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A Paradigm Shift in Dyslipidemia Management in Primary Care: A 12-Month Cohort Study

Open AccessPublished:April 08, 2022DOI:https://doi.org/10.1016/j.clinthera.2022.03.004

      Abstract

      Purpose

      LDL-lowering therapy is beneficial to reduce the risk of cardiovascular disease (CVD). Higher statin doses lower LDL-C levels and prevent CVD; however, they increase adverse events, such as muscle-related adverse events and new-onset diabetes mellitus (DM). Ezetimibe combined with statin therapy improves LDL-C–lowering levels and tolerability in patients with established CVD. We aimed to analyze the efficacy and safety of a fixed-dose rosuvastatin and ezetimibe (R+E) combination therapy in intermediate-risk patients with hypercholesterolemia and no DM after 12 months of visiting a primary physician.

      Methods

      This multicenter, open-label, single-arm, prospective observational study involved 5717 patients from 258 primary health care centers in Korea enrolled between 2016 and 2018. Patients had no DM or previous CVD but had cardiovascular risk factors and were taking a statin or a fixed-dose combination of E (10 mg) + R (5, 10, or 20 mg). We analyzed 700 patients using propensity score matching.

      Findings

      A fixed-dose R+E combination therapy significantly reduced LDL-C in 5/10 mg R+E (29.35%), 10/10 mg R+E (36.19%), and 20/10 mg R+E (41.83%) compared with statin monotherapy (19.09%) at 12-month follow-up (P = 0.017). Compared with statin monotherapy, HDL-C levels increased in 5/10 mg R+E (mean change at 12 months; P = 0.004), and triglyceride levels decreased in 10/10 mg R+E (mean change at 12 months; P = 0.033). The fixed-dose R+E combination therapy was associated with fewer adverse events and a neutral effect on glucose deterioration compared with statin monotherapy at 12 months of follow-up.

      Implications

      In a possible paradigm shift, a fixed-dose R+E combination therapy may be beneficial for primary cardiovascular prevention with potent LDL-lowering efficacy and tolerability; however, further large prospective studies are needed.

      Keywords

      Introduction

      The prevalence of hypercholesterolemia (defined as a total cholesterol [TC] level ≥240 mg/dL or the use of lipid-lowering drugs) increased markedly from 8.8% in 2007 to 18.0% in 2018, according to the 2007-2018 Korea National Health and Nutrition Examination Survey and National Health Insurance Service data.
      Korea Centers for Disease Control and Prevention
      Korea Health Statistics 2018: Korea National Health and Nutrition Examination Survey (KNHANES Ⅶ-3).
      In 2018, 45.6% of men and 31.3% of women older than 20 years were diagnosed with dyslipidemia when defined as satisfying 1 of the following criteria: serum lowLDL-C level ≥160 mg/dL, serum HDL level <40 mg/dL, and serum triglyceride (TG) level ≥200 mg/dL. Considering cardiovascular risk factors, such as hypertension, smoking, and cardiovascular family history, the cutoff level of LDL to define dyslipidemia is lower and the prevalence of dyslipidemia may be considerably higher. Despite advances in dyslipidemia treatment modalities, its prevalence in Korea has continuously increased from 2010 to 2015.
      • Jeong J.S.
      • Kwon H.S.
      Prevalence and Clinical Characteristics of Dyslipidemia in Koreans.
      LDL-lowering therapy is essential for the secondary and primary prevention of cardiovascular disease (CVD). Statin therapy is the first choice for LDL-lowering treatment. Ezetimibe was approved by the US Food and Drug Administration in 2002 and is a new class of cholesterol-lowering agents that inhibit cholesterol absorption in the intestine.
      • Earl J.
      • Kirkpatrick P.
      Ezetimibe.
      Ezetimibe monotherapy lowers LDL-C by approximately 18%.
      • Dujovne C.A.
      • et al.
      Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia.
      However, greater cholesterol-lowering efficacy is achieved with coadministration of statins, with 21% to 30% additional LDL-C lowering efficacy compared with statin therapy.
      • Pearson T.A.
      • et al.
      A community-based, randomized trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: the ezetimibe add-on to statin for effectiveness (EASE) trial.
      ,
      • Hildemann S.K.
      • et al.
      Dual cholesterol inhibition with ezetimibe/simvastatin in pre-treated hypercholesterolaemic patients with coronary heart disease or diabetes mellitus: prospective observational cohort studies in clinical practice.
      Combination therapy of statin and ezetimibe not only has a greater LDL-C–lowering effect than statin monotherapy
      • Strilchuk L.
      • et al.
      An overview of rosuvastatin/ezetimibe association for the treatment of hypercholesterolemia and mixed dyslipidemia.
      but also produces additional cardiovascular risk reduction in several studies, such as in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial.
      • Cannon C.P.
      • et al.
      Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes.
      Statin therapy also produces cardiovascular benefits in patients with cardiovascular risk factors without established atherosclerotic vascular disease. Treatment with rosuvastatin (10 mg/d) lowered cardiovascular events by approximately 24% (hazards ratio [HR] = 0.76; 95% CI, 0.64–0.88) in intermediate-risk patients according to the Heart Outcomes Prevention Evaluation 3 trial.
      • Yusuf S.
      • et al.
      Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease.
      In that study, some adverse events (AEs), such as cataract surgery (P = 0.02) and muscle-related symptoms (P = 0.005) were reported, although there was no significant excess development of diabetes mellitus (DM) and cancers. A higher statin dose treatment of 20 mg of rosuvastatin in apparently healthy persons reduced primary major cardiovascular events by approximately 44% (HR = 0.46; 95% CI, 0.46–0.69) in the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin study.
      • Ridker P.M.
      • et al.
      Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.
      However, administration of 20 mg of rosuvastatin increased the incidence of newly diagnosed DM by 25% (20 mg of rosuvastatin, 3%; placebo, 2.4%; P = 0.01). In primary cardiovascular prevention, greater LDL-C lowering results in a better clinical outcome. Despite the definite benefits of statin treatment, high-dose statin therapy has been associated with AEs, such as the development of DM and muscle symptoms. In this study, we aimed to analyze the efficacy and safety of fixed-dose rosuvastatin and ezetimibe (R+E) combination therapy in intermediate-risk patients without DM and with dyslipidemia during a 12-month follow-up period.

