2019 Volume 67 Issue 5 Pages 419-425
Patients with type 2 diabetes (T2DM) and hyperlipidemia are with high risk of myocardial infarction (MI) or coronary death events. The combined use of ezetimibe and atorvastatin could improve treatment efficacy and safety. To explore the efficacy and safety of ezetimibe in combination with atorvastatin for the treatment of patients with T2DM and acute coronary syndrome (ACS). This was a non-randomized cohort study of 95 consecutive, treatment-naïve patients with T2DM and ACS treated at the Quanzhou First Hospital of Fujian Province between February 2014 and March 2016. According to the treatment strategy they selected, the patients were categorized into the atorvastatin (n = 46) and atorvastatin + ezetimibe (n = 49) groups. The patients were followed up at 2 weeks and 12 months. The primary endpoints included the incidence of adverse cardiovascular events and changed in blood lipids and high-sensitivity C-reactive protein (hs-CRP). At 12 months, serum total cholesterol (TC), triglycerides, and low-density lipoprotein cholesterol (LDL-C) levels were significantly lower, and high-density lipoprotein cholesterol (HDL-C) levels were significantly higher in the atorvastatin + ezetimibe (EZ) group than in the atorvastatin group (all p < 0.05). The LDL-C control rate at 12 months was significantly higher in the atorvastatin + EZ group compared with the atorvastatin group (p = 0.006). Seven patients in the atorvastatin group were re-hospitalized for angina pectoris, while only one patient in the atorvastatin + EZ group was re-hospitalized for angina pectoris (p = 0.02). The efficacy of atorvastatin + EZ in treating T2DM patients accompanied with ACS was significantly higher than using atorvastatin alone. This combined strategy has good safety profile, and could be recommended for clinical application.
Acute coronary syndrome (ACS) is a group of clinical syndromes leading to unstable angina pectoris (UAP), acute myocardial infarction (MI), and sudden cardiac death. Diabetes mellitus (DM) is a metabolic disease mainly characterized by hyperglycemia. DM is commonly accompanied with hyperlipidemia, and is a common comorbidity of coronary heart disease (CHD).1) The cardiovascular mortality rate of patients with DM and hyperlipidemia is 2–3 folds that of the general population, and the risk of developing MI or coronary death within 10 years is comparable to the risk in patients with a history of myocardial infarction.1) Therefore, it is crucial to control the blood glucose level, reduce lipid level, and stabilize plaques in such patients.1)
A large number of clinical trials have already shown that using statins can reduce low-density lipoprotein cholesterol (LDL-C) levels, and thus substantially decrease the incidence of major cardiovascular events in high-risk populations, but the use of high-dose statins could also increase the risk of potential adverse events.2,3) In addition, the “6% law” of statins, namely doubling the dose of statins on the initial dose could only increase the LDL-C reducing effects by 6%,4) further limits the application of statins in lipid-lowering treatments. Gylling and Miettinen5) have shown that reducing the endogenous cholesterol synthesis in the liver by statins is accompanied with a compensatory increase of exogenous cholesterol intake by the intestinal tract. Indeed, the 4S trial6) showed that among 868 patients with CHD, the incidence of cardiovascular events increased with the increase of dietary cholesterol intake, while the protective effects of statins in such patients disappeared.
