DAPA-GDM: Dapagliflozin and Metformin,Alone and in Combination, in Overweight/Obese Prior GDM Women

• Sponsor: Woman's (Other)
• Overall Status: Completed
• CT.gov ID: NCT02338193
• Collaborator: AstraZeneca (Industry)
• Enrollment: 69
• Location: 1
• Arms: 3
• Actual Duration (Months): 41.7
• Patients Per Site Per Month: 1.7

Study Details

Study Description

Brief Summary

Women with a history of gestational diabetes (GDM) are at substantially increased risk of type 2 diabetes mellitus (T2DM). Compared with the general population, these women are more likely to be overweight or obese. Moreover, weight gain after GDM is significantly associated with T2DM, independent of baseline body weight. Weight gain, particularly increased central adiposity after delivery, is strongly associated with deterioration of β-cell compensation for insulin resistance. Taken together, our findings and other studies support increased abdominal fat as the strongest factor associated with declining B-cell compensation for insulin resistance in prior GDM women at high risk for T2DM. Dapagliflozin is a novel highly selective SGLT2 inhibitor that improves glycemic control by reducing renal glucose reabsorption leading to urinary glucose excretion. Its efficacy and safety has been studied in multiple randomized controlled trials including an add-on to metformin compared with a placebo. To the extent that glucotoxicity contributes to the demise in β-cell function in subjects with impaired glucose, SGLT2 inhibitors also may prove useful in the treatment of "prediabetes." An additional secondary benefit of SGLT2 inhibition is the elimination of calories in the form of glucose. The loss of glucose with attendant caloric loss contributes to weight loss; in addition, improvements in β cell function have been seen. Weight loss seen with SGLT2 inhibitors is similar to that seen with glucagon-like peptide 1 analogs, and may be more acceptable because they are oral agents. A consistent finding in all dapagliflozin studies has been a reduction in blood pressure. The investigators hypothesize that combination dapagliflozin -metformin treatment over a 24-week period will have a greater positive impact on body weight, anthropometric measurements and glycemic and cardiometabolic parameters than dapagliflozin or metformin monotherapy in overweight/obese at-risk women with a history of GDM.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Prevention in Women After GDM Who Are at High-risk	Drug: DAPA/MET XR; Drug: DAPA; Drug: MET XR	Phase 3

Detailed Description

Following written consent, all study patients will undergo the following clinical, metabolic and laboratory evaluations before and during treatment. To ensure that patients remain unidentified, all study subjects will be assigned an individual study identifier which includes the study acronym, patient initials, and unique number. All blood samples will be obtained and results identified and reported using this unique study identifier. A full physical examination will be performed and vital signs (blood pressure, respiration and temperature) determined. Trained personnel using standardized protocols at the baseline and follow-up examination will obtain anthropometric measurements and blood specimens. Absolute body weight, height, waist and hip circumference, body fat distribution (waist/hip ) and waist/height ratio () and blood pressure (BP) will be determined. Body weight will be measured to the nearest 0.1 kg using a calibrated digital scale with participants in light clothing and no shoes. Height will be measured to the nearest centimeter. 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. The circumference measurements will be taken in the upright position using a 15-mm width flexible metric tape held close to the body but not tight enough to indent the skin. Waist circumference (WC) will be measured at the narrowest level midway between the lowest ribs and the iliac crest and hip circumference measured at the widest level over the buttocks while the subjects are standing and breathing normally. The WHR and WHtR will be calculated for measure of body fat distribution.

All patients will randomly be assigned to one of 3 medication treatment groups-- dapagliflozin-metformin (DAP-MET; 5 mg DAP/ MET 1000 mg BID), metformin XR (MET 1000 mg BID) or dapagliflozin (DAP 10 mg QD); all subjects will be allocated to one of these 3 groups based on computer-generated random numbers using a block randomization method. Oral glucose tolerance tests (OGTTs) with glucose (G) and insulin (I) measured at 0, 30, 60, and 120 after glucose load to assess diabetes, fasting (FBG) and mean blood glucose (MBG) concentrations, insulin resistance and pancreatic ß-cell function will be performed prior to randomization and at 20-24 weeks after full doses of study medications are reached. Mean blood glucose (MBG) concentrations will be calculated by summing glucose values obtained at 0,30,60 and 120 minutes during the OGTT and dividing by 4. At the initial lab evaluation, creatinine and calculated eGFR, TSH, and ß-hCG will be determined for study inclusion. Baseline blood samples will also be analyzed for lipid profiles and liver enzymes.

All patients will receive the same counseling concerning the benefits of lifestyle modification through diet and exercise. 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 during follow-up phone calls. Side effects of the treatment and reason for any withdrawals from the study will be recorded.

