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Table of Content Volume 16 Issue 1 - October 2020
Effect of fixed dose combination of vitamin d with atorvastatin on serum lipid levels in hyperlipidemic patients
Abhima M B1*, Vinu Wilson2, Binu S S3, Vijayalekshmi Amma4
1Assistant Professor, Department of Pharmacology, Sree Narayana Institute of Medical Sciences Chalakka Ernakulam, Kerala, INDIA. 2Assistant Professor, Department of Pharmacology, TDMC, Alappuzha, Kerala, INDIA. 3Associate Professor, 4Retired Professor, Department of Pharmacology, Sree Gokulam Medical College and Research Foundation, Venjaramoodu, Kerala, INDIA. Email: drabhima88@gmail.com
Abstract Background: Hyperlipidemia is a well documented risk factor for atherosclerosis, responsible for significant amount of ischemic strokes and heart disease globally. Studies have shown that vitamin D supplementation with atorvastatin has synergistic effects in lowering serum cholesterol concentrations and ameliorating statin-induced myalgia and myopathy. Aim and objective: To estimate the effect of fixed dose combination of 1000 I.U of Vitamin D3 and Atorvastatin 10mg per day for 3 months on serum HDL, VLDL and Triglyceride values in hyperlipidemic patients compared to those on Atorvastatin 10 mg per day alone. Methodology: The study was a Prospective multiple arm analytical observational study. History and medical details and Data of serum lipid profile investigation, routinely checked at 6 weeks intervals in patients of cardiology department, were collected from the 97 recruited patients for 3 months after obtaining written informed consent from each patient. Results: The results of our study showed a significant reduction in VLDL and Triglyceride Cholesterol values in two study groups at 12 weeks compared to baseline. No significant difference was observed between the two groups. 83% of patients in the study showed a significant elevation of HDL Cholesterol from baseline after 3 weeks of treatment. The mean percentage increase in HDL values from baseline to 3 weeks in Atorvastatin –Vitamin D group showed a significant difference compared with the other group. Key Word: Vitamin D, atorvastatin.
INTRODUCTION Hyperlipidemia is the presence of elevated levels of lipids or lipoproteins in the blood.It is an important modifiable risk factor for atherosclerosis leading to 17.3 million deaths per year, likely to be more than 23.6 million by 2030. 1 Globally, about 56% of ischemic heart disease and 18% of strokes are due to raised cholesterol levels. 2 The Indian subcontinent is home to 20% of the world’s population. Cardiovascular diseases (CVD) have become the leading cause of death in India like the developed countries. However, coronary artery disease (CAD) is affecting Indians at least 5-6 years earlier than people of western countries. A recent survey by Indian Council for Medical Research (ICMR) showed that 79% of population they studied had at least one lipid abnormality with regional variations. 3 Reduction in serum cholesterol levels is one of the most important strategies in the prevention and treatment of CAD. This may be achieved by dietary and lifestyle modifications involving restriction of dietary fat intake and regular bodily exercise. However, most patients of hyperlipidemia frequently require lipid-lowering medications to achieve target serum lipid levels. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) and American Heart Association (AHA) guidelines recommend the use of statins for the primary prevention of CAD based on an individual's risk factor profile and serum low-density lipoprotein cholesterol (LDL-C) level. In fact, HMG-CoA reductase inhibitors (statins), the most commonly prescribed lipid-lowering medications are also the most frequently prescribed drugs worldwide Among the various statins, atorvastatin is the single most commonly prescribed HMG-CoA reductase inhibitor worldwide. Various trials of atorvastatin in the primary and secondary prevention of CVDs have demonstrated its beneficial effects in reducing the risk of death or major cardiovascular events compared to other statins. 4 Treatment of hyperlipidemia with statins may cause dose-related side-effects such as elevation of hepatic transaminase levels, myalgia, myositis and uncommonly rhabdomyolysis. Myalgia have also been shown to be associated with vitamin D deficiency and to resolve with correction of the vitamin D deficiency. 5 Based on these studies, pharmaceutical companies have introduced fixed dose combinations of atorvastatin and vitamin D in India, which are being prescribed widely by clinicians. Recently, vitamin D has been increasingly shown to influence the risk of several disorders including cardiovascular diseases. 6 Specifically, vitamin D may have an influence on dyslipidemia and vascular calcification, two important predictors of cardiovascular disease. 7 In spite of being a sunny tropical country, the Indian population has been found to have high prevalence of (70%) of VitD deficiency. 8 Studies exploring the effect of concomitant vitamin D administration on the hypolipidemic effectiveness of statins are scarce in the literature and specifically absent in the Indian population. Therefore, this observational study was conducted to explore the effectiveness of fixed dose combinations of atorvastatin and vitamin D in reducing serum cholesterol levels compared to treatment with atorvastatin alone. Aim and objective: To estimate the effect of fixed dose combination of 1000 I.U of Vitamin D3 and Atorvastatin 10mg per day for 3 months on serum HDL, VLDL and Triglyceride values in hyperlipidemic patients compared to those on Atorvastatin 10 mg per day alone.
