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Efficacy and safety of combination therapy with telmisartan, rosuvastatin, and ezetimibe in patients with dyslipidemia and hypertension: A randomized, double-blind, multicenter, therapeutic confirmatory, phase III clinical trial.
Lee, CJ, Kang, WC, Ihm, SH, Sohn, IS, Woo, JS, Kim, JW, Hong, SJ, Choi, JH, Suh, JW, Seo, JB, et al
Journal of clinical hypertension (Greenwich, Conn.). 2024;(3):262-273
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Abstract
This study aimed to compare and evaluate the efficacy of the blood pressure (BP) control and cholesterol-lowering effects and safety of combination therapy with telmisartan, rosuvastatin, and ezetimibe versus rosuvastatin and ezetimibe double therapy or telmisartan single therapy in dyslipidemia patients with hypertension. After a wash-out/therapeutic lifestyle change period of ≥4 weeks, a total of 100 eligible patients were randomized and received one of three treatments for 8 weeks: (1) telmisartan 80 mg/rosuvastatin 20 mg/ezetimibe 10 mg (TRE), (2) rosuvastatin 20 mg/ezetimibe 10 mg (RE), or (3) telmisartan 80 mg (T). The primary endpoint was the efficacy evaluation of TRE by comparing changes in mean sitting systolic blood pressure (msSBP) and mean percentage change in low-density lipoprotein-C (LDL-C) from baseline after 8 weeks of treatment. The least square (LS) mean (SE) changes in msSBP at 8 weeks compared with baseline were -23.02 (3.04) versus -7.18 (3.09) mmHg in the TRE and RE groups, respectively (p < .0001), and -25.80 (2.74) versus -14.92 (2.65) mmHg in the TRE and T groups, respectively (p = .0005). The percentage changes in the mean (SD) LDL-C at 8 weeks compared with baseline were -54.97% (3.49%) versus -0.17% (3.23%) in the TRE and T groups, respectively (p < .0001). No serious adverse events occurred, and no statistically significant differences in the incidence of overall AEs and adverse drug reactions occurred among the three groups. TRE therapy significantly decreased msSBP and LDL-C compared to RE or T therapy with comparable safety and tolerability profiles.
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Safety and Glycemic Outcomes During the MiniMedTM Advanced Hybrid Closed-Loop System Pivotal Trial in Children and Adolescents with Type 1 Diabetes.
Pihoker, C, Shulman, DI, Forlenza, GP, Kaiserman, KB, Sherr, JL, Thrasher, JR, Buckingham, BA, Kipnes, MS, Bode, BW, Carlson, AL, et al
Diabetes technology & therapeutics. 2023;(11):755-764
Abstract
Background: During MiniMed™ advanced hybrid closed-loop (AHCL) use by adolescents and adults in the pivotal trial, glycated hemoglobin (A1C) was significantly reduced, time spent in range (TIR) was significantly increased, and there were no episodes of severe hypoglycemia or diabetic ketoacidosis (DKA). The present study investigated the same primary safety and effectiveness endpoints during AHCL use by a younger cohort with type 1 diabetes (T1D). Methods: An intention-to-treat population (N = 160, aged 7-17 years) with T1D was enrolled in a single-arm study at 13 investigational centers. There was a run-in period (∼25 days) using HCL or sensor-augmented pump with/without predictive low-glucose management, followed by a 3-month study period with AHCL activated at two glucose targets (GTs; 100 and 120 mg/dL) for ∼45 days each. The mean ± standard deviation values of A1C, TIR, mean sensor glucose (SG), coefficient of variation (CV) of SG, time at SG ranges, and insulin delivered between run-in and study were analyzed (Wilcoxon signed-rank test or t-test). Results: Compared with baseline, AHCL use was associated with reduced A1C from 7.9 ± 0.9% (N = 160) to 7.4 ± 0.7% (N = 136) (P < 0.001) and overall TIR increased from the run-in 59.4 ± 11.8% to 70.3 ± 6.5% by end of study (P < 0.001), without change in CV, time spent below range (TBR) <70 mg/dL, or TBR <54 mg/dL. Relative to longer active insulin time (AIT) settings (N = 52), an AIT of 2 h (N = 19) with the 100 mg/dL GT increased mean TIR to 73.4%, reduced TBR <70 mg/dL from 3.5% to 2.2%, and reduced time spent above range (TAR) >180 mg/dL from 28.7% to 24.4%. During AHCL use, there was no severe hypoglycemia or DKA. Conclusions: In children and adolescents with T1D, MiniMed AHCL system use was safe, A1C was lower, and TIR was increased. The lowest GT and shortest AIT were associated with the highest TIR and lowest TBR and TAR, all of which met consensus-recommended glycemic targets. ClinicalTrials.gov ID: NCT03959423.
