Of the 33 347 patients included in the study, 352 (1.1%) had preexisting CHD at study entry and 952 (2.9%) had preexisting DM. When split into the 4 groups defined on the basis of the presence or absence of each of these diagnoses at study entry, 296 (0.9%) patients had CHD but no DM, 896 (2.7%) had DM but no CHD, and 56 (0.2%) had both diagnoses at study entry. The characteristics of patients at entry into D:A:D, stratified by their CHD and DM status, are shown in .
Characteristics of Patients at Entry in D:A:D According to CHD and DM Status at Study Entry
Patients with either DM or CHD at entry in D:A:D were more likely to be male and were older than their counterparts without these events at study entry. Patients with DM or CHD also had higher levels of total cholesterol and triglycerides and lower HDL cholesterol levels than those without these events, and those with CHD in particular had received more medical interventions with lipid-lowering, antiplatelet and antihypertensive drugs. Greater proportions of patients with DM or CHD had lipodystrophy. Patients with preexisting CHD were more likely to have a family history of cardiovascular disease than those without preexisting CHD. Although exposure to antiretroviral therapy was generally greater in those with preexisting CHD or DM, the differences in duration of exposure were relatively small.
Incidence of CHD
Overall, 698 patients experienced an episode of CHD over 159 971 person-years of follow-up (rate 4.4 per 1000 person-years, 95% CI 4.0 to 4.7). The distribution of events, stratified by the 4 baseline groups, is shown in .
Distribution of First Recurrent CHD Episode Occurring During Follow-Up, Stratified by Each Patient’s CHD and DM Status at Entry in D:A:D
Among patients with preexisting CHD, the rates of a recurrent CHD episode were 101.9 (95% CI 58.3 to 145.5) and 76.4 (95% CI 60.8 to 92.0) per 1000 person-years, respectively, in those with and without DM at study entry. Conversely, in patients without preexisting CHD, the rates of a new CHD episode were 16.4 (95% CI 12.5 to 20.3) and 3.4 (95% CI 3.1 to 3.6) per 1000 person-years, respectively, in those with and without DM at study entry. Compared with patients with no preexisting CHD or DM (the reference group), patients with preexisting CHD were at substantially higher risk of experiencing a recurrent episode of CHD regardless of whether they did (adjusted relative risk [RR] 11.66, 95% CI 7.42 to 18.32, P=0.0001) or did not (adjusted RR 9.04, 95% CI 7.10 to 11.49, P=0.0001) have DM at study entry (). In contrast, the increased risk of an event in those who had preexisting DM but no CHD at study entry, although statistically significant, was smaller (adjusted RR 3.03, 95% CI 2.34 to 3.93, P=0.001). In a regression model that included the main effects of each covariate (and adjustment for other confounders), the adjusted relative risk of a recurrent CHD episode associated with preexisting CHD was 7.52 (95% CI 6.02 to 9.39, P=0.0001) whereas that associated with preexisting DM was 2.41 (95% CI 1.91 to 3.05, P=0.0001). In these models, there was no evidence that the association between DM and the risk of CHD differed according to sex (P value for interaction with female sex 0.85), although the association between DM and CHD appeared to be stronger in older people than in younger people (RR in older people 2.48, 95% CI 1.93 to 3.18; RR in younger people 1.88, 95% CI 0.97 to 3.66; P for interaction=0.004). In contrast, although there was no evidence that the association between preexisting CHD and the risk of a subsequent CHD event differed according to sex (P for interaction=0.42), the association between preexisting CHD and a recurrent CHD event was weaker in older than in younger people (RR in older people 6.06, 95% CI 4.72 to 7.78; RR in younger people 26.07, 95% CI 16.70 to 40.69; P for interaction=0.0001). Both interactions with older age remained unchanged after adjustment for the use of interventions (lipid-lowering, antiplatelet, and antihypertensive medication).
Adjusted RR of CHD episode in patients according to history of CHD or DM. Adjustment for gender, age, cohort, HIV transmission mode, ethnicity, family history of CHD, smoking, and calendar year.
To more formally investigate whether the effect of each diagnosis on a subsequent event differed according to the presence or absence of the other diagnosis, we included a statistical interaction term between the 2 diagnoses. The statistical interaction between the 2 was significant (interaction RR 0.43, 95% CI 0.25 to 0.75, P=0.003), which suggests that the rate of CHD in those with CHD and DM at study entry was lower than would be expected on the basis of the main effects alone. Further analyses then explored the effect of incorporating the use of medical interventions (lipid-lowering therapy, antihypertensive, and antiplatelet medication) and, in a separate model, the impact of adjustment for the latest triglyceride and HDL cholesterol levels; neither adjustment altered our main conclusions (data not shown).
When we considered associations with fatal cardiovascular disease (242 events), we again found a greater impact of preexisting CHD compared with that of DM, although differences were smaller than in the main analysis (). Compared with patients without preexisting DM or CHD, those with preexisting CHD were at 4.61 times (95% CI 2.82 to 7.53, P=0.0001) the risk of a new event if they did not have preexisting DM and at 11.12 (95% CI 5.75 to 21.50, P=0.0001) times the risk if they did. Patients without preexisting CHD but with DM were at 2.82 (95% CI 1.84 to 4.32, P=0.0001) times the risk of a new event compared with those with neither diagnosis at baseline.
Adjusted RR* of New CHD Event in Patients According to History of CHD or DM
Additional sensitivity analyses in which coronary revascularizations were excluded as a component of the composite end point () again reached similar conclusions: Patients with preexisting CHD were at a much higher risk of a recurrent episode of CHD regardless of whether they did (10.62, 95% CI 6.04 to 18.67, P=0.0001) or did not (4.73, 95% CI 3.32 to 6.75, P=0.0001) have DM at study entry. In contrast, those with preexisting DM but not CHD at study entry were at 2.95 (95% CI 2.23 to 3.91, P=0.0001) times the risk of those with neither diagnosis at study entry.
Impact on Development of CHD of New Diagnoses of DM
When all diagnoses of DM (including those that occurred during follow-up) were incorporated, the CHD rate was 3.8 (95% CI 3.5 to 4.1) per 1000 person-years among patients who were not diagnosed with DM. The CHD rate was higher among patients diagnosed with DM, and this rate appeared to increase with longer duration of DM; specifically, the rate was 8.2 (95% CI 4.5 to 13.8) per 1000 person-years among patients followed up within the first 2 years after DM diagnosis, 11.6 (95% CI 6.2 to 19.9) per 1000 person-years among those followed up for >2 years after DM (but in whom the diagnosis was made after entry in D:A:D), and 20.5 (95% CI 16.2 to 24.8) per 1000 person-years among patients with DM before entry in D:A:D. In multivariable analysis, the adjusted RR of a CHD event associated with recent (ie, in the last 2 years) DM diagnosis was 1.35 (95% CI 0.79 to 2.31, P=0.27) compared with patients who did not have DM. The adjusted RR of a CHD event among patients diagnosed with DM for >2 years was 2.30 (95% CI 1.32 to 4.02, P=0.003). Finally, the adjusted RR of a CHD event among patients with a diagnosis of DM before D:A:D enrollment was 2.49 (95% CI 1.97 to 3.15, P=0.0001).