Correlation between COVID-19 vaccination and diabetes mellitus: A systematic review

Table 1 Characteristics of the included studies

Ref.	Country	Study design	Study time span	Population	Sample size (n)	No. of patients with DM (n) T1DM T2DM		Sex (F/M)	Age, median (min-max), yr	Type and name of vaccine	Dose schedule	Related findings
Zhang et al[23]	China	Observational study	Between October 2021 and January 2022	The population is aged ≥ 60 yr with hypertension or (/and) DM	1413	620		661/752	67.6	Vero cell (19nCov-CDC-Tan-HB02)	Two doses (day 0, day 28)	After vaccination, there was no significant abnormal fluctuation in blood glucose in diabetic patients
Marfella et al[24]	Italy	Prospective observational study	December 2020	Healthcare and educator workers	478		201	212/266	18-60	mRNA-BNT162b2 (Pfizer-BioNTech) or ChAdOx1-S (Astra-Zeneca) or mRNA-1273 (Moderna)	One (day 0, day 21) or two (day 52) doses	Significant decrease in the immune response in people with poorly controlled blood glucose
Kılınç-Toker et al[25]	Turkey	Retrospective study	Between August 1, 2021 and October 31, 2021	Hospitalized patients with COVID-19	541	195		282/259	70.2 (21-98)	(CoronaVac) and/or BNT162b2 mRNA (Pfizer-BioNTech)	14 d after dose 2	For hospitalized patients after the second dose, diabetes was not associated with their ICU stay and mortality
Barocci et al[26]	Italy	Observational study	Between December 2020 and June 2021	Healthcare workers and university staff	2845	8		155/129	43-61	ChAdOx1-S and (BNT162b2/BNT162b2 and ChAdOx1-S/ChAdOx1-S)	2 mo after dose 2	DM does not affect antibody levels
Singh et al[27]1	India	Cross-sectional study	Between January 16, 2021 and May 15, 2021	Healthcare workers	5154	0	52	210/305	44.8 ± 13.19	CovishieldTM (ChAdOx1-nCOV) or CovaxinTM (BBV-152)	One (day 21) and two (day 21-28, day 83-97, and day 173-187) doses	People with T2DM had a significantly lower seropositivity rate compared to those without
Singh et al[28]1	India	Longitudinal study	Between January 16, 2021 and November 15, 2021	Healthcare workers	481	0	51	195/286	≤ 60 years, n = 411; > 60 years, n = 70	CovishieldTM (ChAdOx1-nCOV) or CovaxinTM (BBV-152)	3 wk, 3 mo, and 6 mo after dose 2	Participants with T2DM have a lower seropositivity rate at all time points
Shim et al[29]	Korea	Retrospective study	February2021	Vaccination participants	736	48		433/303	51.5 (20-80)	AZD1222, BNT162b2, mRNA-1273 and Ad26.COV2.S	2 wk before and 6 mo after dose 2	Diabetics had a lower rate of neutralizing antibodies after vaccination
Alqassieh et al[30]	Jordan	Prospective observational cohort	Between March and April 2021	Jordanian adults	288	76		189/151	20-60 years, n = 137, > 60 years, n = 151	Pfizer-BioNTech or Sinopharm	6 wk after dose 2	Although DM negatively affected IgG titer, it was not statistically significant
Wan et al[31]	China (Hong Kong)	Population-based study	Between February 23, 2021 and January 31, 2022	Patients with T2DM in Hong Kong electronic case records	350963	0	350963	167073/183890	64.7 ± 1.37/68.1 ± 0.747	BNT162b2 or CoronaVac	Complete at least one dose of vaccination	Patients with T2DM do not appear to have higher risks of AESI and acute diabetic complications after vaccination
Lee et al[32]	South Korea	Questionnaire study	Between March 8, 2021 and March 11, 2021	Healthcare workers	1603	27		1261/342	37.7 ± 10.89	ChAdOx1	7 d after dose 1	DM is associated with an increased risk of grade 3 to 4 adverse reactions after the first dose
Rangsrisaeneepitak et al[33]	Thailand	PSM observational study	Between June 8, 2021 and July 12, 2021	Healthcare workers and T2DM patients	282		94	129/153	30-83	ChAdOx1 nCoV-19 (AZD1222)	56 d after dose 1	People with T2DM had weaker antibody responses than those without diabetes after the first dose
Sourij et al[34]	Austria	Multicentre prospective cohort study	Between April and June 2021	T1DM, T2DM, and healthy participants	150	75	75	68/82	49.2 ± 14.59	BioNTech-Pfizer, Moderna, or AstraZeneca	7 to 14 d after dose 1 and 14 to 21 dafter dose 2	The antibody levels after the second vaccination were comparable in healthy controls and DM patients, irrespective of glycaemic control
