Randomized study of evolocumab in patients with type 2 diabetes and dyslipidaemia on background statin: Pre‐specified analysis of the Chinese population from the BERSON clinical trial

Aim The aim of this study was to evaluate the efficacy and safety of evolocumab with background atorvastatin in Chinese patients with type 2 diabetes mellitus (T2DM) and hyperlipidaemia or mixed dyslipidaemia. Materials and methods This is a pre‐specified analysis of patients in the BERSON study (ClinicalTrials.gov, NCT02662569) in China. Patients initiated background atorvastatin 20 mg/d, after which they were randomized 2:2:1:1 to evolocumab 140 mg every 2 weeks (Q2W) or 420 mg monthly (QM) or to placebo Q2W or QM. Co‐primary endpoints were percentage change in LDL cholesterol (LDL‐C) from baseline to week 12 and from baseline to the mean of weeks 10 and 12. Additional endpoints included atherogenic lipids, glycaemic measures and adverse events (AEs). Results Among 453 patients randomized in China, 451 received at least one dose of study drug (evolocumab or placebo). Evolocumab significantly reduced LDL‐C compared with placebo at week 12 (Q2W, −85.0%; QM, −74.8%) and at the mean of weeks 10 and 12 (Q2W, −80.4%; QM, −81.0%) (adjusted P < 0.0001 for all) when administered with background atorvastatin. Non‐HDL‐C, ApoB100, total cholesterol, Lp(a), triglycerides, HDL‐C and VLDL‐C significantly improved with evolocumab vs placebo. No new safety findings were observed with evolocumab. The incidence of diabetes AEs was higher with evolocumab compared with placebo. There were no differences over time between evolocumab and placebo in measures of glycaemic control. Conclusions In patients in China with T2DM and hyperlipidaemia or mixed dyslipidaemia receiving background atorvastatin, evolocumab significantly reduced LDL‐C and other atherogenic lipids, was well tolerated, and had no notable impact on glycaemic measures.


