Franco Cosmi1, Li Shen2, Michela Magnoli3, William T Abraham4, Inder S Anand5,6, John G Cleland7, Jay N Cohn5, Deborah Cosmi8, Giorgia De Berardis9, Kenneth Dickstein10, Maria Grazia Franzosi3, Lars Gullestad11,12, Pardeep S Jhund2, John Kjekshus11, Lars Køber13, Vito Lepore9, Giuseppe Lucisano9, Aldo P Maggioni14, Serge Masson3, John J V McMurray2, Antonio Nicolucci9, Vito Petrarolo15, Fabio Robusto9, Lidia Staszewsky3, Luigi Tavazzi16, Roberto Teli3, Gianni Tognoni3, John Wikstrand17, Roberto Latini3. 1. Department of Cardiology, Ospedale di Cortona, Cortona, Italy. 2. BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland, UK. 3. Department of Cardiovascular Research, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy. 4. Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH, USA. 5. Division of Cardiovascular Medicine, University of Minnesota, Minneapolis, MN, USA. 6. Department of Cardiology, VA Medical Center, Minneapolis, MN, USA. 7. Robertson Centre for Biostatistics and Clinical Trials, University of Glasgow, Scotland, and Imperial College London, UK. 8. Department of Cardiology, Ospedale di Gubbio, Gubbio, Italy. 9. CORESEARCH - Center for Outcomes Research and clinical Epidemiology, Pescara, Italy. 10. Stavanger University Hospital, Stavanger, and the Institute of Internal Medicine, University of Bergen, Bergen, Norway. 11. Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway. 12. Faculty of Medicine, University of Oslo, Oslo, Norway. 13. Department of Cardiology, Rigshospitalet, University Hospital, Copenhagen, Denmark. 14. ANMCO Research Center, Florence, Italy. 15. Regional Health Agency of Puglia, Bari, Italy. 16. GVM Hospitals of Care and Research, E.S. Health Science Foundation, Cotignola, Italy. 17. Sahlgrenska Academy, Gothenburg University, Sweden.
Abstract
AIMS: Up to one-third of patients with diabetes mellitus and heart failure (HF) are treated with insulin. As insulin causes sodium retention and hypoglycaemia, its use might be associated with worse outcomes. METHODS AND RESULTS: We examined two datasets: 24 012 patients with HF from four large randomized trials and an administrative database of 4 million individuals, 103 857 of whom with HF. In the former, survival was examined using Cox proportional hazards models adjusted for baseline variables and separately for propensity scores. Fine-Gray competing risk regression models were used to assess the risk of hospitalization for HF. For the latter, a case-control nested within a population-based cohort study was conducted with propensity score. Prevalence of diabetes mellitus at study entry ranged from 25.5% to 29.5% across trials. Insulin alone or in combination with oral hypoglycaemic drugs was prescribed at randomization to 24.4% to 34.5% of the patients with diabetes. The rates of death from any cause and hospitalization for HF were higher in patients with vs. without diabetes, and highest of all in patients prescribed insulin [propensity score pooled hazard ratio for all-cause mortality 1.27 (1.16-1.38), for HF hospitalization 1.23 (1.13-1.33)]. In the administrative registry, insulin prescription was associated with a higher risk of all-cause death [odds ratio (OR) 2.02, 95% confidence interval (CI) 1.87-2.19] and rehospitalization for HF (OR 1.42, 95% CI 1.32-1.53). CONCLUSIONS: Whether insulin use is associated with poor outcomes in HF should be investigated further with controlled trials, as should the possibility that there may be safer alternative glucose-lowering treatments for patients with HF and type 2 diabetes mellitus.
RCT Entities:
AIMS: Up to one-third of patients with diabetes mellitus and heart failure (HF) are treated with insulin. As insulin causes sodium retention and hypoglycaemia, its use might be associated with worse outcomes. METHODS AND RESULTS: We examined two datasets: 24 012 patients with HF from four large randomized trials and an administrative database of 4 million individuals, 103 857 of whom with HF. In the former, survival was examined using Cox proportional hazards models adjusted for baseline variables and separately for propensity scores. Fine-Gray competing risk regression models were used to assess the risk of hospitalization for HF. For the latter, a case-control nested within a population-based cohort study was conducted with propensity score. Prevalence of diabetes mellitus at study entry ranged from 25.5% to 29.5% across trials. Insulin alone or in combination with oral hypoglycaemic drugs was prescribed at randomization to 24.4% to 34.5% of the patients with diabetes. The rates of death from any cause and hospitalization for HF were higher in patients with vs. without diabetes, and highest of all in patients prescribed insulin [propensity score pooled hazard ratio for all-cause mortality 1.27 (1.16-1.38), for HF hospitalization 1.23 (1.13-1.33)]. In the administrative registry, insulin prescription was associated with a higher risk of all-cause death [odds ratio (OR) 2.02, 95% confidence interval (CI) 1.87-2.19] and rehospitalization for HF (OR 1.42, 95% CI 1.32-1.53). CONCLUSIONS: Whether insulin use is associated with poor outcomes in HF should be investigated further with controlled trials, as should the possibility that there may be safer alternative glucose-lowering treatments for patients with HF and type 2 diabetes mellitus.
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