Tawinprai et al[35]	Thailand	Prospective cohort study	Between March 31, 2021 and May 5, 2021	Healthcare workers	796	11		517/279	40 (30-57)3	ChAdOx1 (AZD1222)	At least 21 d after dose 1 and before dose 2	DM reduces the immune response to vaccination
Ali et al[18]	Kuwait	Case-control study	August 2021	Non-diabetics and patients with T2DM	262	0	81	126/136	49.3 ± 14.59	BNT162b2 (Pfizer-BioNTech)	At least 3 wk after dose 2	Both neutralizing antibody and IgG antibody titers were significantly lower in the T2DM group than in the non-diabetic group
Karamese et al[36]	Turkey	Descriptive study	March 2021	Participants over 65 years of age who have received two doses of vaccine	235	49		111/124	70.4 ± 4.89	CoronaVac	4 wk after dose 1 and 4 wk after dose 2	Lower rates of antibody response were detected in participants with DM
Lustig et al[37]	Israel	Single-centre, prospective, longitudinal cohort study	Between December 19, 2020 and January 30, 2021	Health-care workers	2607	139		1883/724	47.7 ± 12.59	Pfizer-BioNTech BNT162b2	1-2 wk after dose 1 and 1-2 wk after dose 2	Decreased antibody response in diabetic patients after vaccination
Islam et al[38]	Japan	Cross-sectional study	June 2021	Workers	953	21		654/299	21-75	BNT162b2 (Pfizer-BioNTech)	15 to 71 d after dose 2	Spike IgG antibody titers were lower in the presence of hyperglycemia
Parthymou et al[39]	Greece	Longitudinal observational cohort study	September 2021	Healthcare units participants	712	50		444/268	50.8 ± 11.49	BNT162b2 (BioNTech-Pfizer)	3 wk and 3 mo after Dose2	DM is not an independent factor affecting antibody titers
Priddy et al[40]	New Zealand	Prospective cohort study	Between June 10, 2021 and September 18, 2021	Participants in two centers	285	28		156/1296	52 (16-92)	BNT162b2 (BioNTech-Pfizer)	28 d after dose 2	Participants with diabetes had lower anti-S IgG antibodies compared to those without DM
Naschitz et al[41]	Israel	Retrospective study	May 2021	Residents in long-term geriatric and palliative care and assisted living facilities	304	103		208/96	≥ 60	BNT162b2 (Pfizer-BioNTech)	3-4 mo after dose 2	DM is associated with negative serological results
Güzel et al[42]	Turkey	Prospective study	May 20212	Volunteers, outpatient clinic people, and COVID-19 patients	183	80		98/85	21-60	CoronaVac-SinoVac	21 d after dose 2	IgG antibody levels were significantly lower in patients with DM than in those without DM
Virgilio et al[43]	Italy	Multicenter prospective study	Between June 2021 and December 2021	Residents of long-term care facilities	555	0	140	378/177	82.1	BNT162b2 (Cominarty) Moderna (mRNA-1273)	Before the vaccination, 2 mo, and 6 mo after dose 1	Vaccination in elderly residents with T2DM is associated with a reduced humoral immune response
Patalon et al[44]	Israel	Retrospective cohort study	Between February and May 2021	A large patient cohort from Maccabi Healthcare Services	4740	377		1914/2826	16-59 years, n = 3355; ≥ 60 years, n = 1385	BNT162b2 (BioNTech-Pfizer)	Two vaccinations at intervals of 21 to 27 d	DM is not a relevant factor affecting antibody levels
Mitsunaga et al[45]	Japan	Prospective study	Between April 15, 2021 and June 9, 2021	Hospital’s workers	374	6		264/110	36	BNT162b2 vaccine (COMIRNATY (Tozinameran)	Before vaccination, 7 to 20 d after dose 1, and 7 to 20 d after dose 2	HbA1c higher than 6.5% was a significant suppressor of antibody responses
Papadokostaki et al[46]	Greece	Prospective observational study	Between May and September 2021.	Participants attended the vaccination center	174	14	44	107/67	52.6 ± 10.6	BNT162b2 (BioNTech-Pfizer)	21 d after dose 1, 7-15 d after dose 2, and 70-75 d after dose 2 but before dose 3	It was high and similar after the second dose in both participants with and without DM
Zhao et al[47]	United States	Prospective longitudinal study	Between December 2020 and December 2021	Veterans and healthcare workers	124	39		33/91	20-95	BNT162b2 (Pfizer-BioNTech)	48 h before dose 1 and dose 2, 1 mo, 3 mo, 6 mo, 12 mo after dose 2, and 1 mo after dose 3	DM was significantly associated with a decrease in response intensity after completion of the primary vaccine series, but responses to the third dose were generally robust
