Efficacy and safety of various doses of hybutimibe monotherapy or in combination with atorvastatin for primary hypercholesterolemia: a multicenter, randomized, double-blind, double-dummy, parallel-controlled phase Ⅲ clinical trial / 中华心血管病杂志

Objective: To evaluate the efficacy and safety of hybutimibe monotherapy or in combination with atorvastatin in the treatment of primary hypercholesterolemia. Methods: This was a multicenter, randomized, double-blind, double-dummy, parallel-controlled phase Ⅲ clinical trial of patients with untreated primary hypercholesterolemia from 41 centers in China between August 2015 and April 2019. Patients were randomly assigned, at a ratio of 1∶1∶1∶1∶1∶1, to the atorvastatin 10 mg group (group A), hybutimibe 20 mg group (group B), hybutimibe 20 mg plus atorvastatin 10 mg group (group C), hybutimibe 10 mg group (group D), hybutimibe 10 mg plus atorvastatin 10 mg group (group E), and placebo group (group F). After a dietary run-in period for at least 4 weeks, all patients were administered orally once a day according to their groups. The treatment period was 12 weeks after the first dose of the study drug, and efficacy and safety were evaluated at weeks 2, 4, 8, and 12. After the treatment period, patients voluntarily entered the long-term safety evaluation period and continued the assigned treatment (those in group F were randomly assigned to group B or D), with 40 weeks' observation. The primary endpoint was the percent change in low density lipoprotein cholesterol (LDL-C) from baseline at week 12. Secondary endpoints included the percent changes in high density lipoprotein cholesterol (HDL-C), triglyceride (TG), apolipoprotein B (Apo B) at week 12 and changes of the four above-mentioned lipid indicators at weeks 18, 24, 38, and 52. Safety was evaluated during the whole treatment period. Results: Totally, 727 patients were included in the treatment period with a mean age of (55.0±9.3) years old, including 253 males. No statistical differences were observed among the groups in demographics, comorbidities, and baseline blood lipid levels. At week 12, the percent changes in LDL-C were significantly different among groups A to F (all P<0.01). Compared to atorvastatin alone, hybutimibe combined with atorvastatin could further improve LDL-C, TG, and Apo B (all P<0.05). Furthermore, there was no significant difference in percent changes in LDL-C at week 12 between group C and group E (P=0.991 7). During the long-term evaluation period, there were intergroup statistical differences in changes of LDL-C, TG and Apo B at 18, 24, 38, and 52 weeks from baseline among the statins group (group A), hybutimibe group (groups B, D, and F), and combination group (groups C and E) (all P<0.01), with the best effect observed in the combination group. The incidence of adverse events was 64.2% in the statins group, 61.7% in the hybutimibe group, and 71.0% in the combination group during the long-term evaluation period. No treatment-related serious adverse events or adverse events leading to death occurred during the 52-week study period. Conclusions: Hybutimibe combined with atorvastatin showed confirmatory efficacy in patients with untreated primary hypercholesterolemia, which could further enhance the efficacy on the basis of atorvastatin monotherapy, with a good overall safety profile.

Effect of the costimulatory molecules OX40-OX40 ligand interaction on the expression of NFATc1 in leukocytes of apolipoprotein E-deficient mice / 中华心血管病杂志

<p><b>OBJECTIVE</b>To investigate the effect of OX40/OX40L interaction on the nuclear factor of activated T cells c1 (NFATc1) in ApoE-/- mice.</p><p><b>METHODS</b>Lymphocytes were prepared from mouse spleens after Collar-treated Surgery, then incubated with a range of agonistic anti-OX40 mAbs and inhibitory anti-OX40L mAb to stimulate or inhibit OX40-OX40L interaction in vitro. The expression of NFATc1 mRNA and protein in lymphocytes of ApoE-/- mice was measured by Real Time PCR and flow cytometry, respectively.</p><p><b>RESULTS</b>(1) After stimulating OX40-OX40L signal pathway, the expression of NFATc1 mRNA and protein in leukocytes of ApoE-/- mice was significantly increased, with maximal effect occurring at 20 µg/ml anti-OX40 mAb-stimulated, and peaked at 24 h at any concentration (P < 0.01). (2) Anti-OX40L mAb significantly suppressed the expression of NFATc1 in leukocytes of ApoE-/- mice, with maximal effect occurring at 20 µg/ml anti-OX40L mAb, and peaked at 24 h (P < 0.001).</p><p><b>CONCLUSIONS</b>OX40-OX40L interaction can regulate the mRNA and protein expressions of NFATc1 in lymphocytes of ApoE-/- mice.</p>