H.Robert Superko

Effectiveness of once-nightly dosing of extended-release niacin alone and in combination for hypercholesterolemia∗ ☆

We performed a multicenter, open-label study to determine the long-term safety and efficacy of a new extended-release once-a-night niacin preparation, Niaspan, in the treatment of hypercholesterolemia. Niaspan, 0.5 to 3.0 g once a night at bedtime, was used alone or in combination with a statin (inhibitor of hydroxymethylglutaryl coenzyme A reductase), a bile acid sequestrant, or both. Patients included 269 hypercholesterolemic male and female adults enrolled in a 96-week study, and 230 additional adults for whom short-term safety data were available. The dosages of Niaspan attained by 269 patients were 1,000 mg (95% of patients), 1,500 mg (86%), and 2,000 mg (65%). After 48 weeks of treatment, Niaspan alone (median dose 2,000 mg) reduced low-density lipaprotein (LDL) cholesterol (18%), apolipoprotein B (15%), total cholesterol (11%), triglycerides (24%), and lipoprotein(a) (36%), and increased high-density lipoprotein (HDL) cholesterol (29%). Niaspan plus a statin lowered LDL cholesterol (32%), apolipoprotein B (26%), total cholesterol (23%), triglycerides (30%), and lipoprotein(a) (19%), and increased HDL cholesterol (26%). Reversible elevations of aspartate aminotransferase or alanine aminotransferase more than twice the normal range occurred in 2.6% of patients. One patient discontinued Niaspan because of transaminase elevations. Intolerance to flushing, leading to discontinuation of Niaspan, occurred in 4.8% of patients. The overall rate of discontinuance due to flushing in this study combined with 2 previous randomized trials was 7.3%. In the long-term treatment of hypercholesterolemia, Niaspan produced favorable changes in LDL and HDL cholesterol, triglycerides, and lipoprotein(a). Adverse hepatic effects were minor and occurred at rates similar to those reported for statin therapy.

Differential effects of nicotinic acid in subjects with different LDL subclass patterns

Twenty-six subjects (20 male, 6 female) at high risk for CAD events were treated with moderate doses of nicotinic acid to investigate whether there was a differential lipoprotein response in patients with different LDL subclass patterns. Subjects were selected to have either pattern A (predominance of large LDL, peak particle diameter greater than 262 A, n = 9) or pattern B (predominance of small LDL, peak particle diameter less than 255 A, n = 17) as assessed by 2-16% gradient gel electrophoresis of plasma. Nicotinic acid dose was similar in pattern A (2111 +/- 651 mg/day) and pattern B subjects (1875 +/- 698 mg/day). Total cholesterol and LDL cholesterol decreased by similar amounts in pattern A (-41 +/- 26 mg/dl and -37 +/- 18 mg/dl) and pattern B (-51 +/- 44 mg/dl and -44 +/- 45 mg/dl) subjects. Triglycerides tended to be reduced more in pattern B subjects (-100 +/- 175 mg/dl) compared to pattern A subjects (-23 +/- 34 mg/dl) although this difference was not statistically significant (P = 0.08 for triglycerides log transformed). HDL cholesterol increased significantly more in the pattern B group (11.9 +/- 14.2 mg/dl) compared to pattern A subjects (0.7 +/- 8.5 mg/dl), (P less than 0.04). Similarly, LDL particle diameter increased significantly more in the pattern B subjects (9.8 +/- 6.9 A) compared to the pattern A subjects (3.6 +/- 3.0 A), (P less than 0.02). All pattern B subjects who achieved a plasma triglyceride less than 140 mg/dl converted to pattern A.(ABSTRACT TRUNCATED AT 250 WORDS)

Electron beam tomography and National Cholesterol Education Program guidelines in asymptomatic women.

