Oral Obesity Medicines in the Era of Cardiovascular–Kidney–Metabolic Syndrome (CKM): Beyond Weight Loss Toward Disease Modification

Abstract

Obesity is a major driver of Cardiovascular–Kidney–Metabolic (CKM) syndrome and contributes to the development of atherosclerotic cardiovascular disease, heart failure, atrial fibrillation, chronic kidney disease, and type 2 diabetes. Historically, oral obesity pharmacotherapy was evaluated primarily according to weight loss efficacy. However, the emergence of the CKM framework has shifted therapeutic priorities toward modifying obesity related complications and improving long term clinical outcomes. This review summarizes currently approved oral obesity medications, including first generation agents (orlistat, phentermine/topiramate, and naltrexone/bupropion) and second generation incretin-based therapies (oral semaglutide and orforglipron), within the context of CKM syndrome. First generation agents provide modest-to-moderate weight loss and variable metabolic benefits, but evidence supporting cardiovascular or kidney outcome improvement remains limited and largely observational. In contrast, oral incretin-based therapies demonstrate broader effects across the CKM spectrum, including substantial weight reduction, improved glycemic control, favorable effects on blood pressure and triglycerides, and emerging kidney benefits. Among currently available oral agents, oral semaglutide has the strongest evidence, with the SOUL trial demonstrating a reduction in major adverse cardiovascular events in high-risk individuals with type 2 diabetes. Signals suggesting benefits in heart failure and atrial fibrillation are encouraging but remain exploratory. Orforglipron represents the first non-peptide oral glucagon-like peptide-1 receptor agonist and offers simplified administration with promising metabolic efficacy; however, cardiovascular, kidney, heart failure, and arrhythmia outcome data are still awaited. Collectively, the role of oral obesity pharmacotherapy is evolving from weight management alone toward comprehensive CKM care.

Introduction

Historically, obesity medicines were largely evaluated and selected according to their ability to induce weight loss, with percentage total body weight reduction serving as the principal measure of therapeutic success. However, emerging data show that obesity is a disease far more than mere weight gain, and its management should extend beyond weight alone to include its related complications.1–4 Just as glycated hemoglobin (HbA1c) was once the primary target in type 2 diabetes (T2D) management, current practice now incorporates broader outcomes in therapeutic decision making, moving beyond glycemic control to include associated comorbidities, particularly cardiovascular and kidney disease.5 It is therefore logical to approach obesity in a similar manner: selecting treatments based on the patient’s overall clinical profile and obesity related complications, rather than focusing solely on weight loss.2–4

Cardiovascular Kidney Metabolic Syndrome (CKM) is a syndrome where there are connections between heart disease, kidney disease, type 2 diabetes mellitus and/or obesity leading to poor health outcomes.6 It compromises from 5 stages, starting from stage 0 where there are no CKM risk factors with normal body mass index and waist circumference, normoglycemia, normotension, a normal lipid profile, and no evidence of chronic kidney disease (CKD) or subclinical or clinical cardiovascular disease (CVD), reaching up to stage 4 where a cardiovascular related event is established.6 The disease of obesity lies in stage 1, where it considers a major drive to the advanced CKM stages with all its serious complications.6–9 Obesity severity correlates with premature mortality, with grade III obesity body mass index (BMI) above 40 kg/m² associated with an 8–10-year loss in median survival, highlighting reduced life expectancy as the key clinical consequence of CKM related cardiovascular risk.10 In the United States, obesity and its related complications account for nearly $500 billion in annual direct healthcare costs and an additional $1.2 trillion in indirect productivity losses.11

Within this framework, treatment effects are considered along a continuum, from improvement in stage defining CKM components to reduction in clinical outcomes, while recognizing that these levels of evidence are not equivalent. Oral therapies warrant focused evaluation as a distinct approach with specific considerations related to administration, tolerability, drug interactions, and clinical outcome evidence across CKM stages. This review examines oral obesity medications approved by the United States Food and Drug Administration (FDA) as of June 1, 2026, and evaluates their relevance across the CKM syndrome spectrum. It focuses on established agents, including orlistat, phentermine/topiramate, and naltrexone/bupropion, as well as newer oral incretin-based therapies, including oral semaglutide and orforglipron.

Search Strategy

A targeted narrative literature search was conducted in PubMed/MEDLINE and Google Scholar through June 20, 2026. Search terms combined individual oral obesity medication names with obesity, weight loss, prediabetes, type 2 diabetes, hypertension, hypertriglyceridemia, chronic kidney disease, cardiovascular disease, major adverse cardiovascular events, heart failure, atrial fibrillation, and cardiovascular–kidney–metabolic syndrome. The search was supplemented by relevant US Food and Drug Administration prescribing information, regulatory documents, and contemporary clinical guidelines. Evidence was selected according to relevance to CKM stage specific outcomes and prioritized by evidentiary strength, with pivotal randomized controlled trials and dedicated clinical outcome trials considered first, followed by meta analyses and observational studies when higher level evidence was unavailable. Findings were interpreted according to study design and endpoint type. As this was a narrative review, no formal systematic screening process or risk-of-bias assessment was undertaken.

The Development Story of Oral Obesity Medications

The development of oral obesity pharmacotherapy can be broadly divided into two generations. The first generation comprised traditional oral agents, starting with orlistat, followed by phentermine/topiramate and naltrexone/bupropion.12–14 These medications established obesity as a treatable chronic disease and provided effective non-injectable therapeutic options. However, their efficacy was generally modest to moderate, and long term use was often limited by tolerability concerns, safety considerations, and challenges with adherence.12–14

The second generation emerged from advances in incretin biology. Following the introduction of subcutaneous exenatide, the first glucagon-like peptide-1 receptor agonist (GLP-1RA), considerable efforts were directed toward developing an oral GLP-1 therapy. This proved challenging because peptide-based molecules undergo enzymatic degradation in the gastrointestinal tract and exhibit poor epithelial absorption.15 The major breakthrough in oral GLP-1 therapy came with the development of oral semaglutide.16 It overcame these barriers through co-formulation with the absorption enhancer sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC), enabling gastric absorption of semaglutide.17 Nevertheless, oral peptide delivery remained constrained by strict administration requirements, including fasting intake, and delayed food intake, which may affect absorption efficiency.16,17

More recently, non-peptide oral GLP-1 receptor agonists have sought to overcome these limitations. Orforglipron, the first approved non-peptide oral GLP-1RA for obesity, does not require an absorption enhancer such as SNAC and can be administered without fasting or meal related restrictions.18 This represents a significant advance in convenience and may improve real world adherence. However, as with other GLP-1 receptor agonists, gastrointestinal adverse effects remain common, and long term outcome data continue to emerge. To ensure consistency with current clinical practice, all orforglipron doses discussed throughout this review are presented as the FDA approved tablet equivalent doses. Figure 1 summarizes the timeline of oral approved obesity therapy. Table 1 provides an overview of oral obesity medications.

