Introduction
Methods
Search Strategy
Study Selection and Data Extraction
Risk of Bias
Statistical Analysis
Compliance with Ethics Guidelines
Results
Study Characteristics and Quality Assessment
Network Consistency
Meta-Analysis
Primary Efficacy Outcomes: Glycated Hemoglobin and Body Weight
WMD/OR (95% CI) | |||||||
---|---|---|---|---|---|---|---|
HbA1c, % (lower left side) | 2-h postprandial glucose, mmol/l (upper right side) | ||||||
PLA | − 3.07 (− 4.12, − 2.03) |
− 1.71 (− 2.26, − 1.15)
|
− 1.62 (− 2.68, − 0.56)
|
− 1.95 (− 3.70, − 0.20)
|
− 2.19 (− 3.37, − 1.01)
|
− 1.50 (− 2.99, − 0.01)
| – |
− 0.73 (− 0.84, − 0.62)
|
SGLT2
|
1.37 (0.32, 2.42)
|
1.45 (0.07, 2.84)
| 1.12 (− 0.84, 3.09) | 0.88 (− 0.63, 2.39) | 1.58 (− 0.16, 3.31) | – |
− 0.65 (− 0.73, − 0.56)
| 0.08 (− 0.03, 0.19) |
DPP4
| 0.09 (− 0.82, 0.99) | − 0.24 (− 1.91, 1.42) | − 0.48 (− 1.62, 0.65) | 0.21 (− 1.17, 1.59) | – |
− 0.69 (− 0.80, − 0.57)
| 0.04 (− 0.09, 0.16) | − 0.04 (− 0.13, 0.05) |
SU
| − 0.33 (− 1.73, 1.07) | − 0.57 (− 2.02, 0.88) | 0.12 (− 1.53, 1.78) | – |
− 0.73 (− 0.87, − 0.58)
| − 0.00 (− 0.16, 0.16) | − 0.08 (− 0.22, 0.05) | − 0.04 (− 0.16, 0.08) |
TZD
| − 0.24 (− 2.26, 1.77) | 0.45 (− 1.71, 2.62) | – |
− 0.75 (− 0.95, − 0.55)
| − 0.02 (− 0.24, 0.19) | − 0.10 (− 0.30, 0.09) | − 0.06 (− 0.27, 0.15) | − 0.02 (− 0.26, 0.21) |
AGI
| 0.69 (− 1.10, 2.48) | – |
− 0.49 (− 0.70, − 0.28)
|
0.24 (0.01, 0.46)
| 0.16 (− 0.04, 0.35) | 0.20 (− 0.02, 0.42) | 0.24 (0.00, 0.48) | 0.26 (− 0.02, 0.54) |
Met
| – |
− 0.53 (− 0.94, − 0.11)
| 0.20 (− 0.22, 0.62) | 0.12 (− 0.29, 0.53) | 0.16 (− 0.24, 0.56) | 0.20 (− 0.22, 0.62) | 0.22 (− 0.23, 0.67) | − 0.04 (− 0.49, 0.41) |
Meglitinide
|
Fasting plasma glucose, mmol/l (lower left side) | Body weight, kg (upper right side) | ||||||
---|---|---|---|---|---|---|---|
PLA
|
− 2.23 (− 2.55, − 1.91)
| − 0.11 (− 0.39, 0.18) |
2.00 (1.63, 2.36)
|
2.53 (1.95, 3.10)
|
− 0.82 (− 1.61, − 0.04)
| − 0.62 (− 1.46, 0.23) | – |
− 1.49 (− 1.69, − 1.28)
|
SGLT2
|
2.12 (1.79, 2.45)
|
4.22 (3.86, 4.59)
|
4.76 (4.17, 5.34)
|
1.41 (0.59, 2.22)
|
1.61 (0.75, 2.47)
| – |
− 0.95 (− 1.10, − 0.79)
|
0.54 (0.34, 0.75)
|
DPP4
|
2.10 (1.83, 2.37)
|
2.63 (2.12, 3.14)
| − 0.72 (− 1.48,0.05) | − 0.51 (− 1.30, 0.28) | – |
− 1.11 (− 1.34, − 0.89)
|
0.37 (0.13, 0.62)
| − 0.17 (− 0.34, 0.00) |
SU
|
0.53 (0.03, 1.03)
|
