Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has emerged as a significant therapeutic option for weight management and glycemic control. Initially developed for treating type 2 diabetes, semaglutide has shown promise in promoting substantial and sustained weight loss in individuals with obesity or overweight, even without diabetes. This article explores the long-term use of semaglutide for weight loss, examining its efficacy, safety, and various factors influencing its outcomes.
Introduction to Semaglutide
Semaglutide mimics the effects of the GLP-1 hormone, which plays a crucial role in regulating blood sugar levels and appetite. By activating GLP-1 receptors, semaglutide enhances insulin secretion, suppresses glucagon release, and delays gastric emptying, leading to reduced appetite and food intake. This mechanism of action makes semaglutide an effective tool for weight management.
Efficacy of Semaglutide for Weight Loss
Clinical Trial Evidence
The SELECT trial (Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity) provided compelling evidence of semaglutide's efficacy in promoting weight loss. This trial involved 17,604 adults with preexisting cardiovascular disease, overweight or obesity, but without diabetes. The results showed that semaglutide was associated with a 20% reduction in major adverse cardiovascular events.
A prespecified analysis of the SELECT trial examined the effects of semaglutide on weight and anthropometric outcomes over 208 weeks (4 years). The findings revealed that patients treated with semaglutide experienced significant and sustained weight loss. At 208 weeks, the semaglutide group had a mean weight reduction of -10.2%, compared to -1.5% in the placebo group (P < 0.0001). Additionally, semaglutide was associated with reductions in waist circumference (-7.7 cm) and waist-to-height ratio (-6.9%) compared to placebo (-1.3 cm and -1.0%, respectively; P < 0.0001).
Real-World Evidence
A Cleveland Clinic study published in JAMA Network Open provided real-world evidence of semaglutide's effectiveness. This retrospective cohort study included 3,389 adult patients with obesity who initiated treatment with injectable semaglutide or liraglutide between July 1, 2015, and June 30, 2022. The study found that one year after the initial prescription, patients on semaglutide experienced a mean weight change of -5.1%, compared to -2.2% with liraglutide.
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The study also identified factors associated with long-term weight loss, including the medication's active agent, dosage, treatment indication, and persistence with the medication. Patients who received semaglutide for obesity, were on a high maintenance dose, and persisted with the medication had higher odds of achieving 10% or more weight reduction.
Categorical Weight Loss
In the SELECT trial, categorical weight loss was assessed at week 104. Among patients treated with semaglutide, 67.8% achieved weight loss of ≥5%, 44.2% achieved ≥10%, 22.9% achieved ≥15%, 11.0% achieved ≥20%, and 4.9% achieved ≥25%. In contrast, the corresponding percentages for the placebo group were 21.3%, 6.9%, 1.7%, 0.6%, and 0.1%.
Change in BMI Category
At week 104 of the SELECT trial, 52.4% of patients treated with semaglutide achieved improvement in BMI category compared with 15.7% of those receiving placebo. In the semaglutide group, 12.0% of patients achieved a BMI <25 kg m−2, which is considered the healthy BMI category, compared with 1.2% for placebo. The proportion of patients with obesity (BMI ≥30 kg m−2) fell from 71.0% to 43.3% in the semaglutide group versus 71.9% to 67.9% in the placebo group.
Factors Influencing Long-Term Weight Loss with Semaglutide
Several factors can influence the long-term success of weight loss with semaglutide:
Medication Adherence
Persistence with medication is a critical factor in achieving sustained weight loss. The Cleveland Clinic study found that patients who were persistent with semaglutide at one year experienced a mean weight change of -5.5%, compared to -2.8% among patients who had 90-275 medication coverage days and -1.8% among those with less than 90 covered days.
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Dosage
The dosage of semaglutide also plays a significant role in weight loss outcomes. Patients on a high maintenance dose experienced greater weight loss compared to those on a low maintenance dose. In the Cleveland Clinic study, patients experienced -3.5% mean weight change with low maintenance dose versus -6.6% with high dose.
