Management of Glycemia in Patients With Diabetes Mellitus and CKD

Sulfonylureas 

Agents in this class stimulate insulin secretion from the islet beta cell by binding to the sulfonylurea receptor 1 of the adenosine triphosphate–dependent potassium channel. Sulfonylureas are highly efficacious in the short term, but glycemic efficacy may be attenuated over time more than with other oral agents.35 Sulfonylureas have been studied extensively and are associated with favorable vascular outcomes.6 Because maximum doses of sulfonylureas may be less effective than moderate doses,36 maximizing doses of sulfonylureas is not recommended. The main risk is hypoglycemia; therefore, low starting doses and slow titration are required.

First-generation sulfonylureas are rarely used in the United States and are not discussed here. Of the second-generation sulfonylureas, glyburide undergoes complete hepatic metabolism to 2 weakly active metabolites. These metabolites accumulate in patients with CKD, increasing the risk of hypoglycemia.37, 38, 39, 40 Therefore, it is recommended that glyburide be avoided in patients with CKD. Glimepiride undergoes complete hepatic metabolism to 2 metabolites, which are excreted in urine and feces. The predominantly renally excreted metabolite has weak hypoglycemic activity41 and may build up with renal impairment, increasing the risk of hypoglycemia, including prolonged hypoglycemia.42, 43, 44 Glipizide undergoes near-complete hepatic biotransformation to inactive metabolites, and its half-life is unaffected by kidney function.45 Accordingly, glipizide is the sulfonylurea of choice in patients with CKD. Hypoglycemia remains a risk with glipizide, but considerably less so compared with glyburide or glimepiride.46

Nonsulfonylurea Insulin Secretagogues (glinides) 

Although glinides stimulate insulin secretion by binding to adenosine triphosphate–dependent potassium channels in the pancreatic β islet cell, they are chemically unrelated to sulfonylureas. Clinically, glinides are differentiated from sulfonylureas by a very short half-life and duration of action (3-4 hours) and therefore are administered shortly before meals. Glinides have modest glycemic efficacy and lack clinical outcome data; however, their relatively low risk of hypoglycemia gives them an advantage over sulfonylureas in patients with CKD and mild type 2 diabetes with predominantly postprandial hyperglycemia.

Repaglinide binds to a different site on the sulfonylurea receptor 1 subunit than sulfonylureas. It is completely metabolized by hepatic biotransformation and conjugation to inactive metabolites,47 with no increase in hypoglycemia risk in patients with CKD.48 Nateglinide binds to the same binding site on the sulfonylurea receptor 1 subunit as sulfonylureas. Approximately 15% of nateglinide is excreted unchanged in urine; the remainder is metabolized by the liver to weakly active metabolites and conjugates that are excreted in urine (80%) and feces (20%). In patients with advanced CKD, there is accumulation of an active metabolite of nateglinide, which may increase the risk of hypoglycemia49, 50, 51; therefore, caution is recommended when using this drug in patients with CKD.

Incretin-Based Insulin Secretagogues 

This is the newest class of hypoglycemic agents, developed as a result of improved understanding of the incretin effect on the pathophysiology of type 2 diabetes. The incretin effect is the augmentation of glucose-stimulated insulin secretion by intestinally derived peptides, which are released in the presence of glucose or nutrients in the gut.52 The incretin effect is composed primarily of 2 peptides; glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1. Incretins are rapidly inactivated by the enzyme dipeptidyl peptidase IV (DPP4), resulting in a very short half-life (minutes). The incretin pathway appears to be attenuated in patients with type 2 diabetes, making the pathway a target for the development of new pharmacological agents.52 Currently, there are 2 approved agents in this class; exenatide, a glucagon-like peptide 1 receptor analogue resistant to DPP4 degradation, and sitagliptin, a selective DPP4 inhibitor.

Exenatide has only modest glycemic efficacy, but it is the only hypoglycemic agent associated with weight loss.53 It is administered subcutaneously twice daily about 60 minutes before meals. Its main side effect is dose-dependent nausea and vomiting, but only 4% of patients stop the medication because of gastrointestinal side effects.53 Exenatide is cleared primarily by the kidneys; however, dose adjustment is not required for patients with a creatinine clearance greater than 30 mL/min (>0.5 mL/s). In patients with CKD stage 4/5, clearance of exenatide is significantly decreased (∼10% of normal), and its use is neither recommended nor well tolerated.54

Sitagliptin, currently the only available DPP4 inhibitor, has a modest hypoglycemic efficacy and generally is well tolerated, although there may be a small increased risk of urinary tract infections and nasopharyngitis.53 Advantages of DPP4 inhibitors include a very low risk of hypoglycemia and lack of weight gain. Sitagliptin is administered orally once daily. Because it is excreted mostly unchanged in urine, lower doses are recommended in patients with CKD stages 3 to 5.55, 56 Long-term efficacy and safety of sitagliptin in patients with CKD have not been determined.

Pramlintide is an analogue of amylin, a hormone cosecreted with insulin from pancreatic beta cells in response to meals that contributes to postprandial glucose control.57 Pramlintide is metabolized primarily by the kidney to active metabolites, but no change in dose is required at a creatinine clearance greater than 20 mL/min.58 Because of its low glycemic efficacy, frequent side effects (hypoglycemia and nausea), and somewhat complex administration, pramlintide is not commonly used in clinical practice.

Biguanides 

Metformin, the only biguanide available in the United States, decreases glucose levels primarily by decreasing hepatic glucose output and, to a lesser extent, promoting insulin-mediated glucose uptake in peripheral insulin-target tissues. Metformin is one of the most efficacious oral hypoglycemic agents and is associated with favorable clinical outcomes.7 It is well tolerated, and its most common adverse effect is gastrointestinal disturbance, which can be avoided by starting with a low dose and titrating slowly.59 Unless contraindicated, metformin is the oral hypoglycemic agent of choice as first-line therapy in patients with type 2 diabetes.60 A life-threatening complication of metformin is the development of lactic acidosis, which is exceedingly rare and almost always seen in patients with significant comorbidity, including advanced kidney disease.61 Metformin is excreted unchanged in urine, and the drug accumulates as renal function worsens, especially at GFRs less than 60 mL/min/1.73 m2 (<1 mL/s/1.73 m2), increasing the risk of lactic acidosis. Thus, patients with CKD stage 3 or higher should not be administered metformin.

Thiazolidinediones 

Rosiglitazone and pioglitazone, the 2 available thiazolidinediones in the United States, enhance insulin action in insulin-target tissues through binding to peroxisome proliferator-activated receptor γ (nuclear transcription factors involved in glucose and lipid homeostasis). Thiazolidinediones have glycemic efficacy equivalent to sulfonylureas or metformin, with less hypoglycemia, but also have a slower onset of action (weeks to months). Therefore, these agents are not appropriate for patients with symptomatic hyperglycemia. The currently available thiazolidinediones do not share the hepatotoxicity that was associated with the first agent in the class, troglitazone, but rare isolated cases of idiosyncratic hepatotoxicity were reported. Weight gain is the most common adverse effect of thiazolidinediones, especially when coadministered with insulin or insulin secretagogues. This is caused by both fluid and fat accumulation. Thiazolidinediones may precipitate heart failure and therefore are contraindicated in patients with New York Heart Association class III or IV cardiac status and should be used with caution in patients with preexisting edema. Thiazolidinediones are metabolized extensively by the liver to metabolites with either very weak (rosiglitazone and pioglitazone) or moderate activity (pioglitazone). Pharmacokinetics of thiazolidinediones do not change with decreasing renal function, and no dose adjustment is required in patients with CKD.62, 63, 64

A recent meta-analysis combining data from 42 trials linked rosiglitazone to an increased risk of cardiovascular disease.65 It is not clear whether this finding will be replicated in large trials specifically designed for cardiovascular disease outcomes and whether this represents a class effect.66

α-Glucosidase Inhibitors 

Drugs in this class target postprandial hyperglycemia by inhibiting the intestinal breakdown of oligosaccharides, thereby delaying digestion of ingested carbohydrates. This class of medications has lower glycemic efficacy compared with other hypoglycemic classes, but in a trial of patients with glucose intolerance, the α-glucosidase inhibitor acarbose was reported to decrease the risk of cardiovascular disease events.67 Because carbohydrates are not absorbed, they remain in the colon to be digested by colonic bacteria. Therefore, gastrointestinal disturbances, such as abdominal pain, flatulence, and diarrhea, are major limitations encountered in approximately 50% of patients. Initiation at the lowest available dose and slow titration to the maximum dose attenuates gastrointestinal side effects; however, side effects frequently are unacceptable to patients, leading to discontinuation. Acarbose is metabolized nearly completely and exclusively within the gastrointestinal tract, with less than 2% of an oral dose recovered as active drug or metabolites in urine.68 A second α-glucosidase inhibitor, miglitol, is absorbed systemically and excreted unchanged in urine.

α-Glucosidase inhibitors are excellent agents for monotherapy in obese patients with postprandial hyperglycemia or early mild diabetes. However, given their modest glycemic efficacy, their frequent gastrointestinal effects, and the lack of studies in patients with kidney disease, α-glucosidase inhibitors have a limited role in the treatment of type 2 diabetes in patients with CKD. They may be used in patients with stage 3 CKD, but should be avoided in those with stages 4 and 5 because they were not studied in patients with serum creatinine values greater than 2 mg/dL (>177 μmol/L).69

Insulin 

Insulin is the most effective therapy for patients with diabetes, but there is considerable resistance to its use by patients and health care providers for a variety of reasons, including the need for subcutaneous injection, concern for weight gain, and hypoglycemia.70 Fortunately, the availability of newer insulin analogues enables clinicians to provide more physiological insulin therapy, and new delivery methods and glucose monitoring techniques have facilitated acceptance of intensive insulin treatment.71

Insulin therapy is governed by certain principles, including: (1) individualizing approach, (2) administrating adequate amounts of insulin, (3) providing physiological therapy through administration of both basal (long-acting) and prandial (bolus) insulin, and (4) monitoring and adjusting frequently based on individual responsiveness to therapy. An understanding of the pharmacokinetic profile of available insulin preparations is important in designing effective insulin regimens while minimizing the risk of hypoglycemia.

There are many formulations of basal and prandial insulin available for subcutaneous administration. These preparations can be divided into 4 main classifications: rapid-acting insulin analogues, short-acting insulin (regular human), intermediate-acting insulin (human), and long-acting insulin analogues. Insulin analogues, designed by means of recombinant DNA technology, have structural modifications in the amino-acid sequence of human insulin, resulting in improved (more physiological) time profiles.

Premixed (fixed-ratio) Insulin Preparations 

These preparations of insulin, administered twice daily before breakfast and dinner, are potentially convenient alternative options to basal-prandial combinations. However, premixed insulin also is often less effective because of its inflexibility, and it has significant interindividual variability.

Insulin Delivery 

Insulin administration with syringes is still the most common delivery method; however, several pen-like devices are available that allow improved convenience and accuracy of administration. Insulin pens hold as many as 300 units of insulin and are available either prefilled (disposable) or as durable devices that use cartridges. The patient determines the dose by dialing a knob and injects the insulin through a needle (specifically designed for pens, sold separately) by pushing a button. Despite their added expense, pen use is the preferred method for insulin administration. For motivated patients, an insulin pump provides an alternate route of insulin administration that is effective and safe.

Compared with patients with normal kidney function, patients with impaired kidney function have lower insulin requirements. In the latter group, regular human insulin shows a higher maximal concentration and longer half-life, whereas rapid-acting analogues maintain similar maximum concentration and half-life and are less likely to cause hypoglycemia compared with patients with normal kidney function.28 Thus, rapid-acting insulin analogues are preferred to regular human insulin in patients with CKD. Similarly, long-acting insulin analogues are also preferred to NPH. In general, as GFR decreases, insulin requirements decrease by as much as half, especially after initiation of dialysis therapy.29 Therefore, in patients requiring insulin, clinicians should monitor kidney function closely and adjust insulin doses appropriately as GFR decreases.

Diabetes in Patients on Hemodialysis Therapy 

Based on data from specific studies or predictions from their molecular structure, clearance of most hypoglycemic agents is not significantly affected by hemodialysis.83 In patients receiving hemodialysis, long-acting sulfonylureas are not appropriate because they are more likely to cause hypoglycemia. Short-acting sulfonylureas may be used at low doses. Thiazolidinediones can also be used without dose adjustment. However, in most patients, insulin will be the most appropriate therapy. Rapid-acting insulin analogues are cleared quickly and can be used safely. Long-acting basal insulin can be used in conjunction with rapid-acting analogues, although at low doses to not precipitate hypoglycemia. One major issue specific to hemodialysis patients is that eating patterns often change on dialysis days. Patients may miss meals or eat atypical foods because dialysis sessions often overlap with typical meal times. Other patients may be so fatigued after dialysis that they miss meals later in the day. In these situations, patients treated with secretagogues or mealtime insulin should tailor use of these medications based on their typical eating patterns surrounding dialysis sessions. For example, a patient who typically misses breakfast on a dialysis day should hold the morning dose of secretagogues or breakfast-time insulin, and a smaller dose of oral secretagogues or insulin could be considered with the afternoon meal. Basal insulin dose does not need to be decreased or withheld on dialysis days assuming that total daily intake remains relatively constant.

Diabetes in Patients on Peritoneal Dialysis Therapy 

Peritoneal dialysis poses additional challenges in the management of glycemia, primarily because of systemic absorption of glucose typically found in peritoneal dialysate and varying dialysis regimens. Accordingly, matching insulin dosing with blood glucose levels can be difficult. For patients receiving subcutaneous insulin and continuous ambulatory peritoneal dialysis, a subcutaneous regimen similar to that for patients on hemodialysis therapy could be used, with long-acting basal insulin and rapid-acting insulin with meals. Insulin requirements will likely be greater for most patients on continuous ambulatory peritoneal dialysis therapy because of the glucose in dialysate. For patients on intermittent peritoneal dialysis therapy or such therapies as continuous cycler-assisted peritoneal dialysis, in which glucose absorption fluctuates, use of an insulin preparation with an action profile that matches the length of time of the dialysis treatment is preferred. For example, twice-daily NPH could be used for basal needs, with a greater dose given at bedtime to match the greater glucose absorption from the overnight cycling, and a lower dose given in the morning to match the slow absorption from the daylong dwell. Bolus insulin or an oral agent would also be needed for control of postprandial glucose levels.

Intraperitoneal insulin is an alternative option for patients on peritoneal dialysis therapy84 because insulin is absorbed rapidly and possibly more evenly through the peritoneum than with subcutaneous administration. Disadvantages to using intraperitoneal insulin include an increased time requirement to instill the insulin before the dialysis solution, a possible increase in insulin requirements because of dilution and the possible binding of insulin to the dialysis catheter, and the possibility of peritonitis from the insulin.85 In patients with type 2 diabetes using insulin, rosiglitazone was shown to decrease insulin requirements in patients on continuous ambulatory peritoneal dialysis therapy by about 21%; therefore, adding a thiazolidinedione may be an additional option.86