Effects Of Lipid-lowering Drugs Research Articles

Mendelian randomization study of lipid metabolism characteristics and migraine risk.

The association between serum lipids and migraine is controversial. However, randomized controlled trials have suggested that statins may be efficacious for the prevention of migraine. In this study, we aim to investigate the relationship between lipids metabolism and migraine risk. Single-nucleotide polymorphisms (SNPs), relating to the serum lipid traits and the effect of lipid-lowering drugs that target APOB, CETP, HMGCR, NPC1L1, and PCSK9, were extracted from genome-wide association studies (GWAS) summary data. The GWAS summary data were obtained from the Global Lipids Genetic Consortium (GLGC), the UK Biobank, and the FinnGen study, respectively. Mendelian randomization (MR) analysis was performed to evaluate the association between serum lipid traits and lipid-lowering drugs with migraine risk. Regarding serum lipids, it was found that SNPs related to high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), or triglycerides (TG) levels were not associated with migraine, migraine with aura (MA) or migraine without aura (MO). In addition, genotypes of HMGCR related to higher LDL-C levels were associated with increased risk of migraine (OR = 1.46, p = 0.035) and MA (OR = 2.03, p = 0.008); However, genotypes of PCSK9 related to higher LDL-C levels were associated with decreased risk of migraine (OR = 0.75, p = 0.001) and MA (OR = 0.69, p = 0.004); And genotypes of APOB related to higher LDL-C levels were associated with decreased risk of MO (OR = 0.62, p = 0.000). There is a relationship between lipid metabolism characteristics and migraine risk. Based on the genome-wide association summary data, single-nucleotide polymorphisms (SNPs) related to high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), or triglycerides (TG) level were not associated with risk of migraine, migraine with aura (MA) or migraine without aura (MO). However, genotypes of HMGCR related to higher LDL-C levels have shown an increased risk on migraine and MA. And genotypes of APOB or PCSK9 related to higher LDL-C levels have shown a decreased risk on MO, or migraine and MA, respectively. These results suggested that there may be a relationship between lipid metabolism characteristics and the risk for migraine development.

Effect of Lipid-Lowering Drugs on Renal and Cardiovascular Outcomes in Patients with Chronic Kidney Disease and Dyslipidemia: ARetrospective Cohort Study.

The effects of lipid-lowering drugs (LLDs) on cardiovascular and renal outcomes in patients with advanced chronic kidney disease (CKD) and dyslipidemia are not completely understood. We conducted a retrospective cohort study to evaluate the effect of LLDs on end-stage kidney disease (ESKD), major adverse cardiovascular events (MACEs), and mortality in adult patients with CKD stage 3b, 4, or 5, and dyslipidemia. Participants were recruited between January 1, 2008, and December 31, 2018, and classified as LLD or non-LLD users; the final follow-up date was December 31, 2020. The primary outcome was time to ESKD or death due to renal failure. Sub-distribution hazard regression models adjusted for multivariables, including time-varying lipid profile covariates, were used for the analysis. Among the 6,740 participants, 4,280 patients with CKD and dyslipidemia, including 872 using LLDs and 3,408 not using LLDs, completed the primary analysis. The multivariable analyses showed that LLD users had a significantly lower risk of time to the composite renal outcome (adjusted hazard ratio [aHR], 0.76, 95% confidence interval [CI], 0.65-0.89), and MACE incidence (aHR, 0.75, 95% CI, 0.62-0.93) than did non-LLD users. After adjusting for time-varying covariates of the lipid profile, there was a significant difference in the composite renal outcome (aHR, 0.78, 95% CI, 0.65-0.93) and MACEs (aHR, 0.77, 95% CI, 0.60-0.98). Among adult patients with advanced CKD and dyslipidemia, LLD users had a significantly lower risk of composite renal outcomes and MACEs than non-LLD users. In addition to reducing lipid profile, the use of LLD is associated with renal and cardiovascular protective effects.

