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 2008年４月10日　8:20-8:50 B棟８階　カンファレンス室

2. Original ArticleSimvastatin with or without Ezetimibe in Familial Hypercholesterolemia John J.P. Kastelein, M.D., Ph.D., Fatima Akdim, M.D., Erik S.G. Stroes, M.D., Ph.D., Aeilko H. Zwinderman, Ph.D., Michiel L. Bots, M.D., Ph.D., Anton F.H. Stalenhoef, M.D., Ph.D., F.R.C.P., Frank L.J. Visseren, M.D., Ph.D., Eric J.G. Sijbrands, M.D., Ph.D., Mieke D. Trip, M.D., Ph.D., Evan A. Stein, M.D., Ph.D., Daniel Gaudet, M.D., Ph.D., Raphael Duivenvoorden, M.D., Enrico P. Veltri, M.D., A. David Marais, M.D., Ph.D., Eric de Groot, M.D., Ph.D., for the ENHANCE Investigators N Engl J Med Volume 358(14):1431-1443 April 3, 2008

3. Ezetimibe • 高脂血症治療剤2007年6月11日新発売－小腸コレステロールトランスポーター阻害剤－ Ezetimibe diminishes intestinal cholesterol absorption by inhibiting theNiemann–Pick C1-like1 (NPC1L1) enterocyte receptor, License to eat! "Take this pill and I can eat as much eggs and cake as I want." 薬価：250.9円

4. Ezetimibe Simvastatin

5. Enrolment and Outcomes Kastelein JJP et al. N Engl J Med 2008;358:1431-1443

6. Baseline Characteristics of the Patients Kastelein JJP et al. N Engl J Med 2008;358:1431-1443

7. Levels of Lipids, Lipoproteins, Sterols, and C-Reactive Protein at Baseline and after 24 Months of Treatment, with Changes from Baseline

8. Levels of Lipids, Lipoproteins, Sterols, and C-Reactive Protein at Baseline and after 24 Months of Treatment, with Changes from Baseline

9. Effects of Simvastatin and Combined Therapy with Simvastatin plus Ezetimibe on Levels of Cholesterol and Triglycerides

10. インスリン抵抗性改善薬の２型糖尿病患者のIMT変化に及ぼす影響インスリン抵抗性改善薬の２型糖尿病患者のIMT変化に及ぼす影響 Pioglitazone・ Metformin使用 非使用 p<0.05 (n=48) 内中膜複合体厚（ＩＭＴ） DIMT (mm/year) (n=32) 川崎医科大学外来通院２型糖尿病患者80名を経時的に約３年観察

11. Measures of Intima-Media Thickness in Carotid and Femoral Arteries at Baseline and at 24 Months and Changes from Baseline

12. Mean (±SE) Intima-Media Thickness of the Carotid Artery during 24 Months of Therapy

13. Conclusion • In patients with familial hypercholesterolemia, combined therapy with ezetimibe and simvastatin did not result in a significant difference in changes in intima-media thickness, as compared with simvastatin alone, despite decreases in levels of LDL cholesterol and C-reactive protein

14. Study Overview • In a 2-year clinical trial, the addition of ezetimibe to simvastatin had no effect on the progression of atherosclerosis, as measured by carotid-artery intima-media thickness, despite the additional lowering of levels of low-density lipoprotein cholesterol and C-reactive protein by ezetimibe when added to simvastatin • However, the study was not powered to assess clinical end points

15. Before concluding so, we must address the following four questions: First, is the rate of change in carotid intima–media thickness an effective surrogate for the rate of cardiovascular clinical events? Second, how important is statin pretreatment? Third, does the absence of between-group differences in HDL cholesterol and triglycerides make any difference? Fourth, does the ENHANCE study prove that ezetimibe provides no benefit when added to statin therapy or, for that matter, as monotherapy?

16. The results of ongoing trials, such as NCT00202878 (also known as Improved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT]), which will not be available until at least 2011, are expected not only to help define the role of ezetimibe in the treatment of hypercholesterolemia but also to provide insight into the biology of LDL cholesterol lowering and the use of carotid intima–media thickness as a surrogate indicator of coronary events.

17. Distinct patterns of use of ezetimibe emerged in the United States and Canada from 2002 to 2006, a difference that markedly altered the approach to the treatment of hyperlipidemia in the United States. The U.S. pattern increased overall costs, but the effect on clinical outcomes is uncertain.

