Obesity, a multifaceted and chronic condition characterized by excessive fat accumulation, poses significant risks to overall health and is associated with various metabolic and cardiovascular complications. With over two-thirds of Americans considered to be in the overweight or obese body-mass index (BMI) ranges, the need for effective weight loss strategies is greater than ever. While lifestyle interventions are the primary treatment, pharmacological options become crucial when these methods are insufficient. This article provides a detailed analysis of semaglutide and phentermine, two popular weight loss drugs, examining their mechanisms of action, efficacy, and potential side effects.
Obesity: A Growing Global Concern
Obesity is recognized as a multifaceted and long-term condition marked by the abnormal accumulation of body fat, which can negatively impact overall health. Its development is influenced by a mix of genetic predispositions, environmental exposures, behavioral patterns, and metabolic factors. This disorder is not uniform; instead, it manifests in various forms with unique biological and clinical characteristics and is frequently linked to several biomarkers that play a role in its progression and associated health complications.
Obesity occurs when there is an imbalance between the calories consumed and the energy expended, leading to an excessive buildup of fat in the body. It is commonly evaluated using the body mass index (BMI), which is calculated by dividing a person’s weight in kilograms by the square of their height in meters.
Excessive weight gain has been escalating rapidly worldwide, with over one-third of the global population now classified as either overweight or obese. This trend is evident across all age groups and genders, with a more pronounced impact observed among females. Additionally, obesity rates are often linked to the socioeconomic status of nations. As of 2015, an estimated 1.9 billion adults were classified as overweight, including approximately 609 million who were obese, collectively accounting for about 39% of the global population. Recent global statistics reveal that over 1 billion individuals are affected by obesity, including approximately 880 million adults and 159 million children and adolescents as of 2022.
Over the past few decades, obesity rates have surged significantly. Among women, the prevalence rose from 8.8% in 1990 to 18.5% in 2022, while in men, it nearly tripled from 4.8% to 14.0% during the same timeframe. Similarly, childhood obesity has seen a steep increase, with rates for individuals aged 5-19 years climbing from 4% in 1975 to almost 20% by 2022.
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Classifying Obesity
Obesity can be classified using various methods, including body mass index (BMI), abdominal girth (AG), and body fat percentage (BF%). Each of these approaches has its own advantages and limitations. BMI is widely used to determine weight status due to its simplicity and low cost, as it only requires self-reported height and weight. In contrast, body fat percentage (BF%) can be assessed using several techniques, some of which involve advanced equipment and skilled technicians. Alternatively, BF% can be measured through bioelectrical impedance analysis (BIA), which uses electrical currents to differentiate tissue types within the body.
Weight classifications based on BMI are as follows: individuals with a BMI over 25 kg/m² are categorized as overweight, while those exceeding 30 kg/m² are classified as obese. A BMI between 18.5 and 25 kg/m² is considered normal, whereas a BMI below 18.5 kg/m² indicates underweight status. According to WHO guidelines, individuals with a BMI below 18.5 kg/m² are classified as underweight, while those within the 18.5-24.9 range fall under the normal weight category. A BMI of 25-29.9 is considered overweight, whereas obesity is further categorized into the following three classes based on severity: class I obesity (BMI: 30-34.9 kg/m²), class II obesity (BMI: 35-39.9 kg/m²), and class III obesity (BMI: ≥40 kg/m²). These classifications are widely utilized in clinical and research settings to assess obesity-related health risks and guide medical interventions.
A waist-to-hip ratio above 0.90 for men and 0.85 for women is widely recognized as indicative of an increased risk for obesity-related complications. Consequently, this metric is valuable not only for identifying obesity but also for predicting adverse health outcomes associated with abnormal fat distribution.
The Complex Mechanisms Behind Obesity
Obesity can result from a variety of mechanisms. It has been attributed to an imbalance where energy intake significantly exceeds the energy expended by the body. This imbalance causes fat cells to enlarge abnormally, disrupting the nutrient signaling pathways that contribute to obesity. However, recent research suggests that the source and quality of nutrients in a diet are more critical than their quantity for effective weight management and disease prevention. Additionally, genetic predisposition plays a significant role in influencing an individual’s susceptibility to weight gain. Factors such as the accumulation of lipid metabolites, inflammatory processes, and dysfunction in hypothalamic neurons may also contribute to obesity, potentially explaining the biological mechanisms that favor the maintenance of excessive body fat.
Obesity is influenced by multiple factors, including dietary habits, energy balance, family history, lifestyle choices, gut microbiota, genetic predisposition, and epigenetic modifications. Genetic mutations in leptin (LEP), leptin receptor (LEPR), proopiomelanocortin (POMC), melanocortin 4 receptor (MC4R), and fat mass and obesity-associated gene (FTO) play a pivotal role in obesity. These alterations interfere with appetite control, metabolic balance, and energy regulation, contributing to excessive fat accumulation and an elevated risk of obesity. Recent research underscores the significance of small integral membrane protein 1 (SMIM1) - a gene encoding a small membrane protein - in regulating energy metabolism and body weight. The study demonstrates that a deficiency in SMIM1 correlates with a marked reduction in energy expenditure, thereby increasing susceptibility to weight gain and obesity. Functionally, SMIM1 is integral to metabolic processes that sustain energy balance, likely by modulating pathways involved in energy utilization and lipid oxidation. In scenarios where SMIM1 is either absent or its function is compromised, these critical metabolic pathways are less efficient, leading to diminished energy consumption and an accumulation of adipose tissue.
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ABCA1 gene polymorphisms influence metabolic dysfunction in obesity by affecting high-density lipoprotein-very-low-density lipoprotein (HDL-VLDL) metabolism, insulin-glucose regulation, and inflammatory pathways. These variations may contribute to the development of metabolic syndrome and related complications. The study revealed that certain variants are associated with decreased expression of ABCA1 in adipose tissue, which in turn impairs cholesterol efflux and disrupts normal lipid metabolism. This impairment leads to the accumulation of lipids in fat cells, thereby contributing to higher body mass indices and an elevated risk of metabolic syndrome.
Inflammation and adipose tissue buildup in obesity involve several cytokines and immune cells. Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) are frequently elevated, leading to chronic low-grade inflammation and reduced insulin sensitivity. Adipose tissue macrophages (ATMs) are also key players, as they shift to a pro-inflammatory state in obesity. This transition exacerbates inflammation and disrupts adipocyte function, ultimately impairing adipose tissue balance and contributing to broader metabolic disorders.
Obesity is linked to a wide range of complications, including cardiovascular conditions, type 2 diabetes, dyslipidemia, obstructive sleep apnea, and obesity hypoventilation syndrome. Behavioral interventions that encourage healthy eating and increased physical activity are recommended as the primary treatment for weight management. However, these methods often fail to achieve and maintain significant weight loss (greater than 10%) due to adaptive mechanisms, such as reduced energy expenditure and heightened appetite, which act to prevent starvation. When lifestyle modifications alone are insufficient, pharmacological treatments may be introduced to support weight loss, with drug selection tailored to the patient’s existing comorbid conditions. For individuals with severe obesity, bariatric surgery is an option, particularly for those with a BMI over 40 kg/m² or over 35 kg/m² accompanied by at least one comorbidity. Over time, pharmacological approaches to weight management have significantly advanced.
Pharmacological Interventions: Semaglutide and Phentermine
When lifestyle interventions are not sufficient for weight loss, pharmacological treatments become an important option. Among the various drugs studied, phentermine-topiramate and GLP-1 receptor agonists, such as semaglutide, have demonstrated the highest efficacy for lowering total body weight. However, these drugs, along with naltrexone-bupropion, were associated with the greatest number of adverse events leading to discontinuation. Of all the drugs, semaglutide (a GLP-1 receptor agonist) showed the greatest benefit with a similar risk of adverse events as the other drugs.
A systematic review of randomized control trials (RCTs) evaluating weight-lowering drugs versus lifestyle modification identified 143 studies. The drugs identified included GLP-1 agonists, SGLT2 inhibitors, metformin, orlistat, naltrexone-bupropion, pramlintide, and levocarnitine. All drugs except levocarnitine reduced body weight except levocarnitine. All drugs except metformin, SGLT2 inhibitors and pramlintide led to greater than 10% decrease in weight in the majority of participants. The greatest mean difference of percent body weight change was seen with semaglutide (-11.41%, 95% CI -12.54 to -10.27) and phentermine-topiramate (-7.97%, 95% CI -9.28 to -6.66). However, the drugs with the greatest risk (odds ratio) of discontinuation due to adverse events were semaglutide (Odds ratio 2.45), naltrexone-bupropion (2.69), and phentermine-topiramate (2.40).
