Effect of type-2 diabetes mellitus in long-term mortality in older adults: The NEDICES cohort study.

EFFECT OF TYPE-2 DIABETES MELLITUS IN LONG-TERM MORTALITY IN OLDER ADULTS: The NEDICES Cohort Study - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Search Log in Primary site navigation Search Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Diabetes Res Clin Pract . Author manuscript; available in PMC: 2026 Jun 4. Published in final edited form as: Diabetes Res Clin Pract. 2025 Jun 4;226:112291. doi: 10.1016/j.diabres.2025.112291 EFFECT OF TYPE-2 DIABETES MELLITUS IN LONG-TERM MORTALITY IN OLDER ADULTS: The NEDICES Cohort Study A Corbatón-Anchuelo 1, 2 , S Vega-Quiroga 3 , F Bermejo-Pareja 4, 5 , M Fuentes-Ferrer 6 , M Álvarez-González 3 , J Benito-León 4, 7, 8 , F Hawkins-Carranza 5, 8 , M Serrano-Ríos 9, † Author information Article notes Copyright and License information 1 Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM). 2 Cardiovascular Risk Group. Research Institute of Clínico San Carlos University Hospital (IdISSC), Madrid. Spain. 3 Primary Care of Castilla & León Autonomous Community, Sacyl, Spain. 4 Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain. 5 Research Institute University Hospital 12 de Octubre (I+12), Madrid. Spain. 6 Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife. Spain. 7 Neurology Department, University Hospital 12 de Octubre, Madrid. Spain. 8 Department of Medicine, Complutense University, Madrid, Spain. 9 Spanish Academy of Medicine. † Deceased April 2021 Authorship contribution statement FBP and MSR are responsible for conceiving and designing the study. SVQ, FBP and JBL participated actively in the development of the field study. ACA, SVQ, JBL and MAG extracted and curated the data. ACA, SVQ and MFF are responsible for the integrity of the analyses and interpretation of the data. ACA, SVQ and FHC are responsible for the preparation of the draft of the manuscript. FHC and FBP participated in the critical revision and gave final approval of the manuscript to be published. (*) Corresponding author: Dr. Arturo Corbatón Anchuelo, CIBERDEM- Cardiovascular Risk Group. University Hospital Clínico San Carlos, C / Martín Lagos s/n 28040 – Madrid, Fax: +34 91 3303108, arturocorbaton@yahoo.es Issue date 2025 Aug. PMC Copyright notice PMCID: PMC12335756  NIHMSID: NIHMS2091724  PMID: 40480377 The publisher's version of this article is available at Diabetes Res Clin Pract Abstract Aims: To describe the mortality associated with type-2 diabetes mellitus (T2DM) in a Spanish elderly population during a 22-year period. Procedures: Prospective follow-up study (1994–95 to 2017) including 4,998 individuals (≥ 65 years old at baseline) of three communities (one rural) from central Spain. T2DM diagnosis was recorded during a clinical interview in 1994–95 (self-reported and information from their doctors, including treatment). Mortality incidence until 2017 was checked. Results: A total of 4,038 subjects were included, with a mean age of 73.6 (±6.6) years; 1,718 (42.5%) were male and 685 (17.0%) were diagnosed with T2DM. The mortality rate during follow-up was 85.2%. Cardiovascular disease was the most frequent cause of death in DM2 subjects, followed by neoplasm. The mortality hazard ratio found for T2DM compared to non-T2DM subjects was 1.29 (1.16–1.45) after adjusting for multiple risk factors. The effect of TDM2 on the mortality rate remained significant in men (HR:1.27; CI 95%:1.08–1.49;p=0.005) and women (HR:1.32; CI 95%:1.14–1.53;p<0.001), with no differences between sexes (p=0.705). Main conclusion: The sustained reduction in T2DM elderly Spanish subjects’ life expectancy address the necessity of community interventions and campaigns regarding lifestyle modifications and reinforce the need for and adequate and regular TDM2 subjects clinical follow-up. Keywords: T2DM (type 2 diabetes mellitus), elderly, long-term mortality Introduction Diabetes mellitus (DM) is a major well-established cause of morbidity and mortality worldwide and it is included amongst the major preventable chronic conditions in the United States and around the world [ 1 ]. It is also one of the leading causes of death among elderly people [ 1 ], and it increases two to threefold the probability of functional disability and the medical spending compared to healthy individuals [ 2 ]. The highest expenditure per person with diabetes (20–79 years) in 2021 was in the high-income countries (1.16% of the Gross Domestic Product), followed by middle (1.08%), and low-income countries (0.51%) [ 3 ]. According to the International Diabetes Federation (IDF) [ 3 ], Spain was the 9th country with a higher expenditure in 2021 due to DM in subjects aged 20 to 79 years old. With increasing ageing of the population and changes in lifestyle, the prevalence of DM is likely to increase [ 4 ], mainly in low and medium-income countries [ 5 , 6 ], but also in Spain [ 7 ]. One out of three individuals with DM lives in Western