Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Ohkuma Toshiaki Last modified date:2023.11.22

Assistant Professor / Department of Nephrology,Hypertension,and Strokology / Kyushu University Hospital


Papers
1. Toshiaki Ohkuma, Katie Harris, Mark Cooper, Diederick E Grobbee, Pavel Hamet, Stephen Harrap, Giuseppe Mancia, Michel Marre, Anushka Patel, Anthony Rodgers, Bryan Williams, Mark Woodward, John Chalmers, Short-Term Changes in Serum Potassium and the Risk of Subsequent Vascular Events and Mortality: Results from a Randomized Controlled Trial of ACE Inhibitors., Clinical journal of the American Society of Nephrology : CJASN, 10.2215/CJN.00180122, 17, 8, 1139-1149, 2022.08, BACKGROUND AND OBJECTIVES: Hyperkalemia after starting renin-angiotensin system inhibitors has been shown to be subsequently associated with a higher risk of cardiovascular and kidney outcomes. However, whether to continue or discontinue the drug after hyperkalemia remains unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data came from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, which included a run-in period where all participants initiated angiotensin-converting enzyme inhibitor-based therapy (a fixed combination of perindopril and indapamide). The study population was taken as patients with type 2 diabetes with normokalemia (serum potassium of 3.5 to
2. Mai Seki, Toshiaki Nakano, Shigeru Tanaka, Yuta Matsukuma, Kouta Funakoshi, Toshiaki Ohkuma, Takanari Kitazono, Design and methods of an open-label, randomized controlled trial to evaluate the effect of pemafibrate on proteinuria in CKD patients (PROFIT-CKD)., Clinical and experimental nephrology, 10.1007/s10157-023-02322-4, 27, 4, 358-364, 2023.02, BACKGROUND: Hypertriglyceridemia is increasingly considered a residual risk of cardiovascular disease in patients with chronic kidney disease (CKD). Pemafibrate-a novel selective peroxisome proliferator-activated receptor alpha modulator and a new treatment for hypertriglyceridemia in CKD patients-is reported to have fewer side effects in CKD patients than other fibrates. Appropriate control of hypertriglyceridemia can be expected to improve renal prognosis. However, data on the renal protective effect of pemafibrate are limited. This study aims to evaluate the effectiveness of pemafibrate on urinary protein excretion in CKD patients. METHODS: The Pemafibrate, open-label, Randomized cOntrolled study to evaluate the renal protective eFfect In hyperTriglyceridemia patients with Chronic Kidney Disease (PROFIT-CKD) study is an investigator-initiated, multi-center, open-label, parallel-group, randomized controlled trial. Participants are outpatients with hypertriglyceridemia aged 20 years and over, who have received the care of a nephrologist or a diabetologist for more than 3 months. Inclusion criteria include the following: proteinuria (urine protein/creatinine ratio of ≥ 0.15 g/gCr) within three months before allocation, and hypertriglyceridemia (triglycerides ≥ 150 mg/dL and 
3. Yuji Komorita, Toshiaki Ohkuma, Masanori Iwase, Hiroki Fujii, Hitoshi Ide, Yutaro Oku, Taiki Higashi, Ayaka Oshiro, Wakako Sakamoto, Masahito Yoshinari, Udai Nakamura, Takanari Kitazono, Relationship of coffee consumption with a decline in kidney function among patients with type 2 diabetes: The Fukuoka Diabetes Registry., Journal of diabetes investigation, 10.1111/jdi.13769, 2022.02, AIMS/INTRODUCTION: The evidence regarding the effects of coffee consumption on incident chronic kidney disease is inconclusive, and no studies have investigated the relationship in patients with diabetes. We aimed to prospectively investigate the relationship between coffee consumption and the decline in estimated glomerular function rate (eGFR) in patients with type 2 diabetes. MATERIALS AND METHODS: A total of 3,805 patients (2,112 men, 1,693 women) with type 2 diabetes (mean age 64.2 years) and eGFR ≥60 mL/min/1.73 m2 were followed (completion of follow up, 97.6%; median 5.3 years). Coffee consumption was assessed at baseline. The end-point was a decline in eGFR to
4. Hitoshi Ide, Masanori Iwase, Toshiaki Ohkuma, Hiroki Fujii, Yuji Komorita, Yutaro Oku, Taiki Higashi, Masahito Yoshinari, Udai Nakamura, Takanari Kitazono, Usefulness of urinary tubule injury markers for predicting progression of renal dysfunction in patients with type 2 diabetes and albuminuria: The Fukuoka Diabetes Registry., Diabetes research and clinical practice, 10.1016/j.diabres.2022.109840, 186, 109840-109840, 2022.03, AIMS: We prospectively investigated the association of urinary tubule injury markers with estimated glomerular filtration rate (eGFR) decline in Japanese patients with type 2 diabetes. METHODS: Urinary kidney injury molecule 1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), liver-type fatty-acid-binding protein (L-FABP), and urinary albumin-to creatinine ratio (UACR) were measured in 2,685 participants with type 2 diabetes. Renal outcomes were ≥ 30% decline in eGFR from the baseline and annual eGFR decline for 5 years. RESULTS: In normoalbuminuric participants, no tubular markers were associated with ≥ 30% decline in eGFR or annual eGFR changes. In those with UACR ≥ 30 mg/gCr, hazard ratios for ≥ 30% eGFR decline were 1.37 (95% confident interval (CI) 1.07-1.75) for urinary KIM-1 (>1.5 µg/gCr), 1.46 (95% CI 1.13-1.66) for urinary NGAL (>16.4 µg/gCr), and 1.26 (95% CI 0.94-1.66) for urinary L-FABP (>12.5 µg/gCr), 2.61 (95% CI 1.64-4.17) for the combination of 3 tubular markers above the cutoff after multivariable adjustments including UACR and eGFR. CONCLUSIONS: The current study demonstrated that urinary tubule injury markers and their combination were significant predictors for the future eGFR decline in those with type 2 diabetes and albuminuria independently of UACR and eGFR. Urinary tubular markers may be useful to identify high-risk patients with albuminuria..
5. Yuji Komorita, Masae Minami, Yasutaka Maeda, Rie Kishita, Toshiaki Ohkuma, Takanari Kitazono, Onset of type 1 diabetes during bone growth period is associated with increased prevalence of bone fracture: A post-hoc analysis of a cross-sectional study., Journal of diabetes investigation, 10.1111/jdi.13898, 2022.09, In this single-center, cross-sectional study, we demonstrated that the prevalence of fracture was significantly higher in patients who onset type 1 diabetes during 0-4 years, and 10-14 years compared with adult-onset type 1 diabetes. We are aware that this study contains a lot of limitations including non-prospective study design and a small number of participants. However, the results of this study, if followed by a larger cohort study, could provide important insights into the increased risk of fracture in patients with type 1 diabetes, and suggest the need for attention and perhaps early intervention for patients with type 1 diabetes who developed during these periods..
6. Toshiaki Ohkuma, Masanori Iwase, Hiroki Fujii, Hitoshi Ide, Yuji Komorita, Masahito Yoshinari, Yutaro Oku, Taiki Higashi, Ayaka Oshiro, Udai Nakamura, Takanari Kitazono, Constipation and diabetic kidney disease: The Fukuoka Diabetes Registry., Clinical and experimental nephrology, 10.1007/s10157-021-02105-9, 25, 11, 1247-1254, 2021.11, BACKGROUND: Constipation was shown to be associated with higher risk of end-stage kidney disease or incident chronic kidney disease, although evidence in diabetic patients is lacking. The objective of the present study was to examine the association between constipation and diabetic kidney disease (DKD). METHODS: In total, 4826 Japanese outpatients with type 2 diabetes were classified according to presence or absence of constipation (defecation frequency 
7. Yuji Komorita, Toshiaki Ohkuma, Masanori Iwase, Hiroki Fujii, Yutaro Oku, Taiki Higashi, Ayaka Oshiro, Wakako Sakamoto, Masahito Yoshinari, Udai Nakamura, Takanari Kitazono, Polypharmacy and bone fracture risk in patients with type 2 diabetes: The Fukuoka Diabetes Registry., Diabetes research and clinical practice, 10.1016/j.diabres.2021.109097, 181, 109097-109097, 2021.11, AIMS: To prospectively investigate the association between the number of prescribed drugs and the fracture risk in patients with type 2 diabetes. METHODS: Japanese participants with type 2 diabetes (n = 4,706; 2,755 men, 1,951 postmenopausal women; mean age, 66 years) were followed for a median of 5.3 years and grouped on the basis of the number of prescribed drugs at baseline. The main outcomes were fractures at any anatomic site and fragility fractures (fractures at hip and spine sites). RESULTS: During follow-up, any fracture occurred in 662 participants. The overall age- and sex-adjusted fracture incidence rates per 1,000 person-years were 21.2 (0-2 drugs), 28.1 (3-5 drugs), 37.7 (6-8 drugs), and 44.0 (≥9 drugs) (p for trend 
8. Yu Hisadome, Takanori Mei, Hiroshi Noguchi, Toshiaki Ohkuma, Yu Sato, Keizo Kaku, Yasuhiro Okabe, Masafumi Nakamura, Safety and Efficacy of Sodium-glucose Cotransporter 2 Inhibitors in Kidney Transplant Recipients With Pretransplant Type 2 Diabetes Mellitus: A Retrospective, Single-center, Inverse Probability of Treatment Weighting Analysis of 85 Transplant Patients., Transplantation direct, 10.1097/TXD.0000000000001228, 7, 11, e772, 2021.11, Whether sodium-glucose cotransporter 2 (SGLT2) inhibitors can be used effectively and safely in kidney transplant (KT) recipients with pretransplant type 2 diabetes as the primary cause of end-stage renal disease (ESRD) remains unclear. In this study, we retrospectively analyzed the efficacy and safety of SGLT2 inhibitors compared with other oral hypoglycemic agents (OHAs) in KT recipients with pretransplant type 2 diabetes as the primary cause of ESRD. Methods: In this retrospective, observational, single-center, inverse probability of treatment weighting (IPTW) analysis study, we compared the outcomes of SGLT2 inhibitors (SGLT2 group) and other OHAs (control group) following KT. A total of 85 recipients with type 2 diabetic nephropathy as the major cause of ESRD before KT who were treated at our institute between October 2003 and October 2019 were screened and included. The variables considered for IPTW were recipient age, sex, body mass index, history of cardiovascular disease, ABO incompatibility, insulin therapy, estimated glomerular filtration rate (eGFR), and hemoglobin A1c (HbA1c) at the initiation of additional OHAs. Primary endpoints were changes in HbA1c, body weight, and eGFR 1 y after the initiation of additional OHAs. Results: After IPTW analysis, there were 26 patients in the SGLT2 group and 59 patients in the control group (n = 85 overall). The body weights were significantly reduced in the SGLT2 group. There was no statistical difference in changes in HbA1c and eGFR. Similarly, there was no significant difference in the incidence of urinary infection, acute rejection, or other side effects between the groups. Conclusions: Our findings suggested that SGLT2 inhibitors reduced the body weight of KT recipients and were used safely without increasing side effects..
9. Brendon L Neuen, Misghina Weldegiorgis, William G Herrington, Toshiaki Ohkuma, Margaret Smith, Mark Woodward, Changes in GFR and Albuminuria in Routine Clinical Practice and the Risk of Kidney Disease Progression., American journal of kidney diseases : the official journal of the National Kidney Foundation, 10.1053/j.ajkd.2021.02.335, 78, 3, 350-360, 2021.09, RATIONALE & OBJECTIVE: Changes in urinary albumin-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) have been used separately as alternative kidney disease outcomes in randomized trials. We tested the hypothesis that combined changes in UACR and eGFR predict advanced kidney disease better than either alone. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: 91,319 primary care patients assembled from the Clinical Practice Research Datalink in the United Kingdom between 2000 and 2015. EXPOSURES: Changes in UACR and eGFR (categorized as ≥30% increase, stable, or ≥30% decrease), alone and in combination, over a 3-year period. OUTCOMES: The primary outcome was advanced CKD (sustained eGFR 
10. Masanori Iwase, Hitoshi Ide, Toshiaki Ohkuma, Hiroki Fujii, Yuji Komorita, Masahito Yoshinari, Yutaro Oku, Taiki Higashi, Udai Nakamura, Takanari Kitazono, Incidence of end-stage renal disease and risk factors for progression of renal dysfunction in Japanese patients with type 2 diabetes: the Fukuoka Diabetes Registry., Clinical and experimental nephrology, 10.1007/s10157-021-02136-2, 26, 2, 122-131, 2021.09, BACKGROUND: Epidemiological data regarding diabetic kidney disease are accumulated insufficiently in Japan. We prospectively investigated the incidence of end-stage renal disease (ESRD) and risk factors for progression of renal dysfunction in Japanese patients with type 2 diabetes. METHODS: 4904 participants with type 2 diabetes (mean age 65 years, mean estimated glomerular filtration rate (eGFR) 75 mL/min/1.73 m2, proportion of eGFR  
11. Toshiaki Ohkuma, John Chalmers, Mark Cooper, Pavel Hamet, Stephen Harrap, Michel Marre, Giuseppe Mancia, Neil Poulter, Mark Woodward, The comparative effects of intensive glucose lowering in diabetes patients aged below or above 65 years: Results from the ADVANCE trial., Diabetes, obesity & metabolism, 10.1111/dom.14339, 23, 6, 1292-1300, 2021.06, AIMS: For relatively old patients with diabetes, current guidelines recommend adjustment of glycaemic goals based on patients' cognitive function, or coexisting chronic illnesses. However, the evidence which supports the efficacy and safety of intensive glucose lowering in older patients with diabetes is scarce. The objective of the present study was to compare the efficacy and safety of intensive glucose lowering in patients with type 2 diabetes stratified by age (
12. Ayaka Oshiro, Toshiaki Ohkuma, Wakako Sakamoto, Yuji Komorita, Yutaro Oku, Yoichiro Hirakawa, Takanari Kitazono, An adult patient with permanent neonatal diabetes successfully discontinued insulin therapy after initiating sitagliptin added to sulphonylurea., Diabetes, obesity & metabolism, 10.1111/dom.14318, 23, 5, 1213-1214, 2021.05.
