Review| Volume 169, 108438, November 2020

Download started.


New hypoglycaemic therapy in frail older people with diabetes mellitus-phenotypic status likely to be more important than functional status

Published:September 10, 2020DOI:


      Frail older people are largely excluded from clinical trials and therefore glycaemic targets and optimum hypoglycaemic therapy in this group has not been fully investigated. Guidelines generally recommend tight glycaemic control in functionally fit individuals and relaxed targets in frail ones mainly due to the fear of hypoglycaemia. The newly introduced sodium glucose cotransporter-2 inhibitors and the glucagon like peptide-1 receptor agonists have shown benefit that is independent of glycaemic control and a minimal risk of hypoglycaemia. However, guidelines still express caution about its use in frail older people due to fear of other side effects such as weight loss, hypotension and falls. Some frail older people will miss out on the benefits of this new therapy if frailty is considered as a one entity with a blanket application of guidelines. We propose that frailty should be viewed as two distinct metabolically different phenotypes, the sarcopenic-obese, in which new therapy will improve their metabolic profile and should be liberally used if no contraindications, and the anorexic-malnourished phenotype in which the new therapy should be cautiously considered. In other words, glycaemic targets should be driven by individual’s overall function but the use of new therapy should be driven by frailty phenotype.


      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 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


        • Cho N.H.
        • Shaw J.E.
        • Karuranga S.
        • et al.
        IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045.
        Diabetes Res Clin Pract. 2018; 138: 271-281
      1. Sinclair A, Saeedi P, Kaundal, et al. Diabetes and global ageing among 65-99-year-old adults: findings from the International Diabetes Federation Diabetes Atlas, 9(th) edition. Diabetes Res Clin Pract 2020;162: 108078. doi: 10.1016/j.diabres.2020.108078.

        • Chhetri J.K.
        • Zheng Z.
        • Xu X.
        • et al.
        The prevalence and incidence of frailty in pre-diabetic and diabetic community dwelling older population: results from Beijing longitudinal study of aging II (BLSA-II).
        BMC Geriatrics. 2017; 17: 47
        • Howrey B.T.
        • Al Snih S.
        • Markides K.S.
        Frailty and diabetes among Mexican American older adults.
        Ann Epidemiol. 2018; 28: 421-426
        • Castrejon-Perez R.C.
        • Aguilar-Salinas C.A.
        • Gutierrez-Robledo L.M.
        • et al.
        Frailty, diabetes, and the convergence of chronic disease in an age-related condition: a population-based nationwide cross-sectional analysis of the Mexican nutrition and health survey.
        Aging Clin Exp Res. 2018; 30: 935-941
        • Fried L.P.
        • Tangen C.M.
        • Walston J.
        • et al.
        Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: evidence for a phenotype.
        J Gerontol A Biol Sci Med Sci. 2001; 56: M146-M156
        • Dunning T.
        • Sinclair A.
        • Colagiuri S.
        New IDF Guideline for managing type 2 diabetes in older people.
        Diabetes Res Clin Pract. 2014; 103: 538-540
        • Sinclair A.J.
        • Paolisso G.
        • Castro M.
        • et al.
        European Diabetes Working Party for Older People. European Diabetes Working Party for Older People 2011 clinical guidelines for type 2 diabetes mellitus. Executive summary.
        Diabetes Metab. 2011; 37: S27-S38
      2. American Diabetes Association. 12. Older adults: Standards of Medical Care in Diabetes—2020. Diabetes Care 2018;43: S152-S62.

        • Strain W.D.
        • Hope S.
        • Green A.
        • et al.
        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.
        Diabetic Med. 2018; 35: 838-845
      3. Sinclair A, Morley JE, Rodriguez-Ma~nas L, et al. Diabetes mellitus in older people: position statement on behalf of the International Association of Gerontology and Geriatrics (IAGG), the European Diabetes Working Party for Older People (EDWPOP), and the International Task Force of Experts. Diabetes 2012;13: 497–502.

      4. Kirkman SM, Briscoe VJ, Clark N, et al. Consensus Development Conference on Diabetes and Older Adults. Diabetes in older adults: a consensus report. J Am Geriatr Soc 2012;60: 2242–56.

      5. Canada Diabetes Clinical Practice Guidelines Expert Committee, Meneilly GS, Knip A, Miller DB, et al. Diabetes in older people. Can J Diabetes 2018;42: S283–S295.

