Table 1 Key characteristics of the included trials
Trial | Year | Participants, n | Intervention | Control | Median follow-up, years | Mean age (SD), years | Mean diabetes duration, years | Female, n | Mean BMI (SD), kg/m2 | Baseline CVD, n | Baseline HF, n | Mean baseline HbA1c (SD), % | Mean HbA1c reduction, % | Mean bodyweight change, kg |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
UKPDS 33 | 1998 | 3867 | IGC with sulfonylurea or insulin (target fasting blood glucose < 6 mmol/L) | Standard care (diet; target fasting blood glucose < 15 mmol/L) | 10.0 | 53.3 (8.6) | 0.0a | 1508 (39%) | 27.5 (5.2) | NR | NR | 7.1 (1.5) | 0.90 |  + 3.10 |
PROactive | 2005 | 5238 | PPAR agonists (pioglitazone 15 to 45 mg/day) | Placebo | 2.9 | 61.7 (7.7) | 8.0a | 1775 (34%) | 30.8 (0.5) | 5238 (100%) | NR | 8.0 (NR) | 0.50 |  + 4.00 |
ADOPT | 2006 | 4351 | PPAR agonists (rosiglitazone 4 to 8 mg/day) | Metformin (500 to 2000 mg) or glyburide (2.5 to 15 mg) | 4.0 | 56.9 (10.1) | 1.5 | 1840 (42%) | 32.2 (6.4) | NR | 0 (0%) | 7.4 (1.0) | 0.13 (vs. metformin); 0.42 (vs. glyburide) |  + 6.90 (vs. metformin); + 2.50 (vs. glyburide) |
DREAM | 2006 | 5269 | PPAR agonists (rosiglitazone 4 to 8 mg/day) | Placebo | 3.0 | 54.7 (10.9) | 0.0 | 3120 (59%) | 30.9 (5.6) | 0 (0%) | 0 (0%) | NR | 0.50 |  + 2.20 |
ACCORD | 2008 | 10,251 | IGC (target HbA1c < 6.0%) | Standard care (target HbA1c 7.0–7.9%) | 10.0 | 62.2 (6.8) | 10.0 | 3952 (39%) | 32.2 (5.5) | 3608 (35%) | 497 (5%) | 8.3 (1.1) | 1.10 |  + 3.10 |
ADVANCE | 2008 | 11,140 | IGC with gliclazide and other drugs as required (target HbA1c < 6.0%) | Standard care (target HbA1c 7.0–7.9%) | 5.0 | 66.0 (6.0) | 7.9 | 4735 (43%) | 28.0 (5.0) | 3590 (32%) | NR | 7.5 (1.6) | 0.67 |  + 0.70 |
BARI 2D | 2009 | 2368 | Insulin-sensitization therapy with oral treatment | Insulin-provision therapy | 5.3 | 62.4 (8.9) | 10.4 | 701 (30%) | 31.7 (5.4) | 2368 (100%) | 156 (6.6%) | 7.7 (1.6) | 0.50 | − 1.80 |
RECORD | 2009 | 4447 | PPAR agonists (rosiglitazone 4 to 8 mg/day) | Metformin (at a maximum dose of 2550 mg) and sulfonylurea (glibenclamide at a maximun dose of 15 mg or equivalent for different preparations) | 5.5 | 58.4 (8.3) | 7.1 | 2154 (48%) | 31.5 (4.8) | 772 (17.4%) | 21 (0.5%) | 7.9 (0.7) | 0.27 |  + 4.70 |
VADT | 2009 | 1791 | IGC (treatment absolute difference in HbA1c ≤ 1.5%) | Standard care | 5.6 | 60.4 (9.0) | 11.5 | 52 (3%) | 31.2 (3.5) | 723 (40%) | NR | 9.4 (2.0) | 1.50 |  + 4.05 |