Efficacy, Safety and Protective Effects of Lipid Lowering Drugs in Patients with Diabetes

Aim: The aim of the study was to assess the effects of statins and fibrates on the lipid profile of patients with diabetes and to determine their side effects. Methods: It was a transversal study. We included patients with type 1 or 2 diabetes that are followed in an outpatient department, treated for at least 3 months by statins or fibrates.We performed an interrogatory, a medical examination, dietary survey and biological tests for all patients. Results:The mean age was 59.5 ± 9.2 years. Women were 65% of patients. The mean duration of treatment with statins and fibrates was 2.2 ± 2.6 years and 4.9 ± 4.2 years, respectively.Under statin therapy, total cholesterol and LDL cholesterol decreased significantly by 1.02±1.25 mmol/l and 0.32±0.47 mmol/l, respectively, triglycerides and HDL cholesterol decreased insignificantly.Fibrates caused a significant decrease in total cholesterol and triglycerides by 1.15± 2.24 mmol/l and 1.73 ±2.96 mmol/l, respectively and a non-significant decrease in LDL cholesterol and a non-significant increase in HDL cholesterol. No case of significant hepatic cytolysis was noted. Muscle pain was reported by 10.4% and 11.6% of patients on statins and fibrate, respectively.Under statins, the incidence of gastrointestinal symptoms increased significantly. Conclusion: The efficacy of lipid lowering drugs is widely proven. Although side effects are possible, the prescription of lipid lowering drugs should be largely encouraged for better health care of patients with diabetes.

The Burning Necessity for Establishing National Guidelines - Side Effects of Lipid Lowering Drugs and Difficulty of using High Intensity Statins in Pakistani Population

Lipid lowering strategy has been widely used in both the primary as well as the secondary prevention of atherosclerotic cardiovascular disease, particularly in managing patients who are either diagnosed with ischemic heart disease or stroke or face great susceptibility to developing these complications as a result of risk factors like diabetes, hypertension, sedentary lifestyle and so on [1,2]. The mechanism of action of Statins is by inhibition of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase which is the rate-limiting step in cholesterol synthesis [3]. Statins hence have a great impact on the lipid metabolism and play a vital role in prevention of atherosclerotic complications [4]. They reduce LDL-C, Total cholesterol, and Triglyceride levels; slightly increase HDL-C levels [5]; and are also thought to have anti-inflammatory and other plaque stabilization effects, referred to as their pleiotropic properties [6].

Effects of Lipids and Lipoproteins on Mesenchymal Stem Cells Used in Cardiac Tissue Regeneration.

Mesenchymal stem cells (MSCs) have two characteristics of interest for this paper: the ability to self-renew, and the potential for multiple-lineage differentiation into various cells. MSCs have been used in cardiac tissue regeneration for over a decade. Adult cardiac tissue regeneration ability is quite low; it cannot repair itself after injury, as the heart cells are replaced by fibroblasts and lose function. It is therefore important to search for a feasible way to repair and restore heart function through stem cell therapy. Stem cells can differentiate and provide a source of progenitor cells for cardiomyocytes, endothelial cells, and supporting cells. Studies have shown that the concentrations of blood lipids and lipoproteins affect cardiovascular diseases, such as atherosclerosis, hypertension, and obesity. Furthermore, the MSC lipid profiles, such as the triglyceride and cholesterol content, have been revealed by lipidomics, as well as their correlation with MSC differentiation. Abnormal blood lipids can cause serious damage to internal organs, especially heart tissue. In the past decade, the accumulated literature has indicated that lipids/lipoproteins affect stem cell behavior and biological functions, including their multiple lineage capability, and in turn affect the outcome of regenerative medicine. This review will focus on the effect of lipids/lipoproteins on MSC cardiac regenerative medicine, as well as the effect of lipid-lowering drugs in promoting cardiomyogenesis-associated MSC differentiation.

Effects of Lipid Lowering Drugs on Arterial Stiffness: One More Way to Reduce Cardiovascular Risk?