        • Sinclair A.J.
        • Abdelhafiz A.
        • Dunning T.
        • et al.
        An international position statement on the management of frailty in diabetes mellitus: summary of recommendations 2017.
        J Frailty Aging. 2018; 7: 10-20
        • Aronoff S.L.
        • Berkowitz K.
        • Shreiner B.
        • et al.
        Glucose metabolism and regulation: beyond insulin and glucagon.
        Diabetes Spectrum. 2004; 17: 183-190
        • Evans W.J.
        Skeletal muscle loss: cachexia, sarcopenia, and inactivity.
        Am J Clin Nutr. 2010; 91: 1123S-1127S
        • Hughes V.A.
        • Frontera W.R.
        • Roubenoff R.
        • et al.
        Longitudinal changes in body composition in older men and women: role of body weight change and physical activity.
        Am J Clin Nutr. 2002; 76: 473-481
        • Szoke E.
        • Shrayyef M.Z.
        • Messing S.
        • et al.
        Effect of aging on glucose homeostasis: accelerated deterioration of β-cell function in individuals with impaired glucose tolerance.
        Diabetes Care. 2008; 31: 539-543
        • Kim W.
        • Egan J.M.
        The role of incretins in glucose homeostasis and diabetes treatment.
        Pharm Rev. 2008; 60: 470-512
        • Farilla L.
        • Bulotta A.
        • Hirshberg B.
        • et al.
        Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets.
        Endocrinology. 2003; 144: 5149-5158
        • Chia C.W.
        • Egan J.M.
        • Ferrucci L.
        Age-related changes in glucose metabolism, hyperglycemia, and cardiovascular risk.
        Circ Res. 2018; 123: 886-904
        • Bergman H.
        • Ferrucci L.
        • Guralnik J.
        • et al.
        Frailty: an emerging research and clinical paradigm-issues and controversies.
        J Gerontol A Biol Sci Med Sci. 2009; 62A: 731-737
      6. Walston J, Hadley EC, Ferrucci L, et al. Research agenda for frailty in older adults: toward a better understanding of physiology and etiology: summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults. J Am Geriatr Soc 2006;54: 991–1001.

