Incretin-based Therapies Research Articles

Post Hoc Analysis of SURPASS-1 to -5: Efficacy and Safety of Tirzepatide in Adults with Type2 Diabetes are Independent of Baseline Characteristics.

Newer incretin-based therapies for type2 diabetes (T2D) have the potential to substantially reduce glycated hemoglobin (HbA1c) and weight with a low associated risk of hypoglycemia. This study aimed to assess the percentage of participants randomized to tirzepatide or comparator who achieved the composite endpoint of HbA1c ≤ 6.5% and weight reduction ≥ 10% without hypoglycemia across prespecified baseline characteristics: T2D duration (≤ 5, > 5-10, or > 10years), sex, HbA1c (≤ 8.5% or > 8.5%), age (< 65 or ≥ 65years), and body mass index (< 30, 30 to < 35, or ≥ 35kg/m2). This post hoc analysis of SURPASS-1 through -5 evaluated adult study participants with T2D treated with tirzepatide 5, 10, or 15mg versus placebo or active comparator. Missing HbA1c and weight values were imputed from mixed models for repeated measures. Logistic regression was used to compare tirzepatide versus comparators for the percentage of participants reaching the composite endpoint. Across subgroups, the composite endpoint was achieved by a median of approximately 30%, 45%, and 54% of participants who received tirzepatide 5, 10, and 15mg, respectively; this was consistent across baseline subgroups, except that a greater percentage of women than men achieved the composite endpoint. The most common treatment-emergent adverse events were gastrointestinal in nature. In this post hoc analysis, tirzepatide achieved the composite outcome of glycemic control and weight loss with no hypoglycemia, irrespective of baseline characteristics. This may help clinicians as they select suitable treatment in diverse populations. ClinicalTrials.gov: NCT03954834, NCT03987919, NCT03882970. NCT03730662, and NCT04039503.

Incretin-Based Therapies: A Promising Approach for Modulating Oxidative Stress and Insulin Resistance in Sarcopenia.

Recent studies have linked sarcopenia development to the hallmarks of diabetes, oxidative stress, and insulin resistance. The anti-oxidant and insulin sensitivityenhancing effects of incretin-based therapies may provide a promising option for the treatment of sarcopenia. This review aimed to unveil the role of oxidative stress and insulin resistance in the pathogenesis of sarcopenia and explore the potential benefits of incretin-based therapies in individuals with sarcopenia. PubMed, the Cochrane Library, and Google Scholar databases were searched by applying keywords relevant to the main topic, to identify articles that met our selection criteria. Incretin-based therapies manifested anti-oxidant effects by increasing the anti-oxidant defense system and decreasing free radical generation or by indirectly minimizing glucotoxicity, which was mainly achieved by improving insulin signaling and glucose homeostasis. Likewise, these drugs exhibit insulin-sensitizing activities by increasing insulin secretion, transduction, and β-cell function or by reducing inflammation and lipotoxicity. Incretin-based therapies, as modulators of oxidation and insulin resistance, may target the main pathophysiological factors of sarcopenia, thus providing a promising strategy for the treatment of this disease.

Incretin-Based Therapies and Lifestyle Interventions: The Evolving Role of Registered Dietitian Nutritionists in Obesity Care

The emergence of incretin-based therapies, specifically glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and glucose-dependent insulinotropic polypeptide (GIP), as a new class of obesity medications, is dramatically changing obesity care. Use of these medications, known categorically as anti-obesity medications, as part of comprehensive obesity management is associated with significantly greater weight loss and health benefits than found with earlier generation obesity medications. The outcomes reported from medication trials were often achieved in conjunction with lifestyle counseling sessions by a registered dietitian nutritionist (RDN) or other qualified health care professional. Research demonstrates that evidence-based obesity care should incorporate lifestyle interventions. Counseling by a RDN, paired with incretin-based therapies, can play a critical role in supporting adherence to the medication regimen, preventing and managing side effects, adequate nutrient intake, and establishment of lifestyle behaviors for long-term weight and health management. To date, minimal research has been reported on the impact of incretin-based therapies on food and nutrient intake. Until that research is conducted, RDNs and other health professionals can apply knowledge and experience from clients who have undergone other intensive treatments. This article provides considerations for lifestyle interventions, with a focus on medical nutrition therapy (MNT) provided by RDNs, for adults prescribed incretin-based therapies. RDNs have the education and training to provide MNT for people with overweight or obesity, as well as lifestyle counseling on physical activity, stress management, sleep hygiene, goal setting, and other behaviors associated with positive health outcomes. RDNs have a critical role in the integration of incretin-based therapies into obesity management.

