Hypoglycemia in Older People - A Less Well Recognized Risk Factor for Frailty
Abdelhafiz Ahmed H1, Rodríguez-Mañas Leocadio2, Morley John E.3, Sinclair Alan J4,*()
1Department of Elderly Medicine, Rotherham General Hospital, England, Moorgate Road, Rotherham, UK 2Hospital Universitario de Getafe, Department of Geriatrics and School of Health Sciences, Universidad Europea de Madrid, Spain 3Divisions of Geriatric Medicine and Endocrinology, Saint Louis University School of Medicine, St. Louis, USA 4Institute of Diabetes for Older People (IDOP), University of Bedfordshire, Luton LU2 8LE, UK
Recurrent hypoglycemia is common in older people with diabetes and is likely to be less recognized and under reported by patients and health care professionals. Hypoglycemia in this age group is associated with significant morbidities leading to both physical and cognitive dysfunction. Repeated hospital admissions due to frequent hypoglycemia are also associated with further deterioration in patients’ general health. This negative impact of hypoglycemia is likely to eventually lead to frailty, disability and poor outcomes. It appears that the relationship between hypoglycemia and frailty is bidirectional and mediated through a series of influences including under nutrition. Therefore, attention should be paid to the management of under nutrition in the general elderly population by improving energy intake and maintaining muscle mass. Increasing physical activity and having a more conservative approach to glycemic targets in frail older people with diabetes may be worthwhile.
Hypoglycemic episode needing assistance of a third party.
2) Documented symptomatic hypoglycemia:
Symptomatic hypoglycemia and plasma glucose level ≤3.9 mmol/l.
3) Probable symptomatic hypoglycemia:
Symptomatic hypoglycemia but not documented a plasma glucose level.
4) Asymptomatic hypoglycemia:
No symptoms of hypoglycemia but documented plasma glucose level ≤3.9 mmol/l.
5) Relative hypoglycemia:
Symptomatic hypoglycemia but plasma glucose level is >3.9 mmol/l.*
Table 1 The Workgroup classification of hypoglycemic events .
• Symptoms are non-specific.
• Easily misdiagnosed, e. g. stroke, vertigo or visual disturbance.
• Misinterpreted as dementia-related symptoms e.g agitation or behavior change.
• Atypical presentation e.g. confusion or passive delirium.
• Little warning or unawareness of autonomic symptoms.
• Patients with dementia are unable to communicate their feelings or symptoms.
Table 2 Difficulties in recognizing hypoglycemia in older people.
• General physical function decline.
• Reduced ability in performing activities of daily living.
• Complete dependence.
• Frequent falls.
• Increased risk of fractures including hip fracture.
• Frequent hospitalisations.
• Increased risk of vascular disease.
• Impaired cognitive function.
• Increased risk of dementia.
• Increased fear and anxiety.
• Increased social isolation.
• Behavioural changes.
• Increased panic attacks.
• Increased risk of frailty.
• Increased risk of disability.
• Increased risk of mortality.
Table 3 Chronic consequences of hypoglycemia in older people.
Figure 1. Dead in the Bed Syndrome and Hypoglycemia
F: Are you Fatigued?
R: Resistance: Can you walk up a flight of stairs?
A: Ambulation: Can you walk a block?
I: Do you have more than 5 Illnesses?
L: Have you Lost 5% of weight in the last 6 months?
Table 4 Phenotypic criteria for diagnosis of frailty - The FRAIL Scale* 
Figure 2. Hypoglycemia and Frailty - Risk Factors, Complications and Consequences.
• Old age
Acute illness •
Insulin or sulfonylurea therapy
• History of hypoglycaemia
• Care home residency
• Recent hospitalisation
• Hypoglycaemia unawareness
• Blunted counter regulatory responses
• Chronic hepatic or renal dysfunction
• Stroke or transient ischaemic attack
• Multiple medications (≥5)
• Dementia •
Heart failure •
Table 5 Risk factors for hypoglycemia. [15, 74]
McAulay V,Frier BM (2009). Hypoglycemia. In Diabetes in Old Age.Sinclair AJ, Eds. Chichester, UK, John Wiley and Sons. p. 287–310.
