Table 1.
Comprehensive list of incretin receptor-targeting drugs for metabolic disease treatment. Numerous incretin receptor-targeting treatments have been approved (red if in the United States, green if abroad) or are currently in clinical trials or being developed (blue) for metabolic diseases, namely T2DM and obesity, and/or promoting weight loss. Highlighted drugs are in clinical trials for the treatment of AD or PD. While DPP-IV inhibitors do not directly stimulate incretin receptors, they increase levels of endogenous incretins and, thereby, promote incretin receptor signaling, and thus are included in the table. Only Victoza®, Bydureon®, and Byetta® have completed clinical trials for incretin analog treatment for neurodegenerative diseases; Ozempic®, Rybelsus®, Adlyxin®/Lyxumia®, PT320, and NLY01 are currently in clinical trials for neurodegenerative disease treatment.
| Mechanism of Action | Company | Drug Name | Administration | Uses | Other Notes | |
|---|---|---|---|---|---|---|
| GLP-1R Agonist | AstraZeneca | Exenatide | Bydureon ® BCise ™ | Once weekly SC | T2DM | Latest formulation of Bydureon®. |
| Bydureon ® | Once weekly SC | T2DM | 2 mg injection once each week, extended release formulation. Completed clinical trial in severely obese adolescents in 2020 (#NCT02496611). Phase 2 clinical trial (#NCT01971242) for PD patients completed in 2016 (see (a.) Athauda et al. 2017). Additional clinical trials for PD patients ongoing. | |||
| Byetta ® | Twice daily SC | T2DM | Used any time within 1 hour before morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart). In clinical trial (#NCT02442791), neuroprotective effects of Byetta® administration following cardiac arrest showed no significant outcomes (see (b.) Wiberg et al. 2016). Phase 2 clinical trial (#NCT02838589) completed investigating effects on cerebral blood flow. Clinical trials in AD (#NCT01255163; see (c.) Mullins et al. 2019) and PD (*EUCTR2009-018137-37-GB; see (d.) Aviles-Olmos et al. 2013) completed in 2016 and 2013, respectively. | |||
| Sanofi-Aventis | Lixisenatide + insulin glargine | Soliqua ® | Once daily SC | T2DM | Approved for adults with T2DM to lower A1C. 15–60 units of Soliqua® 100/33 per injection. Each unit of Solique 100/33 contains 0.33 mcg lixisenatide and 1 unit of Lantus. | |
| Lixisenatide | Adlyxin®/Lyxumia® | Once daily SC | T2DM | 10 mcg once daily injection for 14 days. On Day 15, dosage increased to 20 mcg once daily. Administered within one hour before the first meal of the day. Currently in phase 2 clinical trial (#NCT03439943) for PD treatment. | ||
| Sanofi-Aventis/Hanmi Pharmaceuticals | Efpeglenatide | HM 11260C | Once weekly SC | T2DM | Completed Phase 3 clinical trial for T2DM treatment (#NCT03353350). | |
| Novo Nordisk | Liraglutide | Victoza ® | Once daily SC | T2DM | Used at any time of day, independent of meals. Use 0.6 mg per day for one week then increase to 1.2 mg, which can be increased to 1.8 mg for additional glycemic control. Clinical trial in AD patients (#NCT01469351) completed in 2013 (see (e.) Gejl et al. 2016). Additional clinical trials for AD and PD patients ongoing. | |
| Saxenda ® | Once daily SC | Weight Loss | 3 mg daily SC injection. | |||
| Liraglutide + insulin degludec | Xultophy ® | Once daily SC | T2DM | 10 units Xultophy® 100/3.6 (10 units insulin degludec, 0.36 mg liraglutide) once daily SC. In patients converting from basal insulin or GLP 1R agonist: 16 units Xultophy® 100/3.6 (16 units insulin degludec, 0.58 mg liraglutide). | ||
| Semaglutide | Ozempic ® | Once weekly SC | T2DM | 0.25 mg (with or without meals). After 4 weeks, dose increased to 0.5 mg once weekly. Can be increased to 1 mg once weekly if needed. Phase 2 clinical trial (#NCT03659682) not yet recruiting in PD patients. | ||
