Can J Diabetes 38 (2014) 334e343
Contents lists available at ScienceDirect
Canadian Journal of Diabetes journal homepage: www.canadianjournalofdiabetes.com
Review
Optimal Medication Dosing in Patients with Diabetes Mellitus and Chronic Kidney Disease Lori MacCallum BScPhm, PharmD, RPh * Sun Life Financial Professor of Wellness and Diabetes Education, Banting and Best Diabetes Centre, Faculty of Medicine and Assistant Professor, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
a r t i c l e i n f o
a b s t r a c t
Article history: Received 11 March 2014 Received in revised form 24 April 2014 Accepted 28 April 2014
Diabetes mellitus is the leading cause of chronic kidney disease (CKD) in Canada. As rates of diabetes rise, so does the prevalence of CKD. Diabetes and CKD are chronic diseases that require multiple medications for their management. Many of the anticipated effects of these medications are altered by the physiologic changes that occur in CKD. Failure to individualize drug dosing in this population may lead to toxicity or decreased therapeutic response, leading to treatment failure. At times this can be challenging for a multitude of reasons, including the limitations of available calculations for estimating renal function, inconsistent dosing recommendations and the lack of dosing recommendations for some medications. Clinicians caring for these patients need to consider an approach of individualized drug therapy that will ensure optimal outcomes. The better understanding that clinicians have of these challenges, the more effective they will be at using the available information as a guide together with their own professional judgement to make appropriate dosing changes. This article discusses the following: 1) physiologic changes that occur in CKD and its impact on drug dosing; 2) advantages and disadvantages of various calculations used for estimating renal function; 3) pharmacokinetic and pharmacodynamic changes of some commonly used medications in diabetes, and finally, 4) an approach to individualized drug dosing for this patient population. Ó 2014 Canadian Diabetes Association
Keywords: chronic kidney disease diabetes medication dosing renal impairment
r é s u m é Mots clés : néphropathie chronique diabète posologie atteinte rénale
Le diabète sucré est la cause principale de la néphropathie chronique (NC) au Canada. Les taux de diabète augmentent, tout comme la prévalence de la NC. Le diabète et la NC sont des maladies chroniques pour lesquelles le traitement exige de nombreux médicaments. Plusieurs des effets anticipés de ces médicaments sont altérés par les modifications physiologiques apparaissant au cours de la NC. Le fait de ne pas individualiser la posologie chez cette population peut mener à l’échec thérapeutique en raison d’une toxicité ou d’une diminution de la réponse thérapeutique. Parfois, cela pose tout un défi pour une multitude de raisons, notamment les limites des calculs disponibles pour estimer le fonctionnement rénal, les recommandations contradictoires de posologie et le manque de recommandations sur la posologie de certains médicaments. Les cliniciens soignant ces patients doivent envisager une approche de pharmacothérapie individualisée qui garantira des résultats optimaux. Plus la compréhension des cliniciens sur ces difficultés sera bonne, plus ils seront efficaces pour utiliser l’information disponible conjointement à leur jugement professionnel pour faire des changements appropriés de posologie. Cet article traite : 1) des modifications physiologiques apparaissant au cours de la NC et de leurs conséquences sur la posologie; 2) des avantages et des désavantages des divers calculs utilisés pour estimer le fonctionnement rénal; 3) des modifications pharmacocinétiques et pharmacodynamiques de certains des médicaments communément utilisés lors de diabète; 4) d’une approche d’individualisation de la posologie pour traiter cette population de patients. Ó 2014 Canadian Diabetes Association
Introduction * Address for correspondence: Lori MacCallum, BScPhm, PharmD, RPh, Banting and Best Diabetes Centre, 200 Elizabeth Street, Room 12E252, Toronto, Ontario M5G 2C4, Canada. E-mail address: [email protected] 1499-2671/$ e see front matter Ó 2014 Canadian Diabetes Association http://dx.doi.org/10.1016/j.jcjd.2014.04.006
Chronic kidney disease (CKD) and diabetes mellitus are both increasing in prevalence. Diabetes continues to be the leading cause of CKD in Canada, identified in 38% of new cases in 2012 (1).