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Glycemic outcomes of children 2-6 years of age with type 1 diabetes during the pediatric MiniMed™ 670G system trial.
Forlenza, GP, Ekhlaspour, L, DiMeglio, LA, Fox, LA, Rodriguez, H, Shulman, DI, Kaiserman, KB, Liljenquist, DR, Shin, J, Lee, SW, et al
Pediatric diabetes. 2022;(3):324-329
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Abstract
BACKGROUND Highly variable insulin sensitivity, susceptibility to hypoglycemia and inability to effectively communicate hypoglycemic symptoms pose significant challenges for young children with type 1 diabetes (T1D). Herein, outcomes during clinical MiniMed™ 670G system use were evaluated in children aged 2-6 years with T1D. METHODS Participants (N = 46, aged 4.6 ± 1.4 years) at seven investigational centers used the MiniMed™ 670G system in Manual Mode during a two-week run-in period followed by Auto Mode during a three-month study phase. Safety events, mean A1C, sensor glucose (SG), and percentage of time spent in (TIR, 70-180 mg/dl), below (TBR, <70 mg/dl) and above (TAR, >180 mg/dl) range were assessed for the run-in and study phase and compared using a paired t-test or Wilcoxon signed-rank test. RESULTS From run-in to end of study (median 87.1% time in auto mode), mean A1C and SG changed from 8.0 ± 0.9% to 7.5 ± 0.6% (p < 0.001) and from 173 ± 24 to 161 ± 16 mg/dl (p < 0.001), respectively. Overall TIR increased from 55.7 ± 13.4% to 63.8 ± 9.4% (p < 0.001), while TBR and TAR decreased from 3.3 ± 2.5% to 3.2 ± 1.6% (p = 0.996) and 41.0 ± 14.7% to 33.0 ± 9.9% (p < 0.001), respectively. Overnight TBR remained unchanged and TAR was further improved 12:00 am-6:00 am. Throughout the study phase, there were no episodes of severe hypoglycemia or diabetic ketoacidosis (DKA) and no serious adverse device-related events. CONCLUSIONS At-home MiniMed™ 670G Auto Mode use by young children safely improved glycemic outcomes compared to two-week open-loop Manual Mode use. The improvements are similar to those observed in older children, adolescents and adults with T1D using the same system for the same duration of time.
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Intake of mother's milk by very-low-birth-weight infants and variation in DNA methylation of genes involved in neurodevelopment at 5.5 years of age.
