1. LIPID LOWERING IN T2D (The Lower the Better?) CONS… TARGETING HARD CVD END POINTS Charles SAAB MD Consultant Endocrinologist DCRP Sacre-Coeur University Hospital-Lebanon MGSD-CASABLANCA April 2011

2. WHAT IS THE BEST WAY TO AVOID INJURIES IF A CAR ACCIDENT OCCURES???

3. BEST IS NOT TO LET ACCIDENTS HAPPENS AVOID INJURIES

4. "The growth of knowledge depends entirely on disagreement“ Karl R. Popper (28 juillet 1902 à Vienne, Autriche - 17 septembre 1994 à Londres

5. DIABETES AND STATIN TTT IS IT FOR ALL?? DIABETES AND STATIN TTT IS IT FOR ALL?? YES THE EARLIER THE BETTER INDEPENDENTLY OF LDL LEVELS

6. 24% SE 2.6 reduction (P<0.00001) BaselineSTATINPLACEBORisk ratio and 95% CI feature(10269)(10267)STATIN betterSTATIN worse Het=0.8 c 2 3 0.40.60.81.01.21.4 LDL (mg/dL) <100285360 100 < 130670881 10871365  130 ALL PATIENTS20422606 (19.9%)(25.4%) Simvastatin: Vascular Event by LDL Heart Protection Study: Lancet 2002

7. IS CVD ONLY AN LDL MATTER??

8. 1.00 0.99 0.98 0.97 0.96 0 0246802468 Years of follow-up Low CRP-low LDL Low CRP-high LDL High CRP-low LDL High CRP-high LDL Ridker et al. N Engl J Med 2002;347:1157–65 Probability of event-free survival Median LDL 124 mg/dL Median CRP 1.5 mg/L CV Event-free Survival Using Combined CRP and LDL-C Measurements

9. IDEAL The Incremental decrease in Endpoints through Aggressive Lipid Lowering Trial

10. IDEAL Study: Effect of Treatment on LDL-C Mean LDL-C = 104 mg/dL Adapted from Pedersen TR et al. JAMA. 2005;294:2437-2445. 0 70 80 90 100 110 120 130 BaselineWeek 12Year 1Year 2Year 3Year 4Year 5 LDL-C (mg/dL) Atorvastatin 80mg Simvastatin 20mg Mean LDL-C = 81 mg/dL 99.8 mg/dl 80 mg/dl 102 mg/dl 79.1 mg/dl

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12. Barter PJ et al. J Am Coll Cardiol 2006;47:492 – 499. | Waters DD et al. J Am Coll Cardiol 2006;48:1793 – 1799. Major Cardiovascular Events According to On-treatment HDL-C: Treating to New Targets (TNT) Trial % Atorvastatin 10 mg Atorvastatin 80 mg Mean LDL-C 73 mg/dL Mean LDL-C 99 mg/dL On-treatment HDL-C (mg/dL) <40 >40-50 >50-60>60 >50-60

13. Major coronary events 50 40 30 20 10 0 0.5 (19) 1.0 (38) 1.5 (58) 2.0 (77) -10 Major vascular events Reduction in LDL-C mmol/L (mg/dL) 50 40 30 20 10 -10 0 0.5 (19) 1.0 (38) 1.5 (58) 2.0 (77) Reduction in LDL-C mmol/L (mg/dL) Proportional reduction in event rate (%SE) CTT Collaborators. Lancet 2005;366:1267–1278. Relationship Between Proportional Reduction in Events and Mean LDL-C Reduction at 1 Year 90056 PATIENTS

14. a = Statin trials. Adapted from Robinson JG, et al. J Am Coll Cardiol. 2005;46(10):1855– 1862. Nonfatal MI and CHD Death Relative Risk Reduction, % –20 100 80 60 40 20 0 LDL-C Reduction, % 253015354020 London Oslo MRC Los Angeles Upjohn LRC NHLBI POSCH 4S a WOSCOPS a CARE a LIPID a AF/TexCaps a HPS a ALERT a PROSPER a ASCOT-LLA a CARDS a Correlation Between LDL-C Lowering and Decreased CHD Risk According to Treatment Modality in a Meta-Regression Analysis National heart lung blood institute

15. Goals for Management of LDL in Patients With Diabetes Guidelines LDL-C Goal Diabetes With CVD a Diabetes Without CVD ESC/EASD 2007 <70 mg/dL (<1.8 mmol/L) <97 mg/dL (<2.5 mmol/L) ADA/AHA/AC C 2007 <70 mg/dL (<1.8 mmol/L) <100 mg/dL (<2.6 mmol/L) JBS2 2005 <77 mg/dL b (<2.0 mmol/L) <77 mg/dL b (<2.0 mmol/L) NCEP ATP III 2004 <70 mg/dL (<1.8 mmol/L) <100 mg/dL (<2.6 mmol/L)

