Selecting Obesity Medications
Recommendations
2.6a In adults with obesity who do not have obesity-related diseases or complications, consider obesity medications as part of the treatment plan to promote weight reduction, prevent further weight gain, and reduce the risk of developing obesity-related diseases and complications A, C (figure 1).
2.6b Obesity medications should be offered as part of initial treatment for obesity to adults with or at high risk of obesity-related diseases or complications A.
2.7 In adults with overweight or obesity and pre-diabetes, the treatment plan should prioritize obesity medications with demonstrated evidence for preventing progression to type two diabetes A, B (figure 2).
2.8 In adults with overweight or obesity and type two diabetes, the preferred obesity medication should be a glucagon-like peptide one receptor agonist (GLP-1RA) or a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide one receptor agonist (dual GIP/GLP-1RA) given their weight reduction and glucose-lowering efficacy A. If a preferred obesity medication is unable to be used, other obesity medications with demonstrated glucose-lowering efficacy may be considered within the context of their risks and adverse effects B (figure 2).
2.9 In adults with overweight or obesity and essential hypertension, the treatment plan should prioritize obesity medications with demonstrated blood pressure reduction benefit A, B (figure 2).
2.10 In adults with overweight or obesity and established atherosclerotic cardiovascular disease, the treatment plan should include a GLP-1RA with demonstrated benefits A, B or a dual GIP/GLP-1RA with potential benefits in reducing cardiovascular events B (figure 2).
2.11 In adults with overweight or obesity and heart failure with preserved ejection fraction, the treatment plan should include a GLP-1RA or dual GIP/GLP-1RA with demonstrated improvements in heart failure-related symptoms A or reduction in heart failure events A, B (figure 2).
2.12 In adults with overweight or obesity and metabolic dysfunction–associated steatohepatitis (MASH) with moderate or advanced fibrosis, the treatment plan should include a GLP-1RA or a dual GIP/GLP-1RA with demonstrated or potential benefits on MASH A, B, C(figure 2).
2.13 In adults with overweight or obesity and moderate-to-severe obstructive sleep apnea, the treatment plan should prioritize obesity medications with demonstrated improvements in sleep apnea A, B, C (figure 2).
2.14 In adults with overweight or obesity and moderate osteoarthritis, the treatment plan should prioritize a GLP-1RA or dual GIP/GLP-1RA with potential improvements in osteoarthritis symptoms B, C (figure 2).
Obesity medications among adults without obesity-related diseases or complications. Among adults without obesity-related diseases or complications, obesity medications are indicated in adults with obesity. *The level of evidence ratings are identified in parentheses. Obesity medications are listed in relative order of benefit within each box where medications with greatest magnitude of benefit are listed first, although most obesity medications have not been compared in direct head-to-head trials. Categorization reflects expected average placebo-subtracted weight loss in meta-analyses to represent the weight-reducing effect of the obesity medication beyond that achieved with lifestyle change alone (51,52). Individual responses may vary. Given that obesity medications should be used in combination with lifestyle changes, the total anticipated weight reduction effect would be the combined effect of the obesity medication plus lifestyle (e.g., >13% loss for high weight-reducing effect obesity medication plus lifestyle). In meta-analyses, lifestyle counseling achieved 2.6% weight reduction (2); however, intensive behavioral therapy typically results in greater magnitude of weight reduction relative to lower intensity lifestyle counseling. Therefore, the combination of obesity medication with intensive behavioral therapy may result in greater total anticipated weight reduction effect. Of note, the maximum dose of semaglutide and liraglutide approved to treat obesity differs from the doses of these medications approved to treat type 2 diabetes. †To date, phentermine has only been studied in short-term RCTs (≤6 months duration). ‡Barriers to long-term use may include adverse medication effects, insurance coverage, out-of-pocket costs, etc.
Obesity medications among adults with obesity-related diseases and complications. Among adults with obesity-related diseases or complications, obesity medications are indicated in adults with overweight or obesity. *Obesity medications are identified as “demonstrated benefit” if there is A-level evidence of benefit in the specified outcome for each obesity-related disease or complication. Obesity medications with B- or C-level evidence for these outcomes are identified as having “potential benefit.” Obesity medications are listed in relative order of benefit where medications with greatest benefit are listed first; to date, no head-to-head trials have compared these outcomes in obesity medications. The level of evidence ratings are identified in parentheses. †Barriers to long-term use may include adverse medication effects, insurance coverage, out-of-pocket costs, etc. AHI, apnea hypopnea index; ASCVD, atherosclerotic cardiovascular disease; BP, blood pressure; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HTN, hypertension; MACE, major adverse cardiovascular events; MASH, metabolic dysfunction–associated steatohepatitis; OA, osteoarthritis; OSA, obstructive sleep apnea; PreDM, prediabetes; T2D, type 2 diabetes.
