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PubMed2004

Statins induce apoptosis in rat and human myotube cultures by inhibiting protein geranylgeranylation but not ubiquinone.

Statins are widely used to treat lipid disorders. These drugs are safe and well tolerated; however, in <1% of patients, myopathy and/or rhabdomyolysis can develop. To better understand the mechanism of statin-induced myopathy, we examined the ability of structurally distinct statins to induce apoptosis in an optimized rat myotube model. Compound A (a lactone) and Cerivastatin (an open acid) induced apoptosis, as measured by TUNEL and active caspase 3 staining, in a concentration- and time-dependent manner. In contrast, an epimer of Compound A (Compound B) exhibited a much weaker apoptotic response. Statin-induced apoptosis was completely prevented by mevalonate or geranylgeraniol, but not by farnesol. Zaragozic acid A, a squalene synthase inhibitor, caused no apoptosis on its own and had no effect on Compound-A-induced myotoxicity, suggesting the apoptosis was not a result of cholesterol synthesis inhibition. The geranylgeranyl transferase inhibitors GGTI-2133 and GGTI-2147 caused apoptosis in myotubes; the farnesyl transferase inhibitor FTI-277 exhibited a much weaker effect. In addition, the prenylation of rap1a, a geranylgeranylated protein, was inhibited by Compound A in myotubes at concentrations that induced apoptosis. A similar statin-induced apoptosis profile was seen in human myotube cultures but primary rat hepatocytes were about 200-fold more resistant to statin-induced apoptosis. Although the statin-induced hepatotoxicity could be attenuated with mevalonate, no effect was found with either geranylgeraniol or farnesol. In studies assessing ubiquinone levels after statin treatment in rat and human myotubes, there was no correlation between ubiquinone levels and apoptosis. Taken together, these observations suggest that statins cause apoptosis in myotube cultures in part by inhibiting the geranylgeranylation of proteins, but not by suppressing ubiquinone concentration. Furthermore, the data from primary hepatocytes suggests a cell-type differential sensitivity to statin-induced toxicity.

Alkyl and Aryl Transferases↗
PubMed2005

Statins and PPARalpha agonists induce myotoxicity in differentiated rat skeletal muscle cultures but do not exhibit synergy with co-treatment.

Statins and fibrates (weak PPARalpha agonists) are prescribed for the treatment of lipid disorders. Both drugs cause myopathy, but with a low incidence, 0.1-0.5%. However, combined statin and fibrate therapy can enhance myopathy risk. We tested the myotoxic potential of PPAR subtype selective agonists alone and in combination with statins in a differentiated rat myotube model. A pharmacologically potent experimental PPARalpha agonist, Compound A, induced myotoxicity as assessed by TUNEL staining at a minimum concentration of 1 nM, while other weaker PPARalpha compounds, for example, WY-14643, Gemfibrozil and Bezafibrate increased the percentage of TUNEL-positive nuclei at micromolar concentrations. In contrast, the PPARgamma agonist Rosiglitazone caused little or no cell death at up to 10 muM and the PPARdelta ligand GW-501516 exhibited comparatively less myotoxicity than that seen with Compound A. An experimental statin (Compound B) and Atorvastatin also increased the percentage of TUNEL-positive nuclei and co-treatment with WY-14643, Gemfibrozil or Bezafibrate had less than a full additive effect on statin-induced cell killing. The mechanism of PPARalpha agonist-induced cell death was different from that of statins. Unlike statins, Compound A and WY-14643 did not activate caspase 3/7. In addition, mevalonate and geranylgeraniol reversed the toxicity caused by statins, but did not prevent the cell killing induced by WY-14643. Furthermore, unlike statins, Compound A did not inhibit the isoprenylation of rab4 or rap1a. Interestingly, Compound A and Compound B had differential effects on ATP levels. Taken together, these observations support the hypothesis that in rat myotube cultures, PPARalpha agonism mediates in part the toxicity response to PPARalpha compounds. Furthermore, PPARalpha agonists and statins cause myotoxicity through distinct and independent pathways.

Adenosine Triphosphate↗
PubMed2002

Benefits of immediate initiation of statin therapy following successful coronary stent implantation in patients with stable and unstable angina pectoris and Q-wave acute myocardial infarction.

