September 10th, 2012

Drug Monograph
Tradjenta Linagliptin
Introduction
Linagliptin, a novel xanthine-derived dipeptidyl peptidase (DPP)-4 inhibitor,
was approved by the FDA on May 2nd, 2011. It is the newest addition to the
DPP-4 inhibitor class and has demonstrated safety and efficacy in eight
double-blind, placebo-controlled clinical studies involving approximately
3800 patients.
Pharmacology
DPP-4 inhibitors lower blood glucose through enhancement of glucosedependent insulin synthesis and secretion by preventing DPP-4-mediated
degradation of endogenous incretin hormones, like glucagon-like peptide
(GLP)-1 and glucose-dependent insulinotropic peptide (GIP). Besides their
actions on insulin, incretin hormones also regulate glucose homeostasis
through inhibition of glucagon secretion, thereby decreasing glucose
production. In addition to providing better glucose control, research has
shown evidence of DPP-4 inhibitors improving islet cell function as well as
cell sensitivity to glucose.
Pharmacokinetics
Absolute bioavailability of ~30%. May be administered with
Absorption
or without food
Tmax
~1.5 hours postdose
Vd is approximately 1,110 L (extensively distributed to
Distribution
tissues)
Protein
Relatively high protein binding of 75-99% that varies
binding
depending on the drug concentration
Minor elimination, with only a small fraction metabolized to
Metabolism
an inactive metabolite
Majority (~90%) is excreted unchanged with ~80%
Elimination eliminated via the enterohepatic system and ~5% eliminated
via the urine
Effective t1/2 of ~12 hours with a biphasic decline in plasma
Half-life
concentration and a long terminal t1/2 of >100 hours.
FDA Approved Indication(s)
Type 2 diabetes mellitus: As an adjunct to diet and exercise to improve
glycemic control in adults with type 2 diabetes mellitus as monotherapy or
combination therapy.
Dosage and Administration

The usual dosage for T2DM is 5mg once daily.

However, when used in combination with a sulfonylurea or insulin, a lower
dose may be required of the sulfonylurea or insulin to decrease the risk of
hypoglycemia.
Special Populations
Renal function impairment: No dose adjustment is recommended.
Hepatic function impairment: No dose adjustment is recommended.
Elderly: No dose adjustment is recommended.
Children: Safety and effectiveness have not been established.
Adverse Effects
Hypoglycemia: 15% combined with metformin/sulfonylurea
<1% combined with metformin, pioglitazone
<1% monotherapy
Other system adverse events:
CNS
Headache (6%)
Endocrine &
Hyperuricemia (3%), lipids increased (3%),
metabolic
triglycerides increased (2%), weight gain (2%)
Neuromuscular &
Arthralgia (6%), back pain (6%)
skeletal
Respiratory:
Nasopharyngitis (6%), cough (2%)
<1% (Limited to important or life-threatening): Angioedema,
hypersensitivity, and pancreatitis
Monitoring Parameters
HbA1c and serum glucose
Pregnancy/Lactation Considerations
Pregnancy: Category B
Lactation: Excretion in breast milk unknown, use caution
Precautions/Contraindications
Contraindications: Hypersensitivity to linagliptin or any component of the
formulation
Precautions:
Concomitant use of insulin/sulfonylurea may increase the risk of
hypoglycemia. Monitor blood glucose closely; dosage reduction of
insulin/sulfonylurea may be required.
Linagliptin should not be used in patients with DKA or type 1 diabetes
mellitus due to lack of efficacy.

Drug Interactions
Linagliptin is a substrate of CYP3A4 and p-glycoprotein.
Interacting Drug
Example
Description
Class
CYP3A4 strong
May decrease linagliptins therapeutic
Rifampin
inducers
effect.
Ritonavir
CYP3A4 strong
Linagliptins pharmacologic effects and
Ketoconaz
inhibitors
adverse reactions may be increased.
ole
Efficacy/Clinical Trial
Citation

Purpose

Methods

Del Prato S, Barnett AH, Huisman H, et al. Effect of linagliptin

monotherapy on glycaemic control and markers of beta-cell
function in patients with inadequately controlled type 2
diabetes: a randomised controlled trial. Diabetes Obes Metab.
2011;13:258267.
To assess the safety and efficacy of linagliptin 5 mg when
given for 24 weeks to patients with type 2 diabetes who were
either treatment-naive or who had received one oral
antidiabetes drug (OAD).
Study Design:
Randomized, double blind, parallel-group study
including patients enrolled from 66 trial sites in 11
countries.
Following a 2 weeks placebo run-in for patients not pretreated, and a 6 weeks washout period with the last 2
weeks a placebo run-in for patients pre-treated with 1
OAD, eligible patients were randomized to either
treatment with linagliptin 5 mg or placebo (2:1 ratio) for
24 weeks
The primary endpoint was change from baseline in
HbA1c after 24 weeks of treatment (adjusted for
baseline HbA1c and previous OAD).
Secondary endpoints: absolute response, relative
response, reduction from baseline in HbA1c by visit over
time, change from baseline in fasting plasma glucose
(FPG), and MTT(change in 2-hr postprandial glucose
from baseline).
The safety criteria were incidence and intensity of
adverse events, withdrawals because of adverse events,

