The Impact of COVID-19 on Diabetes Mellitus and Hypertension: A Retrospective Study

COVID-19 is a pathogenic virus that caused a pandemic outbreak in December 2019. The impact of this virus may be severe in the patients having co-morbidities like diabetes, hypertension, Chronic Kidney Disease, cardiovascular disease, etc. Aim and Objectives: This study Aims in Assessing the impact of COVID-19 on Diabetic and Hypertensive patients as well as COVID-19 patients without any co-morbidities. Objective of this is to evaluate the association between COVID-19 and its risk factors (diabetes and hypertension) and to evaluate whether the severity of the symptoms in COVID-19 patients is due to comorbidities or past medications. Methodology: A Retrospective study was conducted in SRM Hospital (Medical Records Department) for a period of 3 Months with the study population 670 at the age group of 25, known case of Diabetes and Hypertension. Cases of Pregnant women are excluded from the study. The patients were grouped into 4 categories 1) control group (patient without any co-morbidities) 2) diabetic patients 3) Hypertensive patient 4) Diabetic+Hypertension patient and studied their prescribing pattern by collecting the past medication history. Original Research Article Pavithra et al.; JPRI, 33(43B): 68-77, 2021; Article no.JPRI.73026 69 Results and Discussion: There is a significant decrease in a lymphocyte in covid-19 Type 2 diabetic patients in our study. These results suggest that different mechanism exists for hypertension and diabetes mellitus as risk factors for covid-19. It is also known that these patients have impaired immune response to many infections [30]. In our retrospective study, we collected 670 covid-19 cases. It consists of 12.5% of diabetic patients and 6.6% of hypertensive patients. This study compared COVID-19 patients without any comorbidity (neither Type 2 diabetes mellitus nor hypertension) with covid19 patients with comorbidities (Type 2 diabetes mellitus and hypertension). COVID-19 patients with T2DM have an increased level of D-dimer compared to nonT2DM patients. Conclusion: Diabetic and hypertensive patients affected with COVID-19 are low in our study. Out of the total study population, only 12.5% are diabetic, 6.56% are hypertensive, and 9.25% were both diabetic and hypertensive. But when comparing in terms of severity, hypertensive and diabetic patients have severe effects than the control patients. In simpler terms, not every person who has diabetes and hypertension are affected with COVID-19, but those who were affected by COVID-19 showed more severity than the patients who don't have any comorbidities


INTRODUCTION
In December 2019, a pandemic outbreak occurred in China which spread all over the world that caused severe mortality and morbidity globally. World Health Organisation [WHO] named this novel virus COVID-19, a pathogenic virus. It is a positive-sense-single-stranded RNA virus with glycoprotein spikes on the outer surface [1,2,3]. Symptoms for covid-19 include fever, cough, shortness of breath, muscle ache, tiredness, sore throat, headache, chest pain, nausea, and vomiting [4]. A febrile with chills and respiratory issues were seen in starting phase of infected patients. Some of the patients have asymptomatic conditions [4]. Men develop more complications compared to women [5,6]. Complications due to SARS-CoV2 include multiple organ failure, sepsis, septic shock, cardiovascular complications, acute pericarditis, left ventricular dysfunction, acute myocardial injury, arrhythmias, heart failure, Massive pulmonary embolism, necrotising pneumonia, coagulopathy, venous thromboembolism, elevated D-dimer and prolonged prothrombin time, laryngitis and laryngeal edema. Hypertension, diabetes, cardiovascular complications, respiratory complications patients face severe effects due to COVID-19 infections [5][6][7][8][9]. Most of the comorbidities occur to men than women. Laboratory examination includes WBC, lymphocyte, C-reactive protein, D-dimer, whole blood counts. When the patients get positive primarily, there will be decreased WBC, lymphocyte, increased C-reactive protein, LDH, liver enzymes, D-dimer. These blood counts, lymphopenia, eosinopenia, and neutrophil/lymphocyte ratio are ≥3.13 means it indicates a severe scenario. Decreased blood lymphocytes, imbalance alterations of multiorgan, and increased D-dimer results in critical patients [5,10]. The main focus of this study is to determine the impact or the effect of COVID-19 on the conditions such as hypertension and diabetes mellitus by comparing their laboratory investigations. The mechanism states that the entry for the SARS-CoV2 virus in Hypertensive patients is by ACE 2 inhibitors. This ACE 2 inhibitors can be present in many organ systems, which includes the cardiovascular system and respiratory system. The SARS-CoV2 enzyme catalyzes angiotensin II to angiotensin I, which is a peptide [11]. Hypertension may be a risk factor for COVID-19 patients with severity and mortality [9]. Diabetic patients are more prone to COVID-19. There was a bidirectional relationship between COVID-19 and Diabetes. Even obesity and Type 2 diabetes have a strong relationship which leads to severe infection. In diabetes, there is no exact mechanism of diabetes on COVID-19 till now, but it may lead to infection such as MERS & SARS in an in-vitro study conducted in animal models [12,13]. The common factors associated with the poor prognosis in COVID-19 include advanced age and pre-existing conditions such as diabetes and hypertension. This study helps in the assessment of the impact of COVID-19 on diabetic and hypertensive patients. There is minimal evidence on the clinical characteristics and outcome of hospitalized COVID-19 with or without diabetes mellitus and hypertension in the south-Indian population.