Statin therapy reduces clinical events in patients with stable coronary artery disease. Recent data indicate that the beneficial effects of statin therapy may also extend to patients experiencing an acute ischemic coronary event. However, the potential role of statins to further modify clinical outcome in patients undergoing coronary stent implantation has not been addressed. Therefore, we investigated whether the initiation of statin therapy immediately after successful coronary stent implantation improves short-term clinical outcome in 704 patients (335 patients with stable angina pectoris [AP], 224 patients with unstable AP, and 145 patients with Q-wave acute myocardial infarction [AMI]). Compared with the lowest risk group (patients with stable AP receiving statin therapy), patients with unstable AP (RR 6.9, 95% confidence interval [CI] 1.5 to 31, p = 0.004) and patients with Q-wave AMI (RR 7.6, 95% CI 1.5 to 37, p = 0.004) experienced an increased risk for the occurrence of the primary combined end point of cardiac death and AMI. Importantly, initiation of statin therapy abrogated the increased risk in patients with unstable AP to the level of patients with stable AP receiving statin therapy (RR 1.5, 95% CI 0.2 to 11, p = 0.7). In contrast, statin therapy did not affect the RR in patients with Q-wave AMI during 6-month follow-up (RR 7.9, 95% CI 1.6 to 39 vs RR 7.6, 95% CI 1.5 to 37, p = NS). The beneficial effects of statin therapy after successful coronary stent implantation in unstable AP were most prominent during the first 4 weeks after the ischemic episode. Statins appear to contribute to the rapid transformation of unstable coronary artery disease into a stable condition with a very low event rate over the forthcoming 6 months in patients with unstable AP undergoing successful coronary stent implantation.

Angina Pectoris↗
PubMed2003

Potential cost-effectiveness of C-reactive protein screening followed by targeted statin therapy for the primary prevention of cardiovascular disease among patients without overt hyperlipidemia.

BACKGROUND: Evidence suggests that statin therapy reduces the rate of cardiovascular events among patients with low lipid levels but elevated C-reactive protein levels. However, no cost-effectiveness analyses have been performed to assist in determining whether large-scale randomized trials are merited to test this hypothesis. METHODS: We used a Markov model to estimate the benefits, costs, and incremental cost-effectiveness of C-reactive protein screening followed by targeted statin therapy for elevated C-reactive protein levels, compared with dietary counseling alone, for the primary prevention of cardiovascular events among patients with low-density lipoprotein cholesterol levels <149 mg/dL. All costs were in 2000 U.S. dollars. RESULTS: The potential incremental cost-effectiveness ratio for screening followed by statin therapy compared with no screening and no statin therapy was $48,100 per quality-adjusted life-year (QALY) for 58-year-old men and $94,400 per QALY for 58-year-old women. Screening was most cost-effective for 65-year-old men ($42,600 per QALY) and least cost-effective for 35-year-old women ($207,300 per QALY). Our results were most sensitive to the baseline risk of coronary heart disease, the cost of statin therapy, and the efficacy of statin therapy for preventing myocardial infarction in patients with high C-reactive protein levels. If a 58-year-old man who smokes and is hypertensive was considered, screening for C-reactive protein followed by statin therapy would be cost saving if the cost of statin therapy was reduced to $500 per year. If the cost of statin therapy was reduced to $1 per day, the cost-effectiveness of screening would be $4900 per QALY for 58-year-old men and $19,600 per QALY for women of the same age. If the costs associated with elective revascularization (percutaneous coronary intervention or coronary artery bypass surgery) were included in the base case analyses, the incremental cost-effectiveness ratios for screening would be $40,100 per QALY for 58-year-old men and $87,300 per QALY for women. CONCLUSION: A strategy involving C-reactive protein screening to target statin therapy for the primary prevention of cardiovascular disease among middle-aged patients without overt hyperlipidemia could be relatively cost-effective and, in some cases, cost saving.

Adult↗
PubMed2003

Statins (HMG-CoA reductase inhibitors) reduce CD40 expression in human vascular cells.

