Pharmacologic Treatment of Obesity

Introduction

According to the Centers for Disease Control (CDC) and the National Center for Health Statistics, 42.5% of American adults are obese. This presents a major challenge since obesity is associated with several comorbidities is the dominant risk factor that is tightly linked to the development of type 2 diabetes (T2D), since it increases insulin resistance and glucose intolerance, as well as contributing to the risk of cardiovascular (CV) complications. Importantly, obesity is also one of the most important modifiable risk factors for the prevention of T2D. The older and newest pharmacologic options for weight management in adults with and without diabetes are described below.

Qsymia (Phentermine/Topiramate ER)

This fixed-dose combination of phentermine and topiramate ER was approved by the Food and Drug Anministration (FDA) in 2012 as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults who are obese (body mass index (BMI) ≥30 kg/m²) or who are overweight (BMI ≥27 kg/m²) with at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, or T2D). Qsymia is contraindicated in pregnancy and in patients with glaucoma, hyperthyroidism, and during or within 14 days following administration of an MAOI.

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 also is not known, although it may be due to its effects on both appetite suppression and satiety enhancement induced by a combination of pharmacologic effects.

Efficacy

The efficacy of this combination phentermine/topiramate ER on weight loss in conjunction with reduced caloric intake and increased physical activity was studied in two randomized, double-blind, placebo-controlled studies in obese patients (Study 1) and in obese and overweight patients with two or more significant comorbidities (Study 2). Both studies had a 4-week titration period, followed by 52 weeks of treatment, and the two co-primary efficacy outcomes after 1 year of treatment were percent weight loss from baseline and treatment response defined as achieving ≥5% weight loss from baseline. Patients with T2D were excluded from participating in Study 1. During both 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.

After 1 year of treatment with Qsymia, all dosage levels resulted in statistically significant weight loss compared with placebo (Study 1: Qsymia -10.9 kg [SE = 0.4 kg] vs placebo -1.6 kg [SE = 0.4 kg] change from baseline [P <0.0001]; Study 2: Qsymia -9.8 kg [SE = 0.3 kg] vs placebo -1.2 kg [SE = 0.3] change from baseline [P <0.0001]). A significantly greater proportion of patients randomized to receive phentermine/topiramate ER also achieved ≥5% and ≥10% weight loss compared with patients receiving placebo.

Safety

In clinical trials with the fixed-dose, single-capsule formulations of phentermine/topiramate ER, adverse events that occurred at a rate of ≥5% and at a rate ≥1.5 times placebo included paraesthesia, dizziness, dysgeusia, insomnia, constipation and dry mouth. In the 1-year placebo-controlled clinical studies, the rates of discontinuation due to adverse events were 11.6%, 11.6%,17.4%, and 8.4% for patients receiving 3.75 mg/23 mg Qsymia, 7.5 mg/46 mg Qsymia, 15 mg/92 mg Qsymia and placebo, respectively.

Prescribing Qsymia

Qsymia is taken once daily in the morning with or without food; dosing in the evening should be avoided due to the potential for insomnia. Dosing is titrated, beginning with 3.75 mg phentermine/23 mg topiramate daily for 14 days, followed by an increase to a once-daily dose of 7.5 mg/46 mg. Weight loss should be evaluated after 12 weeks of Qsymia 7.5 mg/46 mg treatment and if patients have not lost at least 3% of baseline body weight then treatment should be discontinued or escalated, since it is unlikely the patients will achieve meaningful weight loss with continued treatment at a 7.5 mg/46 mg dose.

To escalate dose, increase to Qsymia 11.25 mg/69 mg for 14 days, followed by dosing at 15 mg/92 mg once daily. Evaluate weight loss after an additional 12 weeks of treatment and discontinue if patients have not lost at least 5% of baseline body weight. Discontinue Qsymia 15 mg/92 mg gradually by taking a dose every other day for at least 1 week prior to stopping treatment altogether, due to the possibility of precipitating a seizure. Additional dosing considerations apply to patients with renal or hepatic impairment.

