Concomitant Use Of Statins Research Articles

The risk of myopathy associated with thiazolidinediones and statins in patients with type 2 diabetes: A nested case-control analysis

Background: The implementation of more aggressive goals for low-density lipoprotein cholesterol lowering in subjects with type 2 diabetes (T2D) and the expected increase in the use of statins is likely to increase the concomitant use of thiazolidinediones (TZDs) and statins. Objective: This study evaluated whether concomitant use of TZDs and statins is associated with an increased risk of myopathic events in subjects with T2D. Methods: This was a nested case-control study in subjects with T2D. Cases and controls were identified from a cohort of 125,394 subjects with T2D in the Integrated Healthcare Information Services database. Each case with a myopathic event (rhabdomyolysis, myositis, myopathy, or myalgia) was matched to up to 6 controls by age (±5 years), sex, calendar year of diagnosis of a myopathic event, and length of follow-up in the database. Incident cases of myopathy were identified using the following International Classification of Diseases, Ninth Revision codes: 359.x for myopathy, 728.88 for rhabdomyolysis, and 729.1 for unspecified myalgia and myositis. Prescription claims were used as a proxy for drug exposure. Five categories of exposure were employed: statins only, TZDs only, concomitant TZDs and statins, other antidiabetic agents only, and neither statins nor antidiabetic agents. Exposure to statins and/or TZDs within 90 days before the case index date was defined as recent exposure, and exposure at any time before the case index date was defined as ever exposure. Concomitant exposure to TZDs and statins, either recent or ever, was defined by an overlap of at least 30 days in the days supply of TZDs and statins during the exposure period. Results: The 3696 cases of myopathy were matched with 21,871 controls. The adjusted odds ratio (OR) for myopathic events for ever exposure to concomitant TZDs and statins compared with statins alone was 1.03 (95% CI, 0.83-1.26). Compared with neither statins nor antidiabetic agents, ever use of statins alone was associated with an increased likelihood of myopathic events (adjusted OR = 1.36; 95% CI, 1.12-1.64). The likelihood of myopathic events was not significantly different for TZDs compared with other antidiabetic agents. Conclusion: In this population of subjects with T2D, concomitant use of statins and TZDs was not associated with an increased risk of myopathic events beyond that conferred by statins alone.

WO4-OR-6 LOW-DENSITY LIPOPROTEINS NEGATIVELY REGULATE HSP 27 PHOSPHORYLATION IN VASCULAR SMOOTH MUSCLE CELLS

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are effective in reducing the risk of coronary events, and are generally very well tolerated. However, simvastatin, lovastatin, cerivastatin and atorvastatin are biotransformed in the liver primarily by cytochrome P450 (CYP) 3A4, and clinical experience has shown that the risk of adverse effect, such as myopathy, increases with concomitant use of statins with drugs that substantially inhibit CYP 3A4 at therapeutic doses. Indeed, pharmacokinetic interactions (e.g. increased bioavailability), myositis, and rhabdomyolysis have been reported following concurrent use of atorvastatin, cerivastatin, simvastatin or lovastatin and cyclosporine A, mibefradil or nefazodone. In contrast, fluvastatin (mainly metabolized by CYP 2C9) and pravastatin (eliminated by other metabolic routes) are less subject to this interaction. Nevertheless, an increase in pravastatin bioavailability has been reported in the presence of cyclosporine A, possibly because of an interaction at the level of biliary excretion. In summary, some statins may have lower adverse drug interaction potential than others, which is an important determinant of safety during long-term therapy.

Statin Therapy Does not Seem to Benefit Giant Cell Arteritis

Since statins interfere with a variety of immune-inflammatory pathways shared by atherosclerosis and giant cell arteritis (GCA), they might be potentially useful as adjunctive therapy to glucocorticosteroids in GCA. Our aim was to examine whether concomitant use of statins had any potential benefit in GCA. Retrospective follow-up study of an unselected population of 121 patients with GCA. A comparative analysis between patients with and without statin therapy was performed. At the time of the GCA diagnosis, 30 patients (25%) had already been receiving statins and continued taking them during the corticosteroid treatment. No statistically significant reduction in the incidence of severe ischemic complications (including visual manifestations, jaw claudication, cerebrovascular accidents, ischemic heart disease, and limb claudication due to large artery stenosis) was observed in this group compared with the remaining patients. When we analyzed follow-up data, we found no significant differences between groups in terms of frequency of relapses, incidence of aortitis, and percentage of patients recovered from GCA. The duration of therapy and corticosteroids requirements among patients in permanent remission was similar in both groups. We did not observe a significant benefit derived from the use of statins at low to moderate doses in the incidence of severe ischemia or the disease outcome.

