Version May 2024
INTRODUCTION — Chronic kidney disease (CKD) is associated with insulin resistance, and in patients with diabetes, glycemic control may deteriorate as kidney function declines. In advanced CKD, however, there is a marked reduction in insulin clearance, leading to a decrease in insulin requirement or even the cessation of insulin therapy in patients with type 2 diabetes. Because of the uncertainty in predicting diabetes medication requirements, an individualized approach is essential for patients who have advanced CKD or are initiating dialysis.
This topic reviews monitoring glycemic control, glycemic targets, and suggested treatment regimens for patients with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 who are not on dialysis as well as for patients on hemodialysis or peritoneal dialysis. The treatment of hyperglycemia in patients with mildly to moderately decreased eGFR (30 to 59 mL/min/1.73 m2) and in kidney transplant recipients is discussed elsewhere:
MONITORING GLYCEMIA
Chronic glycemia — Measures of chronic glycemia (eg, glycated hemoglobin) are used to determine the overall efficacy of diabetes management with the aim of reducing risk for long-term complications:
●Glycated hemoglobin (A1C) – We assess chronic glycemic control in patients with diabetes and predialysis chronic kidney disease (CKD) or end-stage kidney disease (ESKD) with glycated hemoglobin (hemoglobin A1C, A1C) as we do in patients with diabetes and normal kidney function. When there is a disparity between the A1C values and blood glucose values, we rely on the glucose values; either glucose monitoring with fingersticks and a glucose meter or continuous glucose monitoring (CGM) may be used. (See "Measurements of chronic glycemia in diabetes mellitus", section on 'Unexpected or discordant values' and "Measurements of chronic glycemia in diabetes mellitus", section on 'CGM to estimate average glucose'.)
The linear relationship between average glucose and A1C is similar in patients with and without CKD, although the relationship is weaker with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 [1]. Most of the inaccuracy in the relationship between A1C and mean blood glucose in the setting of advanced CKD and hemodialysis is due to altered red cell turnover, especially in the setting of treatment with erythropoiesis-stimulating agents (ESAs). Rapid red cell turnover leads to a greater proportion of younger red cells and falsely low A1C values.
In some older A1C assays, there was analytical interference from carbamylated hemoglobin (formed in the presence of elevated concentrations of urea), leading to false elevations in the A1C level. This is no longer a problem with most A1C assays [2]. It is important to be aware of the specific assay used in each dialysis facility and the extent to which kidney disease and other factors affect the accuracy of A1C measurements. Laboratories should only use A1C assay methods certified by the NGSP. (See "Measurements of chronic glycemia in diabetes mellitus", section on 'Standardization of the assay'.)
●Glycated albumin – Some reports suggest that measurement of glycated albumin more accurately assesses glycemic control in this population [3-6]. Although glycated albumin also reflects mean glycemia, it reflects glycemic control over a much shorter interval (7 to 14 days, compared with 60 to 120 days for A1C). Glycated albumin measurements may not be reliable in patients with proteinuria or in those on peritoneal dialysis. In addition, in a small study in patients with type 2 diabetes and CKD undergoing intravenous iron or ESA therapy, A1C (compared with glycated albumin and other markers of glycemic control) was most closely associated with mean blood glucose [7]. There are few long-term clinical trials evaluating the relationship between glycated albumin and risk of chronic complications of diabetes [8-10]. For these reasons, we prefer monitoring glycemic control with A1C. (See "Measurements of chronic glycemia in diabetes mellitus", section on 'Glycated hemoglobin (A1C)'.)
Daily glucose measurements — Measurements of instantaneous glucose levels (self-monitoring of blood glucose [with fingersticks and a glucose meter] and real-time CGM) are used to manage diabetes from hour-to-hour and day-to-day, to aid in dose selection in insulin-treated patients, and for safety.
All patients with diabetes mellitus who use insulin and some patients who take other glucose-lowering medications that can cause hypoglycemia should measure their blood glucose concentrations to help maintain safe, target-driven glucose control. The effectiveness of self-monitoring in patients with type 2 diabetes who do not use hypoglycemic agents is less certain. The indications for and practical points about blood glucose monitoring, including CGM, are reviewed elsewhere. (See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus".)
There are no long-term outcome data for patients on dialysis using CGM. A small study in patients on hemodialysis reported more frequent treatment changes, better glycemic control, and no increased risk of hypoglycemia [11]. Glucose metrics available through use of CGM, particularly time (percent) in target range (70 to 180 mg/dL), might support treatment decisions for individual patients who have A1C values discordant with self-monitored blood glucose measures or clinical symptoms. In addition, CGM can be particularly helpful when initiating new anti-hyperglycemic therapy or adjusting current medications to ensure achievement of glycemic targets and avoidance of hypoglycemia.
