"
"
Professor Paola Fioretto
University of Padova
Department of Medical and Surgical Sciences
Padova, Italy
University of Padova
Department of Medical and Surgical Sciences
Padova, Italy
Chronic kidney disease and the T2DM patient
As we have seen in Chapter 2, declining kidney function is a significant
problem in T2DM (affecting as much as 40% of patients 1, not only with
regard to the long-term prognosis for the person with this condition, but
also because of the implications for the therapeutic management of
hyperglycaemia, the root cause, via different pathogenetic pathways,
of diabetic chronic complications.
As an example of how renal impairment impacts T2DM management,
we only need to look at the incidence of hypoglycaemia among T2DM
patients who also have some degree of chronic kidney disease (CKD).
These patients are at a 240% higher risk of hypoglycaemia compared
with those patients with normal renal function.2 That is a huge difference
and one that undoubtedly changes the attitudes of the patients
towards their medication and makes clinicians think twice before prescribing
certain anti-diabetic agents. The main reason for this huge increase
in the risk of hypoglycaemia is the fact that the kidneys play
a pivotal role in the clearance and degradation of insulin, as well as
several oral agents.
The kidney clears insulin via two distinct routes. The first route entails
glomerular filtration, while the second involves diffusion from the peritubular
capillaries.3 With renal clearance impaired, the half-life of insulin
is prolonged via a number of mechanisms and there is a concomitant
decrease in the insulin requirement of the T2DM patient.3 This relationship
between kidney function and the clearance of insulin means that
hypoglycaemia in T2DM patients with CKD is a particular hazard where
any compounds that stimulate the production of insulin are being used;
notably the secretagogues (see below). For example, around 74% of
sulphonylurea (SU) -induced severe hypoglycaemic events occur in
patients with declining renal function.4
Regardless of these risks, the recent Kidney Disease Outcome Quality
Initiative (KDOQI) clinical practice guidelines and clinical practice
recommendations for diabetes and chronic kidney disease maintain
that target HbA1c levels should be <7% irrespective of the presence or
absence of CKD. The rationale for this seemingly strict guidance is that
hyperglycaemia is the fundamental cause of vascular organ complications,
including kidney disease.5 Furthermore, intensive treatment of
hyperglycaemia is the most effective approach to prevent diabetic
As we have seen in Chapter 2, declining kidney function is a significant
problem in T2DM (affecting as much as 40% of patients 1, not only with
regard to the long-term prognosis for the person with this condition, but
also because of the implications for the therapeutic management of
hyperglycaemia, the root cause, via different pathogenetic pathways,
of diabetic chronic complications.
As an example of how renal impairment impacts T2DM management,
we only need to look at the incidence of hypoglycaemia among T2DM
patients who also have some degree of chronic kidney disease (CKD).
These patients are at a 240% higher risk of hypoglycaemia compared
with those patients with normal renal function.2 That is a huge difference
and one that undoubtedly changes the attitudes of the patients
towards their medication and makes clinicians think twice before prescribing
certain anti-diabetic agents. The main reason for this huge increase
in the risk of hypoglycaemia is the fact that the kidneys play
a pivotal role in the clearance and degradation of insulin, as well as
several oral agents.
The kidney clears insulin via two distinct routes. The first route entails
glomerular filtration, while the second involves diffusion from the peritubular
capillaries.3 With renal clearance impaired, the half-life of insulin
is prolonged via a number of mechanisms and there is a concomitant
decrease in the insulin requirement of the T2DM patient.3 This relationship
between kidney function and the clearance of insulin means that
hypoglycaemia in T2DM patients with CKD is a particular hazard where
any compounds that stimulate the production of insulin are being used;
notably the secretagogues (see below). For example, around 74% of
sulphonylurea (SU) -induced severe hypoglycaemic events occur in
patients with declining renal function.4
Regardless of these risks, the recent Kidney Disease Outcome Quality
Initiative (KDOQI) clinical practice guidelines and clinical practice
recommendations for diabetes and chronic kidney disease maintain
that target HbA1c levels should be <7% irrespective of the presence or
absence of CKD. The rationale for this seemingly strict guidance is that
hyperglycaemia is the fundamental cause of vascular organ complications,
including kidney disease.5 Furthermore, intensive treatment of
hyperglycaemia is the most effective approach to prevent diabetic
nephropathy and, along with hypertensive therapy, to slow the progression
of established kidney disease.5 For example, further analyses of
the ADVANCE trial data published in 2009 showed that tight glycaemic
control reduces the risk of new or worsening nephropathy (Figure 1).6
These effects are additive to those of blood pressure levels, without
evidence of interaction.
of established kidney disease.5 For example, further analyses of
the ADVANCE trial data published in 2009 showed that tight glycaemic
control reduces the risk of new or worsening nephropathy (Figure 1).6
These effects are additive to those of blood pressure levels, without
evidence of interaction.
In addition, data suggests that achieving and maintaining target HbA1c
levels may improve survival and slow and/or prevent complications in
people with T2DM and kidney failure who are on dialysis. In a study
by Kalantar-Zadeh et al., higher HbA1c values were associated with a
higher risk of mortality after adjusting for potential confounders.7
The take home message is that tight glycaemic control is imperative for
people with T2DM, including those who also have concomitant renal
impairment. These recommendations leave the management of T2DM
in something of a quandary because the first and second line therapies,
namely metformin and SUs, are either contraindicated in renal impairment
or have to be used with caution due to the risk of complications
(e.g. hypoglycaemia). So, in view of this paradox, what can clinicians
on the ground do? Should they go on using the established therapies
and put the patient at risk of complications, or look at the emerging
anti-diabetic therapies that can be used safely in T2DM patients with
renal impairment thanks to their non-renal route of elimination?
Chapter 4 looks at these emerging therapies in greater detail, while the
remainder of this chapter reviews the impact of kidney disease on glycaemic
control as well as a brief overview of the current T2DM therapies
and their limitations, specifically in patients with renal impairment.
levels may improve survival and slow and/or prevent complications in
people with T2DM and kidney failure who are on dialysis. In a study
by Kalantar-Zadeh et al., higher HbA1c values were associated with a
higher risk of mortality after adjusting for potential confounders.7
The take home message is that tight glycaemic control is imperative for
people with T2DM, including those who also have concomitant renal
impairment. These recommendations leave the management of T2DM
in something of a quandary because the first and second line therapies,
namely metformin and SUs, are either contraindicated in renal impairment
or have to be used with caution due to the risk of complications
(e.g. hypoglycaemia). So, in view of this paradox, what can clinicians
on the ground do? Should they go on using the established therapies
and put the patient at risk of complications, or look at the emerging
anti-diabetic therapies that can be used safely in T2DM patients with
renal impairment thanks to their non-renal route of elimination?
Chapter 4 looks at these emerging therapies in greater detail, while the
remainder of this chapter reviews the impact of kidney disease on glycaemic
control as well as a brief overview of the current T2DM therapies
and their limitations, specifically in patients with renal impairment.