Simvastatin-Induced Rhabdomyolysis Following Cyclosporine Treatment for Uveitis

The purpose of this study was to heighten awareness of a potentially life-threatening drug interaction in patients with chronic uveitis treated with cyclosporine. A 69-year-old female with chronic posterior uveitis was treated with cyclosporine while on concomitant oral simvastatin for hypercholesterolemia. Rhabdomyolysis developed with acute renal failure from the probable interaction between these drugs. Discontinuation of simvastatin and cyclosporine resulted in resolution of rhabdomyolysis and normalization of renal function. Statins are associated with a small, dose-related risk of myopathy, myositis, and rhabdomyolysis. Cyclosporine is a potent inhibitor of simvastatin metabolism, and may therefore facilitate simvastatin-induced rhabdomyolysis. Concomitant use of statins and cyclosporine should be avoided.

Randomized trial of effects of continuous combined HRT on markers of lipids and coagulation in women with acute coronary syndromes: WHISP Pilot Study

Randomized trials have not demonstrated coronary heart disease benefit from hormone replacement therapy (HRT). We hypothesized that low-dose HRT may avoid harm. We studied the effects of HRT on lipids and coagulation in women with acute coronary syndromes. A total of 100 post-menopausal women >55 years were enrolled between 2 and 28 days after an acute coronary syndrome and randomized to oral oestradiol-17beta 1 mg plus norethisterone acetate 0.5 mg daily, or matching placebo, and followed for up to 12 months. Levels of lipids, lipoproteins, and haemostasis markers were measured at baseline, 3, and 6 months. There were no significant differences in lipid levels between the two groups, probably due to concomitant statin use. Antithrombin and factor VII levels were significantly lower in the HRT group, whereas fibrinogen was significantly decreased in the placebo group. No evidence of increased coagulation activation was observed, nor of adverse cardiovascular outcomes [odds ratio (OR) 0.63 (95% confidence intervals 0.31-1.31)]. Low-dose HRT may give cardiovascular benefit. These findings require confirmation in a full clinical trial with evaluation of cardiovascular outcomes as the primary objective.

Section 5: Management of Asymptomatic Patients With Reduced Left Ventricular Ejection Fraction

Section 5: Management of Asymptomatic Patients With Reduced Left Ventricular Ejection Fraction

Pravastatin Decreases Blood Pressure in Hypertensive and Hypercholesterolemic Patients Receiving Antihypertensive Treatment

Previous studies have suggested that the lipid-lowering agents, statins, may help reduce blood pressure (BP). The goal of the present study was to characterize the effect of pravastatin on BP in hypercholesterolemic and hypertensive patients already receiving antihypertensive drugs. Eighty-two patients with hypercholesterolemia were retrospectively studied before and after 3 months of treatment with pravastatin. Forty-four patients had hypertension (HT group) and were receiving antihypertensive treatment, while the remaining 38 patients were normotensive (NT group). Patients in the HT group were further subdivided into those with uncontrolled or controlled BP. Pravastatin treatment significantly reduced systolic BP (SBP) in the HT group (134+/-16 to 130+/-13 mmHg, p<0.005) but not in the NT group (124+/-10 to 123+/-9 mmHg, p=0.52), despite the fact that treatment significantly reduced low-density lipoprotein cholesterol in both groups (HT group 178+/-27 to 132+/-17 mg/dl, p<0.0001; NT group 169+/-27 to 125+/-21 mg/dl, p<0.0001). Further, pravastatin significantly decreased SBP in the uncontrolled BP group (148+/-7 to 138+/-12 mmHg, p<0.005) but not in the controlled BP group (122+/-10 to 123+/-9 mmHg, p=0.72). Concomitant use of statins and antihypertensive drugs could result in improved BP control in hypertensive patients with hypercholesterolemia.

Endurance training reduces circulating inflammatory markers in persons at risk of coronary events: Impact on plaque stabilization?

Inflammatory pathways are involved in destabilization of atherosclerotic plaques. We assessed the hypothesis that endurance training decreases circulating concentrations of inflammatory markers in persons with coronary artery disease (CAD) and cardiovascular risk factors (CVRFs). Thirty-two subjects with CAD and/or CVRFs joined a 12-week supervised endurance training. We found a significant decrease of the chemokines interleukin (IL)-8 (pre: 3.9 ± 0.6, change: −1.2 ± 0.4 pg/ml, −21%, p = 0.002) and monocyte chemoattractant protein-1 (pre: 213 ± 9, change: −20.4 ± 8.2 pg/ml, −5%, p = 0.03). Diabetes mellitus (DM) significantly influenced changes of IL-8 ( p = 0.002). IL-8 substantially dropped by 39% in diabetics. Moreover, matrix metalloproteinase-9 (MMP-9) highly significantly decreased in response to training (pre: 750 ± 98, change: −278 ± 77 ng/ml, −18%, p = 0.005). Exercise-induced changes of MMP-9 were influenced by concomitant use of statins ( p = 0.038). We observed a particularly strong MMP-9 reduction of 44% in patients treated with statins. Acute phase reactants IL-6 (pre: 1.7 ± 0.3, change: +0.25 ± 0.7 pg/ml, +4%, p = 0.58) and high sensitivity C-reactive protein (pre: 2.1 ± 0.5, change: −0.25 ± 0.4 mg/l, −9%, p = 0.54) did not change in response to training. In conclusion, endurance training decreased circulating chemokines and MMP-9, which may in part explain its beneficial effect on coronary risk. Patients with DM or treated with statins because of hypercholesterolemia may particularly take advantage.

