Hypoglycemics for the treatment of type 2 diabetes in patients with chronic kidney disease: a focus on new agents.
Subject: Kidney diseases (Diagnosis)
Kidney diseases (Complications and side effects)
Kidney diseases (Drug therapy)
Type 2 diabetes (Risk factors)
Type 2 diabetes (Analysis)
Hypoglycemic agents (Health aspects)
Hypoglycemic agents (Analysis)
Authors: Lori D., Victor Fang
PharmD, Wazny
Raymond, Colette B.
Pub Date: 01/01/2012
Publication: Name: CANNT Journal Publisher: Canadian Association of Nephrology Nurses & Technologists Audience: Trade Format: Magazine/Journal Subject: Health care industry Copyright: COPYRIGHT 2012 Canadian Association of Nephrology Nurses & Technologists ISSN: 1498-5136
Issue: Date: Jan-March, 2012 Source Volume: 22 Source Issue: 1
Product: Product Code: 2834121 Antidiabetic Preparations NAICS Code: 325412 Pharmaceutical Preparation Manufacturing SIC Code: 2834 Pharmaceutical preparations
Geographic: Geographic Scope: Canada Geographic Code: 1CANA Canada
Accession Number: 283970445
Full Text: Objectives

After reading this article, the reader will be able to:

* Compare and contrast currently available pharmacological agents for type 2 diabetes.

* Understand the benefits and limitations of new hypoglycemics and their place in therapy.

* Understand the benefits and limitations of each pharmacological agent in patients with chronic kidney disease.

Introduction

This article will review the use of medications to treat type 2 diabetes in patients with chronic kidney disease (CKD). The efficacy, advantages and limitations of each medication and considerations and recommendations for their use will be discussed. New hypoglycemic agents will be highlighted.

Epidemiology

CKD is commonly complicated by the presence of other health conditions (Go, Chertow, Fan, McCulloch, & Hsu, 2004). Diabetes is very common among patients with CKD, affecting approximately 50.8% of patients in Canada receiving dialysis, and is the leading cause of renal failure in Canada (Arbor Research Collaborative for Health; Canadian Diabetes Association, 2008). Pharmacotherapy of diabetes is complicated in patients with CKD due to changes in the absorption, distribution, metabolism, and elimination of endogenous insulin and hypoglycaemic medications.

Goals of therapy

The goals for glycemic control in diabetics with CKD are the same as other people with diabetes (Canadian Diabetes Association, 2008). A target glycated hemoglobin (A1C) of 7% or less is the recommendation for most patients with type 2 diabetes (Canadian Diabetes Association, 2008). Reduction of A1C to 7% can reduce the risk of developing microalbuminuria and associated complications in patients with type 2 diabetes (UKPDS Group, 1998; Shichiri, Kishikawa, Ohkubo, & Wake, 2000). Studies suggest that reducing A1C to less than 7% may reduce macroalbuminuria and that optimal control of hyperglycemia may help preserve renal function. However, the strength of this evidence is limited by small patient numbers (Shichiri et al., 2000; Brocco et al., 2001; Holman et al., 1983; Viberti, Bilous, Mackintosh, Bending, & Keen, 1983). It is important to note that the accuracy of A1C readings correlating to glycemic control in patients on hemodialysis has been debated. A1C assays should use highperformance liquid chromatography and be standardized to the Diabetes Control and Complications Trial (DCCT) assay to minimize the production of uremia-induced carbamylated hemoglobin, which can falsely increase A1C readings (Sharif & Baboolal, 2010). A1C readings are increased in patients with iron or folate deficiences. Metabolic acidosis, common in predialysis CKD patients, also leads to increased A1C levels (Sharif & Baboolal, 2010). Factors that falsely decrease A1C readings include blood loss, during treatment or from frequent blood sampling, in patients receiving hemodialysis, shortened red blood cell survival, red blood cell transfusions, and treatment with erythropoietic stimulating agents (Uzu et al., 2009). Hence, A1C readings of patients with CKD may be over or underestimating actual average blood glucose levels (Morgan, Marenah, Jeffcoate, & Morgan, 1996). The A1C should be interpreted along with the patient's home blood glucose readings before making a determination of diabetic control.

