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If at First the Statin Fails . . . Try, Try Again!

cvictorg

cvictorg

Member
zkt said:
"A report from the CDC estimates that of the 71 million patients with hyperlipidemia in the United States, only 34 million are treated. Of these patients, 12 million have uncontrolled lipid levels and 1.4 million are refractory or “intolerant” to statins."

If at First the Statin Fails . . . Try, Try Again! - Consultant Live
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Berkeley HeartLab


Statin Induced Myopathy (SLCO1B1) Genotype | Boston Heart Diagnostics
SLCO1B1 Genotype Predicts Ability to Metabolize Statins

Three SLCO1B1 genotypes have been identified and classified in terms of their effect on statin metabolism in the liver—normal (T/T), heterozygote (T/C), and homozygote (C/C):

The T/T genotype (valine/valine) is classified as normal. These patients have a normal ability to metabolize statins (about 70% of the population). Standard doses of statins are recommended for LDL-C lowering and CVD risk reduction.

The T/C genotype (valine/alanine) is classified as an intermediate metabolizer. These patients have a decreased ability to metabolize statins (about 26% of the population). They are at a four-fold increased risk for developing statin induced myopathy. They also achieve less LDL-C lowering from the statin that they receive.

The C/C genotype (alanine/alanine) is classified as a poor metabolizer. These patients have a significantly decreased ability to metabolize statins (up to 5% of the population). They are at a seventeen-fold increased risk of developing myopathy on statin therapy.

Additionally, individuals carrying the T/C or C/C genotype are less responsive to statins for LDL-C lowering than those carrying the T/T genotype.

The Clinical Pharmacogenomics Implementation Consortium: CPIC Guideline for SLCO1B1 and Simvastatin-Induced Myopathy
The SLCO1B1*5 Genetic Variant is Associated with Statin-Induced Side Effects
MMS: Error
The Pharmacogenomics Journal - Differential effect of the rs4149056 variant in SLCO1B1 on myopathy associated with simvastatin and atorvastatin
when subjects were stratified by statin type, the SLCO1B1 rs4149056 genotype was significantly associated with myopathy in patients who received simvastatin, but not in patients who received atorvastatin. Our findings provide further support for a role for SLCO1B1 genotype in simvastatin-associated myopathy, and suggest that this association may be stronger for simvastatin compared with atorvastatin.

SNPwatch: Gene Variant May Increase Risk for Rare Side Effect of Cholesterol-Lowering Drugs | The 23andMe Blog
Out of about 6,000 people taking 80 mg daily of simvastatin (the usual dose is 20-40 mg), researchers identified 85 who either had myopathy or whose bloodwork suggested they were on the verge of developing it. When these people were compared to 90 people who were on high-dose simvastatin but had no signs of muscle problems, the researchers found that one C at rs4149056 increased a person’s odds of myopathy 4.9 times (compared to people with two Ts) and two Cs increased the odds 16.9 times.

The researchers also found an association between rs4149056 and myopathy in the Heart Protection Study, which compared about 10,200 people taking 40 mg of simvastatin with a similar number of people taking a placebo. In this case, however, the effect of the SNP was much smaller – each C increased the odds of myopathy only 2.6 times. Only 23 of the simvastatin-taking patients in this study had myopathy.

The myopathy experienced by both sets of patients in the New England Journal of Medicine report was mild and reversible. There is, however, a potentially fatal (but even more rare) form of muscle breakdown called rhabdomyolysis that has also been linked to statins. More research will be needed to investigate whether rs4149056 is also associated with rhabdomyolysis.

In addition to simvastatin, five other statins are available in the United States: lovastatin (Mevacor/Altocor), pravastatin (Pravachol/Selektine/Lipostat), fluvastatin (Lescol), atorvastatin, (Lipitor/Torvast), and rosuvastatin (Crestor). The authors of the study say that their findings likely apply to those drugs as well — myopathy is known to be a side-effect of all statins and variants in the gene where rs41419056 is found are known to affect blood levels of several statins.

http://www.medscape.com/viewarticle/809552?t=1&topol=1
In the 165 patients taking rosuvastatin, nearly all the explainable variability in blood concentrations could be attributed to two reduced-function polymorphisms, one in the uptake transporter gene SLCO1B1 (p<0.001) and the other in the efflux transporter gene ABCG2 (p<0.01), the group writes. In the 134 patients on atorvastatin, explainable blood-level variability was split between two polymorphisms in SLCO1B1 (p<0.01 and p<0.05, respectively) and the activity of cytochrome P3A (CYP3A). The analyses were adjusted for gender, age, body-mass index, ethnicity, statin dose, and time from last dose and echo a 2008 study that concluded that two SLCO1B1 variants were associated with simvastatin-related myopathy, as reported by heartwire. The screening concept is currently being applied to simvastatin therapy at least at one major center.
 
