Comparative Evaluation of the Safety and Efficacy of HMG-CoA Reductase Inhibitor Monotherapy in the Treatment of Primary Hypercholesterolemia

1995 ◽  
Vol 29 (7-8) ◽  
pp. 743-759 ◽  
Author(s):  
Irene Hsu ◽  
Sarah A Spinier ◽  
Nelda E Johnson
Keyword(s):  
Clinical Trials ◽  
Reductase Inhibitor ◽  
Efficacy And Safety ◽  
Comparative Efficacy ◽  
Hmg Coa Reductase ◽  
Primary Hypercholesterolemia ◽  
Reductase Inhibitors ◽  
Hmg Coa Reductase Inhibitors ◽  
Hmg Coa Reductase Inhibitor ◽  
Coa Reductase

Objective: To evaluate the comparative efficacy and safety of the 4 currently available hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, fluvastatin, lovastatin, pravastatin, and simvastatin, in the treatment of primary hypercholesterolemia. Data Sources: English-language clinical studies, abstracts, and review articles identified from MEDLINE searches and bibliographies of identified articles. Unpublished data were obtained from the Food and Drug Administration in accordance with the Freedom of Information Act. Study Selection: Placebo-controlled and comparative studies of HMG-CoA reductase inhibitor monotherapy in the treatment of primary hypercholesterolemia. Data Extraction: Pertinent studies were selected and the data were synthesized into a review format. Data Synthesis: The chemistry, pharmacology, and pharmacokinetics of the 4 HMG-CoA reductase inhibitors are reviewed. Clinical trials evaluating the hypocholesterolemic efficacy of the HMG-CoA reductase inhibitors are examined, and results on the comparative efficacy and safety of these agents are summarized. On a milligram-per-milligram basis, simvastatin is twice as potent as lovastatin and pravastatin. The hypocholesterolemic effects of fluvastatin appear to be approximately 30% less than that of lovastatin. In posttransplant patients receiving cyclosporine, safety has been documented for low doses of lovastatin and simvastatin, but when a higher dosage of an HMG-CoA reductase inhibitor is warranted, pravastatin should be considered the drug of choice because of a lower incidence of myopathy. Relevant data on the incidence of adverse effects are presented. Pertinent outcomes data from clinical trials evaluating the effect of HMG-CoA reductase inhibitors on atherosclerosis regression and coronary mortality, as well as published economic analyses of cholesterol-lowering agents, are summarized. Recommendations on the selection of an HMG-CoA reductase inhibitor in various clinical situations are provided. Conclusions: The literature supports the comparable safety and tolerability of all 4 currently available HMG-CoA reductase inhibitors. Therefore, the choice of an HMG-CoA reductase inhibitor should depend on the extent of cholesterol lowering needed to meet the recommended treatment goal established by the National Cholesterol Education Program. Direct comparative studies are needed to confirm the relative, long-term cost-effectiveness of the various HMG-CoA reductase inhibitors in the treatment of primary hypercholesterolemia.

scholarly journals Subcutaneous administration of HMG-CoA reductase inhibitors in hyperlipidaemic and normal rats

1992 ◽  
Vol 26 (4) ◽  
pp. 269-280 ◽  
Author(s):  
Jaap Joles ◽  
Nel Willekes-Koolschijn ◽  
Hein Koomans ◽  
Arie van Tol ◽  
Tini Geelhoed-Mieras ◽  
...  
Keyword(s):  
Reductase Inhibitor ◽  
Plasma Lipids ◽  
Reductase Activity ◽  
Plasma Cholesterol ◽  
Subcutaneous Administration ◽  
Hmg Coa Reductase ◽  
Reductase Inhibitors ◽  
Hmg Coa Reductase Inhibitors ◽  
Hmg Coa Reductase Inhibitor ◽  
Coa Reductase

