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Research
Original Investigation
Effect o f Metformin Added to Insulin on Glycemic Control
Among Overweight/Obes e Adolescents With Type 1Diabetes
A Randomized Clinical Trial
Ingrid M. Libman, MD, PhD; Kellee M. Miller, PhD; Linda A. DiMeglio, MD, MPH; Kathleen E. Bethin, MD, PhD;
Michelle L. Katz, MD, MPH; Avni Shah, MD; Jill H. Simmons, MD; Michael J. Haller, MD; Sripriya Raman, MD;
William V. Tamborlane, MD; Julie K. Coffey, MSN, ARNP, CPNP; Ashleigh M. Saenz, MPH; Roy W. Beck, MD, PhD;
Kristen J, Nadeau, MD; fo rth eT ID Exchange Clinic Network M etform in RCT Study Group
im p o r t a n c e Previous studies assessing the effec t of m etformin on glycemic contro l in
adolescents with type 1diabetes have produced inconclusive results.
o b j e c t i v e To assess the efficacy and safety o f metform in as an adjunct to insulin in treating
overweigh t adolescents with type 1diabetes.
DESIGN, SETTING, A ND PARTICIPANTS Multicenter (26 pediatric endocrinology clinics),double-blind, placebo-controlled randomized clinical trial involving 140 adolescents aged 12.1
to 19.6 years (mean [SD] 15.3 [1.7] years) with mean type 1diabetes duration 7.0 (3.3) years,
mean body mass index (BMI) 94th (4) percentile, mean total daily insulin 1.1 (0.2) U/kg, and
mean HbAlc 8.8% (0.7%).
g Author Audio Interview at
jama.com
J Supplemental content at
jama.com
CMEQuizat
jamanetw orkcme.com and
CME Questions page 2301
INTERVENTIONS Randomization to receive metformin (n = 71) ( < 2 0 0 0 mg/d) or placebo
(n = 69).
MAIN OUTCOMES AND MEASURES Primary outcome was change in HbAlc from baseline to 26
weeks adjusted fo r baseline HbAlc. Secondary outcomes included change in blinded
continuous glucose monitor indices, tota l daily insulin, BMI, waist circumference, body
composition, blood pressure, and lipids.
RESULTS Between October 2013 and February 2014,140 participants were enrolled. Baseline
HbAlc was 8.8% in each group. At 13-week follow-up, reduction in HbAlc was greater w ith
metform in (-0.2 %) than placebo (0.1%; mean difference, -0.3 % [95% Cl, -0.6 % to 0.0% ];
P = .02). However, this differential effect was not sustained at 26-week follow up when mean
change in HbAlc from baseline was 0.2% in each group (mean difference, 0 % [95% Cl, -0 .3%
to 0.3%]; P = .92). At 26-week follow-up, to tal daily insulin per kg of body weight was
reduced by at least 25% from baseline among 23% (16) o f participants in the metformin
group vs 1% (1) of participants in the placebo group (mean difference, 21% [95% Cl, 11% to
32%]; P = .003), and 24% (17) of participants in the metform in group and 7% (5) of
participants in the placebo group had a reduction in BMI z score of 10% or greater from
baseline to 26 weeks (mean d ifference, 17% [95% Cl, 5% to 29%]; P = .01). Gastrointestinaladverse events were reported by more participants in the metformin group than in the
placebo group (mean difference, 36% [95% Cl, 19% to 51%]; P < .001).
CONCLUSIONS AND RELEVANCE Among overweight adolescents w ith type 1diabetes, the
addition o f metform in to insulin did no t improve glycemic control after 6 months. Of multiple
secondary end points, findings favored metformin only for insulin dose and measures of
adiposity; conversely, use of metform in resulted in an increased risk for gastrointestinal
adverse events. These results do no t support prescribing metformin to overweight
adolescents w ith type 1diabetes to improve glycemic control.
TRIAL REGISTRATION clinicaltrials.org Identifier: NCT01881828
JAMA. 2015;3l4(21):2241-2250. doi:10.1001/jama.2015.16174
Author A ffi liat ions : Author
affiliations are listed at the end of this
article.
Corresponding Author: Kellee M.
