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Pi-Sunyer X, et al. "A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management". New England Journal of Medicine. 2015. 373(1):11-22.
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Clinical Question

In obese patients, does a glucagon like peptide-1 analogue, such as Liraglutide, have a potential benefit for weight loss as a once daily 3.0mg subcutaneous injection, compared to lifestyle intervention alone?

Bottom Line

In patients given the 3.0mg subcutaneous injection of Liraglutide as an adjunct to lifestyle intervention, their body weight was significantly reduced as compared to the placebo patient population.

Major Points

Liraglutide is a drug that can be used for weight loss and weight management. This drug can also be used as an antidiabetic agent. Liraglutide is given at higher doses when it is used for weight loss. This drug should only be used for a select group of patients that meet a certain criteria. Obesity can lead to other health problems in the future such as hypertension, nonalcoholic fatty liver disease, joint pain, sleep apnea, asthma, etc. These diseases can be life threatening, and can affect the quality of someone’s life.

Patients were given Liraglutide at increasing doses until the patient reached a maximum dose of 3.0mg. The patients were started at 0.6mg and each week it increased by 0.6mg. The study was 56 weeks long and 3,731 patients were involved in a double blinded trial. These patients did not have type 2 diabetes, and they had a BMI over 30 or a BMI of at least 27 with treated or untreated dyslipidemia or hypertension.

The major criticism is that Novo Nordisk funded this project and it benefits them personally as a company. There was no guidelines provided in the article. They stated what they gave each patient, but they did not cite where they got this information from.

Guidelines

Saxenda Dosing Guideline (September 2016)

Inject Liraglutide once daily at any time throughout the day. The starting dose is 0.6 mg per day for 1 week. Each week the dose will increase by 0.6mg. By the fifth week the patient will be at the 3mg dose.

  • Inject medication into abdomen, thigh, or upper arm.
  • Nausea is a common side effect, especially seen when tapering up on the medication
  • Other side effects include diarrhea, constipation, headache, vomiting, low blood sugar, tiredness, dizziness, stomach pain, and changes in enzyme.

Design

  • Randomized, double-blind, placebo-controlled trial
  • N=3731
    • Liraglutide at a dose of 3.0mg with lifestyle modifications (n= 2487)
    • Lifestyle modification alone (n=1244)
  • Setting: 191 sites in 27 countries in Europe, North America, South America, Africa, Asia, and Australia
  • Enrollment: June 1st, 2011 until March 18th, 2013
  • Mean follow-up: 1.5 years with a 2 year extension
  • Analysis: intention-to-treat
  • Primary outcome: change in body weight and the proportions of patients losing at least 5% and more than 10% of their initial body weight over 56 weeks.

Population

Inclusion Criteria

  • Patients 18 years or older
  • Stable Body Weight
  • BMI of 30 or higher
  • BMI 27 or higher if the patient had treated or untreated dyslipidemia or hypertension

Exclusion Criteria

  • Type 1 Diabetes
  • Type 2 Diabetes
  • The use of medication 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

Baseline Characteristics

  • Population
    • Liraglutide group: 2487
    • Placebo group: 971
  • Age
    • Liraglutide group: 45.2 ±12.1
    • Placebo group: 45.0±12.0
  • Weight (kg)
    • Liraglutide group: 106.2±21.2
    • Placebo group: 106.2±21.7
  • Body mass index
    • Liraglutide group: 38.3±6.4
    • Placebo group: 38.3±6.3

Interventions

  • Patients were randomly assigned in a 2:1 ratio, to receive once-daily subcutaneous injections of Liraglutide: starting at a dose of 0.6 mg weekly, increasing by 0.6-mg increments to 3.0 mg, and indicates the groups were blinded. The two groups being blinded were the placebo group and the group that received Liraglutide. Those who did not receive the medication were given the placebo throughout the dosing increase.
  • Patients were classified according to prediabetes status and BMI (≥30 vs. <30)
  • At 56 weeks, patients in the Liraglutide group who did not have prediabetes were randomly assigned in a 1:1 ratio to continue receiving Liraglutide or to switch to placebo for 12 weeks.
  • Patients were evaluated every 2 weeks until week 8 and every 4 weeks up until week 44. Then they were evaluated on weeks 50, 56, 58, 60, 64, 68, and 70.
  • Patients who dropped out of the trial were followed up with on week 56 for record of weight and side effects.

