Tali Cukierman-Yaffe1, Hertzel C Gerstein2, Helen M Colhoun3, Rafael Diaz4, Luis-Emilio García-Pérez5, Mark Lakshmanan5, Angelyn Bethel5, Denis Xavier6, Jeffrey Probstfield7, Matthew C Riddle8, Lars Rydén9, Charles Messan Atisso5, Stephanie Hall10, Purnima Rao-Melacini10, Jan Basile11, William C Cushman12, Edward Franek13, Matyas Keltai14, Fernando Lanas15, Lawrence A Leiter16, Patricio Lopez-Jaramillo17, Valdis Pirags18, Nana Pogosova19, Peter J Raubenheimer20, Jonathan E Shaw21, Wayne H-H Sheu22, Theodora Temelkova-Kurktschiev23. 1. Endocrinology Institute, Gertner Institute, Sheba Medical Center, Ramat-Gan, Israel; Epidemiology Department, Sackler School of Medicine, Herceg Institute of Aging, Tel Aviv University, Tel Aviv, Israel. 2. Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada. Electronic address: gerstein@mcmaster.ca. 3. University of Edinburgh, Edinburgh, UK. 4. Estudios Clínicos Latino América, Rosario, Argentina. 5. Eli Lilly and Company, Indianapolis, IN, USA. 6. St John's Medical College, Bangalore, India. 7. Department of Medicine, University of Washington, Seattle, WA, USA. 8. Department of Medicine, Oregon Health and Science University Portland, OR, USA. 9. Department of Medicine K2, Karolinska Institutet, Stockholm, Sweden. 10. Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada. 11. Medical University of South Carolina, Charleston, SC, USA. 12. Memphis Veterans Affairs Medical Center, Memphis, TN, USA. 13. Mossakowski Medical Research Centre, Polish Academy of Sciences and Central Clinical Hospital, Warsaw, Poland. 14. Semmelweis University, Hungarian Institute of Cardiology, Budapest, Hungary. 15. Universidad de La Frontera, Temuco, Chile. 16. Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, ON, Canada. 17. Masira Research Institute, Medical School, Universidad de Santander, Bucaramanga, Colombia. 18. Latvijas Universitate, Riga, Latvia. 19. National Medical Research Center of Cardiology, Moscow, Russia. 20. Department of Medicine, University of Cape Town, Cape Town, South Africa. 21. Baker Heart and Diabetes Institute, Melbourne, VIC, Australia. 22. Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan. 23. Robert Koch Medical Center, Sofia, Bulgaria.
Abstract
BACKGROUND: Diabetes is an independent risk factor for cognitive impairment. We aimed to investigate the association between the glucagon-like peptide-1 (GLP-1) receptor agonist dulaglutide and cognitive impairment as an exploratory analysis within the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial. METHODS: REWIND is a randomised, double-blind placebo-controlled trial at 371 sites in 24 countries. We included men and women (aged ≥50 years) with either established or newly diagnosed type 2 diabetes and additional cardiovascular risk factors, glycated haemoglobin of up to 9·5% (80 mmol/mol) on a maximum of two oral glucose-lowering drugs with or without basal insulin, and a body-mass index of at least 23 kg/m2. Participants were randomly assigned (1:1) subcutaneous injections once a week of either dulaglutide (1·5 mg) or an equal volume of matching placebo. Randomisation was done using a computer-generated code with stratification by site. Participants and all study personnel were masked to treatment allocation until the database was locked. Participants were followed up at least every 6 months for the composite primary outcome of stroke, myocardial infarction, or death from cardiovascular or unknown causes. Cognitive function was assessed at baseline and during follow-up using the Montreal Cognitive Assessment (MoCA) and Digit Symbol Substitution Test (DSST). We present here the exploratory primary cognitive outcome, which was the first occurrence of a follow-up score on MoCA or DSST that was 1·5 SDs or more below the baseline mean score in the participant's country. All analyses were done using an intention-to-treat approach. The REWIND trial is registered with ClinicalTrials.gov, NCT01394952. FINDINGS:Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were randomly assigned to either dulaglutide (n=4949) or placebo (n=4952). During median follow-up of 5·4 (IQR 5·1-5·9) years, 8828 participants provided a baseline and one or more follow-up MoCA or DSST scores, of whom 4456 were assigned dulaglutide and 4372 were assignedplacebo. The cognitive outcome occurred in 4·05 per 100 patient-years in participants assigned dulaglutide and 4·35 per 100 patient-years in people assignedplacebo (hazard ratio [HR] 0·93, 95% CI 0·85-1·02; p=0·11). After post-hoc adjustment for individual standardised baseline scores, the hazard of substantive cognitive impairment was reduced by 14% in those assigned dulaglutide (HR 0·86, 95% CI 0·79-0·95; p=0·0018). INTERPRETATION: Long-term treatment with dulaglutide might reduce cognitive impairment in people with type 2 diabetes. Further studies of this drug focused on brain health and cognitive function are clearly indicated. FUNDING: Eli Lilly and Company.
