Safety of GLP-1 and Dual GLP-1/GIP Receptor Agonists in Preconception, Pregnancy, and Lactation: A Systematic Review of Maternal, Fetal, and Neonatal Outcomes.

Incretin hormones are peptides released in the intestine in response to the presence of nutrients in its lumen. The main incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 stimulates insulin secretion, inhibits glucagon secretion at pancreatic α cells and has also extrapancreatic influences as slowing of gastric emptying which increases the feeling of satiety. GIP is the main incretin hormone in healthy people, causative of most the incretin effects, but the insulin response after GIP secretion in type 2 diabetes mellitus (T2DM) is strongly reduced. Therefore, in the past GIP has been considered an unappealing therapeutic target for T2DM. This conception has been changing during recent years, since it has been reported that resistance to GIP can be reversed and its effectiveness restored by improving glycemic control. This fact paved the way for the development of a GIP receptor agonist-based therapy for T2DM, looking also for the possibility of finding a combined GLP-1/GIP receptor agonist. In this framework, the novel dual GIP and GLP-1 receptor agonist tirzepatide seems to be not just a new antidiabetic medication. Administered as a subcutaneous weekly injection, it is a manifold single pharmacological agent that has the ability to significantly lower glucose levels, as well as improve insulin sensitivity, reduce weight and amend dyslipidemia favorably modifying the lipid profile. Tirzepatide and additional dual GLP-1/GIP receptor agonists that could eventually be developed in the future seem to be a promising furthest advance for the management of several cardiometabolic settings. Obviously, it is too early to be overly hopeful since it is still necessary to determine the long-term effects of these compounds and properly verify the potential cardiovascular benefits. Anyway, we are currently facing a novel and very appealing therapeutic option.

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists (RAs) mimic naturally occurring GLP-1 and GIP and are highly effective anti-diabetic and anti-obesity agents. In addition to their robust acute and long-term effects on weight, metabolism, and blood pressure, these agents also reduce cardiovascular mortality as well as stroke risk and associated consequences. A replicated and convergent body of preclinical evidence also indicates that incretin receptor agonists activate molecular effectors critical to neuroplasticity, neuroprotection, and anti-apoptosis. Herein, we propose that GLP-1 RAs and GIP RAs are promising transdiagnostic mechanistically informed therapeutics in the treatment and prevention of multiple domains of psychopathology, including general cognitive, reward, and motivation systems and mental disorders. Major neurocognitive disorders (eg, Alzheimer's Disease, Parkinson's Disease), alcohol and substance use disorders, traumatic brain injury, and depressive disorders are near-term therapeutic targets. In addition, GLP-1 RAs and GIP RAs have robust effects on comorbidities that differentially affect persons with mental disorders (eg, cardiovascular, cerebrovascular, and metabolic disorders) and psychotropic drug-related weight gain.

Dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have emerged as a novel therapeutic class with potential relevance for cardiovascular prevention, particularly in the context of obesity and type 2 diabetes mellitus. Incretin physiology provides the biological foundation for this approach, as GLP-1 and GIP exert complementary metabolic and vascular effects. While GLP-1 receptor agonists have demonstrated well-established reductions in major adverse cardiovascular events, GIP has regained interest due to evidence suggesting preserved vascular and anti-atherosclerotic actions despite reduced insulinotropic efficacy in diabetes. Dual receptor agonism integrates these pathways, leading to substantial improvements in cardiometabolic risk factors. Agents such as tirzepatide induce marked and sustained weight loss, with significant reductions in visceral adiposity, a key driver of cardiovascular disease. These effects are accompanied by robust improvements in glycemic control and insulin sensitivity, resulting in attenuation of glucotoxicity and lipotoxicity, both of which contribute to endothelial dysfunction and myocardial injury. Additional benefits include reductions in blood pressure, favorable modulation of lipid profiles, and suppression of systemic inflammatory markers, alongside improvements in endothelial function and vascular stiffness.Pharmacologically, dual GLP-1/GIP receptor agonists are engineered to provide balanced receptor activation, allowing superior metabolic efficacy compared with single GLP-1 receptor agonists. Clinical trial data indicate cardiovascular safety and improvements in surrogate cardiovascular endpoints, with reductions in major cardiometabolic risk factors comparable to those achieved with established incretin therapies. However, definitive evidence of incremental cardiovascular outcome benefits remains limited.