Arterial stiffness (AS) is considered an independent predictor of cardiovascular disease (CVD) events. Among lipid lowering drugs, statins have a beneficial effect on AS, independent of their hypolipidaemic effect. Based on 3 meta-analyses and other studies, this effect is compound- and doserelated. Potent statins at high doses are more effective than less powerful statins. Ezetimibe (± statin) also seems to decrease AS in patients with dyslipidaemia. Fibrates have no effect on AS. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have data that beneficially affect all AS risk factors, suggesting a beneficial effect on artery compliance. However, there is no direct measurement of their effect on AS indices. In patients with dyslipidaemia, prescribing high dose statins (± ezetimibe) will not only decrease low-density lipoprotein cholesterol levels but also improve AS (in addition to other effects). This effect on AS may contribute to the observed reduction in vascular events.

The effect of atorvastatin on penile intracavernosal pressure and cavernosal morphology in normocholesterolemic rats.

A debate is open on the effects of lipid-lowering drugs on sexual function. We aimed to investigate the effect of atorvastatin use on penile intracavernosal pressure (ICP) and cavernosal morphology. Fourteen mature male Sprague-Dawley-rats were randomly assigned to either the control group (which received standard food and water ad libitum) or the atorvastatin group (which received standard food, water, and statin) for twelwe weeks. At the end of the study, ICPs were measured with cavernosometry. Penectomy specimens were histologically examined. The following mean values were obtained for the control and atorvastatin groups, respectively: pre-study body weights (350±16.9 g and 331.4±24.9 g); post-study body weights (356±18 g and 368±22.5 g (p>0.05); ICPs at 5 V (5.96±5.16 mmHg and 2.11±1.22 mmHg (p=0.07)); ICPs at 10 V (18.28±14.1 mmHg and 5.56±5.58 mmHg) (p=0.09); testosterone (1.23±0.78 and 0.78±0.58 mmol/dL) (p=0.39); blood glucose (151±22 mg/dL and 168.6±16.2 mg/dL) (p=0.12); triglyceride (93.4±19.8 mg/dL and 52.1±18.6 mg/dL) (p=0.01); total cholesterol (50.2±7.2 mg/dL and 47.7±6.6 mg/dL) (p=0.51); and low-density lipoprotein (LDL) cholesterol (10.0±4.4 mg/dL and 3.5±2.1 mg/dL) (p=0.01). The mean collagen thickness was similar (p=0.09); but the mean elastin thickness increased in the atorvastatin group (p=0.01). The present study showed that the use of atorvastatin reduced the intracavernosal pressure in 10 V stimulation, and minimally decreased testosterone levels in rats, within a short period of time. When statin treatment is considered for its protective properties on cardiovascular system or for its lipid-lowering effect. It should be kept in mind that atorvastatin may also adversely contribute to erectile dysfunction.

Lipid-lowering response in subjects with the p.(Leu167del) mutation in the APOE gene

Background and aimsThe aim of this work was to compared the effect of lipid lowering drugs among familial hypercholesterolemia (FH) subjects with a functional mutation in LDLR (LDLR FH) and FH with the p.(Leu167del) mutation in APOE. MethodsWe retrospectively selected all adults with the p.(Leu167del) mutation on lipid-lowering treatment (n = 22) attending the Lipid Unit at the Hospital Miguel Servet. Age and sex matched LDLR FH from the same Unit were randomly selected as a control group (n = 44). ResultsThe mean percentage reduction in LDLc was significantly higher in the p.(Leu167del) carriers (−52.1%) than in the LDLR FH (−39.7%) (p = 0.040) when on high intensity statins. Similar differences between groups were observed in non-HDLc −49.4% and −36.4%, respectively (p = 0.030). ConclusionsSubjects with p.(Leu167del) mutation have a higher lipid-lowering response to statins with or without ezetimibe than LDLR FH. This supports the use of genetics for a more efficient management of FH.

The Complex Interplay between Lipids, Immune System and Interleukins in Cardio-Metabolic Diseases.

