Clinical trial NCT01234649
Conditions: Gestational Diabetes Mellitus Type 2 Diabetes Mellitus Metabolic Syndrome Impaired Glucose Tolerance Disorder of Glucose Regulation
Keywords: gestational diabetes mellitus type 2 diabetes mellitus metabolic dysfunction impaired fasting glucose impaired glucose tolerance incretin mimetic
Sponsor: Woman's
Start date: 2011-08-11; Completion date: 2019-06-14
Enrollment: 153 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A diagnosis of gestational diabetes mellitus (GDM)has significant implications for the future health of the mother. GDM is often the culmination of years of unrecognized and unmodified diabetes risk factors that lead to overt and occult clinical manifestations during pregnancy. Systematic reviews of older studies conclude that 35-60% women with gestational diabetes will develop type 2 diabetes (DM2) at rates much greater than control groups who did not have glucose intolerance during pregnancy. Liraglutide may potentially delay disease progression in GDM considering the beta -(ß-)cell function improvement in DM2 and ß-cell mass shown to increase in animal models. This study will examine if the addition of liraglutide to metformin therapy is more effective than metformin alone in improving insulin sensitivity and normalizing insulin secretion in at-risk overweight/obese women with prior GDM.

Detailed description:
Gestational diabetes is often the culmination of years of unrecognized and unmodified diabetes risk factors that lead to overt and occult clinical manifestations during pregnancy. . Despite the high and increasing rate of type 2 diabetes in Louisiana, the medical community does not have reliable estimates of the number of woman living in southern Louisiana who develop diabetes subsequent to GDM. Systematic reviews of older studies conclude that 35-60% women with gestational diabetes will develop type 2 diabetes at rates much greater than control groups who did not have glucose intolerance during pregnancy. The higher rates were in studies of particular ethnic groups in the U.S. Recently, follow-up programs elsewhere also have identified increasing rates of type 2 diabetes by 5-10 years after GDM: 9-43% type 2 diabetes in Europe and 11-21% in Asia. The frequency of type 2 diabetes is influenced by BMI, weight gain after pregnancy, family history of diabetes, fasting and postchallenge glucose levels during and after pregnancy, postpartum insulin resistance and inadequate β-cell secretion, and the need for pharmacological treatment during pregnancy. However, the risk factors are unable to predict all cases of subsequent type 2 diabetes: the biggest risk factor is a GDM pregnancy. Presently, in the literature, there are described new, more efficient methods of diabetes prevention in groups with a high risk of this disorder, which involve both, lifestyle modification and pharmacological therapies. Lifestyle intervention was found to reduce the incidence of type 2 diabetes by 58% and metformin by 31% as compared with placebo. The use of rosiglitazone in subjects with prediabetes resulted in a 60% reduction of the diabetes incidence rate. Studies are needed for optimal postpartum and long-term health of women who have had GDM. Considerable recent evidence suggests that incretin-based therapies may be useful for the treatment of DM2 because continuous administration of glucagon-like peptide 1 (GLP-1) produces substantial improvements in glucose control and ß-cell function in subjects with type 2 diabetes. Infusion of GLP-1 improves first and second-phase insulin secretion suggesting that early GLP-1 therapy may preserve ß-cell function in subjects with IGT or mild DM2. Whereas native GLP-1 has a very short half-life, the GLP-1 analogue liraglutide has a prolonged action (t1/2=13 h) suitable for once-daily injection. Liraglutide may potentially delay disease progression in GDM considering the ß-cell function improvement in DM2 and ß-cell mass shown to increase in animal models. This study will examine if the addition of liraglutide to metformin therapy is more effective than metformin alone in improving metabolic parameters in at-risk overweight/obese women with prior GDM

Arms: arm 1: Metformin XR plus Liraglutide Metformin extended release (XR) 500 mg qd 2 weeks 500 mg bid 2 weeks 500 mg am, 1000 mg pm- 2 weeks 1000 mg bid- 84 weeks (end study) Liraglutide - start .6 mg SC QD step up to 1.2 mg to a max dose of 1.8 mg SC QD as tolerated arm 2: Metformin plus Placebo Metformin 500 mg qd 2 weeks 500 mg bid 2 weeks 500 mg am, 1000 mg pm- 2 weeks 1000 mg bid -84 weeks (end study) Placebo-start 1 injection SC QD step up to a max dose as tolerated
Interventions: intervention 1: Metformin XR plus placebo intervention 2: Metformin XR plus liraglutide
Intervention descriptions: intervention 1: Metformin plus Placebo Metformin 500 mg qd 2 weeks 500 mg bid 2 weeks 500 mg am, 1000 mg pm- 2 weeks 1000 mg bid -98 weeks (end study) Placebo-start 1 injection SC QD step up to a max dose as tolerated intervention 2: Metformin XR-500 qd for 2 weeks, 500 mg bid 2 weeks; 500 mg am, 1000 mg pm- 2 weeks - 1000 bid final dose Liraglutide- start 0.6 mg SC QD step up to 1.2 mg to a max dose of 1.8 mg SC QD as tolerated during the 4-wk non-forced dose-escalation period ( maximum allowed dose of 1.8 mg SC QD)

Protocol documents:
Prot_SAP_000.pdf: 
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Project Title: 
Effects of intervention with the GLP-1 analog liraglutide 
plus metformin versus metformin monotherapy in 
overweight/obese women with metabolic defects and 
recent history of gestational diabetes mellitus (GDM) 
 
 
Principal Investigators: Karen Elkind-Hirsch, M.Sc., PhD 
Renee Harris, M.D. 
 
. 
 
Address 
 
 
Woman’s Metabolic Health Center 
 
 
 
 
Woman's Health Research Department 
 
 
 
 
500 Rue de la Vie, Suite 513 
 
 
 
 
Baton Rouge, LA  70817 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Trials registration number- NCT01234649 


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Effects of intervention with the GLP-1 analog liraglutide plus metformin versus metformin 
monotherapy in overweight/obese women with metabolic defects and recent history of 
gestational diabetes mellitus (GDM) 
 
Project Overview/Summary 
 
The objective of the present proposal is to compare the clinical, endocrine and metabolic 
effects of therapy with combination liraglutide and metformin to metformin monotherapy in 
overweight women with a recent history of GDM.  This study will serve as a pilot investigation 
to open perspectives for future investigations combining insulin-sensitizing drugs with different 
mechanisms of action in former GDM women especially overweight women for whom standard 
treatment with metformin is less effective 
 
Primary Objective:  
 To determine if the addition of liraglutide to metformin therapy is more effective than 
monotherapy with metformin in improving pancreatic beta cell compensation (ß-cell 
glucose sensitivity and rate sensitivity) in overweight/obese women with prior GDM who 
are at high risk of developing Type 2 diabetes (DM2). 
Secondary Objective(s) 
 To determine if the addition of liraglutide to metformin therapy is more effective than 
monotherapy with metformin in improving insulin sensitivity in overweight/obese 
women with prior GDM who are at high risk of developing Type 2 diabetes (DM2). 
 To determine the impact of liraglutide in combination with metformin compared to 
metformin monotherapy on anthropometric measures in overweight/obese women with 
prior GDM who are at risk of developing DM2. 
 To determine if the addition of liraglutide to metformin therapy is more effective than 
metformin alone in improving cardiometabolic markers (lipid profile and blood pressure) 
in overweight/obese women with prior GDM who are at risk of developing DM2. 
Study Background and Rationale 
Gestational diabetes mellitus (GDM) is defined as “any degree of glucose intolerance 
with onset or first recognition during pregnancy.”1  This simple definition belies the complexity 
of a condition that spans a spectrum of glycemia, pathophysiology, and clinical effects and for 


