Pharmacologic Treatment

Introduction

The development and approval of new antiobesity drugs is particularly challenging. In addition to safety concerns, the Food and Drug Administration (FDA) criteria for a drug to be approved for treatment of obesity are quite stringent. A new agent must induce statistically significant placebo-adjusted weight loss of ≥5% at 1 year or that ≥35% of patients should achieve >5% weight loss (which must be at least twice that induced by placebo). In addition, the FDA also requires that the medication shows evidence of improvement in metabolic biomarkers, including blood pressure (BP), lipids and glycemia.

The search for safe and effective pharmacologic weight-loss agents began in the late 19th century with the discovery that sheep thyroid extract increased metabolic rate and induced significant weight loss. However, the use of thyroid hormone treatment in euthyroid patients increased the risk of cardiac arrhythmias and cardiac arrest. Subsequently, many different classes of pharmacologic agents, such as centrally acting amphetamine derivatives and 5-HT–releasing agents appeared (and then disappeared) over the next half century. As a result, very few approved weight-loss drugs were available prior to 2012 (Table 9-1).

Centrally acting amphetamine derivatives (desoxyephedrine, phentermine and diethylpropion) were among the earliest pharmacologic agents used for weight loss. However, growing concerns about cardiovascular (CV) risk and abuse potential led to a decline in their use by the early 1970s. Although still available in many countries, phentermine and diethylpropion were largely superseded in the 1970s and 1980s by the 5-HT–releasing agents fenfluramine and dexfenfluramine. In the early 1990s, evidence of superior efficacy over either compound given alone led to the widespread use in the United States of the combined treatment with phentermine and fenfluramine (fen-phen). Within only a few years, reports of cardiac valvulopathy associated with fenfluramine and dexfenfluramine (particularly in combination with phentermine) resulted in withdrawal of these two agents from the market. Although fenfluramine and dexfenfluramine were withdrawn due to safety concerns, phentermine as monotherapy was considered safe and was not withdrawn from the market. Phentermine continued to be the most commonly prescribed drug.

Despite an inauspicious history, the pharmacologic management of obesity is at an exciting crossroad. Research has identified many new therapeutic targets. Currently available treatment options in the United States include phentermine, orlistat, a fixed-dose combination of phentermine and topiramate extended-release (ER), a fixed-dose combination of naltrexone sustained release (SR) and bupropion SR, liraglutide, semaglutide and tirzepatide. Semaglutide, which was approved in June 2021, and tirzepatide, which was approved in November 2023, have demonstrated a strikingly significant weight reduction induced by a therapeutic agent, with one third of patients achieving efficacy comparable to metabolic and bariatric surgeries. Notably, lorcaserin, a selective 5-HT2C receptor agonist which has been previously been used, was withdrawn from the market in February 2020 due to increased risk of various cancers.

Currently, seven antiobesity medications are approved by the FDA:

• Phentermine
• Orlistat
• A fixed-dose combination of phentermine and topiramate ER
• A fixed-dose combination of naltrexone SR and bupropion SR
• Liraglutide
• Semaglutide
• Tirzepatide

The choice of which antiobesity pharmacotherapy to initiate must be individualized to the patient taking into consideration their goals, their unique challenges with weight loss, the presence of any co-existing medical conditions, and any contraindications to specific medications or drug-drug interactions. Once a medication is initiated, patients should be assessed at regular intervals (preferably at least monthly for the first three months) to assess its efficacy, which is typically defined as ≥5% total body weight loss at three months, and to assess its safety. If a medication is not effective, or if it is causing intolerable side effects, it should be discontinued and a different medication started. If a patient is successful with any given medication but reaches a weight loss plateau (typically defined as no weight loss over 1-3 months), the medication should not be discontinued abruptly as it may lead to weight regain. Instead, consider increasing the dose of that medication if possible or adding on a different medication which may target a different pathway and lead to additional weight loss. Given that obesity is a chronic disease, any medication that is started for the treatment of obesity should be considered a long-term medication and patients will require long-term treatment and follow-up to ensure weight loss maintenance. Clinical trials, including STEP 4 and SURMOUNT-4 (see the semaglutide and tirzepatide sections below) support the idea that discontinuing medications at the patient’s desired goal weight may lead to weight regain, and therefore is typically not recommended.

Table 9-2 provides summaries of the prescribing information for these medications. The rest of this section is dedicated to sections discussing the currently available agents. These sections include discussion of the currently published trials that support the safety and efficacy of each drug. However, it is important to keep in mind that this is a rapidly developing field, with many other studies in the pipeline, especially for the newer agents (i.e., GLP-1 receptor agonists).

Phentermine

Phentermine, approved in 1959, has historically been the most commonly prescribed antiobesity agent in the United States. Phentermine is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of this class (e.g., amphetamines). It is believed to suppress appetite. The approved duration of treatment is only 3 months because of a lack of understanding of the chronic nature of obesity, and because the safety data for phentermine came from a short-term study. Phentermine is approved for use in adolescents 17 years of age and older.

Efficacy

The efficacy of continuous vs intermittent phentermine was evaluated in an early 36-week, double-blind, placebo-controlled study in 108 women who had overweight or obesity. Patients were randomized into three groups: one group received phentermine continuously for 36 weeks, another group received placebo continuously and the third group alternated phentermine and placebo every 4 weeks (Figure 9-1). The mean weight loss was -12.2 and -13.0 kg in patients who received phentermine continuously and intermittently, compared with -4.8 kg in the group treated with placebo. Attrition was 41% and data were presented for completers only. Statistical differences were not reported. Individual responses to therapy were variable but irrespective of the method employed, weight loss diminished with duration of treatment. Furthermore, there seemed to be no advantage in taking phentermine continuously.

Studies investigating the use of phentermine alone for weight loss published in the 1960s and 1970s typically presented only completer analyses and had high dropout rates leading to an overstatement of efficacy. A more recent study by Aronne and colleagues investigating the differences in weight loss using phentermine alone vs in combination reported weight loss of 5.1% at 28 weeks.

Safety

The most common treatment-emergent adverse events (TEAEs) with phentermine include:

• Dizziness
• Dry mouth
• Difficulty sleeping
• Irritability
• Nausea
• Vomiting
• Diarrhea
• Constipation.

Prescribing, Dosing and Administration

The recommended dosage of phentermine is 15 mg to 37.5 mg orally once daily before breakfast or 1 to 2 hours after breakfast, or 8 mg up to three times daily 30 minutes before meals (Table 9-2). Dosage should be individualized to obtain an adequate response (in this case, appetite suppression) with the lowest effective dose. For example, a sufficient dose for some patients may be as low as a half tablet of the 8 mg daily tablet. Other patients may benefit from taking a half tablet of 37.5 mg twice daily. Administration in the late evening should be avoided because it may lead to insomnia.

Consider prescribing phentermine to patients who would benefit from appetite suppression.

Phentermine is not recommended for use in pediatric patients ≤16 years of age. Phentermine is a schedule IV controlled substance.

Orlistat

Orlistat is indicated for the treatment of obesity, including weight loss and weight maintenance, when used in conjunction with a reduced-calorie diet. It also is indicated to reduce the risk for weight regain after prior weight loss. Orlistat is approved for use in adults and children and adolescents 12 years of age or older. Unlike the other weight-loss agents which reduce appetite and/or enhance energy expenditure, orlistat inhibits pancreatic and gastric lipases, thereby reducing fat absorption from the gut.

Efficacy

The efficacy of orlistat was demonstrated in a 4-year, double-blind, prospective study in which 3305 patients were randomized to lifestyle changes plus either orlistat 120 mg or placebo three times daily. Patients had a BMI ≥30 and normal (79%) or impaired (21%) glucose tolerance (IGT). Mean weight loss after 4 years was significantly greater with orlistat (5.8 vs 3.0 kg with placebo; P <0.001) and similar between orlistat recipients with impaired or normal glucose tolerance at baseline (Figure 9-2). In addition to causing significant weight loss after 4 years relative to placebo, the cumulative incidence of diabetes was 9.0% with placebo and 6.2% with orlistat, corresponding to a risk reduction of 37.3% (P <0.0032).

Safety

Most common TEAEs with orlistat (5% and at least twice that of placebo) include:

• Oily spotting
• Flatus with discharge
• Fecal urgency
• Fatty/oily stool
• Oily evacuation
• Increased defecation
• Fecal incontinence.

Prescribing, Dosing and Administration

Orlistat is available in a 60 mg capsule (over the counter) and a 120 mg capsule (prescription). The recommended dosage of orlistat is one capsule three times a day with each main meal containing fat during or up to 1 hour after the meal (Table 9-2).

• Advise patients to take a nutritionally balanced, reduced-calorie diet that contains approximately 30% of calories from fat.
• Distribute the daily intake of fat, carbohydrate and protein over three main meals.
• Advise patients to take a multivitamin containing fat-soluble vitamins to ensure adequate nutrition.

Phentermine/Topiramate ER

This fixed-dose combination formulation of phentermine and topiramate ER (phen/top ER) was approved by the FDA in 2012 as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults who have obesity (BMI ≥30) or overweight (BMI ≥27) and at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, or Type 2 Diabetes (T2D)). Phentermine is also approved by the FDA as monotherapy for the treatment of obesity, as above. Topiramate is FDA approved as monotherapy for the treatment of epilepsy (1996) and for migraine prophylaxis (2004).

Although the exact mechanism of action is not known, the effect of phentermine on body weight is likely mediated by release of catecholamines in the hypothalamus, resulting in reduced appetite and decreased food consumption, but other metabolic effects may also be involved. The precise mechanism of action of topiramate on body weight is also not known, although it may be due to its effects on both appetite suppression and satiety enhancement induced by a combination of pharmacologic effects with various neurotransmitters. The combination of phentermine with topiramate has been shown to have a greater weight-loss benefit than either medication alone while mitigating the side-effect profile.

Efficacy

The efficacy of phen/top ER on weight loss was assessed in two 1-year randomized, double-blind, placebo-controlled studies (EQUIP and CONQUER), and a 2-year extension trial (SEQUEL). Both studies included a 4-week titration period followed by 52 weeks of treatment. The SEQUEL study was a placebo-controlled, double-blind, 52-week extension (for a total of 108 weeks of treatment) in patients who completed the CONQUER study. During these studies, a well-balanced, reduced-calorie diet to result in an approximate 500 kcal/day decrease in caloric intake was recommended to all patients and patients were offered nutritional and lifestyle modification counseling. The two co-primary efficacy outcomes in these studies after 1 or 2 years of treatment were:

• Percent weight loss from baseline
• Treatment response defined as achieving ≥5% weight loss from baseline.

The efficacy results from these trials of phen/top ER are summarized in Table 9-3.

The EQUIP trial included only patients with class II and III obesity (BMI ≥35 with no upper limit), while the CONQUER trial included patients with both overweight and obesity (BMI 27-45) with ≥2 significant comorbidities, including elevated BP or requirement for ≥2 antihypertensive medications; triglycerides >200-400 mg/dL or treatment with ≥2 lipid-lowering agents; elevated fasting plasma glucose (FPG) (>100 mg/dL) or diabetes; and/or waist circumference ≥102 cm for men or >88 cm for women. Patients with T2D were excluded from participating in the EQUIP study while diabetic patients were neither specifically included nor excluded in the CONQUER study.

EQUIP

This trial randomized a total of 1,267 patients to receive placebo, phen/top ER 3.75/23 mg, or phen/top ER 15/92 mg once daily. Overall, mean age was 42.7 years, BMI was 42.0, mean waist circumference was 120.8 cm and 83% were female, with a substantial representation of Black patients (16% to 18%). There were no significant between-group differences in any baseline variable. A total of 59.9% of randomized patients completed the study regardless of whether they continued taking their assigned treatment (52.9% placebo, 61.0% phen/top ER 3.75/23 mg, 66.4% phen/top ER 15/92 mg; (P <0.0001 for difference), while 53.7% reported taking the assigned study drug/placebo for the full intended treatment period (46.9% placebo, 57.3% phen/top ER 3.75/23 mg, 58.8% phen/top ER 15/92 mg; P = 0.0003 for difference). The most common reasons for discontinuation were lost to follow-up or withdrawal of consent (more common in placebo than active treatment groups) or AEs (more common in active treatment than placebo groups). Overall, discontinuations were lower in patients receiving active treatments.

Treatment with each phen/top ER dosage resulted in statistically significant weight loss from baseline compared with placebo during 56 weeks of treatment (Figure 9-3). The percent weight loss from baseline was significantly greater with phen/top ER 15/92 mg than with phen/top ER 3.75/23 mg. In addition, a significantly greater proportion of patients randomized to either dosage of phen/top ER achieved weight loss of either ≥5% or ≥10% (Table 9-3). In this study in which all patients had obesity, a separate analysis showed that these results did not differ significantly according to baseline BMI.

CONQUER

In this trial, a total of 2,487 patients were randomized to treatment with placebo (n = 979), phen/top ER 7.5/46 mg (n = 488), or phen/top ER 15/92 mg (n = 981) once daily. Baseline patient characteristics were similar across treatment groups: 70% patients were women and 86% were White. Overall, 11% of patients were Black. The mean age for the whole group was 51.1 years, mean body weight was 103.1 kg and BMI was 36.6. At baseline, 52% of patients had hypertension, 36% had hypertriglyceridemia, 68% had IGT or IFG (including T2D) and 16% had T2D. Overall, half of patients had ≥3 protocol-specified comorbidities and virtually all (98%) had abdominal obesity. A total of 38% of patients prematurely discontinued the study drugs (43% placebo, 31% phen/top ER 7.5/46 mg, and 36% in the phen/top ER 15/92 mg groups). However, 69% of all randomized patients had an endpoint (week 56) assessment.

Compared with placebo, both dosages of phen/top ER resulted in and maintained significantly greater weight losses throughout the 56-week course of treatment (Figure 9-4). The reductions from baseline body weight with both dosages of phen/top ER were significantly greater than with placebo (Table 9-3). In addition, the reduction with phen/top ER 15/92 mg was significantly greater compared with phen/top ER 7.5/46 mg. Significantly more patients who received either phen/top ER dosages achieved a ≥5% and/or ≥10% weight reduction from baseline compared with placebo. Significantly more patients achieved these goals with the phen/top ER 15/92 mg dosage compared with the lower dosage.

Long-Term Efficacy

SEQUEL

The study was a placebo-controlled, double-blind, 108-week extension study in which volunteers who had completed the CONQUER study continued with their original randomly assigned treatment: placebo (n = 227), phen/top ER 7.5/46 mg (n = 153), or phen/top ER 15/92 mg (n = 295) to complete a total of 108 weeks of treatment. All patients participated in a lifestyle-modification program. Baseline demographic, anthropometric and clinical characteristics, including comorbidities, were similar among patients in all three treatment arms of the study. Overall, 84.0% of patients completed the extension study, including 86.3% of those assigned to placebo, 82.5% of those assigned to phen/top ER 7.5/46 mg and 83.1% of those in the phen/top ER 15/92 mg group.

Patients in both active treatment arms experienced significantly greater percentage weight losses compared with those in the placebo arm and these weight losses were maintained at all time points during 108 weeks of treatment compared with placebo (Figure 9-5). At week 108, the mean percentage changes from baseline in body weight were significantly greater (P <0.0001) in the phen/top ER groups compared with placebo (-1.8%, -9.3%, and -10.5% with placebo, phen/top ER 7.5/46 mg, and phen/top ER 15/92 mg, respectively). In addition, significantly greater proportions of patients treated with each dosage of phen/top ER achieved weight losses of ≥5% and ≥10% compared with placebo-treated patients (Table 9-3).

Secondary Efficacy Endpoints

All three of these trials also assessed changes from baseline in metabolic, CV and anthropomorphic risk factors associated with obesity.

In the EQUIP trial, patients treated with phen/top ER 15/92 mg had significantly greater changes compared with those in the placebo group in:

• Systolic blood pressure (SBP) and diastolic blood pressure (DBP)
• Heart rate
• Total cholesterol
• LDL cholesterol
• HDL cholesterol
• Triglycerides
• Fasting glucose
• Waist circumference (Table 9-4).

Patients in the phen/top ER 3.75/23 mg group experienced numerically, but not always significantly different changes, except the changes in systolic blood pressure (SBP) and waist circumference were significant.

In the CONQUER study, phen/top ER 15/92 mg compared with placebo showed significant changes in:

• BP
• Waist circumference
• Concentrations of lipids
• Fasting glucose and insulin (Table 9-4).

Improvements in risk factors were most pronounced in patients with pre-existing comorbid diseases. In patients with hypertension at baseline, there were greater reductions in SBP with both dosages of phen/top ER than with placebo and more patients had their antihypertensive drugs withdrawn in the phen/top ER 7.5/46 mg group. Patients with diabetes at baseline had greater reductions in A1C with both dosages. Patients with prediabetes had greater reductions in fasting blood glucose and fewer patients progressed to T2D.

In the SEQUEL study, treatment with phen/top ER 15/92 mg compared with placebo resulted in significantly greater changes from baseline in:

• Lipid parameters and triglycerides
• Fasting glucose and insulin
• Waist circumference (Table 9-4).

In the phen/top ER 7.5/46 mg group, changes were significantly greater compared with placebo in LDL cholesterol, triglycerides, fasting insulin, A1C and waist circumference. Among patients without diabetes at baseline, the annualized incidence rates for progression to T2D were 3.7%, 1.7% and 0.9% in the placebo, phen/top ER 7.5/46 mg and phen/top ER 15/92 mg treatment groups, respectively. These findings indicate a 54% reduction in the progression to T2D.

Safety

In the 1-year clinical trials with phen/top ER, AEs that occurred at a rate of ≥5% and at a rate at least 1.5 times placebo included paresthesia, dizziness, dysgeusia, insomnia, constipation and dry mouth (Table 9-5). Dose-related trends in the incidences of such AEs were noted. Other less frequent events occurring more commonly with the highest phen/top ER dosage included:

• Depression
• Irritability
• Alopecia
• Anxiety
• Disturbance in attention
• Hypoesthesia.

Serious adverse events (AEs) were similar across treatment groups. Most AEs reported were mild in severity and the rates of serious AEs were similar across treatment groups.

In the 1-year placebo-controlled clinical studies, the rates of discontinuations due to AEs were:

• Phen/top ER 3.75/23 mg: 11.6%
• Phen/top ER 7.5/46 mg: 11.6%
• Phen/top ER 15/92 mg: 17.4%
• Placebo: 8.4%.

The most common AEs that led to discontinuation of treatment are shown in Table 9-5.

In the SEQUEL study, the most common treatment emergent AEs were upper respiratory tract infection, constipation, paresthesia, sinusitis and dry mouth. The types of TEAEs that occurred between weeks 56 and 108 were similar to those reported in the overall CONQUER population sample from weeks 0 to 56. However, the incidence of individual TEAEs was markedly lower in the second year (weeks 56 to 108) than in the first year (weeks 0 to 56). The incidences of serious AEs from weeks 0 to 108 were 6.2% with placebo, 5.9% with both phen/top ER 3.75/23 mg and phen/top ER 7.5/46 mg and 8.1% with phen/top ER 15/92 mg. The percentage of patients who discontinued due to AEs by week 108 was also similar across treatment groups (3.1%, 4.5% and 4.4% in the placebo, phen/top ER 7.5/46 mg and phen/top ER 15/92 mg groups, respectively).

Prescribing, Dosing and Administration

Phen/top ER is available in four dosage levels of phentermine and topiramate ER (Table 9-2). The lowest-dose formulation contains phentermine 3.75 mg and topiramate ER 23 mg, the mid-level formulation contains phentermine 7.5 mg and topiramate ER 46 mg and the highest dosage formulation contains phentermine 15 mg and topiramate ER 92 mg. Another dosage level containing phentermine 11.25 mg and topiramate ER 69 mg is recommended for use during dosage titration, ie, during a 14-day period while escalating to the maintenance dose of 15/92 mg. The dosages of the individual component agents are considerably lower than the previously approved maximum recommended doses for other indications. This was by design in order to minimize AEs.

Consider prescribing phen/top for patients requiring appetite suppression and enhanced satiety. Additionally, consider this medication for patients who also have migraines, as the topiramate may help with migraine prophylaxis.

Phen/top ER should be taken once daily in the morning with or without food. Avoid dosing in the evening due to the possibility of insomnia. Gradual dose titration is required (Table 9-2).

All dosage formulations of phen/top ER are controlled in Schedule IV of the Controlled Substances Act because they contain phentermine, a Schedule IV drug. Topiramate ER is not controlled as a Schedule IV drug. The FDA requires a Risk Evaluation and Mitigation Strategy to inform women of reproductive potential about the increased risk of orofacial clefts in fetuses exposed to phen/top during the first trimester of pregnancy.

Naltrexone SR/Bupropion SR

Bupropion is a norepinephrine and dopamine reuptake inhibitor that was approved by the FDA as an antidepressant (1989) and for smoking cessation (1997). Naltrexone is an opioid antagonist that was approved by the FDA for the treatment of opioid dependence (1984) and the treatment of alcohol use disorder (1994). The fixed-dose formulation of naltrexone SR/bupropion SR (nal/bup) was developed based on preclinical evidence that this combination has complementary actions in the CNS that result in reduced food intake. Bupropion stimulates hypothalamic proopiomelanocortin (POMC) neurons, with downstream effects to reduce food intake and increase energy expenditure. Naltrexone blocks opioid receptor-mediated POMC autoinhibition, augmenting POMC firing in a synergistic manner. Given the known individual effects of naltrexone and bupropion on addiction (alcohol and nicotine, respectively), a fixed combination of nal/bup was hypothesized to induce weight loss through sustained modulation of CNS reward pathways. Nal/bup was approved by the FDA for the treatment of obesity in 2014.

Efficacy

The efficacy of nal/bup was assessed in several clinical trials that used various dosage combinations. An early dose-ranging study in a total of 419 patients with uncomplicated obesity randomized patients to 24 weeks of treatment with bupropion SR (400 mg/day), immediate-release naltrexone (48 mg/day), or placebo and three combination therapy groups consisting of immediate-release naltrexone, 16, 32, or 48 mg/day, plus bupropion SR (400 mg/day), with a 24-week extension. A minimal diet and exercise component was also included. Weight loss with combination therapy was statistically significant vs monotherapy for all three nal/bup combinations with the exception of nal/bup 48/360 mg vs bupropion. Weight loss with nal/bup continued after week 24.

Subsequent, four 56-week phase 3 trials (Contrave Obesity Research I [COR-I], Contrave Obesity Research II [COR-II], Contrave Obesity Research Behavioral Modification [COR-BMOD] and Contrave Obesity Research-Diabetes [COR-Diabetes]) enrolled patients with obesity (BMI 30-45) or overweight and obesity (BMI 27-45) with dyslipidemia and/or hypertension to 56 weeks of treatment with fixed-dose combination formulations of nal/bup or placebo. All patients in the COR-I, COR-II and COR-Diabetes trials were also prescribed a mild hypocaloric diet and exercise. All patients in the COR-BMOD trial were prescribed an energy-reduced diet and 28 group behavioral modification sessions. The co-primary endpoints in all of these trials were percentage change in weight and the proportion of participants who lost ≥5% weight at week 56. All trials included a ~3-week dose escalation period. The efficacy results from these trials of nal/bup are summarized in Table 9-6.

COR-I

In the COR-I study, 1742 patients were randomized in a 1:1:1 ratio to receive placebo, nal/bup 16/360 mg or nal/bup 32/360 mg. Throughout the study, decreases in body weight were greater with nal/bup (Figure 9-6). At week 56, the mean changes in body weight with both nal/bup 16/360 mg (-5.0%) and nal/bup 32/360 mg (-6.1%) were significantly greater (P <0.0001) than with placebo (-1.3%). The change with nal/bup 32/360 mg was significantly greater (P <0.0099) than with nal/bup 16/360 mg (Table 9-6). In addition, significantly greater (P <0.0001) proportions of patients in both nal/bup groups had a decrease in body weight of ≥5% and ≥10% compared with those who received placebo (Figure 9-6).

COR-II

The COR-II study randomized 1496 patients in a 2:1 ratio to nal/bup 32/360 mg or placebo for up to 56 weeks. Patients in the nal/bup 32/360 mg arm with a <5% weight loss at visits between weeks 28 and 44 inclusive were re-randomized (double-blind, 1:1 ratio) to continue receiving nal/bup 32/360 mg or escalate to nal/bup 48/360 mg for the remainder of the study. In the modified intent-to-treat (mITT)-LOCF population, weight loss was significantly greater for nal/bup 32/360 mg vs placebo at week 28 (6.5% vs 1.9%; P <0.001) and was maintained with continued double-blind treatment through week 56 (6.4% vs 1.2; P <0.001). In addition, nal/bup 32/360 mg was associated with significantly larger proportion of participants achieving ≥5%, ≥10% and ≥15% weight loss both in the mITT-LOCF and “completer” populations vs placebo at weeks 28 and 56 (Figure 9-7).

COR-BMOD

Given that intensive behavioral modification programs (BMOD) have been shown to significantly increase weight loss compared with treatment by weight loss medication, the COR-BMOD trial was designed to assess the efficacy of nal/bup 32/360 mg added to a BMOD program compared with BMOD alone. A total of 793 participants (BMI = 36.5 ± 4.2) were randomly assigned in a 1:3 ratio to placebo + BMOD (n = 202); or nal/bup 32/360 mg + BMOD (n = 591). All participants also were prescribed an energy-reduced diet. Throughout the study, decreases in body weight in the mITT-LOCF population were significantly (P <0.001) greater with nal/bup 32/360 mg + BMOD compared with placebo + BMOD (Figure 9-8). At week 56, the mean changes in body weight were significantly greater with nal/bup + BMOD than with BMOD alone (-11.5 % and -7.3%, respectively; P <0.001) (Table 9-6). Similarly, significantly greater (P <0.001) proportions of patients in the nal/bup + BMOD group had a decrease in body weight of ≥5% and ≥10% compared with those who received placebo + BMOD (Figure 9-8).

COR-Diabetes

The efficacy and safety of nal/bup in patients with overweight and diabetes was assessed in the COR-Diabetes trial. 505 individuals with overweight/obesity and T2D with or without background oral antidiabetes drugs were randomized 2:1 to 32 mg/360 mg nal/bup or placebo. In the modified ITT population, nal/bup resulted in significantly greater weight reduction (-5.0% vs -1.8%; P <0.001) and proportion of patients achieving ≥5% weight loss (44.5% vs 18.9%, P <0.001) compared with placebo (Figure 9-9).

Secondary Efficacy Endpoints

In addition to the primary efficacy endpoints, the COR-I, COR-II, COR-BMOD and COR-Diabetes studies also assessed several secondary efficacy endpoints, including changes from baseline in CV, metabolic and anthropometric risk factors associated with obesity. The results are summarized in Table 9-7.

In the COR-1 trial, patients who received either nal/bup 16/360 mg or nal/bup 32/360 mg had significantly greater changes compared with placebo in lipid parameters (HDL-cholesterol, and triglycerides), SBP and DPB, HOMA-IR, and waist circumference. In addition, changes with nal/bup 32/360 mg were significantly greater for fasting glucose and fasting insulin.

In the COR-II study, changes from baseline in all but DBP and fasting glucose were significantly different from the results with placebo.

In the COR-BMOD trial, there were significant changes with nal/bup + BMOD compared with placebo + BMOD in HDL cholesterol, triglycerides, fasting insulin, HOMA-IR and waist circumference. Changes in BP were not assessed.

In COR-Diabetes, nal/bup treatment was associated with improvements in glycemic control and select cardiovascular disease (CVD) risk factors, as shown by significantly greater A1C reduction, percent of patients achieving A1C <7% (53 mmol/mol) and improvement in triglycerides and HDL cholesterol compared with placebo. Nal/bup was associated with higher incidence of nausea, constipation and vomiting. No difference was observed between groups in the incidence of depression, suicidal ideation, or hypoglycemia.

Safety

Nal/bup was generally well-tolerated in the four 56-week, randomized, placebo-controlled trials. Nausea, generally mild to moderate and transient, typically occurring during the dose-escalation period, was the most frequent AE (29.8%, 29.2%, 34.1% and 32.5% in COR-I, COR-II, COR-BMOD and COR-Diabetes respectively). Other AEs reported noticeably more frequently by patients treated with nal/bup included headache, constipation, dizziness, vomiting and dry mouth (Table 9-8). Treatment with nal/bup was not associated with increased reports of depressive or suicidal events compared with placebo.

Prescribing, Dosing and Administration

Nal/bup is available as film-coated, extended-release tablets containing 8 mg naltrexone HCl and 90 mg bupropion HCl and should be taken in the morning and evening. Nal/bup dosing should initially be started as one tablet daily in the morning and escalated by 1 tablet per week during the first 4 weeks, arriving at a total daily dosage of two tablets twice daily from week 4 onwards (Table 9-2).

Total daily doses greater than two tablets twice daily (32 mg/360 mg mg per day) are not recommended. Nal/bup should not be taken with a high-fat meal because of a resulting significant increase in bupropion and naltrexone systemic exposure. Nal/bup should be discontinued if ≥5% weight loss is not achieved by week 12.

Consider prescribing nal/bup to help with appetite suppression and decreased cravings. Providers can also consider prescribing this medication for patients who are also trying to quit smoking, or who are trying to cut back on alcohol intake.

Liraglutide

Liraglutide is a glucagon-like peptide-1 (GLP-1) that is an GLP-1 analogue of human GLP-1, a gut-derived incretin hormone. Liraglutide binds and activates the GLP-1 receptor (i.e., is a GLP-1 receptor agonist), a cell-membrane embedded signaling receptor that is expressed in multiple brain regions that regulate appetite and caloric intake. Liraglutide additionally acts on pancreatic β cells to potentiate glucose-dependent insulin secretion and inhibit glucagon secretion, and in the gastrointestinal tract to inhibit gastric emptying. Native GLP-1 has a short elimination half-life (1 to 2 minutes), whereas liraglutide has a half-life of about 13 hours and therefore can be administered once a day by subcutaneous injection. Liraglutide 1.8 mg daily has been approved for the treatment of T2D, having a significant effect on improving A1C, weight, blood pressure and lipids. Since many patients on liraglutide experienced a dose-dependent weight loss, it appeared to be an attractive treatment option for obesity. Liraglutide 3.0 mg was subsequently approved by the FDA for the treatment of obesity in 2014. Liraglutide 3.0 mg is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial BMI of 30 or greater or 27 or greater in the presence of at least one weight-related comorbid condition. In December 2020, the FDA approved the use of liraglutide for chronic weight management in patients aged 12 and older who have obesity, as defined by specific BMI cut-offs for age and sex that correspond to a BMI 30 or higher for adults, and who weigh more than 60 kg (132 pounds).

Efficacy

In dose-ranging studies, liraglutide 3 mg was found to result in greater weight loss compared to placebo or orlistat. Liraglutide reduced blood pressure and reduced the prevalence of prediabetes. An 84-week, open-label extension following this study switched liraglutide/placebo recipients to liraglutide 2.4 mg after 1 year, then to 3 mg. In the ITT-LOCF population, the mean weight loss from randomization to year 1 was significantly greater with all liraglutide doses compared with placebo and was dose-dependent.

Weight loss for those on liraglutide 3 mg for 2 years was also significantly greater than with orlistat. In addition to weight loss, mean change in waist circumference was significantly greater with liraglutide 3 mg vs placebo. With liraglutide 3 mg, the 2-year prevalence of prediabetes and metabolic syndrome decreased by 52% and 59%, with improvements in BP and lipids. Greater weight loss was also observed in pediatric patients aged between 12 and 18, with 3 mg subcutaneous once-daily injection resulting in greater weight loss compared to placebo measured by change from baseline in the BMI standard deviation score.

SCALE Obesity and Pre-diabetes

The efficacy of liraglutide 3 mg as an adjunct to diet and exercise on weight loss was examined in a 56-week trial. 3731 participants with obesity (BMI ≥30) or overweight (BMI ≥27) with ≥1 comorbidity (excluding T2D) were randomized to once-daily subcutaneous treatment with liraglutide 3 mg or placebo in combination with a 500 kcal/day deficit diet and exercise. Randomization was stratified by pre-diabetes status (according to ADA 2010 criteria) and BMI. The co-primary endpoints included change in body weight and the proportions of patients with ≥5% and >10% weight loss from baseline. After 56 weeks of treatment, patients receiving liraglutide 3 mg showed significantly greater loss of body weight of 8% from baseline compared with those receiving placebo (2.6%; P <0.0001) (Figure 9-10). Proportions of patients losing ≥5%,>10% and >15% of body weight with liraglutide 3 mg were 63.2%, 33.1%, and 14.4% respectively, compared with 27.1%, 10.6% and 3.5%, respectively, in patients who received the placebo (P <0.001 for all comparisons) (Figure 9-10).

In conjunction with weight loss, treatment with liraglutide 3 mg reduced waist circumference by -8.19 cm compared with -3.94 cm with placebo (P <0.0001). Furthermore, treatment with liraglutide 3 mg improved blood glucose levels. In fact, in the studies, liraglutide expressed a specific effect on preventing diabetes, converting nearly 70% of the subjects with prediabetes to normoglycemia, blood pressure and lipids levels (Table 9-9). Loss of body weight was independent of prediabetes status at screening and baseline BMI.

SCALE Diabetes

This trial was a 56-week, randomized, placebo-controlled, double-blind clinical trial that demonstrated the effect of liraglutide 3 mg on weight loss and involved 846 adults with obesity or overweight and T2D. All treatment groups followed a reduced-calorie diet and increased physical activity program. Like in SCALE Obesity and Pre-diabetes, the co-primary endpoints were change in body weight and the proportions of patients achieving ≥5% and >10% weight loss from baseline. At 56 weeks, adults treated with liraglutide 3 mg achieved significantly greater mean weight loss of 5.9% compared with 2.0% with placebo (P <0.0001) (Figure 9-11). More patients achieved a weight loss of 5% or more in the liraglutide 3 mg (54.3%) and liraglutide 1.8 mg (40.4%) groups, compared to the placebo (21.4%; P <0.001 for either liraglutide group vs placebo).

Liraglutide treatment also significantly increased the proportion of patients achieving >10% weight loss: 25.2% in the liraglutide 3 mg group (compared to 6.7% with the placebo; P <0.001) and 15.9% in the liraglutide 1.8 mg group (P <0.001 vs the placebo). Waist circumference was also significantly reduced with liraglutide 3 mg (-6 cm) compared with placebo (-2.8 cm, P ≤0.0004). Liraglutide 3 mg reduced systolic blood pressure by 3.0 mm Hg compared with 0.4 mm Hg with placebo (P <0.05), although no significant difference was observed in diastolic blood pressure. Compared with baseline, liraglutide 3 mg significantly improved total cholesterol (-4%) and fasting lipid levels, including VLDL, HDL and triglycerides (-13%, +3% and -14%, respectively). Liraglutide 3 mg also improved levels of CRP by -27% compared with placebo (P ≤0.0002). In addition, treatment with liraglutide 3 mg provided statistically significantly greater improvements in CV disease risk factors, such as blood pressure and cholesterol, compared with placebo in combination with diet and physical activity (Table 9-9).

SCALE Maintenance

The efficacy of liraglutide in maintaining weight loss achieved with a low-calorie diet was examined in the SCALE maintenance study. Four hundred twenty-two adult patients with overweight/obesity who lost ≥5% of their initial weight during a caloric restriction period were randomly assigned to receive subcutaneous liraglutide 3 mg/day or placebo for 56 weeks. Diet and exercise counseling were provided throughout the trial. Participants lost a mean 6% of screening weight during the caloric restriction period. From randomization to week 56, weight decreased an additional mean 6.2% with liraglutide and 0.2% with placebo (P <0.0001) (Figure 9-12). Significantly more participants receiving liraglutide (81.4%) maintained the ≥5% run-in weight loss compared with those receiving placebo (48.9%; P <0.0001). Similarly, more patients in the liraglutide group lost ≥5% of their randomization weight than in the placebo group (50.5 vs 21.8%; P <0.0001). These results suggest that liraglutide, in conjunction with diet and exercise, maintained weight loss achieved by caloric restriction and induced further weight loss over 56 weeks. Improvements in some CV disease risk factors, such as BMI, waist circumference and glycemic parameters, were also observed compared to placebo.