Lipids and inflammation regulate each other. Early studies on this topic focused on the systemic effects that the acute inflammatory response—and interleukins—had on lipid metabolism. Today, in the era of the obesity epidemic, whose primary complications are cardio-metabolic diseases, attention has moved to the effects that the nutritional environment and lipid derangements have on peripheral tissues, where lipotoxicity leads to organ damage through an imbalance of chronic inflammatory responses. After an overview of the effects that acute inflammation has on the systemic lipid metabolism, this review will describe the lipid-induced immune responses that take place in peripheral tissues and lead to chronic cardio-metabolic diseases. Moreover, the anti-inflammatory effects of lipid lowering drugs, as well as the possibility of using anti-inflammatory agents against cardio-metabolic diseases, will be discussed.

The effects of lipid lowering drugs on neuroinflammation in metabolic syndrome mice

People get used to high‐calorie and refined dishes diet and lack of physical exercises with rapid modern lifestyles change. Those bad habits contribute to the increasing prevalence of metabolic syndrome. The peripheral chronic inflammatory responses are related to the adipose tissue accumulation and hyperlipidemia in the metabolic syndrome patients. Depression is an important comorbidity with metabolic syndrome. The inflammatory cytokines secreted by activated inflammatory cells in peripheral tissue would induce central neural inflammation. Chronic brain inflammation may be linked to depression. We hypothesize that depression occurrence in metabolic syndrome patients is due to the peripheral and central neural inflammation. We evaluated whether fenofibrate or Statin could improve depression‐like behavior in metabolic syndrome mice. The metabolic syndrome mice were induced by high‐fat‐diet. The depression‐like behaviors in metabolic syndrome mice were analyzed by tail suspension test, open field test and sucrose preference test. After 4‐week treatment of fenofibrtae and Statin, the depression‐like behavior in mice were analyzed and then sacrificed. The expressions of inflammatory cytokines in the brain of mice were detected by RT‐PCR. The activation of macrophage and microglia were analyzed using IHC stain. The results showed that body weight, TG, TC in serum and adipose tissue weight of mice were increased after high‐fat‐diet fed. That confirmed metabolic syndrome was induced successfully in the mice. In behavior analysis, fenofibrate decreased immobility times of tail suspension, increased number of line crossing of open field test, and increase sucrose intake of sucrose preference test indicating that PPARα activation may improve depression‐like behavior. The data showed that fenofibrate could improve depression level in metabolic syndrome mice.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Weekly Integral Dose and Use of Lipid Lowering Drugs Are Associated With Worsening of Functional Outcomes in Prostate Cancer Patients Treated With IMRT

IMRT allows the delivery of highly conformal doses to target, but increases body integral dose due to irradiation of a larger volume of tissue at lower doses. We previously showed that higher weekly integral pelvic dose (weekID) was associated with adverse functional outcomes at RT end in patients (pts) with localized prostate cancer treated with IMRT (RO 2016). This analysis aimed to model worsening of functional and nonfunctional items from EORTC QLQ-C30, all plausibly related to fatigue. Patients from two prospective multicentric trials were evaluated, involving either conventional (78 Gy, 2 Gy/Fr) or hypo-fractionated (HF) (60-75.2 Gy, 2.35-3 Gy/Fr) RT alone, without lymph node irradiation. Collected clinical factors were: comorbidities, drugs, hormone therapies, previous surgeries, smoking, age, BMI. Integral dose was calculated as the product of mean body dose and body volume. WeekID was used to properly consider different fractionations. Worsening (RT end vs baseline) of EORTC QLQ-C30 scores in Physical/Role/Social Functioning scales and Fatigue was evaluated: 2 point worsening was considered for subscales including >2 items, 1 point worsening for 2 items subscales. Outcome measures for the analysis were defined as worsening in at least 2 (Wrs2) or 3 (Wrs3) subscales. Models incorporating weekID and clinical factors were developed using multivariable logistic regression (MVL). Complete data for 254 pts were available. The table summarizes the cohorts. The MVL for Wrs2 included weekID (OR = 1.05, continuous variable) and use of lipid lowering drugs (LLD, OR = 1.5). Calibration was good: slope = 1.01 (Rˆ2 = 0.80) in the development cohort and 1.05 (Rˆ2 = 0.90) in the validation dataset. The model for Wrs3 included the same factors (weekID OR = 1.06 and LLD OR = 2.3) with calibration slopes of 1.05 (Rˆ2 = 0.96) and 0.72 (Rˆ2 = 0.70), in the development and validation cohorts, respectively. Worsening of functional and non-functional quality of life symptoms was significantly associated with use of lipid lowering drugs and weekID, suggesting a higher impairment effect of hypofractionation in the acute phase (possible fraction size related inflammatory response or effect on blood cell counts). The effect of lipid lowering drugs is interesting, as they were found to be a risk factor for urinary toxicity in a large population (Palorini R&O 2016). These drugs are usually prescribed for vasculopathies: the present result thus bolsters the clue that pts with potential microangiopathic disease exhibit a possible enhanced sensitivity to RT-induced damage.

