Article

Statins, Low-Density Lipoprotein Cholesterol, and Risk of Cancer

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

We sought to assess whether statin-mediated reductions in low-density lipoprotein cholesterol (LDL-C) are associated with an increased risk of cancer. We recently reported an inverse association between on-treatment LDL-C levels and incident cancer in statin-treated patients enrolled in large randomized controlled trials, raising concern that LDL-C lowering by statins may increase cancer risk. However, meta-analyses suggest a neutral overall effect of statins on incident cancer. A systematic literature search identified 15 eligible randomized controlled trials of statins with >or=1,000 person-years of follow-up that provided on-treatment LDL-C levels and rates of incident cancers (19 statin and 14 control arms, 437,017 person-years cumulative follow-up, and 5,752 incident cancers). In the statin arms, meta-regression analysis demonstrated an inverse association between on-treatment LDL-C and incident cancer, with an excess of 2.2 (95% confidence interval: 0.7 to 3.6) cancers per 1,000 person-years for every 10 mg/dl decrement in on-treatment LDL-C (p=0.006). The corresponding difference among control arms was 1.2 (95% confidence interval: -0.2 to 2.7, p=0.09). Compared with the control arms, the statin regression line was significantly shifted leftward, such that similar rates of incident cancer were associated with lower on-treatment LDL-C (p<0.05). Meta-regression demonstrated that statins lack an effect on cancer risk across all levels of on-treatment LDL-C. There is an inverse association between on-treatment LDL-C and incident cancer. However, statins, despite producing marked reductions in LDL-C, are not associated with an increased risk of cancer.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... Patients with RA have a worse mortality experience than patients who do not have RA, and CVD is a significant contributor to the mortality burden 7 . Indeed, of all the comorbidities affecting patients with RA, other than lung disease, CVD confers the greatest risk of premature mortality 8,9,10,11,12 . CVD accounts for about 40% to 50% of all deaths in RA 1,2,10 and occurs a decade earlier than in a non-RA cohort 10 . ...
... Indeed, of all the comorbidities affecting patients with RA, other than lung disease, CVD confers the greatest risk of premature mortality 8,9,10,11,12 . CVD accounts for about 40% to 50% of all deaths in RA 1,2,10 and occurs a decade earlier than in a non-RA cohort 10 . In addition to the more traditional variables of CV risk, specific forms of heart disease also affect the morbidity and mortality of patients with RA, including pericardial disease, myocardial inflammation, cardiac amyloidosis, and nonatherosclerotic coronary disease, which may manifest as arrhythmias, particularly atrial fibrillation, ventricular arrhythmias, and valvular heart disease including valvular fibrosis, calcifications, rheumatoid nodules, and noninfectious endocarditis, especially in patients with high levels of joint disease activity and severity. ...
Article
Patients with rheumatoid arthritis (RA) are at increased risk for cardiovascular disease (CVD), including peripheral vascular disease, stroke, myocardial infarction, and heart failure compared to the general population1,2. The absolute CV risk is estimated to be up to 2-fold increased1,2. The risk is increased because of chronic, systemic inflammation, as well as premature atherosclerosis. In addition to the risk inherent to the underlying disease, conventional risk factors are major contributors to the increase in recurrence of CVD, including dyslipidemia, hypertension (HTN), obesity, smoking, and diabetes3. In this edition of The Journal , Barber, et al report on the experience of using CV risk indicators in clinical practice4. In 2 cohorts of patients, 1 in which patients enrolled into an early RA disease clinic and the other where patients enrolled into a biologic registry, the authors report on the frequencies with which CVD indicators are assessed. These are summarized in a baseline 10-year Framingham Risk Score for those patients whose risk is identified by the Framingham Risk Score, age 30–74 years, and not taking a baseline statin. As anticipated, patients in the biologics cohort generally had more active disease, had worse functional status, were more likely to have erosive disease, and had extraarticular disease. The quality indicators assessed as CVD risk factors in the study included evidence of discussion of increased CV risk with the patient, formal CV risk assessment, assessment of smoking status and offer of smoking cessation counseling, screening for HTN and communication of HTN findings to the patient’s primary care provider, measurement of lipid profile, screening for diabetes, exercise counseling, and body mass index screening and lifestyle counseling, as well as documented attempts to reduce glucocorticoid usage and communication of the … Address correspondence to Dr. E.L. Matteson, Mayo Clinic and Mayo Foundation, 200 1st St., South West, Rochester, Minnesota 55905, USA; E-mail: matteson.eric{at}mayo.edu
... There is in fact a significant correlation between total fat intake and the risk of cancer. But also cholesterol accumulation may cause prostate cancer [13], an inverse association between on-treatment LDL-cholesterol and incident cancer has been found [14] as well as an inverse association of serum cholesterol with many cancers [14]- [16]. On the basis of these facts, it seems necessary to develop meat products with a healthier fat fraction. ...
... There is in fact a significant correlation between total fat intake and the risk of cancer. But also cholesterol accumulation may cause prostate cancer [13], an inverse association between on-treatment LDL-cholesterol and incident cancer has been found [14] as well as an inverse association of serum cholesterol with many cancers [14]- [16]. On the basis of these facts, it seems necessary to develop meat products with a healthier fat fraction. ...
Article
Full-text available
Eight different types of Bologna type cooked sausages apart from the control were produced in order to reduce the fat content (15%, 30%, 45%), replace the animal fat by olive oil (3%, 6.5% and 10%) as well as concomitant reduction and replacement of animal fat (30% of fat reduction with 2% of olive oil as an animal fat replacer). Quality attributes such as texture, water binding and color were monitored. Texture and water binding of fat reduced and fat replaced samples were quite similar to the control while color was strongly affected by the fat reduction and replacement. Fat reduction led to a redder cooked sausage and the addition of olive oil to a more yellow product. Chemical analysis revealed no major changes among samples apart from protein and fat content and fatty acid profile. Noteworthy, cooked sausage with more than 6.5% of olive oil achieved the World Health Organization’s recommendation on the nutritional fat index ((polyunsaturated + monounsaturated)/saturated fatty acid ≥ 2) which is very relevant to the development of healthier formulations. Cooked sausages with 45% of fat reduction and 30% fat reduced with 2% of olive oil were considered as the best by the panelists, which in addition had a balanced nutritional content by a lower caloric content. We concluded that fat reduction (up to 45%) and replacement (up to 10%) are possible with acceptable sensory quality and improved nutritional composition. When replacing animal fats by plant oils, the color of the product, which has a strong influence in the sensory acceptability of Bologna type cooked sausages, is affected. Therefore it must be controlled for a proper product development of meat products containing vegetable oils.
... Several epidemiological studies have reported that serum lipid abnormalities, including elevated total cholesterol, LDL-cholesterol and triglycerides and reduced HDL-cholesterol, increase the risk of breast cancer [44][45][46]. In the present study, we also found higher BMI, elevated TC, TG and LDL levels and reduced HDL levels in patients with breast cancer than those in healthy controls, which is consistent with previous study [44][45][46]. ...
... Several epidemiological studies have reported that serum lipid abnormalities, including elevated total cholesterol, LDL-cholesterol and triglycerides and reduced HDL-cholesterol, increase the risk of breast cancer [44][45][46]. In the present study, we also found higher BMI, elevated TC, TG and LDL levels and reduced HDL levels in patients with breast cancer than those in healthy controls, which is consistent with previous study [44][45][46]. Moreover, it also has been reported that higher levels of fasting plasma glucose have been associated with an increased breast cancer risk [47,48]. ...
Article
Full-text available
Background Retinol binding protein 4 (RBP4) is a recently identified adipokine that is elevated in patients with obesity or type 2 diabetes. A growing body of research has shown that RBP4 is associated with several types of cancer. However, no studies have investigated the relationship between serum RBP4 levels and breast cancer risk. We performed a case-control study to evaluate the association between serum RBP4 levels and the risk of breast cancer. Methods From August 2012 to December 2013, four-hundred subjects including 200 patients diagnosed with primary breast cancer and 200 matched healthy women were consecutively enrolled from Affiliated Hospital of Qingdao University Medical College. Blood samples were collected from healthy controls and breast cancer patients before commencement of treatment. Enzyme-linked immunosorbent assay was used to evaluate the serum RBP4 levels in separated serum samples. Meanwhile, the characteristics of breast cancer cases and controls were collected from medical records and pathological data. Results The serum levels of RBP4 were significantly higher in patients with breast cancer than that in the healthy control group (33.77±9.92 vs. 28.77±6.47μg/ml, P < 0.05). Compared to the subjects in the lowest quartile of serum RBP4 level, the adjusted ORs (95% CIs) is 2.16(1.01–4.61) and 2.07 (1.07–4.00) for women in the second and highest RBP4 tertile, respectively. For breast cancer patients, patients with PR or ER negative displayed significantly higher serum RBP4 levels than those with PR or ER positive. Conclusion Our results for the first time suggested serum RBP4 levels could be associated with the risk of breast cancer. However, further prospective studies are essential to confirm these observed results.
... A possibility of the carcinogenic effect of statins has been described in some observational studies on breast cancer [219], lymphoid malignancies [220], prostate cancer [221], bladder cancer [222], any malignancies [223], cancer in elderly patients [224,225], and in a meta-analysis or commentaries [212,226,227]. However, other studies found no such effect [228][229][230]. ...
Article
Full-text available
The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, are administered as first-line therapy for hypercholesterolemia, both as primary and secondary prevention. Besides the lipid-lowering effect, statins have been suggested to inhibit the development of cardiovascular disease through anti-inflammatory, antioxidant, vascular endothelial function-improving, plaque-stabilizing, and platelet aggregation-inhibiting effects. The preventive effect of statins on atherothrombotic stroke has been well established, but statins can influence other cerebrovascular diseases. This suggests that statins have many neuroprotective effects in addition to lowering cholesterol. Furthermore, research suggests that statins cause pro-apoptotic, growth-inhibitory, and pro-differentiation effects in various malignancies. Preclinical and clinical evidence suggests that statins inhibit tumor growth and induce apoptosis in specific cancer cell types. The pleiotropic effects of statins on cardiovascular and cerebrovascular diseases have been well established; however, the effects of statins on cancer patients have not been fully elucidated and are still controversial. This review discusses the recent evidence on the effects of statins on cardiovascular and cerebrovascular diseases and cancer. Additionally, this study describes the pharmacological action of statins, focusing on the aspect of ‘beyond lipid-lowering’.
... A meta-analysis that included 15 randomized controlled trials suggested that on-treatment LDL-C was negatively associated with cancer. 31 However, ...
Article
Objective The objective of this study was to investigate the association between total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and non-high-density lipoprotein cholesterol (non-HDL-C) with atherosclerotic cardiovascular disease (ASCVD) or cancer in a male population in the Kailuan cohort of China. Methods This prospective study included 68,769 Chinese male adults from Kailuan cohort of China who had a standardized medical examination between 2006 and 2007 and were followed up for approximately 8 years until occurrence of ASCVD, cancer or death or until December 31, 2014. Cox regression models were used to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs). Multivariable analysis was adjusted for age, cigarette smoking, alcohol consumption, physical activity, hypertension, diabetes mellitus and BMI at baseline. Results During follow-up, 2,916 males developed ASCVD and 1,884 developed cancer. Compared with the lowest quartile, the upper-most quartiles of TC, LDL-C and non-HDL-C were all associated with increased ASCVD risk (HR 1.53, 95% CI 1.37-1.70; HR 1.16, 95% CI 1.05-1.28; HR 1.55, 95% CI 1.39-1.72); however, the upper-most quartiles of TC, LDL-C and non-HDL-C were all negatively associated with cancer (HR 0.84, 95% CI 0.74-0.95; HR 0.82, 95% CI 0.72-0.93; HR 0.80, 95%CI 0.70-0.90) and these associations were present after exclusion of incident cancers during the first 4 years of follow-up. Conclusion In this Kailuan cohort study, we report that high TC, LDL-C and non-HDL-C concentrations increased ASCVD incidence in a male population and that these lipid profiles were inversely associated with total cancer and several individual cancers. This article is protected by copyright. All rights reserved.
... Statins, are inhibitors of cholesterol synthesis, and are used for the treatment of dyslipidemia and prevention of cardiovascular disease (10). New research suggests that LDL decreasing by use of high-dose Statins, increases the risk of cancer and Makes the likelihood of damage to the liver by increased dose (11). In the present study the impact of the amount of sugar cane extract on serum HDL-c and LDL-c and atheroma plaque has been checked. ...
Article
Full-text available
Introduction: Sugar cane is a giant plant of grain products. Regarding the benefits of the use of medications with herbal origin, in the present study the impact of sugar cane extract on atherosclerosis and LDL-c and HDL-c in the serum of hypercholesterolemic rabbits was studied. Materials and methods: 24 adult male New Zealand rabbits race with an average weight of 2 kg were classified into four groups: the control group had a normal diet, Sham group and the 1 , 2 experimental group were cholesteroled with 2% high cholesterol regime and received drug solvent, sugar cane extract with 3.7 and 7.4 mg/kg doses as an oral treatment per day, respectively . After eight weeks of treatment, Blood were collected and subjected for measuring of LDL-C and HDL-c. For histological studies, Aorta was removed and was fixed in formalin %10. SPSS with ANOVA was applied for data analysis. Results: The results demonstrated treatment via sugar cane extract with 3.7 and 7.4 mg/kg per day, significant reduction in LDL-c and significant increase in HDL-c, in compare with Sham group, was occurred. In addition, histological examination showed that treatment by 3.7 and 7.4 mg/kg per day of Sugar cane extract (the experimental groups 1, 2, respectively), prevented atheroma plaques. Conclusion: Sugar cane extract may be effective in reducing the amount of LDL-c and increasing HDL-c and prevents the formation of atheroma plaques. Keywords: Sugar cane, LDL-c, HDL-c, atherosclerosis
... Per contro, nel 2007, una metanalisi [19] di 23 RCT ha documentato un'associazione significativa fra il rischio di cancro e i più bassi valori di colesterolo LDL raggiunti con la somministrazione di statine. Nell'agosto 2008 il dato è stato confermato [20] analizzando i dati di 15 RCT, per un totale di 96.840 pazienti. L'incidenza di cancro, tuttavia, correlava con la riduzione della concentrazione di colesterolo LDL, e non con l'assunzione di statine, risultando sostanzialmente uguale sia nel gruppo in trattamento attivo sia nel gruppo in placebo (12,7 vs 12,6 per 1.000 persone/anno, rispettivamente). ...
... There are a number of studies suggesting that an excessively low level of total cholesterol might be an increased risk for cancer mortality [50][51][52][53][54][55]. Recently, some studies have reported that lower levels of LDL-C are associated with higher rates of incident cancers [56]. Kikuchi et al. suggested that lower serum levels of total cholesterol are associated with higher oxidative DNA damage and linking to an increased risk of cancer [50]. ...
Article
Purpose: In recent years, the potential risk of cancer associated with statin use has been a focus of much interest. However, it remains uncertain whether statin therapy is associated with cancer risk. To examine the association between statin use and the risk of cancer, we conducted data mining using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and a large organized database of claims constructed by a database vendor (The Japan Medical Data Center Co., Ltd, Tokyo, Japan [JMDC]). Methods: Relevant reports in the FAERS, which included data from the first quarter of 2004 through the end of 2012, were identified and analyzed. The reporting odds ratio (ROR) was used to detect spontaneous report signals and was calculated using the case/non-case method. Additionally, signals were detected via the information component (IC) using the IC025 metric. Furthermore, event sequence symmetry analysis (ESSA) was applied to identify the risk of cancer following treatment with statins over the period January 2005 to July 2013. Results: In the FAERS database analyses, significant signals for colorectal cancer and pancreatic cancer were found for statins as a class. In the ESSA, significant associations between statin use and colorectal cancer and pancreatic cancer were found, with adjusted sequence ratios (95% confidence intervals) of 1.20 (1.08-1.34) and 1.31 (1.13-1.53), respectively, at an interval of 48 months. Conclusions: Multi-methodological approaches using different algorithms and databases suggest that statin use is associated with an increased risk for colorectal cancer and pancreatic cancer.
... Given the rapid onset of cholesterol lowering by statin therapy and the relatively long latency period required for colorectal carcinogenesis, we believe the modestly increased cancer risk associated with reduction in serum cholesterol concentration observed in statin users was related to cholesterol lowering from undiagnosed malignancy and not a causal association with statin therapy. To our knowledge, the only other study to examine the association between reduction in serum cholesterol and cancer risk was a meta-analysis of statin clinical trials, which combined all cancers, had shorter follow-up, and lacked patient-level data [29]. Combining all cancers risks bias towards the null if the effect is not universal across all cancers. ...
