Managing 'Burnt-Out' Diabetes
The concept of "the lower the better" with respect to blood glucose is being rethought.
Diabetes mellitus (DM) represents the most common etiology of end-stage renal disease (ESRD) requiring maintenance dialysis therapy in the United States.
About half of all patients receiving dialysis in this country are diabetic, and they suffer from a higher rate of morbidity and mortality compared with nondiabetic patients. Because diabetes plays such a significant role in our nation's public health, glycemic control has been emphasized as a means to prevent the many complications of this disease.
The treatment targets established for glycemic control have been based on studies of patients with normal kidney function, specifically the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS). The results of these studies have primarily shown a significant reduction in microvascular complications with better glycemic control (Kidney Int. 1995;47:1703-1720 and Lancet. 1998;352:837-853).
Reductions in macrovascular complications have also been linked to glycemic control, but these benefits became apparent only after prolonged (i.e., decades-long) follow-up in patients with new-onset or early-stage DM. Most recently, three large randomized controlled trials found that in patients with long-standing DM and advanced cardiovascular disease, strict glycemic control was of no benefit or could even be harmful (N Engl J Med. 2008;358:2545-2559, 2008;358:2560-2572, and 2009;360:129-139).
These trials in patients with normal kidney function leave nephrologists in a quandary about what glycemic targets to recommend for diabetes patients with various stages of CKD. The high degree of morbidity and mortality seen in such patients begs for new treatment strategies, and given the pivotal role of diabetes in many of the common comorbidities seen in CKD patients, targeting hyperglycemia seems to be a logical approach to improving their outcomes.
But since the concept of “the lower the better” seems to be taking a hit even in patients with normal kidney function, applying data from the general population to patients who have kidney disease would be reckless without critical assessment of the characteristics of the disease state, the available treatment regimens, and the outcomes of these regimens in this specific group of patients.
There are plenty of reasons to believe that diabetic patients with CKD and especially those with ESRD display unique disease characteristics. Observational studies examining outcomes as a function of blood sugar control in dialysis patients have shown conflicting results, and clinical trials of hyperglycemia therapy have not been conducted in this patient population.
Furthermore, the physiologic changes in glucose and insulin metabolism that occur as a result of decreased kidney function can alter the course of DM in ways that have not yet been fully characterized. Last but not least, the pharmacokinetic changes related to decreased kidney function add an additional layer of complexity to our therapeutic approach.
Effects of CKD on glucose homeostasis
Abnormal glycemic control is a long recognized complication in patients with advanced CKD. Even nondiabetic patients with ESRD can display mild fasting hyperglycemia and abnormal glucose tolerance, suggesting that the uremic state in itself alters normal glucose homeostasis.
Spontaneous hypoglycemia is also a known complication in ESRD, underscoring the complex nature of the uremic dysregulation of glucose homeostasis in CKD. The reason for the abnormal glucose homeostasis in CKD is postulated to be multifactorial and related to both the decreased glomerular filtration rate (GFR) and to dialytic therapies (Am J Kidney Dis. 2008;52:766-777).
Changes in insulin metabolism. Renal insulin clearance is reduced as GFR declines below a level of approximately 15-20 mL/min/1.73 m2. Hepatic clearance of insulin is also diminished in uremia but improves after the initiation of dialysis. Opposing the effects of diminished insulin clearance are a decrease in insulin production and an increase in insulin resistance in ESRD.
The reason for the diminished insulin secretion in ESRD is unclear, but it is believed to be related to hyperparathyroidism and activated vitamin D deficiency, based on observations indicating improved insulin secretion after medical or surgical treatment of hyperparathyroidism and following the administration of activated vitamin D.
The site of insulin resistance is likely the muscle tissue, possibly as a result of certain uremic toxins. Given the complex changes in insulin metabolism, insulin requirements can be difficult to predict in ESRD patients, who require close monitoring and individualized therapy.
Mode of dialysis. Abnormal insulin metabolism has been linked to the accumulation of uremic toxins, and the removal of such toxins through dialysis therapy has been shown to result in improved insulin sensitivity and glucose tolerance. Counteracting this beneficial effect of dialysis, however, is the glucose load provided by both hemodialysis (HD) and peritoneal dialysis (PD), which can lead to worsening of hyperglycemia.
PD, in particular, can result in significantly higher glucose intake from dialysate, especially in patients requiring a more highly concentrated solution to achieve ultrafiltration goals. The effects of the dialysate-derived glucose are complex: It contributes to caloric intake, lowers energy expenditure, limits amino acid losses, and stimulates insulin secretion, but it can also suppress appetite.
The practical significance of the changes in glucose homeostasis remains unclear in patients with CKD and ESRD. A considerable number of patients with non-dialysis-dependent CKD display marked “improvement” in their hyperglycemia, occasionally returning to normoglycemia (Figure 1).
Kalantar-Zadeh and colleagues demonstrated a similar finding in ESRD patients (Diabetes Care. 2007;30:1049-1055). In our study of hemoglobin A1c (HbA1c) levels in 662 male U.S. veterans with non-dialysis-dependent CKD (mean estimated GFR 39±17 mL/min/1.73m2), 246 (37%) had an HbA1c <7%, 76 (11.5%) had an HbA1c <6%, and 9 (1.4%) had an HbA1c <5% (CP Kovesdy, personal communication). What distinguishes such patients with normoglycemic or “burnt-out” diabetes from their counterparts who continue to display hyperglycemia is unclear.
Also unclear is the extent to which the lower blood sugars seen in such patients are in fact advantageous, as some observational studies have suggested that dialysis patients with the lowest HbA1c levels suffer significantly higher mortality rates. Because overcorrection of hyperglycemia and the induction of hypoglycemia can result in significant worsening of outcomes, the clinical impact of burnt-out diabetes must be examined carefully to determine the extent to which spontaneous improvement in blood glucose control is beneficial because of alleviated hyperglycemia as opposed to being detrimental by virtue of a lower threshold of hypoglycemia.