INTRODUCTION

For decades, lipid management focused on treating lipoprotein numbers. The 2026 guidelines instead emphasize individualized cardiovascular risk, earlier intervention, and lower low-density lipoprotein (LDL) targets for patients at highest risk. Patient Nick Smith is a 68-year-old male recently seen by the cardiologist. He currently takes several medications: metformin, empagliflozin, metoprolol succinate, sacubitril/valsartan, rosuvastatin, and loratadine. He has a past medical history of type 2 diabetes mellitus, hyperlipidemia, hypertension, heart failure with reduced ejection fraction (38%), and seasonal allergies. He is also a current smoker with a 15-pack-year smoking history. He has no history of myocardial infarction, ischemic stroke, peripheral artery disease, or coronary revascularization. Reviewing the cardiologist’s notes, his LDL-C is 91 mg/dL and his PREVENT Score is 10.2%.

Nick’s prescriber reviews the new guideline and pauses. Nick has several cardiovascular risk factors, but has never had an ASCVD event. Is this primary or secondary prevention? Does he need a coronary artery calcium (CAC) scan? Does his heart failure change the classification?  And is the statin dose sufficient? Rather than guess, the prescriber calls clinical pharmacist George Johnson and requests a complete lipid-management assessment.

Atherosclerotic Cardiovascular Disease  

Atherosclerosis, or the buildup of plaque within an artery, is a leading cause of death in the United States.¹ In 2023, cardiovascular disease caused 1 in 3 deaths nationwide.² As plaques grow, they progressively occlude arteries and can eventually rupture. Plaque rupture triggers local platelet-rich thrombus (clot) formation, leading to acute coronary syndromes (unstable angina or myocardial infarction [heart attack]), and sudden cardiac death. In cerebral circulation, atherosclerosis can reduce blood flow or promote thrombus formation, leading to ischemic stroke.³Two considerations guide lipoprotein management.³ The first consideration is determining if patients have established atherosclerotic cardiovascular disease (ASCVD), and the second is establishing individualized lipid goals based on the patient’s cardiovascular risk. This risk-based approach allows clinicians to tailor lifestyle interventions and initiate lipid-lowering therapy (LLT) to reduce the likelihood of future cardiovascular events. Strong evidence supports cholesterol management as the preferred method to reduce mortality and preventable cardiac deaths and improve quality of life.³

High LDL can cause catastrophic cardiovascular events and stroke later in life. Unfortunately, patients do not experience bothersome symptoms until the damage is done. New evidence suggests that higher LDL-C values starting earlier in life are strong predictors of ASCVD events in adulthood.⁴ So, screening patients early and periodically, minimizing modifiable risk factors, and initiating aggressive early lipid-lowering interventions are important.⁵ After an ASCVD event, secondary prevention is imperative to reduce the risk of another event.

Cholesterol Screening Blueprint

When clinicians examine lipid panels for patients, they need to use standardized methods for measuring lipoprotein levels.³ Total cholesterol is the sum of high-density lipoprotein (HDL, also called the good cholesterol), LDL, and the very-low-density lipoprotein (VLDL) component of triglyceride (TG) levels.⁶ The 2026 American College of Cardiology/American Heart Association (ACC/AHA) guidelines define high total cholesterol as levels greater than 200 mg/dL. LDL is considered high above 100 mg/dL. HDL should remain above 40 mg/dL in men and 50 mg/dL in women. Non–HDL is calculated by subtracting HDL from total cholesterol or adding together the LDL and VLDL, with values above 130 mg/dL considered high. Non-HDL is important in determining other lipoproteins besides LDL that can contribute to atherosclerosis.

The guidelines also recommend measuring lipoprotein(a), a cholesterol-carrying lipoprotein, at least once. Its normal levels are less than 75 nmol/L with intermediate levels between 75 and 125 nmol/L. Levels above 125 nmol/L independently increase the risk for ASCVD.⁷ Genetics heavily influences lipoprotein(a) levels, and levels remain relatively unchanged after age 5, meaning testing once is often sufficient.⁸

LDL-C measurements may underestimate the number of circulating atherogenic particles. In patients who are taking lipid-lowering therapy (LLT) and have high TG levels, cardiometabolic disease, or diabetes despite LDL-C at goal, apolipoprotein B (ApoB) is useful to determine if therapeutic intensification is warranted.³,⁹,¹⁰ ApoB is the main structural protein found in LDL, VLDL, intermediate-density lipoprotein (IDL), and lipoprotein(a) particles. Elevated ApoB at therapeutic LDL levels suggests persistent atherogenic particle burden that may increase residual ASCVD risk. Many patients with diabetes who have normal cholesterol levels also have elevated ApoB concentrations.¹¹ ApoB is a useful adjunct to traditional lipid measurements to determine if clinicians should intensify LLT.³

TGs should be below 150 mg/dL.³ While high TG levels contribute to ASCVD risk, LDL is the primary lipid target for risk reduction. However, TG levels above 500 mg/dL increase the risk of pancreatitis. Lipoprotein and TG thresholds may change based on a patient’s cardiovascular risk factors and history, meaning interventions may be appropriate even when lipid values fall below these cutoffs.³

Between 2017 and 2020, nearly 90 million adults aged 20 or older had elevated total cholesterol (200 mg/dL or greater).¹² Increasing age, comorbidities, and established ASCVD are factors that call for increased screening frequency. Additionally, one in five adolescents had an LDL above 130 mg/dL.¹³ Pediatricians should screen children between the ages of 9 and 11 at least once, and again between the ages of 17 and 21.¹² Children with obesity or diabetes may need more frequent screening. Diabetes, heart failure, hypertension, current or former smoking history, or consistently high LDL levels warrant more frequent testing. Clinicians should order lipid panels for patients with established ASCVD every 4 to 12 weeks after initiating or titrating LLT, and then every 6 to 12 months thereafter. ³

PAUSE AND PONDER: Can LDL values be too low?

Defining ASCVD, Calculating PREVENT Scoring, and Personalizing Primary Prevention Goals

Determining if patients are at risk for ASCVD (and the level of risk) or have experienced an ASCVD event is critical. Whether or not a patient has established ASCVD greatly impacts their risk for future cardiovascular events, and their treatment goals. In short, the best predictor of a future event is a past event in this case.

Because atherosclerosis affects the body systemically, clinical ASCVD can manifest in the heart and in other vascular areas.³ Locally, ASCVD can result in myocardial infarction (ST-segment elevation [STEMI] and non-ST-segment elevation [NSTEMI]), unstable angina, or the need for arterial revascularization, such as bypass or stents. Ischemic stroke or a transient ischemic attack (TIA) can result if clots embolize and travel to the brain. Finally, plaque buildup in lower extremity arteries leads to peripheral artery disease (PAD). Heart failure, hypertension, and atrial fibrillation do not, by themselves, constitute clinical ASCVD. Patients with these conditions who have no established ASCVD and should not receive lipid-lowering therapy for secondary prevention.

Before clinicians can establish an individualized LDL-C target, they must first calculate the patient’s Predicting Risk of Cardiovascular Disease EVENTs (PREVENT) score.¹⁴ For patients aged 30 to 79 with an LDL-C of 70 to 189 mg/dL, the PREVENT score gauges patients’ 10- and 30-year ASCVD risk to determine optimal LDL-C targets and whether LLT is warranted. (The AHA provides an online calculator here: https://professional.heart.org/en/guidelines-and-statements/prevent-calculator.) The scoring system estimates an individual’s percentage risk of cardiovascular disease using age, systolic blood pressure, total cholesterol, HDL, estimated glomerular filtration rate, and body mass index (BMI).¹⁴ These factors guide LLT initiation. Clinicians can also input comorbidities such as diabetes, current smoking, or patients’ current use of lipid-lowering or antihypertensive medications. The scoring system breaks patients into four categories.³

• Low-risk patients have a 10-year risk of less than 3%.
• In borderline-risk patients who have a 3% to less than 5% risk, clinicians should discuss the risks versus benefits of initiating LLT with the patient.
• For intermediate-risk patients (5% to less than 10%), LLT is indicated, with moderate-high intensity statins preferred.
• High-risk patients with a 10% or greater PREVENT score should start a high-intensity statin or optimize LLT with other medications.

In patients who have not experienced an ASCVD event, primary prevention strategies focus on reducing cardiovascular risk using less intensive interventions with higher LDL treatment thresholds. Primary prevention targets also depend on patient-specific risk factors. Risk factors include

• Age 65 years or older
• Chronic kidney disease
• Current smoker
• Diabetes
• Heart failure
• Heterozygous familial hypercholesterolemia
• Hypertension
• LDL value above 100 mg/dL despite optimized LLT

For patients who do not have these risk factors, an LDL goal of below 100 mg/dL is adequate to reduce their risk of ASCVD. For patients at high risk for ASCVD (PREVENT score 10% or higher), clinicians should target an LDL goal of below 70 mg/dL.³ Prior guidelines favored less stringent goals for primary prevention, but lower LDL levels have been consistently linked to decreased ASCVD risk.

Personalizing Secondary Prevention of ASCVD

In patients with established ASCVD, the new ACC/AHA guidelines recommend aggressive lipid management—these patients are at the highest risk of additional ASCVD events. Secondary prevention targets also depend on defining patients as very high risk for another ASCVD event or not. Very high risk is defined as

• 2 or more previous major ASCVD events, or
• 1 major ASCVD event and 2 or more high-risk conditions (defined in primary prevention)

The target for those at very high risk is an LDL of less than 55 mg/dL.³ The guidelines also indicate that an LDL goal of less than 70 mg/dL is acceptable for patients without high-risk factors for another ASCVD event. However, most patients require lower LDL targets. Evidence suggests that there is no clear lower LDL threshold at which LDL reduction harms patients. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) and Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trials demonstrated that patients with LDL-C values below 30 mg/dL experienced the lowest rates of cardiovascular events without an increase in adverse safety outcomes.¹⁵,¹⁶ So, clinicians can intensify LLT to achieve very low LDL levels without increasing safety concerns.

For all patients, a TG level of below 150 mg/dL is optimal, but slight elevations contribute less to ASCVD risk than LDL-C elevations do. Figure 1 depicts primary and secondary prevention cholesterol goals.

Figure 1. Cholesterol Targets for Primary and Secondary Prevention of ASCVD

George begins by confirming that Nick has no established ASCVD. Although diabetes, hypertension, HFrEF, and smoking increase his cardiovascular risk, none converts his treatment to secondary prevention. So, Nick is receiving LLT for primary prevention. A PREVENT score of 10.2% puts him in the high-risk category, for which the LDL goal is below 70 mg/dL.

