lipophilic (fat) and water soluble statin treatment

Last reviewed 02/2022

Statins can be classified into water soluble and lipid soluble (lipophilic) statins

Water soluble statins

• pravastatin and rosuvastatin

Lipid soluble statins

• apart from pravastatin and rosuvastatin all other available statins - atorvastatin, cerivastatin, fluvastatin, lovastatin and simvastatin - are lipophilic

Metabolism (hepatic and enteric) via the cytochrome P450 system

• lipophilic statins (atorvastatin, fluvastatin, lovastatin, simvastatin) undergo hepatic and enteric metabolism via the cytochrome P450 (CYP450) system (1,2,3,4)
• water soluble statins
  • rosuvastatin and pravastatin are excreted largely unchanged
    • these statins are minimally metabolized by the cytochrome P450 enzyme system before elimination (5)
    • pravastatin and rosuvastatin have therefore been not shown to participate in any clinically relevant drug-drug interactions with CYP450 agents

Insulin resistance:

• lipophilic statins may have adverse metabolic consequences that include impaired insulin secretion and promotion of insulin resistance (1)
• hydrophilic statins
  • pravastatin improves insulin sensitivity in some patients (1)
  • rosuvastatin
    • does not change insulin sensitivity in patients with metabolic syndrome or familial combined hyperlipidemia. However, it increases the incidence of type 2 diabetes (4). Interestingly, rosuvastatin increases the rate of onset of new diabetes in a dose-dependent manner (hazard ratio = 1.10, 1.14, and 1.26, respectively)

Muscle-related symptoms and rhabomyolysis:

• Statin toxicity, as assessed by CK elevations and rhabdomyolysis in randomized trials, also appears to be dose-dependent but not related to the degree to which plasma LDL-C is reduced. In the PRIMO study, muscle-related symptoms occurred with the various regimens as follows (6,7):
  • Fluvastatin XL 40 mg - 5.1%
  • Pravastatin 40 mg- 10.9%
  • Atorvastatin 40 to 80 mg- 14.9%
  • Simvastatin 40 to 80 mg- 18.2%.
  • thus the PRIMO study suggests that fluvastatin and pravastatin have less muscle related symptoms compared to other statins in this particular study (6)
    
    
• more recent studies indicate that rosuvastatin, another hydrophilic statin, may be well tolerated in those who do not tolerate other statins, though no head-to-head trial has been done (8,9)
  
  
• therefore if concern about muscle reated symptoms then use of water soluble statins (pravastatin, rosuvastatin) or modified release fluvastatin are treatment options if a previous statin was stopped because of muscle related symptoms (not rhabdomyolysis where further statin treatment is contraindicated). With respect to use of water soluble statins in this instance, pravastatin is the initial statin suggested for use
  • "..Long-acting fluvastatin or a statin with less cytochrome P dependence, such as pravastatin, is often successful. For patients whose myopathy has recurred with multiple statin rechallenges or whose lipid-lowering goal requires a more potent therapy, rosuvastatin in alternate-day or once- or twice-a-week schedules is efficacious and well tolerated in many patients. Of note, however, although such alternate-day therapies may produce excellent reductions in cholesterol levels, these regimens have not been proven to reduce cardiovascular end points. .." (7)

Reference:

• 1) Kanda M et al. Effects of atorvastatin and pravastatin on glucose tolerance in diabetic rats mildly induced by streptozotocin. Biol Pharm Bull 2003; 26: 1681-1684.
• 2) Koh KK et al. Differential metabolic effects of pravastatin and simvastatin in hypercholesterolemic patients. Atherosclerosis 2009; 204:483-490
• 3) McTaggart F et al. Preclinical and clinical pharmacology of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Am J Cardiol 2001; 87 5A: 28B-32B.
• 4) Sattar N et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010; 375: 735-742.
• 5) Martin PD et al. Metabolism, excretion, and pharmacokinetics of rosuvastatin in healthy adult male volunteers.Clin Ther. 2003 Nov;25(11):2822-35.
• 6) Bruckert E, Hayem G, Dejager S, et al. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients - the PRIMO study. Cardiovasc Drugs Ther 2005; 19:403- 414.
• 7) Fernandez G et al. Statin myopathy: a common dilemma not reflected in clinical trials. Cleve Clin J Med. 2011 Jun;78(6):393-403
• 8) Backes JM, Venero CV, Gibson CA, et al. Effectiveness and tolerability of every-other-day rosuvastatin dosing in patients with prior statin intolerance. Ann Pharmacother 2008; 42:341-346.
• 9) Backes JM, Moriarty PM, Ruisinger JF, et al. Effects of once weekly rosuvastatin among patients with a prior statin intolerance. Am J Cardiol 2007; 100:554-555