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American Journal of Kidney Diseases

Hypoglycemia-Related Hospitalizations and Mortality Among Patients With Diabetes Transitioning to Dialysis

  • Connie M. Rhee
    Correspondence
    Address for Correspondence: Connie M. Rhee, MD, MSc, Harold Simmons Center for Chronic Disease Research and Epidemiology, University of California Irvine School of Medicine, 101 The City Dr S, City Tower, Ste 400, Orange, CA 92868.
    Affiliations
    Harold Simmons Center for Chronic Disease Research and Epidemiology, University of California Irvine School of Medicine, Orange, CA
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  • Csaba P. Kovesdy
    Affiliations
    Division of Nephrology, University of Tennessee Health Science Center, Memphis, TN

    Nephrology Section, Memphis Veterans Affairs Medical Center, Memphis, TN
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  • Amy S. You
    Affiliations
    Harold Simmons Center for Chronic Disease Research and Epidemiology, University of California Irvine School of Medicine, Orange, CA
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  • John J. Sim
    Affiliations
    Kaiser Permanente of Southern California, Los Angeles, CA
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  • Melissa Soohoo
    Affiliations
    Harold Simmons Center for Chronic Disease Research and Epidemiology, University of California Irvine School of Medicine, Orange, CA
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  • Elani Streja
    Affiliations
    Harold Simmons Center for Chronic Disease Research and Epidemiology, University of California Irvine School of Medicine, Orange, CA

    Tibor Rubin Veterans Affairs Medical Center, Long Beach, CA
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  • Miklos Z. Molnar
    Affiliations
    Division of Nephrology, University of Tennessee Health Science Center, Memphis, TN

    Division of Transplant Surgery, Methodist University Hospital Transplant Institute, Memphis, TN

    Division of Transplant Surgery, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN

    Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary
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  • Alpesh N. Amin
    Affiliations
    Department of Medicine, University of California Irvine School of Medicine, Orange, CA
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  • Kevin Abbott
    Affiliations
    Division of Kidney, Urologic and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
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  • Danh V. Nguyen
    Affiliations
    Department of Medicine, University of California Irvine School of Medicine, Orange, CA
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  • Kamyar Kalantar-Zadeh
    Affiliations
    Harold Simmons Center for Chronic Disease Research and Epidemiology, University of California Irvine School of Medicine, Orange, CA

    Tibor Rubin Veterans Affairs Medical Center, Long Beach, CA
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      Rationale & Objective

      Diabetic patients with declining kidney function are at heightened risk for hypoglycemia. We sought to determine whether hypoglycemia-related hospitalizations in the interval before dialysis therapy initiation are associated with post–end-stage renal disease (ESRD) mortality among incident patients with ESRD with diabetes.

      Study Design

      Observational cohort study.

      Setting & Participants

      US veterans from the national Veterans Affairs database with diabetes and chronic kidney disease transitioning to dialysis therapy from October 2007 to September 2011.

      Exposure

      Hypoglycemia-related hospitalizations during the pre-ESRD period and antidiabetic medication regimens.

      Outcome

      The outcome of post-ESRD all-cause mortality was evaluated relative to pre-ESRD hypoglycemia. The outcome of pre-ESRD hypoglycemia-related hospitalization was evaluated relative to antidiabetic medication regimens.

      Analytic Approach

      We examined whether the occurrence and frequency of pre-ESRD hypoglycemia-related hospitalizations are associated with post-ESRD mortality using Cox regression models adjusted for case-mix covariates. In a subcohort of patients prescribed 0 to 2 oral antidiabetic drugs and/or insulin, we examined the 12 most commonly prescribed antidiabetic medication regimens and risk for pre-ESRD hypoglycemia-related hospitalization using logistic regression models adjusted for case-mix covariates.

      Results

      Among 30,156 patients who met eligibility criteria, the occurrence of pre-ESRD hypoglycemia-related hospitalization(s) was associated with higher post-ESRD mortality risk: adjusted HR (aHR), 1.25; 95% CI, 1.17-1.34 (reference group: no hypoglycemia hospitalization). Increasing frequency of hypoglycemia-related hospitalizations was independently associated with incrementally higher mortality risk: aHRs of 1.21 (95% CI, 1.12-1.30), 1.47 (95% CI, 1.19-1.82), and 2.07 (95% CI, 1.46-2.95) for 1, 2, and 3 or more hypoglycemia-related hospitalizations, respectively (reference group: no hypoglycemia hospitalization). Compared with patients who were prescribed neither oral antidiabetic drugs nor insulin, medication regimens that included sulfonylureas and/or insulin were associated with higher risk for hypoglycemia.