Figure 1.

Timeline of FDA Approval of Oral Medications for Obesity.

Abbreviations: FDA, United States Food and Drug Administration; ER, extended release.

Table 1.

Overview of Oral Obesity Medications*

Medication	MOA	Key AEs and Drug Interactions	Contraindications
Orlistat.19 1st generation	GI lipase inhibitor; reduces dietary fat absorption	Oily spotting, flatus with discharge, fatty/oily stool, fecal incontinence, reduced absorption of fat-soluble vitamins It may reduce absorption of fat-soluble vitamins/medications: amiodarone, antiseizure medications, levothyroxine, and warfarin	Pregnancy, Chronic malabsorption syndrome, Cholestasis, Hypersensitivity
Phentermine/Topiramate ER.20 1st generation	Sympathomimetic + anorectic	Paresthesia, dizziness, insomnia, constipation, dry mouth, ↑heart rate, teratogenicity It may interacts with MAOI, alcohol, non-potassium sparing diuretics, antiepileptic drugs, and oral contraceptives.	Pregnancy, glaucoma, hyperthyroidism, MAOI use within 14 days, hypersensitivity
Naltrexone/Bupropion ER.21 1st generation	POMC activation with opioid-feedback blockade	Nausea, constipation, headache, vomiting, dizziness, insomnia, ↑BP/heart rate, seizure risk It may interacts with MAOI, opioid containing medications, digoxin, and alcohol.	Pregnancy, uncontrolled HTN, seizure disorder, anorexia/bulimia, chronic opioid use, MAOI use within 14 days
Oral Semaglutide.22 Second generation	GLP-1 RA	Nausea, vomiting, diarrhea, constipation It may alter the absorption of concomitant oral medications with a narrow therapeutic index.	Pregnancy, Personal/family history of MTC, MEN2, hypersensitivity
Orforglipron.23 Second generation	Non-peptide GLP-1 RA	Nausea, vomiting, diarrhea, constipation It may interacts with Simvastatin, other drugs metabolized via the CYP3A system, and alter the absorption of concomitant oral medications with a narrow therapeutic index.	Pregnancy, Personal/family history of MTC, MEN2, hypersensitivity

Note: *This is non-exhaustive list.

Abbreviations: AE, adverse event; BP, blood pressure; ER, extended release; GI, gastrointestinal; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HTN, hypertension; MAOI, monoamine oxidase inhibitor; MEN2, multiple endocrine neoplasia type 2; MOA, mechanism of action; MTC, medullary thyroid carcinoma; POMC, pro-opiomelanocortin.

Stage 1 CKM

Metabolic dysfunction represents the earliest manifestations of CKM syndrome.6 Within the CKM staging framework, overweight or obesity and prediabetes are defining features of stage 1, while the development of type 2 diabetes marks progression to stage 2.6 This excess and dysfunctional adipose tissue, particularly visceral adiposity, drives insulin resistance, chronic kidney disease, and ultimately cardiovascular disease.7–10 As a modifiable risk factor present across all stages of CKM syndrome, excess adiposity is a central therapeutic target, making effective obesity management fundamental to improving long term CKM related adverse health outcomes.6

Currently, prediabetes is increasingly recognized not only as a precursor to type 2 diabetes but also as an independent marker of cardiovascular risk.24 Emerging evidence suggests that remission of prediabetes may confer substantial and durable cardiovascular benefits, including significant reductions in the risk of cardiovascular death and hospitalization for heart failure over subsequent decades.25 These findings support a shift from merely delaying diabetes progression toward actively targeting metabolic remission as a strategy for cardiovascular prevention.25,26 Current guidelines advocate a comprehensive weight management strategy that combines lifestyle intervention with obesity pharmacotherapy and, when appropriate, metabolic bariatric surgery, targeting weight reduction of at least 5%–10% to improve CKM spectrum.26 In this section, we examine how these pharmacologic agents influence these interconnected conditions.

First Generation

Orlistat produces modest but durable weight loss through peripheral inhibition of gastric and pancreatic lipases, reducing dietary fat absorption.19 In the 4-year XENDOS trial, orlistat plus lifestyle intervention achieved greater mean weight loss than lifestyle intervention alone, 5.8 kg versus 3 kg.27 It even showed a 37.3% relative reduction in new onset type 2 diabetes, with cumulative diabetes incidence of 6.2% versus 9%; this preventive effect was mainly explained by benefit in participants with impaired glucose tolerance.27

Phentermine/topiramate extended release is among the most effective older oral obesity therapies.2–4 Its exact mechanism is not fully defined, but phentermine is thought to suppress appetite through sympathomimetic/noradrenergic pathways, while topiramate may contribute through effects on satiety and reduced food intake, possibly involving gamma-aminobutyric acid (GABA) mediated and glutamatergic pathways.28 In CONQUER, mean percentage weight change at 56 weeks was −7.8% with phentermine/topiramate 7.5/46 mg and −9.8% with 15/92 mg. This weight loss was sustained to 108 weeks in SEQUEL, with reductions of approximately 9.3% and 10.5%, respectively.13,29 In participants with prediabetes and/or metabolic syndrome, phentermine/topiramate reduced progression to type 2 diabetes by 70.5% with 7.5/46 mg and 78.7% with 15/92 mg over 108 weeks.30

Naltrexone/bupropion produces moderate weight loss through complementary effects on central appetite-regulatory pathways. Bupropion stimulates hypothalamic proopiomelanocortin (POMC) neurons, while naltrexone blocks opioid-mediated autoinhibition, enhancing and sustaining their anorectic effect.31 In the Phase 3 COR-I trial, naltrexone/bupropion achieved a mean weight loss of 6.1% in 56 weeks, and 48% of treated participants achieved at least 5% weight loss versus 16% receiving placebo.31

In a network meta-analysis, all approved oral obesity medications demonstrated superior weight loss compared with placebo. The estimated weight reduction was 3.1% for orlistat (22 randomized controlled trials [RCTs]), 8.8% for phentermine/topiramate (5 RCTs), and 4.8% for naltrexone/bupropion (2 RCTs).32 The magnitude of weight loss varies substantially across agents, highlighting the importance of individualized treatment selection based on patient characteristics, complications, other comorbidities, and therapeutic goals.

