Effect of Ezetimibe on LDL-C Lowering and Atherogenic Lipoprotein Profiles in Type 2 Diabetic Patients Poorly Controlled by Statins

<div><p>Background</p><p>There exists a subpopulation of T2DM in whom first-line doses of statin are insufficient for optimally reducing LDL-C, representing a major risk of CVD. The RESEARCH study focuses on LDL-C reduction in this population along with modifications of the lipid profiles leading to residual risks.</p><p>Methods</p><p>Lipid changes were assessed in a randomized, multicenter, 12-week, open-label study comparing a high-potency statin (10mg of atorvastatin or 1mg of pitavastatin) plus ezetimibe (EAT: n = 53) with a double dose of statin (20mg of atorvastatin or 2mg of pitavastatin) (DST: n = 56) in DM subjects who had failed to achieve the optimal LDL-C targets. Lipid variables were compared with a primary focus on LDL-C and with secondary focuses on the percentage of patients who reached the LDL-C targets and changes in the levels of RLP-C (remnant like particle cholesterol) and sd-LDL-C, two characteristic atherogenic risks of DM.</p><p>Results</p><p>The reduction of LDL-C (%), the primary endpoint, differed significantly between the two groups (-24.6 in EAT vs. -10.9 in DST). In the analyses of the secondary endpoints, EAT treatment brought about significantly larger reductions in sd-LDL-C (-20.5 vs. -3.7) and RLP-C (-19.7 vs. +5.5). In total, 89.4% of the patients receiving EAT reached the optimized treatment goal compared to 51.0% of the patients receiving DST. The changes in TC (-16.3 vs. -6.3) and non-HDL-C (-20.7 vs. -8.3) differed significantly between the two groups.</p><p>Conclusion</p><p>Ezetimibe added to high-potency statin (10 mg of atorvastatin or 1 mg of pitavastatin) was more effective than the intensified-dose statin (20 mg of atorvastatin or 2 mg of pitavastatin) treatment not only in helping T2DM patients attain more LDL-C reduction, but also in improving their atherogenic lipid profiles, including their levels of sd-LDL-C and RLP-C.</p><p>We thus recommend the addition of ezetimibe to high-potency statin as a first line strategy for T2DM patients with insufficient statin response.</p><p>Trial Registration</p><p>The UMIN Clinical Trials Registry <a href="https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000003155&language=E/UMIN000002593" target="_blank">UMIN000002593</a></p></div

Changes in LDL cholesterol (box plots).

<p><b>A. Percentage reduction of LDL-C after 12 weeks of treatment:</b> The solid bar represents the percent change in DST and the dotted bar represents the percent change in EST. B. <b>LDL-C values before and after 12 weeks of treatment:</b> The white bars represent basal values before treatment and the black bars represent values after treatment. The dotted textile indicates EAT therapy and the solid bar indicates DST therapy. n.s., not significant; *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001.</p

The changes in atherogenic lipid profiles (box plots).

<p>A, C: The percent changes in sd-LDL-C and RLP-C, respectively. B, D: sd-LDL-C and RLP-C values before and after the 12 weeks of treatment, respectively. The ‘before treatment’ values are shown as white bars and the ‘after treatment’ values are shown as black bars. n.s., not significant; *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001.</p

Baseline Characteristics of treatment groups.

<p>Baseline Characteristics of treatment groups.</p

Flow of Patients in the RESEARCH Study.

<p>One hundred and nine patients were randomized. Fifty-six patients were assigned to the double intensified dose statin therapy (DST) group and 53 patients were assigned to the ezetimibe-add-on therapy (EAT) group. The analysis was performed on 51 patients in the EAT group and 56 patients in the DST group. T2DM: type 2 diabetes mellitus.</p

Changes in basic lipid biochemistry (box plots).

<p>A, C: The percent changes in non-HDL-C and ApoB, respectively. B: Non-HDL-C values before and after the 12 weeks of treatment. D, E, F: The percent changes in TC, HDL-C, and TG, respectively. The ‘before treatment’ values are shown as solid bars and the ‘after treatment’ values are shown as dotted bars. The bars representing the DST group are white and the bars representing the EAT group are black. n.s., not significant; *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001.</p

Demographic profiles of treatment groups.

<p>Demographic profiles of treatment groups.</p

Achievement rates in each treatment group.

<p>The bars representing the DST group are white and the bars representing the EAT group are black.</p