Comparison of switch to the highest dose of rosuvastatin vs. add-on nicotinic acid vs. add-on fenofibrate for mixed dyslipidaemia

Authors


  • Disclosures Dr Evangelos Liberopoulos, Dimitri Mikhalidis and Moses Elisaf have given talks, attended conferences and participated in trials and advisory boards sponsored by various pharmaceutical companies, including Astra-Zeneca, Abbott and Merck Sharpe and Dohme (MSD). No conflict of interest declared.
  • Clinical Trials gov: NCT 01010516.
  • Linked Comment: Wierzbicki. Int J Clin Pract 2013; 67: 391–3.

  • Linked Comment: www.youtube.com/IJCPeditorial

Correspondence to:

Dr Evangelos N Liberopoulos MD FASA FRSH, Assistant Professor of Internal Medicine, University of Ioannina Medical School, 45 110 Ioannina, Greece

Tel.: +302651007502

Fax: +302651007016

Email: vaglimp@yahoo.com

Summary

Background

Use of a statin at a standard dose may be insufficient for the treatment of mixed dyslipidaemia. Whether switch to the highest dose of rosuvastatin (40 mg) or add-on nicotinic acid (NA) or fenofibrate is more efficacious remains unknown.

Patients and methods

This was a prospective, randomised, open-label, blinded end-point (PROBE) study. We recruited 100 patients with mixed dyslipidaemia who were treated with a statin at a standard dose but had not achieved lipid targets. Patients were randomised to switch to the highest approved dose of rosuvastatin (40 mg), add-on extended release nicotinic acid (ER-NA)/l-aropiprant (LRPT) or to add-on micronised fenofibrate for 3 months. The primary end-point was the change in non-high-density lipoprotein cholesterol (non-HDL-C) levels.

Results

Ninety patients completed the study. Non-HDL-C decreased in all groups (by 23, 24 and 7% in the rosuvastatin, ER-NA/LRPT and fenofibrate group, respectively, p < 0.01 for all compared with baseline and p < 0.01 for all compared with fenofibrate group). Low-density lipoprotein cholesterol (LDL-C) decreased by 23 and 19% in the rosuvastatin and ER-NA/LRPT group, respectively (p < 0.01 compared with baseline), but not in the add-on fenofibrate group. Add-on ER-NA/LRPT was associated with the greatest HDL-C increase, while add-on ER-NA/LRPT and add-on fenofibrate were associated with the greatest triglyceride decrease. Twenty-four per cent of patients initially randomised to add-on ER-NA/LRPT dropped out because of side effects.

Conclusions

In conclusion, switch to the highest dose of rosuvastatin and add-on ER-NA/LRPT may be better options compared with add-on fenofibrate for the management of patients with mixed dyslipidaemia not on treatment goals with a statin at a standard dose.

What's known

  • Mixed dyslipidaemia can be a therapeutic challenge as monotherapy with conventional statin doses may only partially correct all the underlying metabolic defects. The next step in patients with mixed dyslipidaemia not on treatment goals despite treatment with a statin at a standard dose remains debatable. Switch to the highest approved dose of rosuvastatin (40 mg) or addition of fenofibrate or nicotinic acid comprises three possible options.

What's new

  • Switch to the highest dose of rosuvastatin and add-on extended release nicotinic acid/laropiprant may be better options compared with add-on fenofibrate for the management of patients with mixed dyslipidaemia not on treatment goals with a statin at a standard dose.

Introduction

Mixed dyslipidaemia is characterised by elevated levels of triglycerides (TGs), low levels of high-density lipoprotein cholesterol (HDL-C) and increased low-density lipoprotein cholesterol (LDL-C) concentration [1]. LDL-C remains the primary therapeutic target in the management of dyslipidaemia [2]. However, the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) recommends non-HDL-C as a secondary therapeutic target in patients at LDL-C goal but with high TGs (> 200 mg/dl; 2.26 mmol/l) [2]. Rosuvastatin has the greatest LDL-C-lowering potency, while it significantly reduces in a dose-dependent way TGs and modestly increases HDL-C [3]. Thus, switch to the highest dose (40 mg/day) of rosuvastatin may represent a potent therapeutic option in patients on a standard statin dose not on target for LDL-C and non-HDL-C levels.

