This column is dedicated to providing information on the medical management of obesity, which includes diet, exercise, behavioral change, and medication.
Craig Primack, MD, FACP, FAAP, Medical Bariatrician/Certified Medical Obesity Specialist/Co-Medical Director, Scottsdale Weight Loss Center PLLC, Scottsdale, Arizona
Wendy Scinta, MD, MS, FAAFP, Medical Director, Medical Weight Loss of NY, BOUNCE Program for Childhood Obesity, Fayetteville, New York; Clinical Assistant Professor of Family Medicine, Upstate Medical University, Syracuse, New York
This month: Saxenda as a Treatment Option for Chronic Weight Management—A Review
by Wendy Scinta, MD, MS, FAAFP
Obesity is a public health problem wordlwide. Until recently, physicians had limited options for treating obesity with pharmacotherapy. Since 2012, four drugs have been approved by the United States Food and Drug Administration for weight loss or weight maintenance. This column provides a brief overview of the most recent therapy—Saxenda (liraglutide [rDNA origin] injection).
Bariatric Times. 2016;13(6):28–30.
Obesity has been declared a public health problem as well as a global epidemic. Currently, two-thirds of the United States adult population has overweight or obesity and one-third of our children has overweight or obesity.[1,2] The physical toll of obesity has led to the prediction that this generation of Americans will not live as long as their parents for the first time since immunizations were introduced. Currently, 1 in 5 American deaths are now associated with obesity, a rate that is three times higher than previously estimated.
Successful nonsurgical treatment of obesity involves a multidisciplinary approach that includes nutrition, behavioral modification, exercise, and medical management. A significant component of the obesity medicine specialist’s arsenal of medical management tools is pharmacotherapy. Once an area of minimal options, pharmacotherapy has exploded in the last three years, with the latest addition coming from Novo Nordisc. In December 2014, the United States Food and Drug Administration (FDA) approved Saxenda® (liraglutide [rDNA origin] injection [Novo Nordisk, Plainsboro, New Jersey), for subcutaneous use, as a
treatment for chronic weight management in addition to a reduced-calorie diet and physical activity. Saxenda is one of four drugs approved by the FDA for weight loss or maintenance in the past four years. In 2012 and 2013, the FDA approved lorcaserin (Belviq, Eisai Inc., Woodcliff Lake, New Jersey) and phentermine/extended-release topiramate (Qysmia, Vivus, Inc., Mountain View, California). In 2014, Contrave® (Takeda Pharmaceuticals America, Inc., Deerfield, Illinois) was also approved. Contrave is an extended-release formulation of naltrexone HCL, an opioid antagonist, and bupropion HCL, an inhibitor of the reuptake of dopamine and norepinephrine.
This month’s column provides a brief overview of Saxenda (liraglutide [rDNA origin] injection).
Background and Indications
Saxenda is approved for use in adults with a body mass index (BMI) of 30kg/m2 or more or BMI of 27kg/m2 or more who have at least one weight-related condition, such as hypertension, type 2 diabetes mellitus (T2DM), or high cholesterol (dyslipidemia). It contains the same active ingredient (liraglutide) as Victoza, a drug also manufactured by Novo Nordisk and approved for the treatment of adult T2DM. After Victoza was approved, researchers discovered that many patients experienced weight maintenance and even weight loss as a side effect. Saxenda contains a higher dose of liraglutide than Victoza (3mg verses 1.8mg).
Manufacturer literature states that Saxenda is not for the treatment of T2DM and should not be used with Victoza or any other GLP-1 receptor agonist or insulin.
Mechanism of Action
Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist. GLP-1 is a neuropeptide and an incretin secreted by the intestinal L cells and the brain stem (nucleus tractus solitarus). GLP-1 receptors are found in the stomach, pancreas, and intestine as well as in the central nervous system (CNS), including the hypothalamus and the brain stem. GLP-1 has a multitude of functions depending on its location. GLP-1 stimulates the release of insulin from the pancreas. It also increases the volume of beta cells and regulates and controls the release of glucagon. It works on appetite signals in the brain, slowing the gastric emptying process and increasing an individual’s feeling of fullness during and between the meals.
Studies have examined the effectiveness of liraglitude at various doses for weight loss in patients with overweight or obesity. The most notable programs are the Liraglutide Effect and Action in Diabetes (LEAD) and the Satiety and Clinical Adiposity, Liraglutide Evidence (SCALE). Both programs included randomized, double-blind, placebo-controlled trials funded by Novo Nordisk.
