Statins Abstracts 3

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The effects of 2 weeks of statin treatment on mitochondrial respiratory capacity in middle-aged males: the LIFESTAT study.
            (Asping et al., 2017) Download
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 Q 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 Q 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.

Impact of coenzyme Q-10 on parameters of cardiorespiratory fitness and muscle performance in older athletes taking statins.
            (Deichmann et al., 2012) Download
Many older athletes take statins, which are known to have potential for muscle toxicity. The adverse effects of statins on muscles and the influence thereof on athletic performance remain uncertain. Coenzyme Q-10 (CoQ10) may improve performance and reduce muscle toxicity in older athletes taking statins. This trial was designed to evaluate the benefits of CoQ10 administration for mitochondrial function in this population. Twenty athletes aged ≥ 50 years who were taking stable doses of statins were randomized to receive either CoQ10 (200 mg daily) or placebo for 6 weeks in a double-blind, placebo-controlled, crossover study to evaluate the impact of CoQ10 on the anaerobic threshold (AT). Several secondary endpoints, including muscle function, cardiopulmonary exercise function, and subjective feelings of fitness, were also assessed. The mean (SD) change in AT from baseline was -0.59 (1.2) mL/kg/min during placebo treatment and 2.34 (0.8) mL/kg/min during CoQ10 treatment (P = 0.116). The mean change in time to AT from baseline was significantly greater during CoQ10 treatment than during placebo treatment (40.26 s vs 0.58 s, P = 0.038). Furthermore, muscle strength as measured by leg extension repetitions (reps) increased significantly during CoQ10 treatment, with a mean (SD) increase from baseline of 1.73 (2.9) reps during placebo treatment versus 3.78 (5.0) reps during CoQ10 treatment (P = 0.031). Many other parameters also tended to improve in response to CoQ10 treatment. Treatment with CoQ10 improved AT in comparison with baseline values in 11 of 19 (58%) subjects and in comparison with placebo treatment values in 10 of 19 (53%) subjects. Treatment with CoQ10 (200 mg daily) did not significantly improve AT in older athletes taking statins. However, it did improve muscle performance as measured by time to AT and leg strength (quadriceps muscle reps). Many other measures of mitochondrial function also tended to improve during CoQ10 treatment.

Pantethine, a derivative of vitamin B5, favorably alters total, LDL and non-HDL cholesterol in low to moderate cardiovascular risk subjects eligible for statin therapy: a triple-blinded placebo and diet-controlled investigation.
            (Evans et al., 2014) Download
High serum concentration of low-density lipoprotein cholesterol (LDL-C) is a major risk factor for coronary heart disease. The efficacy of pantethine treatment on cardiovascular risk markers was investigated in a randomized, triple-blinded, placebo-controlled study, in a low to moderate cardiovascular disease (CVD) risk North American population eligible for statin therapy, using the National Cholesterol Education Program (NCEP) guidelines. A total of 32 subjects were randomized to pantethine (600 mg/day from weeks 1 to 8 and 900 mg/day from weeks 9 to 16) or placebo. Compared with placebo, the participants on pantethine showed a significant decrease in total cholesterol at 16 weeks (P=0.040) and LDL-C at 8 and 16 weeks (P=0.020 and P=0.006, respectively), and decreasing trends in non-high-density lipoprotein cholesterol at week 8 and week 12 (P=0.102 and P=0.145, respectively) that reached significance by week 16 (P=0.042). An 11% decrease in LDL-C from baseline was seen in participants on pantethine, at weeks 4, 8, 12, and 16, while participants on placebo showed a 3% increase at week 16. This decrease was significant between groups at weeks 8 (P=0.027) and 16 (P=0.010). The homocysteine levels for both groups did not change significantly from baseline to week 16. Coenzyme Q10 significantly increased from baseline to week 4 and remained elevated until week 16, in both the pantethine and placebo groups. After 16 weeks, the participants on placebo did not show significant improvement in any CVD risk end points. This study confirms that pantethine lowers cardiovascular risk markers in low to moderate CVD risk participants eligible for statins according to NCEP guidelines.