Workgroup on Hypoglycemia, American Diabetes Association, Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia (2005). Diabetes Care, 28: 1245–1249.
Fatourechi MM,Kudvay C,Murad MH,Elamin MB,Tabini CC,Montori VM (2009). Clinical review: Hypoglycemia with intensive insulin therapy: a systematic review and meta-analyses of randomized trials of continuous subcutaneous insulin infusion versus multiple daily injections, J Clin Endocrinol Metab, 94: 729–740.
Jaap A,Jones G,McCrimmon R,Deary IJ,Frier BM (1998). Perceived symptoms of hypoglycemia in elderly type 2 diabetic patients treated with insulin. Diabet Med, 15: 398–401.
Abdelhafiz AH,Bailey C,Loo BE,Sinclair A (2013). Hypoglycemic symptoms and hypoglycemia threshold in older people with diabetes-a patient perspective. JNHA, 17: 899–902
Bonds DE,Miller ME,Dudl J,Feinglos M,Ismail-Beigi F,Malozowski S,Seaquist E,Simmons DL,Sood A (2012). Severe hypoglycemia symptoms, antecedent behaviors, immediate consequences and association with glycemia medication usage: Secondary analysis of the ACCORD clinical trial data. BMC Endocrine Disorders, 12:5.
Matyka K,Evans M,Lomas J,Cranston I,Macdonald I,Amiel SA (1997). Altered hierarchy of protective responses against severe hypoglycemia in normal aging in healthy men. Diabetes Care, 20: 135–141.
Graveling AJ,Frier BM (2010). Impaired awareness of hypoglycaemia: a review. Diab Metab, 36: S64–S74.
Cryer PE (2005). Mechanisms of hypoglycemia-associated autonomic failure and its component syndromes in diabetes. Diabetes, 54: 3592–3601.
Shorr RI,Ray WA,Daugherty JR,Griffin MR (1997). Incidence and risk factors for serious hypoglycemia in older persons using insulin or sulfonylureas. Arch Intern Med, 157: 1681–1686.
UK Prospective Diabetes Study (UKPDS) Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) (1998). Lancet, 352: 837–853.
Moore TJ,Cohen MR,Furberg CD (2007). Serious adverse drug events reported to the Food and Drug Administration, 1998–2005. Arch Intern Med, 167: 1752–1759.
Budnitz DS,Shehab N,Kegler SR,Richards CL (2007). Medication use leading to emergency department visits for adverse drug events in older adults. Ann Intern Med, 147: 755–765.
Tschöpe D,Bramlage P,Binz C,Krekler M,Deeg E,Gitt AK (2012). Incidence and Predictors of Hypoglycemia in Type 2 Diabetes. BMC Endocr Disord, doi: .
Bramlage P,Gitt AK,Binz C,Krekler M,Deeg E,Tschöpe D (2012). Oral antidiabetic treatment in type-2 diabetes in the elderly: balancing the need for glucose control and the risk of hypoglycemia. Cardiovascular Diabetology, doi: .
Chen LK,Lin MH,Lai HY,Hwang SJ (2008). Care of patients with diabetes mellitus in long-term care facilities in Taiwan: diagnosis, glycemic control, hypoglycemia, and functional status. J Am Geriatr Soc, 56: 1975–1976.
Abdelhafiz AH,Sinclair AJ (2009). Hypoglycemia in residential care homes. Br J Gen Pract, 59: 49–50.
Goto A,Arah OA,Goto M,Terauchi Y,Noda M (2013). Severe hypoglycemia and cardiovascular disease: systematic review and meta-analysis with bias analysis. BMJ, 347:f4533 doi: .
Yau CK,Eng C,Cenzer IS,Boscardin WJ,Rice-Trumble K,Lee SJ (2012). Glycosylated Hemoglobin and Functional Decline in Community-Dwelling Nursing Home-Eligible Elderly Adults with Diabetes Mellitus. J Am Geriatr Soc, 60: 1215–1221.
