Drug evaluation monograph:

Institution name heading : Drug Information Center- Ibn Sina Hospital.

Generic name: liraglutide

Brand name: Victoza 6 mg/mL
Manufacturer: Novo Nordisk
Therapeutic category: Antidiabetic Agent, Glucagon-Like
Peptide-1 (GLP-1) Receptor
Agonist
AHFS classification: 682006
Available similar hospital agents: Saxenda 6 mg/mL

Therapeutic indication & FDA approval status:

• Approval status: : Yes (approved January 25th, 2010)
• Therapeutic indication: adjunct to diet and exercise, to improve glycemic
control in type 2 diabetes.

 Dose and dosage forms:

 Normal dose :
o Adult: 0.6 mg once daily for 1 week; then increase to 1.2 mg once daily.

Pediatric: not recommended for use in pediatric patients.

Geriatric: 0.6 mg once daily for 1 week; then increase to 1.2 mg once daily.
 Dose in renal / Hepatic impairment:
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 There are no dosage adjustments provided in the manufacturer’s labeling
 Available dosage forms:
0.6 mg .

 Pharmacological data:
Liraglutide is a long acting analog of human glucagon-like peptide-1 (GLP-1) (an incretin
hormone) which increases glucose-dependent insulin secretion, decreases inappropriate
glucagon secretion, increases B-cell growth/replication, slows gastric emptying, and
decreases food intake. Liraglutide administration results in decreases in hemoglobin A1c
by approximately 1%.
 Bioavailability / Pharmacokinetics :

 Distribution: Vd: SubQ: ~13 to 25 L; IV: 0.07 L/kg .

 Protein binding: >98%
 Metabolism: Endogenously metabolized by dipeptidyl peptidase IV (DPP-IV) and
endogenous endopeptidases (Croom, 2009); metabolism occurs slower than
that seen with native GLP-1.
 Bioavailability: SubQ: ~55%.
 Half-life, elimination: ~13 hours.
 Time to peak, plasma: 8 to 12 hours.
 Excretion: Urine (6%, as metabolites); feces (5%, as metabolite. 2
Study ( 1)

Title: Efficacy and safety of liraglutide versus placebo added to basal insulin
analogues( glargine or detemir) with or without metforminin patients with type 2
diabetes: a randomized, placebo-controlled trial.
_____________________________________
Mothed : In 26-week, double-blind, parallel-group study, conducted in clinics
or hospitals, 451 subjects.were randomized 1:1 to once-daily liraglutide 1.8mg
, or placebo. Randomization was stratified according to screening HbA1c
(≤8.0% vs >8.0%), Liraglutide or placebo was initiated at thee quivalent dose
of 0.6mg/day and the dose was increased in weekly increments of 0.6mg to a
final dose of 1.8mg/day .

All subjects were treated with stable doses of basal insulin analogue
(glargine or detemir; ≥20U/day) ± metformin (≥1500mg/day)for at least 8
weeks before enrolment.

_____________________________________
Result :

1. After 26weeks of treatment, HbA1c was reduced more with

liraglutide than with placebo added to a basal insulin
analogue±metformin [−1.3% (−14.2mmol/mol) vs −0.1%
(−1.2mmol/mol)], with an estimated treatment difference
(ETD)of−1.2%or−13.0mmol/mol[ 95% confidence interval (CI)
−1.4; −1.0% or −15.2; −10.8mmol/mol]; p<0.0001.
2. Levels of FPG decreased more from baseline to week 26 with
liraglutide than with placebo [−1.4mmol/l vs −0.2mmol/l; ETD:
−1.3mmol/l (95% CI −1.7; −0.9); p<0.0001.
3. .Statistically significant reductions in total cholesterol, LDL,
very-low-density lipoprotein (VLDL) cholesterol and
triglycerides were observed with liraglutide compared with
placebo.