Therefore, the combined use of statins with another lipid-lowering agent could improve the LDL-C control rate, reduce the risk of cardiovascular risks, and minimize the adverse effects of statins. The lipid-lowering agent ezetimibe (EZ) can selectively inhibit the activity of Niemann–Pick C1-like 1 (NPC1L1) to reduce the intake of cholesterol by the intestinal tract, and thus decrease the plasma cholesterol levels and liver cholesterol deposits.7–9) In addition, EZ can also improve insulin resistance, and thus allow the patients with metabolic syndrome and type 2 diabetes mellitus (T2DM) to achieve additional beneficial effects from statins.7–9)
To date, some clinical studies have shown that the combined use of EZ and statins could help increasing the efficacy and safety of treating CHD.10) For instance, the Study of Heart and Renal Protection (SHARP) study11) showed that using 20 mg simvastatin + 10 mg EZ could significantly reduce LDL-C levels, while the incidence of major atherosclerotic events (including cardiac death, MI, and non-hemorrhagic stroke) was 17% lower than in the single-drug treatment group. These findings demonstrated that the reduction of the incidence of the major vascular events and major atherosclerotic events could be attributed to the enhancement of EZ on statins in reducing LDL-C levels.12) The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) study13) used EZ and simvastatin in combination, and found that the risk of cardiovascular mortality, non-lethal MI, and non-lethal stroke was 10% lower than when using simvastatin alone, but the combined use of EZ did not reduce the all-cause mortality of the patients. The Plaque REgression with Cholesterol absorption Inhibitor or Synthesis inhibitor Evaluated by IntraVascular UltraSound (PRECISE-IVUS) study14) showed that the combined use of atorvastatin and EZ could more effectively reverse coronary artery plaques when treating ACS or stable CHD.
Nevertheless, combined lipid-lowing treatments is also controversial. Indeed, Kastelein et al.15) showed in the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) study that although the combined use of EZ and simvastatin could greatly reduce LDL-C levels, the difference in the carotid intima-media thickness (cIMT) was not statistically significant between the combined and single medication groups after the 24-month follow-up. The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study16) also showed that the combined use of simvastatin and EZ could not reduce the progression of aortic stenosis. Furthermore, the current international guidelines recommend that for individuals with extremely high risk of cardiovascular events, statins should be used as the preferred drugs to reduce LDL-C levels to <70 mg/dL or by >50% of the baseline levels; if this target is not achieved, EZ can be used in combination.17) For patients with two extremely high risk factors, i.e., ACS and T2DM,1) combined drug therapy could be started upfront instead of after LDL-C levels failed to be reduced to the target, which implies delays in reaching optimal LDL-C levels.
Therefore, due to insufficient evidence and to controversies, the present study aimed to investigate the efficacy and safety of combined use of EZ and atorvastatin for the treatment of patients with T2DM and ACS.
This was a non-randomized cohort study of 95 consecutive, treatment-naïve patients with T2DM and ACS (acute ST-segment elevation myocardial infarction [STEMI], acute non-ST-segment elevation myocardial infarction [NSTEMI], and UAP) treated at the Department of Gerontology, Quanzhou First Hospital of Fujian Province between February 2014 and March 2016.
The patients were informed by the physicians of the advantages and disadvantages of the two treatment strategies. The clinicians informed the patients of their condition (with prognosis, risk of cardiovascular event, etc.), of the study objective, and of the economic expenditure associated with the two options. They were invited to carefully weigh the costs against the risk of cardiovascular event. They were invited to discuss this balance with the physician. Thereafter, the patients were free to decide whether they wanted to participate or not.
The inclusion criteria were: 1) met the diagnostic criteria of T2DM and ACS; and 2) did not receive statins or any other lipids-modulating drugs in the past 15 d. The exclusion criteria were: 1) allergy to statins or EZ; 2) active liver diseases, or liver dysfunction (ALT or aspartate aminotransferase (AST) level >1.5-folds the upper limits of normal [ULN]) (because atorvastatin can aggravate liver damage); 3) hypothyroidism (because atorvastatin can increase the risk of rhabdomyolysis in this condition); 4) history of alcohol or drug abuse (because it can lead to liver damage); 5) homozygous familial hypercholesterolemia or familial dyslipoproteinemia (because of extremely high LDL-C levels that may be refractory to treatment, which would bias the results); 6) myalgia or myasthenia of unknown cause, or creatine kinase (CK) level >1.5-fold of ULN (because atorvastatin can aggravate muscle damage); or 7) rheumatic immunologic diseases or tumors (because treatments for these conditions can affect blood lipids and bias the results).
Hence, 103 patients were recruited based on the inclusion criteria, among which 49 chose statins alone and 54 chose statins + EZ group. In the atorvastatin group, one patient was excluded for hypothyroidism, one for alcohol abuse, and one for using anti-tumor drugs. In the atorvastatin + EZ group, two patients were excluded for AST > 1.5 folds of ULN, one for using glucocorticoids to treat systemic lupus erythematosus, one for alcohol abuse, and one for using anti-tumor drugs. Finally, 46 patients in the atorvastatin group and 49 in the atorvastatin + EZ group were included in the final analysis.
