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CLINICAL FOCUS: GERIATRICS
© Hospital Practice, Volume 39, Issue 1, February 2011, ISSN – 2154-8331 7
Incretin Therapies in the Management of Elderly
Patients with Type 2 Diabetes Mellitus
Isabelle Bourdel-Marchasson,
MD, PhD1
Anja Schweizer, PhD2
Sylvie Dejager, MD, PhD3
1Pôle de Gérontologie Clinique,
Centre Henri Choussat, Hôpital
Xavier Arnozan, Bordeaux, France;
2Novartis Pharma AG, Basel,
Switzerland; 3Novartis Pharma SAS,
Rueil Malmaison, France
Correspondence: Sylvie Dejager, MD, PhD,
Novartis Pharma SAS,
2 et 4 rue Lionel Terray,
F-92 506 Rueil Malmaison,
France.
Tel: +33 1 55 47 63 39
Fax: +33 1 55 47 65 93
E-mail: sylvie.dejager@novartis.com
Abstract: Aging is characterized by a progressive increase in the prevalence of type 2 diabetes
mellitus (T2DM), which approaches 20% by age 70 years. Older patients with T2DM are a very
heterogeneous group with multiple comorbidities, an increased risk of hypoglycemia, and a
greater susceptibility to adverse effects of antihyperglycemic drugs, making treatment of T2DM
in this population challenging. The risk of severe hypoglycemia likely represents the greatest
barrier to T2DM care in the elderly. Although recent guidelines recommend more flexibility in
treating this population with individualized targets, inadequate glycemic control is still closely
linked to poor outcome in elderly patients. Incretins (glucose-dependent insulinotropic poly-
peptide [GIP] and glucagon-like peptide-1 [GLP-1]) are hormones released post-meal from
intestinal endocrine cells that stimulate insulin secretion and suppress postprandial glucagon
secretion in a glucose-dependent manner. “Incretin therapies,” comprising the injectable GLP-1
analogs and oral dipeptidyl peptidase-4 (DPP-4) inhibitors, are promising new therapies for use
in older patients because of their consistent efficacy and low risk of hypoglycemia. However,
data with these new agents are still scarce in this population, which has not been particularly well
represented in clinical trials, highlighting the need for additional specific studies. The objective
of this article is to provide an overview of the available data and potential role of these novel
incretin therapies in managing T2DM in the elderly. With the exception of the DPP-4 inhibi-
tor vildagliptin, there is no published trial to date dedicated to this population, although a few
studies are currently ongoing. Therefore, available data from elderly subgroups of individual
studies were also reviewed when available, as well as pooled analyses by age subgroups across
clinical programs conducted with incretin therapies.
Keywords: type 2 diabetes mellitus; elderly; hypoglycemia; GLP-1 analogs; DPP-4 inhibitors
Introduction
Type 2 diabetes mellitus (T2DM) in older adults is a major public health issue affecting
an increasing number of individuals worldwide.1,2 Aging is a prominent contributor
to the T2DM pandemic, as well as obesity and sedentary lifestyle. The prevalence
of T2DM increases with age, reaching a plateau of about 20% by age 70 years; half
of individuals with T2DM are aged $ 65 years.3 Older patients have an increased
prevalence of cardiovascular risk factors, T2DM-related morbidity and mortality, and
comorbidities, such as renal impairment, congestive heart failure, cognitive disorders,
social isolation and depression, physical disability, and frailty.4 They also frequently
use polypharmacy, posing an increased risk of drug interactions, and are at greater risk
of adverse events (AEs), especially severe hypoglycemia with the use of antidiabetic
agents.5 Thus, management of T2DM in the elderly is particularly challenging, although
it has surprisingly received little attention, resulting in a paucity of data regarding the
use of pharmacological agents in this age group. Care of older patients with T2DM is
further complicated by a lack of prospective clinical studies to help define treatment
8 © Hospital Practice, Volume 39, Issue 1, February 2011, ISSN – 2154-8331
Bourdel-Marchasson et al
goals specific to this population, since findings in younger
patients should not be extrapolated to elderly patients, and
even less so to the frail elderly. Furthermore, elderly patients
constitute a very heterogeneous population with regard to
disease duration, health status, and coexisting disorders and
treatments, a situation that further supports individualized
approaches to T2DM management.6
The risk of hypoglycemia is likely the major complicating
factor of antidiabetic treatment in the elderly.7 It is more
common and has more severe consequences in older patients,
who are more frequently unaware of hypoglycemia.8 The
issues of comorbidities, polypharmacy, and frailty combined
with the risk of hypoglycemia further limit therapeutic
choices in the elderly. There is good evidence to suggest
that the use of novel incretin therapies could offer signifi-
cant advantages in older patients with T2DM based on their
glucose-dependent mechanism of action, low risk of hypo-
glycemia, and efficacy in improving glycemic control while
exhibiting a benign side effect profile.9,10 These agents act by
improving α- and β-cell sensitivity to glucose via an increase
in active glucagon-like peptide-1 (GLP-1). This results in
glucose-sensitive modulation of insulin and glucagon secre-
tion, maintaining glucose levels in a more physiologic range
without exposing patients to increased risk of hypoglycemia.
The present article aims to summarize the specificities in
the management of T2DM in the elderly, briefly discuss the
current treatments used in this population, and present an
overview of the more recent data for new incretin therapies
(eg, GLP-1 analogs and dipeptidyl peptidase-4 [DPP-4]
inhibitors). Literature for consideration was obtained
primarily through a search of PubMed and Embase (ISI
Web of Science for abstracts) to identify articles published
in English relevant to the therapeutic management of older
patients with T2DM, focusing on GLP-1 analogs and
DPP-4 inhibitors, and supplemented with searches of the
European Medicines Agency (EMEA) and US Food and Drug
Administration (FDA) Web sites, as well as other sources. In
addition, a manual search was undertaken to determine if the
pivotal studies included analysis by age subgroups.
