“A Comparative Study of Efficacy of Atorvastatin Alone and Atorvastatin with Omega-3 Fatty Acids Combination in Patients with Hyperlipidaemia Attending Tertiary Care Hospital”

Background: Current treatment with statins has become an integral part of vascular diseases but monotherapy has a significant residual event rate. Due to particularly one of the factor associated with atherogenic lipid phenotype that is characterized by a low high-density lipoprotein (HDL) cholesterol and increase in non-HDL cholesterol like Low-Density Lipoprotein (LDL). Omega-3 Fatty acids have demonstrated a preventiverole in primary and, particularly secondary cardiovascular diseases. Hence this study was planned to compare the efficacy of Atorvastatin alone with Atorvastatin and Omega-3 fatty acids in treatment in hyperlipidaemia patients. Methods: The study was comparative, randomized, and prospective and open labeled conducted in MI patients. A total of 100 patients were selected based on inclusion and exclusion criteria. They were divided randomly into two Groups (Group–A and Group-B). Group-A was given Atorvastatin 10mg/day and Group-B was given Atorvastatin 10mg/day and Omega-3 fatty acids 600mg/day for 6 months. Follow up was done every month and efficacy was measured by assessing the lipoprotein levels in serum. Results: The results were compared before treatment and after 6 months treatment.The levels Original Research Article Srinivasa et al.; JPRI, 33(45B): 482-490, 2021; Article no.JPRI.74791 483 were significantly decreased Total Cholesterol (TC), LDL, Low-Density Lipoprotein (VLDL), Triglycerides (TG) and HDL levels were increased in Group–A and Group-B. When these results compared between two Groups the HDL levels were increased also it shown high significance (<0.001) but there were no significance changes in other cholesterol levels. Conclusion: The present study results showed that Atorvastatin and Omega-3 fatty acids treatment was more effective than Atorvastatin alone treatment in improving HDL-C levels from base line and it may have a additive effect in major coronary artery diseases.


INTRODUCTION
Hyperlipidemia patients have roughly twice the risk of developing Coronary Heart Disease (CHD) as compared to those with normal total cholesterol levels [1]. Over the past decade, Statins use has shown strong evidence in preventing cardiovascular morbidity and mortality but still there is controversy due to conflicting results in various types of studies [2][3][4] According to WHO, an estimated 7.2 million people died from CHD in 2008, representing approximately 12% of deaths worldwide [5].
Lipoproteins are classified into five types and these are responsible for synthesis of cell membrane, several biochemical functions like precursor for hormonal synthesis and fat-soluble vitamins [6]. Several studies have reported that Hyperlipidemia leads to several-fold increased risk of CHD. Among five lipoproteins LDL-C and HDL-C had a major role in increasing the risk of cardiovascular events, including myocardial infarction and stroke [7]. Pathological changes occurred in the setting of acute coronary syndrome (ACS), such as endothelial dysfunction, activation of inflammatory and coagulation cascades, and thrombus formation. The low HDL levels reflected disturbances in triglyceride metabolism.
Recently antiatherosclerotic properties of HDL have been discovered with the process of cholesterol clearance and named as Reverse Cholesterol Transfer (RCT) [8,9].
Currently statins are primarily used to lower cholesterol bio-synthesis and this will be protective against the cardiovascular disorders. The mode of action is via inhibition 3-Hydroxy-3methyl glutaryl (HMG) CoA reductase -a rate limiting enzyme for cholesterol bio-synthesis pathway [10]. Based on risk of atherosclerosis, primary target is lowering LDL levels and secondary target is raising HDL levels [11,12]. Many clinical and meta-analysis studies have shown statins to be effective in approximately lowering the LDL levels by 20 -50% as well as TG levels by 10 -20% and causing a possible net increase in HDL levels by 5 -10%. Despite this, a large number of patients are still at high cardiovascular risk even after statin monotherapy.13 Emerging therapies for restoring the normal levels of lipoproteins is to target various pathways like clearance of cholesterol and pro-atherogenic lipoproteins modifications [13][14][15][16][17][18].
Many Clinical trials of prescription omega-3 fatty acids as monotherapy or as an adjunct to statin therapy have supported its efficacy for improving the lipid profile (reducing triglycerides and triglyceride-rich lipoproteins and raising HDL-C) in individuals with hypertriglyceridemia or mixed dyslipidemia [18,19]. This combination therapy may be preferable to drug combinations for treatment of combined hyperlipidaemia. Hence, the present study was planned to assess the safety and efficacy of Atorvastatin alone and Atorvastatin and omega-3 fatty acids in MI patients with Hyperlipidemia in the department of Medicine, in collaboration with department of pharmacology, Vijayanagara Institute of Medical Sciences (VIMS) a tertiary care hospital, Bellary.

