bims-mitost 2019-04-21 papers

bims-mitost

Biomed News

on Mitochondrial toxicity and statins

Issue of 2019‒04‒21
eight papers selected by
Yvonne Will
Scientia-Consultants LLC

Trial of atorvastatin for the primary prevention of cardiovascular events in patients with rheumatoid arthritis (TRACE RA): A multicenter, randomized, placebo controlled trial.
Sub-optimal cholesterol response to initiation of statins and future risk of cardiovascular disease.
Longitudinal Impacts of Gastric Bypass Surgery on Pharmacodynamics and Pharmacokinetics of Statins.
Prevalence and factors associated with statin use in high-risk patients with type 1 diabetes from a specialized diabetes unit.
Prescribing statins among patients with type 2 diabetes: The clinical gap between the guidelines and practice.
The effect of atorvastatin on cardiometabolic risk factors in women with non-classic congenital adrenal hyperplasia: A pilot study.
The extent to which statins have improved cardiovascular outcomes: Lessons from randomized trials and observational studies of "real world" practice in people with diabetes.
Prehospital statin use and low-density lipoprotein cholesterol levels at admission in acute coronary syndrome patients with history of myocardial infarction or revascularization: Findings from the Improving Care for Cardiovascular Disease in China (CCC) project.

Arthritis Rheumatol. 2019 Apr 15.

Trial of atorvastatin for the primary prevention of cardiovascular events in patients with rheumatoid arthritis (TRACE RA): A multicenter, randomized, placebo controlled trial.

Kitas GD, Nightingale P, Armitage J, Sattar N, Belch JJF, Symmons DPM, .

OBJECTIVE: Rheumatoid arthritis (RA) is associated with increased cardiovascular event (CVE) risk. The impact of statins in RA is not established. We assessed whether atorvastatin is superior to placebo for the primary prevention of CVE in RA patients.METHODS: Randomized, double-blind, placebo-controlled trial designed for 80% power at p<0.05 to detect a 32% CVE risk reduction based on an estimated 1.8% per annum (pa) event rate. Patients aged >50 years or with RA duration >10 years; without clinical atherosclerosis, diabetes, or myopathy; received atorvastatin 40mg daily or matching placebo. Primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, transient ischemic attack, or any arterial revascularization. Secondary/tertiary endpoints included plasma lipids and safety.
RESULTS: 3002 patients (mean age 61 years, 74% female) were followed for a median 2.51 years (IQR 1.90-3.49) [7,827 patient-years] - early termination was due to lower than expected event rate (0.77% pa). Among patients allocated atorvastatin 24/1504 (1.6%) had a primary endpoint, compared with 36/1498 (2.4%) on placebo (hazard ratio 0.66, 95%CI 0.39-1.11, p=0.115); adjusted hazard ratio (0.60, 95%CI 0.32-1.15, p=0.127). At trial end, patients on atorvastatin had 0.77±0.04 mmol/L lower LDL-cholesterol compared to placebo (p<0.0001); CRP (mg/L) was also significantly lower on atorvastatin than placebo (2.59 (0.94-6.08) vs. 3.60 (1.47-7.49) - p<0.0001). CVE risk reduction per mmol/L LDLc reduction was 42% (95%CI -14%-70%). Adverse events in the atorvastatin (298 (19.8%)) and placebo (292 (19.5%)) groups were similar.
CONCLUSION: Atorvastatin 40mg daily was safe and resulted in significantly greater reduction of LDLc than placebo in patients with RA. The 40% (adjusted) CVE risk reduction is consistent with the Cholesterol Treatment Trialists' Collaboration meta-analysis of statin effects in other populations. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/art.40892
Heart. 2019 Apr 15. pii: heartjnl-2018-314253. [Epub ahead of print]

Sub-optimal cholesterol response to initiation of statins and future risk of cardiovascular disease.

Akyea RK, Kai J, Qureshi N, Iyen B, Weng SF.

