Lp(a) and cardiovascular diseases

Many large-scale studies have explored the relationship between Lp(a) and cardiovascular diseases, consistently finding an association between high Lp(a) levels and atherosclerosis, heart attacks, or stroke; Lp(a) has been validated as a significant, independent risk factor for heart disease.

Lp(a) promotes the recruitment of immune cells called monocytes to the intima, the innermost layer of blood vessels and arteries facing the blood stream. Once monocytes have migrated to the intima, they can become engorged with oxidized LDL—becoming “foam”cells—and initiate atherosclerotic lesion formation.

Lp(a) contributes to thrombosis (blood clot formation) that could result in a heart attack or stroke. Clot formation in the arterial wall, called “mural thrombosis,” contributes to the growth of atherosclerotic lesions; “occlusive thrombosis,” on the other hand, blocks an artery and triggers a heart attack or stroke. Lp(a) may also enhance coagulation, which could further contribute to thrombotic events.

Lp(a) is found in few species, mainly those that do not synthesize vitamin C. Since the absence of detectable Lp(a) in most species—almost all of which synthesize vitamin C—does not seem to be biologically disadvantageous, it was also proposed that vitamin C serves as a surrogate for Lp(a).

As a surrogate for vitamin C and owing to its pro-clotting functions, Pauling and his colleague suggested that Lp(a) might help repair lesions in the arterial wall caused by mechanical stress, free radicals, and/or sub-optimum collagen synthesis when vitamin C concentrations are insufficient. However, atherosclerosis results from the chronic, pathological deposition of Lp(a). A corollary is that adequate vitamin C status in humans, such as that achieved by sufficient intake, may help prevent arterial damage and reduce the need for the deposition of Lp(a) and/or lower its levels, thus preventing the development of atherosclerotic plaque.

Depletion of vitamin C increases the permeability of the vascular wall, thereby contributing to the infiltration of Lp(a) and leading to plaque formation and mural thrombosis. In chronic vitamin C insufficiency, the prolonged action and accumulation of Lp(a) may result in the development of plaque (mural thrombosis)

 

Lysine—by binding to Lp(a)—may quickly remove Lp(a) from plaque and also prevent its deposition in developing plaque.

Unfortunately, no controlled clinical trials have yet been published to validate or refute this.

Lysine is found in the diet, and it can be used in the body as a precursor to synthesize carnitine, an amino acid critical for mitochondrial energy production in cells. In his first case report on the amelioration of angina with vitamin C and lysine, Pauling noted that vitamin C is important in the hydroxylation reactions that synthesize carnitine from lysine. A number of studies have found that carnitine supplementation, as an adjunct to conventional therapy, is useful in treating heart disease, including heart attacks, heart failure, angina, and peripheral arterial disease.

 

Source:

Linus Pauling Institute | Oregon State University

Stephen Lawson
LPI Administrative Officer

VITAMIN C, LYSINE, AND LIPOPROTEIN(a) IN ATHEROSCLEROSIS AND ANGINA PECTORIS

Comparing Statin Drugs

Question:

For the dyslipidemic patient, how do we differentiate between the statins; ie, when should one be used preferentially over the other? Are there significant clinical differences among them?

Statins are widely prescribed for the treatment of dyslipidemia. These drugs are hydroxymethylglutaryl-coenzyme A reductase inhibitors, also known as HMG-CoA reductase inhibitors. They work by reversibly and competitively inhibiting the enzyme necessary for conversion of HMG-CoA to mevalonate, the rate-limiting step in hepatic cholesterol synthesis. This leads to increased low density lipoprotein (LDL)-receptor expression on the hepatocyte surface, increased uptake of LDL, and decreased circulating LDL.^1,2 Statins also decrease triglycerides and modestly increase high density lipoprotein (HDL) levels.

While all statins have the same mechanism of action, they differ in terms of chemistry, pharmacokinetics, potency, cost, and approved indications. The following is a summary of some of the more important distinguishing characteristics.

