Advertisement

GLP-1 receptor agonists and SGLT2 inhibitors for older people with type 2 diabetes: A systematic review and meta-analysis

  • Thomas Karagiannis
    Correspondence
    Corresponding author at: Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Konstantinoupoleos 49, 54642 Thessaloniki, Greece.
    Affiliations
    Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
    Search for articles by this author
  • Apostolos Tsapas
    Affiliations
    Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Diabetes Centre, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Harris Manchester College, University of Oxford, Oxford, United Kingdom
    Search for articles by this author
  • Eleni Athanasiadou
    Affiliations
    Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
    Search for articles by this author
  • Ioannis Avgerinos
    Affiliations
    Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
    Search for articles by this author
  • Aris Liakos
    Affiliations
    Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
    Search for articles by this author
  • David R. Matthews
    Affiliations
    Harris Manchester College, University of Oxford, Oxford, United Kingdom

    Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, United Kingdom
    Search for articles by this author
  • Eleni Bekiari
    Affiliations
    Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Diabetes Centre, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
    Search for articles by this author

      Highlights

      • In patients ≥65 years, GLP-1 RAs reduced atherosclerotic oucomes.
      • In patients ≥65 years, SGLT2 inhibitors reduced heart failure and renal outcomes.
      • Some benefits were more pronounced in older patients compared to those <65 years.
      • Results for patients ≥75 years were based on limited data from primary studies.

      Abstract

      Aims

      To assess the cardiovascular effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose co-transporter-2 (SGLT2) inhibitors in older people with type 2 diabetes.

      Methods

      PubMed, Embase, and Cochrane library were searched up to November 2020 for cardiovascular outcomes trials with GLP-1 RAs or SGLT2 inhibitors that reported results for older patients with type 2 diabetes. Random-effects meta-analyses were conducted for different age subgroup categories.

      Results

      A total of 11 studies (93,502 patients) were included. Consistent with their effect in the overall population, in patients ≥65 years, GLP-1 RAs reduced major adverse cardiovascular events (MACE) (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.80–0.92), cardiovascular death, stroke, and myocardial infarction. In the same age subgroup, SGLT2 inhibitors reduced MACE (HR, 0.90; 95% CI, 0.83–0.98) but had a neutral effect on its components. They also reduced heart failure hospitalization (HR, 0.62; 95% CI, 0.51–0.76), an effect that was not evident in patients <65 years, and the composite renal endpoint (HR, 0.57; 95% CI, 0.43–0.77). Meta-analyses for patients ≥75 years yielded similar results.

      Conclusions

      In older adults with diabetes, GLP-1 RAs reduced MACE and its components. SGLT2 inhibitors reduced MACE, and heart failure and renal outcomes.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Diabetes Research and Clinical Practice
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

      1. International Diabetes Federation. IDF Diabetes Atlas 9th edition 2019. https://www.diabetesatlas.org/en/sections/demographic-and-geographic-outline.html (accessed November 27, 2020).

        • Munshi M.N.
        • Meneilly G.S.
        • Rodríguez-Mañas L.
        • Close K.L.
        • Conlin P.R.
        • Cukierman-Yaffe T.
        • et al.
        Diabetes in ageing: pathways for developing the evidence base for clinical guidance.
        Lancet Diabetes Endocrinol. 2020; 8: 855-867https://doi.org/10.1016/S2213-8587(20)30230-8
        • Sinclair A.J.
        • Abdelhafiz A.H.
        • Forbes A.
        • Munshi M.
        Evidence-based diabetes care for older people with Type 2 diabetes: a critical review.
        Diabet Med. 2019; 36: 399-413https://doi.org/10.1111/dme.13859
        • Cegelka A.
        Guidelines abstracted from the American Geriatrics Society guidelines for improving the care of older adults with diabetes mellitus: 2013 update.
        J Am Geriatr Soc. 2013; 61: 2020-2026https://doi.org/10.1111/jgs.12514
      2. Older adults Standards of medical care in diabetes- 2020.
        Diabetes Care. 2020; 43: S152-62https://doi.org/10.2337/dc20-S012
        • Seidu S.
        • Cos X.
        • Brunton S.
        • Harris S.B.
        • Jansson S.P.O.
        • Mata-Cases M.
        • et al.
        A disease state approach to the pharmacological management of Type 2 diabetes in primary care: a position statement by Primary Care Diabetes Europe.
        Prim Care Diabetes. 2020; https://doi.org/10.1016/j.pcd.2020.05.004
        • Sinclair A.J.
        • Heller S.R.
        • Pratley R.E.
        • Duan R.
        • Heine R.J.
        • Festa A.
        • et al.
        Evaluating glucose-lowering treatment in older people with diabetes: lessons from the IMPERIUM trial.
        Diabetes, Obes Metab. 2020; 22: 1231-1242https://doi.org/10.1111/dom.14013
      3. Cardiovascular disease and risk management: Standards of medical care in diabetes- 2020. Diabetes Care 2020;43:S111–34. https://doi.org/10.2337/dc20-S010.

