ArticleLiterature Review

Effect of the Magnitude of Lipid Lowering on Risk of Elevated Liver Enzymes, Rhabdomyolysis, and Cancer. Insights From Large Randomized Statin Trials

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Abstract

We sought to assess the relationship between the magnitude of low-density lipoprotein cholesterol (LDL-C) lowering and rates of elevated liver enzymes, rhabdomyolysis, and cancer. Although it is often assumed that statin-associated adverse events are proportional to LDL-C reduction, that assumption has not been validated. Adverse events reported in large prospective randomized statin trials were evaluated. The relationship between LDL-C reduction and rates of elevated liver enzymes, rhabdomyolysis, and cancer per 100,000 person-years was assessed using weighted univariate regression. In 23 statin treatment arms with 309,506 person-years of follow-up, there was no significant relationship between percent LDL-C lowering and rates of elevated liver enzymes (R2 <0.001, p = 0.91) or rhabdomyolysis (R2 = 0.05, p = 0.16). Similar results were obtained when absolute LDL-C reduction or achieved LDL-C levels were considered. In contrast, for any 10% LDL-C reduction, rates of elevated liver enzymes increased significantly with higher statin doses. Additional analyses demonstrated a significant inverse association between cancer incidence and achieved LDL-C levels (R2 = 0.43, p = 0.009), whereas no such association was demonstrated with percent LDL-C reduction (R2 = 0.09, p = 0.92) or absolute LDL-C reduction (R2 = 0.05, p = 0.23). Risk of statin-associated elevated liver enzymes or rhabdomyolysis is not related to the magnitude of LDL-C lowering. However, the risk of cancer is significantly associated with lower achieved LDL-C levels. These findings suggest that drug- and dose-specific effects are more important determinants of liver and muscle toxicity than magnitude of LDL-C lowering. Furthermore, the cardiovascular benefits of low achieved levels of LDL-C may in part be offset by an increased risk of cancer.

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... Some patients taken the allowed dose also showed mild symptoms www.nature.com/scientificreports/ of liver injury following long-lasting treatment with statins 40,41 . Thus, it is likely that statins dose and duration is more essential determinants of hepato-and myo-toxicity than hypocholesterolemia 42 . Our results also showed that TQ and/or BP treatment could ameliorate hepatitis induced by fluvastatin and restored liver function. ...
... Introduced 40 years ago, statins rarely cause liver disease in humans, they only induce a mild increase in liver enzymes 38,39,41 . On rare occasions, they may induce a larger increase and on those occasions a different statin should be used 42 . Among the seven statins used in clinical practice, fluvastatin is actually one of the least used. ...
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Hepatitis is one of earlier, but serious, signs of liver damage. High doses of statins for a long time can induce hepatitis. This study aimed to evaluate and compare the therapeutic potential of thymoquinone (TQ) and bee pollen (BP) on fluvastatin (F)-induced hepatitis in rats. Rats were randomly divided into: group 1 (G1, control), G2 (F, hepatitis), G3 (F + TQ), G4 (F + BP), and G5 (F + TQ + BP). Single treatment with TQ or BP relieved fluvastatin-induced hepatitis, with best effect for the combined therapy. TQ and/or BP treatment significantly (1) reduced serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transpeptidase, and total bilirubin, (2) decreased malondialdehyde levels and increased level of reduced glutathione, and activities of glutathione peroxidase and catalase in the liver, (3) improved liver histology with mild deposition of type I collagen, (4) increased mRNA levels of transforming growth factor beta 1, nuclear factor Kappa B, and cyclooxygenase 1 and 2, and (5) decreased tumor necrosis factor alpha and upregulated interleukin 10 protein in the liver. These data clearly highlight the ability of TQ and BP combined therapy to cause better ameliorative effects on fluvastatin-induced hepatitis than individual treatment by each alone. Liver damage constitutes one of the main causes of hepatocellular carcinoma (HCC) that leads to death worldwide 1-3. Hepatitis is one of earlier signs of liver damage, which is characterized by inflammatory cells infiltration, congestion of blood vessels, and cellular degenerative changes. Hepatitis could be induced by a viral infection, microbial metabolites, metabolic and autoimmune diseases, environmental toxicants, and alcohol and drug abuse 1,3,4. If hepatitis was left for a long time without suitable treatments, other complicated liver disorders such as fibrosis and cirrhosis would be developed and in advanced cases become risk factors for HCC 5. Lipid-lowering drugs statins, including fluvastatin, prevents cholesterol biosynthesis by inhibiting hydroxyl-methyl-glutaryl co-enzyme A (HMG-CoA) reductase activity 6. Higher doses of statins were reported to induce hepatotoxicity and myotoxicity 7,8. Rats administrated fluvastatin (24 mg/kg/day) for 7 days suffered from notable hepatotoxicity 7. Treatment with high doses of fluvastatin disturbs liver function as evidenced by elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum levels and induces myopathy as revealed by high serum AST and creatine kinase levels in rats 8. Alternative therapeutic strategies using natural products have been traditionally utilized in the treatment of liver damage and cancer 9-13. Among these medicinal natural products, Nigella sativa and its main phytochemical component thymoquinone (TQ) have several health beneficial properties, such as antioxidant, anti-inflammatory, immune-stimulant, anti-bacterial, hypoglycemic, and anti-arthritic activities 14-18. Due to their potent antioxidant, anti-inflammatory properties, TQ relieved hepatotoxicity induced by carbon tetrachloride (CCl 4) in mice 19 , and by 2,3,7,8-tetrachlorodibenzo-p-dioxin 20 , ethanol 21 and gentamicin 22 in rats by inhibiting oxidative stress, inflammation, and apoptosis. TQ also attenuated chemically-induced liver fibrosis in mice 23. The honeybees gather bee pollen (BP) as a supply of nutrients for their hives. Male flowers' reproductive cells produce pollen grains, that contain large amounts of phenolic compounds, phytochemicals, flavonoids, carotenoids, amino acids, minerals, and vitamins 24,25. However, the exact ingredients of BP differ based on OPEN
... 103 An evaluation of changes in liver enzymes following rising doses of statins gave indication that for any 10% LDL-C reduction, the rates of elevated liver enzymes increased significantly with higher statin doses. 104 The rate of elevated liver enzymes per 100 000 person-years with highdose lovastatin was 2.5 times higher compared with low-dose lovastatin and significantly higher than intermediate-dose lovastatin. Likewise, liver enzymes with higher doses of simvastatin (80 mg and 40 mg) were 1.6 times greater compared with low-dose simvastatin and the rate of elevated liver enzymes with high-dose atorvastatin was four times larger compared with low-dose atorvastatin. ...
... The association between statins and cancer risk was supported by an early analysis of statin trials, which indicated an inverse correlation between achieved LDL-C and risk of cancer. 104 A major risk factor for cancer occurrence upon statin treatment is the age of recipients. This was evident in the PROSPER study, where mean age at entry was 75 years and CV event reduction was offset by an equal increase in cancer mortality. ...
Article
Treatment with statins, inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, has proven beneficial preventive effects on cardiovascular events. However, discontinuation due to intolerance and nonadherence remain two of the major gaps in both primary and secondary prevention. This leads many patients with high-risk of atherosclerotic cardiovascular disease (ASCVD) to be inadequately treated or not to achieve the target lipid level goals, and as consequence they undergo an increased risk of cardiovascular events. The aim of this review is thus to give an overview of the reasons for discontinuation and on the possible mechanisms behind them. Although statins, as a class, are generally safe, they are associated with an increased risk of diabetes mellitus and hepatic transaminase elevations. Incidence of cataracts or cognitive dysfunction and others presented in the literature (e.g., proteinuria and haematuria) have been never confirmed to have a causal link. Conversely, debated remains the effect on myalgia. Muscle side effects are the most commonly reported, although myalgia is still believed by some to be the result of a nocebo/drucebo effect. Concerning mechanisms behind these side effects no clear conclusions have been reached. Thus, if on one side it is important to identify individuals either at higher risk to develop a side effect, or with confirmed risk factors and conditions of statin intolerance, on the other side alternative strategies should be identified to avoid an increased ASCVD risk.
... Statin-370 associated liver abnormalities (aminotransferase levels) are 371 rare, mild, dose-related, and not related to reduction in 372 LDL-C. Thus, drug-and dose-specific effects are more 373 important determinants of liver and muscle toxicity than 374 magnitude of LDL-C lowering [52,53]. They are also 375 usually temporary, and it is possible to return to baseline 376 levels after 2-4 weeks [52,53]. ...
... Thus, drug-and dose-specific effects are more 373 important determinants of liver and muscle toxicity than 374 magnitude of LDL-C lowering [52,53]. They are also 375 usually temporary, and it is possible to return to baseline 376 levels after 2-4 weeks [52,53]. Persistent elevation of 377 ALT more than three times the upper limit of normal 378 (ULN) were observed in B 1% of patients treated with 379 statins. ...
Article
Statin therapy is very effective and safe for preventing and treating cardiovascular disease regardless of cholesterol levels; however, it can be associated with various adverse events (myalgia, myopathy, rhabdomyolysis, and diabetes mellitus, among others). Throughout the world patients frequently discontinue statin therapy without medical advice due to perceived side effects, and consequently increase their risk for cardiovascular events. In the case of statin intolerance it may be advisable to change the dose, change to a different statin, try alternate-day statin therapy, or, if intolerance is associated with all statins even at the lowest dose, then non-statin drugs and certain nutraceuticals can be considered. This review focuses on the definition of statin intolerance and on the development of clinical and therapeutic strategies for its management, including emerging alternative therapies.
... risk of liver test abnormalities and that monitoring was not warranted in patients taking a low-to-moderate dose other than at the onset of therapy [63]. Another meta-analysis of 75,317 subjects addressed the issue of effect of higher vs. lower intensity statin therapy on liver toxicity [64]. It included 23 statin arms for 0.9-6 years of follow-up. ...
... notes: CaRE-cholesterol and recurrent events; ldl-C-low-density lipoprotein cholesterol; lipid-long-term intervention with pravastatin in ischemic disease; RCTs-randomised controlled trial; WoSCopS-West of Scotland coronary prevention study. Meta-analysis Number of RCTs Patients Duration Drug used Liver toxicity prospective pravastatin pooling project [59] 3 (lipid/CaRE/ WoSCopS) 19,768 5 years pravastatin 40 mg no excess of liver function abnormalities denus et al. [63] 13 49,275 48 weeks-6 years pravastatin 40 mg only fluvastatin associated with odds of having liver test abnormalities lovastatin 30-45 mg Simvastatin 30 mg Fluvastatin 40-80 mg alsheikh-ali et al. [64] 23 statin arms 75,317 0.9-6 years lovastatin 20-80 mg drug-and dose-specific effects are more important determinants of liver toxicity than magnitude of ldl-C lowering ...
... risk of liver test abnormalities and that monitoring was not warranted in patients taking a low-to-moderate dose other than at the onset of therapy [63]. Another meta-analysis of 75,317 subjects addressed the issue of effect of higher vs. lower intensity statin therapy on liver toxicity [64]. It included 23 statin arms for 0.9-6 years of follow-up. ...
