The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) influence metabolism through strong effects on pancreatic hormone secretion but also in a pancreas-independent manner. Here, we investigated the isolated extrapancreatic effects of endogenous GIP and GLP-1 by applying hormone receptor antagonists in totally pancreatectomized individuals. Twelve totally pancreatectomized individuals each underwent four 270-min liquid mixed meal tests (480 kcal) in a randomized study design with infusions of the GIP receptor antagonist GIP(3-30)NH2 (800 pmol/kg/min), the GLP-1 receptor antagonist exendin(9-39)NH2 (450 pmol/kg/min), GIP(3-30)NH2 + exendin(9-39)NH2, and saline (placebo), respectively. Blood samples, appetite-related measures, heart rate, blood pressure, and ad libitum food intake data were collected. Participants continued their basal insulin but omitted bolus insulin in the morning of the experiment. Infusions of GIP(3-30)NH2 and GIP(3-30)NH2 + exendin(9-39)NH2 attenuated meal-induced inhibition of bone resorption (carboxy-terminal collagen crosslinks) (nadir [mean ± SD] to 84 ± 9% and to 85 ± 8% of baseline, compared to placebo (64 ± 15%) (ps <0.05)). During exendin(9-39)NH2 and exendin(9-39)NH2 + GIP(3-30)NH2 co-infusion, GLP-1 plasma responses increased (ps <0.05). Infusion of GIP(3-30)NH2 or exendin(9-39)NH2 did not affect other measurements. Endogenous GIP contributes to the regulation of postprandial bone resorption independently of pancreatic factors. In contrast, GIP receptor and/or GLP-1 receptor antagonism had no measurable effects on glucose metabolism, gastric emptying, appetite, food intake, triglycerides, or haemodynamics, supporting a pancreatic contribution to some of these effects of the endogenous hormones, although the surgical reconstruction may have influenced the sensitivity of the targets.

The effects of a 12-week lifestyle intervention on incretin response during an oral glucose tolerance test in Latino youth with obesity and impaired glucose tolerance.

Enteroendocrine hormonal response after the ingestion of cola beverages with sucrose and non-nutritive sweeteners in healthy adults: A randomized crossover trial.

Development and validation of an LC-MS/MS method for Tirzepatide, a dual GIP/GLP-1 receptor agonist, in rat plasma for application to a pharmacokinetic study.

In type 1 diabetes, glucose-dependent insulinotropic polypeptide (GIP) increases glucagon secretion during low plasma glucose and improves time in the glycaemic range during daytime. To explore the glucose-stabilising potential of GIP in type 1 diabetes, we evaluated the effects of exogenous and endogenous GIP on plasma glucose excursions in a setting of excess prandial insulin and physical activity after meal ingestion. In a randomised, placebo-controlled, double-blind crossover design, 12 men with type 1 diabetes underwent three separate study days involving a 4.5-h continuous intravenous infusion of GIP, the GIP receptor antagonist GIP(3-30)NH2, and placebo, respectively, during which ingestion of a standardised mixed meal with subcutaneous injection of excess prandial insulin (125% of normal dose) was followed by 30 min of intermediate resistance bicycling (to increase the risk of postprandial hypoglycaemia). The GIP infusion did not protect against hypoglycaemia, but compared to GIP(3-30)NH2 infusion, it attenuated postprandial maximum plasma glucose by 1.5 ± 0.5 mmol/L (mean ± standard error of the mean) (p = 0.048). GIP(3-30)NH2 did not exacerbate glucose excursions or risk of hypoglycaemia compared with placebo. The amount of glucose infused to avoid plasma glucose <2.5 mmol/L was similar on all three study days. No differences were found in C-peptide, insulin or glucagon levels. GIP did not prevent hypoglycaemia following excess prandial insulin and physical activity after meal ingestion in males with type 1 diabetes, but it reduced peak postprandial plasma glucose compared to GIP(3-30)NH2.