This study was approved by the Ethics Committee of the Quanzhou First Hospital of Fujian Province. Each patient provided a written informed consent.
TreatmentsAll patients received nitrate esters, aspirin, clopidogrel, low molecular heparin, angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), β-receptor blocker, and oral blood glucose-lowering agents as routine treatments. Percutaneous coronary intervention (PCI) was also performed for the patients with corresponding indications.
For the patients in the atorvastatin group, oral atorvastatin (Pfizer; Lipitor™, 20 mg qn) was used. For the patients in the atorvastatin + EZ group, oral atorvastatin (Pfizer; Lipitor™, 20 mg qn) was used in combination with EZ (Merck; trade name: Zetia™, 10 mg qn) for treatment. All patients were treated for 12 months. The patients were followed up at 2 weeks and 12 months. The last follow-up of the last patient was on March 13, 2017. Compliance was assessed by patient inquiry.
Primary and Secondary EndpointsPrimary EndpointsThe primary endpoints were: incidence of adverse cardiovascular events (including sudden cardiac death, non-lethal MI, stroke, and hospitalization for angina pectoris), and changes of blood lipid (total cholesterol (CH), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and LDL-C) and of high-sensitivity C-reactive protein (hs-CRP).
Secondary EndpointsThe secondary endpoints included the changes of liver function (ALT), renal function (creatinine (Cr)), CK, creatine kinase isoenzyme (CK-MB), troponin I (TnI), fasting blood glucose (FBG), 2-h postprandial blood glucose (PBG), and glycosylated hemoglobin (HbA1c).
Safety AssessmentThe adverse effects including gastrointestinal reactions, weakness, myalgia, and skin rash at 2 weeks and 12 months. Increase of ALT and AST to >3-fold of ULN as well as the increase of CK >10-fold of ULN were recorded. The indications for ending the treatment were: 1) intolerable adverse effects; 2) CK levels increased >3-fold of ULN; or 3) developed severe liver damages, with ALT, AST, or bilirubin levels increased to >3-fold of ULN. Full biochemistry analyses and hs-CRP were measured by the wet-biochemical method with a fully automatic biochemical analyzer (AU5800, Beckman Coulter, Brea, CA, U.S.A.), using the Beckman Coulter reagents. TnI was measured by chemiluminescence assay (ARCHITECT; Abbott Laboratories, Abbott Park, IL, U.S.A.) using the reagents from Abbott. HbA1c levels were measured by HPLC (HLC-723GB; Tosoh, Tokyo, Japan) using the reagents from Tosoh.
Statistical AnalysisSince this was a non-randomized study, no sample size calculation was carried out before the study and the patients were recruited over a defined period of time. Based on the occurrence of cardiovascular events in the present study, a post hoc power analysis (StatMate 2.0, GraphPad Software Inc., San Diego, CA, U.S.A.) showed that using 46 and 49 patients had a >95% power in detecting a change of about 15% in the rates of events between the two groups.
The Kolmogorov–Smirnov test was used to confirm the normal distribution of continuous variables. Normally distributed continuous data were presented as means ± standard deviation (S.D.) and analyzed using the paired or unpaired Student’s t-test, as appropriate. Categorical variables were presented as proportions and analyzed using the chi-square or the Fisher’s exact test, as appropriate. Two-sided p-values <0.05 were considered statistically significant. All analyses were performed using SPSS 13.0 (SPSS Inc., Chicago, IL, U.S.A.).