Article
Full-text available
Background: Several prior studies have found an association between statin use and reduced risk of colorectal cancer. We hypothesized that these findings may be due to systematic bias and examined the independent association of colorectal cancer risk with statin use, serum cholesterol, and change in cholesterol concentration. Methods and findings: 22,163 colorectal cancer cases and 86,538 matched controls between 1995 and 2013 were identified within The Health Improvement Network (THIN) a population-representative database. Conditional logistic regression models estimated colorectal cancer risk with statin use, serum total cholesterol (mmol/L), and change in total cholesterol level. We confirmed a decreased risk of colorectal cancer with statin use (long-term: odds ratio [OR], 0.95; 95% confidence interval [CI], 0.91-0.99; short-term: OR, 0.92; 95% CI, 0.85-0.99). However, to assess whether the observed association may result from indication bias, a subgroup analysis was conducted among patients prescribed a statin. In this subgroup (n = 5,102 cases, n = 19,032 controls), 3.1% of case subjects and 3.1% of controls discontinued therapy. The risk of colorectal cancer was not significantly different among those who continued statin therapy and those who discontinued (OR, 0.98; 95% CI, 0.79-1.22). Increased serum cholesterol was independently associated with decreased risk of colorectal cancer (OR, 0.89 per mmol/L increase; 95% CI, 0.87-0.91); the association was only present if serum cholesterol was measured near the cancer diagnosis (<6 mo: OR, 0.76; 95% CI, 0.47-0.61; >24 mo: OR, 0.98; 95% CI, 0.93-1.03). Decreases in serum total cholesterol >1 mmol/L ≥1 year prior to cancer diagnosis were associated with subsequent colorectal cancer (statin users: OR, 1.25; 95 CI%, 1.03-1.53; nonusers: OR, 2.36; 95 CI%, 1.78-3.12). As an observational study, limitations included incomplete data and residual confounding. Conclusions: Although the risk of colorectal cancer was lower in statin users versus nonusers, no difference was observed among those who continued versus discontinued statin therapy, suggesting the potential for indication bias. The association between decreased serum cholesterol and colorectal cancer risk suggests a cholesterol-lowering effect of undiagnosed malignancy. Clinical judgment should be used when considering causes of cholesterol reduction in patients, including those on statin therapy.
... For prostate cancer, the literature is mixed, as studies have reported both protective associations [23] and no association with statin use [7,44,45]. In particular, several meta-analyses have not reported any association between prostate cancer and statin use [1,16,34]. ...
Article
Full-text available
Purpose of review: Statins are one of the most widely prescribed drug classes in the USA. This review aims to summarize recent research on the relationship between statin use and cancer outcomes, in the context of clinical guidelines for statin use in patients with cancer or who are at high risk for cancer. Recent findings: A growing body of research has investigated the relationship between statins and cancer with mixed results. Cancer incidence has been more extensively studied than cancer survival, though results are inconsistent as some large meta-analyses have not found an association, while other studies have reported improved cancer outcomes with the use of statins. Additionally, two large studies reported increased all-cancer survival with statin use. Studies on specific cancer types in relation to cancer use have also been mixed, though the most promising results appear to be found in gastrointestinal cancers. Few studies have reported an increased risk of cancer incidence or decreased survival with statin use, though this type of association has been more commonly reported for cutaneous cancers. The overall literature on statins in relation to cancer incidence and survival is mixed, and additional research is warranted before any changes in clinical guidelines can be recommended. Future research areas include randomized controlled trials, studies on specific cancer types in relation to statin use, studies on populations without clinical indication for statins, elucidation of underlying biological mechanisms, and investigation of different statin types. However, studies seem to suggest that statins may be protective and are not likely to be harmful in the setting of cancer, suggesting that cancer patients who already take statins should not have this medication discontinued.
... Mounting evidence has established that low plasma levels of low-density lipoprotein cholesterol are associated with an increased risk of future cancer (Benn et al, 2011). Furthermore, in a long-term follow-up study, moderate total serum cholesterol was found to have a protective effect on 40-year cancer mortality (Panagiotakos et al, 2005), and an analysis of large statin randomised controlled trials demonstrated an inverse association between on-treatment low-density lipoprotein cholesterol levels and incident cancer (Alsheikh-Ali et al, 2008). ...
Article
The BJC is owned by Cancer Research UK, a charity dedicated to understanding the causes, prevention and treatment of cancer and to making sure that the best new treatments reach patients in the clinic as quickly as possible. The journal reflects these aims. It was founded more than fifty years ago and, from the start, its far-sighted mission was to encourage communication of the very best cancer research from laboratories and clinics in all countries. The breadth of its coverage, its editorial independence and it consistent high standards, have made BJC one of the world's premier general cancer journals. Its increasing popularity is reflected by a steadily rising impact factor.
... Lower circulating total (TC) [1][2][3], high-density lipoprotein (HDL-C) [4] and low-density lipoprotein cholesterols (LDL-C) [5] have been shown to be associated with an increase risk of total cancer, as well as cancer of the lung, prostate, stomach or colon [6,7]. Although these observed associations have been ascribed to the presence of preclinical cancer that decreases cholesterol levels [8,9], the association remained significant in several studies even after excluding cancer incidence that occurred during early period of follow up [2,6]. ...
Article
Full-text available
Lower serum total (TC), high-density lipoprotein (HDL-C) and low-density lipoprotein cholesterols (LDL-C) have been linked to an increased risk of cancer in various sites, but its underlying mechanism remains unclear. In an attempt to clarify the association between cholesterol levels and oxidative DNA damage, we investigated the relationship between serum cholesterol and urinary 8-hydroxydeoxyguanosine levels in a Japanese working population. The study subjects were 294 men and 209 women aged 21-66 years in two Japanese municipal offices. Urinary 8-hydroxydeoxyguanosine (8-OHdG) was measured using an automated high-pressure liquid chromatography. Linear regression analysis was used to examine the associations of urinary 8-OHdG with TC, HDL-C and LDL-C levels with adjustment for sex, age, smoking and body mass index. Subgroup analyses were conducted by smoking status in men and age in women. Analysis of covariance was employed to estimate adjusted means of urinary 8-OHdG across TC category. After multivariate adjustment, urinary 8-OHdG levels were inversely associated with serum TC levels (β = -0.0015, p < 0.05) and LDL-C levels (β = -0.0012, p = 0.07). The inverse association with TC was apparent among smoking men (β = -0.0017, p < 0.05) and among women aged less than 48 years (β = -0.0040, p < 0.01). 8-OHdG decreased as TC increased (up to 219 mg/dL); subjects with TC levels of <160 mg/dL had a 17.4% higher adjusted mean of 8-OHdG than did those with TC levels of 200-219 mg/dL. Results suggest that circulating low TC levels are associated with higher oxidative DNA damage.
... The use of statins causes reduction in serum LDL level, coronary artery diseases and finally reduction in mortality rates 47,48 . But, this set of drugs is known to have many side effects like myopathy, rhabdomyolysis, reduction in hepatic enzymes, nausea, dizziness and digestive tract problems, as well as elevation in cancer risk, liver damage and an increased risk of new-onset diabetes mellitus [49][50][51][52][53] . Life-threatening rhabdomyolysis and idiopathic polyneuropathy represent the most important muscular symptoms [54][55][56][57][58][59][60] . ...
Article
Full-text available
Introduction: Treatment of cardiovascular risk factors seems to be necessary and involves a number of changes in drug treatment and lifestyle. This study aimed to evaluate the effects of Matricaria chamomilla L. hydroalcoholic extract on antioxidant activity, atherosclerotic plaques, lipid profile and inflammatory indicators in rats. Methods: Thirty male Wistar rats were divided into five experimental groups consisting of group 1 (Sham; normal dietary), group 2 (control; high cholesterol diet (2%)), group 3 (high cholesterol diet plus 55 mg/kg of chamomile hydroalcoholic extract), group 4 (high cholesterol diet plus 110 mg/kg of chamomile hydroalcoholic extract), and group 5 (high cholesterol diet plus 10 mg/kg of lovastatin). At the beginning and end of the study, blood samples of all the animals were taken for determination of antioxidant activity and the level of biochemical parameters. The hearts and aorta were also isolated for ontological tests. Results: No symptom of plaque formation was observed in experimental groups 3, 4 and 5 that received the high cholesterol diet. High cholesterol diet (2%) resulted in a significant increase in serum cholesterol level, TG and LDL-c levels in groups 2 and 3 as compared to group 1 (P<0.001). No significant difference was observed in serum cholesterol, TG and LDL-c levels in experimental groups 4 and 5, compared to experimental group 1. In group 4, serum HDL-c concentration did not show significant changes as compared to group 1. In groups 4 and 5, no significant change was observed in inflammatory factors as compared to group 1. The levels of superoxide dismutase in red blood cells and malondialdehyde in plasma of groups 3 and 5 showed no significant change when compared with group 1. Conclusion: Chamomile led to the management and correction of changes in risk factors of cardiovascular diseases.
... Part of the reason why coffee is so important, may be that the coffee intake is high in Norway. Coffee consumption is quite high in Norway and the other Nordic countries as compared to the rest of the world [28]. According to the International Coffee Organization (ICO) 2012, the average per capita consumption was highest in Finland (11.7 kg/year), followed by Norway (9.4 kg), Denmark (8.9 kg) and Sweden (8.1 kg), while in other European countries it was somewhat lower: Switzerland (7.4 kg), Germany (6.8 kg), Austria (6.8 kg), Belgium (6.4 kg), Netherlands (6.3 kg), Italy (5.6 kg) and France (5.4 kg) [29]. ...
Article
Full-text available
Fruit and vegetable intake has been found to reduce the risk of cardiovascular disease, certain types of cancer and diabetes mellitus. It is possible that antioxidants play a large part in this protective effect. However, which foods account for the variation in antioxidant intake in a population is not very clear. We used food frequency data from a population-based sample of women to identify the food items that contributed most to the variation in antioxidant intake in Norwegian diet. We used data from a study conducted among participants in the Norwegian Breast Cancer Screening Program (NBCSP), the national program which invites women aged 50-69 years to mammographic screening every 2 years. A subset of 6514 women who attended the screening in 2006/2007 completed a food frequency questionnaire (FFQ). Daily intake of energy, nutrients and antioxidant intake were estimated. We used multiple linear regression analysis to capture the variation in antioxidant intake. The mean (SD) antioxidant intake was 23.0 (8.5) mmol/day. Coffee consumption explained 54 % of the variation in antioxidant intake, while fruits and vegetables explained 22 %. The twenty food items that contributed most to the total variation in antioxidant intake explained 98 % of the variation in intake. These included different types of coffee, tea, red wine, blueberries, walnuts, oranges, cinnamon and broccoli. In this study we identified a list of food items which capture the variation in antioxidant intake among these women. The major contributors to dietary total antioxidant intake were coffee, tea, red wine, blueberries, walnuts, oranges, cinnamon and broccoli. These items should be assessed in as much detail as possible in studies that wish to capture the variation in antioxidant intake.
... Currently, there is no evidence that statin-induced low LDL cholesterol levels are harmful, and studies also suggest that the lower the LDL cholesterol level is, the higher the cardioprotective effect will be. 39,40 Recent guidelines indicate that the ideal LDL level for those with no known risk factors for heart disease is < 130 mg dL À1 (3Á4 mmol L À1 ), while for those with risk factors, the target LDL may be < 70-100 mg dL À1 (1Á8-2Á6 mmol L À1 ). 41 One limitation of this study is that we investigated only the use of simvastatin as active management for venous ulcers, and not for maintenance therapy or prevention once the ulcers had closed. ...
Article
Background Although the standard treatment for venous ulcers is compression, drugs may be used as adjunctive therapy. Simvastatin has shown potential wound-healing properties, however, no studies have investigated its use for venous ulcers. This study assessed the efficacy and safety of simvastatin in venous ulcer healing when combined with standard treatment for ulcers. MethodologyThis was a randomized, double-blind, placebo-controlled trial. Outcome measures were proportion of healed ulcers, healing time, total surface area healed, and dermatology life quality indices (DLQI). Results66 patients were randomized, 32 in the simvastatin and 34 in the control group. Among ulcers ≤ 5 cm, 100% healed in the simvastatin group, while 46% healed in the control group (RR 0.11, 95% CI: 0.02 – 0.77). The average healing time for ulcers ≤ 5 cm was 6.89 ± 0.78 weeks and 8.40 ± 1.13 weeks for simvastatin and control groups, respectively (p value = 0.0001). Among ulcers > 5 cm, 50% in the simvastatin group had closure, with a mean healing time of 9.17 ± 1.07 weeks. None of the ulcers of this size closed among the placebo group (RR 0.5, 95% CI: 0.28 – 0.88). The simvastatin group had lower DLQIs (p value = 0.0004) post-treatment. There were no documented adverse effects. Conclusion Simvastatin 40mg/daily, in addition to standard wound care and compression, is associated with a significant improvement in healing rate and healing time, as well and improved patient quality of life when compared with placebo in the management of venous ulcers.This article is protected by copyright. All rights reserved.
... doznu zavisnost rizika od karcinoma od sniženja LDL-H: za svakih 10 mg% sniženja LDL-H, rizik se povećava za 2.2 slučaja karcinoma na 1000 bolesnik-godina. 19 Od mnogih komentara jedan je posebno zanimljiv jer tvrdi: "Niski LDL je posledica, a ne uzrok kancera". 20 Lucidnost ove opaske smanjuje podatak da je njen autor zagovornik maksimalnih sniženja LDL-H do 50 mg%. ...
Article
Full-text available
"Statins are generally well tolerated, their serious side effects are infrequent, and much less important than the reduction of mortality and morbidity". This sentence is commonly used to describe the importance of efficacy over tolerability, particularly in clinical studies in secondary prevention of CV risk. This assumption belies the fact that many patients are not regularly included in, or were excluded from, randomized clinical trials (RCT) designed to provide relevant committees with side effect profiles for drugs under investigation. In the real life, however, patients such as the elderly, individuals with small body size, women, those with kidney and liver failure, hypothyroidism, multisystem disease and alcoholics are not left untreated where a statin may be indicated. As a result, one would expect a higher incidence of side effects than declared in the requisite SPCs (summaries of product charactetristics). This is the main scientific standpoint for those who claim that the side effects are underestimated; the manipulations of marketing also serve to downgrade the side effects of statins. RCTs that address secondary prevention include high-risk patients. Their aim is to demonstrate the efficacy in reduction of hard clinical endpoints, morbidity and mortality, whereas any undesirable effects are of secondary importance. However, special attention is paid to symptomatic complaints due to muscle damage: myalgia, myositis, myopathy and rhabdomyolysis (when serum CK levels are elevated), and to asymptomatic elevation of hepatic enzymes ALT and AST levels, indicative of hepatotoxicity. A significant proportion of space in SPCs is devoted to Special warnings and precautions for use and to measures for the prevention of side effects. As with other effective drugs, side effects of statins should be taken seriously, even though some side effects are not regarded serious enough to restrict the use of these drugs. Many clinicians disregard the fact that patients may be expected to continue treatment with statins for 20-30 years, and that data for long-term tolerability are lacking. In primary prevention studies, there is a significant discrepancy between single clinical trials and meta-analyses regarding side effects. Some large and important clinical trials indicate that statins induce anxiety, depression, memory loss, suicidal behavior, diabetes and cancer - without significant reduction of CV risk - despite significant reductions of LDL-C levels. In contrast, meta-analyses are almost unanimous in claiming that statins significantly reduce both LDL-C levels and CV risk without toxicity. In some meta-analyses, the authors mention that side effects were not reported regularly, or they may indicate flaws in the inclusion criteria to justify indicating caution before prescribing a statin for primary prevention in low risk patients. The use of statins is not as high in Serbia and Republic of Srpska as in the some wealthier parts of the world. Before excessive use of these drugs prevail, a review of medical problems resulting from their uncontrolled use might help doctors to make an informed decision whether to include new patients into this large human medical experiment. A little foresight may thus prevent many undesirable effects, particularly in low risk patients.
... Possible explanations include the independent role of the lipoprotein(a), which has not been measured in this study, 35 and the increased risk of death from other cardiovascular causes such as cancer, at an LDL-C < 84 mg/dL. 36,37 Although a recent study presented a stepwise increase in CHD according to the baseline LDL-C in young adults, 19 this did not refute our results because its reference value was defined as LDL-C < 100 mg/dL, without further categorization. Moreover, the top quartile of LDL-C in our study showed a clear increase in the risk of CVD, which was in agreement with previous studies, where higher LDL-C was significantly associated with an increased risk of ASCVD. ...