countries, according to the International Diabetes Federation (IDF) [ 3 ]. In 2021 the total number of people with DM in the world was 537 million, representing 10.5 % of the world population and significantly about 50 % of them being undiagnosed, mostly in low- and medium-income countries. Moreover, the prevalence of T2DM in the elderly is high, especially among older individuals aged ≥75 years [ 4 ]. In Europe, there is no adequate pooled data except for a study linking social inequalities to the prevalence and incidence of T2DM. In this study [ 8 ], the prevalence of T2DM in men aged 50 years and over ranged from 8.4 % [95% CI: 6.3–10.4] in Denmark to 15.3 % [95% CI: 12.5–18.1] in Spain, while in women ranged from 4.5 % [95% CI: 2.6–6.5] in Switzerland to 14.2 % [95% CI:11.8–16.6] in Spain. In France the prevalence of DM peaks at age 75–79 years, affecting 19.7 % of men and 14.2 % of women at that age [ 4 ]. Regarding the elderly US people, it oscillates between 19.6 % and 21.6 % [ 9 ]. Nevertheless, only very few surveys have been carried out in Spain to describe the long-term mortality in adults with T2DM, specifically older subjects, that could show the correlation between expenditure in T2DM subjects and its outcomes. In general Spanish population, a cross-sectional descriptive observational study on 15 years waves (1998–2013) found that standardized mortality rates (SMR) were lower in the center and north-east of the national territory (Galicia, Castilla La Mancha, and Madrid Autonomous Communities) until 2008, a difference that partially disappeared in 2013 when 17 out of 50 provinces showed an SMR < 20/100,000 subjects. Moreover, SMR for DM fell markedly, by 25.3 % in men and by 41.4 % in women from 1998 to 2013 [ 10 ]. In another retrospective, observational study based on electronic medical records, HF and CKD were the first and most common manifestations during a seven-year follow-up in T2DM patients, with a significantly higher impact on mortality and rehospitalization rates [ 11 ]. Thus, information on long term T2DM mortality in Spain is limited, and to our knowledge, no prospective population-based studies have yet addressed this issue, even in the elderly. The advances in primary, secondary and tertiary prevention [ 12 , 13 ], as well as the new drugs approved for DM treatment in these years [ 14 – 19 ], have smoothened the mortality rates between subjects with and without DM, as confirmed in some studies [ 20 , 21 ]. Therefore, a higher prevalence would not necessarily mean higher mortality. The scarce information on the T2DM elderly mortality in Spain convinced us to evaluate the data from the NEDICES (Neurological Disorders in Central Spain) study. This cohort is a sizeable population-prospective-based study carried out from 1994 until 2017 (last mortality evaluation) whose aim was the epidemiological study of elderly neurological and chronic disorders. It has contributed to the knowledge in Spain, of the epidemiology of cognitive impairment, dementia, stroke, and elderly neurodegenerative disorders (dementing disorders, Parkinson’s disease, and essential tremor) [ 22 – 24 ] (more data in https://www.ciberned.es/en/research-programmes/projects/nedices ). Because of the uncertainties relating to survival in Spanish older adults with T2DM, which could have significant implications for health resources and policies, our aim was to study the effect of T2DM on the mortality during a long period of time in the NEDICES cohort, providing a more up-to-date assessment of the T2DM risk of mortality, and if this effect was different according to sex. Material and Methods Sites and population of the NEDICES cohort The NEDICES cohort sampled three geographic areas to obtain a cohort of older adults with different cultural and socioeconomic backgrounds. The study population comprised elderly participants over 65 years taken from the census of three communities in central Spain. A) Las Margaritas (approximately 14,800 inhabitants), a working-class neighborhood in Getafe (Greater South Madrid). B) Lista, high-income professional-class vicinity in Salamanca district in Central Madrid [approximately 150,000 inhabitants). C) 38 villages of the agricultural region municipality of Arévalo (125 km northwest of Madrid) (approximately 9,000 inhabitants, 24 % over 65 years of age). The three areas were selected according to the following criteria: a) there were approximately 2,000 elderly inhabitants; b) it existed a computer-based registry of elders’ medical data in the primary care physician (PCP) setting, and c) there already existed a close relationship between the NEDICES investigators and the local PCP and health authorities. Moreover, these areas had sufficient differences in social structures to allow the study of elderly samples with different lifestyles and risk factors. There was no sampling in Margaritas and Arevalo County because the reference population was nearly 2,000 people (adequate sample for the objectives