Diabetes and risks from COVID-19

April 8, 2020

Jamie Hartmann-Boyce, Elizabeth Morris, Clare Goyder, Jade Kinton, James Perring, David Nunan, Kamlesh Khunti

On behalf of the Oxford COVID-19 Evidence Service Team

Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences

University of Oxford (JHB; DN)

Nuffield Department of Primary Care Health Sciences

University of Oxford (EM; CG)

Medical Sciences Division, University of Oxford (JP; JK)

University of Leicester, UK (KK)

Correspondence to jamie.hartmann-boyce@phc.ox.ac.uk

VERDICT

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 due to a paucity of data.

BACKGROUND

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.

CURRENT EVIDENCE



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).

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.

AUTHORS

Jamie Hartmann-Boyce is a departmental lecturer and Deputy Director of the Evidence-Based Health Care DPhil programme within the Centre for Evidence-Based Medicine in the Nuffield Department of Primary Care Health Sciences, University of Oxford. She has type 1 diabetes. @jhb19

Elizabeth Morris is a General Practitioner, and Wellcome Trust Doctoral Research Fellow at the Nuffield Department of Primary Care Health Sciences, University of Oxford. Her research focuses on interventions to support people with type 2 diabetes. @Lmo_Ox

Clare Goyder is a General Practitioner in Oxford and a Wellcome Trust Doctoral Fellow at the Nuffield Department of Primary Care Health Sciences, University of Oxford.

James Perring is a 5th year medical student at St. Catherine’s College, Oxford.

Jade Kinton is a 4th year medical student at Exeter College, Oxford.

David Nunan is a Senior Research Fellow at the Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences, University of Oxford. He is also an Editor at the BMJ Evidence-Based Medicine journal and Director of PG Certificate in Teaching Evidence-Based Health Care; @dnunan79

Kamlesh Khunti is Professor of Primary Care Diabetes & Vascular Medicine University of Leicester, UK and is a General Practitioner.

SEARCH TERMS

Searches for this review and the companion review of management of diabetes during the COVID-19 pandemic were run by Nia Roberts, subject librarian, between the 25 and 31st March, using the following terms.

