The review searched peer-reviewed literature, clinical-trial registries, regulatory documents, and official sponsor sources for evidence available through August 2026. It covered approved, under-review, and investigational therapies, giving priority to randomized controlled trials, mechanistic studies, consensus and guideline documents, and human studies of biomarkers, treatment response, and omics-based stratification. Because this was a narrative review rather than a systematic review or meta-analysis, the authors did not register a formal protocol, conduct duplicate study selection or risk-of-bias assessment, or pool results quantitatively. Sponsor communications and registry records were used to describe development or regulatory status when information was not yet available in peer-reviewed publications, and such findings were treated as provisional.

Coexisting obesity and type 2 diabetes form a heterogeneous metabolic phenotype. Excess adiposity, particularly visceral and ectopic fat, can contribute to insulin resistance, inflammation, disturbed adipokine signaling, fatty liver, and impaired glucose regulation, while the two conditions together are associated with cardiovascular disease, chronic kidney disease, metabolic dysfunction-associated steatotic liver disease, heart failure, obstructive sleep apnea, osteoarthritis, and several cancers. People with the same body-mass index and hemoglobin A1c can nevertheless differ substantially in beta-cell reserve, liver fat, insulin resistance, appetite biology, inflammatory activity, skeletal muscle status, kidney function, cardiovascular vulnerability, and medication tolerance. These differences are relevant to treatment, but most have not been validated as predictive biomarkers for choosing one anti-obesity drug over another.

Clinical trials have established weight and glycemic benefits for several incretin-based therapies. Liraglutide demonstrated greater weight reduction than placebo in the SCALE Diabetes trial among adults with overweight or obesity and type 2 diabetes, and its lower antidiabetic dose reduced major adverse cardiovascular events in the LEADER trial. Tirzepatide, which activates GIP and GLP-1 receptors, has established efficacy for body weight and HbA1c. By August 2026, oral semaglutide 25 mg had received US Food and Drug Administration approval for chronic weight management, while the non-peptide oral GLP-1 receptor agonist orforglipron had also received approval. These results support the effectiveness of incretin therapies at population level; they do not show that a molecular test can identify which patient will derive the greatest benefit from one agent rather than another.

More complex drug candidates extend beyond single-receptor incretin therapy. Retatrutide is an investigational weekly GLP-1, GIP, and glucagon receptor agonist whose peer-reviewed phase 2 trial reported dose-dependent weight reduction approaching 24% at 48 weeks; sponsor-reported phase 3 results indicated a mean reduction of 28.3% at 80 weeks with the 12-mg dose. Survodutide, pemvidutide, and mazdutide combine GLP-1 activity with glucagon receptor activation, and amylin-based programs include CagriSema, amycretin, petrelintide, cagrilintide, and eloralintide. MariTide combines GLP-1 agonism with GIP antagonism and is being developed as a monthly injectable. These programs have different phases, populations, formulations, and levels of evidence, so their results should not be treated as interchangeable or ranked conclusively from indirect comparisons.

The biological rationale for these drugs extends beyond appetite suppression. Hormones including GLP-1, GIP, glucagon, peptide YY, and amylin connect the gut, brain, liver, adipose tissue, skeletal muscle, pancreas, kidney, and cardiovascular system. Genomics can capture inherited variation associated with insulin secretion, fat distribution, hepatic lipid metabolism, drug metabolism, and adverse-event susceptibility. Epigenomics may reflect the influence of obesity, hyperglycemia, aging, inflammation, and environmental exposures on metabolic tissues, while transcriptomics and proteomics can illuminate inflammation, tissue remodeling, and organ stress. Metabolomics and lipidomics can track small molecules and lipids associated with insulin resistance, lipotoxicity, and liver disease, and the microbiome may influence incretin secretion, bile-acid metabolism, intestinal barrier function, and gastrointestinal tolerability. These layers are complementary, but biological plausibility is not equivalent to validated clinical utility.

Human studies illustrate why stronger validation is required. In an analysis of 13,123 participants in the MetGen consortium, the SLC2A2 rs8192675 variant was associated with a 0.17-percentage-point greater HbA1c reduction with metformin; among participants with obesity, the CC versus TT genotype was associated with a 0.33-percentage-point greater reduction. A study of 233 adults with type 2 diabetes found that the TT genotype at GLP1R rs10305420 was associated with optimal glycemic response to liraglutide, with an odds ratio of 3.28, a 95% confidence interval of 1.41 to 7.65, and P=0.006. These are candidate pharmacogenetic markers rather than prescribing rules, because neither has been independently validated in a prospective trial showing that genotype-guided treatment improves outcomes. Cross-sectional metabolomic patterns associated with metformin or sulfonylurea response likewise remain exploratory.

A predictive biomarker must also be distinguished from a pharmacodynamic marker. A predictive marker identifies, before treatment, which therapy should provide greater benefit than an alternative. A pharmacodynamic marker instead records a biological change after treatment and may clarify how a drug acts. In 259 adults with type 2 diabetes participating in a phase 2b randomized trial, treatment-induced changes in branched-chain amino acid-related metabolites and lipid species correlated with improvements in HbA1c, HOMA2-IR, and proinsulin, but the study did not establish a pretreatment predictive effect. Multi-omics algorithms face further obstacles, including overfitting, batch effects, platform differences, reproducibility problems, poor calibration, and a lack of transportability across laboratories and populations. Artificial intelligence can integrate molecular, clinical, imaging, digital, and behavioral data, but model sophistication cannot substitute for prospective evidence that its recommendations improve care.

