A previous diagnosis of diabetes mellitus is known to be a significant risk factor for increased Covid-19-related severity and worse outcomes, including higher hospital admission rates over time. In this prospective study we aimed to understand why this is the case using population-level data. We have extended our understanding of this observation by quantifying how much a diagnosis of diabetes increases the risk of hospital admission after a Covid-19 infection in Greater Manchester, UK. The RR of hospital admission vs matched controls was higher for individuals with T1DM than individuals with T2DM and comparable to that described by Barron et al. [4] for patients requiring hospital treatment for Covid-19 infection. Hospital admission rates remained higher after infection for up to 3 months (Fig. 1). This is one of the few analyses to report hospital admission rates for people with T1DM and Covid-19 infection.
Our analysis suggests a protective effect of metformin in people with T2DM. This is a novel finding in relation to the consequences of a Covid-19 infection, but is in keeping with a large body of evidence regarding the benefits of metformin in reducing the likelihood of severe consequences of T2DM [10]. The opposite association was seen in T1DM, likely because metformin is mostly given to people with T1DM who are overweight.
We found substantive overlap between the factors that put people at increased risk of admission with T2DM compared to the background population, such as hypertension or raised BMI. A very strong effect of ethnicity was seen in individuals with T2DM as previously described [5, 11, 12]. The multivariate model accounted for 49% of the variation in risk of admission from the base model. COPD and Townsend index also increased the risk of admission for individuals with T2DM. The association of lower total and LDL-cholesterol with an increased likelihood of hospital admission may relate to the application of more intensive statin dose titration in people with established cardiovascular disease, resulting in lower total and LDL-cholesterol levels in these individuals.
We have shown that for individuals with T1DM and those with T2DM, age, non-Caucasian ethnicity, eGFR, hypertension, a history of respiratory disorder and BMI and additionally in individuals with T2DM social disadvantage and SMI are factors that relate independently to a less favourable outcome in the 28 days following a Covid-19 infection, here manifesting as hospital admission. Furthermore being prescribed an ACE inhibitor or antiplatelet agent (associated with hypertension and diagnosed cardiovascular disease) was also associated with an increased likelihood of admission as was social disadvantage as measured by the Townsend index.
The underlying causes and processes that determine which individuals develop a severe clinical course requiring hospitalisation following Covid-19 infection will be complex and multifactorial. Some of these will determine how the innate and the acquired immune systems deal with the virus whereas other factors will clearly relate to how well an infected individual can regulate and maintain homeostasis following gross perturbations in the metabolic pathways and physiological processes. The likelihood is that in a proportion of individuals with diabetes the already existing consequences of associated pathologies and multi-comorbidity will in part explain why Covid-19 has such severe consequences.
It should be mentioned that the advent of treatment of hospitalised patients with dexamethasone, when patients are hospitalised with the pulmonary consequences of a Covid-19 infection, has significantly reduced mortality rates across the world [13]. Use of this drug continues to influence outcomes positively as new virus variants have emerged. Additional agents are also now available for Covid-19-affected patients who become severely unwell [14].
Within our analysis to determine what may differentiate individuals with diabetes and from those without diabetes regarding likelihood of admission, a lower eGFR and higher average blood glucose (as reflected by HbA1c) are shown to be potential differentiating factors. Both have been previously linked to an impaired cell-mediated immune response [15], which is critical for effective acquired immunity to a Covid-19 infection.
It has been reported that within T2DM both a diagnosis of COPD [16] and non-white ethnicity [17] resulted in a higher likelihood of hospital admission. Previously we reported that being older was the major risk factor for death in people with T2DM, as also observed in the general population [18].
Vitamin D level may be a differentiating factor linked to a more adverse outcome for people with T2DM, is important and is further evidence for the influence of vitamin D levels on Covid-19 outcome [19, 20], although this remains an area of much debate.
As we go forward in the ‘post pandemic’ world, where new variants of the Covid-19 may arise, any evidence concerning factors that confer greater risk of hospitalisation in people with T1DM and T2DM will be helpful. This can be seen in the context that potential pathogenic links between the Covid-19 and diabetes mellitus include the influence of glucose homeostasis and potentially altered immune status on the progression of the SARS-CoV-2 viral infection once established [21].
Much remains to be determined about why having diabetes increases the risk of likelihood of serious consequences of a Covid-19 infection. Parveen et al. [22] reported that both a diagnosis of diabetes and of hypertension had a negative effect on the health status of patients with Covid-19 and pointed out that large prevalence studies were required. There were similar conclusions from Abdi et al. [23], as supported by our findings.
We report that the presence of COPD/asthma in association with a diagnosis of T2DM increased the likelihood of admission as previously described [24, 25], but also that a diagnosis of SMI was associated with an increased likelihood of admission. This accords with previous findings reported by Lee et al. in a Korean study [26] and may relate to many people with SMI being in relatively poor health and being in a more disadvantaged sociodemographic situation.
Our findings indicate that being on clopidogrel, aspirin or an ACE inhibitor is related to an increased risk of hospital admission within patients with diabetes. This is likely to relate to these agents only being given to people with hypertension, proteinuria and/or a history of vascular disease. Nevertheless we found that much of the elevated likelihood of admission in individuals with diabetes cannot be accounted for by risk factors that have been measured in the course of routine care.
Dexamethasone for the treatment of an acute Covid-19 infection can increase blood glucose levels [13] particularly in people with diabetes. Therefore, frequent blood glucose monitoring and personalized adjustment of medications are required [27], with addition of glucose-lowering therapy sometimes being necessary.
Much less has been published about outcomes in T1DM following Covid-19 infection. Ebekozien et al. [28] described the most common presenting symptoms and outcomes for 64 people with T1DM who have confirmed or suspected Covid-19. More than 50% of all cases reported hyperglycemia, and nearly one-third of patients experienced diabetic ketoacidosis.
We suggest that while individuals with particular conditions have a higher risk for admission or dying following a Covid-19 infection, this might be explained by there being a composite/multifactorial measure of immunological/metabolic resilience and reserve capacity for dealing with acute inflammation and infection. Resilience vs vulnerability would likely exist on a continuum and be largely influenced by such key factors as age, body mass index, respiratory health/capacity, underlying immunodeficiency/autoimmunity status, renal function, cardiovascular health and current/latent infections.
In the same way that we have developed a ‘frailty score’ we do not have a Covid-19 infection resilience score in people with diabetes. Such an approach would provide a cornerstone for planning any future prevention strategies.
Strengths/Limitations
A limitation common to all Covid-19 research is that during the first few months of the pandemic there was limited capacity to test for Covid-19 infection, and so the true prevalence is unknown and can only be estimated. Thus there is the likelihood of there being an underestimate of the total number of positive Covid-19 test results. However there is no reason to suspect that this would affect individuals with diabetes vs those without diabetes differentially. A strength is that by matching our cohort on the date of positive coronavirus test, as well as age and sex, we are able to correct for this and focus on the differences between the diabetes cohort and the general population.
A further limitation is that the data only covers Greater Manchester and we have relied on general practice record coded diagnoses.