"
"
The incretin effect
DPP-4 inhibition as a means of controlling blood sugar levels has attracted
considerable attention in recent decades. In order to understand
how DPP-4 inhibitors work, it is pertinent to briefly review the incretin
hormones and the physiological phenomenon known as the incretin
effect.
Insulin and glucagon play a central role in blood sugar homeostasis;
they are influenced by a group of gastrointestinal hormones – the incretins.
More than a century ago it was suggested that a hormone produced
by the gastrointestinal tract stimulated secretory activity in the
pancreas.1 Building on these ideas it was later discovered that eating
promotes a much greater degree of insulin secretion compared with
simply infusing glucose into the circulation, thus bypassing the gut.1 This
phenomenon was termed the incretin (the crude intestinal extract being
named secretin, with excretin stimulating the exocrine portion of
the pancreas, and incretin acting on the endocrine pancreas) effect
and it has since become clear that it involves several hormones (incretin
hormones) of which the most important are glucagon-like peptide-1
(GLP-1) and gastric inhibitory peptide (glucose-dependent insulinotropic
peptide or GIP).1
Both GLP-1 and GIP are similar to glucagon in terms of their amino
acid sequence. The former is secreted primarily by L-cells, which occur
most abundantly in the ileum, colon and rectum, but also, to a
lesser degree, in the upper gastrointestinal (GI) tract while the latter is
secreted by K-cells in the duodenum/upper jejunum. The incretin hormones,
GLP-1 and GIP, are released throughout the day, with levels increasing
several-fold in response to a meal (Figure 1).2 They act on the
pancreas augmenting glucose-induced insulin secretion. GLP-1 also
suppresses glucagon secretion (GIP tends to stimulate glucagon secretion).
3 When blood glucose concentrations are normal or elevated,
GLP-1 and GIP stimulate insulin production and release from pancreatic
b-cells thereby enhancing glucose uptake by insulin-dependent
tissues, effects that are complemented by the ability of GLP-1 to lower
glucagon secretion from the pancreatic a-cells (Figure 1).2 Decreased
glucagon levels, along with higher insulin levels, lead to reduced gluconeogenesis
in the liver, thus lowering blood glucose levels in the fasting
and fed states (Figure 1).2
Dr Thomas Hach
TA Metabolism
Boehringer Ingelheim Pharma GmbH & Co. KG
Ingelheim, Germany
Professor Michael Nauck
Diabeteszentrum Bad Lauterberg
Bad Lauterberg im Harz, Germany
DPP-4 inhibition as a means of controlling blood sugar levels has attracted
considerable attention in recent decades. In order to understand
how DPP-4 inhibitors work, it is pertinent to briefly review the incretin
hormones and the physiological phenomenon known as the incretin
effect.
Insulin and glucagon play a central role in blood sugar homeostasis;
they are influenced by a group of gastrointestinal hormones – the incretins.
More than a century ago it was suggested that a hormone produced
by the gastrointestinal tract stimulated secretory activity in the
pancreas.1 Building on these ideas it was later discovered that eating
promotes a much greater degree of insulin secretion compared with
simply infusing glucose into the circulation, thus bypassing the gut.1 This
phenomenon was termed the incretin (the crude intestinal extract being
named secretin, with excretin stimulating the exocrine portion of
the pancreas, and incretin acting on the endocrine pancreas) effect
and it has since become clear that it involves several hormones (incretin
hormones) of which the most important are glucagon-like peptide-1
(GLP-1) and gastric inhibitory peptide (glucose-dependent insulinotropic
peptide or GIP).1
Both GLP-1 and GIP are similar to glucagon in terms of their amino
acid sequence. The former is secreted primarily by L-cells, which occur
most abundantly in the ileum, colon and rectum, but also, to a
lesser degree, in the upper gastrointestinal (GI) tract while the latter is
secreted by K-cells in the duodenum/upper jejunum. The incretin hormones,
GLP-1 and GIP, are released throughout the day, with levels increasing
several-fold in response to a meal (Figure 1).2 They act on the
pancreas augmenting glucose-induced insulin secretion. GLP-1 also
suppresses glucagon secretion (GIP tends to stimulate glucagon secretion).
3 When blood glucose concentrations are normal or elevated,
GLP-1 and GIP stimulate insulin production and release from pancreatic
b-cells thereby enhancing glucose uptake by insulin-dependent
tissues, effects that are complemented by the ability of GLP-1 to lower
glucagon secretion from the pancreatic a-cells (Figure 1).2 Decreased
glucagon levels, along with higher insulin levels, lead to reduced gluconeogenesis
in the liver, thus lowering blood glucose levels in the fasting
and fed states (Figure 1).2
Dr Thomas Hach
TA Metabolism
Boehringer Ingelheim Pharma GmbH & Co. KG
Ingelheim, Germany
Professor Michael Nauck
Diabeteszentrum Bad Lauterberg
Bad Lauterberg im Harz, Germany
Incretin hormones stimulate insulin release from pancreatic β-cells in a
glucose-dependent manner (i.e. the insulin release happens only when
glucose concentrations are normal or elevated, as typically observed
in response to glucose ingestion); therefore the glucose-lowering effect
they elicit does not result in hypoglycaemia. There is even evidence to
suggest that GLP-1 may stimulate increases in β-cell mass and function;
attributes we’ll consider later in this chapter.4 5
The incretin effect and T2DM
Several abnormalities have been observed in the entero-insular axis in
T2DM patients.6 These defects include:
zzReduced GLP-1 response to food (Figure 2).7 8 This has not been uniformly
confirmed, the majority of studies showing unchanged GLP-1 secretion
comparing T2DM patients and healthy control subjects (Figure 3).9
zzA somewhat decreased potency of GLP-1 in stimulating the release of insulin
(Figure 3).10 However, exogenous GLP can still lower glucose concentrations
into the normal range in patients with T2DM.
zzAn almost complete loss of insulin secretion in response to even high doses
of GIP.11 12
zzSuppression of glucagon secretion is impaired during oral glucose tolerance
tests (OGTTs) as opposed to isoglycaemic intravenous glucose infusion.13
This is also true in healthy subjects,14 so it is not an abnormality in T2DM.
glucose-dependent manner (i.e. the insulin release happens only when
glucose concentrations are normal or elevated, as typically observed
in response to glucose ingestion); therefore the glucose-lowering effect
they elicit does not result in hypoglycaemia. There is even evidence to
suggest that GLP-1 may stimulate increases in β-cell mass and function;
attributes we’ll consider later in this chapter.4 5
The incretin effect and T2DM
Several abnormalities have been observed in the entero-insular axis in
T2DM patients.6 These defects include:
zzReduced GLP-1 response to food (Figure 2).7 8 This has not been uniformly
confirmed, the majority of studies showing unchanged GLP-1 secretion
comparing T2DM patients and healthy control subjects (Figure 3).9
zzA somewhat decreased potency of GLP-1 in stimulating the release of insulin
(Figure 3).10 However, exogenous GLP can still lower glucose concentrations
into the normal range in patients with T2DM.
zzAn almost complete loss of insulin secretion in response to even high doses
of GIP.11 12
zzSuppression of glucagon secretion is impaired during oral glucose tolerance
tests (OGTTs) as opposed to isoglycaemic intravenous glucose infusion.13
This is also true in healthy subjects,14 so it is not an abnormality in T2DM.
The DPP-4 enzyme
Discovered in 1967, the DPP-4 enzyme has attracted a great deal of
interest because of its role in a number of important cellular processes,
not least of all its function in blood sugar homeostasis. This enzyme occurs
as a membrane bound form abundant in several body tissues (e.g.
kidney, heart and liver) and a free form that circulates in the blood
stream. It is classed as a glycoprotein and a serine exopeptidase that
cleaves peptides with proline and alanine in the pen-ultimate N-terminal
position in a diverse range of substrates, including regulatory peptides
(e.g. GLP-1 and GIP), chemokines, neuropeptides, and vasoactive
peptides.15 Especially intact GLP-1 (sequence [7-36 amide] or [7-37]) is
avidly attacked and degraded (products [9-36 amide] or [9-37]). Even
during a continuous intravenous infusion, only 15 % of GLP-1 remains in
its intact, biologically active state.16 DPP-4 thus limits and terminates the
biological activity of GLP-1 (and, to a lesser degree, GIP).
DPP-4 inhibitors
Background and mode of action
The DPP-4 enzyme is very important in the incretin system as it rapidly
inactivates the incretin hormones, GLP-1 and GIP, thereby regulating
their effects (Figure 4).2 Following the discovery that GLP-1 and GIP
are degraded various inhibitors of the DPP-4 enzyme were identified.
These findings paved the way for a novel means of reducing blood
glucose levels via modulation of the incretin effect; namely prolonging
the effect of native GLP-1, the biological activity of which is limited by
a half-life of less than 2 minutes.17 Inhibition of DPP-4 has been shown
to increase endogenous GLP-1 levels by 2-to-3 fold, thereby improving
insulin secretion, suppressing glucagon, and lowering blood sugar.
Discovered in 1967, the DPP-4 enzyme has attracted a great deal of
interest because of its role in a number of important cellular processes,
not least of all its function in blood sugar homeostasis. This enzyme occurs
as a membrane bound form abundant in several body tissues (e.g.
kidney, heart and liver) and a free form that circulates in the blood
stream. It is classed as a glycoprotein and a serine exopeptidase that
cleaves peptides with proline and alanine in the pen-ultimate N-terminal
position in a diverse range of substrates, including regulatory peptides
(e.g. GLP-1 and GIP), chemokines, neuropeptides, and vasoactive
peptides.15 Especially intact GLP-1 (sequence [7-36 amide] or [7-37]) is
avidly attacked and degraded (products [9-36 amide] or [9-37]). Even
during a continuous intravenous infusion, only 15 % of GLP-1 remains in
its intact, biologically active state.16 DPP-4 thus limits and terminates the
biological activity of GLP-1 (and, to a lesser degree, GIP).
DPP-4 inhibitors
Background and mode of action
The DPP-4 enzyme is very important in the incretin system as it rapidly
inactivates the incretin hormones, GLP-1 and GIP, thereby regulating
their effects (Figure 4).2 Following the discovery that GLP-1 and GIP
are degraded various inhibitors of the DPP-4 enzyme were identified.
These findings paved the way for a novel means of reducing blood
glucose levels via modulation of the incretin effect; namely prolonging
the effect of native GLP-1, the biological activity of which is limited by
a half-life of less than 2 minutes.17 Inhibition of DPP-4 has been shown
to increase endogenous GLP-1 levels by 2-to-3 fold, thereby improving
insulin secretion, suppressing glucagon, and lowering blood sugar.
Administration
Crucially, in terms of patient convenience, DPP-4 inhibitors are orally
active. Furthermore, sitagliptin, saxagliptin, linagliptin and alogliptin
only have to be taken once a day, while vildagliptin is taken twice
a day. With many oral antidiabetic drugs (OADs), a dose-finding period
is required at the initiation of therapy, in which the most appropriate
dose for a particular patient is determined. With DPP-4 inhibitors,
a dose-finding period is unnecessary due to the way in which they act,
the speed with which they act and the fact that gastrointestinal disturbances,
such as nausea and vomiting are not common problems.
These characteristics of DPP-4 inhibitors make them suitable for use in
combination regimens.18-21
Efficacy
HbA1c lowering
Currently, there are four DPP-4 inhibitors on the market: sitagliptin, vildagliptin,
saxagliptin and linagliptin, while the arrival of alogliptin onto the
market is imminent. All of these agents have a unique mechanism of
action compared with the other OADs, namely their ability to potentiate
the activity of GLP-1 and enhance insulin secretion in a glucosedependent
manner.22 Numerous randomised controlled clinical trials have
demonstrated that DPP-4 inhibitors can reduce HbA1c, fasting plasma
glucose (FPG) and postprandial glucose (PPG) versus placebo. Tables
1–4 present some of the key information from the sitagliptin, vildagliptin,
saxagliptin and alogliptin clinical trials. The efficacy of linagliptin is discussed
in some detail later in this chapter.
Crucially, in terms of patient convenience, DPP-4 inhibitors are orally
active. Furthermore, sitagliptin, saxagliptin, linagliptin and alogliptin
only have to be taken once a day, while vildagliptin is taken twice
a day. With many oral antidiabetic drugs (OADs), a dose-finding period
is required at the initiation of therapy, in which the most appropriate
dose for a particular patient is determined. With DPP-4 inhibitors,
a dose-finding period is unnecessary due to the way in which they act,
the speed with which they act and the fact that gastrointestinal disturbances,
such as nausea and vomiting are not common problems.
These characteristics of DPP-4 inhibitors make them suitable for use in
combination regimens.18-21
Efficacy
HbA1c lowering
Currently, there are four DPP-4 inhibitors on the market: sitagliptin, vildagliptin,
saxagliptin and linagliptin, while the arrival of alogliptin onto the
market is imminent. All of these agents have a unique mechanism of
action compared with the other OADs, namely their ability to potentiate
the activity of GLP-1 and enhance insulin secretion in a glucosedependent
manner.22 Numerous randomised controlled clinical trials have
demonstrated that DPP-4 inhibitors can reduce HbA1c, fasting plasma
glucose (FPG) and postprandial glucose (PPG) versus placebo. Tables
1–4 present some of the key information from the sitagliptin, vildagliptin,
saxagliptin and alogliptin clinical trials. The efficacy of linagliptin is discussed
in some detail later in this chapter.
