(2018), examined outcomes based upon the presence of DM.[76] Patients with DM were generally older and women. There were 4,933 patients with DM in IMPROVE-IT, representing 27% of the intervention and control group. In patients with DM, statin plus ezetimibe reduced the seven-year Kaplan-Meier (KM) event rate in the composite endpoint more than statins alone (HR: 0.85, 95% CI: 0.78 0.94, NNT=18). In patients without DM, the absolute difference in the primary composite outcome was 0.7% and not statistically different over a seven-year period (HR: 0.98, 95% CI: 0.91 1.04). When the authors applied the TRS tool, all patients with DM had a statistically significant benefit regardless of risk. However, in patients without DM and determined to be at low to intermediate risk based upon the TRS tool, no benefit was observed with combination therapy. There were no differences in CV or all-cause mortality regardless of CV risk.[76] Safety The addition of ezetimibe to statins is not associated with a greater risk for hepatic toxicity, cancer, or gallbladder-related conditions, but it is unclear if the risk of myopathy or rhabdomyolysis is increased because of imprecision in the data and low event rates.[76,81] Summary The addition of ezetimibe to statins (e.g., simvastatin) reduces CV event endpoints without changing mortality, similar to maximizing the statin dose.[75,76,80,81] The greatest reduction in CV events occurred in patients with DM or in those with three or more risk factors. There is no evidence for an increased risk of cancer, hepatotoxicity, or gallbladder-related diagnoses with the addition of ezetimibe to statins, but the effect on muscle-related complaints is less clear. As this is a Reviewed, New-replaced recommendation, the Work Group systematically reviewed evidence related to this recommendation.[75,76,80,81] The Work Group s confidence in the quality of the evidence was moderate. 