Eyes on Korean Data: Lipid Management in Korean DM Patients

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1 Eyes on Korean Data: Lipid Management in Korean DM Patients ICDM Luncheon Symposium Sung Rae Kim MD PhD Division of Endocrinology and Metabolism The Catholic University of Korea

2 Causes of Death in People with Diabetes Ischemic Heart Disease Other Heart Disease Diabetes Cancer Stroke Infection Other Geiss LS, et al. In: Diabetes in America, 2nd ed Bethesda, MD: NIH; 1995.

3 Clinical Guidelines for Diabetes UK Prospective Diabetes Study (UKPDS): Order of importance for predicting CHD Variable P value 1. LDL-C < HDL-C HbA 1c Systolic BP Smoking Baseline epidemiologic data from 2,693 T2D patients using stepwise multivariate Cox models Modified from Turner RC, et al. BMJ 1998;316:823-28

4 Clinical Guidelines for Diabetes Joint European Task Force Diabetic patients have much higher total CVD risk than comparable nondiabetics Treatment goals for BP and lipids in diabetic patients should be more ambitious ADA - Statin therapy should be added to lifestyle therapy, regardless of baseline lipid levels, for diabetic patients: with overt CVD (A) without CVD who are over the age of 40 and have one or more other CVD risk factors. (A)

5 NCEP ATP III Risk Category LDL-C Goal Initiate TLC High risk: CHD or CHD risk equivalents (10-year risk >20%) Moderately high risk: 2+ risk factors (10-year risk 10% to 20%) Moderate risk: 2+ risk factors (10 year risk <10%) Lower risk: 0-1 risk factor Clinical Guidelines for Diabetes <100 mg/dl (optional goal: <70 mg/dl) 100 mg/dl Consider Drug Therapy 100 mg/dl (<100 mg/dl: consider drug options) <130 mg/dl 130 mg/dl 130 mg/dl ( mg/dl: consider drug options) <130 mg/dl 130 mg/dl 160 mg/dl <160 mg/dl 160 mg/dl 190 mg/dl ( mg/dl: LDLlowering drug optional) Grundy, S. et al., Circulation 2004;110:

6 Lipid Goals in Patients With Diabetes ADA & ACC Statement (Consensus statement from the ADA and the ACC foundation) Goals LDL cholesterol (mg/dl) Non-HDL cholesterol (mg/dl) ApoB (mg/dl) Highest-risk patients, including those with 1) known CVD or 2) diabetes plus one or more additional major CVD risk factor <70 <100 <80 High-risk patients, including those with 1) no diabetes or known clinical CVD but two or more additional major CVD risk factors or 2) diabetes but no other major CVD risk factors <100 <130 <90 Other major risk factors (beyond dyslipoproteinemia) include smoking, hypertension, and family history of premature CAD ADA. Diabetes Care 2008;31:

7 Clinical Guidelines for Diabetes 2011 ESC/EAS Guideline Risk category LDL-C goal Evidence Very High CV Risk: Known CVD, T2DM or T1DM with microalbuminuria, CKD, SCORE level: 10% ~70 mg/dl and/or 50% reduction in level when target level cannot be reached Class I, A High CV Risk: Very high levels of individual risk factors, SCORE level: 5% and <10% Moderate Risk: SCORE level: 5% and <10% ~100 mg/dl Class IIa, A ~115 mg/dl Class IIa, C

8 Percent (%) Prevalence of Hyper-LDL-cholesterolemia according to diabetic status in Korea 50 Nondiabetes Diabetes % % 24.4% 25.8% % 7.5% 7.5% 13.4% 8.4% 18.2% 10.0% 12.0% 11.9% 12.9% Year 2011 KNHANES

9 Awareness rate in Korea Awareness rate All subjects Total 6.1 (0.4) 8.8 (1.0) 11.2 (0.6) 11.9 (0.6) 13.7 (0.7) Men 7.3 (0.7) 10.6 (1.6) 11.5 (1.0) 11.4 (0.8) 12.7 (1.1) Women 5.2 (0.5) 7.3 (0.9) 10.9 (0.7) 12.3 (0.8) 14.6 (0.9) Nondiabetic subjects Total 5.3 (0.4) 7.7 (1.0) 10.1 (0.6) 10.4 (0.6) 11.0 (0.7) Men 6.6 (0.7) 9.5 (1.6) 11.2 (1.1) 9.9 (0.9) 10.4 (1.1) Women 4.5 (0.5) 6.1 (1.0) 9.1 (0.8) 10.8 (0.8) 11.5 (0.8) Diabetic subjects Total 12.9 (1.8) 18.4 (3.4) 19.2 (1.8) 23.4 (2.2) 34.6 (3.0) Men 12.2 (2.5) 17.5 (5.6) 14.1 (2.5) 22.3 (3.1) 29.7 (3.8) Women 13.6 (2.7) 19.6 (4.4) 23.9 (2.6) 24.5 (2.8) 39.8 (3.9) 2011 KNHANES