Second Generation

Oral Semaglutide

Oral semaglutide was first established as a glucose lowering therapy for type 2 diabetes through the PIONEER program, in which the approved diabetes doses of 3, 7, and 14 mg once daily improved HbA1c and produced dose related weight loss that exceeded liraglutide.33 In real world data, the dose of 14 mg for weight loss in patients without diabetes resulted in about 5.7% total body weight loss after 1 year.34 Higher doses were tested in PIONEER PLUS, where oral semaglutide 25 mg and 50 mg achieved greater reductions in both HbA1c and body weight than 14 mg in adults with inadequately controlled type 2 diabetes.35 This dose escalation provided the clinical rationale for studying oral semaglutide as an obesity therapy. In OASIS 4, the pivotal trial of oral semaglutide 25 mg once daily in adults with obesity without diabetes, mean body weight decreased by 13.6% at 64 weeks, confirming clinically meaningful efficacy at the approved obesity dose.16 The 50 mg dose had previously shown greater weight loss, with a mean reduction of 15.1% at 68 weeks versus 2.4% with placebo but was not put forward for approval.16,36 Importantly, the evidence for diabetes prevention should be stated carefully. Oral semaglutide has not yet been tested in a dedicated diabetes-prevention outcomes trial; however, in an OASIS 4 analysis, 71.1% of participants with prediabetes receiving oral semaglutide 25 mg reverted to normoglycemia at 64 weeks, compared with 33.3% with placebo.16

Orforglipron

Orforglipron is a once-daily, nonpeptide oral GLP-1RA designed for administration without food or water restrictions. In the phase 3 ATTAIN-1 trial, adults with obesity without diabetes achieved mean weight reductions of 7.5%, 8.4%, and 11.2% with the 5.5 mg, 9 mg, and 17.2 mg tablet equivalent doses, respectively, compared with 2.1% with placebo at 72 weeks.18 Among participants with prediabetes at baseline, 74.6%–83.7% of those receiving orforglipron achieved normoglycemia at week 72, compared with 44.6% receiving placebo.18 The role of orforglipron beyond weight loss induction was subsequently evaluated in the ATTAIN-MAINTAIN trial. Among participants who had previously achieved substantial weight loss with semaglutide or tirzepatide, those randomized to oral orforglipron progressed to where they were likely to do if they were started on orforglipron from the start. This therefore represents less weight loss compared to semaglutide and tirzepatide, but still substantial improvements from baseline prior to starting any medication.37 These findings suggest that oral orforglipron may offer a practical solution for people not wanting to or unable to continue injectable incretin-based therapies. However, because orforglipron undergoes hepatic metabolism predominantly via cytochrome P450 3A4 (CYP3A4), relevant drug to drug interactions with strong CYP3A4 inhibitors and inducers should be considered when selecting concomitant therapies.23 Table 2 explores the applications of oral obesity medications in CKM stage 1.

Table 2.

Applications of Oral Obesity Medications in CKM Stage 1

Medication	Weight Loss	Glycemic Outcome/Diabetes Prevention Evidence
Orlistat.27,32 1st generation	5.8 kg at 4 years in XENDOS; weight loss 3.1% in network meta-analysis	37.3% relative reduction in incident T2D (6.2% vs 9.0%)
Phentermine/topiramate ER.13,29,30,32 1st generation	7.8%–9.8% at 56 weeks; 9.3%–10.5% at 108 weeks; weight loss 8.8% in network meta-analysis	Reduced progression to T2D by 70.5% (7.5/46 mg) and 78.7% (15/92 mg) over 108 weeks
Naltrexone/bupropion ER.31,32 1st generation	6.1% at 56 weeks; weight loss 4.8% in network meta-analysis	No dedicated diabetes-prevention or prediabetes outcomes reported
Oral semaglutide.16,36 Second generation	13.6% with 25 mg at 64 weeks; 15.1% with 50 mg at 68 weeks	71.1% of participants with prediabetes reverted to normoglycemia versus 33.3% with placebo
Orforglipron.18 Second generation	7.5%–11.2% at 72 weeks, depending on dose	74.6%–83.7% of participants with prediabetes achieved normoglycemia versus 44.6% with placebo

Abbreviations: T2D, type 2 diabetes; ER, extended release; Reversion from prediabetes to normoglycemia should not be interpreted as equivalent to demonstrated prevention of incident type 2 diabetes.

Stage 2–3 CKM

CKM syndrome stage 2 is characterized by the presence of metabolic risk factors, moderate- to high risk CKD according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria, or both, in the absence of subclinical or clinical CVD.6,26 Key risk factors include hypertension (HTN), hypertriglyceridemia (HTG), type 2 diabetes, and CKD. At this stage, management extends beyond the preventive strategies implemented in CKM stages 0 and 1 and shifts toward treatment of metabolic and renal abnormalities to reduce the risk of progression to overt cardiovascular disease.6,26

CKM syndrome stage 3 represents a high risk primary prevention population and is defined by the presence of subclinical CVD, including atherosclerotic cardiovascular disease or heart failure, very-high risk CKD according to KDIGO risk stratification, or a high predicted cardiovascular risk, as reflected by a 10-year PREVENT-CVD risk equation score exceeding 20%.6,26

As individuals progress from CKM stage 1 to stages 2–3, therapeutic priorities evolve from weight reduction alone toward comprehensive cardiometabolic risk factor management.26 Consequently, the value of obesity pharmacotherapy should be assessed not only by its effect on body weight, but also by its ability to improve glycemic control, blood pressure, lipid abnormalities, kidney outcomes, and cardiovascular risk. In the following section, we review the evidence supporting the effects of available oral obesity therapies across these interconnected cardiovascular–kidney–metabolic domains.

First Generation

Type 2 Diabetes Mellitus

In patients with established type 2 diabetes, first generation oral obesity therapies provide varying degrees of weight reduction and glycemic improvement. Orlistat shows a modest improvement in body weight and fasting blood glucose, with HbA1c reductions of approximately 0.6% reported in clinical trials.38 Phentermine/topiramate combination 15/92 mg on the other hand has demonstrated greater metabolic efficacy, with studies reporting HbA1c reductions of approximately 1.6% in individuals with type 2 diabetes, largely in parallel with its 9.4% body weight loss.39 More recently, combination strategies incorporating phentermine/topiramate with GLP-1 RAs have attracted interest in clinical practice, particularly among patients requiring more intensive weight management. However, the available evidence remains limited to small observational studies. In one report, combination therapy was associated with reduced insulin requirements, weight loss approaching 27% over 18 months, accompanied by marked improvement in glycemic control, with HbA1c decreasing from 15.1% to 6.2%.40 While these findings are encouraging, they should be considered hypothesis generating until confirmed in larger controlled studies.40 Naltrexone/bupropion has mild effect with established type 2 diabetes. In the diabetes trial, naltrexone/bupropion produced greater reductions in HbA1c than placebo (−0.6% vs −0.1%), with a higher proportion of participants achieving HbA1c <7%.41 Its use in individuals already receiving incretin-based therapy has also been evaluated. In a post hoc analysis of the LIGHT trial, the addition of naltrexone/bupropion was associated with greater 1-year weight loss than placebo among participants with type 2 diabetes receiving background incretin therapy, including a placebo adjusted weight reduction of 5.2% in those treated with GLP-1 RAs.42 These findings suggest that naltrexone/bupropion may remain a useful adjunctive option for individuals with type 2 diabetes who require additional weight reduction despite incretin-based therapy.

