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Journal Club

Journal Club. Peters SA1, Huxley RR2, Woodward M3 . Diabetes as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 64 cohorts, including 775 385 individuals and 12 539 strokes . Lancet . 2014 Mar 6. pii : S0140-6736(14)60040-4

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Journal Club

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  1. Journal Club Peters SA1, Huxley RR2, Woodward M3. Diabetes as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 64 cohorts, including 775 385 individuals and 12 539 strokes. Lancet. 2014 Mar 6. pii: S0140-6736(14)60040-4 Polidori D, Mari A, Ferrannini E. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves model-based indices of beta cell function in patients with type 2 diabetes. Diabetologia. 2014 Mar 1 埼玉医科大学　総合医療センター　内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田　昌文　 Matsuda, Masafumi 2014年3月20日8:30-8:55 ８階　医局

  2. The Japan Public Health Center Study Stroke 2011; 42: 2611-2614

  3. The Japan Public Health Center Study Stroke 2011; 42: 2611-2614

  4. Stroke 2000; 31: 2616-2622

  5. 3. Antiplatelet Agents • Recommendations • Consider aspirin therapy (75–162 mg/day) as a primary prevention strategy in those with type 1 or type 2 diabetes at increased cardiovascular risk (10-year risk >10%). This includes most men aged >50 years or women aged >60 years who have at least one additional major risk factor (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria). C • Aspirin should not be recommended for CVD prevention for adults with diabetes at low CVD risk (10-year CVD risk <5%, such as in men aged <50 years and women aged <60 years with no major additional CVD risk factors), since the potential adverse effects from bleeding likely offset the potential benefits. C • In patients in these age-groups with multiple other risk factors (e.g., 10-year risk 5–10%), clinical judgment is required. E • Use aspirin therapy (75–162 mg/day) as a secondary prevention strategy in those with diabetes with a history of CVD. A • For patients with CVD and documented aspirin allergy, clopidogrel (75 mg/day) should be used. B • Dual antiplatelet therapy is reasonable for up to a year after an acute coronary syndrome. B ADA: 2014 Clinical Practice Recommendations Diabetes Care. 37(suppl1):s1-s99, 2014.

  6. Treatment • In patients with known CVD, consider ACE inhibitor therapy C and use aspirin and statin therapy A (if not contraindicated) to reduce the risk of cardiovascular events. • In patients with a prior MI, β-blockers should be continued for at least 2 years after the event. B • In patients with symptomatic heart failure, avoid thiazolidinedione treatment. C • In patients with stable CHF, metformin may be used if renal function is normal but should be avoided in unstable or hospitalized patients with CHF. B ADA: 2014 Clinical Practice Recommendations Diabetes Care. 37(suppl1):s1-s99, 2014.

  7. 血糖介入による心血管疾患イベント抑制 -15%　有意差あり Lancet 2009; 373: 1765–72

  8. 血糖介入による脳血管疾患イベント抑制 -7%　有意差なし Lancet 2009; 373: 1765–72

  9. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands (S A E Peters PhD); Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK (S A E Peters); School of Population Health, University of Queensland, Brisbane, QLD, Australia (Prof R R Huxley DPhil); The George Institute for Global Health, University of Sydney, Sydney, Australia (Prof M Woodward PhD); Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA (M Woodward); and The George Institute for Global Health, Nuffield Department of Population Health, University of Oxford, Oxford, UK (M Woodward) http://dx.doi.org/10.1016/S0140-6736(14)60040-4

  10. Background Diabetes mellitus is a major cause of death and disability worldwide and is a strong risk factor for stroke. Whether and to what extent the excess risk of stroke conferred by diabetes differs between the sexes is unknown. We did a systematic review and meta-analysis to estimate the relative effect of diabetes on stroke risk in women compared with men.

  11. Methods We systematically searched PubMed for reports of prospective, population-based cohort studies published between Jan 1, 1966, and Dec 16, 2013. Studies were selected if they reported sex-specific estimates of the relative risk (RR) for stroke associated with diabetes, and its associated variability. We pooled the sex-specific RRs and their ratio comparing women with men using random-effects meta-analysis with inverse-variance weighting.

  12. WOMEN

  13. MEN

  14. Findings Data from 64 cohort studies, representing 775 385 individuals and 12 539 fatal and non-fatal strokes, were included in the analysis. The pooled maximum-adjusted RR of stroke associated with diabetes was 2·28 (95% CI 1·93–2·69) in women and 1·83 (1·60–2·08) in men. Compared with men with diabetes, women with diabetes therefore had a greater risk of stroke—the pooled ratio of RRs was 1·27 (1·10–1·46; I2=0%), with no evidence of publication bias. This sex differential was seen consistently across major predefined stroke, participant, and study subtypes.

  15. Interpretation The excess risk of stroke associated with diabetes is significantly higher in women than men, independent of sex differences in other major cardiovascular risk factors. These data add to the existing evidence that men and women experience diabetes-related diseases differently and suggest the need for further work to clarify the biological, behavioural, or social mechanisms involved.

