No significant association between dipeptidyl peptidase-4 inhibitors and adverse outcomes of COVID-19

Table 1 Characteristics of patients with type 2 diabetes in dipeptidyl peptidase-4 inhibitor and non-dipeptidyl peptidase-4 inhibitor groups before and after propensity score matching

	Unmatched			Matched (1:3)3
Parameter	DPP4i4 (n = 142)	Non-DPP4i5 (n = 1115)	SD	DPP4i4 (n = 111)	Non-DPP4i5 (n = 333)	SD
Clinical characteristics on admission
Age, median (IQR)	63 (55-67)	64 (56.5-69)	-0.107	63 (55.5-67)	64 (56-69)	-0.068
Male gender, n (%)	66 (46.48)	588 (52.74)	-0.125	57 (51.35)	159 (47.75)	0.072
Female gender, n (%)	76 (53.52)	527 (47.26)	0.125	54 (48.65)	174 (52.25)	-0.072
Heart rate, median (IQR)	82 (75-91)	85 (78-98)	-0.192	82.5 (75-97.25)	82 (76-96)	0.032
Respiratory rate, median (IQR)	20 (19-21)	20 (19-21)	0.030	20 (19-20)	20 (19-21)	0.014
DBP, median (IQR)	80 (73.25-90)	80 (72-89)	0.116	80 (72-91)	80 (74-89)	0.018
SBP, median (IQR)	133 (123-146)	133 (121-145)	0.070	133 (123-146)	135 (122-148)	-0.021
SpO2, median (IQR)	97 (95-98)	97 (95-98)	0.018	97 (95-98)	97 (95-98)	0.049
Comorbidities on admission
Heart failure, n (%)	0 (0.00)	3 (0.27)	-0.073	0 (0.00)	0 (0.00)	0
Coronary heart disease, n (%)	16 (11.27)	150 (13.45)	-0.066	13 (11.71)	44 (13.21)	-0.045
Cerebrovascular diseases, n (%)	5 (3.52)	41 (3.68)	-0.008	4 (3.60)	16 (4.80)	-0.060
Chronic liver disease, n (%)	0 (0.00)	25 (2.24)	-0.214	0 (0.00)	0 (0.00)	0
Chronic renal diseases, n (%)	2 (1.41)	23 (2.06)	-0.050	2 (1.80)	3 (0.90)	0.078
Chronic obstructive pulmonary disease, n (%)	1 (0.70)	9 (0.81)	-0.012	1 (0.90)	3 (0.90)	0
Background anti-diabetic drugs1
1 type, n (%)	24 (16.90)	526 (47.17)	-0.686	24 (21.62)	82 (24.62)	-0.071
2 types, n (%)	47 (33.10)	439 (39.37)	-0.131	47 (42.34)	133 (39.94)	0.049
3 types, n (%)	52 (36.62)	135 (12.11)	0.596	39 (35.14)	113 (33.93)	0.025
≥ 4 types, n (%)	19 (13.38)	12 (1.08)	0.489	1 (0.90)	5 (1.50)	-0.055
Insulin, n (%)	81 (57.04)	607 (54.44)	0.052	59 (53.15)	184 (55.26)	-0.042
Chest CT on admission
Bilateral lesions, n (%)	119 (92.25)	957 (90.71)	0.055	91 (91.92)	289 (92.33)	-0.015
Laboratory examination on admission
Leukocyte count > 9.5 × 109/L, n (%)	16 (11.35)	101 (9.41)	0.063	13 (11.71)	29 (8.95)	0.091
Neutrophil count > 6.3 × 109/L, n (%)	22 (15.60)	166 (15.47)	0.004	18 (16.22)	53 (16.36)	-0.004
Lymphocyte count < 1.1, 109/L, n (%)	55 (39.01)	437 (40.73)	-0.035	42 (37.84)	130 (40.12)	-0.047
Red blood count < 3.5 (for female), 4.0 (for male) × 1012/L, n (%)	61 (43.26)	480 (44.73)	-0.030	48 (43.24)	156 (48.15)	-0.099
C-reactive protein increase > ULN2, n (%)	36 (49.32)	298 (50.85)	-0.031	26 (44.07)	98 (56.32)	-0.247
Procalcitonin level increase > ULN2, n (%)	54 (46.96)	399 (44.19)	0.056	39 (43.82)	132 (48.18)	-0.087
ALT increase > 40 U/L, n (%)	22 (15.83)	234 (21.89)	-0.155	16 (14.68)	53 (16.46)	-0.049
eGFR, median (IQR)	104.20 (90.60-119.76)	101.18 (84.33-119.66)	0.088	103.78 (90.77-116.18)	101.33 (83.55-117.81)	0.028
D-dimer > ULN2, n (%)	62 (49.60)	526 (53.08)	-0.070	51 (52.04)	148 (50.00)	0.041
LDL-c > 3.4 mmol/L, n (%)	25 (22.73)	135 (15.96)	0.172	16 (19.51)	51 (19.54)	-0.001

