Ascend Media

VOL. 13, NO. 2 I THE AMERICAN JOURNAL OF MANAGED CARE I S47

New Technologies and Therapies
in the Management of Diabetes
Curtis L. Triplitt, PharmD, CDE
Address correspondence to: Curtis L. Triplitt, PharmD, CDE, The University of Texas Health
Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900. E-mail:
Curtis.Triplitt@uhs-sa.com.
Abstract
Although there are numerous effective
pharmacotherapeutic agents available to
treat type 2 diabetes, 5% to 10% of the
population with diabetes experience
secondary failure. To help combat this
issue, it is imperative that clinicians
understand the limitations of some
current therapies. Secondary failure can
be due to decreasing beta cell function,
poor adherence to treatment, weight gain,
reduction of exercise, changes in diet,
or illness.
Glycemic control and cardiovascular risk
reduction are of paramount concern;
however, the nonglycemic effects of
several new therapies to treat diabetes
may be advantageous and positively
affect the long-term cost of therapy.
The discoveries of amylin and glucagon-
like peptide-1 have furthered our under-
standing of the abnormalities involved
in diabetes, enabling the development
of additional therapeutic options. Incretin-
based therapy, including incretin mimetics
such as exenatide and the yet-to-be-
approved dipeptidyl peptidase-4 inhibi-
tors, and new basal and inhaled insulin
may change the way we currently treat
type 2 diabetes.
(Am J Manag Care. 2007;13:S47-S54)
I REPORTS I
A
lthough lifestyle measures are the cornerstone of diabetes
therapy, most patients will also require pharmacotherapy to
achieve target glucose concentrations. Different classes of
antidiabetic agents affect glucose homeostasis through dis-
tinct mechanisms (Figure 1).
1
Sulfonylureas and the nonsulfonylurea
secretagogues (meglitinides) increase endogenous insulin secretion;
alpha-glucosidase inhibitors delay intestinal carbohydrate absorption;
thiazolidinediones (TZDs) enhance insulin sensitivity primarily by
increasing peripheral glucose disposal, but also suppress hepatic glucose
production; and metformin, a biguanide, decreases hepatic glucose pro-
duction, but also increases peripheral glucose disposal to some extent.
1
Despite the number of conventional agents at our disposal, many
patients are unable to attain or maintain glycemic goals. The United
Kingdom Prospective Diabetes Study of glycemic control with insulin,
sulfonylurea, or metformin monotherapy found that approximately
50% of patients were unable to maintain glycemic goals (glycosylated
hemoglobin [A1C] <7%) by 3 years, and 75% did not maintain
glycemic control by 9 years.
2
A retrospective study of a health mainte-
nance organization database reported that 26% of patients treated with
insulin plus an oral agent and 13% to 30% of those receiving combi-
nation therapy with oral agents achieved optimal glycemic control
(A1C <7%).
3
Although conventional therapy should allow for much better
results, unmet needs exist with these therapies. Some of these needs
can be addressed with newer agents with different mechanisms of
action. Several novel antidiabetic agents have recently become avail-
able or are likely to be approved within the next several months. The
challenge is to integrate these agents appropriately into the treatment
paradigm in ways that will make the best use of their unique attributes.
Insulin
Two new options in insulin therapy have recently become avail-
able. Insulin detemir (Levemir), a long-lasting basal insulin, was
approved by the US Food and Drug Administration (FDA) in 2005,
and an inhaled form of insulin (Exubera) was approved in early 2006.

Reports
S48 I www.ajmc.com I APRIL 2007
Figure 2 shows the pharmacokinetics of these new
analogs in comparison with other forms of insulin.
4-6
Insulin Detemir. Insulin detemir has a unique
structure that results in a prolonged duration of
action for up to 24 hours. The insulin molecule is
acylated with a 14-carbon fatty acid, which allows it
to bind reversibly to albumin at the injection site
and in plasma. Albumin binding, together with
self-association of the molecules at the site of sub-
cutaneous (SC) injection, is responsible for the pro-
tracted action of insulin detemir.
