Low‐dose empagliflozin as adjunct‐to‐insulin therapy in type 1 diabetes: A valid modelling and simulation analysis to confirm efficacy
Aim To confirm the observed reduction in HbA1c for the 2.5 mg dose in EASE‐3 by modelling and simulation analyses. Materials and methods Independent of data from EASE‐3 that tested 2.5 mg, we simulated the effect of a 2.5 mg dose through patient‐level, exposure‐response modelling in the EASE‐2 clini...
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| Veröffentlicht in: | Diabetes, obesity & metabolism obesity & metabolism, 2020-03, Vol.22 (3), p.427-433 |
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| creator | Perkins, Bruce A. Soleymanlou, Nima Rosenstock, Julio Skyler, Jay S. Laffel, Lori M. Liesenfeld, Karl‐Heinz Neubacher, Dietmar Riggs, Matthew M. Johnston, Curtis K. Eudy‐Byrne, Rena J. Elmokadem, Ahmed George, Jyothis T. Marquard, Jan Nock, Valerie |
| description | Aim
To confirm the observed reduction in HbA1c for the 2.5 mg dose in EASE‐3 by modelling and simulation analyses.
Materials and methods
Independent of data from EASE‐3 that tested 2.5 mg, we simulated the effect of a 2.5 mg dose through patient‐level, exposure‐response modelling in the EASE‐2 clinical study. A primary semi‐mechanistic model evaluated efficacy considering clinical insulin dose adjustments made after treatment initiation that potentially limited HbA1c reductions. The model was informed by pharmacokinetic, insulin dose, mean daily glucose and HbA1c data, and was verified by comparing the simulations with the observed HbA1c change in EASE‐3. One of two empagliflozin phase 3 trials in type 1 diabetes (EASE‐3 but not EASE‐2) included a lower 2.5 mg dose. A placebo‐corrected HbA1c reduction of 0.28% was demonstrated without the increased risk of diabetic ketoacidosis observed at higher doses (10 mg and 25 mg). Since only one trial included the lower dose, we aimed to confirm the observed reduction in HbA1c for the 2.5 mg dose by modelling and simulation analyses.
Results
The simulated 26‐week mean HbA1c change was −0.41% without insulin dose adjustment and −0.29% at 26 weeks with insulin dose adjustment. A simplified (descriptive) model excluding insulin dose and mean daily glucose confirmed the –0.29% HbA1c change that would have been observed had the EASE‐2 population received a 2.5 mg dose for 26/52 weeks.
Conclusions
The HbA1c benefit of low‐dose empagliflozin directly observed in the EASE‐3 trial was confirmed by two modelling and simulation approaches. |
