What is the evidence for use, monitoring parameters, and treatment goals of agents for weight loss approved in the last 10 years?

Introduction
Obesity is a health condition involving excessive body fat, which increases the risk of developing other chronic conditions such as hypertension, type 2 diabetes mellitus (T2DM) , and cardiovascular disease .¹ Before the COVID-19 pandemic, the prevalence of obesity in the United States from 2017 to March of 2020 was reported by the Centers for Disease Control and Prevention (CDC) at 41.9%.²  The pandemic has since fueled obesity in much of the nation with reports from the American Psychological Association (APA) stating that 42% of surveyed adults reported an average weight gain of 29 pounds.

The CDC and the National Institutes of Health (NIH) continue to recommend that individuals who are obese (body mass index [BMI] > 30 kg/m²) or overweight (BMI 25 to 29.9 kg/m²) with comorbid conditions (e.g., prediabetes, diabetes, hypertension, and dyslipidemia) should aim to lose 5% to 10% of their total body weight.^3,4 Recent advances in obesity management have identified 3 major treatment modalities which include lifestyle modifications, pharmacotherapy, and weight-loss procedures.⁵ Lifestyle interventions, also referred to as behavioral weight control, are recommended as first-line treatment for obesity because they have the most robust evidence of weight loss and long-term health benefits.^6,7 These interventions revolve around dietary changes, increase in physical exercise, and behavioral modifications.

Pharmacotherapy and weight-loss procedures are typically reserved for patients that have previously failed to achieve adequate weight loss through lifestyle modifications alone.⁸ Currently approved weight-loss medications promote satiety through neuronal stimulation, blocking absorption of fat, or preventing glucose reabsorption in the kidney. Weight loss is a continuous process, and it is likely for weight gain to return once these medications are discontinued. There are 5 medications approved by the U.S. Food and Drug Administration (FDA) for the long-term (>12 weeks) treatment of obesity: orlistat (Xenical, Alli), phentermine/topiramate ER (Qsymia), naltrexone/bupropion ER (Contrave), liraglutide (Saxenda), and semaglutide (Wegovy).^9-14 All of these agents, except orlistat, were recently approved within the last 10 years. Therefore, it is important to understand the key differences between these newer pharmacotherapies in order to select an appropriate agent for weight loss. Table 1 summarizes general information regarding these 4 recently approved agents for obesity.

Clinical Guideline Recommendations

The American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) published a comprehensive review of clinical practice guidelines for the medical care of patients with obesity in 2016.⁵ The weight-loss goal for patients who are overweight or obese ranges from 5% to 15% depending on weight-related comorbidities. These guidelines further support evidence-based lifestyle therapy as first-line treatment for obesity, which consists of healthy meal plans, physical activity, and behavioral interventions. Pharmacotherapy may be considered after lifestyle modifications have failed to prevent progressive weight gain. The AACE/ACE does not recommend one weight-loss medication over another, but rather promotes the selection of an agent based on individual patient clinical characteristics. To note, these guidelines were published in 2016, prior to the FDA-approval of semaglutide (Wegovy) in 2021 and the removal of lorcaserin (Belviq) in 2020.

Other published guidelines for obesity management are published by the United States Veterans Health Administration (VHA) (2020) and the Endocrine Society (2015).^8,15 Both of these guidelines recommend diet and exercise as a first-line treatment for obesity management. Pharmacotherapy with FDA-approved medications should be considered for patients with a BMI ≥ 30 kg/m² or BMI ≥ 27 kg/m² and at least one comorbid condition associated with obesity (such as hypertension, diabetes, dyslipidemia, cardiovascular disease, or obstructive sleep apnea). The Endocrine Society recommends an assessment of safety and efficacy of a newly initiated medication at 3 months.⁸ If the patient has lost 5% of their baseline weight after 3 months, the weight loss medication should be continued. When selecting between weight-loss medications, both guidelines recommend selecting medications based on patient-specific factors and medication-related factors. The VHA recognizes phentermine/topiramate ER, naltrexone/bupropion ER, orlistat, and liraglutide as acceptable agents for chronic weight loss management.¹⁵

