Severe hypertriglyceridemia with insulin resistance is associated with systemic inflammation: reversal with bezafibrate therapy in a randomized controlled trial.
OBJECTIVE
To determine whether hypertriglyceridemia is associated with systemic inflammation, which may contribute to the increased cardiovascular risk in patients who have hypertriglyceridemia. In addition, we investigated whether fibrates reverse this inflammatory state.


METHODS
Serum lipid levels, body mass index, insulin resistance, and inflammatory parameters were compared between 18 patients who had severe hypertriglyceridemia without cardiovascular disease and 20 normolipidemic controls. We measured the ex vivo production capacity of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 after whole-blood stimulation with lipopolysaccharide, as well as circulating levels of C-reactive protein and fibrinogen. A randomized controlled trial was conducted to determine whether bezafibrate (400 mg administered daily for 6 weeks) affected these parameters in hypertriglyceridemic patients.


RESULTS
When compared with normolipidemic controls, hypertriglyceridemic patients had significantly lower high-density lipoprotein (HDL) cholesterol and higher triglyceride levels, body mass index, and insulin resistance. In addition, hypertriglyceridemic patients had a significantly higher production capacity of TNF-alpha (mean difference, 11 700 pg/mL; 95% confidence interval [CI]: 7800 to 15,700 pg/mL]) and IL-6 (mean difference, 20,400 pg/mL; 95% CI: 7800 to 32,900 pg/mL), and higher levels of C-reactive protein (mean difference, 0.8 mg/L; 95% CI: 0.1 to 2.4 mg/L) and fibrinogen (mean difference, 0.8 g/dL; 95% CI: 0.3 to 1.3 g/dL). Bezafibrate therapy significantly increased HDL cholesterol levels, reduced triglyceride and insulin resistance levels, and reduced production capacity of TNF-alpha and IL-6, as well as levels of C-reactive protein and fibrinogen.


CONCLUSIONS
Systemic inflammation is present in patients who have the clinical phenotype that is associated with severe hypertriglyceridemia, and may contribute to the increased risk of cardiovascular disease in these patients. Bezafibrate has anti-inflammatory effects in these patients.
Jonkers
Iris J
IJ
Department of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Mohrschladt
Martina F
MF
Westendorp
Rudi G
RG
van der Laarse
Arnoud
A
Smelt
Augustinus H
AH
D001629:Bezafibrate / Q000627:therapeutic use*; D001786:Blood Glucose / Q000032:analysis; D002097:C-Reactive Protein / Q000032:analysis; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D005340:Fibrinogen / Q000032:analysis; D006801:Humans; D015228:Hypertriglyceridemia / Q000188:drug therapy / Q000378:metabolism*; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D066298:In Vitro Techniques; D007249:Inflammation; D018836:Inflammation Mediators / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000096:biosynthesis; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D001786:Blood Glucose; D000960:Hypolipidemic Agents; D018836:Inflammation Mediators; D007328:Insulin; D015850:Interleukin-6; D008055:Lipids; D014409:Tumor Necrosis Factor-alpha; D005340:Fibrinogen; D002097:C-Reactive Protein; D001629:Bezafibrate