Table 1

Baseline characteristics of all included studies

StudyParticipants and baseline dataIntervention/outcomes
Dapagliflozin
Bailey et al14
Setting: multicentre (n=80)
Design: four-arm, double-blind, placebo-controlled RCT, dual therapy. Only 10 mg arm included in NMA
Follow-up: 24 weeks; 102 weeks		N: 534
Participants: patients with type 2 diabetes inadequately controlled with metformin (≥1500 mg/day)
Age (years): dapa 10 mg+metformin 52.7, SD 9.9; placebo+metformin 53.7, SD 10.3
HbA1c (%): dapa 10 mg+metformin 7.92, SD 0.82; placebo+metformin 8.11, SD 0.96
BMI (kg/m2): dapa 10 mg+metformin 31.2, SD 5.1; placebo+metformin 31.8, SD 5.3		Interventions

  • 10 mg dapa once daily+metformin

Comparator

  • Placebo+metformin

Outcomes

  • Primary outcomes: change in HbA1c from baseline to 24 weeks

  • Other outcomes: change in FPG, change in total body weight, the proportion of patients achieving an HbA1c <7% at 24 weeks, change in HbA1c percentage at week 24 for patients with a baseline HbA1c of 9% or more and percentage change from baseline in bodyweight, and decreases in bodyweight of 5% or more

Bolinder et al11
Setting: multicentre (n=40) in Bulgaria, Czech Republic, Hungary, Poland and Sweden
Design: two-arm, double-blind, placebo-controlled RCT in dual therapy
Duration: 24 weeks		N: 180
Participants: patients with type 2 diabetes inadequately controlled with metformin (≥1500 mg/day)
Age (years): dapa 10 mg+metformin 60.6, SD 8.2; placebo+metformin 60.8, SD 6.9
HbA1c (%): dapa 10 mg+metformin 7.19, SD 0.44; placebo+metformin 7.16, SD 0.53. Note the very low baseline level
BMI (kg/m2): dapa 10 mg+metformin 32.1, SD 3.9; placebo+metformin 31.7, SD 3.9		Intervention

  • 10 mg dapa once daily (n=89)+metformin

Comparator

  • Placebo (n=91)+metformin

Outcomes

  • Primary outcome: change from baseline at week 24 in total body weight

  • Other outcomes: change from baseline at week 24 in waist circumference, total FM as measured by DEXA; proportion of patients achieving a body weight reduction of at least 5% at week 24

Ferrannini et al15
Setting: multicentre (n=85) in the USA, Canada, Mexico and Russia
Design: double-blind, parallel-group, placebo-controlled, phase 3 RCT in monotherapy
Duration: 24 weeks		N: 274
Participants: patients with type 2 diabetes mellitus inadequately controlled with diet and exercise, naïve to treatment
Age (years): dapa 10 mg 50.6, SD 9.97; placebo 52.7, SD 10.3
HbA1c (%): dapa 10 mg 8.01, SD 0.96; placebo 7.84, SD 0.87
BMI (kg/m2): dapa 10 mg+metformin 33.6, SD 5.4; placebo+metformin 32.3, SD 5.5		Intervention

  • 10 mg dapa (n=70)

Comparator

  • Placebo (n=75)

Outcomes

  • Primary outcome: change from baseline in HbA1c at week 24

  • Other outcomes: change from baseline at week 24 in FPG and body weight

Henry et al12
—Two studies (focusing on study 2)
Setting: multicentre (n=131)—hospitals and clinics in North America, Latin America, Europe and Asia
Design: double-blind, active controlled trials in dual therapy
Duration: 24 weeks		N: 638
Participants: patients with type 2 diabetes inadequately controlled with diet and exercise, naïve to treatment
Age (years): dapa 10 mg+metformin 51.5, SD 10.1; placebo+metformin 52.7, SD 10.4
HbA1c (%): dapa 10 mg+metformin 9.1, SD 1.3; placebo+metformin 9.1, SD 1.3
BMI (kg/m2): NR		Intervention

  • 10 mg dapa+metformin XR (n=211)

Comparator

  • Placebo+metformin XR (n=208)

Outcomes

  • Primary outcome: change from baseline in HbA1c at week 24

  • Secondary/other outcomes: change from baseline at week 24 in FPG and body weight