Several practical questions also remain unresolved. Weight loss is not synonymous with preserved muscle health: dual-energy X-ray absorptiometry-derived lean mass includes water and other non-fat tissues, not only contractile skeletal muscle. Trials therefore need more specific muscle assessments, including appendicular lean mass and muscle cross-sectional area or volume measured by computed tomography or magnetic resonance imaging, together with functional outcomes such as handgrip strength, chair-stand performance, gait speed, and the Short Physical Performance Battery. These measures are particularly important for older adults and people with frailty or sarcopenic obesity. Durability is another concern. Participants in the STEP 1 extension regained a substantial portion of previously lost weight after withdrawal of semaglutide 2.4 mg, while withdrawal from tirzepatide in SURMOUNT-4 was followed by weight regain and partial reversal of several cardiometabolic risk-marker improvements. Long-term evaluation must also address gastrointestinal adverse events, gallbladder disease, pancreatitis concerns, heart-rate changes, dehydration, malnutrition, and changes in muscle quantity or function.

The review argues that the next decisive step is not simply identifying more molecular associations, but testing whether they are predictive, reproducible, and clinically useful. Future trials should prespecify candidate biomarkers, formally test interactions between treatment and biomarker status, and include people with diverse ancestries and relevant conditions such as kidney disease, heart failure, fatty liver disease, frailty, and longer-standing diabetes. Metabolic endpoints such as weight, HbA1c, and time in range should be separated from intermediate markers such as liver fat, blood pressure, lipids, and albuminuria, and both should remain distinct from adjudicated cardiovascular and kidney outcomes. Combination, sequencing, induction-maintenance, and de-escalation strategies also require dedicated randomized trials. Until prospective studies show that molecularly guided prescribing improves efficacy, safety, persistence, patient-reported outcomes, or efficiency beyond high-quality conventional care, multi-omics remains a research framework for generating and testing precision-treatment hypotheses rather than a clinically validated component of routine prescribing.

Subject of Research: Multi-omics and anti-obesity drug selection in type 2 diabetes

Article Title: Diabesity: an old term, a modern challenge — multi-omics and precision anti-obesity pharmacotherapy in type 2 diabetes

Article References: Hoffmann, K., Pucek, W. F., Skrzypek, W., Kierzkowski, F., Ratajczak, P., Maggio, V., Rizzo, M., El-Tanani, M., Rabbani, S. A., Bhongade, B., Satyam, S. M., Talath, S., Rangraze, I. R., Wali, A. F., Ibraheem, W., El-Tanani, Y., Ispas, S., Bryl, W., & Paczkowska, A. (2026). Diabesity: an old term, a modern challenge — multi-omics and precision anti-obesity pharmacotherapy in type 2 diabetes. Journal of Pharmacy & Pharmaceutical Sciences, 29, Article 17560. https://doi.org/10.3389/jpps.2026.17560

Image Credits: AI Generated

DOI: 10.3389/jpps.2026.17560

Keywords: type 2 diabetes, obesity, anti-obesity pharmacotherapy, multi-omics, precision medicine, incretin therapies, biomarkers, clinical trials, body composition, Diabesity, term, modern

The biological foundation for these effects lies in the incretin hormones themselves. GLP-1 is secreted by enteroendocrine L cells in the distal small intestine and colon, rising rapidly after meals rich in carbohydrates and fats. It enhances glucose-dependent insulin secretion, suppresses glucagon under hyperglycemic conditions, delays gastric emptying, and promotes satiety. GIP, its counterpart, is released by K cells in the duodenum and proximal jejunum and similarly boosts insulin secretion in a glucose-dependent manner. Both hormones are rapidly degraded by the enzyme dipeptidyl peptidase-4, which is why pharmaceutical versions have been engineered to resist degradation and act for days or weeks. Crucially, GLP-1 receptors are found not only in the pancreas but also in the gastrointestinal tract, the central nervous system, the heart, blood vessels, and the kidneys, providing a mechanistic basis for effects that extend well beyond blood sugar control.

The review details how GLP-1 receptor agonism may protect the cardiovascular system through several converging routes. Central receptor activation enhances satiety and reduces energy intake, and the resulting weight loss improves blood pressure, glycemic control, and lipid metabolism. Experimental and clinical evidence also points to direct anti-inflammatory, antioxidative, and vascular effects that improve endothelial function and attenuate fibrosis and cellular injury. In the kidneys, receptor activation promotes natriuresis, partly through modulation of sodium transport in the proximal tubule, and may influence kidney hemodynamics and glomerular hyperfiltration. However, the authors caution that GLP-1 receptor expression in the human kidney appears more restricted than previously assumed, meaning kidney protection likely arises from a combination of direct and indirect mechanisms, including improvements in glycemia, body weight, blood pressure, vascular function, and inflammation.

