Dyslipidemia Treatment in the Elderly: A Pharmacologic Overview

The current prevalence of dyslipidemia is 30% to 70%, and it is well known that cardiovascular disease (CVD) is a major cause of worldwide morbidity and mortality. Although statins have been shown to have an “unequivocal” benefit in reducing atherosclerotic cardiovascular disease (ASCVD), the use of these medications in the elderly population (adults >75 years old) is controversial.¹

Led by Wilbert S. Aronow, MD, professor of medicine and senior associate program director of the Cardiology Fellowship Program at Westchester Medical Center in Valhalla, New York, researchers conducted a review of drug therapy for dyslipidemia in elderly patients, published in Drugs and Aging.¹

Previous research has shown that prevalence of CVD, including ischemic heart disease and stroke, increases substantially from 40% at ages 40-59 years to 70%-75% at ages 60-79 years and again to 79%-86% at age ≥80 years.² In addition, after an initial acute myocardial infarction (MI) in adults, there is a ≤20% risk for recurrent acute MI within 5 years.³ Taken together, these data “highlight the tremendous ASCVD burden in the elderly,” according to Dr Aronow and colleagues.¹

Currently, there are several drug categories that affect cholesterol metabolism that can be used to manage dyslipidemia, particularly low-density lipoprotein cholesterol (LDL-C), the primary lipid measurement used for risk evaluation.^1,4 Available drug categories include ezetimibe, niacin, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, fibrates, omega-3 fatty acids, and statins.

Ezetimibe

Several studies have evaluated the safety and efficacy of ezetimibe-plus-statin combination therapies in patients age ≥65 years.¹ A pooled analysis of 4 randomized controlled trials (RCTs) found this therapy “demonstrated greater efficacy in reducing plasma levels of LDL-C regardless of age grouping.”¹ Similarly, the landmark IMPROVE-IT (ClinicalTrials.gov identifier NCT00202878) study found that simvastatin-plus-ezetimibe combination therapy resulted in significant reductions in the incidence of primary composite endpoints, including cardiovascular (CV) death, major coronary event, or nonfatal stroke. This particular combination therapy resulted in a 20% reduction in the incidence of the primary endpoint in participants age ≥75 years compared with a 3% reduction in the <75-year age group.¹

“These findings support the safe and efficacious addition of ezetimibe to statin therapy in an older patient population,” Dr Aronow and colleagues noted. “The current indication for ezetimibe in the management of dyslipidemia is only for secondary prevention.”¹

Niacin

Because of its unique, broad effect on lipid metabolism, niacin (nicotinic acid) has been used as a dyslipidemia treatment since the 1950s¹; however, despite early clinical trials demonstrating CV benefits,¹ 2 large-scale RCTs (AIM-HIGH [ClinicalTrials.gov identifier NCT00120289] and HPS2-THRIVE [ClinicalTrials.gov identifier NCT0046130]) did not confirm that these benefits exist.¹

In AIM-HIGH, researchers found that, despite “favorable changes in cholesterol parameters,” no significant difference in the primary composite endpoint — CV death, nonfatal MI, ischemic stroke, or high-risk acute coronary syndrome — was noted in the 3414 patients included in the study.¹ Similarly, in HPS2-THRIVE, results showed “no significant reduction in the incidence of major vascular events… in the niacin-laropiprant group when compared with placebo.”¹

“The results of AIM-HIGH and HPS2-THRIVE suggest the lack of additional benefit of raising [high-density lipoprotein cholesterol] levels with niacin once LDL-C is at an optimal level,” Dr Aronow and colleagues wrote.¹ “Considering the lack of benefit and the increase in adverse events associated with niacin, this medication should not be used in an elderly population.”¹

