Low-density lipoprotein cholesterol response to statins according to comorbidities and co-medications: A population-based study.

BACKGROUND: The response of low-density lipoprotein cholesterol (LDL-C) to statin therapy is variable, and may be affected by the presence of co-morbid conditions or the use of concomitant medications. Systematic variation in the response to statins based on these factors could affect the selection of the statin treatment regimen in population subgroups. We investigated whether common comorbidities and co-medications had clinically important effects on statin responses in individual patients. METHODS: This register-based cohort study included 89,006 simvastatin or atorvastatin initiators with measurements of pre-statin and on-statin LDL-C levels, in Denmark, 2008-2018. We defined statin response as the percentage reduction in LDL-C, and used linear regression to estimate percentage reduction differences (PRD) according to 175 chronic comorbidities and 99 co-medications. We evaluated both the statistical significance (P-values corrected for multiple testing) and the clinical importance (PRD of 5 percentage points or more) of the observed associations. RESULTS: Concomitant use of oral blood-glucose lowering drugs, which included metformin in 96% of treated individuals, was associated with a greater response to statin therapy that was both statistically significant and clinically important, with a PRD of 5.18 (95% confidence interval: 4.79 to 5.57). No other comorbidity or co-medication reached the prespecified thresholds for a significant, clinically important effect on statin response. Overall, comorbidities and co-medications had little effect on statin response, and altogether explained only 1.7% of the total observed population variance. CONCLUSION: Most of the studied comorbidities and co-medications did not have a clinically important effect on statin response, suggesting no need to modify treatment regimens. However, use of metformin was associated with a significantly enhanced LDL-C response to statins, suggesting that lower statin doses may be effective in patients taking metformin.

Effectiveness of low-density lipoprotein cholesterol reduction with lipid lowering therapy for secondary prevention amongst older individuals: a nationwide cohort study.

BACKGROUND: Data about the clinical benefit from initial low-density lipoprotein cholesterol (LDL-C) reduction with lipid lowering treatment for secondary prevention and risk of major vascular events amongst older as compared with younger individuals treated during routine clinical care are limited. We investigated this in a nationwide cohort. METHODS: Individuals aged ≥ 50 years with a first-time hospitalisation for a cardiovascular event (index event, including acute coronary syndrome, non-haemorrhagic stroke, transient ischaemic attack and coronary revascularisation), 1 January 2008 to 31 October 2018, who subsequently used lipid lowering treatment, and had an LDL-C measurement before and after the event were included. Hazard ratios (HRs) for major vascular events per 1 mmol/L reduction in LDL-C were estimated for the included 21,751 older and 22,681 younger individuals (≥/<70 years old) using Cox regression. RESULTS: LDL-C lowering was associated with a 12% lower risk of major vascular events in older individuals per 1 mmol/L reduction in LDL-C (HR 0.88, 95% confidence interval [CI] 0.84-0.93), with no significant difference compared with the risk reduction amongst younger individuals (HR 0.88, 95% CI 0.83-0.93; P-value for difference between age groups: 0.86). The risk reduction was more pronounced when post hoc restricting, as a proxy for compliance, to new users with an LDL-C reduction above the lowest decile for both older (0.81, 95% CI 0.73-0.90) and younger (0.81, 95% CI 0.72-0.91) individuals. CONCLUSIONS: This study strongly supports a similar relative clinical benefit of LDL-C reduction with lipid lowering treatment for secondary prevention of major vascular events amongst individuals aged ≥70 and <70 years.

LDL-C Reduction With Lipid-Lowering Therapy for Primary Prevention of Major Vascular Events Among Older Individuals.