The FDA has approved several obesity medications as adjuncts to a reduced-calorie meal plan and increased physical activity in individuals with obesity or individuals with overweight and the presence of at least one obesity-related disease or complication. Historically, label-defined eligibility criteria were BMI ≥30 kg/m2 or ≥27 kg/m2 with one or more obesity-related disease or complication; however, these thresholds are no longer included in the labels of several obesity medications (ie, phentermine-topiramate, liraglutide, semaglutide, and tirzepatide). Table 3 describes the mechanisms of action and dosing for all FDA-approved obesity medications. Most obesity medications are approved for long-term treatment; the exception is monotherapy with phentermine or other adrenergic agents (eg, diethylpropion) that were approved for short-term use. Obesity medications are invaluable components of initial treatment in adults who already have or who are at high risk of developing obesity-related diseases or complications, as they can significantly mitigate the progression of these conditions.4 6 47 48 If individuals with obesity-related diseases or complications initially decline obesity medication, it may be appropriate to reevaluate their interest in this treatment option at follow-up.
Mechanisms of action and dosing of obesity medications for adults
All FDA-approved obesity medications have demonstrated weight-reduction efficacy in clinical trials.18 38–42 50 In a network meta-analysis, in comparison with placebo at study end point, orlistat was associated with 3.1% greater weight reduction (22 RCTs), phentermine-topiramate was associated with 8.8% greater weight reduction (5 RCTs), naltrexone-bupropion was associated with 4.8% greater weight reduction (2 RCTs), liraglutide was associated with 4.5% greater weight reduction (10 RCTs), semaglutide was associated with 11.9% greater weight reduction (13 RCTs), and tirzepatide was associated with 16.2% greater weight reduction (6 RCTs).51 Of note, these meta-analyses include RCTs of adults with obesity who do and do not have obesity-related diseases and complications, and other network meta-analyses have reported similar results.2 3
To date, phentermine has only been studied in short-term RCTs (28 weeks or less)50 52–54; however, a 2019 observational study demonstrated that long-term phentermine use was associated with significant weight reduction: individuals prescribed the medication for ≥12 months experienced a 7.4% greater weight reduction compared with those with ≤3 months.55 This analysis also showed no significant increase in the risks of cardiovascular disease or death among individuals prescribed phentermine long term. In individuals without cardiovascular disease, serious psychiatric disease, or substance use disorder, phentermine monotherapy may be an effective and safe option for achieving sustained weight reduction, with the caveat that no long-term efficacy and safety trial data currently exist.56 57 Long-term phentermine monotherapy is an off-label use, as this medication is only FDA-approved for short-term use, and healthcare professionals should be aware that some geographic areas may legally restrict this approach. Long-term phentermine monotherapy may be considered after discussion of the benefits and risks of all obesity medications, including those FDA-approved for long-term use. Phentermine is a schedule IV controlled substance, and therefore healthcare professionals should perform an in-person examination and evaluation, preferably with ECG, prior to prescribing this medication. The starting dose of phentermine should be 15 mg daily or less, and the dose may be increased based on tolerability and treatment response. Healthcare professionals should consider monthly follow-up, including monitoring of blood pressure and pulse, until the phentermine dose is stable, with follow-up every 3–6 months for long-term treatment to maintain health goals. Phentermine is one of the most prescribed obesity medications in the U.S.58
Prior research has shown that adverse effects from obesity medications contribute to individuals discontinuing the medication.2 59 Therefore, healthcare professionals should advise individuals of the adverse effects associated with each obesity medication and discuss strategies to minimize or manage these effects (table 1). For example, glucagon-like peptide one receptor agonists (GLP-1RAs) and a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide one receptor agonist (dual GIP/GLP-1RA) are associated with gastrointestinal adverse effects including nausea, diarrhea, constipation, and dyspepsia,60–62 which may be managed by decreasing portion sizes, decreasing intake of high-fat foods, increasing intake of high-fiber foods, avoiding long intervals between meals, and eating the last meal ≥2 hour before bedtime.63 64
For an individual with obesity who does not have any obesity-related diseases or complications, the primary treatment goal is to prevent the development of these conditions (Figure 1). Healthcare professionals should perform a comprehensive medical evaluation before selecting a medication to ensure safety and efficacy. Pharmacotherapy is an important tool for managing obesity, particularly when lifestyle interventions alone are insufficient to achieve and sustain weight reduction.53 The amount of weight reduction necessary to prevent obesity-related diseases and complications varies from person to person, and the healthcare professional should consider cost, access, tolerability, and individual preferences in the decision-making. Current costs of each obesity medication are summarized in table 4.