Cardiovascular protection
Long-term safety data for DPP-4 inhibitors are not yet available. However,
there is evidence to suggest these agents may confer some degree
of cardiovascular protection.63 64 Further data to support or refute
this hypothesis is currently being collected in large, prospective studies.63
A number of meta-analyses have recently been published that investigate,
in detail, the cardiovascular safety of OADs. Sitagliptin was not
associated with an increased risk of major adverse cardiovascular
events.65 Likewise, vildagliptin was not associated with an increased risk
of adjudicated cardiovascular and cerebrovascular events, even in
a patient population that included subjects at increased risk of these
events.66
Long-term safety data for DPP-4 inhibitors are not yet available. However,
there is evidence to suggest these agents may confer some degree
of cardiovascular protection.63 64 Further data to support or refute
this hypothesis is currently being collected in large, prospective studies.63
A number of meta-analyses have recently been published that investigate,
in detail, the cardiovascular safety of OADs. Sitagliptin was not
associated with an increased risk of major adverse cardiovascular
events.65 Likewise, vildagliptin was not associated with an increased risk
of adjudicated cardiovascular and cerebrovascular events, even in
a patient population that included subjects at increased risk of these
events.66
Preservation of β-cell function
There is growing evidence that progressive β-cell dysfunction is crucial
for the development and progression of T2DM,67 68 the exact nature of
which is still not fully understood, although several β-cell “aggressors”
have been identified (Figure 5).69 In patients with T2DM it has been observed
there is a reduced islet number and/or diminished b-cell mass
in the pancreas due to increased apoptosis and inadequate regeneration.
70 β-cells are known to have a very low antioxidant capacity,
which has the potential to render them vulnerable to oxidative stress
by reactive oxygen and nitrogen species.71 This process is believed to
be central in the impairment of b-cell function during the development
of T2DM. 71
Although T2DM is associated with a progressive decline in b-cell function,
it has been shown that certain pharmacological treatments, such
as DPP-4 inhibitors, metformin and TZDs can ameliorate b-cell function.
72-74 In-vivo studies, usually performed in young rodents, have demonstrated
that DPP-4 inhibitors exhibit favourable actions on islet and
b-cell mass, morphology, and survival.74 75 Since similar beneficial effects
were not observed with sulphonylurea treatment, it is believed that the
effects on insulin-secreting cells in these in-vivo studies are mediated
through specific actions of the drug(s) directly on b-cells rather than by
an improvement of the metabolic milieu.76
There is growing evidence that progressive β-cell dysfunction is crucial
for the development and progression of T2DM,67 68 the exact nature of
which is still not fully understood, although several β-cell “aggressors”
have been identified (Figure 5).69 In patients with T2DM it has been observed
there is a reduced islet number and/or diminished b-cell mass
in the pancreas due to increased apoptosis and inadequate regeneration.
70 β-cells are known to have a very low antioxidant capacity,
which has the potential to render them vulnerable to oxidative stress
by reactive oxygen and nitrogen species.71 This process is believed to
be central in the impairment of b-cell function during the development
of T2DM. 71
Although T2DM is associated with a progressive decline in b-cell function,
it has been shown that certain pharmacological treatments, such
as DPP-4 inhibitors, metformin and TZDs can ameliorate b-cell function.
72-74 In-vivo studies, usually performed in young rodents, have demonstrated
that DPP-4 inhibitors exhibit favourable actions on islet and
b-cell mass, morphology, and survival.74 75 Since similar beneficial effects
were not observed with sulphonylurea treatment, it is believed that the
effects on insulin-secreting cells in these in-vivo studies are mediated
through specific actions of the drug(s) directly on b-cells rather than by
an improvement of the metabolic milieu.76
Safety and tolerability
Besides their demonstrated efficacy in lowering blood glucose levels,
DPP-4 inhibitors have proven to be safe and well tolerated, with an
overall incidence of adverse events similar to placebo.19-21 The incidence
of specific adverse events is not increased with DPP-4 inhibitor
treatment compared with placebo, and the dropout rates from studies
due to adverse events are low.77
In some studies, upper respiratory tract infection, nasopharyngitis and
headache have been reported in patients treated with DPP-4 inhibitors;
a truly enhanced frequency has not been established.77 Even though
DPP-4 inhibitors appear to be generally well tolerated, the collective experience
with these drugs in the clinical setting has been relatively short;
therefore, long-term surveillance is critical for the detection of potential
adverse events that may occur rarely or following long-term use.77
In addition to its role in blood sugar homeostasis, the DPP-4 enzyme may
play a role in the immune system (CD26, a marker of activated T-lymphocytes,
is identical to DPP-4) and perhaps also in tumour biology.78 79
Extensive animal toxicology studies with high doses and long duration,
however, do not provide evidence to support the theory that DPP-4
inhibitors have the potential to cause or promote tumours. A recent
analysis of the FDA adverse events reporting database has been much
debated, with the preliminary conclusion that the findings of an elevated
risk for acute pancreatitis and pancreatic carcinoma found in
the case of sitagliptin80 contradict findings from other analyses, are in
part biologically implausible, and most likely are the result of reporting
bias. However, a final judgement cannot be made based on findings
currently available, and results from larger and longer duration clinical
trials and other methods of surveillance need to be waited for to allow
firmer conclusions.
Hypoglycaemia
An important consideration in the tolerability of OAD therapy is hypoglycaemia;
however, compared to some of the OADs on the market,
DPP-4 inhibitors are associated with a low incidence of hypoglycaemia
thanks to their novel mode of action.18 DPP-4 inhibitors avoid the risk of
hypoglycaemia in two ways:
zzGLP-1, the levels of which are increased by DPP-4 inhibition, suppresses
glucagon release only at euglycaemia, but not at hypoglycaemic plasma
glucose concentrations.81
zzDPP-4 inhibitors may, in addition, enhance α-cell responsiveness to the
suppressive effects of hyperglycaemia and the stimulatory effects of hypoglycaemia,
as shown for vildagliptin.82
Besides their demonstrated efficacy in lowering blood glucose levels,
DPP-4 inhibitors have proven to be safe and well tolerated, with an
overall incidence of adverse events similar to placebo.19-21 The incidence
of specific adverse events is not increased with DPP-4 inhibitor
treatment compared with placebo, and the dropout rates from studies
due to adverse events are low.77
In some studies, upper respiratory tract infection, nasopharyngitis and
headache have been reported in patients treated with DPP-4 inhibitors;
a truly enhanced frequency has not been established.77 Even though
DPP-4 inhibitors appear to be generally well tolerated, the collective experience
with these drugs in the clinical setting has been relatively short;
therefore, long-term surveillance is critical for the detection of potential
adverse events that may occur rarely or following long-term use.77
In addition to its role in blood sugar homeostasis, the DPP-4 enzyme may
play a role in the immune system (CD26, a marker of activated T-lymphocytes,
is identical to DPP-4) and perhaps also in tumour biology.78 79
Extensive animal toxicology studies with high doses and long duration,
however, do not provide evidence to support the theory that DPP-4
inhibitors have the potential to cause or promote tumours. A recent
analysis of the FDA adverse events reporting database has been much
debated, with the preliminary conclusion that the findings of an elevated
risk for acute pancreatitis and pancreatic carcinoma found in
the case of sitagliptin80 contradict findings from other analyses, are in
part biologically implausible, and most likely are the result of reporting
bias. However, a final judgement cannot be made based on findings
currently available, and results from larger and longer duration clinical
trials and other methods of surveillance need to be waited for to allow
firmer conclusions.
Hypoglycaemia
An important consideration in the tolerability of OAD therapy is hypoglycaemia;
however, compared to some of the OADs on the market,
DPP-4 inhibitors are associated with a low incidence of hypoglycaemia
thanks to their novel mode of action.18 DPP-4 inhibitors avoid the risk of
hypoglycaemia in two ways:
zzGLP-1, the levels of which are increased by DPP-4 inhibition, suppresses
glucagon release only at euglycaemia, but not at hypoglycaemic plasma
glucose concentrations.81
zzDPP-4 inhibitors may, in addition, enhance α-cell responsiveness to the
suppressive effects of hyperglycaemia and the stimulatory effects of hypoglycaemia,
as shown for vildagliptin.82
Even though DPP-4 inhibitor treatment by itself is associated with a minimal
risk of hypoglycaemia, caution is required when they are added to
agents, which themselves can cause hypoglycaemia, such as SUs or insulin.
Recently updated prescribing information in the US recommends
that when sitagliptin is used with insulinotropic agents, a lower dose of
the latter may be required to reduce the risk of hypoglycaemia.83 If at
all possible, this combination should be avoided.
Weight gain
Weight gain is another important concern in OAD therapy as some
compounds, such as SUs, non-SU secretagogues and TZDs are associated
with significant increases in weight.84 Clinical studies have demonstrated
that DPP-4 inhibitors are body-weight neutral.77
Other safety issues
Angioedema has been reported in patients receiving vildagliptin and
concomitant ACE inhibitors. Also, there have been incidences of skin
lesions with vildagliptin, including blistering and ulceration, in nonclinical
toxicology studies.85 Vildagliptin has not been approved in the U.S.
due to a lack of studies in patients with renal impairment. In addition, in
those markets where vildagliptin is approved, liver function monitoring
is recommended with vildagliptin at three-month intervals during the
first year and periodically thereafter.21 With saxagliptin, a dose-related
mean decrease in absolute lymphocyte count was observed during
clinical development, but the clinical relevance of this is unknown.86
Post-marketing reports of serious hypersensitivity reactions in patients
treated with sitagliptin have been reported. These reactions include
anaphylaxis, angioedema, and exfoliative skin conditions including
Stevens-Johnson syndrome.20 Pending approval and the appropriate
dose reduction, sitagliptin and saxagliptin may be used in patients with
renal impairment. Alogliptin has been withdrawn from the FDA approval
process due to insufficient cardiovascular safety data, but it has
been approved in Japan.
Elimination and implications for renal impairment
The DPP-4 inhibitors, sitagliptin, vildagliptin, saxagliptin and alogliptin
are primarily excreted via the kidneys. This route of elimination has
obvious implications for the use of these agents in patients with renal
impairment. Consequently, the prescribing information for sitagliptin,
vildagliptin and saxagliptin in the EU recommend these agents should
not be used in patients with moderate or severe renal impairment.19-21
The equivalent information in the US recommends these agents can be
used in patients with moderate and severe renal impairment with the
appropriate dose adjustment.83
risk of hypoglycaemia, caution is required when they are added to
agents, which themselves can cause hypoglycaemia, such as SUs or insulin.
Recently updated prescribing information in the US recommends
that when sitagliptin is used with insulinotropic agents, a lower dose of
the latter may be required to reduce the risk of hypoglycaemia.83 If at
all possible, this combination should be avoided.
Weight gain
Weight gain is another important concern in OAD therapy as some
compounds, such as SUs, non-SU secretagogues and TZDs are associated
with significant increases in weight.84 Clinical studies have demonstrated
that DPP-4 inhibitors are body-weight neutral.77
Other safety issues
Angioedema has been reported in patients receiving vildagliptin and
concomitant ACE inhibitors. Also, there have been incidences of skin
lesions with vildagliptin, including blistering and ulceration, in nonclinical
toxicology studies.85 Vildagliptin has not been approved in the U.S.
due to a lack of studies in patients with renal impairment. In addition, in
those markets where vildagliptin is approved, liver function monitoring
is recommended with vildagliptin at three-month intervals during the
first year and periodically thereafter.21 With saxagliptin, a dose-related
mean decrease in absolute lymphocyte count was observed during
clinical development, but the clinical relevance of this is unknown.86
Post-marketing reports of serious hypersensitivity reactions in patients
treated with sitagliptin have been reported. These reactions include
anaphylaxis, angioedema, and exfoliative skin conditions including
Stevens-Johnson syndrome.20 Pending approval and the appropriate
dose reduction, sitagliptin and saxagliptin may be used in patients with
renal impairment. Alogliptin has been withdrawn from the FDA approval
process due to insufficient cardiovascular safety data, but it has
been approved in Japan.
Elimination and implications for renal impairment
The DPP-4 inhibitors, sitagliptin, vildagliptin, saxagliptin and alogliptin
are primarily excreted via the kidneys. This route of elimination has
obvious implications for the use of these agents in patients with renal
impairment. Consequently, the prescribing information for sitagliptin,
vildagliptin and saxagliptin in the EU recommend these agents should
not be used in patients with moderate or severe renal impairment.19-21
The equivalent information in the US recommends these agents can be
used in patients with moderate and severe renal impairment with the
appropriate dose adjustment.83
Guidelines
DPP-4 inhibitors have become an important part of the T2DM treatment
strategy, to the extent where a number of the relevant guidelines make
specific recommendations concerning the use of these compounds in
people with this condition (Table 5).
DPP-4 inhibitors have become an important part of the T2DM treatment
strategy, to the extent where a number of the relevant guidelines make
specific recommendations concerning the use of these compounds in
people with this condition (Table 5).
Other incretin therapies
DPP-4 inhibitors are not the only incretin therapies available for the
management of T2DM. Exenatide and liraglutide are two other drugs
that act on the incretin system. Instead of impeding the degradation
of native GLP-1, exenatide mimics GLP-1, whereas as liraglutide is an
analogue of this incretin (both stimulate GLP-1 receptors and, thus, are
GLP-1 receptor agonists). In this section we will compare and contrast
these agents with the DPP-4 inhibitors.
Exenatide is a peptide hormone and a synthetic version of exendin-4, a
hormone found in the saliva of the venomous lizard, the Gila monster.
This hormone is composed of 39 amino acids, of which >50% are the
same as those found in human GLP-1.92 The actions this drug has on the
body in terms of glucose homeostasis are very similar to GLP-1. However,
unlike endogenous or human recombinant GLP-1, it is more resistant
to being broken down by the DPP-4 enzyme because of its different
molecular structure, thereby extending its duration of action in vivo.92
Liraglutide is a human GLP-1 analogue produced by recombinant DNA
technology in a species of yeast (Saccharomyces cerevisiae). The
linked amino acids that form the backbone of liraglutide are genetically
engineered so that it bears a small fatty-acid chain, an addition
to the hormone that renders it more resistant to degradation by the
DPP-4 enzyme. This modification extends the half-life of liraglutide in the
body.93
Differentiating DPP-4 inhibitors from GLP-1 mimetics and
analogues
Administration
Being peptides, both exenatide and liraglutide would be digested in the
GI tract if they were swallowed as an oral formulation; therefore, they
must be administered via subcutaneous injection into the abdomen,
upper thigh or arm. Exenatide must be injected twice a day, whereas
liraglutide only needs to be injected once a day.94 95 Oral administration
of a drug is more convenient for the patient than an injection and this
route of administration may be a barrier to using exenatide and liraglutide
in patients with such preferences.