Kidney disease and implications for monitoring glycaemic
control
HbA1c is the gold standard for determining glycaemic control in people
with T2DM. However, there is concern that this measure may be affected
by the degree of kidney dysfunction or the haematological complications
of kidney disease (e.g. iron deficiency, haemolysis, shorter red
blood cell lifespan, or acidosis).8
One small study compared correlations between HbA1c measurements
and blood glucose in patients with moderate to severe kidney disease
who did not require dialysis to those of patients without kidney disease.
The study found no difference in the magnitude of the correlations
between HbA1c and blood glucose between these patient groups.9
Therefore, HbA1c is as effective as an indicator of glycaemic control in
patients with and without kidney disease. These data are strongly supportive
of applying a target HbA1c level of <7.0% to patients not requiring
dialysis but who have kidney disease.5 10
The correlation between HbA1c and blood glucose in haemodialysis
patients is unclear and results from relevant studies are conflicting.
Consequently, T2DM patients receiving dialysis are worthy of special
consideration. One study concluded that HbA1c was an underestimate
of glycaemic control in dialysis patients.9 On the other hand, a second
study concluded that HbA1c measures >7.5% were likely to be an overestimate
of glycaemic control.11 There is no evidence that haemodialysis
treatment acutely changes the HbA1c measure.12 Further studies
are needed to clarify the interpretation of HbA1c in patients receiving
dialysis. Lower HbA1c has been associated with lower mortality risk in
patients receiving haemodialysis.7 13 In view of these data, the current
recommendations are also to aim for an HbA1c <7.0% in T2DM patients
who are on dialysis.5 10
Current T2DM treatments and how they should be used in
patients with declining renal function
In this section, we briefly review the mode of action and the key clinical
characteristics of the various medications used in the management
of T2DM. In particular, we consider how declining renal function in patients
with T2DM influences the use of each of these medications (summarised
in Table 1). Insulin therapy will not be discussed, although it is
well known that the insulin dose needs to be reduced in patients with
CKD, given that insulin is metabolised by the kidney. Thus, patients with
CKD on insulin are at higher risk of hypoglycaemia and frequent blood
glucose monitoring is necessary.
control
HbA1c is the gold standard for determining glycaemic control in people
with T2DM. However, there is concern that this measure may be affected
by the degree of kidney dysfunction or the haematological complications
of kidney disease (e.g. iron deficiency, haemolysis, shorter red
blood cell lifespan, or acidosis).8
One small study compared correlations between HbA1c measurements
and blood glucose in patients with moderate to severe kidney disease
who did not require dialysis to those of patients without kidney disease.
The study found no difference in the magnitude of the correlations
between HbA1c and blood glucose between these patient groups.9
Therefore, HbA1c is as effective as an indicator of glycaemic control in
patients with and without kidney disease. These data are strongly supportive
of applying a target HbA1c level of <7.0% to patients not requiring
dialysis but who have kidney disease.5 10
The correlation between HbA1c and blood glucose in haemodialysis
patients is unclear and results from relevant studies are conflicting.
Consequently, T2DM patients receiving dialysis are worthy of special
consideration. One study concluded that HbA1c was an underestimate
of glycaemic control in dialysis patients.9 On the other hand, a second
study concluded that HbA1c measures >7.5% were likely to be an overestimate
of glycaemic control.11 There is no evidence that haemodialysis
treatment acutely changes the HbA1c measure.12 Further studies
are needed to clarify the interpretation of HbA1c in patients receiving
dialysis. Lower HbA1c has been associated with lower mortality risk in
patients receiving haemodialysis.7 13 In view of these data, the current
recommendations are also to aim for an HbA1c <7.0% in T2DM patients
who are on dialysis.5 10
Current T2DM treatments and how they should be used in
patients with declining renal function
In this section, we briefly review the mode of action and the key clinical
characteristics of the various medications used in the management
of T2DM. In particular, we consider how declining renal function in patients
with T2DM influences the use of each of these medications (summarised
in Table 1). Insulin therapy will not be discussed, although it is
well known that the insulin dose needs to be reduced in patients with
CKD, given that insulin is metabolised by the kidney. Thus, patients with
CKD on insulin are at higher risk of hypoglycaemia and frequent blood
glucose monitoring is necessary.
Secretagogues
Sulphonylureas (SUs)
SUs are a mainstay in T2DM treatment. They trigger insulin release by
binding to ATP-dependent potassium channels on pancreatic β-cells
(Figure 2).14 15 They are administered orally, once, twice or three times a
day shortly before a meal.14 15
This class of antidiabetics is divided into first, second and third generation
types; however the first generation SUs (e.g. chloropropamide and
tolbutamide) are rarely used today.14 15 The second and third generation
SUs (e.g. glibenclamide, gliclazide, glipizide and glimepiride) are
more commonly prescribed, as they offer improved efficacy and tolerability.
14 15
SUs are widely used to treat T2DM and are often combined with metformin
alone or, more rarely, metformin and a thiazolidinedione (TZD),
especially in those patients where metformin alone fails to provide adequate
glycaemic control.14 15
Typical adverse events associated with the use of SUs include hypoglycaemia,
weight gain, nausea, vomiting, diarrhoea, constipation, loss
of appetite, abdominal pain, bloating, indigestion, liver function problems,
blood disorders, allergic skin reactions, etc.14 15
The clearance of any SU and its metabolites is highly dependent on
kidney function, and severe prolonged episodes of hypoglycaemia as
a result of SU use have been described in dialysis patients.16 In patients
with Stage 3–5 CKD, first-generation SUs should be avoided (Table 1).
Of the newer generation SUs, glipizide is recommended because it is
metabolised into inactive metabolites by the liver and then excreted
by the kidney, and consequently there is a lower risk of hypoglycaemia
(Table 1).5
Meglitinides
Only two meglitinides are available (repaglinide and nateglinide) and
they work in a similar way to SUs, except they bind to a different site on
the ATP-dependent potassium channel (Figure 2). The net effect is an
increase in insulin secretion, although they have a shorter duration of
action than SUs.15
Meglitinides are taken orally up to three times a day with, or not longer
than 30 minutes before, meals.15 They are often used in combination
with metformin.15 Meglitinides are generally better tolerated than SUs
and typical adverse events associated with these agents include hypo
Sulphonylureas (SUs)
SUs are a mainstay in T2DM treatment. They trigger insulin release by
binding to ATP-dependent potassium channels on pancreatic β-cells
(Figure 2).14 15 They are administered orally, once, twice or three times a
day shortly before a meal.14 15
This class of antidiabetics is divided into first, second and third generation
types; however the first generation SUs (e.g. chloropropamide and
tolbutamide) are rarely used today.14 15 The second and third generation
SUs (e.g. glibenclamide, gliclazide, glipizide and glimepiride) are
more commonly prescribed, as they offer improved efficacy and tolerability.