SIDEBAR: When to Reclassify with Coronary Artery Calcium (CAC) Scoring?¹⁷,¹⁸

Coronary Artery Calcium (CAC) refers to calcium deposits within the heart’s arterial walls. This noninvasive imaging test performed with a noncontrast cardiac scan is specific to atherosclerotic plaques, meaning it is a precise way to detect early cardiovascular disease. CAC at any level indicates subclinical coronary atherosclerosis, but it does not transform the patient into someone with clinical ASCVD or automatically place everyone into the same treatment category. CAC is principally a selective risk-reclassification tool when the treatment decision remains uncertain.

Coronary artery calcium (CAC) is specific to atherosclerotic plaques and strongly predicts ASCVD risk. It can help refine risk estimates. In adults without established ASCVD who have a borderline or intermediate 10-year PREVENT-ASCVD risk (3% to less than 10%), CAC measurement may be considered when uncertainty remains about whether to initiate lipid-lowering therapy. CAC also guides treatment in asymptomatic men aged 40 years and older and women aged 45 years and older previously not receiving LLT. In patients with CAC scores greater than 0 Agatston Units (AU; a score that reflects both the area and density of calcified plaque in the coronary arteries) who are at borderline risk, clinicians should initiate LLT.

Interestingly, elite endurance athletes can have increased CAC scores without significant risk for atherosclerosis.¹⁹,²⁰ However, increased plaque calcification may serve a cardioprotective role, as calcified plaques are more stable and less likely to rupture and cause thrombosis than lipid-rich, vulnerable plaques. Further research is needed to clarify this association. Athletes with elevated CAC scores should not stop exercising, as exercise is cardioprotective.²⁰

The prescriber asks if a CAC scan would reclassify Nick’s ASCVD risk. George explains that a scan is unlikely to change how Nick is treated. Nick’s PREVENT score, age, and concurrent conditions are clear indications for LLT. A CAC scan is useful if providers are uncertain about initiating LLT, not if patients are already indicated.

Special Population Lipid Targets

Many patients’ concurrent conditions influence recommended lipid goals. For example, primary ASCVD prevention for adults with diabetes has an LDL goal of below 100, or below 70 in the presence of high-risk factors or a PREVENT score of 5% or higher.²¹ Diabetes significantly increases the risk of ASCVD, warranting early guideline-directed risk assessment and lipid-lowering interventions by clinicians.²² Chronic kidney disease, heart failure, and HIV also warrant early LDL lowering, targeting levels under 100 mg/dL if patients have no additional risk factors and under 70 mg/dL in higher-risk patients.³

Patients older than 75 may require individualized lipid management rather than strict adherence to LDL targets. LLT still reduces the risk of major cardiovascular events, but data are limited on lower lipid levels for patients in this age group.²³ While LLT is safe and effective in this population, evidence supporting very low LDL targets is more limited. Poor functional status, frailty, and polypharmacy put these patients at an increased risk for adverse effects and potential injury. Clinician-based decision-making is essential to weigh the cardiovascular benefits of stringent lipid targets against the potential negative impact on patients’ quality of life.²⁴ In patients with limited life expectancy, the risk of a major cardiovascular event is low. So, if patients experience negative effects from aggressive lipid management, clinicians should consider less intensive management.

In pregnant patients, cholesterol targets increase with each trimester of gestation. Maternal lipid levels progressively increase as the fetus grows, with triglycerides demonstrating the largest increase. Consequently, standard lipid goals are not applicable to this population, so the need for LLT is clinician-guided and only warranted in very high-risk individuals.²⁵

Current evidence has not established a lower LDL threshold at which treatment becomes harmful. Patients at very high ASCVD risk may benefit from LDL levels below 30 mg/dL, provided therapy is clinically indicated, tolerated, and monitored. All clinicians need to remember that “lower is better” does not mean “lower everyone’s cholesterol levels indiscriminately.”

PAUSE AND PONDER: Which lipid-lowering medications bypass hepatic metabolism and may offer advantages in select patients with hepatic or renal dysfunction?

Lifestyle Interventions

Multimodal lifestyle modifications are the backbone of any lipid-lowering regimen, and prescribers should initiate them in all patients who meet the criteria for intervention.³ Dietary modifications emphasize consumption of fruits, vegetables, legumes, whole grains, fiber, and foods with low saturated fats and high mono- and poly-unsaturated fats. To examine the optimal diet to lower LDL, researchers compared the Mediterranean diet to a vegan diet.²⁶ At 16 weeks, patients on a vegan diet decreased their LDL by an average of 15 mg/dL, while the Mediterranean diet failed to show a statistically significant decrease. These data are limited by small sample size—only 62 participants—so more data is needed.²⁶ However, many patients prefer diets that include meat and meat products, rendering vegan diets unsustainable. Any nutritional intervention that lowers LDL and weight is beneficial, provided patients adhere to the diet indefinitely. When coupled with other lifestyle modifications, dietary modifications can lower LDL and reduce the risk of developing ASCVD. Triglyceride-lowering diets decrease added sugars, refined carbohydrates, saturated fats, and alcohol—these modifications can lower TG levels by over 70%.²⁷

Weight loss significantly decreases LDL and TG levels as well. A meta-analysis of 73 randomized controlled trials with more than 32,000 participants discovered that for every kilogram (2.2 pounds) of weight lost, LDL decreases by up to 1.3 mg/dL and TG levels decrease by 4 mg/dL.²⁸ The AHA recommends 150 minutes or more of moderate- to high-intensity aerobic exercise with resistance training to reduce the likelihood of cardiovascular events.³ A meta-analysis conducted by the AHA demonstrated that weekly moderate-intensity exercise decreased the risk of cardiovascular mortality by 23%.²⁹ The analysis followed 3.4 million patients over 12 years, and found that 150 minutes of moderate-intensity aerobic exercise per week yielded a mortality benefit and a 17% decrease in new cardiovascular disease. Combining interventions can drastically lower LDL levels and, rarely, eliminate the need to initiate LLT altogether.²⁹

Lipid-Lowering Medications—Statins

Medications augment lifestyle modifications when lifestyle modifications fail to decrease cholesterol below accepted thresholds. Statins are the backbone of LLT due to their robust ability to decrease LDL.⁶ Low-, moderate-, and high-intensity statins decrease patients’ LDL values by 30%, 30-49%, and 50% or more, respectively. Figure 2 depicts statin intensity categories, available drugs, and equipotent statin doses.³⁰

Figure 2. Statin Intensity Classifications and Equipotent Daily Doses

Statins reduce LDL by competitively inhibiting the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase enzyme, the rate-limiting enzyme in hepatic cholesterol synthesis.³¹ Statin-induced enzyme inhibition decreases hepatic cholesterol synthesis, meaning less LDL circulates throughout the body. After the initial LDL reduction achieved with the starting dose, each subsequent statin dose doubling lowers LDL by an additional 6% to 8%.³² Statins also decrease inflammation through antioxidant properties and stimulate the immune system. The liver primarily metabolizes statins. The liver cytochrome P450 (CYP) 3A4 enzyme metabolizes atorvastatin, simvastatin, and lovastatin, whereas CYP2C9 metabolizes fluvastatin and rosuvastatin to a lesser extent. Statins are eliminated through both hepatic and renal pathways, although the extent of renal excretion varies by agent. Therefore, statin dose adjustments may be necessary in patients with liver or kidney impairment. Statins are contraindicated in patients with active liver disease. Simvastatin is strictly contraindicated with CYP3A4 strong inhibitors, and has a maximum daily dose of 10 mg with diltiazem, verapamil, and dronedarone.³³ The maximum simvastatin daily dose for patients taking amiodarone, amlodipine, and ranolazine is 20 mg. Technician recognition of new drug interactions is crucial to prevent adverse effects and decreased efficacy. Pharmacy technicians can identify new statin drug interactions by reviewing medication profiles, recognizing interaction alerts, and promptly notifying pharmacists of suspected interactions to prevent adverse effects. Clinicians should dose adjust statins in patients taking CYP enzyme inducers or inhibitors.

Common Strong CYP3A4 inhibitors include:

• Ritonavir
• Itraconazole
• Ketoconazole
• Cobicistat
• Grapefruit Juice

Common Strong CYP3A4 and CYP2C9 inducers include:

• Rifampin
• Carbamazepine
• Phenytoin
• Phenobarbital

Common Strong CYP2C9 inhibitors include:

• Sulfamethoxazole/Trimethoprim
• Amiodarone
• Fluconazole

Statin-associated muscle symptoms (SAMS) are the most commonly reported adverse effects associated with statin therapy.³¹ SAMS manifests as muscle aches, pain, and soreness primarily in the larger muscle groups of the body—the thighs, hips, and shoulders. High statin doses, advanced age, decreased thyroid function, diabetes, fibromyalgia, and CKD contribute to a patient’s risk of developing SAMS. The incidence of SAMS increases greatly with concurrent fibrates, which are medications that reduce high TGs. Gemfibrozil is contraindicated with some statins (e.g., simvastatin) and should generally be avoided because it increases the risk of SAMS. ³⁴

As noted above, strong evidence suggests that most muscle symptoms are not attributable to statins.³⁵ Authors of a meta-analysis of 19 trials and 35,000 patients concluded that up to 90% of muscle symptoms attributed to statin therapy were not due to the medication.³¹ Instead, underlying conditions and advanced age played a large role in the misinterpretation. To classify a patient as statin intolerant, clinicians should rechallenge with at least two statins at the lowest approved dose.³⁵ Additionally, switching from statins that are highly lipid-soluble like atorvastatin and simvastatin to a highly water-soluble statin like rosuvastatin could decrease muscle symptoms, but data are inconsistent.³⁶ When initiating statins, clinicians should inform patients that the risk of statin-associated adverse effects is small and the cardiovascular benefits far outweigh the negative aspects of the medication. If patients experience severe muscle symptoms, creatine kinase measurements should be taken to rule out rare, life-threatening muscle breakdown like rhabdomyolysis.³¹

Other rare adverse effects include mild nausea, diarrhea, or constipation, and small increases in blood sugar.³¹ Advising patients to take the medication with food and in the evening alleviates stomach discomfort. For statins with shorter half-lives (simvastatin and lovastatin), evening administration is traditionally recommended because hepatic cholesterol synthesis is greatest overnight. However, statins with longer half-lives, such as atorvastatin, and rosuvastatin maintain therapeutic activity throughout the day and may be taken at any time. Figure 3 summarizes statin administration instructions and counseling.

