INTRODUCTION:

SARS-CoV-2, the coronavirus that causes COVID-19 is a single stranded RNA virus that interacts with angiotensin enzyme 2 (ACE2) receptors on the cell membrane triggering inflammatory pathways leading to severe acute respiratory distress which might be fatal^1,2. The virus also has thrombotic consequences and might impose changes on the cardiovascular system.

The severity of Covid 19 is associated with alteration of the amount of cytokines release, mainly interleukin6 (IL-6) leading to pulmonary inflammation and lung damage^3-5. SARS-Co-V2 was found to affect carbohydrate metabolism leading to accumulation of fat inside the cells which provide an environment for survival of the virus in the body, this may explain why patients with high blood sugar and cholesterol levels are at a higher risk to develop COVID-19⁶. Covid-19 causes endothelial dysfunction and dysregulated immune response through microvascular damage and Statins were found to have beneficial effects on the clinical events by improving the endothelial and vascular functions⁷. In addition to their effect on cholesterol concentration in the cell membrane, Statins also trigger anti-inflammatory and vascular protection responses, both of these mechanisms affect SARS-CoV-2 virus entry into the cell. Statins also exhibit anti-thrombotic and immunomodulatory effects at different levels which could improve the vascular function⁸. Prior research suggested reduced mortality as the result of Statin use and recommended to give Statins for patients with confirmed Covid-19⁹. Fenofibrate, a cholesterol-lowering drug, has been confirmed to be used for the treatment of COVID-19 because of its ability to reduce fat accumulation in the cell membrane with consequent prevention of virus reproduction. This could downgrade COVID-19 severity to a mild disease^{10, 11}. It has been concluded that COVID-19 viral infection causes the lung cells to start building up fat and Fenofibrate administration initiates the process of fat burning by binding and activating DNA site that is blocked by the virus¹¹. The effect of Statins against COVID-19 was analysed in many previous works but the effect of Fenofibrate on the course of the virus was studied in vitro and there are ongoing studies on human being and this work was conducted to study the effect of Fenofibrate on COVID-19 patients as compared to Statins.

MATERIALS AND METHODS:

This retrospective, observational, open blind study was conducted at Al-Shafa Hospital, Baghdad, Iraq. The study included a cohort of 300 patients with Covid-19 infection who had variable symptoms depending on the severity of the illness and had been treated according to the Iraqi National Guidelines for Covid-19 management. The patients were divided into three groups based on the treatment they received. Group 1 which included 100 patients who received the standard treatment protocol for Covid-19. Another 100 patients with Covid-19 infection in the second group received the standard treatment in addition to their regular cholesterol-lowering medication (Statins). The third group involved 100 patients who were on Fenofibrate (TRICOR®) as a medication for hyperlipidaemia and also received the standard Covid-19 treatment in hospital.

The demographic characteristics of the patients were retrieved, these include age, gender, weight, pre-existing co-morbidities (hypertension, diabetes mellitus, SLE, SHD, asthma, chronic bronchitis, COPD, and hepatitis B or C), the duration of the Covid-19 disease, length of stay in hospital, and severity of the disease; and the need for oxygen therapy or mechanical ventilation or admission to ICU were also recorded. The common symptoms of COVID-19 such as cough, exertional dyspnoea, shortness of breath, sore throat, sneezing, tightness of the chest, running nose, loss of smell or taste were recorded. Other symptoms include headache, tiredness, agitation in addition to myalgia, joints pain, insomnia as well as other Covid-19 related gastrointestinal symptoms (abdominal pain, diarrhoea, vomiting, loss of appetite) were also analysed and compared between the three groups.

The primary endpoint of these patients was defined as negative RT-PCR on day-6 post-inclusion. The result was confirmed by performing 2 sets of PCR test after symptoms appearing at least 24hr interval and a negative CT thorax for Covid-19. Re-testing was done 14 days after discharge from hospital as part of patients’ follow-up. The severity of illness was assessed according to the Iraqi National Guidelines for managing COVID-19 (Appendix 2). Mild cases are those involve patients with mild symptoms and clinically has no signs of pneumonia or on imaging. Moderate cases; however, involve patients with fever, respiratory symptoms and systemic and imaging manifestations of pneumonia. Severe cases on the other hand, involve patients showing respiratory distress with respiratory rate more than 30/minute, oxygen saturation less than 93%, PaO2/FiO2 less than 300, or lung infiltrates more than 50% of the lung field within 24hr on CT Thorax. Critically ill patients involve those who have one or more of the following: ARDS, sepsis, altered level of consciousness, multi organ failure, respiratory failure requiring mechanical ventilation, or patients with cytokine release syndrome (Ferritin more than 600ug/L, LDH more than 250, elevated D-Dimer, elevated serum IL-6 more than three times).

