Mayo Clinic Proceedings Home

Severe Hypoglycemia Attributable to Intensive Glucose-Lowering Therapy Among US Adults With Diabetes

Population-Based Modeling Study, 2011-2014



      To estimate the contemporary prevalence of intensive glucose-lowering therapy among US adults with diabetes and model the number of hypoglycemia-related emergency department (ED) visits and hospitalizations that are attributable to such intensive treatment.

      Patients and Methods

      US adults with diabetes and glycated hemoglobin (HbA1c) levels less than 7.0% who were included in the National Health and Nutrition Examination Survey (NHANES) between 2011 and 2014. Participants were categorized as clinically complex if 75 years or older or with 2 or more activities of daily living limitations, end-stage renal disease, or 3 or more chronic conditions. Intensive treatment was defined as any glucose-lowering medications with HbA1c levels of 5.6% or less or 2 or more with HbA1c levels of 5.7% to 6.4%. First, we quantified the proportion of clinically complex and intensively treated individuals in the NHANES population. Then, we modeled the attributable hypoglycemia-related ED visits/hospitalizations over a 2-year period based on published data for event risk.


      Almost half (48.8% [10,719,057 of 21,980,034]) of US adults with diabetes (representing 10.7 million US adults) had HbA1c levels less than 7.0%. Among them, 32.3% (3,466,713 of 10,719,057) were clinically complex, and 21.6% (2,309,556 of 10,719,057) were intensively treated, with no difference by clinical complexity. Over a 2-year period, we estimated 31,511 hospitalizations and 30,954 ED visits for hypoglycemia in this population; of these, 4774 (95% CI, 954-9714) hospitalizations and 4804 (95% CI, 862-9851) ED visits were attributable to intensive treatment.


      Intensive glucose-lowering therapy, particularly among vulnerable clinically complex adults, is strongly discouraged because it may lead to hypoglycemia. However, intensive treatment was equally prevalent among US adults, irrespective of clinical complexity. Over a 2-year period, an estimated 9578 hospitalizations and ED visits for hypoglycemia could be attributed to intensive diabetes treatment, particularly among clinically complex patients. Patients at risk for hypoglycemia may benefit from treatment deintensification to reduce hypoglycemia risk and treatment burden.

      Abbreviations and Acronyms:

      ADL (activities of daily living), AGS (American Geriatric Society), CKD (chronic kidney disease), ED (emergency department), HbA1c (glycated hemoglobin), NHANES (National Health and Nutrition Examination Survey), PSA (probabilistic sensitivity analysis)
      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 Mayo Clinic Proceedings
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Nathan D.M.
        • Genuth S.
        • Lachin J.
        • et al.
        • Diabetes Control Complications Trial Research Group
        The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.
        N Engl J Med. 1993; 329: 977-986
        • Nathan D.M.
        • Cleary P.A.
        • Backlund J.Y.
        • et al.
        • Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group
        Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.
        N Engl J Med. 2005; 353: 2643-2653
        • Holman R.R.
        • Paul S.K.
        • Bethel M.A.
        • Matthews D.R.
        • Neil H.A.
        10-Year follow-up of intensive glucose control in type 2 diabetes.
        N Engl J Med. 2008; 359: 1577-1589
        • Nathan D.M.
        • Bayless M.
        • Cleary P.
        • et al.
        • DCCT/EDIC Research Group
        Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study at 30 years: advances and contributions.
        Diabetes. 2013; 62: 3976-3986
      1. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group.
        Lancet. 1998; 352: 854-865
      2. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.
        Lancet. 1998; 352: 837-853
        • Conlin P.R.
        • Colburn J.
        • Aron D.
        • Pries R.
        • Tschanz M.P.
        • Pogach L.
        Synopsis of the 2017 U.S. Department of Veterans Affairs/U.S. Department of Defense Clinical Practice Guideline: management of type 2 diabetes mellitus.
        Ann Intern Med. 2017; 167: 655-663
        • American Diabetes Association
        6. Glycemic Targets: Standards of Medical Care in Diabetes-2018.
        Diabetes Care. 2018; 41: S55-S64
        • Garber A.J.
        • Abrahamson M.J.
        • Barzilay J.I.
        • et al.
        Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm – 2018 executive summary.
        Endocr Pract. 2018; 24: 91-120
        • American Diabetes Association
        11. Older Adults: Standards of Medical Care in Diabetes-2018.
        Diabetes Care. 2018; 41: S119-S125
        • Tseng C.
        • Soroka O.
        • Maney M.
        • Aron D.C.
        • Pogach L.M.
        Assessing potential glycemic overtreatment in persons at hypoglycemic risk.
        JAMA Intern Med. 2014; 174: 259-268
        • Lipska K.J.
        • Ross J.S.
        • Miao Y.
        • Shah N.D.
        • Lee S.J.
        • Steinman M.A.
        Potential overtreatment of diabetes mellitus in older adults with tight glycemic control.
        JAMA Intern Med. 2015; 175: 356-362
        • Thorpe C.T.
        • Gellad W.F.
        • Good C.B.
        • et al.
        Tight glycemic control and use of hypoglycemic medications in older veterans with type 2 diabetes and comorbid dementia.
        Diabetes Care. 2015; 38: 588-595
        • McCoy R.G.
        • Lipska K.J.
        • Yao X.
        • Ross J.S.
        • Montori V.M.
        • Shah N.D.
        Intensive treatment and severe hypoglycemia among adults with type 2 diabetes.
        JAMA Intern Med. 2016; 176: 969-978
        • Centers for Disease Control and Prevention
        Diabetes Data & Statistics. Diabetes Surveillance Data, 2014.
        Date: 2018
        Date accessed: April 16, 2018
        • Sue Kirkman M.
        • Briscoe V.J.
        • 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: 2342-2356
        • ORIGIN Trial Investigators
        Predictors of nonsevere and severe hypoglycemia during glucose-lowering treatment with insulin glargine or standard drugs in the ORIGIN trial.
        Diabetes Care. 2015; 38: 22-28
        • Misra-Hebert A.D.
        • Pantalone K.M.
        • Ji X.
        • et al.
        Patient characteristics associated with severe hypoglycemia in a type 2 diabetes cohort in a large, integrated health care system from 2006 to 2015.
        Diabetes Care. 2018; 41: 1164-1171
        • Davis T.M.
        • Brown S.G.
        • Jacobs I.G.
        • Bulsara M.
        • Bruce D.G.
        • Davis W.A.
        Determinants of severe hypoglycemia complicating type 2 diabetes: the Fremantle diabetes study.
        J Clin Endocrinol Metab. 2010; 95: 2240-2247
        • Miller C.D.
        • Phillips L.S.
        • Ziemer D.C.
        • Gallina D.L.
        • Cook C.B.
        • El-Kebbi I.M.
        Hypoglycemia in patients with type 2 diabetes mellitus.
        Arch Intern Med. 2001; 161: 1653-1659
        • McCoy R.G.
        • Lipska K.J.
        • Herrin J.
        • Jeffery M.M.
        • Krumholz H.M.
        • Shah N.D.
        Hospital readmissions among commercially insured and Medicare Advantage beneficiaries with diabetes and the impact of severe hypoglycemic and hyperglycemic events.
        J Gen Intern Med. 2017; 32: 1097-1105
        • Karter A.J.
        • Warton E.M.
        • Lipska K.J.
        • et al.
