Zareini et al. Cardiovasc Diabetol (2019) 18:79 https://doi.org/10.1186/s12933-019-0883-4 Cardiovascular Diabetology ORIGINAL INVESTIGATION Open Access Heart failure and the prognostic impact and incidence of new-onset of diabetes mellitus: a nationwide cohort study B. Zareini1*, Rasmus Rørth2, Anders Holt1, Ulrik M. Mogensen2, Christian Selmer3, Gunnar Gislason1, Morten Schou1, Lars Køber2, Christian Torp‑Pedersen4,5, Morten Lamberts1 and Søren Lund Kristensen2 Abstract Background: Prevalent diabetes at the time of heart failure (HF) diagnosis is associated with a higher risk of death, but the incidence and prognostic importance of new‑onset diabetes in patients with established HF remains unknown. Methods: Patients with a frst hospitalization for HF in the period 2003–2014 were included and stratifed according to history of diabetes. Annual incidence rates of new‑onset diabetes were calculated and time‑dependent multivaria‑ ble Cox regression models were used to compare the risk of death in patients with prevalent and new‑onset diabetes with patients without diabetes as reference. The model was adjusted for age, sex, duration of HF, educational level and comorbidity. Covariates were continuously updated throughout follow‑up. Results: A total of 104,522 HF patients were included in the study, of which 21,216 (19%) patients had diabetes at baseline, and 8164 (10%) developed new‑onset diabetes during a mean follow‑up of 3.9 years. Patients with new‑onset diabetes and prevalent diabetes were slightly younger than patients without diabetes (70 vs. 74 and 77, respectively), more likely to be men (62% vs. 60% and 54%), and had more comorbidities expect for ischemic heart disease, hypertension and chronic kidney disease which were more prevalent among patients with prevalent diabe‑ tes. Incidence rates of new‑onset diabetes increased from around 2 per 100 person‑years in the frst years following HF hospitalization up to 3 per 100 person‑years after 5 years of follow‑up. A total of 61,424 (59%) patients died during the study period with event rates per 100 person‑years of 21.5 for new‑onset diabetes, 17.9 for prevalent diabetes and 13.9 for patients without diabetes. Compared to patients without diabetes, new‑onset diabetes was associated with a higher risk of death (adjusted HR 1.47; 95% CI 1.42–1.52) and prevalent diabetes was associated with an intermediate risk (HR 1.19; 95% CI, 1.16–1.21). Conclusion: Following the frst HF hospitalization, the incidence of new‑onset diabetes was around 2% per year, ris‑ ing to 3% after 5 years of follow‑up. New‑onset diabetes was associated with an increased risk of death, compared to HF patients with prevalent diabetes (intermediate risk) and HF patients without diabetes. Keywords: Heart failure, Type 2 diabetes mellitus, Prognosis *Correspondence: [email protected] 1 Department of Cardiology, Herlev and Gentofte University Hospital, Niels Andersens vej 65, Gentofte, 2900 Copenhagen, Denmark Full list of author information is available at the end of the article © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zareini et al. Cardiovasc Diabetol (2019) 18:79 Page 2 of 10 Background prescriptions to assess diabetes status have been vali- Heart failure (HF) and diabetes frequently co-exist and dated previously with a positive predictive value of 97% in the most contemporary trials of heart failure, one out and 95%, respectively [8–10]. of three patients had a history of diabetes [1]. Hypergly- cemia has been associated with changes in cardiac struc- Defnition of comorbidities and medical therapy ture, cardiac function, increased atherosclerosis, and the Comorbidities were identifed through ICD codes existence of a specifc diabetic cardiomyopathy pheno- from hospital records up to 10 years prior to the index type has been suggested [2–4]. Conversely, HF has been date, and continuously updated throughout the follow- associated with insulin resistance and hyperglycemia in up period (see Appendix: Table 2 for details and ICD a severity-dependent manner [5–7]. Despite previous codes). Information on concomitant medical therapy was studies establishing the detrimental prognosis of patients obtained from dispensed prescriptions as listed in the with HF and diabetes, the interplay of this bidirectional Danish National Prescription Registry and defned by at relationship has not been fully elucidated Specifcally, least one redeemed prescription of the drug 6 months the mortality risk associated with new-onset diabetes