Drug Monograph
Tradjenta® Linagliptin
September 10th, 2012
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 glucose-dependent 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 β islet cell function as well as α
cell sensitivity to glucose.
Pharmacokinetics
Absorption
Absolute bioavailability of ~30%. May be administered with or without food
Tmax
~1.5 hours postdose
Distribution
Vd is approximately 1,110 L (extensively distributed to tissues)
Relatively high protein binding of 75-99% that varies depending on the drug
Protein binding
concentration
Minor elimination, with only a small fraction metabolized to an inactive
Metabolism
metabolite
Majority (~90%) is excreted unchanged with ~80% eliminated via the
Elimination
enterohepatic system and ~5% eliminated via the urine
Effective t1/2 of ~12 hours with a biphasic decline in plasma concentration and a
Half-life
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%)
Hyperuricemia (3%), lipids increased (3%), triglycerides increased (2%),
Endocrine & metabolic
weight gain (2%)
Neuromuscular & skeletal Arthralgia (6%), back pain (6%)
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 Class
Example
Description
CYP3A4 strong inducers
Rifampin
May decrease linagliptin’s therapeutic effect.
Ritonavir
Linagliptin’s pharmacologic effects and adverse
CYP3A4 strong inhibitors
Ketoconazole reactions may be increased.
Efficacy/Clinical Trial
Citation
Purpose
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;13:258–267.
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).
Methods
Criteria
Results
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 pre-treated, 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, 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 α = 0.05 (two-sided) based on the full analysis
set (FAS).
Inclusion
 18-80 years with a BMI≤40 kg/m2
 HbA1c between 6.5 and 9.0% in pre-treated patients and between 7.0 and
10% in treatment-naïve 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 β-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.
Conclusion
Critique
Safety
 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 β-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-Shreveport’s 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/ucm253501.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.