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 6 月 25 日 8:30-8:55 ８階 医局 Adam G Tabak, Markus Jokela, Tasnime N Akbaraly, Eric J Brunner, Mika Kivimaki, Daniel R Witte Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study Lancet online June 8, 2009 Robert R Henry, A Michael Lincoff, Sunder Mudaliar, Michael Rabbia, Cathy Chognot, Matthias Herz Effect of the dual peroxisome proliferator-activated receptor-α/γ agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomised, dose-ranging study Lancet online June 8, 2009

3. Department of Epidemiology and Public Health, University College London, London, UK (A G Tabak MD, M Jokela PhD, T N Akbaraly PhD, E J Brunner PhD, Prof M Kivimaki PhD, D R Witte MD); Semmelweis University Faculty of Medicine, 1st Department of Medicine, Budapest, Hungary (A G Tabak); Department of Psychology, University of Helsinki, Helsinki, Finland (M Jokela); INSERM U888 and University Montpellier 1, Montpellier, France (T N Akbaraly); Finnish Institute of Occupational Health, Helsinki, Finland (Prof M Kivimaki); and Steno Diabetes Center, Gentofte, Denmark (D R Witte) www.thelancet.com Published online June 8, 2009

4. All 35–55-year-old non-industrial British civil servants working in London offices (UK) of 20 departments were invited to participate in this study. 10 308 (6895 men) were recruited between August, 1985, and April, 1988 (phase 1).26 Between August, 1991, and December, 1994 (phase 3), all participants known to be alive and in the country were invited to the screening clinic for an oral glucose tolerance test, and 6058 men and 2758 women (85 ・ 5% of the original sample) attended.

5. Background Little is known about the timing of changes in glucose metabolism before occurrence of type 2 diabetes. We aimed to characterise trajectories of fasting and postload glucose, insulin sensitivity, and insulin secretion in individuals who develop type 2 diabetes.

6. We analysed data from our prospective occupational cohort study (Whitehall II study) of 6538 (71% male and 91% white) British civil servants without diabetes mellitus at baseline. During a median follow-up period of 9 ・ 7 years, 505 diabetes cases were diagnosed (49 ・ 1% on the basis of oral glucose tolerance test). We assessed retrospective trajectories of fasting and 2-h postload glucose, homoeostasis model assessment (HOMA) insulin sensitivity, and HOMA β-cell function from up to 13 years before diabetes diagnosis (diabetic group) or at the end of follow- up (non-diabetics). Methods

7. 103 94 12797 mg/dl 10.2 6.5 65.9 36.1 microU/ml

8. Figure 1: Fasting (A) and 2-h postload (B) glucose trajectories before diagnosis of diabetes or the end of follow-up Numbers are 505 incident diabetes cases and 6033 non-diabetics. Time 0 is diagnosis for incident diabetes cases or end of follow-up for non-diabetics. Multilevel longitudinal modelling was done using linear growth model for non-diabetic and piecewise approach, including cubic terms for time, for incident diabetic individuals with oral glucose tolerance test fasting glucose (A) and 2-h glucose (B) as outcomes. Analysis was adjusted for age, sex, ethnic origin, and study phase. Estimations were done for a hypothetical population consisting of 71% male, 91% white individuals aged 63 years at time 0 years. Error bars show 95% CI for the fixed effects. Tables show the number of measurements for each year at and before diabetes diagnosis or the end of follow-up. 126mg/dl 108mg/dl

9. Figure 1: Fasting (A) and 2-h postload (B) glucose trajectories before diagnosis of diabetes or the end of follow-up Numbers are 505 incident diabetes cases and 6033 non-diabetics. Time 0 is diagnosis for incident diabetes cases or end of follow-up for non-diabetics. Multilevel longitudinal modelling was done using linear growth model for non-diabetic and piecewise approach, including cubic terms for time, for incident diabetic individuals with oral glucose tolerance test fasting glucose (A) and 2-h glucose (B) as outcomes. Analysis was adjusted for age, sex, ethnic origin, and study phase. Estimations were done for a hypothetical population consisting of 71% male, 91% white individuals aged 63 years at time 0 years. Error bars show 95% CI for the fixed effects. Tables show the number of measurements for each year at and before diabetes diagnosis or the end of follow-up. 198mg/dl

