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Prescribing Statins to Reduce Cardiovascular Disease: 10 Common Misconceptions

      Statins (HMG-CoA reductase inhibitors) are one of the most widely prescribed medications in the world. However, their use in patients is often inappropriate because these medications have some unique properties not shared with other pharmaceuticals. This Commentary lists 10 common misconceptions concerning statins (Table 1) and provides documentation supporting statin’s unique characteristics.
      • 1.
        Statins reduce the hepatic production of cholesterol by inhibiting the hepatic enzyme HMG co-A reductase, but this activity by itself does not lower the circulating concentration of cholesterol. Brown and Goldstein in 1985 received the Nobel Prize for demonstrating that low-density lipoprotein cholesterol (LDLc) was lowered by increasing the hepatic number of surface LDLc receptors and that individuals with defective or absent low-density lipoprotein (LDL) receptors are hypercholesterolemic. Any activity that reduces the quantity of cholesterol in the liver will result in an increase in hepatic LDL receptors. It is this downstream activity of statins that results in a reduction of circulating LDLc.
        • Silverman M.G.
        • Ference B.A.
        • Im K.
        • et al.
        Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis.
      • 2.
        Because of their short half-life, this misconception was true when the low-potency statins were first introduced. However, as stated in their label approved by the US Food and Drug Administration (FDA) the newer high-potency statins may be taken at any time during the day or night. For example, the elimination half-life of rosuvastatin is 19 hours and that of atorvastatin is 13 hours. Rosuvastatin is minimally metabolized, but atorvastatin’s suppression of HMG-CoA reductase is extended to 20 to 30 hours by its active metabolites. This patient convenience factor is another reason to only use high-potency statins in treating patients.
        • Jones P.H.
        • Davidson M.H.
        • Stein E.A.
        • et al.
        Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial).
      • 3.
        Statins have been shown to reduce acute coronary events after acute coronary symptoms, including chest pain, diaphoresis, and radiation of pain to the arm and jaw. However, this effect of statins is not thought to be directly related to statins’ hypolipidemic effects because lowering cholesterol in plaques may take months. Alternatively, the anti-inflammatory effects of statins occur rapidly, thereby stabilizing unstable plaques and reducing inflammation. Coronary atherosclerosis is an inflammatory disease as indicated by an elevation in C-reactive protein, which statins effectively reduce.
        • Ray K.K.
        • Cannon C.P.
        • McCabe C.H.
        • et al.
        Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 Trial.
      • 4.
        One of the proven side effects of high-potency statins is impairment of glucose tolerance. For individuals who have prediabetes, the small elevation of HbA1c caused by statins can increase the A1c into the diabetic range (eg, raising the HbA1c from 6.4% to 6.5%). However, even without statin therapy, prediabetes progresses to diabetes in the majority of individuals. The impairment of glucose tolerance can be counterbalanced by increasing the quantity of diabetic medications such as metformin. This diabetogenic effect appears to be dose related because in a randomized controlled trial with 10 mg/d of rosuvastatin, no increase in diabetes was observed.
        • Davidson M.
        • Ma P.
        • Stein E.A.
        • et al.
        Comparison of effects on low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with rosuvastatin versus atorvastatin in patients with type IIa or IIb hypercholesterolemia.
        However, in another RCT using 20 mg/d of rosuvastatin, a small increase in diabetes was observed. A detailed analysis of this diabetogenic effect suggested that the development of diabetes “hastened the development of diabetes by only six months.” In no population so far studied, have the benefits of statins been exceeded by the risk of developing diabetes.
        • Ridker P.M.
        • Pradhan A.
        • MacFadyen J.G.
        • Libby P.
        • Glynn R.J.
        Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial.
      • 5.
        It is common practice to prescribe statins at ever-increasing dosages until the LDLc goal is reached. However, this is not the optimal approach to statin therapy for 2 reasons. First, the side effects (myalgias and glucose intolerance) are positively related to the statin dose. Second, the increase in LDLc-lowering efficacy is only increased 7% for each doubling of the dose.
        • Roberts W.C.
        The rule of 5 and the rule of 7 in lipid-lowering by statin drugs.
        The reason for this truncated effect is that statins increase PCSK9 with each dosage increase. PCSK9 increases the degradation of hepatic LDL receptors, thereby preventing additional LDLc reduction. The best approach for statin use is to use rosuvastatin 10 mg in concert with ezetimibe 10 mg because these pharmaceutical agents work at difference anatomical locations.
        • Torimoto K.
        • Okada Y.
        • Mori H.
        • et al.
        Efficacy of combination of ezetimibe 10 mg and rosuvastatin 2.5 mg versus rosuvastatin 5 mg monotherapy for hypercholesterolemia in patients with type 2 diabetes.
      • 6.
