Efficacy and Safety in Patients With Type 2 Diabetes Mellitus and Cardiovascular Disease

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01042977
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 964
• Locations: 135
• Arms: 2
• Duration (Months): 33.1
• Patients Per Site: 7.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study is carried out to assess whether dapagliflozin improves glycemic control, decreases fasting plasma glucose levels, body weight and blood pressure when added to patient's existing medications and how it compares with their usual treatment without added dapagliflozin. Safety data will be collected and analysed to confirm that treatment with dapagliflozin is safe and well tolerated in patients who have diabetes and cardiovascular disease

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus; Cardiovascular Disease; Inadequate Glycaemic Control	Drug: Dapagliflozin; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 964 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A 24-week, Multicentre, Randomised, Double-blind,Age-stratified, Placebo Controlled Phase III Study With an 80-week Extension Period to Evaluate the Efficacy and Safety of Dapagliflozin 10 mg Once Daily in Patients With T2DM and Cardiovascular Disease, Who Exhibit Inadequate Glycaemic Control on Usual Care
• Study Start Date: Mar 1, 2010
• Actual Primary Completion Date: May 1, 2011
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 dapagliflozin 10 mg tablet	Drug: Dapagliflozin; 10 mg tablet, oral, once daily, 24- week treatment and 80-week extension period
Placebo Comparator: 2 matching placebo tablet	Drug: Placebo; matching placebo tablet, oral, once daily, 24- week treatment and 80-week extension period

Outcome Measures

Primary Outcome Measures

1. Adjusted Mean Change in HbA1c Levels [Baseline to Week 24]

   To compare the glycemic efficacy of dapagliflozin 10 mg versus placebo when added to usual care in type 2 diabetes patients with cardiovascular disease, measured as the mean change in HbA1c from baseline to week 24.

2. Proportion of Responders Meeting All Criteria of a 3-item Endpoint of Clinical Benefit [Baseline to Week 24]

   To compare the clinical benefit of dapagliflozin 10 mg versus placebo when added to usual care in type 2 diabetes patients with cardiovascular disease at week 24, measured as the proportion of responders for a 3-item endpoint of clinical benefit, defined as an absolute drop of 0.5% or more from baseline HbA1c, and a relative drop of 3% or more from baseline for total body weight, and an absolute drop of 3 mmHg or more from baseline in seated systolic blood pressure.

Secondary Outcome Measures

1. Adjusted Mean Percent Change in Body Weight [Baseline to Week 24]

   To compare the mean percent change in body weight from baseline to week 24 between dapagliflozin 10 mg versus placebo.

2. Proportion of Participants With a Reduction From Baseline of 5% or More in Body Weight in Participants With Baseline BMI ≥27 kg/m² [Baseline to Week 24]

   To compare the proportion of participants with BMI baseline ≥27 kg/m2 with a reduction from baseline of 5% or more in body weight with dapagliflozin 10 mg versus placebo from baseline to week 24. Least Squares Mean represents the percent of participants adjusted for baseline body weight and age stratum.

3. Adjusted Mean Change in Systolic Blood Pressure at Week 8 (LOCF) [Baseline to Week 8]

   To compare the mean change in seated systolic blood pressure from baseline to week 8 between dapagliflozin 10 mg versus placebo.

4. Adjusted Mean Change in Seated Systolic Blood Pressure at Week 24 (LOCF) [Baseline to Week 24]

   To compare the mean change in seated systolic blood pressure from baseline to week 24 between dapagliflozin 10 mg versus placebo.

5. Adjusted Mean Change in Seated Systolic Blood Pressure (SBP) at Week 8 (LOCF) in Participants With Baseline SBP>=130 mmHg [Baseline to Week 8]

   To compare the mean change in seated systolic blood pressure (SBP) in participants with baseline seated SBP ≥130 mmHg achieved with dapagliflozin versus placebo from baseline to week 8.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Type 2 diabetes mellitus.