Treatment Indication
The indication for which semaglutide is prescribed can also affect weight loss outcomes. Patients who received semaglutide for obesity treatment experienced greater weight loss compared to those who received it for type 2 diabetes. In the Cleveland Clinic study, patients who received the medications for type 2 diabetes experienced -3.2% in mean weight change compared to -5.9% for obesity treatment.
Baseline Characteristics
Baseline characteristics such as BMI, sex, and race can also influence weight loss outcomes. In the SELECT trial, women had a greater difference in mean weight loss with semaglutide versus placebo compared to men. Additionally, patients from Asia and of Asian race experienced slightly lower mean weight loss.
Safety and Tolerability of Semaglutide
Adverse Events
Semaglutide is generally well-tolerated, but it can cause side effects, primarily gastrointestinal in nature. The most common side effects include nausea, vomiting, diarrhea, constipation, and abdominal pain. These side effects are usually mild to moderate and tend to diminish over time.
In the SELECT trial, semaglutide was associated with increased rates of trial product discontinuation. Discontinuations increased as BMI class decreased. However, semaglutide was associated with fewer serious adverse events. For each BMI category (<30, 30 to <35, 35 to <40 and ≥40 kg m−2) there were lower rates (events per 100 years of observation) of serious adverse events with semaglutide compared to placebo.
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Contraindications
Semaglutide is contraindicated in individuals with a history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, and during pregnancy. It is also important to exercise caution when prescribing semaglutide to patients with a history of pancreatitis or gallbladder disease.
Anesthetic Risks
Semaglutide therapy is associated with potential anesthetic risks, such as pulmonary aspiration or residual gastric content. The delayed gastric emptying caused by semaglutide can increase the risk of aspiration during anesthesia. Therefore, careful consideration is warranted when using semaglutide in patients undergoing surgery. Some experts suggest modifying pre-operative guidelines to account for patients using semaglutide.
Long-Term Considerations
Weight Regain
One of the major challenges in weight management is weight regain after discontinuing treatment. Studies have shown that people who go off semaglutide eventually regain much of their lost weight. Therefore, long-term maintenance strategies are essential to sustain weight loss achieved with semaglutide.
Combination with Lifestyle Interventions
Semaglutide is most effective when combined with lifestyle interventions, including diet and exercise. Patients taking semaglutide should prioritize a healthy diet rich in fruits, vegetables, whole grains, lean protein, and healthy fats. Regular physical activity is also crucial for maintaining weight loss and improving overall health.
Psychological and Social Factors
The psychological and social aspects of weight loss should not be overlooked. Patients taking semaglutide may experience changes in body image, self-esteem, and social interactions. It is important to provide counseling and support to help patients adjust to these changes and maintain a healthy relationship with food and their bodies.
Potential Benefits Beyond Weight Loss
Cardiovascular Benefits
Semaglutide has demonstrated significant cardiovascular benefits in clinical trials. In the SELECT trial, semaglutide was associated with a 20% reduction in major adverse cardiovascular events. Additionally, semaglutide has been shown to lower blood pressure and reduce the odds of heart attacks or strokes.
Neuroprotective Effects
Emerging evidence suggests that semaglutide may have neuroprotective effects and could potentially be used in the treatment of Alzheimer's disease. Semaglutide has been associated with decreased amyloid-beta plaque deposition and neuroinflammation, which are hallmarks of Alzheimer's disease.
Kidney Protection
The FLOW clinical trial investigated whether semaglutide can slow the progression of chronic kidney disease (CKD) in people with type 2 diabetes. The results showed that semaglutide demonstrated benefits for kidney-specific outcomes, cardiovascular death, and other secondary outcomes, including a slower decline in kidney function.
Polycystic Ovary Syndrome (PCOS)
Semaglutide has shown promise in improving outcomes for women with PCOS. Studies have found that semaglutide can promote weight loss, improve hyperinsulinism and hyperandrogenism, normalize total testosterone levels, and reduce insulin resistance markers in women with PCOS.