Explore studies of exenatide.
Managed care analysis of exenatide (GLP-1 agonist: weight loss, injectable), sitagliptin (DPP-4 inhibitor: oral, weight neutral), and pramlintide (amylin analog: injectable, weight loss) for T2DM positioning — incretin drugs transforming diabetes pharmacotherapy economics.
VanDeKoppel, Shawna; Choe, Hae Mi; Sweet, Burgunda V · Review
Exenatide significantly attenuated resting forearm blood flow (FBF) at 3 hours after the meal (P = 0.003) and showed a trend at 6 hours (P = 0.056) compared to placebo. This means exenatide blunted the vasodilation (blood vessel widening) that normally happens after eating. Exenatide also had beneficial metabolic effects: it prevented the post-meal glucose spike (glucose actually decreased at 2 hours while it rose with placebo and saxagliptin) and abated the transient triglyceride increase. Only the exenatide group did not show a significant insulin surge. No differences were found in peak forearm blood flow, plasma nitrotyrosine (an oxidative stress marker), or plasma 8-iso-prostaglandin F2alpha between groups. Free fatty acids declined in all groups but less markedly with exenatide. The researchers concluded the vascular effects were primarily endothelium-independent, meaning exenatide altered blood flow through mechanisms other than the vessel lining's nitric oxide system.
Hamidi, Vala; Riggs, Kayla; Zhu, Liang; Bermudez Saint Andre, Karla; Westby, Christian; Coverdale, Sara; Dursteler, Amy; Wang, Hongyu; Miller Iii, Charles; Taegtmeyer, Heinrich; Gutierrez, Absalon D · Randomized Controlled Crossover Trial
The study tested exenatide across three levels of evidence: In frataxin-deficient mice, exenatide improved glucose handling through enhanced insulin content and secretion. More importantly, it induced frataxin protein and iron-sulfur cluster-containing proteins in both pancreatic beta cells and brain tissue. It was also protective to sensory neurons in dorsal root ganglia, the neurons that die in Friedreich ataxia. In patient-derived induced pluripotent stem cells (iPSCs) differentiated into beta cells and sensory neurons, GLP-1 analogs induced frataxin expression, reduced oxidative stress, and improved mitochondrial function. In a pilot human trial, Friedreich ataxia patients treated with exenatide for 5 weeks showed modest frataxin induction in platelets. While modest, this is the first demonstration that a GLP-1 drug can increase frataxin in actual patients. The mechanism involves GLP-1 receptor (incretin receptor) activation, identifying this receptor as a new therapeutic target for Friedreich ataxia.
Igoillo-Esteve, Mariana; Oliveira, Ana F; Cosentino, Cristina; Fantuzzi, Federica; Demarez, Céline; Toivonen, Sanna; Hu, Amélie; Chintawar, Satyan; Lopes, Miguel; Pachera, Nathalie; Cai, Ying; Abdulkarim, Baroj; Rai, Myriam; Marselli, Lorella; Marchetti, Piero; Tariq, Mohammad; Jonas, Jean-Christophe; Boscolo, Marina; Pandolfo, Massimo; Eizirik, Décio L; Cnop, Miriam · Translational (Mouse + IPSC + Pilot Human Trial)
Exenatide is a peptide drug given by injection because it is destroyed in the gut and cannot cross the intestinal wall. Hydrophobic ion pairing (HIP) makes peptides lipophilic by pairing them with surfactant counterions. Two surfactant types were tested: cationic THA (tetraheptylammonium bromide) and anionic DOC (sodium docusate). Both formed stable complexes with exenatide. Exenatide-THA was more lipophilic (log D of 2.29 in simulated intestinal fluid vs 1.2 for exenatide-DOC). When loaded into lipid nanocarriers (41% Capmul MCM, 15% Captex 355, 40% Cremophor RH, 4% propylene glycol), the THA formulation showed: - 10-fold enhancement in intestinal apparent membrane permeability vs free exenatide - 28.0% ± 5.2% relative oral bioavailability in healthy rats The DOC formulation achieved 3-fold permeability enhancement and 16.3% ± 6.6% bioavailability. Neither formulation caused significant hemolytic activity at 0.25% concentration, indicating safety for oral use.
Ismail, Ruba; Phan, Thi Nhu Quynh; Laffleur, Flavia; Csóka, Ildikó; Bernkop-Schnürch, Andreas · Pharmaceutical Formulation + Animal Pharmacokinetics
Dulaglutide reduced HbA1c 0.24% more than liraglutide in real-world clinical practice (p=0.003), confirmed by meta-analysis of observational studies.
Morieri, Mario Luca; Rigato, Mauro; Frison, Vera; Simioni, Natalino; D'Ambrosio, Michele; Tadiotto, Federica; Paccagnella, Agostino; Lapolla, Annunziata; Avogaro, Angelo; Fadini, Gian Paolo · Observational
Exenatide improved MDS-UPDRS Part III motor scores by 3.1-5.6 points versus controls, with effects persisting after drug cessation, but evidence certainty remains low.
