• Become aware of the NCEP ATP III guidelines for cholesterol management.
• Discuss the mechanisms of action of the 5 classes of lipid-lowering agents.
• Indentify medications that belong in each class of lipid-lowering agents.

Lecture outline:

Inhibitors of cholesterol synthesis: statins (check an animation on their mechanism of action).

Inhibitors of bile acid absorption.

Cholesterol absorption inhibitors.

Fibrates.

Niacin (vitamin B3 or nicotinic acid)

Essential Evidence Plus

In this podcast Dr. Ebell and Dr. Wilkes (National Public Radio) discuss the JUPITER trial: Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein

Listen the podcast on JUPITER trial.

“JUPITER is notable for the unacknowledged exclusion of a population that may be at increased risk for dose-related adverse effects of rosuvastatin.”

Adriane Fugh-Berman, M.D.
Georgetown University Medical Center
Washington, DC 20007
ajf29@georgetown.edu 

“JUPITER was stopped early, after a median follow-up of 1.9 years. The number of patients who would need to be treated for 2 years to prevent the occurrence of one primary end point was 95. Ridker et al. extrapolate these results by a projection over a 5-year treatment period. This estimation should be viewed critically, since the study has most of  the characteristics of a  truncated trial”.
“The majority of randomized clinical trials that are stopped early because of an observed benefit of the treatment under investigation are industry-funded drug trials that are stopped at the first interim analysis, with  the results published  in a high-impact medical journal”.

Luc A. Pierard, M.D., Ph.D.
University Hospital Sart Tilman
B 4000 Liege, Belgium
lpierard@chu.ulg.ac.be

Read the correspondence section for further comments.

Related links:

• The JUPITER trial: Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. NEJM, November 2008.
• Expanding the Orbit of Primary Prevention — Moving beyond JUPITER
• Breaking News: The Jupiter Trial. Clinical Correlations: The NYU Internal Medicine Blog

On January 25, 2008, FDA announced that it would be reviewing data from the ENHANCE trial (Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia). (http://www.fda.gov/cder/drug/early_comm/ezetimibe_simvastatin.htm). Preliminary results from this trial had indicated that there was no significant difference between Vytorin and simvastatin-treated patients in the thickness of the carotid (neck) arteries despite greater lowering of LDL (bad) cholesterol with Vytorin compared to simvastatin. The thickness of the carotid arteries, also known as carotid intima-media thickness or cIMT, is a marker of risk for cardiovascular disease. The preliminary results from the ENHANCE trial raised several questions, some of which involve the relationship of cIMT to LDL cholesterol levels and the role of cIMT in drug development.

The FDA has completed its review of the final clinical study report of ENHANCE. Following two years of treatment, carotid artery thickness increased by 0.011 mm in the Vytorin group and by 0.006 mm in the simvastatin group. The difference in the changes in carotid artery thickness between the two groups was not statistically significant. However, the levels of LDL cholesterol decreased by 56% in the Vytorin group and decreased by 39% in the simvastatin group. The difference in the reductions in LDL cholesterol between the two groups was statistically significant.

The results from ENHANCE do not change FDA’s position that an elevated LDL cholesterol is a risk factor for cardiovascular disease and that lowering LDL cholesterol reduces the risk for cardiovascular disease. Based on current available data, patients should not stop taking Vytorin or other cholesterol lowering medications and should talk to their doctor if they have any questions about Vytorin, Zetia, or the ENHANCE trial.
ENHANCE was a randomized, double-blind, active-controlled trial conducted in patients with heterozygous familial hypercholesterolemia (HeFH). A total of 725 patients were randomized 1:1 to receive either Vytorin 10/80 (ezetimibe 10 mg plus simvastatin 80 mg) or simvastatin 80 mg for 2 years. The primary efficacy outcome was the change in ultrasound-determined carotid artery thickness (or cIMT).

