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Is there a need to optimize glycemic control in hemodialyzed diabetic patients?

2006; Elsevier BV; Volume: 70; Issue: 8 Linguagem: Inglês

10.1038/sj.ki.5001886

1523-1755

Bo Feldt‐Rasmussen,

Neurological and metabolic disorders

The report of Williams et al. gives rise to at least two important questions regarding diabetic patients on maintenance hemodialysis: (1) Does glycemic control play a significant role? (2) Is HbA1c a reliable measure of glycemic control? These questions are discussed. It is recommended that you treat ESRD patients with diabetes according to guidelines given for patients without ESRD. The report of Williams et al. gives rise to at least two important questions regarding diabetic patients on maintenance hemodialysis: (1) Does glycemic control play a significant role? (2) Is HbA1c a reliable measure of glycemic control? These questions are discussed. It is recommended that you treat ESRD patients with diabetes according to guidelines given for patients without ESRD. This month, Williams et al.1.Williams M. et al.Hemodialyzed type I and type II diabetic patients in the US: characteristics, glycemic control, and survival.Kidney Int. 2006; 70: 1503-1509Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar (this issue) publish an interesting analysis of primary data on glycemic control and survival of diabetic patients from a large United States end-stage renal disease (ESRD) database. Patients were drawn from among 76 178 ESRD patients treated with hemodialysis at Fresenius Medical Care, North America, between 1 October and 31 December 2002. Among the many interesting results, I found three to be of particular interest. First, only a weak correlation between hemoglobin A1c (HbA1c) and random glucose values was observed. Second, the mean HbA1c among all type I and type II diabetic patients was very good, 6.77%, which is lower than normally observed in groups of diabetic patients without ESRD. Third, there was no correlation between HbA1c and survival at 12 months. This raises at least two important questions: (1) Does glycemic control play any significant role in diabetic patients on maintenance hemodialysis? (2) Is HbA1c a reliable measure of glycemic control in these patients? Since the publication of two landmark studies, the Diabetes Control and Complication Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS), the importance of tight glycemic control with HbA1c values less than 7% has not been challenged.2.Anonymous Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. The Diabetes Control and Complications (DCCT) Research Group.Kidney Int. 1995; 47: 1703-1720Abstract Full Text PDF PubMed Scopus (691) Google Scholar, 3.Anonymous Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.Lancet. 1998; 352: 837-853Abstract Full Text Full Text PDF PubMed Scopus (17299) Google Scholar The DCCT showed that intensive diabetes therapy delayed the onset and slowed the progression of retinopathy, nephropathy, and neuropathy in type I diabetic patients. Only seven subjects in the entire study developed urinary albumin excretion rates in the range of clinical diabetic nephropathy, so the study was not powered to detect effects on progression to ESRD. The indications were, however, that such an effect could be anticipated.2.Anonymous Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. The Diabetes Control and Complications (DCCT) Research Group.Kidney Int. 1995; 47: 1703-1720Abstract Full Text PDF PubMed Scopus (691) Google Scholar In a follow-up study, long-term beneficial effects on development of cardiovascular disease were also demonstrated.4.Nathan D.M. Cleary P.A. Backlund J.Y. et al.Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.N Engl J Med. 2005; 353: 2643-2653Crossref PubMed Scopus (3781) Google Scholar In the UKPDS, which studied type II diabetic patients, glycemic control also played an important role in reducing the risk of microvascular complications.4.Nathan D.M. Cleary P.A. Backlund J.Y. et al.Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.N Engl J Med. 2005; 353: 2643-2653Crossref PubMed Scopus (3781) Google Scholar In a more advanced stage of renal disease, it was shown that poor pre-dialysis glycemic control is a predictor of mortality in type II diabetic patients on maintenance hemodialysis.5.Wu M.S. Yu C.C. Yang C.W. et al.Poor pre-dialysis glycaemic control is a predictor of mortality in type II diabetic patients on maintenance haemodialysis.Nephrol Dial Transplant. 