RCT Entities:
BACKGROUND:Diabetes is an independent risk factor for cognitive impairment. We aimed to investigate the association between the glucagon-like peptide-1 (GLP-1) receptor agonist dulaglutide and cognitive impairment as an exploratory analysis within the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial. METHODS: REWIND is a randomised, double-blind placebo-controlled trial at 371 sites in 24 countries. We included men and women (aged ≥50 years) with either established or newly diagnosed type 2 diabetes and additional cardiovascular risk factors, glycated haemoglobin of up to 9·5% (80 mmol/mol) on a maximum of two oral glucose-lowering drugs with or without basal insulin, and a body-mass index of at least 23 kg/m2. Participants were randomly assigned (1:1) subcutaneous injections once a week of either dulaglutide (1·5 mg) or an equal volume of matching placebo. Randomisation was done using a computer-generated code with stratification by site. Participants and all study personnel were masked to treatment allocation until the database was locked. Participants were followed up at least every 6 months for the composite primary outcome of stroke, myocardial infarction, or death from cardiovascular or unknown causes. Cognitive function was assessed at baseline and during follow-up using the Montreal Cognitive Assessment (MoCA) and Digit Symbol Substitution Test (DSST). We present here the exploratory primary cognitive outcome, which was the first occurrence of a follow-up score on MoCA or DSST that was 1·5 SDs or more below the baseline mean score in the participant's country. All analyses were done using an intention-to-treat approach. The REWIND trial is registered with ClinicalTrials.gov, NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were randomly assigned to either dulaglutide (n=4949) or placebo (n=4952). During median follow-up of 5·4 (IQR 5·1-5·9) years, 8828 participants provided a baseline and one or more follow-up MoCA or DSST scores, of whom 4456 were assigned dulaglutide and 4372 were assigned placebo. The cognitive outcome occurred in 4·05 per 100 patient-years in participants assigned dulaglutide and 4·35 per 100 patient-years in people assigned placebo (hazard ratio [HR] 0·93, 95% CI 0·85-1·02; p=0·11). After post-hoc adjustment for individual standardised baseline scores, the hazard of substantive cognitive impairment was reduced by 14% in those assigned dulaglutide (HR 0·86, 95% CI 0·79-0·95; p=0·0018). INTERPRETATION: Long-term treatment with dulaglutide might reduce cognitive impairment in people with type 2 diabetes. Further studies of this drug focused on brain health and cognitive function are clearly indicated. FUNDING: Eli Lilly and Company.
Authors: Hertzel C Gerstein; Eric E Smith; Chinthanie Ramasundarahettige; Dipika Desai; Philip Awadalla; Philippe Broet; Sandra Black; Trevor J B Dummer; Jason Hicks; Alan Moody; Jean-Claude Tardif; Koon K Teo; Jennifer Vena; Salim Yusuf; Douglas S Lee; Matthias G Friedrich; Sonia S Anand Journal: J Clin Endocrinol Metab Date: 2021-01-23 Impact factor: 5.958
Authors: Clive Ballard; Dag Aarsland; Jeffrey Cummings; John O'Brien; Roger Mills; Jose Luis Molinuevo; Tormod Fladby; Gareth Williams; Pat Doherty; Anne Corbett; Janet Sultana Journal: Nat Rev Neurol Date: 2020-09-16 Impact factor: 42.937
Authors: Zhongqi Li; Xinyi Chen; Joaquim S L Vong; Lei Zhao; Junzhe Huang; Leo Y C Yan; Bonaventure Ip; Yun Kwok Wing; Hei-Ming Lai; Vincent C T Mok; Ho Ko Journal: Commun Biol Date: 2021-06-02