... notes: CaRE-cholesterol and recurrent events; ldl-C-low-density lipoprotein cholesterol; lipid-long-term intervention with pravastatin in ischemic disease; RCTs-randomised controlled trial; WoSCopS-West of Scotland coronary prevention study. Meta-analysis Number of RCTs Patients Duration Drug used Liver toxicity prospective pravastatin pooling project [59] 3 (lipid/CaRE/ WoSCopS) 19,768 5 years pravastatin 40 mg no excess of liver function abnormalities denus et al. [63] 13 49,275 48 weeks-6 years pravastatin 40 mg only fluvastatin associated with odds of having liver test abnormalities lovastatin 30-45 mg Simvastatin 30 mg Fluvastatin 40-80 mg alsheikh-ali et al. [64] 23 statin arms 75,317 0.9-6 years lovastatin 20-80 mg drug-and dose-specific effects are more important determinants of liver toxicity than magnitude of ldl-C lowering ...
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apollo Hospitals, new delhi, india; c lipid association of india, new delhi, india; d Medicine, The Tamil nadu dr MgR Medical University, Chennai, india; e Snn Specialities Clinic, Chennai, india; f Clinical lead for lipids and CVd prevention, Royal Free nHS Foundation Trust Hospital, london, UK; g department of Cardiology, g. B. pant Hospital, new delhi, india; h Fortis Hospital, new delhi, india; i department of Endocrinology, indraprastha apollo Hospital, new delhi, india; j Centre for Cardiac Sciences, Kokilaben dhirubhai ambani Hospital, Mumbai, india; k nephrology Research, Fortis Escort, Kidney & Urology institute, new delhi, india; l george institute of global Health, new delhi, india; m Fortis-C-doC Centre of Excellence for diabetes, Metabolic diseases and Endocrinology, new delhi, india; n department of Medicine, Maulana azad Medical College & attached Hospital, new delhi, india; o department of neurology, indraprastha apollo Hospitals, new delhi, india; p department of nephrology, indraprastha apollo Hospitals, new delhi, india; q department of Rheumatology, indraprastha apollo Hospitals, new delhi, india; r division of Clinical & preventive Cardiology, Medanta Heart institute, Medanta Hospital, gurugram, india; s department of Cardiology, Medanta Hospital, gurugram, india; t non-invasive Cardiology, Max Super Speciality Hospital, Saket, new delhi, india; u Royal Free london nHS Foundation Trust, london, UK; v department of Cardiology, Max Healthcare institute ltd., Saket, new delhi, india; w department of Endocrinology, pt. BdSpgiMS, Rohtak, india; x department of Cardiology, King george's Medical University, lucknow, india; y department of Cardiology, all india institute of Medical Sciences, new delhi, india; z department of Endocrinology, artemis Hospital, gurugram, india; aa department of internal Medicine, Sahyadri Speciality Hospital, pune, india; ab department of Cardiology, indraprastha apollo Hospitals, new delhi, india; ac department of Endocrinology & Metabolism, aiiMS, new delhi, india; ad department ABSTRACT These Lipid Association of India (LAI) recommendations refer to specific patient populations. They follow the previously published LAI part 1 recommendations. These part 2 LAI recommendations focus on specific patient groups. These include patients with heart failure, chronic kidney disease, non-alcoholic fatty liver disease, cerebrovascular disease, thyroid disorders, inflammatory joint diseases, familial hypercholesterolaemia and human immunodeficiency virus infection. We also consider women, the elderly and post-transplantation patients. The current recommendations are based, as much as possible, on available data from Indian populations.
... Some patients taken the allowed dose also showed mild symptoms www.nature.com/scientificreports/ of liver injury following long-lasting treatment with statins 40,41 . Thus, it is likely that statins dose and duration is more essential determinants of hepato-and myo-toxicity than hypocholesterolemia 42 . Our results also showed that TQ and/or BP treatment could ameliorate hepatitis induced by fluvastatin and restored liver function. ...
... Introduced 40 years ago, statins rarely cause liver disease in humans, they only induce a mild increase in liver enzymes 38,39,41 . On rare occasions, they may induce a larger increase and on those occasions a different statin should be used 42 . Among the seven statins used in clinical practice, fluvastatin is actually one of the least used. ...
Article
Full-text available
Hepatitis is one of earlier, but serious, signs of liver damage. High doses of statins for a long time can induce hepatitis. This study aimed to evaluate and compare the therapeutic potential of thymoquinone (TQ) and bee pollen (BP) on fluvastatin (F)-induced hepatitis in rats. Rats were randomly divided into: group 1 (G1, control), G2 (F, hepatitis), G3 (F + TQ), G4 (F + BP), and G5 (F + TQ + BP). Single treatment with TQ or BP relieved fluvastatin-induced hepatitis, with best effect for the combined therapy. TQ and/or BP treatment significantly (1) reduced serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transpeptidase, and total bilirubin, (2) decreased malondialdehyde levels and increased level of reduced glutathione, and activities of glutathione peroxidase and catalase in the liver, (3) improved liver histology with mild deposition of type I collagen, (4) increased mRNA levels of transforming growth factor beta 1, nuclear factor Kappa B, and cyclooxygenase 1 and 2, and (5) decreased tumor necrosis factor alpha and upregulated interleukin 10 protein in the liver. These data clearly highlight the ability of TQ and BP combined therapy to cause better ameliorative effects on fluvastatin-induced hepatitis than individual treatment by each alone.
... Рациональная Фармакотерапия в Кардиологии 2014; 10(2) Урсодезоксихолевая кислота и терапия статинами (исследование РАКУРС) Статины являются основой современной терапии по коррекции нарушений липидного обмена и показаны большинству больных с высоким риском сердечно-сосудистых осложнений [1]. Многолетний клинический опыт применения статинов убедительно показал, что длительная терапия статинами в целом достаточно безопасна [2][3][4][5][6]. Менее ясен вопрос о безопасности длительной терапии статинами у больных с исходно нарушенной функцией печени. ...
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Aim. To assess the potential of ursodeoxycholic acid (UDCA) in the prevention of liver dysfunction in patients with cardiovascular diseases (CVD) and high risk of cardiovascular events (CVE) with indications for statins use.Material and methods. Patients (n=262, age 60.1±8.9 years) took statins for secondary prevention of CVE in observational cohort study. The follow-up duration was 6 months. UDCA was recommended for all patients because of liver diseases and/or biliary tract. Some of the patients with high treatment compliance strictly followed recommendations to take UDCA, and another part of the patients with low treatment compliance did not take UDCA. Comparison of these groups allowed highlighting UDCA effects.Results. Controlled lipid-lowering therapy in combination with UDCA resulted in a significant reduction in total cholesterol (TC) and low density lipoprotein cholesterol levels after 6 months of follow-up to 4.3 mmol/L and 2.3 mmol/L, respectively (p<0.001). Deterioration in the dynamics of alanine-aminotransferase (ALT), aspartate aminotransferase (AST), creatinphosphokinase (CPK) and gamma glutamine transferase (GGT), as well as increase in serum bilirubin was not found. Moreover, in general significant decrease in ALT, AST, GGT and alkaline phosphatase (p<0.001) was observed, the levels of total serum bilirubin and CPK did not change at the end of the study (p=0.65 and p=0.16, respectively). Taking UDCA simultaneously with statins led to additional reduction in TC and low density cholesterol compared with statin monotherapy (p=0.01).Conclusion. One of the affordable and effective ways to deal with a wider statin use in patients with liver and biliary tract disorders is their co-administration with UDCA.
... -Lipid-lowering may increase cancer risk (Alsheikh-Ali et al., 2007;Pignone et al., 2000). ...
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Evidence Based Healthcare Reform
... Two subjects were reported with liver enzyme elevation during intervention. A similar report was noted in the previous studies (Alsheikh-Ali et al., 2007;Armitage, 2007) with two ideas. Firstly, higher dose of statin had increased risk of AST elevations in the studies. ...
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Red yeast rice (RYR) has been used as an alternative treatment for hyperlipidemia. According to the previous studies, other compounds, besides monacolin K in RYR, may also reduce the serum lipid level. This study aims at examining the efficacy of monacolin K-rich and Gamma-Aminobutyric Acid (GABA)-rich RYR (Monascus pilosus) with regards to treating hyperlipidemia in a randomized control, double-blind clinical trial. In the research, we assigned 50 eligible subjects to monacolin K-rich RYR, GABA-rich RYR and placebo groups ( n = 1 6 , 17, 17, respectively). The concentrations of TC, LDL-C, HDL, TG and blood biochemical data were evaluated at different phases: before applying (visit 1), after 1-month (visit 2), 2-month (visit 3), 3-month (visit 4) of providing the intervention and 1-month after ending the test food (visit 5) among three groups. During the 3-month intervention, the serum TC and LDL-C levels decreased significantly in the monacolin K group compared to the baseline and the other two groups. The Serum TG level declined steadily but was not statistically significant. Meanwhile, no marked differences in the serum HDL level were revealed among the three groups. Most safety assessment data had minor variation except two subjects (in monacolin K and GABA group separately) reported elevated liver enzymes. Monacolin K-rich RYR can reduce cholesterol as expected, while the GABA-rich RYR performed non-significant reduction on serum triglyceride. The research results demonstrate that using different concentrations and ratios between monacolin K and GABA could be beneficial for antihyperlipidemia.
... Statin treatment is strongly recommended for patients with cardiovascular disease, while no recommendations have been made for patients with hypocholesterolemia (4,5). On the other hand, a J-or U-shaped rela-tionship between the serum cholesterol level and all-cause mortality has been reported in patients with life-threatening diseases such as cancer (6)(7)(8) or chronic obstructive pulmonary disease (9). Such a relationship has been referred to as the "lipid paradox" in studies on rheumatoid arthritis (10,11) and acute coronary disease (12)(13)(14). ...
Article
Objectives The aim of this study was to assess the relationship between hypercholesterolemia (HC) and clinical events through a percutaneous coronary intervention (PCI) registry. Background HC is a well-known independent risk factor for long-term cardiovascular events after PCI. However, it has been reported to be associated with a lower risk of adverse events in patients with cancer or acute coronary syndrome. Methods We analyzed the relationship between HC and adverse events in patients treated with everolimus-eluting stents (EESs) through the Tokyo-MD PCI study (an all-comer, multicenter, observational registry). The propensity score method was applied to select two groups with similar baseline characteristics. Results The unadjusted population included 1,536 HC patients and 330 non-HC patients. Propensity score matching yielded 314 matched pairs. After baseline adjustment, the outcomes of HC patients were significantly better than those of the non-HC patients with respect to the primary endpoint, which was a combination of mortality from all causes, nonfatal myocardial infarction (MI), nonfatal neurological events, and major bleeding (hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.39-0.81; p=0.002), and the secondary endpoints, which included a combination of mortality from all causes, nonfatal MI, and nonfatal neurological events (HR 0.59, 95% CI 0.39-0.88; p=0.01), and major bleeding (HR 0.42, 95% CI 0.20-0.88; p=0.02). A subgroup analysis showed age as an interaction factor for the primary endpoint (interaction p=0.035). Conclusion HC was associated with better outcomes in patients who underwent EES implantation, even after baseline adjustment.
... 42 Hace unos años, un gran metaanálisis, que incluyó 309.000 personas-años de seguimiento, encontró una asociación entre los niveles de LDL alcanzados con el tratamiento con estatinas y el riesgo de cáncer. 43 Sin embargo, un reciente ECR que incluyó 20.536 pacientes tratados durante 5 años demostró que las estatinas no producen un cambio en la incidencia de cáncer a 11 años. 44 En la misma línea, un metaanálisis que incluyó 27 estudios y 175.000 individuos con un seguimiento de 5 años demostró que el tratamiento con estatinas no tiene efecto sobre la incidencia o mortalidad de ningún tipo de cáncer. ...
