IMPROVING OUTCOMES FOR DIABETIC PATIENTS ON DIALYSIS

Selection and Dosing of Medications for Management of Diabetes in Patients with Advanced Kidney Disease
James B. Reilly and Jeffrey S. Berns
Renal-Electrolyte and Hypertension Division, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

ABSTRACT Diabetes mellitus is a leading cause of kidney disease worldwide. A large and expanding array of treatments for diabetes is available to improve glycemic control, including newer classes of drugs, such as thiazolidinediones and incretin-based therapies. The presence of impaired kidney function with reduced glomerular ltration rate should inuence choices, dosing, and monitoring of hypoglycemic agents, as some agents require a dosing adjustment in patients with kidney disease and some are entirely contraindicated. This article reviews the clinical use of insulin and other antidiabetic therapies, focusing on pharmacokinetic properties and dosing in patients with advanced kidney disease.

Diabetes mellitus remains a leading cause of kidney disease and end-stage renal disease (ESRD) in the United States and around the world. Avoidance of hyperglycemia has been shown in many studies to slow progression of diabetic chronic kidney disease (CKD) and also to reduce microvascular and macrovascular morbidity and mortality (13). The importance of tight glucose control and identifying optimal targets in patients who already have advanced kidney disease is somewhat controversial, but observational data show that poor glycemic control is associated with unfavorable outcomes in patients with kidney disease (4,5). Treatment of hyperglycemia remains greatly important to the health of patients with kidney disease, and the arsenal of therapy available to physicians is expanding constantly. However, effective, safe glycemic control requires adjustment of medication regimens appropriate to the patients level of kidney function, as the pharmacokinetic and safety proles of many of these therapies change as kidney function declines over time. This review will describe the clinical use and pharmacokinetic proles of major diabetic therapies and identify preferred choices, dosing, and monitoring of agents for patients both with severe CKD and dialysis patients. Special attention will be paid to the newer agents, including thiazoladinediones (TZDs), meglinitide analogs, glucagon-like peptide-1 (GLP-1) analogs, and dipeptidyl peptidase-4 (DPP-4) inhibitors.
Address correspondence to: Jeffrey S. Berns, MD, Hospital of the University of Pennsylvania, 1 Founders Pavilion, 3400 Spruce Street, Philadelphia, PA 19104, Tel.: +1-215-662-7934, Fax: +1-215-615-1688, or e-mail: bernsj@uphs.upenn.edu. Seminars in DialysisVol 23, No 2 (MarchApril) 2010 pp. 163168 DOI: 10.1111/j.1525-139X.2010.00703.x 2010 Wiley Periodicals, Inc. 163

Insulins In contrast to endogenously secreted insulin, which is degraded by the liver, exogenous insulin is primarily eliminated by the kidneys. Insulin is freely ltered at the glomerulus, and then extensively reabsorbed in the proximal tubule. Filtered insulin is taken up across the apical membrane of the proximal tubular epithelial cells, and then enzymatically degraded into peptide fragments of various sizes, which are subsequently reabsorbed. There is also uptake and degradation of insulin by peritubular endothelial cells, with total renal clearance exceeding GFR (6). As renal failure progresses, peritubular insulin uptake increases, compensating for the decline in degradation of ltered insulin until the GFR decreases to less than approximately 20 ml min. With lower levels of GFR insulin clearance decreases further and overall requirements for exogenous insulin often decline (710). If this is not anticipated, then the risk of symptomatic hypoglycemia can increase. The pharmacokinetics of various insulin preparations has not been well studied in patients with varying degrees of renal dysfunction, and there are no absolute guidelines dening appropriate dosing adjustments of insulin that should be made based on the level of GFR. It is generally recommended that when the GFR decreases to between 10 and 50 ml min, the insulin dosage should be reduced by 25%, and when the GFR decreases to <10 ml min, the insulin dosage should be reduced by 50% from previous amounts (11,12). Once patients start dialysis, they often require less exogenous insulin as peripheral insulin resistance improves with initiation of dialysis (10,11). This may be counterbalanced by increased food intake as the anorexia of advanced CKD resolves with dialysis, so careful monitoring of blood glucose levels is important.

