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 2015 年 11 月 19 日 8:30-8:55 ８階 医局 Lind M, Hirsch IB, Tuomilehto J, Dahlqvist S, Ahrén B, Torffvit O, Attvall S, Ekelund M, Filipsson K, Tengmark BO, Sjöberg S, Pehrsson NG. Liraglutide in people treated for type 2 diabetes with multiple daily insulin injections: randomised clinical trial (MDI Liraglutide trial). BMJ Oct 28;351:h5364. doi: /bmj.h5364. Ma J, Ward EM, Siegel RL, Jemal A. Temporal Trends in Mortality in the United States, JAMA Oct 27;314(16): doi: /jama

1 Institute of Medicine, University of Gothenburg, Gothenburg, Sweden 2 Department of Medicine, Uddevalla Hospital, NU Hospital Group, Uddevalla, Sweden 3 University of Washington, Seattle, WA, US 4 Centre for Vascular Prevention, Danube-University, Krems, Austria; Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland; Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia 5 Lund University, Lund, Sweden 6 Citydiabetes, Stockholm, Sweden 7 Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Medicine, Halland County Hospital, Halmstad, Sweden 8 Statistiska Konsultgruppen, Gothenburg, Sweden BMJ 2015; 351 doi: (Published 28 October 2015)

Study question What are the effects of liraglutide, an incretin based treatment, on glycaemic control in people with type 2 diabetes treated with multiple daily insulin injections?

Methods The study was a randomised, double blind, placebo controlled trial with a parallel group design carried out at 13 hospital based outpatient clinics and one primary care unit in Sweden. Patients were considered eligible for inclusion if they had type 2 diabetes and inadequate glycaemic control (HbA1c concentrations ≥58 mmol/mol (7.5%) and ≤102 mmol/mol (11.5%)), a body mass index of kg/m2, and required multiple daily insulin injections. Overall, 124 participants were randomised 1:1 to subcutaneous liraglutide or placebo by minimisation allocation. The main outcome measure was change in HbA1c level from baseline to week 24.

Study answer and limitations Liraglutide was associated with a significant reduction of 16.9 mmol/mol (1.5%) in HbA1c versus 4.6 mmol/mol (0.4%) for placebo, difference −12.3 mmol/mol (95% confidence interval −15.8 to −8.8 mmol/mol; −1.13%, −1.45 to −0.81 mmol/mol). Body weight was significantly reduced in participants in the liraglutide compared with placebo group (3.8 v 0.0 kg, difference −3.8, −4.9 to −2.8 kg), and total daily insulin doses were significantly reduced, by 18.1 units and 2.3 units (difference −15.8, −23.1 to −8.5 units). Reductions in mean and standard deviation of glucose levels estimated by masked continuous glucose monitoring were significantly greater in the liraglutide group than placebo group (−1.9 and −0.5 mmol/L). Neither group experienced severe hypoglycaemic events nor were there any significant differences in symptomatic or asymptomatic non-severe hypoglycaemia (<4.0 or <3.0 mmol/L). The mean number of non-severe symptomatic hypoglycaemic events (<4.0 mmol/L) during follow-up was 1.29 in the liraglutide group and 1.24 in the placebo group (P=0.96). One of the study’s limitations was its relatively short duration. Sustained effects of liraglutide have, however, been found over lengthier periods in connection with other treatment regimens. Cardiovascular safety and potential adverse events during longer exposure to liraglutide need to be evaluated. Nausea was experienced by 21 (32.8%) participants in the liraglutide group and 5 (7.8%) in the placebo group and 3 (5%) and 4 (7%) participants in these groups, respectively, had any serious adverse event.

What this study adds Adding liraglutide to multiple daily insulin injections in people with type 2 diabetes improves glycaemic control without an increased risk of hypoglycaemia, reduces body weight, and enables patients to lower their insulin doses. Funding, competing interests, data sharing This study was an investigator initiated trial, supported in part by Novo Nordisk and InfuCare. Potential competing interests have been reported and are available on thebmj.com. Study registration EudraCT

Message 毎日のインスリン頻回注射を要する 2 型糖尿病患 者 124 人を対象に、リラグルチドの併用効果を無 作為化二重盲検試験で検証（ MDI Liraglutide 試験）。リラグルチド群ではプラセボ群に比べ、 HbA1c 値（ベースラインから 24 週時の低下率 1.5 ％対 0.4 ％；差－ 1.13 ％、 95 ％ CI, － － 0.81 ）、体重、インスリンの 1 日投与量が有 意に低下した。

1 Surveillance and Health Services Research Program, Intramural Research Department, American Cancer Society, Atlanta, Georgia 2 Intramural Research Department, American Cancer Society, Atlanta, Georgia JAMA. 2015;314(16): doi: /jama

Importance: A systematic and comprehensive evaluation of long-term trends in mortality is important for health planning and priority setting and for identifying modifiable factors that may contribute to the trends. Objective: To examine temporal trends in deaths in the United States for all causes and for the 6 leading causes.

