Healthgrades for Professionals

When to Consider Add-On Therapies to Statins

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The decision to treat high cholesterol often comes down to a patient’s risk of developing cardiovascular disease. When determining treatment, I consider their age, sex, race/ethnicity, and level of cholesterol, of course, as well as cardiovascular risk factors such as high blood pressure, presence of diabetes or pre-diabetes, high triglycerides, obesity, and family history. If a patient is at very low risk, then I may consider treating high cholesterol with lifestyle modification alone, instructing dietary changes, increased physical activity, and strategies to get to a healthy weight. However, if a patient has a high risk of cardiovascular disease or one of the major health conditions recommended to start statin therapy (e.g. very high cholesterol, diabetes, or a prior heart attack or stroke), I’ll recommend statin therapy or other lipid lowering therapies.

When it comes to lifestyle changes, I encourage patients to increase fiber in their diet and use plant sterols and stanols instead of butter or animal-based margarine. But ultimately many patients require pharmacologic therapy, of which statins are the major drug used. Statins inhibit HMG-CoA reductase, an enzyme that’s key to the cholesterol synthesis pathway. As a result, they decrease the cholesterol synthesis in the body by the liver, and therefore they decrease the amount of circulating cholesterol. The most common side effects of statins are myalgias, which can at times be intolerable. I encourage my patients to report any side effects to me so we can reevaluate their treatment plan. Often, a different statin or different dose will work just as well without the side effects.

When is it time for an add-on therapy?

When working to lower LDL cholesterol, we aim for a specific target. For people with prior heart attack or stroke, for example, their LDL cholesterol should be less than 70 mg/dL. Statins are often well tolerated, but in some patients, the muscle aches or other side effects are just not manageable. If they’re on a maximally tolerated statin and their LDL cholesterol is not quite reaching their goal, I’ll consider prescribing an add-on therapy to help get their numbers where they need to be.

Typically, our first move is to add ezetimibe, a non-statin medication that decreases absorption of cholesterol from the intestines. This drug usually provides an additional 15 to 20% reduction in LDL cholesterol. I’ll consider adding a stronger therapy, like a PCSK9 inhibitor, for patients whose cholesterol is highly elevated despite a statin, for patients who aren’t able to tolerate a statin at all, or for those with heterozygous familial hypercholesterolemia. These patients require much more robust LDL lowering, and the PCSK9 inhibitor can often accomplish that. These drugs increase the number of LDL receptors on the liver so there’s less cholesterol in the blood. If a patient has experienced a previous cardiovascular event and requires a lot more cholesterol reduction, we’ll usually choose a PCSK9 inhibitor.

There are other, less commonly used add-on therapies available, such as bile acid sequestrants. However, there is a new add-on therapy that recently became available called bempedoic acid. It works on the same pathway of cholesterol synthesis that statins inhibit, but it impacts the pathway earlier on and is specific to the liver, not the muscles, which is why patients on this drug don’t experience the muscle aches sometimes associated with statins. A combination medication of bempedoic acid and ezetimibe is on the market now and can lower cholesterol by ~40%, although there are no cardiovascular outcomes data as of yet.

There are also several new drugs in development that lower cholesterol through novel mechanisms. One example is a drug called inclisiran. It is a small interfering RNA (siRNA) therapy (pending FDA approval) that prevents the production of the target protein in the liver thereby increasing hepatic uptake of LDL cholesterol and clearance from the bloodstream which decreases cholesterol levels significantly. It is only given twice per year by injection making it very attractive for patient adherence and ease. Once that’s available, it will hopefully be a helpful option for patients who require a step-up to statin treatment.

How do we measure success?

Of course, once a patient has reached their personalized cholesterol level goal, we still need to assess residual risk. I always take into account other risk factors that may not be well controlled. High triglycerides, for example, may necessitate other lifestyle modifications or pharmacological therapy. And once we get one risk factor managed, we’ll need to maintain that control and make sure others are addressed on an ongoing basis. Success, to me, means we’ve gotten a patient’s risk factors to optimal levels for optimal risk reduction to prevent a cardiovascular event later on.

It’s important for my medical colleagues to keep in mind that cholesterol must be treated in the context of risk, and we must take advantage of the tools we have, like risk calculators and coronary calcium scoring, to better risk stratify when to start statin therapy and when to include add-ons. It’s crucial to include patients in the conversation so they’re informed of their risk and the reasons why we’ve prescribed a particular regimen.

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