Specificities of T2DM in the Elderly
Population
Higher Risk and More Severe Consequences
of Hypoglycemia
Hypoglycemia is a frequent AE of antidiabetic drugs that
raise insulin levels independently of blood glucose, such as
insulin secretagogues (eg, sulfonylureas [SUs] and glinides)
and exogenous insulin. No standard definition of hypoglyce-
mia has been used in clinical trials and observational studies,
with highly variable rates reported in the literature, making it
difficult to assess the true incidence.7 While the frequency of
hypoglycemia clearly increases with increasing age, the real
prevalence is even more difficult to estimate in the elderly
population, in whom nonrecognition of hypoglycemia is
more common.11
Indeed, older patients have poor knowledge of hypo-
glycemia and may not recall their episodes, resulting in
underestimated hypoglycemia prevalence in the elderly
population.11,12 Its ascertainment is further confounded by
the fact that symptoms can be difficult to recognize, as the
elderly are more likely to have confusion, disorientation,
or other neuroglycopenia-related symptoms that can mimic
other medical conditions.13 In the Real-Life Effectiveness
and Care Patterns of Diabetes Management (RECAP-DM)
study (mean age, 62.9 years), advancing age was unexpect-
edly associated with significantly less frequent hypoglyce-
mic symptoms (odds ratio, 0.982; 95% confidence interval
[CI], 0.971–0.993), but the authors hypothesized that this
was partly attributable to overly conservative treatment by
physicians of the older patients, and also reflected under-
recognition, more common in elderly patients.14 In fact,
there is an age-related impairment of hypoglycemia aware-
ness, which is associated with an increased reaction time
and decreased ability to take corrective actions.15 It has
been shown that older patients were less able to perceive
neuroglycopenic and autonomic symptoms (independent
of the counterregulatory hormonal response), suggesting
that the aged brain displays a diminished capability to
perceive physiological and cognitive alterations due to
hypoglycemia, which likely contributes to the increased
probability of severe hypoglycemia in this age group.15
In older patients, consequences of hypoglycemia
include geriatric syndromes, such as falls and behavior
disorders, particularly in demented patients.6 Severe epi-
sodes in this age group are associated with more serious
complications and increased hospitalizations, including
treatment of fractures secondary to falls, acute renal insuf-
ficiency, and major cardiovascular events with significant
mortality. Patient age was a significant predictor of hypo-
glycemia requiring medical assistance in Action to Control
Cardiovascular Risk in Diabetes (ACCORD), with a 3%
increase in risk with every 1-year increase in baseline age
(P , 0.0001).16 Findings in the recent Veterans Affairs
Diabetes Trial (VADT) and ACCORD trials of intensive
versus standard treatment of T2DM have drawn attention
© Hospital Practice, Volume 39, Issue 1, February 2011, ISSN – 2154-8331 9
Incretin Therapies for Elderly Patients with T2DM
to the importance of hypoglycemia and its avoidance.17 In
the VADT, it was found that severe hypoglycemia within
the preceding 90 days was associated with increased risk
of cardiovascular mortality in both treatment groups.
In ACCORD, while not accounting for the differences in
mortality between the intensive and standard treatments,
the occurrence of severe hypoglycemia was also associated
with significantly increased annual mortality both in the
intensive and standard control arm.18
Further, among older patients with T2DM, a history
of single or multiple severe hypoglycemic episodes was
associated with a graded increased risk of dementia for
patients with $ 3 episodes (adjusted hazard ratio, 1.94;
95% CI, 1.42–2.64) in a recent longitudinal cohort study
of 16 667 patients from Kaiser Permanente in Northern
California.19 On the whole, greater attention must be given
to hypoglycemia risk when managing older patients, in
whom hypoglycemia is associated with many adverse
consequences for which they are already at increased risk.20
Higher Prevalence of Micro- and
Macrovascular Complications
and Excess Risk of Functional Decline,
Including Cognitive Disorders
Type 2 diabetes mellitus is associated with a continuing
increase in incidence of the classic micro- and macrovas-
cular complications as patients age,21 and remains a signifi-
cant contributor to mortality and reduced life expectancy
in elderly patients.22 However, aside from these traditional
long-term complications of T2DM, which are highly preva-
lent in the elderly, the T2DM geriatric population has an
excess risk of a number of other clinical conditions, includ-
ing functional decline, physical disability, falls, fractures,
cognitive impairment, and depression.23
Type 2 diabetes mellitus has been associated with the
presence of functional disability, defined as difficulty in
performing routine physical tasks, which significantly
influences the clinical care of older adults and profoundly
affects their quality of life.24 In the recent National
Health and Nutrition Examination Survey (NHANES)
1999–2006, older adults with T2DM had a 2 to 3 times
increased prevalence of functional disabilities than those
without T2DM, with variable associations attributable to
T2DM-related comorbidities and glycated hemoglobin
(HbA1c).25 Type 2 diabetes mellitus is also one of the
strongest correlates of poor lower extremity performance.
Rapid declines in leg muscle strength and quality, and
accelerated loss of muscle mass have been documented
in older individuals with T2DM in the Health, Aging, and
Body Composition study,26 and older men and women with
T2DM are at increased risk of falls and injuries.
Although cognitive abilities also deteriorate with age
in patients without T2DM, T2DM is uniquely associated
with an increased risk of developing cognitive problems.
In a study by Munshi et al,27 one-third of the population
of patients aged $ 70 years presenting to a geriatric dia-
betes clinic were affected. Cognitive dysfunction in this
population was associated with poor diabetes control. In
a community-based cohort study of people aged 59 to 71
years at baseline, patients with T2DM had an unfavorable
evolution of cognitive performance over 4 years compared
with patients who had normal glucose tolerance despite
similarly high initial cognitive function.28 Depression is
also more frequent in patients with T2DM and can further
aggravate cognitive deficits, with a significant and negative
association with poor metabolic control.29
Disease Heterogeneity: Need to Adopt
Treatment Goals to Functional Status
The elderly T2DM population represents a highly hetero-
geneous group with a wide spectrum of T2DM duration,
life expectancy, and coexisting medical conditions. When
discussing treatment goals in the elderly, an important
distinction should be made between patients with advanced
disease and comorbidities and patients with late-onset
disease who are in overall good health.4
It is now well recognized that implementing intensive
therapy with stringent goals should be done early in the
disease to capitalize on the so-called “legacy effect,” as
shown in the recently reported UK Prospective Diabetes
Study (UKPDS) 10-year follow-up study.30 In elderly
patients with new-onset T2DM, tighter glycemic control
may be more appropriate because good glycemic control
has been shown to provide important benefits, including
improved cognitive function31 and nutritional status, while
greater caution is needed for patients with longer disease
duration. It still remains unknown how glycemic control
affects morbidity and mortality in elderly patients, and
the French GERODIAB prospective cohort study, which
will follow 1000 patients aged $ 70 years for 5 years,
should provide some information in this regard.32 For now,
the European Diabetes Working Party for Older Persons
guidelines recommend that in the presence of frailty,
treatment goals be flexible (target HbA1c , 8%), with the
primary aims of preserving quality of life and avoiding
hypoglycemia and AEs.
10 © Hospital Practice, Volume 39, Issue 1, February 2011, ISSN – 2154-8331
Bourdel-Marchasson et al
Traditional Antidiabetic Agents
for Use in the Elderly
This section briefly summarizes the key advantages and limi-
tations of the currently available pharmacological treatments
of T2DM other than novel incretin-based therapies.
Metformin
Metformin, which has been available for . 50 years, is
the recommended first-line therapy in all patients with
T2DM, including the elderly, unless contraindicated. While
contraindications, such as impaired renal or cardiac function,
pose restrictions on the use of metformin in the elderly, it
is increasingly recognized that contraindications should not
be based solely on age, and that patients should be given
an opportunity to use the drug when possible.33 That said,
metformin should be used with care in the frail elderly, with
reduced daily doses and progressive titration and with strict
monitoring of renal function. The risk of lactic acidosis
(an extremely rare event but one with high mortality) is
increased in patients with reduced creatinine clearance and
with organ failure or other illnesses causing tissue hypoxia.
Thus, metformin must be used with caution in all settings
at risk of tissue hypoxia, such as respiratory or cardiac
dysfunction, even if congestive heart failure as an absolute
contraindication is questioned more frequently when present
in isolation.34 A recent study aiming to establish pragmatic
limits of renal impairment in patients being considered for
treatment with metformin concluded that an estimated glo-
merular filtration rate (GFR) of # 30 mL/min should be an
absolute contraindication to the drug.35
Metformin acts by sensitizing the liver to the effects of
insulin and thus does not expose patients to hypoglycemia.