¹Background anti-diabetic drugs were defined as the number of types of combined oral hypoglycemic agents and the proportion of patients using insulin.

²Upper limit of normal was defined according to criteria in each hospital and normal ranges of tests in each hospital.

³In the propensity score matched model, age, gender, heart rate, blood pressure, SpO₂ < 95%, computed tomography-diagnosed bilateral lung lesions, incidence of increased neutrophil count, leukocyte count, C-reactive protein, procalcitonin, alanine transaminase, D-dimer, low density lipoprotein cholesterol and decreased lymphocyte count, estimated glomerular filtration rate, comorbidities (chronic obstructive pulmonary disease, cerebrovascular diseases, chronic liver disease, and chronic renal diseases), the numbers of oral hypoglycemic agents, and the proportion of insulin usage were matched.

⁴Patients with type 2 diabetes who received dipeptidyl peptidase-4 inhibitors (DPP4i) throughout the whole 28-d follow-up period were enrolled in the DPP4i cohort.

⁵Patients with type 2 diabetes who never received DPP4i but took other anti-diabetic drugs throughout the observation time during hospitalization were classified as the non-DPP4i group. Data are n (%) or medians (IQR).

DPP4i: Dipeptidyl peptidase-4 inhibitors; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; SpO₂: Pulse oxygen saturation; ALT: Alanine transaminase; eGFR: Estimated glomerular filtration rate; LDL-c: Low density lipoprotein cholesterol; IQR: Interquartile range; SD: Standardized difference; ULN: Upper limit of normal; CT: Computed tomography.

Table 2 Associations of in-hospital use of dipeptidyl peptidase-4 inhibitors with coronavirus disease 2019 outcomes in propensity score matched analysis followed by logistic regression and mixed-effect Cox model analyses [n = 444, n (%)]

	Logistic regression model				Mixed-effect Cox model
Parameter	DPP4i (n = 111)	Non-DPP4i (n = 333)	Adjusted1 OR (95%CI)	P value3	Adjusted2 HR (95%CI)	P value3
Primarily outcome
All-cause mortality	2 (1.8)	11 (3.3)	0.58 (0.12,2.68)	0.48	0.44 (0.09,2.11)	0.31
Secondary outcome
Septic shock	1 (0.9)	4 (1.2)	0.78 (0.09,7.05)	0.82	0.66 (0.07,6.13)	0.71
Acute respiratory distress syndrome	17 (15.3)	51 (15.3)	1.06 (0.58,1.95)	0.85	1.02 (0.59,1.77)	0.95
Acute kidney injury	1 (0.9)	3 (0.9)	1.03 (0.11,10.03)	0.98	1.04 (0.11,10.07)	0.97
Acute liver injury	10 (9.0)	20 (6.0)	1.6 (0.72,3.54)	0.25	1.62 (0.74,3.53)	0.23
Acute cardiac injury	11 (9.9)	24 (7.2)	1.53 (0.71,3.28)	0.28	1.35 (0.65,2.79)	0.42
Any	30 (27)	84 (25.2)	1.17 (0.71,1.94)	0.54	1.06 (0.69,1.62)	0.79

¹Logistic regression model adjusted the incidence of increased C-reactive protein between DPP4i and non-DPP4i groups.

²Cox proportional hazard model using the hospital site as a random effect and adjusting the incidence of increased C-reactive protein.

³P values were calculated based on logistic regression model and mixed-effect Cox model, respectively.

Data are n (%). Measures of associations are adjusted odds ratios and hazard ratios. DPP4i: Dipeptidyl peptidase-4 inhibitors; OR: Odds ratio; HR: Hazard ratio; CI: Confidence interval.