Study Design

• Study Type: Interventional
• Actual Enrollment: 69 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized Study Evaluating Dapagliflozin and Metformin, Alone and in Combination, in Overweight Women With a Recent History of Gestational Diabetes Mellitus: Effects on Anthropometric Measurements and Cardiometabolic Abnormalities
• Actual Study Start Date: Sep 22, 2015
• Actual Primary Completion Date: Feb 13, 2019
• Actual Study Completion Date: Mar 13, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: DAPA/MET Extended Release (XR) Dapagliflozin plus metformin XR- 5 mg/1000 mg with meal for 4 weeks DAPA/MET XR- 5mg/1000 mg BID final dose for 20 weeks	Drug: DAPA/MET XR; final dose- 5 mg dapagliflozin/1000 mg glucophage XR BID for 20-24 weeks; Other Names: Xigduo 5mg/1000 mg
Active Comparator: Dapaglifloxin Dapagliflozin- 10 mg once daily before first meal for 24 weeks	Drug: DAPA; 10 mg dapagliflozin QD for 20-24 weeks; Other Names: Farxiga 10 mg
Active Comparator: Metformin XR Metformin XR with 500 mg once a day for 2 weeks, followed by 500 mg twice a day for 2 weeks, followed by 500 mg in the morning (AM), 1000 mg in the evening ( PM) for 2 weeks, with 1000 mg twice a day as the final dose for 20 weeks	Drug: MET XR; 1000 mg Metformin XR BID for 20-24 weeks; Other Names: Glucophage XR 500 mg

Outcome Measures

Primary Outcome Measures

1. Change in Body Weight [Change from baseline (time 0) to study end (24 weeks)]

   Change in absolute body weight with combination therapy compared to monotherapy from baseline to week 24

Secondary Outcome Measures

1. Change in Percent Body Weight [Change from baseline (time 0) to study end (24 weeks)]

   Change in percent body weight with combination therapy compared to monotherapy from baseline to week 24

2. Body Mass Index (BMI) [24 weeks of treatment]

   BMI (measure of overall adiposity) in combination therapy compared to monotherapy after 24 weeks of treatment

3. Waist Circumference (WC) [24 weeks of treatment]

   Waist size (measure of truncal adiposity)with combination therapy compared to monotherapy after 24 weeks of treatment

4. Waist- to -Hip Ratio (WHR; Measure of Central Adiposity) [24 weeks of treatment]

   Waist-to-hip ratio with combination therapy compared to monotherapy after 24 weeks of treatment

5. Waist-to-height Ratio (WHtR) [24 weeks of treatment]

   Waist divided by height a( measure of central adiposity) with combination therapy compared to monotherapy after 24 weeks of therapy

6. Diastolic Blood Pressure (DBP) [24 weeks of treatment)]

   Diastolic blood pressure with combination therapy compared to monotherapy after 24 weeks of treatment

7. Systolic Blood Pressure (SBP) [24 weeks of treatment]

   Systolic blood pressure with combination therapy compared to monotherapy after 24 weeks of therapy

8. Liver Enzymes [24 weeks of treatment]

   ALT/AST ratio with combination therapy compared to monotherapy after 24 weeks of treatment

9. Total Cholesterol Levels (CHOL) [24 weeks of treatment]

   Cholesterol levels with combination therapy compared to monotherapy after 24 weeks of treatment

10. Triglyceride (TRG) Levels [24 weeks of treatment]

    Triglyceride levels with combination therapy compared to monotherapy after 24 weeks of treatment

11. Fasting Blood Glucose (FBG) [24 weeks of treatment]

    Fasting blood glucose levels with combination therapy compared to monotherapy after 24 weeks of treatment

12. Mean Blood Glucose (MBG) During an OGTT [24 weeks of treatment]

    Mean blood glucose after glucose load with combination therapy compared to monotherapy after 24 weeks of treatment

13. Fasting Insulin Sensitivity (HOMA-IR) [24 weeks of treatment]

    HOMA index of insulin resistance calculated from fasting insulin and glucose with combination therapy compared to monotherapy after 24 weeks of treatment

14. Matsuda Sensitivity Index (SI OGTT) [24 weeks of treatment]

    Surrogate measure of insulin sensitivity derived from OGTT with combination therapy compared to monotherapy after 24 weeks of treatment

15. First Phase Insulin Secretion (IGI/HOMA-IR) [24 weeks of treatment]

    Corrected early insulin response to glucose challenge [(insulinogenic index (IGI)/ divided by fasting insulin resistance index (HOMA-IR)] with combination therapy compared to monotherapy after 24 weeks of treatment

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• • Overweight/obese (BMI >25) females 18 years to 45 years of age, who experienced gestational diabetes (GDM) during recent (within 12 months) pregnancy

• postpartum metabolic abnormalities determined by a 75 g oral glucose tolerance test (Inclusive of prior GDM women with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both (IFG/IGT) postpartum)

• Completed lactation

• Using adequate contraception during study period unless sterilized

• Written consent for participation in the study

Exclusion Criteria:

• Cholestasis during the past pregnancy

• Any hepatic diseases in the past (viral hepatitis, toxic hepatic damage, jaundice of unknown etiology), gallstones, abnormal liver function tests or renal impairment (elevated serum creatinine levels or abnormal creatinine clearance

