There are certain things in life that are inevitable; death, taxes and, for the physician, patient intolerance of their medication. Statins are wonderful drugs which have revolutionized medicine and almost single handedly reduced the global burden of heart disease. Statins lower “bad cholesterol” (LDL, low density lipoprotein) and raise the “good cholesterol” (HDL, high density lipoprotein). In addition, statins have anti-inflammatory effects that contribute to their ability to lower heart disease. Unfortunately, statins have side effects including raising liver enzymes and causing muscle pains. Many patients cannot tolerate statins due to muscle symptoms.. What is statin intolerance? What new medications are available for patients with statin intolerance?
There are many medications available to treat high cholesterol. However, to be deemed beneficial a medication must meet two requirements. Number one, it must lower LDL substantially. Number two, it must reduce major adverse cardiac outcomes (heart attack, stroke, cardiac death). Medications such as welchol, niacin, fenofibrate, fish oil (omega 3 fatty acids) lower LDL cholesterol, but do not reduce cardiac risk and are therefore not part of the modern cardiac armamentarium. Statins fulfill the criteria by lowering cholesterol and reducing cardiac events. For every 2 mg/dl reduction in LDL, there is a 1% reduction in cardiac outcomes. For example lowering LDL from 140 mg/dl to 100 mg/dl (a reduction of 40 mg/dl) not only reduces cardiac events by 20%, but also lowers mortality by 10%. The most common reason patients cite for stopping their statin is muscle pain. Muscle symptoms include soreness, aching, weakness or cramping and affect large muscle groups (such as the thigh). Muscle pain causing statin intolerance has been reported between 5% and 50% of patients. A recent large study (including 4 million patients) determined that true statin intolerance occurred in about 9% of patients taking a statin. Statin intolerance has been defined by the FDA as " the inability to tolerate at least two statins at the lowest approved doses due to muscle symptoms". Risk factors for statin intolerance include female sex, obesity, underactive thyroid, diabetes, alcohol use, chronic liver or kidney disease, use of calcium channel blocker, and the use of high doses of statin. Factors not associated include smoking and high blood pressure. Statin induced muscle pain usually occurs early in treatment (the first few weeks up to two months). However, the enormous benefit of statins is such that treatment should not be abandoned if a patient reacts to a single agent. Other statins should be tried and dosing altered to try to keep them on the medication. If a patient is truly statin intolerant after several tries, then there are new, nonstatin alternatives.
The first alternative medication for the statin intolerant patient is ezetimbe (Zetia). Ezetimbe alone reduces LDL by 18% and in combination with simvastatin 25%. The combination medication lowers the risk for cardiac events by 8%. Ezetimbe is rarely used by itself, rather it is used to lower the statin dose while still providing cardiac protection. The next class of agents are the PCSK9 inhibitors alirocumab (Praluent) and evolucumab (Repatha) which were approved for use by the FDA in 2015. These medications are given by a self-administered injection under the skin (much like an insulin shot) every two weeks. They lower the LDL by a whopping 58% (Praluent) and 64% (Repatha) and lower cardiac event rates by 15%. The next agent is inclisiran (Leqvio) which was approved for use by the FDA in December 2021. It too is an injectable medication but this is given every six months. Inclisiran has been tested in patients with familial hypercholesterolemia who still have high levels of LDL despite taking a statin. In these patients, inclisiran lowers LDL by 50% on top of statin treatment. Trials are ongoing evaluating inclisiran’s ability to lower cardiac events. In addition, it has not been tested in statin intolerant patients. However, it may prove very useful in this population. Side effects include only injection site reactions and no muscle pain. The last medication is bempedoic acid (Nexletol) which the FDA approved in February 2020. Bempedoic acid has been tested in patients with statin intolerance. Alone it lowers LDL by 21% and in combination with ezetimbe LDL is lowered 38%. Importantly, bempedoic acid was recently shown to lower the cardiac event rate by 13%. In addition, it seems to have anti-inflammatory properties (like statins) whereas ezetimbe and PCSK9 inhibitors do not. Side effects include gout and gallstones but no muscle symptoms. All of these characteristics make it a good alternative for statin intolerant patients.
Despite a plethora of good alternatives, the principal is to have patients take a statin. Fortunately, there are other medications if they cannot continue on statins. In terms of life’s inevitabilities, physicians can’t reduce the tax burden. However, there are now viable options for patients with statin intolerance that also reduce the risk for cardiac death. Two out of three ain’t bad.