        There are 3 documented side effects of statin therapy: myalgias, glucose intolerance, and hemorrhagic strokes (which occur only in patients with poorly controlled hypertension). Myalgias are rare but well documented. Glucose intolerance leading to diabetes occurs in a statin-dose relationship as described. Many studies have examined mental aberrations (eg, depression, Alzheimer disease, confusion, etc.), but there are as many studies showing a benefit as showing this side effect.
        • Collins R.
        • Reith C.
        • Emberson J.
        • et al.
        Interpretation of the evidence for the efficacy and safety of statin therapy.
      • 7.
        The coronary artery calcium score predicts cardiovascular outcome; the higher the score, the more likely is a cardiovascular event. Therefore, many patients believe that reversal of atherosclerosis with statins should lead to a reduction in score. However, one characteristic of a stable atherosclerotic plaque is the abundance of calcium. A consequence of this anatomical observation is that statins may increase plaque stability by increasing plaque calcium. Therefore, statins will not reduce coronary calcium, but they do slow its accumulation.
        • Puri R.
        • Nicholls S.J.
        • Shao M.
        • et al.
        Impact of statins on serial coronary calcification during atheroma progression and regression.
      • 8.
        The fact that statins can cause myalgia is well known to all caregivers. However, what is not appreciated is the rare incidence of this side effect. Randomized blinded-controlled trials in which there is a choice of a statin or placebo is the best way to assess the incidence of statin-induced myalgias. When this is done, the incidence is approximately 1 in 1000 statin users. However, it is also dose dependent with the worst reported incidence occurring with 80 mg/d of simvastatin. The reason for this confusion is probably the nocebo effect (ie, experiencing a negative reaction to medication because of the perception it is harmful). Muscle aches are common in all populations without statin use and when an individual is placed on a statin, they expect to have muscle aches.
        • Brewer H.B.
        Benefit-risk assessment of rosuvastatin 10 to 40 milligrams.
      • 9.
        There are 3 statins considered to be high potency: simvastatin, atorvastatin, and rosuvastatin. The incidence of rhabdomyolysis caused by these 3 statins is markedly different at the highest available dosages. In 2011, the FDA added a warning label to simvastatin that the danger of rhabdomyolysis at 80 mg/d was too great to prescribe it at this dosage. In 2010, more than 2 million individuals were on this medication. Because the LDLc-lowering capability of simvastatin is significantly less than rosuvastatin at equivalent dosages, there is currently no clinical reason to prescribe simvastatin.
        • Brewer H.B.
        Benefit-risk assessment of rosuvastatin 10 to 40 milligrams.
      • 10.
        In a clinical trial of “N of one” (ie, a blinded study in which a statin is alternated with a placebo), only 1 individual out of 8 tested who believed they were statin/myalgia intolerant could correctly identify which treatment was the statin. These 8 individuals were certain that they could not tolerate statins. It was of interest that of 50 individuals recruited for the study who were certain they were statin intolerant, 42 volunteers would not agree to participate in the 1-on-1 trial.
        • Joy T.R.
        • Monjed A.
        • Zou G.Y.
        • Hegele R.A.
        • McDonald C.G.
        • Mahon J.L.
        N-of-1 (single-patient) trials for statin-related myalgia.
        It can be concluded that it is not possible to accurately tell who is statin intolerant from the clinical history.
      Table 1
      Prescribing Statins to Reduce Cardiovascular Disease: 10 Common Misconceptions
       1. Statins lower plasma LDLc by inhibiting the hepatic production of cholesterol.
       2. Because the major production of LDLc occurs at night, high-potency statins should be taken in the evening before bed time.
       3. Statins are recommended for acute coronary symptoms because they rapidly reduce LDLc and thereby prevent additional cardiovascular events.
       4. In low-risk populations, the risk of developing diabetes from statins exceeds the potential benefit of statin’s reduction of atherosclerosis.
       5. Statins work best when used as monotherapy and the dose increased as necessary to obtain the recommended LDLc goal.
       6. Proven side effects of statins include myalgia, diabetes, and mental aberrations.
       7. Statin therapy that significantly reduces LDLc may also reduce the coronary artery calcium score.
       8. Blinded, randomized controlled clinical trials have demonstrated that the incidence of statin’s main side effect (ie, myalgias) is about 1 in 50 individuals prescribed a statin.
       9. At maximal dosage, all high-potency statins result in similar rhabdomyolytic events
       10. Individuals who are certain that they cannot take statins because of myalgias are able to identify the statin when given either a placebo or a high-potency statin.
      LDLc = low-density lipoprotein cholesterol.

      Conclusion

      Statins are a safe and effective medication to prevent cardiovascular events. Their optimal use depends on a thorough knowledge of their pharmacological properties. These include stimulation of PCSK9 protein, enhancement of coronary artery calcium, and hepatic stimulation of LDL receptor number. The goal of caregivers should be minimizing potential side effects and maximizing the reduction of LDL cholesterol. This goal can be achieved through using the lowest dose feasible and combining the statin with another hypocholesterolemic medication (eg, ezetimibe) that has its primary function at an anatomical site other than the liver.

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        • Davidson M.H.
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