Modern views on pathogenesis of cognitive impairment in patients with type 2 diabetes mellitus

Currently, the features of the pathogenesis of cognitive impairment in patients with diabetes mellitus are being actively studied. The study of the mutual influence of these pathologies is of particular relevant not only in connection with a decrease in cognitive functions in patients with diabetes mellitus, but also due to the fact that the management of diabetes mellitus requires a thorough approach to the implementation of doctor’s recommendations and self-control on the part of the patient himself. The degree of cognitive impairment has a direct impact on patient compliance and, consequently, on the management and control of the disease. A comprehensive strategy is necessary for the prevention and progression of cognitive impairments in patients with diabetes mellitus. This strategy should include minimizing modifiable risk factors, controlling comorbidities, maintaining a healthy lifestyle, following a diet, engaging in regular physical activity, and medication therapy. Also, one of the key aspects is the control of blood glucose levels. Regular monitoring and maintaining a stable level of sugar can significantly reduce the risk of developing cognitive impairments in diabetic patients. This review also analyzes the effects of oral hypoglycemic drugs, incretin-based therapy and insulin on the risk of developing cognitive impairments. This review examines important aspects of the role of pathogenetic links and clinical manifestations of type 2 diabetes mellitus in the development of cognitive impairment and the possibility of influencing their development and rate of progression. Understanding these relationships will help develop effective strategies for the prevention and treatment of cognitive impairments in patients with diabetes mellitus.

Incretin hormones: Revolutionizing the treatment landscape for kidney and liver diseases in type 2 diabetes and obesity.

Several ongoing trials are evaluating incretin-based therapies, including GLP-1 receptor agonists, for their effects on CKD and MASLD. These studies will offer insights into their potential for metabolic diseases in people with type 2 diabetes and obesity.

Pulmonary outcomes of incretin-based therapies in COPD patients receiving single-inhaler triple therapy

IntroductionPatients with chronic obstructive pulmonary disease (COPD) on triple therapy often face exacerbations and comorbidities. Emerging evidence suggests that glucagon-like peptide-1 (GLP-1) analogs may reduce the risk of exacerbation in patients with COPD and type 2 diabetes mellitus (T2DM). This study investigates the impact of GLP-1 analogs on pulmonary outcomes in patients with COPD on single-inhaler triple therapy (SITT) and T2DM.MethodsWe conducted a retrospective cohort study using the TriNetX database and analysed adult patients with COPD and T2DM who received SITT between April 2005 and July 2023. Patients were categorized into GLP-1 analog and dipeptidyl peptidase-4 inhibitors (DPP4i) cohorts. The primary efficacy outcome was COPD exacerbation and the secondary efficacy outcomes were pneumonia, acute respiratory distress syndrome, intubation, oxygen dependence, and all-cause mortality. The secondary outcomes were serious gastrointestinal adverse events.ResultsWe included 6898 patients, with 4184 receiving GLP-1 analogs and 2714 receiving DPP4i. After matching, 1751 GLP-1 analog users were matched with 1751 DPP4i users. GLP-1 analog users had an 18% lower risk of COPD exacerbation (hazard ratio [HR], 0.82 [95% CI: 0.71–0.94]), a 28% reduced risk of pneumonia (HR, 0.72 [95% CI: 0.61–0.85]), a 34% reduced risk of oxygen dependence (HR, 0.66 [95% CI: 0.47–0.91]), and a 40% decreased risk of all-cause mortality (HR, 0.60 [95% CI: 0.47–0.77]). No significant serious gastrointestinal adverse events were observed.ConclusionGLP-1 analogs may be associated with reduced COPD exacerbations, pulmonary comorbidities, and mortality in patients with COPD receiving SITT and T2DM, with no significant serious gastrointestinal safety concerns.

