Precision obesity medicine: A phenotype-guided framework for pharmacologic therapy across the lifespan

Cardiovascular disease remains the leading cause of death in people with obesity, even in the absence of diabetes. Obesity contributes to ASCVD and HF via metabolic, inflammatory, and hemodynamic mechanisms. Visceral and epicardial fat deposition drives insulin resistance, endothelial dysfunction, and neurohormonal activation. Heart Failure with Preserved Ejection Fraction (HFpEF), in particular, has emerged as an obesity-mediated phenotype characterized by impaired compliance, elevated filling pressures, and limited exercise tolerance. As discussed by Tuccinardi et al., AOMs targeting adiposity and CV risk offer a novel treatment paradigm, mirroring recent T2D strategies [9] (Figs. 1 and 2; Tables 1 and 6) (see Supplementary Material for Clinical Takeaways).

Semaglutide

In the SELECT trial, semaglutide 2.4 mg once weekly (OW) reduced MACE (CV death, nonfatal myocardial infarction (MI), stroke) by 20% (HR 0.80; 95% CI 0.72–0.90) and all-cause mortality by 19% in subjects with obesity and established ASCVD but without diabetes [4]. In STEP-HFpEF, semaglutide 2.4 OW improved Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) (+ 7.8 points), 6-minute walk distance (6MWD) (+ 20.3 m), reduced C Reactive Protein (CRP) (−43.5% vs. −7.3%) and body weight (− 13.3% vs. − 2.6%), and showed a lower, though exploratory, HF event rate (HR 0.08; 95% CI 0.00–0.42) [5]. Semaglutide should be preferred as first-line AOM in people with obesity and established ASCVD or HFpEF, even in the absence of diabetes, based on robust CV benefit.

Tirzepatide

Though CVOT data are pending, post hoc SURMOUNT-1 analyses showed reduced 10-year ASCVD risk and improved blood pressure, lipids, and inflammation in participants without diabetes [10]. In the SUMMIT trial, tirzepatide significantly lowered the composite of CV death or HF hospitalization (HR 0.62; 95% CI 0.41–0.95), driven by reduced HF hospitalizations (HR 0.54; 95% 0.34–0.85), with no significant effect on CV death. It also improved KCCQ-CSS (+ 6.9 points, placebo subtracted) and 6MWD (18.3 m; 95% CI, 9.9–26.7) [11]. Tirzepatide should be preferred for people with obesity and HFpEF; the CV (MACE) benefit in obesity appears promising but awaits dedicated CVOT data SURMOUNT MMO Trial, ClinicalTrials.gov (ID NCT05556512).

Liraglutide

In a 3-year trial in 2254 participants with obesity and prediabetes, liraglutide 3.0 mg improved CV risk factors including blood pressure and lipids [12]. No data support liraglutide for HF prevention in obesity without diabetes. In a post hoc analysis from SCALE randomized controlled trials found that liraglutide 3.0 mg was not associated with increased cardiovascular risk compared to the comparator groups (placebo or orlistat). However, the results are limited by a small number of events and retrospective adjudication [13]. Liraglutide may be considered in people with obesity and elevated CV risk who are not candidates for more potent agents; not explicitly recommended for HF.

Orlistat

The XENDOS trial reported modest weight loss and BP reduction, with a neutral cardiovascular profile [14]. Orlistat may be considered when centrally acting AOMs are contraindicated, though long-term efficacy is limited.

Naltrexone/Bupropion

The LIGHT trial was terminated early; the impact of MACE remains unknown [15]. Sympathomimetic effects (↑HR, BP) limit its use in ASCVD or HF. EMA recommends annual cardiovascular evaluation due to possible long-term risks. This combination is not recommended for people with ASCVD or HF due to potential hemodynamic stress and lack of outcome data, especially when alternatives with proven benefits are available.

Phentermine/Topiramate

No CVOTs exist. Though effective for weight loss, phentermine's sympathomimetic profile (↑HR, BP) necessitates caution in high-risk people. EQUIP showed modest BP and lipid improvement, but cardiovascular safety is uncertain [16]. Noteworthy, the combination Phentermine/Topiramate is FDA- but not EMA-approved. It is therefore not a viable option in Europe. This combination is not recommended for high-risk people with ASCVD or HF, especially when alternatives with proven benefit are available.

CKD is a common and serious complication of obesity, amplifying cardiovascular risk, impairing quality of life, and limiting therapeutic options. Its pathophysiology involves glomerular hyperfiltration, intrarenal inflammation, and ectopic fat accumulation in the renal sinus and perirenal space, exacerbated by hypertension, insulin resistance, and dyslipidemia. Even modest renal impairment alters drug clearance and increases adverse effect risk, making AOM use in CKD a high-stakes clinical decision (Figs. 1 and 2; Tables 1 and 6) (See Supplementary Material for Clinical Takeaways).

Semaglutide

In the SELECT trial, semaglutide 2.4 mg reduced a composite renal endpoint (≥ 50% eGFR decline, macroalbuminuria onset, or need for renal replacement therapy) by 22% vs. placebo [17]. This prespecified endpoint occurred alongside major adverse CV events and all-cause mortality reductions, suggesting a comprehensive cardio-renal-metabolic effect. Semaglutide up to 1 mg OW was found to be safe in dialysis patients with obesity in a prospective observational study, but its use remains not permitted in clinical practice for this population [18]. Semaglutide should be preferred as first-line AOM in people with obesity and CKD, including non-diabetic populations, based on renal and CV outcome data.

Tirzepatide

Although not yet assessed in a dedicated renal outcome trial, tirzepatide has shown consistent renal benefits across subgroups. In SUMMIT (HFpEF + obesity), tirzepatide improved creatinine–and cystatin C–based eGFR and reduced UACR, though these were secondary and not prespecified endpoints [11]. SURMOUNT-1 post hoc analyses confirmed favorable shifts in renal biomarkers in participants with obesity and no diabetes [19]. Tirzepatide may be considered when semaglutide is not tolerated, although renal benefits remain to be confirmed in dedicated trials (TREASURE-CKD, ClinicalTrials.gov ID NCT05536804).

Orlistat

As a non-systemic lipase inhibitor, orlistat may be considered in CKD where systemic agents are unsuitable. A small study of patients with stage 3–5 CKD facilitated Weight loss and preserved renal function over 2 years, improving transplant eligibility [20]. A population study showed reduced risk of incident CKD stage ≥ 3 (HR 0.78), CV events, and mortality [21]. However, oxalate nephropathy remains a concern, particularly in advanced CKD, requiring close monitoring. Orlistat may be considered in people with moderate-to-severe CKD when incretin therapies are contraindicated, with close renal monitoring.

Naltrexone/Bupropion

No renal-specific data are available. Its sympathomimetic effects (↑BP, HR) raise concern for renal harm in moderate-to-severe CKD. Without outcome data and given the potential hemodynamic burden, this combination should be avoided in CKD. This combination is not recommended to people with moderate-to-severe CKD (eGFR < 60 mL/min/1.73 m²), given uncertain benefit and safety concerns.

Phentermine/Topiramate ER

The EQUIP trial (15) showed efficacy in weight loss and cardiometabolic risk factors, but renal outcomes were not evaluated. Phentermine's sympathomimetic activity and topiramate's partial renal clearance raise concerns, especially in reduced eGFR, due to risks of acidosis and nephrolithiasis. This combination is not recommended in moderate-to-severe CKD. This combination is not recommended to people with eGFR < 60 or with nephrolithiasis risk, due to potential for harm and lack of renal outcome data.

