Clinical Application of Weight Loss Drugs (Part 2): Combined Intervention Strategies and Safety Management for Special Populations

(2) Cyproterone dihydroxymorphone (naltrexone)-bupropion: In September 2014, the FDA approved the combination of naltrexone and bupropion as a long-term adjunctive weight-loss medication in the United States. However, the current AACE/ACE obesity treatment guidelines do not recommend this drug as a first-line weight-loss medication, but it can be prescribed for obese patients who also need to quit smoking. This drug is contraindicated in pregnant women, patients with uncontrolled hypertension, seizures, eating disorders, and patients using other bupropion-containing products. Naltrexone is an opioid receptor antagonist used to treat alcohol and opioid dependence; bupropion is a dopamine and norepinephrine reuptake inhibitor used to treat depression and prevent weight gain during smoking cessation; the two work synergistically to control appetite and reduce overeating. Naltrexone reduces energy intake by inhibiting the effects of hormones on cells. Bupropion increases satiety and metabolism through central action, leading to weight loss, but can cause adverse reactions such as nausea, constipation, headache, and insomnia. It has also been found to have teratogenic effects on the fetus. Currently, this combination therapy is only used for obese patients. A meta-analysis of four phase III clinical trials found that after one year of treatment with naltrexone/bupropion, the average weight loss was 4.7%, but blood pressure improvement was not significant. The current recommended treatment regimen is: starting with one tablet daily (naltrexone 8mg and bupropion 90mg), increasing to one tablet twice daily after one week, and then increasing to two tablets twice daily after four weeks. Common adverse reactions include nausea (30%), constipation (15%), and headache (14%), followed by insomnia, vomiting, dizziness, and dry mouth, with an average incidence of 7%-10%. The cardiovascular safety of naltrexone/bupropion remains uncertain, and other potential side effects are still under observation. II. The combination of weight loss medication and lifestyle management: Changing the environment and lifestyle is key to preventing overweight/obesity and is the foundation of treatment for all obese patients, and should be maintained throughout the treatment process. This mainly includes a reasonable diet, increased physical activity and exercise, and correction of behaviors and habits that lead to overeating or insufficient activity. A significant number of patients can achieve their treatment goals through these measures. However, in necessary situations and for specific patients, medication or surgery should also be actively used to control weight gain or loss and reduce and manage complications. Weight-loss medications are only an adjunct to lifestyle interventions and should not be used alone; this argument is recommended as Level A evidence in domestic and international weight-loss guidelines. Current evidence suggests that medication helps patients improve their adherence to lifestyle therapy, alleviate obesity-related complications, and enhance their quality of life, while also helping to prevent the progression of related complications. Especially for patients with obesity and related complications, medication combined with lifestyle interventions can be considered the first-line treatment. The European Guidelines for Adult Obesity Management recommend that medication be initiated in addition to lifestyle modifications for patients with a BMI ≥ 30 kg/m² or a BMI ≥ 27 kg/m² with comorbid obesity. The Obesity Group of the Endocrinology Branch of the Chinese Medical Association recommends that patients with a BMI ≥ 28 kg/m² or a BMI ≥ 24 kg/m² and comorbid obesity who have failed to lose 5% of their weight after 36 months of diet control and increased physical activity alone, or whose weight is still trending upwards, may consider incorporating medication as an adjunct to treatment. In summary, with adequate dietary, exercise, and behavioral therapy, adding anti-obesity medication can help improve the health of obese patients, especially those who have failed to lose weight through diet or exercise alone, and can benefit from a prescription for weight-loss medication.

Reducing energy intake through a balanced diet is the most important part of weight loss treatment. Daily total energy intake should be reduced (500-750 kcal reduction is recommended) while maintaining a balanced diet. A reasonable dietary structure can meet the body's nutritional needs, improve patient compliance, improve eating habits, reduce risk factors for metabolic diseases, and achieve clinical benefits. Regarding dietary structure, the AACE/ACE obesity treatment guidelines recommend a Mediterranean diet, low in carbohydrates and fat, high in protein, and vegetarian, and formula-based dietary alternatives can also be considered.

Physical activity is an integral part of weight loss treatment, maintaining a relatively healthier state by reducing total body fat and increasing muscle mass. The AACE/ACE obesity treatment guidelines recommend that beginners gradually increase the amount and intensity of exercise, with the ultimate goal of moderate-intensity exercise for a total of 300 minutes per week (minimum 150 minutes), including 35 aerobic exercise sessions and 23 resistance training sessions per week. The involvement of a professional fitness coach to develop an individualized exercise plan based on the patient's fitness level can improve the effectiveness of the treatment.

Behavioral interventions include self-monitoring of weight, food intake and physical activity, clear and reasonable goal setting, education on obesity, nutrition and physical activity, face-to-face and group meetings, stimulus control methods, systematic problem-solving approaches, cognitive adjustment methods (e.g., cognitive behavioral therapy), motivational interviews, stress reduction, behavioral constraints, psychological counseling, and mobilization of social support institutions. Lifestyle management for all overweight/obese individuals should include behavioral interventions to strengthen adherence to low-energy diet plans and increase physical activity prescriptions. This can be effectively implemented through a multidisciplinary team including nutritionists, nurses, educators, physical trainers or coaches, and clinical psychologists.

An analysis of past and present popular weight-loss drugs reveals that while there are many types, the long-term safety of these drugs remains unclear. Domestic obesity treatment guidelines explicitly state that weight-loss drugs are not recommended for children, pregnant and lactating women, those with a history of adverse reactions to these drugs, those currently taking other selective serotonin reuptake inhibitors, or those using them for cosmetic purposes. During weight-loss drug treatment, regular follow-up is essential for timely adjustments. The AACE/ACE obesity treatment guidelines recommend evaluating efficacy after 3 months of drug treatment. If weight loss is >5% in non-diabetic patients and >3% in diabetic patients, it is considered effective, and drug treatment can continue. For ineffective patients, medication should be discontinued, and the overall treatment plan reassessed. To avoid potential adverse reactions, follow-up for those using centrally acting weight-loss drugs should initially be at least every 2-4 weeks, and after 3 months, this can be reduced to monthly. Furthermore, the following points should be noted in clinical practice: ① For patients with coronary heart disease and arrhythmias, orlistat and lorcaserin are the first-line treatments, while other drugs have the potential to affect blood pressure and heart rate and are not recommended. ② Patients with chronic kidney disease should not use weight-loss drugs in the end-stage of the disease. For some patients with strong indications for medication, orlistat and liraglutide may be considered, but caution is needed as oxalate nephropathy and volume depletion caused by vomiting and diarrhea can worsen kidney damage. For patients with mild to moderate renal impairment, weight-loss drugs can be used, but some drugs require dosage reduction, and renal function should be closely monitored. ③ Patients with severe liver damage should not use weight-loss drugs. ④ Orlistat and liraglutide have a potential risk of causing pancreatitis; if an acute pancreatitis attack occurs, the medication should be discontinued immediately.