Introduction

The pandemic of Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has infected more than 650 million people worldwide, causing more than 6.6 million deaths globally at the time of writing [1]. The expression of angiotensin-converting enzyme 2 (ACE2), the entry receptor for SARS-CoV-2, has been found not only in the respiratory system but also in extrapulmonary systems including the pancreas [2], raising concerns about new-onset diabetes after SARS-CoV-2 infection from the potential direct effect on pancreatic beta cells [3].

Several nationwide cohorts have investigated into this issue [4]. A cohort using the database from the United States (US) Department of Veteran Affairs showed 40% excess risk of incident diabetes with a median follow-up of 1 year, mostly type 2 diabetes [5]. Similarly, a study using German nationwide database showed 30% excess risk of incident type 2 diabetes after SARS-CoV-2 infection with a median follow-up duration of 4 months, compared to other acute respiratory illness [6]. However, a cohort study in the United Kingdom (UK) showed that the increased risk of incident diabetes persisted up to 12 weeks after SARS-CoV-2 infection [7]. Of note, there are differences between Asians and Caucasians in the pathophysiology of type 2 diabetes. At any given BMI, compared to Caucasians, Asians have more visceral adiposity, which is metabolically more adverse and contributes to lipotoxicity and insulin resistance [8]. This interethnic difference can modify the risks of incident diabetes after SARS-CoV-2 infection, which remains to be elucidated among Asians. Furthermore, with the emergence of SARS-CoV-2 variants where Omicron variants are the predominant strains at the time of writing, it remains to be determined whether the risks of incident diabetes following SARS-CoV-2 might differ compared with previous variants. There were indeed suggestions of fewer long COVID symptoms and burdens with Omicron variants compared to previous variants [9,10].

COVID-19 vaccination has shown efficacy in reducing severe disease, developed based on different technology platforms. At the time of writing, more than 12 billion doses of COVID-19 vaccination have been administered [1]. At least 15 cases of type 1 diabetes have been reported after both mRNA and inactivated COVID-19 vaccines [11]. There were also cases of acute hyperglycaemic crises, either on a background of known type 2 diabetes or as the first presentation of type 2 diabetes, following COVID-19 vaccination [12]. Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) and molecular mimicry are among the postulated mechanisms [11]. Little is known regarding the glycaemic status of nondiabetic individuals around the time of COVID-19 vaccination. Besides, case reports and series do not quantify the absolute risk of incident diabetes and inform if COVID-19 vaccination is associated with an increased risk of new-onset diabetes, especially since onset of type 2 diabetes after COVID-19 vaccination is expected to be underreported. Such information is essential to inform clinical practice and guide patients regarding COVID-19 vaccine uptake and the subsequent follow-up and monitoring.

It has been shown that COVID-19 vaccination may decrease the severity of symptoms of long COVID [13]. Following the same line of thought, COVID-19 vaccination may modify the risk trajectory of incident diabetes following SARS-CoV-2 infection. It is important to understand the role of COVID-19 vaccination in the risk of new-onset diabetes after SARS-CoV-2 infection, as the number of COVID-19 survivors keeps increasing globally.

As of November 2022, the Hong Kong Government Vaccination Programme provides 2 main authorised COVID-19 vaccines: CoronaVac (inactivated whole-virus vaccine) from Sinovac Biotech (Hong Kong) Limited and BNT162b2 (monovalent mRNA vaccine) from BioNTech/Fosun Pharma in China (equivalent to the Pfizer-BioNTech vaccine outside China) [14,15]. Hence, we conducted this population-based study to evaluate the incidence of diabetes (i) associated with COVID-19 vaccination, and (ii) following SARS-CoV-2 infection, with further stratifications according to vaccination status and SARS-CoV-2 variants.

