Article 94: Sibutramine and Energy-Depleting Agents, Lipase Inhibitors

Pharmacological effects: ① Effects on neurotransmitters: Appetite is regulated by the satiety center and feeding center in the hypothalamus. Increased levels of catecholamines such as norepinephrine, dopamine, and serotonin in the synapses of central pathways can lead to a feeling of satiety, reduced food intake, and increased thermogenesis. Sibutramine and its metabolites, the secondary amine N₁ and the primary amine H, can inhibit the reuptake of serotonin, norepinephrine, and dopamine from the presynaptic membrane, increase the catecholamine content in the synaptic cleft, resulting in a feeling of satiety, reduced food intake, and increased thermogenesis, thereby leading to weight loss. In a double-blind, placebo-controlled trial of 12 obese women, the treatment group received sibutramine 10–30 mg/day for 2 weeks. The results showed that their total energy intake decreased by 18% compared to the placebo group, plasma adrenaline levels increased, and heart rate increased. ② Effects on the cardiovascular system: Placebo-controlled trials have shown that sibutramine has a significant effect on raising blood pressure, with an average increase of 1.53 kPa in systolic blood pressure, an average increase of 0.56 kPa in diastolic blood pressure, and an average increase of 7.9 beats/min in heart rate, but no effect on stroke volume or cardiac output, and no significant changes in electrocardiogram parameters.

Clinical application: 5-10 mg/day. If weight loss is less than 1% of original body weight after 4 weeks of use, the dose can be increased to 15 mg/day, but the total dose should not exceed 15 mg/day. Studies have shown that with long-term use of 10 mg/day, compared with the control group, there is a significant weight loss of approximately 5-6 kg after 1 year. It can also reduce visceral fat, significantly decrease the waist-to-hip ratio, and improve obesity-related conditions such as impaired glucose tolerance, hyperlipidemia, and hyperuricemia. After very low-calorie therapy, 86% of patients taking sibutramine were able to maintain their weight loss. A double-blind, placebo-controlled trial reportedly showed that the treatment group, given 10-20 mg of sibutramine once daily for 52 weeks, experienced a weight loss of 5-7.5 kg, while the placebo group experienced a weight loss of 1.5-3.5 kg, showing a significant difference between the two groups. Another 24-week study reported that the treatment group, receiving sibutramine 10–30 mg once daily on a low-calorie diet, showed significantly different weight loss compared to the placebo group. The study also showed that the magnitude of weight loss was dose-related, and that men experienced greater weight loss than women. Obesity is a risk factor for cardiovascular diseases such as hyperlipidemia, diabetes, and hypertension; weight control can reduce the incidence of cardiovascular disease. Sibutramine has been reported to have a significant weight-loss effect in treating obese patients with type 2 diabetes. In 91 patients with type 2 diabetes, treated with sibutramine 15 mg/day for 12 weeks, the weight loss was 2.4 kg in the treatment group and 0.1 kg in the placebo group. In 113 obese patients with hypertension (21.28/11.97 kPa) (BMI 27–40), oral sibutramine 10 mg/day resulted in weight loss of 4.4 kg in the treatment group and 2.2 kg in the placebo group. Sibutramine is used to treat obese individuals with hyperlipidemia. Compared to the placebo group, the treatment group showed a significant difference in weight loss; very low-density lipoprotein (VLDL) decreased by 12.5%, while other lipid indices showed no significant changes; the greater the weight loss, the better the improvement in lipid indices. Weight rebound after discontinuation of the drug is a common phenomenon in obesity treatment, and sibutramine is no exception. After taking sibutramine 20 mg/day for 20 weeks and then discontinuing, weight rebound occurred shortly afterward, and the rebound was more rapid in those who had lost the most weight while taking the drug. Rebound typically occurs within 3 months after discontinuation.

Adverse reactions: This product is well tolerated. Common adverse reactions include headache, dry mouth, anorexia, insomnia, and constipation. An 8-week study reported that patients receiving sibutramine 20 mg/day had an increased incidence of headache, as well as increased irritability, restlessness, and excitability. Cardiovascular side effects mainly include increased blood pressure and heart rate, but these usually return to normal levels one month after discontinuation.