of the study). For Lista area, a representative and proportional random sample of 2,113 elderly subjects obtained from the municipal census of the neighborhood, and stratified by age and sex, was selected from the reference population (more than 24,000 elderly people). This survey covered the household and nursing home populations of the three communities. We have reported elsewhere a detailed account of the background, study population, and methods of the survey [ 22 – 24 ]. Participants and data collection Up-to-date lists of residents were generated from population registers. In each community, survey eligibility was restricted to residents aged 65 years or older who were present there on December 31, 1993. Eligible persons who had moved away from the survey area were not traced. For the Lista area, a representative sample of 2,000 individuals, stratified by age and sex, was selected from the reference population (more than 24,000 older adults). In Margaritas and Arévalo, there was no sampling because the reference population was nearly 2,000 individuals. Each eligible individual was invited to participate in the survey by mail. Post mail followed by telephone calls were used to invite participation and explain confidentiality procedures. Community relations and ethical aspects The survey was announced locally by newspapers, radio, and television. As previously mentioned, a letter from the local health and municipal authorities accompanied the invitation and telephone number to arrange an interview. The study, conducted following the principles of the Helsinki Declaration of 1975, was approved by two university hospitals’ institutional ethical review committees, the University Hospital “12 de Octubre” and the University Hospital “La Princesa” both in Madrid. Every survey participant or their legal guardians gave written informed consent. In this informed consent, the name and address of the PCP were included. To avoid conflicts with local physicians, the medical staff of the NEDICES survey did not offer treatment. The newly detected cases of all chronic diseases (neurologic, psychiatric, or systemic) were communicated to each PCP. Methods of the field survey and data on survival. This study consisted of a baseline survey (1994–1995) and data provided by the Spanish National Institute of Statistics (INE) on the population and its deaths (date and diagnosis) during the period from 1994 to 2017. Cross-sectional survey (1994 to 1995) At baseline, trained interviewers performed a face-to-face evaluation. The interviews were carried out at the Primary Care Centre closest to the subject’s home and carried out with the elderly person and a companion. The evaluation comprised a 500-item screening questionnaire assessing demographic information, health status (including medical and neurologic disorders), cardiovascular and neurological disease risk factors, and variables about lifestyle (e.g., consumption of alcohol, smoking habits, self-reported health). Subjects were asked to provide the medication (and its containers) they had been taking during the previous week, as well as any medical records available. A short form of the questionnaire was mailed to unavailable participants for face-to-face or telephone screening. The registered study population consisted of 6,395 participants, but 481 were ineligible (e.g., census issues, incorrect address, death), leaving 5,914 eligible participants. Of the 5,914 eligible participants, 52 (0.9 %) had died, 292 [4.9 %) refused, and 292 (4.9 %) were unreachable (contact failure). The remaining 5,278 [89.2 %) population-based older adults (of whom 57.6 % were women, with a mean age of 74.31 ± 6.97 years) agreed to participate. For the main analyses of this study, the prevalence of T2DM in the cross-sectional survey was defined as a (self-reported) previous medical diagnosis of T2DM, the use of DM medication, or both. Diagnosis of hypertension and hypercholesterolemia were obtained following the same methodology, as appropriate questions were asked regarding the diagnosis, duration and treatment during the face-to-face interview. Regarding the smoking habit, it was categorized as “never” or “active” if he/she smokes or has smoked regularly during his/her lifetime, defined as at least one unit of any tobacco product per week. The consumption of ethanol was categorized as “never” or “active”, the latter defined as at least one cup of any alcoholic beverage per week during his/her lifetime. Physical activity was assessed using an adapted version (four items) of the Rosow-Breslau physical function measure [ 25 ] and classified as follows: (a) sedentary lifestyle (i.e., only minimal house chores or short walks at home); (b) light PA (i.e., regular house chores, walks independently at home); (c) moderate activity (i.e., regular house chores, walks up to one kilometer per day) and; (d) high activity) i.e., performs heavy housework, walks more than one kilometer, or engages in regular sports. The