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The dark side of the moon: safety profi le of statins Gastón A. Rodríguez-Granillo Sin dejar lugar para el debate, las estatinas reducen sig-nifi cativamente el riesgo de eventos cardiovasculares y la mortalidad de toda causa en pacientes con enferme-dad coronaria establecida. 1,2 Las estatinas han demos-trado incluso promover la regresión de la aterosclero-sis coronaria aparentemente a través de múltiples me-canismos, modifi cando la composición de la placa, re-duciendo la infl amación y mejorando la función en-dotelial. 3-6 Es por tanto probable que el efecto antia-teroesclerótico de las estatinas sea pleiotrópico y efec-tivo contra los dos principales mecanismos de progre-sión de la placa ateromatosa: la disfunción endotelial y la ruptura de placa. La enorme evidencia a favor de las estatinas en la pre-vención de eventos fatales y no fatales y en numerosos puntos fi nales subrogantes ha llevado a la utilización masiva de estos agentes, incluso en prevención prima-ria. 7,8 Las estatinas son de hecho la clase de drogas más vendida en los Estados Unidos, siendo la atorvastatina una de las drogas más vendidas de la historia. 9-11 El JUPITER fue un estudio multicéntrico que inclu-yó 18.000 individuos sanos con LDL < 130 mg/dl y proteína C reactiva > 2 mg/l, que fueron aleatorizados a rosuvastatina 20 mg o placebo. 12 Al demostrar una reducción signifi cativa del punto fi nal primario en pa-cientes sin indicación de estatinas según las guidelines del Adult Treatment Panel (ATP) III, este estudio ge-neró un enorme entusiasmo ya que antes del JUPITER los estudios que demostraron benefi cio con estatinas en prevención primaria se limitaban a una población de alto riesgo incluyendo individuos con diabetes, hi-percolesterolemia, antecedentes familiares de enferme-dad coronaria prematura, enfermedad vascular perifé-rica, o individuos con riesgo global incrementado. 7,13-15 Hasta hace muy poco tiempo, las estatinas eran consi-deradas drogas muy seguras, bien toleradas y de prime-ra línea tanto en prevención secundaria como prima-ria, con mínimos efectos adversos (EA) reversibles (ele-vación de transaminasas, miopatía) y con extrema in-frecuencia severos (rabdomiólisis). De hecho, según los mismos pacientes, generalmente los médicos tratan-tes descartan la posibilidad de atribuir a las estatinas la ocurrencia incluso de los EA más comunes. 16 Al inhibir la HMG-CoA reductasa, las estatinas blo-quean la vía de la síntesis de mevalonato en un estadio temprano. Además de colesterol, esta vía genera un nú-mero de productos biológicamente relevantes como la coenzima Q10 y proteínas isopreniladas. Por otra par-te, el colesterol en sí mismo no sólo es un producto final , sino también un intermediario en la producción de corticosteroides, ácidos biliares y vitamina D, entre otros. 17-19 El estudio JUPITER, lejos de las luminarias, dejó un dato preocupante, un incremento del 27% del ries-go de diabetes incidental con la administración de ro-suvastatina comparada con placebo. Esto condujo a la publicación de un metaanálisis que incluyó 5 estu-dios (PROVE-IT, A to Z, TNT, IDEAL y SEARCH) con 32.752 pacientes, en el cual se confi rmaron los ha-llazgos del JUPITER, con un incremento del riesgo de diabetes del 12% de la terapia intensiva versus el tra-tamiento convencional, con un nuevo caso de diabetes por cada 498 pacientes tratados contra un evento cardiovascular prevenido por cada 155 pacientes trata-dos. 20,21 No debiera llamar la atención entonces el re-ciente comunicado que emitió la Food and Drug Administration (FDA), donde reconoce que el tratamien-to con estatinas puede asociarse a una elevación de los niveles de glucemia y de hemoglobina glicosilada, 22 siendo importante recalcar que todas las guidelines re-comiendan en diabéticos objetivos de LDL < 100, u opcionalmente de < 70 mg/dl. Artículo de Revisión
... They suggest that adverse effects may be more correlated with a certain statin at a specific dose such as simvastatin 80 mg. [42] Similarly, a meta-analysis of 26 randomized controlled trials showed that further LDL-C reduction is associated with a reduction in major adverse CV events and suggested that high-intensity statins are safe to be recommended either as atorvastatin 80 mg or a combination of simvastatin 40 mg with other lipid-lowering medications. [17] There are several medications including ezetimibe, fenofibrate, niacin, and omega-3 fats, which can be used in combination therapy for achieving the further LDL-C reduction and favorable effects on levels of triglycerides and non-HDL-C. ...
Article
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Use of statin therapy in patients with type 2 diabetes mellitus (T2DM) has been recommended by most clinical guidelines. Cardiovascular disease (CVD) is a leading cause of morbidity and mortality among T2DM patients. It has been proved that statins are effective for primary or secondary CVD prophylaxis. Reports have highlighted the underutilization of statins in clinical practice and the suboptimal adherence to guideline recommendations. This review article points to summarize the current evidence confirming the role of statins in T2DM patients and to provide an overview of factors that may affect statins' prescribing patterns and compliance in clinical practice. Initiatives to enhance statin therapy prescribing should recognize the comprehensive nature of the prescribing process. Attempts to assure proper statin prescribing and utilization can help in achieving better clinical outcomes of statin therapy.
... In these trials, cholesterol lowering has been in the order of 20-40%, with a commensurate relative risk reduction in clinical events. Despite their wellestablished benefits and corresponding recommendations from expert bodies, statins are widely underused in the "real world" of clinical practice (Alsheikh et al., 2007;Kane and Lipsky, 2000;Hey-Hadavi et al., 2007). Studies also suggest, that patients" adherence to satins therapy is suboptimal and the persistence among those newly prescribed statins is poor. ...
Article
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Dyslipidemia is a major risk factor for cardiovascular disease, the leading cause of death worldwide. Statins have been shown to significantly reduce morbidity and mortality in patients with coronary artery disease and in patients with hyperlipidemia. However, there is a significant gap between expected and actual benefits; this may be attributed to poor adherence to statin therapy. Literature search was conducted by using Pubmed, Wiley interscience, and EMBASE electronic databases for relevant studies for the meta-analysis. Inclusion criteria in this analysis were randomized controlled trials, retrospective analysis of data from randomized controlled trials, and observational studies. Adherence to statin therapy is suboptimal in both primary and secondary prevention of cardiovascular disease. The aim of this metanalysis was to assess non-adherence rates to statins in patients enrolled in both primary and secondary cardiovascular diseases prevention and to evaluate the impact of statins non-adherence over time on cardiac morbidity and mortality. Causes of non-adherence to statins are shown a discrepancy and include patient factors, practitioner factors and health system factors. Non-adherence is associated with adverse health outcomes and increased costs of health care. Non-adherence to statins is a significant issue for the prevention and treatment of cardiovascular disease. Increased awareness of the causes and solutions for overcoming non-adherence including safer prescribing, improvent in physician-patient alliance and reduction in drug costs, will enhance the cost-effectiveness of the use of statins and significantly improve patient care and outcomes.
... However in Simvastatin group statically significant reductions were found among T.BIL, but statically significant elevation was found among ALP in female and reduction in male and more elevation found in ALP in patients >60 years comparing with other age groups. Review of the literature demonstrated controversial effects of Simvastatin on cholesterol and hepatic function, some studies reported an elevations of liver parameters during Simvastatin therapy [12,[19][20][21][22][23] whereas others studies showed that Simvastatin has no effect on liver parameters [24,25]. Regarding the fluctuation group, in general for all patients there was significant effect on the lipid parameters less than the use of Simvastatin or Fluvastatin separately. ...
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Objective: The study was aimed to evaluate Simvastatin and Fluvastatin effects on patients with hypercholesterolemia. Methods: For 6 months, 141 patients administered Simvastatin (GpA), 100 administered Fluvastatin (GpB) and 100 fluctuated between them (GpC). Post treatment, in GpA, Triglycerides, total Bilirubin (T.BIL), Cholesterol and Low Density Lipoprotein (LDL) were significantly reduced. Alkaline Phosphatase (ALP) and Alanine Aminotransferase (ALT) elevated reduced in females and elevated in males. T.BIL reduced in both males and females. Results: In GpB, Glutamyltransferase elevated and Cholesterol and LDL reduced. Albumin elevated in females and reduced in males and the opposite in Triglycerides. Significant difference between age groups in Albumin, Globulin, and ALT was found. In GpC, Asprtate Aminotransferase (AST) elevated and ALT, Cholesterol, Triglycerides and LDL reduced in all patients. Albumin and ALT elevated in males and reduced in females. Significant difference between age groups in Albumin, T.BIL and AST was found. Conclusions: Fluvastatin or simvastatin had variable effects on lipid parameters in patients with hypercholesterolemia and associated with mild effect on liver. Simvastatin was more effective to reach antihypercholesterolemic goal. Effects were related to gender, age and continuation on the same medication. Patients lab data periodic monitoring during therapy is useful to reach antihypercholesterolemic goal and observe any serious liver parameters elevation.
... As a result, since 2012 the FDA no longer recommends routine monitoring of liver function in patients on statins. Recent recommendations only include baseline transaminase level testing without routine periodic monitoring [7,115,116]. Finally, recent data from a metaanalysis of 27 RCTs which included 175,000 persons, suggested that statins are not associated with an additional cancer risk [117]. ...
Article
Background: Pharmacotherapy is of increasing interest in peripheral arterial disease (PAD), with novel therapies aiming at different factors contributing to the disease. For antiplatelet therapy, there is no unanimous agreement regarding the nature or duration of optimal antiplatelet therapy so as to reduce major adverse cardiovascular and limb-related events (e.g. repeat interventions and amputations). However, evidence on novel more potent antithrombotic agents, drug combinations and personalized antiplatelet therapy for PAD patients is accumulating. Similarly, statins are now considered as a standard of care in PAD patients, due to their multiple actions which include plaque stabilization, antiinflammatory properties and regression of atheroma. Conclusion: This review focuses on current evidence available for various antiplatelet regimens and statin therapy for PAD and discusses future perspectives. We consider randomized controlled trials, together with the most important reviews and meta-analyses. Treatment algorithms based on currently available data.
... For instance, utilization of moderate/ high-intensity statins is a common method for achieving the LDL-C goal. However, increasing the intensity of statins may lead to a high risk of adverse events, which results in low compliance and thus unsatisfactory goal attainment [7][8][9]. Moreover, in China, there is only one category of statin, simvastatin, which happens to be a low-intensity statin, on the National Essential Drugs List [10]. ...
