Introduction
Cardio vascular diseases (CVD) are the leading cause of disease burden globally.1, 2 It is a multi factorial in etiology and dyslipidemia is a major risk factor for coronary artery disease (CAD).3 The low density lipoprotein cholesterol (LDL-C) and non-high density lipoprotein cholesterol (non HDL-C) are atherogenic lipid particles while high density lipoprotein cholesterol (HDL-C) is inversely associated with risk of CVD.4, 5, 6 Elevated levels of atherogenic lipids are the result of combinations of faulty diet, physical inactivity and genetic predispositions. The Statins are potent and safer lipid lowering drugs primarily effective in lowering levels of LDL-C. The incremental reduction in LDL-C by doubling the dose of Statins is just about 6% and risk of incident adverse effects increases with increasing dose of Statins.7 The fenofibrate is more potent than statins in lowering levels of triglycerides and elevating HDL-C.8, 9, 10 The LDL-C is reduced by about 5-20%.11 Mixed dyslipidemia characterized by elevated LDL-C and triglyceride is the most commonly observed dyslipidemia in patients of CAD. The guidelines recommend high dose statins for primary and secondary prevention in high-risk patients.12, 13, 14 Fenofibrate are recommended if Non-HDL-C goals are not achieved after maximum recommended dose of statins. Post hoc analysis of clinical trials with fenofibrate have revealed significant reduction in CV events in patients with elevated triglycerides at baseline.13, 15 The statin and fenofibrate acts at different targets in lowering lipids thus we hypothesize that combination regimen would be more effective in achieving the lipid target goals than high dose statin in patients with mixed dyslipidemia. There are limited trials comparing safety and efficacy of combination of statins with fenofibrate with high dose statins in patients with mixed dyslipidemia. 16, 17 Thus we aimed to compare the lipid lowering efficacy and safety of combination of moderate dose rosuvastatin and fenofibrate with high dose rosuvastatin in patients of stable CAD with mixed dyslipidemia.
Materials and Methods
Set up, study design, patient population and sample size
The patients with established stable CAD with mixed dyslipidemia visiting outdoor services of Cardiology department of tertiary care hospital of Indira Gandhi Medical College (IGMC) Hospital Shimla in HP, India were the target patient population enrolled. The study was prospective randomized open label blinded endpoint parallel arm trial. The sample size was calculated based on assumptions and 179 patients were included in the study (Figure 1).
Definitions
The stable CAD:18 was labeled if patients of CAD had any one of the following
History of documented myocardial infarction,
History of percutaneous coronary intervention (PCI) of more than 3 months duration
Coronary artery bypass grafting (CABG) of more than 3 months duration.
Angiographic evidence of obstructive CAD.
Mixed dyslipidemia
Patients were labeled to have mixed dyslipidemia if had LDL-C of more than 100 mg/dl, and Triglyceride of >150 mg/dl estimated after more than 10 hours of fasting off lipid lowering drugs for one week.
Exclusion criteria
The patients were excluded from enrollment if had any one of the following;
Scheduled for CABG or PCI,
History of PCI/CABG within preceding 3 months,
History of hypersensitivity/intolerance for rosuvastatin or to fenofibrate,
History of diagnosed hereditary or acquired myopathy
Impaired renal function (eGFR<45 ml/minute/1.73m2,
Active liver disease
Uncontrolled diabetes mellitus (hemoglobin A1c ≥ 8.5%), or untreated
Hypothyroidism or hyperthyroidism
Patient judged to be poor compliant for follow up evaluation.
The patients not willing to participate.
Ethical approval & patient enrollment
Baseline data collection
The self-reported data of demographics, health behavior, cardio metabolic risk factors, relevant medical history was recorded as per structured data recording format. Following questionnaire-based data recording patients were examined to record anthropometrics, to measure BMI and waist circumference and BP using validated tools and following standard guidelines. Three reading of BP were recorded using mercury sphygmomanometer after 5 minutes of rest at about one-minute intervals and average was used for analysis. The 5 ml of plasma venous blood was drawn after overnight fasting state to measure total cholesterol, Triglyceride, HDL-C in auto analyzer Model Arba Transasia using standard kits, LDL-C was derived using Friedwald formula. Serum SGOT, SGPT, CPK, creatinine, HbA1c was also measured to assess the safety of the study drugs using standard kits.
