Sulphonylurea monotherapy for patients with type 2 diabetes mellitus
Información
- DOI:
- https://doi.org/10.1002/14651858.CD009008.pub2Copiar DOI
- Base de datos:
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- Cochrane Database of Systematic Reviews
- Versión publicada:
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- 30 abril 2013see what's new
- Tipo:
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- Intervention
- Etapa:
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- Review
- Grupo Editorial Cochrane:
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Grupo Cochrane de Trastornos metabólicos y endocrinos
- Copyright:
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- Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Autores
Contributions of authors
Bianca Hemmingsen: development of protocol, undertaking of searches, selection of trials, data extraction, bias risk assessment of trials, data analysis, contact person, development of review.
Jeppe Schroll: selection of trials, data extraction, bias risk assessment of trials, data analysis, development of review.
Søren S. Lund: development of protocol, development of review.
Jørn Wetterslev: development of protocol, advised on statistical methods to be used, data analysis, development of review.
Christian Gluud: development of protocol, development of review.
Allan Vaag: development of protocol, development of review.
David Sonne: selection of trials, data extraction, bias risk assessment of trials, development of review.
Lars H. Lundstrøm: development of protocol, selection of trials, data extraction, bias risk assessment of trials, development of review.
Thomas Almdal: development of protocol, selection of trials, data extraction, bias risk assessment of trials, development of review.
Sources of support
Internal sources
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Copenhagen Trial Unit, Rigshospitalet, Denmark.
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Cochrane Metabolic and Endocrine Disorders Group, Germany.
External sources
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The Copenhagen Insulin and Metformin Therapy Group, Other.
Declarations of interest
The lead author is Bianca Hemmingsen who has no conflict to be declared.
Søren Søgaard Lund, Allan Vaag and Thomas Almdal have reported equity in Novo Nordisk A/S. Søren Søgaard Lund received fees from Novo Nordisk A/S for speaking and received compensation for travel expenses for congress participation from MSD (Merck). Allan Vaag received fees from Novo Nordisk A/S, Sanofi Aventis and Eli Lily for speaking. Thomas Almdal was employed at Steno Diabetes Center, Gentofte, Denmark during the development of the protocol and the review. Steno Diabetes Center is an academic institution owned by Novo Nordisk A/S. Søren Søgaard Lund and Allan Vaag were employed at Steno Diabetes Center when the protocol was published and the work on the review was initiated. Søren Søgaard Lund is now employed with Boehringer Ingelheim, Ingelheim, Germany and Allan Vaag at Rigshospitalet, Copenhagen, Denmark.
Due to an inappropriate interpretation of the conflict of interest (CoI) policy valid at the time of the publication of this review by the Cochrane Metabolic and Endocrine Disorders Group (CMED) there was a breach of the Cochrane Collaboration's CoI. The policy stated: "If a review has been done, or is proposed, by people who are employed by a pharmaceutical or medical devices company that relates to the products of that company, it will be referred to the Funding Arbiter. In such circumstances, The Cochrane Collaboration will insist on a multi‐disciplinary review team with a majority of the team of authors not being employed by the relevant company." Due to the fact that the majority of authors of this review had no CoI the CMED assumed that no CoI existed but missed to refer this to the Funding Arbiter, thereby creating a breach of policy.
Acknowledgements
The authors would like to thank Karla Bergerhoff, the Trials Search Co‐ordinator of the Cochrane Metabolic and Endocrine Disorders Group, and Sarah Klingenberg, the Trials Search Co‐ordinator of the Cochrane Hepato‐Biliary Group, for their assistance in developing the search strategy. We acknowledge TrygFonden for providing funding for this systematic review. We would like to thank Drs Andy Diehl, Koide, Paolo Moghetti, van de Laar, Andrew Harrower, Leif Hermann and Kåre Birkeland for providing additional information. The authors would like to thank Angel Rodriguez and Mads Engelmann from Lilly for providing additional data. We also thank Xia Yun for extracting data of the Chinese articles and Naoya Sakamoto for extracting data from Japanese articles. Additional data for the APPROACH and ADOPT trials were submitted by GlaxoSmithKline Pharmaceuticals, Metabolic & Cardiovascular Unit. Additional data for Madsbad 2001, Marbury 1999 and Wolffenbuttel 1999 were provided by Novo Nordisk. Novo Nordisk provided data for two unpublished trials (AGEE/DCD/056/UK and AGEE/DCD/047/B/F/I).
Version history
| Published | Title | Stage | Authors | Version |
| 2015 Jul 29 | Sulphonylurea monotherapy for patients with type 2 diabetes mellitus | Review | Bianca Hemmingsen, Jeppe B Schroll, Søren S Lund, Jørn Wetterslev, Christian Gluud, Allan Vaag, David Peick Sonne, Lars H Lundstrøm, Thomas P Almdal | |
| 2013 Apr 30 | Sulphonylurea monotherapy for patients with type 2 diabetes mellitus | Review | Bianca Hemmingsen, Jeppe B Schroll, Søren S Lund, Jørn Wetterslev, Christian Gluud, Allan Vaag, David Peick Sonne, Lars H Lundstrøm, Thomas P Almdal | |
| 2011 Feb 16 | Non‐incretin insulin secretagogues for patients with type 2 diabetes mellitus | Protocol | Bianca Hemmingsen, Lars H Lundstrøm, Christina Hemmingsen, Søren S Lund, Jørn Wetterslev, Christian Gluud, Allan Vaag, Thomas Almdal | |
Differences between protocol and review
David Peick Sonne and Jeppe Schroll joined as authors after publication of the protocol. Christina Hemmingsen withdrew as an author after publication of the protocol.
The title of the review is different from the protocol as we only were allowed by the Cochrane Metabolic and Endocrine Disorders Group to focus on the sulphonylureas.
After advice from the Cochrane Metabolic and Endocrine Disorder Group, we changed the inclusion criteria for trials to a duration of 24 weeks or more and avoided combination therapies.
It was not predefined to search the Food and Drug Administration web site.
We have renamed the macrovascular complications as non‐fatal macrovascular outcomes, as it was more in line with the definition in the protocol. The microvascular complication outcome was renamed as microvascular outcome.
We originally planned to assess baseline imbalance and early stopping as bias components, but did not do this, based on decisions taken at the Cochrane Colloquium 2010.
When no differences in mean and standard deviations for the continuous outcomes were reported in trials, we used the end of follow‐up values, if available.
We originally planned only to report the results of the fixed‐effect model in case of discrepancy between the two models. On request from the Cochrane Metabolic and Endocrine Disorder Group we reported both results, if heterogeneity was present.
The comparison of all sulphonylureas versus each comparator was made post hoc due to little power for each sulphonylurea generation.
Appendix 5 of the protocol (adverse events) was deleted as this would have given rise to double entry of data.
We did not search for ongoing trials.
We performed best‐worst case scenario and worst‐best case scenario for the primary outcomes.
The assessment of change in weight from baseline was not described in the protocol.
Trial sequential analysis was performed for all trials, and not only trials with low risk of bias due to limited data.
Keywords
MeSH
Medical Subject Headings (MeSH) Keywords
Medical Subject Headings Check Words
Adult; Humans;
Study flow diagram.
N = number of references
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1 Sulphonylureas versus placebo, Outcome 1 All‐cause mortality.
Comparison 1 Sulphonylureas versus placebo, Outcome 2 All‐cause mortality; best‐worst case scenario.
Comparison 1 Sulphonylureas versus placebo, Outcome 3 All‐cause mortality; worst‐best case scenario.
Comparison 1 Sulphonylureas versus placebo, Outcome 4 Cardiovascular mortality.
Comparison 1 Sulphonylureas versus placebo, Outcome 5 Non‐fatal macrovascular outcomes.
Comparison 1 Sulphonylureas versus placebo, Outcome 6 Non‐fatal myocardial infarction.
Comparison 1 Sulphonylureas versus placebo, Outcome 7 Amputation of lower extremity.
Comparison 1 Sulphonylureas versus placebo, Outcome 8 Nephropathy.
Comparison 1 Sulphonylureas versus placebo, Outcome 9 Retinopathy.
Comparison 1 Sulphonylureas versus placebo, Outcome 10 Change in fasting blood glucose from baseline (mmol/L).
Comparison 1 Sulphonylureas versus placebo, Outcome 11 Change in HbA1c from baseline (%).
Comparison 1 Sulphonylureas versus placebo, Outcome 12 Change in BMI from baseline (kg/m2).
Comparison 1 Sulphonylureas versus placebo, Outcome 13 Change in weight from baseline (kg).
Comparison 1 Sulphonylureas versus placebo, Outcome 14 Adverse events.
Comparison 1 Sulphonylureas versus placebo, Outcome 15 Drop‐outs due to adverse events.
Comparison 1 Sulphonylureas versus placebo, Outcome 16 Mild hypoglycaemia.
Comparison 1 Sulphonylureas versus placebo, Outcome 17 Severe hypoglycaemia.
Comparison 1 Sulphonylureas versus placebo, Outcome 18 Cancer.
Comparison 1 Sulphonylureas versus placebo, Outcome 19 Intervention failure.
Comparison 2 Sulphonylureas versus metformin, Outcome 1 All‐cause mortality.
Comparison 2 Sulphonylureas versus metformin, Outcome 2 All‐cause mortality; best‐worst case scenario.
Comparison 2 Sulphonylureas versus metformin, Outcome 3 All‐cause mortality; worst‐best case scenario.
Comparison 2 Sulphonylureas versus metformin, Outcome 4 Cardiovascular mortality.
Comparison 2 Sulphonylureas versus metformin, Outcome 5 Non‐fatal macrovascular outcomes.
Comparison 2 Sulphonylureas versus metformin, Outcome 6 Non‐fatal myocardial infarction.
Comparison 2 Sulphonylureas versus metformin, Outcome 7 Non‐fatal stroke.