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which there is a wide diversity of opinion regarding detection and clinical management.  GDM is 
one of the most frequent metabolic disorders occurring during pregnancy that complicates both, 
the course of pregnancy and the delivery and also has significant implications for the future 
health of the mother.  Approximately 7% of all pregnancies in the United States are complicated 
by gestational diabetes resulting in more than 200,000 cases annually,2 but the prevalence ranges 
from 1% to 14% of all pregnancies.3 depending on the population studied and the diagnostic tests 
employed.  Although the precise definition of gestational diabetes, its clinical significance and its 
treatment protocols remain controversial, it is clear that GDM increases the risk of pregnancy 
complications and strongly predicts the subsequent development of diabetes in the mother and 
her offspring.4-6 
Insulin resistance and beta cell dysfunction are the main pathophysiological factors of 
GDM just as they are for diabetes outside of pregnancy.7-8  Insulin resistance is a significant 
factor for many women who eventually develop GDM.  It is possible that recurrent episodes of 
heightened insulin resistance, such as with recurrent GDM, place high demands on the pancreas 
and contribute to an eventual decline in beta cell function that leads to type 2 diabetes (DM2) in 
high-risk individuals.  Peters and coworkers9 studied 666 Latino women with a history of GDM. 
Among the 87 (13%) who completed an additional pregnancy, the rate ratio of DM2 increased 
significantly in comparison to women without an additional pregnancy.  There may be a finite 
level of pancreatic “beta cell reserve” that is further depleted with recurring GDM.  Although the 
longevity of beta cell function may be genetically determined, some individuals may respond to 
repeated demands on pancreatic insulin secretion (as seen in normal pregnancy, obesity, and 
polycystic ovarian disease) in a way that eventually exhausts beta cell reserve leading to the 
development of frank diabetes mellitus.  After an index pregnancy with GDM, gestational 
diabetes recurs in 30-84% of subsequent pregnancies.10,11  Interestingly, for the nonpregnant 
population, decreasing insulin resistance through diet and exercise or medications such as 
metformin or rosiglitazone has been shown to reduce the risk of subsequent type 2 diabetes or 
delay its onset.12-14  Gestational diabetes is also a strong risk factor for the development of 
diabetes mellitus at a later stage of life in previous GDM woman.  Among all the risk factors of 
DM2, the experience of GDM is the strongest one.  The incidence of various forms of diabetes in 
this group balances from 10 to 60% over a period from 2 to 10 years.  Russell et al15 found that 
36% of GDM women had some degree of persistent abnormal glucose tolerance when tested at 


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any time postpartum. Recently, Nelson et al16 found that 8.9% of patients tested immediately 
postpartum had diabetes, and another 31.3% had other glucose metabolism abnormalities; only 
55.8% had normal 2-hour glucose tolerance tests.  Thus, women with previous GDM constitute 
an ideal group for primary diabetes prevention.  
Gestational diabetes is a common medical problem that results from an increased 
severity of insulin resistance as well as an impairment of the compensatory increase in insulin 
secretion. A diagnosis of GDM has significant implications for the future health of the mother. 
Approximately 40% to 60% of women with a diagnosis GDM will exhibit further deterioration 
of carbohydrate metabolism.  GDM is often the culmination of years of unrecognized and 
unmodified diabetes risk factors that lead to overt and occult clinical manifestations during 
pregnancy. Pregnancy, in essence, serves as a metabolic stress test and uncovers underlying 
insulin resistance and ß-cell dysfunction.  Postpartum management of women with GDM is 
critical because of their markedly increased risk of DM2 in the future.  Women with prior GDM 
have substantial rates of impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and 
DM2 after pregnancy.  Women with a history of GDM are also at increased risk of other 
cardiovascular risk factors, such as obesity, hypertension, dyslipidemia, and the metabolic 
syndrome as well as subclinical atherosclerosis.  Taken together, these findings suggest that 
GDM identifies a population of young women at increased risk for cardiovascular disease 
(CVD).  Presently, in the literature, there are described new, more efficient methods of diabetes 
prevention in groups with a high risk of this disorder, which involve both, lifestyle modification 
and pharmacological therapies.  In the 2.8 years of Diabetes Prevention Program (DPP) 
randomized clinical trial, diabetes incidence in a nonpregnant population with impaired glucose 
tolerance was reduced by 58% with intensive lifestyle intervention and 31% with metformin 
compared with placebo.17 .  Treatment of insulin resistance with the thiazolidinedione drug, 
troglitazone, improved insulin sensitivity and reduced the incidence of type 2 diabetes for nearly 
5 years in Hispanic women with prior gestational diabetes17. During a median follow-up of 30 
months on blinded medication, average annual diabetes incidence rates in the 236 women who 
returned for at least one follow-up visit were 12.1 and 5.4% in women assigned to placebo and 
troglitazone, respectively.  Clinical studies using rosiglitazone or pioglitazone for a period of 3 
years have demonstrated a beneficial effect of both agents in improving insulin sensitivity and 
recovery or improvement of ß-cell function, which are sustained in some individuals over 


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time.19,20  Treatment of Hispanic women with a history of GDM with pioglitazone improved -
cell compensation for insulin resistance; 3 years of pioglitazone treatment given to Hispanic 
women with prior gestational diabetes was associated with stable pancreatic ß-cell function and a 
relatively low rate of diabetes (4.6% per year vs. 13.1% on placebo).19  The use of rosiglitazone 
for 3 years in subjects with prediabetes resulted in a 60% reduction of the diabetes incidence 
rate.20   
Incretin mimetics are a new class of pharmacological agents with multiple 
antihyperglycemic actions that mimic some effects of endogenous incretin hormones, including 
glucose-dependent enhancement of insulin secretion.  Glucose lowering induced by glucagon-
like peptide-1 (GLP-1) seems to be mediated by a potent insulin-releasing action as well as a 
range of other effects, including inhibition of glucagon secretion and gastric emptying, increased 
satiety, stimulation of glucose-uptake, and gluconeogenesis.  GLP-1 also seems to exert trophic 
effects on the cells, stimulating growth and differentiation and inhibiting cytokine- and free 
fatty acid- cytokine- and free fatty acid beta-cell-induced apoptosis.21  Given the pivotal role of 
β-cell dysfunction in the progressive nature of GDM to DM2, the fact that certain GLP-1 analogs 
promote β-cell replication/neogenesis/mass in animal models is promising from the standpoint of 
modifying the pathophysiology of this condition.  Liraglutide is a long-acting GLP-1 derivative, 
designed for once daily administration.22-25  Liraglutide has 97% homology with GLP-1 and 
resists DPP-IV degradation by FA acylation and albumin binding.26  Single-dose kinetic studies 
in DM2 subjects revealed a half-life of 10.0 ± 3.5 h, allowing for single daily-dose 
administration27, whereas native GLP-1 with a very short half-life of 1.5 ± 0.35 min has limited 
clinical value.28  The mechanisms of liraglutide action appear to be analogous to those exerted by 
endogenous incretins, thus liraglutide, can control diabetes by multiple actions through 
increasing insulin and lowering glucagon, yet it has a rapid and sustained glycemic effect and is 
associated with weight reduction.29, 30  All actions are predictably strictly glucose-dependent, 
with low hypoglycemia risk and counterregulatory response to hypoglycemia not being impaired. 
Liraglutide has been shown to enhance several ß-cell function parameters, and the enhancement 
was correlated with the improvement in glycemic control.31  Liraglutide may potentially delay 
disease progression in GDM considering the ß-cell function improvement in DM2 and ß-cell 
mass shown to increase in animal models.32, 33  
 


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Rationale 
 
Women with previous GDM comprise a target group for future intervention trials with 
the aim to prevent or delay development of DM2.  While a large number of studies have 
demonstrated reductions between 25 and 67% in the incidence of diabetes over 2.5 to 6-year 
intervention periods in subjects with prediabetes (IFG, IGT or both), most participants remain in 
a pre-diabetic state.  Less often presented were the number of participants who did not progress 
to diabetes but in fact had a reduction in insulin resistance and normalization of pancreatic beta 
cell function.  Postpartum follow up of women with a history of GDM is inadequate. The risk 
level for women with GDM suggests that these women may benefit from both preventive 
interventions and regular screening.   
 
