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 2009 年７月９日 8:30-8:55 ８階 医局 Mauer M, Zinman B, Gardiner R, Suissa S, Sinaiko A, Strand T, Drummond K, Donnelly S, Goodyer P, Gubler MC, Klein R. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med. 2009 Jul 2;361(1):40-51. Li S, Shin JJ, Ding EL, van Dam RM. Adiponectin levels and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. 2009 Jul 8;302(2):179-88. Review.

2. From the Departments of Pediatrics (M.M., A.S., T.S.) and Medicine (M.M.), University of Minnesota, Minneapolis; Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto (B.Z., S.D.); the Departments of Medicine (R.G.), Epidemiology and Biostatistics (S.S.), and Pediatrics (K.D., P.G.), McGill University, Montreal; Hopital Necker– Enfants Malades, Paris (M.C.G.); and the Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison (R.K.). N Engl J Med 2009;361:40-51.

3. Background Nephropathy and retinopathy remain important complications of type 1 diabetes. It is unclear whether their progression is slowed by early administration of drugs that block the renin– angiotensin system.

4. We conducted a multicenter, controlled trial involving 285 normotensive patients with type 1 diabetes and normoalbuminuria and who were randomly assigned to receive losartan (100 mg daily), enalapril (20 mg daily), or placebo and followed for 5 years. The primary end point was a change in the fraction of glomerular volume occupied by mesangium in kidney-biopsy specimens. The retinopathy end point was a progression on a retinopathy severity scale of two steps or more. Intention-to-treat analysis was performed with the use of linear regression and logistic-regression models. Methods

11. Serious adverse events and adverse events are mutually exclusive. The events are classified according to the Coding Symbols for Thesaurus of Adverse Reaction Terms, fifth edition, of the Food and Drug Administration. † Among metabolic or nutritional events, for serious adverse events, 12 episodes of hyperglycemia and ketoacidosis occurred in a single patient, and for adverse events, transient hyperkalemia occurred in one patient receiving enalapril and transient elevation of the serum creatinine level occurred in one patient receiving losartan, with neither requiring discontinuation of the study drug. ‡ Among respiratory-system events, chronic cough occurred in 12 patients receiving enalapril (2 of whom discontinued enalapril for this reason), 6 receiving losartan, and 4 receiving placebo.

12. A total of 90% and 82% of patients had complete renal-biopsy and retinopathy data, respectively. Change in mesangial fractional volume per glomerulus over the 5-year period did not differ significantly between the placebo group (0.016 units) and the enalapril group (0.005, P = 0.38) or the losartan group (0.026, P = 0.26), nor were there significant treatment benefits for other biopsy-assessed renal structural variables. The 5-year cumulative incidence of microalbuminuria was 6% in the placebo group; the incidence was higher with losartan (17%, P = 0.01 by the log-rank test) but not with enalapril (4%, P = 0.96 by the log-rank test). As compared with placebo, the odds of retinopathy progression by two steps or more was reduced by 65% with enalapril (odds ratio, 0.35; 95% confidence interval [CI], 0.14 to 0.85) and by 70% with losartan (odds ratio, 0.30; 95% CI, 0.12 to 0.73), independently of changes in blood pressure. There were three biopsy-related serious adverse events that completely resolved. Chronic cough occurred in 12 patients receiving enalapril, 6 receiving losartan, and 4 receiving placebo. Results

13. Early blockade of the renin– angiotensin system in patients with type 1 diabetes did not slow nephropathy progression but slowed the progression of retinopathy. (ClinicalTrials.gov number, NCT00143949.) Conclusion

15. Departments of Epidemiology (Drs Li and van Dam) and Nutrition (Drs Shin, Ding, and van Dam), Harvard School of Public Health, Boston, Massachusetts; Framingham Union Hospital Metro West Medical Center, Framingham, Massachusetts (Dr Shin); and Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston (Dr van Dam). JAMA. 2009;302(2):179-188

16. BACKGROUND The association of obesity with development of type 2 diabetes may be partly mediated by altered secretion of adipokines by adipose tissue. Greater adiposity downregulates secretion of adiponectin, an adipokine with anti-inflammatory and insulinsensitizing properties. The strength and consistency of the relation between plasma adiponectin and risk of type 2 diabetes is unclear. To systematically review prospective studies of the association of plasma adiponectin levels and risk of type 2 diabetes.

17. METHODS Data Sources A systematic search of the MEDLINE, EMBASE, and Science Citation Index Expanded databases using adiponectin and diabetes and various synonyms and reference lists of retrieved articles up to April 10, 2009. Study Selection We included prospective studies with plasma adiponectin levels as the exposure and incidence of type 2 diabetes as the outcome variable. Data Extraction Two reviewers independently extracted data and assessed study quality. Generalized least- squares trend estimation was used to assess dose- response relationships. Pooled relative risks and 95% confidence intervals were calculated using random- effects models to incorporate between-study variation.

18. Search was conducted to identify articles up to April 10, 2009. Figure 1. Selection of Studies for Meta-analysis

27. RESULTS Thirteen prospective studies with a total of 14 598 participants and 2623 incident cases of type 2 diabetes were included in the meta-analysis. Higher adiponectin levels were monotonically associated with a lower risk of type 2 diabetes. The relative risk of type 2 diabetes was 0.72 (95% confidence interval, 0.67-0.78) per 1–log μg/mL increment in adiponectin levels. This inverse association was consistently observed in whites, East Asians, Asian Indians, African Americans, and Native Americans and did not differ by adiponectin assay, method of diabetes ascertainment, duration of follow-up, or proportion of women. The estimated absolute risk difference (cases per 1000 person-years) per 1–log μg/mL increment in adiponectin levels was 3.9 for elderly Americans and 30.8 for Americans with impaired glucose tolerance.

28. CONCLUSION Higher adiponectin levels are associated with a lower risk of type 2 diabetes across diverse populations, consistent with a dose-response relationship.