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Glycemic Management in ESRD and Earlier Stages of CKD
Mark E. Williams, MD,1 and Rajesh Garg, MD2
The management of hyperglycemia in patients with kidney failure is complex, and the goals and methods
regarding glycemic control in chronic kidney disease (CKD) are not clearly defined. Although aggressive
glycemic control seems to be advantageous in early diabetic nephropathy, outcome data supporting tight
glycemic control in patients with advanced CKD (including end-stage renal disease [ESRD]) are lacking.
Challenges in the management of such patients include therapeutic inertia, monitoring difficulties, and the
complexity of available treatments. In this article, we review the alterations in glucose homeostasis that occur
in kidney failure, current views on the value of glycemic control and issues with its determination, and more
recent approaches to monitor or measure glycemic control. Hypoglycemia and treatment options for patients
with diabetes and ESRD or earlier stages of CKD also are addressed, discussing the insulin and noninsulin
agents that currently are available, along with their indications and contraindications. The article provides
information to help clinicians in decision making in order to provide individualized glycemic goals and
appropriate therapy for patients with ESRD or earlier stages of CKD.
Am J Kidney Dis. 63(2)(S2):S22-S38. ª 2014 by the National Kidney Foundation, Inc.
INDEX WORDS: Chronic kidney disease (CKD); hyperglycemia; diabetes mellitus; hemoglobin A1c (HbA1c);
end-stage renal disease (ESRD).
EXECUTIVE SUMMARY
The management of hyperglycemia in patients with
kidney failure has special challenges. The difficulty is
due in part to the complexity of treatment and in part
to lack of convincing data supporting the benefits of
tight glycemic control. This article reviews metabolic
changes in kidney failure, current views on glycemic
goals, and treatment options for patients with diabetes
and end-stage renal disease (ESRD) or earlier stages
of chronic kidney disease (CKD).
Multifactorial alterations in glucose homeostasis
occur when kidney function declines. Insulin resistance increases in CKD due to accumulation of uremic toxins, chronic inflammation, excess visceral fat,
oxidative stress, metabolic acidosis, and vitamin D
deficiency. It generally is acknowledged that insulin
resistance is a feature of uremia, irrespective of kidney disease cause. Recent data suggest that alterations
in body metabolism with CKD may alter adipose
tissue patterns that are consistent with a more proinflammatory and insulin-resistant state. Decreased
From the 1Renal Division, Joslin Diabetes Center; and 2Division of Endocrinology, Diabetes and Hypertension, Brigham and
Women’s Hospital, Boston, MA.
Received June 5, 2013. Accepted in revised form October 8,
2013.
This article is part of a supplement that was developed with
funding from Novo Nordisk.
Address correspondence to Mark E. Williams, MD, Harvard
Medical School, Joslin Diabetes Center, 1 Joslin Pl, Boston,
MA 02215. E-mail: [email protected]
2014 by the National Kidney Foundation, Inc.
0272-6386/$36.00
http://dx.doi.org/10.1053/j.ajkd.2013.10.049
S22
adiponectin concentrations also are seen in CKD and
may contribute to the insulin resistance. Erythropoietin deficiency also may contribute to insulin resistance. Increased insulin resistance in turn may
contribute to increased risk of cardiovascular disease
in patients with CKD.
Glycemic management in patients with type 2
diabetes and CKD has become increasingly complex
over the last 2 decades. Challenges in improving
glycemic control in patients with advanced CKD
(including ESRD) include therapeutic inertia, monitoring difficulties, and the complexity of available
treatments.
According to the NKF-KDOQI (National Kidney
Foundation–Kidney Disease Outcomes Quality
Initiative) guidelines, HbA1c targets are no different in
diabetic patients with and without CKD. However, it
now is well understood that HbA1c level may overestimate glycemic control in kidney patients: HbA1c
levels appear to be lower, leading to underestimation
of hyperglycemia. A lack of correspondence in clinical studies between HbA1c level and other measures
of glycemia has inspired concerns about the validity
of the latter in predicting outcomes in patients with
advanced CKD (including ESRD). Other measures of
glycemic control, such as glycated albumin, may be
more useful in CKD. Glycated albumin increasingly
is proposed as a better measure of glycemic control in
patients with diabetes and CKD, but in patients with
nephrotic-range proteinuria, glycated albumin levels
may be falsely reduced.
No randomized clinical trial has yet evaluated the
effects of glycemic control in patients with ESRD.
Observational data from the national ESRD database
Am J Kidney Dis. 2014;63(2)(suppl 2):S22-S38
Glycemic Management in CKD and ESRD
have been contradictory, with one study showing no
impact of HbA1c level on mortality and another
showing that higher HbA1c levels are associated with
increased risk of death. Overall, the relationship between glycemic control and survival outcomes seems
weaker in the setting of ESRD. Moreover, the risk of
hypoglycemia is greater in patients with reduced
kidney function. The pathogenesis of hypoglycemia
in patients with CKD is complex and includes derangements in glucose metabolism, decreased insulin
degradation, and changes in drug metabolism. Severe
hypoglycemia is known to increase the risk of poor
clinical outcomes in patients with diabetes. Therefore,
higher glycemic targets may be appropriate in patients
with CKD with more comorbid conditions.
Regarding the treatment of hyperglycemia, insulin
traditionally has been considered the safest antidiabetic agent in the presence of kidney failure. Although
most patients need basal and nutritional insulin, it is
important to individualize the insulin regimen. Some
of the new noninsulin agents are considered safe and
efficacious, and some may even be preferable over
insulin.
Use of noninsulin agents may not only avoid the
psychological stress of insulin injections for some
patients, but also reduce the risk of hypoglycemia.
Metformin does not cause hypoglycemia; however,
it is contraindicated in patients with moderate to
severe kidney failure due to the risk of lactic
acidosis. Thiazolidinediones do not increase the risk
of hypoglycemia and are relatively safe in CKD, but
may cause fluid retention leading to heart failure.
Dipeptidyl peptidase 4 (DPP-4) inhibitors are
becoming more popular for the treatment of hyperglycemia in patients with CKD because of their
better tolerability and low risk of hypoglycemia.
Some agents (sitagliptin and saxagliptin) may need
dose adjustment for reduced estimated glomerular
filtration rate (eGFR). Long-term data for their safety
and efficacy are still lacking. Glucagon-like peptide
1 (GLP-1) receptor agonists are associated with more
severe side effects of nausea and vomiting in patients
with ESRD and may not be well tolerated. Other
drugs, such as alpha-glucosidase inhibitors, bile acid
sequestrants, dopamine 2 agonists, and amylin mimetics, are of limited use in patients with CKD.
There are few head-to-head clinical trials comparing
various antidiabetic agents, and none has been conducted in patients with CKD.
Glycemic management is complex when diabetes is
complicated by diabetic nephropathy. Although
aggressive glycemic control has been shown to alter
the clinical course of early diabetic kidney disease,
data supporting the benefits of tight glycemic control
on outcomes in patients with advanced CKD
(including ESRD) are lacking. In the absence of better
clinical trial data, glycemic management continues to
be based on individualized decision making.
