The Effects of Fenofibric Acid Alone and With Statins on the Prevalence of Metabolic Syndrome and Its Diagnostic Components in Patients With Mixed Dyslipidemia

Three similarly designed, phase III, randomized, double-blind, 12-week studies evaluated the efficacy and safety of FA in combination with either rosuvastatin (3), simvastatin (4), or atorvastatin (2). After a 6-week lipid-altering drug washout period, all studies enrolled patients with mixed dyslipidemia (HDL cholesterol <40 mg/dl [<1.04 mmol/l] for men, <50 mg/dl [<1.30 mmol/l] for women; triglycerides [TGs] ≥150 mg/dl [≥1.70 mmol/l]; and LDL cholesterol ≥130 mg/dl [≥3.37 mmol/l]). Patients were assigned in a 2:2:2:2:2:1 ratio to 1 of 6 treatment arms: FA 135 mg monotherapy; low-dose statin monotherapy; FA 135 mg + low-dose statin; moderate-dose statin monotherapy; FA 135 mg + moderate-dose statin; or high-dose statin monotherapy. Each study used a different statin, and the respective doses of low-, moderate-, or high-dose statin were rosuvastatin 10, 20, or 40 mg, or simvastatin or atorvastatin 20, 40, or 80 mg. Data were pooled across the 3 studies. For further details regarding patients and study design, see the article by Jones et al. (5).

Assessments included the number and percent of patients with metabolic syndrome (6) at the final visit for each treatment group, as well as the number and percent of patients having individual metabolic syndrome diagnostic criteria at the baseline visit and at the final visit. In order to be included in these analyses, patients were required to have a final visit value for each metabolic syndrome diagnostic criteria. Waist circumference was not measured at final visit; baseline values were carried forward.

Mean changes from baseline to final value in weight, blood pressure, and fasting glucose were analyzed using a one-way ANOVA, comparing combination therapy with corresponding-dose monotherapies. Percent changes in efficacy parameters were compared between combination therapy and corresponding-dose monotherapies as previously described (2,–4).

Baseline data for all five metabolic syndrome criteria were available for 2,654 treated patients, and 2,190 (82.5%) patients had metabolic syndrome at baseline. The percent of patients with metabolic syndrome at baseline was generally similar within each of the 6 treatment groups and ranged from 79.9% (low-dose statin) to 85.8% (high-dose statin). Across all treatment groups, 569 (26%) had a diagnosis of type 2 diabetes (supplemental appendix A, available in the online appendix at http://care.diabetesjournals.org/cgi/content/full/dc10-0357/DC1), and 461 (21.1%) received treatment with at least 1 antidiabetes drug.

Of the 2,190 patients in the metabolic syndrome subgroup, 2,003 patients had a final visit value for all metabolic syndrome criteria (with the exception of waist circumference since baseline values were carried forward). Following 12 weeks of therapy in the 3 trials, FA + low- or moderate-dose statin reduced the number of patients meeting the diagnostic criteria for metabolic syndrome by 35.7 and 35.9%, respectively, compared with monotherapy with low-, moderate-, or high-dose statin (15.5, 16.6, and 13.8%, respectively). FA alone reduced metabolic syndrome diagnosis by 25.7%.

The percent of patients at baseline who met each individual metabolic syndrome criterion was comparable among all treatment groups (Table 1). At the final visit, FA + statin substantially reduced the prevalence of the metabolic syndrome diagnostic criteria regarding HDL cholesterol and TG compared with statin monotherapy. The prevalence of the blood pressure metabolic syndrome criteria decreased slightly at the final visit in each treatment group. At the final visit, the prevalence of the fasting blood glucose criterion was decreased slightly following treatment with FA monotherapy or FA + statin but increased slightly in the statin monotherapy groups.

