Obesity is a disease that requires chronic management and is associated with serious comorbidities including type 2 diabetes, heart disease, obstructive sleep apnea (OSA), certain types of cancer and a decreased life expectancy. Risk of morbidity and mortality increases with the severity of obesity, which is a complex and multifactorial disease, the course of which is influenced by genetic, physiological, environmental and psychological factors.
A global increase in obesity prevalence is a public health issue that has severe cost implications to healthcare systems. In 2011-2012 in the U.S., approximately 35 percent of adults, or nearly 80 million persons, were living with obesity.
Danish biopharmaceutical firm Novo Nordisk’s Saxenda is a once-daily glucagon-like peptide-1 (GLP-1) analog with 97% similarity to naturally occurring human GLP-1, a hormone that is released in response to food intake. Like human GLP-1, Saxenda regulates appetite and lowers body weight through decreased food intake. As with other GLP-1 receptor agonists, liraglutide stimulates insulin secretion and reduces glucagon secretion in a glucose-dependent manner. These effects can lead to a reduction of blood glucose. Saxenda was evaluated in the SCALE (Satiety and Clinical Adiposity Liraglutide Evidence in Nondiabetic and Diabetic people) phase 3 clinical trial program, which involved more than 5,000 study participants who have obesity (BMI 30 kg/m2 ) or who are overweight (BMI 27 kg/m2 ) with comorbidities.
Saxenda was approved by the FDA on December 23, 2014, as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with obesity (BMI 30 kg/m2) or who are overweight (BMI 27 kg/m2) with at least one weight-related comorbidity. Saxenda also received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) on January 22, 2015.
SCALE Obesity and Pre-diabetes Clinical Trial
The SCALE Obesity and Pre-diabetes trial was a randomized, double-blind, placebo-controlled, multinational trial conducted in Africa, Asia, Europe and the United States in non-diabetic adults with obesity and non-diabetic adults who are overweight with comorbidities. There were 3,731 participants randomized to treatment with Saxenda (liraglutide [rDNA origin] injection) or placebo in combination with reduced-calorie diet and increased physical activity. In addition, participants were further stratified to 56 weeks or 160 weeks of treatment based on pre-diabetes status at baseline screening.
Objectives of this trial — the largest of the phase 3a trials in the SCALE clinical development program encompassing more than 5,000 adults with obesity or adults who are overweight with comorbidities — were to demonstrate clinically meaningful weight loss at 56 weeks, as well as to investigate the long-term potential efficacy of Saxenda to delay the onset of type 2 diabetes in participants with pre-diabetes at baseline screening.
A new Original Investigation paper entitled “Efficacy of Liraglutide for Weight Loss Among Patients With Type 2 Diabetes – The SCALE Diabetes Randomized Clinical Trial“ (JAMA. 2015;314(7):687-699. doi:10.1001/jama.2015.9676 ) has been published in The Journal of the American Medical Association (JAMA), coauthored by Melanie J. Davies, MD of the Diabetes Research Centre, University of Leicester, UK; Richard Bergenstal, MD of the International Diabetes Center, Park Nicollet Health Services, in Minneapolis, Minnesota; Bruce Bode, MD of the Atlanta Diabetes Associates, Atlanta, Georgia; Robert F. Kushner, MD of Northwestern University, Chicago, Illinois; Andrew Lewin, MD of the National Research Institute, Los Angeles, California; Trine Vang Skjth, Arne Haahr Andreasen, MSc, MD, and Christine Bjrn Jensen, MD, of Novo Nordisk A/S, Sborg, Denmark; and Ralph A. DeFronzo, MD of the Texas Diabetes Institute, San Antonio.
The paper’s objective was to investigate efficacy and safety of liraglutide vs placebo for weight management in adults with overweight or obesity and type 2 diabetes, and the coauthors note that while weight loss of five to 10 percent can improve type 2 diabetes and related comorbidities. few safe, effective weight-management drugs are currently available.
