People with diabetes (PWD) have been identified as being at increased risk of serious illness from COVID-19. Understanding and quantifying this risk is key to enabling patients, carers, and healthcare professionals to make informed choices about ways to manage risk in PWD during the COVID-19 pandemic.
This rapid review sets out to answer the following questions:
- Are PWD at increased risk of contracting COVID-19?
- Do PWD experience worse outcomes with COVID-19?
- Do clinical and/or demographic characteristics moderate the relationship between diabetes and COVID-19?
A companion review looks at the management of diabetes during the COVID-19 pandemic.
Are People with diabetes at increased risk of contracting COVID-19?
People with diabetes (PWD) are considered at increased risk of infection, and a narrative review has extended this to infection with COVID-19. However, as testing is still limited, whether or not PWD are more likely to contract COVID-19 is unclear. The data we currently have predominantly comes from hospitalised cohorts. A systematic review and meta-analysis of 8 studies in predominantly Chinese populations (n = 46,248, searches run 25 Feb 2020) found diabetes was the second most prevalent co-morbidity (after hypertension) in people hospitalised with COVID-19, with 8% (95% CI 6%-11%) of the infected population confirmed as having diabetes. However, the authors report significant heterogeneity across studies and did not assess the quality of included studies. They also included a large national database that was also the source of data in smaller included studies, increasing the risk of double counting. A separate systematic review and meta-analysis of six studies (n = 1527; four studies included in the former review), found that 9.7% (6.9%–12.5%) of patients with confirmed COVID-19 had diabetes. The authors state quality of included studies was assessed but the results are not presented or discussed.
Population prevalence of diabetes in people over 30 years old in Hubei province (where most of the studies in both reviews came from) was estimated to be 5.6% (4.3%-7.0%) but the validity of this figure is unclear. Data from a study across China estimated population prevalence of diabetes to be approximately 11%. Our searches did not uncover data from other countries on the proportion of people with COVID-19 with diabetes.
According to the CDC, those with diabetes who get COVID-19 are more likely to experience these complications. In studies from China, as many as 22% of patients who were hospitalized with a severe coronavirus infection had diabetes.
Generally speaking, people with diabetes have a higher risk of getting infections due to the way the disease affects the immune system. The immune system normally protects the body from infections by preventing germs from entering our bodies and fighting them off if they do. Studies suggest that in patients with diabetes, important immune cells, and proteins that help cells “talk” to each other, don’t work as well as they should. If your immune system isn’t working well, also know as being immunocompromised, infections can progress more quickly
Diabetes doesn’t only impact the immune system, though. People with diabetes are also more likely to have other serious health conditions, such as high blood pressure and heart disease, which make COVID-19 complications even more likely.
Does diabetes increase the risk of COVID-19 severity?
Three systematic reviews have analysed whether PWD are more likely to have severe cases of COVID-19. All found clinically significant increased risk.. The same systematic review and meta-analysis of 8 studies already cited found an increased risk of severe disease in PWD, though the finding is highly uncertain due to wide confidence intervals including both decreased and increased risk (OR 2.07, 95% CI: 0.89- 4.82). A second systematic review and meta-analysis (pre-print; not peer-reviewed) of nine studies (n = 1936; 5 studies also included in the former review), found a substantial association between diabetes and greater COVID-19 severity (OR 2.67, 95% CI 1.91 to 3.7). A third systematic review already cited (6 studies, n = 1527, at least four studies included in the former reviews) found a high level of statistical heterogeneity (I2 = 67%) resulting in uncertainty of the effect estimates; in pooled data diabetes accounted for 11.7% of ICU/severe cases compared to 4.0% of non-ICU/severe cases (RR 2.21, 95% CI 0.88 to 5.57).
In the second review, the data extracted differ considerably to those extracted from the same studies included in the other two reviews. It is unclear to what extent confounding variables (e.g. age, other comorbidities such as hypertension and cardiovascular disease) were taken into account, and what criteria were used to define disease severity in all three reviews.
Two studies synthesise data on mortality. A Chinese Centre for Disease Control and Prevention report summarising data from 72,314 cases found an overall case-fatality rate (CFR) of 2.3% (1023 deaths among 44,672 confirmed cases). In PWD the CFR was 7.3% for diabetes. A small, multi-centre cohort study in China (n = 191) found diabetes was associated with significantly higher odds of in-hospital death in univariable analysis (OR 2.85, 95% CI 1.35 to 6.05). They did not run a multivariable model including diabetes (though did so for other conditions). The interpretation of CFRs in the current pandemic is challenging.
Finally, a retrospective review of 1,590 laboratory-confirmed hospitalised patients in China across 575 hospitals analysed composite endpoints: admission to ICU, intensive ventilation, or death, and found that after adjusting for age and smoking status, diabetes significantly increased risk (hazard ratio 1.59, 95% CI 1.03–2.45). 34.6% of severe cases were in PWD compared to 14.3% in non-severe cases. This data overlaps with that presented in the reviews above but is presented separately here due to the calculation of an adjusted hazard ratio.
COVID-19 is a new disease and there is limited information regarding risk factors for severe disease. Based on currently available information and clinical expertise, older adults and people of any age who have serious underlying medical conditions might be at higher risk for severe illness from COVID-19.