Vitamin D3 effects on lipids differ in statin and non-statin-treated humans: superiority of free 25-OH D levels in detecting relationships.
            (Kane et al., 2013) Download
CONTEXT:  Inverse associations between 25-OH vitamin D levels and cardiovascular morbidity and mortality have been reported. OBJECTIVES:  Our goals were to 1) investigate effects of correcting inadequate D status on lipids, 2) determine whether free 25-OH D is better correlated with lipids than total 25-OH D. DESIGN:  A randomized, double-blind placebo-controlled trial was performed. SETTING:  Participants resided in the general community. PARTICIPANTS:  Adults with inadequate D status were randomized to D3: 14 men, 12 women, age 60 ± 8 years (mean ± SD) or placebo: 12 men, 11 women: 59 ±12 years. INTERVENTION:  Responses to 12-week oral vitamin D3 titrated (1000-3000 IU/d) to achieve 25-OH D levels ≥25 ng/mL were compared to placebo. MAIN OUTCOME MEASURES:  Measurements were 25-OH D (tandem mass spectometry), free 25-OH D (direct immunoassay), lipids (directly measured triglyceride, cholesterol, and subfractions; plant sterols and cholesterol synthesis precursors), and safety labs before and after 6 and 12 weeks D3 or placebo. Data were analyzed by repeated measures ANOVA and linear regression. RESULTS:  Vitamin D3 was titrated to 1000 IU/d in 15/26 (58%), to 2000 IU/d in 10, and 3000 IU/d in one patient. D3 had no effect on cholesterol or cholesterol subfractions except for trends for decreases in atorvastatin-treated patients (cholesterol, P = .08; low-density lipoprotein [LDL] cholesterol, P = .05). Decreased campesterol concentrations (P = .05) were seen with D3 but not placebo in statin-treated patients. Relationships between total 25-OH D and lipids were not detected, but inverse linear relationships were detected between free 25-OH D and triglycerides (P = .03 for all participants [n = 49], P = .03 in all statin-treated [n = 19], and P = .0009 in atorvastatin-treated [n = 11]), and between free 25-OH D and LDL cholesterol (P = .08 overall, P = .02 in all statin-treated, and P = .03 for atorvastatin-treated), and total cholesterol (P = .09 overall; P = .04 for all statin-treated, and P = .05 for atorvastatin-treated). CONCLUSIONS:  Vitamin D lipid-lowering effects appear limited to statin-treated patients and are likely due to decreased cholesterol absorption. Relationships between lipids and D metabolites were only detected when free 25-OH D was measured, suggesting the superiority of determining free 25-OH D levels compared to total 25-OH vitamin D levels when analyzing biologic responses.


 

Simvastatin effects on skeletal muscle: relation to decreased mitochondrial function and glucose intolerance.
            (Larsen et al., 2013) Download
OBJECTIVES:  Glucose tolerance and skeletal muscle coenzyme Q(10) (Q(10)) content, mitochondrial density, and mitochondrial oxidative phosphorylation (OXPHOS) capacity were measured in simvastatin-treated patients (n = 10) and in well-matched control subjects (n = 9). BACKGROUND:  A prevalent side effect of statin therapy is muscle pain, and yet the basic mechanism behind it remains unknown. We hypothesize that a statin-induced reduction in muscle Q(10) may attenuate mitochondrial OXPHOS capacity, which may be an underlying mechanism. METHODS:  Plasma glucose and insulin concentrations were measured during an oral glucose tolerance test. Mitochondrial OXPHOS capacity was measured in permeabilized muscle fibers by high-resolution respirometry in a cross-sectional design. Mitochondrial content (estimated by citrate synthase [CS] activity, cardiolipin content, and voltage-dependent anion channel [VDAC] content) as well as Q(10) content was determined. RESULTS:  Simvastatin-treated patients had an impaired glucose tolerance and displayed a decreased insulin sensitivity index. Regarding mitochondrial studies, Q(10) content was reduced (p = 0.05), whereas mitochondrial content was similar between the groups. OXPHOS capacity was comparable between groups when complex I- and complex II-linked substrates were used alone, but when complex I + II-linked substrates were used (eliciting convergent electron input into the Q intersection [maximal ex vivo OXPHOS capacity]), a decreased (p < 0.01) capacity was observed in the patients compared with the control subjects. CONCLUSIONS:  These simvastatin-treated patients were glucose intolerant. A decreased Q(10) content was accompanied by a decreased maximal OXPHOS capacity in the simvastatin-treated patients. It is plausible that this finding partly explains the muscle pain and exercise intolerance that many patients experience with their statin treatment.