Contrave (Naltrexone/Bupropion)

Contrave is a combination of two FDA-approved drugs, naltrexone and bupropion in an ER formulation. Naltrexone is an opioid antagonist approved to treat alcohol and opioid dependence. Bupropion is an aminoketone antidepressant approved to treat depression and seasonal affective disorder and as an aid to smoking cessation treatment. Contrave is approved as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial BMI of 30 kg/m² or greater (obese) or 27 kg/m² or greater (overweight) in the presence of at least one weight-related comorbidity. Contrave is contraindicated in the following conditions:

• Uncontrolled hypertension
• Seizure disorder or a history of seizures
• Concomitant use of other bupropion-containing products
• Bulimia or anorexia nervosa, which increase the risk for seizure
• Chronic opioid or opiate agonist (e.g., methadone) or partial agonists (e.g., buprenorphine) use, or acute opiate withdrawal
• Patients undergoing an abrupt discontinuation of alcohol, benzodiazepines, barbiturates and antiepileptic drugs
• Concomitant administration of an MAOI
• Pregnancy.

Efficacy

The effect of Contrave in conjunction with lifestyle modifications was assessed on weight loss and weight maintenance in four 56-week double blind, randomized, placebo controlled clinical trials enrolling 4,536 patients (CONTRAVE Obesity Research, or COR-I, COR-II, COR-BMOD and COR-Diabetes). The co-primary endpoints of these trials were the proportion of patients achieving ≥5% reduction in body weight and percent change from baseline body weight. Patients receiving Contrave lost significantly more weight than patients receiving placebo in COR-I (-4.1 kg [95% CI, -4.9, -3.3], P <0.001), COR-BMOD (-3.2 kg [95% CI, -4.5, -1.8], P <0.001) and COR-Diabetes (-2.0 kg [95% CI, -3.0, -1.0], P <0.001). In all four trials, the proportion of patients who achieved ≥5% or ≥10% body weight loss from baseline was greater for patients receiving Contrave compared with placebo.

Safety

The safety of Contrave was evaluated in conjunction with lifestyle modifications in 4754 overweight or obese patients enrolled in five double-blind placebo controlled trials for up to 56 weeks. Overall, 24% of subjects receiving Contrave discontinued treatment because of an adverse event compared with 12% of subjects receiving placebo. The most common adverse reactions leading to discontinuation were nausea, headache and vomiting. Warnings and precautions are issued for several adverse reactions associated with Contrave, including suicidal behavior and ideation, neuropsychiatric symptoms, seizures, increase in BP and heart rate, allergic reactions and angle-closure glaucoma.

Bupropion, a component of Contrave, is a dopamine and norepinephrine reuptake inhibitor and has properties similar to antidepressants. For this reason, Contrave has a boxed warning for the increased risk of suicidal thoughts and behaviors associated with antidepressant drugs. In clinical trials, the proportion of patients reporting adverse reaction related to psychiatric and sleep disorders was higher for patients receiving Contrave compared with placebo and included sleep disorders (13.8% Contrave, 8.4% placebo), depression (6.3% Contrave, 5.9% placebo) and anxiety (6.1% Contrave, 4.4% placebo). Although Contrave is not approved for smoking cessation treatment, it also has a boxed warning for the serious neuropsychiatric reactions that have occurred in patients taking bupropion for smoking cessation. Patients receiving Contrave should be observed for neuropsychiatric reactions and instructed to contact a healthcare professional if they occur.

Prescribing Contrave

Contrave is administered orally twice daily, once in the morning and evening and should not be taken with high-fat meals, since this significantly increases bupropion and naltrexone systemic exposure. The dose is escalated weekly during the first month of treatment, reaching a total dose of 32 mg/360 mg Contrave at week 4 (two tablets in the morning and evening). This dose is continued for the rest of the duration of treatment. Patients who have not lost 5% of baseline body weight at 12 weeks should discontinue treatment with Contrave, since it is unlikely they will achieve meaningful weight loss with continued treatment.

The dose of Contrave should be adjusted for patients with renal impairment or hepatic impairment and in patients concomitantly receiving a CYP2B6 inhibitor (e.g., clopidogrel). Additionally, at least 14 days should elapse between switching a patient to or from a MAOI antidepressant.

