"
"
Unmet needs in T2DM therapy
As we have seen in Chapter 1, T2DM is a huge, global problem. Many
treatments are available to tackle this chronic and potentially serious
condition, but the fact is that, in many patients, long-term glycaemic
control and adherence to therapies is far from optimal; limited by a
lack of sustained efficacy, safety and tolerability issues and product
label restrictions. These problems are compounded in those patients
with comorbidities that interfere with diabetes therapy, such as renal
impairment.
Beyond HbA1c in assessing treatment efficacy
Assessing the degree to which glycaemic control is achieved hinges on
a number of parameters. If these targets are not met then glycaemia is
considered to be uncontrolled. These targets are as follows:
zzHbA1c: <7.0%1
zzFPG: 3.9 – 7.2 mmol/L (70 – 130 mg/dl)2
zz2-hour postprandial blood glucose: <7.8 mmol/L (<140 mg/dl)3, 4 up to <10
mmol/L (<180 mg/dl)5
As these targets indicate whether glycaemia is controlled or not, they
relate directly to the efficacy of any given therapy in lowering blood
glucose levels in patients with T2DM. For this reason, the level of efficacy
of any treatment will remain an important decision factor in choosing
the most appropriate agent.
HbA1c, as a proxy for efficacy, is the current gold standard in monitoring
treatment and informing management decisions in people with diabetes.
6 However, using this measure in isolation is not without its limitations.6
HbA1c reflects the mean blood glucose level during the preceding six
to eight weeks, but this is true only for the population as a whole, not
the individual patient.6 For assessing the efficacy of a given treatment
in the future we should take a more holistic approach. It is known that
about 33% of people diagnosed as having T2DM based on postprandial
(PPG) hyperglycaemia have normal fasting plasma glucose (FPG).7 It
has been shown that the deleterious effects of dysglycaemia – daily
excursions in FPG and PPG – develop before diabetes is diagnosed.8
As we have seen in Chapter 1, T2DM is a huge, global problem. Many
treatments are available to tackle this chronic and potentially serious
condition, but the fact is that, in many patients, long-term glycaemic
control and adherence to therapies is far from optimal; limited by a
lack of sustained efficacy, safety and tolerability issues and product
label restrictions. These problems are compounded in those patients
with comorbidities that interfere with diabetes therapy, such as renal
impairment.
Beyond HbA1c in assessing treatment efficacy
Assessing the degree to which glycaemic control is achieved hinges on
a number of parameters. If these targets are not met then glycaemia is
considered to be uncontrolled. These targets are as follows:
zzHbA1c: <7.0%1
zzFPG: 3.9 – 7.2 mmol/L (70 – 130 mg/dl)2
zz2-hour postprandial blood glucose: <7.8 mmol/L (<140 mg/dl)3, 4 up to <10
mmol/L (<180 mg/dl)5
As these targets indicate whether glycaemia is controlled or not, they
relate directly to the efficacy of any given therapy in lowering blood
glucose levels in patients with T2DM. For this reason, the level of efficacy
of any treatment will remain an important decision factor in choosing
the most appropriate agent.
HbA1c, as a proxy for efficacy, is the current gold standard in monitoring
treatment and informing management decisions in people with diabetes.
6 However, using this measure in isolation is not without its limitations.6
HbA1c reflects the mean blood glucose level during the preceding six
to eight weeks, but this is true only for the population as a whole, not
the individual patient.6 For assessing the efficacy of a given treatment
in the future we should take a more holistic approach. It is known that
about 33% of people diagnosed as having T2DM based on postprandial
(PPG) hyperglycaemia have normal fasting plasma glucose (FPG).7 It
has been shown that the deleterious effects of dysglycaemia – daily
excursions in FPG and PPG – develop before diabetes is diagnosed.8
The degree to which FPG and PPG influence overall glycaemia is relatively
complex, but we know that PPG contributes ~70% to the total
glycaemic load in patients who are fairly well controlled (HbA1c <7.3%).
In patients who are very poorly controlled (HbA1c >10.2) it is FPG that
contributes around 70% to the total glycaemic load (Figure 1).7, 9 Furthermore,
there is a Iinear relationship between the risk of CV death and the
2-hour oral glucose tolerance test (OGTT).7 These data suggest that all
the parameters for assessing glycaemia (HbA1c, FPG, and PPG) should
be considered in the management of T2DM.7 In assessing the efficacy of
a T2DM therapy we should take into account not only its ability to lower
HbA1c, but also its ability to normalise the blood glucose excursions that
can occur during the day i.e. the spikes in FPG and PPG.10, 11
complex, but we know that PPG contributes ~70% to the total
glycaemic load in patients who are fairly well controlled (HbA1c <7.3%).
In patients who are very poorly controlled (HbA1c >10.2) it is FPG that
contributes around 70% to the total glycaemic load (Figure 1).7, 9 Furthermore,
there is a Iinear relationship between the risk of CV death and the
2-hour oral glucose tolerance test (OGTT).7 These data suggest that all
the parameters for assessing glycaemia (HbA1c, FPG, and PPG) should
be considered in the management of T2DM.7 In assessing the efficacy of
a T2DM therapy we should take into account not only its ability to lower
HbA1c, but also its ability to normalise the blood glucose excursions that
can occur during the day i.e. the spikes in FPG and PPG.10, 11
Beyond glycaemic measures in assessing treatment efficacy
In addition to glycaemic parameters for assessing the efficacy of T2DM
treatment, it is becoming increasingly clear that other parameters beyond
glycaemic control are important. T2DM is a complex condition
that is often part of a much broader metabolic syndrome that manifests
itself with obesity, hypertension and dyslipidaemia. Also, the side
effects associated with some treatments can have a negative impact
on the patient’s quality of life.12
In addition to glycaemic parameters for assessing the efficacy of T2DM
treatment, it is becoming increasingly clear that other parameters beyond
glycaemic control are important. T2DM is a complex condition
that is often part of a much broader metabolic syndrome that manifests
itself with obesity, hypertension and dyslipidaemia. Also, the side
effects associated with some treatments can have a negative impact
on the patient’s quality of life.12
In terms of dyslipidaemia it is known that pioglitazone is associated with
improvements in triglycerides, HDL cholesterol, LDL particle concentration,
and LDL particle size, whereas rosiglitazone is not.13 Rosiglitazone
has since been associated with a number of adverse effects, but this
example illustrates the point that the variation in efficacy of the various
T2DM treatments, even those in the same therapeutic class, extends
beyond simple glucose lowering.
Obesity can complicate the management of diabetes by increasing
insulin resistance and blood glucose concentrations as well as negatively
impacting lipidaemia,14 but it is well known that some T2DM treatments,
such as SUs, Glinides, and TZDs are associated with significant
increases in weight.15 Impact on body weight and in turn lipidaemia
will be increasingly recognised as an important measure of efficacy for
new and emerging T2DM treatments. Some new therapies have demonstrated
favourable characteristics with regard to body weight. For
example, the DPP-4 inhibitors are weight neutral and the GLP-1 mimetics/
analogues can reduce body weight significantly.16-20
Treatment adherence and the needs of the patient
Intimately related to the clinical parameters of efficacy discussed
above is the perennial problem of treatment adherence. The full benefits
of a T2DM treatment are only gained if the patient takes the medications
as prescribed. It has been generally acknowledged for years
that non-adherence rates for chronic illness regimens and for lifestyle
changes are ~ 50%.21 As a group, patients with diabetes find it difficult
to adhere to their treatment regimens.22
Complex regimens
One treatment-related factor that is known to influence adherence is
regimen complexity. It is well known that people with diabetes have
to take several medications every day for their T2DM and concurrent
conditions.23 Given the fact that patients often have to take different
medications, with different dosage frequencies, at different times of
the day, it is hardly surprising that many of them are unable to follow
treatment regimens closely.23 Simplifying treatment regimens using
single pill formulations that can be taken at any time of the day can
potentially help patients to adhere to their medication and consequently
improve the clinical efficacy of T2DM treatments.21
improvements in triglycerides, HDL cholesterol, LDL particle concentration,
and LDL particle size, whereas rosiglitazone is not.13 Rosiglitazone
has since been associated with a number of adverse effects, but this
example illustrates the point that the variation in efficacy of the various
T2DM treatments, even those in the same therapeutic class, extends
beyond simple glucose lowering.
