A Phase III Study of BMS-512148 (Dapagliflozin) in Patients With Type 2 Diabetes Who Are Not Well Controlled on Metformin Alone

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00528879
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 915
• Locations: 75
• Arms: 4
• Duration (Months): 32
• Patients Per Site: 12.2
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this clinical research study is to learn whether dapagliflozin can help reduce blood sugar levels in participants with Type 2 diabetes that is not well controlled on metformin alone. The safety of this treatment will also be studied.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes	Drug: Dapagliflozin; Drug: Placebo; Drug: Metformin	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 915 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Phase 3 Trial to Evaluate the Safety and Efficacy of Dapagliflozin in Combination With Metformin in Subjects With Type 2 Diabetes Who Have Inadequate Glycemic Control on Metformin Alone
• Study Start Date: Sep 1, 2007
• Actual Primary Completion Date: Nov 1, 2008
• Actual Study Completion Date: May 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo + Metformin Participants received dapagliflozin-matching placebo once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Drug: Placebo; Dapagliflozin-matching placebo administered as tablets orally once daily for up to 102 weeks; Drug: Metformin; Open-label metformin administered as ≥1500 mg per day for up to 102 weeks
Experimental: Dapagliflozin, 2.5 mg + Metformin Participants received dapagliflozin, 2.5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Drug: Dapagliflozin; Tablets administered orally as a 2.5-, 5-, or 10-mg dose once daily for up to 102 weeks; Other Names: BMS-512148 ; Drug: Metformin; Open-label metformin administered as ≥1500 mg per day for up to 102 weeks
Experimental: Dapagliflozin, 5 mg + Metformin Participants received dapagliflozin, 5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Drug: Dapagliflozin; Tablets administered orally as a 2.5-, 5-, or 10-mg dose once daily for up to 102 weeks; Other Names: BMS-512148 ; Drug: Metformin; Open-label metformin administered as ≥1500 mg per day for up to 102 weeks
Experimental: Dapagliflozin, 10 mg + Metformin Participants received dapagliflozin, 10 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Drug: Dapagliflozin; Tablets administered orally as a 2.5-, 5-, or 10-mg dose once daily for up to 102 weeks; Other Names: BMS-512148 ; Drug: Placebo; Dapagliflozin-matching placebo administered as tablets orally once daily for up to 102 weeks; Drug: Metformin; Open-label metformin administered as ≥1500 mg per day for up to 102 weeks

Outcome Measures

Primary Outcome Measures

1. Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF]) [From Baseline to Week 24]

   HbA1c was measured as percent of hemoglobin by a central laboratory. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. HbA1c measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 4, 8, 12, 16, 20, and 24 in the double-blind period.

Secondary Outcome Measures

1. Adjusted Mean Change From Baseline in Fasting Plasma Glucose at Week 24 (Last Observation Carried Forward [LOCF]) [From Baseline to Week 24]

   Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Data after rescue medication was excluded from this analysis. Fasting plasma glucose was measured as milligrams per deciliter (mg/dL) by a central laboratory. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication.

2. Adjusted Mean Change From Baseline in Total Body Weight at Week 24 (Last Observation Carried Forward [LOCF]) [From Baseline to Week 24]

   Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Adjusted mean change from baseline in total body weight at Week 24 (or the last postbaseline measurement prior to Week 24 if no Week 24 assessment was available was determined. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Body weight measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 of the double-blind period.

3. Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) [From Baseline to Week 24]

   Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Percent adjusted for baseline HbA1c. Therapeutic glycemic response is defined as HbA1c <7.0%. Data after rescue medication was excluded from this analysis. HbA1c was measured as a percent of hemoglobin.

4. Adjusted Mean Change From Baseline in Hemoglobin A1c (HbA1c) in Participants With Baseline HbA1c ≥9.0% at Week 24 (Last Observation Carried Forward [LOCF]) [From Baseline to Week 24]

   Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. HbA1c was measured as percent of hemoglobin by a central laboratory. The population included those randomized participants who received treatment and had a baseline HbA1c > 9.0%. Data after rescue medication were excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication.

5. Adjusted Mean Change From Baseline in Total Body Weight at Week 24 in Participants With Baseline Body Mass Index (BMI) ≥27 kg/m^2 (Last Observation Carried Forward [LOCF]) [From Baseline to Week 24]

   Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Adjusted mean change from baseline in total body weight at Week 24 (or the last postbaseline measurement prior to Week 24 if no Week 24 assessment was available was determined.) Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Body weight measurements were obtained during the qualification and lead-in Periods and on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 of the double-blind period.

6. Adjusted Mean Change From Baseline in Hemoglobin A1c (HbA1c) in Participants With Baseline Body Mass Index (BMI) ≥27 kg/m^2 at Week 24 (Last Observation Carried Forward [LOCF]) [From Baseline to Week 24]

   Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Adjusted for baseline HbA1c. HbA1c was measured as percent of hemoglobin by a central laboratory. Data after rescue medication were excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication.

7. Adjusted Mean Change From Baseline in Fasting Plasma Glucose at Week 1 (Last Observation Carried Forward [LOCF]) [From Baseline to Week 1]

   Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Data after rescue medication was excluded from this analysis. Fasting plasma glucose was measured by a central laboratory. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication.

8. Adjusted Percentage of Participants Achieving Hemoglobin A1c (HbA1C) ≤6.5% at Week 24 (Last Observation Carried Forward [LOCF]) [From Baseline to Week 24]

   Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Percent adjusted for baseline HbA1c. Data after rescue medication was excluded from this analysis. HbA1c was measured as a percent of hemoglobin.

Other Outcome Measures

1. Number of Participants With Adverse Events (AEs), Hypoglycemia Events, Related AEs, Death as Outcome, Serious AEs (SAEs), Related SAEs, SAEs Leading to Discontinuation, AEs Leading to Discontinuation, and Hypoglycemia Events Leading to Discontinuation [From Baseline to end of Long-term Period (Week 102)]

   AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related=having certain, probable, possible, or missing relationship to study drug. Events captured from baseline to last dose plus 4 days for AEs and plus 30 days for SAEs during the double-blind 12-week period. Data after rescue included.

2. Number of Participants With Laboratory Test Results Meeting the Criteria for Laboratory Abnormality [Day 1 to Week 102]

   BUN=blood urea nitrogen; preRX=pretreatment; ULN=upper limit of normal; AST=aspartate aminotransferase; ALT=alanine aminotransferase; ALP=alkaline phosphatase. Phosphorus, inorganic (low): ages 17-65 years, ≤1.8 mg/dL; ages≥66 years, ≤2.1 mg/dL. Phosphorus, inorganic (high): ages 17-65 years, ≥5.6 mg/dL; ages≥66 years, ≥5.6 mg/dL. Phosphorus, inorganic (low) ≤1.8 mg/dL if age 17-65 or ≤2.1 mg/dL if age ≥66. Calcium, total (high): ≥1 mg/dL from ULN and ≥0.5 mg/dL from preRx value.