Article
Full-text available
Aims Dyslipidaemia is a modifiable cardiovascular risk factor with prognostic implications. Current strategies for lipid management in young adults are largely based on expert recommendations. We investigated the risks of death and cardiovascular disease in relation to each lipid component to establish evidence for primary prevention in young adults. Methods In this nationwide population-based cohort study, we analysed 5,688,055 statin-naïve subjects, aged 20–39 years, undergoing general health check-ups between 2009 and 2014. The endpoint was a composite of clinical events including death, myocardial infarction (MI), and stroke. We compared the incidence and risk of clinical events according to each lipid variable. Results During follow-up (median 7.1 years), clinical events occurred in 30,330 subjects (0.53%): 16,262 deaths (0.29%), 8578 MIs (0.15%), and 5967 strokes (0.10%). The risk of clinical events gradually increased with increasing total cholesterol (TC) and triglycerides and decreasing high-density lipoprotein cholesterol (HDL-C), largely driven by MI. Low-density lipoprotein cholesterol (LDL-C) had a J-shaped association with clinical events, showing the lowest risk for LDL-C of 84–101 mg/dL. Among lipid variables, triglycerides remained the sole independent predictor (adjusted hazard ratio, 1.20; p < 0.001) after adjusting for conventional risk factors. Conclusions For statin-naïve young adults, the risk of clinical events was proportional to lipid levels, positively with TC and triglycerides, negatively with HDL-C, and J-shaped with LDL-C. Triglycerides had an independent and the strongest association with the clinical events. Screening and intervention for abnormal lipid levels, particularly triglycerides, from an early age might be of clinical value.
... Individual observational studies have reported positive (Kitahara et al., 2011;Strohmaier et al., 2013), inverse (Kitahara et al., 2011;Strohmaier et al., 2013;Melvin et al., 2012;Katzke et al., 2017), and no association (Salonen, 1982;JPHC Study Group et al., 2009;Van Hemelrijck et al., 2012;Ma et al., 2016) between circulating levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides with the risk of overall and site-specific cancers. Different cancer types have distinct underlying pathophysiology, and meta-analyses of observational studies highlight a likely complex relationship which varies according to both lipid fraction (Vílchez et al., 2014;Alsheikh-Ali et al., 2008) and cancer type (Ma et al., 2016;Lin et al., 2017;Passarelli and Newcomb, 2016;Yao and Tian, 2015). Furthermore, cancer can lower cholesterol levels for up to 20 months before diagnosis (Kritchevsky et al., 1991). ...
Article
Full-text available
Laboratory studies have suggested oncogenic roles of lipids, as well as anticarcinogenic effects of statins. Here we assess the potential effect of statin therapy on cancer risk using evidence from human genetics. We obtained associations of lipid-related genetic variants with the risk of overall and 22 site-specific cancers for 367,703 individuals in the UK Biobank. In total, 75,037 individuals had a cancer event. Variants in the HMGCR gene region, which represent proxies for statin treatment, were associated with overall cancer risk (odds ratio [OR] per one standard deviation decrease in low-density lipoprotein [LDL] cholesterol 0.76, 95% confidence interval [CI] 0.65-0.88, p=0.0003) but variants in gene regions representing alternative lipid-lowering treatment targets (PCSK9, LDLR, NPC1L1, APOC3, LPL) were not. Genetically predicted LDL-cholesterol was not associated with overall cancer risk (OR per standard deviation increase 1.01, 95% CI 0.98-1.05, p=0.50). Our results predict that statins reduce cancer risk but other lipid-lowering treatments do not. This suggests that statins reduce cancer risk through a cholesterol independent pathway.
... Individual observational studies have reported positive (Kitahara et al., 2011;Strohmaier et al., 2013), inverse (Kitahara et al., 2011;Strohmaier et al., 2013;Melvin et al., 2012;Katzke et al., 2017), and no association (Salonen, 1982;JPHC Study Group et al., 2009;Van Hemelrijck et al., 2012;Ma et al., 2016) between circulating levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides with the risk of overall and site-specific cancers. Different cancer types have distinct underlying pathophysiology, and meta-analyses of observational studies highlight a likely complex relationship which varies according to both lipid fraction (Vílchez et al., 2014;Alsheikh-Ali et al., 2008) and cancer type (Ma et al., 2016;Lin et al., 2017;Passarelli and Newcomb, 2016;Yao and Tian, 2015). Furthermore, cancer can lower cholesterol levels for up to 20 months before diagnosis (Kritchevsky et al., 1991). ...
Article
Full-text available
Laboratory studies have suggested oncogenic roles of lipids, as well as anticarcinogenic effects of statins. Here we assess the potential effect of statin therapy on cancer risk using evidence from human genetics. We obtained associations of lipid-related genetic variants with the risk of overall and 22 site-specific cancers for 367,703 individuals in the UK Biobank. In total, 75,037 individuals had a cancer event. Variants in the HMGCR gene region, which represent proxies for statin treatment, were associated with overall cancer risk (odds ratio [OR] per one standard deviation decrease in low-density lipoprotein [LDL] cholesterol 0.76, 95% confidence interval [CI] 0.65–0.88, p=0.0003) but variants in gene regions representing alternative lipid-lowering treatment targets (PCSK9, LDLR, NPC1L1, APOC3, LPL) were not. Genetically predicted LDL-cholesterol was not associated with overall cancer risk (OR per standard deviation increase 1.01, 95% CI 0.98–1.05, p=0.50). Our results predict that statins reduce cancer risk but other lipid-lowering treatments do not. This suggests that statins reduce cancer risk through a cholesterol independent pathway.
... Individual observational studies have reported positive (Kitahara et al., 2011;Strohmaier et al., 2013), inverse (Kitahara et al., 2011;Strohmaier et al., 2013;Melvin et al., 2012;Katzke et al., 2017), and no association (Salonen, 1982;JPHC Study Group et al., 2009;Van Hemelrijck et al., 2012;Ma et al., 2016) between circulating levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides with the risk of overall and site-specific cancers. Different cancer types have distinct underlying pathophysiology, and meta-analyses of observational studies highlight a likely complex relationship which varies according to both lipid fraction (Vílchez et al., 2014;Alsheikh-Ali et al., 2008) and cancer type (Ma et al., 2016;Lin et al., 2017;Passarelli and Newcomb, 2016;Yao and Tian, 2015). Furthermore, cancer can lower cholesterol levels for up to 20 months before diagnosis (Kritchevsky et al., 1991). ...
Article
Full-text available
Laboratory studies have suggested oncogenic roles of lipids, as well as anticarcinogenic effects of statins. Here we assess the potential effect of statin therapy on cancer risk using evidence from human genetics. We obtained associations of lipid-related genetic variants with the risk of overall and 22 site-specific cancers for 367,703 individuals in the UK Biobank. In total, 75,037 individuals had a cancer event. Variants in the HMGCR gene region, which represent proxies for statin treatment, were associated with overall cancer risk (odds ratio [OR] per one standard deviation decrease in low-density lipoprotein [LDL] cholesterol 0.76, 95% confidence interval [CI] 0.65–0.88, p=0.0003) but variants in gene regions representing alternative lipid-lowering treatment targets (PCSK9, LDLR, NPC1L1, APOC3, LPL) were not. Genetically predicted LDL-cholesterol was not associated with overall cancer risk (OR per standard deviation increase 1.01, 95% CI 0.98–1.05, p=0.50). Our results predict that statins reduce cancer risk but other lipid-lowering treatments do not. This suggests that statins reduce cancer risk through a cholesterol independent pathway.
... Epidemiological data, Mendelian studies, and meta-analyses have suggested safety concerns regarding higher incidence of cancer, DM, and haemorrhagic stroke with very low levels of LDL-C. 11,34,35 A recent Treat Stroke to Target trial showed numerically higher 38% and 27% RR of intracranial haemorrhage and incident DM with more intensive treatment, which was not statistically significant. 10 However, our larger meta-analysis of treatments achieving LDL-C levels below 70 mg/dL did not confirm these hazards. ...
Article
Aim The 2018 American Heart Association/American College of Cardiology/Multi-Society Cholesterol Guidelines recommended the addition of non-statins to statin therapy for high-risk secondary prevention patients above a low-density lipoprotein cholesterol (LDL-C) threshold of ≥70 mg/dL (1.8 mmol/L). We compared effectiveness and safety of treatment to achieve lower (<70) vs. higher (≥70 mg/dL) LDL-C among patients receiving intensive lipid-lowering therapy (statins alone or plus ezetimibe or proprotein convertase subtilisin/kexin type 9 inhibitors). Methods and results Eleven randomized controlled trials (130 070 patients), comparing intensive vs. less-intensive lipid-lowering therapy, with follow-up ≥6 months and sample size ≥1000 patients were selected. Meta-analysis was reported as random effects risk ratios (RRs) [95% confidence intervals] and absolute risk differences (ARDs) as incident cases per 1000 person-years. The median LDL-C levels achieved in lower LDL-C vs. higher LDL-C groups were 62 and 103 mg/dL, respectively. At median follow-up of 2 years, the lower LDL-C vs. higher LDL-C group was associated with significant reduction in all-cause mortality [ARD −1.56; RR 0.94 (0.89–1.00)], cardiovascular mortality [ARD −1.49; RR 0.90 (0.81–1.00)], and reduced risk of myocardial infarction, cerebrovascular events, revascularization, and major adverse cardiovascular events (MACE). These benefits were achieved without increasing the risk of incident cancer, diabetes mellitus, or haemorrhagic stroke. All-cause mortality benefit in lower LDL-C group was limited to statin therapy and those with higher baseline LDL-C (≥100 mg/dL). However, the RR reduction in ischaemic and safety endpoints was independent of baseline LDL-C or drug therapy. Conclusion This meta-analysis showed that treatment to achieve LDL-C levels below 70 mg/dL using intensive lipid-lowering therapy can safely reduce the risk of mortality and MACE.
... With the use of hydroxy-methyl-glutaryl coenzyme A reductase inhibitors (statins) for DL, while the reduction of T-Chol has been achieved and the suppression of coronary artery disease events and the reduction of mortality have been shown in many large clinical trials, there are many reports of increased deaths from nonatherosclerotic diseases due to malignant diseases. [27][28][29] For example, in the Cholesterol and Recurrent Events (CARE) trial, there was a significant increase in breast cancer in the pravastatin group [30] ; moreover, Iwata et al reported an elevated risk of lymphoid malignancy with statin use among Japanese patients. [31] Other increases in prostate cancer [32] and bladder [33] have been reported. ...
Article
Full-text available
Although the relationship between cardiovascular diseases and malignant diseases has recently attracted attention, the associations of cardiovascular risk factors and clinical outcomes in cancer patients remain to be elucidated. We performed a retrospective, observational study that explored the clinical outcomes of patients with cancer or with a history of cancer.We enrolled 30,706 consecutive adult cancer patients from Kumamoto University Hospital. We investigated mortality and morbidity, including cardiovascular conditions (dyslipidemia [DL]/diabetes mellitus [DM]/hypertension [HT]). The primary endpoint was all-cause mortality.Of the enrolled patients, 9032 patients (29.4%) died within the follow-up period. The Kaplan-Meier analysis demonstrated that in the groups classified according to the number of DL/DM/HT (LDH) factors, the LDH1 and LDH2 groups had a significantly higher probability of the primary endpoint than the LDH0 group (P < .001 and P < .001, respectively), whereas there were no significant differences between the LDH0 group and LDH3 group (P = .963). Univariate Cox proportional hazards regression analyses of mortality complemented by the multiple imputation method including various factors demonstrated that the presence of DL in cancer patients was a significant negative predictor of mortality (hazard ratio = 0.79, P < .01).The all-cause mortality rate did not always increase as the number of LDH factors increased. The present study revealed that the presence of DL is a negative risk factor for all-cause mortality in cancer patients.
... A possibility of the carcinogenic effect of statins has been described in some observational studies on breast cancer [206], lymphoid malignancies [207], prostate cancer [208], bladder cancer [209], any malignancies [210], cancer in the elderly patients [211,212], and in a meta-analysis or commentaries [199,213,214]. However, other studies found no such effect [215][216][217]. ...
Preprint
The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, are administered as first-line therapy for hypercholesterolemia, both as primary and secondary prevention. Besides the lipid-lowering effect, statins have been suggested to inhibit the development of cardiovascular disease through anti-inflammatory, antioxidant, vascular endothelial function-improving, plaque-stabilizing, and platelet aggregation-inhibiting effects. The preventive effect of statins on atherothrombotic stroke has been well established, but statins can influence other cerebrovascular diseases. This suggests that statins have many neuroprotective effects in addition to lowering cholesterol. Furthermore, research suggests that statins cause pro-apoptotic, growth-inhibitory, and pro-differentiation effects in various malignancies. Preclinical and clinical evidence suggests that statins inhibit tumor growth and induce apoptosis in specific cancer cell types. The pleiotropic effects of statins on cardiovascular and cerebrovascular diseases have been well established; however, the effects of statins on cancer patients have not been fully elucidated and are still controversial. This review discusses the recent evidence on the effects of statins on cardiovascular and cerebrovascular diseases and cancer. Additionally, this study describes the pharmacological action of statins, focusing on the aspect of ‘beyond lipid-lowering.’
Article
Unlabelled: Cholesterol (CH) is a vital component of cell membranes and of their function. It is entirely justified to warn against haphazard aggressive CH lowering, especially now, when more effective CH-modifying medications are entering the market. Enormous success in lowering the human toll of atherosclerosis and cardiovascular disease (CVD) by treating abnormally elevated lipids may be off set by the therapeutic risk. There are warning reports that low cholesterol is associated with malignity. There is a pressing need to evaluate all reports related to the risk of low CH body stores. New cholesterol management guidelines presented by American professional cardiology societies in November 2013 have reinforced the need to critically evaluate the management with statins and with other CH lowering medications (Tab. 1, Fig. 3, Ref. 58). Keywords: total cholesterol (CH), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), cardiovascular disease (CVD), hydroxy-methylglutaryl coenzyme A reductase (HMGCR), randomized control trial (RCT), cancer, statin, low cholesterol risk, lipid treatment guideline.
Article
Large-scale randomized controlled trials (RCTs) have well demonstrated the beneficial effects of cholesterol-lowering treatment with statins in patients at high risk of vascular disease. However, large statin RCTs were usually restricted to the typical 5 to 6 years. Moreover, non-cardiovascular events, especially the risk of cancer, probably failed to emerge within a restricted period of 6 years. The aim of this study was to evaluate the long-term efficacy and safety of statin treatment by performing a meta-analysis of statin RCTs with extended follow-up beyond 6 years. Six RCTs with post-trial follow-up were eligible for inclusion, involving 47 296 patients with total follow-up ranging from 6.7 to 14.7 years. During the post-trial period, all the surviving participants were advised to take a statin and the cholesterol level were almost identical between the original statin group and the original placebo group. Over the entire 6.7 to 14.7 years of follow-up, a significant reduction in the rates of all-cause mortality (relative risk 0.90, 95% confidence interval 0.85 to 0.96; P=0.0009), cardiovascular mortality (0.87, 0.81 to 0.93; P<0.0001) and major coronary events (0.79, 0.72 to 0.86; P<0.00001) was observed in favor of the original statin group. During 2-year post-trial period, further reduction in all-cause mortality (0.83, 0.74 to 0.93; P=0.001), cardiovascular mortality (0.81, 0.69 to 0.95; P=0.01) and major coronary events (0.77, 0.63 to 0.95; P=0.01) was observed among initially statin-treated patients. Over the entire follow-up period, statin treatment did not increase the incidence of cancers (0.99, 0.95 to 1.04; P=0.79), deaths from cancers (1.00, 0.93 to 1.07; P=0.98) and non-cardiovascular mortality (0.95, 0.90 to 1.00; P=0.07). In conclusion, statin treatment beyond 6 years is effective and safe in patients at high risk of vascular events. Moreover, earlier treatment with statin may not only preserve the initial benefit but also have further survival benefit for additional 2 years. Further studies are called for to explore the underlying mechanisms.
Article
Background Apolipoprotein E2 (ApoE2) is a pleiotropic protein that influences several aspects of cancer metabolism and development. Evading apoptosis is a vital factor for facilitating cancer cell growth. However, the role and mechanism of ApoE2 in regulating cell apoptosis of pancreatic cancer remain unclear. Methods In this study, we firstly detected the mRNA and protein expressions of ApoE2 in PANC-1 and Capan-2 cells by real-time polymerase chain reaction and Western blotting. We then performed TUNEL and flow cytometric analyses to explore the role of recombinant human ApoE2, pCMV6-ApoE2 and siApoE2 in the apoptosis of PANC-1 and Capan-2 cells. Furthermore, we investigated the molecular mechanism through which ApoE2 affected apoptosis in PANC-1 cells using immunofluorescence, immunoprecipitation, Western blotting and co-immunoprecipitation analysis. Results ApoE2 phosphorylated ERK1/2 and inhibited pancreatic cancer cell apoptosis. In addition, our data showed that ApoE2/ERK1/2 altered the expression and mitochondrial localization of BCL-2 via activating CREB. ApoE2/ERK1/2/CREB also increased the total BCL-2/BAX ratio, inhibited the opening of the mitochondrial permeability transition pore and the depolarization of mitochondrial transmembrane potential, blocked the leakage of cytochrome-c and the formation of the apoptosome, and consequently, suppressed mitochondrial apoptosis. Conclusions ApoE2 regulates the mitochondrial localization and expression of BCL-2 through the activation of the ERK1/2/CREB signaling cascade to evade the mitochondrial apoptosis of pancreatic cancer cells. ApoE2 may be a distinct prognostic marker and a potential therapeutic target for pancreatic cancer.