Of particular importance to patients receiving peritoneal dialysis is the finding that some glucose monitors (those using the enzyme glucose dehydrogenase pyrroloquinoline quinone) will give falsely elevated readings in patients who have received treatments containing other sugars, including icodextrin in peritoneal dialysis fluids [12]. This effect can persist for two weeks after stopping icodextrin (see "Peritoneal dialysis solutions"). New test strips have been designed to minimize interference with nonglucose sugars [13].
GLYCEMIC TARGETS — The glycated hemoglobin (A1C) target that is associated with the best outcome in patients with chronic kidney disease (CKD) has not been established. Clinical practice guidelines recommend an individualized A1C target ranging from <6.5 to <8 percent, depending upon patient factors, such as risk of hypoglycemia, presence of cardiovascular disease, and life expectancy [14,15]:
●Patients not on dialysis (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) – For most patients with an eGFR <30 mL/min/1.73 m2 who are not on dialysis, we suggest using an A1C target of approximately 7 percent, although the risks and benefits of targeting this goal are uncertain. Data supporting this goal are from studies of patients without CKD and are discussed elsewhere. (See "Glycemic control and vascular complications in type 2 diabetes mellitus", section on 'Choosing a glycemic target'.)
●Patients on dialysis – For patients who are on dialysis, we individualize the A1C goal based upon the risk of hypoglycemia and presence of comorbid conditions. For patients who are relatively young (<50 years) and without significant comorbid conditions, we suggest an A1C goal that is close to 7 percent (eg, 6.5 to 7.5). However, among older patients with multiple comorbid conditions, the A1C goal is closer to 8 percent (eg, 7.5 to 8).
Although benefits associated with better glycemic control in patients on dialysis have been reported in several small observational studies [16-18], other larger observational studies have found no significant correlation between tight glycemic control and survival [19-23]. In a meta-analysis of observational studies of patients on hemodialysis, compared with A1C values of 6.5 to 7.4 percent, baseline (hazard ratio [HR] 1.14, 95% CI 1.09-1.19) and mean (HR 1.29, 95% CI 1.23-1.35) A1C values ≥8.5 percent were associated with an increase in mortality [24]. Among patients recently initiating hemodialysis, there was an increase in mortality associated with A1C values ≤5.4 percent. Such observational studies cannot establish a causal relationship between A1C levels and outcomes.
TREATMENT
General management — All patients with diabetes should participate in a comprehensive diabetes self-management education program, which includes individualized instruction on nutrition, physical activity, optimizing metabolic control, and preventing complications. For patients with type 2 diabetes, the majority of whom have overweight (body mass index [BMI] ≥25 to 29.9 kg/m2) or obesity (BMI ≥30 kg/m2), major emphasis should be placed on reducing caloric intake, increasing physical activity, and behavior modification to achieve weight loss. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Diabetes education'.)
The additional burden of chronic kidney disease (CKD) dietary requirements (such as salt, protein, and volume restrictions) may further complicate diets in patients with diabetes. (See "Nutritional considerations in type 2 diabetes mellitus".)
Approach to pharmacologic therapy — Pharmacologic therapies for the treatment of hyperglycemia include oral agents, noninsulin injectable agents, and insulin. Although metformin is the most commonly used drug to treat type 2 diabetes, it should not be used in patients with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 because of an increased risk of lactic acidosis. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are being used increasingly to slow the progression of kidney disease in diabetes. They are relatively weak glucose-lowering medications and have reduced glycemic efficacy in individuals with an eGFR <30 to 45 mL/min/1.73 m2, with some differences in each medication depending on the labeling. In this setting, additional agents may be necessary to achieve glycemic goals; nonetheless, an SGLT2 inhibitor may be initiated for kidney protection in individuals with an eGFR as low as 20 mL/min/1.73 m2 [15]. (See 'Medications not recommended for hyperglycemia' below and "Treatment of diabetic kidney disease", section on 'Type 2 diabetes: Treat with additional kidney-protective therapy'.)
Our approach, which is largely in agreement with guidelines from the American Diabetes Association and Kidney Disease: Improving Global Outcomes (KDIGO), is described below (algorithm 1) [14,15,25].