Median monthly AWP and NADAC of maximum dose of obesity medications*
Pre-diabetes
In individuals with obesity, weight reduction is highly effective in preventing or delaying progression to type two diabetes (T2D), particularly in high-risk people with pre-diabetes or metabolic syndrome. T2D prevention is dependent on weight-reduction magnitude, as evident from the Diabetes Prevention Program that demonstrated near-maximal T2D prevention was observed at ∼10% wt reduction with lifestyle intervention.65 Figure 2 and table 5 summarize outcomes of obesity medications among individuals with pre-diabetes. For example, an RCT employing phentermine-topiramate achieved 10% wt reduction and reduced incident T2D by 79%,66 which is a relatively similar T2D reduction to that achieved with metabolic-bariatric surgery.67 68 Orlistat also reduces incident T2D by 37%.69
Summary of key evidence to inform obesity medication selection, by populations with specific obesity-related diseases and complications*
More recent studies with GLP-1RA obesity medications are consistent with a weight-reduction goal of ∼10% to prevent T2D progression. An RCT of liraglutide 3 mg produced 6.1% wt reduction and reduced T2D progression by 79%.70 Semaglutide 2.4 mg was highly effective in converting pre-diabetes to normoglycemia,71 and 9.7% wt reduction with semaglutide was associated with 73% reduction in risk of developing T2D compared with placebo over ∼4 years of observation in the SELECT RCT.72 Tirzepatide 15 mg led to a 93% T2D reduction associated with 19.7% wt reduction in the 3 year SURMOUNT-1 extension study73; this T2D prevention benefit may reflect incretin effects of the GLP-1 component and GIP bioeffects in addition to weight reduction.74 75
Type 2 Diabetes
While the relationship between obesity and pathogenesis of T2D is complex, weight reduction represents highly effective therapy for both glycemic management and amelioration of obesity-related diseases and complications. The value of weight reduction as a primary treatment approach in T2D, whether at initial diagnosis or in conjunction with glucose-lowering therapy at any time over the disease course, is emphasized in the ADA’s “Standards of Care in Diabetes”.76 Healthcare professionals should be aware that people with T2D typically lose less weight than individuals without this diagnosis.77 All obesity medications FDA-approved for long-term treatment have been studied in RCTs that enrolled people with T2D (figure 2 and table 5).2 78–83 Weight reduction with obesity medication consistently lowers A1C and reduces the need for diabetes medications when compared with lifestyle alone.78–84 With obesity medications, individuals with T2D and obesity also experience blood pressure reductions, improvements in lipids, decreased hepatic transaminases, and improvements in cardiovascular risk biomarkers. Three medications approved for obesity (ie, liraglutide, semaglutide, and tirzepatide) also have an indication for glycemic management,84–86 although maximum approved doses for T2D are lower for liraglutide and semaglutide than approved doses for obesity.
