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Current Drug Metabolism, 2011, 12, 57-69 57
Antidiabetic Agents in Patients with Chronic Kidney Disease and End-Stage Renal
Disease on Dialysis: Metabolism and Clinical Practice
Masanori Abe1,*, Kazuyoshi Okada1 and Masayoshi Soma1,2
1
Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine,
Tokyo, Japan; 2Division of General Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
Abstract: Numerous drugs with different mechanisms of action and different pharmacologic profiles are being used with the aim of im-
proving glycemic control in patients with type 2 diabetes. Therapeutic options for patients with type 2 diabetes and chronic kidney dis-
ease (CKD) are limited because a reduced glomerular filtration rate results in the accumulation of certain drugs and/or their metabolites.
Conventional oral hypoglycemic agents, such as sulfonylurea (SU), are not suitable due to the risk of prolonged hypoglycemia; further-
more, metformin is contraindicated for moderate to advanced CKD. Therefore, in order to achieve good glycemic control, insulin injec-
tion therapy remains the mainstay of treatment in diabetic patients with moderate to advanced CKD, particularly in those receiving dialy-
sis therapy. However, some agents have been used even in patients with CKD. Repaglinide and mitiglinide are rapid- and short-acting in-
sulinotropic SU receptor ligands. They are rarely accompanied by hypoglycemia, and are attractive therapeutic options even in the dialy-
sis population. In addition, alpha-glucosidase inhibitors are rarely accompanied by hypoglycemia and are administered without dose ad-
justments in dialysis patients. However, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines recom-
mended that alpha-glucosidase inhibitors should be avoided in patients with advanced stage CKD and on dialysis. Furthermore,
mitiglinide is not currently used in the US. Thus, recommended oral antidiabetic agents differ between countries. Moreover, dipeptidyl
peptidase-4 inhibitors and incretin mimetics are new antihyperglycemic agents, which may be used more frequently in the future in pa-
tients with type 2 diabetes and CKD. Here, we describe the pharmacokinetics, metabolism, clinical efficacy, and safety of oral antidia-
betic agents for patients with CKD, including those receiving dialysis.
Keywords: Antidiabetic agent, chronic kidney disease, clinical practice, DPP-4 inhibitor, end-stage renal disease, metabolism, type 2 diabe-
tes mellitus.
INTRODUCTION agents, such as sulfonylurea (SU), are not suitable due to the risk of
The number of patients with primary diabetic nephropathy un- prolonged hypoglycemia; furthermore, metformin is contraindi-
dergoing dialysis continues to increase. The prognosis is worse for cated. Therefore, in order to achieve good glycemic control, insulin
diabetic patients undergoing dialysis than for patients with primary injection therapy remains the mainstay of treatment in diabetic pa-
glomerular nephropathy, and diabetic patients with chronic kidney tients with moderate to advanced CKD, particularly in those receiv-
disease (CKD) who are undergoing dialysis also have an increased ing dialysis therapy. However, some agents have been used in pa-
risk of cardiovascular morbidity and a complicated disease course. tients with CKD and were found to be effective and safe even in
Recent clinical evidence has suggested that strict glycemic control those on dialysis. Therefore, some agents may be useful therapeutic
reduces the risk of cardiovascular disease, which is the main cause options for the management of diabetes.
of death in diabetic patients [1, 2]. Thus, good glycemic control can Here we review the effect and metabolism of antidiabetic
decrease cardiovascular and other diabetes-related causes of death, agents in kidney disease, with a focus primarily on reports pub-
leading to better survival rates in diabetic patients [3-5]. Diabetic lished since 1990. An electronic search of the MEDLINE biblio-
patients on long-term dialysis therapy, however, no longer need to graphic database was performed through PubMed
achieve good glycemic control to prevent deterioration of kidney (www.ncbi.nlm.nih.gov/sites/entrez) by using relevant key search
function. Nevertheless, good control may still prevent or slow the terms including pharmacokinetics, diabetes mellitus, renal failure,
progression of retinopathy, neuropathy, and possibly macrovascular renal impairment, kidney disease, drug metabolism, and antidia-
disease [6]. Survival improves with better glycemic control in pa- betic drug. Reference lists of original studies, narrative reviews, and
tients on peritoneal dialysis [7] and hemodialysis therapy [8]. After previous systematic reviews were also examined. Finally, select
adjustment for age and sex, hemoglobin A1c was found to be a information from drug manufacturers was also reviewed. Here, we
significant predictor of survival (hazard ratio, 1.133 per 1.0% in- describe the pharmacokinetics, metabolism, clinical efficacy, and
crease in HbA1c; 95% confidence interval, 1.028-1.249; P = 0.012) safety of oral antidiabetic agents for diabetic patients with CKD,
[8]. including those on dialysis.
Numerous drugs with different mechanisms of action and dif-
Classification of Antidiabetic Agents and their Pharmacother-
ferent pharmacologic profiles are being used with the aim of im-
apy
proving glycemic control in patients with type 2 diabetes. Thera-
peutic options for patients with diabetes with CKD and end-stage As shown in Table 1, several pharmacologic agents other than
renal disease (ESRD) are limited because a reduced glomerular insulin preparations are available for the management of type 2
filtration rate (GFR) results in the accumulation of certain drugs diabetes. These agents all lower blood glucose levels, but there is an
and/or their metabolites [9]. Conventional oral hypoglycemic increasing awareness that they may modify the natural history of
diabetes in different ways. Insulin secretagogues can be classified
as sulphonylureas (SUs) and meglitinides. Alpha-glucosidase in-
*Address correspondence to this author at the Division of Nephrology, hibitors are modifiers of glucose absorption, and thiazolidinediones
Hypertension and Endocrinology, Department of Internal Medicine, Nihon are insulin sensitizers. Incretin-related therapies include dipeptidyl
University School of Medicine, 30-1, Oyaguchi Kami-chou, Itabashi-ku, peptidase-4 (DPP-4) inhibitors and incretin mimetics. DPP-4 inhibi-
Tokyo 173-8610, Japan; Tel: +81-3-3972-8111; Fax: +81-3-3972-1098; tors are oral antidiabetic agents, whereas incretin mimetics are used
E-mail: abe.masanori@nihon-u.ac.jp
by subcutaneous injection.
1389-2002/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd.