| INTRODUCTION
China carries the highest diabetes burden of any country worldwide, 1 with an estimated prevalence of 10.9% in 2013. 2 Consistent with observations in Western populations, diabetes is a major risk factor for developing cardiovascular disease (CVD) in Chinese adults. 3 Furthermore, as is the case globally, Chinese patients with type 2 diabetes mellitus (T2DM) have an increased risk of cardiovascular events, including cardiovascular death, myocardial infarction, hypertension and stroke. [4][5][6][7] Low-density lipoprotein cholesterol (LDL-C) is the primary target in the treatment of dyslipidaemia in patients with T2DM, [8][9][10][11] as elevated LDL-C has been associated with increased risk of CVD and cardiovascular events. [12][13][14] Chinese guidelines for the treatment of dyslipidaemia in high-risk patients with T2DM recommend statinbased therapy for maintaining LDL-C below 1.8 mmol/L. 11 Despite the availability of statin therapy in China and Southeast Asia, attainment of recommended LDL-C levels has been suboptimal, with 60% to 72% of patients with T2DM in community clinics or hospitals failing to achieve recommended LDL-C levels. [15][16][17][18] Observational, pharmacological and pharmacogenetic studies suggest that statin-related adverse reactions occur at higher rates among Chinese patients than would be observed in a global population. 19 Suboptimal reduction in LDL-C among Chinese patients may, therefore, be driven by intolerance to high-potency high-dose statin treatment, and under-utilization may be driven by statin-related adverse reactions. 19,20 Consequently, there is an urgent unmet need for novel lipid-lowering therapies for addition to the maximally-tolerated statin dose in China.
Analyses from phase 2 and 3 clinical trials have consistently shown that evolocumab, a human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduces LDL-C without adversely affecting objective measures of glycaemic control in patients with or without diabetes. [21][22][23][24][25] In the global, randomized, double-blind, 12-week phase 3 BERSON study (N = 986), in which approximately half of the patients with T2DM and hyperlipidaemia or mixed dyslipidaemia were enrolled from Chinese centres, efficacy results from the global population showed that evolocumab significantly reduced LDL-C and improved other lipid levels compared with placebo when administered in combination with background atorvastatin. 26,27 In the global population, evolocumab was safe and well tolerated, with no notable changes in glycaemic measures throughout the study. This prespecified analysis of the BERSON study was designed to investigate the efficacy and safety of evolocumab combined with background atorvastatin in patients at Chinese centres.
Briefly, patients were between 18 and 80 years of age, had been diagnosed with T2DM, were receiving stable pharmacological therapy for diabetes for at least 6 months, had HbAIc of 10% or less and fasting triglyceride levels of 4.5 mmol/L or less (≤400 mg/dL). Patients undergoing statin therapy at screening were obliged to have LDL-C of at least 2.6 mmol/L (≥100 mg/dL); those not undergoing statin therapy at screening were obliged to have LDL-C of at least 3.4 mmol/L (≥130 mg/dL). It was required that the lipid-lowering therapy status of patients remained unchanged for at least four weeks before LDL-C screening. The study design and rationale, as well as full inclusion and exclusion criteria, were described previously. 26,27 This prespecified analysis includes only patients who were randomized at centres in China. The study was conducted in accordance with the Guidelines on Good Clinical Practice and with the Ethical Standards for Human Experimentation established by the Declaration of Helsinki. An independent review board or independent ethics committee at each study site reviewed the study and approved the protocol and subsequent amendments to the study protocol. An external, independent data monitoring committee (DMC) periodically reviewed study data, and analyses for the DMC were provided by an independent biostatistical group. All patients provided informed consent before participation.
Because most Chinese patients cannot tolerate the high-intensity statin treatment recommended by the ACC/AHA, 8 atorvastatin 20 mg once daily (QD) was selected, based on Chinese dyslipidaemia guidelines and the expected LDL-C response in Chinese patients. [28][29][30] More recent guidelines in China are consistent with this approach. 11 At screening and at each subsequent visit, patients were instructed to maintain their diet, as well as any allowed therapy and exercise regimen. The last dose of evolocumab or placebo was given at week 8 for QM patients and at week 10 for Q2W patients. The final study visit was at week 12 for QM patients and a phone visit at week 14 for Q2W patients. Baseline covariates for subgroup analysis of coprimary efficacy endpoints included statin therapy at study entry (yes vs no), age, sex, race, baseline LDL-C, family history of premature coronary heart disease, baseline PCSK9, body mass index, hypertension, status as current smoker, ≥2 baseline CHD risk factors and triglycerides. Treatment assignment was blinded to the sponsor's study team, investigators, site staff and patients throughout the study and remained blinded until unblinding of the clinical database. This pre-specified analysis presents study results for all randomized patients enrolled at Chinese centres who received at least one one dose of study drug, that is, the China full analysis set (CFAS). The efficacy of evolocumab compared with placebo in the CFAS concerning the co-primary endpoints (percentage change from baseline in LDL-C at week 12 and the mean of weeks 10 and 12) and the continuous co-secondary endpoints was compared using repeated-measures linear mixed-effects models with terms for treatment group, a stratification factor (statin therapy at study entry [yes vs no]), scheduled visit and interaction of treatment with the scheduled visit. In the CFAS, each independent dose frequency (Q2W and QM) was allocated a significance level of 0.025 for the co-primary endpoints. 33 LDL-C target achievement was assessed using the Cochran-Mantel-Haenszel test, adjusted by existence of statin therapy at study entry (yes vs no).

| Study assessments
Safety assessments were summarized descriptively. As part of the China analyses, a subgroup analysis of co-primary endpoints was also performed for Chinese vs non-Chinese patients in FAS. Baseline characteristics for subgroup analysis of co-primary efficacy endpoints included existence of statin therapy at study entry, age, sex, baseline LDL-C, baseline PCSK9 level, body mass index, hypertension, current smoking status, baseline coronary heart disease risk factors and baseline triglycerides.

