A systematic review and meta-analysis of the impact of GLP-1 receptor agonists and SGLT-2 inhibitors on cardiovascular outcomes in biologically healthy older adults
DOI:
https://doi.org/10.15277/bjd.2021.292Keywords:
type 2 diabetes, older adults, major adverse cardiovascular events, cardiovascular outcome trials, GLP-1 receptor agonists, SGLT-2 inhibitorsAbstract
Background: Unintentional weight loss is a hallmark of frailty and is associated with poor outcomes in older adults with type 2 diabetes. As such, the role of pharmacological therapies that facilitate weight loss – namely, sodium- glucose co-transporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists – remains uncertain in fitter older adults. We performed a systematic review and meta-analysis to evaluate these agents on major adverse cardiovascular events (MACE) in older adults eligible for participation in cardiovascular outcome trials.
Methods: A literature search was performed in MEDLINE, EMBASE, CINAHL, Cochrane Central Registry of Controlled Trials (CENTRAL) and CNKI from inception to 29 June 2020. A class-specific meta-analysis was conducted in older adults (>65 years at recruitment) and compared with the similar analysis in younger (<65 years) adults.
Results: Of 761 unique studies identified, nine met the criteria for inclusion, five using GLP-1 receptor agonists and four with SGLT-2 inhibitors. GLP-1 receptor agonists in older adults were associated with a 15.3% (OR 0.847 (95% CI 0.788 to 0.910)) reduction in MACE events, similar to the 16% benefit seen in younger adults. The use of SGLT-2 inhibitors reduced MACE in older participants by 16.9% (OR 0.831 (95% CI 0.699 to 0.989)), numerically superior to the impact in younger patients (OR 0.936 (95% CI 0.787 to 1.113).
Conclusions: GLP-1 receptor agonists and SGLT-2 inhibitors reduced MACE outcomes in older adults who were eligible to participate in clinical trials. Whereas this is reassuring for the biologically robust, it should not be extrapolated to frail older adults without further investigation.
References
Forouhi NG, Wareham NJ. Epidemiology of diabetes. Medicine (Abingdon) 2014;42(12):698–702. https://doi.org/10.1016/j.mpmed.2014.09.007
Sinclair AJ, Gadsby R, Penfold S, Croxson SC, Bayer AJ. Prevalence of diabetes in care home residents. Diabetes Care 2001;24:1066–8. https://doi.org/10.2337/diacare.24.6.1066
Strain WD, Hope SV, Green A, Kar P, Valabhji J, Sinclair AJ. Type 2 diabetes mellitus in older people: a brief statement of key principles of modern day management including the assessment of frailty. A national collaborative stakeholder initiative. Diabet Med 2018;35(7):838–45. https://doi.org/10.1111/dme.13644
Grieve DJ, Cassidy RS, Green BD. Emerging cardiovascular actions of the incretin hormone glucagon-like peptide-1: potential therapeutic benefits beyond glycaemic control? Br J Pharmacol 2009;157(8):1340–51. https://doi.org/10.1111/j.1476-5381.2009.00376.x
Mehta A, Marso SP, Neeland IJ. Liraglutide for weight management: a critical review of the evidence. Obes Sci Pract 2017;3(1):3–14. https://doi.org/10.1002/osp4.84
Chao EC, Henry RR. SGLT2 inhibition--a novel strategy for diabetes treatment. Nat Rev Drug Discov 2010;9(7):551–9. https://doi.org/10.1038/nrd3180
Garg V, Verma S, Connelly K. Mechanistic insights regarding the role of SGLT2 inhibitors and GLP1 agonist drugs on cardiovascular disease in diabetes. Prog Cardiovasc Dis 2019;62(4):349–57. https://doi.org/10.1016/ j.pcad.2019.07.005
Shamseer L, Moher D, Clarke M, et al. Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015: elaboration and explanation. BMJ 2015;350:g7647. https://doi.org/10.1136/bmj.g7647. Correction. BMJ 2016;354:i4086. https://doi.org/10.1136/bmj.i4086