The purpose of this review is to highlight the role of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists (GLP-1/GIP RAs) in managing cardiovascular-kidney-metabolic (CKM) syndrome, focusing on their cardiovascular (CV) and kidney-protective effects beyond glycemic control. In multiple randomized controlled trials, GLP-1 RAs were demonstrated to confer significant benefits in reducing CV events and preserving kidney function in patients with preexisting atherosclerotic cardiovascular disease (ASCVD) and those at high CV risk. Current guidelines, including those from the Kidney Disease: Improving Global Outcomes (KDIGO) initiative and the American Diabetes Association (ADA), underscore the therapeutic potential of these agents for managing chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM), and metabolic syndrome. Additionally, emerging data suggests their utility beyond T2DM. This review summarizes the evidence supporting these guidelines, along with newer findings not yet fully integrated into clinical practice. It also examines the role of pharmacists and multidisciplinary teams, safety considerations, and practical strategies for managing common adverse effects. The integration of GLP-1 RAs and dual GLP-1/GIP RAs into clinical practice offers substantial benefits for patients, both with and without diabetes. Pharmacists play a pivotal role in recommending evidence-based treatments for those at high CV and kidney risk, educating patients, addressing social determinants of health, and bridging gaps across multidisciplinary care teams.

Background/Objectives: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have revolutionised obesity and type 2 diabetes management through effective weight loss and metabolic regulation. However, their increasing use has led to reports of adverse aesthetic and functional effects, particularly affecting facial and ocular tissues. Methods: A comprehensive literature review was conducted in October 2025 across PubMed, Embase, and Medline using the terms "GLP-1 receptor agonist," "Ozempic face," "facial lipoatrophy," "ocular surface disease," "orbital fat," and related combinations. Studies reporting facial, periorbital, orbital, or ocular surface changes associated with GLP-1 or GLP-1/GIP receptor agonists were included. Reference lists were screened to identify additional sources. Results: Evidence suggests that GLP-1 and dual GLP-1/GIP receptor agonists may contribute to rapid facial volume loss, dermal fat atrophy, and periocular hollowing-collectively termed "Ozempic face." The mechanism is multifactorial, involving both weight-loss-related fat depletion and potential modulation of adipocyte differentiation. Ocular surface improvements have been observed in some studies. Radiologic data demonstrate preferential superficial midface fat loss, informing potential aesthetic correction strategies. Conclusions: GLP-1-based therapies, while clinically effective, can result in perceptible adnexal and periocular changes with aesthetic and functional implications. Awareness of these effects is crucial for multidisciplinary management. Future prospective studies are warranted to clarify mechanisms and guide individualised reconstructive and rejuvenative interventions.

In the management of hypertension, only limited advances have been made over the past decades. Recent studies highlight the potential of next-generation incretin-based therapeutics, such as GLP-1 RAs (glucagon-like peptide-1 receptor agonists) like semaglutide and dual GLP-1/GIP (glucose-dependent insulinotropic polypeptide) receptor agonists like tirzepatide. These drugs not only promote weight loss but also substantially lower blood pressure (BP) and reduce cardiovascular end points. The extent to which incretin-based therapies improve disease outcomes via weight loss versus so-called direct tissue effects is the subject of great interest, not only for BP but also for other clinical outcomes. Although, incretin-based therapeutics were initially not designed to treat hypertension, clinical studies demonstrate an impressive reduction in BP in patients treated with these agents, with an even more pronounced effect in patients with obesity and hypertension. The current hypertension guidelines must address the robust evidence supporting the use of incretin-based therapeutics in patients with hypertension. A caveat is that no trial to date has used BP reduction as the primary end point when investigating the interaction between GLP-1 or GLP-1/GIP receptor agonists and antihypertensive medications. However, in patients with type 2 diabetes or a body mass index >27 kg/m2, these drugs are widely used and lower BP. Taken together, incretin-based therapeutics represent a promising therapeutic tool to improve both BP and cardiovascular outcomes and help evolve the landscape of hypertension treatment.

Introduction Despite there being a wide range of medicines available for the treatment of type 2 diabetes, the high rate of mortality suggests treatment needs to be improved. Only a few medicines have shown long-term effectiveness in obesity, and new medicines are urgently needed. Areas covered A multiple-ascending dose phase 1b clinical trial of a new drug retatrutide (LY3437943), which in addition to stimulating Glucagon-like peptide 1 (GLP-1) and Glucose-dependent insulinotropic polypeptide (GIP) receptors, stimulates glucagon receptors, in subjects with type 2 diabetes. Retatrutide was relatively safe and pharmacokinetics support once-weekly dosing. Expert opinion The role of stimulating glucagon receptors in the treatment of type 2 diabetes and/or obesity is poorly defined and needs to be clarified. Although retatrutide may be superior to the GLP-1 receptor agonist dulaglutide in reducing plasma glucose and body weight, this is not a meaningful comparison, as another GLP-1 receptor agonist (semaglutide) is more potent than dulaglutide at this and may have similar efficacy to retatrutide. Retatrutide also needs to be compared to another Eli Lilly and Company drug, the combined GLP-1 and GIP receptor agonist, tirzepatide. The safety of retatrutide needs to be determined in larger and longer trials.

Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial

A recent article highlighted the hepatic benefits of intermittent fasting, particularly during Ramadan. However, the rising use of glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists (RAs) is altering public behavior, leading to decreased interest in diet and exercise. With a focus on hepatic health, we analyzed global search trends using Google Trends™ data from January 1, 2022 to December 31, 2024, focusing on the keywords "fasting", "intermittent fasting", "diet", "nutrition", "liver", Semaglutide ("Ozempic"™, the most widely known GLP-1 RA) and Tirzepatide ("Mounjaro"™, a newer dual GLP-1 and GIP RA). Search interest for "intermittent fasting" and "diet" showed a significant decline over time (Spearman's rho: -0.582 and -0.605, respectively, both P < 0.001), while interest in "fasting" and "nutrition" remained stable. Search interest for Semaglutide, Tirzepatide, "fasting and liver", "diet and liver" and Semaglutide and "liver" increased (Spearman's rho: +0.914, +0.936, +0.369, +0.297 and +0.808, respectively, all P < 0.001). These findings suggest a trend of shifting away from traditional dieting toward broader health concerns, likely influenced by the increasing use of GLP-1/GIP RAs.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease globally, yet it lacks any approved pharmacological therapies. Dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists have shown clinical promise, but their causal effect on MASLD remains unestablished. This study uses genetic evidence to evaluate the causal role of dual GLP-1R/GIPR agonists on MASLD and to explore its underlying mechanisms. Using a novel approach combining Mendelian randomization (MR) and Bayesian colocalization, we constructed a high-confidence genetic proxy for dual GLP-1R/GIPR agonists based on five genetic variants strongly associated with both mRNA expression and HbA1c levels. We then performed two-sample MR to assess the causal effect of this genetically proxied effect on MASLD and related metabolic risk abnormalities. Genetically proxied dual GLP-1R/GIPR agonists was causally associated with a substantially reduced risk of MASLD (OR: 0.24, 95% CI: 0.08-0.75, P=0.01). This protective effect was accompanied by significant improvements in systemic metabolic health, including increased high-density lipoprotein cholesterol (Beta: 0.39, 95% CI: 0.13-0.66, P=3.40×10-3), reduced triglycerides (Beta: -0.29, 95% CI: -0.42 to -0.17, P=1.57×10-6), and enhanced insulin sensitivity (Beta: 0.89, 95% CI: 0.36-1.42, P=9.58×10-4). This study provides causal evidence that dual GLP-1R/GIPR agonists protects against MASLD. The mechanism likely involves broad improvements in lipid metabolism and insulin sensitivity. These findings offer strong genetic validation for this therapeutic strategy and provide a compelling rationale for its continued clinical development for the treatment of MASLD.

208-OR: Comparable Improvement in NAFLD, Weight Loss, and Lipid Metabolism in Rats Treated with Dual GLP-1–GIP Receptor Agonist (Tirzepatide) and Gastric Sleeve