11. Figure 2: Homoeostasis model assessment (HOMA) insulin sensitivity (A) and HOMA β-cell function trajectories (B) before diagnosis of diabetes or the end of follow-up Numbers are 505 incident diabetes cases and 6033 non-diabetics. Time 0 is diagnosis for incident diabetes cases or end of follow-up for non-diabetics. Multilevel longitudinal modelling was done using linear growth model for non-diabetic and non-piecewise or piecewise approach, including linear or quadratic terms for time, for incident diabetic individuals with HOMA2-%S (A) and HOMA2-%B (B) as outcomes. Analysis was adjusted for age, sex, ethnic origin, and study phase. Estimations were done for a hypothetical population consisting of 71% male, 91% white individuals aged 63 years at time 0 years. Error bars show 95% CI for the fixed effects. Tables show the number of measurements for each year at and before diabetes diagnosis or the end of follow-up. HOMA2-%S=homoeostasis model assessment insulin sensitivity. HOMA2- %B=homoeostasis model assessment β-cell function.

12. Figure 2: Homoeostasis model assessment (HOMA) insulin sensitivity (A) and HOMA β-cell function trajectories (B) before diagnosis of diabetes or the end of follow-up Numbers are 505 incident diabetes cases and 6033 non-diabetics. Time 0 is diagnosis for incident diabetes cases or end of follow-up for non-diabetics. Multilevel longitudinal modelling was done using linear growth model for non-diabetic and non-piecewise or piecewise approach, including linear or quadratic terms for time, for incident diabetic individuals with HOMA2-%S (A) and HOMA2-%B (B) as outcomes. Analysis was adjusted for age, sex, ethnic origin, and study phase. Estimations were done for a hypothetical population consisting of 71% male, 91% white individuals aged 63 years at time 0 years. Error bars show 95% CI for the fixed effects. Tables show the number of measurements for each year at and before diabetes diagnosis or the end of follow-up. HOMA2-%S=homoeostasis model assessment insulin sensitivity. HOMA2- %B=homoeostasis model assessment β-cell function.

13. Multilevel models adjusted for age, sex, and ethnic origin confirmed that all metabolic measures followed linear trends in the group of non-diabetics (10 989 measurements), except for insulin secretion that did not change during follow-up. In the diabetic group (801 measurements), a linear increase in fasting glucose was followed by a steep quadratic increase (from 5 ・ 79 mmol/L to 7 ・ 40 mmol/L) starting 3 years before diagnosis of diabetes. 2-h postload glucose showed a rapid increase starting 3 years before diagnosis (from 7 ・ 60 mmol/L to 11 ・ 90 mmol/L), and HOMA insulin sensitivity decreased steeply during the 5 years before diagnosis (to 86 ・ 7%). HOMA β-cell function increased between years 4 and 3 before diagnosis (from 85 ・ 0% to 92 ・ 6%) and then decreased until diagnosis (to 62 ・ 4%). Results

14. In this study, we show changes in glucose concentrations, insulin sensitivity, and insulin secretion as much as 3–6 years before diagnosis of diabetes. The description of biomarker trajectories leading to diabetes diagnosis could contribute to more-accurate risk prediction models that use repeated measures available for patients through regular check-ups. Funding Medical Research Council (UK); Economic and Social Research Council (UK); British Heart Foundation (UK); Health and Safety Executive (UK); Department of Health (UK); National Institute of Health (USA); Agency for Health Care Policy Research (USA); the John D and Catherine T MacArthur Foundation (USA); and Academy of Finland (Finland). Conclusion

16. Department of Medicine, University of California at San Diego and VA San Diego Healthcare System, San Diego, CA, USA (Prof R R Henry MD, S Mudaliar MD); Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, USA (Prof A M Lincoff MD); Hoff mann-La Roche, Nutley, NJ, USA (M Rabbia MA); and F Hoff mann-La Roche AG, Basel, Switzerland (C Chognot PhD, M Herz MD) www.thelancet.com Published online June 8, 2009

17. Figure: Synergistic beneficial actions of balanced PPAR-α/γ agonists Apo AI=apolipoprotein A1. Apo AII=apolipoprotein A2. Apo CIII=apolipoprotein C3. FA=fatty acids. FFA=free fatty acids. Figure adapted from Balakumar and colleagues and Fievet and colleagues

18. Aleglitazar is a peroxisome proliferator- activated receptor agonist (hence a PPAR modulator ) with affinity to PPARα and PPARγ, This class includes muraglitazar and tesaglitazar. Both were discontinued owing to safety concerns, including increase in serum creatinine and decrease in glomerular filtration rate (tesaglitazar) or increased risk of cardiovascular events (muraglitazar).