Efficacy
Both DPP-4 inhibitors and GLP-1 mimetics/analogues differ in their efficacy
and adverse event profiles. In clinical trials exenatide treatment
was shown to be safe and efficacious. This GLP-1 mimic significantly
DPP-4 inhibitors are not the only incretin therapies available for the
management of T2DM. Exenatide and liraglutide are two other drugs
that act on the incretin system. Instead of impeding the degradation
of native GLP-1, exenatide mimics GLP-1, whereas as liraglutide is an
analogue of this incretin (both stimulate GLP-1 receptors and, thus, are
GLP-1 receptor agonists). In this section we will compare and contrast
these agents with the DPP-4 inhibitors.
Exenatide is a peptide hormone and a synthetic version of exendin-4, a
hormone found in the saliva of the venomous lizard, the Gila monster.
This hormone is composed of 39 amino acids, of which >50% are the
same as those found in human GLP-1.92 The actions this drug has on the
body in terms of glucose homeostasis are very similar to GLP-1. However,
unlike endogenous or human recombinant GLP-1, it is more resistant
to being broken down by the DPP-4 enzyme because of its different
molecular structure, thereby extending its duration of action in vivo.92
Liraglutide is a human GLP-1 analogue produced by recombinant DNA
technology in a species of yeast (Saccharomyces cerevisiae). The
linked amino acids that form the backbone of liraglutide are genetically
engineered so that it bears a small fatty-acid chain, an addition
to the hormone that renders it more resistant to degradation by the
DPP-4 enzyme. This modification extends the half-life of liraglutide in the
body.93
Differentiating DPP-4 inhibitors from GLP-1 mimetics and
analogues
Administration
Being peptides, both exenatide and liraglutide would be digested in the
GI tract if they were swallowed as an oral formulation; therefore, they
must be administered via subcutaneous injection into the abdomen,
upper thigh or arm. Exenatide must be injected twice a day, whereas
liraglutide only needs to be injected once a day.94 95 Oral administration
of a drug is more convenient for the patient than an injection and this
route of administration may be a barrier to using exenatide and liraglutide
in patients with such preferences.
Efficacy
Both DPP-4 inhibitors and GLP-1 mimetics/analogues differ in their efficacy
and adverse event profiles. In clinical trials exenatide treatment
was shown to be safe and efficacious. This GLP-1 mimic significantly
reduced HbA1C by -0.4% to -0.86% and body weight by 1.6kg to 2.8kg depending
on the dose and the study.96-98 A study has shown that liraglutide
is superior to sitagliptin in terms of HbA1c reduction (-1.5% vs. -0.9%).99 In a
head-to-head study, liraglutide also out-performed exenatide; reducing
HbA1c by -1.12% compared with -0.79% for exenatide.100
With increasing interaction of GLP-1 or GLP-1 receptor agonists with
GLP-1 receptors, as obtained with both GLP-1 analogues (high, pharmacological
concentrations) and DPP-4 inhibitors (near-physiological
concentrations, approximately 2-3 fold above placebo levels), there
are significant effects on the pancreatic islets and the respective glucose
homeostasis. Higher concentrations (which may not be reached
with DPP-4 inhibitor therapy due to their mechanism of action) are
needed to slow down gastric emptying and to reduce appetite – characteristics
of exenatide and liraglutide. Significant weight loss is one of
the major advantages of GLP-1 mimetic/analogue therapy.
Safety and tolerability
In terms of safety tolerability, exenatide and liraglutide appear to be
generally well tolerated, although they are associated with gastrointestinal
adverse events, such as nausea, diarrhoea and vomiting.101 Both,
exenatide and liraglutide have been shown to be associated with improved
cardiovascular disease risk factors.102 103 Exenatide should not
be used in patients with severe renal impairment or end-stage renal disease
and should be used with caution in patients with renal transplantation.
94 Liraglutide should be used with caution in renal impairment due
to limited experience in this patient population.95 Acute pancreatitis is
a potential concern for all incretin-based therapies. There have been
reports of acute pancreatitis in people treated with exenatide. Albeit
rare, these prompted the regulatory bodies to release safety warnings
regarding the use of this drug.94 It seems that acute pancreatitis is not
limited to the GLP-1 mimetics. As of January 2010 88 cases of acute
pancreatitis in patients taking sitagliptin had been reported to the FDA,
prompting a revision of the package insert for this drug as well.104 The
recent analysis of the FDA adverse events reporting database concludes
that careful long-term monitoring of patients treated with GLP-1 mimetics
or DPP-4 inhibitors is required.80
Linagliptin – key characteristics
Linagliptin is a forthcoming addition to the DPP-4 inhibitor class. This section
looks at the key attributes of this drug, especially those that differentiate
it from the other DPP-4 inhibitors.
on the dose and the study.96-98 A study has shown that liraglutide
is superior to sitagliptin in terms of HbA1c reduction (-1.5% vs. -0.9%).99 In a
head-to-head study, liraglutide also out-performed exenatide; reducing
HbA1c by -1.12% compared with -0.79% for exenatide.100
With increasing interaction of GLP-1 or GLP-1 receptor agonists with
GLP-1 receptors, as obtained with both GLP-1 analogues (high, pharmacological
concentrations) and DPP-4 inhibitors (near-physiological
concentrations, approximately 2-3 fold above placebo levels), there
are significant effects on the pancreatic islets and the respective glucose
homeostasis. Higher concentrations (which may not be reached
with DPP-4 inhibitor therapy due to their mechanism of action) are
needed to slow down gastric emptying and to reduce appetite – characteristics
of exenatide and liraglutide. Significant weight loss is one of
the major advantages of GLP-1 mimetic/analogue therapy.
Safety and tolerability
In terms of safety tolerability, exenatide and liraglutide appear to be
generally well tolerated, although they are associated with gastrointestinal
adverse events, such as nausea, diarrhoea and vomiting.101 Both,
exenatide and liraglutide have been shown to be associated with improved
cardiovascular disease risk factors.102 103 Exenatide should not
be used in patients with severe renal impairment or end-stage renal disease
and should be used with caution in patients with renal transplantation.
94 Liraglutide should be used with caution in renal impairment due
to limited experience in this patient population.95 Acute pancreatitis is
a potential concern for all incretin-based therapies. There have been
reports of acute pancreatitis in people treated with exenatide. Albeit
rare, these prompted the regulatory bodies to release safety warnings
regarding the use of this drug.94 It seems that acute pancreatitis is not
limited to the GLP-1 mimetics. As of January 2010 88 cases of acute
pancreatitis in patients taking sitagliptin had been reported to the FDA,
prompting a revision of the package insert for this drug as well.104 The
recent analysis of the FDA adverse events reporting database concludes
that careful long-term monitoring of patients treated with GLP-1 mimetics
or DPP-4 inhibitors is required.80
Linagliptin – key characteristics
Linagliptin is a forthcoming addition to the DPP-4 inhibitor class. This section
looks at the key attributes of this drug, especially those that differentiate
it from the other DPP-4 inhibitors.
Pharmacology and pharmacokinetics
The affinity of linagliptin for the DPP-4 enzyme is high, which results in a
slow dissociation of this compound from its substrate. Compared with
vildagliptin, linagliptin has a 10-fold slower dissociation/off-rate.105 The
very low dissociation of linagliptin complements the potency of this
drug, which is the highest in its class.105 Linagliptin has the highest selectivity
for DPP-4 relative to DPP-8 and DPP-9 of all the DPP-4 inhibitors.106-110
Linagliptin is 10,000 times more selective for DPP-4 than it is for either
DPP-8 or DPP-9. This has potential implications for the tolerability and
long-term safety of linagliptin, since the specific functions of DPP-8 and
DPP-9 have not yet been elucidated. A high selectivity for DPP-4 reduces
the likelihood of possible adverse effects related to the inadvertent
inhibition of DPP-8 and DPP-9.111
Early clinical studies involving healthy volunteers demonstrated that
linagliptin is rapidly absorbed following oral administration of a 5 mg
dose. Peak plasma concentrations were reached after 1.5 hours. As a
consequence of the tight binding of linagliptin to its substrate it has a
long terminal half-life of more than 100 hours, but this does not contribute
to the accumulation of the drug. The effective half-life for accumulation
of linagliptin is approximately 12 hours. After once-daily dosing,
steady-state plasma concentrations of 5 mg linagliptin are reached by
the third dose.112 The co-administration of a high-fat meal with linagliptin
had no clinically relevant effects on pharmacokinetics; therefore
it may be administered with or without food.
Perhaps the most salient of linagliptin’s pharmacokinetic characteristics
is its primarily non-renal route of excretion. Renal excretion accounts for
only 5% of the dose. One main metabolite was detected during the
course of preclinical studies, but this was found to be pharmacologically
inactive. With its primarily non-renal route of elimination linagliptin
can be used in patients with any degree of renal or liver impairment or
cardiac insufficiency. No warnings/precautions, dose adjustments and
additional monitoring of renal or liver function are required in patients
treated with linagliptin.
Efficacy
Linagliptin was tested in a large clinical trial program involving >6,500
patients in more than 40 countries. These randomised, controlled studies
have shown that linagliptin reduces HbA1c in all stages of T2DM and in
combination with all currently used treatment regimens. In addition, improvements
in FPG, PPG and β-cell function have been demonstrated.
Key information from these studies is summarised in Table 6. As monotherapy,
linagliptin has been shown to provide a significant and clini
The affinity of linagliptin for the DPP-4 enzyme is high, which results in a
slow dissociation of this compound from its substrate. Compared with
vildagliptin, linagliptin has a 10-fold slower dissociation/off-rate.105 The
very low dissociation of linagliptin complements the potency of this
drug, which is the highest in its class.105 Linagliptin has the highest selectivity
for DPP-4 relative to DPP-8 and DPP-9 of all the DPP-4 inhibitors.106-110
Linagliptin is 10,000 times more selective for DPP-4 than it is for either
DPP-8 or DPP-9. This has potential implications for the tolerability and
long-term safety of linagliptin, since the specific functions of DPP-8 and
DPP-9 have not yet been elucidated. A high selectivity for DPP-4 reduces
the likelihood of possible adverse effects related to the inadvertent
inhibition of DPP-8 and DPP-9.111
Early clinical studies involving healthy volunteers demonstrated that
linagliptin is rapidly absorbed following oral administration of a 5 mg
dose. Peak plasma concentrations were reached after 1.5 hours. As a
consequence of the tight binding of linagliptin to its substrate it has a
long terminal half-life of more than 100 hours, but this does not contribute
to the accumulation of the drug. The effective half-life for accumulation
of linagliptin is approximately 12 hours. After once-daily dosing,
steady-state plasma concentrations of 5 mg linagliptin are reached by
the third dose.112 The co-administration of a high-fat meal with linagliptin
had no clinically relevant effects on pharmacokinetics; therefore
it may be administered with or without food.
Perhaps the most salient of linagliptin’s pharmacokinetic characteristics
is its primarily non-renal route of excretion. Renal excretion accounts for
only 5% of the dose. One main metabolite was detected during the
course of preclinical studies, but this was found to be pharmacologically
inactive. With its primarily non-renal route of elimination linagliptin
can be used in patients with any degree of renal or liver impairment or
cardiac insufficiency. No warnings/precautions, dose adjustments and
additional monitoring of renal or liver function are required in patients
treated with linagliptin.
Efficacy
Linagliptin was tested in a large clinical trial program involving >6,500
patients in more than 40 countries. These randomised, controlled studies
have shown that linagliptin reduces HbA1c in all stages of T2DM and in
combination with all currently used treatment regimens. In addition, improvements
in FPG, PPG and β-cell function have been demonstrated.
Key information from these studies is summarised in Table 6. As monotherapy,
linagliptin has been shown to provide a significant and clini
cally meaningful treatment option for T2DM patients including those
whose treatment options are limited due to renal impairment.
As monotherapy and in combination with metformin and metformin
and a SU, linagliptin was proven to be most efficacious in patients with
higher baseline HbA1c values. In addition to significantly lowering HbA1c
(Table 6), linagliptin as monotherapy also had favourable effects on
FPG and 2h PPG. At 24 weeks these glycaemic parameters were reduced
by -23 mg/dL (-1.3 mmol/L) and -58 mg/dL (-3.2 mmol/L), respectively
versus placebo.113
As an add-on to metformin, linagliptin therapy significantly reduced
HbA1c at 24 weeks (Table 6), and also yielded significant, placebocorrected
reductions in mean FPG (-23 mg/dL, or -1.3 mmol/L) and 2h
PPG (- 67 mg/dl).114 Likewise, triple therapy (metformin + SU + linagliptin)
significantly reduced HbA1c (Table 6). The placebo-adjusted reduction
in FPG with this triple therapy regimen was -13 mg/dL at 24 weeks.115
In initial combination therapy with a pioglitazone, linagliptin therapy
significantly reduced HbA1c (Table 6).116
whose treatment options are limited due to renal impairment.
As monotherapy and in combination with metformin and metformin
and a SU, linagliptin was proven to be most efficacious in patients with
higher baseline HbA1c values. In addition to significantly lowering HbA1c
(Table 6), linagliptin as monotherapy also had favourable effects on
FPG and 2h PPG. At 24 weeks these glycaemic parameters were reduced
by -23 mg/dL (-1.3 mmol/L) and -58 mg/dL (-3.2 mmol/L), respectively
versus placebo.113
As an add-on to metformin, linagliptin therapy significantly reduced
HbA1c at 24 weeks (Table 6), and also yielded significant, placebocorrected
reductions in mean FPG (-23 mg/dL, or -1.3 mmol/L) and 2h
PPG (- 67 mg/dl).114 Likewise, triple therapy (metformin + SU + linagliptin)
significantly reduced HbA1c (Table 6). The placebo-adjusted reduction
in FPG with this triple therapy regimen was -13 mg/dL at 24 weeks.115
In initial combination therapy with a pioglitazone, linagliptin therapy
significantly reduced HbA1c (Table 6).116
cally meaningful treatment option for T2DM patients including those
whose treatment options are limited due to renal impairment.
As monotherapy and in combination with metformin and metformin
and a SU, linagliptin was proven to be most efficacious in patients with
higher baseline HbA1c values. In addition to significantly lowering HbA1c
(Table 6), linagliptin as monotherapy also had favourable effects on
FPG and 2h PPG. At 24 weeks these glycaemic parameters were reduced
by -23 mg/dL (-1.3 mmol/L) and -58 mg/dL (-3.2 mmol/L), respectively
versus placebo.113
As an add-on to metformin, linagliptin therapy significantly reduced
HbA1c at 24 weeks (Table 6), and also yielded significant, placebocorrected
reductions in mean FPG (-23 mg/dL, or -1.3 mmol/L) and 2h
PPG (- 67 mg/dl).114 Likewise, triple therapy (metformin + SU + linagliptin)
significantly reduced HbA1c (Table 6). The placebo-adjusted reduction
in FPG with this triple therapy regimen was -13 mg/dL at 24 weeks.115
In initial combination therapy with a pioglitazone, linagliptin therapy
significantly reduced HbA1c (Table 6).116
whose treatment options are limited due to renal impairment.
As monotherapy and in combination with metformin and metformin
and a SU, linagliptin was proven to be most efficacious in patients with
higher baseline HbA1c values. In addition to significantly lowering HbA1c
(Table 6), linagliptin as monotherapy also had favourable effects on
FPG and 2h PPG. At 24 weeks these glycaemic parameters were reduced
by -23 mg/dL (-1.3 mmol/L) and -58 mg/dL (-3.2 mmol/L), respectively
versus placebo.113
As an add-on to metformin, linagliptin therapy significantly reduced
HbA1c at 24 weeks (Table 6), and also yielded significant, placebocorrected
reductions in mean FPG (-23 mg/dL, or -1.3 mmol/L) and 2h
PPG (- 67 mg/dl).114 Likewise, triple therapy (metformin + SU + linagliptin)
significantly reduced HbA1c (Table 6). The placebo-adjusted reduction
in FPG with this triple therapy regimen was -13 mg/dL at 24 weeks.115
In initial combination therapy with a pioglitazone, linagliptin therapy
significantly reduced HbA1c (Table 6).116
Safety and tolerability
The linagliptin studies conducted to date have demonstrated weight
neutrality in mono- and combination therapies. Additionally, there was
no increased risk of hypoglycaemia attributed to linagliptin use in monotherapy
or combination therapy with metformin or pioglitazone. Like
the other DPP-4 inhibitors, the overall incidence rate of adverse events
reported for linagliptin was similar to placebo (55.0% versus 53.8%). Discontinuation
of therapy due to adverse events was higher in patients
who received placebo as compared to linagliptin 5 mg (3.6 % versus
2.3 %). The most frequently reported adverse event in the linagliptin
clinical trial programme was hypoglycaemia because of those cases
observed in the triple combination study (metformin + sulphonylurea +
linagliptin). The incidence of hypoglycaemia in this study was 22.9% in
the treatment arm compared with 14.8% in the placebo arm. None of
these cases of hypoglycaemia was classified as severe.
The linagliptin studies conducted to date have demonstrated weight
neutrality in mono- and combination therapies. Additionally, there was
no increased risk of hypoglycaemia attributed to linagliptin use in monotherapy
or combination therapy with metformin or pioglitazone. Like
the other DPP-4 inhibitors, the overall incidence rate of adverse events
reported for linagliptin was similar to placebo (55.0% versus 53.8%). Discontinuation
of therapy due to adverse events was higher in patients
who received placebo as compared to linagliptin 5 mg (3.6 % versus
2.3 %). The most frequently reported adverse event in the linagliptin
clinical trial programme was hypoglycaemia because of those cases
observed in the triple combination study (metformin + sulphonylurea +
linagliptin). The incidence of hypoglycaemia in this study was 22.9% in
the treatment arm compared with 14.8% in the placebo arm. None of
these cases of hypoglycaemia was classified as severe.
What do these attributes mean for patients with T2DM?
It is anticipated that the primarily non-renal route of elimination of linagliptin
will allow this compound to be used in people with renal insufficiency
without dose adjustments. This has potentially important implications
for T2DM management in light of the fact that at least a third of
people with diabetes have some degree of renal impairment and that
many current T2DM treatments are contraindicated in patients with
renal impairment.84 122
The high potency of linagliptin means that a low dose of linagliptin can
be administered to T2DM patients in small tablets; features that are crucial
to the good tolerability of a drug and the willingness of people with
T2DM to take their medication as prescribed. Additionally, these attributes
lend linagliptin to inclusion in fixed-dose combinations. The high
selectivity of linagliptin for the DPP-4 enzyme rather than DPP-8 or DPP-9
is reassuring, in that no untoward off-target interactions are expected,
helping to confer a placebo-like tolerability profile. As linagliptin binds
tightly to the DPP-4 enzyme, a single dose taken at any time of the day
is sufficient to provide a full 24 hours of glycaemic control.
It is anticipated that the primarily non-renal route of elimination of linagliptin
will allow this compound to be used in people with renal insufficiency
without dose adjustments. This has potentially important implications
for T2DM management in light of the fact that at least a third of
people with diabetes have some degree of renal impairment and that
many current T2DM treatments are contraindicated in patients with
renal impairment.84 122
The high potency of linagliptin means that a low dose of linagliptin can
be administered to T2DM patients in small tablets; features that are crucial
to the good tolerability of a drug and the willingness of people with
T2DM to take their medication as prescribed. Additionally, these attributes
lend linagliptin to inclusion in fixed-dose combinations. The high
selectivity of linagliptin for the DPP-4 enzyme rather than DPP-8 or DPP-9
is reassuring, in that no untoward off-target interactions are expected,
helping to confer a placebo-like tolerability profile. As linagliptin binds
tightly to the DPP-4 enzyme, a single dose taken at any time of the day
is sufficient to provide a full 24 hours of glycaemic control.
Chapter 4 Summary
zzEating promotes a much greater degree of insulin secretion compared with
intravenous injection of glucose. This is the incretin effect, a physiological
phenomenon mediated by the incretin hormones, notably glucagon-like
peptide-1 (GLP-1) and gastric inhibitory peptide (GIP).
zzIncretin hormones elicit an increase in glucose-dependent insulin secretion
and suppress glucagon secretion as well as increasing sensitivity to insulin
and glucose uptake in the peripheral tissues, independent of insulin secretion.
zzGLP-1 may stimulate increases in β-cell mass and function (animal and cell
line studies).
zzIn people with T2DM there are several defects in the incretin effect:
◦◦ Decreased potency of GLP-1 in stimulating the production and release
of insulin.
◦◦ An almost complete loss of late-phase insulin secretion in response to GIP.
◦◦ Suppression of glucagon secretion is impaired during oral glucose tolerance
tests (OGTTs) as opposed to isoglycaemic intravenous glucose infusion.
zzDPP-4 inhibitors can enhance and prolong the effects of endogenous GLP-1
by inhibiting the enzyme that rapidly degrades this incretin hormone.
zzThese DPP-4 inhibitors are orally active, do not require a dose-finding period
and two of the three types currently available only have to be taken
once a day.
zzDPP-4 inhibitors can significantly reduce HBA1c, FPG and PPG. There is also
some evidence to suggest they may preserve β-cell function and provide
some degree of cardiovascular protection. However, studies proving a
lasting improvement in the course of diabetes progression still have to be
initiated.
zzGenerally, DPP-4 inhibitors have proven to be safe and well tolerated, with
an overall incidence of adverse events similar to placebo.
◦◦ DPP-4 inhibitor treatment is associated with a low incidence of hypoglycaemia
due to their glucose-dependent mode of action (as derived from
studies with GLP-1).
◦◦ DPP-4 inhibitors are body-weight neutral.
◦◦ Specific issues with vildagliptin may be angioedema, skin lesions and elevation
in liver enzymes (with uncertain impact on the spectrum of adverse
events observed with clinical use). Saxagliptin has been associated
with a minor decrease in absolute mean lymphocyte count, again with
uncertain clinical significance.
◦◦ All the currently available DPP-4 inhibitors (sitagliptin, saxagliptin, vildagliptin
and alogliptin) are primarily excreted via the kidneys with implications for
their use in people with renal impairment (dose reduction or avoidance of
use in that particular population).
◦◦ The suspicion has been raised based on analyses from an adverse events
reporting database located at the FDA that pancreatitis and pancreatic
carcinoma may be observed more often with sitagliptin treatment, but
this evidence is considered non-convincing due to the nature of this database
and the high likelihood for reporting bias.
zzEating promotes a much greater degree of insulin secretion compared with
intravenous injection of glucose. This is the incretin effect, a physiological
phenomenon mediated by the incretin hormones, notably glucagon-like
peptide-1 (GLP-1) and gastric inhibitory peptide (GIP).
zzIncretin hormones elicit an increase in glucose-dependent insulin secretion
and suppress glucagon secretion as well as increasing sensitivity to insulin
and glucose uptake in the peripheral tissues, independent of insulin secretion.
zzGLP-1 may stimulate increases in β-cell mass and function (animal and cell
line studies).
zzIn people with T2DM there are several defects in the incretin effect:
◦◦ Decreased potency of GLP-1 in stimulating the production and release
of insulin.
◦◦ An almost complete loss of late-phase insulin secretion in response to GIP.
◦◦ Suppression of glucagon secretion is impaired during oral glucose tolerance
tests (OGTTs) as opposed to isoglycaemic intravenous glucose infusion.
zzDPP-4 inhibitors can enhance and prolong the effects of endogenous GLP-1
by inhibiting the enzyme that rapidly degrades this incretin hormone.
zzThese DPP-4 inhibitors are orally active, do not require a dose-finding period
and two of the three types currently available only have to be taken
once a day.
zzDPP-4 inhibitors can significantly reduce HBA1c, FPG and PPG. There is also
some evidence to suggest they may preserve β-cell function and provide
some degree of cardiovascular protection. However, studies proving a
lasting improvement in the course of diabetes progression still have to be
initiated.
zzGenerally, DPP-4 inhibitors have proven to be safe and well tolerated, with
an overall incidence of adverse events similar to placebo.
◦◦ DPP-4 inhibitor treatment is associated with a low incidence of hypoglycaemia
due to their glucose-dependent mode of action (as derived from
studies with GLP-1).
◦◦ DPP-4 inhibitors are body-weight neutral.
◦◦ Specific issues with vildagliptin may be angioedema, skin lesions and elevation
in liver enzymes (with uncertain impact on the spectrum of adverse
events observed with clinical use). Saxagliptin has been associated
with a minor decrease in absolute mean lymphocyte count, again with
uncertain clinical significance.
◦◦ All the currently available DPP-4 inhibitors (sitagliptin, saxagliptin, vildagliptin
and alogliptin) are primarily excreted via the kidneys with implications for
their use in people with renal impairment (dose reduction or avoidance of
use in that particular population).
◦◦ The suspicion has been raised based on analyses from an adverse events
reporting database located at the FDA that pancreatitis and pancreatic
carcinoma may be observed more often with sitagliptin treatment, but
this evidence is considered non-convincing due to the nature of this database
and the high likelihood for reporting bias.
zzSeveral guidelines make specific recommendations concerning the use of
DPP-4 inhibitors.
zzExenatide and liraglutide are injected incretin therapies.
◦◦ They are effective in reducing HbA1c as well as body weight.
◦◦ They are generally well tolerated and the most common adverse events
are gastrointestinal disturbances.
◦◦ Exenatide should not be used in patients with severe renal impairment or
end-stage renal disease and liraglutide should only be used with caution
in renal impairment.
◦◦ Acute pancreatitis is a potential concern for all incretin-based therapies,
including DPP-4 inhibitors and GLP-1 mimetics/analogues.
zzLinagliptin is a relatively new addition to the DPP-4 inhibitor market. It has the
following characteristics:
◦◦ A very high affinity for its substrate and a high level of potency compared
with the other compounds in its class.
◦◦ 10,000 times more selective for DPP-4 than it is for either DPP-8 or DPP-9.
◦◦ Rapidly absorbed and has a long terminal half-life of more than 100 hours.
◦◦ Administered as a single 5 mg tablet at any time of the day with or without
food.
◦◦ Primarily excreted non-renally; therefore it can be used without dose adjustments
or warnings in patients with renal impairment.
◦◦ In clinical trials, linagliptin alone or in combinations with other OADs has
demonstrated its ability to improve HbA1c, FPG, PPG and β-cell function.
◦◦ Linagliptin is weight neutral and has proved to be well tolerated.
DPP-4 inhibitors.
zzExenatide and liraglutide are injected incretin therapies.
◦◦ They are effective in reducing HbA1c as well as body weight.
◦◦ They are generally well tolerated and the most common adverse events
are gastrointestinal disturbances.
◦◦ Exenatide should not be used in patients with severe renal impairment or
end-stage renal disease and liraglutide should only be used with caution
in renal impairment.
◦◦ Acute pancreatitis is a potential concern for all incretin-based therapies,
including DPP-4 inhibitors and GLP-1 mimetics/analogues.
zzLinagliptin is a relatively new addition to the DPP-4 inhibitor market. It has the
following characteristics:
◦◦ A very high affinity for its substrate and a high level of potency compared
with the other compounds in its class.
◦◦ 10,000 times more selective for DPP-4 than it is for either DPP-8 or DPP-9.
◦◦ Rapidly absorbed and has a long terminal half-life of more than 100 hours.
◦◦ Administered as a single 5 mg tablet at any time of the day with or without
food.
◦◦ Primarily excreted non-renally; therefore it can be used without dose adjustments
or warnings in patients with renal impairment.