• Cardiovascular disease

• Uninterrupted anti-diabetic treatment for at least 8 weeks before enrolment

Exclusion Criteria:

• Patients with type 1 diabetes or diabetes insipidus

• Patients with 3 or more oral anti-hyperglycaemic drugs with or without insulin and/or poorly controlled diabetes

• Any clinically significant illness, which would compromise the patient's safety and their participation in the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Birmingham	Alabama	United States
2	Research Site	Scottsdale	Arizona	United States
3	Research Site	Anaheim	California	United States
4	Research Site	Bell Gardens	California	United States
5	Research Site	Chino	California	United States
6	Research Site	Chula Vista	California	United States
7	Research Site	Huntington Beach	California	United States
8	Research Site	Los Angeles	California	United States
9	Research Site	Mission Hills	California	United States
10	Research Site	Redondo Beach	California	United States
11	Research Site	Riverside	California	United States
12	Research Site	Sacramento	California	United States
13	Research Site	San Diego	California	United States
14	Research Site	Torrance	California	United States
15	Research Site	Aventura	Florida	United States
16	Research Site	Boca Raton	Florida	United States
17	Research Site	Bradenton	Florida	United States
18	Research Site	Brooksville	Florida	United States
19	Research Site	Clearwater	Florida	United States
20	Research Site	Dania	Florida	United States
21	Research Site	Delray Beach	Florida	United States
22	Research Site	New Smyrna Beach	Florida	United States
23	Research Site	Orlando	Florida	United States
24	Research Site	Springfield	Illinois	United States
25	Research Site	Avon	Indiana	United States
26	Research Site	Franklin	Indiana	United States
27	Research Site	Greenfield	Indiana	United States
28	Research Site	Muncie	Indiana	United States
29	Research Site	Waterloo	Iowa	United States
30	Research Site	Topeka	Kansas	United States
31	Research Site	Paducah	Kentucky	United States
32	Research Site	Alexandria	Louisiana	United States
33	Research Site	Rockville	Maryland	United States
34	Research Site	Kalamazoo	Michigan	United States
35	Research Site	Livonia	Michigan	United States
36	Research Site	Billings	Montana	United States
37	Research Site	Berlin	New Jersey	United States
38	Research Site	Brick	New Jersey	United States
39	Research Site	Asheboro	North Carolina	United States
40	Research Site	Fargo	North Dakota	United States
41	Research Site	Cincinnati	Ohio	United States
42	Research Site	Oklahoma City	Oklahoma	United States
43	Research Site	Altoona	Pennsylvania	United States
44	Research Site	Erie	Pennsylvania	United States
45	Research Site	Holland	Pennsylvania	United States
46	Research Site	Lancaster	Pennsylvania	United States
47	Research Site	Media	Pennsylvania	United States
48	Research Site	Philadelphia	Pennsylvania	United States
49	Research Site	Austin	Texas	United States
50	Research Site	Corpus Christi	Texas	United States
51	Research Site	Dallas	Texas	United States
52	Research Site	Irving	Texas	United States
53	Research Site	Richardson	Texas	United States
54	Research Site	San Antonio	Texas	United States
55	Research Site	Sugarland	Texas	United States
56	Research Site	Alexandria	Virginia	United States
57	Research Site	Manassas	Virginia	United States
58	Research Site	Buenos Aires	Caba	Argentina
59	Research Site	Rosario	Santa Fe	Argentina
60	Research Site	Cordoba		Argentina
61	Research Site	Salta		Argentina
62	Research Site	Santa Fe		Argentina
63	Research Site	Blacktown	New South Wales	Australia
64	Research Site	Broadmeadow	New South Wales	Australia
65	Research Site	Hornsby	New South Wales	Australia
66	Research Site	Wollongong	New South Wales	Australia
67	Research Site	Carina Heights	Queensland	Australia
68	Research Site	Kippa-ring	Queensland	Australia
69	Research Site	Adelaide	South Australia	Australia
70	Research Site	Bedford Park	South Australia	Australia
71	Research Site	Keswick	South Australia	Australia
72	Research Site	Box Hill	Victoria	Australia
73	Research Site	Heidelberg	Victoria	Australia
74	Research Site	Herston		Australia
75	Research Site	Wien		Austria
76	Research Site	Blagoevgrad		Bulgaria
77	Research Site	Pernik		Bulgaria
78	Research Site	Pleven		Bulgaria
79	Research Site	Russe		Bulgaria
80	Research Site	Sevlievo		Bulgaria
81	Research Site	Sofia		Bulgaria
82	Research Site	Stara Zagora		Bulgaria
83	Research Site	Varna		Bulgaria
84	Research Site	Calgary	Alberta	Canada
85	Research Site	Edmonton	Alberta	Canada
86	Research Site	Moncton	New Brunswick	Canada
87	Research Site	Bay Roberts	Newfoundland and Labrador	Canada
88	Research Site	Halifax	Nova Scotia	Canada
89	Research Site	Etobicoke	Ontario	Canada
90	Research Site	Ottawa	Ontario	Canada
91	Research Site	Scarborough	Ontario	Canada
92	Research Site	Thornhill	Ontario	Canada
93	Research Site	Toronto	Ontario	Canada
94	Research Site	Mirabel	Quebec	Canada
95	Research Site	Quebec		Canada
96	Research Site	Santiago	Region Metropolitana	Chile
97	Research Site	Damme		Germany
98	Research Site	Dortmund		Germany
99	Research Site	Homburg		Germany
100	Research Site	Munster		Germany
101	Research Site	Wangen		Germany
102	Research Site	Ajka		Hungary
103	Research Site	Balatonfured		Hungary
104	Research Site	Budapest		Hungary
105	Research Site	Esztergom		Hungary
106	Research Site	Gyor		Hungary
107	Research Site	Komarom		Hungary
108	Research Site	Mosonmagyarovar		Hungary
109	Research Site	TAT		Hungary
110	Research Site	Veszprem		Hungary
111	Research Site	Bialystok		Poland
112	Research Site	Chrzanow		Poland
113	Research Site	Gdansk		Poland
114	Research Site	Grodzisk Mazowiecki		Poland
115	Research Site	Ilawa		Poland
116	Research Site	Kielce		Poland
117	Research Site	Krakow		Poland
118	Research Site	Leczna		Poland
119	Research Site	Leczyca		Poland
120	Research Site	Lodz		Poland
121	Research Site	Lublin		Poland
122	Research Site	Mragowo		Poland
123	Research Site	Nowy Sacz		Poland
124	Research Site	Plock		Poland
125	Research Site	Poznan		Poland
126	Research Site	Ruda Slaska		Poland
127	Research Site	Skierniewice		Poland
128	Research Site	Sopot		Poland
129	Research Site	Tarnow		Poland
130	Research Site	Torun		Poland
131	Research Site	Warszawa		Poland
132	Research Site	Wroclaw		Poland
133	Research Site	Zabrze		Poland
134	Research Site	Zgierz		Poland
135	Research Site	Zielona Gora		Poland