Comparison 2 Sulphonylureas versus metformin, Outcome 8 Amputation of lower extremity.
Comparison 2 Sulphonylureas versus metformin, Outcome 9 Peripheral revascularisation.
Comparison 2 Sulphonylureas versus metformin, Outcome 10 Microvascular outcomes.
Comparison 2 Sulphonylureas versus metformin, Outcome 11 Nephropathy.
Comparison 2 Sulphonylureas versus metformin, Outcome 12 Retinal photocoagulation.
Comparison 2 Sulphonylureas versus metformin, Outcome 13 Change in fasting blood glucose from baseline (mmol/L).
Comparison 2 Sulphonylureas versus metformin, Outcome 14 Change in HbA1c from baseline (%).
Comparison 2 Sulphonylureas versus metformin, Outcome 15 Change in BMI from baseline (kg/m2).
Comparison 2 Sulphonylureas versus metformin, Outcome 16 Change in weight from baseline (kg).
Comparison 2 Sulphonylureas versus metformin, Outcome 17 Adverse events.
Comparison 2 Sulphonylureas versus metformin, Outcome 18 Serious adverse events.
Comparison 2 Sulphonylureas versus metformin, Outcome 19 Drop‐outs due to adverse events.
Comparison 2 Sulphonylureas versus metformin, Outcome 20 Mild hypoglycaemia.
Comparison 2 Sulphonylureas versus metformin, Outcome 21 Moderate hypoglycaemia.
Comparison 2 Sulphonylureas versus metformin, Outcome 22 Severe hypoglycaemia.
Comparison 2 Sulphonylureas versus metformin, Outcome 23 Cancer.
Comparison 2 Sulphonylureas versus metformin, Outcome 24 Intervention failure.
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 1 All‐cause mortality.
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 2 All‐cause mortality; best‐worst case scenario.
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 3 All‐cause mortality; worst‐best case scenario.
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 4 Cardiovascular mortality.
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 5 Non‐fatal macrovascular outcomes.
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 6 Non‐fatal myocardial infarction.
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 7 Non‐fatal stroke.
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 8 Amputation of lower extremity.
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 9 Cardial revascularisation.
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 10 Peripheral revascularisation.
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 11 Microvascular outcomes.
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 12 Nephropathy.
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 13 Retinopathy.
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 14 Retinal photocoagulation.
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 15 Change in fasting blood glucose from baseline (mmol/L).
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 16 Change in HbA1c from baseline (%).
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 17 Change in BMI from baseline (kg/m2).
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 18 Change in weight from baseline (kg).
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 19 Adverse events.
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 20 Serious adverse events.
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 21 Drop‐outs due to adverse events.
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 22 Mild hypoglycaemia.
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 23 Moderate hypoglycaemia.
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 24 Severe hypoglycaemia.
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 25 Cancer.
Comparison 3 Sulphonylureas versus thiazolidinediones, Outcome 26 Intervention failure.
Comparison 4 Sulphonylureas versus insulin, Outcome 1 All‐cause mortality.
Comparison 4 Sulphonylureas versus insulin, Outcome 2 All‐cause mortality; best‐worst case scenario.
Comparison 4 Sulphonylureas versus insulin, Outcome 3 All‐cause mortality; worst‐best case scenario.
Comparison 4 Sulphonylureas versus insulin, Outcome 4 Cardiovascular mortality.
Comparison 4 Sulphonylureas versus insulin, Outcome 5 Non‐fatal myocardial infarction.
Comparison 4 Sulphonylureas versus insulin, Outcome 6 Non‐fatal stroke.
Comparison 4 Sulphonylureas versus insulin, Outcome 7 Amputation of lower extremity.
Comparison 4 Sulphonylureas versus insulin, Outcome 8 Microvascular outcomes.
Comparison 4 Sulphonylureas versus insulin, Outcome 9 Nephropathy.
Comparison 4 Sulphonylureas versus insulin, Outcome 10 Retinopathy.
Comparison 4 Sulphonylureas versus insulin, Outcome 11 Retinal photocoagulation.
Comparison 4 Sulphonylureas versus insulin, Outcome 12 Change in fasting blood glucose from baseline (mmol/L).
Comparison 4 Sulphonylureas versus insulin, Outcome 13 Change in HbA1c from baseline (%).
Comparison 4 Sulphonylureas versus insulin, Outcome 14 Change in BMI from baseline (kg/m2).
Comparison 4 Sulphonylureas versus insulin, Outcome 15 Change in weight from baseline (kg).
Comparison 4 Sulphonylureas versus insulin, Outcome 16 Adverse events.
Comparison 4 Sulphonylureas versus insulin, Outcome 17 Drop‐outs due to adverse events.
Comparison 4 Sulphonylureas versus insulin, Outcome 18 Mild hypoglycaemia.
Comparison 4 Sulphonylureas versus insulin, Outcome 19 Severe hypoglycaemia.
Comparison 4 Sulphonylureas versus insulin, Outcome 20 Cancer.
Comparison 4 Sulphonylureas versus insulin, Outcome 21 Intervention failure.
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 1 All‐cause mortality.
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 2 All‐cause mortality; best‐worst case scenario.
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 3 All‐cause mortality; worst‐best case scenario.
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 4 Cardiovascular mortality.
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 5 Non‐fatal macrovascular outcomes.
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 6 Non‐fatal myocardial infarction.
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 7 Non‐fatal stroke.
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 8 Amputation of lower extremity.
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 9 Cardial revascularisation.
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 10 Peripheral revascularisation.
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 11 Microvascular outcomes.
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 12 Nephropathy.
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 13 Retinopathy.
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 14 Retinal photocoagulation.
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 15 Change in fasting blood glucose from baseline (mmol/L).
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 16 Change in HbA1c from baseline (%).
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 17 Change in BMI from baseline (kg/m2).
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 18 Change in weight from baseline (kg).
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 19 Adverse events.
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 20 Serious adverse events.
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 21 Drop‐outs due to adverse events.
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 22 Mild hypoglycaemia.
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 23 Moderate hypoglycaemia.
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 24 Severe hypoglycaemia.
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 25 Cancer.
Comparison 5 Sulphonylureas versus alpha‐glucosidase inhibitors, Outcome 26 Intervention failure.
Comparison 6 Sulphonylureas versus incretin‐based intervention, Outcome 1 All‐cause mortality.
Comparison 6 Sulphonylureas versus incretin‐based intervention, Outcome 2 All‐cause mortality; best‐worst case scenario.
Comparison 6 Sulphonylureas versus incretin‐based intervention, Outcome 3 All‐cause mortality; worst‐best case scenario.
Comparison 6 Sulphonylureas versus incretin‐based intervention, Outcome 4 Cardiovascular mortality.
Comparison 6 Sulphonylureas versus incretin‐based intervention, Outcome 5 Non‐fatal macrovascular outcomes.
Comparison 6 Sulphonylureas versus incretin‐based intervention, Outcome 6 Non‐fatal myocardial infarction.
Comparison 6 Sulphonylureas versus incretin‐based intervention, Outcome 7 Non‐fatal stroke.
Comparison 6 Sulphonylureas versus incretin‐based intervention, Outcome 8 Amputation of lower extremity.
Comparison 6 Sulphonylureas versus incretin‐based intervention, Outcome 9 Cardial revascularisation.
Comparison 6 Sulphonylureas versus incretin‐based intervention, Outcome 10 Peripheral revascularisation.
Comparison 6 Sulphonylureas versus incretin‐based intervention, Outcome 11 Microvascular outcomes.
Comparison 6 Sulphonylureas versus incretin‐based intervention, Outcome 12 Nephropathy.
Comparison 6 Sulphonylureas versus incretin‐based intervention, Outcome 13 Retinopathy.
Comparison 6 Sulphonylureas versus incretin‐based intervention, Outcome 14 Retinal photocoagulation.
Comparison 6 Sulphonylureas versus incretin‐based intervention, Outcome 15 Change in fasting blood glucose from baseline (mmol/L).
Comparison 6 Sulphonylureas versus incretin‐based intervention, Outcome 16 Change in HbA1c from baseline (%).
Comparison 6 Sulphonylureas versus incretin‐based intervention, Outcome 17 Change in BMI from baseline (kg/m2).
Comparison 6 Sulphonylureas versus incretin‐based intervention, Outcome 18 Change in weight from baseline (kg).
Comparison 6 Sulphonylureas versus incretin‐based intervention, Outcome 19 Adverse events.
Comparison 6 Sulphonylureas versus incretin‐based intervention, Outcome 20 Serious adverse events.
Comparison 6 Sulphonylureas versus incretin‐based intervention, Outcome 21 Drop‐outs due to adverse events.
Comparison 6 Sulphonylureas versus incretin‐based intervention, Outcome 22 Mild hypoglycaemia.
Comparison 6 Sulphonylureas versus incretin‐based intervention, Outcome 23 Severe hypoglycaemia.
Comparison 6 Sulphonylureas versus incretin‐based intervention, Outcome 24 Intervention failure.
Comparison 7 Sulphonylureas versus meglitinide, Outcome 1 All‐cause mortality.
Comparison 7 Sulphonylureas versus meglitinide, Outcome 2 All‐cause mortality; best‐worst case scenario.
Comparison 7 Sulphonylureas versus meglitinide, Outcome 3 All‐cause mortality; worst‐best case scenario.
Comparison 7 Sulphonylureas versus meglitinide, Outcome 4 Cardiovascular mortality.
Comparison 7 Sulphonylureas versus meglitinide, Outcome 5 Non‐fatal macrovascular outcomes.
Comparison 7 Sulphonylureas versus meglitinide, Outcome 6 Non‐fatal myocardial infarction.
Comparison 7 Sulphonylureas versus meglitinide, Outcome 7 Non‐fatal stroke.
Comparison 7 Sulphonylureas versus meglitinide, Outcome 8 Amputation of lower extremity.