Ji et al17
Setting: multicentre (n=40) in China (n=26), Korea (n=5), Taiwan (n=5) and India (n=4)
Design: double-blind, placebo-controlled, parallel-group, RCT, monotherapy
Duration: 24 weeks		N: 393
Participants: patients with type 2 diabetes naïve to drug treatment (prescription medication for diabetes including Chinese traditional medicines for diabetes, or prescription medication for diabetes for <24 weeks since diagnosis)
Age (years): dapa 10 mg 51.2, SD 9.89; placebo 49.9, SD 10.87
HbA1c (%): dapa 10 mg 8.28, SD 0.95; placebo 8.35, SD 0.95
BMI (kg/m2): dapa 10 mg 25.76, SD 3.43; placebo 25.93, SD 3.64		Intervention

  • 10 mg dapa (n=133)

Comparator

  • Placebo (n=132)

Outcomes

  • Primary outcome: change from baseline in HbA1c at week 24

  • Other outcomes: change from baseline in FPG at week 24; change from baseline in 2 h PPG at week 24; change from baseline in total body weight at week 24; proportion of patients achieving HbA1c levels of <7% at week 24

Kaku et al23 2014
Setting: multicentre (n=NR) in Japan
Design: double-blind, parallel-group, placebo-controlled RCT, monotherapy
Duration: 24 weeks		N: 261
Participants: patients with type 2 diabetes naïve to drug treatment
Age (years): dapa 10 mg 57.5, SD 9.3; placebo 60.4, SD 9.7
HbA1c (%): dapa 10 mg 7.46, SD 0.61; placebo 7.50, SD 0.63
BMI (kg/m2): dapa 10 mg 26.6, SD 4.52; placebo 25.22, SD 4.39		Intervention

  • 10 mg dapa (n=1)

Comparator

  • Placebo (n=132)

Outcomes

  • Primary outcome: change from baseline in HbA1c at week 24

  • Other outcomes: change from baseline in FPG and body weight at week 24; change from baseline in total body weight in patients with baseline BMI of≥25 kg/m2; fasting insulin and C peptide; seated SBP overall and in patients with baseline seated SBP≥130 mmHg; fasting lipids; proportion of patients achieving HbA1c levels of <7% at week 24 in patients with baseline HbA1c ≥7% and proportion of patients discontinuing treatment due to lack of efficacy or rescued for failing to maintain FPG below prespecified rescue criteria after 24 weeks, and safety

Canagliflozin
Lavalle-Gonzalez et al19
Setting: multicentre (n=169) in 22 countries
Design: double-blind, placebo-controlled and active-controlled trial, dual therapy
Duration: 26 weeks		N: 1284
Participants: patients with type 2 diabetes inadequately controlled with metformin
Age (years): cana 100 mg+metformin 55.5, SD 9.4; cana 300 mg+metformin 55.3, SD 9.2; placebo+metformin 55.3, SD 9.8
HbA1c (%): cana 100 mg+metformin 7.9, SD 0.9; cana 300 mg+metformin 7.9, SD 0.9; placebo+metformin 8.0, SD 0.9
BMI (kg/m2): cana 100 mg+metformin 32.4, SD 6.4; cana 300 mg+metformin 31.4, SD 6.3; placebo+metformin 31.1, SD 6.1		Intervention

  1. Cana 100 mg+metformin (n=368)

  2. Cana 300 mg+metformin (n=367)

Comparator

  1. Placebo+metformin (n=186)

Outcomes

  • Primary outcome: change in HbA1c from baseline to week 26

  • Other outcomes: proportion of patients achieving an HbA1c level of <7.0%; change in FPG, 2 h PPG and SBP; change in body weight, triglycerides and HDL-C

Stenlof et al13
Setting: multicentre (n=NR) in 17 countries
Design: double-blind, placebo-controlled, phase 3 RCT, monotherapy
Duration: 26 weeks		N: 584
Participants: patients with type 2 diabetes inadequately controlled with diet and exercise and also on antihypoglycaemic agents who underwent washout (8 weeks and diet and exercise period with placebo run-in period) of the agent
Age (years): cana 100 mg 55.1, SD 10.8; cana 300 mg 55.3, SD 10.2; placebo 55.7, SD 10.9
HbA1c (%): cana 100 mg 8.1, SD 1.0; cana 300 mg 0, SD 1.0; placebo 8.0, SD 1.0
BMI (kg/m2): cana 100 mg 31.3, SD 6.6; cana 300 mg 31.7, SD 6.0; placebo 31.8, SD 6.2		Intervention

  1. Cana 100 mg (n=195)

  2. Cana 300 mg (n=197)

Comparator

  1. Placebo (n=192)

Outcomes

  • Primary outcome: change in HbA1c from baseline to week 26

  • Other outcomes: proportion of patients reaching HbA1c <7.0%; changes from baseline at week 26 in FPG and SBP; per cent changes from baseline in body weight, HDL-C and triglycerides