14 15
SUs are widely used to treat T2DM and are often combined with metformin
alone or, more rarely, metformin and a thiazolidinedione (TZD),
especially in those patients where metformin alone fails to provide adequate
glycaemic control.14 15
Typical adverse events associated with the use of SUs include hypoglycaemia,
weight gain, nausea, vomiting, diarrhoea, constipation, loss
of appetite, abdominal pain, bloating, indigestion, liver function problems,
blood disorders, allergic skin reactions, etc.14 15
The clearance of any SU and its metabolites is highly dependent on
kidney function, and severe prolonged episodes of hypoglycaemia as
a result of SU use have been described in dialysis patients.16 In patients
with Stage 3–5 CKD, first-generation SUs should be avoided (Table 1).
Of the newer generation SUs, glipizide is recommended because it is
metabolised into inactive metabolites by the liver and then excreted
by the kidney, and consequently there is a lower risk of hypoglycaemia
(Table 1).5
Meglitinides
Only two meglitinides are available (repaglinide and nateglinide) and
they work in a similar way to SUs, except they bind to a different site on
the ATP-dependent potassium channel (Figure 2). The net effect is an
increase in insulin secretion, although they have a shorter duration of
action than SUs.15
Meglitinides are taken orally up to three times a day with, or not longer
than 30 minutes before, meals.15 They are often used in combination
with metformin.15 Meglitinides are generally better tolerated than SUs
and typical adverse events associated with these agents include hypo
glycaemia, weight gain, allergic skin reactions, liver function problems,
abdominal pain, nausea, diarrhoea, vomiting, constipation and visual
disturbances.17
Repaglinide does not require a dose adjustment in T2DM patients with
Stage 3-5 CKD or those who are on dialysis (Table 1).18 Indeed, the renal
clearance of repaglinide is <10%. Nateglinide on the other hand should
be avoided in Stage 3-5 CKD and in patients who are on dialysis (Table 1)18,
since it is metabolised into active metabolites and could therefore expose
patients with CKD to the risk of severe hypoglycaemia.
abdominal pain, nausea, diarrhoea, vomiting, constipation and visual
disturbances.17
Repaglinide does not require a dose adjustment in T2DM patients with
Stage 3-5 CKD or those who are on dialysis (Table 1).18 Indeed, the renal
clearance of repaglinide is <10%. Nateglinide on the other hand should
be avoided in Stage 3-5 CKD and in patients who are on dialysis (Table 1)18,
since it is metabolised into active metabolites and could therefore expose
patients with CKD to the risk of severe hypoglycaemia.
Sensitisers
Biguanides
Metformin, the only biguanide currently available, is the gold-standard
antidiabetic agent, and is typically the first-line drug therapy in T2DM
patients when exercise or diet intervention have failed to achieve adequate
glycaemic control.19 This compound decreases hepatic gluconeogenesis
and increases the uptake of glucose by the peripheral tissues,
especially the skeletal muscle (Figure 3).15
Metformin is widely used because of its effectiveness, good tolerability
profile and low cost. It is commonly the basis for second- and third-line
combination therapies.15 Taken up to three times a day, with or after
a meal.19 Typical adverse events associated with the use of metformin
include: nausea, vomiting, diarrhoea, abdominal pain, loss of appetite,
(these often diminish after the initial stages of treatment), metallic
taste, reduced absorption of vitamin B12, lactic acidosis, allergic skin
reaction, general allergic reaction and liver function problems.19
Metformin does not exhibit the risk of hypoglycaemia associated with
some of the other drug classes used to treat T2DM. However, special
care must be taken when it is used in patients with CKD. There is an
increased risk of lactic acidosis, even in patients with mild impairment
of kidney function, which is likely due to the accumulation of the drug
and its metabolites.20 Metformin is contraindicated in male patients
with a serum creatinine >1.5 mg/dl and in female patients with serum
creatinine >1.4 mg/dl (Table 1).5 This concept, however, has recently
been challenged by some authors, who suggest its safe treatment option
in patients with stable CKD.21
Biguanides
Metformin, the only biguanide currently available, is the gold-standard
antidiabetic agent, and is typically the first-line drug therapy in T2DM
patients when exercise or diet intervention have failed to achieve adequate
glycaemic control.19 This compound decreases hepatic gluconeogenesis
and increases the uptake of glucose by the peripheral tissues,
especially the skeletal muscle (Figure 3).15
Metformin is widely used because of its effectiveness, good tolerability
profile and low cost. It is commonly the basis for second- and third-line
combination therapies.15 Taken up to three times a day, with or after
a meal.19 Typical adverse events associated with the use of metformin
include: nausea, vomiting, diarrhoea, abdominal pain, loss of appetite,
(these often diminish after the initial stages of treatment), metallic
taste, reduced absorption of vitamin B12, lactic acidosis, allergic skin
reaction, general allergic reaction and liver function problems.19
Metformin does not exhibit the risk of hypoglycaemia associated with
some of the other drug classes used to treat T2DM. However, special
care must be taken when it is used in patients with CKD. There is an
increased risk of lactic acidosis, even in patients with mild impairment
of kidney function, which is likely due to the accumulation of the drug
and its metabolites.20 Metformin is contraindicated in male patients
with a serum creatinine >1.5 mg/dl and in female patients with serum
creatinine >1.4 mg/dl (Table 1).5 This concept, however, has recently
been challenged by some authors, who suggest its safe treatment option
in patients with stable CKD.21
Thiazolidinediones (TZDs)
The TZDs rosiglitazone and pioglitazone are currently available for the
treatment of T2DM. The use of rosiglitazone in the treatment of T2DM has
been marred by a meta-analysis, which demonstrated an increased
risk of myocardial infarction (significant) and death from cardiovascular
causes (borderline significance) in patients receiving this TZD.22
For these reasons, its use has been discontinued in Europe.
TZDs bind to a peroxisome proliferator-activated receptor γ (PPAR γ) on
the cell nucleus, eliciting a variety of effects, the net result of which is a
decrease in insulin resistance allowing more glucose to enter the cells.15
TZDs are taken once or twice daily with or without food and they are
often used in combination with metformin or metformin plus another
antidiabetic drug, such as a SU.23 24
Typical adverse events include, weight gain oedema, heart failure,
blood disorders, increase in blood lipids, increased appetite, increased
risk of bone fractures (women), and visual disturbances.23 24
Of considerable interest is the suggestion that TZDs may prevent or slow
the progression of kidney disease in people with T2DM independently
of glycaemic control.25 Several small studies have reported a greater
reduction in albuminuria in patients administered TZDs.8 However, there
has been no evidence to support an independent association between
TZD use and actual prevention of diabetic kidney disease. TZDs
have been demonstrated to be effective without increasing the risk
of hypoglycaemic episodes in patients with CKD, including those receiving
dialysis,12 26 27 and in patients who require therapy for glycaemic
control after a kidney transplant.28 As TZDs undergo hepatic metabolism,
no adjustment in dosing is required in any stage of CKD, or for those
patients on dialysis or who have had a kidney transplant (Table 1).8 One
concern, however, of using TZDs in T2DM patients with renal impairment
is that the risk of fluid retention and heart failure may be exacerbated8;
thus they should be used with caution in patients with CKD. Nevertheless,
fluid retention can be adequately controlled by diuretics.
