1. Plasma Lipids at diagnosis of Type 2 Diabetes UKPDS study group, Diabetes Care 1997; 20: 1683-1687 1.4 (55)1.1 (43) 1.0 (39)HDL-C mmol/l (mg/dl) 1.8 (159) 3.9 (151) 5.8 (224) 1574 Type 2 WOMEN 1.2 (103) 3.4 (132) 5.3 (205) 52 Control 1.1 (95) 3.5 (135) 5.6 (217) 143 Control 1.8 (159) 3.6 (139) 5.5 (213) 2139 Type 2 MEN TG mmol/l (mg/dl) LDL-C mmol/l (mg/dl) TC mmol/l (mg/dl) N UKPDS

2. MRFIT: DM type 2 and cardiovascular mortality Stamler J et al. Diabetes Care 16(2): 434 - 444, 1993 0 20 40 60 80 100 120 140 160 < 4.7 4.7-5.15.2-5.75.8-6.26.3-6.76.8-7.2³ 7.3 mmol/L CV mortality per 10.000 person years Diabetes No diabetes total cholesterol

3. Diabetes LDL particles ‘Normal’ LDL-cholesterol however: ‘Normal’ LDL-cholesterol No Diabetes LDL particles LDL-apo B LDL-apo B/CE LDL-CE/TG LowCHD risk High Diabetes and Dyslipidemia LDL- size and diabetes M. Austin JAMA 1988; 269: 1916

4. LDL diameter vs plasma TG R= -0.88 23 24 25 26 27 28 012345 6 Plasma TG (mmol/L) LDL diameter (nm) Scheffer et al; Clin Chem 1997;43:1904-12

5. Austin M et al. Circulation. 1990;82:495-506. Phenotype A Phenotype B 10 20 30 40 50 60 70 80 90 100 % Cumulative frequency 0 20406080100120140160180200220240260280300500 TG (mg/dL) Cumulative Distribution of Adjusted Plasma TG Levels: LDL Phenotypes A and B

7. The Consequences of Increased Triglyceride Concentrations Coagulation  factor VII activity  factor X activity  PAI-1 concentration  platelet aggregation Lipids  “small dense LDL”  Chylomicron remnants  VLDL remnants  HDL-cholesterol

8. Atherosclerosis “The Overall Picture”

9. Clinical Trials of Lipid Therapy in Diabetic Subjects (subgroup analysis) Haffner Diabetes Care; 1: 1998 StudyjournalNLDL-CBaselineCHD loweringLDL-Creduction Primary prevention Helsinki HSDiabetes135-6 %4,9 mmol/l-60 % (ns) Care 1992191 mg/dl AFCAPS/TEXCAPSJAMA 1998264-25%3.9 mmol/l-43 % (ns) 150 mg/dl Secondary prevention CARENEJM 1996586-28 %3,5 mmol/l-25 % (p=0.05) 137 mg/dl 4SDiabetes202-36 %4,8 mmol/l-55 % (p=0.002) Care 1997186 mg/dl

10. Risk Reduction 4 S trial Estimated CHD reduction after treating 100 CHD patients for 6 years Expected fatal and non fatal Ml’s Number of prevened Fatal and non fatal MI’s patients with diabetes patients without diabetes 49 29 24 9 Pyörälä K et al. Diabetes Care 20(4): 614 - 620, 1997

11. Post-CABG: Effect of Aggressive Lipid Lowering on a Subgroup of Patients With Diabetes

12. Management Of Lipids in Patients with Diabetes Mellitus Type 2

13. Clear Instructions to Our Patients

14. Risk Factor Management General Rules Risk factor assessment Setting goals for therapy –Primary prevention –Secondary prevention Specific modalities of therapy based on impact and practicality –Lipid management –Asperin use –Blood pressure control –Smoking cessation –Glycemic control –Weight management