      Methods

      Study Design

      This multicenter, open-label, single-arm, prospective observational study involved 5717 enrolled patients between 2016 and 2018 from 258 primary health care centers. The clinical trial protocol and method of obtaining informed consent were approved by the Korean Food and Drug Administration and the local ethics review boards of each hospital. The study was conducted in accordance with the ethics principles of the current Declaration of Helsinki, and patients signed informed consent documents before any relevant laboratory tests being conducted.

      Study Population

      Patients who met the following eligibility criteria for dyslipidemia of the Korean Society of Lipid and Atherosclerosis were enrolled: (1) LDL-C level >100 mg/dL in previous statin users, (2) LDL-C level >130 mg/dL with >2 risk factors, and (3) LDL-C level >160 mg/dL with 1 or no risk factors. Five risk factors to stratify the need for lipid-lowering agents without established CVD were as follows: (1) age (men, ≥45 years; women, ≥55 years); (2) family history of early-onset coronary artery disease; (3) hypertension; (4) history of smoking; and (5) low HDL-C level (<40 mg/dL). Intermediate-risk patients were defined as an annual risk of major cardiovascular events of approximately 1%. All the participants in this study cohort were of Asian ethnicity (domestic Korean). Primary physicians could decide to prescribe moderate-intensity statins or statins and ezetimibe combination therapy in statin-naive patients with dyslipidemia. They could change the statin-to-statin and ezetimibe combination in previous statin users for further LDL lowering.
      Patients were eligible for this study if they met the following inclusion criteria to rule out DM at the first visit: (1) no history of a diagnosis of type 2 DM, (2) no history of prescribed glucose-lowering agents, and (3) no typical DM symptoms (polyuria, polydipsia, and unexplained weight loss). Exclusion criteria in this study were (1) known DM, (2) pregnant or lactating women, and (3) those receiving corticosteroid treatment. The follow-up visits were at 6 and 12 months after enrollment. At each visit, all participants were examined by physicians on prescribed days and on observed days concerning additional medicine and any symptoms (myalgia, muscle weakness, or nausea). Blood tests were performed to determine lipid profiles in the early morning, 8 hours after midnight fasting. To discriminate between newly diagnosed DM, glycated hemoglobin (HbA1c), fasting blood glucose, and, if possible, 2-hour blood glucose levels after a 75-g oral glucose tolerance test were examined. Additional visits were permitted based on physicians’ decisions or if the patients wished to evaluate the efficacy and tolerability of the medication.

