The DYS Lipidemia International Study China (DYSIS-China) in 2012 based on the data from 122 hospitals covering 22 counties found that most patients receiving lipid-lowering therapy in China were at high or very high risk of atherosclerotic cardiovascular diseases (1, 2). Over the last 10 years, blood lipid control in China has substantially improved and the overall low-density lipoprotein-cholesterol (LDL-C) control rate increased from 8.9% in 2007 to 61.5% in 2012 (3, 4); however, the control of blood lipids in very high-risk patients is still poor. Most patients use statin monotherapy, since statin is the first-line therapy for lipid-lowering (5, 6). However, the average difference between LDL-C levels after treatment and target LDL-C levels in high-risk/extremely high-risk patients is still >30 mg/dl (0.777 mmol/l), indicating the lack of efficiency of statin monotherapy (7). Notably, patients using moderate-intensity statins had the highest LDL-C and non-high-density lipoprotein-cholesterol (non-HDL-C) compliance rates, while the use of high-intensity statin had the lowest LDL-C compliance rate. This is consistent with the conclusion of the Intensive Lipid-lowering Intervention Study for Patients with Acute Coronary Syndrome in China (CHILLAS): high-intensity statin does not enable Chinese patients to obtain additional lipid-lowering benefits, and moderate-intensity statin lipid-lowering therapy is suitable for Chinese patients (8, 9). Moreover, for Chinese patients, especially those at high or extremely high risk, combined lipid-lowering therapy might be a new beneficial option.

Hybutimibe, a new cholesterol-absorption inhibitor, exhibits a mechanism of action similar to that of ezetimibe to decrease lipids (10–12). Briefly, hybutimibe inhibits the absorption of cholesterol from food and bile acid, reduces the transport of cholesterol in the small intestine to the liver, limits the storage of cholesterol in the liver, and increases the clearance of cholesterol from the blood (11, 12). Hybutimibe is a new selective cholesterol-absorption inhibitor approved in China. In terms of its difference from ezetimibe, the hydroxyl group in its structure makes binding to glucuronic acid easier, which improves the rate of conversion in the form of glucuronidation (12, 13). Additionally, the overall clearance rate of metabolites of hybutimibe is higher, and the liver burden of patients was reported to be greatly reduced (13, 14). Hybutimibe has completed phase I and II studies in the U.S. and China. The results of the Chinese phase II study showed that, after 8 weeks of treatment, compared with placebo, hybutimibe significantly reduced LDL-C levels and was well-tolerated, whereas its efficacy was comparable with that of ezetimibe (11, 13).

To further evaluate the safety and efficacy of hybutimibe, a randomized, double-blind, multicenter phase III study was designed in hypercholesterolemia patients with atherosclerotic cardiovascular disease and/or “equal-risk diseases” who had not achieved the target blood LDL-C level after being treated with 10 mg of atorvastatin for at least 6 weeks.

From April 2016 to January 2018, a total of 736 patients were screened from 23 centers in China, among whom 377 cases were excluded according to the inclusion and exclusion criteria, 1 case withdrew informed consent, 9 cases were lost to follow-up, 82 withdrew from the trial, and 12 had poor compliance. Thus, finally 255 patients were enrolled in this study: 128 in the hybutimibe plus atorvastatin treatment group and 125 in the atorvastatin treatment group (Figure 2). Among these 255 patients, 2 who did not use the study drugs in the atorvastatin treatment group were excluded from mITT analysis.

A total of 62.06% of the patients were men, while 70.36% had coronary heart disease, 20.16% had suffered stroke, and 46.25% had diabetes. TC, TG, HDL-C, LDL-C, Apo-A1, and Apo B levels at baseline were comparable in the hybutimibe plus atorvastatin and atorvastatin treatment groups (Table 1).

After 12 weeks of treatment, the LDL-C levels changed from 2.61 mmol/L (±0.30) at baseline to 2.18 mmol/L (±0.45) in the hybutimibe plus atorvastatin group and from 2.58 (±0.31) to 2.40 (±0.46) mmol/L in the atorvastatin group (P < 0.0001), in mITT analysis (Table 2). The rate of change in the hybutimibe plus atorvastatin treatment group was significantly higher than that in the atorvastatin treatment group (P < 0.0001); the estimated mean rates of change were −16.39 (95% CI: −19.04, −13.74) and −6.75 (−9.48, −4.02), respectively. We further adjusted for LDL-C level at baseline or LDL-C at baseline, age, and body mass index (BMI), obtaining consistent results (all P < 0.0001). Consistent with this, for PPS analysis, the LDL-C levels were significantly improved for both groups after treatment (all P < 0.0001), and the rate of change in the hybutimibe plus atorvastatin treatment group was significantly higher than that in the atorvastatin treatment group, even after adjusting for LDL-C level at baseline or LDL-C at baseline, age, and BMI (range of P-values: 0.0002–0.0007).