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Reilly and Berns It is recommended that metformin be stopped 23 days before any anticipated surgery or administration of iodinated radiographic contrast media because of the risk of acute kidney injury, with resumption of the drug only after kidney function has clearly remained or returned to a normal baseline (20). Because of the risk of lactic acidosis, metformin should not be used in patients with serum creatinine levels 1.4 mg dl in women and 1.5 mg dl in men. Hemodialysis is effective in clearing metformin from the circulation (16) and has been used successfully for the management of metformin-associated lactic acidosis (21,22). There are also limited reports of use of continuous venovenous hemoltration for management of metformin-associated lactic acidosis (23,24). Alpha-Glucosidase Inhibitors Biguanides The alpha-glucosidase inhibitors acarbose and miglitol decrease postprandial hyperglycemia by blocking the intestinal breakdown of oligosaccharides into simpler sugars. Acarbose is only minimally absorbed from the gastrointestinal tract, where it is largely broken down by intestinal ora and intestinal enzymes into at least 13 metabolites, at least one of which has some biologic activity. Some of the metabolites are partially absorbed, although <2% of a dose of acarbose and the active metabolites appears in the urine. The elimination half-life is approximately 2 hours. In patients with reduced renal function, the plasma levels of the drug and its metabolites can increase several-fold, but the clinical signicance of this is not known. Information about the long-term use of acarbose in patients with reduced kidney function is sparse and its use in patients with later stage 3 and stages 4 and 5 CKD is not recommended (11). Miglitol has greater systemic absorption than acarbose, has minimal protein binding and is not metabolized. However, it does undergo renal excretion and accumulates in patients with impaired kidney function (11). Both acarbose and miglitol may reduce the absorption of other oral hypoglycemic agents (25). Miglitol is not recommended for patients with impaired kidney function (26). Sulfonylureas Sulfonylurea medications have long been a staple in the treatment of type 2 diabetes mellitus. They act primarily by stimulating insulin secretion of the pancreatic beta cells through interaction with a receptor that is a subunit of an adenosine triphosphate (ATP)-sensitive potassium channel, although it has been postulated that they may have additional extrapancreatic effects as well. These medications are well absorbed after oral administration and are highly protein bound in plasma. This protein binding can be reduced by other medications with higher protein-binding afnities, thus increasing free sulfonylurea plasma levels (26). The rst-generation sulfonylureas included acetohexamide, chlorpropamide, tolazamide, and tolbutamide. These drugs are now rarely used in the United

Since a reduced GFR increases the half-life and maximal serum concentration of regular human insulin, but not of rapid-acting analogs, rapid-acting insulin analogs are preferred over regular human insulin in advanced CKD, as the risk of hypoglycemia may be less. Caution is recommended when using long-acting insulin regimens but use of long-acting basal insulin like glargine is generally acceptable in patients with kidney disease and is preferred to use of NPH insulin (13). Insulin detemir binds to serum albumin after injection so its use may be less predictable in patients with nephrotic syndrome and hypoalbuminemia. Clearly it is important to monitor the patients blood glucose levels closely at multiple times of the day, particularly as the level of kidney function declines over time, and alter insulin regimens as required to avoid hypoglycemia.

Metformin and phenformin comprise the class of oral hypoglycemic known as the biguanides. Metformin has been widely prescribed for the treatment of type 2 diabetes mellitus for many years. Because of its association with a severe, and sometimes fatal, lactic acidosis, phenformin was removed from the market many years ago and its use will not be discussed further in this review. While metformin has been demonstrated to act as an agonist for the insulin receptor tyrosine kinase in some animal models, in humans it primarily inhibits hepatic gluconeogenesis by interfering with mitochondrial oxidation (14). Metformin also stimulates insulin-mediated glucose utilization by peripheral tissues. Used as monotherapy, or in combination with other diabetic medications, it has also been shown to have other physiologic cardiovascular effects beyond those related to control of blood glucose levels. Metformin is not protein bound and is eliminated unchanged by the kidneys through both glomerular ltration and tubular secretion, with an elimination half-life that has been reported to range from 1.5 to 8.7 hours (11,15). Approximately 90% of a dose is excreted within 1224 hours (16,17). Elimination of metformin is reduced in patients with reduced GFR. Cimetidine inhibits tubular secretion and overall clearance of metformin (16,18), and coadministration with metformin is not recommended. The most common side effects of metformin are gastrointestinal disturbances, including nausea, metallic taste, and diarrhea. A rare, but serious side effect of metformin is lactic acidosis (19). The estimated incidence of metformin-induced lactic acidosis, which has a mortality of approximately 3050%, is approximately 0.03 cases per 1000 patient-years, much less than that seen with phenformin (14). As GFR declines, accumulation of metformin is thought to increase the risk for development of lactic acidosis. Additional risk factors for metformin-induced lactic acidosis include congestive heart failure, advanced age, alcohol use, administration of iodinated radiographic contrast media (potentially causing acute kidney injury), and other conditions associated with hypoxemia or hypotension (15).

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States, and so we will not discuss them further. Second-generation sulfonylureas currently available in the United States include glipizide, glyburide, and glimepiride. The elimination half-life with chronic use of these newer agents ranges from 7 to 14 hours, with effective durations of action of up to 24 hours. Glipizide is hepatically metabolized into several inactive metabolites (11,17,27). Less than 10% of a dose of glipizide is excreted unchanged in the urine, with approximately 60% excreted as metabolites. Glipizide clearance and elimination half-life, which is 24 hours in normal individuals, are unaffected by reduced GFR and therefore dose adjustment in patients with CKD is not necessary (28). Several of the metabolites of glipizide accumulate in patients with reduced GFR, including one that may have a small amount of activity, although this does not appear to cause an increased risk of hypoglycemia (28). Because of its favorable pharmacokinetics in patients with reduced GFR, glipizide should be the sulfonylurea of choice in patients with advanced kidney dysfunction. Caution should be used with the extended release form of the drug, as few data are available regarding its safety in patients with CKD. Glyburide undergoes extensive hepatic metabolism to several metabolites that undergo equal biliary and renal excretion (11,17,29). Approximately 50% of a dose appears in the feces, with most of the remainder excreted as metabolites in the urine. Less than 5% of the parent compound is recovered in the urine. The clearance of glyburide does not correlate with the level of kidney function, and the parent drug does not appear to accumulate in patients with reduced GFR (30), although the elimination half-life and insulin area under the curve (AUC) may be slightly greater in hemodialysis patients than normal controls (31). Some of glyburides metabolites have hypoglycemic activity (30,32), which can increase the likelihood of hypoglycemia in patients with renal failure (3335). Therefore, glyburide should be used with great caution in these patients, especially considering that glipizide has a more favorable pharmacokinetic prole in patients with CKD. Glimepiride is also hepatically metabolized, with two major metabolites, one of which has been shown to have some pharmacologic activity. The elimination half-life is approximately 58 hours. Approximately 60% of a dose appears in the urine, with the remainder appearing in feces. Virtually all of the urinary excretion is as metabolites, with little or no parent drug excreted in the urine (36). Glimepiride does not accumulate in patients with reduced GFR, but urinary excretion of its metabolites is reduced. Prolonged hypoglycemia has been reported with the use of glimepiride in patients with reduced GFR (11,35,37), so the drug should be used very cautiously if at all in such patients. Thiazolidinediones The TZDs rosiglitazone and pioglitazone, as well as troglitazone, an earlier drug removed from the market for hepatotoxicity, act on the peroxisome proliferator-activated receptor-c (PPAR-c) and decrease