        Development and validation of a tool to identify patients with type 2 diabetes at high risk of hypoglycemia-related emergency department or hospital use.
        JAMA Intern Med. 2017; 177: 1461-1470
        • Festa A.
        • Heller S.R.
        • Seaquist E.
        • Duan R.
        • Hadjiyianni I.
        • Fu H.
        Association between mild and severe hypoglycemia in people with type 2 diabetes initiating insulin.
        J Diabetes Complications. 2017; 31: 1047-1052
        • Quilliam B.J.
        • Simeone J.C.
        • Ozbay A.B.
        Risk factors for hypoglycemia-related hospitalization in patients with type 2 diabetes: a nested case-control study.
        Clin Ther. 2011; 33: 1781-1791
        • Bonds D.E.
        • Miller M.E.
        • Bergenstal R.M.
        • et al.
        The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study.
        BMJ. 2010; 340: b4909
        • Zoungas S.
        • Patel A.
        • Chalmers J.
        • et al.
        • ADVANCE Collaborative Group
        Severe hypoglycemia and risks of vascular events and death.
        N Engl J Med. 2010; 363: 1410-1418
        • McCoy R.G.
        • Van Houten H.K.
        • Ziegenfuss J.Y.
        • Shah N.D.
        • Wermers R.A.
        • Smith S.A.
        Increased mortality of patients with diabetes reporting severe hypoglycemia.
        Diabetes Care. 2012; 35: 1897-1901
        • Khunti K.
        • Davies M.
        • Majeed A.
        • Thorsted B.L.
        • Wolden M.L.
        • Paul S.K.
        Hypoglycemia and risk of cardiovascular disease and all-cause mortality in insulin-treated people with type 1 and type 2 diabetes: a cohort study.
        Diabetes Care. 2015; 38: 316-322
        • Lee A.K.
        • Warren B.
        • Lee C.J.
        • et al.
        The association of severe hypoglycemia with incident cardiovascular events and mortality in adults with type 2 diabetes.
        Diabetes Care. 2018; 41: 104-111
        • Goto A.
        • Arah O.A.
        • Goto M.
        • Terauchi Y.
        • Noda M.
        Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis.
        BMJ. 2013; 347: f4533
        • Feinkohl I.
        • Aung P.P.
        • Keller M.
        • et al.
        • Edinburgh Type 2 Diabetes Study (ET2DS) Investigators
        Severe hypoglycemia and cognitive decline in older people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study.
        Diabetes Care. 2014; 37: 507-515
        • Liu S.
        • Zhao Y.
        • Hempe J.M.
        • Fonseca V.
        • Shi L.
        Economic burden of hypoglycemia in patients with type 2 diabetes.
        Expert Rev Pharmacoecon Outcomes Res. 2012; 12: 47-51
        • McCoy R.G.
        • Van Houten H.K.
        • Ziegenfuss J.Y.
        • Shah N.D.
        • Wermers R.A.
        • Smith S.A.
        Self-report of hypoglycemia and health-related quality of life in patients with type 1 and type 2 diabetes.
        Endocr Pract. 2013; 19: 792-799
        • Rodríguez-Gutiérrez R.
        • Montori V.M.
        Glycemic control for patients with type 2 diabetes mellitus: our evolving faith in the face of evidence.
        Circ Cardiovasc Qual Outcomes. 2016; 9: 504-512
        • Optum
        Real world health care experiences from over 150 million unique individuals since 1993.
        • Wallace P.J.
        • Shah N.D.
        • Dennen T.
        • Bleicher P.A.
        • Crown W.H.
        Optum Labs: building a novel node in the learning health care system.
        Health Aff (Millwood). 2014; 33: 1187-1194
        • Sarkar U.
        • Karter A.J.
        • Liu J.Y.
        • Moffet H.H.
        • Adler N.E.
        • Schillinger D.
        Hypoglycemia is more common among type 2 diabetes patients with limited health literacy: the Diabetes Study of Northern California (DISTANCE).
        J Gen Intern Med. 2010; 25: 962-968
        • Lipska K.J.
        • Warton E.M.
        • Huang E.S.
        • et al.
        HbA1c and risk of severe hypoglycemia in type 2 diabetes: the Diabetes and Aging Study.
        Diabetes Care. 2013; 36: 3535-3542
        • Karter A.J.
        • Moffet H.H.
        • Liu J.Y.
        • Lipska K.J.
        Surveillance of hypoglycemia—limitations of emergency department and hospital utilization data.
        JAMA Intern Med. 2018; 178: 987-988
        • Sussman J.B.
        • Kerr E.A.
        • Saini S.D.
        • et al.
        Rates of deintensification of blood pressure and glycemic medication treatment based on levels of control and life expectancy in older patients with diabetes mellitus.
        JAMA Intern Med. 2015; 175: 1942-1949
        • Munshi M.N.
        • Slyne C.
        • Segal A.R.
        • Saul N.
        • Lyons C.
        • Weinger K.
        Simplification of insulin regimen in older adults and risk of hypoglycemia.
        JAMA Intern Med. 2016; 176: 1023-1025

      Linked Article

      • In the Limelight: September 2019
        Mayo Clinic ProceedingsVol. 94Issue 9
        • Preview
          This monthly feature highlights four articles in the current print and online issue of Mayo Clinic Proceedings. These articles are also featured on the Mayo Clinic Proceedings' YouTube Channel ( ).
        • Full-Text
        • PDF