1. Lipids: Is Lower Better For Diabetic Patients? Prof. Samir Helmy Assaad -Khalil Department of Internal Medicine Unit of Diabetes, Lipidology & Metabolism Alexandria University, Alexandria, Egypt MGSD Morocco; Friday, April 29, 2011

2. Agenda  Epidemiological data  EBM derived from clinical trials  Evidence in patients with T2DM  What is Desirable Cholesterol?

3. Elevated Cholesterol Is a Risk Factor for Cardiovascular Disease (CVD) Elevated serum cholesterol is associated with increased risk of 1–3  CHD  Reinfarction  CVD mortality 4 All-cause CHD Stroke CHD=coronary heart disease; MRFIT=Multiple Risk Factor Intervention Trial. 1. Kannel WB. Am J Cardiol. 1995;76:69C–77C; 2. Anderson KM et al. JAMA. 1987;257:2176–2180; 3. Kannel WB et al. Ann Intern Med. 1971;74:1–12; 4. Neaton JD et al. Arch Intern Med. 1992;152:1490–1500. 0 10 20 30 40 50 <160 (4.13) 160–199 (4.13–5.14) 200–239 (5.17–6.18)  240 (6.20) CVD Mortality Rate a MRFIT (N=350,977) 4 Serum Cholesterol, mg/dL (mmol/L)

4. Correlation Between LDL-C & Cardiovascular Mortality: The Framingham Study 1 a Ns refer to person-years. 1. Wilson PWF et al. Circulation. 1998;97:1837–1847. <130 mg/dL (<3.4 mmol/L) (n=11,142 a )(n=10,384 a )(n=8,628 a )(n=15,835 a )(n=10,455 a )(n=11,767 a ) 7.3 2.3 0 5 10 15 20 Age Adjusted 10-Year Death Rates, % of Population Men Women 130–159 mg/dL (3.4–4.11 mmol/L) ≥160 mg/dL (≥4.14 mmol/L) 11.3 6.5 17.3 10.6

5. Log Linear Relationship Between LDL-C and Relative Risk of CHD 1 CHD=coronary heart disease. Log-linear relationship between LDL-C levels and relative risk of CHD. This relationship is consistent with a large body of epidemiologic data and with data available from clinical trials of LDL-lowering therapy. These data suggest that for every 30 mg/dL change in LDL-C, the relative risk of CHD is changed in proportion by about 30%. The relative risk is set at 1.0 for LDL-C=40 mg/dL. 1. Grundy SM et al. Circulation. 2004;110:227–239. Reprinted with permission ©2004, American Heart Association, Inc. Relative Risk of CHD, Log Scale 0 3.7 2.9 2.2 1.3 1.7 LDL-C, mg/dL (mmol/L) 40 (1.0) 100 (2.6) 130 (3.4) 160 (4.1) 190 (4.9) 70 (1.8) 1.0

6. Is Lower LDL-C Better? 1 CHD=coronary heart disease. 1. Grundy SM et al. Circulation. 2004;110:227–239. Reprinted with permission ©2004, American Heart Association, Inc. 1 3.7 2.9 2.2 1.3 1.7 Relative Risk of CHD, Log Scale –30 mg/dL –30% CHD risk 40 (1.0) 100 (2.6) 130 (3.4) 160 (4.1) 190 (4.9) 70 (1.8) LDL-C, mg/dL (mmol/L)

