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27 April 2018
Quantifying residual risk on long-term lipid-lowering therapy
This community-based study highlighted the high absolute residual cardiovascular risk in individuals on long-term lipid-lowering therapy.
Lieb W, Enserro DM, Larson MG, Vasan RS.
Residual cardiovascular risk in individuals on lipid-lowering treatment: quantifying absolute and relative risk in the community.
Open Heart 2018;5:e000722. doi:10.1136/openhrt-2017-000722
Objective: To quantify the risk for incident cardiovascular disease (CVD) events associated with different levels of low-density lipoprotein cholesterol (LDL-C) in a large community-based sample, stratified by the use of lipid lowering therapy (LLT). The study also aimed to assess the burden of subclinical disease at the carotid arteries in these individuals.
Study design: Prospective analysis
Study population: Individuals attending the sixth examination cycle of the Framingham Offspring cohort (1995–1998)
Efficacy variables:
  •  Adjudicated incident CVD events and 10-year probability of a CVD event
  • Carotid ultrasound abnormality, defined as (1) increased (≥80th sex-specific percentile) intima media thickness (IMT), a combined standardized measure including information from the internal and common carotid arteries; (2) an extreme increase of the common carotid IMT ≥1 mm; or (3) significant stenosis (≥25% narrowing) of the common or internal carotid arteries

Subjects were categorized according to one of five groups based on LDL-C levels and lipid lowering therapy:

- Group 1, LDL-C <100 mg/dL, not on LLT

- Group 2, LDL-C ≥100 mg/dL and <130 mg/dL, not on LLT

- Group 3, treated LDL-C <130 mg/dL on LLT

- Group 4,  LDL-C ≥130 mg/dL, not on LLT

- Group 5, treated LDL-C ≥130 mg/dL on LLT

The 10-year probability of a CVD event was calculated according to each group; this was compared for treated versus untreated groups using analysis of variance.

Subclinical disease burden at the carotid arteries was analysed by LDL-C category using age-, sex- and multivariable-adjusted logistic regression models with group 1 (LDL-C <100 mg/dL, not on LLT) as the referrent.  This model included age, sex, systolic blood pressure, antihypertensive medication, smoking and diabetes mellitus. The odds for ‘carotid ultrasound abnormality’ were compared for individuals on LLT versus untreated individuals using age-, sex- and multivariable-adjusted logistic regression models.

Main results:

This analysis included data from 3,012 Framingham Study subjects (mean age, 58.4 years; 55% women) who were free of CVD at baseline (see Table 1).


Table 1. Categorization of subjects in the analysis (LDL-C in mg/dL)


Group 1

LDL-C <100, no LLT

Group 2

LDL-C ≥100 and <130, no LLT

Group 3

LDL-C <130 , on LLT

Group 4

LDL-C ≥130, no LLT

Group 5

LDL-C ≥130, on LLT







Age mean ±SD, years












LDL-C mean ±SD, mg/dl






On statin n (%)



140 (83%)


84 (64%)

LDL-C low-density lipoprotein cholesterol; LLT lipid-lowering therapy; SD standard deviation


Over a median of 13.7 years follow-up, 548 (255 women) developed an incident CVD event (Table 2).

  • Individuals on LLT (groups 3 and 5) had approximately three times the absolute risk of a CVD event compared with those in group 1 (reference).
  • Compared with reference group 1, individuals on LLT had a statistically significant increase in the relative hazard for incident CVD in multivariable-adjusted analyses. There was also a significant increase in subclinical carotid atherosclerosis in individuals with LDL-C levels ≥130 mg/dL not on LLT, as well as in both groups on LLT. However, on adjustment for the presence of subclinical atherosclerosis, there was only a modest reduction in the hazard ratios for incident CVD (by about 5%).


Table 2. Incident CVD events and subclinical atherosclerosis (LDL-C in mg/dL)


Group 1

LDL-C <100, no LLT

Group 2

LDL-C ≥100 and <130, no LLT

Group 3

LDL-C <130, on LLT

Group 4


≥130, no LLT

Group 5

LDL-C ≥130, on LLT







Incident CVD






Crude CVD event rates per 1000 patient-years (95% CI)


(6.8 to 11.3)


(11.9 to 16.2)


(19.5 to 34.0)


(13.3 to 17.2)


(16.2 to 31.9)

Incident CVD events; Adjusted HR (95% CI)











Subclinical atherosclerosis






Adjusted odds ratio for carotid US abnormality

(95% CI)










CI confidence interval; CVD cardiovascular disease; HR hazard ratio; LDL-C low-density lipoprotein cholesterol; LLT lipid lowering therapy; *p<0.05, **p<0.01 versus reference
Authors’ conclusion: There is substantial residual CVD risk in individuals on LLT, compared with participants with optimal LDL-C (<100 mg/dL), even when LDL-C levels <130 mg/dL are reached.


There is indisputable evidence that LDL-C is causal for atherosclerotic CVD, and therefore guidelines for CVD prevention focus on LDL-C lowering therapeutic strategies as one of the key approaches for reducing cardiovascular risk.1-3 Statins, the first-line LDL-C lowering therapy, are efficacious in reducing cardiovascular risk.4 Yet even with attainment of guideline-recommended LDL-C levels, it is recognized that a substantial residual cardiovascular risk persists; this issue has been the ongoing focus of the Residual Risk Reduction Initiative.5

This study aimed to quantify the residual cardiovascular risk of individuals on long-term LLT, which has so far been poorly defined. The specific focus was on absolute cardiovascular risk in primary prevention individuals on LLT, both for those attaining LDL-C levels <130 mg/dL, and those with LDL?C above these levels.  Absolute risk for incident CVD was about 3-fold higher in individuals on LLT (irrespective of LDL-C levels) than those with LDL-C levels <100 mg/dL who were not on treatment. Further analyses showed that this substantial residual cardiovascular risk may be partly explained by a worse cardiovascular risk factor profile; individuals in groups 3 and 5 (on LLT) had a higher prevalence of blood pressure lowering treatment (42-59% versus 16-24% in individuals not on LLT) and were also more likely to have diabetes (15-22% versus 6-7% in individuals not on LLT).  Adjustment for subclinical carotid disease burden only moderately attenuated this residual cardiovascular risk.

In conclusion, these findings reaffirm the high residual cardiovascular risk that persists despite long-term LLT and attainment of guideline-recommended LDL-C goals. These findings underline the importance of a multifactorial approach to CVD prevention, considering both established and other risk factors to reduce this substantial residual cardiovascular risk.


1. Ference BA, Ginsberg HN, Graham I et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38:2459-2472.

2. Catapano AL, Graham I, De Backer G et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Association for Cardiovascular Prevention &amp; Rehabilitation (EACPR). Atherosclerosis 2016;253:281-344.

3. Piepoli MF, Hoes AW, Agewall S et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016;37:2315-2381.

4. Collins R, Reith C, Emberson J et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016;388:2532-2561.

5. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014;13:26.

Key words residual cardiovascular risk; lipid lowering therapy; absolute risk; subclinical atherosclerosis