Supplemental Table 2. Randomized clinical trials of treatment intensification beyond monotherapy including an SGLT2 inhibitor

Clinical Trials Study Number / Background Therapy / Comparators / Baseline HbA1c (%) & FPG / Length (primary outcome) / Primary Outcome Results / Select Secondary Outcomes Results / Safety and Tolerability Points of Interest
NCT01106677[69] / Metformin / Canagliflozin 100mg (CANA100) QD (n=368),
Canagliflozin 300mg QD (CANA300), (n=367),
Sitagliptin (sita) 100 mg QD, (n=366),
Sitagliptin + Placebo
(n=183) / 7.9%
169.2 mg/dl / 26 weeks / Change in A1c:
CANA300: -0.77%
CANA100: --0.62%
Sita: -0.66% / Change in FPG at week 52 (mg/dl):
CANA300: -36.0
CANA100: -27.0
Sita: -18.0
Change in Body Weight (kg) at week 52:
CANA300: -3.7
CANA100: -3.3
Sita: -1.2
Change in blood pressure (mmHg) at week 52: Systolic:
CANA300: -4.7
CANA100: -3.5
Sita: -0.7
Diastolic:
CANA300: -1.8
CANA100: -1.8
Sita: -0.3 / (At Week 52)
UTI:
CANA300: 4.9%
CANA100: 7.9%
Sita: 6.3%
Sitagliptin/Placebo: 6.6%
Genital Infection:
Increased incidence of genital mycotic infections in both CANA300 and CANA100
HYPO:
CANA300: 4.7%
CANA100: 5.0%
Sita: 4.2%
Sitagliptin/Placebo: 2.7%
SAEs:
Canagliflozin 300mg: 3.3%
Canagliflozin 100mg: 4.1%
Sitagliptin: 4.9%c
Sitagliptin/Placebo: 3.8%
NCT00968812[70] / Metformin / Canagliflozin 100mg QD (n=483),
Canagliflozin 300mg QD (n=485),
Glimepiride (up to 6 mg or 8 mg QD), (n=482) / 7.8%
167.4 mg/dl / 52 weeks / Change in A1c:
CANA100: –0.82%
CANA300: -0.93%
Glimepiride:
–0.81% / Change in Body Weight (kg):
CANA300: -0.7
CANA100: -0.6
Glimepiride: +0.7 / UTI:
CANA300: 6%
CANA100: 6%
Glimepiride: 5%
Genital Infection:
CANA300: 11.1%
CANA100: 8.9%
Glimepiride: 1%
HYPO:
CANA300: 5%
CANA100: 6%
Glimepiride: 34%
Blood Pressure(mmHg):
CANA300: -4.6
CANA100: -3.3
Glimepiride: +0.2
Diastolic:
CANA300: -2.5
CANA100: -1.8
Glimepiride -0.1
SAEs:
CANA300: - 5%
CANA100: - 5%
Glimepiride - 8%
NCT00528879[74] / Metformin / Dapagliflozin 10mg (DAPA10) QD (n=135),
Dapagliflozin 5mg (DAPA5) (n=137),
Dapagliflozin 2.5mg (DAPA2.5) (n=137)
Placebo (n=137) / 8.1%
162.9 mg/dl / 102 weeks / Change in A1c:
DAPA10: -0.78%
DAPA5: -0.58%
DAPA2.5: -0.48%
Placebo: +0.02% / Change in FPG (mg/dl)
DAPA10: -24.5
DAPA5: -26.5
DAPA2.5: -19.3
Placebo -10.4
Change in Body Weight (kg):
DAPA10: -1.74
DAPA5: -1.70
DAPA2.5: -1.10
Placebo: +1.36 / UTI:
DAPA10: - 11.9%
DAPA5: - 5.8%
DAPA2.5: - 4.4%
Placebo- 5.8%
Genital Infection:
DAPA10: 12.6
DAPA5: 5mg 14.6%
DAPA2.5: 11.7%
Placebo 5.1%
HYPO:
DAPA10: -5.2%
DAPA5: - 5.1%
DAPA2.5: - 3.6%
Placebo- 5.8%
Change in blood pressure:
Systolic:
DAPA10: -0.3
DAPA5: -1.1
DAPA2.5: -0.7
Placebo +1.5
Diastolic:
DAPA10: -1.2
DAPA5: -1.5
DAPA2.5: -0.1
Placebo -1.0
SAEs:
DAPA10: 10.4%
DAPA5: 6.6%
DAPA2.5: - 10.9%
Placebo- 10.2%
NCT01606007[57] / Metformin / Dapagliflozin 10mg (n=179),
Saxagliptin 5mg(SAXA5, n=176),
Dapagliflozin 10mg/Saxagliptin 5mg (n=179) / 8.9%
186 mg/dl / 24 weeks / Change in A1c:
DAPA10: -1.20%
SAXA5: -0.88%
DAPA10/SAXA5: -1.47% / Change in FPG (mg/dl):
DAPA10: -32
SAXA5: -14
DAPA10/SAXA5: -38
Change in Body Weight (kg):
DAPA10: -2.4
SAXA5: 0.0
DAPA10/SAXA5: -2.1
% with < 7.0% A1c:
DAPA10: 22%
SAXA5: 18%
DAPA10/SAXA5: 41% / UTI:
DAPA10: 5%
SAXA5: 5%
DAPA10/SAXA5: 0.6%
Genital Infection:
DAPA10: 6%
SAXA5: 0.6%
DAPA10/SAXA5: 0%
HYPO:
DAPA10: 1%