We evaluated 110 women having GDM in their index pregnancies between 6-12 weeks 
after delivery.  A 75-g oral glucose tolerance test (OGTT) was performed with insulin and 
glucose measured.  From the oral glucose tolerance (OGTT) data, it is possible to derive reliable 
indexes of insulin sensitivity and pancreatic beta-cell (ß-cell) function. 35-45  We quantified 
insulin sensitivity using the OGTT insulin sensitivity index of Matsuda and DeFronzo (SIOGTT) 
because of its simplicity and good correlation with measurements generated by the clamp 
technique (the gold standard).37  Fasting insulin resistance index was calculated using the 
Homeostasis Model Assessment of Insulin Resistance (HOMA-IR).36.  ß-cell secretory capacity 
was determined by dividing the insulinogenic index (IGI= Ins30-0/Glu30-0) by HOMA-IR 
(IGI/HOMA-IR) and by calculating the insulin secretion-sensitivity index (IS-SI).40-45  The IS-SI 
expresses the overall ability of the beta cell to increase its release rate relative to insulin 
resistance in response to a glucose stimulus and reveals the progressive ß-cell dysfunction 
originally demonstrated using the disposition index.  Our research was designed to evaluate the 
insulin secretory responses to oral glucose in women with former gestational diabetes (fGDM), 
and to determine if the insulin secretory response present in these subjects is appropriate for the 
degree of insulin resistance. 
 
Insulin sensitivity and ß-cell secretory capacity derived from fasting values (HOMA-IR) 
and glucose-stimulated measures (SIOGTT and IGI/HOMA) were calculated for all 110 former 
gestational diabetic (fGDM) women.  Our findings demonstrated that measurement of insulin 
status using the 2 h-OGTT can actually identify distinct groups of fGDM women with 
differences in insulin sensitivity, β-cell function, and glycemia in the early postpartum period.  


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When only OGTT glucose results were used, 24 (22%) fGDM women showed some form of 
glucose abnormality (IFG, IGT or IFG/IGT).  Insulin resistance determined by the HOMA-IR 
model was observed in 46 (42%) fGDM of the assessed women within 3 months of delivery 
while the SIOGTT and IGI/HOMA identified 98 (89%) fGDM women with a postpartum 
metabolic abnormality.  Based on OGTT-derived indices of insulin secretion, it was quite clear 
that ß-cell function progressively deteriorates with worsening of glucose tolerance.  Poor ß-cell 
compensation for insulin resistance was evident in all fGDM women with abnormal glucose 
tolerance (DM2, IFG and/or IGT).  Furthermore, we observed that 68 (62%) fGDM women had 
one or more lipid level abnormalities (LDL, TRG or TRG/HDL ratio.).  These abnormal lipid 
profiles were more prevalent in white fGDM women (65%) compared with non-white fGDM 
women (50%).  However, non-white fGDM had significantly higher blood pressure than white 
fGDM women.  The purpose of this study trial is to compare the efficacy of pharmacological 
treatment with liraglutide in combination with metformin to metformin monotherapy in a 
population of overweight women with a history of GDM who are at high risk for the 
development of diabetes.  This study will examine if the addition of liraglutide to metformin 
therapy is more effective than metformin alone in improving metabolic parameters in 
overweight/obese women with prior GDM who are at risk of developing DM2.  No studies to 
date have examined the use of GLP-1 receptor analogues in the treatment of women with 
previous GDM.  We predict that the administration of liraglutide in combination with metformin 
will be more effective in improving ß-cell compensatory function than metformin alone.  Given 
the ability of the combination therapy to prevent or delay a decline in glucose tolerance, we also 
will determine whether combination liraglutide-metformin treatment alters the development or 
progression of cardiometabolic risk more effectively than monotherapy with metformin. 
Study Design  
Subjects will be recruited using flyers distributed in the obstetric clinics and pathology 
laboratory associated with Woman’s Hospital.  Overweight females who are 18 years of age, 
had GDM in the previous 12 months (diagnosis of GDM using Carpenter-Coustan criteria 
according to Fifth International Workshop—Conference on Gestational Diabetes Mellitus2) and 
meet all inclusion/exclusion criteria will be offered participation in the study.   
 
 


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Major Inclusion Criteria 
 Adult female 18 years to 45 years of age who experienced GDM within 52 weeks of 
index pregnancy  
 Actual BMI >25 kg/ m2  
 Written consent for participation in the study  
 Patient completed lactation 
 Dysglycemia (impaired fasting glucose [IFG}, impaired glucose tolerance [IGT} or 
IFG/IGT) and/or ß-cell dysfunction postpartum requiring pharmacological intervention 
(except type 1 or 2 diabetes) 
Major Exclusion Criteria 
 Personal or family history of medullary thyroid carcinoma or in patients with Multiple 
Endocrine Neoplasia syndrome type 2      
 History of pancreatitis  
 Significant cardiovascular, cerebrovascular, renal, or hepatobiliary diseases in the past 
(viral hepatitis, toxic hepatic damage, jaundice of unknown etiology)  
 Serum AST and/or ALT level exceeding more than twice normal laboratory values        
 Uncontrolled clinically significant hypertension  Fasting serum triglycerides ≥800 mg/dl 
at screening.   
 Lipid-lowering medications must have been maintained at the same dose for 3 months 
prior to enrollment 
 Cholestasis during the past pregnancy  
 Presence of contradictions for GLP-1 receptor agonist or metformin administration such 
as allergy or hypersensitivity 
 Current use of metformin, thiazolidinediones, dipeptidyl peptidase-4 inhibitors or GLP-1 
receptor agonist medications.  
 Use of drugs known to exacerbate glucose tolerance.   
 Use of prescription or over-the-counter weight-loss drugs 
 Diabetes postpartum or history of diabetes or prior use of medications to treat diabetes 
except gestational diabetes  


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 Renal impairment (e.g., serum creatinine levels ≥1.4 mg/dL for women and eGFR less 
than 60 mL/minute/1.73 m2  
 History or currently undergoing chemotherapy or radiotherapy for cancer 
 Pregnancy planned during the coming two years 
 Currently breastfeeding 
 Exclusion criteria include any condition, which in the opinion of the investigator would 
place the subject at increased risk or otherwise make the subject unsuitable for 
participation in the study 
 
