HMG– Coenzyme A Reductase Inhibitors

Medical Rationale

What is HMG-CoA reductase?

It is the rate limiting enzyme in the formation of cholesterol. HMG-CoA reductase inhibitors are used to “inhibit” this enzyme from creating cholesterol.

HMG-CoA---HMG-CoA reductase--à Mevalonate

Why does cholesterol matter?

There are two types of cholesterol: “good” cholesterol (High Density Lipoproteins, HDL) and “bad” cholesterol (Low Density Lipoproteins, LDL). The good cholesterol is necessary for daily function. The bad cholesterol, however, is known to be the cause of many things detrimental to your health. One of the main health problems caused by over production of LDL cholesterol is atherosclerosis. This is a condition leading to hardening of the arteries.

What types of HMG-CoA reductase medications are available?

There are several different medications in this class of medications. The following medications are examples (this list is not all-inclusive):

· Lipitor (Atorvastatin)

· Mevacor (Lovastatin)

· Lescol (Fluvastatin)

· Zocor (Simvastatin)

· Pravachol (Pravastatin)

 

 

Biochemical Targets and Mechanisms

As previously mentioned, HMG-CoA reductase converts HMG-CoA to Mevalonate and HMG-CoA reductase inhibitors inhibit this reaction. All of the following information was found at the web site located on the related links page of this site.

Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Cholesterol and triglycerides circulate in the bloodstream as part of lipoprotein complexes. With ultracentrifugation, these complexes separate into HDL (high-density lipoprotein), IDL (intermediate-density lipoprotein), LDL (low-density lipoprotein), and VLDL (very-low-density lipoprotein) fractions. Triglycerides (TG) and cholesterol in the liver are incorporated into VLDL and released into the plasma for delivery to peripheral tissues. LDL is formed from VLDL and is catabolized primarily through the high-affinity LDL receptor. Clinical and pathologic studies show that elevated plasma levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and apolipoprotein B (apo B) promote human atherosclerosis and are risk factors for developing cardiovascular disease, while increased levels of HDL-C are associated with a decreased cardiovascular risk.

In animal models, LIPITOR lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL; LIPITOR also reduces LDL production and the number of LDL particles. LIPITOR reduces LDL-C in some patients with homozygous familial hypercholesterolemia (FH), a population that rarely responds to other lipid-lowering medication(s).”

Metabolic Outcomes and health benefits

I am sure you are wondering how this all fits together. What does it really do to the cholesterol in your body? How does it help or hinder your health? Well, the LDL cholesterol formed by HMG-CoA Reductase is inhibited. Therefore, decreased the LDL levels in the body. This decrease in LDL levels decreases your risks in developing cardiovascular (heart) disease. This drop in LDL allows for an increase in HDL cholesterol.

Side Effects

All of the following information is based on material found at the web address located on the related links page of this site. I encourage you to visit this site for more information.

I am sure you are well aware that side effects are involved with almost every drug. The following are side effects that occur most commonly.

· Constipation

· Diarrhea

· Dizziness

· Gas

· Headache

· Heartburn nausea

· Rash

· Stomach pain

· Fever

The next list is a set of rare side effects and your physician should be seen if they occur while taking HMG-CoA Reductase Inhibitors.

· Fever

· Muscle cramps

· Severe stomach pain

· Unusual tiredness or weakness

 

History of Development

 

“Hyperlipidemia is recognized as one of the major risk factors for the development of coronary artery

disease and progression of atherosclerotic lesions. Dietary therapy together with hypolipidemic drugs

are central to the management of hyperlipidemia, which aims to prevent atherosclerotic plaque

progression, induce regression, and so decrease the risk of acute coronary events in patients with

 pre-existing coronary or peripheral vascular disease. In patients at high risk of coronary artery disease

 but without evidence of atherosclerosis, treatment is designed to prevent the premature development

of coronary artery disease, whereas in those with hypertriglyceridemia, treatment aims to prevent the

development of hepatomegaly, splenomegaly, and pancreatitis. The 3-hydroxy-3-methylglutaryl

coenzyme A (HMG-CoA) reductase inhibitors, or statins, are the most potent lipid-lowering agents

currently available, and their use in the treatment of hyperlipidemia provides the focus for this review.

 Particular emphasis is given to cerivastatin, a new HMG-CoA reductase inhibitor that combines potent

 cholesterol-lowering properties with significant triglyceride-reducing effects. Recently completed

primary and secondary intervention trials have shown that the significant reductions in low-density

lipoprotein (LDL) cholesterol achieved with statins result in significant reductions in morbidity and

mortality associated with coronary artery disease as well as reductions in the incidence of stroke and

 total mortality. Such benefits occur early in the course of statin therapy and have led to suggestions

that these drugs may possess antiatherogenic effects over and above their capacity to lower

atherogenic lipids and lipoproteins. Experimental studies have also shown statin-induced improvement

s in endothelial function, decreased platelet thrombus formation, improvements in fibrinolytic activity,

and reductions in the frequency of transient myocardial ischemia.”

