Search Medication
| Level | Qualifying studies |
|---|---|
| A | Systematic review or meta-analysis of human trials |
| B | Human RDBPC trials. ≥ 2 studies and/or 1 study with ≥ 50 subjects |
| C | Human RDBPC trials or RCTs. 1 study < 50 subjects |
| D | Human trials or in-vivo animal trials |
| N/A | Insufficient evidence to suggest that any significant nutrient depletions exist |
Results for Simvastatin: 9
Evidence Rating ScaleBeta Carotene
Summary: Some of the decreases in serum lipid soluble antioxidant vitamins reported in short-term statin interventions may become attenuated when therapy continues longer. The relative antioxidant capacity of LDL particles increased during the 52-week treatment, suggesting that the oxidation resistance of LDL particles did not become impaired and that their atherogenicity did not increase.
Some of the decreases in serum lipid soluble antioxidant vitamins reported in short-term statin interventions may become attenuated when therapy continues longer. The relative antioxidant capacity of LDL particles increased during the 52-week treatment, suggesting that the oxidation resistance of LDL particles did not become impaired and that their atherogenicity did not increase.
A modified Mediterranean-type diet rich in omega-3 fatty acids efficiently potentiated the cholesterol-lowering effect of simvastatin, counteracted the fasting insulin-elevating effect of simvastatin, and, unlike simvastatin, did not decrease serum levels of beta-carotene and ubiquinol-10.
Copper
Summary: Statin treatment was associated with a significant reduction in mean serum copper (9%).
Statin treatment was associated with a significant reduction in mean serum copper (9%).
CoQ10
Summary: The meta-analysis showed a significant reduction in plasma CoQ10 concentrations following treatment with statins.
The meta-analysis showed a significant reduction in plasma CoQ10 concentrations following treatment with statins.
Regardless of its definition, statin intolerance is an important phenomenon, leading to a poorer control of the LDL cholesterol levels among high-risk Japanese patients. We need to understand the risk factors, as well as the potential nocebo effect, so that we can accurately discriminate the pseudo statin intolerance from true statin intolerance and reduce their LDL cholesterol more effectively using the golden standard drug. Alternatively, we could consider using other LDL-lowering therapies, such as ezetimibe, PCSK9 inhibitors and fibrates, or some agents that have been shown as add-on/alternative therapies to statins, such as certain nutraceuticals, or coenzyme Q107–9).
The meta-analysis showed a significant reduction in plasma CoQ10 concentrations following treatment with statins. Further well-designed trials are required to confirm our findings and elucidate their clinical relevance.
Several trials demonstrate coenzyme Q10 depletion subsequent to statin initiation.42,43 There is conjecture about this depletion as the cause of statin–associated adverse effects (e.g., myopathy) with exogenous coenzyme Q10 supplementation as a possible mediating treatment. This assertion is refuted by a more recent crossover trial44 that found no significant coenzyme Q10 drop after initiation of selected statins. Several doxorubicin (Adriamycin) trials, mostly in animal models, have noted a reduction in cardiac coenzyme Q10 depletion and cardiotoxicity associated with coadministration of coenzyme Q10. The clinical implications on disease state and adverse reaction profile with coenzyme Q10 supplementation in depleted states requires further evaluation.
Simvastatin and the combination of simvastatin and ezetimibe significantly decrease plasma CoQ10 levels whereas ezetimibe monotherapy does not. There is a significant correlation between the CoQ10 level decrease and the decrease in total and LDL-C levels in all three treatment groups, suggesting that the CoQ10 decrease may reflect the decrease in the levels of its lipoprotein carriers and might not be statin-specific. The statin-associated CoQ10 reduction is not abrogated through ezetimibe coadministration. Changes of CoQ10 levels are independent of cholesterol synthesis and absorption.