All subjects will verbally provide a medical and gynecological history, and if they are 
eligible and sign a medical release form, their prenatal records will be obtained to confirm their 
pregnancy history and postpartum status.  If eligible, participants will give written informed 
consent for participation in the Woman’s Hospital Foundation Institutional Review Board-
approved study.   An oral glucose tolerance test (OGTT) with glucose (G) and insulin (I) 
measured at 0, 30, 60, and 120 after glucose load to assess diabetes, insulin resistance and 
pancreatic ß-cell function will be performed between 6-52  weeks postpartum.  Glucose tolerance 
will be defined as normal, impaired glucose tolerance (IGT) or diabetic according to the criteria 
of the American Diabetes Association. 34  A measure of insulin sensitivity will be estimated 
using a single fasting G-I level by the homeostasis model assessment index (HOMA-IR).  From 
the OGTT, we will use the derived composite whole-body insulin sensitivity index (ISIOGTT).  
Beta cell function will be resolved by mathematical modeling from the OGTT.  The 
insulinogenic index (IGI; 
I/
Glu30–0) divided by HOMA and corrected insulin response at 
glucose peak (CIRGluPea); indexes of ß-cell activity, will be computed from insulin and glucose 
levels measured during the OGTT.   An insulin secretion-sensitivity index (IS-SI) will be derived 
by applying the concept of the disposition index (which expresses the relationship between 
insulin sensitivity and insulin secretion) to measurements obtained during the 2-h OGTT .This 
index expresses the overall ability of the beta cell to increase its release rate relative to insulin 
resistance in response to a glucose stimulus. This approach of interpreting B-cell function is 
critical because the amount of insulin secreted by the ß-cell is very dependent on the prevailing 
degree of level of peripheral insulin sensitivity and reveals the progressive loss of ß-cell function 
in individuals with impaired glucose tolerance. 35-45  Only those women with previous GDM who 


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demonstrate dysglycemia (IFG ,IGT or IFG/IGT) and/or ß-cell dysfunction that necessitates 
medication added to diet and exercise intervention will be recruited for the study and thus will 
not be inclusive of women with diabetes postpartum.  The baseline blood samples from the 
OGTT will also be analyzed for a lipid profile which includes total cholesterol, triglycerides, 
HDL and LDL cholesterol, TSH, liver enzymes, creatinine with eGFR, and quantitative ßhCG 
levels.  A negative serum pregnancy test is a prerequisite for commencing treatment.   
All consented patients will come into the outpatient tower for a clinic visit.  A full 
physical examination will be performed including measurement of body mass index (BMI), 
waist: hip (W: H) ratio and blood pressure (BP).  The total body adiposity (total fatness), defined 
as the accumulation of body fat without regard to regional distribution, will be expressed as BMI 
and calculated as weight (kg)/ height (m) 2, whereas the W:H ratio is a measure of body fat 
distribution.  Height will be measured to the nearest centimeter and weight measured by a sliding 
weight balance to the nearest 0.1 kg.  Waist circumference will be measured at the minimum 
circumference between the rib cage and iliac crest (in centimeters) and hip circumference at the 
level of the largest circumference around the buttocks by trained clinicians using tape measures 
from the same manufacturer.  The circumference measurements will be taken in the upright 
position using 15-mm width flexible metric tapes held close to the body but not tight enough to 
indent the skin.  Cardiovascular risk will be assessed biochemically using lipoprotein profile 
(total cholesterol, triglycerides, HDL, calculated LDL), and by total body fat and its distribution 
W: H ratio.   
Randomization and Allocation 
 
 
At randomization, all study participants will be assigned to an 80 [+4 weeks] 
medication treatment group.  A computer-generated randomization schedule using a block 
randomization method will be used.  The treatment allocation ratio will be 1:1.  Drug will be 
packaged and labeled according to the randomization schemes.  Subjects who are randomized 
will be assigned the next sequential subject number. Once randomized, the subjects will begin 
treatment with the allocated study drug or placebo.  All personnel involved in the study will be 
blinded to which treatment arm the patients have been randomized.  The drug and placebo will 
look identical and not have any identifying characteristics.  
 
Subjects will be equally randomized to one of two treatment groups: Metformin + 
Liraglutide or Metformin + Placebo.   All patients will be taking either liraglutide 6 mg/ml or 


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placebo solution for injection in a 3 ml pre-filled pen which is self-administered via 
subcutaneous injection once per day in the abdomen or thigh.  For patients taking liraglutide, 
treatment will be initiated at 0.6 mg subcutaneous, increased to 1.2 mg and then to 1.8 mg 
subcutaneous, as tolerated, during the 4-wk non-forced dose-escalation period up to a maximum 
allowed dose of 1.8 mg subcutaneous daily.  Placebo-treated subjects will undergo the same non-
forced dose-escalation regimen, using matching injections.  All patients will be receiving therapy 
with metformin which will be started at an initial dose of metformin of 500 mg daily (with 
dinner) for 2 weeks.  They then will be increased to a metformin dose of 500 mg BID (breakfast 
and dinner).  The dose will be increased to 500 mg am, 1000 mg pm (with breakfast and dinner) 
for 2 weeks and then increased to the final dose of 1000 mg BID (breakfast and dinner) until the 
end of the study.  For patients who cannot tolerate the full dose of metformin in combination 
with liraglutide, the metformin dose will be adjusted at the discretion of the physician to a level 
that is tolerable.  The physician investigator or research nurse will dispense a ten-week supply of 
the appropriate study medication to the subject at the time of randomization and every ten weeks 
thereafter. All patients will have a urine pregnancy test performed to document they are not 
pregnant prior to receiving the next 10 weeks of medication.  Appointments will be made to 
return every ten weeks to receive a new supply of medication.  All patients will receive the same 
counseling concerning the benefits of lifestyle modification through diet and exercise.  Patients 
in each group will receive standardized dietary advice and appropriate written information on a 
balanced weight-reducing diet.  The patients will be also encouraged to increase daily exercise 
(such as walking, using stairs), although this will not be formally assessed.  The participants will 
receive further encouragement to adhere to the regime at their 32 (+4) week, 56 (+4) week and 
80 (+4) week review visits and during follow-up phone calls.   
 
Oral glucose tolerance tests with glucose (G) and insulin (I) measured at 0, 30, 60, and 
120 after glucose load to assess diabetes, insulin resistance and pancreatic ß-cell function will be 
performed 32 (+4) weeks after study medications are started.  Testing will be repeated at 56 (+4) 
weeks and 80 (+4 weeks) after treatment start.  The baseline blood samples from the OGTT will 
also be analyzed for liver enzymes, TSH, creatinine with eGFR (baseline and 56 weeks only), 
and lipid profile.  Subjects will remain on treatment unless they are diagnosed with DM2 during 
an OGTT or a random blood test at which time final testing will be performed.   They will be 
withdrawn from the study and they will be referred to a specialist for additional treatment of 


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diabetes. In subjects who complete 80 (+4) weeks of treatment, all study medications will be 
stopped and subjects will be asked to return for routine OGTT testing by their physician. 
Primary Study Endpoint:  
 An index of insulin secretion in relation to insulin resistance (IS-SI) will be calculated.  
Thus, β-cell compensatory capacity will be evaluated by the insulin sensitivity-secretion 
index (IS-SI) defined as the product of composite insulin sensitivity index and first-phase 
insulin release index (insulinogenic index).   
Secondary Study Endpoint(s): 
 Indexes of insulin sensitivity and secretion using the serum glucose and insulin 
concentrations obtained in the fasting state and during the 2hr OGTT with INS will be 
computed by several measures previously validated in women.  Changes in insulin 
resistance –baseline {HOMA-IR} and composite insulin sensitivity index [ISIOGTT], and 
pancreatic ß-cell function (corrected insulin response [CIRglupeak] and insulinogenic 
index [IGI])/HOMA-IR 
 Anthropometric measurements [BMI, absolute body weight, waist circumference, waist: 
hip ratio,  
 Cardiometabolic risk measures [lipids, liver enzymes; blood pressure] 
 Development of diabetes, impaired glucose tolerance or impaired fasting glucose based 
on positive OGTT.  Glucose tolerance will be defined as normal, impaired glucose 
tolerance (IGT) or diabetic according to the criteria of the American Diabetes 
Association.1  Patients diagnosed with diabetes will be withdrawn from the study and 
referred to a specialized physician.  
Biochemical assays and calculations 
Laboratory Measures: Hormonal and metabolic parameters will be measured at baseline (6-52 
weeks postpartum), and after 32 (+4) weeks, 56 (+4) weeks and 80 (+4) weeks treatment 
intervention following an overnight fast.  Blood samples will be obtained in the fasting state and 
½, 1 and 2 h after a standardized 75-g oral glucose load.  Blood samples will be centrifuged, 
divided into aliquots, and stored at –70°C until assayed.  Plasma glucose levels will be 
determined with a glucose analyzer using the glucose oxidase method (Glucose Reagent Kit, 
Bayer Newbury, UK).  Plasma insulin will be determined in all samples in duplicate by 
microparticle enzyme immunoassay (Abbott AxSYM System, Abbott Laboratories, Abbott Park, 


