Journal Club 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 2012 年 8 月 2 日 8:30-8:55 ８階 医局 Aschner P, Chan J, Owens DR, Picard S, Wang E, Dain MP, Pilorget V, Echtay A, Fonseca V; EASIE investigators. Insulin glargine versus sitagliptin in insulin-naive patients with type 2 diabetes mellitus uncontrolled on metformin (EASIE): a multicentre, randomised open-label trial. Lancet Jun 16;379(9833): Epub 2012 Jun 9. Gallwitz B, Guzman J, Dotta F, Guerci B, Simó R, Basson BR, Festa A, Kiljański J, Sapin H, Trautmann M, Schernthaner G. Exenatide twice daily versus glimepiride for prevention of glycaemic deterioration in patients with type 2 diabetes with metformin failure (EUREXA): an open-label, randomised controlled trial. Lancet Jun 16;379(9833): Epub 2012 Jun 9.

Diabetologia 55: , 2012, Diabetes Care Apr. 19, 2012

Lancet 2012; 379: 2262–69 Pontificia Universidad Javeriana, Hospital Universitario San Ignacio, Bogota, Colombia (Prof P Aschner MD); The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region, China (Prof J Chan FRCP); Centre for Endocrine and Diabetes Science, Cardiff University, Cardiff, UK (Prof D R Owens MD); Point Medical Rond Point de la Nation, Dijon, France (S Picard MD); Sanofi, Bridgewater, NJ, USA (E Wang PhD); Sanofi, Paris, France (M-P Dain MD, V Pilorget MD); Rafi c Hariri University Hospital, Beirut, Lebanon (A Echtay MD); and Tulane University Medical Center, New Orleans, LA, USA (Prof V Fonseca MD)

Background In people with type 2 diabetes, a dipeptidyl peptidase-4 (DPP-4) inhibitor is one choice as second-line treatment after metformin, with basal insulin recommended as an alternative. We aimed to compare the efficacy, tolerability, and safety of insulin glargine and sitagliptin, a DPP-4 inhibitor, in patients whose disease was uncontrolled with metformin.

Methods In this comparative, parallel, randomised, open-label trial, metformin-treated people aged 35–70 years with glycated haemoglobin A1c (HbA1c) of 7–11%, diagnosis of type 2 diabetes for at least 6 months, and body-mass index of 25–45 kg/m² were recruited from 17 countries. Participants were randomly assigned (1:1) to 24-week treatment with insulin glargine (titrated from an initial subcutaneous dose of 0·2 units per kg bodyweight to attain fasting plasma glucose of 4·0–5·5 mmol/L) or sitagliptin (oral dose of 100 mg daily). Randomisation (via a central interactive voice response system) was by random sequence generation and was stratified by centre. Patients and investigators were not masked to treatment assignment. The primary outcome was change in HbA1c from baseline to study end. Efficacy analysis included all randomly assigned participants who had received at least one dose of study drug and had at least one on-treatment assessment of any primary or secondary efficacy variable. This trial is registered at ClinicalTrials.gov, NCT

All participants received a glucose meter to record self-monitored glucose values. Individuals randomly assigned to insulin glargine implemented insulin titration to attain self-monitored fasting plasma glucose concentrations between 4 ・ 0 mmol/L and 5 ・ 5 mmol/L (inclusive). The initial subcutaneous dose was 0 ・ 2 units per kg of bodyweight injected at dinner or bedtime using a prefilled SoloSTAR pen. The dose was either decreased by two units if fasting plasma glucose concentration was less than 4 ・ 0 mmol/L with or without symptomatic hypoglycaemia, increased by two units if the concentration was 5 ・ 6–7 ・ 7 mmol/L, and increased by four units if the concentration was greater than 7 ・ 7 mmol/L. Participants monitored fasting plasma glucose daily and generally used the middle of the past three values to undertake the titration twice a week. Selfmonitored glucose values and insulin doses were reviewed by an international titration committee on an ongoing basis via a website and the study investigators were contacted by if titration was inadequate. Minor departures from the algorithm were allowed, although the final decision rested with the investigator. Participants in the sitagliptin group received a fixed oral dose of 100 mg once daily taken in the morning either with or without food and no changes in dose were allowed during the trial. 4, 5.5, 7.7 mmol/L = 72, 99, 139 mg/dl