7. Correlation Between LDL-C Lowering & Decreased CHD Risk in Primary & Secondary Prevention Trials With Statins 1–3 Reproduced from Rosenson. (2004). 1 CHD=coronary heart disease; Atv=atorvastatin; Pra=pravastatin; Sim=simvastatin; PROVE-IT=Pravastatin or AtorVastatin Evaluation and Infection Therapy; IDEAL=Incremental Decrease in Endpoints through Aggressive Lipid Lowering; ASCOT=Anglo-Scandinavian Cardiac Outcomes Trial; AFCAPS=Air Force Coronary Atherosclerosis Prevention Study; 4S=Scandinavian Simvastatin Survival Study; CARE=Cholesterol And Recurrent Events Trial; HPS=Heart Protection Study; LIPID=Long-term Intervention with Pravastatin in Ischaemic Disease; TNT=Treating to New Targets: WOSCOPS=West of Scotland Coronary Prevention Study. 1. Rosenson RS. Expert Opin Emerg Drugs. 2004;9(2):269–279; 2. LaRosa JC et al. N Engl J Med. 2005;352(14):1425–1435; 3. Pedersen TR et al. JAMA. 2005;294(19):2437–2445. Event, % 0 30 25 20 15 10 5 Statin Placebo Mean Treatment LDL-C at Follow-up, mg/dL (mmol/L) 080 (2.1) 140 (3.6) 200 (5.2) 100 (2.6) 40 (1.0) 120 (3.1) 180 (4.7) 60 (1.6) 160 (4.1) 4S CARE HPS LIPID HPS CARE LIPID PROVE-IT (Atv) PROVE-IT (Pra) ASCOT AFCAPS ASCOT AFCAPS WOSCOPS Secondary Prevention Primary Prevention IDEAL (Atv) IDEAL (Sim) TNT (Atv 80 mg) TNT (Atv 10 mg) NCEP 2001 NCEP 2004

8. Correlation Between LDL-C Lowering & Decreased CHD Risk According to Treatment Modality in a Meta-Regression Analysis 1,a Reprinted from Journal of the American College of Cardiology, 46(10), Robinson JG, Smith B, Maheshwari N, et al, Pleiotropic effects of statins: benefits beyond cholesterol reduction? A meta-regression analysis, 1855–1862, Copyright © ( 2005), with permission from Elsevier. CHD=coronary heart disease; MI=myocardial infarction; MRC=Medical Research Council; LRC=Lipid Research Clinics; NHLBI=National Heart, Lung, and Blood Institute; POSCH=Program on the Surgical Control of the Hyperlipidemias; 4S=Scandinavian Simvastatin Survival Study; WOSCOPS=West of Scotland Coronary Prevention Study; CARE=Cholesterol And Recurrent Events Trial; LIPID=Long-term Intervention with Pravastatin in Ischaemic Disease; AF/TexCAPS=Air Force/Texas Coronary Atherosclerosis Prevention Study; HPS=Heart Protection Study; ALERT=Assessment of LEscol in Renal Transplantation; PROSPER=PROspective Study of Pravastatin in the Elderly at Risk; ASCOT-LLA=Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm; CARDS=Collaborative Atorvastatin Diabetes Study. a Analysis included 19 trials of high-risk primary prevention and secondary prevention (CHD, cardiovascular disease, renal transplant, diabetes) patients; b Statin trials. 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 b WOSCOPS b CARE b LIPID b AF/TexCaps b HPS b ALERT b PROSPER b ASCOT-LLA b CARDS b

9. Each LDL-C Reduction of 1 mmol/L (39 mg/dL) Reduced CHD Risk by Over 20% in a MetaAnalysis 1,a CHD=coronary heart disease. a Meta-analysis of 62 randomized, controlled clinical studies that included 216,616 patients with CHD (secondary prevention), without CHD (primary prevention), or with or without CHD. b Fatal or nonfatal myocardial infarction. 1. Gould AL et al. Clin Ther. 2007;29(5):778–794. Relative Risk Reduction, % –26.6 –28.0 –28.8 –27.5 –26.5 –25.5 0 CHD Events b CHD Mortality –26.0 –27.0 –28.0

10. Each LDL-C Reduction of 1 mmol/L (39 mg/dL) Reduced Major Coronary Events a by 23% in a Meta-Analysis b of Statin Trials 1 Each 1 mmol/L (39 mg/dL) reduction also reduced  All-cause mortality (P<0.0001)  CHD mortality (P<0.0001)  Nonvascular mortality (P=NS) CHD=coronary heart disease. a Major coronary event=nonfatal myocardial infarction or death due to CHD. b Meta-analysis of 14 trials of patients with CHD (47%), history of diabetes (21%), and history of hypertension (55%). c In the 14 trials analyzed, the control group was placebo in 11 trials, lower statin doses in 1 trial, no treatment in 1 trial, and usual care in 1 trial. 1. Cholesterol Treatment Trialists’ (CTT) Collaborators. Lancet. 2005;366:1267–1278. Pooled Statin Groups (n=45,054) Pooled Control c Groups (n=45,002) P<0.001 Statin vs Control 7.4 9.8 0 2 4 6 8 10 12 Patients With Major Coronary Events, %

