: 0.30-0.60 respectively (compared to placebo group), P-trend <0.00001
- Adjusted for covariates (including lower baseline lipid levels): HR: 0.86; CI 95% 0.50-1.49, HR: 0.61; CI 95% 0.44-0.83, HR: 0.41; CI 95% 0.29-0.58 respectively (compared to placebo group), P-trend <0.00001
- There was a significant relationship between per cent cholesterol reduction and incident event rates, within individuals allocated to rosuvastatin, P =0.01

• Similar analyses of percentage non-HDL-C and apoB reduction showed comparable results
• Similar findings were obtained using tertiles of per cent LDL-C reduction for group assignment
• Analyses that were limited to individuals within specific on-treatment achieved LDL-C windows (50-75 mg/dL) lead to a similar conclusion

Conclusion

The variability in per cent reduction of LDL-C, non-HDL-C and apoB following statin therapy is wide between individuals. The magnitude of these reductions is directly related to this of risk reduction. The percentage LDL-C reduction may be considered for inclusion into statin therapy guidelines as well as for enrolment criteria regarding adjunctive lipid-lowering PCSK9 inhibitors, in addition to absolute lipid targets. PCSK9 inhibitors may be clinically less effective in individuals with a highly reduced percentage LDL-C following statin therapy, and vice versa.

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References

1. Boekholdt SM, Hovingh GK, Mora S, et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events. A meta-analysis of statin trials. J Am Coll Cardiol 2014;64:485-494
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3. Anderson TJ, Grégoire J, Hegele RA, et al. 2012 update  of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardio 2013;29:151-167
4. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in the adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889-2934
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