T-chol <200mg/dl <5.18mmol/ HDL-C 35mg/dl=0.91 mmol/L, LDL-C 3mmol/L = 116mg/dl Triglyceride <250 mg/dl <2.8mmol/L, 150 mg/dl =1.69mmol/L

Figure 3: HbA1c (A), HbA1c less than 7% or 6·5% (B), in a 24-week study comparing glargine versus sitagliptin in patients with type 2 diabetes who did not respond to metformin monotherapy HbA1c=glycated haemoglobin A1c. SMFPG=self-monitored fasting plasma glucose. *p<0 ・ †p=0 ・ ‡p=0 ・ 0008 versus sitagliptin (endpoint).

Figure 3: self-monitored fasting plasma glucose (C) and seven-point self- monitored blood glucose profiles during a 24-h period (D) in a 24-week study comparing glargine versus sitagliptin in patients with type 2 diabetes who did not respond to metformin monotherapy HbA1c=glycated haemoglobin A1c. SMFPG=self-monitored fasting plasma glucose. *p<0 ・ †p=0 ・ ‡p=0 ・ 0008 versus sitagliptin (endpoint). 4, 5.5, 7.7 mmol/L = 72, 99, 139 mg/dl

Findings 732 people were screened and 515 were randomly assigned to insulin glargine (n=250) or sitagliptin (n=265). At study end, adjusted mean reduction in HbA1c was greater for patients on insulin glargine (n=227; –1 ・ 72%, SE 0 ・ 06) than for those on sitagliptin (n=253; –1 ・ 13%, SE 0 ・ 06) with a mean difference of –0 ・ 59% (95% CI –0 ・ 77 to –0 ・ 42, p<0 ・ 0001). The estimated rate of all symptomatic hypoglycaemic episodes was greater with insulin glargine than with sitagliptin (4 ・ 21 [SE 0 ・ 54] vs 0 ・ 50 [SE 0 ・ 09] events per patient-year; p<0 ・ 0001). Severe hypoglycaemia occurred in only three (1%) patients on insulin glargine and one (<1%) on sitagliptin. 15 (6%) of patients on insulin glargine versus eight (3%) on sitagliptin had at least one serious treatment-emergent adverse event.

Interpretation Our results support the option of addition of basal insulin in patients with type 2 diabetes inadequately controlled by metformin. Long-term benefits might be expected from the achievement of optimum glycaemic control early in the course of the disease. Funding Sanofi.

Diamant M.: Choosing a blood-glucose-lowering agent after metformin Lancet. 379(9833):2221-2, 2012 To date, however, there is insufficient evidence to guide clinicians in choice of the second agent after metformin. Arguments of benefit that go beyond glucose control need to be provided. Therefore, the use of composite endpoints, additionally encompassing favourable effects on bodyweight, hypoglycaemia risk, blood pressure, and lipids, all of which might improve patients’ cardiovascular risk, has been advocated to enable evaluation of an agent’s true benefit. At present, it is unclear whether initiation of basal insulin in the early stage of type 2 diabetes translates into longer term outcome benefits or whether its early use is ultimately off set by progressive weight gain and more hypoglycaemic events, both of which could result in increased cardiovascular risk, higher cost, and poor quality of life.

Message Metformin の次の選択で注射薬と経口薬を比較 している。 グラルギンインスリン vs DPP-4 阻害薬 そもそも A1C が 8.5% などという集団でインスリ ンや SU 薬でないと血糖管理できないと感じるの で、 「インスリンも選択肢となりうる」という結論で あるが、現実的にはとても疑問。（ SU 薬が本来 の適用と思われる集団） ちなみに ORIGIN 研究では、あまり差がなさそ う。