      Outcome Measurements

      The primary end points of this study were mean change absolute decrease in LDL-C levels from baseline to after 12 months of treatment with statin or fixed-dose R+E combination therapy. The secondary end points were mean change and absolute decrease in LDL-C levels from baseline to 6 months using statin treatment or fixed-dose R+E combination therapy. The mean change and absolute decrease in TG, HDL-C, and TC from baseline to 6 months and at 12 months were also evaluated. Tolerability was assessed based on the incidence of AEs and development of new-onset type 2 DM in terms of the following: HbA1c level ≥6.5%, fasting blood glucose level after 8 hours of fasting ≥126 mg/dL, 2-hour blood glucose level after a 75-g oral glucose tolerance test ≥200 mg/dL, or typical DM symptoms (polyuria, polydipsia, and unexplained weight loss), with random blood glucose levels ≥200 mg/dL.

      Statistical Analysis

      All statistical analyses were performed using R software, version 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria). This observational study used 1-to-3 propensity score matching to minimize confounding bias. In total, 700 patients (statin monotherapy group, n = 175; fixed-dose R+E combination therapy group, n = 525) were selected using the propensity score, which was adjusted for age, sex, body mass index (BMI), prior medical history, the status of preceding drugs for dyslipidemia, duration of dyslipidemia, smoking status, and alcohol consumption status.
      The primary end point was calculated for each group (statin monotherapy and fixed-dose R+E combination therapy) as the difference between baseline and 12 months in LDL-C levels using a paired t test. Moreover, we used a 2-sample t test to examine whether there was a significant reduction in LDL-C levels between patients in the statin group and in the fixed-dose R+E combination groups. Furthermore, we performed ANOVA among 3 specified fixed-dose R+E combination groups according to rosuvastatin doses (5, 10, and 20 mg).
      Similarly, we calculated the primary end points and computed the secondary end points using paired t and 2-sample t tests and ANOVA. However, we added a comparison between baseline and 6 months, and we assessed not only LDL-C but also HDL-C, TG, and TC levels.
      In the case of AEs, we standardized AEs according to MedDRA (version 19.0) and prioritized preferred term and system organ class. We calculated the number of patients with AEs and AE cases with these proportions using AE classes. AE classes include AEs, serious AEs, adverse drug reactions (ADRs), and serious ADRs. We used the Fisher exact test for the contingency table because the expected values were <5. In addition, we presented the number of patients with AEs and the proportion of each group in terms of the result, severity, appropriate measures, treatment status, and relation to drugs with AEs and measured the relative risk of new-onset DM and AEs in the entire sample.

      Results

      Baseline Characteristics

      In total, 700 patients were included in the analysis with propensity score matching. Patients were divided into statin monotherapy (n =175) and fixed-dose R+E combination therapy (5/10 mg, n = 280; 10/10 mg, n = 196; 20/10 mg, n = 49) groups. Mean (SD) age was similar in both statin monotherapy (61.06 [11.03] years) and fixed-dose R+E combination therapy groups (60.58 [11.02] years), although the 20/10 mg R+E group was relatively younger but without significant difference. The sex ratio in all groups was 1:1 for men and women. The mean (SD) BMI of all patients was 25.21 (3.27) kg/m2, and no significant differences were found among the groups. Baseline mean (SD) LDL-C levels for each group were 109.51 (40.64) mg/dL in the statin monotherapy group and 118.13 (49.23) mg/dL in the fixed-dose R+E combination therapy groups. Baseline TC, HDL-C, and TG levels were not significantly different between the groups, except for the TG level in the 10/10 mg R+E group, which was higher than that of the statin monotherapy group (176.36 [108.13] mg/dL vs 149.33 [78.93] mg/dL; P < 0.005) (Table I).
      Table IBaseline characteristics of participants.
      CharacteristicStatin (n = 175)R+E (n = 525)5/10 mg R+E (n=280)10/10 mg R+E (n=196)20/10 mg R+E (n=49)F/χ
      • Jeong J.S.
      • Kwon H.S.
      Prevalence and Clinical Characteristics of Dyslipidemia in Koreans.
      P
      Age, mean (SD), y61.06 (11.03)60.58 (11.02)60.85 (10.85)61.04 (10.95)57.16 (11.94)1.8310.140
      Sex, No. (%)
       Male88 (12.6)271 (38.7)132 (18.9)113 (16.1)26 (3.7)5.2400.155
       Female87 (12.4)254 (36.3)148 (21.1)83 (11.9)23 (3.3)
      Current smoker, No. (%)25 (14.3)77 (14.7)37 (13.2)31 (15.8)9 (18.3)3.1240.425
      BMI, mean (SD), kg/m225.21(3.52)25.20 (3.19)24.98 (3.05)25.33 (3.41)25.98 (2.96)1.4650.223
      LDL-C, mg/dL109.51 (40.64)118.13 (49.23)117.01 (49.76)118.57 (49.06)122.82 (47.53)1.6750.171
      HDL-C, mg/dL53.19 (11.10)50.88 (12.73)50.88 (12.88)50.85 (13.04)51.03 (10.66)1.5230.207
      TG, mg/dL149.33 (78.93)169.46 (95.52)166.52 (88.64)176.36 (108.13)158.63 (77.94)2.8030.039
      TC, mg/dL186.56 (45.95)193.42 (54.90)193.01 (54.92)193.34 (55.32)196.09 (54.09)0.7850.503
      BMI = body mass index; R+E = fixed-dose rosuvastatin and ezetimibe combination therapy; TC = total cholesterol; TG = triglyceride.