◦◦ In clinical trials, linagliptin alone or in combinations with other OADs has
demonstrated its ability to improve HbA1c, FPG, PPG and β-cell function.
◦◦ Linagliptin is weight neutral and has proved to be well tolerated.
References
1. Creutzfeldt W, Ebert R. New developments in the incretin concept. Diabetologia
1985;28(8):565-73.
2. Drucker DJ. The biology of incretin hormones. Cell metabolism 2006;3(3):153-65.
3. Meier JJ, Gethmann A, Nauck MA, Gotze O, Schmitz F, Deacon CF, et al. The
glucagon-like peptide-1 metabolite GLP-1-(9-36) amide reduces postprandial
glycemia independently of gastric emptying and insulin secretion in humans.
American journal of physiology. Endocrinology and metabolism 2006;290(6):E1118-23.
4. Drucker DJ. Glucagon-like peptides: regulators of cell proliferation, differentiation,
and apoptosis. Mol Endocrinol 2003;17(2):161-71.
5. Farilla L, Hui H, Bertolotto C, Kang E, Bulotta A, Di Mario U, et al. Glucagon-like
peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats.
Endocrinology 2002;143(11):4397-408.
6. Knop FK, Vilsboll T, Hojberg PV, Larsen S, Madsbad S, Volund A, et al. Reduced
incretin effect in type 2 diabetes: cause or consequence of the diabetic state?
Diabetes 2007;56(8):1951-9.
7. Toft-Nielsen MB, Damholt MB, Madsbad S, Hilsted LM, Hughes TE, Michelsen BK, et al.
Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic
patients. The Journal of clinical endocrinology and metabolism 2001;86(8):3717-23.
8. Vilsboll T, Krarup T, Deacon CF, Madsbad S, Holst JJ. Reduced postprandial concentrations
of intact biologically active glucagon-like peptide 1 in type 2 diabetic
patients. Diabetes 2001;50(3):609-13.
9. Nauck MA, Vardarli I, Deacon CF, Holst JJ, Meier JJ. Secretion of glucagon-like
peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia 2011;
54(1):10-8.
10. Kjems LL, Holst JJ, Volund A, Madsbad S. The influence of GLP-1 on glucose-stimulated
insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic
subjects. Diabetes 2003;52(2):380-6.
11. Vilsboll T, Krarup T, Madsbad S, Holst JJ. Defective amplification of the late phase
insulin response to glucose by GIP in obese Type II diabetic patients. Diabetologia
2002;45(8):1111-9.
12. Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved
incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human
gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. The Journal
of clinical investigation 1993;91(1):301-7.
13. Knop FK, Vilsboll T, Madsbad S, Krarup T, Holst JJ. Lack of suppression of glucagon
during OGTT but not during isoglycemic IVGTT in patients with type 2 diabetes.
Diabetes 2006;55 (Suppl. 1).
14. Meier JJ, Deacon CF, Schmidt WE, Holst JJ, Nauck MA. Suppression of glucagon
secretion is lower after oral glucose administration than during intravenous glucose
administration in human subjects. Diabetologia 2007;50(4):806-13.
15. Chen X. Biochemical properties of recombinant prolyl dipeptidases DPP-IV and
DPP8. Adv Exp Med Biol 2006;575:27-32.
16. Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Willms B, Holst JJ. Both subcutaneously
and intravenously administered glucagon-like peptide I are rapidly degraded
from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes
1995;44(9):1126-31.
17. Deacon CF, Nauck MA, Meier J, Hucking K, Holst JJ. Degradation of endogenous
and exogenous gastric inhibitory polypeptide in healthy and in type 2 diabetic
subjects as revealed using a new assay for the intact peptide. The Journal of clinical
endocrinology and metabolism 2000;85(10):3575-81.
18. Pratley RE, Salsali A. Inhibition of DPP-4: a new therapeutic approach for the treatment
of type 2 diabetes. Current medical research and opinion 2007;23(4):919-31.
19. Bristol-Myers Squibb Pharmaceuticals Ltd and AstraZeneca EEIG. Onglyza® Summary
of Product Characteristics. June, 2009.
20. Merck Sharpe & Dohme Ltd. Januvia® Summary of Product Characteristics. 2009.
21. Novartis Europharm Ltd. Galvus® Summary of Product Characteristics. 2009.
22. Levetan C. Oral antidiabetic agents in type 2 diabetes. Current medical research
and opinion 2007;23(4):945-52.
23. Hanefeld M, Herman GA, Wu M, Mickel C, Sanchez M, Stein PP. Once-daily sitagliptin,
a dipeptidyl peptidase-4 inhibitor, for the treatment of patients with type 2 diabetes.
Current medical research and opinion 2007;23(6):1329-39.
1. Creutzfeldt W, Ebert R. New developments in the incretin concept. Diabetologia
1985;28(8):565-73.
2. Drucker DJ. The biology of incretin hormones. Cell metabolism 2006;3(3):153-65.
3. Meier JJ, Gethmann A, Nauck MA, Gotze O, Schmitz F, Deacon CF, et al. The
glucagon-like peptide-1 metabolite GLP-1-(9-36) amide reduces postprandial
glycemia independently of gastric emptying and insulin secretion in humans.
American journal of physiology. Endocrinology and metabolism 2006;290(6):E1118-23.
4. Drucker DJ. Glucagon-like peptides: regulators of cell proliferation, differentiation,
and apoptosis. Mol Endocrinol 2003;17(2):161-71.
5. Farilla L, Hui H, Bertolotto C, Kang E, Bulotta A, Di Mario U, et al. Glucagon-like
peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats.
Endocrinology 2002;143(11):4397-408.
6. Knop FK, Vilsboll T, Hojberg PV, Larsen S, Madsbad S, Volund A, et al. Reduced
incretin effect in type 2 diabetes: cause or consequence of the diabetic state?
Diabetes 2007;56(8):1951-9.
7. Toft-Nielsen MB, Damholt MB, Madsbad S, Hilsted LM, Hughes TE, Michelsen BK, et al.
Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic
patients. The Journal of clinical endocrinology and metabolism 2001;86(8):3717-23.
8. Vilsboll T, Krarup T, Deacon CF, Madsbad S, Holst JJ. Reduced postprandial concentrations
of intact biologically active glucagon-like peptide 1 in type 2 diabetic
patients. Diabetes 2001;50(3):609-13.
9. Nauck MA, Vardarli I, Deacon CF, Holst JJ, Meier JJ. Secretion of glucagon-like
peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia 2011;
54(1):10-8.
10. Kjems LL, Holst JJ, Volund A, Madsbad S. The influence of GLP-1 on glucose-stimulated
insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic
subjects. Diabetes 2003;52(2):380-6.
11. Vilsboll T, Krarup T, Madsbad S, Holst JJ. Defective amplification of the late phase
insulin response to glucose by GIP in obese Type II diabetic patients. Diabetologia
2002;45(8):1111-9.
12. Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved
incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human
gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. The Journal
of clinical investigation 1993;91(1):301-7.
13. Knop FK, Vilsboll T, Madsbad S, Krarup T, Holst JJ. Lack of suppression of glucagon
during OGTT but not during isoglycemic IVGTT in patients with type 2 diabetes.
Diabetes 2006;55 (Suppl. 1).
14. Meier JJ, Deacon CF, Schmidt WE, Holst JJ, Nauck MA. Suppression of glucagon
secretion is lower after oral glucose administration than during intravenous glucose
administration in human subjects. Diabetologia 2007;50(4):806-13.
15. Chen X. Biochemical properties of recombinant prolyl dipeptidases DPP-IV and
DPP8. Adv Exp Med Biol 2006;575:27-32.
16. Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Willms B, Holst JJ. Both subcutaneously
and intravenously administered glucagon-like peptide I are rapidly degraded
from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes
1995;44(9):1126-31.
17. Deacon CF, Nauck MA, Meier J, Hucking K, Holst JJ. Degradation of endogenous
and exogenous gastric inhibitory polypeptide in healthy and in type 2 diabetic
subjects as revealed using a new assay for the intact peptide. The Journal of clinical
endocrinology and metabolism 2000;85(10):3575-81.
18. Pratley RE, Salsali A. Inhibition of DPP-4: a new therapeutic approach for the treatment
of type 2 diabetes. Current medical research and opinion 2007;23(4):919-31.
19. Bristol-Myers Squibb Pharmaceuticals Ltd and AstraZeneca EEIG. Onglyza® Summary
of Product Characteristics. June, 2009.
20. Merck Sharpe & Dohme Ltd. Januvia® Summary of Product Characteristics. 2009.
21. Novartis Europharm Ltd. Galvus® Summary of Product Characteristics. 2009.
22. Levetan C. Oral antidiabetic agents in type 2 diabetes. Current medical research
and opinion 2007;23(4):945-52.
23. Hanefeld M, Herman GA, Wu M, Mickel C, Sanchez M, Stein PP. Once-daily sitagliptin,
a dipeptidyl peptidase-4 inhibitor, for the treatment of patients with type 2 diabetes.
Current medical research and opinion 2007;23(6):1329-39.
24. Scott R, Wu M, Sanchez M, Stein P. Efficacy and tolerability of the dipeptidyl
peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2
diabetes. International journal of clinical practice 2007;61(1):171-80.
25. Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H. Efficacy and safety
of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with
type 2 diabetes mellitus. Diabetologia 2006;49(11):2564-71.
26. Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE.
Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic
control in patients with type 2 diabetes. Diabetes care 2006;29(12):2632-7.
27. Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP. Efficacy and safety of the
dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide,
in patients with type 2 diabetes inadequately controlled on metformin alone:
a randomized, double-blind, non-inferiority trial. Diabetes, obesity & metabolism
2007;9(2):194-205.
28. Scott R, Loeys T, Davies MJ, Engel SS. Efficacy and safety of sitagliptin when added
to ongoing metformin therapy in patients with type 2 diabetes. Diabetes, obesity &
metabolism 2008;10(10):959-69.
29. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Efficacy and safety of the
dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in
patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes
care 2006;29(12):2638-43.
30. Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE. Effect
of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor,
and metformin on glycemic control in patients with type 2 diabetes. Diabetes care
2007;30(8):1979-87.
31. Qi D, Teng R, Jiang M, et aI. Two-year treatment with sitagliptin and initial combination
therapy of sitaglitpin and metformin provides substantial and durable glycaemic
control in patients with type 2 diabetes. Diabetologia 2008;519(Suppl1):S36.
32. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P. Efficacy and safety of the dipeptidyl
peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients
with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebocontrolled,
parallel-group study. Clinical therapeutics 2006;28(10):1556-68.
33. Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P. Efficacy and safety of
the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes
mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin.
Diabetes, obesity & metabolism 2007;9(5):733-45.
34. Arjona Ferreira J, Dobs A, Goldstein B. Triple combination therapy with sitagliptin,
metformin and rosiglitazone improves glycaemic control in patients with type 2
diabetes. Diabetologia 2008;51(Suppl 1):S365.
35. Ahren B, Landin-Olsson M, Jansson PA, Svensson M, Holmes D, Schweizer A. Inhibition
of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces
glucagon levels in type 2 diabetes. The Journal of clinical endocrinology and
metabolism 2004;89(5):2078-84.
36. Pratley RE, Jauffret-Kamel S, Galbreath E, Holmes D. Twelve-week monotherapy
with the DPP-4 inhibitor vildagliptin improves glycemic control in subjects with type 2
diabetes. Hormone and metabolic research = Hormon- und Stoffwechselforschung
= Hormones et metabolisme 2006;38(6):423-8.
37. Pi-Sunyer FX, Schweizer A, Mills D, Dejager S. Efficacy and tolerability of vildagliptin
monotherapy in drug-naive patients with type 2 diabetes. Diabetes research and
clinical practice 2007;76(1):132-8.
38. Dejager S, Razac S, Foley JE, Schweizer A. Vildagliptin in drug-naive patients with
type 2 diabetes: a 24-week, double-blind, randomized, placebo-controlled,
multiple-dose study. Hormone and metabolic research = Hormon- und Stoffwechselforschung
= Hormones et metabolisme 2007;39(3):218-23.
39. Rosenstock J, Baron MA, Dejager S, Mills D, Schweizer A. Comparison of vildagliptin
and rosiglitazone monotherapy in patients with type 2 diabetes: a 24-week,
double-blind, randomized trial. Diabetes care 2007;30(2):217-23.
40. Scherbaum WA, Schweizer A, Mari A, Nilsson PM, Lalanne G, Wang Y, et al. Evidence
that vildagliptin attenuates deterioration of glycaemic control during 2-year treatment
of patients with type 2 diabetes and mild hyperglycaemia. Diabetes, obesity
& metabolism 2008;10(11):1114-24.
41. Bosi E, Camisasca RP, Collober C, Rochotte E, Garber AJ. Effects of vildagliptin on
glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled
with metformin. Diabetes care 2007;30(4):890-5.
peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2
diabetes. International journal of clinical practice 2007;61(1):171-80.
25. Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H. Efficacy and safety
of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with
type 2 diabetes mellitus. Diabetologia 2006;49(11):2564-71.
26. Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE.
Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic
control in patients with type 2 diabetes. Diabetes care 2006;29(12):2632-7.
27. Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP. Efficacy and safety of the
dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide,
in patients with type 2 diabetes inadequately controlled on metformin alone:
a randomized, double-blind, non-inferiority trial. Diabetes, obesity & metabolism
2007;9(2):194-205.
28. Scott R, Loeys T, Davies MJ, Engel SS. Efficacy and safety of sitagliptin when added
to ongoing metformin therapy in patients with type 2 diabetes. Diabetes, obesity &
metabolism 2008;10(10):959-69.
29. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Efficacy and safety of the
dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in
patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes
care 2006;29(12):2638-43.
30. Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE. Effect
of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor,
and metformin on glycemic control in patients with type 2 diabetes. Diabetes care
2007;30(8):1979-87.
