Long-term safety and efficacy of anacetrapib in patients with atherosclerotic vascular disease.

AIMS: REVEAL was the first randomized controlled trial to demonstrate that adding cholesteryl ester transfer protein inhibitor therapy to intensive statin therapy reduced the risk of major coronary events. We now report results from extended follow-up beyond the scheduled study treatment period. METHODS AND RESULTS: A total of 30 449 adults with prior atherosclerotic vascular disease were randomly allocated to anacetrapib 100 mg daily or matching placebo, in addition to open-label atorvastatin therapy. After stopping the randomly allocated treatment, 26 129 survivors entered a post-trial follow-up period, blind to their original treatment allocation. The primary outcome was first post-randomization major coronary event (i.e. coronary death, myocardial infarction, or coronary revascularization) during the in-trial and post-trial treatment periods, with analysis by intention-to-treat. Allocation to anacetrapib conferred a 9% [95% confidence interval (CI) 3-15%; P = 0.004] proportional reduction in the incidence of major coronary events during the study treatment period (median 4.1 years). During extended follow-up (median 2.2 years), there was a further 20% (95% CI 10-29%; P < 0.001) reduction. Overall, there was a 12% (95% CI 7-17%, P < 0.001) proportional reduction in major coronary events during the overall follow-up period (median 6.3 years), corresponding to a 1.8% (95% CI 1.0-2.6%) absolute reduction. There were no significant effects on non-vascular mortality, site-specific cancer, or other serious adverse events. Morbidity follow-up was obtained for 25 784 (99%) participants. CONCLUSION: The beneficial effects of anacetrapib on major coronary events increased with longer follow-up, and no adverse effects emerged on non-vascular mortality or morbidity. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomized trials of lipid-modifying agents to assess their full benefits and potential harms. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN) 48678192; ClinicalTrials.gov No. NCT01252953; EudraCT No. 2010-023467-18.

Plasma mevalonate as a measure of cholesterol synthesis in man.

Measurement of mevalonic acid (MVA) concentrations in plasma or 24-h urine samples is shown to be useful in studies of the regulation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and cholesterol synthesis. Plasma MVA concentrations, measured either at 7-9 a.m. after an overnight fast, or throughout the 24-h cycle, were compared with cholesterol synthesis rates that were measured by the sterol balance method: plasma MVA concentrations were directly related to the rate of whole body cholesterol synthesis (r = 0.972; p less than 0.001; n = 18) over a tenfold range of cholesterol synthesis rates. Moreover, hourly examination of MVA concentrations throughout the day demonstrated that interventions such as fasting or cholesterol feeding cause suppression of the postmidnight diurnal rise in plasma MVA concentrations, with little change in the base-line of the rhythm. Thus, the daily rise and fall of plasma MVA appears to reflect changes in tissues and organs, such as the liver and intestine, that are known to be most sensitive to regulation by fasting or by dietary cholesterol. The hypothesis that short-term regulation of HMG-CoA reductase in tissues is quickly reflected by corresponding variations in plasma MVA was tested by using a specific inhibitor of HMG-CoA reductase, mevinolin, to block MVA synthesis. Mevinolin caused a dose-dependent lowering of plasma MVA after a single dose; and in patients who received the drug twice a day for 4 wk, it decreased 24-h urinary MVA output. Significant lowering of plasma cholesterol was achieved through administration of mevinolin at doses that only moderately limit MVA production.

Cholesterol-lowering effect of mevinolin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme a reductase, in healthy volunteers.

Mevinolin reduces cholesterol synthesis by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The safety and effectiveness of this agent was evaluated in a double-blind, placebo-controlled study in 59 healthy men (serum cholesterol 3.88--7.76 mmol/liter) in five centers. Subjects maintained their usual diet and activities. Doses of 6.25, 12.5, 25, or 50 mg twice daily for 4 wk produced mean reductions of total serum cholesterol fo 23--27% [vs. placebo (4%), P less than 0.01]. Mean low density lipoprotein cholesterol fell 35--45%, while high density lipoprotein and very low density lipoprotein cholesterol, and triglycerides were not significantly affected. Mean apolipoprotein B fell 27--34%. 50 mg was not significantly more effective than 6.25 mg. Mevinolin was generally well tolerated, and no serious clinical or laboratory abnormalities occurred. One subject (12.5 mg) was withdrawn because of abdominal pain and diarrhea. These results suggest that if long-term safety can be demonstrated, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase are likely to prove useful in the treatment of hypercholesterolemia.