LEAD Program. Liraglutide was assessed in the LEAD program, a 26-week, phase III clinical trial series.[9–14]
The LEAD program included various arms to study the efficacy and safety of liraglitude used alone and in combination with commonly used oral antidiabetic drugs (e.g., sulfonylurea, metformin) versus placebo. Though the series was not intended to study weight loss, the LEAD trials concluded that liraglutide was associated with weight reduction (3%), and, in most instances, the reduction from baseline was significantly greater than that seen with comparators. LEAD investigators also found that liraglutide was generally well tolerated, and nausea was the most frequent adverse event reported.
DURATION-6. The DURATION-6 trial also lasted 26 weeks and compared 1.8mg liraglutide daily with the anti-diabetic agent sustained-release exenatide (SR exenatide) 2mg once weekly in patients with T2DM inadequately controlled on oral hypoglycemic agents. They found that weight loss, which was a secondary endpoint, was significantly greater in the liraglutide arm (-3.57kg with liraglutide versus -2.68kg SR exenatide, p = 0.0005).
SCALE Series. The SCALE series evaluated the weight loss efficacy of liraglutide as an adjunct therapy to diet and physical activity in patients with obesity.
SCALE Diabetes. Davies et al reported the results of SCALE Diabetes, a 56-week randomized, double-blind, placebo-controlled, parallel-group trial with 12-week observational off-drug follow-up period. The study was conducted at 126 sites in nine countries between June 2011 and January 2013. Participants (N=846; mean BMI 37kg/m2) were randomized to one of three groups: 1) once-daily, subcutaneous liraglutide 3.0mg (n=423), liraglutide 1.8mg (n=211), or placebo (n=212).
About half of individuals on 3.0mg liraglutide lost five percent or more of their body their weight at the end of the trial, compared to 35.6 percent in the liraglitude 1.8mg group and 13.8 percent on placebo. Similarly, weight loss greater than 10 percent occurred in more participants who received liraglitude: 23.4, 14.4, and 4.3 percent of individuals in the liraglitude 3.0mg, 1.8mg, and placebo groups, respectively.
SCALE Obesity and Prediabetes. The SCALE Obesity and Prediabetes trial included more than four times the amount of participants of the SCALE Diabetes Trial. Like SCALE Diabetes, this was a 56-week randomized, double-blind, placebo-controlled trial. Pi-Sunyer et al studied a total of 3,731 patients without T2DM that fell into the following BMI catergories: 1) BMI of 30kg/m2 or more or 2) BMI of 27kg/m2 or more and treated or untreated dyslipidemia or hypertension. Study participants received either once-daily subcutaneous injections of liraglutide 3.0mg (n=2,487) or placebo (n=1,244 patients).
More than half of the patients in the liraglutide group (63.2%) lost at least five percent of their body weight and 33.1 percent lost more than 10 percent of their body weight compared to 27.1 and 10.6 percent, respectively for placebo.
SCALE Maintenance. The SCALE Maintenance randomized study sought to assess the efficacy of liraglutide in maintaining weight loss achieved with a low-calorie diet (LCD).
The researchers randomly assigned 422 participants (≥18 years, BMI ≥30kg/m2 or ≥27kg/m2 with comorbidities) who lost ≥5 percent of initial weight during a LCD run-in to receive either liraglutide 3.0mg per day or placebo (subcutaneous administration) for 56 weeks.
They found that 81.4 percent of participants receiving liraglutide maintained the five percent or more run-in weight loss, compared with 48.9 percent of those receiving placebo. Additionally, about half of the participants in the liraglutide group went on to lose more weight. The SCALE Maintenance trial concluded that liraglutide, with diet and exercise, maintained weight loss achieved by an LCD and induced further weight loss over 56 weeks.
SCALE Sleep Apnea. In another study of liraglutide 3.0mg compared to placebo, Blackman et al investigated whether liraglutide was efficacious in producing weight loss and thus reducing severity of obstructive sleep apnea (OSA) in patients after 32 weeks.
A total of 359 patients with obesity and either moderate or severe OSA who were not using continuous positive airway pressure (CPAP) were randomized to receive liraglutide 3.0mg (n=180) or placebo (n=179) as adjunct to diet and exercise.
The researchers found that the mean reduction in apnea-hypopnea index (AHI) was greater with liraglutide than with placebo (P=0.0150), thus confirming that weight loss improves OSA-related parameters. They also found that liraglutide produced greater mean percentage weight loss compared with placebo (P<0.0001).
