1Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea.
2Division of Endocrinology and Metabolism, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
3Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, the Catholic University of Korea, Seoul, Korea.
4Department of Internal Medicine, Gwangmyeong Sungae Hospital, Gwangmyeong, Korea.
5Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
6Division of Endocrinology and Metabolism, Department of Internal Medicine, Chosun University College of Medicine, Gwangju, Korea.
7Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Seoul, Korea.
8Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea.
9Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.
Copyright © 2017 Korean Diabetes Association
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
This manuscript is simultaneously published in the Diabetes Metabolism Journal and the Korean Journal of Internal Medicine by the Korean Diabetes Association and the Korean Association of Internal Medicine.
CONFLICTS OF INTEREST: No potential conflict of interest relevant to this article was reported.
Study | Included trials (n) | Results |
---|---|---|
Palmer et al. (2016) [8] | 301 RCTs comparing 2 glu- cose-lowering drug classes for treatment of T2DM for 24 weeks' or longer duration |
No significant differences in the associations between any of 9 available classes of glucose-lowering drugs (alone or in combination) and the risk of cardiovascular or all-cause mortality All drugs were effective when added to metformin. |
Mishriky et al. (2015) [7] | 16 RCTs comparing DPP4i to SU as add-on therapy to metformin |
A significantly greater reduction in HbA1c from baseline to 12 weeks with SU vs. DPP4i (MD, 0.21%; 95% CI, 0.06–0.35) No significant difference at 52 and 104 weeks (MD, 0.06%; 95% CI, 0.03–0.15; and MD, 0.02%; 95% CI, 0.13–0.18, respectively) SU was associated with weight gain and DPP4i with weight loss at all time-points. The incidence of hypoglycemia at 12, 52, and 104 weeks was significantly greater with SU (20%, 24%, and 27% respectively) compared to DPP4i (6%, 3%, and 4% respectively). |
Zhou et al. (2016) [9] |
14 RCTS comparing DPP4i to SU (5,480 patients ran- domised to DPP4i and 5,214 patients randomised to SU) |
Compared with SU, DPP4i were associated with a smaller decline in HbA1c (WMD, weighted mean differences, 0.08%; 95% CI, 0.03–0.14; P=0.001), and resulted in weight loss of 1.945 kg (95% CI, –2.237 to –1.653; P<0.0001). The effect of DPP4i lowering FPG was inferior to that of SU (WMD, 0.268 mmol/L; 95% CI, 0.151–0.385; P<0.0001), and similar in reducing PPG (WMD, 0.084 mmol/L; 95% CI, –0.701 to 0.869; P=0.833). DPP4i had a favorable insulin resistance and low risk for AE and hypoglycemia. |
Foroutan et al. (2016) [10] | 10 RCTs comparing DPP4i to SU as add-on therapy to metformin (10,139 subjects) |
DPP4i compared to SU produced a non-significant difference in HbA1c% change whereas a significant decrease in the rate of hypoglycemic events was observed in favor of DPP4i. DPP4i was associated with significant weight loss (2.2 kg) compared to SU. |
RCT, randomized controlled trial; T2DM, type 2 diabetes mellitus; DPP4i, dipeptidyl peptidase-4 inhibitor; SU, sulfonylurea; MD, mean difference; CI, confidence interval; HbA1c, glycosylated hemoglobin; WMD, weighed mean difference; FPG, fasting plasma glucose; PPG, postprandial glucose; AE, adverse events.
