Cardiometabolic disease, comorbidities and risk of death: findings using data from large-scale electronic health records

Background Myocardial infarction (MI), stroke and diabetes are separately associated with increased risk of mortality but it is uncertain if their combined effects are proportional, amplified or less than the expected risk of each disease individually. In addition, patients with these conditions tend to also have other long-term comorbidities. How the relationship between cardiometabolic disease and risk of death is modified by the presence of comorbidity is unclear. Purpose We investigated the separate and combined effects of MI, stroke and diabetes on all-cause mortality, and examined the impact of comorbidity on these associations. Methods We selected a patient cohort of 2,007,731 (51% women) aged ≥16 years at registration with their general practice, using large-scale UK primary care electronic health records that were linked to the national death registry. We identified patients with a recorded diagnosis of MI, stroke, diabetes or none before 2005 (baseline), and classified the patient cohort into mutually exclusive categories of their baseline disease status. For each group, we also extracted information on another major 53 long-term conditions prior to baseline. The cohort was followed until death, deregistration from the practice or censored at the end of study (31 Dec 2014). We used Cox regression, and tested for departure from additivity and multiplicativity to assess interaction. Results At baseline, the mean age of the cohort was 51 (SD=18) years and 7% (N=145,910) had a cardiometabolic disease. Over an average follow-up of 7 (SD=3) years, 270,036 died (mean age of death=79 years). After adjusting for baseline age and sex, the hazard ratio (HR) (95% confidence interval [CI]), relative to those without cardiometabolic disease, were as follows: diabetes=1.53 (1.51 to 1.55), MI=1.54 (1.51 to 1.56), stroke=1.87 (1.84 to 1.90), diabetes and MI=2.16 (2.09 to 2.23), MI and stroke=2.39 (2.28 to 2.49), diabetes and stroke=2.56 (2.47 to 2.65), and all three=3.17 (2.95 to 3.41). After adjusting for the 53 comorbidities, the HR (95% CI) were attenuated: diabetes=1.37 (1.35 to 1.39), MI=1.25 (1.23 to 1.27), stroke=1.49 (1.46 to 1.52), diabetes and MI=1.60 (1.55 to 1.65), MI and stroke=1.52 (1.45 to 1.59), diabetes and stroke=1.91 (1.84 to 1.98), and all three=1.77 (1.64 to 1.91). The results did not materially changed with adjustment for smoking and deprivation level. Test for interaction revealed some minor synergistic effects when cardiometabolic disease co-occurred but excess risks were lower than expected for two combined vs individual disease effects; no significant interaction was seen for all three vs individual disease effects. Conclusion MI, stroke and diabetes are associated with excess mortality, which was partly due to associated chronic conditions. We found no evidence that the co-occurrence of these three conditions contribute to a higher excess mortality than expected from each of them separately. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): NIHR Oxford Biomedical Research Centre; Oxford Martin School, University of Oxford