Alpha-glucosidase inhibitors (AGIs)
Acarbose, miglitol and voglibose are the currently available AGIs. In
contrast to the other anti-diabetic agents, AGIs have no effect on insulin
secretion or sensitivity, as they are essentially non-systemic.15 These
compounds inhibit enzymes in the small intestine that are responsible
for breaking down carbohydrates into monosaccharides, thereby reducing
the amount of monosaccharides, namely glucose that are
transported through the intestinal wall into the bloodstream.15 AGIs are
taken three times a day with the first mouthful of food.29
The TZDs rosiglitazone and pioglitazone are currently available for the
treatment of T2DM. The use of rosiglitazone in the treatment of T2DM has
been marred by a meta-analysis, which demonstrated an increased
risk of myocardial infarction (significant) and death from cardiovascular
causes (borderline significance) in patients receiving this TZD.22
For these reasons, its use has been discontinued in Europe.
TZDs bind to a peroxisome proliferator-activated receptor γ (PPAR γ) on
the cell nucleus, eliciting a variety of effects, the net result of which is a
decrease in insulin resistance allowing more glucose to enter the cells.15
TZDs are taken once or twice daily with or without food and they are
often used in combination with metformin or metformin plus another
antidiabetic drug, such as a SU.23 24
Typical adverse events include, weight gain oedema, heart failure,
blood disorders, increase in blood lipids, increased appetite, increased
risk of bone fractures (women), and visual disturbances.23 24
Of considerable interest is the suggestion that TZDs may prevent or slow
the progression of kidney disease in people with T2DM independently
of glycaemic control.25 Several small studies have reported a greater
reduction in albuminuria in patients administered TZDs.8 However, there
has been no evidence to support an independent association between
TZD use and actual prevention of diabetic kidney disease. TZDs
have been demonstrated to be effective without increasing the risk
of hypoglycaemic episodes in patients with CKD, including those receiving
dialysis,12 26 27 and in patients who require therapy for glycaemic
control after a kidney transplant.28 As TZDs undergo hepatic metabolism,
no adjustment in dosing is required in any stage of CKD, or for those
patients on dialysis or who have had a kidney transplant (Table 1).8 One
concern, however, of using TZDs in T2DM patients with renal impairment
is that the risk of fluid retention and heart failure may be exacerbated8;
thus they should be used with caution in patients with CKD. Nevertheless,
fluid retention can be adequately controlled by diuretics.
Alpha-glucosidase inhibitors (AGIs)
Acarbose, miglitol and voglibose are the currently available AGIs. In
contrast to the other anti-diabetic agents, AGIs have no effect on insulin
secretion or sensitivity, as they are essentially non-systemic.15 These
compounds inhibit enzymes in the small intestine that are responsible
for breaking down carbohydrates into monosaccharides, thereby reducing
the amount of monosaccharides, namely glucose that are
transported through the intestinal wall into the bloodstream.15 AGIs are
taken three times a day with the first mouthful of food.29
Due to their novel mode of action, the main adverse events associated
with the use of AGIs are gastrointestinal in nature and include
flatulence, diarrhoea, abdominal pain, nausea, vomiting and indigestion.
Less commonly encountered adverse events include liver function
problems, oedema, blood disorders and allergic skin reactions.29
With respect to their use in diabetic kidney disease, AGIs and their metabolites
may result in hepatic damage; however, the relevant mechanisms
have not been elucidated.30 For this reason, this drug class is not
recommended for patients with a serum creatinine >2 mg/dl (Table 1).5
GLP-1 mimetics - exenatide
Exenatide is the only GLP-1 mimetic. This product is a synthetic version
of a hormone found in the venom of the gila monster lizard.31 Exenatide
binds to the same cellular receptor as GLP-1 and therefore elicits the
same effects, i.e. stimulation of insulin production and release from the
pancreatic β-cells thereby enhancing glucose uptake by the tissues.31
Exenatide is administered twice daily by subcutaneous injection into
the skin of the abdomen, thigh, or arm, any time within the 60-minute
period before the first and last meals of the day.32 Exenatide is effective
in reducing HbA1c, without exposing the patient to the risk of hypoglycaemia,
and is associated with sustained weight loss. Exenatide is
only indicated for use in combination with metformin and/or a SU when
these oral therapies fail to provide adequate glycaemic control.32 Exenatide
adverse events are commonly gastrointestinal in nature, including
nausea and vomiting. Pancreatitis, headache, and dizziness
have also been encountered, but are rare.32
Exenatide is eliminated almost entirely by glomerular filtration with
subsequent proteolytic degradation in the kidney. In a small study in
patients with CKD, exenatide was well tolerated in patients with mildmoderate
renal impairment (GFR>30 ml/min), but not in patients with
end stage renal disease (ESRD). Thus the manufacturers recommend
no dose adjustment in patients with Stage 1-2 CKD. In patients with
Stage 3 CKD, dose escalation from 5μg to 10μg should proceed conservatively
(Table 1).32 Finally, the manufacturers recommend that exenatide
is not used in T2DM patients with Stage 4-5 CKD (GFR<30 ml/
min), or those patients on dialysis (Table 1).32
with the use of AGIs are gastrointestinal in nature and include
flatulence, diarrhoea, abdominal pain, nausea, vomiting and indigestion.
