1. Journal Club 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 2012 年 10 月 11 日 8:30-8:55 ８階 医局 NICE-SUGAR Study Investigators, Finfer S, Liu B, Chittock DR, Norton R, Myburgh JA, McArthur C, Mitchell I, Foster D, Dhingra V, Henderson WR, Ronco JJ, Bellomo R, Cook D, McDonald E, Dodek P, Hébert PC, Heyland DK, Robinson BG. Hypoglycemia and risk of death in critically ill patients. N Engl J Med. 2012 Sep 20;367(12):1108-18. Fox CS, Matsushita K, Woodward M, Bilo HJ, Chalmers J, Heerspink HJ, Lee BJ, Perkins RM, Rossing P, Sairenchi T, Tonelli M, Vassalotti JA, Yamagishi K, Coresh J, de Jong PE, Wen CP, Nelson RG; for the Chronic Kidney Disease Prognosis Consortium. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. Lancet. 2012 Sep 21. pii: S0140-6736(12)61350-6. doi: 10.1016/S0140-6736(12)61350-6.

2. 入院患者総死亡率 Mortality Rate During Hospitalization

3. Medical ICU での高血糖と死亡率

4. Surgical ICU でのインスリン強化療法による 死亡率減少

5. 重症入院患者へのインスリン治療：死亡 率 （無作為ランダム化研究のメタ解析） 35 publications, n=8478

6. Diabetes Care 32:1153–1157, 2009

8. Assessment, Randomization, and Follow-up of the Study Patient The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297

9. Baseline Characteristics of the Study Patients The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297

10. Blood Glucose Management and Levels, Calorie Administration, and Corticosteroid Treatment, According to Treatment Group The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297

11. Data on Blood Glucose Level, According to Treatment Group The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297

12. Probability of Survival and Odds Ratios for Death, According to Treatment Group The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297

13. The members of the writing committee for the Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation (NICE- SUGAR) Investigators (listed in the Appendix) assume responsibility for the content of this article. N Engl J Med 2012;367:1108-18.

14. BACKGROUND Whether hypoglycemia leads to death in critically ill patients is unclear.

15. METHODS We examined the associations between moderate and severe hypoglycemia (blood glucose, 41 to 70 mg per deciliter [2.3 to 3.9 mmol per liter] and ≤40 mg per deciliter [2.2 mmol per liter], respectively) and death among 6026 critically ill patients in intensive care units (ICUs). Patients were randomly assigned to intensive or conventional glucose control. We used Cox regression analysis with adjustment for treatment assignment and for baseline and postrandomization covariates.

16. *Moderate hypoglycemia was defined as a blood glucose value of 70 mg per deciliter (3.9 mmol per liter) or less, and severe hypoglycemia as a blood glucose value of 40 mg per deciliter (2.2 mmol per liter) or less. In this analysis, patients with severe hypoglycemia (all of whom had moderate hypoglycemia also, as defined) were included in the group for comparison with those with no hypoglycemia. The factors included in the multivariate analysis were those with P values of less than 0.20 in the univariate analysis. † Scores on the Acute Physiology and Chronic Health Evaluation (APACHE) II range from 0 to 71, with higher scores indicating an increased risk of death. ‡ The body-mass index (BMI) is the weight in kilograms divided by the square of the height in meters. § To convert value for glucose to millimoles per liter, multiply by 0.05551. The baseline blood glucose value was not included in the multivariate analysis for moderate hypoglycemia because of the P value in the univariate analysis (P = 0.32). ¶ Diabetes at baseline was not included in the multivariate analysis for severe hypoglycemia because of the P value in the univariate analysis (P = 0.22). ‖ Cardiovascular failure was defined as a score of 3 or 4 on the cardiovascular section of the Sequential Organ Failure Assessment (on a scale ranging from 0 to 4 for each of five organ systems, with higher scores indicating more severe organ dysfunction).