Liraglutide for Treatment of Obesity in Adolescents

The efficacy of liraglutide 3 mg as an adjunct to diet and exercise on weight loss was examined in a double-blind, 56-week trial in 251 adolescents (12 to <18 years of age) with obesity and a poor response to lifestyle therapy alone. Following a 12-week lifestyle run-in period, 125 patients were given 3.0 mg subcutaneous liraglutide once daily, while 126 patients were given placebo. Liraglutide was superior to placebo with regard to the change from baseline in the BMI standard-deviation score (SDS) at week 56, with an estimated treatment difference (ETD) of -0.22 (95% CI; P <0.002).

Proportions of patients achieving ≥5% and ≥10% body weight reduction were numerically higher with liraglutide than with placebo (43.3% vs 18.7% for ≥5% weight loss and 26.1% vs 8.1% for ≥10% weight loss). In addition, patients taking liraglutide lost, on average, 2.65% of their body weight while patients receiving the placebo gained an average 2.37% of their body weight. At week 56, there was no substantial difference between treatment groups in the change in glycemic and cardiometabolic variables or in overall weight-related quality of life.

Safety

Liraglutide was well-tolerated in clinical studies (Table 9-10). In the SCALE Obesity and Prediabetes trial, the most common AEs with liraglutide 3 mg were nausea and diarrhea, with most events being mild/moderate in intensity and transient in duration. In the SCALE diabetes trial, the most frequently reported side effects were gastrointestinal disorders and occurred in 65% of people treated with liraglutide 3 mg compared with 39% with placebo. In the SCALE maintenance trial, GI disorders were also reported more frequently with liraglutide (74%) than placebo (45%), but most events were transient and mild or moderate in severity. Discontinuations due to AEs occurred in 9.9% of liraglutide-treated patients and 3.8% of placebo-treated patients and were mostly due to GI events.

In the pediatric study, the most commonly reported mild-to-moderate AEs were gastrointestinal events, including nausea, vomiting and diarrhea, which were reported in 64.8% of patients taking liraglutide and 36.5% of patients taking placebo. Additionally, hypoglycemia occurred in 15% of patients receiving liraglutide compared to 4% of patients receiving placebo. Discontinuation due to AEs occurred in 10.4% of liraglutide-treated adolescent patients and 0% in placebo-treated patients. The incidence of serious AEs in the trial was low and deemed not related to the liraglutide treatment.

The prescribing information for liraglutide includes a black box warning about a potential risk of thyroid C-cell tumors, including medullary thyroid carcinoma (MTC). An increased risk is suspected based on studies in rats and mice; however, these studies used much higher (supratherapeutic) doses of GLP-1 receptor agonists. Furthermore, rodents express much higher levels of GLP-1 receptors in the thyroid than primates; this, combined with the supratherapeutic doses in the rodent studies, makes the significance of the rodent findings to humans unclear. Nevertheless, liraglutide is currently contraindicated in patients with a personal or family history of MTC and in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2).

Prescribing, Dosing, and Administration

Liraglutide is administered subcutaneously once per day (at any time of day, although timing should be consistent) with or without food in the abdomen, thigh, or upper arm (Table 9-2). Use of liraglutide with insulin or insulin secretagogues can increase the risk of hypoglycemia; the doses of the concomitant medications may need to be reduced or discontinued. The liraglutide dose is titrated over the first 5 weeks of treatment, starting at 0.6 mg daily and increasing to 3.0 mg daily from week 5 onwards, in order to reduce the risk of gastrointestinal symptoms. Treatment should also be discontinued in patients who have not lost at least 4% of baseline body weight at 16 weeks, because it is unlikely they will achieve any meaningful weight loss with further treatment.

Consider the use of liraglutide for appetite suppression and increased satiety. Also consider using for patients with concomitant diabetes.

Semaglutide

Semaglutide (1.7 mg or 2.4 mg) is another pharmacological treatment option for chronic weight management, receiving FDA approval in 2021. Similar to liraglutide, semaglutide is a GLP-1 receptor agonist and i.e., GLP-1 mimic, which targets various areas of the brain and GI tract to regulate appetite and food intake. Semaglutide is a subcutaneous injection and is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with obesity (BMI ≥30) or overweight (BMI ≥27) and who have at least one weight-related comorbid condition, (e.g., hypertension, dyslipidemia, or T2D). In December 2022, semaglutide 2.4 mg also received FDA approval (as an adjunct to a reduced calorie diet and increased physical activity) for chronic weight management in pediatric patients 12 years of age and older with obesity, ie, an initial BMI of ≥95^th percentile standardized for age and sex. In March 2024, semaglutide 2.4 mg received FDA approval to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke), in adults with established cardiovascular disease and either obesity or overweight.

Like liraglutide, semaglutide also increases glucose-dependent insulin secretion from pancreatic β cells and improves insulin sensitivity throughout the body, works on the appetite center in the brain to reduce appetite and acts in the gastrointestinal tract to slow gastric emptying and increase satiety. Unlike liraglutide, which is administered daily, semaglutide has an elimination half-life of one week and is therefore administered as a subcutaneous injection of 1.7 mg or 2.4 mg once-weekly. Semaglutide is also available in the United States and other countries for treatment of patients with T2D as semaglutide 0.5 mg, 1.0 mg, or 2.0 mg weekly injection and in an oral formulation as semaglutide 14 mg daily.

Efficacy

The efficacy and safety of semaglutide 2.4 mg were investigated in the phase 3 Semaglutide Treatment Effect in People with Obesity (STEP) program – the largest placebo-controlled clinical trial program for obesity management without a focus on T2D. Results from four 68-week STEP trials demonstrate that semaglutide is superior to the placebo in weight reduction. The first three STEP studies were randomized, double-blind, placebo-controlled trials which included a 16-week dose escalation period prior to reaching 2.4 mg, while STEP 4 was a double-blind, placebo-controlled, randomized withdrawal trial, in which patients receiving semaglutide either continued with the treatment or switched to a placebo after week 20. The approval of semaglutide 2.4 mg for weight management in pediatric patients was based on results from STEP TEENS, a trial that enrolled participants 12 to <18 years of age. In the STEP program, the reduction of body weight has been observed with semaglutide treatment irrespective of age, sex, race, ethnicity, BMI at baseline, body weight (kg) at baseline, or level of renal function impairment. The efficacy of semaglutide for cardiovascular risk reduction was assessed in the SELECT trial, while its efficacy for management of body weight and heart failure (HF) symptoms in patients with obesity-related HF with preserved ejection fraction (HFpEF) was tested in the STEP HFpEF trial. The efficacy of semaglutide on the progression of renal impairment in patients with chronic kidney disease (CKD) and T2D is also being evaluated in the FLOW trial.

STEP 1

STEP 1 was a double-blind trial that enrolled 1961 adult patients with a BMI ≥30 or BMI ≥27 with at least one weight-related comorbid condition, who did not have diabetes. Patients were randomized in a 2:1 ratio to either semaglutide or placebo. The once-weekly injections were combined with reduced-calorie diet (500-kcal deficit per day relative to the energy expenditure estimated at the time they underwent randomization) and increased physical activity (150 minutes per week of physical activity encouraged). The co-primary endpoints were percent change in body weight and ≥5% weight loss at week 68.

The change in body weight from baseline to week 68 was −14.9% in the semaglutide group as compared with −2.4% with placebo, with an ETD of −12.4 % (P <0.0001) (Figure 9-13A). The semaglutide-treated group also demonstrated greater mean weight loss: −15.3 kg compared with −2.6 kg in the placebo group (ETD, −12.7 kg; 95% CI, −13.7 to −11.7). The proportions of patients achieving ≥5%, ≥10% and ≥15% body weight reduction with semaglutide were 86.4%, 69.1% and 50.5% respectively, all significantly higher than in the placebo group (31.5%, 12% and 4.9% respectively; P <0.001) (Figure 9-13B). Greater reduction in the secondary endpoints of waist circumference, BMI and systolic and diastolic blood pressure were also observed with semaglutide. Semaglutide treatment showed beneficial changes in glycated hemoglobin, fasting plasma glucose, c-reactive protein and fasting lipid levels.

STEP 2

The efficacy of semaglutide at 2.4 mg and 1 mg (the maximum dose approved for treatment of T2D at the time) in patients with a BMI ≥27 and T2D was evaluated in STEP 2. This double-blind 68-week trial randomly assigned 1210 adult participants to semaglutide 2.4 mg, semaglutide 1.0 mg, or placebo. The once-weekly injections were combined with a reduced-calorie diet (500-kcal deficit per day relative to the energy expenditure estimated at the time they underwent randomization) and increased physical activity (150 minutes per week of physical activity recommended). As in STEP 1, the co-primary endpoints were percent change in body weight and ≥5% weight reduction at week 68. The changes in weight compared to baseline in the semaglutide 2.4 mg, semaglutide 1.0 mg and placebo groups were -9.6%, -6.9% and -3.5% respectively; with an ETD of -6.2% compared to the placebo, semaglutide 2.4 mg was significantly more effective (P <0.0001) (Figure 9-14A).