Primary Outcomes

Percent change in body weight (%) after 56 weeks

-8.0 ± 6.7% v. -2.6 ± 5.7% (95% CI -5.4 (-5.8 to -5.0); P value= <0.001; NNT=19)

Weight loss (more than 5% of their body weight) after 56 weeks

63.2% v. 27.1% (95% CI 4.8 (4.1 to 5.6); P value= <0.001; NNT=3)

Weight loss (more than 10% of their body weight) after 56 weeks

33.1% v. 10.6% (95% CI 4.3 (3.5 to 5.3); P value= <0.001; NNT=5)

Secondary Outcomes

Body mass index percent reduction after 56 weeks

-3.0 ± 2.6% v. -1.0 ± 2.3% (95% CI -2.0 (-2.2 to -1.9); P value= <0.001; NNT= 50)

Waist circumference (cm) after 56 weeks

-8.2 ± 7.3 v. -3.9 ± 6.6 (95% CI -4.2 (-4.7 to -3.7); P value= <0.001; NNT= 24)

LDL levels (%) after 56 weeks

-3.0% v. -1.0% (95% CI -2.4 (-4.0 to -0.9); P value= 0.002; NNT= 50)

HDL levels (%) after 56 weeks

2.3% v. 0.7% (95% Cl 1.9 (0.7 to 3.0); P value= 0.001; NNT= 63)

VLDL levels (%) after 56 weeks

-13.1% v. -5.5% (95% CI -9.1 (-11.4 to -6.8); P value= <0.001; NNT= 14)

Non-HDL levels (%) after 56 weeks

-5.1% v. -1.8% (95% CI -3.9 (-5.2 to -2.5); P value= <0.001; NNT= 31)

Triglyceride levels (%) after 56 weeks

-13.3% v. -5.5% (95% CI -9.3 (-11.5 to -7.0); P value= <0.001; NNT= 13)

Free fatty acid levels (%) after 56 weeks

1.7% v. 3.5% (95% CI -4.2 (-7.3 to -0.9); P value= 0.01; NNT= 56)

Systolic blood pressure (mm Hg) after 56 weeks

-4.2 ± 12.2 v. -1.5 ± 12.4 (95% CI -2.8 (-3.56 to -2.09); P value= <0.001; NNT= 37)

Diastolic blood pressure (mm Hg) after 56 weeks

-2.6 ± 8.7 v. -1.9 ± 8.7 (95% CI -0.9 (-1.41 to -0.37); P value= <0.001; NNT= 143)

Pulse (beats/min) after 56 weeks

2.5 ± 9.8 v. 0.1 ± 9.5 (95% CI 2.4 (1.9 to 3.0); P value= <0.001; NNT= 42)

Glycated hemoglobin (%) after 56 weeks

-0.30 ± 0.28% v. -0.06 ± 0.30% (95% CI -0.23 (-0.25 to -0.21); P value= <0.001; NNT= 417)

Fasting glucose (mg/dL) after 56 weeks

-7.1 ± 10.8% v. 0.1 ± 10.4% (95% CI -6.9 (-7.5 to -6.3); P value= <0.001; NNT= 15)

Fasting insulin (%) after 56 weeks

-12.6% v. -4.4% (95% CI -8 (-12 to -5); P value= <0.001; NNT= 13)

Fasting C-peptide (%) after 56 weeks

-8.9% v. -7.9% (95% CI -1 (-3 to 2); P value= 0.51)

Subgroup Analysis

Across all subgroups (age, race, gender, body weight and vitals), the data consistently showed favor to Liraglutide as compared to the placebo. The subgroup analysis was comparison of normal glucose patients v. pre-diabetics. There was a lower number of pre-diabetics found in the Liraglutide group as compared to the placebo group after 56 weeks. The percent of pre-diabetics found in the Liraglutide group after 56 weeks was 30.8% and the percent of pre-diabetics found in the placebo group after 56 weeks was 67.3% at the screening. The analysis showed an odds ratio of 4.9 (95% CI, 4.0 to 5.9) and a P value of <0.001, the NNT= 3 for patients with pre diabetics at 56 weeks.