PCSK9 Inhibitors

Both evolocumab and alirocumab have been “extensively tested” for the indication of reducing LDL-C.¹ Evolocumab safety and efficacy was examined in 2 open-label, randomized extension studies (OSLER [ClinicalTrials.gov identifier NCT01439880] and OSLER-2 [ClinicalTrials.gov identifier NCT01854918]), which found that evolocumab had “similar potency” in reducing LDL-C across age groups, with overall similar rates of adverse events but higher rates of neurocognitive adverse events.¹ Similarly, investigators in the FOURIER (ClinicalTrials.gov identifier NCT0176433) clinical trial found that evolocumab treatment was associated with a 15% reduction in the primary composite endpoint of CV death, MI, stroke, hospitalization for unstable angina, and coronary revascularization, with no significant between-group differences in adverse event rates. Of additional significance are the data indicating that evolocumab benefits were consistent across age subgroups (ages <65 years and ≥65 years).¹

“These results support the use of PCSK9 inhibitors to further lower LDL-C levels and improve [CV] outcomes,” Dr Aronow and colleagues noted.¹ Although numerous societal guidelines recommend that physicians consider the addition of PCSK9 inhibitors, Dr Aronow and colleagues also added that the cardiology community is still waiting for the publication of data from the ODYSSEY Outcomes (ClinicalTrials.gov identifier NCT01663402) clinical trial, presented in March 2018.¹

Fibrates

Fibrate use in ASCVD management is based on data indicating that higher levels of nonfasting triglycerides and triglyceride-rich lipoproteins are “important independent risk factors for CVD.”¹ Although fibrates, including gemfibrozil and fenofibrate, have been shown to lower triglyceride plasma levels by 30%-50% and increase HDL-C levels by 5%-15%,¹ there is limited safety and outcome data regarding the use of fibrate therapies in older adults.

Results of the Helsinki Heart Study were not generalizable because of the enrollment of middle-aged men only¹; however, results of the VA-HIT (ClinicalTrials.gov identifier NCT00005676) study found that gemfibrozil therapy led to a significant reduction in primary composite outcome risks, including coronary heart disease (CHD) death or nonfatal MI.¹ Conversely, the FIELD study (International Standard Randomized Controlled Trials Number ISRCTN64783481) results indicated that fenofibrate therapy did not result in a significant reduction of the primary composite outcomes (CHD death or nonfatal MI).¹ Data from the ACCORD (ClinicalTrials.gov identifier NCT00000620) study showed that fenofibrate-plus-simvastatin therapy did not result in a reduction of rates of fatal CV events, nonfatal MI, or nonfatal stroke.¹ In addition, new fibrate use in elderly adults has been linked with an increase in serum creatinine levels and a “small 90-day absolute increase in hospitalizations and nephrologist consultations,” according to the results of a population-based cohort study of 19,000 patients.¹

“Overall, available data do not support the routine use of fibrate medications for ASCVD risk reduction in older adults for primary or secondary prevention, either alone or in combination with statins,” Dr Aronow and colleagues concluded.¹

Omega-3 Fatty Acids

Omega-3 fatty acids target serum lipids and lipoproteins as well as very low-density lipoprotein cholesterol concentrations. Decreases in triglycerides ≤45% have been noted as associated with omega-3 fatty acid treatments.¹

Although early trial data examining fish consumption and marine omega-3 fatty acid supplementation demonstrated a cardioprotective effect,¹ more recent research data failed to show the protective effects of omega-3 fatty acids on either mortality or CV health.¹ Results of the Alpha Omega (ClinicalTrials.gov identifier NCT00127452) trial, a randomized study of ~5000 older adults with previous MIs showed that treatment with eicosapentaenoic plus docosahexaenoic acids did not reduce the rates of major CV events.¹ The OMEGA (ClinicalTrials.gov identifier NCT00251134) RCT found similar results in a slightly younger patient population.¹

Most recently, meta-analyses of RCTs of ~78,000 and 112,000 patients found that supplementation with omega-3 fatty acids had “no significant association with fatal or nonfatal CHD or any major vascular events¹; however, data from the REDUCE-IT (ClinicalTrials.gov identifier NCT01492361) RCT found that treatment with icosapent ethyl 2 g/d has a reduced risk for primary composite study outcomes, including CV death, nonfatal MI or stroke, coronary revascularization, or unstable angina.

