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Journal Club

This study examines the association between adding or switching to sulfonylureas and the risk of cardiovascular events, hypoglycemia, and mortality in patients with type 2 diabetes. The study utilizes a large cohort of patients initiating metformin monotherapy.

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Journal Club

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  1. Journal Club Douros A, Dell'Aniello S, Yu OHY, Filion KB, Azoulay L, Suissa S Sulfonylureas as second line drugs in type 2 diabetes and the risk of cardiovascular and hypoglycaemic events: population based cohort study. BMJ. 2018 Jul 18;362:k2693. doi: 10.1136/bmj.k2693. Fenske W, Refardt J, Chifu I, Schnyder I, Winzeler B, Drummond J, Ribeiro-Oliveira A Jr, Drescher T, Bilz S, Vogt DR, Malzahn U, Kroiss M, Christ E, Henzen C, Fischli S, Tönjes A, Mueller B, Schopohl J, Flitsch J, Brabant G, Fassnacht M, Christ-Crain M. A Copeptin-Based Approach in the Diagnosis of Diabetes Insipidus. N Engl J Med. 2018 Aug 2;379(5):428-439. doi: 10.1056/NEJMoa1803760. 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 2018年9月20日　8:30-8:55 2階　医局

  2. メトホルミンが生命予後に及ぼす影響 （UKPDS34） 相対リスク events/1,000pts/yrs 検定 （p） エンドポイント Met 強化療法 糖尿病関連 イベント 29.8 40.1 0.0034 糖尿病関連死 7.5 10.30.11 全死亡率 13.5 18.9 0.021 SU ＋Met SU alone vs SU alone 糖尿病関連死 16.8 6.6 1.96 0.039 全死亡率 30.3 19.1 1.60 0.041 致死的心筋梗塞 11.0 6.2 1.79 0.14 非致死的心筋梗塞 9.4 15.0 0.62 0.15 突然死 1.9 1.2 1.61 0.60 心不全 5.9 3.7 1.59 0.38 狭心症 7.4 11.5 0.64 0.24 致死的脳卒中 3.2 0.6 5.25 0.09 非致死的脳卒中 6.6 7.6 0.88 0.76 下肢切断 1.3 0.6 2.12 0.53 癌死 9.0 3.7 2.47 0.056 UK Prospective Diabetes Study Group : Lancet,352,854,1998.

  3. ビグアナイドとSUの併用は総死亡率を上昇させるビグアナイドとSUの併用は総死亡率を上昇させる １．Diabetes Metab Res Rev 2004;20:44-47 All-cause mortality in diabetic patients treated with combinations of sulfonylureas and biguanides 総死亡率は、ビグアナイド使用では、男性では、２．０８、女性では、１．６８の相対危険率 ２．ClinCardiol 2001;24:151-158 Oral antidiabetic treatment in patients with coronary disease: time-related mortality on combined glyburide/metformin therapy over 7.7-year follow up 総死亡率は、ビグアナイドとSUの併用療法で、hazard ratioが１．５３である。 ３．Diabetologia 2000;43:558-560 Increased mortality in type II diabetic patients using sulphonylurea and metformin In combination: a population-based observational study

  4. metformin Metforminmonotherapy carried the lowest risk of cancer. metformin & SU

  5. 1Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, 3755 Cote Ste-Catherine, H-461 Montréal, QC H3T 1E2, Canada 2Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montréal, QC, Canada 3Institute of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany 4Division of Endocrinology, Jewish General Hospital, Montréal, QC, Canada 5Division of Clinical Epidemiology, Department of Medicine, McGill University, Montréal, QC, Canada 6Gerald Bronfman Department of Oncology, McGill University, Montréal, QC, Canada BMJ. 2018 Jul 18;362:k2693. doi: 10.1136/bmj.k2693.

