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埼玉医科大学　総合医療センター　内分泌・糖尿病内科埼玉医科大学　総合医療センター　内分泌・糖尿病内科Department of Endocrinology and Diabetes, Department of Endocrinology and Diabetes,

Saitama Medical Center, Saitama Medical UniversitySaitama Medical Center, Saitama Medical University

松田　昌文松田　昌文Matsuda, MasafumiMatsuda, Masafumi

20102010年３月４日　年３月４日　 8:30-8:558:30-8:55８階　医局８階　医局

Fritsche A, Larbig M, Owens D, Häring HU; GINGER study group.Comparison between a basal-bolus and a premixed insulin regimen in individuals with type 2 diabetes-results of the GINGER study.Diabetes Obes Metab. 2010 Feb;12(2):115-23.

Hovorka R, Allen JM, Elleri D, Chassin LJ, Harris J, Xing D, Kollman C, Hovorka T, Larsen AM, Nodale M, De Palma A, Wilinska ME, Acerini CL, Dunger DB.Manual closed-loop insulin delivery in children and adolescents with type 1 diabetes: a phase 2 randomised crossover trial.Lancet. 2010 Feb 27;375(9716):743-751. Epub 2010 Feb 4.

Diabetes Obes Metab. 12(2):115-23, 2010

Background and AimTo compare the efficacy and safety of an intensified insulin regimen, using insulin glargine (glargine) once daily and pre-meal insulin glulisine (glulisine) (basal-bolus), with a conventional therapy, using premixed insulin (premix) twice daily.

MethodThis 52-week, open-label, randomized, multinational, multicentre trial included 310 subjects with type 2 diabetes (T2D) on premix, with or without metformin, who were randomized to a basal-bolus regimen with glargine and glulisine (n = 153; mean ± s.d. age 60.2 ± 7.5 years; HbA1c 8.6 ± 0.8%; weight 87.0 ± 15.1 kg; T2D duration 12.8 ± 5.8 years) or twice-daily premix (n = 157; age 60.9 ± 7.8 years; HbA1c 8.5 ± 0.9%; weight 84.3 ± 15.0 kg; T2D duration 12.5 ± 6.8 years). The primary endpoint was change in HbA1c from baseline to endpoint.

Figure 1. Trial profile.

*Including one person who withdrew after being provided with premixed insulin but not administering the medication;

†All subjects who received at least one dose and had both baseline HbA1c and at least one measurement of HbA1c during treatment.

ResultsMean decrease in baseline-to-endpoint HbA1c for basal-bolus vs. premix was −1.31 vs. −0.80% (difference: −0.476%; 95% Cl: −0.714, −0.238; p = 0.0001, ANCOVA). More subjects reached HbA1c ≤7.0% in the basal-bolus group than in the premix group [68 (46.6%) vs. 43 (27.9%); p = 0.0004], while they also experienced significantly lower mean ± s.d. daytime (−2.7 ± 2.3 vs. −2.3 ± 2.5 mmol/l; p = 0.0033) and postprandial (−3.1 ± 2.6 vs. −2.5 ± 2.8 mmol/l; p < 0.0001) blood glucose. Endpoint daily insulin doses were 98.0 ± 48.7 vs. 91.3 ± 44.3 IU (p = 0.2104); mean weight gain was +3.6 ± 4.0 vs. +2.2 ± 4.5 kg (p = 0.0073). Mean number of overall hypoglycaemic events with basal-bolus and premix was 13.99 and 18.54 events/patient year, respectively (difference: −3.90; 95% CI: −10.40, 2.60; p = 0.2385).

ConclusionAn intensified basal-bolus regimen using glargine/glulisine results in a significantly superior glycaemic control vs. premix therapy in a population with long-standing insulin-treated T2D, with no increase in the rates of hypoglycaemia.