Santotoribio et al[48]	Spain	Descriptive, retrospective, observational, and cross-sectional study	Between November 1, 2020 and March 31, 2021	Infected patients and vaccinated subjects	175	17		112/63	51.0 (19-89)	Pfizer-BioNTech	At least 21 d after dose 2	Serum antibody levels did not decrease significantly in patients with DM
Mehta et al[49]	India	Observational cohort study	Between March 2021 and October 2021	Vaccinated patients with AIRDs	495	63		416/79	56.5	AZD1222 (AstraZeneca)	4 wk and10-14 wk after dose 2	DM was significantly associated with lower anti-RBD antibodies
Ajlan et al[50]	Saudi Arabia	PSM prospective study	June 14, 20222	Patients from a large hospital	431	191		136/295	51.3 ± 16.29	BNT162b2 or ChAdOx1	7 d after dose 1 and dose 2, and 2 wk after dose 1 and dose 2	There was no difference in the primary outcome between the two vaccine platforms. Unresponsiveness was mainly linked to DM
Billany et al[51]	United Kingdom	Prospective observational study	March 2021	Maintenance hemodialysis patients	94	43		38/56	62.1 ± 12.29	BNT162b2 or AZD1222	28 d after dose 1	There was no difference in antibody testing with or without DM
Aberer et al[52]	Austria	Multicenter prospective study	Between April and June 2021	DM patients	74	58	16	NR	T1DM: 39.5 ± 14.1; T2DM: 60.6 ± 6.2	BioNTech-Pfizer and Moderna and AstraZeneca	First dose	No change in insulin dose before and after vaccination. Vaccination significantly reduced TIR in T1DM patients, but had no effect on TIR in T2DM patients
Piccini et al[53]	Italy	Observational cohort study	Between March and June 2021	T1DM patients	39	39	0	17/22	18.7 ± 2.19	mRNA-BNT162b1 (Pfizer-BioNTech) and Moderna (mRNA-1273)	One (day 7, day 14) and two (day 7, day 14) doses and 14 d after dose 1 and dose 2	COVID-19 vaccination was safe and not associated with significant perturbation of glycemic control in patients with T1DM
Heald et al[54]1	United Kingdom	Observational cohort study	Between January 14, and March 7, 2021	T1DM patients	20	20	0	11/9	53 (26-70)	mRNA-BNT162b2 (Pfizer-BioNTech) and Oxford /AstraZeneca	7 d before and 7 d after dose 1	COVID-19 vaccination can cause temporary relative hyperglycemia in people with T1DM. No relationship between vaccine type and blood glucose perturbation
D'Onofrio et al[55]	Italy	Observational cohort study	July 13, 20212	T1DM (AD) patients	35	35		14/21	36 (27-51)3	mRNA-BNT162b2 (Comirnaty)	14 d before and 3 d after dose 1 and dose 2	No significant differences in TIR, TAR, TBR, and CV between, after, and before the COVID-19 vaccination in T1DM patients
Heald et al[56]1	United Kingdom	Survey and evaluation study	Between January 5, 2021 and April 4, 2021	Adults (18 years of age or more) with T1DM	97	97	0	51/46	44 (18-70)	Pfizer-BioNTech or Oxford-AstraZeneca	7 d before and 7 dafter dose 1	In T1DM, vaccination can cause a temporary perturbation of interstitial glucose. There is no difference between vaccines
Gouda et al[57]	Greece	Observational study	March 2022	T1DM patients	1358	135	0	72/63	11.7 (5-18)	BNT162b2 (Pfizer-BioNTech), Moderna (mRNA-1273), or AstraZeneca	7 d before and 7 d after dose 1, dose 2, and dose 3	SARS-CoV-2 vaccination in children and adolescents with T1DM is safe and is not associated with immediate glucose imbalance
Sakurai et al[58]	Japan	Case report	December 11, 20212	Healthy woman	1			1/0	36	mRNA-BNT162b2 (Pfizer-BioNTech)	First dose	mRNA vaccine is associated with new-onset T1DM
Patrizio et al[59]	Italy	Case report	September 15, 20212	T2DM patient	1	0	1	0/1	52	mRNA-BNT162b2 (Pfizer-BioNTech)	Second dose	T1DM may be triggered after SARS-CoV-2 vaccination
Aydoğan et al[60]	Turkey	Case series	Between May 2021 and October 2021	One had Hashimoto's thyroiditis, and the other 3 were healthy	4			1/3	27-56	mRNA-BNT162b2 (Pfizer-BioNTech) or CoronaVac	Second dose	Vaccination with BNT162b2 may trigger T1DM
Sato et al[61]	Japan	Case report	April 19, 20222	Malignant melanoma patient	1			0/1	43	mRNA-based SARS-CoV-2 vaccination	Second dose	mRNA vaccine may trigger T1DM