Less commonly encountered adverse events include liver function
problems, oedema, blood disorders and allergic skin reactions.29
With respect to their use in diabetic kidney disease, AGIs and their metabolites
may result in hepatic damage; however, the relevant mechanisms
have not been elucidated.30 For this reason, this drug class is not
recommended for patients with a serum creatinine >2 mg/dl (Table 1).5
GLP-1 mimetics - exenatide
Exenatide is the only GLP-1 mimetic. This product is a synthetic version
of a hormone found in the venom of the gila monster lizard.31 Exenatide
binds to the same cellular receptor as GLP-1 and therefore elicits the
same effects, i.e. stimulation of insulin production and release from the
pancreatic β-cells thereby enhancing glucose uptake by the tissues.31
Exenatide is administered twice daily by subcutaneous injection into
the skin of the abdomen, thigh, or arm, any time within the 60-minute
period before the first and last meals of the day.32 Exenatide is effective
in reducing HbA1c, without exposing the patient to the risk of hypoglycaemia,
and is associated with sustained weight loss. Exenatide is
only indicated for use in combination with metformin and/or a SU when
these oral therapies fail to provide adequate glycaemic control.32 Exenatide
adverse events are commonly gastrointestinal in nature, including
nausea and vomiting. Pancreatitis, headache, and dizziness
have also been encountered, but are rare.32
Exenatide is eliminated almost entirely by glomerular filtration with
subsequent proteolytic degradation in the kidney. In a small study in
patients with CKD, exenatide was well tolerated in patients with mildmoderate
renal impairment (GFR>30 ml/min), but not in patients with
end stage renal disease (ESRD). Thus the manufacturers recommend
no dose adjustment in patients with Stage 1-2 CKD. In patients with
Stage 3 CKD, dose escalation from 5μg to 10μg should proceed conservatively
(Table 1).32 Finally, the manufacturers recommend that exenatide
is not used in T2DM patients with Stage 4-5 CKD (GFR<30 ml/
min), or those patients on dialysis (Table 1).32
GLP-1 analogues - liraglutide
Liraglutide is the only human GLP-1 analogue currently available. It is
produced by recombinant DNA technology in a species of yeast (Saccharomyces
cerevisiae).33 The amino acids that form the backbone of
liraglutide are genetically engineered to have a small fatty-acid chain,
which renders the peptide more resistant to degradation by the DPP-4
enzyme, allowing it to act for longer in the body.34
Liraglutide has a good efficacy and tolerability profile, but currently it is
only indicated for use in combination with metformin and/or a SU when
these oral therapies fail to provide adequate glycaemic control.33 Liraglutide
is administered once daily by subcutaneous injection into the
abdomen, upper thigh or arm, at any time of the day, regardless of
when meals are eaten.33
The adverse events associated with liraglutide are commonly gastrointestinal
in nature, although hypoglycaemia, pancreatitis, headache,
dizziness and thyroid problems have also been encountered, albeit
rarely.33
Liraglutide is degraded by endogenous peptidase and does not have
a renal clearance. A small study evaluated the pharmacokinetics,
safety and tolerability in patients with a wide range of renal function,
from normal to ESRD; there was no association between renal status
and exposure to the active drug or side effects. Thus, no specific dose
adjustment is needed in CKD. Nevertheless, it is not recommended for
use in patients with stage 3 CKD or above, due to a lack of experience
with this product in these patients (Table 1).33
Amylin analogues
Pramlintide is the only amylin analogue available. It mimics the effects
of the amylin produced by the pancreatic β-cells, namely, slowing gastric
emptying and suppressing the secretion of glucagon, the hormone
that opposes the effects of insulin.35
Because it is a hormone, pramlintide has to be administered via subcutaneous
injection prior to meals.35 Common adverse events associated
with the use of pramlintide include nausea, hypoglycaemia, vomiting,
headache, abdominal pain, weight loss and fatigue.35
For those patients with a GFR of <20 ml/min/1.73 m2 no dose adjustment
of pramlintide is required (Table 1). However, there is a lack of clinical
experience in patients with more severe renal impairment; therefore
pramlintide is not recommended in these patient populations (Table 1).5
Liraglutide is the only human GLP-1 analogue currently available. It is
produced by recombinant DNA technology in a species of yeast (Saccharomyces
cerevisiae).33 The amino acids that form the backbone of
liraglutide are genetically engineered to have a small fatty-acid chain,
which renders the peptide more resistant to degradation by the DPP-4
enzyme, allowing it to act for longer in the body.34
Liraglutide has a good efficacy and tolerability profile, but currently it is
only indicated for use in combination with metformin and/or a SU when
these oral therapies fail to provide adequate glycaemic control.33 Liraglutide
is administered once daily by subcutaneous injection into the
abdomen, upper thigh or arm, at any time of the day, regardless of
when meals are eaten.33
The adverse events associated with liraglutide are commonly gastrointestinal
in nature, although hypoglycaemia, pancreatitis, headache,
dizziness and thyroid problems have also been encountered, albeit
rarely.33
Liraglutide is degraded by endogenous peptidase and does not have
a renal clearance. A small study evaluated the pharmacokinetics,
safety and tolerability in patients with a wide range of renal function,
from normal to ESRD; there was no association between renal status
and exposure to the active drug or side effects. Thus, no specific dose
adjustment is needed in CKD. Nevertheless, it is not recommended for
use in patients with stage 3 CKD or above, due to a lack of experience
with this product in these patients (Table 1).33
Amylin analogues
Pramlintide is the only amylin analogue available. It mimics the effects
of the amylin produced by the pancreatic β-cells, namely, slowing gastric
emptying and suppressing the secretion of glucagon, the hormone
that opposes the effects of insulin.35
Because it is a hormone, pramlintide has to be administered via subcutaneous
injection prior to meals.35 Common adverse events associated
with the use of pramlintide include nausea, hypoglycaemia, vomiting,
headache, abdominal pain, weight loss and fatigue.35
For those patients with a GFR of <20 ml/min/1.73 m2 no dose adjustment
of pramlintide is required (Table 1). However, there is a lack of clinical
experience in patients with more severe renal impairment; therefore
pramlintide is not recommended in these patient populations (Table 1).5
DPP-4 inhibitors
These compounds are covered in greater detail in Chapter 4; suffice
to say here that EU prescribing information for sitagliptin and vildagliptin
recommends that these agents should not be used in patients with
Stage 3-5 CKD (Table 1).36 37 Saxagliptin can be used in these patients,
but a dose reduction is recommended (Table 1).38 In the EU, it is recommended
that none of these compounds be used in dialysis patients.36-38
The equivalent information in the US recommends that sitagliptin, vildagliptin
and saxagliptin can be used in Stage 3-5 CKD with the appropriate
dose adjustment.39-41 Linagliptin, also covered in greater detail in
Chapter 4, is the only compound in this class that is primarily excreted
via bile and the gut, a characteristic that has important implications
for the potential management of T2DM patients with declining renal
function.
These compounds are covered in greater detail in Chapter 4; suffice
to say here that EU prescribing information for sitagliptin and vildagliptin
recommends that these agents should not be used in patients with
Stage 3-5 CKD (Table 1).36 37 Saxagliptin can be used in these patients,
but a dose reduction is recommended (Table 1).38 In the EU, it is recommended
that none of these compounds be used in dialysis patients.36-38
The equivalent information in the US recommends that sitagliptin, vildagliptin
and saxagliptin can be used in Stage 3-5 CKD with the appropriate
dose adjustment.39-41 Linagliptin, also covered in greater detail in
Chapter 4, is the only compound in this class that is primarily excreted
via bile and the gut, a characteristic that has important implications
for the potential management of T2DM patients with declining renal
function.
Limitations of current therapies
The central aim of T2DM management is to maintain near to normal
blood glucose levels accomplished via a daily regimen of diet, exercise
and antidiabetic agents or insulin injections, without exposing the
patients to the risk of hypoglycaemia and weight gain. Unfortunately,
the very nature of the disease and the strict, daily regimen for its management
are a perfect recipe for very poor compliance.
Oral antidiabetic agents (OADs) are a cornerstone of T2DM treatment;
however, these compounds fail to provide sustainable and sufficient
glycaemic control. Large, long-term trials, such as UKPDS and ADOPT
have demonstrated that the glycaemic lowering effect of T2DM treatments
decreases with time.42 43 The UKPDS trial demonstrated that after
three years of monotherapy with OADs, 50% of patients were adequately
controlled. However, after nine years of monotherapy only a
quarter of patients still maintained adequate glycaemic control.43
The underlying reason for OADs being unable to provide sustainable
glycaemic control is a declining glycaemic response, which in turn is a
consequence of differences in genotypes interacting with external environmental
factors to produce an in-vivo milieu that varies from person
to person thus influencing the effects of a medication.44 The differences
between people with T2DM, both physiologic and genetic and how a
greater understanding of these factors can lead to individualised treatments
for patients are discussed in more detail in Chapter 5. For the
purposes of this chapter and the limitations of current treatments, the
variables that influence the individual response to OAD are as follows:45
zzDuration of diabetes.
zzBaseline HbA1c (reflecting the severity of the disease).
zzAnti-diabetes treatment status (treatment naive vs. treatment non-naive).
zzThe hyperglycaemic treatment strategy (initiation or combination therapy
vs. up-titration of existing therapy).
