Estimating Cardiovascular Benefits of Tirzepatide in Sleep Apnea and Obesity: Insight from the SURMOUNT-OSA Trials.

PURPOSE OF COMMENTARY: This commentary aims to offer a perspective on the effect of tirzepatide on hypoxic burden and provide indirect evidence of cardiovascular risk reduction after tirzepatide for the treatment of obstructive sleep apnea and obesity. It also discusses the role of tirzepatide-induced weight loss in the management of obstructive sleep apnea. RECENT FINDINGS: In the SURMOUNT-OSA phase 3 trials, tirzepatide, a new GIP/GLP-1 receptor co-agonist, reduced the apnea-hypopnea index, hypoxic burden, and body weight in adults with moderate-to-severe obstructive sleep apnea and obesity. The change in apnea-hypopnea index is clinically relevant, but its impact on cardiovascular mortality remains unclear. Conversely, hypoxic burden predicts cardiovascular mortality across populations independent of AHI. We attempted to postulate the magnitude of cardiovascular benefits of tirzepatide based on the reduction in hypoxic burden. Tirzepatide treatment for obstructive sleep apnea and obesity seems to result in hypoxic burden values associated with a lower cardiovascular mortality rate and thus might attenuate the negative cardiovascular impact of hypoxic burden.

A Rare Case of Tirzepatide-Induced Hepatotoxicity.

Tirzepatide is the first dual incretin glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor activator approved for the management of type II diabetes mellitus. This drug was also recently approved by the Food and Drug Administration as a management option for patients with obesity. Tirzepatide has been also reported to be beneficial in reducing liver fat content. Although its efficacy is well described in the literature, no cases of tirzepatide-induced hepatotoxicity have been reported. We report a case of a 37-year-old woman with metabolic syndrome who was noted to have elevated liver enzymes secondary to tirzepatide use.

Tirzepatide Prescribing Practices and Efficacy in Patients with Diabetes and Chronic Kidney Disease at a Large Tertiary Care Center in the United States.

Purpose: Chronic kidney disease is a frequent complication of diabetes mellitus. Tirzepatide is the first dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for glycemic control in patients with type 2 diabetes. We present the efficacy and prescribing practices of tirzepatide in a cohort with diabetes and chronic kidney disease in a large tertiary care setting. Methods: We retrospectively identified new outpatient tirzepatide prescriptions in adults ≥18 years with diabetes and chronic kidney disease stages 1-5 from 2022 to 2023 across the Barnes Jewish Hospital system (St Louis, Missouri). Results: We identified 102 subjects with chronic kidney disease and diabetes who started tirzepatide between 2022 and 2023, and used for ≥6 months. Mean duration of tirzepatide use in our cohort was 13.89 ± 2.51 months. Among subjects who stopped, 57% (n=4) were due to limited medication availability or lack of insurance coverage. Tirzepatide use led to a significant reduction in hemoglobin A1c by 1.15%, weight by nearly 10%, systolic and diastolic blood pressure, and total cholesterol (p<0.05 for all). Conclusion: We found that tirzepatide was an effective therapy with significant benefits on glycemic control, blood pressure, cholesterol, and weight in subjects with diabetes and chronic kidney disease treated at a tertiary care facility.

Tirzepatide as an innovative treatment strategy in a pre-clinical model of obesity-driven endometrial cancer.

OBJECTIVE: Interventions that combat obesity and its associated metabolic perturbations may decrease incidence and improve outcomes of endometrial cancer (EC). Potential options for weight loss include pharmacotherapeutic interventions such as tirzepatide, a dual-acting glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) receptor agonist. Given this, we explored the anti-obesity and anti-tumorigenic effects of tirzepatide in our pre-clinical mouse model of endometrioid EC. METHODS: Starting at 4 weeks of age, Lkb1fl/flp53fl/fl mice were fed a low-fat diet vs a high-fat diet to generate a lean or obese phenotype. Nine weeks after induction of EC, obese and lean mice were randomized to receive tirzepatide for 4 weeks. Body and tumor weights, tumor transcriptomic and metabolomic profiles, and serum metabolic markers and chemokines were assessed. RESULTS: Both obese and lean mice began to lose body weight after 2 weeks of tirzepatide treatment, ultimately achieving a significant weight loss of 20.1 % in obese mice and 16.8 % in lean mice. Tirzepatide improved obesity-induced serum adiponectin, leptin, GIP, and C-reactive protein levels. Furthermore, tirzepatide relative to vehicle, effectively reduced tumor growth in obese and lean mice, inhibited the ErbB signaling and glycolysis/gluconeogenesis in tumors of obese mice, and increased O-linked glycosylation biosynthesis and phospholipase D signaling in tumors of lean mice. CONCLUSION: Tirzepatide decreased both mouse weight and tumor growth via effects on metabolic and immune pathways in the EC tumors that differed between obese and lean mice. This novel weight loss treatment deserves further evaluation as an innovative strategy in the management of EC.