The prescriber discusses doubling Nick’s rosuvastatin dose to 10 mg. George points out that rosuvastatin 5 mg and 10 mg are both moderate-intensity doses, and because Nick’s LDL remains above his goal, his dose should be increased to a high-intensity dose. George recommends increasing to rosuvastatin 20 mg, granted Nick agrees with the plan and has no contraindications. George also recommends obtaining a repeat lipid panel in 4 to 12 weeks to monitor adherence and response.

Nonstatin Lipid-Lowering Medications

A staple of oral nonstatin therapy, ezetimibe (Zetia) does not decrease cholesterol synthesis—instead, it inhibits intestinal absorption of dietary cholesterol by blocking the Niemann-Pick C1-Like-1 (NPC1L1) transporter. ³⁷ Ezetimibe decreases LDL levels by 13% to 20%, making it a useful adjunct to statin therapy, or as monotherapy for less intensive lipid lowering.³⁷ Prescribers should not use ezetimibe in people who have moderate and severe hepatic impairment, but the medication is generally well tolerated. Limited adverse effects include headache, congestion, and sore throat—a rarity for the majority of patients.

For patients who require drastic reductions in LDL with or without statin therapy, subcutaneous proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor injections decrease LDL-C by 45-65%.³ The medication blocks PCSK9 enzymatic activity, raising levels of LDL-receptors in the body, allowing the liver to remove more LDL from the bloodstream. When the ACC/AHA published cholesterol guidelines in 2018, clinicians lacked sufficient evidence to determine the long-term effects of the monoclonal antibody PCSK9 inhibitors evolocumab (Repatha) and alirocumab (Praluent).⁶ Today, more recent studies demonstrate that evolocumab and alirocumab significantly reduce heart attack, stroke, and cardiovascular death over a five-year period.³⁸,³⁹ Injected into the abdomen, thigh, or upper buttock once every few weeks, these medications offer less frequent dosing than any other lipid-lowering medication. Patients rarely experience significant adverse effects; injection-site reactions and hypersensitivity reactions occur most frequently.⁴⁰

Additionally, the 2018 AHA/ACC cholesterol guidelines did not include inclisiran (Leqvio), a novel small-interfering RNA PCSK9 inhibitor that blocks production of the PCSK9 protein in the liver.⁶ The Lancet Diabetes & Endocrinology published data demonstrating the twice-yearly injection provided sustained LDL reductions and medication tolerability in patients over a four-year period.⁴¹ The updated 2026 AHA/ACC guidelines recommend inclisiran as an alternative to monoclonal antibody PCSK9 inhibitors, but high cost and absence of completed cardiovascular outcome evidence are barriers for initiation. ³ Another difference between inclisiran and the monoclonal antibody PCSK9 inhibitors evolocumab and alirocumab is that a healthcare professional must administer inclisiran. For patients who want less frequent administration or prefer not to inject their medication themselves, inclisiran is a useful alternative.

PCSK9 inhibitors excel in older adults. Researchers at the Erasmus MC Cardiovascular Institute concluded that patients older than 70 taking evolocumab and alirocumab had medication safety and efficacy profiles similar to those under 70.⁴²

In July 2026, the FDA approved the first oral PCSK9 inhibitor, enlicitide (Lipfendra), but the guidelines do not address the medication because it received approval after they were published.⁴³ Decreasing LDL by 56% over 24 weeks, the medication has similar efficacy to injectable PCSK9 inhibitors, but is roughly half the out-of-pocket cost of injectables at $315 per month.⁴⁴ PCSK9-targeting therapies have demonstrated efficacy in lowering LDL-C regardless of formulation, including injectable monoclonal antibodies, injectable small interfering RNA (siRNA), and oral agents.

Clinicians can confidently prescribe PCSK9 inhibitors or ezetimibe as an adjunct or alternative to traditional statin therapy due to their robust reductions in LDL and low adverse effect profile.

The 2026 AHA/ACC guidelines added bempedoic acid (Nexletol), an adenosine triphosphate citrate lyase (ACL) inhibitor, as an alternative for statin-intolerant patients, or an alternative medication.⁴⁵ Bempedoic acid acts two enzymatic steps upstream from statins and reduces LDL by around 20%.⁴⁶ However, bempedoic acid is metabolized via glucuronidation and not a CYP enzyme, but data regarding dose adjustments is limited. Adverse effects include cold or flu-like symptoms, muscle spasms, back and stomach pain. In CLEAR Outcomes, which enrolled 13,970 statin-intolerant patients, bempedoic acid reduced the relative risk of major adverse cardiovascular events by 13% over a median follow-up of 40.6 months. The trial included patients at high risk for ASCVD or with established ASCVD who reported being unable or unwilling to receive statins due to adverse effects. After treatment with bempedoic acid, LDL values dropped from an average of 139 mg/dL to 107 mg/dL, a 30 mg/dL decrease compared to placebo.⁴⁵ Bempedoic acid is also available with ezetimibe as a once-daily fixed-dose combination tablet (Nexlizet; bempedoic acid 180 mg/ezetimibe 10 mg).⁴⁷

Finally, bile acid sequestrants—colesevelam, colestipol, and cholestyramine—are members of a lipid-lowering medication class that decreases LDL without being systemically absorbed, making them a viable option for pregnant patients.³ At full doses, they lower LDL by 15% to 30%.⁴⁸ Gastrointestinal adverse effects like nausea, vomiting, constipation, and bloating prevent some patients from reaching higher doses. Bile acid sequestrants should generally be avoided with TG levels above 300 mg/dL, but contraindications vary by agent. Dosage formulations may also contribute to intolerance. All three available agents come as oral powders for suspension which some patients describe as having a chalky texture or bitter aftertaste. However, colesevelam and colestipol have tablet formulations. Patients with partial biliary obstruction and those who are pregnant or planning to become pregnant may benefit from this medication class. However, more effective therapies are preferred for most other patients.

Administration instructions, storage, and patient counseling points can be found in Figure 3.

Figure 3. Lipid-Lowering Therapy Quick Guide³

Triglyceride Lowering Medications

Statins remain the foundation for TG-lowering therapy.³ While fibrates, niacin, and prescription-strength omega-3 fatty acids have been shown to reduce TG levels, they fail to reduce the risk of cardiovascular events and ASCVD.⁴⁹ The Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial (REDUCE-IT) trial demonstrates that icosapent ethyl (Vascepa) is beneficial in certain patient populations with high TG but normal LDL.⁵⁰  In patients with TG levels surpassing 1,000 mg/dL, the apolipoprotein C-III (apoC-III) inhibitor reduces TG levels and the risk for pancreatitis by 63%.⁵¹

Eight weeks later, Nick reports no adverse effects from rosuvastatin 20 mg daily. His repeat LDL has decreased to 78 mg/dL—closer to his goal but still above 70 mg/dL. The prescriber calls George again to ask what the next steps should be. George tells the prescriber that because Nick only needs modest additional LDL lowering, ezetimibe 10 mg is warranted. Ezetimibe is a once-daily pill that can be taken at the same time as Nick’s statin, is generally well-tolerated, and can lower LDL-C by an additional 13% to 20%.

PAUSE and PONDER: If a patient who has an LDL of 53 mg/dL on a moderate-intensity statin has had a heart attack, is a high-intensity statin warranted?

Lipid-Lowering Therapy Treatment Algorithm

With defined lipid targets, initiating or optimizing LLT is crucial to reduce patients’ risk for ASCVD.

For patients without established ASCVD and an LDL of 70 to 189, the 2026 AHA/ACC guidelines recommend using the PREVENT scoring system to estimate ASCVD risk.³ The guidelines recommend initiating a statin in patients with an intermediate risk (5%) or above, while those with borderline risk (3% to less than 5%) should engage in shared decision-making with their clinician regarding treatment initiation. The guidelines support moderate-intensity statin initiation in intermediate risk patients, with high-intensity statins indicated in higher risk patients. Unlike previous guidelines, which emphasized percent LDL reduction from baseline, the 2026 recommendations incorporate individualized LDL targets.⁶ If maximally tolerated statin therapy fails to reduce a patient’s LDL target, additional therapy—ezetimibe or a PCSK9 inhibitor—is necessary to reduce all-cause mortality and CV events.^52,53,54 Bempedoic acid is a possible alternative, but ezetimibe and PCSK9 inhibitors alongside statins provide greater LDL reductions and are better tolerated.³

The 2026 AHA/ACC cholesterol guidelines recommend initiation or titration to a high-intensity statin for all patients with established ASCVD, regardless of comorbidities, risk factors, or baseline LDL.³ As previously discussed, if patients remain above the LDL goal of 55 mg/dL, clinicians should add ezetimibe, a PCSK9 inhibitor, or bempedoic acid.³

Age and PREVENT score guide statin therapy for patients with diabetes who do not have established ASCVD.³ The 2026 AHA/ACC guidelines recommend initiating at least a moderate-intensity statin, regardless of PREVENT score or LDL. For patients aged 30 to 39 years with PREVENT scores greater than 3%, clinicians should discuss cardiovascular risk reduction before considering moderate-intensity statin therapy. Beyond 75 years old, clinicians should engage in benefit-risk discussions with patients regarding statin therapy.³

Several lipid-lowering medications should be avoided in pregnant patients or patients who wish to become pregnant. Technician and pharmacist recognition of potentially harmful medications to the fetus, known as teratogens, is vital to prevent birth defects, premature births, and fetal harm. Because lipid management goals change with each trimester, lifestyle management is the safest option and can effectively manage high LDL and TG levels throughout pregnancy.³ Women should stop statins one to two months before attempting to become pregnant or as soon as pregnancy is discovered. Some studies suggest statins decrease birth weights, and increase the risk of preterm birth, eclampsia, and preeclampsia.^55,56 Newer data suggests that statin exposure during pregnancy is not associated with major fetal defects, and that spontaneous abortion rates could reflect other confounding factors like maternal comorbidities.⁵⁶

More data is needed to make definitive conclusions, but in 2021 the FDA revised statin warnings, indicating high-risk pregnant patients with established ASCVD could continue statin therapy when appropriate.⁵⁷ Statins should still be avoided when breastfeeding. Clinicians should continue statin therapy only after conducting an individualized risk assessment and engaging in shared decision-making with the patient. Limited evidence for alternative lipid-lowering therapies leaves bile acid sequestrants (BAS) as the only evidence-based medication class for cholesterol reduction during pregnancy because they are not systemically absorbed.³ Unfortunately, BAS can impair fat-soluble vitamins (vitamin A, D, E, K) and folic acid, which can impact the fetus, maternal health, and milk production.⁵⁸ To address TG levels above 500 mg/dL, fibrates and prescription-strength omega-three ethyl esters (DHA and EPA) can be initiated after the first trimester.⁵⁹

Dialysis status determines the optimal lipid-lowering therapy for patients with chronic kidney disease (CKD).³ Guidelines support primary prevention with a moderate-intensity statin with or without ezetimibe for patients 40 to 75 years old with an LDL of 70 to 189 mg/dL for patients not on dialysis. In contrast, statins have not demonstrated cardiovascular outcome benefits in patients receiving dialysis.⁶⁰  

Finally, patients with human immunodeficiency virus (HIV) are at heightened risk for ASCVD, particularly heart attack.⁶¹ Moderate-intensity statins reduce ASCVD risk in this population. However, many antiretroviral medications strongly inhibit CYP3A4, requiring clinicians to monitor for drug interactions and statin-related adverse effects.

