STATINS & NEWER HOPE FOR ATHEROSCLEROSIS ASSOCIATED DISEASES

Introduction

Atherosclerosis-related diseases like coronary artery disease (CAD) and cerebro-vascular disease (CVD) are leading causes of death and disability in the world. It is also recognized that people hailing from Indian subcontinent have a higher probability of dying due to CAD [1]. Truncal obesity, hyperinsulinaemia and dyslipidaemia are some factors responsible for this. Elevated plasma low density lipoprotein cholesterol (LDL-C) is a major risk factor for development of CAD. Elevated high density lipoprotein cholesterol (HDL-C) is protective. Oxidised and glycated LDL-C contributes to cellular events leading to development and progression of atherosclerotic lesions. Correction of dyslipdaemia should therefore be a major treatment strategy both for primary and secondary prevention of these diseases.

Lipid lowering therapy has conclusively demonstrated retardation in rate of progression of coronary arterial narrowing (angiographically proven) and reduction in size of atherosclerotic plaque in humans [2, 3]. Scandinavian simvastatin survival study (4S) by demonstrating reduction in CAD and total mortality by 30% and 42% respectively, has established the value of lipid lowering by statins in CAD patients [4, 5]. In addition to 4S, a meta analysis of 7 secondary prevention studies-using 3 different statins has shown to be associated with a risk reduction of 44% for all-cause mortality [6]. The magnitude of reduction in cardiac events through cholesterol reduction exceeds that established for aspirin and β blockers, drugs which are recognised as corner stone in the treatment of CAD [7]. An overview of 16 randomized trials of statin drugs done between 1991 and 1995 also reveals a clear evidence of benefit on stroke and total mortality [8].

Statin drugs include lovastatin (10–80 mg/d), simvastatin (10–40 mg/d), pravastatin (10–40 mg/d), atorvastatin (10–80 mg/d), and fluvastatin (20–40mg/d). They inhibit the rate limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) in cholesterol biosynthesis. This causes a compensatory increase in the number of hepatic LDL-receptors, which results in a greater uptake of LDL-C leading to a lower plasma level. In patients of primary hypercholesterolaemia treated with statins, reductions from baseline are 20–40% for total cholesterol, 35 to 45% for LDL-C and 10 to 20% for triglycerides (TG). This is accompanied by a 5 to 15% increase in levels of HDL-C. Statins are well tolerated and cause few adverse effects. Mild gastrointestinal upset (6%), transient rise in hepatic enzymes (2%) and myopathy (0.08%) can occur. Rhabdomyolysis has been reported very rarely. Violent death or suicide associated with cholesterol lowering reported earlier has not been supported by all the later studies.

Recommendations for Treatment

With a fasting lipid profile total cholesterol, HDL-C and TG are measured. LDL-C can be calculated by the following formula

LDL-C = Total C—HDL-C—TG/5 (provided TG is < 400 mg/dL)

Elevated plasma cholesterol in the presence of normal levels of TG is almost always due to increased LDL-C, since LDL-C carries 65–75% of cholesterol.

LDL-C treatment guidelines are given in Table – 1 below:-

Levels of LDL-C mg/dL for beginning therapy

	Diet	Drugs	Goal
No CAD and less than 2 risk factors	≥ 160	≥ 190	< 160
No CAD but 2 or more risk factors	≥ 130	≥ 160	< 130
Presence of CAD	> 100	> 130	< 100

Indian patients develop significant CAD with lower cholesterol levels than western patients [9]. It has not yet been established as to what level of LDL-C should constitute the goal in Indians. Whether further decrease in cholesterol is of benefit in western countries will be known after the data from LIPID and CARE studies is analysed.