31. Qi D, Teng R, Jiang M, et aI. Two-year treatment with sitagliptin and initial combination
therapy of sitaglitpin and metformin provides substantial and durable glycaemic
control in patients with type 2 diabetes. Diabetologia 2008;519(Suppl1):S36.
32. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P. Efficacy and safety of the dipeptidyl
peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients
with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebocontrolled,
parallel-group study. Clinical therapeutics 2006;28(10):1556-68.
33. Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P. Efficacy and safety of
the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes
mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin.
Diabetes, obesity & metabolism 2007;9(5):733-45.
34. Arjona Ferreira J, Dobs A, Goldstein B. Triple combination therapy with sitagliptin,
metformin and rosiglitazone improves glycaemic control in patients with type 2
diabetes. Diabetologia 2008;51(Suppl 1):S365.
35. Ahren B, Landin-Olsson M, Jansson PA, Svensson M, Holmes D, Schweizer A. Inhibition
of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces
glucagon levels in type 2 diabetes. The Journal of clinical endocrinology and
metabolism 2004;89(5):2078-84.
36. Pratley RE, Jauffret-Kamel S, Galbreath E, Holmes D. Twelve-week monotherapy
with the DPP-4 inhibitor vildagliptin improves glycemic control in subjects with type 2
diabetes. Hormone and metabolic research = Hormon- und Stoffwechselforschung
= Hormones et metabolisme 2006;38(6):423-8.
37. Pi-Sunyer FX, Schweizer A, Mills D, Dejager S. Efficacy and tolerability of vildagliptin
monotherapy in drug-naive patients with type 2 diabetes. Diabetes research and
clinical practice 2007;76(1):132-8.
38. Dejager S, Razac S, Foley JE, Schweizer A. Vildagliptin in drug-naive patients with
type 2 diabetes: a 24-week, double-blind, randomized, placebo-controlled,
multiple-dose study. Hormone and metabolic research = Hormon- und Stoffwechselforschung
= Hormones et metabolisme 2007;39(3):218-23.
39. Rosenstock J, Baron MA, Dejager S, Mills D, Schweizer A. Comparison of vildagliptin
and rosiglitazone monotherapy in patients with type 2 diabetes: a 24-week,
double-blind, randomized trial. Diabetes care 2007;30(2):217-23.
40. Scherbaum WA, Schweizer A, Mari A, Nilsson PM, Lalanne G, Wang Y, et al. Evidence
that vildagliptin attenuates deterioration of glycaemic control during 2-year treatment
of patients with type 2 diabetes and mild hyperglycaemia. Diabetes, obesity
& metabolism 2008;10(11):1114-24.
41. Bosi E, Camisasca RP, Collober C, Rochotte E, Garber AJ. Effects of vildagliptin on
glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled
with metformin. Diabetes care 2007;30(4):890-5.
42. Bolli G, Dotta F, Rochotte E, Cohen SE. Efficacy and tolerability of vildagliptin vs.
pioglitazone when added to metformin: a 24-week, randomized, double-blind
study. Diabetes, obesity & metabolism 2008;10(1):82-90.
43. Ahren B, Gomis R, Standl E, Mills D, Schweizer A. Twelve- and 52-week efficacy of
the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2
diabetes. Diabetes care 2004;27(12):2874-80.
44. Ferrannini E, Fonseca V, Zinman B, Matthews D, Ahren B, Byiers S, et al. Fifty-twoweek
efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes
mellitus inadequately controlled on metformin monotherapy. Diabetes,
obesity & metabolism 2009;11(2):157-66.
45. Garber AJ, Schweizer A, Baron MA, Rochotte E, Dejager S. Vildagliptin in combination
with pioglitazone improves glycaemic control in patients with type 2 diabetes failing
thiazolidinedione monotherapy: a randomized, placebo-controlled study. Diabetes,
obesity & metabolism 2007;9(2):166-74.
46. Garber AJ, Foley JE, Banerji MA, Ebeling P, Gudbjornsdottir S, Camisasca RP, et al.
Effects of vildagliptin on glucose control in patients with type 2 diabetes inadequately
controlled with a sulphonylurea. Diabetes, obesity & metabolism 2008;
10(11):1047-56.
47. Rosenstock J, Aguilar-Salinas C, Klein E, Nepal S, List J, Chen R. Effect of saxagliptin
monotherapy in treatment-naive patients with type 2 diabetes. Current medical
research and opinion 2009;25(10):2401-11.
48. Jadzinsky M, Pfutzner A, Paz-Pacheco E, Xu Z, Allen E, Chen R. Saxagliptin given in
combination with metformin as initial therapy improves glycaemic control in
patients with type 2 diabetes compared with either monotherapy: a randomized
controlled trial. Diabetes, obesity & metabolism 2009;11(6):611-22.
49. DeFronzo RA, Hissa MN, Garber AJ, Luiz Gross J, Yuyan Duan R, Ravichandran S, et al.
The efficacy and safety of saxagliptin when added to metformin therapy in
patients with inadequately controlled type 2 diabetes with metformin alone.
Diabetes care 2009;32(9):1649-55.
50. DeFronzo RA, et al. Once-Daily Saxagliptin Added to Metformin Provides Sustained
Glycemic Control and Is Well Tolerated Over 102 Weeks in Patients With Type 2
Diabetes. Diabetes care 2009;58 (Suppl 1):A147, Abstract 547.
51. Goke B, Gallwitz B, Eriksson J, Hellqvist A, Gause-Nilsson I. Saxagliptin is non-inferior
to glipizide in patients with type 2 diabetes mellitus inadequately controlled on
metformin alone: a 52-week randomised controlled trial. International journal of
clinical practice 2010;64(12):1619-31.
52. Scheen AJ, Charpentier G, Ostgren CJ, Hellqvist A, Gause-Nilsson I. Efficacy and
safety of saxagliptin in combination with metformin compared with sitagliptin in
combination with metformin in adult patients with type 2 diabetes mellitus. Diabetes/
metabolism research and reviews 2010;26(7):540-9.
53. Pfutzner A, Paz-Pacheco E, Allen E, Frederich R, Chen R, Investigators CV. Initial
combination therapy with saxagliptin and metformin provides sustained glycaemic
control and is well tolerated for up to 76 weeks. Diabetes, obesity & metabolism
2011;13(6):567-76.
54. Chacra AR, et al. Saxagliptin added to a submaximal dose of sulphonylurea
improves glycaemic control compared with uptitration of sulphonylurea in patients
with type 2 diabetes: a randomised controlled trial. The International Journal of
Clinical Practice 2009;Published online - doi: 10.1111/j.1742-1241.2009.02143.x.
55. Hollander P, Li J, Allen E, Chen R. Saxagliptin added to a thiazolidinedione improves
glycemic control in patients with type 2 diabetes and inadequate control on
thiazolidinedione alone. The Journal of clinical endocrinology and metabolism
2009;94(12):4810-9.
56. DeFronzo RA, Fleck PR, Wilson CA, Mekki Q. Efficacy and safety of the dipeptidyl
peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate
glycemic control: a randomized, double-blind, placebo-controlled study. Diabetes
care 2008;31(12):2315-7.
57. Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q, Alogliptin Study G. Efficacy and
safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy
in patients with type 2 diabetes inadequately controlled with metformin mono
therapy: a multicentre, randomised, double-blind, placebo-controlled study. International
journal of clinical practice 2009;63(1):46-55.
58. Pratley RE, Kipnes MS, Fleck PR, Wilson C, Mekki Q, Alogliptin Study G. Efficacy and
safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes
inadequately controlled by glyburide monotherapy. Diabetes, obesity & metabolism
2009;11(2):167-76.
pioglitazone when added to metformin: a 24-week, randomized, double-blind
study. Diabetes, obesity & metabolism 2008;10(1):82-90.
43. Ahren B, Gomis R, Standl E, Mills D, Schweizer A. Twelve- and 52-week efficacy of
the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2
diabetes. Diabetes care 2004;27(12):2874-80.
44. Ferrannini E, Fonseca V, Zinman B, Matthews D, Ahren B, Byiers S, et al. Fifty-twoweek
efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes
mellitus inadequately controlled on metformin monotherapy. Diabetes,
obesity & metabolism 2009;11(2):157-66.
45. Garber AJ, Schweizer A, Baron MA, Rochotte E, Dejager S. Vildagliptin in combination
with pioglitazone improves glycaemic control in patients with type 2 diabetes failing
thiazolidinedione monotherapy: a randomized, placebo-controlled study. Diabetes,
obesity & metabolism 2007;9(2):166-74.
46. Garber AJ, Foley JE, Banerji MA, Ebeling P, Gudbjornsdottir S, Camisasca RP, et al.
Effects of vildagliptin on glucose control in patients with type 2 diabetes inadequately
controlled with a sulphonylurea. Diabetes, obesity & metabolism 2008;
10(11):1047-56.
47. Rosenstock J, Aguilar-Salinas C, Klein E, Nepal S, List J, Chen R. Effect of saxagliptin
monotherapy in treatment-naive patients with type 2 diabetes. Current medical
research and opinion 2009;25(10):2401-11.
48. Jadzinsky M, Pfutzner A, Paz-Pacheco E, Xu Z, Allen E, Chen R. Saxagliptin given in
combination with metformin as initial therapy improves glycaemic control in
patients with type 2 diabetes compared with either monotherapy: a randomized
controlled trial. Diabetes, obesity & metabolism 2009;11(6):611-22.
49. DeFronzo RA, Hissa MN, Garber AJ, Luiz Gross J, Yuyan Duan R, Ravichandran S, et al.
The efficacy and safety of saxagliptin when added to metformin therapy in
patients with inadequately controlled type 2 diabetes with metformin alone.
Diabetes care 2009;32(9):1649-55.
50. DeFronzo RA, et al. Once-Daily Saxagliptin Added to Metformin Provides Sustained
Glycemic Control and Is Well Tolerated Over 102 Weeks in Patients With Type 2
Diabetes. Diabetes care 2009;58 (Suppl 1):A147, Abstract 547.
51. Goke B, Gallwitz B, Eriksson J, Hellqvist A, Gause-Nilsson I. Saxagliptin is non-inferior
to glipizide in patients with type 2 diabetes mellitus inadequately controlled on
metformin alone: a 52-week randomised controlled trial. International journal of
clinical practice 2010;64(12):1619-31.
52. Scheen AJ, Charpentier G, Ostgren CJ, Hellqvist A, Gause-Nilsson I. Efficacy and
safety of saxagliptin in combination with metformin compared with sitagliptin in
combination with metformin in adult patients with type 2 diabetes mellitus. Diabetes/
metabolism research and reviews 2010;26(7):540-9.
53. Pfutzner A, Paz-Pacheco E, Allen E, Frederich R, Chen R, Investigators CV. Initial
combination therapy with saxagliptin and metformin provides sustained glycaemic
control and is well tolerated for up to 76 weeks. Diabetes, obesity & metabolism
2011;13(6):567-76.
54. Chacra AR, et al. Saxagliptin added to a submaximal dose of sulphonylurea
improves glycaemic control compared with uptitration of sulphonylurea in patients
with type 2 diabetes: a randomised controlled trial. The International Journal of
Clinical Practice 2009;Published online - doi: 10.1111/j.1742-1241.2009.02143.x.
55. Hollander P, Li J, Allen E, Chen R. Saxagliptin added to a thiazolidinedione improves
glycemic control in patients with type 2 diabetes and inadequate control on
thiazolidinedione alone. The Journal of clinical endocrinology and metabolism
2009;94(12):4810-9.
56. DeFronzo RA, Fleck PR, Wilson CA, Mekki Q. Efficacy and safety of the dipeptidyl
peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate
glycemic control: a randomized, double-blind, placebo-controlled study. Diabetes
care 2008;31(12):2315-7.
57. Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q, Alogliptin Study G. Efficacy and
safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy
in patients with type 2 diabetes inadequately controlled with metformin mono
therapy: a multicentre, randomised, double-blind, placebo-controlled study. International
journal of clinical practice 2009;63(1):46-55.
58. Pratley RE, Kipnes MS, Fleck PR, Wilson C, Mekki Q, Alogliptin Study G. Efficacy and
safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes
inadequately controlled by glyburide monotherapy. Diabetes, obesity & metabolism
2009;11(2):167-76.
59. Pratley RE, Reusch JE, Fleck PR, Wilson CA, Mekki Q, Alogliptin Study G. Efficacy and
safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in
patients with type 2 diabetes: a randomized, double-blind, placebo-controlled
study. Current medical research and opinion 2009;25(10):2361-71.
60. Kaku K, Itayasu T, Hiroi S, Hirayama M, Seino Y. Efficacy and safety of alogliptin added
to pioglitazone in Japanese patients with type 2 diabetes: a randomized, doubleblind,
placebo-controlled trial with an open-label long-term extension study. Diabetes,
obesity & metabolism 2011;13(11):1028-35.
61. Rosenstock J, Inzucchi SE, Seufert J, Fleck PR, Wilson CA, Mekki Q. Initial combination
therapy with alogliptin and pioglitazone in drug-naive patients with type 2 diabetes.
Diabetes care 2010;33(11):2406-8.
62. Bosi E, Ellis GC, Wilson CA, Fleck PR. Alogliptin as a third oral antidiabetic drug in
patients with type 2 diabetes and inadequate glycaemic control on metformin
and pioglitazone: a 52-week, randomized, double-blind, active-controlled, parallelgroup
study. Diabetes, obesity & metabolism 2011;13(12):1088-96.
63. Frederich R, Alexander JH, Fiedorek FT, Donovan M, Berglind N, Harris S, et al. A
systematic assessment of cardiovascular outcomes in the saxagliptin drug development
program for type 2 diabetes. Postgrad Med;122(3):16-27.
64. Monami M, Iacomelli I, Marchionni N, Mannucci E. Dipeptydil peptidase-4 inhibitors
in type 2 diabetes: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc
Dis;20(4):224-35.
65. Williams-Herman D, Engel SS, Round E, Johnson J, Golm GT, Guo H, et al. Safety and
tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246
patients with type 2 diabetes. BMC Endocr Disord;10:7.
