Research Article| Volume 113, P143-151, March 2016

Download started.


Strategies for glucose control in a study population with diabetes, renal disease and anemia (Treat study)

Published:January 18, 2016DOI:


      • Choices of antidiabetic therapy with diminished renal function and anemia.
      • Vary according to level of renal function.
      • Are subject to regional variation.
      • Demonstrate greater reliance on insulin at lowest levels of renal function.


      Glucose lowering medication use among patients with type 2 diabetes and advanced renal disease (eGFR < 60) in a large multinational outcome trial (TREAT) is assessed. We demonstrate statistically significant differences regionally in use of metformin at lower eGFR and increasing reliance upon insulin with/without other medications at low eGFR.


      As renal disease advances, most of the oral anti-diabetic agents requiring renal clearance must be reduced or discontinued. The potential for prolonged hypoglycemia, fluid/volume overload and congestive heart failure may complicate medication choices. In order to evaluate patterns of glycemia management we describe glucose lowering medication use among patients with advanced renal disease and type 2 diabetes in a large multinational outcome trial designed to focus on patients with eGFR < 60 in order to commence a dialog on best practices. We felt that analysis of this data would be able to describe regional variations in treatment within a multinational trial in order to understand potential outcome differences attributed to complications.


      The patients entering this study had moderate glycemic control. Insulin therapy either alone (32%) or in combination with other agents (17%) reflected a shift towards insulin use in those subjects with decreased renal function when compared with standard populations with normal kidney function. The use of multiple oral agents, or oral agents plus insulin was quite common. While gender did not appear to play a role in medication choices, there were significant regional variations. For example, oral agents were used more in North America compared with other regions (Latin America, Australia/Western Europe, Russia/Eastern Europe). Patients enrolled at more advanced ages were less likely to be on a regimen of rapid-acting insulin alone consistent with recommendations that suggest a preference for longer-acting preparations in the geriatric population (1). Higher degrees of obesity were associated more complex treatment regimens. Despite this population being at high risk for cardiovascular events, the use of beta blockers (50%), statins (64%) and aspirin (48%) were relatively low, especially in the group that did not require medications to achieve adequate glycemic control.