Chemistry

Lovastatin, pravastatin, and simvastatin are derived from fungi,

whereas atorvastatin, fluvastatin, and rosuvastatin are synthetic.

Atorvastatin, lovastatin, and simvastatin are lipophilic,

whereas pravastatin, rosuvastatin, and fluvastatin are more hydrophilic.

Lipophilic statins cross the blood-brain barrier more readily, which may lead to central nervous system complaints such as insomnia, although this is rare.

Hydrophilic statins exhibit greater hepatoselectivity and less influence on smooth muscle proliferation.^[1,2]

Pharmacokinetics

Lovastatin's absorption increases when taken with food, whereas absorption of atorvastatin, fluvastatin, and pravastatin decreases when taken with food.

Simvastatin and rosuvastatin are not affected by food intake.^[1]

All statins are extensively bound to plasma proteins with the exception of pravastatin, which is about 50% bound to plasma proteins, making it less likely to displace albumin-bound drugs, such as warfarin.^[1,2]

Lovastatin and simvastatin are prodrugs and must be hydrolyzed to the active hydroxy acid, while other statins are administered in the active hydroxy acid form.

All statins are subject to extensive first-pass metabolism with the exception of pravastatin.^[1,2]

important: Neither pravastatin nor rosuvastatin undergo extensive CYP450 metabolism, which can increase a drug's likelihood of producing muscle toxicity due to drug interactions.

Atorvastatin, lovastatin, and simvastatin are metabolized by the 3A4 isoform, while fluvastatin is metabolized by 2C9. Possible drug interactions include 3A4 inhibitors (azole antifungals, macrolides, calcium channel blockers, cyclosporine, cimetidine, and grapefruit juice); 2C9 inhibitors (omeprazole, ritonavir, azole antifungals); and inducers of both 3A4 and 2C9, such as phenobarbital, rifampin, phenytoin, and carbamazepine.^[1,2]

Rosuvastatin, fluvastatin, simvastatin, and pravastatin are eliminated primarily in the feces, whereas atorvastatin and lovastatin are eliminated primarily in the bile. The dosage of pravastatin should be modified in patients with moderate-to-severe renal impairment, and

dosages of lovastatin, rosuvastatin, and simvastatin should be modified in cases of severe renal impairment. No change in dose is needed for atorvastatin or fluvastatin in these patients.^[2]

Due to their longer half-lives, rosuvastatin and atorvastatin can be administered at any time of day. Other statins have shorter half-lives and should be administered in the evening, when synthesis of endogenous cholesterol occurs.

Potency

Rosuvastatin and atorvastain are the most potent statins with respect to lowering LDL, followed by simvastatin and pravastatin. Differences in increasing HDL or decreasing triglycerides are less clear. Doubling a statin dose produces only about a 5% decrease in total cholesterol and a 7% decrease in LDL concentration, so a more potent statin may be necessary in the case of subtherapeutic response.^[3]

Safety

Rare adverse events include liver or skeletal muscle toxicity, and they occur most often when a statin is given in combination with an interacting drug or with another medication that is also hepatotoxic or myotoxic. More common events include gastrointestinal disturbances, headache, insomnia, myalgia, and rash.^[4] Statins are generally well-tolerated, with low dropout rates from clinical trials.^[1]

All statins are in pregnancy category X, defined by the US Food and Drug Administration as contraindicated in pregnancy.

For patients with renal failure, atorvastatin or fluvastatin may be preferred over the others because they are less affected by renal impairment. In clinical situations where patients must receive multiple medications (eg, patients with HIV/AIDS), pravastatin is least likely to interact because it is not metabolized by CYP450.

Cost

Another important distinguishing feature of statins is their cost to the patient. Brand-only statins (atorvastatin, rosuvastatin, fluvastatin) may be too expensive for some patients, may not be in a patient's insurance formulary, or may require a higher co-payment, compared with statins that are available generically (lovastatin, pravastatin, and simvastatin).