In addition, metformin provides cardiovascular benefit and
possibly reduces risk of a broad range of cancers in patients
with T2DM.36,37
The most common AEs associated with metformin are
gastrointestinal (GI) conditions (eg, abdominal discomfort,
metallic taste, anorexia, nausea, or diarrhea), which can be
more problematic and dose-limiting for elderly patients.5
Furthermore, the optimal metformin dose for older patients
is not known.
Sulfonylureas
Sulfonylureas have also been on the market for decades, with
a well-established glucose-lowering profile. However, these
agents pose considerable risk of hypoglycemia and severe
hypoglycemia, a risk that increases sharply with age and with
decreasing renal function.5 Older SUs with longer time-action
characteristics are associated with greater risk, glyburide
(glibenclamide) or chlorpropamide being more likely to
cause hypoglycemia than the second- and third-generation
agents, such as gliclazide, glipizide, and glimepiride.38
Sulfonylureas are also associated with some weight gain,
partly as a consequence of defensive eating to prevent and/
or treat hypoglycemia. The main limitation restricting the
use of SUs in an older population remains the risk of severe
hypoglycemia.39
Glinides
Glinides, rapid-acting secretagogues with a short half-life,
are administered before meals, which could be an advantage
for people with irregular eating habits. Glinides could be
beneficial in older patients because they target postprandial
hyperglycemia, which is a key physiopathological feature
in the elderly; however, they also pose a significant risk of
hypoglycemia (even if the risk is theoretically lower than
that associated with SUs).5 Experience with these agents is
limited in the elderly population, and influence of age on
pharmacokinetics is unknown.40
α-Glucosidase Inhibitors
α-Glucosidase inhibitors, which act by reducing the rate of
carbohydrate absorption, are effective as monotherapy or in
combination with other agents, especially with diets high in
starch (while much less effective in high-fat diets or diets
based on processed food). They are of potential utility in the
elderly because of the lack of hypoglycemia risk and effect
on postprandial hyperglycemia, but their use is limited by
a very high frequency of adverse GI effects (eg, flatulence
and diarrhea).41
Thiazolidinediones
Thiazolidinediones are also marked by absence of
hypoglycemic risk and are effective insulin-sensitizing
agents. The many limitations of these agents in the elderly
population stem from their association with salt/water
retention, anemia, a 2- to 3-fold increase in congestive
heart failure, increased risk of bone fracture in elderly
women, and diabetic macular edema.42,43 Recently, 1 drug,
rosiglitazone, was taken off the market in Europe (EMEA
recommended the suspension of the marketing autho-
rization September 23, 2010) and its use was severely
restricted in the United States following the conclusion
that data accumulated over the last 3 years support an
increased risk of ischemic heart disease and that its benefits
no longer outweigh its risks.44
© Hospital Practice, Volume 39, Issue 1, February 2011, ISSN – 2154-8331 11
Incretin Therapies for Elderly Patients with T2DM
Insulin
Insulin therapy in people with T2DM is used alone or in
combination with oral antidiabetic drugs (OADs). In older
people, insulin can be used after OAD failure, because of
contraindication to OADs, in case of acute concomitant
disease, or insufficient or irregular food intake.45 Indeed,
insulin therapy is highly adaptable and may be safer than
OADs. Furthermore, insulin therapy allows rapid correction
of hyperglycemia as recommended in critically ill adult
inpatients.46 However, the downside of insulin therapy
is the risk of hypoglycemia. In critically ill patients, the
occurrence of $ 1 severe hypoglycemia event (, 0.4 g/L)
was an independent risk factor for death.47 Recent data on the
prevalence of insulin use in the elderly have been made avail-
able in the French community; insulin use increased with age
from 8% in the 65- to 69-year-old age range to 17% for those
aged $ 80 years in 2007. Insulin was used in combination
with OADs in 10% of people aged $ 65 years. Thus, about
1 in 10 to 1 in 6 elderly people were treated with insulin.
Role of Incretins and Potential
Benefits of Incretin Therapies
in the Elderly
Incretins (glucose-dependent insulinotropic polypeptide [GIP]
and GLP-1) are short-acting hormones released from the gut
in response to food intake. These gut hormones are respon-
sible for the boost in insulin secretion that occurs following
an oral glucose load, the so-called “incretin effect,” defined
as the enhanced insulinotropic potency of oral versus intra-
venous glucose. In addition to stimulating insulin secretion
by the β-cells, they have effects on β-cell mass in animal
studies, and GLP-1 attenuates postprandial glucagon secre-
tion by the α-cells in a glucose-dependent manner, delays
gastric emptying, and promotes a sense of satiety.48
While their metabolic actions rendered these gut
hormones attractive as therapeutic agents, the peptidic nature
of GLP-1 and GIP, together with their very short plasma half-
lives, made them rather unapproachable for therapeutic use;
both GLP-1 and GIP are rapidly degraded and inactivated in
plasma by the enzyme DPP-4. Two approaches have been
used to overcome these limitations, leading to the 2 current
categories of incretin-based therapies: the injectable GLP-1
analogs, which are synthetic peptides resistant to DPP-4 deg-
radation, and the orally available DPP-4 inhibitors, which
increase endogenous incretin levels by preventing their
degradation.48
These novel agents act through a glucose-sensitive
modulation of insulin and glucagon secretion, unlike
indiscriminate insulin secretagogues, such as SUs and
glinides, maintaining glucose levels in a more physiologic
range without exposing patients to increased risk of hypo-
glycemia. This has generated considerable interest for their
use in elderly patients with T2DM.9,10
First Data with Continuous
Administration of Native GLP-1
Insulin is secreted in a pulsatile and orderly fashion, which
is disrupted in T2DM and normal aging. Type 2 diabetes
mellitus in the elderly is characterized by a further reduction
in mean and integrated insulin secretion, basal and pulsatile
insulin production rate, and mass of rapid insulin secretory
pulses. Meneilly et al49 found that these alterations in pulsatile
insulin release can be significantly improved in elderly
obese patients with T2DM by the prolonged administration
of continuous subcutaneous GLP-1. It was also shown that
infusion of GLP-1 preserved the counterregulatory response
to hypoglycemia in healthy volunteers.50
Initial studies using continuous infusions of native
GLP-1 confirmed that the glucose-dependent nature of
GLP-1 insulinotropic effects resulted in less risk of hypo-
glycemia compared with usual glucose-lowering therapy in
16 elderly patients (mean age, 74 years). While HbA1c levels
(7.1%) were equally maintained in both groups, the usual
treatment group had a total of 87 capillary blood glucose
measurements # 3.6 mmol/L during the study, when only
1 such measurement (3.5 mmol/L) was recorded in the
GLP-1 group.51
All of these initial data on GLP-1 infusion substantiates
the potential advantages for the new incretin-based therapies
for elderly patients with T2DM over some of the standard
medications by improving glucose-dependent insulin
secretion.