Methods

The second cohort for evaluating risks following SARS-CoV-2 infection (the second cohort)

The second cohort consisted of COVID-19 patients identified by a first positive result on the SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) test or rapid antigen test (RAT) from January 1, 2020, to March 31, 2022, and people who were never infected up to March 31, 2022. The inclusion period was chosen to capture all COVID-19 cases from the date of the first confirmed cases to the peak of the Omicron wave in Hong Kong. The COVID-19 pandemic and key policies in Hong Kong have been described in S2 Method. The index date was defined as the first date of SARS-CoV-2 infection for COVID-19 patients. To assign pseudo-index dates for people without infection, we matched them with COVID-19 patients based on sex and age. To ensure each non-COVID-19 person could match with a COVID-19 patient, the maximum ratio was used. The index date of COVID-19 patient was then assigned to corresponding non-COVID-19 people. This cohort was followed up till the occurrence of outcomes, death, or August 15, 2022, whichever came first.

Exclusion criteria were (i) age <18 years, (ii) individuals who died on or before the index or pseudo-index date, (iii) individuals who had diabetes before the index or pseudo-index date, and (iv) individuals without HbA1c measurement records before the index or pseudo-index date (Fig 1).

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Fig 1. Flowchart of record linkage and selection procedure.

https://doi.org/10.1371/journal.pmed.1004274.g001

Results

Baseline characteristics

In total, we identified 706,631 people in the first cohort (CoronaVac: n = 176,099; BNT162b2: n = 182,129; unvaccinated: n = 348,403) and 798,578 people in the second cohort (COVID-19 patients, n = 145,452; non-COVID-19 group, n = 653,126) (S3 Table). After excluding those whom we could not identify matched pairs, we included 167,337 CoronaVac recipients and 167,337 matched controls, 158,378 BNT162b2 recipients and 158,378 matched controls, in addition to 145,199 COVID-19 patients and 145,199 matched controls.

In the first cohort, compared with the controls, the vaccination recipients were younger and less likely to have comorbidities. Among the vaccination recipients, 87,754 (52.4%) CoronaVac recipients and 73,500 (46.4%) BNT162b2 recipients have prediabetes, respectively. In the second cohort, compared with controls, COVID-19 survivors were older and had more comorbidities. Among the COVID-19 survivors, 60,348 (41.6%) were fully vaccinated and 25,792 (17.8%) did not receive any COVID-19 vaccines. After matching, the propensity score distributions were highly overlapping (S1 Fig) and the baseline characteristics were balanced between the study population and matched controls, with all SMDs <0.1 (Table 1).

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Table 1. Baseline characteristics of BNT162b2 or CoronaVac recipients, COVID-19 patients, and their respective matched controls after 1:1 propensity score matching.

https://doi.org/10.1371/journal.pmed.1004274.t001

Risk of incident diabetes following COVID-19 vaccination

In the first cohort, we identified 5,760 and 4,411 diabetes cases after receiving CoronaVac and BNT162b2 vaccines, respectively. CoronaVac recipients were followed up for a median of 386 days (interquartile range [IQR] 341 to 435) and BNT162b2 recipients for a median of 384 days (IQR 347 to 429). The median duration from vaccination to onset of diabetes was 178 days (IQR 91 to 283) and 179 days (IQR 91 to 288) for CoronaVac and BNT162b2 recipients, respectively. The cumulative incidences of overall diabetes, type 2 diabetes, and type 1 diabetes between the vaccine recipients and respective control groups are shown in S2 Fig. The crude incidence rates of overall diabetes were 9.08 per 100,000 person-days among CoronaVac recipients and 9.10 per 100,000 person-days among matched controls, and 7.41 per 100,000 person-days among BNT162b2 recipients and 8.58 per 100,000 person-days among matched controls. Compared to matched unvaccinated people, there was no evidence of the associations of CoronaVac or BNT162b2 vaccination with increased risks of overall diabetes (CoronaVac: HR = 0.998 [95% CI 0.962 to 1.035]; BNT162b2: HR = 0.862 [95%CI 0.828 to 0.897]), type 2 diabetes (CoronaVac: HR = 0.997 [95% CI 0.962 to 1.035]; BNT162b2: HR = 0.862 [95% CI 0.828 to 0.898]), and type 1 diabetes (CoronaVac: HR = 1.337 [95% CI 0.300 to 5.949]; BNT162b2: HR = 0.511 [95% CI 0.092 to 2.846]) (Table 2). Among CoronaVac and BNT162b2 recipients, 17 and 9 cases of acute hyperglycaemia and 2 and 5 cases of DKA were observed, respectively. We repeated the subgroup analyses according to age, sex, prediabetes, and previous SARS-CoV-2 infection, which showed consistent results for both types of COVID-19 vaccines (Fig 2). The results of sensitivity analyses that compared the incidence of diabetes following 2 doses of either vaccine with unvaccinated control were consistent with the result of the main analysis (S4 Table).