The 2026 AHA/ACC triglyceride recommendations remain mostly unchanged from the 2018 guidelines.^3,6 LDL management through LLT decreases TG levels concurrently. In most cases, adequate LDL control and lifestyle management maintain healthy TG levels below 150 mg/dL. One major difference is the inclusion of icosapent ethyl (Vascepa) in the 2026 guidelines. The REDUCE-IT trial observed the effect icosapent ethyl had on patients with established ASCVD or diabetes with risk factors for ASCVD. Patients’ TG levels were between 135 and 499 mg/dL and LDL-C values between 41 and 100 mg/dL.⁵⁰ When added to prior statin therapy, twice-daily icosapent ethyl reduced the relative risk of major cardiovascular events by over 20%. The medication also decreased TG levels by 40 mg/dL. So, clinicians can add icosapent ethyl in patients with diabetes and ASCVD risk factors or with established ASCVD already on statin therapy with high triglycerides. In patients with TG levels exceeding 500 mg/dL or familial chylomicronemia syndrome, olezarsen is indicated to reduce the risk of pancreatitis.⁶² Other TG-lowering therapies remain last line and are not recommended in the 2026 guidelines.³

Whether preventing or managing ASCVD, clinicians must individualize lipid goals and consider special populations to reduce cardiovascular events and mortality.³

SIDEBAR: Do patients with heart failure require lipid-lowering therapy? ^3,63,64,65

Heart failure alone is not an indication to initiate statin therapy. Irrespective of ejection fraction, the 2026 AHA/ACC guidelines quantify heart failure as a high-risk cardiovascular condition. Several conditions add to the progression of heart failure, with coronary artery disease being a major contributor. Coronary atherosclerosis restricts blood flow to the heart, increasing the risk of myocardial infarction. The resulting loss of viable cardiac cells triggers compensatory overactivation of the remaining healthy tissue, progressively impairing cardiac function and contributing to the development of heart failure. Lipid-lowering therapy may reduce heart failure-related hospitalizations in some patients with heart failure. However, without another indication for LLT, statins do not reduce sudden cardiac death and major cardiovascular events.

Ten weeks after adding ezetimibe, Nick’s LDL is 65 mg/dL. He reports remaining adherent to his medications and has no new adverse effects. George recommends continuing the regimen and reinforces smoking cessation and lifestyle modifications. The prescriber thanks George for the assessment, as Nick has reached his LDL goals without unnecessary testing or premature initiation of costly injectable medications.

Optimizing Access to New Lipid-Lowering Therapy

The cost of new lipid-lowering medications can prevent patients from receiving guideline-directed treatment. Out-of-pocket costs for bempedoic acid and PCSK9 inhibitors can exceed $700 and $500 per month, respectively.^66,67,68 Inclisiran presents additional coverage challenges because healthcare professionals must administer it in a clinical setting. Patients in low socioeconomic groups can struggle to achieve recommended lipid goals due to cost. Even insured patients frequently encounter stringent prior authorization requirements.⁶⁹ Insurers frequently require medical records, specialist evaluation, and step-therapy requirements with statins before approving PCSK9 inhibitors or bempedoic acid.

Pharmacists and pharmacy technicians can increase medication access by helping patients reduce financial barriers. Many manufacturers offer copay cards that reduce out-of-pocket costs for privately insured patients.⁷⁰ Some manufacturers also provide patient assistance programs that offer free or reduced-price medications.^71,72 These programs often require income documentation and provider approval. Evolocumab’s manufacturer, Amgen, even offers patients a one-time, one-month free trial of evolocumab.⁷³ Coverage for these medications can reduce monthly costs to as little as $50 per month.

Additionally, Medicare Part D has an annual out-of-pocket spending cap of $2,100, meaning covered lipid-lowering therapies cost patients little or nothing after the cap is reached.⁷⁴ Pharmacists and technicians should familiarize themselves with available assistance programs and insurance requirements to identify eligibility and serve patients better. These resources improve medication access, boost adherence, and help patients achieve guideline-directed cholesterol goals to reduce ASCVD risk.

CONCLUSION

The update to the 2026 AHA/ACC Cholesterol Management Guidelines offers new guidance to clinicians on how to optimize lipid-lowering interventions to achieve individualized cholesterol targets. The guidelines equip pharmacists to calculate 10-year ASCVD risk, personalize patients’ estimated risk using the PREVENT-ASCVD equation, reclassify risk with CAC, and reassess treatment success. As newer lipid-lowering therapies are incorporated into standard practice, pharmacists should understand the updated treatment algorithm to improve medication selection and reduce ASCVD events. Pharmacy technicians can enhance patient care through recognition of potential drug interactions, identification of adverse effects, and improvement of medication access.

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INTRODUCTION

On a busy July afternoon, Jillian, a woman in her mid-40s, approaches the pharmacy counter looking tired and jittery. She glances toward the back of the store, as though making sure she knows where the restroom is.  When the pharmacist asks how she can help, she says quietly, "I started having diarrhea more than a week ago." At first, she assumed she had a stomach virus and expected it to resolve in a day or two. Instead, the diarrhea has become more frequent. "It's explosive," she says. "When I have to go, I have to go right now. I haven't been more than a few minutes from a bathroom in days."

She reports having six to eight episodes of watery diarrhea each day, accompanied by cramping, bloating, nausea, and profound fatigue. She has missed three days of work because she is afraid she won't make it to a bathroom in time. She has been drinking plenty of fluids, but feels weak and has little appetite.

She has tried bismuth subsalicylate without relief and wonders whether a stronger over-the-counter medication might finally stop the diarrhea. As the pharmacist asks additional questions, she mentions that she and her husband have been trying to eat healthier. Over the past two weeks, they have eaten several prepackaged salad kits, fresh berries, and homemade smoothies made with fresh basil from a neighborhood farm stand.

The pharmacist considers this history. Acute viral gastroenteritis usually resolves within a few days. Persistent, profuse watery diarrhea during the summer months suggests another possibility.

PAUSE and PONDER: What additional questions should the pharmacy team ask? Which features of this patient's illness warrant referral for medical evaluation?

Seasonal Spotlight: Cyclosporiasis

Cyclosporiasis is a seasonal intestinal infection caused by the microscopic parasite Cyclospora cayetanensis.^1,2 (Table 1 explains how parasites differ from bacteria or viruses.) Although cases occur every year, infections increase during the spring and summer when contaminated fresh produce enters the food supply.³ In 2026, the United States (U.S.) is experiencing a substantial multistate increase in reported cases, prompting investigations by the Centers for Disease Control and Prevention (CDC), the U.S. Food and Drug Administration (FDA), and multiple state health departments.^2-6 The SIDEBAR lists facts every pharmacy employee needs to know.

SIDEBAR: Fast Facts about Cyclosporiasis^1,7-9

• Cause: Infection with the protozoan parasite Cyclospora cayetanensis.
• Transmission: Consumption of food or water contaminated with Cyclospora oocysts—most often in the US via fresh produce.
• Person-to-person spread: Unlike many diarrheal illnesses, freshly shed Cyclospora oocysts require days to weeks in the environment before they become infectious, making direct transmission unlikely.
• Incubation period: Typically about one week (range, two days to two weeks).
• Hallmark symptom: Profuse, watery diarrhea that is often described as explosive.
• Other symptoms: Abdominal cramping, bloating, nausea, fatigue, loss of appetite, weight loss, and low-grade fever. Symptoms may persist for weeks or relapse if untreated.
• Diagnosis: Stool testing specifically ordered to detect Cyclospora. Most commercial laboratories have this as part of their multiplex PCR testing.  Additionally, up to three days of testing is recommended after negative tests, as oocysts shed inconsistently.
• Treatment: Trimethoprim-sulfamethoxazole (TMP-SMX) for 7 to 10 days is the first line treatment. Supportive care includes aggressive fluid replacement. Patients with sulfonamide allergy require alternative management because no highly effective substitute has been established.

This Outbreak Is Different

As of early July 2026, the CDC confirmed domestically acquired cases in at least 37 states, while several affected states reported substantially larger numbers through their own surveillance systems. Michigan has experienced an especially large outbreak, and investigations to identify the contaminated food source remain ongoing. No single food item had been implicated as of July 11, 2026.⁷ Many cyclosporiasis outbreaks are never linked to a single food source because traceback investigations and testing of fresh produce are often difficult.

Although the source of the current outbreak has not been identified, previous U.S. outbreaks have been associated with fresh produce, including^10-12

• Bagged salad mixes
• Cilantro
• Fresh basil
• Raspberries and blackberries
• Romaine and mesclun lettuce
• Snow peas

Identifying Possible Cyclospora Infection

Patients often mistake cyclosporiasis for viral gastroenteritis. The difference is time.¹ Most cases of norovirus, the most common form of viral gastroenteritis, improve within 24 to 72 hours. In contrast, patients with cyclosporiasis often report that their diarrhea has persisted for a week or longer and may even improve briefly before returning. Why? Cyclospora cayetanensis has an unusual life cycle, described in Figure 1, that explains many of the infection's clinical characteristics and public health challenges.