Comparison 7 Sulphonylureas versus meglitinide, Outcome 9 Cardial revascularisation.
Comparison 7 Sulphonylureas versus meglitinide, Outcome 10 Peripheral revascularisation.
Comparison 7 Sulphonylureas versus meglitinide, Outcome 11 Microvascular outcomes.
Comparison 7 Sulphonylureas versus meglitinide, Outcome 12 Nephropathy.
Comparison 7 Sulphonylureas versus meglitinide, Outcome 13 Retinopathy.
Comparison 7 Sulphonylureas versus meglitinide, Outcome 14 Retinal photocoagulation.
Comparison 7 Sulphonylureas versus meglitinide, Outcome 15 Change in fasting blood glucose from baseline (mmol/L).
Comparison 7 Sulphonylureas versus meglitinide, Outcome 16 Change in HbA1c from baseline (%).
Comparison 7 Sulphonylureas versus meglitinide, Outcome 17 Change in BMI from baseline (kg/m2).
Comparison 7 Sulphonylureas versus meglitinide, Outcome 18 Change in weight from baseline (kg).
Comparison 7 Sulphonylureas versus meglitinide, Outcome 19 Adverse events.
Comparison 7 Sulphonylureas versus meglitinide, Outcome 20 Drop‐outs due to adverse events.
Comparison 7 Sulphonylureas versus meglitinide, Outcome 21 Serious adverse events.
Comparison 7 Sulphonylureas versus meglitinide, Outcome 22 Mild hypoglycaemia.
Comparison 7 Sulphonylureas versus meglitinide, Outcome 23 Moderate hypoglycaemia.
Comparison 7 Sulphonylureas versus meglitinide, Outcome 24 Severe hypoglycaemia.
Comparison 7 Sulphonylureas versus meglitinide, Outcome 25 Cancer.
Comparison 7 Sulphonylureas versus meglitinide, Outcome 26 Intervention failure.
Comparison 8 Second‐generation sulphonylureas versus first‐generation sulphonylureas, Outcome 1 All‐cause mortality.
Comparison 8 Second‐generation sulphonylureas versus first‐generation sulphonylureas, Outcome 2 Cardiovascular mortality.
Comparison 8 Second‐generation sulphonylureas versus first‐generation sulphonylureas, Outcome 3 Non‐fatal myocardial infarction.
Comparison 8 Second‐generation sulphonylureas versus first‐generation sulphonylureas, Outcome 4 Non‐fatal stroke.
Comparison 8 Second‐generation sulphonylureas versus first‐generation sulphonylureas, Outcome 5 Amputation of lower extremity.
Comparison 8 Second‐generation sulphonylureas versus first‐generation sulphonylureas, Outcome 6 Microvascular outcomes.
Comparison 8 Second‐generation sulphonylureas versus first‐generation sulphonylureas, Outcome 7 Retinal photocoagulation.
Comparison 8 Second‐generation sulphonylureas versus first‐generation sulphonylureas, Outcome 8 Change in fasting blood glucose from baseline (mmol/L).
Comparison 8 Second‐generation sulphonylureas versus first‐generation sulphonylureas, Outcome 9 Change in HbA1c from baseline (%).
Comparison 8 Second‐generation sulphonylureas versus first‐generation sulphonylureas, Outcome 10 Change in weight from baseline (kg).
Comparison 8 Second‐generation sulphonylureas versus first‐generation sulphonylureas, Outcome 11 Mild hypoglycaemia.
Comparison 8 Second‐generation sulphonylureas versus first‐generation sulphonylureas, Outcome 12 Severe hypoglycaemia.
Comparison 8 Second‐generation sulphonylureas versus first‐generation sulphonylureas, Outcome 13 Cancer.
Comparison 8 Second‐generation sulphonylureas versus first‐generation sulphonylureas, Outcome 14 Intervention failure.
| First‐generation sulphonylureas compared with controls for type 2 diabetes mellitus | ||||
| Patient or population: participants with type 2 diabetes mellitus Settings: outpatients Intervention: first‐generation sulphonylureas (acetohexamide, carbutamide, chlorpropamide, tolbutamide, tolazamide) Comparison: placebo, active comparators | ||||
| Outcomes | Relative effect | No of participants | Quality of the evidence | Comments |
| All‐cause mortality a. Intervention vs placebo b. Intervention vs insulin | a.RR 1.46 (0.87 to 2.45) b. RR 1.18 (0.88 to 1.59) | a. 553 (2) b. 1944 (2) | ⊕⊕⊝⊝ | a. Small sample size (1.5% of the diversity‐adjusted required information size) b. Trial sequential analysis showed that 5.7% of the required information size to detect or reject a 10% RRR was accrued |
| Cardiovascular mortality a. Intervention vs placebo b. Intervention vs insulin | a.RR 2.63 (1.32 to 5.22) b. RR 1.36 (0.88 to 1.48) | a. 553 (2) b. 1944 (2) | ⊕⊕⊝⊝ | a. Small sample size (0.7% of the diversity‐adjusted required information size) b. Trial sequential analysis showed that 1.1% of the required information size to detect or reject a 10% RRR was accrued |
| Non‐fatal macrovascular outcomes 1. Composite 2. Non‐fatal myocardial infarction Intervention vs insulin | 1a. not estimable 2b. RR 1.08 (0.81 to 1.45) | 1a. See comment 2b.1944 (2) | 1a. See comment 2b. ⊕⊕⊝⊝ | 1a. No meta‐analysis possible |
| Microvascular outcomes | Not estimable | See comment | See comment | No meta‐analysis possible |
| Cancer Intervention vs insulin | RR 0.81 (0.29 to 2.27) | 1944 (2) | ⊕⊕⊝⊝ | One study reported any cancer and the other death due to cancer |
| Adverse events 1. All adverse events Intervention vs alpha‐glucosidase inhibitors | 1. RR 0.63 (0.52 to 0.76) 2. RR 0.28 (0.12 to 0.67) | 1. 246 (2) | ⊕⊕⊝⊝ | Trial sequential analysis showed that firm evidence was not established |
| Health‐related quality of life | Not estimable | See comment | See comment | Not investigated |
| GRADE Working Group grades of evidence | ||||
| aDue to imprecision and results of trial sequential analysis. RRR: relative risk reduction | ||||
| Second‐generation sulphonylureas compared with controls for type 2 diabetes mellitus | ||||
| Patient or population: participants with type 2 diabetes mellitus Settings: outpatients Intervention: second‐generation sulphonylureas (glibenclamide or glyburide, glibornuride, gliclazide, glipizide) Comparison: placebo, active comparators | ||||
| Outcomes | Relative effect | No of participants | Quality of the evidence | Comments |
| All‐cause mortality a. Intervention vs metformin b. Intervention vs thiazolidinediones c. Intervention vs insulin d. Intervention vs incretin‐based control e. Intervention vs meglitinide [e. 12 months to 17 months] | a. RR 0.98 (0.61 to 1.58) b. RR 0.92 (0.60 to 1.41) c. RR 0.96 (0.79 to 1.18) d. RR 1.39 (0.52 to 3.68) e. RR 1.44 (0.47 to 4.42) | a. 3528 (6) b. 4955 (7) c. 1642 (4) d. 1503 (2) e. 2038 (7) | ⊕⊕⊝⊝ | a. Trial sequential analysis showed that 2.3% of the required information size to detect or reject a 10% RRR was accrued. b. Results of the random‐effects model. Trial sequential analysis showed that 2.5% of the required information size to detect or reject a 10% RRR was accrued. c. Trial sequential analysis showed that 12.8% of the required information size to detect or reject a 10% RRR was accrued. d. Trial sequential analysis showed that 0.5% of the required information size to detect or reject a 10% RRR was accrued. e. Trial sequential analysis showed that only a minor fraction of the required information size to detect or reject a 10% RRR was accrued. |
| Cardiovascular mortality a. Intervention vs metformin b. Intervention vs thiazolidinediones c. Intervention vs insulin d. Intervention vs meglitinide [d. 12 months to 17 months] | a. RR 1.47 (0.54 to 4.01) b. RR 1.30 (0.55 to 3.07) c. RR 0.96 (0.73 to 1.28) d. RR 0.97 (0.27 to 3.53) | a. 3528 (6) b. 4955 (7) c. 1642 (4) d. 2038 (7) | ⊕⊕⊝⊝ | a. Trial sequential analysis showed that 2.7% of the required information size to detect or reject a 10% RRR was accrued. b. Trial sequential analysis showed that 0.3% of the required information size to detect or reject a 10% RRR was accrued. c. Trial sequential analysis showed that 6.6% of the required information size to detect or reject a 10% RRR was accrued. d. Trial sequential analysis showed that only a minor fraction of the required information size to detect or reject a 10% RRR was accrued. |
