Journal Club
Roumie CL1, Greevy RA2, Grijalva CG3, Hung AM1, Liu X2, Murff HJ1, Elasy
TA1, Griffin MR4.
Association between intensification of metformin treatment with insulin vs
sulfonylureas and cardiovascular events and all-cause mortality among
patients with diabetes.
JAMA. 2014 Jun 11;311(22):2288-96.
Russell SJ1, El-Khatib FH, Sinha M, Magyar KL, McKeon K, Goergen LG,
Balliro C, Hillard MA, Nathan DM, Damiano ER.
Outpatient Glycemic Control with a Bionic Pancreas in Type 1 Diabetes.
N Engl J Med. 2014 Jun 15. DOI: 10.1056/NEJMoa1314474
2014年7月3日 8:30-8:55
８階 医局
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
1Veterans
Health Administration–Tennessee Valley Healthcare System Geriatric
Research Education Clinical Center, HSR&D Center, Nashville, Tennessee
2Department of Medicine, Vanderbilt University, Nashville, Tennessee
3Department of Biostatistics, Vanderbilt University, Nashville, Tennessee
4Department of Health Policy, Vanderbilt University, Nashville, Tennessee
JAMA. 2014;311(22):2288-2296. doi:10.1001/jama.2014.4312.
Importance Preferred second-line
medication for diabetes treatment after
metformin failure remains uncertain.
Objective To compare time to acute
myocardial infarction (AMI), stroke, or death
in a cohort of metformin initiators who
added insulin or a sulfonylurea.
Design, Setting, and Participants Retrospective cohort
constructed with national Veterans Health Administration,
Medicare, and National Death Index databases. The study
population comprised veterans initially treated with metformin from
2001 through 2008 who subsequently added either insulin or
sulfonylurea. Propensity score matching on characteristics was
performed, matching each participant who added insulin to 5 who
added a sulfonylurea. Patients were followed through September
2011 for primary analyses or September 2009 for cause-of-death
analyses.
Main Outcomes and Measures Risk of a composite outcome of
AMI, stroke hospitalization, or all-cause death was compared
between therapies with marginal structural Cox proportional
hazard models adjusting for baseline and time-varying
demographics, medications, cholesterol level, hemoglobin A1c
level, creatinine level, blood pressure, body mass index, and
comorbidities.
sulfonylurea (glyburide,
glipizide, or glimepiride)
insulin (long-acting,
premixed,
or short/fast-acting insulin)
Patients were 95% men and 70% white.
Compared with patients who added a
sulfonylurea, patients who added insulin to
metformin intensified therapy earlier (14
months vs 18 months), had higher median
HbA1c levels (8.5% vs 7.5%), and had a higher
prevalence of comorbidities. The proportion
of patients prescribed metformin + insulin
increased over time, with the odds increasing
by an average of 17% (IQR, 14%-20%) per year
(P < .001).
The cohort included 2948 patients (7%) who
added insulin (47% long-acting, 22% both
long- and short-acting, 17% premixed, and
11% short-acting) and 39 990 patients (92%)
who added a sulfonylurea (55% glipizide, 43%
glyburide, and 2% glimepiride).
statistically significant only for cancer death
Results Among 178 341 metformin monotherapy patients, 2948
added insulin and 39 990 added a sulfonylurea. Propensity score
matching yielded 2436 metformin + insulin and 12 180
metformin + sulfonylurea patients. At intensification, patients had
received metformin for a median of 14 months (IQR, 5-30), and
hemoglobin A1c level was 8.1% (IQR, 7.2%-9.9%). Median follow-up
after intensification was 14 months (IQR, 6-29 months). There were
172 vs 634 events for the primary outcome among patients who
added insulin vs sulfonylureas, respectively (42.7 vs 32.8 events per
1000 person-years; adjusted hazard ratio [aHR], 1.30; 95% CI, 1.071.58; P = .009). Acute myocardial infarction and stroke rates were
statistically similar, 41 vs 229 events (10.2 and 11.9 events per 1000
person-years; aHR, 0.88; 95% CI, 0.59-1.30; P = .52), whereas allcause death rates were 137 vs 444 events, respectively (33.7 and
22.7 events per 1000 person-years; aHR, 1.44; 95% CI, 1.15-1.79;
P = .001). There were 54 vs 258 secondary outcomes: AMI, stroke
hospitalizations, or cardiovascular deaths (22.8 vs 22.5 events per
1000 person-years; aHR, 0.98; 95% CI, 0.71-1.34; P = .87).
Conclusions and Relevance Among patients
with diabetes who were receiving metformin, the
addition of insulin vs a sulfonylurea was
associated with an increased risk of a composite
of nonfatal cardiovascular outcomes and allcause mortality. These findings require further
investigation to understand risks associated with
insulin use in these patients.