Statistical Analysis:

Statistical analyses were performed using the SPSS statistical package for Social Sciences (version 20.0 for Windows, SPSS, Chicago, IL, USA). Numerical data are presented as mean ± SD, categorical data are presented as number and percentage. Chi-square test was used to compare independent variables and ANOVA test was used to compare dependent variables between the studied group. The P-value of < 0.05 was considered statistically significant.

RESULT:

Table 1, figure 1 and figure 2 illustrate the demographic data for the cohort. Patients in the three groups didn’t show variability in their age and gender. Pre-existing Co-morbidities were not varied between the study group, except for Cerebrovascular diseases which was significantly lower in patients who were on Fenofibrate therapy compared to the other groups. Bodyweight was lower in patients using Fenofibrate. Whereas the lipid profile was lower in the control patients who have no history of high cholesterol level in the past compared to patients using antihyperlipidemic drugs (Table 1, figure 1, 2).

Most of Covid-19 symptoms including cough, exertional dyspnoea, SOB, sore throat, sneezing, headache, tiredness, agitation, diarrhea, joint pain, insomnia, myalgia and fatigue were less prevalent in patients administered antihyperlipidemic drugs prior to being hospitalised compared to the control group. Respiratory rate and pulse rate were less in patients using Statins and Fenofibrate drugs compared to the control group, while body temperature and blood pressure (systolic and diastolic) were not significantly varied between the 3 groups. On admission, WBC was less in patients on antihyperlipidemic drugs and the haemogloin level was higher in the Statins’ group compared to the other 2 groups. Moreover, Covid 19 related pulmonary lesions on CT scan were less evident in patients receiving Fenofibrate compared to control patients. The overall duration of Covid-19 disease was less when an antihyperlipidemic drug was used (Table 2, figure 3, 4). Most of Covid-19 patients in this study who were on the antihyperlipidemic drugs prior hospitalisation had presented with mild to moderate condition, whereas most of the control patients were presented with moderate to even critical condition (Table 2, figure 5).

Table 1. Demographic characteristic in the three groups of COVID -19 patients

Item	Group one Treatment with TRICOR (fenofibrate) N=100	Group two Treatment with statin N=100	Group three Control N=100	P value
Age) years)	49.18 ±11.61	48.39 ± 10.33	47.98 ± 13.64	0.770
Weight \kg	87. 21± 5.47	90.06 ± 5.07	89.38 ± 4.41	0.0002, *
Gender N (%)	F=30 (30 %) M=70 (70 %)	F=33 (33%) M=67 (67%)	F=37 (37%) M=63 (63%)	0.574
Lipid profile
LDL-C mgs/dl	227.05 ± 19.14	232.25 ± 22.06	140.18 ± 12.17	0.0002, *
TG mg/dL	321.23 ± 52.00	328.89 ± 49.86	169.92 ± 17.11	0.0002, *
T- cholesterol mgs/dl	273.78 ± 19.98	280.24 ± 23.56	205.51 ± 24.14	0.0002, *
Presenting comorbidity
HT	11 (11%)	19 (19%)	16 (16%)	0.284
DM	5 (5%)	7 (7%)	8 (8%)	0.687
Coronary heart disease	6 (6%)	8 (8%)	9 (9%)	0.719
Cerebrovascular disease	8 (8%)	10 (10%)	11(11%)	0.003 , *
Asthma	4 (4%)	6 (6%)	7 (7%)	0.646
Organ transport	1 (1%)	0 (0%)	0 (0%)	0.366
bronchitis	7 (7%)	9 (9%)	8 (8%)	0.872
COPD	8 (8%)	9 (9%)	6 (6%)	0.719
Hepatitis B or C	1 (1%)	0 (0%)	0 (0%)	0.366

Tukey HSD Post-hoc Test.