Inagaki et al22
Setting: multicenter (n=31) in Japan
Design: double-blind placebo-controlled phase 3 parallel group trial
Duration: 24 weeks		N: 272
Participants: patients with type 2 diabetes inadequately controlled with diet and exercise
Age (years): cana 100 mg 58.4, SD 10.4; placebo 58.2, SD 11.0
HbA1c (%): cana 100 mg 7.98, SD 0.73; placebo 8.04, SD 0.70
BMI (kg/m2): cana 100 mg 25.59, SD 4.20; placebo 25.85, SD 4.39		Intervention

  1. 100 mg canagliflozin (n=90)

Comparator

  1. placebo (n=93)

Outcomes

  • Primary outcome: change from baseline in HbA1c at week 24

  • Other outcomes: proportion of patients achieving HbA1c target of <7%, change in FPG, PG at 2 h OGTT, per cent change in body weight, change in waist circumference, BP, HOMA, per cent change in lipids and safety

Empa
Haring et al16
Setting: multicentre (n=148) in 12 countries (Canada, China, France, Germany, India, Korea, Mexico, Slovakia, Slovenia, Taiwan, Turkey and the USA)
Design: double-blind placebo-controlled phase 3 RCT, dual therapy
Duration: 24 weeks		N: 637
Participants: patients with type 2 diabetes inadequately controlled with diet and exercise and a stable immediate-release metformin regimen
Age (years): empa 10 mg+metformin 55.5, SD 9.9; empa 25 mg+metformin 55.6, SD 10.2; placebo+metformin 56, SD 9.7
HbA1c (%): empa 10 mg+metformin 7.94, SD 0.79; empa 25 mg+metformin 7.86, SD 0.87; placebo+metformin 7.90, SD 0.88
BMI (kg/m2): empa 10 mg+metformin 29.1, SD 5.5; empa 25 mg+metformin 29.7, SD 5.7; placebo+metformin 28.7, SD 5.2		Intervention

  1. 10 mg empa+metformin (n=217)

  2. 25 mg empa+metformin (n=213)

Comparator

  1. Placebo+metformin (n=207)

Outcomes

  • Primary outcome: change from baseline in HbA1c at week 24

  • Other outcomes: change from baseline to week 24 in body weight and MDG; percentage of patients with baseline HbA1c ≥7.0% who had HbA1c level <7% at week 24; change from baseline in FPG, waist circumference, and SBP and DBP at week 24; percentage of patients with >5% reduction in body weight at week 24; use of rescue medication; and safety

Roden et al20
Setting: multicentre (n=124) in 9 countries (Belgium, Canada, China, Germany, India, Japan, Switzerland and USA)
Design: double-blind parallel-group RCT, monotherapy
Duration: 24 weeks		N: 899
Participants: patients with type 2 diabetes with no previous history to treatment (oral or injected hypoglycaemic agents 12 weeks prior to randomisation)
Age (years): empa 10 mg 56.2, SD 11.6; empa 25 mg 53.8, SD 11.6; placebo 54.9, SD 10.9
HbA1c (%): empa 10 mg 7.87, SD 0.88; empa 25 mg 7.86, SD 0.85; placebo 7.91, SD 0.87
BMI (kg/m2): empa 10 mg 28.3, SD 5.5; empa 25 mg 28.2, SD 5.5; placebo 28.7, SD 6.2		Intervention

  1. 10 mg empa (n=224)

  2. 25 mg empa (n=224)

Comparator

  1. Placebo (n=228)

Outcomes

  • Primary outcome: change from baseline in HbA1c at week 24

  • Other outcomes: change from baseline in bodyweight at week 24; change from baseline in SPB and DBP at week 24; proportion of patients with baseline HbA1c level of at least 7% achieving HbA1c level lower than 7.0% at week 24; change from baseline in FPG at week 24; proportion of patients with >5% reduction in bodyweight at week 24; change from baseline in waist circumference at week 24; proportion of patients with uncontrolled BP at baseline who controlled their BP at week 24 (SBP <130 mm Hg and DBP <80 mm Hg); and safety

Luseogliflozin
Seino et al21
Setting: multicentre (n=23) in Japan
Design: double-blind, placebo-controlled, parallel-group, comparative, RCT, monotherapy
Duration: 24 weeks		N: 158
Participants: patients diagnosed with type 2 diabetes on stable diet therapy for ≥6 weeks and not on any antidiabetic drugs
Age (years): luseo 2.5 mg 58.9, SD 10.1; placebo 59.6, SD 9.3
HbA1c (%): luseo 2.5 mg 8.14, SD 0.91; placebo 8.17, SD 0.80
BMI (kg/m2): luseo 2.5 mg 25.98, SD 4.88; placebo 25.34, SD 4.19		Intervention

