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Purpose We evaluated the efficacy and safety of nebivolol and rosuvastatin combination treatment in patients with hypertension and hyperlipidemia. Patients and Methods Eligible patients, after more than 4 weeks of therapeutic lifestyle change, were randomly assigned to three groups: 5 mg nebivolol plus 20 mg rosuvastatin (NEBI/RSV), 20 mg rosuvastatin (RSV), or 5 mg nebivolol (NEBI). Treatments lasted 8 weeks. Results Efficacy was analyzed using data from 276 patients. Sitting systolic and diastolic blood pressures differed between the NEBI/RSV and RSV groups (LSmean difference = -5.89 and -5.99 mmHg; 95% confidence interval [CI] = -9.88 to -1.90 mmHg and -8.13 to -3.84 mmHg, respectively). Reductions in the two pressures did not differ between the NEB/RSV and NEB groups. The percent reduction in low-density lipoprotein (LDL) cholesterol differed between the NEBI/RSV and NEBI groups (LSmean difference = -47.76%, 95% CI = -52.69 to -42.84%) but not between the NEBI/RSV and RSV groups. The blood pressure (BP) control rate was higher in the NEBI/RSV group than in the RVS group (51.09% vs 29.67%, p = 0.003). The LDL cholesterol goal achievement rate was higher in the NEBI/RSV group than in the NEBI group (85.87% vs 11.83%, p < 0.001). The incidence of adverse drug reactions in the NEBI/RSV, RSV, and NEBI groups was 8.51%, 7.45%, and 8.60%, respectively (p = 0.950). Conclusion Nebivolol plus rosuvastatin treatment is effective in reducing BP and LDL cholesterol levels and is safe in patients with hypertension and hypercholesterolemia without the loss of BP or the LDL cholesterol-lowering effect of each drug. Trial Registration CRIS registration number KCT0002148.

Soon Jun Hong,1,* Ki-Chul Sung,2,* Sang-Wook Lim,3 Seok-Yeon Kim,4 Weon Kim,5 Jinho Shin,6 Sungha Park,7 Hae-Young Kim,8 Moo-Yong Rhee9,10 On behalf of MH_APOLLO to read: HM_APOLLO1Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea; 2Department of Cardiology, Gangbuk Samsung Hospital, Sungkyunkwan University College of Medicine, Seoul, Republic of Korea; 3Cardiology Division, Cardiac Center, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea; 4Department of Cardiology, Seoul Medical Center, Seoul, Republic of Korea; 5Department of Internal Medicine, Kyung Hee University Medical Center, Kyung Hee University, Seoul, Republic of Korea; 6Division of Cardiology, Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea; 7Department of Cardiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; 8Department of Health Policy and Management, College of Health Science & Department of Health Care Science, Graduate School, Korea University, Seoul, Republic of Korea; 9Cardiovascular Center, Dongguk University Ilsan Hospital, Goyang-si, Gyeonggi, Republic of Korea; 10College of Medicine, Dongguk University, Gyeongju-si, Gyeongbuk, Republic of Korea*These authors contributed equally to this workCorrespondence: Moo-Yong RheeCardiovascular Center, Dongguk University Ilsan Hospital, 27 Dongguk-Ro, Ilsandong-Gu, Goyang-si, Gyeonggi-do 10326, Republic of KoreaTel +82 31 961 5775Fax +82 31 961 7786Email mooyong_rhee@dumc.or.krPurpose: We evaluated the dose-responsiveness, efficacy, and safety of low-dose triple antihypertensive combination therapies in patients with mild-to-moderate hypertension.Patients and Methods: After a 1 to 2-week placebo run-in period, 248 patients were randomized to the half-dose triple combination (amlodipine 2.5 mg + losartan 25 mg + chlorthalidone 6.25 mg), third-dose triple combination (amlodipine 1.67 mg + losartan 16.67 mg + chlorthalidone 4.17 mg), quarter-dose triple combination (amlodipine 1.25 mg + losartan 12.5 mg + chlorthalidone 3.13mg), amlodipine 10mg, amlodipine 5mg, losartan 100mg, and placebo groups for 8 weeks. The primary outcome was the mean change in systolic blood pressure (SBP) from baseline to week 8.Results: The placebo-corrected SBP reductions of the half-dose, third-dose, quarter-dose combination, amlodipine 10 mg, amlodipine 5 