The rates of change of LDL-C in subgroup analyses stratified by age, sex, history of stroke, and history of diabetes showed a consistent improvement upon treatment with hybutimibe plus atorvastatin, compared with the status upon atorvastatin treatment (Table 3). However, in patients without coronary heart disease, the rate of change of LDL-C was improved upon treatment with hybutimibe plus atorvastatin [−13.14 (95% CI: −18.69, −7.59) vs. −5.87 (95% CI: −12.20, 0.46)], but this was not statistically significant (P = 0.0835).

Regarding the secondary outcomes, we found significant decreases of the rates of change of non-HDL-C (−16.49 ± 13.43 vs. −7.52 ± 13.59%, −16.26 ± 15.82 vs. −8.91 ± 13.51%, −17.45 ± 14.38 vs. −9.17 ± 14.82%, −15.30 ± 17.84 vs. −7.36 ± 15.74%), TC (−12.06 ± 9.57 vs. −5.77 ± 10.12%, −11.67 ± 10.89 vs. −6.96 ± 9.73%, −12.90 ± 10.84 vs. −7.11 ± 11.38%, −11.18 ± 12.67 vs. −5.66 ± 12.29%), and Apo B (−11.88 ± 12.80 vs. −7.07 ± 11.15%, −11.91 ± 12.04 vs. −8.46 ± 11.00%, −12.12 ± 14.25 vs. −8.31 ± 10.33%, −11.05 ± 13.15 vs. −6.46 ± 11.67%) at 2, 4, 8, and 12 weeks (all P < 0.05), but non-significant differences were observed for HDL-C, TG, and Apo-A1 (all P > 0.05; Figures 3A–G).

During the study period, a total of 65 of 128 patients in the hybutimibe plus atorvastatin group and 77 of 125 patients in the atorvastatin group occurred adverse events (AEs; Table 4). The primary AEs were upper respiratory tract infection, dizziness, and abdominal discomfort. AEs with an incidence of ≥5% included upper respiratory tract infection [16 (12.60%) vs. 19 (15.20%)], dizziness [7 (5.51%) vs. 5 (4.00%)], and abdominal discomfort [8 (6.30%) vs. 4 (3.20%)]. Among them, 17 vs. 18 were drug-related AEs, and 3 vs. 6 were drug-related AEs leading to suspension of the trial, 8 vs. 9 were serious AEs, 6 vs. 12 were AEs leading to suspension of the trial, 0 vs. 1 were serious AEs related to the study drugs, and there were no AEs or drug-related AEs leading to death.

We applied a sensitivity analysis included the patients from the First Affiliated Hospital of Hebei Medical University and a consistent main result was concluded. For mITT (5 in treatment and 3 in control group), after 12-week treatment, the change rate of LDL-C from baseline was −17.64 ± 12.87% in treatment group, while it was −7.51± 14.62% in control group, and the difference between two groups was statistically significant (P < 0.0001). The difference between two groups was −10.13% (95% CI: −13.60%, −6.67%). For PPS (5 in treatment and 2 in control group), similar results were found in PPS. After 12-week therapy, LDL-C change rate from baseline was −18.92 ± 12.67% in treatment group, and it was −9.57 ± 13.41% in control group, also the between group difference was −9.35% (95%CI: −13.14%, −5.57%, P < 0.0001).

This randomized, double-blind, paralleled, multicenter phase III study found that hybutimibe plus atorvastatin significantly improved the LDL-C level in hypercholesterolemia patients with atherosclerotic cardiovascular disease and/or “equal-risk diseases” after 12 weeks of treatment, with a mean rate of change of −16.39, compared with atorvastatin monotherapy, for which the mean rate of change was −6.75. Additionally, hybutimibe plus atorvastatin significantly improved non-HDL-C, TC, and Apo B, but had non-significant effects on HDL-C, TG, and ApoA1 levels. The subgroup and sensitivity analyses did not show any inconsistent results and the safety analysis showed that a well tolerability.