3. Number of Participants With Changes in Baseline in Electrocardiogram Findings at Week 102 (Last Observation Carried Forward [LOCF]) [Baseline to Week 102]

   12-Lead electrocardiograms (ECGs) were performed at entry into lead-in period Day -7 visit and Week 24/dnd of treatment visit (LOCF) on participants who were supine. ECGs were assessed by the investigator. Baseline was Day -7 for this parameter. Data after rescue included.The Week 102 value is the last observation, regardless of rescue prior to Week 102 if no Week 102 measurement was available.

4. Mean Changes From Baseline in Seated Systolic Blood Pressure [From Baseline to Week 102]

   Blood pressure values were obtained after the participant was seated quietly for 5 minutes; at least 8 hours after the last ingestion of caffeine, alcohol, or nicotine; and in the same arm (right or left) consistently through out the study. Data after rescue were also included. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication.

5. Mean Changes From Baseline in Seated Diastolic Blood Pressure [From Baseline to Week 102]

   Blood pressure values were obtained after the participant was seated quietly for 5 minutes; at least 8 hours after the last ingestion of caffeine, alcohol, or nicotine; and in the same arm (right or left) consistently through out the study. Data after rescue were also included. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication.

6. Number of Participants With Orthostatic Hypotension [From Baseline to Week 102]

   Orthostatic hypotension was defined as a decrease from supine to standing blood pressure of >20 mm Hg in systolic blood pressure or >10 mm Hg in diastolic blood pressure.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 77 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria

• Males and females, 18 to 77 years old, with type 2 diabetes and inadequate glycemic control

• Participants who have been receiving metformin at a total daily dose ≥1500 mg per day for at least 8 weeks

• C-peptide ≥1.0 ng/mL

• Body mass index ≤45.0 kg/m^2

• Serum creatinine level <1.50 mg/dL for men or <1.40 mg/dL for women.

Key Exclusion Criteria

• Aspartate aminotransferase and/or alanine aminotransferase level >3.0 times the upper limit of normal

• Serum total bilirubin level >2 mg/dL

• Creatinine kinase level >3 times upper limit of normal

• Symptoms of severely uncontrolled diabetes

• Serum creatinine level ≥1.50 mg/dL for men or ≥1.40 mg/dL for women

• Currently unstable or serious cardiovascular, renal, hepatic, hematologic, oncologic, endocrine, psychiatric, or rheumatic diseases

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinical Research Advantage / Desert Clinical Res, Llc	Tempe	Arizona	United States	85282
2	Medical Group Of Encino	Encino	California	United States	91436
3	Valley Research	Fresno	California	United States	93720
4	Randall Shue, D.O.	Los Angeles	California	United States	90023
5	Diabetes Medical Center Of California	Northridge	California	United States	91325
6	Ritchken & First M.D.'S	San Diego	California	United States	92117
7	Encompass Clinical Research	Spring Valley	California	United States	91978
8	Raikhel, Marina	Torrance	California	United States	90505
9	Express Care Clinical Res	Colorado Springs	Colorado	United States	80909
10	Denver Internal Medicine	Denver	Colorado	United States	80209
11	New West Physicians	Golden	Colorado	United States	80401
12	Central Florida Clinical Trials, Inc.	Altamonte Springs	Florida	United States	32701
13	Family Care Associates Of Nw Florida	Chipley	Florida	United States	32428
14	Health Partners Research Foundation	Minneapolis	Minnesota	United States	56440
15	Woodlake Research	Chesterfield	Missouri	United States	63017
16	Nevada Alliance Against Diabetes	Las Vegas	Nevada	United States	89101
17	Diabetes & Endocrinology Consultants, Pc	Morehead City	North Carolina	United States	28557
18	Newark Physician Associates	Newark	Ohio	United States	43055
19	Integris Family Care S. Penn	Oklahoma City	Oklahoma	United States	73159
20	Cumberland Valley Endocrinology Center, Llc	Carlisle	Pennsylvania	United States	17013
21	Banksville Medical Pc	Pittsburgh	Pennsylvania	United States	15216
22	Palmetto Clinical Research	Summerville	South Carolina	United States	29485
23	Southeastern Research Assoc	Taylors	South Carolina	United States	29687
24	Texas Center For Drug Development, P.A.	Houston	Texas	United States	77081
25	Diabetes & Glandular Disease Research Associates, Inc.	San Antonio	Texas	United States	78229
26	S.A.M. Clinical Research Center	San Antonio	Texas	United States	78229
27	Optimum Clinical Research	Salt Lake City	Utah	United States	84102
28	Office Of Dr. Gray	Spokane	Washington	United States	99216
29	Local Institution	Capital Federal	Buenos Aires	Argentina	1034
30	Local Institution	Capital Federal	Buenos Aires	Argentina	1429
31	Local Institution	Capital Federal	Buenos Aires	Argentina	C1056ABJ
32	Local Institution	Capital Federal	Buenos Aires	Argentina	C1425AGC
33	Local Institution	Ciudad Auton.	Buenos Aires	Argentina	C1505CWB
34	Local Institution	Ciudad Auton	Buenos Aires	Argentina	C1408INH
35	Local Institution	Mar Del Plata	Buenos Aires	Argentina	7600
36	Local Institution	Zarate	Buenos Aires	Argentina	2800
37	Local Institution	Villa Carlos Paz	Cordoba	Argentina	5152
38	Local Institution	Buenos Aires		Argentina	1431
39	Local Institution	Cordoba		Argentina	5000
40	Local Institution	Fortaleza	Ceara	Brazil	60021
41	Local Institution	Itajuba	Minas Gerais	Brazil	37502
42	Local Institution	Belem	Para	Brazil	66073
43	Local Institution	Caxias Do Sul	Rio Grande Do Sul	Brazil	95070
44	Local Institution	Porto Alegre	Rio Grande Do Sul	Brazil	90020090
45	Local Institution	Porto Alegre	Rio Grande Do Sul	Brazil	90035
46	Local Institution	Marilia	Sao Paulo	Brazil	17519
47	Local Institution	Rio De Janeiro		Brazil	20211
48	Local Institution	Calgary	Alberta	Canada	T2R 0X7
49	Local Institution	Kelowna	British Columbia	Canada	V1Y 2H4
50	Local Institution	Winnipeg	Manitoba	Canada	R3E 3P4
51	Local Institution	Bathurst	New Brunswick	Canada	E2A 4X7
52	Local Institution	Mount Pearl	Newfoundland and Labrador	Canada	A1N 1W7
53	Local Institution	St-John	Newfoundland and Labrador	Canada	A1E 2E2
54	Local Institution	Sarnia	Ontario	Canada	N7T 4X3
55	Local Institution	Thornhill	Ontario	Canada	L4J 8L7
56	Local Institution	Toronto	Ontario	Canada	M4R 2G4
57	Local Institution	Toronto	Ontario	Canada	M9W 4L6
58	Local Institution	Charlottetown	Prince Edward Island	Canada	C1A 5Y9
59	Local Institution	Drummondville	Quebec	Canada	J2B 7T1
60	Local Institution	Granby	Quebec	Canada	J2G 8Z9
61	Local Institution	L'Ancienne Lorette	Quebec	Canada	G2E 2X1
62	Local Institution	Mirabel	Quebec	Canada	J7J 2K8
63	Local Institution	St-Leonard	Quebec	Canada	H1S 3A9
64	Local Institution	Saskatoon	Saskatchewan	Canada	S7K 3H3
65	Local Institution	Saskatoon	Saskatchewan	Canada	S7K 7H9
66	Local Institution	Df	Distrito Federal	Mexico	11800
67	Local Institution	Guadalajara	Distrito Federal	Mexico	44670
68	Local Institution	Zapopan	Distrito Federal	Mexico	45150
69	Local Institution	Guadalajara	Jalisco	Mexico	44650
70	Local Institution	Guadalajara	Jalisco	Mexico	44670
71	Local Institution	Monterrey	Nuevo Leon	Mexico	64460
72	Local Institution	Monterrey	Nuevo Leon	Mexico	64710
73	Local Institution	Monterrrey	Nuevo Leon	Mexico	64700
74	Local Institution	Tampico	Tamaulipas	Mexico	89109
75	Local Institution	Durango		Mexico	64710