Intervention | Trials | Duration, wk | No. of patients | HbA1c SGLT2i | HbA1c control | Change in HbA1c (mean difference) |
---|---|---|---|---|---|---|
Metformin+SGLT2i vs. Metformin+SU | Cefalu et al. (2013) [14] | 104 | 1,452 | 7.8 | 7.8 | −0.19 (−0.29 to −0.09) |
Nauck et al. (2011) [15] | 208 | 814 | 7.7 | 7.7 | −0.30 (−0.79 to 0.19) | |
Ridderstrale et al. (2014) [16] | 104 | 1,549 | 7.9 | 7.9 | −0.11 (−0.19 to −0.03) | |
Total | −0.15 (−0.21 to −0.08) |
Intervention | Trials | Duration, wk | No. of patients | HbA1c SGLT2i | HbA1c control | Change of HbA1c (mean difference) |
---|---|---|---|---|---|---|
Metformin+SGLT2i vs. Metformin+DPP4i | Lavalle-Gonzalez et al. (2013) [21] | 26 | 1,284 | 7.9 | 7.9 | −0.12 (−0.23 to −0.01) |
Rosenstock et al. (2012) [22] | 12 | 451 | 7.7 | 7.6 | −0.18 (−0.40 to 0.04) | |
Rosenstock et al. (2015) [23] | 24 | 534 | 8.9 | 9.0 | −0.32 (−0.53 to −0.11) | |
DeFronzo et al. (2015) [24] | 52 | 899 | 8.0 | 8.0 | −0.16 (−0.33 to 0.01) |
Study | Included trials (n) | Results |
---|---|---|
Palmer et al. (2016) [8] | 301 RCTs comparing 2 glucose-lowering drug classes for treatment of T2DM for 24 weeks' or longer duration |
No significant differences in the associations between any of 9 available classes of glucose-lowering drugs (alone or in combination) and the risk of cardiovascular or all-cause mortality All drugs were effective when added to metformin. |
Mearns et al. (2015) [44] | 20 RCTs evaluating 13 antihyperglycaemic agents in adults with T2DM experiencing poor glycemic control despite optimized metformin and SU therapy |
Compared with placebo/control, all antihyperglycemic agents reduced HbA1c levels, albeit by differing magnitudes (0.6% for acarbose to 1.20% for liraglutide) SGLT2i reduced weight (1.43–2.07 kg), whereas TZDs, glargine and sitagliptin caused weight gain (1.48–3.62 kg) compared with placebo/control. SGLT2i, rosiglitazone and liraglutide decreased SBP compared with placebo/control, pioglitazone, glargine and sitagliptin (2.41–8.88 mm Hg) Glargine, TZDs, liraglutide, sitagliptin, and canagliflozin increased hypoglycemia risk compared with placebo/control (relative risk, 1.92–7.47), while glargine and rosiglitazone increased hypoglycemia compared with most antihyperglycemic agents (relative risk, 2.81–7.47). Canagliflozin increased the risk of genital tract infection by 3.9-fold compared with placebo/control. |
Downes et al. (2015) [41] | 27 RCTs comparing metformin+SU dual therapy to other triple therapy combinations |
For HbA1c reduction, all triple therapies were statistically superior to metformin+SU dual therapy, except for metformin+TZD+DPP4i. None of the triple therapy combinations demonstrated differences in HbA1c compared with other triple therapies. Metformin+SU+SGLT2i and metformin+SU+GLP-1RA resulted in significantly lower body weight than metformin+SU+DPP4i, metformin+SU+insulin and metformin+SU+TZDs; metformin+SU+DPP4i resulted in significantly lower body weight than metformin+SU+insulin and metformin+SU+TZD. Metformin+SU+insulin, metformin+SU+TZD and metformin+SU+DPP4i increased the odds of hypoglycaemia when compared to metformin+SU. Metformin+SU+GLP-1RA reduced the odds of hypoglycemia compared to metformin+SU+insulin. |
Lee et al. (2016) [42] |
40 RCTS comparing dual therapy to any triple combinations (15,182 participants) |
Compared with none/placebo added to dual therapy, triple combination therapy resulted in significant additional mean reductions in HbA1c from –0.56% (DPP4i) to –0.94% (TZDs). Insulin, TZD and SU were associated with less favourable weight change and GLP-1RA and SGLT2i were associated with more favourable weight change when compared with none/placebo added to dual therapy. Compared with none/placebo added to dual therapy, the odds of hypoglycemia were higher for DPP4i (1.95), SGLT2i (2.27), GLP-1RA (2.61), TZD (2.83), and insulin (5.94). |
Lozano-Ortega et al. (2016) [43] | 30 RCTs comparing SGLT2i to other drugs as add-on therapy to metformin and SU |
The mean change (%) in HbA1c levels compared to placebo was -0.86 for SGLT2i, –0.68 for DPP4i, –0.93 for TZDs, and –1.07 for GLP-1RA, respectively. Only SGLT2i and GLP-1RA led to a weight loss (–1.71 and –1.14 kg, respectively) and decrease in SBP (–3.73 and –2.90 mm Hg, respectively), while all other treatments showed either an increase or no changes in weight or SBP. |
RCT, randomized controlled trial; T2DM, type 2 diabetes mellitus; SU, sulfonylurea; HbA1c, glycosylated hemoglobin; SGLT2i, sodium-glucose cotransporter-2 inhibitor; TZD, thiazolidinedione; SBP, systolic blood pressure; DPP4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA, glucagonlike peptide-1 receptor agonist.