Obesity can complicate the management of diabetes by increasing
insulin resistance and blood glucose concentrations as well as negatively
impacting lipidaemia,14 but it is well known that some T2DM treatments,
such as SUs, Glinides, and TZDs are associated with significant
increases in weight.15 Impact on body weight and in turn lipidaemia
will be increasingly recognised as an important measure of efficacy for
new and emerging T2DM treatments. Some new therapies have demonstrated
favourable characteristics with regard to body weight. For
example, the DPP-4 inhibitors are weight neutral and the GLP-1 mimetics/
analogues can reduce body weight significantly.16-20
Treatment adherence and the needs of the patient
Intimately related to the clinical parameters of efficacy discussed
above is the perennial problem of treatment adherence. The full benefits
of a T2DM treatment are only gained if the patient takes the medications
as prescribed. It has been generally acknowledged for years
that non-adherence rates for chronic illness regimens and for lifestyle
changes are ~ 50%.21 As a group, patients with diabetes find it difficult
to adhere to their treatment regimens.22
Complex regimens
One treatment-related factor that is known to influence adherence is
regimen complexity. It is well known that people with diabetes have
to take several medications every day for their T2DM and concurrent
conditions.23 Given the fact that patients often have to take different
medications, with different dosage frequencies, at different times of
the day, it is hardly surprising that many of them are unable to follow
treatment regimens closely.23 Simplifying treatment regimens using
single pill formulations that can be taken at any time of the day can
potentially help patients to adhere to their medication and consequently
improve the clinical efficacy of T2DM treatments.21
Tolerability is another treatment-related issue that can seriously impact
treatment adherence. T2DM treatment options offer a trade off between
efficacy and tolerability due to product label restrictions and
adverse effects, e.g. weight gain, hypoglycemia, injections, heart failure
and GI problems.24, 25 Common side effects of current treatments
(metformin, SUs, glinides, TZDs, insulin, α-glucosidase inhibitors and GLP-1
mimetics/analogues) are headache, nausea, GI disorders, weight gain
and hypoglycaemia. These side effects are sometimes accompanied
by subsequent, more severe complications, e.g. hypoglycaemia may
influence cardiovascular events and dementia.26, 27 In view of these tolerability
issues, the guidelines make specific recommendations regarding
each class of T2DM treatment (Figure 2).
treatment adherence. T2DM treatment options offer a trade off between
efficacy and tolerability due to product label restrictions and
adverse effects, e.g. weight gain, hypoglycemia, injections, heart failure
and GI problems.24, 25 Common side effects of current treatments
(metformin, SUs, glinides, TZDs, insulin, α-glucosidase inhibitors and GLP-1
mimetics/analogues) are headache, nausea, GI disorders, weight gain
and hypoglycaemia. These side effects are sometimes accompanied
by subsequent, more severe complications, e.g. hypoglycaemia may
influence cardiovascular events and dementia.26, 27 In view of these tolerability
issues, the guidelines make specific recommendations regarding
each class of T2DM treatment (Figure 2).
“Failure-based” treatment strategies
Several large, randomised trials have demonstrated that intensive
treatment can improve outcomes in people with T2DM. For example,
post-trial monitoring data from the UKPDS shows that patients who received
intensive treatment during the study continue to have a significantly
decreased risk of any diabetes-related endpoint over the long
term; an effect that is known as “a legacy of improved outcomes” because
early intensive treatment leaves a legacy of clinical benefits.29, 30
Controlling glycaemia more aggressively, instead of simply waiting for
treatment failure aims to avoid the phenomenon known as ”metabolic
memory”. This concept, which refers to diabetic vascular stresses persisting
after glucose normalisation, has been supported by laboratory
and clinical data.31, 32
The progressive nature of T2DM requires regular monitoring and adjustment
of treatment, but all too often management strategies for this
condition are ‘failure based’, in that there is a tendency to persist with
monotherapy until blood glucose levels are no longer controlled.23
There appears to be inertia in primary care impeding the adoption of
an aggressive, treat-to-target approach (i.e. early enforced normalization
of blood glucose levels) even though the benefits of intensive
management in the short- and long-term have been demonstrated by
some long-term studies.
An early switch to antidiabetic combination treatment that addresses
the dual endocrine defects of insulin resistance and β-cell dysfunction,
would deliver a markedly greater reduction in HbA1c for those patients
who are struggling to meet their glycaemic targets.33
Predictability of treatment response and the need for
individualised treatment
Currently, T2DM management is very much a ‘one treatment fits all’
affair.34 People with T2DM are generally treated in the same way regardless
of underlying differences that may affect their therapeutic response.
34 There is a huge variation in response, which makes it almost
impossible to predict the treatment effect in any given patient.34 Differences
in genotype interact with external environmental factors to produce
an in-vivo milieu that varies from person to person thus impacting
the effects of a medication.34
Analyses have shown that in the USA only 56% of patients diagnosed
and treated for diabetes reach their glycaemic targets, whereas in
Germany the figure is 48% (glycaemic target for both the USA and
Germany is <7% HbA1c).35, 36 This failure in treatment leaves a substantial
Several large, randomised trials have demonstrated that intensive
treatment can improve outcomes in people with T2DM. For example,
post-trial monitoring data from the UKPDS shows that patients who received
intensive treatment during the study continue to have a significantly
decreased risk of any diabetes-related endpoint over the long
term; an effect that is known as “a legacy of improved outcomes” because
early intensive treatment leaves a legacy of clinical benefits.29, 30
Controlling glycaemia more aggressively, instead of simply waiting for
treatment failure aims to avoid the phenomenon known as ”metabolic
memory”. This concept, which refers to diabetic vascular stresses persisting
after glucose normalisation, has been supported by laboratory
and clinical data.31, 32
The progressive nature of T2DM requires regular monitoring and adjustment
of treatment, but all too often management strategies for this
condition are ‘failure based’, in that there is a tendency to persist with
monotherapy until blood glucose levels are no longer controlled.23
There appears to be inertia in primary care impeding the adoption of
an aggressive, treat-to-target approach (i.e. early enforced normalization
of blood glucose levels) even though the benefits of intensive
management in the short- and long-term have been demonstrated by
some long-term studies.
An early switch to antidiabetic combination treatment that addresses
the dual endocrine defects of insulin resistance and β-cell dysfunction,
would deliver a markedly greater reduction in HbA1c for those patients
who are struggling to meet their glycaemic targets.33
Predictability of treatment response and the need for
individualised treatment
Currently, T2DM management is very much a ‘one treatment fits all’
affair.34 People with T2DM are generally treated in the same way regardless
of underlying differences that may affect their therapeutic response.
34 There is a huge variation in response, which makes it almost
impossible to predict the treatment effect in any given patient.34 Differences
in genotype interact with external environmental factors to produce
an in-vivo milieu that varies from person to person thus impacting
the effects of a medication.34
Analyses have shown that in the USA only 56% of patients diagnosed
and treated for diabetes reach their glycaemic targets, whereas in
Germany the figure is 48% (glycaemic target for both the USA and
Germany is <7% HbA1c).35, 36 This failure in treatment leaves a substantial
population exposed to prolonged periods of damaging hyperglycaemia.
34 There is now a consensus that further insight into the differences
between people with T2DM, both physiologic and genetic, should not
only help elucidate the pathogenesis of this disease, but lead to individualised
treatments for patients that will improve glycaemic control,
maximise individual benefit, minimise risk, reduce diabetes complications,
and ultimately provide reductions in global health cost.34 The recent
consensus published in the Journal of Clinical Endocrinology and
Metabolism (Smith et al., 2010) makes a series of recommendations for
increasing understanding of the heterogeneity of T2DM and achieving
the goal of individualising therapy and improving treatment response
(Table 1).34
34 There is now a consensus that further insight into the differences
between people with T2DM, both physiologic and genetic, should not
only help elucidate the pathogenesis of this disease, but lead to individualised
treatments for patients that will improve glycaemic control,
maximise individual benefit, minimise risk, reduce diabetes complications,
and ultimately provide reductions in global health cost.34 The recent
consensus published in the Journal of Clinical Endocrinology and
Metabolism (Smith et al., 2010) makes a series of recommendations for
increasing understanding of the heterogeneity of T2DM and achieving
the goal of individualising therapy and improving treatment response
(Table 1).34
Cardiovascular safety
Completed studies
Numerous observational studies have shown a clear relationship between
hyperglycaemia and cardiovascular (CV) disease. Because of
the known increase in the risk of CV disease in T2DM and the emphasis
on CV safety in the development of T2DM medications by regulatory
authorities there is considerable interest in the degree to which T2DM
treatments influence CV health.37 However, very little is known about
the CV effects of newer T2DM treatments.
