How High Is Too High for Triglycerides and Cardiovascular Risk?

Patrice Wendling

March 18, 2016

TEL-HASHOMER, ISRAEL — In patients with coronary heart disease, even triglyceride levels on the high side of normal (100 to 149 mg/dL) are associated with an increased risk of death, new research shows[1].

"The current threshold for the definition of elevated triglycerides levels for patients with CHD may be higher than desired," Dr Robert Klempfner (Sheba Medical Center, Tel-Hashomer, Israel) and colleagues write in their study, published online March 8, 2016 in Circulation: Cardiovascular Quality and Outcomes.

To clarify the association between different triglyceride levels and long-term all-cause mortality, the authors evaluated 22-year mortality data on 15,355 patients with proven CHD who were screened between 1990 and 1992 for the Bezafibrate Infarction Prevention (BIP) trial, a secondary-prevention trial.

Patients were divided into five groups based on fasting serum triglyceride levels at screening: low-normal triglycerides (<100 mg/dL), high-normal triglycerides (100–149 mg/dL), borderline hypertriglyceridemia (150–199 mg/dL), moderate hypertriglyceridemia (200–499 mg/dL), and severe hypertriglyceridemia (>500 mg/dL).

Most patients were men (81%) and had a history of a previous MI (72%). Notably, more than 90% of patients had received no lipid-modifying medication.

Age- and sex-adjusted survival was 41% in the low-normal triglyceride group vs 37%, 36%, 35% and 25% in groups with progressively higher concentrations of triglycerides (P<0.001), according to the authors.

Mortality Risk by Triglyceride Group (Compared With Low-Normal)*

Triglyceride group HR (95% CI)
High-normal 1.06 (1.01–1.12)
Borderline 1.16 (1.09–1.23)
Moderate 1.29 (1.22–1.37)
Severe 1.68 (1.38–2.06)
*Adjusted for age, HDL cholesterol, body-mass index (BMI), and diabetes

When the investigators assessed triglycerides as a continuous measure, each unit of natural logarithm triglycerides elevation was independently associated with a 26% increase in all-cause mortality adjusted for age and sex only. This association remained significant after adding HDL-C to the model (HR 1.12; 95% CI 1.06–1.18), they report.

Shorter follow-up from the BIP registry also found a stepwise increase in age-adjusted 5-year mortality with increasing triglycerides, but the association was not statistically significant after adjustment for HDL-C and other covariates.

The parent study reported a nonsignificant 9.4% reduction in fatal and nonfatal MI or sudden death with the fibrate drug bezafibrate[2].

"An interesting lesson could be derived from the BIP study: despite a significant HDL-C increase in the bezafibrate treatment arm, the overall benefits were nonsignificant. However, the benefit of bezafibrate in the subgroup of patients with high triglyceride levels was impressive," Klempfner writes. "In all the available five randomized control trials, the beneficial effects of fibrates were highly significant in patients with hypertriglyceridemia."

The study was limited by the inability to adjust for potential confounders such as morbidity and treatment given and the lack of information on cause of death, he notes. Mortality data were obtained by matching patients' identification numbers with their vital status in the National Population Registry.

The authors presumed the deaths were cardiovascular because higher triglyceride levels remained independently associated with all-cause mortality after excluding patients who developed incidental cancers. Further, 8-year follow-up data in randomized BIP patients showed that about 58% of deaths were due to a cardiovascular cause, they note.

This assumption seems to be valid but remains a limitation nonetheless, Drs Karol Watson and Dr Philipp Wiesner (University of California, Los Angeles, CA) write in an accompanying editorial[3].

Other limitations that temper enthusiasm include the lack of follow-up lipid values, follow-up medication use, and ascertainment of important comorbidities, such as diabetes.

Still, the study, with its large numbers of patients and long follow-up, provides useful information and takes on "special importance given that elevations in triglycerides are increasingly common in current-day society," the editorialists write.

National Health and Nutrition Examination Survey (NHANES) data from 1988 to 2010 reveal that 47% of Americans had triglyceride levels >150 mg/dL and 1% had levels >500 mg/dL.

Clinicians have debated for years how to tackle this problem. While lifestyle interventions remain an effective method, trials like ACCORD, AIM-HIGH, and HPS-2 have failed to show a benefit with adding agents, primarily targeting triglycerides, on top of statins.

Antisense apolipoprotein C-III inhibitors have been shown to be effective and safe in lowering triglycerides in early clinical trials, but whether these drugs will be able to improve cardiovascular outcomes remains to be seen.

"Although we search for the true significance of elevated triglycerides in cardiovascular risk and potentially the optimal method to lower triglycerides, we congratulate Klempfner et al on an important study, which provides support for the idea that triglycerides should be taken more seriously as a future target to improve patient outcomes," Watson and Wiesner write.

The authors and editorialists reported no relevant financial relationships.

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