Tirzepatide occupies a distinct pharmacological position as a single peptide that activates both GIP and GLP-1 receptors. Pharmacological studies have shown an imbalanced signaling profile, with greater engagement of the GIP receptor than the GLP-1 receptor and distinct signaling properties at the latter. GIP receptors are expressed in pancreatic beta cells, adipose tissue, and brain regions involved in appetite regulation, and simultaneous activation of both receptors produces complementary effects on glucose regulation, energy intake, and body weight. This dual mechanism underpins the pronounced metabolic efficacy seen across the SURPASS and SURMOUNT trial programs, and it has fueled interest in whether such metabolic gains translate into cardiovascular and kidney protection.

The cardiovascular evidence for single GLP-1 receptor agonists is now firmly established. In the LEADER trial, liraglutide reduced the primary composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke with a hazard ratio of 0.87. REWIND showed a similar benefit for dulaglutide with a hazard ratio of 0.88, HARMONY Outcomes demonstrated a hazard ratio of 0.78 for albiglutide, and AMPLITUDE-O reported a hazard ratio of 0.73 for efpeglenatide. Semaglutide produced a hazard ratio of 0.74 in SUSTAIN-6, and the SELECT trial extended this benefit to people with overweight or obesity and established cardiovascular disease but without diabetes, with a hazard ratio of 0.80. The absence of diabetes in SELECT is particularly significant, demonstrating that glucose lowering is not required for cardiovascular benefit, although the trial does not establish independence from weight loss or other metabolic changes.

The kidney story has evolved more gradually and with important caveats. Early kidney findings from cardiovascular outcome trials were largely prespecified secondary or exploratory composites dominated by albuminuria, a frequent but relatively early marker of kidney damage. In LEADER, the kidney benefit was driven primarily by a reduction in new-onset persistent macroalbuminuria, while doubling of serum creatinine and end-stage kidney disease were not significantly reduced. REWIND showed a similar pattern, with the strongest effect on new macroalbuminuria and no individual significance for sustained eGFR decline or chronic kidney replacement therapy. The review emphasizes that improvement in albuminuria should not be considered equivalent to prevention of progressive loss of kidney function, a distinction that separates the earlier evidence from the dedicated kidney outcome trial FLOW.

FLOW changed the landscape by making chronic kidney disease progression the primary focus. In patients with type 2 diabetes and chronic kidney disease, semaglutide reduced the composite of kidney failure, sustained 50 percent or greater reduction in eGFR, or death from kidney-related or cardiovascular causes by 24 percent, with a hazard ratio of 0.76. Cardiovascular mortality fell with a hazard ratio of 0.71, all-cause mortality with 0.80, and the mean annual decline in eGFR was 1.16 milliliters per minute per 1.73 square meters per year less steep than with placebo. A subsequent prespecified participant-level pooled analysis of SELECT, FLOW, and SOUL, encompassing 30,787 participants across different formulations, doses, and diabetes statuses, found a 16 percent reduction in a harmonized kidney composite, with the association persisting even when cardiovascular death was excluded from the endpoint.

For tirzepatide, the cardiovascular evidence is expanding but remains qualitatively different. The SURPASS-CVOT trial directly compared tirzepatide with dulaglutide in patients with type 2 diabetes and established atherosclerotic cardiovascular disease, finding non-inferiority but not statistical superiority for major adverse cardiovascular events despite greater reductions in body weight and HbA1c. This finding illustrates a central theme of the review: greater metabolic efficacy does not necessarily translate proportionally into greater reduction in hard cardiovascular outcomes. In contrast, the SUMMIT trial produced particularly encouraging results in obesity-related heart failure with preserved ejection fraction, reducing the composite risk of cardiovascular death or worsening heart failure, an effect driven primarily by fewer worsening heart failure events rather than a standalone reduction in cardiovascular mortality.

The kidney evidence for tirzepatide remains the least mature component of its profile. Post-hoc analyses of SURPASS-4 suggest slower eGFR decline, reduced albuminuria, and a lower risk of composite kidney endpoints compared with insulin glargine, and a separate analysis using cystatin C-based estimates supported slower kidney function decline. However, these findings derive from trials not designed or powered to evaluate chronic kidney disease progression, and the review stresses that they should be interpreted as supportive and hypothesis-generating rather than definitive. No dedicated kidney outcome trial exists for tirzepatide, in stark contrast to the FLOW evidence for semaglutide.

The review also addresses combination therapy, safety, and future directions. Contemporary guidelines, including the 2026 AHA/ACC/ADA/ASN guideline, support the use of SGLT2 inhibitors, GLP-1-based therapies, or both in appropriate patients, and meta-analytic evidence suggests GLP-1 receptor agonist benefits are preserved during background SGLT2 inhibitor treatment, although the precise magnitude of incremental benefit from combination therapy remains uncertain. Gastrointestinal adverse events remain the most frequent tolerability limitation, concentrated during dose escalation, while meta-analyses have identified increased risks of gallbladder and biliary disease with both drug classes. Acute pancreatitis has not shown a statistically significant increase in trial meta-analyses, and the excess diabetic retinopathy complications seen with semaglutide in SUSTAIN-6 appear concentrated among patients with pre-existing retinopathy and rapid glycemic improvement. Looking ahead, the triple agonist retatrutide, targeting GLP-1, GIP, and glucagon receptors, is being evaluated in the ongoing TRIUMPH-Outcomes trial, and the authors argue that treatment selection should ultimately follow a phenotype-oriented framework in which the choice of incretin-based therapy reflects the clinical outcome most important to modify, the maturity of evidence supporting that outcome, and patient-specific characteristics rather than metabolic potency alone.