OBJECTIVE: HMG-CoA reductase inhibitors (statins) possess anti-inflammatory and immunomodulatory properties that are independent of their lipid-lowering action. As the CD40-CD40L signaling pathway is implicated in the modulation of inflammatory responses between vascular cells, involving adhesion molecules, pro-inflammatory cytokines, chemokines, we sought to investigate the potential role of statins in regulating the expression of CD40. METHODS AND RESULTS: Using Western blot, flow cytometry and immunohistochemistry analyses, we observed that four different statins reduced IFN-gamma-induced CD40 expression in human vascular cells (endothelial cells, smooth muscle cells, macrophages and fibroblasts). This effect was dose-dependent (from 5 microM to 80 nM) and reversed by addition of L-mevalonate. Activation of vascular cells by human recombinant CD40L, as measured by ELISA for IL-6, IL-8 and MCP-1, was strongly reduced when cells were treated with statins. Immunostaining of human carotid atherosclerotic lesions of patients subjected to statin treatment revealed less CD40 expression on a 'per vascular cell' basis compared to control patients. Although many pleiotropic effects of statins are mediated by nitric oxide synthase (NOS)- or peroxisome proliferator-activated receptor (PPAR)-dependent signaling pathways, we observed similar statin-induced reduction of CD40 expression using NOS inhibitors or different PPAR ligands. CONCLUSION: Statins decrease CD40 expression and CD40-related activation of vascular cells. These effects are partially reversed by the HMG-CoA reductase product L-mevalonate and are mediated by NOS- or PPAR-dependent pathways. Altogether, these findings provide mechanistic insight into the beneficial effects of statins on atherogenesis. They also provide a scientific rationale for the use of statins as immunomodulators after organ transplantation.

Animals↗
PubMed2003

Relationship between effects of statins, aspirin and angiotensin II modulators on high-sensitive C-reactive protein levels.

Statins, aspirin and angiotensin II modulators (A II-M: angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type I receptor blockades) may have an anti-inflammatory effect, but the relationship between the effects of statins, aspirin and A II-M on high-sensitive C-reactive protein (hs-CRP) levels remains to be determined. We examined serum hs-CRP levels in consecutive patients with stable ischemic heart disease (IHD) (n=1231; 65+/-9 years; male/female, 927/304) and without IHD (n=226; 64+/-9 years; male/female, 117/109). Blood samples were collected on the day of catheterization. The hs-CRP levels were significantly higher in the IHD than in the non-IHD patients (0.32+/-0.52 vs. 0.24+/-0.29 mg/dl, P<0.05). Treatment with statins was associated with significantly lower hs-CRP levels in both groups (non-IHD, 0.17+/-0.14 vs. 0.26+/-0.31 mg/dl; IHD, 0.27+/-0.34 vs. 0.35+/-0.59 mg/dl; both P<0.05). hs-CRP levels were significantly lower only in IHD patients treated with A II-M than in those not treated with A II-M (0.28+/-0.34 vs. 0.34+/-0.58 mg/dl, P<0.05). Aspirin did not have any effect on the hs-CRP level in either group. The hs-CRP levels were significantly lower in IHD patients treated with statins and/or A II-M than those treated with neither statins nor A II-M (statin+/A II-M+, 0.28+/-0.29 mg/dl; statin+/A II-M-, 0.26+/-0.36 mg/dl; statin-/A II-M+, 0.28+/-0.37 mg/dl; statin-/A II-M-, 0.38+/-0.66 mg/dl; P<0.01). These results indicate that statins and A II-M, but not aspirin, in commonly used doses have an anti-inflammatory action as assessed by measurement of CRP levels in IHD patients.

Aged↗
PubMed2000

The evolving role of statins in the management of atherosclerosis.

Significant advances in the management of cardiovascular disease have been made possible by the development of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors--"statins." Initial studies explored the impact of statin therapy on coronary artery disease (CAD) progression and regression. Although the angiographic changes were small, associated clinical responses appeared significant. Subsequent large prospective placebo-controlled clinical trials with statins demonstrated benefit in the secondary and primary prevention of CAD in subjects with elevated cholesterol levels. More recently, the efficacy of statins has been extended to the primary prevention of CAD in subjects with average cholesterol levels. Recent studies also suggest that statins have benefits beyond the coronary vascular bed and are capable of reducing ischemic stroke risk by approximately one-third in patients with evidence of vascular disease. In addition to lowering low-density lipoprotein (LDL) cholesterol, statin therapy appears to exhibit pleiotropic effects on many components of atherosclerosis including plaque thrombogenicity, cellular migration, endothelial function and thrombotic tendency. Growing clinical and experimental evidence indicates that the beneficial actions of statins occur rapidly and yield potentially clinically important anti-ischemic effects as early as one month after commencement of therapy. Future investigations are warranted to determine threshold LDL values in primary prevention studies, and to elucidate effects of statins other than LDL lowering. Finally, given the rapid and protean effects of statins on determinants of platelet reactivity, coagulation, and endothelial function, further research may establish a role for statin therapy in acute coronary syndromes.