The management of obesity in patients with T2DM  was recently updated by the American Diabetes Association (ADA) in 2022.¹⁶ Similar to other guidelines, the ADA recommends lifestyle modifications as first-line therapy for patients with T2DM who are overweight or obese. A goal of > 5% weight loss is recommended to improve glycemic control and provide additional cardiovascular benefits. Weight-loss medications have shown to be effective in patients with T2DM in addition to lifestyle therapy by improving glycemic control and delaying the progression of T2DM. The ADA does not recommend one weight-loss medication over another. The medications included in these guidelines are divided into short-term treatment ( 12 weeks): orlistat (Xenical, Alli), phentermine/topiramate ER (Qsymia), naltrexone /bupropion ER (Contrave), liraglutide (Saxenda), and semaglutide (Wegovy). While there is no maximum duration of therapy for these weight-loss medications, the ADA recommends evaluating the patient’s response to therapy after 3 months of use. If > 5% weight loss is achieved by 3 months, it is likely the patient may benefit from continued therapy; however, if < 5% weight loss is observed, or if there are significant safety or tolerability issues, the medication should be discontinued.

Literature Review

All 4 agents below are indicated for weight loss in adjunct to lifestyle modifications for adults with an initial BMI > 30 kg/m² (obese) or BMI > 27 kg/m² (overweight) in the presence of at least 1 weight-related comorbidity.^11-14

Phentermine/topiramate ER
Phentermine/topiramate ER was approved based on 2 randomized controlled trials (RCTs).  The CONQUER (2011) trial demonstrated that after 56 weeks of treatment in overweight or obese patients (BMI between 27 and 45 kg/m²), a 9.8% and 7.8% weight loss was achieved in patients who took phentermine/topiramate 15 mg/92 mg and 7.5 mg/46 mg daily, respectively, compared with 1.2% weight loss in the placebo group (p < 0.0001).¹⁷ Similarly, the EQUIP (2012) study showed that after 56 weeks of treatment in obese patients (BMI between 35 and 71 kg/m²), a 10.9% and 5.1% weight loss was achieved in patients who took phentermine/topiramate 15 mg/92 mg and 3.75 mg/23 mg daily, respectively, compared with 1.6% weight loss in the placebo group (p < 0.0001).¹⁸ A follow-up study, SEQUEL (2012), demonstrated similar efficacy and safety of phentermine/topiramate over a 2-year period.¹⁹

Naltrexone/bupropion ER
Naltrexone/bupropion ER was studied in 4 RCTs that evaluated its safety and efficacy for weight loss in conjunction with lifestyle modifications. The COR-I (2010) and COR-II (2013) trials found that patients that were obese or overweight with dyslipidemia and/or hypertension taking naltrexone/bupropion 32 mg/360 mg daily experienced a 6.1% and 6.4% weight loss compared to 1.3% and 1.2% weight loss with placebo, respectively.^20,21 The COR-BMOD (2011) evaluated the efficacy of naltrexone/bupropion when used together with an intensive behavioral modification program, in addition to the diet and exercise regimens utilized in COR-I and COR-II.²² Participants treated with naltrexone/bupropion 32 mg/360 mg daily in addition to behavioral modifications, diet, and exercise achieved a 9.3% reduction in weight compared to only 5.1% with behavioral modifications, diet, and exercise alone (p < 0.001). Lastly, the COR-Diabetes (2013) enrolled patients that were obese or overweight with T2DM, with or without hypertension and/or dyslipidemia, and found a 5.0% weight reduction with naltrexone/bupropion daily compared to 1.8% with placebo (p < 0.001).²³