| Non‐fatal macrovascular outcomes a. Intervention vs metformin b. Intervention vs thiazolidinediones [1b. 52 weeks to 4 years] c. Intervention vs meglitinide [1c. 12 months to 15 months] a. Intervention vs metformin b. Intervention vs thiazolidinediones [2b. 24 weeks to 4 years] c. Intervention vs meglitinide [2c. 12 months to 17 months] | 1a. RR 0.67 (0.48 to 0.93) 1b. RR 0.91 (0.62 to 1.33) 1c. RR 0.50 (0.20 to 1.20) 2a.RR 1.02 (0.37 to 2.85) 2b. RR 0.68 (0.41 to 1.14) 2c. RR 1.03 (0.26 to 4.08) | 1a. 3018 (3) 1b. 4600 (6) 1c. 866 (3) 2a. 3061 (4) 2b. 4956 (7) 2c. 726 (3) | ⊕⊕⊝⊝ | 1a. Non‐fatal macrovascular outcomes as a composite outcome were not reported in the way we predefined to assess this outcome. Trial sequential analysis showed that 5% of the required information size to detect or reject a 10% RRR was accrued. 1c. The definition of non‐fatal macrovascular outcomes was heterogenous. |
| Microvascular outcomes | Not estimable | See comment | See comment | No meta‐analysis possible |
| Adverse events 1. All adverse events a. Intervention vs placebo b. Intervention vs metformin [3b. 24 weeks to 10.4 years] c. Intervention vs thiazolidinediones [3c. 6 months to 4 years] d. Intervention vs alpha‐glucosidase inhibitors [1d. 24 weeks to 12 months] e. Intervention vs incretin‐based control f. Intervention vs meglitinides [3f. 14 months to 17 months] | 1a. RR 0.91 (0.51 to 1.62) 1b. RR 0.99 (0.97 to 1.01) 1c. RR 0.99 (0.97 to 1.01) 1d. RR 0.64 (0.39 to 1.03) 1f. RR 1.0 (0.95 to 1.06) 2a. RR 0.62 (0.24 to 1.57) 2b.RR 1.19 (0.99 to 1.42) 2c. RR 1.15 (0.98 to 1.36) 2d. RR 0.48 (0.24 to 0.96) 2e. RR 1.00 (0.67 to 1.50) 2f. RR 1.01 (0.78 to 1.32) 3b. RR 5.64 (1.22 to 26.00) 3c. RR 6.11 (1.57 to 23.79) 3f. RR 2.17 (0.53 to 8.91) | 1a. 202 (2) 1b. 3042 (2) 1c. 6491 (10) 1d. 646 (8) 1f. 1829 (5) 2a. 510 (5) 2b. 3567 (7) 2c. 7433 (15) 2d. 970 (9) 2e. 1503 (2) 2f. 2019 (7) 3b. 3637 (4) 3c. 5669 (6) 3f. 1863 (6) | ⊕⊕⊝⊝ | 1d. Results of the random‐effects model. Fixed‐effect model: RR 0.67 (0.52 to 0.86) 2c. Results of the random‐effects model. Fixed‐effect model: RR 1.17 (1.01 to 1.35) 2d. Trial sequential analysis showed that only a minor fraction of the required information size to confirm or reject a 10% RRR was accrued 3b. Trial sequential analysis showed that only 0.1% of the required information size was accrued 3c. Trial sequential analysis showed that a minor fraction of the required information size was accrued |
| Cancer a. Intervention vs thiazolidinediones b. Intervention vs insulin | a. RR 1.02 (0.72 to 1.45) b. RR 0.95 (0.61 to 1.49) | a. 4192 (6) b. 1575 (2) | ⊕⊕⊝⊝ | |
| Health‐related quality of life a. Intervention vs thiazolidinediones b. Intervention vs insulin c. Intervention vs alpha‐glucosidase inhibitors | Not estimable | a. 35 (1) b. 49 (1) c. 35 (1) | ⊕⊝⊝⊝ | a. Inadequately reported, no scale provided b. Authors used short‐form 36 (SF 36), but did not find any significant differences between the interventions c. Inadequately reported, no scale provided |
| GRADE Working Group grades of evidence | ||||
| aDue to imprecision and results of trial sequential analysis. bDue to small sample size and risk of bias. RRR: relative risk reduction | ||||
| Third‐generation sulphonylureas compared with controls for type 2 diabetes mellitus | ||||
| Patient or population: participants with type 2 diabetes mellitus Settings: outpatients Intervention: third‐generation sulphonylureas (gliclazide modified release (MR), glimepiride, glipizide gastrointestinal therapeutic system (GITS)) Comparison: active comparators | ||||
| Outcomes | Relative effect | No of Participants | Quality of the evidence | Comments |
| All‐cause mortality | Not estimable | See comment | See comment | No meta‐analysis possible |
| Cardiovascular mortality | Not estimable | See comment | See comment | No meta‐analysis possible |
| Macrovascular outcomes | Not estimable | See comment | See comment | No meta‐analysis possible |
| Microvascular outcomes | Not estimable | See comment | See comment | No meta‐analysis possible |
| Adverse events 1. All adverse events Interventions vs thiazolidinediones [1. 6 months to 12 months] [2. 24 weeks to 52 weeks] | 1. RR 0.88 (0.78 to 0.99) 2. RR 0.54 (0.15 to 1.97) | 1. 510 (3) 2. 423 (2) | ⊕⊕⊝⊝ | 1. Trial sequential analysis showed that firm evidence was not established |
| Cancer | Not estimable | See comment | See comment | No meta‐analysis possible |
| Health‐related quality of life | Not estimable | See comment | See comment | No meta‐analysis possible |
| GRADE Working Group grades of evidence | ||||
| aDue to imprecision/small sample size and results of trial sequential analysis. RRR: relative risk reduction | ||||
| Characteristic Study ID | Intervention(s) and control(s) | [N] screened | [N] randomised | [N] safety | [N] lost to follow‐up (mortality) | [N] finishing study | [%] of randomised participants finishing study |
| Abbatecola 2006 | I1: glibenclamide C1: repaglinide | ‐ | I1: 79 C1: 77 T: 156 | I1: 73 C1: 74 T: 147 | ‐ | I1: 63 C1: 65 T: 128 | I1: 80 C1: 84 T: 82 |
| ADOPT 2006 | I1: glibenclamide C1: rosiglitazone C2: metformin | 6676 | I1: 1447 C1: 1458 C2: 1455 T: 4360 | I1: 1441 C1: 1456 C2: 1455 T: 4351 | ‐ | I1: 807 C1: 917 C2: 903 T: 2627 | I1: 56 C1: 63 C2: 62 T: 60 |
| AGEE/DCD/046/UK | I1:glibenclamide C1: repaglinide | 313 | I1: 86 C1: 178 T: 264 | I1: 85 C1: 178 T: 264 | ‐ | I1: 57 C1: 111 T: 168 | I1:66 C1: 62 T: 64 |
| AGEE/DCD/047/B/F/I | I1: gliclazide C1: repaglinide | 337 | I1: 99 C1: 206 T: 305 | I1: 99 C1: 206 T: 305 | ‐ | I1: 68 C1: 138 T: 206 | I1: 69 C1: 67 T: 68 |
| Alvarsson 2010 | I1: glibenclamide C1: insulin | 56 | I1: 26 C1: 23 T: 49 | ‐ | I1: 7 C1: 5 T: 12 | I1: 18 C1: 16 T: 34 | I1: 69 C1: 70 T: 70 |
| APPROACH 2010 a | I1: glipizide C1: rosiglitazone | 1147 | I1: 339 C1: 333 T: 672 | I1: 337 C1: 331 T: 668 | I1: 22 C1: 17 T: 39 | I1: 264 C1: 259 T: 523 | I1: 78 C1: 78 T: 78 |
| Birkeland 1994 | I1: glibenclamide I2: glipizide C1: placebo | ‐ | I1: 15 I2: 15 C1: 16 T: 46 | ‐ | I1: 0 I2: 0 C1: 0 T: 0 | I1: 15 I2: 13 C1: 12 T: 40 | I1: 100 I2: 87 C1: 75 T: 87 |
| Birkeland 2002 | I1: glibenclamide C1: insulin | 54 | I1: 18 C1: 18 T: 36 | ‐ | ‐ | ‐ | N/A |
| Campbell 1994 | I1: glipizide C1: metformin | 50 (?) | I1: 24 C1: 24 T: 48 | I1: 24 C1: 24 T: 48 | I1: 0 C1: 0 T: 0 | I1: 24 C1: 24 T: 48 | I1: 100 C1: 100 T: 100 |
| Charbonnel 2005 b | I1: gliclazide C1: pioglitazone | 2412 | I1: 626 C1: 624 T: 1270 | ‐ | I1: 4 C1: 4 T: 8 | I1: 525 C1: 530 T: 1055 | I1: ‐ C1: ‐ T: 83 |
| Collier 1989 | I1: gliclazide C1: metformin | ‐ | I1: 12 C1: 12 T: 24 | I1: 12 C1: 12 T: 24 | ‐ | I1: 12 C1: 12 T: 24 | I1: 100 C1: 100 T: 100 |
| Coniff 1995 | I1: tolbutamide C1: acarbose C2: placebo | ‐ | I1: 72 C1: 76 C2: 72 T: 220 | I1: 71 C1: 74 C2: 72 T: 217 | ‐ | ‐ | N/A |
| Dalzell 1986 | I1: tolbutamide C1: metformin | ‐ | I1: 15 C1: 18 T: 33 | ‐ | ‐ | ‐ | N/A |
| DeFronzo 2005 | I1: glibenclamide C1: metformin | 788 | I1: 209 C1: 210 T: 419 | ‐ | ‐ | I1: 174 C1: 157 T: 331 | I1: 83 C1: 75 T: 79 |
| Deng 2003 | I1: glibenclamide C1: Xiaoyaosan | 160 | I1: 80 C1: 80 T: 160 | ‐ | ‐ | ‐ | N/A |
| Derosa 2003 | I1: glimepiride C1: repaglinide | ‐ | I1: 66 C1: 66 T: 132 | I1: 66 C1: 66 T: 132 | I1: 4 C1: 4 T: 8 | I1: 62 C1: 62 T: 124 | I1: 94 C1: 94 T: 94 |
| Derosa 2004 | I1: glimepiride C1: metformin | ‐ | I1: 81 C1: 83 T: 164 | I1: 81 C1: 83 T: 164 | ‐ | I1: 73 C1: 75 T: 148 | I1:90 C1: 90 T: 90 |
| Diehl 1985 | I1: chlorpropamide C1: insulin | 137 | I1: 40 C1: 37 T: 77 | ‐ | ‐ | I1: 30 C1: 28 T: 58 | I1: 75 C1: 77 T: 75 |
| Ebeling 2001 | I1: glibenclamide C1: pioglitazone C2: placebo | ‐ | I1: 10 C1: 9 C2: 10 T: 29 | ‐ | ‐ | ‐ | N/A |
| Esposito 2004 | I1: glibenclamide C1: repaglinide | 210 | I1: 87 C1: 88 T: 175 | I1: 87 C1: 88 T: 175 | I1: 7 C1: 7 T: 14 | I1: 80 C1: 81 T: 161 | I1: 92 C1: 92 T: 92 |
| Feinböck 2003 | I1: glibenclamide C1: acarbose | ‐ | I1: 111 C1: 108 T: 219 | I1: 93 C1: 59 T: 152 | ‐ | I1: 93 C1: 59 T: 152 | I1: 84 C1: 55 T: 69 |
| Fineberg 1980 c | I1: glipizide C1: tolbutamide | ‐ | I1: ‐ C1: ‐ T: 29 | ‐ | ‐ | I1: 8 C1: 10 T: 18 | I1: ‐ C1: ‐ T: 62 |
| Foley 2009 | I1: gliclazide C1: vildagliptin | ‐ | I1: 546 C1: 546 T: 1092 | I1: 402 C1: 409 T: 811 | I1: 13 C1: 17 T: 30 | I1: 402 C1: 409 T: 811 | I1:74 C1: 75 T: 74 |
| Forst 2003 | I1: glibenclamide C1: insulin | 200 | I1: 68 C1: 75 T: 143 | I1: 68 C1: 75 T: 143 | I1: 0 C1: 0 T: 0 | I1: 68 C1: 75 T: 143 | I1: 100 C1: 100 T: 100 |
| Forst 2005 | I1: glimepiride C1: pioglitazone | 192 | I1: 87 C1: 92 T: 179 | I1: 84 C1: 89 T: 173 | I1: 3 C1: 3 T: 6 | I1: 84 C1: 89 T: 173 | I1:97 C1: 97 T: 97 |
| Hanefeld 2005 | I1: glibenclamide C1: rosiglitazone 2 mg C2: rosiglitazone 4 mg | ‐ | I1: 207 C1: 200 C2: 191 T: 598 | ‐ | I1: 0 C1: 0 C2: 0 T: 0 | I1: 173 C1: 153 C2: 158 T: 484 | I1: 84 C1: 77 C2: 83 T: 81 |
| Harrower 1985 | I1: glipizide I2: gliquidone I3: gliclazide I4: glibenclamide C1: chlorpropamide | ‐ | I1: 24 I2: 22 I3: 22 I4: 23 T: 112 | ‐ | I1: 4 I2: 3 I3: 2 I4: 4 T: 16 | I1: 20 I2: 19 I3: 20 I4: 19 T: 96 | I1: 83 I2: 86 I3: 91 I4: 83 T: 86 |
| Hermann 1991 d | I1: glibenclamide C1: metformin | ‐ | I1: ‐ C1: ‐ T: 25 | I1: 10 C1: 12 T: 22 | ‐ | I1: 10 C1: 12 T: 22 | N/A |
| Hermann 1991a | I1: glibenclamide C1: metformin | ‐ | I1: 34 C1: 38 T: 72 | ‐ | I1: 0 C1: 0 T: 0 | I1: 28 C1: 28 T: 56 | I1: 82 C1: 74 T: 78 |
| Hoffmann 1990 | I1: glibenclamide C1: acarbose | ‐ | I1: 47 C1: 48 T: 95 | ‐ | ‐ | ‐ | N/A |
| Hoffmann 1994 | I1: glibenclamide C1: placebo C2: acarbose | 96 | I1: 27 C1: 30 C2: 28 T: 85 | ‐ | I1: 0 C1: 0 T: 0 | I1: 27 C1: 30 C2: 28 T: 85 | I1: 100 C1: 100 C2: 100 |
| Hollander 1992 | I1: glibenclamide C1: insulin | ‐ | I1: 29 C1: 30 T: 59 | ‐ | ‐ | ‐ | N/A |
| Jain 2006 | I1: glibenclamide C1: pioglitazone | ‐ | I1: 251 C1: 251 T: 502 | ‐ | I1: 21 C1: 22 T: 43 | I1: 128 C1: 134 T: 262 | I1: 50 C1: 53 T: 52 |
| Jibran 2006 | I1: glibenclamide C1: repaglinide | ‐ | I1: 50 C1: 50 T: 100 | ‐ | ‐ | ‐ | N/A |
| Johnston 1997 | I1: glibenclamide C1: placebo C2: miglitol 25 mg C3: miglitol 50 mg | ‐ | I1: 104 C1: 101 C2: 104 C3: 102 T: 411 | ‐ | ‐ | ‐ | N/A |
| Kaku 2011 | I1: glibenclamide C1: liraglutide | 464 | I1: 139 C1: 272 T: 411 | I1: 132 C1: 268 T: 400 | ‐ | I1: 110 C1: 225 T: 335 | I1: 79 C1: 83 T: 82 |
| Kamel 1997 | I1: gliclazide I2: glibenclamide C1: acarbose C2: metformin C3: placebo | ‐ | I1: 9 I2: 8 C1: 10 C2: 6 C3: 10 T: 43 | ‐ | ‐ | ‐ | N/A |
| Kanda 1998 | I1: gliclazide C1: acarbose | 25 | I1: 9 C1: 10 T: 19 | ‐ | ‐ | I1: 9 C1: 10 T: 19 | I1: 100 C1: 100 T: 100 |
| Kovacevic 1997 | I1: glibenclamide C1: acarbose C2: placebo | ‐ | I1: 34 C1: 34 C2: 34 T: 102 | I1: 33 C1: 33 C2: 31 T: 97 | ‐ | I1: 33 C1: 33 C2: 31 T: 97 | I1: 97 C1: 97 C2: 91 T: 95 |
| Lawrence 2004 | I1: gliclazide C1: metformin C2: pioglitazone | 67 | I1: 22 C1: 21 C2: 21 T: 64 | ‐ | I1: 0 C1: 0 C2: 0 T: 0 | I1: 20 C1: 20 C2: 20 T: 60 | I1: 91 C1: 95 C2: 95 T: 94 |
| LEAD‐3 2006 e | I1: glimepiride C1: liraglutide 1.2 mg C2: liraglutide 1.8 mg | ‐ | I1: 248 C1: 251 C2: 247 T: 746 | I1: 248 C1: 251 C2: 246 T: 745 | ‐ | I1: 152 C1: 162 C2: 173 T: 487 | I1: 61 C1: 65 C2: 70 T: 65 |
| Madsbad 2001 | I1: glipizide C1: repaglinide | 320 | I1: 81 C1: 175 T: 256 | I1: 81 C1: 175 T: 256 | ‐ | I1: 58 C1: 140 T: 198 | I1: 72 C1: 80 T: 77 |
| Marbury 1999 | I1: glibenclamide C1: repaglinide | ‐ | I1: 193 C1: 383 T: 576 | I1: 193 C1: 383 T: 576 | ‐ | I1: 115 C1: 216 T: 331 | I1: 60 C1: 56 T: 57 |
| Memisogullari 2009 | I1: gliclazide C1: nothing | ‐ | I1: 26 C1: 30 T: 56 | ‐ | I1:0 C1: 0 T: 0 | ‐ | N/A |
| Nakamura 2004 | I1: glibenclamide C1: pioglitazone C2: voglibose | ‐ | I1: 15 C1: 15 C2: 15 T: 45 | I1: 15 C1: 15 C2: 15 T: 45 | I1: 0 C1: 0 C2: 0 T: 0 | I1: 15 C1: 15 C2: 15 T: 45 | I1: 100 C1: 100 C2: 100 T: 100 |
| Nakamura 2006 | I1: glibenclamide C1: pioglitazone C2: voglibose C3: nateglinide | 78 | I1: 18 C1: 17 C2: 17 C3: 16 T: 68 | I1: 18 C1: 17 C2: 17 C3: 16 T: 68 | I1: 0 C1: 0 C2: 0 C3: 0 T: 0 | I1: 18 C1: 17 C2: 17 C3: 16 T: 68 | I1: 100 C1: 100 C2: 100 C3: 100 T: 100 |
| Nathan 1988 | I1: glibenclamide C1: insulin | ‐ | I1: 16 C1: 15 T: 31 | I1: 16 C1: 15 T: 31 | I1: 0 C1: 0 T: 0 | I1: 16 C1: 15 T: 31 | I1: 100 C1: 100 T: 100 |
| Pagano 1995 f | I1: glibenclamide C1: miglitol | ‐ | I1: 47 C1: 50 T: 100 | I1: ‐ C1: ‐ T: 99 | I1: ‐ C1: ‐ T: 3 | I1: 47 C1: 49 T: 96 | I1: ‐ C1: ‐ T: 96 |
| Perriello 2007 | I1: gliclazide C1: pioglitazone | ‐ | I1: 137 C1: 146 T: 283 | ‐ | ‐ | I1: 135 C1: 140 T: 275 | I1: 99 C1: 96 T: 97 |
| Rosenthal 2002 | I1: glibenclamide C1: acarbose | ‐ | I1: 37 C1: 39 T: 76 | I1: 31 C1: 32 T: 63 | ‐ | I1: 31 C1: 32 T: 63 | I1: 84 C1: 82 T: 83 |
| Salman 2001 | I1: gliclazide C1: acarbose | ‐ | I1: 35 C1: 33 T: 68 | I1: 30 C1: 27 T: 57 | ‐ | I1: 30 C1: 27 T: 57 | I1: 86 C1: 82 T: 84 |
| Segal 1997 | I1: glibenclamide C1: miglitol C2: placebo | ‐ | I1: 69 C1: 67 C2: 65 T: 201 | I1: 69 C1: 67 C2: 65 T: 201 | I1: 11 C1: 12 C2: 6 T: 29 | I1: 50 C1: 49 C2: 58 T: 157 | I1: 72 C1: 73 C2: 89 T: 78 |
| Shihara 2011 | I1: glimepiride C1: pioglitazone | 238 | I1: 95 C1: 96 T: 191 | I1: 86 C1: 91 T: 177 | ‐ | I1: 86 C1: 91 T: 177 | I1: 91 C1: 95 T: 93 |
| Spengler 1992 g | I1: glibenclamide C1: acarbose | ‐ | I1: 36 C1: 36 T: 72 | ‐ | ‐ | I1: 29 C1: 26 T: 55 | I1: 81 C1: 72 T: 76 |
| Sung 1999 | I1: glibenclamide C1: troglitazone | ‐ | I1: 12 C1: 10 T: 22 | ‐ | ‐ | ‐ | N/A |
| Sutton 2002 h | I1: glibenclamide C1: rosiglitazone | 351 | I1: 99 C1: 104 T: 203 | I1: 99 C1: 104 T: 203 | I1: 3 C1: 2 T: 5 | I1: 65 C1: 64 T: 129 | I1: 66 C1: 62 T: 64 |
| Tan 2004 | I1: glimepiride C1: pioglitazone | 584 | I1: 123 C1: 121 T: 244 | I1: 92 C1: 100 T: 192 | I1: 11 C1: 6 T: 17 | I1: 89 C1: 87 T: 176 | I1: 72 C1: 72 T: 72 |
| Tan 2004a | I1: glimepiride C1: pioglitazone | ‐ | I1: 109 C1: 91 T: 200 | I1: 109 C1: 91 T: 200 | ‐ | I1: 68 C1: 55 T: 123 | I1: 62 C1: 60 T: 62 |
| Tan 2005 i | I1: gliclazide C1: pioglitazone | 2412 | I1: 297 C1: 270 T: 567 | ‐ | I1: 4 C1: 2 T: 6 | I1: 127 C1: 147 T: 274 | I1: 43 C1: 54 T: 48 |
| Tang 2004 | I1: glimepiride C1: metformin | ‐ | I1: 33 C1: 29 T: 62 | ‐ | ‐ | ‐ | N/A |
| Teramoto 2007 | I1: glibenclamide C1: pioglitazone | 126 | I1: 46 C1: 46 | I1: 41 C1: 39 T: 80 | ‐ | I1: 41 C1: 39 T: 80 | I1: 89 C1: 85 T: 86 |
| Tessier 1999 | I1: gliclazide C1: metformin | ‐ | I1: 19 C1: 20 T: 39 | ‐ | I1: 1 C1: 2 T: 3 | I1: 18 | I1: 94.7 |
| Tosi 2003 | I1: glibenclamide C1: metformin | ‐ | I1: 22 C1: 22 T: 44 | ‐ | ‐ | I1: 20 C1: 19 T: 39 | I1: 91 C1: 86 T: 89 |
| UGDP 1970 | I1: tolbutamide C1: placebo C1: insulin | ‐ | I1: 204 C1: 205 C2: 210 T: 619 | I1: 75% on tolbutamide C1: 75% on placebo C2: ‐ T: ‐ | ‐ | ‐ | N/A |
| UKPDS 1998 j | Study 1: I1: chlorpropamide I2: glibenclamide I3: glipizide C1: insulin | 7616 | I1: 788 I2: 615 I3: 170 C1: 1156 T: 2729 | ‐ | ‐ | ‐ | N/A |
| UKPDS 34 1998 | I1: chlorpropamide I2: glibenclamide C1: metformin C2: insulin | 4209 | I1: 265 I2: 277 C1: 342 C2: 409 T: 1293 | ‐ | I1: ‐ I2: ‐ C1: ‐ C2: ‐ T: 13 | ‐ | N/A |
| van de Laar 2004 | I1: tolbutamide C1: acarbose | 144 | I1: 50 C1: 48 T: 98 | I1: 48 C1: 48 T: 96 | I1: 5 C1: 16 T: 21 | I1: 43 C1: 32 T: 75 | I1: 86 C1: 67 T: 77 |
| Watanabe 2005 | I1: glibenclamide C1: pioglitazone | ‐ | I1: 15 C1: 15 | I1: 14 C1: 13 | I1: 1 C1: 2 | I1: 14 C1: 13 | I1: 93 C1: 87 |
| Wolffenbuttel 1989 | I1: tolbutamide C1: insulin | ‐ | I1: 6 C1: 7 T: 13 | ‐ | ‐ | ‐ | N/A |
| Wolffenbuttel 1999 | I1: glibenclamide C1: repaglinide | 491 | I1: 140 C1: 288 | I1: 139 C1: 286 | ‐ | I1: 109 C1: 211 T: 320 | I1: 78 C1: 74 T: 75 |
| Yamanouchi 2005 | I1: glimepiride C1: pioglitazone C2: metformin | ‐ | I1: 37 C1: 38 C2: 39 T: 114 | ‐ | I1: 3 C1: 0 C2: 1 T: 4 | I1: 34 C1: 35 C2: 37 T: 106 | I1: 92 C1: 92 C2: 95 T: 93 |
| Zhang 2005 | I1: glipizide C1: rosiglitazone 4 mg C2: rosiglitazone 8 mg | 45 | I1: 8 C1: 8 C2: 8 T: 24 | I1: 8 C1: 8 C2: 8 T: 24 | I1: 0 C1: 0 C2: 0 T: 0 | I1: 8 C1: 8 C2: 8 T: 24 | I1: 100 C1: 100 C2: 100 T: 100 |
