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

Table 3 Outcomes of the studies based on the association between vaccination and diabetes

Ref.	Assessed variables	Findings related to variables	Conclusion	Limitations
Zhang et al[23]	Hypertension, Comorbidity, Side effects	None	After vaccination, no significant abnormal fluctuations in blood glucose values were observed in the DM patients	Lack of data on the duration of antibodies after vaccination in the study population
Marfella et al[24]	HbA1c, Time since vaccination, type of vaccine	On Day 21 after the second vaccine dose, T2DM patients with HbA1c > 7% showed significantly reduced virus-neutralizing antibody capacity than normoglycemic subjects and T2DM patients with good glycaemic control. At 21 d after the first vaccine dose, neutralizing antibody titers and CD4 cytokine responses involving type 1 helper T cells were lower in T2DM patients with HbA1c levels > 7% than in individuals with HbA1c levels ≤ 7%. The reduction of HbA1c levels 52 d after vaccination was associated with neutralizing antibody titers and CD4 cytokine increases	Hyperglycemia at the time of vaccination can worsen the immune response, and proper glycemic control can improve the immune response	The statistical significance of the relevant indicators was relatively low
Kılınç-Toker et al[25]	Age, sex, mixed vaccination, delta variant, BMI, Diabetes, hypertension, COPD, cardiovascular diseases, chronic kidney disease, cancer	Age, male gender, delta variant, and mixed vaccination (CoronaVac plus BioNTech) were associated with death. The delta variant had higher ICU admission and mortality rate	For hospitalized patients who received two doses of the vaccine, diabetes was not associated with their ICU stay and mortality	Retrospective design, short follow-up, and assessment of inpatients only
Barocci et al[26]	Homologous vaccination, heterologous vaccination, type of vaccine, vaccine schedule, sex, age, BMI, smoking, DM, cardiovascular diseases, respiratory tract diseases, previous SARS-CoV-2 infection, side effects	Heterologous vaccination induced a significantly higher humoral response than homologous vaccination. The type of vaccine influenced antibody titers	DM does not affect antibody levels	Results were influenced by anti-S IgG levels in asymptomatic subjects
Singh et al[27]1	Sex, T2DM, age, BMI, side effects, type of vaccine, dose 1, dose 2	Gender, presence of comorbidities, and vaccine type were independent predictors of antibody seropositivity and anti-spike antibody titer levels. Patients with T2DM had a significantly lower seropositivity rate compared to those without the comorbid disease. Seropositivity rates were lower in those with T2DM compared to those without T2DM. Both vaccine recipients had similar mild to moderate adverse events, and none had serious side effects	T2DM is associated with lower seropositivity rates and anti-spike antibody titers	No assessment of the cell-mediated immune response
Singh et al[28]1	Age, previous SARS-CoV-2 infection, sex, BMI, side effects, type of vaccine, dose 1, dose 2, T2DM, blood group, dyslipidemia, ischemic heart disease	The seropositivity rate was significantly higher in the ≤ 60 years age group than in the > 60 years age group at all time points. GMT was significantly higher in participants with past SARS-CoV-2 infection than in SARS-CoV-2-naiveindividuals.	Participants with T2DM had a lower rate of seropositivity at all time points	The sample was drawn from a healthy population with few comorbidities
Shim et al[29]	Age, DM, type of vaccine, side effects, vaccination interval, hypertension, BMI, sex	There were significant differences in general and neutralizing antibodies based on age, vaccine type, vaccination interval, pain score, diabetes, and hypertension	For all vaccines, subjects with diabetes showed lower rates of neutralizing antibody production after vaccination	Vaccination priority policies bring heterogeneity across age groups
Alqassieh et al[30]	Age, type of vaccine, hypertension, cardiovascular disease, DM, sex, BMI	Old people (> 60) had lower IgG titers than their younger counterparts. The use of the Pfizer-Biotech vaccine was positively associated with positive IgG titers, while cardiovascular disease had a negative effect on IgG titers. Although diabetes had a negative impact on positive IgG titers, it was not statistically significant	Although DM negatively affected IgG titer positivity, it was not statistically significant	Samples were collected only once at a specific period (6 wk) after vaccination