INTRODUCTION
potentially could be ameliorated by correcting these
disorders.2,3
Glucose transport across the cell membrane,
mediated by specific transporter proteins, is one of the
primary actions of insulin and is thought to be the
rate-limiting step for glucose uptake in peripheral
tissues.4 In muscle and adipose tissue, insulin triggers
glucose uptake by prompting translocation of an
intracellular pool of glucose transporters to the plasma
membrane. The intracellular actions of insulin are
complicated but increasingly understood. Upon
binding of insulin to its receptor, the latter transduces
the signal by phosphorylating insulin receptor substrate 1 (IRS1) and other such substrates.5 Activation
of multiple downstream targets (glycogen synthase,
protein kinase C, and endothelial nitric oxide synthase
[eNOS] among them) leads to a broad variety of responses, including enhancement of glucose uptake,
glycogenesis, lipogenesis, and cellular proliferation.6
Recent studies have examined the mechanisms and
clinical significance of insulin resistance in CKD.
Insulin resistance in CKD is an acquired defect (due
to known risk factors such as obesity and to metabolic
abnormalities unique to uremia). Proposed determinants in CKD include accumulation of uremic
The management of hyperglycemia in patients with
kidney failure presents special challenges. The difficulty is due in part to the complexity of treatment in
these patients and in part to the lack of data supporting the benefits of tight glycemic control. Therefore, goals of treatment and methods to achieve
glycemic control in patients with chronic kidney
disease (CKD) are not clearly defined. This article
reviews metabolic changes in kidney failure, current
views about glycemic goals, and treatment options for
patients with diabetes and end-stage renal disease
(ESRD) or earlier stages of CKD.
GLUCOSE/INSULIN HOMEOSTASIS
Multifactorial alterations in glucose homeostasis
occur when kidney function declines. Factors that
contribute to the abnormalities in glucose homeostasis
in people with reduced kidney function are shown in
Fig 1. Abnormal insulin metabolism involves reduced
renal insulin clearance, which usually occurs when
CKD reaches stages 4 and 5.1 Reductions in pancreatic insulin secretion also may occur, perhaps related
to hyperparathyroidism and vitamin D deficiency, and
Am J Kidney Dis. 2014;63(2)(suppl 2):S22-S38
S23
Williams and Garg
Figure 1. Overview of glucose/
insulin homeostasis in chronic kidney
disease. Disturbances of glucose metabolism include insulin resistance and
glucose intolerance. Several factors
contribute to hyperglycemia, which may
coexist with hypoglycemia. Adapted
with permission of the National Kidney
Foundation from Kovesdy et al.134
toxins, chronic inflammation, excess visceral fat,
oxidative stress, metabolic acidosis, and vitamin D
deficiency. The specific mechanism involves steps in
the insulin receptor signaling pathway downstream of
the insulin receptor. These steps include the generation of intracellular messengers for insulin,7 glucose
transport, and effects of insulin on an intracellular
enzyme that itself functions in glucose metabolism.8
It generally is acknowledged that insulin resistance
is a characteristic feature of uremia, irrespective of
kidney disease cause. When there is insulin resistance, insulin-stimulated cellular glucose uptake is
compromised. In uremia, insulin-mediated stimulation of peripheral glucose disposal by muscle and
adipose tissue is dramatically affected, but hepatic
glucose uptake continues normally and hepatic
glucose production can be suppressed.9 Similarly, the
antiproteolytic action of insulin and its role in the
translocation of potassium into cells are not affected
in advanced kidney failure.9,10 Because insulin
sensitivity improves with initiation of dialysis therapy, uremic toxins may play a role in the derangements of insulin resistance.11,12 Some evidence
has emerged suggesting that CKD-triggered changes
in body metabolism may alter adipose tissue secretion
patterns. Released adipokines subsequently become
a key source of proinflammatory molecules, which
in turn lead to insulin resistance.13 Plasma adiponectin levels are related inversely to kidney function,
and decreased adiponectin concentrations may be
involved in insulin resistance.14 Oxidative stress also
may influence the production of proinflammatory
molecules in adipose tissue.15 Moreover, erythropoietin deficiency also could be involved in insulin
resistance, as suggested by a clinical report that
found lower mean insulin levels and HOMA-IR
S24
(Homeostasis Model Assessment–Insulin Resistance)
levels in hemodialysis patients treated with recombinant erythropoietin.16
In the setting of CKD, the clinical relevance of
insulin resistance remains incompletely understood.
However, existing evidence is consistent with insulin
resistance in uremia contributing to muscle protein
anabolism10,17 and perhaps other metabolic defects in
uremia.
Clinically, insulin resistance might be involved in
protein-energy wasting, atherosclerosis, and cardiovascular complications in patients with CKD. Recent
attention has focused on the role of insulin resistance in
protein-energy wasting.17 Even dialysis patients who
are not obese and do not have diabetes mellitus have
significant insulin resistance on account of elevated
muscle protein catabolism. The ubiquitin-proteasome
pathway, which is related to suppression of phosphatidylinositol 3 kinase, is involved in the catabolic
process.18,19 Recently, the relationship between
HOMA-IR and fasting whole-body and skeletal muscle
protein turnover was studied with a goal of determining mean skeletal muscle protein synthesis,
breakdown, and net balance in nondiabetic maintenance hemodialysis patients.20 This study found a
correlation between higher HOMA-IR and negative net
skeletal muscle protein. Another recent study, a crosssectional examination of 128 patients with diabetes
from India, looked at the extent of insulin resistance in
individuals with micro-/macroalbuminuric diabetic
kidney disease versus those with normoalbuminuria.21
Although there was no significant difference between
study groups in terms of age, body mass index, diabetes vintage, or glycemic control, mean HOMA-IR
(the measure of insulin resistance) increased with
more severe kidney disease (P , 0.0001). In reality,
Am J Kidney Dis. 2014;63(2)(suppl 2):S22-S38
Glycemic Management in CKD and ESRD
insulin resistance appears to be somewhat variable in
kidney disease, similar to what is seen in other conditions, such as type 2 diabetes and obesity, or even
what is observed in healthy individuals.22
Kidney tissues also respond to insulin, as shown by
physiologic studies. Once this hormone binds to its
receptor, a number of downstream targets (Akt
[protein kinase B], glycogen synthase kinase 3, Ras,
ERK [extracellular signal–regulated kinase], and
protein kinase C) are recruited. Following their activation, a large variety of metabolic effects are triggered. Insulin resistance in the glomerulus is much
like the insulin resistance observed in the endothelium of other vascular tissues, and it is recognized
that the actions of insulin on the glomerulus may be
blunted in the setting of diabetes.6 It has been suggested that this may be involved in the initiation and
progression of glomerular lesions in diabetes.23
Progress in understanding the development of renal
insulin resistance is ongoing. Mima et al23 performed
analyses of insulin signaling and cellular actions
involving the glomerulus and tubules, comparing
diabetic, insulin-resistant, and control states. From
this work emerged a detailed view of impaired insulin
signaling in glomeruli and tubules of diabetic and
insulin-resistant animals that suggested that a subset
of these alterations may be involved in diabetic
glomerulopathy.