Patients not on dialysis
●CKD stage 4 – In patients with CKD stage 4, we suggest a glucagon-like peptide 1 (GLP-1) receptor agonist rather than another agent for glucose lowering (algorithm 1). The GLP-1 receptor agonists dulaglutide, semaglutide, and liraglutide have kidney and cardiovascular protective benefits as well as documented safety in patients with an eGFR >15 mL/min/1.73 m2 [26-30]. GLP-1 receptor agonists should be titrated slowly, monitoring for gastrointestinal side effects, which could precipitate dehydration and acute kidney injury (AKI). Sulfonylureas with the lowest risk of hypoglycemia (glipizide, glimepiride, or gliclazide [not available in the United States], repaglinide, or linagliptin) are alternatives.
●CKD stage 5 – In patients with CKD stage 5 who are not on dialysis, we suggest a sulfonylurea with inactive metabolites and a relatively lower risk for hypoglycemia (eg, glipizide, glimepiride, or gliclazide [not available in the United States]) rather than another agent (algorithm 1). Repaglinide, linagliptin, or cautious use of a GLP-1 receptor agonist are alternatives to sulfonylureas with inactive metabolites. The choice of agent depends upon glycemic goals (see 'Glycemic targets' above); the risk of medication-associated adverse events (hypoglycemia, lactic acidosis); patient comorbidities and preferences; and convenience.
Patients who are unable to achieve their glycemic target with oral agents or a GLP-1 receptor agonist are treated with insulin. The indications for initiating insulin therapy and the principles underlying insulin therapy are the same for patients with nondialysis CKD as for the general diabetic population. (See "General principles of insulin therapy in diabetes mellitus" and "Insulin therapy in type 2 diabetes mellitus".)
●GLP-1 receptor agonists – GLP-1 receptor agonists stimulate glucose-dependent insulin secretion, suppress glucagon levels, delay gastric emptying, and increase satiety. Experience with GLP-1 agonists in patients with reduced kidney function is limited [31-37], and therefore, these agents should be used with caution. They should not be used in combination with dipeptidyl peptidase 4 (DPP-4) inhibitors.
Liraglutide, dulaglutide, and semaglutide (injection) have demonstrated cardiorenal benefit in patients with type 2 diabetes and cardiorenal disease, including a minority of patients with an eGFR between 15 to 30 mL/min/1.73 m2 [26-30]. They are not excreted by the kidneys, and dose reductions with impaired kidney function are not necessary [38]. They may be used in CKD stage 4, but patient education for signs and symptoms of dehydration due to nausea or satiety is warranted to reduce the risk of AKI [38,39]. Dulaglutide should not be used in patients with an eGFR ≤15 mL/min/1.73 m2. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Microvascular outcomes'.)
●Sulfonylureas – Sulfonylureas with the lowest risk of hypoglycemia (eg, glipizide or glimepiride) are reasonable agents for patients who have an eGFR <30 mL/min/1.73 m2 [31-33,37,40]. Gliclazide is a similar agent that is not available in the United States. Glyburide (also known as glibenclamide) and other long-acting sulfonylureas are generally not recommended in any patient with type 2 diabetes because of the risk of hypoglycemia. (See "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus".)
The sulfonylureas are strongly protein bound, particularly to albumin. Thus, elevated plasma drug levels cannot be efficiently reversed by hemodialysis. Furthermore, displacement of these drugs from albumin by beta blockers, salicylates, and warfarin can lead to hypoglycemia due to increased plasma concentration of the free sulfonylurea.
The administration of sulfonylureas in patients with an eGFR <30 mL/min/1.73 m2 who are not on dialysis requires careful attention to dosing and routes of elimination [31-34]. Treatment should be initiated with low doses that can be titrated upward as needed:
•Glipizide – The initial dose is 2.5 mg/day taken 30 minutes before breakfast. Glipizide is a short-acting agent that is metabolized by the liver and primarily excreted in the urine as inactive metabolites.
•Glimepiride – The initial dose is 1 mg/day with breakfast. Glimepiride is primarily metabolized by the liver, with renal excretion of at least one active metabolite. It can be used at low doses in patients with CKD but should be avoided in patients with end-stage kidney disease (ESKD) because of a risk of prolonged hypoglycemia.
•Gliclazide (not available in the United States) – The initial dose is 40 mg daily.
●Repaglinide – Some clinicians use repaglinide (a meglitinide) for patients not on dialysis since it is not cleared by the kidneys. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Choice of initial therapy' and "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus".)
