Simvastatin/fenofibrate combination in the treatment of dyslipidemia: current evidence

Figures & data

Table 1 Effects of simvastatin/fenofibrate combination therapy on lipid and lipoproteins

Study	Type of study	Study population	Mean age (y)	DM (%)	M/F (%)	Follow-up	T reatment	Lipid parameter	% change from basal Statin alone Statin/fibrate
Vega G et al^Citation152	Randomized, double-blinded, placebo, monotherapy and co-administration of study drugs	20 patients with mixed dyslipidemia	53.0±9.2	20/80	none	9 months	Simvastatin 10 mg alone versus simvastatin 10 mg/day plus fenofibrate 200 mg/day	T-Chol	−27.0	−27.0
								TG	−23.0	−52.6
								Non-HDL-C	−30.0	−36.4
								LDL-C	−28.0	−24.5
								Apo B	−21.6	−31.5
								LDL Apo B	−23.0	−25.0
								HDL-C	+06.0	+23.0
								Apo C II	−28.8	−37.9
								Apo C III	−18.4	−26.7
Grundy et al^Citation154	Randomized, double-blinded, active-controlled	618 patients with combined hyperlipidemia	52.7±8.6	49/51	16.5	18 weeks	Simvastatin 20 mg and fenofibrate 160 mg or simvastatin 20 mg versus placebo or fenofibrate	TG	−20.1	−43.0
								T-Chol	−20.3	−26.3
								VLDL-TG	−20.6	−53.5
								Non-HDL-C	−26.1	−35.3
								LDL-C	−26.8	−31.2
								HDL-C	+09.7	+18.6
								Apo B	−22.8	−32.6
								Apo A 1	+04.8	+08.8
Muhlestein et al^Citation143	Randomized, double-blinded, Placebo-control led	300 type 2 DM with mixed dyslipidemia and with and without CVD	60.6	45/55	100	12 weeks	Simvastatin 20 mg plus fenofibrate placebo or fenofibrate 160 mg plus simvastatin placebo or simvastatin 20 mg plus fenofibrate 160 mg	TG	−24.8	−49.4
								T-Chol	−26.1	−27.1
								LDL-C	−34.1	−29.1
								Non-HDL-C	−32.5	−34.3
								HDL-C	+07.4	+13.0
Bays et al^Citation156	Double-blinded, randomized controlled trial	2,201 patients with mixed dyslipidemia	54.8±10.57	51/49	43	52 weeks	Fenofibric acid 135 mg or low, moderate, high statin doses alone or in combination with fenofibric acid	T-Chol	−0.70	−04.7
								TG	−30.5	−04.2
								Non-HDL-C	−04.6	−09.7
								Apo B	−07.0	−09.4
								LDL-C	−03.2	−07.9
								HDL-C	+13.1	+04.8
Mohiuddin et al^Citation158	Double-blinded, randomized, active-controlled prospective study	650 men and women with mixed dyslipidemia and multiple CVD risk factors	54.5±10.32	51	22.9	22 weeks	Fenofibric acid 135 mg or simvastatin 20–40–80 mg or fenofibric acid 135 mg + simvastatin 20–40 mg	T-Chol	−19.8–30.0	−23.9–27.1
								TG	−14.2–22.4	−37.4–42.7
								VLDL-C	−19.2–35.7	−19.2–35.7
								Non-HDL-C	−24.4–35.9	−24.4–35.9
								Apo B	−22.9–33.6	−32.7–31.2
								LDL-C	−22.4–31.7	−24.0–25.3
								HDL-C	+07.2–08.5	+ 17.8–18.9
May et al^Citation155	Randomized, double-blinded, placebo controlled	300 DM patients without CVD and mixed dyslipidemia	61.6±11.5	45/55	100	12 weeks	The patients were randomized to simvastatin 20 mg, fenofibrate 160 mg or simvastatin 20 mg + fenofibrate 160 mg	LDL pattern B	−27.7	−33.9
								Buoyant LDL	−11.6	−11.6
								HDL 2	+0.3	−0.4
								HDL 3	+01.0	+02.3
								Dense VLDL	−06.3	−10.0
								IDL	−12.2	−08.8
								Lp(^a)	+0.6	−0.5
Derosa et al^Citation157	Randomized, double-blinded trial	241 DM patients with combined dyslipidemia without serious CVD	51.6±10.3	50.6	100	12 months	The patients received fenofibrate	T Choi	−20.5	−29.3
							145 mg or simvastatin 40 mg or	TG	−11.8	−38.8
							fenofibrate 145 mg + simvastatin	LDL-C	−22.8	−40.4
							40 mg	HDL-C	−16.5	+34.1
								Apo B	+10.8	−28.7
								Apo A 1	+05.9	+09.4
								Lp(^a)	+10.0	+16.0
Jones et al^Citation159	Double-blinded, 12 week trial	586 patients with mixed dyslipidemia and type 2 DM	58.6±10.0	53/46	21.7	12 weeks	Fenofibric acid 135 mg alone	T Choi	−29.4	−33.6
							or low dose of statin or	TG	−24.2	−43.4
							fenofibric acid in combination	LDL-C	−41.5	−32.6
							with low or moderate doses of	HDL-C	+08.7	+16.3
							statins (rosuvastatin 10–20–40 mg,	Apo B	−32.7	−36.2
							simvastatin 20–40–80 mg, or	Apo A 1	+03.0	+10.3
							atorvastatin 20–40–80 mg)