| doi_str_mv | 10.1111/dom.13945 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7064984</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2329740141</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4435-6b2982dd735f5434ea03edda92ec072ac1d9f6790cd9efa856eb2d2384480c623</originalsourceid><addsrcrecordid>eNp1kc1u1DAQxyMEoqVw4AWQJS5wSOuvJA6HSlX5lBb1Amdr1h5vvXLiECetwokH4MAz8iR4u6UCJHywR5qffprxvyieMnrM8jmxsTtmopXVveKQyVqUTPD6_k3NS9VSflA8SmlLKZVCNQ-LA8FUpRqmDovvq3j989sPGxMS7AbYBO9C_Op7AomA3c69mXJ_ivnyfZpD7kyXOMKwkF25DEgYsR7WOGF6Rc7IFQRvSRcthgxvCPSWJN_NASYfs7aHsCSfyBSJib3zY0fQOW_ALI-LBw5Cwie371Hx-e2bT-fvy9XFuw_nZ6vSSCmqsl7zVnFrG1G5SgqJQAVaCy1HQxsOhtnW1U1LjW3RgapqXHPLhZJSUVNzcVSc7r3DvO7QGuynEYIeRt_BuOgIXv_d6f2l3sQr3dBatkpmwYtbwRi_zJgm3flk8sLQY5yT5oK3jaRMsow-_wfdxnnMn7CjqlpkoVSZermnzBhTGtHdDcOo3mWsc8b6JuPMPvtz-jvyd6gZONkD1z7g8n-Tfn3xca_8Bet8tpg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2356364948</pqid></control><display><type>article</type><title>Low‐dose empagliflozin as adjunct‐to‐insulin therapy in type 1 diabetes: A valid modelling and simulation analysis to confirm efficacy</title><source>Wiley Online Library All Journals</source><creator>Perkins, Bruce A. ; Soleymanlou, Nima ; Rosenstock, Julio ; Skyler, Jay S. ; Laffel, Lori M. ; Liesenfeld, Karl‐Heinz ; Neubacher, Dietmar ; Riggs, Matthew M. ; Johnston, Curtis K. ; Eudy‐Byrne, Rena J. ; Elmokadem, Ahmed ; George, Jyothis T. ; Marquard, Jan ; Nock, Valerie</creator><creatorcontrib>Perkins, Bruce A. ; Soleymanlou, Nima ; Rosenstock, Julio ; Skyler, Jay S. ; Laffel, Lori M. ; Liesenfeld, Karl‐Heinz ; Neubacher, Dietmar ; Riggs, Matthew M. ; Johnston, Curtis K. ; Eudy‐Byrne, Rena J. ; Elmokadem, Ahmed ; George, Jyothis T. ; Marquard, Jan ; Nock, Valerie</creatorcontrib><description>Aim
To confirm the observed reduction in HbA1c for the 2.5 mg dose in EASE‐3 by modelling and simulation analyses.
Materials and methods
Independent of data from EASE‐3 that tested 2.5 mg, we simulated the effect of a 2.5 mg dose through patient‐level, exposure‐response modelling in the EASE‐2 clinical study. A primary semi‐mechanistic model evaluated efficacy considering clinical insulin dose adjustments made after treatment initiation that potentially limited HbA1c reductions. The model was informed by pharmacokinetic, insulin dose, mean daily glucose and HbA1c data, and was verified by comparing the simulations with the observed HbA1c change in EASE‐3. One of two empagliflozin phase 3 trials in type 1 diabetes (EASE‐3 but not EASE‐2) included a lower 2.5 mg dose. A placebo‐corrected HbA1c reduction of 0.28% was demonstrated without the increased risk of diabetic ketoacidosis observed at higher doses (10 mg and 25 mg). Since only one trial included the lower dose, we aimed to confirm the observed reduction in HbA1c for the 2.5 mg dose by modelling and simulation analyses.
Results
The simulated 26‐week mean HbA1c change was −0.41% without insulin dose adjustment and −0.29% at 26 weeks with insulin dose adjustment. A simplified (descriptive) model excluding insulin dose and mean daily glucose confirmed the –0.29% HbA1c change that would have been observed had the EASE‐2 population received a 2.5 mg dose for 26/52 weeks.
