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Journal Club

This study examines whether treatment with pioglitazone can prevent or delay the development of type 2 diabetes in individuals with impaired glucose tolerance. Secondary objectives include improving glycemic control, enhancing insulin secretion and beta cell function, ameliorating insulin resistance, reverting newly diagnosed type 2 diabetic subjects to normal glucose tolerance, and improving risk factors for cardiovascular disease.

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Journal Club

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  1. Journal Club ACT NOW VADT microvascular results 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10月23日　8:20-8:50 B棟８階　カンファレンス室

  2. THIAZOLIDINEDIONES IMPAIRED GLUCOSE TOLERANCE and

  3. DPP (23% ) TZDs PREVENT THE PROGRESSION OF IGT TO T2DM TRIPOD (52% ) PIPOD (62% ) DREAM (62% ) ACT NOW (81% )

  4. DIABETES PREVENTION PROGRAM (n=3234) Intensive Lifestyle Change* Screening (age = 51y; BMI = 34 kg/m2 ) Follow up Metformin, 850 mg bid# = 3 years Standard Lifestyle Change# *Reduce weight by 7%; low-fat diet; exercise for 150 min/wk #Received information on diet and exercise

  5. 60 40 20 0 DIABETES PREVENTION PROGRAM 58% 31% % DecreaseIGT T2DM DIET +EXERCISE METFORMIN

  6. 60 40 20 0 DIABETES PREVENTION PROGRAM 58% 31% % DecreaseIGT T2DM 23% DIET +EXERCISE METFORMIN TROGLIT-AZONE

  7. 15 10 5 0 TROGLITAZONE AND PREVENTION OF T2DM IN INDIVIDUALS WITH IGT: 1.5 YEAR FOLLOW-UP Diabetes Prevention Program, ADA, 2003 *p<0.01 vs LS-Light **p<0.01 vs LS-Heavy * ** Cases Per 100-Patient Treatment Years ** LS-Light MET LS-Heavy TROG

  8. ACT NOW STUDY TOTAL NUMBER OF SUBJECTS SCREENED (n=1850) IGT* (n=602) Placebo (n=299) Pioglitazone (n=302) *Diagnosed with single OGTT (2-hour PG = 140-199 mg/dl)

  9. DREAM: TIME TO OCCURRENCE OF PRIMARY OUTCOME (DIABETES & DEATH): KAPLAN MEIER PLOT Dream Investigators, Lancet, Sept 15, 2006 RR = 62% 0.6 Placebo (n=2634) 0.4 Cumalative Hazard Ratio 0.2 Rosiglitazone(n=2635) 0 0 1 2 3 4 Years

  10. BACKGROUND • Impaired glucose tolerance is a prediabetic state that affects 21 x 106 Americans and 314 x 106 individuals world wide • In the Diabetes Prevention Program, the conversion rate of IGT to T2DM was 11% per year, but conversion rates varying from 3-13% have been reported • Individuals with IGT also are at increased risk for ASCVD

  11. BACKGROUND • From the pathophysiologic standpoint, individuals with IGT are characterized by moderate-to-severe insulin resistance and severely impaired insulin secretion • In the San Antonio Metabolism (SAM) and VAGES Studies, individuals in the upper half of IGT (2-hour PG =170-199 mg/dl) have lost 80% of their beta cell function, as quantitated by the insulin secretion/insulin resistance (disposition) index

  12. BACKGROUND • Thiazolidinediones (TZDs) are potent insulin sensitizers in both muscle and liver and are the only class of drugs that definitively have been shown to preserve beta cell function and cause a durable reduction in HbA1c in type 2 diabetic individual (ADOPT, Chicago, Periscope, Tan et al, Hanefeld et al).