      Primary Outcomes

      Statin monotherapy lowered mean (SD) LDL-C levels to approximately 20.90 (42.09) mg/dL (19.09%) from baseline after 12 months. Patients treated with fixed-dose R+E combination therapy (all dose sum) had lower mean (SD) LDL-C levels of approximately 39.13 (45.15) mg/dL (33.12%) from baseline after 12 months. The LDL-lowering efficacy of the fixed-dose R+E combination therapy was dose dependent (5/10 mg R+E, 34.34 [45.49] mg/dL[29.35%]; 10/10 mg R+E, 42.91 [43.58] mg/dL [36.19%]; and 20/10 mg R+E, 51.37 [46.51] mg/dL [41.83%]; P = 0.017) (Table II and Figure 1). Target LDL achievement of <100 mg/dL was similar in the statin monotherapy group (64.63%) and in the fixed-dose R+E combination therapy groups (69.11%) (P = 0.5212). Fixed-dose R+E combination therapy also had the following dose-dependent target LDL achievement rates: 59.76% in the 5/10 mg R+E group, 76.72% in the 10/10 mg R+E group, and 88.24% in the 20/10 mg R+E group. Target LDL achievement of <70 mg/dL had significant differences in the statin monotherapy group (19.51%) and the fixed-dose R+E combination therapy groups (35.35%) (P = 0.009). Fixed-dose R+E combination therapy reached <70 mg/dL with dose-dependent efficacy (5/10 mg R+E, 29.27%; 10/10 mg R+E, 38.79%; and 20/10 mg R+E, 52.94%), and significant differences were identified in 10/10 mg R+E group (P = 0.0062) and 20/10 mg R+E group (P = 0.0007) compared with statin monotherapy (Table III and Supplemental Figure 1).
      Table IILDL-C and percent change from baseline after treatment of statin or R+E.
      GroupBaseline, Mean (SD)12 Months
      Mean (SD)PMean (SD) ChangeChange, %2-Sample t Test PANOVA P
      Statin (n = 175)109.51 (40.64)88.60 (24.68)<0.001−20.90 (42.09)−19.09
      R+E (n = 525)118.13 (49.23)79.00 (31.49)<0.001−39.13 (45.15)−33.12<0.001
      5/10 mg R+E (n = 280)117.01 (49.76)82.66 (33.27)<0.001−34.34 (45.49)−29.350.0010.017
      10/10 R+E (n = 196)118.57 (49.06)75.66 (28.31)<0.001−42.91 (43.58)−36.19<0.001
      20/10 mg R+E (n = 49)122.82 (47.53)71.45 (30.92)<0.001−51.37 (46.51)−41.83<0.001
      R+E = fixed-dose rosuvastatin and ezetimibe combination therapy.
      Figure 1
      Figure 1LDL-lowering efficacy at 12 months with statin or fixed-dose combination of rosuvastatin and ezetimibe (R+E) treatment. Asterisk indicates 2-sample t test P < 0.001 versus statin group.
      Table IIILDL-C achievement rate after 12 months of treatment of statin or R+E.
      GroupBaseline >100, No.12 Months
      ≤100, No.Reach, %χ
      • Jeong J.S.
      • Kwon H.S.
      Prevalence and Clinical Characteristics of Dyslipidemia in Koreans.
      Test P
      ≤70, No.Reach, %χ
      • Jeong J.S.
      • Kwon H.S.
      Prevalence and Clinical Characteristics of Dyslipidemia in Koreans.
      Test P
      Statin (n = 175)825364.631619.51
      R+E (n = 525)31421769.110.52111135.350.009
      5/10 mg R+E (n = 280)1649859.760.5474829.270.136
      10/10 mg R+E (n = 196)1168976.720.0894538.790.006
      20/10 mg R+E (n = 49)343088.240.0191852.940.001
      R+E = fixed-dose rosuvastatin and ezetimibe combination therapy.