• Presence of significant systemic disease, heart problems including congestive heart failure, history of pancreatitis, or diabetes mellitus (Type 1 or 2)

• Renal impairment (e.g., serum creatinine levels ≥1.4 mg/dL for women, or eGFR <60)

• Significantly elevated triglyceride levels (fasting triglyceride > 400 mg %)

• Untreated or poorly controlled hypertension (sitting blood pressure >160/95mm Hg)

• Prior history of a malignant disease requiring chemotherapy

• Known hypersensitivity or contraindications to use of insulin sensitizers such as metformin or thiazolidinediones

• History of hypersensitivity reaction to dapagliflozin or other SGLT2 inhibitors (e.g. anaphylaxis, angioedema, exfoliative skin conditions)

• Current use of metformin, thiazolidinediones, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT2 inhibitors or weight loss medications (prescription or OTC)

• Uncontrolled thyroid disease (documented normal TSH) or hyperprolactinemia

• Liver enzymes (serum alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST] ) levels exceeding more than twice normal lab values

• Use of drugs known to exacerbate glucose tolerance

• History of diabetes or prior use of medications to treat diabetes except GDM

• Currently lactating

• Eating disorders (anorexia, bulimia) or gastrointestinal disorders

• Suspected pregnancy (documented negative serum pregnancy test within 72 hours before first dose of study drug), desiring pregnancy in next 6 months, breastfeeding, or known pregnancy in last 2 months

• Active or prior history of substance abuse (smoke or tobacco use within past 3 years) or significant intake of alcohol or history of alcoholism

• Patient not willing to use adequate contraception during study period and up to 4 weeks after last dose of study drug (unless sterilized).

• Debilitating psychiatric disorder such as psychosis or neurological condition that might confound outcome variables

• Inability or refusal to comply with protocol

• Not currently participating or having participated in an experimental drug study in previous three months

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Woman's Hospital	Baton Rouge	Louisiana	United States	70815

Sponsors and Collaborators

• Woman's
• AstraZeneca

Investigators

• Principal Investigator: Karen E Elkind-Hirsch, PhD, Woman's Hospital, Louisiana
• Principal Investigator: Renee Harris, MD, Woman's Hospital, Louisiana

Study Documents (Full-Text)

• Informed Consent Form - Aug 31, 2018
• Study Protocol and Statistical Analysis Plan - Jul 10, 2018

More Information

Publications

None provided.

• Responsible Party: Karen Elkind-Hirsch, Director of Research, Woman's
• ClinicalTrials.gov Identifier: NCT02338193
• Other Study ID Numbers: RP-14-012
• First Posted: Jan 14, 2015
• Last Update Posted: Jun 11, 2019
• Last Verified: Jun 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Karen Elkind-Hirsch, Director of Research, Woman's: GDM; T2DM; prediabetes
• Additional relevant MeSH terms: Overweight; Metformin; Dapagliflozin

Study Results

Participant Flow

Recruitment Details	Patients recruited from Woman's Hospital post delivery
Pre-assignment Detail	3 patients not randomized since reluctant to take medication

Arm/Group Title	DAPA/MET XR	Dapaglifloxin	Metformin XR
Arm/Group Description	Dapagliflozin plus metformin XR- 5 mg/1000 mg with meal for 4 weeks DAPA/MET XR- 5mg/1000 mg BID final dose for 20 weeks DAPA/MET XR: final dose- 5 mg dapagliflozin/1000 mg glucophage XR BID for 20-24 weeks	Dapagliflozin- 10 mg once daily before first meal for 24 weeks DAPA: 10 mg dapagliflozin QD for 20-24 weeks	Metformin XR with 500 mg once a day for 2 weeks, followed by 500 mg twice a day for 2 weeks, followed by 500 mg in the AM, 1000 mg in the PM for 2 weeks, with 1000 mg twice a day as the final dose for 20 weeks MET XR: 1000 mg Metformin XR BID for 20-24 weeks
Period Title: Overall Study
STARTED	20	21	25
COMPLETED	17	17	15
NOT COMPLETED	3	4	10

Baseline Characteristics

Arm/Group Title	DAPA/MET XR	Dapaglifloxin	Metformin XR	Total
Arm/Group Description	Dapagliflozin plus metformin XR- 5 mg/1000 mg with meal for 4 weeks DAPA/MET XR- 5mg/1000 mg BID final dose for 20 weeks DAPA/MET XR: final dose- 5 mg dapagliflozin/1000 mg glucophage XR BID for 20-24 weeks	Dapagliflozin- 10 mg once daily before first meal for 24 weeks DAPA: 10 mg dapagliflozin QD for 20-24 weeks	Metformin XR with 500 mg once a day for 2 weeks, followed by 500 mg twice a day for 2 weeks, followed by 500 mg in the AM, 1000 mg in the PM for 2 weeks, with 1000 mg twice a day as the final dose for 20 weeks MET XR: 1000 mg Metformin XR BID for 20-24 weeks	Total of all reporting groups
Overall Participants	20	21	25	66
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	20 100%	21 100%	25 100%	66 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	20 100%	21 100%	25 100%	66 100%
Male	0 0%	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%
Not Hispanic or Latino	20 100%	21 100%	25 100%	66 100%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	6 30%	6 28.6%	10 40%	22 33.3%
White	14 70%	15 71.4%	15 60%	44 66.7%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	20 100%	21 100%	25 100%	66 100%
BMI greater than/equal to 25 (Count of Participants)
Count of Participants [Participants]	20 100%	21 100%	25 100%	66 100%