mg and losartan 100 mg treatments were − 17.2, − 19.5, − 14.9, − 18.5, − 11.3 and − 9.9 mmHg, respectively. The BP control and response rates were significantly higher in the half-dose, third-dose, and quarter-dose combination groups than in the placebo group (all p < 0.01). Despite no intergroup differences in study drug-related adverse events, ankle circumference increased significantly in the amlodipine group compared to those in the combination treatment groups. The quarter-dose combination, amlodipine 5 mg, and losartan 100 mg groups showed similar SBP reduction and BP response rates. The SBP reduction and BP response rate in the third-dose and half-dose combination groups were not significantly different from those in the amlodipine 10 mg group but superior to those in the losartan 100 mg group.Conclusion: Low-dose triple combination therapies could be effective as antihypertensive therapies.Trial Registration: ClinicalTrials.gov identifier NCT03897868.Keywords: hypertension, blood pressure, combination therapy, low-dose, amlodipine, losartan, chlorthalidone

Purpose We evaluated the efficacy and safety of nebivolol and rosuvastatin combination treatment in patients with hypertension and hyperlipidemia. Patients and Methods Eligible patients, after more than 4 weeks of therapeutic lifestyle change, were randomly assigned to three groups: 5 mg nebivolol plus 20 mg rosuvastatin (NEBI/RSV), 20 mg rosuvastatin (RSV), or 5 mg nebivolol (NEBI). Treatments lasted 8 weeks. Results Efficacy was analyzed using data from 276 patients. Sitting systolic and diastolic blood pressures differed between the NEBI/RSV and RSV groups (LSmean difference = −5.89 and −5.99 mmHg; 95% confidence interval [CI] = −9.88 to −1.90 mmHg and −8.13 to −3.84 mmHg, respectively). Reductions in the two pressures did not differ between the NEB/RSV and NEB groups. The percent reduction in low-density lipoprotein (LDL) cholesterol differed between the NEBI/RSV and NEBI groups (LSmean difference = −47.76%, 95% CI = −52.69 to −42.84%) but not between the NEBI/RSV and RSV groups. The blood pressure (BP) control rate was higher in the NEBI/RSV group than in the RVS group (51.09% vs 29.67%, p = 0.003). The LDL cholesterol goal achievement rate was higher in the NEBI/RSV group than in the NEBI group (85.87% vs 11.83%, p < 0.001). The incidence of adverse drug reactions in the NEBI/RSV, RSV, and NEBI groups was 8.51%, 7.45%, and 8.60%, respectively (p = 0.950). Conclusion Nebivolol plus rosuvastatin treatment is effective in reducing BP and LDL cholesterol levels and is safe in patients with hypertension and hypercholesterolemia without the loss of BP or the LDL cholesterol-lowering effect of each drug. Trial Registration CRIS registration number KCT0002148.

Moo-Yong Rhee,1 Sang Hong Baek,2 Weon Kim,3 Chang Gyu Park,4 Seung Woo Park,5 Byung-Hee Oh,6 Sang-Hyun Kim,7 Jae-Joong Kim,8 Joon-Han Shin,9 Byung-Su Yoo,10 Se-Joong Rim,11 Jong-Won Ha,12 Joon Hyung Doh,13Youngkeun Ahn,14 Jei Keon Chae,15 Jeong Bae Park,16 Soon-Kil Kim,17 Cheol Ho Kim18 1Cardiovascular Center, Dongguk University Ilsan Hospital, Goyang, 2Catholic University of Korea, Seoul St Mary’s Hospital, Seoul, 3Cardiovascular Department of Internal Medicine, Kyung Hee University Medical Center, Seoul, 4Division of Cardiology, Guro Hospital, Korea University College of Medicine, Seoul, 5Division of Cardiology, Samsung Medical Center, Seoul, 6Department of Internal Medicine, Seoul National University Hospital, Seoul, 7Division of Cardiology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, 8Division of Cardiology, Asan Medical Center, Seoul, 9Division of Cardiology, Ajou University Hospital, Suwon, 10Division of Cardiology, Wonju Severance Christian Hospital, Wonju, 11Division of Cardiology, GangNam Severance Hospital, Seoul, 12Division of Cardiology, Severance Hospital, Seoul, 13Division of Cardiology, Inje University Ilsan Hospital, Goyang, 14Department of Cardiology, Chonnam National University Hospital, Gwangju, 15Chonbuk National University