      Secondary Outcomes

      The mean (SD) LDL-lowering efficacy of R+E combination therapy (−33.00 [43.40] mg/dL) was also higher than statin monotherapy (−19.92 [41.02] mg/dL) at 6 months of follow-up. Mean (SD) HDL-C levels did not change significantly with statin monotherapy (0.07 [9.89] mg/dL, P = 0.9246 at 6 months; −1.03 [9.38] mg/dL, P = 0.1477 at 12 months). Fixed-dose R+E combination therapy significantly increased mean (SD) HDL-C levels at 12-month follow-up (1.24 [10.99] mg/dL, P = 0.08 at 12 months). The increase in HDL-C was shown predominantly in the 5/10 mg R+E group (3.71% at 12 months, P = 0.0035). Fixed-dose R+E combination therapy lowered serum TG levels approximately 11.0% compared with 6% in statin monotherapy. TG-lowering efficacy was prevalent in the 10/10 mg R+E (15.29%, P = 0.048) and 20/10 R+E mg (23.88%, P = 0.0148) groups at 6 months and in the 10/10 mg R+E (16.38%, P = 0.0333) group at 12 months (Table IV Figures 2A and B).
      Table IVLipid profiles changes from baseline at 6 months and 12 months with statin or R+E.
      GroupBaseline, Mean (SD)6 Months12 Months
      Mean (SD)Paired t

      Test P
      Mean Change2-Sample t

      Test P
      ANOVA

      P
      Mean (SD)Paired t

      Test P
      Mean Change2-Sample t

      Test P
      ANOVA

      P
      LDL-C, mg/dL
      Statin (n = 175)109.51 (40.64)89.59 (26.26)<0.001-19.92 (41.02)88.60 (24.68)<0.001-20.90(42.09)
      R+E (n = 525)118.13 (49.23)85.14 (36.07)<0.001-33.00 (43.40)<0.00179.00 (31.49)<0.001−39.13 (45.15)<0.001
      5/10 mg R+E (n = 280)117.01 (49.76)90.76 (35.98)<0.001-26.25 (41.00)0.110<0.00182.66 (33.27)<0.001−34.34 (45.49)0.0010.017
      10/10 mg R+E (n = 196)118.57 (49.06)81.14 (36.45)<0.001-37.43 (43.94)<0.00175.66 (28.31)<0.001−42.91 (43.58)<0.001
      20/10 mg R+E (n = 49)122.82 (47.53)69.01 (27.69)<0.001-53.81 (45.46)<0.00171.45 (30.92)<0.001−51.37 (46.51)<0.001
      HDL-C, mg/dL
       Statin (n = 175)53.19 (11.10)53.26 (11.23)0.9250.07 (9.89)52.15 (11.82)0.148−1.03 (9.38)
       R+E (n = 525)50.88 (12.73)51.74 (12.61)0.0290.86 (9.00)0.35152.12 (13.06)0.0101.24 (10.99)0.008
       5/10 mg R+E (n = 280)50.88 (12.88)51.50 (12.39)0.2440.62 (8.95)0.5470.71752.76 (13.34)0.0071.89 (11.69)0.0040.356
       10/10 mg R+E (n = 196)50.85 (13.04)51.84 (12.77)0.1420.98 (9.32)0.36351.35 (13.29)0.5090.50 (10.55)0.140
       20/10 mg R+E (n = 49)51.03 (10.66)52.75 (13.39)0.1451.71 (8.09)0.23651.56 (10.32)0.6530.53 (8.15)0.256
      TG, mg/dL
       Statin (n = 175)149.33 (78.93)138.94 (65.01)0.061−10.39 (72.99)139.80 (65.26)0.096−9.53 (75.20)
       R+E (n = 525)169.46 (95.52)152.28 (80.35)<0.001−17.18 (85.46)0.309151.22 (78.14)<0.001−18.24 (90.43)0.209
       5/10 mg R+E (n = 280)166.52 (88.64)159.81 (84.34)0.191−6.71 (85.73)0.6250.008155.35 (77.62)0.034−11.17 (87.90)0.8320.108
       10/10 mg R+E (n = 196)176.36 (108.13)149.40 (78.55)<0.001−26.96 (87.43)0.048147.47 (82.86)<0.001−28.88 (98.75)0.033
       20/10 mg R+E (n = 49)158.63 (77.94)120.76 (51.85)<0.001−37.88 (66.94)0.015142.62 (59.26)0.083−16.01 (63.21)0.545
      TC, mg/dL
       Statin (n = 175)186.56 (45.95)164.57 (29.39)<0.001−21.99 (46.72)162.71 (29.99)<0.001−23.85 (48.03)
       R+E (n = 525)193.42 (54.90)158.86 (41.46)<0.001-34.56 (48.60)0.003154.24 (36.94)<0.001−39.18 (50.36)<0.001
       5/10 mg R+E (n = 280)193.01 (54.92)165.65 (40.37)<0.001-27.37 (48.16)0.239<0.001160.51 (38.02)<0.001−32.50 (50.71)0.0680.002
       10/10 mg R+E (n = 196)193.34 (55.32)154.27 (42.84)<0.001-39.08 (46.67)0.001148.45 (34.41)<0.001−44.90 (48.44)<0.001
       20/10 mg R+E (n = 49)196.09 (54.09)138.49 (32.51)<0.001-57.61 (50.26)<0.001141.56 (33.95)<0.001−54.53 (50.72)<0.001
      R+E = fixed-dose rosuvastatin and ezetimibe combination therapy; TC = total cholesterol; TG = triglyceride.
      Figure 2
      Figure 2Change in LDL-C, HDL-C, triglyceride (TG), and total cholesterol (TC) levels at 6 months (A) and 12 months (B) with statin or fixed-dose combination of rosuvastatin and ezetimibe (R+E) treatment.