| Totalk | I: any sulphonylurea C: any comparator | I: 9707 C: 12,805 T:22,589 | I: 4901 C: 6888 T:11,789 | ||||
| "‐" denotes not reported aThe number of participants finishing the trial is taken from clinicaltrials.gov and is the number of individuals who completed the trial as defined by investigator. bTwenty of the randomised participants are not included in the analysis. It is unknown to which group they belong. Therefore the total number of randomised participants does not equal the sum of the number of randomised patients in each intervention group. cThe number of randomised participants to each comparator group is not reported. Only the 18 participants finishing the trial are described in the publication. dIt is reported that 25 participants were randomised, but only the 22 participants who completed the trial are presented. eData after 52 weeks of double‐blind intervention. From the double‐blind intervention period to the open‐label extension of 91 weeks 84 participants discontinued in the glimepiride group, 70 in the liraglutide 1.2 mg group and 71 in the liraglutide 1.8 mg group. fIt is not described in the publication to which group the three patients who were lost to follow‐up belonged. However, it is stated in the publication that 100 participants were randomised. gA total of 72 participants underwent randomisation, but only 55 participants are included in the analyses of the trial. Eleven participants were excluded because they had received sulphonylurea previously, but the authors did not report to which group they initially were randomised. hIn the publication there is a discrepancy in the number of participants finishing the study. iThe number of patients screened is the number screened to the initial 52 weeks (Charbonnel 2005). jThe numbers for chlorpropamide and insulin interventions are the number of participants randomised to 'Glucose Study 1' plus the number of participants randomised to 'Glucose Study 2'. Lost to follow‐up mortality is not explicitly explained for each antidiabetic intervention group. For 'Glucose Study 1' vital status was unknown for 57 participants in the intensive intervention group (chlorpropamide/glibenclamide/insulin). kThe number of total is not the same as the number of I and C together, as some of the trials only reported the total number of participants randomised (Fineberg 1980; Hermann 1991; Pagano 1995). Several trials did not report the number of participants finishing study. ADOPT: A Diabetes Outcome Progression Trial; APPROACH: Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Type 2 Diabetes Patients with Cardiovascular History; C: control; I: intervention; LEAD‐3: Liraglutide Effect and Action in Diabetes‐3; N/A: not acknowledged; T: total; UKPDS: United Kingdom Prospective Diabetes Study | |||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 5 | 883 | Risk Ratio (M‐H, Random, 95% CI) | 1.51 [0.91, 2.52] |
| 1.1 First‐generation SU | 2 | 553 | Risk Ratio (M‐H, Random, 95% CI) | 1.46 [0.87, 2.45] |
| 1.2 Second‐generation SU | 3 | 330 | Risk Ratio (M‐H, Random, 95% CI) | 4.86 [0.24, 99.94] |
| 1.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 2 All‐cause mortality; best‐worst case scenario Show forest plot | 1 | 57 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 2.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 2.2 Second‐generation SU | 1 | 57 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 2.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 3 All‐cause mortality; worst‐best case scenario Show forest plot | 1 | 57 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 3.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 3.2 Second‐generation SU | 1 | 57 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 3.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 4 Cardiovascular mortality Show forest plot | 5 | 883 | Risk Ratio (M‐H, Random, 95% CI) | 2.64 [1.35, 5.17] |
| 4.1 First‐generation SU | 2 | 553 | Risk Ratio (M‐H, Random, 95% CI) | 2.63 [1.32, 5.22] |
| 4.2 Second‐generation SU | 3 | 330 | Risk Ratio (M‐H, Random, 95% CI) | 2.91 [0.12, 70.71] |
| 4.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 5 Non‐fatal macrovascular outcomes Show forest plot | 1 | 205 | Risk Ratio (M‐H, Random, 95% CI) | 1.32 [0.82, 2.13] |
| 5.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 5.2 Second‐generation SU | 1 | 205 | Risk Ratio (M‐H, Random, 95% CI) | 1.32 [0.82, 2.13] |
| 5.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 6 Non‐fatal myocardial infarction Show forest plot | 1 | 409 | Risk Ratio (M‐H, Random, 95% CI) | 0.80 [0.43, 1.51] |
| 6.1 First‐generation SU | 1 | 409 | Risk Ratio (M‐H, Random, 95% CI) | 0.80 [0.43, 1.51] |
| 6.2 Second‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 6.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 7 Amputation of lower extremity Show forest plot | 1 | 409 | Risk Ratio (M‐H, Random, 95% CI) | 0.20 [0.01, 4.16] |
| 7.1 First‐generation SU | 1 | 409 | Risk Ratio (M‐H, Random, 95% CI) | 0.20 [0.01, 4.16] |
| 7.2 Second‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 7.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 8 Nephropathy Show forest plot | 1 | 409 | Risk Ratio (M‐H, Random, 95% CI) | 1.26 [0.34, 4.61] |
| 8.1 First‐generation SU | 1 | 409 | Risk Ratio (M‐H, Random, 95% CI) | 1.26 [0.34, 4.61] |
| 8.2 Second‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 8.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 9 Retinopathy Show forest plot | 1 | 409 | Risk Ratio (M‐H, Random, 95% CI) | 0.93 [0.67, 1.30] |
| 9.1 First‐generation SU | 1 | 409 | Risk Ratio (M‐H, Random, 95% CI) | 0.93 [0.67, 1.30] |
| 9.2 Second‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 9.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 10 Change in fasting blood glucose from baseline (mmol/L) Show forest plot | 6 | 342 | Mean Difference (IV, Random, 95% CI) | ‐1.35 [‐2.00, ‐0.69] |
| 10.1 First‐generation SU | 1 | 128 | Mean Difference (IV, Random, 95% CI) | ‐2.1 [‐3.19, ‐1.01] |
| 10.2 Second‐generation SU | 5 | 214 | Mean Difference (IV, Random, 95% CI) | ‐1.20 [‐1.94, ‐0.46] |
| 10.3 Third‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 11 Change in HbA1c from baseline (%) Show forest plot | 6 | 342 | Mean Difference (IV, Random, 95% CI) | 1.00 [‐1.21, ‐0.79] |
| 11.1 First‐generation SU | 1 | 128 | Mean Difference (IV, Random, 95% CI) | ‐0.94 [‐1.29, ‐0.59] |
| 11.2 Second‐generation SU | 5 | 214 | Mean Difference (IV, Random, 95% CI) | ‐1.02 [‐1.32, ‐0.72] |
| 11.3 Third‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 12 Change in BMI from baseline (kg/m2) Show forest plot | 3 | 141 | Mean Difference (IV, Random, 95% CI) | ‐0.09 [‐0.59, 0.41] |
| 12.1 First‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 12.2 Second‐generation SU | 3 | 141 | Mean Difference (IV, Random, 95% CI) | ‐0.09 [‐0.59, 0.41] |
| 12.3 Third‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 13 Change in weight from baseline (kg) Show forest plot | 1 | 128 | Mean Difference (IV, Random, 95% CI) | ‐0.40 [‐1.36, 0.56] |
| 13.1 First‐generation SU | 1 | 128 | Mean Difference (IV, Random, 95% CI) | ‐0.40 [‐1.36, 0.56] |
| 13.2 Second‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 13.3 Third‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 14 Adverse events Show forest plot | 3 | 346 | Risk Ratio (M‐H, Random, 95% CI) | 1.23 [0.92, 1.64] |
| 14.1 First‐generation SU | 1 | 144 | Risk Ratio (M‐H, Random, 95% CI) | 1.35 [0.97, 1.88] |
| 14.2 Second‐generation SU | 2 | 202 | Risk Ratio (M‐H, Random, 95% CI) | 0.91 [0.51, 1.62] |
| 14.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 15 Drop‐outs due to adverse events Show forest plot | 6 | 654 | Risk Ratio (M‐H, Random, 95% CI) | 0.67 [0.33, 1.36] |
