These results demonstrated that ezetimibe 10 mg in combination with ongoing simvastatin 20 mg produced significantly greater LDL-C and total cholesterol reductions compared with doubling the dose of simvastatin to 40 mg in patients with primary hypercholesterolemia, T2DM, and CHD not at the LDL-C target < 2.6 mmol/L (< 100 mg/dL) with simvastatin 20 mg/day for at least 6 weeks. In addition, more patients in the combination EZ + simva 10/20 mg group achieved the target LDL-C goal as defined by the NCEP ATP III guidelines than in the simvastatin 40 mg group, although this was not statistically significant. The treatment effect was in favor of EZ + simva with nearly a threefold odds of reaching the LDL-C < 2.6 mmol/L (< 100 mg/dL) vs doubling the dose of simvastatin. The probability of reaching this target was independent of age and HbA1c level at baseline within the range of values of this population. Changes in HDL-C and triglycerides were similar between treatment groups, and these changes were consistent with results of previous trials comparing EZ + simva combination vs statin monotherapy in T2DM patients [19–21]. Treatment with EZ + simva 10/20 mg or simvastatin 40 mg was generally well-tolerated.
The results of this study were consistent with previous studies of similar design and duration conducted in the general population of patients with hypercholesterolemia and CHD [23, 24]. They are also generally consistent in patients with T2DM [18–21, 25]. In clinical studies of patients with T2DM not at the recommended LDL-C target < 2.6 mmol/L (< 100 mg/dL) with a previous statin treatment, EZ + simva was consistently superior to doubling the ongoing statin dose in reducing the LDL-C values and in getting patients to the LDL-C target [18, 20, 21]. Of note, in the present study the reduction in LDL-C that occurred with doubling the dose of simvastatin was higher than that observed in many previous studies of similar design, which showed reductions of < 10% [18, 20, 21]. These effects were also observed in a larger study with similar design to the present one comparing EZ + simva 10/20 mg with atorvastatin 20 mg in hypercholesterolemic CHD patients without diabetes . The reasons for the inconsistency observed in the response to doubling statin dose are not fully understood. We speculate that this could be due to study effect or to good compliance. On the other hand, most studies and post hoc analyses did not include a comparison of goal attainment between patient groups, nor an analysis of factors that predict the odds of achieving goal. One report did show that more patients in the diabetes group achieved the recommended LDL-C goal compared with non-diabetics (83.6% versus 67.2%), although this result was not statistically significant after adjusting for differences in baseline LDL-C levels . In addition, a significant interaction for LDL-C lowering was observed in a preliminary report of a post hoc analysis of patients in the IN-CROSS study, indicating larger between-group reductions in patients with T2DM versus those without T2DM . Further study in larger populations that directly compare the efficacy of combination therapy with statin monotherapy in diabetics vs non-diabetics is warranted.
EZ + simva combination therapy at the usual recommended starting dose of 10/20 mg, and at the next higher dose of 10/40 mg vs the recommended usual starting dose and next highest dose of atorvastatin (10, 20, and 40 mg, respectively), was consistently superior to statin monotherapy in reducing LDL-C levels and attaining LDL-C levels < 1.8 mmol/L (< 70 mg/dL) in T2DM patients [19–21]. The results of the current trial confirm previous findings in patients with T2DM and extend them to include a population of patients treated in outpatient diabetes clinics.
Recent investigations on the changes in the cholesterol homeostasis in patients with CHD and/or diabetes seem to support the concept that a complementary approach targeting both the synthesis and the intestinal absorption of cholesterol can improve the lipid profile of patients who show a poor response to statin monotherapy better than high dose/high potency statin monotherapy [28–30]. It has been suggested that reducing cholesterol absorption using ezetimibe treatment combined with a statin, which lowers hepatic cholesterol synthesis, may be a practical approach to intensive lipid management and goal achievement compared with treatments that reduce synthesis alone [28–30]. This may be of particular relevance in T2DM patients, who have been shown to have higher levels of NPC1L1 mRNA and increased intestinal absorption of biliary and newly synthesized cholesterol. One mechanism by which NPC1L1 may be increased in T2DM patients is through elevated glucose concentrations . Cultured Caco-2/15 cells exposed to high glucose levels displayed a significant increase in protein expression of NPC1L1, and when ezetimibe was added to the culture medium, the action of the glucose was reduced . In addition to differences in NPC1L1 protein expression, a disturbance in the ATP binding cassette (ABC) proteins G5 and G8, which regulate cholesterol homeostasis, may play a role in the dyslipidemia of diabetic patients. Specifically, compared with non-diabetics, diabetic patients have decreased mRNA expression of both ABCG5 and G8, leading to increased levels of sitosterol and cholesterol in chylomicrons . Taken together, these results suggest that both increased NPC1L1 and lower ABCG5 and G8 may lead to an increase in cholesterol absorption in diabetic patients, and targeting both the synthesis and the intestinal absorption of cholesterol in the treatment of diabetic dyslipidemia may be prudent. This view is further supported by the findings obtained in high cardiovascular risk patients, which demonstrated between-group LDL-C reductions in favor of EZ + simva vs rosuvastatin 10 mg in patients who were not at LDL-C target prior to switch and suggested that there was a high proportion of poor responders to statin therapy in this group . Additional clinical trials to assess cardiovascular outcomes with ezetimibe added to statin therapy are ongoing.
In the present study, both treatment regimens had similar safety and tolerability profiles during the study period. Despite higher baseline laboratory values in the simvastatin group, there were no reports of increased ALT or AST ≥ 3 × ULN nor CK ≥ 5 × ULN in this treatment group during the study, nor were there reports of increases in ALT, AST, or CK in the EZ + simva 10/20 mg group. Accordingly, neither the addition of ezetimibe to simvastatin 20 mg nor doubling the dose of simvastatin to 40 mg resulted in reports of myopathy or rhabdomyolysis. These results are consistent with expectations for these drugs at the doses given and with previous trials in this patient population [17–19, 25, 33]. Although the incidence of serious adverse events was low, this study was relatively small and not powered nor of sufficient duration to assess the prevalence of rare adverse events. Clinical trial registration: NCT00423488