BACKGROUND: Reducing low-density lipoprotein (LDL) cholesterol with lipid-lowering therapy has consistently been shown to lower the risk of cardiovascular disease in primary prevention trials where the majority of individuals are aged <70 years. For older individuals, however, evidence is less clear. OBJECTIVES: In this study, the authors sought to compare the clinical effectiveness of lowering LDL cholesterol by means of lipid-lowering therapy for primary prevention of cardiovascular disease among older and younger individuals in a Danish nationwide cohort. METHODS: We included individuals aged ≥50 years who had initiated lipid-lowering therapy from January 1, 2008, to October 31, 2017, had no history of atherosclerotic cardiovascular disease, and had a baseline and a within-1-year LDL cholesterol measurement. We assessed the associated risk of major vascular events among older individuals (≥70 years) by HRs per 1 mmol/L reduction in LDL cholesterol compared with younger individuals (<70 years). RESULTS: For both the 16,035 older and the 49,155 younger individuals, the median LDL cholesterol reduction was 1.7 mmol/L. Each 1 mmol/L reduction in LDL cholesterol in older individuals was significantly associated with a 23% lower risk of major vascular events (HR: 0.77; 95% CI: 0.71-0.83), which was equal to that of younger individuals (HR: 0.76; 95% CI: 0.71-0.80; P value for difference = 0.79). Similar results were observed across all secondary analyses. CONCLUSIONS: Our study supports a relative clinical benefit of lowering LDL cholesterol for primary prevention of major vascular events in individuals aged ≥70 years similarly as in individuals aged <70 years.

Effect of Simvastatin Treatment on Mitochondrial Function and Inflammatory Status of Human White Adipose Tissue.

BACKGROUND: Statin therapy has shown pleiotropic effects affecting both mitochondrial function and inflammatory status. However, few studies have investigated the concurrent effects of statin exposure on mitochondrial function and inflammatory status in human subcutaneous white adipose tissue. OBJECTIVES: In a cross-sectional study, we investigated the effects of simvastatin on mitochondrial function and inflammatory status in subcutaneous white adipose tissue of 55 human participants: 38 patients (19 females/19 males) in primary prevention with simvastatin (> 40 mg/d, > 3 mo) and 17 controls (9 females/8 males) with elevated plasma cholesterol. The 2 groups were matched on age, body mass index, and maximal oxygen consumption. METHODS: Anthropometrics and fasting biochemical characteristics were measured. Mitochondrial respiratory capacity was assessed in white adipose tissue by high-resolution respirometry. Subcutaneous white adipose tissue expression of the inflammatory markers IL-6, chemokine (C-C motif) ligand 2 (CCL2), CCL-5, tumor necrosis factor-α, IL-10, and IL-4 was analyzed by quantitative PCR. RESULTS: Simvastatin-treated patients showed lower plasma cholesterol (P < .0001), low-density lipoprotein (P < .0001), and triglyceride levels (P = .0116) than controls. Simvastatin-treated patients had a lower oxidative phosphorylation capacity of mitochondrial complex II (P = .0001 when normalized to wet weight, P < .0001 when normalized to citrate synthase activity [intrinsic]), and a lower intrinsic mitochondrial electron transport system capacity (P = .0004). Simvastatin-treated patients showed higher IL-6 expression than controls (P = .0202). CONCLUSION: Simvastatin treatment was linked to mitochondrial respiratory capacity in human subcutaneous white adipose tissue, but no clear link was found between statin exposure, respiratory changes, and inflammatory status of adipose tissue.

Coenzyme Q10 Supplementation in Statin Treated Patients: A Double-Blinded Randomized Placebo-Controlled Trial.

Myalgia and new-onset of type 2 diabetes have been associated with statin treatment, which both could be linked to reduced coenzyme Q10 (CoQ10) in skeletal muscle and impaired mitochondrial function. Supplementation with CoQ10 focusing on levels of CoQ10 in skeletal muscle and mitochondrial function has not been investigated in patients treated with statins. To investigate whether concomitant administration of CoQ10 with statins increases the muscle CoQ10 levels and improves the mitochondrial function, and if changes in muscle CoQ10 levels correlate with changes in the intensity of myalgia. 37 men and women in simvastatin therapy with and without myalgia were randomized to receive 400 mg CoQ10 daily or matched placebo tablets for eight weeks. Muscle CoQ10 levels, mitochondrial respiratory capacity, mitochondrial content (using citrate synthase activity as a biomarker), and production of reactive oxygen species were measured before and after CoQ10 supplementation, and intensity of myalgia was determined using the 10 cm visual analogue scale. Muscle CoQ10 content and mitochondrial function were unaltered by CoQ10 supplementation. Individual changes in muscle CoQ10 levels were not correlated with changes in intensity of myalgia. CoQ10 supplementation had no effect on muscle CoQ10 levels or mitochondrial function and did not affect symptoms of myalgia.