Recently, the contribution of the kidneys to glucose
homeostasis by processes such as gluconeogenesis
and glucose filtration and reabsorption has been
studied in both apparently healthy individuals and
those with diabetes.24 Under normal conditions, up to
180 g/d of glucose may be filtered by the glomerulus.
Essentially all this filtered glucose is reabsorbed in
the proximal tubule because of secondary active
transport through 2 sodium-dependent glucose transporter (SGLT) proteins. Most glucose reabsorption
achieved occurs through sodium-glucose cotransporter 2 (SGLT2), which is found in the S1 segment
of the proximal tubule.25 Of note, renal reabsorption
of glucose may increase in type 2 diabetes, and
this pathway is the target of recently developed oral
“hypoglycemic” agents. In particular, SGLT2 inhibitors have been evaluated as new treatments for
diabetes.26 Reports indicate that SGLT2 inhibitors, by
inducing glucosuria, can improve glycemic control in
patients with type 2 diabetes while avoiding the danger
of triggering severe hypoglycemia.27 Although SGLT2
mediates 90% of glucose reabsorption in the kidneys, SGLT inhibitors at best appear to inhibit half that
amount. In 2013, canagliflozin became the first SGLT2
inhibitor to be approved in the United States.28 A second SGLT2 inhibitor, dapagliflozin, is approved in
Europe and many others are at advanced stages of
development.29,30
Am J Kidney Dis. 2014;63(2)(suppl 2):S22-S38
GLYCEMIC CONTROL: ITS VALUE AND ITS
DETERMINATION IN CKD
Glycemic management in patients with diabetes
(predominantly type 2) and CKD has become
increasingly complex, in part reflecting controversies
about safety/efficacy as applied to type 2 diabetes.31
Challenges cited in improving glycemic control in
patients with advanced CKD include therapeutic
inertia, monitoring difficulties, and complexity regarding the use of available treatments.32
Hemoglobin A1c (HbA1c) is the standard measure
for glucose monitoring in patients without kidney
impairment. According to NKF-KDOQI guidelines,
currently recommended HbA1c targets in the setting
of CKD are no different from those for the general
diabetic population; that is, ,7.0%, although the
seminal glycemic control trials in type 1 and type 2
diabetes have excluded patients with significantly
decreased kidney function.33 Although HbA1c combined with home glucose monitoring is the mainstay
for assessing glycemic control, until recently, available evidence regarding the role of tight glycemic
control on morbidity and mortality in patients with
advanced CKD was sparse.
HbA1c remains the most widely used index of
glycemic control in the diabetic population. Superior
glycemic control helps prevent diabetic CKD and
other diabetic microvascular complications in individuals without CKD. Since the DCCT (Diabetes
Control and Complications Trial)34 and UKPDS (UK
Prospective Diabetes Study)35 showed that HbA1c
levels are strong predictors of the risk of microvascular complications in type 1 and type 2 diabetes,
respectively, glycohemoglobin level has been the
main focus of diabetes management. Strict glycemic
control was found to reduce the risk of developing
albuminuria, and in those with elevated baseline
albumin-creatinine ratios, progression was found to
be reduced with strict glycemic control. In a recent
observational report from the Alberta Kidney Disease
Network,36 in patients with diabetes and non–dialysisdependent CKD stages 3-5, higher HbA1c levels were
associated with markedly worse outcomes, including
progression of kidney disease regardless of baseline
estimated glomerular filtration rate (eGFR). The
renoprotective effect associated with intensive control
of glycemia in type 2 diabetes also was suggested
by the recent ADOPT (A Diabetes Outcomes Prevention Trial) Study.37 Greater durability of glycemic
control in those treated with rosiglitazone (compared
with metformin and glyburide) was associated with a
smaller increase in albuminuria and with preservation
of eGFR. The firm association between glycemic
control and clinical outcomes hinges on the connection between hyperglycemia and elevated HbA1c
S25
Williams and Garg
levels. HbA1c makes up w4% of total hemoglobin in
normal adult erythrocytes. HbA1c level mirrors
average blood glucose concentration over the preceding 3 months or so.38 Firm correlation between
HbA1c and blood glucose levels in those with intact
kidney function has been reported in DCCT34 and the
ADAG (A1c-Derived Average Glucose) Study.39
HbA1c and Reduced Kidney Function
It now is understood that HbA1c level may overestimate glycemic control in kidney patients: HbA1c
levels appear to be lower, leading to underestimation
of hyperglycemia. The unreliability of HbA1c now is
appreciated to occur in several clinical conditions,40
especially hematologic diseases involving anemia or
hemolysis, and has been blamed on the analytical,
biological, and clinical variability associated with
HbA1c levels. Analytical variability is no longer an
issue because of newer assay methods.41 However,
biological and clinical variability of HbA1c levels
persist and limit the utility of this marker in some
patients, even in the general diabetic population, in
which variability arises in part from differential glycation rates. The relationship between HbA1c and
time-averaged serum glucose levels also may vary
across different racial backgrounds.40
More importantly, discrepancies between levels of
HbA1c and other measures of glycemia in clinical
studies42 have inspired questions about the validity of
HbA1c level in predicting outcomes in patients with
advanced CKD. The NKF-KDOQI guidelines for
diabetic CKD accept that there is a deficiency in data
for validating methods for monitoring glycemia in
patients with reduced kidney function.33 The US
Renal Data System (USRDS) reported that the prevalence of HbA1c levels greater than the 7.0% target is
higher for stages 1-2 CKD, but decreases to lower
levels in stages 3-4 CKD.43,44 In our large national
ESRD database analysis, mean HbA1c value is only
6.77%, and only 35% of patient values are .7.0%.45
Inherent biases in the previous HbA1c assays that
might lead to a higher or lower HbA1c level for a
given level of glycemia in patients with CKD
compared with the general population do not appear
to be clinically significant with contemporary assays.
As opposed to the high-performance liquid chromatography assay that was the previous method for
routine laboratory measurement of HbA1c, the current
immunoturbidimetric assay methodology is unaffected by high serum urea nitrogen levels. Instead, the
most commonly mentioned influences on HbA1c level
variability in patients with kidney disease include
anemia and erythropoiesis-stimulating agent treatment. In patients with kidney disease, the red blood
cell life span may be reduced by 30%-70%.46 Shortened erythrocyte survival in ESRD anemia would
S26
be consistent with decreased HbA1c levels on account
of reduced duration of exposure to ambient glucose47 and resulting glycation. Moreover, use of
erythropoiesis-stimulating agents increases the number
of immature red blood cells in circulation, each with
less likelihood for glycosylation. One publication
reported lowering of HbA1c values in a patient, both
when he was treated with an erythropoietin analogue
and also when receiving a darbepoetin analogue.48
It now is understood that HbA1c levels tend to be
lower in patients with diabetes who have reduced
kidney function or who are dependent on dialysis.