Strain WD, Griffiths J. The impact of SGLT-2 inhibitors and GLP-1 analogues on cardiovascular outcomes in non-frail older adults. PROSPERO 2020; CRD42020200601. Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020200601
Moseley AM, Rahman P, Wells GA, et al. Agreement between the Cochrane risk of bias tool and Physiotherapy Evidence Database (PEDro) scale: a meta-epidemiological study of randomized controlled trials of physical therapy interventions. PLoS One 2019;14(9):e0222770. https://doi.org/10.1371/journal.pone.0222770
Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373(23):2247–57. https://doi.org/10.1056/NEJMoa1509225
Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017; 377(13):1228–39. https://doi.org/10.1056/NEJMoa1612917
Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375(4):311–22. https://doi.org/10.1056/NEJMoa1603827
Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet 2018;392(10157):1519–29. https://doi.org/10.1016/S0140-6736(18)32261-X
Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019;394(10193):121–30. https://doi.org/10.1016/S0140-6736(19)31149-3
Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375(19):1834–44. https://doi.org/10.1056/NEJMoa1607141
Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377(7):644–57. https://doi.org/10.1056/NEJMoa1611925
Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373(22):2117–28. https://doi.org/10.1056/NEJMoa1504720
Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380(4):347–57. https://doi.org/10.1056/NEJMoa1812389
Mahaffey KW, Jardine MJ, Bompoint S, et al. Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes mellitus and chronic kidney disease in primary and secondary cardiovascular prevention groups. Circulation 2019;140(9):739–50. https://doi.org/10.1161/CIRCULATIONAHA.119.042007
Kamel HK, Iqbal MA. Body mass index and mortality among hospitalized elderly patients. Arch Intern Med 2001;161(11):1459–60. https://doi.org/10.1001/archinte.161.11.1459
Lang PO, Michel JP, Zekry D. Frailty syndrome: a transitional state in a dynamic process. Gerontology 2009;55(5):539–49. https://doi.org/10.1159/000211949
Cruz-Jentoft AJ, Carpena-Ruiz M, Montero-Errasquin B, Sanchez-Castellano C, Sanchez-Garcia E. Exclusion of older adults from ongoing clinical trials about type 2 diabetes mellitus. J Am Geriatr Soc 2013;61(5):734–8. https://doi.org/10.1111/jgs.12215
Sinclair AJ, Abdelhafiz AH, Forbes A, Munshi M. Evidence-based diabetes care for older people with type 2 diabetes: a critical review. Diabet Med 2019;36(4):399–413. https://doi.org/10.1111/dme.13859
Bruce DG, Davis WA, Davis TME. Glycaemic control and mortality in older people with type 2 diabetes: The Fremantle Diabetes Study Phase II. Diabetes Obes Metab 2018;20(12):2852–9. https://doi.org/10.1111/dom.13469
Forbes A, Murrells T, Mulnier H, Sinclair AJ. Mean HbA1c, HbA1c variability, and mortality in people with diabetes aged 70 years and older: a retrospective cohort study. Lancet Diabetes Endocrinol 2018;6(6):476–86. https://doi.org/10.1016/S2213-8587(18)30048-2
Strain WD, Lukashevich V, Kothny W, Hoellinger MJ, Paldanius PM. Individualised treatment targets for elderly patients with type 2 diabetes using vildagliptin add-on or lone therapy (INTERVAL): a 24 week, randomised, double-blind, placebo-controlled study. Lancet 2013;382(9890):409–16. https://doi.org/10.1016/S0140-6736(13)60995-2
MacDonald MR, Petrie MC, Varyani F, et al. Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur Heart J 2008;29(11):1377–85. https://doi.org/10.1093/eurheartj/ehn153
Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360(2):129–39. https://doi.org/10.1056/NEJMoa0808431
Published
Issue
Section
License
Publish & Transfer of Copyright Agreement
For the mutual benefit and protection of the Author and the Journal Owner/Publisher it is necessary that the Author provides formal written Consent to Publish and Transfer of Copyright before publication of the Work.
