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1 Pre-Diabetes:

2 Copyright 2017 by Sea Courses Inc. All rights reserved. No part of this document may be reproduced, copied, stored, or transmitted in any form or by any means graphic, electronic, or mechanical, including photocopying, recording, or information storage and retrieval systems without prior written permission of Sea Courses Inc. except where permitted by law. Sea Courses is not responsible for any speaker or participant s statements, materials, acts or omissions.

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6 Progression from IGT to type 2 diabetes Diabetes Prevention Program (DPP) 1 At 3 years Finnish Diabetes Prevention Study 2 At 6 years 29% patients IGT T2DM Da Qing IGT and Diabetes Study 3 At 6 years DREAM Trial 3 At 3 years 43% patients IGT T2DM 68% patients IGT T2DM Control populations 25% patients IGT and/or IFG T2DM 1 DPP Research Group. N Engl J Med 2002: 346: ; 2 Lindström J, et al. J Am Soc Nephrol 2003; 14:S108 S113; 3 Pan XR, et al. Diabetes Care 1997; 20: The DREAM Trial Investigators. Lancet 2006; 368:

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8 Relative Risk Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes: Nurses Health Study Nondiabetic throughout the study Prior to diagnosis of diabetes Copyright 2002 American Diabetes Association From Diabetes Care, Vol. 25, 2002; Reprinted with permission from The American Diabetes Association. After diagnosis of diabetes Diabetic at baseline 8

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12 A1c & Outcomes: General Population No History of DM or CVD HR per 1% higher A1c = 1.50 ( ) HR per 1% higher A1c = 1.55 ( ) Selvin et al. NEJM 2010; 362:800

13 Presented at ADA 2011, San

14 There is a difference between preventing diabetes and lowering glucose

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17 Cumulative Probability of Remaining Free of Diabetes Finnish Diabetes Prevention Study: Proportion of Subjects Without Diabetes during the Trial Reached Statistical Significance Study year Intervention Group Control Group Subjects at risk

18 Cumulative incidence (%) Lifestyle (n=1079, p<0.001 vs. Metformin, 40 Metformin (n=1073, p<0.001 vs. Plac) p<0.001 vs. Placebo) 30 The Diabetes Prevention Program (DPP): Percent developing diabetes Placebo (n=1082) All participants Metformin (n=1073, p<0.001 vs. Placebo) Risk reduction 31% by metformin 58% by lifestyle Incidence of Diabetes Years from randomization The DPP Research Group, NEJM 346: , 2002

19 Reduction in diabetes risk versus placebo (%) Subgroup analyses in the DPP Age (y) FPG (mmol/l) BMI (kg/m 2 ) Intensive lifestyle intervention -80 Metformin Diabetes Prevention Program Research Group. N Engl J Med 2002;346:

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22 Cumulative Hazard DREAM Primary Primary Outcome: Rosiglitazone HR = 0.40 ( ); P< Placebo Rosiglitazone No. at Risk Placebo Rosiglitazone Year Placebo Rosiglita

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25 Abnormal β cell

26 In the presence of abnormal glucose Worse beta cell function Glucose is high even though there is relative insulin sensitivity and don t have to put out a lot of insulin to handle it For a given amount of insulin sensitizing, the amount that the beta cell is unloaded depends on where you start on the curve Buchanan et al, Diabetes 51: , 2002 Better beta cell function Glucose is high, but insulin resistance is high and beta cells are capable of putting out a lot of insulin to try to handle it

27 Buchanan et al, Diabetes 51: , 2002

28 Improving insulin sensitivity prevents diabetes in people who don t have severe beta cell dysfunction

29 How can we improve insulin sensitivity? Weight loss/exercise, i.e., lifestyle Metformin (?) TZD s

30 IV METFORMIN- WHERE DOES IT GO? Tissue distribution of [11C]-metformin in healthy subjects after iv administration. Time denotes min after injection Time 8 Time 18 Time 29 Time 46 Time 66 Minutes Jensen JB et al, ADA Scientific Sessions, June 2015, #128-LB

31 Cumulative probability Acarbose risk reduction 25%, p =.0022 Acarbose Placebo Days after randomisation Chiasson J-L et al. Lancet 2002;359:

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33 pm x 10-5 min -1 /pm Effect of DPP-4 Inhibition on Insulin Sensitivity and β-cell Function in IFG Treatment with vildagliptin 100 mg qd (day 56) significantly improved parameters of glucose metabolism, compared with placebo run-in (day 14), but these effects were not sustained after the washout (day 70). Acute Insulin Response to Glucose P<0.05 P< Insulin Sensitivity Index P<0.01 P<0.05 x 10-5 min Disposition Index P<0.05 P< Day Day Day Single-Blind, Single-Treatment Design Utzschneider K et al. Diabetes Care 31: , 2008

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39 Summary and Conclusions: Pre-diabetes is common in the population Pre-diabetes progresses to diabetes in a substantial portion of people Pre-diabetes is associated with multiple morbidities including CV disease, retinopathy, neuropathy Preventing diabetes requires population intervention Metformin and Acarbose are safe drugs to try to prevent diabetes but not very effective. INTENSIVE lifestyle management with weight loss is effective in preventing diabetes TZD s, possibly GLP1RA are effective in preventing diabetes