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 2009 年 5 月 21 日 8:30-8:55 ８階 医局 Marfella R, Barbieri M, Grella R, Rizzo MR, Nicoletti GF, Paolisso G. Effects of vildagliptin twice daily vs. sitagliptin once daily on 24-hour acute glucose fluctuations. J Diabetes Complications Mar 3. [Epub ahead of print] Blaha J, Kopecky P, Matias M, Hovorka R, Kunstyr J, Kotulak T, Lips M, Rubes D, Stritesky M, Lindner J, Semrad M, Haluzik M. Comparison of three protocols for tight glycemic control in cardiac surgery patients. Diabetes Care May;32(5): Epub 2009 Feb 5.

Hyperglycemia Pancreas Liver Muscle  Hepatic glucose production  Rd of glucose Insulin resistance = Mechanism of Action of OHA Biguanide Thiazolidinedione α-glucosidase inhibitor SU drugs, glinides Defect in insuiin secretion Deficiency of Insulin = CHO abserption GutIncretin (GLP-1, DDPIV inhibitor)

Alogliptin Dipeptidyl peptidase-4 inhibitor Sitagliptin Vildagliptin

There is increasing evidence that glycemic disorders such as rapid glucose fluctuations over a daily period might play an important role on diabetic complications. We evaluated the efficacy of sitagliptin 100 mg once daily vs. vildagliptin 50 mg twice daily on daily blood glucose fluctuations in patients with type 2 diabetes that was inadequately controlled by metformin. Background and Aim

Forty-eight-hour continuous subcutaneous glucose monitoring (CSGM) was performed in patients treated with metformin plus vildagliptin (n=18) or sitagliptin (n=20) over a period of 3 months. The mean amplitude of glycemic excursions (MAGE) was used for assessing glucose fluctuations during the day. During a standardized meal, glucagon-like peptide-1 (GLP-1), glucagon, and insulin were measured. Methods

Pharmaceutical Power Plasma DPP-4 activity is inhibited by almost 100% already at 15–30 min, and >80% inhibition lasts for almost 14 h after a single dose of sitagliptin at 100 mg (Herman et al., 2006); Vildagliptin at 50 mg bid inhibits DPP- 4 activity by almost 97% over a daily period (Mari et al., 2005).

Fig. 1. Box plot (a plot type that displays the central line representing the median, the boxes span from the 25th to 75th percentiles, and the error bars extend from the 10th to 90th percentiles) showing the reductions of fasting glycemia (FPG), PPG levels, 24-hour mean plasma glucose (MPG) levels and MAGE in sitagliptin and vildagliptin groups (Panel A). Plasma levels of intact GLP-1(Panel B) and glucagon (Panel C) during 24-h sampling comprising three standardized meals after 3 months of treatment with vildagliptin (○, 50 mg, twice daily) or sitagliptin (■, 100 mg once daily) in type 2 diabetic patients. Values are the mean±S.D. P<.05 compared to the vildagliptin group. The parameter MAGE was designed to quantify major fluctuations of glycemia and to exclude minor ones. Calculation of the MAGE was obtained by measuring the arithmetic mean of the differences between consecutive peaks and nadirs.

CSGM shows large MAGE decrements in the vildagliptin group compared with the sitagliptin group (P<.01). A marked increase in GLP-1 occurred during interprandial period in vildagliptin bid- treated toward sitagliptin 100 mg once daily (Pb<.01). Glucagon was more suppressed during interprandial period in subjects receiving vildagliptin compared to those receiving sitagliptin (P<.01). Summary

Since MAGE (mean amplitude of glycemic excursions ) is associated with an activation of oxidative stress, our data suggest that dipeptidyl peptidase IV inhibition therapy should target not only reducing HbA1c but also flattening acute glucose fluctuations over a daily period. Conclusion

院内血糖管理ガイドライン VIII. DIABETES CARE IN SPECIFIC SETTINGS A. Diabetes care in the hospital Recommendations ● All patients with diabetes admitted to the hospital should have their diabetes clearly identified in the medical record. (E) ● Goals for blood glucose levels: Critically ill surgical patients’ blood glucose levels should be kept as close to 110 mg/dl (6.1 mmol/l) as possible and generally 140 mg/dl (7.8 mmol/l). (A) These patients require an intravenous insulin protocol that has demonstrated efficacy and safety in achieving the desired glucose Critically ill nonsurgical patients’ glycemic targets are less well defined. DIABETES CARE, VOLUME 32, SUPPLEMENT 1, JANUARY 2009 S13

VIII. DIABETES CARE IN SPECIFIC SETTINGS A. Diabetes care in the hospital Recommendations ● Scheduled prandial insulin doses should be appropriately timed in relation to meals and should be adjusted according to point-of-care glucose levels. The traditional sliding-scale insulin regimens are ineffective as monotherapy and are generally not recommended. (C) ● Using correction dose or "supplemental" insulin to correct premeal hyperglycemia in addition to scheduled prandial and basal insulin is recommended. (E) DIABETES CARE, VOLUME 32, SUPPLEMENT 1, JANUARY 2009 S13 院内血糖管理ガイドライン