      Current attempts to compare strategies for diabetes therapy must control for baseline demographic group differences influencing treatment choice. Future recommendations for glycemic control in patients with Grade 3 or higher chronic kidney disease require additional studies, with matched populations. We suggest that evaluation of studies similar to TREAT will assist in determining the optimal therapeutic regimens for populations with moderate to severe renal dysfunction, a condition in which repeated hospitalizations for fluid overload/heart failure add to the high cost of diabetes care.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Diabetes Research and Clinical Practice
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Kirkman M.S.
        • Briscoe V.J.
        • Clark N.
        • Florez H.
        • Haas L.B.
        • Halter J.B.
        • 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
        • Lewis E.J.
        • Hunsicker L.G.
        • Bain R.P.
        • Rohde R.D.
        The effect of angiotensin converting enzyme inhibition on diabetic nephropathy. The Collaborative Study Group.
        N Engl J Med. 1993; 329: 1456-1462
        • Brenner B.M.
        • Cooper M.E.
        • de Zeeuw D.
        • Keane W.F.
        • Mitch W.E.
        • Parving H.H.
        • et al.
        • RENAAL Study Investigators
        Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.
        N Engl J Med. 2001; 345: 861-869
        • Anavekar N.S.
        • McMurray J.J.
        • Velazquez E.J.
        • Solomon S.D.
        • Kober L.
        • Rouleau J.L.
        • et al.
        Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction.
        N Engl J Med. 2004; 351: 1285-1295
        • Yusuf S.
        • Teo K.K.
        • Pogue J.
        • Dyal L.
        • Copland I.
        • Schumacher H.
        • et al.
        • ONTARGET Investigators
        Telmisartan, ramipril, or both in patients at high risk for vascular events.
        N Engl J Med. 2008; 358: 1547-1559
        • Parving H.H.
        • Brenner B.M.
        • McMurray J.J.
        • de Zeeuw D.
        • Haffner S.M.
        • Solomon S.D.
        • et al.
        • ALTITUDE Investigators
        Cardiorenal end points in a trial of aliskiren for type 2 diabetes.
        N Engl J Med. 2012; 367: 2204-2213
        • Gheorghiade M.
        • Böhm M.
        • Greene S.J.
        • Fonarow G.C.
        • Lewis E.F.
        • Zannad F.
        • et al.
        • ASTRONAUT Investigators and Coordinators
        Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: the ASTRONAUT randomized trial.
        JAMA. 2013; 309: 1125-1135
        • Tang W.H.
        • Francis G.S.
        • Hoogwerf B.J.
        • Young J.B.
        Fluid retention after initiation of thiazolidinedione therapy in diabetic patients with established chronic heart failure.
        J Am Coll Cardiol. 2003; 41: 1394-1398
        • Nesto R.W.
        • Bell D.
        • Bonow R.O.
        • Fonseca V.
        • Grundy S.M.
        • Horton E.S.
        • et al.
        Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association.
        Diabetes Care. 2004; 27: 256-263
        • Garber A.J.
        • Abrahamson M.J.
        • Barzilay J.I.
        • Blonde L.
        • Bloomgarden Z.T.
        • Bush M.A.
        • et al.
        American Association of Clinical Endocrinologists comprehensive diabetes management algorithm 2013 consensus statement—executive summary.
        Endocr Pract. 2013; 19: 536-557
        • Inzucchi S.E.
        • Bergenstal R.M.
        • Buse J.B.
        • Diamant M.
        • Ferrannini E.
        • Nauck M.
        • et al.
        Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
        Diabetes Care. 2012; 35: 1364-1379
        • Goldfine A.B.
        • Phua E-J.
        • Abrahamson M.J.
        Glycemic management in patients with coronary artery disease and prediabetes or type 2 diabetes mellitus.
        Circulation. 2014; 129: 2567-2573
        • Menon V.
        • Lincoff M.
        Cardiovascular safety in the development of new drugs for diabetes mellitus.
        Circulation. 2014; 129: 2705-2713
        • Huang E.S.
        • Liu J.Y.
        • Moffet H.H.
        • John P.M.
        • Karter A.J.
        Glycemic control, complications, and death in older diabetic patients: the diabetes and aging study.
        Diabetes Care. 2011; 34: 1329-1336
        • Mix T.-C.
        • Brenner R.M.
        • Cooper M.E.
        • deZeeuw D.
        • Ivanovich P.
        • Levey A.S.
        • et al.
        Rationale- Trial to reduce cardiovascular events with aranesp therapy (TREAT): evolving the management of cardiovascular risk in patients with chronic kidney disease.
        Am Heart J. 2005; 149: 408-413
        • Pfeffer M.A.
        • Burdmann E.A.
        • Chen C.Y.
        • Cooper M.E.
        • de Zeeuw D.
        • Eckardt K.U.
        • et al.
        • Uno H on behalf of the TREAT Investigators
        Baseline characteristics in the trial to reduce cardiovascular events with aranesp therapy (TREAT).
        Am J Kidney Dis. 2009; 54: 59-69
        • Pfeffer M.A.
        • Burdmann E.A.
        • Chen C.Y.
        • Cooper M.E.
        • de Zeeuw D.
        • Eckardt K.U.
        • et al.
        • TREAT Investigators
        A trial of darbopoietin alfa in type 2 diabetes and chronic renal disease.
        N Engl J Med. 2009 19; 361: 2019-2032
        • National Kidney Foundation
        KDOQI clinical practice guideline for diabetes and CKD: 2012 update.
        Am J Kidney Dis. 2012; 60: 850
        • National Center for Chronic Disease Prevention and Health Promotion, Division of Diabetes Translation
        • Centers for Disease Control and Prevention
        National diabetes statistics report.
        National Center for Chronic Disease Prevention and Health Promotion, Division of Diabetes Translation. Centers for Disease Control and Prevention, 4770 Buford Highway Northeast, Mail stop F-73, Atlanta, GA 303412014