SAXA5: 1%
DAPA10/SAXA5: 1%
SAEs:
DAPA10: 1%
SAXA5: 3%
DAPA10/SAXA5: 1%
NCT00984867[73] / Sitagliptin+ Metformin / Dapagliflozin 10mg (DAPA10, n=223),
Placebo (n=224), / 7.9-8.0%
162-163 mg/dl / 24 weeks / Change in A1c:
DAPAP10: - 0.5%
Placebo- 0.0% / Change in A1c in patients with A1c 8%:
DAPA10: -0.8%
Placebo: 0%
Change in FPG (mg/dL):
DAPA10: -24.1
Placebo +3.8
Change in Body Weight (kg):
DAPA10: -2.1
Placebo: -0.3 / UTI:
DAPA10: 4.9%
Placebo: 4.0%
Genital Infection:
DAPA10: 8.4%
Placebo: 0.4%
HYPO:
DAPA10: 2.4%
Placebo: 1.8%
Change in Blood Pressure(mmHg) in patients with baseline SBP 130 mmHg:
Systolic:
DAPA10: -6.0
Placebo: -5.1
SAEs:
DAPA10: 4.4%
Placebo: 4.0%
NCT01422876[59] / Metformin / Empagliflozin 25mg (EMPA25, n=141),
Empagliflozin 10mg (EMPA10, n=140),
Linagliptin 5mg (lina)
n=132,
Empagliflozin 25mg/Linagliptin 5mg (n=137),
Empagliflozin 10mg/Linagliptin 5mg (n=136) / 7.98%
157.9 mg/dl / 24 weeks / Change in A1c:
EMPA25: -0.62%
EMPA10: -0.66%
Lina: -0.70%
EMPA25/Lina: -1.19%
EMPA10/Lina: -1.08% / Change in FPG (mg/dl):
EMPA25: -18.8
EMPA10: -20.8
Lina: -13.1
EMPA25/Lina: -35.3
EMPA10/Lina: -32.2
Change in Body Weight (kg):
EMPA25: -3.2
EMPA10: -2.5
Lina: 5mg -0.7
EMPA25/Lina: -3.0
EMPA10/Lina: -2.6 / UTI:
EMPA25: 12.1%
EMPA10: 9.3%
Lina: 11.4%
EMPA25/Lina: 8.8%
EMPA10/Lina: 8.8%
Genital Infection:
EMPA25: 8.5%
EMPA10: 7.9%
Lina: 5mg 2.3%
EMPA25/Lina: 2.2%
EMPA10/Lina: 5.9%
HYPO:
EMPA25: 3.5%
EMPA10: 1.4%
Lina: 2.3%
EMPA25/Lina: 3.6%
EMPA10/Lina: 2.2%
Week 52 Blood Pressure(mmHg):
Systolic:
EMPA25: 2.8
EMPA10: 3.5
Lina: +0.3
EMPA25/Lina: -3.6
EMPA10/Lina: -2.8
Diastolic:
EMPA25: -1.9
EMPA10: -1.8
Lina: -0.6
EMPA25/Lina: -2.2
EMPA10/Lina: -2.2
SAEs:
EMPA25: 7.1%
EMPA10: 4.3%
Lina: - 6.1%
EMPA25/Lina: 4.4%
EMPA10/Lina: 6.6%
NCT01159600[75] / Metformin / Empagliflozin 25mg (EMPA25, n=213),
Empagliflozin 10mg (EMPA10, n=217),
Placebo (n=207) / 7.9%
153.2 mg/dl / 24 weeks / Change in A1c:
EMPA25: -0.77%
EMPA10: -0.70%
Placebo -0.13% / Change in Weight (kg):
EMPA25: -2.46
EMPA10: -2.08
Placebo: -0.45 / UTI:
EMPA25: 5.6%
EMPA10: 5.1%
Placebo: 4.9%
Genital Infection:
EMPA25: 4.7%
EMPA10: 3.7%
Placebo 0.0%
HYPO:
EMPA25: 1.4%
EMPA10: 1.8%
Placebo- 0.5%
Change in Blood Pressure:
Systolic:
EMPA25: -5.2
EMPA10: -4.5
Placebo: -0.4
Diastolic:
EMPA25: -1.6
EMPA10: -2.0
Placebo- 0.0
SAEs:
EMPA25: 2.3%
EMPA10: 3.2%
Placebo: 3.4%
NCT00881530[76] / Metformin / Empagliflozin 25mg (EMPA25, n=166),
Empagliflozin 10mg (EMPA10, n=166),
Sitagliptin (Sita, n=56) / 7.91%
177.4mg/dl / 90 weeks (12 weeks blinded + 78 week open-label extension) / *^Change in A1c:
EMPA25: - 0.74%
EMPA10: -0.61%
Sita: -0.45% / *^Change in Blood Pressure (mmHg):
Systolic:
EMPA25: -3.0
EMPA10: -3.3
Sita: +1.8
Diastolic:
EMPA25: -2.0
EMPA10: -0.9
Sita: +1.2
Change in Body Weight (kg):
EMPA25: - 4.0
EMPA10: -3.1
Sita: -0.4 / ^UTI:
EMPA25: 9.0%
EMPA10: 12.7%
Sita: 12.5%
Genital Infection:
EMPA25: 3.6%
EMPA10: 3.0%
Sita: 0.0%
HYPO:
EMPA25: 1.8%
EMPA10: 2.4%
Sita: 3.6%
SAEs:
EMPA25- 6.0%
EMPA10: 7.8%
Sita: 16.1%

UTI - Urinary Tract Infection

SAE – Serious Adverse Event

HYPO- Hypoglycemia

*: At end of 78 week extension trial

^: Only captures individuals who participated in both preceding and extension trials (Empagliflozin 25mg/Metformin n= 139, Empagliflozin 10mg/Metformin n=137, Sitagliptin/Metformin n= 56)