13. Yuji Komorita, Masae Minami, Yasutaka Maeda, Rie Yoshioka, Toshiaki Ohkuma, Takanari Kitazono, Prevalence of bone fracture and its association with severe hypoglycemia in Japanese patients with type 1 diabetes., BMJ open diabetes research & care, 10.1136/bmjdrc-2020-002099, 9, 1, 2021.04, INTRODUCTION: Type 1 diabetes (T1D) is associated with higher fracture risk. However, few studies have investigated the relationship between severe hypoglycemia and fracture risk in patients with T1D, and the results are controversial. Besides, none has investigated the risk factors for fracture in Asian patients with T1D. The aim of the present study was to investigate the prevalence of bone fracture and its relationship between severe hypoglycemia and other risk factors in Japanese patients with T1D. RESEARCH DESIGN AND METHODS: The single-center cross-sectional study enrolled 388 Japanese patients with T1D (mean age, 45.2 years; women, 60.4%; mean duration of diabetes, 16.6 years) between October 2019 and April 2020. The occurrence and circumstances of any fracture after the diagnosis of T1D were identified using a self-administered questionnaire. The main outcomes were any anatomic site of fracture and fall-related fracture. Severe hypoglycemia was defined as an episode of hypoglycemia that required the assistance of others to achieve recovery. RESULTS: A total of 92 fractures occurred in 64 patients, and 59 fractures (64%) were fall-related. Only one participant experienced fracture within the 10 years following their diagnosis of diabetes. In logistic regression analysis, the multivariate-adjusted ORs (95% CIs) of a history of severe hypoglycemia were 2.11 (1.11 to 4.09) for any fracture and 1.91 (0.93 to 4.02) for fall-related fracture. Fourteen of 18 participants with multiple episodes of any type of fracture had a history of severe hypoglycemia (p
14. Toshiaki Ohkuma, Masanori Iwase, Hiroki Fujii, Hitoshi Ide, Yuji Komorita, Masahito Yoshinari, Yutaro Oku, Taiki Higashi, Udai Nakamura, Takanari Kitazono, Defecation frequency and glycemic control in patients with diabetes: The Fukuoka Diabetes Registry., Journal of diabetes and its complications, 10.1016/j.jdiacomp.2020.107751, 35, 2, 107751-107751, 2021.02, AIMS: Constipation has been shown to be associated with a higher risk of diabetes. However, few studies have evaluated the relationship between defecation frequency, one of the major symptoms of constipation, and glycemic control in patients with diabetes. The aim of the present study was to determine the relationship between defecation frequency and HbA1c in patients with diabetes. METHODS: We determined the relationship between defecation frequency and HbA1c in 5029 patients with diabetes in the Fukuoka Diabetes Registry, a multi-center prospective cohort study conducted in diabetes specialist outpatient clinic (mean age 64.9 years, men 55%). Participants were classified according to their defecation frequency: ≥7, 3-
15. Masanori Iwase, Yuji Komorita, Toshiaki Ohkuma, Hiroki Fujii, Hitoshi Ide, Masahito Yoshinari, Yutaro Oku, Taiki Higashi, Udai Nakamura, Takanari Kitazono, Incidence of stroke and its association with glycemic control and lifestyle in Japanese patients with type 2 diabetes mellitus: The Fukuoka diabetes registry., Diabetes research and clinical practice, 10.1016/j.diabres.2020.108518, 172, 108518-108518, 2021.02, AIMS: We prospectively investigated the incidence of stroke and its subtypes, risk factors and prognosis in Japanese patients with type 2 diabetes. METHODS: A total of 4,875 participants with type 2 diabetes (mean age 65.4 years, male 57%, previous stroke 10%) were investigated for the development of stroke for 5 years. Risk factors were evaluated using multivariable adjusted Cox proportional models. RESULTS: The incidence rates per 1,000 person-years were 6.7 for new-onset stroke (ischemic 5.5, hemorrhagic 1.2) and 22.7 for recurrent stroke (ischemic 18.8, hemorrhagic 3.8), respectively. Ischemic stroke was significantly associated with age, male, reduced regular physical activity, HbA1c, diabetic kidney disease and previous stroke. Lacunar infarction was significantly associated with obesity, reduced regular physical activity, HbA1c and diabetic kidney disease, whereas atherothrombotic stroke was significantly associated with age, reduced intake of dietary fiber, reduced regular physical activity, HbA1c and previous stroke. Recurrent stroke was significantly associated with depressive symptom. Thirty-day and one-year survival was 76% and 64% for hemorrhagic stroke, and 96% and 91% for ischemic stroke, respectively. CONCLUSIONS: The current study reemphasized the importance of glycemic control and lifestyle modification such as regular physical exercise for stroke prevention in patients with type 2 diabetes..
16. Brendon L Neuen, Toshiaki Ohkuma, Bruce Neal, David R Matthews, Dick de Zeeuw, Kenneth W Mahaffey, Greg Fulcher, Jaime Blais, Qiang Li, Meg J Jardine, Vlado Perkovic, David C Wheeler, Relative and Absolute Risk Reductions in Cardiovascular and Kidney Outcomes With Canagliflozin Across KDIGO Risk Categories: Findings From the CANVAS Program., American journal of kidney diseases : the official journal of the National Kidney Foundation, 10.1053/j.ajkd.2020.06.018, 77, 1, 23-34, 2021.01, RATIONALE & OBJECTIVE: Canagliflozin reduces the risk for cardiovascular and kidney outcomes in type 2 diabetes. This study aimed to assess the relative and absolute effects of canagliflozin on clinical outcomes across different KDIGO (Kidney Disease: Improving Global Outcomes) risk categories based on estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio. STUDY DESIGN: Post hoc analysis of the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. SETTINGS & PARTICIPANTS: The CANVAS Program randomly assigned 10,142 participants with type 2 diabetes at high cardiovascular risk and with eGFR≥30mL/min/1.73m2 to treatment with canagliflozin or placebo. INTERVENTION(S): Canagliflozin or matching placebo. OUTCOMES: The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, with a set of other cardiovascular and kidney prespecified outcomes. RESULTS: Of 10,142 participants, 10,031 (98.9%) had available baseline eGFR and urinary albumin-creatinine ratio data. The proportion of participants in low-, moderate-, high-, and very high-risk KDIGO categories was 58.6%, 25.8%, 10.6%, and 5.0%, respectively. The relative effect of canagliflozin on the primary outcome (HR, 0.86; 95% CI, 0.75-0.97) was consistent across KDIGO risk categories (P trend=0.2), with similar results for other cardiovascular and kidney outcomes. Absolute reductions in the primary outcome were greater within higher KDIGO risk categories (P trend=0.03) with a similar pattern of effect for the composite of cardiovascular death or hospitalization for heart failure (P trend=0.06) and for chronic eGFR slope (P trend = 0.04). LIMITATIONS: Predominantly a low kidney risk population, relatively few participants in higher KDIGO risk categories, and exclusion of individuals with eGFR
17. Hirofumi Tomiyama, Charalambos Vlachopoulos, Panagiotis Xaplanteris, Hiroki Nakano, Kazuki Shiina, Tomoko Ishizu, Takahide Kohro, Yukihito Higashi, Bonpei Takase, Toru Suzuki, Tsutomu Yamazaki, Tomoo Furumoto, Kazuomi Kario, Teruo Inoue, Shinji Koba, Yasuhiko Takemoto, Takuzo Hano, Masataka Sata, Yutaka Ishibashi, Koichi Node, Atsushi Tanaka, Koji Maemura, Yusuke Ohya, Taiji Furukawa, Hiroshi Ito, Toshiaki Ohkuma, Toshiharu Ninomiya, Taishiro Chikamori, Akira Yamashina, Shin-Ichiro Ueda, Usefulness of the SAGE score to predict elevated values of brachial-ankle pulse wave velocity in Japanese subjects with hypertension., Hypertension research : official journal of the Japanese Society of Hypertension, 10.1038/s41440-020-0472-7, 43, 11, 1284-1292, 2020.11, The score based on the office systolic blood pressure, age, fasting blood glucose level, and estimated glomerular filtration rate (SAGE score) has been proposed as a useful marker to identify elevated values of carotid-femoral pulse wave velocity (PWV). The present cross-sectional study was conducted to examine whether the SAGE score is also a useful marker to identify subjects with elevated brachial-ankle PWV values in Japanese subjects with hypertension. We measured the brachial-ankle PWV and calculated the SAGE score in a total of 1019 employees of a Japanese company with hypertension and 817 subjects with hypertension derived from a multicenter study cohort. The analyses in this study were based on data from these two study groups as well as on a composite population of the two (n = 1836). The receiver operating characteristic curve analysis showed that the area under the curve to identify subjects with brachial-ankle PWV values of ≥1800 cm/s was over 0.70 in each of the three study groups. Even after adjustments, a SAGE score ≥7 had a significant odds ratio for identifying subjects with brachial-ankle PWV values ≥1800 cm/s in the 1836 study subjects from the composite occupational and multicenter study cohort (odds ratio = 2.1, 95% confidence interval = 1.4-3.0, P 
18. Yuji Komorita, Masanori Iwase, Hiroki Fujii, Toshiaki Ohkuma, Hitoshi Ide, Tamaki Jodai-Kitamura, Masahito Yoshinari, Yutaro Oku, Taiki Higashi, Udai Nakamura, Takanari Kitazono, Additive effects of green tea and coffee on all-cause mortality in patients with type 2 diabetes mellitus: the Fukuoka Diabetes Registry., BMJ open diabetes research & care, 10.1136/bmjdrc-2020-001252, 8, 1, 2020.10, INTRODUCTION: The impact of consuming green tea or coffee on mortality in patients with diabetes is controversial. We prospectively investigated the impact of each beverage and their combination on mortality among Japanese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: In all, 4923 patients (2790 men, 2133 women) with type 2 diabetes (mean age, 66 years) were followed prospectively (median, 5.3 years; follow-up rate, 99.5%). We evaluated the amount of green tea and coffee consumed using self-administered questionnaires. RESULTS: During the follow-up period, 309 participants died. The consumption of green tea, coffee, and a combination of the beverages was associated with reduced all-cause mortality. Multivariable-adjusted hazard ratios (95% CIs) for green tea were as follows: none 1.0 (referent); 0.85 (0.60-1.22) for ≤1 cup/day; 0.73 (0.51-1.03) for 2-3 cups/day; 0.60 (0.42-0.85) for ≥4 cups/day; and P for trend, 0.002. For coffee, they were: none 1.0 (referent); 0.88 (0.66-1.18) for
19. Megumi Oshima, Bruce Neal, Tadashi Toyama, Toshiaki Ohkuma, Qiang Li, Dick de Zeeuw, Hiddo J L Heerspink, Kenneth W Mahaffey, Gregory Fulcher, William Canovatchel, David R Matthews, Vlado Perkovic, Different eGFR Decline Thresholds and Renal Effects of Canagliflozin: Data from the CANVAS Program., Journal of the American Society of Nephrology : JASN, 10.1681/ASN.2019121312, 31, 10, 2446-2456, 2020.10, BACKGROUND: Traditionally, clinical trials evaluating effects of a new therapy with creatinine-based renal end points use doubling of serum creatinine (equivalent to a 57% eGFR reduction), requiring large sample sizes. METHODS: To assess whether eGFR declines
20. Kazem Rahimi, Milad Nazarzadeh, Ana-Catarina Pinho-Gomes, Mark Woodward, Gholamreza Salimi-Khorshidi, Toshiaki Ohkuma, Raymond Fitzpatrick, Lionel Tarassenko, Mike Denis, John Cleland, Home monitoring with technology-supported management in chronic heart failure: a randomised trial., Heart (British Cardiac Society), 10.1136/heartjnl-2020-316773, 106, 20, 1573-1578, 2020.10, OBJECTIVES: We aimed to investigate whether digital home monitoring with centralised specialist support for remote management of heart failure (HF) is more effective in improving medical therapy and patients' quality of life than digital home monitoring alone. METHODS: In a two-armed partially blinded parallel randomised controlled trial, seven sites in the UK recruited a total of 202 high-risk patients with HF (71.3 years SD 11.1; left ventricular ejection fraction 32.9% SD 15.4). Participants in both study arms were given a tablet computer, Bluetooth-enabled blood pressure monitor and weighing scales for health monitoring. Participants randomised to intervention received additional regular feedback to support self-management and their primary care doctors received instructions on blood investigations and pharmacological treatment. The primary outcome was the use of guideline-recommended medical therapy for chronic HF and major comorbidities, measured as a composite opportunity score (total number of recommended treatment given divided by the total number of opportunities the treatment should have been given, with a score 1 indicating 100% adherence to recommendations). Co-primary outcome was change in physical score of Minnesota Living with Heart Failure questionnaire. RESULTS: 101 patients were randomised to 'enhanced self-management' and 101 to 'supported medical management'. At the end of follow-up, the opportunity score was 0.54 (95% CI 0.46 to 0.62) in the control arm and 0.61 (95% CI 0.52 to 0.70) in the intervention arm (p=0.25). Physical well-being of participants also did not differ significantly between the groups (17.4 (12.4) mean (SD) for control arm vs 16.5 (12.1) in treatment arm; p for change=0.84). CONCLUSIONS: Central provision of tailored specialist management in a multi-morbid HF population was feasible. However, there was no strong evidence for improvement in use of evidence-based treatment nor health-related quality of life. TRIAL REGISTRATION NUMBER: ISRCTN86212709..