19. BACKGROUND Despite previous reports of potential adverse cardiovascular effects of peroxisome proliferator-activated receptor (PPAR) agonists, the promise for PPAR agonists to positively affect risk of cardiovascular disease in patients with type 2 diabetes is of continued interest. The SYNCHRONY study aimed to establish the glucose-lowering and lipid-modifying effects, and safety profile, of the dual PPAR-α and PPAR-γ agonist aleglitazar.

20. METHODS In this double-blind study, patients with type 2 diabetes (either drug-naive or pre-treated with ≤two oral agents) were enrolled from 47 sites in seven countries. After a single-blind, 4–5-week placebo run-in period, 332 patients were randomised double-blind (via an interactive voice-response system) to 16 weeks’ treatment with aleglitazar at once-daily doses of 50 μg, 150 μg, 300 μg, or 600 μg, or matching placebo (n=55 in each group), or to open-label pioglitazone 45 mg once daily (n=57) as a reference. The primary efficacy endpoint was the change in glycosylated haemoglobin (HbA1c) concentration from baseline to the end of treatment. Patients who received at least one dose of study drug and had at least one evaluable post-baseline HbA1c measurement were included in the efficacy analysis. This study is registered with ClinicalTrials.gov, number NCT00388518.

21. Figure 1: Trial profile

22. Table 1: Baseline (after placebo run- in period) demographic and clinical characteristics (safety population)

23. Figure 2: Effect on haemoglobin A1c concentration (A) Absolute change from baseline to end of treatment period (week 16) and (B) over time. Analysis undertaken in the intention-to-treat population, LOCF. p values are versus placebo. LS=least squares. HbA1c=haemoglobin A1c.

25. Figure 3: Effect on fasting plasma glucose (A) Absolute change from baseline to end of treatment period (week 16) and (B) over time. Analysis undertaken in the intention-to-treat population, LOCF. p values are versus placebo. LS=least squares. FPG=fasting plasma glucose.

27. Figure 4: Eff ect on lipid parameters Percentage change from baseline lipid concentrations to end of treatment period (week 16) for (A) triglycerides, (B) HDL cholesterol, (C) LDL cholesterol, and (D) apolipoprotein B. Analysis undertaken in the intention-to-treat population, LOCF. p values are versus placebo. LS=least squares.

30. RESULTS The efficacy analysis excluded six patients (n=0 in pioglitazone group; n=1 in each of placebo, 50 μg, 150 μg, and 600 μg aleglitazar groups; and n=2 in 300 μg aleglitazar group). Aleglitazar significantly reduced baseline HbA1c versus placebo in a dose-dependent manner, from –0 ・ 36% (95% CI 0 ・ 00 to –0 ・ 70, p=0 ・ 048) with 50 μg to –1 ・ 35% (– 0 ・ 99 to –1 ・ 70, p<0 ・ 0001) with 600 μg. The trend of changes over time suggests that the maximum effect of aleglitazar on HbA1c concentration was not yet reached after 16 weeks of treatment. Oedema, haemodilution, and weight gain occurred in a dose-dependent manner. However, at aleglitazar doses less than 300 μg, no patients had congestive heart failure, frequency of oedema was similar to placebo (one case at 50 μg, two at 150 μg, and three with placebo) and less than with pioglitazone (four cases), and bodyweight gain was less than with pioglitazone (0 ・ 52 kg at 150 μg vs 1 ・ 06 kg).

31. CONCLUSION The favourable balance in the safety and efficacy profile of aleglitazar represents encouraging short-term clinical data for this agent and provides good evidence to enter phase III investigation. Funding: F Hoff mann-La Roche AG (Switzerland).