  6. Objective To assess whether adding or switching to sulfonylureas is associated with an increased risk of myocardial infarction, ischaemic stroke, cardiovascular death, all cause mortality, and severe hypoglycaemia, compared with remaining on metformin monotherapy in patients with type 2 diabetes.

  7. Design Population based cohort study. Setting General practices contributing data to the UK Clinical Practice Research Datalink. Participants Patients with type 2 diabetes initiating metformin monotherapy between 1998 and 2013. Main outcome measures Using the prevalent new-user cohort design we matched 1:1 patients adding or switching to sulfonylureas with those remaining on metformin monotherapy on high-dimensional propensity score, haemoglobin A1c, and number of previous metformin prescriptions. The two groups were compared using Cox proportional hazards models to estimate adjusted hazard ratios and 95% confidence intervals for the study outcomes.

  8. We used the UK Clinical Practice Research Datalink (CPRD) linked to the Hospital Episode Statistics (HES) and Office for National Statistics (ONS) databases. The CPRD is a large primary care database which contains the medical records for over 14 million people registered at over 680 general practices.

  9. Fig 1 | Flowchart showing the base and study cohorts. HES =Hospital Episode Statistics; ONS=Office for National Statistics; CPRD=Clinical Practice Research Datalink.

  10. Fig 2 | Forest plot summarising the primary analysis and all sensitivity analyses

  11. Results Among 77 138 metformin initiators, 25 699 added or switched to sulfonylureas during the study period. During a mean follow-up of 1.1 years, sulfonylureas were associated with an increased risk of myocardial infarction (incidence rate 7.8 v 6.2 per 1000 person years, hazard ratio 1.26, 95% confidence interval 1.01 to 1.56), all cause mortality (27.3 v 21.5, 1.28, 1.15 to 1.44), and severe hypoglycaemia (5.5 v 0.7, 7.60, 4.64 to 12.44) compared with continuing metformin monotherapy. There was a trend towards increased risks of ischaemic stroke (6.7 v 5.5, 1.24, 0.99 to 1.56) and cardiovascular death (9.4 v 8.1, 1.18, 0.98 to 1.43). Compared with adding sulfonylureas, switching to sulfonylureas was associated with an increased risk of myocardial infarction (hazard ratio 1.51, 95% confidence interval, 1.03 to 2.24) and all-cause mortality (1.23, 1.00 to 1.50). No differences were observed for ischaemic stroke, cardiovascular death, or severe hypoglycaemia.

  12. Conclusions Sulfonylureas as second line drugs are associated with an increased risk of myocardial infarction, all cause mortality, and severe hypoglycaemia, compared with remaining on metformin monotherapy. Continuing metformin when introducing sulfonylureas appears to be safer than switching.