Peacock et al49 looked at HbA1c and glycated albumin
levels in 307 patients with diabetes, about five-sixths
of whom were hemodialysis dependent, with the rest
without evident kidney disease. In patients treated by
dialysis, the ratio of glycated albumin to HbA1c level
was higher, implying that HbA1c level substantially
underestimated serum glucose levels. More recently,
Chen et al50 reported mean glucose levels that were
5%-10% higher in patients with stages 3-4 CKD than
an estimated average glucose value calculated from
the same HbA1c level applied to patients without
reduced kidney function. Recently, a study examined
4-day continuous glucose monitoring in patients with
type 2 diabetes treated by maintenance hemodialysis (n 5 19) with a larger group of patients with
type 2 diabetes but without nephropathy (n 5 39).51
Although continuous glucose monitoring results were
comparable with glucose concentrations according to
the glucose meter in all patients, HbA1c and mean
glucose concentrations showed strong correlation in
only the nondialysis group (r 5 0.71); by contrast, they
were correlated weakly in those receiving hemodialysis
(r 5 0.47). In this study, hemodialysis patients were
treated with erythropoiesis-stimulating agents and had
lower hemoglobin levels than the nondialysis group
(11.6 vs 13.6 g/dL; P , 0.0001).
Glycemic Control and Outcomes in ESRD
Effects of glycemic control in patients with ESRD
have not yet been studied in a randomized clinical
trial. Recent observational studies have added significantly to the available evidence, albeit with relatively
contrasting results and substantial methodological
differences.45,52,53 Using a large national ESRD
database, Williams et al45 found that mortality curves
in patients with diabetes did not differ when grouped
by HbA1c levels, with no correlation between glycohemoglobin levels and 12-month mortality risk singly
or adjusted for case-mix and laboratory values. Results from Kalantar-Zadeh et al52 in a similar-sized
retrospective database analysis differed, showing
that greater HbA1c levels were associated with
increased risk of death. HbA1c levels . 10% were
found to be associated with a 41% greater risk for
Am J Kidney Dis. 2014;63(2)(suppl 2):S22-S38
Glycemic Management in CKD and ESRD
Figure 2. Relation between glycemic control and hemodialysis survival
in 24,875 hemodialysis patients with
a follow-up of 3 years, using timedependent survival models with repeated measures and multiple case-mix
adjustments. Data were collected at
baseline and every quarter to a maximum of 3 years’ follow-up. Extremes
of glycemia were associated weakly
with survival in the study population.
*P 5 0.001; yP 5 0.05. Abbreviation:
HbA1c, glycated hemoglobin. Reproduced with permission of the American
Society of Nephrology from Williams
et al.53
all-cause and cardiovascular death. The study used
longer follow-up, time-dependent survival models,
and adjustments for surrogates of malnutrition and
inflammation. A subsequent report by Williams et al53
modified its analysis to more directly match that of
Kalantar-Zadeh et al52 and found that glycemia is
associated with poorer survival only at concentration
extremes.
As a result of these studies, it is evident that the
connection between glycemic control and survival
outcomes is weaker in the setting of ESRD (Fig 2). In
particular, higher HbA1c targets may be preferable in
patients with more comorbid conditions,54 an approach supported by a recent regression analysis
involving HbA1c levels and mortality from the
DOPPS (Dialysis Outcomes and Practice Patterns
Study).55 In another observational study, a post hoc
analysis of 4D (Die Deutsche Diabetes Dialyse
Studie), a graded relationship between inferior glycemic control and mortality due to sudden cardiac
death was reported.56 During a median follow-up of
4 years, using patients with HbA1c levels , 6.0% as
the comparator, patients with sudden cardiac death
were identified. Patients with HbA1c levels . 8.0%
had a more than 2-fold higher risk of sudden death
compared with those with HbA1c levels # 6.0%
(HR, 2.14). Furthermore, with each 1% increase in
HbA1c level, the risk of sudden death, after statistical
adjustments, increased by 18%. The impact of HbA1c
level on sudden death led to increased risks of both
cardiovascular events and mortality, although the
prevalence of myocardial infarction was not affected.
Sudden death was the single largest cause of mortality
(26%). The specific mechanism by which poor glycemic control might lead to sudden death is not clear.
A recent report of 23,296 patients with diabetes and
eGFRs of 15-60 mL/min/1.73 m2 evaluated outcomes
Am J Kidney Dis. 2014;63(2)(suppl 2):S22-S38
according to baseline HbA1c levels (,7%, 7%-9%,
and .9%)36 over a median follow-up of 3.8 years.
For stages 3-4 CKD, higher HbA1c levels were
associated with increased risk of death.
Alternative Measures of Glycemic Control
Given the variability in HbA1c levels, there are
serious questions about the wisdom of relying on this
test as the only measure of glycemia in patients with
diabetes and CKD. Fructosamine represents glycated
serum proteins that have stable ketoamines (carbonyl
group of glucose reacting with the protein’s amino
group) in their structure. Fructosamine level is
becoming more available for the monitoring of diabetes treatment, but its correlation with fasting serum
glucose levels may not be as strong,40 and the issue of
correcting values for total protein or albumin concentrations is unresolved. Also, Chen et al50 reported
that compared with patients with normal kidney
function and for the same glucose concentration,
patients with CKD have fructosamine levels that also
are lower than expected. Of note, false elevations in
fructosamine levels may result from nitroblue tetrazolium assay interference by serum uric acid.57 In a
recent report, elevated fructosamine levels were
associated with infection and all-cause hospitalization
in 100 patients with diabetes who were on hemodialysis therapy.58
Relative to the limited reliance on fructosamine
level, glycated albumin level increasingly is proposed
as a better measure of glycemic control in patients
with diabetes who have CKD, with a reference range
of 0.6%-3.0% using column chromatography. Albumin undergoes nonenzymatic glycation in a manner
similar to hemoglobin and represents the bulk of the
serum glycated proteins. Because the residence time
of serum albumin is shorter (half-life w 20 days),59 it
S27
Williams and Garg
Figure 3. Relationship between longitudinal measurements of glycated albumin and hospitalization rates within 17
days of the measurement in 444 patients
with end-stage renal disease and diabetes mellitus (presented by quintile).
Higher glycated albumin rates were
associated with increased hospitalization
and, in a best-fit model, with poorer survival (data not shown). Reproduced with
permission of the American Society of
Nephrology from Freedman et al.62
represents shorter glucose exposure and should be
checked monthly. Glycated albumin is a readout of
glycemic control for just the 1-2 weeks preceding
sampling.60 It can be assayed with a bromocresol
purple method and expressed as percentage relative to
total albumin. Using this method, a reference value of
w12% for nondiabetic American individuals with
normal kidney function has been reported,49 with a
modestly wider reference interval versus the more
compressed range of measured values for HbA1c.
Although not influenced by age or erythrocyte
lifespan, anemia, or erythropoietin, glycated albumin
has not been validated in dialysis patients. The test’s
precision may suffer in periods of abnormal protein
turnover, such as from inflammation, hypercatabolic
states, peritioneal dialysis, proteinuria, albumin infusions, or gastrointestinal protein losses. In patients
with nephrotic-range proteinuria, glycated albumin
levels may be falsely reduced. However, there
now is an improved assay that is not affected by
changes in serum albumin level. Another factor in
favor of measuring glycated albumin is that unlike
HbA1c, it may have in vivo effects involved in the
pathogenesis of diabetic complications,61 such as
being an Amadori-modified reaction product capable
of inducing oxidative stress and enhancing proinflammatory responses.
