Associations between cardiometabolic comorbidities and mortality in adults with cancer: multinational cohort study

DavilaBatistaV, etal . BMJMED 2025;4:e000909. doi:10.1136/bmjmed-2024-000909 1 OPEN ACCESSOPEN ACCESS ORIGINAL RESEARCHORIGINAL RESEARCH ►Additional supplemental material is published online only. To view, please visit the journal online (https:// doi. org/ 10. 1136/ bmjmed2024000909). For numbered affiliations see end of article. Correspondence to: Dr Heinz Freisling, International Agency for Research on Cancer, Lyon, France; FreislingH@ iarc. fr Cite this as: BMJMED 2025;4:e000909. doi:10.1136/ bmjmed-2024-000909 Received: 2 March 2024 Accepted: 24 February 2025 Associations between cardiometabolic comorbidities and mortality in adults with cancer: multinational cohortstudy Veronica DavilaBatista,1,2,3 Vivian Viallon,1 Emma Fontvieille,1 Anna Jansana,1 Mirjam Kohls,1,4 Nicola P Bondonno,5 Anne Tjønneland,5,6 Christina C Dahm,7 Christian S Antoniussen,7 Verena Katzke,8 Rashmita Bajrachaya,8 Matthias B Schulze ,9,10 Claudia Agnoli,11 Fulvio Ricceri,12 Salvatore Panico,13 Raul ZamoraRos,14 Miguel RodriguezBarranco,3,15,16 Pilar Amiano,3,17 MariaDolores Chirlaque,3,18 Conchi MorenoIribas,19 Keren Papier,20 Konstantinos K Tsilidis,21,22 Dagfinn Aune ,21,23,24 Marc J Gunter,1,21 Elisabete Weiderpass,1 Mazda Jenab,1 Pietro Ferrari,1 Heinz Freisling1 WHAT IS ALREADY KNOWN ON THIS TOPIC ⇒A history of comorbidity in adults with cancer has been consistently associated with reduced overall survival and, less consistently, with cancer specific survival ⇒Comorbid conditions are often grouped into comorbidity indexes or counts, which conceal how specific conditions might affect cancer survival differently or whether comorbid conditions interact in their association with cancer survival WHAT THIS STUDY ADDS ⇒The findings suggest that adults with cancer who had a history of type 2 diabetes or cardiovascular diseases, or both, had a survival disadvantage compared with those with no history of these comorbidities ⇒This survival disadvantage was also seen for less common cancers, such as brain, stomach, ovarian, and bladder cancers HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICY ⇒Clinicians treating people with cancer are encouraged to optimally manage cardiometabolic comorbidities ⇒Further research on effectively converting the study’s findings into practical benefits for patients with cancer with cardiometabolic comorbidities would be valuable ABSTRACT OBJECTIVE To examine separate and joint associations between preexisting cardiometabolic comorbidities and all cause and cause specific mortality in adults with cancer. DESIGN Multinational cohort study. SETTING Seven European countries from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, 1 January 1992 to 31 December 2013. PARTICIPANTS 26 987 participants (54% women) who developed a first primary cancer. 2113 had a history of type 2 diabetes, 1529 had a history of cardiovascular disease, and 531 had a history of both, at the time of diagnosis of cancer. MAIN OUTCOME MEASURES Hazard ratios (95% confidence intervals, CIs) for associations between preexisting cardiometabolic comorbidities and all cause and cause specific mortality in adults with cancer, estimated with multivariable Cox regression models. Associations were also estimated by groups of five year relative survival of cancer (survival ≤40%, 4080%, and ≥80%) according to Surveillance, Epidemiology, and End Results (SEER) statistics, and for the most common site specific cancers. RESULTS At the time of diagnosis of cancer, 84.5% (n=22 814) of participants had no history of a cardiometabolic disease, 7.8% (n=2113) had a history of type 2 diabetes, 5.7% (n=1529) had a history of cardiovascular disease, and 2.0% (n=531) had a history of both cardiovascular disease and type 2 diabetes. 12 782 deaths (10 492 cancer deaths) occurred over a mean followup period of 7.2 years. After multivariable adjustments, preexisting comorbidities were positively associated with all cause mortality, with hazard ratios 1.25 (95% CI 1.17 to 1.34), 1.30 (1.21 to 1.39), and 1.60 (1.42 to 1.80) for participants with type 2 diabetes, cardiovascular disease, or both, respectively, compared with participants with no cardiometabolic comorbidity. Corresponding hazard ratios for cancer specific mortality were 1.13 (95% CI 1.05 to 1.22), 1.13 (1.04 to 1.23), and 1.33 (1.16 to 1.53), respectively. Associations for all cause mortality were stronger among participants with cancers with a five year relative survival ≥80%. In a subsample, duration of type 2 diabetes (Pinteraction=0.73) or cardiovascular disease (Pinteraction=0.24), categorised as <5 years or ≥5 years, did not modify associations between these comorbidities and all cause mortality. CONCLUSIONS In this study, cardiovascular disease or type 2 diabetes, or a combination of both, before a diagnosis of cancer, was associated with increased mortality (all cause mortality, and cancer and cardiovascular disease specific mortality). These findings support a direct role of cardiometabolic comorbidities on the prognosis of cancer. Introduction The proportion of adults in the general population with multiple long term chronic conditions is rising rapidly,1 and >50% of adults with cancer have at least one other chronic condition.2–4 Coexistence of disorders in the presence of a primary disease, such as cancer, is defined as comorbidity.5 Comorbidity at the time of a diagnosis of cancer is often associated with a compromised health status and reduced quality of life,6 7 and has practical implications for BMJ Medicine: first published as 10.1136/bmjmed-2024-000909 on 21 March 2025. Downloaded from https://bmjmedicine.bmj.com on 1 June 2025 by guest. Protected by copyright, including for uses related to text and