      Limitations

      Residual confounding cannot be excluded.

      Conclusions

      Among incident patients with ESRD with diabetes, a dose-dependent relationship between frequency of pre-ESRD hypoglycemia-related hospitalizations and post-ESRD mortality was observed. Further study of diabetic management strategies that prevent hypoglycemia as patients with chronic kidney disease transition to ESRD are warranted.

      Index Words

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      References

        • Alicic R.Z.
        • Tuttle K.R.
        Management of the diabetic patient with advanced chronic kidney disease.
        Semin Dial. 2010; 23: 140-147
        • Saran R.
        • Robinson B.
        • Abbott K.C.
        • et al.
        US Renal Data System 2016 annual data report: epidemiology of kidney disease in the United States.
        Am J Kidney Dis. 2017; 69: A7-A8
        • Kalantar-Zadeh K.
        • Kovesdy C.P.
        • Streja E.
        • et al.
        Transition of care from pre-dialysis prelude to renal replacement therapy: the blueprints of emerging research in advanced chronic kidney disease.
        Nephrol Dial Transplant. 2017; 32: ii91-ii98
        • Lukowsky L.R.
        • Kheifets L.
        • Arah O.A.
        • Nissenson A.R.
        • Kalantar-Zadeh K.
        Patterns and predictors of early mortality in incident hemodialysis patients: new insights.
        Am J Nephrol. 2012; 35: 548-558
        • Rhee C.M.
        • Leung A.M.
        • Kovesdy C.P.
        • Lynch K.E.
        • Brent G.A.
        • Kalantar-Zadeh K.
        Updates on the management of diabetes in dialysis patients.
        Semin Dial. 2014; 27: 135-145
        • Diabetes Control and Complications Trial Research Group
        • Nathan D.M.
        • Genuth S.
        • Lachin J.
        • et al.
        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
        • United Kingdom Prospective Diabetes Study (UKPDS)
        13: Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years.
        BMJ. 1995; 310: 83-88
        • Action to Control Cardiovascular Risk in Diabetes Study Group
        • Gerstein H.C.
        • Miller M.E.
        • Byington R.P.
        • et al.
        Effects of intensive glucose lowering in type 2 diabetes.
        N Engl J Med. 2008; 358: 2545-2559
        • Duckworth W.
        • Abraira C.
        • Moritz T.
        • et al.
        Glucose control and vascular complications in veterans with type 2 diabetes.
        N Engl J Med. 2009; 360: 129-139
        • Ismail-Beigi F.
        • Craven T.
        • Banerji M.A.
        • et al.
        Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial.
        Lancet. 2010; 376: 419-430
        • Patel A.
        • MacMahon S.
        • Chalmers J.
        • et al.
        Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
        N Engl J Med. 2008; 358: 2560-2572
        • 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
        • Abe M.
        • Kalantar-Zadeh K.
        Haemodialysis-induced hypoglycaemia and glycaemic disarrays.
        Nat Rev Nephrol. 2015; 11: 302-313
        • Gosmanov A.R.
        • Gosmanova E.O.
        • Kovesdy C.P.
        Evaluation and management of diabetic and non-diabetic hypoglycemia in end-stage renal disease.
        Nephrol Dial Transplant. 2016; 31: 8-15
        • Ricks J.
        • Molnar M.Z.
        • Kovesdy C.P.
        • et al.
        Glycemic control and cardiovascular mortality in hemodialysis patients with diabetes: a 6-year cohort study.
        Diabetes. 2012; 61: 708-715
        • Lipska K.J.
        • Ross J.S.
        • Wang Y.
        • et al.
        National trends in US hospital admissions for hyperglycemia and hypoglycemia among Medicare beneficiaries, 1999 to 2011.
        JAMA Intern Med. 2014; 174: 1116-1124
        • Zaccardi F.
        • Davies M.J.
        • Dhalwani N.N.
        • et al.
        Trends in hospital admissions for hypoglycaemia in England: a retrospective, observational study.
        Lancet Diabetes Endocrinol. 2016; 4: 677-685
