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.

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.

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.

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.

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.

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.