Sponsors and Collaborators

• AstraZeneca
• Bristol-Myers Squibb

Investigators

• Principal Investigator: Dr. Lawrence A Leiter, MD, Division of Endocrinology & Metabolism, St Michael's Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01042977
• Other Study ID Numbers: D1690C00019
• First Posted: Jan 6, 2010
• Last Update Posted: Feb 17, 2014
• Last Verified: Dec 1, 2013

• Keywords provided by AstraZeneca: dapagliflozin; diabetes; cardiovascular disease
• Additional relevant MeSH terms: Cardiovascular Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dapagliflozin

Study Results

Participant Flow

Recruitment Details	First participant enrolled 15 Mar 2010, last part. last visit for 24-week period: 30 May 2011. 1489 part. enrolled, 964 randomized in USA, Canada, Australia, Chile, Argentina and 5 European countries (value presented in 'Enrolment' field). One add. part. treated but not randomized. Part. with T2DM and CVD who showed inadequate glycemic control.
Pre-assignment Detail	During a placebo lead-in period, participants were counselled on dietary and life-style modifications. Anti-diabetic therapy should be kept constant 4 weeks prior to enrolment. Participants eligible for the study were stratified according to age (<65 years or ≥65 years), insulin use and time from most recent qualifying CV event (>1 or ≤1 year).

Arm/Group Title	Dapagliflozin	Placebo
Arm/Group Description	Dapagliflozin 10 mg plus usual care	Placebo plus usual care
Period Title: Overall Study
STARTED	482	483
COMPLETED	441	428
NOT COMPLETED	41	55