Based on data from a previously-conducted cIMT study1 and the anticipated degree of cholesterol lowering with Vytorin and simvastatin, it was projected that 2 years of treatment with Vytorin in ENHANCE would lead to a decrease in cIMT of approximately 0.03 mm whereas treatment with simvastatin would lead to an increase in cIMT of approximately 0.02 mm. There are several possible explanations for why the larger reduction in LDL cholesterol observed in the Vytorin group did not translate into significant improvement in cIMT. These include:

• enrollment of a patient population who had received prior lipid-altering or statin therapy and had relatively normal cIMT values at baseline which may make it harder to demonstrate a reduction or improvement in cIMT with Vytorin compared with simvastatin therapy

• the 2-year duration of ENHANCE which may have been too short to see a favorable effect of cholesterol lowering on cIMT

• some other unknown properties of ezetimibe that may negate the beneficial effects of LDL lowering on cIMT.

An ongoing trial known as IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) is examining whether treatment with Vytorin reduces the risk for cardiovascular events (composite endpoint of CV death, major coronary events, and stroke) compared with simvastatin alone. This trial of 18,000 patients is scheduled to be completed in 2012. IMPROVE-IT will provide additional data regarding Vytorin’s effect on the risk for cardiovascular disease.

Pending the results from IMPROVE-IT, patients should not stop taking Vytorin or other cholesterol lowering medications and should talk to their doctor if they have any questions about these medications.

Ezetimibe (Zetia) is an inhibitor of intestinal cholesterol absorption approved to reduce LDL cholesterol levels. Simvastatin (Zocor) is a lipid-lowering drug (“statin”) approved to reduce LDL (bad) cholesterol and increase HDL (good) cholesterol levels and reduce the risk of cardiovascular events such as heart attack and stroke. Vytorin is a combination of ezetimibe and simvastatin approved for reducing LDL and increasing HDL cholesterol levels.

This follow-up communication is in keeping with FDA’s commitment to informing the public about its ongoing safety reviews of drugs.

The FDA urges both healthcare professionals and patients to report side effects from the use of lipid lowering drugs to the FDA’s MedWatch Adverse Event Reporting program
on-line at www.fda.gov/medwatch/report.htm
by returning the postage-paid FDA form 3500 (available in PDF format at www.fda.gov/medwatch/getforms.htm) to 5600 Fishers Lane, Rockville, MD 20852-9787
faxing the form to 1-800-FDA-0178
by phone at 1-800-332-1088

1 Smilde T, et al. Effect of aggressive versus conventional lipid lowering on athersclerosis progression in familial hypercholesterolemia (ASAP): a prospective, randomized double-blind study; Lancet 2001;357:577-581.

Source: FDA CER. Update of Safety Review Follow-up to the January 25, 2008 Early Communication about an Ongoing Data Review for Ezetimibe/Simvastatin (marketed as Vytorin), Ezetimibe (marketed as Zetia), and Simvastatin (marketed as Zocor)

Statin Use and the Risk of ALS

A recent FDA analysis provides new evidence that using statins does not increase the risk of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease also known “Lou Gehrig’s Disease.” Cholesterol-lowering statins such as Lipitor (atorvastatin calcium) and Zocor (simvastatin) have been shown to reduce the risk of heart disease in a wide variety of patients.

FDA undertook its review after receiving a higher than expected number of reports of ALS in its adverse event reporting system. FDA’s report, which was published recently in the journal Pharmacoepidemiology and Drug Safety, was a pooled analysis of 41 clinical trials ranging from 6 months to 5 years duration. In this analysis, the incidence of ALS was 4.2 cases per 100,000 patient-years in trial patients treated with statins, and 5.0 cases per 100,000 patient-years in patients receiving placebo. These results showed that patients treated with a statin did not have an increased incidence of ALS compared with placebo patients. FDA will continue to evaluate additional data as it becomes available.

Additional Information:

FDA MedWatch Safety Alert. Statin drugs and amyotrophic lateral sclerosis (ALS). September 30, 2008.

http://www.fda.gov/medwatch/safety/2008/safety08.htm#Statin

Statins mechanism of action

HMG CoA:  Side effects:

H epatotoxicity
M yositis [aka rhabdomyolysis]

_ Contraindications:
G irl during pregnancy/G rowing children

_ Interactions:
C oumarin/ C yclosporine

Also, check a related animation on their mechanism of action.