Aim and Objective
To assess the impact of COVID-19 on diabetic and hypertensive patients.
To evaluate the association between COVID-19 and its risk factors (diabetes and hypertension) and to evaluate whether the severity of the symptoms in COVID-19 patients is due to comorbidities or past medications.

MATERIALS AND METHODS
A Retrospective study was conducted in SRM Hospital (Medical Records Department) for a period of 3 Months with the study population 670 at the age group of 25, known case of Diabetes and Hypertension. Cases of Pregnant women are excluded from the study. The patients were grouped into 4 categories 1) control group (patient without any co-morbidities) 2) diabetic patients 3) Hypertensive patient 4) Diabetic+Hypertension patient and studied their prescribing pattern by collecting the past medication history.

Statistical Analysis
Statistical analysis was carried out using GRAPH PAD PRISM, unpaired t-test and MS-EXCEL. Data are expressed as mean ± standard deviation and P-value

Procedure
Patient demographic information such as age, gender was collected between May 1 and July 28, 2020, at SRM hospital, kattankulathur and recorded. Patients previous medical history were also collected. Hematological parameters, such as Hb, neutrophil, lymphocytes, WBC, platelet were compiled, and the vital signs such as temperature, pulse rate, respiration rate, SPO2 were noted. All the patients included in this study have undergone an RT-PCR test with a test result of positive sign, and the D-DIMER test has been conducted in every individual patient. This study comprises of total 670 COVID-19 infected patients, of which 458 were male patients (68.35%), 212 female patients (31.64%).
From the collected data, the patients were categorized into four groups,

Anti-Diabetic Drugs Prescribing Pattern in Study Population (Past Medication History)
Many studies stated the prior usage of antidiabetic and antihypertensive drugs might worsen or be associated with COVID-19. In that view, we were also involved in collecting the medication details of the diabetic and hypertensive patients. In the diabetic group of patients, we classified the drugs according to their various anti-diabetic drug classes, such as sulfonylureas, Biguanide, DPP4, α glucosidase inhibitor, SGLT-2, Insulin and combination including sulfonylureas + Biguanide, DPP4 + Biguanide.
Out of 146 diabetic patients, we found that 44 patients were using sulfonylureas, 62 were found to use Biguanide, 10 patients were found to use DPP4, 12 patients have found to use α glucosidase inhibitor, 8 people use sulfonylureas + Biguanide, 2 of the patient use DPP4 + Biguanide, 6 patients use SGLT-2, 24 patients use Insulin. 16 patient follows traditional treatment such as Ayurveda, Siddha, and homeopathy.
This includes the patient who uses both Antihypertensive and Anti-diabetic drugs (DM+HTN patient).

Antihypertensive Drugs Prescribing Pattern in Study Population
In the case of the hypertensive patient, we classified the medications into their respective antihypertensive classes such as β blocker, calcium channel blocker, Angiotensin II Receptor Blocker (ARB), α adrenergic blocker, α +β blocker, Angiotensin-Converting Enzyme Inhibitor (ACE Inhibitor).
Out of 106 hypertensive patients, 14 patients use β blocker, 32 patients use calcium channel blocker, 40 patients use ARB, 4 patients use α adrenergic blocker, 2 patients use α+β blocker, 2 people use ACE Inhibitor, 16 people are not at the regular use of medication or discontinued the treatment.
COVID-19 patient has been found with or without symptoms. We classified them into symptomatic and asymptomatic groups.
1. In the control group of patients, 288 presented with symptoms, and 192 were without symptoms or asymptomatic. 2. In a diabetic group of patients, 78 presented with symptoms and 6 were without symptoms.
3. In the hypertensive group of patients, 40 presented with the symptom, and 4 were without the symptom. 4. In diabetes + hypertension group of patients, 54 presented with the symptom, and 8 were without symptoms.
This data classification shows that people involved in this study were majorly found to be symptomatic (68.7%), whereas asymptomatic is 31.3%.