intensity level of PA was weighted based on the number of hours spent within the secondary category multiplied by 2; light PA by 1.2; moderate PA by 1.4; and high PA by 1. Next, different cut-off points were calculated based on quartile distribution to classify the subjects as follows: ≤ 15.6 hours (sedentary group), ≤ 17.6 hours (light PA group), ≤ 19.4 hours (high PA group) [ 24 ]. Regarding self-rated health, it was assessed with only one question: “In general terms, how would you describe your health: very good, good, fair, poor, or very poor?” that was rated with 1 [very good] to 5 [very poor] points. Measurements and anthropometric data were obtained from participants by their primary care physician. Analytic Sample Construction. The flow chart at each step of the NEDICES survey is shown in Figure 1 . Of the 5,278 participants screened at baseline (1994 to 1995), 280 were excluded from the follow-up because there was no information regarding DM diagnosis at baseline, leaving in the study 4,998 from which 830 (16.6 %) were subjects with diabetes. Of these, 47 were excluded due to lack of information provided by the INE and 913 due to lack of information on any of the main risk factors with which the complete analysis was performed (hypertension, hypercholesterolemia, tobacco, and alcohol consumption). Thus, this analysis was performed in 4,038 subjects of which 685 (17.0 %) were subjects with DM. 596 subjects (14.8 %) remained alive in 2017. Fig 1. Cohort study flowchart outlines and sample enrollment according to DM diagnosis. Open in a new tab * DM: diabetes mellitus. * INE: Spain’s National Statistics Institute. ⱡ Clinical missing information on alcohol, smoking habit, hypercholesterolemia or high blood pressure . Statistical analysis Qualitative variables are shown with their absolute and relative frequency distribution. Quantitative variables are summarized with the mean and standard deviation (SD). For the comparison of baseline characteristics according to the diagnosis of T2DM, the chi-square test was used for qualitative variables, and the parametric Student’s t-test for quantitative variables. The prevalence of T2DM diagnosis at baseline was compared by age group using the Cochran-Armitage test for trend. The probability of survival was estimated depending on the T2DM diagnosis using the Kaplan-Meier method. Comparisons of the curves were performed using the log-rank test. A Cox regression model was fitted to evaluate the effect of T2DM diagnosis on the mortality rate for any reason. Those baseline characteristics that presented statistically significant differences according to T2DM and/or were clinically relevant as factors related to mortality were included as confounders. The interaction term between T2DM and sex was included to explore differences in the mortality rate of T2DM by sex. As some of these confounding factors were missing in some subjects, we tested a crude model and several models including at least 70 % of the total subjects. Model 1 included age, sex, study area, hypertension, perceived health, cultural level and number of treatment drugs, including > 90 % subjects; model 2 included the same variables as model 1 plus hypercholesterolemia, smoking status and alcohol consumption with > 80 % included subjects; model 3 the same as model 2 plus the body mass index and the physical activity with > 70 % included subjects. For all tests, a significant value of 5 % was accepted. Statistical analyses were performed with STATA software (15.1 version, StataCorp LLC, Texas, USA). Results The demographic and lifestyle features of the 4,038 included subjects (57.5 % women) are depicted in Table 1 . Slightly more than a third of the individuals (34.2 %) included at baseline were 65 to 69 years old. Regarding the study area, there was a significantly higher proportion of T2DM women in Margaritás working-class area (51 vs. 35.4 %, p < 0.001). A lower education level was found in TDM2 as compared to non-T2DM women (p < 0.001) but not in men. A higher proportion of non-T2DM men and women felt in very good or good health as compared to T2DM counterparts (p < 0.001). Instead, a higher proportion of T2DM men and women were diagnosed with hypercholesterolemia and hypertension (p < 0.001). T2DM men and women were less frequently active alcohol drinkers than their non-DM2 counterparts (p = 0.023 and < 0.001, respectively). Oppositely, no differences were found for smoking status in T2DM vs. non-DM men and women. Regarding BMI, more overweight and obese women were found in the T2DM group (p < 0.001). No differences in BMI were found for men. Moreover, sedentarism was more frequent in T2DM subjects (p = 0.013). As expected, the number of treatment drugs was higher in T2DM subjects (p < 0.001), that were treated with an average of 1.41 drugs per day. Table 1. Characteristics of the included participants from the baseline survey (1994–5), according to diabetes mellitus status and sex. Characteristics Men Women