4
A very small
percent of albumin molecules are actually bound,
however, and there are no known drugdrug inter-
actions between insulin detemir and other drugs
that bind albumin.
4,7
The pharmacokinetics of insulin detemir are
dose-dependent, with lower doses resulting in a
shorter duration of action (Table).
8
In clinical stud-
ies, the average daily insulin detemir dose was 0.38
U/kg for adults with type 1 diabetes and 0.77 U/kg
for adults with type 2 diabetes.
7
At these doses,
activity is maintained for approximately 20 to 24
hours, peaking at 8 to 9 hours after administration.
8
Insulin detemir is typically given once- or twice-
daily by SC injection.
7
Studies have reported that insulin detemir has
less within-subject variability and a lower risk of
hypoglycemia, particularly nocturnal hypoglycemia,
than human neutral protamine Hagedorn insulin.
9
Treatment with insulin detemir also resulted in
lower within-subject variability than insulin
glargine.
10,11
Inhaled Insulin. The first inhaled form of
insulin to be approved by the FDA is Exubera, an
insulin inhalation powder. Exubera consists of blis-
ters containing human insulin inhalation powder,
which is administered using the Exubera inhaler.
12
The 1-mg and 3-mg doses are approximately equiv-
alent to 3 IU and 8 IU of SC regular human insulin,
respectively.
Randomized studies have shown that the efficacy
of inhaled insulin is comparable with subcutaneously
I Figure 1. Pathophysiological Basis of Conventional Diabetes Therapies
Adapted with permission from Reference 1.
TZDs indicates thiazolidinediones.
New Technologies and Therapies in the Management of Diabetes
VOL. 13, NO. 2 I THE AMERICAN JOURNAL OF MANAGED CARE I S49
injected prandial human insulin in patients with type
1 and type 2 diabetes.
13,14
In patients with type 2 dia-
betes, inhaled insulin therapy was associated with
improved glycemic control compared with rosiglita-
zone in patients whose diabetes was not controlled by
diet and exercise.
15
Another study evaluated the
switch to or addition of inhaled insulin in subjects
not at goal despite oral combination therapy.
16
Inhaled insulin, alone or in combination with oral
therapy, resulted in significant reductions in A1C
compared with continuing combination oral therapy
alone (mean adjusted reductions of 1.4% and 1.7%,
respectively). A1C levels <7% were achieved by
32% of patients in the inhaled insulin plus oral ther-
apy group, 17% of patients in the inhaled insulin
monotherapy group, and 1% of patients who
remained on oral combination therapy.
16
Patient satisfaction and quality of life outcomes,
including burden, convenience, pain, and psycho-
logical well-being, were significantly higher with
inhaled insulin treatment compared with SC insulin
in patients with type 1 diabetes.
14
Patient preference
for this form of insulin therapy was further demon-
strated in a study in which patients with type 1 or
type 2 diabetes were allowed to switch therapies at
the end of a 12-week randomized phase comparing
inhaled insulin with subcutaneously injected human
insulin. Eighty-five percent of patients who were
randomized to inhaled insulin continued treatment,
whereas only 13% switched to SC insulin. In the
group randomized to SC insulin, only 21% contin-
ued treatment; whereas 76% switched to inhaled
insulin.
17
Treatment satisfaction scores were signifi-
cantly higher among patients receiving inhaled
insulin in both phases of this study.
Moreover, in a study of theoretical treatment
choices among patients with type 2 diabetes failing
to achieve target glycemic control despite lifestyle
and/or oral agent treatment, the availability of
inhaled insulin as a treatment option significantly
increased the proportion of patients who would
theoretically choose insulin overall. Patients were
3 times more likely to choose insulin therapy when
inhaled insulin was available, and inhaled insulin
was the most frequently chosen treatment option.
18
As with subcutaneously injected insulin, the
most frequent adverse event with inhaled insulin is
hypoglycemia. Frequency of hypoglycemia was sim-
ilar in the clinical trials that compared inhaled and
SC insulin.