Conclusions
The HbA1c benefit of low‐dose empagliflozin directly observed in the EASE‐3 trial was confirmed by two modelling and simulation approaches.</description><identifier>ISSN: 1462-8902</identifier><identifier>EISSN: 1463-1326</identifier><identifier>DOI: 10.1111/dom.13945</identifier><identifier>PMID: 31858718</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>antidiabetic drug ; Antidiabetics ; Clinical trials ; Diabetes ; Diabetes mellitus (insulin dependent) ; Diabetic ketoacidosis ; dose–response relationship ; empagliflozin ; Insulin ; Ketoacidosis ; Obesity ; Original ; Pharmacokinetics ; Simulation ; sodium‐glucose co‐transporter‐2 inhibitor ; type 1 diabetes</subject><ispartof>Diabetes, obesity & metabolism, 2020-03, Vol.22 (3), p.427-433</ispartof><rights>2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.</rights><rights>2019. 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-c4435-6b2982dd735f5434ea03edda92ec072ac1d9f6790cd9efa856eb2d2384480c623</citedby><cites>FETCH-LOGICAL-c4435-6b2982dd735f5434ea03edda92ec072ac1d9f6790cd9efa856eb2d2384480c623</cites></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.13945$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fdom.13945$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,1416,27923,27924,45573,45574</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31858718$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Perkins, Bruce A.</creatorcontrib><creatorcontrib>Soleymanlou, Nima</creatorcontrib><creatorcontrib>Rosenstock, Julio</creatorcontrib><creatorcontrib>Skyler, Jay S.</creatorcontrib><creatorcontrib>Laffel, Lori M.</creatorcontrib><creatorcontrib>Liesenfeld, Karl‐Heinz</creatorcontrib><creatorcontrib>Neubacher, Dietmar</creatorcontrib><creatorcontrib>Riggs, Matthew M.</creatorcontrib><creatorcontrib>Johnston, Curtis K.</creatorcontrib><creatorcontrib>Eudy‐Byrne, Rena J.</creatorcontrib><creatorcontrib>Elmokadem, Ahmed</creatorcontrib><creatorcontrib>George, Jyothis T.</creatorcontrib><creatorcontrib>Marquard, Jan</creatorcontrib><creatorcontrib>Nock, Valerie</creatorcontrib><title>Low‐dose empagliflozin as adjunct‐to‐insulin therapy in type 1 diabetes: A valid modelling and simulation analysis to confirm efficacy</title><title>Diabetes, obesity & metabolism</title><addtitle>Diabetes Obes Metab</addtitle><description>Aim
To confirm the observed reduction in HbA1c for the 2.5 mg dose in EASE‐3 by modelling and simulation analyses.
Materials and methods
Independent of data from EASE‐3 that tested 2.5 mg, we simulated the effect of a 2.5 mg dose through patient‐level, exposure‐response modelling in the EASE‐2 clinical study. A primary semi‐mechanistic model evaluated efficacy considering clinical insulin dose adjustments made after treatment initiation that potentially limited HbA1c reductions. The model was informed by pharmacokinetic, insulin dose, mean daily glucose and HbA1c data, and was verified by comparing the simulations with the observed HbA1c change in EASE‐3. One of two empagliflozin phase 3 trials in type 1 diabetes (EASE‐3 but not EASE‐2) included a lower 2.5 mg dose. A placebo‐corrected HbA1c reduction of 0.28% was demonstrated without the increased risk of diabetic ketoacidosis observed at higher doses (10 mg and 25 mg). Since only one trial included the lower dose, we aimed to confirm the observed reduction in HbA1c for the 2.5 mg dose by modelling and simulation analyses.
Results
The simulated 26‐week mean HbA1c change was −0.41% without insulin dose adjustment and −0.29% at 26 weeks with insulin dose adjustment. A simplified (descriptive) model excluding insulin dose and mean daily glucose confirmed the –0.29% HbA1c change that would have been observed had the EASE‐2 population received a 2.5 mg dose for 26/52 weeks.
