Our preferred first-line approach to elevated LDL cholesterol is rosuvastatin, a high-intensity statin option that aligns with guideline-based LDL-C lowering when medication therapy is indicated.¹ Rosuvastatin is hydrophilic (water-soluble) and relatively selective compared with more lipophilic statins, which may limit passive diffusion into extrahepatic tissues, although muscle symptoms can still occur. ^2,3 Rosuvastatin is also among the most potent statins on a milligram-for-milligram basis; in the STELLAR trial, rosuvastatin produced greater LDL-C reductions than atorvastatin, pravastatin, and simvastatin across studied dose ranges.⁴

We recommend statins as our primary strategy not just for cholesterol reduction, but for their cardiovascular risk-reduction benefits. Statin therapy reduces major vascular events and vascular mortality in a wide range of appropriate primary- and secondary-prevention patients.^5,6 Statins also have favorable cholesterol effects that may include reduced vascular inflammation, improved endothelial function, plaque stabilization, and antithrombotic activity.⁵ In high-risk settings, clinical benefit can begin within weeks to months: the MIRACL trial found that intensive statin therapy started 24 to 96 hours after acute coronary syndrome reduced recurrent ischemic events during the first 16 weeks.⁷

We also understand that some patients prefer to avoid statins because of personal preference, prior intolerance, or side effects. Furthermore current ACC/AHA guidance recognizes that patients with established atherosclerotic cardiovascular disease (ASCVD), diabetes, familial hypercholesterolemia, chronic kidney disease, HIV, or multiple risk-enhancing factors may require lower LDL-C goals and combination lipid-lowering therapy when lifestyle measures and statins alone are not enough.¹

For these situations, we are comfortable prescribing several nonstatin or triglyceride-focused medications that may be appropriate depending on the clinical scenario:

• Ezetimibe (Zetia): Ezetimibe selectively inhibits intestinal cholesterol absorption by targeting NPC1L1, reducing absorption of dietary and biliary cholesterol. It is generally well tolerated and lowers LDL-C by about 15%-22% as monotherapy, with additional LDL-C lowering when combined with a statin.⁸
• Fenofibrate: Fenofibrate is mainly used when triglycerides are very high, generally ≥500 mg/dL and especially ≥1000 mg/dL, with the goal of lowering triglycerides enough to reduce pancreatitis risk. It can also improve triglyceride-driven lipid abnormalities in severe hypertriglyceridemia.⁹
• Repatha (evolocumab): Evolocumab is a PCSK9 monoclonal antibody given as a subcutaneous injection every 2 weeks or monthly. In FOURIER, evolocumab lowered LDL-C by 59% at 48 weeks and reduced cardiovascular events when added to background statin therapy. It is particularly useful for patients with familial hypercholesterolemia, established ASCVD requiring additional LDL-C reduction, statin intolerance, or LDL-C above goal despite maximally tolerated therapy.^1,10
• Bempedoic Acid (Nexletol): Bempedoic acid is an oral ATP-citrate lyase inhibitor that works upstream of HMG-CoA reductase in the cholesterol-synthesis pathway. It is activated mainly in the liver because the activating enzyme ACSVL1 is not present in skeletal muscle, making it a useful option for patients with statin-associated muscle symptoms.¹¹ In CLEAR Outcomes, bempedoic acid lowered LDL-C by about 21% relative to placebo and reduced major adverse cardiovascular events in statin-intolerant patients.¹² It is also available as Nexlizet, a fixed-dose combination of bempedoic acid plus ezetimibe that provides greater LDL-C lowering than either agent alone.¹³
• Vascepa (icosapent ethyl): Icosapent ethyl is a prescription, high-purity eicosapentaenoic acid (EPA) ethyl ester that lowers triglycerides. In REDUCE-IT, icosapent ethyl 2 g twice daily reduced cardiovascular events in high-risk, statin-treated patients with elevated triglycerides.¹⁴ It is most relevant for patients with persistent triglyceride elevation despite statin therapy and appropriate lifestyle treatment.^9,14

We tailor lipid treatment based on the patient’s lipid profile, ASCVD risk, diabetes status, triglyceride level, kidney and liver considerations, medication tolerance, cost/access, and personal preferences. The goal is not to prescribe whatever is most familiar; the goal is to choose the evidence-based therapy, or combination of therapies, most likely to reduce that patient’s long-term cardiovascular risk.¹

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References

1. Blumenthal RS, Morris PB, Gaudino M, et al. 2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of dyslipidemia: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2026;153(17):e1154-e1276. doi:10.1161/CIR.0000000000001423
2. Climent E, Benaiges D, Pedro-Botet J. Hydrophilic or lipophilic statins? Front Cardiovasc Med. 2021;8:687585. doi:10.3389/fcvm.2021.687585
3. Mueller AM, Liakoni E, Schneider C, et al. The risk of muscular events among new users of hydrophilic and lipophilic statins: an observational cohort study. J Gen Intern Med. 2021;36(9):2639-2647. doi:10.1007/s11606-021-06651-6
4. Jones PH, Davidson MH, Stein EA, et al; STELLAR Study Group. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial). Am J Cardiol. 2003;92(2):152-160. doi:10.1016/S0002-9149(03)00530-7
5. Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation. 2004;109(23 Suppl 1):III39-III43. doi:10.1161/01.CIR.0000131517.20177.5a
6. Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-1681. doi:10.1016/S0140-6736(10)61350-5
7. Schwartz GG, Olsson AG, Ezekowitz MD, et al; Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL Study: a randomized controlled trial. JAMA. 2001;285(13):1711-1718. doi:10.1001/jama.285.13.1711
8. Phan BAP, Dayspring TD, Toth PP. Ezetimibe therapy: mechanism of action and clinical update. Vasc Health Risk Manag. 2012;8:415-427. doi:10.2147/VHRM.S33664
9. Virani SS, Morris PB, Agarwala A, et al. 2021 ACC Expert Consensus Decision Pathway on the management of ASCVD risk reduction in patients with persistent hypertriglyceridemia: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2021;78(9):960-993. doi:10.1016/j.jacc.2021.06.011
10. Sabatine MS, Giugliano RP, Keech AC, et al; FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722. doi:10.1056/NEJMoa1615664
11. Pinkosky SL, Newton RS, Day EA, et al. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat Commun. 2016;7:13457. doi:10.1038/ncomms13457
12. Nissen SE, Lincoff AM, Brennan D, et al; CLEAR Outcomes Investigators. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. 2023;388(15):1353-1364. doi:10.1056/NEJMoa2215024
13. Ballantyne CM, Laufs U, Ray KK, et al. Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high cardiovascular disease risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol. 2020;27(6):593-603. doi:10.1177/2047487319864671
14. Bhatt DL, Steg PG, Miller M, et al; REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22. doi:10.1056/NEJMoa1812792