Study | Included trials (n) | Results |
---|---|---|
Palmer et al. (2016) [ | 301 RCTs comparing 2 glu- cose-lowering drug classes for treatment of T2DM for 24 weeks' or longer duration | No significant differences in the associations between any of 9 available classes of glucose-lowering drugs (alone or in combination) and the risk of cardiovascular or all-cause mortality All drugs were effective when added to metformin. |
Mishriky et al. (2015) [ | 16 RCTs comparing DPP4i to SU as add-on therapy to metformin | A significantly greater reduction in HbA1c from baseline to 12 weeks with SU vs. DPP4i (MD, 0.21%; 95% CI, 0.06–0.35) No significant difference at 52 and 104 weeks (MD, 0.06%; 95% CI, 0.03–0.15; and MD, 0.02%; 95% CI, 0.13–0.18, respectively) SU was associated with weight gain and DPP4i with weight loss at all time-points. The incidence of hypoglycemia at 12, 52, and 104 weeks was significantly greater with SU (20%, 24%, and 27% respectively) compared to DPP4i (6%, 3%, and 4% respectively). |
Zhou et al. (2016) [ | 14 RCTS comparing DPP4i to SU (5,480 patients ran- domised to DPP4i and 5,214 patients randomised to SU) | Compared with SU, DPP4i were associated with a smaller decline in HbA1c (WMD, weighted mean differences, 0.08%; 95% CI, 0.03–0.14; P=0.001), and resulted in weight loss of 1.945 kg (95% CI, –2.237 to –1.653; P<0.0001). The effect of DPP4i lowering FPG was inferior to that of SU (WMD, 0.268 mmol/L; 95% CI, 0.151–0.385; P<0.0001), and similar in reducing PPG (WMD, 0.084 mmol/L; 95% CI, –0.701 to 0.869; P=0.833). DPP4i had a favorable insulin resistance and low risk for AE and hypoglycemia. |
Foroutan et al. (2016) [ | 10 RCTs comparing DPP4i to SU as add-on therapy to metformin (10,139 subjects) | DPP4i compared to SU produced a non-significant difference in HbA1c% change whereas a significant decrease in the rate of hypoglycemic events was observed in favor of DPP4i. DPP4i was associated with significant weight loss (2.2 kg) compared to SU. |
Intervention | Trials | Duration, wk | No. of patients | HbA1c SGLT2i | HbA1c control | Change in HbA1c (mean difference) |
---|---|---|---|---|---|---|
Metformin+SGLT2i vs. Metformin+SU | Cefalu et al. (2013) [ | 104 | 1,452 | 7.8 | 7.8 | −0.19 (−0.29 to −0.09) |
Nauck et al. (2011) [ | 208 | 814 | 7.7 | 7.7 | −0.30 (−0.79 to 0.19) | |
Ridderstrale et al. (2014) [ | 104 | 1,549 | 7.9 | 7.9 | −0.11 (−0.19 to −0.03) | |
Total | −0.15 (−0.21 to −0.08) |
Intervention | Trials | Duration, wk | No. of patients | HbA1c SGLT2i | HbA1c control | Change of HbA1c (mean difference) |
---|---|---|---|---|---|---|
Metformin+SGLT2i vs. Metformin+DPP4i | Lavalle-Gonzalez et al. (2013) [ | 26 | 1,284 | 7.9 | 7.9 | −0.12 (−0.23 to −0.01) |
Rosenstock et al. (2012) [ | 12 | 451 | 7.7 | 7.6 | −0.18 (−0.40 to 0.04) | |
Rosenstock et al. (2015) [ | 24 | 534 | 8.9 | 9.0 | −0.32 (−0.53 to −0.11) | |
DeFronzo et al. (2015) [ | 52 | 899 | 8.0 | 8.0 | −0.16 (−0.33 to 0.01) |
Study | Included trials (n) | Results |
---|---|---|
Palmer et al. (2016) [ | 301 RCTs comparing 2 glucose-lowering drug classes for treatment of T2DM for 24 weeks' or longer duration | No significant differences in the associations between any of 9 available classes of glucose-lowering drugs (alone or in combination) and the risk of cardiovascular or all-cause mortality All drugs were effective when added to metformin. |