      Tolerability Outcome

      HbA1c and fasting glucose levels were monitored in 33 of 175 patients (18.86%) with statin monotherapy and in 149 of 525 patients (28.38%) with fixed-dose R+E combination therapy. Statin monotherapy did not increase HbA1c (−0.09% [0.23%], P = 0.1498) and fasting glucose (0.54 [12.02] mg/dL, P = 0.7263) levels at 6 and 12 months. All doses of fixed-dose R+E combination therapy produced no significant change in HbA1c (−0.05% [0.29%], P = 0.0853) and fasting glucose (0.37 [13.08] mg/dL, P = 0.7030) levels; however, at 12 months, 5/10 mg R+E therapy was associated with significantly lower HbA1c (−0.10% [0.25%], P = 0.0021) levels, although no change in fasting glucose was observed (Supplemental Table I).
      New-onset DM was evaluated through measuring HbA1c, fasting glucose and random glucose levels, and newly diagnosed reports. During the 12-month study period, the incidence of new-onset DM in statin monotherapy was 0.64% (n = 5). The incidence of new-onset DM did not differ between the fixed-dose R+E combination groups (0.47%, n = 23), although the highest incidence was observed in the 20/10 mg R+E (1.81%, n = 6) group (Supplemental Table II).
      Elevated liver enzyme levels were reported in 3 patients (1.71%) in the statin monotherapy group and in 2 patients (0.38%) in the fixed-dose R+E combination therapy group, which were unrelated to dose. Concerns of musculoskeletal and connective tissue disorders, including myalgia, were reported in 4 patients (2.28%) in the statin monotherapy group and in 8 patients (1.52%) in the fixed-dose R+E combination groups, which were unrelated to dose.
      Composite ADRs and serious ADRs did not differ significantly between the statin monotherapy group and the fixed-dose R+E combination groups. Moreover, no patients stopped taking medication because AEs, as summarized in Table V, with detailed data shown in Supplemental Table III.
      Table VAdverse events at 12 months.
      Statin Group

      (n = 175)
      R+E

      (n = 525)
      5/10 mg R+E

      (n = 280)
      10/10 mg R+E

      (n = 196)
      20/10 mg R+E

      (n = 49)
      No. (%)No. of EventsNo. (%)No. of Eventsn (%)No. eventsNo. (%)No. of EventsNo. (%)No. of Events
      Adverse events19 (10.90)2827 (5.14)509 (3.21)914 (7.14)364 (8.16)5
      Fisher exact test P0.0130.0020.2730.791
      Serious adverse events3 (1.71)31 (0.19)10 (0.00)01 (0.51)10 (0.00)0
      Fisher exact test P0.0500.0560.347>0.99
      Adverse drug reactions0 (0.00)011 (2.10)115 (1.79)55 (2.55)51 (2.04)1
      Fisher exact test P0.0740.1620.0630.219
      Serious adverse drug reactions0 (0.00)00 (0.00)00 (0.00)00 (0.00)00 (0.00)0
      Fisher exact test P>0.99>0.99>0.99>0.99
      R+E = fixed-dose rosuvastatin and ezetimibe combination therapy.