ORIGIN | 2012 | 12,537 | Insulin glargine (target fasting blood glucose < 5.3 mmol/L) | Standard care | 6.2 | 63.5 (7.9) | 5.4 | 4386 (35%) | 29.9 (5.3) | 7378 (59%) | NR | 6.4 (NR) | 0.30 |  + 2.10 |
EXAMINE | 2013 | 5380 | DPP-4i (alogliptin 25 mg/day) | Placebo | 1.5 | 61.0 (10.0) | 7.2a | 1729 (32%) | 28.3 (NR) | 5380 (100%) | 1501 (28%) | 8.0 (1.1) | 0.36 |  + 0.06 |
Look AHEAD | 2013 | 5145 | Intensive lifestyle intervention | Standard care | 9.6 | 58.8 (6.9) | 5.0a | 3063 (60%) | 35.9 (5.9) | 714 (14%) | NR | 7.3 (1.2) | 0.22 | − 4.00 |
SAVOR-TIMI 53 | 2013 | 16,492 | DPP-4i (saxagliptin 5 mg/day) | Placebo | 2.1 | 65.1 (8.5) | 10.3a | 5455 (33%) | 31.2 (5.6) | 12,959 (79%) | 2105 (13%) | 8.0 (1.4) | 0.20 | − 0.10 |
AleCardio | 2014 | 7226 | PPAR agonists (aleglitazar 150 μg/day) | Placebo | 2.0 | 61.0 (10.0) | 8.6 | 1966 (27%) | 28.7 (NR) | 7226 (100%) | 759 (11%) | 7.8 (1.7) | 0.60 |  + 3.70 |
ELIXA | 2015 | 6068 | GLP-1RA (lixisenatide 20 μg/day) | Placebo | 2.1 | 59.9 (9.7) | 9.2 | 1861 (31%) | 30.1 (5.6) | 6068 (100%) | 1358 (22%) | 7.7 (1.3) | 0.27 | − 0.70 |
EMPA-REG OUTCOME | 2015 | 7020 | SGLT2i (empagliflozin 10 or 25 mg/day) | Placebo | 3.1 | 63.1 (8.6) | 57% > 10 yearsb | 2004 (24%) | 30.6 (5.3) | 7020 (100%) | 706 (10%) | 8.1 (0.8) | 0.57 | − 2.00 |
TECOS | 2015 | 14,671 | DPP-4i (sitagliptin 100 mg/day) | Placebo | 3.0 | 65.5 (8.0) | 11.6 | 4297 (29%) | 30.2 (5.6) | 10,863 (74%) | 2643 (18%) | 7.2 (0.5) | 0.29 | − 0.05 |
IRIS | 2016 | 3876 | PPAR agonists (pioglitazone 30 mg/day) | Placebo | 4.8 | 63.5 (10.6) | 0.0 | 1338 (35%) | 29.9 (10.5) | 3876 (100%) | 0 (0%) | 5.8 (0.4) | 0.06 |  + 0.00 |
LEADER | 2016 | 9340 | GLP-1RA (liraglutide 1.8 mg/day) | Placebo | 3.8 | 64.2 (7.2) | 12.8 | 3337 (36%) | 32.5 (6.3) | 7598 (81%) | 1667 (18%) | 8.7 (1.6) | 0.40 | − 2.30 |
SUSTAIN-6 | 2016 | 3297 | GLP-1RA (semaglutide 0.5 or 1.0 mg/week) | Placebo | 2.1 | 64.6 (7.4) | 13.9 | 1295 (39%) | 32.8 (6.2) | 2735 (83%) | 777 (24%) | 8.7 (1.5) | 0.85 | − 3.61 |
OMNEON | 2017 | 4202 | DPP-4i (omaligliptin 25 mg/week) | Placebo | 1.8 | 63.6 (8.5) | 12.1 | 1254 (30%) | 31.3 (5.5) | 4202 (100%) | 641 (15%) | 8.0 (0.9) | 0.30 | − 0.08 |
CANVAS Program | 2017 | 10,142 | SGLT2i (canagliflozin 100 or 300 mg/day) | Placebo | 2.4 | 63.3 (8.3) | 13.5 | 3633 (36%) | 32.0 (5.9) | 6656 (66%) | 1461 (14%) | 8.2 (0.9) | 0.58 | − 1.60 |
