ABSTRACT

The definition of elderly is arbitrary. In this chapter we will define elderly as greater than 75 years of age because both the US and European lipids guidelines use this age to differentiate therapy recommendations. Atherosclerotic cardiovascular disease (ASCVD) is a major cause of morbidity and mortality in the elderly. Age is a key risk factor for ASCVD and with identical risk factors the 10-year risk of an ASCVD event markedly increases with age. In fact, an older individual with excellent risk factors can still have a high risk for having an ASCVD event. ASCVD begins early in life and progresses until it leads to clinical events later in life. The age that one develops clinical manifestations of ASCVD is dependent on the severity of individual risk factors, the number of risk factors, and the duration of exposure to the risk factors. Elderly individuals have a long exposure to risk factors so even when the risk factors are relatively modest the cumulative effects can be sufficient to result in clinical ASCVD events. This explains why age is such a key variable in determining the risk of developing an ASCVD event. Cardiovascular outcome studies have demonstrated that lowering LDL-C levels with statins, ezetimibe, or PCSK 9 monoclonal antibodies will reduce ASCVD events in elderly patients with pre-existing cardiovascular disease (secondary prevention). In elderly patients without cardiovascular disease (primary prevention) the available data does not definitively demonstrate a decrease in ASCVD events with statin or ezetimibe therapy but is suggestive of a benefit (note there are no primary prevention trials with PCSK9 inhibitors). Additional data is required to determine if bempedoic acid and icosapent ethyl reduce ASCVD events in patients ≥ 75 years of age. Studies are currently underway to provide definitive information on whether statin therapy is beneficial as primary prevention in the elderly. In deciding whether to treat an elderly patient with lipid lowering drugs one needs to consider the following factors; the higher the LDL-C level the greater the benefit of lowering LDL-C, the greater the decrease in LDL-C the greater the benefit, the higher the absolute risk of ASCVD the greater the benefit of lowering LDL-C, life expectancy, competing non-cardiovascular disorders, risk of drug side effects, potential for drug interactions, and patient preferences. In elderly patients without pre-existing ASCVD one should estimate the patient’s risk of developing ASCVD events and in conjunction with the general principles described above discuss with the patient a treatment plan. Determining the coronary calcium score can be helpful if there is uncertainty regarding the appropriate decision. If the decision is to treat our goal in primary prevention patients is often an LDL-C < 100mg/dL but in high-risk patients our goal may be an LDL-C < 70mg/dL. Elderly patients with ASCVD should be treated with lipid lowering drugs to reduce ASCVD unless there are contraindications. At a minimum our goal is an LDL-C < 70mg/dL but we would prefer an LDL-C < 55mg/dL if they can be achieved with a statin + ezetimibe. In very high-risk patients our goal is an LDL-C < 55mg/dL and adding a PCSK9 inhibitor may be required to achieve these levels in some patients. Age per se should not be used to withhold therapy with lipid lowering drugs that can reduce the risk of ASCVD events. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Due to a decreasing birth rate and a longer life expectancy the population is getting older. According to the US census in 2020 there were approximately 50 million people between 65 and 84 years of age (14.9% of the total population) and approximately 6 million between 85 and 99 years of age (1.89% of the total population). The number of Americans ages 65 and older is projected to increase to 82 million by 2050 (23% of the total population). World-wide there are 703 million people aged 65 or older, which is projected to reach 1.5 billion by 2050 (1 in 6 people). It is well recognized that atherosclerotic cardiovascular disease (ASCVD) increases with age and is a major cause of morbidity and mortality in the elderly. In addition to an increased risk of coronary artery disease there is more than a doubling of the prevalence of peripheral arterial disease, cerebrovascular disease, and abdominal aortic aneurism with each decade of life (1). Unfortunately, the elderly (≥ 75 years of age) have not been well represented in lipid lowering cardiovascular outcome trials.

The definition of elderly is arbitrary. In this chapter we will define elderly as greater than 75 years of age because both the US and European guidelines use this age to differentiate therapy recommendations. In both the “Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines” and the “2019 ESC/EAS Guidelines for the Management of Dyslipidemias: Lipid Modification to Reduce Cardiovascular Risk” the recommendations for those over 75 years of age differ from recommendations for younger individuals (2,3). Thus, where possible we will focus on studies in individuals greater than 75 years of age.