| Rybelsus ® | Oral once daily | T2DM | 7 mg or 14 mg tablets. Approved to lower A1C, may help with weight loss. Currently recruiting for phase 3 clinical trials (#NCT04777409, #NCT04777396) in early AD patients. | |||
| Wegovy ® | Once weekly SC | Obesity | 2.4 mg weekly SC injection. | |||
| IcoSema | Once weekly SC | T2DM | Semaglutide + insulin icodec. Phase 3 clinical trial (#NCT05259033) currently recruiting. | |||
| NASH | Daily SC | NASH/NAFLD | Phase 2 clinical trial (#NCT02970942) completed. NASH measurements are primary outcome with NAFLD as secondary outcome measure. | |||
| ----------------- | NN9926, NN9927 | Oral | T2DM | Long acting, new molecular entities currently in development. | ||
| Eli Lilly | Dulaglutide | Trulicity ® | Once weekly SC | T2DM | 0.75 or 1.5 mg SC injection once weekly from single dose pen. | |
| Beijing Dongfang Biotech Co., Ltd. | Exendin-4 | JY09 | Once dailly SC | T2DM | Phase 1 clinical trial (#NCT04354090) completed. Exendin-4 + human Immunoglobulin G2 (IgG2) Fc fragment. | |
| Peptron | Exenatide SR | PT320 | Biweekly SC | T2DM/Obesity/PD | Formerly PT302. Proprietary formulation allows for injection with smaller needle to reduce injection pain. Phase 1 clinical trial (#NCT00964262) completed for treatment of T2DM. Phase 2 clinical trials completed in South Korea for T2DM. Phase 2 clinical tral in PD patients in progress (#NCT04269642). | |
| Intarcia | Exenatide | ITCA 650 | Long term implant | T2DM | Implant with potential to offer 6 month exenatide delivery with 1 year delivery options in development. Phase 3 clinical trials have been completed with New Drug Application (NDA) submitted to the Food and Drug Administration (FDA) (pending approval). | |
| vTv Therapeutics | ----------------- | TTP273 | Oral once or twice daily | T2DM | Non-peptide GLP-1R agonist. Completed phase 2 clinical trial (#NCT02653599) for T2DM treatment. | |
| CSPC ZhongQi Pharmaceutical Technology Co., Ltd. | Recombinant Exenatide | rExenatide-4 | SC twice daily | T2DM | Phase 3 clinical trial (#NCT03239119) in Chinese T2DM patients initiated, but not yet recruiting. | |
| Oramed | Exenatide Oral | ORMD-0901 | Oral | T2DM | US FDA cleared Investigational New Drug (IND) application for trials in humans as of September 2018. | |
| Shanghai Biolaxy | Exenatide | Nodexen | Oral | T2DM | Nanoparticle oral delivery. Clinical trials ongoing in China. | |
| Jiangsu Hengrui Medicine Co. Ltd. | Loxenatide | PEX168 | Once weekly SC | T2DM | Phase 3 clinical trial in progress (#NCT02477969). This is a PEGylated formulation. | |
| Shanghai Benemae Pharmaceutical | ----------------- | Beinaglutide | 3x daily SC | T2DM/Obesity | Phase 4 clinical trial recruiting (#NCT05005741). Approved for use in China in 2016. | |
| Zydus Lifesciences Ltd. | ----------------- | ZYD1 | Oral and SC | T2DM | Phase 1 clinical trial completed (#NCT01972893). | |
| PegBio Co., Ltd. | ----------------- | PB-119 | Once weekly SC | T2DM | Phase 3 clinical trial (#NCT04504396) recruiting. This is a PEGylated exenatide formulation. | |
| Regor Pharmaceuticals Inc. | ----------------- | RGT001-075 | Oral once daily | T2DM | Phase 2 clinical trial (#NCT05297045) in progress. | |
| CSPC Baike (Shandong) Biopharmaceutical Co., Ltd. | ----------------- | TG103 | Once weekly SC | Obesity | Phase 2 clinical trial (#NCT05299697) recruiting. | |
| Hansoh Pharmaceuticals | Polyethylene Glycol Loxenatide | Fu Laimei ® | Once weekly SC | T2DM | Approved in China for adults with poor blood glucose control. Recommended dose 0.1–0.2 mg/week. | |
| Neuraly Inc. | Exenatide | NLY01 | Once weekly SC | PD/AD | This is a PEGylated formulation. Phase 1 clinical trial completed in 2019 (#NCT03672604; see (f.) Yun et al. 2018). Phase 2 clinical trial ongoing in patients with PD (#NCT04154072). | |
