D. Roger Illingworth

Lovastatin (Mevinolin) in the Treatment of Heterozygous Familial Hypercholesterolemia: A Multicenter Study

STUDY OBJECTIVE To evaluate the efficacy and tolerability of lovastatin under controlled conditions in heterozygous familial hypercholesterolemia. DESIGN Randomized, double-blind, placebo-controlled, multicenter trial. SETTING Five lipid clinics with a central laboratory and coordinating center. PATIENTS 101 adult patients with heterozygous familial hypercholesterolemia. INTERVENTIONS Patients were on a lipid-lowering diet throughout the study. After a 4-week placebo baseline period, patients were randomized to five equal treatment groups. Each group received a different sequence of placebo or lovastatin 5 to 40 mg twice daily or 20 to 40 mg once daily in the evening, during three consecutive 6-week periods. MEASUREMENTS AND MAIN RESULTS The mean reductions in total plasma cholesterol and low-density lipoprotein cholesterol across the dosage ranges were 14% to 34% and 17% to 39%, respectively (p compared with zero and placebo less than 0.01). High-density lipoprotein cholesterol and apolipoproteins AI and AII rose slightly. Apolipoprotein B fell substantially at the higher dosage levels (-23% at 40 mg twice daily, p less than 0.01), indicating a reduction in the concentration of circulating low-density lipoprotein particles. Maximum response was achieved in 4 to 6 weeks. Twice-daily dosing was slightly more efficient than once-daily dosing. Of those patients receiving 40 mg twice a day, 89% had a fall in low-density lipoprotein cholesterol of at least 20%, and 61% had a fall of at least 40%. Adverse effects attributable to lovastatin were minimal, and no patient was withdrawn from the study. CONCLUSION Lovastatin was well tolerated and effective in the treatment of familial hypercholesterolemia.

The Efficacy and Six-Week Tolerability of Simvastatin 80 and 160 mg/Day

The hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin is the most effective of the currently approved hypolipidemic drugs and has been shown to reduce mortality and coronary morbidity in patients with coronary artery disease. For these patients the United States National Cholesterol Education Program advocates reducing low-density lipoprotein (LDL) cholesterol to <100 mg/dl. However, in some patients this cannot be achieved using monotherapy with simvastatin 40 mg/day, the current maximal recommended dose. To evaluate the effectiveness of extending the dosage range, 156 subjects with LDL cholesterol >160 mg/dl and triglycerides (TG) <350 mg/dl were randomized to simvastatin at doses of 40, 80, and 160 mg/day in a 26 week, double-blind, 3-period, complete block crossover study. Each active treatment period was 6 weeks in duration with intervening 2 week washout periods. Median reductions from baseline in LDL cholesterol were 41%, 47%, and 53% in the 40-, 80-, and 160-mg groups, respectively. The corresponding reductions in plasma TG were 21%, 23%, and 33%. High-density lipoprotein (HDL) cholesterol increased by 6% to 8% in each group. One patient (0.7%) taking 160 mg developed myopathy; 1 patient (0.7%) taking 80 mg, and 3 (2.1%) taking 160 mg had transaminase elevations > 3 times the upper limit of normal. No new or unexpected adverse effects were observed. We conclude that simvastatin at doses of 80 and 160 mg/day provides additional efficacy with a low short-term incidence of adverse effects; our results support the continued investigation of simvastatin at these doses.

Dietary omega-3 fatty acids prevent carbohydrate-induced hypertriglyceridemia

Dietary fish oils rich in omega-3 fatty acids are remarkably hypotriglyceridemic in both normal and hypertriglyceridemic subjects. This present study was designed to examine the hypothesis that dietary fish oils could prevent the usual sharp increase in plasma triglyceride and very low-density lipoprotein (VLDL) levels that occur physiologically after the induction by a high-carbohydrate diet. Seven healthy volunteers consumed three experimental liquid formula diets: the baseline diet (45% fat, 10% protein, 45% carbohydrate) and two high-carbohydrate diets (15% fat, 10% protein, 75% carbohydrate), one as a control diet and the other containing fish oil. The baseline and control dietary fats were a mixture of peanut oil and cocoa butter, whereas the fish oil diet contained high levels of omega-3 fatty acids. The plasma triglyceride levels rose from 105 mg/dL during baseline diet to 194 mg/dL during the high-CHO control diet (P less than 0.005). VLDL triglyceride levels increased from 69 to 156 mg/dL (P less than 0.005) and VLDL cholesterol from 18 to 34 mg/dL (P less than 0.005). When fish oil was substituted for the control fats, plasma triglyceride levels fell from 194 to 75 mg/dL (P less than 0.005), VLDL triglyceride and cholesterol levels were reduced from 156 to 34 mg/dL (P less than 0.005) and from 34 to 12 mg/dL (P less than 0.005), respectively. These effects were noted by two to three days after beginning the fish oil diet. Thus, dietary omega-3 fatty acids from fish oil rapidly and markedly reduced VLDL triglyceride levels even in the face of a high-carbohydrate diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Rhabdomyolysis after taking atorvastatin with Gemfibrozil