LIPID LEVELS IN THE ELDERLY

Lipid levels in US adults from the National Health and Nutrition Examination Survey (NHANES) 2003-2004 are shown in Table 1 (4). Compared to 30–69-year-olds there is a slight decrease in LDL-C, non-HDL-C, and triglycerides with similar HDL-C levels in individuals 70-79 years of age. Other cross-sectional studies have reported similar results (5-11). Prospective studies with longitudinal follow-up have also observed small decreases in total cholesterol, LDL-C, and HDL-C levels in men and women as they become elderly (6,7,9,12-14). It should be noted that the changes in lipid levels reported with aging are relatively small and vary somewhat from study to study. The clinical significance of these small changes is uncertain.

Studies have demonstrated that older individuals have an exaggerated postprandial lipemia compared with younger individuals (15,16). While elevated postprandial triglycerides is associated with an increased risk of ASCVD whether this plays a causal role in increasing ASCVD is uncertain.

It is well recognized that with increasing age the likelihood of other medical disorders increases and this can affect lipid levels. For example, inflammation and infections can decrease LDL-C and HDL-C levels (17). Additionally, poor nutrition due to illness or social-economic factors could decrease lipid levels in the elderly. Finally, frailty is a syndrome associated with aging and increases with age. It is usually associated with a lowering of total, LDL-C, and non-HDL cholesterol levels (18-20).

AGE IS AN IMPORTANT RISK FOR ATHEROSCLEROTIC CARDIOVASCULAR DISEASE

The clearest way to illustrate the importance of age as a key risk factor for atherosclerotic cardiovascular disease (ASCVD) is to compare the 10-year risk at different ages using an updated version of the AHA/ACC pooled cohort equation. Shown in table 2 are four examples of the effect of age on 10-year risk in different clinical situations that demonstrate the marked effect of age on ASCVD risk. Similarly, using the SCORE risk calculator for determining the 10-year risk of fatal cardiovascular disease also demonstrates the very large impact of age on risk (figure 1). It is obvious that age is a major determinant of ASCVD risk.

Figure 1.

Systematic Coronary Risk Estimation chart for European populations at high cardiovascular disease risk (from 2019 ESC/EAS Guidelines for the management of dyslipidaemias (3)).

In fact, an older individual with excellent risk factors can have a high risk for having an ASCVD event. For example, using the AHA/ACC pooled cohort equation a 75-year-old white male with a total cholesterol of 180mg/dL, an HDL-C of 50mg/dL, a blood pressure of 120/80 mmHg, who is not diabetic, doesn’t smoke, and is on no medications still has a 10-year risk for an ASCVD event of 21.7%. A 75-year-old white female with the same risk factors also has a relatively high 10-year risk (14.1%). Using the SCORE estimator (figure 1) for a fatal CVD event it is also apparent that many older individuals, particularly males, are at high risk even when they are non-smokers with an excellent total cholesterol and blood pressure. For example, a 70-year-old male, non-smoker with a total cholesterol of 160mg/dL and systolic BP of 120 mmHg still has a 13% 10-year risk of death from CVD.

WHY ARE OLDER INDIVIDUALS AT HIGHER RISK FOR ASCVD?

It is widely recognized that atherosclerosis begins early in life and slowly progresses ultimately resulting in clinical manifestations later in life (21). Numerous studies have demonstrated the presence of atherosclerosis in young individuals (22-27). In the Bogalusa Heart Study autopsies were performed on 204 young people 2 to 39 years of age (22,28). In the coronary arteries fatty streaks were very common (50 percent at 2 to 15 years of age and 85 percent at 21 to 39 years of age). More advanced raised fibrous-plaque lesions in the coronary arteries were present in 8 percent of individuals 2 to 15 years of age and 69 percent of individuals 26 to 39 years of age. The extent of the atherosclerotic lesions correlated positively with BMI, systolic and diastolic BP, total cholesterol, LDL-C, and triglyceride levels and negatively with HDL-C levels. The extent of the atherosclerotic lesions was greatest in individuals who had multiple risk factors. The Pathobiological Determinants of Atherosclerosis in Youth [PDAY] study examined the effect of risk factors for atherosclerosis in 1079 men and 364 women 15 through 34 years of age who died due to accidents, homicide, or suicide (23,29). Atherosclerosis of the aorta and right coronary artery was measured and increased with age, LDL-C levels, glycohemoglobin levels, BMI, and smoking while HDL-C levels were negatively associated with the extent of fatty streaks and raised lesions in the aorta and right coronary artery. Finally, in a study of US service members (mean age 25.9 years; range 18-59 years; 98.3% male) who died of combat or unintentional injuries (n= 3832) the effect of risk factors on coronary atherosclerosis was determined (27). Atherosclerosis prevalence was increased by age, dyslipidemia, hypertension, and obesity. Taken together these studies clearly demonstrate that atherosclerosis begins early in life with the prevalence increasing with age and the extent and onset of lesions is influenced by risk factors, including dyslipidemia.