The gut microbiota metabolism of pomegranate or walnut ellagitannins yields two urolithin-metabotypes that correlate with cardiometabolic risk biomarkers: Comparison between normoweight, overweight-obesity and metabolic syndrome

Urolithins are microbial metabolites produced after consumption of ellagitannin-containing foods such as pomegranates and walnuts. Parallel to isoflavone-metabolizing phenotypes, ellagitannin-metabolizing phenotypes (urolithin metabotypes A, B and 0; UM-A, UM-B and UM-0, respectively) can vary among individuals depending on their body mass index (BMI), but correlations between urolithin metabotypes (UMs) and cardiometabolic risk (CMR) factors are unexplored. We investigated the association between UMs and CMR factors in individuals with different BMI and health status. UM was identified using UPLC-ESI-qToF-MS in individuals consuming pomegranate or nuts. The associations between basal CMR factors and the urine urolithin metabolomic signature were explored in 20 healthy normoweight individuals consuming walnuts (30g/d), 49 healthy overweight-obese individuals ingesting pomegranate extract (450mg/d) and 25 metabolic syndrome (MetS) patients consuming nuts (15g-walnuts, 7.5g-hazelnuts and 7.5g-almonds/d). Correlations between CMR factors and urolithins were found in overweight-obese individuals. Urolithin-A (mostly present in UM-A) was positively correlated with apolipoprotein A-I (P≤0.05) and intermediate-HDL-cholesterol (P≤0.05) while urolithin-B and isourolithin-A (characteristic from UM-B) were positively correlated with total-cholesterol, LDL-cholesterol (P≤0.001), apolipoprotein B (P≤0.01), VLDL-cholesterol, IDL-cholesterol, oxidized-LDL and apolipoprotein B:apolipoprotein A-I ratio (P≤0.05). In MetS patients, urolithin-A only correlated inversely with glucose (P≤0.05). Statin-treated MetS patients with UM-A showed a lipid profile similar to that of healthy normoweight individuals while a poor response to lipid-lowering therapy was observed in MB patients. UMs are potential CMR biomarkers. Overweight-obese individuals with UM-B are at increased risk of cardiometabolic disease, whereas urolithin-A production could protect against CMR factors. Further research is warranted to explore these associations in larger cohorts and whether the effect of lipid-lowering drugs or ellagitannin-consumption on CMR biomarkers depends on individuals' UM. NCT01916239 (https://clinicaltrials.gov/ct2/show/NCT01916239) and ISRCTN36468613 (http://www.isrctn.com/ISRCTN36468613).

Effects of Lipid-Lowering Drugs on Vancomycin Susceptibility of Mycobacteria.