1997; 12: 2105-2110Crossref PubMed Scopus (128) Google Scholar Bearing these results in mind, it is disappointing that only a few minor studies have been able also to demonstrate beneficial effects of improved glycemic control in ESRD patients.2.Anonymous Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. The Diabetes Control and Complications (DCCT) Research Group.Kidney Int. 1995; 47: 1703-1720Abstract Full Text PDF PubMed Scopus (691) Google Scholar, 6.Oomichi T. Emoto M. Tabata T. et al.Impact of glycemic control on survival of diabetic patients on chronic regular hemodialysis: a 7-year observational study.Diabetes Care. 2006; 29: 1496-1500Crossref PubMed Scopus (143) Google Scholar More comprehensive studies, such as that of Williams et al.,1.Williams M. et al.Hemodialyzed type I and type II diabetic patients in the US: characteristics, glycemic control, and survival.Kidney Int. 2006; 70: 1503-1509Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar find no effect at all. This report raises serious questions about the existence of any such association, when it cannot be confirmed in an analysis of a clinical database including more than 23 000 patients. Should this discourage attempts to aim for low HbA1c values in ESRD patients? Many clinicians would probably find a point in arguing that regardless of the lack of documented effects on survival, there still is good reason to improve glycemic control. After all, it is likely that such a treatment strategy would be beneficial in order to prevent progression of other diabetic complications such as retinopathy, neuropathy, and macrovascular disease. Are there any sufficiently validated methods for monitoring the glycemic level in ESRD patients? Clinical treatment of diabetic patients, as well as studies of effects of improved glycemic control, obviously relies on proper methods to monitor the glycemic level over longer periods of time. Is HbA1c a reliable method in patients with ESRD? Indications are that it is not.1.Williams M. et al.Hemodialyzed type I and type II diabetic patients in the US: characteristics, glycemic control, and survival.Kidney Int. 2006; 70: 1503-1509Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 7.Ansari A. Thomas S. Goldsmith D. Assessing glycemic control in patients with diabetes and end-stage renal failure.Am J Kidney Dis. 2003; 41: 523-531Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 8.Joy M.S. Cefalu W.T. Hogan S.L. Nachman P.H. Long-term glycemic control measurements in diabetic patients receiving hemodialysis.Am J Kidney Dis. 2002; 39: 297-307Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar Significant problems exist in demonstrating a clinically relevant association between HbA1c and glycemic levels in patients on peritoneal dialysis,7.Ansari A. Thomas S. Goldsmith D. Assessing glycemic control in patients with diabetes and end-stage renal failure.Am J Kidney Dis. 2003; 41: 523-531Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar as well as in patients on maintenance hemodialysis.1.Williams M. et al.Hemodialyzed type I and type II diabetic patients in the US: characteristics, glycemic control, and survival.Kidney Int. 2006; 70: 1503-1509Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 8.Joy M.S. Cefalu W.T. Hogan S.L. Nachman P.H. Long-term glycemic control measurements in diabetic patients receiving hemodialysis.Am J Kidney Dis. 2002; 39: 297-307Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar These problems have, in many reports, been neglected or described as being of minor importance, leaving the impression that there are problems but that they can be overcome. Among the arguments is the fact that HbA1c can be reliably measured and provide valid results (of HbA1c concentration) for most patients with ESRD if an appropriate methodology is used. Does this HbA1c value also reflect mean blood glucose over a longer period of time? Apparently not. Thus, in the study of Williams et al.,1.Williams M. et al.Hemodialyzed type I and type II diabetic patients in the US: characteristics, glycemic control, and survival.Kidney Int. 2006; 70: 1503-1509Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar only a weak correlation with mean random glucose was observed (R2, 0.37; standard error, 1.36). This confirms previous observations by another group reporting a similar poor correlation.8.Joy M.S. Cefalu W.T. Hogan S.L. Nachman P.H. Long-term glycemic control measurements in diabetic patients receiving hemodialysis.Am J Kidney Dis. 2002; 39: 297-307Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar The problem is depicted and clearly demonstrated in Figure 1 (from the article by Joy et al.8.Joy M.S. Cefalu W.T. Hogan S.L. Nachman P.H. Long-term glycemic control measurements in diabetic patients receiving hemodialysis.Am J Kidney Dis. 2002; 39: 297-307Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar). A mean blood glucose of 180 mg/dl can be found in the presence of an HbA1c level between 6.2% and 9%. Furthermore, the HbA1c level may be systematically underestimated in patients on hemodialysis because of the reduced lifespan of the erythrocytes. Although the potential risk of underestimating HbA1c is still debated, data from the study of Williams et al.1.Williams M. et al.Hemodialyzed type I and type II diabetic patients in the US: characteristics, glycemic control, and survival.Kidney Int. 2006; 70: 1503-1509Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar suggest that it is a significant clinical problem. Take, for instance, the mean HbA1c of 6.7% among all diabetic patients and of 7.5% among the (few) type I diabetic patients observed in the study.1.Williams M. et al.Hemodialyzed type I and type II diabetic patients in the US: characteristics, glycemic control, and survival.Kidney Int. 2006; 70: 1503-1509Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar These values are surprisingly low and prompt one to speculate as to whether the diagnosis of diabetes has been correct in all patients. The UKPDS, which compared intensive