Figure 1 presents the patient flowchart. Table 1 presents the baseline characteristics of the patients. Both groups were similar for all variables.
| Atorvastatin (n = 46) | Atorvastatin + EZ (n = 49) | p | |
|---|---|---|---|
| Age (years) | 56.3 ± 5.9 | 55.8 ± 6.4 | 0.76 |
| Male, n (%) | 25 (54.3%) | 26 (53.06%) | 0.90 |
| Smoking history, n (%) | 20 (43.5%) | 23 (46.9%) | 0.24 |
| Hypertension, n (%) | 23 (50%) | 25 (51.0%) | 0.92 |
| LVEF (%) | 54.3 ± 6.8 | 54.0 ± 6.3 | 0.68 |
| STEMI, n (%) | 12 (26.1%) | 14 (28.6%) | 0.079 |
| NSTEMI, n (%) | 16 (34.8%) | 15 (30.6%) | 0.66 |
| UAP, n (%) | 18 (39.1%) | 20 (40.8%) | 0.87 |
| PCI n (%) | 31 (67.4%) | 30 (61.2%) | 0.53 |
| ALT (U/L) | 23 ± 11 | 25 ± 6 | 0.66 |
| Cr (mmol/L) | 81 ± 33 | 76 ± 24 | 0.59 |
| HbA1c (%) | 7.2 ± 1.2 | 7.3 ± 1.3 | 0.71 |
EZ: ezetimibe; LVEF: left ventricular ejection fraction; STEMI: ST-elevated myocardial infarction; NSTEMI: non-ST-elevated myocardial infarction; UAP: unstable angina pectoris; PCI: percutaneous coronary intervention; ALT: alanine transaminase; Cr: creatinine; HbA1c: glycated hemoglobin.
Compared with the baseline levels, the FBG, PBG, and HbA1c levels at 2 weeks and 12 months of treatment were not significantly different between the two groups (all p > 0.05) (Table 2).
| Baseline | 2 weeks | 12 months | ||
|---|---|---|---|---|
| FBG (mmol/L) | Atorvastatin | 7.09 ± 2.31 | 7.15 ± 3.01 | 7.18 ± 3.10 |
| Atorvastatin + EZ | 7.12 ± 2.36 | 7.03 ± 2.43 | 7.10 ± 2.68 | |
| p | 0.86 | 0.81 | 0.90 | |
| PBG (mmol/L) | Atorvastatin | 12.11 ± 3.52 | 11.94 ± 4.01 | 12.32 ± 3.96 |
| Atorvastatin + EZ | 11.96 ± 3.41 | 11.68 ± 3.69 | 11.99 ± 3.85 | |
| p | 0.82 | 0.91 | 0.83 | |
| HbA1c (%) | Atorvastatin | 7.2 ± 1.2 | 7.2 ± 1.4 | 7.2 ± 1.3 |
| Atorvastatin + EZ | 7.3 ± 1.3 | 7.3 ± 1.3 | 7.2 ± 1.3 | |
| p | 0.79 | 0.80 | 0.89 | |
EZ: ezetimibe; FBG: fasting blood glucose; PBG: postprandial blood glucose; HbA1c: glycated hemoglobin.
Serum TC, TG, LDL-C, and HDL-C levels were not significantly different between the two groups at baseline. At 2 weeks, serum TC, TG, and LDL-C levels in both groups were significantly lower than the baseline levels (p < 0.05), but without difference between the two groups (all p > 0.05). In addition, HDL-C levels did not change (p > 0.05). The HDL-C level was also not significantly different between the atorvastatin and atorvastatin + EZ groups (p > 0.05) (Table 3).
| Blood lipid levels | Baseline | 2 weeks | ||||
|---|---|---|---|---|---|---|
| Atorvastatin | Atorvastatin + EZ | p | Atorvastatin group | Atorvastatin + EZ | p | |
| TC (mmol/L) | 5.96 ± 1.24 | 5.82 ± 1.16 | 0.65 | 3.23 ± 1.11 | 3.19 ± 0.99 | 0.72 |
| TG (mmol/L) | 2.61 ± 0.62 | 2.46 ± 0.51 | 0.51 | 1.58 ± 0.56 | 1.49 ± 0.43 | 0.91 |
| LDL-C (mmol/L) | 3.86 ± 0.92 | 3.78 ± 0.79 | 0.58 | 2.19 ± 0.34 | 2.03 ± 0.29 | 0.69 |
| HDL-C (mmol/L) | 0.33 ± 0.09 | 0.34 ± 0.11 | 0.94 | 0.35 ± 0.09 | 0.36 ± 0.11 | 0.93 |
EZ: ezetimibe; TC: total cholesterol; TG: triglycerides; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol.