21. Toshiaki Ohkuma, Sanne A E Peters, Min Jun, Stephen Harrap, Mark Cooper, Pavel Hamet, Neil Poulter, John Chalmers, Mark Woodward, Sex-specific associations between cardiovascular risk factors and myocardial infarction in patients with type 2 diabetes: The ADVANCE-ON study., Diabetes, obesity & metabolism, 10.1111/dom.14103, 22, 10, 1818-1826, 2020.10, AIM: To examine possible sex differences in the excess risk of myocardial infarction (MI) consequent to a range of conventional risk factors in a large-scale international cohort of patients with diabetes, and to quantify these potential differences both on the relative and absolute scales. MATERIALS AND METHODS: Eleven thousand and sixty-five participants (42% women) with type 2 diabetes in the ADVANCE trial and its post-trial follow-up study, ADVANCE-ON, were included. Cox regression models were used to estimate hazard ratios (HRs) for associations between risk factors and MI (fatal and non-fatal) by sex, and the women-to-men ratio of HRs (RHR). RESULTS: Over a median of 9.6 years of follow-up, 719 patients experienced MI. Smoking status, smoking intensity, higher systolic blood pressure (SBP), HbA1c, total and LDL cholesterol, duration of diabetes, triglycerides, body mass index (BMI) and lower HDL cholesterol were associated with an increased risk of MI in both sexes. Furthermore, some variables were associated with a greater relative risk of MI in women than men: RHRs were 1.75 (95% CI: 1.05-2.91) for current smoking, 1.53 (1.00-2.32) for former smoking, 1.18 (1.02-1.37) for SBP, and 1.13 (95% CI, 1.003-1.26) for duration of diabetes. Although incidence rates of MI were higher in men (9.3 per 1000 person-years) compared with women (5.8 per 1000 person-years), rate differences associated with risk factors were greater in women than men, except for HDL cholesterol and BMI. CONCLUSIONS: In patients with type 2 diabetes, smoking, higher SBP and longer duration of diabetes had a greater relative and absolute effect in women than men, highlighting the importance of routine sex-specific approaches and early interventions in women with diabetes..
22. Masanori Iwase, Yuji Komorita, Hiroki Fujii, Toshiaki Ohkuma, Hitoshi Ide, Masahito Yoshinari, Yutaro Oku, Taiki Higashi, Udai Nakamura, Takanari Kitazono, Incidence of severe hypoglycemia and its association with serum adiponectin in Japanese patients with type 1 and insulin-treated type 2 diabetes: The Fukuoka Diabetes Registry., Journal of diabetes investigation, 10.1111/jdi.13253, 11, 5, 1258-1264, 2020.09, AIMS/INTRODUCTION: The incidence of severe hypoglycemia and its risk factors including an insulin-sensitizing adipokine, adiponectin, were prospectively investigated in Japanese patients with type 1 or insulin-treated type 2 diabetes. MATERIALS AND METHODS: A total of 207 participants with type 1 diabetes (mean age 55 years) and 1,396 with insulin-treated type 2 diabetes (mean age 65 years) from the local diabetes registry were followed for 5 years (follow-up rate 99%). Severe hypoglycemia was defined as events requiring the assistance of others for recovery from hypoglycemia. RESULTS: The incidence of severe hypoglycemia was 9.2 per 100 person-years in those with type 1 diabetes, and 2.3 per 100 person-years in those with insulin-treated type 2 diabetes, respectively. For type 1 diabetes, the risk was significant in those with a history of severe hypoglycemia within the previous year, slow eating and higher serum adiponectin (the highest vs the lowest in quartile hazard ratio 2.36, 95% confidence interval 1.22-4.69). For insulin-treated type 2 diabetes, the risk included age ≥65 years, history of severe hypoglycemia within the previous year, alcohol consumption ≥60 g/day, larger insulin dose and higher serum adiponectin (the highest vs the lowest in quartile, hazard ratio 2.95, 95% confidence interval 1.22-4.69). For all participants, the incidence of severe hypoglycemia increased along with serum adiponectin (age- and sex-adjusted hazard ratio 1.65 per 1 standard deviation increase of log serum adiponectin, 95% confidence interval 1.45-1.87). CONCLUSIONS: The incidence of severe hypoglycemia was prospectively determined, and the association between severe hypoglycemia and higher serum adiponectin was observed in Japanese patients with type 1 and insulin-treated type 2 diabetes..
23. Jingyan Tian, Toshiaki Ohkuma, Mark Cooper, Stephen Harrap, Giuseppe Mancia, Neil Poulter, Ji-Guang Wang, Sophia Zoungas, Mark Woodward, John Chalmers, Effects of Intensive Glycemic Control on Clinical Outcomes Among Patients With Type 2 Diabetes With Different Levels of Cardiovascular Risk and Hemoglobin A1c in the ADVANCE Trial., Diabetes care, 10.2337/dc19-1817, 43, 6, 1293-1299, 2020.06, OBJECTIVE: To study whether the effects of intensive glycemic control on major vascular outcomes (a composite of major macrovascular and major microvascular events), all-cause mortality, and severe hypoglycemia events differ among participants with different levels of 10-year risk of atherosclerotic cardiovascular disease (ASCVD) and hemoglobin A1c (HbA1c) at baseline. RESEARCH DESIGN AND METHODS: We studied the effects of more intensive glycemic control in 11,071 patients with type 2 diabetes (T2D), without missing values, in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, using Cox models. RESULTS: During 5 years' follow-up, intensive glycemic control reduced major vascular events (hazard ratio [HR] 0.90 [95% CI 0.83-0.98]), with the major driver being a reduction in the development of macroalbuminuria. There was no evidence of differences in the effect, regardless of baseline ASCVD risk or HbA1c level (P for interaction = 0.29 and 0.94, respectively). Similarly, the beneficial effects of intensive glycemic control on all-cause mortality were not significantly different across baseline ASCVD risk (P = 0.15) or HbA1c levels (P = 0.87). The risks of severe hypoglycemic events were higher in the intensive glycemic control group compared with the standard glycemic control group (HR 1.85 [1.41-2.42]), with no significant heterogeneity across subgroups defined by ASCVD risk or HbA1c at baseline (P = 0.09 and 0.18, respectively). CONCLUSIONS: The major benefits for patients with T2D in ADVANCE did not substantially differ across levels of baseline ASCVD risk and HbA1c..
24. Crystal ManYing Lee, Mark Woodward, G David Batty, Alexa S Beiser, Steven Bell, Claudine Berr, Espen Bjertness, John Chalmers, Robert Clarke, Jean-Francois Dartigues, Kendra Davis-Plourde, Stéphanie Debette, Emanuele Di Angelantonio, Catherine Feart, Ruth Frikke-Schmidt, John Gregson, Mary N Haan, Linda B Hassing, Kathleen M Hayden, Marieke P Hoevenaar-Blom, Jaakko Kaprio, Mika Kivimaki, Georgios Lappas, Eric B Larson, Erin S LeBlanc, Anne Lee, Li-Yung Lui, Eric P Moll van Charante, Toshiharu Ninomiya, Liv Tybjaerg Nordestgaard, Tomoyuki Ohara, Toshiaki Ohkuma, Teemu Palviainen, Karine Peres, Ruth Peters, Nawab Qizilbash, Edo Richard, Annika Rosengren, Sudha Seshadri, Martin Shipley, Archana Singh-Manoux, Bjorn Heine Strand, Willem A van Gool, Eero Vuoksimaa, Kristine Yaffe, Rachel R Huxley, Association of anthropometry and weight change with risk of dementia and its major subtypes: A meta-analysis consisting 2.8 million adults with 57 294 cases of dementia., Obesity reviews : an official journal of the International Association for the Study of Obesity, 10.1111/obr.12989, 21, 4, e12989, 2020.04, Uncertainty exists regarding the relation of body size and weight change with dementia risk. As populations continue to age and the global obesity epidemic shows no sign of waning, reliable quantification of such associations is important. We examined the relationship of body mass index, waist circumference, and annual percent weight change with risk of dementia and its subtypes by pooling data from 19 prospective cohort studies and four clinical trials using meta-analysis. Compared with body mass index-defined lower-normal weight (18.5-22.4 kg/m2 ), the risk of all-cause dementia was higher among underweight individuals but lower among those with upper-normal (22.5-24.9 kg/m2 ) levels. Obesity was associated with higher risk in vascular dementia. Similarly, relative to the lowest fifth of waist circumference, those in the highest fifth had nonsignificant higher vascular dementia risk. Weight loss was associated with higher all-cause dementia risk relative to weight maintenance. Weight gain was weakly associated with higher vascular dementia risk. The relationship between body size, weight change, and dementia is complex and exhibits non-linear associations depending on dementia subtype under scrutiny. Weight loss was associated with an elevated risk most likely due to reverse causality and/or pathophysiological changes in the brain, although the latter remains speculative..
25. Toshiaki Ohkuma, Luc Van Gaal, Wayne Shaw, Kenneth W Mahaffey, Dick de Zeeuw, David R Matthews, Vlado Perkovic, Bruce Neal, Clinical outcomes with canagliflozin according to baseline body mass index: results from post hoc analyses of the CANVAS Program., Diabetes, obesity & metabolism, 10.1111/dom.13920, 22, 4, 530-539, 2020.04, AIMS: Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce several cardiovascular risk factors, including plasma glucose, blood pressure, albuminuria and body weight. Long-term treatment lowers risks of cardiovascular and renal events. The objective of this post hoc analysis was to determine the effects of canagliflozin treatment versus placebo on clinical outcomes in relation to body mass index (BMI). MATERIALS AND METHODS: The CANVAS Program randomized 10 142 participants with type 2 diabetes to canagliflozin or placebo. These analyses tested the consistency of canagliflozin treatment effects across BMI levels for cardiovascular, renal, safety and body weight outcomes in three groups defined by baseline BMI:
26. Toshiaki Ohkuma, Sophia Zoungas, Min Jun, Liu Lisheng, Giuseppe Mancia, Michel Marre, Anthony Rodgers, Bryan Williams, Mark Woodward, John Chalmers, Intensive glucose-lowering and the risk of vascular events and premature death in patients with decreased kidney function: The ADVANCE trial., Diabetes, obesity & metabolism, 10.1111/dom.13878, 22, 3, 452-457, 2020.03, To assess the effects of intensive glucose control on the risk of major clinical outcomes according to estimated glomerular filtration rate (eGFR) levels in people with type 2 diabetes. Of 11 140 ADVANCE trial participants, 11 096 with baseline eGFR measurements were included, and classified into three eGFR groups: ≥90 mL/min/1.73 m2 ; 60 to 89 mL/min/1.73 m2 ; and 
27. Yuji Komorita, Masanori Iwase, Yasuhiro Idewaki, Hiroki Fujii, Toshiaki Ohkuma, Hitoshi Ide, Tamaki Jodai-Kitamura, Masahito Yoshinari, Ai Murao-Kimura, Yutaro Oku, Udai Nakamura, Takanari Kitazono, Impact of hip fracture on all-cause mortality in Japanese patients with type 2 diabetes mellitus: The Fukuoka Diabetes Registry., Journal of diabetes investigation, 10.1111/jdi.13076, 11, 1, 62-69, 2020.01, AIMS/INTRODUCTION: Patients with type 2 diabetes mellitus have an increased hip fracture risk. We investigated the relationship between hip fracture and all-cause death in patients with type 2 diabetes in comparison with cardiovascular disease (CVD) or end-stage renal disease (ERSD). MATERIALS AND METHODS: In total, 4,923 Japanese participants with type 2 diabetes (mean age 65 years, 2,790 men, 2,133 women) were followed for a median of 5.3 years (follow-up rate 99.5%). We evaluated the associations between the presence of hip fracture (n = 110), upper limb fracture (n = 801), CVD (n = 1,344), ESRD (n = 104) and all-cause death by logistic regression analysis. RESULTS: A total of 309 participants died during follow up. Multivariate-adjusted odds ratios (ORs) for all-cause mortality were significantly higher in participants with hip fractures than those without hip fractures (OR 2.67, 95% confidence interval [CI] 1.54-4.41), whereas the ORs for upper limb fracture were not significant. The ORs for all-cause mortality were significantly higher in participants with CVD than those without CVD (OR 1.78, 95% CI, 1.39-2.70) and ESRD (OR 2.36, 95% CI 1.32-4.05). The ORs for all-cause mortality of hip fracture were not affected by further adjustment for CVD and ESRD (OR 2.74, 95% CI 1.58-4.54). The cause of death was infection (40.0%), malignant neoplasm (25.0%) and CVD (15.0%) among participants with hip fracture. CONCLUSIONS: Hip fractures were associated with an increased risk of death among Japanese patients with type 2 diabetes, independently of CVD and ESRD..
