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7 September 2021
PESA study: elevated triglycerides associate with subclinical atherosclerosis
In this report from the PESA (Progression of Early Subclinical Atherosclerosis) study, triglyceride (TG) levels ≥150 mg/dL (≥1.7 mmol/L) were associated with subclinical atherosclerosis, even if low-density lipoprotein cholesterol (LDL-C) levels were normal.
Raposeiras-Roubin S, Rosselló X, Oliva B et al. Triglycerides and residual atherosclerotic risk. J Am Coll Cardiol 2021;22: 3031 – 41.
STUDY SUMMARY
Objective: To investigate the association between serum TG levels and early atherosclerosis and vascular inflammation in healthy individuals.
Study design: PESA is an observational, longitudinal, prospective cohort study to evaluate determinants of atherosclerosis and its progression.
Study population: This analysis included 3,754 middle-aged individuals (mean age 45.5 years, 61% men) with low (85%) to moderate cardiovascular risk recruited between June 2010 and February 2014. Mean LDL-C was 133 mg/dL: 27.8% of individuals had levels within guideline-defined normal ranges of <100 and <116 mg/dL for moderate– and low cardiovascular risk, respectively. Mean serum TG was 92.2 mg/dL; 10.5% had TG ≥150 mg/dL.
Main study variables: • Serum TG, stratified as ≥150 mg/dL and <150 mg/dL (either <100 mg/dL or 100 to 149 mg/dL).
• Presence of subclinical atherosclerotic plaques, assessed by 2-dimenional (2D) vascular ultrasound
• Coronary artery calcium score (CACS), determined by computed tomography
• Vascular inflammation, assessed by hybrid fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)
Methods: Adjusted regression models were used to assess the relationship between TG and the number of non-coronary atherosclerotic territories. The association between TG and vascular inflammation was assessed by logistic regression.
Results:

There was a stepwise increase in the prevalence of subclinical atherosclerosis plaques with increasing TG category (Table).

Table. Prevalence of subclinical atherosclerosis (%) by TG category

 

<100 mg/dL

(N=2580)

100-149 mg/dL

(N=781)

≥150 mg/dl

(N=393)

Subclinical atherosclerosis (%)

52.5

68.8

73.0

  1 territory

  2 territories

  ≥3 territories

47.5

22.9

29.6

31.2

23.8

45.0

27.0

19.8

53.2

Subclinical atherosclerosis

Odds ratio (95% CI)

Reference

1.16 (0.98-1.36)

p=0.074

1.35 (1.08-1.68)

p=0.003

CI confidence interval

Compared with individuals with TG <100 mg/dL, those with TG ≥150 mg/dL had a higher prevalence of noncoronary atherosclerosis (odds ratio 1.35, 95% CI: 1.08 to 1.68; p= 0.008). This association was evident irrespective of LDL-C concentration: odds ratio 1.42, 95% CI: 1.11 to 1.80 in individuals with high LDL-C and 1.85, 95% CI 1.08 to 3.18 in those with normal or low LDL-C levels.

Individuals with TG ≥150 mg/dl also had a 2-fold higher risk of arterial 18F-FDG uptake (adjusted odds ratio 2.09, 95% CI 1.29 to 3.40; p = 0.003) compared with those with TG <100 mg/dL. There was no association between TG and CACS.

Authors’ conclusion: In individuals with low to moderate cardiovascular risk, hypertriglyceridemia was associated with subclinical atherosclerosis and vascular inflammation, even in participants with normal LDL-C levels.

COMMENT

There is accumulating evidence to support a role for elevated TG (a surrogate for TG-rich lipoproteins and their cholesterol load) in the causal pathway for atherosclerosis (1,2). Persistent uncertainty remains, however, regarding the level at which elevated TG become clinically relevant. The current study aimed to provide insights into this question by investigating the association of TG and subclinical atherosclerosis and vascular inflammation as early markers of cardiovascular events in moderate to low-risk individuals. The PESA cohort used in this report was appropriate, given that the majority (85%) of individuals were at low cardiovascular risk.

The results of this study show that already at TG 100-149 mg/dL there is evidence of increased prevalence of subclinical atherosclerosis in this lower-risk cohort. For individuals with TG ≥150 mg/dL this association was significant, both for all atherosclerotic plaques and non-coronary plaques (35% increase in prevalence compared with individuals with TG<100 mg/dL, p<0.001). Furthermore, this association was present even in individuals with ‘normal’ LDL-C levels, according to guideline-recommended goals (3). Serum TG levels were also associated with general arterial inflammation and with inflamed atherosclerotic plaques, a precursor of cardiovascular risk. While these findings do not demonstrate causality, they lend support to the premise that therapeutic strategies aimed at lowering TG levels, even in individuals at moderate to low risk with normal LDL-C levels, can improve cardiovascular disease prevention.

The findings from this study also have relevance for considerations relating to the ‘goal’ for TG-lowering therapy. Currently, the 2019 European Society of Cardiology/European Atherosclerosis Society dyslipidemia guidelines advise that a TG level <150 mg/dL (<1.7 mmol/L) is desirable but fall short of recommending TG goals due to insufficient data from cardiovascular outcomes studies. In high to very high-risk patients with TG levels >200 mg/dL (2.3 mmoL/L), statin treatment is recommended if lifestyle intervention is inadequate (3).

Taken together, these findings from the PESA study have relevance for reconsideration of the level at which TG should be targeted for therapeutic intervention. In lower risk individuals with elevated TG this may help to delay progression of subclinical cardiovascular disease, even if LDL-C levels are normal. Furthermore, among individuals at higher risk, targeting TG ≥150 mg/dL may reduce the residual risk of cardiovascular events among a background of well-controlled LDL-C levels. Results from the PROMINENT trial with pemafibrate will provide critical insights (4).

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. Sandesara PB, Virani SS, Fazio S, Shapiro MD. The forgotten lipids: triglycerides, remnant cholesterol, and atherosclerotic cardiovascular disease risk. Endocr Rev 2019;40:537-57.
3. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111-88.
4. Pradhan AD, Paynter NP, Everett BM, et al. Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study. Am Heart J 2018;206:80-93.
Key words remnant cholesterol; direct assay; cardiovascular risk; PROMINENT