* Group 1 vs Group 2

** Group 1 vs Group 3

*** Group 2 vs Group 3

Table 2. Sign and symptoms in the three groups of COVID -19 patients

Item	Group one Treatment with TRICOR (fenofibrate)	Group two Treatment with statin	Group three control	P value
Systemic signs and symptoms
Cough	42 (42%)	46 (46%)	64 (64%)	0.004 , *
Exertional dyspnea	37 (37%)	40 (40%)	59 (59%)	0.003 , *
SOB	43 (43%)	35 (35%)	56 (56%)	0.010 ***
Sore throat	32 (32%)	30 (30%)	49 (49%)	0.009 , *
Sneezing	8 (8%)	10 (10 %)	20 (20 %)	0.023 , *
chest tightness	14 (14%)	19 (19%)	17 (17%)	0.633
Runny nose	4 (4%)	7 (7%)	6 (6%)	0.646
Loss of smell or taste	51 (51%)	55 (55 %)	60 (60 %)	0.439
Headache	50 (50%)	46 (46 %)	66 (66 %)	0.011 , *
Tiredness	19 (19%)	21 (21 %)	24 (24 %)	0.685
Abdominal pain	16 (16%)	13 (13%)	15 (15%)	0.829
Agitation	8 (8%)	11 (11 %)	28 (28 %)	0.0001 , *
Diarrhea	26 (26%)	30 (30%)	34 (34%)	0.466 , *
Vomiting	17 (17%)	22 (22%)	20 (20%)	0.669
Loss of appetite	20 (20%)	25 (25%)	31 (31%)	0.201
Myalgia and fatigue	28 (28%)	32 (32%)	58 (58%)	0.0001 , *
Joint pain	34 (34%)	40 (40%)	72 (72%)	0.0001 , *
Insomnia	43 (43%)	50 (50%)	74 (74%)	0.00001 , *
Vital signs
Temperature	38.3 ± 0.55	38.50 ± 0.57	38.49 ± 0.52	0.1649
RR	23.01 ± 5.44	24.98 ± 5.90	28.23 ± 5.55	0.0001 , *
PR	92.48 ± 7.09	93.1 ± 8.38	104.92 ± 8.70	0.0001 , *
SBP	127.68 ± 16.03	128.91 ± 14.31	129.21 ± 20.76	0.801
DBP	82.12 ± 7.60	82.57 ± 6.19	81.85 ± 10.56	0.826
Biochemicals parameters
WBCc	12617 ± 1891.2	12770.1 ± 2060.33	15132.5 ± 1943.7	0.0001 , *
Hb	12.50 ± 0.77	13.18 ± 0.85	12.462 ± 1.18	0.0001 , **
Chest CT on admission
Unilateral lesion	18 (18%)	38 (38%)	22 (22%)	0.002 , **
Bilateral lesions	43 (43%)	30 (30%)	64 (64%)	0.0001 , *
Process (days)
Starting signs and symptoms	5.08 ±1.80	5.32 ± 1.72	4.98 ± 1.96	0.402
Hospital stay	13.49 ± 4.92	14.03 ± 3.31	19.53 ± 4.76	0.0001 , *
Condition severity
Mild	39 (39%)	32 (32%)	14 (14%)	0.000 , *
Moderate	38 (38%)	35 (35%)	22 (22%)	0.0417
Severe	16 (16%)	22 (22%)	47 (47%)	0.000 , *
Critical	7 (7%)	11 (11%)	17 (17%)	0.0295 **
Need for RCU	7 (7%)	11 (11%)	17 (17%)	0.0295 **
Need for oxygen supply	29 (29%)	41 (41%)	72 (72%)	0.0001 , , **
Complete recovery	98 (98%)	97 (97%)	94 (94%)	0.293
Death	2 (2%)	3 (3%)	6 (6%)	0.293

Tukey HSD Post-hoc Test.

