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 2014 年 11 月 13 日 8:30-8:55 ８階 医局 Rugge JB, Bougatsos C, Chou R. Screening and Treatment of Thyroid Dysfunction: An Evidence Review for the U.S. Preventive Services Task Force. Ann Intern Med. 2014 Oct 28. doi: 10.7326/M14-1456. Hansen L, Iqbal N, Ekholm E, Cook W, Hirshberg B. Postprandial Dynamics of Plasma Glucose, Insulin, and Glucagon in Patients with Type 2 Diabetes Treated with Saxagliptin Plus Dapagliflozin Add-On to Metformin Therapy. Endocr Pract. 2014 Nov 4:1-29.

2. Dr. Rugge: Oregon Health & Science University, Mail Code FM, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239. Drs. Bougatsos and Roger Chou: Oregon Health & Science University, Mail Code BICC, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239. Ann Intern Med. 2014 Oct 28. doi: 10.7326/M14-1456.

3. Background: In 2004, the U.S. Preventive Services Task Force found insufficient evidence to recommend thyroid screening. Purpose: To update the 2004 U.S. Preventive Services Task Force review on the benefits and harms of screening and treatment of subclinical and undiagnosed overt hypothyroidism and hyperthyroidism in adults without goiter or thyroid nodules.

4. Data Sources: MEDLINE and Cochrane databases through July 2014. Study Selection: Randomized, controlled trials and observational studies of screening and treatment. Data Extraction: One investigator abstracted data, and a second investigator confirmed; 2 investigators independently assessed study quality.

11. Data Synthesis: No study directly assessed benefits and harms of screening versus no screening. For subclinical hypothyroidism (based on thyroid-stimulating hormone levels of 4.1 to 11.0 mIU/ L), 1 fair-quality cohort study found that treatment of subclinical hypothyroidism was associated with decreased risk for coronary heart disease events versus no treatment. No study found that treatment was associated with improved quality of life, cognitive function, blood pressure, or body mass index versus no treatment. Effects of treatment versus no treatment showed potential beneficial effects on lipid levels, but effects were inconsistent, not statistically significant in most studies, and of uncertain clinical significance (difference, － 0.7 to 0 mmol/L [ － 28 to 0 mg/dL] for total cholesterol levels and － 0.6 to 0.1 mmol/L [ － 22 to 2 mg/dL] for low-density lipoprotein cholesterol levels). Treatment harms were poorly studied and sparsely reported. Two poor quality studies evaluated treatment of subclinical hyperthyroidism but examined intermediate outcomes. No study evaluated treatment versus no treatment of screen-detected, undiagnosed overt thyroid dysfunction.

12. Limitations: English-language articles only, no treatment study performed in the United States, and small trials with short duration that used different dosage protocols. Conclusion: More research is needed to determine the clinical benefits associated with thyroid screening. Primary Funding Source: Agency for Healthcare Research and Quality.

13. Message 無作為化比較試験 / 観察研究の既発表論文を対 象に、 2004 年に米国予防医学作業部会 （ USPSTF ）が実施した甲状腺機能障害の検診 / 治療の利益 / 不利益に関するエビデンスのレ ビューをアップデート。検診の有無による利益 / 不利益を直接的に検証した研究は見つからず、検 診に関連する臨床効果を検証する研究を実施する 必要性が示唆された。

15. From: 1 Bristol-Myers Squibb, Princeton, NJ, USA; 2 AstraZeneca, Mölndal, Sweden; 3 AstraZeneca, Wilmington, DE, USA;

16. Objective: To analyze changes in plasma glucose, insulin, and glucagon in relation to glycemic response during treatment with dual add-on of saxagliptin (SAXA) plus dapagliflozin (DAPA) to metformin XR (MET) compared with SAXA add-on or DAPA add-on alone to MET in patients with type 2 diabetes mellitus (T2DM) poorly controlled with MET.