Total Total (%) Non-T2DM # n (%) T2DM # n (%) P Total (%) Non-T2DM # n (%) T2DM # n (%) p Total (%) Non-T2DM # n (%) T2DM # n (%) p Demographics (n = 4,038) Age 73.1 ± 6.4 73.2 ± 6.4 72.3 ± 6.4 0.034 74.0 ± 6.8 74.0 ± 6.8 73.9 ± 6.6 0.766 73.6 ± 6.6 73.7 ± 6.7 73.3 (6.5) 0.207 - mean ± SD - Age groups 65–69 633 (36.8) 522 (35.6) 111 (44.0) 747 (32.2) 611 (32.4) 136 (31.4) 1,380 (34.2) 1,133 (33.8) 247 (36.1) - years - 70–74 485 (28.2) 414 (28.2) 71 (28.2) 648 (27.9) 529 (28.0) 119 (27.5) 1,133 (28.1) 943 (28.1) 229 (27.7) 0.708 75–79 294 (17.1) 263 (17.9) 31 (12.3) 416 (17.9) 331 (17.5) 85 (19.6) 710 (17.6) 594 (17.7) 116 (16.9) 80–84 192 (11.2) 167 (11.4) 25 (9.9) 0.059 299 (12.9) 240 (12.7) 59 (13.6) 0.723 491 (12.2) 407 (12.1) 84 (12.3) ≥ 85 114 (6.6) 100 (6.8) 14 (5.6) 210 (9.1) 176 (9.3) 34 (7.9) 324 (8.0) 276 (8.2) 48 (7.0) Total 1,718 (42.5) 1,466 (85.3) 252 (14.7) 2,320 (57.5) 1,887 (81.3) 433 (18.7) 4,038 (100) 3,353 (83.0) 685 (17.0) Study Area Lista 493 (28.7) 423 (28.9) 70 (27.8) 714 (30.8) 641 (34.0) 73 (16.9) 1,207 (29.9) 1,064 (31.7) 143 (20.9) Arévalo Country 626 (36.4) 545 (37.2) 81 (32.1) 0.143 717 (30.9) 578 (30.6) 139 (32.1) < 0.001 1,343 (33.3) 1,123 (33.5) 220 (32.1) < 0.001 Margaritas 599 (34.9) 498 (34.0) 101 (40.1) 889 (38.3) 668 (35.4) 221 (51.0) 1,488 (36.8) 1,166 (34.8) 322 (47.0) Total 1,718 1,466 252 2,320 1,887 433 4,038 3,353 685 Education * Illiterates** 128 (7.5) 111 (7.6) 17 (6.7) 399 (17.3) 283 (15.1) 116 (26.9) 527 (13.1) 394 (11.8) 133 (19.4) Able to read & write 732 (42.8) 615 (42.2) 117 (46.4) 939 (40.6) 763 (40.6) 176 (40.7) 1,671 (41.6) 1,378 (41.3) 293 (42.8) 0.577 < 0.001 < 0.001 Primary 526 (30.8) 456 (31.3) 70 (27.8) 725 (31.4) 612 (32.6) 113 (26.2) 1,251 (31.1) 1,068 (32.0) 183 (26.8) Secondary/University 323 (18.9) 275 (18.9) 48 (19.0) 247 (10.7) 220 (11.7) 27 (6.3) 570 (14.2) 495 (14.8) 75 (11.0) Total * 1,709 1,457 252 2,310 1,878 432 4,019 3,335 684 Perceived health Very Good 177 (10.4) 161 (11.1) 16 (6.4) 229 (10.0) 206 (11.1) 23 (5.4) 406 (10.2) 367 (11.1) 39 (5.8) Good 921 (54.2) 803 (55.3) 118 (47.4) 1,008 (44.2) 859 (46.3) 149 (34.8) 1,929 (48.4) 1,662 (50.3) 267 (39.4) < 0.001 < 0.001 < 0.001 Fair 444 (26.1) 369 (25.4) 75 (30.1) 735 (32.2) 560 (30.2) 175 (40.9) 1,179 (29.6) 929 (28.1) 250 (36.9) Bad 125 (7.4) 90 (6.2) 35 (14.1) 234 (10.3) 167 (9.0) 67 (15.7) 359 (9.0) 257 (7.8) 102 (15.1) Very bad 33 (1.9) 28 (1.9) 5 (2.0) 76 (3.3) 62 (3.3) 14 (3.3) 109 (2.7) 90 (2.7) 19 (2.8) Total * 1,700 1,451 249 2,282 1,854 428 3,982 3,305 677 Hypercholesterolemia † Yes 404(25.2) 320 (23.4) 84 (35.7) 741 (34.6) 565 (32.3) 176 (44.7) 1,145 (30.6) 885 (28.4) 260 (41.3) <0.001 < 0.001 < 0.001 No 1,200 (74.8) 1,049 (76.6) 151 (64.3) 1,402 (65.4) 1,184 (67.7) 218 (55.3) 2,602 (69.4) 2,233 (71.6) 369 (58.7) Total 1,604 (42.8) 1,369 (85.3) 235 (14.7) 2,143 (57.2) 1,749 (81.6) 394 (18.4) 3,747 (100) 3,118 (83.2) 629 (16.8) Alcohol intake * Yes 789 (45.9) 684 (46.7) 105 (41.7) 377 (16.3) 339 (18.0) 38 (8.8) 1,166 (33.8) 1,023 (30.5) 143 (20.9) No 689 (46.6) 568 (45.4) 121 (53.5) 0.023 1,590 (80.8) 1,260 (78.8) 330 (89.7) <0.001 2,279 (66.2) 1,828 (64.1) 451 (75.9) <0.001 Total 1,478 1,252 226 1,967 1,599 368 3,445 2,851 594 Smoking status * Current smoker 330 283(22.6) 47 (20.6) 70 61 (3.8) 9 (2.4) 400 (11.6) 344 (12.1) 56 (9.4) Non-smoker (including former smokers) 1,151 970 (77.4) 181 (79.4) 0.510 1,898 1,539 (96.2) 359 (97.6) 0.202 3,049 (85.4) 2,509 (87.9) 540 (90.6) 0.065 Total 1,481 1,253 228 1,968 1,600 368 3,449 2,853 596 Hypertension * ¥ Yes 726 (42.4) 592 (40.5) 134 (53.4) 1,324 1,025 (54.6) 299 (69.5) 2,050 (50.8) 1,617 (48.4) 433 (63.6) No 986 (57.6) 869 (59.5) 117 (46.6) < 0.001 985 (42.7) 299 (69.5) 131 (30.5) < 0.001 1,971 (48.8) 1,723 (51.6) 248 (36.4) < 0.001 Total 1,712 1,461 251 2,309 1,879 430 4,021 3,340 681 Body Mass Index 26.9 ± 4.0 26.9 ± 4.0 27.4 ± 4.0 0.092 28.0 ± 5.6 27.8 ± 5.5 28.9 ± 6.2 0.002 27.5 ± 5.0 27.3 ± 4.9 28.3 ± 5.5 < 0.001 - Kg/m 2 – - mean ± SD - Body Mass Index * < 20 14 (1.0) 12 (1.0) 2 (0.9) 27 (1.6) 25 (1.8) 2 (0.7) 41 (1.3) 37 (1.5) 4 (0.8) - Kg/m 2 - 20 – 24.99 417 (30.0) 362 (30.8) 55 (25.7) 505 (30.3) 432 (31.7) 73 (24.2) 922 (30.2) 794 (31.2) 128 (24.8) 25–30 696 (50.0) 583 (49.5) 113 (52.8) 0.517 619 (37.2) 499 (36.6) 120 (39.7) 0.015 1,315 (43.0) 1,082 (42.6) 233 (45.2) 0.080 >30 264 (19.0) 220 (18.7) 44 (20.6) 515 (30.9) 408 (29.9) 107 (35.4) 779 (25.5) 628 (24.7) 151 (29.3) Total 1,391 1,177 214 1,666 1,364 302 3,057 2,541 516 Physical Activity * Sedentary 428 (30.7) 349 (29.5) 79 (37.6) 445 (24.5) 348 (23.4) 97 (29.8) 873 (21.6) 697 (26.1) 176 (32.8) Low 374 (26.9) 319 (27.0) 55 (26.2) 499 (27.5) 417 (28.0) 82 (25.2) 873 (21.6) 736 (27.6) 137 (25.6) 0.084 0.062 0.013 Moderate 316 (22.7) 272 (23.0) 44 (21.0) 383 (21.1) 325 (21.8) 58 (17.8) 699 (17.3) 597 (22.4) 102 (19.0) High 274 (19.7) 242 (20.5) 32 (15.2) 487 (26.8) 398 (26.7) 89 (27.3) 761 (18.8) 640 (24.0) 121 (22.6) Total 1,392 1,182 210 1,814 1,488 326 3,206 2670 536 