Xu, J, Shin, J, McGee, M, Unger, S, Bando, N, Sato, J, Vandewouw, M, Patel, Y, Branson, HM, Paus, T, et al
The American journal of clinical nutrition. 2022;(4):1038-1048
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Abstract
BACKGROUND Mechanisms responsible for associations between intake of mother's milk in very-low-birth-weight (VLBW, <1500 g) infants and later neurodevelopment are poorly understood. It is proposed that early nutrition may affect neurodevelopmental pathways by altering gene expression through epigenetic modification. Variation in DNA methylation (DNAm) at cytosine-guanine dinucleotides (CpGs) is a commonly studied epigenetic modification. OBJECTIVES We aimed to assess whether early mother's milk intake by VLBW infants is associated with variations in DNAm at 5.5 y, and whether these variations correlate with neurodevelopmental phenotypes. METHODS This cohort study was a 5.5-y follow-up (2016-2018) of VLBW infants born in Ontario, Canada who participated in the Donor Milk for Improved Neurodevelopmental Outcomes trial. We performed an epigenome-wide association study (EWAS) to test whether percentage mother's milk (not including supplemental donor milk) during hospitalization was associated with DNAm in buccal cells during early childhood (n = 143; mean ± SD age: 5.7 ± 0.2 y; birth weight: 1008 ± 517 g). DNAm was assessed with the Illumina Infinium MethylationEPIC array at 814,583 CpGs. In secondary analyses, we tested associations between top-ranked CpGs and measures of early childhood neurodevelopment, e.g., total surface area of the cerebral cortex (n = 41, MRI) and Full-Scale IQ (n = 133, Wechsler Preschool and Primary Scale of Intelligence-IV). RESULTS EWAS analysis demonstrated percentage mother's milk intake by VLBW infants during hospitalization was associated with DNAm at 2 CpGs, cg03744440 [myosin XVB (MYO15B)] and cg00851389 [metallothionein 1A (MT1A)], at 5.5 y (P < 9E-08). Gene set enrichment analysis indicated that top-ranked CpGs (P < 0.001) were annotated to genes enriched in neurodevelopmental biological processes. Corroborating these findings, DNAm at several top identified CpGs from the EWAS was associated with cortical surface area and IQ at 5.5 y (P < 0.05). CONCLUSIONS In-hospital percentage mother's milk intake by VLBW infants was associated with variations in DNAm of neurodevelopmental genes at 5.5 y; some of these DNAm variations are associated with brain structure and IQ.This trial was registered at isrctn.com as ISRCTN35317141 and at clinicaltrials.gov as NCT02759809.
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Comparison of the Efficacy and Safety of Atorvastatin 40 mg/ω-3 Fatty Acids 4 g Fixed-dose Combination and Atorvastatin 40 mg Monotherapy in Hypertriglyceridemic Patients who Poorly Respond to Atorvastatin 40 mg Monotherapy: An 8-week, Multicenter, Randomized, Double-blind Phase III Study.
Woo, JS, Hong, SJ, Cha, DH, Kim, KS, Kim, MH, Lee, JW, Jeong, MH, Jeong, JO, Lee, JH, Jeon, DS, et al
Clinical therapeutics. 2021;(8):1419-1430
Abstract
PURPOSE Residual cardiovascular risk in patients with hypertriglyceridemia, despite optimal low-density lipoprotein cholesterol levels being achieved with intensive statin treatment, is a global health issue. The purpose of this study was to investigate the efficacy and tolerability of treatment with a combination of high-dose atorvastatin/Ω-3 fatty acid compared to atorvastatin + placebo in patients with hypertriglyceridemia who did not respond to statin treatment. METHODS In this multicenter, randomized, double-blind, placebo-controlled study, patients who had residual hypertriglyceridemia after a 4-week run-in period of atorvastatin treatment were randomly assigned to receive UI-018 (fixed-dose combination atorvastatin/Ω-3 fatty acid 40 mg/4 g) or atorvastatin 40 mg + placebo (control). The primary efficacy end points were the percentage change from baseline in non-high density lipoprotein cholesterol (non-HDL-C) level at the end of treatment and the adverse events recorded during treatment. A secondary end point was the percentage change from baseline in triglyceride level. FINDINGS After 8 weeks of treatment, the percentage changes from baseline in non-HDL-C (-4.4% vs +0.6%; p = 0.02) and triglycerides (-18.5% vs +0.9%; p < 0.01) were significantly greater in the UI-018 group (n = 101) than in the control group (n = 99). These changes were present in subgroups of advanced age (≥65 years), status (body mass index ≥25 kg/m2), or without diabetes. The prevalences of adverse events did not differ between the 2 treatment groups. IMPLICATIONS In patients with residual hypertriglyceridemia despite receiving statin treatment, a combination of high-dose atorvastatin/Ω-3 fatty acid was associated with a greater reduction of triglyceride and non-HDL-C compared with atorvastatin + placebo, without significant adverse events.