Indications and Contraindications: Sibutramine is indicated for obesity, generally requiring an initial BMI greater than 30, along with risk factors such as diabetes and hyperlipidemia. The initial dose is 10 mg once daily. If a weight loss of 1.8 kg is achieved within 4 weeks, it is considered effective. If the effect is not significant, the dose can be increased to 15 mg once daily. It is contraindicated in patients with coronary heart disease, heart failure, arrhythmia, stroke, severe liver or kidney dysfunction, and severe hypertension. Blood pressure should be monitored regularly after starting medication. If persistently elevated blood pressure or heart rate occurs, the medication should be discontinued and the patient observed. Caution should be exercised when using sibutramine in patients with narrow-angle glaucoma and a history of epilepsy.

Drug Interactions: This product is contraindicated in patients using monoamine oxidase inhibitors (such as phenelzine, isoniazid, etc.) or who have used monoamine oxidase inhibitors within the past two weeks, as the two drugs may have an antagonistic effect when used together. Avoid using it in combination with drugs that raise blood pressure and increase heart rate, such as ephedrine, phenylpropanolamine, and adrenaline. It should not be used in combination with drugs that inhibit cytochrome P450, such as erythromycin, ketoconazole, and cimetidine, as the combination of the two can inhibit the metabolism of sibutramine, leading to increased blood drug concentration, enhanced effect, and increased adverse reactions.

Drugs that promote weight loss by consuming the body's energy are called energy-consuming agents. They mainly include the following two categories:

(1) Thyroid hormones: Theoretically, thyroid hormones can increase the body's metabolic rate and increase energy consumption, making them ideal for weight loss. However, the effects of thyroid hormones are mainly on proteins. Increased thyroid hormone levels in the body hinder the conversion of creatine to creatinine and the production of phosphocreatine in muscles, leading to muscle lesions, accelerating protein breakdown, increasing bone calcium loss, and particularly having adverse effects on the cardiovascular system. Therefore, the use of thyroid hormone drugs for weight loss is currently not recommended.

(2) Hypoglycemic drugs: Hypoglycemic drugs are mainly divided into two categories: insulin preparations and oral hypoglycemic agents. Since obese patients often have hyperinsulinemia, using insulin to treat obesity is impractical. Biguanides, an oral hypoglycemic agent, promote anaerobic glycolysis in muscles, producing large amounts of lactic acid; it also promotes glucose absorption and oxidation in adipose tissue and inhibits gluconeogenesis in the liver. Its main side effects are appetite suppression and weight loss. For weight loss in obese individuals, the main concern is the side effects of biguanides. The main biguanide drug is metformin. The dosage of metformin is 0.5–1.5 g/day, divided into 2–3 oral doses, with a maximum dose not exceeding 2 g/day. Common side effects of biguanides include gastrointestinal reactions such as bitter taste, metallic taste, anorexia, nausea, vomiting, and diarrhea, thus making them suitable for weight loss. Occasionally, allergic reactions occur, manifesting as skin erythema and urticaria. Because biguanides promote anaerobic glycolysis and produce lactic acid, they can easily induce lactic acidosis in hypoxic conditions such as liver and kidney dysfunction, hypovolemic shock, or heart failure. Therefore, they are contraindicated in patients with these conditions. Caution should be exercised when using them in elderly patients.

The main drug in this category is orlistat, marketed as Xeroxone in Chinese. This drug is a highly specific pancreatic lipase inhibitor. It binds to lipase in the intestines, inhibiting its activity, slowing the hydrolysis of dietary fat in the gastrointestinal tract, reducing fat absorption, and thus aiding in weight loss. In healthy individuals, an oral dose of 120 mg three times daily can inhibit fat absorption by 30%, reducing energy intake by 837 kJ. 83% of the oral dose is excreted in the feces, with a half-life of 14–19 hours.

Dosage: 120 mg, three times daily, orally, can be used long-term.

Efficacy: Studies have shown that after one year of taking orlistat 120 mg three times daily, the average weight loss of patients was 9.2%, a significant difference compared to the control group. This drug not only significantly reduces the weight of obese patients but also improves their blood lipid levels and lowers blood pressure in obese patients with hypertension.

Side effects: Steatorrhea, abdominal pain, and bloating may occur, often most pronounced in the initial stages of use. With prolonged use, the body gradually develops tolerance. This medication can inhibit the hydrolysis and absorption of fat-soluble vitamins A, D, E, and beta-carotene; therefore, multivitamin supplementation is recommended while taking this medication. Some studies suggest that this medication should be used with caution in high-risk groups for breast cancer. The safety of this medication requires further long-term follow-up observation to confirm.