Semaglutide Versus Other Glucagon-Like Peptide-1 Agonists for Weight Loss in Type 2 Diabetes Patients: A Systematic Review and Meta-Analysis.

Obesity places patients at higher risk for numerous problems, including prediabetes, type 2 diabetes mellitus (T2DM), hypertension, metabolic syndrome, cardiovascular disease, and nonalcoholic fatty liver disease. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are antidiabetic drugs that have a recognized effect on weight loss. This systematic review analyzed semaglutide against alternative GLP-1 agonists in facilitating weight loss and evaluated their associated adverse events (AEs) in diabetic patients. A systematic search following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was performed using PubMed, Embase, and Cochrane Library for studies comparing semaglutide and other GLP-1 RAs for weight loss. A narrative synthesis and meta-analysis using SPSS program version 29 were performed to analyze the differences in weight loss between cohorts. Nine studies with 5,445 patients whose mean age was 60.01 years (55.5-70) and mean follow-up of 32.5 weeks (4-58.7) were included. The meta-analysis showed that semaglutide had a greater mean weight loss compared to liraglutide (-6.08, 95% confidence interval (Cl) = -8.40, -3.75) and dulaglutide (-2.85, 95% CI = -5.59, 0.11). Tirzepatide had a greater mean weight loss compared to semaglutide (-3.78, 95% CI = -5.52, -2.04). Common AEs included minor and moderate gastrointestinal events. In conclusion, GLP-1 RAs have shown efficacy in reducing body weight in T2DM patients. Semaglutide, liraglutide, dulaglutide, tirzepatide, and exenatide demonstrated mean weight loss reductions of 4.81 kg, 2.81 kg, 4.03 kg, 9.7 kg, and 1.9 kg, respectively, with high rates of minimal to moderate-severity AEs. Semaglutide demonstrated increased numerical weight loss compared to its comparators (dulaglutide, liraglutide, and exenatide). However, tirzepatide, a dual-agonist, produced greater weight loss compared to semaglutide. The paucity of comparative head-to-head trials prevents a definitive conclusion of the superiority of one GLP-1 RA over another.

Decreased risk of recurrent acute pancreatitis with semaglutide and tirzepatide in people with type 2 diabetes or obesity with a history of acute pancreatitis: A propensity matched global federated TriNetX database-based retrospective cohort study.

BACKGROUND: Acute pancreatitis (AP) is a significant health concern with potential for recurrent episodes and serious complications. The risk of recurrence in type 2 diabetes (T2D) or obesity can be influenced by various factors and treatments, including GLP-1 receptor agonists (GLP-1RAs). This study evaluates the risk of recurrent AP among patients with a history of the condition, focusing on the effects of different GLP-1RA treatments. OBJECTIVES: Our objective is to compare the recurrence risks of AP between patients treated with different GLP-1RAs. METHODS: We conducted a retrospective cohort study using the TriNetX platform, encompassing 258,238 individuals with T2D or obesity who have a history of AP. We assessed the recurrence of AP over a five-year period, analyzing data on treatment regimens, with a focus on the use of Semaglutide, Tirzepatide, and other GLP-1RAs. RESULTS: GLP-1RA users experienced significantly lower recurrence rates of AP, with those without risk factors showing GLP-1RA users had a recurrence rate of 13.8 % compared to 40.9 % for non-users. Semaglutide and Tirzepatide showed the most favorable outcomes; Semaglutide users had lower recurrence rates than Exenatide (10.1 % vs. 27 %) and slightly lower than Dulaglutide (13.6 % vs. 15.4 %), though not statistically significant with Dulaglutide. Tirzepatide users displayed the lowest recurrence risk at 6.2 %, significantly lower than those on Semaglutide (11.7 %). CONCLUSIONS: GLP-1RAs, particularly Semaglutide and Tirzepatide, are associated with a reduced risk of recurrent AP in people with T2D or obesity. The differential risk profile between these drugs highlights the need for further studies and personalized treatment plans.