Randomization procedure and intervention
The eligible patients volunteering to participate were assigned, to Fixed Dose Combination (FDC) or to high dose statin arms randomly using computer generated random numbers after baseline data collection. The odd numbers were assigned FDC arm and even number were assigned High Dose Rosuvastatin (HDR) arm. In the FDC arm patients were prescribed 20 mg of rosuvastatin and 145 mg of fenofibrate once a day and in high dose statin group was given 40 mg of rosuvastatin once a day. All patients were advised to follow regular exercise and for intake of vegetables and fruits and avoid fast foods and fried foods throughout the study. The addition of other lipid lowering medications was prohibited during the study period. The rest of the treatment was as per discretion of the treating physician.
Follow up visits for monitoring adverse reactions
Patients were advised to report any time if they experience any adverse symptoms. However regular follow up was scheduled at one month and at 3 months. Patients were withdrawn from the study if they experienced any serious adverse events during the follow-up period, including two fold increase from upper level of reference values in the levels of alanine transaminase and (ALT) and aspartate transaminase (AST) and or increase in creatine phosphokinase (CPK) levels to ≥3 times the upper limit of normal range, associated with muscular symptoms; unexplained CPK elevation 5 or more times the upper limit of normal without muscle symptoms at one month and or fixed drug eruption; or occurrence of serious drug reactions of any kind during follow up visit.
Outcomes evaluation
The self-reported adverse symptoms and or reactions were recorded unblended. However, the lab personnel measuring lipids and other safety biomarkers were blinded of treatment assignment. To evaluate the efficacy and safety of combination regimen with high dose Rosuvastatin arm the repeat lipids, SGOT, SGPT, CPK, blood glucose and HbA1c levels were measured at the end of 3 months after about 10 hours of fasting state using same auto analyzer and standard kits and following the standard protocol.
Statistical analyses
The study sample was described as categorical variables were reported as counts and percentages for categorical variables and mean± standard deviation (SD) for normally distributed continuous variables and median and interquartile range at 1stand 3rd quartile for none normally distributed continuous variables. The distribution of demographics, health behavior, cardio metabolic risk factors and medication history were compared between study arms with chi square test for categorical variables and unpaired t test for continuous variables with normal distribution and Mann Whitney test for not normally distributed variables. The lipid lowering efficacy of HDR and FDC was evaluated by comparing significance of differences in the percentage mean change from baseline levels of LDL-C, HDL-C, Non-HDL-C and triglyceride, using unpaired t test for normally distributed and Mann Whitney test for non-normal distributed continuous variables. The significance of differences in proportion of study population in each treatment arms achieving target goals of LDL-C (<70 mg/dl), Non-HDL-C and HDL-C (<100 mg/dl) were tested using X2 test. As per protocol analysis was done to compare efficacy and safety of the study drugs. Two tailed significances at <0.05 were taken as statistically significant. The data was analyzed using statistical software STATA version 13.
Results
Study population enrollment
Details of patient screening and enrollment are described in patient selection flow chart Figure 1. Out of 291 patients; only 179 patients fulfilled the eligibility criteria, 88 patients were randomly assigned to HDR arm (40mg per day) and 89 patients to FDC arm (fenofibrate 145mg per day with rosuvastatin 20 mg per day). Five patients were withdrawn from study due to adverse drug reactions in HDR arm. Seven patients were lost to follow up four in high dose group and three in combination group, thus follow up was complete in 95.1% in HDR arm and 96.6% in FDC arm. The follow up period of 3 months was completed by 79 patients in HDR arm and 86 patients in FDC arm and their data was used for analysis.
Characteristics of the study sample
The detailed description of socio demographics, medical history, health behavior, distribution of CV risk factors are reported in Table 1, Table 2. In brief both the study groups were matched for; demographics, health behavior and CV risk factor distribution and medications. The study sample in both arms was middle age predominantly male population. The majority of the patients had past history of Myocardial infarction in both arms.
