A glycosylated Fc‐fused glucagon‐like peptide‐1 receptor agonist exhibits equivalent glucose lowering to but fewer gastrointestinal side effects than dulaglutide
Aim To evaluate the pharmacokinetic and pharmacodynamic properties of a novel glycosylated Fc‐fused glucagon‐like peptide‐1(GLP‐1‐gFc) receptor agonist with distinctive receptor binding affinity, designed to improve in vivo stability and safety relative to the commercial GLP‐1 analogue dulaglutide,...
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| Veröffentlicht in: | Diabetes, obesity & metabolism obesity & metabolism, 2020-08, Vol.22 (8), p.1455-1468 |
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| creator | An, In Bok Byun, Mi Sun Yang, Sang In Choi, Yuri Woo, Jung Won Jang, Hak Chul Sung, Young Chul |
| description | Aim
To evaluate the pharmacokinetic and pharmacodynamic properties of a novel glycosylated Fc‐fused glucagon‐like peptide‐1(GLP‐1‐gFc) receptor agonist with distinctive receptor binding affinity, designed to improve in vivo stability and safety relative to the commercial GLP‐1 analogue dulaglutide, and assess its safety profile and pharmacokinetics in healthy humans.
Materials and Methods
We constructed GLP‐1‐gFc and determined its binding affinity and potency using in vitro instrumental and cell‐based analyses followed by in vivo comparison of the glucose‐lowering and gastrointestinal side effects between GLP‐1‐gFc and dulaglutide. A phase 1 clinical trial was conducted to confirm the efficacy and safety profile of GLP‐1‐gFc.
Results
GLP‐1‐gFc showed 10‐fold less binding affinity and 4‐fold less potency than dulaglutide in in vitro. A potency‐adjusted dose delayed HbA1c increase comparable with that of dulaglutide (Change for 6 weeks: 2.4 mg/kg GLP‐1‐gFc, 4.34 ± 0.40 vs. 0.6 mg/kg dulaglutide, 4.26 ± 0.22; n.s.). However, the equivalent efficacy dose and higher dose did not induce malaise‐related responses (blueberry bar consumption, g/mouse: 2.4 mg/kg GLP‐1‐gFc, 0.15% ± 0.03% vs. 0.6 mg/kg dulaglutide, 0.04% ± 0.01%; P |
| doi_str_mv | 10.1111/dom.14058 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7383507</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2420897026</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4438-5ae5ccef1eb8c63be089a530a32ffe1bb7b2bf8b9f21db7811cdfa052446e8523</originalsourceid><addsrcrecordid>eNp1kU1uFDEQhVsIREJgwQWQJVYsOvFP_3g2SFFCACkoG1hbtrvc4-BpT2x3wuw4ArfgXpyEmpkQwQJvXGU_fVVPr6peMnrM8JwMcXXMGtrKR9UhazpRM8G7x7ua13JB-UH1LOdrSmkjZP-0OhBcsKal7WH185SMYWNj3gRdYCAX9tf3H27OWI5htnqMEz4E_xXIGtbFD4AtIwksdjGRrcDnQuDb0htfMoGb2d_qAFPZAWIGEuIdJD-NpERi5kIcYE9GnUuKfiqQi590IBnhBJwDi5iy1BMZ5qARsp36vHridMjw4v4-qr5cvPt89qG-vHr_8ez0srYNeqtbDa214BgYaTthgMqFbgXVgiOYGdMbbpw0C8fZYHrJmB2cpi1vmg5ky8VR9XbPXc9mBYNFH0kHtU5-pdNGRe3Vvz-TX6ox3qpeSNHSHgGv7wEp3szoTV3HOaG_rHjDcZ2e8g5Vb_Yqm2LOCdzDBEbVNlOFmapdpqh99fdKD8o_IaLgZC-48wE2_yep86tPe-RvZoS03w</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2420897026</pqid></control><display><type>article</type><title>A glycosylated Fc‐fused glucagon‐like peptide‐1 receptor agonist exhibits equivalent glucose lowering to but fewer gastrointestinal side effects than dulaglutide</title><source>Wiley-Blackwell Journals</source><source>MEDLINE</source><creator>An, In Bok ; Byun, Mi Sun ; Yang, Sang In ; Choi, Yuri ; Woo, Jung Won ; Jang, Hak Chul ; Sung, Young Chul</creator><creatorcontrib>An, In Bok ; Byun, Mi Sun ; Yang, Sang In ; Choi, Yuri ; Woo, Jung Won ; Jang, Hak Chul ; Sung, Young Chul</creatorcontrib><description>Aim
To evaluate the pharmacokinetic and pharmacodynamic properties of a novel glycosylated Fc‐fused glucagon‐like peptide‐1(GLP‐1‐gFc) receptor agonist with distinctive receptor binding affinity, designed to improve in vivo stability and safety relative to the commercial GLP‐1 analogue dulaglutide, and assess its safety profile and pharmacokinetics in healthy humans.