Cholesterol, LDL↗
PubMed2002

Estrogen, statins, and polyunsaturated fatty acids: similarities in their actions and benefits-is there a common link?

OBJECTIVES: To investigate whether there is any common link between estrogen, statins, and polyunsaturated fatty acids (PUFAs), which have similar actions and benefits. METHODS: To critically review the literature pertaining to the actions of estrogen, statins, and various PUFAs. RESULTS: Estrogen, statins, and PUFAs enhance nitric oxide synthesis, suppress the production of proinflammatory cytokines such as tumor necrosis factor(alpha), interleukin-1, interleukin-2, and interleukin-6, show antioxidant-like and antiatherosclerotic properties, have neuroprotective actions, and by themselves or their products inhibit tumor cell proliferation and improve osteoporosis. Estrogen, statins, and PUFAs not only have similar actions but also appear to interact with each other. For instance, the binding of estrogen to its receptor on the cell membrane may be determined by its lipid content, statins and PUFAs inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, statins influence the metabolism of PUFAs, and PUFA deficiency enhances 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Statins and PUFAs inhibit tumor cell proliferation, suppress ras activity, and may prevent neurodegeneration and improve cognitive functions such as learning and memory. This suggests that PUFAs might be mediators of the actions of statins. Estrogen boosts cognitive performance in women after menopause and may protect against Alzheimer's disease. CONCLUSIONS: The common link between estrogen, statins, and PUFAs may be nitric oxide. Hence, a combination(s) of estrogen or its derivatives, statins, and various PUFAs may form a novel approach in the management of various conditions such as hyperlipidemias, coronary heart disease, atherosclerosis, osteoporosis, cancer, neurodegenerative conditions, and to improve memory.

Alzheimer Disease↗
PubMed2005

Statins and the risk of colorectal cancer.

BACKGROUND: Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and effective lipid-lowering agents. Statins inhibit the growth of colon-cancer cell lines, and secondary analyses of some, but not all, clinical trials suggest that they reduce the risk of colorectal cancer. METHODS: The Molecular Epidemiology of Colorectal Cancer study is a population-based case-control study of patients who received a diagnosis of colorectal cancer in northern Israel between 1998 and 2004 and controls matched according to age, sex, clinic, and ethnic group. We used a structured interview to determine the use of statins in the two groups and verified self-reported statin use by examining prescription records in a subgroup of patients for whom prescription records were available. RESULTS: In analyses including 1953 patients with colorectal cancer and 2015 controls, the use of statins for at least five years (vs. the nonuse of statins) was associated with a significantly reduced relative risk of colorectal cancer (odds ratio, 0.50; 95 percent confidence interval, 0.40 to 0.63). This association remained significant after adjustment for the use or nonuse of aspirin or other nonsteroidal antiinflammatory drugs; the presence or absence of physical activity, hypercholesterolemia, and a family history of colorectal cancer; ethnic group; and level of vegetable consumption (odds ratio, 0.53; 95 percent confidence interval, 0.38 to 0.74). The use of fibric-acid derivatives was not associated with a significantly reduced risk of colorectal cancer (odds ratio, 1.08; 95 percent confidence interval, 0.59 to 2.01). Self-reported statin use was confirmed for 276 of the 286 participants (96.5 percent) who reported using statins and whose records were available. CONCLUSIONS: The use of statins was associated with a 47 percent relative reduction in the risk of colorectal cancer after adjustment for other known risk factors. Because the absolute risk reduction is likely low, further investigation of the overall benefits of statins in preventing colorectal cancer is warranted.

Aged↗
PubMed2001

Randomized clinical trials and recent patterns in the use of statins.

