Diabetes and Hyperlipidemia

Transcription

1 Diabetes and Hyperlipidemia State of the art 2010 Lars Rydén Karolinska Institutet Stockholm, Sweden

2 Diabetes and hyperlipidemia

3 Diabetes and hyperlipidemia Treatment targets

4 Treatment targets Lipid category mmol/l mg/dl Cholesterol Total 4.5 <175 LDL HDL men >1.0 >40 women >1.2 >46 Triglycerides <1.7 <150 Total/HDL cholesterol <3 (Rydén, Standl et al Europ Heart J 2007; 28:88 )

5 Diabetes and hyperlipidemia Treatment targets Epidemiology and cardiovascular risk

6 Prevalence dyslipidemia(%) Dyslipidemia - common in diabetes The BOTNIA study n age years Glucose tolerance Normal IFG/IGT 7 98 Diabetes Male Female Dyslipidemia TG 1.7 mmol/l ( 66 mg/dl) and/or HDL men/women <0.9 mmol/l (35 mg/dl) women <1.0 mmol/l (39 mg/dl) (Isomaa et al Diabetes Care 2001;24:683) Normal IFG/IGT Diabetes Glucose metabolism

7 Lipid profile in patients with and without diabetes (1) mmol/l mg/dl mmol/l mg/dl Men Women Men Women p< DM No DM DM No DM DM No DM DM No DM Total cholesterol LDL-Cholesterol (UKPDS Diabetes Care 1997; 20:1663)

8 Lipid profile in patients with and without diabetes (2) mmol/l mg/dl mmol/l mg/dl Men p<0.02 Women p< Men p<0.001 Women p< DM No DM DM HDL- Cholesterol No DM DM No DM DM Triglycerides No DM (UKPDS Diabetes Care 1997; 20:1663)

9 10 year CHD mortality Risk factors and diabetes Vulnerability to hypercholesterolemia by diabetic state Rate Diabetes 10 year CHD mortality (per 10 3 ) 30 No diabetes Serum cholesterol (mmol/l) (Stamler et al. Diabetes Care 1993;16:434)

10 Risk factors and diabetes Estimated Hazard Ratio for coronary artery disease patients with type 2 diabetes in UKPDS Age (years) LDL mmol/l HDL mmol/l 0.1 mmol/l (4 mg/dl) increase in HDL = 15% decrease in CVD endpoints HbA1c (%) Syst BP (mm Hg) Smoking (Turner et al. UKPDS 23. BMJ 1993;98:316)

11 Diabetes and hyperlipidemia Treatment targets Epidemiology and cardiovascular risk Statin therapy Secondary and primary prevention

12 Major CV events (%) Heart Protection Study subgroup with diabetes Patients Diabetes n = Simvastatin 40 mg/day or placebo P< Placebo Simvastatin Proportionate reduction % Coronary mortality 20 Stroke 24 Revascularization 17 Major vascular events 22 Follow up (years) (HPS Collaborative Group: Lancet 2003; 361: 2005)

13 Risk reduction by LDL reduction and diabetic state Lancet 2008; 371:117 Diabetes (no) Type Events Follow up (mean years) 4.3 Outcome measure Effect of decreasing LDL by 1 mmol/l (CTT Collaborators Lancet 2008; 371:117 )

14 Risk reduction by LDL reduction and diabetic state Reduction by 1 mmol/l (39 mg/dl) decrease in LDL-cholesterol Event Diabetes No diabetes Total mortality 0.91 ( ) 0.87 ( ) Major vascular 0.79 ( ) 0.79 ( ) Major coronary 0.78 ( ) 0.77 ( ) Overall reduction 20% (CTT Collaborators Lancet 2008; 371:117 )

15 Risk reduction by LDL reduction and diabetic state Reduction by 1 mmol/l (39 mg/dl) decrease in LDL-cholesterol Subgroups with similar overall reduction Diabetes type 1 or 2 Age and sex Blood pressure Hypertension BMI Smoking status Other blood lipids Level of CV risk Initial LDL level down to 2.6 mmol/l (100 mg/dl) (CTT Collaborators Lancet 2008; 371:117 )

16 Major coronary events (%) Statins in patients with and without diabetes From the 4 S and CARE trials 70 No diabetes Diabetes S - simvastatin CARE - pravastatin placebo statin (Kreisberg RA et al. Am J Cardiol 1998;82:67U) LDL-Cholesterol mmol/l mg/dl

17 Treating to New Targets subgroup with diabetes Patients n= Diabetes + CAD + LDL <3.4 mmol/l (<130 mg/dl) Atorvastatin Follow up (median) Endpoint First major CV-event LDL cholesterol at end of treatment Atorvastatin 10 Atorvastatin or 80 mg/day 4.9 years 2.5 mmol/l (99 mg/dl) 2.0 mmol/l (77 mg/dl) (Shephard et al: Diabetes care 2006; 29:1220)

18 Proportion with major CV events (%) Treating to New Targets subgroup with diabetes Atorvastatin 10 mg 18% Atorvastatin 80 mg 14% HR 0.75 (95% CI ) p = Follow up (years) (Shephard et al: Diabetes care 2006; 29:1220)

