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American Journal of Kidney Diseases

Glycemic Control and Mortality in Diabetic Patients Undergoing Hemodialysis: Much More to Learn

      Related Article, p. 84
      People with end-stage renal disease (ESRD) who have diabetes have poorer survival than those without diabetes. The latest report from the US Renal Data System (USRDS) shows that 49% of people with diabetes who are treated with renal replacement therapy (RRT) are alive after 3 years compared with 63% of individuals who have a primary diagnosis of glomerulonephritis (note that these data are adjusted for age and other factors).
      • Collins A.J.
      • Foley R.N.
      • Herzog C.
      • et al.
      US Renal Data System 2012 annual data report.
      In the United Kingdom, the percentage of people aged 18-64 years receiving RRT who survive for 3 years is 15% less for those who have diabetes than for those who do not; however, the rates for patients older than 65 years are almost identical (∼47% for both).
      • Feest T.
      • Fogarty D.
      • MacPhee I.
      • et al.
      UK Renal Registry
      15th Annual Report of the Renal Association.
      The prevalence of diabetes (mainly type 2) is projected to increase to 552 million by 2030,

      International Diabetes Federation. IDF Diabetes Atlas. 5th ed. Brussels, Belguim, 2012 Update. www.idf.org/diabetesatlas/5e/update2012. Accessed August 8, 2013.