7765 Exploring the Synergistic Effect of GHRH Receptor Agonist MR-409 and Incretin-based Therapies in Type 1 Diabetes Using a Low-dose Streptozotocin Model

Abstract Disclosure: M. Gonzalez Medina: None. R. Louzada: None. V. Pita-Grisanti: None. M. Blandino: None. T. Cui: None. W. Sha: Owner/Co-Owner; Self; WS. is co-inventor on GHRH agonists MR-409 patent, assigned to the University of Miami and the Veterans Affairs. R. Cai: Owner/Co-Owner; Self; R.C. is co-inventor on GHRH agonists MR-409 patent, assigned to the University of Miami and the Veterans Affairs. A.V. Schally: Owner/Co-Owner; Self; A.V.S. is co-inventor on GHRH agonists MR-409 patent, assigned to the University of Miami and the Veterans Affairs.. E. Bernal-Mizrachi: None. Patients with type 1 diabetes (T1D) have decreased functional β-cell mass due to inflammatory cell infiltration and cytokine-induced β-cell death. Clinical trials using a combination of immunomodulatory agents and β-cell protecting medications such as GLP1-R agonists (GLP1-Ra) are being considered. A potential limitation for the clinical efficacy of GLP1-R agonists is the loss of GLP-1-R at the cell surface in states of hyperglycemia. Hence, novel agents that enhance β-cell survival and proliferation through parallel pathways could improve responses to GLP1-R agonists and/or synergistically potentiate β-cell responses. Previous studies have demonstrated beneficial effects of growth hormone-releasing hormone receptor agonists (GHRH-Ra), such as MR-409 on islet preconditioning in transplantation models. Our previous studies showed that GHRH-Ra protects β-cells from autoimmune injury in vitro and improves glucose levels in a model of high-dose streptozotocin-induced diabetes via stimulation of the cAMP/PKA/CREB/IRS2 axis. However, the effects of combination of incretin-based therapy with GHRHRa on β-cell survival in T1D models have not yet been explored. Using the low-dose STZ model in C57/B6 mice, we investigated how MR-409 alone or in combination with GLP1-R agonists (Exendin-4 or Ex-4) promotes β-cell survival and prevents T1D. Low-dose STZ treated mice received daily MR-409 and Ex-4 injections, either alone or in combination for six weeks. We found that, STZ-treated mice that received either MR-409, Ex-4 or combination exhibited better glucose homeostasis while the combination failed to induce any additional effect. Interestingly, glucose tolerance and insulin levels were improved only in the MR-409-treated mice. β-cell mass was similarly increased in mice that received MR-409, Ex-4 and combination groups compared to the vehicle-treated. Further, treatment of human islets with MR-409 and/or Ex-4 induced insulin receptor substrate 2 (IRS2) expression, a master regulator of survival and growth in β-cells, while the combination of both therapies did not have any additional effect. Experiments in human islets exposed to proinflammatory cytokines treatment demonstrated that MR-409 and/or Ex-4 was associated with a decrease in β-cell death and improved insulin secretory function by activation of the cAMP/PKA/CREB/IRS2 axis. These studies demonstrate that although there was no evidence for a synergistic effect between MR-409 and Ex-4, MR-409 appears to have more potent effects on improving glucose tolerance and insulin levels when compared to the long-term effect of Ex-4 in a low-dose STZ model, suggesting that MR-409 could be an alternative therapeutic agent in the treatment of β-cell death in T1D. Presentation: 6/2/2024

Association of incretin-based therapies with hepatobiliary disorders among patients with type 2 diabetes: a case series from the FDA adverse event reporting system.