Clinical Data with GLP-1 Analogs
Several receptor agonists that are resistant to DPP-4
degradation have been synthesized. These analogs of
GLP-1 include exenatide (a synthetic form of exendin-4,
isolated from saliva of the Gila monster) and liraglutide,
both already available on the market, and compounds, such
as CJC-1131, albiglutide, and taspoglutide, which are cur-
rently in development, although development of taspoglutide
has recently been stopped. As clinical study programs of the
new compounds in development progress, data pertaining
to elderly subgroups may be anticipated. However, nothing
is currently published, and no trial dedicated to the elderly
population is registered on ClinicalTrials.gov.
12 © Hospital Practice, Volume 39, Issue 1, February 2011, ISSN – 2154-8331
Bourdel-Marchasson et al
Exenatide
Exenatide, used by twice-daily injection, was the first incretin
mimetic introduced to T2DM therapy (approved in 2005 in
the United States).
Pharmacokinetic Data
Age had no effect on exenatide pharmacokinetics.52 Exenatide is
cleared through the kidneys and, while no dosing modification
is needed in patients with moderate renal impairment (other
than conservative dose escalation from 5–10 µg in patients
with creatinine clearance 30–50 mL/min), exenatide is not
recommended for use in patients with severe renal impairment
(creatinine clearance , 30 mL/min) or end-stage renal disease.
In vivo interaction studies suggest that exenatide has no effect on
CYP2C9 or CYP3A4, and the risk for inhibition of other CYP
isoenzymes is considered to be low. However, exenatide delays
gastric emptying, and can therefore delay the absorption, and to
some extent, decrease the extent of absorption of concomitantly
administered drugs.
Clinical Data Relevant to the Elderly Population
Exenatide has been studied through an extensive clinical
program, notably with the pivotal AC2993 Diabetes
Management for Improving Glucose Outcomes (AMIGO)
studies on add-on therapy to metformin, SU, or both.52
However, exenatide trials thus far have mostly been con-
ducted in middle-aged patients (mean age, 52–60 years),
and no subgroup analyses of pooled data in the elderly have
been published. However, based on the US Byetta prescrib-
ing information (October 2009), the clinical program overall
included 282 patients aged $ 65 years, and no differences in
safety or effectiveness were observed between these elderly
patients and younger patients.53 In addition, in the European
Public Assessment Report (EPAR) scientific discussion,54
data from 165 patients aged $ 70 years treated with exena-
tide in clinical studies were presented. These patients were
thinner, had a somewhat lower baseline HbA1c, and had a
higher prevalence of mild renal impairment compared with
patients aged , 70 years. The older population had a greater
decrease in HbA1c and, even more so, in weight compared
with the younger patients. There were only 36 patients aged
$ 75 years, which was not sufficient to allow evaluation.
Because the systematic search did not return any elderly-
related publication, a manual search was undertaken to
additionally assess whether any analysis of the data by
age group had been included the main pivotal studies.55–59
However, none of these publications provided data on the
elderly subgroups.
It is worth noting that the increased risk of hypoglycemia
reported when exenatide is combined with SUs suggests
that this combination should be used with caution in the
elderly population, and a reduction in the dose of SU is
generally recommended to reduce this risk. In addition, the
weight loss induced (which tended to be greater in older vs
younger patients) could be damaging in the oldest subjects
(aged . 75 years). A long-acting release formulation
for a once-weekly injection that could provide greater
improvements in glycemic control than exenatide twice daily
is in clinical development.60 However, no data on elderly
patients are yet available.
Liraglutide
Liraglutide is a GLP-1 analog, also administered by
subcutaneous injection, which has a prolonged half-life that
permits once-daily administration.
Pharmacokinetic Data
With respect to its use in the elderly, no clinically significant
differences in liraglutide pharmacokinetics were found
between elderly and younger patients.61 A pharmacokinetic
study in a cohort of 24 subjects with varying degrees of
renal impairment suggested no safety concerns regarding
the use of liraglutide in patients with renal impairment,
as renal dysfunction was not found to increase exposure
of liraglutide. There is, however, limited experience with
liraglutide in patients beyond mild-stage renal disease.62
Liraglutide has no clinically relevant potential to inhibit or
induce cytochrome P450 drug-metabolizing enzymes. No
clinically relevant drug interaction related to protein binding
is anticipated either. However, the delay in gastric emptying
with liraglutide may potentially influence absorption of
concomitantly administered oral drugs, especially drugs
with poor solubility and a small therapeutic window, such
as warfarin. Diarrhea (reported by 12.6% of patients treated
with liraglutide) may also affect the absorption of concomi-
tant oral drugs.
Clinical Data Relevant to the Elderly Population
The phase 3 clinical development program Liraglutide Effect
and Action in Diabetes (LEAD) involved . 4000 patients
worldwide to investigate the efficacy and tolerability of lira-
glutide (n = 2735) as monotherapy and in combination with
various OADs. Patients enrolled in the 6 LEAD studies were
aged 18 to 80 years (mean age, 53–58 years), but no pooled
analysis has been published (nor is available in abstract form)
providing data on the elderly population. Additionally, when
© Hospital Practice, Volume 39, Issue 1, February 2011, ISSN – 2154-8331 13
Incretin Therapies for Elderly Patients with T2DM
checking all of the individual publications from the LEAD
1–6 program, no age subgroup data are presented in any of
the studies.63–68 The only information provided was a state-
ment in LEAD-1 that neither age, gender, nor body mass
index (BMI) affected the trends in efficacy.65
However, data pertaining to the elderly population
can be found in the EPAR scientific discussion, in which
data were provided for the groups aged , 60, . 60,
. 70, and . 75 years. Results on HbA1c were comparable
between age groups, but an increase in the total AE rate
was seen with liraglutide, while no such increase was
observed with active and total comparators. An overview
of AEs in the subpopulations of the elderly patients (aged
. 65, . 70, and . 75 years) was provided. The rates of AEs,
serious adverse events (SAEs), and withdrawals due to AEs
increased by age for liraglutide 1.2 mg and 1.8 mg. The rate
of AEs—events per 1000 subject-year exposure (SYE)—
was clearly higher for elderly patients aged . 70 years with
liraglutide (1.2 mg [5102.3] and 1.8 mg [6103.4]) compared
with placebo (3441.6) and active comparator (2018.0). This
higher rate of AEs was primarily driven by higher rates of
GI AEs, particularly for patients aged . 70 years. The rates
of GI AEs were as follows for the subgroups, , 65, . 65,
and . 70 years, respectively: liraglutide 0.6 mg, 712, 985,
and 1018; liraglutide 1.2 mg, 1117, 1132, and 1669; and lira-
glutide 1.8 mg, 1385, 1955, and 2222. This is reflected in the
current summary of product characteristics,69 which mentions
that patients aged . 70 years may be more susceptible to GI
AEs. The number of elderly patients aged . 75 years was
too low (total of 40 for both doses) to draw firm conclusions
in this subgroup.
Overall, hypoglycemic events were rare, but increased
when liraglutide was added to an SU (dual or triple therapy).
Although no hypoglycemic data specific to the elderly have
been provided, a reduction in the dose of SUs should be
considered, and these combinations should be used with cau-
tion in the elderly population. Thus far, there is no published
study of liraglutide dedicated to the elderly population, and a
search in ClinicalTrials.gov did not show any ongoing trial
registered in this population.