Baseline Characteristics

Arm/Group Title	Dapagliflozin	Placebo	Total
Arm/Group Description	Dapagliflozin 10 mg plus usual care	Placebo plus usual care	Total of all reporting groups
Overall Participants	480	482	962
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	63.9 (7.60)	63.6 (7.02)	63.8 (7.31)
Sex: Female, Male (Count of Participants)
Female	159 33.1%	159 33%	318 33.1%
Male	321 66.9%	323 67%	644 66.9%
Race/Ethnicity, Customized (Number) [Number]
White	454 94.6%	449 93.2%	903 93.9%
Black/African American	9 1.9%	10 2.1%	19 2%
Asian	6 1.3%	7 1.5%	13 1.4%
Other	11 2.3%	16 3.3%	27 2.8%
HbA1c (Percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percent]	8.04 (0.759)	8.08 (0.795)	8.06 (0.777)
Body weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	94.53 (17.804)	93.23 (16.842)	93.88 (17.332)
Systolic Blood Pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	134.9 (14.53)	134.6 (13.96)	134.7 (14.24)
Number of participants with BMI >= 27 kg/m2 at baseline (Number) [Number]
< 25 kg/m²	15 3.1%	31 6.4%	46 4.8%
>= 25 kg/m²	465 96.9%	451 93.6%	916 95.2%
>= 27 kg/m²	428 89.2%	416 86.3%	844 87.7%
>= 30 kg/m²	339 70.6%	325 67.4%	664 69%

Outcome Measures

1. Primary Outcome

Title	Adjusted Mean Change in HbA1c Levels
Description	To compare the glycemic efficacy of dapagliflozin 10 mg versus placebo when added to usual care in type 2 diabetes patients with cardiovascular disease, measured as the mean change in HbA1c from baseline to week 24.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set, participants with non-missing baseline and Week 24 (LOCF) values

Arm/Group Title	Dapagliflozin	Placebo
Arm/Group Description	Dapagliflozin 10 mg plus usual care	Placebo plus usual care
Measure Participants	474	471
Least Squares Mean (95% Confidence Interval) [Percent]	-0.33 (0.0434)	0.07

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin, Placebo
	Comments	H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significant at alpha=0.025 (2-sided). A hierarchical closed testing procedure was used to control Type I error across the primary & key secondary objectives
	Method	ANCOVA
	Comments	with treatment group and stratum as effects and baseline value as covariate for each endpoint
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.40
	Confidence Interval	(2-Sided) 95%; -0.50 to -0.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0489
	Estimation Comments	with stratum = age-by-insulin use-by-time from most recent qualifying CV event

2. Primary Outcome

Title	Proportion of Responders Meeting All Criteria of a 3-item Endpoint of Clinical Benefit
Description	To compare the clinical benefit of dapagliflozin 10 mg versus placebo when added to usual care in type 2 diabetes patients with cardiovascular disease at week 24, measured as the proportion of responders for a 3-item endpoint of clinical benefit, defined as an absolute drop of 0.5% or more from baseline HbA1c, and a relative drop of 3% or more from baseline for total body weight, and an absolute drop of 3 mmHg or more from baseline in seated systolic blood pressure.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set, subjects with non-missing baseline and Week 24 (LOCF) values

Arm/Group Title	Dapagliflozin	Placebo
Arm/Group Description	Dapagliflozin 10 mg plus usual care	Placebo plus usual care
Measure Participants	468	469
Number (95% Confidence Interval) [Percentage of participants]	10.0 (0.7) 2.1%	1.9 (7.3) 0.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin, Placebo
	Comments	H0: proportion(treat) minus proportion(placebo) = 0 versus the alternative HA: proportion(treat) minus proportion(placebo) =/= 0
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significant at alpha=0.025 (2-sided). A hierarchical closed testing procedure was used to control Type I error across the primary & key secondary objectives
	Method	Cochran-Mantel-Haenszel
	Comments	with age-by-insulin use-by-time from most recent qualifying CV event as stratum
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	7.0
	Confidence Interval	(2-Sided) 95%; 4.3 to 9.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Adjusted Mean Percent Change in Body Weight
Description	To compare the mean percent change in body weight from baseline to week 24 between dapagliflozin 10 mg versus placebo.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set, subjects with non-missing baseline and Week 24 (LOCF) values

Arm/Group Title	Dapagliflozin	Placebo
Arm/Group Description	Dapagliflozin 10 mg plus usual care	Placebo plus usual care
Measure Participants	480	481
Least Squares Mean (95% Confidence Interval) [Percentage of Body Weight]	-2.53 (0.1770)	-0.61 (0.1736)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin, Placebo
	Comments	H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significant at alpha=0.05 (2-sided). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure
	Method	ANCOVA
	Comments	with treatment group and stratum as effects and baseline value as covariate
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.93
	Confidence Interval	(2-Sided) 95%; -2.31 to -1.54
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1957
	Estimation Comments	with stratum = age-by-insulin use-by-time from most recent qualifying CV event

