1. Diabetes Mellitus Chun-Jen Lin, MD Taipei Veterans General Hospital - BS control and stroke

2. DM is associated with a substantially increased risk for first ischemic stroke AHA guideline for primary stroke prevention, 2011 The adjusted RR is in the range of 1.5 to 3.7 Abott et al., JAMA 1987, Odonnell et al., Lancet 2010, Almdal et al., Arch Int Med 2004, Emerging et al., Lancet 2010

3. Get With The Guidelines-Stroke in Taiwan, Circulation 2010 Taiwan Stroke Registry

4. Diagnosis of DM HbA1c > 6.5% Fasting blood sugar > 126 mg/dl Postpradial blood sugar > 200 mg/dl during OGTT (75g) Random > 200 mg ADA guideline 2014

5. Selvin et al., NEJM 2010 N=11092 ~15-yrs f/u

6. DM diagnosed CAD Stroke

7. DM control with stroke prevention

8. Steno-2 Study Gade et al., NEJM 2003  patients with type 2 diabetes and microalbuminuria

9. N=63 N=67 Gade et al., NEJM 2003

10. Mean f/u: 7.8 yrs

11. Gade et al., NEJM 2003

12.  Further f/u: 13.3 yrs Steno-2 Study

13. Review of clinical trials Jay et al., Circulation 2009

14. Meta-analysis Diab Vasc Dis Res 2010 No benefits in the intensive treated patients

15. Interpretations Not only BS, but also all vascular risk factors are important! The risk of hypoglycemia in intensive glycemic controls may outweigh the benefits Only those with short-duration of DM, young, minimal CVD may have benefit from intensive glycemic control. Jay et al., Circulation 2009, AHA guideline of stroke treatment 2014

16. Treatment Targets HbA1c < 7% Fasting blood sugar 70-130 mg/dl Peak postprandial blood sugar < 180 mg/dl ADA guideline 2014

17. BS control in acute stroke

18. Christopher et al., Lancet Neurol 2007 UK Glucose Insulin in Stroke Trial (GIST-UK)

20. Glycemic control in acute stroke Quinn et al., Cardiovas ther 2010 ESO: < 180 mg/dl AHA: < 200 mg/dl Treatment target 

21. Options for Antidiabetic Treatment Glucose dependent GLP-1 Mimetics (Exenatide, Liraglutide)  -Glucosidase Inhibitors (Acarbose, Miglitol, Voglibose) DPP-4 Inhibitors (Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin, Alogliptin) Glucose independent Exogenous Insulin Glinides Sulfonylurea Metformin Pioglitazone Insulin Resistance Inhibition of Glucose Resorption Insulin Secretion

22. ADA guideline 2014

24. 工商服務 健保價： 29.7 元

25. Significant lowering of urinary albumin/creatinine ratio by treatment with Pioglitazone in type 2 diabetic patients -15 +2 -20 -10 0 10 Schernthaner et al JCEM 2004; 89:6086 Hanefeld et al Diab.Care 2004; 28:141 Matthews et al Diab.Metab Res.Rev. 2005; 21:167-174 -10 +6 p<0.027 -19 p<0.002 p<0.017 SU +Metformin (n=313) Pioglitazone (n=597) Metformin (n=597) PIO +Metformin (n=317) Metformin +SU (n=320) PIO +SU (n=319) Change of urinary albumin/creatinine ratio after 52 weeks (%)

26. Cardiovascular Calcium Scoring Carotid Intima Medial Thickness CHICAGO TRIAL: A Study Evaluating Carotid Intimal- Medial Thickness in Atherosclerosis using Pioglitazone Objective: Demonstrate the impact of Pioglitazone vs Glimepiride on atherosclerosis as measured by CIMT and EBCT in 400 patients with type 2 diabetes mellitus (18 month treatment period) The Chicago Trial has been presented at the AHA 2006 in Chicago Mazzone T et al. JAMA 2006; 296:2572–258 Davidson M et al. Circulation 2008 ;117:2123-2130

27. Study Diagram CHICAGO TRIAL Screening Week –7 W0 W4 W8 W16 W24 W32 W40 W48 W60 W72 CIMT CIMT CIMT CIMT Pioglitazone 15-45mg QD Glimepiride 1-4mg QD