data mining, AI training, and similar technologies. DavilaBatistaV, etal . BMJMED 2025;4:e000909. doi:10.1136/bmjmed-2024-0009092 OPEN ACCESSOPEN ACCESS clinical care, such as complicating the choice of cancer treatment or increasing the risk of readmission to hospital.5 8 The most common comorbid conditions at the time of diagnosis of cancer are cardiovascular diseases and type 2 diabetes.4 In an umbrella review of metaanalyses, type 2 diabetes was associated with an increased risk of death from cancer,9 but heterogeneity between studies was high and the relation was unclear for most cancer types. A recommendation was that future studies should account for stage of cancer at diagnosis, investigate cause specific mortality, and consider type 2 diabetes (and cardiovascular disease) identified during followup in prospective designs to avoid misclassification of comorbidity status.9–11 Similarly, a history of cardiovascular diseases, such as myocardial infarction or stroke, could affect survival in individuals with cancer, especially among older patients with cancer where mortality related to cardiovascular disease can be higher than cancer mortality.12 Previous studies focused on patients with cancer in hospital settings with a primary diagnosis of cardiovascular disease, or cancer as a risk factor for death from cardiovascular disease.13–15 Other gaps in this area are links between a history of type 2 diabetes or cardiovascular disease and cancer survival that might depend on the type of cancer or the prognosis of cancer.5 Another question relates to the effect of type 2 diabetes or cardiovascular disease on cancer specific mortality and other specific causes of death. In the Women’s Health Initiative cohort,15 a history of type 2 diabetes was positively associated with both cardiovascular disease specific and cancer specific deaths.16 Furthermore, the time interval (duration) between the occurrence of a comorbidity and a diagnosis of cancer has rarely been investigated. This information could be important, as shown in a cohort study where new onset diabetes was associated with an increased risk of pancreatic cancer death, whereas diabetes of longer duration (≥2 years) was not.17 The objective of this study was to investigate separate and joint associations between a history of type 2 diabetes and cardiovascular disease at the time of diagnosis of cancer and all cause and cause specific mortality. We also aimed to examine effect modification of the associations with duration of cardiometabolic comorbidities, and investigated these relations by site specific cancers and by groups of cancers based on their five year relative survival. Methods Study population The European Prospective Investigation into Cancer and Nutrition (EPIC) study is a population based, multinational prospective cohort study, carried out in 23 centres across 10 European countries (Denmark, France, Germany, Greece, Italy, the Netherlands, Norway, Spain, Sweden, and the UK). More than 520 000 participants (70% women), mostly aged 3570 years, were recruited between 1992 and 2000 and have been followed up for cancer events, type 2 diabetes, cardiovascular disease, and mortality status.18–20 The study populations were samples of convenience and were recruited from the general population with a few exceptions. In France, Norway, Utrecht (the Netherlands), and Naples (Italy), only women were recruited. In France, state school employees were recruited. Centres in Utrecht and Florence (Italy) included women attending a local population based breast cancer screening programme. Some centres in Italy and Spain recruited members of local blood donor associations. In Oxford (UK), half of the cohort were participants following a lactoovo vegetarian or vegan diet.18 For our analysis, we excluded participants from France, Greece, and Norway, because incident events of type 2 diabetes or cardiovascular disease, or both, were not determined in these countries (n=140 284). We also excluded participants with a missing lifestyle questionnaire at baseline (n=6360), missing information on type 2 diabetes status (n=56 986), missing date of diagnosis of incident type 2 diabetes or cardiovascular disease, or both (n=101), missing end of followup date (n=1774), prevalent cancers at recruitment (n=13 042), and participants without a first primary cancer diagnosis (n=288 831). After all exclusions, 26 987 participants were available for analysis (online supplemental figure 1). Data for sex were taken from information in the EPIC study rather than from patient reported gender. Identifying first primary cancers The incident primary cancer was established based on ICD10 (international classification of diseases, 10th revision) and ICDO3 (international classification of diseases for oncology, third revision) codes, excluding nonmelanoma skin cancer and in situ tumour histology. Incident cancers were identified through linkage of the EPIC cohort with cancer registries in Denmark, Italy, the Netherlands, Spain, Sweden, and the UK, and a combination of health insurance records, cancer pathology registries, and active followup in Germany.18 Tumour stage at diagnosis was categorised as localised, advanced (regional or distant metastatic cancer combined because this distinction was unavailable for 30% of advanced cancers), or no staging (staging was missing for 100% of participants in the Netherlands and for 33% in all other countries). Identifying type 2 diabetes and cardiovascular disease Diagnoses of type 2 diabetes (ICD10, E11) were identified from multiple sources across different centres, including selfreport, linkage to primary care registers, secondary care registers, drug treatment use BMJ Medicine: first published as 10.1136/bmjmed-2024-000909 on 21 March 2025. Downloaded from https://bmjmedicine.bmj.com