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Tofogliflozin long-term effects on atherosclerosis progression and major clinical parameters in patients with type 2 diabetes mellitus lacking a history of cardiovascular disease: a 2-year extension study of the UTOPIA trial.
Katakami, N, Mita, T, Yoshii, H, Shiraiwa, T, Yasuda, T, Okada, Y, Kurozumi, A, Hatazaki, M, Kaneto, H, Osonoi, T, et al
Cardiovascular diabetology. 2023;(1):143
Abstract
BACKGROUND This study aimed to assess the long-term effects of tofogliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on atherosclerosis progression and major clinical parameters in patients with type 2 diabetes lacking an apparent history of cardiovascular disease. METHODS This was a prospective observational 2-year extension study of the "Using TOfogliflozin for Possible better Intervention against Atherosclerosis for type 2 diabetes patients (UTOPIA)" trial, a 2-year randomized intervention study. The primary endpoints represented changes in the carotid intima-media thickness (IMT). Secondary endpoints included brachial-ankle pulse wave velocity (baPWV) and biomarkers for glucose metabolism, lipid metabolism, renal function, and cardiovascular risks. RESULTS The mean IMT of the common carotid artery (IMT-CCA) significantly decreased in both the tofogliflozin (- 0.067 mm, standard error 0.009, p < 0.001) and conventional treatment groups (- 0.080 mm, SE 0.009, p < 0.001) throughout the follow-up period; however, no significant intergroup differences in the changes (0.013 mm, 95% confidence interval (CI) - 0.012 to 0.037, p = 0.32) were observed in a mixed-effects model for repeated measures. baPWV significantly increased in the conventional treatment group (82.7 ± 210.3 cm/s, p = 0.008) but not in the tofogliflozin group (- 17.5 ± 221.3 cm/s, p = 0.54), resulting in a significant intergroup difference in changes (- 100.2 cm/s, 95% CI - 182.8 to - 17.5, p = 0.018). Compared to the conventional treatment group, tofogliflozin significantly improved the hemoglobin A1c and high-density lipoprotein cholesterol levels, body mass index, abdominal circumference, and systolic blood pressure. The frequencies of total and serious adverse events did not vary significantly between the groups. CONCLUSIONS Tofogliflozin was not associated with improved inhibition of carotid wall thickening but exerted long-term positive effects on various cardiovascular risk factors and baPWV while showing a good safety profile.
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Effect of Bone Resorption Inhibitors on Serum Cholesterol Level and Fracture Risk in Osteoporosis: Randomized Comparative Study Between Minodronic Acid and Raloxifene.
Ohta, H, Uemura, Y, Sone, T, Tanaka, S, Soen, S, Mori, S, Hagino, H, Fukunaga, M, Nakamura, T, Orimo, H, et al
Calcified tissue international. 2023;(4):430-439
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Abstract
The positive link between osteoporosis and hypercholesterolemia has been documented, and bone resorption inhibitors, such as nitrogen-containing bisphosphonates (N-BP) and selective estrogen receptor modulators (SERMs), are known to reduce serum cholesterol levels. However, the relationship between the baseline cholesterol level and incident fracture rate under the treatment using the bone resorption inhibitors has not been documented. We investigated the relation between vertebral fracture incident and the baseline cholesterol levels and cholesterol-lowering effect of N-BP and SERM in osteoporosis through a prospective randomized open-label study design. Patients with osteoporosis (n = 3986) were allocated into two groups based on the drug used for treatment: minodronic acid (MIN) (n = 1624) as an N-BP and raloxifene (RLX) as an SERM (n = 1623). Serum levels of cholesterol and incidence of vertebral fracture were monitored for 2 years. The vertebral fracture rates between the two groups were compared using the pre-specified stratification factors. The patients receiving MIN with baseline low-density lipoprotein (LDL)-cholesterol level of ≥ 140 mg/dL, high-density lipoprotein cholesterol level < 40 mg/dL, age group of ≥ 75 years, and T score of BMD ≥ -3 SD had significantly lower vertebral fracture rates than those receiving RLX (incidence rate ratios (IRR) 0.45 [95% confidence interval (CI) 0.30 0.75, p = 0.001], 0.25 [95% CI 0.09 0.65, p = 0.005], 0.71 [95% CI 0.56 0.91, p = 0.006], 0.47 [95% CI 0.30 0.75, p = 0.0012], respectively). The cholesterol-lowering effect was stronger in the RLX group than in the MIN group, regardless of prior statin use. These results indicated that MIN treatment was more effective in reducing fracture risk in patients with higher LDL cholesterol levels, although its cholesterol-lowering ability was lesser than the RLX treatment.Trial registration University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR), No. UMIN000005433; date: April 13, 2011.