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Efficacy of a fixed dose combination of irbesartan and atorvastatin (Rovelito®) in Korean adults with hypertension and hypercholesterolemia.
Ihm, SH, Shin, J, Park, CG, Kim, CH
Drug design, development and therapy. 2019;:633-645
Abstract
PURPOSE Coexistence of hypertension (HTN) and hypercholesterolemia is a major synergistic and modifiable risk factor for cardiovascular disease (CVD). Thus, a fixed-dose combination (FDC) of anti-HTN drugs and statins may be useful for treating CVD. This study evaluated the efficacy of an FDC of irbesartan and atorvastatin (Rovelito®) in Korean patients. PATIENTS AND METHODS Patients with HTN and hypercholesterolemia were screened for this prospective, observational, descriptive, multi-center, phase IV study. Eligible patients were administered with Rovelito for 3 months. Dose adjustment was allowed based on the physician's discretion. Blood pressure (BP) goal was <140/90 mmHg, and blood lipid goal was based on Adult Treatment Panel III. Compliance with therapeutic lifestyle modification and safety of the study drugs were evaluated. RESULTS Of the 2,777 patients enrolled in this study, 931 were analyzed for clinical efficacy. BP and low-density lipoprotein cholesterol (LDL-C) goals were achieved in 801 (86.04%) and 797 (85.61%) patients, respectively. For the BP goal, higher baseline BP and higher body mass index were risk factors for treatment failure. For LDL-C goal, baseline LDL-C level, number of concomitant drugs, smoking status, and alcohol consumption were risk factors for treatment failure. Of the 931 participants, 694 (74.54%) achieved the treatment goals for both BP and LDL-C. Smoking status, alcohol consumption, number of concomitant drugs, and higher baseline LDL-C and BP levels were risk factors for treatment failure in both BP and LDL-C goals. Adherence with Rovelito was 97.90%±5.79%, and incidence of adverse events was 4.19% (116). CONCLUSION FDC of irbesartan and atorvastatin (Rovelito) could be extremely helpful in treating patients with both HTN and hypercholesterolemia. Poor metabolic profiles were risk factors for poor treatment response and the reason for choosing Rovelito. Therapeutic lifestyle modification should still be underscored despite the 75% treatment success rate with Rovelito for both conditions.
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The Effect of Prior Continuous Glucose Monitoring Use on Glycemic Outcomes in the Pivotal Trial of the MiniMed™ 670G Hybrid Closed-Loop System.
Cordero, TL, Garg, SK, Brazg, R, Bailey, TS, Shin, J, Lee, SW, Kaufman, FR
Diabetes technology & therapeutics. 2017;(12):749-752
Abstract
A 3-month pivotal trial using the MiniMed™ 670G hybrid closed-loop (HCL) system in adolescent and adult patients with type 1 diabetes (T1D), relative to a 2-week baseline run-in period, resulted in increased sensor glucose (SG) values in target range (71-180 mg/dL), reduced HbA1c levels, and no events of diabetic ketoacidosis or severe hypoglycemia ( Clinicaltrials.gov : NCT02463097). This brief report evaluated how prior continuous glucose monitoring (CGM) experience influenced glycemic outcomes, in the same pivotal trial. HbA1c levels and the percentage of SG values in low, high, and in-target ranges were analyzed from participants (n = 124) completing the Hybrid Closed-Loop Pivotal Trial in T1D. There were 78 individuals comprising the prior CGM group and 46 comprising the no prior CGM group. Compared to baseline, HbA1c was reduced from 7.4% ± 0.9% to 6.9% ± 0.7% for the prior CGM group and from 7.5% ± 0.9% to 6.8% ± 0.5% for the no prior CGM group. For those with prior CGM experience, the mean percentage of in-target SG values increased from 66.9% ± 12.5% to 72.6% ± 9.1%, and for those with no prior CGM experience it increased from 66.6% ± 11.7% to 71.5% ± 8.5%. Similar improvement in glucose values in the low and high ranges, relative to baseline, was observed for both groups. Resulting outcomes, from baseline to study end, did not differ between each group. These findings suggest that individuals without prior CGM experience, and those already using CGM, will benefit similarly with use of the FDA-approved MiniMed 670G HCL system therapy.