Safety and tolerability of cholesterol lowering with simvastatin during 5 years in the Scandinavian Simvastatin Survival Study.

BACKGROUND: Long-term safety is an important consideration in the selection and use of drugs, such as lipid-lowering agents, that are prescribed to reduce the risk of clinical events during long periods. METHODS: The Scandinavian Simvastatin Survival Study was designed to evaluate the effects of cholesterol lowering with simvastatin on mortality and morbidity in patients with coronary heart disease. The 4444 patients aged 35 to 70 years (mean, 58.9 years) with angina pectoris or previous myocardial infarction and serum cholesterol levels of 5.5 to 8.0 mmol/L (213-310 mg/dL) receiving a lipid-lowering diet were randomly assigned to take double-blind treatment with simvastatin, 20 to 40 mg once daily, or placebo. In addition to previously reported end-point events, detailed clinical and laboratory safety data were collected during a median follow-up period of 5.4 years (range in survivors, 4.9-6.2 years). RESULTS: The only clearly drug-related serious adverse event during the 5.4-year median follow-up period was a single reversible case of myopathy. The frequencies of persistent elevations of hepatic aminotransferase levels above 3 times the upper limit of normal and of nonviral hepatitis in the simvastatin and placebo treatment groups were not significantly different. Examination of the lens showed no between-group differences, and no previously unrecognized adverse effects of the drug were observed. There were no significant between-group differences in adverse events in any body system. In particular, the frequency of adverse events related to the central nervous system was similar in both groups. CONCLUSION: The safety profile of simvastatin, 20 to 40 mg daily, over 5 years was excellent.

Changes in estrogen receptor levels during deciduomata development in the pseudopregnant rat.

The presence of a cytoplasmic estradiol receptor with an affinity constant of 10(10)M-1 has been demonstrated in the differentiated fibroblasts comprising the deciduomata in pseudopregnant rats. The receptor had a sedimentation coefficient of 6S in sucrose density gradients containing a physiological concentration of salt, and estradiol binding was completely abolished by a hundred-fold excess of unlabeled estradiol. During the early stages of decidualization (days 2 and 3), the decidualized uterine horn or isolated deciduomal tissue contained a concentration of receptor comparable to that in non-gravid uteri from rats ovariectomized at estrus. By day 5 of decidualization, the concentration of estradiol binding in deciduomal tissue decreased to about one-half the concentration measurable at days 2 and 3 of decidualization despite continued tissue growth until day 7. By day 7 of decidualization, estradiol binding had decreased to about 20% of the concentration on days 2 and 3 of decidualization. Cytosol from untreated uterine horns of rats bearing deciduomata bound the same amount of estradiol through day 7 as that in uteri of rats ovariectomized at estrus. These observations are discussed in terms of steroid hormone involved in deciduomal growth and regression.

Changes in progesterone receptor levels during deciduomata development in the pseudopregnant rat.

A specific cytoplasmic progesterone receptor has been identified and quantified in the deciduomata of the pseudopregnant rat. The receptor had a sedimentation coefficient of 6-7S on sucrose density gradients and was inactivated by proteolytic enzymes, sulfhydryl blocking agents and elevated temperature. The equilibrium association constant for the binding of progesterone by the deciduomal receptor was determined to be approximately 10(9)M-1. The concentrations of progesterone receptor sites in cytosols prepared from deciduomata on day 3 and 5 of decidualization were 3.4 +/- 0.3 X 10(-10)M and 3.6 +/- 0.4 X 10(10)M, respectively, when normalized to a protein concentration of 1 mg/ml. These concentrations of progesterone receptor sites were similar to that measured in the uterine cytosol of estrous rats or in the contralateral untreated uterine horn of rats undergoing decidualization. Following day 5 of decidualization the concentrations of progesterone receptor sites decreased linearly so that by day 7 the concentration was approximately one-half that at days 3 and 5. The physiological significance of the progesterone receptor and the decrease in its concentration with time are discussed with regard to their influence on the decidualization reaction.