Moreover, the presence of risk factors early in life is associated with an increase in atherosclerosis later in life (30-32). A meta-analysis that included 4380 participants from 4 prospective studies that collected cardiovascular risk factor data during childhood (age 3 to 18 years) and measured carotid intima-media thickness (CIMT) in adulthood (age 20 to 45 years) reported that total cholesterol, triglycerides, BP, and BMI measured in childhood were predictive of elevated CIMT in adults (33). Additionally, increased LDL-C and/or decreased HDL-C during adolescence predict an increase in CIMT later in life (34). Importantly, an increased total cholesterol or BP early in life also predicted an increased risk of developing cardiovascular disease later in life (35-38).

Genetic studies have further illustrated the key role of risk factors and duration of exposure to the risk factor as key variables determining the time when clinical manifestations of ASCVD occur. In patients with homozygous familial hypercholesterolemia (FH) LDL-C are markedly elevated and cardiovascular events can occur early in life. Greater than 50% of untreated patients with homozygous FH develop clinically significant ASCVD by the age of 30 and cardiovascular events can occur before age 10 in some patients (39). In patients with heterozygous FH LDL-C levels are elevated but not to the levels seen with homozygous FH and cardiovascular events occur later in life but still at a relatively younger age. Untreated males with heterozygous FH have a 50% risk for a fatal or non-fatal myocardial infarction by 50 years of age whereas untreated females have a 30% chance by age 60 (39). Conversely, individuals with genetic variants in PCSK9, HMG-CoA reductase, LDL receptor, NPC1L1, or ATP citrate lyase that lead to a decrease in LDL-C levels have a reduced risk of developing cardiovascular events (40,41). The relationship between genetic disorders that alter LDL-C levels and the time to develop clinical cardiovascular events is illustrated in figure 2. The figure clearly illustrates that the age when one clinically manifests ASCVD depends on the level of LDL-C. With very high LDL-C levels clinical events occur early in life and with low LDL-C levels events will occur at an older age leading to the concept of LDL years.

Figure 2.

Relationship between cumulative LDL-C exposure and age of developing cardiovascular disease. (from (41)).

The degree and duration of other risk factors also seems to play a role in when the clinical manifestations of ASCVD are expressed. For example, for cigarette smoking, cigarettes/day, smoking duration, and pack-years all increase the risk of cardiovascular disease (42). Interestingly smoking fewer cigarettes/day for a longer duration was more deleterious than smoking more cigarettes/day for a shorter duration (42,43). Additionally, while smoking cessation lowers the risk of ASCVD events an increased risk persists for decades after smoking cessation (44). These observations suggest that the effect of smoking is related to the number of cigarettes smoked and the duration of the smoking (i.e., pack years). Similarly, in patients with diabetes glycemic control and duration of diabetes influences the development of ASCVD complications (45-48). At any given age, a 10-year longer diabetes duration was associated with a 1.1-1.5-fold increased risk of stroke and 1.5-2.0-fold increased risk of MI (45).

Thus, ASCVD begins early in life and progresses until it leads to clinical events such as a myocardial infarction or stroke later in life. The age that one develops clinical manifestations of ASCVD is dependent on the severity of individual risk factors, the number of risk factors, and the duration of exposure to the risk factors. Elderly individuals have a long exposure to risk factors so even when the risk factors are relatively modest the cumulative effects can be sufficient to result in clinical ASCVD events. This explains why age is such a key variable in determining the risk of developing an ASCVD event.

DOES LIPID LOWERING REDUCE EVENTS IN THE ELDERLY

Below we discuss lipid lowering drug studies that report the effect on cardiovascular outcomes that are relevant to clinical decisions in elderly individuals. For additional and more detailed information on lipid lowering cardiovascular outcome studies see the Endotext chapters on “Cholesterol Lowering Drugs” and “Triglyceride Lowering Drugs” (49,50).

Statins

Few statin studies have focused on lowering LDL-C in elderly patients, which we define as individuals greater than 75 years of age. The Prosper Trial determined the effect of pravastatin 40mg/day (n= 2891) vs. placebo (n= 2913) on cardiovascular events in older subjects (70-82 years of age) with pre-existing vascular disease or who were at high risk for vascular disease (51). The average age in this trial was 75 years of age and approximately 45% had cardiovascular disease. As expected, pravastatin treatment lowered LDL-C by 34% compared to the placebo group. The primary end point was coronary death, non-fatal myocardial infarction, and fatal or non-fatal stroke, which was reduced by 15% (HR 0.85, 95% CI 0.74-0.97, p=0.014). However, in the individuals without pre-existing cardiovascular disease pravastatin did not significantly reduce ASCVD events (HR 0.94; CI 0.77–1.15). In contrast, in individuals with cardiovascular disease pravastatin therapy significantly reduced ASCVD events (HR 0.78, CI 0.66–0.93). Thus, this study demonstrated benefits of statin therapy in the elderly with cardiovascular disease but failed to demonstrate benefit in the elderly without cardiovascular disease.

