Effectiveness of Combination Therapy With Statin and Another Lipid-Modifying Agent Compared With Intensified Statin Monotherapy: A Systematic Review

Study Questions:

What are the clinical benefits, adherence, and harms of lower-intensity statin combination therapy with those of higher-intensity statin monotherapy among adults at high risk for atherosclerotic cardiovascular disease (ASCVD)?


A review was conducted using data sources MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from inception to July 2013, with an updated MEDLINE search through November 2013. Studies were limited to randomized, controlled trials published in English. Two reviewers extracted information on study design, population characteristics, interventions, and outcomes (deaths, ASCVD events, low-density lipoprotein cholesterol [LDL-C], adherence, and adverse events). Two independent reviewers assessed risk of bias.


A total of 36 trials were included. Low-intensity statin plus bile acid sequestrant decreased LDL-C 0%-14% more than mid-intensity monotherapy among high-risk hyperlipidemic patients. Mid-intensity statin plus ezetimibe decreased LDL-C 5%-15% and 3%-21% more than did high-intensity monotherapy among patients with ASCVD and diabetes mellitus, respectively. Evidence was insufficient to evaluate LDL-C for fibrates, niacin, and ω-3 fatty acids. Evidence was also insufficient for long-term clinical outcomes, adherence, and harms for all regimens.


Clinicians could consider using lower-intensity statin combined with bile acid sequestrant or ezetimibe among high-risk patients intolerant of or unresponsive to statins; however, this strategy should be used with caution given the lack of evidence on long-term clinical benefits and harms.


The review provides data to estimate whether low- or mid-intensity dosing with other hypolipidemic agents could or should be preferred in patients who are intolerant or not on target with statins. But as the authors conclude, the data provide no evidence of the benefit of combination therapy when compared to low- or moderate-dose statins.

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Lipoproteins, LDL, Cholesterol, LDL, Azetidines, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypolipidemic Agents, Cardiovascular Diseases, Niacin, Diabetes Mellitus, MEDLINE

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