 

This information was found on the website listed in the related links portion of this site.  It is an article written by Davignon J. Farnier.

Clinical Trials and Post Clinical observations/experiences

There have been many clinical trials and observations conducted to gain further knowledge of these medications. The following set of trials were performed on Lipitor, one of the most commonly used HMG-CoA Reductase Inhibitors.  The web address from which this information was attained is listed in the related links section of this site.

· Information on the relationship of Lipitor to heart disease

· patients with hypercholesterolemia (high cholesterol) taking Lipitor

· The effects of Lipitor on patients with hypertriglyceridemia

· There is information directed towards the usage of Lipitor with other health conditions

 

Interesting or Unusual Discoveries Associated with Development

Medications are now being tested for other uses besides their intended use.  HMG-CoA Reductase Inhibitors have some other unique uses.  All information that is quoted is sited on the related links page of this site

·  “the prevention of cognitive impairment in elderly persons. Serum lipoprotein

                   Levels may be important predictors of cognitive function, and drugs that lower

            cholesterol may be effective for the prevention of cognitive impairment.”

 

· “Statin Therapy Decreases the Risk of Osteonecrosis in Patients Receiving Steroids”

·  

· “HMG-CoA reductase inhibitors are associated with reduced mortality in ESRD patients”

 

 

 

  

 

Medical Rationale

 

What is a bile acid sequestrant?

Another class of cholesterol medications is the bile acid sequestrants.  Generally classified as hypolipidemic agents, this group fights hypercholesterolemia by lowering serum LDL levels by inhibiting the circulation of bile acids in the body and preventing their ability to be reabsorbed in the gut.

 

What types of bile acid sequestrants are available?

There are a few different bile acid sequestrants on the market. Some of these include:

Questran (cholestyramine)

Colestid (colestipol)

Welchol (colesevelam)

 

Biochemical Targets and Mechanisms

 

Bile acid sequestrants work to lower serum LDL levels by binding bile acids together in the intestines. This causes a larger portion of bile acids to be excreted in the stool instead of returning to the liver.  Therefore, the liver must produce more by converting cholesterol into bile acids, leading to lowered blood cholesterol levels. Bile acid sequestrants have been found to work more efficiently at lowering serum LDL levels when used in combination with an HMG-CoA reductase inhibitor medication or niacin.

 

Side Effects

 

The most common side effects of bile acid sequestrants are gastrointestinal in nature.  Some of the side effects include:

· Constipation

· Abdominal pain

· Bloating

· Vomiting

· Diarrhea

· Weight loss

· Flatulence

 

Also, bile acid sequestrants can cause vitamin deficiencies because these medications cause reduced absorption of vitamins A, D, E, and K.

 

Clinical Trials and Post Clinical Observations/Experiences

 

             Welchol is the one of the more commonly prescribed of the bile acid sequestrant medications.  Several clinical trials have been conducted with this medication.  The main focus of the clinical trials was to determine whether therapy with Welchol alone was sufficient to lower patient’s LDL cholesterol levels or if it was necessary to administer the drug with an HMG-CoA reductase inhibitor.  The separate clinical trials were:

·             Determining the percentage change in lipid concentration in the blood after 24 weeks of therapy using              Welchol only.

· Determining the percentage change in lipid concentration in the blood using Welchol in combination with an HMG-CoA reductase inhibitor

In these studies, all of  the trials consistent in showing that the therapeutic value of Welchol was enhanced if used in conjunction with another cholesterol lowering medication.

 

Information discussed in this segment was found on websites listed in the related links segment of this webpage.

 

 

            

            

             Several clinical studies have shown that that the development of atherosclerosis (hardening of the arteries) has been associated with increased levels of total cholesterol, low density lipoprotein cholesterol and apolipoprotein B (the primary apolipoprotein of low density lipoproteins). Decreased levels of high density lipoprotein cholesterol and apolipoprotein A (HDL transport complex) are also associated with the development of atherosclerosis.  Reductions in the levels of total cholesterol, LDL cholesterol, apolipoprotein B, and total triglycerides can be produced by fenofibric acid. Fenofibric acid is the active metabolite of fenobibrate, which also raises HDL and apolipoprotein A levels.                