Glycemic control should be considered part of a multifaceted approach to managing patients with CKD (Levin et al., 2008). It is also important to assess the patients' cardiovascular risks and steps should be taken, as necessary, to manage hypertension and dyslipidemia. To best optimize health outcomes, patients should also be encouraged to make any necessary lifestyle changes, such as nutritional management, smoking cessation and increasing physical activity.

Pharmacotherapy

The pharmacologic management of hyperglycemia should be individualized for each patient. Patient factors such as degree of hyperglycemia, risk for hypoglycemia and other comorbidities should be considered to guide clinical judgment. Pharmacotherapy should be initiated if glycemic targets are not met after two to three months of lifestyle modifications (Canadian Diabetes Association, 2008). For patients with an A1C greater than or equal to 9% at presentation, pharmacotherapy should be initiated along with lifestyle recommendations (Canadian Diabetes Association, 2008). Combination therapy with two agents may be considered in these patients. Timely adjustments to regimens and dosages should be made to target an ideal A1C within six to 12 months (Canadian Diabetes Association, 2008). A review of each class of agents is presented in Table 1 (conventional agents, page 34) and Table 2 (new agents, page 35).

Metformin

Metformin is considered a first-line agent for the treatment of hyperglycemia in most patients with type 2 diabetes (Canadian Diabetes Association, 2008). This is, in part, due to data suggesting reduced cardiovascular disease outcomes and all-cause mortality, no weight gain, lack of hypoglycemia when used alone, and low cost (Lipska, Bailey, & Inzucchi, 2011). Recent studies have also suggested that metformin may decrease the risk of breast and prostate cancer and cancer-related mortality in diabetic patients (Belda-Iniesta, Pernia, & Simo, 2011). It is recommended for patients with type 2 diabetes with concomitant stage 1 or 2 CKD and stable renal function (Sanofiaventis, 2009). Although the product monograph warns against its use in patients with a creatinine clearance less than 60 ml/ minute, some experts advocate that metformin may be continued in stage 3 patients already taking metformin before the diagnosis of renal dysfunction (Arroyo et al., 2011). Metformin should be discontinued in the presence of acute changes in renal function or if a patient is experiencing an illness that may lead to acute changes in renal function such as vomiting, diarrhea or severe dehydration (Levin et al., 2008). Regardless of renal function, all patients on metformin should be counselled on monitoring for these signs of illness. Metformin is contraindicated in patients with stage 4 or 5 CKD or an estimated glomerular filtration rate (eGFR) of less than 30 ml/min/1.73m2 as advanced CKD may increase the risk of lactic acidosis (K/ DOQI Workgroup, 2005). However, the actual risk of lactic acidosis has come under scrutiny, and some studies suggest that the benefits from metformin pharmacotherapy may outweigh its potential risks in patients with type 2 diabetes and renal insufficiency (McCormack, Johns, & Tildesley, 2005).

Insulin

Insulin pharmacotherapy provides the greatest reduction in A1C. For patients with significant hyperglycemia at presentation (A1C [grater than or equal to] 9%), insulin is considered an appropriate initial therapy (Canadian Diabetes Association, 2008). Insulin may also be considered an add-on agent for patients with inadequate glycemic control with other medications (Canadian Diabetes Association, 2008). Insulin may be used in patients with CKD but it must be used cautiously, particularly in patients with Stage 4-5 CKD. The kidney is responsible for one third of insulin metabolism and the presence of renal insufficiency may lead to a longer half-life, increasing the risk of hypoglycemia in these patients (Hasslacher & Wittmann, 2003). Compared to patients without renal impairment, patients with advanced CKD will likely have lower insulin requirements (Rave, Heise, Pfutzner, Heinemann, & Sawicki, 2001). It is recommended that treatment be individualized for patients by carefully titrating to desired glycemic targets and closely monitoring for hypoglycemia.

