Download file (Tradjenta (linagliptin) Monograph)

Nick Wytiaz
University of Pittsburgh
APPE – LifeCare Hospital
June 13, 2011
[email protected]
Monograph: TRADJENTA (linagliptin)
I. Introduction
Diabetes, a chronic disease of improper insulin production or use, affects over 25 million Americans,
with 95% of these cases presenting as diabetes mellitus type 2 (DM2). Many oral and injectable
medications are available to treat DM2, with the goals of controlling blood glucose levels and
preventing micro- and macro-vascular complications. The American Diabetes Association
recommends the following targets of DM2 patients: glycosylated hemoglobin (A1C) <7.0%, fasting
plasma glucose (FPG) 70-130 mg/dL, and post-prandial (PPG) <180 mg/dL.
Tradjenta (linagliptin), a dipeptidyl peptidase-4 (DPP-4) inhibitor, is the newest oral agent
approved by the FDA in May 2011 for the management of diabetes. Linagliptin is indicated for
adults with diabetes mellitus type 2 (DM2), along with diet and exercise, to improve blood glucose
control. As with other DDP-4 inhibitors, linagliptin can be used as monotherapy or in combination
with other DM2 therapies, including metformin, sulfonylurea, and pioglitazone. While linagliptin is
the third agent to enter the DPP-4 class in the US, following sitagliptin (Januvia) and saxagliptin
(Onglyza), the new agent presents with some unique features.
II.
Pharmacology
DPP-4 inhibitors represent a relatively new approach to DM2 treatment with a unique mechanism
of action compared to other classes of diabetes medications. Like other agents of this class,
linagliptin is a potent, selective inhibitor of DPP-4, an enzyme that degrades the incretin hormones
glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic peptide (GIP).
GLP-1 and GIP are naturally occurring hormones, which are released by endocrine cells in the
epithelium of the small intestines at a low basal level throughout the day and spike immediately
after meal intake. These hormones target the beta-cells of the pancreas by increasing insulin
secretion and suppressing glucagon secretion in response to elevated blood glucose levels. In
addition, GLP-1 also reduces glucagon secretion from pancreatic alpha-cells, resulting in a
reduction in hepatic glucose output. By binding to the DPP-4 enzyme, DPP-4 inhibitors increase the
concentrations of GIP and GLP-1. This stimulates the release of insulin in a glucose-dependent
manner and decreases levels of glucagon in circulation, which helps to control blood glucose levels
in DM2 patients.
Pharmacodynamics
Linagliptin binds to DPP-4 in a reversible manner and thus increases the concentrations of incretin
hormones. This, in turn, glucose-dependently increases insulin secretion and lowers glucagon
secretion, resulting in a better regulation of the glucose homeostasis. Linagliptin binds selectively to
DPP-4 and selectively inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations
approximating therapeutic exposures.
Pharmacokinetics
After a single 5mg dose in both healthy volunteers and DM2 patients:
Tmax=1.5 hrs
AUC=139 nmol*h/L
Bioavail(po) = 30%
Vd = 1110L
Cmax=8.9 nmol/L
Prot Binding = 70-80% (at high conc, DPP-4 fully saturated)
Excretion = 80% (enterohepatic), 5% (urine)
T1/2=12 hours
III.