The proportions of patients losing ≥5% of body weight with semaglutide 2.4 mg, semaglutide 1.0 mg and placebo injections at week 68 were reported as 68.8%, 57.1% and 28.5% respectively (P <0.001 for semaglutide 2.4 mg vs placebo) (Figure 9-14B). Semaglutide 2.4 mg was also superior to the placebo in the confirmatory secondary endpoints of ≥10% weight loss (45.6% vs 28.7%; P <0.0001) (Figure 9-14B) and ≥15% weight loss (25.8% vs 13.7%; P <0.0001) (Figure 9-14B). Furthermore, 67.5% of patients treated with 2.4 mg semaglutide achieved a target A1C of 6.5% or less, compared to 60.1% of patients treated with 1.0 mg of semaglutide and 15.5% in the placebo group. Overall, the study has demonstrated that the once-weekly injection of semaglutide 2.4 mg is more effective at reducing body weight in patients with obesity and T2D than the lower dose of semaglutide 1.0 mg or placebo.

STEP 3

The efficacy of semaglutide in combination with intensive therapy has been evaluated in STEP 3, a double-blind trial enrolling 611 adult patients with a BMI ≥30 (or BMI ≥27 with at least one weight-related comorbid condition) who did not have diabetes. Patients were randomized in a 2:1 ratio to either semaglutide 2.4 mg or placebo. The once-weekly injections were combined with a reduced-calorie diet (500-kcal deficit per day relative to the energy expenditure estimated at the time they underwent randomization) for the first 8 weeks and intense behavioral therapy for entire 68-week duration of the study. The behavioral therapy consisted of 30 individual counselling sessions with a registered dietician. Like in STEP 1 and STEP 2, the co-primary endpoints were percentage change in body weight and ≥10% weight loss by week 68.

The change in body weight from baseline to week 68 was −16% in the semaglutide group compared with −5.7% with placebo (ETD −10.3%; P <0.001) (Figure 9-15A). Proportions of patients achieving a weight loss of ≥5%, ≥10% and ≥15% with semaglutide at week 68 were 86.6%, 75.3% and 55.8% respectively - significantly higher than in the placebo group (47.6%, 15% and 13.2% respectively; P <0.001 for all comparisons) (Figure 9-15B). Semaglutide also demonstrated superiority to the placebo in the secondary efficacy endpoints of waist circumference change (difference -8.3 cm; P <0.001) and systolic blood pressure change (difference -3.9 mm Hg; P = 0.001). Improvements were also observed in diastolic blood pressure, BMI and glycated hemoglobin parameters.

STEP 4

The fourth study of the STEP program investigated the effect of continuing or withdrawing semaglutide treatment on weight loss maintenance. STEP 4 was a double-blind trial recruiting 902 adult patients with a BMI ≥30 (or BMI ≥27 with at least one weight-related comorbid condition) and without diabetes. All patients received subcutaneous once-weekly injections of semaglutide during the run-in period of 20 weeks (including 16 weeks of dose escalation), after which they were randomly assigned to continue to receive semaglutide 2.4 mg or placebo for the remaining 48 weeks of the trial. The primary endpoint was percent change in body weight from week 20 to week 68.

At week 20, the participants exhibited a mean weight loss of -10.6%. At week 68, the semaglutide group reported an additional -7.9% weight change (from week 20) and an overall change of -17.4%, while the placebo group gained 6.9% in body weight between weeks 20 and 68 and showed an overall weight change of -5.0% at 68 weeks (Figure 9-16A). The proportions of patients who lost ≥5%, ≥10%, ≥15%, or ≥20% of body weight between weeks 20 and 68 with continued semaglutide (88.7%, 79.0%, 63.7% and 39.6% respectively) were higher than in the placebo-switch group (47.6%, 20.4%, 9.2% and 4.8% respectively) (Figure 9-16B).

STEP TEENS

The efficacy and safety of semaglutide in adolescents was assessed in STEP TEENS, a double-blind trial that enrolled a total of 201 patients 12 to <18 years of age with obesity (defined as a BMI ≥95^th percentile for age and sex) or overweight (defined as a BMI ≥85^th percentile for age and sex); patients with overweight were required to have at least one coexisting weight-related condition, but only one enrolled patient did not have obesity. Eligible patients were randomized (2:1) to receive either subcutaneous semaglutide 2.4 mg once weekly or a matching placebo for 68 weeks, in addition to a lifestyle intervention. The primary endpoint was percentage change in BMI from baseline, assessed at week 68.

Patients in the semaglutide group achieved a significantly greater change in BMI from baseline at week 68 (-16.1%) compared to those in the placebo group (0.6%; P <0.001) (Figure 9-17A). Significantly more patients in the semaglutide group (73%) achieved the secondary confirmatory endpoint of 5% or greater reduction in body weight, compared to patients who received the placebo (18%; P <0.001) (Figure 9.17B). Compared to patients in the placebo group, numerically more patients in the semaglutide group achieved a BMI reduction of ≥5% and body weight reduction of ≥10%, ≥15% and ≥20% (Figure 9-17B).

SELECT

The SELECT trial, a multicenter, double-blind, randomized, placebo-controlled study, assessed the efficacy of semaglutide for the prevention of major adverse cardiovascular events (MACE) in patients without T2D. Semaglutide was previously shown to significantly reduce the risk of MACE in a population of patients with T2D in the SUSTAIN-6 trial. In SELECT, a total of 17,604 patients ≥45 years of age with CVD and a BMI of ≥27 but no T2D were randomized (1:1) to receive a once-weekly subcutaneous dose of semaglutide 2.4 mg (gradually escalated from 0.25 mg to 0.5, 1.0, 1.7 and 2.4 mg every 4 weeks over the first 16 weeks of the trial) or a matching placebo. A composite of death from CV causes, non-fatal myocardial infarction, or non-fatal stroke was the primary cardiovascular endpoint in the trial.

In the semaglutide group (n = 8,803), a primary endpoint event occurred in 569 patients (6.5%), compared to 701 patients (8.0%) in the placebo group (n = 8801) (P <0.001) (Figure 9-18). Semaglutide thus reduced the risk of a primary endpoint event by 20%. However, semaglutide did not demonstrate superiority to the placebo for the first secondary endpoint in the statistical testing hierarchy – death from CV causes: 223 (2.5%) vs 262 (3.0%) patients in the semaglutide and placebo groups, respectively; P = 0.07. Therefore, superiority was not assessed for other secondary endpoints, including heart failure and death from any cause. Semaglutide also resulted in numerical body weight and waist circumference reduction from baseline, compared to the placebo. A limitation of this study is that it only evaluated the effects of semaglutide on subjects with pre-existing CVD and excluded those without known atherosclerotic disease, therefore the cardioprotective effect on this group is unknown.

STEP HFpEF

The efficacy of semaglutide was also assessed in patients with obesity-related HFpEF, an increasingly prevalent condition with limited treatment options. The double-blind STEP HFpEF trial enrolled a total of 529 patients with HFpEF and a BMI of ≥30, randomizing them (1:1) to receive a once-weekly subcutaneous injection of either semaglutide 2.4 mg or a matching placebo for 52 weeks. The dual primary endpoints, assessed at week 58, were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) and the change from baseline in body weight. The KCCQ-CSS is a 23-item, standardized instrument that assesses HF symptoms (e.g., fatigue, edema, dyspnea), functional (physical and social) limitation and quality of life. The scores range from 0 to 100; higher scores indicate fewer symptoms and limitations.

At week 58, semaglutide resulted in significant improvement from baseline in both the KCCQ-CSS score (16.6 points vs 8.7 points with the placebo; P <0.001) and weight change (-13.3% vs -2.6% with the placebo; P <0.001). Patients in the semaglutide group also achieved significant improvements in the confirmatory secondary endpoints of change from baseline in the 6-minute walk distance (21.5 meters vs 1.2 meters with the placebo; P <0.001) and change from baseline in the CRP level (-43.5%, compared to -7.3% with the placebo; P <0.001).

Other STEP Trials

Two other STEP trials have been published to date: STEP 5 and STEP 6. The double-blind, randomized STEP 5 trial compared the long-term (104-week) efficacy of semaglutide 2.4 mg once-weekly to that of a placebo in adult patients with BMI ≥30 or BMI ≥27 and at least one weight-related comorbidity (excluding T2D). Semaglutide demonstrated superiority to the placebo, with a greater change in body weight from baseline (-15.2% vs -2.6%) (P <0.0001) and with more patients achieving ≥5% weight loss from baseline (77.1% vs 34.4%) (P <0.0001) at week 104. The STEP 6 trial assessed the efficacy of semaglutide for weight management in adult patients from East Asia (Japan and South Korea) with a BMI ≥27 and ≥2 weight-related comorbidities or BMI ≥35 with ≥1 weight-related comorbidity. Patients were randomized to receive a 68-week course of semaglutide 2.4 mg (or a matching placebo) or semaglutide 1.7 mg (or a matching placebo) once-weekly. Semaglutide was superior to the placebo in this population, achieving significantly greater body weight reduction from baseline at both the 2.4 mg (-13.2%) and the 1.7 mg (-9.6%) dose compared to the placebo (-2.1%) (P <0.0001 for both comparisons).

FLOW

Flow is an ongoing randomized, double-blind, parallel-group, placebo-controlled superiority trial comparing semaglutide 1.0 mg vs placebo as an adjunct to standard care on the progression of renal impairment in patients with CKD and T2D. The study enrolled 3,534 people in 28 different countries. The study objective was to demonstrate a delayed progression of CKD to ultimately lower renal and cardiovascular mortality. The trial protocol included an interim analysis when a prespecified number of primary endpoint events occurred that allowed the trial to stop early due to efficacy. The trial has met these prespecified criteria and therefore the closing of the trial has been initiated. Results are expected in 2024.

