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12 September 2008
Nonfasting triglycerides predict risk of ischemic stroke in a Danish population cohort Results from the Copenhagen City Heart Study

Demonstration of an association between nonfasting triglycerides levels and risk of ischemic stroke opens new perspectives for reducing residual risk of this particularly frequent type of major macrovascular events

Freiberg JJ, Tybjærg-Hansen A, Jensen JS, Nordestgaard BG.
Summary
Comments & References
STUDY SUMMARY
Methods
The Copenhagen City Heart Study, a prospective, Danish population-based cohort study was used to test the hypothesis that elevated levels of nonfasting triglycerides (TGs) are associated with risk of ischemic stroke in men and women in the general population.
    1. A prospective study covered the period from baseline at the 1976-1978 examination through July 2007. This study was conducted in 13,956 white women and men aged 20 to 93 years, of Danish descent, drawn randomly from the national Danish Civil Registration system and in whom nonfasting TGs were measured.
    2. A cross-sectional study was conducted in 9,637 individuals who attended the 1991-1994 examination, since levels of nonfasting remnant lipoprotein cholesterol as well as nonfasting TGs were measured at this examination. Levels of these two metabolically-linked lipid parameters were compared in those who developed or did not develop (controls) ischemic stroke.
Main results
  • In the prospective study, 1,529 participants had a first ischemic stroke during the follow-up period. Cumulative incidence of ischemic stroke increased with rising levels of nonfasting TGs (log-rank trend, p <0.001). Figure 1 indicates the risk of ischemic stroke according to nonfasting TGs levels stratification.
    Absolute 10-year risk of ischemic stroke ranged from 2.6% (in men <55 years with nonfasting TG levels <89 mg/dL (1.0 mmol/l)) to 16.7% (in men aged 55 years or older with levels of 443 mg/dL (5.0 mmol/l) or greater). Corresponding values in women were 1.9% and 12.2%.
  • In the cross-sectional study, levels of nonfasting TGs and remnant cholesterol were significantly higher in both men and women having experienced an ischemic stroke than in controls (Tables 1 and 2).

COMMENT

Whereas the role of fasting TGs on ischemic stroke risk has been a matter of debate, a potential role of nonfasting TGs was suggested in 2 studies reporting strong associations between nonfastingTGs and coronary1 or global cardiovascular risk.2 Data from the Copenhagen City Heart Study provide evidence that the association between nonfasting TGs and macrovascular risk particularly applies to ischemic stroke risk. For measurement of both nonfasting TGs and remnants lipoproteins cholesterol, blood samples were drawn between 8 AM and 4 PM, and 82% of participants had eaten a meal within the last 3 hours of blood sampling. The prospective study detected a significant association between linear increases in levels of nonfasting triglycerides and increases in risk of ischemic stroke. This was corroborated by the cross-sectional study showing significantly higher levels of nonfasting TGs in patients having experienced a first stroke event.

Nonfasting triglycerides: a valuable target to reduce residual risk of ischemic stroke

These results draw attention to nonfasting TGs not only as a useful parameter to help better predict cardiovascular risk, but also as a therapeutic target to reduce residual risk of ischemic stroke persisting even after intensive LDL-C-lowering therapy. The efficacy and limits of intensive LDL-C-lowering therapy have been well documented in the SPARCL study,3 a secondary prevention trial of atorvastatin 80 mg per day vs. placebo, in which a mean LDL-C level of 73 mg/dL (1.9 mmol/l) was achieved. This study reported a significant 22% reduction in relative risk of ischemic stroke. A secondary analysis suggested that patients who benefited most of treatment with atorvastatin were those who had the greatest reduction in LDL-C.4 However, in an explanatory analysis of the same study,5 low HDL-C was the only lipid factor associated with an outcome stroke. Elevated TGs were not, but only fasting TGs were measured. The SPARCL investigators concluded that raising HDL-C levels in addition to lowering LDL-C might be an effective means of reducing residual stroke risk. On the other hand, the Copenhagen City Heart Study suggests that both LDL-C and TGs – more precisely, nonfasting TGs – should be targeted. Both studies provide evidence suggesting that treating atherogenic dyslipidemia is one of the key measures to reduce the residual risk of ischemic stroke.

Nonfasting triglycerides measurement needs standardization before being used in clinical practice

 The clinical value of nonfasting triglycerides to assess cardiovascular risk has been challenged due to the variability of triglycerides levels following fatty meals intake. However, according to the authors, the variability observed during fat-tolerance tests does not reflect what happens during everyday food intake . Nevertheless, they acknowledge that time and content of the most recent meal should be standardized before using nonfasting TGs in clinical practice.

hj

Figure 1. Prospective study: hazard ratios for ischemic stroke by increasing levels of nonfasting TGs
at baseline (up to 31 years of complete follow-up).
All hazard ratios were calculated vs. nonfasting triglyceride levels < 89 mg/dl (1.0 mmol/l).

 

Table 1. Cross-sectional study: nonfasting TG (mg/dL)

 
 

Patients with ischemic stroke

Controls

p

Men 191 (IQR, 131-259) 148 (IQR, 104-214) <0.01
Women 167 (IQR, 121-229) 127 (IQR, 91-181) <0.05

 

Table 2. Cross-sectional study: remnant cholesterol (mg/dL)

 
 

Patients with ischemic stroke

Controls

p

Men 38 (IQR, 26-51) 29 (IQR, 20-42) <0.01
Women 33 (IQR, 24-45) 25 (IQR, 18-35) <0.05
(IQR: interquartile range)
References
  1. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298(3):299-308.
  2. Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA. 2007;298(3):309-316.
  3. Amarenco P, Bogousslavsky, Callahan A, et al., The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-Dose Atorvastatin after Stroke or Transient Ischemic Attack. N Engl J Med 2006;355:549-59.
  4. Amarenco P, Goldstein LB, Szarek M, et al., SPARCL Investigators. Effects of intense low-density lipoprotein cholesterol reduction in patients with stroke or transient ischemic attack: the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Stroke 2007;38:3198–204.
  5. Amarenco P, Goldstein LB, Callahan A, et al. Baseline blood pressure, low- and high-density lipoproteins, and triglycerides and the risk of vascular events in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Atherosclerosis (in press).