24. A causal relationship is plausible because hypoglycemia may increase mortality by means of impairment of autonomic function, alteration of blood flow and composition, white-cell activation, vasoconstriction, and the release of inflammatory mediators and cytokines. These mechanisms are consistent with our finding that the hazard ratio for death from distributive shock was significantly increased among both patients with moderate hypoglycemia and those with severe hypoglycemia. Severe hypoglycemia may also be associated with a prolonged QT interval, which confers a predisposition to potentially fatal cardiac arrhythmias, but we did not find a significant association between hypoglycemia and death from arrhythmias in our study. An alternative explanation is that hypoglycemia occurs as a result of disease processes that confer a predisposition to death and that hypoglycemia thus represents a marker, rather than a cause, of an increased risk of death.

25. According to the current recommendation of the American Diabetes Association, a target blood glucose concentration of 144 to 180 mg per deciliter (8.0 to 10.0 mmol per liter) is likely to reduce the risk of hypoglycemia in critically ill patients.

26. RESULTS Follow-up data were available for 6026 patients: 2714 (45.0%) had moderate hypoglycemia, 2237 of whom (82.4%) were in the intensive-control group (i.e., 74.2% of the 3013 patients in the group), and 223 patients (3.7%) had severe hypoglycemia, 208 of whom (93.3%) were in the intensive-control group (i.e., 6.9% of the patients in this group). Of the 3089 patients who did not have hypoglycemia, 726 (23.5%) died, as compared with 774 of the 2714 with moderate hypoglycemia (28.5%) and 79 of the 223 with severe hypoglycemia (35.4%). The adjusted hazard ratios for death among patients with moderate or severe hypoglycemia, as compared with those without hypoglycemia, were 1.41 (95% confidence interval [CI], 1.21 to 1.62; P 1 day vs. 1 day, P = 0.01), those who died from distributive (vasodilated) shock (P<0.001), and those who had severe hypoglycemia in the absence of insulin treatment (hazard ratio, 3.84; 95% CI, 2.37 to 6.23; P<0.001).

27. CONCLUSIONS In critically ill patients, intensive glucose control leads to moderate and severe hypoglycemia, both of which are associated with an increased risk of death. The association exhibits a dose–response relationship and is strongest for death from distributive shock. However, these data cannot prove a causal relationship. (Funded by the Australian National Health and Medical Research Council and others; NICESUGAR ClinicalTrials.gov number, NCT00220987.)

28. Message 重症患者 6026 人を対象に、低血糖と死亡 の関連を検討（ NICE-SUGAR 試験）。中 等度低血糖群の 82.4 ％、重度低血糖群の 74.2 ％が強化血糖コントロールを受けてい た。低血糖でない群に対する調整後死亡ハ ザード比は中等度群 1.41 、重度群 2.10 だった。低血糖は死亡リスク上昇に関連し たが、因果関係は証明できなかった。 2009 年に発表されたデータの詳細が 2012 年に発表されました！？

30. National Heart, Lung, and Blood Institute’s Framingham Heart Study (C S Fox MD) and the Center for Population Studies (C S Fox) Framingham, MA, USA; Division of Endocrinology, Brigham and Women’s Hospital and Harvard Medical School, Boston MA, USA (C S Fox); John Hopkins Bloomberg School of Public Health, Baltimore, MD, USA (K Matsushita MD, Prof M Woodward PhD, Prof J Coresh MD); The George Institute for Glocal Health, University of Sydney, Sydney, NSW, Australia (Prof M Woodward, Prof J Chalmers MD); Department of Internal Medicine, Isala Clinics, Zwolle, Netherlands (Prof H J G Bilo MD); Department of Clinical Pharmacology (H J Lambers Heerspink PharmD) and Department of Nephrology (Prof P E de Jong MD) University Medical Centre Groningen, University of Groningen, Groningen, Netherlands; Kaiser Permanente Hawaii Region, Moanalua Medical Center, Honolulu, HI, USA (B J Lee MD); Nephrology Department, Geisinger Medical Center, Danville, PA, USA (R M Perkins MD); Steno Diabetes Center, Gentofte, Denmark (Prof P Rossing MD); HEALTH, University of Aarhus, Aarhus, Denmark (Prof P Rossing); Department of Public Health, Dokkyo Medical University School of Medicine, Shimotugagun-Mibu, Japan (T Sairenchi PhD); Ibaraki Health Plaza, Ibaraki Health Service Association, Mito, Japan (T Sairenchi, K Yamagishi MD); Department of Medicine, University of Alberta, Edmonton, AB, Canada (Prof M Tonelli MD); US National Kidney Foundation, New York, NY, USA (J A Vassalotti MD); Department of Public Health Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan (K Yamagishi); Osaka Medical Centre for Health Science and Promotion, Osaka, Japan (K Yamagishi); China Medical University Hospital, Taichung, Taiwan (C-P Wen MD); Institute of Population Health Science, National Health Research Institutes, Zhunan, Taiwan (C-P Wen); and National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix AZ, USA (R G Nelson MD) www.thelancet.com Published online September 24, 2012 http://dx.doi.org/10.1016/S0140-6736(12)61350-6