Mulvaney, Caroline A; Duarte, Gonçalo S; Handley, Joel; Evans, David Jw; Menon, Suresh; Wyse, Richard; Emsley, Hedley Ca · Systematic Review
GLP-1 receptor agonists upregulate mucin expression in airways via p38 MAPK, exacerbating emphysematous phenotypes in obstructive lung disease models.
Nohara, Hirofumi; Nakashima, Ryunosuke; Kamei, Shunsuke; Fujikawa, Haruka; Ueno-Shuto, Keiko; Kawakami, Taisei; Eto, Yuka; Suico, Mary Ann; Li, Jian-Dong; Kai, Hirofumi; Shuto, Tsuyoshi · Animal
Semaglutide subcutaneous was superior to dulaglutide and exenatide ER for HbA1c and weight reduction in head-to-head trials, with both semaglutide and dulaglutide showing cardiovascular and renal benefits.
Patel, Dhiren · Review
Lixisenatide showed 5-fold lower cAMP signaling potency than exendin-4 despite equal binding affinity, with slower GLP-1 receptor recycling. An N-terminal His1→Phe1 substitution improved the pharmacology of both ligands.
Pickford, Philip; Lucey, Maria; Fang, Zijian; Bitsi, Stavroula; de la Serna, Jorge Bernardino; Broichhagen, Johannes; Hodson, David J; Minnion, James; Rutter, Guy A; Bloom, Stephen R; Tomas, Alejandra; Jones, Ben · Animal Study
GLP-1 RAs increased bone mineral density at multiple skeletal sites over 52 weeks, while placebo showed significant bone loss at the spine, femoral neck, and total hip.
Cai, Ting-Ting; Li, Hui-Qin; Jiang, Lan-Lan; Wang, Hui-Ying; Luo, Meng-Hui; Su, Xiao-Fei; Ma, Jian-Hua · Rct
Across 200,148 participants and 396,457 person-years, GLP-1 RAs showed cardiovascular safety with potential MACE benefit for liraglutide (PE range 0.53-0.95) and no association with pancreatitis, pancreatic cancer, breast cancer, or hypoglycemia.
Caparrotta, Thomas M; Templeton, Jack B; Clay, Thomas A; Wild, Sarah H; Reynolds, Rebecca M; Webb, David J; Colhoun, Helen M · Systematic Review
Venom-derived peptides from diverse species (bees, cone snails, sea anemones, scorpions, snakes, spiders) show potential for glycemic control, building on the proven success of exendin-4/exenatide.
Coulter-Parkhill, Aimee; McClean, Stephen; Gault, Victor A; Irwin, Nigel · Review
Combined ADMSC + exenatide therapy showed superior renoprotective effects versus ADMSCs alone in diabetic rats, with significant improvement in kidney function and reduced inflammatory, fibrotic, and apoptotic markers.
Habib, Heba A; Heeba, Gehan H; Khalifa, Mohamed M A · Preclinical Animal Study
Both exendin-4 and semaglutide improved outcomes when given right after brain injury in newborn mice. The drugs reduced the size of the damaged brain area, increased survival rates, and improved locomotor function in both short-term and long-term assessments. The mechanism involved upregulation of the PI3K/AKT signaling pathway (a cell survival pathway) and increased cAMP levels (a molecule that helps cells communicate). The drugs also reduced inflammation after oxygen-glucose deprivation in brain cells.
Poupon-Bejuit, Laura; Geard, Amy; Millicheap, Nathan; Rocha-Ferreira, Eridan; Hagberg, Henrik; Thornton, Claire; Rahim, Ahad A · Animal Study
After 6 weeks of treatment in rats with metabolic syndrome: - Exenatide improved ejection fraction by 3% vs untreated MetS group - Dulaglutide improved ejection fraction by 7% vs untreated MetS group - Histology showed reduced cardiomyocyte cross-sectional area: 11% reduction with exenatide, 18% with dulaglutide - Both drugs reduced oxidative stress biomarkers - Dulaglutide showed a slight advantage overall
Ravic, Marko; Srejovic, Ivan; Novakovic, Jovana; Andjic, Marijana; Sretenovic, Jasmina; Muric, Maja; Nikolic, Marina; Bolevich, Sergey; Alekseevich Kasabov, Kirill; Petrovich Fisenko, Vladimir; Stojanovic, Aleksandra; Jakovljevic, Vladimir · Animal Study
After subcutaneous injection in rats: - Liraglutide: apparent half-life 9.1 hours, delayed peak plasma levels, bioavailability ~10% - Exenatide: half-life ~1 hour, bioavailability ~100% Lymphatic uptake was low for both peptides (<0.5% of dose), though lymph-to-plasma concentration ratios exceeded 1 at several early timepoints, suggesting some direct lymph uptake. The single-chain C16 palmitic acid on liraglutide did not substantially boost lymphatic transport. The authors suggest that if lymphatic delivery is desired, more lipophilic conjugates (like diacylglycerols) with higher albumin or lipoprotein binding would be needed.