Indacrinone: modification of diuretic, uricosuric, and kaliuretic actions by amiloride.

The response to indacrinone, a new indanone diuretic, was studied in 12 healthy subjects. Ten milligrams alone and in combination with either 2.5 mg or 5 mg amiloride was given in a randomized double-blind study with placebo control to study its action and to assess the optimum combination. Indacrinone alone induced an increase in urine flow rate and in sodium, potassium, and hydrogen ion excretion for at least 8 hr. Indacrinone also induced an initial uricosuria in the first 4 hr, followed by urate retention in the subsequent 12 to 24 hr, with no resultant change in the mean 24-hr urate excretion and minimal changes in the serum urate concentrations. The addition of 2.5 mg amiloride to the 10 mg indacrinone lowered potassium excretion to control levels, whereas addition of 5 mg amiloride resulted in net retention of potassium. With both doses of amiloride, the increased free hydrogen ion excretion after indacrinone returned to placebo levels. There were minor increases in serum creatinine, consistent with volume depletion due to the diuresis. There was a reduction in urinary calcium excretion. Our study shows that the combination of 10 mg indacrinone and 2.5 mg amiloride induces useful diuresis with minimal overall effect on urate, potassium, and hydrogen ion excretion.

Dynamics and kinetics of ophthalmic timolol.

Timolol is a beta adrenergic antagonist in 0.25% or 0.5% eyedrop solution for glaucoma. In a double-blind crossover study in healthy males we measured systemic beta blockade, intraocular pressure, and timolol kinetics after the first and ninth 12-hourly dose of a 0.5% ophthalmic solution. Timolol ophthalmic and placebo were each given as 2 drops to each eye with precautions to prevent the normal loss of drug in tears and overflow (high dose) and as 1 drop to each eye with no special precautions (standard therapeutic dose). Exercise tachycardia, measured at 70 and 255 min after administration of drug, was lower at both levels. Postexercise 1-sec forced expiratory volume (FEV1) was not affected. Intraocular pressure measured at 3 and 8 hr after drug was lower at both dose levels. Timolol was consistently present in urine but was not detectable in most plasma samples. Dynamic effects were not greater after the ninth than after the first dose, and the urinary excretion data provided no evidence of drug cumulation.

Enhancement of uricosuric properties of indacrinone by manipulation of the enantiomer ratio.

Racemic indacrinone is a high-ceiling, relatively long-acting diuretic. Both enantiomers have uricosuric activity, but the diuretic activity resides predominantly in the (-) enantiomer. Usual therapeutic doses of racemic indacrinone have only transient uricosuric activity, so that, as with other diuretics, hyperuricemia occurs. Sixty-five healthy men participated in a multicenter, double-blind, randomized, balanced, incomplete-block study comparing the effects on plasma urate and urate clearance of indacrinone (-) enantiomer 10 mg given concomitantly with 0, 10, 20, 40, and 80 mg (+) enantiomer (10/0, 10/10, 10/20, 10/40, 10/80), as single daily doses for 7 days. Hydrochlorothiazide (HCTZ) 50 mg daily and ticrynafen (T) 250 mg daily were controls. Each subject received two of the seven treatments, so that there were 18 subjects per treatment. On days 7 to 8, morning (mean of 0-hr values on days 7 and 8), HCTZ, 10/0, 10/10, and 10/20 elevated plasma urate by 8% to 16%. 10/40 was approximately isouricemic, and 10/80 and T lowered plasma urate by 13% and 41%. There were corresponding changes in urate clearance.

Effect of antacids on the bioavailability of diflunisal in the fasting and postprandial states.

