Effects of Metformin on COVID-19 Patients with Type 2 Diabetes: A Retrospective Study

Figures & data

Table 1 Baseline Demographics and Clinical Characteristics in COVID-19 Patients with T2D Stratified by Metformin

	All Patients (n=571)	Metformin (n=241)	Non-Metformin (n=330)	P
Age, years	65.0(57.0–72.0)	63.0(56.0–70.0)	66.0(60.0–73.0)	<0.001
Gender, male (%)	306(53.6)	129(53.5)	177(53.6)	NS
Respiratory rate, breaths/min	20.0(19.0–21.0)	20.0(18.0–20.0)	20.0(19.0–22.0)	0.002
Systolic blood pressure, mmHg	134.0(123.0–145.0)	135.0(122.0–144.8)	134.0(124.0–145.0)	0.831
Diastolic blood pressure, mmHg	80.0(74.0–88.0)	81.0(74.0–89.8)	80.0(75.0–88.0)	0.169
Severity categories (n,%)				0.018
Mild	357(62.5%)	158(65.6%)	199(60.3%)
Moderate	4(0.7%)	3(1.2%)	1(0.3%)
Severe	174(30.5%)	73(30.3%)	101(30.6%)
Critical	36(6.3%)	7(2.9%)	29(8.8%)
Symptoms onset to admission, n (%)
Fever	379(66.4%)	158 (65.6%)	221 (67.0%)	0.788
Snot	15(2.6%)	9(3.7%)	6(1.8%)	0.189
Sore throat	25(4.4%)	12(5.0%)	13(3.9%)	0.680
Cough	369(64.9%)	159(66.0%)	210(63.6%)	0.595
Expectoration	80(14.0%)	40(16.6%)	40(12.1%)	0.143
Dyspnea	77(13.5%)	32(13.3%)	45(13.6%)	NS
Chest tension	113(19.8%)	54(22.4%)	59(17.9%)	0.202
Chest pain	10(1.8%)	6(2.5%)	4(1.2%)	0.409
Palpitation	16(2.8%)	5(2.1%)	11(3.3%)	0.448
Edema	3(0.5%)	1(0.4%)	2(0.6%)	NS
Stomachache	9(1.6%)	5(2.1%)	4(1.2%)	0.504
Diarrhea	32(5.6%)	14(5.8%)	18(5.8%)	NS
Fatigue	285(49.9%)	121(50.2%)	164(49.7%)	0.933
Comorbidities on admission, n (%)
Hypertension	347(60.8%)	148(62.7%)	199(61.0%)	0.725
Coronary heart disease	74(13.0%)	22(9.1%)	52(15.8%)	0.023
Heart failure	6(1.1%)	1(0.4%)	5(1.5%)	0.391
Arrhythmia	6(1.1%)	2(0.8%)	4(1.2%)	0.979
Cardiomyopathy	8(1.4%)	3(1.2%)	5(1.5%)	NS
Cerebrovascular disease	51(8.9%)	16(6.6%)	35(10.6%)	0.105
COPD	6(1.1%)	3(1.2%)	3(0.9%)	NS
Chronic kidney disease	26(4.6%)	6(2.5%)	20(6.1%)	0.065
Chronic liver disease	17(3.0%)	10(4.1%)	7(2.1%)	0.212

Notes: Data were n (%) or median (IQR). P values were calculated by Mann–Whitney U-test for non-normally distributed continuous variables and Fisher’s exact test or χ² test for categorical variables. P < 0.05 was considered significant between metformin group vs non-metformin group.

Abbreviations: T2D, type 2 diabetes; COVID-19, coronavirus disease 2019; COPD, chronic obstructive pulmonary disease; IQR, interquartile range; NS, not significant.