on 1 June 2025 by guest. Protected by copyright, including for uses related to text and data mining, AI training, and similar technologies. DavilaBatistaV, etal . BMJMED 2025;4:e000909. doi:10.1136/bmjmed-2024-000909 3 OPEN ACCESSOPEN ACCESS (drug registers), hospital admission, and mortality data.19 Incident cardiovascular disease events (nonfatal or fatal coronary heart disease or stroke) were defined by codes 410414 and 430438 of ICD9 (international classification of diseases, ninth revision) and codes I20I25 and I60I69 of ICD10, and were identified by active followup through questionnaires, medical records, hospital morbidity registers, contact with medical professionals, retrieving and assessing death certificates, or verbal autopsy, as detailed previously.20 Type 2 diabetes and cardiovascular disease were independently determined by trained medical staff. Prevalent type 2 diabetes and cardiovascular disease events were identified with selfreported questionnaires at recruitment.21 No information on the duration of disease was available for these patients with prevalent disease. Mortality outcomes and follow‐up Death was the primary endpoint in this study. Information on the cause and date of death was established from record linkages with cancer registries, boards of health, and death indices in Denmark, Italy, the Netherlands, Spain, Sweden, and the UK, or from active followup (enquiries by mail or telephone to municipal registries or regional health departments or to physicians or hospitals) in Germany. The end of followup of participants was from December 2009 to December 2013 for countries with record linkage and to the last known contact with participants in Germany (December 2009). Loss to followup was low (1.5%).21 ICD10 codes were used to classify the underlying cause of death grouped into common causes: cancer (C00D48), circulatory system or cardiovascular death (I00I99), and other cause of death (nonC00D48 or I00I99). Covariates Data on sociodemographic characteristics, lifestyle behaviours, and reproductive and medical history were collected at recruitment with questionnaires.21 Information on habitual diet was collected by validated country or centre specific dietary questionnaires at recruitment21 and used to estimate total energy intake (kcal/day), alcohol intake (g/day), and the components of the Mediterranean diet score (range 018 units).22 Height and weight were measured at recruitment with a standardised protocol; in the Oxford centre, height and weight were self‐reported. Body mass index was calculated and categorised as <25, 25-<30, and ≥30. Selfreported menopausal status was categorised as premenopausal, perimenopausal, or postmenopausal. If data were incomplete, women aged ≥55 years at recruitment were classified as postmenopausal. History of hypertension at recruitment (no, yes, or unknown) was determined based on a combination of medical history, measurements by trained health professionals at recruitment (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg, or both), or selfreported information of receiving antihypertensive treatment.23 Statistical analysis Cardiometabolic disease status was modelled with a four level categorical variable as no cardiometabolic comorbidity (reference), type 2 diabetes, cardiovascular disease, and type 2 diabetes with cardiovascular disease. KaplanMeier curves for overall survival according to preexisting cardiometabolic comorbidities were estimated. The survival time scale was from the date of a diagnosis of cancer until the date of death or censoring. KaplanMeier curves were also grouped by age at cancer diagnosis, stage at cancer diagnosis, smoking status at baseline, and five year relative survival of the diagnosed cancer (survival <40%, 4080%, and ≥80%) according to the Surveillance, Epidemiology, and End Results (SEER) statistics (online supplemental table 1).24 Because the sample size for specific analyses of cancer type was limited for many cancers, we grouped cancers by five year relative survival to account for survival differences. Cox proportional hazard regression was used to estimate hazard ratios and 95% confidence intervals (CIs) for overall mortality and cause specific mortality associated with preexisting cardiometabolic comorbidities. Because we were interested in answering an aetiological question, we implemented cause specific hazard models rather than a subdistribution hazard model, which is more appropriate for clinical prediction.25 Followup time was from the date of diagnosis of the first incident cancer until death or censoring date. The multivariable models were grouped by age at recruitment (five year categories), country, smoking status (never, former, current smoking, and unknown), stage at cancer diagnosis, and categories of five year relative survival of the diagnosed cancer according to SEER, and adjusted for sex (men, women), educational level (none, primary school, technical or professional school, secondary school, university, or unknown), alcohol intake (continuous, g/day), total energy intake (continuous, kcal/day), Mediterranean diet score (continuous, units), physical activity (inactive, moderately inactive, moderately active, active, or unknown),26 body mass index (continuous), hypertension (yes, no, or unknown), menopausal status (premenopause, perimenopause, postmenopause, or men), and hormone treatment (no, yes, unknown, or men). We assumed linearity in associations between continuous covariates and outcomes. Missing values in any of the categorical covariates were treated as a separate category. Confounder adjustment was based on previous knowledge, as depicted in a directed acyclic graph (online supplemental figure 2). For analyses on cause specific mortality, participants who died from a cause other than the one BMJ Medicine: first