insulin resistance. They also increase the peripheral utilization of insulin and decrease hepatic gluconeogenesis (26). Because PPAR-c is expressed in multiple areas of the kidney, there have been many postulated potential benets of these agents in the CKD and ESRD populations, related mainly to their hemodynamic, antiproliferative, and anti-inammatory effects in diseases such as diabetic nephropathy (38). Despite much early promise, the long-term benets of these drugs are still controversial, although their use remains widespread, including in CKD and ESRD patients. Both rosiglitazone and pioglitazone are virtually completely hepatically metabolized, each forming several metabolites. Both drugs are also highly protein bound, primarily to albumin. Rosiglitazone has an elimination half-life of 34 hours. There are two major metabolites, neither of which is biologically active, and <1% of the parent drug appears in the urine unchanged (11). Pioglitazone has an elimination half-life of approximately 37 hours and six metabolites, of which three are active (11). Neither parent compound nor their active metabolites accumulate in patients with reduced GFR (3941). In fact, with both drugs, the AUC is less in patients with severe renal failure, perhaps because of reduced protein binding. Hemodialysis does not affect the pharmacokinetics of these drugs. In continuous ambulatory peritoneal dialysis (CAPD) patients, the half life of rosiglitazone is increased, but the AUC and average maximum plasma concentration (Cmax) is unchanged compared with normal controls (42). It is therefore not necessary to reduce the dosages of pioglitazone and rosiglitazone in patients with reduced GFR (11,26). Although there are no clinically signicant dosing issues for thiazolidinediones in patients with moderate or severe kidney dysfunction, their safety and tolerability proles raise some issues for CKD and dialysis patients. In particular, the side effect most worrisome to nephrologists is uid retention, which most often manifests as edema and congestive heart failure (43). In a subset of patients, expansion of plasma volume occurs through mechanisms that are likely multifactorial. Increased sodium reabsorption in the collecting duct is considered to be the primary renal site of increased sodium reabsorption with TZDs, with experimental evidence both for and against a role of TZDs on function of the distal nephron renal epithelial sodium channel (ENaC) as well as transport proteins in the proximal tubule (4448). TZDs additionally increase sympathetic nervous activity and alter endothelial permeability (49,50) which may also contribute signicantly to uid retention. To what extent this particular side effect of the TZDs is clinically important in patients with advanced CKD, and especially in dialysis patients is unclear, although several studies have suggested that some hemodialysis and peritoneal dialysis patients may experience weight gain with TZD therapy (5153). Effects of TZDs on cardiovascular morbidity and mortality have been somewhat controversial, with oftenconicting study results. A 2007 meta-analysis found that use of rosiglitazone was associated with a signicant increase in risk of myocardial infarction and a trend toward greater risk of cardiovascular death (54). This

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Reilly and Berns inhibitors are the most recently approved diabetic treatments. Incretin hormones, such as GLP-1, are released after meals and serve to stimulate pancreatic insulin secretion, temper glucagon release, and slow gastric emptying (6769). Exenatide, the rst GLP-1 analog used in clinical practice, is an injectable therapy derived from the saliva of the Gila monster that has been shown to be effective in conjunction with more conventional oral therapies to improve glycemic control, particularly postprandial hyperglycemia (70,71). Exenatide reaches peak concentrations within 2 hours of administration, and is predominantly eliminated by the kidneys, with a half life of 2.5 hours in patients with normal renal function (72,73). The elimination half-life increases to 3.2 hours in patients with moderately reduced GFR (3150 ml min) and up to 6 hours in patients with GFR < 30 ml min or ESRD, associated with an increase in AUC with potentially toxic blood levels detected (72). For this reason, it is recommended that treatment be started with a 50% dose reduction (5 mcg twice daily) in patients with creatinine clearance 3050 ml min, titrating to full dose of 10 mcg twice daily only if tolerated and necessary for glycemic control. Exenatide is not recommended if creatinine clearance is <30 ml min. Liraglutide, a new injectable GLP-1 analog approved in Europe but currently pending FDA approval in the United States, may be safer in severe CKD and ESRD, as reduced GFR does not alter its metabolism or excretion (70,74,75). DPP-4 Inhibitors Two DPP-4 inhibitors, sitagliptin and saxagliptin, are currently FDA approved for treatment of patients with Type 2 diabetes mellitus. DPP-4 is an enzyme responsible for degradation of GLP-1, and antagonism of this enzyme has been postulated to potentiate incretin effects and reduce hyperglycemia, especially after meals. Sitagliptin is an oral, once-daily DPP-4 inhibitor that is primarily cleared by the kidneys. In normal, healthy subjects, 7580% of the drug is excreted unchanged in the urine (76). In patients with moderate kidney disease (creatinine clearances 30 50 ml min), the AUC increases more than twofold, and in patients with more severe kidney disease, including ESRD, the AUC increases by approximately fourfold. The drug is not effectively dialyzed (77). Based on these ndings, a 50% dose reduction (50 mg daily rather than the usual dose of 100 mg) is recommended in patients with moderate kidney disease, and a 75% dose reduction is recommended in patients with more advanced kidney disease and those on dialysis (77,78). Saxagliptin is another orally administered, once-daily DPP-4 recently approved by the FDA (79). Although the drug is primarily dependent upon the cytochrome P450 3A4 5 (CYP3A4 5) system for its metabolism, studies in animals indicate that renal metabolism and excretion contribute signicantly to elimination of saxagliptin (80). The major metabolite of saxagliptin is