Diabetologia 55: , 2012, Diabetes Care Apr. 19, 2012

Lancet 2012; 379: 2270–78 Department of Medicine IV, Eberhard-Karls-University Tubingen, Tubingen, Germany, (Prof B Gallwitz MD); Celaya Centre for Specialist Medicine, Guanajuato, Mexico (J Guzman MD); Department of Internal Medicine, Endocrine and Metabolic Sciences, Policlinico Le Scotte, Sienna, Italy (F Dotta MD); Hospital Brabois and Centres d’Investigation Clinique Inserm, CHU de Nancy, Vandoeuvre-Les-Nancy, France (B Guerci MD); Vall d’Hebron Research Institute and Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas, Carlos III Health Institute, Barcelona, Spain (R Simo MD); Eli Lilly and Company, St Cyr au Mont D’Or, France (B R Basson MSc); Eli Lilly and Company, Vienna, Austria (A Festa MD); Eli Lilly Polska, Warsaw, Poland (J Kiljański MD); Eli Lilly and Company, Suresnes, France (H Sapin MSc); Lilly Deutschland, Hamburg, Germany (M Trautmann MD); and Department of Medicine I, Rudolfstiftung Hospital, Vienna, Austria (Prof G Schernthaner MD)

Background Glycaemic control deteriorates progressively over time in patients with type 2 diabetes. Options for treatment escalation remain controversial after failure of first-line treatment with metformin. We compared add-on exenatide with glimepiride for durability of glycaemic control in patients with type 2 diabetes inadequately controlled by metformin alone.

Methods We did an open-label, randomised controlled trial at 128 centres in 14 countries between Sept 5, 2006, and March 29, Patients aged 18–85 years with type 2 diabetes inadequately treated by metformin were randomly assigned via a computer-generated randomisation sequence to receive exenatide twice daily or glimepiride once daily as add-on to metformin. Randomisation was stratified by predetermined categories of glycated haemoglobin (HbA1C) concentration. The primary outcome was time to inadequate glycaemic control and need for alternative treatment, defined as an HbA1c concentration of more than 9% after the first 3 months of treatment, or more than 7% at two consecutive visits after the first 6 months. Analysis was by intention to treat. This trial is registered with EudraCT, number , and ClinicalTrials.gov, number NCT

Randomisation and masking We used a computer-generated randomisation sequence to randomly assign patients, in a 1:1 ratio, to receive either exenatide or glimepiride. Randomisation was stratified by HbA1c categories of 7 ・ 3% and less, more than 7 ・ 3% to 8 ・ 2% and less, and more than 8 ・ 2%. Before database lock the study team were masked to group assignment and statistical anlyses were planned with no knowledge of groups. Eligible participants had type 2 diabetes; were overweight to obese (body-mass index [BMI] ≥25 kg/m 2 to <40 kg/m 2 ); aged 18–85 years; had been on stable, maximum tolerated doses of metformin; and had developed suboptimum glycaemic control, defined by a glycated haemoglobin (HbA1c) concentration of 6 ・ 5% and more or 9 ・ 0% and less.

Procedures Exenatide was injected subcutaneously within 60 min before breakfast and evening meals, starting at 5 μg twice daily for 4 weeks, followed by 10 μg twice daily for the remaining study period. If patients had daily episodes of nausea for more than 1 week, the 10 μg dose was reduced to 5 μg twice daily and could be increased again after nausea subsided. The recommended starting dose for patients in the glimepiride group was 1 mg per day, given once daily immediately before breakfast. Attending physicians established the glimepiride dose as per their usual practice, and investigators were instructed to adjust the dose every 4 weeks, according to tolerability, up to the maximum tolerated dose in accordance with the country specific summary of product characteristics. Concomitant metformin was continued throughout the study for all patients, in the same form and at the same dose as used at study entry

Study outcomes The primary outcome was time to inadequate glycaemic control, defined as an HbA1c concentration of more than 9% after the first 3 months of treatment, or more than 7% at two consecutive visits 3 months apart after the first 6 months. We defined treatment failure in line with recommendations of diabetes associations and the known timecourse of changes in HbA1c concentration, and allowed quick identification of patients with poor glycaemic control who needed alternative treatment. Because the primary outcome was a time-to-event measure, we regarded a study period of 2–3 years as appropriate. Patients who had treatment failure were discontinued, but could enrol in an extension study to examine further treatment options; findings from this study will be described elsewhere. Secondary outcomes were markers of β-cell function, bodyweight, hypoglycaemia, and surrogate markers of cardiovascular risk (blood pressure and heart rate).