Schwartz AV,Vittinghoff E,Sellmeyer DE, et al (2008). Diabetes-Related Complications, Glycemic Control, and Falls in Older Adults. Diabetes Care, 31: 391–396.
Nelson JM,Dufraux K,Cook PF (2007). The Relationship Between Glycemic Control and Falls in Older Adults. J Am Geriatr Soc, 55: 2041–2044.
Signorovitch JE,Macaulay D,Diener M,Yan Y,Wu EQ,Gruenberger JB,Frier BM (2013). Hypoglycemia and accident risk in people with type 2 diabetes mellitus treated with non-insulin anti-diabetes drugs. Diab Obes Metab, 15: 335–341.
Johnston SS,Conner C,Aagren M,Ruiz K,Bouchard J (2012). Association between hypoglycemic events and fall-related fractures in Medicare-covered patients with type 2 diabetes. Diab Obes Metab, 14: 634–643.
Puar TH,Khoo JJ,Cho LW,Xu Y,Chen YT,Chuo AM,Poh CB,Ng JM (2012). Association Between Glycemic Control and Hip Fracture. J Am Geriatr Soc, 60: 1493–1497.
Nonami M,Cresci B,Colombini A,Pala L,Balzi D,Gori F,Chiasserini V,Marchionni N,Rotella CM,Mannucci E (2008). Bone Fractures and Hypoglycemic Treatment in Type 2 Diabetic Patients. Diabetes Care, 31: 199–203.
Whitmer RA,Karter AJ,Yaffe K,Quesenberry CPJr,Selby JV (2009). Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA, 301: 1565–1572.
Bruce DG,Davis WA,Casey GP,Starkstein SE,Clarnette RM,Foster JK,Almeida OP,Davis TM (2008). Predictors of cognitive impairment and dementia in older people with diabetes. Diabetologia, 51: 241–248.
Bruce DG,Davis WA,Casey GP, et al (2009). Severe hypoglycaemia and cognitive impairment in older patients with diabetes: the Fremantle Diabetes Study. Diabetologia, 52: 1808–1815.
Aung PP,Strachan MWJ,Frier BM,Butcher I,Deary IJ,Price JF (2012). Severe hypoglycemia and late-life cognitive ability in older people with Type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabet. Med, 29: 328–336.
Wild D,von Maltzahn R,Brohan E,Christensen T,Clauson P,Gonder-Frederick L (2007). A critical review of the literature on fear of hypoglycemia in diabetes: Implications for diabetes management and patient education. Patient Educ Couns, 68: 10–15.
Morley JE (2013). Syncope. J Am Med Dir Assoc, 14: 311–312.
Vinik AI,Maser RE,Ziegler D (2011). Autonomic imbalance: Prophet of doom or scope for hope?. Diabet Med, 28: 643–651.
Gerstein HC,Miller ME,Byington RP, et al (2008). Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med, 358: 2545–2559.
Huang ES,Liu JY,Moffet HH,John PM,Karter AJ (2011). Glycemic Control, Complications and Death in Older Diabetic Patients. Diabetes Care, 34: 1329–1336.
Currie CJ,Peters JR,Tynan A,Evans M,Heine RJ,Bracco OL,Zagar T,Poole CD (2010). Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study. Lancet, 375: 481–489.
Ray KK,Seshasai SR,Wijesuriya S,Sivakumaran R,Nethercott S,Preiss D,Erqou S,Sattar N (2009). Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet, 373: 1765–1772.
Kim TN,Park MS,Yang SJ, et al (2010). Prevalence and determinant factors of sarcopenia in patients with type 2 diabetes: the Korean Sarcopenic Obesity Study (KSOS). Diabetes Care, 33: 1497–1499.
Selvin E,Steffes MW,Zhu H, et al (2010). Glycated hemoglobin, diabetes and cardiovascular risk in nondiabetic adults. N Engl J Med, 362: 800–811.
Bergman H,Ferrucci L,Guralnik J Hogan DB,Hummel S,Karunananthan S,Wolfson C (2009). Frailty: An emerging research and clinical paradigm-issues and controversies. J Gerontol A Biol Sci Med Sci, 62A: 731–737.