Saxenda (Liraglutide)

Liraglutide is a human glucagon-like peptide-1 (GLP-1) receptor agonist (RA) that activates the GLP-1 receptor in pancreatic β cells. Activation of the receptor increases intracellular cyclic AMP, leading to insulin secretion in the presence of elevated glucose concentrations. Insulin secretion decreases once blood glucose subsides, which limits episodes of hypoglycemia. The lower dose liraglutide (0.6, 1.2 and 1.8 mgs) is marketed as Victoza; the higher dose of 3.0 mg is marketed as Saxenda. This higher dose of liraglutide 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 kg/m² or greater (obese) or 27 kg/m² or greater (overweight) in the presence of at least one weight-related comorbid condition.

It is also indicated for pediatric patients aged 12 years and older with a body weight above 60 kg and an initial BMI corresponding to 30 kg/m² for adults (obese) by international cut-offs. Liraglutide is contraindicated during pregnancy, in patients with a personal or family history of medullary thyroid carcinoma (MTC) and in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2). Note that liraglutide for the treatment of obesity is formulated at a higher dose than liraglutide for the treatment of T2D.

Efficacy

The efficacy of liraglutide for chronic weight management in conjunction with reduced caloric intake and increased physical activity was assessed in three 56-week randomized, double-blind, placebo-controlled trials in adult patients and one trial in adolescent patients (aged 12 to <18). The primary efficacy endpoints of Study 1 and 2 were mean percent change in body weight and the percentages of patients achieving ≥5% and ≥10% weight loss from baseline to week 56. The primary efficacy endpoints of trial 3 were the mean percent change in body weight from randomization to week 56, the percentage of patients not gaining >0.5% body weight from randomization to week 56 and the percentage of patients achieving ≥5% weight loss from randomization to week 56.

In all 3 studies with adult patients, a significantly greater number of patients receiving liraglutide achieved ≥5% and ≥10% weight loss compared with patients receiving placebo, with liraglutide-receiving patients losing significantly more weight (Study 1: -7.4% with liraglutide vs -3.0% with placebo; estimated treatment difference [ETD]: -4.5% [95% CI, -5.2; -3.8], P <0.0001]; Study 2: -5.4% with liraglutide vs -1.7% with placebo; ETD: -3.7% [95% CI, -4.7; -2.7], P <0.0001]; Study 3: -4.9% with liraglutide vs 0.3% with placebo; ETD: -5.2% [95% CI, -6.8; -3.5], P <0.0001]). In Study 3, significantly fewer liraglutide-treated patients gained >0.5% of body weight from randomization to week 56. In the adolescent trial, liraglutide demonstrated superiority to the placebo with regard to the primary endpoint (change from baseline in the BMI standard deviation score at week 56; ETD from the placebo -0.22 [95% CI, -0.37; -0.08]; P <0.002).

Safety

The safety of liraglutide was evaluated in five double-blind, placebo controlled clinical trials that enrolled a total of 3384 overweight or obese patients for at least 32 weeks. Patients received liraglutide for a mean treatment duration of 45.9 weeks in addition to diet and exercise counseling. Adverse events led to the withdrawal of 9.8% of patients treated with liraglutide and 4.3% of patients treated with placebo. The most common adverse events leading to discontinuation were nausea, vomiting and diarrhea. Adverse events experienced by ≥9% of patients receiving liraglutide and more frequently than patients receiving placebo, were nausea, diarrhea, constipation, vomiting and dyspepsia.

Warnings and precautions are issued for several adverse reactions associated with liraglutide, including the risk of thyroid C-cell tumors, acute pancreatitis, acute gallbladder disease, heart rate increase, renal impairment, hypersensitivity reactions, suicidal behavior and ideation and risk for hypoglycemia with concomitant use of anti-diabetic therapy. Liraglutide causes dose-dependent and treatment duration–dependent thyroid C-cell tumors in rats and mice. Although it is not known whether liraglutide will cause C-cell tumors in humans, it is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2.