The addition of nicotinic acid (NA) or fenofibrate to current statin treatment is currently recommended to achieve non-HDL-C goal [2, 4, 5]. Fenofibrate is primarily used for its TG-lowering effect, while it modestly raises HDL-C level. On the other hand, fenofibrate effect on LDL-C is variable, ranging from small decrease to no change or even a slight increase in individuals with hypertriglyceridaemia [6]. NA possesses broad spectrum lipid-modifying properties, as it decreases the levels of both LDL-C and TGs (by approximately 5–20 and 20–50% respectively). Furthermore, NA comprises the most effective currently available treatment for raising HDL-C levels and exerts a number of pleiotropic effects [2, 7, 8]. The launch of a newer fixed combination of extended release (ER) NA with laropiprant (LRPT) seems to mitigate both the intensity and frequency of flushing ([9].).

The next step in patients with mixed dyslipidaemia not on treatment goals despite treatment with a statin at a standard dose remains debatable. Intensifying of statin treatment or addition of fenofibrate or NA comprise of three possible options. In this context, we aimed to compare the efficacy of switch to the highest dose of rosuvastatin (40 mg) vs. add-on ER-NA/LRPT vs. add-on micronised fenofibrate in these patients. The primary end-point was the changes in non-HDL-C levels. Secondary end-points were the changes of LDL-C, TGs and HDL-C levels. To the best of our knowledge, this is the first time that these three treatment options are directly compared.

Methods

Study population

Consecutive subjects with mixed dyslipidaemia attending the Outpatient Lipid and Obesity Clinic of the University Hospital of Ioannina, Ioannina, Greece were recruited. Eligible patients were those treated for at least 3 months with a standard statin dose (10–40 mg simvastatin or 10–20 mg atorvastatin or 5–10 mg rosuvastatin) and their non-HDL-C levels were above treatment targets [2]. Subjects with TGs > 500 mg/dl (5.65 mmol/l), renal disease (serum creatinine levels > 1.6 mg/dl; 141 μmol/l), hypothyroidism [thyroid stimulating hormone (TSH) > 5 IU/ml] and liver disease [alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels > threefold upper limit of normal (ULN) in two consecutive measurements] were excluded. Patients with hypertension and/or diabetes were considered eligible if they were on stable medication for at least 3 months and their blood pressure and glucose were adequately controlled (no change in their treatment was allowed during study period).

This was a prospective, randomised, open-label, blinded end-point (PROBE) study. All patients were seen by specialists in our lipid clinic. Patients were randomly allocated (without a wash-out phase) to switch to open-label high-dose rosuvastatin (40 mg/day) or to add-on-current-statin treatment with ER-NA/LRPT (1000/20 mg/day for the first 4 weeks followed by 2000/40 mg/day for the next 8 weeks) or to add-on micronised fenofibrate (200 mg/day) for a total of 3 months. This study design is relevant to every day clinical practice when the treating physician is in dilemma what to do in a patient who has failed to achieve lipid targets while on conventional statin treatment.

All patients were given similar dietary advice according to NCEP ATP III guidelines [2]. Compliance with treatment and lifestyle habits were assessed by questionnaire and tablet count. Flushing symptoms were assessed 8 hours after administration of study treatments using a questionnaire similar to the previously validated Flushing Symptom Questionnaire, which assesses the incidence, severity, duration and bothersomeness of individual symptoms (redness, warmth, tingling and itching) using a 11-point scale (higher scores indicate worse symptoms) [10]. All study participants gave their written informed consent prior to enrolment. The protocol was approved by the Ethics Committee of the University Hospital of Ioannina and registered at ClinicalTrials.gov (NCT01010516).

Laboratory measurements

Blood samples for laboratory tests were obtained at baseline and 12 weeks after study onset following a 12 h overnight fast. Levels of total cholesterol (TC), HDL-C and TG, fasting plasma glucose (FPG), AST, ALT, creatine kinase (CK), uric acid and serum creatinine were determined enzymatically at the laboratory of the University Hospital of Ioannina on an Olympus AU 600 analyser (Olympus Diagnostica GmbH, Hamburg, Germany). LDL-C was calculated using the Friedewald equation. Clinically significant elevations in AST/ALT values were defined as > threefold the ULN on two consecutive occasions (reference range 10–35 IU/l), whereas clinically significant elevations in CK were defined as > 10-fold the ULN (reference range 25–160 IU/l). Glomerular filtration rate (GFR) was calculated by the Modification of Diet in Renal Disease (MDRD) equation [11]. All laboratory determinations were performed blindly with regard to treatment allocation.