Mearns et al. (2015) [ | 20 RCTs evaluating 13 antihyperglycaemic agents in adults with T2DM experiencing poor glycemic control despite optimized metformin and SU therapy | Compared with placebo/control, all antihyperglycemic agents reduced HbA1c levels, albeit by differing magnitudes (0.6% for acarbose to 1.20% for liraglutide) SGLT2i reduced weight (1.43–2.07 kg), whereas TZDs, glargine and sitagliptin caused weight gain (1.48–3.62 kg) compared with placebo/control. SGLT2i, rosiglitazone and liraglutide decreased SBP compared with placebo/control, pioglitazone, glargine and sitagliptin (2.41–8.88 mm Hg) Glargine, TZDs, liraglutide, sitagliptin, and canagliflozin increased hypoglycemia risk compared with placebo/control (relative risk, 1.92–7.47), while glargine and rosiglitazone increased hypoglycemia compared with most antihyperglycemic agents (relative risk, 2.81–7.47). Canagliflozin increased the risk of genital tract infection by 3.9-fold compared with placebo/control. |
Downes et al. (2015) [ | 27 RCTs comparing metformin+SU dual therapy to other triple therapy combinations | For HbA1c reduction, all triple therapies were statistically superior to metformin+SU dual therapy, except for metformin+TZD+DPP4i. None of the triple therapy combinations demonstrated differences in HbA1c compared with other triple therapies. Metformin+SU+SGLT2i and metformin+SU+GLP-1RA resulted in significantly lower body weight than metformin+SU+DPP4i, metformin+SU+insulin and metformin+SU+TZDs; metformin+SU+DPP4i resulted in significantly lower body weight than metformin+SU+insulin and metformin+SU+TZD. Metformin+SU+insulin, metformin+SU+TZD and metformin+SU+DPP4i increased the odds of hypoglycaemia when compared to metformin+SU. Metformin+SU+GLP-1RA reduced the odds of hypoglycemia compared to metformin+SU+insulin. |
Lee et al. (2016) [ | 40 RCTS comparing dual therapy to any triple combinations (15,182 participants) | Compared with none/placebo added to dual therapy, triple combination therapy resulted in significant additional mean reductions in HbA1c from –0.56% (DPP4i) to –0.94% (TZDs). Insulin, TZD and SU were associated with less favourable weight change and GLP-1RA and SGLT2i were associated with more favourable weight change when compared with none/placebo added to dual therapy. Compared with none/placebo added to dual therapy, the odds of hypoglycemia were higher for DPP4i (1.95), SGLT2i (2.27), GLP-1RA (2.61), TZD (2.83), and insulin (5.94). |
Lozano-Ortega et al. (2016) [ | 30 RCTs comparing SGLT2i to other drugs as add-on therapy to metformin and SU | The mean change (%) in HbA1c levels compared to placebo was -0.86 for SGLT2i, –0.68 for DPP4i, –0.93 for TZDs, and –1.07 for GLP-1RA, respectively. Only SGLT2i and GLP-1RA led to a weight loss (–1.71 and –1.14 kg, respectively) and decrease in SBP (–3.73 and –2.90 mm Hg, respectively), while all other treatments showed either an increase or no changes in weight or SBP. |
RCT, randomized controlled trial; T2DM, type 2 diabetes mellitus; DPP4i, dipeptidyl peptidase-4 inhibitor; SU, sulfonylurea; MD, mean difference; CI, confidence interval; HbA1c, glycosylated hemoglobin; WMD, weighed mean difference; FPG, fasting plasma glucose; PPG, postprandial glucose; AE, adverse events.
HbA1c, glycosylated hemoglobin; SU, sulfonylurea; SGLT2i, sodium-glucose cotransporter-2 inhibitor.
HbA1c, glycosylated hemoglobin; DPP4i, dipeptidyl peptidase-4 inhibitor; SGLT2i, sodium-glucose cotransporter-2 inhibitor.
RCT, randomized controlled trial; T2DM, type 2 diabetes mellitus; SU, sulfonylurea; HbA1c, glycosylated hemoglobin; SGLT2i, sodium-glucose cotransporter-2 inhibitor; TZD, thiazolidinedione; SBP, systolic blood pressure; DPP4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA, glucagonlike peptide-1 receptor agonist.