Conclusions
The HbA1c benefit of low‐dose empagliflozin directly observed in the EASE‐3 trial was confirmed by two modelling and simulation approaches.</description><subject>antidiabetic drug</subject><subject>Antidiabetics</subject><subject>Clinical trials</subject><subject>Diabetes</subject><subject>Diabetes mellitus (insulin dependent)</subject><subject>Diabetic ketoacidosis</subject><subject>dose–response relationship</subject><subject>empagliflozin</subject><subject>Insulin</subject><subject>Ketoacidosis</subject><subject>Obesity</subject><subject>Original</subject><subject>Pharmacokinetics</subject><subject>Simulation</subject><subject>sodium‐glucose co‐transporter‐2 inhibitor</subject><subject>type 1 diabetes</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><recordid>eNp1kc1u1DAQxyMEoqVw4AWQJS5wSOuvJA6HSlX5lBb1Amdr1h5vvXLiECetwokH4MAz8iR4u6UCJHywR5qffprxvyieMnrM8jmxsTtmopXVveKQyVqUTPD6_k3NS9VSflA8SmlLKZVCNQ-LA8FUpRqmDovvq3j989sPGxMS7AbYBO9C_Op7AomA3c69mXJ_ivnyfZpD7kyXOMKwkF25DEgYsR7WOGF6Rc7IFQRvSRcthgxvCPSWJN_NASYfs7aHsCSfyBSJib3zY0fQOW_ALI-LBw5Cwie371Hx-e2bT-fvy9XFuw_nZ6vSSCmqsl7zVnFrG1G5SgqJQAVaCy1HQxsOhtnW1U1LjW3RgapqXHPLhZJSUVNzcVSc7r3DvO7QGuynEYIeRt_BuOgIXv_d6f2l3sQr3dBatkpmwYtbwRi_zJgm3flk8sLQY5yT5oK3jaRMsow-_wfdxnnMn7CjqlpkoVSZermnzBhTGtHdDcOo3mWsc8b6JuPMPvtz-jvyd6gZONkD1z7g8n-Tfn3xca_8Bet8tpg</recordid><startdate>202003</startdate><enddate>202003</enddate><creator>Perkins, Bruce A.</creator><creator>Soleymanlou, Nima</creator><creator>Rosenstock, Julio</creator><creator>Skyler, Jay S.</creator><creator>Laffel, Lori M.</creator><creator>Liesenfeld, Karl‐Heinz</creator><creator>Neubacher, Dietmar</creator><creator>Riggs, Matthew M.</creator><creator>Johnston, Curtis K.</creator><creator>Eudy‐Byrne, Rena J.</creator><creator>Elmokadem, Ahmed</creator><creator>George, Jyothis T.</creator><creator>Marquard, Jan</creator><creator>Nock, Valerie</creator><general>Blackwell Publishing Ltd</general><general>Wiley Subscription Services, Inc</general><scope>24P</scope><scope>WIN</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TK</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>202003</creationdate><title>Low‐dose empagliflozin as adjunct‐to‐insulin therapy in type 1 diabetes: A valid modelling and simulation analysis to confirm efficacy</title><author>Perkins, Bruce A. ; Soleymanlou, Nima ; Rosenstock, Julio ; Skyler, Jay S. ; Laffel, Lori M. ; Liesenfeld, Karl‐Heinz ; Neubacher, Dietmar ; Riggs, Matthew M. ; Johnston, Curtis K. ; Eudy‐Byrne, Rena J. ; Elmokadem, Ahmed ; George, Jyothis T. ; Marquard, Jan ; Nock, Valerie</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4435-6b2982dd735f5434ea03edda92ec072ac1d9f6790cd9efa856eb2d2384480c623</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>antidiabetic drug</topic><topic>Antidiabetics</topic><topic>Clinical trials</topic><topic>Diabetes</topic><topic>Diabetes mellitus (insulin dependent)</topic><topic>Diabetic ketoacidosis</topic><topic>dose–response relationship</topic><topic>empagliflozin</topic><topic>Insulin</topic><topic>Ketoacidosis</topic><topic>Obesity</topic><topic>Original</topic><topic>Pharmacokinetics</topic><topic>Simulation</topic><topic>sodium‐glucose co‐transporter‐2 inhibitor</topic><topic>type 1 diabetes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Perkins, Bruce A.</creatorcontrib><creatorcontrib>Soleymanlou, Nima</creatorcontrib><creatorcontrib>Rosenstock, Julio</creatorcontrib><creatorcontrib>Skyler, Jay S.</creatorcontrib><creatorcontrib>Laffel, Lori M.</creatorcontrib><creatorcontrib>Liesenfeld, Karl‐Heinz</creatorcontrib><creatorcontrib>Neubacher, Dietmar</creatorcontrib><creatorcontrib>Riggs, Matthew M.</creatorcontrib><creatorcontrib>Johnston, Curtis K.