Although first recognized in humans in 1977, scientists spent more than a decade debating this parasite’s identity.^13-15  At various times, the organism was referred to as "coccidia-like bodies," reflecting its resemblance to coccidial parasites, or "cyanobacterium-like bodies," and some investigators even suspected it was a blue-green alga before it was formally identified as Cyclospora cayetanensis in 1993.  Large multistate outbreaks linked to imported Guatemalan raspberries in 1996 transformed Cyclospora from an obscure tropical parasite into a major foodborne pathogen of international public health importance.^13-15

PAUSE and PONDER: Why is person-to-person transmission of Cyclospora cayetanensis not possible?

People become infected by swallowing sporulated oocysts—the environmentally mature form of the parasite—on contaminated food or in contaminated water.^16,17 After ingestion, the parasite infects cells lining the small intestine, where it multiplies and causes inflammation that leads to watery diarrhea and other gastrointestinal symptoms. Infected individuals shed unsporulated (immature) oocysts in the stool.16,17 Freshly passed oocysts are not immediately infectious. Instead, they must remain in the environment for one to two weeks under favorable conditions before they mature (sporulate) and become capable of infecting another person.^3,16

This delay explains two important features of cyclosporiasis^1,3:

• Person-to-person transmission is uncommon because freshly shed oocysts cannot immediately infect another individual.
• Fresh produce is a common vehicle for infection because fruits, vegetables, and herbs can become contaminated in the field or during irrigation, allowing oocysts time to mature before the food is harvested and consumed.

Jillian seems relieved to have a possible diagnosis and a plan to see her primary care provider. Suddenly, she looks worried again. She says, “I feed some raw fruits and vegetables to my dogs! Will they get this?”

Here’s a not-so-fun fact: humans are the only known host for Cyclospora cayetanensis.16 Jillian’s dogs will not become ill from Cyclospora cayetanensis. Contamination of food or water occurs through exposure to human feces rather than infected animals.16 How does human fecal contamination get onto produce? See the SIDEBAR.

SIDEBAR: How Does Human Fecal Material End Up on Fresh Produce?^5,6

Most people picture an obvious sanitation failure, but contamination is usually much less dramatic.^6,18 Fresh produce can become contaminated when irrigation or wash water is contaminated with sewage, when an infected worker harvests or packs produce without adequate hand hygiene, or when toilet or handwashing facilities are unavailable or improperly maintained. Contamination may also occur during harvesting, packing, or processing if proper hygiene and sanitation practices are not followed.^6,18 Food safety is ultimately about human behavior and infrastructure, not just microorganisms.

Because humans are the only known host for Cyclospora cayetanensis, preventing contamination depends on worker health and hygiene, safe water sources, proper sewage disposal, and field sanitation.^6,18 The FDA's Produce Safety Rule requires covered farms to provide toilet facilities, handwashing stations, employee hygiene training, and procedures designed to prevent produce contamination.^6,18

Recognizing Cyclosporiasis: Symptoms and Patient Clues

Jillian’s case is classic. Cyclosporiasis’s hallmark symptom is profuse, watery diarrhea, often described as explosive.8,19 Patients frequently report an overwhelming urgency to reach a restroom and may avoid work, social activities, or travel because they cannot predict when another episode will occur. Other symptoms commonly include abdominal cramping, bloating, nausea, loss of appetite, fatigue, low-grade fever, and weight loss. Vomiting is less common than diarrhea.^8,19

The illness’s prolonged nature places patients—particularly older adults and individuals with underlying medical conditions—at risk for dehydration and electrolyte abnormalities. Although healthy adults usually recover without long-term complications, prolonged diarrhea can lead to dehydration, electrolyte disturbances, and weight loss, particularly in older adults, young children, and individuals who are immunocompromised.^8,19

When a patient asks for help finding an antidiarrheal, ask a few simple questions:

• How long have the symptoms lasted?
• How many episodes do you experience each day?
• Is the diarrhea watery or bloody?
• Have over-the-counter medications helped?
• Have you recently eaten fresh berries, salad, herbs, or other raw produce?
• Have you traveled recently or attended a large gathering where food was served?

A patient like Jillian who says, "I thought it was a stomach bug, but it's been over a week and I'm still having explosive diarrhea," should be referred for medical evaluation.

Pharmacy personnel should encourage patients to seek prompt medical evaluation if they experience

• Watery diarrhea lasting more than 3 to 5 days
• Severe or persistent diarrhea accompanied by dehydration
• Inability to maintain adequate fluid intake
• Fever, bloody stools, or severe abdominal pain
• Significant weight loss
• Symptoms in an immunocompromised patient or other individual at high risk for complications

Diagnosis and Treatment

Diagnosing cyclosporiasis can be challenging because routine bacterial stool cultures do not detect Cyclospora cayetanensis, and many commonly ordered gastrointestinal multiplex PCR panels do not include this parasite. Healthcare providers should ensure that the selected diagnostic test specifically includes Cyclospora when the infection is suspected.^1,8,20 Patients with persistent diarrhea should inform their healthcare provider about the duration of symptoms, recent travel, and consumption of fresh produce. If they don’t, healthcare providers need to ask.

Diagnosis may be made by identifying the characteristic round Cyclospora oocysts (which are round and a size equivalent to one-tenth the width of a human hair) in stool specimens or, more commonly, by using molecular methods such as PCR when the selected test panel includes Cyclospora. Because infected individuals may shed relatively few oocysts—and may not shed them consistently—a single negative stool specimen does not rule out infection. Sometimes, symptomatic patients do not shed a sufficient quantity of oocysts in their stool; these patients, called low level shedders, might need to submit several specimens collected on different days.^5,20 When clinical suspicion remains high, healthcare providers may request stool samples collected on multiple days.

PAUSE and PONDER: A patient fills a prescription for TMP-SMX and says the prescriber told him to use “supportive care.” He doesn’t really know what that means. What would you say?

Treatment

The treatment of choice is trimethoprim-sulfamethoxazole (TMP-SMX).8,9 For immunocompetent adults, the recommended adult regimen is one double-strength tablet (TMP 160 mg/SMX 800 mg) orally twice daily for seven to 10 days.  The pediatric dose for children older than two months is 8 to 10 mg/kg TMP and 40 to 50 mg/kg SMX per day, orally, in two divided doses for seven to 10 days. Both Bactrim and ciprofloxacin work similarly on the protozoan parasite as they do on bacteria. Bactrim inhibits its ability for folate synthesis it needs for survival, while ciprofloxacin inhibits its DNA replication. Importantly, it needs a functional immune system for cure; those with immunocompromise, it may result in stasis and secondary prophylaxis is generally recommended.^8,9

Fluid replacement is an essential component of treatment because prolonged watery diarrhea can lead to dehydration and electrolyte imbalances. The pharmacy team should encourage patients to8

• Drink small, frequent amounts of fluid rather than large volumes at one time if nausea is present.
• Use an oral rehydration solution (ORS) (e.g., Pedialyte or other commercially available ORS) when diarrhea is moderate to severe or prolonged. ORS products contain an appropriate balance of water, sugar, and electrolytes to promote intestinal absorption.
• Consume clear fluids such as water, broth, or diluted sports drinks if an ORS is unavailable. (ORS remains the preferred option.)

Some beverages may worsen diarrhea or contribute to dehydration and should be avoided, including^21-23

• Alcohol
• Excessive caffeine (coffee, energy drinks)
• Sugar-sweetened beverages such as regular soda or undiluted fruit juice, which can increase osmotic diarrhea
• Sugar-free beverages containing poorly absorbed sugar alcohols (e.g., sorbitol or mannitol), which may also worsen osmotic diarrhea
• Patients should be recommended to have ORS available at home.

Patients who are unable to keep fluids down, experience dizziness or fainting, produce very little urine, or develop signs of severe dehydration should seek immediate medical attention. Pediatric patients with any level of dehydration should seek medical attention. Patients with diabetes should monitor blood glucose more frequently during diarrheal illness because dehydration and changes in food intake may affect glycemic control. Patients who continue to have diarrhea after completing treatment—or whose symptoms recur—should contact their healthcare provider.³  Relapses are part of the disease.¹²

Over-the-counter antidiarrheal medications, may provide temporary symptomatic relief in otherwise healthy adults but do not eradicate Cyclospora cayetanensis.20 (And note that Cyclospora typically does not cause bloody diarrhea; if a patient has bloody stools or high fever, they may have an invasive bacterial infection rather than cyclosporiasis.) Patients with persistent watery diarrhea lasting more than several days should be referred for medical evaluation rather than repeatedly self-treating with over-the-counter products.²⁰ Antidiarrheals should be avoided in patients with bloody diarrhea or high fever unless directed by a healthcare provider.^8,20

Management becomes more complicated in patients with sulfonamide allergies. Research has yet to identify a highly effective alternative to TMP-SMX.⁸ Depending on the severity of the illness and the nature of the allergy, clinicians may recommend symptomatic treatment, consider an alternative antimicrobial  such as ciprofloxacin, supported by limited evidence, or pursue TMP-SMX desensitization in carefully selected patients.+

Food Safety and Prevention

Fresh produce is the most common source of infection because people often eat it raw. Previous U.S. outbreaks have been linked to cilantro, basil, raspberries, blackberries, and leafy greens.^10-12 However, any fresh fruit or vegetable exposed to contaminated irrigation water or poor sanitation practices may become contaminated. The 1996 raspberry outbreak was so large that it fundamentally changed how public health agencies investigate produce-associated outbreaks. Before then, most people associated foodborne illness with meat, eggs, or dairy—not fresh berries.^13-15

Rinsing produce under running water is recommended because it removes dirt and may reduce contamination, but it cannot be relied upon to remove or eliminate all Cyclospora oocysts.⁶ The parasite's hardy outer shell allows it to survive under environmental conditions that would eliminate many bacteria and viruses. Experts don’t recommend soap, bleach, or commercial produce washes because they have not been shown to eliminate Cyclospora and may leave harmful residues on food. Refrigeration does not kill the parasite. Freezing may reduce viability but should not be relied upon to prevent infection.⁶

PAUSE and PONDER: If washing doesn't work, why bother?

In short, washing reduces contamination, even though it doesn't guarantee safety.

Jillian listens to the information about washing vegetables, and she sighs, “We were eating better. Now we can’t even have a salad.” The pharmacist says, "I understand why you feel that way," and continues, "But I don't want this experience to keep you from eating healthy foods. The answer isn't to avoid salads forever. It's to pay attention to food recalls and practice good food safety." He also tells her, “In otherwise healthy individuals this is not fun, but it is important to continue eating healthy foods.”