Outcome Measures

1. Primary Outcome

Title	Change in Body Weight
Description	Change in absolute body weight with combination therapy compared to monotherapy from baseline to week 24
Time Frame	Change from baseline (time 0) to study end (24 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DAPA/MET XR	Dapaglifloxin	Metformin XR
Arm/Group Description	Dapagliflozin plus metformin XR- 5 mg/1000 mg with meal for 4 weeks DAPA/MET XR- 5mg/1000 mg BID final dose for 20 weeks DAPA/MET XR: final dose- 5 mg dapagliflozin/1000 mg glucophage XR BID for 20-24 weeks	Dapagliflozin- 10 mg once daily before first meal for 24 weeks DAPA: 10 mg dapagliflozin QD for 20-24 weeks	Metformin XR with 500 mg once a day for 2 weeks, followed by 500 mg twice a day for 2 weeks, followed by 500 mg in the AM, 1000 mg in the PM for 2 weeks, with 1000 mg twice a day as the final dose for 20 weeks MET XR: 1000 mg Metformin XR BID for 20-24 weeks
Measure Participants	17	17	15
Mean (Standard Deviation) [kilograms]	-21.5 (14)	-12.5 (20)	-4.4 (18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DAPA/MET XR, Dapaglifloxin, Metformin XR
	Comments	One Way ANOVA with Bonferroni contrast if p>0.05
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.032
	Comments
	Method	ANOVA
	Comments

2. Secondary Outcome

Title	Change in Percent Body Weight
Description	Change in percent body weight with combination therapy compared to monotherapy from baseline to week 24
Time Frame	Change from baseline (time 0) to study end (24 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DAPA/MET XR	Dapaglifloxin	Metformin XR
Arm/Group Description	Dapagliflozin plus metformin XR- 5 mg/1000 mg with meal for 4 weeks DAPA/MET XR- 5mg/1000 mg BID final dose for 20 weeks DAPA/MET XR: final dose- 5 mg dapagliflozin/1000 mg glucophage XR BID for 20-24 weeks	Dapagliflozin- 10 mg once daily before first meal for 24 weeks DAPA: 10 mg dapagliflozin QD for 20-24 weeks	Metformin XR with 500 mg once a day for 2 weeks, followed by 500 mg twice a day for 2 weeks, followed by 500 mg in the AM, 1000 mg in the PM for 2 weeks, with 1000 mg twice a day as the final dose for 20 weeks MET XR: 1000 mg Metformin XR BID for 20-24 weeks
Measure Participants	17	17	15
Mean (Standard Deviation) [percent weight loss from baseline]	-4.9 (3.1)	-3.2 (4.5)	-1.1 (4.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DAPA/MET XR, Metformin XR
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANOVA
	Comments	One Way ANOVA with Bonferoni contrast test

3. Secondary Outcome

Title	Body Mass Index (BMI)
Description	BMI (measure of overall adiposity) in combination therapy compared to monotherapy after 24 weeks of treatment
Time Frame	24 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DAPA/MET XR	Dapaglifloxin	Metformin XR
Arm/Group Description	Dapagliflozin plus metformin XR- 5 mg/1000 mg with meal for 4 weeks DAPA/MET XR- 5mg/1000 mg BID final dose for 20 weeks DAPA/MET XR: final dose- 5 mg dapagliflozin/1000 mg glucophage XR BID for 20-24 weeks	Dapagliflozin- 10 mg once daily before first meal for 24 weeks DAPA: 10 mg dapagliflozin QD for 20-24 weeks	Metformin XR with 500 mg once a day for 2 weeks, followed by 500 mg twice a day for 2 weeks, followed by 500 mg in the AM, 1000 mg in the PM for 2 weeks, with 1000 mg twice a day as the final dose for 20 weeks MET XR: 1000 mg Metformin XR BID for 20-24 weeks
Measure Participants	17	17	15
Mean (Standard Deviation) [kg/m2]	33 (6.2)	33.7 (7.7)	31 (5.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DAPA/MET XR, Dapaglifloxin, Metformin XR
	Comments	Factorial repeated measures ANOVA with Bonferroni contrast test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	ANOVA
	Comments

