Current and emerging treatments for hypercholesterolemia: A focus on statins and proprotein convertase subtilisin/kexin Type 9 inhibitors for perioperative clinicians
Statins are a mainstay of hyperlipidemia treatment. These drugs inhibit the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase and have beneficial effects on atherosclerosis including plaque stabilization, reduction of platelet activation, and reduction of plaque proliferation and inflammation. Statins also have a benefit beyond atherosclerotic plaque, including anticoagulation, vasodilatation, antioxidant effects, and reduction of mediators of inflammation. In the perioperative period, statins appear to contribute to improved outcomes via these mechanisms. Both vascular and nonvascular surgery patients have been shown in prospective studies to have lower risk of adverse cardiac outcomes when initiated on statins preoperatively. However, not all patients can tolerate statins; the search for novel lipid-lowering therapies led to the discovery of the proprotein convertase subtilisin/kexin Type 9 (PCSK9) inhibitors. These drugs are fully-humanized, injectable monoclonal antibodies. With lower PCSK9 activity, low-density lipoprotein cholesterol (LDL-C) receptors are more likely to be recycled to the hepatocyte surface, where they serve to clear plasma LDL-C. Evidence from several prospective studies shows that these new agents can significantly lower LDL-C levels. While PCSK9 inhibitors offer hope of effective therapy for patients with familial hyperlipidemia or intolerance of statins, several important questions remain, including the results of long term cardiovascular outcome studies. The perioperative effects of new LDL-C-lowering drugs are unknown at present but are likely to be similar to the older agents.
Lazar et al. concluded that the use of low-cost generic statin therapy in the primary prevention of CAD was cost-effective, but suggested under certain conditions expanding to more aggressive prescribing would be cost-effective.[21] Their analysis used the benchmark of $4.00 USD per month for statin therapy based on the fact that the majority of statins are now generic; however, some of the high-intensity statins and ezetimibe are considerably more expensive (approximately $250 USD per month). Lazar and his team took into consideration the incidence of cardiovascular accidents, death rates, and the costs of medical treatment associated with these events compared to the current low cost of statin therapies.
After noncardiac surgery, cardiovascular complications are the leading cause of morbidity and mortality, affecting 3% of patients.[27,28] Statins may improve outcomes simply by lowering cholesterol levels and decreasing the incidence of atherogenesis and endothelial dysfunction. However, it appears that statins provide beneficial effects via nonlipid-lowering mechanisms as well. These pleiotropic effects include vasodilatation, reduced inflammation and thrombogenicity, antioxidant effects, and reduction in C-reactive protein (CRP).[29] Further, statins help to stabilize atherosclerotic plaque and produce antiplatelet effect.
According to several national guidelines,[4,6] statins are recommended as first-line therapy for CAD because a significant body of literature supports their use for primary prevention, particularly in higher risk patients. Statin therapy is also supported for secondary prevention in known cardiovascular disease patients or those with the risk equivalent.[7] A meta-analysis of over 90,000 participants determined that reducing LDL-C levels by an average of 39 mg/dL will yield a 23% reduction in cardiovascular risk over 5 years.[8]
Effective statin therapy will reduce LDL-C, reduce triglycerides, and modestly raise HDL levels. In the past, guidelines to prevent CAD suggested patients achieve a LDL-C level <100 mg/dL, which limits the formation of plaque in coronary arteries. Newer guidelines do not address a targeted LDL-C level but target the types of patients that should lower their LDL-C levels.[4]
Multiple studies indicate that patients previously intolerant of statins can tolerate them when reinitiated at a later time and possibly with a different agent.[15,16,17,18,19] Statin-intolerant patients can be managed with alternative therapies, including switching to another statin or use of intermittent dosage regimens, as well as nonstatin lipid-lowering drugs (e.g., ezetimibe and fibrates).[20]
Stati ns. Statins are the treatment of choice and best-known drug therapy against hypercholesterolaemia. They are also the most used drug at present. This family comprises different compounds and the two most representative ones are simvastatin and atorvastatin. They act by reducing cholesterol within the liver, which means it subsequently captures more cholesterol from the bloodstream and therefore decreases levels in circulation. At high doses it can reduce LDL (“bad”) cholesterol levels by up to 50%.
There are several strategies to reduce cholesterol with medicines. For instance, there are drugs that decrease cholesterol production in the liver or which enable the liver to capture or “clean” more cholesterol from the blood. Alternatively, some medicines reduce the amount of cholesterol absorbed from food or promote its intestinal elimination.
Ezetimibe. Ezetimibe acts by reducing cholesterol absorption in the intestine. It is very well tolerated and associated with LDL cholesterol reductions of 15%–20%.
The ideal values a patient aims to reach to prevent a cardiovascular problem should be estimated as soon as they start receiving treatment to reduce their cholesterol levels. This is known as a cholesterol target. These goals are usually established for LDL or “bad” cholesterol.
Aphaeresis. For people with serious genetic cholesterol disorders and very high blood levels, in addition to normal drug therapy or that they do not tolerate the medication, there are techniques for removing cholesterol from the blood (aphaeresis) which are similar to dialysis for people with kidney disease, but much simpler and better tolerated.
Thus, depending on if they are receiving secondary or primary prevention and their risk factors, their personal LDL target could be 70, 100, or 115–130 mg/dL, for example.
All patients who have previously experienced a cardiovascular problem should receive cholesterol-lowering treatment, regardless of the levels they had before the event: this is known as secondary prevention treatment. In this case the aim of the treatment is to lower the risk of another cardiovascular event, as reducing cholesterol is a common protective element for improving the state of the damaged arteries, whether due to tobacco, high blood pressure, diabetes, cholesterol or a combination of these or other risk factors.