Clinical Data with DPP-4 Inhibitors
In contrast with GLP-1 receptor agonists, orally available
DPP-4 inhibitors prolong the activity and enhance the
action of endogenous incretins physiologically at the time
of their secretion. Dipeptidyl peptidase-4 inhibitors are
generally associated with a rather low hypoglycemic risk
and weight neutrality, in part because of less hypoglycemia-
related defensive eating. As opposed to the GLP-1 analogs,
DPP-4 inhibitors do not promote slowing of gastric empty-
ing, do not induce significant weight loss, and are not asso-
ciated with GI AEs. Several DPP-4 inhibitors are available
and 3 are already approved: sitagliptin (European Union,
United States, and Japan), vildagliptin (European Union
and Japan), and saxagliptin (European Union and United
States). Two are currently in late development: alogliptin
(approved in Japan) and linagliptin.
Sitagliptin
Sitagliptin was the first DPP-4 inhibitor approved in T2DM
therapy.
Pharmacokinetic Data
Age did not affect the pharmacokinetics of sitagliptin to
a meaningful extent (age range unknown).70 Sitagliptin
is excreted largely unchanged (∼79% of the administered
dose) by the kidneys; the changes in pharmacokinetic
parameters of sitagliptin in patients with mild renal impair-
ment were not considered clinically relevant and no dosage
adjustments are required in these patients. In patients with
moderate (creatinine clearance, 30–50 mL/min) or severe
renal impairment (creatinine clearance , 30 mL/min),
including patients with end-stage renal disease on hemo-
dialysis, plasma area under the curve levels increased
by approximately 2- and 4-fold, respectively, relative to
healthy volunteers. Consequently, dosage adjustments are
required in these patients (United States) or usage is not
recommended (European Union). Sitagliptin is not highly
bound to plasma proteins (38%), is not an inhibitor of CYP
isoenzymes (CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19, or 2B6),
and does not induce the CYP3A4 isoenzyme. Therefore,
the likelihood of clinically meaningful interactions between
sitagliptin and drugs utilizing these isoenzymes or interac-
tions mediated by plasma protein binding displacement is
low.70
Clinical Data Relevant to the Elderly Population
An extensive clinical program has been conducted with
sitagliptin but the majority of the data available involve
middle-aged patients (mean age, 54–57 years), and there
is no published article focusing specifically on elderly
patients. During a systematic search in Medline, Embase,
and ISI Web of Science, only 2 abstracts were identified
and no full publication is yet available.71,72
The first abstract71 presented data from a randomized,
placebo-controlled, 24-week study conducted in patients
14 © Hospital Practice, Volume 39, Issue 1, February 2011, ISSN – 2154-8331
Bourdel-Marchasson et al
with T2DM aged $ 65 years (n = 206; age range not
reported) treated with sitagliptin monotherapy (100 or
50 mg/day). After 7 days of treatment with sitagliptin,
the mean change from baseline in average blood glucose
(determined by self-monitored blood glucose measure-
ments taken before and 2 hours after morning and evening
meals) was −23.5 mg/dL relative to placebo (P , 0.001).
After 24 weeks, from a mean baseline HbA1c of 7.8%, the
mean changes for HbA1c, fasting plasma glucose (FPG),
and 2-hour post-meal glucose were −0.7%, −27 mg/dL,
and −61 mg/dL, respectively, relative to placebo (all
P , 0.001). Clinical AEs overall, SAEs, and discontinua-
tions due to AEs occurred in 46% and 53%, 7% and 13%,
and 5% and 3% of patients in the sitagliptin and placebo
groups, respectively. No AEs of hypoglycemia were
reported. The authors concluded that rapid improvement
in glycemic status was observed in this study with good
tolerability and no hypoglycemia in these elderly patients
when administered sitagliptin monotherapy.
The second abstract72 presented results from a pooled
analysis to evaluate the consistency of efficacy of sitagliptin
monotherapy by age, gender, and BMI. It showed that the
efficacy (HbA1c and FPG) was similar in the group of patients
aged $ 65 years (n = 126), in patients aged , 50 years, and
in patients in the 50- to 65-year-old age range; the mean age
of the older subgroup was not stated in the abstract.
In addition, 1 sitagliptin trial targeted patients with
impaired renal function, and this study tended to recruit
older persons, with a mean age of 68 years.73 In this
54-week, randomized, double-blind study, patients were
allocated (2:1) to sitagliptin (n = 65, for 54 weeks) or the
sequence of placebo (n = 26, for 12 weeks) followed by
active treatment with glipizide (for 42 weeks). Patients with
moderate renal insufficiency received sitagliptin 50 mg/
day and those with severe renal insufficiency 25 mg/day.
Glipizide treatment was initiated at 2.5 or 5 mg/day and
uptitrated to a maximum of 20 mg/day. After 12 weeks,
the mean placebo-subtracted difference in HbA1c with sita-
gliptin was −0.4% (−0.7, −0.1). At 54 weeks, the overall
incidence of AEs was generally similar between groups.
The authors concluded that sitagliptin was generally well
tolerated and provided effective glycemic control in patients
with T2DM and moderate-to-severe renal insufficiency,
including patients with end-stage renal disease on dialysis.
A recent pooled safety analysis, which included data
from 10 246 patients with T2DM who received either
sitagliptin 100 mg/day (n = 5429) or a comparator agent
(placebo or active comparator; n = 4817) from 19 studies
of 12 weeks to 2 years duration was recently published.
However, while patients in the total cohort had an average
age of 55 years (range, 19–91 years), with 18% of the popu-
lation aged $ 65 years, separate results were not presented
in the group of patients aged $ 65 years.74
An additional manual search within individual studies
conducted to look for additional data in older subgroups
generally confirmed that the treatment effects on HbA1c
were consistent across subgroups defined by age, as shown
in the pooled analysis.72
Finally, 2 studies of sitagliptin in elderly patients
registered on ClinicalTrials.gov are currently ongoing: a
small phase 2 study (NCT00451113; 30 patients aged $ 65
years) and a larger phase 3 study versus glimepiride with
400 patients (aged 65–85 years), which just started recruit-
ing (NCT01189890).75,76 An earlier study (NCT00305604)
has been completed but the results were never published
because of “many limitations of the study, such as early
termination leading to small numbers of participants ana-
lyzed and technical problems with measurement leading to
unreliable or un-interpretable data.”77
Vildagliptin
Vildagliptin was the second DPP-4 inhibitor approved in the
European Union and is currently approved in . 75 countries
worldwide (excluding the United States).