A meta-analysis by the Cholesterol Treatment Trialists of 28 trials with 14,483 of 186,854 found a reduction in LDL-C levels with statin therapy that was similar in the participants ≥75 years of age compared to younger individuals. Moreover, statin therapy resulted in a decrease in cardiovascular events in all age groups including participants ≥75 years of age (Figure 3) (52). In the participants ≥75 there was a 13% reduction in ASCVD events per 39mg/dL decrease in LDL-C (RR 0.87; 95% CI 0.77–0.99). This analysis included four trials done exclusively among people with heart failure or receiving renal dialysis, for whom statin therapy shows little or no benefit (50). A second analysis was performed after elimination of these four trials and there was an 18% reduction in ASCVD events per 39mg/dL decrease in LDL-C (RR 0.82; 95%CI 0.70-0.95). Similar to the Prosper Trial a decrease in ASCVD events was clearly demonstrated in individuals with pre-existing cardiovascular disease (secondary prevention) but in individuals without pre-existing cardiovascular disease (primary prevention) the decrease in ASCVD events was not statistically significant (Figure 4- analysis included all studies). After excluding the trials in patients with heart failure or receiving renal dialysis, statin therapy reduced major ASCVD events by 26% per 39mg/dL decrease in LDL-C (RR 0.74; 95% CI0.60 − 0.91) in patients with pre-existing cardiovascular disease but only by 8% in patients without pre-existing cardiovascular disease (RR 0.92; 95%CI 0.72 − 1.16).

Figure 3.

Effect of Statin Treatment on Major Vascular Events. Modified from (44).

Figure 4.

Effect of Statin Treatment on Major Vascular Events in Individuals With and Without Pre-Existing Cardiovascular Disease. Modified from (44).

A statin trial not included in the Cholesterol Treatment Trialists meta-analysis was carried out in patients with an ischemic stroke or a transient ischemic attack who were treated with statins and/or ezetimibe with a target LDL-C level < than 70mg/dL (n= 1430) or an LDL-C 90mg/dL to 110mg/dL (n= 1430) (53). The primary end point was ischemic stroke, myocardial infarction, new symptoms leading to urgent coronary or carotid revascularization, or death from cardiovascular causes. The mean LDL-C level was 65mg/dL in the lower-target group and 96 mg/dL in the higher-target group. After median of 3.5 years the primary end point occurred in 8.5% of the patients in the lower-target group and 10.9% of the patients in the higher target group (HR 0.78; 95% CI 0.61 to 0.98; P=0.04). In patients < 65 years of age only a 7% decrease in the primary end point was observed (HR 0.93; 95%CI 0.63–1.36) whereas more impressive decreases in the primary endpoint were observed in patients 65-75 years of age (37% decrease; HR 0.63 95% CI 0.42–0.95) and > 75 years of age (23% decrease; HR 0.77; 95%CI 0.49–1.22). These results are consistent with the Cholesterol Treatment Trialists meta-analysis demonstrating that elderly patients with pre-existing cardiovascular disease lowering LDL-C levels reduces ASCVD events.

There are observational studies demonstrating that statin treatment for the primary prevention of ASCVD is effective in older patients (54-59). For example, in US veterans ≥75 years of age and free of ASCVD at baseline, new statin use was significantly associated with a lower risk of ASCVD events (HR 0.92; 95% CI 0.91-0.94) and cardiovascular mortality (HR 0.80; 95% CI 0.78-0.81) when compared to statin nonusers (55). Similarly, in a Danish nationwide cohort initiation of statin therapy in patients > 70 years of age without pre-existing cardiovascular disease there was a 23% lower risk of major vascular events per 39mg/dL decrease in LDL-C (HR 0.77; 95% CI 0.71-0.83), which was similar to what was observed in younger individuals (54). Finally, in nursing home residents without ASCVD statin use reduced all-cause mortality in individuals with and without dementia (59). These observational studies while suggestive of a benefit of statin therapy for primary prevention in older individuals cannot provide definitive proof as there is always the possibility of residual confounding. Nevertheless, they provide additional support that statin therapy provides benefits in elderly patients without pre-existing cardiovascular disease.