Sponsors and Collaborators

• AstraZeneca
• Bristol-Myers Squibb

Investigators

• Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT00528879
• Other Study ID Numbers: MB102-014 LT; MB102-014
• First Posted: Sep 12, 2007
• Last Update Posted: Oct 20, 2015
• Last Verified: Sep 1, 2015

• Keywords provided by AstraZeneca: Diabetes Mellitus, Type 2; Diabetes Mellitus; Endocrine System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Metformin; Hypoglycemic Agents; Pharmacologic Actions; Physiological Effects of Drugs
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Metformin; Dapagliflozin

Study Results

Participant Flow

Pre-assignment Detail	Of 915 participants enrolled, 562 completed a qualification period. Of these 562 participants, 546 were randomized and received treatment and 16 were excluded due to adverse events (1), no longer meeting study criteria (7), poor compliance or noncompliance (3), withdrawn consent (4), and lost to follow-up (1).

Arm/Group Title	Placebo + Metformin	Dapagliflozin, 2.5 mg + Metformin	Dapagliflozin, 5 mg + Metformin	Dapagliflozin, 10 mg + Metformin
Arm/Group Description	Participants received dapagliflozin-matching placebo once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 2.5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 10 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks
Period Title: Short-term Period (Day 1 to Week 24)
STARTED	137	137	137	135
Completed the Period	119	121	122	121
COMPLETED	115	120	122	119
NOT COMPLETED	22	17	15	16
Period Title: Short-term Period (Day 1 to Week 24)
STARTED	115	120	122	119
COMPLETED	73	82	89	95
NOT COMPLETED	42	38	33	24

Baseline Characteristics

Arm/Group Title	Placebo + Metformin	Dapagliflozin, 2.5 mg + Metformin	Dapagliflozin, 5 mg + Metformin	Dapagliflozin, 10 mg + Metformin	Total
Arm/Group Description	Participants received dapagliflozin-matching placebo once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 2.5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 10 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Total of all reporting groups
Overall Participants	137	137	137	135	546
Age (Years) [Mean (Full Range) ]
Mean (Full Range) [Years]	53.7	55.0	54.3	52.7	53.9
Age, Customized (Number) [Number]
Younger than 65 years	114 83.2%	116 84.7%	119 86.9%	118 87.4%	467 85.5%
65 to younger than 75 years	23 16.8%	19 13.9%	17 12.4%	16 11.9%	75 13.7%
75 years and older	0 0%	2 1.5%	1 0.7%	1 0.7%	4 0.7%
Sex: Female, Male (Count of Participants)
Female	61 44.5%	67 48.9%	68 49.6%	58 43%	254 46.5%
Male	76 55.5%	70 51.1%	69 50.4%	77 57%	292 53.5%
Race/Ethnicity, Customized (Number) [Number]
White	124 90.5%	117 85.4%	118 86.1%	121 89.6%	480 87.9%
Black/African American	2 1.5%	5 3.6%	6 4.4%	4 3%	17 3.1%
Asian	3 2.2%	3 2.2%	4 2.9%	1 0.7%	11 2%
Native Hawaiian/Other Pacific Islander	0 0%	0 0%	1 0.7%	0 0%	1 0.2%
American Indian/Alaskan Native	1 0.7%	2 1.5%	2 1.5%	4 3%	9 1.6%
Other	7 5.1%	10 7.3%	6 4.4%	5 3.7%	28 5.1%
Female Age (Number) [Number]
50 Years and younger	25 18.2%	18 13.1%	22 16.1%	22 16.3%	87 15.9%
Older than 50 years	36 26.3%	49 35.8%	46 33.6%	36 26.7%	167 30.6%
Body Mass Index (Number) [Number]
<25 kg/m^2	9 6.6%	4 2.9%	12 8.8%	12 8.9%	37 6.8%
≥25 kg/m^2	128 93.4%	133 97.1%	125 91.2%	123 91.1%	509 93.2%
≥27 kg/m^2	115 83.9%	120 87.6%	111 81%	106 78.5%	452 82.8%
≥30 kg/m^2	79 57.7%	77 56.2%	81 59.1%	75 55.6%	312 57.1%

Outcome Measures

1. Primary Outcome

Title	Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF])
Description	HbA1c was measured as percent of hemoglobin by a central laboratory. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. HbA1c measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 4, 8, 12, 16, 20, and 24 in the double-blind period.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants who received study medication and had nonmissing HbA1c values at baseline and Week 24 (LOCF)