* Group 1 vs Group 2

** Group 1 vs Group 3

*** Group 2 vs Group 3

Figure 1. Demographic characteristic in the three groups of COVID -19 patients

Figure 2: Presenting comorbidity in the three groups of COVID -19 patients

Figure 3: Sign and symptoms in the three groups of COVID -19 patients

Figure 4: vital signs in the three groups of COVID -19 patients

Figure 5: severity of disease and outcomes in the three groups of COVID -19 patients

DISCUSSION:

Although many previous studies have emphasized the positive effect of Statins on the course, severity and mortality of COVID-19 disease^12-14, to date we have only small number of published reports about Fenofibrate and its effect on the course of the disease. This work demonstrated that the use of Statins or Fenofibrate prior to infection has an impact on a person’s severity of SARS-CoV-2 infection and the disease outcome and complications. The results of our study showed that the prevalence of a cough, exertional dyspnoea, shortness of breath, sore throat, sneezing, a headache, agitation, myalgia and fatigue, joint pain and insomnia were less in patients using Statins or Fenofibrate. Moreover, the severity of these symptoms was less in these patients compared to control patients. These results are confirmed by the presence of mild cases for most of the patients who were on Statins or on Fenofibrate (table 2). This result is consistent with many other studies conducted on this field^{15, 16}. The most understandable hypothesis or explanation is that cholesterol-modifying drugs have been proved to exert antiviral, immunomodulatory and anti-inflammatory effects¹⁷.

The antihyperlipidemic drugs inhibit the synthesis and systemic absorption of cholesterol, and hence they alter the target cell membrane cholesterol of the virus. Furthermore, the Cholesterol-lowering drugs have other non-lipid related effects that have a beneficial impact on the duration and severity of COVID-19 disease, these include anti-inflammatory, atherosclerotic plaque stabilising, immunomodulatory and anti-thrombotic effects. For these reasons, many studies have recommended that with SARS-CoV-2 infection it is safe to continue on antihyperlipidemic drugs for patients suffering from dyslipidemia¹⁸. Meanwhile, other studies have recommended the initiation of antihyperlipidemic drugs for patients presented with severe COVID-19 disease¹⁹.

Our results were supported by Ehrlich et al study when comparing the effect of Statins and Fenofibrate for COVID-19. The study was conducted on patients using either Statins or Fenofibrate and patients without antihyperlipidemic drugs²⁰. The result of our study confirms that the use of either Statins or Fenofibrate has a beneficial effect on the COVID-19 disease. In this study, patients receiving Statins or Fenofibrate showed less tachycardia and tachypnoea compared to those who were not on any antihyperlipidemic drugs. Moreover, patients on antihyperlipidemic drugs were less frequently needed admission to ICU and oxygen supplement and showed less lung lesions on CT scans. In addition, the duration of hospitalisation was shorter in patients already on Statins or Fenofibrate. This confirms the recommendation of using antihyperlipidemic drugs in severe cases to prevent life-threatening cardiovascular complications and to improve patient’s outcome.

Although Bajwa et al²¹ found that Statin therapy at the admission into the Intensive Care Unit was not associated with a lower rate of developing acute respiratory distress syndrome (ARDS). Our study confirms that the length of stay in hospital, whether it was in the ICU or on the ward, was significantly lower among those using Statins or Fenofibrate. The same finding by Daniels et al²² which showed that statins can reduce the time to recovery. Although there was no statistically significant benefit for the use of Statins or Fenofibrate on the reduction of mortality rate, which it could be due to small data, but still the number of deaths in our study was lower in Statins and Fenofibrate groups, a reflection of many other retrospective studies which have shown that Statins had decreased the mortality in patients with COVID-19^{23, 24}. We recommend a large-scale study to confirm this result.

CONCLUSION:

Both Statins and Fenofibrate have a positive impact in reducing the COVID-19 symptoms, severity, duration of the disease and improving outcome. Furthermore, this result confirms the recommendation of using antihyperlipidemic drugs in moderate to severe cases for SARS-CoV-2 infection and to continue the use of these drugs for patients who already take antihyperlipidemic drugs throughout the disease course.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this research.

ACKNOWLEDGMENTS:

The authors would like to thank the University of Philadelphia for the support and all of the participants.

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Received on 28.01.2022 Modified on 03.03.2022

Research J. Pharm. and Tech 2022; 15(11):5132-5138.

DOI: 10.52711/0974-360X.2022.00863