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Effects of sodium bicarbonate bath on the quality of sleep: An assessor-blinded, randomized, controlled, pilot clinical trial.
Tamaoki, S, Matsumoto, S, Sasa, N, Hoei, T, Tojo, R, Nakamura, T, Aoyagi, Y
Complementary therapies in clinical practice. 2023;:101714
Abstract
BACKGROUND Sleep is fundamental to a healthy life, and sleep disorders are an important health issue in healthcare. Whole-body warm water bathing is a non-pharmacological, safe (non-invasive), and widely used method for comforting. Here, we explored the feasibility and preliminary effectiveness of sodium bicarbonate bath (SBB) on sleep quality. METHODS Healthy adults without sleep disturbances were randomly assigned to shower baths (SHB), tap-water baths (TWB, placebo tablets), or SBB. All participants took a bath (shower, tap-water, or SBB) once a day for 10 min, after dinner, for 7 days. Sleepscan-derived sleep parameters, including total sleep time (TST), symptom questionnaires, and salivary α-amylase concentration were evaluated as outcome measures. RESULTS Forty participants were enrolled (14, 13, and 13 in SHB, TWB, and SBB groups, respectively) and 38 participants completed the trial (13, 12, and 13, respectively). The recruitment, adherence, and completion rates were 90.9% (40/44), 95.0% (38/40), and 95.0% (38/40), respectively. The SBB group showed a significant increase (12.35 [mean]±10.07 [standard deviation] min) in the mean TST at 1-week post-intervention (p = 0.0041) than the SHB (-1.81 ± 14.58 min; p = 0.0231) and TWB (4.54 ± 10.97 min; p = 0.0377) groups. The TST scores at 1-week post-intervention, sleep onset latency, wake after sleep onset, and sleep efficiency were significantly different between the groups. Sleep satisfaction by questionnaire was significantly improved with intervention in the SBB group than that in the SHB and TWB groups. Salivary α-amylase levels significantly improved in the SBB and TWB groups than in the SHB group, with the change being greater in the SBB group. CONCLUSIONS SBB for 7 days had positive effects that improved sleep quality of adults. Further studies are needed to examine the efficacy and safety of SBB for prolonged usage in people diagnosed with insomnia, using objective sleep measurements, and to investigate potential sleep-enhancing mechanisms of action.
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Different changes in the biomarker C-terminal telopeptides of type II collagen (CTX-II) following intra-articular injection of high molecular weight hyaluronic acid and oral non-steroidal anti-inflammatory drugs in patients with knee osteoarthritis: a multi-center randomized controlled study.
Ishijima, M, Nakamura, T, Shimizu, K, Hayashi, K, Kikuchi, H, Soen, S, Omori, G, Yamashita, T, Uchio, Y, Chiba, J, et al
Osteoarthritis and cartilage. 2022;(6):852-861
Abstract
OBJECTIVES We previously reported, based on a multicenter randomized-control study, that the efficacy of intra-articular injections of hyaluronic acid (IA-HA) was not inferior to that of oral non-steroidal anti-inflammatory drugs (NSAIDs) in patients with knee osteoarthritis (OA). However, the molecular effects on the pathophysiology of knee OA remain unclear. C-terminal telopeptides of type II collagen (CTX-II) is reported to primarily originate from the interface between articular cartilage and subchondral bone, which is a site of potential remodeling in OA. We performed a predefined sub-analysis of the previous study to compare the changes of urinary CTX-II (uCTX-II) in response to IA-HA to those in response to NSAID for knee OA. DESIGN A total of 200 knee OA patients were registered from 20 hospitals and randomized to receive IA-HA (2,700 kDa HA, 5 times at 1-week intervals) or NSAID (loxoprofen sodium, 180 mg/day) for 5 weeks. The uCTX-II levels were measured before and after treatment. RESULTS The uCTX-II levels were significantly increased by IA-HA treatment (337.7 ± 193.8 to 370.7 ± 234.8 ng/μmol Cr) and were significantly reduced by NSAID treatment (423.2 ± 257.6 to 370.3 ± 250.9 ng/μmol Cr). The %changes of uCTX-II induced by IA-HA (11.6 ± 29.5%) and NSAID (-9.0 ± 26.7%) was significantly different (between-group difference: 20.6, 95% confidence intervals: 10.6 to 30.6). CONCLUSIONS While both IA-HA and NSAID improved symptoms of knee OA, uCTX-II levels were increased by IA-HA and reduced by NSAIDs treatment, suggesting these treatments may improve symptoms of knee OA through different modes of action.
