Statins are primarily used to lower blood cholesterol levels, specifically low-density lipoprotein cholesterol (LDL-C). They can potentially lower LDL-C levels by 20% to 55%, depending largely on their potency.¹ Statins are classified as high, moderate, or low intensity, according to their expected ability to lower LDL-C (Table 1).¹

As a result, statins are recommended as first-line therapy for nearly all persons with—or at risk of developing—atherosclerotic cardiovascular disease (ASCVD). Their ability to lower LDL-C translates to significant reductions in cardiovascular events, including heart attacks and strokes.¹

Table 1. Classification of Statins Based on Potency^*

Abbreviations: ACC = American College of Cardiology; AHA = American Heart Association; BID = twice daily; FDA = US Food and Drug Administration; LDL-C = low-density lipoprotein cholesterol; QD = once daily; RCTs = randomized controlled trials; XL = extended release.
*Adopted from the ACC/AHA clinical practice guideline on the management of blood cholesterol.¹
†LDL-C lowering that should occur with the dosage listed below each intensity, based on estimates of percent reductions from data across large populations. However, individual responses to statin therapy are expected to vary in clinical practice.¹
‡Although simvastatin 80 mg was evaluated in RCTs and is technically capable of greater LDL-C lowering, initiation of simvastatin 80 mg/day or titration to 80 mg/day is not recommended by the FDA because of the increased risk of myopathy, including rhabdomyolysis.¹

In general, the more LDL-C levels are lowered by statin therapy, the greater the subsequent risk reduction.¹ However, the magnitude of LDL-C lowering varies in clinical practice^1,2 based on numerous factors including age-related changes in physiologic processes, racial/ethnic differences in responses, tolerability of statin-associated adverse effects, and concomitant drugs involved in interactions.¹

For example, patients who identify as South Asian are at heightened risk of ASCVD and may have a greater (or lesser) response to certain statins. Those who identify as East Asian may have increased sensitivity to certain statins, which may confer greater risk for adverse effects.^1,3,4

Decisions to initiate or continue statin therapy in older adults should be made in the context of clinician-participant shared decision-making. This includes a risk discussion of the potential for statin-associated adverse effects and drug interactions, as well as participant preferences and values.¹

For instance, it is reasonable for clinicians to review participants' racial/ethnic features that can influence ASCVD risk and statin response to adjust the choice of statin or intensity of therapy.¹ A discussion of racial/ethnic differences, including genetically based differences such as polymorphisms in the SLCO1B1 and ABCG2 genes, is beyond the scope of this article but has been reviewed in the ACC/AHA clinical guideline on the management of blood cholesterol¹ and elsewhere.⁵ To aid in shared decision-making, the ACC/AHA guideline provides recommendations for statin therapy in older adults, several of which are outlined below.

Selected Recommendations for Statin Therapy in Older Adults

Adults 40-75 Years Old

For primary prevention in adults 40-75 years of age without severe hypercholesterolemia (LDL-C levels ≥190 mg/dL) or diabetes mellitus, clinicians and participants should engage in shared decision-making before initiating statin therapy.¹

Adults >75 Years Old

Primary Prevention

For adults older than 75 years of age, the evidence for statin therapy in primary prevention is not strong, so clinical assessment of risk status in the context of clinician-participant shared decision-making is needed to decide whether to initiate or continue statin therapy.¹

• Nonetheless, it may be reasonable to initiate a moderate-intensity statin in adults >75 years of age with an LDL-C level of 70 to 189 mg/dL.¹

• On the other hand, in adults >75 years of age, it may be reasonable to stop statin therapy for primary prevention when functional decline (physical or cognitive), multimorbidity, frailty, or reduced life expectancy limits the potential benefits of statins.^1,6

• In the palliative care setting of advanced, life-limiting illness (i.e., participants with life expectancy <1 year), at least one clinical trial demonstrated that stopping statin therapy is safe and may be associated with benefits, including improved quality of life and reduced medication costs.⁶

• Another ongoing trial (NCT05178420) aims to assess the safety and potential benefits of statin discontinuation in primary prevention for the ever-growing population of older adults (aged ≥70 years) with multimorbidity.⁷

In adults 76 to 80 years of age with an LDL-C level of 70 to 189 mg/dL, it may be reasonable to measure coronary artery calcium (CAC) to reclassify those with a CAC score of zero to avoid statin therapy for primary prevention.¹

• This individualized disease-guided approach is simple and easy to implement in routine clinical practice.⁸
  
  
• Moreover, withholding statin therapy in patients without CAC could spare a significant proportion of older adults from taking a medication that would benefit only a few.⁸

Secondary Prevention

For secondary prevention in adults older than 75 years of age with clinical ASCVD, it is reasonable to initiate or continue moderate- or high-intensity statin therapy, after a clinician-participant discussion of potential benefits and risks.¹

• Similarly, it may be reasonable to initiate or continue statin therapy in adults >75 years of age with diabetes mellitus.¹

Safety Concerns associated with Statin Therapy in Older Adults

Statin therapy is usually well-tolerated and safe.¹ On the other hand, statin-associated adverse effects and drug interactions are more likely to occur in older adults, compared with their younger counterparts, and might negatively impact quality of life.⁷ Older age, multimorbidity, and polypharmacy are well-established risk factors for developing adverse effects and experiencing drug interactions during statin therapy.

