A study reported in the journal Cell Metabolism on April 30 adds to the evidence that people with type 2 diabetes (T2D) are at greater risk of a poor outcome should they become infected with the virus that causes COVID-19.
But there is some encouraging news: people with T2D whose blood sugar is well controlled fare much better than those with more poorly controlled blood sugar.
“We were surprised to see such favourable outcomes in well-controlled blood glucose group among patients with COVID-19 and pre-existing type 2 diabetes,” says senior author Hongliang Li of Renmin Hospital of Wuhan University.
“Considering that people with diabetes had much higher risk for death and various complications, and there are no specific drugs for COVID-19, our findings indicate that controlling blood glucose well may act as an effective auxiliary approach to improve the prognosis of patients with COVID-19 and pre-existing diabetes.”
More than 500 million people around the world have T2D.
While it was clear that people with this condition fare worse with COVID-19, Li and colleagues wondered what role a person’s blood glucose control might have on those outcomes.
To find out, they conducted a retrospective longitudinal multi-centered study including 7,337 confirmed COVID-19 cases enrolled among 19 hospitals in Hubei Province, China.
Of those, 952 people had T2D and the other 6,385 did not. Among those with diabetes, 282 had well-controlled blood glucose; the other 528 did not.
The data showed that people admitted to the hospital with COVID-19 and T2D required more medical interventions.
Despite those interventions, they also had significantly higher mortality (7.8% vs. 2.7%) as well as a greater incidence of multiple organ injury.
However, those with well-controlled blood sugar and COVID-19 were less likely to die than those whose blood glucose was poorly controlled. Meanwhile, those with well-managed T2D also received less of other medical interventions including supplemental oxygen and/or ventilation, and had fewer health complications.
The researchers say the new findings offer three main messages for people with diabetes:
- People with diabetes have a higher risk to die from COVID-19 and develop more severe complications after infection. Therefore, they should take extra precautions to avoid becoming infected.
- People with diabetes should take extra care to keep their blood sugar under good control during the pandemic.
- Once infected, patients with diabetes should have their blood glucose level controlled to maintain it in the right range, in addition to any other needed treatments.
The researchers say they will continue to study the relationship between T2D and COVID-19 outcomes. The hope is to learn more about the underlying biology that is leading to poorer outcomes for people with T2D and high blood sugar.
Funding: This work was supported by grants from the National Key R&D Program of China, the National Science Foundation of China, the Major Research Plan of the National Natural Science Foundation of China, the Hubei Science and Technology Support Project, and Medical Flight Plan of Wuhan University.
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.
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.
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).
- 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.