A further limitation of current therapies is their ability to treat T2DM people
with co-morbidities, most notably chronic kidney disease. As part
of the overarching metabolic syndrome, T2DM and kidney disease are
intimately linked and the progression of the latter is definitely dependent
on how the former is managed. As we have seen, many of the
widely used OADs are a very blunt instrument when it comes to managing
blood glucose levels in T2DM patients with concomitant kidney
disease. Many of these compounds are excreted renally and kidney
disease potentiates their activity resulting in a variety of complications.
The central aim of T2DM management is to maintain near to normal
blood glucose levels accomplished via a daily regimen of diet, exercise
and antidiabetic agents or insulin injections, without exposing the
patients to the risk of hypoglycaemia and weight gain. Unfortunately,
the very nature of the disease and the strict, daily regimen for its management
are a perfect recipe for very poor compliance.
Oral antidiabetic agents (OADs) are a cornerstone of T2DM treatment;
however, these compounds fail to provide sustainable and sufficient
glycaemic control. Large, long-term trials, such as UKPDS and ADOPT
have demonstrated that the glycaemic lowering effect of T2DM treatments
decreases with time.42 43 The UKPDS trial demonstrated that after
three years of monotherapy with OADs, 50% of patients were adequately
controlled. However, after nine years of monotherapy only a
quarter of patients still maintained adequate glycaemic control.43
The underlying reason for OADs being unable to provide sustainable
glycaemic control is a declining glycaemic response, which in turn is a
consequence of differences in genotypes interacting with external environmental
factors to produce an in-vivo milieu that varies from person
to person thus influencing the effects of a medication.44 The differences
between people with T2DM, both physiologic and genetic and how a
greater understanding of these factors can lead to individualised treatments
for patients are discussed in more detail in Chapter 5. For the
purposes of this chapter and the limitations of current treatments, the
variables that influence the individual response to OAD are as follows:45
zzDuration of diabetes.
zzBaseline HbA1c (reflecting the severity of the disease).
zzAnti-diabetes treatment status (treatment naive vs. treatment non-naive).
zzThe hyperglycaemic treatment strategy (initiation or combination therapy
vs. up-titration of existing therapy).
A further limitation of current therapies is their ability to treat T2DM people
with co-morbidities, most notably chronic kidney disease. As part
of the overarching metabolic syndrome, T2DM and kidney disease are
intimately linked and the progression of the latter is definitely dependent
on how the former is managed. As we have seen, many of the
widely used OADs are a very blunt instrument when it comes to managing
blood glucose levels in T2DM patients with concomitant kidney
disease. Many of these compounds are excreted renally and kidney
disease potentiates their activity resulting in a variety of complications.
The future of managing T2DM patients with declining renal
function
In view of the limitations of the current therapies when it comes to managing
T2DM patients with declining renal function, there is a pressing
need for antihyperglycaemic agents that can be used safely and without
dose adjustment or additional drug-related monitoring in this patient
population. We need to remember this is by no means a small proportion
of the total T2DM population, so any new treatments that fulfil
these criteria have the potential to benefit a huge number of people.
There are a number of promising new treatment options for T2DM on
the horizon and some of these belong to established OAD classes, yet
they offer the advantage of being safe to use without dose reduction in
patients with kidney disease. These new treatments and an increased
accuracy in phenotyping the patient with T2DM will be instrumental in
individualising the management of this chronic disease.
Chapter 3 Summary
zzDeclining renal function has a significant impact on the way that T2DM is
managed.
zzT2DM patients with impaired renal function are at a 240% higher risk of
hypoglycaemia compared with those patients with normal renal function.
zzThe kidneys play a critical role in the clearance and degradation of insulin
and most antidiabetic agents
zzThis is particular problem with antidiabetic agents that stimulate the release
of insulin.
zzKDOQI guidelines recommend a target HbA1c level of <7% regardless of
whether a patient has renal impairment or is on dialysis.
zzHbA1c is accurate for monitoring blood glucose control, even in patients
with declining renal function, although there are still concerns in dialysis
patients.
zzThe majority of drugs available to treat hyperglycaemia are affected by
kidney function and therefore should be either avoided or used in reduced
doses for patients with CKD.
zzSome new antidiabetics can be used safely in renal impairment and dialysis,
as they are not eliminated by the kidneys.
zzCurrent therapies for T2DM have many limitations, especially when it comes
to treating T2DM patients with comorbidities.
zzNew therapies that lower blood glucose levels safely in patients with declining
renal function have the potential to benefit a huge number of people.
function
In view of the limitations of the current therapies when it comes to managing
T2DM patients with declining renal function, there is a pressing
need for antihyperglycaemic agents that can be used safely and without
dose adjustment or additional drug-related monitoring in this patient
population. We need to remember this is by no means a small proportion
of the total T2DM population, so any new treatments that fulfil
these criteria have the potential to benefit a huge number of people.
There are a number of promising new treatment options for T2DM on
the horizon and some of these belong to established OAD classes, yet
they offer the advantage of being safe to use without dose reduction in
patients with kidney disease. These new treatments and an increased
accuracy in phenotyping the patient with T2DM will be instrumental in
individualising the management of this chronic disease.
Chapter 3 Summary
zzDeclining renal function has a significant impact on the way that T2DM is
managed.
zzT2DM patients with impaired renal function are at a 240% higher risk of
hypoglycaemia compared with those patients with normal renal function.
zzThe kidneys play a critical role in the clearance and degradation of insulin
and most antidiabetic agents
zzThis is particular problem with antidiabetic agents that stimulate the release
of insulin.
zzKDOQI guidelines recommend a target HbA1c level of <7% regardless of
whether a patient has renal impairment or is on dialysis.
zzHbA1c is accurate for monitoring blood glucose control, even in patients
with declining renal function, although there are still concerns in dialysis
patients.
zzThe majority of drugs available to treat hyperglycaemia are affected by
kidney function and therefore should be either avoided or used in reduced
doses for patients with CKD.
zzSome new antidiabetics can be used safely in renal impairment and dialysis,
as they are not eliminated by the kidneys.
zzCurrent therapies for T2DM have many limitations, especially when it comes
to treating T2DM patients with comorbidities.
zzNew therapies that lower blood glucose levels safely in patients with declining
renal function have the potential to benefit a huge number of people.
References:
1. Koro CE, et al. Antidiabetic medication use and prevalence of chronic kidney
disease among patients with type 2 diabetes mellitus in the United States. Clin.
Therapeutics 2009;31(11):2608-2617.