Statistical analysis

We used G*Power 3.0.10 to calculate sample size. It was estimated that a sample size of 90 would give an 80% power to detect a 6% difference in the reduction of non-HDL-C concentration between the three groups at a two-sided significance level of 0.05. We included 100 patients allowing for a drop-out rate of ~10%. The analysis only included the patients who completed the study as per protocol. Values are given as mean ± standard deviation (SD) and median (range) for parametric and non-parametric data respectively. Continuous variables were tested for lack of normality by the Kolmogorov–Smirnov test, and logarithmic transformations were accordingly performed for non-parametric variables. The paired-sample t-test was used for assessing the effect of treatment in each group. Analysis of covariance (ANCOVA), adjusted for baseline values, was used for comparisons between groups. The Chi-squared test was used for the comparison of percentages between groups. Significance was defined as p < 0.05. Analyses were performed using the Statistical Package for the Social Sciences (spss) 15.0 (SPSS Inc, Chicago, IL).

Results

Recruitment took place from October 2009 to September 2011, and follow-up ended in December 2011. Initially, 100 Caucasian patients were enrolled (= 33, 34 and 33 in the switch to the highest dose of rosuvastatin, add-on ER-NA/LRPT and add-on fenofibrate group respectively). Ten patients dropped out because of side effects (see below). Eventually, ninety subjects (47 men, 59 ± 11 years) completed the study (= 32, 26, 32 in the switch to the highest dose of rosuvastatin, add-on ER-NA/LRPT and add-on fenofibrate group, respectively) and these are included in the final analysis. No significant differences in baseline data were found across groups regarding demographic characteristics and serum metabolic parameters (Table 1). Compliance rate was > 90% in all participants who completed the study. No changes in body weight, dietary habits (including salt intake), antihypertensive or antidiabetic medications were reported during follow-up.

Table 1. Baseline characteristics of patients who completed the study* (n = 90)
 Switch to the highest dose of rosuvastatinAdd-on-statin ER-NA/LRPTAdd-on-statin micronised fenofibratep
  1. *Values are expressed as mean ± standard deviation [except for triglycerides which are expressed as median (range)]. ACEIs, angiotensin converting enzyme inhibitors; ARBs, angiotensin receptor blockers; BMI, body mass index; ER-NA/LRPT, extended release nicotinic acid/laropiprant; HCTZ, hydrochlorothiazide; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MDRD eGFR, modification of diet in renal disease-estimated glomerular filtration rate; NS, not significant; TC, total cholesterol.

N (men/women)32 (17/15)26 (14/12)32 (16/16)NS
Age, years62 ± 1058 ± 1459 ± 12NS
Hypertension (%)17 (53)14 (54)16 (50)NS
Diabetes (%)6 (19)6 (23)6 (19)NS
Metabolic syndrome (%)17 (53)15 (58)18 (56)NS
Smoking (%)10 (31)9 (35)9 (28)NS
BMI, kg/m229.1 ± 2.529.1 ± 3.128.8 ± 3.2NS
TC, mg/dl (mmol/l)205 ± 40 (5.5 ± 1.0)200 ± 42 (5.2 ± 1.1)200 ± 37 (5.2 ± 1.0)NS
Triglycerides, mg/dl (mmol/l)190 (173–210) [2.2 (2.0–2.4)]213 (190–254) [2.4 (2.2–2.9)]218 (189–260) [2.5 (2.1–2.9)]NS
HDL-C, mg/dl (mmol/l) 50 ± 10 (1.2 ± 0.3) 47 ± 11 (1.2 ± 0.3)45 ± 9 (1.2 ± 0.2)NS
LDL-C, mg/dl (mmol/l)116 ± 40 (3.2 ± 1.0)109 ± 35 (2.9 ± 0.9)112 ± 32 (2.9 ± 0.8)NS
Non-HDL-C, mg/dl (mmol/l)155 ± 40 (4.0 ± 1.0)153 ± 37 (4.0 ± 1.0)155 ± 34 (4.0 ± 0.9)NS
Fasting plasma glucose, mg/dl (mmol/l)95 ± 23 (5.3 ± 1.3)105 ± 20 (5.8 ± 1.1)100 ± 11 (5.6 ± 0.6)NS
Serum uric acid, mg/dl (μmol/l)5.8 ± 1.5 (345 ± 89)6.1 ± 1.5 (363 ± 89)6.3 ± 1.3 (375 ± 77)NS
Serum creatinine, mg/dl (μmol/l)0.9 ± 0.2 (69 ± 15)1.0 ± 0.2 (76 ± 15)1.0 ± 0.1 (76 ± 8)NS
MDRD eGFR, ml/min/1.73 m274 ± 2275 ± 2373 ± 23NS
Medications at baseline
 Aspirin (%)9 (28)8 (31)7 (22)NS
 Beta blockers (%) 9 (28)8 (31)9 (28)NS
 HCTZ (%)11 (34)10 (38)10 (31)NS
 ACEIs/ARBs (%)13 (41)11 (42)12 (38)NS
 Calcium channel blockers (%)8 (24)8 (31)10 (31)NS
 Metformin (%)6 (19)6 (23)5 (16)NS
 Pioglitazone (%)2 (7)1 (4)3 (9)NS
 Sulfonylurea (%)4 (13)3 (12)2 (6)NS
 Atorvastatin 5–20 mg/day (%)11 (34)9 (35)12 (38)NS
 Simvastatin 10–40 mg/day (%)11 (34)9 (35)9 (28)NS
 Rosuvastatin 5–10 mg/day (%)10 (31)8 (31)11 (34)NS