− 2.82 (− 3.63, − 2.01)
|
− 2.61 (− 3.45, − 1.77)
| – |
− 1.26 (− 1.60, − 0.91)
| 0.23 (− 0.13, 0.59) |
− 0.31 (− 0.62, − 0.00)
| − 0.14 (− 0.43, 0.15) |
TZD
|
− 3.35 (− 4.27, − 2.43)
|
− 3.14 (− 4.09, − 2.20)
| – |
− 1.07 (− 1.42, − 0.71)
|
0.42 (0.03, 0.82)
| − 0.12 (− 0.47, 0.22) | 0.05 (− 0.33, 0.43) | 0.19 (− 0.27, 0.65) |
AGI
| 0.21 (− 0.90, 1.31) | – |
− 0.26 (− 0.71, 0.18) |
1.23 (0.77, 1.69)
|
0.69 (0.27, 1.10)
|
0.86 (0.41, 1.30)
|
1.00 (0.48, 1.51)
|
0.81 (0.27, 1.34)
|
Met
| – |
− 0.92 (− 1.70, − 0.15)
| 0.56 (− 0.22, 1.34) | 0.02 (− 0.74, 0.78) | 0.19 (− 0.55, 0.93) | 0.33 (− 0.46, 1.12) | 0.14 (− 0.69, 0.97) | − 0.67 (− 1.53, 0.20) |
Meglitinide
|
All−cause mortality (lower left side) | Major adverse cardiovascular event (upper right side) | ||||||
---|---|---|---|---|---|---|---|
PLA
| 0.55 (0.27, 1.11) | 0.55 (0.27, 1.15) | 0.80 (0.37, 1.74) | 1.82 (0.30,11.06) | – | – | – |
0.62 (0.22, 1.75) |
SGLT2
| 1.01 (0.53, 1.94) | 1.46 (0.77, 2.77) | 3.33 (0.57,19.43) | – | – | – |
0.62 (0.24, 1.63) | 1.01 (0.44, 2.30) |
DPP4
| 1.45 (0.97, 2.15) | 3.29 (0.63, 17.23) | – | – | – |
0.82 (0.29, 2.29) | 1.32 (0.62, 2.81) | 1.31 (0.76, 2.25) |
SU
| 2.28 (0.43, 12.14) | – | – | – |
0.29 (0.02, 3.93) | 0.46 (0.04, 5.77) | 0.46 (0.04, 5.77) | 0.35 (0.03, 3.90) |
TZD
| – | – | – |
0.63 (0.01, 35.60) | 1.01 (0.02, 55.81) | 1.01 (0.02, 55.81) | 0.77 (0.01, 40.26) | 2.18 (0.02, 224.15) |
AGI
| – | – |
1.48 (0.08, 28.09) | 2.40 (0.13, 43.52) | 2.40 (0.13, 43.52) | 1.82 (0.11, 30.81) | 5.16 (0.13, 211.75) | 2.37 (0.02, 290.39) |
Met
| – |
0.79 (0.01, 45.95) | 1.28 (0.02, 69.84) | 1.28 (0.02, 66.94) | 0.97 (0.02, 49.23) | 2.75 (0.03, 275.42) | 1.26 (0.00, 334.66) | 0.53 (0.00, 67.59) |
Meglitinide
|
Serious adverse events (lower left side) | Hypoglycemia (upper right side) | ||||||
---|---|---|---|---|---|---|---|
PLA
| 0.73 (0.48, 1.10) | 0.70 (0.45, 1.10) |
6.52 (4.07, 10.45)
| 0.74 (0.35, 1.57) | 0.95 (0.17, 5.30) | 1.00 (0.37, 2.73) |
6.27 (2.24, 17.56)
|
0.79 (0.60, 1.05) |
SGLT2
| 0.97 (0.66, 1.43) |
8.99 (6.21, 13.01)
| 1.02 (0.51, 2.04) | 1.31 (0.24, 7.19) | 1.38 (0.52, 3.67) |
8.64 (3.22, 23.21)
|
0.95 (0.72, 1.26) | 1.20 (0.93, 1.56) |
DPP4
|
9.26 (7.11, 12.05)
| 1.05 (0.55, 1.99) | 1.35 (0.26, 7.09) | 1.42 (0.58, 3.49) |
8.89 (3.43, 23.08)
|
0.94 (0.69, 1.26) | 1.18 (0.93, 1.51) | 0.98 (0.83, 1.16) |