Modern Challenges in Type 2 Diabetes: Balancing New Medications with Multifactorial Care.

Type 2 diabetes mellitus (T2DM) is a prevalent chronic metabolic disorder characterized by insulin resistance and progressive beta cell dysfunction, presenting substantial global health and economic challenges. This review explores recent advancements in diabetes management, emphasizing novel pharmacological therapies and their physiological mechanisms. We highlight the transformative impact of Sodium-Glucose Cotransporter 2 inhibitor (SGLT2i) and Glucagon-Like Peptide 1 Receptor Agonist (GLP-1RA), which target specific physiological pathways to enhance glucose regulation and metabolic health. A key focus of this review is tirzepatide, a dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors. Tirzepatide illustrates how integrating innovative mechanisms with established physiological pathways can significantly improve glycemic control and support weight management. Additionally, we explore emerging treatments such as glimins and glucokinase activators (GKAs), which offer novel strategies for enhancing insulin secretion and reducing glucose production. We also address future perspectives in diabetes management, including the potential of retatrutide as a triple receptor agonist and evolving guidelines advocating for a comprehensive, multifactorial approach to care. This approach integrates pharmacological advancements with essential lifestyle modifications-such as dietary changes, physical activity, and smoking cessation-to optimize patient outcomes. By focusing on the physiological mechanisms of these new therapies, this review underscores their role in enhancing T2DM management and highlights the importance of personalized care plans to address the complexities of the disease. This holistic perspective aims to improve patient quality of life and long-term health outcomes.

Risk of major adverse cardiovascular events and all-cause mortality under treatment with GLP-1 RAs or the dual GIP/GLP-1 receptor agonist tirzepatide in overweight or obese adults without diabetes: a systematic review and meta-analysis.

Background: Among the currently approved antiobesity medications, the glucagon-like-peptide-1 receptor-agonists (GLP-1 RAs) liraglutide and semaglutide, and the dual glucose-dependent-insulinotropic-polypeptide (GIP)/GLP-1 RA tirzepatide have been suggested to reduce cardiovascular-risk in overweight or obesity without diabetes. Objectives: The objective of this study was to evaluate the cardio- and neuroprotective potential of these novel agents in the nondiabetic overweight/obese adult population. Data sources and methods: A systematic review and meta-analysis of randomized-controlled clinical trials (RCTs) was performed to estimate the risk of major adverse cardiovascular events (MACE), all-cause and cardiovascular mortality in overweight or obese adults without diabetes treated with GLP-1 or GIP/GLP-1 RAs (vs placebo). Secondary outcomes included the risk of myocardial infarction (MI) and stroke. Results: Sixteen RCTs (13 and 3 on GLP-1 RAs and tirzepatide, respectively) comprising 28,168 participants were included. GLP-1 or GIP/GLP-1 RAs reduced MACE (odds ratio (OR): 0.79; 95% confidence interval (CI): 0.71-0.89; p < 0.01; I 2 = 0) and all-cause mortality (OR: 0.80; 95% CI: 0.70-0.92; p < 0.01; I 2 = 0), while there was a trend toward lower cardiovascular-mortality (OR: 0.84; 95% CI: 0.71-1.01; p = 0.06; I 2 = 0%) compared to placebo. Additionally, GLP-1 or GIP/GLP-1 RAs reduced the odds of MI (OR: 0.72; 95% CI: 0.61-0.86; p < 0.01; I 2 = 0%) and nonfatal-MI (OR: 0.72; 95% CI: 0.61-0.85; p < 0.01; I 2 = 0%); while no associations between antiobesity treatment and fatal-MI, stroke, nonfatal, or fatal stroke were uncovered. Conclusion: GLP-1 and GIP/GLP-1 RAs reduce cardiovascular-risk and all-cause mortality in overweight or obese adults without diabetes. Additionally, GLP-1 RAs and GIP/GLP-1 RAs attenuate the risk of MI. Since data on stroke are still limited, future RCTs are warranted to evaluate the neuroprotective potential of these novel antiobesity agents. Trial registration: PROSPERO CRD42024515966.