28. Alexandra K Lee, Mark Woodward, Dan Wang, Toshiaki Ohkuma, Bethany Warren, A Richey Sharrett, Bryan Williams, Michel Marre, Pavel Hamet, Stephen Harrap, John W Mcevoy, John Chalmers, Elizabeth Selvin, The Risks of Cardiovascular Disease and Mortality Following Weight Change in Adults with Diabetes: Results from ADVANCE., The Journal of clinical endocrinology and metabolism, 10.1210/clinem/dgz045, 105, 1, 2020.01, CONTEXT: Weight loss is strongly recommended for overweight and obese adults with type 2 diabetes. Unintentional weight loss is associated with increased risk of all-cause mortality, but few studies have examined its association with cardiovascular outcomes in patients with diabetes. OBJECTIVE: To evaluate 2-year weight change and subsequent risk of cardiovascular events and mortality in established type 2 diabetes. DESIGN AND SETTING: The Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation was an international, multisite 2×2 factorial trial of intensive glucose control and blood pressure control. We examined 5 categories of 2-year weight change: >10% loss, 4% to 10% loss, stable (±10% gain. We used Cox regression with follow-up time starting at 2 years, adjusting for intervention arm, demographics, cardiovascular risk factors, and diabetes medication use from the 2-year visit. RESULTS: Among 10 081 participants with valid weight measurements, average age was 66 years. By the 2-year examination, 4.3% had >10% weight loss, 18.4% had 4% to 10% weight loss, and 5.3% had >10% weight gain. Over the following 3 years of the trial, >10% weight loss was strongly associated with major macrovascular events (hazard ratio [HR], 1.75; 95% confidence interval [CI], 1.26-2.44), cardiovascular mortality (HR, 2.76; 95% CI, 1.87-4.09), all-cause mortality (HR, 2.79; 95% CI, 2.10-3.71), but not major microvascular events (HR, 0.91; 95% CI, 0.61-1.36), compared with stable weight. There was no evidence of effect modification by baseline body mass index, age, or type of diabetes medication. CONCLUSIONS: In the absence of substantial lifestyle changes, weight loss may be a warning sign of poor health meriting further workup in patients with type 2 diabetes..
29. Hirofumi Tomiyama, Toshiaki Ohkuma, Toshiharu Ninomiya, Hiroki Nakano, Chisa Matsumoto, Alberto Avolio, Takahide Kohro, Yukihito Higashi, Tatsuya Maruhashi, Bonpei Takase, Toru Suzuki, Tomoko Ishizu, Shinichiro Ueda, Tsutomu Yamazaki, Tomoo Furumoto, Kazuomi Kario, Teruo Inoue, Shinji Koba, Yasuhiko Takemoto, Takuzo Hano, Masataka Sata, Yutaka Ishibashi, Koichi Node, Koji Maemura, Yusuke Ohya, Taiji Furukawa, Hiroshi Ito, Taishiro Chikamori, Akira Yamashina, Brachial-Ankle Pulse Wave Velocity Versus Its Stiffness Index β-Transformed Value as Risk Marker for Cardiovascular Disease., Journal of the American Heart Association, 10.1161/JAHA.119.013004, 8, 24, e013004, 2019.12, Background The difference in the predictive ability of the brachial-ankle pulse wave velocity (baPWV) and its stiffness index β-transformed value (β-baPWV, ie, baPWV adjusted for the pulse pressure) for the development of pathophysiological abnormalities related to cardiovascular disease or future occurrence of cardiovascular disease was examined. Methods and Results In study 1, a 7-year prospective observational study in cohorts of 3274 men and 3490 men, the area under the curve in the receiver operator characteristic curve analysis was higher for baPWV than for β-baPWV for predicting the development of hypertension (0.73, 95% CI=0.70 to 0.75 versus 0.59, 95% CI=0.56 to 0.62; P
30. Brendon L Neuen, Toshiaki Ohkuma, Bruce Neal, David R Matthews, Dick de Zeeuw, Kenneth W Mahaffey, Greg Fulcher, Qiang Li, Meg Jardine, Richard Oh, Hiddo L Heerspink, Vlado Perkovic, Effect of Canagliflozin on Renal and Cardiovascular Outcomes across Different Levels of Albuminuria: Data from the CANVAS Program., Journal of the American Society of Nephrology : JASN, 10.1681/ASN.2019010064, 30, 11, 2229-2242, 2019.11, BACKGROUND: If SGLT2 inhibitors protect the kidneys by reducing albuminuria as hypothesized, people with type 2 diabetes mellitus (T2DM) with higher albuminuria should benefit more. METHODS: We conducted a post-hoc analysis of data from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, which randomized 10,142 participants with T2DM and high cardiovascular risk to canagliflozin or placebo. We assessed effects of canagliflozin on renal, cardiovascular, and safety outcomes by baseline albuminuria. The trial included 2266 participants (22.3%) with moderately increased albuminuria (urinary albumin/creatinine ratio [UACR] 30-300 mg/g) and 760 (7.5%) with severely increased albuminuria (UACR >300 mg/g) at baseline. RESULTS: Canagliflozin lowered albuminuria with greater proportional reductions in those with moderately and severely increased albuminuria (P heterogeneity
31. Megumi Oshima, Min Jun, Toshiaki Ohkuma, Tadashi Toyama, Takashi Wada, Mark E Cooper, Samy Hadjadj, Pavel Hamet, Stephen Harrap, Giuseppe Mancia, Michel Marre, Bryan Williams, John Chalmers, Mark Woodward, Vlado Perkovic, The relationship between eGFR slope and subsequent risk of vascular outcomes and all-cause mortality in type 2 diabetes: the ADVANCE-ON study., Diabetologia, 10.1007/s00125-019-4948-4, 62, 11, 1988-1997, 2019.11, AIMS/HYPOTHESIS: Some studies have reported that annual change in eGFR (eGFR slope) is associated with the future risk of end-stage kidney disease, cardiovascular disease and death in general or chronic kidney disease cohorts. However, the benefits of using eGFR slopes for prediction of major clinical outcomes in diabetes are unclear. METHODS: We used data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial and the ADVANCE Post-Trial Observational Study (ADVANCE-ON). After excluding the first 4 months during which an acute fall in eGFR was induced by the initiation of an ACE inhibitor and diuretic combination agent, eGFR slopes were estimated by linear mixed models, using three measurements of eGFR at 4, 12 and 24 months after randomisation over 20 months, and categorised according to quartiles. Cox regression models were used to evaluate adjusted HRs for the study's primary outcome, a composite of major renal events, major macrovascular events and all-cause mortality during the subsequent follow-up from 24 months after randomisation. RESULTS: A total of 8,879 participants (80%) were included in this cohort. The mean age was 65.6 years (SD 6.3), the mean eGFR was 75 ml min-1 (1.73 m)-2 (SD 17) and the median urinary albumin/creatinine ratio was 14 μg/mg (interquartile range 7-38). The mean eGFR slope was -0.63 ml min-1 (1.73 m)-2 year-1 (SD 1.75). Over a median follow-up of 7.6 years following the 20-month eGFR slope ascertainment period, 2,221 participants (25%) met the primary outcome. An annual substantial decrease in eGFR (lowest 25%, 0.33) had no significant association with the risk of the primary outcome (HR 0.96 [95% CI 0.86, 1.07]). CONCLUSIONS/INTERPRETATION: Our study supports the utility of eGFR slope in type 2 diabetes as a surrogate endpoint for renal outcomes, as well as a prognostic factor for identifying individuals at high risk of cardiovascular disease and all-cause mortality. TRIAL REGISTRY NUMBER: ClinicalTrials.gov registration no. NCT00145925 and no. NCT00949286..
32. Tadashi Toyama, Oliver van den Broek-Best, Toshiaki Ohkuma, David Handelsman, Louise M Waite, Markus J Seibel, Robert Cumming, Vasi Naganathan, Cathie Sherrington, Vasant Hirani, Amanda Y Wang, Associations of Impaired Renal Function With Declines in Muscle Strength and Muscle Function in Older Men: Findings From the CHAMP Study., The journals of gerontology. Series A, Biological sciences and medical sciences, 10.1093/gerona/glz100, 74, 11, 1812-1820, 2019.10, BACKGROUND: Advanced kidney disease is associated with reduced muscle strength and physical performance. However, associations between early stages of renal impairment and physical outcomes are unclear. METHODS: The Concord Health and Ageing in Men Project is a prospective study of 1,705 community-dwelling men aged 70 years and older. Participants with estimated glomerular filtration rate (eGFR) more than 30 mL/min/1.73 m2 were included and further divided into four eGFR categories. Physical parameters including grip strength, gait speed, appendicular lean mass (ALM, a sum of skeletal mass of arms and legs), ALM adjusted for body mass index (ALMBMI), and muscle function (measured using grip strength divided by arm lean mass) were assessed at both baseline and 5-year follow-up. Associations between kidney function and changes in physical parameters were analyzed using linear and logistic regression models. RESULTS: Our study included 789 men with a median age of 75 years and median eGFR of 72 mL/min/1.73 m2 at baseline. Over 5 years, grip strength, gait speed, ALMBMI, and muscle function all declined in the whole cohort, compared with baseline. The multivariable analyses showed that poorer renal function was associated with more rapid declines in grip strength, gait speed, and muscle function in participants with mild-to-moderate renal impairment (GFR category stage G3, eGFR
33. Masanori Iwase, Hiroki Fujii, Yasuhiro Idewaki, Udai Nakamura, Toshiaki Ohkuma, Hitoshi Ide, Yuji Komorita, Tamaki Jodai-Kitamura, Masahito Yoshinari, Takanari Kitazono, Prospective study of cancer in Japanese patients with type 2 diabetes: the Fukuoka Diabetes Registry., Diabetology international, 10.1007/s13340-019-00390-0, 10, 4, 260-267, 2019.10, Background: Although the association between type 2 diabetes and cancer has been reported, few epidemiological studies have been conducted in Japanese patients whose leading cause of death is cancer. We prospectively studied the incidence of site-specific cancer, risk factors for developing cancer, cancer death, and survival in Japanese patients with type 2 diabetes. Methods: We followed 4923 participants (mean age, 65 years) with type 2 diabetes attending an outpatient diabetes clinic for a median of 5.3 years (follow-up rate, 99.0%). Results: During the follow-up period, cancer occurred in 450 participants (incidence rate, 22.3/1000 person-years in men and 12.2/1000 person-years in women). In men, prostate cancer was the most common cancer (4.3/1000 person-years), colorectal cancer was the second (3.6/1000 person-years), and gastric cancer was the third (3.3/1000 person-years). In women, colorectal cancer was the most common cancer (2.6/1000 person-years), gastric cancer was the second (2.0/1000 person-years), and breast cancer was the third (1.4/1000 person-years). Smoking, male sex, low-density lipoprotein cholesterol, family history of cancer, and reduced intake of isoflavone daidzein were significant risk factors for developing cancer using multivariable Cox proportional hazards models. The leading cancer death was lung cancer in men and pancreatic cancer in women. The survival was the best for prostate cancer and the worst for pancreatic cancer (2-year cancer-specific survival 95.4%, 30.0%, respectively). Conclusions: Since the leading cause of death in patients with type 2 diabetes is cancer in Japan, clinicians should be aware of epidemiological data regarding cancer besides diabetic complications..
34. Toshiaki Ohkuma, Yuji Komorita, Sanne A E Peters, Mark Woodward, Diabetes as a risk factor for heart failure in women and men: a systematic review and meta-analysis of 47 cohorts including 12 million individuals., Diabetologia, 10.1007/s00125-019-4926-x, 62, 9, 1550-1560, 2019.09, AIMS/HYPOTHESIS: The prevalence of diabetes and heart failure is increasing, and diabetes has been associated with an increased risk of heart failure. However, whether diabetes confers the same excess risk of heart failure in women and men is unknown. The aim of this study was to conduct a comprehensive systematic review with meta-analysis of possible sex differences in the excess risk of heart failure consequent to diabetes. Our null hypothesis was that there is no such sex difference. METHODS: A systematic search was conducted in PubMed for population-based cohort studies published between January 1966 and November 2018. Studies were selected if they reported sex-specific estimates of RRs for heart failure associated with diabetes, and its associated variability, which were adjusted at least for age. Random-effects meta-analyses with inverse variance weighting were used to obtain pooled sex-specific RRs and women-to-men ratio of RRs (RRRs) for heart failure associated with diabetes. RESULTS: Data from 47 cohorts, involving 12,142,998 individuals and 253,260 heart failure events, were included. The pooled multiple-adjusted RR for heart failure associated with type 1 diabetes was 5.15 (95% CI 3.43, 7.74) in women and 3.47 (2.57, 4.69) in men, leading to an RRR of 1.47 (1.44, 1.90). Corresponding pooled RRs for heart failure associated with type 2 diabetes were 1.95 (1.70, 2.22) in women and 1.74 (1.55, 1.95) in men, with a pooled RRR of 1.09 (1.05, 1.13). CONCLUSIONS/INTERPRETATION: The excess risk of heart failure associated with diabetes is significantly greater in women with diabetes than in men with diabetes. PROSPERO registration: CRD42019135246..