Currently, the ongoing STRENGTH (ClinicalTrials.gov identifier NCT02104817) RCT is evaluating the ASCVD risk reduction potential of omega-3 carboxylic acid-plus-statin therapy in high-risk patients with CVD and hypertriglyceridemia.

“Overall, available data are not entirely supportive of marine omega-3 fatty acid supplementation to reduce ASCVD risk as part of primary or secondary preventive strategies,” noted Dr Aronow and colleagues; however, these treatments “can be considered for ASCVCD prevention in a subgroup of patients at high residual CVD risk… despite statin treatment.”¹

Statins

There is a wealth of data surrounding the use of statin therapy for patients with ASCVD. Specifically, the strongest, most consistent evidence of statin efficacy is found in secondary prevention studies of patients with established ASCVD.¹ The Simvastatin Survival Study was the first large-scale RCT to demonstrate the efficacy of statin therapy in secondary prevention.¹ A 34% relative risk reduction in both all-cause mortality and major CHD events was noted in a subgroup analysis of patients 65-70 years old.¹ Similarly, the CARE study found that, in a subgroup analysis of patients ages 65-75 years, pravastatin therapy resulted in a 40% relative risk reduction in stroke, a 32% risk reduction in major CHD events, and a 45% reduction in CHD death.¹

Multiple RCTs have established the efficacy of statin therapy for primary prevention in patients age <75 years. In particular, these studies have found that statins reduce the major [CV] event relative risk by 20% to 30%,¹ with data for elderly patients (age >75 years) derived from subgroup analyses of larger studies. The Air Force/Texas Coronary Atherosclerosis Prevention Study was the first primary prevention trial to include elderly patients, with 22% of the patient population (N=6605) age >65 years.¹ Study results found that lovastatin therapy decreased the incidence of a first acute major coronary event (nonfatal MI, unstable angina, or sudden cardiac death) by 37% overall and by 30% in the elderly subgroup.¹

Despite these trials, “[v]ery few data exist regarding the effectiveness of statin use for primary prevention in those ≥75 years of age,” noted Dr Aronow and colleagues, who added that this limitation was recognized by current treatment guidelines.¹

A recent ALLHAT-LLT (ClinicalTrials.gov identifier NCT00000542) substudy assessed the use of pravastatin use for primary prevention in older patients and found that the treatment was not associated with an improvement in either mortality or CHD event rates; this result was consistent in patients both <75 years old and >75 years old.¹ Another recent population-based cohort study of 46,864 patients ≥75 years old found that statin treatment was not associated with a reduction in ASCVD or all-cause mortality.¹

Dr Aronow and colleagues noted that, with the increase in polypharmacy and potential medication interactions, “the risk of adverse events is an important consideration for elderly patients on statin therapy.”¹ For example, results of the USAGE study indicated that muscle symptoms may occur in ≤29% of patients beginning statin therapy.¹ Subgroup analyses of patients enrolled in the JUPITER trial found no significant differences in serious adverse events among patients treated with rosuvastatin,¹ although a subgroup analysis of patients in the PROVE-IT (ClinicalTrials.gov identifier NCT00382460) trial found that atorvastatin 80 mg/d resulted in similar adverse effect incidences in both older and younger patients.¹

Other potential adverse outcomes include asymptomatic increases in concentrations of liver transaminases, which are seen with all statin therapies but are “not clearly associated with an increased risk of liver disease.”^1,5 In addition, there is “ambiguity” about how previously reported risks for new-onset diabetes might affect an elderly population with a reduced life expectancy.¹ Multiple meta-analyses indicated that statin use may be associated with a “modest but statistically significant increase in the risk of new-onset diabetes.”¹