Effect of 6 weeks of very low-volume high-intensity interval training on oral glucose-stimulated incretin hormone response.

Introduction: Decreased fasting and oral glucose-stimulated incretin hormone concentrations following moderate-intensity continuous endurance training interventions have been reported in glucose-tolerant people, however results are conflicting. The effect of more time-efficient, very low-volume, high-intensity interval training (HIT) on circulating incretin hormone levels has never been studied.Materials and methods: Ten sedentary and overweight-to-obese participants (4 women and 6 men; age 43 ± 6 years (mean ± SD); BMI 30.2 ± 3.2 kg∙m-2; HbA1c 35 ± 5.1 mmol∙mol-1 (5.3 ± 0.3%); VO2max 30 ± 5 ml∙min-1∙kg-1) from the Copenhagen cohort of the METAPREDICT trial underwent 6 weeks of supervised low-volume HIT (3 sessions per week: 7 × 1 min at ∼100% VO2max separated by 1 min of active recovery). We measured glucose, insulin, C-peptide, glucagon, GLP-1 and GIP concentrations during a frequently sampled 75 g oral glucose tolerance test as well as VO2max and body composition before and after the intervention.Results: Training compliance was 100%. Relative VO2max improved after the intervention (median 2.69 ml∙min-1∙kg-1, IQR [0.43; 3.14], p = 0.037) while there were no significant effects on body weight and composition. No significant effects on oral glucose-stimulated glucose and hormone responses or estimates of insulin sensitivity and ß-cell function were observed.Conclusion: Low-volume HIT improved aerobic fitness, but neither affected glucose tolerance nor oral glucose-stimulated incretin hormone responses in sedentary and overweight-to-obese people.Highlights Ten sedentary, overweight-to-obese, glucose-tolerant participants underwent 6 weeks of supervised, very low-volume HIT.Aerobic fitness improved.Fasting and oral glucose-stimulated incretin hormone concentrations were not affected.

Atorvastatin impairs liver mitochondrial function in obese Göttingen Minipigs but heart and skeletal muscle are not affected.

Statins lower the risk of cardiovascular events but have been associated with mitochondrial functional changes in a tissue-dependent manner. We investigated tissue-specific modifications of mitochondrial function in liver, heart and skeletal muscle mediated by chronic statin therapy in a Göttingen Minipig model. We hypothesized that statins enhance the mitochondrial function in heart but impair skeletal muscle and liver mitochondria. Mitochondrial respiratory capacities, citrate synthase activity, coenzyme Q10 concentrations and protein carbonyl content (PCC) were analyzed in samples of liver, heart and skeletal muscle from three groups of Göttingen Minipigs: a lean control group (CON, n = 6), an obese group (HFD, n = 7) and an obese group treated with atorvastatin for 28 weeks (HFD + ATO, n = 7). Atorvastatin concentrations were analyzed in each of the three tissues and in plasma from the Göttingen Minipigs. In treated minipigs, atorvastatin was detected in the liver and in plasma. A significant reduction in complex I + II-supported mitochondrial respiratory capacity was seen in liver of HFD + ATO compared to HFD (P = 0.022). Opposite directed but insignificant modifications of mitochondrial respiratory capacity were seen in heart versus skeletal muscle in HFD + ATO compared to the HFD group. In heart muscle, the HFD + ATO had significantly higher PCC compared to the HFD group (P = 0.0323). In the HFD group relative to CON, liver mitochondrial respiration decreased whereas in skeletal muscle, respiration increased but these changes were insignificant when normalizing for mitochondrial content. Oral atorvastatin treatment in Göttingen Minipigs is associated with a reduced mitochondrial respiratory capacity in the liver that may be linked to increased content of atorvastatin in this organ.