Pharmacokinetic Data
Age does not influence the pharmacokinetics of vildagliptin
to any meaningful extent. Vildagliptin is hydrolyzed to a
pharmacologically inactive metabolite. Urinary excretion is
the primary route of elimination, with approximately 85%
of a dose excreted in urine (mostly as inactive metabolite,
23% as unchanged drug) and approximately 15% excreted
in the feces.78 Vildagliptin is not currently approved
for patients with a GFR , 50 mL/min, while no dose
adjustment is needed for patients above that threshold. Two
large clinical studies are ongoing to assess the long-term
safety of vildagliptin in patients with moderate and severe
renal impairment (NCT00646542 and NCT00616811).79,80
Vildagliptin is not metabolized by CYP450 to any quanti-
fiable extent in vitro and does not inhibit or induce major
CYP450 enzymes. In line with these characteristics, clinical
pharmacology studies showed little risk of drug interactions
when vildagliptin was administered with drugs commonly
used in elderly patients. Vildagliptin is not extensively
bound to plasma proteins (9.3%), which further limits the
potential for drug interactions.78
© Hospital Practice, Volume 39, Issue 1, February 2011, ISSN – 2154-8331 15
Incretin Therapies for Elderly Patients with T2DM
Clinical Data Relevant to the Elderly Population
The extensive clinical program conducted for vildagliptin
included a large number of older patients with T2DM, permit-
ting generation of a significant amount of data on treatment
in this group, with pooled analyses published in the popula-
tion aged $ 65 years and, more recently, in the population
aged $ 75 years. The clinical program also included the
first specific study of DPP-4 inhibitor use in this population.
A first pooled analysis of data from randomized, double-
blind, phase 3 monotherapy trials of vildagliptin included
374 patients aged $ 65 years (mean age, 70 years) and 1890
patients aged , 65 years.81 At entry, older patients had higher
rates of cardiovascular risk factors and comorbidities (eg,
hypertension, dyslipidemia, renal impairment, and coronary
artery disease) and were taking twice as many concomitant
medications. The older subgroup also had lower HbA1c,
FPG, and body weight at baseline than the younger patients.
Treatment with vildagliptin (100 mg/day) was associated
with at least as good improvement in HbA1c and FPG in older
patients (−1.2% and −1.5 mM, respectively) as in younger
patients (−1.0% and −1.1 mM, respectively) despite starting
from lower mean baseline values, and was associated with
minor weight loss (−0.9 kg in older patients vs −0.2 kg in
younger patients). For older patients receiving vildagliptin,
AEs were somewhat less common than in older patients
receiving an active comparator (68.1%). Elderly vildagliptin
patients with mild renal impairment had no increase in AE
frequency (62.0%) compared with younger vildagliptin
patients with mild renal impairment (62.1%) or older patients
without renal impairment (64.3%). Confirmed hypoglycemia
occurred in only 0.8% of the elderly vildagliptin population,
and none of the episodes were considered severe.81
These beneficial characteristics of treatment with
vildagliptin in the elderly were confirmed in a random-
ized, double-blind trial comparing vildagliptin (100 mg/
day) with metformin (1500 mg/day) over 6 months in 335
treatment-naïve patients aged $ 65 years.82 Patients in this
study had a mean age of 71 years (range, 65–93 years), a
mean baseline HbA1c of 7.7%, and a mean BMI of 29.6 kg/
m2; 92% received concomitant medications, and . 50%
had mild renal insufficiency (GFR, 50–80 mL/min/1.73 m2).
Glycated hemoglobin was reduced to a similar extent with
vildagliptin (−0.64%) and metformin (−0.75%), meeting
the prespecified noninferiority criterion. The mean values
at 6 months were 7.1% and 7.0%, respectively. Despite this
improvement in glycemic control, no hypoglycemia was
reported with vildagliptin, whereas 2 metformin patients
(1.2%) experienced mild hypoglycemia. Vildagliptin was
better tolerated, with both the overall incidence of AEs
(44.3% vs 50.3%) and the incidence of discontinuations due
to AEs (4.2% vs 7.9%) being lower in the vildagliptin group.
This was driven mainly by significantly better GI tolerability
with vildagliptin than with metformin, with GI AEs occurring
in 15.0% versus 24.8% of patients, respectively (diarrhea,
3.0% with vildagliptin vs 13.3% with metformin at the daily
dose of 1500 mg).82
Recently, clinical experience with vildagliptin in a
patient population with T2DM aged $ 75 years has been
published from a pooled analysis of phase 2 and 3 clinical
trials.83 This pooled analysis showed that vildagliptin was
both effective and well tolerated in patients with a mean
age of 77 years who constituted a representative mix of a
very elderly population. Although somewhat less obese
than the younger patients (BMI, 29.4 vs 31.5 kg/m2), they
had a higher prevalence of additional cardiovascular risk
factors; . 30% had a high cardiovascular risk status based
on previous cardiovascular history and . 70% had renal
impairment. Changes in HbA1c with vildagliptin in patients
aged $ 75 years were −0.9% from a baseline of 8.3% with
monotherapy (P , 0.0001) and −1.1% from a baseline of
8.5% with add-on therapy to metformin (P = 0.0004), and
these reductions were similar to those seen in patients aged
, 75 years. No confirmed hypoglycemic events, including
severe events, were reported. Safety was assessed in 301
patients aged $ 75 years. The overall incidences of AEs and
SAEs were comparable between younger and older patients
treated with vildagliptin. Furthermore, AEs, drug-related
AEs, and SAEs were reported with a lower frequency in
elderly patients receiving vildagliptin (133.9; 14.5 and 8.8
events per 100 SYE, respectively) than in elderly patients
receiving a comparator (200.6; 21.8 and 16.5 events per
100 SYE, respectively) (Table 1).
The finding of minimal risk of hypoglycemia among
elderly patients treated with vildagliptin, as seen in the
2 pooled analyses and the comparative trial with metfor-
min in an exclusive elderly population discussed above,
is further corroborated by individual vildagliptin studies
on patients at increased risk for hypoglycemia, in which
significant proportions of the studies’ populations were
aged $ 65 years.
In a study on early T2DM patients who had very mild
hyperglycemia (mean HbA1c at baseline, 6.7%) and were thus
at increased risk for hypoglycemia with glucose-lowering
treatment, 144 of the 306 patients randomized to the placebo-
controlled study were aged $ 65 years.84 Over 2 years (1-year
study and 1-year extension), no vildagliptin-treated patients
16 © Hospital Practice, Volume 39, Issue 1, February 2011, ISSN – 2154-8331
Bourdel-Marchasson et al
reported hypoglycemia despite an improvement in glycemic
control with vildagliptin treatment versus placebo (significant
placebo difference of 0.5% after 2 years).85
At the other end of the disease spectrum, a study of
vildagliptin add-on therapy to insulin included 296 patients,
approximately one-third of whom were aged $ 65 years.86
The elderly patients in this study (mean age, 71 years) had a
mean duration of T2DM of 18.2 years, 7.2 years of insulin use
(mean daily dose, 66 U/day), and a baseline HbA1c of 8.4%.