Several large, long-term studies have investigated the CV safety of T2DM
treatments, i.e. UKPDS, ACCORD, ADVANCE and VADT, all of which
failed to show that intensive glucose control significantly reduces CV
events.33, 38-40 Indeed, ACCORD was terminated early due to higher
(non-significant) mortality in the intensive treatment group, which has
led to the conclusion in some quarters that intensive glucose control
not only has no effect on the risk of CV events, but can even be harmful
in patients at high CV risk.38 It is possible to argue that in the UKPDS
metformin was associated with an improvement in CV mortality (this is
supported by recent meta-analyses – see the end of this chapter).41 This
follow-up study of the tight glucose intervention in the UKPDS showed
that intensive glucose control was associated with a significant reduction
in the risk for myocardial infarction, diabetes-related deaths and
all-cause mortality.41 This suggests that early, strict glucose control generates
a legacy that is eventually translated into CV protection. Currently,
this is nothing more than a hypothesis that requires testing.41
The PROACTIVE study showed that pioglitazone can reduce the risk
of secondary macrovascular events in a high-risk patient population
with T2DM and established macrovascular disease; however, the study
failed on the primary composite endpoint and only demonstrated CV
benefit on a secondary endpoint.42-45
The RECORD trial demonstrated that while the addition of rosiglitazone
to glucose-lowering therapy did not increase the risk of overall mortality
and morbidity, it did increase the risk of heart failure.46 In the STOPNIDDM
trial, acarbose was associated with a CV benefit, however, this
was a trial in IGT, not T2DM, and the number of observed CV events was
very low.47 Whether early insulin treatment results in a beneficial effect
on the CV system remains an open question,47 but one that the ORIGIN
trial will attempt to answer, the first results of which are expected in
2012. The Steno-2 study demonstrated CV risk improvement, but this is
a small study and the multi-factorial interventions make it impossible to
attribute the observed effect to a single compound.48
Completed studies
Numerous observational studies have shown a clear relationship between
hyperglycaemia and cardiovascular (CV) disease. Because of
the known increase in the risk of CV disease in T2DM and the emphasis
on CV safety in the development of T2DM medications by regulatory
authorities there is considerable interest in the degree to which T2DM
treatments influence CV health.37 However, very little is known about
the CV effects of newer T2DM treatments.
Several large, long-term studies have investigated the CV safety of T2DM
treatments, i.e. UKPDS, ACCORD, ADVANCE and VADT, all of which
failed to show that intensive glucose control significantly reduces CV
events.33, 38-40 Indeed, ACCORD was terminated early due to higher
(non-significant) mortality in the intensive treatment group, which has
led to the conclusion in some quarters that intensive glucose control
not only has no effect on the risk of CV events, but can even be harmful
in patients at high CV risk.38 It is possible to argue that in the UKPDS
metformin was associated with an improvement in CV mortality (this is
supported by recent meta-analyses – see the end of this chapter).41 This
follow-up study of the tight glucose intervention in the UKPDS showed
that intensive glucose control was associated with a significant reduction
in the risk for myocardial infarction, diabetes-related deaths and
all-cause mortality.41 This suggests that early, strict glucose control generates
a legacy that is eventually translated into CV protection. Currently,
this is nothing more than a hypothesis that requires testing.41
The PROACTIVE study showed that pioglitazone can reduce the risk
of secondary macrovascular events in a high-risk patient population
with T2DM and established macrovascular disease; however, the study
failed on the primary composite endpoint and only demonstrated CV
benefit on a secondary endpoint.42-45
The RECORD trial demonstrated that while the addition of rosiglitazone
to glucose-lowering therapy did not increase the risk of overall mortality
and morbidity, it did increase the risk of heart failure.46 In the STOPNIDDM
trial, acarbose was associated with a CV benefit, however, this
was a trial in IGT, not T2DM, and the number of observed CV events was
very low.47 Whether early insulin treatment results in a beneficial effect
on the CV system remains an open question,47 but one that the ORIGIN
trial will attempt to answer, the first results of which are expected in
2012. The Steno-2 study demonstrated CV risk improvement, but this is
a small study and the multi-factorial interventions make it impossible to
attribute the observed effect to a single compound.48
Definitive proof for CV protection afforded by T2DM treatment is scant
to say the least, so much so that the spectre of increased CV risk due to
T2DM treatment looms large in the minds of many experts.
The results from these trials may relate to the particular drugs used rather
than difference between intensive and conventional management.
There have been many high profile cases concerning the use of some
compounds and an associated increase in CV events with the most
infamous being rosiglitazone and to a lesser extent the first generation
SU, tolbutamide.49, 50 Naturally, these fears have placed the TZDs, as a
class, under great scrutiny, but the fact remains that large trials and
meta-analyses (i.e. PROactive, Nissen and Wolski’s meta-analyses and
RECORD) do not provide definitive answers with regard to the CV safety
of these compounds.42, 46, 50, 51
Prompted by these concerns, the FDA conducted a systematic review
of epidemiologic studies of CV risk in patients treated with rosiglitazone
or pioglitazone,52 the results of which are consistent with results of the
same organisation’s meta-analyses of randomised clinical trials with
these two TZDs.53 The salient point from these analyses is that it is highly
likely that rosiglitazone therapy is associated with increased risk of adverse
CV outcomes.53
Ongoing studies
There are a number of ongoing trials investigating the CV outcomes
associated with T2DM treatment. The driving force behind the relatively
recent initiation of these large trials, often involving more than 10,000
patients, is the fact the regulatory bodies now require CV safety on all
new and emerging T2DM treatments. These CV outcome trials are summarised
in Table 2.
to say the least, so much so that the spectre of increased CV risk due to
T2DM treatment looms large in the minds of many experts.
The results from these trials may relate to the particular drugs used rather
than difference between intensive and conventional management.
There have been many high profile cases concerning the use of some
compounds and an associated increase in CV events with the most
infamous being rosiglitazone and to a lesser extent the first generation
SU, tolbutamide.49, 50 Naturally, these fears have placed the TZDs, as a
class, under great scrutiny, but the fact remains that large trials and
meta-analyses (i.e. PROactive, Nissen and Wolski’s meta-analyses and
RECORD) do not provide definitive answers with regard to the CV safety
of these compounds.42, 46, 50, 51
Prompted by these concerns, the FDA conducted a systematic review
of epidemiologic studies of CV risk in patients treated with rosiglitazone
or pioglitazone,52 the results of which are consistent with results of the
same organisation’s meta-analyses of randomised clinical trials with
these two TZDs.53 The salient point from these analyses is that it is highly
likely that rosiglitazone therapy is associated with increased risk of adverse
CV outcomes.53
Ongoing studies
There are a number of ongoing trials investigating the CV outcomes
associated with T2DM treatment. The driving force behind the relatively
recent initiation of these large trials, often involving more than 10,000
patients, is the fact the regulatory bodies now require CV safety on all
new and emerging T2DM treatments. These CV outcome trials are summarised
in Table 2.
Should the results of the above trials be overwhelmingly positive, they
will prove that T2DM treatments can provide benefits beyond simply
lowering blood glucose levels. The data will provide an insight into the
cardiovascular safety and potential cardiovascular protection of the
compounds being investigated. The results of these trials in conjunction
with an increased knowledge of disease genetics and drug mode of
actions could stimulate a reappraisal of T2DM management.
