Triglyceride Puzzle: Do TG Metabolites Better Predict Risk?

August 23, 2023

Triglyceride (TG) levels are a measure of cardiovascular (CV) risk and a target for therapy, but a focus on TG levels as a bad guy in CV risk assessments may be missing the mark, a population-based cohort study suggests.

It concluded, very preliminarily, that it may be the vigor of TG metabolism more than plasma levels that are associated with bad outcomes.

The analysis, based on 30,000 participants in the Copenhagen General Population Study, saw sharply increased risks for all-cause mortality, CV mortality, and cancer mortality over 10 years among those with robust TG metabolism.

Those significant risks, gauged by concentrations of two molecules considered markers of TG metabolic rate, were independent of body-mass index (BMI) and a range of other TG-linked risk factors, including plasma TG levels themselves.

All-cause mortality jumped 31% for plasma levels of glycerol in the highest vs lowest quartiles and rose 18% for highest-quartile levels of β-hydroxybutyrate. In parallel, CV mortality climbed 37% for glycerol and 18% for β-hydroxybutyrate in the study, published August 14 in the European Heart Journal.

The findings "implicate triglyceride metabolic rate as a risk factor for mortality not explained by high plasma triglycerides or high BMI," the report states. The study, it continues, may be the first to link increased mortality to more active TG metabolism — according to levels of the two biomarkers — in the general population.

The results were "really, really surprising," senior author Børge G. Nordestgaard, MD, DMSc, told | Medscape Cardiology. They are "completely novel" and "may make people think differently" about TG and mortality risk.

Given their unexpected findings, the group conducted further analyses for evidence that the metabolite-mortality associations weren't independent. "We tried to stratify them away, but they stayed," said Nordestgaard, of the University of Copenhagen, Denmark.

In a weight-stratified analysis, for example, findings were similar in people with normal weight and with overweight and who were obese, Nordestgaard observed. "Even in the ones with normal weight by World Health Organization criteria, we saw the same and maybe even stronger relationships" between TG metabolism and mortality.

The report is careful to note the retrospective cohort study's limitations, but its findings "at most support an association, not causation," Michael Miller, MD, Hospital of the University of Pennsylvania, Philadelphia, observed for | Medscape Cardiology. Therefore, it can't answer "whether and to what extent glycerol and/or β-hydroxybutyrate independently contribute to mortality beyond triglyceride levels per se."

Assessing levels of the two biomarkers "was an interesting way to indirectly assess whole-body TG metabolism," but they were not fasting levels, said Miller, who wasn't part of the study.

Also, the analysis doesn't account for heparinization and other factors "that artificially raise glycerol levels" and suffers in other ways "from the inherent limitations of residual confounding," said Miller, who is also chief of medicine at Corporal Michael J Crescenz VA Medical Center, Philadelphia.

The analysis tracked 30,000 men and women, participants in the much larger Copenhagen General Population Study cohort, for a median of 10.7 years. During that time, 9897 of them died.

Plasma levels of glycerol and β-hydroxybutyrate, the report notes, were measured using high-throughput nuclear magnetic resonance spectroscopy.

Glycerol levels greater than 80 µmol/L represented the highest quartile and those less than 52 µmol/L the lowest quartile. The corresponding β-hydroxybutyrate quartiles were greater than 154 µmol/L and less than 91 µmol/L, respectively.

Hazard Ratios for 10-year Mortality for TG Metabolite Levels in Highest vs Lowest Quartiles
Type of Mortality Glycerol, HR (95% CI) β-hydroxybutyrate, HR (95% CI)
All-cause 1.31 (1.22 - 1.40) 1.18 (1.11 - 1.26)
Cardiovascular 1.37 (1.18 - 1.59) 1.18 (1.03 - 1.35)
Cancer 1.24 (1.11 - 1.39) 1.16 (1.05 - 1.29)
Other causes 1.45 (1.28 - 1.66) 1.23 (1.09 - 1.39)

Mortality risks were independent not only of BMI and TG levels but also of age, greater waist circumference, many other standard CV risk factors, chronic obstructive pulmonary disease, diabetes, insulin use, and CV comorbidities and medications.

Nordestgaard, who also stressed that the findings are only hypothesis-generating, speculated that glycerol and β-hydroxybutyrate could potentially serve as biomarkers for predicting risk or guiding therapy and, indeed, might be amenable to risk-factor modification. "But I have absolutely no data to support that."

The study was funded by the Independent Research Fund, and by Johan Boserup and Lise Boserups Grant. Nordestgaard reported consulting for or giving talks sponsored by AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Esperion, and Silence Therapeutics. The other authors report no conflicts. Miller has disclosed serving as a scientific adviser for Amarin and 89bio.

Eur Heart J. 2023;ehad330. Full text

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