Repaglinide acts at the sulfonylurea receptor to increase insulin secretion but is much shorter acting than sulfonylureas and is principally metabolized by the liver, with less than 10 percent renally excreted [31-34].
In patients with an eGFR <40 mL/min/1.73 m2, initiation of repaglinide should be with 0.5 mg before the largest meal and then advanced to 0.5 mg prior to other meals, as needed. Repaglinide has not been studied in patients with an eGFR <20 mL/min/1.73 m2. (See "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus", section on 'Dosing and monitoring'.)
Nateglinide (another meglitinide) is hepatically metabolized, with renal excretion of active metabolites. With decreased kidney function, these metabolites can accumulate and cause hypoglycemia [31,32,34]. This drug should therefore be avoided in patients with advanced CKD or ESKD.
●DPP-4 inhibitors – Limited data suggest that DPP-4 inhibitors (eg, linagliptin, sitagliptin, saxagliptin) are effective and relatively safe in patients with CKD [32-34,37]. Linagliptin is only minimally excreted in the urine (<10 percent), and it is the only DPP-4 inhibitor that does not require a dose (5 mg once daily) adjustment in the setting of kidney failure [41,42]. (See "Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus", section on 'Efficacy in chronic kidney disease'.)
Sitagliptin is largely excreted in the urine, with 70 to 80 percent of an oral dose appearing unchanged in the urine [43]. If sitagliptin is used among patients with an eGFR <30 mL/min/1.73 m2, a dose reduction to 25 mg daily (usual dose 100 mg daily) is recommended.
Saxagliptin and its primary active metabolite are excreted in the urine (total urinary excretion approximately 60 to 75 percent); a daily dose of 2.5 mg is the recommended dose for patients with an eGFR <45 mL/min/1.73 m2.
Experience with other drugs of this class in patients with CKD or ESKD is limited.
●Insulin – Among patients who are treated with insulin, the starting dose of insulin may need to be lower than would ordinarily be used for patients with normal kidney function. CKD is associated with decreased kidney and ultimately hepatic metabolism of insulin (see "Carbohydrate and insulin metabolism in chronic kidney disease"). As a result, the following dose recommendations have been made for insulin dosing in this setting if the patient is reaching his or her glycemic target [44-46]:
•No dose adjustment is required if the eGFR is >50 mL/min/1.73 m2.
•The insulin dose should be reduced to approximately 75 percent of baseline when the eGFR is between 10 and 50 mL/min/1.73 m2.
•The dose should be reduced by as much as 50 percent when the eGFR is <10 mL/min/1.73 m2.
The initial dose of intermediate- or long-acting insulin in patients without CKD is approximately 10 units or 0.2 units/kg (algorithm 2). Thus, in a patient with an eGFR between 10 and 50 mL/min/1.73 m2, the initial dose would be approximately 7 units (75 percent of 10 units) once daily at bedtime.
The balance between altered insulin resistance and insulin clearance as kidney dysfunction progresses is difficult to predict in any individual patient, so insulin adjustment is often largely empiric. Thus, it is important that blood glucose levels be monitored closely and that individually appropriate dose adjustments in insulin therapy be made. Continuous glucose monitoring (CGM) can be used to assist insulin adjustment treatment plans and mitigate the risk of hypoglycemia. (See 'Daily glucose measurements' above.)
Patients on hemodialysis — For most patients on hemodialysis, we use insulin rather than oral agents. KDIGO guidelines suggest that insulin, DPP-4 inhibitors, thiazolidinediones, sulfonylureas, or alpha-glucosidase inhibitors may be used for glycemic control in patients on hemodialysis (algorithm 1) [14]. There are few data evaluating the use of oral agents or GLP-1 receptor agonists in patients requiring dialysis [37,47-49].
The principles of insulin therapy are the same for patients on dialysis as for other patients with diabetes, and several different insulin regimens can be used (algorithm 2). For patients on hemodialysis, the initial dose of insulin should be decreased by approximately 50 percent, as described above for patients with nondialysis CKD and an eGFR <10 mL/min/1.73 m2. The dose should be titrated upward, as indicated by blood glucose monitoring. Most patients will require more insulin than this initial dose. (See "General principles of insulin therapy in diabetes mellitus" and "Insulin therapy in type 2 diabetes mellitus".)
A consensus approach does not exist to the choice of insulin in patients with diabetes and ESKD [45]. Some suggest that long-acting insulin preparations should be avoided, while others feel that such agents should be used.