Thus, in older patients with cardiovascular disease lowering LDL-C levels with statins clearly reduces cardiovascular events but in older patients without cardiovascular disease the data demonstrating that statins reduce cardiovascular events is less robust but suggests a reduction in ASCVD events.

Ezetimibe

IMPROVE-IT TRIAL

The IMPROVE-IT Trial tested whether the addition of ezetimibe to statin therapy would provide an additional beneficial effect in patients with the acute coronary syndrome (60). The IMPROVE-IT Trial was a large trial with over 18,000 patients randomized to simvastatin 40mg vs. simvastatin 40mg + ezetimibe 10mg per day. On treatment LDL-C levels were 70mg/dL in the statin alone group vs. 54mg/dL in the statin + ezetimibe group. There was a small but significant 6.4% decrease in major cardiovascular events (cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization, or stroke) in the statin + ezetimibe group (HR 0.936; 95% CI 0.887-0.988; p=0.016). Cardiovascular death, non-fatal MI, or non-fatal stroke were reduced by 10% (HR 0.90; 95% CI 0.84-0.97; p=0.003). The effect of age on the benefits of statin + ezetimibe therapy is shown in figure 5. In elderly individuals (≥ 75 years of age) the combination of ezetimibe and simvastatin reduced ASCVD events.

Figure 5.

Primary endpoint in the IMPROVE-IT trial in different age groups. Modified from (60).

EWTOPIA 75 TRIAL

EWTOPIA 75 was a multicenter, randomized trial in Japan that examined the preventive efficacy of ezetimibe for patients aged ≥75 years (mean age 80.6 years), with elevated LDL-C (≥140 mg/dL) without a history of coronary artery disease (primary prevention) who were not taking lipid lowering drugs (61). Patients were randomized to ezetimibe 10mg (n=1,716) or usual care (n=1,695) and followed for 4.1 years. The primary outcome was a composite of sudden cardiac death, myocardial infarction, coronary revascularization, or stroke. In the ezetimibe group LDL-C was decreased by 25.9% and non-HDL-C by 23.1% while in the usual care group LDL-C was decreased by 18.5% and non-HDL-C by 16.5% (p<0.001 for both lipid parameters). By the end of the trial 9.6% of the patients in the usual care group and 2.1% of the ezetimibe group were taking statins. Ezetimibe reduced the incidence of the primary outcome by 34% (HR 0.66; P=0.002). Additionally, composite cardiac events were reduced by 60% (HR 0.60; P=0.039) and coronary revascularization by 62% (HR 0.38; P=0.007) in the ezetimibe group vs. the control group. There was no difference in the incidence of stroke or all-cause mortality between the groups. It should be noted that the reduction in cardiovascular events was much greater than one would expect based on the absolute difference in LDL-C levels (121mg/dL in ezetimibe group vs. 132mg/dL in usual care group). As stated by the authors “Given the open-label nature of the trial, its premature termination, and issues with follow-up, the magnitude of benefit observed should be interpreted with caution.” Nevertheless, this study suggests that lowering LDL-C in elderly individuals without cardiovascular disease can reduce ASCVD events.

RACING TRIAL

The RACING trial was a randomized, open-label trial in patients with ASCVD carried out in South Korea (62). Patients were randomly assigned to either rosuvastatin 10 mg with ezetimibe 10 mg (n= 1894) or rosuvastatin 20 mg (n= 1886). The primary endpoint was cardiovascular death, major cardiovascular events, or non-fatal stroke. The median LDL-C level during the study was 58mg/dL in the combination therapy group and 66mg/dL in the statin monotherapy group (p<0.0001). The primary endpoint occurred in 9.1% of the patients in the combination therapy group and 9.9% of the patients in the high-intensity statin monotherapy group (non-inferior). Non-inferiority was observed in patients with baseline LDL-C levels < 100mg/dL and >100mg/dL (63).

In the RACING trial 574 participants (15.2%) were aged ≥75 years and there was no difference in the primary endpoint between the combination therapy group and the high-intensity statin monotherapy group in these elderly participants (64). However, in participants ≥75 years of age moderate-intensity statin with ezetimibe combination therapy was associated with lower rates of drug related intolerance with drug discontinuation or dose reduction (2.3% vs 7.2%; P = 0.010).