Current Drug Classes for DM2
Class
Specific Agents
Mechanism of Action
Alpha-glucosidase
inhibitor (AGI)
Acarbose
(Precose)
Competitively blocks
enzyme alphaglucosidase in brush
borders of small
intestine
3rd line due to lower or
equivalent overall glucose
lowering effect compared to
other therapies and/or
limited clinical data or
relative expense
3rd line due to lower or
equivalent overall glucose
lowering effect compared to
other therapies and/or
limited clinical data or
relative expense
Tier-1, well-validated core
therapy after lifestyle
modification
Miglitol
Role in Therapy
American Diabetes Association
Amylin analog
Pramlintide
(Symlin)
Slows gastric emptying
leading to feeling of early
satiety, decreases
postprandial glucagon
secretion
Biguanide
Metformin
Dipeptidyl
peptidase-4
(DPP-4) inhibitor
Saxagliptin
(Onglyza)
Inhibits hepatic
gluconeogenesis,
glycogenolysis, enhances
insulin sensitivity
Inhibits degradation of
endogenous incretins
which increase insulin
secretion, decrease
glucagon secretion
Glucagon-like,
peptide-1 (GLP1) or incretin
mimetic
Exenatide
(Byetta)
Insulin
Sitagliptin
(Januvia)
Liraglutide
(Victoza)
Long-acting,
rapid-acting,
premixed
combos
Stimulates GLP-1
receptors which
increases production of
insulin in response to
high blood glucose
levels, inhibits
postprandial glucagon
release, slows gastric
emptying
Insulin replacement
therapy
3rd line due to lower or
equivalent overall glucose
lowering effect compared to
other therapies and/or
limited clinical data or
relative expense
Tier-2 therapies. In
selected clinical settings
(when hypoglycemia or
weight loss is major
consideration), these
can be considered only when
in conjunction with lifestyle
modification and metformin,
when additional A1C
lowering is desired
Tier-1, well-validated core
therapies to be used with
lifestyle modification and
metformin, when additional
A1C lowering is desired
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American Assoc of Endocrinologists
/ American College of Endocrinology
One of several preferred
agents, after metformin, for
patients with impaired
postprandial glucose as
monotherapy or as add-on
therapy to metformin in pts
with A1C values 6.5-7.5%
Possible adjunct to insulin in
patients receiving
prandial insulin
Initial therapy after lifestyle
modification
One of several preferred
agents, after metformin, for
patients with impaired
postprandial glucose /
elevated fasting plasma
glucose as monotherapy or
add-on therapy in pts with A1C
6.5-7.5% or as add-on therapy
to metformin in pts with A1C
7.6-9%. Can be considered as
part of a multi-drug regimen
with metformin, in drug-naïve,
asymptomatic pts if A1C >9%
One of several preferred
agents, after metformin, for pts
with impaired post prandial
glucose / elevated fasting
plasma glucose as monotherapy or add-on therapy in
pts with A1C 6.5- 7.5% or as
add-on therapy to metformin
in pts with A1C 7.6-9%
Prefer GLP-1 agonists over
DPP-4 inhibitors because of
better reductions in PPG & wt
3rd line agents in pts with A1C
6.5-9%, to be used after failure
to meet goals on triple oral
therapy with other agents. In
patients with A1C >9%, insulin
should be used in pts who fail
other therapies or those with
symptoms of hyperglycemia
Meglitinide
Nateglinide
(Starlix)
Stimulates pancreatic
insulin secretion
Repaglinide
(Prandin)
Sulfonylurea –
1st generation
3rd line due to lower or
equivalent overall glucose
lowering effect compared to
other therapies and/or
limited clinical data or
relative expense
Not preferred
Add-on therapy to metformin
in patients with impaired
postprandial glucose and A1C
6.5% to 9%
Chlorpropamide
Tolazamide
Tolbutamide
Glyburide
Glipizide
Glimepiride
Stimulates pancreatic
insulin secretion
Stimulates pancreatic
insulin secretion
Tier-1, well-validated core
therapies when used with
lifestyle modification and
metformin, for additional
A1C lowering
Add-on to metformin in
patients with elevated
fasting plasma glucose and
A1C 6.5% to 9% or as
part of a multi-drug regimen
with metformin, in drug-naïve,
asymptomatic patients with
A1C > 9%
Thiazolidinedione
(TZD)
Pioglitazone
(Actos)
Enhances insulin
sensitivity in muscle and
fat by increasing
glucose transporter
expression
Tier-2 therapy (when
hypoglycemia is a concern)
Clinicians should carefully
consider whether to use
these agents vs. insulin or
sulfonylureas as 2nd line
therapy
Others-bile acid
sequestrant
Colesevelam
(Welchol)
May reduce hepatic
insulin resistance
leading to reduction in
hepatic glucose
production, have effect
on molecular mediators
of glucose metabolism,
reduce intestinal
glucose absorption
Role not defined
One of several preferred
agents, after metformin, as
monotherapy in patients with
A1C 6.5-7.5% or as add-on
therapy to metformin in
patients with A1C 7.6-9%. Can
also be considered as part of a
multi-drug regimen with
metformin, in drug-naïve,
asymptomatic patients with
A1C >9%. Also consider if
metabolic syndrome and
nonalcoholic fatty liver disease
One of several preferred
agents as add-on to metformin
in patients with A1C 6.5-7.5%
Sulfonylurea –
2nd generation
Not preferred
V.
Dosing & Administration
The recommended dose of linagliptin is 5 mg PO once daily. The medication can be taken without
regards to meals. No dosage titration is recommended. Unlike other DPP-4 inhibitors, no dosing
adjustment is necessary for patients with impaired renal or hepatic function. Both saxaglipin and
sitagliptin require dose reductions in patients with renal dysfunction. Saxagliptin does not require
dose adjustments for hepatic impairment. Sitagliptin can be dosed normally in mild-moderate
hepatic dysfunction (Child-Pugh class A or B). However, no information is available on its use in
severe hepatic dysfunction (Child-Pugh class C).