Effects of coenzyme Q10 supplementation (300 mg/day) on antioxidation and anti-inflammation in coronary artery disease patients during statins therapy: a randomized, placebo-controlled trial.
            (Lee et al., 2013) Download
BACKGROUND:  High oxidative stress and chronic inflammation can contribute to the pathogenesis of coronary artery disease (CAD). Coenzyme Q10 is an endogenous lipid-soluble antioxidant. Statins therapy can reduce the biosynthesis of coenzyme Q10. The purpose of this study was to investigate the effects of a coenzyme Q10 supplement (300 mg/d; 150 mg/b.i.d) on antioxidation and anti-inflammation in patients who have CAD during statins therapy. METHODS:  Patients who were identified by cardiac catheterization as having at least 50% stenosis of one major coronary artery and who were treated with statins for at least one month were enrolled in this study. The subjects (n = 51) were randomly assigned to the placebo (n = 24) and coenzyme Q10 groups (Q10-300 group, n = 27). The intervention was administered for 12 weeks. The concentrations of coenzyme Q10, vitamin E, antioxidant enzymes activities (superoxide dismutase, catalase, and glutathione peroxidase), and inflammatory markers [C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6)] were measured in the 42 subjects (placebo, n = 19; Q10-300, n = 23) who completed the study. RESULTS:  The levels of the plasma coenzyme Q10 (P < 0.001) and antioxidant enzymes activities (P < 0.05) were significantly higher after coenzyme Q10 supplementation. The levels of inflammatory markers (TNF-α, P = 0.039) were significantly lower after coenzyme Q10 supplementation. The subjects in the Q10-300 group had significantly higher vitamin E (P = 0.043) and the antioxidant enzymes activities (P < 0.05) than the placebo group at week 12. The level of plasma coenzyme Q10 was significantly positively correlated with vitamin E (P = 0.008) and antioxidant enzymes activities (P < 0.05) and was negatively correlated with TNF-α (P = 0.034) and IL-6 (P = 0.027) after coenzyme Q10 supplementation. CONCLUSION:  Coenzyme Q10 supplementation at 300 mg/d significantly enhances antioxidant enzymes activities and lowers inflammation in patients who have CAD during statins therapy. TRIAL REGISTRATION:  ClinicalTrials.gov Identifier: NCT01424761.

Effect of niacin on high-density lipoprotein apolipoprotein A-I kinetics in statin-treated patients with type 2 diabetes mellitus.
            (Pang et al., 2014) Download
OBJECTIVE:  To investigate the effect of extended-release (ER) niacin on the metabolism of high-density lipoprotein (HDL) apolipoprotein A-I (apoA-I) in men with type 2 diabetes mellitus on a background of optimal statin therapy. APPROACH AND RESULTS:  Twelve men with type 2 diabetes mellitus were recruited for a randomized, crossover design trial. Patients were randomized to rosuvastatin or rosuvastatin plus ER niacin for 12 weeks and then crossed over to the alternate therapy after a 3-week washout period. Metabolic studies were performed at the end of each treatment period. HDL apoA-I kinetics were measured after a standardized liquid mixed meal and a bolus injection of d3-leucine for 96 hours. Compartmental analysis was used to model the data. ER niacin significantly decreased plasma triglyceride, plasma cholesterol, non-HDL cholesterol, low-density lipoprotein cholesterol, and apoB (all P<0.05) and significantly increased HDL cholesterol and apoA-I concentrations (P<0.005 and P<0.05, respectively). ER niacin also significantly increased HDL apoA-I pool size (6,088 ± 292 versus 5,675 ± 305 mg; P<0.001), and this was attributed to a lower HDL apoA-I fractional catabolic rate (0.33 ± 0.01 versus 0.37 ± 0.02 pools/d; P<0.005), with no significant changes in HDL apoA-I production (20.93 ± 0.63 versus 21.72 ± 0.85 mg/kg per day; P=0.28). CONCLUSIONS:  ER niacin increases HDL apoA-I concentration in statin-treated subjects with type 2 diabetes mellitus by lowering apoA-I fractional catabolic rate. The effect on HDL metabolism was independent of the reduction in plasma triglyceride with ER niacin treatment. Whether this finding applies to other dyslipidemic populations remains to be investigated.