Morley JE (2009). Developing novel therapeutic approaches to frailty. Curr Pharm Des, 15: 3384–3395.
Fried LP,Tangen CM,Walston J Newman AB,Hirsch C,Gottdiener J,Seeman T,Tracy R,Kop WJ,Burke G,McBurnie MA (2001). Frailty in older adults: Evidence for a phenotype. J Gerontol A Biol Sci Med Sci, 56A: M146–M56.
Peña FG,Theou O,Wallace L, et al (2014). Comparison of alternate scoring of variables on the performance of the frailty index. BMC Geriatrics, 14:25 doi: .
Song X,Mitnitski A,Rockwood K (2010). Prevalence and 10-Year Outcomes of Frailty in Older Adults in Relation to Deficit Accumulation. J Am Geriatr Soc, 58: 681–687.
Rockwood K,Song X,MacKnight C,Bergman H,Hogan DB,McDowell I,Mitnitski A (2005). A global clinical measure of fitness and frailty in elderly people. Can Med Assoc J, 173: 489–495.
Woo J,Leung J,Morley JE (2012). Comparison of frailty indicators based on clinical phenotype and the multiple deficit approach in predicitng mortality and physical limitation. J Am Geriatr Soc, 60: 1478–1486.
Abellan van Kan G,Rolland YM,Morley JE,Vellas B (2008). Frailty: Toward a clinical definition. J Am Med Dir Assoc, 9: 71–72.
Morley JE,Malmstrom TK,Miller DK (2012). A simple frailty questionnaire (FRAIL) predicts outcomes in middle aged African Americans. J Nutr Health Aging, 16: 601–608.
Ravindrarajah R,Lee DM,Pye SR, et al (2013). The ability of three different models of frailty to predict all-cause mortality: Results from the European Male Aging Study (EMAS). Arch Gerontol Geriatr, 57: 360–368.
Hyde Z,Flicker L,Almeida OP,Hankey GJ,McCaul KA,Chubb SA,Yeap BB (2010). Low free testosterone predicts frailty in older men: The health in men study. J Clin Endocrinol Metab, 95: 3165–3172.
Lopez D,Flicker L,Dobson A (2012). Validation of the frail scale in a cohort of older Australian women. J Am Geriatr Soc, 60: 171–173.
Buchman AS,Yu L,Wilson RS,Schneider JA,Bennett DA (2013). Association of brain pathology with the progression of frailty in older adults. Neurology, 80: 1–7.
Morley JE,Vellas B,van Kan GA, et al (2013). Frailty consensus: A call to action. J Am Med Dir Assoc, 14: 392–397.
Walston J,Hadley EC,Ferrucci L, et al (2006). 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, 54: 991–1001.
Gruenewald TL,Seeman TE,Karlamangla AS,Sarkisian CA (2009). Allostatic Load and Frailty in Older Adults. J Am Geriatr Soc, 57: 1525–1531.
Kalyani RR,Varadhan R,Weiss CO,Fried LP,Cappola AR (2012). Frailty Status and Altered Glucose-Insulin Dynamics. J Gerontol A Biol Sci Med Sci, 67: 1300–1306.
Hubbard RE,Lang IA,Llewellyn DJ,Rockwood K (2010). Frailty, Body Mass Index, and Abdominal Obesity in Older People. J Gerontol ABiol Sci Med Sci, 65A: 377–381.
Beers MH,Berkow R (eds). The Merck manual of geriatrics. Medical services, USMEDSA, USHH. Section 1. Nutritional disorders. Malnutrition; 2000–2004.
Lee JSW,Auyeung TW,Leung J,Kwok T,Leung PC,Woo J (2010). The effect of diabetes mellitus on age-associated lean mass loss in 3153 older adults. Diabet Med, 27: 1366–1371.
Landi F,Onder G,Bernabei R (2013). Sarcopenia and diabetes: Two sides of the same coin. J Am Med Dir Assoc, 14: 540–541.