Article
Full-text available
Several commonly used medications have been associated with increased cancer risk in the literature. Here, we evaluated the strength and consistency of these claims in published meta-analyses. We carried out an umbrella review of 74 meta-analysis articles addressing the association of commonly used medications (antidiabetics, antihyperlipidemics, antihypertensives, antirheumatics, drugs for osteoporosis, and others) with cancer risk where at least one meta-analysis in the medication class included some data from randomized trials. Overall, 51 articles found no statistically significant differences, 13 found some decreased cancer risk, and 11 found some increased risk (one reported both increased and decreased risks). The 11 meta-analyses that found some increased risks reported 16 increased risk estimates, of which 5 pertained to overall cancer and 11 to site-specific cancer. Six of the 16 estimates were derived from randomized trials and 10 from observational data. Estimates of increased risk were strongly inversely correlated with the amount of evidence (number of cancer cases) (Spearman's correlation coefficient = -0.77, P < 0.001). In 4 of the 16 topics, another meta-analysis existed that was larger (n = 2) or included better controlled data (n = 2) and in all 4 cases there was no statistically significantly increased risk of malignancy. No medication or class had substantial and consistent evidence for increased risk of malignancy. However, for most medications we cannot exclude small risks or risks in population subsets. Such risks are unlikely to be possible to document robustly unless very large, collaborative studies with standardized analyses and no selective reporting are carried out.
Article
Full-text available
The primary objective of this study is to examine the race-specific associations between statin use and overall mortality, as well as cardiovascular and cancer mortality, among blacks and whites in the Southeastern United States (US). Little is known about these associations in blacks. The Southern Community Cohort Study is an ongoing, prospective cohort study, which enrolled from 2002 through 2009 nearly 86,000 participants aged 40-79 years. We used Cox regression models to estimate race-specific hazard ratios (HRs) and 95% confidence intervals (CI) for overall and cause-specific mortality associated with statin use based on self-reported hypercholesterolemia and treatment at cohort entry. Mean age at cohort entry was 51.4 years in blacks (n=48,825) and 53.5 years in whites (n=18,560). Sixty-one percent of participants were women. Whites were more likely to have self-reported hypercholesterolemia (40% versus 27%, P<0.001), and to report being treated with either statins (52% versus 47%, P<0.001) or combination lipid therapy (9% versus 4%, P<0.001) compared with blacks, regardless of sex. During follow-up (median: 5.6 years) 5,199 participants died. Compared with untreated hypercholesterolemic individuals, statin use was associated with reduced all-cause mortality (adjusted HR [aHR] 0.86; 95% CI 0.77-0.95) and cardiovascular disease mortality overall (aHR 0.75; 95% CI 0.64-0.89) and among whites (aHR 0.67; 95% CI 0.50-0.90), blacks (aHR, 0.80; 95% CI 0.65-0.98), men (aHR 0.70; 95% CI 0.55-0.90), and women (aHR 0.79; 95% CI 0.63-0.99) (P>0.05 for race and sex interaction). Statin use was not associated with cancer mortality overall or in subgroup analyses. Regardless of race or sex, self-reported statin use was linked to reduced all-cause and cardiovascular disease mortality. However, factors contributing to the modestly lower statin use and markedly lower prevalence of self-reported hypercholesterolemia among blacks remain to be determined.
Article
Background: The aim of this study was to perform a meta-analysis comparing by gender the cardiovascular outcomes related to statin therapy in primary prevention including recent large trials. Methods: A systematic search of medical literatures was performed to identify randomized placebo and standardcare-controlled endpoint trials of statins with sex-specific outcome data, which were reported from 1994 to April 2012. Summary estimates of relative risks (RRs) of the therapy were calculated by using a random-effects model for women and men without CVD. Results: Total eight studies with 59,744 participants were included (22,490 women, 37,254 men). Although statin treatment reduced the risk of total mortality (RR 0.70; 95% confidence interval [CI], 0.53 to 0.93), the risks of major coronary events (RR 0.62; 95% CI 0.37 to 1.04) and cerebrovascular events (RR 0.69; 95% CI 0.45 to 1.03) were not reduced by statin treatment in women without CVD. Although major adverse events and total cancer were not increased in both male and female patients taking statin, the stratified analysis by gender revealed higher risk of development of diabetes mellitus (DM) in female patients (RR 1.50; 95% CI 1.11 to 2.01). Conclusions: Statin treatment was less beneficial in women without CVD with regard to lowering adverse clinical outcomes when compared to men.
Article
To analyze the association between cancer incidence and oral diabetes therapy (biguanide, sulfonylurea, thiazolidinedione, meglitinide) in men and women with type 2 diabetes mellitus. A retrospective analysis of the electronic health record-based Cleveland Clinic Diabetes Registry (25,613 patients) was cross-indexed with the histology-based Tumor Registry (48,051 cancer occurrences) over an 8-year period (1998-2006). Multiple imputations were used to account for missing data. Cox regression with propensity scores was used to model time to development of incident cancer in each of the imputed datasets and the results were pooled. During 51,994 person follow-up years, 892 incident cancer cases were identified; prostate (14.5%) and breast (11.7%) malignancies were most frequent. In women, thiazolidinedione use was associated with a 32% decreased cancer risk compared to sulfonylurea use (HR 0.68 [95% CI 0.48-0.97] in the adjusted analysis). Comparison of insulin secretagogues (sulfonylurea, meglitinide) versus insulin sensitizers (biguanide, thiazolidinedione) demonstrated a 21% decreased cancer risk in insulin sensitizers (HR 0.79 [95% CI 0.64-0.98] in the adjusted analysis). Oral diabetes therapy showed no significant difference in men. Adjustments were made for age, BMI, LDL, HDL, triglycerides, CHD, diabetes oral monotherapy, race, gender, hemoglobin A1c, statin use, income, insulin use, GFR, new diabetes status, prior cancer, prior cerebrovascular accident (stroke or transient ischemic event), systolic/diastolic blood pressure, tobacco use (ever/never), and the propensity score for receiving a biguanide. Oral insulin sensitizers, particularly thiazolidinedione, are associated with decreased malignancy risk in women with type 2 diabetes mellitus.
Article
A customized screening program for gastric cancer would optimize the benefits of screening endoscopy. This study investigated the risk factors for gastric cancer detected during screening, and factors affecting clinical outcomes. From April 2000 to December 2010, subjects who underwent screening endoscopy at Asan Medical Center were included. To investigate risk factors, age and sex-matched control group were selected. The clinical outcomes of gastric cancer identified during screening (screening group) were compared with age, sex and date of diagnosis-matched subjects who were diagnosed with gastric cancer in the outpatient clinic (outpatient group). Of 109,530 subjects, 327 were diagnosed with gastric cancer. The median age of the screening group was 63.6 years (interquartile range: 56-71 years), and the male to female ratio was 2.4:1. When comparing with the control group, H. pylori seropositivity (odds ratio [OR] 2.933, p<0.001), carcinoembryonic antigen (OR 8.633, p=0.004), family history of gastric cancer (OR 2.254, p=0.007), and drinking (OR 3.312, p<0.001) were independent positive risk factors, and the use of aspirin a negative risk factor for gastric cancer (OR 0.445, p=0.012) in multivariate analysis. Low density lipoprotein cholesterol (hazard ratio [HR] 0.987, p=0.005), cancer antigen 19-9 (HR 21.713, p<0.001), resectability (HR 59.833, p<0.001), and family history (HR 0.308, p=0.009) were independent risk factors for death. The 5-year survival rate was significantly higher in the screening group than in the outpatient group (p<0.001). Early detection of gastric cancer by screening endoscopy while asymptomatic enhances patient outcomes, especially in high risk groups.
Article
Numerous epidemiological and prospective studies have shown a direct relationship between total cholesterol and low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (cardiovascular morbidity and mortality). In many intervention studies with more than 100,000 subjects, statins have shown a powerful and significant reduction of cardiovascular events and a decrease in cardiovascular and overall mortality, far superior to those produced by any other lipid-lowering group.Consequently statins are considered to be safe and well tolerated and are the first choice in the treatment of hypercholesterolemia and in cardiovascular disease prevention. If targets are not reached, other pharmacological groups must be associated (resins, nicotinic acid, ezetimibe, fibrates, etc.). Moreover, when hypercholesterolemia is associated with low concentrations of high-density lipoprotein (HDL)-cholesterol and high triglyceride levels, the association of statins with nicotinic acid, fibrates or omega-3 should be considered.Some questions remain to be answered: what LDL-C levels are desirable in secondary prevention? Which individuals might benefit from treatment in primary prevention? Which lipid-lowering drug is the most suitable to combine with statins and diminish cardiovascular risk in each situation? The present article reviews these important points.
Article
Drs Koh and Quon express their concerns about our review on aggressive treatment with statins.1 They specifically express concern about the possible carcinogenic potential of statins. They cite the 2007 metaanalysis of 23 statin trials by Alsheikh-Ali et al,2 which reported that within the statin-treated groups, those with the lowest absolute on-treatment low-density lipoprotein (LDL) values had a higher incidence of cancers during the course of …
Owing to the progressive aging of the population, and the fact that cardiovascular disease (CVD) is the leading cause of death among the elderly, the prevention of CVD in the elderly is becoming increasingly important. Although there is no doubt that statin treatment should be used for reducing CVD risk in the elderly in secondary prevention in the same way as in younger individuals, the evidence that such treatment really prolongs life in elderly subjects in primary prevention is still not so clear. However, it seems that it does reduce CVD morbidity in elderly individuals. Because of limited evidence regarding the benefit of such therapy, particularly in very old subjects (older than 80-85 years), the decision whether to treat or not treat an elderly individual with statins in primary prevention should be based on good clinical judgment and considering the individual subject's situation regarding comorbidities, polypharmacy, and possible adverse effects.
Article
Background: The incidence of small intestine neuroendocrine tumours is increasing, but few studies have investigated risk factors for their occurrence, suggesting that family history of any cancers, smoking, and previous cholecystectomy are associated with an increased risk. Such studies investigated small series, or examined cancer registries without direct interviews. Aim: We therefore aimed at clarifying risk and protective factors for the occurrence of sporadic small intestine neuroendocrine tumours (SI-NETs). Patients and methods: Multicentre case-control study. Patients prospectively evaluated with histologic diagnosis of SI-NETs, excluding familial syndromes. Controls with non-neoplastic/non-chronic disorders seen at GI outpatients clinics, matched (4:1) for sex and age. All directly interviewed by means of a specific questionnaire on potential risk and protective factors. Cases and controls compared by Fisher test or Student's t test for categorical or continuous variables. Explanatory variables analysed by simple logistic regression analysis, with multivariate stepwise variable-selection procedure performed; p < 0.05 was significant. Results: 215 SI-NETs and 860 controls enrolled. Family history (FH) of colorectal cancer (8.8 vs. 5%), and breast cancer (10.2 vs. 4.8%), heavy smoking (24.7 vs. 14.8%) and drinking >21 alcohol units per week (7.4 vs. 3.8%), were all significantly more frequent in SI-NETs than controls. Multivariate analysis showed that FH of colorectal cancer (OR 2.23; 95% CI 1.29-3.84, p = 0.003), FH of breast cancer (OR 2.05; 95% CI 1.13-3.69, p = 0.01) and smoking (OR 1.47; 95% CI 1.07-2.03, p = 0.01) and in particular heavy-smoking (OR 1.94; 95% CI 1.29-3.84, p = 0.0008) were associated with an increased risk for carcinoid occurrence, while use of aspirin was a protective factor (OR 0.20; 95% CI 0.06-0.65, p = 0.008). Conclusion: Family history of colorectal and breast cancer, and smoking seem to be risk factors for the development of small intestine neuroendocrine tumours, while use of aspirin might to be a protective factor. These factors partially overlap with those associated with colorectal cancer, but are different from those previously associated with pancreatic neuroendocrine tumours. These findings may suggest that the mechanisms of carcinogenesis for endocrine cells in different sites can be specific, and similar to those of their exocrine counterparts.
Article
Full-text available
The therapeutic indications of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) include hypercholesterolaemia and the prevention of cardiovascular events. Statins are well tolerated and beyond their unambiguous positive cardiovascular effects there are a steadily increasing number of pleiotropic actions emerging. In this regard, growth inhibition, apoptosis, anti-inflammatory and immunmodulatory actions have been attributed to statins. The antiproliferative effects have been the basis for massive preclinical investigations to elucidate a functional role for statins in carcinogenesis and tumor cell growth. However, preclinical and clinical studies are conflicting, although there is accumulating evidence that statins are capable to suppress and decrease the incidence and recurrence of some human cancers. Given the fact that statins are well tolerated they might also have some impact in combinations with conventional and targeted chemotherapy. While synergism has been shown for many combinations in vitro this does not hold true yet in the clinics. Here we review the rational behind usage of statins in oncological set- tings. Positive effects have been observed in patients with melanoma and cancers from the breast, colon, prostate, lung, liver and hematologic tissues. However, substantial evidence from clinical studies is still weak and confounded by several factors, which are inherent in the study design. The majority of the studies are observational or of retrospective nature. Definitely, there is substantial need for larger, prospective randomized, placebo-controlled trials. Finally, we conclude that statins at the current status of evidence should not be recommended in the prevention or during progression of any cancers, however, individual statins may have beneficial effects in specific tumor subgroups.
Article
Statins reduce cardiovascular mortality and morbidity as well as cardiovascular events in patients with a very high risk of cardiovascular disease (CVD) and also in subjects with high or moderate risk by reducing the levels of low-density lipoprotein cholesterol (LDL-C). Although they are considered to be drugs with a very good safety profile, because of their wide use there are many concerns that their adverse effects might compromise their proven beneficial effects. Therefore this article reviews all the data and provides an evidence-based insight what are the proven adverse effects of statins and what are the "myths" about them. The most important side effects include myopathy and rhabdomyolysis. Another side effect is increased activity of liver tests which occurs occasionally and is reversible. However, recent studies even suggest that statin therapy can improve hepatic steatosis. It is beyond any doubt that statins do slightly increase the incidence of type 2 diabetes mellitus in people with two or more components of metabolic syndrome but the cardiovascular benefits of such a treatment by far exceed this risk. Statin therapy has also been associated with some adverse renal effects, eg. acute renal failure, but recent data suggest even a possible protective effect of these drugs on renal dysfunction. Concerns that statins might increase cancer have not been proven. On the contrary, several studies have indicated a possible benefit of these drugs in patients with different types of cancer. Early concerns about cognitive dysfunction and memory loss associated with statins use could not be proven and most recent data even suggest a possible beneficial effect of statins in the prevention of dementia. Systematic reviews and clinical guidelines suggest that the cardiovascular benefits of statins by far out-weight non-cardiovascular harms in patients with cardiovascular risk.