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Malnutrition-associated high bleeding risk with low thrombogenicity in patients undergoing percutaneous coronary intervention.
Nakanishi, N, Kaikita, K, Ishii, M, Kuyama, N, Tabata, N, Ito, M, Yamanaga, K, Fujisue, K, Hoshiyama, T, Kanazawa, H, et al
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2022;(5):1227-1235
Abstract
BACKGROUND AND AIMS Although antithrombotic treatments are established for coronary artery disease (CAD), they increase the bleeding risk, especially in malnourished patients. The total thrombus-formation analysis system (T-TAS) is useful for the assessment of thrombogenicity in CAD patients. Here, we examined the relationships among malnutrition, thrombogenicity and 1-year bleeding events in patients undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS This was a retrospective analysis of 300 consecutive CAD patients undergoing PCI. Blood samples obtained on the day of PCI were used in the T-TAS to compute the thrombus formation area under the curve. We assigned patients to two groups based on the geriatric nutritional risk index (GNRI): 102 patients to the lower GNRI group (≤98), 198 patients to the higher GNRI group (98<). The primary endpoint was the incidence of 1-year bleeding events defined by Bleeding Academic Research Consortium criteria types 2, 3, or 5. The T-TAS levels were lower in the lower GNRI group than in the higher GNRI group. Kaplan-Meier analysis showed worse 1-year bleeding event-free survival in the lower GNRI group compared with the higher GNRI group. The combined model of the GNRI and the Academic Research Consortium for High Bleeding Risk (ARC-HBR) had good calibration and discrimination for bleeding risk prediction. In addition, having a lower GNRI and ARC-HBR positivity was associated with 1-year bleeding events. CONCLUSION A lower GNRI could reflect low thrombogenicity evaluated by the T-TAS and determine bleeding risk in combination with ARC-HBR positivity.
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Rationale, design and baseline characteristics of the effect of canagliflozin in patients with type 2 diabetes and microalbuminuria in the Japanese population: The CANPIONE study.
Miyamoto, S, Heerspink, HJL, de Zeeuw, D, Toyoda, M, Suzuki, D, Hatanaka, T, Nakamura, T, Kamei, S, Murao, S, Hida, K, et al
Diabetes, obesity & metabolism. 2022;(8):1429-1438
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Abstract
AIM: To evaluate the effect of canagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor, on albuminuria and the decline of estimated glomerular filtration rate (eGFR) in participants with type 2 diabetes and microalbuminuria. METHODS The CANPIONE study is a multicentre, randomized, parallel-group and open-labelled study consisting of a unique 24-week preintervention period, during which the rate of eGFR decline before intervention is estimated, followed by a 52-week intervention and a 4-week washout period. Participants with a geometric mean urinary albumin-to-creatinine ratio (UACR) of 50 and higher and less than 300 mg/g in two consecutive first-morning voids at two different time points, and an eGFR of 45 ml/min/1.73m2 or higher, are randomly assigned to receive canagliflozin 100 mg daily or to continue guideline-recommended treatment, except for SGLT2 inhibitors. The first primary outcome is the change in UACR, and the second primary outcome is the change in eGFR slope. RESULTS A total of 258 participants were screened and 98 were randomized at 21 sites in Japan from August 2018 to May 2021. The mean baseline age was 61.4 years and 25.8% were female. The mean HbA1c was 7.9%, mean eGFR was 74.1 ml/min/1.73m2 and median UACR was 104.2 mg/g. CONCLUSIONS The CANPIONE study will determine whether the SGLT2 inhibitor canagliflozin can reduce albuminuria and slow eGFR decline in participants with type 2 diabetes and microalbuminuria.
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Incidence of Hip and Subtrochanteric/Femoral Shaft Fractures in Postmenopausal Women With Osteoporosis in the Phase 3 Long-Term Odanacatib Fracture Trial.