4. Secondary Outcome

Title	Waist Circumference (WC)
Description	Waist size (measure of truncal adiposity)with combination therapy compared to monotherapy after 24 weeks of treatment
Time Frame	24 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DAPA/MET XR	Dapaglifloxin	Metformin XR
Arm/Group Description	Dapagliflozin plus metformin XR- 5 mg/1000 mg with meal for 4 weeks DAPA/MET XR- 5mg/1000 mg BID final dose for 20 weeks DAPA/MET XR: final dose- 5 mg dapagliflozin/1000 mg glucophage XR BID for 20-24 weeks	Dapagliflozin- 10 mg once daily before first meal for 24 weeks DAPA: 10 mg dapagliflozin QD for 20-24 weeks	Metformin XR with 500 mg once a day for 2 weeks, followed by 500 mg twice a day for 2 weeks, followed by 500 mg in the AM, 1000 mg in the PM for 2 weeks, with 1000 mg twice a day as the final dose for 20 weeks MET XR: 1000 mg Metformin XR BID for 20-24 weeks
Measure Participants	17	17	15
Mean (Standard Deviation) [centimeters]	95.6 (12.7)	95 (16.6)	91.7 (11.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DAPA/MET XR, Dapaglifloxin, Metformin XR
	Comments	Factorial repeated measures ANOVA with Bonferroni contrast test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.012
	Comments
	Method	ANOVA
	Comments

5. Secondary Outcome

Title	Waist- to -Hip Ratio (WHR; Measure of Central Adiposity)
Description	Waist-to-hip ratio with combination therapy compared to monotherapy after 24 weeks of treatment
Time Frame	24 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DAPA/MET XR	Dapaglifloxin	Metformin XR
Arm/Group Description	Dapagliflozin plus metformin XR- 5 mg/1000 mg with meal for 4 weeks DAPA/MET XR- 5mg/1000 mg BID final dose for 20 weeks DAPA/MET XR: final dose- 5 mg dapagliflozin/1000 mg glucophage XR BID for 20-24 weeks	Dapagliflozin- 10 mg once daily before first meal for 24 weeks DAPA: 10 mg dapagliflozin QD for 20-24 weeks	Metformin XR with 500 mg once a day for 2 weeks, followed by 500 mg twice a day for 2 weeks, followed by 500 mg in the AM, 1000 mg in the PM for 2 weeks, with 1000 mg twice a day as the final dose for 20 weeks MET XR: 1000 mg Metformin XR BID for 20-24 weeks
Measure Participants	17	17	15
Mean (Standard Deviation) [Ratio]	0.81 (0.055)	0.80 (.06)	0.83 (.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DAPA/MET XR, Dapaglifloxin, Metformin XR
	Comments	Factorial repeated measures ANOVA with Bonferroni contrast test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	ANOVA
	Comments

6. Secondary Outcome

Title	Waist-to-height Ratio (WHtR)
Description	Waist divided by height a( measure of central adiposity) with combination therapy compared to monotherapy after 24 weeks of therapy
Time Frame	24 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DAPA/MET XR	Dapaglifloxin	Metformin XR
Arm/Group Description	Dapagliflozin plus metformin XR- 5 mg/1000 mg with meal for 4 weeks DAPA/MET XR- 5mg/1000 mg BID final dose for 20 weeks DAPA/MET XR: final dose- 5 mg dapagliflozin/1000 mg glucophage XR BID for 20-24 weeks	Dapagliflozin- 10 mg once daily before first meal for 24 weeks DAPA: 10 mg dapagliflozin QD for 20-24 weeks	Metformin XR with 500 mg once a day for 2 weeks, followed by 500 mg twice a day for 2 weeks, followed by 500 mg in the AM, 1000 mg in the PM for 2 weeks, with 1000 mg twice a day as the final dose for 20 weeks MET XR: 1000 mg Metformin XR BID for 20-24 weeks
Measure Participants	17	17	15
Mean (Standard Deviation) [ratio]	0.58 (.06)	0.57 (.09)	0.56 (.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DAPA/MET XR, Dapaglifloxin, Metformin XR
	Comments	Factorial repeated measures ANOVA with Bonferroni contrast
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.023
	Comments
	Method	ANOVA
	Comments

7. Secondary Outcome

Title	Diastolic Blood Pressure (DBP)
Description	Diastolic blood pressure with combination therapy compared to monotherapy after 24 weeks of treatment
Time Frame	24 weeks of treatment)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DAPA/MET XR	Dapaglifloxin	Metformin XR
Arm/Group Description	Dapagliflozin plus metformin XR- 5 mg/1000 mg with meal for 4 weeks DAPA/MET XR- 5mg/1000 mg BID final dose for 20 weeks DAPA/MET XR: final dose- 5 mg dapagliflozin/1000 mg glucophage XR BID for 20-24 weeks	Dapagliflozin- 10 mg once daily before first meal for 24 weeks DAPA: 10 mg dapagliflozin QD for 20-24 weeks	Metformin XR with 500 mg once a day for 2 weeks, followed by 500 mg twice a day for 2 weeks, followed by 500 mg in the AM, 1000 mg in the PM for 2 weeks, with 1000 mg twice a day as the final dose for 20 weeks MET XR: 1000 mg Metformin XR BID for 20-24 weeks
Measure Participants	17	17	15
Mean (Standard Deviation) [mmHG]	79 (11)	77.8 (11)	79 (7.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DAPA/MET XR, Dapaglifloxin, Metformin XR
	Comments	Factorial repeated measures ANOVA with Bonferroni contrast
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	ANOVA
	Comments