The superiority of glycated albumin to HbA1c
level was concluded in 2 recent studies of kidney
patients.60,61 The first, a study from Japan of 538
maintenance hemodialysis patients with type 2 diabetes, 828 hemodialysis patients without diabetes, and
365 patients with diabetes but without significantly
reduced kidney function, found significantly lower
HbA1c levels relative to blood glucose or glycated
albumin levels with dialysis patients compared with
those without reduced kidney function.61 The ratio of
glycated albumin to HbA1c level (with a previously
S28
reported ratio of w3.0 in the absence of ESRD) was
2.93 in patients without CKD and 3.81 in those on
dialysis therapy. In a subsequent study from the
United States, the ratio again was significantly higher
in patients with ESRD (2.72 vs 2.07).49
Evidence linking glycemic control, as determined
by serum glycated albumin level, to diabetic ESRD
outcomes is now emerging. Freedman et al62 analyzed
the association between 3 measures—glycated albumin, HbA1c, and serum glucose—and outcomes
(hospitalization and survival) in patients with diabetes
who were undergoing dialysis (90% hemodialysis;
Fig 3). Quarterly serum glycated albumin levels were
measured for up to 2.3 years in 444 prevalent patients
with ESRD. Time-dependent analyses were used to
compare these measurements with available HbA1c
and monthly random serum glucose levels. Mean
serum glycated albumin level was 21.5% 6 6.0%
(SD) and HbA1c level was 6.9% 6 1.6%. Increasing
concentrations of glycated albumin, but not of HbA1c
or random serum glucose, predicted hospitalization
and survival. However, it is unclear what the therapeutic target range should be in CKD. A fourth potential marker of glycemia in patients with reduced
kidney function, serum 1,5-anhydroglucitol (1,5-AG)
level, recently was reported.63 The study suggested
that 1,5-AG levels were not influenced by moderately
reduced kidney function.
PERITONEAL DIALYSIS
Although no randomized comparison trials are
available, several analyses of observational data over
the years have indicated that patients with ESRD who
begin treatment with hemodialysis or peritoneal
dialysis have similar outcomes.64 Subgroup analyses
now suggest that hemodialysis may be associated
with improved survival in some patients with diabetes, with a survival disadvantage emerging after
Am J Kidney Dis. 2014;63(2)(suppl 2):S22-S38
Glycemic Management in CKD and ESRD
24 months among diabetic patients with at least one
comorbid condition and/or who were older than 65
years.65 Modality-survival effect modification by
diabetes has been shown in other studies, including
one incorporating a propensity-matched mortality
comparison.66 In addition, diabetic patients undergoing peritoneal dialysis more rapidly develop peritoneal fibrosis and loss of ultrafiltration.67
Exposure to glucose from peritoneal dialysis fluid,
which is absorbed systemically in significant
amounts, accentuates the metabolic abnormalities of
diabetes and metabolic syndrome.68 The addition of
intraperitoneal insulin, while uncommon, is the most
physiologic approach to the management of major
fluctuations in blood glucose levels in diabetic patients.69 However, it requires higher doses than the
conventional subcutaneous approach due to dilution
and adsorption to the plastic surface of the dialysis
solution delivery system. Glycemic control also may
be achieved by reduced reliance on hypertonic
dextrose solutions through substitution of icodextrin
solution, a glucose polymer minimally absorbed
across the peritoneal membrane. Icodextrin is the
only alternative to dextrose approved in the United
States for use in the long dwell of the peritoneal
dialysis cycle. An important patient safety issue with
its use is the development of spurious hyperglycemia: oligosaccharide metabolites such as maltose
lead to erroneous blood glucose measurements
specific to glucose dehydrogenase/pyrroloquinolinequinone cofactor–based glucometers, with large
overestimation of glucometer glucose levels compared with finger-stick or laboratory values.70
HYPOGLYCEMIA
Patients with diabetes and progressively declining
kidney function are at increased risk for hypoglycemia. Diabetes treatment options for patients with
advanced CKD therefore may be limited due to safety
and tolerability concerns. Because the risk of adverse
events related to hypoglycemia may be greater in
patients with reduced kidney function, attention
increasingly is being given to the risks of hypoglycemia (glucose , 70 mg/dL) in patients with diabetes
and CKD. In recent diabetes guidelines, there is
greater concern than in the past about the dangers of
hypoglycemia.31 The American Diabetes Association
(ADA) has recommended a target HbA1c level
, 7.0% or as close to normal and as safely as possible
without unacceptable hypoglycemia.71 However, with
increasing emphasis on tight glycemic control targets,
hypoglycemia, often iatrogenic, is a growing concern
with use of insulin secretagogues, missed meals,
advanced age, duration of diabetes, and unawareness
of hypoglycemia, factors that might increase the risk
of hypoglycemia.72 However, published reviews of
Am J Kidney Dis. 2014;63(2)(suppl 2):S22-S38
glycemic control in patients with diabetic CKD typically mention hypoglycemia only in passing. The
greatest risk of harm is in patients with both CKD and
diabetes, especially the elderly,73 in whom hypoglycemic episodes may be difficult to diagnose. Partly as
a result of mounting concerns about hypoglycemia,
the ADA’s Standards of Medical Care in Diabetes
recommends less stringent HbA1c targets (ie, 7.5%8.0%) as appropriate for patients with advanced
complications, extensive comorbid conditions, or severe hypoglycemia.31
Adverse sequelae of hypoglycemia could be part
of the reason behind the outcomes from 3 recent
studies, ACCORD (Action to Control Cardiovascular
Risk in Diabetes),74 ADVANCE (Action in Diabetes and Cardiovascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation),75
and VADT (Veterans Affairs Diabetes Trial),76
which tried to determine whether more aggressive
diabetes management than previously recommended
(with a goal of achieving HbA1c levels near 6.0%)
would reduce cardiovascular risk in patients with
long-standing diabetes. Hypoglycemic episodes were
more frequent in the intensive therapy arms of all 3
studies, and in the ACCORD trial, the rate of such
episodes requiring medical assistance was 3 times
higher in the intensive group. In ADVANCE, severe
hypoglycemia was nearly twice as common in the
intensive control group, and half the patients in the
low-HbA1c group experienced at least a minor hypoglycemic event. All 3 trials failed to demonstrate
that intensive therapy had a cardiovascular benefit.
Information for hypoglycemia and kidney disease
generally has emerged through case reports, small
series, and reviews. In the ADVANCE trial analysis,
higher creatinine levels were an independent risk
factor for severe hypoglycemia. ESRD unrelated to
diabetes is the second most frequent cause of hypoglycemia in hospitalized patients77 and carries a high
mortality rate.78 As many as half the maintenance
hemodialysis patients with diabetes may experience
hypoglycemia over a 3-month period.79
The pathogenesis of hypoglycemia in patients with
diabetic CKD is complex, particularly because there
are other derangements in glucose metabolism in
kidney failure. Consistent glycemic control is difficult
to achieve in patients with ESRD due to altered
glucose metabolism related to insulin resistance,
impaired insulin secretion, and decreased insulin
degradation, as well as effects on drug metabolism,
adding further complexity to glycemic management.