Table 2 Laboratory Parameters of COVID-19 Patients with T2D in the Metformin and Non-Metformin Groups

	All Patients (n=571)	Metformin (n=241)	Non-Metformin (n=330)	P
Whole blood test, median (IQR)
White blood cells, ×10^9/L	6.09(4.94–7.50)	6.00(5.00–7.43)	6.20(4.90–7.50)	0.961
Neutrophils, ×10^9/L	3.80(2.90–5.25)	3.64(2.91–4.94)	3.92(2.89–5.33)	0.216
Lymphocytes, ×10^9/L	1.49(1.05–1.97)	1.53(1.16–2.05)	1.38(0.99–1.92)	0.010
Monocytes, ×10^9/L	0.48(0.37–0.61)	0.49(0.40–0.62)	0.47(0.35–0.60)	0.021
Eosinophils, ×10^9/L	0.12(0.06–0.20)	0.12(0.07–0.19)	0.11(0.05–0.21)	0.635
Basophils, ×10^9/L	0.03(0.01–0.04)	0.03(0.02–0.04)	0.02(0.01–0.04)	0.001
Red blood cells, ×10^12/L	4.00(3.61–4.41)	4.12(3.77–4.48)	3.92(3.53–4.32)	<0.001
Hemoglobin, g/L	121.00(109.00–133.00)	126.00(114.00–135.00)	119.00(106.00–131.00)	<0.001
Platelet, ×109/L	217.00(174.00–266.00)	216.00(178.00–263.00)	217.00(171.00–268.00)	0.822
Symptom onset to admission, median (IQR)
k, mmol/L	4.24(3.94–4.55)	4.26(3.97–4.58)	4.20(3.91–4.53)	0.146
Na, mmol/L	140.50(138.28–142.19)	139.70(137.30–141.40)	140.90(138.90–142.90)	<0.001
Cl, mmol/L	104.80(101.80–106.90)	103.60(100.78–106.10)	105.50(102.53–107.50)	<0.001
Ca2, mmol/L	2.17(2.09–2.27)	2.20(2.14–2.29)	2.15(2.06–2.25)	<0.001
BUN, mmol/L	5.05(4.03–6.64)	5.02(4.03–6.26)	5.12(4.02–6.83)	0.540
CRE, μmol/L	62.50(51.64–75.00)	58.62(49.34–72.40)	65.25(54.05–76.91)	<0.001
UA, μmol/L	260.00(206.52–320.85)	261.00(210.50–319.00)	259.00(203.00–326.00)	0.802
Blood glucose, mmol/L	7.38(5.69–9.97)	7.96(6.05–11.76)	7.14(5.31–9.14)	<0.001
TP, g/L	65.59(61.26–69.41)	66.34(62.46–69.67)	64.75(60.22–69.12)	0.008
Albumin, g/L	37.20(33.80–40.17)	37.99(35.00–40.70)	36.50(32.87–39.84)	0.001
TBIL, μmol/L	10.28(7.66–13.00)	10.29(7.95–12.80)	10.00(7.40–13.04)	0.461
DBIL, μmol/L	3.00(2.10–4.40)	2.90(2.10–4.10)	3.00(2.13–4.60)	0.534
ALT, U/L	20.11(13.70–31.58)	19.80(13.91–30.15)	20.80(13.50–33.20)	0.820
γ-GGT, U/L	27.30(18.50–44.50)	27.38(18.57–45.10)	27.30(18.42–43.43)	0.778
ALP, U/L	72.10(61.55–91.28)	72.10(59.43–88.75)	72.15(62.70–93.02)	0.300
LDH, U/L	178.85(155.60–225.87)	167.50(148.70–210.88)	184.00(158.20–239.30)	0.002
αHBDH, U/L	135.70(116.20–173.25)	128.47(112.08–155.75)	141.60(120.63–185.60)	0.001
CK-MB, U/L	8.80(6.90–12.10)	8.70(6.88–11.90)	8.91(7.20–12.63)	0.159
Chest CT on Admission, n (%)				0.240
Unilateral lesion, n (%)	28(4.9%)	15(6.9%)	13(4.4%)
Bilateral lesion, n (%)	483(84.6%)	201(93.1%)	282(95.6%)

Notes: Data were n (%) or median (IQR). P values were calculated by Mann–Whitney U-test for non-normally distributed continuous variables and χ² test for categorical variables. P < 0.05 was considered significant between metformin group vs non-metformin group.