OBJECTIVESnThis investigation was designed to determine the relationship between National Cholesterol Education Program (NCEP) ATP-II lipid guidelines and subclinical atherosclerosis, defined by electron beam tomography (EBT) calcified coronary plaque, in asymptomatic women.nnnBACKGROUNDnNCEP guidelines are used to identify women at increased risk for coronary artery disease (CAD) on the basis of low density lipoprotein cholesterol (LDLC) and high density lipoprotein cholesterol (HDLC) values. The relationship of the guidelines to subclinical atherosclerosis is unknown.nnnMETHODSnA total of 304 asymptomatic women underwent lipid and EBT evaluation and were classified as: 1) NCEP higher risk, with LDLC > or =130 mg/dl and/or HDLC <35 mg/dl, or lower risk with LDLC <130 mg/dl and HDLC > or =35 mg/dl; and 2) EBT+ if any calcified plaque was noted or EBT- if there was no calcified plaque.nnnRESULTSnForty-two percent of patients were EBT+, with a mean score of 227 and percentile of 73%; 58% were EBT-. Women who were EBT+ had significantly higher total cholesterol, LDLC and triglycerides than EBT- women, but only with ages < or =55 years; women >55 years demonstrated no differences. NCEP higher risk women made up 53.5% of the EBT+ and 37.7% of the EBT- groups; NCEP lower risk women accounted for 46.5% of the EBT+ and 62.3% of the EBT- groups. Assuming a higher risk in subjects with EBT-defined subclinical CAD than in those without, only 58.6% of the total group would be correctly identified by NCEP guidelines as either higher or lower risk, with correct identification of 65.5% of the younger and 52.2% of the older women. There was no correlation between either calcium percentile or score and any lipid measurement.nnnCONCLUSIONSnThis study demonstrates the shortcomings of employing NCEP guidelines to identify asymptomatic women with subclinical CAD, particularly women >55 years, and suggests increased utilization of EBT for primary prevention in the female population.

Long-term blood cholesterol-lowering effects of a dietary fiber supplement

BACKGROUNDnThe study evaluated the blood cholesterol-lowering effects of a dietary supplement of water-soluble fibers (guar gum, pectin) and mostly non-water-soluble fibers (soy fiber, pea fiber, corn bran) in subjects with mild to moderate hypercholesterolemia (LDL cholesterol, 3.37-4.92 mmol/L).nnnMETHODSnAfter stabilization for 9 weeks on a National Cholesterol Education Program Step 1 Diet, subjects were randomly assigned to receive 20 g/d of the fiber supplement (n = 87) or matching placebo (n = 82) for 15 weeks and then receive the fiber supplement for 36 weeks. The efficacy analyses included the 125 subjects (58 fiber; 67 placebo) who were treatment and diet compliant. One hundred two (52 fiber; 50 placebo) completed the 15-week comparative phase. Of these subjects 85 (45 fiber; 40 placebo) elected to continue in the 36-week noncomparative extension phase.nnnRESULTSnThe mean decreases during the 15-week period for LDL cholesterol (LDL-C), total cholesterol (TC), and LDL-C/HDL-C ratio were greater (P < 0.001) in the fiber group. The mean changes from pre-treatment values in LDL-C, TC, and LDL-C/HDL-C ratio for subjects in the fiber group were -0.51 mmol/L (-12.1%), -0.53 mmol/L (-8.5%), and -0.30 (-9.4%), respectively. The corresponding changes in the placebo group were -0.05 mmol/L (-1.3%), -0.05 mmol/L (-0.8%), and 0.05 (1.5%), respectively. The fiber supplement had no significant effects (P > 0.05) on HDL cholesterol (HDL-C), triglyceride, iron, ferritin, or vitamin A or E levels. Similar effects were seen over the subsequent 36-week noncomparative part of the study.nnnCONCLUSIONSnThe fiber supplement provided significant and sustained reductions in LDL-C without reducing HDL-C or increasing triglycerides over the 51-week treatment period.