POINT OF CARE TESTING POCT （ Point of Care Testing ）は、患者さんが いるその場で、簡便・迅速に実施する臨床検査 [ 薬 ] SMBG=self monitoring of blood glucose （ 測定ではない！ ISO で誤差は血糖 が 75mg/dl 以上で ±20% なら OK ）

Surgical ICU でのインスリン強化療法による 死亡率減少 周術期（主に術後）に は、 血糖を 200mg/dl 程度 にする治療に比較し 100mg/dl 前後にする と死亡率が半減する。

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 周術期（主に術後）に は、 血糖を 200mg/dl 程度 にする治療に比較し 100mg/dl 前後にする と死亡率が半減する。 心筋梗塞ではそれほど の差はない。

12 のプロトコールとの比較 Diabetes Care 30:1005, 2007 に追加 Graphic Protocol variableYNBothYYNANANA/Y adjustable

Yale 大学プロトコール／若干の修正 Diabetes Care 27:461, 2004 を改変

Yale 大学プロトコールの実施例 67 y.o. male, 外傷による多発骨折，臓器損傷

Evaluation of insulin sensitivity (Graphic example)

Glucose Control Summary (All subjects Kameda Medical Center ) Partly presented at the 44 th EASD, Sep. 8-11, 2008, Rome, Italy, Diabetologia 51(Supplement 1): S440, 2008

Diabetes Care 32:757–761, Department of Anaesthesia, Resuscitation and Intensive Medicine, Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic; the 2Institute of Metabolic Science, University of Cambridge, Cambridge, U.K., the 3Department of Anaesthesiology and Resuscitation, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; the 4Department of Cardiothoracic Surgery, Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic; and the 53rd Department of Medicine, Charles University in Prague, and 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic.

We performed a randomized trial to compare three insulin-titration protocols for tight glycemic control (TGC) in a surgical intensive care unit: an absolute glucose (Matias) protocol, a relative glucose change (Bath) protocol, and an enhanced model predictive control (eMPC) algorithm. Aim

A total of 120 consecutive patients after cardiac surgery were randomly assigned to the three protocols with a target glycemia range from 4.4 to 6.1 mmol/l. Intravenous insulin was administered continuously or in combination with insulin boluses (Matias protocol). Blood glucose was measured in 1- to 4-h intervals as requested by the protocols. Methods

J Clin Endocrinol Metab 92: 2960–2964, 2007 Matias

Anaesth Intensive Care 2004; 32:311–316 Bath

Intensive Care Med (2008) 34:1224–1230 Insulin-Infusion-Schemata Initial insulin Infusion rate Adjustment of Insulin-infusion rate: BG mmol/l Infusion rate U/h BG mmol/l RATE < Call physician. Stop insulin infusion. Administer 30ml 30% glucose iv. BG control in 30 min → BG >6.1 mg/dl continue insulin infusion with 50% of the previous infusion rate Stop insulin infusion. BG control in 30 min → if BG did not increase, administer 30ml 30% glucose iv. If BG > 6.1 mg/dl continue insulin infusion with 50% of the previous infusion rate. 8.1– – 4.3 If actual insulin infusion rate > 5U/h: reduce infusion rate by 2U/h. If actual insulin infusion rate ≤ 5U/h: reduce infusion rate by 0.5U/h. > Target-range. No change. 6.2 – 8.0 If BG lower compared to the previous test: no change. If BG equal or higher compared to the previous test: increase infusion rate by 0.5 U/h. 8.1 – 10.0 If BG lower compared to the previous test: no change. If BG equal or higher compared to the previous test: increase infusion rate by 1.0 U/h – 13.9 If BG lower compared to the previous test: no change. If BG equal or higher compared to the previous test: increase infusion rate by 1.5 U/h Increase infusion rate by 2U/h. If BG > 14.0 mg/dl in 3 consecutive samples; increase infusion rate by 50% and call physician. > 22.2Call physician. eMPC

Figure 1— Blood glucose concentrations and time to target range, expressed as means ± SEM, in patients after cardiac surgery controlled by the Matias, Bath, and eMPC protocols.

The eMPC algorithm gave the best performance as assessed by time to target (8.8 ± 2.2 vs ± 1.0 vs ± 1.9 h; eMPC vs. Matias vs. Bath, respectively; P 8.3 mmol/l (1.3 ± 1.2 vs ± 2.2 vs. 6.5 ± 2.0%; P < 0.05), and sampling interval (2.3 ± 0.1 vs. 2.1 ± 0.1 vs. 1.8 ± 0.1 h; P<0.05). However, time in hypoglycemia risk range (2.9–4.3 mmol/l) in the eMPC group was the longest (22.2 ± 1.9 vs ± 1.5 vs ± 1.6; P < 0.05). No severe hypoglycemic episode (<2.3 mmol/l) occurred in the eMPC group compared with one in the Matias group and two in the Bath group. Results

The eMPC algorithm provided the best TGC without increasing the risk of severe hypoglycemia while requiring the fewest glucose measurements. Overall, all protocols were safe and effective in the maintenance of TGC in cardiac surgery patients. Conclusion