Top

06-21-2018 | Hypoglycemia | Review | Article

Hypoglycemia Among Patients with Type 2 Diabetes: Epidemiology, Risk Factors, and Prevention Strategies

Journal: Current Diabetes Reports

Authors: Richard Silbert, Alejandro Salcido-Montenegro, Rene Rodriguez-Gutierrez, Abdulrahman Katabi, Rozalina G. McCoy

Abstract

Purpose of Review

Hypoglycemia is the most common and often treatment-limiting serious adverse effect of diabetes therapy. Despite being potentially preventable, hypoglycemia in type 2 diabetes incurs substantial personal and societal burden. We review the epidemiology of hypoglycemia in type 2 diabetes, discuss key risk factors, and introduce potential prevention strategies.

Recent Findings

Reported rates of hypoglycemia in type 2 diabetes vary widely as there is marked heterogeneity in how hypoglycemia is defined, measured, and reported. In randomized controlled trials, rates of severe hypoglycemia ranged from 0.7 to 12 per 100 person-years. In observational studies, hospitalizations or emergency department visits for hypoglycemia were experienced by 0.2 (patients treated without insulin or sulfonylurea) to 2.0 (insulin or sulfonylurea users) per 100 person-years. Patient-reported hypoglycemia is much more common. Over the course of 6 months, 1–4% non-insulin users reported need for medical attention for hypoglycemia; 1–17%, need for any assistance; and 46–58%, any hypoglycemia symptoms. Similarly, over a 12-month period, 4–17% of insulin-treated patients reported needing assistance and 37–64% experienced any hypoglycemic symptoms. Hypoglycemia is most common among older patients with multiple or advanced comorbidities, patients with long diabetes duration, or patients with a prior history of hypoglycemia. Insulin and sulfonylurea use, food insecurity, and fasting also increase hypoglycemia risk. Clinical decision support tools may help identify at-risk patients. Prospective trials of efforts to reduce hypoglycemia risk are needed, and there is emerging evidence supporting multidisciplinary interventions including treatment de-intensification, use of diabetes technologies, diabetes self-management, and social support.

Summary

Hypoglycemia among patients with type 2 diabetes is common. Patient-centered multidisciplinary care may help proactively identify at-risk patients and address the multiplicity of factors contributing to hypoglycemia occurrence.

CDC. National Diabetes Statistics Report, 2017: estimates of diabetes and its burden in the United States. Centers for Disease Control and Prevention. National Center for Chronic Disease Prevention and Health Promotion. 2017. https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf. Accessed January 21 2018.

WHO. World Health Organization Global Report on Diabetes. Geneva: World Health Organization; 2016. http://apps.who.int/iris/bitstream/10665/204871/1/9789241565257_eng.pdf?ua=1. Accessed February 26, 2018

Holmes HM, Hayley DC, Alexander GC, Sachs GA. Reconsidering medication appropriateness for patients late in life. Arch Intern Med. 2006;166(6):605–9. https://doi.org/10.1001/archinte.166.6.605.PubMedCrossRef

Cryer PE. Hypoglycemia: still the limiting factor in the glycemic management of diabetes. Endocr Pract. 2008;14(6):750–6. https://doi.org/10.4158/EP.14.6.750.PubMedCrossRef

•• Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med. 2010;363(15):1410–8. https://doi.org/10.1056/NEJMoa1003795. This post hoc analysis of the ADVANCE trial examined the patient- and treatment-specific risk factors for hypoglycemia. Furthermore, this study found that severe hypoglycemia, irrespective of the study arm, significantly increased the risks of all-cause mortality (HR 2.69; 95% CI, 1.97–3.67), cardiovascular mortality (HR 2.68; 95% CI, 1.72–4.19), major macrovascular events (HR 2.88; 95% CI, 2.01–4.12), and major microvascular events (HR 1.81; 95% CI, 1.19–2.74). PubMedCrossRef

Goto A, Arah OA, Goto M, Terauchi Y, Noda M. Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis. BMJ. 2013;347:f4533. https://doi.org/10.1136/bmj.f4533.PubMedCrossRef

Cryer PE. Death during intensive glycemic therapy of diabetes: mechanisms and implications. Am J Med. 2011;124(11):993–6. https://doi.org/10.1016/j.amjmed.2011.08.008.PubMedPubMedCentralCrossRef

• Bonds DE, Miller ME, Bergenstal RM, Buse JB, Byington RP, Cutler JA, 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. https://doi.org/10.1136/bmj.b4909. In this post hoc analysis of the ACCORD trial, patients who experienced severe hypoglycemia had a significantly higher risk of all-cause mortality irrespective of allocation to the intensive or standard treatment arm. However, hypoglycemia was the direct cause of death in only one of 451 deaths in the study. PubMedPubMedCentralCrossRef

• Khunti K, Davies M, Majeed A, Thorsted BL, Wolden ML, Paul SK. 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(2):316–22. https://doi.org/10.2337/dc14-0920. This study retrospectively analyzed the data of insulin-treated patients (10,422 with type 2 diabetes), with a mean follow-up of 4.8 years, demonstrating an association between hypoglycemia events and cardiovascular events (HR 1.61; 95% CI 1.17–2.22) and mortality (HR 1.61, CI 1.17–2.22). PubMedCrossRef

10.

• McCoy RG, Shah ND, Van Houten HK, Wermers RA, Ziegenfuss JY, Smith SA. Increased mortality of patients with diabetes reporting severe hypoglycemia. Diabetes Care. 2012;35(9):1897–901. https://doi.org/10.2337/dc11-2054. This study demonstrated that patient self-report of severe hypoglycemia was associated with 3.4-fold increase in 5-year all-cause mortality after controlling for diabetes type, comorbidity burden, and glycemic control. This finding reinforced the importance of screening patients at risk of hypoglycemia at each clinical encounter. PubMedPubMedCentralCrossRef

11.

