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How to link glucose control to cv outcomes

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Outline
1.CV risk of DM patient
2.Glucose to CV outcome - Intensive control vs Conventional control
3.Hypoglycemia
4.Different drugs, different outcomes
5.Expect to Future

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How to link glucose control to cv outcomes

  1. 1. 藥師:陳翊齊 報告日期:103. 04. 18
  2. 2. Why this Topic ?? 糖尿病共照網納入藥師 小弟熟悉的領域 流行病學 藥物流行病學
  3. 3. 聲明 本人無與任何廠商有關係 本人無領任何廠商的演講費 本人無購買任何廠商的股票 MOS早餐是由本人自掏腰包購買 逐片吐司審查,絕無下毒,安心食用 藥師 陳翊齊
  4. 4. Outline  CV risk of DM patient  Glucose - Intensive control vs Conventional control  Hypoglycemia  Different drugs, different outcomes  Expect to Future
  5. 5. 糖尿病藥物發展  1980 年代以前  SulfonylUrea  Insulin (NPH & RI)  1990 年代  Metformin  α-glucosidase inhibitor  Meglitinide  2000 年代至今  PPAR-γ agonist  新型胰島素  DPP-4 inhibitor  GLP-1 agonist  SGLT-2 antagonist Exubera® Afrezza® Bydureon® Tanzeum® Canagliflozin Dapagliflozin
  6. 6. Mortality and Causes of Death in a National Sample of Diabetic Patients in Taiwan Diabetes Care 27:1605–1609, 2004 28.8% + 9.0% + 10.5% +0.3% = 48.6%
  7. 7. Diabetes Care 23:1103–1107, 2000 49.4% Cardiovasucular death 49.1% Cardiovasucular death Diabetes Care July 1998 vol. 21 no. 7 1138-1145
  8. 8. 7-year incidence rates of MI (fatal and nonfatal) 0 5 10 15 20 25 30 35 40 45 50 no DM, no prior MI no DM, prior MI DM, no prior MI DM, prior MI N Engl J Med 1998;339:229-34.) 3.5% 18.8% 20.2% 45% P<0.001 P<0.001
  9. 9. UK Prospective Diabetes Study  Multicenter RCT  1977 to 1997  5,102 patients with newly-diagnosed type 2 diabetes recruited between 1977 and 1991
  10. 10. UKPDS Study design Intensive Conventional Intensive 2,729 Intensive with sulfonylurea(glibenclamide or chlorpropramide)/insulin 1,138 (411 overweight) Conventional with diet 342 (all overweight) Intensive with metformin UKPDS 33 Trial end 1997 P 5,102 Newly-diagnosed type 2 diabetes 744 Diet failure FPG >15 mmol/l 149 Diet satisfactory FPG <6 mmol/l Dietary Run-in 4209 Randomisation 1977-1991 UKPDS 34 N Eng J Med 2008; 359
  11. 11. Association of glycemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35)  Prospective observational study  3642 patients BMJ 2000;321:405–12
  12. 12. UKPDS 33  Multicenter RCT  3867 newly diagnosed type 2 DM  Intensive (SU/insulin) vs conventional  Follow 10 years  HbA1c 7.0% vs 7.9% 0 0.2 0.4 0.6 0.8 1 1.2 DM related endpoint Any DM related death All cause mortality End point RR=0.88(0.79-0.99) P=0.029 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 Myocardial infraction Stroke Amputation or death from PVD Microvascular endpoint End point RR=0.84(0.71-1.00) P=0.052 RR=0.75(0.60-0.93) P=0.0099 Lancet 1998; 352: 837–53
  13. 13. UKPDS 80  10-year Post-Trial Monitoring from 1997 to 2007  Annual follow-up of the survivor cohort  Clinic-based for first five years  Questionnaire-based for last five years  Median overall follow-up 17 (16 to 30) years Intensive (SU/Ins) vs. Conventional glucose control N Engl J Med 2008;359:1577-89.
  14. 14. ACCORD study  Action to Control CardiOvascular Risk in Diabetes study  10,251 type 2 DM patients (Mean history 10 years)  Primary outcome:CVD event  Baseline HbA1c 8.3% (Mean)  End of the trial HbA1c:6.4% vs 7.5% N Engl J Med 2008;358:2545-59.
  15. 15. ACCORD study N Engl J Med 2008;358:2545-59.
  16. 16. ADVANCE study  Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation  11,140 type 2 DM patients (Mean history 8 years)  5 years of follow-up  Primary outcome:Macro and Microvascular event  Baseline HbA1c:7.5%  End point HbA1c:6.5% vs 7.3% N Engl J Med 2008;358:2560-72.
  17. 17. ADVANCE study N Engl J Med 2008;358:2560-72.
