Resistance and intolerance to statins

Nutr Metab Cardiovasc Dis. 2014 Oct;24(10):1057-66. doi: 10.1016/j.numecd.2014.05.009. Epub 2014 Jun 6.

Abstract

Background and aims: Many patients treated with statins are considered statin-resistant because they fail to achieve adequate reduction of low density lipoprotein cholesterol (LDL-C) levels. Some patients are statin-intolerant because they are unable to tolerate statin therapy at all or to tolerate a full therapeutic statin dose because of adverse effects, particularly myopathy and increased activity of liver enzymes.

Results: The resistance to statins has been associated with polymorphisms in the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA-R), P-glycoprotein (Pg-P/ABCB1), breast cancer resistance protein (BCRP/ABCG2), multidrug resistance-associated proteins (MRP1/ABCC1 and MRP2/ABCC2), organic anion transporting polypeptides (OATP), RHOA, Nieman-Pick C1-like1 protein (NPC1L1), farnesoid X receptor (FXR), cholesterol 7alpha-hydroxylase (CYP7A1), Apolipoprotein E (ApoE), proprotein convertase subtilisin/kexin type 9 (PCSK9), low density lipoprotein receptor (LDLR), lipoprotein (a) (LPA), cholesteryl ester transfer protein (CETP), and tumor necrosis factor α (TNF-α) genes. However, currently, there is still not enough evidence to advocate pharmacogenetic testing before initiating statin therapy. Patients with inflammatory states and HIV infection also have diminished LDL-C lowering as a response to statin treatment. Pseudo-resistance due to nonadherence or non-persistence in real-life circumstances is probably the main cause of insufficient LDL-C response to statin treatment.

Conclusions: If a patient is really statin-resistant or statin-intolerant, several other treatment possibilities are nowadays available: ezetimibe alone or in combination with bile acid sequestrants, and possibly in the near future mipomersen, lomitapide, or monoclonal antibodies against PCSK9.

Keywords: Ezetimibe; Intolerance; LDL-cholesterol; PCSK9; Resistance; Statins.

Publication types

  • Review

MeSH terms

  • Anticholesteremic Agents / therapeutic use
  • Azetidines / therapeutic use
  • Benzimidazoles / therapeutic use
  • Bile Acids and Salts / therapeutic use
  • Cholesterol, LDL / blood
  • Drug Resistance / genetics*
  • Drug Therapy, Combination
  • Drug Tolerance / genetics*
  • Ezetimibe
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
  • Hypercholesterolemia / drug therapy
  • Multidrug Resistance-Associated Protein 2
  • Pharmacogenetics
  • Polymorphism, Genetic

Substances

  • ABCC2 protein, human
  • Anticholesteremic Agents
  • Azetidines
  • BMS201038
  • Benzimidazoles
  • Bile Acids and Salts
  • Cholesterol, LDL
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Multidrug Resistance-Associated Protein 2
  • Ezetimibe