Yakou et al[62]	Japan	Case series	December 21, 20212	T1DM patients	2	2	0	2/0	52-71	mRNA-BNT162b2 (Pfizer-BioNTech)	Second dose	A temporary decrease in insulin secretion after vaccination
Mishra et al[63]	India	Case series	Between January 18, 2021 and March 4, 2021	T2DM patients	3	0	3	1/2	58-65	Covishield™ (ChAdOx1-nCOV) (AstraZeneca)	First dose	Vaccination may result in a mild and temporary increase in blood glucose levels
Abu-Rumaileh et al[64]	Jordan	Case report	January 14, 2021	Hypertension patient	1			0/1	58	mRNA-BNT162b1 (Pfizer-BioNTech)	Second dose	COVID-19 vaccine has a risk of causing new-onset T2DM
Sasaki et al[65]	Japan	Case report	December 13, 20212	Osteoporosis, mild glucose intolerance	1	0	0	1/0	73	Moderna (Spikevax, mRNA-1273)	Second dose	The development of T1DM is attributable to the COVID-19 vaccination
Lee et al[66]	United States	Case Series	June 30, 20212	T2DM and hypertension patients	3	0	2	1/2	52-87	mRNA-BNT162b1 (Pfizer-BioNTech) and Moderna (Spikevax, mRNA-1273)	First dose	Vaccination may trigger a hyperglycemic episode and DKA
Edwards et al[67]	United Kingdom	Case Series	April 2021	Hypertension, hypothyroidism, and pre-diabetes	3			0/3	53-68	Covishield™ (ChAdOx1-nCOV)	First dose	The first administration of the COVID-19 vaccine can trigger an acute hyperglycemic crisis
Ganakumar et al[68]	India	Case series	November 2021	T1DM	2	2	0	1/1	20-25	COVISHIELD (ChAdOx1 nCoV-19) or COVAXIN (BBV152)	1 to 4 d after dose 2	COVID-19 Vaccination has the potential to induce DKA
Zilbermint et al[69]	United States	Case report	September 11, 20212	T1DM	1	1	0	1/0	24	Moderna (mRNA-1273)	15 h after dose 2	A plausible mechanism exists between COVID-19 vaccination and DKA
Yaturu et al[70]	United States	Case report	May 2021	Hypertension, primary hyperparathyroidism, and obesity patient	1	0	1	0/1	56	BNT162b2 (Pfizer-BioNTech)	Right after the second dose	COVID-19 Vaccination has the potential to induce HHS
Kshetree et al[71]	United States	Case report	NR	Hypertension and pre-diabetes	1	1	0	0/1	69	mRNA vaccine	2 mo after dose 3	COVID-19 mRNA vaccine has the potential to induce DKA
Prasad[72]	India	Case report	March 2021	Patient with T2DM	1	0	1	1/0	73	Covishield	6 d after dose 1	Vaccination may cause glycaemic disturbances
Sasaki et al[73]	Japan	Case report	January 4, 20222	Healthy person	1	1	0	1/0	45	BNT162b2 (Pfizer-BioNTech)	1 d after dose 1	COVID-19 vaccine might trigger the onset of fulminant T1DM in susceptible individuals
Yano et al[74]	Japan	Case report	November 11, 20212	Healthy person	1	1	0	1/0	51	Moderna (mRNA-1273)	28 d after dose 1	COVID-19 vaccination can induce T1DM in some individuals
Ohuchi et al[75]	Japan	Case report	November 20212	Cutaneous malignant melanoma with axillary lymph node metastasis	1	1	0	0/1	45	BNT162b2 (Pfizer-BioNTech)	3 d after dose 2	There is a highly suspicious causal relationship between fulminant T1DM and COVID-19 vaccination

¹The authors are the same, but the individual studies are different, including different phases, different samples, and different data.

²Take the date of receipt of the manuscript.

³Median (25^th-75^th percentile).

⁴Sample size for completing the second dose.

⁵Sample size for fully completed questionnaires.

⁶Contains a Non-binary participant.

⁷Age (mean ± SD) is divided according to BNT162b2 and CoronaVac groups.

⁸Sample size for T1DM, of which 70 received at least one dose of the vaccine and the other 65 were unvaccinated.

⁹mean ± SD.

NA: Not available; NR: Not reported; COVID-19: Coronavirus disease 2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; PSM: Propensity score matching; HbA1c: Glycated hemoglobin; TIR: Time in range; DM: Diabetes mellitus; T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus; HHS: Hyperosmolar hyperglycemic syndrome; DKA: Diabetic ketoacidosis; AD: Autoimmune diabetes; AIRDs: Autoimmune Rheumatic Diseases; AESI: Adverse events of special interest; F: Female; M: Male; ICU: Intensive care unit; TAR: Time above range; TBR: Time below range; CV: Coefficient variation.