Plasma Lipids at diagnosis of Type 2 Diabetes UKPDS study group, Diabetes Care 1997; 20: (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

MRFIT: DM type 2 and cardiovascular mortality Stamler J et al. Diabetes Care 16(2): , < ³ 7.3 mmol/L CV mortality per person years Diabetes No diabetes total cholesterol

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

LDL diameter vs plasma TG R= Plasma TG (mmol/L) LDL diameter (nm) Scheffer et al; Clin Chem 1997;43:

Austin M et al. Circulation. 1990;82: Phenotype A Phenotype B % Cumulative frequency TG (mg/dL) Cumulative Distribution of Adjusted Plasma TG Levels: LDL Phenotypes A and B

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

Atherosclerosis “The Overall Picture”

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 mg/dl AFCAPS/TEXCAPSJAMA %3.9 mmol/l-43 % (ns) 150 mg/dl Secondary prevention CARENEJM %3,5 mmol/l-25 % (p=0.05) 137 mg/dl 4SDiabetes %4,8 mmol/l-55 % (p=0.002) Care mg/dl

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 Pyörälä K et al. Diabetes Care 20(4): , 1997

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

Management Of Lipids in Patients with Diabetes Mellitus Type 2

Clear Instructions to Our Patients

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

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

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

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: Garg A. Treatment of diabetic dyslipidemia. Am JCardiol. 1998;81(4A):47B-51B. Target (mg/dl) Plasma LipidAcceptableIdeal Triglycerides Total cholesterol LDL-cholesterol Non-HDL-cholesterol HDL-cholesterol3545

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

Baseline Lipid Profile Atorvastatin mmol/l mg/dl TC TG HDL-C LDL-C Simvastatin mmol/lmg/dl

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

Change in IMT after 1 and 2 years

% 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 %

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

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

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

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

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

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

Unexpected Dangers Diabetes & Lipids