      and many of these individuals will develop kidney failure. Although there are signs that the proportion of people with diabetes developing ESRD may be declining (particularly for type 1), the absolute numbers are continuing to increase, especially in Southeast Asia.
      • Collins A.J.
      • Foley R.N.
      • Herzog C.
      • et al.
      US Renal Data System 2012 annual data report.
      The majority of deaths among people with diabetes treated with RRT are from cardiovascular disease (CVD) and infection
      • Collins A.J.
      • Foley R.N.
      • Herzog C.
      • et al.
      US Renal Data System 2012 annual data report.
      • Feest T.
      • Fogarty D.
      • MacPhee I.
      • et al.
      UK Renal Registry
      15th Annual Report of the Renal Association.
      ; experimental and epidemiologic evidence support diabetes having a direct role in the pathogenesis of and susceptibility to these complications.
      • Brownlee M.
      Biochemistry and molecular cell biology of diabetic complications.
      • Shah B.R.
      • Hux J.E.
      Quantifying the risk of infectious diseases for people with diabetes.
      However, the precise relationship between hyperglycemia and survival in patients treated with RRT remains uncertain. Accordingly, there are limited data supporting specific treatment strategies in this high-risk population.
      In this issue of AJKD, Hill et al
      • Hill C.J.
      • Maxwell A.P.
      • Cardwell C.R.
      • et al.
      Glycated hemoglobin and risk of death in diabetic patients treated with hemodialysis: a meta-analysis.
      report results of a meta-analysis of studies evaluating associations between glycated hemoglobin (HbA1c) level and mortality in diabetic patients treated with hemodialysis (HD). The authors obtained patient-level data or asked investigators to reanalyze their results according to a standard reporting template. For 83,684 individuals enrolled in 9 observational studies and 1 randomized controlled trial, the authors found that both baseline and mean HbA1c levels ≥ 8.5% (≥69 mmol/mol) were associated with hazard ratios (HRs) for death of 1.14 (95% confidence interval [CI], 1.09-1.19) and 1.29 (95% CI, 1.23-1.35), respectively, adjusted for age, sex, diabetes type, time on HD therapy, and hemoglobin concentration. Relationships with HbA1c levels were similar for incident and prevalent HD patients, defined as dialysis for 90 or fewer days or more than 90 days, respectively. Low HbA1c levels (≤6.4% [≤46 mmol/mol]) also were associated with significantly increased mortality, but only for incident patients (HR, 1.29; 95% CI, 1.23-1.35). The authors conclude that their analysis supports the adoption of an HbA1c target < 8.5% (<69 mmol/mol) for diabetic patients treated with HD.
      More cautious conclusions may be warranted because we need to be wary of assuming that reducing HbA1c level has a clinical benefit on mortality and CVD based on association data only. The UKPDS (UK Prospective Diabetes Study) showed a linear relationship between achieved HbA1c level and CVD in people with newly diagnosed type 2 diabetes without kidney failure such that a 1% (11-mmol/mol) reduction in updated mean HbA1c level was associated with a 14% (95% CI, 8%-21%) reduction in risk of myocardial infarction.
      • Stratton I.M.
      • Adler A.I.
      • Neil A.W.
      • et al.
      Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational studies.
      Although derived from a randomized controlled trial of intensive versus conventional hypoglycemic therapy, this analysis was performed in only 79% of the trial population. Notably, subsequent large clinical trials evaluating the impact of intensive glycemic control on cardiovascular outcomes in people with type 2 diabetes along with meta-analyses of these studies have been performed and have failed to confirm a significant CVD benefit.
      • Ray K.K.
      • Seshasai S.R.
      • Wijesuriya S.
      • et al.
      Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials.
      • Kelly T.N.
      • Bazzano L.A.
      • Fonseca V.A.
      • Thethi T.K.
      • Reynolds K.
      • He J.
      Glucose control and cardiovascular disease in type 2 diabetes.
      • Skyler J.S.
      • Bergenstal R.
      • Bonow R.O.
      • et al.
      Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE and VA Diabetes Trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association.
      One study demonstrated greater mortality from acute myocardial infarction for those in the intensive treatment arm.
      Action to Control Cardiovascular Risk in Diabetes Study Group
      Effects of intensive glucose lowering in type 2 diabetes.
      There are multiple reasons why intensive glycemic control has not been universally beneficial. Although diabetes and lesser degrees of glucose intolerance are associated with increased rates of CVD, it is possible that other atherogenic risk factors, such as dyslipidemia and hypertension, both of which are associated with hyperglycemia, have more important roles. Thus, correcting hyperglycemia alone may not be enough. A multifactorial approach to CVD risk factor correction, as adopted in the Steno 2 Trial that enrolled people with type 2 diabetes and chronic kidney disease (defined by microalbuminuria), showed a significant reduction in mortality and ESRD after 13 years of follow-up.
      • Gaede P.
      • Lund-Anderson H.
      • Parving H.-H.
      • Pedersen O.
      Effect of a multi-factorial intervention on mortality in type 2 diabetes.