Incretin therapies, including dipeptidyl peptidase-4 inhibitors (DPP-4is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs), are crucial for type 2 diabetes treatment. Evidence on their association with gallbladder, biliary diseases and liver injury remains inconsistent. This study evaluated the association between incretin therapies and hepatobiliary adverse events using FDA's Adverse Event Reporting System (FAERS) data. Case reports involving incretin therapies and hepatobiliary events from January 2006 to December 2023 were extracted from FAERS. The association between these agents and hepatobiliary adverse events (hAEs) was analyzed using reporting odds ratios and empirical Bayesian geometric means. Descriptive analyses were conducted to characterize the demographic and clinical features of the hAE cases. Additionally, subgroup analyses calculated reporting odds ratios to evaluate the strength of association between specific incretin drugs and hAEs. Among 68,351 case reports associated with incretin-based therapies, 1,327 (1.941%) involved hepatobiliary adverse events. DPP-4 inhibitors demonstrated statistically significant associations with multiple hepatobiliary events like cholelithiasis, cholecystitis chronic, and biliary diseases. In contrast, GLP-1 receptor agonists showed weaker associations, primarily linked to gallbladder and biliary disease risks. Subgroup analyses revealed stronger positive correlations with hepatobiliary events for liraglutide and semaglutide among GLP-1 agonists, and for sitagliptin, linagliptin, and vildagliptin among DPP-4 inhibitors. The pooled reporting odds ratio of 2.85 indicated a positive correlation between these drugs and studied adverse events. This study found statistically significant associations between DPP-4 inhibitors and hepatobiliary adverse events like cholelithiasis and cholecystitis. GLP-1 agonists showed weaker gallbladder/biliary disorder links but higher acute cholecystitis risk. Subgroup analyses revealed varying correlations among specific drugs, potentially dose-dependent. Further large-scale studies are needed to evaluate class effect differences and elucidate mechanisms for guiding clinical use.

Incretin-based therapies and cancer: Are they enemies or allies?

Incretin-based therapies and cancer: Are they enemies or allies?

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

ObjectivesThe 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. MethodsDiet-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. ResultsCalorie 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. ConclusionsOur 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.

Achieving equitable access to incretin-based therapies in cardiovascular care

The role of incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP1RAs) and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists, in the management of type 2 diabetes mellitus (T2DM) and obesity has been increasingly recognized, along with significant cardiovascular (CV) benefits. Despite the clinical efficacy of incretin-based therapies, high costs, suboptimal access, limited insurance coverage, and therapeutic inertia present substantial barriers to widespread adoption. Overcoming these obstacles is essential for the equitable initiation, access, and utilization of incretin-based therapies. Clinicians must make targeted efforts to ensure health equity in the use of these and other advanced therapies.

Incretin hormone agonists: Current and emerging pharmacotherapy for obesity management.

Obesity continues to be a significant global health challenge, affecting over 800 million individuals worldwide. Traditional management strategies, including dietary, exercise, and behavioral interventions, often result in insufficient and unsustainable weight loss. Lifestyle modification remains the cornerstone of obesity management, providing the foundation for other strategies. While options such as bariatric surgery remain an effective intervention for severe obesity, it is associated with its own set of risks and is typically reserved for patients who have not achieved the desired results with pharmacotherapy and lifestyle interventions. Incretin hormone agonists represent a significant advancement in the pharmacotherapy of obesity, offering substantial weight reduction and cardiometabolic benefits. Agents like liraglutide, semaglutide, and tirzepatide supported by key clinical trials such as Satiety and Clinical Adipose Liraglutide Evidence (SCALE), Semaglutide Treatment Effect in People with Obesity (STEP) program trials, and Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1) have demonstrated remarkable efficacy in promoting weight loss and improving metabolic outcomes. Additionally, novel therapies, including dual and triple incretin agonists, are under investigation and hold the potential for further advancements in obesity treatment. These novel therapies can be categorized by their mechanisms of action and route of administration into oral glucagon-like peptide-1 (GLP-1) receptor agonists, triple agonists (targeting GLP-1, glucose-dependent insulinotropic polypeptide [GIP], and glucagon receptors), and glucagon receptor-GLP-1 receptor co-agonists. Other innovative approaches include oral GIP-GLP-1 receptor co-agonists, and the combination of long-acting amylin receptor agonists with GLP-1 receptor agonists. The ongoing development of incretin-based therapies and the expanding availability of currently available agents are expected to enhance clinical outcomes further and reduce the burden of obesity-related health complications. This review aims to discuss the mechanisms and efficacy of current and emerging incretin hormone agonists for obesity management.

Curbing the Obesity Epidemic: Should GLP-1 Receptor Agonists Be the Standard of Care for Obesity?