Effect of fluvastatin on low-density lipoprotein peak particle diameter☆

The effect of fluvastatin on low-density lipoprotein (LDL) particle diameter was investigated in 42 hypercholesterolemic patients. Fluvastatin reduced LDL cholesterol significantly but had no effect on LDL particle diameter; it also had no differential effect on patients classified as LDL pattern A (large LDL), pattern B (small LDL), or I (intermediate LDL).

Relation of coronary artery calcium identified by electron beam tomography to serum lipoprotein levels and implications for treatment.

This study was designed to determine whether the National Cholesterol Education Program (NCEP) lipid guidelines accurately identify subclinical atherosclerosis and whether low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels are related to the extent and prematurity of coronary artery disease (CAD) as determined by electron beam tomography (EBT). Out of personal concern for CAD risk, 930 consecutive asymptomatic subjects, without clinical CAD and on no lipid-lowering agents, underwent EBT. Calcium score and percentile were correlated with total cholesterol (TC), LDL-C, HDL-C, triglycerides, and demographic parameters. A calcium score of > 0 (EBT+) was found in 55% of patients; 45% of patients had a 0 score (EBT-). Mean age (58.0 +/- 10.5 vs 49.3 +/- 9.7 years, p = 0.0001), TC (218 +/- 39 vs 211 +/- 41 mg/dl, p = 0.006), LDL-C (136 +/- 36 vs 127 +/- 27 mg/dl, p = 0.005), and TC/HDL-C (4.6 +/- 1.4 vs 4.2 +/- 1.5, p = 0.0001) were significantly higher and HDL-C (52.2 +/- 17.6 vs 55.4 +/- 19.3 mg/dl, p = 0.008) lower in the EBT+ compared with EBT- group. In the EBT+ group, 75.1% of subjects had LDL-C < 160 mg/dl and would not be advised to use lipid-lowering medications according to NCEP guidelines. In subjects with LDL-C < 160 mg/dl, 51.8% of subjects were EBT+, as were 46.1% of those with LDL-C < 100 mg/dl. There were no significant differences in the calcium scores throughout the entire range of all lipid parameters; calcium percentiles were virtually identical within lipid value subgroups. We conclude that asymptomatic patients with EBT-defined subclinical atherosclerosis are not reliably identified by NCEP guidelines, and TC, LDL-C, HDL-C, TC/HDL-C, and triglyceride levels do not correlate with either the extent or prematurity of calcified plaque burden.

Association of lipoprotein subclass distribution with use of selective and non-selective beta-blocker medications in patients with coronary heart disease

The relationship of beta-blocker drug use to plasma low density lipoprotein-cholesterol (LDL-C), lipoprotein mass distribution, (LDL, Sf0-12), intermediate density lipoproteins (IDL, Sf12-20), very low density lipoproteins (VLDL, Sf20-400), and high density lipoproteins (HDL, F(1.2)0-9) were examined in 206 men with coronary heart disease. Thirty-three used non-selective (NSEL), 49 used selective (SEL), and were compared to 124 who used no beta-blockade (NoBB). No significant between group differences were seen for potentially confounding variables. LDL and IDL mass, total cholesterol and LDL-cholesterol were not significantly different between groups. HDL-C was significantly lower in both NSEL (P < 0.005) and SEL (P < 0.01). NSEL and SEL had significantly lower HDL mass (P < 0.005 and P < 0.005) and SEL (P < 0.01 and P = 0.06), and HDL3 mass (P < 0.01 and P < 0.05). VLDL mass was significantly higher (P < 0.02) only in NSEL. Small LDL (Sf0-7) was not significantly different between groups and large LDL (Sf7-12) was significantly lower in NSEL (P < 0.05) and SEL (P < 0.05). LDL peak Sf was significantly lower in both NSEL (P < 0.005) and SEL (P < 0.02) compared to NoBB. Despite the lack of differences in levels of LDL-cholesterol, beta-blocker use is associated with a significant difference in the distribution of larger, more buoyant to smaller, more dense LDL particles. Reduced HDL levels in subjects on beta-blockade therapy are associated with reductions in both HDL2 and HDL3 subclasses.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic Disorders Contribute to Subclinical Coronary Atherosclerosis in Patients With Coronary Calcification