      However, the improvement in glycemia in the intensive treatment arm of this trial was relatively modest (HbA1c, 0.5% [6 mmol/mol]) compared to the 15–mm Hg reduction in systolic blood pressure and 50–mg/dL reduction in low-density lipoprotein cholesterol level that also occurred. Thus, glycemic improvement alone may have been a relatively minor contributor to the overall mortality benefit.
      HbA1c level also has limitations as a measure of glycemia, particularly in the ESRD population. Changes in red blood cell turnover affect percent glycation, making it difficult to interpret HbA1c in dialysis patients. Alternative estimates of average blood glucose level, such as glycated albumin
      • Kim J.-K.
      • Park J.T.
      • Oh J.
      • et al.
      Estimating average glucose levels from glycated albumin in patients with end-stage renal disease.
      or fructosamine level,
      • Mittman N.
      • Desiraju B.
      • Hazil I.
      • et al.
      Serum fructosamine versus glycosylated hemoglobin as an index of glycemic control, hospitalisation, and infection in diabetic hemodialysis patients.
      have been proposed but have problems with assay standardization, lack of familiarity in clinical use, and poorly defined relationships with clinical outcomes. Additionally, all these estimates of glycemia have the drawback of being averages and therefore not informing us about glucose variability; this is important because both hyper- and hypoglycemia have been implicated in sudden death in the non-ESRD diabetic population.
      • Stevens R.J.
      • Stratton I.M.
      • Coleman R.L.
      • Matthews D.R.
      • Adler A.I.
      • Holman R.R.
      Risk factors for myocardial infarction case fatality and stroke case fatality in type 2 diabetes.
      • Bonds D.E.
      • Miller M.E.
      • Dudl J.
      • et al.
      Severe hypoglycemia symptoms, antecedent behaviors, immediate consequences and association with glycemia medication usage: secondary analysis of the ACCORD clinical trial data.
      • Goto A.
      • Arah O.A.
      • Goto M.
      • Terauchi Y.
      • Noda M.
      Severe hypoglycemia and cardiovascular disease: systematic review and meta-analysis with bias analysis.
      Recent studies using continuous glucose monitoring in diabetic patients treated with HD show wide and somewhat unpredictable swings in glycemia, with most studies showing lower levels on dialysis days, particularly when lower dialysate glucose concentrations are used.
      • Kazempour-Ardebili S.
      • Tam F.W.K.
      • Lecamwasam V.L.
      • et al.
      Assessing glycemic control in maintenance hemodialysis patients with type 2 diabetes.
      • Riveline J.-P.
      • Teynie J.
      • Belmouaz S.
      • et al.
      Glycaemic control in type 2 diabetic patients on chronic haemodialysis: use of a continuous glucose monitoring system.
      • Jung H.S.
      • Kim H.I.
      • Kim M.J.
      • et al.
      Analysis of hemodialysis-associated hypoglycemia in patients with type 2 diabetes using a continuous glucose monitoring system.
      • Mirani M.
      • Berra C.
      • Finazzi S.
      • et al.
      Inter-day glycemic variability assessed by continuous glucose monitoring in insulin-treated type 2 diabetes patients on hemodialysis.
      • Sobngwi E.
      • Ashuntantang G.
      • Ndounia E.
      • et al.
      Continuous interstitial glucose monitoring in non-diabetic subjects with end-stage renal disease undergoing maintenance haemodialysis.
      In studies that showed an increased rate of hypoglycemia on dialysis days, hypoglycemia occurred most often in the hours following the dialysis treatment. Interestingly, the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial of intensive glycemic therapy in type 2 diabetes, which was conducted in a population with largely normal kidney function, showed that a higher HbA1c level was associated with more frequent severe hypoglycemia.
      • Miller M.E.
      • Bonds D.E.
      • Gerstein H.C.
      • 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.
      Therefore, it is possible that some of the excess mortality seen in patients with higher HbA1c levels, as reported by Hill et al,
      • Hill C.J.
      • Maxwell A.P.
      • Cardwell C.R.
      • et al.
      Glycated hemoglobin and risk of death in diabetic patients treated with hemodialysis: a meta-analysis.
      may partly be due to hypoglycemia. One other interesting finding from Hill et al
      • Hill C.J.
      • Maxwell A.P.
      • Cardwell C.R.
      • et al.
      Glycated hemoglobin and risk of death in diabetic patients treated with hemodialysis: a meta-analysis.
      was that an increase in incident HD patients' HbA1c levels to ≥ 8.5% (≥69 mmol/mol) was associated with higher mortality. This suggests that acute worsening of glycemia and greater glycemic variability may lead to increased mortality. Accordingly, reducing glycemic swings, both high and low, might be the objective, rather than lowering overall HbA1c level.
      What about other diabetes complications? Hyperglycemia is a major risk factor for retinopathy development, and there are strong data from both the DCCT (Diabetes Control and Complications Trial)
      The Diabetes Control and 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.
      The Diabetes Control and Complications Trial (DCCT)–Epidemiology of Diabetes Interventions of Complications Trial (EDIC) Research Group
      Effective intensive therapy on the microvascular complications of type 1 diabetes mellitus.