35. Toshiaki Ohkuma, Min Jun, John Chalmers, Mark E Cooper, Pavel Hamet, Stephen Harrap, Sophia Zoungas, Vlado Perkovic, Mark Woodward, Combination of Changes in Estimated GFR and Albuminuria and the Risk of Major Clinical Outcomes., Clinical journal of the American Society of Nephrology : CJASN, 10.2215/CJN.13391118, 14, 6, 862-872, 2019.06, BACKGROUND AND OBJECTIVES: Whether combining changes in eGFR and urine albumin-to-creatinine ratio (UACR) is more strongly associated with outcomes compared with either change alone is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We analyzed 8766 patients with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation Observational (ADVANCE-ON) study. Changes in eGFR and UACR (baseline to 2 years) were defined as ≥40% decrease, minor change, and ≥40% increase. The primary outcome was the composite of major macrovascular (nonfatal or fatal myocardial infarction, nonfatal or fatal stroke, or cardiovascular death), major kidney events (requirement for kidney replacement therapy or kidney death), and all-cause mortality. RESULTS: Over a median of 7.7 years of follow-up, 2191 primary outcomes were recorded. Strong linear associations between eGFR and UACR changes and subsequent risk of the outcome were observed. For eGFR, the hazard ratios were 1.58 (95% confidence interval [95% CI], 1.27 to 1.95) for a decrease ≥40% and 0.82 for an increase ≥40% (95% CI, 0.64 to 1.04) compared with minor change. For UACR, the hazard ratios were 0.96 (95% CI, 0.85 to 1.07) for a decrease ≥40% and 1.32 (95% CI, 1.19 to 1.46) for ≥40% increase compared with minor change. Compared with dual minor changes, both an eGFR decrease ≥40% and a UACR increase ≥40% had 2.31 (95% CI, 1.67 to 3.18) times the risk of the outcome, with evidence of interaction between the two markers. CONCLUSIONS: Clinically meaningful decreases in eGFR and increases in UACR over 2 years, independently and in combination, were significantly associated with higher risk of major clinical outcomes..
36. Faisal Rahman, John W McEvoy, Toshiaki Ohkuma, Michel Marre, Pavel Hamet, Stephen Harrap, Giuseppe Mancia, Anthony Rodgers, Elizabeth Selvin, Bryan Williams, Paul Muntner, John Chalmers, Mark Woodward, Effects of Blood Pressure Lowering on Clinical Outcomes According to Baseline Blood Pressure and Cardiovascular Risk in Patients With Type 2 Diabetes Mellitus., Hypertension (Dallas, Tex. : 1979), 10.1161/HYPERTENSIONAHA.118.12414, 73, 6, 1291-1299, 2019.06, The optimal blood pressure (BP) goal in patients with diabetes mellitus remains controversial. We examined whether benefits and risks of intensified antihypertensive therapy in diabetes mellitus are influenced by either baseline BP or cardiovascular disease (CVD) risk. We studied 10 948 people with diabetes mellitus, at moderate-to-high risk, in the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation). Cox models were used to determine whether baseline BP category or CVD risk modified the outcomes of combination perindopril-indapamide treatment, compared with placebo. During 4.3 years of follow-up, treatment with perindopril-indapamide versus placebo reduced mortality and major vascular (macrovascular or microvascular) events. There was no evidence of differences in these effects, regardless of baseline systolic BP (evaluated down to
37. Tadashi Toyama, Brendon L Neuen, Min Jun, Toshiaki Ohkuma, Bruce Neal, Meg J Jardine, Hiddo L Heerspink, Muh Geot Wong, Toshiharu Ninomiya, Takashi Wada, Vlado Perkovic, Effect of SGLT2 inhibitors on cardiovascular, renal and safety outcomes in patients with type 2 diabetes mellitus and chronic kidney disease: A systematic review and meta-analysis., Diabetes, obesity & metabolism, 10.1111/dom.13648, 21, 5, 1237-1250, 2019.05, AIM: The use of sodium glucose co-transporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) has been limited, primarily because glycaemic efficacy is dependent on kidney function. We performed a systematic review and meta-analysis to assess the efficacy and safety of SGLT2 inhibitors in patients with T2DM and CKD, defined as estimated glomerular filtration rate (eGFR)
38. Hirofumi Tomiyama, Toshiaki Ohkuma, Toshiharu Ninomiya, Chisa Mastumoto, Kazuomi Kario, Satoshi Hoshide, Yoshikuni Kita, Toyoshi Inoguchi, Yasutaka Maeda, Katsuhiko Kohara, Yasuharu Tabara, Motoyuki Nakamura, Takayoshi Ohkubo, Hirotaka Watada, Masanori Munakata, Mitsuru Ohishi, Norihisa Ito, Michinari Nakamura, Tetsuo Shoji, Charalambos Vlachopoulos, Victor Aboyans, Akira Yamashina, Steno-Stiffness Approach for Cardiovascular Disease Risk Assessment in Primary Prevention., Hypertension (Dallas, Tex. : 1979), 10.1161/HYPERTENSIONAHA.118.12110, 73, 3, 508-513, 2019.03.
39. Toshiaki Ohkuma, Min Jun, Anthony Rodgers, Mark E Cooper, Paul Glasziou, Pavel Hamet, Stephen Harrap, Giuseppe Mancia, Michel Marre, Bruce Neal, Vlado Perkovic, Neil Poulter, Bryan Williams, Sophia Zoungas, John Chalmers, Mark Woodward, Acute Increases in Serum Creatinine After Starting Angiotensin-Converting Enzyme Inhibitor-Based Therapy and Effects of its Continuation on Major Clinical Outcomes in Type 2 Diabetes Mellitus., Hypertension (Dallas, Tex. : 1979), 10.1161/HYPERTENSIONAHA.118.12060, 73, 1, 84-91, 2019.01, Discontinuation of angiotensin-converting enzyme (ACE) inhibitor is recommended if patients experience ≥30% acute increase in serum creatinine after starting this therapy. However, the long-term effects of its continuation or discontinuation on major clinical outcomes after increases in serum creatinine are unclear. In the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation), 11 140 diabetes mellitus patients were randomly assigned to perindopril-indapamide or placebo after a 6-week active run-in period. The current study included 11 066 participants with 2 serum creatinine measurements recorded before and during the active run-in period (3 weeks apart). Acute increase in creatinine was determined using these 2 measurements and classified into 4 groups: increases in serum creatinine of
40. Toshiaki Ohkuma, Sanne A E Peters, Mark Woodward, Is there evidence for sex differences in the association between diabetes and cancer? Reply to Dankner R, Boker LK, Freedman LS [letter]., Diabetologia, 10.1007/s00125-018-4761-5, 62, 1, 201-201, 2019.01.
41. Yuji Komorita, Masanori Iwase, Hiroki Fujii, Hitoshi Ide, Toshiaki Ohkuma, Tamaki Jodai-Kitamura, Akiko Sumi, Masahito Yoshinari, Udai Nakamura, Takanari Kitazono, The serum creatinine to cystatin C ratio predicts bone fracture in patients with type 2 diabetes: The Fukuoka Diabetes Registry., Diabetes research and clinical practice, 10.1016/j.diabres.2018.10.021, 146, 202-210, 2018.12, AIMS: Sarcopenia is involved in the pathogenesis of increased fracture risk associated with diabetes. The serum creatinine to cystatin C (Cr/CysC) ratio has been reported as a surrogate marker for muscle mass. We aimed to prospectively investigate the relationship between the Cr/CysC ratio and fracture risk. METHODS: We followed 1911 postmenopausal women and 2689 men with type 2 diabetes (mean age, 66 years) for a median of 5.3 years, and divided into Cr/CysC ratio quartiles by sex. The primary outcome was fragility fractures and the secondary outcome was any fracture. RESULTS: Fragility fractures occurred in 192 participants, and any fracture occurred in 645 participants. Multivariate-adjusted hazard ratios (95% CI) for fragility fractures were 2.15 (1.19-3.88) (Q1), 1.63 (0.89-2.98) (Q2), 1.34 (0.72-2.51) (Q3) and 1.0 (ref.) (Q4) in postmenopausal women, and 1.75 (0.64-4.50) (Q1), 2.09 (0.83-5.26) (Q2), 1.56 (0.58-4.18) (Q3) and 1.0 (ref.) (Q4) in men. Those for any fracture were 1.46 (1.07-1.98) (Q1), 1.33 (0.98-1.81) (Q2), 1.40 (1.03-1.88) (Q3) and 1.0 (ref.) (Q4) in postmenopausal women, and 2.33 (1.54-3.54) (Q1), 2.02 (1.54-3.04) (Q2), 1.13 (0.71-1.78) (Q3) and 1.0 (ref.) (Q4) in men. CONCLUSIONS: A lower Cr/CysC ratio is a significant risk factor for fractures in patients with type 2 diabetes..
42. Brendon L Neuen, Toshiaki Ohkuma, Bruce Neal, David R Matthews, Dick de Zeeuw, Kenneth W Mahaffey, Greg Fulcher, Mehul Desai, Qiang Li, Hsiaowei Deng, Norm Rosenthal, Meg J Jardine, George Bakris, Vlado Perkovic, Cardiovascular and Renal Outcomes With Canagliflozin According to Baseline Kidney Function., Circulation, 10.1161/CIRCULATIONAHA.118.035901, 138, 15, 1537-1550, 2018.10, BACKGROUND: Canagliflozin is approved for glucose lowering in type 2 diabetes and confers cardiovascular and renal benefits. We sought to assess whether it had benefits in people with chronic kidney disease, including those with an estimated glomerular filtration rate (eGFR) between 30 and 45 mL/min/1.73 m2 in whom the drug is not currently approved for use. METHODS: The CANVAS Program randomized 10 142 participants with type 2 diabetes and eGFR >30 mL/min/1.73 m2 to canagliflozin or placebo. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, with other cardiovascular, renal, and safety outcomes. This secondary analysis describes outcomes in participants with and without chronic kidney disease, defined as eGFR
43. Toshiaki Ohkuma, Sanne A E Peters, Mark Woodward, Sex differences in the association between diabetes and cancer: a systematic review and meta-analysis of 121 cohorts including 20 million individuals and one million events., Diabetologia, 10.1007/s00125-018-4664-5, 61, 10, 2140-2154, 2018.10, AIMS/HYPOTHESIS: Diabetes has been shown to be a risk factor for some cancers. Whether diabetes confers the same excess risk of cancer, overall and by site, in women and men is unknown. METHODS: A systematic search was performed in PubMed for cohort studies published up to December 2016. Selected studies reported sex-specific relative risk (RR) estimates for the association between diabetes and cancer adjusted at least for age in both sexes. Random-effects meta-analyses with inverse-variance weighting were used to obtain pooled sex-specific RRs and women-to-men ratios of RRs (RRRs) for all-site and site-specific cancers. RESULTS: Data on all-site cancer events (incident or fatal only) were available from 121 cohorts (19,239,302 individuals; 1,082,592 events). The pooled adjusted RR for all-site cancer associated with diabetes was 1.27 (95% CI 1.21, 1.32) in women and 1.19 (1.13, 1.25) in men. Women with diabetes had ~6% greater risk compared with men with diabetes (the pooled RRR was 1.06, 95% CI 1.03, 1.09). Corresponding pooled RRRs were 1.10 (1.07, 1.13) for all-site cancer incidence and 1.03 (0.99, 1.06) for all-site cancer mortality. Diabetes also conferred a significantly greater RR in women than men for oral, stomach and kidney cancer, and for leukaemia, but a lower RR for liver cancer. CONCLUSIONS/INTERPRETATION: Diabetes is a risk factor for all-site cancer for both women and men, but the excess risk of cancer associated with diabetes is slightly greater for women than men. The direction and magnitude of sex differences varies by location of the cancer..
