Glycaemic control is associated with COVID-19 breakthrough infections

Patients' characteristics might also influence the efficacy of vaccines against COVID-19. We show that poor glycaemic control is associated with a decreased immune response to Pfizer vaccine and also with an increased incidence of breakthrough infections in patients with Type 2 Diabetes.

Despite extensive vaccination campaigns, COVID-19 is still spreading in many countries. Massive vaccination has dropped COVID-19 related mortality and hospitalizations but has only partially halted virus circulation. The major determinants of vaccination failure and of the incidence of breakthrough infections are the effect of time on waning immunity and the emergence of new viral variants escaping pre-existing immunity1. However, also patients' intrinsic characteristics might favour the development of COVID-19 despite full vaccination against SARS-CoV-2, as suggested for obesity and Type 2 Diabetes (T2D)2

Patients with T2D usually have a decreased immune response to both natural infections and vaccination. Among other factors, glycaemic control is a key determinant of immune responses in patients with T2D3. However, whether glycaemic control influences the response to COVID-19 vaccines and in turn the development of breakthrough infections was unknown. 

To explore this issue, we recruited patients with T2D among healthcare and educator workers undergoing the first full cycle of vaccination with the Pfizer mRNA vaccine. We followed them for one year, testing a range of immune and biochemical parameters during five successive visits, including glycated haemoglobin (HbA1c), the most commonly used marker to evaluate glycaemic control.

At the end of the study, we categorized the patients (n=494) according to the degree of glycaemic control observed at the five visits, i.e. by creating two groups of subjects having the one-year mean of HbA1c < (good control) or > 7% (poor control). 

Patients with poor control showed significantly lower immune responses when compared with patients with good control. Indeed, their plasma had a lower virus neutralization ability, as assessed with an in vitro test evaluating antibody-mediated responses to a specific portion of the virus. In addition, when stimulating their T cells, a subtype of lymphocytes required to properly mount immune responses against the virus, with a pool of antigens (the stimulatory portion of any infective agent) of SARS-CoV-2 their response in terms of T cells expressing three key immune mediators, i.e. interferon-γ (IFNγ), interleukin-2 (IL-2), and tumour necrosis factor- α (TNF-α), was less pronounced. 

Of note, the levels of all these immune parameters were well correlated with the degree of glycaemic control.

To explore if this attenuated immune response to vaccine also translates into a increased incidence of infections, we compared the incidence of COVID-19 in the two groups. We recorded 31 (10.5%) breakthrough cases among the 298 T2D patients with poor control and 7 breakthrough infections among the 196 (3.6%) T2D patients with good glycaemic control. This means that patients with good control have a lower risk to test positive for COVID-19, even after adjusting the statistical analysis for a range of other risk factors. Among these other factors, also smoking status and sex were significantly associated with the incidence of breakthrough infections, with non-smokers and females being less likely to test positive. 

As any other observational study, these findings do not imply causality. However, this new evidence  suggests that optimizing glycaemic control and avoid smoking in the period following vaccination might improve vaccine's effectiveness and might decrease the chances of testing positive for COVID-19 in patients with T2D. 

Among other limitations of the study, an important point is that we did not record data relative to the severity of COVID-19 nor about the presence/absence of symptoms, since we only collected data relative to PCR-positive nasopharyngeal swab. Thus, whether glycaemic control or any other factor influences the development of severe COVID-19 in vaccinated patients with T2D requires further investigation.

In summary, even though a randomized clinical trial is needed to conclude that lowering HbA1c after vaccination reduces COVID-19 incidence among patients with T2D, these results uncover for the first time a role for glycaemic control as a candidate mediator of anti-COVID-19 vaccine efficacy within the T2D population, suggesting that this specific aspect of diabetes management might contribute to the success of the vaccination program.


1- Lipsitch, M., Krammer, F., Regev-Yochay, G. et al. SARS-CoV-2 breakthrough infections in vaccinated individuals: measurement, causes and impact. Nat Rev Immunol 22, 57–65 (2022).

2- Stefan, N. Metabolic disorders, COVID-19 and vaccine-breakthrough infections. Nat Rev Endocrinol 18, 75–76 (2022).

3- Peleg, A.Y., Weerarathna, T., McCarthy, J.S. and Davis, T.M.E. (2007), Common infections in diabetes: pathogenesis, management and relationship to glycaemic control. Diabetes Metab. Res. Rev., 23: 3-13.

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