Sulfonylureas (glyburide, gliclazide, tolbutamide)

Sulfonylureas are widely used for the treatment of type 2 diabetes and include glyburide, gliclazide and tolbutamide. These agents work by increasing the responsiveness of pancreatic beta cells to glucose, resulting in an increase in insulin secretion. They may be used as monotherapy or in combination with other agents. Sulfonylureas are considered to have good efficacy in A1C lowering. However, their side effect profile is considered a limitation to use in patients at increased risk of hypoglycemia such as the elderly and patients with CKD. Nonetheless, due to differences in pharmacokinetics some sulfonylureas are considered appropriate for the treatment of hyperglycemia in patients with CKD. First generation sulfonylureas, like chlorpropamide, should generally be avoided due to active metabolites and hypoglycemia risk. However, tolbutamide is exclusively hepatically metabolized and may be used in patients with CKD(American Society of Health-Systems Pharmacists, 2011c). Caution should be exercised when using second generation sulfonylureas, particularly glyburide, as it has renally excreted active metabolites and cases of prolonged hypoglycemia in patients with advanced CKD have been reported. Gliclazide is the preferred secondgeneration sulfonylurea for patients with advanced CKD as it does not have any active metabolites and does not require dose adjustments for stage 3, 4, or 5 CKD (National Kidney Foundation, 2002).

Meglitinides (repaglinide and nateglinide)

Meglitinides are short-acting insulin secretagogues that work similarly to sulfonylureas by increasing insulin secretion from pancreatic beta cells. Being structurally different from sulfonylureas, meglitinides may be a useful alternative for patients with an allergy or intolerance to sulfonylureas. These medications are an appropriate choice for patients with type 2 diabetes with inadequate glycemic control from lifestyle changes or as an adjunct to pharmacotherapy. Repaglinide (Gluconorm[R]) and nateglinide (Starlix[R])are both approved to be used in combination with metformin (Novartis Pharmaceuticals, 2009; Novo Nordisk, 2010). Repaglinide may also be used in combination with rosiglitazone if there is an intolerance to metformin (Novo Nordisk, 2010). Repaglinide is mainly hepatically metabolized, with renal excretion accounting for less than 10% (Snyder & Berns, 2004). It has a good safety profile for patients with renal impairment and may even be an appropriate choice for patients with more severe CKD (Hasslacher & Multinational Repaglinide Renal Study Group, 2003). Nateglinide is also hepatically metabolized but should be used with caution in patients with renal impairment, as active metabolites are produced and accumulation of these metabolites has been observed (Inoue et al., 2003)

Thiazolidinediones (rosiglitazone and pioglitazone)

Thiazolidinediones or "glitazones" work to improve insulin sensitivity and glucose utilization in various tissues. Although the exact mechanism of action is not well understood, these effects are thought to be achieved through activation of peroxisome proliferator-activated receptors (PPARs). Rosiglitazone (Avandia[R]) and pioglitazone (Actos[R]) are considered appropriate adjuncts to metformin. They may also be considered as an option for monotherapy when unsatisfactory glycemic control is seen with all other oral hypoglycemics, as monotherapy or combination therapy (GlaxoSmithKline, 2011; Takeda Canada, 2011). The use of thiazolidinediones is limited by reports and warnings about serious adverse events associated with these agents. A warning for the use of rosiglitazone was recently issued by Health Canada about increased risk of serious cardiac events (Health Canada, 2010). Health Canada has also warned about the use of pioglitazone and its potential to increase the risk of bladder cancer (Health Canada, 2011). Rosiglitazone and pioglitazone are almost exclusively hepatically metabolized and do not require dose adjustments in patients with reduced renal function (Charpentier, Riveline, & Varroud-Vial, 2000). Hemodialysis has also been found to not have a significant effect on the pharmacokinetics of these agents (Charpentier et al., 2000). However, rosiglitazone should be used cautiously, if at all, in patients with severe CKD due to limited clinical data and concerns for increased cardiac events (GlaxoSmithKline, 2011).

DPP-IV Inhibitors (sitagliptin, saxagliptin and linagliptin)

Sitagliptin (Januvia[R]), saxagliptin (Onglyza[R]) and linagliptin (Trajenta[R]) work by inhibiting the enzyme dipeptidyl peptidase IV (DPP-IV), which is responsible for the degradation of the endogenous hormone incretin (also known as glucagon-like peptide-1 or GLP-1). The release of incretin in response to meals helps to regulate blood glucose levels by increasing insulin release, prolonging the effects of insulin, and inhibiting glucagon release (Langley, Suffoletta, & Jennings, 2007). Incretin has also been shown to slow gastric emptying and increase satiety. In patients with type 2 diabetes, the incretin effect is usually limited or completely lost (Langley et al., 2007). Sitagliptin and linagliptin are both approved in Canada as an appropriate choice for monotherapy in patients with type 2 diabetes (Boehringer Ingelheim, 2011; Merck, 2010). Saxagliptin does not have an approved indication for monotherapy (Bristol-Myers Squibb-AstraZeneca, 2011). Sitagliptin, saxagliptin and linagliptin are also indicated as an adjunct to metformin or a sulfonylurea when monotherapy with either agent does not result in adequate glycemic control (Boehringer Ingelheim, 2011; Bristol-Myers Squibb-AstraZeneca, 2011; Merck, 2010). To account for a potential increased risk of hypoglycemia when adding these agents to a sulfonylurea, the dose of the sulfonylurea should be initially reduced by 50% and titrated up, as needed (Gupta & Kalra, 2011; Scheen, 2010). For patients with creatinine clearance of 50 ml/minute or higher (CKD Stage 1-early Stage 3), sitagliptin and saxagliptin may be used without dosage adjustments. In patients with a creatinine clearance of 30 ml/min to 49 ml/min (CKD Stage 3), sitagliptin's area under the curve (AUC) was increased two-fold compared to patients without CKD. In patients with a creatinine clearance of less than 30 ml/ min or on hemodialysis (CKD Stage 4-5), a four-fold increase in AUC was seen compared to patients without CKD (Merck & Co., 2010). With saxagliptin, patients with a creatinine clearance of less than 50 ml/min were observed to have a 2.1-fold increase in drug and a 4.5-fold increase in its major metabolite (Bristol-Myers Squibb, 2009). Product monographs in Canada for both agents do not recommend their use in patients with CKD Stage 3-5 due to limited experience in this subset of patients (Bristol-Myers Squibb-AstraZeneca, 2011; Merck, 2010). However, at least one study has suggested that sitagliptin provides effective glycemic control at reduced doses in patients with moderate to severe impairment and the U.S. product monograph provides dosing recommendations (Table 2) (Chan et al., 2008; Merck & Co., 2010). However, sitagliptin is only available in Canada as a 100 mg unscored tablet, so it is difficult to reduce the dose to 25 mg and 50 mg, as recommended in the U.S. monograph. The 100 mg tablets may be split, as needed for reduced dosing, but there is currently no stability data on the split tablets (Merck Canada). Similarly, several studies of saxagliptin recommended a reduced dose in patients with CKD Stage 3-5 and the U.S. product monograph provides some dosing recommendations (Boulton et al., 2011; Bristol-Myers Squibb, 2009; Nowicki et al., 2011). For patients with renal impairment, linagliptin does have one key advantage over the established DPP-IV inhibitors in that it primarily undergoes non-renal elimination and is extensively eliminated through the enterohepatic system (Gupta & Kalra, 2011). Dose adjustments for linagliptin are not required in patients with CKD Stage 1-3 (Boehringer Ingelheim, 2011). Although some studies suggest that renal impairment has a minimal impact on the pharmacokinetics of linagliptin, its use is currently not recommended in patients with CKD Stage 4-5 due to limited experience as per the Canadian monograph (Barnett, 2011; Boehringer Ingelheim, 2011; Graefe-Mody et al., 2011). However, the U.S. product monograph states that no adjustment is required (Boehringer Ingelheim Pharmaceuticals, 2011).