Wan et al[31]	Dose 1, dose 2, HbA1c, side effects	None	Patients with T2DM do not appear to have higher risks of AESI and acute diabetic complications after vaccination	Adverse events are defined using diagnosis codes and may be biased by underdiagnosis or misclassification
Lee et al[32]	Sex, age, DM, type of vaccine, BMI	Being young, female or underweight, and having diabetes were associated with an increased risk of developing grade 3 to 4 adverse reactions after the first dose of the ChAdOx1nCoV-19 vaccine	DM is associated with an increased risk of grade 3 to 4 adverse reactions after the first dose of vaccine, especially in women	Sample from relatively healthy subjects working in hospitals
Rangsrisaeneepitak et al[33]	T2DM, age, sex, BMI, side effects	After the first dose of AZD1222, the antibody response was weaker in T2DM patients than in non-diabetic patients. The seroconversion rate was higher in the control group than in the diabetic group. Older age was associated with a weaker antibody response in older diabetic patients. The GMC of SARS-CoV-2 IgG antibodies at 56 d was significantly lower in diabetic patients than in age- and sex-matched controls. In the age- and sex-matched controls, SARS-CoV-2 IgG antibody levels were significantly higher in women than in men. During the first 24 h, injection site reactions were more common in diabetic patients than in healthy controls	After the first dose of AZD1222, the antibody response was weaker in T2DM patients than in non-diabetic patients	Participants in the control group were healthcare workers, so natural immunity may have been a confounding factor
Sourij et al[34]	T2DM, eGFR, HbA1c, side effects, T1D	Age and renal function were significantly associated with the extent of antibody levels. The most common side effect was injection site reactions, with a significantly lower rate in patients with T2DM	The antibody levels after the second vaccination were comparable in healthy controls and in DM patients, irrespective of glycaemic control	Focused only on the humoral immune response after vaccination, but did not investigate the cellular immune response
Tawinprai et al[35]	DM, hematologic disease, sex, age, time since the first dose of vaccination, BMI, side effects, cardiovascular disease, hypertension, dyslipidemia, end-stage kidney disease	Participants with diabetes or hematologic comorbidities had lower concentrations of anti-RBD antibodies. Anti-RBD antibody concentrations were significantly higher in female participants than in male participants. The immune response was lower in older participants. Anti-RBD antibody concentrations were significantly higher at 2 and 3 mo post-vaccination than at 1-mo post-vaccination	Participants with diabetes or hematologic comorbidities had lower concentrations of anti-RBD antibodies	The presence of participants who did not complete two anti-RBD antibody assays withdrew from the study
Ali et al[18]	T2DM, age, sex, BMI, comorbidity, previous SARS-CoV-2 infection, hypertension	T2DM is associated with lower titers of neutralizing and IgG antibodies	Both neutralizing antibody and IgG antibody titers were significantly lower in the T2DM group than in the non-diabetic group	Participants in the study were self-selected verbally and through job advertisements
Karamese et al[36]	T2DM, age, hypertension, COPD, dose 1, dose 2	Lower antibody response rates were detected in participants with T2DM and in those aged 65 years and older	DM patients have lower antibody levels	The study population was an advanced age group with a high number of comorbidities
Lustig et al[37]	Age, sex, DM, immunosuppression, hypertension, heart disease, autoimmune disorders, BMI	Lower antibody concentrations are consistently associated with males, older age, immunosuppression, diabetes, hypertension, heart disease, and autoimmune disorders	Lower IgG concentrations and lower detectable IgA antibodies were observed in DM patients, indicating a reduced antibody response to vaccination in these patients	The sample was drawn from a healthy population with few comorbidities
Islam et al[38]	Hyperglycemia, FPG, age, sex, BMI, hypertension, smoking, alcohol consumption	Spike IgG antibody titers were lower in the presence of hyperglycemia and IFG	Vaccine recipients with diabetes and IFG had lower concentrations of SARS-CoV-2 spike IgG antibodies than the vaccine recipients with normoglycemia did	Associations observed in cross-sectional studies do not necessarily indicate causality