44. Akiko Sumi, Masanori Iwase, Udai Nakamura, Hiroki Fujii, Toshiaki Ohkuma, Hitoshi Ide, Tamaki Jodai-Kitamura, Yuji Komorita, Masahito Yoshinari, Takanari Kitazono, Impact of age at menarche on obesity and glycemic control in Japanese patients with type 2 diabetes: Fukuoka Diabetes Registry., Journal of diabetes investigation, 10.1111/jdi.12839, 9, 5, 1216-1223, 2018.09, AIMS/INTRODUCTION: A younger age at menarche is associated with obesity and type 2 diabetes in adult life. The impact of early-onset menarche on obesity and glycemic control in type 2 diabetes has not been investigated. The present study examined the relationship between age at menarche and obesity and glycemic control in type 2 diabetes. MATERIALS AND METHODS: A total of 2,133 patients with type 2 diabetes aged ≥20 years were divided into groups according to age at menarche (≤11, 12, 13, 14 and ≥15 years). A retrospective cohort study examined the association of menarcheal age with adiposity and hemoglobin A1c . RESULTS: Age at menarche was inversely associated with body mass index (BMI) and abdominal circumference (P
45. Toshiaki Ohkuma, Toshiharu Ninomiya, Hirofumi Tomiyama, Kazuomi Kario, Satoshi Hoshide, Yoshikuni Kita, Toyoshi Inoguchi, Yasutaka Maeda, Katsuhiko Kohara, Yasuharu Tabara, Motoyuki Nakamura, Takayoshi Ohkubo, Hirotaka Watada, Masanori Munakata, Mitsuru Ohishi, Norihisa Ito, Michinari Nakamura, Tetsuo Shoji, Charalambos Vlachopoulos, Victor Aboyans, Akira Yamashina, Ankle-brachial index measured by oscillometry is predictive for cardiovascular disease and premature death in the Japanese population: An individual participant data meta-analysis., Atherosclerosis, 10.1016/j.atherosclerosis.2018.05.048, 275, 141-148, 2018.08, BACKGROUND AND AIMS: The ankle-brachial index (ABI) is a predictor of cardiovascular disease (CVD) and premature death. However, few studies on this marker are available in the general Asian populations. This study aimed to investigate the association between ABI measured with oscillometry and the risk of these outcomes. METHODS: We conducted an individual participant data meta-analysis in 10,679 community-dwelling Japanese individuals without a history of CVD. The primary outcome was a composite of CVD events and all-cause mortality. RESULTS: During an average of 7.8 years of follow-up, 720 participants experienced the primary outcome. The multivariable-adjusted hazard ratios (HRs) of the primary outcome significantly increased with a lower ABI. The HRs were 1.07 (95% confidence interval [CI] 0.91-1.27) for ABI of 1.00-1.09, HR 1.37 (95% CI 1.04-1.81) for ABI of 0.91-0.99, and HR 1.60 (95% CI 1.06-2.41) for ABI of ≤0.90, compared with ABI of 1.10-1.19. Furthermore, a high ABI (≥1.30) was associated with a greater risk of outcome (HR 2.42 [95% CI 1.14-5.13]). Similar tendencies were observed for CVD events alone and all-cause mortality alone. Addition of ABI to a model with the Framingham risk score marginally improved the c-statistics (p = 0.08) and integrated discrimination improvement (p
46. Karin Rådholm, John Chalmers, Toshiaki Ohkuma, Sanne Peters, Neil Poulter, Pavel Hamet, Stephen Harrap, Mark Woodward, Use of the waist-to-height ratio to predict cardiovascular risk in patients with diabetes: Results from the ADVANCE-ON study., Diabetes, obesity & metabolism, 10.1111/dom.13311, 20, 8, 1903-1910, 2018.08, AIMS: Patients with type 2 diabetes have a high risk of cardiovascular disease (CVD). Central obesity has been particularly associated with this risk relationship. We aimed to evaluate waist to height ratio (WHtR) as a predictor of risk in such patients. METHODS: WHtR was evaluated as a predictor of the risk of CVD and mortality amongst 11 125 participants with type 2 diabetes in the ADVANCE and ADVANCE-ON studies, and was compared with body mass index (BMI), waist circumference and waist hip ratio (WHR). Primary outcome was a composite of death from CVD, non-fatal myocardial infarction or non-fatal stroke. Secondary outcomes were myocardial infarction, stroke, cardiovascular death and death from any cause. Cox models were used, with bootstrapping to compare associations between anthropometric measures for the primary outcome. RESULTS: Median follow-up time was 9.0 years. There was a positive association between WHtR and adverse outcomes. The hazard ratio (HR) (confidence interval), per SD higher WHtR, was 1.16 (1.11-1.22) for the primary endpoint, with no heterogeneity by sex or region, but a stronger effect in individuals aged 66 years or older. The other 3 anthropometric measurements showed similar associations, although there was evidence that WHtR marginally outperformed BMI and WHR. Based on commonly used BMI cut-points, the equivalent WHtR cut-points were estimated to be 0.55 and 0.6, with no evidence of a difference across subgroups. CONCLUSIONS: In patients with diabetes, WHtR is a useful indicator of future adverse risk, with similar effects in different population subgroups..
47. Hirofumi Tomiyama, Toshiaki Ohkuma, Toshiharu Ninomiya, Chisa Mastumoto, Kazuomi Kario, Satoshi Hoshide, Yoshikuni Kita, Toyoshi Inoguchi, Yasutaka Maeda, Katsuhiko Kohara, Yasuharu Tabara, Motoyuki Nakamura, Takayoshi Ohkubo, Hirotaka Watada, Masanori Munakata, Mitsuru Ohishi, Norihisa Ito, Michinari Nakamura, Tetsuo Shoji, Charalambos Vlachopoulos, Akira Yamashina, Simultaneously Measured Interarm Blood Pressure Difference and Stroke: An Individual Participants Data Meta-Analysis., Hypertension (Dallas, Tex. : 1979), 10.1161/HYPERTENSIONAHA.118.10923, 71, 6, 1030-1038, 2018.06, We conducted individual participant data meta-analysis to examine the validity of interarm blood pressure difference in simultaneous measurement as a marker to identify subjects with ankle-brachial pressure index 5 mm Hg as being associated with a significant odds ratio for the presence of ankle-brachial pressure index 15 mm Hg was associated with a significant Cox stratified adjusted hazard ratio for subsequent stroke (hazard ratio, 2.42; 95% confidence interval, 1.27-4.60; P
48. Yuji Komorita, Masanori Iwase, Hiroki Fujii, Toshiaki Ohkuma, Hitoshi Ide, Tamaki Jodai-Kitamura, Akiko Sumi, Masahito Yoshinari, Udai Nakamura, Dongchon Kang, Takanari Kitazono, Impact of Body Weight Loss From Maximum Weight on Fragility Bone Fractures in Japanese Patients With Type 2 Diabetes: The Fukuoka Diabetes Registry., Diabetes care, 10.2337/dc17-2004, 41, 5, 1061-1067, 2018.05, OBJECTIVE: There is growing evidence that weight loss is associated with increased fracture risk in the general population. As patients with diabetes often lose weight intentionally or unintentionally, we aimed to investigate prospectively the relationship between weight loss from maximum body weight and fracture risk. RESEARCH DESIGN AND METHODS: A total of 4,706 Japanese participants with type 2 diabetes (mean age 66 years), including 2,755 men and 1,951 postmenopausal women, were followed for a median of 5.3 years and were divided according to weight loss from maximum weight:
49. Masanori Iwase, Hiroki Fujii, Udai Nakamura, Toshiaki Ohkuma, Hitoshi Ide, Tamaki Jodai-Kitamura, Akiko Sumi, Yuji Komorita, Masahito Yoshinari, Takanari Kitazono, Incidence of diabetic foot ulcer in Japanese patients with type 2 diabetes mellitus: The Fukuoka diabetes registry., Diabetes research and clinical practice, 10.1016/j.diabres.2018.01.020, 137, 183-189, 2018.03, AIMS: Although diabetic foot ulcer (DFU) is a serious diabetic complication, there have been no large-scale epidemiological studies of DFU in Japan. We prospectively investigated the incidences of DFU and limb amputation, the risk for developing DFU, and mortality in Japanese patients with type 2 diabetes. METHODS: We followed 4870 participants (mean age, 65 years) with type 2 diabetes attending an outpatient diabetes clinic for a median of 5.3 years (follow-up rate, 97.7%). The primary outcome was the development of DFU. RESULTS: During the follow-up period, DFU occurred in 74 participants (incidence rate, 2.9/1000 person-years) and limb amputation in 12 (incidence rate, 0.47/1000 person-years). DFU recurrence was observed in 21.4% of participants with history of DFU. History of DFU, chronic kidney disease (estimated glomerular filtration rate
50. Toshiaki Ohkuma, Mark Woodward, John Chalmers, Response to Comment on Ohkuma et al. Cardiac Stress and Inflammatory Markers as Predictors of Heart Failure in Patients With Type 2 Diabetes: The ADVANCE Trial. Diabetes Care 2017;40:1203-1209., Diabetes care, 10.2337/dci17-0060, 41, 3, e39, 2018.03.
51. Min Jun, Toshiaki Ohkuma, Sophia Zoungas, Stephen Colagiuri, Giuseppe Mancia, Michel Marre, David Matthews, Neil Poulter, Bryan Williams, Anthony Rodgers, Vlado Perkovic, John Chalmers, Mark Woodward, Changes in Albuminuria and the Risk of Major Clinical Outcomes in Diabetes: Results From ADVANCE-ON., Diabetes care, 10.2337/dc17-1467, 41, 1, 163-170, 2018.01, OBJECTIVE: To assess the association between 2-year changes in urine albumin-to-creatinine ratio (UACR) and the risk of clinical outcomes in type 2 diabetes. RESEARCH DESIGN AND METHODS: We analyzed data from 8,766 participants in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation Post-Trial Observational Study (ADVANCE-ON). Change in UACR was calculated from UACR measurements 2 years apart, classified into three groups: decrease in UACR of ≥30%, minor change, and increase in UACR of ≥30%. By analyzing changes from baseline UACR groups, categorized into thirds, we repeated these analyses accounting for regression to the mean (RtM). The primary outcome was the composite of major macrovascular events, renal events, and all-cause mortality; secondary outcomes were these components. Cox regression models were used to estimate hazard ratios (HRs). RESULTS: Over a median follow-up of 7.7 years, 2,191 primary outcomes were observed. Increases in UACR over 2 years independently predicted a greater risk of the primary outcome (HR for ≥30% UACR increase vs. minor change: 1.26; 95% CI 1.13-1.41), whereas a decrease in UACR was not significantly associated with lower risk (HR 0.93; 95% CI 0.83-1.04). However, after allowing for RtM, the effect of "real" decrease in UACR on the primary outcome was found to be significant (HR 0.84; 95% CI 0.75-0.94), whereas the estimated effect on an increase was unchanged. CONCLUSIONS: Changes in UACR predicted changes in the risk of major clinical outcomes and mortality in type 2 diabetes, supporting the prognostic utility of monitoring albuminuria change over time..
52. Akiko Sumi, Udai Nakamura, Masanori Iwase, Hiroki Fujii, Toshiaki Ohkuma, Hitoshi Ide, Tamaki Jodai-Kitamura, Yuji Komorita, Masahito Yoshinari, Yoichiro Hirakawa, Atsushi Hirano, Michiaki Kubo, Takanari Kitazono, The gene-treatment interaction of paraoxonase-1 gene polymorphism and statin therapy on insulin secretion in Japanese patients with type 2 diabetes: Fukuoka diabetes registry., BMC medical genetics, 10.1186/s12881-017-0509-1, 18, 1, 146-146, 2017.12, BACKGROUND: Although statins deteriorate glucose metabolism, their glucose-lowering effects have emerged in some situations. Here, we assessed whether these effects are a consequence of statins' interaction with paraoxonase (PON)1 enzyme polymorphism. METHODS: Adult Japanese type 2 diabetes patients (n = 3798) were enrolled in a cross-sectional study. We used Q192R polymorphism of the PON1 gene as a representative single-nucleotide polymorphism and focused on the effects of the wild-type Q allele, in an additive manner. For patients with and without statin therapy, the associations of this allele with fasting plasma glucose (FPG), HbA1c, C-peptide, HOMA2-%β, and HOMA2-IR were investigated separately using a linear regression model, and were compared between groups by testing interactions. Sensitivity analyses were performed using propensity score to further control the imbalance of characteristics between groups. RESULTS: Among patients with statin therapy, there were linear associations of the number of Q alleles with decreased FPG and HbA1c, and with increased serum C peptide and HOMA2-%β (all P 
53. Yuji Komorita, Masanori Iwase, Hiroki Fujii, Toshiaki Ohkuma, Hitoshi Ide, Tamaki Jodai-Kitamura, Akiko Sumi, Masahito Yoshinari, Udai Nakamura, Dongchon Kang, Takanari Kitazono, Serum adiponectin predicts fracture risk in individuals with type 2 diabetes: the Fukuoka Diabetes Registry., Diabetologia, 10.1007/s00125-017-4369-1, 60, 10, 1922-1930, 2017.10, AIMS/HYPOTHESIS: Serum adiponectin has been reported to impact upon fracture risk in the general population. Although type 2 diabetes is associated with increased fracture risk, it is unclear whether serum adiponectin predicts fractures in individuals with type 2 diabetes. The aim of the study was to prospectively investigate the relationship between serum adiponectin and fracture risk in individuals with type 2 diabetes. METHODS: In this study, data was obtained from The Fukuoka Diabetes Registry, a multicentre prospective study designed to investigate the influence of modern treatments on the prognoses of patients with diabetes mellitus. We followed 4869 participants with type 2 diabetes (mean age, 65 years), including 1951 postmenopausal women (defined as self-reported amenorrhea for >1 year) and 2754 men, for a median of 5.3 years. The primary outcomes were fractures at any site and major osteoporotic fractures (MOFs). RESULTS: During the follow-up period, fractures at any site occurred in 682 participants, while MOFs occurred in 277 participants. Age-adjusted HRs (95% CIs) of any fracture and MOFs for 1 SD increment in log e -transformed serum adiponectin were 1.27 (1.15, 1.40) and 1.35 (1.17, 1.55) in postmenopausal women and 1.22 (1.08, 1.38) and 1.40 (1.15, 1.71) in men, respectively. HRs (95% CIs) of MOFs for hyperadiponectinaemia (≥ 20 μg/ml) were 1.72 (1.19, 2.50) in postmenopausal women and 2.19 (1.23, 3.90) in men. The per cent attributable risk of hyperadiponectinaemia for MOFs was as high as being age ≥70 years or female sex. CONCLUSIONS/INTERPRETATION: Higher serum adiponectin levels were significantly associated with an increased risk of fractures at any site and with an increased risk of MOFs in individuals with type 2 diabetes, including postmenopausal women..