Subject of Research: Cardiovascular and kidney effects of GLP-1 receptor agonists and tirzepatide in cardiovascular-kidney-metabolic syndrome

Article Title: Beyond glycemic control: cardiovascular and kidney benefits of GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonist tirzepatide: a narrative review

Article References: Kierzkowski, F., Skrzypek, W., Bryl, W., Paczkowska, A., & Hoffmann, K. (2026). Beyond glycemic control: cardiovascular and kidney benefits of GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonist tirzepatide: a narrative review. Frontiers in Endocrinology, 17, Article 1977433. https://doi.org/10.3389/fendo.2026.1977433

Image Credits: AI Generated

DOI: 10.3389/fendo.2026.1977433

Keywords: GLP-1 receptor agonists, tirzepatide, semaglutide, cardiovascular-kidney-metabolic syndrome, chronic kidney disease, obesity, type 2 diabetes, heart failure with preserved ejection fraction, FLOW trial, SELECT trial, SURPASS-CVOT, incretin therapies

The scientific backdrop is striking. Years before pivotal trial data existed, researchers including Ronald Grunstein and colleagues argued in the journal Sleep that incretin-based pharmacotherapy could positively disrupt the management of obesity-related sleep apnea, challenging the field’s heavy reliance on mechanical therapies and its limited engagement with weight management as a principal therapeutic strategy. That prediction has now matured into clinical reality. Tirzepatide, a dual agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, produces substantial weight reduction, and the SURMOUNT-OSA program demonstrated meaningful reductions in sleep-disordered breathing measures among participants with obesity. Secondary analyses published in Nature Medicine have extended the picture, linking tirzepatide to improvements in obstructive sleep apnea-related cardiometabolic risk markers. For a disorder in which excess adipose tissue drives airway collapse through anatomical loading, reduced lung volumes, and inflammatory and ventilatory effects, a drug that targets the underlying biology is not simply an adjunct. It is, for some patients, a disease-modifying therapy.

Yet the editorial’s central argument is not a celebration of pharmacology. It is a careful examination of professional boundaries. Sleep medicine specialists, the authors acknowledge, may feel conflicted about prescribing obesity-directed pharmacotherapy to improve sleep apnea. The sources of that conflict are concrete: uncertainty about scope of practice, weight stigma, operational burden, access and cost concerns, and limited training in weight management. For many sleep clinicians, the new era requires a shift from counseling patients about weight and referring medication management elsewhere, toward deciding which parts of weight management now belong within sleep medicine itself. Prescribing medication, the authors note, is generally within the legal reach of physicians, which makes this boundary more difficult to draw than those involving oral appliance fabrication or upper-airway surgery, where specialized technical skills clearly separate the fields.

To frame the problem, the editorial offers a geometric metaphor that is likely to circulate widely in sleep medicine education. Picture two overlapping circles. One circle is sleep medicine: diagnosis of sleep apnea, physiologic phenotyping, symptom assessment, positive airway pressure therapy, oral appliance therapy, surgical referral, adherence support, and objective reassessment of sleep-disordered breathing. The second circle is obesity medicine and metabolic care: obesity diagnosis and staging, pharmacotherapy, nutrition, physical activity, behavioral support, medication safety, cardiometabolic risk management, bariatric surgery referral, and weight maintenance. The overlap between the two circles is what the authors call obesity-informed sleep apnea care, and it is in this intersection that the future of the specialty is being negotiated.

Crucially, the authors insist that this overlap does not require every sleep physician to become an obesity medicine specialist. What it does require is enough competence, structure, and humility to guide patients through a therapy that now directly touches the sleep disorder being treated. In the overlap zone, sleep clinicians identify patients with sleep apnea and obesity who may benefit from weight-based therapy, counsel without stigma, explain that weight loss may improve but not necessarily eliminate sleep apnea, integrate pharmacologic weight-loss therapy with positive airway pressure and other established treatments, monitor sleep-specific outcomes, and determine when repeat sleep testing is needed. The editorial is equally clear about what should not happen. Abdication, treating obesity pharmacotherapy as someone else’s concern even when it alters apnea severity, symptoms, hypoxic burden, and follow-up testing, serves no one. Neither does overreach, the assumption that every sleep physician must deliver comprehensive obesity care.

The distinction between the overlap zone and comprehensive obesity medicine is drawn with technical precision. Full obesity medicine encompasses complete obesity staging, long-term pharmacologic management across multiple indications, complex adverse-effect monitoring, nutritional assessment, medication interactions, eating disorder concerns, pregnancy considerations, bariatric surgery selection, weight-regain management, stigma management, and longitudinal cardiometabolic care. Some sleep physicians may pursue this deeper expertise, including formal certification through the American Board of Obesity Medicine, a pathway the authors encourage. But they argue that such certification should not define the minimum identity of a sleep specialist. The analogy they invoke is restless legs syndrome, a condition in which sleep clinicians routinely evaluate iron status and prescribe iron therapy while recognizing that complex anemia, malabsorption, pregnancy, or kidney disease may require broader medical evaluation. The boundary, they write, is neither abandonment nor annexation. It is competent ownership of the sleep-relevant problem, with collaboration when the underlying condition exceeds sleep-specific expertise.