4. Secondary Outcome

Title	Proportion of Participants With a Reduction From Baseline of 5% or More in Body Weight in Participants With Baseline BMI ≥27 kg/m²
Description	To compare the proportion of participants with BMI baseline ≥27 kg/m2 with a reduction from baseline of 5% or more in body weight with dapagliflozin 10 mg versus placebo from baseline to week 24. Least Squares Mean represents the percent of participants adjusted for baseline body weight and age stratum.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set, subjects with baseline BMI ≥27 kg/m2 and Week 24 (LOCF) values

Arm/Group Title	Dapagliflozin	Placebo
Arm/Group Description	Dapagliflozin 10 mg plus usual care	Placebo plus usual care
Measure Participants	428	415
Least Squares Mean (95% Confidence Interval) [Percentage of participants]	18.4 (1.051) 3.8%	4.8 (1.876) 1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin, Placebo
	Comments	H0: proportion(treat) minus proportion(placebo) = 0 versus the alternative HA: proportion(treat) minus proportion(placebo) =/= 0
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significant at alpha=0.05 (2-sided). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure
	Method	Regression, Logistic
	Comments	Based on methodology of Zhang, Tsiatis & Davidian and Davidian, Tsiatis, Zhang & Lu, with adjustment for baseline total body weight and age stratum
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	13.6
	Confidence Interval	(2-Sided) 95%; 9.4 to 17.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.149
	Estimation Comments

5. Secondary Outcome

Title	Adjusted Mean Change in Systolic Blood Pressure at Week 8 (LOCF)
Description	To compare the mean change in seated systolic blood pressure from baseline to week 8 between dapagliflozin 10 mg versus placebo.
Time Frame	Baseline to Week 8

Outcome Measure Data

Analysis Population Description

Full Analysis Set, subjects with non-missing baseline and Week 8 (LOCF) values

Arm/Group Title	Dapagliflozin	Placebo
Arm/Group Description	Dapagliflozin 10 mg plus usual care	Placebo plus usual care
Measure Participants	473	479
Least Squares Mean (95% Confidence Interval) [mmHg]	-1.85 (0.7105)	0.86 (0.7135)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin, Placebo
	Comments	H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0007
	Comments	Significant at alpha=0.05 (2-sided). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure
	Method	ANCOVA
	Comments	with treatment group and stratum as effects and baseline value as covariate
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.71
	Confidence Interval	(2-Sided) 95%; -4.28 to -1.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.7977
	Estimation Comments	with stratum = age-by-insulin use-by-time from most recent qualifying CV event

6. Secondary Outcome

Title	Adjusted Mean Change in Seated Systolic Blood Pressure at Week 24 (LOCF)
Description	To compare the mean change in seated systolic blood pressure from baseline to week 24 between dapagliflozin 10 mg versus placebo.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis set, subjects with non-missing baseline and Week 24 (LOCF) values

Arm/Group Title	Dapagliflozin	Placebo
Arm/Group Description	Dapagliflozin 10 mg plus usual care	Placebo plus usual care
Measure Participants	473	479
Least Squares Mean (95% Confidence Interval) [mmHg]	-2.70 (0.7109)	0.32 (0.7140)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin, Placebo
	Comments	H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	Significant at alpha=0.05 (2-sided). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure
	Method	ANCOVA
	Comments	with treatment group and stratum as effects and baseline value as covariate
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.02
	Confidence Interval	(2-Sided) 95%; -4.59 to -1.46
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.7983
	Estimation Comments	with stratum = age-by-insulin use-by-time from most recent qualifying CV event

7. Secondary Outcome

Title	Adjusted Mean Change in Seated Systolic Blood Pressure (SBP) at Week 8 (LOCF) in Participants With Baseline SBP>=130 mmHg
Description	To compare the mean change in seated systolic blood pressure (SBP) in participants with baseline seated SBP ≥130 mmHg achieved with dapagliflozin versus placebo from baseline to week 8.
Time Frame	Baseline to Week 8

Outcome Measure Data

Analysis Population Description

Full Analysis set, participants with baseline seated SBP ≥130 mmHg and Week 8 (LOCF) value