This study aims to investigate how Bifidobacterium breve BBr60 improves obesity-related metabolic disorders by modulating the gut microbiota-SCFAs axis, thereby affecting inflammatory factors and metabolic hormones. A randomized, double-blind, placebo-controlled trial was conducted. A total of 75 individuals with obesity subjects (BMI ≥ 28) were enrolled and randomly assigned to either the BBr60 intervention group (10billion CFU daily) and the placebo group. After the 12-week intervention, 65 participants (BBr60: n = 33; placebo: n = 32) completed the study and were included in the primary analysis. All participants received standardized nutritional counseling aimed at a moderate energy intake (~ 1800kcal/day, including a daily intake of 25g of dietary fiber.). Every week, we call participants at a fixed time to inquire about their weekly diet and weight changes, and provide dietary suggestions for the following week based on the inquiry results. Participants were instructed to maintain their usual physical activity levels throughout the study. The composition of the gut microbiota was analyzed by 16S sequencing, fecal SCFAs were detected by GC-MS, and serum levels of IL-27, IL-1β, and metabolic hormones were measured using ELISA technology. Metabolic indicators such as body weight, body fat percentage, and HOMA-IR were also assessed. The BBr60 intervention significantly increased fecal butyrate levels (p < 0.001), accompanied by a decrease in IL-1β levels (p < 0.05) and an upregulation of IL-27 (p < 0.01). In terms of metabolic hormones, leptin (LEP), adiponectin (ADPN), connecting peptide (C-P), pancreatic polypeptide (PP), peptide YY (PYY), Glucose-dependent insulinotropic polypeptide (GIP), and Glucagon-Like Peptide-1 (GLP-1) were all significantly elevated (p < 0.05), while Homeostasis Model Assessment for Insulin Resistance(HOMA-IR) was significantly reduced in the BBr60 group (p < 0.05). In the control group, C-P, PP, and GIP were significantly increased (p < 0.05), whereas LEP, ADPN, PYY, GLP-1, and HOMA-IR showed no difference before and after the 12-week period. Correlation analysis indicated that butyrate levels were significantly positively correlated with GLP-1 and IL-27, and negatively correlated with IL-1β. Bifidobacterium breve BBr60, by remodeling the gut microbiota-SCFAs axis, inhibits the pro-inflammatory factor IL-1β, activates the anti-inflammatory signal IL-27, and synergistically regulates the metabolic hormone network (such as GLP-1, ADPN), significantly improving obesity-related metabolic disorders. This study provides a theoretical basis and intervention targets for the clinical application of probiotics targeting the "microbiota-SCFAs-inflammation/hormone axis," and future research can explore precise probiotic treatment regimens based on individual microbiota characteristics.

The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) promotes insulin secretion, lowers blood glucose levels, and is increasingly linked to bone remodeling. Native GIP is quickly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4), whereas (D-Ala2)GIP is a novel GIP analog engineered to resist DPP-4 degradation. Tumor necrosis factor-alpha (TNF-α), a key proinflammatory cytokine, promotes osteoclastogenesis and is notably upregulated during orthodontic tooth movement (OTM). This study aimed to evaluate the effects of (D-Ala2)GIP on TNF-α-induced osteoclast formation and bone resorption in vivo, as well as on OTM and related root resorption. Mice received daily supracalvarial injections of TNF-α with or without (D-Ala2)GIP for 5 days. The (D-Ala2)GIP-treated group showed significantly reduced osteoclast formation, bone resorption, and expression of osteoclastic markers TRAP and cathepsin K, compared to the group that received TNF-α alone. OTM was induced in mice by applying a nickel-titanium closed-coil spring, and mice were treated with either phosphate-buffered saline (PBS) or (D-Ala2)GIP every 2 days. After 12 days, the (D-Ala2)GIP-treated group showed significantly reduced tooth movement and fewer osteoclasts and odontoclasts on the compression side compared to the PBS control. These findings suggest that (D-Ala2)GIP inhibits OTM, potentially by suppressing TNF-α-driven osteoclastogenesis and bone resorption.

Incretin hormones, including glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), along with glucagon, are regulators of appetite, energy balance, and fat metabolism. Despite their recognized functions, reference values for these hormones in children have not previously been established. This study aimed to establish age- and sex-specific reference percentiles and z-scores for GLP-1, GIP, and glucagon in children and to examine their associations with insulin resistance, lipid status, and metabolic syndrome. Data were derived from the cohort of the study Childhood Health, Activity, and Motor Performance School Study Denmark (CHAMPS study DK) including 485 school children without metabolic syndrome. Age was positively associated with GLP-1 levels in both sexes, while GIP levels showed an inverse relationship with age in girls. Insulin sensitivity, as measured by Homeostatic Model Assessment 2 for Insulin Resistance (HOMA2-IR), was positively associated with GLP-1 z-scores in boys and glucagon z-scores in girls. Age, sex and insulin sensitivity are important determinants of incretin and glucagon hormone levels in children. The reference percentiles and z-scores generated in this study provide a framework for future studies in pediatric metabolic health and disease. This study provides age- and sex-specific reference values for glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon in children and adolescents. This is the first publication presenting percentiles and z-scores for GLP-1 and GIP in children which is of value for future pediatric comparisons. Knowledge about normal physiology is of major importance for future research in the upcoming area of GLP-1, GIP and glucagon as potential biomarkers for metabolic disorders.

