Dyslipidemia & Hypertriglyceridemia Pharmacotherapy

Current Risk Assessment

The 2026 American College of Cardiology/American Heart Association (ACC/AHA) multisociety dyslipidemia guideline replaces the older pooled cohort equations with PREVENT-ASCVD for primary-prevention risk assessment in adults aged 30–79 years. PREVENT-ASCVD 10-year risk is categorized as low (<3%), borderline (3% to <5%), intermediate (5% to <10%), or high (≥10%). Lipid-lowering therapy is recommended at intermediate and high risk, is reasonable at borderline risk after clinician–patient discussion, and may also be considered at low 10-year risk when LDL-C is 160–189 mg/dL or, for adults aged 30–59 years, 30-year ASCVD risk is ≥10%. Adults aged 40–75 years with diabetes, stage 3 or 4 chronic kidney disease (CKD), or human immunodeficiency virus (HIV) are recommended lipid-lowering therapy regardless of LDL-C level (American Heart Association, 2026b; Marrs & Kostoff, 2026).

Measure lipoprotein(a) [Lp(a)] at least once in adulthood. An Lp(a) ≥125 nmol/L (50 mg/dL) is a risk-enhancing factor and should prompt more intensive management of LDL-C and other modifiable risk factors. Selective apolipoprotein B (ApoB) testing and coronary artery calcium (CAC) scoring can further refine risk when treatment intensity remains uncertain (American Heart Association, 2026b).

Absolute LDL-C Goals Are Back

Risk group	Typical LDL-C goal
Borderline primary prevention (PREVENT 3% to <5%)	<100 mg/dL when lipid-lowering therapy is chosen
Intermediate primary prevention (PREVENT 5% to <10%)	<100 mg/dL
High-risk primary prevention (PREVENT ≥10%)	<70 mg/dL
Clinical ASCVD, not very high risk	<70 mg/dL
Very-high-risk secondary prevention	<55 mg/dL

Percentage LDL-C reduction still matters, but the 2026 guideline reintroduces absolute LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) treatment goals, with lower targets at higher ASCVD risk (American Heart Association, 2026b).

Therapeutic Lifestyle Counseling Remains Foundational

Drug therapy does not replace lifestyle treatment. Emphasize a dietary pattern that replaces saturated fats with unsaturated fats, increases soluble fiber and plant-forward foods, supports healthy weight, and limits highly refined carbohydrates. Regular physical activity, tobacco cessation, and attention to sleep and metabolic health reinforce ASCVD risk reduction. Alcohol deserves particular attention when triglycerides are elevated because it can substantially worsen hypertriglyceridemia (Marrs & Kostoff, 2026).

Secondary Prevention: Established ASCVD

Clinical ASCVD includes prior myocardial infarction (MI) or acute coronary syndrome (ACS), atherosclerotic angina, arterial revascularization, ischemic stroke or transient ischemic attack (TIA) of atherosclerotic origin, and peripheral artery disease (PAD). These patients generally require high-intensity or maximally tolerated statin therapy and additional LDL-C-lowering therapy when the achieved response remains above the risk-appropriate goal (Marrs & Kostoff, 2026; American Heart Association, 2026b).

Severe Primary Hypercholesterolemia

Untreated LDL-C ≥190 mg/dL generally warrants intensive lipid-lowering therapy without requiring a risk calculator to justify treatment. Severe elevation should also raise concern for familial hypercholesterolemia, particularly with premature ASCVD or a strong family history. Evaluate secondary causes such as hypothyroidism and nephrotic disease (Marrs & Kostoff, 2026).

Familial Hypercholesterolemia and Pediatric Considerations

Marked LDL elevation, tendon xanthomas, premature ASCVD, or a strong family history should raise concern for familial hypercholesterolemia and prompt family/cascade evaluation. Children and adolescents require pediatric lipid thresholds, risk assessment, and dosing rather than direct application of adult PREVENT-ASCVD treatment algorithms. Early identification matters because lifelong LDL exposure drives risk; pediatric pharmacotherapy should follow pediatric or familial-hypercholesterolemia-specific guidance when lifestyle treatment alone is insufficient (Marrs & Kostoff, 2026).

Statins Remain Foundational Therapy

Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, reduce hepatic cholesterol synthesis, and increase hepatic LDL-receptor activity. They remain first-line therapy for most primary- and secondary-prevention patients in whom pharmacotherapy is indicated (Marrs & Kostoff, 2026).

Intensity	Expected LDL-C reduction	Examples
High	≥50%	Atorvastatin 40–80 mg; rosuvastatin 20–40 mg
Moderate	30–49%	Atorvastatin 10–20 mg; rosuvastatin 5–10 mg; simvastatin 20–40 mg; pravastatin 40–80 mg; pitavastatin 1–4 mg

Assess the Response, Not Just the Prescription

Repeat the lipid panel approximately 4–12 weeks after initiating or changing therapy. Assess the percentage LDL-C reduction, absolute goal, adherence, tolerability, and whether the achieved response matches the patient’s risk. A high-intensity statin producing very little LDL-C reduction should prompt reassessment before being labeled adequate therapy (Marrs & Kostoff, 2026).