Prediabetes, defined by impaired fasting glucose, impaired glucose tolerance, or elevated HbA1c, represents a critical window for metabolic intervention in people with obesity. Excess adiposity drives insulin resistance, β-cell dysfunction, and hepatic steatosis, contributing to progressive dysglycemia. AOMs that induce meaningful weight loss can restore normoglycemia and reduce diabetes risk. (Figures 1 and 2) (See Supplementary Material for Clinical Takeaways).

Semaglutide

In STEP 1, semaglutide 2.4 mg OW led to 10–15% Weight loss and restoration of normoglycemia in 84.1% of prediabetic participants over 68 weeks [3]. Improvements in HOmeostatic Model Assessment for Insulin Resistance (HOMA-IR) index, fasting glucose, and HbA1c further support its use as a first-line agent in obesity-related prediabetes.

In STEP 10, OW semaglutide 2.4 mg resulted in significant Weight loss of approximately 12% over 68 weeks compared to placebo in people with obesity and prediabetes. Normoglycemia was restored in a substantially higher proportion of participants receiving semaglutide versus placebo. Improvements in fasting glucose, HbA1c, and insulin sensitivity measures further validate semaglutide's efficacy and safety as a treatment option for obesity-associated prediabetes [22]. Semaglutide should be preferred in people with obesity and prediabetes, based on high rates of diabetes prevention and metabolic improvement.

Tirzepatide

In SURMOUNT-1, tirzepatide 15 mg OW achieved 22.5% mean Weight loss and a 94% risk reduction in diabetes progression over 72 weeks in participants with prediabetes [2]. Post hoc analyses confirmed insulin sensitivity and glycemic marker improvements [10]. In a specially designed trial for Obesity Treatment and Diabetes Prevention involving people with overweight or obesity and prediabetes, tirzepatide caused significant, dose-dependent weight loss (− 12.3% with 5 mg, − 18.7% with 10 mg, and − 19.7% with 15 mg compared to − 1.3% with placebo; P < 0.001) and significantly lowered the incidence of T2D (1.3% vs. 13.3%; HR 0.07; P < 0.001) [23]. Tirzepatide should be preferred in people with obesity and prediabetes, when greater weight loss is needed.

Metformin

The Diabetes Prevention Program showed that metformin 850 mg BID reduced T2D incidence by 31% over 2.8 years, with greater benefits for younger people with higher Body Mass Index (BMI) [24]. While cost-effective and well-tolerated, its modest weight effect (~ 2–3 kg) limits its utility when weight loss is a primary goal. It is not specifically approved for prediabetes. Metformin may be considered in prediabetes, especially when cost or tolerability is a concern; less effective for weight-driven glycemic reversal.

Acarbose Used adjunctively, acarbose modestly lowers weight ~ 0.5 kg (difference 0·77 kg [95% CI 0·01–1·54] compared to placebo) by delaying carbohydrate absorption and promoting satiety [25]. Acarbose may be considered adjunctively in select people with postprandial hyperglycemia, though limited by GI side effects and minimal weight benefit.

Orlistat

In XENDOS, orlistat reduced T2D incidence by 45% over four years [14], with a ~ 2.9 kg greater weight loss versus placebo and modest insulin sensitivity gains. Due to dietary fat restrictions, GI side effects and adherence challenges may limit its broader use. Orlistat may be considered when incretin-based therapies are contraindicated, particularly in early-stage dysglycemia.

Phentermine/Topiramate ER

In a post hoc CONQUER analysis, phentermine/topiramate ER reduced T2D progression by 48–78% over 56 weeks, depending on dose and baseline glycemia, driven by up to 10.9% weight loss and improved insulin sensitivity [26]. This combination may be considered in prediabetes requiring more potent weight loss, pending psychiatric and CV risk profile.

Naltrexone/Bupropion

Although not formally tested in T2D prevention trials, data from COR-I [27] and COR-II [28] showed reductions in fasting glucose and HOMA-IR. This agent may be considered in people with obesity, emotional eating, and mild dysglycemia without significant CV risk.

Obesity and T2D share common mechanisms, insulin resistance, chronic low-grade inflammation, ectopic lipid accumulation, and progressive β-cell failure. Over 80% of people with T2D suffer from overweight or obesity. Weight loss of ≥ 5–15% is associated with meaningful reductions in HbA1c, insulin needs, and cardiometabolic complications. AOMs now play a central role in managing both weight and glucose in this population (Figs. 1 and 2; Tables 2 and 6) (see Supplementary Material for Clinical Takeaways).

Semaglutide

In STEP 2, semaglutide 2.4 mg led to 9.6% mean weight loss in people with T2D, as expected, slightly less than in non-diabetic populations; HbA1c reductions of ~ 1.6% and improved insulin sensitivity were observed [29].

It should be preferred in people with T2D and obesity who require combined Weight and glycemic control. Based on the MACE reduction observed in SUSTAIN 6 [30], it should be preferred in patients with established ASCVD (secondary prevention).

Tirzepatide

Tirzepatide outperforms other AOMs in glycemic and weight outcomes. In SURPASS-1 to −5, Weight loss ranged from 11 to 15%. SURMOUNT-2 (obesity + T2D) confirmed 14.7% mean Weight loss at 15 mg over 72 weeks [31]. HbA1c reduction − 2.08%, with 84% of participants achieving HbA1c < 7.0%, and 49% HbA1c < 5.7%. In the SURPASS 2 trial, tirzepatide 15 mg action improves insulin secretion, reduces glucagon and hepatic glucose output, and shows better glycemic control than the semaglutide 1 mg OW [32]. It should be preferred in people with T2D and obesity when both HbA1c and weight burden are high, or when semaglutide is insufficient. It currently offers the most potent dual effect on glycemia and weight.

Liraglutide

Liraglutide 3.0 mg achieved ~ 6.0% Weight loss and 1.3% Hba1c reductions in the SCALE Diabetes trial [33]. At 1.8 mg, it reduced MACE by 13% (primary outcome) and CV mortality by 22% in LEADER [34]. It may be considered in patients with ASCVD or when daily injection is preferred; a valid alternative if weekly agents are not tolerated.

Non-Incretin AOMs in T2D

Orlistat

Orlistat achieved 2.9–3.4% greater weight loss and modest HbA1c reductions (0.3–0.5%) vs. placebo, mostly via improved insulin sensitivity [14]. GI side effects and modest efficacy limit its utility. It may be considered in people unable to use systemic AOMs, but adherence and efficacy are limited.

Naltrexone/Bupropion

In COR-Diabetes, naltrexone/bupropion yielded − 5% weight loss and − 0.6% HbA1c reductions [35]. It may be considered in those needing potent weight loss without CV/psychiatric contraindications.

Phentermine/Topiramate ER

In a pooled subgroup analysis including T2D subjects of the CONQUER and the OB-202/DM-230 Study, the 15/92 mg dose reduced HbA1c by 0.4% (placebo subtracted) and led to up to 9.4% Weight loss over 56 weeks [36]. It is helpful in patients where weight loss is the primary goal. However, sympathomimetic effects limit its use in uncontrolled hypertension or ASCVD. It may be considered in selected people with emotional eating and controlled BP/psychiatric history.

