Burnt Out ? The Phenomenon of Type 2 Diabetes Mellitus in End-Stage Renal Disease

Hypoglycemic Episodes

At the 2-month follow-up visit with the CPS, Mr. A reported having 5 hypoglycemic episodes in the past 30 days. He also stated he would forget to take his insulin aspart dose before dinner about 3 to 4 times a week but would take it 30 to 60 minutes after the meal. Mr. A did not bring his glucometer or SMBG readings to the visit, but he indicated that his blood glucose levels continued to fluctuate and were elevated when consuming carbohydrates.

Laboratory tests 1 month prior to the 2-month follow-up visit showed HbA_1c of 7.3%, which had increased from his previous level of 6.1%. He was counseled on the proper administration of insulin aspart and lifestyle modifications. A fructosamine level was ordered at this visit to further assess his glycemic control. A follow-up appointment and laboratory workup (fructosamine and HbA_1c) were scheduled for 2 months from the visit (Table 3).

Mr. A was educated on the unreliability of his HbA_1c levels secondary to his condition of ESRD on HD. He was counseled on the purpose of fructosamine and how it may be a better predictor of his glycemic control and morbidity. Mr. A continued to be followed closely by the primary care CPS for T2DM management.

Discussion

Management of T2DM in patients with ESRD presents challenges for clinicians in determining HbA_1c goals and selecting appropriate medication options. The 2012 Kidney Disease Outcomes Quality Initiative (KDOQI) diabetes guideline does not recommend treatment for patients with substantially reduced kidney function to a target HbA_1c < 7% due to risk of hypoglycemia.¹³ Although a target HbA_1c > 7% is suggested for these patients, little is known about appropriate glycemic control in these patients as there is a paucity of prospective, randomized clinical trials that include patients with advanced CKD.¹³

Moreover, many oral antidiabetic medications and their metabolites are cleared by the kidneys and, therefore, pose with potential harm for patients with CKD. Because of this, insulin is the medication of choice for patients with ESRD.⁷ Although insulin requirements may diminish with worsening kidney function, insulin provides the safest method of glycemic control. Insulin dosing can be individualized according to a patient’s renal status as there is no uniformity in renal dose adjustments. There are some noninsulin antidiabetic agents that can be used in ESRD, but use of these agents requires close monitoring and evaluation of the medication’s pharmacokinetics (Table 4). Overall, medication management can be a difficult task for patients with T2DM and ESRD, but antidiabetic regimens may be reduced or discontinued altogether in burnt-out diabetes.

One of 3 patients with T2DM and ESRD on dialysis has burnt-out diabetes, defined as a phenomenon in which glucose homeostasis is altered to cause normoglycemia, spontaneous hypoglycemia, and decreased insulin requirements in established patients with T2DM.⁵ Although Mr. A had a normal-to-low HbA_1c, he did not meet these criteria. Due to his elevated SMBG readings, he did not have normoglycemia and did require an increase in his basal insulin dose. Therefore, our patient did not have burnt-out diabetes.

Mr. A represents the relevant issue of inappropriately and unreliably low HbA_1c levels due to various factors in ESRD. Our patient did not receive a blood transfusion in the past 2 years and was not on ESA therapy; nevertheless, Mr. A was a patient with ESRD on HD with a diagnosis of anemia. These diagnoses are confounders for low HbA_1c values. When fructosamine levels were drawn for Mr. A on September 11, 2018 and November 6, 2018, they correlated well with his serum glucose and SMBG readings. This indicated to the CPS that the patient’s glycemic control was poor despite a promising HbA_1c level.

This patient’s case and supporting evidence suggests that other measures of glycemic control (eg, fructosamine) can be used to supplement HbA_1c, serum glucose, and glucometer readings to provide an accurate assessment of glycemic control in T2DM. Fructosamine also can assist HbA_1c with predicting morbidity and potentially mortality, which are of great importance in this patient population.

Kalantar-Zadeh and colleagues conducted a study of 23,618 patients with T2DM on dialysis to observe mortality in association with HbA_1c.⁵ This analysis showed that patients with HbA_1c levels < 5% or > 8% had a higher risk of mortality; higher values of HbA_1c (> 10%) were associated with increased death risk vs all other values. In the unadjusted analysis, HbA_1c levels between 6 and 8% had the lowest death risk (hazard ratios [HR] 0.8 - 0.9, 95% CI) compared with those of higher and lower HbA_1c ranges.⁵ In nonanemic patients, HbA_1c > 6% was associated with increased death risk, whereas anemic patients did not show this trend.

Other studies made similar observations. In 2001, Morioka and colleagues published an observational study of 150 patients with DM on intermittent hemodialysis. The study analyzed survival and HbA_1c levels at 1, 3, and 5 years. The study found that at 1, 3, and 5 years, patients with HbA_1c < 7.5% had better survival than did patients with HbA_1c > 7.5% (3.6 years vs 2.0 years, P = .008). Morioka and colleagues also found that there was a 13% increase in death per 1% increase in HbA_1c.¹⁴ Oomichi and colleagues conducted an observational study of 114 patients with T2DM and ESRD on intermittent hemodialysis. Patients with fair control (HbA_1c 6.5 - 8%) and good control (HbA_1c < 6.5%) were compared with patients with poor control (HbA_1c > 8%); it was found that the poor control group had nearly triple the mortality when compared with the good and fair control groups (HR = 2.89, P = .01).¹⁵ Park and colleagues also saw a similar observation in a study of 1,239 patients with ESRD and DM; 70% of these patients were on intermittent hemodialysis. Patients with poor control (HbA_1c ≥ 8%) had worse survival outcomes than those with HbA_1c < 8% (HR 2.2, P < .001).¹⁶

Our patient case forced us to ask the question, “What should our patient’s HbA_1c goals be?” In the study by Oomichi and colleagues, a HbA_1c level of 8% has usefulness as a “signpost for management of glycemic control.”¹⁵ All patients’ goals should be individualized based on various factors (eg, age, comorbidities), but based on the survival studies above, a HbA_1c goal range of 6 to 8% may be optimal.

Conclusions

Patients with T2DM and ESRD on dialysis may have higher morbidity and mortality rates than the rates of those without T2DM. It has been shown in various studies that very low HbA_1c (< 5%) and high HbA_1c (> 8%) are associated with poor survival. Some patients with T2DM on dialysis may experience burnt-out diabetes in which they may have normoglycemia and a HbA_1c below goal; despite these facts, this condition is not positive and can be linked to bad outcomes. In patients with T2DM and ESRD, insulin is the antidiabetic medication of choice, and we recommend a HbA_1c target of 6 to 8%. In this patient population, consider using fructosamine levels or other measures of glycemic control to supplement HbA_1c and glucose values to provide a better assessment of glycemic control, morbidity, and mortality. Larger clinical trials are needed to assist in answering questions regarding mortality and optimal HbA_1c targets in burnt-out diabetes.