Liu S, Zhao Y, Hempe JM, Fonseca V, Shi L. Economic burden of hypoglycemia in patients with type 2 diabetes. Expert Rev Pharmacoecon Outcomes Res. 2012;12(1):47–51. https://doi.org/10.1586/erp.11.87.PubMedCrossRef

12.

Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP Jr, Selby JV. Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA. 2009;301(15):1565–72. https://doi.org/10.1001/jama.2009.460.PubMedPubMedCentralCrossRef

13.

Jacobson AM, Musen G, Ryan CM, Silvers N, Cleary P, Waberski B, et al. Long-term effect of diabetes and its treatment on cognitive function. N Engl J Med. 2007;356(18):1842–52. https://doi.org/10.1056/NEJMoa066397.PubMedCrossRef

14.

McCoy RG, Van Houten HK, Ziegenfuss JY, Shah ND, Wermers RA, Smith SA. Self-report of hypoglycemia and health-related quality of life in patients with type 1 and type 2 diabetes. Endocr Pract. 2013;19(5):792–9. https://doi.org/10.4158/ep12382.or.PubMedCrossRef

15.

American Diabetes Association Workgroup on Hypoglycemia. Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care. 2005;28(5):1245–9. https://doi.org/10.2337/diacare.28.5.1245.CrossRef

16.

ADA. American Diabetes Association Standards of Medical Care in Diabetes—2013. Diabetes Care. 2013;36(Supplement 1):S11–66. https://doi.org/10.2337/dc13-S011.CrossRef

17.

ADA. American Diabetes Association Standards of Medical Care in Diabetes—2018. Section 6. Glycemic targets. Diabetes Care. 2018;41(Supplement 1):S55–64. https://doi.org/10.2337/dc18-S006.CrossRef

18.

ADA. American Diabetes Association Standards of Medical Care in Diabetes—2017. Section 6. Glycemic targets. Diabetes Care. 2017;40(Supplement 1):S48–56. https://doi.org/10.2337/dc17-S009.CrossRef

19.

Sarkar U, Karter AJ, Liu JY, Moffet HH, Adler NE, 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(9):962–8. https://doi.org/10.1007/s11606-010-1389-7.PubMedPubMedCentralCrossRef

20.

Lipska KJ, Warton EM, Huang ES, et al. HbA1c and risk of severe hypoglycemia in type 2 diabetes: the Diabetes and Aging Study. Diabetes Care. 2013;36(11):3535–42.PubMedPubMedCentralCrossRef

21.

• Karter AJ, Moffet HH, Liu JY, Lipska KJ. Surveillance of hypoglycemia—limitations of emergency department and hospital utilization data. JAMA Intern Med. 2018. https://doi.org/10.1001/jamainternmed.2018.1014. This study demonstrated that only 5% of severe hypoglycemic events experienced by patients with diabetes culminate in an emergency department visit or hospitalization event.

22.

Ginde AA, Blanc PG, Lieberman RM, Camargo CA Jr. Validation of ICD-9-CM coding algorithm for improved identification of hypoglycemia visits. BMC Endocr Disord. 2008;8:4. https://doi.org/10.1186/1472-6823-8-4.PubMedPubMedCentralCrossRef

23.

Hodge MC, Dixon S, Garg AX, Clemens KK. Validation of an International Statistical Classification of Diseases and Related Health Problems 10th Revision Coding Algorithm for Hospital Encounters with Hypoglycemia. Can J Diabetes. 2017;41(3):322–8. https://doi.org/10.1016/j.jcjd.2016.11.003.PubMedCrossRef

24.

Heller S, Chapman J, McCloud J, Ward J. Unreliability of reports of hypoglycaemia by diabetic patients. BMJ. 1995;310(6977):440. https://doi.org/10.1136/bmj.310.6977.440.PubMedPubMedCentralCrossRef

25.

Moffet HH, Warton EM, Siegel L, Sporer K, Lipska KJ, Karter AJ. Hypoglycemia patients and transport by EMS in Alameda County, 2013-15. Prehosp Emerg Care. 2017;21(6):767–72. https://doi.org/10.1080/10903127.2017.1321707.PubMedCrossRef

26.

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(9131):854–65.

27.

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(9131):837–53.

28.

Wright AD, Cull CA, Macleod KM, Holman RR, Group U. Hypoglycemia in type 2 diabetic patients randomized to and maintained on monotherapy with diet, sulfonylurea, metformin, or insulin for 6 years from diagnosis: UKPDS73. J Diabetes Complicat. 2006;20(6):395–401. https://doi.org/10.1016/j.jdiacomp.2005.08.010.PubMedCrossRef

29.

ORIGIN Trial Investigators. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367(4):319–28. https://doi.org/10.1056/NEJMoa1203858.CrossRef

30.

Group AC, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560–72. https://doi.org/10.1056/NEJMoa0802987. CrossRef

31.

Action to Control Cardiovascular Risk in Diabetes Study G, Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545–59. https://doi.org/10.1056/NEJMoa0802743.CrossRef

32.

Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, 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.PubMedCrossRef

33.

Rodriguez-Gutierrez R, Montori VM. Glycemic control for patients with type 2 diabetes mellitus: our evolving faith in the face of evidence. Circ Cardiovasc Qual Outcomes. 2016;9(5):504–12. https://doi.org/10.1161/CIRCOUTCOMES.116.002901.PubMedPubMedCentralCrossRef

34.

Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, 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.PubMedCrossRef

35.

Neal B, Perkovic V, Mahaffey KW, 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(7):644–57. https://doi.org/10.1056/NEJMoa1611925.PubMedCrossRef

36.

Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, 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.PubMedPubMedCentralCrossRef

37.

Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–26. https://doi.org/10.1056/NEJMoa1307684.PubMedCrossRef

38.

Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232–42. https://doi.org/10.1056/NEJMoa1501352.PubMedCrossRef

39.

White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327–35. https://doi.org/10.1056/NEJMoa1305889.PubMedCrossRef

40.

Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Kober LV, 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.PubMedCrossRef

41.

Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, 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.PubMedCrossRef

42.

Marso SP, McGuire DK, Zinman B, Poulter NR, Emerson SS, Pieber TR, et al. Efficacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med. 2017;377(8):723–32. https://doi.org/10.1056/NEJMoa1615692.PubMedPubMedCentralCrossRef

43.

• Elliott L, Fidler C, Ditchfield A, et al. Hypoglycemia event rates: a comparison between real-world data and randomized controlled trial populations in insulin-treated diabetes. Diabetes Ther. 2016;7(1):45–60. This structured literature review directly compares the rates of hypoglycemia among insulin-treated adults with type 1 and type 2 diabetes as reported in randomized controlled trials (RCTs) and real-world data (RWD). For patients with type 2 diabetes, rates of severe, non-severe, and nocturnal events were all higher in studies relying on RWD, though the differences were much lower than those for patients with type 1 diabetes. This reinforces the importance of using real-world estimates to understand hypoglycemia risk and counsel patients about risks and benefits of glucose-lowering therapy. PubMedPubMedCentralCrossRef

44.

Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med. 2011;365(21):2002–12. https://doi.org/10.1056/NEJMsa1103053.PubMedCrossRef

45.

• McCoy RG, Lipska KJ, Herrin J, Jeffery MM, Krumholz HM, Shah ND. 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(10):1097–105. https://doi.org/10.1007/s11606-017-4095-x. This study analyzed 594,146 hospitalizations among commercially insured and Medicare Advantage beneficiaries with diabetes between 2009 and 2014 and found that 1.3% of all hospitalizations were for the primary diagnosis of hypoglycemia. This is the first study to place hospitalizations for hypoglycemia and hyperglycemia in the context of all hospitalizations among adults with diabetes in the USA. PubMedCrossRefPubMedCentral

46.

Pettersson B, Rosenqvist U, Deleskog A, et al. Self-reported experience of hypoglycemia among adults with type 2 diabetes mellitus (Exhype). Diabetes Res Clin Pract. 2011;92(1):19–25.PubMedCrossRef

47.

Stargardt T, Gonder-Frederick L, Krobot KJ, et al. Fear of hypoglycaemia: defining a minimum clinically important difference in patients with type 2 diabetes. Health Qual Life Outcomes. 2009;7:91. https://doi.org/10.1186/1477-7525-7-91.PubMedPubMedCentralCrossRef

48.

Chan SP, Ji LN, Nitiyanant W, Baik SH, Sheu WH. Hypoglycemic symptoms in patients with type 2 diabetes in Asia-Pacific—real-life effectiveness and care patterns of diabetes management: the RECAP-DM study. Diabetes Res Clin Pract. 2010;89(2):e30–2. https://doi.org/10.1016/j.diabres.2010.05.008.PubMedCrossRef

49.

Marrett E, Radican L, Davies MJ, et al. Assessment of severity and frequency of self-reported hypoglycemia on quality of life in patients with type 2 diabetes treated with oral antihyperglycemic agents: a survey study. BMC Res Notes. 2011;4:251.PubMedPubMedCentralCrossRef

50.

Rauh SP, Rutters F, Thorsted BL, et al. Self-reported hypoglycaemia in patients with type 2 diabetes treated with insulin in the Hoorn Diabetes Care System Cohort, the Netherlands: a prospective cohort study. BMJ Open. 2016;6(9):e012793.PubMedPubMedCentralCrossRef

51.

Henderson JN, Allen KV, Deary IJ, et al. Hypoglycaemia in insulin-treated type 2 diabetes: frequency, symptoms and impaired awareness. Diabet Med. 2003;20(12):1016–21.PubMedCrossRef

52.

Akram K, Pedersen-Bjergaard U, Carstensen B, et al. Frequency and risk factors of severe hypoglycaemia in insulin-treated type 2 diabetes: a cross-sectional survey. Diabet Med. 2006;23(7):750–6.PubMedCrossRef

53.

Ratzki-Leewing A, Harris SB, Mequanint S, Reichert SM, Belle Brown J, Black JE, et al. Real-world crude incidence of hypoglycemia in adults with diabetes: results of the InHypo-DM study, Canada. BMJ Open Diabetes Res Care. 2018;6(1). https://doi.org/10.1136/bmjdrc-2017-000503.

54.

•• Emral R, Pathan F, Cortes CAY, et al. Self-reported hypoglycemia in insulin-treated patients with diabetes: results from an international survey on 7289 patients from nine countries. Diabetes Res Clin Pract. 2017;134:17–28. The International Operations HAT (IO HAT) study retrospectively and prospectively assessed the incidence of hypoglycemia among adults with insulin-treated diabetes (type 1 and type 2) in nine countries (Bangladesh, Colombia, Egypt, Indonesia, Philippines, Singapore, South Africa, Turkey, and United Arab Emirates) and highlighted the discrepancy between prospectively and retrospectively reported rates. Hypoglycemia was retrospectively reported by patients with type 2 diabetes at the rate of 1.6 event/patient/month and prospectively identified at the rate of 2.4 events/patient/month, while hospitalizations for hypoglycemia occurred at the rate of 0.026 event/patient/month. PubMedCrossRef

55.