Obesity is increasingly common in people with Autoimmune diabetes, complicating glycemic control and metabolic health. As noted by Maddaloni et al., this "double diabetes" phenotype combines autoimmune β-cell failure with insulin resistance and visceral adiposity [48]. Excess fat mass in Autoimmune diabetes heightens insulin requirements and contributes to hepatic steatosis, systemic inflammation, and microvascular and skeletal complications. Exogenous insulin may worsen weight gain and glycemic variability, fueling a cycle of dysmetabolism [49].

AOMs and bariatric surgery are emerging tools to reduce metabolic overload and insulin demand, even without β-cell recovery (Figs. 1 and 2, Supplementary Table 1) (see Supplementary Material for Clinical Takeaways).

Semaglutide

In a real-world cohort of 50 adults with T1D and overweight/obesity, semaglutide use over 12 months led to significant weight loss and HbA1c improvement, without increased hypoglycemia risk [50]. Combined with automated insulin delivery, Semaglutide resulted in an average weight loss of − 8.8 kg (95% CI, − 10.6 to −7.0). Each group experienced two severe hypoglycemia events, and no cases of diabetic ketoacidosis were reported. These effects probably indicate appetite suppression and insulin regulation sensitization [51]. It may be considered in selected people with T1D and obesity to reduce insulin requirement and body weight, with appropriate monitoring.

Tirzepatide

In a retrospective study of 51 T1D people with obesity, tirzepatide was associated with 8.5% mean Weight loss, 0.9% HbA1c reduction, and a 31.6% decrease in daily insulin dose over 8 months, with no increase in hypoglycemia; GI symptoms were the main side effect; overall tolerability was high [52].

Semaglutide and tirzepatide demonstrated significant weight loss and improved glycemic control in overweight and obese adults with T1D over 12 months. Semaglutide users experienced an average Weight loss of 9.1% (approximately 8.7 kg), while tirzepatide users lost 21.4% of their body weight (approximately 49.4 lbs). Both groups also showed reductions in HbA1c: a 0.54% decrease for semaglutide and a 0.68% decrease for tirzepatide, with statistical significance (P < 0.0001) [53].

Tirzepatide may be considered in selected patients with T1D, marked obesity and insulin resistance, though its off-label use requires close glycemic monitoring.

MASLD (formerly NAFLD) reflects the hepatic manifestation of systemic metabolic dysfunction. Its progressive subtype, MASH (previously NASH), is defined histologically by ballooning, lobular inflammation, and fibrosis. Obesity is the principal driver, promoting insulin resistance, visceral adiposity, dyslipidemia, and inflammation.

Sustained weight loss ≥ 10% is the cornerstone of MASH treatment but rarely achieved through lifestyle alone. AOMs capable of inducing substantial weight loss have emerged as disease-modifying agents. Incretin-based therapies are currently the most promising for histologic resolution, fibrosis regression, and transaminase normalization (Figs. 1 and 2; Tables 4 and 6) (see Supplementary Material for Clinical Takeaways).

Semaglutide

In a 72-week phase 2 RCT of 1197 participants with biopsy-confirmed MASH and F2–F3 fibrosis, semaglutide 0.4 mg/day achieved a significant MASH resolution in 59% vs. 17% with placebo [54]. Fibrosis improvement (43% vs. 33%) did not reach significance, likely due to study duration. Semaglutide also reduced liver fat, which was assessed using magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF), transaminases, and non-invasive fibrosis markers. Though not yet approved, off-label use is widespread, especially in people with T2D or metabolic Syndrome. In the Phase 3 ESSENCE trial, semaglutide 2.4 mg OW significantly improved liver histology in 800 patients with MASH and moderate-to-advanced fibrosis over 72 weeks. Resolution of steatohepatitis without worsening fibrosis occurred in 62.9% of semaglutide-treated patients compared to 34.3% in the placebo group (P < 0.001). Additionally, 36.8% of the semaglutide group experienced reduced liver fibrosis without worsening steatohepatitis, versus 22.4% in the placebo group (P < 0.001). The combined endpoint of both outcomes was achieved in 32.7% of the semaglutide group compared to 16.1% in the placebo group (P < 0.001) [55]. Semaglutide should be preferred in people with overweight/obesity and biopsy-proven MASH or MASLD with fibrosis and concurrent T2D or metabolic syndrome. Although not yet approved, off-label use is shared and supported by robust RCT data.

Tirzepatide

In a 52-week phase 2b trial in 157 participants with biopsy-proven MASH, tirzepatide significantly increased resolution of MASH without worsening of fibrosis compared to placebo: 44% with 5 mg, 56% with 10 mg, and 62% with 15 mg versus 10% in the placebo group (P < 0.001 for all doses). Fibrosis improvement without MASH worsening was also more frequent with tirzepatide (51–55% vs. 30% with placebo), with gastrointestinal events being the most common adverse effects, generally mild to moderate [56]. Tirzepatide may be considered in people with MASH and high weight burden or insulin resistance, especially when semaglutide is not tolerated.

Liraglutide

The LEAN study showed 39% of patients on liraglutide 1.8 mg achieved MASH resolution without fibrosis worsening, compared to 9% with placebo [57]. Liraglutide also reduced fibrosis progression and improved liver enzymes and hepatic insulin sensitivity. Liraglutide may be considered in early MASLD or if higher-potency incretins are not tolerated. Effect less robust in advanced fibrosis.

Orlistat

Although biopsy-controlled data are lacking, orlistat improves steatosis, ALT, and insulin sensitivity in MASLD when paired with lifestyle changes. A meta-analysis confirmed modest reductions in liver fat and enzymes but did not affect liver fibrosis. Benefits were not significant in NASH patients [58]. Weight loss (~ 3–4%) is modest, and GI side effects may limit adherence. Orlistat may be considered in early MASLD when incretin-based therapies are contraindicated; monitor for GI intolerance.

Naltrexone/Bupropion

Evidence in MASLD is limited and indirect. Some studies suggest modest reductions in hepatic fat and transaminases, but no histologic data support use [59]. It may be considered in MASLD/MASH; may be cautiously considered in patients with mild steatosis and emotional eating, avoiding use in hepatic dysfunction.

Phentermine/Topiramate ER

In CONQUER and related analyses, this combination reduced ALT and improved insulin sensitivity. Weight loss ranges from 10 to 12%, aligning with MASH remission thresholds, though no biopsy-controlled trials exist [60]. This combination may be considered in patients with visceral obesity and MASLD when incretins are unsuitable, though it lacks histologic efficacy data.

OA is a progressive degenerative joint disease marked by cartilage breakdown, bone remodeling, and chronic pain, especially in weight-bearing joints. Obesity contributes to OA through both biomechanical overload and metabolic inflammation. Adipose-derived cytokines (e.g., IL-6, TNF-α, leptin) promote chondrocyte catabolism and systemic inflammation, worsening joint degeneration [61].

Epidemiological data show that each 5-unit BMI increase raises knee OA risk by 35% [62]. Weight loss is thus a key intervention, with growing evidence for AOMs and bariatric surgery as disease-modifying approaches. (Figures 1 and 2) (See Supplementary Material for Clinical Takeaways).

Semaglutide

In the STEP 9 trial involving adults with obesity and knee osteoarthritis, semaglutide resulted in significantly greater weight loss (− 13.7% vs. −3.2%), pain reduction (WOMAC − 41.7 vs. −27.5 points), and improvement in physical function (SF-36 + 12.0 vs. +6.5 points) compared to placebo (all P < 0.001) at 68 weeks, with a similar rate of serious adverse events [63]. Semaglutide should be preferred in people with obesity and knee OA who meet criteria for pharmacologic weight management, particularly when pain and function impair quality of life.