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Semaglutide: A GLP-1 Receptor Agonist
Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist. It’s commonly sold under the brand names Wegovy and Ozempic in injectable form and Rybelsus in pill form. Although the FDA approved semaglutide for weight loss in 2021, this medication’s use in treating type 2 diabetes and heart disease dates back to Ozempic’s 2017 approval for reducing the risk of heart attack, stroke, or death in people with type 2 diabetes.
It works by mimicking the GLP-1 hormone, causing your body to produce more insulin, lowering your blood sugar levels, and signaling fullness to your brain. It’s designed for long-term use, but people who take semaglutide may experience weight gain if they stop taking the medication. It can affect your body’s response to insulin and insulin-releasing medications, so your doctor may need to adjust your dosages of these medications to reduce the risk of hypoglycemia (low blood sugar). Injectable versions of semaglutide may also affect the absorption of other medications taken orally, including over-the-counter aspirin and allergy medications.
Efficacy of Semaglutide
RCT evidence demonstrates that semaglutide reduces body weight compared with placebo when added to standard lifestyle modification. Indirect mean and categorical weight loss comparisons show that semaglutide (13.7%) achieve a greater percentage average weight loss than liraglutide (5.0%) and bupropion/naltrexone (4.6%).
In a 2021 study, the researchers noted that those who injected semaglutide showed more of a reduction in body weight compared to other people who took other approved weight loss medications, such as phentermine. But keep in mind that only Wegovy is approved for weight loss, and Ozempic and Rybelsus can be used for that purpose only if a doctor prescribes them off-label.
Phentermine: An Appetite Suppressant
Phentermine is a sympathomimetic amine that stimulates your central nervous system. The FDA first approved it as an appetite suppressant in 1959. It’s sold under the brand names Adipex-P, Lomaira, and Suprenza. It’s also sold in combination with a drug called topiramate in a medication called Qsymia. It’s unclear exactly how phentermine reduces appetite, but it may increase neurotransmitter levels in your brain. This medication’s effectiveness may diminish over time, and it’s approved for use for only 12 weeks. It is considered a controlled substance that can be addictive and carries the risk of withdrawal symptoms and potential side effects such as a racing or irregular heartbeat. This medication is not recommended for use in people with glaucoma, hyperthyroidism, or a history of cardiovascular disease.
Efficacy of Phentermine
RCT evidence demonstrates that phentermine/topiramate reduces body weight compared with placebo when added to standard lifestyle modification. Indirect mean and categorical weight loss comparisons show that phentermine/topiramate (9.1%) achieve a greater percentage average weight loss than liraglutide (5.0%) and bupropion/naltrexone (4.6%).
Potential Side Effects
You may experience unpleasant side effects from one of the two drugs or have a strong preference for one type of medication over the other. It’s important to talk with a healthcare professional about any side effects you may experience.
Possible side effects of semaglutide include:
- Nausea and vomiting
- Constipation or diarrhea
- Headache
- Abdominal pain
- Fatigue
- Hypoglycemia
Possible side effects of phentermine include:
- Insomnia
- Headache
- Fast or irregular heartbeat
- Dry mouth
- Mood changes
- Hypertension
- Heart failure
- Hallucinations
- Reduced sex drive
Additionally, people who take high doses of phentermine may experience withdrawal symptoms. This medication may also impair your ability to perform potentially hazardous tasks such as using heavy machinery or driving a car.
Semaglutide and Phentermine: Can They Be Used Together?
Semaglutide and phentermine can generally be used together since they do not interact. But it’s important to check with your doctor about your specific health needs and whether these drugs are appropriate for your care plan. Both semaglutide and phentermine can be used in combination with diet, exercise, and behavioral changes to help with weight loss.
The Broader Context of Obesity Management
Initial treatment recommendations include lifestyle interventions, such as healthy nutrition, increased physical activity, and behavioral modifications, but weight loss is usually modest, and most people regain weight over time. Since most people do not achieve the desired weight loss with lifestyle modification, medications and surgical interventions are often considered.
Cost-Effectiveness Considerations
We evaluated the cost-effectiveness of semaglutide, liraglutide, phentermine/topiramate, and bupropion/naltrexone plus lifestyle modification compared with standard lifestyle modification alone for weight reduction among patients without preexisting diabetes. At the current price net of rebates, the incremental cost-effectiveness ratio for semaglutide and liraglutide exceeded the commonly accepted thresholds. In contrast, branded phentermine/topiramate was cost-effective, primarily because of its lower price.
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