Stepped approach to weight reduction in adults with obesity
Obesity is a common chronic condition associated with wide-ranging complications, from diabetes and knee osteoarthritis to mental health concerns, necessitating weight reduction. At the Multi-specialties Scientific Conference organized by the Hong Kong Women Doctors Association, Dr Rose Zhao-Wei Ting, Specialist in Endocrinology, Diabetes & Metabolism in private practice in Hong Kong, discussed a stepped approach to weight reduction, including the use of a glucagon-like peptide-1 (GLP-1) analogue. She also shared practical tips for long-term weight management among adults with obesity.
Obesity common in Hong Kong adults
Obesity is a chronic condition with increasing prevalence worldwide over the past several decades. [Metab Clin Exp 2019;92:6-10] “The Hong Kong Population Health Survey 2014–2015 reported that approximately 50 percent of individuals aged 15–84 years were overweight [body mass index (BMI) ≥23.0 kg/m2] or obese [BMI ≥25.0 kg/m2], which is higher than in 2003–2004 [38.8 percent],”said Ting. [https://www.chp.gov.hk/en/resources/29/362.html]
“Obese adults are at high risks of a spectrum of complications. Metabolic syndrome and cardiovascular [CV] diseases, such as diabetes, elevated triglycerides and coronary artery disease, are common comorbidities of obesity. [Because of mechanical stress,] obesity may lead to respiratory or joint issues, including asthma, sleep apnoea and knee osteoarthritis. Furthermore, depression and anxiety are often associated with obesity,” she continued. [Ther Adv Endocrinol Metab 2020;11:2042018820934955]
Weight reduction: Benefits and strategies
“Modest weight reduction may provide clinical benefits for obese individuals,” said Ting.
In a 1-year observational analysis of 5,145 patients with obesity and type 2 diabetes (T2D; mean age, 58.7 years; female, 59.5 percent; baseline BMI, 36.0 kg/m2), weight reduction of 2–<5 percent was associated with favourable outcomes, including 0.05 percent decrease in HbA1c (odds ratio [OR], 1.80; 95 percent confidence interval [CI], 1.44–2.24) and 40 mg/dL decrease in triglycerides (OR, 1.46; 95 percent CI, 1.14–1.87). [Diabetes Care 2011;34:1481-1486]
“A greater degree of weight reduction [5–10 percent] was associated with further benefits, including improved symptoms of knee osteoarthritis and asthma. In individuals with early T2D, remission of T2D may occur at 10–15 percent of body weight loss. These findings suggest that weight loss provides various health benefits in individuals with obesity and obesity-related comorbidities,” noted Ting. [Curr Obes Rep 2017;6:187-194; Clin Exp Allergy 2013;43:36-49;Diabetes Care 2022;45:28-30]
“Weight management usually includes multiple steps, namely, lifestyle and behavioural modifications, pharmacotherapy and metabolic surgery, the choice of which is based on BMI classification and individual characteristics,” said Ting. (Figure 1) [CMAJ 2020;192:E875-E891]
Lifestyle modifications with dietary alternatives
“A popular diet for weight reduction is intermittent fasting [ie, regular switch between fasting and eating],” Ting said. “Despite its effectiveness in weight reduction, hypotension and hypoglycaemia may occur during fasting. Thus, fasting diets should be avoided in patients with diabetes or those receiving treatment with insulin or sulphonylureas.” [Can Fam Physician 2020;66:117-125; Curr Obes Rep 2021;10:70-80]
“Another dietary alternative is ketogenic diet [carbohydrates, <5 percent; fat, >70 percent; protein, 25 percent]. Compared with traditional or Mediterranean diets [carbohydrates, 45–55 percent; fat, 25–35 percent; protein, 18–20 percent], some people believe that a low-carbohydrate or ketogenic diet may provide [additional] weight reduction,” Ting explained.
A clinical study assessed the effect of dietary interventions, including low-carbohydrate and Mediterranean diets, in 322 adults with obesity (mean age, 52 years; BMI, 30.9 kg/m2). Results showed maximum weight loss at 6 months with maintenance at 7–24 months, regardless of dietary pattern. At 24 months, overall weight changes were -4.7 kg for the low-carbohydrate diet and -4.4 kg for the Mediterranean diet. [N Engl J Med 2008;359:229-241] “These findings suggest that the low-carbohydrate and Mediterranean diets may have similar long-term weight loss effects,” commented Ting.
Why is maintaining weight loss challenging?
“Due to metabolic adaptation, long-term maintenance of weight loss is often challenging. Apart from food intake and energy expenditure, body weight is also regulated by the neuroendocrine system,” Ting explained. For instance, GLP-1, an incretin hormone secreted from the intestine, is a neurotransmitter of meal terminal signals of the hypothalamus, which mediates changes in appetite and promotes satiety. [Obes Rev 2020;21:e12949; Nat Rev Dis Primers 2017;3:17-34; J Diabetes Metab Disord 2020;19:1863-1872]
“Tackling neurotransmitter pathways [with medications] may help reduce weight in adults with obesity,” Ting pointed out.