  13. Message SU薬の追加や変更は心血管リスクを伴うようでる。どうしても変更する場合は追加がよいように書いているが．．．

  14. ＜診断基準＞下垂体性ADH分泌異常症　A．バゾプレシン分泌低下症（中枢性尿崩症）完全型及び部分型を対象とする。１．主要項目　（１）主症候　　①口渇　②多飲　③多尿　（２）検査所見　　①尿量は１日3,000mL以上。　　②尿浸透圧は300mOsm/kg以下。　　③水制限試験においても尿浸透圧は300mOsm/kgを越えない。　　④血漿バゾプレシン濃度：血清ナトリウム濃度と比較して相対的に低下する。5％高張食塩水負荷（0.05mL/kg/minで120分間点滴投与）時に、血清ナトリウムと血漿バゾプレシンがそれぞれ、i）144mEq/Lで1.5pg/mL以下、ii）146mEq/Lで2.5pg/mL以下、iii）148mEq/Lで4pg/mL以下、iv）150mEq/L以上で6pg/mL以下である。　　⑤バゾプレシン負荷試験で尿量は減少し、尿浸透圧は300mOsm/kg以上に上昇する。　（３）鑑別診断　多尿を来す中枢性尿崩症以外の疾患として次のものを除外する。　　①高カルシウム血症：血清カルシウム濃度が11.0mg/dLを上回る。　　②心因性多飲症：高張食塩水負荷試験と水制限試験で尿量の減少と尿浸透圧の上昇及び血漿バゾプレシン濃度の上昇を認める。　　③腎性尿崩症：バゾプレシン負荷試験で尿量の減少と尿浸透圧の上昇を認めない。定常状態での血漿バゾプレシン濃度の基準値は1.0pg/mL以上となっている。２．参考事項　（１）血清ナトリウム濃度は正常域の上限に近づく。　（２）T1強調MRI画像における下垂体後葉輝度の低下。ただし、高齢者では正常人でも低下することがある。３．診断のカテゴリー完全型中枢性尿崩症：１（１）の①から③全ての項目を満たし、かつ１（２）の①から⑤全ての項目を満たすもの部分型中枢性尿崩症：１（１）の①から③全ての項目を満たし、かつ１（２）の①、②、⑤を満たし、１（２）の④i）からiv）の１項目を満たすもの＜診断基準＞下垂体性ADH分泌異常症　A．バゾプレシン分泌低下症（中枢性尿崩症）完全型及び部分型を対象とする。１．主要項目　（１）主症候　　①口渇　②多飲　③多尿　（２）検査所見　　①尿量は１日3,000mL以上。　　②尿浸透圧は300mOsm/kg以下。　　③水制限試験においても尿浸透圧は300mOsm/kgを越えない。　　④血漿バゾプレシン濃度：血清ナトリウム濃度と比較して相対的に低下する。5％高張食塩水負荷（0.05mL/kg/minで120分間点滴投与）時に、血清ナトリウムと血漿バゾプレシンがそれぞれ、i）144mEq/Lで1.5pg/mL以下、ii）146mEq/Lで2.5pg/mL以下、iii）148mEq/Lで4pg/mL以下、iv）150mEq/L以上で6pg/mL以下である。　　⑤バゾプレシン負荷試験で尿量は減少し、尿浸透圧は300mOsm/kg以上に上昇する。　（３）鑑別診断　多尿を来す中枢性尿崩症以外の疾患として次のものを除外する。　　①高カルシウム血症：血清カルシウム濃度が11.0mg/dLを上回る。　　②心因性多飲症：高張食塩水負荷試験と水制限試験で尿量の減少と尿浸透圧の上昇及び血漿バゾプレシン濃度の上昇を認める。　　③腎性尿崩症：バゾプレシン負荷試験で尿量の減少と尿浸透圧の上昇を認めない。定常状態での血漿バゾプレシン濃度の基準値は1.0pg/mL以上となっている。２．参考事項　（１）血清ナトリウム濃度は正常域の上限に近づく。　（２）T1強調MRI画像における下垂体後葉輝度の低下。ただし、高齢者では正常人でも低下することがある。３．診断のカテゴリー完全型中枢性尿崩症：１（１）の①から③全ての項目を満たし、かつ１（２）の①から⑤全ての項目を満たすもの部分型中枢性尿崩症：１（１）の①から③全ての項目を満たし、かつ１（２）の①、②、⑤を満たし、１（２）の④i）からiv）の１項目を満たすもの http://www.nanbyou.or.jp/entry/3989

  15. Copeptin Copeptin (also known as CT-proAVP) is a 39-amino acid-long peptide derived from the C-terminus of pre-pro-hormone of arginine vasopressin, neurophysin II and copeptin. Arginine vasopressin (AVP), also known as the antidiuretic hormone (ADH), is involved in multiple cardiovascular and renal pathways and abnormal level of AVP are associated with various diseases. Hence measurement of AVP would useful, but not commonly carried out in clinical practice because of its very short half-life making it difficult to quantify. In contrast, copeptin can be immunologically tested with ease and therefore can be used as a vasopressin surrogate marker. https://en.wikipedia.org/wiki/Copeptin

