Abstract Body (Do not enter title and authors here): Background
Guidelines focus on individuals with triglyceride levels of 200 to 499 mg/dL (2.3 and 5.6 mmol/L), a group for whom triglyceride-lowering therapy does not convincingly decrease risk.

Hypotheses and goals
We re-assessed the hypotheses that triglyceride levels across the full biological range and within this constrained range strongly associate with cardiovascular risk.

Methods
We calculated multivariable adjusted hazard ratios for major cardiovascular events and death according to baseline triglyceride levels 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 200 and 499 mg/dL (2.3 and 5.6 mmol/L) from the Copenhagen General Population Study and the Women’s Health Study, and among 31,372 individuals with mild-to-moderate hypertriglyceridemia participating in the PROMINENT, REDUCE-IT, and STRENGTH randomized trials.

Results
Increasing triglyceride levels across the full range were associated with increasing risk of major cardiovascular events (N=12,241) (Figure 1). In individuals with mild-to-moderate hypertriglyceridemia from the two cohorts, combined hazard ratios (95% confidence interval) for major cardiovascular events (N=3,928) from lowest to highest triglyceride quartile were 1.0 (referent), 0.95 (0.87-1.04), 1.04 (0.95-1.13), and 1.13 (1.04-1.23). In the contemporary trials of patients selected for mild-to-moderate hypertriglyceridemia, the corresponding hazard ratios for major cardiovascular events (N=4,265) from lowest to highest triglyceride quartile were 1.0 (referent), 1.01 (0.93-1.10), 1.05 (0.96-1.14), and 1.10 (1.01-1.19). In neither prospective cohorts nor trials were triglyceride levels strongly associated with risk of cardiovascular or all-cause death within the constrained range.

Conclusions
Contrary to expectations, individuals with mild-to-moderate hypertriglyceridemia may not express the same magnitude of cardiovascular risk as that observed across the full range of plasma triglycerides. Future trials of triglyceride-lowering therapy may want to consider enrollment across a wider range of triglyceride levels if there is no prior history of pancreatitis.