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cvictorg

cvictorg

Member
http://www.medscape.org/viewarticle/481357
Statin Therapy: Risks vs Benefit: An Expert Interview With Eliot A. Brinton, MD

There are differences among the statins in terms of their propensity to cause myopathy. The statins that carry a higher than average overall risk are among the more potent: lovastatin (Mevacor, Merck; Altocor, Andrx; and generic) and simvastatin (Zocor, Merck). Myopathy risk is not, however, simply directly proportional to cholesterol-lowering efficacy, since it appears to be relatively low with atorvastatin (Lipitor, Pfizer), and may not be elevated with rosuvastatin (Crestor, AstraZeneca), which are the most effective for LDL cholesterol lowering. By contrast, the 2 statins that appear to have lower-than-average risk of myopathy are fluvastatin (Lescol, Reliant) and pravastatin (Pravachol, Bristol-Myers Squibb). These can be especially useful in patients with symptoms or risk of myopathy.

Pravastatin has been considered by many as the only safe statin with regard to myopathy. Evidence in the scientific literature, however, is actually stronger for fluvastatin as having the lowest myopathy risk. There are few comparative data between fluvastatin and pravastatin, but in the Assessment of Lescol in Renal Transplantation (ALERT) study, fluvastatin passed perhaps the most severe test of myopathy risk. That trial included more than 2000 patients who had undergone renal transplantation and were taking cyclosporine. Half of these, or about 1000 patients, also took fluvastatin. Surprisingly, over several years of follow-up, the patients receiving both cyclosporine and fluvastatin were at no higher risk for myopathy than those on placebo. This is impressive evidence for a low myopathy risk with fluvastatin. We are often looking to use statins in such high-risk patients, and so the ALERT data are very encouraging with regard to the use of full-dose fluvastatin for atheroprevention when the risk of drug-drug interaction is high.

Fluvastatin and pravastatin each appears to have fewer drug-drug interactions than other statins. Although some clinicians have felt that the safety of pravastatin was primarily due to its water solubility, the other water-soluble statin, rosuvastatin, has yet to be fully proven as safe. Moreover, fluvastatin, which is not water soluble, has excellent safety data, few potential adverse drug-drug interactions, and appears to be as safe as, or even safer in many contexts than pravastatin.

The statins that are metabolized through the cytochrome P450 3A4 systems are more prone to drug-drug interactions because so many medications use the same pathway. Other cytochrome P450 pathways are much less problematic. Two statins are available in extended-release formulation: fluvastatin (Lescol XL, Reliant) and lovastatin (Altocor, Andrx). Both probably reduce the tendency for systemic complications of the drug, such as myopathy and possibly other drug-drug interactions. This is especially important when choosing a statin for a patient who may be at elevated risk of 1 or more drug-drug interactions, due to polypharmacy, frailty, or advanced age.

Both fluvastatin and rosuvastatin are metabolized primarily by the cytochrome P450 2C9 pathway, yet they appear to have different safety profiles. We do not know why this might be. We have much safety evidence for fluvastatin, but little so far for rosuvastatin. Recent concerns about an apparent excess of myopathy induced by high-dose rosuvastatin have prompted the European Union (EU) to make its label for rosuvastatin more conservative regarding the recommended starting doses. Although this only brings the EU label closer to the existing US label for this agent, the FDA has felt the need to alert healthcare practitioners to carefully follow US label instructions to reduce myopathy risk.
 
