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www.medscape.org

This article is a CME certified activity. To earn credit for this activity visit:http://www.medscape.org/viewarticle/769116

CME I n f o r m a t i o n

CME Released: 08/21/2012; Valid for credit through 08/21/2013

Targe t Aud ience

This educational activity is intended for an international audience of healthcare professionals, excluding UShealthcare professionals.

This activity is intended for diabetologists, endocrinologists, nephrologists, cardiologists, internists, generalpractitioners, and primary care physicians, as well as other healthcare professionals who manage diabetespatients with, or at risk for, renal dysfunction.

Goal

The goal of this activity is to improve knowledge of the risks, consequences, and optimal treatment strategies ofdiabetes patients with renal dysfunction.

Learn in g Ob jec t i ves

Upon completion of this activity, participants should be able to:

1. Describe the prevalence, morbidity, and mortality associated with renal dysfunction in people with T2DM2. Discuss the screening and monitoring of diabetes patients at risk of renal impairment, including the use

of appropriate laboratory tests3. Review the importance of, and drug therapies to achieve, adequate glycemic control to improve renal

outcomes in patients with T2DM

4. Compare and contrast pharmacokinetic difference between available DPP-4 inhibitors

Cred i t s Ava i lab le

Non-US Physicians - maximum of 0.50 CPD

All other healthcare professionals completing continuing education credit for this activity will be issued acertificate of participation.

Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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WebMD Global requires each individual who is in a position to control the content of one of its educational

activities to disclose any relevant financial relationships occurring within the past 12 months that could create a

conflict of interest.

M o d e r a t o r

Eleuter io Ferr ann in i , MD

Professor of Internal Medicine; Chief, Metabolism Unit, National Research Council Institute of Clinical

Physiology, University of Pisa School of Medicine, Pisa, Italy

Disclosure: Eleuterio Ferrannini, MD, has disclosed the following relevant financial relationships: Served as an

advisor or consultant for: AstraZeneca Pharmaceuticals LP; Boehringer Ingelheim Pharmaceuticals, Inc.; Bristol-

This activity is designed to be completed within the time designated on the title page; physicians should claimonly those credits that reflect the time actually spent participating in the activity. To successfully earn credit,participants must complete the activity online during the credit eligibility period that is noted on the title page.

Follow these steps to claim a credit certificate for completing this activity:

1. Read the information provided on the title page regarding the target audience, learning objectives, and

author disclosures, read and study the activity content and then complete the post-test questions. If youearn a passing score on the post-test and we have determined based on your registration profile that youmay be eligible to claim CPD credit for completing this activity, we will issue you a CPD credit certificate.

2. Once your CPD credit certificate has been issued, you may view and print the certificate from yourCME/CE Tracker. CPD credits will be tallied in your CME/CE Tracker and archived for 6 years; at anypoint within this time period you can print out the tally as well as the certificates by accessing "Edit YourProfile" at the top of the Medscape Education homepage.

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Myers Squibb Company; Eli Lilly and Company; Merck Sharp & Dohme Corp.; sanofi-aventis

Received grants for clinical research from: Boehringer Ingelheim Pharmaceuticals, Inc.; Eli Lilly and Company;

Merck Sharp & Dohme Corp.

Dr Ferrannini does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics

approvedby the European Medicines Agency.

Dr Ferrannini does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics

not approvedby the European Medicines Agency.

Panel is ts

Georg e L. Bakr is, MD

Professor of Medicine; Director, Hypertensive Diseases Unit, University of Chicago Pritzker School of Medicine,

Chicago, Illinois

Disclosure: George L. Bakris, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Abbott Laboratories; CVRx, Inc.; Medtronic, Inc.; Takeda

Pharmaceuticals North America, Inc.

Served as a speaker or a member of a speakers bureau for: Takeda Pharmaceuticals North America, Inc.

Received grants for clinical research from: Forest Laboratories, Inc.; Novartis Pharmaceuticals Corporation

Dr Bakris does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approvedby the European Medicines Agency.