54. Toshiaki Ohkuma, Min Jun, Mark Woodward, Sophia Zoungas, Mark E Cooper, Diederick E Grobbee, Pavel Hamet, Giuseppe Mancia, Bryan Williams, Paul Welsh, Naveed Sattar, Jonathan E Shaw, Kazem Rahimi, John Chalmers, Cardiac Stress and Inflammatory Markers as Predictors of Heart Failure in Patients With Type 2 Diabetes: The ADVANCE Trial., Diabetes care, 10.2337/dc17-0509, 40, 9, 1203-1209, 2017.09, OBJECTIVE: This study examined the individual and combined effect of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), interleukin-6 (IL-6), and hs-CRP on the prediction of heart failure incidence or progression in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A nested case-cohort study was conducted in 3,098 participants with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. RESULTS: A higher value of each biomarker was significantly associated with a higher risk of heart failure incidence or progression, after adjustment for major risk factors. The hazard ratios per 1-SD increase were 3.06 (95% CI 2.37, 3.96) for NT-proBNP, 1.50 (1.27, 1.77) for hs-cTnT, 1.48 (1.27, 1.72) for IL-6, and 1.32 (1.12, 1.55) for hs-CRP. The addition of NT-proBNP to the model including conventional risk factors meaningfully improved 5-year risk-predictive performance (C statistic 0.8162 to 0.8800; continuous net reclassification improvement [NRI] 73.1%; categorical NRI [10% 5-year risk] 24.2%). In contrast, the addition of hs-cTnT, IL-6, or hs-CRP did not improve the prediction metrics consistently in combination or when added to NT-proBNP. CONCLUSIONS: Only NT-proBNP strongly and consistently improved the prediction of heart failure in patients with type 2 diabetes beyond a wide range of clinical risk factors and biomarkers..
55. Toshiaki Ohkuma, Hirofumi Tomiyama, Toshiharu Ninomiya, Kazuomi Kario, Satoshi Hoshide, Yoshikuni Kita, Toyoshi Inoguchi, Yasutaka Maeda, Katsuhiko Kohara, Yasuharu Tabara, Motoyuki Nakamura, Takayoshi Ohkubo, Hirotaka Watada, Masanori Munakata, Mitsuru Ohishi, Norihisa Ito, Michinari Nakamura, Tetsuo Shoji, Charalambos Vlachopoulos, Akira Yamashina, Proposed Cutoff Value of Brachial-Ankle Pulse Wave Velocity for the Management of Hypertension., Circulation journal : official journal of the Japanese Circulation Society, 10.1253/circj.CJ-17-0636, 81, 10, 1540-1542, 2017.09, BACKGROUND: The optimal cutoff values of the brachial-ankle pulse wave velocity (baPWV) for predicting cardiovascular disease (CVD) were examined in patients with hypertension.Methods and Results:A total of 7,656 participants were followed prospectively. The hazard ratio for the development of CVD increased significantly as the baPWV increased, independent of conventional risk factors. The receiver-operating characteristic curve analysis showed that the optimal cutoff values for predicting CVD was 18.3 m/s. This cutoff value significantly predicted THE incidence of CVD. CONCLUSIONS: The present analysis suggests that the optimal cutoff value for CVD in patients with hypertension is 18.3 m/s..
56. Toshiaki Ohkuma, Masanori Iwase, Hiroki Fujii, Hitoshi Ide, Shinako Kaizu, Tamaki Jodai, Yohei Kikuchi, Yasuhiro Idewaki, Akiko Sumi, Udai Nakamura, Takanari Kitazono, Joint impact of modifiable lifestyle behaviors on glycemic control and insulin resistance in patients with type 2 diabetes: the Fukuoka Diabetes Registry., Diabetology international, 10.1007/s13340-017-0310-6, 8, 3, 296-305, 2017.08, Aims: Little is known about the combined effects of unhealthy lifestyle behaviors on glycemia. The objective of this study was to examine the association between combined modifiable lifestyle and glycemic control, as well as markers of insulin resistance and secretion. Patients and methods: In total, 4,870 patients with type 2 diabetes were sorted by lifestyle scores. Scores were determined by summing the number of unhealthy lifestyle factors that showed a significant association with hemoglobin A1c (HbA1c) (current smoking, decreased dietary fiber intake, eating quickly, inadequate sleep duration, and obesity). The associations between lifestyle score and hemoglobin A1c (HbA1c), homeostasis model assessment of insulin resistance (HOMA2-IR), and β-cell function (HOMA2-%B) were cross-sectionally analyzed. Results: HbA1c increased progressively with increases in lifestyle score (p for trend
57. Toshiaki Ohkuma, Mark Woodward, Min Jun, Paul Muntner, Jun Hata, Stephen Colagiuri, Stephen Harrap, Giuseppe Mancia, Neil Poulter, Bryan Williams, Peter Rothwell, John Chalmers, Prognostic Value of Variability in Systolic Blood Pressure Related to Vascular Events and Premature Death in Type 2 Diabetes Mellitus: The ADVANCE-ON Study., Hypertension (Dallas, Tex. : 1979), 10.1161/HYPERTENSIONAHA.117.09359, 70, 2, 461-468, 2017.08, Visit-to-visit variability in systolic blood pressure (SBP) is a risk factor for cardiovascular events. However, whether it provides additional predictive information beyond traditional risk factors, including mean SBP, in the long term is unclear. The ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) was a randomized controlled trial in patients with type 2 diabetes mellitus; ADVANCE-ON (ADVANCE-Observational) followed-up patients subsequently. In these analyses, 9114 patients without major macrovascular or renal events or death during the first 24 months were included. Data on SBP from 6 visits during the first 24 months after randomization were used to estimate visit-to-visit variability in several ways: the primary measure was the standard deviation. Events accrued during the following 7.6 years. The primary outcome was a composite of major macrovascular and renal events and all-cause mortality. Standard deviation of SBP was log-linearly associated with an increased risk of the primary outcome (P
58. Toshiaki Ohkuma, Toshiharu Ninomiya, Hirofumi Tomiyama, Kazuomi Kario, Satoshi Hoshide, Yoshikuni Kita, Toyoshi Inoguchi, Yasutaka Maeda, Katsuhiko Kohara, Yasuharu Tabara, Motoyuki Nakamura, Takayoshi Ohkubo, Hirotaka Watada, Masanori Munakata, Mitsuru Ohishi, Norihisa Ito, Michinari Nakamura, Tetsuo Shoji, Charalambos Vlachopoulos, Akira Yamashina, Brachial-Ankle Pulse Wave Velocity and the Risk Prediction of Cardiovascular Disease: An Individual Participant Data Meta-Analysis., Hypertension (Dallas, Tex. : 1979), 10.1161/HYPERTENSIONAHA.117.09097, 69, 6, 1045-1052, 2017.06, An individual participant data meta-analysis was conducted in the data of 14 673 Japanese participants without a history of cardiovascular disease (CVD) to examine the association of the brachial-ankle pulse wave velocity (baPWV) with the risk of development of CVD. During the average 6.4-year follow-up period, 687 participants died and 735 developed cardiovascular events. A higher baPWV was significantly associated with a higher risk of CVD, even after adjustments for conventional risk factors (P for trend
59. Hitoshi Ide, Masanori Iwase, Hiroki Fujii, Toshiaki Ohkuma, Shinako Kaizu, Tamaki Jodai, Yohei Kikuchi, Yasuhiro Idewaki, Akiko Sumi, Udai Nakamura, Takanari Kitazono, Comparison of cystatin C- and creatinine-based estimated glomerular filtration rates for predicting all-cause mortality in Japanese patients with type 2 diabetes: the Fukuoka Diabetes Registry., Clinical and experimental nephrology, 10.1007/s10157-016-1296-2, 21, 3, 383-390, 2017.06, BACKGROUND: There is little information about the predictive ability of cystatin C-based estimated glomerular filtration rates (eGFRCys) for all-cause mortality in Asian populations. We compared the discriminatory ability of eGFRCys for all-cause mortality with that of creatinine-based estimated glomerular filtration rates (eGFRCr) in Japanese patients with type 2 diabetes. METHODS: A total of 4869 participants were classified into four categories (eGFR ≤29, 30-59, 60-89, and ≥90 ml/min/1.73 m2) by eGFRCr and eGFRCys, and followed up for a median of 3.3 years. RESULTS: 150 deaths were identified. The multivariable-adjusted risk of all-cause mortality was significantly increased in eGFRCr ≤29 ml/min/1.73 m2 compared with eGFRCr ≥90 ml/min/1.73 m2 [hazard ratio (HR) 2.4 (95 % confidence interval (95 % CI) 1.2-5.0)], whereas it was significantly increased in eGFRCys 59 ml/min/1.73 m2 or lower [30-59 ml/min/1.73 m2, HR 1.9 (95 % CI 1.1-3.5); ≤29 ml/min/1.73 m2, HR 5.8 (95 % CI 2.8-12.0)]. Comparing eGFRCys with eGFRCr, the proportions of participants reclassified to lower and higher eGFR stages were 6.3 and 28.8 %, respectively. The multivariable-adjusted HRs for all-cause mortality were 1.8 (95 % CI 1.1-2.9) and 0.7 (95 % CI 0.4-1.1), respectively. The C statistic of the model including eGFRCys and other risk factors was significantly increased compared with the model including eGFRCr. The net reclassification improvement and the integrated discrimination improvement were significantly positive. CONCLUSIONS: Our findings suggest that eGFRCys has a stronger association with all-cause mortality and is superior to eGFRCr for predicting all-cause mortality in Japanese patients with type 2 diabetes..
60. Toshiaki Ohkuma, Udai Nakamura, Masanori Iwase, Hitoshi Ide, Hiroki Fujii, Tamaki Jodai, Shinako Kaizu, Yohei Kikuchi, Yasuhiro Idewaki, Akiko Sumi, Yoichiro Hirakawa, Takanari Kitazono, Effects of smoking and its cessation on creatinine- and cystatin C-based estimated glomerular filtration rates and albuminuria in male patients with type 2 diabetes mellitus: the Fukuoka Diabetes Registry., Hypertension research : official journal of the Japanese Society of Hypertension, 10.1038/hr.2016.51, 39, 10, 744-751, 2016.10, Cigarette smoking is an important modifiable risk factor for lifestyle diseases. The smoking rate remains high, and the prevalence of diabetes mellitus is increasing in Asian countries; however, few studies have examined the effects of smoking on chronic kidney disease (CKD) in Asian diabetic patients. The aim of the present study was to investigate the association between smoking and its cessation with CKD and its components in patients with type 2 diabetes. A total of 2770 Japanese male patients with type 2 diabetes aged ⩾20 years were divided according to the amount of cigarette smoking and the years since cessation. The associations with CKD, the urinary albumin-creatinine ratio (UACR) and the estimated glomerular filtration rate (eGFR) were cross-sectionally examined. The proportions of CKD and the mean UACR dose-dependently increased with increases in both the number of cigarettes per day and the Brinkman index compared with the never smokers. The creatinine-based eGFR also increased with increases in the amount of smoking, whereas the cystatin C-based eGFR decreased, and their average did not significantly change. These parameters exhibited inverse associations with the years after smoking cessation compared with the association with the amount of smoking. A dose-dependent association of active smoking and a graded inverse association of the years since quitting with CKD enhance the merit of smoking cessation in patients with type 2 diabetes..
61. Yasuhiro Idewaki, Masanori Iwase, Hiroki Fujii, Toshiaki Ohkuma, Hitoshi Ide, Shinako Kaizu, Tamaki Jodai, Yohei Kikuchi, Atsushi Hirano, Udai Nakamura, Michiaki Kubo, Takanari Kitazono, Association of Genetically Determined Aldehyde Dehydrogenase 2 Activity with Diabetic Complications in Relation to Alcohol Consumption in Japanese Patients with Type 2 Diabetes Mellitus: The Fukuoka Diabetes Registry., PloS one, 10.1371/journal.pone.0143288, 10, 11, e0143288, 2015.10, Aldehyde dehydrogenase 2 (ALDH2) detoxifies aldehyde produced during ethanol metabolism and oxidative stress. A genetic defect in this enzyme is common in East Asians and determines alcohol consumption behaviors. We investigated the impact of genetically determined ALDH2 activity on diabetic microvascular and macrovascular complications in relation to drinking habits in Japanese patients with type 2 diabetes mellitus. An ALDH2 single-nucleotide polymorphism (rs671) was genotyped in 4,400 patients. Additionally, the relationship of clinical characteristics with ALDH2 activity (ALDH2 *1/*1 active enzyme activity vs. *1/*2 or *2/*2 inactive enzyme activity) and drinking habits (lifetime abstainers vs. former or current drinkers) was investigated cross-sectionally (n = 691 in *1/*1 abstainers, n = 1,315 in abstainers with *2, n = 1,711 in *1/*1 drinkers, n = 683 in drinkers with *2). The multiple logistic regression analysis for diabetic complications was adjusted for age, sex, current smoking habits, leisure-time physical activity, depressive symptoms, diabetes duration, body mass index, hemoglobin A1c, insulin use, high-density lipoprotein cholesterol, systolic blood pressure and renin-angiotensin system inhibitors use. Albuminuria prevalence was significantly lower in the drinkers with *2 than that of other groups (odds ratio [95% confidence interval (CI)]: *1/*1 abstainers as the referent, 0.94 [0.76-1.16] in abstainers with *2, 1.00 [0.80-1.26] in *1/*1 drinkers, 0.71 [0.54-0.93] in drinkers with *2). Retinal photocoagulation prevalence was also lower in drinkers with ALDH2 *2 than that of other groups. In contrast, myocardial infarction was significantly increased in ALDH2 *2 carriers compared with that in ALDH2 *1/*1 abstainers (odds ratio [95% CI]: *1/*1 abstainers as the referent, 2.63 [1.28-6.13] in abstainers with *2, 1.89 [0.89-4.51] in *1/*1 drinkers, 2.35 [1.06-5.79] in drinkers with *2). In summary, patients with type 2 diabetes and ALDH2 *2 displayed a lower microvascular complication prevalence associated with alcohol consumption but a higher macrovascular complication prevalence irrespective of alcohol consumption..