Real-World Impact of GLP-1 Receptor Agonists on Endoscopic Patient Outcomes in an Ambulatory Setting: A Retrospective Study at a Large Tertiary Center.

Background: Glucagon-like peptide receptor agonists (GLP-1 RAs) are associated with delayed gastric emptying and may increase the risk of aspiration due to retained gastric contents. There are no guidelines on peri-endoscopic use of GLP-1 RAs, and real-world outcomes in an ambulatory setting remain unknown. This study reports real-world data from an ambulatory center associated with a large tertiary hospital. Methods: A retrospective review of electronic medical records was conducted for patients who underwent esophagogastroduodenoscopy (EGD) at a hospital-based outpatient center from January to June 2023. Exclusions included non-elective procedures, current opioid use, altered foregut anatomy, and known gastroparesis. All patients were on GLP-1 RAs before endoscopy and followed standard fasting protocols. Adverse event rates were recorded, and patients were divided into cohorts based on GLP-1 RA use. Univariate and multivariate regression analyses identified risk factors for food retention and complications. Results: A total of 1438 patients underwent elective EGD during the study period. Among the 1046 patients included, 73 (7%) were on GLP-1 RAs. The procedure was aborted in four patients (0.4%) due to gastric food retention, with two (50%) on GLP-1 RAs. Independent risk factors for food retention included GLP-1 RA use (OR: 9.19; 95% CI: 2.73-30.8; p = 0.0003) and diabetes (OR 5.6; 95% CI: 1.72-18.2; p = 0.004). Tirzepatide showed the strongest association (p = 0.0056). Factors that did not impact food retention included A1c, BMI, and gender. Protective factors were age (OR 0.96; 95% CI: 0.93-0.99; p = 0.02) and same-day colonoscopy (OR 0.18; 95% CI: 0.06-0.58; p = 0.003). Conclusions: GLP-1 RA use in diabetics increases the risk of retained gastric contents during elective EGD, particularly with tirzepatide, without increasing aspiration risk. Patients undergoing simultaneous colonoscopy had a lower risk of retained gastric contents. Further studies are needed to evaluate the impact of GLP-1 RAs on gastric food retention and procedural risk.

Tirzepatide's innovative applications in the management of type 2 diabetes and its future prospects in cardiovascular health.

Tirzepatide, a novel GLP-1/GIP dual receptor agonist, shows significant advantages in glycemic management and weight control. By summarizing the results of the SURMOUNT and SURPASS clinical trials, we evaluate the efficacy and safety of tirzepatide in reducing blood glucose and weight. These trials indicate that tirzepatide significantly lowers HbA1c levels (with a maximum reduction of 2.24%) and promotes weight loss (up to 11.2 kg) with good tolerability. However, there are still some challenges in its clinical application, including high treatment costs and gastrointestinal discomfort. Additionally, the safety and efficacy of tirzepatide in special populations, such as patients with renal impairment, require further investigation. Future large-scale clinical trials, such as SURPASS-CVOT and SUMMIT, are expected to further verify the long-term benefits of tirzepatide in cardiovascular health management, providing stronger evidence for its comprehensive treatment of diabetes and its complications.

Absorption, distribution, metabolism, and excretion of tirzepatide in humans, rats, and monkeys.