Pleiotropic Effects

Statins appear to confer clinical benefits that are independent of their lipid lowering activity; these are known as pleiotropic effects.^[6] Statins inhibit synthesis of nonsteroidal isoprenoid compounds, resulting in improvement of endothelial cell function, modification of inflammatory responses, antioxidant effects, antithrombotic effects, and reduction of smooth muscle proliferation and cholesterol accumulation.^[1,2]While there may be subtle differences among the statins in this regard, the exact clinical relevance of this is uncertain.

Reference:
Darrell Hulisz, PharmD
Associate Professor, Department of Family Medicine, Case Western Reserve University School of Medicine, University Hospitals, Case Medical Center, Cleveland, Ohio


Tests on Rosuvastatin (Crestor)

At 6 weeks, rosuvastatin 10-80 mg reduced LDL cholesterol by a mean of 8.2%, 26%, and 12%-18% more than atorvastatin 10-80 mg, pravastatin 10-40 mg, and simvastatin 10-80 mg, respectively.
MEAN % CHANGE FROM BASELINE IN LDL CHOLESTEROL

Rosuvastatin	Atorvastatin	Simvastatin	Pravastatin
10 mg -45.7%	10 mg -36.8%	10 mg -28.3%	10 mg -20.1%
20 mg -52.4%	20 mg -42.6%	20 mg -35%	20 mg -24.4%
40 mg -55%	40 mg -47,8%	40 mg -38.8%	40 mg -29.7%
80 mg -----	80 mg -51.1%	80 mg -45.8%	----- -----

Mean percent changes in HDL cholesterol in rosuvastatin groups were +7.7% to +9.6% compared with +2.1% to +6.8% in all other groups. Across dose ranges, rosuvastatin reduced total cholesterol 4.7% to 18.7% more than the comparators. Rosuvastatin also reduced triglycerides significantly more than simvastatin and pravastatin. In addition, National Cholesterol Education Program (NCEP) Adult Treatment Panel III LDL cholesterol goals were achieved by 82% (10 mg) to 89% (both 20 mg and 40 mg) of rosuvastatin patients and 69% (10 mg), 75% (20 mg), 85% (40 mg), and 82% (80 mg) of atorvastatin patients. The difference was not statistically different between atorvastatin and rosuvastatin except for the 20 mg doses (89% and 75%, respectively).

PHARMACOKINETICS (1-2,16-19)

	Rosuvastatin	Atorvastatin	Simvastatin
Absolute bioavailability	20%	12%	< 5%
Protein binding	88%	98%	95%
Volume of distribution	134 L	565 L	---
Metabolism	Minimal hepatic metabolism. The major metabolite is N-desmethyl rosuvastatin (active) via CYP450 2C9. Greater than 90% of activity is due to rosuvastatin. Clearance is not significantly dependent on CYP450 3A4.	Hydrolyzed by liver (CYP450 3A4)	Hydrolyzed by liver (CYP450 3A4)
Excretion	Feces(90%) Urine(10%)	Feces Urine (2%)	Feces(60%) Urine (13%)
Half-life	19 hours	14 hours	---

CONTRAINDICATIONS (1)

Hypersensitivity to any product component.
Active liver disease or unexplained persistent elevations of serum transaminases.
Pregnancy and lactation.

WARNINGS (1)

HMG-CoA reductase inhibitors have been associated with biochemical abnormalities of liver function. It is recommended that liver function tests be performed before and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically (e.g., semiannually) thereafter.
Use with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease.
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with rosuvastatin and other drugs in this class.
Use with caution in patients with predisposing factors for myopathy, such as renal impairment, advanced age, and hypothyroidism. Discontinue therapy if markedly elevated CK levels occur or myopathy is diagnosed or suspected.
The risk of myopathy may be increased with concurrent use of other lipid-lowering therapies or cyclosporine. Combination therapy with rosuvastatin and gemfibrozil should generally be avoided.
The risk of myopathy may be increased in circumstances which increase rosuvastatin drug levels.
Therapy should be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).

