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4 December 2017
Nonfasting triglycerides and heart failure risk

In two prospective Danish studies, higher concentrations of nonfasting triglycerides at baseline were associated with higher risk of heart failure; however, low-density lipoprotein cholesterol (LDL-C) was not associated with heart failure risk.

Varbo A, Nordestgaard BG. Nonfasting triglycerides, low-density lipoprotein cholesterol, and heart failure risk. Two cohort studies of 113 554 individuals. Arterioscler Thromb Vasc Biol 2017; DOI: 10.1161/ATVBAHA.117.310269
Summary
Comments & References
STUDY SUMMARY
Objective: To investigate whether high concentrations of nonfasting triglycerides and LDL-C are associated with higher risk of heart failure in the general population.
Study design: Two prospective observational association studies
Study population: Data from 103,860 individuals from the Copenhagen General Population Study (55% women, mean age 58 years) and 9,694 from the Copenhagen City Heart Study (56% women, mean age 60 years) were included in this analysis. These individuals had baseline measurements for nonfasting triglycerides and LDL-C.
Efficacy variables: Onset of heart failure, defined by the International Classification of Diseases (ICD) Version 8: codes 427.09-427.11, and ICD Version 10: codes I50.0-I50.9. This was collected from 1977 to 2014 by reviewing all hospital admissions and diagnoses entered in the national Danish Patient Registry and all causes of death entered in the national Danish Causes of Death Registry.
Methods: Individuals were categorized based on levels of nonfasting triglycerides and LDL-C using clinically meaningful cutpoints, i.e. for triglycerides: <1 mmol/L (88 mg/dL), 1-1.99 mmol/L (88-175 mg/dL), 2-2.99 mmol/L (176-263 mg/dL), 3-3.99 mmol/L (264-351 mg/dL), 4-4.99 mmol/L (352-439 mg/dL), and ≥5 mmol/L (440 mg/dL) and for LDL-C: <3 mmol/L (116 mg/dL), 3-3.99 mmol/L (116-154 mg/dL), 4-4.99 mmol/L (155-193 mg/dL), and ≥5 mmol/L (193 mg/dL).

Hazard ratios were estimated with Cox proportional hazards regression models with age as the time scale; individuals with heart failure before study entry were excluded. Multivariable adjustment was made for age, sex, hypertension, lipid-lowering therapy, smoking, and atrial fibrillation.
Main results: Median follow-up time was 6 years (range: 0-11 years) in the Copenhagen General Population Study, and 19 years (range: 0-23 years) in the Copenhagen City Heart Study. During this time 3,593 individuals were diagnosed with heart failure.

In multivariable adjusted analysis of the Copenhagen General Population Study, stepwise higher nonfasting triglycerides were associated with a higher risk of heart failure. While an association between stepwise higher LDL-C and heart failure risk was observed in age and sex-adjusted analyses, this association was not evident after multivariable adjustment (Table).

Table. Multivariable adjusted Hazard ratio (95% confidence interval) for risk of heart failure.

Nonfasting triglycerides; mmol/L (mg/dL)

N

Hazard ratio (95% CI)

<1.0 (<88)

28714

Reference

1-1.99 (88-175)

47865

1.32 (1.06-1.65)

2-2.99 (176-263)

17259

1.69 (1.31-2.19)

3-3.99 (264-351)

6065

1.75 (1.23-2.47)

4-4.99 (352-439)

2177

1.95 (1.15-3.31)

≥5 (≥440)

1780

2.59 (1.48-4.54)

LDL-C; mmol/L (mg/dL)

 

 

<3 (<116)

41875

Reference

3-3.99 (116-154)

39619

1.03 (0.86-1.22)

4-4.99 (155-193)

17903

0.86 (0.68-1.08)

≥5 (≥193)

4463

1.26 (0.86-1.86)

Results were independently confirmed in the Copenhagen City Heart Study, with multivariable adjusted hazard ratios ranging from 1.28 (95% CI, 0.93–1.75) for nonfasting triglycerides of 1-1.99 mmol/L to 2.33 (1.22–4.45) for nonfasting triglycerides ≥5 mmol/L when compared with individuals with nonfasting triglycerides <1 mmol/L.

Mediation analyses showed that 34% (95% CI, 26%–49%) of the risk of heart failure from nonfasting triglycerides could be explained by ischaemic heart disease, 22% (95% CI, 16%–32%) by myocardial infarction, and 13% (95% CI, 9%–18%) by ischaemic heart disease without myocardial infarction (mainly angina pectoris).

Conclusion: Stepwise higher concentrations of nonfasting triglycerides were associated with stepwise higher risk of heart failure; however, concentrations of LDL-C were not associated with risk of heart failure in the general population.

COMMENT

Globally, heart failure poses an increasing burden with repeated hospitalization a key driver of cost. While statins reduce the risk of myocardial infarction (MI) in patients with and without pre-existing heart disease, and therefore in theory should have a beneficial effect on the development of heart failure, there is a lack of conclusive evidence of benefit from prospective placebo-controlled statin trials.1,2 In a meta-analysis of 17 trials, Preiss and co-workers did observe a modest reduction (by 10%) with statin treatment on hospital admission, although there was no difference in risk reduction between those who suffered an MI or not.3 This scenario suggests that other factors may be more important than LDL-C in reducing the risk of development of heart failure.

The results of this study demonstrate an association between elevated triglycerides, a marker for triglyceride-rich lipoproteins and their remnants, and risk for heart failure. At triglycerides ranging from 2-2.99 mmol/L (176-263 mg/dl), there was 69% increase in risk for heart failure, and this increased to more than 250% in individuals with triglycerides ≥5 mmol/L (≥440 mg/dl). In contrast, stepwise increases in LDL-C were not associated with increased risk for heart failure.  This finding is unique in indicating elevated triglycerides as a risk factor for heart failure; the authors make the case for randomized controlled trials to test prospectively whether interventions targeting elevated triglycerides (i.e. triglyceride-rich lipoproteins and their remnants) are able to reduce onset of heart failure.

References

1. Gissi-HF Investigators , Tavazzi L, Maggioni AP et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008;372:1231-9.

2. Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357:2248-61.

3. Preiss D, Campbell RT, Murray HM, et al. The effect of statin therapy on heart failure events: a collaborative meta-analysis of unpublished data from major randomized trials. Eur Heart J 2015;36:1536-46.

Key words triglyceride-rich lipoproteins; triglycerides; heart failure; Copenhagen General Population Study