17. Methods: Double-blind trial in adults with glycated hemoglobin (HbA1c) ≥8.0–≤12.0% randomized to SAXA 5 mg/d plus DAPA 10 mg/d (n=179), or SAXA 5 mg/d and placebo (n=176), or DAPA 10 mg/d and placebo (n=179) added to background MET ≥1500 mg/d. Mean change from baseline in the area under the curve from 0 to 180 minutes (AUC 0–180 min) was calculated for glucose, insulin, and glucagon obtained during a liquid meal tolerance test (MTT).

18. Table 1. Demographics and baseline characteristics Data are mean (SD) or n (%). BMI=body mass index; eGFR=estimated glomerular filtration rate calculated by Modification of Diet in Renal Disease (MDRD) formula; FPG=fasting plasma glucose; HbA1c=glycated hemoglobin; PPG=postprandial plasma glucose.

19. Figure 1. Baseline and week 24 means (SE) for plasma (A, D) glucose, (B, E) insulin, and (C, F) glucagon concentrations during an MTT. DAPA=dapagliflozin; MET=metformin; MTT=meal tolerance test; SAXA=saxagliptin.

20. Figure 2. Adjusted mean change from baseline in AUC 0 to 180 minutes for (A) glucose, (B) insulin, and (C) glucagon at 24 weeks during an MTT. DAPA=dapagliflozin; MET=metformin; MTT=meal tolerance test; SAXA=saxagliptin.

21. Figure 3. Baseline and week 24 means (SE) for plasma (A, D) glucose, (B, E) insulin, and (C, F) glucagon concentrations during an MTT in patients with baseline HbA1c <8%. DAPA=dapagliflozin; HbA1c=glycated hemoglobin; MET=metformin; MTT=meal tolerance test; SAXA=saxagliptin.

22. Figure 4. Baseline and week 24 means (SE) for plasma (A, D) glucose, (B, E) insulin, and (C, F) glucagon concentrations during an MTT in patients with baseline HbA1c ≥8% and <9%. DAPA=dapagliflozin; HbA1c=glycated hemoglobin; MET=metformin; MTT=meal tolerance test; SAXA=saxagliptin.

23. Figure 5. Baseline and week 24 means (SE) for plasma (A, D) glucose, (B, E) insulin, and (C, F) glucagon concentrations during an MTT in patients with baseline HbA1c ≥9%. DAPA=dapagliflozin; HbA1c=glycated hemoglobin; MET=metformin; MTT=meal tolerance test; SAXA=saxagliptin.

24. Figure 6. Adjusted mean change from baseline in AUC 0 to 180 minutes for (A) glucose, (B) insulin, and (C) glucagon at 24 weeks during an MTT in patients with baseline HbA1C of <8%, ≥8% and <9%, and ≥9%. DAPA=dapagliflozin; HbA1c=glycated hemoglobin; MET=metformin; MTT=meal tolerance test; SAXA=saxagliptin.

25. Results: Result: Glucose AUC 0–180 min was reduced more from baseline with SAXA+DAPA+MET (–12940 mg/dL) compared with SAXA+MET (–6309 mg/dL) and DAPA+MET (–11247 mg/dL). Insulin AUC 0–180 min significantly decreased with SAXA+DAPA+MET (–1120 μU/mL) and DAPA+MET (–1019 μU/mL) and increased with SAXA+MET (661 μU/mL). Glucagon AUC 0–180 min increased only with DAPA+MET (2346 pg/mL). Change in glucose (P<0.0001) and insulin (P=0.0003) AUC 0–180 min correlated with change in HbA1c whereas change in glucagon AUC 0–180 min did not (P=0.27).

26. Conclusion: When added to background MET, the combination of SAXA+DAPA provided additional reduction in glucose AUC 0–180 min and HbA1c without the increase in insulin seen with SAXA and without the increase in glucagon seen with DAPA. Change in insulin and glucose but not glucagon AUC 0–180 min correlated with change in HbA1c.

27. Message DPP-4 阻害薬と SLGT2 阻害薬の併用のデータを みると、グルカゴンの上昇がなくインスリンもほ ぼ同等で血糖がより低下するようである。