Tuberculosis is still a cause of major concern, partly due to the emergence of multidrug-resistant strains. New drugs are therefore needed. Vancomycin can target mycobacteria with cell envelope deficiency. In this study, we used a vancomycin susceptibility assay to detect drugs hampering lipid synthesis in Mycobacterium bovis BCG and in Mycobacterium tuberculosis We tested three drugs already used to treat human obesity: tetrahydrolipstatin (THL), simvastatin, and fenofibrate. Only vancomycin and THL were able to synergize on M. bovis BCG and on M. tuberculosis, although mycobacteria could also be inhibited by simvastatin alone. Lipid analysis allowed us to identify several lipid modifications in M. tuberculosis H37Rv treated with those drugs. THL treatment mainly reduced the phthiocerol dimycocerosate (PDIM) content in the mycobacterial cell wall, providing an explanation for the synergy, since PDIM deficiency has been related to vancomycin susceptibility. Proteomic analysis suggested that bacteria treated with THL, in contrast to bacteria treated with simvastatin, tried to recover, inducing, among other reactions, lipid synthesis. The combination of THL and vancomycin should be considered a promising solution in developing new strategies to treat multidrug-resistant tuberculosis.

Abstract 18157: Impact of Betatrophin (ANGPTL8) R59W Mutation for Future Diabetes, and Minimal Modification of Circulating Betatrophin With Strong Statins

Betatrophin (ANGPTL8), also known as “Lipasin” (lipoprotein lipase inhibitor), has been reported as a dual-regulator of glucose and lipid metabolism. Functional variant R59W in betatrophin gene is common in Japanese (minor allele 25%) compared with Caucasian (5%). Little is known about long-term impact of this gene variant, and also about the effect of lipid-lowering drugs on this hormone. Methods: A total of 205 cases with dyslipidemia evaluated with baseline 75gOGTT, and post-heparin lipoprotein lipase activities were registered as a long-term cohort. As lipid-lowering trial, a total of 44 patients (Male 21, Age 65±11 ys) with primary dyslipidemia, and 18 genetically confirmed heterozygous familial hypercholesterolemia (FH) (Male 12, Age 65±10 ys,) were analyzed. Non-FH dyslipidemia was treated with 10mg Atorvastatin, and FH was treated with 20mg Rosuvastatin for 8 weeks. Plasma TG and betatrophin levels were log-transformed for statistical analysis. Results: In long-term cohort, 57 cases already showed diabetic pattern at baseline, 148 cases (Male 82, age 56±15 ys, hetero-FH 48 cases, mean follow-up period 10±3 ys) without diabetes at baseline were finally analyzed. Sixty-two cases (42%) developed newly diabetes mellitus during the follow-up, significantly fewer in FH than non-FH (25% vs. 50%, p <0.005). No differences in BMI, fasting glucose, HbA1c in baseline with R59W genotype. In low LPL activity group (n=31), W carriers showed significant increase in HbA1c compared with RR (2.1±0.5 vs. 0.9±0.4 %, p <0.05), but no differences in normal LPL group. In lipid lowering trial, baseline betatrophin levels were lower in FH group (19±13 vs. 13±6 ng/mL, p <0.05), but no difference with/without R59W variant. Statin treatment slightly decreased betatrophin in dyslipidemia group (-4%, p <0.01) and in FH group (-5%, p <0.01). Changes in betatrophin were positively correlated with changes in LDL-C with statins in both groups. Conclusion: Betatrophin R59W variant was a susceptibility factor of future diabetes mellitus with low LPL activity. Baseline betatrophin levels were lower in FH group than other primary dyslipidemia in lipid-lowering trial. Strong statin treatments slightly decreased betatrophin levels, but effect sizes were minimal.

Lipid mediators in diabetic nephropathy.

The implications of lipid lowering drugs in the treatment of diabetic nephropathy have been considered. At the same time, the clinical efficacy of lipid lowering drugs has resulted in improvement in the cardiovascular functions of chronic kidney disease (CKD) patients with or without diabetes, but no remarkable improvement has been observed in the kidney outcome. Earlier lipid mediators have been shown to cause accumulative effects in diabetic nephropathy (DN). Here, we attempt to analyze the involvement of lipid mediators in DN. The hyperglycemia-induced overproduction of diacyglycerol (DAG) is one of the causes for the activation of protein kinase C (PKCs), which is responsible for the activation of pathways, including the production of VEGF, TGFβ1, PAI-1, NADPH oxidases, and NFҟB signaling, accelerating the development of DN. Additionally, current studies on the role of ceramide are one of the major fields of study in DN. Researchers have reported excessive ceramide formation in the pathobiological conditions of DN. There is less report on the effect of lipid lowering drugs on the reduction of PKC activation and ceramide synthesis. Regulating PKC activation and ceramide biosynthesis could be a protective measure in the therapeutic potential of DN. Lipid lowering drugs also upregulate anti-fibrotic microRNAs, which could hint at the effects of lipid lowering drugs in DN.