From this conceptual framework, the editorial derives a practical implementation model with three layers. The first is universal sleep medicine competency: every sleep physician should understand obesity as a chronic, biologically mediated disease rather than a failure of willpower, know the sleep apnea-relevant evidence for incretin-based therapies, counsel respectfully, recognize when medication may enter the treatment conversation, and know when to refer. The second is structured co-management, in which sleep centers build explicit pathways with primary care, endocrinology, obesity medicine, clinical pharmacy, nutrition, behavioral health, and bariatric surgery. The third is advanced sleep-obesity practice, in which some programs pursue deeper expertise through obesity medicine certification or establish embedded metabolic sleep clinics. This tiered architecture acknowledges the variable readiness of practices, from referral-only models to fully integrated metabolic sleep programs, and it converts a broad clinical question into an actionable agenda.

The institutional machinery behind this shift is already in motion. The American Academy of Sleep Medicine convened an Obesity Management Task Force in 2025 to discover emerging best practices, develop practical member resources, and propose a longer-term strategy. The task force curated physician- and patient-facing resources, modeled obesity management approaches across different practice settings, and surveyed Academy members about readiness, barriers, and implementation needs. In March 2026, the AASM Obesity Management Strategy Summit brought together task force members, Academy leadership and staff, and invited stakeholders from obesity medicine, bariatric surgery, endocrinology, nutrition, and patient advocacy. Through foundational presentations, small-group discussions, multivoting, and effort-impact prioritization, participants identified gaps and staged potential responses. The resulting summit summary, the editorial argues, is more than a meeting report; it is a field map showing where consensus is emerging, where evidence remains incomplete, and where implementation will demand shared work across clinical guidance, education, referral pathways, insurance coverage, stigma reduction, patient engagement, and workforce development.

The educational implications reach into the structure of training itself. The authors call for fellowship curricula that address the bidirectionality of obesity and sleep apnea, weight management pharmacotherapy, respectful communication, medication safety, outcome monitoring, and collaborative care models. Continuing education should help practicing clinicians understand indications, risks, monitoring requirements, and referral thresholds. Future clinical guidelines, they argue, must specify how pharmacologic weight management integrates with positive airway pressure, oral appliances, surgery, positional therapy, and follow-up testing. Accredited sleep centers, they suggest, may eventually need to demonstrate not that they prescribe obesity medications, but that they maintain a coherent pathway for patients who have both sleep apnea and obesity. The textbook of five years from now, the editorial predicts, should contain a serious section on metabolic sleep medicine covering obesity physiology, incretin-based therapies, bariatric surgery outcomes, indications and contraindications for medical or surgical obesity treatment, repeat testing after weight loss, residual sleep apnea, equity of access, stigma, and adherence, without becoming a bariatric medicine textbook in its own right.

The deeper significance of this editorial lies in how it reframes a therapeutic disruption as an exercise in professional self-definition. Grunstein and colleagues originally asked whether incretin-based pharmacotherapy would be a revolution or a pipe dream. The answer, the authors conclude, is neither fantasy nor simple replacement of existing therapies. It is a disruption that demands clinical architecture: clear decisions about which parts of obesity management are necessary for excellent sleep apnea care, which require structured collaboration, and which belong primarily to comprehensive obesity medicine. If sleep medicine answers that question with discipline, humility, and vision, the field can expand its therapeutic reach without losing its center of gravity, and millions of patients whose breathing pauses at night are driven by biology that a prescription can now address may finally receive care designed for the whole of their disease.

Subject of Research: Integration of obesity pharmacotherapy into obstructive sleep apnea care

Article Title: Obesity-informed OSA care: defining the expanding boundary of sleep medicine

Article References: Morgenthaler, T. I., Sepulveda, R., Bandyopadhyay, A., Hawa, R., Khan, S. S., Nowalk, N. C., Stager, L., Tadros, M., Tu, X., Vieira, N. M., & Wojeck, B. (2026). Obesity-informed OSA care: defining the expanding boundary of sleep medicine. Journal of Clinical Sleep Medicine, 22(1), Article 144. https://doi.org/10.1007/s44470-026-00157-w

Image Credits: AI Generated

DOI: 10.1007/s44470-026-00157-w

Keywords: obstructive sleep apnea, obesity medicine, tirzepatide, incretin therapies, sleep medicine, SURMOUNT-OSA, weight management, AASM, positive airway pressure, metabolic sleep medicine, clinical guidelines, medical education

The mechanistic foundations of the three drugs explain much of their divergent behaviour. Semaglutide is a human GLP-1 analog with 94 percent sequence identity to the native hormone, engineered with an Aib substitution at position 8 to resist degradation by the enzyme DPP-4 and a C18 fatty diacid side chain at position 26 that binds albumin and extends its half-life to roughly seven days. Liraglutide, with 97 percent homology, carries a shorter C16 palmitic acid chain that yields a half-life of about 13 hours, confining it to once-daily injection. Tirzepatide, a 39-amino-acid synthetic ‘twincretin’, activates both the GIP and GLP-1 receptors and carries a C20 fatty diacid moiety that prolongs systemic exposure to approximately five days. These structural choices dictate dosing convenience, adherence and, ultimately, how patients experience therapy.