Article
The therapeutic indications of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) include hypercholesterolaemia and the prevention of cardiovascular events. Statins are well tolerated and beyond their unambiguous positive cardiovascular effects there are a steadily increasing number of pleiotropic actions emerging. In this regard, growth inhibition, apoptosis, anti-inflammatory and immunomodulatory actions have been attributed to statins. The anti-proliferative effects have been the basis for massive preclinical investigations to elucidate a functional role for statins in carcinogenesis and tumor cell growth. However, preclinical and clinical studies are conflicting, although there is accumulating evidence that statins are capable to suppress and decrease the incidence and recurrence of some human cancers. Given the fact that statins are well tolerated they might also have some impact in combinations with conventional and targeted chemotherapy. While synergism has been shown for many combinations in vitro this does not hold true yet in the clinics. Here we review the rational behind usage of statins in oncological settings. Positive effects have been observed in patients with melanoma and cancers from the breast, colon, prostate, lung, liver and hematologic tissues. However, substantial evidence from clinical studies is still weak and confounded by several factors, which are inherent in the study design. The majority of the studies are observational or of retrospective nature. Definitely, there is substantial need for larger, prospective randomized, placebo-controlled trials. Finally, we conclude that statins at the current status of evidence should not be recommended in the prevention or during progression of any cancers, however, individual statins may have beneficial effects in specific tumor subgroups. Key Words: 3-Hydroxy-3-methylglutaryl-coenzyme A-reductase inhibitors, Low density lipoprotein cholesterol, Cancer, Breast cancer, Apoptosis, Statins Core tip: The 3-hydroxy-3 methyl CoA (HMG-CoA) reductase inhibitors, the statins are one of the most frequently prescribed drugs in industrialized countries. Statins are well tolerated cholesterol lowering drugs which significantly help to reduce cardiovascular events. Clinical trials and meta-analyzes thereof now accumulate evidence that development of cancer might be reduced in some tissues. In this review the current status of evidence for an anti-cancer effect of statins will be critically evaluated. In particular, colon and prostate cancer are assessed in greater detail. Citation: Künzl M, Wasinger C, Hohenegger M. Statins role in cancer prevention and development-recent meta-analyses. World J Pharmacol 2013; 2(4): 100-106
Article
Full-text available
With the emergence of new lipid-lowering therapies, more patients are expected to achieve substantial lowering of low-density lipoprotein cholesterol (LDL-C). However, there are limited data examining the clinical experience of patients with low (<1.3 mmol/L) or very low (<0.65 mmol/L) levels of LDL-C. To provide information on patients with low LDL-C, we identified and characterized persons with low LDL-C using data from Danish medical databases. Using a population-based clinical laboratory database, we identified adults with at least one LDL-C measurement in northern Denmark between 1998 and 2011 (population approximately 1.5 million persons). Based on the lowest measurement during the study period, we divided patients into groups with low (<1.3 mmol/L), moderate (1.3-3.3 mmol/L), or high (>3.3 mmol/L) LDL-C. We described their demographic characteristics, entire comorbidity history, and 90-day prescription history prior to the lowest LDL-C value measured. Finally, we further restricted the analysis to individuals with very low LDL-C (<0.65 mmol/L). Among 765,503 persons with an LDL-C measurement, 23% had high LDL-C, 73% had moderate LDL-C, and 4.8% had low LDL-C. In the latter group, 9.6% (0.46% of total) had very low LDL-C. Compared with the moderate and high LDL-C categories, the low LDL-C group included more males and older persons with a higher prevalence of cardiovascular disease, diabetes, chronic pulmonary disease, ulcer disease, and obesity, as measured by hospital diagnoses or relevant prescription drugs for these diseases. Cancer and use of psychotropic drugs were also more prevalent. These patterns of distribution became even more pronounced when restricting to individuals with very low LDL-C. Using Danish medical databases, we identified a cohort of patients with low LDL-C and found that cohort members differed from patients with higher LDL-C levels. These differences may be explained by various factors, including prescribing patterns of lipid-lowering therapies.
Article
Full-text available
Objetivo: Evaluar el impacto del tratamiento con estatinas sobre la incidencia y la recurrencia de los eventos cardiovasculares y los cerebrovasculares (prevención primaria y secundaria), los niveles de las fracciones lipídicas y la incidencia de efectos secundarios (el cáncer y la diabetes mellitus) en personas con hipercolesterolemia. Métodos: Se elaboró una guía de práctica clínica siguiendo los lineamientos de la guía metodológica del Ministerio de Salud y Protección Social para recolectar de forma sistemática la evidencia científica y formular las recomendaciones utilizando la metodología GRADE. Resultados: Se evidenció un efecto benéfico del tratamiento farmacológico con estatinas tanto en población de prevención primaria como en prevención secundaria, logrando reducciones clínica y estadísticamente significativas en la mortalidad y en los eventos cardiovasculares y cerebrovasculares. Adicionalmente, el tratamiento intensivo con estatinas mostró mayor reducción en los eventos cardiovasculares y cerebrovasculares ateroscleróticos al compararlo con el tratamiento de intensidad moderada. No se encontraron diferencias significativas en el riesgo de desarrollar cáncer al comparar estatinas frente a placebo pero sí se encontró un incremento de nueve por ciento en el riesgo de presentar diabetes mellitus asociado al tratamiento con estatinas. Conclusiones: Se formulan recomendaciones a favor del uso de estatinas como primera línea de tratamiento de hipercolesterolemia, y se establecen criterios para definir la intensidad de la terapia (alta o moderada respuesta) según el riesgo cardiovascular a 10 años, el nivel de colesterol LDL (cLDL), la edad y los antecedentes personales y los familiares.
Article
On the basis of data obtained from a prospective cohort of Chinese patients with type 2 diabetes mellitus (T2DM), we discuss cancer subphenotypes (risk factors) in patients with T2DM, which can lead to drug-cancer subphenotype interactions. These subphenotypes include HDL cholesterol levels <1.0 mmol/l, co-occurrence of LDL cholesterol levels <2.8 mmol/l and triglyceride levels <1.7 mmol/l, and co-occurrence of LDL cholesterol levels <2.8 mmol/l and albuminuria. The increased risk of cancer associated with low levels of HDL cholesterol, low LDL cholesterol levels plus low triglyceride levels, and low levels of LDL cholesterol plus albuminuria can be reduced by treatment with metformin, renin-angiotensin system (RAS) inhibitors and statins, respectively. Mechanistic studies support the hypothesis that dysregulation of the 5'-AMP-activated protein kinase pathway and crosstalk between the RAS and insulin-like growth factor 1-cholesterol pathways create a cancer-promoting milieu in patients with T2DM. These findings highlight that in Chinese individuals, multiple pathways are implicated in the link between T2DM and cancer, which can generate multiple subphenotypes as well as drug-subphenotype interactions.
Article
Although meta-analyses of statins in primary prevention are designed to provide doctors and patients with better evidence about the risks and potential benefits of treatment, they may ignore important patient-centered outcomes and concerns. We examined all meta-analyses of statins for primary prevention over the last 5 years. We assessed whether each meta-analysis addressed five key points: whether authors examined endpoints based on the use of statin therapy, and not stratified by low-density lipoprotein reduction; whether authors included only studies of statin versus placebo, and not varying doses or brands of statin; whether authors considered commonly cited harms; whether secondary prevention patients were excluded; and, whether overall mortality was examined. We examined 189 articles to identify 24 meta-analyses of statins that made claims regarding primary prevention. Six studies (25 %) reported outcomes as a function of reduction in serum lipid levels rather than treatment received. Seven studies (29 %) included trials of high-dose versus low-dose statin in their analysis. Five studies (21 %) did not examine all-cause mortality. The majority of studies (n = 21, 88 %) failed to exclude patients with known cardiovascular disease, and 22 (92 %) studies failed to assess two of three common safety concerns. Nevertheless, most (n = 20, 83 %) meta-analyses supported the use of statins in primary prevention. Based on our findings, we conclude that most recent meta-analyses of statins for primary prevention do not adequately address the question they seek to answer.
Chapter
Although there is a large body of knowledge on the increased cardiovascular disease (CVD) risk in rheumatoid arthritis (RA), there is a lack of clinical evidence on management of the increased risk.
Article
Purpose of review: Acquired hypocholesterolaemia occurs more commonly than inherited hypocholesterolaemia but has received little attention in the literature. In this review, we discuss the causes and underlying mechanisms of acquired hypocholesterolaemia and its relevance to safety of therapeutically induced decreased LDL cholesterol levels. Recent findings: Hypocholesterolaemia is increasingly identified as cholesterol testing becomes more widespread in the assessment of cardiovascular risk. Lower therapeutic targets for LDL cholesterol are also being achieved more regularly with the introduction of more intensive cholesterol-lowering regimens. Acquired hypocholesterolaemia may be the presenting feature of treatable diseases. Understanding its mechanisms may also provide new treatment approaches for neoplastic disease, such as breast cancer, and infections, such as tuberculosis. Summary: When hypocholesterolaemia is discovered, it is important to identify its cause. Further research into the pathogenesis of hypocholesterolaemia may provide new therapies for primary diseases underlying it.
Article
Background: Although several factors, including heart failure (HF) and inflammation, are known to increase the incidence of cancer, it remains unknown whether HF may increase cancer mortality, especially with a reference to inflammation. Methods and results: We examined 8843 consecutive cardiovascular patients without a prior history of cancer in our CHART-2 Study (mean 68 yrs., female 30.9%). As compared with patients without HF (Stage A/B, N = 4622), those with HF (Stage C/D, N = 4221) were characterized by higher prevalence of diabetes, previous myocardial infarction, atrial fibrillation, and stroke. During the median 6.5-year follow-up (52,675 person-years), 282 cancer deaths occurred. HF patients had significantly higher cancer mortality than those without HF in both the overall (3.7 vs, 2.8%, hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.12-1.79, P = 0.004) and the propensity score-matched cohorts (HR 1.46, 95%CI 1.10-1.93, P = 0.008), which was confirmed in the competing risk models. The multivariable Cox proportional hazard model in the matched cohort showed that HF was associated with increased cancer mortality in patients with C-reactive protein (CRP) ≥ 2.0 mg/L (HR 1.87, 95%CI 1.18-2.96, P = 0.008) at baseline, but not in those with CRP < 2.0 mg/L (HR 0.89, 95%CI 0.54-1.45, P = 0.64) (P for interaction = 0.03). Furthermore, temporal changes in CRP levels were associated with cancer death in the overall cohort; HF patients with CRP ≥ 2.0 mg/L at both baseline and 1-year had significantly increased cancer death, while those with CRP ≥ 2.0 mg/L at baseline and < 2.0 mg/L at 1-year not. Conclusions: These results provide the first evidence that HF is associated with increased cancer death, especially when associated with prolonged inflammation.
Article
Full-text available
Background Emerging evidence suggests that patients with coronary artery disease carry an increased risk of developing malignancy, with deleterious effects on long-term prognosis. Our aim was to ascertain whether baseline plasma lipid levels during acute coronary syndrome (ACS) are associated with malignancy in long-term. Methods This study included 589 patients admitted with ACS to three centers and discharged alive. Plasma lipid levels were assessed on the first morning after admission. Patients were followed for 17 years or until death. Results Five hundred seventy-one patients were free from malignancy at enrollment, of them 99 (17.3%) developed the disease during follow-up and 75 (13.1%) died due to it. Compared to patients without malignancy, those with malignancy showed lower plasma levels of total cholesterol (TC), low-density lipoprotein (LDL), and triglycerides (TG). The groups showed similar statin use rates at any time in follow-up. The incidence rate of neoplasia and neoplastic mortality was higher in patients with baseline TC or LDL values ≤ median; they showed 85 and 72% increased incidence rate of developing malignancy and 133 and 122% increased incidence rate of neoplastic death respectively. No differences were observed relative to HDL and TG levels. In survival analysis using Cox regression with parsimonious models, patients with baseline TC or LDL values > median, respectively, showed risks of 0.6(95% CI 0.4–0.9; p = 0.01) and 0.6(95%CI 0.4–0.9; p = 0.02) for malignancy onset, and 0.5(95% CI 0.3–0.8; p = 0.005) and 0.5(95% CI 0.3–0.8; p = 0.004) for neoplastic death. Similar results were obtained using competitive risk analysis with parsimonious models. Conclusions This long-term prospective study of an unselected real-world patient sample showed that neoplasia onset and mortality are independently associated with low plasma TC and LDL levels at admission for ACS.
Article
Objectives: Although elevated lipid levels predict increased risk of coronary heart disease and death in middle-aged women and men, evidence is mixed if lipid levels measured in later life predict survival to very old ages. We examined lipid levels and survival to age 90 with or without intact mobility in a large cohort of older women. Design: Prospective cohort. Setting: Laboratory collection at a Women's Health Initiative (WHI) center and longitudinal follow-up via mail. Participants: Women aged 68 to 81 years at baseline. Measurements: Serum high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol were collected at baseline. Participant survival status and self-reported mobility was compared across lipid levels. Results: HDL and LDL levels were not associated with survival to age 90 after adjustment for cardiovascular risk factors (HDL: quartile (Q) 2: odds ratio [OR] = 1.14 [95% confidence interval [CI] = .94-1.38]; Q3 OR = 1.08 [95% CI = .88-1.33]; Q4 OR = 1.09 [95% CI = .88-1.35]; LDL: Q2 OR = 1.07 [95% CI = .88-1.31]; Q3 OR = 1.27 [95% CI = 1.04-1.55]; Q4 OR = 1.07 [95% CI = .88-1.31]). Similarly, no associations were observed between HDL and LDL levels and survival to age 90 with mobility disability. High HDL was not associated with survival to age 90 with intact mobility after adjustment for other cardiovascular risk factors. Compared with the lowest LDL quartile, the three upper LDL quartiles were associated with greater odds of survival to age 90 with intact mobility (LDL: Q2 OR = 1.31 [95% CI = .99-1.74]; Q3 OR = 1.43 [95% CI = 1.07-1.92]; Q4 OR = 1.35 [95% CI = 1.01-1.80]; P = .05). Conclusion: Neither higher HDL nor lower LDL levels predicted survival to age 90, but higher LDL predicted healthy survival. These findings suggest the need for reevaluation of healthy LDL levels in older women.
Article
Rating: •Of importance. Introduction: The importance of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial (ClinicalTrials. gov no. NCT00092677) relates to the conclusion of its main outcome, aortic valve stenosis (AVS), and probably even more to the discussion it engendered about a poten- tial unanticipated adverse event: cancer. Aortic stenosis is the most common valvular heart disease in developed countries. Its pathogenesis and pre- ceding abnormalities, including aortic valve sclerosis and calcifi cation, appear to have a number of commonalities with the atherosclerotic process. Therefore, lipid-lowering therapy could be an appropriate tool for the prevention and treatment of AVS. Although preliminary data suggested the benefi ts of such an approach, most of the information came from retrospective and small case-control studies. In fact, one prospective randomized study did not fi nd any effect of lipid-lowering therapy on the progression of AVS. Aims: Therefore, the SEAS trial was designed to study the effects of long-term, intensive cholesterol lowering with daily use of simvastatin and ezetimibe on clinical and echocardiographic outcomes in patients with asymptom- atic mild to moderate AVS and no other indication for lipid-lowering treatment. Methods: This randomized double-blind trial included 1873 patients with mild to moderate asymptomatic aor- tic stenosis who received placebo or 40 mg of simvastatin plus 10 mg of ezetimibe daily. The primary outcome was a composite of major cardiovascular events, including death from cardiovascular causes, aortic valve replace- ment, nonfatal myocardial infarction, hospitalization for unstable angina pectoris, heart failure, coronary artery bypass grafting, percutaneous coronary intervention, and nonhemorrhagic stroke. Secondary outcomes were events related to AVS and ischemic cardiovascular events. Results: After a follow-up of about 4.3 years, the primary outcome had been reached by about 35% of the patients in the simvastatin-ezetimibe group and 38% in the placebo group, which was far from statistically signifi cant (P = 0.59). Likewise, aortic valve replacement was performed in 28% of participants in the simvastatin-ezetimibe group and in 30% of those receiving a placebo (P = 0.97). The only posi- tive outcome of this study came from the signifi cantly lower number of patients having ischemic cardiovascular events in the simvastatin-ezetimibe group than in the placebo group, resulting in an HR of 0.78 (P = 0.02). Conversely, cancer occurred more frequently in the simvastatin-ezetimibe group (105 vs 70; P = 0.01). It was this unexpected adverse event, rather than the primary outcome, that caused the study to garner attention in the press. Discussion: Despite lowering cholesterol levels, this study clearly shows that the combination of a statin (simvas- tatin) and an intestinal cholesterol inhibitor (ezetimibe) did not reduce overall cardiovascular events. The unex- pected increase in cancer in the simvastatin-ezetimibe group also raised serious concerns about the use of this combination.
