Systematic review: comparative effectiveness and harms of combination therapy and monotherapy for dyslipidemia

Ann Intern Med. 2009 Nov 3;151(9):622-30. doi: 10.7326/0003-4819-151-9-200911030-00144.


Background: Statin therapy effectively prevents vascular disease, but treatment targets are often not achieved.

Purpose: To compare the benefits and harms of high-dose statin monotherapy with those of combination therapy in adults at high risk for coronary disease.

Data sources: English-language records from MEDLINE (1966 to 2009), EMBASE (1980 to 2009), and the Cochrane Library (third quarter of 2008).

Study selection: A reviewer screened records, and a second reviewer verified selection of randomized, controlled trials in adult patients that compared combinations of statins and bile-acid sequestrants, fibrates, ezetimibe, niacin, or omega-3 fatty acids with statin monotherapy, as well as nonrandomized comparative studies that were longer than 24 weeks and reported clinical and harms outcomes.

Data extraction: Data were abstracted for studies by using standardized forms, and study quality was rated with a standardized scale and strength of evidence by using the Grading of Recommendations Assessment, Development, and Evaluation approach.

Data synthesis: 102 studies met eligibility criteria. The main analysis compared combination therapy with high-dose statin monotherapy in high-risk patients. Very-low-strength evidence showed that statin-ezetimibe (2 trials; n = 439) and statin-fibrate (1 trial; n = 166) combinations did not reduce mortality more than high-dose statin monotherapy. No trials compared the effect of combination therapy versus high-dose statin monotherapy on the incidence of myocardial infarction, stroke, or revascularization procedures. Two statin-ezetimibe trials (n = 295) demonstrated higher low-density lipoprotein cholesterol goal attainment with combination therapy (odds ratio, 7.21 [95% CI, 4.30 to 12.08]). Trials in lower-risk patients did not show a difference in mortality.

Limitations: Studies were generally short, focused on surrogate outcomes, and were heterogeneous in the sample's risk for coronary disease. Few studies examined treatment combinations other than statin-ezetimibe.

Conclusion: Limited evidence suggests that combinations of lipid-lowering agents do not improve clinical outcomes more than high-dose statin monotherapy. Very-low-quality evidence favors statin-ezetimibe treatment for attainment of low-density lipoprotein cholesterol goals.

Primary funding source: Agency for Healthcare Research and Quality.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review
  • Systematic Review

MeSH terms

  • Anticholesteremic Agents / administration & dosage*
  • Anticholesteremic Agents / adverse effects*
  • Cardiovascular Diseases / prevention & control
  • Cholesterol, HDL / blood
  • Cholesterol, LDL / blood
  • Drug Therapy, Combination
  • Dyslipidemias / blood
  • Dyslipidemias / drug therapy*
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / adverse effects*
  • Medication Adherence
  • Mortality
  • Risk Factors


  • Anticholesteremic Agents
  • Cholesterol, HDL
  • Cholesterol, LDL
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors