The median life expectancy of patients with ESRD starting maintenance dialysis ranges from only 3 to 5 years.1 This high risk for death for patients undergoing maintenance dialysis represents the summative influence of the complications of frequently occurring coexisting illnesses (viz., diabetes mellitus, hypertension, or cardiovascular comorbidity), consequences of uremia, and potential adverse effects of the dialysis procedure. Although laboratory investigations and/or epidemiologic studies have identified a large number of risk factors in each of these three categories, most clinical trials testing the efficacy of various interventions have been unable to demonstrate any significant reduction in mortality for individuals undergoing maintenance dialysis.2–8 This highlights the need to exercise caution in projecting potential benefits on patient-centered outcomes for individuals undergoing maintenance dialysis from studies with surrogate outcome measures.
In patients undergoing peritoneal dialysis (PD), the obligatory systemic absorption of carbohydrates is a potential adverse effect of the dialysis procedure. Patients treated exclusively with conventional dextrose-based PD solutions are estimated to absorb approximately 50–150 g of glucose daily.9 It has been posited that the systemic glucose absorption is atherogenic and hence has the potential to amplify the cardiovascular risk of patients undergoing PD. However, the mechanistic pathways underlying the increase in risk, if any, remain uncertain. There is a demonstrable association between the concentration of dextrose in the PD dialysate and daily mean blood glucose concentration on Continuous Glucose Monitoring (CGM).10 This suggests that conventional PD prescriptions could contribute to worsening of glycemic control, and observational studies have indicated that patients undergoing PD with poor glycemic control have a higher risk for death.11 Increased peritoneal glucose absorption could also lead to adverse outcomes through weight gain and worsening of lipid abnormalities; however, evidence evaluating these potential mechanisms is inconsistent.12–14 Moreover, the only study to examine the relationship between the magnitude of glucose absorption and patient outcomes was unable to demonstrate any association with either risk for death or a need for transfer to hemodialysis.15 It also remains uncertain whether the higher risk for death or transfer to hemodialysis in individuals with a higher prescribed PD glucose concentration is a consequence of systemic glucose absorption or a reflection of low residual renal function or inadequate ultrafiltration capacity.16,17
In addition to concerns about the adverse effects of systemic glucose absorption, a large body of laboratory data suggests that the continued exposure to high concentrations of glucose and glucose degradation products in conventional PD solutions may lead to structural and functional changes in the peritoneal membrane that may eventually lead to peritoneal sclerosis and ultrafiltration failure.18 Glucose-sparing PD regimens have been developed with the hope of minimizing these potential systemic and local adverse effects of glucose. The use of one bag of icodextrin in lieu of glucose is a central component of such glucose-sparing regimens; although icodextrin is absorbed and contributes to the systemic carbohydrate load, it generates a higher volume of ultrafiltration for each gram of carbohydrate absorbed (higher ultrafiltration efficiency).19 This could allow for the use of lower glucose concentrations during the rest of the day and could hence reduce the total daily obligatory carbohydrate absorption. Although these glucose-sparing PD regimens hold promise, the evidence supporting their use thus far has been limited.
In this issue of JASN, Li et al. present the results of two clinical trials that examined the systemic effects of glucose-sparing PD regimens in individuals with diabetes mellitus.20 A total of 251 patients were randomized to treatment with either a conventional glucose-based regimen (n=127) or a glucose-sparing regimen (n=124) in two clinical trials: (1) the Improved Metabolic Control of Physioneal, Extraneal, Nutrineal versus Dianeal only in Diabetic Continuous Ambulatory Peritoneal Dialysis and Automated Peritoneal Dialysis Patients (IMPENDIA) trial, in sites across 10 countries (n=180), and (2) the Evaluation of Dianeal, Extraneal and Nutrineal versus Dianeal only in Diabetic CAPD Patients (EDEN) trial, in sites in Colombia (n=71). In each of the two trials, the study-related procedures were identical: two bags of glucose-based dialysate were replaced with one bag each of icodextrin and amino acid solutions.20 As a result, the investigators were able to significantly reduce the local and systemic exposure to glucose. The two trials differed only in the use of bicarbonate-buffered glucose solutions in the experimental arm of IMPENDIA and lactate-buffered glucose solutions in EDEN; the control group in each of the two trials was treated with lactate-buffered glucose solutions.
Over the 6-month follow-up periods, treatment with the glucose-sparing PD regimen resulted in a significant decrease in the primary outcome measure of glycosylated hemoglobin A1c (HbA1c) (difference between groups, 0.5%; P=0.01), and secondary outcome measures of serum triglycerides (difference, 0.7 mmol/L or 62 mg/dl), very low density lipoprotein (difference, 0.3 mmol/L), and apoB levels (difference, 8.4 mg/dl).20 There was no significant difference between other secondary outcome measures, including total cholesterol or LDL or HDL cholesterol, lipoprotein(a), insulin, or C-peptide levels, health-related quality of life, visceral or subcutaneous fat volume, or left ventricular mass or function.20 However, individuals treated with glucose-sparing regimens were more likely to experience adverse effects, particularly volume overload.20
These two clinical trials represent a substantial advance in our understanding of the potential benefits of and risks associated with glucose-sparing regimens. First, the demonstrable improvement in glycemic control confirms the findings of a previously published smaller clinical trial of 59 participants followed for 12 months.21 Second, the report suggests significant benefits to plasma triglycerides that have not been observed in previous studies that examined the effect of icodextrin substitution alone.22 These differences may, in part, be a result a greater reduction in glucose exposure with the regimens tested in IMPENDIA and EDEN. Third, the metabolic improvements with glucose-sparing regimens did not translate into improvement in health-related quality of life, fat accumulation, or cardiac function. A longer follow-up period may be required to more fully evaluate these outcomes. Finally, the metabolic benefits came at a cost of a higher risk for adverse events, indicating that there are limits beyond which reducing glucose in PD regimens may not be safe.
By better defining the effects of glucose-sparing PD regimens on intermediate outcomes, IMPENDIA and EDEN highlight an important unanswered next question: What are the effects of glucose-sparing regimens on long-term clinical PD outcomes? To address this question, one must ask first whether the metabolic benefits of glucose-sparing regimens could be expected to reduce the cardiovascular risk of patients undergoing PD. Observational studies have shown a nonlinear relationship between HbA1c and clinical outcomes in PD, in which HbA1c levels greater than approximately 8% are associated with increased risk of adverse outcomes.11 This suggests that lowering HbA1c may be beneficial for patients with poor prevailing glycemic control. However, the effect of improving glycemic control on any clinically meaningful outcome in patients undergoing maintenance dialysis has not been examined in well controlled clinical trials to date.
Long-term clinical trials of glucose lowering have been conducted in the general diabetes population, and the results offer insight that may be relevant for the dialysis population. The U.K. Prospective Diabetes Study randomly assigned patients with newly diagnosed type 2 diabetes to conventional or intensive glucose lowering. Although beneficial effects of intensive therapy on microvascular outcomes were significant during the 10-year trial, significant macrovascular benefits emerged only with an additional 10 years of follow-up.23 The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study, and the Veterans Affairs Diabetes Trial (VADT) randomly assigned patients with long-standing type 2 diabetes and a high prevalence of comorbidity to conventional or intensive glucose therapies.24–26 No macrovascular benefits were observed over 3.5, 5, and 6 years of follow-up. In addition, intensive therapy increased risks of hypoglycemia; in the ACCORD study, intensive therapy targeting a HbA1c <6% and achieving a HbA1c of 6.4% resulted in an increased risk of death.24 Together, these studies suggest that glucose lowering requires many years to yield substantial cardiovascular benefits. For PD patients with unfortunately low survival rates, short-term risks of intensive glucose control may frequently outweigh unrealized long-term benefits.
Glucose-sparing PD regimens likely also affect metabolism in manners not captured by HbA1c. For example, the IMPENDIA/EDEN interventions reduced plasma triglyceride concentration. However, like reduction in HbA1c, the long-term health effect of triglyceride reduction is unclear. Randomized controlled clinical trials designed to lower serum triglyceride levels in individuals without kidney disease with either niacin or fenofibrate have not been able to demonstrate any reduction in either nonfatal cardiovascular events or mortality.27,28 Moreover, additional risk factors related to systemic carbohydrate absorption were not fully evaluated. These include, but are not limited to, glycemic variability, hypokalemia, oxidative stress, endothelial dysfunction, and/or loss of residual renal function.
It is important to ensure that any potential cardiovascular benefit with glucose-sparing regimens is not counterbalanced by a higher risk for volume overload, as was observed in the IMPENDIA and EDEN trials. The ultrafiltration and safety profile of both icodextrin and amino acid solutions make them conducive for use in only one exchange each, necessitating the use of glucose for other exchanges. The two clinical trials suggest that if glucose-sparing regimens are used either in clinical practice or future clinical trials, it would be necessary to prescribe sufficient concentration of glucose for the remaining exchanges to ensure adequate ultrafiltration and preclude volume overload.
In summary, IMPENDIA and EDEN were well conducted and important clinical trials that have clarified the effects of glucose-sparing PD regimens on important surrogate outcome measures such as glycemic control and dyslipidemia. The lessons learned from these two trials should inform the conduct of adequately powered clinical trials with longer-term follow-up with hard end points such as mortality or cardiovascular events.
Disclosure
R.M. has received grant support and/or honoraria from Baxter Healthcare and DaVita.
Published online ahead of print. Publication date available at www.jasn.org.
See related article, “Randomized, Controlled Trial of Glucose-Sparing Peritoneal Dialysis in Diabetic Patients,” on pages 1889–1900.
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