Effects of statins on platelet inhibition by a high loading dose of clopidogrel

Background— Recent studies suggested that some HMG-CoA reductase blockers might inhibit the antiplatelet activity of clopidogrel. Therefore, we analyzed how various statins together with a high loading dose of clopidogrel (600 mg) affect platelet aggregation. Methods and Results— Seventy-seven patients with stable angina scheduled for elective coronary stenting were studied. Patients were randomized to receive atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin (each 20 mg), cerivastatin (0.3 mg), or placebo, plus a high loading dose of 600 mg of clopidogrel. ADP-induced platelet aggregation (5 and 20 μmol/L) was determined before and 2 and 4 hours after first clopidogrel administration. All patients were taking aspirin (100 mg/d) regularly. We found that none of the statins significantly influenced inhibition of platelet aggregation by clopidogrel. Conclusions— Concomitant use of statins with clopidogrel does not significantly inhibit antiplatelet activity, at least when clopidogrel is admini...

Physicians’ prescribing attitudes to combined therapy with statins and fibrates

To assess the impact of a package insert revision and a drug-drug interaction warning embedded in a computerized prescription ordering system, on physicians' prescribing of concomitant statins and fibrates. Data were obtained using a computerized prescription order entry system before and after administrative intervention advising of potentially adverse effects of this combined therapy. The number of prescriptions for statins and fibrates were counted monthly from January 1998 to June 2002 at the National Cardiovascular Center (NCVC). Counting was based on information from a prescription database file compiled from a computerized order entry system. The total number of prescriptions and frequency of requests for statins and fibrates were compared with the timing of either package insert revision or introduction of the warning on a computerized prescription ordering system. In addition, laboratory testing of renal function using serum creatinine (Scr) assays in patients treated with combined statins and fibrates was obtained from medical records at two stages during the study period (stage 1, January 1998 to June 1998; stage 2, January 2002 to June 2002). There were 204 prescriptions for concomitant statins and fibrates at the beginning and 50 prescriptions at end of the study period. The number of prescriptions began to decrease in the latter half of 1999 with the percentage of concomitant use of statins and fibrates showing an evident downward trend from January 2001. This acceleration in the downward trend coincided with the introduction of the computerized warning message. Scr levels were measured in 43.8% of patients in stage 1 and in 48.3% of patients in stage 2 in the past month. The percentage of patients having Scr levels measured in the past 6 months was 85.3% in stage 1 and 84.5% in stage 2. There was no significant difference in the percentages of patients whose Scr levels had been measured between the two stages. Revision of package inserts concerning combined therapy of statins and fibrates led to physicians' prescribing fewer of these combinations. A warning message displayed on a computerized prescription order entry system accentuated this effect.

Pharmacological interactions of statins.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are effective in reducing the risk of coronary events, and are generally very well tolerated. However, simvastatin, lovastatin, cerivastatin and atorvastatin are biotransformed in the liver primarily by cytochrome P450 (CYP) 3A4, and clinical experience has shown that the risk of adverse effect, such as myopathy, increases with concomitant use of statins with drugs that substantially inhibit CYP 3A4 at therapeutic doses. Indeed, pharmacokinetic interactions (e.g. increased bioavailability), myositis, and rhabdomyolysis have been reported following concurrent use of atorvastatin, cerivastatin, simvastatin or lovastatin and cyclosporine A, mibefradil or nefazodone. In contrast, fluvastatin (mainly metabolized by CYP 2C9) and pravastatin (eliminated by other metabolic routes) are less subject to this interaction. Nevertheless, an increase in pravastatin bioavailability has been reported in the presence of cyclosporine A, possibly because of an interaction at the level of biliary excretion. In summary, some statins may have lower adverse drug interaction potential than others, which is an important determinant of safety during long-term therapy.

El perfil de seguridad de las estatinas

HMG-CoA reductase inhibitors (statins) are the treatment of choice for patients with hypercholesterolaemia. Several large-scale clinical trials have examined the efficacy and tolerability of statins, providing a wealth of information on their safety and adverse effect profile. Adverse hepatic effect is reflected as asymptomatic elevations in serum levels of aminotransaminases. Myopathy, occasionally leading to myoglobulinuria secondary to rhabdomyolysis, is a rare and potentially fatal complication. Cerivastatin, the last statin approved for use in humans, was voluntarily withdrawn from the market by Bayer, because fatal rhabdomyolysis was most frequently reported with cerivastatin than for other approved statins. The concomitant use of statins with drugs that inhibit CYP3A4 (cyclosporin, erythromycin, clarithromycin, itraconazole, and ketoconazole), may result in increased plasma concentrations of HMG-CoA reductase inhibitors leading occasionally to myotoxicity. Fibric acid derivatives can produce myotoxicity, and the association of both types of drugs increases the risk of this adverse event. The reason for the greater association of rhabdomyolysis with cerivastatin than with other statins is unknown. The efficiency of post marketing drug surveillance programs in different countries, was the clue for the awareness of this problem.