Glycemic Adverse Effects of Sars-CoV-2 Vaccination

Introduction

COVID-19 infection has been shown to worsen glycemic control, trigger hyperglycemic crisis, and possibly induce new-onset diabetes [1, 2]. After the widespread use of COVID-19 vaccination, there have been several case reports and case series that describe similar glyce¬mic complications in close temporal relationship with different types of COVID-19 vaccines. These glycemic effects include a wide range of complications ranging from mild worsening of glycemic control to induction of hyperglycemic crises and new-onset type 1 and type 2 di¬abetes. The timing of occurrence of these glycemic events in relation to administration of COVID-19 vaccine suggests that COVID-19 vac¬cination may be causally related to such events. The main purpose of this article is to review the latest data on the link between COVID-19 vaccination and post-vaccination glycemic complications.

Effect of COVID-19 vaccination on glycemic control in out- patients with diabetes

Mishra et al described 3 patients with type 2 diabetes who exhibited mild elevation of their fasting blood glucose values (from 95-110 mg/ dl to 150-186 mg/dl) and postprandial glucose levels (from 122-165 mg/dl to 150-186 mg/dl) 1-6 days after receiving COVID-19 vaccine (Covishield, Astra-Zeneca) [3]. Glucose values returned to baseline 15-30 days after vaccination [3]. Subsequently, 4 studies examined the effects of COVID-19 vaccines on glycemic control, mostly in patients with type 1 diabetes, using CGM technology with variable results (Table 1) [4-7]. Thus, 2 studies did not report significant ef- fects of various types of COVID-19 vaccines on the time of glu-cose values in range (TIR) (70-180 mg/dl) [4, 5]. However, in the largest available study (n=97), Heald et al [7] showed significant decrease in mean percentage of TIR during the 7 days post-vac-cination (52.2%) compared with the 7 days prior to vaccination (55.0%) (Table 1). In fact, 58% of their patients had reduction in TIR post-vaccination, with 10% having more than 20% reduction in TIR. No effect on variability of glucose values was demonstrat¬ed after vaccination [7]. The results did not change in subgroups of patients classified by age, gender, intercurrent illness, and types of COVID-19 vaccines used (Pfizer-BioNtech and AstraZeneca) [7]. Unfortunately, these authors, did not explore the possible rela¬tionship between vaccine adverse effects and glycemic control [7]. Meanwhile, Aberer et al showed that patients with type 1 diabetes spent significantly less TIR on days on which vaccine adverse ef¬fects occurred (e.g. fever, fatigue, injection site reaction) [6]. Tak¬en together, the above studies conducted in the outpatient setting suggest that COVID-19 vaccination may worsen glycemic control for at least 7 days in a subset of patients with type 1 diabetes. Ad¬verse effects of the COVID-19 vaccines (fever, myalgia, malaise, pain at injection site, etc.) could be one factor contributing to this hyperglycemia.

Table 1: Effects of COVID-19 vaccination on glycemic control in outpatients with diabetes

COVID-19 vaccine-induced new onset immune-mediat-ed type 1 diabetes

Immune-mediated or auto-immune type 1 DM is characterized by positive one or more pancreatic islet autoimmune antibodies such as autoantibodies to islet cell, glutamic acid decarboxylase 65 (GAD-65), zinc transporter 8, and insulin [8]. 5 cases of newly diagnosed immune-mediated type 1 diabetes were reported 7-28 days after receiving first or second dose of several COVID-19 vaccines (mRNA based vaccine of Pfizer-BioNtech and Moder- na or the adenovirus vector-based vaccine of AstraZeneca) (Table 2) [9-12]. One patient had history of autoimmune hypothyroid-ism and another had strong family history of autoimmune diseases [3]. Patients presented with severe hyperglycemia or DKA [10]. The case reported by Patrizio et al was unique because their 52 year-old-man converted from well-controlled type 2 diabetes to immune-mediated type 1 diabetes. In addition, he presented with another auto-immune disorder: Graves’ disease (Table 2) [12].

Table 2: Cases of immune-mediated type 1 diabetes induced by COVID-19 vaccine

COVID-19 vaccine-induced new onset fulminant type 1 diabetes

Fulminant type 1 diabetes is a subtype of type 1 diabetes first de-scribed by Imagawa et al [13] in Japan. It is characterized by dras¬tic onset of DKA, marked hyperglycemia (blood glucose 800 mg/ dl on average), irreversible degeneration of pancreatic β-cells, and near-normal HbA1c levels (<7.0% on average) [13, 14]. In addi¬tion, there is specific class II haplotype closely associated with this disease [14]. Islet-related anti-bodies are usually not detected in fulminant type 1 diabetes [13, 14]. Fulminant type 1 diabetes was initially reported in Japan and Korea. However, it was recently described in other areas of the world as adverse effect of the an¬ti-cancer drugs: check-point inhibitors [15]. Four cases, all from Japan, of new-onset fulminant type 1 diabetes were reported 3-6 days after COVID-19 vaccination (Table 3) [16-19]. However, in the case described by Ohuchi et al [19], patient was also taking the check point inhibitor nivolumab known to rarely cause fulminant type 1 diabetes [15]. Interestingly, other vaccines have been shown to trigger fulminant type 1 diabetes. Yasuda et al [20] reported one case of 54-year-old Japanese man who developed fulminant type 1 diabetes 7 days after receiving influenza vaccine.