Summary Background\Objectives Glucose-dependent insulinotropic polypeptide (GIP) is secreted by enteroendocrine K cells in response to nutrient ingestion. The aims of this study are: 1) to evaluate the cross-sectional associations between plasma GIP change in response to an oral glucose challenge (as a surrogate of GIP secretion) with obesity-related anthropometric measurements, fasting inflammatory biomarkers, and fasting circulating adipokines. 2) to evaluate the feasibility of using postprandial plasma GIP as a biomarker of adiposity-related phenotypes in response to starch-based meals. Methods Fifty normoglycemic women without obesity (19-32 years) were evaluated with an oral glucose tolerance test (OGTT). A feasibility study was conducted in a subset of eight women to estimate responses to starch-based meals (25 g of starch). Postprandial glycemic-related changes in plasma hormones/metabolites were assessed, as well as circulating adipokines and inflammatory biomarkers in fasting conditions. Results The Incremental-GIP change after 2-hour OGTT was significantly associated with waist circumference (rho=0.34; P=0.02), fasting plasma TNF-α (rho=0.54; P=0.0002), and white blood cell count (rho=0.39; P=0.008), but not with MCP-1, total adiponectin, leptin, or the free leptin index. A strong inverse association was found between incremental-GIP change and fasting plasma High-Molecular-Weight (HMW) Adiponectin (rho = -0.50; P = 0.0004), which remained significant after adjusting for age and body mass index. Conclusion An inverse association was found between postprandial GIP levels and circulating HMW-adiponectin levels in humans. This research highlights the suitability of using postprandial plasma GIP as a biomarker for metabolic disturbances of increased adiposity, even in the absence of obesity.

Leptin resistance limits anti-obesity efficacy. We identified a leptin-sensitizing mechanism through tirzepatide (TZP), a glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) dual-agonist. Our tirzepatide clinical trial revealed that circulating leptin levels at baseline correlated with weight loss efficacy in patients with obesity, suggesting leptin and tirzepatide could interact to achieve stronger effects on weight loss. Next, we utilized the diet-induced obesity (DIO) mice and demonstrated the synergistic effects of tirzepatide and leptin combination (TZP+Lep) on weight loss. TZP+Lep treatment further improved hepatic insulin sensitivity and upregulated thermogenetic gene expression in brown adipose tissue. Metabolic profiling under thermoneutrality revealed TZP+Lep treatment further reduced food intake and increased energy expenditure. Tirzepatide sensitized leptin signaling in hypothalamic pro-opiomelanocortin (POMC) and GLP-1R expressing neurons. TZP+Lep synergistically increased POMC neuronal firing by decreasing the inhibitory postsynaptic input. Together, our work showed combining tirzepatide and leptin as a potential way for better maintenance of metabolic homeostasis in obesity management.HighlightsTirzepatide and leptin synergistically promote weight loss through reduced food intake and increased energy expenditure.Tirzepatide and leptin synergistically improve insulin sensitivity and metabolic homeostasis with altered hepatic and adipose gene expression.Tirzepatide sensitizes leptin signaling in hypothalamic GLP-1R and POMC neurons.Tirzepatide and leptin synergistically increase POMC neuronal firing by decreasing inhibitory postsynaptic input.

