New meta-analysis links triglycerides with cardiovascular and all-cause mortality

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5 December 2013

A recently published meta-analysis of 61 studies reaffirms the link between blood triglycerides and cardiovascular (CV) and all-cause mortality.

Liu J, Zeng FF, Liu ZM, Zhang CX, Ling WH, Chen YM. . Effects of blood triglycerides on cardiovascular and all-cause mortality: a systematic review and meta-analysis of 61 prospective studies. Lipids Health Dis 2013;12:159. [Epub ahead of print].

STUDY SUMMARY

Objective

To investigate the association between levels of blood triglycerides and CV and all-cause mortality.

Study design

Meta-analysis of prospective cohort studies in a general population reporting an association between triglycerides and CVD or all-cause mortality (to July 2013). All studies reported the relative risks (RRs) or hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs) according to at least three categories of triglycerides levels, by unit of triglycerides or by logarithmic transformed triglycerides.

Study population

A total of 61 studies were included in the meta-analysis; 33 studies reported data on CVD mortality (17,018 CVD deaths in 726,030 subjects) and 38 studies reported data on all-cause mortality (58,419 all-cause deaths in 330,566 subjects). The median age of subjects at recruitment was 48.0 years and the median duration of study follow-up was 12.0 years. Studies in subjects with diabetes, CVD, dyslipidaemia or cancer were excluded.

Primary variable

RR for the association of blood triglycerides with CVD and all-cause mortality

Methods

The Newcastle-Ottawa Quality Assessment Scale1 was applied to assess the quality of studies, based on selection of subjects, degree of comparability between study groups, and assessment of outcomes. Three separate meta-analyses were conducted to assess risk estimates on the basis of categories of triglycerides levels, unit triglycerides and logarithm of triglycerides. For categorical data, the level of blood triglycerides was categorised according to the Adult Treatment Panel III cholesterol guidelines; lowest group <90 mg/dL (1.02 mmol/L); intermediate group 90-<150 mg/dL (1.02 to <1.70 mmol/L); borderline hypertriglyceridaemia 150-<200 mg/dL (1.70 to <2.26 mmol/L); and hypertriglyceridaemia ≥200 mg/dL (2.26 mmol/L). The intermediate group was the referent. For studies reporting risk estimates by unit triglycerides, the RRs were standardised to a 1 mmol/L increase in blood triglycerides. For studies reporting risk estimates by logarithmically transformed data, the risk estimates per unit of log triglycerides were pooled.

Main results

Data are summarised in Table 1. Overall, each 1 mmol/L increase in triglycerides was associated with 13% increase in CVD mortality and 12%, increase in all-cause mortality. Sensitivity analyses confirmed the robustness of the data.

Table 1. Summary of main findings of meta-analysis

	CVD mortality		All-cause mortality
	RR (95% CI\|)	p-value	RR (95% CI)	p-value
TG groups (mg/dL)
<90	0.83 (0.75,0.93)	0.001	0.94 (0.85,1.03)	0.15
90-<150	1.00 (referent)		1.00 (referent)
150-<200	1.15 (1.03,1.29)	0.015	1.09 (1.02,1.17)	0.011
³200	1.25 (1.05,1.50)	0.013	1.20 (1.04,1.38)	0.011

Per 1 mmol/L TG	1.13 (1.07,1.19)	0.000	1.12 (1.07,1.16)	0.000
Per 1 ln (mmol) TG	1.16 (1.05,1.29)	0.004	1.11 (1.01,1.23)	0.03

ln logarithmically transformed; TG triglycerides
To convert triglycerides from mg/dL to mmol/L, multiply by 0.01129

Author's conclusion

Elevated blood triglycerides were dose-dependently associated with a greater risk of both CVD and all-cause mortality. These findings suggest that controlling triglycerides can help to prevent CVD and other causes of death.

COMMENT

The results of this meta-analysis show that elevated blood triglycerides, a marker for triglyceride-rich lipoproteins (TRLs), are associated with an increased risk for CVD and all-cause mortality in general populations free of CVD or diabetes at baseline. The generalisability of these findings is strengthened by the fact that subjects included in these studies were from America, Europe, Asia and Australia. These data are consistent with previous meta-analyses showing a link between triglycerides and CVD risk, and add to accumulating evidence from experimental models and Mendelian randomisation studies implicating a causal role for TRLs, and their remnants, in the atherosclerotic process.(2-6) Most recently, a genetic study showed that variants associated with pathways involved in TRL metabolism were associated with increased risk for coronary artery disease.(7)

Taken together, these findings reinforce the relevance of elevated TRL (and their remnants), a key component of atherogenic dyslipidaemia, as an important contributor to lipid-related residual CV risk. This is a view consistent with the mission of the Residual Risk Reduction Initiative (R3i), as well as expert bodies, including the European Atherosclerosis Society and International Atherosclerosis Society,8(-10) which propose therapeutic targeting of triglycerides to manage lipid-related residual cardiovascular risk. Thus, it is surprising that the recently published US guidelines for management of cholesterol(11) run counter to current thinking, providing instead a statin-centric focus and omitting discussion of the need to manage lipid abnormalities beyond low-density lipoprotein cholesterol (see From the Editor’s Desk).

References

1. Wells GSB, O'Connell D: The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.
2. Hokanson JE, Austin MA: Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk 1996; 3:213–9.
3. Sarwar N, Danesh J, Eiriksdottir G et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation 2007;115:450-8.
4. Langsted A, Freiberg JJ, Tybjaerg-Hansen A, Schnohr P, Jensen GB, Nordestgaard BG: Nonfasting cholesterol and triglycerides and association with risk of myocardial infarction and total mortality: the Copenhagen City Heart Study with 31 years of follow-up. J Intern Med 2011, 270:65–75.
5. Miller MSN, Ballantyne C, Bittner V et al. Triglycerides and cardiovascular disease: a scientific
statement from the American Heart Association. Circulation 2011;123:2292–333.
6. Varbo A, Benn M, Tybjærg-Hansen A, Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427–36.
7. Do R, Willer CJ, Schmidt EM et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet 2013 Oct 6. doi: 10.1038/ng.2795. [Epub ahead of print].
8. Fruchart JC, Sacks FM, Hermans MP et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient. Diab Vasc Dis Res 2008;5:319-35.
9. Chapman MJ, Ginsberg HN, Amarenco P et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61.
10. The International Atherosclerosis Society. An International Atherosclerosis Society Position Paper: Global recommendations for the management of dyslipidemia. Full report [http://www.athero.org/download/IASPPGuidelines_FullReport_2.pdf].
11. Stone NJ, Robinson J, Lichtenstein AH et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. J Am Coll Cardiol 2013; doi:10.1016/j.jacc.2013.11.002 [Epub ahead of print].