Some clinicians prefer to use oral agents rather than insulin, especially among patients who are already on these agents and have achieved acceptable glycemic control. The preferred agents are glipizide or repaglinide since they are primarily metabolized by the liver, inactive or only very weakly active metabolites are excreted in the urine, and the risk of hypoglycemia is lower than with other oral agents [50]. Although repaglinide drug concentration and elimination half-life are increased marginally in patients with a reduced glomerular filtration rate (GFR), dose reductions are not necessary and this agent may be an appropriate therapy for patients with ESKD [51]. DPP-4 inhibitors (eg, sitagliptin, linagliptin, saxagliptin) are an alternative option [52]. Saxagliptin should be administered after dialysis as it is removed by hemodialysis.
Patients on peritoneal dialysis
●Choice of therapy – For patients who were already on an oral agent with good glycemic control prior to starting peritoneal dialysis, we typically continue the oral agent (algorithm 1). For patients who develop diabetes after starting peritoneal dialysis, we generally treat first with an oral agent. Our choice of agent is similar to what is described above for patients on hemodialysis (see 'Patients on hemodialysis' above). We prefer a sulfonylurea with a relatively lower risk for hypoglycemia (eg, glipizide [initial dose 2.5 mg/day], glimepiride [initial dose 1 mg/day], repaglinide [0.5 mg/day], or linagliptin [5 mg once daily]). Metformin should not be used among patients on peritoneal dialysis because of an increased risk of lactic acidosis [53].
Over time, many patients will require insulin. The principles underlying subcutaneous insulin therapy are the same for patients with nondialysis CKD as for the general diabetic population (see "General principles of insulin therapy in diabetes mellitus" and "Insulin therapy in type 2 diabetes mellitus"). The initial starting dose is similar to that for patients on hemodialysis (decrease the dose used in people without CKD by approximately 50 percent), with upward titration based upon blood glucose monitoring.
●Subcutaneous versus intraperitoneal insulin – We and most other nephrologists prefer subcutaneous insulin for patients on continuous ambulatory peritoneal dialysis (CAPD) or continuous cycler peritoneal dialysis [54]. We do not use intraperitoneal insulin, as it often does not adequately control blood sugars. Even among patients who achieve adequate glycemic control with intraperitoneal insulin alone, the required insulin regimen is very complex since patients often alter CAPD schedules, as well as the timing of meals, necessitating constant adjustment of the intraperitoneal insulin, which is burdensome for the patient.
Other disadvantages of intraperitoneal insulin include the risk of bacterial contamination of dialysate during injection of insulin into the bags [55], the requirement for a higher total insulin dose due to losses into spent dialysate and binding to the plastics in bags and tubing [56-59], and an associated risk of peritoneal fibroblastic proliferation [60] and, perhaps, of hepatic subcapsular steatosis [56]. Another potential concern is that the absorption of insulin may significantly vary among patients or may decline over time in a single individual due to acquired abnormalities in the peritoneal membrane [61]. One study of seven patients suggested that the latter is not a common problem, as there was no difference in insulin absorption after 30 months of CAPD [62].
There are no long-term studies evaluating use of intraperitoneal insulin. A meta-analysis of three trials demonstrated better glycemic control, as assessed by glycated hemoglobin (A1C), with intraperitoneal compared with subcutaneous insulin in CAPD patients, but the insulin dose was more than double with intraperitoneal use [63]. Patients treated with intraperitoneal insulin had lower high-density lipoprotein cholesterol levels and higher triglyceride levels compared with those treated with subcutaneous insulin [63].
●Abnormal or variations in peritoneal kinetics – The selection of oral agents described above assumes that peritoneal transfer kinetics are relatively normal. Patients treated with CAPD who have uncontrolled hyperglycemia should undergo a peritoneal equilibration test. (See "Peritoneal equilibration test".)
High transporters, who can have enormous glucose loads from rapid peritoneal glucose absorption (figure 1), will usually benefit from transfer to nocturnal automated peritoneal dialysis [56,64]. In addition to raising the blood glucose, the rapid glucose absorption lowers the osmotic gradient between dialysate and blood, resulting in reduced ultrafiltration, diminished urea removal, and fluid retention. A vicious cycle is then created, with generalized edema requiring frequent use of 2.5 and 4.25 percent dextrose dialysis solutions, leading to further hyperglycemia.
●Carbohydrate-sparing dialytic regimens – Adjusting the peritoneal dialysis solution may improve glycemic control in some patients. Glucose polymers were introduced to replace glucose-containing solutions by offering the possible advantages of decreased absorption of solute and increased ultrafiltration for a longer period of time. The use of a glucose polymer as an osmotic agent is particularly appealing as a substitute for glucose solutions, particularly in patients with diabetes [65]. (See "Peritoneal dialysis solutions".)