        • Kristensen S.L.
        • Rørth R.
        • Jhund P.S.
        • Docherty K.F.
        • Sattar N.
        • Preiss D.
        • et al.
        Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.
        Lancet Diabetes Endocrinol. 2019; 7: 776-785https://doi.org/10.1016/S2213-8587(19)30249-9
        • Giugliano D.
        • Longo M.
        • Maiorino M.I.
        • Bellastella G.
        • Chiodini P.
        • Solerte S.B.
        • et al.
        Efficacy of SGLT-2 inhibitors in older adults with diabetes: systematic review with meta-analysis of cardiovascular outcome trials.
        Diabetes Res Clin Pract. 2020; 162https://doi.org/10.1016/j.diabres.2020.108114
        • Pinto L.C.
        • Rados D.V.
        • Remonti L.R.
        • Viana L.V.
        • Pulz G.T.
        • Carpena M.P.
        • et al.
        Patient-centered management of type 2 diabetes mellitus based on specific clinical scenarios: systematic review, meta-analysis and trial sequential analysis.
        J Clin Endocrinol Metab. 2020; 105: 3588-3599https://doi.org/10.1210/clinem/dgaa534
        • Cannon C.P.
        • Pratley R.
        • Dagogo-Jack S.
        • Mancuso J.
        • Huyck S.
        • Masiukiewicz U.
        • et al.
        Cardiovascular outcomes with ertugliflozin in type 2 diabetes.
        N Engl J Med. 2020; 383: 1425-1435https://doi.org/10.1056/NEJMoa2004967
        • Perkovic V.
        • Jardine M.J.
        • Neal B.
        • Bompoint S.
        • Heerspink H.J.L.
        • Charytan D.M.
        • et al.
        Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
        N Engl J Med. 2019; 380: 2295-2306https://doi.org/10.1056/NEJMoa1811744
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        • Altman D.
        • Antes G.
        • et al.
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        Ann Intern Med. 2009; 151: 264-269https://doi.org/10.7326/0003-4819-151-4-200908180-00135
        • Sterne J.A.C.
        • Savović J.
        • Page M.J.
        • Elbers R.G.
        • Blencowe N.S.
        • Boutron I.
        • et al.
        RoB 2: a revised tool for assessing risk of bias in randomised trials.
        BMJ. 2019; 366https://doi.org/10.1136/bmj.l4898
        • Richardson M.
        • Garner P.
        • Donegan S.
        Interpretation of subgroup analyses in systematic reviews: a tutorial.
        Clin Epidemiol Glob Heal. 2019; 7: 192-198https://doi.org/10.1016/j.cegh.2018.05.005
        • Zinman B.
        • Wanner C.
        • Lachin J.M.
        • Fitchett D.
        • Bluhmki E.
        • Hantel S.
        • et al.
        Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
        N Engl J Med. 2015; 373: 2117-2128https://doi.org/10.1056/NEJMoa1504720
        • Pfeffer M.A.
        • Claggett B.
        • Diaz R.
        • Dickstein K.
        • Gerstein H.C.
        • Køber L.V.
        • et al.
        Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
        N Engl J Med. 2015; 373: 2247-2257https://doi.org/10.1056/NEJMoa1509225
        • Holman R.R.
        • Bethel M.A.
        • Mentz R.J.
        • Thompson V.P.
        • Lokhnygina Y.
        • Buse J.B.
        • et al.
        Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2017; 377: 1228-1239https://doi.org/10.1056/NEJMoa1612917
        • Marso S.P.
        • Daniels G.H.
        • Frandsen K.B.
        • Kristensen P.
        • Mann J.F.E.
        • Nauck M.A.
        • et al.
        Liraglutide and cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2016; 375: 311-322https://doi.org/10.1056/NEJMoa1603827
        • Husain M.
        • Birkenfeld A.L.
        • Donsmark M.
        • Dungan K.
        • Eliaschewitz F.G.
        • Franco D.R.
        • et al.
        Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
        N Engl J Med. 2019; 381: 841-851https://doi.org/10.1056/NEJMoa1901118
        • Gerstein H.C.
        • Colhoun H.M.
        • Dagenais G.R.
        • Diaz R.
        • Lakshmanan M.
        • Pais P.
        • et al.
        Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
        Lancet. 2019; 394: 121-130https://doi.org/10.1016/S0140-6736(19)31149-3
        • Marso S.P.
        • Bain S.C.
        • Consoli A.
        • Eliaschewitz F.G.
        • Jodar E.
        • Leiter L.A.