Recent reports demonstrate a hypocholesterolaemic effect of daily subcutaneous injections of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in different rat models of hyperlipidaemia. However, this effect is not seen after oral administration of HMG-CoA reductase inhibitors in rats. We found that oral administration of the HMG-CoA reductase inhibitor Simvastatin also had no effect on plasma cholesterol in severely hyperlipidaemic Nagase analbuminaemic rats (NAR). Simvastatin (an apolar compound dissolved in propylene glycol) was infused continuously for 28 days into the subcutis of control Sprague-Dawley rats (SDR) and NAR using an implanted osmotic pump. All doses which were effective in reducing cholesterol in the NAR (reductions up to -60%), reduced apolipoprotein AI but not apolipoprotein B and caused a severe inflammatory reaction in the dermis. Similar toxicity was observed in the SDR. Subcutaneous administration of the vehicle (propylene glycol) did not cause this reaction and did not affect plasma lipids. Administration of Lovastatin in osmotic pumps resulted in a similar inflammatory reaction. Incorporation of Simvastatin into liposomes did not diminish the toxic effect. On the other hand, infusion of Pravastatin (a polar HMG-CoA reductase inhibitor dissolved in isotonic saline) caused no changes in the dermis and had no effect on plasma lipids in NAR or SDR. Liver microsomes prepared from the Pravastatin-treated rats demonstrated a 3- to 4-fold increase in HMG-CoA reductase activity as compared to untreated rats, confirming uptake of the drug. We conclude that continuous subcutaneous administration of the HMG-CoA reductase inhibitors Simvastatin, Lovastatin and Pravastatin for 28 days may not reduce plasma cholesterol in rats by a mechanism which is related to inhibition of HMG-CoA reductase activity in the liver. The decrease of plasma cholesterol effected by subcutaneous infusion of Simvastatin or Lovastatin in NAR coincides with, and may be related to inflammatory changes caused by administering these compounds into the dermis.

Toxicity of a Novel HMG-CoA Reductase Inhibitor in the Common Marmoset (Callithrix jacchus)

1994 ◽  
Vol 13 (5) ◽  
pp. 357-368 ◽  
Author(s):  
K. Owen ◽  
C.R. Pick ◽  
S.E. Libretto ◽  
M.J. Adams
Keyword(s):  
Recovery Period ◽  
Clinical Signs ◽  
Common Marmoset ◽  
Hmg Coa Reductase ◽  
Reductase Inhibitors ◽  
Hmg Coa Reductase Inhibitors ◽  
Chronic Study ◽  
Hmg Coa Reductase Inhibitor ◽  
Alveolar Proteinosis ◽  
Coa Reductase

1 GR95030X, a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, was administered daily to marmosets by gavage. In a Maximum Repeatable Dose (MRD) study, doses of up to 30 mg kg-1 day-1 were administered for 49 days. In a chronic study, animals received dosages equivalent to 0, 1, 2.5, 7,5 and 20 mg kg-1 day-1 for 204 or 205 days. Some animals were maintained without treatment for a recovery period of 29 or 30 days, 2 Clinical signs included poor coat condition, weakness with impaired coordination, lethargy and other behavioural changes, There was also alimentary disturbance, and some deaths occurred at doses of 20 mg kg-1 day-1 and above. 3 Adverse effects upon body weight were seen although some recovery was apparent after the cessation of treatment. 4 Serum cholesterol concentrations were reduced. Very large increases in serum ALT, AST and CK activities were recorded with CK-MM isoenzymes accounting for 80% or more of the total CK enzyme activity. 5 Treatment was associated with muscle fibre atrophy and a sarcolemmal response with little evidence of regeneration. Histological examination revealed vascular changes, glial proliferation and cell death in the brain, with no consistent distribution. Alveolar capillary congestion and alveolar proteinosis indicated that there may have been a reduction in cardiac function. 6 HMG-CoA reductase inhibitors have evident potential to cause myopathy in marmosets. This is believed to be the first report of such an effect.

