From the 2,704 patients in the dataset, 2,111 (78%) were men. The mean age at baseline was 61 years (SD 12). Missing data of depression and diabetes were multiply imputed for 236 patients (9%) and 15 patients (<1%), respectively. At baseline, 1,789 patients (66%) had no diabetes and no depression, 224 patients (8%) had diabetes but no depression, 585 patients (22%) had depression but no diabetes, and 106 patients (4%) had both diabetes and depression. presents the baseline characteristics across these four categories. Those with both diabetes and depression were on average less healthy and had a worse cardiovascular risk profile but were less often current smokers than patients without diabetes and depression. also shows the percentage of missing values that were imputed per baseline variable, which varied between 0 and 9%.
Baseline characteristics for the four diabetes and depression categories using the multiple imputed datasets (N = 2,704)
For 179 patients (7%), data on mortality could not be retrieved. These patients were therefore excluded from the Cox regression analyses. Additional analyses showed that these patients did not differ from those with mortality data regarding presence of depression, diabetes, and the other covariates, except for prior MI. There was a higher prevalence of prior MI in patients whose mortality data could not be retrieved (21 vs. 14%, P = 0.005). Of the remaining 2,525 patients with data on mortality, a total of 439 participants (17%) died during follow-up, of which 175 (7%) were classified as cardiac death. The all-cause mortality rate was 14% (226 of 1,673) for patients without depression and without diabetes, 23% (49 of 210) for patients with diabetes only, 22% (118 of 544) for patients with depression only, and 47% (46 of 98) for patients with both depression and diabetes. The mean follow-up time for the participants was 6.2 years (SD 2.0).
and show the Kaplan-Meier curves for all-cause and cardiac mortality for each strata of diabetes and depression. shows the number of deaths and the HRs for all-cause and cardiac mortality across the four categories of diabetes and depression. Patients who had both diabetes and depression had a considerably higher HR for mortality. For all-cause mortality, the HR was 4.58 (95% CI 3.29–6.37) for the patients with both diabetes and depression in the unadjusted analyses compared with the reference group (patients without diabetes and without depression). The strength of the relationship with mortality decreased to some extent after adjustment for the potential confounders (age, sex, smoking, hypertension, LVEF, previous MI, and Killip class) but remained significant. Furthermore, post hoc comparisons showed that the HR in those with both diabetes and depression was higher compared with patients with diabetes only (full model: 2.10 [1.38–3.21]) and depression only (full model: 2.08 [1.46–2.98]). The association between diabetes, depression, and mortality did not differ by sex; the interaction terms of the diabetes depression categories with sex were not statistically significant. The HR for cardiac mortality in the diabetes and depression group was 5.77 (3.53–9.43) in the unadjusted model and 3.27 (1.97–5.41) in the fully adjusted model. Post hoc comparisons showed that the HR in patients with both diabetes and depression was higher compared with patients with diabetes only (full model: 2.54 [1.32–4.89]) and depression only (full model: 2.10 [1.25–3.54]).
Kaplan-Meier curves for all-cause mortality for each diabetes and depression category (unadjusted analysis).
Kaplan-Meier curves for cardiac mortality for each diabetes and depression category (unadjusted analysis).
Number of deaths and HRs for all-cause and cardiac mortality for the four diabetes and depression categories
When we repeated the Cox regression analysis as an available-case analysis in the nonimputed dataset, approximately similar results were found (data not shown). For example, the HR for all-cause mortality in the fully adjusted model was 1.37 (95% CI 0.95–1.98) for those with diabetes only, 1.32 (1.02–1.71) for those with depression only, and 3.23 (2.25–4.64) for those with both diabetes and depression compared with those without diabetes and depression in the available-case analysis.
For all-cause mortality, the RERI was 1.94 (95% CI 0.37–3.51) in the unadjusted analyses and 1.13 (0.12–2.14) in the fully adjusted analyses. This exceeds the value 0 and, thus, suggests a positive interaction between diabetes and depression as departure from additivity. This means that the joint effect of diabetes and depression is significantly larger than the sum of the individual effects of diabetes and depression, even after controlling for confounders. For cardiac mortality, there was a trend for a positive additive interaction between diabetes and depression, but this was not statistically significant (unadjusted analysis: 2.90 [−0.02 to 5.82]; fully adjusted analysis: 1.42 [−0.21 to 3.06]).
We tested formal statistical (multiplicative) interaction between depression and diabetes for mortality. Although the direction of the multiplicative interaction was positive, this interaction was not significant for all-cause mortality (range P = 0.10–0.20 across the models) and cardiac mortality (range P = 0.21–0.30 across the models).