Prescribing Liraglutide

Liraglutide is administered subcutaneously once daily, at any time of day, with or without food. It should not be used together with insulin and reducing the dose of concomitantly administered insulin secretagogues should be considered to reduce the risk of hypoglycemia. To reduce the likelihood of gastrointestinal symptoms, the dose of liraglutide is titrated over the first 5 weeks of treatment, starting at 0.6 mg daily and increasing by 0.6 mg each week to reach the final 3.0 mg daily dose from week 5 onwards. Dose escalation can be delayed for one additional week if patients do not tolerate an increased dose during the dose escalation period. If patients cannot tolerate the final 3.0 mg dose, then treatment should be discontinued. Patients who have not lost at least 4% of baseline body weight at 16 weeks should discontinue treatment, since it is unlikely they will achieve any meaningful weight loss with continued treatment.

Wegovy (Semaglutide)

Like liraglutide, semaglutide is a human GLP-1 RA with high (94%) sequence homology to the GLP-1 protein. Semaglutide increases insulin secretion from pancreatic β cells and insulin sensitivity throughout the body. It also acts in the gastrointestinal tract and the brain (hypothalamus) to increase satiety. Lower doses of semaglutide (0.25, 0.50, 1.0 and 2.0 mg) are marketed as Ozempic. The higher dose of semaglutide (2.4 mg) is marketed as Wegovy and 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 kg/m² or greater (obese) or 27 kg/m² or greater (overweight) in the presence of at least one weight-related comorbid condition (including T2D). Semaglutide is contraindicated in patients with a personal or family history of MTC, and in patients with MEN 2. It should not be used during pregnancy and should be discontinued at least 2 months before a planned pregnancy. It should not be combined with other GLP-1 RAs. Note that the semaglutide formulation for the treatment of obesity has a higher dosage than semaglutide for the treatment of T2D.

Efficacy

The efficacy of semaglutide for chronic weight management in conjunction with reduced caloric intake and increased physical activity was studied in eight randomized, double-blind trials – seven placebo-controlled trials (68-week long STEP-1, -2, -3, -6, and STEP TEENS; 52-week long STEP HFpEF; and 104-week long STEP-5) and one placebo withdrawal trial (STEP-4) in which patients were randomly switched to placebo or continued taking semaglutide following an initial 20-week period on semaglutide. The primary endpoints in the placebo-controlled trials were: the percent change in body weight at week 52 (STEP HFpEF), week 68 (STEP-1, -2, -3, and -6), or week 104 (STEP-5), the proportion of patients achieving a weight reduction of at least 5% at week 68 (STEP-1, -2, -3, and -6), or week 104 (STEP-5), the percent change in BMI at week 68 (STEP TEENS), and the change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) at week 52 (STEP HFpEF). The primary endpoint of STEP-4 was percent change in body weight from week 20 to week 68.