Tirzepatide

No trial has yet demonstrated direct efficacy of tirzepatide in OA. However, the STOP KNEE-OA phase 4 trial (clinicaltrial.gov n NCT01985165) is underway to assess its impact on delaying knee replacement and improving joint outcomes. Tirzepatide achieves ~ 21% weight loss [2]a level associated with OA symptom relief in other contexts. Tirzepatide may be considered in patients with obesity and OA where greater weight loss is required, pending dedicated OA outcomes.

Orlistat

Orlistat has shown modest OA symptom improvement through > 10% weight loss [14]. GI side effects may limit adherence. Orlistat may be considered when other AOMs are contraindicated or not tolerated, especially in early OA, with adherence counseling.

Naltrexone/Bupropion

While effective for weight reduction, direct OA studies are lacking. Theoretical benefits exist via reduced inflammation and appetite control, but clinical confirmation is absent [64]. Should not be routinely recommended for OA symptom improvement; use only if indicated for other behavioral phenotypes and with caution.

Phentermine/Topiramate ER

This agent induces significant weight loss (10–12%) [26] which may alleviate OA symptoms. However, OA-specific data are lacking, and use remains extrapolative. Based on extrapolated benefits from weight reduction, this combination may be considered in patients with obesity and OA who are not candidates for incretin therapies.

Obstructive Sleep Apnea (OSA) is a prevalent obesity-related complication marked by recurrent upper airway collapse during sleep, causing intermittent hypoxia, hypercapnia, and sleep disruption. It affects 40–60% of people with obesity, with prevalence increasing in parallel with BMI [65]. Visceral fat, pharyngeal adiposity, and reduced airway tone elevate airway collapsibility [66]. Shared mechanisms, leptin resistance, sympathetic activation, and systemic inflammation, link OSA to cardiometabolic risk [67]. OSA is associated with hypertension, arrhythmias, stroke, T2D, MASLD, and HFpEF, and independently increases cardiovascular and all-cause mortality. Integrating OSA management within obesity treatment frameworks is essential. Weight loss remains the cornerstone of OSA management, but pharmacologic agents that induce significant weight loss and potentially modulate central respiratory pathways may offer added benefit (Figs. 1 and 2) (see Supplementary Material for Clinical Takeaways).

Tirzepatide

Tirzepatide became the first drug approved by the FDA for moderate-to-severe OSA in adults with obesity in December 2024. In the phase 3 (SURMOUNT-OSA-1 and − 2), tirzepatide significantly reduced apnea–hypopnea index (AHI) over 52 weeks in adults with moderate-to-severe obstructive sleep apnea and obesity, both with and without background PAP therapy. Mean AHI reductions were − 25.3 and − 29.3 events/hour with tirzepatide vs. − 5.3 and − 5.5 with placebo (P < 0.001 for both trials). Specifically, tirzepatide 15 mg led to a 62.8% reduction in AHI vs. 6.4% with placebo over 52 weeks and alongside Weight loss averaged 18.1%, with concurrent improvements in oxygen saturation, daytime sleepiness, and blood pressure. Benefits were consistent across OSA severity and comorbidities [68]. Tirzepatide should be preferred in people with obesity and moderate-to-severe OSA, particularly when PAP therapy is poorly tolerated or insufficient.

Liraglutide

In the SCALE Sleep Apnea trial, liraglutide 3.0 mg reduced AHI by − 12.2 events/h vs. − 6.1 with placebo (P = 0.015) over 32 weeks, with 5.7% vs. 1.6% weight loss (P < 0.0001) [69]. Modest improvements in oxygenation and blood pressure were also observed. Liraglutide ay be considered in patients with obesity and mild-to-moderate OSA when tirzepatide is contraindicated or unavailable.

Phentermine/Topiramate ER

A 28-week RCT showed that mid/high-dose phentermine/topiramate in 45 subjects with moderate to severe OSA not on positive airway pressure (PAP) treatment significantly reduced AHI (− 31.5 vs. − 16.6 events/h with placebo; P = 0.0084), with improved oxygenation and sleep quality [70]. It may be considered in patients with OSA and obesity where rapid weight loss is indicated, and other agents are not suitable, but caution is warranted in patients with CV risk.

Naltrexone/Bupropion and Orlistat

These agents support weight loss but lack robust evidence for OSA-specific benefit. No high-quality trials have demonstrated consistent reductions in AHI; thus, their role remains secondary and indirect. It may be considered, however, their role is limited to indirect benefit via weight loss.

Bariatric surgery represents the most effective intervention for sustained weight loss and metabolic improvement in people with severe obesity and has demonstrated consistent benefits across a wide range of obesity-related complications. Long-term data confirm robust effects on mortality, cardiometabolic outcomes, renal disease, T2D progression, musculoskeletal function, sleep apnea, liver disease, and cancer risk. (See Supplementary Material for Clinical Takeaways).

Cardiovascular Disease and Heart Failure

In the Swedish Obese Subjects (SOS) study, bariatric surgery reduced all-cause mortality by 29% 0.71 (95% CI, 0.54–0.92), and cardiovascular mortality by 53% 0.47 (95% CI, 0.29–0.76), over a median of 14.7 years compared to matched controls [79]. A meta-analysis of 174,772 participants showed a 49.2% reduction in hazard rate of death (95% CI 46–51, p < 0001), with median life expectancy increased by 6.1 years (95% CI 2–6) compared to usual care. The treatment effect was substantially larger for people with diabetes, indicated by an I² of 95.7% and p < 0001 [80]. It may be considered in T2D or high CV risk with BMI ≥ 35.

Chronic Kidney Disease (CKD)

Surgical weight loss significantly reduces albuminuria and the progression to end-stage renal disease. The SOS study reported reduced end-stage renal disease (ESRD) incidence after surgery (adjusted hazard ratio (HR) = 0.27; 95% CI 0.12–0.60; p = 0.001) [81]. A meta-analysis confirmed improvements in eGFR and proteinuria even among non-diabetic patients [82]. Although this improvement declined somewhat over the 5-year follow-up, eGFR stayed above baseline levels for the CKD group. Notably, eGFR also improved in patients with CKD not directly caused by obesity, supporting the use of surgery in obesity-related CKD when conservative treatments are insufficient. It may be considered when Obesity and CKD progress despite medical therapy.

Type 2 Diabetes (T2D) and Prediabetes

Bariatric surgery can induce long-term T2D remission. In randomized trials, up to 50% of patients maintained remission 10 years after biliopancreatic diversion, while remission after Roux-en-Y gastric bypass was less durable [83]. Microvascular and macrovascular outcomes also improve significantly [72]. Guidelines recommend surgery for patients with BMI ≥ 35 regardless of glycemic control and for BMI 30–34.9 when medical therapy is insufficient [84].

In prediabetes, surgery halts disease progression. In a cohort of 175 people, 82% achieved remission at 1 year, with 58% maintaining remission at 4 years. Predictors included sleeve gastrectomy, younger age, and male sex [85]. It should be preferred for T2D with BMI ≥ 35 or ≥ 30 ² if uncontrolled.