Statin-Associated Muscle Symptoms

Routine creatine kinase (CK) monitoring is not required in asymptomatic patients. Measure CK when significant muscle pain, weakness, tenderness, or dark urine occurs, and evaluate other contributors such as hypothyroidism, exercise, musculoskeletal disease, and drug interactions. Do not diagnose statin intolerance after one unsuccessful trial; lower dose, different statin, or alternate dosing can preserve some statin exposure in appropriate patients (Marrs & Kostoff, 2026).

Statin Liver Monitoring

Obtain hepatic transaminases before starting statin therapy and repeat testing when symptoms or the clinical context suggests hepatotoxicity. Routine serial liver testing is not required in an asymptomatic patient. New unexplained fatigue, anorexia, right-upper-quadrant discomfort, dark urine, or jaundice should prompt reassessment (Marrs & Kostoff, 2026).

Statin Interaction Patterns

Drug interactions can substantially increase statin exposure and myopathy risk. Lovastatin and simvastatin have particularly important interaction potential; risk also rises with gemfibrozil, cyclosporine, azole antifungals, macrolide antibiotics, protease inhibitors, verapamil, amiodarone, and large amounts of grapefruit juice. Review the specific statin and interacting drug before prescribing rather than treating statins as pharmacokinetically interchangeable (Marrs & Kostoff, 2026).

When a Statin Is Not Enough

Nonstatin choices include ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies, inclisiran, and bempedoic acid. Selection depends on the degree of additional LDL-C lowering required, ASCVD risk, statin tolerance, outcome evidence, cost, administration route, adherence, and interactions (Marrs & Kostoff, 2026).

Ezetimibe

Ezetimibe inhibits intestinal Niemann-Pick C1-like 1 (NPC1L1) and lowers LDL-C by about 18% on average. It is a common first oral add-on because it is well tolerated and complements statin therapy (Marrs & Kostoff, 2026).

PCSK9-Targeting Therapy

Alirocumab and evolocumab preserve hepatic LDL receptors and produce large additional LDL-C reductions with cardiovascular outcome benefit. Inclisiran suppresses hepatic PCSK9 synthesis and is dosed initially, again at 3 months, then every 6 months. Inclisiran should replace—not be layered on top of—a PCSK9 monoclonal antibody because combined pathway targeting has no established additional benefit (Marrs & Kostoff, 2026).

Bempedoic Acid

Bempedoic acid inhibits adenosine triphosphate (ATP) citrate lyase upstream of HMG-CoA reductase and can provide additional LDL-C lowering, particularly when statin exposure is limited. Current U.S. labeling includes reduction of major adverse cardiovascular events in adults at increased risk who are unable to take recommended statin therapy. Hyperuricemia and gout remain important adverse effects, and tendon rupture is a labeled warning; discontinue the drug if tendon rupture occurs and use extra caution in patients with tendon risk factors (Marrs & Kostoff, 2026; U.S. Food and Drug Administration, 2025).

Bile Acid Sequestrants

Bile acid sequestrants lower LDL-C without systemic absorption but can worsen triglycerides, create gastrointestinal burden, and interfere with absorption of other medications. Avoid them when triglycerides are ≥300 mg/dL (Marrs & Kostoff, 2026).

Hypertriglyceridemia Requires a Different Framework

For triglycerides (TG) below about 500 mg/dL, management usually emphasizes secondary causes, lifestyle, ASCVD risk, and statin therapy when indicated. Pancreatitis risk becomes increasingly important as TG become severe and is especially prominent at ≥1000 mg/dL, where triglyceride-lowering therapy and dietary intervention become urgent priorities (American Heart Association, 2026b; Marrs & Kostoff, 2026; Oh et al., 2020).

Look for Secondary Causes First

• Poorly controlled diabetes and insulin resistance
• Obesity
• High alcohol intake
• High refined-carbohydrate intake
• Hypothyroidism
• CKD or nephrotic disease
• Pregnancy
• Medications such as selected estrogens, glucocorticoids, retinoids, antipsychotics, beta blockers, thiazides, and immunosuppressants

Fibrates

Fenofibrate and gemfibrozil can substantially lower TG and are most useful when severe hypertriglyceridemia requires pharmacologic treatment. Fenofibrate is generally preferred if a fibrate must be combined with a statin because gemfibrozil carries greater myopathy and rhabdomyolysis risk. Kidney function influences fibrate selection and dosing (Marrs & Kostoff, 2026; Oh et al., 2020).

Icosapent Ethyl Is Not Generic Fish Oil

Icosapent ethyl is purified eicosapentaenoic acid (EPA) and can reduce cardiovascular events in selected statin-treated patients with persistent triglyceride elevation. Over-the-counter fish-oil supplements contain variable EPA/docosahexaenoic acid (DHA) concentrations and are not therapeutically interchangeable with prescription icosapent ethyl. Counsel about increased atrial fibrillation/flutter requiring hospitalization and increased bleeding risk, particularly when antiplatelet or anticoagulant therapy is also used (Marrs & Kostoff, 2026; Oh et al., 2020; U.S. Food and Drug Administration, 2026).

