September/October 2002

Lipid Education Service
Newsbrief
J. David Schnatz, M.D.

Among the abstracts presented at the March 2002 annual meeting of the American College of Cardiology were ones on early lipid lowering therapy at the time of revascularization, the relation of non diabetic glucose values and coronary heart disease (CHD), a new LDL lowering drug and the use of statin and niacin therapy in metabolic syndrome.

Early Lipid Lowering Therapy in Revascularization

Abstract 1102-25 "Effect of Pre-Procedure Lipid Lowering Therapy on In Hospital Mortality Following Percutaneous Coronary Interventions: An Analysis of a Large Multicenter Database" Percutaneous coronary intervention (PCI) was analyzed in 16,932 patients in 8 Michigan hospitals. Nine thousand eighty-four patients were on lipid lowering therapy before the procedure (LLT) and 7,848 were not (No LLT). In hospital mortality was 0.58% (LLT) vs 2.8% (No LLT) (p<0.001).

Abstract 1053-1 "Early and Sustained Survival Benefit Associated with Statin Therapy at the Time of Percutaneous Coronary Intervention" From 1993 through 1999, data on the first 1,000 patients undergoing PCI at the Cleveland Clinic was collected, including baseline, procedural and six month data. Statin therapy was associated with a 60% lower mortality at 30 days (p=0.0007) and 37% reduction at six months (p=0.003).

Taken together, these abstracts support the concept of initiating lipid lowering therapy prior to angioplasty, and are consistent with the argument for initiating such therapy in patients with coronary events while in the hospital.

The Relation Between Non-Diabetic Glucose Values and CHD

Abstract #1059-73 "Fasting Blood Glucose in the Nondiabetic Range is a Continuous and Graded Risk Factor for CHD" The relationship between CHD and fasting glucose in the normal and impaired, or pre-diabetic, range was examined in 2,440 consecutive patients without diabetes mellitus in a preventive cardiology clinic. When glucose increased from the first quintile of 79 mg/dl to the fifth quintile of 100-125 mg/dl, the incidence of CHD increased from 43-65% (p<0.001) and the odds ratio, adjusted for all other risk factors, rose from 1 to 2.78 with the trend being significant (p<0.001) and the 3rd to 5th quintiles each being significantly higher than the first (p<0.001). Age and BMI also increased significantly and HDL decreased significantly from the 1st to 5th quintiles (p<0.001). These data add to the known increase in risk for CHD with diabetes mellitus, and demonstrated a graded increase and risk of CHD with increasing fasting glucose levels.

A New LDL Lowering Drug, Ezetimibe

Ezetimibe (EZE) (Sch58235) is a new cholesterol absorption inhibitor (CAI), developed by Schering-Plough, and currently in Phase III clinical trial testing. CAI's block absorption of cholesterol through action on the enterocyte.

Abstract 1084-90 "Ezetimibe Co-Administered with Simvastatin in 668 Patients With Primary Hypercholesterolemia" After being on an NCEP diet for 2-12 weeks and on placebo (Plc), single blind, for 4 weeks, 668 patients with LDL 145 to 250 mg/dl and TG 350 were randomized to one of the following: Plc, EZE 10mg, Simvastatin (SIM), 10, 20, 40 or 80 mg, and EZE 10mg with 10, 20, 40 or 80 mg of SIM for 12 weeks. EZE gave reductions of 18.1% for LDL, 8.3% for TG as well as a 5.1% increase of HDL. When the pooled results for SIM (n=263) were compared with the pooled results for EZE + SIM (n=274), there was an added reduction of 13.8% for LDL and 7.5% for TG as well as 2.4% increase of HDL (p<0.01 for each). The author's conclude that this combination "offers a highly efficacious new treatment approach to patients with hypercholesterolemia."

Abstract 1084-91 "Ezetimibe Co-Administered with Atorvastatin in 628 Patients with Primary Hypercholesterolemia" In a similar design to the preceding abstract, EZE was combined with Atorvastatin (ATV). EZE, 10mg, gave decreases of 18.1% for LDL and 3.4% for TG with a 4.2% increase in HDL. When EZE was added to ATV, there were additional decreases of 12.1% for LDL, 8% for TG and an increase of 3% for HDL (p<0.01 for each). The conclusions were the same as the preceding study.

Abstract 1084-93 "Does Cholesterol and/or Fat Intake Affect Plasma Lipid Efficacy of Ezetimibe?" The lipid selection criteria and dietary preparation were the same as in the preceding two studies. One thousand seven hundred nineteen patients, 831 men and 888 women, 18 to 86 years of age were studied. One thousand eighty-eight were randomized to EZE and 431 to Plc. Saturated fat and cholesterol ingested was quantitated and patients divided into quartiles, based on this quantitation. The percent change in LDL due to EZE was no different for the lowest and highest quartiles of fat intake.

Abstract 833-4 "Ezetimibe Added to Ongoing Statin Therapy for Treatment of Primary Hypercholesterolemia" EZE, 10mg (n=379) and Plc (n=390) were randomly added to the patients open label statin. EZE produced added decreases of 21.5% for LDL (p<0.001), 11.4% for TG (p<0.01) and an added increase of 1.7% for HDL (p<0.05). These results are consistent with those of the first two EZE abstracts.

Abstract 1084-92 "Ezetimibe Significantly Reduces Low-Density Lipoprotein Cholesterol in Homozygous Familial Hypercholesterolemia" Fifty patients with homozygous familial hypercholesterolemia were on 40mg of ATV or SIM with (n=25) or without (n=25) LDL apheresis. They were randomized, double blind, to 1 of 3 12 week treatments: 1) ATV or SIM, 80mg, 2) EZE, 10mg + ATV or SIM, 40mg or 3) EZE 10mg + ATV or SIM, 80mg. Statin, 80mg, gave a 6.7% LDL decrease, EZE + statin, at either dose, gave a 20.7% LDL decrease (p<0.01) and EZE + statin, 80mg, gave a 27.5% LDL decrease (p<0.01). Thus, EZE offers "a new complimentary pharmacological approach to this high risk population."

The Use of Niacin and Statin Therapy in Metabolic Syndromes

Abstract 1130-73 "Simvastatin Plus Niacin Protect Against Atherosclerosis Progression and Clinical Events in Coronary Artery Disease Patients with Metabolic Syndrome" The Simvastatin (S) and Niacin (N) data from the HDL Atherosclerosis Treatment Study (HATS, May/June 2002 Newsbrief) were analyzed from the standpoint of patients with and without metabolic syndrome (MSyn). MSyn patients had 3 of the following 4 criteria: TG50 mg/dl, HDL<40 (men), <50 (women), blood pressure 130/85 and fasting glucose 110 mg/dl. The mean change in percent coronary stenosis between those with and without MSyn was 41% during the 3 years of follow-up (p=0.02). In those with MSyn, addition of NS decreased the mean change in percent stenosis by 90% (p<0.05). This was associated with decreases of 23% for chol, 30% for LDL, 35% for TG and with a 15% increase in HDL (p<0.001 for all values). The author's concluded that "These data suggest that patients with MSyn should be treated more aggressively and simvastatin plus niacin appear to be an effective therapy."