8. Secondary Outcome

Title	Systolic Blood Pressure (SBP)
Description	Systolic blood pressure with combination therapy compared to monotherapy after 24 weeks of therapy
Time Frame	24 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DAPA/MET XR	Dapaglifloxin	Metformin XR
Arm/Group Description	Dapagliflozin plus metformin XR- 5 mg/1000 mg with meal for 4 weeks DAPA/MET XR- 5mg/1000 mg BID final dose for 20 weeks DAPA/MET XR: final dose- 5 mg dapagliflozin/1000 mg glucophage XR BID for 20-24 weeks	Dapagliflozin- 10 mg once daily before first meal for 24 weeks DAPA: 10 mg dapagliflozin QD for 20-24 weeks	Metformin XR with 500 mg once a day for 2 weeks, followed by 500 mg twice a day for 2 weeks, followed by 500 mg in the AM, 1000 mg in the PM for 2 weeks, with 1000 mg twice a day as the final dose for 20 weeks MET XR: 1000 mg Metformin XR BID for 20-24 weeks
Measure Participants	17	17	15
Mean (Standard Deviation) [mmHg]	125 (12)	124 (13)	119.6 (10.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DAPA/MET XR, Dapaglifloxin, Metformin XR
	Comments	Factorial repeated measures ANOVA with Bonferroni contrast
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	ANOVA
	Comments

9. Secondary Outcome

Title	Liver Enzymes
Description	ALT/AST ratio with combination therapy compared to monotherapy after 24 weeks of treatment
Time Frame	24 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DAPA/MET XR	Dapaglifloxin	Metformin XR
Arm/Group Description	Dapagliflozin plus metformin XR- 5 mg/1000 mg with meal for 4 weeks DAPA/MET XR- 5mg/1000 mg BID final dose for 20 weeks DAPA/MET XR: final dose- 5 mg dapagliflozin/1000 mg glucophage XR BID for 20-24 weeks	Dapagliflozin- 10 mg once daily before first meal for 24 weeks DAPA: 10 mg dapagliflozin QD for 20-24 weeks	Metformin XR with 500 mg once a day for 2 weeks, followed by 500 mg twice a day for 2 weeks, followed by 500 mg in the AM, 1000 mg in the PM for 2 weeks, with 1000 mg twice a day as the final dose for 20 weeks MET XR: 1000 mg Metformin XR BID for 20-24 weeks
Measure Participants	17	17	15
Mean (Standard Deviation) [Ratio]	1.13 (.35)	1.12 (.32)	1.18 (.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DAPA/MET XR, Dapaglifloxin, Metformin XR
	Comments	Factorial repeated measures ANOVA with Bonferroni contrast
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANOVA
	Comments

10. Secondary Outcome

Title	Total Cholesterol Levels (CHOL)
Description	Cholesterol levels with combination therapy compared to monotherapy after 24 weeks of treatment
Time Frame	24 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DAPA/MET XR	Dapaglifloxin	Metformin XR
Arm/Group Description	Dapagliflozin plus metformin XR- 5 mg/1000 mg with meal for 4 weeks DAPA/MET XR- 5mg/1000 mg BID final dose for 20 weeks DAPA/MET XR: final dose- 5 mg dapagliflozin/1000 mg glucophage XR BID for 20-24 weeks	Dapagliflozin- 10 mg once daily before first meal for 24 weeks DAPA: 10 mg dapagliflozin QD for 20-24 weeks	Metformin XR with 500 mg once a day for 2 weeks, followed by 500 mg twice a day for 2 weeks, followed by 500 mg in the AM, 1000 mg in the PM for 2 weeks, with 1000 mg twice a day as the final dose for 20 weeks MET XR: 1000 mg Metformin XR BID for 20-24 weeks
Measure Participants	17	17	15
Mean (Standard Deviation) [mg/dL]	196 (45)	168 (32)	178 (31)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DAPA/MET XR, Dapaglifloxin, Metformin XR
	Comments	Factorial repeated measures ANOVA with Bonferroni contrast test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANOVA
	Comments