Article
Full-text available
Context.— Although cholesterol-reducing treatment has been shown to reduce fatal and nonfatal coronary disease in patients with coronary heart disease (CHD), it is unknown whether benefit from the reduction of low-density lipoprotein cholesterol (LDL-C) in patients without CHD extends to individuals with average serum cholesterol levels, women, and older persons.Objective.— To compare lovastatin with placebo for prevention of the first acute major coronary event in men and women without clinically evident atherosclerotic cardiovascular disease with average total cholesterol (TC) and LDL-C levels and below-average high-density lipoprotein cholesterol (HDL-C) levels.Design.— A randomized, double-blind, placebo-controlled trial.Setting.— Outpatient clinics in Texas.Participants.— A total of 5608 men and 997 women with average TC and LDL-C and below-average HDL-C (as characterized by lipid percentiles for an age- and sex-matched cohort without cardiovascular disease from the National Health and Nutrition Examination Survey [NHANES] III). Mean (SD) TC level was 5.71 (0.54) mmol/L (221 [21] mg/dL) (51st percentile), mean (SD) LDL-C level was 3.89 (0.43) mmol/L (150 [17] mg/dL) (60th percentile), mean (SD) HDL-C level was 0.94 (0.14) mmol/L (36 [5] mg/dL) for men and 1.03 (0.14) mmol/L (40 [5] mg/dL) for women (25th and 16th percentiles, respectively), and median (SD) triglyceride levels were 1.78 (0.86) mmol/L (158 [76] mg/dL) (63rd percentile).Intervention.— Lovastatin (20-40 mg daily) or placebo in addition to a low–saturated fat, low-cholesterol diet.Main Outcome Measures.— First acute major coronary event defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death.Results.— After an average follow-up of 5.2 years, lovastatin reduced the incidence of first acute major coronary events (183 vs 116 first events; relative risk [RR], 0.63; 95% confidence interval [CI], 0.50-0.79; P<.001), myocardial infarction (95 vs 57 myocardial infarctions; RR, 0.60; 95% CI, 0.43-0.83; P=.002), unstable angina (87 vs 60 first unstable angina events; RR, 0.68; 95% CI, 0.49-0.95; P=.02), coronary revascularization procedures (157 vs 106 procedures; RR, 0.67; 95% CI, 0.52-0.85; P=.001), coronary events (215 vs 163 coronary events; RR, 0.75; 95% CI, 0.61-0.92; P=.006), and cardiovascular events (255 vs 194 cardiovascular events; RR, 0.75; 95% CI, 0.62-0.91; P=.003). Lovastatin (20-40 mg daily) reduced LDL-C by 25% to 2.96 mmol/L (115 mg/dL) and increased HDL-C by 6% to 1.02 mmol/L (39 mg/dL). There were no clinically relevant differences in safety parameters between treatment groups.Conclusions.— Lovastatin reduces the risk for the first acute major coronary event in men and women with average TC and LDL-C levels and below-average HDL-C levels. These findings support the inclusion of HDL-C in risk-factor assessment, confirm the benefit of LDL-C reduction to a target goal, and suggest the need for reassessment of the National Cholesterol Education Program guidelines regarding pharmacological intervention. Figures in this Article EPIDEMIOLOGICAL observations have demonstrated consistently a strong positive, continuous, independent, graded relation between plasma total cholesterol (TC) and the incidence of coronary heart disease (CHD). This relation covers a wide range of cholesterol concentrations, including those considered normal or mildly elevated.1- 3 In the Multiple Risk Factor Intervention Trial follow-up of screened men, 69% of deaths from CHD in the first 6 years of follow-up occurred in subjects with TC values between 4.71 and 6.83 mmol/L (182-264 mg/dL).4 In the first 16 years of the Framingham Heart Study, 40% of participants who developed a myocardial infarction had a TC level between 5.17 and 6.47 mmol/L (200-250 mg/dL).5 Large end point studies have demonstrated conclusively that effective cholesterol-lowering treatment can substantially reduce myocardial infarction and other coronary events. In the Scandinavian Simvastatin Survival Study the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin reduced total mortality in patients with CHD by 30% because of a 42% reduction in deaths from CHD.6 Subsequently, pravastatin was shown to reduce fatal and nonfatal coronary events in patients with7 and without8 CHD. However, it is unknown whether benefit from reduction of low-density lipoprotein cholesterol (LDL-C) in patients without CHD (primary prevention) extends to individuals with average serum cholesterol levels, women, and older persons. The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) targeted a cohort of generally healthy middle-aged and older men and women with average TC and LDL-C levels and with below-average high-density lipoprotein cholesterol (HDL-C) levels. The primary end point analysis was the incidence of first acute major coronary events, defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death. The inclusion of unstable angina was a unique feature of this study, and its inclusion as a primary end point reflects the increasing frequency of unstable angina as the initial presentation of CHD in the United States.9
Article
Full-text available
ABSTRACT Context.— Although cholesterol-reducing treatment has been shown to reduce fatal and nonfatal coronary disease in patients with coronary heart disease (CHD), it is unknown whether benefit from the reduction of low-density lipoprotein cholesterol (LDL-C) in patients without CHD extends to individuals with average serum cholesterol levels, women, and older persons. Objective.— To compare lovastatin with placebo for prevention of the first acute major coronary event in men and women without clinically evident atherosclerotic cardiovascular disease with average total cholesterol (TC) and LDL-C levels and below-average high-density lipoprotein cholesterol (HDL-C) levels. Design.— A randomized, double-blind, placebo-controlled trial. Setting.— Outpatient clinics in Texas. Participants.— A total of 5608 men and 997 women with average TC and LDL-C and below-average HDL-C (as characterized by lipid percentiles for an age- and sex-matched cohort without cardiovascular disease from the National Health and Nutrition Examination Survey [NHANES] III). Mean (SD) TC level was 5.71 (0.54) mmol/L (221 [21] mg/dL) (51st percentile), mean (SD) LDL-C level was 3.89 (0.43) mmol/L (150 [17] mg/dL) (60th percentile), mean (SD) HDL-C level was 0.94 (0.14) mmol/L (36 [5] mg/dL) for men and 1.03 (0.14) mmol/L (40 [5] mg/dL) for women (25th and 16th percentiles, respectively), and median (SD) triglyceride levels were 1.78 (0.86) mmol/L (158 [76] mg/dL) (63rd percentile). Intervention.— Lovastatin (20-40 mg daily) or placebo in addition to a low–saturated fat, low-cholesterol diet. Main Outcome Measures.— First acute major coronary event defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death. Results.— After an average follow-up of 5.2 years, lovastatin reduced the incidence of first acute major coronary events (183 vs 116 first events; relative risk [RR], 0.63; 95% confidence interval [CI], 0.50-0.79; P<.001), myocardial infarction (95 vs 57 myocardial infarctions; RR, 0.60; 95% CI, 0.43-0.83; P=.002), unstable angina (87 vs 60 first unstable angina events; RR, 0.68; 95% CI, 0.49-0.95; P=.02), coronary revascularization procedures (157 vs 106 procedures; RR, 0.67; 95% CI, 0.52-0.85; P=.001), coronary events (215 vs 163 coronary events; RR, 0.75; 95% CI, 0.61-0.92; P=.006), and cardiovascular events (255 vs 194 cardiovascular events; RR, 0.75; 95% CI, 0.62-0.91; P=.003). Lovastatin (20-40 mg daily) reduced LDL-C by 25% to 2.96 mmol/L (115 mg/dL) and increased HDL-C by 6% to 1.02 mmol/L (39 mg/dL). There were no clinically relevant differences in safety parameters between treatment groups. Conclusions.— Lovastatin reduces the risk for the first acute major coronary event in men and women with average TC and LDL-C levels and below-average HDL-C levels. These findings support the inclusion of HDL-C in risk-factor assessment, confirm the benefit of LDL-C reduction to a target goal, and suggest the need for reassessment of the National Cholesterol Education Program guidelines regarding pharmacological intervention.
Article
Full-text available
Lowering the blood cholesterol level may reduce the risk of coronary heart disease. This double-blind study was designed to determine whether the administration of pravastatin to men with hypercholesterolemia and no history of myocardial infarction reduced the combined incidence of nonfatal myocardial infarction and death from coronary heart disease. We randomly assigned 6595 men, 45 to 64 years of age, with a mean (+/- SD) plasma cholesterol level of 272 +/- 23 mg per deciliter (7.0 +/- 0.6 mmol per liter) to receive pravastatin (40 mg each evening) or placebo. The average follow-up period was 4.9 years. Medical records, electrocardiographic recordings, and the national death registry were used to determine the clinical end points. Pravastatin lowered plasma cholesterol levels by 20 percent and low-density-lipoprotein cholesterol levels by 26 percent, whereas there was no change with placebo. There were 248 definite coronary events (specified as nonfatal myocardial infarction or death from coronary heart disease) in the placebo group, and 174 in the pravastatin group (relative reduction in risk with pravastatin, 31 percent; 95 percent confidence interval, 17 to 43 percent; P < 0.001). There were similar reductions in the risk of definite nonfatal myocardial infarctions (31 percent reduction, P < 0.001), death from coronary heart disease (definite cases alone: 28 percent reduction, P = 0.13; definite plus suspected cases: 33 percent reduction, P = 0.042), and death from all cardiovascular causes (32 percent reduction, P = 0.033). There was no excess of deaths from noncardiovascular causes in the pravastatin group. We observed a 22 percent reduction in the risk of death from any cause in the pravastatin group (95 percent confidence interval, 0 to 40 percent; P = 0.051). Treatment with pravastatin significantly reduced the incidence of myocardial infarction and death from cardiovascular causes without adversely affecting the risk of death from noncardiovascular causes in men with moderate hypercholesterolemia and no history of myocardial infarction.
Article
Full-text available
Although cholesterol-reducing treatment has been shown to reduce fatal and nonfatal coronary disease in patients with coronary heart disease (CHD), it is unknown whether benefit from the reduction of low-density lipoprotein cholesterol (LDL-C) in patients without CHD extends to individuals with average serum cholesterol levels, women, and older persons. To compare lovastatin with placebo for prevention of the first acute major coronary event in men and women without clinically evident atherosclerotic cardiovascular disease with average total cholesterol (TC) and LDL-C levels and below-average high-density lipoprotein cholesterol (HDL-C) levels. A randomized, double-blind, placebo-controlled trial. Outpatient clinics in Texas. A total of 5608 men and 997 women with average TC and LDL-C and below-average HDL-C (as characterized by lipid percentiles for an age- and sex-matched cohort without cardiovascular disease from the National Health and Nutrition Examination Survey [NHANES] III). Mean (SD) TC level was 5.71 (0.54) mmol/L (221 [21] mg/dL) (51 st percentile), mean (SD) LDL-C level was 3.89 (0.43) mmol/L (150 [17] mg/dL) (60th percentile), mean (SD) HDL-C level was 0.94 (0.14) mmol/L (36 [5] mg/dL) for men and 1.03 (0.14) mmol/L (40 [5] mg/dL) for women (25th and 16th percentiles, respectively), and median (SD) triglyceride levels were 1.78 (0.86) mmol/L (158 [76] mg/dL) (63rd percentile). Lovastatin (20-40 mg daily) or placebo in addition to a low-saturated fat, low-cholesterol diet. First acute major coronary event defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death. After an average follow-up of 5.2 years, lovastatin reduced the incidence of first acute major coronary events (1 83 vs 116 first events; relative risk [RR], 0.63; 95% confidence interval [CI], 0.50-0.79; P<.001), myocardial infarction (95 vs 57 myocardial infarctions; RR, 0.60; 95% CI, 0.43-0.83; P=.002), unstable angina (87 vs 60 first unstable angina events; RR, 0.68; 95% CI, 0.49-0.95; P=.02), coronary revascularization procedures (157 vs 106 procedures; RR, 0.67; 95% CI, 0.52-0.85; P=.001), coronary events (215 vs 163 coronary events; RR, 0.75; 95% CI, 0.61-0.92; P =.006), and cardiovascular events (255 vs 194 cardiovascular events; RR, 0.75; 95% CI, 0.62-0.91; P = .003). Lovastatin (20-40 mg daily) reduced LDL-C by 25% to 2.96 mmol/L (115 mg/dL) and increased HDL-C by 6% to 1.02 mmol/L (39 mg/dL). There were no clinically relevant differences in safety parameters between treatment groups. Lovastatin reduces the risk for the first acute major coronary event in men and women with average TC and LDL-C levels and below-average HDL-C levels. These findings support the inclusion of HDL-C in risk-factor assessment, confirm the benefit of LDL-C reduction to a target goal, and suggest the need for reassessment of the National Cholesterol Education Program guidelines regarding pharmacological intervention.
Article
Full-text available
Percutaneous coronary intervention (PCI) is associated with excellent short-term improvements in ischemic symptoms, yet only three fifths of PCI patients at 5 years and one third of patients at 10 years remain free of major adverse cardiac events (MACE). To determine whether treatment with fluvastatin reduces MACE in patients who have undergone PCI. Randomized, double-blind, placebo-controlled trial conducted at 77 referral centers in Europe, Canada, and Brazil. A total of 1677 patients (aged 18-80 years) recruited between April 1996 and October 1998 with stable or unstable angina or silent ischemia following successful completion of their first PCI who had baseline total cholesterol levels between 135 and 270 mg/dL (3.5-7.0 mmol/L), with fasting triglyceride levels of less than 400 mg/dL (4.5 mmol/L). Patients were randomly assigned to receive treatment with fluvastatin, 80 mg/d (n = 844), or matching placebo (n = 833) at hospital discharge for 3 to 4 years. Survival time free of MACE, defined as cardiac death, nonfatal myocardial infarction, or reintervention procedure, compared between the treatment and placebo groups. Median time between PCI and first dose of study medication was 2.0 days, and median follow-up was 3.9 years. MACE-free survival time was significantly longer in the fluvastatin group (P =.01). One hundred eighty-one (21.4%) of 844 patients in the fluvastatin group and 222 (26.7%) of 833 patients in the placebo group had at least 1 MACE (relative risk [RR], 0.78; 95% confidence interval [CI], 0.64-0.95; P =.01). This result was independent of baseline total cholesterol levels (above [RR, 0.76; 95% CI, 0.56-1.04] vs below [RR, 0.77; 95% CI, 0.57-1.02] the median). In subgroup analysis, the risk of MACE was reduced in patients with diabetes (n = 202; RR, 0.53; 95% CI, 0.29-0.97; P =.04) and in those with multivessel disease (n = 614; RR, 0.66; 95% CI, 0.48-0.91; P =.01) who received fluvastatin compared with those who received placebo. There were no instances of creatine phosphokinase elevations 10 or more times the upper limit of normal or rhabdomyolysis in the fluvastatin group. Fluvastatin treatment in patients with average cholesterol levels undergoing their first successful PCI significantly reduces the risk of major adverse cardiac events.
Article
Full-text available
Although statins reduce coronary and cerebrovascular morbidity and mortality in middle-aged individuals, their efficacy and safety in elderly people is not fully established. Our aim was to test the benefits of pravastatin treatment in an elderly cohort of men and women with, or at high risk of developing, cardiovascular disease and stroke. We did a randomised controlled trial in which we assigned 5804 men (n=2804) and women (n=3000) aged 70-82 years with a history of, or risk factors for, vascular disease to pravastatin (40 mg per day; n=2891) or placebo (n=2913). Baseline cholesterol concentrations ranged from 4.0 mmol/L to 9.0 mmol/L. Follow-up was 3.2 years on average and our primary endpoint was a composite of coronary death, non-fatal myocardial infarction, and fatal or non-fatal stroke. Analysis was by intention-to-treat. Pravastatin lowered LDL cholesterol concentrations by 34% and reduced the incidence of the primary endpoint to 408 events compared with 473 on placebo (hazard ratio 0.85, 95% CI 0.74-0.97, p=0.014). Coronary heart disease death and non-fatal myocardial infarction risk was also reduced (0.81, 0.69-0.94, p=0.006). Stroke risk was unaffected (1.03, 0.81-1.31, p=0.8), but the hazard ratio for transient ischaemic attack was 0.75 (0.55-1.00, p=0.051). New cancer diagnoses were more frequent on pravastatin than on placebo (1.25, 1.04-1.51, p=0.020). However, incorporation of this finding in a meta-analysis of all pravastatin and all statin trials showed no overall increase in risk. Mortality from coronary disease fell by 24% (p=0.043) in the pravastatin group. Pravastatin had no significant effect on cognitive function or disability. Pravastatin given for 3 years reduced the risk of coronary disease in elderly individuals. PROSPER therefore extends to elderly individuals the treatment strategy currently used in middle aged people.
Article
Full-text available
Statins are cholesterol-lowering drugs that have been proven in randomized controlled trials to prevent cardiac events. Recent retrospective analyses have suggested that statins also prevent cancer. To investigate the effect of statin therapy on cancer incidence and cancer death and to analyze the effect of statins on specific cancers and the effect of statin lipophilicity or derivation. A systematic literature search of MEDLINE, EMBASE, CINAHL, Web of Science, CANCERLIT, and the Cochrane Systematic Review Database through July 2005 was conducted using specific search terms. A review of cardiology and cancer abstracts and manual review of references was also performed. Twenty-seven of the 8943 articles (n = 86,936 participants) initially identified met the inclusion criteria, reporting 26 randomized controlled trials of statins, with a mean duration of follow-up of at least 1 year, enrolling a minimum of 100 patients, and reporting data on either cancer incidence (n = 20 studies) or cancer death (n = 22 studies). All data were independently extracted by 3 investigators using a standardized data abstraction tool. Weighted averages were reported as odds ratios (ORs) with 95% confidence intervals (CIs) using a random-effects model (DerSimonian and Laird methods). Statistical heterogeneity scores were assessed with the Q statistic. In meta-analyses including 6662 incident cancers and 2407 cancer deaths, statins did not reduce the incidence of cancer (OR, 1.02; 95% CI, 0.97-1.07) or cancer deaths (OR, 1.01; 95% CI, 0.93-1.09). No reductions were noted for any individual cancer type. This null effect on cancer incidence persisted when only hydrophilic, lipophilic, naturally derived, or synthetically derived statins were evaluated. Statins have a neutral effect on cancer and cancer death risk in randomized controlled trials. We found that no type of cancer was affected by statin use and no subtype of statin affected the risk of cancer.