Dr Bakris does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not


Bernard Charbonne l , MD

Professor of Endocrinology and Metabolic Diseases; Head of Internal Medicine, Endocrinology, and Diabetes,

University of Nantes, Nantes, France

Disclosure: Bernard Charbonnel, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: AstraZeneca Pharmaceuticals LP; Boehringer Ingelheim

Pharmaceuticals, Inc.; Bristol-Myers Squibb Company; Eli Lilly and Company; GlaxoSmithKline; Merck Sharp &

Dohme Corp.; Novartis Pharmaceuticals Corporation; Novo Nordisk; Roche; sanofi-aventis; Takeda

Pharmaceuticals North America, Inc.

Served as a speaker or a member of a speakers bureau for: AstraZeneca Pharmaceuticals LP; BoehringerIngelheim Pharmaceuticals, Inc.; Bristol-Myers Squibb Company; Eli Lilly and Company; GlaxoSmithKline;

Merck Sharp & Dohme Corp.; Novartis Pharmaceuticals Corporation; Novo Nordisk; Roche; sanofi-aventis;

Takeda Pharmaceuticals North America, Inc.



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Dr Charbonnel does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics


Dr Charbonnel does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics

not approvedby the European Medicines Agency.

Mark E. Cooper , MBBS, PhD

Deputy Director and Chief Scientific Officer, Baker IDI Heart & Diabetes Institute, Melbourne, Australia

Disclosure: Mark E. Cooper, MBBS, PhD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Boehringer Ingelheim Pharmaceuticals, Inc.Served as a speaker or a member of a speakers bureau for: Merck & Co., Inc.; SERVIER

Dr Cooper does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics


Dr Cooper does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not


Edi tor

Anne M. Sendayd iego, Pharm D

Scientific Director, WebMD Global, LLC

Disclosure: Anne M. Sendaydiego, PharmD, has disclosed no relevant financial relationships.

St e e r i n g Co m m i t t e e

Anthony Ba rne t t , MD

Emeritus Professor of Medicine, University of Birmingham; Consultant Physician, Diabetes Centre, Heart of

England NHS Foundation Trust, Birmingham, United Kingdom

Disclosure: Anthony Barnett, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Boehringer Ingelheim Pharmaceuticals, Inc.; Eli Lilly and Company;



Served as a speaker or a member of a speakers bureau for: Boehringer Ingelheim Pharmaceuticals, Inc.; Eli

Lilly and Company; Merck Sharp & Dohme Corp.; Novartis Pharmaceuticals Corporation; Novo Nordisk; Roche;

sanofi-aventis; Takeda Pharmaceuticals North America, Inc.

Received grants for clinical research from: Boehringer Ingelheim Pharmaceuticals, Inc.; Eli Lilly and Company;



Mark E. Cooper , MBBS, PhD

Deputy Director and Chief Scientific Officer, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia



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Disclosure: As listed above.

Viv ian A. Fonseca, MD, FRCP

Professor of Medicine and Pharmacology; Tullis-Tulane Alumni Chair in Diabetes; Chief, Section of

Endocrinology, Tulane University Health Sciences Center, New Orleans, Louisiana, USA

Disclosure: Vivian A. Fonseca, MD, FRCP, has disclosed the following relevant financial relationships:Served as an advisor or consultant for: Abbott Laboratories; AstraZeneca Pharmaceuticals LP; Bristol-Myers

Squibb Company; Daiichi Sankyo, Inc.; Eli Lilly and Company; GlaxoSmithKline; Novo Nordisk; Pamlab, L.L.C.;

sanofi-aventis; Takeda Pharmaceuticals North America, Inc.; XOMA LLC

Per-Henr ik Groop, MD, DMSc

Professor of Nephrology, Division of Nephrology, Helsinki University Central Hospital, Helsinki, Finland

Disclosure: Per-Henrik Groop, MD, DMSC, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Abbott Laboratories; Boehringer Ingelheim Pharmaceuticals, Inc.; Cebix

Incorporated; Eli Lilly and Company; Novartis Pharmaceuticals Corporation

Served as a speaker or a member of a speakers bureau for: Boehringer Ingelheim Pharmaceuticals, Inc.; EliLilly and Company; Genzyme Corporation; Merck Sharp & Dohme Corp.; Novartis Pharmaceuticals Corporation;

Novo Nordisk

Received grants for clinical research from: Eli Lilly and Company; Roche

Michael A. Nauck , MD, PhD

Professor of Internal Medicine; Head, Specialist Centre for Diabetes and Metabolic Diseases, Diabetes Centre,

Bad Lauterberg, Germany

Disclosure: Michael A. Nauck, MD, PhD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Amylin Pharmaceuticals, Inc.; AstraZeneca Pharmaceuticals LP; Berlin-

Chemie AG; Boehringer Ingelheim Pharmaceuticals, Inc.; Bristol-Myers Squibb Company; DiartisPharmaceuticals; Eli Lilly and Company; F. Hoffmann-La Roche Ltd; GlaxoSmithKline; Intarcia

Therapeutics, Inc.; MannKind Corporation; Merck Sharp & Dohme Corp.; Novartis Pharmaceuticals Corporation;

Novo Nordisk; sanofi-aventis; Takeda Pharmaceuticals North America, Inc.; Versartis, Inc.; Wyeth

Pharmaceuticals Inc.

Andr e J. Scheen, MD, PhD

Division of Diabetes, Nutrition and Metabolic Disorders and Clinical Pharmacology Unit, Department of

Medicine, Centre Hospitalier Universitaire de Lige, University of Lige, Lige, Belgium

Disclosure: Andre J. Scheen, MD, PhD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Company; Eli

Lilly and Company; GlaxoSmithKline; Merck Sharp & Dohme Corp.; Novartis Pharmaceuticals Corporation;

Novo Nordisk; Pfizer Inc.; sanofi-aventis; SERVIER

Served as a speaker or a member of a speakers bureau for: AstraZeneca Pharmaceuticals LP; Bristol-Myers

Squibb Company; Eli Lilly and Company; GlaxoSmithKline; Merck Sharp & Dohme Corp.; Novartis

Pharmaceuticals Corporation; Novo Nordisk; Pfizer Inc.; sanofi-aventis; SERVIER

Received grants for clinical research from: Novo Nordisk.

Jite n P. Vor a, MD, FRCP

Professor of Medicine; Consultant Physician and Endocrinologist, Royal Liverpool University Hospitals,

Liverpool, United Kingdom

Disclosure: Jiten P. Vora, MD, FRCP, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Abbott Laboratories; Eli Lilly and Company; Merck Sharp & Dohme



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Corp.; Novartis Pharmaceuticals Corporation; Novo Nordisk; sanofi-aventis

Served as a speaker or a member of a speakers bureau for: Abbott Laboratories; Eli Lilly and Company; Merck

Sharp & Dohme Corp.; Novartis Pharmaceuticals Corporation; Novo Nordisk; sanofi-aventis

Received grants for clinical research from: Abbott Laboratories; Eli Lilly and Company; Merck Sharp & Dohme

Corp.; Novartis Pharmaceuticals Corporation; Novo Nordisk; sanofi-aventis

Cont en t Rev iewer

Nafeez Zaw ahir , MD

CME Clinical Director

Disclosure: Nafeez Zawahir, MD has disclosed no relevant financial relationships.

Eleuterio Ferrannini, MD; George L. Bakris, MD; Bernard Charbonnel, MD; Mark E. Cooper, MBBS, PhD

Sl ide 1 .

Eleuterio Ferrannini, MD: Hello, and welcome to Type 2 Diabetes and Chronic Kidney Disease: What Are the

Risks? What Are the Treatments Options?I am Eleuterio Ferrannini, Professor of Internal Medicine and Chief of

the Metabolism Unit at the National Research Council Institute of Clinical Physiology at the University of Pisa

School of Medicine in Pisa, Italy.

For this program, I am joined by George L. Bakris, MD, Professor of Medicine and Director of the Hypertensive

Diseases Unit at the University of Chicago Pritzker School of Medicine in Chicago, Illinois; Bernard Charbonnel,

MD, Professor of Endocrinology and Metabolic Diseases at the University of Nantes, in Nantes, France; andMark E. Cooper, MBBS, PhD, Deputy Director and Chief Scientific Officer at the Baker IDI Heart & Diabetes

Institute in Melbourne, Australia.

CME Released: 08/21/2012; Valid for credit through 08/21/2013



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Sl ide 2 .

In this program, we will be discussing the prevalence of renal dysfunction in patients with type 2 diabetes

mellitus (T2DM), the morbidity and mortality associated with renal impairment, the appropriate use of a

laboratory test to screen and diagnose diabetes patients with renal impairment, the role of glycemic control to

prevent or delay a decline in renal function, and novel treatment options to manage hyperglycemia in diabetes

patients with or at risk for renal dysfunction.

Mark, how significant is the problem of renal dysfunction in patients with T2DM?



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Sl ide 3 .

Mark E. Cooper, MBBS, PhD: People with T2DM often have chronic kidney disease (CKD). As the incidence of

T2DM increases, so will the incidence and prevalence of CKD. In patients with end-stage renal disease (ESRD),

diabetic nephropathy remains the most common cause. Furthermore, in people with T2DM, CKD is a major risk

factor for premature morbidity and mortality; these patients are more likely to have complications including

retinopathy, cardiovascular disease (CVD), and lower-limb amputation.



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Sl ide 4 .

The prevalence of CKD in people with T2DM was measured in the Developing Education on Microalbuminuria

for Awareness of Renal and Cardiovascular Risk in Diabetes (DEMAND) study. In a sample of over 20,000

T2DM patients from 33 countries, the prevalence of microalbuminuria, a feature of early diabetic renal disease,

was almost 40%. 10% of patients had macroalbuminuria, indicating more overt renal disease. Thus,

approximately 50% of T2DM patients evaluated in this study had some degree of renal dysfunction. In addition,

22% of patients in the study (with available data), has an estimated glomerular filtration rate (eGFR) less than 60mL/min/1.73 m2.

Sl ide 5 .

People with T2DM and comorbid CKD are at a particularly high risk of experiencing adverse cardiovascular (CV)

events. In patients with CKD, the prevalence of heart failure and myocardial infarction (MI) is doubled compared

to those patients without CKD.



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Sl ide 6 .

An important clinical problem in people with CKD is that they are at increased risk of experiencing

hypoglycemia. In a pooled study of 3 randomized clinical trials, the incidence of investigator-reported

hypoglycemia and severe hypoglycemia (ie, hypoglycemia that required assistance) both increased with

decreasing eGFR.

Sl ide 7 .

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Dr Ferrannini: I would like to introduce a patient case. John is a 69-year-old white man. He is retired, recently

relocated to your city, and is now seeking a new primary care physician. His past medical history includes T2DM

for approximately 3 years and dyslipidemia for approximately 10 years. He had a right total knee replacement

about 1 year ago. John has a positive family history for T2DM.

Sl ide 8 .

Clinical findings include a body mass index 28.8 kg/m2, blood pressure (BP) of 115/80 mmHg, and a heart rate

is 70 beats/minute. Laboratory measurements include a glycosylated hemoglobin (HbA1c) of 7.8%, total

cholesterol (TC) of 186 mg/dL, low-density lipoprotein cholesterol (LDL-C) of 100 mg/dL, a high-density

lipoprotein-cholesterol (HDL-C) of 45 mg/dL, and triglycerides (TG) of 150 mg/dL. His currents medications

include metformin, 1 g twice daily, rosuvastatin 40 mg once daily, and naproxen 500 mg twice daily.

This patient has not had diabetes for very long. Is it important to document his renal function at this stage?



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Sl ide 9 .

George L. Bakris, MD: It is very important to document this patient's renal function, as his kidney function is

going to be a clear determinant of his CV risk. In a group of over 1 million people within a large, integrated

system of healthcare delivery in the US, the association between renal function and risk of death and CV events

was measured. In this study, both the risk of death and CV events increased as the eGFR decreased below 60

mL/min/1.73 m2. It is critically important to find out what his eGFR is, because it will give you an estimate of hisCV risk.



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Sl ide 10.

Documenting a patient's kidney function also can give you a better estimate of a patient's prognosis. Kidney

Disease: Improving Global Outcomes (KDIGO) initiated a collaborative meta-analysis to examine the

relationship of eGFR to mortality and kidney outcomes. On the basis of analyses in 45 cohorts that included

1,555,332 participants from general, high-risk, and kidney disease populations, KDIGO provided a ranking of

relative risk according to eGFR. In addition, KDIGO retained the current definition for CKD to be an eGFR

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Sl ide 12.