Arm/Group Title	Dapagliflozin	Placebo
Arm/Group Description	Dapagliflozin 10 mg plus usual care	Placebo plus usual care
Measure Participants	300	309
Least Squares Mean (95% Confidence Interval) [mmHg]	-5.33 (0.8612)	-1.89 (0.8612)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin, Placebo
	Comments	H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments	Significant at alpha=0.05 (2-sided). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure
	Method	ANCOVA
	Comments	with treatment group and stratum as effects and baseline value as covariate
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.44
	Confidence Interval	(2-Sided) 95%; -5.35 to -1.53
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.9746
	Estimation Comments	with stratum = age-by-insulin use-by-time from most recent qualifying CV event

Adverse Events

Time Frame	Non-serious / serious adverse events on or after the first day and on or prior to the last day of the 24-week double-blind treatment plus 4/30 days or up to follow-up visit if earlier, or up to and including the start date of extension period if earlier.
Adverse Event Reporting Description	Participants were questioned at each study visit about the occurrence of any health problems and any examination conducted at a study visit was assessed in comparison to the status at study entry.
Arm/Group Title	Dapagliflozin		Placebo
Arm/Group Description	Dapagliflozin 10 mg plus usual care		Placebo plus usual care
All Cause Mortality
	Dapagliflozin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Dapagliflozin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	41/482 (8.5%)		46/483 (9.5%)
Cardiac disorders
Angina unstable	3/482 (0.6%)		2/483 (0.4%)
Myocardial infarction	3/482 (0.6%)		1/483 (0.2%)
Acute coronary syndrome	2/482 (0.4%)		0/483 (0%)
Atrial fibrillation	2/482 (0.4%)		3/483 (0.6%)
Angina pectoris	1/482 (0.2%)		1/483 (0.2%)
Cardiac failure	1/482 (0.2%)		1/483 (0.2%)
Coronary artery disease	1/482 (0.2%)		1/483 (0.2%)
Ventricular tachycardia	1/482 (0.2%)		0/483 (0%)
Acute myocardial infarction	0/482 (0%)		1/483 (0.2%)
Cardiac failure congestive	0/482 (0%)		1/483 (0.2%)
Ear and labyrinth disorders
Acute vestibular syndrome	0/482 (0%)		1/482 (0.2%)
Gastrointestinal disorders
Abdominal pain	1/482 (0.2%)		0/483 (0%)
Gastric haemorrhage	1/482 (0.2%)		0/483 (0%)
Gastric polyps	1/482 (0.2%)		0/483 (0%)
Gastritis	1/482 (0.2%)		0/483 (0%)
Haemorrhoids	1/482 (0.2%)		0/483 (0%)
Rectal haemorrhage	0/482 (0%)		1/483 (0.2%)
Small intestine obstruction	0/482 (0%)		1/483 (0.2%)
General disorders
Chest pain	0/482 (0%)		3/483 (0.6%)
Immune system disorders
Drug hypersensitivity	1/482 (0.2%)		0/482 (0%)
Infections and infestations
Respiratory tract infection	2/482 (0.4%)		1/483 (0.2%)
Bronchitis	1/482 (0.2%)		0/483 (0%)
Osteomyelitis	1/482 (0.2%)		0/483 (0%)
Peritonsillar abscess	1/482 (0.2%)		0/483 (0%)
Gastroenterits	0/482 (0%)		1/483 (0.2%)
Herpes zoster	0/482 (0%)		1/483 (0.2%)
Lung abscess	0/482 (0%)		1/483 (0.2%)
Pneumonia	0/482 (0%)		2/483 (0.4%)
Pyelonephritis	0/482 (0%)		1/483 (0.2%)
Upper respiratory tract infection	0/482 (0%)		1/483 (0.2%)
Injury, poisoning and procedural complications
Excoriation	1/482 (0.2%)		0/482 (0%)
Cervical vertebral fracture	0/482 (0%)		1/482 (0.2%)
Clavicle fracture	0/482 (0%)		1/482 (0.2%)
Contusion	0/482 (0%)		1/482 (0.2%)
Femoral neck fracture	0/482 (0%)		1/482 (0.2%)
Road traffic accident	0/482 (0%)		1/482 (0.2%)
