INTRODUCTION:

Since the first case of the novel coronavirus was reported in Wuhan, China and spread around the world, the number of incidences and deaths has increased very rapidly, posing a major public health challenge for governments and international health organizations^1-3.

As of 8 June 2022, 530 896 347 cases of COVID-19 have been confirmed worldwide, with 6 301 020 deaths, and as of 6 June 2022, a total of 11 854 673 610 people have been vaccinated, according to data from the World Health Organization (WHO)⁴. COVID-19 enters the host cell using angiotensin-converting enzyme II (ACE2) receptor^5,6. COVID-19 binding to cell surface triggers ACE2 receptor down-regulation in lung tissue and causes severe lung symptoms; this explains why the virus is considered as the major cause of acute respiratory syndrome^7-9.

However, studies have shown that’s the presence of chronic diseases such as diabetes mellitus increases the need of intensive care unit (ICU) and the risk for medical complications including death^10,11. A meta-analysis showed that patients with COVID-19 and without diabetes mellitus were less likely to die than diabetic patients¹². Some researchers observed that diabetic patients had excessive uncontrolled responses to inflammatory markers such as CRP and IL-6¹³, and others showed that those patients had significantly higher D-Dimer level than non-diabetic patient¹⁴.

Currently, metformin is used as first-line treatment for T2DM. Interestingly, metformin has been used as an anti-malarial and anti-influenza agent, and lately, an anti-inflammatory, antipyretic, analgesic and anti-viral effects have been proposed for this medication^15-18. During the COVID-19 pandemic, clinical questions have arisen about whether different types of diabetes medications should be continued or discontinued for better patient outcomes. A meta-analysis proved the role of metformin in reducing mortality, and since then researchers have advised its continued use during COVID-19 infection¹⁹. It may be assumed that this anti-inflammatory agent could favorably influence the severity of symptoms in COVID-19 patients with T2DM.

Sulfonylureas constitute the second-line treatment for T2DM²⁰. Both Sulfonylureas therapy and COVID-19 share similar adverse cardiovascular events²¹. Yet, there is no definite study on the effect of using this group of diabetes medication on COVID-19 patient outcomes.

Evidence shows that well-controlled blood glucose and the use of the appropriate hypoglycemic agent have positive effects in improving symptoms and patient survival²². Therefore, identifying treatments associated with poor or good outcomes in patients with COVID-19 has an absolute benefit in reducing disease severity and mortality rate in patients with COVID-19 and diabetes.

MATERIALS AND METHODS:

Study design and participants:

This prospective cohort study was conducted at Tishreen hospital in Syria from 1 January 2021 to 30 June 2021. 430 laboratory-confirmed COVID-19 cases were admitted to the hospital, of which 109 patients were included in our study. The diagnosis of COVID-19 was based on symptoms, positive real-time polymerase chain reaction (RT-PCR) for COVID-19 on nasopharyngeal swab according to WHO interim guideline²³, and/or radiological findings of interstitial pneumonia on computed tomography (CT) scan.

Exclusion criteria were as follows: age <50 and >72 years, Previous use of glucocorticoids, patients with type-1 diabetes mellitus, chronic respiratory diseases, acute or chronic kidney failure, heart or liver failure, immunosuppressant patients (in the context of chemotherapy or taking immunosuppressive drugs) and pregnancy.

Among the 109 COVID-19 patients included in the study, 68 patients were diagnosed with T2DM according to the WHO criteria for T2DM²⁴. Diabetic patients were divided into 2 groups based on their HbA1c levels: ˂6.5% (Well-controlled) and ≥ 6.5% (Less-controlled).

Data collection and measurements:

The demographic information (age and gender), Hypoglycemic therapy prior and during hospitalization were collected.

Laboratory testing including fasting blood glucose (Glu), Glycated hemoglobin (HbA1c), D-dimer (DDI), C-reactive protein (CRP), lactate dehydrogenase (LDH), white blood cells (WBC), neutrophile to lymphocyte ratio (NLR) were tested, and blood oxygen saturation (SPO2) was measured at the time of admission of patients with COVID-19. Clinical outcomes including length of hospital stay, and death were monitored.

Statistical analysis:

Data was analyzed using the Statistical Package for Social Sciences (SPSS) version 25. Chi-square test was used to test for significant differences between categorical groups. Independent sample t-test was also used to compare the means of two independent groups. P-values <0.05 were considered statistically significant.

This study was approved by the bioethics committee at Tishreen University No. 2191 dated 1/6/2021.

RESULTS:

Population characteristics:

109 admissions met our inclusion criteria, of which 68 patients (62.4%) were males. The mean age of all patients was 62.4 years. The other quantitative variables included in our study are presented in Table 1.