Levy JC, Davies MJ, Holman RR. Continuous glucose monitoring detected hypoglycaemia in the Treating to Target in Type 2 Diabetes Trial (4-T). Diabetes Res Clin Pract. 2017;131:161–8. https://doi.org/10.1016/j.diabres.2017.01.022.PubMedCrossRef

56.

Gehlaut RR, Dogbey GY, Schwartz FL, Marling CR, Shubrook JH. Hypoglycemia in type 2 diabetes—more common than you think: a continuous glucose monitoring study. J Diabetes Sci Technol. 2015;9(5):999–1005. https://doi.org/10.1177/1932296815581052.PubMedPubMedCentralCrossRef

57.

Malkani S, Kotwal A. Frequency and predictors of self-reported hypoglycemia in insulin-treated diabetes. J Diabetes Res. 2017;2017:7425925. https://doi.org/10.1155/2017/7425925.PubMedPubMedCentralCrossRef

58.

Brož J, Brabec M, Žďárská DJ, Fedáková Z, Hoskovcová L, You JY, et al. Fear of driving license withdrawal in patients with insulin-treated diabetes mellitus negatively influences their decision to report severe hypoglycemic events to physicians. Patient Prefer Adherence. 2015;9:1367.PubMedPubMedCentralCrossRef

59.

Ohashi Y, Wolden ML, Hyllested WJ, Brod M. Diabetes management and daily functioning burden of non-severe hypoglycemia in Japanese people treated with insulin. J Diabetes Investig. 2017;8(6):776–82. https://doi.org/10.1111/jdi.12642.

60.

Brod M, Rana A, Barnett A. H. Impact of self-treated hypoglycaemia in type 2 diabetes: a multinational survey in patients and physicians. Curr Med Res Opin. 2012;28(12):1947–58.PubMedCrossRef

61.

Douros A, Yin H, Yu O, H Y, et al. Pharmacologic differences of sulfonylureas and the risk of adverse cardiovascular and hypoglycemic events. Diabetes Care. 2017;40(11):1506–13. https://doi.org/10.2337/dc17-0595.

62.

•• Karter AJ, Warton EM, Lipska KJ, 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(10):1461–70. In this study, Karter and colleagues develop and validate in three different healthcare delivery systems an efficient risk model predicting the 12-month risk of hospitalization or emergency department visit for hypoglycemia for adults with type 2 diabetes. This model stratifies patients as being at high (>5%), intermediate (1–5%), or low (<1%) risk of hypoglycemia utilization events based on six variables: total number of prior hypoglycemia-related hospitalization or emergency department visits, total number of emergency department visits for any cause in the past year, insulin use, sulfonylurea use, presence of stage 4 and 5 chronic kidney disease, and age ≥77 years. PubMedCrossRef

63.

•• Schloot NC, Haupt A, Schutt M, et al. Risk of severe hypoglycemia in sulfonylurea-treated patients from diabetes centers in Germany/Austria: how big is the problem? Which patients are at risk? Diabetes Metab Res Rev. 2016;32(3):316–24. Schloot et al. studied a large population of sulfonylurea-treated patients in a real-life setting. They reported an event rate of severe hypoglycemia of 3.9 per 100 patient-years, identifying several key risk factors associated with hypoglycemia, including lack of diabetes education, older age, and impaired kidney function. PubMedCrossRef

64.

Persson F, Nystrom T, Jorgensen ME, et al. Dapagliflozin is associated with lower risk of cardiovascular events and all-cause mortality in people with type 2 diabetes (CVD-REAL Nordic) when compared with dipeptidyl peptidase-4 inhibitor therapy: a multinational observational study. Diabetes Obes Metab. 2018;20(2):344–351. https://doi.org/10.1111/dom.13077.

65.

•• Lipska KJ, Yao X, Herrin J, et al. Trends in drug utilization, glycemic control, and rates of severe hypoglycemia, 2006-2013. Diabetes Care. 2017;40(4):468–75. This study examined the contemporaneous trends in the pharmacological management of type 2 diabetes, glycemic control, and rates of hospitalizations and emergency department visits for severe hypoglycemia among 1.66 million U.S. adults. Lipska et al found that despite the increasing use of GLP-1 receptor agonists and DPP-4 inhibitors, which are associated with a lower risk of hypoglycemia, the overall rates of severe hypoglycemia did not change between 2006 and 2013 (1.3 event/100 person-years). Hypoglycemia rates were highest among the elderly, those with multiple comorbidities, and those with insulin/sulfonylurea use. Glycemic control improved over time in the elderly but worsened in younger and healthier patients. PubMedCrossRef

66.

•• Pathak RD, Schroeder EB, Seaquist ER, Zeng C, Lafata JE, Thomas A, et al. Severe hypoglycemia requiring medical intervention in a large cohort of adults with diabetes receiving care in U.S. Integrated Health Care Delivery Systems: 2005-2011. Diabetes Care. 2016;39(3):363–70. https://doi.org/10.2337/dc15-0858. This study examined the prevalence of severe hypoglycemia requiring emergency department care or hospitalization among 917,440 adults with diabetes (not separated by diabetes type) within a large integrated healthcare delivery system in the USA between 2005 and 2011. Annual rates of severe hypoglycemia ranged from 1.4 to 1.6/100 person-years and were higher among older patients; patients treated with insulin, sulfonylurea, and beta-blockers; and patients with chronic kidney disease, heart failure, cardiovascular disease, depression, and higher HbA1c. PubMedCrossRef

67.

CMS. MDS 3.0 Frequency Report: fourth quarter 2017. Centers for Medicare & Medicaid Services. 2017. https://www.cms.gov/Research-Statistics-Data-and-Systems/Computer-Data-and-Systems/Minimum-Data-Set-3-0-Public-Reports/Minimum-Data-Set-3-0-Frequency-Report.html. Accessed February 22 2018.