Among study completers, non-HDL-C level decreased in all treatment groups by 23, 24 and 7% in the rosuvastatin, ER-NA/LRPT and fenofibrate group respectively (p < 0.01 compared with baseline, p = NS for the comparisons between rosuvastatin and ER-NA/LRPT groups and p < 0.01 for the comparisons with the fenofibrate group). LDL-C level decreased by 23 and 19% in the rosuvastatin and ER-NA/LRPT group respectively (p < 0.01 compared with baseline, p = NS for comparisons between the 2 groups), while add-on fenofibrate was not associated with any change in LDL-C levels (Table 2).

Table 2. Lipid profile at baseline and 3 months later*
 Baseline3 monthsPercentage change (%)
  1. *Values are expressed as mean ± standard deviation [except for triglycerides which are expressed as median (range)]. †p < 0.01 vs. baseline. ‡p < 0.001 vs. baseline. §p < 0.01 vs. switch to the highest dose of rosuvastatin group. ¶p < 0.01 vs. add-on-statin ER-NA/LRPT group. **p < 0.01 vs. add-on-statin fenofibrate group. ER-NA: extended release nicotinic acid; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; LRPT: laropiprant; non-HDL-C: non-high-density lipoprotein cholesterol; TC: total cholesterol.

TC, mg/dl (mmol/l)
 Switch to the highest dose of rosuvastatin205 ± 40 (5.5 ± 1.0)171 ± 27 (4.1 ± 0.7)−17‡,**
 Add-on ER-NA/LRPT200 ± 42 (5.2 ± 1.1)170 ± 37 (4.4 ± 1)−15‡,**
 Add-on fenofibrate200 ± 37 (5.2 ± 1.0)192 ± 36 (5.0 ± 0.9)−4†
Triglycerides, mg/dl [mmol/l]
 Switch to the highest dose of rosuvastatin190 (173–210) [2.3 (2.0–2.4)]152 (140–184) [1.9 (1.6–2.1)]−20‡
 Add-on ER-NA/LRPT213 (190–254) [2.4 (2.2–2.9)]132 (119–178) [1.5 (1.3–1.8)]−38‡,§
 Add-on fenofibrate218 (189–260) [2.5 (2.1–2.9)]142 (118–170) [1.6 (1.3–1.9)]−35‡,§
HDL-C, mg/dl (mmol/l)
 Switch to the highest dose of rosuvastatin50 ± 10 (1.2 ± 0.3)51 ± 9 (1.4 ± 0.2)+2†
 Add-on ER-NA/LRPT47 ± 11 (1.2 ± 0.3)53 ± 16 (1.4 ± 0.4)+13†,§,**
 Add-on fenofibrate45 ± 9 (1.2 ± 0.2)48 ± 7 (1.2 ± 0.2)+7‡,§
LDL-C, mg/dl (mmol/l)
 Switch to the highest dose of rosuvastatin116 ± 40 (3.2 ± 1.0)89 ± 24 (1.9 ± 0.6)−23‡,**
 Add-on ER-NA/LRPT109 ± 35 (2.9 ± 0.9)88 ± 34 (2.4 ± 0.9)−19‡,**
 Add-on fenofibrate112 ± 32 (2.9 ± 0.8)114 ± 33 (3  ± 0.9)+1
Non-HDL-C, mg/dl (mmol/l)
 Switch to the highest dose of rosuvastatin155 ± 40 (4.2 ± 1.0)120 ± 23 (2.8 ± 0.6)−23‡,**
 Add-on ER-NA/LRPT153 ± 37 (3.8 ± 1.0)117 ± 34 (3.1 ± 0.9)−24‡,**
 Add-on fenofibrate155 ± 34 (3.8 ± 0.9)144 ± 36 (3.7 ± 0.9)−7†