Article
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Background: Hyperlipidemia is a common disease in China. Although 88.9 % of the Chinese population taking lipid-lowering medications has already used a statin, only 61.5 % of the population has reached the goal of low-density lipoprotein cholesterol. Thus, many patients in China seek help from Traditional Chinese Medicine. Yirui capsules are an innovative Chinese Medicine which are designed to improve the blood lipid state in patients with hyperlipidemia. However, there is still a lack of high-quality evidence from clinical trials to support the application. Therefore, we designed a clinical trial to evaluate the safety and efficacy of Yirui capsules for use by patients with hyperlipidemia. Methods/design: This is a multicenter, randomized, double-blinded, placebo-controlled trial. Based on lifestyle modification therapy, eligible patients will randomly be assigned to the Yirui capsule or the placebo group. The primary outcome is the percentage of participants who reach the goal of 30 % low-density lipoprotein cholesterol decline at treatment end-point. The secondary outcomes include the changes from baseline to treatment endpoint in low-density lipoprotein cholesterol, total cholesterol, triglyceride, high-density lipoprotein cholesterol, apolipoprotein A, apolipoprotein B, non-high-density lipoprotein cholesterol, MOS 36-Item Short-Form Health Survey scoring, total and individual item scoring of symptomatic grading and quantifying scale, and body mass index. Discussion: The main ingredients of the Yirui capsule are perilla oil, Folium Ginkgo (Yinxingye), Radix Salviae miltiorrhizae (Danshen), Fructus Crataegi (Shanzha), Rhizoma Alismatis (Zexie), and Radix Notoginseng (Sanqi), which are expected to improve the blood lipid state. This randomized placebo-controlled trial will comprehensively evaluate the effectiveness and safety of Yirui capsules against hyperlipidemia in the hope of providing a new adjunctive Chinese medicine option for clinical practice in dyslipidemia treatment. Trial registration: ChiCTR-IOR-15006496 . Registered on 29 May 2015. Protocol version: WXJ.YRJN-HBT-V1.0 (21 Jan 2015).
... They also found no difference in muscle pain or weakness between participants treated with simvastatin 40 mg OD or placebo for 5 years or in the number who discontinued treatment due to musculoskeletal problems [39]. Adverse reactions increase at higher doses [51]; hence we chose to use 40 mg OD in our present study. The incidence of fatal rhabdomyolysis has been estimated at 0.12% per 1 million prescriptions on the basis of data derived from the US Food and Drug Administration databases and the National Prescription Audit Plus [50]. ...
Article
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Dementia is very common in Down syndrome (trisomy 21) adults. Statins may slow brain amyloid ß (Aß, coded on chromosome 21) deposition and therefore delay Alzheimer disease onset. One prospective cohort study with Down syndrome adults found participants on statins had reduced risk of incident dementia, but there are no randomised controlled trials (RCTs). Evidence is sparse on the best instruments to detect longitudinal cognitive decline in older Down syndrome adults. Methods TOP-Cog was a feasibility/pilot double-blind RCT of 12 months simvastatin 40mg versus placebo for the primary prevention of dementia in Alzheimer disease in Down syndrome adults aged 50 years or older. Group allocation was stratified by age, apolipoprotein E ε4, and cholesterol level. Recruitment was from multiple general community sources over 12 months. Adults with dementia, or simvastatin contraindications, were excluded. Main outcomes were recruitment and retention rates. Cognitive decline was measured with a battery of tests; secondary measures were adaptive behaviour skills, general health, and quality of life. Assessments were conducted pre-randomisation and 12 months post-randomisation. Blood Aβ40/Aβ42 levels were investigated as a putative biomarker. Results were analysed on an intention-to-treat basis. A qualitative sub-study was conducted and analysed using the Framework approach to determine recruitment motivators/barriers, and participation experience. Results We identified 181 (78%) of the likely eligible Down syndrome population, and recruited 21 (11.6%), from an area with a general population size of 3,135,974. Recruitment was highly labour intensive. Thirteen (62%) completed the full year. Results favoured the simvastatin group. The most appropriate cognitive instrument (regarding ease of completion and detecting change over time) was the Memory for Objects test from the Neuropsychological Assessment of Dementia in Intellectual Disabilities battery. Cognitive testing appeared more sensitive than proxy-rated adaptive behaviour, quality of life, or general health scores. Aβ40 changed less for the simvastatin group (not statistically significant). People mostly declined to participate because of not wanting to take medication, and not knowing if they would receive simvastatin or placebo. Participants reported enjoying taking part. Conclusion A full-scale RCT is feasible. It will need 37% UK population coverage to recruit the required 160 participants. Information/education about the importance of RCT participation is needed for this population.
... Although a few studies challenged the relationship of dose and SILI [26], most studies have demonstrated that using a higher dose of statin can easily induce liver injury [23,27,28]. Our study also validated that dose is a risk factor of SILI. ...
Article
Aim: Statin-induced liver injury (SILI) is quite rare, but may be severe. Little is known about the impact of chronic hepatitis B infection (CHBI) on SILI. We aimed to investigate the risk factors and outcome of SILI, with special reference to its interaction with CHBI. Methods: Patients with SILI were recruited from our hospital, and three-to-one drug-matched controls were randomly selected. The clinical data of the patients were then compared. Results: A total of 108 patients with SILI and 324 controls were enrolled. The patients with SILI were both older and had a higher statin dose than the controls. There was no predilection of liver injury associated with the 7 available statins. Among the SILI patients, there was no statistical difference between the baseline and peak liver enzyme tests, and latency and severity between hepatitis B carriers (n = 16) and non-carriers (n = 92). High dose of statin and age were the 2 independent risk factors of SILI (OR and 95% CI: 1.93, 1.08-3.35, P = 0.025, and 1.73, 1.07-2.80, P = 0.027, respectively). Permanent discontinuation of statin was noted in 50 (46.3%) patients with SILI due to severe SILI or recurrent hepatotoxicity after re-challenge of other statins. Conclusion: High dose of statin and old age may increase patient susceptibility to SILI; however, CHBI and abnormal baseline liver tests are not risk factors of SILI. Nonetheless, SILI is still worthy of notice, because nearly half of the overt cases discontinued statin treatment due to severe hepatotoxicity in this study.
... Statins have been used for decades in the primary and secondary prevention of CVD among children and adults, males and females, diabetics and nondiabetics , who are at moderate to high risk of CVD [2] . Statins are known to have a good safety record but are associated with side effects, the most common of which are related to muscle [3],[4],[5],[6],[7] . The ubiquity of statin usage has focused attention on their side effects because, although relative rates of adverse events are low, the absolute numbers affected are high. ...
Article
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Statin therapy has demonstrated remarkable efficacy in reducing mortalities associated with cardiovascular diseases through preventing myocardial infarction and ischaemic stroke. Despite the proven benefits of statins in this context, there are growing concerns among patients and physicians on the safety of short-term and long-term use and their adverse effects, especially muscle toxicity, resulting in non-adherence and withdrawal of the treatment. Reports and publications on a variety of statin-associated side effects, with major focus on myopathy as the most commonly reported side effect, were reviewed. The incidence, diagnosis, prevention and management of statin-induced adverse effects are outlined in this updated review to highlight the importance of statin use in high-risk populations, and to reduce the rate of under-prescription and withdrawal of the treatment. Key points: Side effects of statins, including muscle aches, diabetes and liver function test abnormalities, are increasingly recognised. Statin-related muscle side effects have recently been systematically classified. Rare autoimmune phenomena related to statin therapy, including necrotising myopathy, interstitial lung disease and lupus-like reactions, are now recognised. Statins increase the risk of transition to diabetes in susceptible individuals with the metabolic syndrome. There is little systematic evidence to link cognitive impairment with statin therapy.
... Статины (ингибиторы ГМГ-КоА редуктазы) являются основой современной терапии нарушений липидного обмена и показаны большинству больных с высоким риском сердечно-сосудистых осложнений [1]. Многолетний клинический опыт применения статинов убедительно доказал, что длительная терапия статинами в целом достаточно безопасна [2][3][4][5][6]. ...
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Aim. To evaluate the differences between a group of patients treated with ursodeoxycholic acid (UDCA) during the study period and a group of patients not treated with UDCA by pseudo-randomization using Propensity Score Matching.Material and methods. 262 patients aged 60.1±8.9 years, taking statins for the secondary prevention of cardiovascular complications were included into a 6-month observational cohort study. The UDCA intake was recommended to all the patients due to the presence of liver and/or bile duct diseases. One part of the patients strictly followed medical recommendations and used UDCA, while the other part of the patients wasn’t taking UDCA. This allowed comparing the effect of UDCA in these groups.Results. Propensity Score Matching method allowed forming two groups of patients of 52 people each with similar main clinical and demographic characteristics. A more significant decrease in the levels of total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) (up to 4.0 mmol/L and 1.92 mmol/L, respectively; p<0.001) after 6 months was found in patients treated with lipid-lowering therapy in combination with UDCA as compared with patients without UDCA (up to 4.52 mmol/L and 2.6 mmol/L, respectively; p<0.05). No ALT, AST, CPK, LDH activity deterioration and no bilirubin serum level increase was found. Due to statin treatment the target levels of LDL-C by the end of the study were achieved in 31% of the patients of UDCA-group. Target levels of LDL-C were not achieved in any of the patients of the group without UDCA (p<0.001). There was demonstrated a high adherence to UDCA therapy.Conclusion. Combined therapy with statins and UDCA is effective and safe in patients with high cardiovascular risk and concomitant liver disease. Co-administration of statins with UDCA is promising in the treatment of hyperlipidemia in patients with low tolerance to statins. However, additional controlled studies are required.
... Современные клинические рекомендации предлагают использовать все более и более интенсивную терапию этими препаратами, для чего статины требуется назначать в достаточно больших дозах [1,2].Последнее обстоятельство в известной мере повышает риск появления побочных эффектов. Статины в целом являются безопасными препаратами, однако иногда они способны давать побочные эффекты со стороны мышц и со стороны печени [3][4][5]. Послед-ние, как было неоднократно доказано в исследованиях, как правило, бывают незначительными по выраженности и обратимыми [6][7][8]. Тем не менее практические врачи нередко преувеличивают потенциальную опасность применения статинов в отношении печени, т.е. ...
Article
Aim. To study the opinion of doctors about the possibility of statins prescription to patients with cardiovascular diseases and concomitant chronic liver diseases.Material and methods. Сross-sectional questioning of the random sample of physicians was performed. Results. 70 physicians (internists - 61.4%, cardiologists - 20.0%, neurologists - 5.7%, endocrinologists - 4.3%, and others) were interviewed. Work experience in the specialty of doctors was 25 years (14; 32.5). 22.9% of doctors completely exclude the possibility of statins prescription to patients with cardiovascular disease if they have concomitant liver disease. 70% of physicians consider it possible to use statin therapy in patients with liver disease, but only under certain conditions. Only a third of them, mostly internists, are ready to prescribe statins under condition of acceptable initial transaminase changes, and almost half of these doctors consider it possible to use statin therapy in patients with concomitant liver diseases only when serum transaminase levels are normal.Conclusion. The physicians often and sometimes unreasonably find it impossible to use statin in patients with cardiovascular diseases and concomitant chronic liver diseases.
... It is mostly considered that the analysis could not reveal the unhelpfulness of ezetimibe in non-diabetic patients. However, some studies suggest that regular doses are sufficient in most cases [19,20], while others suggest that high-dose statin medication increases the risk of de novo diabetes [21] and the risk of elevated liver enzymes, rhabdomyolysis, and cancer [22]. Therefore, in order to assist ACS patients in coping with future major cardiovascular disease treatment, this study aims to examine the rehospitalization risk due to ACS or stroke for diabetic and non-diabetic patients after recovering from ACS. ...
