The lipid-lowering efficacy and cardiovascular benefits of statins (statins) have been repeatedly demonstrated and well established. However, because of their widespread use, many adverse reactions associated with these drugs have been frequently reported. In 2011, experts in cardiovascular medicine and clinical lipidology in China developed expert opinions on five major issues related to statins and cancer risk, kidney damage, risk of new-onset diabetes, liver damage, and myopathy.
The potential risks and benefits of statin use have become a public health concern for Chinese physicians and patients in general. In this regard, the Working Group on Safety Evaluation of Statins has reached an Expert Consensus on Safety Evaluation of Statins after thorough discussions on the main safety issues of statins and their management countermeasures. Famous cardiovascular experts in China, such as Hu Dayi, Zhao Huanping, Li Jianjun, Ye Ping, Zhao Dong, Guo Yifang, Li Yong and other expert professors, participated in the development of the consensus. The full text of the consensus was published in the November 2014 issue of the Chinese Journal of Cardiovascular Diseases.
The abstract is as follows.
I. Statin and hepatic safety
Relevant contraindications: statin is contraindicated in patients with active liver disease, persistent elevation of unexplained transaminases and elevation of liver enzymes above 3 times the upper limit of normal for any reason, decompensated cirrhosis and acute liver failure. Statin may be safely administered to patients with non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). Chronic liver disease or compensated cirrhosis is not a contraindication to these drugs.
Clinical management: China’s guidelines for the prevention and treatment of dyslipidemia recommend that liver function be reviewed 4-8 weeks after the start of statin therapy and gradually adjusted to once every 6-12 months if there is no abnormality; if AST or ALT exceeds 3 times the upper limit of normal (ULN), dosing should be suspended and liver function should still be reviewed weekly until it returns to normal. Mild elevation of liver enzymes less than 3 times the upper limit of normal is not a contraindication to treatment, and patients can continue to take statin, and the elevated ALT may fall on its own in some patients.
Statin and muscle safety
Clinical management: Only elevated blood CK without other evidence of muscle damage such as myalgia or muscle weakness is not statin-induced muscle damage. In contrast, the presence of muscle weakness or myalgia, even if CK is normal, suggests statin-induced muscle injury. Myocardial biopsy is not recommended when these conditions occur. Current national and international guidelines recommend testing CK before starting statin therapy and monitoring it regularly during treatment. CK should be monitored promptly when symptoms of muscle discomfort or weakness and brown urine excretion occur during statin administration, and statin therapy should be discontinued immediately if myositis occurs or is highly suspected.
The management of other conditions is as follows.
(1) If the patient reports possible muscle symptoms, CK should be tested and compared to pre-treatment levels. Since hypothyroid patients are prone to myopathy, thyrotropin levels should also be tested in patients with muscle symptoms.
(2) If the patient has muscle tenderness, pressure or pain with or without elevated CK, common causes such as exercise and physical exertion should be ruled out. Moderate activity is recommended for patients who have these symptoms and are on a combination of medications.
(3) When a patient has muscle tenderness, tenderness or pain with no or moderate elevation of CK (3-10 x ULN), follow-up, weekly testing of CK levels should be performed until drug effects have been ruled out or symptoms worsen (the drug should be discontinued promptly). If CK is progressively elevated on continuous testing, careful consideration should be given to reducing the statin dose or temporarily discontinuing the drug. Then decide if or when to start statin therapy again.
(4) Once a patient develops rhabdomyolysis, statin therapy should be discontinued. If necessary, hospitalize for intravenous hydration therapy. Once recovered, the risk-one benefit profile of statin therapy should be carefully reassessed.
For patients who have experienced rhabdomyolysis from statin administration, consider the following.
(1) Change the type of statin: for patients who are susceptible to myopathy or are receiving statin therapy again after discontinuation, try to use a statin that has a relatively low potential to induce myopathy.
(2) Adjust the drug dose: If myopathy is associated with high-dose statin intensive treatment, reduce the statin dosage and closely observe the clinical symptoms and laboratory index changes.
(3) Intermittent dosing: The relatively long plasma half-life (15-20h) of rosuvastatin and atorvastatin provides the possibility of intermittent statin treatment.
(4) Drug combination therapy: adding other lipid-regulating drugs (such as ezetimibe, fibrates, extended-release niacin, etc.) to statin can not only achieve the goal of comprehensive lipid regulation, but also reduce the drug dosage of statin therapy alone and reduce the occurrence of related myopathy.
(5) Coenzyme Q10 supplementation: Some studies have confirmed that supplementation with coenzyme Q10 therapy can improve the symptoms of myopathy, but the exact efficacy remains to be verified.