Background: Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) with or without glucose-dependent insulinotropic polypeptide (GIP) are Food and Drug Administration approved for patients with type 2 diabetes (T2D) and weight loss and are increasingly being used off-label in patients with type 1 diabetes (T1D). We evaluated all-cause mortality and health care resource utilization (HCRU) among patients with T1D receiving GLP-1 RA or GLP-1 RA/GIP dual agonist over a 2-year period. Methods: Using the TriNetX database, we identified patients with T1D using ICD-10 codes, excluding those with T2D or sodium-glucose cotransporter-2 inhibitor use. Patients with T1D were divided into two cohorts of 4212 patients each based on whether or not they received a GLP-1 single/dual receptor agonist (comparison cohort vs. control cohort). We performed 1:1 propensity matching for demographics (age, sex, race), body mass index, hemoglobin A1c, and several comorbidities. Primary outcomes included all-cause mortality, HCRU, endoscopic procedures, and use of gastrointestinal prescriptions. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for all outcomes except all-cause mortality, for which Cox regression analysis was performed to obtain the hazard ratio (HR) over 2 years. Results: The cohorts were predominantly white and female. Compared to the control cohort, patients taking GLP-1 single/dual receptor agonists had lower rates of all-cause mortality (HR = 0.18, 95% CI: 0.11-0.30, P < 0.0001), all-cause hospitalizations (OR = 0.30, 95% CI: 0.20-0.45, P < 0.0001), emergency department (ED) visits (OR = 0.56, 95% CI: 0.43-0.71, P < 0.0001), endoscopy use (OR = 0.52, 95% CI: 0.38-0.70, P < 0.0001), laxative prescription (OR = 0.52, 95% CI: 0.43-0.63, P < 0.0001), and prokinetic prescription (OR = 0.74, 95% CI: 0.57-0.96, P = 0.0238). No significant differences were observed for diabetic ketoacidosis (P = 0.1030), antiemetic prescription (P = 0.2950), and hypoglycemia (P = 0.7474). Discussion: These findings suggest that use of GLP-1 RA/GIP analogs in patients with T1D was associated with significantly lower HCRU, including hospitalizations and ED visits, and reduced all-cause mortality. Further studies are warranted to confirm these observational findings.

Chronic exposure to arsenic is associated with an increased risk of developing diabetes mellitus. Quinic acid (QA), a cyclic polyol compound with known antioxidant and anti-inflammatory properties, was evaluated for its protective effects against sodium arsenite (SA)-induced hyperglycemia and hepatotoxicity in mice. In this study, mice were divided into 6 groups: control, SA (10mg/kg), QA (200mg/kg), and three groups receiving SA + QA at doses of 50, 100, or 200mg/kg. After 28 days of treatment, fasting blood glucose was measured, followed by a glucose tolerance test. On day 30, blood samples were collected for analysis of serum liver enzymes, triglycerides, and cholesterol. Hepatic oxidative stress markers, inflammatory markers, glucagon-like peptide-1 levels, and serum levels of gastric inhibitory polypeptide and insulin were also measured. Hepatic glucose transporter protein 2 (GLUT2) expression was assessed by Western blot. Histological analysis of liver and pancreatic tissues was also performed. Arsenic exposure resulted in impaired glucose tolerance, oxidative stress, inflammation, and liver injury. Treatment with QA significantly reduced these effects, restored antioxidant defenses, reduced inflammatory responses, and improved glycemic control. Western blot analysis showed that GLUT2 protein expression was decreased in the SA group, whereas QA increased hepatic GLUT2 expression in a dose-dependent manner.

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) play central roles in metabolic and cardiovascular regulation. GLP-1 receptor agonists (GLP-1RAs) are established therapies for type 2 diabetes mellitus (T2DM) and obesity because of their insulinotropic effects, weight reduction, and proven cardiovascular benefit in trial level. In contrast, GIP was historically overlooked due to reduced β-cell responsiveness in T2DM. The development of dual GIP/GLP-1 receptor agonists has reshaped this view. Tirzepatide, the first-in-class co-agonist, an antidiabetic medication to treat type 2 diabetes and for weight loss, provides superior glycemic control and weight loss compared with selective GLP-1RAs in clinical trials, demonstrating synergistic actions between the two incretin pathways. This review summarizes key physiology, pathophysiology, and therapeutic evidence in incretin biology. We describe secretion patterns, receptor distributions, and distinct actions of GIP and GLP-1, as well as alterations in incretin signaling in T2DM and obesity. Cardiovascular protective mechanisms are outlined, including improvements in lipid metabolism, reductions in blood pressure, enhanced endothelial nitric oxide activity, suppression of macrophage inflammation, decreased foam-cell formation, and stabilization of atherosclerotic plaques. At the therapeutic level, emerging directions-such as dual and triple agonists-and unresolved questions regarding long-term vascular effects of GIP and the potential for genotype-guided incretin therapy are also discussed. Collectively, these findings highlight an emerging shift toward integrated incretin-axis modulation as a therapeutic strategy for metabolic and cardiovascular disease.

