R3i Editorial

Whether elevated triglycerides represent a causal risk factor has been much debated. However, increasing recent evidence provides a strong case for support. This month’s Landmark article adds to this story.

The Bezafibrate Infarction Prevention (BIP) study, a large randomized outcomes study, was designed to assess the efficacy of bezafibrate in preventing cardiovascular events in high risk patients. Results on completion of the trial showed no significant benefit with bezafibrate for the primary outcome (a composite of fatal and nonfatal myocardial infarction plus sudden death)¹. The report featured this month describes 22-year mortality data on 15,355 patients screened for the BIP trial². Death was verified by National Registry data. The results showed a graded increase in risk of all-cause mortality with successively higher fasting triglyceride levels, which was independent of high-density lipoprotein cholesterol (HDL-C) concentration. Each unit increase in natural logarithm fasting triglycerides was associated with a 26% increase in all-cause mortality. Moreover, even patients with fasting triglyceride levels considered desirable according to current European dyslipidaemia guidelines (i.e. <150 mg/dl)³, were at increased risk of mortality. While the survival rate for patients with severe hypertriglyceridaemia (>500 mg/dl) was only 25%, those patients with lower levels (<100 mg/dl) had higher survival (41%).

These findings add evidence regarding two key questions concerning the causality of triglycerides. First, the study shows that even moderately elevated fasting triglycerides increase the risk of cardiovascular events and all-cause death, adding support to observational and genetic studies demonstrating a causal role of triglycerides in atherosclerotic vascular disease ^4-6. However, we must also acknowledge the limitations of these data. The original study was performed at a time when the standard of care in dyslipidaemia management differed from current practice; indeed, >90% of patients did not receive lipid-modifying therapy at enrolment.

The next leading question is whether targeting elevated triglycerides reduces cardiovascular outcomes, particularly in high-risk patients. Evidence from this 22-follow-up of BIP that individuals with lower triglycerides had higher survival is encouraging but not definitive. For a clear answer on this question, we need to await the results of ongoing outcomes studies with omega-3 fatty acids (REDUCE-IT and STRENGTH); in addition, other novel therapies, such as pemfibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, may also offer potential benefit ^7-9.

This Landmark report describes an important study, which adds to the evidence that triglycerides should be considered more seriously as a future target to improve clinical outcomes. This premise is also highly topical, in the light of the increasing pandemic of diabetes, in which elevated triglycerides are a typical feature. Indeed, in the US, data from the National Health and Nutrition Examination Survey (NHANES), has shown an upward trend for elevated triglycerides; in 2010, nearly 50% of individuals had fasting triglyceride levels >150 mg/dl ¹⁰. It is also clear that current management approaches fail to adequately address this issue ¹¹.

Taken together, the increasing body of evidence argues for serious consideration of management of elevated triglycerides in future guidelines, a view which is clearly shared by the Residual Risk Reduction Initiative. The missing part of the puzzle is whether targeting elevated triglycerides reduces cardiovascular events against a background of current standard of care. For this, we eagerly look forward to results from ongoing and planned trials in patients receiving modern standard of care lipid management, for answers.

References

1. Secondary prevention by raising HDL cholesterol and reducing triglycerides
in patients with coronary artery disease. Circulation 2000;102:21–7.
2. 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;9:100-8.
3. 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.
4. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547-63.
5. Do R, Willer CJ, Schmidt EM et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet 2013;45:1345-52.
6. Do R, Stitziel NO, Won HH et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature 2015; 518: 102-6.
7. 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). ClinicalTrials.gov Identifier: NCT01492361. https://clinicaltrials.gov/ct2/show/NCT01492361#
8. Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia (STRENGTH). ClinicalTrials.gov Identifier: NCT02104817. https://clinicaltrials.gov/show/NCT02104817
9. Landmark Trial Entitled "PROMINENT" To Explore The Prevention Of Heart Disease In Diabetic Patients With High Triglycerides And Low HDL-C. http://www.bizjournals.com/prnewswire/press_releases/2016/01/12/CL94522
10. Carroll MD, Kit BK, Lacher DA, Shero ST, Mussolino ME. Trends in lipids and lipoproteins in US adults, 1988-2010. JAMA. 2012;308:1545–54.
11. Karlson BW, Palmer MK, Nicholls SJ et al. VOYAGER meta-analysis of the impact of statin therapy on low-density lipoprotein cholesterol and triglyceride levels in patients with hypertriglyceridemia. Am J Cardiol 2016 [Epub ahead of print].