Tirzepatide is a once-weekly GIP/GLP-1 receptor agonist used for treatment of type 2 diabetes (T2D) in adults and was recently approved for treatment of obesity. To determine the absorption, distribution, metabolism, and excretion (ADME) of tirzepatide, [14C]-radiolabeled tirzepatide was investigated in both humans and preclinical species. [14C]-Tirzepatide was prepared by incorporating four 14C's in the linker region between the amino acid backbone and the di-acid moiety. Healthy male participants received a single subcutaneous dose of approximately 2.9 mg tirzepatide containing approximately 100 µCi of [14C]-tirzepatide. Preclinical studies were conducted in male Sprague Dawley and Long Evans rats administered a single dose of 3 mg kg-1 (133 µCi/kg) of [14C]-tirzepatide, and male cynomolgus monkeys administered a single dose of 0.5 mg kg-1 (20 µCi/kg) of [14C]-tirzepatide. Following a single SC dose of [14C]-tirzepatide in humans, the majority of the excreted dose was recovered within 480 h. Renal excretion was identified as a principal route of elimination in all species with approximately 66 % of the administered radioactivity recovered in urine, while approximately 33 % was eliminated in feces in humans. Metabolite analysis of tirzepatide revealed the parent drug was the major circulating component in human, rat, and monkey plasma. Metabolites identified in human plasma were similar to circulating metabolites found in rats and monkeys with no circulating metabolites representing >10 % of the total radioactive drug-related exposure. Intact tirzepatide was not observed in urine or feces in any species. Tirzepatide was primarily metabolized via proteolytic cleavage of the amino acid backbone, ß-oxidation of the C20 diacid moiety, and amide hydrolysis. ClinicalTrials.gov identifier: NCT 04,311,424.

Glucagon-like Receptor-1 agonists for obesity: Weight loss outcomes, tolerability, side effects, and risks.

Background: This review investigates the side effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) like liraglutide, semaglutide, and tirzepatide, medications known for their efficacy in promoting weight loss among individuals with obesity. The rationale is rooted in understanding the balance between their therapeutic benefits and associated risks. Methods: This was a comprehensive clinical review, including systematic reviews, meta-analyses, randomized controlled trials (RCTs), and cohort studies. Data were extracted from databases such as PubMed, Scopus, Embase, MEDLINE, and Google Scholar, focusing on the tolerability, severity, and risks of these medications. Results: GLP-1RAs demonstrated significant weight loss outcomes. In clinical trials, liraglutide showed a placebo-corrected weight loss of around 5 %, semaglutide 12 %, and tirzepatide 18 %. Common side effects were predominantly gastrointestinal, including nausea, diarrhea, constipation, and vomiting. Rare serious adverse events included gallbladder disorders and acute pancreatitis. In, addition, multiple studies identify new risks associated with GLP-1RAs including increased aspiration risk during anesthesia due to delayed gastric emptying and challenges with bowel preparation for colonoscopies. Conclusion: While GLP-1RAs are effective in managing obesity, their use is associated with gastrointestinal side effects and rare but serious adverse events. The findings underscore the importance of individualized dosing and thorough patient assessment. Continuous research and vigilant monitoring are essential to optimize their safe use. Further studies are needed to refine guidelines, particularly regarding new concerns such as delayed gastric emptying and its implications for anesthesia.

[A new era for incretins : from GLP-1 receptor agonists to co-agonists and poly-agonists]. / Une nouvelle ère pour les incrétines : des agonistes des récepteurs du GLP-1 aux co-agonistes et poly-agonistes.

Incretin gut hormones, especially glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), raise a huge interest in diabetology. GLP-1 receptor agonists have gained a privileged role in the management of type 2 diabetes (T2D). They improve glucose control without inducing hypoglycaemia, while promoting weight loss. Furthermore, they protect people with T2D against atherosclerotic cardiovascular disease and contribute to reduce the risk of heart failure and chronic kidney disease, two other common complications of T2D. A recent innovation consists in the development of co-agonists that target both GIP and GLP-1 receptors. Whereas the co-infusion of GIP and GLP-1 failed to further reduce hyperglycaemia of T2D compared to GLP-1 single infusion, tirzepatide, an original dual unimolecular biaised GIP/GLP-1 agonist, showed a remarkable improvement of glucose control in the SURPASS programme in patients with T2D. Consequently, it is now commercialized in many countries for the management of T2D. GLP-1/glucagon (GCG) co-agonists and GIP/GLP-1/GCG poly-agonists are currently in development, aiming to benefit from the favourable effects of GCG on energy expenditure and liver lipid metabolism, while mitigating the hyperglycaemic effects of this hormone thanks to balanced effects of GLP-1 and/or GIP. They might occupy in the future an interesting place in the management of obesity and its metabolic complications among which T2D and liver steatosis.

