Background: Recent studies have shown mixed results regarding the effectiveness of intensive glucose-lowering therapy in reducing risk for cardiovascular events.

Objective: To determine whether attaining hemoglobin A(1c) (HbA(1c)) _targets of 6.5% or less or 7.0% or less for glycemic control at baseline provides differential benefits for patients with high versus low-to-moderate levels of comorbidity.

Design: 5-year longitudinal observational study of patients with type 2 diabetes. Patients were categorized into high and low-to-moderate comorbidity subgroups by using the Total Illness Burden Index (TIBI), a validated patient-reported measure of comorbidity.

Setting: 101 diabetes outpatient clinics and 103 general practitioners' clinics in Italy.

Patients: 2613 (83%) of 3074 patients with type 2 diabetes, sampled randomly from diabetes outpatient clinic rosters and recruited consecutively from general practitioners' clinics, who completed the baseline questionnaire.

Measurements: TIBI score, total mortality, and incident cardiovascular events. Hazard ratios (HRs) were adjusted for age and sex.

Results: Attaining an HbA(1c) level of 6.5% or less at baseline was associated with lower 5-year incidence of cardiovascular events in the low-to-moderate comorbidity subgroup (adjusted HR, 0.60 [95% CI, 0.42 to 0.85]; P = 0.005) but not in the high comorbidity subgroup (adjusted HR, 0.92 [CI, 0.68 to 1.25]; P = 0.61; P for subgroup by HbA(1c) interaction = 0.048). Similarly, attaining a baseline HbA(1c) level of 7.0% predicted fewer cardiovascular events in the low-to-moderate comorbidity subgroup (adjusted HR, 0.61 (CI, 0.44 to 0.83; P = 0.001) but not in the high comorbidity subgroup (adjusted HR, 0.88 [CI, 0.66 to 1.17]; P = 0.38; P for subgroup by HbA(1c) interaction = 0.093).

Limitations: The observational nature of the study does not allow causal inference. The length of the data collection period was limited. Information on clinical management was not available.

Conclusion: Patients with the high levels of comorbidity common in type 2 diabetes may receive diminished cardiovascular benefit from intensive blood glucose control. Comorbidity should be considered when tailoring glucose-lowering therapy in patients with type 2 diabetes.

Primary funding source: Pfizer of Italy.