28. Week 24Week 48Week 72 Baseline -0.010 LS Mean Change from Baseline Posterior Wall CIMT (mm) 0.005 0.010 0.015 -0.005 0.000 GlimepiridePioglitazone HCI -0.013 (95% CI: -0.024, -0.002) Treatment group difference, Final Visit LS mean (SE) Baseline CIMT (mm) 0.779 (0.008) GLM (N=186) 0.771 (0.008) PIO (N=175) Mean Change in Average CIMT CHICAGO TRIAL: A Study Evaluating Carotid Intima-Media Thickness in Atherosclerosis comparing Pioglitazone versus Glimepiride

29. Risk of MI, IHD or a composite of major Macrovascular Events from Meta-analyses of Trials with Rosiglitazone or Pioglitazone versus Comparators Schernthaner G & Chilton R. Diab.Metab.Obes 2010 Rosiglitazone meta-analyses Hazard or Odds or Risk Ratio 3.50.00.51.01.52.02.53.0 GSK-ICT (MI)  7,8,20,21  Dahbreh & Econom opoulos (MI, lowest estimate)  19  Selvin et al. (CV morbidity)  22  Friedrich et al. (MI) a  25  Friedrich et al. (IHD) a  25  Schuster et al. (MI)  17  FDA (Serious IHD)  9,21  Nissen & Wolski (MI)  6  Sing et al. (MI)  10  Bracken (MI, incl.RECORD)  18  Psaty & Furberg (MI)  16  Monami et al. (MI)  23  GSK-ICT (IHD)  7,8,20,21  Diamond et al. (MI, highest estimate)  15  Bracken (MI, excl.RECORD)  18  Dahbreh & Econom opoulos (MI, lowest estimate)  19  Diamond et al. (MI, lowest estimate)  15  FDA (IHD)  9,21  FDA (CV death/MI/Stroke)  7,8,20,21  GSK-ICT (CV death/MI/Stroke)  7,8,20,21  Manucci et al (Non-fatal coronary events)  24  Manucci et al (Non-fatal MI)  24  Pioglitazone meta-analyses Selvin et al (CV morbidity, incl.PROactive)  22  Manucci et al (Non-fatal coronary events)  33  Lincoff et al (Death/MI/stroke, excl.PROactive)  28  Selvin et al (CV morbidity, incl.PROactive)  22  Nagajothi et al (MI)  34  Lincoff et al (Death/MI)  28  Lincoff et al (Death/MI/stroke, incl. PROacitve)  28  Perez et al (Death/MI/stroke, incl.PROactive)  29  Lincoff et al (MI)  28  Perez et al (Death/MI/stroke, excl.PROactive)  29 

30. Protection of multiple Organs by Actos (Pioglitazone)  47% of SecondaryStroke in Patients with previous Stroke (PROactive)  28% of Re-Infarction in Patients with previous MI (PROactive)  37% of Acute Coronary Syndrome after previous MI (PROactive)  21% of MI, Stroke & Death in Patients with CKD (PROactive) Stop of Progression of Coronary Atherosclerosis (PERISCOPE)  Microalbuminuria (QUARTET)  51% Mortality in Patients on Hemodialysis (USA) Reduction of CIMT (Carotid artery Intima- Media Thickness) (CHICAGO) Reduction of Inflammation & Necrosis in NASH (Nonalcoholic Steatohepatitis)  50% Risk for Hepatocellular Ca Scherthaner et al., Diab therap 2013

31. Who needs TZD ?

33. Take Home Massages HbA1c is a better marker than fasting sugar for therapeutic monitoring. Intensive BS control alone does not provide additional benefits in regard of stroke prevention. TZD is one of OADs that target at insulin resistance. Suitable for patients especially with increased waist circumference, low HDL cholesterol level, and fatty liver. Proved to be not associated with bladder cancer.

34. Thank you for your attention! Chun-Jen Lin, MD zenlin1981@hotmail.com Taipei Veterans General Hospital Chun-Jen Lin, MD zenlin1981@hotmail.com Taipei Veterans General Hospital