Type 1 Diabetes (T1D)

Though remission is not expected, bariatric surgery reduces insulin requirements, weight, and HbA1c in T1D patients. In this 5-year retrospective analysis of patients with T1D undergoing either sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB), total Weight loss reached 14.2% after SG and 22.6% after RYGB. Importantly, median daily insulin requirements decreased substantially from 140.5 units preoperatively to 77.5 units at 1 year, and remained lower at 90.0 units at 5 years. The reduction was more pronounced and durable following RYGB compared to SG [86]. Careful perioperative management is essential due to the risk of diabetic ketoacidosis. It may be considered in obesity with T1D to improve obesity and its related complications and reduce insulin requirements.

Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD/MASH)

A comprehensive systematic review and meta-analysis assessed the histological effects of bariatric surgery on nonalcoholic fatty liver disease (NAFLD) in patients, analyzing 3,093 paired liver biopsies from 32 cohort studies. Bariatric surgery was associated with significant improvements in hepatic histology: steatosis resolved in 66% of cases, lobular inflammation in 50%, hepatocellular Ballooning in 76%, and fibrosis in 40%. The overall NAFLD activity score notably decreased (mean difference − 2.39; 95% CI, − 3.20 to − 1.58; P < 0.001), supporting the capacity of surgery-induced Weight loss to reverse key pathological features of NAFLD. However, 12% of patients developed new or worsening liver disease, particularly fibrosis [87]. While no RCTs directly comparing surgery and pharmacotherapy for NASH exist, a recent network meta-analysis incorporating 24 surgical and non-surgical trials confirms the superior efficacy of bariatric surgery in achieving NASH resolution (79% vs. 29% with drugs), with comparable effects on fibrosis improvement. These findings highlight the need to consider surgery among therapeutic options for eligible patients with NASH [88]. It should be preferred in advanced MASH, especially with fibrosis.

Osteoarthritis (OA)

Bariatric surgery improves OA symptoms, reduces pain, and enhances function. A prospective study of 82 patients observed significant improvement at 6 and 12 months post-RYGB [89]. In the LABS-2 study, up to 77% of people reported clinically essential improvements in knee or hip pain at 3 years, with most benefits persisting at 7 years (65–72%). Although some decline was observed over time, meaningful gains in mobility and function remained substantial, supporting bariatric surgery as an effective strategy for managing obesity-related osteoarthritis [90]. It should be preferred in disabling OA where weight loss is a goal.

Obstructive Sleep Apnea (OSA)

Bariatric surgery has a significant impact on the severity of OSA in people with obesity, as demonstrated by a 2023 meta-analysis of 32 studies including 2,310 patients. The procedure was associated with substantial reductions in body mass index (–11.9 kg/m²), apnea-hypopnea index (–19.3 events/hour), and respiratory disturbance index (–33.9 events/hour), with approximately 65% of patients achieving remission of OSA. These findings confirm the efficacy of bariatric surgery in alleviating OSA symptoms; however, the incomplete remission rate underscores that obesity is not the sole driver of OSA, and anatomical or neuromuscular factors likely contribute to its persistence [91]. It should be preferred in moderate-severe OSA with obesity.

Cancer Risk Reduction

Surgical Weight loss reduces the incidence of obesity-related cancers. A Swedish matched cohort study found a 33% reduction in cancer risk over 10 years [92]. The SPLENDID trial demonstrated a 32% lower incidence of obesity-related cancers and a 48% reduction in cancer-related mortality after RYGB or sleeve gastrectomy [93]. There is no evidence of increased cancer risk post-surgery, but long-term nutritional monitoring is essential. It may be preferred in younger people with high lifetime cancer risk.

Childhood obesity is strongly associated with earlier onset of cardiometabolic deterioration, mechanical complications (OA, and OSA), and psychosocial burden. Management should focus on behavioral and family-based strategies. Effective interventions include limiting sugar-sweetened beverages, promoting active play, and ensuring healthy foods and age-appropriate portions at home. Active caregiver involvement is essential, with family-centered behavioral counselling shown to be the most effective approach. Both the American Academy of Pediatrics (AAP) and the European Childhood Obesity Group emphasize that lifestyle modification remains the cornerstone of treatment in this age group) [98]. Besides, even the EASO-EFAD statement highlights the role of lifestyle intervention for the treatment of obesity in children [99]. While lifestyle modification remains first-line, its limited long-term success in severe obesity has led to expanded pharmacological options [100]. The 2023 AAP guideline recommends that children aged between 8 and 11 age with obesity may be offered weight loss pharmacotherapy, according to medication indications, risks, and benefits, as an adjunct to health behavior and lifestyle treatment [101]. Similarly, the 2025 Canadian Clinical Practice Guidelines (CPCG) recommend pharmacological intervention in combination with behavioral and psychological interventions [100]. Both guidelines recommend prescription of GLP1RA (liraglutide and semaglutide); and consider the off-label prescription of metformin even though findings on the Weight loss effect are inconsistent. While the 2023 AAP CPG recognize orlistat is not commonly prescribed in clinical practice owing to the Limited tolerability, the CPCG suggests against the use of the molecule. The 2023 AAP CPG also recommends phentermine/topiramate. As of 2025, five agents, semaglutide, liraglutide, orlistat, setmelanotide and metreleptin are FDA and EMA-approved for chronic weight management in adolescents ≥ 12 years, while phentermine/topiramate is exclusively FDA approved. Setmelanotide is FDA and EMA approved in children > 2 years old in selected cases of genetic and syndromic obesities. In July the FDA extended liraglutide's approval to include children aged 6 to 11years old. Prescribing typically requires pediatric endocrinology authorization. Nonetheless, barriers remain, including access, reimbursement, and provider experience disparities. Multidisciplinary care remains critical for growth monitoring, psychosocial assessment, and treatment adherence. While pharmacotherapy may delay surgery, it does not replace its role in adolescents with severe obesity and comorbidities. Surgery remains indicated for youth with BMI ≥ 120% of the 95th percentile or BMI ≥ 40 kg/m², or ≥ 35 kg/m² with severe complications [100]. Pharmacological therapy has transformed pediatric obesity management. Semaglutide currently shows the highest efficacy, followed by liraglutide and phentermine/topiramate [102]. Used within multidisciplinary care models, these agents yield significant improvements in BMI, metabolic health, and quality of life. The big issues are about bone health and neurodevelopment in children and adolescents, and about pubertal development in children. Ongoing long-term studies in children and adolescents, i.e. the STEP TEENS Weight Maintenance NN9536-7752 (clinicaltrials.gov), will ascertain the effect on bone growth and maturation. Ongoing success will rely on early identification, individualized therapy, and long-term support (Figs. 1 and 2; Table 7) (see Supplementary Material for Clinical Takeaways).

Pharmacotherapy in this age range should only be considered in specialized centers, with intensive lifestyle therapy. Long-term safety data are limited.

Adolescents with severe obesity (≥ 120% of the 95th percentile) and comorbidities such as prediabetes, PCOS, or MAFLD may benefit from pharmacotherapy and for them the pharmacological treatment in particular with Phentermine/Topiramate ER is cost effective [110, 111]. GLP-1 RAs are particularly suited for those with increased hunger, insulin resistance, or MASH. Multidisciplinary support, including nutrition, behavioral therapy, and psychological screening, is critical due to the elevated risk of eating and mood disorders during adolescence.

