How to choose statins?

Statins play an important role in the field of lipid-lowering and plaque-stabilizing. Currently, there are seven types of statins commonly used in clinical practice (atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, and pitavastatin). Due to the different chemical structures of each statin, its physicochemical properties and clinical applications are different [1-2].

1. Lipid-lowering intensity

There are certain differences in the extent to which different types and doses of statins can lower cholesterol, but when the dose of any statin is doubled, the further reduction in low-density lipoprotein cholesterol (LDL-C) is only about 6%, the so-called "6% statin effect."

Table 1 Cholesterol-lowering effect of statins

2. Half-life

Lovastatin, simvastatin, pravastatin and fluvastatin: about 1 to 4 hours. Atorvastatin, rosuvastatin and pitavastatin: more than 10 hours[4].

3. Hydrophilicity/lipophilicity

Generally, statins with high lipophilicity can easily enter the liver (to exert their effects), muscle cells and the blood-brain barrier, and may have effects on the central nervous system and muscles. Statins with high hydrophilicity have good solubility and are not easy to enter muscle cells and the blood-brain barrier. They only exert their effects in the liver and have relatively little effect on the central nervous system and muscles[5].

• Lipophilic: Lovastatin, Simvastatin, Fluvastatin, Pitavastatin

• Hydrophilic: Pravastatin, Rosuvastatin

• Amphiphilic (water- and lipid-soluble): Atorvastatin

The order of lipophilicity is: pravastatin < rosuvastatin < atorvastatin < fluvastatin < pitavastatin < lovastatin < simvastatin

4. Drug metabolism

• Atorvastatin, simvastatin, lovastatin: Mainly metabolized through the CYP3A4 pathway

• Fluvastatin: Mainly metabolized via the CYP2C9 pathway

• Rosuvastatin: approximately 10% metabolized via CYP2C9 pathway

• Pitavastatin: Only minimally metabolized by CYP2C9 (labeled as virtually not metabolized by CYP)

• Pravastatin: not metabolized by CYP

Therefore, pravastatin, pitavastatin, and rosuvastatin are less likely to interact with other drugs that require CYP metabolism.

5. Time to take medication

The timing of taking medication is mainly related to two factors: the half-life of the drug and the effect of food.

• Atorvastatin, rosuvastatin: have a longer half-life and can be taken at a fixed time of day;

• Simvastatin, pravastatin, fluvastatin, pitavastatin: short half-life, take before bedtime;

• Lovastatin: Food promotes absorption, take with dinner

6. Adverse Reactions

The overall incidence of adverse reactions to statins in the Chinese population is 7.46%. The order of incidence is gastrointestinal symptoms (3.942%) > liver symptoms (1.295%) > muscle symptoms (1.173%) > neurological symptoms (0.653%). In addition, there are other adverse reactions such as new-onset diabetes [6]. Among them, the adverse reaction of myalgia can be predicted through genetic testing.

• Abnormal liver function

Abnormal liver function is mainly manifested by elevated transaminase, with an incidence of about 0.5% to 3.0% and is dose-dependent. Studies have shown that atorvastatin is one of the statins commonly used in clinical practice and has a high incidence of liver damage, which mainly occurs within 3 months of taking the drug, mostly in males, middle-aged and elderly patients, and patients with underlying diseases. Most of them have mild liver damage and a good prognosis [7].

• Muscle adverse reactions

Statin-related muscle complications include myalgia, myositis, myopathy, and rhabdomyolysis, with an incidence of 1% to 5% (RCT study results) or 5% to 10% (observational study results). Rhabdomyolysis is rare.

The incidence of rhabdomyolysis is higher when lovastatin, simvastatin, or atorvastatin is used alone than when pravastatin or fluvastatin is used alone. Rhabdomyolysis is a rare and serious adverse reaction to statins[8]. The mechanism is currently unclear, but it may be related to the inhibition of drug metabolism, which leads to increased blood drug concentrations and inhibits the biosynthesis of coenzyme Q10.

• Effects on blood sugar

Long-term use of statins increases the risk of new-onset diabetes, which is a statin effect. The incidence of new-onset diabetes is higher when using high-intensity statins than when using regular-dose statins (12% vs. 9%).

Atorvastatin, rosuvastatin, simvastatin, and fluvastatin: have similar effects on impaired glycemic control in normoglycemic subjects and patients with type 2 diabetes.
Pitavastatin, pravastatin: have a neutral effect on blood sugar regulation, and pitavastatin can even improve blood sugar control in diabetic patients.

The protective effect of statins on cardiovascular disease is greater than the risk of new-onset diabetes. Whether they are people at high risk of diabetes or patients with diabetes, those who have indications for statin treatment should insist on taking statins.

• Other adverse reactions

Other adverse reactions of statins include headache, insomnia, depression, and gastrointestinal symptoms such as indigestion, diarrhea, abdominal pain, and nausea.

7. Drug selection for special patients

• For patients with diabetes, pitavastatin and pravastatin are preferred;

• For patients with abnormal renal function, atorvastatin is the first choice, and fluvastatin is contraindicated; when patients with abnormal renal function use statins, the dosage should be appropriately reduced;

• For patients with abnormal liver function, pravastatin and pitavastatin are preferred. When the transaminase level rises more than 3 times the upper limit of normal, the dose should be reduced or the drug should be discontinued;

• When used in combination with multiple cardiovascular drugs, pravastatin, pitavastatin and rosuvastatin are preferred[9].

References:

1. Joint Expert Committee on the Revision of the Chinese Blood Lipid Management Guidelines. Chinese Blood Lipid Management Guidelines (2023). Chinese Journal of Cardiovascular Diseases, 2023, 51(03):221-255. DOI:10.3760/cma.j.cn112148-20230119-00038

2. Chinese expert consensus on the use of statins in elderly patients with dyslipidemia (2015), Chinese Journal of Internal Medicine, 2015:467-4773.

3. Deng Jianwei, Guo Dong, Zhou Honghao. Research progress on pharmacokinetics of statins for lowering blood lipids[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2007, (08): 850-860.

4. Lipid Metabolism Group of the Endocrinology Branch of the Chinese Medical Association. Expert consensus on the prevention and treatment of type 2 diabetes combined with dyslipidemia in China (revised version 2017)[J]. Chinese Journal of Endocrinology and Metabolism, 2017, 33(11):925-936.

5. Li Dandan, Tao Tao. Effects of chemical structure and physicochemical properties of statins on their efficacy and pharmacokinetic properties[J]. Chinese Journal of Pharmaceutical Industry, 2012, 43 (06): 497-502.

6. National Cardiovascular Disease Expert Committee, Cardiovascular Metabolic Medicine Committee. Chinese expert consensus on clinical diagnosis and treatment of statin intolerance[J]. Chinese Journal of Circulation, 2024, 39(2): 105-114.

7. Jiang Linshuang, Chen Maowei. Analysis of clinical characteristics of atorvastatin-induced liver injury[J/OL]. Chinese General Practice, 1-5[2024-03-28]. http://kns.cnki.net/kcms/detail/13.1222.r.20231201.1006.002.html.

8. Caso G, Kelly P, McNurlan MA, et al. Effect of coenzyme q10 on myopathic symptoms in patients treated with statins［J］． Am J Cardiol, 2007, 99(10):1409.

9. Han Jiahao, Liu Tiantian, Gao Yan. Study on statin-related myopathy and its mechanism[J]. Chinese Journal of Geriatric Cardiovascular and Cerebrovascular Diseases, 2018, 20 (11): 1221-1223.