Article
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Background: The purpose of this study is to investigate whether the risks of rehospitalization caused by acute coronary syndrome (ACS) or stroke would have significant differences between diabetic and non-diabetic patients from ACS. Methods: This was a retrospective study of 364 inpatients with ACS from 2017 to 2019. Logistic regression models included gender, age group, and the principal diagnosis of hospitalization as controlling variables which were used to analyze the dataset. Results: About 10% of patients are hospitalized after recovery. Moreover, regardless of suffering from diabetes, the risk of rehospitalization does not appear to show a significant difference. In comparison with non-diabetic patients, the odds ratio of rehospitalization of diabetic patients was 0.94 (95% CI: 0.46-1.93, p-value = 0.8639) after controlling for the effects of gender, age group, and the principal diagnosis of hospitalization. Conclusions: Diabetic patients seem to perform well in controlling LDL-C (low-density lipoprotein cholesterol) after ACS recoveries.
... Ticagrelor and statins are often co-prescribed, especially among post-myocardial infarction patient population, and both drugs are metabolized by the same cytochrome P450 (CYP) 3A4. Ticagrelor acts as a competing substrate for the enzyme and delays the metabolism of statins leading to its accumulation [11]. In addition, due to the same competing metabolism in the liver, some of the hydrophilic statins are retained during acute kidney insufficiency. ...
Article
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Ever since evidence about the increased risk of stent thrombosis with drug eluting stents (DES) surfaced in 2005, the Food and Drug Administration (FDA) has recommended the use of dual antiplatelet therapy (aspirin with P2Y12 inhibitor) following DES placement. The PLATO trial demonstrated lower mortality rates with the use of Ticagrelor when compared to clopidogrel (9.8% vs. 11.7%, p<0.001) when treating patients with acute coronary syndrome. Given their pleiotropic benefits, statins are today the second most prescribed drug in the United States and often co-prescribed with Ticagrelor. FDA's post market surveillance of Ticagrelor use along with statins in post-myocardial infarction care is now revealing novel and serious adverse events. We present two cases of rhabdomyolysis and acute renal failure (ARF) which develop while the patients were on statins and Ticagrelor. Case 1: A 66-year-old female presented with bilateral thigh pain for 3 days. One month prior to presentation, she was managed for non-ST segment elevation myocardial infarction (NSTEMI) and had been started on aspirin, ticagrelor and simvastatin. Laboratory values revealed creatinine kinase (CK) level at 40,000 U/L and creatinine 3.2 mg/dL suggesting rhabdomyolysis and ARF. Case 2: A 63-year-old male presented with generalized body aches and fatigue for 4 days. He had sustained STEMI two months before and received two drug eluting stents (DES) and aspirin, ticagrelor and rosuvastatin had been initiated. CK was 380,000 U/L and creatinine 7.94 mg/dL suggesting rhabdomyolysis and ARF. Both patients presented with rhabdomyolysis and acute renal failure within weeks after ticagrelor and statin were commenced. A review of the literature indicated that 11 similar cases of ticagrelor-induced ARF and rhabdomyolysis had been reported. Ticagrelor competes with statins when metabolized by cytochrome P450 (CYP) 3A4 leading to statin retention, leading to major adverse effects like rhabdomyolysis and acute renal failure. Our review is intended to alert clinicians about this important drug interaction.
... Genetic polymorphism associated with statin-induced myopathy in Chinese coronary artery disease patients (Liu et al., 2017). Several studies have demonstrated that using a higher dose of statin can easily induce liver injury (Alsheikh-Ali et al., 2007;Kasliwal et al., 2007;Chen et al., 2014;Naiqiong et al., 2017;Bandyopadhyay et al., 2018). ...
Article
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Background: Several studies have demonstrated that using a higher dose of statin can easily induce liver injury and myopathy. Low-density lipoprotein cholesterol (LDL-C) is a well-established modifiable risk factor for cardiovascular disease; however, the large majority of Chinese patients cannot meet the target level of LDL-C recommended by the Chinese expert consensus. Evolocumab has been demonstrated to reduce LDL-C by approximately 60% in many studies. Nevertheless, whether combined evolocumab and moderate-intensity statin is as effective in lowering LDL-C and decreasing incidence of MACE in Chinese patients presenting with the acute phase of acute coronary syndrome (ACS) remains unknown. Therefore, the “Evolocumab added to Moderate-Intensity Statin therapy on LDL-C lowering and cardiovascular adverse events in patients with Acute Coronary Syndrome” (EMSIACS) is conducted. Methods: The EMSIACS is a prospective, randomized, open-label, parallel-group, multicenter study involving analyzing the feasibility and efficacy of evolocumab added to moderate-intensity statin therapy on lowering LDL-C levels in adult Chinese patients hospitalized for acute phase ACS. The sample size calculation is based on the primary outcome, and 500 patients will be planned to recruit. Patients are randomized in evolocumab arm (evolocumab 140mg every 2weeks plus rosuvastatin 10mg/day or atorvastatin 20mg/day) and statin-only arm (rosuvastatin 10mg/day or atorvastatin 20mg/day). The primary outcome is the percentage change in LDL-C in weeks 4 and week 12 after treatment. The secondary outcome is the occurrence of MACE after 12weeks and 1year of treatment. Discussion: If the EMSIACS trial endpoints prove statistically significant, the evolocumab added to moderate-intensity statin therapy will have the potential to effectively lower subjects’ LDL-C levels, especially for the Chinese patients with acute phase ACS. However, if the risk of MACE is not significantly different between the two groups, we may extend follow-up time for secondary outcome when the clinical trial is over. Clinical trial registration : The study is registered to ClinicalTrials.gov (NCT04100434), which retrospectively registered on November 24, 2020.
... Following these guidelines, many patients with dyslipidemia are treated with statins, and positive outcomes have been reported due to drug use. In patients with CVD risk factors, statins decrease the risk and improve the survival rate [13], and serum cholesterol levels in patients taking statins are inversely correlated with cancer risk [14]. At sufficiently high doses, statin use is associated with a reduced incidence of cancer [15] and a reduced rate of cancer-related mortality compared to non-statin users [16]. ...
Article
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Background: In aging populations, the number of people with high cholesterol levels is increasing. Appropriate management of high cholesterol levels with drugs such as statins may prevent secondary diseases. Despite many studies on the effects of statins on various types of cancer, the effectiveness of lipid-lowering therapy in preventing cancer remains controversial. This study aimed to evaluate its long-term effect on developing gastrointestinal (GI) cancer in patients with dyslipidemia. Methods: This study used the National Health Insurance Sampling (NHIS) cohort data (2002-2015), which included patients with dyslipidemia without diabetes, and measured patients' adherence to lipid-lowering therapy using the medication possession ratio. We used the Cox proportional hazard ratio (HR) to identify the association between the continuity of lipid-lowering therapy and the risk of GI cancer. We also evaluated the association between a combination of lipid-lowering drugs and a reduced risk of GI cancer. Results: A total of 49,351 patients were diagnosed with dyslipidemia, of which 579 were diagnosed with GI cancer. Patients with higher adherence to lipid-lowering therapy had a significantly reduced risk of GI cancer compared to patients without drugs, and high adherence was associated with a reduced incidence of all types of GI cancer. Specifically, the combination of statins and ezetimibe or fibrates appears to reduce GI cancer risk effectively. Overall, the continuity of lipid-lowering therapy had a protective effect on GI cancer in middle-aged and elderly patients with dyslipidemia compared to non-users. Conclusions: Our findings suggest that the continuity of lipid-lowering therapy is vital in patients with dyslipidemia. In addition, for individuals vulnerable to GI cancer, combination therapy may be associated with more effective protection against GI cancer. Healthcare providers need patient education and monitoring to improve drug adherence in patients with dyslipidemia.
... We also found that the lowest TC and LDL-C levels were associated with higher mortality in all the age groups. Cholesterol is important for many body functions including brain metabolism and intracellular transport, and very low cholesterol could increase the susceptibility to cancer, hemorrhagic stroke, or fatal diseases with infectious origins, such as respiratory and gastrointestinal diseases [25][26][27] . ...
Article
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Midlife lipid levels are important predictors of cardiovascular diseases, yet their association with mortality in older adults is less clear. We aimed to (1) identify lipid profiles based on cholesterol, triglycerides, and apolipoproteins using cluster analysis, and (2) investigate how lipid profiles and lipid levels at different ages are associated with later-life all-cause and cardiovascular mortality. We used data from 98,270 individuals in the Swedish AMORIS cohort who had blood measurements between 1985–1996 and were followed until 2012. Over the follow-up (mean 18.0 years), 30,730 (31.3%) individuals died. Three lipid profiles were identified. Compared with reference profile, a high lipid profile (low ApoA-I and high total cholesterol (TC), triglycerides, ApoB, and ApoB/ApoA-I ratio) at ages 39–59 or 60–79 was associated with higher all-cause mortality. A high lipid profile at ≥ 80 years, however, did not confer higher mortality. For the specific markers, high TC (≥ 7.25 mmol/L) was associated with higher all-cause mortality in ages 39–59 but lower mortality in ages 60–79 and ≥ 80. Low ApoA-I (< 1.28 g/L) and high ApoB/ApoA-I ratio (≥ 1.18), on the other hand, were associated with higher cardiovascular mortality regardless of age at lipid measurement, highlighting their potential relevance for survival in both young and older individuals.
... Statins have pleiotropic effects, including reducing vascular inflammation, decreasing smooth muscle proliferation, and immunomodulation [13][14][15]. In addition, using statins to achieve healthy serum cholesterol levels protects against cancer risk [16], reduces cancerrelated mortality, and increases survival rates for colorectal and pancreatic cancer [17][18][19]. ...
Article
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Background: Statins play a role in lowering serum cholesterol and are known to have pleiotropic effects in a variety of diseases, including cancer. Despite the beneficial effects of statins in dyslipidemia patients, the treatment rate for dyslipidemia in Korea remains low, and evidence supporting the continued use of statins is lacking. The purpose of this study was to evaluate the effect of continued statin use and dosage on patient mortality after diagnosis of dyslipidemia and gastrointestinal (GI) cancer. Methods: We used data from the National Health Insurance Sampling (NHIS) cohort to evaluate patients diagnosed with dyslipidemia from 2002 to 2015. A total of 901 GI cancer patients with dyslipidemia and 62,727 non-cancer dyslipidemia patients were included in the study. During the study period, each patient's medication possession ratio (MPR) after diagnosis was evaluated as a measure of continued statin use. Statin dosage was measured based on a defined daily dose (DDD). Finally, we used Cox-proportional hazard ratios to identify associations between the continual use of statins and mortality in patients with dyslipidemia and GI cancer. Results: In our study, mortality decreased with increasing MPR and reached significance in MPRs exceeding 50% for GI cancer patients and 75% for dyslipidemia patients compared to patients that did not use statins. Moreover, patients with high MPRs had significantly reduced 5-year mortality compared to non-users, and cause-specific mortality analyses revealed that high MPR was associated with decreased colorectal cancer death. We did not find a significant dose-response relationship between statins and mortality. Conclusion: Our findings suggest that continued statin use after diagnosis is associated with reduced patient mortality. Altogether, these results support the continued use of statins in dyslipidemia patients with and without GI cancer and highlight the importance of patient education by healthcare providers.
... Besides, a key finding of our study regarding cancer suggested that low cholesterol could be linked to high rates of cancer-associated deaths. Although a few studies of statins indicated that statin therapy increases cancer incidence [30][31][32], it was still challenging to elucidate the connection between low cholesterol and cancer disease mortality. Previous studies on liver cancer reported an increased level of cholesterol [33,34]. ...