58 Current Drug Metabolism, 2011, Vol. 12, No. 1 Abe et al.
Table 1. Dosing Adjustment by CKD Stage for Drugs Used to Treat Hyperglycemia
Dosing Recommendation
Dosing Recommendation
Class Drug CKD Stage 3,4, or
Dialysis
Kidney Transplant
Acetohexamide Avoid Avoid

Reduce dose by 50% when
First-generation Chlorpropamide GFR < 70 and 50 mL/min/1.73m2 Avoid
sulfonylureas Avoid when GFR < 50 mL/min/1.73m2
Tolazamide Avoid Avoid

Tolbutamide Avoid Avoid
Preferred sulfonylurea Preferred sulfonylurea

Glipizide No dose adjustment necessary No dose adjustment necessary
Not available in Japan Not available in Japan
Preferred sulfonylurea Preferred sulfonylurea

Second-generation No dose adjustment necessary No dose adjustment necessary
sulfonylureas Gliclazide
Not available in US Not available in US
Caution should be applied in Japan Avoid in Japan
Glyburide Avoid Avoid
Glimepiride Initiate at low dose, 1mg daily Avoid

No dose adjustment necessary No dose adjustment necessary
Repaglinide Initiate at 0.5 mg dose when Initiate at low dose
GFR < 40 mL/min/1.73m2 Not available in Japan
Meglitinides
Nateglinide Initiate at low dose, 60 mg before each meal Avoid
No dose adjustment necessary Initiate at low dose 5 mg before each meal

Mitiglinide
Not available in US Not available in US
Not recommended in patients with
Not recommended in US
Acarbose sCr > 2 mg/dL in US
Caution should be applied in Japan
No dose adjustment necessary in Japan
Not recommended in patients with sCr >

Not recommended in US
Alpha-glucosidase Miglitol 2 mg/dL in US
Caution should be applied in Japan
inhibitors Caution should be applied in Japan
Not available in US Not recommended in US

Voglibose
No dose adjustment necessary in Japan No dose adjustment necessary in Japan
Contraindicated with kidney dysfunction defined as sCr

Biguanides Metformin Avoid
1.5 mg/dL in men or 1.4 mg/dL in women
Rosiglitazone No dose adjustment necessary No dose adjustment necessary

Thiazolidinediones
Pioglitazone No dose adjustment necessary No dose adjustment necessary
Reduce dose by 50% (50 mg/day) when GFR < 50 and 30
Sitagliptin mL/min/1.73m2 and by 75 % (25 mg/day) when GFR Reduced dose by 75% (25 mg/day)
< 30 mL/min/1.73m2
Initiate at low dose Initiate at low dose

Vildagliptin
DPP-4 inhibitors Not available in US Not available in US
Reduce dose by 50% (12.5 mg/day) when GFR < 50 and
30 mL/min/1.73m2 and by 75% Reduced dose by 75% (6.25 mg/day)
Alogliptin
(6.25 mg/day) when GFR < 30 mL/min/1.73m2 Not available in US
Not available in US
Not recommended in patients with

GFR < 30 mL/min/1.73m2
Caution should be applied when
Exenatide Avoid
Incretin mimetics GFR > 30 and < 50 mL/min/1.73m2
No dose adjustment necessary when
GFR > 50 and < 80 mL/min/1.73m2
Liraglutide No dose adjustment necessary No dose adjustment necessary

No dose adjustment necessary for GFR20-50
Amylin analog Pramlintide mL/min/1.73m2 No data available
Not available in Japan
Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate; sCr. Serum creatinine. Adopted from [6], [20], [21], [27], [28], [36], [80], [109], [118], and [128].
Antidiabetic Agents in CKD and ESRD Current Drug Metabolism, 2011, Vol. 12, No. 1 59
Characteristics of the Pharmacokinetics in Chronic Kidney Dis- nant route of elimination, the pharmacokinetics and/or pharma-
ease codynamics may be altered in patients with renal impairment.
Many drugs bind to serum proteins, primarily albumin. How- Therefore, caution will be needed to avoid hypoglycemia when
ever, as the plasma concentration of albumin in patients with renal using SU agents in patients with advanced stage CKD and those on
impairment is commonly decreased, the concentrations of unbound dialysis. The main clinically relevant pharmacokinetics of glipizide,
drugs are increased. For drugs with a low hepatic extraction rate gliclazide, and glimepiride are summarized in Table 2.
and high protein binding rate, the overall rate of drug elimination is
Meglitinides
related to unbound plasma concentration and intrinsic clearance of
the liver. Assuming that the intrinsic capacity of the liver remains Three insulin secretagogues, nateglinide, repaglinide, and
unchanged, total clearance will increase and half-life will tend to mitiglinide, are currently in clinical use because of their rapid onset
decrease for drugs such as phenytoin and warfarin. Furthermore, of action resulting in improvement in hyperglycemia. The main
kidney disease differentially affects uptake and efflux transporters differences between these three meglitinides, which are of potential
and metabolic enzymes in the liver and gastrointestinal tract, interest for use in the management of patients with type 2 diabetes,
changes likely to be caused by uremic toxins. A change in systemic are summarized in Table 3. After oral administration, repaglinide is
bioavailability might be caused by reduced gastrointestinal absorp- almost completely metabolized in the liver by CYP enzymes, prin-
tion, which has been observed in patients with severe renal impair- cipally CYP2C8 (70%) and CYP3A4 (30%) [22, 23]. Repaglinide
ment for cyclosporine, ibuprofen, and levocabastine [10-12]. In undergoes oxidative biotransformation by CYP3A4 to metabolites
addition, it was reported that reductions in the expression and func- M2 (dicarboxylic acid) and M1 (aromatic amine) or direct conjuga-
tion of intestinal P-glycoprotein (P-gp) and multidrug resistance- tion with glucuronic acid to form M7 (acyl glucuronide), all of
associated protein-2 increased expression of hepatic P-gp and which are inactive metabolites. Repaglinide undergoes hepatic
multidrug resistance-associated protein-2 and decreased expression OATP1B1-mediated uptake, followed by CYP2C8- and CYP3A4-
of hepatic organic anion-transporting polypeptide (OATP) in ure- mediated metabolism, and then biliary excretion which is likely
mia [13, 14]. Numerous reports of known OATP, P-gp, and/or cy- mediated, at least partially, by P-gp, with <8% of the parent drug
tochrome P450 (CYP) substrates exhibiting altered pharmacokinet- being excreted unchanged in the urine [24]. The drug exhibits a
ics in patients with kidney disease suggest that uremia affects these nearly 4-fold increase in half-life after 1 week of treatment, and
elimination pathways and illustrates the clinical importance of al- significantly increases the area under the curves (AUCs) after both
tered nonrenal clearance [15, 16]. Therefore, caution is required single and multiple dosing in patients with advanced CKD (creatin-
since uremia differentially affects these pathways in the liver and ine clearance (CrCl) <30 mL/min) when compared to subjects with
gastrointestinal tract and leads to a decreased protein binding rate. normal renal function (CrCl >80 mL/min) [24]. No difference in
maximal plasma concentrations was observed, thereby suggesting
Sulphonylureas that bioavailability of the orally administered drug is not affected
Insulin secretagogues increase endogenous insulin levels. These by kidney disease and that metabolism and transport in the gastroin-
agents work by binding to SU receptors or nearby sites, resulting in testinal tract are therefore unchanged [25]. These data suggest that
closure of ATP-sensitive potassium channels of the pancreatic beta hepatic clearance of repaglinide, mediated by OATP1B1, CYP2C8,
cell, depolarization of the cell membrane, calcium influx, and sub- CYP3A4, and/or possibly P-gp, is decreased in subjects with ad-
sequently insulin release. The University Diabetes Group Project vanced CKD [25]. Thus, uremia leads to decreased activity of he-
raised concerns that first-generation secretagogues may be associ- patic and intestinal CYPs, including CYP3A, secondary to reduced
ated with increased cardiovascular risk and mortality [17]. The protein and gene expression.
United Kingdom Prospective Diabetes Study (UKPDS) [18] and In vitro data have demonstrated that nateglinide is predomi-
more recently the ADVANCE study [19] demonstrated that newer nantly metabolized by CYP isoenzymes CYP2C9 (70%) and
agents (glipizide [18] and gliclazide [19]) do not appear to confer CYP3A4 (30%) [24]. However, the metabolites of nateglinide have
such a risk and are associated with benefits when used to achieve insulin secretion properties. Therefore, the half-life of this drug is
tighter glycemic control. As these agents increase endogenous insu- prolonged in patients with renal impairment and this can result in
lin levels, they are associated with an increased risk of hypoglyce- hypoglycemic episodes. On the other hand, the metabolism of
mia. This risk is mitigated when shorter-acting agents are used. mitiglinide differs from that of repaglinide and nateglinide [26].
However, many of the first-generation SU agents (i.e., acetohex- Although mitiglinide is metabolized in the kidney and liver, and
amide, chlorpropamide, tolazamide, and tolbutamide) are contrain- predominantly metabolized to the glucuronic acid conjugate (74%)
dicated in the dialysis population. The second-generation SU and hydroxide (<25%), these metabolites have little insulin secre-
glimepiride is contraindicated in dialysis patients, but low-dose tory activity [27]. Mitiglinide selectively inhibits the ATP-
initiation can be used in patients with CKD [20]. Glipizide and dependent K+ channel (Kir6.2/SUR1) of pancreatic beta cells with a
gliclazide are the preferred agents and no dose adjustment has been higher affinity for Kir6.2/SUR1 than for the other two insuli-
necessary in a dialysis population in US [6]. Glipizide is eliminated notropic SU receptor ligands (mitiglinide > repaglinide > nateg-
primarily by hepatic biotransformation; <10% of a dose is excreted linide) [28]. These results suggest that mitiglinide acts specifically
as unchanged drug in urine and feces, while approximately 90% is on pancreatic beta cells to induce secretion of insulin and has few
excreted as biotransformation products in urine (80%) and feces unwanted effects on the cardiovascular system. As mitiglinide is
(10%) [21]. The major metabolites of glipizide are products of aro- rarely accompanied by hypoglycemia, it is an attractive therapeutic
matic hydroxylation that have no hypoglycemic activity. A minor option even in the dialysis population in Japan, although it is not
metabolite which accounts for <2% of a dose, an acetylamino-ethyl available in US. Therefore, it is considered that the likelihood of
benzene derivative, is reported to have one-tenth to one-third of the hypoglycemia is low with mitiglinide, even in patients with renal
hypoglycemic activity compared to the parent compound. Glipizide impairment, compared with nateglinide. The time to maximum
is 98-99% bound to serum proteins, primarily to albumin. The mean concentration (Tmax) and the half-life of mitiglinide in patients re-
terminal elimination half-life of glipizide ranges from 2 to 5 h after ceiving dialysis are approximately 0.41 and 11.7 h, respectively.
single or multiple doses in patients with type 2 diabetes [21]. There Because the half-life of mitiglinide is 1.48 and 3.22 h in patients
is only limited information regarding the effects of renal impair- with normal renal function and stage 3 CKD, respectively, care
ment on the disposition of glipizide. However, as glipizide is highly must be taken to avoid excessive blood glucose reduction when
protein bound and hepatic biotransformation is the predomi- mitiglinide is given to patients with renal impairment.
Table 2. Main Clinically Relevant Pharmacokinetic Differences of Glipizide, Gliclazide, and Glimepiride
Characteristics Glipizide Gliclazide Glimepiride
Tmax (h) 6-12 4-6 2.5

Half-life (h) 2-5 10.4 5-8
Cyclohexyl hydroxy methyl derivative
Primary metabolites Aromatic hydroxylation (inactive) Inactive metabolites
(active 40% of glimepiride)
Absolute bioavailability (%) 100 100 107
Fraction bound to protein 98-99 85-97 99
Molecular weight 445.55 323.41 490.63
Excreted in feces (%) 10 10-20 35
Excreted in urine (%) 80 60-70 58
Proportion excreted unchanged (%) 10 1 0.5
Glipizide may interact with CYP2C9 Gliclazide may interact with CYP2C9 Glimepiride may interact with CYP2C9
Drug-drug interaction
inducers or inhibitors inducers or inhibitors inducers or inhibitors
Adopted from [6], [20], and [21].
Table 3. Main Clinically Relevant Pharmacokinetic Differences between the Three Meglitinides
Characteristics Repaglinide Nateglinide Mitiglinide
Therapeutic dose (mg/day) 1.5-16 90-360 7.5-30

Half-life (h) 0.5-1 1.1-1.5 1.2
Administration With each meal preprandially With each meal preprandially With each meal preprandially
Active metabolite No Yes No

Fraction bound to protein High High High
Renal excretion Low Intermediate Low
Dose reduction with renal impairment No Initiate at low dose Initiate at low dose
Gemfibrozil increases repaglinide con-

Drug-drug interaction centration and half-life Nateglinide inhibits CYP2C9 No
Inhibitors of CYP3A4 system
Dose reduction with CYP3A4 inhibitors Yes No No

Combining repaglinide and gemfibrozil is
Initiate doses of 2C9 substrates (e.g.,
not recommended. If clinically necessary,
amiodarone, fluoxetine, phenytoin, and
Managing the interaction reduce the doses of repaglinide and -
warfarin) at lower doses and monitor
monitor blood glucose carefully to avoid
carefully
hypoglycemia
Adopted from [6], [24], [25], and [28].
In our previous study, there were a few cases of hypoglycemia also effectively improved fasting plasma glucose in dialysis pa-
even though the dose of mitiglinide was low compared with other tients.
clinical studies in patients with normal renal function [29-31]. The
daily dose of mitiglinide (23 mg) was adequate, as evidenced by the Alpha-Glucosidase Inhibitors
fact that it was able to induce significant reductions in glycemic The enzyme alpha-glucosidase is located in the gut and hydro-
parameters such as fasting plasma glucose, hemoglobin A1c, gly- lyzes oligosaccharides, trisaccharides, and disaccharides into
cated albumin, and homeostasis model assessment for insulin resis- glucose in the brush border of the small intestine. The antihyper-
tance (HOMA-IR) levels [32]. This suggests that appropriate blood glycemic action of alpha-glucosidase inhibitors results from the
glucose levels can be maintained even at a low dose of mitiglinide, reversible inhibition of membrane-bound intestinal alpha-glucoside
not only during the postprandial period but also before meals, due hydrolase enzymes. Alpha-glucosidase inhibitors decrease the rate
to the prolonged half-life of mitiglinide in patients on dialysis com- of breakdown of complex carbohydrates so that less glucose is ab-
pared with the half-life in those with normal renal function. We sorbed and postprandial hyperglycemia is lowered. In contrast to
noted that mitiglinide significantly improved glycemic control, SUs, alpha-glucosidase inhibitors do not enhance insulin secretion.
triglyceride levels, and interdialytic weight gain even when admin- The side effects are mainly gastrointestinal and include flatulence
istered for only a short duration [33]. Thus, we considered that and diarrhea. An example of an alpha-glucosidase inhibitor is
mitiglinide not only improved hemoglobin A1c and glycated albu- acarbose, which has been shown to reduce hyperglycemia and has
min, the overall index of glycemic control in type 2 diabetes, but also been found to have beneficial effects by reducing the risk of
cardiovascular disease and slowing the progression to diabetes in glycemic control, it is not associated with weight gain [39]. The
patients with hyperglycemia and normal renal function [34, 35]. In UKPDS demonstrated that when used as monotherapy in newly
addition, alpha-glucosidase inhibitors rarely induce hypoglycemia diagnosed, obese diabetic participants, the relative risk of myocar-
and are administered without dose adjustment in the dialysis popu- dial infarction was reduced by 30% [40]. The most common side
lation in Japan [36]. However, the National Kidney Foundation effect of metformin is gastrointestinal disturbance; however, it has
Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) guide- mild anorectic effects and has been shown to have beneficial car-
lines recommend that alpha-glucosidase inhibitors including acar- diovascular effects [41-43]. Metformin is absorbed via the small
bose and miglitol are to be avoided [6]. The main differences be- intestine and the absolute bioavailability is approximately 50-60%.
tween three alpha-glucosidase inhibitors, which are of potential Intravenous single-dose studies in normal subjects demonstrate that
interest for use in the management of patients with type 2 diabetes, metformin is excreted unchanged in the urine and does not undergo
are summarized in Table 4. hepatic metabolism (no metabolites have been identified in hu-
Acarbose is metabolized exclusively within the gastrointestinal mans) or biliary excretion [44]. Renal clearance of metformin is
tract, principally by intestinal bacteria, but also by digestive en- approximately 3.5-fold greater than creatinine clearance, which
zymes. Within 96 h of ingestion, 51% of an oral dose was excreted indicates that tubular secretion via human organic cation transporter
in the faces as unabsorbed drug-related radioactivity [37]. Because 2 is the major route of metformin elimination [45]. Following oral
acarbose acts locally within the gastrointestinal tract, low systemic administration, approximately 90% of the absorbed drug is elimi-
bioavailability of the parent compound is therapeutically desirable. nated via the renal route within the first 24 h, with a plasma elimi-
A fraction of these metabolites (approximately 34% of the dose) nation half-life of approximately 6.2 h. In blood, the elimination
was absorbed and subsequently excreted in the urine. The major half-life is approximately 17.6 h, suggesting that erythrocyte mass
metabolites have been identified as 4-methylpyrogallol derivatives may be a compartment of distribution. Single-dose and steady-state
(i.e., sulfate, methyl, and glucuronide conjugates). In addition, one pharmacokinetics of metformin were compared between patients
metabolite (formed by cleavage of a glucose molecule from acar- with normal renal function (CrCl >90 mL/min), mild impaired renal
bose) also has alpha-glucosidase inhibitory activity [37]. This me- function (CrCl 61-90 mL/min), moderate impaired renal function
tabolite, together with the parent compound, recovered from the (CrCl 31-60 mL/min), and severe impaired renal function (CrCl 10-
urine, accounts for <2% of the total administered dose. Although 30 mL/min). In patients with moderate to severe impaired renal
<2% of an oral dose of acarbose was absorbed as active drug, pa- function, C max and AUC were increased 173% and 390%, respec-
tients with severe renal impairment (CrCl <25 mL/min) attained tively, compared to the patients with normal renal function. In pa-
increases about 5-fold higher for peak plasma concentration of tients with decreased renal function, based on measured CrCl, the
acarbose and 6-fold higher for AUC values than subjects with nor- plasma half-life of metformin is prolonged and renal clearance is
mal renal function [37]. Because long-term clinical trials in diabetic decreased in proportion to the decrease in CrCl [45]. Therefore,
patients with significant renal dysfunction have not been conducted, metformin should be avoided in patients with moderate to severe
treatment of these patients with acarbose is not recommended [37]. CKD including those on dialysis since the risk of metformin accu-
mulation and lactic acidosis increases in line with the degree of
Miglitol, another alpha-glucosidase inhibitor, is not metabolized impairment of renal function. Furthermore, the fixed combination
in humans or in any other animal species studied thus far [38]. No of repaglinide and metformin (PrandiMetR , Novo Nordisk,
metabolites have been detected in plasma, urine, or feces, indicating Bagsvaerd, Denmark) should be avoided in patients with impaired
a lack of either systemic or presystemic metabolism. Miglitol is renal function. Although the plasma protein-binding capacity of
eliminated by renal excretion as unchanged drug [38]. Patients with metformin is low (1.1-2.8%), metformin is dialyzable with a clear-
CrCl <25 mL/min taking the miglitol 25 mg 3 times daily exhibited ance of up to 170 mL/min [46]. Therefore, hemodialysis may be
a greater than 2-fold increase in miglitol plasma levels when com- useful for the removal of accumulated drug from patients in whom
pared to subjects with CrCl >60 mL/min [38]. Dose adjustment to metformin overdose is suspected.
correct for the increased plasma concentrations is not feasible be-
cause miglitol acts locally. However, treatment of patients with Thiazolidinedione
CrCl <25 mL/min with miglitol is not recommended because the
Diabetes leads to ESRD and predisposes patients to a higher
safety of miglitol in these patients has not yet been elucidated [38].
cardiovascular risk and chronic inflammatory conditions via multi-
There has been speculation that alpha-glucosidase inhibitors are
factorial mechanisms, including insulin resistance [47, 48]. Insulin
more effective in Japanese diabetics, as the Japanese diet has his-
resistance, as assessed by HOMA-IR, is an independent predictor of
torically consisted of mainly carbohydrates, in particular rice. None
cardiovascular mortality in patients with ESRD [49]. Rosiglitazone
of the earlier studies, however, evaluated the efficacy of a alpha-
and pioglitazone are potent peroxisome proliferator-activated recep-
glucosidase inhibitor alone for patients with CKD and on dialysis.
tor gamma (PPAR) agonists belonging to a class of oral antidia-
Our group previously compared the effects of voglibose monother-
betic agents known as thiazolidinediones. PPAR agonists are insu-
apy with the effects of an add-on therapy, pioglitazone combined
lin sensitizers that reduce insulin resistance, increase glucose uptake
with voglibose, in type 2 diabetics on dialysis [36]. We found that
in muscles and adipose tissue, and decrease hepatic glucose produc-
the alpha-glucosidase inhibitor monotherapy reduced hemoglobin
tion [50, 51].
A1c levels approximately 0.4% in patients on dialysis. Furthermore,
our results suggested that voglibose is effective for maintaining the The two available glitazones (rosiglitazone and pioglitazone)
glycemic state, as it neither worsened nor improved the glycemic have an adequate oral bioavailability and are extensively metabo-
control in patients with a high level of insulin resistance during the lized by the liver. The main differences between thiazolidinediones
treatment period. Thus, we demonstrated that combination therapy of potential interest for use in the management of patients with type
with pioglitazone is more effective than voglibose monotherapy in 2 diabetes are summarized in Table 5. Rosiglitazone is mainly me-
achieving good glycemic control in type 2 diabetic patients with tabolized by CYP2C8 into inactive metabolites, and <1% of the
insulin resistance. parent drug appears in the urine in unchanged form [52, 53]. The
half-life of rosiglitazone is similar in patients with ESRD and in
Biguanide healthy individuals, and can therefore be administered to ESRD
With the exception of insulin, metformin is the most studied patients without dose adjustment or risk of causing hypoglycemia
therapy for type 2 diabetes. Metformin does not cause increased [54-56]. Pioglitazone is metabolized by CYP3A4 and CYP2C8/9
insulin levels, but rather decreases hepatic glucose output by sup- [57]. Metabolites of pioglitazone are more active than those of
pressing fasting gluconeogenesis. Although effective at improving rosiglitazone and are excreted predominantly in bile. The
Table 4. Main Clinically Relevant Pharmacokinetic Differences between the Three alpha-glucosidase Inhibitors
Characteristics Acarbose Miglitol Voglibose
Therapeutic dose (mg/day) 75-300 75-300 0.6-0.9

Half-life (h) 2 2 Not absorbed in blood
Administration With each meal preprandially With each meal preprandially With each meal preprandially
Metabolized within the gastrointestinal

Metabolism Not metabolized Not metabolized
tract
Very low (<2% of the total
Active metabolite No metabolites No metabolites
administered dose)
Fraction bound to protein Low Low Low (in vitro)
Renal excretion < 2% of oral dose Predominant None
KDOQI: Not recommended in patients
KDOQI: Not recommended in patients with sCr > 2mg/dL, EU: No dose adjust- No in Japan
Dose reduction with renal impairment
with sCr > 2mg/dL ment is necessary in patients with CrCl > Not available in US
25 mL/min
Substrate for CYP No No No
Intestinal adsorbents (e.g., charcol) and
digestive enzyme preparations containing
Intestinal adsorbents (e.g., charcol) and
carbohydrate-splitting enzymes (e.g.,
digestive enzyme preparations containing
amylase, pancreatin) may reduce the
Drug-drug interactions and managing the carbohydrate-splitting enzymes (e.g.,
effect of acarbose and should not be taken No
interaction amylase, pancreatin) may reduce the
concomitantly.
effect of miglitol and should not be taken
Acarbose may affect the bioavailability of
concomitantly
digoxin, which may require digoxin dose
adjustment
Adopted from [6], [36], [37], and [38].
Table 5. Main Clinically Relevant Pharmacokinetic Differences between the Two Thiazolidinediones
Characteristics Rosiglitazone Pioglitazone
Therapeutic dose (mg/day) 4-8 15-45

Half-life (h) 3-4 5.4
Administration Once or twice daily Once daily
Active metabolite Active metabolites M-III and M-IV have hypoglycemic

No
potency 40-60% that of pioglitazone
Fraction bound to protein High High
Molecular weight 473.52 392.90
Renal excretion Low Low
Dose reduction with renal impairment No No
Drug-drug interactions Gemfibrozil increases rosiglitazone AUC and half-life Pioglitazone may interact with CYP3A4 inducers or
by inhibiting CYP2C8 inhibitors
Dose reduction with CYP3A4 inhibitors No Yes
Managing the interaction If combination treatment with gemfibrozil and rosiglita- If combined use of pioglitzanoe withCYP3A4 inducer is
zone is necessary, decrease rosiglitazone doses by 50- necessary, consider reducing dose of pioglitazone and
75% and monitor blood glucose carefully to avoid hypo- monitor blood glucose carefully to avoid hypoglycemia
glycemia
Adopted from [6], [52], [53], and [57].
pioglitazone metabolites, M-III and M-IV, do not accumulate in administered irrespective of the time of dialysis. Because of the
CKD. The pharmacokinetic profile of pioglitazone was found to be high molecular weight (392 Da), high protein-binding capacity
similar in healthy subjects and patients with moderately or severely (>98%), and predominant hepatic metabolism of pioglitazone, its
impaired renal function who did not require dialysis [57], while for pharmacokinetic profile is similar in patients with normal renal
those who did require dialysis [58], pioglitazone was found to have function and CKD, and in those undergoing dialysis therapy. How-
a Tmax of 1.8 h and a half-life of 5.4 h [57]. Therefore, a post- ever, thiazolidinediones have the potential to cause or exacerbate
dialysis supplementary dose is not required, and pioglitazone can be heart failure and should be used with caution in patients with he-
patic injury. Furthermore, it was reported that rosiglitazone is asso- without diabetes apparently improved the insulin sensitivity and
ciated with a significant increase in the risk of myocardial infarc- reduced the systolic and diastolic blood pressure due to the vasodi-
tion [59, 60]. In contrast, pioglitazone improved the cardiovascular latory effects of thiazolidinediones. Nonetheless, thiazolidinediones
outcome in type 2 diabetes patients who were not dependent on must be used with caution as they tend to increase fluid retention
dialysis therapy [61]. Therefore, further investigation is required to and can be associated with congestive heart failure.
determine whether these two drugs belonging to the thiazolidinedi-
one group are associated with cardiovascular events in type 2 diabe- DPP-4 Inhibitors
tes patients receiving dialysis. New compounds targeting the so-called incretin hormone sys-
Rosiglitazone and pioglitazone have been reported to (1) reduce tem may offer some advantages regarding many adverse events
insulin requirements, (2) play various roles in lipid metabolism, associated with other oral glucose-lowering agents. The intestinal
fibrinolysis, coagulation, and platelet aggregation, (3) ameliorate hormone glucagon-like peptide-1 (GLP-1) stimulates insulin secre-
albuminuria, (4) protect against impairment of endothelial function, tion in a glucose-dependent manner. However, its meal-induced
and (5) have an anti-inflammatory effect [62-65]. When used for secretion is generally decreased in patients with type 2 diabetes, and
the clinical management of type 2 diabetes and ESRD, thiazolidin- this may contribute to the amplification of postprandial hypergly-
ediones are primarily metabolized in the liver and will not accumu- cemia. GLP-1 is rapidly inactivated by the enzyme dipeptidylpepti-
late in patients with CKD. They might also improve uremia- dase-4 (DPP-4) [77]. Therefore, an effective way to potentiate post-
associated insulin resistance and confer benefits at the metabolic, prandial GLP-1 response is the use of selective DPP-4 inhibitors
inflammatory, vascular, and hemodynamic levels [65]. Agrawal et [78, 79]. The main differences between DPP-4 inhibitors of poten-
al. studied the effects of an add-on therapy of rosiglitazone admin- tial interest for use in the management of patients with type 2 diabe-
istered in combination with an SU (glyburide, gliclazide, or glipiz- tes are summarized in Table 6 [80].
ide) over a 6-month period in type 2 diabetics with mild to moder- Sitagliptin
ate renal impairment after SU monotherapy had failed to confer Sitagliptin is a highly selective, oral, once-daily, DPP-4 inhibi-
adequate glycemic control. Their results showed similar efficacy in tor approved for the treatment of patients with type 2 diabetes [81].
patients with normal renal function and in those with mild to mod- DPP-4 inhibitors slow the degradation and the inactivation of the
erate renal impairment [66]. Insulin resistance may lead to hyper- incretins, GLP-1 and glucose-dependent insulinotropic polypeptide
triglyceridemia through two independent mechanisms: first, by [77]. These two incretins regulate glucose homeostasis by stimulat-
enhancing hepatic synthesis of very low-density lipoprotein and ing insulin release, while GLP-1 also suppresses glucagon release.
triglycerides due to compensatory hyperinsulinemia, and second, by Both of these effects of incretins are glucose dependent [82].
decreased removal of triglycerides due to impaired regulation of CYP3A4 is the major CYP isozyme responsible for the limited
lipoprotein lipase activity by insulin [67]. It has been reported that oxidative metabolism of sitagliptin, with some minor contribution
pioglitazone administration is associated with mean decreases in from CYP2C8. However, the contribution of the CYP system in
triglyceride levels and mean increases in high-density lipoprotein sitagliptin metabolism is so small that clinically relevant drug-drug
(HDL)-cholesterol without consistent changes in the mean levels of interactions via CYP3A4 or CYP2C8 would probably be negligible
total cholesterol or low-density lipoprotein (LDL)-cholesterol in [83]. This is in contrast to reports of other glucose-lowering agents
non-uremic patients [68]. such as sulfonylureas, meglitinides (repaglinide), and thiazolidin-
Thiazolidinediones are known to reduce HOMA-IR and levels ediones (rosiglitazone). Sitagliptin is primarily renally eliminated
of high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis with approximately 80% of the oral dose excreted unchanged in the
factor-alpha (TNF-), and increase adiponectin levels in patients urine [84, 85]. Excretion is thought to be via active secretion and
not undergoing dialysis. In patients undergoing peritoneal dialysis, glomerular filtration [85, 86]. Following single oral doses of sita-
thiazolidinediones have been reported to reduce hs-CRP levels, but gliptin, plasma sitagliptin exposure increases with decreasing renal
levels of interleukin-6 (IL-6) and TNF- were not reduced [47, 63]. function, as determined by 24-h CrCl. Relative to subjects with
In a short-term study of dialysis patients, thiazolidinediones were normal or mildly impaired renal function, patients with moderate
reported to reduce the levels of hs-CRP but not adiponectin [69]. It renal insufficiency (CrCl 30-50 mL/min), severe renal insufficiency
has been reported that pioglitazone treatment reduced the levels of (CrCl <30 mL/min, not on dialysis) or ESRD on dialysis had ap-
hs-CRP, IL-6, and TNF- and increased the high-molecular weight proximately 2.3-fold, 3.8-fold, or 4.5-fold higher plasma sitagliptin
adiponectin level, even in hemodialysis patients [70]. Furthermore, exposures, respectively, and the Cmax increased by 1.4-fold to 1.8-
the dosage of erythropoiesis-stimulating agents (ESA) was signifi- fold [87]. Tmax was significantly increased in patients with ESRD,
cantly reduced during pioglitazone treatment with improvement in and the terminal half-life increased with decreasing renal function.
insulin resistance and a decrease in the levels of inflammatory cy- Compared with values in subjects with normal renal function (13.1
tokines. Therefore, it was suggested that ESA responsiveness is h), the terminal half-life values of sitagliptin in those with mild,
enhanced with improvement in insulin resistance by long-term pio- moderate, and severe renal impairment, and ESRD were raised to
glitazone treatment [70]. 16.1, 19.1, 22.5, and 28.4 h, respectively. The fraction of dose re-
Potential side effects of PPAR treatment include fluid reten- moved by dialysis was low with 13.5% and 3.5% for dialysis initi-
tion, hemodilution, and weight gain. Thiazolidinedione-induced ated at 4 and 48 h post dose, respectively. Plasma protein binding of
weight gain is mediated through an increase in subcutaneous adi- 38% was not altered in uremic plasma from patients with renal
pose tissue accumulation and possibly a vasodilatory effect leading impairment. Based on these findings, to achieve plasma sitagliptin
to total-body fluid retention [71-73]. In any case, the higher risk of concentrations comparable to those in patients with normal renal
heart failure in patients receiving combination treatments of insulin function [88], sitagliptin dose adjustments are recommended for
and thiazolidinediones (2-3% in the combination group versus 1% patients with type 2 diabetes and moderate to severe renal insuffi-
in the monotherapy group) underscores the need for caution when ciency, as well as for those with ESRD requiring dialysis. Chan et
administering these therapies [74]. Pioglitazone administration is al. reported that sitagliptin dose-adjustment treatment reduced he-
associated with reductions in both systolic and diastolic blood pres- moglobin A1c by 0.7% at 54 weeks in patients with moderate to
sure [75]. This is consistent with the findings of a study of the ef- severe renal insufficiency, including those on peritoneal dialysis
fects of rosiglitazone on insulin resistance and blood pressure in [88].
patients with essential hypertension but without diabetes [76]; a Vildagliptin
decline in systolic blood pressure was correlated with an improve- Because vildagliptin is not a CYP enzyme substrate, and does
ment in insulin sensitivity. Rosiglitazone treatment in hypertensives not inhibit or induce CYP enzymes, it is unlikely to interact with
Table 6. Main Clinically Relevant Pharmacokinetic Differences Between the Five Dipeptidylpeptidase-4 Inhibitors
Characteristics Sitagliptin Vildagliptin Alogliptin Saxagliptin Linagliptin
Therapeutic dose (mg/day) 100 250 12.5-25 5 5

Half-life Long Short Long Short Very long
(but active metabolite)
Administration Once daily Twice daily Once daily Once daily Once daily
Active metabolite No No No Yes No
Fraction bound to protein Intermediate Low Low Very low High
Molecular weight 523.32 303.40 465.51 333.43 472.54
Renal excretion Predominant Intermediate Predominant Predominant Low
Dose reduction with renal impairment Yes No Yes Yes Probably not
(25-50 mg) (12.5-6.25 mg) (2.5 mg)
Drug-drug interaction No No No Yes No
Dose reduction with CYP3A4 inhibitors No No No Yes No
(2.5 mg)
Adopted from [80].
co-medications that are substrates, inhibitors, or inducers of these urine [93]. In patients with type 2 diabetes, alogliptin was also pri-
enzymes [89, 90]. Vildagliptin does not affect the metabolic clear- marily excreted renally (mean fraction of drug excreted in urine
ance of co-medications metabolized by CYP1A2, CYP2C8, from 0-72 h after dosing, 60.8-63.4%), with a renal clearance rate
CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 [80]. of 165-254 mL/min; this is slightly higher than the normal GFR,
Based on an in vitro recombinant DPP-4 assay, the inhibitory con- suggesting the occurrence of some active renal secretion. Metabo-
centration 50% (IC50) for vildagliptin is 2 nM. In humans, the effi- lism of alogliptin constituted a minor pathway; although N-
cacy of vildagliptin against the DPP-4 enzyme also shows a low in demethylated metabolite (M-I) is pharmacologically active and has
vivo IC50 (4.5 nM), which suggests a higher potency than that re- exhibited a similar potency and degree of selectivity for DPP-4 as
ported for sitagliptin (IC50 26 nM) [85, 91]. Vildagliptin is rapidly the parent compound in vitro, the AUC and Cmax of M-I was <1%
absorbed in fasting humans after a single oral dose of 100 mg; ab- of the AUC and Cmax of parent drug, confirming that it is a minor
sorption is high (>85.4%) and dose recovery complete. The major metabolite in humans [94]. The results of a single-dose (50 mg)
circulating components in the plasma were unchanged drug and pharmacokinetic study in patients with renal impairment showed an
main metabolite (M20.7) which was not biologically active. Elimi- increase in alogliptin exposure compared with healthy volunteers:
nation of vildagliptin mainly involves renal excretion of unchanged approximately 1.7-, 2.1-, 3.2-, and 3.8-fold increase in patients with
parent drug and cyano group hydrolysis with little CYP involve- mild, moderate, and severe renal impairment, and in patients with
ment, suggesting a low potential for drug-drug interaction when co- ESRD, respectively [80, 95]. Based on these findings, to achieve
administered with CYP inhibitors/inducers. Moreover, vildagliptin plasma alogliptin concentrations comparable to those in patients
is unlikely to inhibit the metabolic clearance of co-medications with normal renal function, alogliptin dose adjustments are recom-
metabolized by CYP enzymes [92]. mended for patients with type 2 diabetes and moderate to severe
In patients with mild, moderate, and severe renal impairment, renal insufficiency, including those with ESRD requiring dialysis.
and ESRD patients on hemodialysis, systemic exposure to vilda- Saxagliptin
gliptin was increased (Cmax 8-66%; AUC 32-134%) compared to The metabolism of saxagliptin is primarily mediated by
subjects with normal renal function. However, changes in exposure CYP3A4/5. The major metabolite of saxagliptin is also a selective,
to vildagliptin did not correlate with the severity of renal function. reversible, competitive DPP-4 inhibitor, which is 50% less potent
In contrast, exposure of the main metabolite (M20.7) increased with than saxagliptin [96]. The fact that the metabolite of saxagliptin is
increasing severity of renal function (AUC 1.6- to 6.7-fold), but this pharmacologically active is in contrast to the other DPP-4 inhibitors
effect has no clinically relevant consequences because the metabo- whose metabolites are inactive. Saxagliptin is cleared by both me-
lite is pharmacologically inactive. The elimination half-life of vil- tabolism and renal excretion. The effects of renal impairment and
dagliptin was not affected by renal function. Half of all patients in dialysis on the pharmacokinetics of saxagliptin have been deter-
the global development program exposed to the marketed doses of mined [80]. The degree of renal impairment did not affect the Cmax
vildagliptin as monotherapy had either mild or moderate renal im- of saxagliptin or its major metabolite. In subjects with mild renal
pairment at study baseline. Vildagliptin was effective and well tol- impairment, AUC from time 0 to infinity (AUC ) values of saxa-
erated in this population [80]. According to the labeling, no dosage gliptin and its major metabolite were 1.2- and 1.7-fold higher, re-
adjustment of vildagliptin is required in patients with mild renal spectively, than mean AUC values in controls. Corresponding
impairment. In clinical practice, special precautions are advised for values were 1.4- and 2.9-fold higher in subjects with moderate renal
the use of vildagliptin in patients with moderate to severe renal impairment, and 2.1- and 4.5-fold higher in those with severe im-
impairment, including those on dialysis. pairment. A 4-h dialysis session removed 23% of the saxagliptin
Alogliptin dose. AUC values for saxagliptin and, to a greater extent, its major
Alogliptin was rapidly absorbed (median Tmax, 1-2 h) and metabolite were correlated with the degree of renal impairment,
slowly eliminated (mean T1/2, 12.4-21.4 h), primarily via urinary whereas Cmax values were not well correlated. Kidney function
excretion (mean fraction of drug excreted unchanged in urine from should be assessed before initiating saxagliptin therapy and patients
0-72 h after dosing, 60-71%) in healthy subjects. The metabolites with moderate to severe kidney impairment should receive no >2.5
M-I (N-demethylated) and M-II (N-acetylated) accounted for <2% mg/day [97]. Saxagliptin can be taken after dialysis in patients with
and <6%, respectively, of alogliptin concentrations in plasma and ESRD.
Linagliptin with transient hypovolemia, treatment may worsen renal function.