Effect of Liraglutide on Body Weight in Overweight or Obese Subjects With Type 2 Diabetes: SCALE – Diabetes was a fifty-six week randomized (2:1:1), double-blind, placebo-controlled, parallel-group trial with a 12-week observational off-drug follow-up period. The study was conducted at 126 sites in 9 countries between June 2011 and January 2013. Of 1361 participants assessed for eligibility, 846 were randomized. Inclusion criteria were body mass index of 27.0 or greater, age 18 years or older, taking 0 to 3 oral hypoglycemic agents (metformin, thiazolidinedione, sulfonylurea) with stable body weight, and glycated hemoglobin level 7.0% to 10.0%.
SCALE participants were administered once-daily, subcutaneous liraglutide (3.0 mg) (n=423), liraglutide (1.8 mg) (n=211), or placebo (n=212), all as adjunct to 500 kcal/d dietary deficit and increased physical activity (150 min/wk).
The trial’s three coprimary end points were: relative change in weight, proportion of participants losing five percent or more, or more than 10 percent, of baseline weight at week 56.
Weight loss of five percent or greater occurred in 54.3 percent of subjects with liraglutide (3.0 mg), in 40.4 percent with liraglutide (1.8 mg) vs 21.4 percent with a placebo. Weight loss greater than 10 percent occurred in 25.2 percent who received liraglutide (3.0 mg) and 15.9 percent with liraglutide (1.8 mg) vs 6.7 percent with placebo. More gastrointestinal disorders were reported with liraglutide (3.0 mg) vs liraglutide (1.8 mg) and placebo. No pancreatitis was reported.
Data from the SCALE Obesity and Pre-diabetes trial presented at The Endocrine Society’s 97th Annual Meeting (ENDO) earlier this year noted that the 63.2 percent of adult participants with obesity or who are overweight with comorbidities, and who had achieved a clinically meaningful body weight reduction of at least five percent of their body weight at 56 weeks (i.e., weight loss responders), demonstrated greater improvements across a range of efficacy outcomes with the drug candidate Saxenda (liraglutide [rDNA origin] injection) treatment in combination with a reduced-calorie diet and increased physical activity, compared with participants who had weight loss of less than five percent (i.e., non-responders).
In addition to weight loss, improvements across a number of secondary endpoints were also observed in the responder population (Saxenda and placebo). A greater improvement was seen in fasting plasma glucose (FPG) in Saxenda responders compared with placebo responders. In addition, treatment with Saxenda was associated with a greater reduction in systolic blood pressure (SBP) compared with placebo in both responders and non-responders. Improvements in physical health scores (as measured by the SF-36 questionnaire) were seen with Saxenda and placebo responders compared with non-responders.
“These are important findings as they show that for adults with obesity or who are overweight with comorbidities, losing 5% to 10% of their body weight can help improve comorbidities, including fasting plasma glucose and blood pressure,” says Dr. Patrick O’Neil, Professor of Psychiatry and Behavioral Sciences at the Medical University of South Carolina and SCALE clinical trial investigator. “Those who responded, losing five percent or more of their body weight, not only saw improvements in cardiometabolic risk factors but also in quality of life outcomes, compared with those who did not respond, for both liraglutide and placebo treatment.”
Across the SCALE clinical development program, Saxenda (liraglutide [rDNA origin] injection) was generally well tolerated. The most common side effects observed were related to the gastrointestinal system. In the SCALE Obesity and Pre-diabetes trial, rates of adverse events were similar in both responders and non-responders. The number of adverse events leading to trial withdrawal was lower in responders compared with non-responders. The most common adverse reactions to Saxenda, reporting in five percent or greater include: nausea, hypoglycemia, diarrhea, constipation, vomiting, headache, decreased appetite, dyspepsia, fatigue, dizziness, abdominal pain, and increased lipase.
The investigators conclude that among overweight and obese participants with type 2 diabetes, use of subcutaneous liraglutide (3.0 mg) daily, compared with placebo, resulted in weight loss over 56 weeks, but further studies are needed to evaluate longer-term efficacy and safety.
The Journal of the American Medical Association
Novo Nordisk A/S
Medical University of South Carolina