High or abnormal cholesterol levels, inflammation, and endothelial dysfunction play a key role in atherosclerosis and plaque buildup, the most common cause of heart attacks and strokes. (Endothelial dysfunction refers to impaired functioning of the inner lining of blood vessels on the heart’s surface. It results in these vessels inappropriately narrowing instead of widening, which limits blood flow.) There are many different types of cholesterol, including high density lipoprotein (HDL, or good, cholesterol); triglycerides (a byproduct of excess calories consumed, which are stored as fat); and low-density lipoprotein (LDL, or bad cholesterol).
It’s well established that lowering LDL cholesterol, sometimes regardless of whether or not you have high cholesterol, improves cardiovascular outcomes. But do older adults reap the same benefits from lowering cholesterol, and do they face additional risks?
Lowering LDL reduces cardiovascular risk
Studies have consistently shown that lowering LDL cholesterol reduces the risk of cardiovascular death, heart attacks, strokes, and the need for cardiac catheterizations or bypass surgeries. This has been shown in those with established coronary artery disease, as well as in high-risk patients without coronary artery disease.
Lifestyle changes can decrease cholesterol numbers by about 5% to 10%, while cholesterol-lowering medication can decrease LDL cholesterol by 50% or more. Therefore, while lifestyle modifications like a heart-healthy diet (the Mediterranean diet, for example), quitting smoking, regular exercise, and weight loss are critical to reducing cardiovascular risk, medications are often needed to provide additional cardiovascular protection.
Statins, including atorvastatin (Lipitor), simvastatin (Zocor), rosuvastatin (Crestor), and pravastatin (Pravachol), are the mainstay therapy for lowering LDL. Statins work by reducing your own body’s production of cholesterol, which promotes uptake of LDL circulating in the blood by the liver. But not all of the benefit of statins can be explained by decreasing LDL alone. Studies show that statins have favorable effects on inflammation, endothelial dysfunction, and plaque stabilization (when plaque breaks apart, it can cause a heart attack or stroke). Statins have been around for about 40 years, so we have quite a bit of information on their short- and long-term safety and effectiveness.
Ezetimibe (Zetia) is a different type of LDL-lowering drug. Taken as a pill, it lowers cholesterol by inhibiting its absorption in the small intestines. Ezetimibe is mainly used as an add-on medication to statins to achieve further LDL lowering, or on its own in people who cannot tolerate statins. In older adults, ezetimibe alone was found to reduce cardiovascular events but not stroke.
PCSK9 inhibitors are a newer class of cholesterol-lowering drugs. They work by allowing more LDL receptors to remain in the liver, thus allowing the liver to sweep more LDL cholesterol out of the bloodstream. PCSK9 inhibitors have been shown to decrease LDL cholesterol by about 60%. There are two PCSK9 inhibitors on the market, evolocumab (Repatha) and alirocumab (Praluent), and both must be taken by injection every few weeks.
LDL lowering therapies: Are they safe for older adults?
The clinical benefit of lowering LDL cholesterol in older adults has been a point of contention, because people ages 75 and older are not usually included in large numbers in clinical trials. Some have even argued that the risks of LDL-lowering treatment may outweigh benefits for older adults compared to younger adults. But the evidence debunks this myth.
Meta-analyses and clinical trials indicate that statin use is not associated with increased risk of muscle injury, cognitive impairment, cancer, or hemorrhagic stroke compared with those not using statins, regardless of age. Likewise, in clinical trials, risk of liver or kidney injury is similar in people taking statins or a placebo, regardless of age. A prospective study evaluating liver safety in very elderly patients found statins to be safe overall in patients ages 80 and older.
The most common side effect of statins is muscle aches, which occur less than 1% of patients. Even if one type of statin causes side effects in a person, another statin may not. Statins can raise blood sugars, but this is unlikely to lead to type 2 diabetes in anyone not already at high risk for the condition. Similarly, ezetimibe use is largely safe, with diarrhea and upper respiratory infections being the most common side effects. Notably, the safety profile for ezetimibe plus statins is the same as for statins alone, even in older adults. And finally, PCSK9 inhibitors have not been found to increase risk of diabetes, neurocognitive disorders, liver injury, or muscle injury.
The evidence for LDL-lowering therapies in older adults
The question remains: do the benefits of cholesterol-lowering treatments outweigh the risks for older adults? In a systematic review and meta-analysis published in The Lancet, researchers evaluated the clinical benefit of statin and non-statin cholesterol-lowering therapy for older adults. They did this by extracting and re-analyzing data from previous studies that had evaluated statin and non-statin cholesterol-lowering treatments. The analysis included 21,492 patients ages 75 and older. Of these, 54.1% of patients had been enrolled in statin trials; 28.9% in ezetimibe trials; and 16.4% in PCSK9 inhibitor trials.
The investigators made these important observations:
Older patients have a 40% higher risk of major cardiovascular events than younger patients (5.7% versus 4.1%).
For every 38-mg/dL reduction in LDL cholesterol, older patients taking LDL-lowering therapies enjoyed a 26% reduction in risk of major cardiovascular events.
LDL lowering prevented cardiovascular events to a similar degree in older and younger adults.
In older adults, statin and non-statin LDL-lowering therapies were similarly effective for preventing most major cardiovascular events. The exception was stroke, for which non-statin therapy was slightly more effective; this is likely driven by the use of PCSK9 inhibitors.
The analysis above largely represented older patients with existing cardiovascular disease. There are ongoing trials that will help evaluate the utility of statins in older patients as a primary prevention for major cardiovascular events.
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