Vytorin may inhibit, reverse proinflammatory effects of diet in patients with type 2 diabetes

SAN DIEGO — Combination therapy with Vytorin to treat high cholesterol and triglyceride levels in the blood appears to provide an anti-inflammatory effect and to reduce proinflammatory mediators after consumption of fatty foods, according to research presented here.

In a cohort feeding challenge involving 20 patients with type 2 diabetes, Vytorin (ezetimibe/simvastatin, Merck) reversed the action of cream from stimulating toll-like receptors 4 and 2 (TLR-4 and TLR-2) to paradoxically suppressing their appearance.

“Clearly, while lowering the concentrations of lipids, as expected, ezetimibe/simvastatin combination exerts a potent anti-inflammatory effect,” Paresh Dandona, MD, PHD, FRCP, FACP, FACE, of the State University of New York at Buffalo, told Endocrine Today.

Paresh Dandona

Dandona and colleagues randomly assigned 10 men and 10 women with comparable age, BMI and HbA1c at baseline to the combination drug or placebo for 6 weeks.

The researchers assessed the effects after ingestion of 33 g cream (300 calories); cream induces reactions in the body similar to those seen after consuming a high-fat, high-carbohydrate meal, with increases in cellular and molecular indices of inflammation by peripheral blood mononuclear cells (MNC), according to the researchers.

The investigators collected fasting and post-challenge blood samples at baseline and at 6 weeks.

With ezetimibe/simvastatin, total cholesterol and LDL cholesterol concentrations were lowered significantly at 6 weeks (P < .05), as expected.

Cream intake acutely induced increases in MNC expression of interleukin-1 beta (by 105 ± 18%), tumor necrosis factor-alpha (by 97 ± 12%), glycoprotein CD68 (by 48 ± 8%), platelet endothelial cell adhesion molecule (by 66 ± 10%), TLR-4 (by 84 ± 11%) and TLR-2 (by 67 ± 9%) at week 0.

Compared with baseline, the MNC expression of IL-1 beta and CD68 expression also dropped in the fasting state (by 21 ± 7 and 24 ± 10, respectively, P < .05) at week 0 with ezetimibe/simvastatin; similar decreases were seen following cream (by 74 ± 15% and 68 ± 13%, respectively, compared with increases at week 0; P < .05).

The increase in expression of tumor necrosis factor-alpha and platelet endothelial cell adhesion molecule after cream also was suppressed (by 67 ± 14% and 45 ± 9%, respectively, compared with increases at week 0) with ezetimibe/simvastatin.

Further, a paradoxical suppression of the cream-induced increases in TLR-2 and TLR-4 (by 21 ± 8% and 18 ± 7%, respectively) was observed after the ingestion of cream at 6 weeks with the drug.

Ezetimibe/simvastatin also suppressed fasting- and cream-induced increases in plasma lipopolysaccharide concentrations (by 24% and 26%, P < .05, compared with baseline at week 0). Fasting concentrations of C-reactive protein, free fatty acids and IL-18 also decreased (by 32 ± 11%, 19 ± 8%, and 15 ± 4%, respectively; P < .05) with the drug.

The data did not indicate whether the ezetimibe or simvastatin is responsible for the effects. The researchers note further investigation is needed.

“The use of ezetimibe/simvastatin combination not only exerts a potent chronic anti-inflammatory effect in the fasting state, but also acutely after the intake of fat as cream,” Dandona said. “This is particularly relevant that this effect has been demonstrated in MNC since the various cells in this fraction, the monocyte in particular, which when inflamed and with an increased expression of CD68 becomes a macrophage and becomes a foam cell in the atherosclerotic plaque. Furthermore, when armed with increased PECAM, its trans-endothelial transfer into the ub-endothelium is facilitated.” – by Allegra Tiver

Reference:

Dandona P. PP28-3. Presented at: The Endocrine Society Annual Meeting; March 5-8, 2015, San Diego.

Disclosure: Dandona reports no relevant financial disclosures.