BACKGROUND: Three landmark trials involving 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) were published between 1994 and 1996 (the Scandinavian Simvastatin Survival Study [4S], the West of Scotland Coronary Prevention Study, and the Cholesterol and Recurrent Events trial). These trials provided evidence that lipid-lowering therapy decreases cardiovascular events, including mortality. Whether these recent data caused a shift toward statin use has not been evaluated. METHODS: Data from the National Ambulatory Medical Care Survey in 1980, 1981, 1985, and 1989 through 1998 were used. We analyzed 5053 visits by patients taking lipid-lowering medications to office-based physicians selected by stratified random sampling. The main outcome measure was use of specific lipid-lowering medications, including statins. RESULTS: In 1980 resins and niacin were the most commonly used lipid-lowering medications. By 1985 rising use of fibrates caused reductions in niacin use and resin use. By 1989 statins replaced fibrates as the most heavily used medications. Statin use climbed continuously thereafter, accounting for 90% of visits by patients treated for hypercholesterolemia in 1998. In time series analyses, increases in overall statin use were temporally unrelated to the publication of clinical trials, although the 4S trial may have contributed to a shift from older statins to simvastatin. For patients receiving lipid-lowering therapy in 1993 to 1998, statin use was significantly more likely for female patients, white patients, and patients visiting cardiologists. CONCLUSIONS: Although the market for lipid-lowering medications is dominated by statins, the rise in statins predated the recent clinical trials supporting their use.

Aged↗
PubMed1990

Characterization of two populations of statin and the relationship of their syntheses to the state of cell proliferation.

Statin has previously been identified to be a 57-kD protein present in the nuclei of quiescent and senescent human fibroblasts, but not in their replicating counterparts (Wang, E. 1985. J. Cell Biol. 100: 545-551). In the present report we demonstrate by immunoprecipitation analysis of fractionated cellular extracts the existence of two populations of statin. The Triton X-100-soluble statin is found in replicating sparse cultures as well as in quiescent confluent cultures and quiescent serum-starved cultures of young human fibroblasts, but the Triton X-100-insoluble, nuclear envelope-localized statin is present only in the quiescent cultures. Two-dimensional gel analysis of the immunoprecipitated cellular fractions reveals that both populations of statin have an isoelectric point of 5.3. Pulse-chase experiments show that statin is synthesized as a 57-kD polypeptide and is not processed from a precursor of different molecular mass. Experiments on serum stimulation of quiescent cells show that synthesis of the Triton X-100-insoluble statin decreases rapidly during the transition from the G0 to S phase, and that this decrease is accompanied by a slower reduction in synthesis of the Triton X-100-soluble statin. These results suggest that the cellular expression of the two populations of statin may be associated with the mechanisms controlling the transition between the growing state and the quiescent state and confirm the previous finding that the Triton X-100-insoluble, nuclear envelope-localized statin could be used as a marker for cells arrested at the G0 phase of the cell cycle.

Cell Cycle Proteins↗
PubMed2002

The impact of the use of statins on the prevalence of dementia and the progression of cognitive impairment.

BACKGROUND: Previous evidence suggests that treatment with 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors (statins) has a positive impact on dementia. We decided to investigate the association between the use of statins and the prevalence of dementia and statins' impact on the progression of cognitive impairment. METHODS: This is a case-control and a retrospective cohort study of a community-based ambulatory primary care geriatric practice. We included a convenience sample of all patients (N = 655, mean age 78.7 +/- 0.3 years, 85% Caucasian, 74% women) with hypercholesterolemia or dementia, or using statins. We compared those using statins with those who do not with respect to the clinical diagnosis of dementia and its subtypes and the progression of cognitive impairment. RESULTS: At the initial visit, 35% had dementia, and 17% were using statins. After covariate adjustments, patients on statins were less likely to have dementia (odds ratio [OR] for dementia based on composite definition = 0.23; 95% confidence interval [CI] [0.1-0.56], p =.001, OR Alzheimer's disease = 0.37; 95% CI [0.19-0.74], p =.005, OR vascular dementia = 0.25; 95% CI [0.08-0.85], p =.027). At follow-up, patients on statins showed an improvement on their Mini-Mental Status Examination score by 0.7 +/- 0.4 compared to a decline by 0.5 +/- 0.3 in controls, p =.025 (OR for no change or improvement on statins = 2.81; 95% CI [1.02-8.43], p =.045) and scored higher on the Clock Drawing Test (difference of 1.5 +/- 0.1, p =.036). CONCLUSIONS: The use of statins is associated with a lower prevalence of dementia and has a positive impact on the progression of cognitive impairment.

Aged↗
PubMed2007

Statin use and risk of colorectal cancer.