10 Treatment rate in Korea Treatment rate All subjects Total 1.9 (0.2) 3.0 (0.4) 3.8 (0.3) 5.2 (0.4) 7.4 (0.6) Men 1.9 (0.4) 3.2 (0.7) 3.0 (0.4) 4.4 (0.5) 6.3 (0.8) Women 1.9 (0.3) 2.8 (0.5) 4.6 (0.4) 6.0 (0.6) 8.4 (0.8) Nondiabetic subjects Total 1.3 (0.2) 2.3 (0.4) 3.0 (0.3) 4.1 (0.4) 5.3 (0.5) Men 1.6 (0.4) 2.5 (0.7) 2.4 (0.5) 3.0 (0.5) 4.5 (0.7) Women 1.2 (0.2) 2.0 (0.6) 3.5 (0.4) 5.0 (0.5) 6.0 (0.6) Diabetic subjects Total 7.3 (1.4) 9.5 (2.3) 10.0 (1.4) 14.4 (1.7) 23.6 (2.8) Men 4.5 (1.5) 8.1 (3.0) 7.0 (1.7) 14.5 (2.6) 16.0 (0.6) Women 10.1 (2.4) 11.2 (3.6) 12.9 (2.0) 14.4 (2.3) 28.2 (3.9) 2011 KNHANES

11 Control rate in Korea Control rate Diabetic subjects (LDL-C goal : LDL-C <100 mg/dl) Total 41.9 (11.9) 70.4 (11.8) 45.1 (7.4) 62.6 (6.5) 62.6 (5.6) Men 62.5 (20.1) 81.8 (17.4) 63.2 (12.6) 70.7 (9.7) 64.3 (9.8) Women 33.6 (13.5) 61.1 (15.3) 36.7 (8.6) 55.1 (8.9) 61.6 (7.3) Diabetic subjects with 1 or more risk factor of CAD (LDL-C goal : LDL-C <70 mg/dl) Total 8.6 (5.6) 17.1 (9.1) 14.8 (5.3) 23.6 (5.3) 22.2 (4.8) Men 19.6 (17.8) (12.2) 27.4 (7.8) 30.0 (10.1) Women 4.3 (4.2) 31.2 (15.0) 9.9 (4.7) 19.8 (6.9) 17.2 (5.4) 2011KNHANES

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13 Enrollment of diabetic Pts with hypercholesterolemia Patients who visited clinic between May I and Aug 31, 2010 Patients with minimum 3 months pre-index eligibility(n=2,691) Exclude patients without laboratory results at baseline and final visit(n=2,591) Exclude patients missing data to calculate Framingham 10-yr risk(n=2,093) Diabetes Metab J. 2011; 35:

14 Target attainment rate (%) Low LDL-C Goal Attainment Rate in Korean Patients with Diabetes Baseline Final Visit Overall Highest-Risk pts. High-Risk pts. Multi-center, retrospective, non-interventional, observational study, total 2,591 enrolled patients Diabetes Metab J. 2011; 35:

15 LDL-C goal attainment rate (%) Gap between Physician s Perception and Guidelines At Goal Doctor's Perception Guideline LDL-C goal attainment and actual results according to the 2008 ADA/ACC guidelines Multi-center, retrospective, non-interventional, observational study, total 2,591 enrolled patients Diabetes Metab J. 2011; 35:

16 Physician Treatment Strategies to achieve Target Goals (By physicians answers to a survey) (%) 80 Base : n= Adding drugs Change drugs Increasing Increasing Maintain dosage dosage & adding drugs current therapy Diabetes Metab J. 2011; 35:

17 Physician Treatment Strategies to achieve Target Goals (By chart review) (%) 70 Base : n=2, Up titration Down titration Drug change No change No drug Multi-center, retrospective, non-interventional, observational study, total 2,591 enrolled patients Diabetes Metab J. 2011; 35:

18 AMADEUS Study A Multicenter, eight weeks treatment, single step titration, open label with Atorvastatin starting dose 10 mg, 20 mg, 40 mg assessing the percentage of Korean Diabetes Mellitus Dyslipidemic Patients achieving LDL cholesterol target Study

19 Deus : God, Amor : love the most AMADEUS : God love the most Amadeus Mozart (Mozart was a great musician of his time) J Diabetes Investig. 2013;4:

20 Background NCEP and ATP III guideline Treating cardiovascular risk factors in patients with type 2 diabetes as aggressively as non-diabetic patients in high risk CHD category Therapy for diabetic dyslipidemia is directed to first lowering serum LDL cholesterol levels (< 100 mg/dl) by statin in patients with type 2 diabetes If serum triglyceride levels are >200 mg/dl, the non HDL cholesterol goal becomes a secondary target Evidence for a decrease in cardiovascular events among patients with type 2 diabetes has accumulated from several major statin trials CARDS PROVE-IT JUPITER

21 Background Despite multiple guidelines and supporting data, overall achieving LDL cholesterol target goals falls far below expectations in type 2 diabetes Main factors for this failure may be associated with selection of an inappropriate starting dose and difficulties in dose up-titration to reach the target goal More recently, several clinical trials have shown that patient-tailored statin therapy according to individual s CHD risk or their baseline LDL cholesterol value allows for a larger number of patients to achieve target LDL cholesterol NASDAC ATGOAL ACTFAST