The use of inhaled insulin is contraindicated in
patients with unstable or poorly controlled lung dis-
ease and in those who smoke, including those who
stopped smoking less than 6 months before consider-
ation for treatment with Exubera. The use of Exubera
in patients with underlying lung disease, such as
I Table. Dose-dependent Pharmacokinetics of Insulin Detemir*
Dose (U/kg)
Parameter 0.1 0.2 0.4 0.8 1.6
Onset of action (h) 2.0 2.0 1.6 1.1 0.8
Time to peak (h) 3.2 6.2 8.6 9.3 8.7
Duration of action (h) 5.7 12.1 19.9 22.7 23.2
*Data shown are mean values.
Source: Reference 8.
I Figure 2. Pharmacokinetics of Different Forms of Insulin
NPH indicates neutral protamine Hagedorn.
Sources: References 4-6.
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S50 I www.ajmc.com I APRIL 2007
asthma or chronic obstructive pulmonary disease, is
not recommended, because the safety and efficacy of
Exubera in this population have not been estab-
lished. All patients should have spirometry (forced
expiratory volume in 1 second [FEV
1
]) assessed
before initiating therapy. Assessment of lung diffu-
sion capacity of carbon monoxide (DLCO) should
be considered. Pulmonary function assessment
should be repeated 6 months after initiation and
annually thereafter.
12
During the 2-year clinical trials,
declines from baseline FEV
1
of
>
20% were observed
in 1.5% of patients treated with inhaled insulin
compared with 1.3% in the comparator group, and
declines from baseline DLCO
>
20% occurred in
5.1% of patients treated with inhaled insulin com-
pared with 3.6% in the comparator group.
12
Amylinomimetics
Amylin is a neuroendocrine hormone that is co-
secreted with insulin from pancreatic beta cells in
response to meals. Amylin inhibits postprandial
glucagon secretion, slows the rate of gastric empty-
ing, enhances satiety, and reduces food intake.
Together, these amylin-mediated activities result in
the suppression of postprandial glucose excur-
sions.
19,20
Because of the co-localization of amylin
and insulin within beta cells, patients with type 1
diabetes have an absolute deficiency of both, where-
as patients with type 2 diabetes have a relative defi-
ciency of both hormones, including a markedly
impaired amylin and insulin response to meals.
21
Native amylin is insoluble and aggregates in
solution, and therefore is not suitable for pharmaco-
logic administration. The development of a soluble
peptide analog of amylin, pramlintide, circumvent-
ed this difficulty and allowed clinical studies of
amylin-based therapy.
22
In 2005, pramlintide was
approved by the FDA for use in patients with dia-
betes treated with mealtime insulin who have not
achieved glycemic goals.
23
Clinical studies have shown that pramlintide
treatment significantly reduces postprandial
glucagon secretion in insulin-treated patients with
type 1 or type 2 diabetes, leading to improved post-
prandial glycemic control.
19
Sustained reductions in
A1C levels are observed in response to pramlintide
treatment, ranging from about 0.1% to 0.67% in
patients with type 1 diabetes and from 0.3% to
0.62% in patients with type 2 diabetes.
22
The most
frequent side effect of pramlintide is nausea, which
is generally mild to moderate and diminishes over
time. Higher doses are associated with a greater
incidence of nausea.
22
For this reason, pramlintide
dosage is titrated on the basis of response and toler-
ability. Because pramlintide improves glycemic con-
trol and often results in decreased caloric intake, it
has been associated with an increased incidence of
insulin-induced hypoglycemia, particularly in
patients with type 1 diabetes. Initial prandial
insulin dose reductions, along with starting pram-
lintide at a low dose, are therefore required when
initiating therapy.
23
Incretin-based Therapy
The Incretin Effect. In healthy nondiabetic
subjects, oral administration of glucose produces a
substantially enhanced insulin response compared
with intravenous administration of glucose that
results in a similar glucose excursion. This discrep-
ancy has been called the incretin effect, and this
effect is diminished in people with type 2 diabetes.
24
Subsequent studies identified 2 primary gut-derived
hormones that are responsible for most of the
incretin effect: glucose-dependent insulinotropic
peptide (GIP) and glucagon-like peptide-1 (GLP-
1). GLP-1 is a better therapeutic target and has
accordingly been studied to a greater extent.