Research conducted outside of the LEAD and SCALE programs show similar weight loss efficacy results. Astrup et al[20,21] evaluated short-term weight loss and safety/tolerability with liraglutide in a randomized, double-blind, placebo-controlled 20-week trial among individuals with obesity (body-mass index 30–40kg/m2) without T2DM. The trial ran from January 2007 to April 2009. They compared liraglitude with orlistat in 19 sites in Europe among 564 individuals (18–65 years of age) that were randomly assigned to one of four liraglutide doses (1.2mg, 1.8mg, 2.4mg, or 3.0mg, n=90–95) or to placebo (n=98) administered once a day subcutaneously, or orlistat (120mg, n=95) three times a day orally.
They found that participants on liraglutide lost significantly more weight than did those on placebo. Mean weight loss with liraglutide 1.2mg, 1.8mg, 2.4mg, and 3.0mg was 4.8kg, 5.5kg, 6.3kg, and 7.2kg, respectively. Mean weight loss was 2.8kg with placebo and 4.1kg with orlistat. Nausea and vomiting occurred more often in individuals on liraglutide than in those on placebo, but adverse events rarely led to discontinuation of treatment. They concluded that liraglutide is well tolerated and sustains weight loss over two years.
The most common side effects observed across all clinical trials were nausea, diarrhea, constipation, vomiting, hypoglycemia, and decreased appetite. These GI side effects can be decreased dramatically by slowing down the titration.
Dosing, side effects, and Contraindications
The recommended dose of Saxenda is 3mg subcutaneously once daily, injected into the abdomen, thigh, or upper arm. Prescribing information provides a dose escalation chart recommending 0.6mg daily during Week 1 of treatment and increasing weekly by 0.6mg until the maintenance dose is achieved at approximately Week 5. Patients may also consider delaying dose escalation for approximately one additional week if they find they cannot tolerate an increased dose during the escalation period. Further, if a patient cannot tolerate the 3mg dose, treatment should be discontinued, as efficacy has not been established at the lower doses.
According to prescribing information, physicians should evaluate patients after 16 weeks on Saxenda. If the patient has not lost at least four percent of his or her baseline body weight, he or she should discontinue using the drug since it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.
Saxenda is contraindicated in patients with a personal or family history of MTC (medullary thyroid carcinoma) and in patients with MEN II (multiple endocrine neoplasia syndrome type 2). The boxed warning states the following: Liraglutide causes dose-dependent and treatment duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of race and mice. It is unknown whether Saxenda causes thyroid C- cell tumors including medullary thyroid carcinoma (MTC) in humans, as human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined. Saxenda is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the risk of MTC with the use of Saxenda and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with Saxenda.
Other contraindications include hypersensitivity to liraglutide or any product components and pregnancy.
Additional warnings, such as usage in patients with pancreatitis, gallbladder disease, and renal impairment, and precautions are detailed in the prescribing information and REMS (Risk Evaluation and Mitigation Strategy) at http://www.saxendarems.com/ Physicians should review these prior to prescribing Saxenda.
Coverage and Patient/Clinician Assistance Programs
Insurance coverage of the drug varies and is dependent on the patient’s individual plan. Novo Nordisk offers a savings card for patients with and without prescription drug coverage (https://www.saxenda.com/savings.html). Additionally, clinicians may request patient sample kits that include material needed for a 17-day supply of the drug, a patient savings card, and information on patient programs offered by the company (https://www.saxendapro.com/practice-resources/for-your-patients/saxendacare.html).
Saxenda has been shown to be safe, effective, and well tolerated by patients. Studies indicate that Saxenda is effective as a weight loss and weight management treatment option when combined with a reduced-calorie diet and physical activity. A significant percentage of patients in the LEAD and SCALE programs experienced losses of at least five-percent of their initial weight. Many patients achieved more than 10 percent weight loss. Findings across all trials were consistent in concluding that patients who received liraglutide in any dosing experienced more weight loss than those who received placebo.
Additionally, research has shown that liraglutide can help patients maintain weight loss. The SCALE Maintenance trial reported 81.4 percent of participants receiving liraglutide maintained weight loss and about half of them experienced even more weight loss during 56 weeks.
Clinicians should consider Saxenda as one of many available treatment options for patients with a BMI of 30kg/m2 or more or BMI of 27kg/m2 or more who have at least one weight-related condition.
FUNDING: No funding was provided for this article.
FINANCIAL DISCLOSURES: Dr. Scinta is a speaker for Belviq (Eisai Inc., Woodcliff Lake, New Jersey), Contrave (Takeda Pharmaceuticals U.S.A., Inc., Deerfield, Illinois), and Saxenda (Novo Nordisk, Plainsboro, New Jersey).