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Clinical efficacy and cost-effectiveness of lanthanum carbonate as second-line therapy in hemodialysis patients in Japan.
Goto, S, Komaba, H, Moriwaki, K, Fujimori, A, Shibuya, K, Nishioka, M, Kim, JI, Yoshiya, K, Shin, J, Hasegawa, H, et al
Clinical journal of the American Society of Nephrology : CJASN. 2011;(6):1375-84
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BACKGROUND AND OBJECTIVES Lanthanum carbonate (LC) is a nonaluminum, noncalcium phosphate binder that is effective for hyperphosphatemia in dialysis patients. However, its efficacy and cost-effectiveness as second-line therapy have not been fully examined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We first conducted a multicenter, open-label, 16-week clinical trial to examine the effect of additive LC in 116 hemodialysis patients who had uncontrolled hyperphosphatemia with conventional phosphorus-lowering therapy alone. Based on these clinical data, a state transition model was developed to evaluate the benefits and costs associated with LC as second-line therapy. Reduced risks for cardiovascular morbidity and mortality among patients treated with LC arise through more of the population achieving the target phosphorus levels. Uncertainty was explored through sensitivity analysis. RESULTS After 16 weeks of additive LC treatment, mean serum phosphorus levels decreased from 7.30 ± 0.90 to 5.71 ± 1.32 mg/dl, without significant changes in serum calcium or intact parathyroid hormone levels. A subsequent cost-effectiveness analysis showed that compared with conventional treatment, additive LC incurred an average additional lifetime cost of $22,054 per person and conferred an additional 0.632 quality-adjusted life years (QALYs). This resulted in an incremental cost-effectiveness ratio of $34,896 per QALY gained. Applying a cost-effectiveness threshold of $50,000 per QALY, a probabilistic sensitivity analysis showed that additive LC had a 97.4% probability of being cost-effective compared with conventional treatment. CONCLUSIONS Our results indicate that the use of LC as second-line therapy would be cost-effective among hemodialysis patients with uncontrolled hyperphosphatemia in Japan.
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Health-related quality of life in patients with pulmonary arterial hypertension.
Taichman, DB, Shin, J, Hud, L, Archer-Chicko, C, Kaplan, S, Sager, JS, Gallop, R, Christie, J, Hansen-Flaschen, J, Palevsky, H
Respiratory research. 2005;(1):92
Abstract
BACKGROUND Improved outcomes with expanding treatment options for patients with pulmonary arterial hypertension present the opportunity to consider additional end-points in approaching therapy, including factors that influence health-related quality of life. However, comparatively little is known about health-related quality of life and its determinants in patients with pulmonary arterial hypertension. METHODS Health-related quality of life was evaluated in a cross sectional study of 155 outpatients with pulmonary arterial hypertension using generic and respiratory-disease specific measurement tools. Most patients had either World Health Organization functional Class II or III symptoms. Demographic, hemodynamic and treatment variables were assessed for association with health-related quality of life scores. RESULTS Patients with pulmonary arterial hypertension suffered severe impairments in both physical and emotional domains of health-related quality of life. Patients with idiopathic ("primary") pulmonary arterial hypertension had the best, and those with systemic sclerosis the worst health-related quality of life. Greater six-minute walk distance correlated with better health-related quality of life scores, as did functional Class II versus Class III symptoms. Hemodynamic measurements, however, did not correlate with health-related quality of life scores. No differences in health-related quality of life were found between patients who were being treated with calcium channel antagonists, bosentan or continuously infused epoprostenol at the time of quality of life assessment. CONCLUSION Health-related quality of life is severely impaired in patients with pulmonary arterial hypertension and is associated with measures of functional status. Specific associations with impaired health-related quality of life suggest potential areas for targeted intervention.