Dr Bakris: The International Diabetes Federation (IDF) and the National Institute for Health and Clinical

Excellence (NICE) clinical guidelines recommend screening all people with T2DM annually for renal dysfunction

staring at diabetes diagnosis. At that time, serum creatinine (SCr) should be measured and the degree of

albuminuria should be categorized. GFR can be estimated from the measure SCr using an equation such as the

Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation, which is the latest iteration of theModification of Diet in Renal Disease equation. The CKD-EPI equation provides a good estimate of GFR,

especially over a wide-range of GFRs (ie, between 20 and 70 mL/min/1.73 m2).

Blood pressure and glycemic control are important determinants of CKD.



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Sl ide 13.

It is also important to remember that microalbuminuria by itself, in the absence of any other laboratory/clinical

abnormality, does not signify kidney disease. It does, however, signify an increased inflammatory state that

could be associated with kidney disease in the future and will need to be monitored over time. Thus, national

guidelines recommend to categorize the degree of albuminuria by measuring urinary albumin excretion

annually.

Dr Ferrannini: Is it important to look for changes over time?

Dr Bakris: Yes, absolutely.

Dr Ferrannini: How important is adequate glycemic control our patient, or any patient with or at risk for reduced

renal function?



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Sl ide 14.

Bernard Charbonnel, MD: Hyperglycemia is a critical factor for the development of microvascular

complications, including nephropathy in people with T2DM. It is why early attainment of tight glycemic control in

diabetes patients is critical for reducing the risk of nephropathy and preventing further renal damage.

Sl ide 15.



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In the United Kingdom Prospective Diabetes Study (UKPDS), which evaluated newly diagnosed T2DM patients,

microvascular complications occurred more frequently in patients with higher HbA1c, illustrating the benefit of

tight glycemic control in people with T2DM. In fact, for example, every 1% decrease in HbA1c obtained in this

study, a 37% reduction in microvascular endpoints, including nephropathy and retinopathy, was observed.

Sl ide 16.

Similarly, in a population-based cohort study in Canada, which evaluated T2DM patients with established

nephropathy (eGFR less than 60 mL/min), improved glycemic control was associated with a lower risk of ESRD.



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Sl ide 17.

It is important to realize that it takes time for improvements in microalbuminuria to result with glucose control in

people with T2DM. In the UKPDS study, significant reductions in microalbuminuria were not noted until after 9

years of good glycemic control, thus, highlighting the importance of providing early and consistent

hyperglycemic treatment in T2DM patients with, or at risk for, renal dysfunction.

Sl ide 18.



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In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, intensive glycemic control was

associated with reductions in albuminuria. In over 10,000 patients with T2DM, intensive glycemic treatment

(HbA1c less than 6.0%) reduced the risk for microalbuminuria by 15% and the risk for macroalbuminuria by 28%

compared with standard glycemic therapy (HbA1c 7.0%-7.9%). Improvements in SCr were not observed in the

ACCORD study, possibly due to the relatively short duration of the study.

Sl ide 19.

Similarly, in the ADVANCE study, patients achieving intensive glucose control (HbA1c less than 6.5%) had

reductions in microalbuminuria incidence and macroalbuminuria incidence as well as a reduced risk for renal

function worsening and ESRD compared with patients achieving standard glucose control (HbA1c of 7.3%).



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Sl ide 20.

An HbA1c goal of less than 7% is generally recommended in most people with T2DM. However, as outlined by

the recent American Diabetes Association/European Association for the Study of Diabetes Position Statement

on the management of hyperglycemia in type 2 diabetes, less stringent goals (eg, 7.5%-8.0%) may be

appropriate for patients with a long duration of disease, history of severe hypoglycemia, limited life expectancy,

advanced complications, extensive comorbid conditions, and in those in whom the target is difficult to attain.

Dr Ferrannini: Our patient does not have hypertension; however, how important is blood pressure (BP) control,

in general, in diabetes patients with, or at risk for, reduced renal function?



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Sl ide 21.

