Very low LDL-C levels are safe and effective in high-risk post-ACS patients

Long-term Safety and Efficacy of Achieving Very Low Levels of Low-Density Lipoprotein Cholesterol: A Prespecified Analysis of the IMPROVE-IT Trial

Literature - Giugliano RP, Wiviott SD, Blazing MA, et al. - JAMA Cardiol. 2017; published online ahead of print


The IMPROVE-IT study showed that the combination of ezetimibe and simvastatin improved cardiovascular (CV) outcomes in patients with a recent acute coronary syndrome (ACS), compared with simvastatin monotherapy [1]. However, there are concerns about lowering cholesterol too much, since there are data showing an association with an increased risk for cancer, intracranial haemorrhage and death, whereas experimental data suggest that high doses of statins may cause brain and optic pathology [2-5].

In this pre-specified analysis, the safety and efficacy of very low LDL-C levels (<30 mg/dL) at 1 month were assessed, using data from 15 281 patients included in the IMPROVE-IT study. Patients were subdivided based on quartiles of LDL-C level at month 1 (<30, 30-49, 50-69 and ≥70 mg/dL).

Main results

  • An LDL-C level <30 mg/dL at 1 month was observed in 6.4% of patients and their time-weighted average LDL-C level after randomisation was 34 mg/dL (IQR 27-44 mg/dL) over a median of 6 years’ follow-up.
  • There were several significant differences in baseline characteristics when stratified by either achieved LDL-C level or treatment group.
  • The rate of new, worsening or relapsing malignancies reported: 9.0%, 8.6%, 8.7% and 7.5%, (unadjusted P for trend = 0.04) for the 4 groups from lowest to highest achieved LDL-C level. However, this was no longer statistically significant after accounting for baseline characteristics (adjusted P for trend = 0.14).
  • There were no differences in the other pre-specified safety endpoints, including serious muscle events, elevation in aminotransferases levels greater than 3 times the normal level (2.2% for LDL-C level<30 mg/dL and 1.8-2.1% in the other 3 groups), gall-bladder adverse events (3.6% for LDL-C <30 mg/dL and 3.2-3.6% in the other 3 groups) or neurocognitive events (2.1% for LDL-C <30mg/dL and 2.3-2.9% in the other 3 groups), haemorrhagic stroke (0.3% for LDL-C <30 mg/dL and 0.4-0.9% in the other 3 groups), HF requiring hospitalisation (4.6% for LDL-C <30 mg/dL and 3.4-4.2% in the other 3 groups) or non-CV death (5.8% for LDL-C <30 mg/dL and 4.9-5.6% in the other 3 groups).
  • There were no differences in the adjusted risk for cataract-related adverse events across the groups compared with the reference group with LDL-C level ≥70 mg/dL (OR for <30 mg/dL 1.12, 95% CI 0.78-1.62, OR for 30-49 mg/dL 1.20, 95%CI 0.96-1.50, OR for 50-69 mg/dL 1.08, 95% CI 0.86-1.34).
  • In the very low LDL-C level group, the unadjusted Kaplan-Meier rate of the primary efficacy endpoint (CV death, myocardial infarction or stroke) at 7 years was 31.9% compared with 36.0% in patients who achieved an LDL-C level ≥70 mg/dL at 1 month (adjusted HR 0.79, 95% CI 0.69-0.91, P<0.001).


Very low LDL-C levels at 1 month were associated with a similar safety profile compared with higher LDL-C levels. Moreover, LDL-C levels below currently recommended targets were associated with even further numerical reductions in CV events. These results support the use of intensive lipid-lowering therapy in very high-risk post-ACS patients.


1. Cannon CP, BlazingMA, Giugliano RP, et al; IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387-2397.

2. Kritchevsky SB. Dietary lipids and the low blood cholesterol-cancer association. Am J Epidemiol. 1992;135(5):509-520.

3. Neaton JD, Blackburn H, Jacobs D, et al; Multiple Risk Factor Intervention Trial Research Group. Serum cholesterol level and mortality findings for men screened in the Multiple Risk Factor Intervention Trial. Arch Intern Med. 1992;152(7):1490-1500.

4. Tirschwell DL, Smith NL, Heckbert SR, et al. Association of cholesterol with stroke risk varies in stroke subtypes and patient subgroups. Neurology. 2004;63(10):1868-1875.

5. Berry PH, MacDonald JS, Alberts AW, et al. Brain and optic system pathology in hypocholesterolemic dogs treated with a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Am J Pathol. 1988;132(3):427-443.

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