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Dyslipidemia in Patients with T2DM

Dyslipidemia in Patients with T2DM. 林樹福醫師 新陳代謝科 內科部 Grand Round Oct. 21, 2011. Conclusions. 糖尿病常併發心血管疾病 糖尿病常伴有血脂異常 Statin 有效降低 LDL 並顯著減少糖尿病人心血管疾病發生及死亡 生活型態改變，積極控制血壓及血糖也可以減少糖尿病併發症及死亡. Case Presentation.

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Dyslipidemia in Patients with T2DM

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  1. Dyslipidemia in Patients with T2DM 林樹福醫師 新陳代謝科 內科部 Grand Round Oct. 21, 2011

  2. Conclusions • 糖尿病常併發心血管疾病 • 糖尿病常伴有血脂異常 • Statin有效降低 LDL 並顯著減少糖尿病人心血管疾病發生及死亡 • 生活型態改變，積極控制血壓及血糖也可以減少糖尿病併發症及死亡

  3. Case Presentation A 44 year-old male presented with weight loss 10 kg (85→75 kg) in recent 3 months and polydipsia for 1 month

  4. Case Presentation A 44 year-old male presented with weight loss 10 kg (85→75 kg) in recent 3 months and polydipsia for 1 month • BH: 171 cm • Weight: 85 kg (發病前) • BMI: 29 (發病前) • BP: 139/91 mm-Hg • A smoker (1 pack/day for 20 yrs) • No family history of cardiovascular disease

  5. Case Presentation A 44 year-old male presented with weight loss 10 kg (85→75 kg) in recent 3 months and polydipsia for 1 month • BH: 171 cm • Weight: 85 kg (發病前) • BMI: 29 (發病前) • BP: 139/91 mm-Hg • A smoker (1 pack/day for 20 yrs) • No family history of cardiovascular disease

  6. Increasing Prevalence of T2DM in Taiwan 約140萬人 林口長庚醫院照顧約3.3萬名糖尿病人其中約65%由新陳代謝科治療 (門診 2010) Adapted from Chang CH et al. Diabet Med 2010, 27, 636-643

  7. 2010年國人十大死因 26.4% 死於心血管疾病

  8. A Higher Prevalence of Macrovascular Disease in Diabetic Patients in Taiwan Chang C. Diabetes Res Clin Pract. 2000;50 Suppl 2:S49-59

  9. Causes of Mortality in DM Most died of CVD Diabetes Care 1998;21:1138-45.

  10. 第2型糖尿病人發生心血管事件的風險 Modifiedfrom Stratton IM, et al. BMJ 321;405-412,2000 資料來源:中華民國糖尿病學會

  11. 及早、積極、持續控制血糖可以減低心血管事件,但是…及早、積極、持續控制血糖可以減低心血管事件,但是… DCCT Study Research Group. N Engl J Med 1993;329:977-986 DCCT/EDIC Study Research Group. N Engl J Med 2005;353:2643-53 Chiasson et al. JAMA. 2003;290:486-494 UKPDS Group. Lancet 1998; 352: 837–53 The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-59 The ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-72 Duckworth et al. N Engl J Med 2009;360:129-39 中華民國糖尿病學會

  12. Factors Contributing to Cardiometabolic Risk 1 2 3 4 6 5 Diabetes Care 2008;31:811–822

  13. Factors Contributing to Cardiometabolic Risk 1 2 3 4 6 5 Diabetes Care 2008;31:811–822

  14. The Features of Diabetic Dyslipidemia • High triglyceride • Low HDL (but increased concentration of small dense HDL) • Increased concentration of small dense LDL particles Nat Clin Pract Endocrinol Metab 2009;5:150-9.

  15. The Metabolic Scheme for Delipidation Cascade of TRL Particles Derived from Liver (VLDL) and Intestine (chylomicrons) (Triglyceride Rich Lipoproteins) Taskinen MR. Diabetologia (2003) 46:733–749

  16. Proposed Mechanisms Behind the Generation of Small Dense LDL and Small Dense HDL in T2DM Taskinen MR. Diabetologia (2003) 46:733–749

  17. The Patient’s Lipid Data Fenofibrate Metformin

  18. LDL-C and HDL-C are Risk Factors for Coronary Artery Disease in T2DM 131 (3.35) (49) (195) (117) (39) (176) LDL-C (mmol/l) HDL-C (mmol/l) 65 (1.7) • Increment of 39 mg/dl of LDL-C: 1.57-fold increased risk of coronary artery disease • Increment of 3.9 mg/dl of HDL-C: 0.15-fold decrease in risk UKPDS 23. BMJ 1998; 316: 823–28.