vs. prior to the index date. Te following drugs were prevalent diabetes in patients with HF has never been recorded at inclusion baseline: angiotensin-converting investigated. Our purpose was to investigate the inci- enzyme inhibitors (ACE), angiotensin II receptor block- dence of new-onset diabetes following a diagnosis of HF ers (ARB), calcium channel blockers, loop diuretics, and compare its prognostic impact on the risk of death thiazides, digoxin, platelet inhibitors (acetylic acid and with that of HF patients with prevalent diabetes and adenosine diphosphate receptor inhibitor), mineralocor- without diabetes. ticoid receptor antagonists (MRA), statins, beta-block- ers, insulin, metformin, sulfonylurea, thiazolidinedione Methods (TZD), dipeptidyl peptidase-4 (DPP-4) inhibitor, gluca- Data sources gon-like peptide-1 (GLP-1) receptor agonist, sodium-glu- In Denmark, every resident is assigned a unique personal cose cotransporter-2 (SGLT2) inhibitor and patients who identifcation number enabling individual-level linkage treated with a combination of two anti-diabetic drugs. between nationwide health care registries. Te Dan- DPP-4 inhibitors, GLP-1 receptor agonists and SGLT2 ish National Patient Registry entails information on all inhibitors were combined in one group defned as newer hospital admissions from 1978 and forward. Each hos- antidiabetic medication for further statistical analysis pital contact is coded with a primary diagnosis and sev- (see Appendix: Table 2 on details regarding details and eral secondary diagnoses according to Te International ATC codes). Classifcation of Disease, Eighth Revision (ICD-8) until 1993, and Te International Classifcation of Disease, Outcome measures Tenth Revision (ICD-10) from 1994 onwards. Te Danish Te outcomes of the study were new-onset diabetes and National Prescription Registry holds information (dos- all-cause death. Patients were followed to new-onset dia- age, dates, and Anatomical Terapeutic Chemical (ATC) betes, death, emigration or end of study (31 December codes on all prescriptions dispensed from a pharmacy 2015). since 1995 and the Danish Civil Registration System records vital-status. Statistics Baseline characteristics were described by the use Study population of proportions for categorical variables with means We included adults (older than 18 years) with a frst- and standard deviations (SD) or medians and inter- time diagnosis of HF in hospital discharge records in the quartile ranges (IQR) for continuous variables. Dif- period 2003–2014. Te index date (date of inclusion) was ferences between groups were tested by use of the 30 days after discharge from the hospital. Chi square test for categorical variables, non-para- metric test for non-normally distributed continuous Defnition of diabetes status variables and parametric for normally distributed Prevalent diabetes was defned by at least one prescrip- continuous variables. Annual incidence rates of new- tion of a glucose-lowering drug and/or a previous ICD onset diabetes were calculated per 100 person-years. code of diabetes 6 months prior to the index date. New- In analyses of all-cause death, we treated new-onset onset diabetes was defned by a frst claimed prescrip- diabetes as a time-dependent variable and com- tion of a glucose-lowering drug and/or an ICD code of pared the risk with prevalent diabetes patients and diabetes after index date in patients with no prior his- patients free of diabetes as reference. To account tory of diabetes. Combining the use of ICD codes and for the longer duration of HF in patients with Zareini et al. Cardiovasc Diabetol (2019) 18:79 Page 3 of 10 new-onset diabetes, follow-up time was split into Results 1-year intervals from inclusion date, and according Of 104,522 HF patients included in the study, 21,216 to calendar year in 3-year intervals. These variables (19%) patients had diabetes at baseline, and 8164 (10%) were included in the adjusted model. Comorbid- patients without diabetes at baseline developed new- ity and antidiabetic medication were continuously onset diabetes during the follow-up period (Fig. 1). updated throughout follow-up, and age was updated Patient characteristics of all three groups are shown at the beginning of each interval. A multivariable in Table 1 (with the baseline for the new-onset diabe- Cox proportional hazards analysis was performed tes group being time of diabetes diagnosis). Patients to compare hazard ratios of death according to dia- with new-onset