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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

    ([email protected]).

    2241

    mailto:[email protected]:[email protected]

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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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     jama .com JAMA December 1,2015 Volume 314, Num ber 21 2247

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       T  a   b   l  e   3 .

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    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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    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 ,    

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