Simvastatin and the combination of simvastatin and ezetimibe significantly decrease plasma CoQ10 levels whereas ezetimibe monotherapy does not. There is a significant correlation between the CoQ10 level decrease and the decrease in total and LDL-C levels in all three treatment groups, suggesting that the CoQ10 decrease may reflect the decrease in the levels of its lipoprotein carriers and might not be statin-specific. The statin-associated CoQ10 reduction is not abrogated through ezetimibe coadministration. Changes of CoQ10 levels are independent of cholesterol synthesis and absorption.
Subjects receiving simvastatin with CoQ10 in the treatment phase increased total serum CoQ10 whereas serum CoQ10 decreased in the simvastatin and placebo group.
Simvastatin decreased levels of total cholesterol by 20.8%, LDL cholesterol by 29.7%, triglycerides by 13.6%, apolipoprotein B by 22.4%, alpha-tocopherol by 16.2%, beta-carotene by 19.5%, and ubiquinol-10 by 22.0% (P<.001 for all) and increased levels of HDL cholesterol by 7.0% (P<.001) and serum insulin by 13.2% (P =.005). Glucose levels remained unchanged in all groups. The effects of dietary treatment and simvastatin were independent and additive.A modified Mediterranean-type diet rich in omega-3 fatty acids efficiently potentiated the cholesterol-lowering effect of simvastatin, counteracted the fasting insulin-elevating effect of simvastatin, and, unlike simvastatin, did not decrease serum levels of beta-carotene and ubiquinol-10.
Our results suggest that 20 mg/day of simvastatin does not have significant risk of hepatotoxicity and ubiquinol supplementation may, at the miRNA level, provide potential beneficial changes to reduce the effects of coenzyme Q10 deficiency in the liver.
Our data show that the treatment with HMG-CoA reductase inhibitors lowers both total cholesterol and CoQ10 plasma levels in normal volunteers and in hypercholesterolemic patients. CoQ10 is essential for the production of energy and also has antioxidative properties. A diminution of CoQ10 availability may be the cause of membrane alteration with consequent cellular damage.
Low-density lipoprotein (LDL) cholesterol and coenzyme Q10 decreased significantly in both groups. Simvastatin caused a faster initial LDL cholesterol lowering than atorvastatin (p=0.01), but the overall effect after 12 weeks of atorvastatin and simvastatin was similar. Plasma myeloperoxidase and malondialdehyde did not change during the study period in the two groups. Urinary F2-isoprostanes decreased gradually and significantly in the atorvastatin group but not in the simvastatin group, but the between-group difference was not significant. Urinary 8-hydroxy-2-deoxyguanosine did not change in the two groups.
Our data show that the treatment with HMG-CoA reductase inhibitors lowers both total cholesterol and CoQ10 plasma levels in normal volunteers and in hypercholesterolemic patients. CoQ10 is essential for the production of energy and also has antioxidative properties. A diminution of CoQ10 availability may be the cause of membrane alteration with consequent cellular damage.
Significant changes in the healthy volunteer group were detected for total cholesterol and CoQ10 levels, which underwent about a 40% reduction after the treatment. The same extent of reduction, compared with placebo was measured in hypercholesterolemic patients treated with pravastatin or simvastatin. Our data show that the treatment with HMG-CoA reductase inhibitors lowers both total cholesterol and CoQ10 plasma levels in normal volunteers and in hypercholesterolemic patients. CoQ10 is essential for the production of energy and also has antioxidative properties. A diminution of CoQ10 availability may be the cause of membrane alteration with consequent cellular damage.
Simvastatin or low density lipoprotein apheresis decreased serum CoQ10 concentrations along with decreasing serum cholesterol. Oral CoQ10 supplementation in diabetic patients receiving HMG-CoA RI significantly (p < 0.001) increased serum CoQ10 from 0.81 +/- 0.24 to 1.47 +/- 0.44 mumol 1(-1), without affecting cholesterol levels. It significantly (p < 0.03) decreased cardiothoracic ratios from 51.4 +/- 5.1 to 49.2 +/- 4.7%. In conclusion, serum CoQ10 levels in NIDDM patients are decreased and may be associated with subclinical diabetic cardiomyopathy reversible by CoQ10 supplementation.