INITIAL DOSE

For hypercholesterolemia and mixed dyslipidemia, 10 mg orally once daily. Consider 5 mg orally once daily for patients requiring less aggressive LDL-C reductions or who are at risk for myopathy. Consider 20 mg orally once daily for patients with marked hypercholesterolemia (LDL-C > 190 mg/dL). For homozygous familial hypercholesterolemia, 20 mg orally once daily.

DOSE ADJUSTMENT
After initiation, lipid levels should be analyzed within 2 to 4 weeks and dosage adjusted accordingly. For patients with creatinine clearance < 30 mL/min/1.73 m(2) not on hemodialysis, the starting dose should be 5 mg once daily and not to exceed 10 mg once daily. When used in combination with gemfibrozil, the dose should not exceed 10 mg once daily. When used in combination with cyclosporine, the dose should not exceed 5 mg once daily.
The use of 80 mg was stopped due to rhabdomyolysis and renal impairment during trials. The myotoxic potential (myopathy) of rosuvastatin 10 mg to 40 mg is similar to other statins. Recommendations for liver function test monitoring are similar with most other statins. Due to concerns regarding renal toxicity (proteinuria), the manufacturer will conduct postmarketing surveillance to assess any link between rosuvastatin and kidney problems. Additional studies include an atherosclerosis regression trial, an intervascular ultrasound study, outcome studies, a study in patients with renal failure on dialysis, and a study in patients with elevated C-reactive protein.

Antibiotics and Statins

Some antibiotics, including erythromycin, clarithromycin, itraconazole, ketoconazole and miconazole, can increase your risk of muscle damage if taken with atorvastatin or simvastatin.

Speak to your doctor if you are taking atorvastatin or simvastatin and need to take one of these antibiotics. Your doctor may advise you to stop taking atorvastatin or simvastatin or take a lower dose of the statin while you are on the course of antibiotics.

The antibiotic daptomycin should also not be taken in combination with any statin.

Source: NHS

CoQ10, Garlic and Atherosclerosis

In a new study, researchers recruited 65 middle-aged men with CAC scores of 10 or more. CAC is a “coronary artery calcium” scan. A score of 10 suggests mild to moderate plaque build-up.

For one year, researchers gave the men a placebo, or a combination of CoQ10 and garlic extract. Results showed that C-reactive protein (CRP) went up in the placebo group, and down in the intervention arm.

As I’ve mentioned before, CRP is an inflammation marker. Inflammation is one of the key players in plaque build-up.

Ready for the kicker? Arterial plaque progression was FOUR TIMES higher with placebo compared to the intervention group.

Just imagine if a drug could do that. Drug executives would kill for a product that could get those results.

Too bad for them. They’ll have to rely on natural treatments like the rest of us.

CoQ10, of course, is the super-antioxidant that repairs free-radical damage to the heart muscle. And alternative doctors have known about the heart-health benefits of garlic for eons.

More recently, research shows that red blood cells convert garlic components into a molecule that REDUCES inflammation.

Sources:

“Aged garlic extract and coenzyme Q10 have favorable effect on inflammatory markers and coronary atherosclerosis progression: A randomized clinical trial” Journal of Cardiovascular Disease Research, Vol. 3, No. 3, July- September 2012, jcdronline.com

Statin side effects: Weigh the benefits and risks

Statin side effects can be uncomfortable, making it seem like the risks outweigh the benefits of these powerful cholesterol-lowering medications. Consider the risks and benefits.

By Mayo Clinic staff

Doctors often prescribe statins for people with high cholesterol to lower their total cholesterol and reduce their risk of a heart attack or stroke. Most people taking statins will take them for the rest of their lives unless they can achieve normal cholesterol levels through diet, exercise, weight loss and nutritional supplements. This can make statin side effects more difficult to manage.