Table 3 Differences of glycemic control efficacy in dipeptidyl peptidase-4 inhibitors group vs non-dipeptidyl peptidase-4 inhibitors group (n = 444)

Parameter	DPP4i (n = 111)	Non-DPP4i (n = 333)	P value4
Glycemic control efficacy during hospitalization
Median of FBG, median (IQR)	8.01 (6.75-10.31)	8.35 (6.48-11.12)	0.84
Median of GLU, median (IQR)	10.55 (8.70-12.58)	10.70 (8.90-13.45)	0.90
Max FBG, median (IQR)	11.18 (7.82-13.92)	10.50 (7.33-15.48)	0.95
Max GLU, median (IQR)	14.90 (12.40-19.10)	16.30 (13.30-20.55)	0.30
Min FBG, median (IQR)	6.67 (5.30-7.98)	6.74 (5.39-8.76)	0.54
Min GLU, median (IQR)	7.10 (5.00-9.30)	7.10 (5.65-8.90)	0.87
FBG > 7 mmol/L, day/total days1 (%)	9.09 (4.26-16.67)	6.52 (2.67-13.64)	0.05
GLU > 11.1 mmol/L, day/total days2 (%)	9.09 (5.56-23.75)	10.00 (4.08-25.40)	0.81
Titrating time3, median (IQR)	4.00 (1.00-9.00)	3.00 (1.00-11.00)	0.71

¹The day/total days of FBG > 7 mmol/L was defined as the days with FBG > 7 mmol/L as a percentage of the entire observation period.

²The day/total days of GLU > 11.1 mmol/L was defined as the days with GLU > 11.1 mmol/L as a percentage of the entire observation period.

³Titrating time was defined as the number of days that FBG met the normal range for the first time since admission.

⁴P values were calculated based on Kruskal-Wallis rank sum test.

Data are n (%) or medians (IQR). DPP4i: Dipeptidyl peptidase-4 inhibitors; FBG: Fasting blood glucose; GLU: Random blood glucose; Max: Maximum; Min: Minimum; IQR: Interquartile range.

Table 4 Incidences and adjusted odds ratios of glycemic control efficacy and side effects in dipeptidyl peptidase-4 inhibitors group compared to non-dipeptidyl peptidase-4 inhibitors group [n = 444, n (%)]

Parameter	DPP4i (n = 111)	Non-DPP4i (n = 333)	Adjusted5 OR (95%CI)	P value6
FBG < 7 mmol/L	47 (42.3)	150 (45.0)	0.91 (0.59,1.4)	0.67
GLU < 11.1 mmol/L	29 (26.1)	102 (30.6)	0.78 (0.48,1.27)	0.31
Hyperglycemia requiring treatment1	16 (14.4)	69 (20.7)	0.65 (0.36,1.17)	0.15
Hypoglycemia2	1 (0.9)	1 (0.3)	2.96 (0.18,47.95)	0.44
Metabolic acidosis	3 (2.7)	8 (2.4)	1.21 (0.31,4.66)	0.79
Lactic acidosis	1 (0.9)	5 (1.5)	0.62 (0.07,5.42)	0.67
Elevation of lactic acid3	12 (10.8)	29 (8.7)	1.33 (0.65,2.72)	0.44
Probability to discontinue current regimen4	16 (14.4)	75 (22.5)	0.58 (0.32,1.04)	0.07

¹Hyperglycemia requiring treatment was defined as the proportion of patients with elevated blood glucose and temporarily treated with insulin.

²Hypoglycemia was defined when fasting blood glucose < 3 mmol/L.

³The elevation of lactic acid was identified as > 2.2 mmol/L.

⁴Probability to discontinue current regimen was defined as proportion of patients who added insulin treatment on the basis of existing hypoglycemic regimens.

⁵Logistic regression model adjusted the incidence of increased C-reactive protein between DPP4i versus non-DPP4i groups.

⁶P values were calculated based on logistic regression model.

Data are n (%). Measures of associations are adjusted odds ratios. DPP4i: Dipeptidyl peptidase-4 inhibitors; FBG: Fasting blood glucose; GLU: Random blood glucose; OR: Odds ratio; CI: Confidence interval.