Abbreviations: BUN, blood urea nitrogen; UA, uric acid; TP, total protein; TBIL, total bilirubin; DBIL, direct bilirubin; ALT, alanine aminotransferase; γ-GGT, γ-gamma-glutamyl-transferase; ALP, alkaline phosphatase; LDH, lactate dehydrogenase; αHBDH, α-hydroxybutyrate dehydrogenase; CK-MB, creatine kinase-myocardial band; CT, computed tomography.

Table 3 Treatment and Clinical Outcome in T2DM Patients Between the Metformin and Non-Metformin Groups

	All Patients (n=571)	Metformin (n=241)	Non-Metformin (n=330)	P
In-hospital medication
Traditional Chinese medicine, n (%)	477(83.5%)	200(83.0%)	277(84.2%)	0.700
Arbidol hydrochloride capsules, n (%)	270(47.3%)	120(49.8%)	178(53.9%)	0.327
Antivirals, n (%)	284(49.7%)	125(51.9%)	159(48.2%)	0.384
Antibiotic, n (%)	248(43.4%)	97(40.2%)	151(45.8%)	0.190
Satins, n (%)	103(18.0%)	41(17.0%)	62(18.8%)	0.586
Thiazine diuretics, n (%)	70(12.3%)	25(10.4%)	45(13.6%)	0.240
β-blocker, n (%)	111(19.4%)	50(20.7%)	61(18.5%)	0.500
Calcium antagonists, n (%)	233(40.8%)	116(48.1%)	117(35.6%)	0.003
ACEI/ARB, n (%)	52(9.1%)	27(11.2%)	25(7.6%)	0.143
Cardiotonic drug, n (%)	29(5.1%)	9(3.7%)	20(6.1%)	0.211
Vasodilator, n (%)	48(8.4%)	17(7.1%)	31(9.4%)	0.327
Human serum albumin, n (%)	70(12.3%)	22(9.1%)	48(14.5%)	0.051
Human immunoglobulin, n (%)	34(6.0%)	13(5.4%)	21(6.4%)	0.629
Insulin, n (%)	174(30.5%)	89(36.9%)	85(25.8%)	0.004
Acarbose, n (%)	258(45.2%)	166(68.9%)	92(27.9%)	<0.001
Gliclazide, n (%)	58(10.2%)	41(17.0%)	17(5.2%)	<0.001
Hormone, n (%)	71(12.4%)	30(17.8%)	41(19.2%)	0.725
Clinical outcome
Hospitalization n time (days)	15(9–22)	16(10–23)	14(8–22)	0.012
In-hospital mortality and invasive mechanical ventilation, n (%)	39(6.8%)	8(3.3%)	31(9.4%)	0.004

Notes: P values were shown as χ² test for categorical variables t. Data were presented as medians and interquartile range (Q1–Q3). P < 0.05 was considered significant between metformin group vs non-metformin group.

Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker. Data were n (%) or median (IQR).

Figure 1 Kaplan-Meier Survival Curves for patients with COVID-19 and T2D with and without Metformin treatment.

Table 4 Hazard Ratios for Primary and Secondary Outcomes Between Individuals in the Metformin and the Non-Metformin Groups

	Adjusted* HR (95% CI)	P
Primary outcomes
In-hospital mortality and invasive mechanical ventilation	0.376(0.154–0.922)	0.033
Secondary outcomes
Acute cardiac events	0.216(0.078–0.595)	0.003
Severe respiratory failure	0.189(0.063–0.561)	0.003
ARDS	0.199(0.039–1.026)	0.054
Secondary infection	0.281(0.070–1.132)	0.074

Notes: The p values were calculated based on mixed-effect Cox proportional hazard model. *Adjusted for age, sex, hypertension, COPD, blood glucose.

Abbreviations: HR, hazard ratio; CI, confidence interval.