Article
Full-text available
Background: The link between total cholesterol (TC) and all-cause and specific mortality has not been elucidated. Herein, we aimed to evaluate the effect of TC levels on all-cause, cardiovascular disease (CVD), and cancer mortality. Methods: All data analyzed were obtained from the National Health and Nutrition Examination Survey 1999-2014. The relationship between levels of TC and mortality was determined through Cox proportional hazard regression analysis coupled with multivariable adjustments. Two-piecewise linear regression models and Cox models with penalized splines were applied to explore nonlinear and irregular shape relationships. Kaplan-Meier survival curve and subgroup analyses were conducted. Results: The sample studied comprised 14,662 men and 16,025 women, categorized as 25,429 adults aged 18-65 and 5,258 adults over 65 years old. A total of 2,570 deaths were recorded. All-cause, cardiovascular, and cancer mortality showed U-curve associations after adjusting for confounding variables in the restricted cubic spline analysis. Hazard ratios (HRs) of all-cause and cancer mortality were particularly negatively related to TC levels in the lower range < 200 mg/dL, especially in the range < 120 mg/dL (HR 1.97; 95% CI 1.38, 2.83, HR 2.39; 95% CI 1.21, 4.71, respectively). However, the HRs of cardiovascular disease mortality in the range < 120 mg/dL were the lowest (HR 0.60; 95% CI 0.15, 2.42). In the upper range, a TC range of ≥ 280 mg/dL was correlated with mortality as a result of CVD and cancer (HR 1.31; 95% CI 0.87, 1.97 and HR 1.22; 95% CI 0.82, 1.79). The lowest cumulative survival rate of all-cause mortality was recorded in the lowest TC-level group, while the lowest cumulative survival rate of CVD mortality was recorded in the highest TC-level group. Conclusions: A nonlinear association of TC level with all-cause, cancer, and CVD mortality in the American population was observed, suggesting that too low or too high serum total cholesterol levels might correlate with adverse outcomes.
... Statins are 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitors administered as therapy for lipid disturbances. 1,2,3 They control high lipid levels and lower low-density lipoprotein (LDL) as well as cholesterol. 2 Although they are considered first-line therapy, they cause various adverse effects. ...
... What's more, liver abnormalities caused by statins are rare, dose-related, and mild, and it is possible to return to baseline levels after 2-4 weeks. Finally, in most of the liver disease, statins should be not only used but also recommended, as they significantly reduce the risk of CVD events, mortality, and even primary liver cancer (the only contraindication are acute liver diseases) [31,32]. ...
Chapter
Statins reduce circulating concentrations of low-density lipoprotein cholesterol (LDL-C) and thereby are effective at reducing cardiovascular (CV) events and mortality in primary and secondary prevention. As with all drugs, statins cause adverse effects in some patients. Statin intolerance occurs when adverse effects limit the maximum dose of statin (partial statin intolerance) or cause patients to cease statin therapy (complete statin intolerance). Statin intolerance is associated with poor clinical outcomes; however, many patients (even 90–95%) who initially report intolerance can tolerate some degree of statin therapy. In order that all patients receive optimal lipid-lowering therapy, it is essential that the relatively small number of patients with true intolerance is differentiated from those with symptoms misattributed to statin therapy (the drucebo effect). This chapter provides an overview of the diagnosis of statin intolerance and provides management advice aimed at achieving optimal lipid-lowering in these patients. Approaches such as dose reduction, alternate-day dosing, and add-on drugs and nutraceuticals can be effective in reaching this aim.
... Besides, a key nding in cancer of our study suggested that low cholesterol could be linked to high cancer-associated deaths. Although a few studies of statins indicated that statin therapy increases cancer incidence [28][29][30], it was still challenging to elucidate the connection between low cholesterol and cancer disease mortality. Previous studies on liver cancer reported an increased level of cholesterol [31,32]. ...
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Background: The link between total cholesterol (TC) and all-cause and specific mortality has not been elucidated. Herein, we aimed to evaluate the effect of TC levels on all-cause, cardiovascular disease (CVD), and cancer mortality. Methods: All data analyzed were obtained from the National Health and Nutrition Examination Survey 1999-2014. The relationship between levels of TC and mortality was determined through Cox proportional hazard regression analysis coupled with multivariable adjustments. Two-piecewise linear regression model and Cox models with penalized splines were applied to explore non-linear and irregular shape relationships. Kaplan-Meier survival curve and subgroup analyses were conducted. Results: The sample studied comprised 17853 men and 18922 women, categorized as 27927 adults aged 18–65 years and 8848 adults more than 65 years old. A total of 4441 deaths were recorded. All-cause, cardiovascular, and cancer mortality showed U-curve associations with nadir at 213 mg/dL, 200 mg/dL, and 218mg/dL after adjusting for confounding variables in the restricted cubic spline analysis. HRs of all-cause, CVD, and cancer mortality was particularly negatively related to TC levels in the lower range <200 mg/dL, especially in the range <120 mg/dL (HR 1.95; 95% CI 1.59, 2.38, HR 1.78; 95% CI 1.16, 2.72, HR 2.18; 95% CI 1.46, 3.25, respectively). The lowest cumulative survival rate was recorded in the lowest TC level group. Conclusions: A U-curve association of TC level with all-cause, cancer, and CVD mortality in the American population was observed, suggesting that too low or too high serum total cholesterol levels might correlate with adverse outcomes.
... Povišanje vrednosti transaminaz se pojavi pri približno 3 % bolnikov, navadno v prvem letu od uvedbe terapije, in spontano izzveni kljub nadaljevanju jemanja statinov (53)(54)(55). Hepatotoksičnost je najverjetneje značilnost vseh statinov in je povezana s povečevanjem njihovega odmerka (56,57). ...
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Zdravila iz skupine statinov so v zadnjih več kot 20 letih ena najpogosteje predpisovanih zdravil. Poleg znižanja koncentracije holesterola LDL namreč zelo pomembno znižajo srčnožilno obolevnost in umrljivost. Statini kompetitivno zavirajo aktivno mesto reduktaze HMG-CoA prvega in ključnega hitrost omejujočega encima v mevalonatni poti. Ta mehanizem je poleg zmanjšanja vrednosti holesterola LDL najverjetneje odgovoren tudi za večino stranskih učinkov, čeprav za to ni zanesljivih dokazov. Najpogostejši stranski učinki, ki so tudi vzrok za prekinitev zdravljenja, so povezani z mišičnimi bolečinami, čeprav natančne razširjenosti ne poznamo, saj ni enotne definicije teh stranskih učinkov. Drugi stranski učinki so še novo nastala sladkorna bolezen tipa 2, hepatotoksičnost, hemoragična možganska kap in nevrološke motnje. Vsem tem stranskim učinkom navkljub je korist zdravljenja s statini mnogo večja od navedenih stranskih učinkov. Kljub novim terapijam za znižanje holesterola LDL in zato zmanjšani srčnožilni umrljivosti bo terapija s statini še naslednjih nekaj let ostala prva izbira tako pri primarni kot tudi sekundarni preventivi, saj še ni dovolj podatkov o dolgoročni učinkovitosti in predvsem varnosti novih zdravil. Nikakor pa ne smemo zanemariti niti ekonomskega vidika, saj je stroškovna učinkovitost statinov v primerjavi z novimi zdravili zaenkrat še mnogo večja.
... The risk of statin-associated elevation of liver enzymes, or rhabdomyolysis, was not related to the magnitude of LDL-C reduction 25 . The asymptomatic elevation in transaminases, after taking statins and generally occurring in the first months of treatment, were reversible and they returned to normal on stopping statin treatment, with dose reduction, or even spontaneously with continuation of the same statin dosage 26 . ...
... Use of antibiotics is indeed a risk factor to develop cancer (Boursi et al., 2015;Petrelli et al., 2019) and cholesterol lowering drugs have been proven to be carcinogenic in mice (Newman and Hulley, 1996). A study combining several clinical trials of cholesterol lowering drugs found a signiŁcant association between the magnitude of the cholesterol lowering eŀect and cancer risk (Alsheikh-Ali et al., 2007). ...
Book
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Modern nutrition is all about calories, fats, proteins, and carbohydrates. What our DNA? To make DNA we need the amino acids aspartate, glutamine and glycine. That is covered by the recommended daily intake of protein. But we need one more ingredient: Formate. What is formate? Where it comes from? What if my formate intake is low? What if I eat too much formate? This book provides the answer to these questions.
Chapter
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death and disability in adults age 75 and older. Lipid levels may be reduced by means of diet modifications and increased physical exercise. Although statin therapy reduces LDL‐C levels irrespective of age, evidence supporting the reduction of ASCVD events by statin therapy in adults age 75 and older is limited. Lipoprotein metabolism is affected by the ageing process. Evidence from randomized controlled trials (RCTs) supporting the benefit of statin therapy for the primary and secondary prevention of fatal and non‐fatal ASCVD events in adults younger than 75 is substantial and consistent. The clinical signs of dyslipidaemia are poor or misleading in older subjects. The pharmacological treatment of dyslipidaemia in elderly patients requires a careful evaluation of the risk‐benefit ratio and a personalized approach.
Chapter
Adhering to a healthy dietary pattern—specifically the modernized Mediterranean diet—may be critical to reduce breast cancer (BC) risk in high-risk women and in women who wish to decrease their BC risk. In the context of the Mediterranean diet, it is important to increase plant and marine n-3 and decrease plant and animal n-6. High flavonoid intake—which increases n-3—should be encouraged as it is associated with lower BC risk. To reduce insulin resistance and diabetes—which are associated with an increased BC risk—women should increase fiber consumption and favor low-GI foods. Women should choose organic foods because of their effect on the n-3/n-6 ratio and because they contain fewer contaminants—and lower levels of each contaminant—in particular endocrine disruptors. Finally, any drug thought to increase diabetes and/or BC risk—in particular, the statins and certain antihypertensive medications—should be prohibited. To lower blood pressure or to decrease the risk of cardiovascular disease, physicians do have lifestyle strategies, and it would be tragically unwise to persist in prescribing anticholesterol statins and antihypertensive drugs in women wishing to decrease their BC risk.
Article
Statins are one of the most widely used drugs worldwide as first-line drugs for the treatment of hyperlipidemia and the prevention and treatment of cardiovascular diseases. Most of the side effects of statins are known to be mild, and mainly hepatotoxicity and various muscle symptoms are known. Recently, there have been studies on concerns about an increase in the incidence of diabetes after using statins, but it was found that the benefits sufficiently outweigh the risk of side effects. Therefore, the use of statins in the appropriate group should be actively performed, and it seems that the side effects can be prevented through close physical observation and appropriate examination.