Diflunisal is long-acting salicylate derivative. We examined the effect of single concomitant doses of three antacids on diflunisal bioavailability under fasting or fed conditions (30 min after finishing a standard meal). With the use of an open, randomized, and balanced design, one 250-mg diflunisal tablet was given to each of 12 healthy men under six conditions: fasted, no antacid; fed, no antacid; fasted, 15 ml of aluminum hydroxide gel; fed, 15 ml of aluminum hydroxide gel; fasted, 10 ml magnesium hydroxide suspension; and fed, 15 ml of an aluminum hydroxide/magnesium hydroxide mixture. Diflunisal plasma 0- to 48-hr area uiven to each of 12 healthy men under six conditions: fasted, no antacid; fed, no antacid; fasted, 15 ml of aluminum hydroxide gel; fed, 15 ml of aluminum hydroxide gel; fasted, 10 ml magnesium hydroxide suspension; and fed, 15 ml of an aluminum hydroxide/magnesium hydroxide mixture. Diflunisal plasma 0- to 48-hr area uiven to each of 12 healthy men under six conditions: fasted, no antacid; fed, no antacid; fasted, 15 ml of aluminum hydroxide gel; fed, 15 ml of aluminum hydroxide gel; fasted, 10 ml magnesium hydroxide suspension; and fed, 15 ml of an aluminum hydroxide/magnesium hydroxide mixture. Diflunisal plasma 0- to 48-hr area under the time curve (AUC), peak plasma concentrations, and 0-to 96-hr urinary excretion were determined. Food (alone) decreased peak plasma concentrations by 16% (P less than 0.05) but did not affect AUC or urinary excretion. Under fasting conditions, aluminum hydroxide reduced AUC by 26% (P less than 0.01), peak plasma concentrations by 46% (P less than 0.01), and urinary excretion by 14% (P less than 0.05). Magenisuum hydroxide suspension (in the fasting state) increased the early plasma concentrations (by 130% at 0.5 hr and 64% at 1 hr, P less than 0.05) and increased AUC by 10% (P less than 0.05) but had no effect on urinary excretion. In the fed state neither aluminum hydroxide nor the aluminum hydroxide/magnesium hydroxide mixture had any detectable effect.

Rapid and substantial lowering of human serum cholesterol by mevinolin (MK-803), an inhibitor of hydroxymethylglutaryl-coenzyme A reductase.

Mevinolin (MK-803) is a potent inhibitor of HMG-CoA reductase. After a placebo run-in period, mevinolin 5,15 or 50 mg, or placebo was given twice daily for 7-11 days under double -blind conditions ot 4 groups of 6 normocholesterolemic male volunteers. After 7 days, mean serum cholesterol fell 14%, 25% and 24% on 5, 15 and 50 mg, respectively, which was significantly greater than the fall on placebo (4%) in the case of the two higher doses (P less than 0.01). Serum triglycerides did not change significantly. Mevinolin was generally well-tolerated and there were no serious adverse effects.

Efficacy and long-term adverse effect pattern of lovastatin.

The efficacy of lovastatin, a potent inhibitor of HMG CoA reductase, has been established by numerous studies. At doses of 40 mg administered twice daily, lovastatin produces a mean reduction in total plasma cholesterol of 33%, attributable to a reduction in low-density lipoprotein cholesterol of 41%. The drug also produces a mean increase in high-density lipoprotein cholesterol of 9%, and a reduction in the high- and low-density lipoprotein cholesterol ratio of 44%. The serious reported adverse effects of lovastatin are myopathy (0.5%) and asymptomatic but marked and persistent increases in transaminases (1.9%). Both are reversible when therapy is discontinued. Myopathy has occurred mainly in patients with complicated histories who were receiving concomitant therapy with immunosuppressive drugs, gemfibrozil or niacin. In an ongoing long-term safety study, 744 patients have received lovastatin for an average duration of 2.5 years up to March 1988. Fifteen patients (2.0%) have been withdrawn because of drug-attributable adverse events: raised transaminases (9), skin rash (2), gastrointestinal symptoms (2), myopathy (1) and insomnia (1). No effect of the drug on the human lens has been observed up to the date mentioned above. Lovastatin has been available in the United States since September 1987. By March 1988, the drug had been prescribed for approximately 250,000 patients. This clinical experience has confirmed the tolerability observed in clinical trials. The good adverse-effect profile of lovastatin is thus now supported both by a substantial body of data in patients treated for over 2 years in clinical trials, and by experience in clinical use with a large number of patients since the drug has been available for prescription.

Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin.