        • Castrejón-Pérez R.C.
        • Gutiérrez-Robledo L.M.
        • Cesari M.
        • Pérez-Zepeda M.U.
        Diabetes mellitus, hypertension and frailty: A population-based, cross-sectional study of Mexican older adults.
        Geriatr Gerontol Int. 2016;
        • Lee S.
        • Lee S.
        • Harada K.
        • et al.
        Relationship between chronic kidney disease with diabetes or hypertension and frailty in community-dwelling Japanese older adults.
        Geriatr Gerontol Int. 2016;
        • Fried L.P.
        • Tangen C.M.
        • Walston J.
        • et al.
        Frailty in older adults: evidence for a phenotype.
        J Gerontol A Biol Sci Med Sci. 2001; 56A: M146-M156
        • Rockwood K.
        • Mitnitski A.
        Frailty in relation to the accumulation of deficits.
        J Gerontol A Biol Sci Med Sci. 2007; 62: 722-727
        • Kovesdy C.P.
        • Park J.C.
        • Kalantar-Zadeh K.
        Glycemic control and burnt-out diabetes in ESRD.
        Semin Dial. 2010; 23: 148-156
        • Sjoblom P.
        • Tengblad A.
        • Lofgren U.B.
        • et al.
        Can diabetes medication be reduced in elderly patients? An observational study of diabetes drug withdrawal in nursing home patients with tight glycaemic control.
        Dib Res Clin Pract. 2008; 82: 197-202
        • Abdelhafiz A.H.
        • Chakravorty P.
        • Gupta S.
        • et al.
        Can hypoglycaemic medications be withdrawn in older people with type 2 diabetes?.
        Int J Clin Pract. 2014; 68: 790-792
        • Abdelhafiz A.H.
        • Sinclair A.
        Low HbA1c and increased mortality risk-is frailty a confounding factor?.
        Aging Dis. 2014; 6
        • Kalyani R.R.
        • Varadhan R.
        • Weiss C.O.
        • et al.
        Frailty status and altered glucose-insulin dynamics.
        J Gerontol A Biol Sci Med Sci. 2012; 67: 1300-1306
        • Goulet E.D.
        • Hassaine A.
        • Dionne I.J.
        • et al.
        Frailty in the elderly is associated with insulin resistance of glucose metabolism in the postabsorptive state only in the presence of increased abdominal fat.
        Exp Gerontol. 2009; 44: 740-744
        • Baumgartner R.N.
        Body composition in healthy aging.
        Ann N Y Acad Sci. 2000; 904: 437-448
        • Batsis J.A.
        • Mackenzie T.A.
        • Lopez-Jimenez F.
        • et al.
        Sarcopenia, sarcopenic obesity, and functional impairments in older adults: national health and nutrition examination surveys 1999–2004.
        Nutr Res. 2015; 35: 1031-1039
        • Buchner D.M.
        • Larson E.B.
        • Wagner E.H.
        • et al.
        Evidence for a non-linear relationship between leg strength and gait speed.
        Age Ageing. 1996; 25: 386-391
        • Baumgartner R.N.
        • Wayne S.J.
        • Waters D.L.
        • et al.
        Sarcopenic obesity predicts instrumental activities of daily living disability in the elderly.
        Obes Res. 2004; 12: 1995-2004
        • Hirani V.
        • Naganathan V.
        • Blyth F.
        • et al.
        Longitudinal associations between body composition, sarcopenic obesity and outcomes of frailty, disability, institutionalisation and mortality in community-dwelling older men: the concord health and ageing in men project.
        Age Ageing. 2017; 46: 413-420
        • Kim T.N.
        • Park M.S.
        • Ryu J.Y.
        • et al.
        Impact of visceral fat on skeletal muscle mass and vice versa in a prospective cohort study: the Korean sarcopenic obesity study (KSOS).
        PLoS ONE. 2014; 9e115407
        • Srikanthan P.
        • Hevener A.L.
        • Karlamangla A.S.
        Sarcopenia exacerbates obesity-associated insulin resistance and dysglycemia: findings from the National health and nutrition examination survey III.
        PLoS ONE. 2010; 5e10805
        • Chung J.-Y.
        • Kang H.-T.
        • Lee D.-C.
        • et al.
        Body composition and its association with cardiometabolic risk factors in the elderly: a focus on sarcopenic obesity.
        Arch Gerontol Geriatr. 2013; 56: 270-278
        • Lim H.-S.
        • Park Y.-H.
        • Suh K.
        • et al.
        Association between sarcopenia, sarcopenic obesity, and chronic disease in Korean elderly.
        J Bone Metab. 2018; 25: 187-193
        • Baek S.
        • Nam G.
        • Han K.
        • et al.
        Sarcopenia and sarcopenic obesity and their association with dyslipidemia in Korean elderly men: the 2008–2010 Korea National health and nutrition examination survey.
        J Endocrinol Invest. 2014; 37: 247-260
        • Zinman B.
        • Wanner C.
        • Lachin J.M.
        • et al.
        EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
        N Engl J Med. 2015; 373: 2117-2128
        • Wanner C.
        • Inzucchi S.E.
        • Lachin J.M.
        • et al.
        EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes.
        N Engl J Med. 2016; 375: 323-334
        • Neal B.
        • Perkovic V.
        • Mahaffey K.W.
        • et al.
        Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes.
        N Engl J Med. 2017; 377: 644-657
        • Perkovic V.
        • Zeeuw D.
        • Mahaffey K.W.
        • et al.
        Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials.
        Lancet Diabetes Endocrinol. 2018; 6: 691-704
        • 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: 2295-2306
        • Wiviott S.D.
        • Raz I.
        • Bonaca M.P.