SU
|
0.11 (0.06, 0.20)
|
0.15 (0.03, 0.78)
|
0.15 (0.06, 0.39)
| 0.96 (0.38, 2.40) |
1.46 (0.89, 2.38) |
1.84 (1.15, 2.95)
|
1.53 (1.01, 2.32)
|
1.56 (1.03, 2.35)
|
TZD
| 1.28 (0.22, 7.61) | 1.35 (0.45, 4.08) |
8.48 (2.85, 25.24)
|
0.38 (0.07, 2.11) | 0.48 (0.09, 2.65) | 0.40 (0.07, 2.16) | 0.40 (0.07, 2.21) | 0.26 (0.05, 1.48) |
AGI
| 1.05 (0.16, 6.99) | 6.61 (0.97, 44.95) |
1.16 (0.28, 4.80) | 1.47 (0.36, 6.04) | 1.22 (0.30, 4.90) | 1.24 (0.31, 5.03) | 0.80 (0.19, 3.40) | 3.07 (0.34, 27.51) |
Met
|
6.27 (1.69, 23.29)
|
– | – | – | – | – | – | – |
Meglitinide
|
Urinary tract infection (lower left side) | Diarrhea (upper right side) | |||||
---|---|---|---|---|---|---|
PLA
| 0.80 (0.50, 1.28) |
0.67 (0.45, 0.99)
| 0.72 (0.46, 1.12) | 0.56 (0.28, 1.12) | 1.09 (0.26, 4.60) | 1.29 (0.47, 3.57) |
1.21 (0.90, 1.64) |
SGLT2
| 0.83 (0.52, 1.35) | 0.89 (0.55, 1.44) | 0.70 (0.34, 1.46) | 1.36 (0.30, 6.17) | 1.61 (0.56, 4.62) |
1.12 (0.82, 1.51) | 0.92 (0.71, 1.19) |
DPP4
| 1.07 (0.79, 1.44) | 0.84 (0.47, 1.51) | 1.62 (0.37, 7.23) | 1.93 (0.75, 4.93) |
1.11 (0.78, 1.57) | 0.91 (0.71, 1.18) | 0.99 (0.78, 1.26) |
SU
| 0.79 (0.44, 1.42) | 1.52 (0.34, 6.89) | 1.80 (0.67, 4.83) |
0.73 (0.23, 2.34) | 0.61 (0.19, 1.91) | 0.66 (0.22, 2.01) | 0.66 (0.21, 2.08) |
TZD
| 1.93 (0.39, 9.53) | 2.29 (0.76, 6.92) |
3.37 (0.13, 86.25) | 2.78 (0.11, 70.81) | 3.03 (0.12, 76.25) | 3.05 (0.12, 77.54) | 4.60 (0.15, 139.81) |
AGI
| 1.19 (0.20, 6.92) |
– | – | – | – | – | – |
Met
|
Secondary Efficacy Outcomes: FPG and 2-h PPG
Primary Safety Outcomes: MACEs and All-Cause Mortality
Secondary Safety Outcomes: Hypoglycemia, SAEs, UTI and Diarrhea
Ranking of Interventions and Cluster Analysis
Treatments | SUCRA values | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
HbA1c | 2-h PPG | FPG | Body weight | All-cause mortality | MACE | Hypoglycemia | SAE | UTI | Diarrhea | |
Placebo |
0.1
|
0.7
|
2.1
| 39.1 | 32.5 | 27.9 | 46.9 | 42 | 68 | 26 |
SGLT-2 Inhibitor | 77.5 |
95.1
|
97.3
|
100
| 60.1 | 81.5 | 74.1 |
77.6
| 31.5 | 49.2 |
DPP-4 inhibitor | 45.8 | 45.8 | 39.7 | 48.9 | 60.6 |
82.7
|
77.7
| 48.7 | 47.9 | 73.5 |
Sulfonylurea | 63.3 | 42 | 62.9 | 16.4 | 40.3 | 42.6 |
6.4
| 50.7 | 52.6 | 62.5 |
Thiazolidinedione | 76.2 | 59 | 78.7 |
0.3
|
75.1
|
15.2
| 72.1 |
9.7
|
75.3
|
83.9
|
AGI |
79.3
| 67.4 | 56.7 | 76.4 | 51.4 | NAj | 60.6 | 84.8 |