Diminished renal insulin clearance, as GFR decreases
to 15-20 mL/min/1.73 m2, prolongs the action of insulin. Aside from the liver, the kidneys represent the
main site for insulin degradation, and as kidney
function declines, so does the ability to remove
S29
Williams and Garg
insulin. Reductions in kidney mass and diminished
kidney function lead to decreased renal gluconeogenesis, a major source of glucose production from
precursor molecules during starvation. Preliminary
findings hint that the risk of hypoglycemia is particularly high in patients with diabetic ESRD who have
more glycemic variability.80
The health effects of hypoglycemia can be severe.
There may be hypoglycemic unawareness. Episodes
of cold sweats, agitation, dizziness, disorientation,
slurred speech, fatigue, and decreased level of consciousness are typical. A case of hypoglycemia
complicated by central pontine myelinolysis and
quadriplegia has been described.81 Severe hypoglycemia can powerfully stimulate the sympathetic nervous system and may bring about acute secondary
adverse cardiovascular outcomes, such as chest pain
due to coronary vasoconstriction and ischemia,
myocardial infarction, serious cardiac arrhythmias
including QT prolongation and ventricular arrhythmias, and sudden death.82 Severe hypoglycemia is
known to increase the risk of poor outcomes in patients with diabetes.83 Fear of iatrogenic hypoglycemia may result in poor glycemic control and further
risk of diabetic complications.
MANAGEMENT OF HYPERGLYCEMIA
Pharmacologic management of diabetes mellitus in
patients with decreased kidney function is complicated by several factors, including (1) altered insulin
resistance and glucose metabolism, (2) altered pharmacokinetics and safety profile of antihyperglycemic
agents, (3) concerns about the effect of drugs on
kidney function, (4) altered nutritional status, and (5)
higher risk of hypoglycemia. Therefore, when kidney
function starts deteriorating in a patient with diabetes,
pharmacologic management needs frequent changes
and/or dose adjustments. Moreover, the benefits of
tight glycemic control in patients with kidney failure
may not be the same as for patients in the early stages
of diabetes without decreased kidney function, and
the risk of hypoglycemia may outweigh the benefits
of tight glycemic control. Therefore, goals for glycemic control need to be revised and readjusted.
Insulin traditionally has been considered the safest
antidiabetic agent in the presence of kidney failure.
However, many new noninsulin agents are safe and
effective, and some may be even better than insulin,
as explained next.
INSULIN THERAPY IN PATIENTS WITH DECREASED
KIDNEY FUNCTION
Insulin is metabolized partly in the kidneys, and in
the presence of CKD, insulin action is prolonged.84
Therefore, the risk of hypoglycemia is increased in
CKD and one study suggested an insulin dose
reduction of w50% in these patients.85 Some patients
on dialysis therapy may require different doses on
different days due to the effect of dialysis on insulin
sensitivity.86 Basic tenets of insulin therapy in CKD
are the same as in any other patient with diabetes. The
patient needs basal insulin coverage and nutritional
insulin coverage. In a typical insulin regimen, basal
insulin coverage is provided by intermediate- or longacting insulin and nutritional coverage is provided by
short- or rapid-acting insulin (Table 1). Insulin glargine is the longest acting insulin analogue currently
available for clinical use. In kidney failure, its duration of action may be even longer and careful monitoring is needed. Insulin detemir and NPH insulin
may be used once or twice daily for basal coverage.
Regular insulin and rapid-acting insulin analogues
are used commonly for nutritional coverage. The risk
of hypoglycemia theoretically is higher with regular
insulin due to its longer duration of action than
rapid-acting insulin analogues, which may have the
additional advantage of more flexibility in CKD. Due
to their quick onset and shorter duration of action,
they sometimes can be used after meals in patients
with unreliable oral intake. Studies of hemodialysis
patients have shown the pharmacokinetics of rapidacting insulin analogues to be more favorable for
nutritional coverage.87-89
Although most patients need basal insulin and
nutritional insulin, it is important to individualize the
insulin regimen. Some patients can achieve their
glycemic goals using 1 or 2 injections of basal insulin alone, whereas others may need complex
Table 1. Profiles of Available Insulins
Insulin Type
Insulin Name
Onset of Action
Peak Effect
Duration
Typical Use
Other Remarks
Rapid acting
Lispro, aspart, glulisine
5-15 min
1-2 h
4-6 h
Nutritional
Can be taken after meals
if food intake is unreliable
Short acting
Regular
30 min
2-4 h
6-8 h
Nutritional
Used in IV insulin infusion
Intermediate or
long acting
NPH
1-2 h
4-8 h
12-18 h
Basal
1-23/d
Glargine
2h
No peak
20-24 h
Basal
13/d
Detemir
2h
3-9 h
16-24 h
Basal
13/d
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Am J Kidney Dis. 2014;63(2)(suppl 2):S22-S38
Class
Compound
Primary Physiologic Action
Advantages
Disadvantages
Role in Kidney Failure
Cost
Biguanides
Metformin
Activates AMP-kinase; Y
hepatic glucose
production
Extensive experience; no
hypoglycemia; weight
neutral; likely Y CVD
GI side effects; lactic acidosis; B12
deficiency; multiple contraindications
including kidney failure, acidosis,
hypoxia, infection, dehydration, older
age
Cannot be used with
SCr . 1.5 mg/dL in
men and .1.4 mg/dL
in women
Low
Sulfonylureas
Glyburide, glipizide,
glimepiride, gliclazide
Closes KATP channels on
b-cell membrane; [
insulin secretion
Extensive experience; Y
microvascular
complications
Hypoglycemia; weight gain; low
durability; blunts myocardial ischemic
preconditioning?
Use with caution
Low
Meglitinides
Repaglinide, nateglinide
Closes KATP channels on
b-cell membrane; [
insulin secretion
Y Postprandial glucose
excursions; dosing flexibility
Hypoglycemia; weight gain; frequent
dosing
Safer than
sulfonylureas
High
Thiazolidinediones
Pioglitazone,
rosiglitazone
PPAR-g activator; [
insulin sensitivity
No hypoglycemia; durability;
Y triglycerides, [ HDL-C; Y
CVD? (pioglitazone)
Weight gain; edema/heart failure; bone
fractures; [ MI? (rosiglitazone);
bladder cancer? (pioglitazone)
Safe, but concerns
about fluid retention
High
a-Glucosidase
Acarbose, miglitol
Slows carbohydrate
digestion/absorption
No hypoglycemia;
nonsystemic; Y
postprandial glucose
excursions; Y CVD events?
GI side effects; dosing frequency;
modest Y HbA1c
Contraindicated in
kidney failure with
SCr . 2 mg/dL
Moderate
Sitagliptin, vildagliptin,
saxagliptin,
linagliptin, alogliptin
Exenatide, exenatide
extended release,
liraglutide
[ GLP-1 and GIP; [
insulin, Y glucagon
No hypoglycemia; well
tolerated
Modest Y HbA1c; pancreatitis?; urticaria
Safe and effective
High
[ Insulin; Y glucagon; Y
gastric emptying; [
satiety
Weight loss; no
hypoglycemia; [ b-cell
mass?; CV protection?