Arm/Group Title	Placebo + Metformin	Dapagliflozin, 2.5 mg + Metformin	Dapagliflozin, 5 mg + Metformin	Dapagliflozin, 10 mg + Metformin
Arm/Group Description	Participants received dapagliflozin-matching placebo once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 2.5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 10 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks
Measure Participants	134	135	133	132
Mean (Standard Error) [Percent]	-0.30 (0.0718)	-0.67 (0.0715)	-0.70 (0.0722)	-0.84 (0.0724)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 2.5 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	Tested at alpha=0.019, applying the Dunnett adjustment
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.38
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1014
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 5 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Tested at alpha=0.019, applying the Dunnett adjustment
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.41
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1016
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 10 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Tested at alpha=0.019, applying the Dunnett adjustment
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.54
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1021
	Estimation Comments

2. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Fasting Plasma Glucose at Week 24 (Last Observation Carried Forward [LOCF])
Description	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Data after rescue medication was excluded from this analysis. Fasting plasma glucose was measured as milligrams per deciliter (mg/dL) by a central laboratory. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants who received study medication and who had nonmissing fasting plasma glucose values at baseline and Week 24 (LOCF)

Arm/Group Title	Placebo + Metformin	Dapagliflozin, 2.5 mg + Metformin	Dapagliflozin, 5 mg + Metformin	Dapagliflozin, 10 mg + Metformin
Arm/Group Description	Participants received dapagliflozin-matching placebo once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 2.5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 10 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks
Measure Participants	136	137	136	132
Mean (Standard Error) [mg/dL]	-6.0 (2.673)	-17.8 (2.663)	-21.5 (2.679)	-23.5 (2.721)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 2.5 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0019
	Comments	Statistically significant according to hierarchical testing procedure (p<0.05).
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-11.8
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.774
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 5 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Statistically significant according to hierarchical testing procedure (p<0.05).
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-15.5
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.781
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 10 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Statistically significant according to hierarchical testing procedure (p<0.05).
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-17.5
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.819
	Estimation Comments

3. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Total Body Weight at Week 24 (Last Observation Carried Forward [LOCF])
Description	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Adjusted mean change from baseline in total body weight at Week 24 (or the last postbaseline measurement prior to Week 24 if no Week 24 assessment was available was determined. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Body weight measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 of the double-blind period.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants who received study medication and had nonmissing total body weights at baseline and Week 24 (LOCF)

Arm/Group Title	Placebo + Metformin	Dapagliflozin, 2.5 mg + Metformin	Dapagliflozin, 5 mg + Metformin	Dapagliflozin, 10 mg + Metformin
Arm/Group Description	Participants received dapagliflozin-matching placebo once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 2.5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 10 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks
Measure Participants	136	137	137	133
Mean (Standard Error) [Kilograms]	-0.89 (0.2368)	-2.21 (0.2357)	-3.04 (0.2358)	-2.86 (0.2392)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 2.5 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Statistically significant according to hierarchical testing procedure (p<0.05).
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.32
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.3344
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 5 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Statistically significant according to hierarchical testing procedure (p<0.05).
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.16
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.3344
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 10 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Statistically significant according to hierarchical testing procedure (p<0.05).
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.97
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.3365
	Estimation Comments

4. Secondary Outcome

Title	Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF])
Description	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Percent adjusted for baseline HbA1c. Therapeutic glycemic response is defined as HbA1c <7.0%. Data after rescue medication was excluded from this analysis. HbA1c was measured as a percent of hemoglobin.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants who received study medication and were not missing baseline and Week 24 (LOCF) values

Arm/Group Title	Placebo + Metformin	Dapagliflozin, 2.5 mg + Metformin	Dapagliflozin, 5 mg + Metformin	Dapagliflozin, 10 mg + Metformin
Arm/Group Description	Participants received dapagliflozin-matching placebo once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 2.5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 10 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks
Measure Participants	134	135	133	132
Number [Percentage of participants]	25.9 18.9%	33.0 24.1%	37.5 27.4%	40.6 30.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 2.5 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1775
	Comments	Statistically significant according to hierarchical testing procedure (p<0.05).
	Method	Modified logistic regression
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	7.1
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 5 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0275
	Comments	Statistically significant according to hierarchical testing procedure (p<0.05).
	Method	Modified logistic regression
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	11.7
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 10 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0062
	Comments	Statistically significant according to hierarchical testing procedure (p<0.05).
	Method	Modified logistic regression
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	14.7
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Hemoglobin A1c (HbA1c) in Participants With Baseline HbA1c ≥9.0% at Week 24 (Last Observation Carried Forward [LOCF])
Description	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. HbA1c was measured as percent of hemoglobin by a central laboratory. The population included those randomized participants who received treatment and had a baseline HbA1c > 9.0%. Data after rescue medication were excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants who received study medication, who had baseline HbA1c ≥9.0%, and who had nonmissing HbA1c values at Week 24 (LOCF)

Arm/Group Title	Placebo + Metformin	Dapagliflozin, 2.5 mg + Metformin	Dapagliflozin, 5 mg + Metformin	Dapagliflozin, 10 mg + Metformin
Arm/Group Description	Participants received dapagliflozin-matching placebo once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 2.5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 10 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks
Measure Participants	22	17	34	18
Mean (Standard Error) [Percent]	-0.53 (0.2345)	-1.21 (0.2660)	-1.37 (0.1875)	-1.32 (0.2595)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 2.5 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.68
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.3515
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 5 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0068
	Comments	Statistically significant according to hierarchical testing procedure (p<0.05).
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.84
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.3022
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 10 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0290
	Comments	Statistically significant according to hierarchical testing procedure (p<0.05).
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.78
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.3535
	Estimation Comments

6. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Total Body Weight at Week 24 in Participants With Baseline Body Mass Index (BMI) ≥27 kg/m^2 (Last Observation Carried Forward [LOCF])
Description	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Adjusted mean change from baseline in total body weight at Week 24 (or the last postbaseline measurement prior to Week 24 if no Week 24 assessment was available was determined.) Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Body weight measurements were obtained during the qualification and lead-in Periods and on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 of the double-blind period.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants who received study medication, who had baseline BMI ≥27 kg/m^2, and who had nonmissing total body weight measurements at Week 24 (LOCF)

Arm/Group Title	Placebo + Metformin	Dapagliflozin, 2.5 mg + Metformin	Dapagliflozin, 5 mg + Metformin	Dapagliflozin, 10 mg + Metformin
Arm/Group Description	Participants received dapagliflozin-matching placebo once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 2.5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 10 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks
Measure Participants	114	120	111	108
Mean (Standard Error) [Kilograms]	-1.01 (0.2630)	-2.39 (0.2564)	-3.21 (0.2661)	-3.09 (0.2737)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 2.5 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.38
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.3681
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 5 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Statistically significant according to hierarchical testing procedure (p<0.05).
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.19
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.3745
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 10 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Statistically significant according to hierarchical testing procedure (p<0.05).
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.08
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.3791
	Estimation Comments

