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Journal Club
Writing Group for the DCCT/EDIC Research Group, Orchard TJ, Nathan DM, Zinman B,
Cleary P, Brillon D, Backlund JY, Lachin JM.
Association between 7 years of intensive treatment of type 1 diabetes and long-term
mortality.
JAMA. 2015 Jan 6;313(1):45-53.
Abdul-Ghani MA1, Puckett C, Triplitt C, Maggs D, Adams J, Cersosimo E, DeFronzo RA.
Initial combination therapy with metformin, pioglitazone and exenatide is more effective
than sequential add-on therapy in subjects with new-onset diabetes. Results from the
Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT): a
randomized trial.
Diabetes Obes Metab. 2015 Mar;17(3):268-75.
2015年2月19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
1型糖尿病
DCCT/EDIC
-42%
（P=0.02）
0.12
心
血
管
イ
ベ
ン
ト
の
累
積
発
生
率
0.10
従来療法群（N=589）
0.08
0.06
A1C 7.4% vs 9.1%
A1C 8.0% vs 8.2%
0.04
0.02
強化療法群（N=593）
0.00
0
1
2
3
4
5
No. at Risk
強化療法群
従来療法群
705
714
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21
観察期間（年）
683
688
629
618
113
92
N Engl J Med 2005; 353: 2643-53.
Diabetic retinopathy cumulative incidence
Secondary prevention
76%
conventional
54%
Incidence
Incidence
Primary prevention
conventional
intensive
intensive
years
years
conventional
conventional
intensive
intensive
4
FIG. 2. Estimated cumulative
incidence of further 3-step
progression of retinopathy from
DCCT closeout, by DCCT
treatment group, through EDIC
year 4, for adolescents (A) and
for adults (B); through EDIC
year 10, for adolescents (C) and
for adults (D). Subjects with
prior scatter photocoagulation
during DCCT (7 adolescents and
29 adults) were excluded from
analyses. Based on Weibull
regression models adjusted for
the level of retinopathy at the
end of the DCCT, primary vs.
secondary cohort, the A1C value
on entry to the DCCT, and
diabetes duration at DCCT
baseline. Hazard reduction was
for intensive therapy compared
with conventional therapy.
Diabetes 59:1244–1253, 2010
Figure 1. Cumulative Incidence of an Impaired Glomerular Filtration Rate, According to Treatment Group. An impaired glomerular
filtration rate (GFR) was defined as a sustained estimated GFR of less than 60 ml per minute per 1.73 m2 of body-surface area. The
cumulative incidence of an impaired GFR is shown according to the group to which the participants had been randomly assigned in
the Diabetes Control and Complications Trial, with death accounted for as a competing risk. The hazard ratio and P value were
calculated with the use of a Cox proportional-hazards model with a robust estimate of confidence limits according to the method of
Lin and Wei16 and the robust Wald test.
de Boer IH, Sun W, Cleary PA, Lachin JM, Molitch ME, Steffes MWZinman B, ; DCCT/EDIC Research Group:
Intensive diabetes therapy and glomerular filtration rate in type 1 diabetes. N Engl J Med. 2011; 365: 2366-76
University of Pittsburgh, Pittsburgh, Pennsylvania (Orchard); Massachusetts
General Hospital, Harvard Medical School, Boston, Massachusetts (Nathan);
Lunefeld Tanenbaum Research Institute, Mount Sinai Hospital, University of
Toronto, Toronto, Ontario, Canada (Zinman); The George Washington
University Biostatistics Center, Rockville, Maryland (Cleary, Backlund, Lachin);
Cornell University Medical Center, New York, New York (Brillon).
JAMA. 2015;313(1):45-53.
Importance Whether mortality in type 1
diabetes mellitus is affected following
intensive glycemic therapy has not been
established.
Objective
To determine whether mortality differed
between the original intensive and
conventional treatment groups in the longterm follow-up of the Diabetes Control and
Complications Trial (DCCT) cohort.
Design, Setting, and Participants After the DCCT (1983-1993) ended,
participants were followed up in a multisite (27 US and Canadian academic
clinical centers) observational study (Epidemiology of Diabetes Control and
Complications [EDIC]) until December 31, 2012. Participants were 1441
healthy volunteers with diabetes mellitus who, at baseline, were 13 to 39
years of age with 1 to 15 years of diabetes duration and no or early
microvascular complications, and without hypertension, preexisting
cardiovascular disease, or other potentially life-threatening disease.
Interventions and Exposures
During the clinical trial, participants were randomly assigned to receive
intensive therapy (n = 711) aimed at achieving glycemia as close to the
nondiabetic range as safely possible, or conventional therapy (n = 730) with
the goal of avoiding symptomatic hypoglycemia and hyperglycemia. At the
end of the DCCT, after a mean of 6.5 years, intensive therapy was taught
and recommended to all participants and diabetes care was returned to
personal physicians.