Given their weight reduction and glucose-lowering benefits, healthcare professionals should strongly consider a GLP-1RA or dual GIP/GLP-1RA obesity medication as part of the treatment plan in people with obesity and T2D. In the SURMOUNT-2 RCT involving people with T2D and obesity, tirzepatide 15 mg produced weight reduction of 14.7% and resulted in a 2.1% A1C reduction, with nearly half of people achieving normal A1C values (<5.7%).78 In the STEP 2 RCT, semaglutide 2.4 mg resulted in a 9.6% wt reduction and A1C lowering of 1.6%.79 The SCALE Diabetes trial in people with obesity and T2D demonstrated that liraglutide 3 mg produced a 6.0% wt reduction and 1.3% A1C reduction.80 Severe hypoglycemic episodes were uncommon in individuals randomized to tirzepatide, semaglutide, and liraglutide in these trials.78–80
If a GLP-1RA or dual GIP/GLP-1RA obesity medication cannot be used, then other obesity medications may be considered. In people with T2D and obesity, phentermine-topiramate 15/92 mg resulted in 9.4% wt reduction and A1C lowering of 1.6%.81 Naltrexone-bupropion 32/360 mg led to a 5% wt reduction in people with obesity and T2D and A1C lowering of 0.6%.82 Orlistat resulted in 6.2% wt reduction and 0.3% A1C decrease in this population.83
Hypertension
Hypertension is an obesity-related disease,87 88 and one of the benefits of weight reduction is lowering blood pressure. Greater weight reduction leads to greater improvements in systolic and diastolic blood pressure with intensive lifestyle intervention.45 Blood pressure lowering in individuals with and without hypertension is observed with most obesity medications (figure 2 and table 5).18 41 42 89–94 For example, tirzepatide 15 mg reduced systolic and diastolic blood pressure by 7.2 mmHg and 4.8 mmHg, respectively,18 and a substudy using 24 hours ambulatory monitoring found that tirzepatide substantially reduced daytime and nighttime blood pressures in individuals with elevated baseline systolic pressure.95 It should be noted that tirzepatide, semaglutide, liraglutide, and phentermine-topiramate, on average, cause small increases in resting heart rate (∼2–4 bpm), although some individuals may experience larger increases (∼10–20 bpm). This heart rate change is not clinically detrimental to most individuals, as the rate-pressure product (heart rate×systolic blood pressure),96–98 which indicates workload on the heart, remains favorable due to blood pressure reductions. Healthcare professionals should be aware that naltrexone-bupropion does not reduce blood pressure commensurate with weight reduction,89 and both naltrexone-bupropion and phentermine are contraindicated in individuals with uncontrolled hypertension.
Atherosclerotic Cardiovascular Disease
Obesity contributes to atherosclerotic cardiovascular disease (ASCVD) development through multiple mechanisms,99 and the duration of obesity and visceral adiposity are strong predictors of coronary artery disease in epidemiologic studies.100 The magnitude of weight reduction achieved may be particularly critical for ASCVD,99 as modest weight reduction with intensive lifestyle intervention did not reduce the rate of cardiovascular events in adults with T2D and obesity101; a post hoc analysis of this RCT found that only participants who achieved ≥10% wt reduction had significant reductions in cardiovascular events.102 In adults with obesity and established ASCVD, the treatment plan should include a GLP-1RA with demonstrated benefits or dual GIP/GLP-1RA with potential benefits in reducing cardiovascular events as well as weight reduction (figure 2 and table 5).
Semaglutide reduces cardiovascular events among high-risk individuals (eg, those with prior ASCVD or T2D).103 In the SELECT RCT, semaglutide 2.4 mg resulted in a 20% reduction in adverse cardiovascular outcomes (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in adults with BMI ≥27 kg/m2 and established cardiovascular disease without diabetes.4 Further, semaglutide produced durable weight reduction104 and significantly reduced new-onset diabetes and a composite kidney outcome (driven by reductions in new-onset macroalbuminuria).105 While a cardiovascular outcomes trial evaluating liraglutide 3.0 mg has not been performed, liraglutide 1.8 mg (T2D-approved dose) reduces cardiovascular events in people with T2D at increased cardiovascular risk, including among participants with obesity.5 Similar findings were observed with liraglutide 3.0 mg vs pooled comparators in the SCALE trials (HR 0.42; 95% CI 0.17 to 1.08),106 but this analysis was underpowered due to low event rates.
A cardiovascular outcomes trial of dual GIP/GLP-1RA obesity medication has not yet been published; however, there is evidence to support potential ASCVD benefits. Tirzepatide has been shown to significantly improve cardiovascular risk factors (eg, blood pressure, cholesterol, systemic inflammation, and glycemic management) in people with obesity.18 107 In a SURMOUNT-1 trial post hoc analysis, tirzepatide significantly reduced the predicted 10 year risk of ASCVD events compared with placebo.108 Moreover, in a prespecified participant-level pooled analysis of the SURPASS program, tirzepatide did not increase the risk of major adverse cardiovascular events in people with T2D vs pooled comparators (HR 0.80; 95% CI 0.57 to 1.11).109
The LIGHT trial, which randomized people with BMI 27–50 kg/m2 at increased cardiovascular risk to naltrexone-bupropion, was designed to evaluate cardiovascular outcomes. In the primary analysis (conducted after 50% of planned events), naltrexone-bupropion did not reduce major adverse cardiovascular events compared with placebo.110 However, due to unplanned early termination after public release of confidential interim data, the LIGHT trial was unable to rigorously establish the safety and efficacy of naltrexone-bupropion compared with placebo. Moreover, most participants permanently discontinued study medication by 1 year post-randomization. There are no cardiovascular outcomes trials for orlistat, phentermine, or phentermine-topiramate.
