LY2409021、これは、イーライリリー社が開発している、血糖値をさげる、グルカゴン受容体拮抗薬です。グルカゴンに、「拮抗」する作用をもっているので、脂肪を分解せず、体重は増えます。脂肪肝も悪化させ、血圧もあげます。ということで、今は、治験は中断しているようですが、以下のように、最近になって論文が多く発表されている薬剤です。そのせいか、今年のアメリカ糖尿病学会2020では、この薬についての発表は、ありませんでした。やはり、体重を増やすという薬の承認は、これから、難しくなるのかもしれません。

よって、イーライリリー社は、GIP/GLP-1受容体作動薬(LY3298176)、を次の大型製品として、発売をねらっており、おそらく、糖尿病治療薬としてはオゼンピックと、抗肥満治療薬としては、サクセンダと、Head to Headで、勝負してくるかもしれません。

以下が、LY2409021の代表的な論文です。

Treatment with LY2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes.
Guzman CB, Zhang XM, Liu R, Regev A, Shankar S, Garhyan P, Pillai SG, Kazda C, Chalasani N, Hardy TA.
Diabetes Obes Metab. 2017 Nov;19(11):1521-1528. doi: 10.1111/dom.12958. Epub 2017 Jun 8.
PMID: 28371155 Free article. Clinical Trial.
RESULTS: A significant increase in HFF was seen with LY2409021 vs sitagliptin (least squares [LS] mean difference 3.72%; P < .001) and placebo (4.44%; P < .001), accompanied by significant elevations in alanine aminotransferase levels with LY2409021 vs sitagli …

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Treatment with the glucagon receptor antagonist LY2409021 increases ambulatory blood pressure in patients with type 2 diabetes.
Kazda CM, Frias J, Foga I, Cui X, Guzman CB, Garhyan P, Heilmann C, Yang JA, Hardy TA.
Diabetes Obes Metab. 2017 Aug;19(8):1071-1077. doi: 10.1111/dom.12904. Epub 2017 Mar 27.
PMID: 28191913 Clinical Trial.
Small but significant changes in serum lipid and aminotransferase levels were observed with LY2409021 treatment (all P  < .05 vs placebo). ...These effects may limit the clinical utility of LY2409021 as a chronic treatment for type 2 diabetes....

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Evaluation of Efficacy and Safety of the Glucagon Receptor Antagonist LY2409021 in Patients With Type 2 Diabetes: 12- and 24-Week Phase 2 Studies.
Kazda CM, Ding Y, Kelly RP, Garhyan P, Shi C, Lim CN, Fu H, Watson DE, Lewin AJ, Landschulz WH, Deeg MA, Moller DE, Hardy TA.
Diabetes Care. 2016 Jul;39(7):1241-9. doi: 10.2337/dc15-1643. Epub 2015 Dec 17.
PMID: 26681715 Clinical Trial.
LY2409021, a potent, selective small-molecule glucagon receptor antagonist that lowers glucose was evaluated for efficacy and safety in patients with type 2 diabetes. ...Phase 2a study patients were randomized to 10, 30, or 60 mg of LY2409021 or placebo for 12 weeks …

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Short-term administration of the glucagon receptor antagonist LY2409021 lowers blood glucose in healthy people and in those with type 2 diabetes.
Kelly RP, Garhyan P, Raddad E, Fu H, Lim CN, Prince MJ, Pinaire JA, Loh MT, Deeg MA.
Diabetes Obes Metab. 2015 Apr;17(4):414-22. doi: 10.1111/dom.12446. Epub 2015 Mar 2.
PMID: 25656305 Clinical Trial.
Safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) assessments were made after single doses and in patients receiving once-daily doses of LY2409021 (5, 30, 60 or 90 mg) for 28 days. ...Significant glucose-lowering was observed with LY2409021 at dose …

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Response to Comment on Kazda et al. Evaluation of Efficacy and Safety of the Glucagon Receptor Antagonist LY2409021 in Patients With Type 2 Diabetes: 12- and 24-Week Phase 2 Studies. Diabetes Care 2016;39:1241-1249.
Kazda CM, Ding Y, Kelly RP, Garhyan P, Shi C, Lim CN, Fu H, Watson DE, Lewin AJ, Landschulz WH, Deeg MA, Moller DE, Hardy TA.
Diabetes Care. 2016 Nov;39(11):e199-e200. doi: 10.2337/dci16-0030.
PMID: 27926898 No abstract available.

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Erratum. Evaluation of Efficacy and Safety of the Glucagon Receptor Antagonist LY2409021 in Patients With Type 2 Diabetes: 12- and 24-Week Phase 2 Studies. Diabetes Care 2016;39:1241-1249.
Kazda CM, Ding Y, Kelly RP, Garhyan P, Shi C, Lim CN, Fu H, Watson DE, Lewin AJ, Landschulz WH, Deeg MA, Moller DE, Hardy TA.
Diabetes Care. 2017 Jun;40(6):808. doi: 10.2337/dc17-er06. Epub 2017 Apr 18.
PMID: 28420698 Free PMC article. No abstract available.

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Comment on Kazda et al. Evaluation of Efficacy and Safety of the Glucagon Receptor Antagonist LY2409021 in Patients With Type 2 Diabetes: 12- and 24-Week Phase 2 Studies. Diabetes Care 2016;39:1241-1249.
Agrawal S, Gupta Y.
Diabetes Care. 2016 Nov;39(11):e198. doi: 10.2337/dc16-1340.
PMID: 27926897 No abstract available.

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Nonconventional glucagon and GLP-1 receptor agonist and antagonist interplay at the GLP-1 receptor revealed in high-throughput FRET assays for cAMP.
Chepurny OG, Matsoukas MT, Liapakis G, Leech CA, Milliken BT, Doyle RP, Holz GG.
J Biol Chem. 2019 Mar 8;294(10):3514-3531. doi: 10.1074/jbc.RA118.005682. Epub 2019 Jan 8.
PMID: 30622136 Free PMC article.
The GluR allosteric inhibitors LY2409021 and MK 0893 antagonized glucagon and GLP-1 action at the GLP-1R, whereas des-His(1)-[Glu(9)]glucagon antagonized glucagon action at the GluR, while having minimal inhibitory action versus glucagon or GLP-1 at the GLP-1R. ...