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IL).  Levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C) and triglycerides 
will be determined in the initial basal sample using standard enzymatic colorimetric assays on an 
automated clinical chemistry analyzer whereas low-density lipoprotein cholesterol (LDL-C) will 
be calculated according to the Friedewald equation.  Serum creatinine, liver enzymes, AST, and 
ALT will be measured using standard automated kinetic enzymatic assay.  Circulating levels of 
TSH and ßhCG will be measured using a two-site sandwich immunoassay with direct 
chemiluminometric technology (Diagnostic Products, Los Angeles, CA).  The intra- and 
interassay coefficients of variation are less than 7 and 11%, respectively, over the sample 
concentration range.   
Insulin sensitivity and secretion:  
Indexes of insulin sensitivity and secretion using the serum glucose and insulin 
concentrations obtained in the fasting state and during the 2hr OGTT with INS will be computed 
by 
several 
measures 
previously 
validated 
in 
premenopausal 
women.35 
 
Insulin 
resistance/sensitivity will be calculated using homeostasis model assessment (HOMA-IR), which 
is based on fasting insulin and glucose concentrations36 and the Matsuda insulin sensitivity 
index, which takes into account mean insulin and glucose levels following oral glucose 
stimulation. 37  
Basal insulin resistance measurement The homeostasis model assessment of insulin resistance 
(HOMA-IR) will be calculated from fasting plasma glucose and insulin concentrations according 
to the report by Matthews et al. 36 with the formula: HOMA-IR = FIRI x FPG divided by 22.5, 
where FIRI is the fasting insulin concentration (microunits per milliliter) and FPG is the fasting 
glucose level (millimoles per liter).  Lower HOMA-IR values indicate greater insulin sensitivity, 
whereas higher HOMA-IR values indicate lower insulin sensitivity (insulin resistance).  
Indexes of insulin sensitivity from the OGTT.  Originally proposed by Matsuda and 
DeFronzo37, the composite whole body insulin sensitivity index (ISIOGTT) is an insulin sensitivity 
index that reflects a composite estimate of hepatic and muscle insulin sensitivity determined from 
OGTT data.   The ISIOGTT is a measure of peripheral insulin sensitivity derived from the values 
of insulin (microunits per milliliter) and glucose (milligrams per deciliter) obtained from the 
OGTT and the corresponding fasting values.  ISI(OGTT) = 10,000/
[(Gfasting
 x Ifasting) x (GOGTTmean 
x IOGTTmean)], where fasting glucose and insulin data are taken from time 0 of the OGTT and 
mean data represent the average glucose and insulin values obtained during the entire OGTT. The 


Revised 9/19/17 
14
square root is used to correct for nonlinear distribution of insulin, and 10,000 is a scaling factor in 
the equation. ISIOGTT correlates reasonably well with estimates of whole body insulin sensitivity 
determined by the glucose clamp. The fasting component reflects hepatic insulin sensitivity, 
whereas the mean of the dynamic data primarily represents skeletal muscle insulin sensitivity. 
This partitioning concept has recently been validated using glucose clamp studies.38 
Insulin secretion was estimated by two methods. Insulin secretory function will be estimated 
from the OGTT using the corrected insulin response at peak glucose (CIRGluPeak) calculated as 
(100 x Insulin glucose peak[microunits per milliliter)]/{Glu glupeak(milligrams per deciliter)] - [Glu 
glupeak(mg/dl)])] –70 mg/dl)]. ]}.39  Corrected insulin response is a useful indicator of ß-cell 
activity: the higher the CIRGluPea, the greater the insulin secretion for the same glucose stimulus.  
Early phase insulin secretion (insulinogenic index [IGI]) is calculated as the ratio between 
serum insulin and blood glucose concentrations 30 min after the glucose load.40  The IGI is 
calculated from the OGTT data as the ratio of the increment of insulin to that of glucose 30 min 
after a glucose load {
insulin (0–30 min) in microunits per milliliter divided by the 
glucose 
(0–30 min) in mg per deciliter.41  This index has been shown previously to correlate strongly 
with the first phase of insulin response following an intravenous glucose tolerance test.42  
Pancreatic β-cell function [IGI/HOMA-IR] is best estimated by the acute insulin response to 
glucose corrected for by the relative insulin resistance.43 
To evaluate beta cell function in relation to insulin sensitivity, an insulin secretion-sensitivity 
index (IS-SI) will be calculated from the product of the insulinogenic index (IGI) and the ISIOGTT 
based on the existence of the /predicted hyperbolic relationship between these two measures.44 
Based on this relationship of insulin sensitivity and insulin secretion, changes in insulin secretion 
may reflect one of three scenarios regarding ß-cell function.  No change in the relationship would 
result in ß-cell function moving along the curve.  The second would be one in which ß-cell 
function was improved; this would be characterized by a change in the relationship between 
insulin sensitivity and the insulin response with a shift to the right of or above the curve.  Finally, 
a decrease in ß-cell function would be characterized by a shift to the left of or below the curve. 
The insulin secretion/insulin resistance (disposition) index calculated as the product of insulin 
secretion measured with (
I0–30/ G0–30) and ISIOGTT has been shown to have excellent power to 
predict onset of type 2 diabetes.45 
Concomitant Medications and Therapy:   


Revised 9/19/17 
15
 
None of the patients will be allowed to take medications likely to influence metabolic 
profiles except thyroid supplementation.  The following medications cannot be used immediately 
prior to or concomitant with the treatment therapy;  drugs known to affect gastrointestinal 
motility, lipid lowering agents (statins), other medications known to affect carbohydrate 
metabolism (glucocorticoids, anabolic steroids) or anti-diabetes medications (metformin, 
thiazolidinediones, GLP-1 receptor agonists, pramlintide; DPP4 inhibitors).  Vitamins and 
topical medications can continue to be used.  Barrier contraception, IUD and hormonal 
contraceptives are also permitted. 
Safety Measures:   
 
This protocol and the associated Informed Consent as well as any addenda or 
amendments, must be reviewed and approved by the Woman’s Hospital Foundation Institutional 
Review Board (WHIRB) review committee prior to the start of the study.  All revisions to this 
Protocol are considered “protocol amendments” these must be approved in advance, in writing, 
by the WHIRB.  Every patient will have given her written informed consent prior to participating 
in the study.  Prior to participation in this trial, each subject will have an opportunity to ask 
questions and will sign (and date) a written Informed Consent, which must be witnessed.  The 
signed consent forms will be filed with the investigator's study charts for each subject.  Any 
subject may voluntarily withdraw from the study at any time without prejudicing treatment. 
 
