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Other methods for treating cholesterol problems

Scientists are looking into other methods to treat cholesterol problems. Cholesterol ester transfer protein inhibitors may be able to stop or even "reverse" cholesterol transport for HDL to VLDL or IDL, thus improving the HDL/LDL ratio. Microsomal triglyceride transfer protein (MTP) inhibitors would, like statins, affect cholesterol production in the liver. Early concerns are that side effects could include liver disease (cirrhosis). Acyl cholesterol acyl transferase inhibitors (ACAT) would prevent conversion of the cholesterol molecule to the form that is stored along the arterial walls. Unfortunately, this also means the cholesterol isn't stored in the places it should be stored in – the adrenals and gonads. Scientists are searching for an ACAT inhibitor that stops only cholesterol storage in the arteries.

Fibrates

Fibrates, also called fibric acid derivatives, work by stimulating expression of numerous proteins involved in metabolism of lipids. This results in the accelerated breakdown of triglycerides, and it is for people with high triglycerides that fibrates have been most used. They can also increase HDL levels in the blood by 20%. The major effects of the fibrates are to lower plasma triglyceride and raise HDL-C levels. Fibrates are effective for treatment of combined hyperlipidemia, hypoalphalipoproteinemia and hypertriglyceridemia. The risk of muscle toxicity may increase when patients take both statins and fibrates. Two fibrates are approved for cholesterol problems in the US: Gemfibrozil and Fenofibrate. Fibrates are sometimes used as accessory therapy in combinaton with a statin.

One risk when fibrates are given in combination with statins is that they appear to affect metabolism (breakdown) of that statins and increase the concentration in the bloodstream. This can result in the unintended consequence of more severe side effects from the statin drug.

A study of diabetes patients called the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) found fenofibrate lowered the risk of cardiovascular disease in diabetes patients, but it was not significantly better than statins.

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Niacin inhibits hormone sensitive lipase in fatty tissue, thus lowering fatty acid levels in the blood, and thereby lowering the body’s production of cholesterol and triglycerides. Niacin also results in higher HDL levels. Scientists speculate this is due to a decrease in the rate of elimination of apolipoprotein apoA1, which is the apolipoprotein most associated with HDL.

Nicotinic acid

Patients diagnosed with hypercholesterolemia, hypoalphalipoproteinemia and hyperlipidemia can be treated with nicotinic acid. Nicotinc acid produces positive results based on dosage (a range of 1-3 g per day) in lowering VLDL and LDL-C levels. There are side effects and patient intolerance can limit dosage. More on niacin for cholesterol problems.

Intestinal Agents

Ezetimibe

Ezetimibe is an oral medication that prevents the intestines from absorbing cholesterol. Although most serum cholesterol is synthesized inside the body, some of it comes from diet. The idea behind ezetimibe is that by reducing the effect of dietary cholesterol, a reduction in overall serum cholesterol levels can be effected. Ezetimibe is selective and stops cholsterol, but not the absorption of triglycerides, bile acids or fat soluble vitamins. It targets the NPC1L1 protein on the enterocyte in the small intestine.

The other selling point of ezetimibe is that it avoids the side effects of statins, although that is not as clear. There is anecdotal evidence of ezetimibe patients reporting muscle weakness. The clinical benefit of ezetimibe-and-statin therapy or ezetimibe monotherapy is unproven.

Bile acid sequestrants

Patients with mild to moderate LDL-C elevations are effectively treated with bile acid sequestrants. Cholestramine or colestiol dosages lower LDL-C from 10 to 24 percent. Colesevelam may also produce similar results. These medications work in the digestive system by binding with bile and thereby preventing the reabsorption to the bloodstream. With less bile in the liver, less cholesterol is synthesized.

Typical doses are 24 to 30 g/day for cholestramine and colestiol and only 2 to 4 g/day for colesevelam. These are much higher quantities than you typically see in drugs that enter the bloodstream (like statins) because the medicines physically bond to the bile in the intestines. Patients with elevated LDL-C might also benefit from the addition of bile acid sequestrants in combination with nicotinic acid and a statin. Side effects hamper bile acid sequestrant usage. These effects are mostly in the digestive system and can include bloating and cramping.

Blocking absorption in the digestive system

There is an over-the-counter margarine that stops the body from absorbing cholesterol in the digestive system. Margarine is defined as a butter substitute made from vegetable oils. The plant equivalent of cholesterol is sitosterol. A chemical modification (partial hydrogenation) of sitosterol is used for cooking and when eaten, inhibits the “sterol pumps” in the digestive system.

One interesting method of lowering cholesterol isn’t a drug; it involves swallowing a resin that binds with bile acid. In the intestines the resin participates in an ion exchange reaction and effectively pulls bile from the body. Less bile is recycled and the liver compensates by using cholesterol to produce more bile. Regular use of these resins, cholestryamine and colestipol, can result in a steady-state reduction of LDL levels by 10-25%. Because the resins are swallowed but not digested (they pass through) they can produce abdominal discomfort and interfere with absorption of drugs and nutrients.

Somewhat similar is a plan to deliver statins via the colon. Oxford Pharmascience is developing a system using atorvastatin and simvastatin which are said to be effective at lower doses if given through colonic methods.

PCSK9 inhibitors

In 2015 the FDA approved two cholesterol drugs that are classified as proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors.

Alirocumab which is sold under the brand name Praluent and evolocumab which is sold under the name Repatha were both approved for sale. The FDA specifically approved them for patients with an inherited condition called familial hypercholesterolemia (HeFH), and for people with atherosclerosis-related cardiovascular problems for whom statins aren’t working well enough. Combining alirocumab with atorvastatin has produced good results in a trial.

Both of these new medicines are monoclonal antibodies. They are not taken as a pill, but must be injected. They essentially supplement the immune system and block the PCSK9 protein. In the body this protein reduces the normal removal of LDL from the bloodstream. By blocking PCSK9, the drugs allow the body to function more efficiently in getting rid of the bad cholesterol.

These PCSK9 inhibitors are very expensive, however, running over $10,000 per year per patient.

Inclisiran is a PCSK9 inhibitor developed by Alnylam Pharmaceuticals that is administered every six months. It is in Phase 2 clinical trials.

The drug Repatha was approved in 2015 and in 2017 the results of a large study found this medicine produced a 15 percent "reduction in the combined risk of having a heart attack or stroke or dying from cardiovascular disease". Several cardiologists were quoted as lauding the results and saying it ushered in a new era for cholsterol control.

Fish Derivatives

A study published in The New England Journal of Medicine found a regimen that combines statins and the fatty acid EPA reduced incidence of cardiovascular events in a population of high-risk patients. EPA is eicosapentaenoic acid and can be taken from certain fish. This research framework was the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) which is used for many studies on cardiovascular health.

Summary

Drug (generic name) Type Brand name(s)
Cholestyramine Bile acid sequestrant Questran
Colestipol Bile acid sequestrant Colestid
Colesevelam Bile acid sequestrant Welchol
Gemfibrozil Fibrate Lopid
Fenofibrate Fibrate Lofibra and TriCor
Niacin B Vitamin Niaspan and Niacor
Ezetimibe Digestive absorption inhibitor Zetia
Alirocumab PCSK9 inhibitor Praluent
Evolocumab PCSK9 inhibitor Repatha
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