Safety

Semaglutide was generally well tolerated in clinical trials (Table 9-11). In STEP 1, 74.2% of patients in the semaglutide-treated group reported transient mild-to-moderate GI AEs, compared to 47.9% in the placebo group; these occurred primarily during the dose-escalation period. Gallbladder-related disorders (mostly cholelithiasis) were reported in 2.6% and 1.2% of participants in the semaglutide and placebo groups, respectively. In STEP 2, 63.5% of patients receiving semaglutide 2.4 mg, 57.5% receiving semaglutide 1.0 mg and 34.3% receiving placebo reported transient mild-to-moderate GI AEs. In STEP 3, 82.2% of patients in the semaglutide-treated group and 63.2% in the placebo group reported transient mild-to-moderate GI AEs. Serious AEs were reported in 9.1% and 2.9% of patients in the semaglutide and placebo groups, respectively. In STEP 4, 84% of participants reported AEs during the run-in period of the trial, with 71.4% reporting GI tract disorders. In STEP TEENS, the frequency of AEs was comparable in the semaglutide and placebo groups (79% vs 81%, respectively) as was the frequency of serious AEs (11% vs 9%); however, GI AEs were numerically more common in the semaglutide group (62%) compared to the placebo group (42%).

In the SELECT trial of semaglutide safety and efficacy in a population of patients with CVD, serious AEs occurred at a significantly lower frequency in the semaglutide group (33.4%) than in the placebo group (36.4%; P <0.001). Among serious AEs, those that were significantly less common with semaglutide compared to placebo included cardiac disorders (11.5% vs 13.5%; P <0.001), infections and infestations (7.1% vs 8.4%; P = 0.001) and surgical and medical procedures (4.9% vs 6.2%; P <0.001). By contrast, AEs leading to permanent discontinuation of the study agent were more common with semaglutide (16.6%) than with placebo (8.2%; P <0.001).

In the STEP HFpEF trial, AEs were numerically more common with placebo (26.7%) than with semaglutide (13.3%). Although the rates of GI AEs were similar in the semaglutide and placebo group (2.7% vs 2.6%, respectively), numerically more AEs led to discontinuation in the semaglutide group (13.3%) compared to the placebo group (5.3%) and GI disorder was more common as a cause of discontinuation with semaglutide (9.5%) than with placebo (5.3%).

The prescribing information for semaglutide comes with a black box warning about a potential risk of thyroid C-cell tumors, which was determined from studies in rodents that used much higher doses of GLP-1 receptor agonists. Since rodents express much higher levels of GLP-1 receptors in the thyroid than primates and the doses used in rodent studies were supratherapeutic, the significance of these findings to humans is not clear. Like liraglutide, semaglutide is contraindicated in patients with a history (including family history) of MTC and in patients with MEN 2.

Prescribing, Dosing and Administration

Semaglutide 2.4 mg is administered subcutaneously once weekly (Table 9-2). Injections (in the abdomen, thigh, or upper arm) should be given on the same day of the week and at any time of day, with or without meals. Use of semaglutide with insulin or insulin secretagogues can increase the risk of hypoglycemia; the doses of the concomitant medications may need to be reduced or discontinued. Semaglutide is available in five dosage strengths for the treatment of obesity: 0.25 mg, 0.5 mg, 1.0 mg, 1.7 mg and 2.4 mg.

Per the package insert, treatment should be initiated at a 0.25 mg weekly dose and the dosage should be escalated every four weeks to 0.5 mg, 1.0 mg and 1.7 mg before reaching the final maintenance dose of 1.7 mg or 2.4 mg at week 13 or week 17, respectively. For pediatric patients, only the 2.4 mg dose is approved for maintenance. If patients do not tolerate a dose, escalation can be delayed for 4 weeks or the dose may be reduced. If the patient does not tolerate the final 2.4 mg dose, the dose can be decreased to 1.7 mg. In clinical practice, the lowest effective dose is often used. If a dose is missed, semaglutide should either be immediately administered (when the next dose is scheduled for >48 hours away) or skipped (when the next dose is scheduled for <48 hours away). In cases where more than 2 consecutive doses are missed, the package insert states that treatment can either be continued at the maintenance dose, or reinitiated with dose escalation. In clinical practice, re-initiating the dose escalation is often deemed the safer option.

Consider prescribing semaglutide 2.4 mg weekly for appetite suppression and increased satiety. Also consider using it for patients with concomitant diabetes.

Tirzepatide

In 2023, tirzepatide became the newest pharmacological agent to receive FDA approval for chronic weight management. Tirzepatide is indicated an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial BMI of ≥30 (obesity) or ≥27 (overweight) in the presence of at least one weight-related comorbid condition (eg, hypertension, dyslipidemia, T2D, obstructive sleep apnea, or CVD). Like liraglutide and semaglutide, tirzepatide is a synthetic peptide that acts an a GLP-1 receptor agonist. However, unlike liraglutide and semaglutide, tirzepatide also acts as a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, making it a dual agonist, ie, a mimic of two incretin hormones; this dual mechanism likely increases its efficacy.

Owing to its elimination half-life of 5 days, tirzepatide is administered once weekly, as a subcutaneous injection. It is available in the following dosage forms (in a single-dose pen): 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg and 15 mg per 0.5 mL. It is also available, under a different brand name, for the treatment of T2D, for which it received approval in 2022.

Efficacy

The efficacy of tirzepatide was assessed in the SURMOUNT clinical trial program, which included 4 phase 3 studies: SURMOUNT-1, -2, -3 and -4. Each of the SURMOUNT trials was double-blind and placebo-controlled and all had percentage change in body weight from randomization to the end of treatment as a primary endpoint. SURMOUNT-1 and -2 were fixed-dose studies, while SURMOUNT-3 and -4 were maximum tolerated dose (MTD) studies. The approval of tirzepatide for chronic weight management was based on results from SURMOUNT-1 and -2. With a reported weight loss differential of up to 17.8% compared to the placebo, tirzepatide is the most effective of the currently approved anti-obesity drugs.

SURMOUNT-1

SURMOUNT-1 was a 72-week trial designed to test the weight loss efficacy of tirzepatide in patients with overweight or obesity but no T2D. A total of 2539 adult patients with either BMI ≥30 or BMI ≥27 with at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, obstructive sleep apnea, or CVD) were randomized (1:1:1:1) to receive a weekly subcutaneous dose of tirzepatide 5 mg, 10 mg, 15 mg, or a matching placebo. Patients with T2D were excluded. Percent change in weight from baseline and proportion of patients achieving a weight loss of ≥5% were the co-primary endpoints. Efficacy was assessed using two estimands: the treatment regimen estimand (TRE; assessing efficacy in all randomized patients regardless of treatment discontinuation) and the efficacy estimand (assessing the treatment effect for randomized participants provided that the treatment was administered as intended).

At week 72, percent weight change in all tirzepatide dose groups was greater than that for placebo, for both the TRE and the efficacy estimand (tirzepatide 5 mg: -15.0%; tirzepatide 10 mg: -19.5%; tirzepatide 15 mg: -20.9%; placebo: -3.1%; P <0.001 for all comparisons to the placebo for the treatment efficacy estimand) (Figure 9-19A-B). More patients in each tirzepatide group achieved the other co-primary endpoint of ≥5% weight loss compared to the placebo group, for both the TRE (tirzepatide 5 mg: 85.1%; tirzepatide 10 mg: 88.9%; tirzepatide 15 mg: 90.9%; placebo: 34.5%; P <0.001 for all comparisons to the placebo) and the efficacy estimand (tirzepatide 5 mg: 89.4%; tirzepatide 10 mg: 96.2%; tirzepatide 15 mg: 96.3%; placebo: 27.9%) (Figure 9-19C-D). Significantly more patients in the tirzepatide groups also achieved the secondary endpoints of ≥10%, ≥15% and ≥20% weight loss (P <0.001 for all comparisons to the placebo) and numerically more patients achieved the exploratory endpoint of ≥25% weight loss (statistical significance not assessed) (Figure 9-19C-D).

SURMOUNT-2

The SURMOUNT-2 trial assessed the efficacy of tirzepatide in a patient population with T2D and overweight or obesity. Eligible adult patients (BMI ≥27, glycated hemoglobin 7-10% [53-86 mmol/mol]) (n = 938) were randomized (1:1:1) to receive tirzepatide 10 mg, 15 mg, or a matching placebo as a subcutaneous once-weekly injection for 72 weeks. The co-primary endpoints, percent change in body weight from baseline and proportion of patients achieving ≥5% weight loss, were identical to those of SURMOUNT-1, as were the two estimands: the TRE (which included all patients who were randomized) and the efficacy estimand (which included randomized patients who remained on the study treatment for the entire efficacy assessment duration of the trial).