L. MacCallum / Can J Diabetes 38 (2014) 334e343
Currently, more than 50% of patients receiving dialysis in Canada have a diagnosis of diabetes (1). Diabetic nephropathy is the most common form of CKD in people with diabetes. However, other forms of kidney disease may develop as well, and as many as 50% of people with diabetes will have signs of kidney damage in their lifetime (2). In view of the large number of patients who have diabetes and CKD, clinicians need to familiarize themselves with the unique needs of this population as it relates to drug dosing. Physiologic changes that occur with CKD can have an impact on drug therapy by altering both pharmacokinetics and pharmacodynamics. Pharmacokinetics refers to what the body does to the drug in terms of absorption, distribution, metabolism and excretion. Pharmacodynamics refers to what the drug does to the body. In addition, patients receiving hemodialysis and continuous ambulatory peritoneal dialysis may require supplemental dosing owing to removal of drugs during dialysis. Failure to individualize drug therapy for people with kidney disease can result in toxicity or decreased therapeutic response. An approach to therapy that includes critical assessment of both patient and drug characteristics is essential to ensure optimal patient outcomes.
Pharmacokinetic Changes in CKD The excretion of drugs by the kidneys is the net result of 3 processes, all of which take place in the nephron: glomerular filtration, tubular secretion and tubular reabsorption. During glomerular filtration, small molecular weight drugs and those not bound to plasma proteins filter from the blood into Bowman’s capsule and are eliminated in the urine. Large molecular weight drugs or those bound to plasma proteins cannot be filtered and are poorly excreted by glomerular filtration. Tubular secretion is an active process that is responsible for the elimination of most drugs. It involves 2 carrier systems: basic carriers that transport basic drugs and acidic carriers for acidic drugs. Finally, tubular reabsorption is a passive process whereby the flow of drug back into the blood occurs because water is resorbed from the kidney tubules by diffusion, and some drugs are transported along with it. With CKD, reduced renal excretion of parent drug and/or its metabolites as a result of decreased filtration and secretion can lead to accumulation, necessitating a decrease in drug dosage to prevent toxicity (3). In CKD, the volume of distribution of many drugs is increased because of volume expansion, reduced plasma protein binding and increased tissue binding (3). Volume of distribution is a proportionality constant that relates the plasma concentration to the amount of drug in the body and is used to determine the loading dose (see equations below). In some cases, a measurement of total drug concentration may be misleading. Monitoring unbound drug concentration may be necessary, especially for drugs that have a narrow therapeutic range, are highly protein bound and have variability in the free fraction of drug (e.g. phenytoin). The kidneys are also responsible for the metabolism of some drugs, and that can be altered in persons with CKD. Generally, metabolism in the kidneys leads to a metabolite that is more readily excreted in the urine (4). There is also a growing body of literature demonstrating that non-renal clearance (gastrointestinal and hepatic drug metabolism) is reduced in people with CKD because of changes in efflux transporters, as well as cytochrome P450 (CYP) enzymes in the liver and other organs (3).
Amount of drug in body ¼ VD plasma concentration; where VD is volume of distribution.
Loading dose ¼ desired CpSS VD patient’s weight; where CpSS is desired plasma drug concentration at steady state.
335
Table 1 Chronic kidney disease staging GFR category
GFR (mL/min/1.73m2)
Terms
G1 G2 G3a G3b G4 G5
90 60e89 45e59 30e44 15e29 60 mL/min Meormin
No dose adjustment
CKD 3 eGFR 30-59 mL/min
CKD 4 eGFR 15-29 mL/min
Reduce dose
Use alternave agent
Alpha-glucosidase Inhibitor Acarbose No dose No dose adjustment adjustment DPP-4 Inhibitors
Linaglipn
No dose adjustment
Sitaglipn
No dose adjustment
GLP-1 Receptor Agonists Exenade No dose adjustment Liraglude No dose adjustment Meglinides Nateglinide Repaglinide Sulfonylureas
Glimepiride
Glyburide
Canagliflozin
Lower dose 2.5 mg once Use daily alternave ( < 50 mL/min) agent. Use lowest dose Lower dose (50 mg (25 mg daily) daily) (30-49 mL/min)
Experience in paents with endstage renal disease or on dialysis is limited. Use with cauon in these paents. Should not be used in paents on dialysis. Risk of accumulaon
No dose adjustment required No dose adjustment required Risk of hypoglycemia, consider lower dose
Risk of hypoglycemia, consider lower dose
No dose adjustment
No dose adjustment
No dose adjustment
Risk of drug accumulaon with declining renal funcon, especially if acute.
