Journal Club

1. Journal Club Rosenstock J, Allison D, Birkenfeld AL, Blicher TM, Deenadayalan S, Jacobsen JB, Serusclat P, Violante R, Watada H, Davies M; PIONEER 3 Investigators. Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With Sulfonylurea: The PIONEER 3 Randomized Clinical Trial. JAMA. 2019 Mar 23. doi: 10.1001/jama.2019.2942 埼玉医科大学　総合医療センター　内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田　昌文　 Matsuda, Masafumi 2019年5月2日　8:30-8:55 ４階　医局

2. https://cdn.jamanetwork.com/ama/content_public/journal/jama/937946/joi190026va.png?Expires=2147483647&Signature=l-DSohJ~80IKc1vEILpTWaCUMBPEK9gCb4v-O3OwInA9Nk-BBukZ7yQ3fQ9425Mj4K6grjqaNSw1u4DZ25bvdMsygr2MKdBJvRfTrmH6Kgo7YQ4a5xe8tqf4JNgMCmZ8T1H0TRuEg~TQFlX4frMZQM1yp-wVkWBoE9Zg2ra7-5ALqtbM2XSa72uTgywrDURK2cMupSYeCaPoYj8mjHmDNyDgry-~CDipzVbpZdwCcmSly4-YHr5Bw~vEKYZ4eVfJuwSarkr7aEnEOB3Xli-f4YR4fvE0M1WL9j-UbswIIVQJ~a3OYPUWBDAZEIGMktsTOsLDYLQ6R5MdzJQsM4~QOQ__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGAhttps://cdn.jamanetwork.com/ama/content_public/journal/jama/937946/joi190026va.png?Expires=2147483647&Signature=l-DSohJ~80IKc1vEILpTWaCUMBPEK9gCb4v-O3OwInA9Nk-BBukZ7yQ3fQ9425Mj4K6grjqaNSw1u4DZ25bvdMsygr2MKdBJvRfTrmH6Kgo7YQ4a5xe8tqf4JNgMCmZ8T1H0TRuEg~TQFlX4frMZQM1yp-wVkWBoE9Zg2ra7-5ALqtbM2XSa72uTgywrDURK2cMupSYeCaPoYj8mjHmDNyDgry-~CDipzVbpZdwCcmSly4-YHr5Bw~vEKYZ4eVfJuwSarkr7aEnEOB3Xli-f4YR4fvE0M1WL9j-UbswIIVQJ~a3OYPUWBDAZEIGMktsTOsLDYLQ6R5MdzJQsM4~QOQ__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA

3. Julio Rosenstock, MD1; Dale Allison, MD2; Andreas L. Birkenfeld, MD3,4; Thalia Marie Blicher, MD5; Srikanth Deenadayalan, MD5; Jacob Bonde Jacobsen, MSc5; Pierre Serusclat, MD6; Rafael Violante, MD7; Hirotaka Watada, MD, PhD8; Melanie Davies, MD9; for the PIONEER 3 Investigators 1Dallas Diabetes Research Center at Medical City, Dallas, Texas 2Hillcrest Family Health Center, Waco, Texas 3Department of Medicine III, Carl Gustav Carus University Hospital, Technische Universität Dresden, Dresden, Germany 4Paul Langerhans Institute Dresden, Helmholtz Center Munich at Technische Universität Dresden, Dresden, Germany 5Novo Nordisk A/S, Søborg, Denmark 6Endocrinology, Diabetology and Nutrition, Clinique Portes du Sud, Venissieux, France 7Departamento Endocrinología, Instituto Mexicano del Seguro Social, Ciudad Madero, Mexico 8Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan 9Diabetes Research Centre, University of Leicester, Leicester, England JAMA. 2019 Mar 23. doi: 10.1001/jama.2019.2942

4. Importance Phase 3 trials have not compared oral semaglutide, a glucagon-like peptide 1 receptor agonist, with other classes of glucose-lowering therapy. Objective To compare efficacy and assess long-term adverse event profiles of once-daily oral semaglutide vs sitagliptin, 100 mg added on to metformin with or without sulfonylurea, in patients with type 2 diabetes.

5. Design, Setting, and Participants Randomized, double-blind, double-dummy, parallel-group, phase 3a trial conducted at 206 sites in 14 countries over 78 weeks from February 2016 to March 2018. Of 2463 patients screened, 1864 adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea were randomized. Interventions Patients were randomized to receive once-daily oral semaglutide, 3 mg (n = 466), 7 mg (n = 466), or 14 mg (n = 465), or sitagliptin, 100 mg (n = 467). Semaglutide was initiated at 3 mg/d and escalated every 4 weeks, first to 7 mg/d then to 14 mg/d, until the randomized dosage was achieved. Main Outcomes and Measures The primary end point was change in glycated hemoglobin (HbA1c), and the key secondary end point was change in body weight, both from baseline to week 26. Both were assessed at weeks 52 and 78 as additional secondary end points. End points were tested for noninferiority with respect to HbA1c (noninferiority margin, 0.3%) prior to testing for superiority of HbA1c and body weight.