Abbreviations: Apo A I, apolipoprotein A I; Apo C II, apolipoprotein C II; Apo B, apolipoprotein B; Apo C, apolipoprotein C; CVD, cardiovascular disease; DM, diabetes mellitus; HDL, high-density lipoprotein; HDL 2, high-density lipoprotein 2; HDL 3, high-density lipoprotein 3; HDL-C, high-density lipoprotein cholesterol; IDL, intermediate density lipoprotein; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein A; M/F, male/female; Non-HDL-C, total cholesterol – HDL-C; T-Chol, total cholesterol; TG, triglycerides; VLDL-C, very low-density lipoprotein cholesterol; VLDL-TG, very low-density lipoprotein triglycerides.

Table 2 Effects of simvastatin/fenofibrate combination therapy on cardiovascular end points

Study	Type of study	Study population	Mean age (years)	M/F (%)	DM (%)	Follow-up	Treatment	Outcomes	Cardiovascular end points
ACCORD lipid trial^Citation51	Randomized double blind	5,518 type 2 DM with multiple CV risk factors or ASCVD	62.3±6.8	69.3/30.7	100	4.7 years	All patients received simvastatin ≤40 mg (open label) and fenoflbrate 160 mg or placebo	Nonfatal myocardial infarction, nonfatal stroke or death from ASCVD	• No differences in primary cardiovascular outcomes were observed (10.3% vs 1 1.3%)^† • Patients with high levels of TG and low levels of HDL-C outcome rate: 12.4% vs 17.3% in placebo group^††
Karbasi-Afshar et al^Citation163	Randomized clinical trial	124 patients with dyslipidemia and CVD	54.3±5.6	46.7/53.2	13.2	12 months	Simvastatin 20–60 mg/day and fenofibrate 200 mg/day or simvastatin 20–60 mg/day	Myocardial structure and function in CAD patients with dyslipidemia	Combination therapy • Change in left ventricular ejection fraction^* • Increase in left ventricular mass index^** • Exercise test time (min) increased^*** • Metabolic task index increased^*
Davidson et al^Citation164	Double blinded, placebo controlled study	682 patients with mixed dyslipidemia and history of CAD or risk equivalent	61	68/32	50.0	104 weeks	Atorvastatin 40 mg plus fenoflbric acid 135 mg or placebo	Rate of change from baseline through week 104 of the mean posterior-wall cIMT	Combination therapy • No decrease in the progression of cIMT • Changes in the posterior wall cIMT were larger in participants: ○ ≥60 years of age ○ History of CAD ○ Prior statin use ○ Highest tertile of baseline cIMT ○ Middle tertile of baseline TG

Notes: ^†P=0.32; ^††P-values not reported; *P=0.01; **P=0.039; ***P=0.001.