  18. 18. VADT study  investigators in the Veterans Affairs Diabetes Trial  1791 military veterans (type 2 DM history:11.5 years)  5.6 years follow-up  Primary outcome:CVD event  Baseline HbA1c:9.4%  End point HbA1c:6.9% vs 8.4%
  19. 19. META-ANALYSIS  UKPDS  ACCORD  ADVANCE  VADT Diabetologia (2009) 52:2288–2298
  20. 20. Intensive Glucose Control  Lowering Macrovascular outcomes  Longer follow up  Early intervention (Legacy effect)  Meta - Analysis  Lowering Microvascular outcomes  QOL improve  Early intervention
  21. 21. Revisiting the links between glycaemia, diabetes and cardiovascular disease Diabetologia (2013) 56:686–695
  22. 22. Emergency Hospitalization for Adverse Drug Events in Older Americans N Engl J Med 2011;365:2002-12.
  23. 23. Association of Clinical Symptomatic Hypoglycemia With Cardiovascular Events and Total Mortality in Type 2 Diabetes Diabetes Care 36:894–900, 2013  Taiwan Data base (10 years)  PAI-FENG HSU MD
  24. 24. Hypoglycemia  ADVANCE group  Severe Hypoglycemia and Risks of Vascular Events and Death N Engl J Med 2010;363:1410-8. BMJ 2010;340:b4909
  25. 25. Hypoglycemia – a major predictor of cardiovascular death in VADT http://spo.escardio.org/eslides/view.aspx?ee vtid=48&fp=3914
  26. 26. Hypoglycemia & Arrhythmia Diabetes Care Volume 37, January 2014
  27. 27. Hypoglycemia  ORIGIN study  12537 IFG, IGT, Type 2 DM patients  Insulin Glargine vs. Standard care  Follow 6.2 years  End point HbA1c:6.3% vs 6.5% N Engl J Med 2012;367:319-28. European Heart Journal doi:10.1093/eurheartj/eht332
  28. 28. Total mortality in ACCORD Diabetes Care 33:983–990, 2010
  29. 29. UKPDS 34 (Metformin)  Multicenter RCT  753 Overweight type 2 DM patients (New diagnosed )  Intensive (Metformin) vs. Conventional  Follow 10 years  End point HbA1c: 7.4% vs 8.0% 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Any DM related End point DM related death All-cause mortality Myocardial Infraction End point (Metformin) HR = 0.68 (0.53-0.87) HR = 0.58 (0.37-0.91) HR = 0.64 (0.45-0.91) HR = 0.61 (0.41-0.89) HR = 0.58 (0.37-0.91) HR = 0.64 (0.45-0.91) HR = 0.61 (0.41-0.89) 0 0.2 0.4 0.6 0.8 1 1.2 1.4 Any DM related End point DM related death All-cause mortality Myocardial Infraction End point (SU/Insulin) 0 0.5 1 1.5 2 2.5 Stroke Peripheral vascular disease Microvascular disease End point (Metformin) Lancet 1998; 352: 854–65
  30. 30. Metformin 使用限制  GI upset (20-30%)  Chronic Heart Failure  Creatinine > 1.5 mg/dL in males & >1.4mg/dL in females  Radiologic Contrast study for 48 hr after
  31. 31. Metformin treatment is associated with a low risk of mortality in diabetic patients with heart failure: a retrospective nationwide cohort study  10,920 hospitalised for first time HF with DM  Observational time:2.5 years Diabetologia (2010) 53:2546–2553
  32. 32. Creatinine ??  Metformin Maxium dose:3000 mg  eGFR > 30 mL/min per 1.73 m2  Metformin  eGFR > 60:Safe  eGFR 60-45:Increase Creatinine monitor frequence  eGFR 45-30:Half dose initially  eGFR < 30:Stop Metformin Diabetes Care 2011; 34: 1431-7. • ADA • EASD • NICE • Diabetes Australia • CDA • JDS • NKF KDOQI
  33. 33. Sulfonylurea  Association of sulfonylurea treatment with all-cause and cardiovascular mortality:A systematic review and meta-analysis of observational studies  20 studies (n = 551,912 patients)  SU vs non-SU Sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1479164112465442
  34. 34. Sulfonylurea  Retrospective nationwide cohort study  Danmark  1997-2006  9876 users of GLDs admitted with MI Cardiovascular Diabetology 2010, 9:54
  35. 35. European Heart Journal (2011) 32, 1900–1908
  36. 36. Data From the CPRD  New analysis reported at the EASD meeting,  UK Clinical Practice Research Datalink (CPRD)  More than 10 million patients  SU vs Metformin (Monotherapy) European Association for the Study of Diabetes. Abstracts 200 and 201, presented Thursday, September 26, 2013. All-cause mortality 1000 person-years Metformin 13.6 death Sulfonylurea 44.6 death
  37. 37. Sulfonylurea receptor  Sulfonylurea Receptor-1  Sulfonylurea Receptor-2A J Am Coll Cardiol. 1998;31(5)950-956
  38. 38. Acarbose  STOP-NIDDM  Acarbose vs. Placebo  IGT patient HR = 0.51(0.28-0.95) p=0.03 JAMA 2003; 290:486-494
  39. 39. Alpha-glucosidase inhibitors for type 2 diabetes mellitus  It remains unclear whether alpha-glucosidase inhibitors influence mortality or morbidity in patients with type 2 diabetes.  Conversely, they have a significant effect on glycemic control and insulin levels. DOI: 10.1002/14651858.CD003639.pub2
  40. 40. Ace study  Multicentre, RCT  China & Hong Kong  7500 patients with CVD or IGT  Hu Dayi (Cardiology)  Pan Changyu (Endocrine)
  41. 41. Thiazolidinedione  IGT Prevent to T2DM  Mono-therapy failure in T2DM  Pioglitazone  Rosiglitazone:DREAM, ADOPT, RECORD  Pioglitazone:PROACTIVE
  42. 42. Rosiglitazone (DREAM)  The DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial  Prevent IGT progress to Type 2 DM  5269 IFT or IGT patient HR = 0.40 (0.35-0.46) Increase BW = +2.2 kg (p<0.0001) The Lancet 2006 DOI:10.1016/S0140-6736(06)69420-8
  43. 43. Rosiglitazone (ADOPT)  4360 patients Newly type 2 DM  Rosiglitazone, Metformin, Glyburide Edema:14.1% vs 7.2% vs 8.5% N Engl J Med 2006;355:2427-43.