The findings in this case indicate that atorvastatin, like other DL-3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, may increase the risk of myositis and rhabdomyolysis when used in combination with gemfibrozil.

Long-term effects of low-density lipoprotein apheresis using an automated dextran sulfate cellulose adsorption system

Abstract The short-term effectiveness of low-density lipoprotein (LDL) apheresis using a dextran sulfate cellulose adsorption column technique was previously examined in a 9- center, 22-week controlled trial in 64 patients with familial hypercholesterolemia (FH) who did not adequately respond to diet and drug therapy. Forty-nine patients (40 treatment, 9 controls) subsequently received LDL apheresis procedures as part of an optional follow-up phase. This study reports on the long-term safety, lipid lowering, and clinical efficacy of LDL apheresis for the 5-year period that includes both the initial controlled study and follow-up phase. During this time, patients received a total of 3,902 treatments of which 3,314 treatments were given during the follow-up phase. Adverse events were infrequent, occurring in 142 procedures (3.6%). Immediate reduction in LDL cholesterol was 76% both in homozygotes and in heterozygotes. Patients with homozygous FH had a progressive decrease in pretreatment LDL cholesterol level along with an increase in high-density lipoprotein (HDL) cholesterol level. There was no appreciable change in pretreatment lipoprotein level over time in heterozygotes. The rate of cardiovascular events during therapy with LDL apheresis and lipid-lowering drugs was 3.5 events per 1,000 patient-months of treatment compared with 6.3 events per 1,000 patient-months for the 5 years before LDL apheresis therapy. These findings support the long-term safety and clinical efficacy of LDL apheresis in patients with heterozygous and homozygous FH who are inadequately controlled with drug therapy.

The influence of apolipoprotein E phenotype on the response to lovastatin therapy in patients with heterozygous familial hypercholesterolemia

Apolipoprotein E (apo E) phenotypes have been previously shown to influence plasma lipoprotein concentrations in normal populations and to affect the response to some lipid lowering drugs. The purpose of the present study was to determine if variations in the apo E phenotype also affect basal lipoprotein concentrations in patients with heterozygous familial hypercholesterolemia (FH) and if the apo E phenotype influenced their subsequent response to lovastatin. Apo E phenotypes were determined on plasma from 134 FH patients. The relative frequencies of the epsilon 2, epsilon 3, and epsilon 4 alleles were .090, .772, and .138, respectively. Plasma triglycerides were found to be 34% higher in E3/2 heterozygotes relative to E3/3 patients. Baseline concentrations of low-density lipoprotein (LDL) cholesterol in untreated FH patients were not influenced by the apo E phenotype; the hypolipidemic response to lovastatin (20 or 40 mg twice daily) was also independent of the apo-E phenotype of the patients.

Treatment of refractory familial hypercholesterolemia by low-density lipoprotein apheresis using an automated dextran sulfate cellulose adsorption system

A subgroup of patients with familial hypercholesterolemia (FH) respond inadequately to standard diet and drug therapy, and are therefore at high risk for the premature development or progression of coronary artery disease. This study evaluated low-density lipoprotein (LDL) cholesterol and lipoprotein (a) removal in a multicenter, controlled trial with a new LDL apheresis procedure (Liposorber LA-15 System). The study comprised patients with FH who had not responded adequately to diet and maximal drug therapy. There were 54 patients with heterozygous FH (45 randomized to treatment and 9 control subjects) and 10 with homozygous FH (all of whom received LDL apheresis). The study included three 6-week treatment phases and a 4-week rebound phase. Treatments were administered at 7- to 14-day intervals. Mean acute reductions in LDL cholesterol were 76% in heterozygous FH patients and 81% in homozygous ones. Time-averaged levels of LDL cholesterol were reduced 41% (243 to 143 mg/dl) in heterozygous FH patients and 53% (447 to 210 mg/dl) in homozygous ones. The substantial acute reduction of lipoprotein (a) (means: 65%, heterozygous FH; 68%, homozygous FH) has not been reported with other therapies. The Liposorber LA-15 System represents an important therapeutic option in FH patients who respond inadequately to diet and drug therapy.

