Impact of Glycemic Control on Risk of Infections in Patients With Type 2 Diabetes

A Population-Based Cohort Study

Anil Mor; Olaf M. Dekkers; Jens S. Nielsen; Henning Beck-Nielsen; Henrik T. Sørensen; Reimar W. Thomsen

Disclosures

Am J Epidemiol. 2017;186(2):227-236. 

In This Article

Results

Among the 69,318 patients with type 2 diabetes, more than half (55%) were male. The median age was 63.3 years (interquartile range, 53.5–72.6 years), the median duration of recorded diabetes before the first HbA1c measurement was 2.1 months (interquartile range, 0.6–5.8 months), and 73% were taking glucose-lowering drugs at the time of their first HbA1c measurement (Web Table 1). The mean HbA1c value at baseline was 7.50% (standard deviation, 1.9), 35% of patients had an HbA1c value of 7.50% or more, and a small proportion (4%) had an HbA1c value less than 5.50%. Compared with patients with a reference HbA1c value of 5.50%–6.49%, patients with higher HbA1c values at baseline were more likely to be male, were younger, had less comorbidity and less statin use, and were more likely to use glucose-lowering drugs at onset (except those with HbA1c values greater than or equal to 10.50%) (Web Table 1).

A total of 48,442 patients (70%) received systemic antiinfective agents in the community during a follow-up period comprising 123,113 patient-years at risk, yielding an overall incidence rate of 393.5 (95% confidence interval (CI): 390.0, 397.0) per 1,000 patient-years (Table 1). A total of 16,227 patients (23%) experienced hospital-treated infection over a follow-up period comprising 259,524 patient-years at risk, yielding an incidence rate of 62.5 (95% CI: 61.6, 63.5) per 1,000 patient-years (Table 2).

Early Baseline HbA1c Concentration

The incidence rates of community-treated infections and hospital-treated infections appeared to decrease with increasing baseline HbA1c values (Table 1 and Table 2). After adjustment for variables associated with a high baseline HbA1c concentration (including younger age and less comorbidity), we observed no increase in the rates of community-treated infections and hospital-treated infections per 1% increase in baseline HbA1c (adjusted hazard ratios were 0.99 (95% CI: 0.99, 1.00) and 1.01 (95% CI: 1.00, 1.02), respectively). Compared with the reference HbA1c value of 5.50%–6.49%, a baseline HbA1c value less than 5.50% was associated with increased rates of community-treated infection (adjusted hazard ratio (HR) = 1.06, 95% CI: 1.01, 1.12) and hospital-treated infection (adjusted HR = 1.29, 95% CI: 1.19, 1.40), while adjusted hazard ratios were close to unity in categories of increasing baseline HbA1c values (Figure 1 and Figure 2).

Figure 1.

Adjusted hazard ratios for community-treated infection among persons with type 2 diabetes, by baseline (dotted-dashed line), updated mean (solid line), updated time-weighted mean (dashed line), and latest updated (dotted line) hemoglobin A1c (HbA1c) concentration, northern Denmark, 2000–2012. Hazard ratios were adjusted for age, sex, comorbidity (Charlson Comorbidity Index (CCI) score), micro- and macrovascular diabetes complications not covered in the CCI, duration of diabetes, alcoholism-related conditions, marital status, concurrent use of statins/corticosteroids/immunosuppressive drugs, calendar period of diabetes diagnosis, and type of glucose-lowering drug regimen as of the index date. Bars, 95% confidence intervals.

Figure 2.

Adjusted hazard ratios for hospital-treated infection among persons with type 2 diabetes, by baseline (dotted-dashed line), updated mean (solid line), updated time-weighted mean (dashed line), and latest updated (dotted line) hemoglobin A1c (HbA1c) concentration, northern Denmark, 2000–2012. Hazard ratios were adjusted for age, sex, comorbidity (Charlson Comorbidity Index (CCI) score), micro- and macrovascular diabetes complications not covered in the CCI, duration of diabetes, alcoholism-related conditions, marital status, concurrent use of statins/corticosteroids/immunosuppressive drugs, calendar period of diabetes diagnosis, and type of glucose-lowering drug regimen as of the index date. Bars, 95% confidence intervals.