Materials and Methods
We constructed GLP‐1‐gFc and determined its binding affinity and potency using in vitro instrumental and cell‐based analyses followed by in vivo comparison of the glucose‐lowering and gastrointestinal side effects between GLP‐1‐gFc and dulaglutide. A phase 1 clinical trial was conducted to confirm the efficacy and safety profile of GLP‐1‐gFc.
Results
GLP‐1‐gFc showed 10‐fold less binding affinity and 4‐fold less potency than dulaglutide in in vitro. A potency‐adjusted dose delayed HbA1c increase comparable with that of dulaglutide (Change for 6 weeks: 2.4 mg/kg GLP‐1‐gFc, 4.34 ± 0.40 vs. 0.6 mg/kg dulaglutide, 4.26 ± 0.22; n.s.). However, the equivalent efficacy dose and higher dose did not induce malaise‐related responses (blueberry bar consumption, g/mouse: 2.4 mg/kg GLP‐1‐gFc, 0.15% ± 0.03% vs. 0.6 mg/kg dulaglutide, 0.04% ± 0.01%; P < .01) or QT interval changes (mean at 14‐20 hours, mSc: 0.28 mg/kg GLP‐1‐gFc, 0.0‐8.0 vs. 0.07 mg/kg dulaglutide, 8.0‐27.7; n.s.), observed as safety variables in rats and monkeys, compared with those of dulaglutide. Glucose reductions in an oral glucose tolerance test were significant at day 3 postdose without severe gastrointestinal adverse events and pulse rate changes in healthy subjects.
Conclusions
These results suggest that GLP‐1‐gFc could be used as a novel GLP‐1 receptor agonist with better safety than dulaglutide to maximize therapeutic benefits in subjects with type 2 diabetes.</description><identifier>ISSN: 1462-8902</identifier><identifier>EISSN: 1463-1326</identifier><identifier>DOI: 10.1111/dom.14058</identifier><identifier>PMID: 32314505</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Affinity ; Agonists ; Animals ; Blood Glucose ; Diabetes ; Diabetes mellitus (non-insulin dependent) ; Diabetes Mellitus, Type 2 ; drug development, dulaglutide, GLP‐1 analogue, glycaemic control, type 2 diabetes ; GLP-1 receptor agonists ; Glucagon ; Glucagon-Like Peptide-1 Receptor ; Glucagon-Like Peptides - adverse effects ; Glucagon-Like Peptides - analogs & derivatives ; Glucose ; Glucose tolerance ; Glycated Hemoglobin A - analysis ; Hypoglycemic Agents - adverse effects ; Immunoglobulin Fc Fragments - adverse effects ; Mice ; Original ; Peptides ; Pharmacodynamics ; Pharmacokinetics ; Rats ; Recombinant Fusion Proteins ; Safety ; Side effects</subject><ispartof>Diabetes, obesity & metabolism, 2020-08, Vol.22 (8), p.1455-1468</ispartof><rights>2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.</rights><rights>2020. This article is published under http://creativecommons.org/licenses/by-nc/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4438-5ae5ccef1eb8c63be089a530a32ffe1bb7b2bf8b9f21db7811cdfa052446e8523</citedby><cites>FETCH-LOGICAL-c4438-5ae5ccef1eb8c63be089a530a32ffe1bb7b2bf8b9f21db7811cdfa052446e8523</cites><orcidid>0000-0001-8156-469X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fdom.14058$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fdom.14058$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32314505$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>An, In Bok</creatorcontrib><creatorcontrib>Byun, Mi Sun</creatorcontrib><creatorcontrib>Yang, Sang In</creatorcontrib><creatorcontrib>Choi, Yuri</creatorcontrib><creatorcontrib>Woo, Jung Won</creatorcontrib><creatorcontrib>Jang, Hak Chul</creatorcontrib><creatorcontrib>Sung, Young Chul</creatorcontrib><title>A glycosylated Fc‐fused glucagon‐like peptide‐1 receptor agonist exhibits equivalent glucose lowering to but fewer gastrointestinal side effects than dulaglutide</title><title>Diabetes, obesity & metabolism</title><addtitle>Diabetes Obes Metab</addtitle><description>Aim
To evaluate the pharmacokinetic and pharmacodynamic properties of a novel glycosylated Fc‐fused glucagon‐like peptide‐1(GLP‐1‐gFc) receptor agonist with distinctive receptor binding affinity, designed to improve in vivo stability and safety relative to the commercial GLP‐1 analogue dulaglutide, and assess its safety profile and pharmacokinetics in healthy humans.
Materials and Methods
We constructed GLP‐1‐gFc and determined its binding affinity and potency using in vitro instrumental and cell‐based analyses followed by in vivo comparison of the glucose‐lowering and gastrointestinal side effects between GLP‐1‐gFc and dulaglutide. A phase 1 clinical trial was conducted to confirm the efficacy and safety profile of GLP‐1‐gFc.
Results
GLP‐1‐gFc showed 10‐fold less binding affinity and 4‐fold less potency than dulaglutide in in vitro. A potency‐adjusted dose delayed HbA1c increase comparable with that of dulaglutide (Change for 6 weeks: 2.4 mg/kg GLP‐1‐gFc, 4.34 ± 0.40 vs. 0.6 mg/kg dulaglutide, 4.26 ± 0.22; n.s.). However, the equivalent efficacy dose and higher dose did not induce malaise‐related responses (blueberry bar consumption, g/mouse: 2.4 mg/kg GLP‐1‐gFc, 0.15% ± 0.03% vs. 0.6 mg/kg dulaglutide, 0.04% ± 0.01%; P < .01) or QT interval changes (mean at 14‐20 hours, mSc: 0.28 mg/kg GLP‐1‐gFc, 0.0‐8.0 vs. 0.07 mg/kg dulaglutide, 8.0‐27.7; n.s.), observed as safety variables in rats and monkeys, compared with those of dulaglutide. Glucose reductions in an oral glucose tolerance test were significant at day 3 postdose without severe gastrointestinal adverse events and pulse rate changes in healthy subjects.
Conclusions
These results suggest that GLP‐1‐gFc could be used as a novel GLP‐1 receptor agonist with better safety than dulaglutide to maximize therapeutic benefits in subjects with type 2 diabetes.</description><subject>Affinity</subject><subject>Agonists</subject><subject>Animals</subject><subject>Blood Glucose</subject><subject>Diabetes</subject><subject>Diabetes mellitus (non-insulin dependent)</subject><subject>Diabetes Mellitus, Type 2</subject><subject>drug development, dulaglutide, GLP‐1 analogue, glycaemic control, type 2 diabetes</subject><subject>GLP-1 receptor agonists</subject><subject>Glucagon</subject><subject>Glucagon-Like Peptide-1 Receptor</subject><subject>Glucagon-Like Peptides - adverse effects</subject><subject>Glucagon-Like Peptides - analogs & derivatives</subject><subject>Glucose</subject><subject>Glucose tolerance</subject><subject>Glycated Hemoglobin A - analysis</subject><subject>Hypoglycemic Agents - adverse effects</subject><subject>Immunoglobulin Fc Fragments - adverse effects</subject><subject>Mice</subject><subject>Original</subject><subject>Peptides</subject><subject>Pharmacodynamics</subject><subject>Pharmacokinetics</subject><subject>Rats</subject><subject>Recombinant Fusion Proteins</subject><subject>Safety</subject><subject>Side effects</subject><issn>1462-8902</issn><issn>1463-1326</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNp1kU1uFDEQhVsIREJgwQWQJVYsOvFP_3g2SFFCACkoG1hbtrvc4-BpT2x3wuw4ArfgXpyEmpkQwQJvXGU_fVVPr6peMnrM8JwMcXXMGtrKR9UhazpRM8G7x7ua13JB-UH1LOdrSmkjZP-0OhBcsKal7WH185SMYWNj3gRdYCAX9tf3H27OWI5htnqMEz4E_xXIGtbFD4AtIwksdjGRrcDnQuDb0htfMoGb2d_qAFPZAWIGEuIdJD-NpERi5kIcYE9GnUuKfiqQi590IBnhBJwDi5iy1BMZ5qARsp36vHridMjw4v4-qr5cvPt89qG-vHr_8ez0srYNeqtbDa214BgYaTthgMqFbgXVgiOYGdMbbpw0C8fZYHrJmB2cpi1vmg5ky8VR9XbPXc9mBYNFH0kHtU5-pdNGRe3Vvz-TX6ox3qpeSNHSHgGv7wEp3szoTV3HOaG_rHjDcZ2e8g5Vb_Yqm2LOCdzDBEbVNlOFmapdpqh99fdKD8o_IaLgZC-48wE2_yep86tPe-RvZoS03w</recordid><startdate>202008</startdate><enddate>202008</enddate><creator>An, In Bok</creator><creator>Byun, Mi Sun</creator><creator>Yang, Sang In</creator><creator>Choi, Yuri</creator><creator>Woo, Jung Won</creator><creator>Jang, Hak Chul</creator><creator>Sung, Young Chul</creator><general>Blackwell Publishing Ltd</general><general>Wiley Subscription Services, Inc</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TK</scope><scope>H94</scope><scope>K9.</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-8156-469X</orcidid></search><sort><creationdate>202008</creationdate><title>A glycosylated Fc‐fused glucagon‐like peptide‐1 receptor agonist exhibits equivalent glucose lowering to but fewer gastrointestinal side effects than dulaglutide</title><author>An, In Bok ; Byun, Mi Sun ; Yang, Sang In ; Choi, Yuri ; Woo, Jung Won ; Jang, Hak Chul ; Sung, Young Chul</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4438-5ae5ccef1eb8c63be089a530a32ffe1bb7b2bf8b9f21db7811cdfa052446e8523</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Affinity</topic><topic>Agonists</topic><topic>Animals</topic><topic>Blood Glucose</topic><topic>Diabetes</topic><topic>Diabetes mellitus (non-insulin dependent)</topic><topic>Diabetes Mellitus, Type 2</topic><topic>drug development, dulaglutide, GLP‐1 analogue, glycaemic control, type 2 diabetes</topic><topic>GLP-1 receptor agonists</topic><topic>Glucagon</topic><topic>Glucagon-Like Peptide-1 Receptor</topic><topic>Glucagon-Like Peptides - adverse effects</topic><topic>Glucagon-Like Peptides - analogs & derivatives</topic><topic>Glucose</topic><topic>Glucose tolerance</topic><topic>Glycated Hemoglobin A - analysis</topic><topic>Hypoglycemic Agents - adverse effects</topic><topic>Immunoglobulin Fc Fragments - adverse effects</topic><topic>Mice</topic><topic>Original</topic><topic>Peptides</topic><topic>Pharmacodynamics</topic><topic>Pharmacokinetics</topic><topic>Rats</topic><topic>Recombinant Fusion Proteins</topic><topic>Safety</topic><topic>Side effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>An, In Bok</creatorcontrib><creatorcontrib>Byun, Mi Sun</creatorcontrib><creatorcontrib>Yang, Sang In</creatorcontrib><creatorcontrib>Choi, Yuri</creatorcontrib><creatorcontrib>Woo, Jung Won</creatorcontrib><creatorcontrib>Jang, Hak Chul</creatorcontrib><creatorcontrib>Sung, Young Chul</creatorcontrib><collection>Wiley Open Access</collection><collection>Wiley-Blackwell Free Backfiles(OpenAccess)</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Diabetes, obesity & metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>An, In Bok</au><au>Byun, Mi Sun</au><au>Yang, Sang In</au><au>Choi, Yuri</au><au>Woo, Jung Won</au><au>Jang, Hak Chul</au><au>Sung, Young Chul</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A glycosylated Fc‐fused glucagon‐like peptide‐1 receptor agonist exhibits equivalent glucose lowering to but fewer gastrointestinal side effects than dulaglutide</atitle><jtitle>Diabetes, obesity & metabolism</jtitle><addtitle>Diabetes Obes Metab</addtitle><date>2020-08</date><risdate>2020</risdate><volume>22</volume><issue>8</issue><spage>1455</spage><epage>1468</epage><pages>1455-1468</pages><issn>1462-8902</issn><eissn>1463-1326</eissn><abstract>Aim
To evaluate the pharmacokinetic and pharmacodynamic properties of a novel glycosylated Fc‐fused glucagon‐like peptide‐1(GLP‐1‐gFc) receptor agonist with distinctive receptor binding affinity, designed to improve in vivo stability and safety relative to the commercial GLP‐1 analogue dulaglutide, and assess its safety profile and pharmacokinetics in healthy humans.
Materials and Methods
We constructed GLP‐1‐gFc and determined its binding affinity and potency using in vitro instrumental and cell‐based analyses followed by in vivo comparison of the glucose‐lowering and gastrointestinal side effects between GLP‐1‐gFc and dulaglutide. A phase 1 clinical trial was conducted to confirm the efficacy and safety profile of GLP‐1‐gFc.
Results
GLP‐1‐gFc showed 10‐fold less binding affinity and 4‐fold less potency than dulaglutide in in vitro. A potency‐adjusted dose delayed HbA1c increase comparable with that of dulaglutide (Change for 6 weeks: 2.4 mg/kg GLP‐1‐gFc, 4.34 ± 0.40 vs. 0.6 mg/kg dulaglutide, 4.26 ± 0.22; n.s.). However, the equivalent efficacy dose and higher dose did not induce malaise‐related responses (blueberry bar consumption, g/mouse: 2.4 mg/kg GLP‐1‐gFc, 0.15% ± 0.03% vs. 0.6 mg/kg dulaglutide, 0.04% ± 0.01%; P < .01) or QT interval changes (mean at 14‐20 hours, mSc: 0.28 mg/kg GLP‐1‐gFc, 0.0‐8.0 vs. 0.07 mg/kg dulaglutide, 8.0‐27.7; n.s.), observed as safety variables in rats and monkeys, compared with those of dulaglutide. Glucose reductions in an oral glucose tolerance test were significant at day 3 postdose without severe gastrointestinal adverse events and pulse rate changes in healthy subjects.
Conclusions
These results suggest that GLP‐1‐gFc could be used as a novel GLP‐1 receptor agonist with better safety than dulaglutide to maximize therapeutic benefits in subjects with type 2 diabetes.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>32314505</pmid><doi>10.1111/dom.14058</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0001-8156-469X</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Diabetes, obesity & metabolism, 2020-08, Vol.22 (8), p.1455-1468 |
| issn | 1462-8902 1463-1326 |
| language | eng |
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| source | Wiley-Blackwell Journals; MEDLINE |
| subjects | Affinity Agonists Animals Blood Glucose Diabetes Diabetes mellitus (non-insulin dependent) Diabetes Mellitus, Type 2 drug development, dulaglutide, GLP‐1 analogue, glycaemic control, type 2 diabetes GLP-1 receptor agonists Glucagon Glucagon-Like Peptide-1 Receptor Glucagon-Like Peptides - adverse effects Glucagon-Like Peptides - analogs & derivatives Glucose Glucose tolerance Glycated Hemoglobin A - analysis Hypoglycemic Agents - adverse effects Immunoglobulin Fc Fragments - adverse effects Mice Original Peptides Pharmacodynamics Pharmacokinetics Rats Recombinant Fusion Proteins Safety Side effects |
| title | A glycosylated Fc‐fused glucagon‐like peptide‐1 receptor agonist exhibits equivalent glucose lowering to but fewer gastrointestinal side effects than dulaglutide |
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