Dr Bakris: BP control is very important. In an analysis of long-term clinical trials in patients with diabetic or

nondiabetic kidney disease, lower achieved systolic BP (down to levels around 132-134 mm Hg) was associated

with greater preservations of kidney function (ie, eGFR).

For many years the recommended BP goal in people with T2DM was less than 130/80 mm Hg. Unfortunately,however, this endpoint has not been achieved in many randomized clinical trials studying patients with diabetic

and nondiabetic kidney disease. Systolic BP between 130 and 140 mm Hg has been achieved, which results in

a slowing, but not halting of renal disease progression. Under optimal circumstances, the average reduction in

eGFR is approximately 3-4 mL/min in people with diabetic nephropathy. Clearly is it important to control BP in

order to preserve renal function.



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Sl ide 22.

The UKPDS demonstrated that reducing BP results in significant beneficial effects in people with T2DM. Tight

BP control (144/82 mm Hg) was associated with reductions in diabetes-related death, all-cause mortality, MI,

stroke, and microalbuminuria compared with patients that achieved less-tight BP control (154/87 mm Hg).

Benefits were observed in people with a systolic BP of 144 mm Hg, which is above the recommended goal BP

of less than 130 mm Hg.



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Sl ide 23.

Dr Ferrannini: Let us now return to our patient, John. His SCr was 1.5 mg/dL, which translates to an eGFR of

46 mL/min/1.73 m2. His albumin:creatinine ratio is 60 mg/g creatinine.

What considerations would you make in selecting an antihyperglycemic regimen in this or another diabetes

patient with some degree of kidney disease?

Sl ide 24.

Dr Charbonnel: The first topic that I would like to discuss is the use of metformin in diabetes patients with CKD.

Metformin is the usual first-line agent to use when lifestyle modifications have failed to control hyperglycemia.

However, metformin is eliminated via the kidneys and some (rare) cases of lactic acidosis have been reported

with in diabetes patients with CKD.

Metformin is a safe hypoglycemic agent to use in T2DM patients with CKD. Alternative antihyperglycemic agents

are associated with greater safety concerns. Sulfonylureas and insulin are associated with severe hypoglycemia

and thiazolidinediones are associated with fluid retention.



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Sl ide 25.

A critical review of the literature supports the safe use of appropriate doses of metformin in diabetes patients

with renal impairment. Metformin can be used safely in diabetes patients with eGFR of 30-60 mL/min. Dose

reduction should be considered in patients with eGFR lower than 45 mL/min. Metformin should not be used in

patients with eGFR higher than 30 mL/min.

Sl ide 26.



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Other traditional antihyperglycemic agents, including sulfonylureas, glinides, thiazolidinediones, and insulin are

available to treat hyperglycemia in patients with T2DM. Sulfonylureas are primarily eliminated via the kidneys.

Sulfonylureas are also associated with a high risk of hypoglycemia. Therefore, since the risk of hypoglycemia is

increased in patients with CKD, the risk of hypoglycemia will be even higher in those diabetes patients taking a

sulfonylurea with concomitant renal impairment. Patients should be monitored closely for signs and symptoms of

hypoglycemia.

First-generation sulfonylureas should be avoided in diabetes patients with renal impairment. With respect to the

second-generations sulfonylureas, shorter-acting agents are preferred compared with longer-acting agents.

Glinides are primarily eliminated via the cytochrome P450 system and therefore can be used in CKD patients

without dose adjustments.

When using a thiazolidinedione such as pioglitazone, the dose does not need to be adjusted in patients with

renal impairment. Fluid retention, however, is common with these agents and, therefore, fluid status must be

carefully monitored in these patients.

Insulin is often used in diabetes patients with CKD, however, insulin is degraded by the kidneys, which may

result in a higher risk of hypoglycemia. Insulin doses must be carefully titrated to avoid excess hypoglycemia indiabetes patients with renal impairment.

Sl ide 27.

When using many different antihyperglycemic agents, adjustment in the dose for renal function is required. A

clear unmet need exists for safe and efficacious antihyperglycemic therapies, ideally without the need for dose

adjustments that can be used in diabetes patients with CKD.



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Sl ide 28.