  16. Message 前向きコホート研究64件（被験者77万5385人、脳卒中1万2539件）を対象に、糖尿病（DM）患者の脳卒中リスクの性差をシステマティックレビューとメタ解析で推算。DM患者における脳卒中の調整後最大相対リスクは女性2.28、男性1.83で、男性に比べ女性で脳卒中リスクが有意に高かった（相対リスク比1.27、I2=0％）。 日本の研究は有意差は？だが男性が高い

  17. Luseogliflozin FIG. 1. SGLT2 inhibitors in late-stage clinical trials. Based upon their PK/PD relationship, we postulate that their mechanism of action is related to secretion and/or active reabsorption in the proximal tubule and slow off rate from the SGLT2 target. Liu JJ, Lee T, DeFronzo RA.: Why Do SGLT2 inhibitors inhibit only 30-50% of renal glucose reabsorption in humans? Diabetes. 2012 Sep;61(9):2199-204. 2012年11月1日 Journal Club

  18. approved

  19. D. Polidori (*): Janssen Research & Development, LLC, 3210 MerryfieldRow,San Diego, CA 92121, USA A. Mari: Institute of Biomedical Engineering, National Research Council,Padua, Italy E. Ferrannini: Department of Clinical and Experimental Medicine, University ofPisa School of Medicine, Pisa, Italy

  20. Aims/hypothesis In rodent models of diabetes, treatment with sodium glucose co-transporter 2 (SGLT2) inhibitors improves beta cell function. This analysis assessed the effects of the SGLT2 inhibitor, canagliflozin, on model-based measures of beta cell function in patients with type 2 diabetes.

  21. Methods Data from three Phase 3 studies were analysed, in which: (Study 1) canagliflozin 100 and 300 mg were compared with placebo as monotherapy for 26 weeks; (Study 2) canagliflozin 100 and 300 mg were compared with placebo as add-on to metformin + sulfonylurea for 26 weeks; or (Study 3) canagliflozin 300 mg was compared with sitagliptin 100 mg as add-on to metformin + sulfonylurea for 52 weeks. In each study, a subset of patients was given mixed-meal tolerance tests at baseline and study endpoint, and model-based beta cell function parameters were calculated from plasma glucose and C-peptide.

  22. Modelling analysis Beta cell function was assessed from the FS-MMTT using a model that describes the relationship between insulin secretion and glucose concentration [19, 20]. The model expresses insulin secretion (in pmol min−1 m−2) as the sum of two components. The first of these components consists of a dose–response function relating the insulin secretion rate and the absolute glucose concentration at any time point during the MMTT. Characteristic parameters of the dose–response function are the mean slope over the observed glucose range, denoted as beta cell glucose sensitivity, and the insulin secretion rate (ISR) at a fixed glucose level of 9 mmol/l (i.e. ISR at 9 mmol/l glucose). The second insulin secretion component, termed the derivative component, represents the dependence of insulin secretion on the rate of change of glucose concentration and is determined by a single parameter, denoted as rate sensitivity, that is related to early insulin release [21]. The model parameters were estimated from glucose and C-peptide concentrations by regularised least squares, as previously described [19]. The ISR was calculated from the model every 5 min. The integral of insulin secretion during the 3 h MMTT was denoted as total insulin secretion, and insulin clearance was calculated by dividing total insulin secretion by plasma insulin AUC. Insulin clearance was calculated only for participants with at least five measurements of plasma insulin during the MMTT. Insulin sensitivity was estimated from the MMTT data using the oral glucose insulin sensitivity (OGIS) index as previously described [22, 23]. To account for this, UGE-corrected OGIS values (OGISc) were calculated by subtracting renal glucose clearance (calculated as UGE divided by plasma glucose AUC during the MMTT) from the OGIS value to provide a more appropriate index of insulin sensitivity for assessing the effects of canagliflozin treatment.

  23. Placebo 100mg CANA 300mg CANA

  24. Placebo 100mg CANA 300mg CANA

  25. 100mg SITA 300mg CANA

  26. Results In Studies 1 and 2, both canagliflozin doses increased beta cell glucose sensitivity compared with placebo. Placebo-subtracted least squares mean (LSM) (SEM) changes were 23 (9) and 18 (9) pmol min−1 m−2 (mmol/l)−1 with canagliflozin 100 and 300 mg, respectively (p < 0.002, Study 1), and 16 (8) and 10 (9) pmol min−1 m−2 (mmol/l)−1 (p < 0.02, Study 2). In Study 3, beta cell glucose sensitivity was minimally affected, but the insulin secretion rate at 9 mmol/l glucose increased to similar degrees from baseline with canagliflozin and sitagliptin [LSM (SEM) changes 38 (8) and 28 (9) pmol min−1 m−2, respectively; p < 0.05 for both].

  27. Conclusions/interpretation Treatment with canagliflozin for 6 to 12 months improved model-based measures of beta cell function in three separate Phase 3 studies.

  28. Message SGLT-2阻害薬（Canagliflozin）のインスリン分泌能に及ぼす影響を調べた。インスリン分泌が改善している。 （インスリン感受性について尿からの糖排出の評価は難しい。）

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