2. Davis TM, Brown SG, Jacobs IG, Bulsara M, Bruce DG, Davis WA. Determinants of
severe hypoglycemia complicating type 2 diabetes: the Fremantle diabetes study.
J Clin Endocrinol Metab;95(5):2240-7.
3. Rabkin R, Ryan MP, Duckworth WC. The renal metabolism of insulin. Diabetologia
1984;27(3):351-7.
4. Haneda M, Morikawa A. Which hypoglycaemic agents to use in type 2 diabetic
subjects with CKD and how? Nephrol Dial Transplant 2009;24(2):338-41.
5. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for
Diabetes and Chronic Kidney Disease. Am J Kidney Dis 2007;49(2 Suppl 2):S12-154.
6. Zoungas S, de Galan BE, Ninomiya T, Grobbee D, Hamet P, Heller S, et al. Combined
effects of routine blood pressure lowering and intensive glucose control on macrovascular
and microvascular outcomes in patients with type 2 diabetes: New results
from the ADVANCE trial. Diabetes Care 2009;32(11):2068-74.
7. Kalantar-Zadeh K, Kopple JD, Regidor DL, Jing J, Shinaberger CS, Aronovitz J, et al.
A1C and survival in maintenance hemodialysis patients. Diabetes Care 2007;30(5):
1049-55.
8. Cavanaugh KL. Diabetes management issues for patients with chronic kidney
disease. Clinical Diabetes 2007;25(3):90-97.
9. Morgan L, Marenah CB, Jeffcoate WJ, Morgan AG. Glycated proteins as indices
of glycaemic control in diabetic patients with chronic renal failure. Diabet Med
1996;13(6):514-9.
10. ADA. Standards of medical care in diabetes. Diabetes Care 2011;34 Suppl 1:S11-61.
11. Joy MS, Cefalu WT, Hogan SL, Nachman PH. Long-term glycemic control measurements
in diabetic patients receiving hemodialysis. Am J Kidney Dis 2002;39(2):297-307.
12. Thompson-Culkin K, Zussman B, Miller AK, Freed MI. Pharmacokinetics of rosiglitazone
in patients with end-stage renal disease. J Int Med Res 2002;30(4):391-9.
13. Morioka T, Emoto M, Tabata T, Shoji T, Tahara H, Kishimoto H, et al. Glycemic
control is a predictor of survival for diabetic patients on hemodialysis. Diabetes
Care 2001;24(5):909-13.
14. Williams G, Pickup JC. Handbook of Diabetes, 3rd Edition: Wiley-Blackwell, 2004.
15. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review.
JAMA 2002;287(3):360-72.
16. Krepinsky J, Ingram AJ, Clase CM. Prolonged sulfonylurea-induced hypoglycemia in
diabetic patients with end-stage renal disease. Am J Kidney Dis 2000;35(3):500-5.
17. Daiichi Sankyo. Prandin® Summary of Product Characteristics. 2009.
18. ADA. Executive summary: Standards of medical care in diabetes--2010. Diabetes
Care 2010;33 Suppl 1:S4-10.
19. Merck Sharpe & Dohme Ltd. Glucophage® Summary of Product Characteristics.
2009.
20. Davidson MB, Peters AL. An overview of metformin in the treatment of type 2
diabetes mellitus. Am J Med 1997;102(1):99-110.
21. Nye HJ, Herrington WG. Metformin: The Safest Hypoglycaemic Agent in Chronic
Kidney Disease? Nephron Clin Pract 2011;118(4):c380-c383.
22. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and
death from cardiovascular causes. N Engl J Med 2007;356(24):2457-71.
23. GlaxoSmithKline. Avandia® Summary of Product Characteristics. 2008.
24. Takeda. Actos Summary of Product Characteristics. 2007.
25. Sarafidis PA, Bakris GL. Protection of the kidney by thiazolidinediones: an assessment
from bench to bedside. Kidney Int 2006;70(7):1223-33.
26. Chapelsky MC, Thompson-Culkin K, Miller AK, Sack M, Blum R, Freed MI. Pharmaco-.
kinetics of rosiglitazone in patients with varying degrees of renal insufficiency. J Clin
Pharmacol 2003;43(3):252-9.
27. Mohideen P, Bornemann M, Sugihara J, Genadio V, Sugihara V, Arakaki R. The
metabolic effects of troglitazone in patients with diabetes and end-stage renal
disease. Endocrine 2005;28(2):181-6.
1. Koro CE, et al. Antidiabetic medication use and prevalence of chronic kidney
disease among patients with type 2 diabetes mellitus in the United States. Clin.
Therapeutics 2009;31(11):2608-2617.
2. Davis TM, Brown SG, Jacobs IG, Bulsara M, Bruce DG, Davis WA. Determinants of
severe hypoglycemia complicating type 2 diabetes: the Fremantle diabetes study.
J Clin Endocrinol Metab;95(5):2240-7.
3. Rabkin R, Ryan MP, Duckworth WC. The renal metabolism of insulin. Diabetologia
1984;27(3):351-7.
4. Haneda M, Morikawa A. Which hypoglycaemic agents to use in type 2 diabetic
subjects with CKD and how? Nephrol Dial Transplant 2009;24(2):338-41.
5. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for
Diabetes and Chronic Kidney Disease. Am J Kidney Dis 2007;49(2 Suppl 2):S12-154.
6. Zoungas S, de Galan BE, Ninomiya T, Grobbee D, Hamet P, Heller S, et al. Combined
effects of routine blood pressure lowering and intensive glucose control on macrovascular
and microvascular outcomes in patients with type 2 diabetes: New results
from the ADVANCE trial. Diabetes Care 2009;32(11):2068-74.
7. Kalantar-Zadeh K, Kopple JD, Regidor DL, Jing J, Shinaberger CS, Aronovitz J, et al.
A1C and survival in maintenance hemodialysis patients. Diabetes Care 2007;30(5):
1049-55.
8. Cavanaugh KL. Diabetes management issues for patients with chronic kidney
disease. Clinical Diabetes 2007;25(3):90-97.
9. Morgan L, Marenah CB, Jeffcoate WJ, Morgan AG. Glycated proteins as indices
of glycaemic control in diabetic patients with chronic renal failure. Diabet Med
1996;13(6):514-9.
10. ADA. Standards of medical care in diabetes. Diabetes Care 2011;34 Suppl 1:S11-61.
11. Joy MS, Cefalu WT, Hogan SL, Nachman PH. Long-term glycemic control measurements
in diabetic patients receiving hemodialysis. Am J Kidney Dis 2002;39(2):297-307.
12. Thompson-Culkin K, Zussman B, Miller AK, Freed MI. Pharmacokinetics of rosiglitazone
in patients with end-stage renal disease. J Int Med Res 2002;30(4):391-9.
13. Morioka T, Emoto M, Tabata T, Shoji T, Tahara H, Kishimoto H, et al. Glycemic
control is a predictor of survival for diabetic patients on hemodialysis. Diabetes
Care 2001;24(5):909-13.