68.

Patell R, Nigmatoulline D, Bena J, et al. Hyperglycemia and hypoglycemia in patients with diabetes in skilled nursing facilities. Endocr Pract. 2017;23(4):458–65.PubMedCrossRef

69.

Davis KL, Wei W, Meyers JL, et al. Use of basal insulin and the associated clinical outcomes among elderly nursing home residents with type 2 diabetes mellitus: a retrospective chart review study. Clin Interv Aging. 2014;9:1815–22.PubMedPubMedCentralCrossRef

70.

Chandrakumar A, Vikas PV, Tharakan PG, et al. Prevalence of hypoglycemia among diabetic old age home residents in South India. Diabetes Metab Syndr. 2016;10(1 Suppl 1):S144–6.PubMedCrossRef

71.

Mitchell BD, Vietri J, Zagar A, et al. Hypoglycaemic events in patients with type 2 diabetes in the United Kingdom: associations with patient-reported outcomes and self-reported HbA1c. BMC Endocr Disord. 2013;13:59.PubMedPubMedCentralCrossRef

72.

Bonds DE, Miller ME, Dudl J, Feinglos M, Ismail-Beigi F, Malozowski S, et al. Severe hypoglycemia symptoms, antecedent behaviors, immediate consequences and association with glycemia medication usage: secondary analysis of the ACCORD clinical trial data. BMC Endocr Disord. 2012;12:5. https://doi.org/10.1186/1472-6823-12-5.PubMedPubMedCentralCrossRef

73.

Cahn A, Mosenzon O, Bhatt DL, Leibowitz G, Yanuv I, Rozenberg A, et al. Hypoglycaemia manifestations and recurrent events: lessons from the SAVOR-TIMI 53 outcome study. Diabetes Obes Metab. 2017;19(7):1045–50. https://doi.org/10.1111/dom.12903.PubMedCrossRef

74.

Miller CD, Phillips LS, Ziemer DC, et al. Hypoglycemia in patients with type 2 diabetes mellitus. Arch Intern Med. 2001;161(13):1653–9.PubMedCrossRef

75.

Festa A, Heller SR, Seaquist E, Duan R, Hadjiyianni I, Fu H. Association between mild and severe hypoglycemia in people with type 2 diabetes initiating insulin. J Diabetes Complicat. 2017;31(6):1047–52. https://doi.org/10.1016/j.jdiacomp.2016.12.014.PubMedCrossRef

76.

Quilliam BJ, Simeone JC, Ozbay AB. Risk factors for hypoglycemia-related hospitalization in patients with type 2 diabetes: a nested case-control study. Clin Ther. 2011;33(11):1781–91. https://doi.org/10.1016/j.clinthera.2011.09.020.PubMedCrossRef

77.

Misra-Hebert AD, Pantalone KM, Ji X, Milinovich A, Dey T, Chagin KM, 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(6):1164–1171. https://doi.org/10.2337/dc17-1834.

78.

Davis TM, Brown SG, Jacobs IG, et al. Determinants of severe hypoglycemia complicating type 2 diabetes: the Fremantle Diabetes Study. J Clin Endocrinol Metab. 2010;95(5):2240–7.PubMedCrossRef

79.

Bramlage P, Gitt AK, Binz C, et al. Oral antidiabetic treatment in type-2 diabetes in the elderly: balancing the need for glucose control and the risk of hypoglycemia. Cardiovasc Ther. 2012;11:122.

80.

Solomon MD, Vijan S, Forma FM, Conrad RM, Summers NT, Lakdawalla DN. The impact of insulin type on severe hypoglycaemia events requiring inpatient and emergency department care in patients with type 2 diabetes. Diabetes Res Clin Pract. 2013;102(3):175–82. https://doi.org/10.1016/j.diabres.2013.09.013.PubMedCrossRef

81.

Investigators OT. Predictors of nonsevere and severe hypoglycemia during glucose-lowering treatment with insulin glargine or standard drugs in the ORIGIN trial. Diabetes Care. 2015;38(1):22–8. https://doi.org/10.2337/dc14-1329.CrossRef

82.

U. K. Hypoglycaemia Study Group. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia. 2007;50(6):1140–7.CrossRef

83.

•• McCoy RG, Lipska KJ, Yao X, Ross JS, Montori VM, Shah ND. Intensive treatment and severe hypoglycemia among adults with type 2 diabetes mellitus: a population-based study. JAMA Intern Med. 2016;176(7):969–78. https://doi.org/10.1001/jamainternmed.2016.2275. This study quantified the prevalence of diabetes overtreatment among commercially insured and Medicare Advantage beneficiaries with non-insulin-requiring type 2 diabetes across the USA and established the association between overtreatment and severe hypoglycemia. McCoy et al found that 18.7% of clinically complex and 26.5% of non-clinically complex patients were potentially overtreated, which increased the risk-adjusted probability of severe hypoglycemia among clinically complex patients from 1.7% over 2 years to 3.0%. Non-clinically complex patients were able to tolerate potential overtreatment without a significant increase in hypoglycemia risk (1.02 versus 1.30% over 2 years). PubMedPubMedCentralCrossRef

84.

Pauly NJ, Brown JD. Prevalence of low-cost generic program use in a nationally representative cohort of privately insured adults. J Manag Care Spec Pharm. 2015;21(12):1162–70. https://doi.org/10.18553/jmcp.2015.21.12.1162.PubMedCrossRef

85.

• Miller ME, Bonds DE, Gerstein HC, Seaquist ER, Bergenstal RM, Calles-Escandon J, et al. The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study. BMJ. 2010;340:b5444. https://doi.org/10.1136/bmj.b5444. This post hoc analysis of the ACCORD trial examined the patient- and treatment-specific risk factors for hypoglycemia. PubMedPubMedCentralCrossRef

86.