Abbreviations: ACCORD, The Action to Control Cardiovascular Risk in Diabetes; DM, diabetes mellitus; CV, cardiovascular; ASCVD, atherosclerotic cardiovascular disease; CVD, cardiovascular disease; CAD, coronary artery disease; cIMT, carotid intima media thickness; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; M/F, male/female; vs, versus.

Vega GL, Ma PT, Cater NB, et al. Effects of adding fenofibrate (200 mg/day) to simvastatin (10 mg/day) in patients with combined hyperlipidemia and metabolic syndrome. Am J Cardiol. 2003;91(8):956–960.

 Web of Science ®Google Scholar

Grundy SM, Vega GL, Yuan Z, Battisti WP, Brady WE, Palmisano J. Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial). Am J Cardiol. 2005;95(4):462–468.

 PubMed Web of Science ®Google Scholar

Muhlestein JB, May HT, Jensen JR, et al. The reduction of inflammatory biomarkers by statin, fibrate, and combination therapy among diabetic patients with mixed dyslipidemia: the DIACOR (Diabetes and Combined Lipid Therapy Regimen) study. J Am Coll Cardiol. 2006;48(2):396–401.

 Web of Science ®Google Scholar

Bays HE, Jones PH, Mohiuddin SM, et al. Long-term safety and efficacy of fenofibric acid in combination with statin therapy for the treatment of patients with mixed dyslipidemia. J Clin Lipidol. 2008;2(6):426–435.

 PubMed Web of Science ®Google Scholar

Mohiuddin SM, Pepine CJ, Kelly MT, et al. Efficacy and safety of ABT-335 (fenofibric acid) in combination with simvastatin in patients with mixed dyslipidemia: a phase 3, randomized, controlled study. Am Heart J. 2009;157(1):195–203.

 Web of Science ®Google Scholar

May HT, Anderson JL, Pearson RR, et al. Comparison of the effects of simvastatin alone versus fenofibrate alone versus simvastatin plus fenofibrate on lipid subparticle profiles in diabetic patients with mixed dyslipidemia (from the Diabetes and Combined Lipid Therapy Regimen study). Am J Cardiol. 2008;101(4):486–489.

 Web of Science ®Google Scholar

Derosa G, Maffioli P, Salvadeo SA. Fenofibrate, simvastatin and their combination in the management of dyslipidaemia in type 2 diabetic patients. Curr Med Res Opin. 2009;25(8):1973–1983.

 PubMed Web of Science ®Google Scholar

Jones PH, Cusi K, Davidson MH, et al. Efficacy and safety of fenofibric acid co-administered with low- or moderate-dose statin in patients with mixed dyslipidemia and type 2 diabetes mellitus: results of a pooled subgroup analysis from three randomized, controlled, double-blind trials. Am J Cardiovasc Drugs. 2010;10(2):73–84.

 Web of Science ®Google Scholar

ACCORD Study Group, Grinsberg HN, Elam MB, et al. Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus. N Engl J Med. 2010;362(17):1563–1574.

 PubMed Web of Science ®Google Scholar

Karbasi-Afshar R, Shahmari A, Saburi A. Echocardiographic and exercise test findings in patients with dyslipidemia and coronary artery disease before and after treatment with simvastatin with or without fenofibrate. Int Cardiovas Res J. 2011;5(4):143–147.

 Google Scholar

Davidson MH, Rosenson RS, Maki KC, et al. Effects of fenofibric acid on carotid Intima-media thickness in patients with mixed dyslipidemia on atorvastatin therapy: randomised placebo, controlled study (FIRST). Arterioscler Thromb Vasc Biol. 2014;34(6):1298–1306.

 Web of Science ®Google Scholar