  16. From the University of Leipzig, Department of Endocrinology and Nephrology (W.F., A.T.), and Leipzig University Medical Center, Integrated Research and Treatment Center Adiposity Diseases (W.F.), Leipzig, the Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg (I.C., M.K., M.F.), and the Clinical Trial Center (U.M.) and Central Laboratory (M.F.), University Hospital Würzburg, Würzburg, MedizinischeKlinik und Poliklinik IV, Ludwig-Maximilians-Universität, Munich (J.S.), the Department of Neurosurgery, University Hospital Hamburg-Eppendorf, Hamburg (J.F.), and Experimental and Clinical Endocrinology, University Hospital Lübeck, Lübeck (G.B.) — all in Germany; the Clinic of Endocrinology, Diabetology and Metabolism (J.R., I.S., B.W., E.C., M.C.-C.) and the Clinical Trial Unit (D.R.V.), Department of Clinical Research, University of Basel and University Hospital Basel, Basel, the Department of Endocrinology, Kantonsspital St. Gallen, St. Gallen (T.D., S.B.), the Department of Endocrinology, Inselspital Bern, Bern (E.C.), the Department of Endocrinology, LuzernerKantonsspital, Lucerne (C.H., S.F.), and the Division of Endocrinology, Diabetology and Metabolism, Medical University Clinic, Kantonsspital Aarau, Aarau (B.M.) — all in Switzerland; and Faculdade de Medicina da UFMG, Universidade Federal de Minas Gerais (J.D., A.R.-O.), and Hermes Pardini Institute (J.D.), Belo Horizonte, Brazil. N Engl J Med. 2018 Aug 2;379(5):428-439. doi: 10.1056/NEJMoa1803760.

  17. Background The indirect water-deprivation test is the current reference standard for the diagnosis of diabetes insipidus. However, it is technically cumbersome to administer, and the results are often inaccurate. The current study compared the indirect water-deprivation test with direct detection of plasma copeptin, a precursor-derived surrogate of arginine vasopressin.

  18. Methods From 2013 to 2017, we recruited 156 patients with hypotonic polyuria at 11 medical centers to undergo both water-deprivation and hypertonic saline infusion tests. In the latter test, plasma copeptin was measured when the plasma sodium level had increased to at least 150 mmol per liter after infusion of hypertonic saline. The primary outcome was the overall diagnostic accuracy of each test as compared with the final reference diagnosis, which was determined on the basis of medical history, test results, and treatment response, with copeptin levels masked.

  19. 1.4.1.1. The water deprivation test will be performed either one day before or one day after the hypertonic saline infusion test according to the originally described protocol from Miller et al [9]. Patients undergo complete fluid and food restriction from midnight, and urine volume, -osmolality, blood pressure, heart rate, and body weight are monitored in 2-hour intervals starting at 08.00h. Venous blood samples for measurement of serum (sodium, osmolality, urea, glucose), plasma EDTA (copeptin) and plasma heparin (AVP) are taken at the beginning (at 08.00h) and at the end of test protocol immediately before the administration of desmopressin. Additional measurement of sodium and osmolality are up to the treating physician or they are mandatory if urine osmolality has reached a plateau with variation of less than 10% or if urine osmolality decreases in two subsequent measurements. Fluid deprivation is continued until a serum sodium concentration ≥ 150mmol/L has been reached, or until the patient has lost 3-5% of the initial body weight. At this point, the participant receives an intravenous injection of 4μg desmopressin, the urine excreted within the first 30 min thereafter is discarded and the final urine specimen for determination of osmolality is collected 60 min (or at the first possible time point) after desmopressin injection (table 5, appendix 1). Having finished the dehydration test, the patient will also quantify the subjective burden of the dehydration test (see visual analogue scale at table 5, appendix 1).