        • 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
        • Zoungas S.
        • Patel A.
        • Chalmers J.
        • et al.
        Severe hypoglycemia and risks of vascular events and death.
        N Engl J Med. 2010; 363: 1410-1418
        • Zhao Y.
        • Shi Q.
        • Wang Y.
        • Fonseca V.
        • Shi L.
        Economic burden of hypoglycemia: utilization of emergency department and outpatient services in the United States (2005-2009).
        J Med Econ. 2016; 19: 852-857
        • Moen M.F.
        • Zhan M.
        • Hsu V.D.
        • et al.
        Frequency of hypoglycemia and its significance in chronic kidney disease.
        Clin J Am Soc Nephrol. 2009; 4: 1121-1127
        • Kong A.P.
        • Yang X.
        • Luk A.
        • et al.
        Hypoglycaemia, chronic kidney disease and death in type 2 diabetes: the Hong Kong diabetes registry.
        BMC Endocr Disord. 2014; 14: 48
        • Papademetriou V.
        • Lovato L.
        • Doumas M.
        • et al.
        Chronic kidney disease and intensive glycemic control increase cardiovascular risk in patients with type 2 diabetes.
        Kidney Int. 2015; 87: 649-659
        • Cho A.
        • Noh J.W.
        • Kim J.K.
        • et al.
        Prevalence and prognosis of hypoglycaemia in patients receiving maintenance dialysis.
        Intern Med J. 2016; 46: 1380-1385
        • Molnar M.Z.
        • Gosmanova E.O.
        • Sumida K.
        • et al.
        Predialysis cardiovascular disease medication adherence and mortality after transition to dialysis.
        Am J Kidney Dis. 2016; 68: 609-618
        • Sumida K.
        • Molnar M.Z.
        • Potukuchi P.K.
        • et al.
        Association of slopes of estimated glomerular filtration rate with post-end-stage renal disease mortality in patients with advanced chronic kidney disease transitioning to dialysis.
        Mayo Clin Proc. 2016; 91: 196-207
        • Sumida K.
        • Molnar M.Z.
        • Potukuchi P.K.
        • et al.
        Prognostic significance of pre-end-stage renal disease serum alkaline phosphatase for post-end-stage renal disease mortality in late-stage chronic kidney disease patients transitioning to dialysis.
        Nephrol Dial Transplant. 2018; 33: 264-273
        • Sumida K.
        • Molnar M.Z.
        • Potukuchi P.K.
        • et al.
        Association between vascular access creation and deceleration of estimated glomerular filtration rate decline in late-stage chronic kidney disease patients transitioning to end-stage renal disease.
        Nephrol Dial Transplant. 2017; 32: 1330-1337
        • Eby E.L.
        • Van Brunt K.
        • Brusko C.
        • Curtis B.
        • Lage M.J.
        Dosing of U-100 insulin and associated outcomes among Medicare enrollees with type 1 or type 2 diabetes.
        Clin Interv Aging. 2015; 10: 991-1001
        • Katon W.J.
        • Young B.A.
        • Russo J.
        • et al.
        Association of depression with increased risk of severe hypoglycemic episodes in patients with diabetes.
        Ann Fam Med. 2013; 11: 245-250
        • 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
        • Romley J.A.
        • Gong C.
        • Jena A.B.
        • Goldman D.P.
        • Williams B.
        • Peters A.
        Association between use of warfarin with common sulfonylureas and serious hypoglycemic events: retrospective cohort analysis.
        BMJ. 2015; 351: h6223
        • US Department of Veterans Affairs; Health Services Research and Development Service; VA Information Resource Center
        VIReC Research User Guide: VHA Medical SAS Datasets FY2006-2007.
        VA Information Resource Center, Hines, IL2007
        • Ravel V.
        • Ahmadi S.F.
        • Streja E.
        • et al.
        Pain and kidney function decline and mortality: a cohort study of US veterans.
        Am J Kidney Dis. 2016; 68: 240-246
        • Deyo R.A.
        • Cherkin D.C.
        • Ciol M.A.
        Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases.