Tirzepatide and the new era of twincretins for diabetes

While awaiting randomized controlled trial results, analyses of electronic heath record data can further our understanding of the effectiveness glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists for substance use disorders without medication treatment options, such as cannabis and stimulant use disorders. Many efficacious behavioral and medication treatments exist for substance use disorders (SUDs), but these treatments often have important limitations. Behavioral options that include cognitive–behavioral therapy and contingency management can effectively treat a variety of SUDs [1, 2], but these interventions are limited by their expense, availability of trained clinicians and the motivation and time commitment required of those seeking treatment [3, 4]. SUD medications are similarly impacted by access, cost and motivational barriers [3], with further structural barriers in some countries [5, 6] resulting from unique concerns about the potential for misuse or diversion of highly effective opioid agonist treatments [7]. Along with these limitations, many individuals with SUD may not benefit from a specific treatment, highlighting the need for ongoing medication and behavioral therapy development. Qeadan et al. [8] provide intriguing evidence that glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists are linked to reduced incidence of alcohol intoxication and opioid overdose in individuals with alcohol use disorder or opioid use disorder, respectively. Using electronic health record (EHR) data from a US sample, they found a 50% reduction in the incidence of medical visits for alcohol intoxication and a 40% reduction in the incidence of opioid overdose. When combined with animal evidence [9] and emerging but more mixed evidence from human experimental and observational studies [10-12], Qeadan et al.’s [8] methodological perspective strengthens the case for double-blind, randomized controlled trials (RCTs) to evaluate the effectiveness of these medications for SUD. Indeed, the diverse sets of methodologies and samples that support effectiveness of GIP and GLP-1 receptor agonists further increase the case for RCTs, and addictions research needs these diverse methodological perspectives to truly understand the causes and develop treatments for SUD. Medication treatment options for alcohol, nicotine/tobacco and opioid use disorders or dependence may be limited for reasons noted above, but at least such options exist. This is not the case for stimulant and cannabis use disorders, where no approved medications are available [13-15]. Thus, a clear direction for future research is to test the efficacy of GIP and GLP-1 receptor agonists for treatment of psychostimulant and cannabis use disorders. While the ultimate standard will be the effectiveness of these medications in double-blind RCTs, researchers should also consider using available administrative data such as Qeadan et al. [8] to evaluate outcomes for stimulant and cannabis use disorders. Together with animal studies and re-analysis of existing human study data, rapid evaluation of EHR data can motivate and inform design of RCTs that will ultimately determine utility of these medications for cannabis, stimulant and other SUDs. In addition to evaluations of GLP-1 and GIP-1 agonists for stimulant and cannabis use disorders using EHR data, administrative data sets offer a rich opportunity to evaluate other medications for reuse as treatments for SUDs. In the past, only very perceptive clinicians and researchers could identify promising medications for repurposing to treat SUD, but with exponential increases in computing power and newer machine-learning and artificial intelligence methods, opportunities exist for large-scale exploratory investigations that identify promising medication candidates for later hypothesis-driven evaluation. Ultimately, caution is needed when approaching use of GIP and GLP-1 receptor agonists for SUD, as Leggio et al. [16] have highlighted. Regulatory approval is a necessary step before any use of these medications for SUD [16], but in the meantime use of existing data to investigate their utility for stimulant and cannabis use treatment and exploration of large data for other potential therapies for SUD should move forward to advance the scope of treatment options for SUD. Ty S. Schepis: Conceptualization; funding acquisition; writing - original draft. This article was funded by the US Department of Health and Human Services, the National Institutes of Health, and the National Institute on Drug Abuse (R01DA043691). T.S.S. receives research support from the US National Institute on Drug Abuse, the US Substance Abuse and Mental Health Services Administration and the US Food and Drug Administration.

Bilateral quinolinic acid-induced lipid peroxidation, decreased striatal monoamine levels and neurobehavioral deficits are ameliorated by GIP receptor agonist D-Ala2GIP in rat model of Huntington's disease

BACKGROUND: Tirzepatide is a novel once-a-week dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist that is used as an addition to diet and exercise to improve blood glucose in adults with type 2 diabetes. It is the first dual glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptor agonist that has been approved by the US Food and Drug Administration. The SURPASS-2 clinical trial demonstrated superiority of tirzepatide 10 mg and 15 mg over semaglutide 1 mg in glycated hemoglobin A1c reduction and weight loss from baseline to week 40. Economic analyses to support coverage and access decision-making for tirzepatide are limited. OBJECTIVES: To evaluate the cost-effectiveness of tirzepatide 10 mg vs semaglutide 1 mg injection over 52 weeks of treatment regarding A1c reduction and weight loss from the perspective of the US health care payer. METHODS: A decision tree model over a 52-week time horizon was developed to identify incremental treatment-related costs of once-weekly tirzepatide 10 mg vs semaglutide 1 mg injection. Costs were divided by mean reduction in A1c and change in body weight from baseline to week 52 observed in the SURPASS-2 clinical trial. In addition to efficacy, probabilities of adverse events, discontinuation, and need for rescue therapy were derived from the SURPASS-2 study. Drug costs in 2022 US dollars were based on wholesale acquisition cost. Costs associated with adverse events were sourced from the published literature. One-way sensitivity analyses were conducted. RESULTS: Treatment with once-weekly tirzepatide 10 mg injection was associated with a higher cost and larger reduction in A1c and body weight after 52 weeks, compared with once-weekly semaglutide 1 mg injection. The incremental cost-effectiveness ratio for tirzepatide vs semaglutide was $2,247 per 1% reduction in A1c and $237 per 1 kg weight loss. One-way sensitivity analysis suggested that incremental cost-effectiveness ratios were most sensitive to the drug costs and treatment effect on A1c and weight. CONCLUSIONS: Once-weekly tirzepatide 10 mg was associated with higher cost and greater reduction in A1c and weight vs semaglutide. Tirzepatide 10 mg is cost-effective compared with semaglutide 1 mg if payers' willingness-to-pay threshold exceeds $2,247 for 1% reduction in A1c level and $237 for 1 kg weight loss.