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Expanding the triglyceride range in clinical trials: therapeutic opportunities
Ask T Nordestgaard1,2, Aruna D Pradhan1, Brendan M Everett1,3
1Center for Cardiovascular Disease Prevention, Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
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.
Insights
High triglycerides increase cardiovascular risk across the full biological range. However, mild-to-moderate hypertriglyceridaemia may not show the same elevated risk magnitude. Future trials should consider wider triglyceride level enrollment.
Area of Science:
- Cardiology
- Endocrinology
- Public Health
Background:
- Current guidelines for managing high triglycerides focus on levels between 2.3 and 5.6 mmol/L.
- This study re-assessed the association between triglycerides across the full biological range and cardiovascular risk.
Purpose of the Study:
- To evaluate the association between triglycerides across the full biological range and cardiovascular risk.
- To compare cardiovascular risk in individuals with mild-to-moderate hypertriglyceridaemia versus the general population.
Main Methods:
- Calculated hazard ratios for major cardiovascular events and death using data from the Copenhagen General Population Study, Women's Health Study, and the PROMINENT, REDUCE-IT, and STRENGTH trials.
- Analyzed data from 119,573 individuals across the full triglyceride range and 27,757 individuals with mild-to-moderate hypertriglyceridaemia.
Main Results:
- Increasing triglycerides across the full range (0.3 to 11.2 mmol/L) correlated with higher cardiovascular event risk.
- In cohorts and trials, higher triglyceride quartiles showed a modest increase in cardiovascular event risk, but not strongly associated with death.
- Individuals with mild-to-moderate hypertriglyceridaemia did not exhibit the same magnitude of cardiovascular risk.
Conclusions:
- Mild-to-moderate hypertriglyceridaemia may not carry the same cardiovascular risk as seen across the entire spectrum of triglyceride levels.
- Future triglyceride-lowering therapy trials could benefit from including participants with a wider range of triglyceride levels, excluding those with pancreatitis or excessive alcohol intake.
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