In healthy men, lauric acid (C12) and L-tryptophan (Trp), when administered intraduodenally in loads of 1.26 and 0.42 kJ/min (0.3 and 0.1 kcal/min), respectively, that are individually ineffective, stimulate glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK), when combined. Both hormones slow gastric emptying, suppress energy intake and lower postprandial glucose. We have now investigated the hypothesis that combined intraduodenal administration of these nutrients reduces postprandial glucose in type 2 diabetes. In a randomised, blinded (investigators and participants), crossover study performed in the University of Adelaide Clinical Research Facility, 11 men with type 2 diabetes (age: 69±7 years; HbA1c: 51±5 mmol/mol [6.8±0.3%]; BMI: 28±1 kg/m2), each received, on four separate occasions, 45 min intraduodenal infusions of C12 (1.26 kJ/min), Trp (0.42 kJ/min), C12+Trp (1.68 kJ/min), or 0.9% saline (control), 30 min before a mixed-nutrient drink (350 ml, 2092 kJ (500kcal), 74 g carbohydrate) containing 100 mg 13C-acetate. Plasma glucose, GLP-1, glucose-dependent insulinotropic polypeptide (GIP), insulin, C-peptide and CCK concentrations were measured at baseline, following treatments alone, and for 180 min post-drink. Gastric emptying was assessed via 13C-acetate breath test. C12+Trp, but not C12 or Trp, reduced overall (p=0.02) and peak (mmol/l; control: 11.1±0.6, Trp: 10.3±0.5, C12: 10.7±0.6, C12+Trp: 9.8±0.5; p=0.01) plasma glucose. C12+Trp slowed gastric emptying (p=0.001), and increased pre-drink plasma GLP-1, GIP and CCK (all p<0.05), without affecting insulin or C-peptide. No treatment effects were observed postprandially. In type 2 diabetes, intraduodenal C12+Trp lowers postprandial glucose, probably primarily by slowing of gastric emptying and mediated by GLP-1 and CCK. These findings support further exploration of nutrient-based gastrointestinal strategies to optimise glycaemic management in type 2 diabetes. Australian New Zealand Clinical Trials Registry ( www.anzctr.org.au ) ACTRN12623000778684 FUNDING: JAS and VB were each supported by Adelaide Scholarship International stipends, provided by the University of Adelaide (JAS, 2021-2025; VB, 2017-2020) and CFB by a National Health and Medical Research Council (NHMRC) Senior Research Fellowship (Grant 1103020, 2016-2023). The research was supported by a Diabetes Australia Research Project Grant (2021-2022) to CFB.

Simultaneous control of HbA1c, lipid profile, BP and body weight is essential for preventing chronic complications of type 2 diabetes. Glucagon-like peptide-1 (GLP-1)-based therapies improve all these variables but whether the dual GLP-1 / glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide is superior to semaglutide in attaining therapeutic targets remains unclear. We performed a post hoc analysis of the SURPASS-2 trial, a randomised phase 3 study including 1879 adults with type 2 diabetes. Participants were randomised to receive tirzepatide (5, 10 or 15 mg) or semaglutide (1 mg). In this analysis, we compared the effects of tirzepatide vs semaglutide on the attainment of standard (HbA1c<53 mmol/mol [7%], BP <140/90 mmHg, LDL-cholesterol <1.8 mmol/l, >10% weight loss) and intensive (HbA1c <48 mmol/mol [6.5%], BP <130/80 mmHg, LDL-cholesterol <1.4 mmol/l , >15% weight loss) therapeutic targets at 40 weeks. In the SURPASS-2 trial, at baseline, 19% of participants were on target for attaining no standard goals, 59% for one goal and 21% for two or more goals. For intensive therapeutic targets, 58% of participants were on target for attaining zero goals, 38% for one goal and 4% for two goals. All doses of tirzepatide increased the number of achieved standard and intensive targets compared with semaglutide. For standard targets, 34% of participants treated with semaglutide met three or more targets, compared with 42%, 53% and 57% with tirzepatide 5, 10 and 15 mg, respectively. For intensive targets, 8% of participants treated with semaglutide met three or more targets, vs 15%, 20% and 29% with tirzepatide. Regarding specific therapeutic goals, tirzepatide increased the odds of achieving standard and intensive targets for HbA1c (HbA1c<53 mmol/mol [7%], OR 1.50 [95% CI 1.12, 2.00]; HbA1c <48 mmol/mol [6.5%], OR 1.88 [95%CI 1.49, 2.36]) and weight loss (weight loss >10%, OR 2.72 [95% CI 2.14, 3.47]; weight loss >15%, OR 3.86 [95% CI 2.69, 5.55]) and the intensive target for BP (OR 1.45 [95% CI 1.17, 1.81]). Tirzepatide improves therapeutic target attainment compared with semaglutide in type 2 diabetes. Longer trials are needed to confirm benefits on long-term prognosis. Data for this post hoc analysis was accessed through the Vivli (Center for Global Clinical Research Data) platform ( https://vivli.org ) with the Vivli ID 00009964.