25
GLP-1 inhibits postprandial glucagon release
and stimulates glucose-dependent insulin secre-
tion.
26,27
This hormone also slows gastric emptying
and enhances satiety.
26,28
At least in animals, at the
cellular level GLP-1 appears to stimulate beta cell
growth and survival and reduce apoptosis, leading
to increases in beta cell mass (Figure 3).
26-29
Unfortunately, GLP-1 has an in vivo half-life of
less than 2 minutes, which prevents it from being an
attractive therapeutic candidate. The major meta-
bolic pathway for GLP-1 is degradation by dipep-
tidyl peptidase-4 (DPP-4); this enzyme cleaves the
NH-2 terminus of GLP-1 and related peptides,
including GIP.
30
Two strategies have been pursued
to allow therapeutic agents to circumvent this rapid
degradation: incretin mimetics, which involve
GLP-1 agonists or analogs that are resistant to DPP-
4mediated degradation, and DPP-4 inhibitors,
that prolong the half-life of endogenous GLP-1.
Incretin Mimetics. The only currently available
New Technologies and Therapies in the Management of Diabetes
VOL. 13, NO. 2 I THE AMERICAN JOURNAL OF MANAGED CARE I S51
incretin mimetic is exenatide (Byetta), a GLP-1
agonist that was approved by the FDA in 2005 as
adjunctive therapy for patients with type 2 diabetes
who are taking metformin and/or a sulfonylurea, or
a TZD with or without metformin. Exenatide is a
synthetic analog of exendin-4, a peptide found in
Gila monster saliva, that binds to and activates the
human GLP-1 receptor.
25,31
In 30-week clinical tri-
als, exenatide at a dose of 10 g SC twice daily
reduced A1C levels by a placebo-subtracted 0.9%
to 1.0% in patients with type 2 diabetes who were
receiving treatment with metformin and/or a sul-
fonylurea. These trials also reported a dose-depend-
ent weight loss of 1.6 to 2.8 kg from baseline with
exenatide at the 10-g twice-daily dose.
32-34
Patients who received exenatide in the original
30-week placebo-controlled trials were eligible for
entry into a 1-year open-label extension trial. Long-
term data from this study indicate that A1C reduc-
tions in response to exenatide were sustained over
82 weeks (30-week controlled trial + 1-year open-
label extension). Greater A1C reductions are seen
with higher baseline A1C levels (Figure 4), with
reductions of 1.6% to 2% in patients with baseline
A1C
>
9%.
35
The sustained reductions in A1C may be related
to the effects of exenatide on pancreatic beta cells.
Consistent with the known activities of GLP-1,
exenatide promotes beta cell proliferation and dif-
ferentiation in animal models and also enhances
beta cell function in patients with type 2 diabetes.
36
Weight loss did not plateau but continued
throughout 82 weeks of exenatide treatment, with a
mean reduction from baseline of 4.4 kg. Weight loss
occurred in the absence of formal nutrition or exer-
cise instructions and was not dependent on nausea.
Improvements in other cardiovascular risk factors,
including increases in high-density lipoprotein and
decreases in diastolic blood pressure, were also
observed.
35
Exenatide enhances endogenous insulin secre-
tion in a glucose-dependent manner (ie, insulin
secretion diminishes as glucose levels decrease into
the normal range). This should reduce the risk for
hypoglycemia with exenatide. As might be expect-
ed, exenatide in combination with metformin was
associated with no greater incidence of hypo-
glycemia than exenatide plus placebo.
33
Addi-
tionally, under hypoglycemic conditions in healthy
controls, exenatide does not impair the counterreg-
ulatory response to hypoglycemia.
37
In contrast to
the situation with exenatide, sulfonylurea-induced
insulin secretion is not glucose-dependent, and
increased rates of hypoglycemia have been observed
when exenatide was added to the regimen of
patients treated with sulfonylureas or sulfonylureas
plus metformin.