66. Schweizer A, Dejager S, Foley JE, Couturier A, Ligueros-Saylan M, Kothny W. Assessing
the cardio-cerebrovascular safety of vildagliptin: meta-analysis of adjudicated
events from a large Phase III type 2 diabetes population. Diabetes, obesity & metabolism;
12(6):485-94.
67. Kahn SE. The relative contribution of insulin resistance and beta-cell dysfunction to
the pathophysiology of type 2 diabetes. Diabetologia 2003;46:3-19.
68. Marchetti P, Dotta F, Lauro D, Purrello F. An overview of pancreatic beta-cell defects
in human type 2 diabetes: implications for treatment. Regul Pept 2008;146(1-3):4-11.
69. Donath MY, Storling J, Maedler K, Mandrup-Poulsen T. Inflammatory mediators
and islet beta-cell failure: a link between type 1 and type 2 diabetes. J Mol Med
2003;81(8):455-70.
70. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and
increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52(1):
102-10.
71. Drews G, Krippeit-Drews P, Dufer M. Oxidative stress and beta-cell dysfunction.
Pflugers Arch 2010;460(4):703-18.
72. Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, et al. Preservation
of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological
treatment of insulin resistance in high-risk hispanic women. Diabetes 2002;51(9):
2796-803.
73. Kitabchi AE, Temprosa M, Knowler WC, Kahn SE, Fowler SE, Haffner SM, et al. Role of
insulin secretion and sensitivity in the evolution of type 2 diabetes in the diabetes
prevention program: effects of lifestyle intervention and metformin. Diabetes 2005;
54(8):2404-14.
74. Pospisilik JA, Martin J, Doty T, Ehses JA, Pamir N, Lynn FC, et al. Dipeptidyl peptidase IV
inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocininduced
diabetic rats. Diabetes 2003;52(3):741-50.
75. Mu J, Woods J, Zhou YP, Roy RS, Li Z, Zycband E, et al. Chronic inhibition of dipeptidyl
peptidase-4 with a sitagliptin analog preserves pancreatic beta-cell mass and
function in a rodent model of type 2 diabetes. Diabetes 2006;55(6):1695-704.
76. Marchetti P, Lupi R, Del Guerra S, Bugliani M, D’Aleo V, Occhipinti M, et al. Goals
of treatment for type 2 diabetes: beta-cell preservation for glycemic control.
Diabetes care 2009;32 Suppl 2:S178-83.
77. Ahren B. Emerging dipeptidyl peptidase-4 inhibitors for the treatment of diabetes.
Expert opinion on emerging drugs 2008;13(4):593-607.
78. Havre PA, Abe M, Urasaki Y, Ohnuma K, Morimoto C, Dang NH. The role of CD26/
dipeptidyl peptidase IV in cancer. Front Biosci 2008;13:1634-45.
79. Masur K, Schwartz F, Entschladen F, Niggemann B, Zaenker KS. DPPIV inhibitors extend
GLP-2 mediated tumour promoting effects on intestinal cancer cells. Regul Pept
2006;137(3):147-55.
safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in
patients with type 2 diabetes: a randomized, double-blind, placebo-controlled
study. Current medical research and opinion 2009;25(10):2361-71.
60. Kaku K, Itayasu T, Hiroi S, Hirayama M, Seino Y. Efficacy and safety of alogliptin added
to pioglitazone in Japanese patients with type 2 diabetes: a randomized, doubleblind,
placebo-controlled trial with an open-label long-term extension study. Diabetes,
obesity & metabolism 2011;13(11):1028-35.
61. Rosenstock J, Inzucchi SE, Seufert J, Fleck PR, Wilson CA, Mekki Q. Initial combination
therapy with alogliptin and pioglitazone in drug-naive patients with type 2 diabetes.
Diabetes care 2010;33(11):2406-8.
62. Bosi E, Ellis GC, Wilson CA, Fleck PR. Alogliptin as a third oral antidiabetic drug in
patients with type 2 diabetes and inadequate glycaemic control on metformin
and pioglitazone: a 52-week, randomized, double-blind, active-controlled, parallelgroup
study. Diabetes, obesity & metabolism 2011;13(12):1088-96.
63. Frederich R, Alexander JH, Fiedorek FT, Donovan M, Berglind N, Harris S, et al. A
systematic assessment of cardiovascular outcomes in the saxagliptin drug development
program for type 2 diabetes. Postgrad Med;122(3):16-27.
64. Monami M, Iacomelli I, Marchionni N, Mannucci E. Dipeptydil peptidase-4 inhibitors
in type 2 diabetes: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc
Dis;20(4):224-35.
65. Williams-Herman D, Engel SS, Round E, Johnson J, Golm GT, Guo H, et al. Safety and
tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246
patients with type 2 diabetes. BMC Endocr Disord;10:7.
66. Schweizer A, Dejager S, Foley JE, Couturier A, Ligueros-Saylan M, Kothny W. Assessing
the cardio-cerebrovascular safety of vildagliptin: meta-analysis of adjudicated
events from a large Phase III type 2 diabetes population. Diabetes, obesity & metabolism;
12(6):485-94.
67. Kahn SE. The relative contribution of insulin resistance and beta-cell dysfunction to
the pathophysiology of type 2 diabetes. Diabetologia 2003;46:3-19.
68. Marchetti P, Dotta F, Lauro D, Purrello F. An overview of pancreatic beta-cell defects
in human type 2 diabetes: implications for treatment. Regul Pept 2008;146(1-3):4-11.
69. Donath MY, Storling J, Maedler K, Mandrup-Poulsen T. Inflammatory mediators
and islet beta-cell failure: a link between type 1 and type 2 diabetes. J Mol Med
2003;81(8):455-70.
70. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and
increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52(1):
102-10.
71. Drews G, Krippeit-Drews P, Dufer M. Oxidative stress and beta-cell dysfunction.
Pflugers Arch 2010;460(4):703-18.
72. Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, et al. Preservation
of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological
treatment of insulin resistance in high-risk hispanic women. Diabetes 2002;51(9):
2796-803.
73. Kitabchi AE, Temprosa M, Knowler WC, Kahn SE, Fowler SE, Haffner SM, et al. Role of
insulin secretion and sensitivity in the evolution of type 2 diabetes in the diabetes
prevention program: effects of lifestyle intervention and metformin. Diabetes 2005;
54(8):2404-14.
74. Pospisilik JA, Martin J, Doty T, Ehses JA, Pamir N, Lynn FC, et al. Dipeptidyl peptidase IV
inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocininduced
diabetic rats. Diabetes 2003;52(3):741-50.
75. Mu J, Woods J, Zhou YP, Roy RS, Li Z, Zycband E, et al. Chronic inhibition of dipeptidyl
peptidase-4 with a sitagliptin analog preserves pancreatic beta-cell mass and
function in a rodent model of type 2 diabetes. Diabetes 2006;55(6):1695-704.
76. Marchetti P, Lupi R, Del Guerra S, Bugliani M, D’Aleo V, Occhipinti M, et al. Goals
of treatment for type 2 diabetes: beta-cell preservation for glycemic control.
Diabetes care 2009;32 Suppl 2:S178-83.
77. Ahren B. Emerging dipeptidyl peptidase-4 inhibitors for the treatment of diabetes.
Expert opinion on emerging drugs 2008;13(4):593-607.
78. Havre PA, Abe M, Urasaki Y, Ohnuma K, Morimoto C, Dang NH. The role of CD26/
dipeptidyl peptidase IV in cancer. Front Biosci 2008;13:1634-45.
79. Masur K, Schwartz F, Entschladen F, Niggemann B, Zaenker KS. DPPIV inhibitors extend
GLP-2 mediated tumour promoting effects on intestinal cancer cells. Regul Pept
2006;137(3):147-55.
80. Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic,
and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology
2011;141(1):150-6.
81. Nauck MA, Heimesaat MM, Behle K, Holst JJ, Nauck MS, Ritzel R, et al. Effects of
glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions,
and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp
experiments in healthy volunteers. The Journal of clinical endocrinology and metabolism
2002;87(3):1239-46.
82. Ahren B, Schweizer A, Dejager S, Dunning BE, Nilsson PM, Persson M, et al. Vildagliptin
enhances islet responsiveness to both hyper- and hypoglycemia in patients with
type 2 diabetes. The Journal of clinical endocrinology and metabolism 2009;94(4):
1236-43.
83. Merck Sharpe & Dohme Ltd. Januvia® US Prescribing Information. 2010.
84. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review.
JAMA 2002;287(3):360-72.
85. Novartis Europharm Ltd. Galvus® Prescribing Information. 2010.
86. Bristol-Myers Squibb Pharmaceuticals Ltd and AstraZeneca EEIG. Onglyza® Prescribing
Information. 2010.
87. Rodbard HW, Jellinger PS, Davidson JA, Einhorn D, Garber AJ, Grunberger G, et al.
Statement by an American Association of Clinical Endocrinologists/American
College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm
for glycemic control. Endocr Pract 2009;15(6):540-59.
88. ADA. Standards of medical care in diabetes--2009. Diabetes care 2009;32 Suppl 1:
S13-61.
89. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical
management of hyperglycemia in type 2 diabetes: a consensus algorithm for the
initiation and adjustment of therapy: a consensus statement of the American
Diabetes Association and the European Association for the Study of Diabetes.
Diabetes care 2009;32(1):193-203.
90. Sibal L, P.D. H. Management of type 2 diabetes: NICE guidelines. Clin Med 2009;9(4):
353-57.
91. International Diabetes Federation, Clinical guidelines taskforce. Global guideline for
type 2 diabetes. Brussels: International Diabetes Federation, 2005.
92. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes
care 2003;26(10):2929-40.
93. 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.
94. Eli-Lilly. Byetta 5 micrograms solution for injection SPC. 2009.
95. NovoNordisk. Victoza 6 mg/ml solution for injection in pre-filled pen. 2009.
96. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide
(exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with
type 2 diabetes. Diabetes care 2004;27(11):2628-35.
97. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide
(exendin-4) on glycemic control and weight over 30 weeks in metformin-treated
patients with type 2 diabetes. Diabetes care 2005;28(5):1092-100.
98. Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS, et al. Effects
of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2
diabetes treated with metformin and a sulfonylurea. Diabetes care 2005;28(5):1083-91.
99. Pratley RE, Nauck M, Bailey T, Montanya E, Cuddihy R, Filetti S, et al. Liraglutide
versus sitagliptin for patients with type 2 diabetes who did not have adequate
glycaemic control with metformin: a 26-week, randomised, parallel-group, openlabel
trial. Lancet;375(9724):1447-56.
100. Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, et al. Liraglutide
once a day versus exenatide twice a day for type 2 diabetes: a 26-week
randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009;
374(9683):39-47.
101. Holst JJ, Deacon CF, Vilsboll T, Krarup T, Madsbad S. Glucagon-like peptide-1, glucose
homeostasis and diabetes. Trends Mol Med 2008;14(4):161-8.
102. Klonoff DC, Buse JB, Nielsen LL, Guan X, Bowlus CL, Holcombe JH, et al. Exenatide
effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in
patients with type 2 diabetes treated for at least 3 years. Current medical research
and opinion 2008;24(1):275-86.
and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology
2011;141(1):150-6.
81. Nauck MA, Heimesaat MM, Behle K, Holst JJ, Nauck MS, Ritzel R, et al. Effects of
glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions,
and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp
experiments in healthy volunteers. The Journal of clinical endocrinology and metabolism
2002;87(3):1239-46.
82. Ahren B, Schweizer A, Dejager S, Dunning BE, Nilsson PM, Persson M, et al. Vildagliptin
enhances islet responsiveness to both hyper- and hypoglycemia in patients with
type 2 diabetes. The Journal of clinical endocrinology and metabolism 2009;94(4):
1236-43.
83. Merck Sharpe & Dohme Ltd. Januvia® US Prescribing Information. 2010.
84. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review.
JAMA 2002;287(3):360-72.
85. Novartis Europharm Ltd. Galvus® Prescribing Information. 2010.
86. Bristol-Myers Squibb Pharmaceuticals Ltd and AstraZeneca EEIG. Onglyza® Prescribing
Information. 2010.
87. Rodbard HW, Jellinger PS, Davidson JA, Einhorn D, Garber AJ, Grunberger G, et al.
Statement by an American Association of Clinical Endocrinologists/American
College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm
for glycemic control. Endocr Pract 2009;15(6):540-59.
88. ADA. Standards of medical care in diabetes--2009. Diabetes care 2009;32 Suppl 1:
S13-61.
89. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical
management of hyperglycemia in type 2 diabetes: a consensus algorithm for the
initiation and adjustment of therapy: a consensus statement of the American
Diabetes Association and the European Association for the Study of Diabetes.
Diabetes care 2009;32(1):193-203.
90. Sibal L, P.D. H. Management of type 2 diabetes: NICE guidelines. Clin Med 2009;9(4):
353-57.
91. International Diabetes Federation, Clinical guidelines taskforce. Global guideline for
type 2 diabetes. Brussels: International Diabetes Federation, 2005.
92. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes
care 2003;26(10):2929-40.
93. 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.
94. Eli-Lilly. Byetta 5 micrograms solution for injection SPC. 2009.
95. NovoNordisk. Victoza 6 mg/ml solution for injection in pre-filled pen. 2009.
96. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide
(exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with
type 2 diabetes. Diabetes care 2004;27(11):2628-35.
97. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide
(exendin-4) on glycemic control and weight over 30 weeks in metformin-treated
patients with type 2 diabetes. Diabetes care 2005;28(5):1092-100.
98. Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS, et al. Effects
of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2
diabetes treated with metformin and a sulfonylurea. Diabetes care 2005;28(5):1083-91.
99. Pratley RE, Nauck M, Bailey T, Montanya E, Cuddihy R, Filetti S, et al. Liraglutide
versus sitagliptin for patients with type 2 diabetes who did not have adequate
glycaemic control with metformin: a 26-week, randomised, parallel-group, openlabel
trial. Lancet;375(9724):1447-56.
100. Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, et al. Liraglutide
once a day versus exenatide twice a day for type 2 diabetes: a 26-week
randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009;
374(9683):39-47.
101. Holst JJ, Deacon CF, Vilsboll T, Krarup T, Madsbad S. Glucagon-like peptide-1, glucose
homeostasis and diabetes. Trends Mol Med 2008;14(4):161-8.
102. Klonoff DC, Buse JB, Nielsen LL, Guan X, Bowlus CL, Holcombe JH, et al. Exenatide
effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in
patients with type 2 diabetes treated for at least 3 years. Current medical research
and opinion 2008;24(1):275-86.
103. Courreges JP, Vilsboll T, Zdravkovic M, Le-Thi T, Krarup T, Schmitz O, et al. Beneficial
effects of once-daily liraglutide, a human glucagon-like peptide-1 analogue, on
cardiovascular risk biomarkers in patients with Type 2 diabetes. Diabet Med 2008;
25(9):1129-31.
104. Olansky L. Do incretin-based therapies cause acute pancreatitis? J Diabetes Sci
Technol 2010;4(1):228-29.
105. Thomas L, Eckhardt M, Langkopf E, Tadayyon M, Himmelsbach F, Mark M. (R)-8-(3-
amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazoli n-2-ylmethyl)-3,7-
dihydro-purine-2,6-dione (BI 1356), a novel xanthine-based dipeptidyl peptidase 4
inhibitor, has a superior potency and longer duration of action compared with
other dipeptidyl peptidase-4 inhibitors. The Journal of pharmacology and experimental
therapeutics 2008;325(1):175-82.
106. Biftu T, Feng D, Qian X, Liang GB, Kieczykowski G, Eiermann G, et al. (3R)-4-[(3R)-3-
Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(2,2,2-trifluoro ethyl)-1,4-diazepan-2-one,
a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.
Bioorg Med Chem Lett 2007;17(1):49-52.
107. Brandt I, Joossens J, Chen X, Maes MB, Scharpe S, De Meester I, et al. Inhibition
of dipeptidyl-peptidase IV catalyzed peptide truncation by Vildagliptin ((2S)-{[(3-
hydroxyadamantan-1-yl)amino]acetyl}-pyrrolidine-2-carbonitrile). Biochem Pharmacol
2005;70(1):134-43.
108. Deacon CF, Holst JJ. Saxagliptin: a new dipeptidyl peptidase-4 inhibitor for the
treatment of type 2 diabetes. Advances in therapy 2009;26(5):488-99.
109. Feng J, Zhang Z, Wallace MB, Stafford JA, Kaldor SW, Kassel DB, et al. Discovery of
alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl
peptidase IV. Journal of medicinal chemistry 2007;50(10):2297-300.
110. Matsuyama-Yokono A, Tahara A, Nakano R, Someya Y, Nagase I, Hayakawa M, et
al. ASP8497 is a novel selective and competitive dipeptidyl peptidase-IV inhibitor
with antihyperglycemic activity. Biochem Pharmacol 2008;76(1):98-107.
111. Kirby M, Yu DM, O’Connor S, Gorrell MD. Inhibitor selectivity in the clinical application
of dipeptidyl peptidase-4 inhibition. Clin Sci (Lond);118(1):31-41.
112. Heise T, Graefe-Mody EU, Huttner S, Ring A, Trommeshauser D, Dugi KA. Pharmacokinetics,
pharmacodynamics and tolerability of multiple oral doses of linagliptin,
a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients. Diabetes, obesity
& metabolism 2009;11(8):786-94.
113. Baseline HbA1c: 8.0% linagliptin-treated group; 8.0% placebo group; Full analysis
set (FAS), Last observation carried forward (LOCF). ADA 70th Scientific Sessions;
2010; Orlando, Florida, USA.
114. Baseline HbA1c: 8.09% linagliptin-treated group; 8.02% placebo group; full analysis
set (FAS), Last observation carried forward (LOCF) ADA 70th Scientific Sessions;
2010; Orlando, Florida, USA.
115. Linagliptin monotherapy improves glycaemic control and measures of beta-cell
function in Type 2 diabetes. ADA 70th Scientific Sessions; 2010; Orlando, Florida,
USA.
116. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone
in patients with inadequately controlled Type 2 diabetes. ADA 70th Scientific Sessions;
2010; Orlando, Florida, USA.
117. Kawamori R, Inagaki N, Araki E, Watada H, Hayashi N, Horie Y, et al. Linagliptin
monotherapy provides superior glycaemic control versus placebo or voglibose with
comparable safety in Japanese patients with type 2 diabetes: a randomized,
placebo and active comparator-controlled, double-blind study. Diabetes, obesity
& metabolism 2011.
118. Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle HJ, Dugi KA. Effect of
linagliptin monotherapy on glycaemic control and markers of beta-cell function in
patients with inadequately controlled type 2 diabetes: a randomized controlled
trial. Diabetes, obesity & metabolism 2011;13(3):258-67.
119. Taskinen MR, Rosenstock J, Tamminen I, Kubiak R, Patel S, Dugi KA, et al. Safety and
efficacy of linagliptin as add-on therapy to metformin in patients with type 2
diabetes: a randomized, double-blind, placebo-controlled study. Diabetes, obesity
& metabolism 2011;13(1):65-74.
120. Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons
with type 2 diabetes inadequately controlled by a combination of metformin and
sulphonylurea: a 24-week randomized study. Diabet Med 2011;28(11):1352-61.
effects of once-daily liraglutide, a human glucagon-like peptide-1 analogue, on
cardiovascular risk biomarkers in patients with Type 2 diabetes. Diabet Med 2008;
25(9):1129-31.
104. Olansky L. Do incretin-based therapies cause acute pancreatitis? J Diabetes Sci
Technol 2010;4(1):228-29.
105. Thomas L, Eckhardt M, Langkopf E, Tadayyon M, Himmelsbach F, Mark M. (R)-8-(3-
amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazoli n-2-ylmethyl)-3,7-
dihydro-purine-2,6-dione (BI 1356), a novel xanthine-based dipeptidyl peptidase 4
inhibitor, has a superior potency and longer duration of action compared with
other dipeptidyl peptidase-4 inhibitors. The Journal of pharmacology and experimental
therapeutics 2008;325(1):175-82.
106. Biftu T, Feng D, Qian X, Liang GB, Kieczykowski G, Eiermann G, et al. (3R)-4-[(3R)-3-
Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(2,2,2-trifluoro ethyl)-1,4-diazepan-2-one,
a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.
Bioorg Med Chem Lett 2007;17(1):49-52.
107. Brandt I, Joossens J, Chen X, Maes MB, Scharpe S, De Meester I, et al. Inhibition
of dipeptidyl-peptidase IV catalyzed peptide truncation by Vildagliptin ((2S)-{[(3-
hydroxyadamantan-1-yl)amino]acetyl}-pyrrolidine-2-carbonitrile). Biochem Pharmacol
2005;70(1):134-43.
108. Deacon CF, Holst JJ. Saxagliptin: a new dipeptidyl peptidase-4 inhibitor for the
treatment of type 2 diabetes. Advances in therapy 2009;26(5):488-99.
109. Feng J, Zhang Z, Wallace MB, Stafford JA, Kaldor SW, Kassel DB, et al. Discovery of
alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl
peptidase IV. Journal of medicinal chemistry 2007;50(10):2297-300.
110. Matsuyama-Yokono A, Tahara A, Nakano R, Someya Y, Nagase I, Hayakawa M, et
al. ASP8497 is a novel selective and competitive dipeptidyl peptidase-IV inhibitor
with antihyperglycemic activity. Biochem Pharmacol 2008;76(1):98-107.
111. Kirby M, Yu DM, O’Connor S, Gorrell MD. Inhibitor selectivity in the clinical application
of dipeptidyl peptidase-4 inhibition. Clin Sci (Lond);118(1):31-41.
112. Heise T, Graefe-Mody EU, Huttner S, Ring A, Trommeshauser D, Dugi KA. Pharmacokinetics,
pharmacodynamics and tolerability of multiple oral doses of linagliptin,
a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients. Diabetes, obesity
& metabolism 2009;11(8):786-94.
113. Baseline HbA1c: 8.0% linagliptin-treated group; 8.0% placebo group; Full analysis
set (FAS), Last observation carried forward (LOCF). ADA 70th Scientific Sessions;
2010; Orlando, Florida, USA.
114. Baseline HbA1c: 8.09% linagliptin-treated group; 8.02% placebo group; full analysis
set (FAS), Last observation carried forward (LOCF) ADA 70th Scientific Sessions;
2010; Orlando, Florida, USA.
115. Linagliptin monotherapy improves glycaemic control and measures of beta-cell
function in Type 2 diabetes. ADA 70th Scientific Sessions; 2010; Orlando, Florida,
USA.
116. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone
in patients with inadequately controlled Type 2 diabetes. ADA 70th Scientific Sessions;
2010; Orlando, Florida, USA.
117. Kawamori R, Inagaki N, Araki E, Watada H, Hayashi N, Horie Y, et al. Linagliptin
monotherapy provides superior glycaemic control versus placebo or voglibose with
comparable safety in Japanese patients with type 2 diabetes: a randomized,
placebo and active comparator-controlled, double-blind study. Diabetes, obesity
& metabolism 2011.
118. Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle HJ, Dugi KA. Effect of
linagliptin monotherapy on glycaemic control and markers of beta-cell function in
patients with inadequately controlled type 2 diabetes: a randomized controlled
trial. Diabetes, obesity & metabolism 2011;13(3):258-67.
119. Taskinen MR, Rosenstock J, Tamminen I, Kubiak R, Patel S, Dugi KA, et al. Safety and
efficacy of linagliptin as add-on therapy to metformin in patients with type 2
diabetes: a randomized, double-blind, placebo-controlled study. Diabetes, obesity
& metabolism 2011;13(1):65-74.
120. Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons
with type 2 diabetes inadequately controlled by a combination of metformin and
sulphonylurea: a 24-week randomized study. Diabet Med 2011;28(11):1352-61.
121. Gomis R, Espadero RM, Jones R, Woerle HJ, Dugi KA. Efficacy and safety of initial
combination therapy with linagliptin and pioglitazone in patients with inadequately
controlled type 2 diabetes: a randomized, double-blind, placebo-controlled study.
Diabetes, obesity & metabolism 2011;13(7):653-61.
122. 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):2608-17.
123. Vollmer K, Holst JJ, Baller B et al (2008) Predictors of incretin concentrations in subjects
with normal, impaired, and diabetic glucose tolerance. Diabetes 57:678–687.
124. Theodorakis MJ, Carlson O, Michopoulos S et al (2006) Human duodenal enteroendocrine
cells: source of both incretin peptides, GLP-1 and GIP. Am J Physiol
(Endocrinol Metab) 290:E 550–559.
125. Muscelli E, Mari A, Casolaro A et al (2008) Separate impact of obesity and glucose
tolerance on the incretin effect in normal subjects and type 2 diabetic patients.
Diabetes 57:1340–1348.
126. Vilsbøll T, Krarup T, Sonne J et al (2003) Incretin secretion in relation to meal size and
body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus.
J Clin Endocrinol Metab 88:2706–2713.
127. Ryskjaer J, Deacon CF, Carr RD et al (2006) Plasma dipeptidyl peptidase-IV activity
in patients with type-2 diabetes mellitus correlates positively with HbA1c levels, but
is not acutely affected by food intake. Eur J Endocrinol 155:485–493.
128. Salinari S, Bertuzzi A, Asnaghi S, Guidone C, Manco M, Mingrone G (2009) First-phase
insulin secretion restoration and differential response to glucose load depending on
the route of administration in type 2 diabetic subjects after bariatric surgery. Diabetes
Care 32:375–380.
129. Knop FK, Vilsboll T, Hojberg PV, et al. The insulinotropic effect of GIP is impaired in
patients with chronic pancreatitis and secondary diabetes mellitus as compared
to patients with chronic pancreatitis and normal glucose tolerance. Regul Pept
2007;144(1-3):123-130.
combination therapy with linagliptin and pioglitazone in patients with inadequately
controlled type 2 diabetes: a randomized, double-blind, placebo-controlled study.
Diabetes, obesity & metabolism 2011;13(7):653-61.
122. 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):2608-17.
123. Vollmer K, Holst JJ, Baller B et al (2008) Predictors of incretin concentrations in subjects
with normal, impaired, and diabetic glucose tolerance. Diabetes 57:678–687.
124. Theodorakis MJ, Carlson O, Michopoulos S et al (2006) Human duodenal enteroendocrine
cells: source of both incretin peptides, GLP-1 and GIP. Am J Physiol
(Endocrinol Metab) 290:E 550–559.
125. Muscelli E, Mari A, Casolaro A et al (2008) Separate impact of obesity and glucose
tolerance on the incretin effect in normal subjects and type 2 diabetic patients.
Diabetes 57:1340–1348.
126. Vilsbøll T, Krarup T, Sonne J et al (2003) Incretin secretion in relation to meal size and
body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus.
J Clin Endocrinol Metab 88:2706–2713.
127. Ryskjaer J, Deacon CF, Carr RD et al (2006) Plasma dipeptidyl peptidase-IV activity
in patients with type-2 diabetes mellitus correlates positively with HbA1c levels, but
is not acutely affected by food intake. Eur J Endocrinol 155:485–493.
128. Salinari S, Bertuzzi A, Asnaghi S, Guidone C, Manco M, Mingrone G (2009) First-phase
insulin secretion restoration and differential response to glucose load depending on
the route of administration in type 2 diabetic subjects after bariatric surgery. Diabetes
Care 32:375–380.
129. Knop FK, Vilsboll T, Hojberg PV, et al. The insulinotropic effect of GIP is impaired in
patients with chronic pancreatitis and secondary diabetes mellitus as compared
to patients with chronic pancreatitis and normal glucose tolerance. Regul Pept
2007;144(1-3):123-130.
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