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.
This study demonstrates that simvastatin lowers both LDL-C and apo B plasma levels together with the plasma and platelet levels of CoQ10, and that CoQ10 therapy prevents both plasma and platelet CoQ10 decrease, without affecting the cholesterol lowering effect of simvastatin.
The present results indicate that simvastatin but not pravastatin may cause worsening of the myocardial mitochondrial respiration during ischaemia, probably because of reduction of the myocardial coenzyme Q10 level.
Our results suggest that the significant decline in circulating alpha-tocopherol and coenzyme Q10 concentrations was mainly a function of the decrease in serum total cholesterol concentrations.
In conclusion, serum CoQ10 levels in NIDDM patients are decreased and may be associated with subclinical diabetic cardiomyopathy reversible by CoQ10 supplementation.
The observed decline of the levels of CoQ10H2 and CoQ10 in plasma and of CoQ10H2, CoQ10 and vit E in lymphocytes following a 3 month statin therapy might lead to a reduced antioxidant capacity of LDL and lymphocytes, and probably of tissues such as liver, that have an elevated HMG-CoA reductase enzymatic activity. However, this reduction did not appear to induce a significant oxidative stress in blood, since the levels of the other antioxidants, the pattern of PUFA as well as the oxidative damage to PUFA and proteins resulted unchanged. The concomitant administration of ubiquinone with statins, leading to its increase in plasma, lymphocytes and liver may cooperate in counteracting the adverse effects of statins, as already pointed out by various authors on the basis of human and animal studies.
Despite reduced plasma vitamin E and coenzyme Q10, 20 mg of simvastatin therapy is associated with a significantly increased coenzyme Q10/LDL-cholesterol ratio and vitamin E/LDL-cholesterol ratio. Simvastatin treatment is not associated with impairment in left ventricular systolic or diastolic function in hypercholesterolaemic subjects after 6 months of treatment.
Even though simvastatin treatment did not induce coenzyme Q deficiency in plasma, heart and liver of the diabetic-hypercholesterolaemic rats as compared to the control levels, it was not able to prevent completely the changes in antioxidant/oxidant balance induced by diabetes and hypercholesterolaemia. The results highlight the importance of studying the effect of statins on the coenzyme Q levels in the animal models of pathological conditions known to change the initial antioxidant defence system.
In the present study, even a high dose of statin did not show a cholesterol lowering effect, therefore depletion of CoQ10 following statin treatment in rats is not clear. More clinical studies are needed for therapeutic use of CoQ10 as an antioxidant in prevention of degenerative diseases independent of statin therapy.
We conclude that the administration of simvastatin under the condition of NO-deficiency reduced the level of CoQ in the heart and skeletal muscle what may participate in adverse effect of statins under certain clinical conditions.
These results suggested that oral administration of simvastatin suppresses the biosynthesis of CoQ, which shares the same biosynthesis pathway as cholesterol up to farnesyl pyrophosphate, thus compromising the physiological function of reduced CoQ, which possesses antioxidant activity. However, these undesirable effects induced by simvastatin were alleviated by coadministering CoQ(10) with simvastatin to mice. Simvastatin also reduced the activity of NADPH-CoQ reductase, a biological enzyme that converts oxidized CoQ to the corresponding reduced CoQ, while CoQ(10) administration improved it. These findings may also support the efficacy of coadministering CoQ(10) with statins.
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.
Ubiquinone serum levels were lower in statin-treated patients (0.75 mg l−1±0.04) than in untreated hypercholesterolaemic patients (0.95 mg l−1±0.09; P<0.05). We conclude that statin therapy can be associated with high blood lactate/pyruvate ratio suggestive of mitochondrial dysfunction. It is uncertain to what extent low serum levels of ubiquinone could explain the mitochondrial dysfunction.
This study demonstrates that simvastatin lowers both LDL-C and apo B plasma levels together with the plasma and platelet levels of CoQ10, and that CoQ10 therapy prevents both plasma and platelet CoQ10 decrease, without affecting the cholesterol lowering effect of simvastatin.