Shorr RI, Ray WA, Daugherty JR, Griffin MR. Incidence and risk factors for serious hypoglycemia in older persons using insulin or sulfonylureas. Arch Intern Med. 1997;157(15):1681–6.PubMedCrossRef

87.

Kostev K, Dippel FW, Rathmann W. Predictors of hypoglycaemia in insulin-treated type 2 diabetes patients in primary care: a retrospective database analysis. Prim Care Diabetes. 2014;8(2):127–31. https://doi.org/10.1016/j.pcd.2013.10.001.PubMedCrossRef

88.

Bruderer SG, Bodmer M, Jick SS, Bader G, Schlienger RG, Meier CR. Incidence of and risk factors for severe hypoglycaemia in treated type 2 diabetes mellitus patients in the UK—a nested case-control analysis. Diabetes Obes Metab. 2014;16(9):801–11. https://doi.org/10.1111/dom.12282.PubMedCrossRef

89.

Feinkohl I, Aung PP, Keller M, Robertson CM, Morling JR, McLachlan S, et al. Severe hypoglycemia and cognitive decline in older people with type 2 diabetes: the Edinburgh type 2 diabetes study. Diabetes Care. 2014;37(2):507–15. https://doi.org/10.2337/dc13-1384.PubMedCrossRef

90.

Schopman JE, Geddes J, Frier BM. Prevalence of impaired awareness of hypoglycaemia and frequency of hypoglycaemia in insulin-treated type 2 diabetes. Diabetes Res Clin Pract. 2010;87(1):64–8.PubMedCrossRef

91.

Seligman HK, Bolger AF, Guzman D, Lopez A, Bibbins-Domingo K. Exhaustion of food budgets at month’s end and hospital admissions for hypoglycemia. Health Aff (Millwood). 2014;33(1):116–23. https://doi.org/10.1377/hlthaff.2013.0096.CrossRef

92.

Seligman HK, Jacobs EA, Lopez A, Sarkar U, Tschann J, Fernandez A. Food insecurity and hypoglycemia among safety net patients with diabetes. Arch Intern Med. 2011;171(13):1204–6. https://doi.org/10.1001/archinternmed.2011.287.PubMedPubMedCentralCrossRef

93.

Seligman HK, Davis TC, Schillinger D, Wolf MS. Food insecurity is associated with hypoglycemia and poor diabetes self-management in a low-income sample with diabetes. J Health Care Poor Underserved. 2010;21(4):1227–33. https://doi.org/10.1353/hpu.2010.0921. PubMedPubMedCentralCrossRef

94.

•• Basu S, Berkowitz SA, Seligman H. The monthly cycle of hypoglycemia: an observational claims-based study of emergency room visits, hospital admissions, and costs in a commercially insured population. Med Care. 2017;55(7):639–45. https://doi.org/10.1097/MLR.0000000000000728. In this nationwide U.S. study conducted among commercially insured adults in the USA, Basu and colleagues demonstrated the association between household income and risk of hypoglycemia-related emergency department visits and hospitalizations, thereby highlighting the potential impact of food insecurity even among insured adults. Patients with household incomes below the national median had a higher rate of severe hypoglycemia overall (203.4 vs. 149.6 events/100,000 person-years), and this risk rose further in the last week of the month, compared to patients with higher household incomes whose hypoglycemia risk remained constant over the course of each month. Moreover, this rise in hypoglycemia among lower-income patients was mitigated by an increase in federal nutrition program benefits, demonstrating how social service/support interventions can help reduce hypoglycemia risk and improve health. PubMedPubMedCentralCrossRef

95.

Shen JJ, Washington EL. Identification of diabetic complications among minority populations. Ethn Dis. 2008;18(2):136–40.PubMed

96.

Karter AJ, Lipska KJ, O’Connor PJ, Liu JY, Moffet HH, Schroeder EB, et al. High rates of severe hypoglycemia among African American patients with diabetes: the surveillance, prevention, and Management of Diabetes Mellitus (SUPREME-DM) network. J Diabetes Complicat. 2017;31(5):869–73. https://doi.org/10.1016/j.jdiacomp.2017.02.009.PubMedPubMedCentralCrossRef

97.

Aldasouqi S, Sheikh A, Klosterman P, Kniestedt S, Schubert L, Danker R, et al. Hypoglycemia in patients with diabetes who are fasting for laboratory blood tests: the Cape Girardeau Hypoglycemia En Route Prevention Program. Postgrad Med. 2013;125(1):136–43. https://doi.org/10.3810/pgm.2013.01.2629.PubMedCrossRef

98.

Halimi S, Levy M, Huet D, et al. Experience with vildagliptin in type 2 diabetic patients fasting during Ramadan in France: insights from the VERDI Study. Diabetes Ther. 2013;4(2):385–98.PubMedPubMedCentralCrossRef

99.

Salti I, Bénard E, Detournay B, Bianchi-Biscay M, Le Brigand C, Voinet C, et al. A population-based study of diabetes and its characteristics during the fasting month of Ramadan in 13 countries. Results of the Epidemiology of Diabetes and Ramadan 1422/2001 (EPIDIAR) Study. Diabetes Care. 2004;27(10):2306–11. https://doi.org/10.2337/diacare.27.10.2306.PubMedCrossRef

100.

Aravind SR, Al Tayeb K, Ismail SB, et al. Hypoglycaemia in sulphonylurea-treated subjects with type 2 diabetes undergoing Ramadan fasting: a five-country observational study. Curr Med Res Opin. 2011;27(6):1237–42.PubMedCrossRef

101.