        • et al.
        Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
        N Engl J Med. 2016; 375: 1834-1844https://doi.org/10.1056/NEJMoa1607141
        • Neal B.
        • Perkovic V.
        • Mahaffey K.W.
        • De Zeeuw D.
        • Fulcher G.
        • Erondu N.
        • et al.
        Canagliflozin and cardiovascular and renal events in type 2 diabetes.
        N Engl J Med. 2017; 377: 644-657https://doi.org/10.1056/NEJMoa1611925
        • Wiviott S.D.
        • Raz I.
        • Bonaca M.P.
        • Mosenzon O.
        • Kato E.T.
        • Cahn A.
        • et al.
        Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2019; 380: 347-357https://doi.org/10.1056/NEJMoa1812389
        • Gilbert M.P.
        • Bain S.C.
        • Franek Edward
        • Jodar-Gimeno Esteban
        • Nauck M.A.
        • Pratley Richard
        • et al.
        Effect of liraglutide on cardiovascular outcomes in elderly patients: a post hoc analysis of a randomized controlled trial.
        Ann Intern Med. 2019; 170: 423-426https://doi.org/10.7326/M18-1569
        • Gerstein H.C.
        • Colhoun H.M.
        • Dagenais G.R.
        • Diaz R.
        • Lakshmanan M.
        • Pais P.
        • et al.
        Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial.
        Lancet. 2019; 394: 131-138https://doi.org/10.1016/S0140-6736(19)31150-X
        • Gerstein H.C.
        • Hart R.
        • Colhoun H.M.
        • Diaz R.
        • Lakshmanan M.
        • Botros F.T.
        • et al.
        The effect of dulaglutide on stroke: an exploratory analysis of the REWIND trial.
        Lancet Diabetes Endocrinol. 2020; 8: 106-114https://doi.org/10.1016/S2213-8587(19)30423-1
        • Leiter L.A.
        • Bain S.C.
        • Hramiak I.
        • Jódar E.
        • Madsbad S.
        • Gondolf T.
        • et al.
        Cardiovascular risk reduction with once-weekly semaglutide in subjects with type 2 diabetes: a post hoc analysis of gender, age, and baseline CV risk profile in the SUSTAIN 6 trial.
        Cardiovasc Diabetol. 2019; 18https://doi.org/10.1186/s12933-019-0871-8
        • Perkovic V.
        • de Zeeuw D.
        • Mahaffey K.W.
        • Fulcher G.
        • Erondu N.
        • Shaw W.
        • et al.
        Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials.
        Lancet Diabetes Endocrinol. 2018; 6: 691-704https://doi.org/10.1016/S2213-8587(18)30141-4
        • Rådholm K.
        • Figtree G.
        • Perkovic V.
        • Solomon S.D.
        • Mahaffey K.W.
        • De Zeeuw D.
        • et al.
        Canagliflozin and heart failure in type 2 diabetes mellitus: results from the CANVAS program.
        Circulation. 2018; 138: 458-468https://doi.org/10.1161/CIRCULATIONAHA.118.034222
        • Zhou Z.
        • Lindley R.I.
        • Rådholm K.
        • Jenkins B.
        • Watson J.
        • Perkovic V.
        • et al.
        Canagliflozin and stroke in type 2 diabetes mellitus: results from the randomized CANVAS Program Trials.
        Stroke. 2019; 50: 396-404https://doi.org/10.1161/STROKEAHA.118.023009
        • Cahn A.
        • Mosenzon O.
        • Wiviott S.D.
        • Rozenberg A.
        • Yanuv I.
        • Goodrich E.L.
        • et al.
        Efficacy and safety of dapagliflozin in the elderly: analysis from the DECLARE-TIMI 58 study.
        Diabetes Care. 2020; 43: 468-475https://doi.org/10.2337/dc19-1476
        • Zinman B.
        • Inzucchi S.E.
        • Lachin J.M.
        • Wanner C.
        • Fitchett D.
        • Kohler S.
        • et al.
        Empagliflozin and cerebrovascular events in patients with type 2 diabetes mellitus at high cardiovascular risk.
        Stroke. 2017; 48: 1218-1225https://doi.org/10.1161/STROKEAHA.116.015756
        • Monteiro P.
        • Bergenstal R.M.
        • Toural E.
        • Inzucchi S.E.
        • Zinman B.
        • Hantel S.
        • et al.
        Efficacy and safety of empagliflozin in older patients in the EMPA-REG OUTCOME® trial.
        Age Ageing. 2019; 48: 859-866https://doi.org/10.1093/ageing/afz096
      4. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al., eds. Cochrane Handbook for Systematic Reviews of Interventions version 6.1 (updated September 2020). Cochrane, 2020. Available from www.training.cochrane.org/handbook n.d.