It is concluded that simvastatin may lower the plasma CoQ concentration and this may be greater than the reduction in cholesterol. The possible adverse effect of simvastatin on the metabolism of CoQ may be clinically important and requires further study.
In this study we observed decreased serum levels but an enhancement in muscle tissue ubiquinone levels in patients with hypercholesterolemia after 4 weeks of simvastatin treatment. These results indicate that ubiquinone supply is not reduced during short-term statin treatment in the muscle tissue of subjects in whom myopathy did not develop.
In HepG2 cells, simvastatin decreased mitochondrial CoQ10 levels, and at higher concentrations was associated with a moderately higher degree of cell death, increased DNA oxidative damage and a reduction in ATP synthesis. Supplementation of CoQ10, reduced cell death and DNA oxidative stress, and increased ATP synthesis. It is suggested that CoQ10 deficiency plays an important role in statin-induced hepatopathy, and that CoQ10 supplementation protects HepG2 cells from this complication.
In strong contrast, simvastatin stimulated these enzymes dramatically, and reduced coenzyme Q10 levels in liver and heart. Altogether these findings clearly differentiate the OSC inhibitor Ro 48-8.071 from simvastatin, and support the view that OSC is a distinct key component in the regulation of the cholesterol synthesis pathway.
Glutathione
Summary: Administration of simvastatin (80 mg/kg, po. evening dose) and gemfibrozil (600 mg/kg, po twice) for 30 days produced significant decrease in the level of reduced glutathione, superoxide dismutase, catalase and increase in the level of lipid peroxidation and various serum parameters (creatine phosphokinase, lactate dehydrogenase, serum glutamate oxaloacetate transaminase, creatinine, urea and blood urea nitrogen). This suggested involvement of oxidative stress in rhabdomyolysis. Increase in the level of reduced glutathione, superoxide dismutase, catalase and decrease in the level of lipid peroxidation and serum parameters after administration of antioxidant CoQ10 (10 mg/kg.ip) proved the protective effect of CoQ10 in rhabdomyolysis.
Administration of simvastatin (80 mg/kg, po. evening dose) and gemfibrozil (600 mg/kg, po twice) for 30 days produced significant decrease in the level of reduced glutathione, superoxide dismutase, catalase and increase in the level of lipid peroxidation and various serum parameters (creatine phosphokinase, lactate dehydrogenase, serum glutamate oxaloacetate transaminase, creatinine, urea and blood urea nitrogen). This suggested involvement of oxidative stress in rhabdomyolysis. Increase in the level of reduced glutathione, superoxide dismutase, catalase and decrease in the level of lipid peroxidation and serum parameters after administration of antioxidant CoQ10 (10 mg/kg.ip) proved the protective effect of CoQ10 in rhabdomyolysis.
Co-administration of simvastatin and ezetimibe has an additive cholesterol-lowering effect. Simvastatin, ezetimibe and simvastatin + ezetimibe significantly increased oxygen consumption, membrane potential and glutathione content, and decreased levels of ROS, thereby improving mitochondrial function.
The significant decrease in serum total and LDL-cholesterol concentrations caused by simvastatin was associated with an increase in serum N-acetyl-beta-glucosaminidase activity, ascorbic acid, plasminogen activator inhibitor (PAI-1) , vonWillebrand factor, E-selectin (P<0.01) and vascular endothelial growth factor concentrations and with a decrease in plasma glutathione levels.
Omega 3
Summary: In addition, simvastatin increased the AA:EPA ratio from 15.5 to 18.8 (P<.01), and tended to increase the AA:DHA ratio (P=.053). Thus, simvastatin lowered serum fatty acid concentrations while also altering the relative percentages of important PUFAs.
In addition, simvastatin increased the AA:EPA ratio from 15.5 to 18.8 (P<.01), and tended to increase the AA:DHA ratio (P=.053). Thus, simvastatin lowered serum fatty acid concentrations while also altering the relative percentages of important PUFAs.