11. Secondary Outcome

Title	Triglyceride (TRG) Levels
Description	Triglyceride levels with combination therapy compared to monotherapy after 24 weeks of treatment
Time Frame	24 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DAPA/MET XR	Dapaglifloxin	Metformin XR
Arm/Group Description	Dapagliflozin plus metformin XR- 5 mg/1000 mg with meal for 4 weeks DAPA/MET XR- 5mg/1000 mg BID final dose for 20 weeks DAPA/MET XR: final dose- 5 mg dapagliflozin/1000 mg glucophage XR BID for 20-24 weeks	Dapagliflozin- 10 mg once daily before first meal for 24 weeks DAPA: 10 mg dapagliflozin QD for 20-24 weeks	Metformin XR with 500 mg once a day for 2 weeks, followed by 500 mg twice a day for 2 weeks, followed by 500 mg in the AM, 1000 mg in the PM for 2 weeks, with 1000 mg twice a day as the final dose for 20 weeks MET XR: 1000 mg Metformin XR BID for 20-24 weeks
Measure Participants	17	17	15
Mean (Standard Deviation) [mg/dL]	119 (59)	89.8 (39)	212 (64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DAPA/MET XR, Dapaglifloxin, Metformin XR
	Comments	Factorial repeated measures ANOVA with Bonferroni contrast test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.004
	Comments
	Method	ANOVA
	Comments

12. Secondary Outcome

Title	Fasting Blood Glucose (FBG)
Description	Fasting blood glucose levels with combination therapy compared to monotherapy after 24 weeks of treatment
Time Frame	24 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DAPA/MET XR	Dapaglifloxin	Metformin XR
Arm/Group Description	Dapagliflozin plus metformin XR- 5 mg/1000 mg with meal for 4 weeks DAPA/MET XR- 5mg/1000 mg BID final dose for 20 weeks DAPA/MET XR: final dose- 5 mg dapagliflozin/1000 mg glucophage XR BID for 20-24 weeks	Dapagliflozin- 10 mg once daily before first meal for 24 weeks DAPA: 10 mg dapagliflozin QD for 20-24 weeks	Metformin XR with 500 mg once a day for 2 weeks, followed by 500 mg twice a day for 2 weeks, followed by 500 mg in the AM, 1000 mg in the PM for 2 weeks, with 1000 mg twice a day as the final dose for 20 weeks MET XR: 1000 mg Metformin XR BID for 20-24 weeks
Measure Participants	17	17	15
Mean (Standard Deviation) [mg/dL]	89 (7.9)	91 (9.2)	87 (4.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DAPA/MET XR, Dapaglifloxin, Metformin XR
	Comments	Factorial repeated measures ANOVA with Bonferroni contrast test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.02
	Comments
	Method	ANOVA
	Comments

13. Secondary Outcome

Title	Mean Blood Glucose (MBG) During an OGTT
Description	Mean blood glucose after glucose load with combination therapy compared to monotherapy after 24 weeks of treatment
Time Frame	24 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DAPA/MET XR	Dapaglifloxin	Metformin XR
Arm/Group Description	Dapagliflozin plus metformin XR- 5 mg/1000 mg with meal for 4 weeks DAPA/MET XR- 5mg/1000 mg BID final dose for 20 weeks DAPA/MET XR: final dose- 5 mg dapagliflozin/1000 mg glucophage XR BID for 20-24 weeks	Dapagliflozin- 10 mg once daily before first meal for 24 weeks DAPA: 10 mg dapagliflozin QD for 20-24 weeks	Metformin XR with 500 mg once a day for 2 weeks, followed by 500 mg twice a day for 2 weeks, followed by 500 mg in the AM, 1000 mg in the PM for 2 weeks, with 1000 mg twice a day as the final dose for 20 weeks MET XR: 1000 mg Metformin XR BID for 20-24 weeks
Measure Participants	17	17	15
Mean (Standard Deviation) [mg/dL]	109.5 (15.2)	110.1 (17.8)	112.5 (15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DAPA/MET XR, Dapaglifloxin, Metformin XR
	Comments	Factorial repeated measures ANOVA with Bonferroni contrast test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.012
	Comments
	Method	ANOVA
	Comments

14. Secondary Outcome

Title	Fasting Insulin Sensitivity (HOMA-IR)
Description	HOMA index of insulin resistance calculated from fasting insulin and glucose with combination therapy compared to monotherapy after 24 weeks of treatment
Time Frame	24 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DAPA/MET XR	Dapaglifloxin	Metformin XR
Arm/Group Description	Dapagliflozin plus metformin XR- 5 mg/1000 mg with meal for 4 weeks DAPA/MET XR- 5mg/1000 mg BID final dose for 20 weeks DAPA/MET XR: final dose- 5 mg dapagliflozin/1000 mg glucophage XR BID for 20-24 weeks	Dapagliflozin- 10 mg once daily before first meal for 24 weeks DAPA: 10 mg dapagliflozin QD for 20-24 weeks	Metformin XR with 500 mg once a day for 2 weeks, followed by 500 mg twice a day for 2 weeks, followed by 500 mg in the AM, 1000 mg in the PM for 2 weeks, with 1000 mg twice a day as the final dose for 20 weeks MET XR: 1000 mg Metformin XR BID for 20-24 weeks
Measure Participants	17	17	15
Mean (Standard Deviation) [Index]	2.6 (1.6)	2.4 (1.4)	1.8 (0.84)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DAPA/MET XR, Dapaglifloxin, Metformin XR
	Comments	Factorial repeated measures ANOVA with Bonferroni contrast test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	ANOVA
	Comments

