Grand RoundOct. 21, 2011

ConclusionsStatin LDL

A 44 year-old male presented with weight loss 10 kg (8575 kg) in recent 3 months and polydipsia for 1 month

A 44 year-old male presented with weight loss 10 kg (8575 kg) in recent 3 months and polydipsia for 1 month BH: 171 cm Weight: 85 kg () BMI: 29 () BP: 139/91 mm-Hg A smoker (1 pack/day for 20 yrs) No family history of cardiovascular disease

A 44 year-old male presented with weight loss 10 kg (8575 kg) in recent 3 months and polydipsia for 1 month BH: 171 cm Weight: 85 kg () BMI: 29 () BP: 139/91 mm-Hg A smoker (1 pack/day for 20 yrs) No family history of cardiovascular disease

AC (mg/dl)PC(mg/dl)A1C(%)TC(mg/dl)HDL-C(mg/dl)LDL-C(mg/dl)TG(mg/dl)Cr(mg/dl)ALT(U/L)2008/9/2030842014.53274611130.7317

*Adapted from Chang CH et al. Diabet Med 2010, 27, 636-6433.365%( 2010)

26.4%

128.4%210.8%37.0%46.2%55.7%64.6%73.6%83.4%92.9%102.8%

Chang C. Diabetes Res Clin Pract. 2000;50 Suppl 2:S49-59

Diabetes Care 1998;21:1138-45.Most died of CVD

2Modified from Stratton IM, et al. BMJ 321;405-412,2000:

DCCT Study Research Group. N Engl J Med 1993; 329:977-986DCCT/EDIC Study Research Group. N Engl J Med 2005;353:2643-53Chiasson et al. JAMA. 2003;290:486-494UKPDS Group. Lancet 1998; 352: 83753The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-59 The ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-72Duckworth et al. N Engl J Med 2009;360:129-39,

Diabetes Care 2008;31:811822126345

Diabetes Care 2008;31:811822126345

The Features of Diabetic Dyslipidemia High triglycerideLow HDL (but increased concentration of small dense HDL)Increased concentration of small dense LDL particlesNat Clin Pract Endocrinol Metab 2009;5:150-9.

AC (mg/dl)PC(mg/dl)A1C(%)TC(mg/dl)HDL-C(mg/dl)LDL-C(mg/dl)TG(mg/dl)Cr(mg/dl)ALT(U/L)2008/9/2030842014.53274611130.7317

Taskinen MR. Diabetologia (2003) 46:733749(Triglyceride Rich Lipoproteins)

Taskinen MR. Diabetologia (2003) 46:733749

UKPDS 23. BMJ 1998; 316: 82328. Increment of 39 mg/dl of LDL-C: 1.57-fold increased risk of coronary artery disease Increment of 3.9 mg/dl of HDL-C: 0.15-fold decrease in risk131(3.35)LDL-C (mmol/l)HDL-C (mmol/l)(117)(176)(39)(49)(195)65(1.7)

Dr. Michael S. BrownDr. Joseph L. GoldsteinScience 1986;232:34-47Nat Rev Drug Discov 2003;2:517-26

Nat Rev Drug Discov. 2003;2:517-26Lovastatin became available by prescription, first of the classWithdrawal of Cerivastatin

Lancet 1994;344:1383-1389Nat Rev Drug Discov 2003;2:517-26

Cause of death Simvastatin (n = 2,221) Placebo (n = 2,223) Risk reduction Coronary 11118942% (p < 0.00001) Other cardiovascular 1825Non-cardiovascular 4649All causes 18225630% (p = 0.0003)

N Engl J Med 2005;352:1425-35Event rates for HPS, CARE, and LIPID are for death from CHD and nonfatal myocardial infarction. Event rates for 4S and the TNT Study also include resuscitation after cardiac arrest.Mean LDL levels4S: ~190 mg/dlLIPID: ~150 mg/dlCARE: ~140 mg/dlHPS: ~130 mg/dlTNT: ~100 mg/dl

Ischemic strokeAny coronary eventCHD deathUnknown strokeAny strokeAny major vascular eventHemorrhagic strokeNon-fatal MILancet 2010; 376: 167081

Ischemic strokeAny coronary eventCHD deathUnknown strokeAny strokeAny major vascular eventsHemorrhagic strokeNon-fatal MILancet 2010; 376: 167081

Modified from DIABETES CARE 2010,33, SUPPLEMENT 1, S11-S61

HPS-DM Simvastatin 40 mg vs. placeboCARDS Atorvastatin 10 mg vs. placeboASPEN 1 Atorvastatin 10 mg vs. placebo4S-DM Simvastatin 2040 mg vs. placeboASPEN 2 Atorvastatin 10 mg vs. placeboHPS-DM Simvastatin 40 mg vs. placeboCARE-DM Pravastatin 40 mg vs. placeboTNT-DM Atorvastatin 80 mg vs. 10 mg