This review summarizes emerging evidence on the use of the dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist (RA) tirzepatide in improving obstructive sleep apnea (OSA) outcomes in individuals with obesity. Tirzepatide has demonstrated significant reductions in apnea-hypopnea index (AHI) among patients with OSA and coexisting obesity. It has recently become the first medication approved by the U.S. Food and Drug Administration (FDA) specifically for moderate-to-severe OSA in adults with obesity. In addition to weight loss, tirzepatide has been associated with reduced cardiovascular, hepatic, and renal events, suggesting broader systemic benefits. As a dual GIP/GLP-1 RA, tirzepatide represents a promising therapy for OSA in individuals with obesity, offering benefits of both weight reduction and symptom improvement. Given the high burden and underdiagnosis of OSA, particularly in populations with obesity, it should be considered earlier in the treatment algorithm, either in combination with or as an alternative to traditional therapies.

BackgroundTirzepatide, a dual incretin agonist of the glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors, has favorable effects on glycemic control and body weight. The effects on cardiovascular outcomes are uncertain.MethodsWe conducted an active-comparator–controlled, double-blind, noninferiority trial in which patients with type 2 diabetes and atherosclerotic cardiovascular disease were randomly assigned in a 1:1 ratio to receive a weekly subcutaneous injection of tirzepatide (up to 15 mg) or dulaglutide (1.5 mg), an agent that has been shown to reduce the incidence of cardiovascular events. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke and was tested for noninferiority of tirzepatide to dulaglutide with a margin of 1.05 for the upper limit of the 95.3% confidence interval for the hazard ratio. An upper limit of less than 1.00 was considered to indicate superiority of tirzepatide to dulaglutide.ResultsA total of 13,299 patients underwent randomization; 134 were subsequently excluded because they did not meet inclusion criteria. The modified intention-to-treat population thus included 6586 patients in the tirzepatide group and 6579 in the dulaglutide group. The mean (±SD) age of the patients was 64.1±8.8 years, 29.0% were women, the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 32.6±5.5, the mean glycated hemoglobin level was 8.4±0.9%, and the mean duration of diabetes was 14.7±8.8 years. A primary end-point event occurred in 801 patients (12.2%) in the tirzepatide group and 862 (13.1%) in the dulaglutide group (hazard ratio, 0.92; 95.3% confidence interval, 0.83 to 1.01; P=0.003 for noninferiority; P=0.09 for superiority). The incidence of adverse events appeared to be similar in the two groups, although more gastrointestinal adverse events were observed in the tirzepatide group.ConclusionsAmong patients with type 2 diabetes and atherosclerotic cardiovascular disease, tirzepatide was noninferior to dulaglutide with respect to a composite of death from cardiovascular causes, myocardial infarction, or stroke. (Funded by Eli Lilly; SURPASS-CVOT ClinicalTrials.gov number, NCT04255433.)