4. no statistically significant differences were observed between

treatments for HDL cholesterol or free fatty acid levels.
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 There were significantly more confirmed minor hypoglycaemic
episodes reported with liraglutide than with placebo, with an ETR of
2.00 (95% CI 1.03; 3.89); p=0.04.
_____________________________________

Conclusion : Adding liraglutide to a basal insulin analogue±metformin

significantly improved glycaemic control, body weight and systolic blood
pressure compared with placebo. Typical gastrointestinal symptoms and minor
hypoglycaemia were more frequent with liraglutide.

Study ( 2 )

Title: Liraglutide Versus Sitagliptin in a 24-week, Multicenter, Open-label, Randomized,

Parallel-group Study in Japanese Type 2 Diabetes Mellitus Patients Responding
Inadequately to a Sulfonylurea and/or One or Two Other Oral Antidiabetic Drugs (JDDM
33).
_____________________________________
Mothed :
This 24-week, open-label, randomized, parallel-group study was
conducted at 21 primary care centers in Japan. For liraglutide 0.9mg
n=50, sitagliptin 50-100mg n=49, All analyses were performed and
treatment with a sulfonylurea and/or one or two non-sulfonylurea oral
antidiabetic drugs for greater than or equal to eight weeks before
enrollment were eligible and were treated for 24 weeks.
_____________________________________

Result :
1.HbA1c decreased in both groups, and the reduction was significantly
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 greater throughout in the liraglutide group except for Week 24
(0.59 ± 0.80 vs. 0.24 ± 0.94%; P = 0.0525).
2.Fasting plasma glucose (FPG) decreased significantly in the liraglutide
group compared with the sitagliptin group (-21.15 ± 31.22 vs.
+0.46 ± 39.39 mg/dL; P = 0.0014).
3.Homeostasis model assessment of β cell function and C-peptide
increased significantly in the liraglutide group but not in the sitagliptin group.
Hypoglycemic symptoms and adverse events occurred in four and nine
patients, respectively, in the liraglutide group, and in two and five patients,
respectively, in the sitagliptin group.

Conclusion :
1. Treatment with liraglutide or sitagliptin together with a sulfonylurea
improved HbA1c in Japanese T2DM patients in primary care.
2. Both drugs were associated with low rates of adverse events and
hypoglycemia. The improvement in β cell function probably
contributed to the improvement in glycemic control in the liraglutide
group.

Study( 3)
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o Title: Efficacy and Safety Comparison of Liraglutide, Glimepiride ,and
Placebo , All in Combination With Metformin , in Type 2 Diabetes.
_____________________________________

Mothed : In this 26-week, double-blind, double-dummy,

placebo- and active-controlled, parallel-group trial, 1,091
subjects were randomly assigned (2:2:2:1:2) to once- daily
liraglutide (either 0.6, 1.2, or 1.8 mg/day injected
subcutaneously), to placebo, or to glimepiride (4 mg once daily).
All treatments were in combination therapy with metformin (1g
twice daily).

_____________________________________
Result :
 A1C values were significantly reduced in all liraglutide groups
versus the placebo group (P 0.0001) with mean decreases of 1.0%
for 1.8 mg liraglutide, 1.2 mg liraglutide,and glimepiride and 0.7% for
0.6 mg liraglutide and an increase of 0.1% for placebo.
 Body weight decreased in all liraglutide groups (1.8–2.8 kg)
compared with an increase in the glimepiride group (1.0 kg; P
0.0001).
 The incidence of minor hypoglycemia with liraglutide(3%) was
comparable to that with placebo but less than that with glimepiride
(17%; P 0.001).
 Nausea was reported by 11–19% of the liraglutide-treated subjects
versus 3–4% in the placebo and glimepiride groups. The incidence of
nausea declined over time.