MATERIAL AND METHODS Present study was a Prospective Multiple Arm Analytical Observational study carried out at Sree Gokulam Medical College and Research Foundation, Trivandrum during January 2014 to July 2015. Study population was Hyperlipidemic Patients attending OPD Of Department Of Cardiology. Inclusion Criteria:
Exclusion Criteria:
A valid written consent was taken from patients after explaining study to them. Data was collected with pretested questionnaire. Demographic details, medical history and treatment particulars were collected using a case record form. Data of serum lipid profile investigation, routinely checked at 6 weeks intervals in patients of cardiology department, were collected from the recruited patients. Lipid profile was estimated using SIEMENS RxL Integrated Autoanalyzer System in Biochemistry laboratory of Sree Gokulam medical college and Research Foundation, Trivandrum. Total cholesterol was estimated using SIEMENS CHOL Flex reagent Catridge with an intra-assay variance of 0.84% and an inter-assay variance of 1.3%. LDL Cholesterol was estimated using SIEMENS ALDL Flex reagent Catridge with an intra-assay variance of 1.6%. HDL cholesterol was estimated using SIEMENS AHDL Flex reagent Catridge with an intra-assay variance of (2.3%) and an inter-assay variance of (2.4%). Triglycerde levels were estimated using SIEMENS TG Flex reagent Catridge with an intra-assay variance of .7% and an inter-assay variance of 1.1%. VLDL were calculated using Friedewald formula- TG/5 (19) Change in serum LDL cholesterol levels at the end of 6 weeks and 12 weeks in hyperlipidemic patients on combination of 1000 I.U of vitamin D3 and atorvastatin 10 mg per day compared to those on atorvastatin 10 mg per day alone. Change in serum HDL, VLDL and Triglyceride levels at the end of 6 weeks and 12 weeks in hyperlipidemic patients on combination of 1000 I.U of vitamin D3 and atorvastatin 10 mg per day compared to those on atorvastatin 10 mg per day alone. The data was entered in Microsoft® Excel worksheet and imported into SPSS version 20 for analysis.
RESULTS The study consecutively monitored 97 hyperlipidemic patients in whom the study drugs were prescribed by the treating physicians from January 2014 to July 2015. In our study, The mean age and BMI of patients were 53 ± 6 yrs and 25.7 ± 1 kg/m2¬, respectively. Of the 97 hyperlipidemic patients, 13 (13%) were diabetic, 23 (23%) had coronary artery disease and 13 (13%) were hypertensive. Among these hyperlipidemic patients, 48 were prescribed Atorvastatin alone and 49 were prescribed Atorvastatin - Vitamin D fixed dose combination (FDC) by the treating physicians. The common Atorvastatin-vitamin D FDCs being prescribed by the physicians were Atorsave-D® and D-Aztor® The baseline characteristics of patients in the two treatment groups are shown in Table 1. Significant reductions in serum VLDL cholesterol and serum triglycerides and elevation of HDL cholesterol were observed in both the treatment groups at 6 and 12 weeks of treatment compared to respective baseline values (Table 2 ). However, changes in these outcome measures were not different between the two treatment groups at 6 or 12 weeks of treatment. Patients in both treatment groups had variable changes in serum HDL cholesterol, VLDL cholesterol and serum triglyceride values at 6 and 12 weeks compared to baseline values. Therefore, we did two post-hoc sub-group analyses of the two treatment groups, viz. (1) between patients who improved and (2) between those who deteriorated, with respect to the above mentioned variables. In the first sub-group analysis, comparison of percentage increase in HDL cholesterol and percentage decrease in VLDL cholesterol and triglyceride levels among patients who improved in these parameters in both treatment groups at different time-points showed significantly higher percentage elevation in HDL cholesterol in Atorvastatin-Vitamin D FDC group compared to Atorvastatin group alone at 12 weeks ( Table 3). In the second sub-group analysis, comparison of percentage decrease in HDL cholesterol and percentage increase in VLDL cholesterol and triglyceride levels among patients who deteriorated in these parameters in both treatment groups at different time-points did not show any difference between the groups at 6 or 12 weeks (Table 4).