  20. 1.4.1.2. The hypertonic saline test will be performed before or at least 12h after the water deprivation test, starting in the morning between 08.00h and 11.00h. Patients are lying in a supine position, before two indwelling cannulae are placed into the antecubital veins, one for venous sampling and one for intravenous saline infusion. After a 30-minute rest, three basal blood samples are taken (1x tube of 7.5ml EDTA plasma, and 2x tube of 4.7ml lithium heparin) for measurement of baseline serum sodium, potassium, glucose, urea and osmolality concentrations, and plasma copeptin and AVP levels. Blood for plasma AVP radioimmunoassay is taken into a chilled syringe, placed into a chilled lithium heparin tube, and is directly centrifuged at 5C° before storage at -80C° until shipment. Plasma copeptin samples are taken into EDTA tubes, centrifuged within 1 hour after withdrawal at 5°C and stored at -20C° until shipment. Hypertonic saline infusion (3% saline, 513mOsm/L) will be given first as bolus of 250ml within 10 to 15 minutes and then at a rate of 0.15mL per kilogram body weight per minute until patient has reached a serum sodium concentration of ≥150mmol/L or (if necessary in care cases) for a maximum of 3 hours. Venous samples for measurement of plasma EDTA, plasma heparin and blood gas analyses will be taken at 30 minute intervals [8], [10], [11], [12] (table 4, appendix 1). After a sodium of ≥150mmol/L has been reached, the patient is required to drink at least 30ml/kg body weight within 30 minutes. Thereafter glucose 5% is infused, 500ml within 40 to 60 minutes. For safety reasons, serum sodium concentration will additionally be controlled at 1 hour after the beginning of glucose 5% infusion to make sure that serum sodium levels did decrease into the normal range. After finishing the test protocol, the patient will quantify the self-perceived burden of the hypertonic saline test protocol on a visual analogue scale (see table 4, appendix 1).

  21. 1.4.2.1 For the diagnostic interpretation of the water deprivation test results, the combination of the maximally reached urine concentration during dehydration and the change in urine osmolality after desmopressin injection in percentage constitutes the primary test determinant, [9]. Patients with a maximum urine concentration < 300mOsm/kg and a rise in urine osmolality of more than 50% following desmopressin injection are diagnosed as complete central DI; a maximum urine concentration between 300 to 800mOsm/kg with a urinary response between 9-50% after desmopressin injection is attributed to the diagnosis partial central DI, whilst a urinary response below 9% is related to PP. Finally, patients with a maximum urinary concentration < 300mOsm/kg and an urinary response to desmopressin of <10% are determined as nephrogenic DI [9].

  22. 1.4.2.2 The diagnostic interpretation of the water deprivation test plus plasma copeptin measurement is conducted in two different ways: firstly, the diagnostic copeptin cut-off values derived from a previous post-hoc analysis [7] will be prospectively validated assuming that a baseline copeptin level > 20pmol/L suggests nephrogenic DI, a baseline copeptin level < 2.6pmol/L diagnoses complete central DI, delta copeptin (08.00-16.00h) to serum sodium (16.00h) ≥ 20pmol/l/mmol/l*1000 identifies PP, and a ratio < 20pmol/l/mmol/l*1000 identifies patients with partial central DI. Secondly, for all patients reaching hypertonic serum osmolality levels above 300mOsm/kg, the final copeptin hormone concentration measured at the end of the dehydration period is plotted against the corresponding serum osmolality on a nomogram describing the physiological relationship between plasma copeptin and serum osmolality as defined before. The hormone data point is then interpreted against the area of normality for plasma copeptin versus serum osmolality as follows: copeptin levels residing within the area of normality are indicative for diagnosis of PP, subnormal copeptin levels below the normal range are defined as partial central DI, levels above the normal range diagnose nephrogenic DI, and copeptin levels below 2.6pmol/L are defined as complete central DI [8], [12], [11]. The collected plasma samples will be stored at -20°C until usage (see 3.6).