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VI.
Adverse Drug Reactions
ADR
Additional Therapy
Frequency*
Nasopharyingitis
5.8%
Hypoglycemia
MET + SU
22.9%
Cough
MET + SU
2.4%
Hypertriglyceremia
SU
2.4%
Weight Gain
PIO
2.3%
Arthralgias
MET
5.7%
Back Pain
MET
6.4%
Headache
MET
5.7%
* Based on clinical trials LIN = linagliptin 5mg
PIO = pioglitazone (> 15 mg/day)
Comparator
Placebo (5.5%)
Placebo + MET + SU (14.8%)
Placebo + MET + SU (1.1%)
Placebo + SU (0.0%)
Placebo + PIO (0.8%)
Glimepiride + MET (3.5%)
Glimepiride + MET (5.2%)
Glimepiride + MET (4.2%)
MET = metformin (> 1500 mg/day)
SU = sulfonylurea
The incidence of hypoglycemia was similar to placebo when linagliptin was administered as
monotherapy or in combination with metformin alone or pioglitazone.
Other adverse reactions reported included hypersensitivity (urticaria, angioedema, localized skin
exfoliation, or bronchial hyperreactivity), and myalgia.
Pancreatitis was reported in 8 of 4687 patients receiving linagliptin (1 per 538 patient-years) vs. 0
of 1183 patients treated with placebo (0 in 433 person-years). Post-marketing reports of acute
pancreatitis in patients taking Januvia have prompted a change in the “Warnings and Precautions”
section of the package, recommending the prompt discontinuation of Januvia if pancreatitis is
suspected. While it is still too soon to tell if the rate of pancreatitis with linagliptin is similar to that
of Januvia, it seems reasonable to discontinue linagliptin if a patient showed signs of pancreatitis.
VII.
Drug Interactions
Nearly 90% of linagliptin is excreted from the body unchanged. Since only a small portion of the
drug is metabolized, drug interactions are rare. Preclinical studies have shown linagliptin to be a
weak CYP3A4 inhibitor and a P-glycoprotien substrate. However, it does not significantly affect
other 3A4 or p-glycoprotein substrates when given at therapeutic levels.
Rifampin, a strong P-glycoprotein and CYP3A4 inducer, has been shown to decrease linagliptin
exposure. Though its clinical significance was not studied, the interaction suggests that the efficacy
of linagliptin may be reduced when administered with rifampin or other strong P-glycoprotein or
CYP3A4 inducers. Thus, use of linagliptin in combination with such medications should be avoided.
VIII. Contraindications / Precautions
Linagliptin is contraindicated in patients with a history of hypersensitivity reaction to the
medication (e.g. urticaria, angioedema, or bronchial hyperreactivity), type 1 diabetes, or diabetic
ketoacidosis.
Use of linagliptin in combination with an insulin secretagogue, such as a sulfonylurea, was
associated with a higher rate of hypoglycemia. Therefore, a lower dose of the insulin secretagogue
may be required to reduce the risk of hypoglycemia.
Pregnancy Category B – no adequate, well-controlled studies in pregnant women. In animal studies,
linagliptin was not teratogenic in therapeutic dose, but was found to cross the placenta into the
fetus and be secreted into the breast milk. Based on available information, linagliptin should only
be used in pregnancy if clearly needed.
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IX.
Clinical Trial Review
Lingliptin has been studied as monotherapy and in combination with metformin, glimepiride, and
pioglitazone therapy in approximately 3800 patients with DM2, who were randomized in 8 doubleblind, placebo-controlled clinical safety and efficacy studies.
Monotherapy
Two double-blind, placebo-controlled clinical trials, of 18-week and 24-week duration, were
conducted to evaluate the efficacy and safety of linagliptin monotherapy. In both studies, patients
currently on an antihyperglycemic agent discontinued the medication and underwent a diet,
exercise, and drug washout period of 6 weeks. An open-label placebo run-in was conducted for all
patients during the final 2 weeks of the washout period. Patients with inadequate glycemic control
(A1C 7-10%) after the washout period were randomized, while patients not currently on
antihyperglycemic agents (off therapy for at least 8 weeks) with inadequate glycemic control (A1C
7-10%) were randomized after completing the 2-week open-label placebo run-in period.