6. Inclusion criteria 1. Informed consent obtained before any trial-related activities. Trial-related activities are defined as any procedures that are carried out as part of the trial, including activities to determine suitability for the trial. 2. Male or female, age ≥18 years at the time of signing informed consent. For Japan only: Male or female, age ≥20 years at the time of signing informed consent. 3. Diagnosed with type 2 diabetes ≥90 days prior to day of screening. 4. HbA1c 7.0–10.5% (53–91 mmol/mol) (both inclusive). 5. Stable daily dose of metformin (≥1500 mg or maximum tolerated dose as documented in the patient medical record) alone, or in combination with sulfonylurea (≥half of the maximum approved dose according to local label or maximum tolerated dose as documented in the patient medical record), within 90 days prior to the day of screening.

7. Exclusion criteria 1. Known or suspected hypersensitivity to trial products or related products. 2. Previous participation in this trial. Participation is defined as signed informed consent. 3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using adequate contraceptive methods (adequate contraceptive measures as required by local regulation or practice). For Germany only: Only highly effective methods of birth control are accepted (i.e. one that results in ≤1% per year failure rate when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine device), or sexual abstinence or vasectomized partner. For United Kingdom only: Adequate contraceptive measures are defined as established use of oral, intravaginal, transdermal combined estrogen and progestogen hormonal methods of contraception; oral, injected or implanted progestogen only hormonal methods of contraception; placement of an intrauterine device or intrauterine hormone releasing system, bilateral tubal occlusion, barrier methods of contraception (condom or occlusive cap with spermicidal foam/gel/film/cream/suppository), female sterilization, vasectomized partner (where partner is sole partner of patient), or true abstinence (when in line with preferred and usual lifestyle). For Brazil only: For women who expressly declare free of the risk of pregnancy, either by not engaging in sexual activity or by having sexual activity with no birth potential risk, use of contraceptive method will not be mandatory. For Japan only: Adequate contraceptive measures are abstinence (not having sex), diaphragm, condom (by the partner), intrauterine device, sponge, spermicide or oral contraceptives. 4. Receipt of any investigational medicinal product within 90 days before screening. For Brazil only: Participation in other trials within one year prior to screening visit (visit 1) unless there is a direct benefit to the research patient at the investigator’s discretion. 5. Any disorder, which in the investigator’s opinion might jeopardize patient’s safety or compliance with the protocol. 6. Family or personal history of MEN2 or MTC. 7. History of pancreatitis (acute or chronic). 8. History of major surgical procedures involving the stomach potentially affecting absorption of trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery). 9. Any of the following: myocardial infarction, stroke or hospitalization for unstable angina and/or transient ischemic attack within the past 180 days prior to the day of screening. 10. Patients presently classified as being in NYHA Class IV. 11. Planned coronary, carotid or peripheral artery revascularization known on the day of screening. 12. Renal impairment defined as eGFR <60 mL/min/1.73 m2 as per CKD-EPI. 13. Treatment with any medication for the indication of diabetes or obesity, other than stated in the inclusion criteria, in a period of 90 days before the day of screening. An exception is short-term insulin treatment for acute illness for a total of ≤14 days. 14. Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus photography or dilated fundoscopy performed within 90 days prior to randomization. 15. History or presence of malignant neoplasms within the last 5 years (except basal and squamous cell skin cancer and in-situ carcinomas). Abbreviation: CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration fate; MEN2, multiple endocrine neoplasia type 2; MTC, medullary thyroid carcinoma; NYHA, New York Heart Association.

12. Interventions Because food intake impairs absorption of oral semaglutide, patients were instructed to administer trial products (eAppendix 2 in Supplement 1) in the morning, in a fasting state, with up to half a glass of water (approximately 120 mL) at least 30 minutes before having breakfast or taking any other oral medication (including background glucose-lowering medication). Oral semaglutide treatment was initiated with the 3-mg/d dosage, then escalated to 7 mg/d after 4 weeks and 14 mg/d after a further 4 weeks, until the randomized dosage was achieved; sitagliptin was initiated and maintained at 100 mg/d. Patients also received background metformin with or without sulfonylurea, maintained at the stable, pretrial dosage. Intensification of existing background glucose-lowering medication and/or initiation of new glucose-lowering medication was prescribed as an add-on to randomized treatment for patients with persistent or unacceptable hyperglycemia, based on predefined fasting plasma glucose and/or HbA1c criteria (eTable 2 in Supplement 1). All patients were to continue in the trial even if they prematurely discontinued the trial product and/or received additional glucose-lowering medications. Patients prematurely discontinuing the trial product could receive any glucose-lowering drug, excluding other GLP-1RAs or DPP-4 inhibitors, before final follow-up visit at investigator discretion.