Treatment Number of drugs 0.55 (± 0.77) 1.24 (± 1.12) < 0.001 0.76 (±0.84) 1.51 (± 1.07) < 0.001 0.79 (± 0.91) 0.66 (± 0.82) 1.41 (± 1.09) < 0.001 mean (SD) †† Open in a new tab # Non-T2DM; participants without diabetes. T2DM: participants with diabetes. * For diverse reasons, not all participants had information on each characteristic. ¥ Blood pressure ≥ 140/90 mm hg † Total Cholesterol ≥ 200 mg/dl †† Standard deviation. The crude prevalence of T2DM, according to age categories is displayed in Table 2 . The prevalence of T2DM in the survey (1994–1995) was 17.0 % (95 % CI: 15.8–18.2), higher in women than men: 18.7 % (95 % CI: 17.1–20.3) vs. 14.7 % (95 % CI: 13.1–16.4). Table 2. Total crude prevalence of diabetes mellitus in the baseline survey according to age categories. Men Women Total % (95 % CI) Age (years) Crude p † Crude p † Crude p † Cross-sectional (1994) 65–69 17.5 (14.8–20.8) 18.4 (15.6–21.5) 17.9 (16.0–20.0) 70–74 14.6 (11.8–18.1) 0.014 18.4 (15.6–21.5) 0.948 16.8 (14.7–19.1) 0.226 75–79 10.5 (7.5–14.6) 20.4 (16.8–24.6) 16.3 (13.8–19.2) 80–84 13.0 (8.9–18.6) 19.7 (15.6–24.6) 17.1 (14.0–20.7) >84 12.3 (7.3–19.7) 16.2 (11.8–21.8) 14.8 (11.3–19.1) Total 14.7(13.1–16.4) 18.7 (17.1–20.3) 17.0 (15.8–18.2) Open in a new tab † Cochran-Armitage test for trend By 31 st December 2017, 3,442 subjects (85.2 %) from the 4,038 followed subjects had dead, 616 in the TDM2 group (89.9 %). As of the subjects’ death causes ( Table 3 ), the most important aetiology in the T2DM group was the cardiovascular group (18.6 %), followed by neoplasms (14.4 %), oppositely to the non-DM group, where neoplasms were the main group (17.7 %). Regarding the cardiovascular group, stroke of ischemic origin, was significantly more frequent in the T2DM group (p < 0.001), especially women ( Suppl. Table 1 ). Moreover, it is important to notice that T2DM was the third most frequent death diagnosis followed by main cognitive impairment ( Table 3 ). The death reason was not found in 33 subjects (< 1 % of the dead subjects). Table 3. Subjects’ death causes. Cause DM (%) † Non-DM (%) † Total (%) † p Cardiovascular disease Subtype Ischemic cardiomyopathy Acute myocardial infarct 42 (6.2) 154 (4.6) 196 (4.9) 0.091 Angor 0 (0) 2 (0.1) 2 (0) -- Other 19 (2.8) 93 (2.8) 112 (2.8) 0.991 Total 61 (9.0) 249 (7.5) 310 (7.7) 0.192 Stroke Ischemic 24 (3.5) 33 (1.0) 57 (1.4) <0.001 Haemorragic 12 (1.8) 48 (1.4) 60 (1.5) 0.534 Others 23 (3.4) 131 (3.9) 154 (3.8) 0.486 Total 59 (8.7) 212 (6.4) 271 (6.8) 0.030 Ischemic lower limb 6 (0.9) 17 (0.5) 23 (0.6) 0.262 Total 126 (18.5) 478 (14.4) 604 (15.1) 0.006 Neoplasm 98 (14.4) 592 (17.8) 690 (17.2) 0.034 Main cognitive impairment 40 (5.9) 198 (6.0) 238 (5.9) 0.934 Diabetes mellitus 45 (6.6) 32 (1.0) 77 (1.9) <0.001 High blood pressure 13 (1.9) 89 (2.7) 102 (2.5) 0.286 Others 290 (42.3) 1,408 (42.0) 1,698 (42,1) 0.868 Unknown 4 (0.6) 29 (0.9) 33 (0.8) 0.641 Death 616 (89.9) 2,826 (84.3) 3,442 (85.2) <0.001 Total 685 3,353 4,038 Open in a new tab DM: diabetes mellitus. Death causes according to the Spanish National Statistics Institute (INE) by 31st December 2017. In 33 cases (4 DM subjects) the cause of death is unknown. † Percentage of the whole subjects excluding unknown cases. Cumulative survival of subjects according to Kaplan-Meier curves is shown in Figure 2 . Survival was higher in the non-DM group (p < 0.001). Similar trends were found in the Kaplan-Meier curves according to sex (p < 0.001, figures not shown). Mean individuals survival time was two years higher for non-DM subjects as compared to T2DM ( Table 4 ): 14.08 vs. 11.99 years (p < 0.001). Women had a mean survival time more than two years higher in both groups: T2DM men 10.52 vs. women 12.72 years (p < 0.001); non-DM men 12.83 vs. women 15.13 years (p < 0.001). Fig 2. Cumulative survival of subjects categorized according to DM diagnosis. Open in a new tab Table 4. Subjects’ survival time according to DM diagnosis. Men * Women * Total * Diabetes x̄ M x̄ M x̄ M No 12.72 (12.36–13.08) 12.01 (11.49–12.53) 15.13 (14.81–15.45) 15.52 (15.04–16.01) 14.08 (13.83 – 14.32) 14.04 (13.63 – 14.46) Yes 10.52 (9.69–11.35) 9.18 (7.87–10.49) 12.83 (12.17–13.50) 11.75 (10.83–12.67) 11.99(11.46 – 12.51) 10.99 (10.35 – 11.63) Overall 12.40 (12.07–12.73) 11.62 (11.15–12.08) 14.70 (14.41–14.99) 14.94 (14.46–15.42) 13.72 (13.50 – 13.94) 13.46 (13.09 – 13.84) Open in a new tab n = 4,038. x̄: mean. M: median. 