Emerging therapeutic classes
DPP-4 inhibitors
DPP-4 inhibitors are oral anti-diabetics. They do not require an uptitration
period, are weight neutral and are associated with significant
improvements in glucose control in patients with T2DM by preventing the
inactivation of the incretin hormone GLP-1, which stimulates glucosedependent
insulin secretion and suppresses glucagon secretion.16
DPP-4 inhibitors are efficacious over a broad range of HbA1c levels.
They have shown to be effective as both monotherapy and as add-on
therapy to metformin, SUs, TZDs and insulin in subjects who lack adequate
glycaemic control.16 In addition to their demonstrated efficacy
as mono- and add-on therapy they are also generally safe and have a
placebo-like tolerability profile.16
Long-term safety data for DPP-4 inhibitors is still lacking, although they
are now included in the most recent US and European guidelines2, 62
There are concerns regarding the ubiquitous tissue expression (liver,
lung, lymphocytes, etc) of the DPP enzymes, their role in tumour suppression
and their interaction with other hormones besides GLP-1.63-67 To
date there is nothing in the safety record of DPP-4 inhibitors to suggest
these concerns have any clinical grounding Also, due to the way that
sitagliptin, vildagliptin and saxagliptin are cleared from the body, their
use is not recommended in patients with moderate to severe renal insufficiency
and because they have not been studied in severe hepatic
insufficiency their use is also not recommended in the these patients
(vildagliptin should not be used in any type of hepatic impairment).68-70
Linagliptin on the other hand can be used without dose adjustment in
all stages of renal impairment. Table 3 presents a ‘SWOT’ analysis of the
DPP-4 inhibitors.
will prove that T2DM treatments can provide benefits beyond simply
lowering blood glucose levels. The data will provide an insight into the
cardiovascular safety and potential cardiovascular protection of the
compounds being investigated. The results of these trials in conjunction
with an increased knowledge of disease genetics and drug mode of
actions could stimulate a reappraisal of T2DM management.
Emerging therapeutic classes
DPP-4 inhibitors
DPP-4 inhibitors are oral anti-diabetics. They do not require an uptitration
period, are weight neutral and are associated with significant
improvements in glucose control in patients with T2DM by preventing the
inactivation of the incretin hormone GLP-1, which stimulates glucosedependent
insulin secretion and suppresses glucagon secretion.16
DPP-4 inhibitors are efficacious over a broad range of HbA1c levels.
They have shown to be effective as both monotherapy and as add-on
therapy to metformin, SUs, TZDs and insulin in subjects who lack adequate
glycaemic control.16 In addition to their demonstrated efficacy
as mono- and add-on therapy they are also generally safe and have a
placebo-like tolerability profile.16
Long-term safety data for DPP-4 inhibitors is still lacking, although they
are now included in the most recent US and European guidelines2, 62
There are concerns regarding the ubiquitous tissue expression (liver,
lung, lymphocytes, etc) of the DPP enzymes, their role in tumour suppression
and their interaction with other hormones besides GLP-1.63-67 To
date there is nothing in the safety record of DPP-4 inhibitors to suggest
these concerns have any clinical grounding Also, due to the way that
sitagliptin, vildagliptin and saxagliptin are cleared from the body, their
use is not recommended in patients with moderate to severe renal insufficiency
and because they have not been studied in severe hepatic
insufficiency their use is also not recommended in the these patients
(vildagliptin should not be used in any type of hepatic impairment).68-70
Linagliptin on the other hand can be used without dose adjustment in
all stages of renal impairment. Table 3 presents a ‘SWOT’ analysis of the
DPP-4 inhibitors.
GLP-1 mimetics and analogues
Exenatide and liraglutide are injected drugs that also act on the incretin
system. Instead of impeding the degradation of native GLP-1
like DPP-4 inhibitors, exenatide mimics GLP-1, whereas as liraglutide is
an analogue of this incretin. Both of these agents offer considerable
reductions in blood glucose levels and body weight (see Chapter 4).
In addition, exenatide has been shown to have favourable effects on
lipidaemia.71 The drawbacks of GLP-1 mimetics/analogues include
their need to be injected, gastrointestinal side effects and a potential
link with acute pancreatitis. Table 4 presents a ‘SWOT’ analysis of these
agents.
Exenatide and liraglutide are injected drugs that also act on the incretin
system. Instead of impeding the degradation of native GLP-1
like DPP-4 inhibitors, exenatide mimics GLP-1, whereas as liraglutide is
an analogue of this incretin. Both of these agents offer considerable
reductions in blood glucose levels and body weight (see Chapter 4).
In addition, exenatide has been shown to have favourable effects on
lipidaemia.71 The drawbacks of GLP-1 mimetics/analogues include
their need to be injected, gastrointestinal side effects and a potential
link with acute pancreatitis. Table 4 presents a ‘SWOT’ analysis of these
agents.
SGLT-2 inhibitors
In the kidneys, two transporter proteins, sodium-glucose co-transporter-
1 (SGLT-1) and SGLT-2 are crucial in regulating the reuptake of sodium
and glucose back into ultra-filtrated blood.72 Inhibiting SGLT-2 has
been identified as a way of reducing glucose re-uptake and therefore
reducing blood glucose levels. 72
No compounds in this class are currently available on the market. Dapagliflozin
has filed for approval, while canagliflozin/empagliflozin are in
Phase 3 development. Initial SGLT-2 inhibitor data shows there are no
excessive losses of fluid, sodium, or potassium; very low risk of hypoglycaemia;
significant reductions in HbA1c (~0.7%) modest weight loss
(1 to 4 kg) and a lowering of systolic blood pressure (1 to 4 mmHg).72-
75 Potential drawbacks of SGLT-2 inhibition include a slight increase
in urine volume and a tendency to increase urinary tract infections
and genital mycosis. The latter drawback is thought to be due to the
increased levels of glucose in the urine, which supports the growth of
yeasts, etc.72 Table 5 presents a ‘SWOT’ analysis of the SGLT-2 inhibitors.
In the kidneys, two transporter proteins, sodium-glucose co-transporter-
1 (SGLT-1) and SGLT-2 are crucial in regulating the reuptake of sodium
and glucose back into ultra-filtrated blood.72 Inhibiting SGLT-2 has
been identified as a way of reducing glucose re-uptake and therefore
reducing blood glucose levels. 72
No compounds in this class are currently available on the market. Dapagliflozin
has filed for approval, while canagliflozin/empagliflozin are in
Phase 3 development. Initial SGLT-2 inhibitor data shows there are no
excessive losses of fluid, sodium, or potassium; very low risk of hypoglycaemia;
significant reductions in HbA1c (~0.7%) modest weight loss
(1 to 4 kg) and a lowering of systolic blood pressure (1 to 4 mmHg).72-
75 Potential drawbacks of SGLT-2 inhibition include a slight increase
in urine volume and a tendency to increase urinary tract infections
and genital mycosis. The latter drawback is thought to be due to the
increased levels of glucose in the urine, which supports the growth of
yeasts, etc.72 Table 5 presents a ‘SWOT’ analysis of the SGLT-2 inhibitors.
11β-HSD1 inhibitors
This enzyme is responsible for the regeneration of cortisol from its inert
form, cortisone (Figure 3). Inhibitors of 11β-HSD1 have reached Phase
IIb clinical trials for the treatment of T2DM. These compounds act by
decreasing the cortisol generated in liver and adipose tissue, thereby
reducing tissue-specific gluconeogenesis and fatty acid metabolism.76
11β-HSD1 inhibitors are predicted to be at least weight neutral, if not
leading to some weight loss. In addition, they should improve glycaemia
without inducing hypoglycaemia.76 The concern of physiologists is
that if you artificially reduce the level of circulating cortisol by means of
the 11β-HSD1 pathway, you run the risk of adrenal gland compensation
and activation of the hypothalamic-pituitary-adrenal (HPA) axis,
resulting in the production of more cortisol.76 In this scenario, the
adrenal glands might also simultaneously produce excess adrenal
androgens, which, at high concentrations are associated with numerous
negative effects.
To date, these fears have not been borne out in animal studies where
the complete deletion of the 11β-HSD1 gene in mice had, overall, inconclusively
minimal effects on adrenal action.76 Harno and White
(2010) conclude that 11β-HSD1 inhibition represent a compelling treatment
strategy for T2DM.76 Table 6 presents a ‘SWOT’ analysis of the
11β-HSD1 inhibitors.