After 6 months, HbA1c was reduced by −0.7% from baseline
in elderly patients (P , 0.001 vs placebo). Despite the robust
reduction in HbA1c, vildagliptin treatment in the subgroup
of patients aged $ 65 years was associated with a lower
frequency of confirmed hypoglycemia compared with
placebo; hypoglycemic events occurred in 13% of patients
treated with vildagliptin (2.32 events per patient-year) versus
26% of patients treated with placebo (2.64 events per patient-
year).86 In a double-blind extension of this study, HbA1c was
reduced by −0.9% from baseline with vildagliptin 50 mg
twice daily after 1-year total treatment in elderly patients,
and the hypoglycemia benefit was still evident in this elderly
subgroup. Confirmed hypoglycemic events occurred at a rate
of 2.1 per patient-year, compared with 3.3 per patient-year in
placebo patients in the core phase of the study.87
A 10-fold reduction in risk of hypoglycemia was also
observed among the large subgroup of 712 elderly patients
(aged $ 65 years) included in a comparative trial of
vildagliptin versus glimepiride as add-on combination therapy
Table 1. Data from the Population of T2DM Patients Aged $ 75 Years in the Vildagliptin Clinical Program (All Studies’ [Excluding
Open-Label] Safety Populations)
Aged $ 75 Years Aged , 75 Years
Vilda 50 mg bid
N = 132
Comparatorsa
N = 169
Vilda 50 mg bid
N = 5984
Comparatorsa
N = 6041
Mean ± SD or n (%)
Age (years)
Age range (years)
76.9 ± 1.9
75–84
77.0 ± 2.4
75–89
54.9 ± 10.1
19–74
55.9 ± 10.1
19–74
Sex
Male (%)
Female (%)
56 (42.4)
76 (57.6)
93 (55.0)
76 (45.0)
3307 (55.3)
2677 (44.7)
3306 (54.7)
2735 (45.3)
BMI (kg/m2)29.4 ± 4.6 28.9 ± 4.1 31.5 ± 5.4 31.3 ± 5.5
HbA1c (%) 8.3 ± 1.0 7.9 ± 1.1 8.3 ± 1.1 8.0 ± 1.1
Duration of T2DM (years)
Disease duration group
$ 2 years
$ 5 years
$ 10 years
6.3 ± 7.7
78 (59.1)
58 (43.9)
29 (22.0)
5.9 ± 7.9
101 (59.8)
56 (33.1)
31 (18.3)
4.1 ± 5.0
3316 (55.4)
1842 (30.8)
658 (11.0)
4.5 ± 5.2
3535 (58.5)
2063 (34.1)
717 (11.9)
Mean Exposure (Weeks) 55.0 37.4 62.6 55.2
AEs
n (%)
SYE-adjb
86 (65.2)
133.9
114 (67.5)
200.6
4139 (69.2)
147.9
4174 (69.1)
177.3
Drug-related AEs
n (%)
SYE-adjb
18 (13.6)
14.5
24 (14.2)
21.8
943 (15.8)
14.9
1325 (21.9)
26.0
SAEs
n (%)
SYE-adjb
12 (9.1)
8.8
19 (11.2)
16.5
533 (8.9)
7.8
538 (8.9)
8.9
Discontinuation due to AEs
n (%)
SYE-adjb
10 (7.6)
7.2
9 (5.3)
7.5
337 (5.6)
4.7
391 (6.5)
6.1
Deaths
n (%)
SYE-adjb
0 (0.0)
0.0
2 (1.2)
1.7
24 (0.4)
0.3
21 (0.3)
0.3
n = number of patients with an AE; a patient with multiple occurrences of an AE under 1 treatment is counted only once in the AE category for that treatment. Only AEs that
caused study drug to be permanently discontinued are summarized in that category.
aPlacebo plus active comparators.
bIncidence per 100 SYE.
Adapted with permission from Diabetes Obes Metab.83
Abbreviations: AE, adverse event; bid, twice daily; BMI, body mass index; HbA1c, glycated hemoglobin; SAE, serious adverse event; SD, standard deviation; SYE-adj, subject
year exposure-adjusted; T2DM, type 2 diabetes mellitus; Vilda, vildagliptin.
© Hospital Practice, Volume 39, Issue 1, February 2011, ISSN – 2154-8331 17
Incretin Therapies for Elderly Patients with T2DM
with metformin.88 Over 1 year, while similar improvement
in glycemic control was seen in both treatment groups,
hypoglycemia occurred in 1.4% of vildagliptin-treated
older patients compared with 15.6% of glimepiride-treated
older patients. This benefit was confirmed following an
additional 1-year treatment period with 2.1% of older patients
experiencing $ 1 hypoglycemic event in the vildagliptin
group (18 events) versus 17.5% of older patients in the
glimepiride group (202 events) (P , 0.001).89
The observed beneficial hypoglycemia profile with
vildagliptin may be explained by the improved counter-
regulation seen with vildagliptin in patients with T2DM.
It was indeed shown that under hypoglycemia induced
by a hyperinsulinemic hypoglycemic clamp, vildagliptin
significantly increased the glucagon increment versus
placebo (by 38%), thus improving α-cell responsiveness to
the stimulatory effect of hypoglycemia.90
Saxagliptin
Saxagliptin is the latest addition in Europe and the United
States to the approved oral drugs for the management of
T2DM.
Pharmacokinetic Data
There was a , 2-fold difference in the pharmacokinetics of
either saxagliptin or its active metabolite in older patients
(aged $ 65 years) compared with younger subjects (aged
18–45 years), indicating no need for dose adjustments
in the elderly population.9 1 Saxagliptin is eliminated
through renal excretion and metabolism. Saxagliptin is
metabolized primarily by cytochromes P450 CYP3A4/5
and the major metabolite is pharmacologically active,
which is an important difference when compared with
other DPP-4 inhibitors.91 Saxagliptin is not bound to plasma
proteins, but strong inhibitors of CYP3A4 are expected to
affect the pharmacokinetics of saxagliptin. When coadmin-
istered with ketoconazole, dose reduction of saxagliptin is
recommended by US prescribing information.92 The drug
interactions between saxagliptin and the CYP3A4/5 inducers
carbamazepine, dexamethasone, phenobarbital, and
phenytoin have not been evaluated.
Clinical Data Relevant to the Elderly Population
The systematic literature search showed that clinical trial
data on saxagliptin were primarily presented as abstracts
in conferences, particularly in the elderly population, for
which only 1 abstract was identified, with no full publica-
tion yet available.
This abstract93 presented the results of a pooled analysis of
5 double-blind, placebo-controlled, phase 3 studies of T2DM
patients (aged 18–77 years) conducted to examine the effi-
cacy and safety of saxagliptin 5 mg/day in younger (aged ,
65 years) versus older (aged $ 65 years) patients. Data were
combined from patients receiving saxagliptin as monotherapy
or as add-on therapy to metformin, glibenclamide, or a thia-
zolidinedione for 24 weeks versus placebo. In older patients
(n = 138), the placebo-subtracted change from baseline in
HbA1c was −0.55% (reduction of −0.73% from baseline with
saxagliptin and −0.17% with placebo), similar to that in the
younger subgroup (−0.67%). No specific safety data were
provided from this pooled analysis in the abstract, but overall
AE rates with saxagliptin were reported to be comparable
with placebo both in younger and older patients.93
One pooled analysis across 8 randomized, phase 2/3 trials
evaluating saxagliptin (n = 3356 treated at 2.5- to 100-mg/
day doses) in patients with T2DM was conducted to assess
the relative risk for cardiovascular events and published as
a full article. The median age of this pooled population was
only 54 years (interquartile range, 47–61 years) and therefore
no data for the elderly could be provided from this analysis.94
In addition, a randomized, double-blind, 52-week study of
saxagliptin versus glimepiride is registered on ClinicalTrials.
gov as currently recruiting patients aged $ 65 years with
T2DM inadequately controlled by metformin monotherapy
(NCT01006603, called Saxagliptin Compared to Glimepiride
in Elderly Type 2 Diabetes Patients, With Inadequate
Glycemic Control on Metformin [GENERATION]).95
Alogliptin
The DPP-4 inhibitor alogliptin is still in development in
Europe and the United States but is already approved in
Japan.