Obesity manifests differently across age groups. In adults aged 18–65, it is often driven by cardiometabolic or behavioral factors, supporting phenotype-guided pharmacotherapy. In older adults (≥ 65), obesity frequently coexists with sarcopenia, frailty, or chronic pain, warranting treatments that focus on preserving mobility, independence, and quality of life. Therapeutic strategies must be individualized: younger adults may benefit from targeting ASCVD risk, diabetes prevention, or NAFLD; older adults require agents with high tolerability, minimal appetite suppression, and caution to avoid muscle loss and drug interactions (Figs. 1 and 2) (See Supplementary Material for Clinical Takeaways).

This age group is addressed throughout the manuscript, with treatment considerations integrated across all phenotypes and obesity-related complications.

In people ≥ 65 years, the primary aim of pharmacotherapy is to preserve function, reduce obesity-related complications (e.g., osteoarthritis, cardiometabolic risk), and avoid harm. Weight loss is secondary to maintaining muscle mass, nutritional status, and autonomy. Data from RCTs specific to weight outcomes in this population are limited; most safety and efficacy data derive from cardiovascular outcome trials (CVOTs) using AOMs.

Preferred Agents:

Sarcopenic obesity is a distinct phenotype defined by the coexistence of excess adiposity and reduced skeletal muscle mass and/or strength. It is particularly prevalent among older adults and people with chronic diseases such as T2D, CKD, and cardiovascular disease, and is associated with increased risks of frailty, falls, disability, hospitalization, and mortality [117]. The diagnostic challenge lies in the fact that fat mass can obscure the progressive loss of muscle, leading to under recognition when using BMI alone.

The condition arises from the interplay between anabolic resistance, chronic low-grade inflammation, insulin resistance, physical inactivity, and mitochondrial dysfunction. These mechanisms lead to muscle catabolism despite caloric excess, creating a therapeutic paradox: while weight loss may improve metabolic risk, it can further deplete lean mass and compromise physical function if not carefully managed.

In this context, the primary therapeutic goal is not to achieve maximal Weight reduction, but rather to preserve or recover muscle mass and strength. Gradual Weight loss of 5–10% may be beneficial, provided it is accompanied by gains in mobility, improved cardiometabolic parameters, or reductions in visceral adiposity. Rapid or unsupervised weight loss should be avoided, particularly in frail people, due to the risk of disproportionate muscle loss.

Core interventions include a protein intake of ≥ 1.2 g/kg body Weight per day, up to 1.5 g/kg/day during caloric restriction, distributed evenly across meals to optimize anabolic signaling [118]. Supervised, progressive resistance training 2–3 times per week is critical for preserving type II muscle fibers, enhancing strength and balance, and remains the most evidence-based non-pharmacologic intervention in this setting. Micronutrient optimization, especially with ≥ 800 IU/day of vitamin D and adequate calcium, is important for muscle function and fall prevention [119]. The SARC-F questionnaire is a validated tool for routine screening; a score ≥ 4 indicates probable sarcopenia and warrants further assessment with DXA, BIA, handgrip strength, or gait speed testing [120].

Pharmacologic management must support functional preservation and minimize unintended loss of lean mass. Among approved agents, liraglutide 3.0 mg daily has demonstrated modest weight reduction (~ 6%) while maintaining lean mass when paired with adequate protein intake and physical activity [74]. Its cardiovascular safety and slow kinetics make it especially suitable for older or frail people. Orlistat is another suitable option, producing ~ 3–4% weight loss without central appetite suppression. It is particularly appropriate in polymedicated patients, though requires supplementation with fat-soluble vitamins.

More potent agents such as tirzepatide and high-dose semaglutide induce substantial weight loss (~ 15–24%) and reduce both fat and lean mass. However, recent data show that roughly two-thirds of weight loss is derived from adipose tissue, indicating a relatively favorable fat-to-lean mass loss ratio [121]. Nevertheless, their use in sarcopenic obesity requires concurrent resistance training and nutritional support to mitigate functional decline [122].

Caution should be exercised with naltrexone/bupropion, since frail or cognitively impaired people can poorly tolerate neuropsychiatric side effects like agitation, insomnia, and anxiety. In summary, the management of sarcopenic obesity must balance metabolic improvement with the preservation of functional reserve. Lifestyle interventions remain central, and pharmacotherapy should be selected and monitored with attention to lean mass preservation, micronutrient adequacy, and physical performance (Figs. 1 and 2) (see Supplementary Material for Clinical Takeaways).

Emotional eating refers to consuming food in response to negative emotions (e.g., anxiety, sadness, stress) rather than physiological hunger. This behavior is common in people with obesity and contributes to poor weight loss outcomes, high relapse rates, and risk of binge eating disorder. Neurobiologically, it involves hyperactivity in cortico-limbic circuits, such as the amygdala, insula, and orbitofrontal cortex, which can override satiety signals and drive compulsive intake [123, 124]. For this population, pharmacologic success may depend on weight loss and the drug's effects on reward processing, craving, and disinhibition (Figs. 1 and 2) (see Supplementary Material for Clinical Takeaways).

BED is the most common eating disorder in people with obesity, affecting up to 30% of patients in bariatric and weight management settings [130]. It is characterized by recurrent episodes of uncontrolled eating and significant distress, and is associated with psychiatric comorbidities (e.g., depression, anxiety, and substance use) and increased metabolic risk [131]. Neuroimaging studies reveal dysfunction in corticostriatal-limbic pathways, particularly in the orbitofrontal cortex, nucleus accumbens, and insula [132, 133]. Pharmacologic approaches in BED aim to reduce both weight and binge episodes by targeting reward, satiety, and impulse regulation. At the same time, cognitive behavioral therapy remains first-line, pharmacotherapy is often necessary in moderate-to-severe cases, especially when obesity coexists [134]. (Figures 1 and 2) (See Supplementary Material for Clinical Takeaways).

Obesity is a recognized risk factor for multiple malignancies, including endometrial, postmenopausal breast, colorectal, pancreatic, esophageal adenocarcinoma, and hepatocellular carcinoma. Large-scale epidemiologic cohorts and Mendelian randomization studies have established a dose-dependent association between adiposity and cancer incidence and mortality [143]. Mechanistically, this relationship is driven by chronic low-grade inflammation, insulin resistance, increased levels of insulin and IGF-1, elevated estrogen and adipokines such as leptin, and impaired immune surveillance, all of which contribute to tumor initiation, proliferation, and evasion of apoptosis [144].

Intentional Weight loss via lifestyle intervention or bariatric surgery improves many of these pathways and has been associated with reduced cancer risk. Notably, metabolic surgery leads to long-term reductions in systemic inflammation, improvements in insulin sensitivity, normalization of sex hormone levels, and enhanced immune competence. In the SPLENDID cohort, bariatric surgery was associated with a 32% lower incidence of obesity-related cancers and nearly 50% reduction in cancer-specific mortality over a 10-year follow-up [93].

As AOMs are increasingly used in clinical practice, long-term oncologic safety has become important, especially for incretin-based therapies. Initial concerns arose from rodent models suggesting a risk of C-cell hyperplasia and thyroid malignancy, though these findings have not consistently translated to humans. A 2025 meta-analysis by Silverii et al. that pooled 50 randomized trials, GLP-1 RA were associated with a modest but significant increase in thyroid cancer risk (MH-OR 1.55, 95% CI 1.05–2.27), particularly in longer-duration studies. No other cancer types showed significant associations [145]. Current regulatory guidance maintains that GLP-1 RAs and GIP-GLP1RA are contraindicated in people with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (MEN2).

Pancreatic cancer has also been a historical concern with incretin-based agents. However, Data from 37 RCTs and 19 real-world studies involving over 46,000 patients showed no significant increase in pancreatic cancer risk with GLP-1RAs (OR 0.25, 95% CI 0.03–2.24; P = 0.21) compared to placebo [146].