We showed that the combination of hybutimibe plus atorvastatin is associated with significant improvements in LDL-C (−16.39%), non-HDL-C (−15.30%), TC (−11.18%), and Apo B (−11.05%) levels in patients with atherosclerotic cardiovascular disease and risk equivalents, although clinical benefits on HDL-C, TG, and Apo-A1 were not observed compared with atorvastatin monotherapy. The efficacy of hybutimibe plus atorvastatin was noted, irrespective of previous therapy, age, and a history of coronary heart disease, stroke, or diabetes. A previous double-blind study included 628 patients with baseline LDL-C of 145–250 mg/dL (3.756–6.475 mmol/L) and triglycerides of ≤350 mg/dL (3.955 mmol/l) who were randomly assigned to receive one of the following for 12 weeks: ezetimibe (10 mg/d); atorvastatin (10, 20, 40, or 80 mg/d); ezetimibe (10 mg) plus atorvastatin (10, 20, 40, or 80 mg/d); or placebo (16). This study found that the co-administration of ezetimibe provided a significant additional 12% reduction of LDL-C, 3% increase of HDL-C, 8% reduction of triglyceride, and 10% reduction of high sensitivity C-reactive protein vs. atorvastatin alone (16). Ezetimibe plus atorvastatin provided LDL-C reductions of 50–60%, TC reductions of 30–40%, and HDL-C increases of 5–9%, depending on the dose of atorvastatin. Although we did not make a head-to-head comparison of ezetimibe and hybutimibe in this study, we applied several comparisons in pharmacokinetic and efficacy since these two drugs share a similar mechanism in lowering lipids. Compared with ezetimibe, hybutimibe showed a smaller effect on LDL-C reduction, however, the treatment duration of this study was only 12 weeks, and our study included the patients with a wide age range of 18–75 years, thus it is difficult to identify which one is more efficient. The chemical construction changes in hybutimibe make it easier to bind to glucuronic acid, which led to more excretion of hybutimibe (15.6% of dose) than ezetimibe (11% of dose) in urine (11). Additionally, the peak time of hybutimibe is 0.5–12 h, while it is 4–12 h for ezetimibe, which means hybutimibe can quickly reach the treatment levels and play its drug efficacy faster in human body (12). As we know, these current studies are large different in study design, such as inclusion and exclusion criteria of participants, treatment duration and dosage, sample size, and ethnicity difference in participants, which result in substantially differences in lipid-lowering effects, thus the comparison across the studies should be more cautiously. Taken all these together, hybutimibe might be a potential efficacy drug for lipid lowering, although its efficacy and safety warrant further large scaled and long-duration study to verify.

It has been reported that using ezetimibe together with atorvastatin can increase the risk of side effects such as liver damage and a rare but serious condition called rhabdomyolysis, which involves the breakdown of skeletal muscle tissue (9, 17). In some cases, rhabdomyolysis can cause kidney damage (18) and even death (19, 20). Rhabdomyolysis was not observed in either group in the present study, although five patients in the combination therapy group and seven in the monotherapy group reported elevated creatinine kinase (CK) levels. Five AEs in the monotherapy group and only two in the combination therapy group were related to the study drugs. Only two cases in the combined treatment group reported a lack of elevation of CK levels to ≥10 times the upper limit of the normal range. In summary, our phase III study suggested that the combination of hybutimibe and atorvastatin does not cause additional side effects and has acceptable safety and tolerability. Since this study was only performed for a short period, had a small sample size, and only included Chinese patients, there is a need for further assessment of long-term and rare side effects, especially regarding the interactions with food and drugs.

All patients included in this study had combination with atherosclerotic cardiovascular disease and or “equal-risk diseases,” and also did not achieve the target blood LDL-C level after treatment with 10 mg of atorvastatin for at least 6 weeks. These patients are generally at high or very high risk of atherosclerotic cardiovascular diseases (1). As we know, whether identifying the high and very-high-risk atherosclerotic cardiovascular disease patients is disputable (21). In a clinical context, the identification of high-risk patients is important in order to match patients with particular treatment intensities. Although evidence reported that long-term and high-intensity statin treatment might introduce a series of side effects, such as neurological effects, gastrointestinal hemorrhage, muscle pain and damage, liver damage, increased blood glucose, and a risk of type 2 diabetes (22), Statins are the most thoroughly studied and time-tested treatment for cardiovascular prevention and treatment and are very well-tolerated by the vast majority of users, with rates of serious complications that are exceeding rare (23). A study including 27,775 patients found that the “very high-risk” patients defined in accordance with the 2018 AHA/ACC/Multisociety guidelines had nearly three times higher risk of developing future ASCVD events than those without a very high risk (24). This study suggested that it is important to identify populations with a very high risk of atherosclerotic cardiovascular diseases and that these patients should undergo intensive lipid-lowering therapy (1).

A possible limitation of this study is that the sample size was small, reducing the statistical power in several subgroup analyses and when exploring the heterogeneity of hybutimibe plus atorvastatin combination therapy for lipid control. In addition, all patients in this study were Chinese, so care should be taken when extrapolating the current conclusion to other populations. Moreover, the efficacy and safety in other ethnic groups need further evaluation. We used the mITT to evaluate the primary outcome which is slightly different from the ITT analysis, because we considered 2 patients without use any study drugs. Finally, this was a short-term follow-up study, so a study with a large sample size is needed to confirm the longer-term efficacy and safety, especially for atherosclerotic cardiovascular outcomes.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Ethics Committee of the First Hospital of Peking University [No. (2015) Drug Registration No. (56)]. The patients/participants provided their written informed consent to participate in this study.

LQ: conceptualization. JC, XL, XQ, and CD: data collection. XC, XGu, WX, and SZ: statistical analysis. YD, MZ, KH, and LT: data interpretation and supervision. XGuo, FW, GF, and JL: visualization and project administration. YH: writing and editing of the manuscript. All authors have read and approved the final manuscript.

This study was supported by National science and technology major projects-new drugs creation and development [Grant Number 2013ZX09402101].

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.