        • et al.
        Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2019; 380: 347-357
        • Marso S.P.
        • Daniels G.H.
        • Brown-Frandsen K.
        • 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: 311-322
        • Mann J.F.E.
        • Orsted D.D.
        • Brown-Frandsen K.
        • et al.
        Liraglutide and renal outcomes in type 2 diabetes.
        N Engl J Med. 2017; 377: 839-848
        • Marso S.P.
        • Bain S.C.
        • Consoli A.
        • et al.
        Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
        N Engl J Med. 2016; 375: 1834-1844
        • Husain M.
        • Birkenfeld A.L.
        • Donsmark M.
        • et al.
        Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.
        N Engl J Med. 2019; 381: 841-851
        • Gerstein H.C.
        • Colhoun H.M.
        • Dagenais G.R.
        • et al.
        Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
        Lancet. 2019; 394: 121-130
        • Hernandez A.F.
        • Green J.B.
        • 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: 1519-1529
        • Pfeffer M.A.
        • Claggett B.
        • Diaz R.
        • Dickstein K.
        • Gerstein H.C.
        • Køber L.V.
        • et al.
        ELIXA Investigators. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
        N Engl J Med. 2015; 373: 2247-2257
        • Holman R.R.
        • Bethel M.A.
        • Mentz R.J.
        • et al.
        EXSCEL Study Group. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2017; 377: 1228-1239
        • Tuttle K.R.
        • Lakshmanan M.C.
        • Rayner B.
        • et al.
        Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial.
        Lancet Diabetes Endocrinol. 2018; 6: 605-617
        • Heuvelman V.D.
        • Van Raalte D.H.
        • Smits M.M.
        Cardiovascular effects of glucagon-like peptide 1 receptor agonists: from mechanistic studies in humans to clinical outcomes.
        Cardiovasc Res. 2020; 116: 916-930
        • Monteiro P.
        • Bergenstal R.M.
        • Toural E.
        • et al.
        Efficacy and safety of empagliflozin in older patients in the EMPA-REG OUTCOME trial.
        Age Ageing. 2019; 48: 859-866
        • Cahn A.
        • Mosenzon O.
        • Wiviott S.D.
        • et al.
        Efficacy and safety of dapagliflozin in the elderly: analysis from the DECLARE-TIMI 58 Study.
        Diabetes Care. 2020; 43: 468-475
        • Giugliano D.
        • Longo M.
        • Ida Maiorino M.
        • 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; 108114
        • Gilbert M.P.
        • Bain S.C.
        • Franek E.
        • et al.
        on behalf of the LEADER Trial Investigators. Effect of liraglutide on cardiovascular outcomes in elderly patients: a post hoc analysis of a randomized controlled trial.
        Ann Intern Med. 2019; 170: 423-426
        • Leiter L.A.
        • Bain S.C.
        • Hramiak I.
        • 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; 18: 73
        • Abdelhafiz A.H.
        • Rodrigues-Manas L.
        • Morley J.
        • et al.
        Hypoglycemia in older people - a less well recognized risk factor for frailty.
        Aging Dis. 2015; 6: 156-167
        • Abdelhafiz A.H.
        • Sinclair A.J.
        Cognitive frailty in older people with type 2 diabetes mellitus: the central role of hypoglycaemia and the need for prevention.
        Curr Diab Res. 2019; 19: 15
        • Sinclair A.
        • Dunning T.
        • Rodriguez-Manas L.
        Diabetes in older people: new insights and remaining challenges.
        Lancet Diabetes Endocrinol. 2015; 3: 275-285
        • Sun F.
        • Wu S.
        • Wang J.
        • et al.
        Effect of glucagon-like peptide-1 receptor agonists on lipid profiles among type 2 diabetes: a systematic review and network meta-analysis.
        Clin Ther. 2015; 37 (225-41.e8)
        • Katout M.
        • Zhu H.
        • Rutsky J.
        • et al.
        Effect of GLP-1 mimetics on blood pressure and relationship to weight loss and glycemia lowering: results of a systematic meta-analysis and meta-regression.
        Am J Hypertens. 2014; 27: 130-139
        • Carbone L.J.
        • Angus P.W.
        • Yeomans N.D.
        Incretin-based therapies for the treatment of non-alcoholic fatty liver disease: a systematic review and meta-analysis.
        J Gastroenterol Hepatol. 2016; 31: 23-31
      7. Onoviran OF, Li D, Smith ST, et al. Effects of glucagon-like peptide 1 receptor agonists on comorbidities in older patients with diabetes mellitus. Ther Adv Chronic Dis 2019;10: 2040622319862691.

        • Sasaki T.
        • Sugawara M.
        • Fukuda M.
        Sodium-glucose cotransporter 2 inhibitor-induced changes in body composition and simultaneous changes in metabolic profile: 52-week prospective LIGHT (Luseogliflozin: the Components of Weight Loss in Japanese Patients with Type 2 Diabetes Mellitus) Study.
        J Diabetes Investig. 2019; 10: 108-117
        • Cefalu W.T.
        • Leiter L.A.
        • Yoon K.H.
        • et al.
        Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial.
        Lancet. 2013; 382: 941-950
      8. Davies MJ, D'Alessio DA, Fradkin J, et al. 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 2018;41:2669–701.

        • Sinclair A.J.
        • Heller S.R.
        • Pratley R.E.
        • et al.
        Evaluating glucose-lowering treatment in older people with diabetes: lessons from the IMPERIUM trial.
        J. Diabetes Obes Metab. 2020;