If you have high low-density lipoprotein (LDL) cholesterol, your health care provider may prescribe medicine in addition to lifestyle changes to control your LDL cholesterol level.
The body needs bile acids and makes them by breaking down LDL cholesterol. Niacin, or nicotinic acid. Niacin is a B vitamin that can improve all lipoprotein levels.
A newer type of medicine called PCSK9 inhibitors lowers cholesterol. These medicines are primarily used in people who have familial hypercholesterolemia, a genetic condition that causes very high levels of LDL cholesterol.
You are 40–75 years old with diabetes and an LDL cholesterol level of 70 mg/dL or higher. You are 40–75 years old with a high risk of developing heart disease or stroke and an LDL cholesterol level of 70 mg/dL or higher. Talk with your health care team about how you can lower your risk for heart disease.
Cholesterol Lowering Medications. Type of Medicine. How It Works. Statins. Statin drugs lower LDL cholesterol by slowing down the liver’s production of cholesterol. They also increase the liver’s ability to remove LDL cholesterol that is already in the blood.
Diet and exercise are the best initial treatment for children age 2 and older who have high cholesterol, or who are obese. Children age 10 and older might be prescribed cholesterol-lowering drugs, such as statins, if they have extremely high cholesterol levels.
Good sources include oats, peas, beans, apples, citrus fruits and carrots. Increasing physical activity. Maintaining a healthy body weight. With familial hypercholesterolemia, your doctor likely will also recommend that you take medication to help lower your LDL cholesterol levels.
Adults who have familial hypercholesterolemia usually have LDL cholesterol levels over 190 mg/dL (4.9 mmol/L). Children who have the disorder often have LDL cholesterol levels over 160 mg/dL (4.1 mmol/L). In severe cases, LDL cholesterol levels can be over 500 mg/dL (13 mmol/L).
If you also have high triglycerides, your doctor may prescribe: 1 Fibrates. The medications fenofibrate (Tricor) and gemfibrozil (Lopid) decrease triglycerides by reducing your liver's production of very-low-density lipoprotein (VLDL) cholesterol and by speeding up the removal of triglycerides from your blood. VLDL cholesterol contains mostly triglycerides. 2 Niacin. Niacin (Niaspan) decreases triglycerides by limiting your liver's ability to produce LDL and VLDL cholesterol. But niacin doesn't usually provide any additional benefit than using statins alone. Niacin has also been linked to liver damage and stroke, so most doctors now recommend it only for people who can't take statins. 3 Omega-3 fatty acid supplements. Omega-3 fatty acid supplements can help lower your triglycerides. They are available by prescription or over-the-counter. If you choose to take over-the-counter supplements, get your doctor's OK first. Omega-3 fatty acid supplements could affect other medications you're taking.
PCSK9 inhibitors. These newer drugs — alirocumab (Praluent) and evolocumab (Repatha) — help the liver absorb more LDL cholesterol, which lowers the amount of cholesterol circulating in the blood. They're injected under the skin every few weeks and are very expensive.
The Food and Drug Administration recently approved alirocumab (Praluent) and evolocumab (Repatha) for people who have a genetic condition that causes very high levels of LDL. These drugs may also be used for people who have had heart attacks or strokes and need additional lowering of their LDL levels.
If you are diagnosed with familial hypercholesterolemia, doctors usually recommend that your first-degree relatives — such as siblings, parents and children — be checked for the disorder. This will allow treatment to begin early, if needed.
There is clear evidence that dieta ry reduction in total and saturated fat , weight loss in over weight patients, aerobic exercise, and addition of plant stanols/sterols to the diet leads to a decrease in LDL-cholesterol and an increase in HDL-cholesterol. [59] .
Ezetimibe may be added to maximally tolerated statin therapy when the LDL-cholesterol level remains ≥70 mg/dL. [54] Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun 18;139 (25):e1082-143. https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000625?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed http://www.ncbi.nlm.nih.gov/pubmed/30586774?tool=bestpractice.com
High-intensity statin therapy is recommended after a clinician-patient discussion in patients with a high risk of 10-year atherosclerotic cardiovascular disease (ASCVD) (≥20%). [54] Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun 18;139 (25):e1082-143. https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000625?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed http://www.ncbi.nlm.nih.gov/pubmed/30586774?tool=bestpractice.com
If high-intensity statin therapy is contraindicated or associated with significant adverse effects, use maximally tolerated statin therapy.
Help to control your cholesterol levels. For some people, lifestyle changes, such as a healthier diet and more exercise , may prevent or treat unhealthy cholesterol levels. For others with high cholesterol, medication may also be needed. Work with your doctor to develop a treatment plan that’s right for you.
For some people, lifestyle changes, such as a healthier diet and more exercise, may prevent or treat unhealthy cholesterol levels. For others with high cholesterol, medication may also be needed.
They help decrease triglyceride secretion and clear triglycerides. The amount of marine-derived omega-3 PUFAs needed to significantly lower triglyceride (2 to 4 g) is hard to get from a daily diet alone, so supplementing with capsules may be needed.
Niacin is a B vitamin that limits the production of blood fats in the liver. Take this only if your doctor has prescribed it. It lowers triglycerides and has mild LDL-lowering action.
ACL inhibitors work in the liver to block the production of cholesterol. They are used in combination with lifestyle changes and statins to further decrease LDL cholesterol in adults with familial heterozygous hypercholesterolemia and patients with heart disease that need to further lower their LDL.
They bind to and inactivate a protein on cells found in the liver to lower LDL (bad) cholesterol. Some names are alirocumab and evolocumab.
Statins are most effective at lowering LDL (bad) cholesterol. They also help lower triglycerides (blood fats) and raise HDL (good) cholesterol. Talk to your doctor about the possible side effects before starting statins. Most side effects are mild and go away as your body adjusts.