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Fig 2. Forest plot of HRs (95% CIs) for incident diabetes in different subgroup analyses.

https://doi.org/10.1371/journal.pmed.1004274.g002

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Table 2. Crude incidence rate of outcomes for CoronaVac or BNT162b2 recipients, COVID-19 patients, and respective matched controls, and HR of events for CoronaVac or BNT162b2 recipients and COVID-19 patients in comparison with their respective matched controls.

https://doi.org/10.1371/journal.pmed.1004274.t002

Discussion

Our study quantified the risks of incident diabetes after COVID-19 vaccination and evaluated the impact of COVID-19 vaccination and SARS-CoV-2 variants on the risks of incident diabetes after SARS-CoV-2 infection. There was no evidence of increased risks of incident diabetes following COVID-19 vaccination. On the other hand, we observed an increased risk of incident diabetes following SARS-CoV-2 infection. The increased risk was observed for type 2 diabetes, but not for type 1 diabetes. Interestingly, the observed excess risk of incident diabetes following SARS-CoV-2 infection was lower for Omicron variants compared with earlier variants. Furthermore, fully vaccinated individuals might be protected from the increased risk of diabetes following SARS-CoV-2 infection. Taken together, our results provide important reassurance for adults to get fully vaccinated to protect themselves against adverse outcomes of SARS-CoV-2 infection and its long-term sequelae, including the risk of diabetes.

To date, incident diabetes following COVID-19 vaccination has only been reported in case reports and series, summarised by Pezzaioli and colleagues recently [11]. These were all cases of type 1 diabetes, aged between 27 and 73 years, mostly following mRNA vaccination, occasionally reported following inactivated and adenovirus-vectored vaccination. The time of onset varied from 3 days to 2 months postvaccination. In addition, a few further cases of acute hyperglycaemic crises have been described following COVID-19 vaccination, with relatively preserved C-peptide levels on presentation, raising suspicion of an entity of vaccine-induced hyperglycaemia [12,36]. Our cohort study clarified these concerns using a population-based dataset and appropriate unvaccinated controls, demonstrating no evidence of increased risks of incident diabetes following COVID-19 vaccination. For BNT162b2, the incidence rate of diabetes was lower for vaccinated than for unvaccinated individuals. As our study was observational in nature, we could not firmly establish the causal relationship for BNT162b2 lowering the risk of incident diabetes. Unmeasured confounders could have accounted for this apparent protective effect, e.g., BNT162b2 recipients were younger and might have also adopted healthier lifestyle behaviours associated with the reduction in risks of incident diabetes. It is also possible that individuals with symptoms of undiagnosed diabetes were less likely to get vaccinated due to concerns about vaccine safety or efficacy.

In particular, the incidence of type 1 diabetes following COVID-19 vaccination was not increased and was in the order of 1 in 100,000, comparable to the background incidence rate of type 1 diabetes in Asian populations reported in the literature, which, in turn, is lower than that in the Caucasian populations [37]. Similarly, there was no increase in the risks of new-onset type 2 diabetes following COVID-19 vaccination. No studies have previously investigated the glycaemic status of nondiabetic individuals around the time of COVID-19 vaccination. On the other hand, there were studies of patients with diabetes for their perivaccination glycaemic control. Aberer and colleagues reported in patients with type 1 and type 2 diabetes monitored using continuous glucose monitoring system that time in range, below range, and above range did not substantially change following COVID-19 vaccination in the short term [38], consistent with the observations in our cohort of individuals without preexisting diabetes.