Table 3: Cases of fulminant type 1 diabetes induced by COVID-19 vaccine

COVID-19 vaccine-induced hyperglycemic crises in pa¬tients without history of diabetes

10 patients presented with hyperglycemic crises i.e. diabetic keto-acidosis (DKA) or hyperglycemic hyperosmolar state (HHS), or a mixture of both, 3-36 days after receiving the first or second dose of COVID-19 vaccines (summarized in Table 4) [21-24]. These patients had clinical and biochemical profiles of type 2 diabetes. Thus, they were obese (body mass index 31.1-35.0 kg/m2) with ab¬sent islet antibodies and normal C-peptide levels. Because HbA1c values were not available right before vaccination, it cannot be ex¬cluded that these patients might have undiagnosed type 2 diabetes prior to vaccination. It should be emphasized that hyperglycemia of recent onset has the largest influence on raising HbA1c levels [25]. Thus, 50% of the HbA1c levels are determined by the plasma glucose levels in the preceding 1-month period [26]. Hence, these patients presenting with extremely elevated HbA1c values (12.0-17.1%) few weeks after COVID-19 vaccination could still have new onset type 2 diabetes. The course of type 2 diabetes triggered by COVID-19 vaccine appears to carry favorable prognosis. In¬deed, hyperglycemia was controlled with metformin alone or met-formin + dulaglutide few weeks after resolution of hyperglycemic crisis [22, 23].

Table 4: COVID-19 vaccine-induced hypertensive crises in patients with new-onset type 2 diabetes*

COVID-19 vaccine-induced hyperglycemic crises in patients with type 1 and type 2 diabetes

In patients with known diagnosis of type 1 and type 2 diabetes, COVID-19 vaccination may exacerbate diabetes control acutely and result in hyperglycemic crisis [23, 24, 27, 28]. Table 5 summa- rizes data from 7 patients (3 patients with type 1 and 4 with type 2 diabetes) who developed hyperglycemic crises 15 hours to 10 days after receiving the first or second doses of COVID-19 vaccines [23, 24, 27, 28]. Interestingly, the 2 patients reported by Lee et al had well-controlled type 2 diabetes (their HbA1c levels were 7.0 and 7.5%) and had previous COVID-19 infection approximately 1 year earlier. After resolution of hyperglycemic crisis, diabetes control was achieved by metformin alone in all 4 patients with type 2 diabetes [23, 24].

Table 5: COVID-19 vaccine-induced hyperglycemic crises in patients with pre-existing type 1 and type 2 diabetes

Mechanisms of COVID-19 vaccine induced diabetes

The mechanisms underlying COVID-19 vaccine-induced new-on-set diabetes or worsening of pre-existing diabetes are not fully un-derstood. They are likely multifactorial and take place in a small subgroup of predisposed subjects. One possibility is that inflam-matory and/or immunological response to the vaccine may result in acute stress and release of anti-insulin hormones (cortisol, cat-echolamines, growth hormone) precipitating hyperglycemic crisis [29]. Moreover, common adverse effects of COVID-19 vaccines such as malaise, mild fever, and myalgia may be contributing stressful factors. In addition, some authors propose the molecular mimicry or cross-reactivity theory and the autoimmune/Inflamma-tory syndrome induced by adjuvants (ASIA). Molecular mimicry refers to a close similarity between certain pathogenic elements contained in the vaccine and specific human proteins [30]. It fol¬lows that cross-reactivity may occur when amino acid homolo¬gy exists between the pathogen and a given self-tissue protein. Thus, antibodies developed against the spike protein of SARS-CoV-2 following COVID-19 vaccination might cross react with human pancreatic tissues to trigger an autoimmune disorder such as type 1 diabetes in susceptible individuals. In fact, Vojdani et al [31] have shown that anti-spike antibodies of SARS-CoV-2 react strongly with the GAD-65, one of the major antigens involved in immune-mediated type 1 diabetes [8]. The ASIA theory entails de¬velopment of an autoimmune disease due to the use of adjuvants in the vaccine. Adjuvants are immunological molecules that po-tentiate imunogenecity response of a vaccine [32]. However, in predisposed subjects, adjuvants may trigger autoimmune diseas¬es [33]. Acute pancreatitis could be another potential mechanism by causing damage of pancreatic β-cells. Several cases of acute pancreatitis were reported shortly after COVID-19 vaccines [34-37]. However, all cases of COVID-19 vaccine-induced pancreati¬tis resolved after few weeks, and no hyperglycemia was recorded [34-37]. Furthermore, computed tomography of the pancreas per¬formed in 2 patients who presented with fulminant type 1 diabetes after COVID-19 vaccination was unremarkable [17, 18].

Conclusions and current needs

Available data suggest that COVID-19 vaccines may induce new-onset type 1 and type 2 diabetes as well as temporary exacer- bation of glycemic control in patients with prevalent diabetes rang-ing from mild hyperglycemia to hyperglycemic crises. Although the incidence of these complications is most likely underreported, it may be still considered uncommon given the large number of people who received COVID-19 vaccines worldwide so far. Un-fortunately, the limited current data does not indicate any specif-ic patient predisposing factors or vaccine type that may increase the risk of vaccine-induced diabetes or worsening hyperglycemia. Physicians should be aware of this uncommon adverse effect of COVID-19 vaccines. In addition, patients with diabetes should be counselled about the possibility of deterioration of glycemic control post-vaccination and asked to monitor their blood glucose values closely for several weeks after receiving first and second dose of COVID-19 vaccine. Equally important, physicians and nurses should inquire about prior COVID-19 vaccination in pa¬tients presenting with hyperglycemic crises or new onset diabetes. Cases suspected to be triggered by the vaccine should be reported to the Federal Drug Administration (FDA) and the manufacturer. No doubt, the benefits of vaccination against COVID-19 far out¬weigh its risks. However, every effort must be pursued to prevent and promptly treat the adverse effects of COVID-19 vaccines.

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