In the 18-week study, 76 patients were randomized to placebo and 151 to linagliptin 5mg. Only
patients ineligible for metformin were recruited for the 18-week study. Reasons a patient was
considered unsuitable for metformin included GI adverse events (93%) or elevated serum
creatinine levels (male >1.5 mg/dL, female >1.4 mg/dL; 7%).
For the 24-week study, 167 patients were randomized to placebo and 336 to linagliptin 5 mg.
Treatment with linagliptin 5mg daily provided statistically significant improvements in A1C, FPG,
and 2-hour PPG compared with placebo (Table 1). Improvement in A1C compared with placebo
was not affected by gender, age, race, prior anti-hyperglycemic therapy, baseline BMI, or a standard
index of insulin resistance. Change in body weight did not differ significantly between groups.
Table 1. Monotherapy Studies
18-Week Study
24-Week Study
Linagliptin 5mg Placebo Linagliptin 5mg
Placebo
A1C
Number of Patients
147
Mean baseline
8.1
Change from baseline
-0.4*
% achieving A1C <7%
28%*
FPG (mg/dL)
Number of Patients
138
Mean baseline
178.4
Change from baseline
-13.3*
2-hr PPG (mg/dL)
Number of Patients
NA
Mean baseline
NA
Change from baseline
NA
* Statistically significant (p<0.001)
73
8.1
0.1
15%
333
8.0
-0.4*
25%*
163
8.0
0.3
12%
66
175.6
7.2
318
164
-8.5*
149
166
14.8
NA
NA
NA
67
258
-33.5*
24
244
24.9
Combination Therapy
A total of 701 patients with inadequately controlled DM2 (A1C 7-10%) participated in a 24-week,
randomized, double-blind, placebo-controlled study to assess the efficacy of linagliptin in
combination with metformin. Patients already on metformin (n = 491) at a dose of at least 1500 mg
per day were randomized after completing a 2-week open-label placebo run-in period. Patients on
metformin and another antihyperglycemic agent (n = 207) were randomized after a run-in period
of ~6 weeks on metformin (min 1500mg/day) monotherapy. Patients were randomized to the
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addition of either once daily linagliptin 5mg or placebo. Patients who failed to meet specific
glycemic goals during the studies were treated converted to glimepiride as “rescue therapy”. In
combination with metformin, linagliptin provided statistically significant improvements in A1C,
FPG, and 2-hour PPG compared with placebo (Table 2). A similar decrease in body weight was
observed for both treatment groups.
An 18-week study evaluated the efficacy of linagliptin in patients not achieving adequate glycemic
control (A1C <7%) on sulfonylurea monotherapy. 245 received linagliptin 5mg once daily (n=161)
or placebo (n=84). All oral antidiabetic agents other than sulfonyureas were withdrawn at the
beginning of the study. Patients then underwent a 4-week washout prior to a 2-week run in.
Sulfonylurea dosing remained consistent for each patient throughout the study duration. At the end
of 18 weeks, patients in the linagliptin/sulfonylurea group experienced a mean A1C change from
baseline of -0.47% compared to the placebo / sulfonylurea group (p<0.0001).
A similar study evaluated the efficacy of linagliptin 5mg once daily in patients inadequately
controlled (A1C 7% to 10%) with a combination of metformin and sulfonylurea. Patients were
randomized to adjunctive linagliptin (n=793) or placebo (n=265) for the 24-week study. Patient
characteristics were similar at baseline, with the majority (73.3%) having had DM2 for at least 5
years prior to study enrollment. The difference in mean change from baseline A1C was -0.62% in
the linagliptin group compared with placebo (p<0.0001). Patients with a baseline A1C >7% were
more likely to acheive goal A1C (<7%) when treated with linagliptin (29.2%) compared with
placebo (8.1%, p<0.0001).
In another study, linagliptin plus pioglitazone was compared with pioglitazone monotherapy.
Linagliptin / pioglitazone therapy resulted in an adjusted mean reduction in A1C of 0.5% compared
with pioglitazone alone. Patients in the pioglitazone / linagliptin group experienced a mean A1C
change from baseline of -1.1% compared to a change of -0.6% in patients taking pioglitazone alone
(p<0.0001). Reductions in fasting plasma glucose were also significantly greater for the
combination group (p<0.0001) and were more likely to achieve a target A1C <7% compared with
those on placebo / pioglitazone.