Main Outcomes and Measures
Total and cause-specific mortality was assessed through annual contact
with family and friends and through records over 27 years’ mean follow-up.
Results Vital status was ascertained for 1429 (99.2%)
participants. There were 107 deaths, 64 in the conventional
and 43 in the intensive group. The absolute risk difference
was −109 per 100 000 patient-years (95% CI, −218 to −1),
with lower all-cause mortality risk in the intensive therapy
group (hazard ratio [HR] = 0.67 [95% CI, 0.46-0.99]; P = .045).
Primary causes of death were cardiovascular disease (24
deaths; 22.4%), cancer (21 deaths; 19.6%), acute diabetes
complications (19 deaths; 17.8%), and accidents or suicide
(18 deaths; 16.8%). Higher levels of glycated hemoglobin
(HbA1c) were associated with all-cause mortality (HR = 1.56
[95% CI, 1.35-1.81 per 10% relative increase in HbA1c];
P < .001), as well as the development of albuminuria
(HR = 2.20 [95% CI, 1.46-3.31]; P < .001).
Conclusions and Relevance After a mean
of 27 years’ follow-up of patients with type 1
diabetes, 6.5 years of initial intensive
diabetes therapy was associated with a
modestly lower all-cause mortality rate
when compared with conventional therapy.
Trial Registration
clinicaltrials.gov Identifiers: NCT00360815
and NCT00360893
Message
1型糖尿病（DM）患者の死亡率が血糖コントロー
ルの影響を受けるかを、血糖コントロールと合
併症に関する大規模臨床試験（DCCT試験）参加
者1441人の長期追跡（EDIC試験）から検討。平
均27年の追跡の結果、全死因死亡リスクは標準
療法に対して強化療法群で低く（ハザード比
0.67）、絶対リスク差は10万人年当たり－109
だった。
September, 8, 2008 in Rome at EASD meeting
BETA CELL FAILURE IN
T2DM: CAN IT BE
PREVENTED?
Ralph A. DeFronzo, M.D.
Professor of Medicine
Division of Diabetes
UTHSCSA
ADA ALGORITHM
Lifestyle + Metformin
HbA1c > 7.0%
Add
Basal Insulin
Add
Sulfonylurea
Add
Glitazone
Intensify
Insulin
Add Glitazone or
Basal Insulin
Add SU or
Basal Insulin
PATHOPHYSIOLOGIC BASED
(DEFRONZO) ALGORITHM
TRIPLE COMBINATION:
Pioglitazone + Metformin
+ Exenatide
HbA1c < 6.0%
1.Diabetes Division, University of Texas Health Science Center at San Antonio,
San Antonio, TX, USA
2.GI Dynamics, Lexington, MA, USA
Aim
To test our hypothesis that initiating therapy with
a combination of agents known to improve insulin
secretion and insulin sensitivity in subjects with
new-onset diabetes would produce greater, more
durable reduction in glycated haemoglobin
(HbA1c) levels, while avoiding hypoglycaemia
and weight gain, compared with sequential
addition of agents that lower plasma glucose but
do not correct established pathophysiological
abnormalities.
Methods
Drug-naïve, recently diagnosed subjects with type
2 diabetes mellitus (T2DM) were randomized in
an open-fashion design in a single-centre study to
metformin/pioglitazone/exenatide (triple therapy;
n = 106) or an escalating dose of metformin
followed by sequential addition of sulfonylurea
and glargine insulin (conventional therapy;
n = 115) to maintain HbA1c levels at <6.5% for
2 years.
Study Design
Eligible participants were consecutively randomized based on age, sex, BMI, diabetes duration and HbA1c level to
receive either initial triple combination therapy with metformin/pioglitazone/exenatide or metformin with sequential
addition of glipizide and then basal insulin glargine (conventional therapy) to maintain HbA1c levels at <6.5%.
Participants were randomized consecutively and were matched on age, sex, BMI, initial HbA1c level and diabetes
duration. There was no limit on the upper value of HbA1c (the range of initial HbA1c was 6.5–14%). Participants
with initial HbA1c <9.0% (36% of participants) and HbA1c ≥ 9.0% were evenly randomized to the two arms.