  1. 2.5 mg luseo (n=79)

Comparator

  1. Placebo (n=79)

Outcomes

  • Primary: change in HbA1c from baseline to end of treatment

  • Others: plasma glucose, insulin, glucagon, serum CPR, intact

Ipragliflozin
Kashiwagi et al24
Setting: multicentre (n=34) in Japan
Design: double-blind, placebo-controlled RCT with a 28 weeks open-label extension
Duration: 24 weeks with a 28 weeks open-label extension		N: 168
Participants: patients with type 2 diabetes of ≥12 weeks of duration, treated with metformin for ≥6 weeks and with an HbA1c level of 7.4–9.9% and BMI of 20–45 kg/m2
Age (years): ipra 50 mg 56.2, SD 10.67; placebo 57.7, SD 9.24
HbA1c (%): ipra 50 mg 8.25, SD 0.719; placebo 8.38, SD 0.738
BMI (kg/m2): ipra 50 mg 25.96, SD 4.410; placebo 25.47, SD 3.092		Intervention

  1. Ipra 50 mg+metformin (n=112)

Comparator

  1. Placebo+metformin (n=56)

Outcomes

  • Primary outcome: change in HbA1c from baseline to end of treatment

  • Other outcomes: body weight, waist circumference, FPG, FSI, plasma leptin, and adiponectin levels, HOMA-R and HOMA-β and safety outcomes

Togoliflozin
Kaku et al23
Setting: multicentre (n=33) in specialists and non-specialists hospital in Japan
Design: double-blind, placebo-controlled, parallel-group RCT
Duration: 24 weeks		N: 235
Participants: patients with type 2 diabetes naïve to drug therapy but, only treated with diet and exercise for ≥8 weeks before screening, HbA1c level of ≥7.3% to <10.3%, BMI of ≥18.5 to <45 kg/m2, per cent changes in HbA1c and body weight from the provisional registration visit to the final registration visit of ≤10% and <5%, respectively, controlled BP and those requiring antihypertensives only those who did not require changing of their dosing regimen. Patients using other antidiabetic drugs were eligible if they had stopped their drug ≥8 weeks before the provisional registration. (HbA1c reported in Japan Diabetes Society or JDS units but, converted to NGSP units)
Age (years): tofo 10 mg 58.6, SD 9.8; tofo 20 mg 56.6, SD 10.2; tofo 40 mg 57.0, SD 9.1; placebo 56.8, SD 9.9
HbA1c (%): tofo 10 mg 8.45, SD 0.75; tofo 20 mg 8.34, SD 0.81; tofo 40 mg 8.37, SD 0.77; placebo 8.41, SD 0.78
BMI (kg/m2): tofo 10 mg 25.07, SD 3.53; tofo 20 mg 24.99, SD 4.55; tofo 40 mg 25.78, SD 4.10; placebo 26.00, SD 4.11		Intervention

  1. Tofo 10 mg (n=59)

  2. Tofo 20 mg (n=60)

  3. Tofo 40 mg (n=59)

Comparator

  1. Placebo (n=57)

Outcomes

  • Primary outcome: change in HbA1c from baseline to end of treatment

  • Other outcomes: 24 h FPG, 2 h PPG, fasting and 2 h postprandial insulin, glycoalbumin, body weight, pancreatic β-cell function (HOMA-β), insulin resistance (HOMA-R) and Matsuda index, insulin, serum lipid levels, adiponectin, BP and waist circumference, and safety outcomes

  • BMI, body mass index; cana, canagliflozin; CPR, C peptide immunoreactivity; dapa, dapagliflozin; DBP, diastolic blood pressure; DEXA, dual-energy X-ray absorptiometry; empa, empagliflozin; FM, fat mass; FPG, fasting plasma glucose; FSI, fasting serum insulin; HbA1c, glycated haemoglobin; HDL-C, high-density lipoprotein cholesterol; HOMA-R, homeostasis model assessment of insulin resistance; HOMA-β, homeostasis model assessment of β-cell function; ipra, ipragliflozin; luseo, luseogliflozin; NMA, network meta-analysis; NR, not reported; OGTT, oral glucose tolerance test; PPG, postprandial glucose; RCT, randomised controlled trial; SBP, systolic blood pressure; tofo, tofogliflozin.