Simvastatin improves mitochondrial respiration in peripheral blood cells.

Statins are prescribed to treat hypercholesterolemia and to reduce the risk of cardiovascular disease. However, statin users frequently report myalgia, which can discourage physical activity or cause patients to discontinue statin use, negating the potential benefit of the treatment. Although a proposed mechanism responsible for Statin-Associated Myopathy (SAM) suggests a correlation with impairment of mitochondrial function, the relationship is still poorly understood. Here, we provide evidence that long-term treatment of hypercholesterolemic patients with Simvastatin at a therapeutic dose significantly display increased mitochondrial respiration in peripheral blood mononuclear cells (PBMCs), and platelets compared to untreated controls. Furthermore, the amount of superoxide is higher in mitochondria in PBMCs, and platelets from Simvastatin-treated patients than in untreated controls, and the abundance of mitochondrial superoxide, but not mitochondrial respiration trends with patient-reported myalgia. Ubiquinone (also known as coenzyme Q10) has been suggested as a potential treatment for SAM; however, an 8-week course of oral ubiquinone had no impact on mitochondrial functions or the abundance of superoxide in mitochondria from PBMCs, and platelets. These results demonstrate that long-term treatment with Simvastatin increases respiration and the production of superoxide in mitochondria of PBMCs and platelets.

Inducible deletion of skeletal muscle AMPKα reveals that AMPK is required for nucleotide balance but dispensable for muscle glucose uptake and fat oxidation during exercise.

OBJECTIVE: Evidence for AMP-activated protein kinase (AMPK)-mediated regulation of skeletal muscle metabolism during exercise is mainly based on transgenic mouse models with chronic (lifelong) disruption of AMPK function. Findings based on such models are potentially biased by secondary effects related to a chronic lack of AMPK function. To study the direct effect(s) of AMPK on muscle metabolism during exercise, we generated a new mouse model with inducible muscle-specific deletion of AMPKα catalytic subunits in adult mice. METHODS: Tamoxifen-inducible and muscle-specific AMPKα1/α2 double KO mice (AMPKα imdKO) were generated by using the Cre/loxP system, with the Cre under the control of the human skeletal muscle actin (HSA) promoter. RESULTS: During treadmill running at the same relative exercise intensity, AMPKα imdKO mice showed greater depletion of muscle ATP, which was associated with accumulation of the deamination product IMP. Muscle-specific deletion of AMPKα in adult mice promptly reduced maximal running speed and muscle glycogen content and was associated with reduced expression of UGP2, a key component of the glycogen synthesis pathway. Muscle mitochondrial respiration, whole-body substrate utilization, and muscle glucose uptake and fatty acid (FA) oxidation during muscle contractile activity remained unaffected by muscle-specific deletion of AMPKα subunits in adult mice. CONCLUSIONS: Inducible deletion of AMPKα subunits in adult mice reveals that AMPK is required for maintaining muscle ATP levels and nucleotide balance during exercise but is dispensable for regulating muscle glucose uptake, FA oxidation, and substrate utilization during exercise.

Mitochondrial adaptations to high intensity interval training in older females and males.