Likewise, no signals have emerged for increased risk of gastrointestinal malignancies. In the SELECT trial involving over 17,000 participants followed for 3.3 years, Semaglutide was not associated with higher incidence of colorectal, gastric, or esophageal cancers [4]. However, a small increase in colorectal cancer was detected in short-term trials (MH-OR 1.27, 95% CI 1.03–1.57), potentially due to increased diagnostic procedures prompted by GLP-1 RA gastrointestinal side effects. GLP-1 RA were not associated with an overall increased cancer risk (MH-OR 1.05, 95% CI 0.98–1.13). A significant reduction in uterine cancer was noted in obesity-focused trials (MH-OR 0.24, 95% CI 0.06–0.94), but not in diabetes trials [145].

Tirzepatide has undergone similar scrutiny. A 2025 meta-analysis of 12 RCTs involving more than 25,000 participants showed no elevated risk of any cancer type, including thyroid (RR 1.07, 0.22–5.12 p = 0.93), pancreatic (RR 0.85, 0.10–7.43 p = 0.89), or gastrointestinal malignancy (RR 0.73, 0.26–2.04 p = 0.54) [147]. While rodent studies previously reported C-cell hyperplasia with tirzepatide, human data to date do not support an increased risk. Long-term follow-up from the SURPASS and SURMOUNT programs is ongoing but has not raised safety concerns to date.

Other pharmacotherapies, such as naltrexone/bupropion, have not been associated with increased cancer risk. The LIGHT trial was terminated early, limiting long-term conclusions, but no oncogenic signals were observed during follow-up [15]. Similarly, no evidence implicates phentermine/topiramate ER in carcinogenesis, though long-term oncologic surveillance data remain sparse. Due to its central nervous system effects and teratogenicity, topiramate should be used cautiously, particularly in populations with neuroendocrine tumor predisposition, despite no direct mechanistic or clinical link [60].

Orlistat, a gastrointestinal lipase inhibitor, has occasionally been associated with case reports of colon and breast cancer. However, a large population-based analysis using UK registry data over 10 years found no increase in colorectal cancer risk [148]. Nevertheless, long-term orlistat use may reduce absorption of fat-soluble vitamins (A, D, E), with potential theoretical implications for immune competence and cancer defense. Patients on extended orlistat therapy should undergo periodic nutritional assessment [149].

In conclusion, the current evidence does not demonstrate a meaningful increase in cancer incidence with approved AOMs. The possible association between GLP-1 RAs and thyroid cancer warrants ongoing surveillance, but the absolute risk remains low. Pharmacologic therapy remains a safe and effective tool in obesity management when used with appropriate clinical judgment and individualized risk–benefit assessment. (Figs. 1 and 2) (See Supplementary Material for Clinical Takeaways).

Partial lipodystrophy Syndromes are rare disorders marked by selective loss of subcutaneous fat, severe insulin resistance, hypertriglyceridemia, and hepatic steatosis. Genetic forms, such as familial partial lipodystrophy types 1–3, typically arise from LMNA, PPARG, or other adipocyte gene mutations, with onset in adolescence or early adulthood. Acquired forms, including Barraquer–Simons syndrome, involve autoimmune mechanisms and cephalocaudal fat loss. HIV-associated lipodystrophy, linked to antiretroviral therapy, presents with variable lipoatrophy and central adiposity, often sharing similar metabolic derangements [150, 151].

In these settings, conventional Weight loss approaches are ineffective. Emerging evidence suggests that semaglutide may improve metabolic outcomes independent of Weight reduction. In a phase 2b randomized placebo-controlled trial, semaglutide 2.4 mg OW significantly reduced abdominal visceral, subcutaneous, and total body fat in people with HIV-associated lipohypertrophy without diabetes [152] (Figs. 1 and 2) (see Supplementary Material for Clinical Takeaways).

Monogenic and syndromic forms of obesity, although rare, offer critical insight into the neuroendocrine regulation of appetite and body weight. These disorders are typically characterized by early-onset severe obesity, hyperphagia, and often endocrine or developmental abnormalities. Advances in molecular genetics have elucidated causative pathways, paving the way for targeted pharmacotherapies.

Congenital leptin deficiency, due to LEP mutations, exemplifies a monogenic obesity with extreme hyperphagia and rapid weight gain. Recombinant leptin therapy in these people produces marked reductions in appetite and weight, underscoring leptin's central role in energy balance [153].

Disruption of the MC4R pathway, via biallelic mutations in POMC, PCSK1, or LEPR, impairs satiety signaling. The melanocortin receptor agonist Setmelanotide has shown efficacy in these conditions, being a selective agonist of the MC4R it mimics the action of the alpha MSH and represents a hormonal replacement therapy. In phase 3 trials, patients with POMC or LEPR deficiency experienced significant weight loss and hunger reduction with favorable safety [108]. The VENTURE trial extended these findings to children aged 2–5 years, including those with Bardet–Biedl syndrome, confirming sustained benefits in early childhood [104].

These results support early genetic screening in children with severe, early-onset obesity and the use of precision therapies like Setmelanotide in genetically confirmed MC4R-pathway disorders. While not generalizable to polygenic obesity, these targeted treatments mark a key advance in personalized obesity care (Figs. 1 and 2) (see Supplementary Material for Clinical Takeaways).

Acquired hypothalamic obesity (HO) is a rare, severe form of secondary obesity resulting from structural or functional damage to the hypothalamus, typically after craniopharyngioma, suprasellar tumors, neurosurgery, or radiotherapy. This disruption impairs key energy balance pathways, including leptin–melanocortin signaling, autonomic tone, and reward-based feeding circuits. Clinically, HO presents with rapid, refractory weight gain, hyperphagia, low energy expenditure, and impaired satiety, features often resistant to conventional lifestyle-based treatment. Setmelanotide, a selective MC4R agonist, has demonstrated promising efficacy in this setting. In a recent phase 2 multicenter trial, patients with acquired HO experienced clinically meaningful weight loss and hunger reduction with good tolerability [154], supporting its use in cases with confirmed melanocortin pathway disruption. From the trial, it seems that young people have better response regarding weight loss and resolution of CVD features than adult patients, even if this was not a direct comparison between the two groups [154].

Semaglutide has also been evaluated off-label in HO. A 2024 real-world study reported moderate weight loss, improved glycemia, and acceptable tolerability in adults with hypothalamic injury, though gastrointestinal side effects and variable response were noted [155]. GLP-1 RAs may thus offer benefit in select cases, particularly where some hypothalamic function is preserved. Given the heterogeneous pathophysiology and limited therapeutic options, pharmacologic management of HO requires a highly individualized, multidisciplinary approach. Agents like Setmelanotide or GLP-1 RAs may be integrated alongside nutritional, behavioral, and endocrine support to optimize clinical outcomes (Figs. 1 and 2) (see Supplementary Material for Clinical Takeaways).

PCOS and obesity share a close and interconnected relationship. PCOS is characterized by oligomenorrhea, hyperandrogenism, and the presence of polycystic ovaries on ultrasound [161]. Obesity is more prevalent among females with PCOS than in the general population; it contributes to the development of PCOS and worsens [161] its clinical features, primarily due to hyperinsulinemia resulting from insulin resistance, which increases ovarian androgen production [162, 163]. Weight loss is recommended for people with PCOS and BMI ≥ 25, as it has been shown to improve both reproductive and metabolic outcomes [161]. According to the 2023 European PCOS guidelines, AOMs and bariatric/metabolic surgery may be considered based on general population guidelines and lifestyle intervention, carefully evaluating potential benefits and side effects [161]. (Fig. 2) (See Supplementary Material for Clinical Takeaways).