Unlike the other DPP-4 inhibitors, linagliptin is extensively Caution is required when initiating or escalating doses of exenatide
protein bound (>80% at the therapeutic dose). Because DPP-4 is from 5 μg to 10 μg in patients with moderate renal impairment
expressed in various tissues but soluble DPP-4 is also present in (CrCl 30-50 mL/min). No dose adjustment of exenatide is required
plasma, binding to soluble DPP-4 may influence the pharmacoki- in patients with mild renal impairment (CrCl 50-80 mL/min).
netics of linagliptin. High-affinity but readily saturable binding of Liraglutide
linagliptin to its target DPP-4 primarily accounted for the concen- Liraglutide is a once-daily human GLP-1 analog for the treat-
tration-dependent plasma-protein binding at therapeutic plasma ment of hyperglycemia in patients with type 2 diabetes. Liraglutide
concentrations of linagliptin [98]. As the DPP-4 binding capacity is has a high degree of sequence identity to human GLP-1, but differs
saturated at low doses, accumulation of linagliptin in tissues is un- by having an Arg34Lys substitution, and a glutamic acid and 16-C
likely, despite the persistence of small amounts in the body [99]. A free fatty acid addition to Lys26 [110]. Its half-life in humans is
recent study investigated the pharmacokinetics and metabolism of approximately 13 h after subcutaneous injection [111], allowing
linagliptin in healthy volunteers [100]. The 14c-labeled drug was once-daily administration. The metabolism of liraglutide is similar
administered orally (10 mg) or intravenously (5 mg). Fecal elimina- to that of large peptides, that is, it is fully degraded in the body
tion was the dominant excretion pathway with 84.7 and 58.2% of [112], and there is no indication that the kidney is a major organ for
the dose, whereas renal excretion accounted for 5.4 and 30.8% of elimination. Liraglutide has shown favorable effects on several
the dose administered orally or intravenously, respectively. Un- parameters of beta cell function and improves early markers of
changed linagliptin was the most abundant radioactive species in all cardiovascular disease [113-117]. The pharmacokinetic parameters
matrices investigated. The main metabolite CD1790 (pharmaco- of liraglutide are essentially independent of renal function [118].
logically inactive) was observed with >10% of parent compound No safety concerns regarding the use of liraglutide in patients with
systemic exposure after oral administration. Although other me- renal impairment have been raised. Renal dysfunction was not
tabolites were identified, they only contributed to a minor extent to found to increase exposure of liraglutide, and patients with type 2
the overall disposition and elimination of the drug. Renal excretion diabetes and renal impairment can be treated with standard regi-
of unchanged linagliptin was <1% after administration of 5 mg mens of liraglutide.
[101]. As absolute bioavailability was determined to be around
30%, renal excretion is a minor elimination pathway of linagliptin Pramlintide
at therapeutic dose levels (in contrast to other DPP-4 inhibitors) and Pramlintide is a synthetic analog of human amylin, a naturally
accordingly, a dose adjustment in patients with renal impairment is occurring neuroendocrine hormone co-secreted with insulin by
not anticipated for linagliptin. pancreatic beta cells [119]. Amylin regulates gastric emptying
[120], suppresses inappropriate postprandial glucagon secretion
Incretin Mimetics [121], and reduces food intake [122]. Through mechanisms similar
GLP-1 belongs to the incretin class of hormones, which exert to those of amylin, pramlintide reduces postprandial glucose, im-
an influence over multiple physiologic functions, including a rapid proving overall glycemic control [123, 124], and increases satiety,
blood glucose-lowering effect in response to enteral nutrient ab- resulting in reduced food intake and weight loss [125-127] in pa-
sorption. Thus, GLP-1 is a potent blood glucose-lowering agent tients with type 1 or 2 diabetes. Pramlintide is administered by sub-
with many potential beneficial effects [102] and may be able to cutaneous injection and is used in patients with diabetes treated
modulate the progression of type 2 diabetes [103-105]. Native with insulin. Pramlintide is provided as an acetate salt of the syn-
GLP-1 is rapidly metabolized by DPP-4, which is found in many thetic 37-amino acid polypeptide, which differs from human amylin
tissues and cell types, as well as in the circulation [106]. Clearance in amino acid sequence by having Ala25Pro, Ser28Pro, and
of native GLP-1 and its metabolites is largely mediated by the kid- Ser29Pro substitutions. In healthy subjects, the half-life of pramlin-
neys [106]. Incretins, such as GLP-1, enhance glucose-dependent tide, which is metabolized primarily by the kidney, is approxi-
insulin secretion and exhibit other antihyperglycemic actions fol- mately 48 min. Des-lys1 pramlintide (2-37 pramlintide), the primary
lowing their release into the circulation from the gut. Exenatide and metabolite, has a similar half-life and is biologically active both in
liraglutide are GLP-1 receptor agonists that enhance glucose- vitro and in vivo in rats. Patients with moderate or severe renal im-
dependent insulin secretion by pancreatic beta cells, suppress inap- pairment (CrCl >20-<50 mL/min) did not show increased pramlin-
propriately elevated glucagon secretion, and slow gastric emptying. tide exposure or reduced pramlintide clearance when compared
Exenatide with subjects with normal renal function [128]. However, no data
are available for dialysis patients, and therefore further clinical
The amino acid sequence of exenatide is partially homologous studies are warranted in this population.
to that of human GLP-1. Exenatide has been shown to bind and
activate the human GLP-1 receptor in vitro. This leads to an in- Target of Glycemic Control in Dialysis Patients
crease in both glucose-dependent synthesis of insulin, and in vitro As stated in the 2007 NKF-K/DOQI and 2007 American Diabe-
secretion of insulin from pancreatic beta cells, by mechanisms in- tes Association (ADA) guidelines, the target hemoglobin A1c level
volving cyclic AMP and/or other intracellular signaling pathways. associated with the best clinical outcome in diabetic dialysis pa-
The pharmacokinetics of exenatide has been studied in subjects tients has not yet been established [6, 129]. Anemia, which results
with normal renal function, mild or moderate renal impairment, and from a short erythrocyte lifespan, theoretically suppresses hemo-
ESRD. The kidney provides the primary route for elimination and globin A1c levels. Therefore, some studies have suggested that the
degradation of exenatide [107]. In subjects with mild to moderate hemoglobin A1c level is not an ideal index for assessing glycemic
renal impairment (CrCl 30-80 mL/min), exenatide exposure was control in diabetic dialysis patients and advanced CKD who receive
similar to that of subjects with normal renal function. However, in ESA [130-132]. By increasing the proportion of young erythrocytes
subjects with ESRD receiving dialysis, mean exenatide exposure in the blood, both anemia and erythropoietin can falsely lower the
increased by 3.4-fold compared to that of subjects with normal hemoglobin A1c level, thereby leading to failure in the diagnosis of
renal function. Exenatide should not be used in patients with severe hyperglycemia. In contrast, the glycated albumin level was reported
renal impairment (CrCl <30 mL/min) or ESRD, and should be used to provide a significantly superior estimation of glycemic control in
with caution in patients who have undergone renal transplantation diabetic dialysis patients [130-132]. The glycated albumin level was
[108, 109]. In patients with ESRD receiving dialysis, single doses not significantly associated with dialysis, hemoglobin level, or
of 5 μg exenatide were not well tolerated due to gastrointestinal erythropoietin dose in these patients. Therefore, glycated albumin,
side effects. Because exenatide may induce nausea and vomiting which is unaffected by the changes in the survival time of erythro-
cytes, has been suggested as a better indicator of glycemic control, [14] Nolin, T.D.; Naud, J.; Leblond, F.A.; Pichette, V. Emerging evi-
and glycated albumin levels may become the target of glycemic dence of impacy of kidney disease on drug metabolism and trans-
control in diabetic dialysis patients. However, there is no clear con- port. Clin. Pharmacol. Ther., 2008, 83(6) 898-903.
sensus on the target hemoglobin A1c and glycated albumin levels [15] Nolin, T.D.; Frye, R.F.; Matzke, G.R. Hepatic drug metabolism and
for a good prognosis of diabetic dialysis patients. This will need to transport in patients with kidney disease. Am. J. Kidney. Dis., 2003,
42(5), 906-925.
be clarified by long-term studies.
[16] Sun, H.; Frassetto, L.; Benet, L.Z. Effects of renal failure on drug
transport and metabolism. Pharmacol. Ther., 2006, 109(1-2), 1-11.
CONCLUSION
[17] Salsburg, D.S. The UGDP study. JAMA, 1971, 218(11), 1704-
Although therapeutic possibilities with oral agents in type 2 1705.
diabetes mellitus are increasing, the presence of CKD is an impor- [18] United Kingdom Prospective Diabetes Study Group (UKPDS).
tant limitation for using the majority of the currently available oral Intensive blood-glucose control with sulphonylureas or insulin
antidiabetic drugs. In recent years, several promising drugs have compared with conventional treatment and risk of complications in
been introduced in the therapeutic armamentarium of affected pa- patients with type 2 diabetes (UKPDS 33). Lancet, 1998,
tients. However, recommended oral antidiabetic agents differ be- 352(9131), 837-853.
tween countries. Therefore, kidney function of each patient should [19] Zoungas, S.; de Galan, B.E.; Ninomiya, T.; Grobbee, D.; Hamet,
P.; Heller, S.; MacMahon, S.; Marre, M.; Neal, B.; Patel, A.;
be assessed before initiating antidiabetic therapy, and careful moni-
Woodward, M.; Chalmers, J.; ADVANCE Collaborative Group;
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Received: October 12, 2010 Revised: January 12, 2011 Accepted: January 14, 2011