| 15.1 First‐generation SU | 1 | 144 | Risk Ratio (M‐H, Random, 95% CI) | 0.75 [0.17, 3.23] |
| 15.2 Second‐generation SU | 5 | 510 | Risk Ratio (M‐H, Random, 95% CI) | 0.62 [0.24, 1.57] |
| 15.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 16 Mild hypoglycaemia Show forest plot | 1 | 134 | Risk Ratio (M‐H, Random, 95% CI) | 12.26 [0.70, 213.33] |
| 16.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 16.2 Second‐generation SU | 1 | 134 | Risk Ratio (M‐H, Random, 95% CI) | 12.26 [0.70, 213.33] |
| 16.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 17 Severe hypoglycaemia Show forest plot | 1 | 46 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 17.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 17.2 Second‐generation SU | 1 | 46 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 17.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 18 Cancer Show forest plot | 2 | 614 | Risk Ratio (M‐H, Random, 95% CI) | 0.54 [0.06, 5.05] |
| 18.1 First‐generation SU | 1 | 409 | Risk Ratio (M‐H, Random, 95% CI) | 0.25 [0.07, 0.88] |
| 18.2 Second‐generation SU | 1 | 205 | Risk Ratio (M‐H, Random, 95% CI) | 2.91 [0.12, 70.71] |
| 18.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 19 Intervention failure Show forest plot | 4 | 794 | Risk Ratio (M‐H, Random, 95% CI) | 0.26 [0.07, 0.94] |
| 19.1 First‐generation SU | 1 | 409 | Risk Ratio (M‐H, Random, 95% CI) | 0.72 [0.44, 1.19] |
| 19.2 Second‐generation SU | 3 | 385 | Risk Ratio (M‐H, Random, 95% CI) | 0.13 [0.04, 0.44] |
| 19.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 8 | 3768 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.61, 1.58] |
| 1.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 1.2 Second‐generation SU | 6 | 3528 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.61, 1.58] |
| 1.3 Third‐generation SU | 2 | 240 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 2 All‐cause mortality; best‐worst case scenario Show forest plot | 5 | 283 | Risk Ratio (M‐H, Random, 95% CI) | 0.72 [0.12, 4.45] |
| 2.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 2.2 Second‐generation SU | 4 | 207 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.10, 10.25] |
| 2.3 Third‐generation SU | 1 | 76 | Risk Ratio (M‐H, Random, 95% CI) | 0.35 [0.01, 8.35] |
| 3 All‐cause mortality; worst‐best case scenario Show forest plot | 5 | 283 | Risk Ratio (M‐H, Random, 95% CI) | 1.81 [0.37, 8.71] |
| 3.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 3.2 Second‐generation SU | 4 | 207 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.10, 10.25] |
| 3.3 Third‐generation SU | 1 | 76 | Risk Ratio (M‐H, Random, 95% CI) | 3.16 [0.34, 29.06] |
| 4 Cardiovascular mortality Show forest plot | 8 | 3768 | Risk Ratio (M‐H, Random, 95% CI) | 1.47 [0.54, 4.01] |
| 4.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 4.2 Second‐generation SU | 6 | 3528 | Risk Ratio (M‐H, Random, 95% CI) | 1.47 [0.54, 4.01] |
| 4.3 Third‐generation SU | 2 | 240 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 5 Non‐fatal macrovascular outcomes Show forest plot | 4 | 3094 | Risk Ratio (M‐H, Random, 95% CI) | 0.67 [0.48, 0.93] |
| 5.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 5.2 Second‐generation SU | 3 | 3018 | Risk Ratio (M‐H, Random, 95% CI) | 0.67 [0.48, 0.93] |
| 5.3 Third‐generation SU | 1 | 76 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 6 Non‐fatal myocardial infarction Show forest plot | 4 | 3061 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.37, 2.85] |
| 6.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 6.2 Second‐generation SU | 4 | 3061 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.37, 2.85] |
| 6.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 7 Non‐fatal stroke Show forest plot | 1 | 44 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 7.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 7.2 Second‐generation SU | 1 | 44 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 7.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 8 Amputation of lower extremity Show forest plot | 1 | 44 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 8.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 8.2 Second‐generation SU | 1 | 44 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 8.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 9 Peripheral revascularisation Show forest plot | 2 | 2946 | Risk Ratio (M‐H, Random, 95% CI) | 1.15 [0.69, 1.92] |
| 9.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 9.2 Second‐generation SU | 2 | 2946 | Risk Ratio (M‐H, Random, 95% CI) | 1.15 [0.69, 1.92] |
| 9.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 10 Microvascular outcomes Show forest plot | 1 | 44 | Risk Ratio (M‐H, Random, 95% CI) | 2.0 [0.20, 20.49] |
| 10.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 10.2 Second‐generation SU | 1 | 44 | Risk Ratio (M‐H, Random, 95% CI) | 2.0 [0.20, 20.49] |
| 10.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 11 Nephropathy Show forest plot | 1 | 44 | Risk Ratio (M‐H, Random, 95% CI) | 1.0 [0.07, 15.00] |
| 11.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 11.2 Second‐generation SU | 1 | 44 | Risk Ratio (M‐H, Random, 95% CI) | 1.0 [0.07, 15.00] |
| 11.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 12 Retinal photocoagulation Show forest plot | 1 | 44 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 12.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 12.2 Second‐generation SU | 1 | 44 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 12.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 13 Change in fasting blood glucose from baseline (mmol/L) Show forest plot | 15 | 4654 | Mean Difference (IV, Random, 95% CI) | 0.20 [‐0.07, 0.48] |
| 13.1 First‐generation SU | 2 | 482 | Mean Difference (IV, Random, 95% CI) | 0.13 [‐0.75, 1.01] |
| 13.2 Second‐generation SU | 11 | 3891 | Mean Difference (IV, Random, 95% CI) | 0.43 [0.10, 0.75] |
| 13.3 Third‐generation SU | 3 | 281 | Mean Difference (IV, Random, 95% CI) | ‐0.22 [‐0.52, 0.08] |
| 14 Change in HbA1c from baseline (%) Show forest plot | 13 | 3632 | Mean Difference (IV, Random, 95% CI) | 0.06 [‐0.16, 0.29] |
| 14.1 First‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 14.2 Second‐generation SU | 10 | 3351 | Mean Difference (IV, Random, 95% CI) | 0.17 [‐0.09, 0.44] |
| 14.3 Third‐generation SU | 3 | 281 | Mean Difference (IV, Random, 95% CI) | ‐0.18 [‐0.43, 0.07] |
| 15 Change in BMI from baseline (kg/m2) Show forest plot | 5 | 322 | Mean Difference (IV, Random, 95% CI) | 0.13 [‐0.69, 0.94] |
| 15.1 First‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 15.2 Second‐generation SU | 3 | 103 | Mean Difference (IV, Random, 95% CI) | 0.25 [‐1.21, 1.70] |
| 15.3 Third‐generation SU | 2 | 219 | Mean Difference (IV, Random, 95% CI) | ‐0.10 [‐1.06, 0.86] |
| 16 Change in weight from baseline (kg) Show forest plot | 7 | 3497 | Mean Difference (IV, Random, 95% CI) | 3.77 [3.06, 4.47] |
| 16.1 First‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 16.2 Second‐generation SU | 7 | 3497 | Mean Difference (IV, Random, 95% CI) | 3.77 [3.06, 4.47] |
| 16.3 Third‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 17 Adverse events Show forest plot | 5 | 3118 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.97, 1.01] |
| 17.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 17.2 Second‐generation SU | 4 | 3042 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.97, 1.01] |
| 17.3 Third‐generation SU | 1 | 76 | Risk Ratio (M‐H, Random, 95% CI) | 3.16 [0.13, 75.16] |
| 18 Serious adverse events Show forest plot | 5 | 3175 | Risk Ratio (M‐H, Random, 95% CI) | 0.94 [0.82, 1.07] |
| 18.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 18.2 Second‐generation SU | 4 | 3011 | Risk Ratio (M‐H, Random, 95% CI) | 0.94 [0.82, 1.07] |