This enzyme is responsible for the regeneration of cortisol from its inert
form, cortisone (Figure 3). Inhibitors of 11β-HSD1 have reached Phase
IIb clinical trials for the treatment of T2DM. These compounds act by
decreasing the cortisol generated in liver and adipose tissue, thereby
reducing tissue-specific gluconeogenesis and fatty acid metabolism.76
11β-HSD1 inhibitors are predicted to be at least weight neutral, if not
leading to some weight loss. In addition, they should improve glycaemia
without inducing hypoglycaemia.76 The concern of physiologists is
that if you artificially reduce the level of circulating cortisol by means of
the 11β-HSD1 pathway, you run the risk of adrenal gland compensation
and activation of the hypothalamic-pituitary-adrenal (HPA) axis,
resulting in the production of more cortisol.76 In this scenario, the
adrenal glands might also simultaneously produce excess adrenal
androgens, which, at high concentrations are associated with numerous
negative effects.
To date, these fears have not been borne out in animal studies where
the complete deletion of the 11β-HSD1 gene in mice had, overall, inconclusively
minimal effects on adrenal action.76 Harno and White
(2010) conclude that 11β-HSD1 inhibition represent a compelling treatment
strategy for T2DM.76 Table 6 presents a ‘SWOT’ analysis of the
11β-HSD1 inhibitors.
Glucagon antagonism
Glucagon plays a central role in glucose homeostasis, namely by increasing
hepatic glucose production and raising blood glucose levels.
Blunting the effects of has long been considered a means of reducing
hyperglycaemia in T2DM. There are two ways in which to limit the
activity of glucagon. Firstly, immuno-neutralisers effectively reduce the
amount of glucagon in the body, but the development of such compounds
for use in humans has not progressed because of limitations imposed
by the delivery methods necessary to achieve significant levels
of exposure for the peptide agents.77
Secondly, and more promisingly, are small molecules that inhibit the
glucagon receptor. Several examples of these are in early Phase 2 clinical
development. They act by preventing glucagon binding to its receptor
and triggering the increased production of glucose.78 Blocking
the action of glucagon is predicted to be an effective means of controlling
hepatic glucose production, thereby lowering fasting and postprandial
hyperglycaemia in T2DM.77 Table 7 presents a ‘SWOT’ analysis
of glucagon receptor antagonists.
Glucagon plays a central role in glucose homeostasis, namely by increasing
hepatic glucose production and raising blood glucose levels.
Blunting the effects of has long been considered a means of reducing
hyperglycaemia in T2DM. There are two ways in which to limit the
activity of glucagon. Firstly, immuno-neutralisers effectively reduce the
amount of glucagon in the body, but the development of such compounds
for use in humans has not progressed because of limitations imposed
by the delivery methods necessary to achieve significant levels
of exposure for the peptide agents.77
Secondly, and more promisingly, are small molecules that inhibit the
glucagon receptor. Several examples of these are in early Phase 2 clinical
development. They act by preventing glucagon binding to its receptor
and triggering the increased production of glucose.78 Blocking
the action of glucagon is predicted to be an effective means of controlling
hepatic glucose production, thereby lowering fasting and postprandial
hyperglycaemia in T2DM.77 Table 7 presents a ‘SWOT’ analysis
of glucagon receptor antagonists.
Interleukin-1β receptor antagonists
Interleukin-1β is a proinflammatory cytokine that inhibits the function
and promotes the apoptosis of pancreatic β-cells.79 β-cells producing
this cytokine have been observed in pancreatic sections obtained from
patients with T2DM. Depending on culture conditions, high glucose levels
have been shown to increase β-cell production and the release of
interleukin-1β, followed by functional impairment and apoptosis.79 Using
an antagonist to prevent interleukin-1β from binding to its receptor
protects human β-cells from glucose-induced functional impairment
and apoptosis.80 This therapeutic approach has the potential to block
the pathogenic progression of T2DM.
Anakinra, a recombinant human interleukin-1–receptor antagonist, is
currently in Phase 2 development. A recent study has demonstrated
that HbA1c levels in T2DM patients treated with this compound for 13
weeks were 0.46% lower than in those treated with placebo.79 In addition,
anakinra was associated with improved β-cell secretory function
and reduced markers of systemic inflammation.79 In terms of safety, no
cases of symptomatic hypoglycaemia or serious, drug related adverse
events were observed during this study.79 Table 8 presents a ‘SWOT’
analysis of interleukin-1β receptor antagonists.
Interleukin-1β is a proinflammatory cytokine that inhibits the function
and promotes the apoptosis of pancreatic β-cells.79 β-cells producing
this cytokine have been observed in pancreatic sections obtained from
patients with T2DM. Depending on culture conditions, high glucose levels
have been shown to increase β-cell production and the release of
interleukin-1β, followed by functional impairment and apoptosis.79 Using
an antagonist to prevent interleukin-1β from binding to its receptor
protects human β-cells from glucose-induced functional impairment
and apoptosis.80 This therapeutic approach has the potential to block
the pathogenic progression of T2DM.
Anakinra, a recombinant human interleukin-1–receptor antagonist, is
currently in Phase 2 development. A recent study has demonstrated
that HbA1c levels in T2DM patients treated with this compound for 13
weeks were 0.46% lower than in those treated with placebo.79 In addition,
anakinra was associated with improved β-cell secretory function
and reduced markers of systemic inflammation.79 In terms of safety, no
cases of symptomatic hypoglycaemia or serious, drug related adverse
events were observed during this study.79 Table 8 presents a ‘SWOT’
analysis of interleukin-1β receptor antagonists.
Beyond glycaemic control
In this chapter we have already discussed the trials that have investigated
the degree to which T2DM treatments influence CV risk. Fifty
percent of people diabetes die from CV disease, primarily heart disease
and stroke,81 so there’s intense interest in defining the degree to
which specific drugs and combinations of drugs influence CV risk.
Since the 1990s, the options for OAD treatment have increased markedly.
The expanded selection has created a need for comparative
data on the risks and benefits of anti-diabetic drugs, particularly in light
of the greater cost of newer agents.82 A meta-analysis of forty clinical
trials shows that metformin is associated with a 26% reduction in the
relative risk of CV mortality compared with SUs, TZDs, glinides and placebo.
82 A meta-analysis is only as good as the studies it includes and
the authors of this particular analysis conclude: “larger, long-term studies
taken to hard endpoints and better reporting of CV events in shortterm
studies will be required to draw firm conclusions about major clinical
benefits and risks related to OADs.”82
It is increasingly evident that controlling weight, hypertension and dyslipidaemia
is tantamount to reducing CVD outcomes in patients with
T2DM.83 Some emerging T2DM treatments, such as the SGLT-2 inhibitors,
have been shown to reduce blood pressure and body weight (1–4 kg).73
As monotherapy or add-on to metformin over periods of 12–24 weeks,
dapagliflozin at a dose of 10 mg/day reduced systolic blood pressure
(3–5 mmHg) and diastolic blood pressure (~2 mmHg) with no apparent
change in heart rate.74, 84, 85 These results are promising, but it remains to
be seen if these agents can sustain this level of blood pressure reduction
in the long term. Sustained improvements in glycaemia and one of
the most important CV risk factors would represent a significant breakthrough
in the management of T2DM. Furthermore, SGLT-2 inhibitors
could offer a clinically meaningful treatment opportunity even in T1DM.86
Certain T2DM therapies have also demonstrated their ability in improving
dyslipidaemia. A meta-analysis shows that metformin significantly
reduces total and low-density lipoprotein (LDL) cholesterol, although
these reductions are rather small.87 In a study in T2DM patients, pioglitazone
improves levels of triglycerides, HDL cholesterol, LDL particle concentration,
and LDL particle size.13 In 3-year open-label extension studies
the incretin therapy exenatide was associated with a 12% decrease
in triglycerides, a 6% decrease in LDL and 24% increase in HDL.71 It has
been postulated that the weight loss/weight neutrality of incretin therapies
contributes to lipid improvements.83 In a four week study the DPP-4
inhibitor vildagliptin was shown to improve postprandial plasma triglyceride
levels.88 Large, long term studies are the only definitive way of
elucidating the influence that T2DM treatments have on CV risk factors.