Formulation differences add a practical dimension to drug selection. Semaglutide is the only agent in the class available as an oral tablet, made possible by the absorption enhancer SNAC, though oral bioavailability is only about one percent and the tablet must be taken fasting with water only. Subcutaneous semaglutide achieves roughly 89 percent bioavailability. Liraglutide requires daily subcutaneous injection, which may deter some patients, while tirzepatide is delivered exclusively as a once-weekly autoinjector. Real-world data show semaglutide achieves approximately 40 percent treatment persistence at one year, higher than liraglutide, and tirzepatide’s weekly dosing is expected to support strong adherence, though long-term real-world outcomes remain pending. Notably, liraglutide is the only one of the three approved for adolescents with both type 2 diabetes and obesity.

On glycaemic control, the review’s synthesis of trial data reveals a clear hierarchy. Subcutaneous semaglutide at 0.5 to 1.0 mg reduced HbA1c by 1.3 to 1.8 percent across the SUSTAIN program, outperforming placebo, sitagliptin, exenatide and basal insulin, while oral semaglutide achieved reductions of 1.3 to 2.0 percent in the PIONEER trials, edging out subcutaneous liraglutide 1.8 mg in PIONEER 4. Liraglutide, tested in the LEAD program at 1.2 and 1.8 mg, produced HbA1c reductions of 0.7 to 1.5 percent. Tirzepatide, however, set a new benchmark: in SURPASS-2, doses of 5, 10 and 15 mg lowered HbA1c by approximately 2.01, 2.24 and 2.30 percent respectively, surpassing semaglutide 1 mg, which achieved 1.86 percent. Pooled analyses indicate more than 90 percent of tirzepatide recipients reached the HbA1c target below 7.0 percent.

Weight outcomes follow a similar pattern. Semaglutide 2.4 mg weekly produced mean weight losses of up to 14.9 percent at 68 weeks in the STEP program and 10.2 percent over four years in the SELECT trial, accompanied by a 7.7 cm reduction in waist circumference. Liraglutide at 3.0 mg daily achieved approximately 4.91 kg of weight loss in meta-analysis, with BMI declines and waist reductions around 3.55 cm. Tirzepatide again led the field: SURPASS trials recorded weight reductions ranging from 5.3 to 17.1 kg depending on dose and comparator, and in the SURMOUNT-4 trial participants with obesity maintained mean reductions of approximately 20.9 percent at 88 weeks. A SURPASS-3 substudy further showed tirzepatide reduced hepatic fat and visceral adipose tissue, with waist circumference falling by up to 18.5 cm at the highest dose.

Lipid modulation, a subtler but clinically relevant domain, also favoured the dual agonist. Semaglutide produced modest reductions of roughly 3 to 6 percent in total cholesterol, 5 to 10 percent in LDL cholesterol and 10 to 15 percent in triglycerides, with slight HDL increases, mechanisms attributed to reduced free fatty acid influx to the liver and enhanced lipoprotein lipase activity. Liraglutide showed mild improvements, particularly in triglycerides and apolipoprotein B, with dose-dependent variability. Tirzepatide delivered the most pronounced effects: meta-analytic estimates showed triglyceride reductions of 13 to 22 percent, total cholesterol reductions of roughly 5 to 7 percent, and HDL increases of 4 to 7 percent, alongside reductions in large triglyceride-rich lipoproteins and small LDL particles. The authors caution, however, that these are surrogate markers whose translation into fewer cardiovascular events remains unproven.

Where hard clinical outcomes exist, the picture becomes more differentiated. In the SUSTAIN-6 cardiovascular outcomes trial, semaglutide reduced three-point major adverse cardiovascular events—cardiovascular death, nonfatal myocardial infarction and nonfatal stroke—by 26 percent, with post hoc analyses suggesting a roughly 35 percent reduction in stroke incidence, the strongest cerebrovascular signal in the class. Liraglutide, in the landmark LEADER trial, achieved a 13 percent MACE reduction driven primarily by significant reductions in cardiovascular death, making it particularly relevant for patients whose dominant risk is mortality. Tirzepatide has not yet completed a dedicated outcomes trial, but a pre-specified meta-analysis of pooled SURPASS data, including the high-risk SURPASS-4 cohort, reported a 27 percent relative risk reduction in three-point MACE and a 46 percent reduction in four-point MACE—promising signals awaiting confirmation from the ongoing SURPASS-CVOT.