At 12 months, serum TC, TG, and LDL-C levels were significantly lower, and HDL-C levels were significantly higher in the atorvastatin + EZ group than in the atorvastatin group (all p < 0.05). In addition, all these indicators were significantly different from baseline (all p < 0.05) (Table 4).
| Blood lipid level | Baseline | 12 months | ||||
|---|---|---|---|---|---|---|
| Atorvastatin | Atorvastatin + EZ | p | Atorvastatin | Atorvastatin + EZ | p | |
| TC (mmol/L) | 5.66 ± 1.24 | 5.82 ± 1.16 | 0.65 | 3.02 ± 0.63 | 2.50 ± 0.52 | 0.05 |
| TG (mmol/L) | 2.61 ± 0.62 | 2.46 ± 0.51 | 0.51 | 1.52 ± 0.41 | 1.11 ± 0.28 | 0.05 |
| LDL-C (mmol/L) | 3.86 ± 0.92 | 3.78 ± 0.79 | 0.58 | 2.09 ± 0.29 | 1.43 ± 0.21 | 0.02 |
| HDL-C (mmol/L) | 0.33 ± 0.09 | 0.34 ± 0.11 | 0.94 | 0.91 ± 0.12 | 1.41 ± 0.13 | 0.03 |
EZ: ezetimibe; TC: total cholesterol; TG: triglycerides; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol.
According to the 2011 ESC/EAS Guidelines for the management of dyslipidemia, the optimal or relative reduction of LDL-C levels should be <1.8 mmol/L or >50% reduction. As shown in Fig. 2A, the LDL-C control rate at 2 weeks was not significantly different between the two groups (p = 0.70). On the other hand, the LDL-C control rate at 12 months was significantly higher in the atorvastatin + EZ group compared with the atorvastatin group (p = 0.006) (Fig. 2B).
At 2 weeks, the CK-MB, TnI, and hs-CRP levels in both groups were significantly lower than baseline levels (all p < 0.05). In addition, hs-CRP levels in the atorvastatin + EZ group were significantly lower than in the atorvastatin group (p < 0.05). CK-MB and TnI levels were not significantly different between the two groups (both p > 0.05) (Table 5).
| Baseline | 2 weeks | 12 months | ||
|---|---|---|---|---|
| TnI (µg/L) | Atorvastatin | 5.45 ± 2.69 | 1.22 ± 0.24 | 0.26 ± 0.06 |
| Atorvastatin + EZ | 6.11 ± 3.02 | 1.02 ± 0.16 | 0.21 ± 0.05 | |
| p | 0.76 | 0.68 | 0.73 | |
| CK-MB (U/L) | Atorvastatin | 103.5 ± 32.5 | 26.4 ± 5.7 | 24.5 ± 6.4 |
| Atorvastatin + EZ | 99.9 ± 41.2 | 29.6 ± 6.1 | 19.3 ± 3.5 | |
| p | 0.81 | 0.68 | 0.46 | |
| hs-CRP (mg/L) | Atorvastatin | 193 ± 40 | 29 ± 7 | 11 ± 3 |
| Atorvastatin + EZ | 186 ± 43 | 8 ± 4 | 9 ± 3 | |
| p | 0.83 | 0.02 | 0.25 | |
TnI: troponin I; CK-MB: creatinine kinase MB; hs-CRP: high-sensitivity C-reactive protein; EZ: ezetimibe.
At 12 months, the CK-MB, TnI, and hs-CRP levels in both groups were significantly lower than baseline levels (all p < 0.05). In addition, the levels of these indicators were all slightly higher in the atorvastatin group than in the atorvastatin + EZ group, but the differences were not statistically significant (all p > 0.05) (Table 5).