published as 10.1136/bmjmed-2024-000909 on 21 March 2025. Downloaded from https://bmjmedicine.bmj.com on 1 June 2025 by guest. Protected by copyright, including for uses related to text and data mining, AI training, and similar technologies. DavilaBatistaV, etal . BMJMED 2025;4:e000909. doi:10.1136/bmjmed-2024-0009094 OPEN ACCESSOPEN ACCESS under study were censored at the date they died. The proportional hazards assumption was tested with Schoenfeld residuals and was met. To test for multiplicative interaction between type 2 diabetes and cardiovascular disease associated with mortality outcomes, we modelled both type 2 diabetes and cardiovascular disease as binary indicators (no/yes) with a multiplicative term (type 2 diabetes×cardiovascular disease) and mutual adjustment. Effect modification by duration of type 2 diabetes or cardiovascular disease on associations with all cause mortality was investigated by comparing a model with, in turn, type 2 diabetes (no/yes) and cardiovascular disease (no/yes), with a model where the time difference between the date of diagnosis of incident type 2 diabetes or cardiovascular disease and the cancer diagnosis was categorised as no type 2 diabetes or cardiovascular disease, <5 years, and ≥5 years. Participants with prevalent cardiovascular disease or type 2 diabetes (at recruitment) were excluded from this analysis because information on duration of disease was not available. Predefined subgroup analyses were carried out by sex, age at cancer diagnosis, educational level, smoking status, categories of body mass index, five year relative survival of cancer, and stage of cancer at diagnosis. All multiplicative interaction models were evaluated with a likelihood ratio test comparing the log difference of the models with and without multiplicative interaction terms between comorbidity status and the potential effect modifier to a χ2 distribution with df equal to the number of terms. In sensitivity analyses: we only included incident type 2 diabetes or cardiovascular disease events to evaluate bias caused by misclassification of selfreported type 2 diabetes or cardiovascular disease at recruitment and caused by covariates being affected by cardiovascular disease or type 2 diabetes; we excluded participants with missing covariate information (complete case analysis) to evaluate the validity of using a missing value indicator (cancer stage at diagnosis was not missing at random, which is why we did not consider multiple imputation); we computed E values, which are defined as the minimum strength of association on the risk ratio scale that an unmeasured confounder would need to have with both the variable and the outcome to fully explain the observed associations27; we adjusted for type of cancer at diagnosis instead of five year relative survival of cancer to evaluate residual confounding by type of cancer; and we adjusted for waist circumference (four categories of sex specific values), which reflects central adiposity, instead of body mass index. All tests were two sided, and P values were considered significant if <0.05. Statistical analyses were performed with Stata/MP 15.1 software (College Station, TX). Patient and public involvement This study used pseudoanonymised data, and hence we had no means of contacting the study participants. Participants of this study were therefore not involved in this research. We intend to engage the public to disseminate the results of our study through the cohort's website (https://epic.iarc.fr/) and the media center of the International Agency for Research on Cancer (https://www.iarc.who.int/). Results Characteristics of study population We included in our study 26 987 participants (54% women) with a first primary incident cancer. Mean age at recruitment and the proportion of men were higher in this cancer subsample than in the overall EPIC cohort: 56.9 years verus 51.4 years and 46% versus 40%, respectively. The distribution for educational level was more similar (eg, 18% v 21% had a university degree). The prevalence of cancer in the EPIC cancer subsample (online supplemental table 1) was similar to cancer occurrence in Europe, and cancers of the breast, colon and rectum, lung, and prostate showed the highest age standardised incidence in 2012.28 At the time of diagnosis of cancer, mean age of participants was 63.5 (standard diviation 8.4) years. We found that 84.5% (n=22 814) of participants had no history of a cardiometabolic disease, 7.8% (n=2113) had a history of type 2 diabetes, but no cardiovascular disease, 5.7% (n=1529) had a history of cardiovascular disease, but no type 2 diabetes, and 2.0% (n=531) had a history of both cardiovascular disease and type 2 diabetes. Table1 shows the characteristics of participants at cancer diagnosis according to preexisting cardiometabolic comorbidities. Cardiometabolic comorbidities and all cause mortality We estimated all cause mortality and found that 12 782 deaths occurred after a median followup of 7.2 years (interdecile range 0.414.5). In unadjusted analyses (figure1), survival was highest among those with no preexisting cardiometabolic comorbidities; survival was gradually reduced for those with type 2 diabetes, cardiovascular disease, and both type 2 diabetes and cardiovascular disease (P<0.001, log rank test for overall comparison between the four groups). This trend was replicated in all analyses by subgroups of stage of cancer at diagnosis, five year relative survival of the cancer, age, and smoking status (online supplemental figure 3). In multivariable adjusted Cox models (figure 2), preexisting comorbidities were positively associated with all cause mortality, with hazard ratios 1.25 (95% CI 1.17 to 1.34), 1.30 (1.21 to 1.39), and 1.60 (1.42 to 1.80) in individuals with type 2 diabetes, cardiovascular disease, and both