This study demonstrates that moderate intensity statin plus ezetimibe was non-inferior to high-intensity statin therapy with regards to cardiovascular death, major cardiovascular events, or non-fatal stroke. The lower prevalence of discontinuation or dose reduction caused by intolerance to the study drug was seen with combination therapy indicating that using a moderate intensity dose of a statin plus ezetimibe is a useful strategy in patients that do not tolerate high intensity statin therapy or where there are concerns about statin toxicity with high doses.

PCSK9 Inhibitors

FOURIER TRIAL

The FOURIER trial was a randomized, double-blind, placebo-controlled trial of evolocumab vs. placebo in 27,564 patients with ASCVD and an LDL-C level of 70 mg/dL or higher who were on statin therapy (65). The primary end point was cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization and the key secondary end point was cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years. Baseline LDL-C levels were 92mg/dL and evolocumab resulted in a 59% decrease in LDL levels (LDL-C level on treatment approximately 30mg/dL). In this trial 6233 of the participants were > 69 years of age and the decrease in LDL was similar in participants > 69 years of age and younger individuals (66). A 14% reduction in the primary endpoint (HR 0.86; 95% CI 0.74–0.99) and a 18% reduction in the secondary endpoint (HR 0.82; 95% CI 0.69–0.98) was observed in the participants > 69 years of age, which was similar to the decreases seen in younger individuals (66). The effect of treatment with evolocumab on the primary and secondary endpoint in specific age groups is shown in table 3 (66). These results demonstrate that lowering LDL-C with a PCSK9 inhibitor decreases ASCVD events in elderly patients.

Table 3.

Effect of Evolocumab Treatment on Cardiovascular Outcomes in Different Age Groups

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	< 65	65-75	>75
Primary Endpoint	HR 0.86; 95%CI 0.78–0.94	HR 0.86; 95%CI 0.76–0.97	HR 0.78; 95%CI 0.60–1.02
Secondary Endpoint	HR 0.79; 95%CI 0.69–0.90	HR 0.82; 95%CI 0.70–0.95	HR 0.78 95%CI 0.58–1.04

For the primary endpoint the P interaction for the three age groups = 0.84.

For the secondary endpoint the P interaction for the three age groups = 0.94.

ODYSSEY Trial

The ODYSSEY trial was a multicenter, randomized, double-blind, placebo-controlled trial involving 18,924 patients who had an acute coronary syndrome 1 to 12 months earlier, an LDL-C level of at least 70 mg/dL, a non-HDL-C level of at least 100 mg/dL, or an apolipoprotein B level of at least 80 mg/dL while on high intensity statin therapy or the maximum tolerated statin dose (67). Patients were randomly assigned to receive alirocumab 75 mg every 2 weeks or matching placebo. The dose of alirocumab was adjusted to target an LDL-C level of 25 to 50 mg/dL. The primary end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. In this trial 5084 (26.9%) individuals were ≥ 65 years of age, 1007 (5.3%) ≥ 75 years of age, and 42 (0.2%) ≥ 85 years of age (68). The baseline and decrease in LDL-C levels were similar in participants ≥65 years of age and those <65 years of age (LDL-C at baseline approximately 94mg/dL and after 4 months of treatment approximately 40mg/dL) (67,68). In the individuals ≥ 65 years of age there was a 22% decrease in the primary endpoint (HR 0.78; 95% CI 0.68–0.91) and in those < 65 years of age a 11% decrease (HR 0.89; 95% CI 0.80–1.00) (68). The secondary endpoint of all-cause death, myocardial infarction, or ischemic stroke was also reduced in the ≥ 65 participants (HR 0.78; 95% CI 0.68–0.90) and < 65 participants (HR 0.91; 0.82–1.02) (68). In participants ≥ 75 years of age the primary endpoint was reduced by 15% (HR 0.85; 95% CI 0.64–1.13) (68). When plotted as a continuous variable the relative benefit of alirocumab over placebo on the primary endpoint was consistent across the entire age range (figure 6).

Figure 6.

Relative benefit of alirocumab at various ages. Modified from reference (68).

These two studies demonstrate that lowering LDL-C with a PCSK9 inhibitor decreases ASCVD events in elderly patients with pre-existing cardiovascular disease.

SIDE EFFECTS OF LIPID LOWERING DRUGS

In this section we will describe the potential side effects of lipid lowering drugs with an emphasis on side effects likely to be seen in the elderly. Elderly patients may be more susceptible to side effects due to decreased renal function, decreased drug metabolism by the liver, polypharmacy leading to drug interactions, and co-morbidities. For a detailed discussion of the side effects of lipid lowering drugs see the Endotext chapters entitled “Cholesterol Lowering Drugs” and “Triglyceride Lowering Drugs” (49,50).