Introduction: High intensity interval training (HIIT) has shown to be as effective as moderate intensity endurance training to improve metabolic health. However, the current knowledge on the effect of HIIT in older individuals is limited and it is uncertain whether the adaptations are sex specific. The aim was to investigate effects of HIIT on mitochondrial respiratory capacity and mitochondrial content in older females and males. Methods: Twenty-two older sedentary males (n = 11) and females (n = 11) completed 6 weeks of supervised HIIT 3 days per week. The training consisted of 5 × 1 min cycling (124 ± 3% of max power output at session 2-6 and 135 ± 3% of max power output at session 7-20) interspersed by 1½ min recovery. Before the intervention and 72 h after last training session a muscle biopsy was obtained and mitochondrial respiratory capacity, citrate synthase activity and proteins involved in mitochondria metabolism were assessed. Furthermore, body composition and ⩒O2max were measured. Results: ⩒O2max increased and body fat percentage decreased after HIIT in both sexes (p < 0.05). In addition, CS activity and protein content of MnSOD and complex I-V increased in both sexes. Coupled and uncoupled mitochondrial respiratory capacity increased only in males. Mitochondrial respiratory capacity normalised to CS activity (intrinsic mitochondrial respiratory capacity) did not change following HIIT. Conclusion: HIIT induces favourable adaptions in skeletal muscle in older subjects by increasing mitochondrial content, which may help to maintain muscle oxidative capacity and slow down the process of sarcopenia associated with ageing.

Plasma Albumin and Incident Cardiovascular Disease: Results From the CGPS and an Updated Meta-Analysis.

OBJECTIVE: We studied the association of plasma albumin with cardiovascular disease (CVD) and explored potential mechanisms behind the association in the CGPS (Copenhagen General Population Study). We also performed a meta-analysis to summarize the association between plasma albumin and CVD in individuals without preexisting CVD. Approach and Results: We included 100 520 individuals without prior CVD with 8247 incident CVD events developed during a median follow-up of 8.5 years. Rates of CVD outcomes were calculated using Cox regression and Fine and Gray competing-risks regression. The association of plasma albumin and CVD was approximately linear and confounder adjustment had little influence on the effect estimates, except for some attenuation after CRP (C-reactive protein) adjustment. In analyses according to subtypes of CVD events, the hazard ratios for each 10 g/L lower plasma albumin were 1.17 (95% CI, 1.08-1.28) for ischemic heart disease, 1.25 (95% CI, 1.09-1.43) for myocardial infarction, 1.37 (95% CI, 1.21-1.54) for any stroke, and 1.46 (95% CI, 1.28-1.68) for ischemic stroke. In the meta-analysis, we combined estimates from prospective and nested case-control studies investigating the association of plasma albumin with CVD. The meta-analysis included 14 studies with 150 652 individuals (12 studies reported events totaling 11 872). The risk ratio for a CVD event per 10 g/L lower plasma albumin was 1.96 (95% CI, 1.43-2.68) in previous studies and 1.85 (95% CI, 1.39-2.47) including our study with 57% weight in the meta-analysis. Exploratory analyses of the mechanism of the association indicated that it was probably not due to fatty acid binding but may be due to the regulation of plasma albumin by inflammation. CONCLUSIONS: There is a robust, independent association of low plasma albumin with CVD, partly explained by plasma albumin as a negative acute-phase reactant. CLINICAL TRIAL REGISTRATION: URL: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=95796. Unique identifier: CRD42018095796.

Aerobic Exercise Performance and Muscle Strength in Statin Users-The LIFESTAT Study.

INTRODUCTION: Statins are widely used in both primary and secondary prevention of cardiovascular disease. The treatment increases the risk of muscle pain (myalgia) which can affect muscle function and levels of physical activity. We investigated whether statin-associated myalgia is coupled to impaired aerobic exercise performance including fat oxidation as well as impaired muscle strength. METHODS: A population-based survey (6000 people) was performed to assess the prevalence of statin-associated myalgia in the Danish population. In addition, 64 statin users in primary prevention with myalgia (M; n = 25; 61 ± 1 yr) or without myalgia (NM; n = 37; 63 ± 1 yr) as well as a control group not taking statins (C; n = 20; 60 ± 2 yr) were enrolled in a cross-sectional study where they performed aerobic exercise and muscle strength tests. RESULTS: The response rate for the survey was 51% and data showed a prevalence of statin-associated myalgia in 19% of responders using statins. The experimental study showed no difference between the groups in aerobic capacity (C, 29 ± 1 mL O2·min·kg; M, 27 ± 1 mL O2·min·kg; NM, 28 ± 1 mL O2·min·kg) or maximal fat oxidation (C, 247 ± 26 mg·min; M, 295 ± 24 mg·min; NM, 279 ± 17 mg·min). Measurements of strength were similar in all three groups including rate of force development (C, 795 ± 56 N·m·s; M, 930 ± 93 N·m·s; NM, 971 ± 57 N·m·s) and leg extension power (C: 2.6 ± 0.2; M: 2.3 ± 0.1; NM: 2.4 ± 0.1 W·kg). All results are mean ± SEM. CONCLUSION: Statin users in primary prevention experiencing myalgia do not have impaired aerobic exercise performance or muscle strength compared to nonmyalgic statin users or control subjects.