Study Design
The study was a comparative, prospective, randomized and open label study. The present study was conducted during the period March 2011 -April 2012. Patients with history of recent MI or post MI, attending the outpatient (OPD)/ in patient (IPD) department of General Medicine, Vijayanagara Institute of Medical sciences (VIMS), Bellary. The study was started before 3 months of the treatment. During 3 months around 210 patients were came to OPD & IPD with history of MI. For selection of the participants by applying exclusion and inclusion criteria 84 patients were excluded. 26 patients were not shown interest to participate in the study.
Reaming 100 participants were included in the study.
A thorough clinical examination was done for all patients and the required laboratory investigations such as routine laboratory tests like Complete blood count, Hemoglobin%, blood sugar, serum creatinine, blood urea and liver function test (LFT), Lipid profile and Electrocardiogram. A total of One Hundred (100) patients were selected for the study by applying Inclusion -Exclusion criteria Fig. 1.
Also, patients who were taking medications, known to affect plasma lipid concentration or known to interact with study medications were excluded from the study. The participants randomly divided into two Groups and named as Group-A and Group-B by simple randomization using random numbers generated by computer software research randomizer. Group-A subjects were given Atorvastatin 10 mg tablet once daily (OD) orally and Group-B subjects were given Atorvastatin 10 mg tablet OD along with Omega-3 fatty acids 300 mg capsule twice daily (BD) (600mg/day). For all the study participants the drugs were dispensed with free of cost during the treatment period (6 months) and were followed up every month till the end of the study Fig. 2.
Clinical Efficacy from week 0 (before the drug intervention) till the end of study (after drug intervention) was assessed by doing lipid profile. It was repeated every month to assessing the change in parameters like reduction in Total cholesterol (TC), Triglycerides (TGs), LDL cholesterol levels and rise in HDL cholesterol in each Group i.e., Group-Aand Group-B. Also Liver function test was repeated at 3 rd month and at the end of the study.
The data was collected and entered into a specially designed proforma (Case Recording Form) for the study. The data was analysed by ttest and P values for independent Groups.

Total cholesterol
After the treatment, total cholesterol levelswere significantly (p<0.001) reduced in both the Groups.In patients who were treated with Atorvastatin(Group A), the mean reduction of total cholesterol levels were 27.80±12.88 and in those treated with Atorvastatin with Omega-3 fatty acids (Group-B) TC levels were 27.90±15.91. The percentage decrease of TC levels in Group-A was 12.66%, Group-B was 12.54%. The percentage decrease in of TC levels in Group-A was 11.5 % and in Group-B it was 13.5%. When Group-B was compared with Group-A the TC levels were not significantly decreased.The difference between them was 0.12%.

HDL cholesterol
After the treatment, in both the Group's total HDL levels were significantly (p<0.001) increased as compared to the baselines levels. In patients who received Atorvastatin alone (Group-A), the mean increase in HDL -cholesterol levels was 2.16±1.01 and in Atorvastatin with Omega-3 fatty acids treated patients (Group-B) it was 3.57±1.26. The percentage increase of HDL cholesterol levels in Group-A was 5.54% and in Group-B it was 9.27%.When Group-B was compared with Group-A the HDL levels were significantly increased. The difference between them was 3.7%.

LDL-cholesterol
After six months treatment, LDL cholesterol levels were significantly (p<0.001) reduced in both the Groups. In Atorvastatin alone treated patients (Group-A), the mean reduction of LDLlevels were 25.63±13.19 and in Atorvastatin with Omega-3 fatty acids treated patients (Group-B),levels were 26.30±15.79. The percentage decrease of LDL cholesterol levels in Group-A was 17.78% and in Group-B was 17.71%.The percentage decrease in LDL levels in Group-A was 11.5% and in Group-B was 13.5%. When Group-B was compared with Group-A the LDL levels were not significantly decreased. The difference between them was 0.7%.

VLDL cholesterol
At end of the treatment period, VLDL cholesterol levels were significantly (p<0.01) reduced in both the Groups.In patients who received Atorvastatin (Group-A), the mean reduction of VLDLcholesterol levels was 4.34±2.51 and in Atorvastatin with Omega-3 fatty acids treated patients (Group-B),it was 5.16±2.62. The percentage decrease in VLDL-C levels in Group-A was 11.57 % and in Group-B it was 13.50%.The percentage decrease in VLDL levels in Group-A was 11.5 % and in Group-B it was 13.5%. When Group-B was compared with Group-A the VLDL levels were not significantly decreased. The difference between them was 1.93% Table 1.

Triglycerides
After six months treatment, triglycerides levels were significantly (p<0.001) reduced in both the Groups. In patients who received Atorvastatin (Group-A), the mean reduction of VLDLcholesterol levels was 21.62±12.65 and in Atorvastatin with Omega-3 fatty acids received patients (Group-B), it was 25.86±13.14. The percentage decrease in TG levels in Group-A was 11.5 % and in Group-B it was 13.5%.When Group-B was compared with Group-A the triglycerides levels were not significantly decreased. The difference between them was 2% Fig. 3.