Leenders M,Verdijk LB,van der Hoeven L,Adam JJ,van Kranenburg J,Nilwik R,van Loon LJ (2013). Patients with type 2 diabetes show a greater decline in muscle mass, muscle strength, and functional capacity with aging. J Am Med Dir Assoc, 14: 585–592.
Rizvi AA (2009). Nutritional challenges in the elderly with diabetes. Intern J Diabetes Mellitus, 1: 26–31.
Zhang Y,Wieffer H,Modha R (2010). The Burden of Hypoglycemia in Type 2 Diabetes: A Systematic Review of Patient and Economic Perspectives. JCOM, 17: 547–57.
Feil DG,Rajan M,Soroka O,Tseng CL,Miller DR,Pogach LM (2011). Risk of Hypoglycemia in Older Veterans with Dementia and Cognitive Impairment: Implications for Practice and Policy. J Am Geriatr Soc, 59: 2263–72.
Sjoblom P,Tengblad A,Lofgren UB,Lannering C,Anderberg N,Rosenqvist U,Mölstad S,Ostgren CJ (2008). Can diabetes medication be reduced in elderly patients? An observational study of diabetes drug withdrawal in nursing home patients with tight glycaemic control. Diab Res Clin Pract, 82: 197–202.
Vischer UM,Safar ME,Safar H,Iaria P,Le Dudal K,Henry O,Herrmann FR,Ducimetière P,Blacher J (2009). Cardiometabolic determinants of mortality in a geriatirc population: Is there a “reverse metabolic syndrome”?. Diab Metab, 35: 108–14.
Bonds DE,Miller ME,Bergenstal RM,Buse JB,Byington RP,Cutler JA,Dudl RJ,Ismail-Beigi F,Kimel AR,Hoogwerf B,Horowitz KR,Savage PJ,Seaquist ER,Simmons DL,Sivitz WI,Speril-Hillen JM,Sweeney ME (2010). The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ, 340: b4909. doi: .
Zoungas S,Patel A,Chalmers J,de Galan BE,Li Q,Billot L,Woodward M,Ninomiya T,Neal B,MacMahon S,Grobbee DE,Kengne AP,Marre M,Heller S (2010). Severe Hypoglycemia and Risks of Vascular Events and Death. N Engl J Med, 363: 1410–1418.
Carson AP,Fox CS,McGuire DK,Levitan EB,Laclaustra M,Mann DM,Muntner P (2010). Low Hemoglobin A1c and Risk of All-Cause Mortality Among US Adults Without Diabetes. Circ Cardiovasc Qual Outcomes, 3: 661–667.
Mehta KM,Pierluissi E,Boscardin WJ,Kirby KA,Walter LC,Chren MM,Palmer RM,Counsell SR,Landefeld CS (2011). A Clinical Index to Stratify Hospitalized Older Adults According to Risk for New-Onset Disability. J Am Geriatr Soci, 59: 1206–1216.
Hubbard RE,O’Mahony MS,Savva GM,Calver BL,Woodhouse KW (2009). Inflammation and frailty measures in older people. J Cell Mol Med, 13: 3103–3109.
Cox DJ,Kovatchev BP,Gonder-Frederick LA,Summers KH,McCall A,Grimm KJ,Clarke WL (2005). Relationships between hyperglycemia and cognitive performance among adults with type 1 and type 2 diabetes. Diabetes Care, 28: 71–77.
Lee SJ,Eng C (2011). Goals of Glycemic Control in Frail Older Patients With Diabetes. JAMA, 305: 1350–1351.
Sinclair A,Morley JE,Rodriguez-Mañas L,Paolisso G,Bayer T,Zeyfang A,Bourdel-Marchasson I,Vischer U,Woo J,Chapman I,Dunning T,Meneilly G,Rodriguez-Saldana J,Gutierrez Robledo LM,Cukierman-Yaffe T,Gadsby R,Schernthaner G,Lorig K (2012). 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 in Diabetes. J Am Med Dir Assoc, 13: 497–502.
Chelliah A,Burge MR (2004). Hypoglycemia in elderly patients with diabetes mellitus: causes and strategies for prevention. Drugs Aging, 21: 511–530.