Phd in MOLECULAR MEDICINE

Thesis title: COVID-19 AND DIABETES: EFFECTS OF A DANGEROUS RELATIONSHIP, FROM CLINICAL MANIFESTATION TO VACCINE EFFICACY

Rationale: At the end of 2019, SARS-CoV-2 was the cause of a pandemic disease named Covid-19, that deeply affect society worldwide. Diabetes mellitus has been described as one of the most important chronic conditions worsening the Covid-19 prognosis, which is worrisome considering that diabetes affects about half a billion people. For this reason, the aim of this project was to assess the relationship between diabetes mellitus and Covid-19 focusing on hospitalization, the impact of lockdown and vaccination. Methods: Four studies have been conducted. All of them with the common aim of elucidating the relationship between diabetes and Covid-19: 1) In the CoViDiab I study, a multicentre study, () we evaluate the risk profile of subjects with type 2 diabetes mellitus (T2D) hospitalized for Covid-19 comparing them with subjects with T2D without signs or symptoms of SARS-CoV-2 infection; 2) in the CoViDiab II, a multicentre retrospective study, we collected and compared data from patients hospitalized for Covid-19 with and without diabetes; 3) in the Glycalock study a retrospective multicentre study (), we compared the differences in glycaemic controls (in terms of HbA1c) in subjects with T2D exposed to lockdown with matched controls with T2D who attended the study centres 1 year before, with a stable glycaemic control; 4) Finally, in CoVaDiab I study, in a prospective monocentric study (), we evaluated efficacy of vaccination with mRNA vaccine towards SARS-CoV-2, in terms of antibody (Ab) response, in people with and without diabetes and we further assessed the short term effects of vaccination on glucose control in subjects with autoimmune diabetes (AD). Results: In CoViDiab study I, a case-control study, performed in subjects with T2D hospitalized for Covid-19 (n=79) compared to subjects with T2D but without Covid-19 (n=158), matched for age and gender, a higher prevalence of chronic obstructive pulmonary disease (COPD) (OR 3.72, 95%CI: 1.42–9.72, p = 0.007) and of chronic kidney disease were found (CKD) (OR 3.08, 95%CI: 1.18–8.06, p=0.022) but no difference in previous cardiovascular disease history. In the CoViDiab study II, 354 patients were enrolled (subjects with diabetes: n=81), and the risk of the primary composite outcome (any of mechanical ventilation, admission to an intensive care unit or death) was higher in subjects with diabetes (Adjusted Odds Ratio (adjOR) 2.04, 95%CI 1.12–3.73, p=0.020) compared to subjects without diabetes. In the Glycalock study, no difference in delta HbA1c was found between the lockdown and control groups (lockdown group −0.1% [−0.5%−0.3%] vs. control group −0.1% [−0.4% −0.2%]; p=0.482). In the lockdown group, subjects with worse psychological well-being, as evaluated by tertiles of the Psychological General Well-Being Index (PGWBS), showed a worsening of HbA1c (p=0.041 for the trend among PGWBS tertiles) and BMI (p=0.022). In the CoVaDiab study I, subjects with diabetes (n=128) showed decreased levels of Ab after one month of vaccination compared to controls (N=202) (1217[747-1887] BAU/mL Vs 1477[942-2556] BAU/mL, p=0.002), even after correction for age and gender (p=0.002). No difference was found between subjects with type 1 DM (T1D) and T2D. After six months, Ab levels significantly decreased in people with and without diabetes, with no differences between groups. Finally, in subjects with AD no significant differences were observed in glucose control, expressed as time in range evaluated by continuous glucose monitoring comparing the 3 days after the SARS-CoV-2 vaccine with the 14 days preceding the vaccine was observed. Conclusion: CKD and COPD and worse metabolic control were risk factors for hospitalization in subjects with diabetes and SARS-CoV-2 infection. Moreover, subjects with diabetes showed a worse prognosis during Covid-19. Subjects with diabetes, regardless of the type of diabetes and glycaemic control, showed an impaired response to vaccination, even if the vaccine was safe in terms of the effect on glucose control in the following days after the vaccination. Finally, subjects with poor psychological well-being may experience a worsening glycaemic control in distressing conditions, such as lockdown, highlighting the relevance of management of people with DM during these difficult times. Nevertheless, patients with good glycaemic control could cope well during distressing conditions, such as lockdown, pointing out the relevance of self-management of disease.