Article
Throughout the usual LDL cholesterol range in Western populations, lower blood concentrations are associated with lower cardiovascular disease risk. In such populations, therefore, reducing LDL cholesterol may reduce the development of vascular disease, largely irrespective of initial cholesterol concentrations. METHODS: 20,536 UK adults (aged 40-80 years) with coronary disease, other occlusive arterial disease, or diabetes were randomly allocated to receive 40 mg simvastatin daily (average compliance: 85%) or matching placebo (average non-study statin use: 17%). Analyses are of the first occurrence of particular events, and compare all simvastatin-allocated versus all placebo-allocated participants. These "intention-to-treat" comparisons assess the effects of about two-thirds (85% minus 17%) taking a statin during the scheduled 5-year treatment period, which yielded an average difference in LDL cholesterol of 1.0 mmol/L (about two-thirds of the effect of actual use of 40 mg simvastatin daily). Primary outcomes were mortality (for overall analyses) and fatal or non-fatal vascular events (for subcategory analyses), with subsidiary assessments of cancer and of other major morbidity. FINDINGS: All-cause mortality was significantly reduced (1328 [12.9%] deaths among 10,269 allocated simvastatin versus 1507 [14.7%] among 10,267 allocated placebo; p=0.0003), due to a highly significant 18% (SE 5) proportional reduction in the coronary death rate (587 [5.7%] vs 707 [6.9%]; p=0.0005), a marginally significant reduction in other vascular deaths (194 [1.9%] vs 230 [2.2%]; p=0.07), and a non-significant reduction in non-vascular deaths (547 [5.3%] vs 570 [5.6%]; p=0.4). There were highly significant reductions of about one-quarter in the first event rate for non-fatal myocardial infarction or coronary death (898 [8.7%] vs 1212 [11.8%]; p<0.0001), for non-fatal or fatal stroke (444 [4.3%] vs 585 [5.7%]; p<0.0001), and for coronary or non-coronary revascularisation (939 [9.1%] vs 1205 [11.7%]; p<0.0001). For the first occurrence of any of these major vascular events, there was a definite 24% (SE 3; 95% CI 19-28) reduction in the event rate (2033 [19.8%] vs 2585 [25.2%] affected individuals; p<0.0001). During the first year the reduction in major vascular events was not significant, but subsequently it was highly significant during each separate year. The proportional reduction in the event rate was similar (and significant) in each subcategory of participant studied, including: those without diagnosed coronary disease who had cerebrovascular disease, or had peripheral artery disease, or had diabetes; men and, separately, women; those aged either under or over 70 years at entry; and--most notably--even those who presented with LDL cholesterol below 3.0 mmol/L (116 mg/dL), or total cholesterol below 5.0 mmol/L (193 mg/dL). The benefits of simvastatin were additional to those of other cardioprotective treatments. The annual excess risk of myopathy with this regimen was about 0.01%. There were no significant adverse effects on cancer incidence or on hospitalisation for any other non-vascular cause. INTERPRETATION: Adding simvastatin to existing treatments safely produces substantial additional benefits for a wide range of high-risk patients, irrespective of their initial cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rates of myocardial infarction, of stroke, and of revascularisation by about one-quarter. After making allowance for non-compliance, actual use of this regimen would probably reduce these rates by about one-third. Hence, among the many types of high-risk individual studied, 5 years of simvastatin would prevent about 70-100 people per 1000 from suffering at least one of these major vascular events (and longer treatment should produce further benefit). The size of the 5-year benefit depends chiefly on such individuals' overall risk of major vascular events, rather than on their blood lipid concentrations alone.
Article
The Kyushu Lipid Intervention Study (KLIS) aimed to investigate the effects of pravastatin in the primary prevention of coronary events and cerebral infarction in Japanese men aged 45-74 years with serum total cholesterol of ≥ 220 mg/dl (5.69 mmol/l). The coronary events included myocardial infarction, coronary artery surgery and angioplasty, cardiac death, and sudden death. A total of 5, 640 patients were recruited, and 3, 061 and 2, 579 were allocated to the pravastatin (10-20 mg/day) and conventional treatment, respectively. They were followed up for 5 years on average. Due to unsuccessful randomization, a protocol-based analysis was carried out with adjustment for coronary risk factors at baseline using the Cox proportional hazards model. For several reasons (serum total cholesterol of≥300 mg/dl, use of drugs excluded in protocol, etc.), 2, 219 men in the pravastain group and 1, 634 in the conventional treatment group were used in the analysis. The baseline total cholesterol levels were 254 mg/dl in the pravastain group and 243 mg/dl in the conventional treatment group. Serum total cholesterol levels fell by 15% in the pravastain group and by 8% with the conventional treatment group. Adjusted relative risks for pravastatin versus conventional treatment were : coronary events 0.86 (one-side p= 0.23), cerebral infarction 0.78 (p= 0.13), and the two outcomes combined 0.81 (p= 0.08). These findings add to evidence that pravastatin use is beneficial in the prevention of coronary events and cerebral infarction in hypercholesterolemic Japanese patients, and suggest that pravastatin may be more protective against cerebral infarction.
Article
Background Obstructive changes often occur in aortocoronary saphenous-vein bypass grafts because of atherosclerosis and thrombosis. We studied whether aggressive lowering of low-density lipoprotein (LDL) cholesterol levels or low-dose anticoagulation would delay the progression of atherosclerosis in grafts. Methods We studied 1351 patients who had undergone bypass surgery 1 to 11 years before base line and who had an LDL cholesterol level between 130 and 175 mg per deciliter and at least one patent vein graft as seen on angiography. We used a two-by-two factorial design to assign patients to aggressive or moderate treatment to lower LDL cholesterol levels (with lovastatin and, if needed, cholestyramine) and to treatment with warfarin or placebo. Angiography was repeated an average of 4.3 years after base line. The primary angiographic outcome was the mean percentage per patient of grafts with a decrease of 0.6 mm or more in lumen diameter. Results As measured annually during the study period, the mean LDL cholesterol level of patients who received aggressive treatment ranged from 93 to 97 mg per deciliter; with moderate treatment, the range was from 132 to 136 mg per deciliter (P<0.001). The mean international normalized ratio was 1.4 in the warfarin group and 1.1 in the placebo group (P<0.001). The mean percentage of grafts with progression of atherosclerosis was 27 percent for patients whose LDL cholesterol level was lowered with aggressive treatment and 39 percent for those who received moderate treatment (P<0.001). There was no significant difference in angiographic outcome between the warfarin and placebo groups. The rate of revascularization over four years was 29 percent lower in the group whose LDL cholesterol level was lowered aggressively than in the group receiving moderate treatment (6.5 percent vs. 9.2 percent, P = 0.03). Conclusions Aggressive lowering of LDL cholesterol levels to below 100 mg per deciliter reduced the progression of atherosclerosis in grafts. Low-dose warfarin did not reduce the progression of atherosclerosis.
Chapter
Subjectivity and ContextBayes Theorem for Two HypothesesComparing Simple Hypotheses: Likelihood Ratios and Bayes FactorsExchangeability and Parametric Modelling*Bayes Theorem for General QuantitiesBayesian Analysis with Binary DataBayesian Analysis with Normal DistributionsPoint Estimation, Interval Estimation and Interval HypothesesThe Prior DistributionHow to Use Bayes Theorem to Interpret Trial ResultsThe "Credibility" of Significant Trial Results*Sequential Use of Bayes Theorem*PredictionsDecision-makingDesignUse of Historical DataMultiplicity, Exchangeability and Hierarchical ModelsDealing with Nuisance Parameters*Computational IssuesSchools of BayesiansA Bayesian ChecklistFurther ReadingKey PointsExercises
Article
Background: Throughout the usual LDL cholesterol range in Western populations, lower blood concentrations are associated with lower cardiovascular disease risk. In such populations, therefore, reducing LDL cholesterol may reduce the development of vascular disease, largely irrespective of initial cholesterol concentrations. Methods: 20,536 UK adults (aged 40-80 years) with coronary disease, other occlusive arterial disease, or diabetes were randomly allocated to receive 40 mg simvastatin daily (average compliance: 85%) or matching placebo (average non-study statin use: 17%). Analyses are of the first occurrence of particular events, and compare all simvastatin-allocated versus all placebo-allocated participants. These "intention-to-treat" comparisons assess the effects of about two-thirds (85% minus 17%) taking a statin during the scheduled 5-year treatment period, which yielded an average difference in LDL cholesterol of 1.0 mmol/L (about two-thirds of the effect of actual use of 40 mg simvastatin daily). Primary outcomes were mortality (for overall analyses) and fatal or non-fatal vascular events (for subcategory analyses), with subsidiary assessments of cancer and of other major morbidity. Findings: All-cause mortality was significantly reduced (1328 [12.9%] deaths among 10,269 allocated simvastatin versus 1507 [14.7%] among 10,267 allocated placebo; p=0.0003), due to a highly significant 18% (SE 5) proportional reduction in the coronary death rate (587 [5.7%] vs 707 [6.9%]; p=0.0005), a marginally significant reduction in other vascular deaths (194 [1.9%] vs 230 [2.2%]; p=0.07), and a non-significant reduction in non-vascular deaths (547 [5.3%] vs 570 [5.6%]; p=0.4). There were highly significant reductions of about one-quarter in the first event rate for non-fatal myocardial infarction or coronary death (898 [8.7%] vs 1212 [11.8%]; p<0.0001), for non-fatal or fatal stroke (444 [4.3%] vs 585 [5.7%]; p<0.0001), and for coronary or non-coronary revascularisation (939 [9.1%] vs 1205 [11.7%]; p<0.0001). For the first occurrence of any of these major vascular events, there was a definite 24% (SE 3; 95% CI 19-28) reduction in the event rate (2033 [19.8%] vs 2585 [25.2%] affected individuals; p<0.0001). During the first year the reduction in major vascular events was not significant, but subsequently it was highly significant during each separate year. The proportional reduction in the event rate was similar (and significant) in each subcategory of participant studied, including: those without diagnosed coronary disease who had cerebrovascular disease, or had peripheral artery disease, or had diabetes; men and, separately, women; those aged either under or over 70 years at entry; and--most notably--even those who presented with LDL cholesterol below 3.0 mmol/L (116 mg/dL), or total cholesterol below 5.0 mmol/L (193 mg/dL). The benefits of simvastatin were additional to those of other cardioprotective treatments. The annual excess risk of myopathy with this regimen was about 0.01%. There were no significant adverse effects on cancer incidence or on hospitalisation for any other non-vascular cause. Interpretation: Adding simvastatin to existing treatments safely produces substantial additional benefits for a wide range of high-risk patients, irrespective of their initial cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rates of myocardial infarction, of stroke, and of revascularisation by about one-quarter. After making allowance for non-compliance, actual use of this regimen would probably reduce these rates by about one-third. Hence, among the many types of high-risk individual studied, 5 years of simvastatin would prevent about 70-100 people per 1000 from suffering at least one of these major vascular events (and longer treatment should produce further benefit). The size of the 5-year benefit depends chiefly on such individuals' overall risk of major vascular events, rather than on their blood lipid concentrations alone.
Article
Drug therapy for hypercholesterolaemia has remained controversial mainly because of insufficient clinical trial evidence for improved survival. The present trial was designed to evaluate the effect of cholesterol lowering with simvastatin on mortality and morbidity in patients with coronary heart disease (CHD). 4444 patients with angina pectoris or previous myocardial infarction and serum cholesterol 5·5-8·0 mmol/L on a lipid-lowering diet were randomised to double-blind treatment with simvastatin or placebo.Over the 5·4 years median follow-up period, simvastatin produced mean changes in total cholesterol, low-density-lipoprotein cholesterol, and high-density-lipoprotein cholesterol of -25%, -35%, and +8%, respectively, with few adverse effects. 256 patients (12%) in the placebo group died, compared with 182 (8%) in the simvastatin group. The relative risk of death in the simvastatin group was 0·70 (95% Cl 0·58-0·85, p=0·0003). The 6-year· probabilities of survival in the placebo and simvastatin groups were 87·6% and 91·3%, respectively. There were 189 coronary deaths in the placebo group and 111 in the simvastatin group (relative risk 0·58, 95% Cl 0·46-0·73), while noncardiovascular causes accounted for 49 and 46 deaths, respectively. 622 patients (28%) in the placebo group and 431 (19%) in the simvastatin group had one or more major coronary events. The relative risk was 0·66 (95% Cl 0·59-0·75, p<0·00001), and the respective probabilities of escaping such events were 70·5% and 79·6%. This risk was also significantly reduced in subgroups consisting of women and patients of both sexes aged 60 or more. Other benefits of treatment included a 37% reduction (p<0·00001) in the risk of undergoing myocardial revascularisation procedures.This study shows that long-term treatment with simvastatin is safe and improves survival in CHD patients.
Article
Having estimated a linear regression with p coefficients, one may wish to test whether m additional observations belong to the same regression. This paper presents systematically the tests involved, relates the prediction interval (for m = 1) and the analysis of covariance (for m > p) within the framework of general linear hypothesis (for any m), and extends the results to testing the equality between subsets of coefficients.