31. Background Chronic kidney disease is characterised by low estimated glomerular fi ltration rate (eGFR) and high albuminuria, and is associated with adverse outcomes. Whether these risks are modified by diabetes is unknown.

32. Methods We did a meta-analysis of studies selected according to Chronic Kidney Disease Prognosis Consortium criteria. Data transfer and analyses were done between March, 2011, and June, 2012. We used Cox proportional hazards models to estimate the hazard ratios (HR) of mortality and end-stage renal disease (ESRD) associated with eGFR and albuminuria in individuals with and without diabetes.

36. Figure 1: Hazard ratios for all-cause and cardiovascular mortality in the combined general and high-risk populations according to eGFR in individuals with and without diabetes (A, B) All-cause mortality. (C, D) Cardiovascular mortality. Panels A and C use one reference point (diamond, eGFR of 95 mL/min per 1 ・ 73 m 2 in the no diabetes group) for both individuals with and without diabetes to show the main effect of diabetes on risk. Panels B and D use separate references (diamonds) in the diabetes and no diabetes groups to assess interaction with diabetes specifically. Hazard ratios were adjusted for age, sex, race, smoking, history of cardiovascular disease, serum total cholesterol concentration, body-mass index, and albuminuria (log albumin-to- creatinine ratio, log protein-to-creatinine, or categorical dipstick proteinuria [negative, trace, 1+, ≥2+]). Blue and red circles denote p<0 ・ 05 as compared with the reference (diamond). Significant interaction between diabetes and eGFR is shown by x signs. eGFR=estimated glomerular filtration rate.

37. Figure 2: Hazard ratios for all-cause and cardiovascular mortality in the combined general and high-risk populations according to ACR in participants with and without diabetes (A, B) All-cause mortality. (C, D) Cardiovascular mortality. Panels A and C use one reference point (diamond, ACR of 5 mg/g in the no diabetes group), for both individuals with and without hypertension to show the main eff ect of diabetes on risk. Panels B and D use separate references (diamonds) in the diabetes and no diabetes groups to assess interaction with diabetes specifi cally. Hazard ratios were adjusted for age, sex, race, smoking, history of cardiovascular disease, serum total cholesterol concentration, body-mass index, and estimated glomerular fi ltration rate. Blue and red circles denote p<0 ・ 05 as compared with the reference (diamond). Signifi cant interaction between diabetes and ACR is shown by x signs. ACR=albumin-to- creatinine ratio.

39. Figure 3: Hazard ratios for end-stage renal disease in the chronic kidney disease populations according to eGFR and ACR in participants with and without diabetes (A, B) eGFR. (C, D) ACR. Panels A and C use eGFR of 50 mL/min per 1 ・ 73 m2 (A) and ACR of 20 mg/g (C) in individuals without diabetes as the reference point (diamond) for both individuals with and without diabetes. Panels B and D use eGFR of 50 mL/min per 1 ・ 73 m2 (B) and ACR of 20 mg/g (D) as the reference points (diamond) in diabetic and non-diabetic groups. Blue and red circles denote p<0 ・ 05 as compared with the reference (diamond). Hazard ratios were adjusted for age, sex, race, smoking, history of cardiovascular disease, serum total cholesterol concentration, body- mass index, and albuminuria (log albumin-to-creatinine ratio, log protein-to-creatinine, or categorical dipstick proteinuria [negative/ trace, 1+, 2+, ≥3+]) or eGFR. eGFR=estimated glomerular fi ltration rate. ACR=albumin-to-creatinine ratio.