14. Williams G, Pickup JC. Handbook of Diabetes, 3rd Edition: Wiley-Blackwell, 2004.
15. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review.
JAMA 2002;287(3):360-72.
16. Krepinsky J, Ingram AJ, Clase CM. Prolonged sulfonylurea-induced hypoglycemia in
diabetic patients with end-stage renal disease. Am J Kidney Dis 2000;35(3):500-5.
17. Daiichi Sankyo. Prandin® Summary of Product Characteristics. 2009.
18. ADA. Executive summary: Standards of medical care in diabetes--2010. Diabetes
Care 2010;33 Suppl 1:S4-10.
19. Merck Sharpe & Dohme Ltd. Glucophage® Summary of Product Characteristics.
2009.
20. Davidson MB, Peters AL. An overview of metformin in the treatment of type 2
diabetes mellitus. Am J Med 1997;102(1):99-110.
21. Nye HJ, Herrington WG. Metformin: The Safest Hypoglycaemic Agent in Chronic
Kidney Disease? Nephron Clin Pract 2011;118(4):c380-c383.
22. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and
death from cardiovascular causes. N Engl J Med 2007;356(24):2457-71.
23. GlaxoSmithKline. Avandia® Summary of Product Characteristics. 2008.
24. Takeda. Actos Summary of Product Characteristics. 2007.
25. Sarafidis PA, Bakris GL. Protection of the kidney by thiazolidinediones: an assessment
from bench to bedside. Kidney Int 2006;70(7):1223-33.
26. Chapelsky MC, Thompson-Culkin K, Miller AK, Sack M, Blum R, Freed MI. Pharmaco-.
kinetics of rosiglitazone in patients with varying degrees of renal insufficiency. J Clin
Pharmacol 2003;43(3):252-9.
27. Mohideen P, Bornemann M, Sugihara J, Genadio V, Sugihara V, Arakaki R. The
metabolic effects of troglitazone in patients with diabetes and end-stage renal
disease. Endocrine 2005;28(2):181-6.
28. Villanueva G, Baldwin D. Rosiglitazone therapy of posttransplant diabetes mellitus.
Transplantation 2005;80(10):1402-5.
29. Bayer. Glucobay SPC. 2009.
30. Charpentier G, Riveline JP, Varroud-Vial M. Management of drugs affecting blood
glucose in diabetic patients with renal failure. Diabetes Metab 2000;26 Suppl 4:73-85.
31. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes
Care 2003;26(10):2929-40.
32. Eli-Lilly. Byetta 5 micrograms solution for injection SPC. 2009.
33. NovoNordisk. Victoza 6 mg/ml solution for injection in pre-filled pen. 2009.
34. Raun K, von Voss P, Gotfredsen CF, Golozoubova V, Rolin B, Knudsen LB. Liraglutide,
a long-acting glucagon-like peptide-1 analog, reduces body weight and food
intake in obese candy-fed rats, whereas a dipeptidyl peptidase-IV inhibitor, vildagliptin,
does not. Diabetes 2007;56(1):8-15.
35. Jones MC. Therapies for diabetes: pramlintide and exenatide. Am Fam Physician
2007;75(12):1831-5.
36. Merck Sharpe & Dohme Ltd. Januvia® Summary of Product Characteristics. 2009.
37. Novartis Europharm Ltd. Galvus® Summary of Product Characteristics. 2009.
38. Bristol-Myers Squibb Pharmaceuticals Ltd and AstraZeneca EEIG. Onglyza® Summary
of Product Characteristics. June, 2009.
39. Bristol-Myers Squibb Pharmaceuticals Ltd and AstraZeneca EEIG. Onglyza® Prescribing
Information. 2010.
40. Merck Sharpe & Dohme Ltd. Januvia® US Prescribing Information. 2010.
41. Novartis Europharm Ltd. Galvus® Prescribing Information. 2010.
42. Goldstein BJ. Clinical translation of “a diabetes outcome progression trial”: ADOPT
appropriate combination oral therapies in type 2 diabetes. J Clin Endocrinol Metab
2007;92(4):1226-8.
43. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive
glucose control in type 2 diabetes. N Engl J Med 2008;359(15):1577-89.
44. Smith RJ, Nathan DM, Arslanian SA, Groop L, Rizza RA, Rotter JI. Individualizing
therapies in type 2 diabetes mellitus based on patient characteristics: what we
know and what we need to know. J Clin Endocrinol Metab 2010;95(4):1566-74.
45. Gavin JR, 3rd, Bohannon NJ. A review of the response to oral antidiabetes agents in
patients with type 2 diabetes. Postgrad Med 2010;122(3):43-51.
Transplantation 2005;80(10):1402-5.
29. Bayer. Glucobay SPC. 2009.
30. Charpentier G, Riveline JP, Varroud-Vial M. Management of drugs affecting blood
glucose in diabetic patients with renal failure. Diabetes Metab 2000;26 Suppl 4:73-85.
31. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes
Care 2003;26(10):2929-40.
32. Eli-Lilly. Byetta 5 micrograms solution for injection SPC. 2009.
33. NovoNordisk. Victoza 6 mg/ml solution for injection in pre-filled pen. 2009.
34. Raun K, von Voss P, Gotfredsen CF, Golozoubova V, Rolin B, Knudsen LB. Liraglutide,
a long-acting glucagon-like peptide-1 analog, reduces body weight and food
intake in obese candy-fed rats, whereas a dipeptidyl peptidase-IV inhibitor, vildagliptin,
does not. Diabetes 2007;56(1):8-15.
35. Jones MC. Therapies for diabetes: pramlintide and exenatide. Am Fam Physician
2007;75(12):1831-5.
36. Merck Sharpe & Dohme Ltd. Januvia® Summary of Product Characteristics. 2009.
37. Novartis Europharm Ltd. Galvus® Summary of Product Characteristics. 2009.
38. Bristol-Myers Squibb Pharmaceuticals Ltd and AstraZeneca EEIG. Onglyza® Summary
of Product Characteristics. June, 2009.
39. Bristol-Myers Squibb Pharmaceuticals Ltd and AstraZeneca EEIG. Onglyza® Prescribing
Information. 2010.
40. Merck Sharpe & Dohme Ltd. Januvia® US Prescribing Information. 2010.
41. Novartis Europharm Ltd. Galvus® Prescribing Information. 2010.
42. Goldstein BJ. Clinical translation of “a diabetes outcome progression trial”: ADOPT
appropriate combination oral therapies in type 2 diabetes. J Clin Endocrinol Metab
2007;92(4):1226-8.
43. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive
glucose control in type 2 diabetes. N Engl J Med 2008;359(15):1577-89.
44. Smith RJ, Nathan DM, Arslanian SA, Groop L, Rizza RA, Rotter JI. Individualizing
therapies in type 2 diabetes mellitus based on patient characteristics: what we
know and what we need to know. J Clin Endocrinol Metab 2010;95(4):1566-74.
45. Gavin JR, 3rd, Bohannon NJ. A review of the response to oral antidiabetes agents in
patients with type 2 diabetes. Postgrad Med 2010;122(3):43-51.
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