(coronavirus*[Title] OR coronovirus*[Title] OR coronoravirus*[Title] OR coronaravirus*[Title] OR corono-virus*[Title] OR corona-virus*[Title] OR “Coronavirus”[Mesh] OR “Coronavirus Infections”[Mesh] OR “Wuhan coronavirus” [Supplementary Concept] OR “Severe Acute Respiratory Syndrome Coronavirus 2″[Supplementary Concept] OR COVID-19[All Fields] OR CORVID-19[All Fields] OR “2019nCoV”[All Fields] OR “2019-nCoV”[All Fields] OR WN-CoV[All Fields] OR nCoV[All Fields] OR “SARS-CoV-2”[All Fields] OR HCoV-19[All Fields] OR “novel coronavirus”[All Fields]) AND ((diabetes mellitus[MeSH Terms]) OR (diabet* OR “metabolic disease”)) Filters: Systematic Reviews Pubmed 5 (coronavirus*[Title] OR coronovirus*[Title] OR coronoravirus*[Title] OR coronaravirus*[Title] OR corono-virus*[Title] OR corona-virus*[Title] OR “Coronavirus”[Mesh] OR “Coronavirus Infections”[Mesh] OR “Wuhan coronavirus” [Supplementary Concept] OR “Severe Acute Respiratory Syndrome Coronavirus 2″[Supplementary Concept] OR COVID-19[All Fields] OR CORVID-19[All Fields] OR “2019nCoV”[All Fields] OR “2019-nCoV”[All Fields] OR WN-CoV[All Fields] OR nCoV[All Fields] OR “SARS-CoV-2”[All Fields] OR HCoV-19[All Fields] OR “novel coronavirus”[All Fields]) AND ((diabetes mellitus[MeSH Terms]) OR (diabet* OR “metabolic disease”)) Pubmed 36 (coronavirus OR COVID-19) AND diabetes TRIP 36 (coronavirus OR COVID-19) AND diabetes Google (coronavirus OR COVID-19) AND diabetes Google Scholar (coronavirus*[Title] OR coronovirus*[Title] OR coronoravirus*[Title] OR coronaravirus*[Title] OR corono-virus*[Title] OR corona-virus*[Title] OR “Coronavirus”[Mesh] OR “Coronavirus Infections”[Mesh] OR “Wuhan coronavirus” [Supplementary Concept] OR “Severe Acute Respiratory Syndrome Coronavirus 2″[Supplementary Concept] OR COVID-19[All Fields] OR CORVID-19[All Fields] OR “2019nCoV”[All Fields] OR “2019-nCoV”[All Fields] OR WN-CoV[All Fields] OR nCoV[All Fields] OR “SARS-CoV-2”[All Fields] OR HCoV-19[All Fields] OR “novel coronavirus”[All Fields]) AND (((((“Diabetes Mellitus, Type 1″[Mesh]) OR “Diabetes Complications”[Mesh]) OR (“Diabetes Mellitus”[Mesh] (AND “Comorbidity”[Mesh] OR”Hypertension”[Mesh]))) OR (“Insulin”[Mesh] OR “Hypoglycemic Agents”[Mesh])) OR ((“type 1 diabetes”[Title/Abstract] OR “type i diabetes”[Title/Abstract] OR insulin[Title/Abstract]) OR (diabet*[Title/Abstract] AND (complications[Title/Abstract] OR retinopathy[Title/Abstract] OR nephropathy)[Title/Abstract]))) PubMed 30 diabetes LitCOVID 29 Search: (influenza OR pneumonia OR SARS OR MERS OR severe respiratory infections OR acute respiratory infections OR “Respiratory Tract Infections”[Mesh]) AND (((((“Diabetes Mellitus, Type 1″[Mesh]) OR “Diabetes Complications”[Mesh]) OR (“Diabetes Mellitus”[Mesh] (AND “Comorbidity”[Mesh] OR”Hypertension”[Mesh]))) OR (“Insulin”[Mesh] OR “Hypoglycemic Agents”[Mesh])) OR ((“type 1 diabetes”[Title/Abstract] OR “type i diabetes”[Title/Abstract] OR insulin[Title/Abstract]) OR (diabet*[Title/Abstract] AND (complications[Title/Abstract] OR retinopathy[Title/Abstract] OR nephropathy)[Title/Abstract]))) Filters: Systematic Reviews, from 2005 – 2020 PubMed 30 (diabetes OR diabetic AND (systematicreviews[Filter])) AND (influenza OR pneumonia OR SARS OR MERS OR severe respiratory infections OR acute respiratory infections OR “Respiratory Tract Infections”[Mesh]) PubMed 56 (coronavirus OR COVID-19) AND (“type 1 diabetes” OR “type i diabetes” OR insulin OR “diabetic neuropathy” OR “diabetic retinopathy”) Google (coronavirus OR COVID-19) AND (“type 1 diabetes” OR “type i diabetes” OR insulin OR “diabetic neuropathy” OR “diabetic retinopathy”) Google Scholar (coronavirus OR COVID-19) AND diabetes AND (“social distancing” OR “social Isolation” OR shielding OR hadwashing OR handwashing OR “infection control” OR masks OR masking) Google (coronavirus OR COVID-19) AND diabetes AND (“social distancing” OR “social Isolation” OR shielding OR hadwashing OR handwashing OR “infection control” OR masks OR masking) Google Scholar ((influenza OR pneumonia OR SARS OR MERS OR severe respiratory infections OR acute respiratory infections OR “Respiratory Tract Infections”[Mesh])) AND (((“social distance”[Title/Abstract] OR “social distancing”[Title/Abstract] OR “social isolation”[Title/Abstract] OR handwashin[Title/Abstract] OR hand-washing[Title/Abstract] OR “hand hygiene”[Title/Abstract] OR masks[Title/Abstract] OR masking[Title/Abstract]) OR (infection control[Title])) OR ((((“Hand Disinfection”[Mesh]) OR “Infection Control”[Mesh:NoExp]) OR “Patient Isolation”[Mesh]) OR “Masks”[Mesh])) AND diabetes PubMed 22 Search: ((discontinu*[Title/Abstract] OR stop*[Title/Abstract]) AND (((“Metformin”[Mesh]) OR “Hypoglycemic Agents”[Mesh]) OR (metformin[Title/Abstract] OR gliflozin*[Title/Abstract] OR sglt2 inhibitor*[Title/Abstract] OR sglt-2 inhibitor*[Title/Abstract] OR sodium glucose transporter-2 inhibitor*[Title/Abstract] OR dipeptidyl peptidase inhibitor*[Title/Abstract] OR glucoside hydrolase inhibitor*[Title/Abstract] OR amylin receptor agonist*[Title/Abstract]))) AND (diabetes mellitus[MeSH Terms] OR diabet*[Title/Abstract]) Filters: Systematic Reviews PubMed 27 Search: ((discontinu*[Title] OR stop*[Title] OR persist*[Title] OR non-persist*[Title] OR complian*[Title] OR non-complian*[Title] OR adhere*[Title] OR non-adhere*[Title]) AND (((“Metformin”[Mesh]) OR “Hypoglycemic Agents”[Mesh]) OR (metformin[Title/Abstract] OR gliflozin*[Title/Abstract] OR sglt2 inhibitor*[Title/Abstract] OR sglt-2 inhibitor*[Title/Abstract] OR sodium glucose transporter-2 inhibitor*[Title/Abstract] OR dipeptidyl peptidase inhibitor*[Title/Abstract] OR glucoside hydrolase inhibitor*[Title/Abstract] OR amylin receptor agonist*[Title/Abstract]))) AND (diabetes mellitus[MeSH Terms] OR diabet*[Title/Abstract]) Filters: Systematic Reviews PubMed 22 ((((“Metformin”[Mesh]) OR “Hypoglycemic Agents”[Mesh]) OR (metformin[Title/Abstract] OR gliflozin*[Title/Abstract] OR sglt2 inhibitor*[Title/Abstract] OR sglt-2 inhibitor*[Title/Abstract] OR sodium glucose transporter-2 inhibitor*[Title/Abstract] OR dipeptidyl peptidase inhibitor*[Title/Abstract] OR glucoside hydrolase inhibitor*[Title/Abstract] OR amylin receptor agonist*[Title/Abstract])) AND ((sick day rule* OR sick day advice* OR sick day manag* OR (“sick day” AND medication*) OR sick day[ti] OR sick days[ti]) AND (english[Filter])) AND ((english[Filter]) AND (2010:2020[pdat]))) OR ((sick day rule* OR sick day advice* OR sick day manag* OR (“sick day” AND medication*) OR sick day[ti] OR sick days[ti]) AND (diabetes mellitus[MeSH Terms] OR diabet*[Title/Abstract]) AND ((english[Filter]) AND (2010:2020[pdat]))) PubMed 53 “sick day rules” OR “sick daye management” OR “sick day advice” Google intercurrent illness AND diabetes PubMed intercurrent illness AND diabetes Google

REFERENCES

All references are available as hyperlinks from the text.