Heart Failure With Preserved Ejection Fraction
Obesity is a leading driver of heart failure with preserved ejection fraction (HFpEF) onset and progression,111–115 and individuals with obesity and HFpEF display unique clinicopathological features (eg, increased plasma volume and greater cardiac remodeling) when compared with individuals with HFpEF without obesity.116 Modest weight reduction among individuals with obesity and HFpEF through lifestyle change improves aerobic capacity, New York Heart Association functional class, and quality of life.117 In adults with obesity and HFpEF, the treatment plan should include a GLP-1RA or dual GIP/GLP-1RA with demonstrated improvements in heart failure (HF)-related symptoms or events (figure 2 and table 5).
In the STEP-HFpEF RCT, semaglutide 2.4 mg significantly improved HF-related symptoms and functional limitations and reduced body weight (11% placebo-subtracted reduction) in people with BMI ≥30 kg/m2 and chronic symptomatic HF with left ventricular ejection fraction (LVEF) ≥45%.46 In pooled analyses, semaglutide improved exercise function and natriuretic peptide levels,118 reduced diuretic requirements,119 and attenuated adverse myocardial remodeling.120 In a prespecified pooled analysis of the STEP-HFpEF Program, SELECT, and FLOW trials, semaglutide reduced cardiovascular death or HF events by 31% compared with placebo in participants with HF and LVEF ≥40%.121
Tirzepatide has also been shown to reduce HF events in people with obesity and stable chronic HFpEF. Among individuals with BMI ≥30 kg/m2 and HF with LVEF ≥50% enrolled in the SUMMIT RCT, tirzepatide improved HF-related health status and reduced the rate of cardiovascular death or a worsening HF event by 38%,48 although number of events was relatively low (36 with tirzepatide and 56 with placebo). Additional benefits on body weight (12% placebo-controlled reduction), exercise function, left ventricular mass, and paracardiac adipose tissue were also observed.122 123
Metabolic Dysfunction–Associated Steatohepatitis
Metabolic dysfunction–associated steatohepatitis (MASH) is defined as the presence of steatohepatitis and no alcohol consumption or consumption in amounts unlikely to directly cause adverse liver outcomes (alcohol intake <20 g/day for women and <30 g/day for men).124 Fibrosis is a predictor of disease progression125 and is strongly linked to liver-related outcomes and death.126 Histologically, fibrosis is staged based on severity and distribution of scar tissue. Clinically significant fibrosis is defined as stage ≥F2 (moderate; sinusoidal and portal fibrosis), advanced fibrosis is F3 (ie, bridging fibrosis, usually central-to-portal or central-to-central bridges), and F4 is cirrhosis.124 Among people with MASH, weight reduction of ≥10% may be needed to reverse steatohepatitis and improve fibrosis.127 In adults with obesity and MASH with moderate or advanced fibrosis, a GLP-1RA or dual GIP/GLP-1RA is preferred for obesity treatment because of the benefits or potential benefits on MASH (figure 2 and table 5). While not specifically tested among individuals with MASH, healthcare professionals should be aware that the dose of naltrexone-bupropion needs to be adjusted in the setting of moderate hepatic impairment.