_____________________________________

Conclusion : In subjects with type 2 diabetes, once-daily liraglutide

induced similar glycemic control, reduced body weight , and lowered the
occurrence of hypoglycemia compared with glimepiride, when both
had background therapy of metformin.
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 Safety profile / comparison :
 Adverse Effect/ Toxicity

Drug More common Rare

Gastrointestinal: Gastrointestinal:
liraglutide diarrhea acute pancreatitis, acute
constipation gallbladder disease.
vomiting
Dyspepsia Metabolic:
upper abdominal pain Dehydration
Nausea
Cardiovascular:
Metabolic:
Hypoglycemia, anorexia, Cardiac conduction
decreased appetite disorder, tachycardia

Cardiovascular Dermatologic:
Increases in mean
resting heart rate Urticaria
Hypotension
Dermatologic: Pruritus

Rash Endocrine

Endocrine Goiter

Increased blood calcitonin

levels
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 Drug More common Rare

Dermatologic Dermatologic
Metformin Erythema, pruritus, urticarial
Rash, nail disorder, increased
sweating Metabolic:

Lactic acidosis
Metabolic
Gastrointestinal
Hypoglycemia
Flatulence
Gastrointestinal Indigestion, abdominal
discomfort, abnormal stools,
Diarrhea dyspepsia.
Nausea Nervous system
 Behavior change similar to
Vomiting being drunk
Nervous system  difficulty with concentrating
 drowsiness
Lightheadedness, taste disturbances
 lack or loss of strength
 restless sleep

Drug More common Rare

Respiratory Respiratory
Sitagliptin
Nasopharyngitis, upper Interstitial lung disease
respiratory infection, pharyngitis,
Gastrointestinal
Gastrointestinal:
Acute pancreatitis, including fatal and
Abdominal pain, nausea, non-fatal hemorrhagic
diarrhea, gastroenteritis
Nervous system
Nervous system
Dizzines
 Headache, Anxiety, cold
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 Drug More common Rare

glimepiride
Difficulty with
light-colored stools
swallowing
dark urine dizziness
pain in the upper right part of the fast heartbeat
stomach hives
unusual bruising or bleeding itching
diarrhea swelling around
the eyes, face,
fever lips, or tongue
sore throat shortness of
breath

 Cost comparison ( course of treatment ) in atrial fibrillation patents :

Estimated Yearly
Drug Usual dose Price of the Number of Unit Cost
Cost Impact
box tab in box

Liraglutide
Once daily 516.65 SR 2 pen 258.32 SR 3099.9 SR
(Victoza) 0.6 mg

Medformin 500 mg one tablet 16.00 SR 50 tablets 0.32 SR 116.8 SR

Medformin 1000
one tablet 20.00 SR 30 tablets 0.66 SR 243.33 SR
mg

Glimepiride
One tablet 23.15 SR 30 tablets 0.77 SR 281 SR
(Amaryl) 1mg
Glimepiride
One tablet 37.65 SR 30 tablets 1.255 SR 458 SR
(Amaryl) 2mg
Glimepiride
one tablet 52.35 SR 30 tablets 1.745 SR 636 SR
(Amaryl) 3mg

Sitagliptin
(Januvia ) One table 140.35 SR 28 tablets 5.1 SR 1861.4 SR
100mg
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 Summary:
Liraglutide belongs in a class of drug called incretin mimetics .
Liragiutide is an injectable drug that reduces the level of sugar in the blood.
It is used for treating type 2 diabetes and is similar to exenatide .

 Recommendation:
Efficacy was better with Liragiutide more than in glimepiride and sitagliptin .
But the Adverse Effects were more in the Liragiutide.
The optimal management is combination of liraglutide or sitagliptin together
with a sulfonylurea (glimepiride) to improved HbA1c and with low rates of adverse
events, hypoglycemia and improvement in β cell function .

 References:
 www.uptodate.com
 www.drugs.com
 www.empr.com
 medicinenet.com
 everydayhealth.com
 rxlist.com
 MICROMEDEX

Done by:
Bashayir hameid
Sameera
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