In patients with T2DM, incretin-based agents provide clinically important reductions in HbA1c with a low risk for

hypoglycemia and neutral or beneficial effects on body weight. While, several clinical and practical differences

exist between dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists,

either class may be considered for hyperglycemia treatment in diabetes patients with CKD.

Dr Ferrannini: The potential role of DPP-4 inhibitors in the treatment of diabetes patients with renal dysfunction

has been mentioned. What are some of the differences between the available DPP-4 inhibitors?



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Sl ide 29.

Dr Cooper: DPP-4 inhibitors are effective in reducing HbA1c levels. However, as most are renally excreted,

caution is needed when selecting them for treatments in patients with CKD, as dose adjustment may be needed.

Sl ide 30.

The importance of this is as can be seen in this slide, is that linagliptin, for example, has only less than 5% renal

excretion, whereas the other gliptins are at least 50 and up to almost 90% cleared by the kidneys; therefore, if



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you have a person with renal impairment, you have a potential for accumulation of some of these DPP-4

inhibitors and therefore dose adjustment or contraindication is sometimes needing to be considered.

Fortunately, we have one DPP-4 inhibitor, linagliptin, which does not need the dose altered with people with low

GFR, and so this is clearly an appropriate drug to consider with chronic kidney disease.

Sl ide 31.

Linagliptin has been shown to effectively reduce HbA1c in diabetes patients with no, mild, or moderate renal

impairment. A similar reduction in HbA1c (approximately 0.6%) is observed in all three patient populations,

which is consistent with the glucose reductions observed with other DPP-4 inhibitors.



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Sl ide 32.

Dr Ferrannini: In summary, impairment of renal function is much more common in people with T2DM than

previously considered, especially as the diabetes population ages. Even in patients with a short duration of

diabetes disease, there is a need to assess renal function. Serum creatinine, eGFR, and degree of proteinuria

should be monitored regularly over the duration of patients' T2DM.

Adequate control of BP is important to preserve renal function in people with T2DM. While a BP of less than

130/80 mm Hg is currently recommended in T2DM patient, this level of control is often difficult to achieve. In

general, therefore, the lowest level of BP that does not induce side effects or complications should be the goal.



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Sl ide 33.

It is equally critical to achieve adequate glycemic control to preserve renal function in people with T2DM. An

HbA1c of less than 7.0% is recommended for most patients, however, this goal should be individualized

according to patient needs and factors.

Several different classes of antihyperglycemic agents are available to treat people with T2DM. It is important toselect agents that effectively reduce blood glucose without exposing the patient to unnecessary safety risks.

Traditional antihyperglycemic agents are often associated with clinical challenges, including hypoglycemia with

sulfonylureas, fluid retention with thiazolidinediones, as well as the need for dosage adjustments in patients with

renal dysfunction.

DPP-4 inhibitors are new, incretin-based therapies available to treat hyperglycemia in people with T2DM.

Generally speaking, DPP-4 inhibitors are very well-tolerated and efficacious drugs; however, pharmacokinetic

differences exist between the available agents. Sitagliptin, saxagliptin, and vildagliptin are primarily eliminated

via the kidneys. These agents are either not recommended in patients with renal dysfunction or their doses must

be adjusted based on the degree of renal dysfunction in the patient. Linagliptin is primarily eliminated by

hepatic/nonrenal routes of elimination, therefore dose adjustments are not required in patients with mild,moderate, or severe CKD.



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Sl ide 34.

Thank you for viewing this program. We hope that you found it interesting and that the information will help you

manage your diabetes patients who have, or are at risk for, CKD.

This transcript has been edited for style and clarity.


Disclaimer

The information contained in this activity is provided for general medical education purposes only and is notmeant to substitute for the independent medical judgment of a physician relative to diagnostic and treatmentoptions for a specific patient's medical condition. The viewpoints expressed in this activity are those of theauthors/faculty and do not necessarily reflect the views of WebMD Global LLC, its affiliated companies or anycompany that supports educational programming on www.medscape.org. You should exercise your professionaljudgment in evaluating these materials and consult other relevant sources before undertaking any treatmentbased on these materials. Please consult your local prescribing information prior to making any treatment

decisions based on information contained in this educational activity.

Medscape Education 2012 WebMD Global, LLC



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