      and UKPDS
      UK Prospective Diabetes Study (UKPDS) Group
      Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
      that glycemic correction prevents both the development and progression of eye complications. Similarly, neuropathy and foot infections leading to amputation are more common in individuals with worse glycemic control, and both these end points were reduced in the Steno 2 Trial.
      • Gaede P.
      • Lund-Anderson H.
      • Parving H.-H.
      • Pedersen O.
      Effect of a multi-factorial intervention on mortality in type 2 diabetes.
      Although none of the patients in these studies were receiving RRT, the same relationships may hold true for people on dialysis therapy.
      What should we make of the association between HbA1c level ≤ 6.4% (≤46 mmol/mol) and increased mortality in incident patients? It is likely that to achieve this HbA1c level, these patients experienced episodes of hypoglycemia, putting them at risk of sudden death.
      The Diabetes Control and 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.
      It also is possible that their nutritional and/or clinical status may have been poor when starting HD therapy. Either way, the implication is that clinicians should pay close attention to diabetes therapy and surveillance for hypoglycemia in patients with low HbA1c levels.
      There are drawbacks of the analysis of Hill et al.
      • Hill C.J.
      • Maxwell A.P.
      • Cardwell C.R.
      • et al.
      Glycated hemoglobin and risk of death in diabetic patients treated with hemodialysis: a meta-analysis.
      The choice of HbA1c categories was somewhat arbitrary and does not correspond to current guidelines
      National Kidney Foundation
      KDOQI clinical practice guideline for diabetes and CKD: 2012 update.
      Kidney Disease: Improving Global Outcomes (KDIGO) CKD Workgroup
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
      or previous information from major studies such as the DCCT.
      The Diabetes Control and 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.
      As with all retrospective studies, key clinical information often is unavailable. For example, most of the studies analyzed did not differentiate between individuals with type 1 versus type 2 diabetes. We do not know retinopathy status, so the number of patients with ESRD due to diabetes versus those with coexisting ESRD and diabetes are unclear. We do not know what hypoglycemic therapy was used, although most patients likely were taking insulin. Finally, we have no information for blood pressure, blood lipid level, and ethnicity. Ethnicity is especially important because 3 of the studies were from Japan and survival of Japanese patients with diabetes on HD therapy (2-year survival, 85%)
      • Hayashino Y.
      • Fukuhara S.
      • Akiva T.
      • et al.
      Diabetes, glycaemic control and mortality risk in patients on haemodialysis: the Japanese Dialysis Outcomes and Practice Patterns Study.
      is much better than that reported by the USRDS (2-year survival, 61%),
      • Collins A.J.
      • Foley R.N.
      • Herzog C.
      • et al.
      US Renal Data System 2012 annual data report.
      although worse than for those without diabetes (2-year survival in Japanese patients, 91%).
      • Hayashino Y.
      • Fukuhara S.
      • Akiva T.
      • et al.
      Diabetes, glycaemic control and mortality risk in patients on haemodialysis: the Japanese Dialysis Outcomes and Practice Patterns Study.
      Current guidance for glycemic control for people with diabetes treated with HD are extrapolated from the non-ESRD population and therefore are based on opinion rather than evidence.
      National Kidney Foundation
      KDOQI clinical practice guideline for diabetes and CKD: 2012 update.
      Kidney Disease: Improving Global Outcomes (KDIGO) CKD Workgroup
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
      We need much more information about the optimum management of diabetes in this high-risk and increasingly common group of patients. Key research questions include the following:
      • Is HbA1c level a sufficient measure of glycemia or do fructosamine and/or glycated albumin levels offer advantages?
      • Is it glycemic variability and specifically hypoglycemia that contribute to cardiovascular risk, rather than average blood glucose level?
      • What role, if any, do continuous glucose monitoring systems have for determining therapeutic adjustments for people with diabetes treated with HD?
      • What is the optimum glucose concentration in the dialysate?
      • What non–insulin-based therapies are safe and effective in diabetic patients with ESRD?
      • How should insulin doses and diet be adjusted on dialysis versus nondialysis days?
      Although some of these questions are being addressed in ongoing and planned studies, as an endocrinology and nephrology community, we have been too slow to address them and urgently need to build collaborations to achieve better outcomes for our patients. Until then, an HbA1c target < 8.5% (<69 mmol/mol) probably is reasonable based on opinion and the data from Hill et al,
      • Hill C.J.
      • Maxwell A.P.
      • Cardwell C.R.
      • et al.
      Glycated hemoglobin and risk of death in diabetic patients treated with hemodialysis: a meta-analysis.
      as well as others.

      Acknowledgements

      Support: None.
      Financial Disclosure: The author declares that he has no relevant financial interests.

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