Les hormones digestives à effet incrétine, en particulier le «glucagon-like peptide-1¼ (GLP-1) et le «glucose-dependent insulinotropic polypeptide¼ (GIP) suscitent un intérêt considérable en diabétologie. Les agonistes des récepteurs du GLP-1 ont acquis une place de choix dans la prise en charge des patients avec un diabète de type 2 (DT2). Ils améliorent le contrôle glycémique, sans provoquer des hypoglycémies, tout en faisant perdre du poids. De plus, ils protègent contre les maladies cardiovasculaires athéromateuses. Enfin, ils contribuent à réduire le risque d'insuffisance cardiaque et de maladie rénale chronique, deux autres complications fréquentes du DT2. Une innovation récente consiste dans le développement de co-agonistes ciblant à la fois les récepteurs du GLP-1 et du GIP. Alors que la co-infusion de GIP et de GLP-1 ne réduit pas davantage l'hyperglycémie du DT2 qu'une perfusion isolée de GLP-1, le tirzépatide, un agoniste biaisé unimoléculaire original à effet double sur les récepteurs GIP/GLP-1, a montré une amélioration remarquable du contrôle glycémique, tout en favorisant l'amaigrissement, dans le programme SURPASS chez le patient avec DT2. Ce médicament est maintenant commercialisé dans de nombreux pays. Des co-agonistes GLP-1/glucagon (GCG) et des poly-agonistes GIP/GLP-1/GCG sont actuellement développés, profitant des effets favorables du glucagon sur les dépenses énergétiques et le métabolisme lipidique hépatique, tout en maîtrisant les effets hyperglycémiants de cette hormone grâce aux actions balancées du GLP-1 et/ou du GIP. Ils pourraient occuper à l'avenir une place intéressante dans le traitement de l'obésité et ses complications métaboliques dont le DT2 et la stéatopathie hépatique.

Bypassing Prescribers and Pharmacists: Online Purchasing of Semaglutide and Tirzepatide "For Research Purposes".

Unscrupulous manufacturers provide consumers with ways to circumvent access controls by purchasing drug products outside the legitimate prescription drug supply chain. Manufacturers are selling vials containing semaglutide and tirzepatide to consumers without a prescription for "research purposes only" and/or "not for human consumption," but frequently without the supplies and knowledge they would need to dissolve the active ingredient, draw it up into a syringe, and inject it into the body. Avoiding prescribers allows consumer access to products where the risk may outweigh the benefits and quality standards may not be met. It also makes it difficult to prevent drug interactions or perform adequate patient monitoring and follow-up.

The effectiveness and sustainability of health outcomes from a holistic digital weight-loss service with concomitant initiation of tirzepatide: A pragmatic randomized controlled trial in the UK.

AIM: To measure the effectiveness and sustainability of the Juniper UK digital weight-loss service (DWLS), which delivers 6 months of personalized, proactive lifestyle coaching supplemented with tirzepatide to patients through a multidisciplinary team (MDT). METHODS: An observer-blinded randomized controlled trial (RCT) will be conducted on a cohort of non-diabetic patients of the Juniper DWLS in the UK. Participants in both the intervention and control groups will receive weekly subcutaneous injections of 2.5 mg tirzepatide for 4 weeks, uptitrating the dose to 5.0 mg from weeks 5 to 8, and by 2.5 mg every 4 weeks until reaching 15 mg in week 21, which they will maintain until the end of the intervention period at 6 months, when participants will be taken off the medication. The intervention group will receive personalized weeklylifestyle coaching with a focus on protein intake and resistance training for 6 months. Participants in the control group will attend a diet and exercise group counselling session at programme inception and will be sent a summary of the session's content at months 2 and 4. Aside from these events, health coaches will only interact with control group participants on a reactive basis. From month 6 to month 12, participants from both groups will no longer have access to their MDTs. The trial's co-primary endpoints include weight loss, fat-free to fat-mass ratio and composite strength measures at 12 months (6 months following the end of treatment), compared with baseline. Secondary endpoints include percentage change in weight, fat-free to fat-mass ratio, and composite strength from baseline to 6 months, side effect incidence, and change in cardiometabolic risk factors at 12 months. Quality of life and programme engagement represent the study's exploratory endpoints. RESULTS: A total of 688 participants enrolled in the study, with a mean age of 44.6 (± 11.4) years and a mean body mass index of 34.8 (± 7.5) kg/m2; 81.0% of participants are women, and 72.8% are of White ethnicity. More than three-quarters of participants have at least one co-morbidity, with dyslipidaemia (42.4%), hypertension (35.3%) and high cholesterol (31.8%) being the most prevalent conditions. CONCLUSIONS: This RCT will be the first to assess the effectiveness and sustainability of a real-world intensive, multidisciplinary DWLS, and it should highlight the potential of such a service for long-term obesity treatment compared with programmes that deliver standard health counselling.