  OBJECTIVE: To assess low-density lipoprotein cholesterol (LDL-C) response in patients after initiation of statins, and future risk of cardiovascular disease (CVD).METHODS: Prospective cohort study of 165 411 primary care patients, from the UK Clinical Practice Research Datalink, who were free of CVD before statin initiation, and had at least one pre-treatment LDL-C within 12 months before, and one post-treatment LDL-C within 24 months after, statin initiation. Based on current national guidelines, <40% reduction in baseline LDL-C within 24 months was classified as a sub-optimal statin response. Cox proportional regression and competing-risks survival regression models were used to determine adjusted hazard ratios (HRs) and sub-HRs for incident CVD outcomes for LDL-C response to statins.
RESULTS: 84 609 (51.2%) patients had a sub-optimal LDL-C response to initiated statin therapy within 24 months. During 1 077 299 person-years of follow-up (median follow-up 6.2 years), there were 22 798 CVD events (12 142 in sub-optimal responders and 10 656 in optimal responders). In sub-optimal responders, compared with optimal responders, the HR for incident CVD was 1.17 (95% CI 1.13 to 1.20) and 1.22 (95% CI 1.19 to 1.25) after adjusting for age and baseline untreated LDL-C. Considering competing risks resulted in lower but similar sub-HRs for both unadjusted (1.13, 95% CI 1.10 to 1.16) and adjusted (1.19, 95% CI 1.16 to 1.23) cumulative incidence function of CVD.
CONCLUSIONS: Optimal lowering of LDL-C is not achieved within 2 years in over half of patients in the general population initiated on statin therapy, and these patients will experience significantly increased risk of future CVD.

Keywords:  electronic medical records; epidemiology; lipoproteins and hyperlipidemia

DOI:  https://doi.org/10.1136/heartjnl-2018-314253
Obes Surg. 2019 Apr 19.

Longitudinal Impacts of Gastric Bypass Surgery on Pharmacodynamics and Pharmacokinetics of Statins.

El-Zailik A, Cheung LK, Wang Y, Sherman V, Chow DS.

  PURPOSE: Undergoing Roux-en-Y gastric bypass (RYGB) is expected to affect orally administered drug absorption. Statins are commonly prescribed to patients with obesity for the prevention of atherosclerotic cardiovascular diseases by lowering cholesterol. This is the first longitudinal prospective study on impacts of RYGB on weight loss, pharmacodynamics, and pharmacokinetics of atorvastatin, rosuvastatin, and simvastatin, and their active metabolites, up to 1-year post-surgery.METHODS: Forty-six patients were recruited, five patients on atorvastatin, twelve on rosuvastatin, nine on simvastatin, and twenty on no statin. The concentrations of atorvastatin, rosuvastatin, and simvastatin with their active metabolites were monitored.
RESULTS: Mean plasma concentrations of atorvastatin and metabolites and rosuvastatin normalized by the unit dose [(nM)/(mg/kg)] decreased by 3- to 6-month post-surgery. Conversely, simvastatin and its metabolite concentrations increased up to 6-month post-surgery, then declined to preoperative levels by 1-year post-surgery. The metabolisms of atorvastatin to hydroxyl-metabolites and simvastatin to simvastatin acid were decreased after RYGB. The weight loss and PD outcomes were comparable between statin and non-statin groups suggesting the key impacts were from RYGB. The discontinuation or reduction of dose of atorvastatin or rosuvastatin post-RYGB exhibited rebounds of LDL levels in some subjects, but the rebound was not apparent with patients on simvastatin pre-surgery.
CONCLUSION: Discontinuations of statin dosing post-RYGB require LDL monitoring and reducing the dose to half seems to have better results. Patients on statin treatment post-RYGB should be followed-up closely based on our pharmacokinetic findings, to ensure therapeutic effects of the treatment with minimal adverse effects.

Keywords:  Active metabolites; Pharmacodynamics; Pharmacokinetics; Roux en-Y gastric bypass; Statins

DOI:  https://doi.org/10.1007/s11695-019-03885-6
Endocrinol Diabetes Nutr. 2019 Apr 15. pii: S2530-0164(19)30058-8. [Epub ahead of print]

Prevalence and factors associated with statin use in high-risk patients with type 1 diabetes from a specialized diabetes unit.

Amor AJ, Ortega E, Giménez M, Cofán M, Blanco J, Pané A, Boswell L, Vinagre I, Esmatjes E, Conget I.

  INTRODUCTION: The use of statins in non-selected type 1 diabetes (T1D) populations is low. We assessed the prevalence and factors associated with statin treatment in patients meeting criteria for this therapy for primary prevention of cardiovascular disease (CVD).MATERIAL AND METHODS: From 2015 to 2018, T1D patients from a tertiary hospital were selected. Inclusion criteria were: ≥40 years-old, diabetic nephropathy, or T1D duration ≥10 years with ≥1 cardiovascular risk factor (CVRF). A standardized cardiovascular risk evaluation protocol was performed. Prevalence of statin treatment was evaluated according to presence of several CVRFs, and multivariable models were constructed to assess independent determinants of statin use.
RESULTS: We included 241 patients (50% women, age 48.2±9.9 years, T1D duration 26.6±9.0 years). Diabetic retinopathy and nephropathy, active smoking, and hypertension were present in 38%, 12%, 28%, and 27%, respectively. Overall, 43% of patients were on statins and 27% had LDL-cholesterol <100mg/dl. Statin users were older, and had higher body mass index (BMI), prevalence of kidney dysfunction, and hypertension (p<0.05 for all). However, among both T1D-related and classical CVRFs, only hypertension (odds ratio [OR], 2.96; 95% confidence interval [CI] 1.48-5.91) and BMI (OR, 1.08; CI, 1.01-1.16) were independently associated with statin use in multiple regression analysis.
CONCLUSIONS: Less than half of T1D patients from a tertiary hospital who met criteria for statin use were on treatment. Hypertension and BMI emerged as the only CVRFs independently associated with statin therapy. New strategies are needed to better address CVD prevention in this very high-risk population.