Statins

An umbrella review of meta-analyses of observational studies and randomized controlled trials examined 278 unique non-CVD outcomes from 112 meta-analyses of observational studies and 144 meta-analyses of RCTs and found that the only adverse effects associated with statin therapy were the development of diabetes and muscle disorders (84). For a detailed discussion of the side effects of statin therapy a scientific statement from the American Heart Association provides a comprehensive review (85).

DIABETES

After many years of statin use it was recognized that statins increase the risk of developing diabetes. In a meta-analysis of 13 trials with over 90,000 subjects, there was a 9% increase in the incidence of diabetes during follow-up among subjects receiving statin therapy (86). All statins appear to increase the risk of developing diabetes. In comparisons of intensive vs. moderate statin therapy, Preiss et al observed that patients treated with intensive statin therapy had a 12% greater risk of developing diabetes compared to subjects treated with moderate dose statin therapy (87). Older subjects, obese subjects, and subjects with high glucose levels were at a higher risk of developing diabetes while on statin therapy. In the Prosper trial in elderly subjects (70-82 years of age; average age 75), diabetes developed in 6.6% of patients treated with pravastatin vs. 5.1% of patients in the placebo group (51). Thus, statins may be unmasking and accelerating the development of diabetes that would have occurred naturally in these subjects at some point in time. In patients without risk factors for developing diabetes, treatment with statins does not appear to greatly increase the risk of developing diabetes.

In balancing the benefits and risks of statin therapy it is important to recognize that an increase in plasma glucose levels is a surrogate marker for an increased risk of developing micro and macrovascular disease (i.e., an increase in plasma glucose per se is not an event but rather increases the risk of future events). In contrast, statin therapy is preventing actual clinical events that cause morbidity and mortality. Furthermore, it may take many years for an elevated blood glucose to induce diabetic complications while the reduction in cardiovascular events with statin therapy occurs relatively quickly (after one-year benefits are seen). Finally, the number of patients needed to treat with statins to avoid one cardiovascular event is much lower (10-20 depending on the type of patient) than the number of patients needed to treat to cause one patient to develop diabetes (100–200 for one extra case of diabetes) (88). Patients on statin therapy, particularly those with risk factors for the development of diabetes, should be periodically screened for the development of diabetes with measurement of fasting glucose and/or HbA1c levels.

COGNITIVE DYSFUNCTION

Several randomized clinical trials have examined the effect of statin therapy on cognitive function and have not indicated any increased risk (for review see (89-92)). The Prosper Trial was designed to determine whether statin therapy will reduce cardiovascular disease in older subjects (age 70-82) (51). In this trial cognitive function was assessed repeatedly and no difference in cognitive decline was found in subjects treated with pravastatin compared to placebo (51,93). In the Heart Protection Study over 20,000 patients were randomized to simvastatin 40mg or placebo and again no significant differences in cognitive function was observed between the statin vs. placebo group (94). Additionally, a Cochrane review examined the effect of statin therapy in patients with established dementia and identified 4 studies with 1154 participants (95). In this analysis no benefit or harm of statin therapy on cognitive function could be demonstrated in this high-risk group of patients. Thus, randomized clinical trials do not indicate a significant association between statins and cognitive function.

MUSCLE

The most common side effect of statin therapy is muscle symptoms and many patients will discontinue the use of statins due to muscle symptoms. These can range from life threatening rhabdomyolysis, which is very rare, to myalgias, which are a common complaint (96). The risk of serious muscle disorders due to statin therapy is very small, particularly if one is aware of the potential drug interactions that increase the risk. In a case-control study with a cohort of 252,460 new users of lipid-lowering medications in U.S. health plans 21 cases of rhabdomyolysis were compared to 200 controls without rhabdomyolysis (97). Statin users >65 years of age had four times the risk of hospitalization for rhabdomyolysis than those under age 65.

The Cholesterol Treatment Trialists analyzed individual participant data on the development of muscle symptoms from 19 double-blind trials of statin versus placebo with 123,940 participants and four double-blind trials of a more intensive vs. a less intensive statin regimen with 30,724 participants (98). After a median follow-up of 4.3 years 27.1% of the individuals taking a statin vs. 26.6% on placebo reported muscle pain or weakness representing a 3% increase greater than placebo (risk ratio- 1.03; 95% CI 1.01-1.06) (Table 5). The specific muscle symptoms caused by statin therapy, myalgia, muscle cramps or spasm, limb pain, other musculoskeletal pain, or muscle fatigue or weakness were similar to those caused by placebo. The slight increase in muscle symptoms in the statin treated individuals was manifest in the first year of therapy but in the later years muscle symptoms were similar in the statin treated and placebo groups. The relative risk of statin induced muscle symptoms was greater in women than men. Intensive statin treatment with 40-80 mg atorvastatin or 20-40 mg rosuvastatin resulted in a higher risk of muscle symptoms than less intensive or moderate-intensity regimens but different statins at equivalent LDL-C lowering doses had similar effects on muscle symptoms. As shown in figure 7 muscle pain or weakness was slightly increased in patients > 65 years of age and similar in patients > 65 and ≤ 75 and those > 75 years of age. It should be noted that in individuals > 75 years of age the occurrence of muscle pain or weakness occurred in 39.6% of the individuals on the placebo, demonstrating the very high occurrence of muscle symptoms in this age group.

