Liraglutide associated with sustained weight loss in patients with obesity
Obesity is a chronic disease with treatments available aside from lifestyle modification. At an interview with MIMS Doctor, Dr Francis CC Chow, Specialist in Endocrinology, Diabetes & Metabolism in private practice in Hong Kong, stressed the importance of recognizing obesity as a chronic illness. He also discussed how pharmacologic treatment, such as the glucagon-like peptide-1 (GLP-1) receptor agonist (RA) liraglutide (Saxenda®, Novo Nordisk), alongside lifestyle changes, may help patients achieve sustained weight loss and also provide other health benefits to improve patient outcomes.
Obesity as a chronic disease
“Obesity is recognized as a chronic disease by several global organizations and major regulatory bodies,” stressed Chow. “The World Obesity Federation [WOF] perhaps provides the most comprehensive position on obesity, defining obesity as a chronic, relapsing and progressive disease process that may be considered as a global epidemic requiring immediate preventive action and control.” [Obes Rev 2017;18:715-723]
“Obesity is a complex and multifactorial disease. The ideal treatment should address underlying factors of obesity, such as excessive energy intake, inactive lifestyle and smoking, to successfully achieve a healthy and sustained reduction in body weight,” he continued. “Complete assessment and consideration of associated morbidities are required, including assessment of the mental [eg, depression], mechanical [eg, sleep apnoea, chronic back pain] and metabolic [eg, cancers, cardiovascular diseases, dyslipidaemia, hypertension, coronary heart disease, infertility] aspects of the patient’s health.” [Science 2005;307:1909-1914; Obes Rev 2010;11:808-809; BMC Public Health 2009;9:88; Arch Gen Psychiatry 2010;67:220-229; Arch Gen Psychiatry 2006;63:824-830; Gastroenterology 2006;130:2023-2030; Prev Med 2010;51:18-23; Prev Chronic Dis 2009;6:A48]
Management of patients with obesity
“We usually follow recommendations of the American Heart Association, American College of Cardiology and The Obesity Society for obesity management, which stress that diet and exercise remain the cornerstone of weight loss interventions,” said Chow. “Along with diet, physical activity and behavioural therapy, initiation of pharmacotherapy such as liraglutide is recommended in patients with BMI ≥30 m2/kg or in those with BMI ≥27 m2/kg who have comorbidities. Surgery may be offered to patients with BMI ≥35 m2/kg, when pharmacotherapy and lifestyle changes have been unsuccessful.” [J Am Coll Cardiol 2014;63(25 Pt B):2985-3023; Saxenda Hong Kong prescribing information]
“Treatment should be individualized, particularly for Asian patients, who are known to have a lower BMI cut-off [-2.5 m2/kg] whilst having greater central or abdominal adiposity vs non-Asian populations,” said Chow. [Lancet 2004;363:157-163]"
Liraglutide as a weight management adjunct to lifestyle changes
GLP-1 is a gut-derived incretin hormone that is also secreted in the brain. It is known to stimulate insulin and suppress glucagon secretion, inhibit gastric emptying, and reduce appetite and food intake. GLP-1 RAs exploit these therapeutic targets by enhancing incretin action while remaining degradation-resistant. [Scand J Gastroenterol 1996;31:665-670; J Comp Neurol 1999;403:261-280; Gastroenterology 2007;132:2131-2157; Lancet 2006;368:1696-1705]
Initially approved as a treatment for diabetes, liraglutide is the only injectable GLP-1 RA approved by the US FDA, European Medicines Agency and in Hong Kong specifically for weight management in adult patients with BMI ≥30 m2/kg or those with BMI ≥27 m2/kg to <30 m2/kg and ≥1weight-related comorbidity (eg, prediabetes or type 2 diabetes mellitus [T2DM], hypertension, dyslipidaemia, or obstructive sleep apnoea). It is administered via subcutaneous injections, starting at 0.6 mg QD and increasing to a maximum dose of 3.0 mg QD via weekly increments of 0.6 mg. [www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206321Orig1s000Approv.pdf; www.ema.europa.eu/en/medicines/human/EPAR/saxenda; Saxenda Hong Kong prescribing information]
“While treatment with an appetite suppressant is required to assist in reducing energy intake, with time, changes in mindset and behaviour will occur, enabling patients to develop greater self-control in energy intake, physical exercise and overall body weight, even in the absence of treatment,” said Chow. “For these reasons and cost considerations, pharmacotherapy for weight management is often aimed at dose reduction and treatment cessation.”
SCALE Obesity and Prediabetes trial
The SCALE (Satiety and Clinical Adiposity—Liraglutide Evidence in Nondiabetic and Diabetic Individuals) Obesity and Prediabetes trial was a 56-week, randomized, double-blind, placebo-controlled, multinational trial involving 3,731 adults without diabetes who were either obese or overweight with comorbidities. Participants received either liraglutide or placebo in combination with a reduced-calorie diet and increased physical activity. [N Engl J Med 2015;373:11-22]
Liraglutide after 1 year of treatment
At week 56, patients who received liraglutide demonstrated a mean weight loss of 8.4±7.3 kg vs 2.8±6.5 kg for those who received placebo (−5.6 kg difference; 95 percent confidence interval [CI], -6.0 to -5.1; p<0.001, with last-observation-carried-forward [LOCF] imputation). (Figure 1) A total of 63.2 percent of patients in the liraglutide group vs 27.1 percent of those in the placebo group lost >5 percent of body weight (p<0.001), while 33.1 percent vs 10.6 percent lost >10 percent of body weight (p<0.001).
Liraglutide after 3 years of treatment
“The clinical benefits of weight loss, including its effects on comorbidities such as cardiovascular disease and diabetes, may be seen in the range of a sustained 5–10 percent loss of starting body weight,” noted Chow. [J Am Coll Cardiol 2014;63(25 Pt B):2985-3023]
“The SCALE Obesity and Prediabetes trial showed a sustained 7.1 percent weight loss with liraglutide treatment after 3 years, with greater mean and categorical weight loss achieved in the liraglutide vs placebo group,” said Chow. (Figure 2) [Lancet 2017;389:1399-1409]
This sustained weight loss also translated to metabolic benefits. By week 160, liraglutide was associated with a 79 percent relative risk reduction in T2DM onset (hazard ration [HR] 0.21, 95 percent CI, 0.13 to 0.34) and 2.7 times delay in onset of diabetes vs placebo. (Figure 3) [J Am Coll Cardiol 2014;63(25 Pt B):2985-3023]
At both 1 and 3 years, liraglutide 3.0 mg was associated with higher mean scores on health-related quality of life measures vs placebo, which included assessments of the impact of weight on participants’ quality of life. Adverse events with liraglutide were mostly mild or moderate nausea and diarrhoea, which were generally well tolerated. [N Engl J Med 2015;373:11-22; Lancet 2017;389:1399-1409]
Treatment with liraglutide 3.0 mg for up to 3 years, combined with a reduced-calorie diet and increased physical activity, is associated with clinically sustained weight loss and additional health benefits in terms of a reduced risk of T2DM in high-risk individuals with prediabetes and excess weight or obesity.