15. Suggested Risk Factor Target Levels RISK FACTORGOAL Blood pressure130/80 mm Hg HbA1c<7.5% BMI<25kg/m 2 Waist circumference males<98 cm females<88 cm Urinary albumin excretion<30 mg/day

16. Lipid Management Glycaemic Control Glucose lowering in untreated diabetics will improve the lipidprofile Better glycaemic control, independent of mode of therapy, further improves the lipidprofile Unfortunately target lipid levels are not achieved with good glycaemic control in most patients

17. Lipid Targets for Patients with Type 2 Diabetes Mellitus Haffner SM. Management of dyslipidemia in adults withdiabetes [American Diabetes Association position state-ment].Diabetes Care. 1998;21:160-178. Garg A. Treatment of diabetic dyslipidemia. Am JCardiol. 1998;81(4A):47B-51B. Target (mg/dl) Plasma LipidAcceptableIdeal Triglycerides200150 Total cholesterol200170 LDL-cholesterol130100 Non-HDL-cholesterol160130 HDL-cholesterol3545

18. ASAP Study Design 2 years Simvastatin 40 mg 326 patients Atorvastatin 80 mg FH LDL-C >212 mg/dL TG <400 mg/dL Patient population B-mode US Patients are initiated on atorvastatin 40 mg or simvastatin 20 mg. Doses are doubled at Week 4 Primary efficacy parameter: Change in carotid and femoral IMT B-mode US

19. Baseline Lipid Profile Atorvastatin mmol/l mg/dl TC9.99 386 TG1.86 165 HDL-C1.17 45 LDL-C8.00 309 Simvastatin mmol/lmg/dl 10.27 396 1.85 164 1.16 45 8.33 322

20. Cholesterol lowering (n=325) Atorvastatin (80 mg) TC- 42%5.73 mmol/l 221 mg/dl TG- 29%1.23 mmol/l 109 mg/dl HDL +13%1.32 mmol/l »mg/dl LDL- 51%3.88 mmol/l 150 mg/dl Simvastatin (40 mg) - 34%6.71 mmol/l 259 mg/dl -17 %1.41 mmo/l 125 mg/dl + 13 %1.30 mmol/l 50 mg/dl - 41 %4.81 mmol/l 186 mg/dl

21. Change in IMT after 1 and 2 years

22. % patients with progression Atorvastatin Progression female35.1 % male 31.8 % Regression female64.9 % male68.2 % Simvastatin Progression female57.4 % male58.1 % Regression female42.5 % male41.9 %

23. Priorities for Treatment Strategies of Diabetic Dyslipidemia LDL-cholesterol lowering Triglyceride lowering HDL-cholesterol raising Other approaches –Non-HDL cholesterol –Apo B –Remnants

24. Future Directions Ongoing Trials with Lipid Lowering Focus HPSSimvastatin CARDSAtorvastatin ASPENAtorvastatin LDS Cerivastatin / Fenofibrate DAISFenofibrate FIELDFenofibrate

25. Walking Compared With Vigorous Physical Activity and Risk of Type 2 Diabetes in Women A Prospective Study Frank B. Hu, MD, PhD, Donald J. Sigal, MD; Janet W. Rich-Edwards, ScD; Graham A. Colditz, MD, DrPH; Caren G. Solomon, MD, MPH; Walter C. Willett, MD, DrPH; Frank E. Speizer, MD; JoAnn E. Manson, MD, DrPH JAMA, October 20, 1999—Vol 282, No. 15, 1433

26. Walking Compared With Vigorous physical Activity and Risk of type 2 Diabetes in Women

27. JAMA, October 20, 1999—Vol 282, No. 15, 1433 Walking Compared With Vigorous physical Activity and Risk of type 2 Diabetes in Women

28. Summary Diabetes and Lipids – (patho)physiology Diabetes and cardiovascular complications –Women! Glycemic control and risk reduction Small dense LDL-particles Completed statin trials Management of lipids in diabetics

29. Unexpected Dangers Diabetes & Lipids