</creatorcontrib><creatorcontrib>Eudy‐Byrne, Rena J.</creatorcontrib><creatorcontrib>Elmokadem, Ahmed</creatorcontrib><creatorcontrib>George, Jyothis T.</creatorcontrib><creatorcontrib>Marquard, Jan</creatorcontrib><creatorcontrib>Nock, Valerie</creatorcontrib><collection>Wiley-Blackwell Open Access Titles</collection><collection>Wiley Free Content</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>MEDLINE - Academic</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>Perkins, Bruce A.</au><au>Soleymanlou, Nima</au><au>Rosenstock, Julio</au><au>Skyler, Jay S.</au><au>Laffel, Lori M.</au><au>Liesenfeld, Karl‐Heinz</au><au>Neubacher, Dietmar</au><au>Riggs, Matthew M.</au><au>Johnston, Curtis K.</au><au>Eudy‐Byrne, Rena J.</au><au>Elmokadem, Ahmed</au><au>George, Jyothis T.</au><au>Marquard, Jan</au><au>Nock, Valerie</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Low‐dose empagliflozin as adjunct‐to‐insulin therapy in type 1 diabetes: A valid modelling and simulation analysis to confirm efficacy</atitle><jtitle>Diabetes, obesity & metabolism</jtitle><addtitle>Diabetes Obes Metab</addtitle><date>2020-03</date><risdate>2020</risdate><volume>22</volume><issue>3</issue><spage>427</spage><epage>433</epage><pages>427-433</pages><issn>1462-8902</issn><eissn>1463-1326</eissn><abstract>Aim
To confirm the observed reduction in HbA1c for the 2.5 mg dose in EASE‐3 by modelling and simulation analyses.
Materials and methods
Independent of data from EASE‐3 that tested 2.5 mg, we simulated the effect of a 2.5 mg dose through patient‐level, exposure‐response modelling in the EASE‐2 clinical study. A primary semi‐mechanistic model evaluated efficacy considering clinical insulin dose adjustments made after treatment initiation that potentially limited HbA1c reductions. The model was informed by pharmacokinetic, insulin dose, mean daily glucose and HbA1c data, and was verified by comparing the simulations with the observed HbA1c change in EASE‐3. One of two empagliflozin phase 3 trials in type 1 diabetes (EASE‐3 but not EASE‐2) included a lower 2.5 mg dose. A placebo‐corrected HbA1c reduction of 0.28% was demonstrated without the increased risk of diabetic ketoacidosis observed at higher doses (10 mg and 25 mg). Since only one trial included the lower dose, we aimed to confirm the observed reduction in HbA1c for the 2.5 mg dose by modelling and simulation analyses.
Results
The simulated 26‐week mean HbA1c change was −0.41% without insulin dose adjustment and −0.29% at 26 weeks with insulin dose adjustment. A simplified (descriptive) model excluding insulin dose and mean daily glucose confirmed the –0.29% HbA1c change that would have been observed had the EASE‐2 population received a 2.5 mg dose for 26/52 weeks.
Conclusions
The HbA1c benefit of low‐dose empagliflozin directly observed in the EASE‐3 trial was confirmed by two modelling and simulation approaches.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>31858718</pmid><doi>10.1111/dom.13945</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Diabetes, obesity & metabolism, 2020-03, Vol.22 (3), p.427-433 |
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| source | Wiley Online Library All Journals |
| subjects | antidiabetic drug Antidiabetics Clinical trials Diabetes Diabetes mellitus (insulin dependent) Diabetic ketoacidosis dose–response relationship empagliflozin Insulin Ketoacidosis Obesity Original Pharmacokinetics Simulation sodium‐glucose co‐transporter‐2 inhibitor type 1 diabetes |
| title | Low‐dose empagliflozin as adjunct‐to‐insulin therapy in type 1 diabetes: A valid modelling and simulation analysis to confirm efficacy |
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