Patients will be educated about the side effects and use of liraglutide 6.0 mg/ml for 
injection in a 3 ml pre-filled pen and the injection system.  The most common adverse events 
related to liraglutide are headache, nausea, dyspepsia and vomiting, and are generally of mild-to-
moderate intensity.  Liraglutide is classified as a pregnancy category C drug.  The GLP-1 
receptor agonist exenatide has been shown to cause reduced fetal and neonatal growth in mice.  
Irregular fetal skeletal growth has been reported in rabbit and mouse models at dosages 
significantly higher than the normal dosage range.  Four unintended pregnancies were reported 
during GLP-1 receptor agonist exenatide clinical development program through 30 June 2004.  
GLP-1 receptor agonist treatment was discontinued immediately.  The pregnancies resulted in 
healthy babies born at 35, 37, and 39 weeks of gestation (one woman had an elective abortion).  
Two of the subjects were using oral contraceptives and also received antibiotic agents 
approximately 1 month prior to discovery of the pregnancies.  Based on this limited experience, 
there is no indication of any detrimental effects of GLP-1 receptor agonists on either the mother 


Revised 9/19/17 
16
or the fetus during pregnancy.  In the event of pregnancy, it is unlikely that liraglutide would 
cause any direct untoward fetal effects, given the very low potential for liraglutide to cross the 
placental barrier.  The drug has not been adequately studied in nursing mothers or pediatric 
patients.  In previous studies, the GLP-1 receptor agonist exenatide has been found in the milk of 
lactating mice in low concentrations, so it should be used with caution in nursing mothers.  If 
patients become pregnant during the study, liraglutide will be stopped immediately. 
Patients starting metformin therapy will be advised that they may have minor 
gastrointestinal side effects.  The most common side effects of metformin are diarrhea, nausea or 
vomiting, flatulence, indigestion, abdominal discomfort and rarely, a metallic taste in the mouth.  
These acute reversible adverse effects occur in 5–20% of patients treated with metformin.  The 
symptoms are dose related and remit if the dose is reduced, sometimes an increase in the dose can 
later be tolerated.  Taking the drug with or after food, and starting therapy with low dosages that 
may be increased slowly can minimize these.  The dose can then be increased slowly at intervals 
of two weeks.  Lactic acidosis is the biguanide-related adverse effect of most concern with an 
estimated incidence of less than 0.01 to 0.08 cases.  Should a patient have lactic acidosis 
attributable to metformin, the drug can be removed by hemodialysis.  Other contraindications to 
the use of metformin include concurrent liver disease and a previous history of lactic acidosis.  
Metformin therapy will also be stopped if the blood lactate concentration is substantially 
increased by any illness.  Metformin therapy will be temporarily suspended for all major surgical 
procedures that involve restriction of fluid intake.  Metformin is classified as a United States 
Food and Drug Administration category B drug (i.e., "no evidence of risk in humans").  This 
means that, while there is no evidence of teratogenesis or adverse fetal effects, insufficient data 
exist to state that harm does not occur.  Metformin does cross the placenta, prompting a cautious 
approach to its use in pregnancy.  There have been several published reports of the use of 
metformin during pregnancy, predominantly in women with insulin resistance and PCOS.  Some 
clinicians routinely use metformin to treat diabetes in pregnant women.  However, most experts 
believe that if medication is needed to control blood sugar during pregnancy, insulin is the drug 
of choice, not an oral antihyperglycemic agent.  If patients become pregnant during the study, 
metformin will be stopped immediately. 
For safety, all subjects who enter the study are evaluable.  Subjects will be monitored for 
safety by assessment of adverse events, physical exams, vital signs and laboratory values.  


Revised 9/19/17 
17
Continued patient safety assessment will be carried out and all adverse events documented and 
reported to the WHIRB.  On each visit, compliance with treatment will be checked with 
questions about the side-effects and a subjective evaluation of the tolerability of the administered 
drug; the patients will also asked about incidental missed administrations. 
Adverse Event Procedures    
 
An adverse event is defined as any untoward medical occurrence in a clinical study 
subject administered a pharmaceutical product, and which does not necessarily have a causal 
relationship with the treatment.  An adverse event can therefore be any unfavorable or 
unintended sign (including an abnormal laboratory finding), symptom, or disease that is 
temporally associated with the use of a pharmaceutical product, whether or not it is considered 
related to that product.  All observed or volunteered adverse events regardless of treatment group 
or suspected causal relationship to study drug will be recorded in the patient’s record.  Events 
involving adverse drug reactions, illnesses with onset during the study, or exacerbations of pre-
existing illnesses will be recorded.  Exacerbation of pre-existing illness may include worsening 
or increase in severity of signs or symptoms of the illness, increase in frequency of signs and 
symptoms of an intermittent illness, or the appearance of a new manifestation/complication.  
Exacerbation of a pre-existing illness should be considered when a patient/subject requires new 
or additional concomitant drug or non-drug therapy for the treatment of that illness during the 
trial.  Lack of or insufficient clinical response, benefit, efficacy, therapeutic effect, or 
pharmacologic action, will not be recorded as an adverse event.  The investigator will make the 
distinction between exacerbation of pre-existing illness and lack of therapeutic efficacy.  In 
addition, clinically significant changes in physical examination findings and abnormal objective 
test findings (e.g., laboratory, x-ray, ECG) will also be recorded as adverse events.  Any 
abnormal test result that is determined to be an error does not require reporting as an adverse 
event.   
In order to avoid vague, ambiguous, or colloquial expressions, the adverse event term 
will be recorded using standard medical terminology rather than the subject’s own words.  Every 
attempt will be made to describe the adverse event in terms of a diagnosis.  All related signs, 
symptoms and abnormal test results will be grouped together as a diagnosis if applicable and 
recorded as a single adverse event.  All adverse events will be evaluated for intensity and causal 
relationship with use of the study medication.  For all adverse events, sufficient information 


Revised 9/19/17 
18
should be obtained by the investigator to determine the causality of the adverse event (i.e., study 
drug or other illness).  Follow-up of the adverse event, after the date of therapy discontinuation, 
is required if the adverse event or its sequelae persist.  Follow-up is required until the event or its 
sequelae resolve or stabilize at a level acceptable to the investigator or his/her designated 
representative.  Clinically significant changes, in the judgment of the investigator, in physical 
examination findings (abnormalities) will be recorded as adverse events.  All subjects who have 
adverse events, whether or not the adverse events are considered associated with the use of the 
study medication, will be monitored until the adverse event resolves, stabilizes, or becomes 
chronic.  The clinical course of the adverse event will be followed according to accepted 
standards of medical practice, even after the end of the observation period, until a satisfactory 
explanation for the adverse event is found or the investigator considers it medically justifiable to 
terminate follow-up.  
SERIOUS ADVERSE EVENTS:  A SERIOUS ADVERSE EVENT (SAE) IS ANY ADVERSE 
DRUG EXPERIENCE OCCURRING AT ANY DOSE THAT: 
1. 
results in death; 
2. 
is life-threatening (adverse drug experience that places the patient/subject at immediate 
risk of death from the reaction as it occurred, i.e., it does not include a reaction that, had it 
occurred in a more severe form, might have caused death); 
3. 
results in inpatient hospitalization or prolongation of existing hospitalization; 
4. 
results in a persistent or significant disability/incapacity (defined as a substantial 
disruption of a person’s ability to conduct normal life functions); or 
5. 
results in congenital anomaly/birth defect. 
6. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug experiences when, based upon 
appropriate medical judgment, they may jeopardize the patient/subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition.  Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse 
 
The term “severe” is often used to describe the intensity (severity) of a specific event (as 
in mild, moderate, or severe pain); the event itself, however, may be of relatively minor medical 