Cardiovascular EventsNo MI or cardiovascular death events were found during treatment and follow-up. Seven patients in the atorvastatin group were re-hospitalized for angina pectoris, while only one patient in the atorvastatin + EZ group was re-hospitalized for angina pectoris (p = 0.02) (Table 6).
| Group | n | Recurrent angina pectoris | Non-lethal MI | Stroke | Sudden cardiac death | p |
|---|---|---|---|---|---|---|
| Atorvastatin | 46 | 7 (15.2%) | 1 (2.2%) | 0 | 0 | 0.02 |
| Atorvastatin + EZ | 49 | 1 (2.0%) | 0 | 0 | 0 |
EZ: ezetimibe; MI: myocardial infarction.
The CK levels at 2 weeks in both groups were significantly lower than the baseline values (p < 0.05), without difference between the two groups (p > 0.05). The CK levels at 12 months in both group were also significantly lower than the baseline values (p < 0.05), and the levels in the atorvastatin group were significantly higher than in the atorvastatin + EZ group (p < 0.05). ALT and Cr in both groups during treatment were not significantly different from baseline (p > 0.05), without difference between the two groups (all p > 0.05) (Table 7).
| Group | n | ALT (U/L) | Cr (µmol/L) | CK (U/L) | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Baseline | 2 weeks | 12 months | Baseline | 2 weeks | 12 months | Baseline | 2 weeks | 12 months | ||
| Atorvastatin | 46 | 23 ± 8 | 26 ± 14 | 27 ± 15 | 81 ± 33 | 80 ± 34 | 86 ± 32 | 516 ± 93 | 102 ± 35 | 181 ± 47 |
| Atorvastatin + EZ | 49 | 25 ± 9 | 25 ± 15 | 26 ± 14 | 76 ± 23 | 82 ± 30 | 79 ± 29 | 523 ± 89 | 98 ± 26 | 98 ± 26 |
| p | 0.82 | 0.88 | 0.9 | 0.61 | 0.69 | 0.56 | 0.91 | 0.85 | 0.03 | |
EZ: ezetimibe; ALT: alanine transaminase; Cr: creatinine; CK: creatine kinase.
Patients with T2DM and hyperlipidemia are with high risk of MI or coronary death events. The combined use of EZ and atorvastatin could improve treatment efficacy and safety, but this approach is still controversial. Therefore, the aim of the present study was to explore the efficacy and safety of EZ in combination with atorvastatin for the treatment of patients with T2DM and ACS. The results showed that the efficacy of atorvastatin + EZE in treating T2DM patients accompanied with ACS was significantly higher than using atorvastatin alone. This combined strategy has good safety profile, and could be recommended for clinical application. These results are supported by previous studies in Chinese populations.18–20)
Studies have demonstrated that the coronary artery lesions in patients with ACS and T2DM are more severe than those in patients without T2DM, leading to poorer prognosis.21) Therefore, aggressive lipid-lowering treatment is recommended for patients with T2DM to control their LDL-C levels. According to the 2016 guidelines from the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS), the primary treatment target of LDL-C <1.8 mmol/L and secondary targets of non-HDL-C <2.6 mmol/L and apoB <80 mg/dL should be aimed at for: 1) patients with T2DM with coronary heart disease or chronic renal disease; 2) patients with T2DM, >40 years of age, without cardiovascular disease but with at least one cardiivascular risk factor; or 3) patients with T2DM and evidence of target organ damage.17) The current international guidelines recommend that for individuals with extremely high risk of cardiovascular events, statins should be used first to reduce LDL-C levels, followed by the addition of EZ in case of failure to reach the targets.17) The novelty of the present study is that for patients with two extremely high risk factors, i.e., ACS and T2DM,1) combined drug therapy could be started upfront instead of after LDL-C levels failed to be reduced to the target. Therefore, this approach could avoid delays in reaching optimal LDL-C levels.
