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Glycemic Control, Sepsis Risk, and Mortality in Type 2 Diabetes
TAKE-HOME MESSAGE
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In this 10-year follow-up study, the relationship between glycosylated hemoglobin (HbA1c) in patients with type 2 diabetes and the risk of sepsis was assessed. Individuals with type 2 diabetes were identified from a national database and followed until their first episode of sepsis (defined as the presence of an ICD-10 code for sepsis in the electronic medical record). No difference in time to sepsis was determined in patients with diabetes compared with control patients, but a "U-shaped" association between the level of HbA1c and risk for sepsis development as observed. This "U-shaped" association persisted even when data were adjusted for age, gender, smoking, diabetes treatment, BMI, and other coexisting conditions. Furthermore, individuals with type 2 diabetes who developed sepsis had a higher mortality compared with non-diabetic controls, while the value of HbA1c was not associated with mortality outcomes.
- Extremes in HbA1c values were associated with a higher hazard ratio for sepsis even when adjusted for relevant comorbid conditions.
abstract
This abstract is available on the publisher's site.
Access this abstract nowOBJECTIVE
To investigate the nature of the relationship between HbA1c and sepsis among individuals with type 2 diabetes, and to assess the association between sepsis and all-cause mortality in such patients.
RESEARCH DESIGN AND METHODS
We included 502,871 individuals with type 2 diabetes recorded in the Swedish National Diabetes Register and used multivariable Cox regression and restricted cubic spline analyses to assess the association between time-updated HbA1c values and sepsis occurrence between 1 January 2005 and 31 December 2015. The association between sepsis and death was examined using multivariable Cox regression analysis.
RESULTS
Overall, 14,534 (2.9%) patients developed sepsis during the study period. On multivariable Cox regression analysis, compared with an HbA1c of 48-52 mmol/mol (6.5-6.9%), the adjusted hazard ratio for sepsis was 1.15 (95% CI 1.07-1.24) for HbA1c <43 mmol/mol (6.1%), 0.93 (0.87-0.99) for HbA1c 53-62 mmol/mol (7.0-7.8%), 1.05 (0.97-1.13) for HbA1c 63-72 mmol/mol (7.9-8.7%), 1.14 (1.04-1.25) for HbA1c 73-82 mmol/mol (8.8-9.7%), and 1.52 (1.37-1.68) for HbA1c >82 mmol/mol (9.7%). In the cubic spline model, a reduction of the adjusted risk was observed within the lower HbA1c range until 53 mmol/mol (7.0%), with a hazard ratio of 0.78 (0.73-0.82) per SD; it increased thereafter (P for nonlinearity <0.001). As compared with patients without sepsis, the adjusted hazard ratio for death among patients with sepsis was 4.16 (4.03-4.30).
CONCLUSIONS
In a nationwide cohort of individuals with type 2 diabetes, we found a U-shaped association between HbA1c and sepsis and a fourfold increased risk of death among those developing sepsis.
Additional Info
Disclosure statements are available on the authors' profiles:
Glycemic Control and Risk of Sepsis and Subsequent Mortality in Type 2 Diabetes
Diabetes Care 2021 Oct 29;[EPub Ahead of Print], A Balintescu, M Lind, MA Franko, A Oldner, M Cronhjort, AM Svensson, B Eliasson, J MårtenssonFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Nearly 50 million cases of sepsis and 11 million sepsis-related deaths were recorded worldwide in 2017. Although the association of diabetes with infection and sepsis is well-established, studies investigating risk factors for sepsis among people living with type 2 diabetes (T2D) have been limited by lack of adjustment for potential confounders. In this nationwide cohort of 502,871 individuals with T2D, there was a U-shaped association between HbA1c and sepsis with the nadir at an HbA1c of 7%. This association was adjusted for numerous potential confounders and was robust to sensitivity analyses that excluded or censored individuals with immunosuppression as well as with other methods of assessing HbA1c.
These findings are consistent with those of other studies showing a U- or J-shaped relationship between HbA1c and other outcomes such as mortality and cardiovascular disease. This well-done study provides further support for the concept that some patients may benefit from HbA1c targets with not only an upper bound but also a lower bound. This study provides some intuitive clues about the potential characteristics of such patients based on the risk factors for sepsis (ie, older age, longer diabetes duration, and greater burden of comorbidities). Randomized controlled trials are needed to test this hypothesis in the context of newer therapies like SGLT2 inhibitors and GLP1-receptor agonists that do not cause hypoglycemia.