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Current Drug Metabolism, 2011, 12, 57-69 57

Masanori Abe1,*, Kazuyoshi Okada1 and Masayoshi Soma1,2

1389-2002/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd.

Acetohexamide Avoid Avoid

Tolazamide Avoid Avoid

Preferred sulfonylurea Preferred sulfonylurea

Preferred sulfonylurea Preferred sulfonylurea

Glyburide Avoid Avoid

Glimepiride Initiate at low dose, 1mg daily Avoid

No dose adjustment necessary Initiate at low dose 5 mg before each meal

Not recommended in patients with sCr >

Not available in US Not recommended in US

Contraindicated with kidney dysfunction defined as sCr

Rosiglitazone No dose adjustment necessary No dose adjustment necessary

Initiate at low dose Initiate at low dose

Not recommended in patients with

Liraglutide No dose adjustment necessary No dose adjustment necessary

Characteristics Glipizide Gliclazide Glimepiride

Tmax (h) 6-12 4-6 2.5

Characteristics Repaglinide Nateglinide Mitiglinide

Therapeutic dose (mg/day) 1.5-16 90-360 7.5-30

Active metabolite No Yes No

Gemfibrozil increases repaglinide con-

Dose reduction with CYP3A4 inhibitors Yes No No

Characteristics Acarbose Miglitol Voglibose

Therapeutic dose (mg/day) 75-300 75-300 0.6-0.9

Metabolized within the gastrointestinal

Adopted from [6], [36], [37], and [38].

Characteristics Rosiglitazone Pioglitazone

Therapeutic dose (mg/day) 4-8 15-45

Active metabolite Active metabolites M-III and M-IV have hypoglycemic

Adopted from [6], [52], [53], and [57].

Characteristics Sitagliptin Vildagliptin Alogliptin Saxagliptin Linagliptin

Therapeutic dose (mg/day) 100 250 12.5-25 5 5

Linagliptin with transient hypovolemia, treatment may worsen renal function.

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