Revised 9/19/17 
19
significance (such as severe headache).  By contrast, the term “serious” is used to describe an 
event based on an event outcome or actions usually associated with events that pose a threat to a 
patient’s life or functioning.  Seriousness (not severity) serves as a guide for defining regulatory 
reporting obligations.  The collection of serious adverse event information will begin at the 
signing of informed consent and continue through 30 days after administration of the last dose of 
study medication.  Regardless of the above criteria, any additional adverse experiences which an 
investigator considers serious should be immediately reported.  If an SAE occurs, the 
investigator should initiate appropriate support procedures. 
All serious adverse events regardless of treatment group or suspected relationship to 
study drug must be reported to MedWatch in an expedited manner.  The investigator will 
determine expectedness by referring to the most current version of the Investigator’s Brochure in 
conjunction with any sponsor-generated IND Safety Reports.  Since the trial is being conducted 
under a physician’s IND, Drs. Harris and Elkind-Hirsch are responsible for submitting all IND 
Safety Reports to the Food and Drug Administration (FDA).  The FDA 3500A Form with built-
in instructions will be downloaded at: http://www.fda.gov/medwatch/getforms.htm.  They will 
also be reported immediately to the Woman’s Hospital Foundation Institutional Review Board at 
(225) 924-8516 and Woman’s Health Research Department at (225) 231-5275.  After submitting 
an expedited MedWatch 3500A report to the FDA, a courtesy copy will be sent by fax to 
NovoNordisk.  NovoNordisk Safety personnel may fax a follow-up form to the study site to 
request additional information or clarification of information that was included on the FDA 
3500A Report.  Queries that address medical issues must be signed by a medically qualified 
(MD, DO) principal or sub-investigator.  In cases where the investigator learns of the SAE after 
its occurrence and resolution, the time and circumstances of the event will be recorded.  The 
reporting requirements will still be followed. 
Any serious adverse event or death will be reported immediately independent of the 
circumstances or suspected cause if it occurs or comes to the attention of the investigator at any 
time during the study through the last follow-up visit required by the protocol or 30 days after 
the last administration of study drug, whichever comes later.  Any serious adverse event 
occurring at any other time after completion of the study will be promptly reported if a causal 
relationship to study drug is suspected.  The only exception to these reporting requirements are 
serious adverse events that occur during a pre-randomization/washout run-in period, during 


Revised 9/19/17 
20
which placebo alone or no active study drug or no protocol-specified background drug is 
administered.  
Discontinuations:  
The reason for a subject discontinuing from the study will be recorded in the patient chart.  
A discontinuation occurs when an enrolled subject ceases participation in the study, regardless of 
the circumstances, prior to completion of the protocol.  The investigator must determine the 
primary reason for discontinuation.  Withdrawal due to adverse event will be distinguished from 
withdrawal due to insufficient response according to the definition of adverse event noted earlier.  
The final evaluation required by the protocol will be performed at the time of study 
discontinuation.  The investigator will record the reason for study discontinuation, provide or 
arrange for appropriate follow-up (if required) for such subjects, and document the course of the 
subject’s condition.  They will also to be reported to Woman’s Hospital Foundation Institutional 
Review Board at (225) 924-8516 and Woman’s Health Research Department at (225) 231-5275.  
Sample Size Computation and Power Analysis  
A priori sample size analysis was performed using the online calculator provided by the 
Massachusetts 
General 
Hospital 
Mallinckrodt 
General 
Clinical 
Research 
Center 
(http://hedwig.mgh.harvard.edu/sample_size/size.html).  Because the possible advantages of 
combination treatment over metformin alone rely on the presumed positive effects of liraglutide 
on pancreatic ß-cell function parameters, we used the difference in a surrogate marker of insulin 
secretion relative to insulin resistance as the primary outcome for sample size analysis.  An 
experimental design including a total of 118 patients would have power above 0.80 to detect 
differences in the IS-SI index between treatments such as those previously reported using a 
similar experimental design.46 
We plan on recruiting 150 overweight women with a recent history of GDM to be studied.  
The estimated enrollment: of 75/group for an average follow up of 60 weeks of treatment (range 
32-84 weeks) will be our intent-to-treat population.  This sample size is projected to provide 
power 0.8 to detect a 20% difference in insulin action indices between treatment groups at a 
median follow-up of 24 months. The calculation was adapted to allow for significant dropout rate 
(20-22%) for completion of the full trial of 80 (+4) weeks of treatment.  Subjects who drop out 
of the trial will not be replaced 


Revised 9/19/17 
21
Statistical Analysis Plan:   
The primary outcome measure is the insulin sensitivity-secretion index (IS-SI) and 
secondary outcome measures include changes in lipid and hepatic enzyme levels, anthropometric 
parameters, insulin sensitivity and pancreatic ß-cell function, and glucose tolerance status.  
Continuous variables will be tested for normality of distribution using the Kolmogorov-Smirov 
test.  Natural log transformations of skewed variables will be used where necessary in 
subsequent analyses.  For variables with highly skewed distributions, a logarithmic 
transformation will be done first and the geometric means reported instead.  Differences in 
effects of drug intervention for continuous variables (in their raw or transformed state) will be 
compared using Subjects/Drug Treatments by trials analyses of variance (ANOVAs).  This 
analysis provides p values for differences between groups/drug treatments (A), differences over 
time (B), and the interaction of group/drug treatment with time (AB).  Otherwise, changes 
between baseline and follow-up measurements will be compared between groups by Wilcoxon’s 
nonparametric methods. Anthropometric measurements (body weight, BMI), blood pressure, 
direct and indirect measurements of carbohydrate metabolism (HOMA, SIOGTT, CIRgp, IGI, and 
ISSI), and measurements of lipid profile (total cholesterol, HDL, LDL), and liver enzymes (ALT, 
AST) will be considered as dependent variables.  The simultaneous effect of various baseline 
characteristics and characteristics at certain study treatment intervals between women who did 
not develop diabetes and women who did during follow-up will be studied with the use of a 
linear multiple regression analysis.  Diabetes and IGT occurrence before and after different 
treatment will be compared with the McNemar test (complex chi square for paired data), which 
formally tests for a change between the observed proportions of 2 related samples.   
All analyses will be conducted with subjects assigned to their initial treatment group, 
using all available data for the period of follow-up relevant to the particular analysis.  Data will 
be analyzed on the basis of intention to treat and also on completed treatment parameters where 
relevant.  Differences of P < 0.05 will be considered statistically significant.  Results will be 
reported as mean +/- standard error of the mean (S.E.M) for quantitative variables and 
percentages for categorical variables unless otherwise noted.  We will perform all statistical 
analyses using SPSS 15.0 for Windows (SPSS, Inc.; Chicago, Ill).   
 


Revised 9/19/17 
22
Study Drugs 
Description 
Both active drug (Liraglutide 6.0 mg/ml injection) and placebo will be supplied by Novo 
Nordisk A/S. as a pre-filled pen for subcutaneous injection. Each liraglutide pre-filled pen 
contains 18 mg/3 ml (6 mg/ml) and will deliver 30 doses of 0.6 mg; 15 doses of 1.2 mg or 10 
doses of 1.8 mg; the placebo pen will deliver equal volumes of vehicle solution only.  Liraglutide 
and placebo are visually identical.  
 
Metformin Hydrochloride XR (extended-release) in 500 mg strength oral tablets will be 
purchased in bulk through the Woman’s Hospital Infusion Pharmacy.  Metformin hydrochloride 
XR is combined with a drug release controlling polymer so that drug is released slowly from the 
dosage form.  The medication will be allocated into appropriate patient dosage regimens by the 
hospital pharmacy personnel.  Dosage of metformin XR will be prescribed according to standard 
directions and not exceeding the maximum recommended daily dose in adults of 2000 mg. 
 
Trial Supplies 
Double-blind Liraglutide or placebo 
Liraglutide 6.0 mg/ml or placebo solution for injection in a 3 mL pre-filled pen will be supplied 
by Novo Nordisk A/S. The pre-filled pen will be provided as a pen-injector. The Investigator 
will provide each subject with Direction for Use for the liraglutide pen-injector at each 
dispensing visit. 
 