24.9
| 34 |
Met | 22.4 | 40.1 | 13.5 | 68.9 |
31.4
| NA | 53.9 | 36.4 | NA |
20.9
|
Meglitinide | 36.4 | NA | 49.2 | NA | 48.6 | NA | 8.4 | NA | NA | NA |
Sensitivity Analysis and Publication Bias
Treatment | Complete analysis | SUCRA | Rank | Excluding single-blinded and unblinded studies | SUCRA | Rank |
---|---|---|---|---|---|---|
MACE | ||||||
SGLT-2 inhibitor | 0.55 (0.27, 1.11) | 81.5 | 2 | 0.57 (0.27, 1.22) | 77.4 | 2 |
DPP-4 inhibitor | 0.55 (0.27, 1.15) | 82.7 | 1 | 0.55 (0.25, 1.20) | 84.4 | 1 |
Sulfonylurea | 0.80 (0.37, 1.74) | 42.6 | 3 | 0.80 (0.36, 1.80) | 43.5 | 3 |
Thiazolidinedione | 1.82 (0.30, 11.06) | 15.2 | 4 | 1.81 (0.29, 11.16) | 15.7 | 4 |
All-cause mortality | ||||||
SGLT-2 inhibitor | 0.62 (0.22, 1.75) | 60.1 | 3 | 0.65 (0.22, 1.89) | 56.2 | 3 |
DPP-4 inhibitor | 0.62 (0.24, 1.63) | 60.6 | 2 | 0.62 (0.23, 1.67) | 60.9 | 2 |
Sulfonylurea | 0.82 (0.29, 2.29) | 40.3 | 6 | 0.82 (0.29, 2.37) | 35.8 | 5 |
Thiazolidinedione | 0.29 (0.02, 3.93) | 75.1 | 1 | 0.29 (0.02, 4.00) | 74.7 | 1 |
AGI | 0.63 (0.01, 35.60) | 51.4 | 4 | 0.77 (0.04, 15.12) | 45.1 | 4 |
Met | 1.48 (0.08, 28.09) | 31.4 | 7 | NAg | NA | NA |
Meglitinide | 0.79 (0.01, 45.95) | 48.6 | 5 | NA | NA | NA |
HbA1c | ||||||
SGLT-2 inhibitor | − 0.73 (− 0.84, − 0.62) | 77.5 | 2 | − 0.72 (− 0.84, − 0.60) | 77.4 | 2 |
DPP-4 inhibitor | − 0.65 (− 0.73, − 0.56) | 45.8 | 5 | − 0.62 (− 0.70, − 0.53) | 43.8 | 5 |
Sulfonylurea | − 0.69 (− 0.80, − 0.57) | 63.3 | 4 | − 0.65 (− 0.77, − 0.54) | 57.2 | 4 |
Thiazolidinedione | − 0.73 (− 0.87, − 0.58) | 76.2 | 3 | − 0.65 (− 0.81, − 0.50) | 58.2 | 3 |
AGI | − 0.75 (− 0.95, − 0.55) | 79.3 | 1 | − 0.99 (− 1.26, − 0.72) | 98.4 | 1 |
Met | − 0.49 (− 0.70, − 0.28) | 22.4 | 7 | − 0.48 (− 0.81, − 0.15) | 30.5 | 7 |
Meglitinide | − 0.53 (− 0.94, − 0.11) | 36.4 | 6 | − 0.49 (− 0.89, − 0.10) | 34.4 | 6 |
Body weight | ||||||
SGLT-2 inhibitor | − 2.23 (− 2.55, − 1.91) | 100 | 1 | − 2.10 (− 2.46, − 1.74) | 98.8 | 1 |
DPP-4 inhibitor | − 0.11 (− 0.39, 0.18) | 48.9 | 4 | − 0.07 (− 0.39, 0.25) | 55.3 | 3 |
Sulfonylurea | 2.00 (1.63, 2.36) | 16.4 | 5 | 2.05 (1.66, 2.44) | 19.6 | 4 |
Thiazolidinedione | 2.53 (1.95, 3.10) | 0.3 | 6 | 2.64 (2.01, 3.27) | 0.4 | 5 |
AGI | − 0.82 (− 1.61, − 0.04) | 76.4 | 2 | − 0.89 (− 2.30, 0.52) | 76.8 | 2 |
Met | − 0.62 (− 1.46, 0.23) | 68.9 | 3 | NA | NA | NA |