ContextRecent studies suggest glucagon-like peptide receptor-1 agonists (GLP-1RA) and glucose-dependent insulinotropic polypeptide (GIP) may contribute to altered calcium metabolism.ObjectiveThis study examines the association between GLP-1RA/GIP-RA use and risk of post-thyroidectomy hypocalcemia.MethodsThis propensity-matched cohort study utilized the TriNetX Platform to analyze adult patients who underwent total thyroidectomy (2010 to 2024). The intervention cohort included patients with a GLP-1RA or GIP-RA prescription 1 year before thyroidectomy; the control group had no GLP-1RA/GIP-RA history. Propensity score matching controlled for demographics and relevant clinical covariates. Primary outcomes included risk of hypocalcemia at 0-1 month, 1-6 months, and 6-12 months after surgery. Using Poisson regression, odds ratios were reported (alpha = 0.05).ResultsAmong 70 665 patients, 1759 (2.59%) received a GLP-1RA or GIP-RA. Each matched cohort contained 1732 patients with similar preoperative parathyroid hormone or calcium levels. The GLP-1RA/GIP-RA cohort had a 12% lower risk of hypocalcemia from 0 to 1 month after surgery (relative risk [RR] 0.88; 95% CI: 0.81-0.97). In the sensitivity analysis considering postoperative calcitriol supplementation, recipients with GLP-1RA/GIP-RAs use were less likely to develop hypocalcemia in the month after surgery (RR 0.84; 0.74-0.96), as were those with GLP-1RA/GIP-RAs who never received calcitriol in the month after surgery (RR 0.81; 0.72-0.90). Under subgroup analysis, semaglutide was the sole agent associated with a reduced risk of hypocalcemia.ConclusionPatients with a history of GLP-1RA/GIP-RA use may experience a lower risk of short-term hypocalcemia after thyroidectomy, suggesting personalized supplementation strategies may be required for this population.

Diabetes mellitus (DM) remains a major global health burden, characterized by chronic hyperglycemia that leads to severe complications such as cardiovascular diseases, nephropathy, and neuropathy, significantly contributing to its high mortality rates. Effective management of post-prandial hyperglycemia is a key therapeutic strategy, with enzyme inhibition emerging as a promising approach. While targeting individual enzymes like alpha-amylase and alpha-glucosidase—responsible for starch breakdown—has shown efficacy, growing evidence suggests that the simultaneous inhibition of multiple key enzymes, including dipeptidyl peptidase-IV (DPP-IV), offers superior glucose regulation by preserving incretin hormones like Glucagon-Like Peptide-1 (GLP-1) and Glucose-Dependent Insulinotropic Peptide (GIP). Medicinal plants, rich in bioactive compounds, have demonstrated the ability to exert multi-targeted inhibitory effects on these enzymes, exhibiting potent synergistic activity that enhances their therapeutic potential. This comprehensive review explores the pivotal roles of alpha-amylase, alpha-glucosidase, and DPP-IV in glucose metabolism and highlights medicinal plants with multi-enzyme inhibitory properties. By emphasizing the significance of synergistic inhibition, this review provides insights into the development of next-generation plant-based anti-diabetic therapeutics, offering a more effective, natural, and safer approach to managing DM.

Tirzepatide is a long-acting agonist for the glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors approved for the treatment of type 2 diabetes mellitus, weight management in obese patients, or overweight patients with at least one weight-related comorbid condition. The clinical effects of tirzepatide are demonstrated by improved glycemic control, reduced overall appetite, decreased food intake, and body weight. Several studies indicated that the vasculoprotective effects and anti-atherosclerotic potential of tirzepatide extend far beyond glycemic control. Tirzepatide stimulates the mobilization and function of endothelial progenitor cells, which facilitates vascular repair and mitigates hyperglycemia-induced damage. Tirzepatide enhances the activity of endothelial nitric oxide synthase, reduces the activity of endothelial activation molecules such as intercellular adhesion molecule 1 and vascular cell adhesion molecule 1, promotes vasodilation, and reduces peripheral vascular resistance. Furthermore, the drug inhibits inflammation by suppressing the expression of pro-inflammatory cytokines, such as tumor necrosis factor α, interleukin-1β, and interleukin-6. Moreover, tirzepatide improves lipid profiles by decreasing total cholesterol, low-density lipoprotein cholesterol, and triglycerides, while increasing high-density lipoprotein cholesterol. By improving endothelial function, reducing inflammation, and lowering body weight, tirzepatide lowers both systolic and diastolic blood pressure. This article summarizes the data with special emphasis on the mechanisms underlying the anti-atherosclerotic and vasoprotective effects of tirzepatide, based on studies conducted to date.