type 2 diabetes BMJ Medicine: first published as 10.1136/bmjmed-2024-000909 on 21 March 2025. Downloaded from https://bmjmedicine.bmj.com on 1 June 2025 by guest. Protected by copyright, including for uses related to text and data mining, AI training, and similar technologies. DavilaBatistaV, etal . BMJMED 2025;4:e000909. doi:10.1136/bmjmed-2024-000909 5 OPEN ACCESSOPEN ACCESS Table 1 | Characteristics of study participants by cardiometabolic comorbidity at the time of diagnosis of cancer Characteristics No comorbidity (n=22 814) Type 2 diabetes (n=2113) Cardiovascular disease (n=1529) Type 2 diabetes and cardiovascular disease (n=531) Sex: Men 9672 (42.4) 1228 (58.1) 1020 (66.7) 397 (74.8) Women 13 142 (57.6) 885 (41.9) 509 (33.3) 134 (25.2) Mean±SD age at recruitment (years) 56.4±7.9 58.3±6.5 61.0±6.6 60.5±6.4 Age at recruitment (years): <50 4160 (18.2) 199 (9.4) 72 (4.7) 25 (4.7) 5065 16 104 (70.6) 1677 (79.4) 1091 (71.4) 402 (75.7) ≥65 2550 (11.2) 237 (11.2) 366 (23.9) 104 (19.6) Mean±SD age at cancer diagnosis (years) 62.7±8.3 67.0±6.9 68.1±6.9 71.0±7.1 Cause of exit from study: Endpoint of study 12 374 (54.2) 987 (46.7) 528 (34.5) 200 (37.7) Died 10 334 (45.3) 1123 (53.2) 995 (65.1) 330 (62.2) Withdrew from study 21 (0.1) 1 (0.1) 1 (0.1) 1 (0.2) Emigrated 85 (0.4) 2 (0.1) 5 (0.3) 0 (0.0) Mean±SD followup survival (years) 7.6±5.3 5.2±4.4 5.5±4.7 3.5±3.4 Educational level: None 977 (4.3) 191 (9.0) 50 (3.3) 26 (4.9) Primary school completed 8037 (35.2) 879 (41.6) 640 (41.9) 251 (47.3) Technical or professional school 6186 (27.1) 540 (25.6) 388 (25.4) 114 (21.5) Secondary school 2878 (12.6) 175 (8.3) 156 (10.2) 44 (8.3) University degree 4185 (18.3) 288 (13.6) 234 (15.3) 78 (14.7) Not specified 551 (2.4) 40 (1.9) 61 (4.0) 18 (3.4) Lifestyle at recruitment Smoking status: Never 9061 (39.7) 739 (35.0) 392 (25.6) 124 (23.4) Former 6888 (30.2) 704 (33.3) 576 (37.7) 222 (41.8) Smoker 6673 (29.3) 654 (31.0) 551 (36.0) 180 (33.9) Unknown 192 (0.8) 16 (0.8) 10 (0.7) 5 (0.9) Mean±SD alcohol intake (g/day) 14.8±20.7 17.0±23.9 16.7±22.3 18.4±26.2 Mean±SD total energy intake (kcal/day) 2032.3±641.8 2040.2±681.0 2062.2±714.6 2017.3±654.6 Mean±SD Mediterranean diet score 2.6±1.0 2.6±1.1 2.4±1.0 2.4±1.0 Physical activity: Inactive 5143 (22.5) 629 (29.8) 458 (30.0) 186 (35.0) Moderately inactive 7648 (33.5) 698 (33.0) 475 (31.1) 171 (32.2) Moderately active 5040 (22.1) 396 (18.7) 290 (19.0) 78 (14.7) Active 4647 (20.4) 375 (17.8) 278 (18.2) 88 (16.6) Unknown 336 (1.5) 15 (0.7) 28 (1.8) 8 (1.5) Body mass index: <25 9976 (43.7) 371 (17.6) 502 (32.8) 76 (14.3) 2530 9432 (41.3) 938 (44.4) 737 (48.2) 261 (49.2) ≥30 3406 (14.9) 804 (38.1) 290 (19.0) 194 (36.5) Clinical characteristics Hypertension: No 11 579 (50.8) 913 (43.2) 471 (30.8) 159 (29.9) Yes 4717 (20.7) 834 (39.5) 589 (38.5) 250 (47.1) Unknown 6518 (28.6) 366 (17.3) 469 (30.7) 122 (23.0) Status menopause: Premenopause 2417 (10.6) 78 (3.7) 36 (2.4) 0 (0.0) Postmenopause 8677 (38.0) 702 (33.2) 417 (27.3) 122 (23.0) Perimenopause or not known 2048 (9.0) 105 (5.0) 56 (3.7) 12 (2.3) Hormone replacement therapy: Never used 9891 (43.4) 724 (34.3) 414 (27.1) 109 (20.5) Yes 2601 (11.4) 132 (6.3) 72 (4.7) 19 (3.6) Unknown 650 (2.9) 29 (1.4) 23 (1.5) 6 (1.1) Clinical cancer Stage of cancer: Continued BMJ Medicine: first published as 10.1136/bmjmed-2024-000909 on 21 March 2025. Downloaded from https://bmjmedicine.bmj.com on 1 June 2025 by guest. Protected by copyright, including for uses related to text and data mining, AI training, and similar technologies. DavilaBatistaV, etal . BMJMED 2025;4:e000909. doi:10.1136/bmjmed-2024-0009096 OPEN ACCESSOPEN ACCESS and cardiovascular disease, respectively, compared with those with no preexisting comorbidities. Adjustment for waist circumference, instead of body mass index, gave similar risk estimates: hazard ratios 1.23 (95% CI 1.15 to 1.32), 1.30 (1.21 to 1.39), and 1.58 (1.40 to 1.78), respectively. The hazard ratio for type 2 diabetes with cardiovascular disease was, as expected, on the multiplicative scale (Pinteraction=0.83). Hazard ratios in unadjusted Cox models had larger effect sizes than the multivariable adjusted Cox models (online supplemental table 2). In contrast, in models that adjusted for type of cancer instead of groups of cancer according to their five year relative survival, we found similar estimates (online supplemental table 2). Results of the multivariable adjusted models were robust across subgroups, as defined by sex, age at cancer diagnosis, educational level, smoking status, categories of body mass index, and cancer stage at diagnosis (online supplemental table 3). Results were also robust to a sensitivity analysis where only incident comorbidities, identified during followup, were considered (after excluding 1998 participants with prevalent type 2 diabetes or cardiovascular disease at recruitment; online supplemental table 4). Similarly, risk estimates were not different when excluding participants with missing information for any covariate (online supplemental table 5). Duration of type 2 diabetes (Pinteraction=0.73) or cardiovascular disease (Pinteraction=0.24), categorised as <5 years or ≥5 years, did not modify associations between these comorbidities and all cause mortality (table2). A secondary analysis with alternative categorisations (<3 years and ≥3 years, and <1 year, 15 years, and >5 years) showed similar results (online supplemental table 6). Cardiometabolic comorbidities and cause specific mortality For cause specific mortality, we identified 10 492 deaths from cancer, 891 deaths from cardiocirculatory events, and 1399 other causes of death. For cancer specific mortality (figure 2), preexisting comorbidities were positively associated with cancer deaths, with hazard ratios 1.13 (95% CI 1.05 to 1.22), 1.13 (1.04 to 1.23), and 1.33 (1.16 to 1.53) for participants with type 2 diabetes, cardiovascular disease, and both type 2 diabetes and cardiovascular disease, respectively. We found an increase in cardiovascular disease specific mortality of about threefold in cancer survivors with preexisting cardiovascular disease (or cardiovascular disease and type 2 diabetes) compared with cancer survivors with no preexisting cardiometabolic comorbidity (figure2). For other causes of death (eg, digestive diseases), we saw strong positive associations in cancer survivors with preexisting type 2 diabetes and in those with type 2 diabetes and cardiovascular disease, compared with cancer survivors with no comorbidity (figure2). Characteristics No comorbidity (n=22 814) Type 2 diabetes (n=2113) Cardiovascular disease (n=1529) Type 2 diabetes and cardiovascular disease (n=531) Localised 6740 (29.5) 522 (24.7) 368 (24.1) 104 (19.6) Metastatic 7297 (2.0) 650 (30.8) 439 (28.7) 138 (26.0) Unknown 8777 (38.5) 941 (44.5) 722 (47.2) 289 (54.4) 5 year relative survival of cancer (%): <40 4899 (21.5) 588 (27.8) 452 (29.6) 147 (27.7) 4080 6597 (28.9) 639 (30.2) 450 (29.4) 179 (33.7) ≥80 11 318 (49.6) 886 (41.9) 627 (41.0) 205 (38.6) Data are number (%) unless indicated otherwise. Covariates, except stage of cancer at diagnosis, were assessed at recruitment into the cohort, and median time difference between the date of recruitment and cancer diagnosis was 6.7 years (interquartile range 3.89.3). SD, standard deviation. Table 1 Continued Time aer cancer (years) No at risk 0 5 10 15 20 25 22 814 2113 1529 531 No comorbidity Type 2 diabetes Cardiovascular disease Type 2 diabetes + cardiovascular disease 14 858 996 753 147 7846 326 285 38 2071 61 59 3 66 3 1 0 0 0 0 0 Probability of survival 0 0.4 0.6 1.0 0.8 0.2 No comorbidity Type 2 diabetes Cardiovascular disease Type 2 diabetes + cardiovascular disease Figure 1 | KaplanMeier curves for overall survival after a diagnosis of cancer by preexisting cardiometabolic comorbidities, in participants with no preexisting cardiometabolic comorbidities, and in those with type 2 diabetes, cardiovascular disease, and both type 2 diabetes and cardiovascular disease BMJ Medicine: first published as 10.1136/bmjmed-2024-000909 on 21 March 2025. Downloaded from https://bmjmedicine.bmj.com on 1 June 2025 by guest. Protected by copyright, including for uses related to text and data mining, AI training, and similar technologies. DavilaBatistaV, etal . BMJMED 2025;4:e000909. doi:10.1136/bmjmed-2024-000909 7 OPEN ACCESSOPEN ACCESS All cause mortality by cancer groups Among all diagnosed cancers, 6086 (23%) had a five year relative survival of <40%, 7865 (29%) a five year relative survival of 4080%, and 13 036 (48%) a five year relative survival of ≥80%. We saw marginally stronger associations between cardiometabolic comorbidities and all cause mortality for cancers with a five year relative survival of ≥80% (figure3). In contrast, for cause specific deaths, we saw some definite associations (table3). For example, compared with participants without preexisting comorbidity, a history of type 2 diabetes was associated with death from cancer only in the group of cancers with the worst prognosis (five year relative survival <40%). All cause mortality by cancer site Online supplemental table 7 shows the associations between cardiometabolic comorbidities and all cause All cause deaths No comorbidity Type 2 diabetes Cardiovascular disease Type 2 diabetes + cardiovascular disease Cancer deaths No comorbidity Type 2 diabetes Cardiovascular disease Type 2 diabetes + cardiovascular disease Cardiovascular disease deaths No comorbidity Type 2 diabetes Cardiovascular disease Type 2 diabetes + cardiovascular disease Deaths from other causes No comorbidity Type 2 diabetes Cardiovascular disease Type 2 diabetes + cardiovascular disease Reference 1.25 (1.17 to 1.34) 1.30 (1.21 to 1.39) 1.60 (1.42 to 1.80) Reference 1.13 (1.05 to 1.22) 1.13 (1.04 to 1.23) 1.33 (1.16 to 1.53) Reference 1.76 (1.38 to 2.25) 2.72 (2.24 to 3.29) 3.53 (2.52 to 4.95) Reference 2.22 (1.84 to 2.68) 1.57 (1.28 to 1.92) 3.01 (2.18 to 4.95) 12354 Cancer comorbidities Hazard ratio (95% CI) Hazard ratio (95% CI) 10 334 1123 995 330 8701 869 690 232 578 93 171 49 1055 161 134 49 No of deaths 22 814 2113 1529 531 22 814 2113 1529 531 22 814 2113 1529 531 22 814 2113 1529 531 No of participants Figure 2 | Hazard ratios (95% confidence intervals, CIs) for associations between preexisting cardiometabolic comorbidities and all cause and cause specific mortality in adults with cancer. Participants were grouped by age at recruitment, country, smoking status, stage of cancer, and five year relative survival of cancer, and adjusted for sex, educational level, alcohol intake, total energy intake, Mediterranean diet score, physical activity, body mass index, and hypertension, and menopausal status and hormone treatment (in women) Table 2 | Hazard ratios and 95% confidence intervals (CIs) for associations between preexisting cardiometabolic comorbidities and all cause mortality in adults with cancer, by duration of type 2 diabetes or cardiovascular disease No of patients* Hazard ratio (95% CI) Type 2 diabetes:† No 23 608 Reference Yes 1381 1.22 (1.13 to 1.33) Duration of type 2 diabetes:† None 23 608 Reference <5 years 863 1.21 (1.10 to 1.34) ≥5 years 518 1.25 (1.09 to 1.42) Cardiovascular diseases:‡ No 23 996 Reference Yes 993 1.30 (1.19 to 1.42) Duration of cardiovascular disease:‡ None 23 996 Reference <5 years 682 1.26 (1.14 to 1.40) ≥5 years 311 1.41 (1.21 to 1.65) Participants were grouped by age at recruitment, country, smoking status, stage of cancer, and five year relative survival of cancer, and adjusted for sex, educational level, alcohol intake, total energy intake, Mediterranean diet score, physical activity, body mass index, and