19 Guideline recommendations Secondary prevention Class Level Elevated LDL- and low HDL are important risk I A factors in patients with diabetes mellitus Statins are first line agents for lowering LDLcholesterol in diabetic patients I A In diabetic patients with CVD statin therapy should be I B initiated regardless of baseline LDL-cholesterol with a treatment target of mmol/l (70-77 mg/dl) (Rydén, Standl et al Europ Heart J 2007; 28:88 )

20 Primary prevention with statins in diabetes The Collaborative Atorvastatin Diabetes Study (CARDS) Patients with type 2 diabetes Age (years) Baseline LDL mmol/l (mg/dl) 3.0 (116) CVD-manifestation Risk factor for CVD retinopathy or albuminuria or smoker or hypertension Randomised treatment None Atorvastatin 10 mg/day n=1 428 Placebo n= (Colhoun HM et al. Lancet 2004;364:685)

21 Major coronary events (%) Primary prevention with statins in diabetes The Collaborative Atorvastatin Diabetes Study (CARDS) 15 Primary endpoint - major coronary event -37% (95 CI: -52 to -17; p=0.001) Placebo 10 Atorvastatin Follow up (years) (Colhoun HM et al. Lancet 2004;364:685)

22 Primary prevention with statins in diabetes The CARDS trial Treatment effects primary and secondary endpoints Major CVE All cause mortality Primary ACS Coron revasc Stroke Mortality Any CVE Any CVE (Colhoun HM et al. Lancet 2004;364:685)

23 Guideline recommendations Primary prevention Class Level Given the high lifetime risk of CVD, it is suggested IIb C that all type 1 patients above age 40 years should be considered for statin therapy. In patients years (type 1 or 2), statin therapy should be considered when other risk factors are present (e.g. microvasc complications, poor glycemic control, hypertension, family history.) (Rydén, Standl et al Europ Heart J 2007; 28:88 )

24 Guideline recommendations Primary prevention Class Level Statin therapy should be considered in adult patients IIb B with type 2 diabetes without CVD if total cholesterol is >3.5 mmol/l (>135 mg/dl) targeting a LDL-cholesterol reduction of 30-40% (Rydén, Standl et al Europ Heart J 2007; 28:88 )

25 Diabetes and hyperlipidemia Treatment targets Epidemiology and cardiovascular risk Statin therapy Secondary and primary prevention Fibrates

26 Atheroprotective effects of HDL Inhibition of adhesion molecule expression Inhibition of LDL oxidation (After Barter et al 1999;Harwood Acad Publ) Promotion of cholesterol efflux

27 Proportionate risk reduction in major fibrate trials Secondary prevention in patients with diabetes Study Fibrate Patients no Clinical Outcomes Helsinki Heart Study Gemfibrozil 135 RR: 68% - MI or sudden death (ns) SENDCAP Bezafibrate 164 RR: 70% - definite CHD events (p=0.01) VA-HIT DAIS Gemfibrozil 769 Fenofibrate 418 RR: 32% - composite endpoint (p=0.004) RR 23% - combined cardiac endpoints (ns) (Koskinen et al. Diabetes Care 1992;15:820. Elkeles et al. Diabetes Care 1998;21:64. Rubins et al. Arch Int Med 2002;162:2597. DAIS Investigators. Lancet 2001;357:905)

28 Fenofibrate Intervention and Event Lowering in Diabetes The FIELD trial Cumulative risk (%) Patients Diabetes ± CVD n = No statins at entry Fenofibrate 200 mg/day Placebo Coronary deaths or myocardial infarction (The FIELD Study Investigators. Lancet 2005; 366:1849)

29 The effect of combination lipid therapy in T2 DM The ACCORD trial Patients n = 5,518 type 2 diabetes Simvastatin + Fenofibrate 200 mg/day Placebo Mean follow up 4.7 years Endpoint CV death or nonfatal MI or stroke Accord Study group. New Engl J Med 2010; 362: 1563

30 The effect of combination lipid therapy in T2 DM The ACCORD trial Accord Study group. New Engl J Med 2010; 362: 1563

31 Guideline recommendations Secondary prevention Class Level In diabetic patients with hypercholesterolaemia IIb B >2mmol/l (177 mg/dl) after having reached the LDL target with statin therapy, statin therapy should be increased to reduce the secondary target of non-hdl cholesterol. In some cases, combination therapy with the addition of ezetemibe, nicotinic acid or fibrates may be considered (Rydén, Standl et al Europ Heart J 2007; 28:88 )

32 Diabetes and hyperlipidemia Treatment targets Epidemiology and cardiovascular risk Statin therapy Secondary and primary prevention Fibrates Multifactorial management

33 Major coronary events (%) Statins in patients with and without diabetes From the 4 S and CARE trials 70 No diabetes Diabetes S - simvastatin CARE - pravastatin placebo statin (Kreisberg RA et al. Am J Cardiol 1998;82:67U) LDL-Cholesterol mmol/l mg/dl

34 Concluding remarks Diabetes and Hyperlipidemia Diabetes and hyperlipidemia common combination with special characteristics statin treatment rewarding need for HDL-increasing drugs Treatment part of a multifactorial management present practice far from satisfactory

35 Diabetes and Hyperlipidemia State of the art Thanks for the attention!