However, the improvements in glycemic control observed with first generation obesity medications appear to be largely mediated by weight loss. In contrast, GLP-1 RAs exert direct glucose lowering effects that extend beyond their impact on body weight, including enhancement of glucose dependent insulin secretion, suppression of glucagon secretion, and early improvements in insulin sensitivity.43–45 Consequently, meaningful reductions in glycemia are often observed before the full weight loss effect is achieved.44,45

Hypertriglyceridemia (HTG)

Among individuals with HTG, the effect of orlistat on triglycerides (TG) remains uncertain. In a 2026 meta-analysis of randomized controlled trials, orlistat did not significantly reduce TG levels in the primary analysis, although a statistically significant reduction emerged after trim-and-fill sensitivity analysis, suggesting a potential benefit that should be interpreted cautiously because of substantial heterogeneity across studies.46 Similarly, no significant effect was observed on low-density lipoprotein cholesterol (LDL-C) in the primary analysis.46 In contrast, orlistat was associated with a modest but statistically significant reduction in high-density lipoprotein cholesterol (HDL-C).46 Phentermine/topiramate was associated with favorable lipid changes that closely paralleled the degree of weight loss achieved. Participants who lost at least 5% of their baseline weight experienced significant reductions in TG, ranging from 14.5% to 39.8%, as well as reductions in non–high-density lipoprotein cholesterol (non-HDL-C) ranging from 9.4% to 14.8%, compared with those who lost less than 5% of their baseline weight.47 Naltrexone/bupropion showed favorable effects on selected lipid parameters in individuals with obesity and type 2 diabetes. Its clearest effect was on TG, which decreased by 11.2% to 0.8% with placebo, while HDL-C increased by 3.0 mg/dL.41 In contrast, LDL-C was not significantly changed.41 Thus, the lipid signal with naltrexone/bupropion appears mainly related to TG reduction and HDL-C improvement, rather than LDL-C lowering. It should be noted that in all previous studies patients were on lipid lowering agents and were not excluded.

Hypertension (HTN)

Blood pressure reduction is among the earliest and most consistent CKM benefits associated with weight loss.48 Several obesity medications have also shown improvements in blood pressure. Evidence has largely been derived from secondary analyses, as most studies were not specifically designed to evaluate hypertension‑related outcomes as primary endpoints. In a meta-analysis of 27 randomized controlled trials, orlistat was associated with modest but statistically significant reductions in systolic and diastolic blood pressure (−1.15 mmHg and −1.07 mmHg, respectively).49 As the magnitude of blood pressure reduction was related to treatment duration rather than baseline blood pressure, these effects are likely driven primarily by sustained weight loss. Phentermine/topiramate has demonstrated favorable effects on systolic blood pressure, although its effects on diastolic blood pressure appear less consistent.50,51 In pooled 1-year clinical trial analyses, the approved doses of 7.5/46 mg and 15/92 mg were associated with reductions in the systolic blood pressure by 5.2 mmHg and reductions in the diastolic by 3.3 and 2.9 mmHg, respectively.50 These findings were partially supported by an 8-weeks randomized ambulatory blood pressure monitoring study, in which phentermine/topiramate 15/92 mg reduced 24-hour systolic blood pressure by 3.3 mmHg, compared with a 0.1 mmHg reduction with placebo and a 1.4 mmHg increase with phentermine 30 mg alone.51 However, in the same study, 24-hour diastolic increased modestly by 0.8 mmHg with phentermine/topiramate, while heart rate increased by 2.6 beats/min.51 Similarly, long term clinical trials reported small increases in heart rate ranging from 0.6 to 1.6 beats/min.50 Collectively, these findings suggest that the principal hemodynamic benefit of phentermine/topiramate is a reduction in SBP, whereas modest increases in heart rate and variable effects on DBP warrant consideration when interpreting its cardiovascular profile.50,51 Unlike other obesity medications that may improve blood pressure parameters, naltrexone/bupropion has been associated with a modest increase in systolic blood pressure by approximately 1.4 mmHg.52 Consequently, its use is contraindicated in patients with uncontrolled hypertension.21

Chronic Kidney Disease (CKD)

CKD is both a consequence of metabolic dysfunction and a potent amplifier of cardiovascular risk.6,26 As kidney function declines, the risk of atherosclerotic cardiovascular disease, heart failure, and cardiovascular mortality rises substantially through the combined effects of traditional cardiovascular risk factors and CKD-specific mechanisms, making cardiovascular risk reduction a central goal of CKD management.26

Although orlistat is largely devoid of systemic effects, rare cases of oxalate nephropathy and acute kidney injury have been reported.19,53–55 Fat malabsorption induced by orlistat increases enteric oxalate absorption and urinary oxalate excretion, potentially resulting in renal oxalate crystal deposition and kidney injury.19 Consequently, the FDA has updated orlistat labeling to warn of acute kidney injury, oxalate stones and oxalate nephropathy.55 Data supporting the use of phentermine/topiramate and naltrexone/bupropion in CKD are limited because patients with significant renal impairment were largely excluded from pivotal trials.56 A contemporary nephrology review concluded that evidence remains insufficient to recommend phentermine/topiramate routinely in CKD and suggested avoiding naltrexone/bupropion because of uncertain renal safety.56 Current labeling recommends dose reduction of both agents in moderate-to-severe renal impairment, with avoidance in end stage kidney disease.20,21

Second Generation

Type 2 Diabetes Mellitus

Oral semaglutide was initially developed and approved for the treatment of type 2 diabetes. The glycemic efficacy was shown in the PIONEER clinical trial program with oral semaglutide 14 mg reducing HbA1c by approximately 1.0%–1.5%.33 This was superior to placebo, sitagliptin, and empagliflozin in head-to-head trials.57–59 Notably, oral semaglutide demonstrated efficacy comparable to that of established injectable GLP-1 RA liraglutide. Oral semaglutide 14 mg reduced HbA1c by 1.2%, compared with 1.1% for injectable liraglutide 1.8 mg, while achieving greater weight loss (−4.4 vs −3.1 kg) at 26 weeks.60 These findings established oral semaglutide as the first oral GLP-1 receptor agonist capable of delivering injectable-level glycemic efficacy with superior weight reduction. Glycemic efficacy was preserved in patients receiving background insulin therapy, supporting its use in more advanced disease.61 Furthermore, in PIONEER PLUS, oral semaglutide demonstrated a dose dependent glycemic effect, mean HbA1c reductions were 1.5%, 1.8%, and 2.0%, and body weight reductions were 4.4, 6.7, and 8.0 kg with oral semaglutide 14, 25, and 50 mg, respectively, at week 52.35 However, nominal dose alone does not reflect semaglutide exposure. The first generation formulation used in the original PIONEER program had lower bioavailability than the enhanced formulation subsequently used in OASIS; consequently, the current oral semaglutide 25 mg formulation achieves a higher plasma exposure than earlier formulations, including those evaluated at higher nominal doses in early dose ranging studies.35,62,63