Shelbaya S, Rakha S. Effectiveness and safety of vildagliptin and vildagliptin add-on to metformin in real-world settings in Egypt—results from the GUARD Study. Curr Med Res Opin. 2017;33(5):797–801.PubMedCrossRef

102.

Rodriguez-Gutierrez R, Ospina NS, McCoy RG, Lipska KJ, Shah ND, Montori VM, et al. Inclusion of hypoglycemia in clinical practice guidelines and performance measures in the care of patients with diabetes. JAMA Intern Med. 2016;176(11):1714–6. https://doi.org/10.1001/jamainternmed.2016.5046.PubMedPubMedCentralCrossRef

103.

Makam AN, Nguyen OK. An evidence-based medicine approach to antihyperglycemic therapy in diabetes mellitus to overcome overtreatment. Circulation. 2017;135(2):180–95. https://doi.org/10.1161/CIRCULATIONAHA.116.022622.PubMedPubMedCentralCrossRef

104.

O’Connor PJ, Desai JR, Butler JC, Kharbanda EO, Sperl-Hillen JM. Current status and future prospects for electronic point-of-care clinical decision support in diabetes care. Curr Diab Rep. 2013;13(2):172–6. https://doi.org/10.1007/s11892-012-0350-z.PubMedPubMedCentralCrossRef

105.

Jha AK, Laguette J, Seger A, Bates DW. Can surveillance systems identify and avert adverse drug events? A prospective evaluation of a commercial application. J Am Med Inform Assoc. 2008;15(5):647–53. https://doi.org/10.1197/jamia.M2634.PubMedPubMedCentralCrossRef

106.

Vimalananda VG, DeSotto K, Chen T, Mullakary J, Schlosser J, Archambeault C, et al. A quality improvement program to reduce potential overtreatment of diabetes among veterans at high risk of hypoglycemia. Diabetes Spectr. 2017;30(3):211–6. https://doi.org/10.2337/ds16-0006.PubMedCrossRefPubMedCentral

107.

•• Schroeder EB, Xu S, Goodrich GK, Nichols GA, O’Connor PJ, Steiner JF. Predicting the 6-month risk of severe hypoglycemia among adults with diabetes: development and external validation of a prediction model. J Diabetes Complicat. 2017;31(7):1158–63. https://doi.org/10.1016/j.jdiacomp.2017.04.004. In this study, Schroeder and colleagues develop and validate two different healthcare delivery systems that are different from Karter et al. (2017) and two risk models predicting the 6-month risk of hospitalization or emergency department visit for hypoglycemia for adults with diabetes (did not differentiate by diabetes type). The full model, which included 16 variables, slightly outperformed the simplified model with six variables. The full model was comprised of patient age, race/ethnicity, diabetes type (type 1 or 2), body mass index, HbA _1c , estimated glomerular filtration rate (eGFR), any hospitalization in the past year, any emergency department visit in the past year, severe hypoglycemic event in the past year, retinopathy, cardiovascular disease, depression, heart failure, insulin, metformin, and number of classes of glucose-lowering medications. The simplified model was comprised of patient age, diabetes type, HbA _1c , eGFR, history of a hypoglycemic event in the prior year, and insulin use. PubMedPubMedCentralCrossRef

108.

• Munshi MN, Slyne C, Segal AR, Saul N, Lyons C, Weinger K. Liberating A1C goals in older adults may not protect against the risk of hypoglycemia. J Diabetes Complicat. 2017;31(7):1197–9. https://doi.org/10.1016/j.jdiacomp.2017.02.014. While diabetes management guidelines and expert consensus recommend that glycemic targets of patients at high risk of hypoglycemia be relaxed in order to prevent future hypoglycemic events, this study demonstrates that such an approach may not be sufficient. In this prospective study, the frequency of hypoglycemic events was monitored by continuous glucose monitoring (CGM) among older adults treated with multiple daily insulin injections or basal insulin with non-insulin agents who had different HbA _1c treatment targets. The duration of hypoglycemia was not different between the HbA _1c groups, regardless of treatment intensity, demonstrating that higher HbA _1c goals may not protect against hypoglycemia. PubMedCrossRef

109.

Munshi MN, Segal AR, Suhl E, et al. Frequent hypoglycemia among elderly patients with poor glycemic control. Arch Intern Med. 2011;171(4):362–4.PubMedPubMedCentralCrossRef

110.

•• Sussman JB, Kerr EA, Saini SD, Holleman RG, Klamerus ML, Min LC, 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(12):1942–9. https://doi.org/10.1001/jamainternmed.2015.5110. This study demonstrates that de-intensification of potentially overtreated older adults with diabetes does not occur often in routine clinical practice (this study was conducted in the U.S. Veterans Health Administration), but when it does, treatment de-intensification is safe as it does not result in a clinically significant or concerning rise in HbA _1c . Glucose-lowering therapy was de-intensified among 27% of patients with HbA _1c <6.0%, 21% of patients with HbA _1c 6.0–6.4%, and 18% of patients with HbA _1c ≥6.5%, demonstrating the remaining opportunities for individualizing and improving the diabetes care among older adults at risk of hypoglycemia.

111.

• Munshi MN, Slyne C, Segal AR, Saul N, Lyons C, Weinger K. Simplification of insulin regimen in older adults and risk of hypoglycemia. JAMA Intern Med. 2016;176(7):1023–5. https://doi.org/10.1001/jamainternmed.2016.2288. In this single-arm intervention study, Munshi and colleagues simplified insulin regimens of 65 older adults with type 2 diabetes who, at baseline, were treated with ≥2 insulin injections per day or with any hypoglycemia on baseline 5-day continuous glucose monitor assessment. Simplification to basal insulin with or without non-insulin agents resulted in reduction in hypoglycemia, reduction in diabetes distress symptoms, reduction in HbA _1c among patients with baseline HbA _1c ≥8%, and slight increase in HbA _1c among patients with baseline HbA _1c <7.0%. This demonstrates the importance of treatment simplification and de-intensification among older adults not only to reduce hypoglycemia but also to improve quality of life and attain safe glycemic targets appropriate for patient age. PubMedCrossRef

112.