  44. 44. Dr. Steven Nissen
  45. 45. Meta-Analysis of Rosiglitazone N Engl J Med 2007;356:2457-71.
  46. 46. JAMA. 2007;298(10):1189-1195 Meta-Analysis of Rosiglitazone
  47. 47. RECORD study N Engl J Med 2007;357:28-38.
  48. 48. Pioglitazone (PROACTIVE)  PROspective pioglitAzone Clinical Trial In macroVascular Events  5238 patients with type 2 diabetes  primary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Lancet 2005; 366: 1279–89
  49. 49. Pioglitazone and Risk of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus A Meta-analysis of Randomized Trials JAMA. 2007;298(10):1180-1188
  50. 50. Bladder Cancer of Pioglitazone News of 103.04.08
  51. 51. Bladder Cancer of Pioglitazone Diabetes Care 34:916–922, 2011
  52. 52. Bladder Cancer of Pioglitazone  Retrospective cohort study (Case-control analysis)  115,727 new users of oral hypoglycaemic agents BMJ 2012;344:e3645
  53. 53. Bladder Cancer of Pioglitazone Study of Taiwanese  2006 - 2009  1,000,000 individuals were randomly sampled from the National Health Insurance database Diabetes Care 35:278–280, 2012
  54. 54. Aleglitazar (PPAR α/γ Agonist) Late Breaking Clinical Trials – ACC 2014 Unpublished DATA
  55. 55. SAVOR TIMI-53 N Engl J Med 2013;369:1317-26.
  56. 56. EXAMINE N Engl J Med 2013;369:1327-35. Sattar N, Results from SAVOR and EXAMINE. DPP-4 inhibitors and CVD, EASD 2013 Sep 26
  57. 57. Why we failure in DPP-4 inhibitor?? N Engl J Med 2013;369:1317-26. N Engl J Med 2013;369:1327-35.
  58. 58. CV outcome trials of DPP-4 inhibitor & GLP-1 agonist Trial Name Drug Number of patients Publish date SAVOR Saxagliptin 16500 Online 2013/09 EXAMINE Alogliptin 5400 Online 2013/09 TECOS Sitagliptin 14500 2014 CAROLINA Linagliptin (vs SU) 6000 2018 EXSCEL Exenatide QW 9500 2018 LEADER Liraglutide 8754 2017
  59. 59. CV outcome trials of SGLT-2 inhibitor Trial Name Drug Number of patients Publish date CANVAS Canagliflozin Ongoing DECLARE TIMI 58 Dapagliflozin Ongoing
  60. 60. Summary  Half of T2DM patient died from Cardiovascular Events  DM patient’s MI risk was equal to post-MI patient  UKPDS 35 shows that HbA1c was a risk marker in T2DM  Intensive glucose control  Lowering Macrovascular outcomes  Longer follow up & Meta – Analysis  Lowering Microvascular outcomes  Early intervention  Risk maker relationship:BP > LDL > HbA1c
  61. 61. Summary  Hypoglycemia was main reason of emergency Hospitalizated Adverse Drug event  Hypoglycemia link to poor CV outcomes in cohort studies, arrhythmia may be a main concern  Metformin is still First line choice of T2DM  eGFR may be better to limit Metformin use  Sulfonylurea increased risk of CV mortality & All-cause mortality (not included Gliclazide )  Acarbose remains unclear in T2DM, but could reduce CV risk in IGT or IFG patients
  62. 62. Summary  TZD may prevented that IGT or IFG progress to T2DM, but increased HF risk  Rosiglitazone increased MI risk in Meta-analysis, but Pioglitazone didn’t  Bladder cancer may be a concern of Pioglitazone, but didn’t show in TW data  DPP-4 inhibitor was safe in CV outcomes, but not in HF hospitalization  Expect GLP-1 Agnoist & SGLT-2 Inhibitor

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