41. Figure 4: Hazard ratios for all-cause mortality according to eGFR in participants with and without diabetes in individuals with and without hypertension from the general population and high-risk cohorts (A, B) Individuals with hypertension. (C, D) Individuals without hypertension. Blue and red circles denote p<0 ・ 05 as compared with the reference (diamond). Signifi cant interaction between diabetes and eGFR is shown by x signs. Hazard ratios were adjusted for age, sex, race, smoking, history of cardiovascular disease, serum total cholesterol concentration, body-mass index, and albuminuria (log albumin-to-creatinine ratio, log protein-to-creatinine, or categorical dipstick proteinuria [negative, trace, 1+, ≥2+])

42. Findings We analysed data for 1 024 977 participants (128 505 with diabetes) from 30 general population and high-risk cardiovascular cohorts and 13 chronic kidney disease cohorts. In the combined general population and high-risk cohorts with data for all-cause mortality, 75 306 deaths occurred during a mean follow-up of 8 ・ 5 years (SD 5 ・ 0). In the 23 studies with data for cardiovascular mortality, 21 237 deaths occurred from cardiovascular disease during a mean follow-up of 9 ・ 2 years (SD 4 ・ 9). In the general and high-risk cohorts, mortality risks were 1 ・ 2–1 ・ 9 times higher for participants with diabetes than for those without diabetes across the ranges of eGFR and albumin-to- creatinine ratio (ACR). With fixed eGFR and ACR reference points in the diabetes and no diabetes groups, HR of mortality outcomes according to lower eGFR and higher ACR were much the same in participants with and without diabetes (eg, for all-cause mortality at eGFR 45 mL/min per 1 ・ 73 m2 [vs 95 mL/min per 1 ・ 73 m2], HR 1 ・ 35; 95% CI 1 ・ 18–1 ・ 55; vs 1 ・ 33; 1 ・ 19–1 ・ 48 and at ACR 30 mg/g [vs 5 mg/g], 1 ・ 50; 1 ・ 35–1 ・ 65 vs 1 ・ 52; 1 ・ 38–1 ・ 67). The overall interactions were not significant. We identified much the same findings for ESRD in the chronic kidney disease cohorts.

43. Interpretation Despite higher risks for mortality and ESRD in diabetes, the relative risks of these outcomes by eGFR and ACR are much the same irrespective of the presence or absence of diabetes, emphasising the importance of kidney disease as a predictor of clinical outcomes. Funding US National Kidney Foundation.

44. Message 慢性腎臓病（ CKD ）患者の有害転帰発生が糖尿病の有無 で変わるかを、約 102 万人のデータのメタ解析で検討。非糖 尿病患者と比べた糖尿病患者の死亡リスクは腎機能によらず 高かった。一方、推算糸球体濾過量（ eGFR ）低値、アルブ ミン / クレアチニン比（ ACR ）高値は糖尿病に関係なくリス クが高かった。転帰予測因子としての腎機能が重要だった。 で、同じ Lancet 誌に高血圧も関係ないと．．． 慢性腎臓病（ CKD ）の有害転帰発生が高血圧の有無で変 わるかを、約 113 万人のデータのメタ解析で検討。推算糸球 体濾過量（ eGFR ）が 95mL/min/1.73m 2 に対する 45mL/min/1.73m 2 の死亡ハザード比は、非高血圧患者 1.77 、高血圧患者 1.24 だった。高血圧に関係なく、慢性腎 臓病は死亡の危険因子となると示唆された。 (Mahmoodi BK et al.Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without hypertension: a meta-analysis.The Lancet, Early Online Publication, 24 September 2012)