Incretin Mimetics (liraglutide and exenatide)

Liraglutide (Victoza[R]) is the first incretin-mimetic, or GLP- 1 receptor agonist to be introduced to the Canadian market. It is a synthetically-produced analogue of GLP-1 that is more resistant to DPP-IV metabolism, resulting in prolonged pharmacologic activity. Liraglutide stimulates the GLP-1 receptors to increase glucose-dependent insulin secretion, suppress glucagon release, promote pancreatic beta-cell proliferation, slow gastric emptying and enhance satiety. Liraglutide is currently indicated as an adjunct to metformin monotherapy or metformin/ sulfonylurea combination therapy when therapies fail to achieve adequate glycemic control in patients with type 2 diabetes (Novo Nordisk, 2011b). In a comparative study with exenatide, liraglutide was found to result in greater improvements in glycemic control (decreased mean A1C by 1.12% compared to 0.79% with exenatide over six weeks, p < 0.0001) and was also found to be better tolerated as well (Buse et al., 2009). Liraglutide is primarily metabolized by proteolysis in a similar manner as endogenous GLP-1, therefore its pharmacokinetics are not significantly affected by hepatic or renal impairment (Russell-Jones, 2010). For patients with CKD Stage 1-2, dose adjustments are not required (Novo Nordisk, 2011b). Limited clinical experience however restricts the use of liraglutide in patients with CKD Stage 3-5, although the U.S. product monograph states that no dosage adjustment is required (Novo Nordisk, 2011a; Novo Nordisk, 2011b). Preliminary evidence has shown an increased incidence of thyroid C-cell tumors in rodents exposed to clinically relevant concentrations of liraglutide. However, it is currently unknown if this is a risk when liraglutide is used in humans. As a precaution, liraglutide is currently contraindicated in patients with a history of medullary thyroid carcinoma or multiple endocrine neoplasias (Novo Nordisk, 2011b).

Exenatide (Byetta[R]) is the second incretin-mimetic, or GLP- 1 receptor agonist to be introduced to the Canadian market. Much like liraglutide, exenatide is also a synthetic GLP-1 analogue with a similar mechanism of action. It is indicated to be used in combination with metformin and/or a sulfonylurea for the treatment of type 2 diabetes when maximally tolerated doses of each fail to provide adequate glycemic control (Novo Nordisk, 2011b). For patients with CKD, no dosage adjustment is required for patients with CKD Stage 1-2 (Novo Nordisk, 2011b). There have been case reports of worsened renal function in patients using exenatide. Some of these patients were on other medications that affected renal function (e.g., ACE inhibitors, NSAIDs) or were dehydrated. In some cases, reversibility of altered renal function was observed when the offending medications were discontinued (Novo Nordisk, 2011b). Therefore exenatide should be used with caution in patients with CKD Stage 3, particularly when initiating therapy or when increasing a dose. It is not recommended to use exenatide in patients with CKD stage 4-5 including those receiving dialysis (Novo Nordisk, 2011b).

Conclusion

Agents useful for patients with type 2 diabetes complicated by CKD are summarized in Tables 1 and 2. While insulin remains the most effective agent at lowering A1C, many patients are resistant to starting subcutaneous injections and would prefer to remain on oral medications for as long as possible. Out of the newer agents available, linagliptin and liraglutide may be used in patients with CKD, but their high cost and moderate reductions in A1C are limiting factors to their widespread use.

RELATED ARTICLE: Hypoglycemics for the treatment of type 2 diabetes in patients with chronic kidney disease: a focus on new agents

By Victor Fang, Lori D. Wazny, PharmD, Colette B. Raymond, PharmD, MSc

1. Targeting an A1C of 7% or less in patients with type 2 diabetes is associated with all of the following except:

(a) reduced risk of developing microalbuminuria

(b) reduced risk of developing macroalbuminuria

(c) improved renal function

(d) preserved renal function

2. For patients on hemodialysis with blood loss due to the hemodialysis treatment or frequent blood draws, which of the following statements regarding A1C readings is the best response?

(a) A1C readings in patients on hemodialysis are accurate representations of glycemic control

(b) caution should be used for A1C readings in patients on hemodialysis as they may be falsely decreased due to blood loss

(c) caution should be used for A1C readings in patients on hemodialysis as they may be falsely increased due to blood loss

(d) A1C readings are inaccurate in patients on hemodialysis and, therefore, do not need to be monitored

3. True or False: Patients with advanced CKD generally have lower insulin requirements.

(a) true

(b) false

4. The preferred sulfonylurea for patients with CKD is:

(a) glyburide

(b) chlorpropamide

(c) metformin

(d) gliclazide

5. The mechanism of action of sitagliptin (Januvia[R]), saxagliptin (Onglyza[R]) and linagliptin (Trajenta[R]) involves:

(a) inhibiting the activity of the DPP-IV enzyme to prolong the effects of incretin

(b) inhibiting the activity of the DPP-IV enzyme to reduce the effects of incretin

(c) inducing the activity of the DPPIV enzyme to prolong the effects of incretin

(d) These agents are structural analogues of endogenous incretin

6. The effects of endogenous incretin include all of the following except:

(a) increase glucose-dependent insulin production from pancreatic beta cells

(b) enhance feelings of satiety

(c) increase gastrointestinal motility

(d) decrease glucagon production from pancreatic alpha cells

7. Which of the following statements are correct?

(a) saxagliptin (Onglyza[R]) has an approved indication for monotherapy in the treatment of type 2 diabetes

(b) due to risk of hypoglycemia, linaglipin (Trajenta[R]) is not recommended in patients taking sulfonylureas

(c) no dosage adjustments are required for saxagliptin (Onglyza[R]) in patients with CKD

(d) cases of acute pancreatitis have been reported with the DPP-IV inhibitors

8. Which of the following statements about liraglutide (Victoza[R]) is correct?

(a) liraglutide (Victoza[R]) is indicated as an appropriate choice for monotherapy in patients with type 2 diabetes

(b) liraglutide (Victoza[R]) is associated with an increased incidence of serious cardiac events

(c) according to the U.S. product monograph, no dosage adjustments are required for patients with renal impairment

(d) liraglutide (Victoza[R]) is given as a subcutaneous injection

9. Which of the following statements about exenatide (Byetta[R]) is false?

(a) use of exenatide is associated with clinically significant weight gain

(b) exenatide is an incretin mimetic

(c) associated side effects include nausea, vomiting, and diarrhea

(d) decreased clearance of exenatide has been observed in patients with moderate to severe renal impairment

10. Which of the following agents is currently contraindicated in patients with a history of medullary thyroid carcinoma or multiple endocrine neoplasias?

(a) linagliptin (Trajenta[R])

(b) liraglutide (Victoza[R])

(c) exenatide (Byetta[R])

(d) pioglitazone (Actos[R])

Copyright [c] 2012 Canadian Association of Nephrology Nurses and Technologists

RELATED ARTICLE: Hypoglycemics for the treatment of type 2 diabetes in patients with chronic kidney disease: a focus on new agents

By Victor Fang, Lori D. Wazny, PharmD, Colette B. Raymond, PharmD, MSc

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By Victor Fang, Lori D. Wazny, PharmD, and Colette B. Raymond, PharmD, MSc

Victor Fang, Pharmacy Student, Faculty of Pharmacy, University of Manitoba, Winnipeg, MB.

Lori D. Wazny, PharmD, Clinical Pharmacist, Winnipeg Regional Health Authority, Manitoba Renal Program, Winnipeg, MB.

Colette B. Raymond, PharmD, MSc, Clinical Pharmacist, Winnipeg Regional Health Authority, Manitoba Renal Program, Winnipeg, MB

Address correspondence to: Lori Wazny, PharmD, Dept. of Pharmaceutical Services, Health Sciences Centre, 820 Sherbrook St., Winnipeg, MB R3A 1R9. Email: Lwazny@hsc.mb.ca
Table 1. Conventional hypoglycemics for the treatment of
type 2 diabetes

Medication              A1C        Advantages      Disadvantages
                     reduction
                        with
                    monotherapy

Metformin           1% to 2%     First line      Side effects:
(Glucophage[R])                  agent for       Abdominal
                                 patients with   discomfort,
                                 type 2          stomach upset,
                                 diabetes.       diarrhea,
                                                 nausea.
                                 Well            Potential for
                                 tolerated,      lactic
                                 good side       acidosis.
                                 effect
                                 profile.

Insulin             1.5% to      Most effective  Requires
                    3.5%         A1C lowering.   injections. High
                                                 risk for
                                                 hypoglycemia.
                                                 Weight gain.

Sulfonylureas       1% to 2%     Widely used,    Side effects:
(e.g.,                           lots of         Hypoglycemia
tolbutamide,                     clinical        (incidence
glyburide,                       experience.     varies among
gliclazide                       Effective A1C   agents), nausea,
[Diamicron[R]])                  lowering.       weight gain.
                                                 Hypoglycemia
                                                 risk restricts
                                                 its use in
                                                 certain patient
                                                 groups.

Meglitinides        0.5% to      Flexible        Potential for
repaglinide         1.5%         dosing as can   hypoglycemia if
(Gluconorm[R])                   skip dose if    a dose is taken
nateglinide                      meal is missed  but meal is
(Starlix[R])                     or add extra    missed.
                                 dose with
                                 extra meals.
                                 Well
                                 tolerated.

Thiazolidinediones  0.5% to      Low risk for    Side effects:
rosiglitazone       1.4%         hypoglycemia.   edema, weight
(Avandia[R])                                     gain.
pioglitazone                                     Rosiglitazone
(Actos[R])                                       may be
                                                 associated with
                                                 an increased
                                                 risk of serious
                                                 cardiac issues.
                                                 Requires special
                                                 consent
                                                 process.{{226
                                                 Canada,
                                                 GlaxoSmithKline
                                                 Health, 2010}}
                                                 Pioglitazone may
                                                 be associated
                                                 with an
                                                 increased risk
                                                 for bladder
                                                 cancer.{{225
                                                 Canada Health,
                                                 2011}}

Medication            Renal considerations

Metformin           May be used in Stage
(Glucophage[R])     1-2 CKD with stable
                    renal function that has
                    been unchanged in the
                    last 3 months.
                    May be continued in
                    Stage 3 CKD already on
                    metformin before
                    diagnosis of renal
                    dysfunction.
                    Contraindicated in
                    patients with a eGFR
                    less than
                    30ml/min/1.73[m.sup.2]
                    (CKD Stage 4-5)

Insulin             Patients with renal
                    impairment have lower
                    insulin requirements
                    compared to patients
                    without renal
                    impairment. No clear
                    consensus on dosage
                    adjustments.
                    Adjustments should be
                    made accordingly to
                    attain desired glycemic
                    targets with close
                    monitoring for
                    hypoglycemia.

Sulfonylureas       Gliclazide preferred in
(e.g.,              patients with CKD, no
tolbutamide,        dose adjustments
glyburide,          required (National
gliclazide          Kidney Foundation
[Diamicron[R]])     2002). Tolbutamide may
                    be used without dose
                    adjustments (American
                    Society of
                    Health-Systems
                    Pharmacists 2011c).
                    Avoid glyburide in
                    patients with CrCl
                    < 50ml/min
                    (American Society of
                    Health-Systems
                    Pharmacists, 2011b).

Meglitinides        Repaglinide: CrCl <
repaglinide         40ml/min recommend
(Gluconorm[R])      initiating at lower
nateglinide         doses (0.5 mg before
(Starlix[R])        meals) and use caution
                    with dose titrations.
                    Nateglinide: use
                    cautiously in patients
                    with CKD as
                    accumulation of
                    metabolites has been
                    observed with regular
                    use (Inoue,et al.,
                    2003).

Thiazolidinediones  Extensively hepatically
rosiglitazone       metabolized, no dosage
(Avandia[R])        adjustments required
pioglitazone        for renal impairment.
(Actos[R])          Pharmacokinetics not
                    affected by
                    hemodialysis.