Lower dose Use alternave agent (5 mcg bid) Use alternave agent (
Contents lists available at ScienceDirect
Canadian Journal of Diabetes journal homepage: www.canadianjournalofdiabetes.com
Review
Optimal Medication Dosing in Patients with Diabetes Mellitus and Chronic Kidney Disease Lori MacCallum BScPhm, PharmD, RPh * Sun Life Financial Professor of Wellness and Diabetes Education, Banting and Best Diabetes Centre, Faculty of Medicine and Assistant Professor, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
a r t i c l e i n f o
a b s t r a c t
Article history: Received 11 March 2014 Received in revised form 24 April 2014 Accepted 28 April 2014
Diabetes mellitus is the leading cause of chronic kidney disease (CKD) in Canada. As rates of diabetes rise, so does the prevalence of CKD. Diabetes and CKD are chronic diseases that require multiple medications for their management. Many of the anticipated effects of these medications are altered by the physiologic changes that occur in CKD. Failure to individualize drug dosing in this population may lead to toxicity or decreased therapeutic response, leading to treatment failure. At times this can be challenging for a multitude of reasons, including the limitations of available calculations for estimating renal function, inconsistent dosing recommendations and the lack of dosing recommendations for some medications. Clinicians caring for these patients need to consider an approach of individualized drug therapy that will ensure optimal outcomes. The better understanding that clinicians have of these challenges, the more effective they will be at using the available information as a guide together with their own professional judgement to make appropriate dosing changes. This article discusses the following: 1) physiologic changes that occur in CKD and its impact on drug dosing; 2) advantages and disadvantages of various calculations used for estimating renal function; 3) pharmacokinetic and pharmacodynamic changes of some commonly used medications in diabetes, and finally, 4) an approach to individualized drug dosing for this patient population. Ó 2014 Canadian Diabetes Association
Keywords: chronic kidney disease diabetes medication dosing renal impairment
r é s u m é Mots clés : néphropathie chronique diabète posologie atteinte rénale
Le diabète sucré est la cause principale de la néphropathie chronique (NC) au Canada. Les taux de diabète augmentent, tout comme la prévalence de la NC. Le diabète et la NC sont des maladies chroniques pour lesquelles le traitement exige de nombreux médicaments. Plusieurs des effets anticipés de ces médicaments sont altérés par les modifications physiologiques apparaissant au cours de la NC. Le fait de ne pas individualiser la posologie chez cette population peut mener à l’échec thérapeutique en raison d’une toxicité ou d’une diminution de la réponse thérapeutique. Parfois, cela pose tout un défi pour une multitude de raisons, notamment les limites des calculs disponibles pour estimer le fonctionnement rénal, les recommandations contradictoires de posologie et le manque de recommandations sur la posologie de certains médicaments. Les cliniciens soignant ces patients doivent envisager une approche de pharmacothérapie individualisée qui garantira des résultats optimaux. Plus la compréhension des cliniciens sur ces difficultés sera bonne, plus ils seront efficaces pour utiliser l’information disponible conjointement à leur jugement professionnel pour faire des changements appropriés de posologie. Cet article traite : 1) des modifications physiologiques apparaissant au cours de la NC et de leurs conséquences sur la posologie; 2) des avantages et des désavantages des divers calculs utilisés pour estimer le fonctionnement rénal; 3) des modifications pharmacocinétiques et pharmacodynamiques de certains des médicaments communément utilisés lors de diabète; 4) d’une approche d’individualisation de la posologie pour traiter cette population de patients. Ó 2014 Canadian Diabetes Association
Introduction * Address for correspondence: Lori MacCallum, BScPhm, PharmD, RPh, Banting and Best Diabetes Centre, 200 Elizabeth Street, Room 12E252, Toronto, Ontario M5G 2C4, Canada. E-mail address: [email protected] 1499-2671/$ e see front matter Ó 2014 Canadian Diabetes Association http://dx.doi.org/10.1016/j.jcjd.2014.04.006
Chronic kidney disease (CKD) and diabetes mellitus are both increasing in prevalence. Diabetes continues to be the leading cause of CKD in Canada, identified in 38% of new cases in 2012 (1).