Carbohydrate-sparing dialytic regimens include:
•Icodextrin, in which carbohydrate absorption is equivalent to a 2.5 percent dextrose bag, but is associated with ultrafiltration of a 4.25 dextrose bag [66]
•Amino acid dialysate solutions, which are available in countries outside the United States
Medications not recommended for hyperglycemia — The following medications are not recommended for the treatment of hyperglycemia in patients with an eGFR <30 mL/min/1.73 m2.
Metformin — Metformin, which is a preferred agent in most patients, should not be used in patients with an eGFR <30 mL/min/1.73 m2 because of an increased risk of lactic acidosis [53]. A discussion of eGFR thresholds for the safe use of metformin as well as dosing of metformin with mildly to moderately reduced eGFR is reviewed in detail separately. (See "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Contraindications' and "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Dosing'.)
SGLT2 inhibitors — The sodium-glucose cotransporter 2 (SGLT2) inhibitors empagliflozin, canagliflozin, and dapagliflozin have demonstrated benefit for cardiorenal outcomes, especially for heart failure hospitalization and risk of kidney disease progression. However, for the treatment of hyperglycemia, SGLT2 inhibitors are not recommended for initiation in patients with an eGFR <30 to 45 mL/min/1.73 m2, with some differences in each medication depending on the labeling. SGLT2 inhibitors have less glycemic efficacy in patients with an eGFR <45 mL/min/1.73 m2, and in this setting, an additional agent may be necessary to achieve glycemic goals. (See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus" and "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Established cardiovascular or kidney disease'.)
Kidney and cardiac benefits have been shown in patients with an eGFR below this threshold. In the setting of declining eGFR, the main reason to prescribe SGLT2 inhibitors is to reduce progression of diabetic kidney disease; they should be prescribed at the lowest dose. (See "Treatment of diabetic kidney disease", section on 'Type 2 diabetes: Treat with additional kidney-protective therapy'.)
Other agents — Other medications that are infrequently used in patients with nondialysis CKD or ESKD include thiazolidinediones and alpha-glucosidase inhibitors:
●Thiazolidinediones (pioglitazone) should be avoided in patients with advanced CKD, especially those with preexisting heart failure, given the risk of edema and heart failure.
Thiazolidinediones enhance tissue sensitivity to insulin and suppress hepatic glucose production via binding to peroxisome proliferator-activated receptor (PPAR) gamma. (See "Thiazolidinediones in the treatment of type 2 diabetes mellitus".)
Pioglitazone, the only drug of this class remaining on the market, is highly protein bound (primarily to albumin) and almost completely metabolized by the liver [31,32,34]. It has three active metabolites, but accumulation of the parent drug and major metabolites does not occur in the setting of CKD. Hemodialysis does not affect pioglitazone's pharmacokinetics.
These agents are associated with heart failure and edema, which may be more frequent in patients also receiving insulin [45]. The mechanism of edema formation with these agents appears to be related to stimulation of PPAR gamma-mediated sodium reabsorption by renal epithelial sodium channels in the collecting duct [67].
●Alpha-glucosidase inhibitors, such as acarbose or miglitol, can be safely used in patients with stage 4 or 5 CKD [14,68]. In general, however, they are minimally effective in lowering glycated hemoglobin (A1C; mean 0.5 to 0.7 percent reduction) and are associated with limiting gastrointestinal side effects [31-34].
These agents slow carbohydrate absorption from the gastrointestinal tract and reduce postprandial blood sugar peaks. (See "Alpha-glucosidase inhibitors for treatment of diabetes mellitus".)
With acarbose, increased levels of the parent drug and metabolites are observed with CKD, but the clinical significance of this is not known. Miglitol is absorbed to a greater extent than acarbose and is largely excreted by the kidneys, with increased accumulation in patients with decreased kidney function. As with acarbose, the clinical significance of this is not known.
TROUBLESHOOTING — Some patients with diabetes have persistent hyperglycemia, severe hyperglycemia, diabetic ketoacidosis, frequent hypoglycemia, or alternating episodes of hyperglycemia and hypoglycemia.