7. Other Pre-specified Outcome

Title	Number of Participants With Adverse Events (AEs), Hypoglycemia Events, Related AEs, Death as Outcome, Serious AEs (SAEs), Related SAEs, SAEs Leading to Discontinuation, AEs Leading to Discontinuation, and Hypoglycemia Events Leading to Discontinuation
Description	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related=having certain, probable, possible, or missing relationship to study drug. Events captured from baseline to last dose plus 4 days for AEs and plus 30 days for SAEs during the double-blind 12-week period. Data after rescue included.
Time Frame	From Baseline to end of Long-term Period (Week 102)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of blinded study medication

Arm/Group Title	Placebo + Metformin	Dapagliflozin, 2.5 mg + Metformin	Dapagliflozin, 5 mg + Metformin	Dapagliflozin, 10 mg + Metformin
Arm/Group Description	Participants received dapagliflozin-matching placebo once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 2.5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 10 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks
Measure Participants	137	137	137	135
At least 1 AE	111 81%	111 81%	111 81%	111 82.2%
At least 1 hypoglycemia event	8 5.8%	5 3.6%	7 5.1%	7 5.2%
At least 1 related AE	28 20.4%	36 26.3%	33 24.1%	45 33.3%
Deaths	1 0.7%	2 1.5%	0 0%	0 0%
At least 1 SAE	14 10.2%	15 10.9%	9 6.6%	14 10.4%
At least 1 related SAE	3 2.2%	0 0%	2 1.5%	1 0.7%
SAEs leading to discontinuation	6 4.4%	3 2.2%	1 0.7%	2 1.5%
AEs leading to discontinuation	9 6.6%	7 5.1%	5 3.6%	6 4.4%
Hypoglycemia events leading to discontinuation	0 0%	0 0%	0 0%	0 0%

8. Other Pre-specified Outcome

Title	Number of Participants With Laboratory Test Results Meeting the Criteria for Laboratory Abnormality
Description	BUN=blood urea nitrogen; preRX=pretreatment; ULN=upper limit of normal; AST=aspartate aminotransferase; ALT=alanine aminotransferase; ALP=alkaline phosphatase. Phosphorus, inorganic (low): ages 17-65 years, ≤1.8 mg/dL; ages≥66 years, ≤2.1 mg/dL. Phosphorus, inorganic (high): ages 17-65 years, ≥5.6 mg/dL; ages≥66 years, ≥5.6 mg/dL. Phosphorus, inorganic (low) ≤1.8 mg/dL if age 17-65 or ≤2.1 mg/dL if age ≥66. Calcium, total (high): ≥1 mg/dL from ULN and ≥0.5 mg/dL from preRx value.
Time Frame	Day 1 to Week 102

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study medication and who had nonmissing laboratory values at baseline and Week 102.

Arm/Group Title	Placebo + Metformin	Dapagliflozin, 2.5 mg + Metformin	Dapagliflozin, 5 mg + Metformin	Dapagliflozin, 10 mg + Metformin
Arm/Group Description	Participants received dapagliflozin-matching placebo once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 2.5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 10 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks
Measure Participants	136	137	136	132
Hematocrit >55%	1 0.7%	2 1.5%	2 1.5%	3 2.2%
Hemoglobin >18 g/dL	1 0.7%	4 2.9%	1 0.7%	5 3.7%
BUN ≥60 mg/d or Urea>21.4 mmol/L	0 0%	0 0%	0 0%	1 0.7%
Creatinine ≥1.5 preRX creatinine	2 1.5%	3 2.2%	4 2.9%	2 1.5%
Creatinine ≥2.5 mg/dL	0 0%	0 0%	1 0.7%	0 0%
Glucose >350 mg/dL	2 1.5%	0 0%	0 0%	1 0.7%
Creatine kinase >5*ULN	2 1.5%	2 1.5%	3 2.2%	3 2.2%
Creatine kinase >10*ULN	1 0.7%	0 0%	2 1.5%	1 0.7%
Calcium, total <7.5 mg/dL	4 2.9%	1 0.7%	2 1.5%	0 0%
Calcium, total (high)	2 1.5%	0 0%	0 0%	0 0%
Potassium, serum ≥6 MEQ/L	6 4.4%	3 2.2%	3 2.2%	2 1.5%
Magnesium, serum <1 mEq/L	1 0.7%	0 0%	0 0%	1 0.7%
Sodium, serum <130 mEq/L	1 0.7%	0 0%	3 2.2%	0 0%
Sodium, serum >150 mEq/L	0 0%	0 0%	1 0.7%	0 0%
Phosphorus, inorganic (high)	1 0.7%	1 0.7%	2 1.5%	5 3.7%
Phosphorus, inorganic (low)	1 0.7%	0 0%	0 0%	0 0%
Albumin/creatinine ratio >1800 mg/g	2 1.5%	0 0%	3 2.2%	1 0.7%
AST elevation 3*ULN	0 0%	0 0%	3 2.2%	2 1.5%
ALT elevation 3*ULN	1 0.7%	3 2.2%	2 1.5%	2 1.5%
ALT elevation 5*ULN	0 0%	0 0%	1 0.7%	0 0%
Total bilirubin elevation >1.5*ULN	2 1.5%	1 0.7%	1 0.7%	4 3%
Total bilirubin elevation >2*ULN	0 0%	0 0%	0 0%	1 0.7%
ALP elevation >1.5*ULN	5 3.6%	5 3.6%	0 0%	2 1.5%

9. Other Pre-specified Outcome

Title	Number of Participants With Changes in Baseline in Electrocardiogram Findings at Week 102 (Last Observation Carried Forward [LOCF])
Description	12-Lead electrocardiograms (ECGs) were performed at entry into lead-in period Day -7 visit and Week 24/dnd of treatment visit (LOCF) on participants who were supine. ECGs were assessed by the investigator. Baseline was Day -7 for this parameter. Data after rescue included.The Week 102 value is the last observation, regardless of rescue prior to Week 102 if no Week 102 measurement was available.
Time Frame	Baseline to Week 102

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study medication and who had nonmissing baseline and Week 102 (LOCF) values