        • Hernandez A.F.
        • Green J.B.
        • Janmohamed S.
        • D’Agostino R.B.
        • Granger C.B.
        • Jones N.P.
        • 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: 1519-1529https://doi.org/10.1016/S0140-6736(18)32261-X
      5. European Medicines Agency. Adequacy of guidance on the elderly regarding medicinal products for human use 2006. https://www.ema.europa.eu/en/documents/scientific-guideline/adequacy-guidance-elderly-regarding-medicinal-products-human-use_en.pdf (accessed November 27, 2020).

      6. U.S. Food and Drug Administration. E7 Studies in Support of Special Populations; Geriatrics; Questions and Answers 2012. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e7-studies-support-special-populations-geriatrics-questions-and-answers (accessed November 27, 2020).

      7. American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2021. Diabetes Care 2021;44:S111–24. https://doi.org/10.2337/dc21-S009.

      8. Buse JB, Wexler DJ, Tsapas A, Rossing P, Mingrone G, Mathieu C, et al. 2019 update to: management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2020;43:487–93. https://doi.org/10.2337/dci19-0066.

        • Heerspink H.J.L.
        • Stefánsson B.V.
        • Correa-Rotter R.
        • Chertow G.M.
        • Greene T.
        • Hou F.-F.
        • et al.
        Dapagliflozin in patients with chronic kidney disease.
        N Engl J Med. 2020; 383: 1436-1446https://doi.org/10.1056/NEJMoa2024816
        • Packer M.
        • Anker S.D.
        • Butler J.
        • Filippatos G.
        • Pocock S.J.
        • Carson P.
        • et al.
        Cardiovascular and renal outcomes with empagliflozin in heart failure.
        N Engl J Med. 2020; 383: 1413-1424https://doi.org/10.1056/nejmoa2022190
        • McMurray J.J.V.
        • Solomon S.D.
        • Inzucchi S.E.
        • Kober L.
        • Kosiborod M.N.
        • Martinez F.A.
        • et al.
        Dapagliflozin in patients with heart failure and reduced ejection fraction.
        N Engl J Med. 2019; 381: 1995-2008https://doi.org/10.1056/NEJMoa1911303
        • James S.
        • Rao S.V.
        • Granger C.B.
        Registry-based randomized clinical trials - a new clinical trial paradigm.
        Nat Rev Cardiol. 2015; 12: 312-316https://doi.org/10.1038/nrcardio.2015.33