Participants randomized to triple therapy were started on metformin 1000 mg/day, pioglitazone 15 mg/day and
exenatide 5 µg twice daily before breakfast and supper. At 1 month, metformin was increased to 2000 mg,
pioglitazone to 30 mg and exenatide to 10 µg twice daily. If, at 3 months, HbA1c was >6.5%, pioglitazone was
increased to 45 mg. Participants receiving conventional therapy were started on metformin 1000 mg/day. If, at
1 month, fasting plasma glucose (FPG) concentration was >6.1 mmol/l (110 mg/dl), metformin was increased to
2000 mg and glipizide started at 5 mg/day. If, at 2 months, FPG was >6.1 mmol/l (110 mg/dl) or HbA1c was >6.5%,
glipizide was increased to 10 mg and then to 20 mg. If, at 3 months, FPG was >6.1 mmol/l (110 mg/dl) or HbA1c
>6.5%, glargine insulin was started at 10 units before breakfast, and escalated weekly by 1–5 units (based on
FPG and HbA1c levels) to 60 units/day to maintain FPG at <6.1 mmol/l (110 mg/dl).
After 3 months, participants were seen every 3 months. FPG, body weight and HbA1c were measured at each
follow-up visit and medication dose was adjusted to maintain FPG at <6.1 mmol/l (110 mg/dl) and HbA1c at <6.5%,
unless hypoglycaemia (blood glucose <3.3 mmol/l (60 mg/dl) or symptoms) was present. Hypoglycaemia was
defined as blood glucose concentration <3.3 mmol/l ( 60 mg/dl).
If HbA1c increased to >6.5% on two consecutive visits (3 months apart, to ensure that the deterioration in
glycaemic control was genuine and not attributable to transient factors) despite maximum antihyperglycaemic
therapy, treatment was defined as having failed for that participant.
All baseline studies were repeated in participants with treatment failure at the time of declaration of treatment
failure and rescue therapy was started. Rescue therapy was short-acting insulin which was started 4–6 units
before each meal and the dose was adjusted based on blood glucose measurements to maintain plasma glucose
concentration <7.8 mmol/l (140 mg/dl) 2 h after meals. Rescue therapy in the triple therapy arm was glargine
insulin which was started at 6–10 units/day and the dose was adjusted to maintain FPG <6.1 mmol/l (110 mg/dl).
Figure S3: 7-point home blood glucose measurements in subjects receiving Triple
Therapy and Conventional Therapy. FPG = fasting plasma glucose; 2h-AB = 2 hours
after breakfast; BL = before lunch; 2h-AL = 2 hours after lunch; BS = before supper; 2hAS = 2 hours after supper; BT = bedtime.
Table S2: Adverse events reported by subjects in the Conventional and Triple
Therapy groups during the 24-month follow-up period.
Conventional Therapy
Triple Therapy
Any adverse event
87%
90%
Hypoglycemia
46%
15%
Edema
1.3%
5.3%
GI side effects
21%
33%
Cancer
1
0
Death
2
0
Fractures
0
0
Table S5. Medication dose at months 6, 12, and 24
Triple Therapy
Combination Therapy
6 mo
12 mo
24 mo
2000
2000
2000
Pioglitazone (mg) 38±8
39±9
39±9
17.4±4
18.0±4
Metformin (mg)
Exenatide (mg)
17.6±4
6 mo
12 mo
24 mo
1932±60 1981±41 1981±41
Glipizide (mg)
12.2±7
13.0±7
13.6±7
Glargine (U/day)
23±16
37±19
50±26
Results
Participants receiving triple therapy experienced a
significantly greater reduction in HbA1c level than those
receiving conventional therapy (5.95 vs. 6.50%; p < 0.001).
Despite lower HbA1c values, participants receiving triple
therapy experienced a 7.5-fold lower rate of hypoglycaemia
compared with participants receiving conventional therapy.
Participants receiving triple therapy experienced a mean
weight loss of 1.2 kg versus a mean weight gain of 4.1 kg
(p < 0.01) in those receiving conventional therapy.
the results of the present study should be viewed as a proofof-concept
the cost-effectiveness evaluation of antidiabetic therapy
should not be limited to the medication cost in relation to
the short term reduction in HbA1c level, but should include
other beneficial metabolic effects of each therapy that affect
the risk of long-termdiabetic complications; for example, the
durability of reduction ofHbA1c, risk of hypoglycaemia,
weight loss and reduction of CVD risk factors.
Conclusion
The results of this exploratory study show that
combination therapy with
metformin/pioglitazone/exenatide in patients with
newly diagnosed T2DM is more effective and
results in fewer hypoglycaemic events than
sequential add-on therapy with metformin,
sulfonylurea and then basal insulin.
Message
DeFronzo先生が2009年頃からずっと推奨されて
きたTriple治療の論文！
今はDPP4阻害薬やSGLT2阻害薬が出てGLP-1受容
体作動薬がない方が一般的かもしれない。
単剤を増やすより、最初から併用は今では当た
り前だが。コスト面がどうかはまた議論がある
だろう。

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