Kidney outcomes reveal mechanistic distinctions with direct clinical implications. Semaglutide cut the risk of new or worsening nephropathy by 36 percent in SUSTAIN-6, slowed eGFR decline in pooled analyses, and extended renal protection to non-diabetic individuals with cardiovascular disease in the SELECT trial, suggesting partially glucose-independent benefit. Liraglutide reduced nephropathy risk by 22 percent in LEADER, but its effect appears largely mediated by improved glycaemic control and blood pressure rather than direct nephroprotection. Tirzepatide, studied in SURPASS-4’s chronic kidney disease cohort, attenuated eGFR decline and reduced macroalbuminuria across all doses, and causal mediation analysis indicated that only 40 to 60 percent of the renal benefit was explained by traditional factors such as HbA1c, blood pressure and weight—implying a substantial glucose-independent component that may make it especially valuable for patients with diabetic kidney disease.

Safety profiles across the class are broadly favourable, dominated by gastrointestinal effects. Nausea, vomiting and diarrhoea are common with all three agents, typically arising during dose escalation and subsiding within four to eight weeks with gradual titration. Tirzepatide produces the highest frequency and severity of gastrointestinal events, including constipation, likely reflecting its GIP receptor activity, followed by semaglutide and then liraglutide, which tends to cause milder, more gradual symptoms. Gallbladder events such as cholelithiasis have been observed with all agents, largely associated with rapid weight loss, and pancreatitis is rare. Hypoglycaemia is uncommon unless the drugs are combined with insulin or sulfonylureas. All three are contraindicated in individuals with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2. In renal impairment, tirzepatide maintains stable pharmacokinetics even in dialysis patients, an advantage over semaglutide and liraglutide, which require caution in end-stage renal disease.

The review’s overarching conclusion is a call for calibrated clinical judgement rather than a declaration of winners. Tirzepatide demonstrably offers the greatest HbA1c and weight reductions, semaglutide combines substantial efficacy with formulation flexibility and the best stroke evidence, and liraglutide provides a proven mortality benefit with the broadest paediatric indication. Yet because every comparison in the analysis is indirect—drawn from separate trials with different populations, comparators and endpoints—the authors insist the findings should be treated as hypothesis-generating, not definitive proof of superiority. They identify direct head-to-head trials, particularly tirzepatide versus higher-dose semaglutide, long-term cardiovascular and renal outcome data for tirzepatide, and evidence in underrepresented populations as critical gaps. Until those trials report, treatment decisions must remain individualized, weighing comorbidities, renal function, tolerability, dosing preferences and each patient’s therapeutic priorities.

Subject of Research: Comparative cardiometabolic effects of the incretin-based therapies semaglutide, liraglutide and tirzepatide in type 2 diabetes and obesity

Article Title: Impact of Semaglutide, Liraglutide and Tirzepatide on Cardiometabolic Outcomes: A Comparative Narrative Review

Article References: Bawadi, H., Abuhijleh, H., Nofal, M., Zakaria, Z. Z., & Al‐Asmakh, M. (2026). Impact of Semaglutide, Liraglutide and Tirzepatide on Cardiometabolic Outcomes: A Comparative Narrative Review. Endocrinology, Diabetes & Metabolism, 9(5), Article e70338. https://doi.org/10.1002/edm2.70338

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DOI: 10.1002/edm2.70338

Keywords: semaglutide, liraglutide, tirzepatide, GLP-1 receptor agonists, type 2 diabetes, obesity, HbA1c, weight loss, cardiovascular outcomes, renal function, lipid profile, incretin therapies

The study, led by Chia Siang Kow and colleagues, took a fresh statistical look at the six clinical studies and ten intervention arms that tracked semaglutide or tirzepatide after treatment discontinuation, drawing on data covering 1776 participants. Rather than relying on simple pooled averages, the researchers reconstructed the arm-level data and applied a Bayesian hierarchical longitudinal model, a statistical framework that jointly models repeated measurements over time while explicitly accounting for variability between study arms. This approach allowed the team to go beyond asking how many kilograms are regained each month and instead translate the trajectory into clinically meaningful milestones, complete with full probability distributions that quantify uncertainty.

The headline finding is that people who stop taking these medications regain an estimated 1.04 kilograms per month on average, with a 95 percent credible interval of 0.80 to 1.29 kilograms per month. The modelled average participant had lost 15.35 kilograms by the time treatment ended. Under the linear model assumed by the researchers, half of that hard-won loss was projected to return within about 7.5 months, and participants were projected to be back at their baseline weight by roughly 15 months after stopping. In practical terms, the clock on the treatment’s benefits starts ticking almost the moment the final injection wears off.

The month-by-month trajectory is particularly striking. Within the follow-up window actually observed in the trials, which extended to 52 weeks, the modelled average weight change was still below baseline at six months, at minus 9.12 kilograms, but by then approximately 41 percent of the initial weight loss had already been regained. At nine months the average was minus 6.01 kilograms, corresponding to 62 percent regained, and by twelve months the average stood at minus 2.90 kilograms, meaning roughly 83 percent of the lost weight had returned. The posterior probability that the average trajectory had regained at least half of the initial weight loss climbed from just 12.5 percent at six months to 86.7 percent at nine months and a near-certain 99.5 percent at one year.