The long-term safety profile of simvastatin, established over 10 years of clinical use, is excellent. The principal adverse effect of all inhibitors of hydroxymethylglutarate co-enzyme A (HMG-CoA) reductase, myopathy, is infrequent. Simvastatin is a substrate for cytochrome P450 3A4 (CYP3A4). CYP3A4 inhibitors can elevate the plasma concentration of HMG-CoA reductase inhibitory activity derived from simvastatin. Clinical experience has shown that concomitant use of potent inhibitors of CYP3A4 increase the risk for myopathy. Evaluation of data from clinical trials and postmarketing surveillance allows assessment of whether concomitant use of weaker CYP3A4 inhibitors, as represented by calcium channel blockers, has any effect on the risk of myopathy. Cases of myopathy in long-term clinical megatrials and in analyses of postmarketing adverse event reports have been surveyed. In megatrials with simvastatin, the overall incidence of myopathy was 0.025%. The proportion of patients developing myopathy who were taking a calcium channel blocker with simvastatin (1 of 3) was similar to the proportion of patients taking a calcium channel blocker overall. Among marketed-use adverse event reports, concomitant medication with a potent CYP3A4 inhibitor was more frequent among reports of myopathy than among reports of nonmusculoskeletal adverse events. No excess use of calcium channel blockers among myopathy reports was observed. We conclude that the overall risk of myopathy during treatment with simvastatin is very low. Potent CYP3A4 inhibitors, especially cyclosporine, significantly increase the risk. There is no evidence that weaker CYP3A4 inhibitors such as calcium channel blockers increase the risk.

Effects of high doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I.

A randomized, blinded, multicenter clinical trial was performed comparing low- and high-dose simvastatin (40 and 80 mg) with comparable doses of atorvastatin (20 and 40 mg) for effects on plasma concentrations of lipoproteins and apolipoprotein A-I over 12 weeks in 842 patients with elevated low-density lipoprotein cholesterol. The 2 agents reduced low-density lipoprotein cholesterol and triglycerides to a comparable degree, but simvastatin raised high-density lipoprotein cholesterol and apolipoprotein A-I more than atorvastatin, suggesting differences in metabolic effects of the 2 agents on plasma lipids and lipoproteins.

Clinical experience with lovastatin.

New information on the tolerability of lovastatin has emerged from an ongoing study of long-term therapy; preliminary results from a large, 48-week clinical trial; and spontaneous reports of adverse events observed during prescription use of the drug in the United States. As of June 1989, 744 patients had received lovastatin for an average duration of 3.6 years in the long-term study. Drug-attributable adverse events necessitated withdrawal of 17 patients (2.3%) from the study. These adverse effects were asymptomatic elevations of transaminases (10), skin rash (3), gastrointestinal symptoms (2), myopathy (1) and insomnia (1). No effect of lovastatin on the human lens was observed. In the 48-week study, 8,245 patients were randomized into 5 equal groups to receive placebo or lovastatin 20 or 40 mg once or twice daily on a double-blind basis. Only 3 cases of myopathy were observed, all in patients taking lovastatin 40 mg twice daily. The incidence of withdrawal from the study because of raised transaminases was approximately 0.1% in the placebo group vs 0.1, 0.7, 0.6 and 1.5% in patients taking lovastatin in doses of 20 mg once daily, 40 mg once daily, 20 mg twice daily and 40 mg twice daily, respectively. Lovastatin has been available in the United States since September 1987. By June 1989, the drug had been prescribed for approximately 1 million patients. Drug-attributable adverse events not observed in clinical trials (such as hypersensitivity reactions and symptomatic hepatitis) have been reported, but the incidence of each appears to be extremely low.

Effect of simvastatin on ischemic signs and symptoms in the Scandinavian simvastatin survival study (4S).

In patients participating in the Scandinavian Simvastatin Survival Study, cholesterol lowering with simvastatin reduced the incidence of carotid bruits and cerebrovascular events as well as new-onset or worsening of angina pectoris and intermittent claudication. These effects suggest that simvastatin may have a general antiatherosclerotic effect not limited to the coronary bed.

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.

Benefits and risks of HMG-CoA reductase inhibitors in the prevention of coronary heart disease: a reappraisal.