This investigation determined the prevalence of low-density lipoprotein (LDL) subclass distribution abnormalities, elevated lipoprotein(a) (Lp(a)), and elevated total plasma homocysteine in asymptomatic subjects with subclinical coronary artery disease determined by electron beam tomography (EBT). Fifty-five percent of subjects were classified as higher risk patients and 45% as lower risk patients, employing the National Cholesterol Education Program (NCEP) lipid criteria. EBT was performed in 296 consecutive asymptomatic subjects, and blood was analyzed for total, LDL, and high-density lipoprotein (HDL) cholesterol, triglycerides, LDL subclass distribution by S(3) gradient gel electrophoresis, Lp(a), and total homocysteine. Disorders of LDL subclass distribution were the most common disorder with 60.6% of the population expressing a distribution in the small regions IIIa + IIIb of >20%; and this was more common in the NCEP higher risk group (LDL cholesterol > or =130 and/or HDL cholesterol <35 mg/dl) (p <0.0004). A Lp(a) value >25 mg/dl was found significantly more often in the NCEP higher (36.9%) compared with lower (14.3%) risk group (p <0.001). None of the laboratory measurements correlated with the calcium score or calcium score percentile rank, with the exception of a weak correlation of mean LDL peak particle diameter and calcium percentile (r = 0.14, p = 0.02). Determination of metabolic disorders in addition to LDL cholesterol and HDL cholesterol increased the diagnostic yield from 55.1%, based on NCEP lipid criteria, to 84.1% with the addition of LDL subclass distribution, Lp(a), and total homocysteine. We conclude that: (1) disorders of LDL subclass distribution and elevated Lp(a) occur frequently in NCEP higher risk patients with subclinical coronary artery disease and are the only identifiable disorders in lower NCEP risk patients; and (2) electron beam tomographic evaluation and determination of LDL subclass distribution and Lp(a) should be considered for incorporation into primary prevention guidelines.

Effects of acute and chronic alcohol consumption on postprandial lipemia in healthy normotriglyceridemic men

Abstract The contribution of alcohol to the atherosclerotic process is controversial. Epidemiologic studies suggest that it has a beneficial effect on the incidence of coronary events and moderate drinkers have less coronary heart disease then nondrinkers.1 The amount consumed, and the manner in which it is consumed, may be a factor. Autopsy studies indicate that alcoholics have less atherosclerosis than moderate or nondrinkers.2 Alcohol is typically consumed in 2 settings, without food or with meals. During a typical 24-hour day, 80% of the time is spent in a postprandial state that involves elevations in postprandial triglyceride-rich lipoproteins that may contribute to atherosclerosis.3 To clarify the effect of alcohol ingestion on postprandial lipids, we investigated the effect of consuming alcohol on fasting and postprandial triglyceride and lipoprotein cholesterol when the alcohol was consumed with food and without food during conditions of chronic alcohol ingestion or abstinence. The interaction of chronic and acute alcohol consumption on postprandial lipemia may shed light on the manner in which alcohol affects lipids and lipoprotein cholesterol, and consequently atherosclerosis.

Exercise and Lipoprotein Metabolism

Physical activity can have a significant effect on plasma lipoproteins and lipoprotein metabolism. The effect of exercise on lipoprotein subclasses is often more significant than is reflected by routine measures of lipoprotein cholesterol. These effects have important clinical implications. Some apolipoprotein levels, with the exception of those of lipoprotein (a), are affected by physical activity. Changes in enzymes, as well as transfer protein, activity can help explain the exercise-induced changes in lipoprotein levels. Understanding the complex interaction between exercise and lipoprotein metabolism will enable the therapeutic use of exercise in the appropriate patient population.