13. eAppendix 2. Trial Product Administration Patients were instructed to administer trial products (regardless of assigned treatment group) in the morning, in a fasting state, with ≤120 mL of water ≥30 minutes before breakfast and ≥30 minutes before any other oral medication (including background glucose-lowering medication). Tablets were to be taken whole. Oral semaglutide and sitagliptin are not visually identical. In order to maintain blinding, patients received two tablets daily; the active drug and a placebo. For both oral semaglutide and sitagliptin, respectively, the active drug and the corresponding placebo tablets were identical with regard to visual appearance, and all oral semaglutide tablets were visually identical to each other, irrespective of dose level.

14. The treatment policy estimand evaluates the treatment effect for all randomized patients regardless of trial product discontinuation or use of rescue medication. This estimand reflects the intention-to-treat principle as defined in ICH guideline E9.16 The estimand reflects the effect of initiating treatment with oral semaglutide compared with initiating treatment with sitagliptin, both potentially followed by either discontinuation of trial product and/or addition of or switch to another glucose-lowering drug. The trial product estimand evaluates the treatment effect for all randomized patients under the assumption that all patients continued taking trial product for the entire planned duration of the trial and did not use rescue medication. This estimand aims at reflecting the effect of oral semaglutide compared with sitagliptin without the confounding effect of trial product discontinuation or use of rescue medication. Trial product discontinuation and initiation of rescue medication are postrandomization events that are accounted for by the treatment policy strategy for the treatment policy estimand and by the hypothetical strategy for the trial product estimand, as defined in draft ICH guideline E9 (Revision 1).17 For the treatment policy estimand, the event (trial product discontinuation or initiation of rescue medication) was considered irrelevant and data collected thereafter were included in the estimation. For the trial product estimand, any data collected after the event were discarded and the estimation relies on statistical modeling to estimate the treatment effect under the assumption that the event had not occurred.

24. Results Among 1864 patients randomized (mean age, 58 [SD, 10] years; mean baseline HbA1c, 8.3% [SD, 0.9%]; mean body mass index, 32.5 [SD, 6.4]; n=879 [47.2%] women), 1758 (94.3%) completed the trial and 298 prematurely discontinued treatment (16.7% for semaglutide, 3 mg/d; 15.0% for semaglutide, 7 mg/d; 19.1% for semaglutide, 14 mg/d; and 13.1% for sitagliptin). Semaglutide, 7 and 14 mg/d, compared with sitagliptin, significantly reduced HbA1c (differences, –0.3% [95% CI, –0.4% to –0.1%] and –0.5% [95% CI, –0.6% to –0.4%], respectively; P < .001 for both) and body weight (differences, –1.6 kg [95% CI, –2.0 to –1.1 kg] and –2.5 kg [95% CI, –3.0 to –2.0 kg], respectively; P < .001 for both) from baseline to week 26. Noninferiority of semaglutide, 3 mg/d, with respect to HbA1c was not demonstrated. Week 78 reductions in both end points were statistically significantly greater with semaglutide, 14 mg/d, vs sitagliptin.

25. Conclusions and Relevance Among adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea, oral semaglutide, 7 mg/d and 14 mg/d, compared with sitagliptin, resulted in significantly greater reductions in HbA1c over 26 weeks, but there was no significant benefit with the 3-mg/d dosage. Further research is needed to assess effectiveness in a clinical setting. Trial Registration ClinicalTrials.gov Identifier: NCT02607865

26. Message 経口セマグルチド、シタグリプチンより血糖改善効果高い 　メトホルミン単独またはスルホニル尿素薬との併用で血糖コントロール不良の2型糖尿病患者1864例を対象に、経口セマグルチドおよびシタグリプチンの上乗せ効果を第IIIa相試験で比較。主要評価項目はベースラインから26週後のHbA1c値の変化量、非劣性マージンを0.3％とした。 　その結果、セマグルチド7mg/日投与群および14mg/日投与群ではシタグリプチン群に比べて、HbA1c値の有意な低下が認められた（差－0.3％［95％CI －0.4-－0.1］および－0.5％［－0.6-－0.4］、いずれもP＜0.001）。3mg/日投与ではシタグリプチンに対する非劣性は示されなかった。 https://www.m3.com/clinical/journal/20261 GLP-1RAが注射製剤でなくなると、管理料がとれなくなるが．．．