95 % CI in brackets. * p < 0.001 for the comparisons of DM against non-DM. The crude Cox regression ( Table 5 ) showed a HR mortality of 1.37 for men and 1.38 for women with T2DM as compared to non-DM subjects (p <0.001), that did not change after adjustment for several confounding factors in the three models. We also categorized subjects in quartiles according to the number of years after T2DM diagnosis at baseline (data not shown in Table 5 ), and found that there were no differences in the Cox regression, but a tendency towards a higher risk of mortality in those subjects with 5 or more years after diagnosis (quartiles 3 and 4): ≥ 5 years HR 1.21 (0.96–1.53), p = 0.108; ≥ 14 years HR 1.21 (0.94–1.55), p = 0.140. Considering vascular disease (coronary artery disease, stroke, or limb ischemia), a significant mortality HR was also found for T2DM individuals: 1.59 (1.31–1.94, p < 0.001). Interestingly, the highest mortality HR in T2DM individuals was found for ischemic stroke: 4.40 (2.60–7.46, p < 0.001). Table 5. HRs of all-cause mortality. Crude p Model 1 p Model 2 p Model 3 p All participants 1.34 (1.23–1.46) <0.001 1.31 (1.19–1.44) <0.001 1.29 (1.16–1.42) <0.001 1.29 (1.16–1.45) <0.001 Men 1.37 (1.22–1.53) <0.001 1.28 (1.13–1.44) <0.001 1.23 (1.08–1.40) 0.001 1.27 (1.08–1.49) 0.005 Women 1.38 (1.20–1.59) <0.001 1.35 (1.17–1.57) <0.001 1.36 (1.17–1.59) <0.001 1.32 (1.14–1.53) <0.001 p-interaction * 0.928 0.553 0.321 0.705 Open in a new tab Data are HRs (95% CI) for people with type 2 diabetes compared with people without diabetes and non-unadjusted (crude model) or adjusted for age, sex, study area, hypercholesterolemia, hypertension, perceived health, cultural level and number of treatment drugs (model 1), or adjusted for the same variables as model 1 plus the smoking status and alcohol consumption (model 2) or adjusted for the same variables as model 2 plus the body mass index and the physical activity (model 3). * The interaction p-value assesses whether the hazard associated with T2DM differs significantly between sexes. Regarding the different models of mortality for T2DM subjects on the multivariate test, they demonstrated an increased risk independently of gender or the included covariates, similar across all models ( Table 5 ). Model 1 (n = 3,681 subjects, 91.2 % of the total subjects) showed a statistically significant mortality HR 1.31 for T2DM subjects. Model 2 (n =3,370 subjects, 83.5 % of the total subjects) and model 3 (2,388 subjects, 70.3 %) showed similar mortality HRs. All-cause mortality risk was slightly higher for women according to the three models (1.35, 1.36 and 1.32, respectively vs 1.28, 1.23 and 1,27 in men). Therefore, none of the models diverged significantly from the mortality HR without adjustment, neither by sex ( Table 5 ). Discussion In this study, the participants were all individuals under care in the Spanish National Healthcare System. We have found that T2DM subjects have a 2-year reduced expected survival time as compared to non-DM subjects throughout for 22 years, after adjusting for several confounding factors, with no differences between sex ( Table 4 ). To our knowledge, this is the first time that a sustained reduction in the associated life expectancy of T2DM elderly subjects (≥ 65 years old) is proven in Spain. We have also found a crude prevalence of T2DM of 17 % in this elderly population, which is in accordance with more recent data in Spain for this age strata [ 7 , 26 ]. T2DM subjects had a 5.4 % excess risk for cardiovascular disease, and 2.3 % for stroke, compared with non-T2DM subjects. The expected survival time in T2DM subjects has been studied for more than 30 years ago, mainly in developed countries, with controversial results. In Europe, the most recent data on a retrospective study from the UK [ 27 ] over a 15-year follow-up period, showed a constant increase in mortality among individuals with T2DM (HR 1.21 and 1.52 among individuals with diagnosis at 50−59 years and 60−74 years, respectively), in accordance with the results herein provided. Nevertheless, these data showed an improvement in the all-cause T2DM subjects’ mortality, as a previous report in the UK in 2014 [ 28 ] demonstrated a twofold increased risk (HR 2.07) of all-cause mortality after adjusting for smoking, in a 7-follow-up year period of subjects aged 40 to 65 years at baseline. Interestingly of this study, was the finding that T2DM with < 55 years of age, were at a greater relative risk than older middle-aged people without T2DM. This is in accordance with a systematic review in 8 countries including the UK [ 29 ], that found that increased mortality was lower when the diagnosis of T2DM was made at an older age than that reported for the general older T2DM population. That the over-mortality of established persons with T2DM decreases with age has been found in several studies carried out in developed countries [ 28 – 31 ]. Even more, in some studies, no excess mortality was found over the ages of 65 or 70 years, as compared with non-DM counterparts [ 29 – 31 ]. However, a significant increase has been reported only for elderly women as compared to men in some studies [ 29 , 30 ]. Nevertheless, the reasons why some studies found small or non-differences in mortality, even in subjects diagnosed at a later age, could be because there was no adjustment for the confounding effect of deprivation [ 34 ], perhaps a degree of under-ascertainment of T2DM in the non-DM cohort [ 35 , 36 ], or alternatively there was a low mean year follow-up period [ 29 , 32 , 37 ]. In