Comparing the Vitals of Control Patient Vs Diabetic Patient Reveals
1. Control patients has significantly higher temperature than Diabetic patients (P-value = 0.001).
2. Diabetic patients have significantly higher systolic pressure than the control patients (P-value = 0.0001). 3. Control patients have significantly higher ESR level than the diabetic patients (P-value = 0.0297). 4. Diabetic patients have a significantly higher D-Dimer value than the control patients (P-value = 0.0058).

Comparing the Control Patient Vs Diabetes + Hypertension Patient Reveals
The SPO2 is significantly higher in control patient than the Diabetic + Hypertensive patients (Pvalue = 0.0467). Diabetic + Hypertensive patients has significantly higher systolic pressure than the control (P-value = 0.0013). The control patients had significantly higher lymphocyte count than Diabetic+ Hypertensive patients (P-value = 0.0493). Diabetic + Hypertensive patients has significantly higher ESR level than the control (Pvalue = 0.0001).

iv) Comparing Diabetic Male Vs Female Patient:
Female patient had significantly higher neutrophil than the male patient (P-value =0.0361).

v) Comparing Hypertensive Male Vs Female Patient:
The male patient had a significantly higher neutrophil count than the female patient (P-value= 0.0257) The male patient had a significantly higher D-Dimer value than the female patient (P-value= 0.0517).

vi) Comparing Diabetic + Hypertensive Male Patients Vs Female Patient:
The male patient had a significantly higher neutrophil count than the female patient (P-value= 0.0319). The male patient had significantly higher D-dimer than the female patient (P-value = 0.0001).

vii) Analysing among the Male Patient of Control and Diabetes:
Control male patient has significantly higher respiration rate than the diabetic male patient (P-value = 0.0073). A diabetic male patient has a significantly higher d-dimer value than the control male patient P-value = 0.0006).

viii) Analysing among the Female Patient of Control and Diabetes:
The diabetic female patient has significantly higher systolic pressure than the control female patient P-value = 0.0124. The diabetic female patient has a significantly higher D-Dimer value than the control female patient P-value = 0.0194.

ix) Analysing among the Male Patient of Control and Diabetes + Hypertension:
The hypertensive male patient has significantly higher systolic and diastolic pressure than the Control male patients p-value = 0.0001. The hypertensive male patient has significantly higher neutrophils than the Control male patients P-value = 0.0225. Control male patients have significantly higher ESR count than the hypertensive male patient p-value = 0.0465.Hypertensive male patients have significantly higher D-dimer value than the Control male patient P-value = 0.0001.

x) Analysing among Female Patients of Control and Hypertension:
The hypertensive female patient has significantly higher systolic and diastolic pressure than the control female patient p-value = 0.0001. The hypertensive female patient has a significantly higher D-dimer value than the control female patient P-value = 0.0057.

xi) Analysing among the Male Patients of Control and Diabetes + Hypertension: Exhibits
Diabetic + hypertensive male patient has significantly higher pulse rate than the Control male patient p-value = 0.0198. Control male patient has significantly higher HB level than the Diabetes + hypertension male patient p value= 0.0106. Diabetic + hypertensive male patient has significantly higher neutrophil count than the Control male patient p-value = 0.0001. Diabetic + hypertensive male patient has significantly higher D-Dimer value than the Control male patient Pvalue = 0.0001.