Following the clinical success of oral semaglutide, orforglipron emerged as the first non-peptide oral GLP-1 RA without the administration restrictions required for peptide-based oral therapies, but with a limited number of drug interaction that may require attention. Across the ACHIEVE program, orforglipron demonstrated substantial and consistent glycemic efficacy in diverse populations with type 2 diabetes. In ACHIEVE-1, HbA1c decreased by 1.24%, 1.47%, and 1.48% with the 2.5 mg, 9 mg, and 17.2 mg doses, respectively.64 Glycemic efficacy remained robust in patients receiving background insulin therapy, where HbA1c reductions ranged from 1.6% to 1.9%.65 The magnitude of glucose lowering was further demonstrated in ACHIEVE-3, in which HbA1c decreased from a baseline of 8.3% by 1.7% and 1.9% with orforglipron 9 mg and 17.2 mg, respectively, at 52 weeks.66 Consistent findings were observed in Japanese patients with type 2 diabetes, where long term treatment produced clinically meaningful HbA1c reductions together with sustained weight loss.67 Despite the glycemic efficacy of orforglipron has been consistently demonstrated across multiple phase 3 trials, the agent has not yet been approved for the treatment of type 2 diabetes.

Although both oral semaglutide and orforglipron represent important advances in oral GLP-1 receptor agonist therapy, emerging evidence suggests distinct efficacy and tolerability profiles. In a population adjusted indirect treatment comparison using data from OASIS 4 and ATTAIN-1, oral semaglutide 25 mg achieved greater weight loss than orforglipron 17.2 mg, with an additional 3.0–3.2 percentage-point reduction in body weight with lower rates of treatment discontinuation due to any adverse event (OR 4.1) and gastrointestinal adverse events (OR 13.9), favoring oral semaglutide.68 However, it should be noted that this does not substitute for a head-to-head trial.

In contrast, among patients with type 2 diabetes receiving currently approved oral semaglutide diabetes doses, ACHIEVE-3 demonstrated greater glycemic and weight loss efficacy with orforglipron 17.2 mg than with oral semaglutide 14 mg.66 At 52 weeks, HbA1c decreased by 1.7% and 1.9% with orforglipron 9 mg and 17.2 mg, respectively, compared with 1.2% and 1.5% with oral semaglutide 7 mg and 14 mg.66 Similarly, body weight decreased by 7.9% and 9.4% with orforglipron versus 4.6% and 6.6% with oral semaglutide. However, these efficacy gains were accompanied by a less favorable tolerability profile, with gastrointestinal adverse events reported in 58%–59% of participants receiving orforglipron compared with 37%–45% receiving oral semaglutide, and treatment discontinuation rates of approximately 9%–10% versus 4%–5%, respectively.66 Orforglipron was also associated with a greater increase in heart rate.66 While the PIONEER PLUS was not a head-to-head comparison with orforglipron, it showed that higher doses oral semaglutide 25 mg and 50 mg reduced HbA1c by 1.8% and 2.0%, respectively, and body weight by 6.7 kg and 8.0 kg, compared with 1.5% and 4.4 kg with oral semaglutide 14 mg.35 Beyond efficacy, a practical advantage of orforglipron is its administration without fasting, water, or meal-timing restrictions, whereas oral semaglutide requires administration on an empty stomach with water followed by a fasting interval. Taken together, the indirect treatment comparison suggests that oral semaglutide may provide more weight reduction and favorable tolerability at approved obesity doses, whereas in ACHIEVE-3 orforglipron appears to deliver further glycemic and weight loss efficacy in comparison to the approved semaglutide diabetes doses, albeit at the expense of increased gastrointestinal adverse effects and treatment discontinuation.

Hypertriglyceridemia (HTG)

Among lipid parameters, triglycerides demonstrated the most consistent and clinically meaningful improvement with both oral semaglutide and orforglipron in adults with obesity without diabetes. In OASIS 4, oral semaglutide 25 mg reduced triglycerides by 18% compared with 8% with placebo, while LDL-C decreased by 4% and HDL-C increased by 3%.16 A similar but numerically greater effect was observed in OASIS 1, where oral semaglutide 50 mg reduced triglycerides by 22.3% compared with 5.3% with placebo, whereas LDL-C changed by −0.6% and HDL-C increased by 4.9%.36 Likewise, in ATTAIN-1, orforglipron improved triglyceride levels compared with placebo, accompanied by favorable reductions in non-HDL cholesterol.18 These findings were further supported by a dedicated meta-analysis, which demonstrated placebo-adjusted reductions of 12.1% in triglycerides, 3.1% in LDL-C, and a 3.6% increase in HDL-C with orforglipron.69 Given the high prevalence of dyslipidemia among individuals with obesity and CKM syndrome, concomitant statin therapy will frequently be required in patients receiving orforglipron. While atorvastatin and rosuvastatin can be coadministered without clinically meaningful pharmacokinetic interactions, orforglipron increases exposure to simvastatin acid, necessitating a maximum recommended simvastatin dose of 20 mg daily during concomitant use.18,23 However, as mentioned in the first generation oral obesity therapies, lipid management agents were not part of the exclusion criteria, and this has to be taken into account.

Hypertension (HTN)

The magnitude of effect differs across oral GLP-1RAs agents and doses. In OASIS 4, oral semaglutide 25 mg reduced systolic blood pressure by 6.8 mmHg compared with 5.4 mmHg with placebo, yielding only a modest placebo-adjusted difference of −1.4 mmHg; diastolic blood pressure decreased by 2.7 mmHg versus 2.1 mmHg, respectively, with a placebo-adjusted difference of −0.7 mmHg.16 In contrast, OASIS 1 showed a clearer signal with oral semaglutide 50 mg, where systolic blood pressure decreased by 6.6 mmHg versus 0.3 mmHg with placebo, and diastolic blood pressure by 2.4 mmHg versus 0.6 mmHg.36 For orforglipron, ATTAIN-1 demonstrated a clinically meaningful reduction in systolic blood pressure, with pooled orforglipron reducing systolic blood pressure by 5.7 mmHg versus 1.4 mmHg with placebo, corresponding to a placebo-adjusted reduction of −4.2 mmHg.18 Diastolic blood pressure also decreased, although more modestly, by 2.4 mmHg versus 1.4 mmHg, with a placebo-adjusted difference of −1.0 mmHg.18 This pattern was supported by the orforglipron meta-analysis, which showed a significant placebo-adjusted systolic blood pressure reduction of −4.3 mmHg, while the diastolic reduction was smaller and not statistically significant at −0.7 mmHg.69 Overall, the most consistent blood pressure benefit for these oral agents is systolic rather than diastolic, with stronger evidence for oral semaglutide 50 mg and orforglipron than for oral semaglutide 25 mg.

