Key result
Higher mild-to-moderate triglycerides linked to ~13% higher risk of major cardiovascular events.
Why the study?
Individuals with mild-to-moderate hypertriglyceridaemia may not express the same magnitude of cardiovascular risk as that observed across the full range of plasma triglycerides.
Observational (n=178,602)
Yes
Individuals with mild-to-moderate hypertriglyceridaemia do not express the same magnitude of cardiovascular risk as seen across the full range of plasma triglycerides, suggesting future trials should enroll across a wider range.
Answers are grounded in this paper and cite their sources.
Challenges uniform risk assumption across triglyceride levels; leaves open optimal enrollment ranges for future lowering trials.
BACKGROUND AND AIMS: Guidelines focus on individuals with triglycerides between 2.3 and 5.6 mmol/L (200 and 499 mg/dL). The hypotheses that triglycerides across the full biological range and within this constrained range associated with cardiovascular risk were re-assessed. METHODS: Multivariable-adjusted hazard ratios for major cardiovascular events and death according to baseline triglycerides among 119 573 individuals with triglycerides across the full biological range from the Copenhagen General Population Study, among 27 757 individuals with baseline triglycerides between 2.3 and 5.6 mmol/L from the Copenhagen General Population Study and the Women's Health Study cohorts, and among 31 272 individuals with mild-to-moderate hypertriglyceridaemia from the PROMINENT, REDUCE-IT, and STRENGTH trials were calculated. RESULTS: Increasing triglycerides across the full range (0.3 to 11.2 mmol/L) were associated with an increasing risk of major cardiovascular events (N = 12 241). In the cohorts, combined hazard ratios [95% confidence interval (triglyceride range in mmol/L)] for major cardiovascular events (N = 3928) from lowest to highest triglyceride quartile were 1.0 [referent (range: < 2.5)], 0.95 [0.87-1.04 (range: 2.5 to <3.0)], 1.04 [0.95-1.13 (range: 3.0 to <3.6)], and 1.13 [1.04-1.23 (range: ≥ 3.6)]. In the three contemporary trials, the corresponding hazard ratios (N = 4265 cardiovascular events) from lowest to highest quartile were 1.0 [referent (ranges for PROMINENT/REDUCE-IT/STRENGTH: < 2.6/2.0/2.2)], 1.01 [0.93-1.10 (ranges: 2.6 to <3.1/2.0 to <2.5/2.2 to <2.7)], 1.05 [0.96-1.14 (ranges: 3.1 to <3.9/2.5 to <3.1/2.7 to < 3.5)] and 1.09 [1.00-1.19 (ranges: ≥ 3.9/3.1/3.5)]. In neither cohorts nor trials were triglycerides across this range strongly associated with risk of cardiovascular or all-cause death. CONCLUSIONS: Individuals with mild-to-moderate hypertriglyceridaemia may not express the same magnitude of cardiovascular risk as that observed across the full range of plasma triglycerides. Future triglyceride-lowering therapy trials may want to consider enrolment across a wider range of triglyceride levels if there is no prior history of pancreatitis nor excessive alcohol intake.
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Nordestgaard et al. (2025) conducted an observational in Hypertriglyceridaemia (n=178,602). Higher triglyceride levels vs. Lowest triglyceride quartile was evaluated on Major cardiovascular events (HR 1.13, 95% CI 1.04-1.23). Higher triglyceride levels in the mild-to-moderate range were weakly associated with major cardiovascular events in cohorts (HR 1.13; 95% CI 1.04-1.23) and trials (HR 1.09; 95% CI 1.00-1.19).
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