Commentaries by Xavier Pi-Sunyer MD, Craig Primack MD, and Amy Articolo DO, FACOOG
Liraglutide 3.0 mg once daily as an adjunct to a reduced-calorie meal plan and physical activity was associated with clinically meaningful and sustained weight loss in a 56-week, randomized, double-blind trial involving more than 3,700 patients who were overweight or obese.
“Liraglutide is an effective weight loss agent that may help individuals lose weight and maintain the loss over time,” said lead author Xavier Pi-Sunyer, MD, Professor of Medicine, Columbia University College of Physicians and Surgeons, New York, NY. This agent “adds a very effective drug with a unique mechanism of action to the armamentarium” for the treatment of obesity, Dr. Pi-Sunyer said.
The study, known as the SCALE trial, was 1 of 3 trials that led to the approval of liraglutide (Saxenda) as an adjunct to a meal plan and physical activity for chronic weight management. The medication was initially approved to improve glycemic control in adults with type 2 diabetes mellitus when combined with a meal plan and physical activity.
The study included 3,731 patients with a body mass index of ≥30 or >27 with treated or untreated dyslipidemia or hypertension. None of the patients had diabetes at baseline.
The liraglutide group showed significantly greater reductions in body weight and greater proportions of patients lowing ≥5% and >10% of their initial body weight (Table).
“When studying the drug in an intent-to-treat, last-observation-carried-forward model, the difference in the treated group vs. untreated group was 5.6 kg (12.3 lb),” commented Craig Primack, MD, Obesity Medicine Certified Physician, Scottsdale Weight Loss Center, Scottsdale, AZ, and Secretary/Treasurer of the American Society of Bariatric Physicians (ASBP). “Patients taking liraglutide lost 5% of their weight 63.2% of the time (2 of 3 patients) and lost 10% of their weight 33.1% of the time (1 of 3 patients). We have to remember that, on their own, patients tend to slowly gain weight year after year and in this controlled study, only 27.1% of the placebo group achieved ≥5% loss and 10.6% achieved >10% loss,” Dr. Primack said.
“We also know that health benefits for weight loss start at 5% weight loss, get pretty significant at 10% weight loss, and are at their maximum at about 15% weight loss, especially when looking at metabolic health (cholesterol, blood pressure and blood sugar/diabetes),” Dr. Primack said.
“This trial also documented that the development of diabetes over the 56 weeks of the trial was much lower in the liraglutide group than in the placebo group,” Dr. Pi-Sunyer said. Patients in the liraglutide groups show significantly improved glycemic control variables (glycated hemoglobin, fasting glucose level, and fasting insulin level) compared with the placebo group (P<0.001 for all variables).
In addition, liraglutide was linked to significant reductions in cardiometabolic risk factors, including waist circumference, blood pressure, and inflammatory markers.
Side Effects Were Primarily Gastrointestinal
The most frequently reported adverse events in the liraglutide groups were gastrointestinal and included nausea (40.2%), diarrhea (20.9%), constipation (20.0%), and vomiting (16.3%). Most of these side effects were mild or moderate in severity. Nausea and vomiting occurred primarily in the first 4 to 8 weeks of treatment.
The liraglutide group had a higher incidence of serious adverse effects compared to the placebo group (6.2% vs 5.0%), including cholelithiasis (0.8% vs 0.4%), acute cholecystitis (0.5% vs 0%), osteoarthritis (0.2 vs. 0%), and acute pancreatitis (0.2% vs 0%).
“The GI side effects do not play a role in the reduced body weight of patients treated with liraglutide,” Dr. Pi-Sunyer said. “The main side effect of the drug is nausea in some persons. The nausea generally improves if one keeps taking the drug for a time, so persistence is important. Also, people with a previous history of pancreatitis should not take this drug,” Dr. Pi-Sunyer added.
“No drug is without side effects, and the increase risk of gallbladder-related events is not surprising,” said Dr. Primack. “My clinical experience with liraglutide 3.0 mg is limited as [this agent was only approved] late this spring, but many patients’ appetites seems so well controlled that we have to remind them to eat regularly. We know gallbladder events increase with infrequent eating and inactive gallbladder function from an extremely low-fat diet," Dr. Primack said.
These findings were based on intent-to-treat data sets and, thus, are not completely representative of clinical medicine, Dr. Primack said. “Completer data, not included here, would show the increased weight loss seen with diet and exercise when compared to the intent-to-treat data,” Dr. Primack added.
Liraglutide Adds to the Clinical Armamentarium for Weight Management
“This is another good tool in the toolbox of obesity treatment for medical providers in North America (approved in the United States and Canada),” commented Dr. Primack. “Liraglutide takes a medication that at lower doses, many providers have been comfortable using for another disease state, diabetes, and translating that comfort with the drug to the treatment of another disease, obesity,” Dr. Primack stated.
“Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist with a 97% homology to our bodies’ native GLP-1,” explained Amy Articolo, DO, FACOOG, Diplomat of the American Board of Obesity Medicine and Secretary/Treasurer of the Obesity Treatment Foundation, a subsidiary of the ASBP. “When used daily as a subcutaneous injection, liraglutide results in uptake in specific brain regions that regulate appetite (the hypothalamus), resulting in satiety. This overall feeling results in less food intake, and less hunger. Individuals can achieve their goals in weight loss, without ‘losing out’ to the battle of hunger,” said Dr. Articolo, who also is Co-Director of WeighUnder in Voorhees, NJ.
“Obesity is a chronic and multifactorial disease with many different causes,” Dr. Articolo continued. “The science behind appetite regulation or, in reality, appetite dysregulation shows how the brain receives multiple and sometimes confusing signals from the body. We understand that for some people, GLP-1 (in addition to other gut hormones) may be disproportionate to other hormones that keep appetite in balance. This is why liraglutide 3.0 mg daily is an effective treatment tool in conjunction with diet and exercise. It gives the body what it needs.” Dr. Articolo said.
Disclosures: The SCALE trial was funded by Novo Nordisk, and both Dr. Primack and Dr. Articolo are on the speakers’ bureau for Novo Nordisk.
September 2, 2015
Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373(1):11-22.