At the end of the study, 43 patients (39.4%) died during hospital stay. The main causes of death were viral pneumonia (58.14%) and cardiovascular events (41.86%).

Table 1: Descriptive statistics of the quantitative variables included in our study

	Number	Minimum	Maximum	Mean	SD
Age (years)	109	50	72	62.37	6.31
HbA1c (%)	48	5.7	8.1	6.54	0.47
SPO2 (%)	109	50	99	82.80	9.89
WBC (* 10^9/L)	104	4.20	27.20	11.13	4.44
NLR	109	1.91	60.67	12.59	10.57
Glu (mg/dL)	97	68	666	215.06	113.40
LDH (U/L)	65	168	3500	681.56	503.38
CRP (mg/L)	108	4	365	117.20	77.76
DDI (ng/mL)	90	26.50	10000.00	1482.30	2329.58
Length of hospital stay (day)	108	0	26	6.94	5.86

Clinical characteristics and outcomes of DM vs. non-DM COVID-19 patients:

Patients with COVID-19 were divided into a diabetes group (DM) which included 68(62.39%) patients and a non-diabetes group (non-DM) which comprised 41 (37.61%) patients.

As shown in Table 2, significantly higher mortality rate was associated with the presence of DM (30.28% vs. 9.17%, p= .012).

In order to understand the mechanism (s) by which diabetes mellitus increases mortality rate, the baseline characteristics and laboratory findings were compared between the two groups.

DM patients had significantly higher Glu concentration than the non-DM patients (242.73 Vs. 163.79, p=.001). Unexpectedly, the plasma level of CRP was significantly lower in DM patients compared to the non-DM(105.14 vs. 136.90mg/L, p=.039). However, no significant difference was found between the two groups in term of age, gender, SPO2, WBC, NLR, LDH, DDI, length of hospital stay (p˃ 0.05) (Table 2).

Table 2: The effect of diabetes mellitus on mortality, clinical characteristics, and laboratory findings.

		Diabetes mellitus N= 68	Non-diabetes mellitus N= 41	P-value	Sig.
Survival	% (N)	32.11 % (35)	28.44 % (31)	.012	S
Death	% (N)	30.28 % (33)	9.17 % (10)
Gender	Male % (N)	36.70% (40)	25.69% (28)	.323	NS
	Female % (N)	25.69% (28)	11.92% (13)
Age (year)	Mean ± SD^a	63.22 ± 6.51	60.95 ± 5.74	.068	NS
	Number	68	41
SPO2 (%)	Mean ± SD	83 ± 9	82 ± 12	.460	NS
	Number	64	39
WBC(*10^9/L)	Mean ± SD	10.75 ± 4.24	11.83 ± 4.75	.234	NS
	Number	67	37
NLR	Mean ± SD	12.54 ± 10.47	12.67 ± 10.84	.951	NS
	Number	68	41
Glu(mg/dl)	Mean ± SD	242.73 ± 121.96	163.79 ± 72.78	.001	S
	Number	63	34
LDH (U/L)	Mean ± SD	604.97 ± 322.90	796.45 ± 683.60	.134	NS
	Number	39	26
CRP(mg/L)	Mean ± SD	105.14 ± 69.07	136.90 ± 87.52	.039	S
	Number	67	41
DDI (ng/mL)	Mean ± SD	1680.48 ± 2445.71	1198.42 ± 2153.13	.337	NS
	Number	53	37
Lengthof hospital stay (day)	Mean ± SD	7.49 ± 6.32	6.03 ± 4.90	.213	NS
	Number	68	40

Table 3: The association between HbA1c and in-hospital mortality rate and the laboratory findings.

		Well-controlled diabetes mellitus N= 20	Less-controlled diabetes mellitus N= 28	P-value	Sig.
Survival	% (N)	25% (12)	35.42% (17)	.960	NS
Death	% (N)	16.67% (8)	22.91% (11)
Gender	Male % (N)	25% (12)	33.33% (16)	.843	NS
	female % (N)	16.67% (8)	25% (12)
Age (year)	Mean ± SD^a	61.50 ± 5.30	62.04 ± 6.42	.761	NS
	Number	20	28
SPO2 (%)	Mean ± SD	79 ± 14.56	82.17 ± 9.20	.372	NS
	Number	20	26
WBC(*10^9/L)	Mean ± SD	12.37 ± 5.84	9.55 ± 3.77	.051	NS
	Number	20	27
NLR	Mean ± SD	14.97 ± 11.25	13.17 ± 2.22	.597	NS
	Number	20	28
Glu (mg/dl)	Mean ± SD	163.61 ± 74.84	221.58 ± 73.01	.014	S
	Number	18	26
LDH(U/L)	Mean ± SD	893.85 ± 770.79	556.92 ± 307.09	.152	NS
	Number	15	13
CRP (mg/L)	Mean ± SD	122.25 ± 75.57	99.62 ± 66.24	.277	NS
	Number	20	28
DDI (ng/mL)	Mean ± SD	885.83 ± 921.56	1202.49 ± 2066.99	.583	NS
	Number	15	21
Length of hospital stay (day)	Mean ± SD	7.15 ± 4.79	10.21 ± 7.29	.108	NS
	Number	20	28

Table 4: The effect of pre-hospital diabetes medications on Mortality, clinical characteristics, and laboratory findings.