This article summarizes the medical management of obesity with an emphasis on incretin-based therapeutics that target the neuro-hormonal basis of obesity. Medications that mimic the effect of incretins, a group of peptide hormones released in response to nutrient intake that regulate appetite, result in potent and durable weight loss. Glucagon-like peptide 1 (GLP-1) agonists and glucose-dependent insulinotropic polypeptide (GIP) agonists such as semaglutide and tirzepatide are approved by the United States Food and Drug Administration (FDA) for the management of obesity. The SELECT trial demonstrated that semaglutide led to a reduction in major adverse cardiovascular events in patients without diabetes who were either overweight and had preexisting cardiovascular disease or obese. The treatment of obesity is critical to prevent the progression of cardiovascular-kidney-metabolic syndrome. Incretin-based therapies offer remarkable weight loss and reduce major cardiovascular adverse events.

Glucagon Stimulation Test and Insulin Secretory Capacity in Clinical Assessment of Incretin-Based Therapy for Diabetes.

Evaluation of insulin secretory capacity is essential to understand the pathophysiological condition of individuals with diabetes and to assess the efficacy of drugs used in treatment of the disease. The 1 mg intravenous glucagon stimulation test (GST) is widely used to evaluate residual β cell function; we previously reported that GST assessment of insulin secretory capacity is useful in assessing the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RAs). However, recent reports indicate that pharmacological concentrations of glucagon stimulate insulin secretion through GLP-1 receptors, confounding the issue. The present studies were undertaken to reassess the reliability of the GST for evaluation of insulin secretory capacity under GLP-1RAs and dipeptidyl peptidase-4 inhibitors (DPP-4is). Our first study comprised individuals initiated with the treatment of GLP-1RAs evaluated by GSTs before and after treatment. Although the fasting C-peptide levels (CPR) were elevated after treatment, the induction of insulin secretion by glucagon was significantly reduced. Our second study compared glucagon-induced insulin secretion between DPP-4i users and non-users, assessed by GST after propensity score matching. While the fasting CPR were similar in the two investigations, glucagon-induced insulin secretion was significantly lower with DPP-4i use. These results suggest that GST might underestimate insulin secretory capacity under incretin-based therapy.

The influence of insulin and incretin-based therapies on renal tubular transport.

The tubular function of the kidney is very complex and is finely regulated by many factors. These include a variety of hormonal signaling pathways which are involved in the expression, activation and regulation of renal transporters responsible for the handling of electrolytes. Glucose-lowering drugs such as insulin and incretin-based therapies, exert a well-known renal protective role in diabetic kidney disease, mainly acting at the glomerular level. In the literature, several studies have described the effect of insulin and the incretin hormones on tubular transport. Most of these studies focused on the variations in excretion and clearance of sodium but did not extensively and systematically investigate the possible variations that these hormones may induce in the tubular regulation of all the other electrolytes, urea metabolism, acid-base balance and urinary pH. While insulin action on the kidney is very well-described, the renal tubular impact of incretin-based therapies is less consistent and the results available are scarce. To our knowledge, this is the first review summarizing the effects induced on renal tubules by insulin, glucagon-like peptide-1 (GLP-1) receptor agonists and serine protease dipeptidyl peptidase-4 (DPP4) inhibitors in both healthy and diabetic human subjects. This is significant because it highlights the existence of a renal-gut and pancreas axis which also has a direct tubular effect and enables a deeper understanding of renal physiology.

Incretin-based therapies for the management of cardiometabolic disease in the clinic: Past, present, and future.

Among newer classes of drugs for type 2 diabetes mellitus (T2DM), glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are incretin-based agents that lower both blood sugar levels and promote weight loss. They do so by activating pancreatic GLP-1 receptors (GLP-1R) to promote glucose-dependent insulin release and inhibit glucagon secretion. They also act on receptors in the brain and gastrointestinal tract to suppress appetite, slow gastric emptying, and delay glucose absorption. Phase 3 clinical trials have shown that GLP-1 RAs improve cardiovascular outcomes in the setting of T2DM or overweight/obesity in people who have, or are at high risk of having atherosclerotic cardiovascular disease. This is largely driven by reductions in ischemic events, although emerging evidence also supports benefits in other cardiovascular conditions, such as heart failure with preserved ejection fraction. The success of GLP-1 RAs has also seen the evolution of other incretin therapies. Tirzepatide has emerged as a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RA, with more striking effects on glycemic control and weight reduction than those achieved by isolated GLP-1R agonism alone. This consists of lowering glycated hemoglobin levels by more than 2% and weight loss exceeding 15% from baseline. Here, we review the pharmacological properties of GLP-1 RAs and tirzepatide and discuss their clinical effectiveness for T2DM and overweight/obesity, including their ability to reduce adverse cardiovascular outcomes. We also delve into the mechanistic basis for these cardioprotective effects and consider the next steps in implementing existing and future incretin-based therapies for the broader management of cardiometabolic disease.