11. Reducing LDL-C by 1 mmol/L Continued to Reduce IHD a Risk During Each Year of Treatment in a Meta Analysis 1,b IHD=ischemic heart disease. a IHD death and nonfatal myocardial infarction. b Meta-analysis of 58 trials. 1. Law MR et al. BMJ. 2003;326:1423–1427. Risk Reduction, % –11 –33 –40 –30 –20 –10 0 –24 –36 Year 1Year 2Years 3–5 Year 6 and After Years of Treatment

12. The 4S Diabetes Sub-study (n=202) P=0.087 P=0.002 P=0.018

13. The Role of Lipid-lowering Therapy in Preventing CHD in Patients with Type 2 Diabetes : A Meta-analysis D.G. Karalis. Clin. Cardiol. 31, 6, 2008: 241–248

14. The Role of Lipid-lowering Therapy in Preventing CHD in Patients with Type 2 Diabetes : A Meta-analysis (continued) D.G. Karalis. Clin. Cardiol. 31, 6, 2008: 241–248

15. An Ideal Level of LDL Cholesterol should be between 40-70 mg/dL What Is the Ideal Level of LDL Cholesterol

16. “Normal” Plasma Cholesterol 700 (18.0) 300 (7.7) 200 (5.2) 150 (3.9) 100 (2.6) 50 (1.3) 0 Plasma cholesterol level mg/dl (mmol/l) Physiologic level for plasma LDL-Cholesterol as predicted from receptor studies 25 mg/dl (0.65mmol/l) FH Homozygotes FH Heterozygotes Normal Adults Newborns Guinea pig Cow Rabbit Rat Sheep Camel Pig

17. What is Desirable Cholesterol?

18. Evolution of NHLBI Supported Guidelines

19. Intensive LDL-C Goals for High Risk Patients *And other forms of atherosclerotic disease. 2  Factors that place a patient at very high risk: established cardiovascular disease plus: multiple major risk factors (especially diabetes); severe and poorly controlled risk factors (e.g., cigarette smoking); metabolic syndrome (triglycerides ≥200 mg/dL + non – HDL-C ≥130 mg/dL with HDL-C <40 mg/dL); and acute coronary syndromes. 1 1. Grundy SM et al. Circulation 2004;110:227 – 239. 2. Smith SC Jr et al. Circulation 2006; 113:2363 – 2372. <100 mg/dL <70 mg/dL Recommended LDL-C treatment goals 2006Update If it is not possible to attain LDL-C 50% with more intensive LDL-C lowering therapy, including drug combinations. ATP III Update 2004 1 20%) 1 <70 mg/dL: Therapeutic option for very high risk patients 1 AHA/ACC guidelines for patients with CHD *,2 <100 mg/dL: Goal for all patients with CHD ,2 <70 mg/dL: A reasonable goal for all patients with CHD 2

20. -0.5 0 0.5 1 1.5 2 5060708090100110120 ASTEROID 3 rosuvastatin A-Plus 2 placebo ACTIVATE 1 placebo CAMELOT 4 placebo REVERSAL 5 pravastatin REVERSAL 5 atorvastatin Mean LDL-C (mg/dL) The relationship between mean LDL-C and change in percent atheroma volume (PAV) in IVUS studies† Change in Percent Atheroma Volume* (%) †ASTEROID and REVERSAL investigated active statin treatment; A-PLUS, ACTIVATE AND CAMELOT investigated non-statin therapies but included placebo arms who received background statin therapy (62%, 80% and 84% respectively). *Median change in PAV from ASTEROID and REVERSAL; LS mean change in PAV from A-PLUS, ACTIVATE AND CAMELOT 1 Nissen S et al. N Engl J Med 2006;354:1253-1263. 2 Tardif J et al. Circulation 2004;110:3372-3377. 3 Nissen S et al. JAMA 2006;295 (13):1556- 1565 4 Nissen S et al. JAMA 2004;292: 2217–2225. 5 Nissen S et al. JAMA 2004; 291:1071–1080 Progression Regression

21. Conclusion  Epidemiological data  Findings in other species  EBM derived from clinical trials  Evidence in patients with T2DM  Studies aiming at regression of atheroma volume All support the view of: “ The lower the better in the context of lipids in patients with diabetes”

22. Thank You!