Updated Mean and Updated Time-weighted Mean HbA1c Concentration

For measures of updated mean HbA1c concentration, there was a clearer association between increasing HbA1c values and incidence rates of community-treated and hospital-treated infection (Table 1 and Table 2). For every 1% increase in updated mean HbA1c values, the adjusted hazard ratio for community-treated infection was 1.01 (95% CI: 1.01, 1.02), and for hospital-treated infection it was 1.06 (95% CI: 1.04, 1.07). Compared with an updated mean HbA1c level of 5.50%–6.49%, rates of community-treated infection were increased both for updated mean HbA1c values less than 5.50% and for increasing values greater than or equal to 6.50% (Table 1, Figure 1). For hospital-treated infection, the association was stronger, and an updated mean HbA1c concentration greater than or equal to 10.50% was associated with an adjusted hazard ratio of 1.55 (95% CI: 1.42, 1.71). For updated time-weighted mean HbA1c values, rates of community-treated infection increased by 2% (adjusted HR = 1.02, 95% CI: 1.01, 1.03) with each 1% increase, and rates of hospital-treated infection increased by 6% (adjusted HR = 1.06, 95% CI: 1.05, 1.07). Infection rates for updated time-weighted mean HbA1c followed a similar gradient as for updated mean HbA1c, with the highest rate being observed in patients with HbA1c values greater than or equal to 10.50% for both community-treated and hospital-treated infections (Table 1 and Figure 1).

Latest Updated HbA1c Concentration

The incidence rates of community-treated and hospital-treated infections were lowest at latest updated HbA1c values of 5.50%–7.49% and increased monotonically with increasing HbA1c levels (Table 1 and Table 2). For every 1% increase in the latest updated HbA1c value, the rate of community-treated infection increased by 3% (adjusted HR = 1.03, 95% CI: 1.02, 1.04) and the rate of hospital-treated infection increased by 6% (adjusted HR = 1.06, 95% CI: 1.05, 1.07). An association with risk of infection was observed, particularly for latest updated HbA1c values of 8.50% or higher, reaching adjusted hazard ratios of 1.19 (95% CI: 1.14, 1.26) for community-treated infection and 1.64 (95% CI: 1.51, 1.79) for hospital-treated infection in patients with HbA1c levels greater than or equal to 10.50% as compared with 5.50%–6.49% (Figure 1 and Figure 2).

Association of Latest Updated HbA1c Value With Specific Community-treated and Hospital-treated Infections

Web Table 2 shows adjusted hazard ratios for specific community- and hospital-treated infection groups associated with every 1% increase in latest updated HbA1c and by different categories of latest updated HbA1c. For community-treated infections, the strongest associations with each 1% increase in the latest updated HbA1c value were observed for the broad-spectrum antibiotics cephalosporins (adjusted HR = 1.38); for dicloxacillin/flucloxacillin, which is normally used to treat Staphylococcus aureus infections (adjusted HR = 1.07); for quinolones (adjusted HR = 1.13); and for antifungal therapy (adjusted HR = 1.13). Adjusted hazard ratios per 1% increase in latest updated HbA1c values were particularly increased for abscesses (HR = 1.17), skin infections (HR = 1.14), and infections of the central nervous system (HR = 1.10) but also for fungal infections (HR = 1.11), viral infections (HR = 1.07), septicemia (HR = 1.08), upper respiratory tract infections (HR = 1.07), urinary tract infections (HR = 1.04), and eye and ear infections (HR = 1.09) (Web Table 2).

Subgroup and Sensitivity Analyses

The relationship between increased risk of infections and higher HbA1c levels was found consistently in all subgroups (shown for latest updated HbA1c levels in Table 3). The impact of a high HbA1c level seemed to be strongest in patients with microvascular complications. Otherwise, the hazards of infection associated with poor glucose control were similar in patients with and without comorbidity, in all age groups, and in patients using and not using glucose-lowering drugs at baseline (Table 3).

When we examined primary and secondary hospital diagnoses of infection as separate outcomes, the associations with HbA1c followed a similar pattern as the overall hospital infection estimates (Web Table 3, Table 4 and Table 5).

Seven percent of patients (5,153/69,318) had used oral corticosteroids within 6 months of their diabetes diagnosis. After exclusion of these patients, analyses on the remaining cohort generated risk estimates identical to the original estimates (e.g., per 1% increase in latest updated HbA1c value, the adjusted hazard ratio was 1.03 (95% CI: 1.02, 1.04) for community-treated infection and 1.06 (95% CI: 1.04, 1.07) for hospital-treated infection).

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