Journal Club

1. Journal Club 亀田メディカルセンター　糖尿病内分泌内科 Diabetes and Endocrine Department, Kameda Medical Center 松田　昌文 Matsuda, Masafumi 2007年７月５日　8:20-8:50 B棟８階　カンファレンス室

3. SU薬の糖代謝への作用 • SU薬 • 速効型インスリン分泌促進薬 膵臓 インスリン ↑ 200 g/日 血 16g 糖 グリコーゲン グリコーゲン 乳 乳 グリコーゲン グリコーゲン 肝臓 酸 酸 筋肉 120g/日 脳 (食事) (食事)

4. 主要なインスリン分泌促進薬の化学構造式 H3C SO2NHCONH N Cl H3C SO2NHCONHCH2CH2CH2CH3 CONHCH2CH2 SO2NHCONH OCH3 H3C (CH3)2CH CONHCHCH2 N CONHCH2CH2 SO2NHCONH CH3 CO2H H5C2 COCH2CHCH2 N CO2H スルホニルウレア（SU）骨格 ベンズアミド（BA）骨格 トルブタミド グリクラジド グリベンクラミド グリメピリド 速効型インスリン分泌促進薬 ナテグリニド ミチグリニド

5. 膵臓β細胞SU受容体への結合

6. SUR1 （膵タイプSU受容体） Ca2+ ATP感受性 Kチャネル 電位依存性 Caチャネル ① ③ × ② SU薬 速効型インスリン分泌促進薬 細胞膜 脱分極 ④ 選択的結合 細胞内Ca2+の増加 K+ ⑤ ［ATP］ の増加 ［ADP］ ブドウ糖 糖代謝 糖輸送担体 （GLUT2） ⑤ インスリン分泌 SU薬・速効型インスリン分泌促進薬の作用機序 Ichikawa K. et al. : Arzneim. -Forsch. / Drug Res. : 52, 605, 2002

7. AIM To compare the pharmacokinetic and pharmacodynamic effects of glimepiride between once and twice-daily dosing in type 2 diabetic patients.

8. Criteria for subjects inclusion criteria: • treated with 2 mg glimepiride alone over 4 weeks duration, • age 40 – 70 years, • weighing less than 25 kg/m2 of body mass index, • HbA1C less than 8.0%. All subjects were free of concomitant illness such as heart disease, hepatic (serum alanine aminotransferase more than the upper limit of normal) or renal (serum creatinine more than the upper limit of normal) dysfunction. None of the patients had a history of severe hypoglycemia, active proliferative retinopathy or clinically significant neuropathy. Concomitant medications without hypoglycemic agents were permitted if the dose was stabilized for one month and during the study.

9. PROTCOL • Prior to the randomized 2-period crossover study, treated with once-daily 2 mg of glimepiride in order to stabilize metabolic control over 3 to 5 weeks as a screening period. • Randomization: 2 mg of glimepiride before breakfast PO QD twice-daily with 1 mg before breakfast and dinner, PO BID • treated for 4 weeks (the first-period of crossover). • Then, the regimen was reversed from that used in the first-period. • Patients were treated by the new regimen for 4 weeks (the second-period of crossover). • During the study period, they were asked to maintain a fixed calorie diet, which was calculated individually based on the ideal body weight and physical activity of each patient. They were also asked to fix meal times at 8 am for breakfast, midday for lunch and 6 pm for dinner. • Subjects were admitted one day before the final day of each period of the study. • On the next day, 24-h profiles for • serum glimepiride concentration, plasma glucose, serum insulin and C-peptide levels • were analyzed. • For the determination of HbA1C and other biochemical parameters, blood was drawn before breakfast. For the pharmacokinetic experiment, • serum glimepiride concentrations: 14 times over 24 hours. • For pharmacodynamic experiment, • plasma glucose levels: 19 times, serum insulin and C-peptide levels: 15 times. • During experiments, each subject was fed an individually fixed-calorie diet three times, which they were asked to maintain before admission. Except for the fixed meals, no food or drink other than water was permitted until completion of studies.

10. Subjects randomize cross 4 weeks 4 weeks 2mg QD QD BID BID QD screening admission admission

12. A 24-hr profile of serum insulin(A) and C-peptide(B) at the last day of each crossover period. 2 mg QD (black circle) or 1 mg BID (white square) glimepiride. Results are shown as mean ± SEM (n = 8).

15. Conclusion In summary, this crossover study demonstrates that the pharmaco-dynamic and safety profiles in once-daily dose of glimepiride in type 2 diabetic patients are not different from those in twice-daily dosing. Once-daily dosing is more suitable for the type 2 diabetic patients treated with glimepiride.

18. Background • Primary aldosteronism was previously believed to account for1% of hypertensive patients; however, recent studies applying the plasma aldosterone (PAC)-toplasma renin activity (PRA) ratio as a screening test have reported a much higher prevalence of this disease, accounting for 10–32% of the patients with essential hypertension and 50% of patients with nondiureticinduced hypokalemia

19. AIM We aimed to determine the prevalence of primary aldosteronismin diabetic subjects with poorly controlled hypertension despite treatment with multiple antihypertensive agents.

20. Screening Method 100 K>3.5 11 21 Screening was performed while subjects continued their usual blood pressure medications. Three blood pressure measurements were taken 5 min apart, and the average of the last two measurements was used for data analysis. Subjects with serum potassium 3.5 mEq/l received KCl (40 mEq/day for 1 week). Once serum potassium was 3.5 mEq/l, subjects were rescreened (because hypokalemia suppresses PAC and lowers the PAC-to-PRA ratio).

22. Conclusion We observed a prevalence of 14% of primary aldosteronism in diabetic subjects with poorly controlled hypertension while taking 3 antihypertensive agents. Accordingly, diabetic patients with poorly controlled hypertension while taking ≧3 antihypertensive drugs should be screened for primary aldosteronism using the PAC-to-PRA ratio followed by salt suppression testing in those with a positive screening ratio.

23. Renin ng/ml (0.3-2.9) Aldosteron pg/ml (35.7-240) Renin ng/ml/hr less than 1 Aldosteron ng/dl more than 12 Furosemide 2hrs Captril 50mg for diagnosis Standing 4hrs Ald(IHA → ↑, APA ↓） ACTH load Ald (IHA →, APA ↑ ） AgII load Ald (IHA ↑, APA →） Dex supp for GRA Ald ↓