Peter Rossing1, Silvio E Inzucchi2, Priya Vart3, Niels Jongs3, Kieran F Docherty4, Pardeep S Jhund4, Lars Køber5, Mikhail N Kosiborod6, Felipe A Martinez7, Piotr Ponikowski8, Marc S Sabatine9, Scott D Solomon9, David L DeMets10, Olof Bengtsson11, Magnus Lindberg11, Anna Maria Langkilde11, Mikaela Sjöstrand11, Bergur V Stefansson11, Cecilia Karlsson11, Glenn M Chertow12, Fan Fan Hou13, Ricardo Correa-Rotter14, Robert D Toto15, David C Wheeler16, John J V McMurray4, Hiddo J L Heerspink17. 1. Steno Diabetes Center Copenhagen, Gentofte, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. 2. Section of Endocrinology, Yale University School of Medicine, New Haven, CT, USA. 3. Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 4. British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK. 5. Department of Cardiology, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark. 6. Saint Luke's Mid America Heart Institute, Kansas City, MO, USA; School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA. 7. University of Cordoba, Cordoba, Argentina. 8. Wroclaw Medical University, Wroclaw, Poland. 9. Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Harvard University, Boston, MA, USA. 10. Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA. 11. BioPharmaceuticals Research & Development, AstraZeneca, Gothenburg, Sweden. 12. Departments of Medicine, Department of Epidemiology, and Department of Population Health, School of Medicine, Stanford University Stanford, CA, USA. 13. Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, Guangzhou, China. 14. National Medical Science and Nutrition Institute Salvador Zubirán, Mexico City, Mexico. 15. Department of Internal Medicine, University of Texas, Southwestern Medical Center, Dallas, TX, USA. 16. Department of Renal Medicine, University College London, London, UK. 17. Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; The George Institute for Global Health, Sydney, Australia. Electronic address: h.j.lambers.heerspink@umcg.nl.
Abstract
BACKGROUND: Chronic kidney disease and heart failure are insulin resistant states associated with a high incidence of diabetes. We assessed the effect of dapagliflozin on new-onset type 2 diabetes in a pooled analysis of patient-level data from the DAPA-CKD and DAPA-HF trials. METHODS: This study is a pooled analysis of individual participant data from two phase 3, randomised, double-blind, placebo-controlled, multicentre, clinical trials. Participants with no history of diabetes and HbA1c less than 6·5% (48 mmol/mol) at baseline were included in this pooled analysis. New-onset type 2 diabetes was a prespecified exploratory endpoint in both DAPA-CKD and DAPA-HF trials and is the focus of this analysis. New-onset type 2 diabetes was identified by serial trial measurements of HbA1c (two consecutive values ≥6·5% [≥48 mmol/mol]) or following a clinical diagnosis of diabetes between trial visits. Time to new-onset type 2 diabetes was analysed in a Cox proportional Hazards model from random assignment to end of treatment. FINDINGS: 4003 participants (1398 [34·9%] from the DADA-CKD trial and 2605 [65·1%] from the DAPA-HF trial) were included in our analysis: 1995 (49·8%) had received dapagliflozin and 2008 (50·2%) had received placebo. Over a median follow-up of 21·2 months (IQR 16·0 to 25·4), 126 (6·3%) of 2008 patients in the placebo group (event rate 3·9 per 100 patient-years) and 85 (4·3%) of 1995 patients in the dapagliflozin group (event rate 2·6 per 100 patient-years) developed type 2 diabetes (hazard ratio 0·67 [95% CI 0·51 to 0·88]; p=0·0040). There was no heterogeneity between studies (p interaction 0·77) and there was no clear evidence that the effect of dapagliflozin varied in prespecified subgroups including sex, age, glycaemic status, BMI, glomerular filtration rate, systolic blood pressure, and baseline cardiovascular medication use. More than 90% of the participants who developed type 2 diabetes had prediabetes at baseline (HbA1c 5·7% to 6·4% [39 to 46 mmol/mol]). Mean HbA1c remained unchanged (placebo-adjusted change in the dapagliflozin group of -0·01% [95% CI -0·03 to 0·01], -0·1 mmol/mol [95% CI -0·3 to 0·1] at 12 months). INTERPRETATION: Treatment with dapagliflozin reduced the incidence of new-onset type 2 diabetes in participants with chronic kidney disease and HF without a reduction in HbA1c. FUNDING: AstraZeneca.
BACKGROUND: Chronic kidney disease and heart failure are insulin resistant states associated with a high incidence of diabetes. We assessed the effect of dapagliflozin on new-onset type 2 diabetes in a pooled analysis of patient-level data from the DAPA-CKD and DAPA-HF trials. METHODS: This study is a pooled analysis of individual participant data from two phase 3, randomised, double-blind, placebo-controlled, multicentre, clinical trials. Participants with no history of diabetes and HbA1c less than 6·5% (48 mmol/mol) at baseline were included in this pooled analysis. New-onset type 2 diabetes was a prespecified exploratory endpoint in both DAPA-CKD and DAPA-HF trials and is the focus of this analysis. New-onset type 2 diabetes was identified by serial trial measurements of HbA1c (two consecutive values ≥6·5% [≥48 mmol/mol]) or following a clinical diagnosis of diabetes between trial visits. Time to new-onset type 2 diabetes was analysed in a Cox proportional Hazards model from random assignment to end of treatment. FINDINGS: 4003 participants (1398 [34·9%] from the DADA-CKD trial and 2605 [65·1%] from the DAPA-HF trial) were included in our analysis: 1995 (49·8%) had received dapagliflozin and 2008 (50·2%) had received placebo. Over a median follow-up of 21·2 months (IQR 16·0 to 25·4), 126 (6·3%) of 2008 patients in the placebo group (event rate 3·9 per 100 patient-years) and 85 (4·3%) of 1995 patients in the dapagliflozin group (event rate 2·6 per 100 patient-years) developed type 2 diabetes (hazard ratio 0·67 [95% CI 0·51 to 0·88]; p=0·0040). There was no heterogeneity between studies (p interaction 0·77) and there was no clear evidence that the effect of dapagliflozin varied in prespecified subgroups including sex, age, glycaemic status, BMI, glomerular filtration rate, systolic blood pressure, and baseline cardiovascular medication use. More than 90% of the participants who developed type 2 diabetes had prediabetes at baseline (HbA1c 5·7% to 6·4% [39 to 46 mmol/mol]). Mean HbA1c remained unchanged (placebo-adjusted change in the dapagliflozin group of -0·01% [95% CI -0·03 to 0·01], -0·1 mmol/mol [95% CI -0·3 to 0·1] at 12 months). INTERPRETATION: Treatment with dapagliflozin reduced the incidence of new-onset type 2 diabetes in participants with chronic kidney disease and HF without a reduction in HbA1c. FUNDING: AstraZeneca.
Authors: Olga González-Albarrán; Cristóbal Morales; Manuel Pérez-Maraver; José Juan Aparicio-Sánchez; Rafael Simó Journal: Diabetes Ther Date: 2022-06-15 Impact factor: 3.595