Article
Context Studies have demonstrated that statins administered to individuals with risk factors for coronary heart disease (CHD) reduce CHD events. However, many of these studies were too small to assess all-cause mortality or outcomes in important subgroups.Objective To determine whether pravastatin compared with usual care reduces all-cause mortality in older, moderately hypercholesterolemic, hypertensive participants with at least 1 additional CHD risk factor.Design and Setting Multicenter (513 primarily community-based North American clinical centers), randomized, nonblinded trial conducted from 1994 through March 2002 in a subset of participants from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).Participants Ambulatory persons (n = 10 355), aged 55 years or older, with low-density lipoprotein cholesterol (LDL-C) of 120 to 189 mg/dL (100 to 129 mg/dL if known CHD) and triglycerides lower than 350 mg/dL, were randomized to pravastatin (n = 5170) or to usual care (n = 5185). Baseline mean total cholesterol was 224 mg/dL; LDL-C, 146 mg/dL; high-density lipoprotein cholesterol, 48 mg/dL; and triglycerides, 152 mg/dL. Mean age was 66 years, 49% were women, 38% black and 23% Hispanic, 14% had a history of CHD, and 35% had type 2 diabetes.Intervention Pravastatin, 40 mg/d, vs usual care.Main Outcome Measures The primary outcome was all-cause mortality, with follow-up for up to 8 years. Secondary outcomes included nonfatal myocardial infarction or fatal CHD (CHD events) combined, cause-specific mortality, and cancer.Results Mean follow-up was 4.8 years. During the trial, 32% of usual care participants with and 29% without CHD started taking lipid-lowering drugs. At year 4, total cholesterol levels were reduced by 17% with pravastatin vs 8% with usual care; among the random sample who had LDL-C levels assessed, levels were reduced by 28% with pravastatin vs 11% with usual care. All-cause mortality was similar for the 2 groups (relative risk [RR], 0.99; 95% confidence interval [CI], 0.89-1.11; P = .88), with 6-year mortality rates of 14.9% for pravastatin vs 15.3% with usual care. CHD event rates were not significantly different between the groups (RR, 0.91; 95% CI, 0.79-1.04; P = .16), with 6-year CHD event rates of 9.3% for pravastatin and 10.4% for usual care.Conclusions Pravastatin did not reduce either all-cause mortality or CHD significantly when compared with usual care in older participants with well-controlled hypertension and moderately elevated LDL-C. The results may be due to the modest differential in total cholesterol (9.6%) and LDL-C (16.7%) between pravastatin and usual care compared with prior statin trials supporting cardiovascular disease prevention. Figures in this Article The important etiologic role of circulating levels of low-density lipoprotein cholesterol (LDL-C) in the development of atherosclerotic coronary heart disease (CHD) is well established. Numerous randomized trials in the 1970s and 1980s affirmed that lowering LDL-C levels with diet and/or drugs, such as bile acid sequestrant resins and fibrates, reduced CHD event rates.1 However, the total cholesterol reductions attained in these trials were modest (approximately 10%), and the correspondingly modest reductions in CHD mortality were offset by small increases in noncardiovascular mortality, with no net effect on overall mortality.1 In the mid-1980s, a new potent and well-tolerated class of drugs, the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) provided the means to conduct randomized trials in which total cholesterol reductions of 20% and greater could be sustained long-term. These trials also allowed questions about the overall benefits and risks of cholesterol lowering to be effectively addressed. The lipid-lowering trial (LLT) component of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)2 (ALLHAT-LLT) was originally envisioned as a free-standing double-blind trial to evaluate the effects of cholesterol lowering with a statin drug in a population that was older and more inclusive than those studied in prior trials. After successful completion of the Cholesterol Reduction In Seniors Program (CRISP),3 a 2-year feasibility study, the concept was modified and incorporated into ALLHAT as a randomized, nonblinded trial comparing pravastatin treatment with a usual care control group in a moderately hypercholesterolemic subset of the planned 40 000 ALLHAT participants. The principal objectives of the ALLHAT-LLT were to evaluate the impact of large sustained cholesterol reductions on all-cause mortality in a hypertensive cohort with at least 1 other CHD risk factor and to assess CHD reduction and other benefits in populations that had been excluded or underrepresented in previous trials, particularly older persons, women, racial and ethnic minority groups, and persons with diabetes.2 Emphasis on primary care settings was deemed important because of the study's substantial implications for these providers and their patients. Despite the publication of more than 20 long-term statin trials4- 13 since ALLHAT began in 1994 and the publication of the National Cholesterol Education Program (NCEP) Adult Treatment Panel Guidelines (ATP III)14 in 2001, ALLHAT-LLT remains the second largest long-term statin trial and addresses a unique population. This article presents results of the pravastatin vs usual care comparison for all-cause mortality and CHD end points in ALLHAT-LLT. Results of the ALLHAT antihypertensive trial appear in an accompanying article.15
Article
Background: The aim of this study was to test the efficacy of a low-dose pravastatin regimen (20 mg daily) in patients with myocardial infarction. Methods: GISSI Prevenzione (GISSI-P) is an open trial on secondary coronary heart disease prevention: 4271 recent acute myocardial infarction patients (< or = 6 months) with total blood cholesterol > or = 200 mg/dl were randomized to low-dose cholesterol-lowering treatment (pravastatin 20 mg daily) or no treatment. GISSI-P was started in 1993 and its story was crossed by the publication of the results of similarly designed clinical trials. The publication of 4S results in 1994 prompted the Data Safety and Monitoring Board (DSMB) and the Steering Committee (SC) to change the protocol so that only patients whose total blood cholesterol was < 250 mg/dl could be randomized whilst patients with total blood cholesterol > 250 mg/dl who had already been enrolled in the study had to be re-evaluated and, if appropriate, pharmacologically treated. The DSMB and the SC agreed to stop randomization prematurely in late 1996 after the publication of CARE results. Results: Mean follow-up time was 23.0 +/- 6.7 months (median 24.3 months). The two treatment groups were well matched at baseline. Pharmacological interventions recommended by the protocol were widely prescribed (antiplatelet agents > 90%, beta-blockers 42.7%, and ACE-inhibitors 40.2%). Mainly because of the on-course modification of the study protocol, 402/2133 (18.8%) patients in the control group started a cholesterol-lowering treatment during follow-up. Conversely, 296/2138 (13.8%) patients permanently stopped taking their tablets. Side effects, however, were the reason for discontinuing therapy in 57 (2.7%) patients in the pravastatin group, and patient reluctance to continue accounted for most of the remainder. After excluding control patients who had started a cholesterol-lowering treatment during follow-up, the following changes of median lipid concentrations in the control group over the whole course were observed: total cholesterol -1.9%; LDL cholesterol -2.9%; triglycerides -2.0%; HDL cholesterol +1.4%. The analysis carried out excluding patients randomized to pravastatin treatment and actually not assuming the drug clearly indicated the cholesterol-lowering efficacy of low-dose pravastatin (total cholesterol -12.5%; LDL cholesterol -18.8%; triglycerides -7.9%; HDL cholesterol +3.4%). During the study 256 (6.0%) patients either died or had a non-fatal stroke or a myocardial infarction, 136 (6.4%) in the control group and 120 (5.6%) in the pravastatin group (relative risk 0.90, 95% confidence interval 0.71-1.15, p = 0.41); 160 patients died, 88 (4.1%) in the control group and 72 (3.4%) in the pravastatin group (relative risk 0.84, 94% confidence interval 0.61-1.14, p = 0.26). The few (n = 28) non-cardiovascular deaths were balanced: 16 (0.8%) in the control group and 15 (0.6%) in the pravastatin group. The reduction of cardiovascular events was more evident in the by-treatment analysis, with coronary heart disease deaths being significantly decreased (relative risk 0.60, 95% confidence interval 0.38-0.96, p = 0.04). The overall frequency of adverse events was similar in the two groups. No significant difference between treatment groups was found for total cases of cancer or at any particular site. Conclusions: Despite the decreased statistical power due to its premature stopping, the results of the GISSI-P suggest that a low-dose treatment with pravastatin (20 mg daily) is effective in reducing blood lipids, and underline the importance of long-term compliance with treatments in the search for a maximal effective dosage. Furthermore, the effects of a statin on total and coronary mortality quantified for the first time in a population exposed to Mediterranean dietary and lifestyle habits are markedly consistent with those obtained in different settings.
Article
A National Heart, Lung, and Blood Institute (NHLBI) Conference was held October 9-10, 1990, to review and discuss existing data on U-shaped relations found between mortality rates and blood total cholesterol levels (TC) in some but not other studies. Presentations were given from 19 cohort studies from the United States, Europe, Israel, and Japan. A representative of each study presented its findings and also submitted tables of proportional hazards regression coefficients for entry TC levels in regard to death, and these were incorporated into a formal statistical overview adjusted for age, diastolic blood pressure, cigarette smoking, body mass index, and alcohol intake, as available. The U-shape for total mortality in men and the flat relation in women resulted largely from a positive relation of TC with coronary heart disease death and an inverse relation with deaths caused by some cancers (e.g., lung but not colon), respiratory disease, digestive disease, trauma, and residual deaths. Risk for combined noncardiovascular, noncancer causes of death decreased steadily across the range of TC. The conference considered possible explanations for the statistical associations found between low TC levels or active TC lowering and certain causes of death. One is that TC is lowered by some disease conditions themselves, such as wasting in chronic pulmonary disease or reduced production and secretion of cholesterol-bearing lipoproteins with liver disease. In this sort of situation, the TC:mortality association found in observational studies may be due to preexisting disease. This was addressed by excluding early deaths from the analysis, which did not change the results. The conference considered as well the biological function of cholesterol, which, if seriously deranged, might hypothetically cause a wide variety of diseases and dysfunction. The conference also considered the biological functions that might provide plausible mechanisms for the associations found. Definitive interpretation of the associations observed was not possible, although most participants considered it likely that many of the statistical associations of low or lowered TC level are explainable by confounding in one form or another. The conference focused on the apparent existence and nature of these associations and on the need to understand their source rather than on any pertinence of the findings for public health policy. Further research is recommended to explain the observed associations of low TC levels (and TC lowering) with certain noncardiovascular diseases. This includes studies of the time course of TC change in disease, the relation of TC to morbidity, further studies of possible epidemiological confounding, monitoring of population trends in TC and mortality, further studies of the relations in women, auditing of noncardiovascular events in trials, studies of cell membrane, genetic and molecular links to cholesterol metabolism, TC level and disease, studies of disease manifestations in specific lipid disorders, and further study of the proposed causal mechanisms linking low TC and hemorrhagic stroke.
Article
In the Expanded Clinical Evaluation of Lovastatin (EXCEL) Study, a multicenter, double-blind, diet- and placebo-controlled trial, we evaluated the efficacy and safety of lovastatin in 8245 patients with moderate hypercholesterolemia. Patients were randomly assigned to receive placebo or lovastatin at a dosage of 20 mg once daily, 40 mg once daily, 20 mg twice daily, or 40 mg twice daily for 48 weeks. Lovastatin produced sustained, dose-related (P<.001) changes as follows (for dosages of 20 to 80 mg/d): decreased low-density lipoprotein—cholesterol level (24% to 40%), increased high-density lipoprotein—cholesterol level (6.6% to 9.5 %), decreased total cholesterol level (17% to 29%), and decreased triglyceride level (10% to 19%). The National Cholesterol Education Program's low-density lipoprotein—cholesterol level goal of less than 4.14 mmol/L (160 mg/dL) was achieved by 80% to 96% of patients, while the less than 3.36 mmol/L (130 mg/dL) goal was achieved by 38% to 83% of patients. The difference between lovastatin and placebo in the incidence of clinical adverse experiences requiring discontinuation was small, ranging from 1.2% at 20 mg twice daily to 1.9% at 80 mg/d. Successive transaminase level elevations greater than three times the upper limit of normal were observed in 0.1% of patients receiving placebo and 20 mg/d of lovastatin, increasing to 0.9% in those receiving 40 mg/d and 1.5% in those receiving 80 mg/d of lovastatin (P<.001 for trend). Myopathy, defined as muscle symptoms with a creatine kinase elevation greater than 10 times the upper limit of normal, was found in only one patient (0.1%) receiving 40 mg once daily and four patients (0.2%) receiving 80 mg/d of lovastatin. Thus, lovastatin, when added after an adequate trial of a prudent diet, is a highly effective and generally well-tolerated treatment for patients with moderate hypercholesterolemia. (Arch Intern Med. 1991;151:43-49)
Article
The randomized, double-blind, placebo-controlled trial described in this report was undertaken to clarify the dose-response relation of lovastatin therapy to lipid-modifying efficacy (lipid/lipoprotein modification) and drug-related adverse events in a population with moderately elevated fasting plasma total cholesterol (240 to 300 mg/dl) and low-density lipoprotein cholesterol (greater than or equal to 160 mg/dl). Men or women (postmenopausal or surgically sterile), aged 18 to 70 years, were entered into the trial with minimal exclusion criteria. After 4 to 6 weeks of an American Heart Association phase I diet or a more stringent diet, 8,245 patients from 362 sites were randomized to 1 of 5 parallel diet and drug treatment groups: placebo (n = 1,663) or lovastatin, 20 mg (n = 1,642) and 40 mg (n = 1,645) with the evening meal, and 20 mg (n = 1,646) or 40 mg twice daily (n = 1,649). The regimen of diet and lovastatin (or placebo) was followed for 48 weeks. The 5 treatment groups were similar at baseline. The total cohort had the following characteristics: 59% were men (mean age 56 years); 92% were white; 59% had completed at least 1 year of education beyond high school; 57% had a history of cardiovascular and associated disease; 40% had a history of hypertension; and 29% had coronary artery disease. Health habits were similar among groups, with 18% of patients reporting cigarette smoking, 14% reporting that they consume greater than 1 alcoholic beverage daily and 67% reporting no strenous exercise. Mean lipid/lipoprotein levels were also similar among groups, with the following average levels: total cholesterol (258 mg/dl), low-density lipoprotein cholesterol (180 mg/dl), high-density lipoprotein cholesterol (45 mg/dl) and triglycerides (median = 155 mg/dl). The large size of this trial, its placebo-controlled, double-blind design and the similarity of treatment groups at baseline should allow clear documentation of the long-term effects of lovastatin treatment and generalization of the results to a substantial portion of patients who may be candidates for lipid-modifying therapy.
Article
In patients with high cholesterol levels, lowering the cholesterol level reduces the risk of coronary events, but the effect of lowering cholesterol levels in the majority of patients with coronary disease, who have average levels, is less clear. In a double-blind trial lasting five years we administered either 40 mg of pravastatin per day or placebo to 4159 patients (3583 men and 576 women) with myocardial infarction who had plasma total cholesterol levels below 240 mg per deciliter (mean, 209) and low-density lipoprotein (LDL) cholesterol levels of 115 to 174 mg per deciliter (mean, 139). The primary end point was a fatal coronary event or a nonfatal myocardial infarction. The frequency of the primary end point was 10.2 percent in the pravastatin group and 13.2 percent in the placebo group, an absolute difference of 3 percentage points and a 24 percent reduction in risk (95 percent confidence interval, 9 to 36 percent; P = 0.003). Coronary bypass surgery was needed in 7.5 percent of the patients in the pravastatin group and 10 percent of those in the placebo group, a 26 percent reduction (P=0.005), and coronary angioplasty was needed in 8.3 percent of the pravastatin group and 10.5 percent of the placebo group, a 23 percent reduction (P=0.01). The frequency of stroke was reduced by 31 percent (P=0.03). There were no significant differences in overall mortality or mortality from noncardiovascular causes. Pravastatin lowered the rate of coronary events more among women than among men. The reduction in coronary events was also greater in patients with higher pretreatment levels of LDL cholesterol. These results demonstrate that the benefit of cholesterol-lowering therapy extends to the majority of patients with coronary disease who have average cholesterol levels.
Article
Systematic reviews of randomized controlled trials often provide the most reliable information on which to base treatment policy. However, to be reliable, such reviews need to contain a high proportion of all the relevant randomized evidence. This relates both to the need to find all trials and the need to analyse data on all participants. One way to achieve this is through a collaboration in which those responsible for the trials supply data on each randomized patient for an individual patient data meta-analysis. However, such projects require more time and resources than more conventional reviews and are still rare. This paper illustrates how they can help to achieve the aim of using complete data in a systematic review.
Article
We developed and evaluated methods for the analysis and interpretation of the baseline risk heterogeneity in meta-analysis of individual patient data (MIPD) based on information on predictive factors. We used data from a typical MIPD of eight clinical trials (1792 patients, 2947 years of follow-up) on the efficacy of high-dose acyclovir in human immunodeficiency virus infection. Cox models with four predictive factors (age, disease state, CD4 cell count and hemoglobin levels) were used to estimate predicted individual hazards both for single trials and for various MIPD modeling methods (simple pooling, adjusted for study, stratified per study, fixed and random effects for predictors). For each study and for each method of MIPD synthesis, we estimated the odds ratio for death in the upper versus the lower quartile of predicted risk (Extreme Quartile Odds Ratio, EQuOR) and the respective rate ratio (Extreme Quartile Rate Ratio, EQuRR). Only the CD4 cell count showed a significantly heterogeneous predictive effect across the eight studies (P =.024). The EQuOR of single studies ranged from 3.5 (little heterogeneity) to 24 (intermediate heterogeneity), substantially lower than the EQuOR of the MIPD (167 to 275, depending on the model used). The EQuRR values ranged from 3.5 to 77 for single studies and from 77 to 116 for the various MIPD models. Predictive modeling can be a major strength of MIPD, when performed and interpreted with standardized approaches. All models consistently show that MIPD may be a study design with extreme heterogeneity of patient baseline risk.
Article
Although the short-term safety and tolerability of statins has been well established, their potential carcinogenicity in the long term is still debated. The goal of this study was to determine whether long-term treatment with statins is associated with an increased risk of fatal and nonfatal cancers. We searched the Medline database between January 1966 and December 1999 for randomized, controlled trials of human subjects in which monotherapy with a statin was compared with placebo. No language restrictions were applied. Only trials with a minimum treatment duration of 4 years and a minimum of 1,000 subjects were included. Studies that did not provide information on fatal or nonfatal cancers were excluded. Data on fatal and nonfatal cancers and all-cause mortality were extracted by a single nonblinded reviewer. Overall crude estimates of risk difference were computed by summing the numerators and denominators of trial-specific risk estimates. Five trials met the inclusion criteria. The estimated differences in absolute risk between treatment and placebo were as follows (negative risks indicate that treatment was safer than placebo): all nonfatal cancers, 0.0% (95% confidence interval [CI]: -0.8% to 0.8%); all fatal cancers, -0.1% (95% CI: -0.7% to 0.4%); all fatal and nonfatal cancers combined, -0.1% (95% CI: -1.0% to 0.7%); and all-cause mortality, -1.5% (95% CI: 2.8% to 0.2%). This study demonstrates no association between statin use over a 5-year period and the risk of fatal and nonfatal cancers. This conclusion is limited by the relatively short follow-up of the studies analyzed. Similar analyses of data from studies with longer follow-up periods would be valuable.
Article
Systematic reviews and meta-analyses that obtain original research data on individual participants enrolled in trials have been described as the gold standard of review. However, they may take longer and be more resource intensive than other types of review. The authors describe potential advantages and disadvantages of the individual patient data (IPD) approach, including benefits from improved data quality, benefits afforded by the type of analyses that can be done, and advantages in achieving consensus around results and interpretation by an international multidisciplinary team. Disadvantages and barriers relating to resource and expertise, negotiating collaboration, and software requirements are also discussed. At the outset, reviewers should consider the methodological factors likely to influence results in their particular review setting, together with time and resource constraints, so that an active decision can be made about whether to extract data from published reports, collect additional or replacement summary data from trialists, or collect IPD.