Parthymou et al[39]	Sex, age, smoking, BMI, DM, hypertension, statin use, vitamin D levels	Age, male gender, and tobacco use are negatively associated with antibody titers after COVID-19 vaccination	Antibody titers were numerically lower in diabetic patients, but this association was not statistically significant	Reliance on questionnaires to record anthropometric parameters and medical history affects reliability
Priddy et al[40]	Age, DM, sex, BMI, race	IgG and neutralization responses decreased with age. Lower responses were associated with age ≥ 75 and DM	Lower responses were associated with DM	Most of the IgG and neutralization tests used are not standardized
Naschitz et al[41]	Cancer, DM, congestive heart failure, sex, age, hypertension, COPD, cerebrovascular disease, chronic liver disease, cognitive disability	Cancer, DM, or congestive heart failure were all associated with having a negative serology result	DM is associated with negative serological results	There was a large age difference between the two sample groups
Güzel et al[42]	Cardiovascular diseases, DM, age, BMI, sex, smoking, vitamin use, viral load, comorbidities	Cardiovascular disease and diabetes were associated with lower IgG antibody levels. In the healthcare workers group, IgG antibody response values were negatively correlated with BMI and age	IgG antibody levels were significantly lower in patients with DM than in those without DM	ELISA test may lead to false positive results
Virgilio et al[43]	Sex, T2DM, insulin therapy	The negative impact of diabetes in determining a steeper antibody decline was greater in female residents than in male residents. T2DM is associated with a reduced humoral immune response after SARS-CoV-2 vaccination. Antibody kinetics in diabetic patients receiving insulin therapy are similar to those in patients without diabetes	Vaccination in elderly residents with type 2 diabetes is associated with a reduced humoral immune response	Data on blood glucose or glycated hemoglobin levels were not specifically collected to assess the control or severity of diabetes
Patalon et al[44]	Sex, age, BMI, COPD, DM, congestive heart failure, inflammatory bowel disease	Females were associated with higher levels of antibodies. Lower antibody levels were observed in higher age groups	DM is not a relevant factor affecting antibody levels	The study population was older and had more comorbidities
Mitsunaga et al[45]	Age, Hypertension, HbA1c, Outdoor exercises, Vaccination interval, BMI, COPD, Dyslipidemia, DM, Autoimmune diseases, Cancer, dose 1, dose 2, BG	Older than 60 years, hypertension, HbA1c higher than 6.5%, and lack of outdoor exercises were significant suppressors of antibody responses, whereas the length of days from the first to the second vaccination longer than 25 d promoted a significant antibody response	HbA1c higher than 6.5% was a significant suppressor of antibody responses	The sample was relatively healthy health workers but did not include participants with serious comorbidities
Papadokostaki et al[46]	Age, DM, dose 1, dose 2, sample testing time, HbA1c, BMI, duration of diabetes, HbA1c	In the diabetic group, Abs-RBD-IgG was significantly correlated with age and time, and dose after vaccination	The humoral immune responses after the second dose were high and similar in participants with and without DM	No comparison between type 1 and type 2 diabetes
Zhao et al[47]	DM, dose 1, dose 2, dose 3, age, end-stage kidney disease, cancer, steroid use, previous SARS-CoV-2 infection, time since vaccination	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. Age and malignancy had a negative effect on the initial strength of the humoral immune response. Being over 65 years, end-stage renal disease, diabetes, and clinical comorbidities of steroid use had a negative effect on the humoral immune response. SARS-CoV-2 infection enhanced the neutralization antibody response to the third dose	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	Small sample size
Santotoribio et al[48]	Age, sex, DM, hypertension, heart disease	None	Serum antibody levels were not significantly reduced in patients with common conditions such as arterial hypertension, diabetes, heart disease, or chronic respiratory disease	No assessment of the cell-mediated immune response
Mehta et al[49]	DM, immunosuppression, vaccination interval, sex, comorbidity	DM, immunosuppression, and vaccination interval were all significantly associated with anti-RBD antibodies	DM patients had significantly lower titers of anti-spiking antibodies than patients without diabetes	The sample group was patients with autoimmune rheumatic diseases with a high proportion of comorbidities