Vascular graft thrombosis	0/482 (0%)		1/482 (0.2%)
Investigations
Blood parathyroid hormone decreased	1/482 (0.2%)		0/482 (0%)
Metabolism and nutrition disorders
Hypoglycaemia	1/482 (0.2%)		0/482 (0%)
Hyperglycaemia	0/482 (0%)		1/482 (0.2%)
Musculoskeletal and connective tissue disorders
Intervertebral disc disorder	1/482 (0.2%)		0/483 (0%)
Intervertebral disc protrusion	1/482 (0.2%)		0/483 (0%)
Osteoarthritis	1/482 (0.2%)		0/483 (0%)
Polyarthritis	1/482 (0.2%)		0/483 (0%)
Back pain	0/482 (0%)		2/483 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adrenal adenoma	1/482 (0.2%)		0/483 (0%)
Basal cell carcinoma	1/482 (0.2%)		0/483 (0%)
Benign salivary gland neoplasm	1/482 (0.2%)		0/483 (0%)
Meningioma	1/482 (0.2%)		0/483 (0%)
Renal neoplasm	1/482 (0.2%)		0/483 (0%)
Bladder cancer	0/482 (0%)		1/483 (0.2%)
Prostate cancer	0/482 (0%)		1/483 (0.2%)
Nervous system disorders
Carotid artery stenosis	2/482 (0.4%)		0/483 (0%)
Dizziness	1/482 (0.2%)		1/483 (0.2%)
Ischaemic stroke	1/482 (0.2%)		1/483 (0.2%)
Spinal cord compression	1/482 (0.2%)		0/483 (0%)
Syncope	1/482 (0.2%)		1/483 (0.2%)
Cerebrovascular accident	0/482 (0%)		2/483 (0.4%)
Transient ischaemic attack	0/482 (0%)		1/483 (0.2%)
Psychiatric disorders
Schizophrenia, paranoid type	0/482 (0%)		1/483 (0.2%)
Renal and urinary disorders
Bladder diverticulum	1/482 (0.2%)		0/483 (0%)
Renal failure	1/482 (0.2%)		0/483 (0%)
Urinary retention	1/482 (0.2%)		0/483 (0%)
Nephrolithiasis	0/482 (0%)		1/483 (0.2%)
Renal failure acute	0/482 (0%)		1/482 (0.2%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	1/482 (0.2%)		1/482 (0.2%)
Skin and subcutaneous tissue disorders
Angioedema	1/482 (0.2%)		0/482 (0%)
Skin ulcer	1/482 (0.2%)		0/482 (0%)
Surgical and medical procedures
Angioplasty	1/482 (0.2%)		0/482 (0%)
Vascular disorders
Peripheral arterial occlusive disease	2/482 (0.4%)		2/482 (0.4%)
Diabetic vascular disorder	1/482 (0.2%)		0/482 (0%)
Circulatory collapse	0/482 (0%)		1/482 (0.2%)
Deep vein thrombosis	0/482 (0%)		1/482 (0.2%)
Extremity necrosis	0/482 (0%)		1/482 (0.2%)
Hypertensive crisis	0/482 (0%)		1/482 (0.2%)
Peripheral ischaemia	0/482 (0%)		1/482 (0.2%)
Thrombosis	0/482 (0%)		1/482 (0.2%)
Other (Not Including Serious) Adverse Events
	Dapagliflozin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	147/482 (30.5%)		134/483 (27.7%)
Endocrine disorders
Hypoglycemia	101/482 (21%)		84/483 (17.4%)
Infections and infestations
Urinary tract infection	27/482 (5.6%)		18/483 (3.7%)
Nasopharyngitis	26/482 (5.4%)		26/483 (5.4%)
Upper respiratory tract infection	15/482 (3.1%)		24/483 (5%)

Limitations/Caveats

For participants who did not complete 8 and/or 24 weeks, respectively, LOCF was used. For HbA1c: excluding data after glycemic rescue, Weight: including data after rescue, SBP: excluding data after anti-hypertensive rescue.

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Certain Agreements

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

If an Investigator requests permission to publish data from this study any such publication is to be agreed with AstraZeneca (AZ) in advance. The investigator agrees to provide AZ as soon as possible with drafts of proposed publications. Unless otherwise agreed, AZ shall have a period of 60 days from receipt of the proposed final manuscript to review it and may within such time require that submission for publication of the manuscript be delayed in order for AZ to file patent applications.