Adverse Events

Comparisons are % of patients on Liraglutide vs. % of patients on placebo.

  • Adverse events that occured in ≥5% of patients (80.3% vs. 63.3%)
    • Nausea (40.2% v. 14.7%)
    • Diarrhea (20.9% v. 9.3%)
    • Constipation (20.0% v. 8.7%)
    • Vomiting (16.3% v. 4.1%)
    • Dyspepsia (9.5% v. 3.1%)
    • Upper Abdominal Pain (5.7% v. 3.5%)
    • Nasopharyngitis (17.2% v. 18.8%)
    • Upper Respiratory Tract Infection (8.6% v. 9.8%)
    • Sinusitis (5.2% v. 5.9%)
    • Influenza (5.8% v. 5.3%)
    • Headache (13.2% v. 12.4%)
    • Dizziness (6.7% v. 4.8%)
    • Decrease Appetite (10.8% v. 3.1%)
    • Back Pain (6.9% v. 8.5%)
    • Arthralgia (5.0% v. 5.7%)
    • Fatigue (7.5% v. 5.2%)
    • Injection-site hematoma (5.7% v. 7.5%)
  • Serious adverse events in ≥0.2% of patients (6.2% v. 5.0%)
    • Cholelithiasis (0.8% v. 0.4%)
    • Cholecystitis acute (0.5% v. 0%)
    • Osteoarthritis (0.2% v. 0%)
    • Intervertebral disc protrusion (0.2% v. 0.1%)
    • Pancreatitis acute (0.2% v. 0%)
    • Cholecystitis (0.2% v. 0%)
    • Breast cancer (0.2% v. 0.1%)
    • Back pain (0.1% v. 0.2%)
    • Uterine leiomyoma (<0.1% v. 0.2%)
    • Cellulitis (<0.1% v. 0.2%)
    • Gastroesophageal reflux disease (0% v. 0.2%)
    • Bronchitis (0% v. 0.2%)
    • Bladder prolapse (0% v. 0.2%)
    • Chest pain (0% v. 0.2%)

Criticisms

1. Novo Nordisk, who sponsored and funded this trial, planned and performed the statically analyses, provided editorial and writing assistance, and provided the trial drugs. The company who would financially benefit from this product is one in the same as the sponsor and overall editor of the publication. Possible bias in favor of use of Liraglutide for weight loss could have played a role in the statistical analyses and writing of this publication.

2.Guidelines were not provided for the dosing of Liraglutide. It was stated that the patients injected 0.6 mg subcutaneously the first week, then the dose was increased 0.6 mg until the patient reached a dose maximum weekly dose of 3 mg.

3.There is no mention in the article of how diet and exercise adherence was monitored. Patients were primarily responsible for reporting their diet and exercise to providers. It is unknown if diet and exercise truly the same from patient-to-patient or if patients were fully adherent to diet and exercise protocols.

4.The randomization of 2:1 (Liraglutide:placebo) may have skewed results. With more patients using the medication for weight loss purposes, there is not a fair opportunity for the results from the placebo to weigh against the results from Liraglutide.

Funding

Funded by Novo Nordisk manufacturers of Liraglutide (Saxenda); SCALE Obesity and Prediabetes.

Further Reading

1. “Stay on Track With Saxenda.” Saxenda, 1 Dec. 2017, www.saxenda.com/how-to-use-saxenda/dosing-schedule.html.

2. “Medication Guide.” Saxenda, Sept. 2016, www.novo-pi.com/saxenda_med.pdf. should we also site the original article we used?

3. “Body Mass Index, Adult.” Lexicomp, 29 Jan. 2016, online.lexi.com/lco/action/doc/retrieve/docid/disandproc/5447568.

4. Pi-Sunyer, X, et al. “A Randomized, Controlled Trial of 3.0mg of Liraglutide in Weight Management”. The New England Journal of Medicine. 2015. 373(1): 11- 22.