Niacin Has a Limited Contemporary Role

Niacin can lower triglycerides and raise high-density lipoprotein cholesterol (HDL-C), but favorable changes in the lipid panel have not translated into enough additional cardiovascular benefit to justify routine addition to effective statin-based therapy. Flushing, hyperglycemia, hyperuricemia, hepatotoxicity, and gastrointestinal effects further limit use. It should not be selected simply to raise HDL-C or cosmetically improve several lipid values (Marrs & Kostoff, 2026).

Pregnancy, Conception, and Lactation

For most patients planning pregnancy who are not at high ASCVD risk, statins should be stopped 1–2 months before conception or when pregnancy is recognized and withheld during pregnancy and lactation. In patients with familial hypercholesterolemia or clinical ASCVD, continuing statin therapy during pregnancy may be reasonable after individualized risk-benefit discussion; hydrophilic statins such as pravastatin have the most pregnancy trial experience. Bile acid sequestrants are a pregnancy-compatible LDL-lowering option but should be avoided when TG are ≥300 mg/dL because they can worsen hypertriglyceridemia (American Heart Association, 2026a).

Most lipid-lowering drugs—including statins, ezetimibe, PCSK9 inhibitors, and fibrates—are generally avoided during lactation, with bile acid sequestrants as a potential option. During pregnancy, severe hypertriglyceridemia (TG ≥500 mg/dL) may require specialist-directed triglyceride lowering; fibrates can be considered after the first trimester or high-dose prescription omega-3 ethyl esters may be used to reduce pancreatitis risk (American Heart Association, 2026a).

Do Not Treat Low HDL-C as an Isolated Drug Target

Low HDL-C is associated with cardiovascular risk, but pharmacologically increasing HDL-C has not reliably improved outcomes. Management should instead address LDL-C and non-HDL-C burden, smoking, exercise, weight, glycemic control, blood pressure, and overall atherosclerotic cardiovascular disease risk (Marrs & Kostoff, 2026).

High-Yield Distinctions

• Use PREVENT-ASCVD rather than the older pooled cohort equation for contemporary primary-prevention risk assessment.
• The 2026 guideline restores absolute LDL-C goals in addition to percentage reduction.
• High-intensity statins lower LDL-C by ≥50%; moderate-intensity therapy lowers LDL-C by about 30–49%.
• Repeat lipids about 4–12 weeks after initiating or changing therapy.
• Muscle symptoms after one statin do not automatically establish statin intolerance.
• PCSK9 monoclonal antibodies have outcome data; inclisiran is useful when infrequent dosing improves feasibility but should replace rather than combine with a PCSK9 monoclonal antibody.
• TG <500 mg/dL usually calls for ASCVD-risk reduction rather than reflexive fibrate therapy.
• Pancreatitis prevention becomes especially important when TG are ≥1000 mg/dL.
• Fenofibrate is preferred over gemfibrozil if a fibrate must be combined with a statin.
• Pregnancy and lactation require a different lipid-treatment framework; bile acid sequestrants are one of the few pregnancy-compatible options.
• Obtain baseline liver testing before statin therapy; routine serial testing is unnecessary without symptoms or another clinical indication.
• Bempedoic acid has cardiovascular outcome benefit in statin-intolerant/high-risk adults but carries hyperuricemia/gout and tendon-rupture warnings.
• Icosapent ethyl can increase atrial fibrillation/flutter hospitalization and bleeding risk, especially with concomitant antithrombotic therapy.

Related YourDNP Resources

• Atherosclerosis
• Coronary Artery Disease and Acute Coronary Syndromes
• Chronic Kidney Disease

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References

American Heart Association. (2026a). Top take-home messages for women’s health clinicians. https://professional.heart.org/en/-/media/PHD-Files-2/Science-News/t/Top-Take-Home-Messages-Womens-Clinicians-GL-Dyslipidemia.pdf

American Heart Association. (2026b, March 13). Top things to know: Guideline on the management of dyslipidemia. https://professional.heart.org/en/science-news/2026-guideline-on-the-management-of-dyslipidemia/top-things-to-know

Marrs, J. C., & Kostoff, M. D. (2026). Dyslipidemia. In M. A. Chisholm-Burns, P. M. Malone, J. M. Kolesar, K. C. Lee, P. B. Bookstaver, & K. R. Matthias (Eds.), Pharmacotherapy principles & practice (7th ed., pp. 478–524). McGraw Hill.

Oh, R. C., Trivette, E. T., & Westerfield, K. L. (2020). Management of hypertriglyceridemia: Common questions and answers. American Family Physician, 102(6), 347–354.

U.S. Food and Drug Administration. (2025). Nexletol (bempedoic acid) prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/211616s024lbl.pdf

U.S. Food and Drug Administration. (2026). Vascepa (icosapent ethyl) prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/202057oRIG1s058lbl.pdf