Patient perspectives on incretin-based weight loss medications and relationship with demographic factors.

Treatment of obesity has been transformed by the recent approval of incretin-based therapies for weight loss (e.g., glucagon-like peptide 1 agonist semaglutide), but little is known about patient perspectives on these medications. Between December 2023 and March 2024, healthcare patients from an academic medical center in the Southeast United States with Body Mass Index ≥30kg/m2 completed a cross-sectional online survey on attitudes toward incretin-based medications. Compared to patients with a bachelor's degree, those without a degree were less likely to be aware of incretin-based pharmacotherapies (96% vs. 78%) and to have discussed pharmacotherapies with a doctor (43% vs. 27%) but had greater interest in using these pharmacotherapies (4.3 vs. 4.7). These pharmacotherapy-related variables did not differ significantly according to gender, race, or financial security. Concerns about side effects, long-term health risks, and potential for weight regain were highly endorsed and were associated with lower interest in using incretin-based therapies and with some demographic factors. Patients reported high interest in lifestyle programs designed for individuals taking anti-obesity medications. Demographic considerations, notably education level, should be factored into the strategy to promote equitable utilization of incretin-based therapies, particularly as their accessibility expands.

Incretin-based therapies for liver disease.

Incretin-based therapies for liver disease.

Are the lipid-lowering effects of incretin-based therapies relevant for cardiovascular benefit?

This review examines the impact of glucagon-like peptide 1 receptor agonists (GLP-1RAs) on lipid profiles in individuals with type 2 diabetes mellitus and/or obesity, crucial for optimizing cardiovascular risk management. GLP-1RAs affect lipid levels by reducing intestinal apolipoprotein B48 production and mesenteric lymph flow, while increasing catabolism of apolipoprotein B100. It remains unknown whether these effects are direct or indirect, but the improvements in lipid levels are strongly correlated to the drug-induced weight loss. Clinical trials demonstrate improvements in lipid profiles, with different effects per agent and dose. We deem it unlikely that improved lipid levels are sufficient to explain the beneficial effects of GLP-1RA on cardiovascular risk, especially given the improvement of many other risk factors (body weight, glycemic control, inflammation) while using these agents. Posthoc mediation analyses of large cardiovascular outcome trials may shed some light on the relative importance of each risk factor. GLP-1RAs improve lipid profiles in clinical trials, but their complete cardiovascular benefits likely involve multifactorial mechanisms beyond lipid modulation.

The role of incretin receptor agonists in the treatment of obesity.

Obesity and its associated metabolic conditions have become a significant global health problem in recent years, with many people living with obesity fulfilling criteria for pharmacological treatment. The development of the glucagon-like peptide-1 receptor agonists for chronic weight management has triggered new interest in the incretins and other hormones as targets for obesity, and investigations into dual and triple co-agonists. The objective of this narrative review was to summarize the available data on approved and emerging incretin-based agents for the treatment of obesity. In clinical trials of currently available agents in people with overweight or obesity, weight loss of between 6% and 21% of baseline body weight has been observed, with between 23% and 94% of participants achieving 10% or higher weight loss, depending on the study and the agent used. Favourable outcomes have also been seen with regard to cardiovascular risk and outcomes, diabetes prevention, metabolic dysfunction-associated steatotic liver disease/steatohepatitis and prevention of weight regain after metabolic surgery. Limitations associated with these agents include high costs, the potential for weight regain once treatment is stopped, the potential loss of lean body mass and gastrointestinal adverse events; potential issues with respect to gallbladder and biliary diseases require further investigation. Many dual and triple co-agonists are still in development, and more data are needed to assess the efficacy, safety and tolerability of these emerging therapies versus the established incretin-based therapies; however, data are promising, and further results are eagerly awaited.