62. Toshiaki Ohkuma, Masanori Iwase, Hiroki Fujii, Shinako Kaizu, Hitoshi Ide, Tamaki Jodai, Yohei Kikuchi, Yasuhiro Idewaki, Yoichiro Hirakawa, Udai Nakamura, Takanari Kitazono, Dose- and time-dependent association of smoking and its cessation with glycemic control and insulin resistance in male patients with type 2 diabetes mellitus: the Fukuoka Diabetes Registry., PloS one, 10.1371/journal.pone.0122023, 10, 3, e0122023, 2015.10, OBJECTIVE: Cigarette smoking is an important modifiable risk factor for cardiovascular diseases. However, the effect of smoking and its cessation on glycemic control in diabetic patients has not been fully examined yet. The aim of the present study was to examine the association of smoking status with glycemic level and markers of insulin resistance and secretion in patients with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: A total of 2,490 Japanese male patients with type 2 diabetes mellitus aged ≥20 years were divided according to smoking status, amount of cigarettes smoked and years since quitting. The associations with glycemic level and markers of insulin resistance and secretion were examined cross-sectionally. RESULTS: HbA1c levels increased progressively with increases in both number of cigarettes per day and pack-years of cigarette smoking compared with never smokers (P for trend = 0.001 and
63. Yohei Kikuchi, Masanori Iwase, Hiroki Fujii, Toshiaki Ohkuma, Shinako Kaizu, Hitoshi Ide, Tamaki Jodai, Yasuhiro Idewaki, Udai Nakamura, Takanari Kitazono, Association of severe hypoglycemia with depressive symptoms in patients with type 2 diabetes: the Fukuoka Diabetes Registry., BMJ open diabetes research & care, 10.1136/bmjdrc-2014-000063, 3, 1, e000063, 2015.03, OBJECTIVE: Although many studies have investigated the clinical characteristics of patients with diabetes with depression in Western populations, there is a lack of information regarding other ethnicities. We studied the association between clinical characteristics and depressive symptoms in Japanese patients with type 2 diabetes. METHODS: A total of 4218 Japanese patients with type 2 diabetes who were not taking antidepressants were divided into four groups according to the Center for Epidemiologic Studies Depression Scale (CES-D) score. The relationship between the severity of depressive symptoms and clinical parameters was examined cross-sectionally. RESULTS: After multivariate adjustments, the severity of depressive symptoms was significantly associated with body mass index, leisure-time physical activity, current smoking, sleep duration, sucrose intake, skipping breakfast, insulin use, severe hypoglycemia, dysesthesia of both feet, history of foot ulcer, photocoagulation, ischemic heart disease, and stroke. ORs for severe hypoglycemia increased significantly with the CES-D score in 2756 sulfonylurea and/or insulin-treated patients after multivariate adjustment including age, sex, duration of diabetes, glycated hemoglobin, insulin use, self-monitoring of blood glucose, leisure-time physical activity, skipping breakfast, dysesthesia of both feet, ischemic heart disease, and stroke (CES-D score ≤9, referent; 10-15, OR 1.64; 16-23, OR 2.09; ≥24, OR 3.66; p for trend
64. Shinako Kaizu, Hiro Kishimoto, Masanori Iwase, Hiroki Fujii, Toshiaki Ohkuma, Hitoshi Ide, Tamaki Jodai, Yohei Kikuchi, Yasuhiro Idewaki, Yoichiro Hirakawa, Udai Nakamura, Takanari Kitazono, Impact of leisure-time physical activity on glycemic control and cardiovascular risk factors in Japanese patients with type 2 diabetes mellitus: the Fukuoka Diabetes Registry., PloS one, 10.1371/journal.pone.0098768, 9, 6, e98768, 2014.09, AIMS/HYPOTHESIS: The effects of leisure-time physical activity (LTPA) on glycemia and cardiovascular risk factors are not fully understood in Asian type 2 diabetic patients, who are typically non-obese. We studied associations between LTPA and glycemia and cardiovascular risk factors in Japanese type 2 diabetic patients. METHODS: A total of 4,870 Japanese type 2 diabetic patients aged ≥ 20 years were divided into eight groups according to their LTPA. We investigated associations between the amount and intensity levels of physical activity (PA) and glycemic control, insulin sensitivity, cardiovascular risk factors, and low-grade systemic inflammation in a cross-sectional study. RESULTS: LTPA was dose-dependently associated with body mass index (BMI), waist circumference, hemoglobin A1c (HbA1c), fasting plasma glucose, homeostasis model assessment of insulin resistance, triglyceride, high density lipoprotein cholesterol, high sensitivity C-reactive protein, and prevalence of metabolic syndrome, but not with blood pressure, low density lipoprotein cholesterol or adiponectin. The amount of PA required to lower HbA1c was greater than that required to improve cardiovascular risk factors. LTPA was inversely associated with HbA1c in non-obese participants but not in obese participants after multivariate adjustments for age, sex, duration of diabetes, current smoking, current drinking, energy intake, cardiovascular diseases, depressive symptoms, and treatment of diabetes. Higher-intensity LTPA, not lower-intensity LTPA was associated with HbA1c after multivariate adjustments with further adjustment including BMI. CONCLUSIONS/INTERPRETATION: LTPA was dose-dependently associated with better glycemic control and amelioration of some cardiovascular risk factors in Japanese type 2 diabetic patients. In addition, increased higher-intensity LTPA may be appropriate for glycemic control..
65. Toshiaki Ohkuma, Hiroki Fujii, Masanori Iwase, Shinako Ogata-Kaizu, Hitoshi Ide, Yohei Kikuchi, Yasuhiro Idewaki, Tamaki Jodai, Yoichiro Hirakawa, Udai Nakamura, Takanari Kitazono, U-shaped association of sleep duration with metabolic syndrome and insulin resistance in patients with type 2 diabetes: the Fukuoka Diabetes Registry., Metabolism: clinical and experimental, 10.1016/j.metabol.2013.12.001, 63, 4, 484-91, 2014.04, OBJECTIVE: Sleep duration is suggested to be associated with adverse health outcomes. However, few studies are available on the impact of sleep duration on metabolic syndrome in patients with diabetes, who were at high risk for cardiovascular diseases (CVD). The objective of the present study was to examine the associations of sleep duration with metabolic syndrome and insulin resistance, a major pathophysiologic feature of metabolic syndrome, in patients with type 2 diabetes. MATERIALS/METHODS: A total of 4402 Japanese patients with type 2 diabetes aged ≥20years were divided into 5 groups according to self-reported sleep duration: less than 5.5h, 5.5-6.4h, 6.5-7.4h, 7.5-8.4h, and more than 8.5h. The associations of sleep duration with metabolic syndrome and other cardiovascular risk factors were examined cross-sectionally. RESULTS: The proportions of patients who had metabolic syndrome increased significantly in both patients with shorter and longer sleep duration compared with those with 6.5-7.4h of sleep (P for quadratic trend
66. Hiroki Fujii, Masanori Iwase, Toshiaki Ohkuma, Shinako Ogata-Kaizu, Hitoshi Ide, Yohei Kikuchi, Yasuhiro Idewaki, Tamaki Joudai, Yoichiro Hirakawa, Kazuhiro Uchida, Satoshi Sasaki, Udai Nakamura, Takanari Kitazono, Impact of dietary fiber intake on glycemic control, cardiovascular risk factors and chronic kidney disease in Japanese patients with type 2 diabetes mellitus: the Fukuoka Diabetes Registry., Nutrition journal, 10.1186/1475-2891-12-159, 12, 159-159, 2013.12, BACKGROUND: Dietary fiber is beneficial for the treatment of type 2 diabetes mellitus, although it is consumed differently in ethnic foods around the world. We investigated the association between dietary fiber intake and obesity, glycemic control, cardiovascular risk factors and chronic kidney disease in Japanese type 2 diabetic patients. METHODS: A total of 4,399 patients were assessed for dietary fiber intake using a brief self-administered diet history questionnaire. The associations between dietary fiber intake and various cardiovascular risk factors were investigated cross-sectionally. RESULTS: Body mass index, fasting plasma glucose, HbA1c, triglyceride and high-sensitivity C-reactive protein negatively associated with dietary fiber intake after adjusting for age, sex, duration of diabetes, current smoking, current drinking, total energy intake, fat intake, saturated fatty acid intake, leisure-time physical activity and use of oral hypoglycemic agents or insulin. The homeostasis model assessment insulin sensitivity and HDL cholesterol positively associated with dietary fiber intake. Dietary fiber intake was associated with reduced prevalence of abdominal obesity, hypertension and metabolic syndrome after multivariate adjustments including obesity. Furthermore, dietary fiber intake was associated with lower prevalence of albuminuria, low estimated glomerular filtration rate and chronic kidney disease after multivariate adjustments including protein intake. Additional adjustments for obesity, hypertension or metabolic syndrome did not change these associations. CONCLUSION: We demonstrated that increased dietary fiber intake was associated with better glycemic control and more favorable cardiovascular disease risk factors including chronic kidney disease in Japanese type 2 diabetic patients. Diabetic patients should be encouraged to consume more dietary fiber in daily life..
67. Toshiaki Ohkuma, Hiroki Fujii, Masanori Iwase, Shinako Ogata-Kaizu, Hitoshi Ide, Yohei Kikuchi, Yasuhiro Idewaki, Tamaki Jodai, Yoichiro Hirakawa, Udai Nakamura, Takanari Kitazono, Association between sleep duration and urinary albumin excretion in patients with type 2 diabetes: the Fukuoka diabetes registry., PloS one, 10.1371/journal.pone.0078968, 8, 11, e78968, 2013.08, OBJECTIVE: Few studies have so far investigated the impact of sleep duration on chronic kidney disease in diabetic patients. The objective of the present study was to examine the relationship between sleep duration and albuminuria in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 4,870 Japanese type 2 diabetic patients ≥20 years of age were divided into six groups according to self-reported sleep duration: less than 4.5 hours, 4.5-5.4 hours, 5.5-6.4 hours, 6.5-7.4 hours, 7.5-8.4 hours and more than 8.5 hours. The association between sleep duration and urinary albumin-creatinine ratio (UACR) was examined cross-sectionally. RESULTS: Both short and long sleep durations were significantly associated with higher UACR levels and higher proportions of patients with albuminuria (≥30 mg/g) and macroalbuminuria (≥300 mg/g) compared with a sleep duration of 6.5-7.4 hours (P for quadratic trend
68. Shunsuke Yamada, Masanori Tokumoto, Toshiaki Ohkuma, Yasuo Kansui, Yoshinobu Wakisaka, Yuji Uchizono, Kazuhiko Tsuruya, Takanari Kitazono, Hiroaki Ooboshi, Slowly progressive and painless thoracic aortic dissection presenting with a persistent Fever in an elderly patient: the usefulness of combined measurement of biochemical parameters., Case reports in medicine, 10.1155/2013/498129, 2013, 498129-498129, 2013.06, Aortic dissection is a fatal medical condition that requires urgent diagnosis and appropriate intervention. Because acute aortic dissection often manifests as sudden onset excruciating chest pain, physicians can easily reach a proper diagnosis. However, some patients with aortic dissection present with varied clinical manifestations without exhibiting typical chest pain, leading to a delayed diagnosis and possible fatality. We herein present the case of an elderly subject with a fever of unknown origin who was ultimately diagnosed with aortic dissection. In the present case, a negative procalcitonin test, increased D-dimer and serum creatinine phosphokinase-BB levels, and reelevation of the CPR level led us to the correct diagnosis..
69. Toshiaki Ohkuma, Hiroki Fujii, Masanori Iwase, Yohei Kikuchi, Shinako Ogata, Yasuhiro Idewaki, Hitoshi Ide, Yasufumi Doi, Yoichiro Hirakawa, Udai Nakamura, Takanari Kitazono, Impact of sleep duration on obesity and the glycemic level in patients with type 2 diabetes: the Fukuoka Diabetes Registry., Diabetes care, 10.2337/dc12-0904, 36, 3, 611-7, 2013.03, OBJECTIVE: Few studies are currently available regarding the influence of sleep duration on glycemic control in diabetic patients. The objective of the current study was to examine the relationship between sleep duration, obesity, and the glycemic level in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 4,870 Japanese type 2 diabetic patients aged ≥20 years were divided into six groups according to their self-reported sleep duration: less than 4.5 h, 4.5-5.4 h, 5.5-6.4 h, 6.5-7.4 h, 7.5-8.4 h, and more than 8.5 h. The associations of sleep duration with obesity and the HbA(1c) levels were examined in a cross-sectional manner. RESULTS: The HbA(1c) levels showed a quadratic association with sleep duration; namely, a shorter or longer sleep duration was associated with a higher level compared with a sleep duration of 6.5-7.4 h (P for quadratic trend