fact, it may be that mortality of T2DM and non-DM subjects diverges in later years after diagnosis, starting at least 7 years following diagnosis [ 32 ]. It could possibly be explained because, in younger T2DM subjects, there is less additional risk besides hyperglycemia compared to older T2DM individuals. Oppositely, in our elderly cohort, we found an increase in mortality only 1 year after diagnosis of diabetes as it occurred in a study conducted in Germany, where interestingly it was higher than the increased mortality found for the same cohort—10 years post-diagnosis [ 38 ]. Similarly, in our study the survival curves of T2DM and non-T2DM groups tended to converge after 20 years of follow-up ( Figure 2 ), indicating that above the age of 85 mortality is only slightly or not increased. Interventions such as smoking cessation, lifestyle modifications, and more efficacy in drugs for diabetes, have led to a reduction in risk factors for this disease, and therefore for cardiovascular diseases and diabetes associated mortality. On the other hand, we have found that cardiovascular diseases are the major cause of premature death in subjects with T2DM, with a 1.59-fold increased risk of cardiovascular mortality and 4.4-fold increased risk for ischemic stroke. The increased mortality of older T2DM people may be up to four times higher than that of older non-DM people [ 29 ]. These results are in accordance with previous studies [ 28 – 31 ], although patterns in high income countries, including Spain, show declining rates of vascular complications and its hospitalizations, as well as death from cardiovascular causes since 2000. This information has been mostly obtained from registries or administrative data sources until 2021 and demonstrates that the largest declines in vascular complications have been observed for older adults [ 39 ]. The strengths of our study included the data sources, with high-quality data on a large representative sample of the central Spanish elderly population, and complete and accurate data on the date and cause of death in the certification by their PCP and provided by the INE. Moreover, we were able to adjust for the most important cardiovascular risk factors at baseline. Another significant strength is the long-term subject’s follow-up, very unusual over a period longer than 15 years in other cohorts. However, we were limited by the extent of missing data for some covariates of interest in several subjects at the first wave carried out in 1994–95. Another possible flaw is that our cohort lacks information on the effect of T2DM drugs and T2DM control during the long follow-up period. No information on other important covariates such as hypertension, hypercholesterolemia, BMI, and physical activity levels during the long follow-up has neither been considered. Effectively, considering changes during the follow-up in those factors could potentially have influenced the mortality outcomes. In conclusion, this is a unique study that demonstrates for the first time a sustained reduction in Spanish T2DM elderly subjects (≥ 65 years) life expectancy after more than 20 years follow-up. Nevertheless, above the age of 85, mortality is only slightly or not increased. Cardiovascular diseases, followed by neoplasms, are the major cause of mortality among elderly individuals with T2DM, while in non-T2DM subjects’ neoplasms were the most frequent cause. Amongst cardiovascular diseases, T2DM elderly subjects are at significant risk of death from ischemic stroke. Therefore, community interventions and campaigns addressing lifestyle modifications, alcohol and smoking cessation and promotion of an adequate and regular TDM2 clinical follow-up, should be reinforced by authorities to reduce the risk factors for this disease, as well as to improve its control and the associated morbidity and mortality. Supplementary Material MMC1 NIHMS2091724-supplement-MMC1.docx (21.7KB, docx) Funding The Spanish Health Research Agency (FIS 93/077, 96/1993 and PI12/0160), the Madrid Autonomous Community (CAM 94/0032 and 96/1993), and the Spanish Office of Science and Technology (PB 1225-C04) have supported NEDICES. Also, some support of the cohort came from: FBP has been supported by grants from non-profit Spanish Foundations such as Fundación Mutua Madrileña (2006–9), Fundación Centro de Investigación Enfermedades Neurológicas (CIEN) and Fundación Neurociencia y Envejecimiento. SVQ received grant funds from Consejería de Sanidad de la Junta de Castilla y León (GRS573/A/10). JBL and FBP received support from R01 NS039422 from the NIH, Bethesda, Maryland, USA. More details about funding can be consulted at https://www.ciberned.es/programas-de-investigacion/proyectos/nedices/historico-del-estudio-nedices . The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Footnotes Declaration of interest The authors have no competing interests. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 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