Keywords:  Cardiovascular disease; Cardiovascular risk factors; Diabetes tipo 1; Enfermedad cardiovascular; Estatinas; Factores de riesgo cardiovascular; Fármacos hipolipidemiantes; Lipid-lowering drugs; Statins; Type 1 diabetes

DOI:  https://doi.org/10.1016/j.endinu.2019.02.004
J Res Med Sci. 2019 ;24 15

Prescribing statins among patients with type 2 diabetes: The clinical gap between the guidelines and practice.

Hammad MA, Syed Sulaiman SA, Aziz NA, Mohamed Noor DA.

  Background: Statins are recommended for cardiovascular protection for people with diabetes (high-risk groups). This study aimed to evaluate the gap between the guidelines of statin utilization and clinical practice among outpatients with type 2 diabetes regarding the patient's age and gender, to assess if this preventive drug is being satisfactorily utilized or not.Materials and Methods: In this cross-sectional study, patients aged <40 or >75 years, pregnant patients, and patients with type 1 diabetes, human immunodeficiency virus, or liver cirrhosis were excluded. Demographics, laboratory parameters, and prevalence of exposure to statin therapy were evaluated. This study was guided by the 2013 American College of Cardiology/American Heart Association cholesterol guidelines. IBM SPSS software was used for data management.
Results: The study cohort involved 576 patients, with age being 58.3 ± 8.9 years. There were 50.5% of females and 49.5% of males. Overall 81.1% of patients aged 58.8 ± 8.8 years were statin users and 18.9% of patients aged 56.2 ± 9 years were statin nonusers. About 83.2% of females and 78.9% of males were prescribed statins. Statin medications included simvastatin 79.2%, atorvastatin 11.6%, lovastatin 5.8%, rosuvastatin 2.1%, and pravastatin 1.3%. Statin users' and nonusers' adherence was 56.5%, and 41.3% (P = 0.004), respectively. The adherence to medication plan of females and males was 55.7% and 51.6%, respectively (P = 0.004).
Conclusion: Patients with diabetes who are at high risk of cardiovascular events, exposure to statin treatment is significantly less than perfect position both in females and males. Nearly one-fifth of the patients with type 2 diabetes are not using statins despite therapeutic necessities.

Keywords:  Age; Malaysia; clinical gap; gender; practice guidelines; statin medication; type 2 diabetes

DOI:  https://doi.org/10.4103/jrms.JRMS_100_18
Pharmacol Rep. 2019 Jan 31. pii: S1734-1140(18)30661-3. [Epub ahead of print]71(3): 417-421

The effect of atorvastatin on cardiometabolic risk factors in women with non-classic congenital adrenal hyperplasia: A pilot study.

Krysiak R, Kowalcze K, Bednarska-Czerwińska A, Okopień B.

  BACKGROUND: Individuals with non-classic congenital adrenal hyperplasia (NC-CAH) often show evidence of hyperandrogenism, including premature pubarche, accelerated linear growth velocity, short final height, hirsutism, acne, alopecia, impaired ovulation, menstrual dysfunction and subfertility. Although statins were found to reduce elevated levels of androgens in subjects with this disorder, no previous study has investigated whether 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors affect cardiometabolic risk factors in patients with NC-CAH.METHODS: We studied 12 women with NC-CAH, 6 of whom because of coexisting hypercholesterolemia received atorvastatin (20-40 mg daily). Circulating levels of lipids, glucose homeostasis markers, plasma levels of androgens, 17-hydroxyprogesterone, high-sensitivity C-reactive protein (hsCRP), uric acid, fibrinogen, homocysteine and 25-hydroxyvitamin D, as well as urinary albumin-to-creatinine ratio (UACR) were determined at the beginning of the study and 12 weeks later.
RESULTS: Beyond affecting plasma lipids, atorvastatin reduced circulating levels of testosterone, dehydroepiandrosterone sulphate, androstenedione and 17-hydroxyprogesterone, and decreased free androgen index. Moreover, atorvastatin caused a decrease in plasma levels/urinary loss of uric acid, hsCRP, homocysteine and UACR, and insignificantly increased circulating levels of 25-hydroxyvitamin D. The drug produced no effect on plasma fibrinogen. The effect of atorvastatin on hsCRP, uric acid, homocysteine, 25-hydroxyvitamin D and UACR correlated with the magnitude of reduction in 17-hydroxyprogesterone and androgens.
CONCLUSION: Our results suggest that statin therapy reduces cardiometabolic risk in women with NC-CAH.