Miller, PhD, Jaeb Center for
Health Research, 15310 Amberly Dr,Ste 350, Tampa, FL 33647
2241
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Research Origina l Investiga tion Metform in for Adolescents With Type 1Diabetes
Despite the traditional phenotype of individuals with
type 1 diabetes as having normal weight or being
underweight, observational studies show, similar to
the general population, increasing numbers of overweight
and obese individuals with type 1diabetes.1Recent data from
the T1D (type 1diabetes) Exchange Clinic registry indicated
that in more than 11 00 0 US children and adolescents with
type 1 diabetes, 24% were overweight and an additional
15% were obese.2 For youth with type 1 diabetes, being over-
weight or obese potentially has serious metabolic conse-
quences, especially during adolescence. Among these indi-
viduals, the high doses of insulin required to overcome the
insulin resistance of obesity and puberty contribute to diffi-
culties in glycemic contro l3'7 and may p romote fur ther
weight gain. In addition, among adolescents with type 1 dia-
betes, insulin resistance has been associated with increases
in cardiovascular risk factors.8
Metformin is an oral glucoselowering agent commonly
used in treating type 2 diabetes. It improves glycemia in type
2 diabetes by several mechanisms including loweringhepatic glucose output and increasing peripheral uptake of
glucose, especially in the muscle.9 A metaanalysis10 showed
that metformin treatment was associated with significantly
low insulin doses but had no effect on hemoglobin Alc
(HbAlc) levels in adults with type 1diabetes. However, stud-
ies in adolescents have been small, of short duration, or
used nonstandard doses of metformin and have produced
inconclusive re su lts.1114 We designed a 6m onth , mult i-
center, placebocontrolled, randomized trial to assess the
effect of the addition of metformin, 2000 mg per day, to
basalbolus insulin trea tment in overweight and obese ado-
lescents with type 1diabetes.
Methods
The trial was conducted at 26 clinical sites of the T1D
Exchange Clinic Network. The protocol and Health Insur-
ance Portability and Accountability Act (HIPAA)compliant
informed consent forms were approved by local institutional
review boards. Written informed consent was obtained from
partic ipan ts aged 18 years and older or from a p aren t or
guardian for younger participants who also assented. Study
oversight was provided by an independent data and safetymonitoring committee. The complete study protocol and
statistical analysis plan are available in Supplement 1.
S t u d y P a r t ic i p a n t s
Major inclusion criteria included presumed autoimmune
type 1diabetes (as indicated by age of diagnosis
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M etfo rm in fo r Adolescents W ith Type 1 Diabetes O rig inal Investigation R esearch
of pubic hair for both sexes, adu lt breasts for adolescent
girls, and ad ult genitalia for adolescent boys) at randomiz a-
t ion; du al energ y xray abso rpt iom etry (DXA) scans
were performed to assess body composition. Participants
with detectable Cpeptide (>0.51 ng/mL; to convert to
nmol/L, multiply by 0.331) at screening had a mixedmeal
tolerance test performed at baseline and 26 weeks. Insulin
use was determined by downloading the insulin pump
(for pum p users) at each visit or by reviewing the log of
insulin injections (kept by injection users) for 1 week before
each visit.
All adverse events were reported regardless of whether
the event was considered treatmentrelated and coded using
the Medical Dictionary for Regulatory Activities. Reportable
severe hypoglycemia was defined as an event characterized
by low blood g lucose that req uired assistance of another p er-
son to actively administer carbohydrate, glucagon, or other
resuscitative actions to treat altered co nsciousness. The
occurrence of diabetic ketoacidosis was defined by criteria
from th e Diabetes Control and Complications Trial.16 Serum
lactate was not routinely measu red an d was assessed only if
deemed clinically indicated.
Outcomes
Pr im ar y O u t c o m e
The primary efficacy outcome was the change in HbAlc level
(assessed at th e central laboratory) from baseline to 26 weeks.
Prespecified seconda ry HbAlc outcomes (HbAlc 0.5%, and absolute increase by >0.5%) also
were assessed.
Other Secondary and Exp lo ra to ry Outcomes
Prespecified secondary and exploratory outcomes included
continuous glucose monitor indices; total daily insulin per kg
of body weight; total basal insulin p er kg of body weight; BMI
pe rcen tile s (analysis us ing z score also perfo rmed) adjuste d
for age and s ex15; wa ist circum ferenc e; body com position
measured by DXA; blood pressure percentiles adjusted for
age, sex, an d heig ht (calculated using CDC reference tables);
serum lipid levels; adipocytokines; inflammatory markers;
and Cpeptide levels. Posthoc binary variables were analyzed
for total daily insulin, BMI, and weight change.