BACKGROUND: Statins have anticancer activity in various cell types, including colon cancer cells. Although epidemiologic data on the relationship between statin use and the risk of colorectal cancer are limited, one case-control study reported a 50% reduction in colorectal cancer risk among statin users. We conducted a population-based case-control study to assess this association with respect to statin type, dose, and duration of use. METHODS: Case patients with adenocarcinoma of the colon or rectum were ascertained from participating hospitals in Massachusetts and the Massachusetts Cancer Registry from January 1, 2001, through November 30, 2004. Age-, sex-, and precinct-matched control subjects were chosen from Massachusetts town lists. Information on statin use and other relevant data were obtained by telephone interview. We used multivariable conditional logistic regression models to estimate odds ratios (ORs). All tests for statistical significance were two-sided. RESULTS: Among 1809 case patients and 1809 matched control subjects, regular use of statins for at least 3 months was not associated with the risk of colorectal cancer (OR = 0.92, 95% confidence interval [CI] = 0.78 to 1.09). There was no consistent trend across dose or duration of use (e.g., for > or = 10 years of use, OR = 0.86, 95% CI = 0.51 to 1.45). The risk of stage IV cancer was, however, statistically significantly lower among statin users than among nonusers (OR = 0.49, 95% CI = 0.26 to 0.91). There was no evidence of an interaction between statin use and nonsteroidal anti-inflammatory drug use. CONCLUSIONS: Overall, use of statins did not appear to be associated with reduced risk of colorectal cancer. The reduced risk of stage IV cancer observed among statin users requires confirmation.

Aged↗
PubMed2000

Age, sex and practice variations in the use of statins in general practice in England and Wales.

BACKGROUND: Statins are highly effective in reducing the risk of sudden cardiac death and other acute coronary events in patients with pre-existing ischaemic heart disease or with raised blood cholesterol levels. However, relatively little is known about how statins are used in primary care. The objectives of this study were to investigate age, sex and inter-practice variations in the prescribing of statins. METHODS: This was an observational study of statin prescribing rates in 288 general practices in England and Wales that contributed data to the General Practice Research Database in 1996. RESULTS: In 1996, 0.7 per cent of men and 0.5 per cent of women received a prescription for a statin. In the subgroup of patients with a general practitioner (GP) diagnosis of ischaemic heart disease, 13.3 per cent of men and 8.2 per cent of women received a prescription for a statin in 1996. Below the age of 65 years, men with ischaemic heart disease were more likely to be prescribed a statin than were women. Patients aged 75 years and over with ischaemic heart disease were unlikely to be prescribed a statin irrespective of their sex. The percentage of patients prescribed statins in individual practices varied from 0.1 to 2.3 per cent in men and from 0 to 2.3 per cent in women. The recorded prevalence of ischaemic heart disease explained only 12 per cent of this variation in men and 7 per cent in women. CONCLUSIONS: There are large age, sex and inter-practice variations in the use of statins in primary care, which are poorly explained by measures of health need. Developing and implementing clinical guidelines to accompany the introduction of new drugs for the management of common chronic disorders should be seen as a priority for GPs, primary care groups and the National Institute of Clinical Excellence.

Adult↗
PubMedDate not supplied

Optimizing LDL-C lowering with statins.

Clinical studies have demonstrated the efficacy of statins in reducing low-density lipoprotein cholesterol (LDL-C) and lowering coronary heart disease risk. However, many patients receiving statin therapy in clinical practice are not achieving their LDL-C goals. Generally, statins are initiated at starting doses, and doses should be titrated as needed until the goal of therapy is achieved or a second lipid-lowering drug is required; titration is required in the majority of patients who receive less efficacious agents. Most patients receiving statin therapy in clinical practice are maintained on their starting dose, and this frequently results in inadequate control of elevated cholesterol levels. A number of factors may limit dose titration in clinical practice, including the cost of therapy, safety of prescribing statins at high doses and the additional office visits required for evaluations and monitoring. There may be several solutions to this problem. The choice of statin appears to be one of the important factors influencing the success of therapy. Selecting a statin that provides greater LDL-C lowering enables more patients to achieve LDL-C goals, and the majority of patients can be effectively treated with starting doses of the more efficacious statins. Another factor influencing the success of therapy is the willingness to add other drugs to a statin to enhance LDL-C lowering. Choices here include niacin, a bile acid sequestrant, and ezetimibe, a new cholesterol absorption inhibitor. Of these approaches, use of a more efficacious statin is preferred to combination therapy because of cost, safety, effectiveness, and simplicity issues.

Cholesterol, LDL↗
PubMed2006

Statin myopathy: an update.