Regarding metabolic syndrome-associated lipid parameters, FA + low- or moderate-dose statin significantly decreased TG compared with FA or corresponding-dose statin monotherapy (P < 0.001) and significantly increased HDL cholesterol (P < 0.001) compared with corresponding-dose statin (Table 1). FA + low- or moderate-dose statin also resulted in similar or greater reductions in non-HDL cholesterol, apolipoprotein B, total cholesterol, VLDL cholesterol, or high-sensitivity C-reactive protein compared with corresponding-dose statin (supplemental appendix B).

The mean changes in glucose were slightly increased in all statin monotherapy groups but were slightly decreased in the FA monotherapy group and essentially unchanged in the FA + statin groups. Mean increases in glucose with statin monotherapy ranged from 2.26 mg/dl (0.13 mmol/l) in the simvastatin 20 mg group to 7.46 mg/dl (0.41 mmol/l) in the atorvastatin 20 mg group. The mean change in fasting glucose was significantly different comparing FA + low- or moderate-dose statin with low- or moderate-dose statin monotherapy, respectively (P ≤ 0.002). Overall, 54 (2.5%) of 2,190 patients in the metabolic syndrome subgroup initiated new antidiabetes medication during the study; percentages were similar among treatment groups. Mean changes in body weight ranged from −0.3 kg in the FA monotherapy group to +0.3 kg in the FA + moderate-dose statin group. Safety results in this metabolic syndrome subgroup were consistent with those observed in the overall population (7) (supplemental appendix C).

This analysis is the first to report the effects of fibrate and statin combinations versus their respective monotherapies on the individual diagnostic components of metabolic syndrome. According to this subgroup analysis, the greatest reduction in the presence of metabolic syndrome occurred with the FA + statin combination, primarily because of the improvements in the TG and HDL cholesterol diagnostic components. Although waist circumference was not measured at the end of the study, the lack of significant weight change in this study made it unlikely that changes in the waist circumference component altered the presence of metabolic syndrome.

Mean glucose levels rose with statins, but this effect was not statin-specific nor did it appear to be dose-related. The combination of FA with statins resulted in essentially no change in fasting blood glucose, similar to a recent report in type 2 diabetic patients (8), suggesting the possibility that FA may have mitigated the glucose-raising effect of statins. In summary, in this analysis of patients with mixed dyslipidemia and metabolic syndrome, FA combined with statins produced greater improvement in multiple metabolic parameters and in the percent of patients meeting diagnostic criteria for metabolic syndrome compared with either agent alone.

Abbott sponsored the studies. H.E.B. has received research grants and consultant and speaker's fees from Abbott as well as other pharmaceutical companies. E.M.R. has been a consultant to Abbott as well as a principal investigator on numerous clinical trials, has received research support from all major pharmaceutical companies (including Abbott), and is on the speakers bureau of AstraZeneca, Merck, Merck-Schering-Plough, and Schering-Plough. J.M.M. has provided consulting services (gratis) for Aegerion and GlaxoSmithKline. M.T.K., K.M.T., C.M.S., K.O., and D.J.S. are Abbott employees and stockholders. No other potential conflicts of interest relevant to this article were reported.

H.E.B. researched the data, contributed to the discussion, and wrote, reviewed, and edited the manuscript. E.M.R. researched the data, contributed to the discussion, and reviewed and edited the manuscript. J.M.M. contributed to the discussion and reviewed and edited the manuscript. M.T.K. researched the data, contributed to the discussion, and reviewed and edited the manuscript. K.M.T. researched the data, contributed to the discussion, and reviewed and edited the manuscript. C.M.S. researched the data, contributed to the discussion, and reviewed and edited the manuscript. K.O. researched the data, contributed to the discussion, and reviewed and edited the manuscript. D.J.S. researched the data, contributed to the discussion, and reviewed and edited the manuscript.

Related data were presented in abstract form at the 7th International Symposium on Multiple Risk Factors in Cardiovascular Diseases (Lorenzini Foundation), Venice, Italy, 22–25 October 2008.

The authors thank Erin Blondell, PhD, of Abbott for providing assistance with the writing and preparation of the manuscript.