Safe ty Outcomes
All reported adverse eve nts were tabulated. The primary
safety outcomes included gastrointestinal events, occur-
rences of lactic acidosis, severe hypoglycemia, and diabetic
ketoacidosis . Changes in serum creat inine and l iver
enzymes also were assessed.
Statistical Analysis
A samp le size of 136 participa nts was plan ned to have 90%
power to det ect a di ffer en ce in ch an ge in HbAjc betwee n
treatment groups and assuming a population difference of
0.5%, standa rd deviation o f 26week values o f 1.0%, corre-
lation between baseline and 26week values of 0.56, type I
error rate of 5% (2sided), and no more than a 15% loss
to followup.
Analyses followed the intenttotreat principle. Partici-
pants who dis continued use of th e stud y drug rema ined in the
study to c omplete followup and w ere analyzed according to
the randomized treatm ent assignment.
Treatment group comparisons for continuous outcomes
were cond ucted using a linear mixed model adjusted for base-
line level of the outcom e variable and rand om ce nter effects.
Treatm ent group differences in binary outcom es were evalu-
ated in logistic regression mo dels adju sted for baseline level
of the ou tcome variable.
The proportions of participants experiencing any ad -
verse event, any related adverse event, any gastrointestinal
event, any even t other than a gastrointestinal event, at least 1
severe hypoglycemic event, and at least 1diabetic ketoac ido-
sis event in each treatment group were compared using the
Fisher exact test. The number of adverse events, new ad-
verse events, serious adverse events, and nonserious adverse
events were com pared betw een groups u sing a Wilcoxon rank
sum test.
Analyses were conducted using SAS version 9.4 (SAS
Institute). A 95% Cl was reported with each mean value. All
P values were 2sided. The primary analysis test of signifi-
cance was condu cted w ith a thresho ld of .05. P values for
secondary analyses were unadjusted for multiple com pari-
sons and should be considered exploratory. The Rubin
method was used to impute missing HbAic data for the pri-
mary analysis.17 Analyses of secondary outcom es w ere p er-
formed for the available measu remen ts (without imputation
for missing data). Analyses were performed on all efficacy
outcome s obtained at 13 weeks by metho ds similar to those
used at 26 weeks. Sensitivity analyses adjusting for potential
confounders and including only eligible participants who
were taking at least 1500 mg of the stu dy d rug at the 26week
visit (perprotocol analysis) were performed.
Results
Between October 2013 and February 2014,140 participants
were ran do miz ed to the m etform in (n = 71) or placebo
(n = 69) group (Figure). The m ean (SD) age of particip ants
was 15.3 (1.7) years (range, 12.1 to 19.6 years); 92 par ticipants
(66%) were female and 103 (74%) were white. Mean HbAlc
was 8.8% (0.7%), mean BMI z score was 1.6 (0.3), and mean
total daily insu lin was 1.1 (0.2) U/kg per day. Table 1 lists ba se-
line characteristics according to tre atme nt group.
Visit Completion
The 26week primary outcom e visit was com pleted by 70 of
71 (99%) participan ts in the metform in group and by all 69
(100%) participants in the placebo group (Figure and eFigure
1in Supplement 2). Telephone call and o ther visit completion
rates were similar between treatment groups (eFigure 1in
Suppleme nt 2).