Hyperglycemia — Inadequate insulin dose and noncompliance (with diet or the insulin regimen) are the most common causes of persistent hyperglycemia (defined as a A1C level >9 percent) in patients on dialysis [69]. An additional problem is that microvascular disease can cause erratic absorption of insulin from the subcutaneous tissue, particularly if the patient does not rotate injection sites [57]. (See "General principles of insulin therapy in diabetes mellitus", section on 'Injection technique'.)
The approach to these issues is the same for patients with chronic kidney disease (CKD) as for those without and is discussed elsewhere. (See "General principles of insulin therapy in diabetes mellitus", section on 'Determinants of insulin efficacy' and "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Indications for a second agent'.)
Severe hyperglycemia and ketoacidosis — Severe hyperglycemia, with serum glucose concentrations occasionally >1000 mg/dL (55 mmol/L), may be observed among patients on dialysis. Unlike those without end-stage kidney disease (ESKD), however, hypovolemia and marked hypernatremia do not occur, since glucosuria is absent in anuric individuals. The net effect is minimal symptoms, even among those with extreme hyperglycemia [70].
However, these patients may have marked hyperkalemia due to potassium efflux from cells in response to extracellular fluid hypertonicity, as well as hyponatremia and acute intravascular volume expansion [71]. Patients with type 1 diabetes may also develop diabetic ketoacidosis.
Instead of fluid replacement, management is principally dependent upon the administration of low doses of intravenous insulin (commonly beginning at a dose of 2 units/hour) [70]. As with all patients with severe hyperglycemia and diabetic ketoacidosis, serum glucose and potassium concentrations must be closely monitored. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment", section on 'Monitoring'.)
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been associated with euglycemic ketoacidosis. This is reviewed in more detail separately. (See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Diabetic ketoacidosis'.)
Hypoglycemia — Frequent or persistent hypoglycemia in patients on dialysis is often due to severe underdialysis, with poor calorie intake, or occult disease, such as infection or malignancy. Frequent adjustment of insulin dose and evaluation of blood glucose diaries or use of continuous glucose monitoring (CGM) are essential in this setting, as is provision of an adequate dialysis dose (see "Prescribing and assessing adequate hemodialysis" and "Prescribing peritoneal dialysis" and "Protein intake in patients on maintenance hemodialysis" and "Assessment of nutritional status in patients on hemodialysis"). Drugs that interfere with the counterregulatory response to hypoglycemia (such as beta blockers) and long-acting insulin and oral agents should be discontinued, if possible, until more stable glycemic control without hypoglycemia is achieved.
Alternating hypoglycemia and hyperglycemia — Patients with ESKD and diabetes often have gastroparesis [57], which complicates the timing of insulin injections as well as oral agents that are taken in relation to food intake. Gastric emptying studies will confirm the diagnosis, which can often be effectively treated with metoclopramide or bethanechol [57]. Improvement in glycemic control may also improve gastric motility. (See "Diabetic autonomic neuropathy of the gastrointestinal tract", section on 'Gastroparesis'.)
Other causes of brittle blood glucose include patient misunderstanding of the timing of insulin injections, poor compliance with dietary restrictions and insulin therapy, erratic eating habits, and poor timing of continuous ambulatory peritoneal dialysis (CAPD) exchanges. These problems can often be corrected with patient re-education. Poor adherence, impaired vision, and a depressive illness should also be sought. (See "Approach to the adult with brittle diabetes or high glucose variability".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults" and "Society guideline links: Diabetic kidney disease".)
SUMMARY AND RECOMMENDATIONS
●General principles – Chronic kidney disease (CKD) is associated with insulin resistance, and in patients with diabetes, glycemic control may deteriorate as kidney function declines. In advanced CKD, however, there is a marked reduction in insulin clearance, leading to a decrease in insulin requirement or even the cessation of insulin therapy in patients with type 2 diabetes. Careful, individualized therapy is essential among patients with advanced CKD or end-stage kidney disease (ESKD). (See 'Introduction' above.)
●Monitoring glycemia
•We assess chronic glycemic control in patients with diabetes and predialysis CKD or ESKD with glycated hemoglobin (A1C) as we do in patients with diabetes and normal kidney function. It is important to be aware of the specific assay used in each dialysis facility and the extent to which kidney disease and other factors affect the relationship of A1C levels and average glycemia. (See 'Chronic glycemia' above.)
•Measurements of instantaneous glucose levels (self-monitoring of blood glucose [with fingersticks and a glucose meter] and real-time continuous glucose monitoring [CGM]) are used to manage diabetes from hour-to-hour and day-to-day, to aid in dose selection in insulin-treated patients, and for safety. CGM may be useful to support treatment decisions for individual patients who have A1C values discordant with self-monitored blood glucose measures or clinical symptoms, or when initiating new anti-hyperglycemic therapy or adjusting current medications to ensure achievement of glycemic targets and avoidance of hypoglycemia. (See 'Daily glucose measurements' above.)