hypertension, and menopausal status and hormone treatment (in women). *In this analysis, 1998 participants with prevalent type 2 diabetes or cardiovascular disease at recruitment were excluded. †P=0.73 from log likelihood ratio test for a comparison of the case event binary model versus the category time duration model. ‡P=0.24 from log likelihood ratio test for a comparison of the case event binary model versus the category time duration model. BMJ Medicine: first published as 10.1136/bmjmed-2024-000909 on 21 March 2025. Downloaded from https://bmjmedicine.bmj.com on 1 June 2025 by guest. Protected by copyright, including for uses related to text and data mining, AI training, and similar technologies. DavilaBatistaV, etal . BMJMED 2025;4:e000909. doi:10.1136/bmjmed-2024-0009098 OPEN ACCESSOPEN ACCESS mortality for the 11 most common site specific cancers. Compared with cancer survivors with no cardiometabolic comorbidity, cancer survivors with preexisting type 2 diabetes, cardiovascular disease, or both type 2 diabetes and cardiovascular disease generally had excess mortality. Exceptions were seen in individuals who received a diagnosis of stomach cancer (largely null association) or endometrial cancer, where an inverse association was observed among women with preexisting type 2 diabetes compared with women with no comorbidity (hazard ratio 0.42, 95% CI 0.20 to 0.91). For some site specific cancers, the observed multiplicative interaction of type 2 diabetes and cardiovascular disease with all cause mortality was greater than expected, such as for ovarian cancer (hazard ratio 3.68, 95% CI 0.95 to 14.21). Discussion Principal findings In this multinational prospective cohort study in almost 27 000 men and women with a first primary cancer diagnosis, 15.5% had a history of cardiometabolic comorbidity (cardiovascular disease or type 2 diabetes, or both) before cancer. These preexisting cardiometabolic comorbidities were associated with early death from all causes, from cancer, from Survival <40% No comorbidity Type 2 diabetes Cardiovascular disease Type 2 diabetes + cardiovascular disease Survival 40-80% No comorbidity Type 2 diabetes Cardiovascular disease Type 2 diabetes + cardiovascular disease Survival >80% No comorbidity Type 2 diabetes Cardiovascular disease Type 2 diabetes + cardiovascular disease Reference 1.28 (1.16 to 1.42) 1.21 (1.08 to 1.35) 1.46 (1.21 to 1.76) Reference 1.16 (1.03 to 1.31) 1.22 (1.07 to 1.39) 1.51 (1.23 to 1.85) Reference 1.35 (1.18 to 1.54) 1.54 (1.35 to 1.75) 2.02 (1.61 to 2.54) 1 1.5 2.0 3.02.5 Cancer comorbidities by 5 year net survival Hazard ratio (95% CI) Hazard ratio (95% CI) 4051 507 413 135 3360 349 283 105 2923 267 299 90 No of deaths 4899 588 452 147 6597 639 450 179 11 318 886 627 205 No of participants Figure 3 | Hazard ratios (95% confidence intervals, CIs) for associations between preexisting cardiometabolic comorbidities and all cause mortality in adults with cancer, by five year relative survival of the diagnosed cancer. Participants were grouped by age at recruitment, country, smoking status, and stage of cancer, and adjusted for sex, educational level, alcohol intake, total energy intake, Mediterranean diet score, physical activity, body mass index, and hypertension, and menopausal status and hormone treatment (in women). Five year relative survival according to the Surveillance, Epidemiology, and End Results (SEER) project (online supplemental table 1)24 Table 3 | Hazard ratios and 95% confidence intervals (CIs) for associations between preexisting cardiometabolic comorbidities and cause specific mortality in adults with cancer, by five year relative survival of the diagnosed cancer Cause of death 5 year relative survival (hazard ratio (95% CI)) Survival <40% Survival 4080% Survival ≥80% Cancer deaths: No cardiometabolic comorbidity Reference Reference Reference Type 2 diabetes 1.26 (1.14 to 1.41) 1.03 (0.90 to 1.18) 1.02 (0.86 to 1.21) Cardiovascular disease 1.12 (1.00 to 1.26) 1.06 (0.91 to 1.23) 1.26 (1.06 to 1.50) Type 2 diabetes and cardiovascular disease 1.38 (1.13 to 1.68) 1.27 (0.99 to 1.62) 1.35 (0.97 to 1.87) Cardiovascular disease deaths: No cardiometabolic comorbidity Reference Reference Reference Type 2 diabetes 0.80 (0.39 to 1.64) 2.62 (1.77 to 3.89) 1.66 (1.16 to 2.36) Cardiovascular disease 4.07 (2.56 to 6.47) 2.71 (1.90 to 3.87) 2.40 (1.83 to 3.14) Type 2 diabetes and cardiovascular disease 3.01 (1.29 to 6.99) 4.36 (2.50 to 7.62) 3.44 (2.09 to 5.65) Other causes: No cardiometabolic comorbidity Reference Reference Reference Type 2 diabetes 2.03 (1.33 to 3.11) 1.65 (1.16 to 2.35) 2.75 (2.11 to 3.56) Cardiovascular disease 1.33 (0.82 to 2.17) 1.38 (0.95 to 2.00) 1.73 (1.31 to 2.29) Type 2 diabetes and cardiovascular disease 2.41 (1.16 to 4.98) 2.19 (1.19 to 4.03) 4.02 (2.57 to 6.30) Participants were grouped by age at recruitment, country, smoking status, and stage of cancer, and adjusted for sex, educational level, alcohol intake, total energy intake, Mediterranean diet score, physical activity, body mass index, and hypertension, and menopausal status and hormone treatment (in women). Five year relative survival of cancer according to the Surveillance, Epidemiology, and End Results (SEER) programme 19752017 of the National Cancer Institute, US Mortality Files.24 BMJ Medicine: first published as 10.1136/bmjmed-2024-000909 on 21 March 2025. Downloaded from https://bmjmedicine.bmj.com on 1 June 2025 by guest. Protected by copyright, including for uses related to text and data mining, AI training, and similar technologies. DavilaBatistaV, etal . BMJMED 2025;4:e000909. doi:10.1136/bmjmed-2024-000909 9 OPEN ACCESSOPEN ACCESS cardiovascular disease, and from other causes. As expected, the hazard of dying from cardiovascular disease and from other causes (including digestive diseases) was