Fenofibrate/simvastatin fixed-dose combination in the treatment of mixed dyslipidemia: safety, efficacy, and place in therapy

Figures & data

Table 1 Pharmacokinetic profile

Simvastatin
Absorption	61%–85% (not altered by food)
First pass extraction	>95% of administered dose
Bioavailability	<5%
Metabolism	CYP4503A4
Tmax	2.5–4 h
Half-life	2 h
Elimination	Feces (58%); urine (13%)
Protein binding	94%–98%
Drug–drug interaction	Gemfibrozil, Cyclosporine, Warfarin, Digoxin
Fenofibrate
Absorption	Better in fed state for micronized particles (160 mg) Independent for nanoparticles (145 mg)
Bioavailability	60%
Metabolism	Hepatic (glucuronidation)
Tmax	3.5 h
Half-life	19–27 h
Elimination	Feces (25%); urine (60%)
Protein binding	99%
Drug–drug interaction	Cyclosporine, Pravastatin, Simvastatin (?),Warfarin, Erythromycin

Table 2 ACCORD LIPID and EYE TRIAL outcomes^58,60

Endpoint		Simvastatin + fenofibrate (N)	Simvastatin + placebo (N)	Hazard ratio (p-value)
Primary outcomes	Major CV event (nonfatal MI, nonfatal stroke or death from CV cause)	291	310	0.92 (0.32)
Secondary outcomes	Primary outcome plus revascularization or hospitalization for CHD	641	667	0.94 (0.3)
	Major CHD event	332	353	0.92 (0.26)
	Nonfatal MI	173	186	0.91 (0.39)
	Stroke	98	88	1.05 (0.8)
	All-cause mortality	302	335	0.91 (0.33)
	Fatal or nonfatal CHD	120	143	0.82 (0.1)
Other	Progression of diabetic retinopathy	52	80	0.6 (0.006)
	Moderate vision loss	227	233	0.95 (0.57)

Abbreviations: CV, cardiovascular; MI, myocardial infarction; CHD, coronary heart disease

Figure 1 Mean relative reduction of total cholesterol levels by adding fibrates.

Abbreviation: TC, total cholesterol.

Table 3 Mean relative reduction of total cholesterol levels by adding fibrates.

Study	Patients treated with fibrates	Simvastatin dose (mg)	Fibrate dose (mg)	Follow-up duration (months)	Relative TC reduction (%)	Reference
ACCORD	2271*	20**	160§	56	−14	^Citation58
Foucher et al	109	20	145	3	−4	^Citation71
	110	40	145	3	−8
DIACOR	100	20	160	3	−27	^Citation67
Stefanutti et al	5	10	200	12	−18	^Citation69
	26	20	200	12	−31
	11	20	300	12	−24
	3	30	200	12	−39
Krysiak et al	24	40	200	3	−14	^Citation75
SAFARI	374	20	160		−43	^Citation64
Shah et al	22	20	200	3	−7	^Citation72
Kayikcioglu et al§§	32	10	250	6	−31	^Citation70
Mohiuddin et al	112	20	135	3	−24	^Citation66
	111	40	135	3	−27

Notes:

* Data refer to number of patients followed up to exit visit;

** maximal statin daily dose was 40 mg but varied during the follow-up, based on lipid lowering response and according to international guidelines (overall average dose was 22.3 mg in fenofibrate group);

§ fenofibrate 54 mg was administered in patients with baseline or incidental eGFR <50 mL/min/1.73 m²;

§§ data refer to everyday administration group.

Abbreviation: TC, total cholesterol.

Figure 2 Principal side effects and clinical benefit of combination therapy.

Notes: Red squares report range of side effect percent resulted in clinical trials. Green squares contain data about clinical benefits. Yellow squares refer to major clinical endpoint that resulted not statistically significant compared to controls (placebo or monotherapy). References are in the brackets. *No overall difference versus placebo or statin monotherapy (depending on the study); **overall lower than in placebo groups.
Abbreviations: ALT, alanine amino transferase; AST, aspartate amino transferase; HDL, high-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein.

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