| Patients
The study was conducted from 14 April 2016 through 6 December 2017. The global study population is described by Lorenzatti et al. 26,27 Overall, 1261 patients were screened at centres in China, of whom  Mean baseline lipid values (SD) Non-HDL-C, mmol/L 2.9 (0.9) 3.0 (0.9)  (Table S1).
Changes from baseline in secondary lipid parameters are summarized in Table 2

| Safety
Among patients enrolled at Chinese centres, the incidence of AEs was greater in the overall evolocumab group than in the overall placebo group (57.6% vs 53.0%) ( Table 3)   F I G U R E 2 Mean percentage change in LDL-C from baseline to scheduled visits in LDL-C for Q2W dosing (A) and QM dosing (B). Vertical lines represent standard error around the mean. No imputation was used for missing values. When the calculated LDL-C was <1.0 mmol/L or triglycerides were > 4.5 mmol/L, calculated LDL-C was replaced with ultracentrifugation LDL-C from the same blood sample, if available at Chinese centres had significant reductions in LDL-C, by 75% to 85%, and in non-HDL-C, by 63% to 81%. Significant improvements in other atherogenic lipid parameters were also observed after 12 weeks of treatment with evolocumab. Furthermore, more than 90% of the Chinese patients who received evolocumab with background atorvastatin of moderate intensity were able to achieve LDL-C values below 1.8 mmol/L (95%-97% with evolocumab vs 24%-25% with placebo).
These results are noteworthy, considering that, in previous studies in Chinese and Southeast Asian community hospitals or clinics, the majority of patients with diabetes and CVD risk factors who received statins or other lipid-lowering therapies did not attain recommended levels of LDL-C. [15][16][17][18] While subgroup analysis of co-primary endpoints showed statistically significant differences in the magnitude of LDL-C reduction between Chinese and non-Chinese populations, treatment effects are directionally consistent, favouring evolocumab, in the two subgroups. Least-squares mean Lp(a) reduction with evolocumab, a co-secondary efficacy endpoint, was also greater in Chinese patients compared with the global population. These findings could not be explained by differences in adherence to the investigational product or to other lipid-lowering therapies, by LDL levels in the placebo groups or by differences in evolocumab pharmacokinetic exposure or serum PCSK9 levels; thus, further investigation may be warranted. Observations in the Chinese population are consistent with results reported in Japanese patients treated with evolocumab over 12 weeks, with least-squares mean LDL-C reductions ranging from 67% to 76%, compared with placebo, when combined with atorvastatin 20 mg daily, and LDL-C less than 1.8 mmol/L was achieved by 96% to 98% of patients. 34 The substantial reductions in LDL-C with evolocumab vs placebo among Chinese patients in the BERSON study are consistent with those observed in prior evolocumab global studies in patients with hypercholesterolaemia or mixed dyslipidaemia, 35 in patients with T2DM, 36 and in a meta-analysis and pooled analysis of data from 12-week phase 3 studies. 24,37 Prior analyses showed that the LDL-C treatment effect with evolocumab is maintained over time in patients with and without diabetes. 21,23 Our results are also consistent with those from a systematic review including 20 randomized controlled studies with PCSK9 inhibitors (alirocumab, bococizumab and evolocumab). 38 The ODYSSEY KT study, which assessed the efficacy and safety of the PCSK9 inhibitor alirocumab in 199 patients at high cardiovascular risk enrolled in South Korea and Taiwan, also showed statistically significant reductions in LDL-C. 39  Although this study was limited to a 12-week follow-up period, Occurring in at least 1% of patients in the evolocumab treatment group. b Includes preferred terms of diabetes mellitus (placebo, 2.0%; evolocumab, 5.6%) and type 2 diabetes mellitus (placebo, 0%; evolocumab, 1.7%).
c Patient was assigned to QM dosing, reported at week 8 visit, remained asymptomatic, and returned to baseline at week 12.