GI side effects; pancreatitis?; kidney
failure?; medullary cancer?;
injectable
High
Amylin mimetics
Pramlintide
Y Glucagon; Y gastric
emptying; [ satiety
Weight loss; Y postprandial
glucose
GI side effects; modest Y HbA1c;
injectable; hypoglycemia w/ insulin;
dosing
Should not be used
due to severe side
effects and concerns
about AKI
No data in kidney
failure, should not be
used
Bile acid sequestrants
Colesevelam
Unknown; Y hepatic
glucose production?
No hypoglycemia; Y LDL
Constipation; [ triglycerides; modest Y
HbA1c, may Y absorption of other
medications
No data
High
Dopamine 2 agonists
Bromocriptine
No hypoglyemia; Y CVD
events?
Modest Y HbA1c; dizziness/syncope;
nausea; fatigue
No data
High
SGLT2 inhibitors
Canagliflozin,
dapagliflozin
Modulates hypothalamic
control of metabolism; [
insulin sensitivity
[ Glucosuria
No hypoglycemia; weight loss
Genitourinary infections
Cannot be used in
kidney failure
High
inhibitors
DPP-4 inhibitors
GLP-1 receptor
agonists
High
S31
Abbreviations: AKI, acute kidney injury; AMP, adenosine monophosphate; CV, cardiovascular; CVD, cardiovascular disease; DPP-4, dipeptidyl peptidase 4; GI, gastrointestinal; GLP-1,
glucagon-like peptide 1; HbA1c, hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; KATP, potassium adenosine triphosphatase pump; LDL, low-density lipoprotein; MI, myocardial
infarction; PPAR-g, peroxisome proliferator-activated receptor g; SCr, serum creatinine; SGLT2, sodium-dependent glucose transporter 2.
Reproduced with permission of American Diabetes Association from Inzucchi et al.31
Glycemic Management in CKD and ESRD
Am J Kidney Dis. 2014;63(2)(suppl 2):S22-S38
Table 2. Noninsulin Antidiabetic Agents
Williams and Garg
multiple daily insulin regimens. Some patients on
multiple daily insulin injections may benefit further
from an insulin pump. Insulin pumps infuse rapidacting insulin on a continuous basis and therefore
insulin doses can be fine-tuned more precisely.
However, an insulin pump is more expensive, requires intense patient involvement, and may not be
appropriate for all patients. No studies are available
to show a lower risk of hypoglycemia with an insulin
pump in CKD.
NONINSULIN HYPOGLYCEMIC AGENTS
Before 1995, sulfonylureas were the only noninsulin agents available in the United States for the
treatment of diabetes. The last 2 decades have seen
many new drug classes coming to market. Although
these new drugs have made the treatment of type 2
diabetes more exciting, they also have added
complexity to the field. There are very few head-tohead comparisons between these agents, and the
benefits of one agent over the other are not always
clear. As a result, passionate debates favoring one
drug over the other have taken place. Several professional organizations have written and revised their
guidelines for drug use in type 2 diabetes.31,90-93
However, these guidelines often do not cover patients with CKD. Patients with CKD often are eligible
for one or more of the noninsulin glucose-lowering
agents. Use of these agents may not only avoid the
psychological stress of insulin injections for some
patients, but also reduce the risk of hypoglycemia. A
summary of currently available noninsulin agents is
given in Table 2.
(eg, glipizide and glimepiride) are relatively safe and
preferred in patients with CKD.96
Biguanides
Metformin is the only biguanide available in the
United States and is the most commonly used drug
for treatment of type 2 diabetes. Metformin is an
insulin sensitizer, with its main site of action in the
liver. Therefore, it does not cause hypoglycemia.
Metformin use also is associated with a small loss
of weight. Moreover, this is the only drug for which
available data are convincing for a decrease in
macrovascular complications of diabetes. However,
metformin is contraindicated in women with serum
creatinine levels . 1.4 mg/dL and men with serum
creatinine levels . 1.5 mg/dL due to the risk of lactic
acidosis.97 Other risk factors for lactic acidosis
include hypoxemia, sepsis, alcohol abuse, liver failure, myocardial infarction, and shock. It is important
to be aware of this risk and stop metformin treatment
promptly when kidney function deteriorates in
patients with diabetes. Some physicians tend to use
metformin until eGFR is ,40 mL/min/1.73 m2 (or
sometimes even ,30 mL/min/1.73 m2) due to its
cardiovascular benefits. However, it seems prudent to
stop this drug treatment and switch to another safer
agent in a patient with deteriorating kidney function.
Studies have shown frequent irrational use of metformin in patients with kidney failure.98 Diarrhea and
gastrointestinal events are other common side effects
of metformin and may create further problems in the
presence of CKD.
Sulfonylureas
Thiazolidinediones
Sulfonylureas lower blood glucose levels by
releasing insulin from the pancreatic b cells. Acting
through sulfonylurea receptors, they close the
adenosine triphosphate (ATP)-sensitive potassium
channels and depolarize the plasma membrane. Depolarization of b-cell membrane leads to degranulation of cells and insulin secretion. Thus, the
effectiveness of sulfonylureas is dependent on insulin release that in turn depends on b-cell reserves.
Patients with longer durations of diabetes often have
poor b-cell reserves and may respond poorly to
sulfonylureas. However, if effective, the glucoselowering effect of these drugs is not dependent on
ambient glucose levels. Therefore, sulfonylureas can
cause unregulated insulin release and the risk of
severe hypoglycemia is high. Long-acting sulfonylureas (eg, glyburide and chlorpropamide) are more
notorious for hypoglycemia.94 Sulfonylurea-induced
hypoglycemia often is severe and can even be lifethreatening in patients with CKD.95 Shorter acting
drugs, especially those metabolized in the liver
Currently, pioglitazone and rosiglitazone are the 2
thiazolidinediones available for clinical use. They
improve insulin sensitivity by acting on the peroxisome proliferator-activated receptor g (PPAR-g)
receptors, mainly in skeletal muscle and adipose
tissue. These agents do not increase the risk of
hypoglycemia and are relatively safe in CKD. Both
agents seem to be effective for glycemic control in
patients on hemodialysis therapy.99-101 Pioglitazone
is the most widely used thiazolidinedione because it
has been shown to have some cardiovascular benefits,102,103 whereas rosiglitazone has been shown to
be associated with increased risk of myocardial
infarction in a meta-analysis.104 Additionally, rosiglitazone recently was shown to be associated with
increased risk of cardiovascular mortality in hemodialysis patients.105 All thiazolidinediones cause
fluid retention that may lead to heart failure, a
problem especially pertinent to patients with CKD.
Their use also is associated with increased risk of
fractures, and more recently, concerns have been
S32
Am J Kidney Dis. 2014;63(2)(suppl 2):S22-S38
Glycemic Management in CKD and ESRD
raised about increased risk of bladder cancer with
pioglitazone.106
DPP-4 Inhibitors
Sitagliptin, saxagliptin, alogliptin, and linagliptin
are the drugs in this class that are approved by the
FDA. Dipeptidyl peptidase 4 (DPP-4) inhibitors are
becoming more popular for the treatment of hyperglycemia in patients with CKD because of their better
tolerability and low risk of hypoglycemia. These
drugs increase concentrations of the endogenous
incretins GLP-1 and GIP. Some agents (sitagliptin
and saxagliptin) may need dose adjustment for
reduced eGFR. Randomized controlled trials have
demonstrated their short-term safety and efficacy in
patients with CKD.107-111 However, long-term data
for their safety and efficacy are still lacking.