Reducing Infection Risk

Although no method completely eliminates the risk of cyclosporiasis, patients can reduce their risk by²⁴

• Washing hands with soap and water before preparing or eating food.
• Rinsing fresh fruits and vegetables under running water before eating, cutting, or cooking them.
• Scrubbing firm produce (e.g., melons, cucumbers, potatoes) with a clean produce brush.
• Refrigerating perishable produce promptly.
• Separating fresh produce from raw meat, poultry, seafood, and their juices to prevent cross-contamination.
• Following FDA recalls and public health advisories during foodborne illness outbreaks.

For most healthy adults, cyclosporiasis is unpleasant but rarely life-threatening. The health benefits of eating fresh fruits and vegetables continue to outweigh the relatively low risk of infection. Patients should follow recommended food safety practices, remain aware of food recalls, and seek medical evaluation promptly if persistent watery diarrhea develops. Individuals who are severely immunocompromised should discuss additional food safety precautions—including avoiding raw produce—with their healthcare providers.

CONCLUSION

Remember Jillian? She didn't come to the pharmacy looking for an antiparasitic medication. She came looking for an antidiarrheal. The pharmacy team's greatest contribution wasn't recommending a product—it was recognizing that her symptoms didn't fit the pattern of a routine stomach virus and ensuring she received appropriate medical evaluation. Tackling outbreaks of this parasitic diarrhea is about recognizing patterns, asking the right questions, and understanding that food safety begins long before food reaches the pharmacy—or the patient.

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INTRODUCTION

Gallbladder disease (GBD; see Sidebar: Types of Gallbladder Disease) is the most common surgical emergency, responsible for 600,000 surgeries per year in the United States.¹ Cholelithiasis, or gallstones, is one of the most common and costly gastrointestinal diseases, affecting more than 20 million Americans annually.² An estimated 115 of every 100,000 of the world’s population will undergo gallbladder removal surgery every year.³

GBD is influenced by genetic and environmental factors, diet, physical activity, and nutrition. The healthcare team should encourage patients to incorporate healthy habits into their lifestyles to reduce the risk of GBD. This continuing education activity will discuss GBD pathology, risk factors, treatment, considerations post-cholecystectomy, and the pharmacy team’s role.

GALLBLADDER DISEASE

The Gallbladder

The gallbladder is the small pear-shaped organ located in the right upper quadrant (RUQ) of the abdomen beneath the liver. It is part of the biliary system, which is a series of ducts in the liver, gallbladder, and pancreas that drain into the small intestine.⁴ The gallbladder acts as a storage pouch for up to 50 mL of bile, also known as “gall.”⁵ Gall became a synonym for bile in the Middle Ages and also meant “embittered spirit.”⁵ In the late 19^th century, gall was used to describe a person having boldness or insolence.⁴

Bile is a yellowish-brown alkaline surfactant (substance that decreases surface tension) continuously produced by the liver.^1,2 It is composed of cholesterol, bilirubin, water, bile salts, phospholipids, and ions. The common bile duct carries bile from the liver to the gallbladder. Fatty foods and proteins released from the stomach into the small intestine stimulate the gallbladder to empty bile into the duodenum via the sphincter of Oddi, which facilitates digestion. Bile salts emulsify lipids in the intestines allowing absorption of dietary fats such as cholesterol and fat-soluble vitamins. Unused bile salts return to the gallbladder through the distal ileum and portal circulation.^1,2

The gallbladder was probably more valuable centuries ago.⁵ Some scientists believe that primitive humans were carnivorous hunters; meals were large, few, and far between.⁵ The gallbladder would have been crucial for digestion of large, high fat meals. The organ wasn’t considered nonessential until the late 1600s, after two Italian doctors discovered that animals could thrive without it.¹ This discovery was forgotten until a German physician successfully performed the first cholecystectomy (surgical removal of the gallbladder) in a human in 1878.^1,6 Figure 1 describes a brief history of the gallbladder, gallstones, and cholecystectomy beginning in the 15^th century.

Today, the gallbladder assists in digestion of fat-soluble vitamins, proving important even for vegetarians.⁵ People can still live a healthy life after gallbladder removal; however, the risk of hepatic problems increases due to impaired fat digestion.⁵

Sidebar: Types of Gallbladder Disease^2,8

• Biliary dyskinesia: gallbladder motility disorder caused by scarring or spasm of sphincter of Oddi, the valve that controls the flow of biliary and pancreatic secretions into the duodenum
• Cholangitis: inflammation of the biliary system
• Cholecystitis: inflammation of the gallbladder
• Choledocholithiasis: common bile duct stones
• Cholelithiasis: gallstones
• Gallbladder empyma: severe acute cholecystitis, a surgical emergency
• Gallbladder pancreatitis: inflammation of the pancreas caused by pancreatic duct obstruction by a gallstone
• Gallbladder perforation: a hole in the gallbladder wall
  • Acute: generalized biliary peritonitis
  • Subacute: acute plus pericholecystic abscess
  • Chronic: cholecystoenteric fistula
• Gallbladder polyps: overgrowths or lesions in the gallbladder wall

This continuing education activity will focus on gallstones and their complications, which may include cholecystitis, choledocholithiasis, and cholangitis. Cholecystectomy (gallbladder removal) is the treatment mainstay for gallstones and pharmacist intervention is most valuable post-cholecystectomy.

Gallstones and Acute Cholecystitis

The most common gallbladder disease is gallstones.⁷ Gallstones commonly form from imbalances in bile constituents and biliary sludge (solids precipitated from bile) caused by slowed gallbladder motility or altered hepatic cholesterol metabolism. Hardened cholesterol or bilirubin become saturated in bile and crystalize, like rock candy, and can lodge in the common bile duct.⁷ Gallbladder hypomotility leads to delayed emptying, resulting in the formation of biliary sludge and consequently, gallstones.⁷

Bilirubin is a substance found in bile resulting from red blood cell breakdown in the liver. It is normally eliminated through the feces. Gallstones caused by bilirubin, or “pigment stones”, are rare and only account for approximately 10% of all gallstones.⁸ Pigment stones are commonly seen in individuals with blood disorders, such as sickle-cell anemia.⁸ Approximately 75% of gallstones in Western countries contain cholesterol as their major component.⁹

The presence of stones in the gallbladder is called cholelithiasis. Most patients with gallstones are asymptomatic and may not have any attributable symptoms during their lifetime.⁸ Asymptomatic cholelithiasis does not require treatment as the risk of symptom development is only about 10% at five years.⁸

Cholelithiasis becomes acute cholecystitis when gallstones block the cystic duct, causing the gallbladder to become inflamed and patients to become symptomatic. Biliary pain—also known as biliary colic—is the most common symptom of cholecystitis. Epigastric (upper-middle abdomen) pain lasting from 30 minutes to several hours radiates around or through the back and may be accompanied by heartburn, bloating, nausea, and/or vomiting. The sharp, stabbing pain generally follows food intake and peaks after the first hour. It is characteristically steady and is severe enough to interfere with activities of daily living. The pain is not relieved with a bowel movement. Women often describe biliary pain as being worse than childbirth.^2,8

Cholecystitis pain from an acute episode usually subsides over one to five hours as the stone dislodges.^3,10 The likelihood that patients experience repeated symptomatic episodes from their gallstones is approximately 38% to 50% annually.⁸ More than 90% of patients presenting with a single episode of biliary colic have recurrent pain within 10 years.¹³

Ultrasound is the best test for diagnosing gallstones and finds most patients with an average of two to 20 stones. The record-setting number of stones was found in England in 1987; a female patient had 23,530 stones removed.⁵ Computerized tomography (CT) can also be used for diagnosis, but it is less accurate than other imaging methods, detecting approximately 75% of gallstones.² Providers can also diagnose by the presence of Murphy’s sign, or pain upon inhalation when the inflamed gallbladder meets the examiner’s hand.⁸ Other diagnostic markers include elevated liver function tests, white cell count, erythrocyte sedimentation rate, and C-reactive protein.⁸ Patients presenting with acute cholecystitis may have experienced several bouts of biliary colic before diagnosis.

Acute cholecystitis diagnosis typically requires admission for pain management and intravenous (IV) fluid rehydration. Nonsteroidal anti-inflammatory drugs (NSAIDS) like ketorolac, diclofenac or indomethacin combat inflammation and promote speedy recovery.⁸ NSAIDS are generally preferred to narcotic analgesics as they are equally effective with fewer adverse effects.² A study of 324 patients given IV ketorolac or meperidine showed both drugs offered similar pain relief but patients in the NSAID group reported fewer adverse effects.² Patients receive broad-spectrum antibiotics (e.g., ciprofloxacin, cefuroxime) to prevent or treat bacterial infection.⁸

Failure to properly treat cholecystitis can lead to severe inflammation, gangrene, sepsis, and life-threatening gallbladder perforation. Cholecystitis can also lead to gallstone pancreatitis if stones in the sphincter of Oddi are not cleared and block the pancreatic duct.²

Chronic Cholecystitis

Repeated episodes of cholecystitis or chronic irritation from gallstones can lead to chronic cholecystitis.¹¹ Chronic cholecystitis more often presents with cholelithiasis (calculous) but can also exist without gallstones (acalculous). Symptomatic patients usually present with dull RUQ pain that radiates around the waist to the middle back. Most patients are afebrile.¹¹

While acute cholecystitis symptoms are sharp and abrupt, chronic cholecystitis symptoms usually develop and worsen over weeks to months.¹¹ Lab values normally elevated in acute disease may not be in chronic disease and therefore cannot be used in diagnosis. Ultrasound of the RUQ is the best diagnostic tool to evaluate the gallbladder for wall thickening and inflammation. Elective cholecystectomy is the preferred treatment for chronic cholecystitis. Patients who are not eligible for or who prefer not to undergo surgery should be closely monitored. A low-fat diet and other lifestyle modifications can help reduce symptom frequency.¹¹

Pharmacists should recognize the differences between presentations of acute versus chronic cholecystitis and refer patients to the nearest emergency department if symptoms are severe.

Choledocholithiasis and Cholangitis

Choledocholithiasis, or common duct stones, are gallstones that have migrated from the gallbladder to the common bile duct via the cystic duct. Approximately 8% to 16% of patients with symptomatic gallstones will also have common bile duct stones.⁸ Common duct stones can be asymptomatic or may lead to complications such as gallstone pancreatitis or acute cholangitis. Cholangitis is inflammation of the biliary system that causes fever, jaundice, and abdominal pain (Charcot triad).⁸ Charcot triad becomes Reynolds pentad when hypotension and altered mental state are also present.⁸ These symptoms develop due to bile stasis and bacterial infection in the biliary tract.