Hospital, Jeonju, 16Department of Cardiology, Cheil General Hospital, Dankook University College of Medicine, Seoul, 17Department of Cardiology, Hanyang University Guri Hospital, Guri, 18Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea Background: The study reported here compared the blood pressure (BP)-lowering efficacy of fimasartan alone with that of fimasartan/hydrochlorothiazide (HCTZ) combination in patients whose BP goal was not achieved after 4 weeks of treatment with once-daily fimasartan 60mg.Methods: Patients with sitting diastolic blood pressure (siDBP) ≥90mmHg with 4 weeks of once-daily fimasartan 60mg were randomly assigned to receive either once-daily fimasartan 60mg/HCTZ 12.5mg or fimasartan 60mg for 4 weeks. After 4 weeks, the dose was increased from fimasartan 60mg/HCTZ 12.5mg to fimasartan 120 mg/HCTZ 12.5 mg or from fimasartan 60mg to fimasartan 120 mg if siDBP was ≥90mmHg.Results: Of the 263 randomized patients, 256 patients who had available efficacy data were analyzed. The fimasartan/HCTZ treatment group showed a greater reduction of siDBP compared to the fimasartan treatment group at Week4 (6.88±8.10mmHg vs 3.38±7.33, P=0.0008), and the effect persisted at Week8 (8.67±9.39mmHg vs 5.02±8.27mmHg, P=0.0023). Reduction of sitting systolic BP in the fimasartan/HCTZ treatment group was also greater than that in the fimasartan treatment group (at Week4, 10.50±13.76mmHg vs 5.75±12.18mmHg, P=0.0069 and, at Week8, 13.45±15.15mmHg vs 6.84±13.57mmHg, P=0.0007). The proportion of patients who achieved a reduction of siDBP ≥10mmHg from baseline and/or a mean siDBP&nbsp

Namyi Gu,1,2 Joo-Youn Cho,3 Kwang-Hee Shin,4 In-Jin Jang,3 Moo-Yong Rhee2,5 1Department of Clinical Pharmacology and Therapeutics, 2Clinical Trial Center, Dongguk University College of Medicine and Ilsan Hospital, Goyang, 3Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, 4Pharmacotherapy & Translational Research Lab., College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 5Cardiovascular Center, Dongguk University College of Medicine and Ilsan Hospital, Goyang, Republic of Korea Abstract: A low sodium diet enhances the hemodynamic effect of renin–angiotensin system blockers. It was suggested that the substrates of P-glycoprotein or cytochrome P450 3A4 were reduced on a high sodium diet. This study aimed to investigate the influence of high sodium diet on the pharmacokinetics and pharmacodynamics of fimasartan, which is a substrate of cytochrome P450 3A4 but not P-glycoprotein. The study design was a two-diet, two-period, two-sequence, randomized, open-label, and crossover with 1-week washout for diet. Eligible subjects were fed with either low sodium (50 mEq/day) diet or high sodium diet (300 mEq/day) for 7 days in the first hospitalization period and the other diet in the second period. On the seventh morning of each period, subjects received a single dose of fimasartan 60 mg in a fasted state. The serial plasma concentrations of fimasartan, serum aldosterone concentration (SAC), and plasma renin activity (PRA) were measured for pharmacokinetic–pharmacodynamic analysis. Sixteen subjects completed the study satisfying the compliance test for diets. Although the mean systemic exposure of fimasartan is slightly (≈10%) decreased on a high sodium diet, the difference was not statistically or clinically significant (P>0.05). The SAC and PRA after fimasartan administration were highly dependent on their baseline levels. The dietary sodium content influenced the baseline of SAC and PRA, but did not influence the ratio change of SAC and PRA after fimasartan treatment. The ratio change of SAC after fimasartan treatment was correlated to the systemic exposure of fimasartan (P0.05). In conclusion, the pharmacokinetics of fimasartan and ratio changes of SAC and PRA after fimasartan treatment were not significantly influenced by dietary sodium content. Keywords: aldosterone, renin activity, angiotensin receptor blocker, aldosterone, renin, cytochrome P450 3A4, P-glycoprotein, healthy, sodium diet