III. Statin and new-onset diabetes
The overall benefit of statins on cardiovascular disease to the risk of new-onset diabetes is 9:1, and the protective effect of statins on cardiovascular disease is much greater than the risk of new-onset diabetes. The use of standard-dose statins is not only effective in reducing cardiovascular events, but is also safe and well tolerated. High-dose statins mildly increased the risk of new diabetes, but the actual hazard of that risk was low both in absolute terms and compared with the reduction of major cardiovascular and cerebrovascular events with statins.
Continued use of such agents is needed in populations suitable for statin use, particularly in those with moderate to high cardiovascular risk and those with definite atherosclerotic cardiovascular disease, and no change in statin application regimen or status is required.
However, because the risk of increased new-onset diabetes with statins is higher in the elderly population than in the younger population, particularly with high-dose or potent statins that may have potential effects on glucose metabolism, care needs to be taken to monitor glycemic changes. Available data suggest that if statin use has an adverse effect on hyperglycemia, this adverse effect is relatively small (an average increase of 0.3% or less) and the effect on glycemic control can be reduced by adjusting the treatment regimen.
When initiating statin therapy, recommendations for patients with undiagnosed diabetes are.
(1) Assess diabetic risk factors as well as the degree of cardiovascular disease risk, and for those at high risk for diabetes, screen for fasting glucose or HbAIC prior to statin initiation.
(2) Emphasize the importance of diet and physical activity to maintain body mass before and during statin use, with the aim of reducing the risk of developing diabetes mellitus and cardiovascular disease. Body mass should be assessed under standard conditions (fasting, no coat, no shoes) at each follow-up observation. Waist circumference should be measured regularly.
(3) Use statins to reduce the risk of cardiovascular disease in accordance with current guidelines, unless the patient has a contraindication.
(4) If the patient is diagnosed with diabetes during statin therapy, emphasize weight loss and glucose-lowering medications, and control blood glucose and HbAlc with indications. give appropriate dietary and behavioral counseling.
IV. Statins and altered cognitive function and neurological impairment
The National Lipid Association recommends that statins have important health benefits for patients at risk for cardiovascular events that far outweigh the risk of cognitive dysfunction side effects. Although cognitive adverse effects of statins may occur in a very small number of individuals, the medical evidence supporting a causal relationship is insufficient or nonexistent. The true incidence of these side effects cannot be determined by currently available data.
Nevertheless, because of the severity of cognitive dysfunction, the widespread use of statins, and the high prevalence of cognitive dysfunction (for many reasons, especially aging), patients’ complaints about cognitive function should be taken seriously and properly evaluated, including appropriate neuropsychological testing in patients whose symptoms persist despite discontinuation of statins. If it is determined that cognitive dysfunction has no other cause, the medication should be discontinued after careful consideration of the benefit-risk ratio.
If a patient develops symptoms of peripheral neuropathy during statin therapy, a systematic evaluation should be done to rule out secondary causes (e.g., diabetes, renal insufficiency, alcohol abuse, vitamin B12 deficiency, cancer, hypothyroidism, acquired immunodeficiency syndrome, or heavy metal toxicity). If no other cause is found, statin therapy may be discontinued for 3-6 months to clarify whether the symptoms of peripheral neuropathy are related to statin therapy. If the neurological symptoms do not improve after discontinuation of statin for a certain period of time, the decision to reactivate statin therapy should be based on a risk-benefit analysis.
V. Statin and kidney damage
The American Lipid Association recommends.
(1) Evaluate renal function before initiating statin therapy, but it is not necessary to routinely perform measurements of serum creatinine and proteinuria during treatment due to observation of adverse effects.
(2) Statin therapy does not generally need to be interrupted if serum creatinine is elevated without signs of rhabdomyolysis. However, in some cases, adjustment of the statin dose is required according to the prescribing information.
(3) The unexpected development of proteinuria during statin therapy does not require interruption of statin therapy or adjustment of statin dose. Efforts should be made to find the cause and adjust the statin dose according to the specific statin prescription information as appropriate.
(4) Chronic renal disease is not a contraindication to statin use. However, certain statin doses should be adjusted according to the severity of renal insufficiency. In addition, a meta-analysis showed that statin therapy is safe in renal transplant and dialysis patients.
Summary
Statins are the most widely used drugs in humans today, and a large body of literature reports a variety of adverse reactions seen clinically in statin recipients, some of which may be directly related to statins. Recognizing and preventing statin-related adverse reactions is important to reduce patient suffering from statins and to enhance the clinical benefit of long-term adherence to statins in patients with atherosclerotic cardiovascular disease.
Adverse reactions to statins are not only related to individual genetics, but also to interactions with drugs (or foods) that patients take at the same time. Statins undergo a complex metabolic regression in the body starting from absorption, to hepatic uptake, metabolism and final elimination from the liver into the human circulation or bile duct. In order to minimize the incidence of statin adverse reactions, it is still wise to start all statins at smaller doses for the Chinese population.