It is important to understand the mathematical machinery behind these numbers. The researchers assumed a constant linear regain slope rather than a curving trajectory, a choice justified because follow-up data were sparse and a prior systematic review had found that adding a nonlinear term did not improve model fit. Each study arm was treated as a repeated-measures trajectory with its own random effects for both the weight loss present at discontinuation and the subsequent regain rate. The Bayesian estimation relied on full Markov chain Monte Carlo sampling, with convergence confirmed by R-hat statistics hovering at approximately 1.00 and large effective sample sizes for the key slope parameters. Estimates extending beyond the maximum observed follow-up of 52 weeks, including the projected return to baseline at 15 months, are explicitly flagged as extrapolations of the average trajectory rather than directly observed outcomes.

One of the most provocative aspects of the analysis is its comparison of the two drugs. Tirzepatide arms showed a numerically faster unadjusted regain rate of 1.10 kilograms per month compared with 0.89 kilograms per month for semaglutide, and projected return to baseline was correspondingly sooner, at roughly 14.5 months versus 17.3 months. But when the researchers adjusted for the magnitude of initial weight loss and post-discontinuation support in a Bayesian meta-regression, the drug difference essentially vanished. The adjusted effect of tirzepatide versus semaglutide was a negligible minus 0.04 kilograms per month, with a posterior probability of only 40.2 percent that tirzepatide regains faster. In other words, the apparent difference in rebound between the two drugs likely reflects differences in how much weight was lost in the first place, not any inherent difference in the physiology of regain.

That observation points to one of the study’s most interesting exploratory findings: greater initial weight loss was itself the strongest directional predictor of faster absolute regain. Each additional 5 kilograms of weight lost during treatment was associated with a 0.20 kilograms per month faster regain slope, a result carrying a 92.1 percent posterior probability, though the credible interval included zero. The authors caution that this association may partly reflect mathematical coupling, since a larger initial loss simply creates more opportunity for absolute regain. Meanwhile, behavioural or lifestyle support after discontinuation showed a directional association with slower regain, an estimated effect of minus 0.19 kilograms per month with an 87.2 percent probability of benefit, but the imprecise estimate means the finding remains inconclusive. With only ten intervention arms available, all meta-regression results are explicitly exploratory and hypothesis-generating rather than definitive.

Sensitivity analyses reinforced the robustness of the core conclusion. A contrast analysis using the randomised differences between intervention and control arms showed a similar direction of effect, though with less precision. A post hoc analysis excluded the three SURPASS-1 arms, which came from a trial of adults with Type 2 diabetes receiving tirzepatide as glucose-lowering monotherapy rather than for weight management. Excluding those arms left the monthly regain slope essentially unchanged at 0.95 kilograms per month, though the projected time to 50 percent regain lengthened to 9.42 months because the average initial weight loss among the remaining arms was greater. The qualitative message of rapid regain survived every stress test the researchers applied.

The clinical implications are considerable. Because discontinuation is common in routine practice, driven by cost, tolerability problems, access restrictions, treatment fatigue and genuine uncertainty about how long therapy should last, the findings suggest that clinicians should plan proactive monitoring within the first several months after stopping treatment, when early regain can be identified and maintenance strategies reassessed. The authors are careful to note that their data do not determine whether dose tapering, lower-dose maintenance, drug switching, intermittent treatment or any specific behavioural programme can prevent regain; those questions require dedicated trials. They also stress that the analysis captured body-weight trajectories only, so any statements about cardiometabolic benefits, cost-effectiveness or the consequences of fixed-duration treatment policies remain hypotheses informed by the weight pattern rather than direct findings.

What the study ultimately delivers is a statistically rigorous quantification of something patients and clinicians have long suspected: incretin-based anti-obesity medications suppress appetite and enable weight loss while they are active, and withdrawing that physiological support removes the very mechanism holding the weight down. Between-study heterogeneity was real but moderate, with a between-arm standard deviation of 6.78 kilograms for initial weight loss and 0.26 kilograms per month for the regain slope, suggesting that while individual experiences vary, the average trajectory is consistently steep. As these drugs reshape obesity medicine and public expectations, the analysis argues that their long-term value must be judged not only by the dramatic losses achieved during treatment but by an honest accounting of what follows when the treatment ends, and by research that extends follow-up beyond one year, reports regain in both absolute and percentage terms, and directly tests the maintenance strategies that patients will increasingly demand.

Subject of Research: Weight regain after discontinuation of the incretin-based anti-obesity medications semaglutide and tirzepatide

Article Title: Weight Regain Trajectories After Discontinuation of Semaglutide or Tirzepatide: A Reconstructed Aggregate‐Data Bayesian Longitudinal Meta‐Analysis

Article References: Kow, C. S., Thiruchelvam, K., Ramachandram, D. S., & Zaihan, A. F. (2026). Weight Regain Trajectories After Discontinuation of Semaglutide or Tirzepatide: A Reconstructed Aggregate‐Data Bayesian Longitudinal Meta‐Analysis. Endocrinology, Diabetes & Metabolism, 9(5), Article e70325. https://doi.org/10.1002/edm2.70325

Image Credits: AI Generated

DOI: 10.1002/edm2.70325

Keywords: semaglutide, tirzepatide, weight regain, obesity, incretin therapies, GLP-1 receptor agonists, Bayesian meta-analysis, treatment discontinuation, weight loss maintenance, anti-obesity pharmacotherapy, Weight, Regain