Reframing Monotherapy and Combination Strategies for Hyperlipidemia

With evolving lipid guidelines and growing therapeutic options, clinicians face increasingly complex decisions in tailoring treatment for hyperlipidemia. A systematic review and network meta-analysis by Zhang et al., published in the European Journal of Medical Research, provides a timely comparison of 21 monotherapy and combination regimens involving statins, ezetimibe, and fibrates for lipid modification in adults with dyslipidemia.

The analysis included 41 randomized controlled trials comprising 18,586 patients, comparing changes in lipid parameters from baseline across various treatments. The primary outcomes were percent change in low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Secondary outcomes included adverse events and withdrawals.

Interventions ranged from low-, moderate-, and high-intensity statins to combination therapies (e.g., statin + ezetimibe, statin + fibrate) and monotherapy with ezetimibe or fibrates.

The findings show that statins remain central, but combinations matter:

• LDL-C lowering:
• Rosuvastatin + ezetimibe ranked highest in reducing LDL-C (mean reduction of −61.7%), followed closely by high-dose rosuvastatin (−58.6%) and atorvastatin + ezetimibe (−57.4%).
• Non-statin monotherapies (fibrate or ezetimibe alone) were substantially less effective.
• HDL-C increase:
• Fenofibrate + atorvastatin was most effective (+14.7%), followed by fenofibrate monotherapy (+13.8%).
• Statins alone had more modest HDL-C effects (e.g., atorvastatin: +7.9%).
• Triglyceride reduction:
• Fenofibrate + atorvastatin led again (−51.2%), highlighting fibrates’ TG-lowering potency.
• Statin monotherapies reduced TGs to a lesser extent, though still clinically relevant.

Across lipid parameters, combination therapies with ezetimibe or fibrates generally outperformed monotherapy—even high-dose statins—in patients requiring multidimensional lipid control.

The incidence of adverse events did not differ significantly across regimens, with no major safety signals identified for combination therapy. However:

• Fibrates were associated with slightly higher withdrawal rates.
• Statin + fibrate combinations did not significantly increase adverse events but warrant cautious use in those at risk for myopathy or renal impairment.

Matching Mechanism to Lipid Profile

The findings reaffirm the dominant LDL-C-lowering role of statins, particularly in high-intensity regimens. Yet they also highlight the limitations of statin monotherapy in patients with combined dyslipidemia—particularly elevated triglycerides or low HDL-C.

Combination regimens with ezetimibe or fibrates appear appropriate for patients with:

• Inadequate LDL-C response despite high-dose statins
• Mixed dyslipidemia (e.g., diabetic or metabolic syndrome profiles)
• Statin intolerance limiting maximal monotherapy dosing

Given the heterogeneous patient population in the included trials, the findings are most applicable to general primary and secondary prevention populations, rather than those with familial hypercholesterolemia or established cardiovascular disease.

While statins remain foundational in lipid management, combination therapy with ezetimibe or fibrates offers additive efficacy, particularly in patients with multidimensional lipid abnormalities. This network meta-analysis supports a tailored, mechanism-matching approach to therapy selection, especially when LDL-C, HDL-C, and triglycerides all require attention.

Study Limitations and Research Needs

Heterogeneity in trial durations and patient populations limits the precision of comparisons across interventions. Additionally, the analysis did not assess long-term clinical outcomes such as cardiovascular events, which are critical for evaluating therapeutic impact. Notably, few trials included newer lipid-lowering agents like bempedoic acid or PCSK9 inhibitors, limiting the relevance of findings to the full spectrum of contemporary treatment options.

Reference
Zhang S, Sun T, Song L, Jin X, Li B. Efficacy and safety of statins, ezetimibe, and fibrates monotherapy or combination therapy for hyperlipidemia: a systematic review and network meta-analysis. Eur J Med Res. 2025;30(1):509. doi:10.1186/s40001-025-02805-y