Albumin excretion in adolescents with diabetes

If you would like to express interest in reviewing or writing papers for the Journal of Renal Nursing, please contact the journal’s editor via email (natasha.devan@markallengroup.com) Albumin excretion in adolescents with diabetes O ver the last 20 years, two longitudinal studies—the Oxford Regional Prospective Study (ORPS) and Nephropathy Family Study (NFS), facilitated by UK research nurses—have improved our understanding of the natural history of microalbuminuria in young people with type 1 diabetes. Microalbuminuria, a marker of early-stage renal damage and an independent risk factor for nephropathy and cardiovascular disease, has been found in around 26% of adolescents with type 1 diabetes 10–20 years after diagnosis. Early increases in urinary albumin excretion predict progression to microalbuminuria and more severe renal disease. In adults with type 1 diabetes, such early increases in albumin excretion have also been associated with risk for cardiovascular disease, but data from adolescents with type 1 diabetes has been lacking. The Adolescent Type 1 Diabetes cardio-renal Intervention Trial (AdDIT), designed to explore the effects of lipid-lowering drugs (statins) and blood pressure lowering drugs (angiotensin-converting-enzyme (ACE) inhibitors) on risk for diabetic nephropathy and cardiovascular disease, has allowed exploration of the relationship between cardiovascular risk and urinary albumin excretion in adolescents with type 1 diabetes. Research nurses in the UK, Australia and Canada screened over 3000 people aged 10–16 years with type 1 diabetes to identify those with higher than average albumin excretion. Participants were found to have renal hyperfiltration and an increase in both risk markers and direct measures of cardiovascular disease. Around 850 participants have now been recruited to a clinical trial of ACE inhibitors and/or statins, which has the potential to change diabetes management during adolescence and improve the long-term prognosis of young patients with type 1 diabetes.

Is irisin an early marker of statin-induced myopathy? Bench to the bedside

Evaluation of: Gouni-Berthold I, Berthold HK, Huh JY et al. Effects of lipid-lowering drugs on irisin in human subjects in vivo and in human skeletal muscle cells ex vivo. PLoS ONE 8(9), e72858 (2013). Irisin is a myokine that has recently gained interest for its role in glucose metabolism. It is known that age and muscle mass are the primary predictors of irisin concentration. However, the underlying mechanisms detailing the pathways affected by irisin are not clear. In this work, levels of irisin were measured in young, healthy individuals. The first part of the study was focused on understanding the regulation of irisin levels based on multiple baseline parameters, such as lipoprotein(a) and cholesterol levels. The second part of the study assessed the effect of lipid-lowering agents – simvastatin and ezetimibe – on serum irisin levels. Furthermore, the authors expanded the study by conducting in vitro experiments on human skeletal muscle cells to understand the biochemical mechanisms regulating the effect of simvastatin on irisin expression.

Lipid-Lowering Drugs Associated With Slower Motor Decline in the Elderly Adults

Vascular risk factors contribute to motor decline in the elderly persons. We investigated the relationship between lipid-lowering drugs (LLDs) use and decline in walking speed (WS) in older adults. Data on 4,009 community-dwelling men and women, aged ≥65 years at baseline, are drawn from the Dijon (France) center of the Three-City study. "Fast" WS was assessed over 6 m at baseline and at 4, 6, 8, and 10 years of follow-up. Mixed linear models were used to determine the relationship between LLDs and change in WS over the follow-up. At baseline, 1,295 (32%) participants used LLDs (statins, n = 643; fibrates, n = 652); mean fast WS was 152.9cm/s and not significantly different between LLDs users and nonusers. In models adjusted for age, sex, cholesterol level, and other covariates, WS decline was 25% slower in LLDs users (difference with nonusers: 0.58cm/s/y, 95% CI: 0.30, 0.86; p < .001). Both fibrates and statins were associated with slower decline, but only the effect of statins was robust in analyses that took missing values into account. The beneficial effect was more pronounced in those on LLDs continuously over the follow-up. Fast WS declined less in those on LLDs, suggesting that the effect of LLDs, statins in particular, extend beyond that on cardiovascular disease in the elderly persons. However, these effects were modest and their clinical relevance is unclear.