Design, Setting, and Participants Joinpoint analysis of US national vital statistics data from 1969 through Exposure Causes of death. Main Outcomes and Measures Total and annual percent change in age-standardized death rates and years of potential life lost before age 75 years for all causes combined and for heart disease, cancer, chronic obstructive pulmonary disease (COPD), stroke, unintentional injuries, and diabetes mellitus.

Data Sources All death data were obtained from the US National Vital Statistics System (NVSS) of the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention, with data abstracted from SEER* Stat software 2 (1969 is the earliest data year available) and data abstracted from public-use multiple cause of death files. 3 The NCHS annually compiles information on death certificates from 50 states and the District of Columbia into public-use multiple cause of death files, in which the underlying cause of death is selected according to the coding and selection rules of the International Classification of Disease (ICD) revision in use at the time of death (ICD-8 for , ICD-9 for , and ICD-10for ). 4 The World Health Organization defines underlying cause of death as “the disease or injury which initiated the train of events leading directly to death, or the circumstances of the accident or violence which produced the fatal injury.” 5

Results Between 1969 and 2013, the age-standardized death rate per decreased from to for all causes (42.9% reduction; 95% CI, 42.8%-43.0%), from to 36.0 for stroke (77.0% reduction; 95% CI, 76.9%- 77.2%), from to for heart disease (67.5% reduction; 95% CI, 67.4%-67.6%), from 65.1 to 39.2 for unintentional injuries (39.8% reduction; 95% CI, 39.3%-40.3%), from to for cancer (17.9% reduction; 95% CI, 17.5%-18.2%), and from 25.3 to 21.1 for diabetes (16.5% reduction; 95% CI, 15.4%-17.5%). In contrast, the rate for COPD increased from 21.0 to 42.2 (100.6% increase; 95% CI, 98.2%-103.1%). However, during the last time segment detected by joinpoint analysis, death rate for COPD in men began to decrease and the declines in rates slowed for heart disease, stroke, and diabetes. For example, the annual decline for heart disease slowed from 3.9% (95% CI, 3.5%-4.2%) during the period to 1.4% (95% CI, −3.4% to 0.6%) during the period (P =.02 for slope difference). Between 1969 and 2013, age-standardized years of potential life lost per 1000 decreased from 1.9 to 1.6 for diabetes (14.5% reduction; 95% CI, 12.6%-16.4%), from 21.4 to 12.7 for cancer (40.6%; 95% CI, 40.2%-41.1%), from 19.9 to 10.4 for unintentional injuries (47.5%; 95% CI, 47.0%-48.0%), from 28.8 to 9.1 for heart disease (68.3%; 95% CI, 68.1%-68.5%), and from 6.0 to 1.5 for stroke (74.8%; 95% CI, 74.4%-75.3%). For COPD, the rate for years of potential life lost did not decrease over this time interval.

Conclusions and Relevance According to death certificate data between 1969 and 2013, an overall decreasing trend in age-standardized death rate was observed for all causes combined, heart disease, cancer, stroke, unintentional injuries, and diabetes, although the rate of decrease appears to have slowed for heart disease, stroke, and diabetes. The death rate for COPD increased during this period.

Message 1969 年から 2013 年まで期間を比較 この調査を行ったのは American Medical Association 。彼らは 1969 年から 2013 年までの間で 年齢標準化の手法を用い、死亡率と平均余命の観点から分析を実施。 その結果、心臓病やがん、脳卒中、糖尿病、不慮の事故などで死亡する人の割合が減少傾向 にあることが明らかとなった。 死亡率から分析した結果、大幅に減少 まず死亡率から分析した結果、全体では 10 万人につき 1279 人から 730 人と死亡者が 40.0 ％減少。 さらに脳卒中も 70.0 ％低下し、心臓病も 40.0 ％、がん 18.0 ％、糖尿病で 17.0 ％、不慮の事故 も 40.0 ％減少していることが判明した。しかし慢性閉塞性肺疾患は ％という結果になる。 平均余命による分析でもほぼ同じ結果 次に平均余命喪失で分析した場合でも、糖尿病の割合は 14.5 ％も減少。さらにがんも 41.0 ％、 不慮の事故は 48.0 ％、心臓病 68.0 ％、脳卒中で 75.0 ％も少なくなっていることが分かった。 ただし、ここでも慢性閉塞性肺疾患はわずかな上昇となる。 この調査を行った研究者らは報告の中で「死亡率の変化にもかかわらずアメリカでは高齢者 が増え、ヘルスケアの提供面でこの先の 10 年間は相当な困難が予想される。初期医療の医師 や老人病専門医の不足、医療コストの増加などが懸念されます」と語っている。 確かに高齢者問題は深刻だが、多くの病気がここまで治るようになったのは、研究者や多く の関係者が積み重ねてきた努力の結果なのだろう。