  13. PRIMARY OBJECTIVE To examine whether treatment of high risk IGT individuals with pioglitazone can prevent or delay the development of type 2 diabetes mellitus (T2DM)

  14. SECONDARY OBJECTIVES To examine, in IGT subjects, whether pioglitazone can: • improve glycemic control (HbA1c, OGTT) • enhance insulin secretion and improve beta cell function (OGTT, FSIVGTT) • ameliorate insulin resistance (Matsuda Index, SI) • revert newly diagnosed type 2 diabetic subjects to a state of NGT • improve risk factors for cardiovascular disease • slow progression of carotid intima media thickness

  15. ELIGIBILITY CRITERIA IGT + fasting plasma glucose = 95-125 mg/dl and at least one of the following: • ≥1 component of the insulin resistance (metabolic) syndrome -ATP III definition • Family history of T2DM • History of GDM • PCOS • Minority ethnic background

  16. STUDY DESIGN • Subjects were recruited over 2 years and then followed for 2 years from the time that the last subject was recruited • After enrollment subjects were started on placebo or pioglitazone, 30 mg/day. Pioglitazone was titrated to 45 mg/day after one month (95% were taking the maximum dose of pioglitazone)

  17. CONVERSION OF IGT TO T2DM WAS ESTABLISHED IF: FPG ≥ 126 mg/dl on follow up visit or 2-Hour PG (OGTT) ≥ 200 mg/dl on annual visit plus Confirmation with OGTT

  18. PRIMARY ENDPOINT Life table analysis of time from randomization to diagnosis of diabetes (Kaplan Meier)

  19. TIME TO OCCURRENCE OF DIABETES (KAPLAN MEIER) Cumulative Hazard Placebo 0.30 6.8% per year 0.25 HR = 0.19 (95%, CI)= 0.09-0.39 p<0.00001 0.20 0.15 0.10 1.5% per year 0.05 Pioglitazone 0 0 20 30 40 10 50 # at risk PLAC 299 PIO 303 215 220 Months

  20. IGT T2DM IGT NGT EFFECT OF PIOGLITAZONE ON GLUCOSE TOLERANCE Placebo (n=299) 45 (6.8%) 84 (28%) 10 (1.5%) 127 (42%) <0.00001 <0.001 Pioglitazone (n=303) P value

  21. 170 160 150 140 CHANGE IN FASTING PLASMA GLUCOSE AS A FUNCTION OF TIME 108 Placebo 2-Hour PG(mg/dl) 104 PLAC PIO Fasting Plasma Glucose (mg/dl) 100 96 Pioglitazone 92 0 10 20 30 40 Time (months)

  22. Placebo Pioglitazone P<0.005 EFFECT OF PIOGLITAZONE AND PLACEBO ON INSULIN SECRETION / INSULIN RESISTANCE INDEX 6 5 4 I/G xMatsuda (0-120) 3 2 1 0 Pre Post Pre Post

  23. EFFECT OF PIOGLITAZONE AND PLACEBO ON DISPOSITION (AIR X SI) INDEX Placebo Pioglitazone P<0.005 1200 800 AIR x SI 400 0 Pre Post Pre Post

  24. Placebo Pioglitazone 10 EFFECT OF PIOGLITAZONE AND PLACEBO ON MATSUDA INDEX OF INSULIN SENSITIVITY P<0.001 8 6 Matsuda Index 4 2 0 Pre Post Pre Post

  25. NGT IGT IGT DM CHANGE IN BETA CELL FUNCTION (∆I/∆G X MATSUDA INDEX AND AIR x SI) IN RELATION TO CHANGE IN GLUCOSE TOLERANCE STATUS AIR x SI ∆I0-120/∆G0-120 X Matsuda Index 8 1400 NGT 1200 6 1000 4 IGT IGT 800 2 DM 600 0 400 PRE POST PRE POST

  26. CONCLUSIONS • Over a mean follow up of 2.6 years, pioglitazone markedly reduced the conversion rate of IGT to T2DM by 81% • IGT subjects in the lowest tertile of beta cell function and insulin sensitivity at baseline are at the highest risk to develop T2DM • Pioglitazone treatment of subjects with IGT was both safe and efficacious during the 4 year study