Primary outcome
FDC regimen was significantly more effective in lowering lipid fraction compared to High Dose Rosuvastatin (HDR). Percentage reduction of mean baseline levels of lipid fractions was significant higher for LDL-C, non-HDL-C and TG levels and percentage increase in HDL-C from baseline level of HDL-C was significantly higher for in FDC arm compared to HDR arm. (Figure 2)
Although proportion of patients achieving target goals of LDL-C and non-HDL-C goals were higher in combination arm but was statistically not significant. (Figure 3)
Effect on cardiometabolic risk factors
The BP, BMI and uric acid decreased significantly in combination arm compared to high dose statin arm. There was no significant difference in HbA1C and fasting blood glucose levels (Table 3).
Safety outcomes
Adverse effects (AE) were experienced by 44.3% and 27.9% of patients in HDR and FDC arms respectively Figure III. The incidence of myalgia was observed in 34.2% (n-27) patients in the HDR Vs. 23.3% (n-20) patients in FDC arm (p=0.16). No cases of rhabdomyolysis were reported. Anorexia was the significantly higher AEs, in the HDR 44.3% vs. 16.3% (p<0.0001), followed by raised serum CPK level 24.1% vs. 10.5% respectively (p<0.03). Although there was a trend of lower level of SGOT and SGPT in FDC but was statistically not significant (Table 4).
Table 1
Baseline characteristics of the study population.
[i] Note: - FDC: Fixed dose combination, HDR: High dose rosuvastatin, PCI: Percutaneous Coronary Intervention, CABG: Coronary Artery Bypass Graft, CVA: Cerebrovascular Accident, PVD: Peripheral Vascular Disease, MI: Myocardial infarction, H/O: History Of, CAD: Coronary Artery Disease, NYHA: New York Heart Association, ACE: Angiotensin converting enzyme, ARB: Angiotensin Receptor Blocker.
Table 2
Baseline distribution of anthropometrics, BP and lipid profile, renal function and transaminases
[i] Note: FDC: Fixed dose combination, HDR: High dose rosuvastatin, BMI: Body Mass Index, HDL-C: High Density Lipoprotein Cholesterol, LDL-C: Low Density Lipoprotein Cholesterol, VLDL-C: Very Low-Density Lipoprotein Cholesterol, Non-HDL-C: Non-High Density Lipoprotein Cholesterol, AST: Aspartate Transaminase, ALT: Alanine Transaminase, HbA1c: Glycated Hemoglobin, eGFR: Estimated Glomerular Filtration Rate.
Table 3
Comparison of lipid lowering efficacy of combination regimen with high dose Rosuvastatin arms
Table 4
Comparison of adverse events between study arms at the end of Follow up
Discussion
Mixed dyslipidemia is a common lipid metabolic disorder characterized by elevated levels of both cholesterol and triglycerides. 13 It has diverse underlying mechanisms thus unlikely to be addressed by lipid lowering agent targeting one pathway. The Statins are potent lipid lowering agent acts by inhibiting intracellular synthesis of cholesterol in hepatocytes resulting in increased expression of surface LDL receptors that enhances uptake of circulating LDL and IDL particles thus lowering the levels of LDL-C primarily. 19 The fibrates enhance the activity of lipoprotein lipase leading to increased hydrolysis of triglycerides and thus decreases level of triglycerides.20 The mixed dyslipidemia represents an important therapeutic challenge since monotherapy only partially correct the underlying metabolic defects.21
The present study was designed to compare the efficacy and safety of high dose rosuvastatin 40 mg with moderate dose rosuvastatin 20 mg and fenofibrate 145 mg on lipid lowering efficacy in patients of stable CAD with mixed dyslipidemia. The combination of statin and fenofibrate was more effective in lowering, total cholesterol, LDL-C, Triglyceride and increase in level of HDL-C. The tolerance to combination lipid lowering agents was better than high dose statin. Five patients in high dose statin group had to be withdrawn from the study due to adverse reactions. There was no significant difference in mean levels of markers of liver injury although proportion of patients with elevation in levels of CPK more than three times above the upper level of normal reference value was significantly higher in high dose statin group.