  19. So, How to ImproveLDL-C?

  20. Dr. Michael S. Brown Dr. Joseph L. Goldstein Nobel Prize Winners in 1985 Science1986;232:34-47 Nat Rev Drug Discov 2003;2:517-26

  21. History of Statins Lovastatin became available byprescription, first of the class Discovery of compectin 4S trial published Withdrawal of Cerivastatin Discovery of Lovastatin Nat Rev Drug Discov. 2003;2:517-26

  22. 4S (Scandinavian Simvastatin Survival Study)(The Pioneer Trial) Lancet 1994;344:1383-1389 Nat Rev Drug Discov 2003;2:517-26

  23. The Lower LDL-C, The Better Preventive Effect of Statin Therapy 30 4S Statin Placebo 25 20 4S Mean LDL levels 4S: ~190 mg/dl LIPID: ~150 mg/dl CARE: ~140 mg/dl HPS:~130 mg/dl TNT: ~100 mg/dl LIPIDStudy LIPIDStudy Events (%) 15 CAREStudy HPSStudy CAREStudy HPSStudy 10 TNT 5 TNT 0 70 0 90 110 130 150 170 190 210 LDL-C (mg/dl) Event rates for HPS, CARE, and LIPID are for death from CHD and nonfatal myocardial infarction. Event rates for 4S and the TNT Study also include resuscitation after cardiac arrest. N Engl J Med 2005;352:1425-35

  24. Statin vs Placebo on Major Vascular Event (n=170,000) Non-fatal MI CHD death Any coronary event Ischemic stroke Hemorrhagic stroke Unknown stroke Any stroke Any major vascular event Lancet 2010; 376: 1670–81

  25. More or Less Statin Therapy on Major Vascular Event (n=170,000) Non-fatal MI CHD death Any coronary event Ischemic stroke Hemorrhagic stroke Unknown stroke Any stroke Any major vascular events Lancet 2010; 376: 1670–81

  26. 降低膽固醇可減少糖尿病患發生心血管疾病的風險(coronary heart disease death/non-fatal MI)(n= 16,032; 10-year risk ) Primary prevention Secondary prevention 4S-DM HPS-DM ASPEN 20 CARDS ASPEN 10 TNT-DM HPS-DM CARE-DM Modified from DIABETES CARE 2010,33, SUPPLEMENT 1, S11-S61

  27. Statin Reduced All Cause Mortality, Including DM(per 39 mg/dl, n = 18,686. 4.3-year risk,14 randomized trials) (P<0.0001) Lancet 2008; 371: 117–25

  28. Predictors of Statin Efficacy (n=170,000) (1) DBP (mm-Hg) Gender Age (yrs) SBP (mm-Hg) Prior vascular disease DM Lancet 2010; 376: 1670–81

  29. Predictors of Statin Efficacy (n=170,000) (2) BMI Smoking eGFR (ml/min/1.73 m2) HDL (mg/dl) Lancet 2010; 376: 1670–81

  30. LDL-C is not a Predictor of Statin’s Efficacy, Too (n=170,000) (LDL-C, mg/dl) Lancet 2010; 376: 1670–81

  31. How About Triglyceride?

  32. Cardiovascular Outcomes in Fibrate Trials Allison B. Goldfine et al. N Engl J Med 2011;365;481-484

  33. Is Statin Plus Fibrate Better Than Statin Alone? (ACCORD Study) • Evaluate cardiovascular risk reduction by simvastatin + fenofibrate in T2DM • Anegativestudyoverall • A benefit for men and possible harm for women(p=0.01) • Elevated triglycerides (TG, 204 mg/dl or higher) + Low levels of HDL-C (34 mg/dl or lower)(p=0.06) N Engl J Med 2010;362:1563-74 Allison B. Goldfine et al. N Engl J Med 2011;365;481-484