Table 2. Combination Therapy Studies
LIN +
Placebo LIN +
MET
+ MET
PIO
Placebo
+ PIO
LIN + SU
Placebo
+ SU
A1C
# Patients
513
175
252
128
158
82
Mean baseline
8.1
8.0
8.6
8.6
8.6
8.6
Change from
-0.5*
0.15
-1.1*
-0.6
-0.5*
-0.1
baseline
% achieving
28.3%*
11.4%
42.9%*
30.5%
15.2%*
3.7%
A1C <7%
FPG (mg/dL)
# Patients
495
159
243
122
155
78
Mean baseline
169.0
163.8
188.4
186.4
180
171
Change from
-10.7*
10.5
-32.6*
-18.4
-8.2*
-1.8
baseline
LIN = linagliptin 5mg
MET = metformin (> 1500 mg/day)
PIO = pioglitazone (> 15 mg/day)
SU = sulfonylurea
* Statistically significant (p<0.005)
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LIN+
MET+ SU
Placebo +
MET + SU
778
8.2
-0.7*
262
8.1
-0.1
31.2%
9.2%
739
159.2
-4.6*
248
162.6
8.1
X.
Cost Comparison
Class
DPP-4 Inhibitors
Drug / Strength
Price* / Quantity
Januvia 25, 50, 100mg $247.66 x30
Onglyza 2.5, 5mg
$247.64 x30
Tradjenta 5mg
$247.66 x30
Biguanides
Metformin 500mg
$70.40 x100
850mg
$119.70 x100
1000mg
$144.01 x100
Sulfonylureas
Glimepiride 1mg
$40.18 x100
2mg
$65.20 x100
4mg
$122.97 x100
Glyburide 1.25mg
$30.30 x100
2.5mg
$30.58 x100
5mg
$52.60 x100
TZDs
Actos 15mg
$183.06 x30
30mg
$279.76 x30
45mg
$303.45 x30
Incretin Mimetics
Byetta 5mcg/1.2mL
$339.28 x1
10mcg/2.4mL $356.12 x1
Victoza 18mg/3mL
$475.91 x3
*All prices derived from Cardinal Health website (www.cardinal.com)
Price per Dose
$8.26
$8.25
$8.26
$0.70
$1.20
$1.44
$0.40
$0.65
$1.23
$0.30
$0.31
$0.53
$6.10
$9.33
$10.12
$5.65
$5.94
$10.58
XI.
Place in Therapy
The American Diabetes Association (ADA), in conjunction with the European Association for the
Study of Diabetes, released an updated consensus statement in 2009 on the treatment of DM2. The
statement segregated treatment options into two tiers. Tier 1 was defined as “well-validated
treatments” while Tier 2 was defined as “less well validated treatments.” The distinctions were
made based on evidence from clinical trials, meta-analyses, and on-going studies evaluating the
safety and efficacy of current diabetic treatment options.
The initial treatment recommendations in tier 1 include lifestyle modifications plus metformin. If
additional therapies are needed, insulin and a sulfonylurea are recommended. In tier 2, pioglitazone
or a GLP-1 agonist (incretin mimetic) is recommended. According to the ADA statement, DPP-4
inhibitors are not listed as a tier 1 or 2 agent. ADA stated that DPP-4 inhibitors lower A1C levels by
0.6% to 0.9%, are weight neutral, and are relatively well tolerated. The DPP-4 inhibitors are listed
as “other therapies” in the current treatment algorithm because these agents are expensive and
long-term safety has not been established.
The American Association of Clinical Endocrinologists (AACE) also released updated guidelines for
the management of diabetes. The 2009 AACE/ACE Diabetes Algorithm for Glycemic Control listed
DPP-4 inhibitors, given as monotherapy or in combination with other oral agents, as one of the
preferred therapies for patients with DM2. Based on these two sets of recommendations and the
favorable aspects of metformin as an initial treatment option, linagliptin seems to be most
appropriate as an add-on therapy for certain patients who need additional glycemic control.
Such examples of its use could include patients who are close to their A1C goal, yet continue to
experience postprandial hyperglycemia; patients for whom hypoglycemia is a major concern, such
as the elderly or those with high fall risk; and patients on metformin, sulfonylurea, or pioglitazone
who can not tolerate other diabetic agents. While linagliptin provides another option for the
management of DM2, immediate uptake and use will be limited due to high cost, limited A1C
reduction, and lack of long-term safety / efficacy data.
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XI.
References
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Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus:
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4. American Diabetes Association. Standards of medical care in diabetes – 2010. Diabetes Care.
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10. Blech S, Ludwig-Schwellinger E, Grafe-Mody EU, Withopf B, Wagner K. The metabolism and
disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans. Drug Metab Dispos.
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11. Januvia [package insert]. Whitehouse Station, NJ: Merck & Co., Inc; 2011.
12. Onglyza [package insert]. Princeton, NJ: Bristo Myers Squibb; 2011.
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