Lipska KJ, Ross JS, Miao Y, Shah ND, Lee SJ, Steinman MA. Potential overtreatment of diabetes mellitus in older adults with tight glycemic control. JAMA Intern Med. 2015;175(3):356–62. https://doi.org/10.1001/jamainternmed.2014.7345.PubMedPubMedCentralCrossRef

113.

Tseng CL, Soroka O, Maney M, Aron DC, Pogach LM. Assessing potential glycemic overtreatment in persons at hypoglycemic risk. JAMA Intern Med. 2014;174(2):259–68. https://doi.org/10.1001/jamainternmed.2013.12963.PubMedCrossRef

114.

de Vries ST, Voorham J, Haaijer-Ruskamp FM, Denig P. Potential overtreatment and undertreatment of diabetes in different patient age groups in primary care after the introduction of performance measures. Diabetes Care. 2014;37(5):1312–20. https://doi.org/10.2337/dc13-1861.PubMedCrossRef

115.

ADA. American Diabetes Association Standards of Medical Care in Diabetes—2018. Section 8. Pharmacologic approaches to glycemic treatment. Diabetes Care 2018;41(Supplement 1):S73-S85. https://doi.org/10.2337/dc18-S008.

116.

de Zoysa N, Rogers H, Stadler M, Gianfrancesco C, Beveridge S, Britneff E, et al. A psychoeducational program to restore hypoglycemia awareness: the DAFNE-HART pilot study. Diabetes Care. 2014;37(3):863–6. https://doi.org/10.2337/dc13-1245. PubMedCrossRef

117.

Beck RW, Riddlesworth TD, Ruedy K, et al. Continuous glucose monitoring versus usual care in patients with type 2 diabetes receiving multiple daily insulin injections: a randomized trial. Ann Intern Med. 2017;167(6):365–74. https://doi.org/10.7326/M16-2855.PubMedCrossRef

118.

Vigersky R, Shrivastav M. Role of continuous glucose monitoring for type 2 in diabetes management and research. J Diabetes Complicat. 2017;31(1):280–7. https://doi.org/10.1016/j.jdiacomp.2016.10.007.PubMedCrossRef

119.

Vigersky RA, Fonda SJ, Chellappa M, Walker MS, Ehrhardt NM. Short- and long-term effects of real-time continuous glucose monitoring in patients with type 2 diabetes. Diabetes Care. 2012;35(1):32–8. https://doi.org/10.2337/dc11-1438.PubMedCrossRef

120.

Zick R, Petersen B, Richter M, Haug C, Group oBotSS. Comparison of continuous blood glucose measurement with conventional documentation of hypoglycemia in patients with type 2 diabetes on multiple daily insulin injection therapy. Diabetes Technol Ther. 2007;9(6):483–92. https://doi.org/10.1089/dia.2007.0230.PubMedCrossRef

121.

Haak T, Hanaire H, Ajjan R, Hermanns N, Riveline J-P, Rayman G. Flash glucose-sensing technology as a replacement for blood glucose monitoring for the management of insulin-treated type 2 diabetes: a multicenter, open-label randomized controlled trial. Diabetes Ther. 2017;8(1):55–73. https://doi.org/10.1007/s13300-016-0223-6.PubMedCrossRef

122.

Greer N, Bolduc J, Geurkink E, Rector T, Olson K, Koeller E, et al. Pharmacist-led chronic disease management: a systematic review of effectiveness and harms compared with usual care. Ann Intern Med. 2016;165(1):30–40. https://doi.org/10.7326/M15-3058.

123.

Downing J, Bollyky J, Schneider J. Use of a connected glucose meter and certified diabetes educator coaching to decrease the likelihood of abnormal blood glucose excursions: the Livongo for Diabetes Program. J Med Internet Res. 2017;19(7):e234. https://doi.org/10.2196/jmir.6659.PubMedPubMedCentralCrossRef

124.

Bravis V, Hui E, Salih S, Mehar S, Hassanein M, Devendra D. Ramadan Education and Awareness in Diabetes (READ) programme for Muslims with type 2 diabetes who fast during Ramadan. Diabet Med. 2010;27(3):327–31. https://doi.org/10.1111/j.1464-5491.2010.02948.x.PubMedCrossRef

125.

Islam NS, Wyatt LC, Taher M, Riley L, Tandon SD, Tanner M, et al. A culturally tailored community health worker intervention leads to improvement in patient-centered outcomes for immigrant patients with type 2 diabetes. Clin Diabetes. 2018;36(2):100–111. https://doi.org/10.2337/cd17-0068.

126.

Perez-Escamilla R, Damio G, Chhabra J, Fernandez ML, Segura-Perez S, Vega-Lopez S, et al. Impact of a community health workers-led structured program on blood glucose control among latinos with type 2 diabetes: the DIALBEST trial. Diabetes Care. 2015;38(2):197–205. https://doi.org/10.2337/dc14-0327.PubMedCrossRef

Be confident that your patient care is up to date

Medicine Matters is being incorporated into Springer Medicine, our new medical education platform.

Alongside the news coverage and expert commentary you have come to expect from Medicine Matters diabetes, Springer Medicine's complimentary membership also provides access to articles from renowned journals and a broad range of Continuing Medical Education programs. Create your free account »