        • Frye R.L.
        • August P.
        • Brooks M.M.
        • Hardison R.M.
        • Kelsey S.F.
        • MacGregor J.M.
        • et al.
        • The BARI 2D Study Group
        A randomized trial of therapies for type 2 diabetes and coronary artery disease.
        N Engl J Med. 2009; 360: 2503-2515
        • Pop-Busui R.
        • Lu J.
        • Brooks M.M.
        • Albert S.
        • Althouse A.D.
        • Escobedo J.
        • et al.
        • BARI 2D Study Group
        Impact of glycemic control strategies on the progression of diabetic peripheral neuropathy in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Cohort.
        Diabetes Care. 2013; 36: 3208-3215
        • Barnett A.H.
        Complementing insulin therapy to achieve glycemic control.
        Adv Ther. 2013; 30: 557-576
        • Bennett W.L.
        • Maruthur N.M.
        • Singh S.
        • Segal J.B.
        • Wilson L.M.
        • Chatterjee R.
        • et al.
        Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations.
        Ann Intern Med. 2011; 154: 602-613
        • Tzoulaki I.
        • Molokhia M.
        • Curcin V.
        • Little M.P.
        • Millett C.J.
        • Ng A.
        • et al.
        Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database.
        BMJ. 2009; 339: b4731
        • Wallia A.
        • Molitch M.E.
        Insulin therapy for type 2 diabetes mellitus.
        JAMA. 2014; 3111: 2315-2325
        • Andrews M.A.
        • O’Malley P.G.
        Diabetes overtreatment in elderly individuals: risk business in need of better management.
        JAMA. 2014; 174: 259-268
        • Andresdottir G.
        • Jensen M.
        • Carstensen B.
        • Parving H-H.
        • Rossing K.
        • Hansen T.
        • et al.
        Improved survival and renal prognosis of patients with type 2 diabetes and nephropathy with improved control of risk factors.
        Diabetes Care. 2014; 37: 1660-1667
        • Pilz S.
        • Rutters F.
        • Nijpels G.
        • Stehouwer C.D.A.
        • Houjlund K.
        • Nolan J.
        • et al.
        Insulin sensitivity and albuminuria: the RISC study.
        Diabetes Care. 2014; 37: 1597-1603
        • Margolis K.
        • O’Connor P.
        • Morgan T.
        • Buse J.
        • Cohen R.
        • Cushman W.
        • et al.
        Outcomes of combined cardiovascular risk factor management strategies in type 2 diabetes: the ACCORD randomized trial.
        Diabetes Care. 2014; 37: 1721-1728
        • Solini A.
        • Penno G.
        • Bonora E.
        • Fondelli C.
        • Orsi E.
        • Trevisan R.
        • et al.
        • Renal insufficiency and Cardiovascular Events Study Group
        Age, renal dysfunction, cardiovascular disease, and antihyperglycemic treatment in type 2 diabetes mellitus: findings from the Renal Insufficiency and Cardiovascular Events Italian Multicenter Study.
        Am Geriatr Soc. 2013; 61: 1253-1261
        • Ismail-Beigi F.
        • Craven T.
        • Banerji M.A.
        • Basile J.
        • Calles J.
        • Cohen R.M.
        • et al.
        • ACCORD trial group
        Effect of intensive treatment of hyperglycemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomized trial.
        Lancet. 2010; 376: 419-430
        • Ninomiya T.
        • Perkovic V.
        • de Galan B.E.
        • Zoungas S.
        • Pillai A.
        • Jardine M.
        • et al.
        • ADVANCE Collaborative Group
        Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes.
        J Am Soc Nephrol. 2009; 20: 1813-1821
        • UK Prospective Diabetes Study 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).
        Lancet. 1998; 352: 837-853
        • UK Prospective Diabetes Study Group
        Effect of intensive blood–glucose control with metformin on complications in overweight patient with type 2 diabetes (UKPDS 34).
        Lancet. 1998; 352: 854-865
        • Garg R.
        • Williams M.E.
        Diabetes management in the kidney patient.
        Med Clin North Am. 2013; 97: 135-156
        • Ferrannini E.
        The target of metformin in type 2 diabetes.
        N Engl J Med. 2014; 371: 1547-1548
        • Roumie C.L.
        • Greevy R.A.
        • Grijalva C.G.
        • Hung A.M.
        • Liu X.
        • Murff H.J.
        • et al.
        Association between intensification of metformin treatment with insulin vs. sulfonylureas and cardiovascular events and all cause mortality among patients with diabetes.
        JAMA. 2014; 311: 2288-2296
        • Salpeter S.
        • Greyber E.
        • Pasternak G.
        • Salpeter E.
        Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus.
        Cochrane Database Syst Rev. 2006; : CD002967


        • Holstein A.
        • Stumvoll M.
        Contraindications can damage your health—is metformin a case in point?.
        Diabetologia. 2005; 48: 2454-2459
        • Inzucchi S.E.
        • Lipska K.J.
        • Mayo H.
        • Bailey C.J.
        • McGuire D.K.
        Metformin in patients with type 2 diabetes and kidney disease: a systematic review.
        JAMA. 2014; 312: 2668-2675
        • Lipska K.J.
        • Bailey C.J.
        • Inzucchi S.E.
        Use of metformin in the setting of mild-to-moderate renal insufficiency.
        Diabetes Care. 2011; 34: 1431-1437
        • Tuot D.S.
        • et al.
        For the CDC CKD Surveillance Team.
        Diabetes Care. 2015; 38: 2059-2067
        • Vlagopoulos P.T.
        • Tighiouart H.
        • Weiner D.E.
        • Griffith J.
        • Pettitt D.
        • Salem D.N.
        • Anemia as a risk factor for cardiovascular disease and all-cause mortality in diabetes: the impact of chronic kidney disease
        • et al.
        J Am Soc Nephrol. 2005; 16: 3403-3410