Based on what we know now, those at high-risk for severe illness from COVID-19 are:
- People 65 years and older
- People who live in a nursing home or long-term care facility
People of all ages with underlying medical conditions, particularly if not well controlled, including:
- People with chronic lung disease or moderate to severe asthma
- People who have serious heart conditions
- People who are immunocompromised
- Many conditions can cause a person to be immunocompromised, including cancer treatment, smoking, bone marrow or organ transplantation, immune deficiencies, poorly controlled HIV or AIDS, and prolonged use of corticosteroids and other immune weakening medications
- People with severe obesity (body mass index [BMI] of 40 or higher)
- People with diabetes
- People with chronic kidney disease undergoing dialysis
- People with liver disease
In summary, issues of heterogeneity, poor reporting and lack of high-quality systematic reviews make it difficult to conclude with confidence the extent to which PWD are at increased risk of severe outcomes with COVID-19. PWD are at higher risk of more severe consequences from infections generally, especially influenza and pneumonia. Diabetes UK advises that COVID-19 can cause more severe symptoms and complications in PWD. Quantification of the increased risk is challenging given the issues with the evidence base we have raised.
A number of possible mechanisms have been proposed for the observed increase in worse clinical outcomes in COVID-19 for PWD, including elevated plasmin levels; imbalance of angiotensin converting enzyme 2 (ACE2) and cytokines; reduced viral clearance; general pathophysiology related to the renin-angiotensin system, insulin resistance, and increased inflammatory markers. However, these are predominately untested hypotheses or theories based on observational data.
What, if anything, moderates the relationship between diabetes and COVID-19 severity?
There is a notable lack of data addressing this question. Both increased age and cardiovascular comorbidities are associated with increased risks for COVID-19 severity, and both are likely to be closely related to diabetes status. It is plausible that BMI, ethnicity, and certain medications all may also play a role. At the time of writing, Diabetes UK stated that everyone with diabetes, including type 1, type 2, and gestational, is at risk of developing a severe illness with COVID-19, but the way it affects people varies person to person (this is true of everyone, not just PWD). They stated that they do not know how the virus may affect people in diabetes remission. The Juvenile Diabetes Research Foundation (JDRF) had indicated that people with type 1 diabetes who have glucose values close to target “may not be at greater risk … unless their situation is complicated by other concerns.” They state that there is currently no good information to tell how type 1 diabetes interacts with COVID-19 and other health aspects to affect risk.
None of the studies reviewed explicitly analyse the risk of severe COVID-19 in people with diabetes using any additional variables. A retrospective review of 1,590 hospitalised patients (which found an increase in composite endpoints for PWD, and is in other systematic reviews but included separately due its more detailed breakdown of the data) noted that subgroup analyses stratifying patients according to their age (<65 years versus =65 years) did not reveal a substantial difference in the strength of associations between the number of comorbidities and mortality related to COVID-19 but did not investigate this within diabetes specifically.
A narrative review (not systematic) noted that in PWD, co-existing heart disease, kidney disease, advanced age and frailty are likely to further increase the severity of COVID-19 but did not offer data to support this. A retrospective cohort study of hospitalized patients in Wuhan (n = 258) (pre-print; not peer-reviewed) found fasting blood glucose to be associated with COVID-19 fatality (Cox proportional hazard model aHR = 1.19, 95% CI 1.08 to 1.31) “adjusting for potential confounders” but does not state which confounders these were. As this was across the whole population studied, it is unclear if this is being driven by a stark contrast between people with and without diabetes or if there is a dose-response relationship within elevated blood glucose. As infection can also lead to higher blood glucose levels in PWD, it is also unclear if this could be a relationship impacted by reverse-causality (e.g. more severe infection causes higher blood glucose levels).
CONCLUSIONS
- There is no evidence on whether people with diabetes (PWD) are more likely to contract COVID-19.
- People with diabetes appear to be at increased risk of having a more severe COVID-19 infection, though evidence quantifying the increased risk is highly uncertain..
- The extent to which clinical and demographic factors moderate the relationship between diabetes and COVID-19 severity is entirely unclear due to a paucity of data.
Disclaimer: the article has not been peer-reviewed; it should not replace individual clinical judgement and the sources cited should be checked. The views expressed in this commentary represent the views of the authors and not necessarily those of the host institution, the NHS, the NIHR, or the Department of Health and Social Care. The views are not a substitute for professional medical advice.
What else can affect my risk for COVID-19 complications?
As we discussed, being immunocompromised can increase your risk for severe illness if you get COVID-19. This can happen with untreated or uncontrolled diabetes, but it can happen with many other conditions, too. For example:
- If you take chemotherapy or other cancer drugs
- If you smoke
- If you’ve had a bone marrow or organ transplant
- If you have an immune deficiency disorder
- If you have HIV or AIDS
- If you take long-term steroids or other medications that suppress the immune system
Other factors that can increase your risk for COVID-19 complications include:
- Being older than 65
- Living in a nursing home or similar facility
- Having a chronic (long-standing) lung disease or moderate to severe asthma
- Having a serious heart condition
- Having chronic kidney or liver disease
- Severe obesity (body mass index of 40 or higher)
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Jamie Hartmann-Boyce, Elizabeth Morris, Clare Goyder, Jade Kinton, James Perring, David Nunan, Kamlesh Khunti