Triglycerides decreased by 38 and 35% in the add-on ER-NA/LRPT and fenofibrate group, respectively (p < 0.01 compared with baseline, p = NS for comparison between the 2 groups), while rosuvastatin was associated with a 20% decrease in TG level (p < 0.01 compared with baseline, p < 0.01 for the comparisons between the rosuvastatin and combination treatment groups). In terms of HDL-C level increase, add-on ER-NA/LRPT was the most potent treatment followed by fenofibrate and rosuvastatin ( + 13,  + 7 and +2%, respectively, p < 0.01 compared with baseline and for all comparisons between groups) (Table 2).

Overall, according to each patient-risk calculation, the non-HDL-C goal was achieved in the 67, 74 and 62% of patients in the highest dose of rosuvastatin, add-on ER-NA/LRPT and fenofibrate groups respectively (p = NS for the comparison between rosuvastatin and ER-NA/LRPT group and p = 0.04 for the comparisons with fenofibrate group). Similarly, LDL-C goal was achieved in the 70 and 68% of patients in the rosuvastatin and add-on ER-NA/LRPT group, respectively (p = NS for the comparison between the 2 groups), while in the add-on fenofibrate group this percentage was significantly lower (55%, p = 0.01 compared with rosuvastatin group and p = 0.03 compared with ER-NA/LRPT group) (Figure 1).

Figure 1.

Percentage of patients who achieved lipid targets in each group *p < 0.05 vs. add-on fenofibrate group ER-NA/LRPT: extended release nicotinic acid/laropiprant Non-HDL-C, non-high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol

Both switch to the highest dose of rosuvastatin and add-on ER-NA/LRPT were associated with increases in FPG (by 5 and 6%, respectively, p < 0.01 compared with baseline, p = NS between the two groups, p < 0.01 compared with fenofibrate group) (Table 3). Add-on fenofibrate was associated with a 10% increase in serum creatinine and 11% decrease in eGFR (p < 0.01 compared with baseline, p < 0.01 compared with the other treatment groups) (Table 3). Serum uric acid levels increased in the ER-NA/LRPT treatment group (+7%, p < 0.01 compared with baseline), decreased in the fenofibrate group (−22%, p < 0.01 compared with baseline), while remained unaltered in the rosuvastatin group (p < 0.01 for all comparisons between groups) (Table 3).

Table 3. Other metabolic parameters at baseline and 3 months later*
 Baseline3 monthsPercentage change (%)
  1. *Values are expressed as mean ± standard deviation. †p < 0.01 vs. baseline. ‡p < 0.01 vs. switch to the highest dose of rosuvastatin group. §p < 0.01 vs. add-on-statin ER-NA/LRPT group. ¶p < 0.01 vs. add-on-statin fenofibrate group. ALT, alanine aminotransferase; AST, aspartate aminotransferase; ER-NA, extended release nicotinic acid; LRPT, laropiprant; MDRD eGFR, modification of diet in renal disease-estimated glomerular filtration rate.