Packaging and Labelling of Trial Products 
 
Liraglutide and placebo will be packed and labelled by Novo Nordisk A/S and provided in non 
subject specific boxes. Labelling will be in accordance with Annex 13, local law and trial 
requirements.  
 
Storage, Handling, Accountability and Destruction of Trial Products 
 


Revised 9/19/17 
23
The trial product will be dispensed to each subject as required according to treatment group and 
under the direction of the study investigator(s). The Investigator will ensure availability of proper 
storage conditions, and study staff will record and evaluate the temperature (at least every 
working day). Storage facilities should be checked frequently. A log to document the 
temperature must be kept on file. No trial product will be dispensed to any person not enrolled in 
the study. 
 
Storage and in-use conditions  
 
The investigator will provide appropriate instructions to study subjects as to the in-use and not 
in-use conditions. These instructions will be in accordance with the local regulatory and legal 
requirements and consistent with the product prescribing information approved by the 
appropriate regulatory authorities.   
Study Timelines 
We anticipate that the proposed study will take 36 months (three years) to complete, including 12 
months for patient recruitment. Table 1 presents the timetable and key activities in the proposed 
research. 
 
Target Start Date: January 2011 
Table 1 
     Phase 
                     Tasks 
I (Months 1-3) 
FDA filing, IRB application, staff training, protocol development, 
drug and placebo receipt 
II (Months 4-16) 
Recruitment of women* 
III (Months (4-34) 
Patient enrollment, treatment, database and data entry, interim 
analyses if needed 
IV (Months (24-36) 
Final data entry, data analyses and publication 
 
 
ADDITIONAL INFORMATION 
Woman’s Hospital is one of the largest, not-for-profit women’s specialty hospitals in the 
United States.  The hospital‘s most valuable asset is its patient population.  Woman’s statistics of 
over 8100 births (2009), 75,000 pap smears, 47,000 mammograms, 300,000 lab tests, and 13,000 


Revised 9/19/17 
24
biopsies annually in a centralized location make it ideal for clinical research studies in women’s 
health.  The ethnic mix is about 60% Caucasian and 40% African American.  In the calendar 
year of 2009, 600 patients with gestational diabetes delivered at Woman’s hospital.  The rate of 
GDM was 7.4% for the year 2009. 
The Physician Tower, which is on the hospital campus, offices approximately 60 private 
obstetrician-gynecologist offices that actively participate in Woman’s Health Research 
Department clinical trials and encourage patient participation.  This study will utilize the 
research staff (nurses, physicians, PhD) of the Woman’s Hospital Health Research Department 
for recruitment and patient consenting.  The Woman’s Hospital Pathology laboratory facility will 
be utilized for all metabolic and glucose tolerance testing.  Study administrative work (IRB 
approval and updates) and statistical analyses will be done through the Woman’s Health 
Research Department.  The staff of the Woman’s Metabolic Health Clinic will be used for all 
patient follow-up, medication instruction and medical care. 
 


Revised 9/19/17 
25
References: 
1.  
American Diabetes Association, Position Statement, Gestational Diabetes Mellitus, 
Diabetes Care Vol. 27 (Supplement I) (2004) January. 
2 
Metzger BE, Buchanan TA, Coustan DR, et al.: Summary and recommendations of the 
Fifth International Workshop—Conference on Gestational Diabetes Mellitus. Diabetes Care 30: 
S251–S260, 2007 
3 
Engelgau MM, Herman WH, Smith PS, German RR, Aubert RE The epidemiology of 
diabetes and pregnancy in the U.S., 1988, Diabetes Care 18 . 1029–1033, 1995  
4 
Bian X, Gao P, Xiong X, Xu H, Qian M, Liu S. Risk factors for development of diabetes 
mellitus in women with a history of gestational diabetes mellitus. Chin Med J (Engl) 
2000;113:759-762 
5 
Damm P. Gestational diabetes mellitus and subsequent development of overt diabetes 
mellitus. Dan Med Bull 1998;45:495-509 
6 
Pallardo F, Herranz L, Garcia-Ingelmo T. Early postpartum metabolic assessment in 
women with prior gestational diabetes. Diabetes Care 1999;22: 1053-1058 
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Hanna F, Peters JR Screening for gestational diabetes; past, present and future, Diabet 
Med 19 (2002), pp. 351–358 
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Catalano PM, Kirwan JP, Haugel-De Mouzon S and King J (2003) Gestational diabetes 
and insulin resistance: role in short- and long-term implications for mother and fetus. J Nutr 
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Peters RK, Kjos SL, Xiang A et al., Long term diabetogenic effect of single pregnancy in 
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10 
Diabetes Prevention Program Research Group: The Diabetes Prevention Program: 
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Med 346:393–403, 2002 
11 
Buchanan T, Xiang A, Peters RK et al., Preservation of pancreatic beta-cell function and 
prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk 
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Gerstein H, Yusuf S, Bosch J et al.,DREAM (Diabetes REduction Assessment with 
ramipril and rosiglitazone Medication) Trial Investigators.  Effect of rosiglitazone on the 


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frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a 
randomized controlled trial, Lancet 2006; 368: 1096-1105 
13 
Kim C, Berger DK, Chamany S. Recurrence of gestational diabetes mellitus: a systematic 
review. Diabetes Care 2007;30:1314-1319 
14 
Kjos S, Buchanan T, Greenspoon J, Montoro M, Bernstein G, Mestman J: Gestational 
diabetes mellitus: the prevalence of glucose intolerance and diabetes mellitus in the first two 
months postpartum. Am J Obstet Gynecol 163:93–98, 1990 
15 
Russell MA, Phipps MG, Olson CL, Welch HG, Carpenter MW. Rates of postpartum 
glucose testing after gestational diabetes mellitus. Obstet Gynecol 2006;108:1456-1462 
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Nelson AL, Hien Le MH, Musherraf Z, et al. Intermediate-term glucose tolerance in 
women with a history of gestational diabetes: natural history and potential associations with 
breastfeeding and contraception. Am J Obstet Gynecol 2008;in press 
17 
Diabetes Prevention Program Research Group: The Diabetes Prevention Program: 
Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J 
Med 346:393–403, 2002 
18 
Azen S, Peters R, Berkowitz K, Kjos S, Xiang A, Buchanan TA: TRIPOD (Troglitazone 
in the Prevention of Diabetes): a randomized, placebo-controlled trial of troglitazone in women 
with prior gestational diabetes mellitus. Control Clin Trials 19:217–231, 1998 
19 
Xiang A, Peters R, Kjos S, Marroquin A, Goico J, Ochoa C, Kawakubo M, Buchanan 
TA: Effect of pioglitazone on pancreatic beta cell function and diabetes risk in Hispanic women 
with prior gestational diabetes. Diabetes 55:517–522, 2006 
20 
Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M, Hoogwerf 
B, Laakso M, Mohan V, Shaw J, Zinman B, Holman RR, on behalf of the DREAM trial 
investigators  Effect of rosiglitazone on the frequency of diabetes in patients with impaired 
glucose tolerance or impaired fasting glucose: a randomized controlled trial. Lancet 368:1096–
1105, 2006 
21 
Bregenholt S, Moldrup A, Blume N, Karisen AE, Nissen-Friedrichsen B, Tornhave D, 
Knudsen LB & Petersen JS. The long-acting glucagon-like peptide-1 analogue, liraglutide, 
inhibits beta-cell apoptosis in vitro. Biochemical and Biophysical Research Communications 
2005; 330: 577–584 


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22 
Agerso H, Vicini P: Pharmacodynamics of NN2211, a novel long acting GLP-1 
derivative. Eur J Pharmacol Sci 19:141–150, 2003 
23 
Degn KB, Juhl CB, Sturis J, Jakobsen G, Brock B, Chandramouli V, Rungby J, Landau 
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