In this chapter we have already discussed the trials that have investigated
the degree to which T2DM treatments influence CV risk. Fifty
percent of people diabetes die from CV disease, primarily heart disease
and stroke,81 so there’s intense interest in defining the degree to
which specific drugs and combinations of drugs influence CV risk.
Since the 1990s, the options for OAD treatment have increased markedly.
The expanded selection has created a need for comparative
data on the risks and benefits of anti-diabetic drugs, particularly in light
of the greater cost of newer agents.82 A meta-analysis of forty clinical
trials shows that metformin is associated with a 26% reduction in the
relative risk of CV mortality compared with SUs, TZDs, glinides and placebo.
82 A meta-analysis is only as good as the studies it includes and
the authors of this particular analysis conclude: “larger, long-term studies
taken to hard endpoints and better reporting of CV events in shortterm
studies will be required to draw firm conclusions about major clinical
benefits and risks related to OADs.”82
It is increasingly evident that controlling weight, hypertension and dyslipidaemia
is tantamount to reducing CVD outcomes in patients with
T2DM.83 Some emerging T2DM treatments, such as the SGLT-2 inhibitors,
have been shown to reduce blood pressure and body weight (1–4 kg).73
As monotherapy or add-on to metformin over periods of 12–24 weeks,
dapagliflozin at a dose of 10 mg/day reduced systolic blood pressure
(3–5 mmHg) and diastolic blood pressure (~2 mmHg) with no apparent
change in heart rate.74, 84, 85 These results are promising, but it remains to
be seen if these agents can sustain this level of blood pressure reduction
in the long term. Sustained improvements in glycaemia and one of
the most important CV risk factors would represent a significant breakthrough
in the management of T2DM. Furthermore, SGLT-2 inhibitors
could offer a clinically meaningful treatment opportunity even in T1DM.86
Certain T2DM therapies have also demonstrated their ability in improving
dyslipidaemia. A meta-analysis shows that metformin significantly
reduces total and low-density lipoprotein (LDL) cholesterol, although
these reductions are rather small.87 In a study in T2DM patients, pioglitazone
improves levels of triglycerides, HDL cholesterol, LDL particle concentration,
and LDL particle size.13 In 3-year open-label extension studies
the incretin therapy exenatide was associated with a 12% decrease
in triglycerides, a 6% decrease in LDL and 24% increase in HDL.71 It has
been postulated that the weight loss/weight neutrality of incretin therapies
contributes to lipid improvements.83 In a four week study the DPP-4
inhibitor vildagliptin was shown to improve postprandial plasma triglyceride
levels.88 Large, long term studies are the only definitive way of
elucidating the influence that T2DM treatments have on CV risk factors.
Intimately linked to T2DM and CV disease is obesity and this is another
area where certain agents may offer significant benefits. It is well known
that some compounds, such as SUs, non-SU secretagogues, insulin and
TZDs are associated with significant increases in weight.15 However, the
incretin therapies, with their novel mode of action, and several of the
emerging therapies are weight neutral or associated with significant
weight loss (reviewed in Chapter 4), which has implications for lipidaemia
and patient quality of life.
In addition to potential CV protection afforded by some drugs there
is also intriguing evidence that certain T2DM treatments may even reduce
the risk of developing cancer. A cohort study has demonstrated
that metformin use reduces the risk of developing cancer by 37%, even
after taking into account various factors such as age, blood sugar control,
smoking and weight.89 The authors of this study conclude “a randomised
trial is needed to assess whether metformin is protective in a
population at high risk for cancer.”89 Treatments such as metformin reduce
insulin resistance and it has been suggested that insulin resistance
is associated with an increased risk of cancer.90 Correspondingly, it has
been found that SUs are associated with a higher risk of cancer-related
mortality than metformin.91
We are still largely in the dark with respect to the full range of effects
associated with the use of T2DM treatments. The ongoing CV outcome
studies outlined earlier in this chapter will go some way to defining the
degree to which several of these treatments influence CV risk, but this
may represent the tip of the physiological iceberg. The widely used
medications used in the treatment of T2DM may have effects way beyond
lowering glycaemia and improving the various risk factors of CV
disease.
area where certain agents may offer significant benefits. It is well known
that some compounds, such as SUs, non-SU secretagogues, insulin and
TZDs are associated with significant increases in weight.15 However, the
incretin therapies, with their novel mode of action, and several of the
emerging therapies are weight neutral or associated with significant
weight loss (reviewed in Chapter 4), which has implications for lipidaemia
and patient quality of life.
In addition to potential CV protection afforded by some drugs there
is also intriguing evidence that certain T2DM treatments may even reduce
the risk of developing cancer. A cohort study has demonstrated
that metformin use reduces the risk of developing cancer by 37%, even
after taking into account various factors such as age, blood sugar control,
smoking and weight.89 The authors of this study conclude “a randomised
trial is needed to assess whether metformin is protective in a
population at high risk for cancer.”89 Treatments such as metformin reduce
insulin resistance and it has been suggested that insulin resistance
is associated with an increased risk of cancer.90 Correspondingly, it has
been found that SUs are associated with a higher risk of cancer-related
mortality than metformin.91
We are still largely in the dark with respect to the full range of effects
associated with the use of T2DM treatments. The ongoing CV outcome
studies outlined earlier in this chapter will go some way to defining the
degree to which several of these treatments influence CV risk, but this
may represent the tip of the physiological iceberg. The widely used
medications used in the treatment of T2DM may have effects way beyond
lowering glycaemia and improving the various risk factors of CV
disease.
Unmet needs and emerging risks/benefits shaping future
trends in the use of T2DM treatments
There are certainly a number of important unmet needs in T2DM, but
how will these shape the management of this condition? How will T2DM
be managed in the next ten or even the next twenty years? Naturally,
this is speculation, but we base it on the information we have reviewed
above and in the previous chapters. We can be fairly certain that metformin
will remain the gold standard antidiabetic treatment simply because
of the long experience with the drug, its high level of efficacy,
good tolerability profile, overall cost-effectiveness and possible benefits
beyond simple glycaemic control (cardiovascular protection and
reduced risk of cancer). In contrast we will very likely see a progressive
move away from SUs, TZDs and glinides due to potential safety and
tolerability issues.
Future trends in the use of incretin therapies such as the DPP-4 inhibitors
and the GLP-1 mimetics/analogues are more difficult to speculate
on. Both are effective in improving glycaemia, but many questions still
linger over this therapeutic approach. In part, these questions have
been addressed by emerging DPP-4 inhibitors that possess high potency,
high selectivity and non-renal elimination. The GLP-1 mimetics and
analogues may become increasingly important because of their very
high level of glycaemic efficacy and associated weight loss, although
the need for subcutaneous injections will always be a significant barrier
to their widespread use.
With metformin as the gold standard the importance of combination
therapy will also continue to rise as those people poorly controlled on
metformin monotherapy are treated with combination regimens containing
familiar OADs and those with novel modes of action that are still
in development.92 The earlier use of combination therapy in T2DM will
probably also increase over time.92 Furthermore, we can expect that
treatment decisions in T2DM will increasingly hinge on a number of factors,
rather than just the glycaemic lowering ability and tolerability profile
of a drug.93, 94 Factors such as comorbidities (e.g. renal impairment),
compliance and adherence, CV protection and cost-effectiveness will
all be important in the more holistic management of T2DM.93, 94
A further likely trend is the increasing influence of patient organisations
and other groups in driving the issue of patient-centric treatment,
which has always been something of a neglected area in the management
of chronic conditions. To improve the way in which individuals
with T2DM are treated we may see a progressive move to tailored
therapy that builds on advances in the understanding of the genetics
of this disease as well as the various products of the drug development
pipeline.
trends in the use of T2DM treatments
There are certainly a number of important unmet needs in T2DM, but
how will these shape the management of this condition? How will T2DM
be managed in the next ten or even the next twenty years? Naturally,
this is speculation, but we base it on the information we have reviewed
above and in the previous chapters. We can be fairly certain that metformin
will remain the gold standard antidiabetic treatment simply because
of the long experience with the drug, its high level of efficacy,
good tolerability profile, overall cost-effectiveness and possible benefits
beyond simple glycaemic control (cardiovascular protection and
reduced risk of cancer). In contrast we will very likely see a progressive
move away from SUs, TZDs and glinides due to potential safety and
tolerability issues.