●Glycemic targets – Target A1C levels should be tailored to the individuals, based upon patient factors, such as risk of hypoglycemia, presence of cardiovascular disease, and life expectancy. A1C targets generally range from <6.5 to <8 percent. (See 'Glycemic targets' above and "Glycemic control and vascular complications in type 2 diabetes mellitus", section on 'Choosing a glycemic target'.)
●Treatment
•General management – All patients with diabetes should participate in a comprehensive diabetes self-management education program, which includes individualized instruction on nutrition, physical activity, optimizing metabolic control, and preventing complications. Pharmacologic therapies for the treatment of hyperglycemia include oral agents, noninsulin injectable agents, and insulin. (See 'General management' above.)
•Pharmacologic therapy – Pharmacologic therapies for the treatment of hyperglycemia include oral agents, noninsulin injectable agents, and insulin. Our approach, which is largely in agreement with guidelines from the American Diabetes Association and Kidney Disease: Improving Global Outcomes (KDIGO), is as follows (algorithm 1):
-Patients not on dialysis – For patient with stage 4 CKD, we suggest a glucagon-like peptide 1 (GLP-1) receptor agonist rather than another agent (Grade 2C). The GLP-1 receptor agonists dulaglutide, semaglutide, and liraglutide have kidney and cardiovascular protective benefits as well as documented safety in patients with an estimated glomerular filtration rate (eGFR) >15 mL/min/1.73 m2. Sulfonylureas with the lowest risk of hypoglycemia (glipizide, glimepiride, or gliclazide [not available in the United States], repaglinide, or linagliptin) are alternatives.
For patients with CKD stage 5 who are not on dialysis, we suggest a sulfonylurea with inactive metabolites and a relatively lower risk for hypoglycemia (eg, glipizide, glimepiride, or gliclazide [not available in the United States]) rather than another agent (Grade 2C). Repaglinide, linagliptin, or cautious use of a GLP-1 receptor agonist are alternatives to sulfonylureas with inactive metabolites.
Patients who are unable to achieve their glycemic target with oral agents or a GLP-1 receptor agonist are treated with insulin. (See 'Patients not on dialysis' above.)
-Patients on hemodialysis – For most patients on hemodialysis, we suggest using insulin rather than oral agents (Grade 2C). Several different insulin regimens can be used (algorithm 2). The initial dose of insulin should be decreased by approximately 50 percent.
However, some clinicians prefer to use oral agents rather than insulin, especially among patients who have already achieved acceptable glycemic control on these agents. (See 'Patients on hemodialysis' above.)
-Patients on peritoneal dialysis – For patients on peritoneal dialysis who are already on an oral agent with good glycemic control prior to starting peritoneal dialysis and for patients who develop diabetes after starting dialysis, we suggest using an oral agent rather than insulin (Grade 2C). The preferred agents and suggested initial doses include glipizide (2.5 mg/day), glimepiride (1 mg/day), repaglinide (0.5 mg/day), or linagliptin (5 mg once daily).
Many patients on peritoneal dialysis will require insulin therapy to achieve adequate glycemic control. For such patients, we suggest the use of subcutaneous, rather than intraperitoneal, insulin (Grade 2C). The initial dose of insulin should be approximately 50 percent of the dose used in people without CKD. (see 'Patients on peritoneal dialysis' above).
-Metformin and sodium-glucose cotransporter 2 (SGLT2) inhibitors should not be used for the treatment of hyperglycemia in patients with advanced CKD or ESKD. In the setting of declining eGFR, SGLT2 inhibitors are often prescribed to reduce progression of diabetic kidney disease. (See 'Medications not recommended for hyperglycemia' above and "Treatment of diabetic kidney disease", section on 'Type 2 diabetes: Treat with additional kidney-protective therapy'.)
●Troubleshooting – Severe hyperglycemia may be observed among patients on dialysis with diabetes. Unlike those without ESKD, hypovolemia and marked hypernatremia do not occur, since glucosuria is absent in anuric individuals. Patients have few symptoms but may have marked hyperkalemia, hyponatremia, and acute intravascular volume expansion. Instead of fluid replacement, management is principally dependent upon the administration of low doses of intravenous insulin. (See 'Troubleshooting' above.)
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