Message

混合型インスリン２回よりも、基本的にはグルリシン＋グラルギンの強化療法が有効性でよく安全性（低血糖の頻度の低さ）も良い！

国際若年性糖尿病財団（ JDRF）Artificial Pancreas Project

Lancet 2010; 375: 743–51

Department of Paediatrics (R Hovorka PhD, J M Allen RN, D Elleri MD, L J Chassin PhD, T Hovorka MSc, A M F Larsen MSc, M Nodale MSc, A De Palma MD, M E Wilinska PhD, C L Acerini MD, Prof D B Dunger MD) and Institute of Metabolic Science (R Hovorka, J M Allen, D Elleri, L J Chassin, J Harris RN, A M F Larsen, M E Wilinska, C L Acerini, Prof D B Dunger), University of Cambridge, Cambridge, UK; and Jaeb Center for Health Research, Tampa, FL, USA (D Xing MPH, C Kollman PhD)

Objective

Closed-loop systems link continuous glucose measurements to insulin delivery. We aimed to establish whether closed-loop insulin delivery could control overnight blood glucose in young people.

Funding: Juvenile Diabetes Research Foundation; European Foundation for Study of Diabetes; Medical Research Council Centre for Obesity and Related Metabolic Diseases; National Institute for Health Research Cambridge Biomedical Research Centre.

MethodWe undertook three randomised crossover studies in 19 patients aged 5–18 years with type 1 diabetes of duration 6・4 years (SD 4・ 0). We compared standard continuous subcutaneous insulin infusion and closed-loop delivery (n=13; APCam01); closed-loop delivery after rapidly and slowly absorbed meals (n=7; APCam02); and closed-loop delivery and standard treatment after exercise (n=10; APCam03). Allocation was by computer-generated random code. Participants were masked to plasma and sensor glucose. In APCam01, investigators were masked to plasma glucose. During closed-loop nights, glucose measurements were fed every 15 min into a control algorithm calculating rate of insulin infusion, and a nurse adjusted the insulin pump. During control nights, patients’ standard pump settings were applied. Primary outcomes were time for which plasma glucose concentration was 3・ 91–8・ 00 mmol/L or 3・ 90 mmol/L or lower. Analysis was per protocol. This trial is registered, number ISRCTN18155883.

Figure 1: Trial design

(A)APCam01 (12 nights per treatment). (B) APCam02 (six nights per treatment).(C)APCam03 (nine nights per treatment).APCam=Artificial Pancreas Project at Cambridge. CSII=continuous subcutaneous insulin infusion. CRF=clinical research facility. Peak VO2=maximum oxygen uptake. Planned 1–3 weeks, but for logistical reasons extended to 24 and 27 days in two patients (*) and to 35 and 36 days in two patients (†)

Figure A2: Plasma glucose, insulin infusion, and plasma insulin during APCam01 (n = 12)

Distribution of insulin infusion rates during APCam01

Figure A3: Plasma glucose, insulin infusion, and plasma insulin during APCam02 (n = 6)

Distribution of insulin infusion rates during APCam02

Figure A4: Plasma glucose, insulin infusion, and plasma insulin during APCam03 (n = 9)

Distribution of insulin infusion rates during APCam03

70mg/dl

72mg/dl54mg/dl36mg/dl

Results17 patients were studied for 33 closed-loop and 21 continuous infusion nights. Primary outcomes did not diff er signifi cantly between treatment groups in APCam01 (12 analysed; target range, median 52% [IQR 43–83] closed loop vs 39% [15–51] standard treatment, p=0・ 06; ≤3・ 90 mmol/L, 1% [0–7] vs 2% [0–41], p=0・13), APCam02 (six analysed; target range, rapidly 53% [48–57] vs slowly absorbed meal 55% [37–64], p=0・ 97; ≤3・ 90 mmol/L, 0% [0–4] vs 0% [0–0], p=0・ 16]), and APCam03 (nine analysed; target range 78% [60–92] closed loop vs 43% [25–65] control, p=0・ 0245, not signifi cant at corrected level; ≤3・ 90 mmol/L, 10% [2–15] vs 6% [0–44], p=0・ 27). A secondary analysis of pooled data documented increased time in the target range (60% [51–88] vs 40% [18–61]; p=0・ 0022) and reduced time for which glucose concentrations were 3・ 90 mmol/L or lower (2・ 1% (0・ 0–10・0) vs 4・ 1% (0・ 0–42・ 0); p=0・ 0304). No events with plasma glucose concentration lower than 3・ 0 mmol/L were recorded during closed-loop delivery, compared with nine events during standard treatment.

Conclusion

Closed-loop systems could reduce risk of nocturnal hypoglycaemia in children and adolescents with type 1 diabetes.

Message

今後は　 CSIIインスリン治療　は血糖センサー付きのポンプになるかもしれない。