Semaglutide demonstrated a significant margin of superiority to the placebo in all STEP studies. The ETD in favor of semaglutide in the change in body weight from baseline was -12.4% (-14.9% with semaglutide vs -2.4% with placebo) in STEP-1 (P <0.0001), -6.2% (-9.6% with semaglutide vs -3.4% with placebo) in STEP-2 (P <0.0001), -10.3% (-16.0% with semaglutide vs -5.7% with placebo) in STEP-3 (P <0.001), -12.6% (-15.2% with semaglutide vs -2.6% with placebo) in STEP-5 (P<0.0001), -11.1% (-13.2% with semaglutide 2.4 mg vs -2.1% with placebo) and -7.5% (-9.6% with semaglutide 1.7 mg vs -2.1% with placebo) in STEP-6 (both P<0.0001), and -10.7% (-13.3% with semaglutide vs -2.6% with placebo) in STEP HFpEF (P<0.001). The proportion of patients who achieved a weight loss of at least 5% was also higher with semaglutide compared to the placebo in STEP-1 (83.5% vs 31.1%; P <0.001), STEP-2 (67.4% vs 30.2%; P <0.0001), STEP-3 (84.8% vs 47.8%; P <0.001), STEP-5 (77.1% vs 34.4%; P<0.0001), and STEP-6 (83% [semaglutide 2.4 mg] and 72% [semaglutide 1.7 mg] vs 21%; P<0.0001). In STEP TEENS, the BMI change for patients in the semaglutide group was significantly greater than for those in the placebo group (-16.1% vs 0.6%; P <0.001), and in STEP HFpEF, the KCCQ-CSS score significantly improved with semaglutide compared to placebo (16.6 points vs. 8.7 points; P <0.001). Semaglutide was also superior to the placebo in the confirmatory secondary endpoints of the proportion of patients achieving at least 5% weight loss (STEP TEENS: 73% vs 18%; P<0.001), proportion of patients achieving at least 10% weight loss (STEP-1: 66.1% vs 12.0%; STEP-2: 44.5% vs 10.2%; STEP-3: 73.0% vs 27.1%; STEP-5: 61.8% vs 13.3%; P <0.001 for STEP-1 and -3, P <0.0001 for STEP-2 and -5), and proportion of patients achieving at least 15% weight loss (STEP-1: 47.9% vs 4.8%; STEP-2: 25.1% vs 4.3%; STEP-3: 53.4% vs 13.2%; STEP-5: 52.1% vs 7.0%; P <0.001 for STEP-1 and -3, P <0.0001 for STEP-2 and -5). The confirmatory secondary endpoints in STEP HFpEF were also significantly improved in the semaglutide group compared to the placebo group (change in the 6-minute walk distance: 21.5 meters vs 1.2 meters; change in CRP level: -43.5% vs -7.3%; both P<0.001).

In STEP-4, maintaining semaglutide treatment resulted in significantly greater change in mean bodyweight from week 20 compared to switching to the placebo (-7.9% with semaglutide vs 6.9% with placebo; ETD -14.8%; P <0.001). Additionally, compared to patients who switched to placebo, more patients who stayed on semaglutide achieved ≥5% weight loss (88.7% vs 47.6%), ≥10% weight loss (79.0% vs 20.4%), ≥15% weight loss (63.7% vs 9.2%), and ≥20% weight loss (39.6% vs 4.8%).

Safety

The prescribing information for semaglutide for obesity contains pooled safety information from the first three randomized, double-blind, placebo controlled clinical trials (STEP-1, -2, and -3). Safety events were evaluated in a total of 2116 patients during the 68 weeks of these three STEP trials and a 7-week off-drug follow-up period. Permanent discontinuation of semaglutide occurred in 6.8% of patients treated with semaglutide and 3.2% of patients in the placebo group. The most common adverse events leading to discontinuation in the semaglutide and placebo group, respectively, were nausea (1.8% vs 0.2%), vomiting (1.2% vs 0%) and diarrhea (0.7% vs 0.1%). Adverse events occurring in 2% or more of patients receiving semaglutide that were more frequent than in the placebo group included nausea, diarrhea, vomiting, constipation, abdominal pain, headache, fatigue, dyspepsia, dizziness, abdominal distension, eructation, hypoglycemia in T2D, flatulence, gastroenteritis, gastroesophageal reflux disease, gastritis, viral gastroenteritis and hair loss.

The prescribing information for semaglutide contains several warnings and precautions about associated conditions, including the risk of thyroid C-cell tumors (also listed in a black box warning in the label), acute pancreatitis, acute gallbladder disease, hypoglycemia, acute kidney injury, hypersensitivity, diabetic retinopathy complications in patients with T2D, heart rate increase and suicidal behavior and ideation. Like liraglutide, semaglutide causes dose-dependent and treatment duration–dependent thyroid C-cell tumors in rodents; despite the unclear significance of these findings in humans, semaglutide is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2.

Prescribing Semaglutide

Semaglutide is administered subcutaneously (in the abdomen, thigh, or upper arm) once weekly, on the same day of the week and at any time of day, with or without meals. It is available in five dosage strengths: 0.25 mg, 0.5 mg, 1 mg, 1.7 mg, 2.4 mg. Semaglutide should be initiated at 0.25 mg weekly and escalated every four weeks to 0.5 mg, 1 mg and 1.7 mg before reaching the maintenance dose of 2.4 mg at week 17 (escalation can be delayed for 4 weeks if patients do not tolerate a dose). If the patient does not tolerate the 2.4 mg dose, the dose can be decreased to 1.7 mg for 4 weeks, after which semaglutide should be discontinued if the patients still does not tolerate the 2.4 mg dose. In case of a missed dose, semaglutide should either be immediately administered (if the next scheduled dose is more than 48 hours away) or skipped (if the next scheduled dose is less than 48 hours away). If more than 2 consecutive doses are missed, semaglutide can either be continued at the maintenance dose, or reinitiated with dose escalation.

