The role of low-density lipoprotein (LDL) cholesterol in atherogenesis is supported
by pathological observations, clinical studies, and many animal experiments.
Observational epidemiological studies have clearly established that high total
or LDL cholesterol and low high-density lipoprotein (HDL) cholesterol are risk
factors for coronary heart disease. The Coronary Drug Project1, completed
in 1975, was designed to assess the safety and efficacy of nicotinic acid and
other lipid-altering drugs in men 30 to 64 years old with a history of myocardial
infarction (MI). Over an observation period of five years, nicotinic acid showed
a statistically significant benefit in decreasing nonfatal, recurrent myocardial
infarctions. The incidence of definite, nonfatal MI was 8.9% for the 1,119 patients
randomized to nicotinic acid versus 12.2% for the 2,789 patients who received
placebo (p < 0.004). Though total mortality was similar in the two groups at
five years (24.4% with nicotinic acid versus 25.4% with placebo; p=N.S.), in
a fifteen-year cumulative follow-up there were 11% (69) fewer deaths in the
nicotinic acid group compared to the placebo cohort (52.0% versus 58.2%; p=0.0004)2.
The Cholesterol-Lowering Atherosclerosis Study (CLAS) was a randomized, placebo-controlled,
angiographic trial testing combined colestipol and nicotinic acid therapy in
162 non-smoking males with previous coronary bypass surgery3. The
primary, per subject cardiac endpoint was global coronary artery change score.
After two years, 61% of patients in the placebo cohort showed disease progression
by global change score (N=82), compared with only 38.8% of drug-treated subjects
(N=80), when both native arteries and grafts were considered (p < 0.005). In
a follow-up to this trial in a subgroup of 103 patients treated for four years,
again, significantly fewer patients in the drug-treated group demonstrated progression
than in the placebo cohort (48% versus 85%, respectively; p < 0.0001)4.
The Familial Atherosclerosis Treatment Study (FATS) in 146 men ages 62 and
younger with apolipoprotein B levels ≥ 125 mg/dL, established coronary artery
disease, and family histories of vascular disease, assessed change in severity
of disease in the proximal coronary arteries by quantitative arteriography5.
Patients were given dietary counseling and randomized to treatment with either
conventional therapy with double placebo (or placebo plus colestipol if the
LDL cholesterol was elevated); lovastatin plus colestipol; or nicotinic acid
plus colestipol. In the conventional therapy group, 46% of patients had disease
progression (and no regression) in at least one of nine proximal coronary segments.
In contrast, progression (as the only change) was seen in only 25% in the nicotinic
acid plus colestipol group. Though not an original endpoint of the trial, clinical
events (death, myocardial infarction, or revascularization for worsening angina)
occurred in 10 of 52 patients who received conventional therapy, compared with
2 of 48 who received nicotinic acid plus colestipol.
Nicotinic acid (but not nicotinamide) in gram doses produces an average 10-20%
reduction in total and LDL cholesterol, a 30-70% reduction in triglycerides,
and an average 20-35% increase in HDL cholesterol. The magnitude of individual
lipid and lipoprotein responses may be influenced by the severity and type of
underlying lipid abnormality. The increase in total HDL is associated with a
shift in the distribution of HDL subfractions (as defined by ultra-centrifugation)
with an increase in the HDL2:HDL3 ratio and an increase
in apolipoprotein A-I content. The mechanism by which nicotinic acid exerts
these effects is notentirely understood, but may involve several actions, including
a decrease in esterification of hepatic triglycerides. Nicotinic acid treatment
also decreases the serum levels of apolipoprotein B-100 (apo B), the major protein
component of the very low-density lipoprotein (VLDL) and LDL fractions, and
of lipoprotein a [Lp(a)], a variant form of LDL independently associated with
coronary risk. The effect of nicotinic acid-induced changes in lipids/lipoproteins
on cardiovascular morbidity or mortality in individuals without pre-existing
coronary disease has not been established.
Following an oral dose, the pharmacokinetic profile of nicotinic acid is characterized
by rapid absorption from the gastrointestinal tract and a short plasma elimination
half-life. At a 1 gram dose, peak plasma concentrations of 15 to 30 Âµg/mL are
reached within 30 to 60 minutes. Approximately 88% of an oral pharmacologic
dose is eliminated by the kidneys as unchanged drug and nicotinuric acid, its
primary metabolite. The plasma elimination half-life of nicotinic acid ranges
from 20 to 45 minutes.
1. The Coronary Drug Project Research Group. Clofibrate and
Niacin in Coronary Heart Disease. JAMA 1975; 231:360-81.
2. Canner PL et al. Fifteen Year Mortality in Coronary Drug
Project Patients: Long-Term Benefit with Niacin. JACC 1986; 8(6):1245-55.
3. Blankenhorn DH et al. Beneficial Effects of Combined Colestipol-Niacin
Therapy on Coronary Atherosclerosis and Coronary Venous Bypass Grafts. JAMA
4. Cashin-Hemphill et al. Beneficial Effects of Colestipol-Niacin
on Coronary Atherosclerosis. JAMA 1990; 264(23):3013-17.
5. Brown G et al. Regression of Coronary Artery Disease as a
Result of Intensive Lipid-Lowering Therapy in Men with High Levels of Apolipoprotein
B. NEJM1990; 323:1289-98.