TreatmentFive participants (7%) in the metformin group and 4 (6%)
in the placebo group discontinued treatme nt prior to the
jama.co m JAM A December 1,2015 Volum e 314, Num ber 21 224 3
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Research O riginal Inves tigation Metform in for Adolescents With Type 1Diabetes
F igure . F low o f S tudy P ar t ic ipan t s : Me t f o rm in f o r Ado lescen t s W i t h Type 1D iabe tes
163 Patients enrolled then screened
23 Excluded
7 Total daily insulin was 10% at screening
3 HbAlc was
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Metformin for Adolescents With Type 1Diabetes Original Investigation Research
Table 1. Baseline Ch aracteristics
Metformin(n = 71)
Placebo(n = 69)
Female sex, No. (%) 44 (62) 48 (70)
Age, mean (SD), y 1 5.4 (1 .7 ) 15.1 (1 .8 )
12-15 y, No. (%) 43 (61) 47 (68)
16-19 y, No. (%)
Race/ethnicity, No. (%)
28 (39) 22 (32)
White 51 (72) 52 (75)
Black 4 (6 ) 5 (7 )
Hispanic or Latino 13 (18) 11 (16)
Asian 2 (3 ) 0
Biracial or mu ltiracial 1 (95th percentile, No. (%) 33 (46) 41 (59)
Tanner staging, No. (%)c
Pubic hair
Stage 1 1 (
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Research Origin al Inves tigation Metform in for Adolescents With Type 1Diabetes
Table 2. Hemoglobin Alc Outcomes
Metformin Placebo Mean Difference
(n = 71) (n = 69) (95% Cl) P Value3
Baseline
HbAlc, mean%
(95% Cl)
8.8 (8.6 to 9.0) 8.8 (8.6 to 9.0)
13 Weeksb
HbAlc, mean %(95% Cl)
8.7 (8.4 to 8.9) 8.9 (8.6 to 9.1)
Change from
baseline to 13
weeks, mean %
(95% Cl)
-0 . 2 ( -0 . 4 t o 0 .0) 0.1 ( -0.1 to 0.3) -0 .3 ( -0 . 6 t o 0 .0) .02
HbAlc, No. (%)
[95% Cl]
Decrease >0.5% 2 0 (2 9) [1 8 to 4 1] 20 (29) [18 to 41] 0 ( -1 7 to 17) .94
Increase >0.5% 12 ( 18 ) [8 to 27 ] 19 (28) [17 to 39] -1 0 ( -2 7 to 7) .13
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M e t f o r m i n ,
M e a n ( 9 5 % C
l )
P l a c e b o , M e a n ( 9 5 % C
l )____________________________________
M e t f o r m i n v s P l a c e b o ,
M e a n A d j u s t e d
D i f f e r e n c e ( 9 5 % C
l )
B a s e l i n e
1 3 W e
e k s
2 6 W e e k s
B a s e l i n e
1 3 W e e k s
2 6 W e e k s
B a s e l i n e
B a s
e l i n e
( n = 7 1 )
( n = 6
8 )
( n = 7 0 )
( n = 6 9 )
( n = 6 8 )
( n = 6 9 )
________
t o 1 3 W e e k s_________
P V a l u e
t o 2 6 W e e k s_________
P V a l u e
jama .com JAMA December 1,2015 Volume 314, Num ber 21 2247
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T a b l e 3 .
S e c o n d a r y O u t c o m e s ( c o n t i n u e d )
2248
Research Original Investigation Metformin for Adolescents With Type 1Diabetes
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JAMA December 1,2015 Volume 314, Number 21 jama.com
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Me tformin for Adolescents With Type 1Diabetes Original Invest igat ion Research
T ab le 4 . Sa f e t y Ou t c ome s
Metformin Placebo
(n = 71) (n = 69) P Value3
No. of adverse eventsb 184 78
No. per pa rticip an t15
Mean (SD) 3 (2 ) 2 (2 )
Median (IQR) 3 (2 -5 ) 2 (1 -3 )
No. o f serious adverse events' 3 3
No. per participant0
Mean (SD) 0 (0 ) 0 ( 0 )
Median (IQR) 0 (0 -0 ) 0 (0 -0 )
No. of nonserious adverse events 181 75
No. per participant
Mean (SD) 3 (2 ) 2 ( 2 )
Median (range) 3 (1-8) 2 (1-3)
Participants w ith adverse events,
No. (%) [95% Cl]
>1 Adverse event 57 (8 0 ) [7 1 -9 0 ] 39 (5 7 ) [4 5 -6 9 ] .003
>1 Related adverse eventd 45 (65 ) [5 3 -7 6 ] 1 G astro intestinal adverse event 50 (70 ) [6 0 -8 1 ] 24 (3 5 ) [2 3 -4 6 ] 1 Adverse event other than
gastrointestinal events
7 ( 1 0 ) [ 3 - 1 7 ] 15 (2 2 ) [1 2 -3 2 ] .06
>1 D iabetic ketoacidosis event 3 (4) [< 1-9] 2 (3) [< 1-7] >.99
>1 Severe hypoglycem ic event 5 (7 ) [1 -1 3 ] 0 .06
Biochemical hypoglycemia
at 6 months"
Percentage of time
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Research Origina l Investiga tion Metformin for Adolescents With Type 1Diabetes
Because changes in the insulin regimen in this study were
left to the discretion of treating clinicians, it is difficult to
determine to what extent the greater reductions in total
dai ly insul in doses in m etformin-t reated part icipants
affected our ability to show treatment-group differences in
changes in HbAlc levels. This difficulty is compounded by
the fact that the re are so many other factors that affect the
changes in HbAlc leve ls-esp ecially in ad olescents. A nother
limitation is that adherence was measured by pill counts,
which may or may n ot have been accurate.