Keywords:  Cardiometabolic risk; Congenital adrenal hyperplasia; Statins; Steroid hormones

DOI:  https://doi.org/10.1016/j.pharep.2019.01.014
Diabetes Obes Metab. 2019 Apr;21 Suppl 1 17-27

The extent to which statins have improved cardiovascular outcomes: Lessons from randomized trials and observational studies of "real world" practice in people with diabetes.

Bengaluru Jayanna M, Robinson JG.

  Statins are the mainstay of therapy for cardiovascular risk reduction in patients with diabetes mellitus. It is estimated that there are more than half a billion patients with diabetes mellitus worldwide and the numbers of prevalent cases of diabetes are expected to increase in both developed and developing countries in the next decade. Statins reduce risk of mortality and morbidity mainly by reducing blood low density cholesterol. Statins, along with other medical treatments, are responsible for about half of the decrease in cardiovascular mortality over the past several decades. Multiple clinical trials have found evidence for statin use in patients with diabetes, for both primary prevention and secondary prevention. The benefit of statins in patients with coronary heart disease and diabetes in terms of absolute risk reduction is twice as much as compared to the risk in patients with coronary heart disease but no diabetes. The proportion of patients with diabetes treated with statins has increased steadily over the past few decades with concurrent decrease in cardiovascular deaths in this high-risk population. However, there are significant unmet needs in cardiovascular risk reduction, due to underutilization of statins and due to residual cardiovascular risk despite maximal statin therapy. Future strategies in population risk reduction in diabetics should include maximal statin therapy, additional treatment with nonstatin therapy and new paradigms of prevention with early intervention with shorter, more intensive therapy to potentially "reverse" atherosclerosis with goals of reducing clinical cardiovascular disease later in life.

Keywords:  cardiovascular disease; dyslipidaemia; lipid-lowering therapy

DOI:  https://doi.org/10.1111/dom.13701
Am Heart J. 2019 Mar 13. pii: S0002-8703(19)30055-9. [Epub ahead of print]212 120-128

Prehospital statin use and low-density lipoprotein cholesterol levels at admission in acute coronary syndrome patients with history of myocardial infarction or revascularization: Findings from the Improving Care for Cardiovascular Disease in China (CCC) project.

Xing Y, Liu J, Hao Y, Liu J, Huo Y, Smith SC, Ge J, Ma C, Han Y, Fonarow GC, Taubert KA, Morgan L, Yang N, Zhou M, Zhao D, .

BACKGROUND: Lowering low-density lipoprotein cholesterol (LDL-C) by statins is a key strategy for secondary prevention of acute coronary syndrome (ACS). However, few studies have examined prehospital statin use and admission LDL-C levels in ACS patients with history of myocardial infarction (MI) or revascularization. This study aimed to assess use of prehospital statins and LDL-C levels at admission in ACS patients with history of MI or revascularization.METHODS: Improving Care for Cardiovascular Disease in China project was a nationwide registry, with 192 participating hospitals reporting details of clinical information of ACS patients from November 2014. By May 2018, 80,282 patients with ACS were included. LDL-C levels were obtained from the initial admission lipid testing.
RESULTS: Of the 80,282 ACS patients, 6,523 with a history of MI or revascularization were enrolled. Among them, 50.8% were receiving lipid-lowering therapy before hospitalization (statin monotherapy in 98.4%, combination in 1.2%). A total of 30.1% of patients had LDL-C < 70 mg/dL at admission. In patients receiving prehospital statins, 36.1% had LDL-C < 70 mg/dL compared to 24.0% without prehospital statins (P < .001). At discharge, 91.8% of patients were treated with statin monotherapy, 90.7% at moderate doses irrespective of prehospital statin use and LDL-C levels at admission.
CONCLUSIONS: Among ACS patients with history of MI or revascularization, half were not being treated with statin therapy prior to admission, and most had not attained LDL-C < 70 mg/dL despite prehospital statin use. There is an important opportunity to provide intensive statin or combination lipid-lowering therapy to these very high risk patients.

DOI: https://doi.org/10.1016/j.ahj.2019.02.019