Pharmacokinetic Data
The pharmacokinetic properties of alogliptin have been
evaluated in healthy adult volunteers, in patients with T2DM,
and in adult patients with renal impairment, and did not alter
to any clinically relevant extent based on age.96 Most of
alogliptin is eliminated through the kidneys as an unchanged
drug (∼70%), and exposure increases in proportion to the
degree of renal insufficiency, which is expected to result
in a need for dose adjustments. Metabolism of alogliptin is
mediated by cytochrome P450 2D6 to 1 active metabolite
and via acetylation to 1 inactive metabolite, both being
rapidly formed. In in vitro studies, alogliptin was 28% to
38% bound to plasma proteins. In healthy volunteers, there
18 © Hospital Practice, Volume 39, Issue 1, February 2011, ISSN – 2154-8331
Bourdel-Marchasson et al
were no clinically relevant effects on the pharmacokinetic
properties of alogliptin when coadministered with metfor-
min, pioglitazone, glibenclamide, norethisterone and ethinyl
estradiol, ciclosporin, atorvastatin, or digoxin.96
Clinical Data Relevant to the Elderly Population
Alogliptin has been studied in double-blind trials of up to
26 weeks duration as monotherapy or in combination with
metformin, glibenclamide, or pioglitazone, or with insulin
therapy. One publication reports results of a pooled analysis
of 6 randomized, double-blind, placebo-controlled, phase 2/3
trials evaluating efficacy and safety of alogliptin (12.5 and
25 mg daily) in T2DM patients aged $ 65 years.97 Mean
baseline characteristics in elderly (mean age, 70 years;
n = 455) and younger (mean age, 52 years; n = 1911) adult
populations were as follows: duration of disease, 10 and
7 years; HbA1c, 8.0% and 8.3%; BMI, 31 and 32 kg/m2;
and FPG, 171 and 178 mg/dL, respectively. There were no
significant differences between the 2 age groups in terms of
improvements in glycemic control with alogliptin. In patients
with an HbA1c baseline value of # 8%, placebo-subtracted
decreases from baseline in HbA1c levels in the alogliptin
12.5- and 25-mg groups were somewhat larger in the elderly
population (−0.62% and −0.61%) than in the younger
population (−0.43% and −0.44%). Corresponding values for
each alogliptin dosage in those with an HbA1c level of . 8%
at baseline were −0.41% and −0.63% in elderly patients and
−0.48% and −0.63% in younger patients. Incidences of any
hypoglycemic event were # 8.3% in all alogliptin groups and
# 10.5% for placebo, with no apparent difference between
elderly and younger patients. Changes in weight were
negligible in all treatment groups in both age categories. The
safety profiles of alogliptin were similar in the age and dose
groups. The authors therefore concluded that alogliptin was
effective and well tolerated in the elderly patients enrolled
in the studies contributing to this pooled analysis.97
In addition, a randomized, double-blind, 52-week study of
alogliptin versus glipizide in older (aged 65–90 years) T2DM
patients is registered in ClinicalTrials.gov and has been com-
pleted, but no results have been posted (NCT00707993).98
Linagliptin
Linagliptin, a new xanthine-based, long-acting DPP-4
inhibitor, is still being developed and currently in phase
3 clinical trials, with very few clinical data published as
yet. The drug is absorbed rapidly to inhibit plasma DPP-4
activity by . 80% over 24 hours. It is not metabolized
appreciably in vivo, but binds extensively to plasma pro-
teins, with elimination occurring primarily in the liver.
Renal excretion is a minor route of elimination (∼7%) and
excretion of unchanged linagliptin is only about 1% so that
dose adjustment in patients with renal impairment is not
anticipated for linagliptin.99
No data are yet available in the elderly population.
However, a randomized, double-blind, 24-week study of
linagliptin versus placebo given as add-on to stable treatment
is registered on ClinicalTrials.gov as currently recruiting
patients aged $ 70 years with T2DM and HbA1c $ 7%
(NCT01084005).100
Conclusion
Elderly patients with T2DM are particularly susceptible to the
effects of hypoglycemia; they are also prone to hypoglycemia
unawareness, which leads to more frequent and severe
episodes. Specific studies exclusively involving elderly
patients are needed to better define appropriate glucose tar-
gets for healthy and frail populations, and to ascertain the
efficacy/safety profiles and impact on quality of life of newer
antidiabetic agents for use in this vulnerable population. With
their physiologically based mode of action and low risk of
hypoglycemia, incretin-based therapies have an interesting
potential for older persons with T2DM.
While no published data specific to the elderly population
are yet available in the literature for GLP-1 analogs,
information can be found from regulatory sources. Glucagon-
like peptide-1 analogs have good efficacy, but in older
patients, their use may be limited by their GI tolerability,
with greater susceptibility and higher rates of GI side effects
reported in patients aged $ 70 years. In addition, one of their
key advantages, weight loss, may be less clinically relevant in
a significant proportion of the very elderly population, while
it would still be advantageous in obese elderly patients. As the
need for subcutaneous injections can be a limitation for some
elderly patients, the current development of formulations
requiring less frequent injections could be of benefit in the
elderly population.
The first data available for DPP-4 inhibitors suggest over-
all that age has limited or no influence on the efficacy and
tolerability/safety profile of these drugs, while more studies
are still ongoing in this age group. Thus far, only 1 study
dedicated to the elderly population has been published with
vildagliptin. Additionally, unlike other newer agents in
T2DM, recent information regarding the use of vildagliptin
in patients aged $ 75 years is available and shows good
efficacy, minimal risk of hypoglycemia, and a favorable
tolerability/safety profile in this patient population.
© Hospital Practice, Volume 39, Issue 1, February 2011, ISSN – 2154-8331 19
Incretin Therapies for Elderly Patients with T2DM
Conflict of Interest Statement
Sylvie Dejager, MD, PhD is employed at Novartis Pharma
SAS, Rueil Malmaison, France. Anja Schweizer, PhD is
employed at Novartis Pharma AG, Basel, Switzerland;
Isabelle Bourdel-Marchasson, MD, PhD is employed at
Université V Segalen Bordeaux 2 and Centre Hospitalier
Universitaire de Bordeaux, France. Isabelle Bourdel-
Marchasson, MD, PhD is on the advisory panel for 2 clinical
trials sponsored by Novartis. She is coordinator for geriatrics
in the French-speaking group for the Study of Diabetes (SFD)
in the Elderly, and has received financial support from Novo-
Nordisk, Servier, and Roche Diagnostic for the activities of
the group as well as speaker fees from NovoNordisk.
15. Bremer JP, Jauch-Chara K, Hallschmid M, Schmid S, Schultes
B. Hypoglycemia unawareness in older compared with middle-
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