32,34
Recently, exenatide received FDA approval for
use in combination with a TZD. Exenatide
decreased A1C by 0.8 0.9% from a baseline of
7.9 0.9% when added to patients with type 2 dia-
betes not at goal despite treatment with a TZD
alone or in combination with metformin. Improved
glycemic control was not associated with a greater
risk of hypoglycemia than placebo and was associat-
ed with a 1.5 3.1-kg weight change.
38
As with
metformin, the mechanism of action of TZDs does
not lead to hypoglycemia, which may make it possi-
ble to employ triple combination therapy without
increasing the risk of hypoglycemia. Additionally,
combination therapy may limit the weight gain
often seen with TZD therapy.
Another incretin mimetic, liraglutide, is cur-
rently undergoing FDA regulatory trials. This com-
pound is an acylated GLP-1 analog that is bound to
albumin and has a half-life of about 12 hours.
25,39,40
A once-daily injection of liraglutide was evaluated
in a double-blind, placebo-controlled, randomized
I Figure 3. Effects of Glucagon-like Peptide-1 (GLP-1) on
Glucose Homeostasis
Sources: References 26-29.
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S52 I www.ajmc.com I APRIL 2007
trial in patients with type 2 diabetes. At the highest
liraglutide dose (0.75 mg), A1C reductions of
0.75% were recorded at 12 weeks; this decrease was
almost identical to that observed in the open-label
comparator arm in which patients received
glimepiride (0.74% reduction).
41
Liraglutide was
also effective in improving glycemic control in met-
formin-treated patients (A1C reduction of 0.8%
over 5 weeks).
42
As with exenatide, liraglutide has
been reported to enhance beta cell function
43
and is
associated with decreases in body weight.
41,42
DPP-4 Inhibitors. The most recent agent to be
approved by the FDA for the treatment of type 2 dia-
betes is sitagliptin (Januvia), an oral, once-daily DPP-
4 inhibitor that can be given alone or in combination
with metformin or a TZD.
44
Sitagliptin-mediated
inhibition of DPP-4 results in an approximately 2- to
3-fold increase in endogenous GIP and GLP-1 lev-
els.
44
A1C reductions of 0.65% were reported when
sitagliptin was administered to metformin-treated
patients,
45
whereas monotherapy was associated with
placebo-subtracted A1C reductions of 0.79% to
0.94%.
46
Sitagliptin-mediated effects were depend-
ent on baseline A1C; patients with baseline levels
>
9% showed placebo-subtracted A1C reductions of
1.5% with sitagliptin monotherapy. A1C reduc-
tions were accompanied by improvements in mea-
sures of beta cell function.
46
Sitagliptin is primarily eliminated via renal
excretion, and 2- to 4-fold increases in plasma lev-
els have been observed in patients with moderate-
to-severe renal insufficiency. For this reason, renal
function testing should be performed before initia-
tion of sitagliptin therapy and periodically during
treatment. Dosage adjustments are recommended in
patients with moderate renal insufficiency and in
patients with severe renal insufficiency or with end-
stage renal disease requiring hemodialysis or peri-
toneal dialysis.
44
Vildagliptin (LAF237) is another oral DPP-4
inhibitor currently in phase 3 trials. Vildagliptin at
a dose of 50 mg once daily was added to ongoing
metformin in a double-blind, placebo-controlled,
randomized trial of patients with type 2 diabetes. In
the vildagliptin arm, A1C levels decreased by 0.6%
over 12 weeks; sustained reductions were observed
in the 40-week extension study. However, during
that time A1C levels in the placebo group contin-
ued to rise, resulting in a between-group difference
of 1.1% after 1 year. Weight reductions in the place-
bo and vildagliptin arms were comparable at 12
weeks and identical (0.2 kg) at 1 year.
47
A separate
study reported that vildagliptin improved beta cell
function in patients with type 2 diabetes by increas-
ing the insulin secretory rate.
48
Management of Type 2 Diabetes in the Future
The choice of diabetic therapies will likely
continue to expand in the coming years.
Additional insulins to be delivered by pulmonary
inhalation and other noninjection delivery sys-
tems are under development and/or in trials.
Other oral antihyperglycemic agents are also
being investigated.
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