Post Test Analysis to Compare
Between Two Groups

Total cholesterol
In Atorvastatin Group (Group-A) the mean reduction of total cholesterol levels was 27.80±12.88 and in combination Group (Group-B) it was 27.90±15.91. In Atorvastatin Group the mean ± standard deviation (SD) of total cholesterol levels after treatment was reduced to 187.80 ± 12.47mg/dl. In Atorvastatin + Omega-3 fatty acids Group reduction was 184.54±13.58 mg/dl (p > 0.05).

HDL cholesterol
In Atorvastatin Group the mean increase in HDL -cholesterol levels was 2.16±1.01 and in combination Group it was 3.57±1.26. In Atorvastatin Group the mean ± standard deviation (SD) of HDL cholesterol levels after treatment was increased to 41.50 ± 1.67 mg/dl. In Atorvastatin + Omega-3 fatty acids Group increased to 42.78±2.08 mg/dl (p < 0.001).

LDL-cholesterol
In Atorvastatin Group the mean reduction of LDLcholesterol levels was 25.63±13. 19 and in combination Group it was 26.30±15.79.In Atorvastatin Group the mean ± standard deviation (SD) of LDL cholesterol levels after treatment was reduced 114.36 ± 12.46mg/dl. In Atorvastatin + Omega-3 fatty acids Group the reduction was 110.20±13.36 mg/dl (p > 0.05).

VLDL cholesterol
In Atorvastatin Group the mean reduction of VLDL-cholesterol levels was 4.34±2.51 and in combination Group it was 5.16±2.62.In Atorvastatin Group the mean ± standard deviation (SD) of VLDL cholesterol levels after treatment was reduced to31.69 ± 1.44mg/dl. In Atorvastatin + Omega-3 fatty acids Group it was 31.55±1.88 mg/dl (p > 0.05) Table 2.

Triglycerides
In Atorvastatin Group the mean reduction triglycerides levels was 21.62±12.65 and in combination Group it was 25.86±13.14 In Atorvastatin Group the mean ± standard deviation (SD) of triglycerides levels after treatment was reduced to 158.48 ± 7.24mg/dl. In Atorvastatin + Omega-3 fatty acids Group it reduced to 157.78±9.44 mg/dl (p > 0.05) Fig. 4.

Age and Sex
Among 100 patients, 82 were male patients and 18 were female patients. So, the incidence of coronary heart disease with Hyperlipidaemia is more in men than in women in our study Groups.
Our study showed 26 patients were less than 40yrs of age, indicating increasing prevalence of CAD in younger population.

DISCUSSION
Several prospective trials have demonstrated that the addition of Omega-3 fatty acid to statins improved cardiovascular mortality [19,20]. In the present study, we assessed the safety and efficacy of six months treatment with atrovastatin in 50 subjects and atrovastatin and Omega-3 fatty acidsin 50 subjects with MI Fig. 5. The efficacy parameters -LDL, HDL and TG levels were significantly reduced in both the Groups. While comparing these parameters in between the Groups, the HDL levels were only significantly raised in Group-B as compared to Group-A. In CVD, improving HDL levels is a secondary target but several clinical studies concluded that reduction of HDL cholesterol could be a greater coronary risk factor than an increase in LDL cholesterol levels [8,9].
The therapeutic target of cardiovascular protective effect and its possible mechanisms have been discussed below. Elevation of HDL levels potentiates the biological properties including anti-atherogenic, anti-thrombotic and anti-inflammatory [21,22]. HDL has ability to uptake and return excess cholesterol from peripheral tissues back to the liver. It also promotes cholesterol removal through various efflux pathways from macrophages in the artery wall and has potential protective effect against arterial disease

CONCLUSION
Current trend of pharmacological approaches are the combination therapies for disorders or diseases to prevent resistance or tolerance development, improve the efficacy or reduce the unwanted effects and improve the patient compliance as well as cost benefit ratio of treatment. In our study, the pathological condition was treated with novel combination but still only minimal beneficial effects have been observed. Our research study was done in a small group of patients with six months duration. Our study suggest that by elevating HDL levels, normal levels of other lipoproteins may be obtained by longer term treatment of the statins with Omega-3 fatty acids. The study limitations are demonstrated short term effect of the drug Atorvastatin 10mg tablet OD along with Omega-3 fatty acids 300mg capsule twice daily (BD) (600mg/day) in small sample size and not proven the reduction cardiovascular abnormal events by improving the lipid profile.

DISCLAIMER
The products used for this research are commonly and predominantly use products in our area of research and country. There is absolutely no conflict of interest between the authors and producers of the products because we do not intend to use these products as an avenue for any litigation but for the advancement of knowledge. Also, the research was not funded by the producing company rather it was funded by personal efforts of the authors.

CONSENT
The patients were explained about the details of the study and a written informed consent was taken from all the patients before including them in the study.

ETHICAL APPROVAL
Ethical clearance was obtained from the Institutional Ethics committee (IEC) of VIMS, Bellary, before the start of study.