For some people, statin side effects can make it seem like the benefit of taking a statin isn't worth it. Before you decide to stop taking a statin, discover how statin side effects can be reduced.

What are statin side effects?

Muscle pain and damage
The most common statin side effect is muscle pain. You may feel this pain as a soreness, tiredness or weakness in your muscles. The pain can be a mild discomfort, or it can be severe enough to make your daily activities difficult. For example, you might find climbing stairs or walking to be uncomfortable or tiring.

Very rarely, statins can cause life-threatening muscle damage called rhabdomyolysis (rab-doe-mi-OL-ih-sis). Rhabdomyolysis can cause severe muscle pain, liver damage, kidney failure and death. Rhabdomyolysis can occur when you take statins in combination with certain drugs or if you take a high dose of statins.

Liver damage
Occasionally, statin use could cause your liver to increase its production of enzymes that help you digest food, drinks and medications. If the increase is only mild, you can continue to take the drug. Rarely, if the increase is severe, you may need to stop taking the drug. Your doctor might suggest a different statin. Certain other cholesterol-lowering drugs, such as gemfibrozil (Lopid) and niacin (Niacor, Niaspan), slightly increase the risk of liver problems in people who take statins.

Although liver problems are rare, your doctor will likely order a liver enzyme test before or shortly after you begin to take a statin. You shouldn't need any additional liver enzyme tests unless you begin to have signs or symptoms of trouble with your liver. Contact your doctor immediately if you have unusual fatigue or weakness, loss of appetite, pain in your upper abdomen, dark-colored urine, or yellowing of your skin or eyes.

Digestive problems
Some people taking a statin may develop nausea, gas, diarrhea or constipation after taking a statin. These side effects are rare. Most people who have these side effects already have other problems with their digestive system. Taking your statin medication in the evening with a meal can reduce digestive side effects.

Rash or flushing
You could develop a rash or flushing after you start taking a statin. If you take a statin and niacin, either in a combination pill such as Simcor or as two separate medications, you're more likely to have this side effect. Taking aspirin before taking your statin medication may help, but talk to your doctor first.

Increased blood sugar or type 2 diabetes
It's possible your blood sugar (blood glucose) level may increase when you take a statin, which may lead to developing type 2 diabetes. The risk is small but important enough that the Food and Drug Administration (FDA) has issued a warning on statin labels regarding blood glucose levels and diabetes. Talk to your doctor if you have concerns.

Neurological side effects
The FDA warns on statin labels that some people have developed memory loss or confusion while taking statins. These side effects reverse once you stop taking the medication. Talk to your doctor if you experience memory loss or confusion. There has also been evidence that statins may help with brain function — in patients with dementia or Alzheimer's, for example. This is still being studied. Don't stop taking your statin medication before talking to your doctor.

Who's at risk of developing statin side effects?

Not everyone who takes a statin will have side effects, but some people may be at a greater risk than are others. Risk factors include:

·        Taking multiple medications to lower your cholesterol

Being female

·        Having a smaller body frame

Being age 65 or older

·        Having kidney or liver disease

Having type 1 or 2 diabetes

·        Drinking too much alcohol (More than two drinks a day for men age 65 and younger and more than one drink a day for women of all ages and men older than 65)

What causes statin side effects?

It's unclear what causes statin side effects, especially muscle pain.

Statins work by slowing your body's production of cholesterol. Your body produces all the cholesterol it needs by digesting food and producing new cells on its own. When this natural production is slowed, your body begins to draw the cholesterol it needs from the food you eat, lowering your total cholesterol.

Statins may affect not only your liver's production of cholesterol but also several enzymes in muscle cells that are responsible for muscle growth. The effects of statins on these cells may be the cause of muscle aches.