Thanks to MedExcel

Can cheap generic statins achieve national cholesterol lowering targets?

Duncan Petty , David Lloyd 1
School of Healthcare, University of Leeds, Leeds; 1 Prescribing Support Unit, The Information Centre for Health and Social Care, Leeds, UK

Objectives: The Department of Health in England recommend that simvastatin and pravastatin should be prescribed in at least 69% of statin prescriptions in primary care on the assumption that these drugs (and at doses prescribed) are as effective as alternatives. We aimed to identify whether primary care trusts (PCTs) that used a high proportion of simvastatin and pravastatin performed as well on the Quality and Outcome Framework (QOF) targets related to cholesterol as those PCTs that used less.

Methods: QOF data were obtained for all PCTs for 2005–2006. National prescribing data for statins was analysed for the same time period. The square of the Pearson correlation was used to assess the association between the two.

Results: The average PCT values for the three QOF indicators for CHD, stroke and diabetes were 78% (range 66–88%), 72% (58–82%) and 79% (67–88%), respectively. The percentage use of simvastatin and pravastatin by PCTs varied from 18–84%, with a mean of 57%. There was no evidence of any association between the use of simvastatin and pravastatin as a percentage of all statin items and success in achieving the QOF targets.

Conclusions: PCTs that had a high proportion of simvastatin and pravastatin use were just as successful achieving cholesterol targets for patients with coronary heart disease, diabetes and stroke as those that used more atorvastatin, rosuvastatin or fluvastatin. This supports the policy to use the less expensive generic statins.

Source: J Health Serv Res Policy 2008;13:99-102

Download podcast | Subscribe with iTunes | Show Notes

Some official information about the trial:

Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein.N Engl J Med. 2008 Nov 20;359(21):2195-2207

HMG CoA reductase inhibitors,or statins are widely prescribed drugs. They are indicated for the treatment of hipercholesterolemia, a condition that increases cardiovascular risk. Currently, the drugs of this group that are available are:

Atorvastatin

Fluvastatin

Lovastatin

Mevastatin

Pitavastatin

Pravastatin

Rosuvastatin

Simvastatin

Mechanism of action. Animation explained

HMG CoA reductase inhibitors competitively inhibit the activity of HMG CoA reductase, the rate-limiting enzyme in cholesterol synthesis. Inhibition of this enzyme results in a transient, modest decrease in cellular cholesterol concentration . The decrease in cholesterol concentration activates a cellular signaling cascade culminating in the activation of sterol regulatory element binding protein (SREBP), a transcription factor that up-regulates expression of the gene encoding the LDL receptor. Increased LDL receptor expression causes increased uptake of plasma LDL, and consequently decreases plasma LDL-cholesterol concentration. Approximately 70% of LDL receptors are expressed by hepatocytes, with the remainder expressed by a variety of cell types in the body.

Clinical uses

• Hypercholesterolemia.
• Familial Hypercholesterolemia (Atorvastatin might be an exception)
• Coronary atherosclerosis
• Prophylaxis for coronary atherosclerosis

Adverse effects and contraindications

• HMG-CoA inhibitors are contraindicated in pregnancy. Limited evidence from animal and human studies indicates that statins should not be taken during pregnancy
• Liver disfunction:Elevations of serum aminotransferase activity (up to three times normal) occur in some patients. This is often intermittent and usually not associated with other evidence of hepatic toxicity. In some patients, who may have underlying liver disease or a history of alcohol abuse, levels may exceed three times normal. This finding portends more severe hepatic toxicity.
• A relatively common side effect of the statins (perhaps 1% of patients) is myositis,that is,infammation of skeletal muscle accompanied by pain,weakness,and high levels of serum creatine kinase. Rhabdomyolysis,i.e.,disintegration of muscle with urinary excretion of myoglobin and
  kidney damage, is serious side effect. The risk of muscle damage is said to increase with
  simultaneous use of the triglyceride-lowering fibrates.

References

[1] Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, Second Edition
by David E. Golan.
[2] Modern Pharmacology with Clinical Applications, Sixth Edition by Charles Craig.[3] Basic & Clinical Pharmacology, 10th Edition by Bertram G. Katzung.