Cefalu 2015.

Study characteristics
Methods	Title: Dapagliflozin's effects on glycemia and cardiovascular risk factors in high‐risk patients with type 2 diabetes: a 24‐week, multicenter, randomized, double‐blind, placebo‐controlled study with a 28‐week extension acronym of trial: NA study design: a multicentre, randomised, double‐blind, placebo‐controlled, international, phase 3 study total duration of study: 24 weeks number of study centres and location: 141 study locations in Europe, Asia, the U.S., Canada, and Argentina date of study: from February 2010 to December 2012
Participants	Cardiovascular disease categories: i) intervention: ASCVD: (100%), HF: NA Qualifying CVD event, n (%): Coronary heart disease; 338 (74.3%), Stroke or TIA; 100 (22.0%), Peripheral artery disease; 15 (3.3%), Not reported 2 (0.4%) ii) comparison: ASCVD: (100%), HF: NA Qualifying CVD event, n (%): Coronary heart disease; 349 (76.0%), Stroke or TIA; 89 (19.4%), Peripheral artery disease; 18 (3.9%), Not reported 3 (0.7%) N randomised: i) intervention: 462, ii) comparison: 460 N lost to follow‐up/withdrawn: i) intervention: 40, ii) comparison: 30 N analysed: i) intervention: 459, ii) comparison: 455 mean age, age range: i) intervention: 62.8 ± 7.0, ii) comparison: 63 ± 7.7 gender (female): i) intervention: 146 (32.1), ii) comparison: 144 (31.4) body mass index (BMI): i) intervention: 32.6 ± 5.9, ii) comparison: 32.9 ± 6.1 diabetes mellitus (DM): (100%) chronic kidney disease (CKD): NA severity of condition (such as the commonly‐used classification system, NYHA classification or the ACC/AHA stages of heart failure): NYHAⅠ‐Ⅲ left ventricular ejection fraction: NA baseline diabetes condition including HbA1c: i) intervention: 8.18 ± 0.84, ii) comparison: 8.08 ± 0.80 smoking history: NA
Interventions	Intervention: once‐daily dapagliflozin 10 mg: SGLT‐2i Comparison: placebo type of active treatment for DM: i) intervention: oral antidiabetic drugs (OAD) 221 (48.6%), OAD plus insulin 158 (34.7%), Insulin only 76 (16.7%) ii) comparison: oral antidiabetic drugs (OAD) 217 (47.3%), OAD plus insulin 165 (35.9%), Insulin only 77 (16.8) concomitant medications: i) intervention: Anti hypertensive 455 (98.9%), ACEi/ARB 408 (88.7%), Diuretics 212 (46.1%), Loop diuretics 81 (17.6%), Lipid‐lowering medications 387 (84.1%), ASA 329 (71.5%) ii) comparison: Antihypertensive 454 (98.3%), ACEi/ARB 409 (88.5%), Diuretics 241 (52.24%), Loop diuretics 100 (21.6%), Lipid‐lowering medications 409 (88.5%), ASA 341 (73.8%)
Outcomes	Primary outcomes: The primary end points evaluated in the overall population and in the predefined age strata included the mean change in HbA1c level from baseline to week 24 and the proportion of responders achieving a three‐item end point of combined clinical benefit at week 24. The three‐item composite end point consisted of an absolute drop from baseline in HbA1c of ≧0.5% (5.5 mmol/mol), a relative drop of ≧3% for total BW, and an absolute drop of ≧3 mmHg from baseline in seated SBP. These end points were also evaluated in a post hoc subgroup analysis of insulin use. Secondary outcomes: Key secondary variables included the mean change in seated SBP from baseline (at weeks 8 and 24), the mean percentage change in BW, and the proportion of patients with baseline BMI of ≧27 kg/m2 with a ≧5% reduction in BW. Other secondary end points included the mean change in seated diastolic blood pressure (DBP), the proportion of patients with seated SBP of <130 mmHg in the group of patients with a baseline seated SBP of ≧130 mmHg, the mean change in BW from baseline, the mean change in HbA1c level in patients with a baseline HbA1c level of ≧8.0% (64 mmol/mol) and an HbA1c level of ≧9.0% (75 mmol/mol), the proportion of patients achieving an HbA1c level of <7.0% (53 mmol/mol), the mean change in FPG at weeks 1 and 24, the proportion of patients rescued for failing to maintain FPG/HbA1c levels below the prespecified rescue criteria at weeks 4, 8, 16, 24, and 52 (see Supplementary Data), the proportion of patients achieving a reduction in HbA1c of ≧0.5% (5.5 mmol/mol), the proportion of patients achieving a reduction in seated SBP from baseline of ≧3 or ≧5 mmHg, and the mean change in calculated average daily insulin dose in patients treated with insulin at baseline.
Notes	Funding for trial: "Acknowledgments. Initial medical writing assistance was provided by Alexandra Silveira, PhD, of PPSI (a PAREXEL company), and was funded by Bristol‐Myers Squibb. Funding. W.T.C. was supported in part by a grant from the National Institute of General Medical Sciences of the National Institutes of Health (1‐U54‐GM‐104940)." Primary endpoint is not feasible in this study: narrative synthesis. This could not be well differentiated from a similar study (Leiter 2014). NCT01031680
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Patients were assigned a unique enrolment number using Interactive Web Response System (IWRS) or Interactive Voice Response System (IVRS) at visit 1 (Enrollment Visit)" in supplement file.
Allocation concealment (selection bias)	Low risk	"Patients were assigned a unique enrolment number using Interactive Web Response System (IWRS) or Interactive Voice Response System (IVRS) at visit 1 (Enrollment Visit)" in supplement file.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind, placebo controlled.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not clearly declared
Incomplete outcome data (attrition bias) All outcomes	Low risk	807 of 922 patients (87.5%) completed 52 weeks of the study.
Selective reporting (reporting bias)	Low risk	Results reported for all measures.
Other bias	Low risk	No other bias.