		Metformin	Sulfonylureas	P-value	Sig.
Survival	% (N)	33.82% (23)	17.65% (12)	.008	S
Death	% (N)	16.18 % (11)	32.35% (22)	.008	S
Pneumonia	% (N)	27.27% (9)	21.21% (7)	.001	S
Cardiovascular events	% (N)	6.06% (2)	45.46% (15)	.001	S
Gender	Male % (N)	27.94 % (19)	30.88 % (21)	.622	NS
Gender	female % (N)	22.06 % (15)	19.12 % (13)	.622	NS
Age (year)	Mean ± SD ^a	61.74 ± 7.26	64.71 ± 5.37	.059	NS
Age (year)	Number	34	34	.059	NS
SPO2 (%)	Mean ± SD	82 ± 9	85 ± 8	.195	NS
SPO2 (%)	Number	33	31	.195	NS
WBC (*10^9/L)	Mean ± SD	9.96 ± 3.99	11.56 ± 4.41	.124	NS
WBC (*10^9/L)	Number	34	33	.124	NS
NLR	Mean ± SD	10.63 ± 9.76	14.45 ± 10.96	.134	NS
NLR	Number	34	34	.134	NS
HbA1c (%)	Mean ± SD	6.75 ± 0.28	6.55 ± 0.65	.208	NS
HbA1c (%)	Number	22	15	.208	NS
Glu (mg/dl)	Mean ± SD	230.12 ± 98.62	257.52 ± 145.10	.378	NS
Glu (mg/dl)	Number	34	29	.378	NS
LDH (U/L)	Mean ± SD	615 ± 353.20	590.05 ± 284.20	.813	NS
LDH (U/L)	Number	23	16	.813	NS
CRP (mg/L)	Mean ± SD	84.10 ± 50.88	126.82 ± 78.83	.010	S
CRP (mg/L)	Number	34	33	.010	S
DDI (ng/mL)	Mean ± SD	1778.64 ± 3149.44	1578.55 ± 1450.72	.769	NS
DDI (ng/mL)	Number	27	26	.769	NS
Length of hospital stay (day)	Mean ± SD	8.85 ± 6.23	6.12 ± 6.21	.074	NS
Length of hospital stay (day)	Number	34	34	.074	NS

Table 5: The relationship between metformin discontinuation and death.

		Metformin discontinuation
		Number	No	Yes	P-value	Sig.
Survival	Survival % (N)	23	38.24% (13)	29.41% (10)	.009	S
Survival	Death % (N)	11	2.94% (1)	29.41% (10)	.009	S

In-hospital metformin discontinuation and mortality:

During hospitalization, 14 patients within the metformin group discontinued treatment and were put on insulin, while the remaining 20 patients continued metformin therapy.

We investigated the effect of metformin discontinuation on the mortality rate in COVID-19 patients. As shown in the Table 5, metformin stopping was significantly associated with increased deaths in COVID-19 diabetic patients (29.41% vs. 2.94% p= .009).

DISCUSSION:

In the present study, we investigated the possible relationship between mortality and the presence of diabetes mellitus in COVID-19 patients. Our results showed that diabetes is associated with a significantly higher risk of death. This is consistent with previous studies suggesting that the presence of DM increases the incidence of death in hospitalized COVID-19 patients^11,12. Recent researches have proposed several mechanisms leading to worse clinical outcomes in COVID-19 patients with DM. This includes hypercoagulability, unregulated inflammatory responses and poor immune response to viral infection as diabetic patients are more susceptible to severe bacterial and viral illnesses and take longer time to recover compared to no diabetic patients^13,14,25. Moreover, a recent study showed a positive relationship between ACE2 expression and the presence of diabetes in COVID-19 patients. ACE2 is thought to be upregulated in diabetic patients, and this is potentially due to diabetic environment, hyperglycemia, and inflammatory cytokine²⁶. Up-regulated ACE2 could play a critical role in progression to severe illness by modulating the ability of the virus to enter target cells.