In contrast to the scant literature on risks of diabetes after COVID-19 vaccination, several large-scale cohort studies have assessed the risks of diabetes following SARS-CoV-2 infection, notably from the US [5], UK [7], and Germany [6]. The primary care database in Germany reported a 30% excess in risk of incident type 2 diabetes among COVID-19 survivors over a median follow-up of 4 months, but no significant increase in risk for other forms of diabetes [6]. A large cohort study in the US of over 180,000 COVID-19 survivors with a median follow-up of 1 year confirmed this increased risk of type 2 diabetes and further suggested that increasing COVID-19 severity was associated with higher risk of incident diabetes. Interestingly, this study reported that participants of African descent had a greater burden of incident diabetes than Caucasian participants, suggesting some interethnic differences in the propensity to develop incident diabetes after SARS-CoV-2 infection [5]. A more recent study utilising the UK healthcare database further divided the risk period into acute COVID-19 (4 weeks), postacute COVID (5 to 12 weeks), and long COVID (13 to 52 weeks) and showed that the risks of incident diabetes increase at least up to 12 weeks postacute COVID before declining. Consistent with the above cohorts, our study also showed that the risk of diabetes increased after SARS-CoV-2 infection. The increase in risk was seen in type 2 diabetes, but not for type 1 diabetes. Of note, the incidence of type 1 diabetes in Asians is lower than that in Caucasians [37]. Hence, the number of events of incident type 1 diabetes was low in our cohort, limiting the power of this analysis. Nonetheless, a post hoc analysis of 55 COVID-19 survivors evaluated at least 3 months after acute COVID-19 had detectable C-peptide levels, suggesting that insulinopenia was not apparent in postacute COVID-19 [39].

In all the aforementioned studies of risk of diabetes after SARS-CoV-2 infection, the inclusion criteria covered the period when COVID-19 vaccination programme commenced globally. Prior to our study, there was limited information regarding the influence of COVID-19 vaccination on the risk of incident diabetes following SARS-CoV-2 infection. Al-Aly and colleagues [40] showed that vaccinated COVID-19 survivors had a lower risk of long COVID compared with unvaccinated COVID-19 survivors, including metabolic disorders (encompassing “diabetes,” “hyperlipidaemia,” and “insulin use” in the study; HR = 0.77 [95% CI 0.68 to 0.87]), suggesting the benefits of COVID-19 vaccination on the risk of incident diabetes following SARS-CoV-2 infection. However, the HR for metabolic disorders following SARS-CoV-2 infection among vaccinated COVID-19 survivors was 1.32 (95% CI 1.26 to 1.39) compared with vaccinated control groups [40]. Similarly, Kwan and colleagues reported lower diabetes risks after COVID-19 infection in vaccinated than in unvaccinated patients in a study done in the US, suggesting a benefit of vaccination [41]. The subgroup analysis in our current study stratified by vaccination status revealed a graded attenuation in risk of incident diabetes among COVID-19 survivors compared with their respective non-COVID controls upon completion of COVID-19 vaccination regime (unvaccinated: HR = 1.69 [95% CI 1.48 to 1.93], partially vaccinated: HR = 1.20 [95% CI 1.09 to 1.33], fully vaccinated: HR = 1.01 [95% CI 0.90 to 1.12]). Our results suggested that there was no significant increase in risk of incident diabetes following SARS-CoV-2 infection only among fully vaccinated individuals, but not for partially vaccinated or unvaccinated individuals. In fact, this may also explain the finding in the subgroup analysis that younger individuals did not have a significant increased risk of incident diabetes, since the proportion of fully vaccinated individuals were higher among younger individuals (55.9%) compared with older one (34.5%). The difference between our results and those reported by Al-Aly and colleagues [40] could be related to our study dedicated to the evaluation of glycaemic status, having matched for prediabetes status at baseline and requiring availability of HbA1c values in each individual prior to the entry of the cohort. Our results concurred with most studies that reported fewer symptoms postacute COVID-19 among the fully vaccinated individuals [42], adding to the literature regarding the benefits of COVID-19 vaccination in reducing incident diabetes as one of the potential manifestations of long COVID. Our results further suggested the consistent ability of various types of COVID-19 vaccination in reducing long COVID, as reviewed by Notarte and colleagues [42]. Possible mechanisms of protection of COVID-19 vaccination against incident diabetes included (i) reducing the severity of SARS-CoV-2 infection and (ii) hastening the clearance of SARS-CoV-2, which, in turn, reducing the exaggerated inflammatory responses in COVID-19.