Cholangitis is most commonly caused by gram-negative (Escherichia coli [25% to 50%], Klebsiella spp. [15% to 20%], Enterobacter spp. [5% to 10%]) intestinal bacteria, and less often by gram-positive bacteria (Enterococcus spp. [10% to 20%]).⁸ Patients require prompt treatment with IV antibiotics such as a broad-spectrum cephalosporin or ciprofloxacin.⁸ Pharmaceutical intervention should be followed by stone removal to prevent septicemia (systemic blood infection), which can be fatal.  Most clinicians recommend that common bile duct stones be removed once discovered, even when asymptomatic.⁸

Risk Factors

Several genetic and environmental factors contribute to gallstone development. Patients with first-degree relatives with history of cholelithiasis are at a three times higher risk of gallstones.⁸ Approximately 60% of patients with acute cholecystitis are female, but the illness is generally more severe in males.² Women experience a higher prevalence because of estrogen’s effects on cholesterol metabolism.¹² Estrogen increases cholesterol synthesis and decreases bile acid production.¹² Progesterone in pregnancy decreases gallbladder contractility leading to stasis, making gallstones 10 to 15 times more common in women who have been pregnant.^8,12 Women with history of biliary colic, gallstones, and the like should be aware of how hormones may affect their risk for recurrence. This is valuable information for pharmacists to consider and an appropriate place to intervene and educate.

European and American populations are more likely to develop gallstones, and Black people of African descent are least likely. Prevalence is highest in Native American populations, with 60% incidence in the Pima Indian populace of southern Arizona.⁸ Table 1 summarizes risk factors for GBD.^2,8,13

GLP-1RAs, glucagon-like peptide 1 receptor agonists; H2RAs, histamine-2-receptor antagonists; HDL, high-density lipoprotein; PPIs, proton-pump inhibitors.

Glucagon-like peptide 1 (GLP1) receptor agonists (GLP-1RAs) are notable for their glucose control and cardiovascular risk reduction for patients with type 2 diabetes mellitus and more recently, for weight loss. Their link to GBD is controversial as GLP1 inhibits gallbladder motility and delays gallbladder emptying.¹⁴ A recent systematic review and meta-analysis of 76 randomized clinical trials shows an association between GLP-1RA use and elevated GBD risk. The risk for gallbladder or biliary diseases were more prominent with higher doses, longer duration, and when used for weight loss.¹⁴ Clinicians should discuss the benefits of using these hypoglycemics for type 2 diabetes or weight loss and whether they outweigh the risk for GBD. Pharmacists can educate patients initiating GLP-1RAs about their benefits, risks, and implications with past medical history of or additional risk factors for GBD. Multiple GLP-1RAs are available in varying doses and pharmacists should continue to counsel patients as doses are increased over time.

Chronic use of gastric acid suppressants may cause cholelithiasis.¹⁵ These drugs impact gut microbiome and may slow gallbladder motility leading to delayed gallbladder emptying. A recent prospective cohort of 0.47 million participants found that regular use of proton-pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs) resulted in increased cholelithiasis risk.¹⁵ Physicians should be aware of this association when prescribing these medications, especially for patients requiring long-term use or those already at high risk for gallstones. Pharmacists should keep these risks in mind when filling prescriptions for their patients on long-term or high-dose H2RAs and PPIs.

Ketamine abuse has been associated with chronic biliary colic. Ketamine was developed in 1962 as an anesthetic.¹⁶ “Street ketamine”, a close analogue of ketamine, is commonly used for its euphoric effects. Ketamine’s onset of action after oral ingestion is about ten minutes and its hallucinogenic effects are short acting, lasting up to two hours. The most common signs of ketamine abuse are hypertension, tachycardia, and abdominal tenderness. Ketamine abuse is also associated with impaired consciousness, dizziness, abdominal pain, and lower urinary tract symptoms.¹⁶ Case reports have shown ketamine abusers presenting with severe bladder dysfunction and recurrent episodes of epigastric pain due to a dilated common bile duct not associated with gallstones.¹⁶ Clinicians should collect detailed drug histories for patients presenting with recurrent abdominal pain, namely biliary colic.

Diets characterized by increased caloric intake with highly refined sugars, high fructose, low fiber, high fat, and consumption of fast food increase the risk of gallstone formation.⁹ Nutrition and lifestyle changes may be beneficial in the prevention of gallstones. Increased physical activity, consuming smaller more frequent meals, and “heart healthy” diets low in cholesterol and fat and high in fiber can reduce risk of cholelithiasis.⁷ Fat should not be completely cut out of the diet as too little fat can also precipitate gallstone formation.

Weight loss can reduce gallstone risk, but rapid weight loss achieved by low-calorie diets (less than 800 kcal/day) or bariatric surgery can cause gallstones.^2,9 Patients should seek professional advice before starting diets promoting very low caloric or high fat intake to achieve rapid weight loss (i.e., Atkins, ketogenic). Pharmacists should be aware of patients who have recently undergone bariatric surgery or are taking drugs or supplements for weight loss. These patients may be at a higher risk for gallstones, especially those with past medical histories of GBD or abdominal colic symptoms.

Some foods and medications seem to be associated with a reduced risk of gallstones:

• Statins alter bile cholesterol and thus affect gallstone formation, suggesting a role in prevention. While the relationship between statins and gallstone formation is conflicting, studies report reduction in symptomatic gallstone disease with statin use.¹⁷
• Ezetimibe, a selective NPC1L1 inhibitor, has been associated with a reduced incidence of cholesterol gallstones in animal studies. The mechanism involves reduced amounts of absorbed cholesterol, decreasing biliary cholesterol saturation, and in turn, reduced rate of cholesterol gallstone formation.¹²
• Vitamin C supplementation has been shown to reduce gallstone prevalence. Researchers have studied vitamin C supplementation’s effects in gallstone formation in guinea pigs; those deficient in vitamin C more often develop gallstones. An observational study of a randomly selected population in Germany (n = 2129) showed a positive correlation between regular vitamin C intake and a reduced gallstone incidence.¹⁸
• Coffee consumption may also offer a protective effect against gallstone formation. Studies suggest coffee stimulates cholecystokinin release, enhancing gallbladder contractility, thereby reducing bile cholesterol crystallization. A 2019 observational analysis published in the Journal of Internal Medicine found a 23% decrease in gallstone formation in subjects consuming six or more cups of coffee daily.¹⁹
• A small study conducted in Spain shows that regular consumption of olive oil containing monounsaturated and polyunsaturated omega-6 fatty acids may prevent gallstones. Similarly, fish (omega-3 fatty acids) and fish oil may reduce triglycerides and prevent gallstones. A group of participants with hypertriglyceridemia taking fish oil supplements for a seven-week study in the Netherlands experienced improved gallbladder motility and a decrease in triglycerides.¹⁰

TREATING GALLBLADDER DISEASE

Endoscopic retrograde cholangiopancreatography (ERCP) is the most common way to identify and remove common duct stones. ERCP is minimally invasive and carries the risk of acute pancreatitis.⁸ This diagnostic tool may also identify duct strictures at which time stents are placed to reduce obstruction and improve biliary flow.^8,10 Timely stent removal (within three to six months) is crucial to prevent occlusion, stent migration, or cholangitis.²² Cholecystectomy is the definitive treatment for symptomatic gallstones and should commence within 48 hours of symptom onset during the acute inflammatory process, before tissue thickening or scarring develops.^8,10

Surgical Intervention: Cholecystectomy

The first gallstone removal surgery was a coincidence. In the mid-19^th century, a physician was performing investigative surgery on a female patient, and when he cut into her gallbladder, several bullet-like objects spilled out.⁵ The first planned gallbladder removal was performed 15 years later.⁵ Before the early 1900s, the surgery was performed through an incision in the RUQ (Kocher’s incision, named after Emil Theodor Kocher, a Swiss physician and medical researcher who performed the first successful cholecystectomy in 1878).^6,8 This invasive procedure was outmoded a few years after Erich Muhe, a German surgeon, performed the first laparoscopic cholecystectomy in 1985.⁸ Today, surgeons perform more than 98% of cholecystectomies laparoscopically, over 70% of which are outpatient day surgeries.⁸

Cholecystectomy is associated with fewer gallbladder-specific complications and shorter length of hospital stay when surgery is elective or performed as a single emergency visit without previous surgical admissions.³ A population-based cohort study of outcomes following surgery for benign GBD showed poorer outcomes and risk of readmissions with delayed cholecystectomy. Many studies define emergency or early surgical intervention as operations performed within 48 to 72 hours of symptom onset. A study of 14,200 patients in Canada discovered patients experienced fewer complications when surgery was performed within seven days of hospital admission.³ These studies show value in offering emergency surgery over delaying cholecystectomy for patients presenting with benign GBD.³

Antibiotic prophylaxis is not routinely recommended for low-risk patients undergoing elective laparoscopic cholecystectomy.¹³ High-risk patients (age older than 60, type 2 diabetes, acute colic within 30 days of surgery, jaundice, acute cholecystitis, or cholangitis) may benefit. Providers should limit prophylaxis to IV cefazolin 1 g as a single dose one hour prior to surgery.¹³

Several studies suggest that pain management before or during, and after laparoscopic cholecystectomy can reduce post-operative pain. A 2018 review of 258 randomized control trials recommended a basic analgesia technique: acetaminophen plus an NSAID or cyclooxygenase-2 inhibitor with local anesthetic infiltration.²¹ Opioids are reserved for breakthrough pain.²¹

Patients are generally discharged a few hours after surgery. Surgeons should be on alert for early signs of complications if there is divergence from the usual course of rapid recovery post-op. Extreme pain shortly after surgery may indicate intra-peritoneal leakage of bile or bowel contents.⁸ Persistent hypotension (low blood pressure) and pain can suggest bleeding. Re-laparoscopy may be necessary to identify and repair these problems and is preferred to diagnostic imaging.⁸

Removal of the gallbladder will not cause weight loss/gain or vitamin deficiencies. Patients should be able to tolerate foods they couldn’t before surgery, but providers should advise them to add those foods back into their diet very slowly. Following gallbladder removal, the liver will continue to make bile, but instead of storing it in the gallbladder, it will drain into the stomach and small intestines. Patients might experience three to five days of soreness post-op and are expected to fully heal within four to six weeks.⁷

Diarrhea and bloating due to alternation of biliary flow are common short-term occurrences after surgery.²² A small percentage (1% to 2%) of patients will have loose stools each time they eat greasy or high-fat meals.⁷ A cystic duct remnant is also possible, potentially leading to stone formation, causing Mirizzi syndrome. Mirizzi syndrome is characterized by fever, jaundice, and RUQ pain due to common hepatic duct obstruction caused by compression from the impacted stone in the remnant cystic duct.²² Endoscopic removal of the stone may be adequate. In rarer cases, surgical excision of the remnant duct may be necessary to prevent further complications.²²

Pharmacologic and Other Non-Surgical Interventions

Nonoperative methods exist for patients unwilling or unable to undergo surgical intervention. Contraindications for laparoscopic cholecystectomy include^10,13

• Absolute: gallbladder cancer (see Sidebar: Gallbladder Cancer), general anesthesia intolerance, giant gallstones, morbid obesity, uncontrolled bleeding disorder
• Relative: advanced cirrhosis/liver failure, bleeding disorder, peritonitis, previous upper abdominal surgeries, septic shock

Gallbladder Cancer²⁰

Gallbladder cancer is a rare malignancy but accounts for almost 50% of biliary cancers. Biliary cancers have a poor five-year survival rate and a high recurrence rate. Factors affecting prognosis are stage at discovery, tumor location, operability, response to chemotherapy, and presence and location of metastases. Early-stage gallbladder cancer may be curable with surgical resection.

