Hyperglycemia and Insulin Resistance Increases Infection-Related Mortality Risk

Individuals with diabetes, non-diabetic hyperglycemia, and insulin resistance have an increased risk for infection-related mortality, according to study results published in European Society of Endocrinology.

Researchers conducted a cohort study based on a subsample of the Kangbuk Samsung Health Study. A total of 682,030 individuals participated in a comprehensive health screening examination between 2005 and 2019. The examination collected demographic, lifestyle factors, medication use, and history data at baseline and follow-up visits. A 10-hour fast was required before each visit, and fasting blood glucose (FBG), hemoglobin A_1c levels, insulin levels, lipid profiles, and high-sensitivity C-reactive protein (hsCRP) levels were recorded.

Insulin resistance in non-diabetic patients was determined by the homeostatic model assessment for insulin resistance (HOMA-IR). Participants’ vital status and cause of mortality were collected via national death certificate data. The cause of death was classified by the International Classification of Diseases and Related Health Problems 10th Revision (ICD-10). Cox proportional hazards regression analyses were utilized to determine HRs for infectious disease-related deaths. 

Participants (N=666,888) were categorized into 4 main groups based on FBG and hemoglobin A_1c levels:

• FBG thresholds less than 5.0 mmol/L, 5.0 to 5.5 mmol/L, 5.6 to 6.9 mmol/L, and at least 7 mmol/L; and
• Hemoglobin A_1c level thresholds less than 36 mmol/mol, 36 to 38 mmol/mol, 39 to 46 mmol/mol, and at least 48 mmol/mol.

Individuals in the reference group had an FBG of 5.0 to 5.5 mmol/L and a hemoglobin A_1c level of 36 to 38 mmol/mol.

Each patient was followed from the initial visit until either the end of follow-up or the date of death, whichever occurred first. Patients were followed up for a median of 8.3 years (IQR, 4.6-12.7). 

In the final analysis, 313 infection-related deaths were reported. The most common causes of infectious-related mortalities were respiratory tract infections (n=161), hepatobiliary tract infections (n=38), and bacterial infections (n=35).

Low and high levels of FBG and hemoglobin A_1c were both associated with an increased risk for infection-related mortality when compared to the reference group; the association followed a J-shaped curve (P <.05).

Compared with the reference FBG level of 5.0 to 5.5 mmol/L, the hazard ratios (HRs) for patients who had FBG levels less than 5.0 mmol/L, 5.6 to 6.9 mmol/L, and at least 7.0 mmol/L were 2.31 (95% CI, 1.47-3.64), 1.65 (95% CI, 1.05-2.60), and 3.41 (95% CI, 1.66-7.00), respectively.

Compared with those in the hemoglobin A_1c reference group, the HRs for patients with hemoglobin A_1c levels of less than 36 mmol/mol, 39 to 46 mmol/mol, and at least 48 mmol/mol, were 1.50 (95% CI, 0.92-2.46), 1.25 (0.80-1.95), and 2.45 (95% CI, 1.24-4.83), respectively. 

Insulin resistance in non-diabetic individuals was quantified as a HOMA-IR score in the 75th percentile or higher. The risk for infection-related mortality was associated with a higher HOMA-IR score. The HR for infection-related deaths in individuals with a HOMA-IR score in the 75th percentile or higher vs those below the 75% percentile was 1.55 (95% CI, 1.04-2.32). 

Limitations of the study include the fact that glycemic status was not confirmed by an oral glucose tolerance test, which could have excluded potentially qualifying participants. 

The researchers conclude, “[O]ur findings support the notion that hyperglycaemia or insulin resistance itself, even in the absence of overt diabetes, may increase risk of infection-related mortality.”