GLP-1 analogue effective as an adjunct for weight management in obesity
A body mass index (BMI) above the normal range is a risk factor for multiple health problems, including chronic diseases. As physiological responses to weight loss favour weight regain, and diet and lifestyle interventions alone may fail to induce sufficient and/or sustained weight reduction, concomitant use of pharmacotherapy may be required. Liraglutide 3.0 mg (Saxenda®, Novo Nordisk), a glucagon-like peptide 1 (GLP-1) analogue, has been shown to effectively reduce body weight and improve glucose metabolism. In an interview with MIMS Doctor, Dr Norman Chan, Specialist in Endocrinology, Diabetes and Metabolism [NR1] in Hong Kong, discussed the use of liraglutide 3.0 mg for sustained weight loss in obese patients.
Obesity: Definition and impact
“While not defined as a disease by the Hong Kong health authority, obesity is recognized as a disease in its own right by the WHO, the American Association of Clinical Endocrinologists [AACE] and the European Association for the Study of Obesity [EASO], among many other organizations,” said Chan.
The WHO defines obesity as abnormal or excessive fat accumulation that may impair health. A BMI of 30 kg/m2 is the threshold for obesity, while ≥25 kg/m2 is classified as overweight. For Asians (Western Pacific region population), the limits are lower, at ≥25 kg/m2 and ≥23 kg/m2, respectively. “Waist circumference is another measure of obesity, where the limits are 90 cm for men and 80 cm for women,” added Chan. [http://www.wpro.who.int/nutrition/documents/docs/Redefiningobesity.pdf. Accessed 30 Oct 2019]
“Many chronic diseases and conditions, such as diabetes, fatty liver, hypercholesterolaemia, hypertension, gallstones, obstructive sleep apnoea, coronary heart disease, osteoarthritis and some cancers [eg, uterine cancer], are more common in obese individuals,” noted Chan. (Figure 1)
Clinical management of obesity
“Significant positive effects on lowering the risk of obesity-related comorbidities are observed with as little as 5 percent reduction in body weight. It is therefore important that overweight or obese individuals make the effort to lose weight, as excess fat may be the root of their chronic health problems,” recommended Chan. (Figure 1)
“There is no fixed BMI value for starting pharmacotherapy to aid weight reduction in overweight or obese patients. Rather, a global assessment including history [eg, whether patients have tried diet and exercise but failed] and genetic predisposition should be carried out for individual patients,” said Chan.
“For example, it is possible for someone with a BMI of 28 kg/m2 to suffer from more obesity-related complications or at a higher risk of comorbidities than another person of the same age and gender with a BMI of 32 kg/m2, due to genetic interplay,” he explained. “Therefore, we should determine patients’ current status, what they are likely to achieve with various kinds of intervention, whether their current complications are damaging their life, and thus how aggressive the weight reduction treatment should be.”
“Treating obesity is unlike treating diseases such as hypertension or diabetes, as patients often want to play an active part in decision-making regarding drug therapy [NR3] for weight reduction,” Chan commented.
“For patients who are not motivated to lose weight, we should educate them on the potential benefits of sustained weight reduction, such as elimination of insulin injections for diabetes control and dose reduction or discontinuation of medications for chronic conditions,” advised Chan. “Drugs for weight reduction can be used until desired results are achieved”
Pharmacotherapy or weight management
Liraglutide, in the form of a subcutaneous injection, is the only GLP-1 analogue approved by the US FDA, the European Medicines Agency and the Hong Kong Department of Health for weight management. It is the most recently available anti-obesity drug in Hong Kong. The recommended starting dose is 0.6 mg/day, which is to be increased by 0.6 mg/day at weekly intervals until a dose of 3.0 mg/day is achieved.
“Liraglutide promotes weight loss through appetite suppression and gastric-emptying delay, giving a feeling of satiety after intake of small amounts of food. It does not cause hypoglycaemia, making it safe for use in patients with or without diabetes,” said Chan.
“We can expect to see results within a few weeks of administration even without a strict diet and exercise regime. In my experience, a sustained weight loss of about 10 percent after 3 months from the initial dose is not uncommon. However, I have encountered a remarkable case of about 36 percent [from 117.3 kg to 74.6 kg] of body mass loss in 9 months,” shared Chan. (Figure 2) [N Engl J Med 2015;373:11-22;
“Although the route of administration is less convenient compared with oral anti-obesity agents, patients can easily administer the injection unaided at home using the 32-gauge 4-mm needle multidose pen provided. In my experience, liraglutide is generally well-tolerated, leading to fewer discontinuations than other anti-obesity agents,” remarked Chan.
“The side effects of liraglutide are generally mild and resolve without the need for pharmacological intervention. The step-up regimen allows patients to adapt quickly and to tolerate the final full treatment dose well,” Chan noted.
Common side effects of liraglutide include nausea, vomiting, constipation, headache, tiredness, dry mouth, low mood and occasionally diarrhoea. “Liraglutide should be used with caution in patients with gastrointestinal [GI] problems such as irritable bowel syndrome or hiatus hernia, since its GI side effects may aggravate their existing GI problems. It should also be used with extra caution in severely depressed patients, as they could theoretically be tipped into being suicidal under liraglutide influence. In addition, patients on antipsychotics should be monitored closely, as liraglutide may interact with some antipsychotic agents,” he cautioned.
Benefits of liraglutide beyond weight loss
According to results of the multinational, randomized, double-blind, placebo-controlled SCALE Obesity and Prediabetes Study, liraglutide 3.0 mg, used as an adjunct to diet and exercise, was effective at reducing body weight (mean weight reductions ± standard deviation [SD], -8.0±6.7 percent vs 2.6±5.7 percent), improving metabolic control (fasting glucose reduction ± SD, -7.1±10.8 mg/dL vs 0.1±10.4 mg/dL; fasting low-density lipoprotein cholesterol reduction, -3.0 percent vs -1.0 percent), and improving health-related quality of life (estimated mean change in Short-Form [36-item] overall physical health score, 3.7 vs 1.9; p<0.001) vs placebo over a 56-week period. [N Engl J Med 2015;373:11-22]
In addition, continued use of liraglutide over 3 years possibly reduced the risk of developing diabetes in obese and prediabetic individuals. Over the 3-year duration of the SCALE trial, adults with prediabetes and a BMI of at least 30 kg/m², and those with a BMI of at least 27 kg/m² and comorbidities, had a 2.7-fold longer time to onset of diabetes with liraglutide vs placebo (95 percent confidence interval [CI], 1.9 to 3.9; p<0.0001), corresponding to a hazard ratio (HR) of 0.21 (95 percent CI, 0.13 to 0.34; p<0.001). [Lancet 2017;389:1399-1409]
In the multinational, randomized, double-blind, placebo-controlled LEADER (trial, which included 9,340 patients, the primary composite outcome of death from cardiovascular causes, nonfatal MI or nonfatal stroke occurred in significantly fewer patients in the liraglutide vs placebo group (13.0 percent vs 14.9 percent; HR, 0.87; 95 percent CI, 0.78 to 0.97; p<0.001 for noninferiority; p=0.01 for superiority). [N Engl J Med 2016; 375:311-322]