Although it has been suggested that diabetes may worsen the outcome of patients with COVID-19 through an increased inflammatory response¹³, we found a significantly lower CRP concentration in diabetic patients compared to non-diabetics. However, half of the diabetic patients enrolled in our study were taking metformin. As known, metformin has favorable effect on reducing CRP levels²⁷, which could, in part, explain the lower CRP levels in these patients. When allocatingdiabetic patients according to HbA1c levels, there was no significant difference in mortality or clinical outcomes between the two glycemic control groups. It is worth mentioning that among the 28 patients whom HbA1c was superior to 6.5%, only three patients had poor glycemic control (HbA1c>7%), while all the rest had an acceptable glycemic control according to the American Diabetes Association (ADA) recommendations²⁸. This could explain in part the lack of a relationship between HbA1c and poor outcomes in COVID-19 patients. Nevertheless, these findings are in agreement with a study in which a non-significant association between HbA1C levels and adverse clinical outcomes in patients was reported²⁹.

Regarding anti-diabetic agents, our study found that pre-hospital use of metformin was associated with a significant lower death rate compared to the pre-hospital use of sulfonylureas. This effect seems to be related to decreased inflammation inferred by lower CRP concentration in the metformin group.

Recently, a meta-analysis of five studies in which 6937 COVID-19 patients were included, metformin was associated with reduced mortality from COVID-19 infection¹⁹. CRP concentration at hospital admission has been reported as a strong predictor of COVID-19 severity and mortality³⁰. Therefore, drugs with anti-inflammatory effects are expected to play an important role in reducing mortality. Furthermore, our results suggest that continued metformin during hospital stay may improve patient outcomes, including in-hospital mortality. The same results were also reported in a recent study conducted in the Philippines³¹.

Several studies suggested potential mechanisms for the favorable effect of metformin on diabetic patient’s outcome during COVID-19 infection. First, metformin is known to participate to ACE2 Ser680 phosphorylation through the activation of AMP-activated protein kinase (AMPK) pathway. This phosphorylation could change the stereotyped shape of this receptor, leading to an improvement in its stability and an increase in its total expression²⁵. ACE2 up-regulation could influence the ACE2/AngII/AT1R axis which in turn suppresses the inflammatory response and the release of pro-inflammatory cytokines by inhibiting macrophage activation and NF-κB signaling²⁶. Second, metformin, as an AMPK activator, reduces the production of ROS and prevents oxidative stress, thus playing an anti-fibrotic function in the lung³⁵. On the other hand, metformin could inhibit the mammalian target of rapamycin (mTOR) signaling via liver kinase B1 (LKB1). The PI3K/AKT/mTOR pathway plays a major role in MERS-CoV infection, and could also be involved in SARS-CoV-2 infection (taking into account the similarities between the two viruses). Therefore, inhibition of mTOR signaling by metformin may reduce SARS-CoV-2 infection and mortality³⁶.

This study is the first to provide evidence of the influence of diabetes treatment on the causes of death of patients with COVID-19. Indeed, according to our results, patients using sulfonylureas were more prone to cardiovascular mortality after COVID-19 infection, and this merits serious investigation into the potential mechanisms underlying this effect.

One of the suggested mechanisms is related to sulfonylurea receptors. Sulfonylureas lower blood sugar by stimulating insulin release by binding to sulfonylurea receptors (SUR1) on pancreatic β cells and inhibiting ATP-sensitive potassium channels²⁸. However, sulfonylureas also bind to similar receptors on myocardial (SUR2A) and vascular smooth muscle (SUR2B) cells, resulting in blockade of cardiac ATP-sensitive potassium channels and myocardial ischemia ²⁹. Moreover, sulfonylurea-induced hypoglycemia can lead to QT interval prolongation, which may also be associated with cardiac ischemia, increased risk of ventricular arrhythmias, myocardial infarction, and sudden cardiac death³⁹.

Finally, it is worth mentioning that metformin has been accused of metabolic acidosis in hospitalized patients with kidney diseases⁴⁰. This led to metformin being discontinued and replaced with insulin for hospitalized patients with COVID-19. However, patients with renal diseases were excluded from our study, so this detrimental effect of metformin was overlooked. We believe that further large-scale studies would yield more precise results.

CONCLUSIONS:

Our study indicates that pre-hospital use of metformin in COVID-19 patients might reduce the mortality rate compared to sulfonylurea by reducing the inflammatory events. In addition, our results suggest that continued metformin during hospital stay may lead to a better prognosis for COVID-19 patients. We also found that taking sulfonylurea is associated with increased mortality compared to metformin, potentially by increasing cardiovascular events.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

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Received on 24.03.2023 Modified on 20.04.2023

Research J. Pharm. and Tech 2023; 16(11):5130-5136.

DOI: 10.52711/0974-360X.2023.00831