 How to relieve statin side effects

To relieve statin side effects, your doctor may recommend several options. Discuss these steps with your doctor before trying them:

·         Take a brief break from statin therapy. Sometimes it's hard to tell whether the muscle aches or other problems you're having are statin side effects or just part of the aging process. Taking a break of 10 to 14 days can give you some time to compare how you feel when you are and aren't taking a statin. This can help you determine whether your aches and pains are due to statins instead of something else.

·         Switch to another statin drug. It's possible, although unlikely, that one particular statin may cause side effects for you while another statin won't. It's thought that simvastatin (Zocor) may be more likely to cause muscle pain as a side effect than other statins when it's taken at high doses. Newer statin drugs are being studied that may have may have fewer side effects.

·         Change your dose. Lowering your dose may reduce some of your side effects, but it may also reduce some of the cholesterol-lowering benefits your medication has. It's also possible your doctor will suggest switching your medication to another statin that's equally effective but can be taken in a lower dose. For example, if you've successfully taken atorvastatin (Lipitor) for a long time at higher doses, your doctor may keep you at this level. However, higher doses aren't recommended if you're new to this medication.

·         Take it easy when exercising. It's possible exercise could make your muscle aches worse. Talk to your doctor about changing your exercise routine.

·         Consider other cholesterol-lowering medications. Taking ezetimibe (Zetia), a cholesterol absorption inhibitor medication, may help you avoid taking higher doses of statins. However, some researchers question the effectiveness of ezetimibe compared with statins in terms of its ability to lower your cholesterol.

·         Don't try over-the-counter (OTC) pain relievers. Muscle aches from statins can't be relieved with acetaminophen (Tylenol, others) or ibuprofen (Advil, Motrin IB, others) the way other muscle aches are. Don't try an OTC pain reliever without asking your doctor first.

·         Try coenzyme Q10 supplements. Coenzyme Q10 supplements may help to prevent statin side effects in some people, though more studies are needed to determine any benefits of taking it. If you'd like to try adding coenzyme Q10 to your treatment, talk to your doctor first to make sure the supplement won't interact with any of your other medications.

Watch for drug interactions

Statins can have several potentially dangerous interactions with other medications and some foods. These interactions can make it more likely you'll have statin side effects. These include:

·         All statins and grapefruit or grapefruit juice. Grapefruit juice contains a chemical that can interfere with the enzymes that break down (metabolize) the statins in your digestive system. This can be dangerous because it's uncertain what the effect would be on your total cholesterol. You should still be able to have some grapefruit or grapefruit juice, but talk to your doctor about limiting how much grapefruit you can have.

·         Lovastatin (Mevacor, Altoprev) or simvastatin (Zocor) and amiodarone (Cordarone). People taking the statins lovastatin or simvastatin, either alone or in combination with amiodarone (Cordarone), a medication for irregular heart rhythms, are at a greater risk of severe statin side effects, such as rhabdomyolysis.

·         All statins and gemfibrozil (Lopid). People who take both gemfibrozil (Lopid) and a statin may be at a greater risk of statin side effects.

·         Mevacor (lovastatin) and HIV drugs. Medicines used to treat HIV (protease inhibitors) should never be taken with Mevacor.

·         All statins and some antibiotic and antifungal medications. If you have a fungal or bacterial infection, be sure to tell your doctor if you take a statin.

·         All statins and some antidepressant medications. It's possible that taking antidepressants, such as nefazodone, and a statin could make you more likely to have muscle aches.

·         All statins and some immunosuppressant medications. If you take a medication to suppress your immune system, such as cyclosporine (Sandimmune), and a statin, you may be more likely to have muscle aches.

Weigh the risks and benefits

Although statin side effects can be annoying, consider the benefits of taking a statin before you decide to stop taking your medication. Remember that statin medications can reduce your risk of a heart attack or stroke, and the risk of life-threatening side effects from statins is very low.

Even if your side effects are frustrating, don't stop taking your statin medication for any period of time without talking to your doctor first. Your doctor may be able to come up with an alternative treatment plan that can help you lower your cholesterol without uncomfortable side effects.