Zepbound (Tirzepatide)

Initially approved for the treatment of T2D, tirzepatide gained an FDA approval for chronic weight management in November 2023. Tirzepatide is indicated as an adjunct to a reduced-calorie diet and increased physical activity in adults with a BMI of ≥30 kg/m2 (obesity) or ≥27 kg/m2 (overweight), and at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, T2D, obstructive sleep apnea, or CVD). Tirzepatide is a synthetic peptide that acts as a dual agonist – a GLP-1 receptor agonist and a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, possibly increasing its effectiveness. Like other GLP-1 agonists, tirzepatide has been demonstrated to cause thyroid C-cell tumor in rats. Although it is unknown whether this data has a significance to humans, tirzepatide is contraindicated for patients with either a personal or family history of MTC and for patients with MEN 2. Due to its effect in delaying gastric emptying, tirzepatide has the potential to modify the absorption of concurrent oral medications. Individuals taking oral contraceptives are advised to consider transitioning to non-oral alternatives or to use a barrier method of contraception for four weeks following the initiation of tirzepatide and for four weeks following any dosage increase. 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.

Efficacy

Before it was approved for chronic weight management, tirzepatide demonstrated marked weight loss-related efficacy in the T2D trials of the SURPASS program. In SURPASS-1, weight change from baseline was -7.9%, -9.3%, and -11.0% with tirzepatide 5, 10, and 15 mg, respectively, compared to -0.9% with placebo. In SURPASS-2, the relative weight change from baseline with 5, 10, and 15 mg of tirzepatide was -8.5%, -11.0%, and -13.1%, compared to -6.7% with semaglutide 1 mg. In SURPASS-3, tirzepatide treatment led to a dose-dependent body weight loss of 8.1-13.9%, while patients in the comparator (insulin degludec) group gained weight; similar results were reported in SURPASS-4, with patients on tirzepatide showing 8.1-13.0% weight loss from baseline, while patients on insulin glargine gained weight. For more detail on the tirzepatide and the SURPASS trials, see Chapter 19.

The efficacy of tirzepatide for chronic weight management was assessed in four double-blind, placebo-controlled trials from the SURMOUNT program – SURMOUNT-1, -2, -3, and -4. Two of these trials were 72-week long fixed-dose studies (SURMOUNT -1 and -2), and two of which were 72-week long (SURMOUNT-3) and 88-week long (SURMOUNT-4) maximum tolerated dose studies. 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). The primary endpoints were percent change in body weight from randomization (for all four studies) and proportion of patients achieving ≥5% body weight loss (for SURMOUNT-1, -2, and -3).