Lead-in calorie restriction enhances the weight-lowering efficacy of incretin hormone-based pharmacotherapies in mice.

OBJECTIVES: The potential benefits of combining lifestyle changes with weight loss pharmacotherapies for obesity treatment are underexplored. Building on recent clinical observations, this study aimed to determine whether "lead-in" calorie restriction before administering clinically approved weight loss medications enhances the maximum achievable weight loss in preclinical models. METHODS: Diet-induced obese mice (DIO) were exposed to 7 or 14 days of calorie restriction before initiating treatment with semaglutide (a glucagon-like peptide-1 receptor (GLP-1R) agonist), tirzepatide (a GLP-1R/glucose insulinotropic peptide receptor (GIPR) co-agonist), or setmelanotide (a melanocortin-4 receptor (MC4R) agonist). Follow-up assessments using indirect calorimetry determined the contributions of energy intake and expenditure linked to consecutive exposure to dieting followed by pharmacotherapy. RESULTS: Calorie restriction prior to treatment with semaglutide or tirzepatide enhanced the weight loss magnitude of both incretin-based therapies in DIO mice, reflected by a reduction in fat mass and linked to reduced energy intake and a less pronounced adaptive drop in energy expenditure. These benefits were not observed with the MC4R agonist, setmelanotide. CONCLUSIONS: Our findings provide compelling evidence that calorie restriction prior to incretin-based therapy enhances the achievable extent of weight loss, as reflected in a weight loss plateau at a lower level compared to that of treatment without prior calorie reduction. This work suggests that more intensive lifestyle interventions should be considered prior to pharmacological treatment, encouraging further exploration and discussion of the current standard of care.

Charting New Territories in Obesity Management- Traditional Techniques to Tirzepatide.

BACKGROUND: Obesity, a pervasive global health challenge affecting more than 2 billion people, requires comprehensive interventions. Traditional approaches, including lifestyle modification, and diverse drugs targeting a gastrointestinal hormone, including glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (Liraglutide, Semaglutide, Exenatide, Albiglutide, Dulaglutide, Lixisenatide, Orlistat, Phentermine/Topiramate, Lorcaserin, Sibutramine, and Rimonabant) offer tailored strategies; yet their effectiveness is limited and some drugs were taken off the market. Moreover, various surgical modalities, such as Roux-en-Y Bypass surgery, sleeve gastrectomy, intragastric balloons, biliopancreatic diversion with duodenal switch, laparoscopic adjustable gastric band, and vagal nerve blockade can be considered but are associated with numerous side effects and require careful monitoring. Consequently, there is a pressing need for novel anti-obesity treatments. METHODS: This comprehensive review was based on the available data to discuss the traditional pharmaceutical and surgical therapeutical strategies for obesity, going further to discuss tirzepatide's mode of action, its outcomes for obesity, and the associated side effects. RESULTS: In this landscape, tirzepatide, initially designed for type 2 diabetes management, emerges as a potential game-changer. Functioning as a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, it not only addresses control but also introduces a fresh perspective on weight reduction. This review intricately explores tirzepatide's mechanism, dissecting insights from clinical studies and positioning it as a major force in obesity treatment. CONCLUSIONS: In the middle of significant shifts in obesity management, tirzepatide presents itself as a promising and cost-effective intervention. Its Food and Drug Administration approval marks a milestone in the realm of obesity therapeutics. Going beyond a recapitulation of findings, the conclusion emphasizes the imperative for ongoing exploration and vigilant safety monitoring in tirzepatide's application.