Papapoulos, S, Bone, H, Cosman, F, Dempster, DW, McClung, MR, Nakamura, T, Restrepo, JFM, Bouxsein, ML, Cohn, D, de Papp, A, et al
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2021;(7):1225-1234
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Abstract
We prospectively assessed, with predefined criteria, the location and rates of all femur fractures (hip, subtrochanteric/femoral shaft [ST/FS], including atypical [AFF] and distal fractures) in women at increased fracture risk during treatment with the cathepsin K inhibitor, odanacatib (ODN), or placebo over 5 years in the Long-Term ODN Fracture Trial (LOFT and LOFT Extension [NCT00529373, EudraCT 2007-002693-66]). ODN was an investigational antiresorptive agent previously in development as an osteoporosis treatment that, unlike bisphosphonates, reduces bone formation only transiently. Women aged ≥65 years with a bone mineral density (BMD) T-score ≤-2.5 at the total hip (TH) or femoral neck (FN) or with a radiographic vertebral fracture and T-scores ≤-1.5 at the TH or FN were randomized (1:1) to receive ODN 50 mg/week or placebo. All patients received vitamin D3 (5600 IU/week) and calcium (total 1200 mg/d); the analysis included 16,071 women. Rates of all adjudicated low-energy femoral fractures were 0.38 versus 0.58/100 patient-years for ODN and placebo, respectively (hazard ratio [HR] = 0.65; 95% confidence interval [CI] 0.51-0.82; nominal p < .001), and for low-energy hip fractures were 0.29 versus 0.56/100 patient-years, respectively (HR = 0.52; 95% CI 0.40-0.67; p < .001). The cumulative incidence of combined hip and ST/FS or hip fractures alone in the ODN group was consistently lower than in the placebo group (1.93% versus 3.11% for combined fractures and 1.53% versus 3.03% for hip fractures at 5 years, respectively). However, low-energy ST/FS fractures were more frequent in ODN-treated women than in placebo-treated women (24 versus 6, respectively). Among these, 12 fractures were adjudicated as AFF in 10 patients treated with ODN (0.03/100 patient-years) compared with none in the 6 placebo-treated women (estimated difference 0.03; 95% CI 0.02-0.06). These results provide insight into possible pathogeneses of AFF, suggesting that the current criteria for diagnosing these fractures may need to be reconsidered. © 2021 American Society for Bone and Mineral Research (ASBMR)..
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Impact of bone mineral density in reducing fracture risk in patients receiving alendronate plus alfacalcidol therapy.
Itoi, E, Uemura, Y, Ohta, H, Nakamura, T, Fukunaga, M, Orimo, H, Shiraki, M
Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association. 2021;(6):1085-1093
Abstract
BACKGROUD Changes in bone mineral density (BMD) are a potential surrogate marker for fracture endpoints in clinical trials. However little is known whether the increase in BMD in response to combination treatment with alendronate plus alfacalcidol is associated with fracture risk reduction. We aimed to evaluate the impact of BMD on fracture risk in osteoporosis patients, using the data from the randomized clinical trial comparing alendronate plus alfacalcidol with alendronate alone. METHODS We selected 412 patients with two or more prevalent vertebral fractures and who had BMD measurements at baseline and after 6, 12, and/or 24 months out of 2022 patients from the database of the Japanese Osteoporosis Intervention Trial. Patients in this subset who received combination treatment with alendronate plus alfacalcidol had shown a lower risk of fracture than patients treated with alendronate alone. We used Poisson regression model analysis to calculate the proportion of treatment effect (PTE) that was attributable to BMD increases in patients receiving combination treatment. RESULTS The highest PTE attributable to changes in BMD was 1.2% in patients with a BMD increase of 3% or more in the lumbar spine. For BMD measurements of the radius, the highest PTE was 2.8% with a BMD increase of 0% or more. For BMD measurements of the metacarpal bone, the highest PTE was 1.2% with a BMD increase of 3% or more. In patients with a BMD greater than or equal to 70% of the young adult mean in the lumbar spine, the PTE attributable to BMD was 0.2%. In patients with a BMD greater than or equal to 70% of the young adult mean in the radius, the PTE attributable to BMD was 0.3%. CONCLUSIONS The additional effects of alfacalcidol in reducing fracture risk do not likely result from increased BMD; other mechanisms remain a possibility.