Chronic Kidney Disease (CKD)

Oral semaglutide and orforglipron may precipitate acute kidney injury in susceptible patients with clinically significant volume depletion from gastrointestinal loss.22,23 Beyond this safety consideration, the available evidence suggests that oral semaglutide and orforglipron are kidney safe and may confer kidney benefit in people with type 2 diabetes in terms of oral semaglutide.

In pooled data from SUSTAIN 6 and PIONEER 6, semaglutide slowed estimated glomerular filtration rate (eGFR) decline compared with placebo, with an estimated treatment difference of 0.59 mL/min/1.73 m²/year, and this benefit appeared consistent with the other cardiometabolic profile.70 However, this analysis combined injectable and oral semaglutide, and albuminuria subgroup analyses were limited to SUSTAIN 6, so the findings support a class/formulation-consistent signal rather than definitive oral specific nephroprotection. More direct evidence comes from SOUL, in which oral semaglutide 14 mg slowed annual eGFR loss compared with placebo, −1.67 versus −2.06 mL/min/1.73 m²/year, with an estimated treatment difference of 0.40 mL/min/1.73 m²/year.71 Real-world data further suggest a stronger effect on albuminuria than on eGFR. In the Renal_ENDO2S-RWD, oral semaglutide reduced urinary albumin-to-creatinine ratio (UACR) by 30.3% and 40.0% at 6 and 12 months in the overall cohort, with larger reductions among participants with albuminuria: 40.2% and 50.7% in those with UACR ≥30 mg/g, and 40.6% and 49.9% in those with UACR ≥300 mg/g.72 In contrast, eGFR slope remained stable rather than improving.72 Taken together, oral semaglutide should be viewed as kidney safe in type 2 diabetes and potentially kidney protective, particularly through albuminuria reduction and modest slowing of eGFR decline. In ACHIEVE-3, participants with an eGFR <45 mL/min/1.73 m² were excluded, limiting conclusions in advanced CKD.66 Over 52 weeks, mean eGFR declined, with no clinically relevant differences between orforglipron and oral semaglutide. However, UACR decreased across all groups, with numerically greater reductions observed with orforglipron (−31.4% with 9 mg and −32.5% with 17.2 mg) than with oral semaglutide (−14.5% with 7 mg and −23.8% with 14 mg).66 These findings suggest a potential favorable effect on albuminuria, although the study was not designed or powered to assess kidney outcomes. Consequently, while these data support renal safety and provide a promising possibility of kidney benefit, dedicated renal outcome trials are required before definitive nephroprotective effects can be established. Great caution is needed when interpreting eGFR when either creatinine or cystatin C are used. Weight loss association with muscle mass loss and adiposity reduction are very likely responsible for the respective changes in creatinine or cystatin C.73 Moreover, when kidney function is assessed using measured glomerular filtration rate (mGFR), determined by iohexol or chromium-51 ethylenediaminetetraacetic acid (51Cr-EDTA) clearance, no significant change is typically observed following weight loss therapy, even when eGFR appears to improve.73 We summarize the key points of CKM stage 2–3 oral obesity medications in Table 3.

Table 3.

Applications of Oral Obesity Medications in CKM Stages 2–3

Medication	HbA1c Reduction	TG Reduction	SBP Change	DBP Change	Kidney Effects
Orlistat.19,38,46,49,53–55 1st generation	~0.6%	No significant reduction	−1.15 mmHg	−1.07 mmHg	AKI, oxalate stones and oxalate nephropathy
Phentermine/Topiramate.20,39,47,50,51,56 1st generation	~1.6%	14.5–39.8% (among participants achieving ≥5% weight loss)	−5.2 mmHg (pooled trials); −3.3 mmHg (ABPM study)	−3.3 to −2.9 mmHg (pooled trials); +0.8 mmHg (ABPM study)	Limited CKD evidence; dose reduction in renal impairment; avoid in ESKD
Naltrexone/Bupropion.21,41,52,56 1st generation	~0.6%	−11.2%	+1.4 mmHg	Not clearly reported	Limited CKD evidence; dose reduction in renal impairment; avoid in ESKD
Oral Semaglutide.16,22,33,35,36,57–61,70–72 Second generation	14 mg: ~1.0–1.5%; 25 mg: 1.8%; 50 mg: 2.0%	25 mg: −18%; 50 mg: −22.3%	25 mg: −6.8 mmHg; 50 mg: −6.6 mmHg	25 mg: −2.7 mmHg; 50 mg: −2.4 mmHg	Generally, kidney safe; Increase risk of AKI due to dehydration; slows eGFR decline and reduces UACR
Orforglipron.18,23,64–66,69 Second generation	9 mg: 1.71% 17.2 mg: 1.91%	−12.1% (placebo-adjusted; meta-analysis)	ATTAIN-1: −5.7 mmHg	ATTAIN-1: −2.4 mmHg	Generally kidney safe signal; Increase risk of AKI due to dehydration; UACR reduction reported; no dedicated kidney outcome trial

Abbreviations: HbA1c, glycated hemoglobin; TG, triglycerides; SBP, systolic blood pressure; DBP, diastolic blood pressure; CKD, chronic kidney disease; AKI, acute kidney injury; eGFR, estimated glomerular filtration rate; UACR, urinary albumin-to-creatinine ratio; ESKD, end-stage kidney disease; ABPM, ambulatory blood pressure monitoring; RWD, real-world data; NS, not statistically significant. Effect estimates are reported using the metric provided in the source studies and should not be directly compared across medications. Where applicable, findings represent changes from baseline, comparator adjusted effects, or pooled estimates as specified in the source studies.

CKM Stage 4

Notably, the link between metabolic risk factors and cardiac outcomes had been recognized well before the formal introduction of the CKM framework.6 This understanding was further reinforced in July 2008, when the FDA Endocrinologic and Metabolic Drugs Advisory Committee voted 14–2 to recommend that all new glucose lowering therapies demonstrate long term cardiovascular safety, either through dedicated outcomes trials or equivalent evidence, to exclude unacceptable cardiovascular risk.74 Stage 4 CKM syndrome is characterized by established cardiovascular disease, including clinical atherosclerotic cardiovascular disease (acute coronary syndrome (ACS), cerebral vascular accident (CVA), peripheral arterial disease (PAD)), heart failure, or atrial fibrillation (AF), in individuals with obesity-related metabolic dysfunction and/or chronic kidney disease.6,26 It is subdivided into stage 4a (without kidney failure) and stage 4b (with kidney failure), as the presence of kidney failure has important therapeutic and prognostic implications. In this stage, the primary therapeutic goal is to reduce the risk of recurrent cardiovascular events through secondary prevention strategies and comprehensive management of coexisting metabolic and kidney disease risk factors.26 In this section, we examine how oral obesity therapies may contribute to addressing the advanced dimension of CKM. A high yield Table 4 includes summary of oral obesity medications in CKM stage 4.

Table 4.