Atorvastatin in the Treatment of Primary Hypercholesterolemia and Mixed Dyslipidemias

1998 ◽  
Vol 32 (10) ◽  
pp. 1030-1043 ◽  
Author(s):  
Helen S Yee ◽  
Nancy T Fong
Keyword(s):  
Clinical Trials ◽  
Clinical Studies ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Hmg Coa Reductase ◽  
Apo B ◽  
Reductase Inhibitors ◽  
Hmg Coa Reductase Inhibitors ◽  
Coa Reductase ◽  
The Impact

OBJECTIVE: To review the efficacy and safety of atorvastatin in the treatment of dyslipidemias. DATA SOURCES: A MEDLINE search (January 1960–April 1998), Current Contents search, additional references listed in articles, and unpublished data obtained from the manufacturer were used to identify data from scientific literature. Studies evaluating atorvastatin (i.e., abstracts, clinical trials, proceedings, data on file with the manufacturer) were considered for inclusion. STUDY SELECTION: English-language literature was reviewed to evaluate the pharmacology, pharmacokinetics, therapeutic use, and adverse effects of atorvastatin. Additional relevant citations were used in the introductory material and discussion. DATA EXTRACTION: Open and controlled animal and human clinical studies published in the English-language literature were reviewed and evaluated. Clinical trials selected for inclusion were limited to those in human subjects and included data from animals if human data were not available. DATA SYNTHESIS: Atorvastatin is a recent hydroxymethylglutarylcoenzyme A (HMG-CoA) reductase inhibitor for the treatment of primary hypercholesterolemia, mixed dyslipidemias, and homozygous familial hypercholesterolemia. In patients who have not met the low-density lipoprotein cholesterol (LDL-C) goal as recommended by the National Cholesterol Education Program Adult Treatment Panel II guidelines, atorvastatin 10–80 mg/d may be used as monotherapy or as an adjunct to other lipid-lowering agents and dietary modifications. In placebo-controlled clinical trials, atorvastatin 10–80 mg/d lowered LDL-C by 35–61% and triglyceride (TG) concentrations by 14–45%. In comparative trials, atorvastatin 10–80 mg/d showed a greater reduction of serum total cholesterol (TC), LDL-C, TG concentrations, and apolipoprotein B-100 (apo B) compared with pravastatin, simvastatin, or lovastatin. In comparison, currently available HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin) lower LDL-C concentrations by approximately 20–40% and TG concentrations by approximately 10–30%. In pooled placebo-controlled clinical trials of up to a duration of 52 weeks, atorvastatin in dosages up to 80 mg/d appeared to be well tolerated. The most common adverse effect of atorvastatin was gastrointestinal upset. The incidence of elevated serum hepatic transaminases may be greater at higher dosages of atorvastatin. The risk of myopathy and/or rhabdomyolysis is increased when an HMG-CoA reductase inhibitor is taken concomitantly with cyclosporine, gemfibrozil, niacin, erythromycin, or azole antifungals. CONCLUSIONS: Atorvastatin appears to reduce TC, LDL-C, TG concentrations, and apo B to a greater extent than do currently available HMG-CoA reductase inhibitors. Atorvastatin may be preferred in patients requiring greater than a 30% reduction in LDL-C or in patients with both elevated LDL-C and TG concentrations, which may obviate the need for combination lipid-lowering therapy. Adverse effects of atorvastatin appear to be similar to those of other HMG-CoA reductase inhibitors and should be routinely monitored. Long-term safety data (>1 y) on atorvastatin compared with other HMG-CoA reductase inhibitors are still needed. Cost-effectiveness studies comparing atorvastatin with other HMG-CoA reductase inhibitors remain a subject for further investigation. Published clinical studies evaluating the impact of atorvastatin on cardiovascular morbidity and mortality are still needed. Additionally, clinical studies evaluating the impact of lipid-lowering therapy in a larger number of women, the elderly (>70 y), and patients with diabetes for treatment of primary and secondary prevention of coronary heart disease are needed.

Reduction of LDL Cholesterol by 25% to 60% in Patients With Primary Hypercholesterolemia by Atorvastatin, a New HMG-CoA Reductase Inhibitor

1995 ◽  
Vol 15 (5) ◽  
pp. 678-682 ◽  
Author(s):  
James W. Nawrocki ◽  
Stuart R. Weiss ◽  
Michael H. Davidson ◽  
Dennis L. Sprecher ◽  
Sherwyn L. Schwartz ◽  
...  
Keyword(s):  
Reductase Inhibitor ◽  
Ldl Cholesterol ◽  
Hmg Coa Reductase ◽  
Primary Hypercholesterolemia ◽  
Hmg Coa Reductase Inhibitor ◽  
Coa Reductase
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