Indeed, studies have demonstrated that using high dose of statins could help reversing ACS and coronary plaques in patients with CHD, as well as improving their prognosis,22,23) but LDL-C levels in many patients are still higher than the target levels despite using relatively high doses of statins, leading to an increased risk of adverse effects such as myositis and liver damages, as well as inducing T2DM.22,23) EZ is a selective cholesterol absorption inhibitor,24) and thus potentially inhibiting the absorption of bile and food cholesterol by intestinal epithelial cells. As EZ is not metabolized by the CYP450 enzymes, there are no interactions between EZ and statins. EZ can induce a compensatory increase of liver cholesterol synthesis, limiting its effect on LDL-C levels when used alone. Therefore, EZ inhibits cholesterol absorption, and statins inhibits cholesterol synthesis, complementarily affecting the metabolism of endogenous and exogenous cholesterol, inhibiting cholesterol absorption and synthesis, and synergetically exerting their lipid-lowering effects.25)
In this study, TC, LDL-C, and TG levels in both groups were lower after lipid-lowering treatment compared with baseline. In addition, the HDL-C levels tended to increase. These results are supported by previous studies in Chinese populations.18–20) These findings suggest that the combined use of EZ plus atorvastatin resulted in higher lipid-lowering effects than using atorvastatin alone. This could be associated with the restriction of the “cholesterol escape” observed when using statins alone.26,27) The blood glucose indicators in the two groups were not significantly changed in this study. No blood glucose increase induced by atorvastatin was found, which could be associated with the use of a routine dose and the relatively short treatment time. The findings of this study showed that after 12 months of treatment, the incidence of liver damage, renal damage, and muscle damage in the atorvastatin + EZ group was not higher than in the atorvastatin group, suggesting that the combined use of EZ did not increase the incidence of statin-related adverse effects. Nevertheless, additional trials with longer study periods are still needed to further investigate the adverse effects of the combined treatment. The SEAS study28) reported that the incidence of cancer was higher in the simvastatin + EZ group compared with the placebo group. In the SHARP study, the safety indicators such as incidence of tumor, myopathy, hepatitis, persistent ALT/AST > 3 ULN, hospitalization or complications related to cholelithiasis, and incidence of pancreatitis, were not significantly different between the treatment and placebo groups.
In the present study, EZ was well tolerated by all patients, but, the follow-up was relatively short and the sample size was relatively small. In our future study, the incidence of adverse effects will be observed in larger sample size and longer follow-up. The CK-MB, TnI, and hs-CRP levels at 12-months of the treatment were all slightly higher in the atorvastatin group than in the atorvastatin + EZ group, but the differences were not statistically significant (p > 0.05). This could be associated with the small sample size and relatively short study time. In contrast, the CK levels in the atorvastatin group was significantly higher than in the atorvastatin + EZ group (p < 0.05), which could be associated with several factors, such as recurrent angina pectoris.
The hs-CRP levels at 2 weeks were lower than at baseline in both groups. In addition, the hs-CRP levels were also lower in the atorvastatin + EZ group than in the atorvastatin group, suggesting that the combined use of atorvastatin + EZ could help rapidly reducing lipid levels and inhibiting inflammatory responses.29,30)
The CK-MB, TnI, and CK levels, as well as the incidence of adverse cardiovascular events were significantly reduced by atorvastatin + EZ compared with atorvastatin alone. Considering that the beneficial effects could be following the combined lipid-lowering treatments, the further decrease of LDL-C could help stabilizing the lipid plagues in the atherosclerotic lesions. In addition, the systemic modulatory effects of EZ on the blood lipid profile of the patients could also exert effective inhibitory effects on the progression of coronary atherosclerosis.
The present study is not without limitations. This study was single-center and with a relatively small sample size and short study time. This was a non-randomized study as the patients were free to select their treatment based on the physician's counseling and their own financial status, inevitably leading to bias. Compliance was assessed by the clinicians using patient-reported information. In China, patients with T2DM can receive compensations from the government for taking drug therapies and undergoing the appropriate examinations in a timely manner, but they are required to visit the hospital and consult specialists. The findings about the efficacy and safety of the combined lipid-lowering treatment strategy are yet to be further verified in more multi-center studies with larger sample sizes and longer follow up time.
In conclusion, compared with atorvastatin treatment, the combined atorvastatin + EZ treatment for patients with T2DM and ACS could more effectively reduce LDL-C levels, increase LDL-C control rate, decrease the incidence of adverse cardiac events compared to atorvastatin alone. In addition, this combined treatment strategy had a good safety profile.
The authors declare no conflict of interest