Fasting plasma glucose, mg/dl (mmol/l)
 Switch to the highest dose of rosuvastatin95 ± 23 (5.3 ± 1.3)100 ± 19 (5.5 ± 1.1)+5†,¶
 Add-on ER-NA/LRPT105 ± 20 (5.8 ± 1.1)111 ± 27 (6.2 ± 1.5)+6†,¶
 Add-on fenofibrate100 ± 11 (5.6 ± 0.6)100 ± 11 (5.6 ± 0.6)0
Serum uric acid, mg/dl (μmol/l)
 Switch to the highest dose of rosuvastatin5.8 ± 1.5 (345 ± 89)5.9 ± 1.6 (351 ± 95)+2
 Add-on ER-NA/LRPT6.1 ± 1.5 (363 ± 89)6.5 ± 1.5 (387 ± 89)+7†,‡
 Add-on fenofibrate6.3 ± 1.3 (375 ± 77)4.9 ± 1.1 (291 ± 65)−22†,‡,§
AST, IU/l
 Switch to the highest dose of rosuvastatin25 ± 526 ± 6+4†
 Add-on ER-NA/laropiprant27 ± 929 ± 10+7†
 Add-on fenofibrate26 ± 726 ± 60
ALT, IU/l
 Switch to the highest dose of rosuvastatin28 ± 927 ± 9−4†
 Add-on ER-NA/laropiprant34 ± 2129 ± 16−15†
 Add-on fenofibrate30 ± 1627 ± 11−10†
Serum creatinine, mg/dl (μmol/l)
 Switch to the highest dose of rosuvastatin0.9 ± 0.2 (80 ± 18)0.9 ± 0.2 (80 ± 18)0
 Add-on ER-NA/LRPT1.0 ± 0.2 (88 ± 18)1.0 ± 0.2 (88 ± 18)0
 Add-on fenofibrate1.0 ± 0.1 (88 ± 9)1.1 ± 0.4 (97 ± 35)+10†,‡,§
MDRD eGFR, ml/min/1.73 m2
 Switch to the highest dose of rosuvastatin74 ± 2274 ± 220
 Add-on ER-NA/LRPT75 ± 2375 ± 240
 Add-on fenofibrate73 ± 2365 ± 22−11†,‡,§

Safety

Of the 100 patients enrolled, eight (24%) of the 34 initially randomised to the ER-NA/laropiprant group dropped out during the study because of flushing (n = 5), epigastric pain (n = 2) and new onset diabetes (n = 1). Also, one (3%) patient of the 33 initially randomised to the rosuvastatin group dropped out because of asymptomatic ALT elevation > threefold ULN and one (3%) patient of the 33 randomised in the fenofibrate group because of serum creatinine elevation (> 20% from baseline).

Discussion

We directly compared for the first time the switch to the highest dose of rosuvastatin with add-on ER-NA/LRPT or add-on micronised fenofibrate in patients with mixed dyslipidaemia on standard statin dose who had not achieved treatment goals. Both the highest dose of rosuvastatin monotherapy and add-on ER-NA/LRPT were associated with similar reductions in non-HDL-C, which were more pronounced compared with add-on fenofibrate treatment. Similarly, highest dose rosuvastatin monotherapy and add-on ER-NA/LRPT were associated with the greatest LDL-C reduction, while add-on fenofibrate was not associated with any change in LDL-C. Of note, add-on ER-NA/LRPT was associated with the largest HDL-C increase, while add-on ER-NA/LRPT and add-on fenofibrate were associated with the greatest TG decrease.

Add-on fenofibrate was associated with less non-HDL-C reduction compared with the other treatment groups, while no change in LDL-C was seen. On the other hand, add-on fenofibrate was associated with a pronounced TG-lowering effect and a higher HDL-C-raising effect compared with rosuvastatin monotherapy. In agreement with previous studies we noticed a significant increase in serum creatinine levels after fenofibrate administration [6, 12]. In fact, a recent observational study suggested that fenofibrate-associated ‘nephrotoxicity’ occurs more frequently than previously reported, particularly in patients with baseline renal disease [13]. However, controversy exists as to whether the fenofibrate-induced creatinine elevation represents a true deterioration in renal function or an increase in the rate of metabolic production of creatinine [14]. As expected, fenofibrate was associated with a significant serum uric acid reduction (by 22%, Table 3). Of note, increased serum levels of uric acid are associated with cardiovascular disease risk factors, including chronic kidney disease, coronary artery disease, stroke, diabetes and hypertension [15-19]. Whether the addition of fenofibrate on statin treatment is associated with a reduction in cardiovascular events is a matter of debate. However, in a prespecified subgroup analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study combination of simvastatin with fenofibrate has been associated with reduced cardiovascular events in diabetic patients with both elevated TGs (> 204 mg/dl; 2.3 mmol/l) and low HDL-C (≤ 34 mg/dl; 0.88 mmol/l) compared with simvastatin monotherapy [20].

