Meta-analysis: Association between triglyceride lowering and reduction of cardiovascular risk

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19 March 2020

In randomized controlled trials, triglyceride lowering is associated with a lower risk of major vascular events, even after adjustment for low-density lipoprotein cholesterol (LDL-C) lowering.

Marston NA, Giugliano RP, Im KA, et al. Association between triglyceride lowering and reduction of cardiovascular risk across multiple lipid-lowering therapeutic classes. A systematic review and meta-regression analysis of randomized controlled trials. Circulation 2019;140:1308–17.

STUDY SUMMARY

Objective:

To investigate the association between the magnitude of lowering of non–high-density lipoprotein cholesterol (non-HDL-C), LDL-C, or triglycerides (TG) and the reduction in major vascular events across trials of fibrates, niacin, and marine omega-3 fatty acids, as well as statins (reference).

Study design:

Systematic review and trial-level meta-regression analysis. Key inclusion criteria were a randomized controlled trial that reported major vascular events.

Study population:

In total, there were 197,270 subjects in 24 trials of TG-lowering nonstatin therapy (9 fibrate trials, 3 niacin trials and 13 omega-3 fatty acids trials; one trial had both fibrate and niacin experimental arms) with 25,218 major vascular events over a median follow-up of 43.8 years. These subjects had a mean age of 63 years and a mean baseline TG level of 163 mg/dL (median, 151 mg/dL; interquartile range, 143–165 mg/dL). These data were compared with data for 177,088 subjects in 25 trials of statin therapy with 20,962 major vascular events.

Study outcome:

The primary outcome was the risk ratio (RR) for major vascular events associated with absolute reductions in lipid parameters.

Methods:

The study incorporated two key analyses. In the first analysis, the association between absolute reduction in non–HDL-C (defined as the difference in achieved non–HDL-C level between the 2 treatment arms) and the RR for major vascular events was established. Subsequently, to determine the contribution from LDL-C and TG, the association between LDL‑C and TG lowering and RR for major vascular events was assessed.

Main results:

Key findings are summarized below and in Table 1.

Reduction in non-HDL-C was strongly associated with a lower risk of major vascular events regardless of the lipid-lowering drug class.
TG lowering was associated with a lower risk of cardiovascular events but to a lesser extent per absolute amount of reduction than with LDL-C.
Each 1 g/d eicosapentaenoic acid was associated with a 7% relative risk reduction in major vascular events (0.93 [95% CI, 0.91–0.95]; p<0.0001). There was no significant association between the dose of docosahexaenoic acid and the relative risk reduction in major vascular events. The benefits of high-dose eicosapentaenoic acid appear to exceed their lipid-lowering effects.

Table 1. Relative risk per 1 mmol/L in lipid parameters

Lipid parameter	RR (95% confidence interval) per 1 mmol/L reduction	p-value
Non-HDL-C	0.79 (0.76–0.82); 0.78 per 40 mg/dL	<0.0001
LDL-C	0.80 (0.76–0.85); 0.79 per 40 mg/dL	<0.0001
TG	0.84 (0.75–0.94); 0.92 per 40 mg/dL	0.0026
Excluding REDUCE-IT
LDL-C	0.79 (0.76–0.83); 0.78 per 40 mg/dL	<0.0001
TG	0.91 (0.81–1.006); 0.96 per 40 mg/dL

Conclusion:

In randomized controlled trials, TG lowering is associated with a lower risk of major vascular events, even after adjustment for LDL-C lowering, although the effect is less than that for LDL-C and attenuated when REDUCE-IT is excluded. Furthermore, the benefits of marine-derived omega-3 fatty acids, particularly high-dose eicosapentaenoic acid, appear to exceed their lipid-lowering effects.

COMMENT

Evidence from observational studies, genetic analyses and Mendelian randomization studies support a causal association between TG and risk for atherosclerotic cardiovascular disease (ASCVD).1 Data from clinical trials of therapies that lower TG, including fibrates, niacin and omega-3 fatty acids, however, have been less definitive. While the REDUCE-IT study demonstrated a significant 25% reduction in major cardiovascular events with high-dose eicosapentaenoic acid in statin-treated patients at high to very high risk of ASCVD, the benefit observed did not equate with the magnitude of TG lowering, implying the involvement of pleiotropic effects.11,12 Thus, the totality of evidence from clinical trials still leaves uncertainty regarding the clinical benefit from TG-lowering, especially when compared with that from lowering LDL-C.

The current analysis aimed to investigate this question, using non–HDL-C, a measure of the total cholesterol load of atherogenic lipoproteins, including LDL (in LDL-C) and very low-density lipoprotein (VLDL, in TG), as the reference measure. TG lowering was associated with a lower risk of vascular events, although the effect was less than that shown for LDL-C lowering, and attenuated when REDUCE-IT was excluded from the analysis.

For clinicians there are important take-home messages from this analysis. First, and consistent with previous findings,13 reduction in non–HDL-C is strongly associated with a reduced risk of major vascular events (by 21% per 1 mmol/L reduction in the current report), and this was consistent irrespective of the class of lipid-lowering therapy. Second, TG lowering is associated with a reduced risk of vascular events, although the magnitude was less than that observed with LDL-C lowering. Third, the reason why previous outcomes studies of TG-lowering treatments (other than REDUCE-IT) failed to show a significant reduction in vascular events was because the magnitude of non-HDL-C lowering was insufficient, usually as the patient populations did not have high baseline TG. Taken together, these findings are instructive for clinical trials of novel agents that lower TG. Provided that clinical trials are conducted in the appropriate patient group (i.e. with high baseline TG), the next 2-3 years will undoubtedly provide key insights to resolve persistent uncertainties regarding the clinical benefit from TG lowering to reduce residual vascular risk.

References

1. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626–35.

2. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol: Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341:410–8.

3. Bezafibrate Infarction Prevention Study. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation 2000;102:21–7.

4. Ginsberg HN, Elam MB, Lovato LC, et al; ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563–74.

5. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;317:1237–45.

6. Keech A, Simes RJ, Barter P, et al; FIELD Study Investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849–61.

7. Boden WE, Probstfield JL, Anderson T, et al; AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–67.

8. Landray MJ, Haynes R, Hopewell JC, et al; HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203–12.

9. Kromhout D, Giltay EJ, Geleijnse JM; Alpha Omega Trial Group. n-3 Fatty acids and cardiovascular events after myocardial infarction. N Engl J Med. 2010;363:2015–26.

10. Bosch J, Gerstein HC, Dagenais GR, et al; ORIGIN Trial Investigators. n-3 Fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 2012;367:309–18.

11. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11–22.

12. Laufs U, Parhofer KG, Ginsberg HN, Hegele RA. Clinical review on triglycerides. Eur Heart J 2020;41:99-109c.

13. Brunner FJ, Waldeyer C, Ojeda F, et al. Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium. Lancet 2019;394:2173-83.

Key words

triglycerides; cardiovascular risk; non-HDL-C; meta-analysis