Elevated triglycerides, a prevalent identifier of high cardiovascular risk

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13 April 2023

In a large cohort study including nearly 400,000 US veterans, elevated triglycerides (TG) helped to identify individuals with established cardiovascular disease or with diabetes alone at high residual cardiovascular risk.

Leatherman S, Ferguson R, Hau C, et al. Increased residual cardiovascular risk in U.S. veterans with moderately elevated baseline triglycerides and well-controlled LDL-C levels on statins. Front Cardiovasc Med 2022; 9:982815. doi: 10.3389/fcvm.2022.982815

STUDY SUMMARY

Objective

To investigate residual cardiovascular risk among subjects with well controlled low-density lipoprotein cholesterol (LDL-C) levels on statin and elevated baseline TG levels (1.7-5.6 mmol/L or 150–499 mg/dL) compared with those with normal TG levels (<1.7 mmol/l or 150 mg/dL).

Study design

Observational retrospective cohort study

Study population

Subjects in the US Veterans Affairs (VA) electronic health records database, who were aged 18 years or older, and had well controlled LDL-C levels (between 1.0 and 2.6 mmol/L or 40–100 mg/dL) and at least one TG measurement in 2010. Subjects had not received TG-lowering therapy.

Study Outcomes

• Major adverse cardiovascular events (MACE): a composite of nonfatal myocardial infarction (MI), nonfatal stroke, unstable angina, coronary revascularization, and cardiovascular death

Methods

Subjects were stratified in three risk groups: (1) no diabetes and no prior cardiovascular event, (2) diabetes and no prior cardiovascular event, and (3) prior cardiovascular event. The data were analyzed for crude event rates, rate ratios, and event rate ratios, adjusted for age, sex, systolic blood pressure, estimated glomerular filtration rate, and weight.

Results

The cohort included 396,189 individuals naïve to TG-lowering therapy of whom 109,195 (28%) had elevated TG. Subjects with elevated TG were younger (mean age 73 versus 77 years), had higher baseline body mass index (BMI, 31.3 versus 28.3 kg/m2), blood pressure, total cholesterol, LDL-C, and haemoglobin A1c (7.2 versus 6.7%) than those with lower TG.

In total, elevated TG was associated with a 5% increased incidence of MACE (adjusted rate ratio 1.05, 95% confidence interval [CI] 1.03 to 1.06). When cardiovascular death was excluded from the endpoint, elevated TG was associated with 16% increased incidence of MACE (rate ratio 1.16, 95% CI 1.13 to 1.18). The association between TG level and MACE outcome did not differ by race or statin intensity. The adjusted rate ratios for each of the three risk groups are summarized below (Table 1).

Table 1. Adjusted rate ratio for MACE and nonfatal MACE stratified by risk group

	No prior CVD or diabetes (n=119,756)	No prior CVD with diabetes (n=83,546)	Prior CVD (n=192,887)
MACE, n (%) Elevated TG Normal TG	3,514 (13.1%) 12,189 (13.1%)	4,150 (14.9%) 7,894 (14.2%)	14,516 (26.6%) 34,679 (25.1%)
MACE, adjusted rate ratio* (95% CI)	0.98 (0.94, 1.01)	1.05 (1.01, 1.09)	1.05 (1.03, 1.07)
Nonfatal MACE, adjusted rate ratio* (95% CI)	1.07 (1.00, 1.15)	1.20 (1.12, 1.27)	1.15 (1.11, 1.18)

* The rate ratio was based on a generalized linear model with Poisson errors based on first occurrence of the event, and adjusted for age, sex, systolic blood pressure, estimated glomerular filtration rate, and weight. CVD cardiovascular disease

Author conclusion

Subjects with elevated TG levels and well-controlled LDL-C on statins showed a modest increase in cardiovascular events compared to those with normal TG. Elevated TG levels were associated with increased cardiovascular events in patients with established cardiovascular disease and with diabetes only, suggesting that elevated TG levels are associated with a similar degree of residual risk in high-risk primary prevention and secondary prevention settings.

COMMENT

In this large observational study of subjects with well-controlled LDL-C levels on a statin, moderately elevated hypertriglyceridemia was prevalent, affecting more than one in four individuals. Those subjects with this dyslipidemia, in secondary prevention and with diabetes, were identified as being at high risk of (recurrent) cardiovascular events. These findings are consistent with an accumulating body of evidence supporting elevated TG-rich lipoproteins, for which TG are a surrogate marker, as a cardiovascular risk factor and an important contributor to residual cardiovascular risk (1,2).

Whether targeting elevated TG in such high-risk individuals reduces residual cardiovascular risk has been the focus of major prospective studies (3-5). To date, only one of these trials – REDUCE-IT with high-dose icosapent ethyl – has demonstrated significant clinical benefit on cardiovascular outcomes (3). Why other studies did not show improvement in cardiovascular outcomes despite lowering of plasma TGs is contentious. Explanations proposed include the nature and dose of omega-3 fatty acids, level of treatment adherence (STRENGTH) (4), as well as potential mode of action in reducing plasma TG (PROMINENT)(5). Thus, the search continues for novel agents that lower TG-rich lipoproteins and remnant cholesterol and reduce residual cardiovascular risk. Inferences from these trials suggest that targeting very low-density lipoprotein production, remnant formation and TG-rich lipoprotein clearance pathways may all be needed to show substantial clinical benefit in high-risk patients with well-controlled LDL-C levels. Among the likely contenders, the development of novel inhibitors of apolipoprotein CIII and ANGPTL3 (angiopoietin-like protein 3) have attracted much interest (6); proof of benefit is awaited from major prospective studies.

References

1. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547-63.
2. Ginsberg HN, Packard CJ, Chapman MJ, et al. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society. Eur Heart J 2021;42:4791-806.
3. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.
4. Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial. JAMA 2020;324:2268-80.
5. Pradhan AD, Glynn RJ, Fruchart JC, et al. Triglyceride lowering with pemafibrate to reduce cardiovascular risk. New Engl J Med 2022; DOI: 10.1056/NEJMoa2210645.
6. Ginsberg HN, Goldberg IJ. Broadening the scope of dyslipidemia therapy by targeting APOC3 and ANGPTL3 (Angiopoietin-Like Protein 3). Arterioscler Thromb Vasc Biol 2022; doi: 10.1161/ATVBAHA.122.317966.

Key words

triglycerides, residual cardiovascular risk, cohort study