Liraglutide
Liraglutide was approved based on 3 RCTs known as the SCALE trials (SCALE, SCALE Maintenance, and SCALE Diabetes).^24-26 Participants in all these studies were randomly assigned to receive either daily liraglutide 3 mg or placebo and were followed over a course of 56 weeks. All 3 studies demonstrated that patients taking liraglutide experienced significantly more weight loss than those on placebo. Patients on 3 mg of liraglutide lost an average of 6% to 8% of baseline body weight compared to an average of 0.2% to 2.6% weight loss in patients on placebo. Furthermore, 50.5% to 63.3% of patients who received liraglutide lost >5% of their baseline weight compared to 21.8% to 27.1% of patients on placebo. In the SCALE Maintenance trial, 81.4% of patients maintained a 5% weight loss after a run-in low-calorie diet phase.²⁵ Most recently, liraglutide was approved for use in adolescents 12 years of age and older after a trial conducted over 56 weeks among 251 patients aged 12 to 17 years.²⁷ This study found that, in addition to lifestyle therapy, patients on 3 mg daily liraglutide had a significant weight loss, on average, of 2.65% from baseline compared to a 2.37% weight gain in patients on placebo.

Semaglutide
Semaglutide was approved for weight loss in adults based on 4 trials known as the STEP trials (STEP 1 to STEP 4).^28-31 Patients in all trials were randomly assigned to receive either daily semaglutide 2.4 mg or placebo and were followed for 68 weeks. The STEP 2 trial included an additional arm that received semaglutide 1 mg.²⁹ All 4 studies demonstrated that patients taking semaglutide experienced significantly more weight loss than those on placebo.^28-31 Patients on 2.4 mg of semaglutide had a mean weight loss ranging from lost an average of 7.9% to 16% of body weight from baseline. Furthermore, 68.8% to 88.7% of patients lost >5% of their baseline weight compared to 28.5% to 47.6% of patients on placebo. Patients in the STEP 1, 3, and 4 studies who lost 10% of their weight or more ranged from 69.1% to 79% of patients on semaglutide compared to 15% to 27% of patients on placebo.^28,30,31 

Comparative Studies
Table 2 provides a summary of a recent systematic review and meta-analysis (Shi et al) of 143 RCTs (N=49,810) evaluating the comparative safety and efficacy of various weight loss agents.³² All medications listed in Table 2, which only summarizes the evidence reported on phentermine/topiramate, naltrexone/bupropion, liraglutide, and semaglutide, significantly lowered body weight compared to lifestyle modifications alone. Other agents that were included in the analysis were orlistat, metformin, sodium-glucose co-transporter-2 (SGLT2) inhibitors, pramlintide, and levocarnitine. Initially, high to moderate certainty evidence indicated that phentermine/topiramate was the most effective weight lowering agent, followed by the GLP-1 receptor agonists. However, after a post-hoc analysis, GLP-1 receptor agonists, specifically semaglutide, demonstrated a significantly greater percentage body weight change (mean difference -11.41; 95% confidence interval [CI], -12.54 to -10.27) and weight loss ≥ 5% (odds ratio 9.82; 95% CI 7.09 to 13.61) than the other medications included in these studies. However, this study was analyzed to have a high risk of bias in the primary outcome because of deviations from the intended interventions and missing outcome data.

Conclusion
Various FDA-approved treatments for chronic weight management differ in their mechanisms, efficacy, safety, and dosing profiles. Pharmacotherapy may be considered after lifestyle modifications have failed to prevent progressive weight gain, and current guidelines (from organizations such as AACE/ACE, ADA, Endocrine Society and VHA) do not recommend one weight-loss medication over another, but rather promote the selection of an agent based on individual patient clinical characteristics and weight loss goals. It is important to understand the key differences between these pharmacotherapies in order to select an appropriate agent in chronic weight loss treatment.

References

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Prepared by:

Ellie Braun and Lubna Hassan
PharmD Candidates Class of 2023
University of Illinois at Chicago College of Pharmacy

Reviewed by:

Faria Munir, PharmD, MS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

Rita Soni, PharmD
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

August 2022

The information presented is current as July 15, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.