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Macrovascular Residual Risk Studies

15 May 2016
BIP analysis reaffirms the link between elevated triglycerides and increased mortality
Analysis of 22-year follow-up data from the Bezafibrate Infarction Prevention (BIP) Study and Registry shows that in patients with established coronary heart disease (CHD), elevated triglycerides are associated with a long-term mortality risk that is independent of high-density lipoprotein cholesterol (HDL-C) levels.
Klempfner R, Erez A, Zekry Sagit B, Goldenberg I, Fisma E, Kopel E, Shlomo N, Israel A, Tenenbaum A. Elevated triglyceride level is independently associated with increased all-cause mortality in patients with established coronary heart disease. Twenty-two–year follow-up of the Bezafibrate Infarction Prevention Study and Registry. Circ Cardiovasc Qual Outcomes 2016;9:100-108.
Objective: To investigate the association between elevated triglycerides and all-cause mortality in a large cohort of patients with established CHD.
Study design: Long-term registry follow-up of the BIP study, a secondary prevention prospective multicentre randomized, placebo-controlled, double-blinded trial (RCT) which evaluated the efficacy of long-term administration of bezafibrate for reduction of coronary events.
Study population: 15,355 patients screened for the BIP trial, mean age 60 ± 7 years, 81% men and 72% with a previous myocardial infarction (MI).
Efficacity measures: All-cause mortality, obtained from the National Population Registry

Patients were divided into 5 groups based on fasting serum triglycerides levels at screening, i.e. (1) low-normal triglycerides (<100 mg/dL); (2) high-normal triglycerides (100–149 mg/dL); (3) borderline hypertriglyceridemia triglycerides (150–199 mg/dL); (4) moderate hypertriglyceridemia (200–499 mg/dL); (5) severe hypertriglyceridemia triglycerides (≥500 mg/dL).

Survival analysis was performed using standardized Kaplan–Meier curves using the conditional approach balancing for sex and age confounders. Multivariate analysis was performed using the Cox-proportional hazards regression method, incorporating natural logarithm (Ln) of triglycerides as a continuous measure. The fully adjusted model included age, sex, body mass index (BMI), serum creatinine level, presence or absence of diabetes mellitus, chronic obstructive pulmonary disease, past MI, cerebrovascular accident, New York Heart Association functional class, systolic blood pressure, diagnosis of malignancy, heart failure, and serum concentrations of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). All statistical tests were 2 sided, with p<0.05 considered statistically significant. 

Results: • Age- and sex-adjusted survival ranged from 41% in the group with triglycerides <100 mg/dl to 25% in the group with triglycerides ≥500 mg/dl.
• In a fully adjusted Cox-regression model including HDL-C, each 1-unit increase in Ln triglycerides was associated with 26% (p=0.016) increased risk of 22-year all-cause mortality.
• The risk of all-cause death increased from 6% (95% CI 1-12%) in patients with screening triglycerides 100-149 mg/dl to 68% (95% CI 38-206%) in those with levels ≥500 mg/dl.
Authors’ conclusion: Elevated triglycerides in patients with established CHD are associated with a long-term mortality risk that is independent of HDL-C levels. Given that the higher mortality risk could be detected in subjects with triglycerides >100 mg/dl, suggests that the current threshold for the definition of elevated triglycerides level for patients with CHD may be higher than desired.


The findings from this 22-year follow-up of the BIP study show a direct association between triglyceride levels and all-cause mortality in patients with CHD, with a 26% increase in risk for each 1-unit increase in triglycerides. Importantly, there was a graded increase in risk extending to triglyceride levels which would be considered desirable (<150 mg/dl or 1.7 mmol/L) in current dyslipidaemia guidelines (1). It should be emphasised that this association was evident even after correcting for conventional risk factors, including HDL cholesterol, thus reaffirming elevated triglycerides as an independent predictor of risk. This analysis has a number of strengths which add to the robustness of these findings. These include the size of the cohort, duration of follow-up, patient population, i.e. patients with established CHD, as well as the use of a national registry to verify death. However, it should be acknowledged that the standards of care at the time of the BIP study differed from modern management.

From emerging genetic data, it is clear that there is revived interest in triglycerides as a causal risk factor for cardiovascular disease. The failure of recent trials of HDL-targeted therapy, most recently ACCELERATE with the cholesteryl ester transfer protein inhibitor, evacetrapib (2), has also added to the resurgence of interest in triglycerides.

The results from this analysis highlight the importance of triglycerides as a causal risk factor, a proposition supported by genetic and observational data (3). However, the jury is still out on whether targeting elevated triglycerides reduces cardiovascular outcomes in patients at high cardiovascular risk. Clearly, there is a need for new trials to test this hypothesis in an appropriate patient population; two trials with different formulations of omega-3 fatty acids are in progress (REDUCE-IT and STRENGTH) (4,5). Furthermore, as highlighted in recent posts, a study with pemfibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, in type 2 diabetes patients with elevated triglycerides will also test this (4). This is truly an exciting time for triglycerides research, with the answer to the eternal question - are triglycerides a risk factor or treatment target – within sight.


1. Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegria E, Chapman MJ, Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus J, Filardi PP, Riccardi G, Storey RF, Wood D. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769-818.

2. Presented by Dr. Stephen J. Nicholls at the American College of Cardiology Annual Scientific Session, Chicago, IL, April 3, 2016, see news from the literature.

3. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547-63.

4. A Study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High Risk Patients With Hypertriglyceridemia and on Statin. The Primary Objective is to Evaluate the Effect of 4 g/Day AMR101 for Preventing the Occurrence of a First Major Cardiovascular Event. (REDUCE-IT). Identifier: NCT01492361.

5. Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia (STRENGTH). Identifier: NCT02104817.

6. Landmark Trial Entitled "PROMINENT" To Explore The Prevention Of Heart Disease In Diabetic Patients With High Triglycerides And Low HDL-C.

Key words triglycerides; Bezafibrate Infarction Prevention Study; triglycerides; mortality; pemfibrate