Arm/Group Title	Placebo + Metformin	Dapagliflozin, 2.5 mg + Metformin	Dapagliflozin, 5 mg + Metformin	Dapagliflozin, 10 mg + Metformin
Arm/Group Description	Participants received dapagliflozin-matching placebo once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 2.5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 10 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks
Measure Participants	137	137	137	135
Baseline normal/Week 102 normal	74 54%	80 58.4%	79 57.7%	82 60.7%
Baseline normal/Week 102 abnormal	7 5.1%	14 10.2%	9 6.6%	8 5.9%
Baseline normal/Week 102 not reported	9 6.6%	6 4.4%	5 3.6%	9 6.7%
Baseline abnormal/Week 102 normal	17 12.4%	11 8%	20 14.6%	10 7.4%
Baseline abnormal/Week 102 abnormal	26 19%	24 17.5%	20 14.6%	25 18.5%
Baseline abnormal/Week 102 not reported	3 2.2%	2 1.5%	3 2.2%	1 0.7%
Baseline not reported/Week 102 normal	1 0.7%	0 0%	1 0.7%	0 0%
Baseline not reportedl/Week 102 abnormal	0 0%	0 0%	0 0%	0 0%
Baseline not reported/Week 102 not reported	0 0%	0 0%	0 0%	0 0%

10. Other Pre-specified Outcome

Title	Mean Changes From Baseline in Seated Systolic Blood Pressure
Description	Blood pressure values were obtained after the participant was seated quietly for 5 minutes; at least 8 hours after the last ingestion of caffeine, alcohol, or nicotine; and in the same arm (right or left) consistently through out the study. Data after rescue were also included. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication.
Time Frame	From Baseline to Week 102

Outcome Measure Data

Analysis Population Description

All randomized participants who received study medication. n=the number of participants not missing baseline and Week t values.

Arm/Group Title	Placebo + Metformin	Dapagliflozin, 2.5 mg + Metformin	Dapagliflozin, 5 mg + Metformin	Dapagliflozin, 10 mg + Metformin
Arm/Group Description	Participants received dapagliflozin-matching placebo once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 2.5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 10 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks
Measure Participants	137	137	137	135
Week 12 (n=125, 129, 129, 126)	-0.1 (1.216)	-1.6 (1.380)	-4.0 (1.206)	-3.0 (1.230)
Week 24 (n=119, 119, 122, 122)	-0.2 (1.229)	-2.1 (1.126)	-4.3 (1.270)	-5.1 (1.329)
Week 50 (n=105, 116, 111, 113)	1.0 (1.440)	-0.1 (1.281)	-2.1 (1.314)	-1.9 (1.472)
Week 102 (n=72, 78, 88, 94)	1.5 (1.610)	0.7 (1.825)	-1.1 (1.412)	-0.3 (1.544)

11. Other Pre-specified Outcome

Title	Mean Changes From Baseline in Seated Diastolic Blood Pressure
Description	Blood pressure values were obtained after the participant was seated quietly for 5 minutes; at least 8 hours after the last ingestion of caffeine, alcohol, or nicotine; and in the same arm (right or left) consistently through out the study. Data after rescue were also included. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication.
Time Frame	From Baseline to Week 102

Outcome Measure Data

Analysis Population Description

All randomized participants who received study medication. n=the number of participants not missing baseline and Week t values.

Arm/Group Title	Placebo + Metformin	Dapagliflozin, 2.5 mg + Metformin	Dapagliflozin, 5 mg + Metformin	Dapagliflozin, 10 mg + Metformin
Arm/Group Description	Participants received dapagliflozin-matching placebo once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 2.5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 10 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks
Measure Participants	137	137	137	135
Week 12 (n=125, 129, 129, 126)	-0.9 (0.763)	-1.3 (0.794)	-2.3 (0.714)	-1.0 (0.758)
Week 24 (n=119, 119, 122, 122)	-0.1 (0.744)	-1.8 (0.863)	-2.5 (0.769)	-1.8 (0.842)
Week 50 (n=105, 116, 111, 113)	0.1 (0.861)	-0.2 (0.714)	-2.4 (0.840)	-1.2 (0.921)
Week 102 (n=72, 78, 88, 94)	-1.0 (0.929)	-0.1 (0.914)	-1.5 (0.861)	-1.2 (1.041)

12. Other Pre-specified Outcome

Title	Number of Participants With Orthostatic Hypotension
Description	Orthostatic hypotension was defined as a decrease from supine to standing blood pressure of >20 mm Hg in systolic blood pressure or >10 mm Hg in diastolic blood pressure.
Time Frame	From Baseline to Week 102

Outcome Measure Data

Analysis Population Description

All randomized participants who received treatment; n=the number of participants who were not missing blood pressure measurements.

Arm/Group Title	Placebo + Metformin	Dapagliflozin, 2.5 mg + Metformin	Dapagliflozin, 5 mg + Metformin	Dapagliflozin, 10 mg + Metformin
Arm/Group Description	Participants received dapagliflozin-matching placebo once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 2.5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 10 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks
Measure Participants	137	137	137	135
Baseline (n=121, 127, 124, 126)	3 2.2%	4 2.9%	4 2.9%	4 3%
Week 1 (n=126, 121, 119, 114)	28 20.4%	26 19%	21 15.3%	19 14.1%
Week 12 (n=123, 128, 127, 125)	6 4.4%	8 5.8%	4 2.9%	5 3.7%
Week 24 (n=116, 114, 118, 121)	10 7.3%	6 4.4%	5 3.6%	3 2.2%
Week 50 (n=103, 115, 109,112)	10 7.3%	6 4.4%	7 5.1%	6 4.4%
Week 102 (n=71, 76, 87, 94)	1 0.7%	1 0.7%	1 0.7%	3 2.2%

13. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Hemoglobin A1c (HbA1c) in Participants With Baseline Body Mass Index (BMI) ≥27 kg/m^2 at Week 24 (Last Observation Carried Forward [LOCF])
Description	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Adjusted for baseline HbA1c. HbA1c was measured as percent of hemoglobin by a central laboratory. Data after rescue medication were excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants who received study medication, who had a BMI ≥27 kg/m^2 at baseline, and who had nonmissing HbA1c values at Week 24 (LOCF)

Arm/Group Title	Placebo + Metformin	Dapagliflozin, 2.5 mg + Metformin	Dapagliflozin, 5 mg + Metformin	Dapagliflozin, 10 mg + Metformin
Arm/Group Description	Participants received dapagliflozin-matching placebo once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 2.5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 10 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks
Measure Participants	113	118	109	104
Mean (Standard Error) [Percent]	-0.31 (0.0792)	-0.69 (0.0774)	-0.71 (0.0806)	-0.88 (0.0826)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 2.5 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.38
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1109
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 5 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments	Statistically significant according to hierarchical testing procedure (p<0.05).
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.40
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1129
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 10 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Statistically significant according to hierarchical testing procedure (p<0.05).
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.57
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1146
	Estimation Comments

14. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Fasting Plasma Glucose at Week 1 (Last Observation Carried Forward [LOCF])
Description	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Data after rescue medication was excluded from this analysis. Fasting plasma glucose was measured by a central laboratory. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication.
Time Frame	From Baseline to Week 1

Outcome Measure Data

Analysis Population Description

All randomized participants who received study medication and who had nonmissing fasting plasma glucose values at baseline and Week 1 (LOCF)

Arm/Group Title	Placebo + Metformin	Dapagliflozin, 2.5 mg + Metformin	Dapagliflozin, 5 mg + Metformin	Dapagliflozin, 10 mg + Metformin
Arm/Group Description	Participants received dapagliflozin-matching placebo once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 2.5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 10 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks
Measure Participants	126	120	121	115
Mean (Standard Error) [mg/dL]	1.2 (1.934)	-6.0 (1.981)	-12.0 (1.976)	-16.5 (2.030)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 2.5 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.1
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.769
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 5 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Statistically significant according to hierarchical testing procedure (p<0.05).
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-13.1
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.762
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 10 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Statistically significant according to hierarchical testing procedure (p<0.05).
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-17.7
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.808
	Estimation Comments

15. Secondary Outcome

Title	Adjusted Percentage of Participants Achieving Hemoglobin A1c (HbA1C) ≤6.5% at Week 24 (Last Observation Carried Forward [LOCF])
Description	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Percent adjusted for baseline HbA1c. Data after rescue medication was excluded from this analysis. HbA1c was measured as a percent of hemoglobin.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants who received study medication and who had HbA1c values at Baseline and Week 24 (LOCF)

