Journal Club Week 2

Paper: Creatine as a Candidate to Prevent Statin Myopathy 
Authors: M Balestrino, E Adriano
Publish Date: July 2, 2019

What are the main points: 

• Statins inhibit guanidinoacetate methyl transferase (GAMT) – last enzyme in creatine synthesis, thus decreasing intracellular content 
  • Could be part of mitochondrial impairment – creatine final acceptor of phosphate in mitochondrial ox phos 
• Creatine supplementation can prevent and reverse statin induced myopathy 

What are the general findings: 

• Shewmon + Craig Creatine Supplementation prevents statin-induced muscle toxicity. 2010
  • Statin alone – myopathy, statin + creatine decrease in myopathy relative to creatine alone 
• These authors 
  • Case study – atorvastatin and simvastatin produced myopathy, no myopathy with simvastatin and creatine 5g/day 

Summarize in your own words: 

• 5g of creatine likely prevents statin myopathy
  • Mechanism is likely related to ensuring repletion of intracellular creatine stores. Creatine deficient due to statin inhibition of GAMT. 

Compare this information to existing understanding of the topic (what’s new, different, contrary to your previous understanding of the topic): 

• New – Never considered using creatine for statin myopathy
• Different – Generally, I’m not a proponent of primary prevention statin therapy with the current guidelines (high dose with 7.5% risk with ASCVD calculator). If creatine truly was eliminate some risk with their use. Still does not address the increase in sterols that could lead to cognitive impairment in susceptible individuals. 
• Contrary – anecdotally and according to some observational studies statins do cause myopathy. There are some larger trials recently showing no increase in myopathy compared to placebo. If there was truly no statin myopathy then creatine supplementation would just be another agent with added cost. 

What conclusion do you come to based on the information and why: 

• I would recommend creatine at a dose of 5g/day in patients who are currently taking statins. Creatine is low risk and is likely mito protective 

What findings would you share with your audience, apply practically: 

• Take creatine – 5g a day is probably reasonable 

Notes: 

• Stated pleiotropic effects of statins – decreased vasc inflammation, decrease markers of platelet adhesion, reduce oxidative stress, stabilize plaques
• Statins not given in 30% of patients with prior stroke – ie tertiary prevention 
• Statin myopathy prevalence 10-13 obs trials, muscular symptoms 7-29%
• Statin myopathy hypotheses – Table 1 
  • Autoimmune – autoantibody to HMGCR – rare and severe 2-3/100,000
  • Mevalonate pathway and end products 
  • Impared CoQ10 and cholesterol content in membrane 
• Creatine function 
  • Cr phosphorylated to PCr 
  • PCr transfers phosphate to ADP to resynthesize ATP 
  • Works as a shuttle brings P to ADP where needed 
    • ATP relatively large and charged so diffusion is hard 
  • Supports maximal effort activities 
  • Consider supplementation in other myopathies – MD, inflammatory myopathies 
• Decrease Creatine content harms muscle function 
  • Mice lacking GATM have decreased strength and atrophy 
  • Mito alterations – shuttle inhibited 
  • ? decreased differentiation of myoblasts into myocytes – did not see anything supporting this 
• Statin reduction in ATP Synthesis 
  • Mitochondrial damage – apparent in statin myopathy 
    •  Different forms of statins – lactone and open hydroxy acid 
      • Lactone more toxic 
• Creatine preventing statin myopathy 
  • Statins open mito transition pore -> apoptosis: potentially prevented via creatine 
  • Dosing: 5g creatine BID loading, maintenance 5g/day
  • ? negative myopathy score with both statin and creatine