Metformin

Metformin has a near-neutral effect on weight, with one meta-analysis finding no effect [164] and others finding small reductions in BMI, approximately of −0.77 kg/m² (95%CI: −1.26, − 0.27) compared to placebo after three months of treatment with 1500 mg/day in women with PCOS [165, 166]. Metformin is recommended in adults with PCOS and a BMI ≥ 25 to improve insulin resistance, glucose and lipid profiles, but not for weight loss [161]. It can also be used for irregular menstrual cycles, to improve pregnancy rates [161]. No benefits on hirsutism are to be expected [161]. Metformin is not recommended for weight loss in PCOS but may be recommended in women with BMI ≥ 25 kg/m² to improve metabolic and reproductive outcomes.

Semaglutide

A few RCTs evaluated semaglutide in PCOS, all at high risk of bias due to small sample size and selective outcome reporting. One study (n = 25) compared semaglutide 1 mg OW to placebo over 16 weeks, demonstrating greater weight loss with semaglutide (− 5.2 kg versus + 1.9 kg with placebo) [167]. Another trial (n = 30) using the same dosing and duration reported a similar benefit, with an estimated treatment difference of − 7.8 kg (− 7.7% in body weight) in favor of semaglutide [168]. No studies have been conducted using the weight-loss–recommended dose of 2.4 mg. Semaglutide may be considered in women with PCOS and obesity who are candidates for pharmacologic weight loss. Larger studies at therapeutic doses are needed to confirm reproductive and metabolic effects.

Tirzepatide

No PCOS-specific data are available. Tirzepatide may be considered in women with PCOS and obesity when substantial weight loss is the primary therapeutic target. Dedicated studies are needed to assess reproductive and metabolic outcomes.

Liraglutide

Liraglutide 3 mg/day led to a significantly greater reduction in body weight (− 5.7%) compared to placebo (− 1.4%), both in addition to lifestyle intervention, over 32 weeks in people with obesity and PCOS (n = 67) [169]. It was also superior to placebo in improving all metabolic outcomes, free androgen index and number of menstrual cycles per year, but no differences in total testosterone were observed [169]. Liraglutide should be considered in PCOS when weight loss and improved menstrual and metabolic parameters are desired. It may be especially useful when insulin resistance is prominent.

Orlistat

A randomized trial (n = 86) evaluated the efficacy of orlistat at a dose of 120 mg three times daily for three months, compared to placebo, both combined with lifestyle intervention [170]. The drug plus lifestyle intervention was superior to placebo plus lifestyle in achieving greater percent weight loss (− 6.37% vs. −2.27%), greater reduction in waist-to-hip ratio (0.76 vs. 0.86), and improvements in total testosterone and lipid profiles [170].However, no significant benefits were observed in other metabolic parameters [170]. Orlistat may be considered in PCOS when systemic exposure is a concern and modest weight loss is acceptable. Gastrointestinal side effects and adherence should be monitored.

Naltrexone/Bupropion

No PCOS-specific data are available.

Phentermine/Topiramate ER

Only one small trial has evaluated this combination in a PCOS population, comparing phentermine 7.5 mg plus topiramate 46 mg ER daily to exenatide 2 mg OW (n = 36 for both arms) [171]. After 24 weeks, mean weight loss with phentermine/topiramate ER in PCOS obese women was 8%, even higher than the 6.6% Weight loss reported at 56 weeks in the general population [171] However, cardiovascular safety concerns persist for this drug, particularly in people with PCOS, who are already at increased risk for cardiovascular complications compared to the general population [172]. Phentermine/topiramate may be considered for short-term use in women with PCOS and severe obesity, but cardiovascular risk must be carefully assessed and monitored.

In resource-constrained health systems, treatment choices for obesity must weigh clinical severity, patient priorities, and economic value. Quality-adjusted life years (QALYs) offer a standardized metric to evaluate cost-effectiveness by quantifying health benefits relative to cost. Interventions are considered cost-effective if their incremental cost-effectiveness ratio (ICER) is below $50,000–$100,000 per QALY in the U.S. or £20,000–£30,000 in the UK [173, 174].

Combining GLP-1 RAs with naltrexone/bupropion targets both homeostatic and hedonic drivers of obesity. GLP-1 analogues enhance satiety via hypothalamic and brainstem circuits, while naltrexone bupropion reduces reward-driven eating and impulsivity through dopaminergic-opioidergic modulation. A real-world study demonstrated that GLP-1 analogues are an effective treatment for weight loss, and the addition of bupropion/naltrexone is associated with greater weight loss including in patients who are initially non-responsive to GLP-1 analogues [187]. Nonetheless, overlapping GI and neuropsychiatric side effects necessitate slow titration and careful monitoring.

In patients with limited access to high-dose GLP-1 RA or intolerant to full titration, combining liraglutide with orlistat may provide modest additional weight loss via peripheral fat absorption blockade. An open-label trial showed greater efficacy than orlistat alone, though gains over liraglutide monotherapy were marginal [188]. This strategy may be considered in cost-constrained or older populations.

This is the most advanced fixed-dose combination in development. Cagrilintide, a long-acting amylin analog, enhances satiety and delays gastric emptying. In a 32-week Phase II trial, semaglutide plus cagrilintide achieved up to 17.1% placebo-subtracted weight loss, exceeding that of semaglutide alone [189]. The ongoing REDEFINE Phase III program may position this pairing as a non-surgical alternative for patients targeting > 15–20% weight loss [78, 190].

Tirzepatide monotherapy induces Weight loss up to 22.5%, reducing the need for adjuncts in most patients. However, in partial responders or those unable to escalate dose, future strategies may involve agents such as peripherally acting cannabinoid type 1 receptor antagonists, FGF21 analogs, amylin mimetics, or emerging triple agonists like retatrutide, which target GLP-1, GIP, and glucagon receptors simultaneously. Early data suggest potential for non-surgical > 25% weight loss, though clinical integration awaits Phase III results. (See Supplementary Material for Clinical Takeaways).

GLP-1 RAs/dual GIP/GLP-1 RAs + ketogenic diet: both liraglutide and tirzepatide have been associated with the ketogenic diet with good results: the association with tirzepatide leading to more significant fat mass loss and muscle mass preservation [191], that with low dose liraglutide (up to 1.8 mg) leading to more significant weight loss and marked insulin resistance improvement [192].

The primary strength of this review lies in its multidimensional framework, integrating high-quality randomized controlled trials, real-world evidence, regulatory documents, and expert consensus to support a phenotype- and complication-oriented treatment strategy for obesity. By organizing evidence across age groups, organ-specific phenotypes, and behavioral traits, this review more closely mirrors clinical complexity than traditional BMI-based guidelines. Moreover, emphasis on cost-effectiveness and safety across diverse populations enhances clinical utility and implementation potential.

However, several limitations should be acknowledged. First, the absence of direct head-to-head trials between different AOMs limits comparative conclusions. Second, behavioral and psychosocial phenotypes remain underrepresented in major trials, constraining generalizability. Third, cost-effectiveness models are highly context-specific and may not extrapolate across healthcare systems.