Abbreviations: CKD = chronic kidney disease, A1C = glycated
hemoglobin, eGFR = estimated glomerular filtration rate,
CrCl = creatinine clearance


Table 2. New hypoglycemic agents for the treatment of type 2 diabetes

Medication         A1C reduction with       Advantages
                       monotherapy

DPP-IV Inhibitors  0.6% to 0.8%        Well tolerated. Low
sitagliptin                            incidence of
(Januvia[R])                           hypoglycemia in both
saxagliptin                            monotherapy and
(Onglyza[R])                           combination therapy.
linagliptin                            Weight neutral.
(Trajenta[R])

Incretin Mimetics  0.8% (exanatide) -  Clinically
liraglutide        1.1% (liraglutide)  significant weight
(Victoza[R])       when added to       loss is seen with
exenatide          metformin and/or    these agents, which
(Byetta[R])        sulfonylurea        may be useful in
                                       obese patients. Low
                                       incidence of
                                       hypoglycemia,
                                       reported cases were
                                       mild in nature.

Medication            Disadvantages           Renal Considerations

DPP-IV Inhibitors  Side effects:             Sitagliptan &
sitagliptin        hypersensitivity          saxagliptan: Moderate
(Januvia[R])       reactions.                CKD (CrCl[greater than
saxagliptin        Post-marketing case       or equal to]30ml/min,
(Onglyza[R])       reports of acute          -50ml/min) Sitagliptin:
linagliptin        pancreatitis and acute    50 mg once daily
(Trajenta[R])      renal failure. Compared   Saxagliptin: 2.5 mg once
                   to conventional oral      daily Severe CKD
                   agents, DPP-IV            (CrCl-30ml/min) or
                   inhibitors are more       dialysis Sitagliptin: 25
                   expensive and not as      mg once daily
                   effective in lowering     Saxagliptin: 2.5 mg once
                   A1C ($95-$100/30 days).   daily (Chan et al, 2008;
                                             Boulton et al., 2011;
                                             Nowicki et al., 2011)
                                             Linagliptin: mainly
                                             eliminated through the
                                             enterohepatic system and
                                             some studies suggest
                                             that renal impairment
                                             has little impact on its
                                             pharmacokinetics (Gupta
                                             & Kalra, 2011). U.S.
                                             monograph states no dose
                                             adjustments necessary
                                             for renal impairment.
                                             Canadian monograph
                                             states not recommended
                                             in those with severe
                                             renal impairment due to
                                             lack of clinical
                                             experience

Incretin Mimetics  Side effects: nausea,     Liraglutide: eliminated
liraglutide        vomiting, diarrhea,       primarily by proteolysis
(Victoza[R])       hypoglycemia. Requires    and clearance is not
exenatide          subcutaneous injections.  significantly affected
(Byetta[R])        Post-marketing case       by renal impairment.
                   reports of acute          U.S. monograph states no
                   pancreatitis.             dose adjustments
                   Post-marketing case       necessary for renal
                   reports of acute kidney   impairment. Canadian
                   injury and worsening      monograph states not
                   renal function. Cost      recommended in those
                   Liraglutide: $250/30      with severe renal
                   days Exenatide: $160/30   impairment due to lack
                   days Liraglutide:         of clinical experience.
                   increased incidence of    Exenatide: Studies have
                   thyroid C-cell tumours    found evidence of
                   in rodents.               decreased clearance of
                   Contraindicated in        exenatide in patients
                   patients with a history   with moderate and severe
                   of medullary thyroid      renal impairment
                   carcinoma or multiple     (Linnebjerg et al.,
                   endocrine neoplasias.     2007). No dosage
                                             adjustment required for
                                             mild renal impairment
                                             (CrCl 50-80 ml/min).
                                             Use with caution in
                                             patients with moderate
                                             renal impairment (CrCl
                                             30-50 ml/min).

Abbreviations: BID = twice daily, TID = three times daily,
QID = four times daily, SC = subcutaneous, CKD = chronic kidney
disease, A1C = glycated hemoglobin, eGFR = estimated glomerular
filtration rate, CrCl = creatinine clearance


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6.   a  b  c  d
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