Although several cholesterol-lowering interventions have reduced coronary heart disease (CHD) events in clinical trials, drug therapy for hypercholesterolaemia has not been as widely used as the US and European guidelines recommend, mainly because until recently there was insufficient clinical trial evidence for improved survival. The Scandinavian Simvastatin Survival Study (4S) is the first trial of lipid-lowering therapy to demonstrate an unequivocal reduction in total mortality. Largely as a result of this study, there is now little disagreement on the necessity to reduce low density lipoprotein (LDL) cholesterol effectively in hypercholesterolaemic patients with CHD. Many physicians believe it is also important to reduce elevated levels of LDL cholesterol in patients without overt coronary disease, but more clinical trial evidence will be required before this is universally accepted. Inhibitors of HMG-CoA reductase are the most effective class of agents for this purpose, and have become widely used. It is likely that the magnitude of risk reduction produced by lipid-lowering therapy is proportional to the degree of cholesterol lowering achieved, which is an important consideration when selecting an agent and deciding the dosage to use. The results of several multicentre comparative trials have clearly established that the 4 members of the class are not all equipotent on a mg basis in terms of their effects on lowering LDL cholesterol. They have shown that the hypolipidaemic effect of simvastatin 5 mg approximately equals that of pravastatin 15 mg and lovastatin 15 mg and that of fluvastatin 40 mg, all given once daily. The tolerability profiles of HMG-CoA reductase inhibitors are excellent. Five-year data are available for simvastatin and lovastatin, and to date there is no good evidence for important differences in safety or tolerability among the class.

A review of clinical trials comparing HMG-CoA reductase inhibitors.

Four drugs that act as specific inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase--lovastatin, pravastatin, simvastatin, and, most recently, fluvastatin--have been approved by regulatory authorities throughout the world. In the present review, we have critically assessed the comparative hypocholesterolemic effects of these four drugs based on direct comparative studies, which were randomized, double-blind, and included more than 25 patients per treatment group. All studies were conducted in patients with primary hypercholesterolemia and the major end point of efficacy was reduction in the plasma concentrations of low-density lipoprotein (LDL)-cholesterol. Eight comparative trials have evaluated the efficacy and safety of lovastatin, simvastatin, or pravastatin, and one recently completed trial has compared lovastatin and fluvastatin. These trials confirm the log-linear dose response curves for all four of these drugs but indicate that on a milligram-for-milligram basis, lovastatin and pravastatin are approximately equipotent, whereas simvastatin is at least twice as effective per milligram of drug administered as lovastatin and pravastatin. Lovastatin at doses of 20 and 40 mg/d was of similar efficacy to fluvastatin at doses of 40 and 80 mg/d and would suggest that on a milligram-for-milligram basis, fluvastatin is half as potent as lovastatin. The side-effect profiles of all four drugs appeared similar, and earlier reports that suggested a higher incidence of sleep disorders in patients treated with the more lipophilic drugs, lovastatin and simvastatin, as compared with pravastatin, are not supported by more recent, controlled clinical trials. We conclude that although the currently available HMG-CoA reductase inhibitors differ in their relative hypolipidemic effects, as a class they constitute the most effective agents available to maximally reduce elevated concentrations of LDL-cholesterol.

Efficacy, pharmacokinetics and tolerability of a somatostatin analogue (L-363,586) in insulin-dependent diabetes mellitus.

To assess the pharmacologic properties and possible use in the treatment of diabetes mellitus of a recently developed analogue somatostatin (L-363,586), the analogue (2, 5, 10 or 40 micrograms/hr), somatostatin (200 micrograms/hr), or placebo were infused intravenously for 5 hours in 6 insulin-dependent diabetic subjects who were given a standard meal containing xylose. The metabolic clearance rate of the analogue (approximately 300 ml/min) was 1/6 that previously reported for somatostatin (approximately 2000 ml/min) and its half-life was approximately 20 times as great as that reported for somatostatin (45 vs 2 min). At a dose of 10 micrograms/hr, the analogue produced suppression of plasma glucagon, growth hormone, glucose, xylose and triglyceride responses to meal ingestion which were comparable to those observed when somatostatin was infused at a rate of 200 micrograms/hr. We conclude that L-363,586 is a long-acting and potent analogue of somatostatin, which has the potential for use as an adjunct to insulin in the treatment of diabetes mellitus.