xii) Analysing among Female Patient of Control And Diabetic + Hypertensive: Shows
Diabetic + hypertensive female patient has significantly higher ESR level than the control female patient P-value = 0.0001.  [14][15][16][17][18]. Though Type 2 diabetes mellitus and hypertension majorly combine, their role independently has not been defined yet. Gao and colleagues found after comparing non-hypertensive on COVID-19 patients with hypertensive on COVID-19 patients, and the hypertensive COVID-19 patients showed a significant increase in the risk of mortality. Hypertension itself is an independent risk factor for worse clinical outcomes [19]. Advanced age, male, sex, history of cardiovascular diseases, chronic kidney disease and tumour also contribute as risk factors. A meta-analysis study with 3994 COVID-19 patients from China showed hypertension, Type 2 diabetes mellitus, history of cardiovascular disease, COPD, CKD has associated with serious outcomes like ICU admission and artificial ventilation. But only Type 2 diabetes mellitus had a significant impact on death. Another recent study and meta-analysis identified Type 2 diabetes mellitus as a risk factor for death. Another report has shown that among COVID-19 patients, 40% of patients had chronic diseases, in which Type 2 diabetes mellitus contribute to 17% [20][21][22][23][24][25][26]. The same report has shown that COVID-19 patients with Type 2 diabetes mellitus have higher mortality when compared to non-Type 2 diabetes mellitus patients. The COVID-19 Type 2 diabetes mellitus patients have unique manifestations and notable laboratory findings compared with non-comorbid patients [27]. This identification and distinguishing between COVID-19 patients without comorbidities and COVID-19 patients with comorbidities may improve diagnosis and proper treatment. Our study compared different laboratory parameters and other parameters between COVID-19 patients with Type 2 diabetes mellitus and hypertensive patients with control populations. Hypertension is one of the most commonly occurring comorbidities in COVID-19 patients. But the role of hypertension on mortality of COVID-19 patients is not known. A randomized trial also showed an immune response against a pathogen increases aortic stiffness, which is a significant determinant of systolic blood pressure [28,29]. The retrospective study conducted by Jacques Amar MD et al. showed WBC, neutrophil, D-dimer was increased in hypertensive COVID-19 patients compared to non-hypertensive patients. In contrast, there is a significant decrease in a lymphocyte in COVID-19 Type 2 diabetic patients in our study. These results suggest that different mechanism exists for hypertension and diabetes mellitus as risk factors for COVID-19. It is also known that these patients have impaired immune response to many infections [30]. In our retrospective study, we collected 670 COVID-19 cases. It consists of 12.5% of diabetic patients and 6.6% of hypertensive patients. We compared COVID-19 patients without any comorbidity (neither Type 2 diabetes mellitus nor hypertension) with COVID-19 patients with comorbidities(Type 2 diabetes mellitus and hypertension). COVID-19 patients with T2DM have an increased level of D-dimer compared to non-T2DM patients. It is similar to the results of an observational study conducted by Yogendra Mishra et al., which also shows an increase of D-dimer in COVID-19 T2DM patients when compared to non-diabetic patients [31]. In comparing hypertensive COVID-19 patients with non-comorbid covid-19 patients, neutrophil count and D-dimer levels are significantly higher in hypertensive covid-19 patients. The retrospective study conducted by Jacques Amar MD et al. shows a similar result of neutrophil and D-dimer increase in hypertensive COVID-19 patients than non-comorbid patients. We also compared male covid-19 diabetic patients with female covid-19 diabetic patients. The female patient had significantly abnormal higher neutrophil than the male. Compared with male and female COVID-19 patients with hypertension, the male patient had significantly abnormal more elevated neutrophil and D-dimer than male patients. We compared only male patients of hypertensive COVID-19 patients with non-comorbid patients who showed hypertensive COVID-19 patients with substantially higher ESR and D-dimer values than non-comorbid patients. There is a controversy that RAS blockers increase the expression of ACE-2 as SARS-COV2 infect cells by binding to the sites of ACE-2 receptors. In this perspective, we also collected a report of drugs consumed by diabetic and hypertensive COVID- 19

CONCLUSION
In summary, Diabetic and hypertensive patients affected with COVID-19 are low in our study. Out of 670 COVID-19 patients, only 12.5% are diabetic, 6.56% are hypertensive, and 9.25% were both diabetic and hypertensive. But when comparing in terms of severity, hypertensive and diabetic patients have severe effects than the control patients. In simpler terms, not every person who has diabetes and hypertension are affected with COVID-19, but those who were affected by COVID-19 showed more severity than the patients who don't have any comorbidities (Diabetes and hypertension).
In gender-wise, the study population has more male patients (458) than female patients (212).
On comparing the laboratory investigation, it is seen that male patients showedmore or high severity than female patients.
Furthermore, studies have to be done to investigate whether hypertensive and diabetic patients' severity are due to condition (Diabetic and Hypertension) or due to the medication used.

LIMITATIONS
Interpretation of the findings is limited by sample size. Its retrospective nature limits this study. Despite these limitations, this study identifies many different lab abnormalities on the COVID-19 patient with Type 2 Diabetes mellitus and Hypertension, which might be helpful for future findings.

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.

STUDY SIGNIFICANCE
The study highlights the efficacy of " Ayurveda, Siddha " which is an ancient tradition, used in some parts of India. This ancient concept should be carefully evaluated in the light of modern medical science and can be utilized partially if found suitable.

CONSENT AND ETHICAL APPROVAL
As per international standard or university standard guideline Patient's consent and ethical approval has been collected and preserved by the authors.