EXSCEL | 2017 | 14,752 | GLP-1RA (exenatide 2 mg/week) | Placebo | 3.2 | 61.9 (9.4) | 13.1 | 5603 (38%) | 32.7 (6.4) | 10,782 (73%) | 2389 (16%) | 8.1 (1.0) | 0.53 | − 1.27 |
ACE | 2017 | 6522 | α-GI (acarbose 50 mg three times/day) | Placebo | 5.0 | 64.3 (8.1) | 0.0 | 1762 (27%) | 25.4 (3.1) | 6522 (100%) | 69 (1%) | 5.9 (0.7) | 0.07 | − 0.64 |
TOSCA.IT | 2017 | 3028 | PPAR agonists (pioglitazone 15 to 45 mg/day) | Sulfonylurea (glibenclamide 5–15 mg or gliclazide 30–120 mg or glimepiride 2–6 mg) | 4.8 | 62.3 (6.5) | 8.5 | 1254 (41%) | 30.3 (4.5) | 335 (11%) | 0 (0%) | 7.7 (0.5) | 0.24 |  + 3.10 |
HARMONY Outcomes | 2018 | 9463 | GLP-1RA (albiglutide 30 or 50 mg/wek) | Placebo | 1.5 | 64.1 (8.7) | 14.1 | 2894 (31%) | 32.3 (5.9) | 9463 (100%) | 1922 (20%) | 8.7 (1.5) | 0.52 | − 0.83 |
DECLARE-TIMI 58 | 2019 | 17,160 | SGLT2i (dapaglifrozin 10 mg/day) | Placebo | 4.2 | 63.9 (6.8) | 11.8 | 6422 (37%) | 32.1 (6.0) | 6974 (41%) | 1724 (10%) | 8.3 (1.2) | 0.42 | − 1.80 |
CARMELINA | 2019 | 6979 | DPP-4i (linagliptin 5 mg/day) | Placebo | 2.2 | 65.9 (9.1) | 14.7 | 2589 (37%) | 31.4 (5.4) | 4081 (58%) | 1873 (27%) | 7.9 (1.0) | 0.36 | − 0.15 |
CREDENCE | 2019 | 4401 | SGLT2i (canagliflozin 100 mg/day) | Placebo | 2.6 | 63.0 (9.2) | 15.8 | 1494 (34%) | 31.3 (6.2) | 2220 (50%) | 652 (15%) | 8.3 (1.3) | 0.25 | − 0.80 |
REWIND | 2019 | 9901 | GLP-1RA (dulaglutide 1.5 mg/week) | Placebo | 5.4 | 66.2 (6.5) | 10.5 | 4589 (46%) | 32.3 (5.7) | 3114 (31%) | 853 (9%) | 7.3 (1.1) | 0.61 | − 1.46 |
PIONEER 6 | 2019 | 3138 | GLP-1RA (oral semaglutide 14 mg/day) | Placebo | 1.3 | 66.0 (7.0) | 14.9 | 1007 (32%) | 32.3 (6.5) | 2695 (85%) | 288 (12%) | 8.2 (1.6) | 0.70 | − 3.40 |
VERTIS CV | 2020 | 8246 | SGLT2i (ertugliflozin 5 or 15 mg/day) | Placebo | 3.0 | 64.4 (8.1) | 13.0 | 2477 (30%) | 31.9 (5.4) | 8246 (100%) | 1958 (24%) | 8.2 (1.0) | 0.50 | − 2.40 |
SCORED | 2021 | 10,584 | SGLT2i (sotagliflozin 200 or 400 mg/day) | Placebo | 1.3 | 69 (63–74), 69 (63–74)c | NR | 4754 (45%) | 31.9 (28.1–36.2), 31.7 (28.0–36.1)c | 5144 (49%) | 3283 (31%) | 8.3 (7.6–9.3), 8.3 (7.6–9.4)c | 0.42 | − 1.16 |
AMPLITUDE-O | 2021 | 4076 | GLP-1RA (efpeglenatide 4 or 6 mg/week) | Placebo | 1.8 | 64.5 (8.2) | 14.9 | 1344 (33%) | 32.7 (6.2) | 3650 (90%) | 737 (18%) | 8.9 (1.5) | 1.24 | − 2.60 |
FREEDOM-CVO | 2022 | 4156 | GLP-1RA (continuously infused exenatide 20 μg/day) | Placebo | 1.3 | 63 (58–68), 63 (57–68)c | NR | 1525 (37%) | 32.4 (28.8–36.6), 31.9 (28.6–36.1)c | 2036 (49%)d | 668 (16%) | 8.0 (7.2–9.3), 8.0 (7.2–9.2)c | 0.84 | − 4.24 |