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Background  Myocardial infarction (MI), stroke and diabetes share underlying risk factors and commonalities in clinical management. We examined if their combined impact on mortality is proportional, amplified or less than the expected risk separately of each disease and whether the excess risk is explained by their associated comorbidities.    Methods  Using large-scale electronic health records, we identified 2,007,731 eligible patients (51% women) and registered with general practices in the UK and extracted clinical information including diagnosis of myocardial infarction (MI), stroke, diabetes and 53 other long-term conditions before 2005 (study baseline). We used Cox regression to determine the risk of all-cause mortality with age as the underlying time variable and tested for excess risk due to interaction between cardiometabolic conditions.    Results  At baseline, the mean age was 51 years, and 7% ( N  = 145,910) have had a cardiometabolic condition. After a 7-year mean follow-up, 146,994 died. The sex-adjusted hazard ratios ( HR ) (95% confidence interval [ CI ]) of all-cause mortality by baseline disease status, compared to those without cardiometabolic disease, were MI = 1.51 (1.49–1.52), diabetes = 1.52 (1.51–1.53), stroke = 1.84 (1.82–1.86), MI and diabetes = 2.14 (2.11–2.17), MI and stroke = 2.35 (2.30–2.39), diabetes and stroke = 2.53 (2.50–2.57) and all three = 3.22 (3.15–3.30). Adjusting for other concurrent comorbidities attenuated these estimates, including the risk associated with having all three conditions ( HR  = 1.81 [ 95% CI  1.74–1.89]). Excess risks due to interaction between cardiometabolic conditions, particularly when all three conditions were present, were not significantly greater than expected from the individual disease effects.    Conclusion  Myocardial infarction, stroke and diabetes were associated with excess mortality, without evidence of any amplification of risk in people with all three diseases. The presence of other comorbidities substantially contributed to the excess mortality risks associated with cardiometabolic disease multimorbidity.    Supplementary Information  The online version contains supplementary material available at 10.1186/s12916-021-02126-x.

Association between cardiometabolic disease multimorbidity and all-cause mortality in 2 million women and men registered in UK general practices