Future trends in the use of incretin therapies such as the DPP-4 inhibitors
and the GLP-1 mimetics/analogues are more difficult to speculate
on. Both are effective in improving glycaemia, but many questions still
linger over this therapeutic approach. In part, these questions have
been addressed by emerging DPP-4 inhibitors that possess high potency,
high selectivity and non-renal elimination. The GLP-1 mimetics and
analogues may become increasingly important because of their very
high level of glycaemic efficacy and associated weight loss, although
the need for subcutaneous injections will always be a significant barrier
to their widespread use.
With metformin as the gold standard the importance of combination
therapy will also continue to rise as those people poorly controlled on
metformin monotherapy are treated with combination regimens containing
familiar OADs and those with novel modes of action that are still
in development.92 The earlier use of combination therapy in T2DM will
probably also increase over time.92 Furthermore, we can expect that
treatment decisions in T2DM will increasingly hinge on a number of factors,
rather than just the glycaemic lowering ability and tolerability profile
of a drug.93, 94 Factors such as comorbidities (e.g. renal impairment),
compliance and adherence, CV protection and cost-effectiveness will
all be important in the more holistic management of T2DM.93, 94
A further likely trend is the increasing influence of patient organisations
and other groups in driving the issue of patient-centric treatment,
which has always been something of a neglected area in the management
of chronic conditions. To improve the way in which individuals
with T2DM are treated we may see a progressive move to tailored
therapy that builds on advances in the understanding of the genetics
of this disease as well as the various products of the drug development
pipeline.
It is well established that obesity, reduced physical activity, and aging
increase susceptibility to T2DM; however, many people exposed to
these risk factors do not develop the disease.95 Recent genome studies
have identified a number of genetic variants that explain some of the
inter-individual variation in diabetes susceptibility.95 In addition to the
genetic markers of T2DM there is also a growing body of evidence suggesting
a role for epigenetic factors (heritable changes in gene function
that occur without a change in the nucleotide sequence) in the
complex interplay between genes and the environment (Figure 4).95
Environmental factors of considerable note include persistent organic
pollutants (POPs), the presence of which have been shown to be related
to the prevalence of diabetes (dose response relationship).96, 97
It has also been suggested that as people become more overweight,
the retention and toxicity of POPs related to the risk of diabetes may
increase.96, 97
increase susceptibility to T2DM; however, many people exposed to
these risk factors do not develop the disease.95 Recent genome studies
have identified a number of genetic variants that explain some of the
inter-individual variation in diabetes susceptibility.95 In addition to the
genetic markers of T2DM there is also a growing body of evidence suggesting
a role for epigenetic factors (heritable changes in gene function
that occur without a change in the nucleotide sequence) in the
complex interplay between genes and the environment (Figure 4).95
Environmental factors of considerable note include persistent organic
pollutants (POPs), the presence of which have been shown to be related
to the prevalence of diabetes (dose response relationship).96, 97
It has also been suggested that as people become more overweight,
the retention and toxicity of POPs related to the risk of diabetes may
increase.96, 97
Understanding the underlying genetic and epigenetic defects in blood
sugar homeostasis and how these interact with environmental factors
(e.g. persistent organic pollutants) will help direct T2DM management,
perhaps drawing on new therapies with novel modes of action that
target specific defect(s).34, 95
Drug development is promising to deliver a range of therapies that
will directly address a number of the unmet needs currently facing the
management of T2DM. Compounds such as the SGLT-2 inhibitors promise
to deliver significant improvements in blood glucose levels as well
sugar homeostasis and how these interact with environmental factors
(e.g. persistent organic pollutants) will help direct T2DM management,
perhaps drawing on new therapies with novel modes of action that
target specific defect(s).34, 95
Drug development is promising to deliver a range of therapies that
will directly address a number of the unmet needs currently facing the
management of T2DM. Compounds such as the SGLT-2 inhibitors promise
to deliver significant improvements in blood glucose levels as well
as reducing body weight, blood pressure and major CV risk factors.
Other agents in clinical development offer a variety of novel modes of
action, some which even target the pathogenesis of T2DM. The arrival
of new drugs onto the market is widely anticipated. However, the enthusiasm
for using new therapies needs to be tempered with data that
validates the safe and effective use of these agents in T2DM.
Other agents in clinical development offer a variety of novel modes of
action, some which even target the pathogenesis of T2DM. The arrival
of new drugs onto the market is widely anticipated. However, the enthusiasm
for using new therapies needs to be tempered with data that
validates the safe and effective use of these agents in T2DM.
Chapter 5 Summary
zzGlycaemic control should take into account FPG and PPG as well as HbA1c.
zzThe effect of treatment on body weight, hypertension, lipidaemia and other
CV risk factors is also very important.
zzTreatment adherence may be improved by better tolerability and reduced
pill burden.
zzThe importance of co-morbidities (e.g. renal impairment) are often
neglected in treatment decisions.
zzT2DM treatment requires regular adjustment and a deliberate treat-to-target
strategy.
zzIntensive management increases the cost of treatment, but can reduce the
cost of complications considerably as well as increasing the time free of
complications.
zzDebate continues regarding the effect of intensive versus conventional
glucose control on the risk of CV events, although a number of large studies
will shed more light on this subject.
zzEmerging treatments will be useful in addressing the unmet needs in T2DM
management:
◦◦ Incretin therapies have been shown to have positive effects on lipidaemia.
◦◦ The SGLT-2 inhibitors can reduce weight and blood pressure –
important CV risk factors.
◦◦ Incretin therapies are weight neutral or are associated with significant
weight loss.
◦◦ Metformin appears to reduce the risk of cancer, while drugs that elicit an
increase in circulating insulin levels (SUs, insulin) may have the opposite
effect.
zzMetformin will most likely remain the gold standard in T2DM management.
zzNew treatments, such as those targeting the incretin system may become
increasingly important, especially in combination therapy.
zzAdvances in our understanding of the disease, its treatment and the needs
of the patient will drive the individualisation of T2DM therapy.
zzGlycaemic control should take into account FPG and PPG as well as HbA1c.
zzThe effect of treatment on body weight, hypertension, lipidaemia and other
CV risk factors is also very important.
zzTreatment adherence may be improved by better tolerability and reduced
pill burden.
zzThe importance of co-morbidities (e.g. renal impairment) are often
neglected in treatment decisions.
zzT2DM treatment requires regular adjustment and a deliberate treat-to-target
strategy.
zzIntensive management increases the cost of treatment, but can reduce the
cost of complications considerably as well as increasing the time free of
complications.
zzDebate continues regarding the effect of intensive versus conventional
glucose control on the risk of CV events, although a number of large studies
will shed more light on this subject.
zzEmerging treatments will be useful in addressing the unmet needs in T2DM
management:
◦◦ Incretin therapies have been shown to have positive effects on lipidaemia.
◦◦ The SGLT-2 inhibitors can reduce weight and blood pressure –
important CV risk factors.
◦◦ Incretin therapies are weight neutral or are associated with significant
weight loss.
◦◦ Metformin appears to reduce the risk of cancer, while drugs that elicit an
increase in circulating insulin levels (SUs, insulin) may have the opposite
effect.
zzMetformin will most likely remain the gold standard in T2DM management.
zzNew treatments, such as those targeting the incretin system may become
increasingly important, especially in combination therapy.
zzAdvances in our understanding of the disease, its treatment and the needs
of the patient will drive the individualisation of T2DM therapy.
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Diabetes Care 2005;28(7):1547-1554.
14. Maggio CA, Pi-Sunyer FX. The prevention and treatment of obesity. Application to
type 2 diabetes. Diabetes Care 1997;20(11):1744-66.
15. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review.
JAMA 2002;287(3):360-72.
16. Ahren B. Emerging dipeptidyl peptidase-4 inhibitors for the treatment of diabetes.
Expert Opin Emerg Drugs 2008;13(4):593-607.
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(exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with
type 2 diabetes. Diabetes Care 2004;27(11):2628-35.
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(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.