Adverse Effects

Table 2 summarizes the most concerning statin-associated adverse effects, noting their relative frequency as reported by a comprehensive review of the evidence base.¹ While infrequent or rare in clinical trials, the most frequently observed adverse effects in clinical practice are statin-associated muscle symptoms (SAMS), reportedly occurring in 5% to 20% of patients.¹ During real-life use (i.e., outside of clinical trials), SAMS are usually reported by patients as subjective myalgias and often result in statin nonadherence, which can adversely impact ASCVD outcomes.¹ Therefore, clinicians should engage older adults in a dialogue about potential benefits and risks before initiating statin therapy to promote shared decision-making, while emphasizing that statin-associated adverse effects often can be prevented and addressed successfully.¹

As an example, in participants with statin-associated adverse effects that are not severe, it is recommended to reassess for predisposing factors and to rechallenge with an alternative statin or an alternative regimen, such as reduced statin dosage with or without concomitant non-statin therapy (e.g., ezetimibe), to achieve maximal LDL-C lowering.¹ In patients at increased ASCVD risk with severe SAMS or recurrent SAMS despite appropriate statin rechallenge, it is recommended to measure creatine kinase levels and to use evidence-based, non-statin therapy that is likely to provide net clinical benefit.¹

Table 2. Statin-Associated Adverse Effects¹

Abbreviations: BMI = body mass index; CK = creatine kinase; DM = diabetes mellitus; FBG = fasting blood glucose; HMGCR = 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase; SAAM, statin-associated autoimmune myopathy; SAMS = statin-associated muscle symptoms; ULN = upper limit of normal.

Drug Interactions

Pharmacokinetic profiles among statins are heterogeneous, as evidenced by differences between agents in their cytochrome P450-mediated metabolism.¹ This heterogeneity can affect the possibility and magnitude of drug-drug interactions (DDIs) involving statins.⁹ Additionally, pharmacogenomic variability and polypharmacy are potential causes of or contributors to statin-involved DDIs.⁹

Selected medications that may potentially interact with statins are listed in the Box. While such lists are useful for screening for potential DDIs, they do not provide insights into the underlying mechanism(s) or clinical significance(s) of drug interactions, nor do they account for pharmacogenomic variability at the individual level. This requires expertise in applying the principles of pharmacodynamics, pharmacokinetics, pharmacogenomics, and chronopharmacology.

In older adults, medication changes occur regularly, whether out of necessity (e.g., initiation for new or worsening conditions, discontinuation due to intolerances) or inadvertently (e.g., unintended stoppage during care transitions, nonadherence). This is important because statin therapy is meant to be a lifetime therapy, whereby medication initiations and/or discontinuations could potentially result in clinically meaningful DDIs involving statins that may change over time.

Potential consequences of statin-involved DDIs include reduced effectiveness, which increases the risk of negative ASCVD outcomes, and higher statin exposures, which predispose patients to statin-associated adverse effects like SAMS and other deleterious sequelae, such as falls attributed to reduced physical activity and possibly sarcopenia.

Risk-mitigation strategies to prevent or abate these consequences include¹:

Conclusion

The clinician-participant risk discussion is an integral part of the shared-decision making process for managing blood cholesterol in older adults. However, this discussion will likely prove inadequate unless an ongoing interaction between the patient and clinician occurs. This involves monitoring the safety and effectiveness of therapy and adherence to therapy, among other facets. Part of deciding whether to initiate or continue statin therapy for an older adult should involve a risk assessment, including a comprehensive review of the entire medication regimen to assess risk of adverse effects and drug interactions.

Pharmacists are experts in medication adherence and uniquely trained in the sciences that govern how medications interact within complex regimens. This expertise enables optimal adherence and proactive identification of risk before harm occurs.

Empowered with technology-driven innovations, such as medication safety analytics and clinical decision support systems, GalenusCare Precision Pharmacists collaborate with clinicians and patients throughout the continuum of care to ensure that medication regimens, including statin therapy, are optimized for older adults.