Oral bile acid dissolution drugs include ursodeoxycholic acid (ursodiol) and chenodeoxycholic acid (chenodiol).²³ Table 2 lists dosing and adverse effects of these medications. Smaller gallstones (0.5 to 1 cm) may be better suited for pharmaceutical intervention but may take up to 24 months to dissolve.² Ursodiol is preferred over chenodiol due to its safer adverse effect profile. Use-limiting adverse effects of chenodiol include dose-dependent diarrhea, hypercholesterolemia, hepatotoxicity, and leukopenia.² Recurrence rate is more than 50% and fewer than 10% of patients with symptomatic gallstones are candidates for this treatment.¹³

Table 2. Oral Bile Acids^2,23,24

* If diarrhea occurs, reduce dose and restart at previous dose when symptoms resolve.

Extracorporeal shock wave lithotripsy is a noninvasive option for symptomatic patients.¹³ Complications such as biliary pancreatitis and liver hematoma are rare, however stone recurrence is common. Recent studies show this procedure is beneficial for large pancreatic and common bile duct stones with similar pain relief and duct clearance outcomes compared to surgery.¹³

The initial approach for pregnant women with symptomatic gallstones is supportive care.¹³ Meperidine is the choice agent for pain control as NSAIDs are not recommended in pregnancy.¹³ Chenodiol is contraindicated in pregnancy.²⁴ Ursodiol has been used in pregnant patients for intrahepatic cholestasis; safety and efficacy of use for gallstones has not been studied.^13,23 Laparoscopic cholecystectomy, when indicated, is safe in all trimesters.¹³

POST-OPERATIVE CONSIDERATIONS AND THE PHARMACY TEAM

Post-Cholecystectomy Syndrome

Persistent or delayed onset abdominal pain after laparoscopic cholecystectomy may indicate post-cholecystectomy syndrome (PCS).²² Additional PCS symptoms include fatty food intolerance, nausea, vomiting, diarrhea, heartburn, indigestion, flatulence, and jaundice. PCS often occurs in the post-operative period but can present months or years after surgery.²² Cholecystectomy carries a low mortality risk, but approximately 10% of patients undergoing cholecystectomy each year develop PCS.²² The risk increases with urgent surgeries and 20% of patients will develop PCS regardless of choledochotomy (surgical incision of common bile duct).²²

PCS etiologies can be extra-biliary (pancreatitis, pancreatic tumors, hepatitis, esophageal diseases, mesenteric ischemia, diverticulitis, peptic ulcer disease) or biliary (bile salt induced diarrhea, retained calculi, bile leak, biliary strictures, stenosis, sphincter dyskinesia) in nature.²² Pathophysiology is related to alterations in bile flow and bile is the main trigger for patients with gastroduodenal symptoms or diarrhea.

The likelihood of diarrhea post-cholecystectomy ranges from 2% to 50% according to various studies.²⁵ Diarrhea usually improves or resolves over the course of weeks to months. As discussed, in the gallbladder’s absence, bile flows straight from the liver into the small intestine continuously. This redirection of bile flow can overwhelm the ileum’s capacity for reabsorption, leading to increased bile acids in the colon and subsequently cholerheic diarrhea (also known as bile acid diarrhea).²⁵ Patients may respond to treatment with bile acid sequestrants, including cholestyramine and colestipol.²⁵

Bile acid sequestrants release chloride and bind bile acid in the intestines, preventing bile acid reabsorption. The drugs do not leave the gastrointestinal tract and are eliminated in the feces. They are indicated for hypercholesterolemia but patients use them off-label for chronic diarrhea due to malabsorption (Table 3). The most common adverse effect of bile acid sequestrants is constipation, which occurs in more than 10% of patients.^26,27 Clinicians should instruct patients to drink plenty of fluid and increase dietary fiber. Most adverse effects are gastrointestinal-related (e.g., abdominal pain, flatulence, bloating, anorexia, nausea, vomiting, dysphagia), and others include^26,27

• Cholestasis and cholecystitis (with colestipol only)
• Dental bleeding and caries
• Diuresis, dysuria, and burnt odor to urine
• Edema
• Worsened hemorrhoids

Bile acid sequestrants bind vitamin K and folate so prescribers should monitor for deficiencies of both. Patients should supplement with folate. Patients may supplement with vitamin K; however preexisting coagulopathy is a contraindication. These drugs should be used with caution in patients with renal insufficiency.^26,27

Table 3. Bile Acid Sequestrants^26,27

^*May cause tooth discoloration or enamel decay. GI, gastrointestinal.

PCS is a temporary diagnosis until further investigation establishes organic or functional diagnosis.²² Misdiagnosis of preexisting conditions is possible. The healthcare team should order a complete blood count and consider patients re-presenting with ongoing or new-onset abdominal pain post-cholecystectomy for CT scan.⁸ Presence of gas and fluid in the gallbladder bed may be normal but fluid or gas build-up elsewhere may indicate a bile leak. Elevated liver function tests may also suggest a bile leak or retained common bile duct stone. The most common cause of PCS is the presence of stones in the biliary tree.¹⁰ ERCP, both diagnostic and therapeutic, is the most common procedural approach to PCS.²²

Medication: Treatment Goals

Pharmacologic treatment goals in GBD are to prevent complications and reduce morbidity.²² Administration of bulking agents like psyllium fiber can help patients with symptoms of irritable bowel syndrome (IBS) and/or diarrhea. Psyllium husk (Metamucil, Benefiber) is an over-the-counter (OTC) option for patients looking to increase fiber intake. It is usually used to treat constipation and works by stimulating intestinal contractility, speeding up the movement of stool through the colon.²⁸ Psyllium can also treat diarrhea by soaking up excess water from the intestines, bulking stool, and promoting regularity.²⁸ Psyllium may reduce absorption and effectiveness of many medications; it is important that patients seek pharmacist counseling before initiating a psyllium fiber regimen.

Antispasmodics (e.g., loperamide) may help patients with IBS symptoms like cramping. Cholestyramine may help symptoms of diarrhea alone. Antacids (Maalox, Mylanta, Tums), H2RAs (e.g., famotidine), and PPIs (e.g., esomeprazole, lansoprazole, omeprazole) can improve gastritis or gastric reflux symptoms by reducing acid production.²² One study showed a correlation between dyspeptic symptoms and gastric bile salt; these patients may benefit from bile acid sequestrants.²² Patients should consult their gastroenterologist for recommended dosing of these drugs, as they may vary depending on clinical presentation and severity of symptoms.

The Pharmacy Team’s Role

Pharmacists and pharmacy technicians are integral members of the healthcare team. Pharmacists can educate patients about GBDs, the risk factors for their development, and how to mitigate them with a proper diet and exercise.

Pharmacy technicians can help by directing patients in the right direction when looking for OTC antacids, fiber supplements, or anti-diarrheal agents. Many patients may not ask questions about OTC products before purchase. Pharmacy technicians are often the patients’ first point of contact in the pharmacy and should ask open-ended questions at the register before or during the transaction.

Patients should use the products as directed by their gastroenterologists. Pharmacy technicians should refer patient questions relating to administration, dosing, adverse effects, and drug interactions to the pharmacist on duty. Consider possible scenarios that may arise in the pharmacy and how pharmacy technicians and pharmacists should approach them:

• Mark is a pharmacy technician at XYZ Pharmacy. Jaclyn enters the pharmacy, approaches the pick-up window, and places several OTC items on the counter. She states she would like to pick up a prescription her doctor called in today. Mark retrieves Jaclyn’s prescription and notices it is for omeprazole 40mg. The items on the counter include Tums, famotidine 20mg, docusate sodium 100mg, and lansoprazole 30mg. Mark knows that omeprazole and lansoprazole are in the same drug class. What questions can Mark ask Jaclyn? Should Mark involve the pharmacist?
• Jaclyn comes back to the pharmacy a week later to pick up a prescription for cholestyramine. She wants to know if she can take this with omeprazole and famotidine. Mark refers Jaclyn’s question to the pharmacist. How should the pharmacist respond to Jaclyn’s question and what counseling points are important to include?

CONCLUSION

Gallbladder diseases typically occur secondary to cholelithiasis. Most gallstone cases are asymptomatic, but some develop into symptomatic disease. Factors that may increase GBD risk include gender, age, family history, ethnicity, diet, and medical conditions. Surgical gallbladder removal is the most common treatment, but many nonsurgical alternatives exist when surgery is nonpreferred or contraindicated. Additionally, PCS can occur months to years after surgery and treatment should be directed based on specific diagnosis post-examination. Healthcare providers should collaborate to develop the best procedural and/or pharmaceutical treatment plan as each patient’s clinical presentation and symptoms will vary.

The pharmacy team should take an active role in GBD management, especially following cholecystectomy. Pharmacy technicians should be wary when patients complain of abdominal pain or attempt to purchase multiple OTC products to treat their symptoms; they should relay specific disease- and drug-related questions to the pharmacist on duty. GBD is a common and highly manageable condition, and patients can live normal and healthy lives once symptoms are properly controlled and treated.

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