Table 1: Baseline characteristics and baseline lipid profile values of the two treatment groups
Table 2: Outcome measures at baseline and after 6 and 12weeks of treatment in the two treatment groups
Table 3: Percentage change at different time-points in sub-groups of patients in the two treatment groups who improved their lipid profile with respect to HDL Cholesterol, VLDL cholesterol and Triglyceride levels
Table 4: Percentage change at different time-points in sub-groups of patients in the two treatment groups who deteriorated with respect to HDL Cholesterol, VLDL cholesterol and Triglyceride levels
DISCUSSION The mean age and BMI of the patients in this study were comparable to that reported in previous studies. 9-11 Among 97 hyperlipidemic patients, 13 % had diabetes mellitus, 13% had hypertension and 23% had coronary artery disease. In a study done in North India among dyslipidemic patients, 22% had hypertension,16% had diabetes which was higher than our study. 12 The mean HDL Cholesterol of patients in our study was 42 ± 5 mg/dL. A study done in South India showed that the mean HDL cholesterol levels were low (40mg/d L). 13 Another Indian study had shown that the mean HDL values of individuals more than 45 years at rural Gujarat is higher than urban Gujarat, Northern and Southern Indian population. 14 The baseline median triglyceride values 99, (80,136) in our study was significantly lower than the median triglyceride values of the previous studies. 15,16 In our study, the median percentage reduction in triglyceride levels at 6 weeks was 4% and at 12 weeks was 6% which was lower compared to previous studies. In one study the median percentage reduction in triglyceride at 6 weeks was 33-39% in patients with baseline triglyceride values >200 mg/dL and 14-17% in those having baseline triglyceride values <200 mg/dL (116). Another study showed a median percentage reduction of 37% in triglyceride values with atorvasatin 10mg after 12 weeks of therapy. 17 A study done by Harold E Bays with Atorvastatin 10mg for 8 weeks showed a median percentage elevation of HDL Cholesterol by 10 (1.2, 16.3) which was higher than the values in our study. 16 Elevation of HDL cholesterol is usually achieved in patients with normal HDL-Cholesterol rather than those with reduced levels. However, those patients who achieved an increase in HDL levels in both groups achieved a median elevation of 5-8% in both groups which is comparable to that reported in literature. 18 It has been documented that Atorvastatin 10 mg reduces LDL cholesterol by 31-35% regardless of the baseline cholesterol levels. 18 In the present study, the mean percentage reduction of LDL Cholesterol values from baseline were maximum at 12 weeks of therapy. The results of our study showed that patients of hyperlipidemia on both the treatments achieved similar reductions in VLDL cholesterol and serum triglyceride levels as well as similar elevation in HDL cholesterol level at 6 weeks and 12 weeks of treatment. There were no differences between the two treatments with respect to hypolipidemic effectiveness or safety over the period of 12 weeks. However, in a post-hoc analysis, it was found that there was higher percentage elevation in HDL cholesterol levels at 12 weeks in Atorvastatin-Vitamin D FDC treated group versus Atorvastatin treated group when compared between sub-group of patients who improved their HDL cholesterol levels in the two arms. A number of studies have suggested an association between vitamin D and HDL cholesterol. A study by Maki et al. demonstrated the significant relationship between 25(OH)D and HDL-C after adjustment for established determinants of the HDL-C, such that with every rise in 10 ng/mL in 25(OH)D, there is 4.2-mg/dL elevation of HDL-C concentration. 19 Another study by Rasa et al., showed that increased serum 25[OH]D levels are associated with large HDL particles. And they concluded that the cardio-protective effect of vitamin D is by promoting the formation of large HDL particles which help in reverse cholesterol transport. 20 Another cross -sectional and retrospective cohort study to evaluate the effect of 25-hydroxyvitamin D levels on lipid levels showed that Vitamin D deficiency was associated with an unfavourable lipid profile while serial elevation of vitamin D levels was associated with a increase in total cholesterol and high-density lipoprotein cholesterol but changes in LDL cholesterol and triglycerides were not significant. 21 Thus, it is possible that addition of vitamin D with statins may help in elevating HDL cholesterol levels in addition to correcting vitamin D deficiency widely prevalent in our country. However, the effect of vitamin D in modulating levels of non-HDL cholesterol needs to be explored further in large interventional studies.
CONCLUSION Addition of Vitamin D have a positive relationship on HDL level.
REFERENCES
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