Niacin improves lipid profile but not endothelial function in patients with coronary artery disease on high dose statin therapy.
            (Philpott et al., 2013) Download
AIMS:  To determine the effect of extended release (ER) niacin on endothelial and vascular function assessed by brachial flow-mediated dilatation (FMD), peak hyperemic velocity (VTiRH) and pulse arterial tonometry (PAT) in patients with established coronary artery disease (CAD), already treated with high dose statins. Endothelial dysfunction is common in patients with established coronary artery disease (CAD) and has prognostic implications. Niacin has proven clinical benefit in patients with CAD, but its additive effect in patients on statin therapy is being evaluated. The effect of niacin on endothelial function, in the presence of optimal LDL cholesterol is unclear. METHODS AND RESULTS:  Sixty-six patients with CAD (mean age 57.9 ± 8.5 yrs) received ER niacin (1500 mg per day) and placebo in a randomized crossover fashion for 3 months of each therapy. All patients received atorvastatin 80 mg per day. FMD, VTiRH and PAT measurements were performed at baseline and after each treatment period. Treatment with niacin improved dyslipidemia parameters (LDL placebo 1.52 ± 0.51 vs. niacin 1.30 ± 0.43; p = 0.004; HDL placebo 0.95 ± 0.16 vs. niacin 1.11 ± 0.22; p < 0.001). However, there was no observed improvement in endothelial function as assessed by FMD (placebo 6.1 ± 4.9 vs. niacin 6.6 ± 4.8%; p = 0.48), VTiRH (placebo 75 ± 28 vs. niacin 78 ± 26 cm; p = 0.23) or PAT (placebo 1.8 ± 0.42 vs. niacin 1.79 ± 0.5; p = 0.43). CONCLUSION:  Niacin as add-on treatment to high dose statins in patients with established CAD significantly improves lipid profile. However, these changes were not associated with improved endothelial or microvascular function. Registered clinical trial with clinicaltrials.gov: NCT00150722.

Statins, Muscle Disease and Mitochondria.
            (Ramachandran and Wierzbicki, 2017) Download
Cardiovascular disease (CVD) accounts for >17 million deaths globally every year, and this figure is predicted to rise to >23 million by 2030. Numerous studies have explored the relationship between cholesterol and CVD and there is now consensus that dyslipidaemia is a causal factor in the pathogenesis of atherosclerosis. Statins have become the cornerstone of the management of dyslipidaemia. Statins have proved to have a very good safety profile. The risk of adverse events is small compared to the benefits. Nevertheless, the potential risk of an adverse event occurring must be considered when prescribing and monitoring statin therapy to individual patients. Statin-associated muscle disease (SAMS) is by far the most studied and the most common reason for discontinuation of therapy. The reported incidence varies greatly, ranging between 5% and 29%. Milder disease is common and the more serious form, rhabdomyolysis is far rarer with an incidence of approximately 1 in 10,000. The pathophysiology of, and mechanisms leading to SAMS, are yet to be fully understood. Literature points towards statin-induced mitochondrial dysfunction as the most likely cause of SAMS. However, the exact processes leading to mitochondrial dysfunction are not yet fully understood. This paper details some of the different aetiological hypotheses put forward, focussing particularly on those related to mitochondrial dysfunction.