Statin Treatment Decreases Mitochondrial Respiration But Muscle Coenzyme Q10 Levels Are Unaltered: The LIFESTAT Study.

BACKGROUND: Myalgia is a common adverse effect of statin therapy, but the underlying mechanism is unknown. Statins may reduce levels of coenzyme Q10 (CoQ10), which is an essential electron carrier in the mitochondrial electron transport system, thereby impairing mitochondrial respiratory function, potentially leading to myalgia. OBJECTIVES: To investigate whether statin-induced myalgia is coupled to reduced intramuscular CoQ10 concentration and impaired mitochondrial respiratory function. METHODS: Patients receiving simvastatin (i.e., statin) therapy (n = 64) were recruited, of whom 25 experienced myalgia (myalgic group) and 39 had no symptoms of myalgia (NS group). Another 20 had untreated high blood cholesterol levels (control group). Blood and muscle samples were obtained. Intramuscular CoQ10 concentration was measured, and mitochondrial respiratory function and reactive oxygen species (ROS) production were measured. Citrate synthase (CS) activity was used as a biomarker of mitochondrial content in skeletal muscle. RESULTS: Intramuscular CoQ10 concentration was comparable among groups. Mitochondrial complex II-linked respiration was reduced in the statin-myalgic and -NS groups compared with the control group. When mitochondrial respiration was normalized to CS activity, respiration rate was higher in the myalgic group compared with the NS and control groups. Maximal ROS production was similar among groups. CONCLUSION: Statin therapy appeared to impair mitochondrial complex-II-linked respiration, but the mitochondrial capacity for complex I+II-linked respiration remained intact. Myalgia was not coupled to reduced intramuscular CoQ10 levels. Intrinsic mitochondrial respiratory capacity was increased with statin-induced myalgia but not accompanied by increased ROS production.

Coenzyme Q10 does not improve peripheral insulin sensitivity in statin-treated men and women: the LIFESTAT study.

Simvastatin is a cholesterol-lowering drug that is prescribed to lower the risk of cardiovascular disease following high levels of blood cholesterol. There is a possible risk of new-onset diabetes mellitus with statin treatment but the mechanisms behind are unknown. Coenzyme Q10 (CoQ10) supplementation has been found to improve glucose homeostasis in various patient populations and may increase muscle glucose transporter type 4 content. Our aim was to investigate if 8 weeks of CoQ10 supplementation can improve glucose homeostasis in simvastatin-treated subjects. Thirty-five men and women in treatment with a minimum of 40 mg of simvastatin daily were randomized to receive either 2 × 200 mg/day of CoQ10 supplementation or placebo for 8 weeks. Glucose homeostasis was investigated with fasting blood samples, oral glucose tolerance test (OGTT) and intravenous glucose tolerance test. Insulin sensitivity was assessed with the hyperinsulinemic-euglycemic clamp. Different indices were calculated from fasting samples and OGTT as secondary measures of insulin sensitivity. A muscle biopsy was obtained from the vastus lateralis muscle for muscle protein analyzes. There were no changes in body composition, fasting plasma insulin, fasting plasma glucose, or 3-h glucose with intervention, but glycated hemoglobin decreased with time. Glucose homeostasis measured as the area under the curve for glucose, insulin, and C-peptide during OGTT was unchanged after intervention. Insulin secretory capacity was also unaltered after CoQ10 supplementation. Insulin sensitivity was unchanged but hepatic insulin sensitivity increased. No changes in muscle GLUT4 content was observed after intervention. CoQ10 supplementation does not change muscle GLUT4 content, insulin sensitivity, or secretory capacity, but hepatic insulin sensitivity may improve.