This study demonstrates that there is a small increase in muscle symptoms that primarily manifests in the first year of therapy. Statin therapy caused approximately 11 additional complaints of muscle pain or weakness per 1000 patients during the first year, but little excess in later years. Of particularly note is that 26.6% of patients taking a placebo had muscle symptoms demonstrating a very high frequency of this clinical complaint (even higher in patients > 75). Given the high prevalence of muscle complaints and the small increase attributed to statins it is very difficult to determine if a muscle complaint is actually due to the statin, which presents great clinical difficulties in patient management.

Table 5.

Effect of Statin vs. Placebo on Muscle Symptoms

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Symptom	Statin Events	Placebo Events	RR (95% CI)
Myalgia	12.0%	11.7%	1·03 (0·99–1·08)
Other musculoskeletal pain	13.3	13.0	1·03 (0·99–1·08)
Any muscle pain	26.9%	26.3%	1·03 (1·01–1·06)
Any muscle pain or weakness	27.1%	26.6%	1·03 (1·01–1·06)

Figure 7.

Occurrence of muscle pain or weakness in different age groups in the Cholesterol Treatment Trialists meta-analysis.

While the results of the randomized trials suggest that muscle symptoms are not frequently induced by statin therapy, in typical clinical settings a significant percentage of patients are unable to tolerate statins due to muscle symptoms (in many studies as high as 5-25% of patients) (99-101). Additionally, when patients know that they are taking a statin they are more likely to have muscle symptoms (i.e. the nocebo effect) (102). Clinically differentiating statin induced myalgias from placebo induced myalgias is difficult, as there are no specific symptoms, signs, or biomarkers that clearly distinguish between the two. Thus, while statin induced myalgias are a real entity careful studies have shown that in the majority of patients with “statin induced muscle symptoms” the symptoms are not actually due to statin therapy. In the clinic it is difficult to be certain whether the muscle symptoms are actually due to true statin intolerance or to other factors.

A detailed discussion of statin induced muscle symptoms and a clinical approach to this problem is presented in the Endotext chapter entitled “Cholesterol Lowering Drugs” (50). In the section “Patients with Statin Intolerance” in this chapter we discuss the clinical approach to treating these patients.

CURRENT GUIDELINES AND LDL-C GOALS

This section discusses guidelines as they pertain to elderly patients.

TREATMENT

LIPID LOWERING DRUGS

Current guidelines and lipid lowering goals are discussed in the guidelines section above. In this section we will focus on clinical decisions regarding the use of lipid lowering drugs. To maximize benefits of lipid lowering therapy we think it is important to achieve LDL-C goals.

CONCLUSION

ASCVD is a major cause of morbidity and mortality in elderly patients. In elderly patients with pre-existing ASCVD randomized clinical trials have shown that lipid lowering drug therapy with statins, ezetimibe, and PCSK9 inhibitors reduce ASCVD events. Thus, most elderly patients with ASCVD should be treated with lipid lowering drugs unless there are contraindications such as limited life expectancy, competing non-cardiovascular disorders, high risk of drug interactions or drug side effects. In elderly patients without ASCVD if they are already taking lipid lowering drugs and if they are tolerating the medications without side effects continuing therapy is usually reasonable as long as the clinical circumstances have not changed. In elderly patients not on lipid lowering therapy and without cardiovascular disease studies have suggested that lipid lowering therapy is beneficial but further studies are required to definitively demonstrate benefit. In these patients one needs to determine the patient’s risk for ASCVD events and then discuss the potential benefits and side effects with the patient to make a shared decision on whether to initiate therapy. Age per se should not be used to withhold therapy with lipid lowering drugs that can reduce the risk of ASCVD events.

ACKNOWLEDGEMENTS

This work was supported by grants from the Northern California Institute for Research and Education. The authors would like to thank Dan Streja, the original author of this chapter, who provided the framework for this updated chapter.

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