Current American College of Cardiology/American Heart Association cholesterol treatment guidelines recommend the use of high-intensity statins (atorvastatin 40-80 mg/d or rosuvastatin 20-40 mg/d) for patients ≤75 years old, and moderate-intensity statins for patients >75 years old.⁶ The 2016 European Society of Cardiology/European Atherosclerosis Society and Canadian Cardiovascular Society guidelines recommend treatment with maximally tolerated statin therapy to attain a treatment goal of LDL-C reduction for secondary prevention, regardless of age.^1,7,8

Primary prevention of ASCVD via statin therapy is recommended for adults 40-75 years old who are either at an intermediate to high risk for ASCVD or who have LDL-C levels ≥190 mg/dL. Treatment thresholds vary by guideline and are based on a variety of risk calculators, including the US Preventive Services Task Force guidelines, the Framingham risk score, systemic coronary risk evaluation, or QRISK^®2 for ASCVD risk estimation.¹

Finally, statin adherence in patients at high risk for ASCVD is “critically important.”^1,9 Over time, reduced adherence rates can reduce the possible expected benefit of statin therapy. As such, careful follow-up for both compliance and safety monitoring is important.

“[W]hile available data are highly supportive of statin therapy for primary prevention of ASCVD in older adults at intermediate to high [CV] risk, data are less robust regarding patients aged >75 years,” Dr Aronow and colleagues wrote. “International dyslipidemia guidelines recognize this limitation and denote statin use in the elderly… as a point of uncertainty.”¹

“Dyslipidemia is one of the strongest risk factors for the development of ASCVD, and the treatment of dyslipidemia for the primary and secondary prevention of atherosclerosis is a critically important aspect of healthcare in the older population,” Dr Aronow and colleagues wrote, noting that statins remain the “gold standard” medical therapy for primary and secondary prevention.¹ The researchers also encouraged the consideration of combination therapies “to facilitate the use of tolerable doses.”¹

“We strongly believe that statins… should be considered for the primary prevention of ASCVD, irrespective of age, after well-informed shared decision-making that takes comorbidity, life expectancy, polypharmacy, frailty, and potential adverse events into consideration,” Dr Aronow and colleagues concluded. “Future studies should evaluate optimal drugs and drug combinations with a high benefit [to] risk ratio for the prevention of ASCVD in older adults.”¹

References

1. Yandrapalli S, Gupta S, Andries G, Cooper HA, Aronow WS. Drug therapy of dyslipidemia in the elderly. Drugs Aging. 2019;36(4):321-340.

2. Yazdanyar A, Newman AB. The burden of cardiovascular disease in the elderly: morbidity, mortality, and costs. Clin Geriatr Med. 2009;25(4):563-577.

3. Kayani WT, Ballantyne CM. Improving outcomes after myocardial infarction in the US population. J Am Heart Assoc. 2018;7(4):e008407.

4. Wadhera RK, Steen DL, Khan I, Giugliano RP, Foody JM. A review of low-density lipoprotein cholesterol, treatment strategies, and its impact on cardiovascular disease morbidity and mortality. J Clin Lipidol. 2016;10(3):472-489.

5. Aronow WS. Lipid-lowering therapy in older persons. Arch Med Sci. 2015;11(1):43-56.

6. Stone NJ, Robinson JG, Lichtenstein AH, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2889-2934.

7. Catapano AL, Graham I, De Backer G, et al; ESC Scientific Document Group. 2016 ESC/EAS guidelines for the management of dyslipidemias. Eur Heart J. 2016;37(39):2999-3058.

8. Anderson TJ, Grégoire J, Pearson GJ, et al. 2016 Canadian Cardiovascular Society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol. 2016;32(11):1263-1282.9.

9. Mortenson MB, Falk E. Primary prevention with statins in the elderly. J Am Coll Cardiol. 2018;71(1):85-94.