Article
Background There is uncertainty regarding the impact of statins on the risk of atherosclerotic cardiovascular disease (ASCVD) and its major complication, acute heart failure (AHF). Objectives The aim of this study was to investigate whether previous statin therapy translates into lower AHF events and improved survival from AHF among patients presenting with an acute coronary syndrome (ACS) as a first manifestation of ASCVD. Methods Data were drawn from the International Survey of Acute Coronary Syndromes Archives. The study participants consisted of 14,542 Caucasian patients presenting with ACS without previous ASCVD events. Statin users before the index event were compared with nonusers by using inverse probability weighting models. Estimates were compared by test of interaction on the log scale. Main outcome measures were the incidence of AHF according to Killip class and the rate of 30-day all-cause mortality in patients presenting with AHF. Results Previous statin therapy was associated with a significantly decreased rate of AHF on admission (4.3% absolute risk reduction; risk ratio [RR]: 0.72; 95% CI: 0.62-0.83) regardless of younger (40-75 years) or older age (interaction P = 0.27) and sex (interaction P = 0.22). Moreover, previous statin therapy predicted a lower risk of 30-day mortality in the subset of patients presenting with AHF on admission (5.2 % absolute risk reduction; RR: 0.71; 95% CI: 0.50-0.99). Conclusions Among adults presenting with ACS as a first manifestation of ASCVD, previous statin therapy is associated with a reduced risk of AHF and improved survival from AHF. (International Survey of Acute Coronary Syndromes [ISACS] Archives; NCT04008173)
Article
The hydroxymethyglutaryl-coenzyme A reductase inhibitors (statins) are a commonly prescribed class of medication for the treatment of hyperlipidemia and coronary artery disease. This class of medication has several proven benefits, including reduction of mortality related to coronary artery disease. A major consideration when prescribing these drugs are the potential for adverse effects, mainly myalgias, myopathy, and hepatotoxicity. In this article, we summarize current data on statin-associated hepatotoxicity and highlight that the risk of clinically significant idiosyncratic drug-induced liver injury is actually quite small. We also review preclinical data suggesting potential hepatoprotective effects of statin therapy.
Article
The atherosclerotic cardiovascular disease (ASCVD) represents the leading cause of death and disability in the elderly. The study of atherosclerosis and the strategies to control ASCVD are evolving. All strategies emphasize the need to lower LDL cholesterol (LDL-C) through an appropriate lifestyle and the use of lipid-lowering drugs, mainly statins. Available evidence coming from clinical trials is useful to inform clinical choices but the older people are poorly represented in those trials. Thus evidence supporting the benefit of statin therapy for primary and secondary prevention of fatal and nonfatal ASCVD events in adults aged 75 years and older are limited. The pharmacological therapy of dyslipidemia is recommended by guidelines provided by international expert panels in adults, while in the elderly it is still a matter of debate. Statins are generally well tolerated drugs but their use in the elderly, especially in fragile ones or with multi-pathology that take many other drugs, requires a careful evaluation of the risk-benefit ratio and a shared decision-making process between doctor and patient.
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Non-alcoholic fatty liver disease (NAFLD) is the primary cause of chronic liver disease. The range is extensive, including hepatocellular carcinoma, cirrhosis, fibrosis, fatty liver, and non-alcoholic steatohepatitis (NASH). NASH is a condition related to obesity, overweight, metabolic syndrome, diabetes, and dyslipidemia. It is a dynamic condition that can regress to isolated steatosis or progress to fibrosis and cirrhosis. Statins exert anti-inflammatory, proapoptotic, and antifibrotic effects. It has been proposed that these drugs could have a relevant role in NASH. In this review, we provide an overview of current evidence, from mechanisms of statins involved in the modulation of NASH to human trials about the use of statins to treat or attenuate NASH.
Article
Atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality in the world despite advances in both interventional cardiology strategies and comprehensive approach to cardiovascular risk factors. Statins constitute the drugs of choice for the management of cardiovascular risk and most dyslipidemias. There is robust evidence about the reduction of major cardiovascular events, whose benefit is dose dependent. In this way a large number of people have an indication of statins, but a percentage close to 20% report to be intolerant. Nevertheless only 5% of the patients treated with statins, are real intolerant. Clinicians should confirm that the adverse effects are really associated with these drugs, to avoid losing the benefit before discontinuation.
Chapter
In the United States, 790,000 people sustain a myocardial infarction annually or one every 40 s (Mozaffarian et al. Circulation 131:e29–322, 2015). Of these, 114,000 will be fatal. Atherosclerosis is a complex, multifactorial disease. Over the course of the past five decades, numerous prospective observational cohort studies have established beyond any doubt that risk for atherosclerotic disease is driven by a number of risk factors, which include dyslipidemia, hypertension, insulin resistance and diabetes mellitus, obesity, cigarette smoking, and age (Stamler et al. JAMA 256:2823–2828, 1986; Castelli Can J Cardiol 4:5A–10A, 1988; Assmann et al. Eur Heart J 19:A2–11, 1998; Goldbourt et al. Br Med J Clin Res Ed 290:1239–1243, 1985; Verschuren et al. JAMA 274:131–136, 1995). The greater the burden of risk factors, the higher the likelihood for developing such manifestations of atherosclerosis as coronary artery disease (CAD), carotid artery disease, and peripheral arterial disease. Atherosclerotic disease is unequivocally associated with increased risk for myocardial infarction, stroke, renal artery disease and renal insufficiency, claudication and lower extremity amputation, and death. Progressive accumulation of lipid in arterial walls resulting in luminal obstruction is a cardinal structural manifestation of atherosclerotic disease. Arresting this process of lipid infiltration and retention is an important goal in modern cardiovascular medicine. Dyslipidemia is highly prevalent in the United States (Toth et al. J Clin Lipidol 6:325–330, 2012). Even when patients are treated, they tend to be undertreated leaving them with significant residual risk for developing atherosclerotic disease and sustaining both primary and secondary acute cardiovascular events (Toth Resid Staff Physician 53:s1–s7, 2007; Punekar et al. Clin Cardiol 38: 483–491, 2015; Punekar et al. Curr Med Res Opin 33:869–876, 2017).
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.
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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
A promising strategy for treatment of EGFR-dependent tumours is EGFR signal transduction suppression via inhibition of HMG-CoA reductase using high doses of statins, popular cholesterol-lowering drugs. The main purpose of this study was to obtain targeted long circulating immunoliposomes containing simvastatin (tLCLS) with anti-EGFR antibody attached to their surface and to test whether they can be effective in treatment of TNBC. The designed tLCLS were characterized in terms of physicochemical properties and long-term stability. In vitro experiments conducted on MDA-MB-231 cells demonstrated that tLCLS induced apoptosis and are characterized by IC50 of 7.5 µM. Treatment of studied cells with tLCLS led to a decrease in membrane order and inhibited PI3K/Akt signalling. Analyses of efficacy of the tLCLS in in vivo experiments in model animals indicate that immunoliposomes were effectively delivered to tumours. Our results showed that regardless of whether tLCLS were administered before or after tumour formation, at the tested dose they inhibited tumour growth by an average of 25% in comparison to the control. However, the results were not statistically significant. The experiments described above allowed us to test the possibility of using immunoliposomes as simvastatin carriers delivering increased amounts of the drug to tumour cells.
Article
Statins beside their main effect on reducing the progression of cardiovascular disease through pharmacological inhibition of the endogenous cholesterol synthesis, have additional pleiotropic effects including antiinflammatory effects mediated through the induction of suppressor regulatory T cells (Tregs). Statin-induced expansion of Tregs reduces chronic inflammation and may have beneficial effects in autoimmune diseases. However, statins could represent a double-edged sword in immunomodulation. Drugs that act by increasing the concentration of Tregs could enhance the risk of cancers, particularly in the elderly and may have adverse effects in neurodegenerative disorders and infectious diseases. In the present paper, we review the experimental studies that evaluate the effects of statins on Treg cells in autoimmune and inflammatory diseases and we discuss potential therapeutic applications of statins in this setting.
Chapter
Statins are an important class of drugs to treat dyslipidemia and have a lot of pleiotropic effects that aid in improving vascular flow, reducing inflammation by decreasing the production of reactive oxygen species (ROS), decreasing the risk of dementia, and improving cognitive functions too. Their extensive utilization on the global scale has made them the most prescribed drugs for preventing coronary heart diseases (CHD). They inhibit the rate-limiting enzyme, β-hydroxy-β-methylglutaryl-CoA reductase (HMGR) of mevalonate pathway that plays an important role in multiple cellular processes by forming various sterol isoprenoids. Further, statins were reported to inhibit the prevalence of Alzheimer’s disease (AD) by inhibiting α- and β-secretases. Therefore, this chapter highlights the recent insights about the probable role of statins in reversing or limiting the cognitive decline in dementia and the possible mechanisms related to this.
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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
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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
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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.
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To examine the relation between low serum total cholesterol concentrations and causes of mortality. Cohort study of men followed up for an average of 14.8 years (range 13.5-16.0 years). One general practice in each of 24 British towns. 7735 men aged 40-59 at screening selected at random from the 24 general practices. Deaths from all causes, cardiovascular causes, cancer, and non-cardiovascular, non-cancer causes. During the mean follow up period of 14.8 years there were 1257 deaths from all causes, 640 cardiovascular deaths, 433 cancer deaths, and 184 deaths from other causes. Low serum cholesterol concentrations (< 4.8 mmol/l), present in 5% (n = 410) of the men, were associated with the highest mortality from all causes, largely due to a significant increase in cancer deaths (age adjusted relative risk 1.6 (95% confidence interval 1.1 to 2.3); < 4.8 v 4.8-5.9 mmol/l) and in other non-cardiovascular deaths (age adjusted relative risk 1.9 (1.1 to 3.1)). Low serum cholesterol concentration was associated with an increased prevalence of several diseases and indicators of ill health and with lifestyle characteristics such as smoking and heavy drinking. After adjustment for these factors in the multivariate analysis the increased risk for cancer was attenuated (relative risk 1.4 (0.9 to 2.0) and the inverse association with other non-cardiovascular, non-cancer causes was no longer significant (relative risk 1.5 (0.9 to 2.6); < 4.8 v 4.8-5.9 mmol/l). The excess risks of cancer and of other non-cardiovascular deaths were most pronounced in the first five years and became attenuated and non-significant with longer follow up. By contrast, the positive association between serum total cholesterol concentration and cardiovascular mortality was seen even after more than 10 years of follow up. The association between comparatively low serum total cholesterol concentrations and excess mortality seemed to be due to preclinical cancer and other non-cardiovascular diseases. This suggests that public health programmes encouraging lower average concentrations of serum total cholesterol are unlikely to be associated with increased cancer or other non-cardiovascular mortality.
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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.
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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.
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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.
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Type 2 diabetes is associated with a substantially increased risk of cardiovascular disease, but the role of lipid-lowering therapy with statins for the primary prevention of cardiovascular disease in diabetes is inadequately defined. We aimed to assess the effectiveness of atorvastatin 10 mg daily for primary prevention of major cardiovascular events in patients with type 2 diabetes without high concentrations of LDL-cholesterol. 2838 patients aged 40-75 years in 132 centres in the UK and Ireland were randomised to placebo (n=1410) or atorvastatin 10 mg daily (n=1428). Study entrants had no documented previous history of cardiovascular disease, an LDL-cholesterol concentration of 4.14 mmol/L or lower, a fasting triglyceride amount of 6.78 mmol/L or less, and at least one of the following: retinopathy, albuminuria, current smoking, or hypertension. The primary endpoint was time to first occurrence of the following: acute coronary heart disease events, coronary revascularisation, or stroke. Analysis was by intention to treat. The trial was terminated 2 years earlier than expected because the prespecified early stopping rule for efficacy had been met. Median duration of follow-up was 3.9 years (IQR 3.0-4.7). 127 patients allocated placebo (2.46 per 100 person-years at risk) and 83 allocated atorvastatin (1.54 per 100 person-years at risk) had at least one major cardiovascular event (rate reduction 37% [95% CI -52 to -17], p=0.001). Treatment would be expected to prevent at least 37 major vascular events per 1000 such people treated for 4 years. Assessed separately, acute coronary heart disease events were reduced by 36% (-55 to -9), coronary revascularisations by 31% (-59 to 16), and rate of stroke by 48% (-69 to -11). Atorvastatin reduced the death rate by 27% (-48 to 1, p=0.059). No excess of adverse events was noted in the atorvastatin group. Atorvastatin 10 mg daily is safe and efficacious in reducing the risk of first cardiovascular disease events, including stroke, in patients with type 2 diabetes without high LDL-cholesterol. No justification is available for having a particular threshold level of LDL-cholesterol as the sole arbiter of which patients with type 2 diabetes should receive statins. The debate about whether all people with this disorder warrant statin treatment should now focus on whether any patients are at sufficiently low risk for this treatment to be withheld.