  34. Relative LDL-Lowering Efficacy of Statin and Statin-Based Therapies aNo incremental benefit of Vytorin on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established. Data from US Food and Drug Administration. June 8, 2011. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm[4]

  35. Safety of Intensive Statin Therapy Modified from Lancet 2007; 370: 1781–90

  36. Metabolism of Statin Modified from Lancet 2007; 370: 1781–90

  37. Drugs that Might Interact with Statins • Cyclosporin • Fibrates • Gemfibrozil, bezafibrate, fenofibrate, and ciprofibrate • Azol anti-fungals • Itraconazole, ketoconazole, and miconazole • Macrolide antibiotics • Erythromycin, telithromycin, and clarithromycin • Anti-arrhthymics • Verapamil, amiodarone • Nefazodone • Protease inhibitors • Amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, nelfi navir, ritonavir, and tipranavir Lancet 2007; 370: 1781–90

  38. Statin to Prevent Vascular Events in Low-Risk Individuals with Elevated CRP (JUPITOR Study) n = 17,802 LDL < 130 mg/dl CRP > 2 mg/dl Placebo vs. Rosuvastatin 20 mg/day N Engl J Med 2008;359:2195-207

  39. Statin to Prevent Vascular Events in ESRD N Engl J Med 2005;353:238-48 N Engl J Med 2009;360:1395-407

  40. EffectofLDL-lowering Therapy in Patients with Chronic Kidney Disease Non-fatalhemorrhagicstroke Non-fatalMI Vasculardeath Coronaryrevascularisation Non-fatalnon-hemorrhagicstroke ModifiedfromColin Baigentetal.Lancet 2011; 377: 2181–92

  41. Statin Dosages in Chronic Kidney Disease Adapted from Clin J Am Soc Nephrol 2011;6:664–678

  42. Is This Good for Taiwanese?全民健康保險降血脂藥物給付規定表

  43. 我們該開立Statin給哪些病人? 30 4S Statin Placebo 25 20 4S LIPIDStudy LIPIDStudy Events (%) 15 CAREStudy HPSStudy CAREStudy HPSStudy 10 TNT 5 TNT 0 70 0 90 110 130 150 170 190 210 LDL-C (mg/dl) N Engl J Med 2005;352:1425-35

  44. LDL的正常值是多少?(Range of LDL Levels in “normal” Adults in Western Industrial Societies) Science1986;232:34-47

  45. Diabetic Patients Who Are F-U at A Clinic (n=86) • Age: 59 ± 13 yrs (30-84) • Sex: M/F = 37/49 • DM duration: 5.0 ± 5.6 yrs (0-21) • AC glucose: 149.6 ± 52.8 mg/dl (67-366) • A1C: 8.4 ± 2.2% (5.6–16.5) • Lipid • TC: 209.4 ± 50.5 mg/dl (105–409) • LDL: 132.2 ± 43.1 mg/dl (17–277) • HDL: 45.8 ±12.0 mg/dl (21–80) • TG: 205.3 ± 219.1 mg/dl (41–1557)

  46. Baseline Cholesterol • TC: 209.4 ± 50.5 mg/dl (105 – 409) • LDL: 132.2 ± 43.1 mg/dl (17 – 277) • HDL: 45.8 ±12.0 mg/dl (21 – 80) Chol > 200 = 53% LDL > 130 = 53.1% (LDL > 100 = 80%)

  47. Baseline Triglyceride (TG) • TG > 500 = 6% • TG/HDL > 5 or TG > 200 and HDL <40 = 21.8 % • TG: 205.3 ± 219.1 mg/dl (41 – 1557)

  48. Treatment Strategies for Lipid (n=86) • Therapeutic lifestyle modification = 48 (55.8%) • Rosuvastatin = 32 (37.2%) • Atorvastatin = 3 (3.5%) • Simvastatin = 1 (1.2%) • Fenofibrate = 2 (2.3%)

  49. Therapeutic Effects of Statins (n=36) 38%

  50. The Potential Benefit to Reduce CV Events Primary prevention Secondary prevention 4S-DM HPS-DM ASPEN 20 CARDS ASPEN 10 TNT-DM HPS-DM CARE-DM 38%

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