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A

ashlee45

Junior Member
cvictorg said:
Berkeley HeartLab


Statin Induced Myopathy (SLCO1B1) Genotype | Boston Heart Diagnostics
SLCO1B1 Genotype Predicts Ability to Metabolize Statins

Three SLCO1B1 genotypes have been identified and classified in terms of their effect on statin metabolism in the liver—normal (T/T), heterozygote (T/C), and homozygote (C/C):

The T/T genotype (valine/valine) is classified as normal. These patients have a normal ability to metabolize statins (about 70% of the population). Standard doses of statins are recommended for LDL-C lowering and CVD risk reduction.

The T/C genotype (valine/alanine) is classified as an intermediate metabolizer. These patients have a decreased ability to metabolize statins (about 26% of the population). They are at a four-fold increased risk for developing statin induced myopathy. They also achieve less LDL-C lowering from the statin that they receive.

The C/C genotype (alanine/alanine) is classified as a poor metabolizer. These patients have a significantly decreased ability to metabolize statins (up to 5% of the population). They are at a seventeen-fold increased risk of developing myopathy on statin therapy.

Additionally, individuals carrying the T/C or C/C genotype are less responsive to statins for LDL-C lowering than those carrying the T/T genotype.

The Clinical Pharmacogenomics Implementation Consortium: CPIC Guideline for SLCO1B1 and Simvastatin-Induced Myopathy
The SLCO1B1*5 Genetic Variant is Associated with Statin-Induced Side Effects
MMS: Error
The Pharmacogenomics Journal - Differential effect of the rs4149056 variant in SLCO1B1 on myopathy associated with simvastatin and atorvastatin
when subjects were stratified by statin type, the SLCO1B1 rs4149056 genotype was significantly associated with myopathy in patients who received simvastatin, but not in patients who received atorvastatin. Our findings provide further support for a role for SLCO1B1 genotype in simvastatin-associated myopathy, and suggest that this association may be stronger for simvastatin compared with atorvastatin.

SNPwatch: Gene Variant May Increase Risk for Rare Side Effect of Cholesterol-Lowering Drugs | The 23andMe Blog
Out of about 6,000 people taking 80 mg daily of simvastatin (the usual dose is 20-40 mg), researchers identified 85 who either had myopathy or whose bloodwork suggested they were on the verge of developing it. When these people were compared to 90 people who were on high-dose simvastatin but had no signs of muscle problems, the researchers found that one C at rs4149056 increased a person’s odds of myopathy 4.9 times (compared to people with two Ts) and two Cs increased the odds 16.9 times.

The researchers also found an association between rs4149056 and myopathy in the Heart Protection Study, which compared about 10,200 people taking 40 mg of simvastatin with a similar number of people taking a placebo. In this case, however, the effect of the SNP was much smaller – each C increased the odds of myopathy only 2.6 times. Only 23 of the simvastatin-taking patients in this study had myopathy.

The myopathy experienced by both sets of patients in the New England Journal of Medicine report was mild and reversible. There is, however, a potentially fatal (but even more rare) form of muscle breakdown called rhabdomyolysis that has also been linked to statins. More research will be needed to investigate whether rs4149056 is also associated with rhabdomyolysis.

In addition to simvastatin, five other statins are available in the United States: lovastatin (Mevacor/Altocor), pravastatin (Pravachol/Selektine/Lipostat), fluvastatin (Lescol), atorvastatin, (Lipitor/Torvast), and rosuvastatin (Crestor). The authors of the study say that their findings likely apply to those drugs as well — myopathy is known to be a side-effect of all statins and variants in the gene where rs41419056 is found are known to affect blood levels of several statins.

http://www.medscape.com/viewarticle/809552?t=1&topol=1
In the 165 patients taking rosuvastatin, nearly all the explainable variability in blood concentrations could be attributed to two reduced-function polymorphisms, one in the uptake transporter gene SLCO1B1 (p<0.001) and the other in the efflux transporter gene ABCG2 (p<0.01), the group writes. In the 134 patients on atorvastatin, explainable blood-level variability was split between two polymorphisms in SLCO1B1 (p<0.01 and p<0.05, respectively) and the activity of cytochrome P3A (CYP3A). The analyses were adjusted for gender, age, body-mass index, ethnicity, statin dose, and time from last dose and echo a 2008 study that concluded that two SLCO1B1 variants were associated with simvastatin-related myopathy, as reported by heartwire. The screening concept is currently being applied to simvastatin therapy at least at one major center.
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CAE, Great information. I like all your post.I will keep visiting this very often.
Thanx for this great work.
 
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