Figure 1: Trial profile The intention-to-treat population consisted of 490 patients randomised to exenatide (five did not receive the study drug and 20 did not have at least one baseline or post- baseline HbA1c measurement) and 487 randomised to glimepiride (six did not receive the study drug and 21 did not have at least one baseline or post-baseline HbA1c measurement). *p=0 ・ 001 for difference between groups.

Table 1: Baseline demographic and clinical characteristics

Consistent with inclusion criteria, patients were taking metformin at close to the recommended maximum dose, with a median dose of 2000 mg per day (IQR 1700–2550). Average treatment time was about 2 years (exenatide group, mean 101 ・ 9 weeks [SD 73 ・ 8]; glimepiride group, 113 ・ 1 weeks [70 ・ 9]). Mean exenatide dose was 17 ・ 35 (4 ・ 07) μg per day and mean glimepiride dose was 2 ・ 01 (1 ・ 02) mg per day. time to inadequate glycaemic control, defined as an HbA1c concentration of more than 9% after the first 3 months of treatment, or more than 7% at two consecutive visits 3 months apart after the first 6 months. Figure 2: Time-to-event curves for patients meeting criteria for treatment failure (A) and for those meeting treatment failure criteria according to baseline HbA1c categories (B) Event rates in figure 2A are Kaplan-Meier estimates. The sharp drop at 9 months corresponds to when patients could first meet the criterion of HbA1c concentration >7 ・ 0% at two consecutive visits after the first 6 months of treatment. HbA1c=glycated haemaglobin A1c.

Bodyweight fell from baseline to endpoint in the exenatide group (–3 ・ 32 kg [SD 5 ・ 45]) and rose in the glimepiride group (1 ・ 15 kg [4 ・ 18]); difference in change from baseline between groups was significant after 4 weeks and at each time thereafter (p<0 ・ 0001).

Findings We randomly assigned 515 patients to the exenatide group and 514 to the glimepiride group, of whom 490 versus 487 were the intention-to- treat population. 203 (41%) patients had treatment failure in the exenatide group compared with 262 (54%) in the glimepiride group (risk difference 12 ・ 4 [95% CI 6 ・ 2–18 ・ 6], hazard ratio 0 ・ 748 [0 ・ 623– 0 ・ 899]; p=0 ・ 002). 218 (44%) of 490 patients in the exenatide group, and 150 (31%) of 487 in the glimepiride group achieved an HbA1c concentration of less than 7% (p<0 ・ 0001), and 140 (29%) versus 87 (18%) achieved concentrations of 6 ・ 5% and less (p=0 ・ 0001). We noted a significantly greater decrease in bodyweight in patients given exenatide than in those given glimepiride (p<0 ・ 0001). Five patients in each treatment group died from causes unrelated to treatment. Significantly fewer patients in the exenatide group than in the glimepiride group reported documented symptomatic (p<0 ・ 0001), nocturnal (p=0 ・ 007), and non-nocturnal (p<0 ・ 0001) hypoglycaemia. Discontinuation because of adverse events (mainly gastrointestinal) was significantly higher (p=0 ・ 0005) in the exenatide group than in the glimepiride group in the first 6 months of treatment, but not thereafter.

Interpretation These findings provide evidence for the benefits of exenatide versus glimepiride for control of glycaemic deterioration in patients with type-2 diabetes inadequately controlled by metformin alone. Funding Eli Lilly and Company; Amylin Pharmaceuticals.

Madsbad S.: Type 2 diabetes: which drug as add-on to metformin? Lancet. 379(9833):2222-3, 2012

Message Metformin の次の選択で注射薬と経口薬を比較 している。 GLP-1 受容体作動薬 vs SU 薬 プロインスリンの値が低すぎるが SU 薬よりも GLP-1 受容体作動薬の注射も選択肢となりうる。 というのはまぁ妥当かもしれない。