Role of pharmacotherapy in weight management
Liraglutide, semaglutide, orlistat, bupropion-naltrexone and phentermine topiramate are US FDA–approved therapeutic agents for long-term treatment of overweight and obesity. [https:// www.niddk.nih.gov/health-information/weight-management/prescription-medications-treat-overweight-obesity]
“In Hong Kong, liraglutide, orlistat and bupropion-naltrexone are available for weight reduction. However, semaglutide is not yet registered for this purpose,” stated Ting. [Saxenda Hong Kong Prescribing Information; Xenical Hong Kong Prescribing Information; Contrave Hong Kong Prescribing Information] “In my practice, liraglutide is often used in adults with obesity, especially those with metabolic conditions such as prediabetes and dyslipidaemia,” said Ting.
Liraglutide for weight reduction in obesity
As a synthetic, long-acting GLP-1 analogue, liraglutide (3.0 mg) can be used as an adjunct to lifestyle intervention in adults with an initial BMI of ≥30 kg/m2, or ≥27 kg/m2 with ≥1 weight-associated comorbidity, including prediabetes and T2D. [Saxenda Hong Kong Prescribing Information]
The efficacy of liraglutide 3.0 mg in reducing body weight was shown in the phase III SCALE Obesity and Prediabetes study of 3,731 participants without diabetes (mean age, 45.1 years; female, 78.5 percent; mean body weight, 106.2 kg; mean BMI, 38.3 kg/m2; prediabetes, 61.2 percent). At 56 weeks, mean body weight was reduced by 9.2 percent with liraglutide 3.0 mg vs 3.5 percent with placebo (p<0.0001). (Figure 2) The rates of weight reduction with liraglutide were similar in prediabetes and normoglycaemia groups. [Diabetologia 2014;57(Suppl 1):abstract 73-OR;
N Engl J Med 2015;373:11-22]
Of note, significantly higher proportions of participants achieved body weight reductions of
≥5 percent, >10 percent and >15 percent at week 56 with liraglutide 3.0 mg vs placebo (p<0.001 for each). (Figure 3)
“The results also showed improvement in cardiometabolic profile with liraglutide 3.0 mg,” Ting said. At 56 weeks, liraglutide was associated with significantly reduced levels of fasting glucose (-0.39 mmol/L vs 5.6 x 10-3 mmol/L) and fasting insulin (-12.6 percent vs -4.4 percent) vs placebo (p<0.001 for both).
Another study of liraglutide 1.8 mg demonstrated a reduced risk of CV complications in 9,340 patients with T2D. At 3.8 years of median follow-up, T2D patients receiving liraglutide 1.8 mg had a significantly lower risk of CV outcomes (ie, first occurrence of death from CV causes, nonfatal myocardial infarction or nonfatal stroke) vs those on placebo (HR, 0.87; 95 percent CI, 0.78–0.97; p<0.001 for noninferiority; p=0.01 for superiority). [N Engl J Med 2016;375:311-322]
Liraglutide was generally well-tolerated. In SCALE Obesity and Prediabetes, a common adverse event associated with liraglutide 3.0 mg was nausea (40.2 percent). However, most cases were transient and occurred within the first 4–8 weeks of treatment initiation.
“Based on the clinical evidence [above], the GLP-1 analogue [ie, liraglutide 3.0 mg] is optimal for adults with obesity, including those with diabetes,” Ting highlighted.
“For individuals who do not lose ≥5 percent of initial body weight after 3 months of liraglutide 3.0 mg QD, however, the treatment should be discontinued,” she reminded. [Saxenda Hong Kong Prescribing Information]
“Metabolic surgery, including gastric band, sleeve gastrectomy and Roux-en-Y gastric bypass, is an effective approach [to weight reduction] in individuals with severe obesity,” Ting said. A European study of adults with obesity (age, 37–60 years; BMI, ≥34 kg/m2 for men, ≥38 kg/m2 for women) who had undergone metabolic surgery (n=2,010) or received usual care (n=2,037) showed that the mean change in body weight after 20 years was -18 percent and -1 percent, respectively. [JAMA 2012;307:56-65]
“Despite the effectiveness and safety, [I found that] individuals with obesity may have concerns about potential risks of surgery, leading to negative attitudes towards this procedure,” Ting commented.
Practical tips on weight management
“Sustainability is important for weight reduction. Therefore, the initial target should be losing 3–5 percent of body weight. In the longer term, a weight loss of >15 percent can be considered,” Ting stated.
“In lifestyle modification, the diet should be tailored to the individual’s nutritional needs and preferences, with balance between potential harms and benefits. Exercise, sleep and mood should also be taken into account,” she advised.
“Biological factors play a role in body weight regulations. Pharmacological treatment with GLP-1 analogue [eg, liraglutide 3.0 mg] can be considered for adults with [obesity who develop] T2D or prediabetes,” she added. “Metabolic surgery is an option for patients with severe obesity.”