The available evidence from large controlled trials among high-risk patients and patients with established atherosclerotic vascular disease demonstrated the efficacy in reducing the risk of cardiovascular events.22, 23, 24, 25, 26, 27 The benefit is function of extent of LDL-C reduction irrespective of baseline LDL-C levels. LDL-C forms the major atherogenic lipoprotein particle; however, non-HDL-C (VLDL, IDL-C) are also important remaining atherogenic lipoproteins particles especially in patients with mixed dyslipidemia. The post hoc analysis of lipid lowering trials have demonstrated reduction in CV events among patients with elevated triglycerides at baseline in fenofibrate arm at background treatment with high dose statin 13, 15 thus substantiating the argument that lowering of non-HDL-C is equally important as is LDL-C in reducing CV events in patients of CAD. The incremental lipid lowering potency of Statins by doubling the dose is by approximately 6%.7 However addition of fenofibrate lowers the LDL-C by about 5 to 20%.11 The combination of statin with fenofibrate was also demonstrated to be more effective in reducing the different atherogenic lipids fractions by the other investigators such as Agouridis et al.28 and Foucher et al. 29
Thus, we argue that combination strategy would be more effective and safer in treating mixed dyslipidemia as against the recommended use of maximum dose of Statins and adding fenofibrate only if TG, non-HDL-C targets are not achieved. Future clinical outcome trials are required to compare the efficacy and safety of combination of moderate dose Statins with Fenofibrate with high dose Statins in patients with mixed dyslipidemia.
Interestingly, the mean SBP and DBP of combination arm was significantly lower than HDR arm (120.17±13.11mmHg vs. 124.3±14.65, p<0.05) and (75.02±09.2 mmHg vs. 80.84±9.55mmHg, p<0.0001), respectively. The mechanism(s) of BP lowering effect of fenofibrate is conjectural but could be mediated by decrease in body fat mass (24.9±3.2 vs. 25.9±3.5 p<0.05), decreased oxidative stress leading to improvement in endothelial function and improved insulin sensitivity. The BP lowering effect of fenofibrate was also documented among salt sensitive hypertensives by Gilbert K et al.30 The mean Uric Acid level was significantly lower in FDC arm compared to HDR (4.93±1.09mg/dL vs. 5.94±1.13mg/dL, p<0.0001), may be an indicator of decrease in oxidative stress. Significant increase in HDL-C level with combination arm may also be contributory factor in reducing oxidative stress as was also observed by other investigators.31, 32, 33, 34 Thus, anti-oxidant and anti-inflammatory effect of fenofibrate could be the some of the underlying mechanisms of favorable effects on cardio metabolic risk factors. There was no significant difference on levels of fasting blood glucose and HbA1c between to study groups however insulin level was no measure to evaluate the effect of studied lipid lowering regimens on insulin sensitivity.
Safety profile of the combination arm was found to be significantly better than high dose arm. No case of rhabdomyolysis or hepatitis with SGOT/SGPT levels more than three times upper reference limit was observed. Decreased appetite was significantly higher in the HDR arm (44.3% vs. 16.3%, p<0.0001) and there was a trend of higher prevalence of myalgia but was statistically insignificant. Proportion of patients with elevated level of CPK was significantly higher in HDR arm (24.1% vs. 10.5%, p<0.03). The similar observations are reported by other investigators.35, 36, 37, 38, 39, 40
Limitations
The symptoms-based reporting of clinical adverse reactions was enquired and recorded by investigator who was not blinded for treatment assigned. Thus, there could be bias in the reported frequencies of adverse reactions. However objective assessment of biomarkers of hepatic and skeletal muscle injury were estimated by lab personals blinded of the treatment assigned.
Conclusion
The combination of moderate dose Rosuvastatin and Fenofibrate is more effective in reducing LDL-C, Non-HDL-C and triglyceride and had better tolerance profile than high dose statin in patients of CAD with mixed dyslipidemia. The BMI, Blood pressure and Uric acid levels were decreased significantly in combination regimen. Future clinical outcome trials are warranted to evaluate the superiority of combination regimen with high dose statin in patients of atherosclerotic vascular disease.