      Discussion

      This propensity-weighted, real-world analysis compared the cholesterol-lowering efficacy and tolerability of a fixed-dose R+E combination therapy with statin monotherapy in Korean patients with non-DM dyslipidemia. A fixed-dose R+E combination therapy lowered LDL-C more than statin monotherapy without increasing AEs or deterioration in glycemic control status. The lowest dose of R+E combination (5/10 mg) therapy was most preferentially prescribed by primary care physicians. The 5/10 mg R+E dose had more potent LDL-C lowering than statin monotherapy and was the most tolerable in terms of glycemic control, with improvement in HbA1c levels and no increase in new-onset DM up to the end of the 12-month follow-up period.
      In this real-world analysis of R+E combination therapy, LDL-C–lowering efficacy was relatively lower than that in randomized controlled studies. In a multicenter, randomized study of R+E (Multicenter Randomized Study of Rosuvastatin and Ezetimibe), R+E combination therapy lowered LDL-C levels approximately 59% from baseline to drug-naive primary hypercholesterolemia in Korea. The combination of the lowest dose (5/10 mg) of R+E lowered LDL-C levels approximately 56%, from a mean of 148 to 66 mg/dL at 8 weeks. The difference in LDL-C–lowering efficacy was approximately 10.9% between rosuvastatin monotherapy and R+E combination therapy.
      • Kim K.J.
      • et al.
      Effect of fixed-dose combinations of ezetimibe plus rosuvastatin in patients with primary hypercholesterolemia: MRS-ROZE (Multicenter Randomized Study of ROsuvastatin and eZEtimibe).
      In the Ildong Rosuvastatin & Ezetimibe randomized controlled trial, R+E combination therapy also lowered LDL-C levels approximately 57% from baseline to primary hypercholesterolemia in Korea. The 5/10 mg R+E combination therapy had a similarly high LDL-C–lowering efficacy of 51.8% from a mean of 160.7 to 76.9 mg/dL at 8 weeks, and the LDL-lowering efficacy difference was 11.3% compared with 5-mg rosuvastatin monotherapy. The participants who were previous statin users had stopped statin use during 4 weeks of the run-in period; thus, baseline LDL-C levels were somewhat high.
      • Hong S.J.
      • et al.
      A Phase III, Multicenter, Randomized, Double-blind, Active Comparator Clinical Trial to Compare the Efficacy and Safety of Combination Therapy With Ezetimibe and Rosuvastatin Versus Rosuvastatin Monotherapy in Patients With Hypercholesterolemia: I-ROSETTE (Ildong Rosuvastatin & Ezetimibe for Hypercholesterolemia) Randomized Controlled Trial.
      In our real-world analysis, previous statin users changed to other statins or a fixed-dose R+E combination therapy immediately after visiting primary care without a statin-free period. Thus, the baseline LDL-C level (statin monotherapy, 109.51 mg/dL; fixed-dose combination of R+E, 118.13 mg/dL) was lower than that in randomized controlled studies. Although the LDL-C–lowering efficacy of R+E was lower (33.12%), the reached mean LDL-C level at 12 months was 79 mg/dL, and the difference with statin monotherapy was 14.03%. Considering drug adherence in real-world data and no statin washout period, fixed-dose R+E combination therapy had consistent LDL-C efficacy compared with statin monotherapy.
      Representative statin-associated AEs are myopathy, myalgia, hepatic enzyme elevation, and increased new-onset DM. Although the benefit of statin treatment for the prevention of cardiovascular events outweighs the disadvantages,
      • Newman C.B.
      • et al.
      Statin Safety and Associated Adverse Events: A Scientific Statement From the American Heart Association.
      the most common cause of discontinued statin therapy is statin-associated AEs.
      • Zhang H.
      • et al.
      Discontinuation of statins in routine care settings: a cohort study.
      Statin-associated AEs are more prevalent in high-dose statin use or high-intensity statin use than in low-dose or low-potency use.
      • Silva M.
      • et al.
      Meta-analysis of drug-induced adverse events associated with intensive-dose statin therapy.
      Ezetimibe is a synthetic 2-azetidinone that acts through inhibiting sterol absorption in the intestine. Ezetimibe monotherapy reduced LDL-C levels by a mean of 17% in 2 randomized controlled trials of patients with primary hypercholesterolemia.
      • Dujovne C.A.
      • et al.
      Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia.
      ,
      • Knopp R.H.
      • et al.
      Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia.
      Although it has a low LDL-lowering potency (<30% reduction), ezetimibe monotherapy is consistently tolerable, and the incidence of muscle-related AEs is relatively low (<1%). In the Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects 3 study, patients who were statin intolerant and who presented with muscle symptoms or muscle enzyme elevation when taking >2 statins were tolerant when switching therapy to 10 mg/d of ezetimibe or 420 mg/mo of evolocumab.