Criteria

Results

physical examination, 12-lead electrocardiogram, vital

signs and clinical laboratory parameters.
Data Analysis
The primary endpoint was assessed using analysis of
covariance (ANCOVA) at the level of = 0.05 (two-sided)
based on the full analysis set (FAS).
Inclusion
18-80 years with a BMI40 kg/m2
HbA1c between 6.5 and 9.0% in pre-treated patients and
between 7.0 and 10% in treatment-nave patients. (An
HbA1c between 7.0-10.0% in both groups was required
at the start of the run-in period.
Exclusion
Myocardial infarction, stroke, or transient ischemic
attack within 6 months of study enrollment
Impaired hepatic function at screening
Receiving rosiglitazone, pioglitazone, GLP-1 analogues,
insulin or antiobesity drugs (e.g. sibutramine,
rimonabant or orlistat) within 3 months of enrolment.
Patients receiving systemic steroids at enrollment or
receiving dose changes in any thyroid hormone
treatment within 6 weeks of screening.
Efficacy
The adjusted mean difference in the change inHbA1c
comparing linagliptin and placebo was 0.69% (p <
0.0001).
Linagliptin treatment resulted in a greater reduction of
FPG (adjusted mean change 1.3 mmol/l; p < 0.0001)
and 2hPPG (adjusted mean change 3.2 mmol/l; p <
0.0001) compared with placebo after 24 weeks.
The improvement in glycaemic control achieved with
linagliptin was associated with enhancement of markers
of -cell function, such as proinsulin/insulin ratio,
HOMA-%B, and DI.
there was no difference in the mean linagliptin trough
levels over time between patients with normal renal
function and those with mild or
moderate renal impairment, 8.0 7.3, 8.0 7.6 and 6.6
1.8 nmol/l, respectively.
Safety

Conclusion

Critique

The most frequently reported adverse events (frequency

>2%) that were more common with linagliptin than
placebo were headache (2.7 vs. 1.2%, respectively),
hypertension (3.6 vs. 1.2%, respectively) and back pain
(2.7 vs. 1.8%, respectively).
Hyperglycemia was the most common adverse event,
occurring in 8.6% of the linagliptin group and in 22.8%
of the placebo group.
Neither body weight nor waist circumference differed
significantly from baseline in either group, confirming
that linagliptin is weight neutral.
Monotherapy with linagliptin produced a significant,
clinically meaningful and sustained improvement in
glycemic control, accompanied by enhanced parameters
of -cell function. The safety profile of linagliptin was
comparable with that of placebo.
Strengths
Large trial that included 11 countries and 66 trial sites
Blinded randomization
Included renal function and drug concentration
evaluation since it is the main clinical difference about
linagliptin vs. other DPP-4 inhibitors
Limitations
No comparison to standard therapy/other DPP-4
inhibitors
Washout period was only 6 weeks for those who had
received a prior OAD, which effects of treatment on
HbA1c may last up to 12 weeks
Short duration of study period and thus inability to
assess the long term effect of chronic treatment on
glycemic control
Ethical concerns of using a non-first line agent as
monotherapy in T2DM even though its class effect on
HbA1c has been shown to be minimal

Cost
The average wholesale price (AWP) of linagliptin is $8.12 per tablet;
therefore, the estimated cost of a 30-day supply is $243.60. The AWP of a
30-day supply of sitagliptin or saxagliptin is similar to that of linagliptin.

Conclusion
Linagliptin has been studied in multiple studies, as monotherapy and as
adjunct therapy with patients inadequately controlled on metformin,
pioglitazone, or a sulfonylurea. Like the other DPP-4 inhibitors, it produces
significant but minor reductions in HbA1c, thereby gaining a place as
adjunct therapy rather than monotherapy in patients with T2DM. Also like
its predecessors, its side effects profile is comparable to placebo and rarely
causes hypoglycemia, but should be used with caution if it is combined with
insulin or a sulfonylurea. However, unlike its predecessors, including
sitagliptin and saxagliptin, it does not require dose adjustment for renal
impairment because it is minimally eliminated via the renal route. This
might give linagliptin substantial advantage over other DPP-4 inhibitors
since renal impairment is a gradual process that accompanies the diabetic
population. Linagliptin can also be used without dose adjustment in hepatic
dysfunction.
In regard to cost, linagliptin is similar to sitagliptin, the DPP-4 inhibitor
most commonly used and the one on LSU-Shreveports formulary.
The only limiting factor that might put linagliptin at a disadvantage to
sitagliptin is its drug interaction profile due to it being a substrate of
CYP3A4, the major metabolizing enzyme for many drugs.
Recommendation
Considering the efficacy, safety, and cost of linagliptin vs. sitagliptin,
linagliptin should be added to the LSU-Shreveport formulary. The main
advantage of doing so would be to offer diabetic patients a safe and
effective alternative to use in the event of renal impairment without having
to worry about adjusting the dose.
References
1. FDA News Release: FDA Approves New Treatment for Type 2
Diabetes. FDA, US Food and Drug Administration.
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm
253501.htm. Updated: May 2, 2011. Accessed: September 8, 2012.
2. Baetta R, Corsini A. Pharmacology of Dipeptidyl Peptidase-4
Inhibitors, Similarities and Differences. Drugs. 2011;71:1441-1467.
3. UpToDate Inc. http://www.uptodate.com/. Accessed September 9,
2012.

4. Facts & Comparisons. http://online.factsandcomparisons.com.

Accessed September 9, 2012.
5. Del Prato S, Barnett AH, Huisman H, et al. Effect of linagliptin
monotherapy on glycaemic control and markers of beta-cell function
in patients with inadequately controlled type-2 diabetes: A
randomized controlled trial. Diabetes Obesity Metab. 2011;13:258
267.
6. Freeman MK. Efficacy and Safety of Linagliptin (Tradjenta) in Adults
With Type-2 Diabetes Mellitus. P T. 2011;36(12):807-812, 842.