  23. 1.4.2.3.The diagnostic categorisation of the water deprivation test plus plasma AVP measurement is performed in correspondence to the determination of plasma copeptin (1.4.2.2): for all patients reaching hypertonic serum osmolality levels above 300mOsm/kg, the final hormone concentration measured at the end of the dehydration period, is plotted against the corresponding serum osmolality on a nomogram. The hormone data point is interpreted in relation to the previously defined area of normality between hormone concentration and serum osmolality as follows: AVP levels residing within the area of normality are suggestive for diagnosis of PP, subnormal AVP levels below the normal range are defined as partial central DI, levels above the normal range diagnose nephrogenic DI, and AVP levels below the hormone detection limit are defined as complete central DI [8], [12], [11].

  24. 1.4.2.4 The diagnostic categorisation of the hypertonic saline infusion test plus plasma copeptin measurement occurs in the same way as previously described for the water deprivation test plus copeptin measurement (see 1.4.2.2). The final plasma copeptin concentration taken directly before stopping the saline infusion, is plotted against the corresponding serum osmolality on a nomogram describing the physiological relationship between plasma copeptin and serum osmolality. The copeptin data point is then interpreted against the area of normality exactly as has been specified above (see 1.4.2.2).

  25. Figure 2. Receiver-Operating-Characteristic (ROC) Curves for the Hypertonic Saline Infusion Test and the Indirect Water-Deprivation Test. Shown are the ROC curves for the discriminative accuracy of the hypertonic saline infusion test and the indirect water-deprivation test. Panel A shows the discriminative accuracy of hypertonic saline–stimulated copeptin levels in differentiating primary polydipsia from central diabetes insipidus (area under the curve [AUC], 0.97; 95% CI, 0.93 to 1.00). The copeptin cutoff level of 4.9 pmol per liter (prespecified) is indicated in red, and the cutoff of 6.5 pmol per liter (derived post hoc) is indicated in blue. I bars in Panel A indicate 95% confidence intervals. Panel B shows the discriminative accuracy of the indirect water-deprivation test (which measures the change in urine osmolality before and after administration of desmopressin) in differentiating primary polydipsia from central diabetes insipidus (AUC, 0.65; 95% CI, 0.56 to 0.75). I bars in Panel B indicate the 95% confidence intervals for the sensitivity and specificity of the indirect water-deprivation test at a 9% cutoff for the increase in urine osmolality after administration of desmopressin. The gray diagonal lines represent the results that would be expected by chance alone.

  26. Results A total of 144 patients underwent both tests. The final diagnosis was primary polydipsia in 82 patients (57%), central diabetes insipidus in 59 (41%), and nephrogenic diabetes insipidus in 3 (2%). Overall, among the 141 patients included in the analysis, the indirect water-deprivation test determined the correct diagnosis in 108 patients (diagnostic accuracy, 76.6%; 95% confidence interval [CI], 68.9 to 83.2), and the hypertonic saline infusion test (with a copeptin cutoff level of >4.9 pmol per liter) determined the correct diagnosis in 136 patients (96.5%; 95% CI, 92.1 to 98.6; P<0.001). The indirect water-deprivation test correctly distinguished primary polydipsia from partial central diabetes insipidus in 77 of 105 patients (73.3%; 95% CI, 63.9 to 81.2), and the hypertonic saline infusion test distinguished between the two conditions in 99 of 104 patients (95.2%; 95% CI, 89.4 to 98.1; adjusted P<0.001). One serious adverse event (desmopressin-induced hyponatremia that resulted in hospitalization) occurred during the water-deprivation test.

  27. Conclusions The direct measurement of hypertonic saline–stimulated plasma copeptin had greater diagnostic accuracy than the water-deprivation test in patients with hypotonic polyuria. (Funded by the Swiss National Foundation and others; ClinicalTrials.gov number, NCT01940614.)

  28. Message 中枢性尿崩症の診断基準が変わるのだろうか？

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