Lancet 2008; 371: 11725

Lancet 2010; 376: 167081Prior vascular diseaseDMAge (yrs)SBP (mm-Hg)DBP(mm-Hg)Gender

Lancet 2010; 376: 167081

Lancet 2010; 376: 167081

AC (mg/dl)PC(mg/dl)A1C(%)TC(mg/dl)HDL-C(mg/dl)LDL-C(mg/dl)TG(mg/dl)Cr(mg/dl)ALT(U/L)2008/9/2030842014.53274611130.7317

Allison B. Goldfine et al. N Engl J Med 2011;365;481-484

Trial Fibrate Follow-up (yr)Patient Population Primary End Point Absolute Event Rate (%) Risk Ratio (95% CI) P ValueControl Fibrate HHS (1982) Gemfibrozil, 1200 mg 54081 men with non-HDL cholesterol 200 mg/dl (primary prevention) Fatal or nonfatal MI, or CAD death84/2030 (4.1)56/2051 (2.7)0.66 (0.47-0.92)

Evaluate cardiovascular risk reduction by simvastatin + fenofibrate in T2DM

A negative study overall A benefit for men and possible harm for women (p=0.01)Elevated triglycerides (TG, 204 mg/dl or higher) + Low levels of HDL-C (34 mg/dl or lower) (p=0.06)N Engl J Med 2010;362:1563-74Allison B. Goldfine et al. N Engl J Med 2011;365;481-484

Trial Fibrate Follow-up (yr)Patient Population Primary End Point Absolute Event Rate (%) Risk Ratio (95% CI) P ValueControl Fibrate ACCORD (2001-2005)Fenofibric acid160 mg 4.75518 men and women with type 2 diabetes on statin therapy (primary and secondary prevention)Nonfatal MI, nonfatal stroke, or death from cardiovascular causes 310/2765 (11.2)291/2753 (10.6)0.92 (0.79-1.08) 0.32

Data from US Food and Drug Administration. June 8, 2011. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm[4]aNo incremental benefit of Vytorin on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.

FluvastatinSimvastatinAtorvastatinRosuvastatinVytorina(Ezetimibe/Simva)% LDL-C40 mg10 mg------30%80 mg20 mg10 mg----38%--40 mg20 mg5 mg10/10 mg41%--80 mg40 mg10 mg10/20 mg47%----80 mg20 mg10/40 mg55%----40 mg10/80 mg63%

Modified from Lancet 2007; 370: 178190

Study (Pt. No)Statin comparisonALT > 3X upper limit of normal(%)CK > 10X upper limit of normal, or myopathy (%)Rhabdomyolysis(%) Non-vascular death(%)PROVEIT (4162)A 80 mg vs P 40 mg 33 vs 1101vs 0150 vs 008 vs 13 Phase Z of the A to Z trial (4497)S 80 mg vs S 20 mg 09 vs 0404 vs 00401 vs 009 vs 09TNT (10 001)A 80 mg vs A10 mg 12 vs 020 vs 0004 vs 006 32 vs 25 IDEAL (8888)A 80 mg vs S 2040 mg 097vs 011014 vs 025%005 vs 00732 vs 35 SPARCL (4731)A 80 mg vs placebo 22 vs 0503 vs 03 01 vs 0149 vs 39

Modified from Lancet 2007; 370: 178190

Metabolism Most important drug interactions increasing myopathy riskFluvastatin CYP2C9 (some CYP2C8 and CYP3A4) Inhibitors of CYP2C9 Simvastatin Mainly CYP3A4 Potent inhibitors of CYP3A4 Atorvastatin CYP3A4 Potent inhibitors of CYP3A4 Rosuvastatin Minimal metabolism (via CYP2CP and some CYP2C19) and biliary excretion

Drugs that Might Interact with StatinsCyclosporinFibrates Gemfibrozil, bezafibrate, fenofibrate, and ciprofibrateAzol anti-fungals Itraconazole, ketoconazole, and miconazoleMacrolide antibiotics Erythromycin, telithromycin, and clarithromycinAnti-arrhthymics Verapamil, amiodaroneNefazodoneProtease inhibitors Amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, nelfi navir, ritonavir, and tipranavirLancet 2007; 370: 178190

N Engl J Med 2008;359:2195-207n = 17,802LDL < 130 mg/dlCRP > 2 mg/dlPlacebo vs. Rosuvastatin 20 mg/day

N Engl J Med 2005;353:238-48N Engl J Med 2009;360:1395-407Statin to Prevent Vascular Events in ESRD

Modified from Colin Baigent et al. Lancet 2011; 377: 218192Non-fatal MINon-fatal hemorrhagic strokeCoronary revascularisationVascular deathNon-fatal non-hemorrhagic stroke