| GIPR Agonist | ----------------- | GIP Peptide | ----------------- | ----------------- | T1DM | GIP peptide completed clinical trial (#NCT03556098) investigating its efficacy as a safeguard against hypoglycemia in patients with Type-1 diabetes mellitus (T1DM). |
| Zealand Pharmaceuticals | ----------------- | ZP4165 | Intra Venous (I.V.) or SC | T2DM | DPP-IV resistance and potentiates GLP-1 mediated weight loss and improved glycemic control in rats (see (g.) Nørregaard et al. 2018). | |
| GLP-1R/GcgR Dual Agonist | Hamni Pharmaceuticals/Janssen Research & Development, LLC | ----------------- | HM12525A/JNJ-64565111 | Once weekly SC | T2DM/Obesity | Phase 2 clinical trial completed (#NCT03586830). |
| Zealand Pharmaceuticals/Boehringer Ingelheim | ----------------- | BI 456906 | Once weekly SC | Obesity | Long lasting analogue of amylin and partially builds on the effects of oxyntomodulin. Completed phase 1 clinical tral (#NCT03175211) to assess safety, tolerability, and pharmacokinetics/pharmacodynamics. Phase 1 trials in Germany for obesity initiated. | |
| Astra Zeneca/MedImmune | ----------------- | MEDI0382 | Daily SC | T2DM | Completed phase 2a (see (h.) Ambery et al. 2018) and phase 2b clinical trials (#NCT03235050). | |
| Sanofi-Aventis | ----------------- | SAR425899 | Daily SC | T2DM/Obesity | Completed phase 1 clinical trial (#NCT03414736; see (i.) Goebel et al. 2018). | |
| Janssen Pharmaceuticals | ----------------- | JNJ-54728518 | ----------------- | T2DM/Obesity | Phase 1 clinical trials initiated for obesity and T2DM in 2016. Pre-clinical trials for obesity also initiated in 2016. | |
| Novo Nordisk | ----------------- | NNC9204-1177 | Once weekly SC | Obesity | Completed phase 1 clinical trial (#NCT03308721). | |
| Prolor/OPKO Biological | ----------------- | OPK-88003 | Once weekly SC | T2DM | Completed phase 2 clinical trial (#NCT03406377). | |
| Spitfire Pharma | ----------------- | SP-1373 | Once daily SC | NASH/T2DM/Obesity | Clinical trial for T2DM and obesity planned for 2019. | |
| Boehringer Ingelheim | ----------------- | BI 456906 | ----------------- | Obesity | Completed phase 1 clinical trial (#NCT03591718) in patients with obesity. | |
| GLP-1R/GLP-2R Dual Agonist | Zealand Pharmaceuticals | ----------------- | Dapiglutide | ----------------- | T2DM | Early phase 1 clinical trials completed (#NCT03994549, #NCT04612517). |
| GLP-1R/GIPR Dual Agonist | Eli Lilly | Tirzepatide | Mounjaro ™ | Once weekly SC | T2DM | Approved for adults with T2DM. Available in 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg doses through auto-injector pen. |
| Novo Nordisk | ----------------- | RG 7697/NNC0090-2746/MAR709 | Once daily SC | T2DM | Completed phase 2 clinical trial (#NCT02205528; see (j.) Frias et al. 2017). | |
| Kariya Pharmaceuticals | ----------------- | KP405 | Info not available | PD/AD | Ready for phase 1 clinical trials. Toxicology studies completed. | |
| Sanofi | ----------------- | SAR438335 | Info not available | T2DM | Currently in phase 1 clinical trals in France. | |
| GLP-1R/GIPR/GcgR Triagonist | Novo Nordisk | ----------------- | NNC9204-1706 | Once daily SC | Obesity | Completed phase 1 clinical trial (#NCT03661879). |
| Hanmi Pharmaceutical Co. Lmtd. | ----------------- | HM15211 | SC | Obesity | Long acting formulation. Current phase 1 clinical trial (#NCT03374241) recruiting (see (k.) Kim et al. 2018 for latest research on compound). | |
| Sanofi | ----------------- | SAR441255 | SC | T2DM/Obesity/NASH | Preclinical. | |
| DPP-IV Inhibition | Astra Zeneca | Saxagliptin | Onglyza ™ | Once daily oral | T2DM | 2.5 or 5 mg regardless of meals. |