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Limited data are available evaluating how the timing and intensity of statin therapy following an acute coronary syndrome (ACS) event affect clinical outcome. To compare early initiation of an intensive statin regimen with delayed initiation of a less intensive regimen in patients with ACS. International, randomized, double-blind trial of patients with ACS receiving 40 mg/d of simvastatin for 1 month followed by 80 mg/d thereafter (n = 2265) compared with ACS patients receiving placebo for 4 months followed by 20 mg/d of simvastatin (n = 2232), who were enrolled in phase Z of the A to Z trial between December 29, 1999, and January 6, 2003. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, readmission for ACS, and stroke. Follow-up was for at least 6 months and up to 24 months. Among the patients in the placebo plus simvastatin group, the median low-density lipoprotein (LDL) cholesterol level achieved while taking placebo was 122 mg/dL (3.16 mmol/L) at 1 month and was 77 mg/dL (1.99 mmol/L) at 8 months while taking 20 mg/d of simvastatin. Among the patients in the simvastatin only group, the median LDL cholesterol level achieved at 1 month while taking 40 mg/d of simvastatin was 68 mg/dL (1.76 mmol/L) and was 63 mg/dL (1.63 mmol/L) at 8 months while taking 80 mg/d of simvastatin. A total of 343 patients (16.7%) in the placebo plus simvastatin group experienced the primary end point compared with 309 (14.4%) in the simvastatin only group (40 mg/80 mg) (hazard ratio [HR], 0.89; 95% confidence interval [CI] 0.76-1.04; P =.14). Cardiovascular death occurred in 109 (5.4%) and 83 (4.1%) patients in the 2 groups (HR, 0.75; 95% CI, 0.57-1.00; P =.05) but no differences were observed in other individual components of the primary end point. No difference was evident during the first 4 months between the groups for the primary end point (HR, 1.01; 95% CI, 0.83-1.25; P =.89), but from 4 months through the end of the study the primary end point was significantly reduced in the simvastatin only group (HR, 0.75; 95% CI, 0.60-0.95; P =.02). Myopathy (creatine kinase >10 times the upper limit of normal associated with muscle symptoms) occurred in 9 patients (0.4%) receiving simvastatin 80 mg/d, in no patients receiving lower doses of simvastatin, and in 1 patient receiving placebo (P =.02). The trial did not achieve the prespecified end point. However, among patients with ACS, the early initiation of an aggressive simvastatin regimen resulted in a favorable trend toward reduction of major cardiovascular events.
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Previous trials have demonstrated that lowering low-density lipoprotein (LDL) cholesterol levels below currently recommended levels is beneficial in patients with acute coronary syndromes. We prospectively assessed the efficacy and safety of lowering LDL cholesterol levels below 100 mg per deciliter (2.6 mmol per liter) in patients with stable coronary heart disease (CHD). A total of 10,001 patients with clinically evident CHD and LDL cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) were randomly assigned to double-blind therapy and received either 10 mg or 80 mg of atorvastatin per day. Patients were followed for a median of 4.9 years. The primary end point was the occurrence of a first major cardiovascular event, defined as death from CHD, nonfatal non-procedure-related myocardial infarction, resuscitation after cardiac arrest, or fatal or nonfatal stroke. The mean LDL cholesterol levels were 77 mg per deciliter (2.0 mmol per liter) during treatment with 80 mg of atorvastatin and 101 mg per deciliter (2.6 mmol per liter) during treatment with 10 mg of atorvastatin. The incidence of persistent elevations in liver aminotransferase levels was 0.2 percent in the group given 10 mg of atorvastatin and 1.2 percent in the group given 80 mg of atorvastatin (P<0.001). A primary event occurred in 434 patients (8.7 percent) receiving 80 mg of atorvastatin, as compared with 548 patients (10.9 percent) receiving 10 mg of atorvastatin, representing an absolute reduction in the rate of major cardiovascular events of 2.2 percent and a 22 percent relative reduction in risk (hazard ratio, 0.78; 95 percent confidence interval, 0.69 to 0.89; P<0.001). There was no difference between the two treatment groups in overall mortality. Intensive lipid-lowering therapy with 80 mg of atorvastatin per day in patients with stable CHD provides significant clinical benefit beyond that afforded by treatment with 10 mg of atorvastatin per day. This occurred with a greater incidence of elevated aminotransferase levels.
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
The Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program issued an evidence-based set of guidelines on cholesterol management in 2001. Since the publication of ATP III, 5 major clinical trials of statin therapy with clinical end points have been published. These trials addressed issues that were not examined in previous clinical trials of cholesterol-lowering therapy. The present document reviews the results of these recent trials and assesses their implications for cholesterol management. Therapeutic lifestyle changes (TLC) remain an essential modality in clinical management. The trials confirm the benefit of cholesterol-lowering therapy in high-risk patients and support the ATP III treatment goal of low-density lipoprotein cholesterol (LDL-C) <100 mg/dL. They support the inclusion of patients with diabetes in the high-risk category and confirm the benefits of LDL-lowering therapy in these patients. They further confirm that older persons benefit from therapeutic lowering of LDL-C. The major recommendations for modifications to footnote the ATP III treatment algorithm are the following. In high-risk persons, the recommended LDL-C goal is <100 mg/dL, but when risk is very high, an LDL-C goal of <70 mg/dL is a therapeutic option, ie, a reasonable clinical strategy, on the basis of available clinical trial evidence. This therapeutic option extends also to patients at very high risk who have a baseline LDL-C <100 mg/dL. Moreover, when a high-risk patient has high triglycerides or low high-density lipoprotein cholesterol (HDL-C), consideration can be given to combining a fibrate or nicotinic acid with an LDL-lowering drug. For moderately high-risk persons (2+ risk factors and 10-year risk 10% to 20%), the recommended LDL-C goal is <130 mg/dL, but an LDL-C goal <100 mg/dL is a therapeutic option on the basis of recent trial evidence. The latter option extends also to moderately high-risk persons with a baseline LDL-C of 100 to 129 mg/dL. When LDL-lowering drug therapy is employed in high-risk or moderately high-risk persons, it is advised that intensity of therapy be sufficient to achieve at least a 30% to 40% reduction in LDL-C levels. Moreover, any person at high risk or moderately high risk who has lifestyle-related risk factors (eg, obesity, physical inactivity, elevated triglycerides, low HDL-C, or metabolic syndrome) is a candidate for TLC to modify these risk factors regardless of LDL-C level. Finally, for people in lower-risk categories, recent clinical trials do not modify the goals and cutpoints of therapy.
Article
Recent trials indicate intensive lipid-lowering therapy beyond traditionally recommended levels in patients with acute coronary syndromes provides increased benefit with respect to cardiovascular endpoints compared with traditional lipid-lowering therapy in such patients (N Engl J Med 2004;50:1495-504, and J Am Col Cardiology 2004;44:1772-9). This study investigated the safety and efficacy of lowering low-density-lipoprotein (LDL) cholesterol <100 mg/dL in patients with stable coronary disease. Eligible patients were men and women 35 to 75 years of age who had clinically evident coronary heart disease. Screening of 18,469 patients took place at 256 sites in 14 countries, with 83.7% of these patients deemed eligible to enter the open-label run-in period of the study. Of these, 5,461 patients were excluded after the open label run in phase. Most exclusions were secondary to failure to meet randomization criteria. There were 10,001 patients ultimately randomized to receive double-blind treatment with either 10 mg or 80 mg daily of atorvastatin. The primary end point was the occurrence of a first major cardiovascular event, defined as death from coronary heart disease, nonfatal nonprocedure-related myocardial infarction, fatal or nonfatal stroke, or resuscitation after cardiac arrest. Randomization took place between July 1998 and December 1999.
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
background Lipid-lowering therapy with statins reduces the risk of cardiovascular events, but the optimal level of low-density lipoprotein (LDL) cholesterol is unclear. methods We enrolled 4162 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and compared 40 mg of pravastatin daily (standard therapy) with 80 mg of atorvastatin daily (intensive therapy). The primary end point was a com- posite of death from any cause, myocardial infarction, documented unstable angina re- quiring rehospitalization, revascularization (performed at least 30 days after randomiza- tion), and stroke. The study was designed to establish the noninferiority of pravastatin as compared with atorvastatin with respect to the time to an end-point event. Follow-up lasted 18 to 36 months (mean, 24). results The median LDL cholesterol level achieved during treatment was 95 mg per deciliter (2.46 mmol per liter) in the standard-dose pravastatin group and 62 mg per deciliter (1.60 mmol per liter) in the high-dose atorvastatin group (P
Article
Summary Background 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. Methods 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. Findings 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).
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: Type 2 diabetes is associated with a substantially increased risk of cardiovascular disease, but the role of lipid-lowering therapy with statins for the primary prevention of cardiovascular disease in diabetes is inadequately defined. We aimed to assess the effectiveness of atorvastatin 10 mg daily for primary prevention of major cardiovascular events in patients with type 2 diabetes without high concentrations of LDL-cholesterol. METHODS: 2838 patients aged 40-75 years in 132 centres in the UK and Ireland were randomised to placebo (n=1410) or atorvastatin 10 mg daily (n=1428). Study entrants had no documented previous history of cardiovascular disease, an LDL-cholesterol concentration of 4.14 mmol/L or lower, a fasting triglyceride amount of 6.78 mmol/L or less, and at least one of the following: retinopathy, albuminuria, current smoking, or hypertension. The primary endpoint was time to first occurrence of the following: acute coronary heart disease events, coronary revascularisation, or stroke. Analysis was by intention to treat. FINDINGS: The trial was terminated 2 years earlier than expected because the prespecified early stopping rule for efficacy had been met. Median duration of follow-up was 3.9 years (IQR 3.0-4.7). 127 patients allocated placebo (2.46 per 100 person-years at risk) and 83 allocated atorvastatin (1.54 per 100 person-years at risk) had at least one major cardiovascular event (rate reduction 37% [95% CI -52 to -17], p=0.001). Treatment would be expected to prevent at least 37 major vascular events per 1000 such people treated for 4 years. Assessed separately, acute coronary heart disease events were reduced by 36% (-55 to -9), coronary revascularisations by 31% (-59 to 16), and rate of stroke by 48% (-69 to -11). Atorvastatin reduced the death rate by 27% (-48 to 1, p=0.059). No excess of adverse events was noted in the atorvastatin group. INTERPRETATION: Atorvastatin 10 mg daily is safe and efficacious in reducing the risk of first cardiovascular disease events, including stroke, in patients with type 2 diabetes without high LDL-cholesterol. No justification is available for having a particular threshold level of LDL-cholesterol as the sole arbiter of which patients with type 2 diabetes should receive statins. The debate about whether all people with this disorder warrant statin treatment should now focus on whether any patients are at sufficiently low risk for this treatment to be withheld.