Incidence of new onset type 2 diabetes in adults living with obesity treated with tirzepatide or semaglutide: real world evidence from an international retrospective cohort study.

Background: Tirzepatide, a novel dual agonist of glucagon-like-peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), has demonstrated greater magnitude of weight loss compared to semaglutide in a phase 3 clinical trial. However, the effect of tirzepatide on incidence of type 2 diabetes (T2D) in individuals with overweight and obesity, and the effect on major adverse cardiovascular outcomes in individuals with pre-existing T2D, remains unknown. Methods: We performed a retrospective cohort study of anonymised electronic medical records using the TriNetX network (TriNetX LLC, Cambridge, MA, USA) a global federated database. The data used in this study was collected on 5th June 2024. Two cohorts of individuals were generated: 1) without pre-existing T2D and, 2) with T2D. We adopted an active comparator new user design on new initiations of either tirzepatide or semaglutide therapy. Analysis began from the index event which was defined as individuals on respective therapy for 6 months only. Analysis of outcomes was conducted off-drug, in individuals without a pre-existing history of the disease of interest. Individuals were followed up for 12 months post the index event. Primary outcome for cohort 1 was incidence of T2D, and for cohort 2 was composite: all-cause mortality, cerebral infarction, acute coronary syndrome, and heart failure. Secondary outcomes for cohort 1 were change in HbA1c and body weight and for cohort 2: incidence of micro- and macrovascular complications, suicidal ideation and/or attempt, and all-cause mortality. We propensity score matched (1:1) for potential confounders: baseline demographics, socioeconomic circumstances, HbA1c, weight, relevant co-morbidities, and anti-obesity, hypoglycaemic and cardioprotective agents. Findings: The study population without T2D consisted of 13,846 individuals, equally split between tirzepatide and semaglutide users. Tirzepatide was associated with both lower risk for incident T2D (HR 0.73, 95% CI 0.58-0.92, p < 0.001) and greater weight loss (-7.7 kg, [95% CI -6.8, -8.5 kg], p < 0.001), compared to semaglutide (-4.8 kg, [95% CI -3.9, -5.6 kg], p < 0.001). In individuals with pre-existing T2D (n = 8446), tirzepatide was associated with lower risk of the composite outcome (HR 0.54, 95% CI 0.38-0.76, p < 0.001), cerebral infarction (HR 0.45, 95% CI 0.24-0.84, p = 0.010) and all-cause mortality (HR 0.33, 95% CI 0.15-0.73, p = 0.004) compared to semaglutide. Interpretation: Tirzepatide is associated with significantly reduced risk of developing T2D and major adverse cardiovascular events in individuals living with obesity and T2D respectively. Randomised controlled trials investigating the utility of dual incretin agonists in the primary prevention of T2D and cardiovascular disease in higher risk populations are now required. Funding: Nil.

Tirzepatide-Related Acute Liver Injury.

Tirzepatide, a modified protein containing 39 amino acids, acts as a dual agonist at the gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, showing great promise in weight-loss treatment. While rare, there have been reports of hepatotoxicity associated with tirzepatide use, and the exact mechanism of liver injury remains unclear. This case report highlights the experience of a 24-year-old female schoolteacher who started her weight-loss journey with tirzepatide. Despite its potential, she developed an idiosyncratic drug-related liver injury after escalating doses of tirzepatide prescribed by a private doctor. Her symptoms of recurrent vomiting, nausea and abdominal pain, initially indicative of hypoglycaemia and mild metabolic disturbances, ultimately revealed acute hepatitis and impaired coagulopathy. This case underscores the need for further research and frequent following of liver enzymes when using tirzepatide for weight loss. LEARNING POINTS: Tirzepatide should be used cautiously, with regular monitoring of liver function tests.If patients develop severe gastrointestinal symptoms or worsening abdominal pain, immediate hospital admission is necessary for further work-up, including a CT abdomen.Daily liver function tests, renal function tests and international normalised ratio (INR) tests should be conducted to identify and manage potential complications.