Message
メトホルミン投与中の糖尿病患者1万4616人を対
象に、インスリンまたはスルホニル尿素薬の追
加効果を後ろ向きコホート研究で比較。主要評
価項目の1000人年当たりの複合転帰（急性心筋
梗塞、脳卒中での入院または全死因死亡）発生
率はインスリン群42.7、スルホニル尿素薬群
32.8だった（調整後ハザード比1.30、P＝
0.009）。
で、差がついたのは がん での死亡。
後ろ向き研究なので、やはりインスリンの方が
わけあり患者に用いた可能性は否定できない。
From the Diabetes Unit and Department of Medicine, Massachusetts General
Hospital and Harvard Medical School (S.J.R., M.S., K.L.M, L.G.G., C.B., M.A.H.,
D.M.N.), and the Department of Biomedical Engineering, Boston University (F.H.E.K., K.M., E.R.D.) — both in Boston.
June 15, 2014DOI: 10.1056/NEJMoa1314474
Background
The safety and effectiveness of
automated glycemic management have
not been tested in multiday studies
under unrestricted outpatient conditions
Methods
In two random-order, crossover studies with
similar but distinct designs, we compared
glycemic control with a wearable, bihormonal,
automated, “bionic” pancreas (bionic-pancreas
period) with glycemic control with an insulin pump
(control period) for 5 days in 20 adults and 32
adolescents with type 1 diabetes mellitus. The
automatically adaptive algorithm of the bionic
pancreas received data from a continuous
glucose monitor to control subcutaneous delivery
of insulin and glucagon.
Beacon'Hill'Study'CONSORT'Flow'Diagram'
Summer&Camp&Study&CONSORT&Flow&Diagram
* Plus–minus values are
means ±SD. To
convert the values for
glucose to millimoles
per liter, multiply by
0.05551.
† All adults had a
stimulated C-peptide
level of less than the
assay limit (<0.1 nmol
per liter).
‡ The body-mass index is
the weight in kilograms
divided by the square
of the height in meters.
§ The estimated
average glucose level
is based on the
glycated hemoglobin
level at screening,
calculated according to
the methods of Nathan
et al.32
The user interface displayed the continuous-glucose-monitor tracing and insulin
and glucagon doses, and allowed announcement of meal size as “typical,” “more
than usual,” “less than typical,” or “a small bite” and the meal type as
“breakfast,” “lunch,” or “dinner.” This triggered a partial meal-priming bolus,
which automatically adapted insulin dosing to meet 75% of the 4-hour
postprandial insulin need for that meal size and type. The first meal-priming bolus
of each type was based on the patient's weight (0.05 U per kilogram).
Adults
The mean carbohydrate consumption during the bionic-pancreas period was 261
g per day. Patients announced approximately two thirds of their meals and snacks
to the bionic pancreas. The mean percentage of insulin given as an automated,
adaptive, meal-priming bolus was 29% of the daily total and 46% of the nonbasal
insulin during days 2 through 5. The mean total daily dose of glucagon during
days 2 through 5 of the bionic-pancreas period was 0.82±0.41 mg (range, 0.32 to
1.75).
Adolescents
Also similar were the mean daily values for carbohydrate consumption (247±79
and 264±69 g per day, respectively; P=0.08). The mean percentage of insulin
given as an automated, adaptive, meal-priming bolus was 26% of the daily total
and 41% of the nonbasal insulin on days 2 through 5. The mean total daily dose of
glucagon on days 2 through 5 of the bionic-pancreas period was 0.72±0.26 mg
(range, 0.22 to 1.34).
Results
Among the adults, the mean plasma glucose level over the 5-day
bionic-pancreas period was 138 mg per deciliter (7.7 mmol per liter),
and the mean percentage of time with a low glucose level (<70 mg
per deciliter [3.9 mmol per liter]) was 4.8%. After 1 day of automatic
adaptation by the bionic pancreas, the mean (±SD) glucose level on
continuous monitoring was lower than the mean level during the
control period (133±13 vs. 159±30 mg per deciliter [7.4±0.7 vs.
8.8±1.7 mmol per liter], P<0.001) and the percentage of time with a
low glucose reading was lower (4.1% vs. 7.3%, P=0.01). Among the
adolescents, the mean plasma glucose level was also lower during
the bionic-pancreas period than during the control period (138±18 vs.
157±27 mg per deciliter [7.7±1.0 vs. 8.7±1.5 mmol per liter],
P=0.004), but the percentage of time with a low plasma glucose
reading was similar during the two periods (6.1% and 7.6%,
respectively; P=0.23). The mean frequency of interventions for
hypoglycemia among the adolescents was lower during the bionicpancreas period than during the control period (one per 1.6 days vs.
one per 0.8 days, P<0.001).
Conclusions
As compared with an insulin pump, a
wearable, automated, bihormonal, bionic
pancreas improved mean glycemic levels,
with less frequent hypoglycemic episodes,
among both adults and adolescents with
type 1 diabetes mellitus.
(Funded by the National Institute of Diabetes and Digestive and
Kidney Diseases and others; ClinicalTrials.gov numbers,
NCT01762059 and NCT01833988.)
Message
1型糖尿病（DM）の成人20人と青少年32人を対象
に、血糖値の連続測定データを基に自動的にイ
ンスリンとグルカゴンを注入する装着型人工膵
臓による血糖管理の有効性を2件のクロスオー
バー試験で検証。インスリンポンプに比べ、人
工膵臓で平均血糖値が低下し（成人でP＜0.001、
青少でP＝0.004）、低血糖エピソードの発現頻
度が減少した。
超超速効型インスリンが出るとグルカゴンはい
らないかもしれないが。