Applications of Oral Obesity Medications in CKM Stage 4

Medication	Clinical ASCVD	Heart Failure	Atrial Fibrillation
Orlistat.19,75,76 1st generation	Observational cohort: lower MACE risk (HR 0.74), myocardial infarction (HR 0.77), and ischemic stroke (HR 0.68)	Lower incident HF risk and improved functional capacity in established HFrEF	No proven AF benefit; May reduce amiodarone absorption and destabilize warfarin anticoagulation through reduced vitamin K absorption.
Phentermine/Topiramate.20,26,50,77–80 1st generation	No ASCVD outcome benefit demonstrated. Nonfavorable	Mixed evidence; cardiomyopathy reports and sympathomimetic activity raise concern in HF. Nonfavorable	No proven AF benefit; increased heart rate and reported AF cases suggest possible arrhythmogenic risk.
Naltrexone/Bupropion.21,26,52,81 1st generation	No ASCVD outcome benefit demonstrated. Nonfavorable.	No dedicated HF data; hemodynamic effects may limit attractiveness in established HF.	No proven AF benefit; use cautiously in patients with AF or tachyarrhythmia risk.
Oral Semaglutide.82–87 Second generation	PIONEER 6: CV safety; SOUL RCT: reduced 3-point MACE (HR 0.86).	SOUL secondary analysis: no overall HF benefit; favorable signal in pre-existing HF, especially HFpEF	Meta-analyses suggest reduced incident AF; lower post ablation recurrence observed.
Orforglipron.88 Second generation	ACHIEVE-4: cardiovascular safety and non-inferiority for MACE-4 (HR 0.84).	No dedicated HF outcomes data currently available.	No proven AF benefit;

Abbreviations: ASCVD, Atherosclerotic cardiovascular disease; AF, Atrial fibrillation; CKM, Cardiovascular–Kidney–Metabolic syndrome; HF, Heart failure; HFpEF, Heart failure with preserved ejection fraction; HFrEF, Heart failure with reduced ejection fraction; HR, Hazard ratio; MACE, Major adverse cardiovascular events; MACE-4, Cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina; OR, Odds ratio; RR, Relative risk. Evidence includes randomized clinical outcomes, secondary/subgroup analyses, observational studies, and meta-analyses, as indicated; these evidence types should not be considered equivalent.

First Generation

Clinical Atherosclerotic Cardiovascular Disease

Evidence on orlistat and hard cardiovascular outcomes remains limited and is largely observational. In a nationwide propensity-score matched cohort study of 36,876 orlistat-treated patients with obesity and 36,876 matched controls, orlistat use was associated with a lower risk of major adverse cardiovascular events (MACE) over a median follow-up of 6 years (HR 0.74, 95% CI 0.66–0.83).75 For ischemic outcomes, the association was directionally favorable, with lower rates of fatal or non-fatal myocardial infarction (HR 0.77, 95% CI 0.66–0.88) and ischemic stroke (HR 0.68, 95% CI 0.56–0.84).75 However, the study did not specifically report acute coronary syndrome as a separate endpoint, and therefore the myocardial infarction signal should not be overinterpreted as comprehensive evidence across the full ACS spectrum. Similarly, the stroke endpoint was limited to ischemic stroke and should not be generalized to all cerebrovascular events. Coronary revascularization rates were not significantly different between groups (HR 1.12, 95% CI 0.91–1.38), suggesting that the observed reduction in myocardial infarction did not translate into a measurable reduction in revascularization procedures.75 Unlike orlistat, evidence supporting cardiovascular benefit with phentermine containing therapies is lacking. Phentermine monotherapy has been associated with a modest increase in heart rate, reflecting its sympathomimetic activity.77 Similarly, naltrexone/bupropion may increase both heart rate and blood pressure.81 Where in a safety interim analyses did not suggest an excess risk of major adverse cardiovascular events; the recent CKM guidelines recommended against using it.26,52 Consequently, these agents are generally avoided in patients with established or unstable cardiovascular disease, limiting their role in advanced stages of CKM syndrome.26,81

Heart Failure

Evidence for heart failure is limited. In the previous matched cohort study, orlistat use was associated with a lower risk of incident heart failure and improved functional capacity in patients with established reduced ejection fraction heart failure.75,76 Although this finding may reflect merely the favorable effects of weight loss and cardiometabolic risk factor improvement. In contrast, the cardiovascular evidence for phentermine/topiramate is mixed. While some studies have generally demonstrated cardiovascular safety in patients with low-to-intermediate cardiovascular risk, reports of cardiomyopathy and its sympathomimetic effects raise concerns in higher risk populations.50,78,79 Therefore, phentermine/topiramate may be a less attractive optionto this population.

Atrial Fibrillation

In patients with atrial fibrillation, orlistat may interfere with key components of AF management. By reducing intestinal fat absorption, it can decrease the bioavailability of lipophilic drugs such as amiodarone, potentially affecting rhythm control.19 Orlistat may also impair vitamin K absorption, resulting in unstable anticoagulation and increased bleeding tendency in patients receiving warfarin; therefore, close monitoring is warranted when these therapies are used concurrently.19 Evidence regarding atrial fibrillation remains inconclusive for both phentermine/topiramate and naltrexone/bupropion. The sympathomimetic effects of phentermine are associated with modest increases in resting heart rate, and case reports have described phentermine associated atrial fibrillation, suggesting that adrenergic stimulation may precipitate AF in susceptible individuals.20,80 Although naltrexone/bupropion has not been directly linked to AF, it may increase heart rate and blood pressure, and dedicated data in patients with established arrhythmias are lacking.21

Second Generation

The cardioprotective effects of GLP-1 receptor agonists appear to extend beyond metabolic improvement alone. Through coordinated actions on endothelial dysfunction, vascular inflammation, oxidative stress, and atherosclerotic plaque biology, GLP-1 receptor activation targets key mechanisms linking excess adiposity to cardiovascular disease.89 These vascular and anti-atherosclerotic effects provide an important mechanistic basis for the expanding role of oral incretin therapies in CKM syndrome.26,89

Clinical Atherosclerotic Cardiovascular Disease

The recent FDA approval of oral semaglutide for chronic weight management and cardiovascular risk reduction establishes an important regulatory precedent that comparable systemic semaglutide exposure between oral and subcutaneous formulations.22 In PIONEER 6, oral semaglutide 14 mg established cardiovascular safety in high risk type 2 diabetes, with major adverse cardiovascular events (MACE; cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) occurring in 3.8% versus 4.8% with placebo, although the trial was not powered to prove superiority.82 This was strengthened by 4-years follow up SOUL trial, in which oral semaglutide significantly reduced 3-points MACE in patients with type 2 diabetes and clinical atherosclerotic cardiovascular disease, chronic kidney disease, or both: 12.0% versus 13.8% with placebo (HR 0.86; 95% CI, 0.77–0.96; P=0.006).83 Therefore, within the CKM spectrum, oral semaglutide has moved beyond risk factor improvement to demonstrated cardiovascular event reduction in high risk patients with type 2 diabetes. Cardiovascular outcomes data for orforglipron remain limited. In ACHIEVE-4, orforglipron demonstrated cardiovascular safety, meeting the prespecified criterion for non-inferiority versus insulin glargine for major adverse cardiovascular events (MACE-4; HR 0.84, 95% CI 0.59–1.20).88 Although fewer MACE events were observed with orforglipron, the trial was not designed to establish cardiovascular superiority, and dedicated outcomes studies are needed to determine whether it reduces cardiovascular risk.