Significantly greater percent weight change was achieved by patients in the tirzepatide group compared to the placebo group in all SURMOUNT trials (SURMOUNT-1: -15.0% with tirzepatide 5 mg, -19.5% with tirzepatide 10 mg, -20.9% with tirzepatide 15 mg vs -3.1% with placebo [for both estimands]; SURMOUNT-2: -12.8% with tirzepatide 10 mg, -14.7% with tirzepatide 15 mg vs -3.2% with placebo [for the TRE], and -13.4% with tirzepatide 10 mg, -15.7% with tirzepatide 15 mg vs -3.2% with placebo [for the efficacy estimand]; SURMOUNT-3: -18.4% with tirzepatide vs 2.5% with placebo [for the TRE], and -21.2% with tirzepatide vs 3.3% with placebo [for the efficacy estimand]; SURMOUNT-4: -5.5% with tirzepatide vs 14.0% with placebo [for the TRE], and -6.7% with tirzepatide vs 14.8% with placebo [for the efficacy estimand]; P<0.001for all comparisons in SURMOUNT-1, -3, and -4, P<0.0001 for both comparisons in SURMOUNT-2). More patients in each tirzepatide group achieved the other primary endpoint of ≥5% weight loss compared to the placebo group, for both the TRE (SURMOUNT-1: 85.1% with tirzepatide 5 mg, 88.9% with tirzepatide 10 mg, 90.9% with tirzepatide 15 mg vs 34.5% with placebo; SURMOUNT-2: 79.2% with tirzepatide 10 mg, 82.8% with tirzepatide 15 mg vs 32.5% with placebo; SURMOUNT-3: 87.5% with tirzepatide vs 16.5% with placebo) and the efficacy estimand (SURMOUNT-1: 89.4% with tirzepatide 5 mg, 96.2% with tirzepatide 10 mg, 96.3% with tirzepatide 15 mg vs 27.9% with placebo; SURMOUNT-2: 81.6% with tirzepatide 10 mg, 86.4% with tirzepatide 15 mg vs 30.5% with placebo; SURMOUNT-3: 94.4% with tirzepatide vs 10.7% with placebo)(P<0.001 for all comparisons in SURMOUNT-1 and -3, P<0.0001 for all comparisons in SURMOUNT-2).

Safety

In line with the SURPASS program, tirzepatide demonstrated good tolerability in all four SURMOUNT trials. Safety was evaluated in a total of 4726 patients. Gastrointestinal events were the most prevalent AEs, occurring more frequently in patients receiving tirzepatide. They included nausea, diarrhea, vomiting, and constipation. Treatment discontinuation rates due to AEs varied in the SURMOUNT trials. in SURMOUNT-1 and -2, the pooled rates were 4.8% in the tirzepatide 5 mg group, 6.3% in the tirzepatide 10 mg group, 6.7% in the tirzepatide 15 mg group, and 3.4% in the placebo group. In SURMOUNT-3, the rates were 10.5% for tirzepatide and 2.1% for placebo, while in SURMOUNT-4 the rates were 1.8% for tirzepatide and 0.9% for placebo.

The prescribing information for tirzepatide contains the following warnings and precautions: risk of thyroid C-cell cancer (also listed as the black box warning), severe gastrointestinal disease, acute kidney injury, acute gallbladder disease, acute pancreatitis, hypersensitivity reactions, hypoglycemia, diabetic retinopathy complication in patients with T2D, and suicidal behavior and ideation. Like liraglutide and semaglutide, tirzepatide causes thyroid C-cell cancer in rats, and is consequently contraindicated in patients with either a personal or family history of MTC and for patients with MEN 2.

Prescribing Tirzepatide

Tirzepatide is administered as a subcutaneous injection in doses of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg, given in the abdomen, thigh, or upper arm. The recommended starting dose is 2.5 mg once a week. The adjustment of the dose should be done in 2.5 mg increments every 4 weeks to a maximum weekly dose of 15 mg, while the recommended maintenance dose is 5 mg, 10 mg, or 15 mg, depending on the patient’s response and tolerability. If a dose is missed, it should be taken as soon as possible or withing 4 days of the scheduled dose; otherwise, it should be skipped, and the regimen continued from the next scheduled dose.

Conclusion

Modest weight loss of 5% to 10% is associated with improving several weight-related CV risk factors, including glycemic control, dyslipidemia and hypertension. In addition, weight-related GERD, arthritis, mobility issues and NASH (non-alcoholic steatohepatitis) are also improved with weight loss. However, many patients have difficulty maintaining even modest weight loss due to the biological factors that preserve weight gain (e.g., hormonal changes). Weight-loss management exclusively through lifestyle interventions is therefore often associated with short-term success, with patients regaining weight within 2 years. Regardless, a large cohort study demonstrated that patients with newly diagnosed T2D who lose approximately 10% of their body weight and then regain it within 2 years maintain improved glycemic and BP control relative to patients with stable weight, demonstrating the positive impact even transient weight loss can provide. The pharmacologic options available to patients, particularly the GLP-1 RAs, have been shown to increase the success of weight loss as well as long-term maintenance.