Reddiar, Sanjeevini Babu; Abdallah, Mohammad; Styles, Ian K; Müllertz, Olivia O; Trevaskis, Natalie L · Animal Pharmacokinetic
Exendin-4 demonstrates neuroprotective effects against both Alzheimer's and Parkinson's disease in preclinical models, operating through anti-inflammatory, anti-oxidative, and neurotrophic mechanisms.
Verma, Aanchal; Chaudhary, Shobhit; Solanki, Kunal; Goyal, Ahsas; Yadav, Harlokesh Narayan · Review
Exendin-4 dose-dependently attenuated responding to incentive cues (reward-predictive stimuli) in rats without affecting free consumption of small sucrose volumes, suggesting GLP-1R activation modulates cue-driven motivation rather than just palatability.
Wakabayashi, Ken T; Baindur, Ajay N; Feja, Malte; Suarez, Mauricio; Chen, Karie; Bernosky-Smith, Kimberly; Bass, Caroline E · Animal Study
PT320 (sustained-release exenatide) preserved mitochondrial function and morphology in PD model mice by reducing Fis1 and increasing Opa1, lowering ROS and preventing cytochrome c release during dopamine neuron degeneration.
Wang, Vicki; Tseng, Kuan-Yin; Kuo, Tung-Tai; Huang, Eagle Yi-Kung; Lan, Kuo-Lun; Chen, Zi-Rong; Ma, Kuo-Hsing; Greig, Nigel H; Jung, Jin; Choi, Ho-Ii; Olson, Lars; Hoffer, Barry J; Chen, Yuan-Hao · Animal Study
Borneol-functionalized lipid nanoparticles delivered exenatide across the BBB at 4.21× the rate of conventional LNPs, reducing α-synuclein to 51.85% and increasing dopamine to 1.85× in Parkinson's disease mice.
Wu, Xiaomei; Yuan, Renxiang; Xu, Yichong; Wang, Kai; Yuan, Hong; Meng, Tingting; Hu, Fuqiang · Animal Study
Exenatide time-dependently modulates the hepatic circadian clock through CNS GLP-1 receptors. Morning-equivalent dosing (ZT12) counteracted clock disruption from irregular eating; evening-equivalent dosing (ZT0) worsened it. CNS GLP-1 receptor knockdown attenuated these effects.
Xu, Pingping; Morishige, Jun-Ichi; Jing, Zheng; Nagata, Naoto; Shi, Yifan; Iba, Tomohiro; Daikoku, Takiko; Ono, Masanori; Maida, Yoshiko; Fujiwara, Tomoko; Fujiwara, Hiroshi; Ando, Hitoshi · Animal Study
Exenatide significantly decreased IL-1β and IFN-γ levels over 48 weeks, while insulin increased both markers. The anti-inflammatory effect of exenatide was independent of changes in weight, waist circumference, and HbA1c, and was associated with improved insulin resistance.
Yang, Xubin; Deng, Hongrong; Lv, Jing; Chen, Xueyan; Zeng, Longyi; Weng, Jianping; Liang, Hua; Xu, Wen · RCT
Exenatide directly inhibited hKv1.5 and hNav1.5 cardiac ion channels, reducing atrial fibrillation susceptibility through electrophysiological modification of atrial cells.
Zhou, Qian; Hao, Guoliang; Xie, Wensen; Chen, Bin; Lu, Wuguang; Wang, Gongxin; Zhong, Rongling; Chen, Jiao; Ye, Juan; Shen, Jianping; Cao, Peng · In Vitro
Exenatide combined with metformin improved insulin resistance more effectively than metformin alone, demonstrating complementary mechanisms for early diabetes management.
Al-Qudah, Abd-Alrahman; Al-Hanaktah, Mohammad; Albadaineh, Reham · Meta Analysis
Review of GLP-1 agonist developments for gestational diabetes explores efficacy evidence, safety concerns, and the potential role of these drugs in pregnancy-related metabolic disease.
Alshehri, Fahad S · Review
Descriptive analysis from VigiAccess global pharmacovigilance database characterizes drug-related problems associated with semaglutide across international reporting systems.
Amirthalingam, Palanisamy · Cohort
Tirzepatide at all doses (5, 10, 15 mg) significantly outperformed GLP-1 RAs for both blood sugar control and weight loss when combined with basal insulin.
Osumili, Beatrice; Sapin, Hélène; Yang, Zhengyu; Ranta, Kari; Paik, Jim S; Blüher, Matthias · Meta Analysis
Metformin and exenatide significantly increased osteoblast and osteoclast numbers at bone defect sites (p=0.007 for both) without affecting overall bone volume.
Ozturk, Hasan; Simsek, Neslihan; Akinci, Levent; Ozgocmen, Meltem; Yigit, Dilek Helvacioglu · Animal Study
The biphasic delivery system (Ex-NPs-gel) provided both rapid initial and sustained long-term exenatide release, achieving prolonged glycemic control compared to standard exenatide injections in diabetic rats.
Pan, Shu; Dong, Nan; Yuan, Haoyang; Zhang, Yu; He, Haibing; Yin, Tian; Wang, Yanjiao; Gou, Jingxin; Tang, Xing · Animal Study