Omega 6
Summary: For the first time in a double-blind randomized study in CHD patients, we report that LLDs significantly alter the metabolism of essential fatty acids that are critically important for the pathogenesis and prevention of CHD. Further studies are urgently needed to examine the effects of higher dosages of statins (as currently proposed to reduce more cholesterol) on these essential fatty acids in the clinical setting and the crucial questions of whether specific dietary intervention (combining low intake of n-6 fatty acids and high intake of n-3 fatty acids) may improve the effectiveness of these drugs.
For the first time in a double-blind randomized study in CHD patients, we report that LLDs significantly alter the metabolism of essential fatty acids that are critically important for the pathogenesis and prevention of CHD. Further studies are urgently needed to examine the effects of higher dosages of statins (as currently proposed to reduce more cholesterol) on these essential fatty acids in the clinical setting and the crucial questions of whether specific dietary intervention (combining low intake of n-6 fatty acids and high intake of n-3 fatty acids) may improve the effectiveness of these drugs.
In addition, simvastatin increased the AA:EPA ratio from 15.5 to 18.8 (P<.01), and tended to increase the AA:DHA ratio (P=.053). Thus, simvastatin lowered serum fatty acid concentrations while also altering the relative percentages of important PUFAs.
Selenium
Summary: One month of simvastatin therapy reduced serum Se levels in patients with diabetes, impaired glucose tolerance, or impaired fasting glucose.
One month of simvastatin therapy reduced serum Se levels in patients with diabetes, impaired glucose tolerance, or impaired fasting glucose.
During the 9-year follow-up, similar plasma selenium declines were observed in all the sub-groups (p=0.33) despite plasma selenium levels being higher in fibrate users and lower in statin users (p=0.0004). The mechanisms underlying these data are not yet totally understood, but considering the risk of selenium deficiency in the elderly and its relationship with poor health status further clinical trial is needed to verify the proposed hypotheses.
Vitamin E
Summary: Some of the decreases in serum lipid soluble antioxidant vitamins reported in short-term statin interventions may become attenuated when therapy continues longer. The relative antioxidant capacity of LDL particles increased during the 52-week treatment, suggesting that the oxidation resistance of LDL particles did not become impaired and that their atherogenicity did not increase.
Some of the decreases in serum lipid soluble antioxidant vitamins reported in short-term statin interventions may become attenuated when therapy continues longer. The relative antioxidant capacity of LDL particles increased during the 52-week treatment, suggesting that the oxidation resistance of LDL particles did not become impaired and that their atherogenicity did not increase.
Total vitamin E levels were reduced in parallel with the reduction in plasma cholesterol.
Despite reduced plasma vitamin E and coenzyme Q10, 20 mg of simvastatin therapy is associated with a significantly increased coenzyme Q10/LDL-cholesterol ratio and vitamin E/LDL-cholesterol ratio. Simvastatin treatment is not associated with impairment in left ventricular systolic or diastolic function in hypercholesterolaemic subjects after 6 months of treatment.
Pravastatin and simvastatin equally reduced LDL-C and alpha-T levels, and increased the alpha-T/LDL-C ratios. Conversely, pravastatin did not affect whereas simvastatin significantly augmented plasma gamma-T levels. Moreover, the gamma-T/LDL-C ratio increased significantly more with simvastatin than with pravastatin. In addition, pravastatin but not simvastatin increased the urinary excretion of gamma-CEHC.
Zinc
Summary: In addition to reducing serum total and low-density lipoprotein (LDL) cholesterol (p < 0.0001), statin treatment was associated with a significant reduction in mean serum zinc (9%, p = 0.03), copper (9%, p < 0.01), caeruloplasmin (24%, p < 0.05), and median CRP (45%, p < 0.03).
In addition to reducing serum total and low-density lipoprotein (LDL) cholesterol (p < 0.0001), statin treatment was associated with a significant reduction in mean serum zinc (9%, p = 0.03), copper (9%, p < 0.01), caeruloplasmin (24%, p < 0.05), and median CRP (45%, p < 0.03).