        J Clin Epidemiol. 1992; 45: 613-619
        • US Department of Veterans Affairs; Health Services Research and Development Service; VA Information Resource Center
        VIReC Research User Guide: VHA Pharmacy Prescription Data.
        2nd ed. VA Information Resource Center, Hines, IL2008
        • Hung A.M.
        • Roumie C.L.
        • Greevy R.A.
        • et al.
        Kidney function decline in metformin versus sulfonylurea initiators: assessment of time-dependent contribution of weight, blood pressure, and glycemic control.
        Pharmacoepidemiol Drug Saf. 2013; 22: 623-631
        • US Department of Veterans Affairs; Health Services Research and Development Service; VA Information Resource Center
        VIReC Resource Guide: VA Corporate Data Warehouse.
        VA Information Resource Center, Hines, IL2012
        • Levey A.S.
        • Stevens L.A.
        • Schmid C.H.
        • et al.
        A new equation to estimate glomerular filtration rate.
        Ann Intern Med. 2009; 150: 604-612
        • US Renal Data System
        USRDS Special Study Center on Transition of Care in CKD.
        USRDS, Bethesda, MD2014
        • Ginsberg J.S.
        • Zhan M.
        • Diamantidis C.J.
        • Woods C.
        • Chen J.
        • Fink J.C.
        Patient-reported and actionable safety events in CKD.
        J Am Soc Nephrol. 2014; 25: 1564-1573
        • Cryer P.E.
        Hypoglycemia, functional brain failure, and brain death.
        J Clin Invest. 2007; 117: 868-870
        • Robinson R.T.
        • Harris N.D.
        • Ireland R.H.
        • Lee S.
        • Newman C.
        • Heller S.R.
        Mechanisms of abnormal cardiac repolarization during insulin-induced hypoglycemia.
        Diabetes. 2003; 52: 1469-1474
        • De Ferrari G.M.
        • Sanzo A.
        • Bertoletti A.
        • Specchia G.
        • Vanoli E.
        • Schwartz P.J.
        Baroreflex sensitivity predicts long-term cardiovascular mortality after myocardial infarction even in patients with preserved left ventricular function.
        J Am Coll Cardiol. 2007; 50: 2285-2290
        • Bakris G.L.
        • Molitch M.E.
        Should restrictions be relaxed for metformin use in chronic kidney disease? Yes, they should be relaxed! What's the fuss?.
        Diabetes Care. 2016; 39: 1287-1291
        • Kalantar-Zadeh K.
        Case 23-2013: a 54-year-old woman with metformin toxicity.
        N Engl J Med. 2013; 369: 1769
        • Kalantar-Zadeh K.
        • Kovesdy C.P.
        Should restrictions be relaxed for metformin use in chronic kidney disease? No, we should never again compromise safety!.
        Diabetes Care. 2016; 39: 1281-1286
        • Kalantar-Zadeh K.
        • Rhee C.M.
        Metformin in chronic kidney disease: more harm than help?.
        Lancet Diabetes Endocrinol. 2015; 3: 579-581
        • Rhee C.M.
        • Kalantar-Zadeh K.
        Restricting metformin in CKD: continued caution warranted.
        Am J Kidney Dis. 2015; 66: 1101-1102
        • Rhee C.M.
        • Kovesdy C.P.
        • Kalantar-Zadeh K.
        Risks of metformin in type 2 diabetes and chronic kidney disease: lessons learned from Taiwanese data.
        Nephron. 2017; 135: 147-153
        • Tuccori M.
        • Filion K.B.
        • Yin H.
        • Yu O.H.
        • Platt R.W.
        • Azoulay L.
        Pioglitazone use and risk of bladder cancer: population based cohort study.
        BMJ. 2016; 352: i1541
        • Nesto R.W.
        • Bell D.
        • Bonow R.O.
        • et al.
        Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. October 7, 2003.
        Circulation. 2003; 108: 2941-2948
        • Napoli N.
        • Chandran M.
        • Pierroz D.D.
        • Abrahamsen B.
        • Schwartz A.V.
        • Ferrari S.L.
        • IOF Bone and Diabetes Working Group
        Mechanisms of diabetes mellitus-induced bone fragility.
        Nat Rev Endocrinol. 2017; 13: 208-219
      1. FDA Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. http://www.fda.gov/Drugs/DrugSafety. Accessed March 20, 2018.