PURPOSE OF REVIEW: Statin therapy has become the mainstay of treatment for lipid lowering, demonstrating cardiovascular risk reduction. Associated with statin popularity are misconceptions and fears of untoward side effects on muscle. This review clarifies the terminology relating to statin-related muscle disease; explores potential pathogenic mechanisms; reviews current estimates of statin myopathy prevalence; and examines diagnosis and management. RECENT FINDINGS: The fundamental mechanism of statin myopathy remains elusive but is believed to be a class effect. The most common explanation for the cause of toxic muscle injury invokes the deficiency of one of three main synthetic products in the 3-hydroxy-3-methylglutaryl-coenzyme A reductase pathway. Recent studies have revealed several patients with statin-induced rhabdomyolysis who also have metabolic muscle defects, indicating that statin use may unmask presymptomatic metabolic myopathies. Although statin-related myotoxicity is believed to be a noninflammatory, toxic myopathy, experimental evidence suggests that it may be triggered by an autoimmune reaction or, conversely, initiate an autoimmune process. The precise mechanism is uncertain. SUMMARY: As a class, statins appear to be usually safe, well tolerated agents with an excellent risk: benefit profile. The etiology and pathogenesis of statin myopathy are poorly understood owing to the relative rarity of its existence.

Humans↗
PubMed2006

Statins in the intensive care unit.

PURPOSE OF REVIEW: Statins are effective lipid-lowering agents used extensively in medical practice. This review summarizes the evidence for statin treatment of cardiovascular patients in the intensive care unit and briefly discusses the role of statins in prevention and treatment of sepsis as a potential future application of statins in critical care. RECENT FINDINGS: Recent studies have extended the use of statin therapy to the acute manifestations of cardiovascular disease and have suggested cholesterol-independent therapeutic benefits, termed pleiotropic effects, which have added a wide scope of potential targets for statin therapy. SUMMARY: Statin therapy should be continued in intensive-care patients in whom statin therapy is warranted due to underlying cardiovascular disease or significant risk thereof. In acute coronary syndromes, statin therapy should be initiated within 24-96 h regardless of pretreatment cholesterol levels. Patients undergoing vascular surgery should receive peri-operative statin therapy. Placebo-controlled clinical trials are required to consolidate the experimental and observational evidence for prevention and treatment of sepsis.

Cardiovascular Diseases↗
PubMedDate not supplied

Effect of statins combined with estradiol on the proliferation of human receptor-positive and receptor-negative breast cancer cells.

OBJECTIVE: Combination of a statin plus estrogen may reveal benefits on the cardiovascular system in postmenopausal women by additively ameliorating both the lipid profile and vascular function. Long-term therapy with estrogens, however, is associated with an increase of breast cancer risk. In contrast, evidence is accumulating that statins may inhibit carcinogenesis because of their central action on important cellular functions. It is of special clinical interest whether a statin/estrogen combination may reduce the most undesired side effect of estrogen therapy, that is, an increase in breast cancer risk. Therefore, in the present in vitro study, for the first time we have compared the effect of five statins on the proliferation of human breast cancer cells alone and in the presence of stimulatory estradiol (E(2)). DESIGN: As cell models, the receptor-positive cell line MCF-7 and the receptor-negative cell line MDA-MB 231 were used. The statins atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin were tested in the concentration range of 1.6 microm to 50 microm alone and in the range of 0.01 nm to 10 microm in combination with E(2). Cell proliferation was measured after 4 days by the adenosinetriphosphate-chemosensitivity test. RESULTS: All statins except pravastatin were able to significantly inhibit dose dependently the cell proliferation of both cell lines. The inhibitory values were between 10% and 90%, whereby the potency was greater in the case of receptor-negative cancer cells. A significant difference in the efficacy of the statins was observed for MCF-7 cells, in which atorvastatin was less effective than the other statins. In contrast, in the presence of E(2), the statins showed similar antiproliferative actions in MCF-7 cells when tested in the concentration range of 0.01 nm to 10 microm. A reduction of cell proliferation of less than 10% was observed at the lower concentrations and between 15% and 25% at the highest concentration of 10 microm. CONCLUSIONS: The present data indicate that statins can inhibit the proliferation of receptor-positive and -negative human breast cancer cells but failed to completely abrogate the E(2)-induced proliferation of receptor-positive breast cancer cells. Clinical trials, however, are necessary to prove this anticarcinogenic action of statins.

Breast Neoplasms↗