substantially increased among cancer survivors with a history of cardiovascular disease and type 2 diabetes, respectively, compared with those with no such history. Cancer specific deaths, however, were also increased in cancer survivors with these cardiometabolic comorbidities compared with those with no comorbidities. The observed joint association between cardiovascular disease and type 2 diabetes and all cause and cause specific mortality was, as expected, on a multiplicative scale. For adults with some cancers, however, an interaction between cardiovascular disease and type 2 diabetes was suggested in their association with mortality (eg, ovarian cancer), which warrants investigation in future studies. We also found that the duration of cardiometabolic comorbidities before cancer did not seem to have a major effect on overall survival among adults with cancer. Comparison with other studies Comorbidity in adults with cancer has been consistently associated with reduced overall survival and, less consistently, with cancer specific survival.5 Previous studies often grouped comorbid conditions into comorbidity indexes or counts,6 which conceal how specific conditions might affect cancer survival differently.29–31 Given the heterogeneity in defining cancer comorbidities, we focused on cardiometabolic diseases, which are among the most common comorbidities in adults with cancer,32 but also originate from shared risk factors (eg, obesity). Associations between comorbidities (in general) and survival tend to be larger for cancers with a better prognosis and for early stage cancer compared with advanced cancer, because patients with diagnoses of cancers with a high mortality rate are more likely to die from cancer, regardless of their comorbidity.5 An exception in our analysis was the finding that a history of type 2 diabetes was associated with an increased cancer specific mortality only in adults who had a diagnosis of a cancer with a poor prognosis (ie, five year relative survival ≤40%). Type 2 diabetes is perhaps associated with faster growing or more aggressive cancers, such as pancreatic cancer. This hypothesis was supported in our cancer site specific analysis, where a history of type 2 diabetes was associated with all cause mortality in adults with pancreatic cancer compared with those who did not have type 2 diabetes (online supplemental table 7). Preexisting diabetes in adults with cancer increased all cause mortality compared with adults who did not have diabetes.11 Respective evidence for site specific cancers suggested increased all cause mortality for cancers of the endometrium, breast, and colorectum, but evidence for other types of cancer is less consistent.9 11 33 34 Our findings are consistent with these site specific cancers and add to the evidence suggesting positive associations between a history of type 2 diabetes and all cause mortality in adults with cancers of the pancreas and prostate (online supplemental table 7). We also found that cancer specific and cardiovascular disease specific mortality was higher in cancer survivors with type 2 diabetes than in those who did not have type 2 diabetes. Effect sizes were much larger for cardiovascular disease specific mortality than for cancer specific mortality. These findings are similar to a study from the Women’s Health Initiative,16 which based their findings on a selfreported history of type 2 diabetes at baseline and was restricted to postmenopausal women. Compared with diabetes, fewer studies reported that preexisting cardiovascular diseases in adults with cancer were associated with higher all cause mortality,13 35–37 cancer specific mortality,35 38 and cardiovascular disease specific mortality35 compared with adults with cancer and no preexisting cardiovascular disease. Our findings are in agreement with other studies and add to the data for less frequently studied cancers, such as brain, stomach, ovarian, and bladder cancers (online supplemental table 7). In this study, we also investigated the joint association between type 2 diabetes and cardiovascular disease and mortality in adults with cancer. Research in individuals with cancer compared with individuals with a combination of cancer and other chronic diseases is needed to improve our understanding of disease interactions. This knowledge is essential for personalised medicine to guide clinical practice and to improve the prognosis in this growing group of patients affected by multiple long term conditions.7 39 40 Although we found little evidence for multiplicative interaction for all cause or cause specific mortality in adults with all cancers combined, we cannot exclude the possibility that type 2 diabetes and cardiovascular disease might interact in their associations with mortality for specific cancers (eg, ovarian cancer). Another gap in our knowledge that we could investigate is the role of duration of preexisting cardiometabolic comorbidities on mortality, which could be important for risk stratification.6 We found no evidence for effect modification by duration of type 2 diabetes (Pinteraction=0.73) with similar all cause mortality estimates for durations of <3 or ≥3 years, or ≥5 years. Duration of cardiovascular disease of ≥5 years was associated with slightly higher all cause mortality than duration of <5 years (Pinteraction=0.24). Information on the management of cardiovascular disease and type 2 diabetes could also provide insights beyond the duration of comorbidity because, for example, metformin treatment has been reported to decrease all cause mortality in adults with endometrial cancer and diabetes.41 BMJ Medicine: first published as 10.1136/bmjmed-2024-000909 on 21 March 2025. Downloaded from https://bmjmedicine.bmj.com on 1 June 2025 by guest. 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