Adapted from Clin J Am Soc Nephrol 2011;6:664678

CKD stageDrug1 to 234 to 5TransplantFluvastatin20 to 80 mg20 to 80 mg10 to 80 mg10 to 40 mgSimvastatin20 to 80 mg10 to 40 mg10 to 20 mg5 to 20 mgAtorvastatin10 to 80 mg10 to 80 mg10 to 80 mg10 to 20 mgRosuvastatin10 to 40 mg10 to 20 mg5 to 10 mg5 mg

N Engl J Med 2005;352:1425-35

Science 1986;232:34-47

Diabetic Patients Who Are F-U at A Clinic (n=86)Age: 59 13 yrs (30-84)Sex: M/F = 37/49DM duration: 5.0 5.6 yrs (0-21)AC glucose: 149.6 52.8 mg/dl (67-366)A1C: 8.4 2.2% (5.616.5)LipidTC: 209.4 50.5 mg/dl (105409)LDL: 132.2 43.1 mg/dl (17277)HDL: 45.8 12.0 mg/dl (2180)TG: 205.3 219.1 mg/dl (411557)

Chol > 200= 53%LDL > 130= 53.1%TC: 209.4 50.5 mg/dl (105 409)LDL: 132.2 43.1 mg/dl (17 277)HDL: 45.8 12.0 mg/dl (21 80)(LDL > 100= 80%)

TG > 500 = 6%TG/HDL > 5 or TG > 200 and HDL

Treatment Strategies for Lipid (n=86)Therapeutic lifestyle modification = 48 (55.8%)Rosuvastatin = 32 (37.2%)Atorvastatin = 3 (3.5%)Simvastatin = 1 (1.2%)Fenofibrate = 2 (2.3%)

38%

38%

ADAs Recommendations of Statin Therapy in DMOvert CVDAge > 40 yrs and have one or more other CVD risk factors For patients at lower risk than above (e.g., without overt CVD and under age 40 years), statin therapy should be considered in addition to lifestyle therapy if LDL >100 mg/dl or Multiple CVD risk factorsP osition Statement of ADA. DIABETES CARE 2011:34;S11-61

ADAs Recommendations of Statin Therapy in DMOvert CVDAge > 40 yrs and have one or more other CVD risk factors For patients at lower risk than above (e.g., without overt CVD and under age 40 years), statin therapy should be considered in addition to lifestyle therapy if LDL >100 mg/dl or Multiple CVD risk factorsP osition Statement of ADA. DIABETES CARE 2011:34;S11-61People who are considered at low risk = Age 40 yrs & LDL < 100 mg/dl = 2.5% in this study

Lipid Goals in Diabetic PatientsLDL < 100 mg/dl, if no overt CVDLDL < 70 mg/dl, if overt CVDA reduction in LDL of 3040% from baseline is an alternative therapeutic goal, if drug-treated patients do not reach the above targets on maximal tolerated statin therapyTriglyceride levels < 150 mg/dl and > HDL cholesterol 40 mg/dl in men and > 50 mg/dl in women, are desirable (LDL cholesterol targeted statin therapy is the preferred strategy)If targets are not reached on maximally tolerated doses of statins, combination therapy using statins and other lipid lowering agents may be considered to achieve lipid targets but has not been evaluated in outcome studies for either CVD outcomes or safetyStatin therapy is contraindicated in pregnancyP osition Statement of ADA. DIABETES CARE 2011:34;S11-61

N Engl J Med 2007;357:2180-3

N Engl J Med 2009;361:2113-22

N Engl J Med 2010;362:906-16.

DIABETES CARE 2011,33, SUPPLEMENT 1, S29-31

TargetThe patients data A1C (%) < 7.014.5 6.0 Blood pressure (mm-Hg) < 130/80 130+/80+ LDL (mg/dl) < 100 (< 70)140 49

T2DM + Persistent microalbuminuria

: A1C less than 6.5%, using metformin, SU, insulin, glitzone: Use of reninangiotensin system blockers, BP

Modified from Clin. Pharmacol. Ther. 81, 636-649 (2007)The Lancet 2010,Volume 375, Issue 9733Here Is The Problem

Lancet, 2010,Volume 375, Issue 9733 : ()-> (2010615)Big Problems !

*Results from a large number of primary and secondary prevention studies with clinical events (e.g., coronary heart disease [CHD] and myocardial infarction) as the primary endpoint have shown that there is a linear relationship between LDL-C and the risk for CHD.1In the Scandinavian Simvastatin Survival Study (4S) in patients with CHD,2 reducing LDL-C from 4.9 to 3.15 mmol/L (188 to 122 mg/dl) decreased the risk of major coronary events by 34%.3,4 More recently, data from both the Heart Protection Study (HPS), the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT) study, and the Treating to New Targets (TNT) study suggest that reducing LDL-C to levels that are substantially below 2.6 mmol/L (100 mg/dl) may be associated with additional benefits:In HPS, reducing LDL-C from