Conclusions
Among overweight adolescents with type 1 diabetes, the ad di
tion o f metformin to insulin did n ot improve glycemic control
after 6 months. Of multiple secondary end points, findings
favored metformin only for insulin dose and m easures of adi
posity; conversely, metformin re sulted in an increased risk forgastrointestinal adverse events. These results do not support pre
scribing metform in to adolescents to improve glycemic control.
ARTICLE INFORMATION
Group Information : T1D Exchange Clinic Network
Metfo rmin RCT Study Group members are listed in
Supplement 2.
Aut ho r Af fi li ati on s: Children's Hospital o f
Pittsburgh of UPMC, P ittsburgh, Pennsylvania
(Libman); Jaeb Center for Health Research, Tampa,
Florida (Miller, Saenz, Beck): Indiana University
School of Medicine, Indianapolis (DiMeglio);
Univers ity at Buffalo School of Medicine and
Biomedical Sciences, Buffalo, New York (Bethin);
Joslin Diabetes Center, Boston, Massachusetts
(Katz); Stanford Univ ersity School of Medicine,
Stanford, California (Shah); Vanderbilt University,
Nashville, Tennessee (Simmons); University of
Florida, Gainesville (Haller); Children's Mercy
Hospita l, Kansas City, Missouri (Raman); Yale
University, New Haven, Connecticut (Tamborlane);
University of Iowa, Iowa City (Coffey); University of
Colorado, Anschutz Medical Campus, Aurora
(Nadeau).
Aut ho r Con tr ib ut ions : Dr Beck had full access to all
o f the data in the study and takes responsibi lity for
the integrity of the data and the accuracy of the
data analysis.Study concept and design: Libman, Miller, Haller,
Raman. Tamborlane, Saenz, Beck, Nadeau.
Acquis ition, analysis, or int erpreta tion o f data:
Libman, Miller, DiMeglio, Bethin, Katz, Shah,
Simmons, Haller, Raman, Tamborlane, Coffey,
Nadeau.
Drafting o f the manuscript: Libman, Miller.
DiMeglio, Shah, Saenz, Nadeau.
Critical revision o f the manuscript for important
intellectual content: Libman. Miller, DiMeglio,
Bethin, Katz, Simmons, Haller, Raman, Tamborlane,
Coffey, Beck. Nadeau.
Statistical analysis: Libman, Miller, DiMeglio.
Obtained funding: Miller. Saenz, Nadeau.
Adm inistra tive, technical, o r material support: Miller,
Bethin. Shah, Haller, Tamborlane, Coffey,
Saenz, Beck.
Study supervision: Miller, DiMeglio, Bethin, Shah,
Haller, Tamborlane, Saenz, Nadeau.
Conflict o f Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential C onflicts of Interest.
Dr Libman reports receipt o f a grant from JDRF and
of grants to the institution from NovoNordisk. Dr
DiMeglio reports receipt o f grants to the institution
from Novo Nordiskand Medtronic. Dr Simmons
reports receipt of a grant from the Helmsley
Foundation. Dr Raman reports recei pt of
remuneration for participation on the protocol
steering committee from JAEB Center for Health
Research, and a gran t from the Jucenile Diabetes
Research Foundation. Dr Tamborlane reports
receipt of consultancy fees from Novo Nordisk.
Dr Beck reports receipt of a grant to the institution
from JRDF. No oth er disclosures were reported.
Funding/Support: Funding was provided by the
Juvenile Diabetes Research Foundation. Part o f
Dr Katz's time was supported by the National
Institu te o f Diabetes and Digestive and Kidney
Diseases (K12DK094721).
Role of th e Funder/Sponsor: The funders had norole in the design and conduct o f the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval o f the m anuscript; and decision to submit
the m anuscript for publication.
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C o p y r i g h t o f J A M A : J o u r n a l o f t h e A m e r i c a n M e d i c a l A s s o c i a t i o n i s t h e p r o p e r t y o f
A m e r i c a n M e d i c a l A s s o c i a t i o n a n d i t s c o n t e n t m a y n o t b e c o p i e d o r e m a i l e d t o m u l t i p l e s i t e s
o r p o s t e d t o a l i s t s e r v w i t h o u t t h e c o p y r i g h t h o l d e r ' s e x p r e s s w r i t t e n p e r m i s s i o n . H o w e v e r ,
u s e r s m a y p r i n t , d o w n l o a d , o r e m a i l a r t i c l e s f o r i n d i v i d u a l u s e .