In the subgroup analysis, we also noted an apparently stronger association between increased risks of incident diabetes and SARS-CoV-2 infection among individuals without prediabetes. This could be related to the inclusion criteria requiring an HbA1c measurement before an index date in all individuals. There could be several postulations for this observation: (i) individuals with prediabetes are already predisposed to the development of diabetes such that the additional impact of SARS-CoV-2 infection may be less significant; and (ii) individuals with prediabetes could have more likely taken lifestyle modifications to reduce their risk of developing diabetes.

With the evolution of the COVID-19 pandemic, Omicron variant of SARS-CoV-2 has become the dominant strain globally. In the stratified analysis, we observed that both non-Omicron and Omicron variants of SARS-CoV-2 were associated with increased risks of incident diabetes following SARS-CoV-2 infection. Interestingly, the excess risk of incident diabetes was lower for Omicron variants compared with non-Omicron variants. This was indeed in keeping with the observations from other studies reporting fewer symptoms of long COVID and less burden of long COVID with Omicron variants [9,10], which could be related to the less severe acute disease in the infection with SARS-CoV-2 Omicron variants [10].

The main strength of our study is that we have quantified the risk of new-onset diabetes following COVID-19 vaccination and further evaluated the risk of incident diabetes following SARS-CoV-2 infection considering the vaccination status and the prevalent SARS-CoV-2 variants using a population-based dataset. We were also able to analyse the risk of new-onset diabetes among recipients of 2 different types of COVID-19 vaccines. Nonetheless, our results should be interpreted bearing certain limitations. First, our results are not generalisable to recipients of types of COVID-19 vaccination other than inactivated and mRNA vaccination. BNT162b2 is currently in use in many jurisdictions around the world, including North America (e.g., US, Canada, Mexico), South America (e.g., Brazil, Chile), Europe (e.g., UK, Switzerland), and Asia (e.g., Japan, Singapore). The jurisdictions where CoronaVac is currently in use are mostly located in Asia and Latin America, including China (where it was developed), Brazil, and Turkey. Second, information on BMI was not available from this cohort. Nonetheless, we have performed PS matching by including diagnosis of obesity in the analysis, and the balance was achieved with SMD <0.1. Third, the proportion of prediabetes in the current study cohort was around 50%, where the prevalence of prediabetes has been reported to be up to 40% among Chinese [43]. The slightly higher proportion of prediabetes individuals in the current study might be due to the requirement of valid HbA1c values before cohort entry for exclusion of individuals with preexisting diabetes, where HbA1c might have been checked among individuals with relatively higher cardiometabolic risks. Fourth, the modifying effects of differences in healthcare service utilisation on the risk of incident diabetes could not be entirely excluded. Individuals with SARS-CoV-2 infection may have more contact with healthcare services, resulting in more diagnostic tests and increased diagnosis of incident diabetes. On the other hand, since infection with Omicron variant is generally associated with less severe symptoms [44], while interaction with health services will be increased in those with symptoms, the effect will be less than with other SARS-CoV-2 variants. Likewise, vaccination reduces the severity of COVID-19 infections, so while those who were vaccinated still have an increased chance of being diagnosed to have diabetes after COVID-19 infection, the increase is less than in unvaccinated people. Fifth, type 1 diabetes was identified through diagnostic coding in the current study, where misclassification bias could not be entirely mitigated. Last but not least, the follow-up period was relatively short in our study to allow evaluation of the risk of chronic diabetic complications. The long-term impact of SARS-CoV-2 infection on diabetes requires continuous surveillance with global concerted efforts.

In conclusion, there was no evidence of increased risks of incident diabetes following COVID-19 vaccination. In contrast, the risk of incident diabetes increased following SARS-CoV-2 infection, especially for type 2 diabetes. This excess risk might be lower among survivors of SARS-CoV-2 infection with Omicron variants compared with previous variants. Fully vaccinated individuals might be protected from the risk of incident diabetes following SARS-CoV-2 infection. Our results should encourage people to get fully vaccinated to protect themselves from severe complications of COVID-19 and the sequelae of long COVID, including the potential risk of incident diabetes.

Supporting information

Acknowledgments

The authors thank the Hospital Authority and the Department of Health for the generous provision of data for this study.