  27. NUMBER NEEDED TO TREAT 23 IGT subjects need to be treated for one year to prevent the development of one case of T2DM

  28. EFFECT OF TZD TREATMENT ON BETA CELL FUNCTION 61 type 2 diabetic subjects Age = 54 y BMI = 29.3 kg/m2 HbA1c = 8.6% FPG = 10.0 mM Double blind, randomized, placebo-controlled, 4 months of treatment OGTT with insulin and C-peptide measurements (ISR) Euglycemic insulin (40 mU/m2.min) clamp SUBJECTS: PROTOCOL: Ferrannini, Gastaldelli, DeFronzo. Am J Physiol Endocrinol Metab. 2007;292:E871-3

  29. EFFECT OF TZD TREATMENT ON BETA CELL FUNCTION TREATMENT GROUPS: GROUP I: Drug naïve + Placebo (n =14) GROUP II: Drug naïve + PIO (n = 9) GROUP III: Drug naïve + ROSI (n = 15) GROUP IV: Sulfonylurea + Placebo (n = 11) GROUP V: Sulfonylurea + PIO (n = 11)

  30. 2.5 0.5 0.5 0 2.0 0 -0.5 1.5 -0.5 -1.0 1.0 -1.5 -1.0 0.5 -2.0 0 -1.5 -2.5 EFFECT OF TZD TREATMENTON GLYCEMIC CONTROL AND BODY WEIGHT PLAC PLAC  HbA1c  FPG (mM)  Weight (kg) TZD TZD TZD PLAC

  31. 2500 2000 1500 1000 500 0 EFFECT OF TZD AND PLACEBO TREATMENT ON ISR IN RELATIONSHIP TO INSULIN RESISTANCE 1 IR Before Rx After Rx * x * *  ISR (AUC)  Glucose (AUC) SU + Placebo SU + PIO Naïve + PIO Naïve + ROSI Naïve + Placebo

  32. HOW DO THE THIAZOL- IDINEDIONES WORK?

  33. THIAZOLIDINEDIONES AND PRESERVATION OF BETA CELL FUNCTION • Direct effect on the beta cell (PPARg) • Amelioration of insulin resistance • Reduction in plasma FFA (lipotoxicity) • Mobilization of toxic lipid metabolites (FACoA, DAG, ceramides) out of the beta cell (lipotoxicity) • Reversal of glucotoxicity

  34. EFFECT OF TROGLITAZONE ON Pdx-1, GLUCOKINASE, AND GLUT2 IMMUNOFLUORESCENSE IN INS-1 CELLS Moibi and Leahy, Diabetes 56:88-95, 2007 160 120 Fluorescence Intensity ( Gray scale units) 80 40 0 GK GLUT2 Pdx-1 * * *

  35. THIAZOLIDINEDIONES AND PRESERVATION OF BETA CELL FUNCTION • Direct effect on the beta cell (PPARg) • Amelioration of insulin resistance • Reduction in plasma FFA (lipotoxicity) • Mobilization of toxic lipid metabolites (FACoA, DAG, ceramides) out of the beta cell (lipotoxicity) • Reversal of glucotoxicity

  36. Miyazaki & DeFronzo, Diabetologia 44: 2210, 2001 Diabetes Care 24: 710, 2001 EFFECT OF THIAZOLIDINEDIONES ON INSULIN-MEDIATED GLUCOSE DISPOSAL * * 10 8 NOGD 6 mg/kg FFM•min 4 GOX 0 Before PIO ROSI

  37. THIAZOLIDINEDIONES AND PRESERVATION OF BETA CELL FUNCTION • Direct effect on the beta cell (PPARg) • Amelioration of insulin resistance • Reduction in plasma FFA (lipotoxicity) • Mobilization of toxic lipid metabolites (FACoA, DAG, ceramides) out of the beta cell (lipotoxicity) • Reversal of glucotoxicity

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