             The activation of the peroxisome proliferator activated receptor α (PPARα) has shown the effects of fenofibric acid in clinical practice in vitro in human hepatocyte cultures and in vivo in transgenic mice. By reducing the production of apoprotein C-III (inhibits lipoprotein lipase activity) and eliminating triglyceride-rich particles from plasma by lipoprotein lipase fenofibrate increases lipolysis.  This decrease in triglycerides changes the size and composition of low density lipoproteins from small, condensed particles, to larger and more buoyant particles. These large particles are more attracted to cholesterol receptors and are catabolized more efficiently.      

             Several clinical trials have shown the effects of fenofibrate on cholesterol levels. These trials include heterozygous familial and nonfamilial hypercholesterolemia and Mixed Dyslipidemia (Fredrickson Types IIa and IIb).  A fenofibrate dose equivalent to 145 mg Tricor was given to patients per day in four randomized, placebo controlled, parallel-group, and double-blind studies. The overall outcome of the Tricor therapy lowered total cholesterol, LDL cholesterol, and LDL/HDL levels.

             Another clinical study included patients with Hypertriglyceridemia (Fredrickson Type IV and V).  It included 147 patients in two randomized, double-blind, placebo-controlled clinical trials.  The effects shown after an 8 week therapy included decreased levels of VLDL triglycerides and VLDL cholesterol levels in patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia. LDL cholesterol levels were often increased in treatment of patients with Type IV hyperlipoproteinemia and elevated triglycerides.

                                                  

Information from this section can be found at http://www.wrongdiagnosis.com/c/cholesterol/intro.htm.

 

 

 

 

                          "According to Wikipedia, niacin (also known as Vitamin B3) is a water soluble vitamin which plays a role in metabolism of energy. One of the functions of niacin is to assist the digestive system. The liver can synthesize niacin from trytophan (essential amino acid). Niacin can be acquired in the body by ingestion of animal products, fruits, vegetables, seeds, and fungi. Niacin, when taken in large doses, increases the level of High density lipoprotein (HDL) or "good" cholesterol in blood. Niacin is also used in the treatment of hyperlipidemia because it reduces Very low density lipoprotein (VLDL) secretion, a precursor of Low density lipoprotein (LDL) or "bad" cholesterol, from the liver and inhibits cholesterol synthesis." The National Library of Medicine states, "Adding niacin to a second drug such as a statin may increase the effects on low-density lipoproteins."(http://www.nlm.nih.gov/medlineplus/druginfo/natural/patient-niacin.html)         

             The positive affects of niacin to adjust the blood lipid levels in the body are shown in a study published in the Archives of Internal Medicine which compared niacin to a cholesterol lowering drug called gemfibrozil or Lopid. The study was a sixteen week long study which included 399 males and females between 21 and 75 years of age. The subjects were required to have high density lipoprotein levels less than 40 mg/l, triglycerides less than 400 mg/l, and low density lipoprotein levels less than 260  mg/l.  The initial dose of niacin was 350 mg of niacin given once a day and this dose was administered at bedtime. The dose was increased as the study progressed until a maintenance dose of 2,000 mg/l  per night was reached.  To compare the treatments 600 mg of gemfibrozil was also administered over sixteen weeks.  Aspirin was given to those subject taking niacin to reduce the side affect of flushing, a feeling of warmth, redness and tingling or itching on the skin. (Information in this paragraph can be found at http://intelegen.com/nutrients/niacin.htm.)

             The results of the study showed that niacin increased the levels of high density lipoprotein over 25%, while gemfibrozil only increased HDL levels by 13.3%.  Niacin lowered low density lipoprotein levels slightly, and gemfibrozil raised the levels of the “bad” cholesterol.  Niacin decreased the amounts of triglycerides by 30% and gemfibrozil lowered the amount of triglycerides by 40%.  In conclusion, the result of the study demonstrated that niacin had an overall improvement on the levels of lipids in the body which exceeded the affects of Lopid.  Niacin has also been shown to help reduce the risk of heart attacks. Niacin needs to be taken on an empty stomach with a full glass of water.  (Information in this paragraph can be found at http://intelegen.com/nutrients/niacin.htm.)

             The side affects of niacin include itching, which normally diminishes after a few weeks, and an increase in growth hormone.  Some people take niacin as a growth hormone stimulant.  If using niacin for this purpose, the vitamin needs to be taken on an empty stomach.  The fat from the food decreases the release of the growth hormone in the blood serum.  Niacin is safe in high doses for cholesterol therapy, however it can increase the liver enzymes.  Therefore, a patient on niacin therapy should have their liver enzyme levels checked every few months to prevent liver toxicity.  (Information in this paragraph can be found at .) The safest form of niacin is inositol hexaniacinate.  This form poses less risk to the liver and normally does not have flushing as a side affect.  The dose of inositol hexaniacinate is 500mg three times a day. Also, a patient should use caution if he is already taking a statin, because mixing the therapies can cause inflammation and pain of the muscles and kidney failure.