versus conventional treatment in type II diabetic patients, found HbA1c values of 7.0% and 7.9%, respectively, and the DCCT, which compared the two treatments in type I diabetic patients, found values of 7.0% and 9.0%, respectively. What are the odds that the true level of glycemic control in large unselected groups of diabetic ESRD patients is better than or almost as good as what was observed in the intensive-treatment groups of the UKPDS and the DCCT? My guess is that the glycemic control in conventionally treated ESRD patients should be poor, considering the fact that, for all we know, they come from a group of patients with poor glycemic control through their diabetic life. Apparently, there is a need to reconsider the value of HbA1c in patients with ESRD. Whereas optimized glycemic control undoubtedly plays a major role in preventing progression of microvascular complications, it is not the only factor of importance. Other factors involved include blood pressure level, hypercholesterolemia, smoking habits, exercise, and so on. This was clearly shown in a study of type II diabetic patients with microalbuminuria, which tested the effects of a multifactorial intervention consisting of angiotensin-converting enzyme inhibitors, blood pressure reduction, glycemic control, statins, vitamins, weight reduction, and exercise.9.Gaede P. Vedel P. Parving H.H. Pedersen O. Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study.Lancet. 1999; 353: 617-622Abstract Full Text Full Text PDF PubMed Scopus (830) Google Scholar This study demonstrated important clinical effects in the intervention group. The multifactorial pathophysiological mechanisms behind micro- and macrovascular complications of diabetes may explain why studies of, or intervention against, only one risk factor may not show any beneficial effects. It is the combined effect of multifactorial intervention that is important. This may in particular be the case in ESRD patients with diabetes, who, in addition to diabetes per se, are carrying so many other risk factors directly associated with their uremic state. Along similar lines, intervention against only one risk factor in the 4D trial (Die Deutsche Diabetes Dialyse Studie) of statins in a population of type II diabetic patients on maintenance hemodialysis also failed to show an effect.10.Wanner C. Krane V. Marz W. et al.Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis.N Engl J Med. 2005; 353: 238-248Crossref PubMed Scopus (2044) Google Scholar So apparently there is no effect of treatment with statins or optimized glycemic control in type II diabetic patients on hemodialysis! But would a multifactorial treatment approach have revealed a synergy between these different treatments? The introduction of multifactorial intervention in all diabetic patients on a nationwide basis in Denmark has been proven to postpone the development of ESRD.11.Sorensen V.R. Hansen P.M. Heaf J. Feldt-Rasmussen B. Stabilized incidence of diabetic patients referred for renal replacement therapy in Denmark.Kidney Int. 2006; 70: 187-191Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar It is therefore important to introduce and focus on such an approach in diabetic patients during their diabetic life, long before they reach the stage of ESRD. What can we do when these patients progress to ESRD? Are there any data indicating that, when starting hemodialysis, we should stop all these interventional measures? To my mind, there is no good reason to discontinue multifactorial intervention in these patients when they reach ESRD, including the optimization of glycemic control. These efforts should continue despite the fact that the evidence so far is not very strong for using any of these individual treatment modalities in diabetic patients with ESRD. Williams et al.1.Williams M. et al.Hemodialyzed type I and type II diabetic patients in the US: characteristics, glycemic control, and survival.Kidney Int. 2006; 70: 1503-1509Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar state that more studies are needed in chronic kidney disease and ESRD patients in order to refine evidence-based recommendations for the appropriate application of tests (such as HbA1c) that are currently used to define glycemic control. I absolutely agree. They also state that more studies are needed to determine evidence-based treatment goals for glycemic control in this patient population.1.Williams M. et al.Hemodialyzed type I and type II diabetic patients in the US: characteristics, glycemic control, and survival.Kidney Int. 2006; 70: 1503-1509Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar Any such study will be very difficult to perform, however, and will have to address multifactorial interventions. While awaiting the results, I will rely on the documentation so amply provided by studies of diabetic patients in earlier stages of disease and recommend that you extend the present guidelines to the treatment of patients with ESRD. Personally, I would require evidence of no effect or harmful effects before changing treatment strategies at the time when the patients enter ESRD. The concept of reverse epidemiology in ESRD patients is intensely debated at this time. The question is whether there also is a need for "reverse evidence-based medicine."