Effects of Lipid-Lowering Drugs on Irisin in Human Subjects In Vivo and in Human Skeletal Muscle Cells Ex Vivo

Context and ObjectiveThe myokine irisin has been proposed to regulate energy homeostasis. Little is known about its association with metabolic parameters and especially with parameters influencing pathways of lipid metabolism. In the context of a clinical trial, an exploratory post hoc analysis has been performed in healthy subjects to determine whether simvastatin and/or ezetimibe influence serum irisin levels. The direct effects of simvastatin on irisin were also examined in primary human skeletal muscle cells (HSKMCs).Design and ParticipantsA randomized, parallel 3-group study was performed in 72 men with mild hypercholesterolemia and without apparent cardiovascular disease. Each group of 24 subjects received a 14-day treatment with either simvastatin 40 mg, ezetimibe 10 mg, or their combination.ResultsBaseline irisin concentrations were not significantly correlated with age, BMI, estimated GFR, thyroid parameters, glucose, insulin, lipoproteins, non-cholesterol sterols, adipokines, inflammation markers and various molecular markers of cholesterol metabolism. Circulating irisin increased significantly in simvastatin-treated but not in ezetimibe-treated subjects. The changes were independent of changes in LDL-cholesterol and were not correlated with changes in creatine kinase levels. In HSKMCs, simvastatin significantly increased irisin secretion as well as mRNA expression of its parent peptide hormone FNDC5. Simvastatin significantly induced cellular reactive oxygen species levels along with expression of pro- and anti-oxidative genes such as Nox2, and MnSOD and catalase, respectively. Markers of cellular stress such as atrogin-1 mRNA and Bax protein expression were also induced by simvastatin. Decreased cell viability and increased irisin secretion by simvastatin was reversed by antioxidant mito-TEMPO, implying in part that irisin is secreted as a result of increased mitochondrial oxidative stress and subsequent myocyte damage.ConclusionsSimvastatin increases irisin concentrations in vivo and in vitro. It remains to be determined whether this increase is a result of muscle damage or a protective mechanism against simvastatin-induced cellular stress.Trial RegistrationClinicalTrials.gov NCT00317993 NCT00317993.

Long-Term Use of Lipid-Lowering Drugs Slows Progression of Carotid Atherosclerosis

Objective— Data on the effect of lipid-lowering drugs (LLD) on carotid atherosclerosis outside clinical trials are limited. The aim of this study was to determine the effect of LLD on change in carotid intima media thickness and total plaque area in a general population. Approach and Results— Subjects were 1532 women and 1442 men who participated in a longitudinal population-based study with ultrasound examination of intima media thickness and total plaque area in the right carotid artery at baseline and after 13 years follow-up. Long-term use of LLD was defined as use for &gt;5 years, any-time use of LLD was defined as use at baseline or at 6 years or at 13 years of follow-up. In multivariable models adjusted for age, sex, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, prevalent cardiovascular disease, and daily smoking, long-term use of LLD had a protective effect on progression of both intima media thickness (β=–0.0387 mm; P =0.002) and total plaque area (β=–0.400 mm 2 ; P =0.006). There was a weaker protective effect of any-time use of LLD on progression of intima media thickness (β=–0.024 mm; P =0.046) and total plaque area (β=–0.318 mm 2 ; P =0.06). Conclusions— LLD protected against progression of carotid atherosclerosis. The protective effect was strongest in long-term users.