Comparison of fluvastatin + fenofibrate combination therapy and fluvastatin monotherapy in the treatment of combined hyperlipidemia, type 2 diabetes mellitus, and coronary heart disease: a 12-month, randomized, double-blind, controlled trial.
BACKGROUND
Diabetes risk is often complicated by a mixed hyperlipoproteinemia not sufficiently controlled by a single antihyperlipidemic drug; however, there are some concerns about the safety of combined statin and fibrate treatments.


OBJECTIVE
The aim of this study was to compare the efficacy and safety profile of fluvastatin + fenofibrate combination therapy and those of fluvastatin monotherapy in the treatment of combined hyperlipidemia, type 2 diabetes mellitus (DM), and coronary heart disease (CHD) (ie, high risk for cardiovascular disease [CVD]).


METHODS
This 12-month, randomized, double-blind, controlled trial was conducted at the University of Pavia, Pavia, Italy. Patients aged 18 to 80 years with combined hyperlipidemia, type 2 DM, and CHD were randomly assigned to receive combination therapy with extended-release fluvastatin 80 mg + micronized fenofibrate 200 mg or monotherapy with extended-release fluvastatin 80 mg. All treatments were given in tablet form, once daily with the evening meal, for 12 months. Lipid variables (low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], total cholesterol [TC], and triglycerides [TG]) at 6 and 12 months were the primary efficacy variables, and glycemic status (glycosylated hemoglobin [HbA(1c)], fasting plasma glucose, and postprandial plasma glucose levels) at 6 and 12 months was the secondary efficacy variable. Tolerability was assessed using physical examination, including vital-sign assessment, body-weight measurement, electrocardiography, adverse events, and laboratory tests. A pharmacoeconomic analysis of both treatment regimens was also carried out using the incremental cost-effectiveness ratio (ICER).


RESULTS
A total of 48 patients (24 men, 24 women; mean [SD] age, 60 [5] years) were enrolled. After 6 months, all primary efficacy variables, except for TG level, showed significant improvements from baseline only in the combination-therapy group (changes: LDL-C, -25%; HDL-C, +12%; and TC, -19%; all, P < 0.05 vs baseline). After 12 months, lipid variables showed significant improvements over baseline in both groups (all, P < 0.05), except for TG in the monotherapy group. Significant changes in LDL-C, HDL-C, and TG were found in the combination-therapy group (-35%, +34%, -32%, respectively) versus the monotherapy group (-25%, +14%, -17%, respectively; all, P < 0.05 between groups). The change from baseline in HbA(1c) level was significant with combination therapy (-12% vs -7%; P < 0.05). Both treatments were well tolerated, with no significant differences in the incidences of adverse events between the 2 groups. The ICER showed that each 1% decrease in LDL-C level achieved with the fenofibrate + fluvastatin combination added a cost of 14.97 Euros/y (US 12.25 US dollars/y), and each 1% increase in HDL-C level added a cost of 7.48 Euros/y (6.12/y US dollars), over the cost of monotherapy.


CONCLUSIONS
In this selected sample of patients with combined hyperlipidemia, type 2 DM, and CHD, the combination of extended-release fluvastatin + micronized fenofibrate was associated with a more improved lipid profile than fluvastatin monotherapy, and was a well-tolerated and cost-effective therapeutic choice to treat these patients at high risk for CVD.
Derosa
Giuseppe
G
Department of Internal Medicine and Therapeutics, University of Pavia, P.le C. Golgi, 2-27100 Pavia, Italy. giuderosa@tin.it
Cicero
Arrigo E G
AE
Bertone
Gianandrea
G
Piccinni
Mario N
MN
Ciccarelli
Leonardina
L
Roggeri
Daniela E
DE
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001786:Blood Glucose / Q000032:analysis; D003327:Coronary Disease / Q000150:complications / Q000188:drug therapy*; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage* / Q000191:economics; D005260:Female; D011345:Fenofibrate / Q000008:administration & dosage* / Q000191:economics; D000077340:Fluvastatin; D006455:Hemoglobins, Abnormal / Q000032:analysis; D006801:Humans; D006949:Hyperlipidemias / Q000150:complications / Q000188:drug therapy*; D000960:Hypolipidemic Agents / Q000008:administration & dosage* / Q000191:economics; D007211:Indoles / Q000008:administration & dosage* / Q000191:economics; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
D001786:Blood Glucose; D003692:Delayed-Action Preparations; D005229:Fatty Acids, Monounsaturated; D006455:Hemoglobins, Abnormal; D000960:Hypolipidemic Agents; D007211:Indoles; D008055:Lipids; C048900:hemoglobin, glycerated; D000077340:Fluvastatin; D011345:Fenofibrate