15. Secondary Outcome

Title	Matsuda Sensitivity Index (SI OGTT)
Description	Surrogate measure of insulin sensitivity derived from OGTT with combination therapy compared to monotherapy after 24 weeks of treatment
Time Frame	24 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DAPA/MET XR	Dapaglifloxin	Metformin XR
Arm/Group Description	Dapagliflozin plus metformin XR- 5 mg/1000 mg with meal for 4 weeks DAPA/MET XR- 5mg/1000 mg BID final dose for 20 weeks DAPA/MET XR: final dose- 5 mg dapagliflozin/1000 mg glucophage XR BID for 20-24 weeks	Dapagliflozin- 10 mg once daily before first meal for 24 weeks DAPA: 10 mg dapagliflozin QD for 20-24 weeks	Metformin XR with 500 mg once a day for 2 weeks, followed by 500 mg twice a day for 2 weeks, followed by 500 mg in the AM, 1000 mg in the PM for 2 weeks, with 1000 mg twice a day as the final dose for 20 weeks MET XR: 1000 mg Metformin XR BID for 20-24 weeks
Measure Participants	17	17	15
Mean (Standard Deviation) [Index]	6.0 (3.2)	6.3 (4.4)	5.42 (2.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DAPA/MET XR, Dapaglifloxin, Metformin XR
	Comments	Factorial repeated measures ANOVA with Bonferroni contrast test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.028
	Comments
	Method	ANOVA
	Comments

16. Secondary Outcome

Title	First Phase Insulin Secretion (IGI/HOMA-IR)
Description	Corrected early insulin response to glucose challenge [(insulinogenic index (IGI)/ divided by fasting insulin resistance index (HOMA-IR)] with combination therapy compared to monotherapy after 24 weeks of treatment
Time Frame	24 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DAPA/MET XR	Dapaglifloxin	Metformin XR
Arm/Group Description	Dapagliflozin plus metformin XR- 5 mg/1000 mg with meal for 4 weeks DAPA/MET XR- 5mg/1000 mg BID final dose for 20 weeks DAPA/MET XR: final dose- 5 mg dapagliflozin/1000 mg glucophage XR BID for 20-24 weeks	Dapagliflozin- 10 mg once daily before first meal for 24 weeks DAPA: 10 mg dapagliflozin QD for 20-24 weeks	Metformin XR with 500 mg once a day for 2 weeks, followed by 500 mg twice a day for 2 weeks, followed by 500 mg in the AM, 1000 mg in the PM for 2 weeks, with 1000 mg twice a day as the final dose for 20 weeks MET XR: 1000 mg Metformin XR BID for 20-24 weeks
Measure Participants	17	17	15
Mean (Standard Deviation) [Index]	1.7 (3.2)	1.1 (1.2)	0.77 (.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DAPA/MET XR, Dapaglifloxin, Metformin XR
	Comments	Factorial repeated measures ANOVA with Bonferroni contrast test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.03
	Comments
	Method	ANOVA
	Comments

Adverse Events

Time Frame	6 months while participating in trial
Arm/Group Title	DAPA/MET XR		Dapaglifloxin		Metformin XR
Arm/Group Description	Dapagliflozin plus metformin XR- 5 mg/1000 mg with meal for 4 weeks DAPA/MET XR- 5mg/1000 mg BID final dose for 20 weeks DAPA/MET XR: final dose- 5 mg dapagliflozin/1000 mg glucophage XR BID for 20-24 weeks		Dapagliflozin- 10 mg once daily before first meal for 24 weeks DAPA: 10 mg dapagliflozin QD for 20-24 weeks		Metformin XR with 500 mg once a day for 2 weeks, followed by 500 mg twice a day for 2 weeks, followed by 500 mg in the AM, 1000 mg in the PM for 2 weeks, with 1000 mg twice a day as the final dose for 20 weeks MET XR: 1000 mg Metformin XR BID for 20-24 weeks
All Cause Mortality
	DAPA/MET XR		Dapaglifloxin		Metformin XR
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/21 (0%)		0/25 (0%)
Serious Adverse Events
	DAPA/MET XR		Dapaglifloxin		Metformin XR
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/21 (0%)		0/25 (0%)
Other (Not Including Serious) Adverse Events
	DAPA/MET XR		Dapaglifloxin		Metformin XR
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/20 (30%)		6/21 (28.6%)		5/25 (20%)
Gastrointestinal disorders
Nausea/diarrhea	1/20 (5%)	1	0/21 (0%)	0	5/25 (20%)	5
Renal and urinary disorders
Yeast infection	5/20 (25%)	5	6/21 (28.6%)	6	0/25 (0%)	0

Limitations/Caveats

Important limitations were the small number completed patients per drug group and only 24 weeks of therapy. Surrogate measures were for central adiposity; use of dual-energy x-ray absorptiometry to measure body composition would increase accuracy

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.