Several other classes of medications are available for the management of hyperlipidemia; however, none of these lipid-lowering therapies have been found to reduce CVD events or mortality in the elderly population.
Ezetimibe
Ezetimibe blocks the absorption of intestinal cholesterol and is typically combined with statin therapy to lower LDL-C. Up until the IMPROVE-IT trial was published in 2015, ezetimibe did not have much use in clinical practice. This landmark trial was a large double-blind study that looked at secondary prevention in patients with ACS, comparing ezetimibe 10 mg and simvastatin 40 mg versus simvastatin 40 mg alone. The authors included patients over the age of 50 (mean age 64) with clinical ASCVD. They found that the addition of ezetimibe to simvastatin did reduce the primary composite outcome (CV mortality, major CV events, or nonfatal stroke) when compared to simvastatin alone [50]. This trial demonstrates clinical benefit with the addition of ezetimibe to statin therapy and adds additional evidence to support a target LDL-C of less than 70 mg/dL; however, the elderly population was not adequately represented in the study to allow extrapolation of these results to older patients.
PCSK-9 Inhibitors
The proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors are a newer class of monoclonal antibodies that were first approved by the US Food and Drug Administration in 2015. Alirocumab and evolocumab, both approved PCSK-9 inhibitors, bind to LDL receptors on the surface of hepatocytes and assist in the internalization of LDL receptors for lysosomal degradation. By inhibiting the binding of PCSK-9 to the LDL receptors, there is an overall increase in LDL receptors available on the cell surface to bind to LDL particles, thereby lowering LDL-C levels. Treatment with these agents are currently considered (in addition to diet and maximally tolerated statin therapy) in adult patients with heterozygous familial hypercholesterolemia or clinical ASCVD requiring further reduction in LDL-C. Two studies were published focusing on the use of PCSK-9 inhibitors: Open-label Study of Long-term Evaluation against LDL Cholesterol (OSLER) and the Tolerability of Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Therapy (ODYSSEY LONG TERM). Overall, these studies demonstrated a 60% reduction of LDL-C among patients with high CVD risk on maximum-tolerated statin therapy. Furthermore, the ODYSSEY LONG TERM trial did find that the rate of major CVD adverse events was significantly lower with alirocumab added to maximum-tolerated statin therapy, with a hazard ratio of 0.52 [51].
One recent study of evolocumab, named the Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER), enrolled patients between the ages of 40 and 85 with 1 major CV risk factor or 2 minor CV risk factors. The primary endpoint was a composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization. Evolocumab lowered major CV events by roughly 15% when added to statin therapy in patients who were at high risk for clinical ASCVD. The mean age of the patients in the trial was 63; however, it is unclear how many of the study participants were elderly [52].
Unfortunately, the studies discussed above do not represent the elderly population well and the agents have not been studied long-term to determine the effects of continued use beyond 2 years. Long-term outcome studies are currently underway; however, it is unknown at this time whether elderly patients are being considered in these studies. It is known that genetic variation of the PCSK-9 locus does lower LDL-C in the elderly but does not significantly lower their risk of vascular disease [51]. At this time, until further evidence is available, we do not recommend the use of PCSK-9 inhibitors in elderly patients.
Nicotinic Acid
Nicotinic acid (Niacin, Niacin ER), also known as vitamin B3, has been utilized for decades as a vitamin supplement, an anti-wrinkle agent, and is known to have neuroprotective effects. It has also been utilized for dyslipidemia and has had some benefits when used alone to decrease cardiovascular disease [53]. Unfortunately the Coronary Drug Project was completed in the 1980s and did not incorporate patients over the age of 64, therefore making the results difficult to apply to elderly patients today [54]. Other literature has been published in recent years to refute that study, claiming there is no additional benefit to using niacin for cardiovascular protection and these studies have included elderly patients. In the AIM-HIGH trial, published in 2011, approximately 46% of the patients were 65 or older. Patients who were previously taking statin therapy that had known cardiovascular disease were enrolled. Niacin added to simvastatin 40–80 mg lowered LDL-C, triglycerides, and increased HDL-C, but the addition of niacin was not proven to help lower the risk of cardiovascular events [55]. The HPS2-THRIVE study enrolled patients with known cardiovascular disease between the ages of 50 and 80 years and found no benefit in preventing CVD when adding niacin to statin therapy [56]. With its side effect profile, risk for increased glucose intolerance, and lack of evidence to demonstrate benefit for prevention of CV events, we do not recommend niacin for use in the elderly at this time.