| Saxagliptin + metformin HCl | Kombiglyze ® XR | Once daily oral | T2DM | Take once daily with evening meal. Available in 5 mg saxagliptin/500 mg metformin HCl, 5 mg saxagliptin/1000 mg metformin HCl, or 2.5 mg saxagliptin/1000 mg metformin HCl doses. | ||
| Merck | Sitagliptin | Januvia ® | Once daily oral | T2DM | 25, 50, or 100 mg with or without food. | |
| Sitagliptin phosphate + metformin HCl | Janumet ® / Janumet ® XR | Oral twice daily/Once daily (XR formula) | T2DM | Combination drug therapy with metformin. XR formulation is an extended release version. Max dosage 100 mg Sitagliptin and 2000 mg metformin HCl. | ||
| Omarigliptin | Marizev ® | Oral once weekly | T2DM | Available in Japan. See (l.) Goldenberg et al. 2017 for phase 3 clinical trial information (#NCT01703221). Possible repositioning of drug for intran asal delivery for PD (see (m.) Ayoub et al. 2018). | ||
| Takeda | Trelagliptin | Zafatek ® | Oral once weekly | T2DM | Approved for use in Japan. Phase 2 clinical trials abandoned in the USA because of costs. | |
| Alogliptin | Nesina ® | Oral once daily | T2DM | 25 mg with or without food. | ||
| Alogliptin + metformin HCl | Kazano ® | Oral twice daily | T2DM | Take oral twce daily with food. Available in 12.5 mg alogliptin/500 mg metformin HCl or 12.5 mg alogliptin/1000 mg metformin HCl doses. Max dosage 25 mg alogliptin/2000 mg metformin HCl per day. | ||
| Alogliptin + pioglitazone | Oseni ® | Oral once daily. | T2DM | Take with or without food. Available in 12.5 or 25 mg alogliptin doses. | ||
| Boehringer Ingelheim | Linagliptin | Tradjenta ® | Oral once daily | T2DM | 5 mg once daily. | |
| Linagliptin + empagliflozin | Glyxambi ® | Oral once daily | T2DM | Take once daily in the morning with or without food. Available in 10 mg empagliflozin/5 mg linagliptin and 25 mg empagliflozin/5 mg linagliptin doses. | ||
| Linagliptin + metformin HCl | Jentadueto ® / Jentadueto ® XR | Oral twice daily/Once daily (XR formula) | T2DM | Combination drug therapy with metformin. XR formulation is an extended release version. Max dosage 2.5 mg linagliptin and 1000 mg metformin HCl. | ||
| Dong-A ST | Evogliptin | Suganon ® | Oral once daily | T2DM | 5 mg once daily. Approved for use in South Korea in 2015. Sold with extended release metformin. | |
| SatRx LLC | Gosogliptin | SatRx ® | Oral | T2DM | Approved for use in Russia. Completed phase 3 clinical trial of safety alone or with metformin compared to Vildagliptin alone or with metformin (#NCT03088670). | |
| LG Life Sciences/Sanofi | Gemigliptin | Zemiglo ™ | Oral once daily | T2DM | Long acting DPP-IV inhibitor. See (n.) Kim et al. 2016 for characterization. | |
| Zealand Pharmaceuticals | Vildagliptin | Galvus ® | Oral once daily | T2DM | 50 mg in combination with metformin (see (o.) Mathieu & Degrande 2008). | |
| Mitsubishi Tanabe Pharma and Daiichi Sankyo | Tenegliptin | Tenelia ® | Oral twice daily | T2DM | 20 mg twice daily. See (p.) Kishimoto 2013. | |
| Zealand Pharmaceuticals | Anagliptin | Suiny ® | Oral twice daily | T2DM | Approved for use in Japan, 200 mg daily. See (q.) Nishio et al. 2015 | |
#:
Visit https://clinicaltrials.gov to locate clinical trials registered in the United States.
*:
Visit https://trialsearch.who.int to locate clinical trials registered internationally.
NASH = nonalcoholic steatohepatitis; NAFLD = nonalcoholic fatty liver disease; SC = subcutaneous injection; T1DM = Type 1 Diabetes Mellitus. Sources: (a) ref(13); (b) ref(256); (c) ref(257); (d) ref(258); (e) ref(259); (f) ref(103); (g) ref(260); (h) ref(261); (i) ref(262); (j) ref(263); (k) ref(264); (l) ref(265); (m) ref(266); (n) ref(267); (o) ref(268); (p) ref(269); (q) ref(270). Table updated from Glotfelty et al., 2019 (12).