Inflammatory biomarkers in patients in Simvastatin treatment: No effect of co-enzyme Q10 supplementation.

PURPOSE: Atherosclerosis is a major risk factor for cardiovascular disease (CVD) and is known to be an inflammatory process. Statin therapy decreases both cholesterol and inflammation and is used in primary and secondary prevention of CVD. However, a statin induced decrease of plasma concentrations of the antioxidant coenzyme Q10 (CoQ10), may prevent the patients from reaching their optimal anti-inflammatory potential. Here, we studied the anti-inflammatory effect of Simvastatin therapy and CoQ10 supplementation. METHODS: 35 patients in primary prevention with Simvastatin (40 mg/day) were randomized to receive oral CoQ10 supplementation (400 mg/d) or placebo for 8 weeks. 20 patients with hypercholesterolemia who received no cholesterol-lowering treatment was a control group. Plasma concentrations of lipids and inflammatory biomarkers (interleukin-6 (IL6); -8 (IL8); -10 (IL10), tumor necrosis factor-α (TNFα); high-sensitivity C reactive protein (hsCRP)) as well as glycated hemoglobin (HbA1c) were quantified before and after the intervention. RESULTS: No significant change in inflammatory markers or lipids was observed after CoQ10 supplementation Patients in Simvastatin therapy had significantly (P < 0.05) lower baseline concentration of IL6 (0.31 ±â€¯0.03 pg/ml), IL8 (1.6 ±â€¯0.1 pg/ml) IL10 (0.16 ±â€¯0.02 pg/ml) and borderline (P = 0.053) lower TNFα (0.88 ±â€¯0.05 pg/ml), but not hsCRP (1.34 ±â€¯0.19 mg/l) compared with the control group (0.62 ±â€¯0.08, 2.6 ±â€¯0.2, 0.25 ±â€¯0.01, 1.07 ±â€¯0.09, and 1.90 ±â€¯0.35, respectively). CONCLUSIONS: Simvastatin therapy has beneficial effects on inflammatory markers in plasma, but CoQ10 supplementation seems to have no additional potentiating effect in patients in primary prevention. In contrast, glucose homeostasis may improve with CoQ10 supplementation.

Glucose homeostasis in statin users-The LIFESTAT study.

BACKGROUND: Statins are widely used to lower cholesterol concentrations in both primary and secondary prevention of cardiovascular disease. The treatment increases the risk of muscle pain (myalgia) and of type 2 diabetes. However, the underlying mechanisms remain disputed. METHODS: We investigated whether statin induced myalgia is coupled to impaired glucose homeostasis using oral glucose tolerance test (OGTT), intravenous glucose tolerance test (IVGTT), and the hyperinsulinemic euglycemic clamp. We performed a cross-sectional study of statin users without CVD (primary prevention) stratified into a statin myalgic (M; n = 25) and a non-myalgic (NM; n = 39) group as well as a control group (C; n = 20) consisting of non-statin users. RESULTS: A reduction in the insulin secretion rate during the OGTT was observed in the myalgic group compared with the non-myalgic group (AUC ISROGTT , C: 1032 (683 - 1500); M: 922 (678 - 1091); NM: 1089 (933 - 1391) pmol·L-1 ·min (median with 25%-75% percentiles), but no other measurements indicated impaired ß-cell function. We found no other differences between the three groups for other measurements in the OGTT, IVGTT, and euglycemic clamp. Muscle protein content of GLUT4 and hexokinase II was similar between the three groups. CONCLUSIONS: We conclude that statin users in primary prevention experiencing myalgia do not have impaired glucose homeostasis compared with other statin users or non-users. We consider this an important aspect in the dialogue between physician and patient regarding statin treatment and adverse effects.