association has not been consistently supported in later studies, however, and there are few data specically addressing use in patients with kidney disease. Recent studies in CKD and ESRD patients have likewise been contradictory. A cohort study of over 2300 hemodialysis patients found that use of rosiglitazone was associated with signicantly higher risk for cardiovascular and allcause mortality compared to other agents (55). However, another cohort study of over 5000 incident dialysis patients with diabetes found that TZD use was associated with better overall survival in non-insulin-dependent diabetic dialysis patients (56). Further study of TZD use in patients with CKD and ESRD, ideally in a randomized trial, is warranted. In the meantime, TZDs can be used safely without need for dose adjustment in patients with kidney disease, with close monitoring for clinical evidence of volume overload and CHF. These agents should be used with great caution in patients with increased risk for CHF, and are contraindicated in patients with NYHA Class III or IV heart failure, in accordance with consensus guidelines from the American Heart Association and the American Diabetes Association and a black box warning in the package labeling (57). Meglinitides Repaglinide and nateglinide are insulin secretagogues indicated for the treatment of type 2 diabetes mellitus. They act by stimulating insulin secretion of the pancreatic beta cell through effects on beta-cell K+-ATP channels, but through a different mechanism than the sulfonylureas (58). These drugs have shorter onset and duration of action compared with the sulfonylureas. Repaglinide is rapidly absorbed following oral administration, and therefore should be taken just before meals. It is primarily hepatically metabolized, with an elimination half-life of 0.61.8 hours (58,59). Less than 10% of a dose appears in the urine, but drug concentration, AUC, and elimination half-life are increased somewhat in patients with reduced GFR (11,60,61), although dosage reductions are not necessary for such patients (62). Nateglinide is also rapidly absorbed and eliminated primarily by hepatic metabolism, with an elimination half-life of approximately 1.21.8 hours. Several of its metabolites are active. Eighty-three percent of the drug appears in the urine, primarily as metabolites, with only approximately 16% as parent drug (58,63). Although reduced GFR does not signicantly increase elimination half-life or plasma concentration of nateglinide (64), plasma protein binding is reduced and accumulation of an active metabolite can occur; this has been associated with development of hypoglycemia (65,66). Therefore, nateglinide should be used very cautiously if at all in patients with advanced kidney disease. GLP-1 Analogues Incretin-based therapies with glucagon-like peptide1(GLP-1) analogues and dipeptidyl peptidase-4 (DPP-4)

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also a biologically active DPP-4 inhibitor. In humans, approximately 25% of a single dose is excreted unchanged in the urine and more than one-third is excreted as the active metabolite. Renal clearance of saxagliptin exceeds GFR in normal subjects, suggesting a component of renal tubular secretion. In a small single-dose study, reduced GFR was associated with an increase in AUC for both saxagliptin and its active metabolite (81). The manufacturer recommends a dose of 2.5 mg once daily for patients with creatinine clearance 50 ml min, including those on dialysis. Saxagliptin and its active metabolite are partially removed by hemodialysis (81). Another DPP-4 inhibitor, vildaglipitin, has been recently reported to be associated with an increased risk of angioedema in patients also receiving ACE inhibitors, suggesting the need for some caution in such patients (82,83). Conclusion In the past several years, a great number of novel diabetic therapies in different categories have been introduced, with the promise of more to come. Given the concurrence of kidney disease in many diabetics, available therapies may be dictated by the patients baseline kidney function and how it evolves over time. Some agents that are used as rst line treatment in patients with normal kidney function, such as metformin, are completely contraindicated in renal failure, while others can be used safely, some with dose adjustments and some at full strength. Most of the commonly used classes of diabetic therapies contain at least one medication that is safe in kidney disease, and these medications should be utilized preferentially in patients who have kidney disease or those who are likely to develop kidney disease in the future. New medications should be evaluated with an eye to potential efcacy and safety in patients with reduced GFR as they are introduced into clinical practice. References
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