1. Slide Source LipidsOnline www.lipidsonline.org CO O C CH 3 COOCH CH 3 Cl CH 3 OC COOC 2 H 5 CH 3 Cl CH 3 OCH 2 CH 3 COOH CH 3 C Fenofibrate Clofibrate Gemfibrozil

2. Slide Source LipidsOnline www.lipidsonline.org Fibric Acid Derivatives Indications:Adjunctive therapy to diet Hypertriglyceridemia (Type IV and V) Combined hyperlipidemia (Type IIb) with low HDL who do not respond to NA Mechanism of Action:Increases peripheral lipolysis and decreases hepatic TG production Efficacy:Decreases TG 25-50% LDL decreases, remains the same or increases Increases HDL 15-25% in hypertriglyceridemia Side Effects:GI upset (8%), cholelithiasis, myositis, abn LFTs Contraindications:Hepatic or renal dysfunction Pre-existing gallbladder disease Intervention Trials:Helsinki Heart Study, LOCAT, BECAIT, VA-HIT, BIP

3. Slide Source LipidsOnline www.lipidsonline.org Helsinki Heart Study Primary-prevention, placebo-controlled trial to determine whether increasing HDL-C levels and decreasing LDL-C levels would reduce incidence of CHD 4,081 dyslipidemic men, aged 40–55 y Subjects randomized to gemfibrozil (600 mg BID) or placebo Study duration: 5 y Frick MH et al. N Engl J Med. 1987;317:1237–1245

4. Slide Source LipidsOnline www.lipidsonline.org Helsinki Heart Study Incidence of CHD Events Numbers inside bars indicate number of cardiac events in each subgroup Manninen V et al. Circulation. 1992;85:37–45 Incidence of cardiac events (per 1,000 person-years) 0 5 10 15 20 HDL-C  42HDL-C  42 Gemfibrozil Placebo TG  200 TG  200 2736 7 9 14 16 8 23 mg/dL:

5. Slide Source LipidsOnline www.lipidsonline.org Angiographic and Clinical Event Trials Summary In angiographic trials, benefits were related to reductions in LDL-C (apoB-100) and increases in HDL-C (apoA-I). Fibrates have shown benefits in patients with: High TG and low HDL-C (Helsinki, BIP) Normal LDL-C and low HDL-C (VA-HIT) Statins have consistently shown the greatest benefits in patients with low HDL-C and average LDL-C (CARE, LIPID, AFCAPS/TexCAPS) or high LDL-C (4S, WOSCOPS).

6. Slide Source LipidsOnline www.lipidsonline.org LDL Particle Size and Apolipoprotein B Predict Ischemic Heart Disease: Quebec Cardiovascular Study Lamarche B et al. Circulation 1997;95:69-75. >25.64 <25.64 LDL Peak Particle Diameter (nm) 1.0 6.2 (p<0.001) Apo B >120 mg/dl 2.0 <120 mg/dl

7. Slide Source LipidsOnline www.lipidsonline.org CHD Prevention Trials with Fibrates in Diabetic Subjects: Subgroup Analyses Primary Prevention Helsinki Heart Study Secondary Prevention VA-HIT Baseline LDL-C, mg/dl (mmol/L) No. LDL-C Lowering Adapted from Koskinen P et al. Diabetes Care 1992;15:820-825; Rubins HB et al. N Engl J Med 1999;341:410-418. Drug Dose Study CHD Reduction Gemfibrozil (1200 mg/d) 135 627 203 (5.2) 112 (2.9) 68% NS 24% p=0.05 6% –

8. Slide Source LipidsOnline www.lipidsonline.org Primary CHD* Prevention in Type 2 Diabetic Patients: The Helsinki Heart Study 5-Year Incidence of CHD (%) Type 2 (n=135) *Myocardial infarction or cardiac death Adapted from Koskinen P et al. Diabetes Care 1992;15:820-825. Others (n=3946) Type 2 on Placebo (n=76) Type 2 on Gemfibrozil (n=59) P<0.02 7.4 3.3 10.5 3.4 P=0.19

9. Slide Source LipidsOnline www.lipidsonline.org hs-CRP as a Risk Factor for Future CVD 1.02.03.04.05.06.0 Relative Risk (upper vs lower quartile) CHD Death MI Stroke CHD PVD CVD CHD 0 MRFIT ( Kuller 1996) PHS (Ridker 1997) CHS/RHPP (Tracy 1997) PHS (Ridker 1998) WHS (Ridker 1998, 2000) MONICA (Koenig 1999) Helsinki (Roivainen 2000) Caerphilly (Mendall 2000) Britain (Danesh 2000)

10. Slide Source LipidsOnline www.lipidsonline.org Trials of Fibrates: Effects on Cardiac Events Frick MH et al. N Engl J Med 1987;317:1237-1245. | Manninen V et al. Circulation 1992;85:37-45. | BIP Study Group. Circulation 2000;102:21-27. | Rubins HB et al. N Engl J Med 1999;341:410-418. * Post hoc analysis of subgroup with TG >200 mg/dL and HDL-C <42 mg/dL. ** Post hoc analysis of subgroup with TG 200 mg/dL and HDL-C <35 mg/dL. *** Difference between placebo and Rx for primary endpoint was statistically significant (p < 0.05). % CHD Death/Nonfatal MI Rx Placebo 2.7 4.1*** 2.7 8.0 13.6 15.0 13.0 22.3 17.3 21.7*** 66% 34% 9% 42% 22% PRIMARY PREVENTION SECONDARY PREVENTION HHS HHS (Post Hoc)* BIP BIP (Post Hoc)** VA-HIT Deaths 2.22.110.49.915.717.4

11. Slide Source LipidsOnline www.lipidsonline.org Study Drug(dose)No. Baseline LDL-C, mg/dl (mmol/L) LDL-C Lowering CHD Reduction Primary Prevention Helsinki Heart StudyGemfibrozil (1200 mg/d) 135203 (5.2) 6%68% NS Secondary Prevention VA-HIT Gemfibrozil (1200 mg/d) 627112* (2.9*) –24% P=.05 DAISFenofibrate (200 mg/d) 4181306%23% NS CHD Prevention Trials with Fibrates in Diabetic Subjects: Subgroup Analyses *Median value Koskinen P et al. Diabetes Care 1992;15:820-825. | Rubins HB et al. N Engl J Med 1999;341:410-418. | DAIS Investigators. Lancet 2001;357:905-910.

12. Slide Source LipidsOnline www.lipidsonline.org