Addition of omega-3 fatty acid and coenzyme Q10 to statin therapy in patients with combined dyslipidemia.
            (Tóth et al., 2017) Download
BACKGROUND:  Statins represent a group of drugs that are currently indicated in the primary and secondary prevention of cardiovascular events. Their administration can be associated with side effects and the insufficient reduction of triacylglyceride (TAG) levels. This study aimed to assess the effect of the triple combination of statins with omega-3 fatty acids and coenzyme Q10 (CoQ10) on parameters associated with atherogenesis and statin side effects. METHODS:  In this pilot randomized double-blind trial, 105 subjects who met the criteria of combined dislipidemia and elevated TAG levels were randomly divided into three groups. In the control group, unaltered statin therapy was indicated. In the second and third groups, omega-3 PUFA 2.52 g/day (Zennix fa Pleuran) and omega-3 PUFA 2.52 g+CoQ10 200 mg/day (Pharma Nord ApS) were added, res//. At the end of the 3-month period (±1 week), all patients were evaluated. RESULTS:  Significant reduction of hepatic enzymes activity, systolic blood preasure, inflammatory markers and TAG levels were detected in both groups in comparison to the control group. Activity of SOD and GPx increased significantly after additive therapy. Coenzyme Q10 addition significantly reduced most of the abovementioned parameters (systolic blood preasure, total cholesterol, LDL, hsCRP, IL-6, SOD) in comparison with the statin+omega-3 PUFA group. The intensity of statin adverse effects were significantly reduced in the group with the addition of CoQ10. CONCLUSIONS:  The results of this pilot study suggest the possible beneficial effects of triple combination on the lipid and non-lipid parameters related to atherogenesis and side effects of statin treatment.

 


 

References

Asping, M, et al. (2017), ‘The effects of 2 weeks of statin treatment on mitochondrial respiratory capacity in middle-aged males: the LIFESTAT study.’, Eur J Clin Pharmacol, 73 (6), 679-87. PubMed: 28246888
Deichmann, RE, CJ Lavie, and AC Dornelles (2012), ‘Impact of coenzyme Q-10 on parameters of cardiorespiratory fitness and muscle performance in older athletes taking statins.’, Phys Sportsmed, 40 (4), 88-95. PubMed: 23306418
Evans, M, et al. (2014), ‘Pantethine, a derivative of vitamin B5, favorably alters total, LDL and non-HDL cholesterol in low to moderate cardiovascular risk subjects eligible for statin therapy: a triple-blinded placebo and diet-controlled investigation.’, Vasc Health Risk Manag, 10 89-100. PubMed: 24600231
Kane, L, et al. (2013), ‘Vitamin D3 effects on lipids differ in statin and non-statin-treated humans: superiority of free 25-OH D levels in detecting relationships.’, J Clin Endocrinol Metab, 98 (11), 4400-9. PubMed: 24030939
Larsen, S, et al. (2013), ‘Simvastatin effects on skeletal muscle: relation to decreased mitochondrial function and glucose intolerance.’, J Am Coll Cardiol, 61 (1), 44-53. PubMed: 23287371
Lee, BJ, et al. (2013), ‘Effects of coenzyme Q10 supplementation (300 mg/day) on antioxidation and anti-inflammation in coronary artery disease patients during statins therapy: a randomized, placebo-controlled trial.’, Nutr J, 12 (1), 142. PubMed: 24192015
Pang, J, et al. (2014), ‘Effect of niacin on high-density lipoprotein apolipoprotein A-I kinetics in statin-treated patients with type 2 diabetes mellitus.’, Arterioscler Thromb Vasc Biol, 34 (2), 427-32. PubMed: 24285582
Philpott, AC, et al. (2013), ‘Niacin improves lipid profile but not endothelial function in patients with coronary artery disease on high dose statin therapy.’, Atherosclerosis, 226 (2), 453-58. PubMed: 23174368
Ramachandran, R and AS Wierzbicki (2017), ‘Statins, Muscle Disease and Mitochondria.’, J Clin Med, 6 (8), PubMed: 28757597
Tóth, Š, et al. (2017), ‘Addition of omega-3 fatty acid and coenzyme Q10 to statin therapy in patients with combined dyslipidemia.’, J Basic Clin Physiol Pharmacol, 28 (4), 327-36. PubMed: 28541926