Expanded-dose simvastatin is effective in homozygous familial hypercholesterolaemia

Patients with homozygous familial hypercholesterolaemia (HFH) have abnormalities in both low-density lipoprotein (LDL) receptor alleles, resulting in severe hypercholesterolaemia and premature coronary heart disease. Limited treatment options are available and the response to drug therapy has been poor. In the present paper, we have evaluated the efficacy and safety of simvastatin at doses beyond the current maximal dose of 40 mg/day in patients with HFH. After a 4 week placebo diet run-in period, 12 patients with well-characterized HFH were randomized to simvastatin 80 mg/day administered in three divided doses (n = 8; group 1) or 40 mg once daily (n = 4; group 2). After 9 weeks, the dose in group 1 was increased to 160 mg/day while the dose in group 2 was kept at 40 mg/day, but with the drug given in three divided doses and treatment continued for an additional 9 weeks. All 12 patients completed the study and there were no serious or unexpected adverse effects. LDL-cholesterol concentrations fell by 14% at the 40 mg/day dose, but were reduced further at the higher doses (25% at the 80 mg/day and by 31% at the 160 mg/day dosage, P < 0.0001). Excretion of urinary mevalonic acid, as an index of in vivo cholesterol biosynthesis, was reduced but did not correlate with reduction in LDL-cholesterol in the individual patients. The magnitude of response to therapy was not predicted by the LDL-receptor gene defect as patients with the same LDL-receptor mutations responded differently to the same dose of simvastatin therapy. The ability of expanded doses of simvastatin (80 or 160 mg/day) to reduce LDL-cholesterol levels in patients with HFH, even if receptor negative, suggests that at these doses, the drug reduces LDL production. Simvastatin therapy, at doses of 80 or 160 mg/day, should therefore be considered in all patients with HFH, either as an adjunct to apheresis, or as monotherapy for those patients who do not have access to apheresis or other such treatment modalities.

Postprandial dyslipidemia: an atherogenic disorder common in patients with diabetes mellitus

The increased risk of coronary artery disease among patients with diabetes mellitus is attributable, in part, to specific disorders of lipoprotein metabolism that are common in this population. These include disordered metabolism of very-low-density lipoprotein and/or chylomicrons that may be proatherogenic. Elevated postprandial triglycerides, peak postprandial triglyceridemia, and late postprandial triglyceride levels have been associated in clinical trials with both early coronary artery and carotid artery atherosclerosis for persons with normal lipid profiles and those with mild-to-moderate hyperlipidemia, independently of established risk factors. If hyperlipidemia cannot be managed through better glycemic control, diet, and exercise, then hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, fibric acid derivatives, and omega-3 fatty acids are safe and effective lipid-altering agents that can be used to correct these disorders.

Lipid-lowering drugs. An overview of indications and optimum therapeutic use.

SummaryDrug treatment of patients with hyperlipoproteinaemia is indicated to reduce the risk of atherosclerosis in patients with increased concentrations of atherogenic lipoproteins, and to lower the plasma concentrations of triglyceride-rich lipoproteins in patients with severe hypertriglyceridaemia who are at risk of abdominal pain and pancreatitis. Such therapy should be initiated only after satisfactory exclusion of secondary causes of hyperlipoproteinaemia, and should be regarded as an adjunct to rather than a substitute for appropriate dietary therapy. Drug therapy should be strongly considered in those patients with concentrations of atherogenic lipoproteins which exceed the 90th to 95th percentile for age.In patients with increased plasma concentrations of low density lipoproteins (LDL), agents which enhance the rate of LDL catabolism (cholestyramine and colestipol) or reduce the rate of LDL synthesis [e.g. nicotinic acid (niacin)] are the ‘drugs of choice’. For those patients with concurrent hypertriglyceridaemia, nicotinic acid is the preferred initial drug, and in both patient groups combined drug therapy is often necessary to attain optimal reductions in LDL cholesterol concentrations. Clofibrate remains the ‘drug of choice’ for the rare patient with type III hyperlipoproteinaemia, whereas the newer agent gemfibrozil should be used in patients with plasma triglyceride concentrations above 1000 mg/dl who are at increased risk of abdominal pain and pancreatitis.Although currently limited to investigational use, mevinolin and related compounds, which are specific inhibitors of the rate-limiting enzyme in cholesterol biosynthesis (HMG Co-A reductase), offer considerable promise in the therapy of patients with primary hypercholesterolaemia due to elevated levels of LDL cholesterol.