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Effect of tofogliflozin on arterial stiffness in patients with type 2 diabetes: prespecified sub-analysis of the prospective, randomized, open-label, parallel-group comparative UTOPIA trial.
Katakami, N, Mita, T, Yoshii, H, Shiraiwa, T, Yasuda, T, Okada, Y, Torimoto, K, Umayahara, Y, Kaneto, H, Osonoi, T, et al
Cardiovascular diabetology. 2021;(1):4
Abstract
BACKGROUND Tofogliflozin, an SGLT2 inhibitor, is associated with favorable metabolic effects, including improved glycemic control and serum lipid profile and decreased body weight, visceral adipose tissue, and blood pressure (BP). This study evaluated the effects of tofogliflozin on the brachial-ankle pulse wave velocity (baPWV) in patients with type 2 diabetes (T2DM) without a history of apparent cardiovascular disease. METHODS The using tofogliflozin for possible better intervention against atherosclerosis for type 2 diabetes patients (UTOPIA) trial is a prospective, randomized, open-label, multicenter, parallel-group, comparative study. As one of the prespecified secondary outcomes, changes in baPWV over 104 weeks were evaluated in 154 individuals (80 in the tofogliflozin group and 74 in the conventional treatment group) who completed baPWV measurement at baseline. RESULTS In a mixed-effects model, the progression in the right, left, and mean baPWV over 104 weeks was significantly attenuated with tofogliflozin compared to that with conventional treatment (- 109.3 [- 184.3, - 34.3] (mean change [95% CI] cm/s, p = 0.005; - 98.3 [- 172.6, - 24.1] cm/s, p = 0.010; - 104.7 [- 177.0, - 32.4] cm/s, p = 0.005, respectively). Similar findings were obtained even after adjusting the mixed-effects models for traditional cardiovascular risk factors, including body mass index (BMI), glycated hemoglobin (HbA1c), total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglyceride, systolic blood pressure (SBP), hypertension, smoking, and/or administration of drugs, including hypoglycemic agents, antihypertensive agents, statins, and anti-platelets, at baseline. The findings of the analysis of covariance (ANCOVA) models, which included the treatment group, baseline baPWV, and traditional cardiovascular risk factors, resembled those generated by the mixed-effects models. CONCLUSIONS Tofogliflozin significantly inhibited the increased baPWV in patients with T2DM without a history of apparent cardiovascular disease, suggesting that tofogliflozin suppressed the progression of arterial stiffness. Trial Registration UMIN000017607. Registered 18 May 2015. ( https://www.umin.ac.jp/icdr/index.html ).
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Phase 1 Studies to Define the Safety, Tolerability, and Pharmacokinetic and Pharmacodynamic Profiles of the Nonsteroidal Mineralocorticoid Receptor Antagonist Apararenone in Healthy Volunteers.
Nakamura, T, Kawaguchi, A
Clinical pharmacology in drug development. 2021;(4):353-365
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Abstract
Apararenone is a long-acting, nonsteroidal mineralocorticoid receptor antagonist (MRA). The safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) profiles of single- and multiple-dose apararenone were assessed in 3 phase 1 randomized, double-blind studies in 223 healthy adults. Study 1 assessed the PK, safety/tolerability, and PD of single-dose apararenone (3.75-640 mg) and multiple-dose apararenone (10-40 mg/day on days 1-14, 320 mg loading dose on day 1 + 10 mg/day on days 2-14, or 40-320 mg loading dose on day 1 + 2.5-20 mg/day on days 2-14) in Caucasian and Black men and women. Study 2 assessed the PK and safety of single-dose apararenone (5-320 mg) in healthy Japanese men. Study 3 assessed the PK, PD, and safety/tolerability of single-dose apararenone (160 or 640 mg) or eplerenone (200 mg; only for 160 mg of apararenone), each after fludrocortisone challenge in Caucasian men. In studies 1 and 2, an approximately dose-proportional increase was observed in PK parameters over the apararenone dose range of 3.75-40 mg; at higher doses, a less than dose-proportional increase was observed. Food, sex, age, and race had no apparent effect on apararenone PK. A long half-life was seen for apararenone and its principal metabolite; in addition, the exposure of the metabolite was lower than that of apararenone. Apararenone suppressed the decrease in urinary sodium and potassium ion ratio that occurs after loading with fludrocortisone. These studies support the mechanism of action of apararenone as an MRA, and further clinical development is warranted.