critical appraisal or journal club presentation- Liraglutide trial

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Journal club
The efficacy and safety of Liraglutide on
weight management
Presented by
Abdulaziz Bagasi
R3 Family Medicine NGH-Jeddah
Supervised by
Dr.Ahmed Sabban
December 2019

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Objectives
• What is Liraglutide ?
• PICO
• Study overview
• Critical appraisal
• Conclusion

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WHAT IS LIRAGLUTIDE?
Glucagon-like
peptide-1
analogue.
97% homology to
human glucagon-
like peptide-1.
Approved for the
treatment of type
2 diabetes at
doses up to 1.8
mg once daily.

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MECHANISM OF ACTION OF (GLP-1)

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HOW TO USE SAXENDA?
Week 5
Week 4
Week 3
Week 2
Week 1
3.0mg
2.4mg
1.8mg
1.2mg
0.6mg

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• To evaluate the efficacy and safety of 3.0 mg of liraglutide, injected
subcutaneously once daily, as an adjunct to a reduced-calorie diet
and increased physical activity
• For weight management in overweight or obese adults who did not
have diabetes at baseline.
The main objective of the study

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BACKGROUN
D
P: patient
Overweight (+Comorbidities)/obese patient
I : intervention
Liraglutide (+diet & exercise)
C : Comparison
Placebo (+diet & exercise)
O : outcome
Weight loss

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Double blind
Methodology

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➢ Study Area:
• At 191 sites in 27 countries in Europe, North America, South America,
Asia, Africa, and Australia.
➢ Study Time
• The study was conducted from June 1, 2011, through March 18, 2013.
Methodology

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3731 patients
2487
Lifestyle intervention
+
liraglutide
1244
lifestyle intervention
+
placebo
Over 56 weeks follow up
Randomizatio
n in 2:1 ratio
Liraglutide, SC
Starting dose; 0.6mg.
weekly 0.6 mg increments
to 3.0 mg.
Inclusion criteria:
• Age ≥ 18 years.
• BMI ≥ 30
OR
• BMI ≥ 27 if the patient
had treated or untreated
dyslipidemia or
hypertension.
Exclusion criteria:
• Type 1 or 2 diabetes
• Medications that cause clinically
significant Weight gain or loss.
• Previous bariatric Surgery
• History of pancreatitis
• History of major depressive or
other severe psychiatric
disorders
• Family or personal history of
multiple endocrine neoplasia
type 2 or familial medullary
thyroid carcinoma.
Methodology (Patient +intervention)

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Methodology

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The prespecified coprimary end points, assessed at week 56 were:
1. Proportion of patients who lost at least 5% of their baseline body
weight.
2. Proportion of patients who lost more than 10% of their baseline
body weight.
Result

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Result

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Absolute Benefit Increase (ABI) Number Needed to Treat (NNT)
Loss of ≥5% body weight (%) 36.2 % 3
Loss of >10% body weight (%) 22.5% 5
Result

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Common Adverse Events Liraglutide Placebo Absolute Risk Increase
(ARI)
Nausea 40.2% 14.7% 25.5%
Diarrhea 20.9% 9.3% 11.6%
Constipation 20% 8.7% 11.3%
Vomiting 16.3% 4.1% 12.2%
Side effects

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RESULTS

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Serious Adverse Events Liraglutide Placebo Absolute Risk
Increase (ARI)
Cholelithiasis 0.8% 0.4% 0.4%
Cholecystitis acute 0.5% 0 0.5%
Osteoarthritis 0.2% 0 0.2%
Pancreatitis acute 0.2% 0 0.2%
Side effects

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• There were no cases of medullary thyroid carcinoma or C-cell
hyperplasia, and liraglutide treatment did not increase serum
calcitonin concentrations.
THYROID CARCINOMA/C-
CELL HYPERPLASIA ??

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ARI = 9%
WHAT ABOUT HYPOGLYCEMIA?

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Validity Result Applicability
Critical appraisal

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Validity
1- Randomization and concealment ?
• Randomization was performed with the use of a telephone or Web-based system
provided by the sponsor
• Patients, investigators, and the sponsor were unaware of the study-group
assignments
2- Were both groups similar?
• The baseline characteristics were similar in the two groups
3-Blindness?
Double-blind trial

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Validity
4- The 3 C’s
o intervention
Both groups received
counseling on lifestyle
modification
ontamination
non
ompliance
Equal

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Validity
5- Were all patients who entered the trial accounted for?
And were they analyzed in the groups to which they were randomized ?
(intention-to-treat analysis and follow up)
Patients who withdrew early were asked to return at week 56 for measurement of
their weight and recording of adverse events.

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Validity
6- Acceptable drop out percentage? (Complete enough)
<20% to maintain the power of the study

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Liraglutide group
(2487)
1789
(71.9%)
Drop out= 28.1%
DROP OUT

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DROP OUT
Placebo group
(1244)
801
(64.4%)
Drop out= 35.6%

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Drop out due to Liraglutide group (2487) Placebo group (1244)
Adverse events 246 (9.9%) 47 (3.8%)
Ineffective therapy 23 (0.9%) 36 (2.9%)
Consent withdrawal 264 (10.6%) 249 (20.0%)
DROP OUT

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Drop out in RCT results in what type of bias ?
• Attrition Bias: is a systematic error caused by unequal loss of
participants from a randomized controlled trial
How to avoid this bias?
• Intention to treat analysis.
DROP OUT

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Absolute Benefit
Increase (ABI)
Number
Needed to Treat
(NNT)
Loss of ≥5%
body weight (%)
36.2 % 3
Loss of >10%
body weight (%)
22.5% 5
Result
1. How large was the treatment effect?
Control Event rate (CER)
Experimental event rate (EER)
Absolute risk reduction (ARR)
Number needed to treat (NNT)

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Result
2. How precise was the estimate of the treatment effect?
A total of 63.2% of the patients in the liraglutide group as compared with
27.1% in the placebo group lost at least 5% of their body weight (P<0.001),
and
33.1% and 10.6%, respectively, lost more than 10% of their body weight
(P<0.001)
 95% confidence interval

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Applicability(IPPP)
I : Intervention
Can you do the intervention as described in the paper ?
P: Population
Is your patient similar to the population in the study?
P: Preferences
Did you examine your patient’s Preferences ?
P: Potential benefits-harm
Are the Potential benefits overweighing the harm ?

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Availability and cost

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Serious allergic reaction
Allergies
Possible thyroid tumors,
including cancer
Tumor
kidney problems (kidney
failure)
Increased heart rate
kidney
Heart
Possible
SIDE
EFFECTS
SAXENDA SIDE EFFECTS
depression or thoughts of
suicide
Psychiatry

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Personal or family history of
Medullary thyroid cancer (MTC),
or Multiple Endocrine Neoplasia
syndrome type 2 (MEN-2).
Prior serious hypersensitivity
reaction to Saxenda or to any of
the product components.
SAXENDA CONTRAINDICATIONS

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Pregnant / planning for
pregnancy
Breastfeeding
SAXENDA CONTRAINDICATIONS

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Pancreatitis
Age <18 years
SAXENDA CONTRAINDICATIONS

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Gastroparesis
Pancreas, kidneys or liver
problems.
SAXENDA (TAKE A CAUTION)

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Other GLP-1 receptor
agonists
Victoza
(liraglutide 1.2/1.8mg)
Insulin
SAXENDA

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3.0 mg of once-daily SC
liraglutide, as an adjunct to diet
and exercise, was associated
with:
clinically meaningful weight loss in
overweight or obese patients,
Reductions in glycemic variables
Conclusion

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Thank you !