22 Background However, few studies previously have focused on the effectiveness of an individualizing starting dose according to baseline LDL cholesterol levels to achieve target goals in patients with type 2 diabetes who were free from CHD Furthermore, little data are available about the efficacy of these flexible starting doses on atherogenic lipid profiles and low grade inflammation in patients with type 2 diabetes

23 Methods Multicenter(18), single-step titration(lipitor 10 mg, 20 mg, 40 mg) Open-label study Pts: Age 18-80, Type 2 DM Pts 440(HbA 1c : below 10%, ADA criteria ) No CAD risk Pt, LDL cholesterol target is below 100 mg/dl LDL-C baseline ITT (n=440) Lipitor 40 mg (n=74) 80 mg Complete n=65 100~129 mg/dl: 10mg 130~159 mg/dl: 20mg 160~220 mg/dl: 40mg Screening Lipitor 20 mg (n=181) Lipitor 10 mg (n=185) 4wk 40 mg 20 mg 8wk Complete n=161 Complete n=177 Visit 1 Visit 2 Visit 3 J Diabetes Investig. 2013;4: ADA: American Diabetes Association, ITT : intention to-treat

24 Result The proportion of patients achieving LDL-C target J Diabetes Investig. 2013;4: ITT : intention to-treat, PP: per-protocol

25 Result Achieving LDL-C target with the initial dose 10 mg (n=185) 10mg (n=172) Dose of change (n=13) ( ) ( ) 10 mg (n=177) 10mg (n=168) 20mg (n=9) ( ) ( ) 20 mg (n=181) 20mg (n=160) Dose of change (n=21) ( ) ( ) 20 mg (n=161) 20mg (n=153) 40mg (n=8) ( ) 100 ( ) 40 mg (n=74) 40mg (n=62) Dose of change (n=12) ( ) ( ) 40 mg (n=65) 40mg (n=60) 80mg (n=5) ( ) 60 ( ) All dose Initial dose Dose of change ( ) ( ) All dose Initial dose Up-titration ( ) ( ) J Diabetes Investig. 2013;4: ITT : intention to-treat, PP: per-protocol

26 Result Change of lipid profile Variables 10 mg (n=185) 20 mg (n=181) 40 mg (n=74) [Unit: mg/dl Total cholesterol (mg/dl) Baseline (mean S.D.) Week 8 (mean S.D.) Change (95% CI) ± ± ( )* ± ± ( )* ± ± ( )* Triglyceride (mg/dl) Baseline (mean S.D.) Week 8 (mean S.D.) Change (95% CI) ± ± ( )* ± ± ( )* ± ± ( )* HDL cholesterol (mg/dl) Baseline (mean S.D.) Week 8 (mean S.D.) Change (95% CI) ± ± ( )* ± ± ( ) ± ± ( ) LDL cholesterol (mg/dl) Baseline (mean S.D.) Week 8 (mean S.D.) Change (95% CI) TC/HDL ratio(mean S.D.) Baseline (mean S.D.) Week 8 (mean S.D.) Change (95% CI) LDL/HDL ratio Baseline (mean S.D.) Week 8 (mean S.D.) Change (95% CI) Non-HDL (mg/dl) Baseline (mean S.D.) Week 8 (mean S.D.) Change (95% CI) J Diabetes Investig. 2013;4: TC: total cholesterol, LDL-C: low density lipoprotein cholesterol, HDL-C: high density lipoprotein ± ± ( )* 4.32 ± ± ( )* 2.64 ± ± ( )* ± ± ( )* ± ± ( )* 4.81 ± ± ( )* 3.14 ± ± ( )* ± ± ( )* ± ± ( )* 41.69% 48.19% 53.43% 5.47 ± ± ( )* 3.86 ± ± ( )* ± ± ( )*

27 Result Change of sd-ldl cholesterol J Diabetes Investig. 2013;4: Sd-LDL: small,dense LDL

28 Result Change of hscrp hscrp <3 mg/l hscrp 3 mg/l J Diabetes Investig. 2013;4: hscrp: high sensitive C-reactive protein

29 Result Change of Adiponectin Adiponectin J Diabetes Investig. 2013;4:

30 Result -Adverse events J Diabetes Investig. 2013;4:

31 Summary Overall, 93.8% of patients achieved their LDL cholesterol target at week 8 (94%, 97% and 85% for the 10, 20 and 40 mg doses, respectively) Among patients who achieved target goal, over 94.5% achieved their LDL cholesterol target with the initial dose (95%, 97% and 87% for the 10, 20 and 40 mg doses, respectively) There were significant reductions in TC, TC/HDL cholesterol ratio, LDL/HDL cholesterol ratio, triglycerides and non-hdl cholesterol compared to baseline at week 8 for all doses Especially, reductions in small dense LDL cholesterol levels were significant after 8 weeks with all doses, and this finding was more prominent in higher doses Significant increases in adiponectin between week 4 and 8 were also observed with all doses Atorvastatin was well tolerated at all doses

32 Thank you for your attention!!