Heart Failure

Oral semaglutide now has direct heart failure outcome data from the SOUL trial population. In this secondary analysis of 9650 adults with whom can be classified as stage 2 CKM or higher, 2229 participants had heart failure at baseline, including preserved, reduced, or unknown ejection-fraction subtypes. The prespecified heart failure composite was heart failure hospitalization, urgent heart failure visit, or cardiovascular death.84 Overall, oral semaglutide did not significantly reduce the composite heart failure outcome in the entire trial population (hazard ratio, 0.90; 95% CI, 0.79–1.03). However, in participants with pre-existing heart failure, it reduced this outcome versus placebo (hazard ratio, 0.78; 95% CI, 0.63–0.96), while no benefit was observed in those without baseline heart failure (hazard ratio, 1.01; 95% CI, 0.84–1.20; interaction P = 0.06).84 This signal appeared stronger in heart failure with preserved ejection fraction (hazard ratio, 0.59; 95% CI, 0.39–0.86), whereas no clear reduction was seen in heart failure with reduced ejection fraction (hazard ratio, 0.98; 95% CI, 0.70–1.38).84 Importantly, the major adverse cardiovascular event benefit of oral semaglutide was broadly consistent regardless of baseline heart failure status, with hazard ratios of 0.83 (95% CI, 0.68–1.01) in those with heart failure and 0.86 (95% CI, 0.75–0.98) in those without heart failure.84 Therefore, oral semaglutide appears promising for reducing heart failure events in patients with type 2 diabetes and established heart failure, particularly those with preserved ejection fraction, but the evidence is not yet equivalent to a dedicated heart failure outcomes trial.

Atrial Fibrillation

The evidence for oral semaglutide is encouraging but not yet definitive. In the recent meta-analysis, semaglutide reduced new onset atrial fibrillation overall, with a signal that was stronger for the oral formulation with a 52% lower atrial fibrillation incidence (odds ratio 0.48, 95% CI 0.24–0.95).85 This direction is consistent with the meta-analysis in type 2 diabetes, where semaglutide reduced atrial fibrillation risk overall (relative risk 0.73, 95% CI 0.54–0.98), and oral semaglutide again showed a significant subgroup signal (relative risk 0.49, 95% CI 0.25–0.97).86 In obesity related atrial fibrillation, semaglutide in both oral and injectable forms was also associated with lower post ablation atrial tachyarrhythmia recurrence, with 80.2% versus 65.2% freedom from recurrence at 18 months and a hazard ratio of 0.52, accompanied by substantial weight reduction.87 However, atrial fibrillation was not the primary endpoint in most trials, and the apparent benefit should be interpreted carefully. A summary can be found in Table 4.

Conclusion

Obesity is a central driver of CKM syndrome, and its management is increasingly shifting beyond weight loss alone toward reducing obesity related complications. This evolution requires clinicians to consider not only the magnitude of weight reduction, but also the broader effects of therapy on glycemic control, kidney health, cardiovascular risk, heart failure, and atrial fibrillation.2–4,6 Among currently available oral obesity medications, first generation agents remain useful and accessible options, particularly for weight reduction and metabolic improvement, although evidence supporting cardiovascular and renal outcome benefits remains limited. In contrast, second generation oral incretin-based therapies have demonstrated a broader impact across the CKM spectrum. Oral semaglutide currently has the most mature evidence base, including proven cardiovascular benefit and emerging signals of benefit in heart failure, atrial fibrillation, and chronic kidney disease, with potential future use in metabolic dysfunction–associated steatohepatitis. Orforglipron has demonstrated substantial efficacy in obesity and type 2 diabetes; two major upstream drivers of CKM which provides a compelling biological rationale for broader downstream benefit. Yet metabolic efficacy is not equivalent to proven organ protection: whether orforglipron reduces major cardiovascular events, kidney failure or kidney related complications, or reverses fibrosis in metabolic dysfunction–associated steatohepatitis remains to be established in dedicated outcome trials. Oral obesity pharmacotherapy should therefore be integrated within a holistic CKM approach, with each claim calibrated to the strength of evidence for the specific therapy and outcome.

Funding Statement

This work received no funding.

Abbreviations

ACS, acute coronary syndrome; AF, atrial fibrillation; BMI, body mass index; CKD, chronic kidney disease; CKM, cardiovascular–kidney–metabolic syndrome; CVA, cerebrovascular accident; CYP3A4, cytochrome P450 3A4; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; FDA, United States Food and Drug Administration; GABA, gamma-aminobutyric acid; GLP-1, glucagon-like peptide-1; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HR, hazard ratio; HTG, hypertriglyceridemia; HTN, hypertension; KDIGO, Kidney Disease: Improving Global Outcomes; LDL-C, low-density lipoprotein cholesterol; MACE, major adverse cardiovascular events; mGFR, measured glomerular filtration rate; PAD, peripheral arterial disease; POMC, proopiomelanocortin; PREVENT-CVD, Predicting Risk of Cardiovascular Disease Events; RCT, randomized controlled trial; SNAC, sodium N-[8-(2-hydroxybenzoyl) amino] caprylate; T2D, type 2 diabetes; TG, triglycerides; UACR, urinary albumin-to-creatinine ratio; ^51Cr-EDTA, chromium-51 ethylenediaminetetraacetic acid.

Data Sharing Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Disclosure

Abdulhameed Alhazmi declares no conflicts of interest. Professor Carel le Roux reports grants from the EU Innovative Medicine Initiative, Irish Research Council, Science Foundation Ireland, Anabio, and the Health Research Board. He serves on advisory boards and speakers panels of Abbvie, Altimmune, Amgen, Arrowhead Pharma, Astrazeneca, Boehringer Ingelheim, Cambrian Biopharma, Eli Lilly, Gila Pharmaceuticals, Herbalife, Irish Life Health, Johnson and Johnson, Keyron, Medscape, Metsera, Morphic Medical, Novo Nordisk, Nymble, Olympus, Orbimed, Pfizer, Rhythm Pharma, Roche, Wave, Zealand Pharma. ClR is the Chair of the Irish Society for Nutrition and Metabolism. ClR received stock options as payment for scientific advisory board functions from Nymble. ClR provides obesity clinical care in the My Best Weight clinic and Beyond BMI clinic and is a co-owner of these clinics.