The addition of ER-NA/LRPT significantly improved all parameters of lipid profile, while exhibiting the most pronounced HDL-C-raising potency among the three regimens. On the other hand, 24% of patients initially randomised to ER-NA/LRPT dropped out because of side effects (mainly flushing). In agreement with previous studies NA was associated with a modest elevation of FPG and uric acid levels [21-23]. The observed ER-NA/LRPT-associated uric acid increase should be taken into consideration especially in patients who receive concomitant medications which raise uric acid levels (e.g. diuretics) or have a history of uric arthritis.

Overall, highest dose rosuvastatin monotherapy and add-on-statin ER-NA/LRPT were both associated with clinically meaningful decreases in both non-HDL-C and LDL-C levels, while add-on-statin ER-NA/LRPT was associated with the greatest HDL-C increase. However, the critical question is whether these results translate into cardiovascular disease risk reduction. Rosuvastatin has been associated with a reduction in cardiovascular disease events in primary prevention and a regression in atherosclerosis in secondary prevention [24, 25]. Specifically, the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) demonstrated that rosuvastatin (20 mg/day) for 2 years reduced major cardiovascular events rate among healthy individuals with low LDL-C concentration (<130 mg/dl; 3.36 mmol/l) but high levels of high sensitivity C reactive protein (hsCRP) (≥ 2 mg/l) [24]. Moreover, in the Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) the highest approved dose of both rosuvastatin (40 mg/day) and atorvastatin (80 mg/day) resulted in significant regression of coronary atheroma volume, determined by analysis of intravascular ultrasound (IVUS) images of matched coronary artery segments acquired at baseline and at 24-month follow-up in patients with angiographically established coronary artery disease ([26].)

Regarding NA-associated clinical benefits, in the HDL Atherosclerosis Treatment Study (HATS) simvastatin plus NA was associated with marked clinical and angiographically measurable benefits in patients with coronary disease and low HDL-C levels [27]. However, in the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) trial add-on-statin ER-NA (1500–2000 mg/day) failed to demonstrate additional benefits in patients with established cardiovascular disease, high TGs and low HDL-C [28]. Specifically, 3414 coronary patients already receiving simvastatin, (40–80 mg/day) plus ezetimibe (10 mg/day) if needed, to maintain a LDL-C of 40–80 mg/dl (1.0–2.1 mmol/l) were randomised to ER-NA (1500–2000 mg/day) or placebo. The trial was stopped after a mean follow-up period of 3 years owing to a lack of efficacy [28]. However, this trial had several limitations. Of note, ER-NA was associated with a 25% increase in HDL-C levels, but paradoxically HDL-C levels were also substantially increased in the placebo group by 10%, so that the difference in HDL-C levels between the two groups was just 4 mg/dl (0.1 mmol/l). The ongoing Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) is designed to assess whether add-on-statin ± ezetimibe ER-NA/LRPT prevents myocardial infarction, stroke or revascularisation procedures in patients with established vascular disease [29].

Study limitations

A major limitation of our study is its open-label design and the relatively small number of participants. On the other hand, it was an adequately powered randomised study with all laboratory determinations being performed blindly. Study design is also relevant to every day clinical practice.

Conclusions

Both switch to the highest dose of rosuvastatin (40 mg) and add-on-current-statin ER-NA/LRPT were associated with greater reductions in non-HDL-C compared with add-on fenofibrate in patients with mixed dyslipidaemia not on goal. Larger, prospective trials should establish if these differences influence cardiovascular risk.

Author contributions

Anastazia Kei: data collection and analysis/interpretation, statistics, critical revision of article. Evangelos Liberopoulos: concept and design, data collection and analysis/interpretation, statistics, critical revision and approval of article. Dimitri Mikhailidis: critical revision and approval of article. Moses Elisaf: concept and design, critical revision and approval of article.

Acknowledgements

This study was conducted independently. No pharmaceutical company supported this study financially or in any other way. We would like to thank Dr. Christos Rizos for his help regarding statistical analysis of data.

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