Ajlan et al[50]	DM, type of vaccine, age, triple immunosuppressive therapy, side effects, sex, time since transplantation	Diabetes and triple immunosuppressive therapy appear to significantly affect the immune response. Triple immunosuppressive therapy and age were identified as significant factors in the lack of response to the vaccine after the second dose. Response rates after the first dose of vaccine with the Pfizer vaccine were higher than those with the AstraZeneca vaccine	Diabetes mellitus and triple immunosuppressive therapy appear to significantly affect response	Lack of immunocompetence control group
Billany et al[51]	Age, immunosuppression, previous SARS-CoV-2 infection, sex, race, DM	Patients with detectable antibodies were younger than patients without detectable antibodies. Patients who were immunosuppressed were less likely to have detectable antibodies than patients who were not immunosuppressed. Patients previously infected with COVID-19 were more likely to have detectable antibodies than those with no history of SARS-CoV-2 infection	There was no difference in antibody testing with or without DM	Small sample size
Aberer et al[52]	TIR, TBR, TAR, T1DM, T2DM, carbohydrate intake, CV	None	At the time of side effects, T1DM patients had significantly less TIR and significantly more TAR, while there was no effect on T2DM patients	Short assessment time and small sample size
Piccini et al[53]	Side effects, dose 1, dose 2, TIR, time in different glucose ranges, mean glucose levels, TDD of insulin, bolus proportion, type of vaccine	Side effects after the vaccination were mild and more frequent after the second dose. No severe adverse reactions were reported	No significant differences in glycemic control and glycemic indices were observed at different times throughout the vaccination cycle and were independent of the vaccine type	Small sample size
Heald et al[54]1	Age, BMI, mode of treatment, sex, HbA1c, type of vaccine, duration of diagnosed T1DM	The fall in the percentage BG on target was also greater for those with a median BMI of 28.1 kg/m2 or more. The fall in the percentage BG on target categorized by additional Metformin/Dapagliflozin was greater than no oral hypoglycemic agents, and the median age ≥ 53 yr was greater than < 53 yr	In T1DM, COVID-19 vaccination can cause a temporary BG disturbance, and this effect is more pronounced in patients taking oral hypoglycemic drugs plus insulin and in the elderly	No analysis of changes in insulin dose in the week following the COVID-19 vaccination
D'Onofrio et al[55]	TIR, TBR, TAR, CV, dose 1, dose 2, insulin dosage, SD	None	Pre- and post-CGM data collected during the two vaccine doses did not show any significant differences between the two groups in terms of TIR, TAR, TBR, CV, and SD	Small sample size
Heald et al[56]1	Medication, HbA1c, oral hypoglycemic drugs plus insulin therapy, age, sex, type of vaccine, duration with diabetes, BMI	COVID-19 vaccination can cause a temporary perturbation of interstitial glucose, an effect that is more pronounced in patients taking oral hypoglycemic agents plus insulin. This effect was more pronounced in those with lower HbA1c	In T1DM, vaccination can cause a temporary perturbation of interstitial glucose. There is no difference between the AstraZeneca and the Pfizer vaccines	The effects of the first and second vaccination on interstitial glucose regulation could not be compared
Gouda et al[57]	TIR, TDD of insulin, dose 1, dose 2, type of vaccine, insulin dosage, average glucose level, bolus insulin, automated bolus	One week after vaccination, there was a slight decrease in TIR along with an increase in mean blood glucose levels, but both were statistically insignificant	No differences in blood glucose or glycemic perturbations were shown before and after vaccination in patients with T1DM. There was no correlation between vaccine side effects and TIR	The effects of the first and second vaccination on interstitial glucose regulation could not be compared

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

COVID-19: Coronavirus disease 2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; BMI: Body mass index; HbA1c: Glycated hemoglobin; TIR: Time in range; TAR: Time above range; TBR: Time below range; CV: Coefficient variation; TDD: Total daily dose; DM: Diabetes mellitus;T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus; AESI: Adverse events of special interest; CGM: Continuous glucose monitoring; GMT: Geometric mean titer; GMC: Geometric mean concentration; Abs-RBD-IgG: Anti-SARS-CoV-2 receptor-binding domain IgG; FPG: Fasting plasma glucose; IFG: Impaired fasting glucose; BG: Blood glucose; eGFR: Estimated glomerular filtration rate; COPD: Chronic Obstructive Pulmonary Disease.