19. 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.
20. Madsbad S, Schmitz O, Ranstam J, Jakobsen G, Matthews DR. Improved glycemic
control with no weight increase in patients with type 2 diabetes after once-daily
treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211):
a 12-week, double-blind, randomized, controlled trial. Diabetes Care 2004;27(6):
1335-42.
21. Delamater AM. Improving patient adherance. Clinical Diabetes 2006;24(2):71-77.
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type 2 diabetes. The British Journal of Diabetes & Vascular Disease 2002;2(290-295).
24. AACE/ACE. Statement by an AACE/ACE Consensus Panel on Type 2 Diabetes Mellitus:
An Algorithm for Glycemic Control. Endocr Pract 2009;15:540-559.
25. ADA. Standards of medical care in diabetes--2008. Diabetes Care 2008;31 Suppl 1:
S12-54.
26. Desouza CV, Bolli GB, Fonseca V. Hypoglycemia, diabetes, and cardiovascular
events. Diabetes Care;33(6):1389-94.
27. Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP, Jr., Selby JV. Hypoglycemic
episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA
2009;301(15):1565-72.
28. Ryden L, Standl E, Bartnik M, Van den Berghe G, Betteridge J, de Boer MJ, et al.
Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary.
The Task Force on Diabetes and Cardiovascular Diseases of the European Society
of Cardiology (ESC) and of the European Association for the Study of Diabetes
(EASD). Eur Heart J 2007;28(1):88-136.
29. UKPDS. Long-term follow-up after tight control of blood pressure in type 2 diabetes.
N Engl J Med 2008;359(15):1565-76.
30. Chalmers J, Cooper ME. UKPDS and the legacy effect. N Engl J Med 2008;359(15):
1618-20.
31. Ceriello A. Hypothesis: the “metabolic memory”, the new challenge of diabetes.
Diabetes Res Clin Pract 2009;86 Suppl 1:S2-6.
32. Ceriello A, Ihnat MA, Thorpe JE. Clinical review 2: The “metabolic memory”: is more
than just tight glucose control necessary to prevent diabetic complications? J Clin
Endocrinol Metab 2009;94(2):410-5.
33. UKPDS. Association of glycaemia with macrovascular and microvascular complications
of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;
321(7258):405-12.
34. Smith RJ, Nathan DM, Arslanian SA, Groop L, Rizza RA, Rotter JI. Individualizing
therapies in type 2 diabetes mellitus based on patient characteristics: what we
know and what we need to know. J Clin Endocrinol Metab 2010;95(4):1566-74.
35. Hoerger TJ, Segel JE, Gregg EW, Saaddine JB. Is glycemic control improving in U.S.
adults? Diabetes Care 2008;31(1):81-86.
36. Yurgin N, Secnik K, Lage MJ. Antidiabetic prescriptions and glycemic control in
German patients with type 2 diabetes mellitus: a retrospective database study.
Clin Ther 2007;29(2):316-25.
37. Goldfine AB. Assessing the cardiovascular safety of diabetes therapies. N Engl J Med
2008;359(11):1092-5.
38. ACCORD, Gerstein HC, Miller ME, Byington RP, Goff DC, Jr., Bigger JT, et al. Effects
of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358(24):2545-59.
39. ADVANCE. Intensive blood glucose control and vascular outcomes in patients with
type 2 diabetes. N Engl J Med 2008;358(24):2560-72.
40. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose
control and vascular complications in veterans with type 2 diabetes. N Engl J Med
2009;360(2):129-39.
41. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive
glucose control in type 2 diabetes. N Engl J Med 2008;359(15):1577-89.
42. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK,
et al. Secondary prevention of macrovascular events in patients with type 2 diabetes
in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular
Events): a randomised controlled trial. Lancet 2005;366(9493):1279-89.
43. Erdmann E, Charbonnel B, Wilcox RG, Skene AM, Massi-Benedetti M, Yates J, et al.
Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting
cardiovascular disease: data from the PROactive study (PROactive 08). Diabetes
Care 2007;30(11):2773-8.
44. Erdmann E, Dormandy J, Wilcox R, Massi-Benedetti M, Charbonnel B. PROactive 07:
pioglitazone in the treatment of type 2 diabetes: results of the PROactive study.
Vasc Health Risk Manag 2007;3(4):355-70.
45. Erdmann E, Dormandy JA, Charbonnel B, Massi-Benedetti M, Moules IK, Skene AM.
The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with
type 2 diabetes and previous myocardial infarction: results from the PROactive
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24(1):275-86.
Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination
therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial.
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47. Chiasson JL, Gomis R, Hanefeld M, Josse RG, Karasik A, Laakso M. The STOP-NIDDM
Trial: an international study on the efficacy of an alpha-glucosidase inhibitor to
prevent type 2 diabetes in a population with impaired glucose tolerance: rationale,
design, and preliminary screening data. Study to Prevent Non-Insulin-Dependent
Diabetes Mellitus. Diabetes Care 1998;21(10):1720-5.
48. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial
intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J
Med 2003;348(5):383-93.
49. Feinglos MN, Bethel MA. Therapy of type 2 diabetes, cardiovascular death, and the
UGDP. Am Heart J 1999;138(5 Pt 1):S346-52.
50. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and
death from cardiovascular causes. N Engl J Med 2007;356(24):2457-71.
51. Nissen SE, Wolski K. Rosiglitazone Revisited: An Updated Meta-analysis of Risk for
Myocardial Infarction and Cardiovascular Mortality. Arch Intern Med 2010.
52. FDA. Systematic review of epidemiologic studies of cardiovascular risk in patients
treated with rosiglitazone or pioglitazone: FDA, 2010.
53. Rosen CJ. The rosiglitazone story − lessons from an FDA Advisory Committee meeting.
N Engl J Med 2007;357(9):844-6.
54. Merck. Update on Cardiovascular Outcomes Study with JANUVIA, 2010.
55. Takeda. Takeda Initiates Cardiovascular Outcomes Trial for Alogliptin, An Investigational
Treatment for Type 2 Diabetes, 2010.
56. AstraZeneca. Bristol-Myers Squibb and AstraZeneca announce the commencement
of the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients
with Diabetes Mellitus Trial (SAVOR-TIMI 53), 2010.
57. Clinical Trials.gov. The ORIGIN Trial (Outcome Reduction With Initial Glargine Intervention),
2010.
58. Clinical Trials.gov. CAROLINA: Cardiovascular Outcome Study of Linagliptin Versus
Glimepiride in Patients With Type 2 Diabetes, 2010.
59. Clinical Trials.gov. BI 10773 Cardiovascular Outcome Event Trial in Type 2 Diabetes
Mellitus Patients., 2010.
60. Clinical Trials.gov. Exenatide Study of Cardiovascular Event Lowering Trial (EXSCEL):
A Trial To Evaluate Cardiovascular Outcomes After Treatment With Exenatide Once
Weekly In Patients With Type 2 Diabetes Mellitus, 2010.
61. Clinical Trials.gov. Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular
Outcome Results - A Long Term Evaluation (LEADER™), 2010.
62. Rodbard HW, Blonde L, Braithwaite SS, Brett EM, Cobin RH, Handelsman Y, et al.
American Association of Clinical Endocrinologists medical guidelines for clinical
practice for the management of diabetes mellitus. Endocr Pract 2007;13 Suppl 1:1-68.
63. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor
agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006;
368(9548):1696-705.
64. Drucker DJ. The biology of incretin hormones. Cell Metab 2006;3(3):153-65.
65. 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.
66. Wesley UV, McGroarty M, Homoyouni A. Dipeptidyl peptidase inhibits malignant
phenotype of prostate cancer cells by blocking basic fibroblast growth factor
signaling pathway. Cancer Res 2005;65(4):1325-34.
67. Wesley UV, Tiwari S, Houghton AN. Role for dipeptidyl peptidase IV in tumor suppression
of human non small cell lung carcinoma cells. Int J Cancer 2004;109(6):855-66.
68. Bristol-Myers Squibb Pharmaceuticals Ltd and AstraZeneca EEIG. Onglyza®
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69. Merck Sharpe & Dohme Ltd. Januvia® Summary of Product Characteristics. 2009.
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