      • Nissen S.E.
      • et al.
      Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial.
      Although the exact mechanism remains unknown, ezetimibe and PCSK9i are very tolerable to patients with hypercholesterolemia and a higher rate of muscle-related AEs due to statin therapy, irrespective of low LDL levels. PCSK9i is also new therapeutic strategy with potent LDL-C–lowering efficacy and tolerability to statin-intolerant patients. Considering the injectable therapy and cost, the ezetimibe and statin combination therapy is preferable strategy. The addition of ezetimibe to statin therapy also did not aggravate muscle-related AEs despite the higher LDL-lowering efficacy of an additional 17% to 25% lowering compared with statin monotherapy.
      • Davidson M.H.
      • et al.
      Striated Muscle Safety of Ezetimibe/Simvastatin (Vytorin).
      Statin therapy, which varies depending on potency, dose, and lipophilicity, is associated with increased insulin resistance, fasting glucose, and the incidence of new-onset DM in clinical studies, especially in patients with baseline DM risk factors (higher fasting glucose, BMI, TG, and history of hypertension).
      • Navarese E.P.
      • et al.
      Meta-Analysis of Impact of Different Types and Doses of Statins on New-Onset Diabetes Mellitus.
      In contrast to statin therapy, ezetimibe monotherapy improved insulin resistance in patients with non-DM metabolic syndrome
      • Nakamura A.
      • et al.
      Impact of decreased insulin resistance by ezetimibe on postprandial lipid profiles and endothelial functions in obese, non-diabetic-metabolic syndrome patients with coronary artery disease.
      and lowered fasting glucose and HbA1c levels in patients with type 2 DM.
      • Nozue T.
      • Michishita I.
      • Mizuguchi I.
      Effects of ezetimibe on glucose metabolism in patients with type 2 diabetes: A 12-week, open-label, uncontrolled, pilot study.
      Although there is a paucity of large clinical trials evaluating the tolerability of new-onset DM with statin and ezetimibe combination therapy, 1 study reported that the addition of ezetimibe to statins did not increase fasting glucose levels compared with statin monotherapy during 96 weeks in patients with non-DM hypercholesterolemia.
      • Toth P.P.
      • et al.
      Ezetimibe Does Not Increase Fasting Glucose Levels More Than Statins Alone in Non-Diabetic, Hypercholesterolemic Patients.
      In a retrospective study that followed up patients for a mean of 7 years, moderate-intensity statin and ezetimibe combination therapy neutralized the increased prevalence rate for new-onset DM compared with high-intensity statin therapy in patients with pre-DM hypercholesterolemia.
      • Barkas F.
      • et al.
      Statin therapy with or without ezetimibe and the progression to diabetes.
      This study has several limitations. The baseline characteristics were not enough to explain all the cardiovascular risks being instructed in real-world analysis. Because we did not allocate the kinds of statin and statin doses, the differences of statin potency might affect the LDL-lowering efficacy and tolerability in the statin monotherapy group. In addition, the adherence for statin and R+E combination therapy was not evaluated in this study. The variant adherence of medications might be associated with low absolute reduction of LDL-C in R+E combination therapy compared with other randomized controlled trials.

      Conclusions

      Fixed-dose R+E combination therapy resulted in high cholesterol-lowering efficacy, tolerable muscle-related AEs, and a neutral effect on glucose metabolism (and even lower HbA1c levels with 5/10 mg R+E combination therapy) compared with statin monotherapy in real-world clinical situations. Additional large clinical studies are recommended to further validate these findings in relation to CVD prevention. In a possible paradigm shift, a fixed-dose R+E combination therapy may be beneficial for primary cardiovascular prevention with potent LDL-lowering efficacy and tolerability.

      Acknowledgments

      All authors were involved in the conception, design of the study, and analysis or interpretation of the data. Jun Hwa Hong and Ung Jeon were involved in drafting the manuscript. All authors approved the final version of the manuscript, including the authorship list.

      Funding Sources

      The research was supported by Hanmi Pharmaceutical Co Ltd (Seoul, Republic of Korea). The sponsor supported the supply of the investigational products, laboratory tests, and clinical research coordinator expenses.

      Declaration of interest

      None.

      Appendix. Supplementary materials

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