Patients in both tirzepatide groups achieved significantly greater percent weight change at week 72 compared to those in the placebo group for the TRE (tirzepatide 10 mg: -12.8%; tirzepatide 15 mg: -14.7%; placebo: -3.2%; P <0.0001 for both comparisons) (Figure 9-20A) and the efficacy estimand (tirzepatide 10 mg: -13.4%; tirzepatide 15 mg: -15.7%; placebo: -3.2%; P <0.0001 for both comparisons) (Figure 9-20B). Compared to patients in the placebo group, more patients in both tirzepatide groups achieved ≥5% body weight loss for both the TRE (tirzepatide 10 mg: 79.2%; tirzepatide 15 mg: 82.8%; placebo: 32.5%; P <0.0001 for both comparisons) (Figure 9-20C) and the efficacy estimand (tirzepatide 10 mg: 81.6%; tirzepatide 15 mg: 86.4%; placebo: 30.6%; P <0.0001 for both comparisons) (Figure 9-20D). SURMOUNT-2 also met all of its key secondary endpoints, with more patients in both tirzepatide groups achieving ≥10%, ≥15% and ≥20% body weight loss compared to patients in the placebo group, for both estimands (Figure 9-19C-D). Both doses of tirzepatide also resulted in a greater proportion of patients achieving the secondary endpoint of ≥25% weight reduction compared to the placebo for both estimands (Figure 9-20C-D).

SURMOUNT-3

The SURMOUNT-3 trial tested the efficacy of tirzepatide in adult patients with BMI ≥27 and without T2D who achieved ≥5% weight loss reduction after an intensive 12-week lifestyle intervention lead-in program. A total of 579 patients were randomized (1:1) to either the MTD (10 mg or 15 mg) of tirzepatide or a matching placebo, given by once-weekly subcutaneous injection for 72 weeks. The co-primary endpoints were percent change from baseline in body weight and proportion of patients achieving ≥5% additional weight loss (i.e., beyond that already achieved by the lifestyle intervention). Efficacy was assessed by the TRE (all randomized participants, regardless of whether they adhered to treatment) and the efficacy estimand (randomized participants who completed the planned treatment course).

At week 72, significantly greater percent weight change was achieved by patients in the tirzepatide group (-18.4% for the TRE and -21.1% for the efficacy estimand) than in the placebo group (2.5% for the TRE and 3.3% for the efficacy estimand; P <0.001 against tirzepatide for both estimands) (Figure 9-21A-B). Significantly more patients achieved the co-primary endpoint of ≥5% body weight reduction with tirzepatide MTD (87.5% for the TRE and 94.4% for the efficacy estimand) than with placebo (16.5% for the TRE and 10.7% for the efficacy estimand; P <0.001 for both comparisons against tirzepatide) (Figure 9-21C-D). Tirzepatide proved superior to the placebo with regard to the proportion of patients achieving the key secondary endpoints of ≥10%, ≥15% and ≥20% weight loss, as well as the exploratory endpoint of ≥25% weight loss (P <0.001 for all comparisons for both estimands) (Figure 9-21C-D).

SURMOUNT-4

The fourth study of the program, SURMOUNT-4, was designed to evaluate the efficacy of tirzepatide in weight loss maintenance in adult patients with a BMI ≥30 or ≥27 with an associated complication, but no T2D. A total of 783 patients underwent a 36-week open-label lead-in period on tirzepatide MTD (10 mg or 15 mg), followed by randomization to either continued tirzepatide MTD or a placebo for a 52-week double-blind treatment period. The primary endpoint was percent change in body weight from randomization (week 36) to the end of the trial (week 88).

At the end of the 36-week open-label lead-in period on tirzepatide 10 mg or 15 mg, subjects experienced an average weight reduction of -20.9%. After randomization, for the TRE, patients in the tirzepatide group had a mean weight change of -5.5%, while those in the placebo group experienced, on average, a weight regain of 14.0% (P <0.001) (Figure 9-22A). Similarly, for the efficacy estimand, patients randomized to continue tirzepatide had a mean additional body weight change of -6.7%, compared to 14.8% for patients in the placebo group (P <0.001). For the TRE, in the continued tirzepatide group, 89.5% of patients maintained at least 80% of their initial weight loss, compared to only 16.6% of patients in the placebo group who maintained at least 80% of their initial weight loss (Figure 9-22B). Across the entire trial (week 0 to 88) for the TRE, significantly more patients in the tirzepatide group achieved a body weight loss of ≥5% (97.3% vs 70.3% for the placebo; P <0.001), ≥10% (92.1% vs 46.2% for the placebo; P <0.001), ≥15% (84.1% vs 25.9% for the placebo; P <0.001) and ≥20% (69.5% vs 12.6% for the placebo; P <0.001) (Figure 9-22C). Finally, for the TRE, significantly more patients treated with tirzepatide (54.5%) achieved the exploratory endpoint of ≥25% weight loss, compared to those who received the placebo (5.0%; P <0.001) (Figure 9-22C). Therefore, withdrawing treatment of tirzepatide led to weight regain, whereas continued treatment led to additional weight loss.

Safety

Overall, tirzepatide was well tolerated in the SURMOUNT clinical trial program. The safety profile of tirzepatide in the SURMOUNT program was similar to that observed in the SURPASS program, which assessed the efficacy of tirzepatide for glycemic control and chronic weight management in patients with T2D. As expected for a GLP-1 agonist, gastrointestinal-related AEs were the most common type of AE in SURMOUNT-1, -2 and -3 and occurred more commonly in patients taking tirzepatide. The three most common AEs in SURMOUNT-3 were nausea (tirzepatide: 39.7%; placebo: 14.0%), diarrhea (tirzepatide: 31.0%; placebo: 9.2%) and constipation (tirzepatide: 23.0%; placebo: 6.8%). In all treatment groups in the first three SURMOUNT trials, the majority (≥90%) of adverse events were mild to moderate in intensity. The safety findings from SURMOUNT-4 were consistent with this, with AEs and serious AEs generally balanced across treatment groups, except for GI AEs which were numerically more common with tirzepatide. Across SURMOUNT-1 and -2, treatment discontinuation due to an AE occurred in 4.8%, 6.3% and 6.7% of patients receiving tirzepatide 5 mg, 10 mg and 15 mg, respectively and 3.4% of patients receiving placebo. In SURMOUNT-3, 10.5% and 2.1% of patients in the tirzepatide and placebo group, respectively, discontinued treatment due to an AE. In SURMOUNT-4, the proportions of patients in the tirzepatide and placebo group who discontinued treatment due to an AE were 1.8% and 0.9%, respectively.

Like that of other GLP-1 agonists, the prescribing information for tirzepatide contains a black box warning about thyroid C-cell tumors, based on data from rats with unclear significance to humans. Like liraglutide and semaglutide, tirzepatide is currently contraindicated for patients with either a personal or family history of MTC and for patients with MEN 2.

Tirzepatide slows gastric emptying and therefore can alter the absorption of other oral medications. Of particular importance, patients who are on concomitant oral contraceptives should either switch to non-oral contraceptives or should be counseled to use a barrier method of contraception for 4 weeks after initiating tirzepatide and for 4 weeks after any dose escalation.

Dosing, Administration and Prescribing

Tirzepatide is administered once weekly by subcutaneous injection in the abdomen, thigh, or upper arm (Table 9-2). It can be injected either by healthcare professionals or by patients, once trained in the proper injection technique. Injection sites should be rotated with each dose. Tirzepatide can be administered at any time of day, with or without meals. Like other GLP-1 agonists, the use of tirzepatide with insulin or an insulin secretagogue may increase the risk of hypoglycemia; therefore, lowering the dose of insulin or insulin secretagogue should be considered. Tirzepatide is available in pre-filled, single-dose pens of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg and 15 mg.

The recommended starting dose is 2.5 mg once weekly, increased after 4 weeks to 5 mg once weekly. The recommended maintenance dose is 5 mg, 10 mg, or 15 mg once weekly, depending on the treatment response and tolerability, with 15 mg being the maximum recommended weekly dose. Dosage should be increased in 2.5 mg increments every 4 weeks until the individualized maintenance dose is reached. A missed dose should be taken as soon as possible within 4 days or 96 hours of the scheduled dose; if more time elapsed since the originally scheduled dose, the dose should be skipped and the regimen continued from the next scheduled dose. If required, the day of administration can be changed, provided that at least 3 days or 72 hours elapsed between two doses.

Consider prescribing tirzepatide for appetite suppression and increased satiety, especially in patients with concomitant T2D.

Summary

Successful treatment of obesity requires a multidisciplinary approach and multimodal therapy including dietary and behavioral strategies. Since not all patients respond to lifestyle modification alone, pharmacologic treatment options can be pursued. There are seven FDA-approved agents currently available in the United States. Effective pharmacotherapy may require either single or multiple agents, and attention to patient medical history is critical to determining the appropriate choice of agent or agents. Patients should be monitored at least monthly for the first three months of treatment, and then at least every three months. The efficacy of the medication should be re-evaluated at each appointment, and behavioral interventions should be reinforced.

Antiobesity pharmacotherapy is intended for long-term use, as obesity is a chronic disease. Continued use of the medication to promote maintenance of weight loss is recommended to help offset the reduction in energy expenditure and the increase in appetite that occurs with weight loss. The future of obesity treatment will likely consist of multiple combinations of agents in conjunction with behavioral approaches in order to achieve clinically significant weight loss. Weight maintenance and relapse prevention justifies a long-term approach requiring chronic treatment and follow-up.