There have been relatively few studies that have assessed the comparative efficacy of the combination of ezetimibe/simvastatin with both atorvastatin and rosuvastatin in the same trial. This is the first report of the consistency of treatment effect of all three of these high-potency lipid-lowering therapies between subgroups of obese and non-obese diabetic patients in the same trial. With obesity reaching global epidemic proportions and its strong relationship to the development of CVD and atherogenic dyslipidemia, it is important to understand the potential utility of lipid lowering drugs in this population. In this post hoc analysis of subgroups of obese and non-obese diabetic subjects, treatment with ezetimibe/simvastatin 10/20 mg resulted in numerically greater reductions in LDL-C compared with rosuvastatin 10 mg only in the non-obese subjects, while the combination of ezetimibe/simvastatin 10/20 mg resulted in greater changes in LDL-C levels compared with doubling the statin dose in subjects in both subgroups regardless of baseline obesity status (obese/non-obese). In addition, a higher proportion of subjects attained all 3 specified treatment targets (LDL-C, non-HDL-C and Apo-B) with ezetimibe/simvastatin 10/20 mg treatment vs doubling the statin dose to atorvastatin 20 mg or simvastatin 40 mg and vs rosuvastatin 10 mg in both subgroups of obese and non-obese subjects. The overall safety and tolerability profile appeared generally comparable and consistent across subgroups and all treatment groups.
The dyslipidemia profile typically observed in obese and diabetic individuals is generally similar and includes high triglycerides (≥200 mg/dL), non-HDL-C, and Apo B levels, increased levels of small, dense LDL-C particles, although often, relatively normal levels of LDL-C, and low HDL-C levels (<40 mg/dL in men and <50 mg/dL in women) [7, 8]. As expected, subjects in the obese subgroup had higher mean baseline triglycerides than subjects in the non-obese subgroup; however, these mean levels were lower than the 200 mg/dL level specified by the NCEP ATP III guidelines that would define patients as having mildly or moderately elevated triglycerides . In addition, they did not have low mean HDL-C levels as would be expected based on typical dyslipidemia profiles in obese patients [7, 8]. Finally, mean LDL-C levels in the obese subjects were comparable to those of the non-obese subjects, with mean levels already at or below 100 mg/dL in all treatment groups, but not reaching the target level of <70 mg/dL as specified by the NCEP ATP III guidelines for very high risk individuals. It is important to note that these baseline numbers reflect treated baseline levels, likely resulting from pre-study treatment and/or the 6-week run-in period during which subjects were treated with a starting dose of simvastatin (20 mg) or atorvastatin (10 mg) and during which they agreed to maintain an approved cholesterol- and glucose-lowering diet. This pre-study treatment may be why the typical dyslipidemia profile was not observed.
The post hoc analysis results from the subgroup of obese subjects were generally consistent with those of the prespecified analysis results from the overall population with regard to percent change from baseline in LDL-C . Specifically, in the overall population, treatment with the combination of ezetimibe/simvastatin resulted in significantly greater reductions in LDL-C and other lipids compared with doubling the baseline statin dose to atorvastatin 20 mg or simvastatin 40 mg, but not compared with rosuvastatin 10 mg. However, in the subgroup of non-obese subjects in the current post hoc analysis, greater reductions in LDL-C were observed in favor of ezetimibe/simvastatin 10/20 mg vs doubling the baseline statin dose to atorvastatin 20 mg or simvastatin 40 mg and vs rosuvastatin 10 mg. These results are consistent with the sensitivity analyses of the overall population which showed statistically significant differences between the combination treatment and rosuvastatin 10 mg (−27.58 vs −22.20; p = 0.002). Moreover, the current sensitivity analysis results are consistent not only with the current exploratory analysis, but also with the primary analysis; however, for the ezetimibe/simvastatin 10/20 mg vs. rosuvastatin 10 mg comparison, the magnitude of the difference appeared to be somewhat higher compared with the main analysis. A previous post hoc analysis conducted in obese and non-obese subjects reported greater reductions with ezetimibe/simvastatin 10/20 mg vs. rosuvastatin 10 mg in both subgroups, however, those patients were not all diabetic . In addition, the results of a study by Furman and colleagues in high risk patients (BMI = 30–31 kg/m2) who had not achieved LDL-C <100 mg/dL while treated with simvastatin demonstrated significantly greater reductions in LDL-C with the combination of ezetimibe/simvastatin vs rosuvastatin and vs atorvastatin (p <0.05) using average doses of 9/64 mg ezetimibe/simvastatin, 18 mg rosuvastatin, and 68 mg atorvastatin, which is consistent with the numerically greater reductions in most lipids vs doubling the statin dose to simvastatin 40 mg or atorvastatin 20 mg or vs rosuvastatin 10 mg observed in the current analysis . One explanation for the inconsistencies between this group of subjects and those in previous studies may be differences in metabolism due to the presence of diabetes, which has been associated with high cholesterol synthesis and reduced cholesterol absorption efficiency regardless of obesity . Larger trials to compare obese and non-obese diabetic patients are needed to fully assess these questions.
Although there is resounding evidence that LDL-C lowering reduces cardiovascular risk, there are also data to demonstrate that the typical dyslipidemia profile observed in diabetic patients, which is shared by obese patients, often results in residual risk even after LDL-C targets are achieved. Consequently, it is essential to consider secondary lipoprotein targets to reduce the atherogenic burden in diabetic patients once they have reached their individual LDL-C goal. Specifically, elevated Apo B and non-HDL-C are both recommended treatment targets for very high risk patients [4, 9]. In this study, regardless of baseline obesity status (obese/non-obese), the combination of ezetimibe/simvastatin treatment resulted in higher percentages of diabetic patients achieving not only the aggressive LDL-C target of <70 mg/dL, but also non-HDL-C <100 mg/dL and Apo-B <80 mg/dL treatment targets compared with doubling the baseline statin dose and compared with rosuvastatin 10 mg. This result is consistent with a previous post hoc analysis of obese and non-obese subjects (of which only 1/3 were diabetic) in which higher percentages of patients achieved specified LDL-C, non-HDL-C and Apo B levels when treated with combination ezetimibe/simvastatin compared with rosuvastatin monotherapy .
The safety and tolerability profiles were generally consistent between treatments and between subgroups, although slightly more subjects taking ezetimibe/simvastatin 10/20 mg discontinued due to AEs compared with the other treatment groups. Previous trials comparing the safety profile of ezetimibe combined with simvastatin vs statins, including a post hoc analysis in obese and non-obese subjects do not suggest that there are significant tolerability differences between these treatments [15, 18]; however, the use of the highest dose (80 mg) of simvastatin has been restricted by the US Food and Drug Administration due to the higher risk of myopathy/rhabdomyolysis . Moreover, previous studies in high-risk diabetic subjects have not indicated tolerability issues with the combination treatment [10, 11].
This study was an exploratory, post hoc analysis and did not include statistical comparisons, nor multiplicity adjustments. Moreover, the study was not powered to detect very rare adverse events and was of relatively short duration. Therefore, the efficacy and safety results should be interpreted with some caution.
These results suggest that regardless of baseline obesity status (obese/non-obese), switching to combination ezetimibe/simvastatin 10/20 mg provides a well-tolerated lipid-lowering effect in diabetic hypercholesterolemic subjects who have not achieved a goal of LDL-C <70 mg mg/dl (1.81 mmol/L) while on simvastatin 20 mg or atorvastatin 10 mg.