18. Simvastatin 10mg 294.8JY 20mg 570.7JY SimvaMerk 10mg 129.5JY 20mg 275.1JY Zetia 10mg 250.9JY Vytorin 10/xx ~$2-3 Zetia 10mg ~$1.5-2 Zocor 10mg ~$1.5

20. Steven E. Nissen, MD, Stephen J. Nicholls, MBBS, PhD, Kathy Wolski, MPH, Richard Nesto, MD, Stuart Kupfer, MD, Alfonso Perez, MD, Horacio Jure, MD, Robert De Larochellière, MD, Cezar S. Staniloae, MD, Kreton Mavromatis, MD, Jacqueline Saw, MD, Bo Hu, PhD,A. Michael Lincoff, MD, E. Murat Tuzcu, MD for the PERISCOPE Investigators Corresponding Author: Steven E. Nissen, MD, Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195 (nissens@ccf.org).

21. Objective and Study Design Objective: To compare the effects of an insulin sensitizer, pioglitazone, with an insulinsecretagogue, glimepiride, on the progression of coronary atherosclerosis in patients with type 2 diabetes. Design, Setting, and Participants: Double-blind, randomized, multicenter trial at 97 academic and community hospitals in North and South America (enrollment August 2003-March 2006) in 543 patients with coronary disease and type 2 diabetes.

22. Methods Interventions: A total of 543 patients underwent coronary intravascular ultrasonography and were randomized to receive glimepiride, 1 to 4 mg, or pioglitazone, 15 to 45 mg, for 18 months with titration to maximum dosage, if tolerated. Atherosclerosis progression was measured by repeat intravascular ultrasonography examination in 360 patients at study completion. Main Outcome Measure: Change in percent atheroma volume (PAV) from baseline to study completion.

23. NS NS ピオグリタゾンは冠動脈ステント留置2型糖尿病例における ステント内再狭窄と再インターベンションの頻度を低減させる －血管内超音波法（IVUS）による定量的評価－ （%） （%） （%） 60 8 80 p=0.0994 p=0.0835 p<0.001 60 6 40 40 4 20 20 2 （MSD） 0 0 0 0 6M 0 6M ステント内 再狭窄 再インター ベンション 新生内膜面積 インデックス HbA1C 冠動脈狭窄部位に2.5mm径ステントを留置した2型糖尿病 44例を対象に、留置後から ピオグリタゾンの投与を開始した群と非投与群に分け6カ月間追跡 　　　ピオグリタゾン群：従来治療に30mg/日を追加投与（23ステント） 　　　対照群：従来治療のみを継続（21ステント） TakagiT. et al.:Am. Heart J.,146,e5,2003.

31. Percent atheroma volume (PAV) where EEMCSA is the external elastic membrane cross-sectional area and LUMENCSA is the luminal crosssectional area.

33. Summary of Findings Least squares mean PAV increased 0.73% (95% CI, 0.33% to 1.12%) with glimepiride and decreased 0.16% (95% CI, −0.57% to 0.25%) with pioglitazone (P=.002). An alternative analysis imputing values for non completers based on baseline characteristics showed an increase in PAV of 0.64% (95% CI, 0.23% to 1.05%) for glimepiride and a decrease of 0.06% (−0.47% to 0.35%) for pioglitazone (between-group P=.02). Mean (SD) baseline HbA1c levels were 7.4% (1.0%) in both groups and declined during treatment an average 0.55% ( 95% CI,−0.68% to −0.42%) with pioglitazone and 0.36% (95% CI, −0.48% to −0.24%) with glimepiride (between-group P=.03). In the pioglitazone group, compared with glimepiride, high-density lipoprotein levels increased 5.7 mg/dL (95% CI, 4.4 to 7.0 mg/dL; 16.0%) vs 0.9 mg/dL (95% CI, −0.3 to 2.1 mg/dL; 4.1%), and median triglyceride levels decreased 16.3 mg/dL (95% CI, −27.7 to −11.0 mg/dL; 15.3%) vs an increase of 3.3mg/dL (95% CI, −10.7 to 11.7 mg/dL; 0.6%) (P<.001 for both comparisons). Median fasting insulin levels decreased with pioglitazone and increased with glimepiride (P.<001). Hypoglycemia was more common in the glimepiride group and edema, fractures, and decreased hemoglobin levels occurred more frequently in the pioglitazone group.

34. Conclusion: Interpretation In patients with type 2 diabetes and coronary artery disease, treatment with pioglitazone resulted in a significantly lower rate of progression of coronary atherosclerosis compared with glimepiride.