Arm/Group Title	Placebo + Metformin	Dapagliflozin, 2.5 mg + Metformin	Dapagliflozin, 5 mg + Metformin	Dapagliflozin, 10 mg + Metformin
Arm/Group Description	Participants received dapagliflozin-matching placebo once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 2.5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Participants received dapagliflozin, 10 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks
Measure Participants	18	29	18	36
Number [Percentage of participants]	13.8 10.1%	20.7 15.1%	14.5 10.6%	25.2 18.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 2.5 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.9
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 5 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8627
	Comments
	Method	Modified logistic regression
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.7
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo + Metformin, Dapagliflozin, 10 mg + Metformin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0149
	Comments	Statistically significant according to hierarchical testing procedure (p<0.05).
	Method	Modified logistic regression
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	11.3
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Arm/Group Title	Placebo + Metformin		Dapagliflozin, 2.5 mg + Metformin		Dapagliflozin, 5.0 mg + Metformin		Dapagliflozin, 10 mg + Metformin
Arm/Group Description	Participants received dapagliflozin-matching placebo once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks		Participants received dapagliflozin, 2.5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks		Participants received dapagliflozin, 5.0 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks		Participants received dapagliflozin, 10 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks
All Cause Mortality
	Placebo + Metformin		Dapagliflozin, 2.5 mg + Metformin		Dapagliflozin, 5.0 mg + Metformin		Dapagliflozin, 10 mg + Metformin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo + Metformin		Dapagliflozin, 2.5 mg + Metformin		Dapagliflozin, 5.0 mg + Metformin		Dapagliflozin, 10 mg + Metformin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/137 (10.2%)		15/137 (10.9%)		9/137 (6.6%)		14/135 (10.4%)
Blood and lymphatic system disorders
Thrombocytopenia	1/137 (0.7%)		0/137 (0%)		0/137 (0%)		0/135 (0%)
Cardiac disorders
Angina pectoris	1/137 (0.7%)		1/137 (0.7%)		0/137 (0%)		0/135 (0%)
Myocardial infarction	0/137 (0%)		2/137 (1.5%)		0/137 (0%)		0/135 (0%)
Angina unstable	1/137 (0.7%)		0/137 (0%)		0/137 (0%)		1/135 (0.7%)
Atrial fibrillation	0/137 (0%)		1/137 (0.7%)		0/137 (0%)		0/135 (0%)
Coronary artery stenosis	1/137 (0.7%)		0/137 (0%)		0/137 (0%)		0/135 (0%)
Myocardial ischaemia	1/137 (0.7%)		1/137 (0.7%)		0/137 (0%)		0/135 (0%)
Arteriosclerosis coronary artery	0/137 (0%)		0/137 (0%)		1/137 (0.7%)		0/135 (0%)
Cardiac arrest	2/137 (1.5%)		0/137 (0%)		0/137 (0%)		0/135 (0%)
Cardio-respiratory arrest	0/137 (0%)		1/137 (0.7%)		0/137 (0%)		0/135 (0%)
Acute myocardial infarction	3/137 (2.2%)		0/137 (0%)		0/137 (0%)		0/135 (0%)
Atrioventricular block second degree	0/137 (0%)		1/137 (0.7%)		0/137 (0%)		0/135 (0%)
Gastrointestinal disorders
Inguinal hernia, obstructive	0/137 (0%)		0/137 (0%)		1/137 (0.7%)		0/135 (0%)
Abdominal pain	0/137 (0%)		0/137 (0%)		1/137 (0.7%)		1/135 (0.7%)
Diabetic gastroparesis	0/137 (0%)		0/137 (0%)		1/137 (0.7%)		0/135 (0%)
General disorders
Necrobiosis	0/137 (0%)		1/137 (0.7%)		0/137 (0%)		0/135 (0%)
Chest pain	0/137 (0%)		0/137 (0%)		0/137 (0%)		2/135 (1.5%)
Hepatobiliary disorders
Cholecystitis	0/137 (0%)		0/137 (0%)		1/137 (0.7%)		0/135 (0%)
Infections and infestations
Dengue fever	0/137 (0%)		1/137 (0.7%)		0/137 (0%)		0/135 (0%)
Bacteraemia	0/137 (0%)		0/137 (0%)		0/137 (0%)		1/135 (0.7%)
Diverticulitis	0/137 (0%)		1/137 (0.7%)		0/137 (0%)		0/135 (0%)
Appendicitis	0/137 (0%)		1/137 (0.7%)		0/137 (0%)		0/135 (0%)
Urinary tract infection	0/137 (0%)		1/137 (0.7%)		0/137 (0%)		0/135 (0%)
Postoperative wound infection	0/137 (0%)		1/137 (0.7%)		0/137 (0%)		0/135 (0%)
Injury, poisoning and procedural complications
Face injury	0/137 (0%)		1/137 (0.7%)		0/137 (0%)		0/135 (0%)
Spinal cord injury cervical	1/137 (0.7%)		0/137 (0%)		0/137 (0%)		0/135 (0%)
Fall	1/137 (0.7%)		1/137 (0.7%)		0/137 (0%)		0/135 (0%)
Urethral injury	0/137 (0%)		0/137 (0%)		0/137 (0%)		1/135 (0.7%)
Head injury	0/137 (0%)		1/137 (0.7%)		0/137 (0%)		0/135 (0%)
Open fracture	0/137 (0%)		0/137 (0%)		0/137 (0%)		1/135 (0.7%)
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	0/137 (0%)		1/137 (0.7%)		1/137 (0.7%)		0/135 (0%)
Rotator cuff syndrome	0/137 (0%)		0/137 (0%)		0/137 (0%)		1/135 (0.7%)
Spinal osteoarthritis	0/137 (0%)		0/137 (0%)		1/137 (0.7%)		0/135 (0%)
Osteoarthritis	0/137 (0%)		0/137 (0%)		0/137 (0%)		1/135 (0.7%)
Arthralgia	0/137 (0%)		1/137 (0.7%)		0/137 (0%)		1/135 (0.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/137 (0%)		0/137 (0%)		0/137 (0%)		1/135 (0.7%)
Malignant melanoma	0/137 (0%)		0/137 (0%)		0/137 (0%)		1/135 (0.7%)
Renal cell carcinoma	1/137 (0.7%)		0/137 (0%)		0/137 (0%)		0/135 (0%)
Lymphocytic leukaemia	1/137 (0.7%)		0/137 (0%)		0/137 (0%)		0/135 (0%)
Rectosigmoid cancer	0/137 (0%)		0/137 (0%)		0/137 (0%)		1/135 (0.7%)
Bladder transitional cell carcinoma	0/137 (0%)		0/137 (0%)		1/137 (0.7%)		0/135 (0%)
Lung neoplasm malignant	1/137 (0.7%)		0/137 (0%)		0/137 (0%)		0/135 (0%)
Basal cell carcinoma	0/137 (0%)		0/137 (0%)		0/137 (0%)		1/135 (0.7%)
Nervous system disorders
Cerebrovascular accident	0/137 (0%)		1/137 (0.7%)		0/137 (0%)		0/135 (0%)
Cervical cord compression	0/137 (0%)		0/137 (0%)		0/137 (0%)		1/135 (0.7%)
Loss of consciousness	0/137 (0%)		1/137 (0.7%)		0/137 (0%)		0/135 (0%)
Transient ischaemic attack	1/137 (0.7%)		0/137 (0%)		0/137 (0%)		0/135 (0%)
Ischaemic stroke	1/137 (0.7%)		0/137 (0%)		0/137 (0%)		0/135 (0%)
Syncope	1/137 (0.7%)		0/137 (0%)		0/137 (0%)		1/135 (0.7%)
Renal and urinary disorders
Calculus ureteric	0/137 (0%)		0/137 (0%)		1/137 (0.7%)		0/135 (0%)
Urinary incontinence	0/137 (0%)		0/137 (0%)		1/137 (0.7%)		0/135 (0%)
Renal failure acute	0/137 (0%)		0/137 (0%)		1/137 (0.7%)		0/135 (0%)
Reproductive system and breast disorders
Breast mass	0/137 (0%)		0/137 (0%)		0/137 (0%)		1/135 (0.7%)
Respiratory, thoracic and mediastinal disorders
Pneumonia aspiration	1/137 (0.7%)		0/137 (0%)		0/137 (0%)		0/135 (0%)
Dyspnoea	0/137 (0%)		0/137 (0%)		1/137 (0.7%)		0/135 (0%)
Other (Not Including Serious) Adverse Events
	Placebo + Metformin		Dapagliflozin, 2.5 mg + Metformin		Dapagliflozin, 5.0 mg + Metformin		Dapagliflozin, 10 mg + Metformin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	84/137 (61.3%)		87/137 (63.5%)		77/137 (56.2%)		83/135 (61.5%)
Gastrointestinal disorders
Vomiting	2/137 (1.5%)		6/137 (4.4%)		7/137 (5.1%)		4/135 (3%)
Diarrhoea	10/137 (7.3%)		7/137 (5.1%)		9/137 (6.6%)		16/135 (11.9%)
Nausea	4/137 (2.9%)		6/137 (4.4%)		4/137 (2.9%)		7/135 (5.2%)
Infections and infestations
Influenza	15/137 (10.9%)		19/137 (13.9%)		20/137 (14.6%)		17/135 (12.6%)
Bronchitis	4/137 (2.9%)		6/137 (4.4%)		5/137 (3.6%)		10/135 (7.4%)
Gastroenteritis	7/137 (5.1%)		5/137 (3.6%)		7/137 (5.1%)		4/135 (3%)
Nasopharyngitis	12/137 (8.8%)		16/137 (11.7%)		8/137 (5.8%)		12/135 (8.9%)
Upper respiratory tract infection	14/137 (10.2%)		9/137 (6.6%)		5/137 (3.6%)		5/135 (3.7%)
Urinary tract infection	8/137 (5.8%)		5/137 (3.6%)		8/137 (5.8%)		16/135 (11.9%)
Pharyngitis	3/137 (2.2%)		7/137 (5.1%)		5/137 (3.6%)		8/135 (5.9%)
Metabolism and nutrition disorders
Dyslipidaemia	5/137 (3.6%)		5/137 (3.6%)		5/137 (3.6%)		7/135 (5.2%)
Musculoskeletal and connective tissue disorders
Back pain	11/137 (8%)		11/137 (8%)		7/137 (5.1%)		18/135 (13.3%)
Pain in extremity	11/137 (8%)		8/137 (5.8%)		3/137 (2.2%)		2/135 (1.5%)
Arthralgia	7/137 (5.1%)		8/137 (5.8%)		10/137 (7.3%)		4/135 (3%)
Nervous system disorders
Headache	8/137 (5.8%)		10/137 (7.3%)		13/137 (9.5%)		15/135 (11.1%)
Dizziness	7/137 (5.1%)		5/137 (3.6%)		6/137 (4.4%)		1/135 (0.7%)
Psychiatric disorders
Depression	2/137 (1.5%)		8/137 (5.8%)		1/137 (0.7%)		3/135 (2.2%)
Respiratory, thoracic and mediastinal disorders
Cough	12/137 (8.8%)		5/137 (3.6%)		5/137 (3.6%)		6/135 (4.4%)
Vascular disorders
Hypertension	13/137 (9.5%)		11/137 (8%)		8/137 (5.8%)		7/135 (5.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.