High-intensity interval training changes mitochondrial respiratory capacity differently in adipose tissue and skeletal muscle.

The effect of high-intensity training (HIT) on mitochondrial ADP sensitivity and respiratory capacity was investigated in human skeletal muscle and subcutaneous adipose tissue (SAT). Twelve men and women underwent 6 weeks of HIT (7 × 1 min at app. 100% of maximal oxygen uptake (VO2max )). Mitochondrial respiration was measured in permeabilized muscle fibers and in abdominal SAT. Mitochondrial ADP sensitivity was determined using Michaelis Menten enzyme kinetics. VO2max , body composition and citrate synthase (CS) activity (skeletal muscle) and mtDNA (SAT) were measured before and after training. VO2max increased from 2.6 ± 0.2 to 2.8 ± 0.2 L O2 /min (P = 0.011) accompanied by a decreased mitochondrial ADP sensitivity in skeletal muscle (Km : 0.14 ± 0.02 to 0.29 ± 0.03 mmol/L ADP (P = 0.002)), with no changes in SAT (Km : 0.12 ± 0.02 to 0.16 ± 0.05 mmol/L ADP; P = 0.186), following training. Mitochondrial respiratory capacity increased in skeletal muscle from 57 ± 4 to 67 ± 4 pmol O2 ·mg-1 ·sec-1 (P < 0.001), but decreased with training in SAT from 1.3 ± 0.1 to 1.0 ± 0.1 pmol O2 ·mg-1 ·sec-1 (P < 0.001). CS activity increased (P = 0.027) and mtDNA was unchanged following training. Intrinsic mitochondrial respiratory capacity was unchanged in skeletal muscle, but increased in SAT after HIT. In summary, our results demonstrate that mitochondrial adaptations to HIT in skeletal muscle are comparable to adaptations to endurance training, with an increased mitochondrial respiratory capacity and CS activity. However, mitochondria in SAT adapts differently compared to skeletal muscle mitochondria, where mitochondrial respiratory capacity decreased and mtDNA remained unchanged after HIT.

The effects of 2 weeks of statin treatment on mitochondrial respiratory capacity in middle-aged males: the LIFESTAT study.

BACKGROUND: Statins are used to lower cholesterol in plasma and are one of the most used drugs in the world. Many statin users experience muscle pain, but the mechanisms are unknown at the moment. Many studies have hypothesized that mitochondrial function could be involved in these side effects. AIM: The aim of the study was to investigate mitochondrial function after 2 weeks of treatment with simvastatin (S; n = 10) or pravastatin (P; n = 10) in healthy middle-aged participants. METHODS: Mitochondrial respiratory capacity and substrate sensitivity were measured in permeabilized muscle fibers by high-resolution respirometry. Mitochondrial content (citrate synthase (CS) activity), antioxidant content, as well as coenzyme Q10 concentration (Q10) were determined. Fasting plasma glucose and insulin concentrations were measured, and whole body maximal oxygen uptake (VO2max) was determined. RESULTS: No differences were seen in mitochondrial respiratory capacity although a tendency was observed for a reduction when complex IV respiration was analyzed in both S (229 (169; 289 (95% confidence interval)) vs. 179 (146; 211) pmol/s/mg, respectively; P = 0.062) and P (214 (143; 285) vs. 162 (104; 220) pmol/s/mg, respectively; P = 0.053) after treatment. A tendency (1.64 (1.28; 2.00) vs. 1.28 (0.99; 1.58) mM, respectively; P = 0.092) for an increased mitochondrial substrate sensitivity (complex I-linked substrate; glutamate) was seen only in S after treatment. No differences were seen in Q10, CS activity, or antioxidant content after treatment. Fasting glucose and insulin as well as VO2max were not changed after treatment. CONCLUSION: Two weeks of statin (S or P) treatment have no major effect on mitochondrial function. The tendency for an increased mitochondrial substrate sensitivity after simvastatin treatment could be an early indication of the negative effects linked to statin treatment.