GLP-1 Receptor Agonists
GLP-1 receptor agonists have a molecular structure
similar to native GLP-1 but are resistant to metabolism by DPP-4. Exenatide and liraglutide are the 2
drugs available in this class. Both are injectable
agents that increase insulin secretion and suppress
glucagon secretion in a glucose-dependent manner
and thus are associated with reduced risk of hypoglycemia. They also slow gastric emptying and suppress appetite, both of which are responsible for
weight loss but can lead to nausea and vomiting.
Liraglutide can be more convenient for patients than
exenatide because it is taken once rather than twice
a day, and a superior glucose-lowering effect of
liraglutide has been noted in a head-to-head comparison with exenatide.112 Exenatide is available in a
once-weekly injectable formulation but that also
seems less effective than liraglutide at lowering
glucose levels.113 Moreover, exenatide undergoes
renal excretion and is not approved for patients with
eGFRs , 30 mL/min/1.73 m2. Conversely, liraglutide is not renally excreted and thus decreased kidney
function has been found to have little effect on its
pharmacokinetics, suggesting its likely safety for use
in patients with kidney disease.114
However, side effects associated with GLP-1 agonists seem to be particularly severe in patients with
ESRD.115 There have been concerns of acute kidney
injury with these agents.116,117 However, a recent
retrospective analysis of an insurance-based database
found no association between exenatide and acute
kidney injury.118 Concerns of acute pancreatitis with
GLP-1 agonists and DPP-4 inhibitors received wide
publicity after a case-control study showed an association between exenatide or sitagliptin and pancreatitis.119 However, 2 larger long-term observational
studies found no association between exenatide and
pancreatitis.120,121 In vitro studies show pancreatic
Am J Kidney Dis. 2014;63(2)(suppl 2):S22-S38
duct metaplasia in rats that may raise the possibility of
pancreatic cancer on long-term use.122 However, no
clinical data are available to show such an association.
Similarly in rats, there is C-cell hyperplasia on exposure to liraglutide, raising concerns about medullary
thyroid carcinoma.123 Again, no clinical data are
available to show such an association and the findings
in rodents seem not to apply in humans.124 Because
GLP-1 agonists can lead to nausea and vomiting, they
are an unfavorable treatment option in CKD.
Meglitinides
These drugs cause insulin release from pancreatic
b cells by mechanisms similar to those of sulfonyl-
ureas, but they are much shorter acting and their
effects are more glucose-level dependent. Therefore,
the risk of hypoglycemia is lower with meglitinides
than with sulfonylureas. Also, they are more effective
for postprandial hyperglycemia. Of the 2 agents,
repaglinide and nateglinide, currently available in the
United States, nateglinide may have a lower risk of
hypoglycemia and has been studied in CKD.125,126
These drugs require frequent dosing because they
need to be taken prior to each meal.
a-Glucosidase Inhibitors
Acarbose and miglitol are the 2 agents available
in this class. a-Glucosidase inhibitors reduce the rate
of digestion and absorption of carbohydrates, resulting in modest reductions in HbA1c levels. Their
main limitation is frequent dosing and gastrointestinal
side effects, mainly flatulence.127 These drugs are
contraindicated in patients with serum creatinine
levels . 2 mg/dL due to the risk of accumulation that
may cause liver failure.128
Bile Acid Sequestrants
Colesevelam is a bile acid sequestrant that originally was used for cholesterol level reduction but now
is approved as an antihyperglycemic agent for type 2
diabetes. Its mechanism of action is poorly understood and it has the main side effect of constipation.
This drug may be a particularly good choice for patients with type 2 diabetes and elevated low-density
lipoprotein cholesterol levels.129 No studies are
available in patients with CKD.
Dopamine-2 Agonists
Bromocriptine is a dopaminergic agent approved
for the treatment of hyperglycemia in type 2 diabetes.
Its mechanism of action is not clear, but it is considered to involve resetting of the circadian rhythm in the
hypothalamus, which leads to lower insulin resistance.130 The main advantage of bromocriptine is its
proven cardiovascular safety profile.131 Specific benefits or harms of its use in CKD are unknown.
S33
Williams and Garg
Amylin Mimetics
Amylin is a hormone synthesized in pancreatic
b cells and cosecreted with insulin. Although its exact
role in glucose control is unknown, it slows gastric
emptying, increases satiety, and also suppresses
glucagon secretion after a meal, actions similar to
GLP-1. Pramlintide is an amylin agonist and can be
used alongside insulin to lower postprandial glycemic
excursions.132 The drug is not useful in CKD and has
limited use even in patients without CKD.
SGLT2 Inhibitors
Canagliflozin is the first SGLT2 inhibitor approved
recently by the US FDA for management of type 2
diabetes.28 Dapagliflozin already was available in
Europe. As mentioned previously, SGLT2 inhibitors
lower glucose levels by increasing glucosuria. They do
not cause hypoglycemia by themselves and are associated with a modest weight loss.30 However, their
antidiabetic effect is limited by osmotic diuresis and
they are associated with increased risk of genitourinary
infections. They are contraindicated in patients with
eGFRs , 45 mL/min/1.73 m2 and must be used at
lower doses at eGFRs of 45-60 mL/min/1.73 m2.
EFFECT OF TREATMENT CHOICES ON KIDNEY
FUNCTION
There are few head-to-head clinical trials comparing various antidiabetic agents, and none of these
trials was conducted in patients with CKD. One recent retrospective study that used regional Veterans
Administration data has suggested that metformin use
may be associated with a lower decline in kidney
function over time compared to the use of sulfonylureas.133 However, these data should be interpreted
with caution because metformin use may have been
avoided in patients at higher risk of kidney failure and
the patients using sulfonylureas may have had poor
glycemic control over years.
SUMMARY
Glycemic management is unavoidable but becomes
complex when diabetes is complicated by diabetic
nephropathy. Although aggressive glycemic control
has been shown to alter the clinical course of early
diabetic kidney disease, data supporting the benefits
of tight glycemic control on clinical outcomes in patients with advanced CKD, including ESRD, are
lacking. Conversely, growing evidence indicates that
glycemic regulation in patients with diabetes and
CKD is difficult. Monitoring is imperfect because
HbA1c levels tend to be lower and may underestimate
the degree of hyperglycemia. The risk of hypoglycemia appears to be increased. Pharmacologic management with antidiabetic drugs in patients with
decreased kidney function is complicated in many
S34
cases by altered pharmacokinetics. In the absence of
better clinical trial supportive data, the practice of
glycemic management will continue to be based on
individualized decision making. Information on
which to base determinations of glycemic goals and
selection of therapy has been reviewed.
ACKNOWLEDGEMENTS
Support: The development of this journal supplement was
funded by Novo Nordisk. Technical editing was provided by
Watermeadow Medical, funded by Novo Nordisk. Costs associated with publication were funded by Novo Nordisk. The authors
received no financial support or remuneration for this work.
Financial Disclosure: The authors declare that they have no
relevant financial interests.
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