17. TT CT/CCCTCCp-value * n34221921111 chd present81717010.033 BMI (kg/m²)22.1±1.522.9±1.322.9±1.123.1±1.10.023 Cholesterol (mg/dl)270.5±51.2266.2±89.4266.4±93.2262±64.5ns LDL183±46.8189±54.8194±53.9174.6±62.5ns HDL65.5±20.653.5±1654±1658.2±17.80.004 VLDL22±13.223±8.823.4±8.819.2±4.8ns Triglycerides (mg/dl) 112±115.4118±181.6118.9±84.596.4±23.8ns Apo B (mg/dl)100±22.6103.3±21.1103±11.1111.5±9.8ns Apo A1 (mg/dl)159±26.8161±24.3161.1±13.3159±22.1ns Lp(a) (mg/dl)6±4.212±14.112.1±8.810.7±3.4ns ROLE OF GENOTYPE IN CHD Link E, et al, for the SEARCH Collaborative Group. N Engl J Med 2008;359:789–799. Copyright © 2008 Massachusetts Medical Society. All rights reserved.

18. Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Cumulative No. and Percentages with Myopathy Year 1Year 5 Genotype Population Frequencyno.% Attributable to genotype no. % of totalno.% Attributable to genotype no. % of total TT0.730120.3400210.6300 CT0.249171.3812.875322.8324.978 CC0.0211615.2515.6981918.5518.497 All genotypes1.000450.9128.463721.5643.360 Cumulative Percentage of Patients Who Have Had a Myopathy 0123456 Years since Starting 80 mg of Simvastatin CC genotype CT genotype TT genotype Link E, et al, for the SEARCH Collaborative Group. N Engl J Med 2008;359:789–799. Copyright © 2008 Massachusetts Medical Society. All rights reserved.

19. Slide Source Lipids Online Slide Library www.lipidsonline.org SMOKER EATER NO SPORT HTN OBESE MULTIPLE STROKES STATIN= 0..DEATH AT WHAT AGE? DEATH = 91 YO NO SMOKING !!!!!! LEAN JOGGING EVERY DAY HTN=0 NO CVD NO DIABETES FIRST MI AT WHAT AGE??? FIRST MI = 50 YO 1874-1965

20. Slide Source: Lipids Online Slide Library www.lipidsonline.org WHAT ELSE?? IN T2D LIPID PROFIL???? CONTROVERSIES IN ACCORD (study) BP/?? GLUCOSE/?? LIPIDS/?? – HDL SHOULD BE INCREASED? – TG SHOULD BE DECREASED?

21. Baseline lipids – mg/dL Simvastatin + Fenofibrate (n=2,765) Simvastatin (n=2,753) Overall (n=5,518) Mean total cholesterol174.7175.7175.2 Mean LDL-C100.0101.1100.6 Mean HDL-C38.038.238.1 Median TG164160162 Baseline Characteristics – Lipids ACCORD Study Group. N Engl J Med March 14, 2010. Epub. ACCORD Lipid

22. Results Results LDL-C target levels were achieved in both groups ACCORD Lipid ACCORD Study Group. N Engl J Med March 14, 2010. Epub. 01234567 No. of Patients Fenofibrate Placebo Mean LDL Cholesterol (mg/dL) Years LDL-C 2747 2735 2593 2591 2505 2484 2417 2375 2361 2364 1477 1480 796 801 248 243 0 60 80 100 120 Placebo Fenofibrate Lipid levels at study close Simvastatin + Fenofibrate (n=2,765) Simvastatin (n=2,753) p value Mean LDL-C (mg/dL)81.180.0p=0.16

23. RESULTS RESULTS There was a significant improvement in TG and HDL-C in the combination group ACCORD Lipid ACCORD Study Group. N Engl J Med March 14, 2010. Epub. 01234567 No. of Patients Fenofibrate Placebo Mean HDL Cholesterol (mg/dL) Years HDL-C 2747 2735 2593 2591 2505 2484 2417 2375 2361 2364 1477 1480 796 801 248 243 0 37 38 39 40 41 42 43 Placebo Fenofibrate 01234567 No. of Patients Fenofibrate Placebo Median Triglycerides (mg/dL) Years Triglycerides 2747 2735 2593 2591 2505 2484 2417 2375 2361 2364 1478 1480 796 801 248 243 0 100 120 140 160 Placebo Fenofibrate Lipid levels at study close Simvastatin + Fenofibrate (n=2,765) Simvastatin (n=2,753) p value Mean HDL-C (mg/dL)41.240.5p=0.01 Median triglycerides (mg/dL) 122.0144.0p=0.001

24. RESULTS Primary endpoint Major CV events (overall population) ACCORD Study Group. N Engl J Med March 14, 2010. Epub. ACCORD Lipid 0 20 40 60 80 100 Proportion with Event (%) 012345678 2765 2753 2644 2634 2565 2528 2485 2442 1981 1979 1160 1161 412 395 249 245 137 131 No. At Risk Fenofibrate Placebo Years 0.92 (95% CI 0.79-1.08), p=0.32 0 10 20 012345678 Placebo Fenofibrate Major CV events defined as CV death, nonfatal MI and nonfatal stroke

25. MY TAILOR IS RICH LIPID LOWERING SHOULD TARGET EACH T2D PATIENT RISK THE EARLIEST AND NOT TO THE LOWEST