In a planned interim analysis of the ESSENCE RCT, semaglutide 2.4 mg significantly improved liver histology compared with placebo in individuals with biopsy-defined MASH and fibrosis stage F2 or F3.7 Mean BMI was 34.3 kg/m2 and 35.0 kg/m2 in the semaglutide and placebo groups, respectively. Resolution of steatohepatitis with no worsening of liver fibrosis occurred in 62.9% of semaglutide participants and 34.3% of placebo; a reduction in liver fibrosis with no worsening of steatohepatitis was reported in 36.8% of semaglutide participants and 22.4% of placebo. Mean weight reduction with semaglutide was 10.5%. Prior phase 2 RCTs of semaglutide among individuals with MASH demonstrated significantly increased likelihood of MASH resolution128 and improved cardiometabolic parameters.129 A meta-analysis (8 RCTs) demonstrated the short-term efficacy and safety of semaglutide in reducing liver fat content and improving liver stiffness compared with placebo.130 Less evidence exists regarding the use of liraglutide in MASH. In a phase 2 RCT of individuals with BMI ≥25 kg/m2 and biopsy-confirmed MASH, liraglutide 1.8 mg demonstrated histological resolution of MASH and slowed fibrosis progression compared with placebo.131 Pilot studies comparing liraglutide 3 mg and structured lifestyle interventions found no significant difference in liver-related outcomes.132 133
Tirzepatide has shown promise in treating MASH. In the phase 2 SYNERGY-NASH RCT, individuals with biopsy-confirmed MASH and stage F2 or F3 fibrosis were randomized to tirzepatide or placebo; 62% of the tirzepatide 15 mg group met criteria for resolution of MASH without worsening of fibrosis at 52 weeks compared with 10% in the placebo group.46 Overall, 51% of tirzepatide 15 mg participants improved at least one fibrosis stage without worsening of MASH as compared with 30% of placebo participants. Mean weight reduction was 15.6% with tirzepatide 15 mg. Lower doses of tirzepatide (5 mg and 10 mg) were also tested and showed benefits relative to placebo.
There currently is no direct evidence evaluating outcomes of the use of GLP-1RA or dual GIP/GLP-1RA obesity medications among individuals with obesity and metabolic dysfunction–associated steatotic liver disease (MASLD). These medications may be an effective and safe option for achieving sustained weight reduction in this population, given the demonstrated or potential benefits on MASH.
Obstructive Sleep Apnea
Obstructive sleep apnea (OSA) is an obesity-related disease characterized by partial or complete upper airway obstruction during sleep, leading to sleep fragmentation and hypoxemia.114 The prevalence of moderate-to-severe OSA, defined as AHI ≥15 events/h on polysomnography, increases with increasing body weight.134 OSA is associated with increased mortality in people with obesity.135 136 A 10% body weight reduction is associated with a 26% lower AHI.134 Weight reduction with intensive lifestyle intervention significantly decreases AHI and increases the likelihood of OSA remission.137 138
Several obesity medications improve OSA in RCTs (figure 2 and table 5),6 139 140 and AHI reduction is strongly related to the weight-reduction magnitude achieved with the obesity medication.139 140 To date, the greatest magnitude of benefit has been with tirzepatide. In the SURMOUNT-OSA trials, once-weekly tirzepatide (10 or 15 mg) significantly reduced AHI by more than 20 events/h compared with placebo in adults with obesity and moderate-to-severe OSA, among individuals treated with and without positive airway pressure (PAP).6 Mean weight reduction with tirzepatide was ≥15%. Over 40% of SURMOUNT-OSA participants treated with tirzepatide experienced improvements in OSA severity to below typical thresholds to recommend PAP therapy. In short-term RCTs, phentermine-topiramate and liraglutide 3.0 mg reduced AHI by 15 and 6 events/h, respectively, compared with placebo among people with obesity and moderate-to-severe OSA.139 140 Inclusion of obesity medications may also have added benefits of improved systolic blood pressure, glycemia, and body weight reduction that individuals with OSA may be unlikely to achieve with PAP therapy alone.141 142 In addition to established OSA treatment approaches (eg, PAP, airway stimulation, and splinting devices), the evidence supports obesity medications as part of the treatment plan for people with obesity and OSA.
Osteoarthritis
Osteoarthritis is an obesity-related disease, particularly knee osteoarthritis.143 144 Weight gains of ≥10% are associated with worsening pain and physical function,145 and weight reduction of similar magnitude may result in symptom improvements.146 In adults with obesity and moderate osteoarthritis, the treatment plan should prioritize a GLP-1RA or dual GIP/GLP-1RA with potential to improve osteoarthritis symptoms (figure 2 and table 5). In a 68 week trial involving individuals with obesity and moderate knee osteoarthritis, semaglutide 2.4 mg significantly improved knee pain scores and reduced body weight compared with placebo49; participants also experienced greater improvements in physical function. Less evidence exists regarding the use of liraglutide in osteoarthritis, which may only have modest benefits in physical function.147 A retrospective cohort study found that individuals prescribed semaglutide, liraglutide, or tirzepatide had a reduced risk of osteoarthritis diagnosis.148 Individuals prescribed tirzepatide had a significantly lower risk of osteoarthritis compared with individuals prescribed semaglutide or liraglutide.
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