L. MacCallum / Can J Diabetes 38 (2014) 334e343
Currently, more than 50% of patients receiving dialysis in Canada have a diagnosis of diabetes (1). Diabetic nephropathy is the most common form of CKD in people with diabetes. However, other forms of kidney disease may develop as well, and as many as 50% of people with diabetes will have signs of kidney damage in their lifetime (2). In view of the large number of patients who have diabetes and CKD, clinicians need to familiarize themselves with the unique needs of this population as it relates to drug dosing. Physiologic changes that occur with CKD can have an impact on drug therapy by altering both pharmacokinetics and pharmacodynamics. Pharmacokinetics refers to what the body does to the drug in terms of absorption, distribution, metabolism and excretion. Pharmacodynamics refers to what the drug does to the body. In addition, patients receiving hemodialysis and continuous ambulatory peritoneal dialysis may require supplemental dosing owing to removal of drugs during dialysis. Failure to individualize drug therapy for people with kidney disease can result in toxicity or decreased therapeutic response. An approach to therapy that includes critical assessment of both patient and drug characteristics is essential to ensure optimal patient outcomes.
Pharmacokinetic Changes in CKD The excretion of drugs by the kidneys is the net result of 3 processes, all of which take place in the nephron: glomerular filtration, tubular secretion and tubular reabsorption. During glomerular filtration, small molecular weight drugs and those not bound to plasma proteins filter from the blood into Bowman’s capsule and are eliminated in the urine. Large molecular weight drugs or those bound to plasma proteins cannot be filtered and are poorly excreted by glomerular filtration. Tubular secretion is an active process that is responsible for the elimination of most drugs. It involves 2 carrier systems: basic carriers that transport basic drugs and acidic carriers for acidic drugs. Finally, tubular reabsorption is a passive process whereby the flow of drug back into the blood occurs because water is resorbed from the kidney tubules by diffusion, and some drugs are transported along with it. With CKD, reduced renal excretion of parent drug and/or its metabolites as a result of decreased filtration and secretion can lead to accumulation, necessitating a decrease in drug dosage to prevent toxicity (3). In CKD, the volume of distribution of many drugs is increased because of volume expansion, reduced plasma protein binding and increased tissue binding (3). Volume of distribution is a proportionality constant that relates the plasma concentration to the amount of drug in the body and is used to determine the loading dose (see equations below). In some cases, a measurement of total drug concentration may be misleading. Monitoring unbound drug concentration may be necessary, especially for drugs that have a narrow therapeutic range, are highly protein bound and have variability in the free fraction of drug (e.g. phenytoin). The kidneys are also responsible for the metabolism of some drugs, and that can be altered in persons with CKD. Generally, metabolism in the kidneys leads to a metabolite that is more readily excreted in the urine (4). There is also a growing body of literature demonstrating that non-renal clearance (gastrointestinal and hepatic drug metabolism) is reduced in people with CKD because of changes in efflux transporters, as well as cytochrome P450 (CYP) enzymes in the liver and other organs (3).
Amount of drug in body ¼ VD plasma concentration; where VD is volume of distribution.
Loading dose ¼ desired CpSS VD patient’s weight; where CpSS is desired plasma drug concentration at steady state.
335
Table 1 Chronic kidney disease staging GFR category
GFR (mL/min/1.73m2)
Terms
G1 G2 G3a G3b G4 G5
90 60e89 45e59 30e44 15e29 60 mL/min Meormin
No dose adjustment
CKD 3 eGFR 30-59 mL/min
CKD 4 eGFR 15-29 mL/min
Reduce dose
Use alternave agent
Alpha-glucosidase Inhibitor Acarbose No dose No dose adjustment adjustment DPP-4 Inhibitors
Linaglipn
No dose adjustment
Sitaglipn
No dose adjustment
GLP-1 Receptor Agonists Exenade No dose adjustment Liraglude No dose adjustment Meglinides Nateglinide Repaglinide Sulfonylureas
Glimepiride
Glyburide
Canagliflozin
Lower dose 2.5 mg once Use daily alternave ( < 50 mL/min) agent. Use lowest dose Lower dose (50 mg (25 mg daily) daily) (30-49 mL/min)
Experience in paents with endstage renal disease or on dialysis is limited. Use with cauon in these paents. Should not be used in paents on dialysis. Risk of accumulaon
No dose adjustment required No dose adjustment required Risk of hypoglycemia, consider lower dose
Risk of hypoglycemia, consider lower dose
No dose adjustment
No dose adjustment
No dose adjustment
Risk of drug accumulaon with declining renal funcon, especially if acute.
Lower dose Use alternave agent (5 mcg bid) Use alternave agent (