| 18.3 Third‐generation SU | 1 | 164 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 19 Drop‐outs due to adverse events Show forest plot | 8 | 3731 | Risk Ratio (M‐H, Random, 95% CI) | 1.18 [0.98, 1.41] |
| 19.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 19.2 Second‐generation SU | 7 | 3567 | Risk Ratio (M‐H, Random, 95% CI) | 1.19 [0.99, 1.42] |
| 19.3 Third‐generation SU | 1 | 164 | Risk Ratio (M‐H, Random, 95% CI) | 0.20 [0.01, 4.20] |
| 20 Mild hypoglycaemia Show forest plot | 6 | 4827 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.16 [2.74, 3.64] |
| 20.1 First‐generation SU | 1 | 607 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.89 [1.00, 3.58] |
| 20.2 Second‐generation SU | 5 | 4056 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.24 [2.80, 3.76] |
| 20.3 Third‐generation SU | 1 | 164 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 21 Moderate hypoglycaemia Show forest plot | 1 | 44 | Risk Ratio (M‐H, Random, 95% CI) | 3.0 [0.13, 69.87] |
| 21.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 21.2 Second‐generation SU | 1 | 44 | Risk Ratio (M‐H, Random, 95% CI) | 3.0 [0.13, 69.87] |
| 21.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 22 Severe hypoglycaemia Show forest plot | 5 | 4408 | Risk Ratio (M‐H, Random, 95% CI) | 4.50 [1.24, 16.31] |
| 22.1 First‐generation SU | 1 | 607 | Risk Ratio (M‐H, Random, 95% CI) | 2.58 [0.24, 28.31] |
| 22.2 Second‐generation SU | 4 | 3637 | Risk Ratio (M‐H, Random, 95% CI) | 5.64 [1.22, 26.00] |
| 22.3 Third‐generation SU | 1 | 164 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 23 Cancer Show forest plot | 1 | 2902 | Risk Ratio (M‐H, Random, 95% CI) | 1.11 [0.76, 1.61] |
| 23.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 23.2 Second‐generation SU | 1 | 2902 | Risk Ratio (M‐H, Random, 95% CI) | 1.11 [0.76, 1.61] |
| 23.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 24 Intervention failure Show forest plot | 9 | 4990 | Risk Ratio (M‐H, Random, 95% CI) | 0.92 [0.60, 1.39] |
| 24.1 First‐generation SU | 1 | 607 | Risk Ratio (M‐H, Random, 95% CI) | 0.63 [0.36, 1.09] |
| 24.2 Second‐generation SU | 7 | 4143 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.60, 1.57] |
| 24.3 Third‐generation SU | 2 | 240 | Risk Ratio (M‐H, Random, 95% CI) | 1.23 [0.43, 3.50] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 8 | 5030 | Risk Ratio (M‐H, Random, 95% CI) | 0.92 [0.60, 1.41] |
| 1.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 1.2 Second‐generation SU | 7 | 4955 | Risk Ratio (M‐H, Random, 95% CI) | 0.92 [0.60, 1.41] |
| 1.3 Third‐generation SU | 1 | 75 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 2 All‐cause mortality; best‐worst case scenario Show forest plot | 5 | 1327 | Risk Ratio (M‐H, Random, 95% CI) | 0.18 [0.06, 0.54] |
| 2.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 2.2 Second‐generation SU | 4 | 1252 | Risk Ratio (M‐H, Random, 95% CI) | 0.18 [0.06, 0.54] |
| 2.3 Third‐generation SU | 1 | 75 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 3 All‐cause mortality; worst‐best case scenario Show forest plot | 5 | 1327 | Risk Ratio (M‐H, Random, 95% CI) | 7.49 [1.39, 40.18] |
| 3.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 3.2 Second‐generation SU | 4 | 1252 | Risk Ratio (M‐H, Random, 95% CI) | 9.76 [0.59, 161.27] |
| 3.3 Third‐generation SU | 1 | 75 | Risk Ratio (M‐H, Random, 95% CI) | 7.18 [0.38, 134.45] |
| 4 Cardiovascular mortality Show forest plot | 8 | 5030 | Risk Ratio (M‐H, Random, 95% CI) | 1.30 [0.55, 3.07] |
| 4.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 4.2 Second‐generation SU | 7 | 4955 | Risk Ratio (M‐H, Random, 95% CI) | 1.30 [0.55, 3.07] |
| 4.3 Third‐generation SU | 1 | 75 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 5 Non‐fatal macrovascular outcomes Show forest plot | 7 | 4675 | Risk Ratio (M‐H, Random, 95% CI) | 0.91 [0.62, 1.33] |
| 5.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 5.2 Second‐generation SU | 6 | 4600 | Risk Ratio (M‐H, Random, 95% CI) | 0.91 [0.62, 1.33] |
| 5.3 Third‐generation SU | 1 | 75 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 6 Non‐fatal myocardial infarction Show forest plot | 7 | 4956 | Risk Ratio (M‐H, Random, 95% CI) | 0.68 [0.41, 1.14] |
| 6.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 6.2 Second‐generation SU | 7 | 4956 | Risk Ratio (M‐H, Random, 95% CI) | 0.68 [0.41, 1.14] |
| 6.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 7 Non‐fatal stroke Show forest plot | 2 | 707 | Risk Ratio (M‐H, Random, 95% CI) | 0.20 [0.02, 1.67] |
| 7.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 7.2 Second‐generation SU | 2 | 707 | Risk Ratio (M‐H, Random, 95% CI) | 0.20 [0.02, 1.67] |
| 7.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 8 Amputation of lower extremity Show forest plot | 2 | 707 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 8.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 8.2 Second‐generation SU | 2 | 707 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 8.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 9 Cardial revascularisation Show forest plot | 2 | 707 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.61, 1.71] |
| 9.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 9.2 Second‐generation SU | 2 | 707 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.61, 1.71] |
| 9.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 10 Peripheral revascularisation Show forest plot | 3 | 3612 | Risk Ratio (M‐H, Random, 95% CI) | 0.87 [0.54, 1.39] |
| 10.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 10.2 Second‐generation SU | 3 | 3612 | Risk Ratio (M‐H, Random, 95% CI) | 0.87 [0.54, 1.39] |
| 10.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 11 Microvascular outcomes Show forest plot | 2 | 235 | Risk Ratio (M‐H, Random, 95% CI) | 0.83 [0.05, 13.16] |
| 11.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 11.2 Second‐generation SU | 2 | 235 | Risk Ratio (M‐H, Random, 95% CI) | 0.83 [0.05, 13.16] |
| 11.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 12 Nephropathy Show forest plot | 2 | 707 | Risk Ratio (M‐H, Random, 95% CI) | 0.11 [0.01, 2.02] |
| 12.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 12.2 Second‐generation SU | 2 | 707 | Risk Ratio (M‐H, Random, 95% CI) | 0.11 [0.01, 2.02] |
| 12.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 13 Retinopathy Show forest plot | 2 | 707 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.06, 15.64] |
| 13.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 13.2 Second‐generation SU | 2 | 707 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.06, 15.64] |
| 13.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 14 Retinal photocoagulation Show forest plot | 2 | 707 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 14.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 14.2 Second‐generation SU | 2 | 707 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 14.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 15 Change in fasting blood glucose from baseline (mmol/L) Show forest plot | 18 | 6731 | Mean Difference (IV, Random, 95% CI) | 0.53 [0.31, 0.75] |
| 15.1 First‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 15.2 Second‐generation SU | 14 | 6076 | Mean Difference (IV, Random, 95% CI) | 0.56 [0.33, 0.79] |
| 15.3 Third‐generation SU | 4 | 655 | Mean Difference (IV, Random, 95% CI) | 0.46 [‐0.22, 1.13] |
| 16 Change in HbA1c from baseline (%) Show forest plot | 21 | 7435 | Mean Difference (IV, Random, 95% CI) | 0.03 [‐0.10, 0.16] |
| 16.1 First‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 16.2 Second‐generation SU | 17 | 6776 | Mean Difference (IV, Random, 95% CI) | 0.06 [‐0.09, 0.20] |
| 16.3 Third‐generation SU | 4 | 659 | Mean Difference (IV, Random, 95% CI) | ‐0.09 [‐0.31, 0.14] |
| 17 Change in BMI from baseline (kg/m2) Show forest plot | 7 | 532 | Mean Difference (IV, Random, 95% CI) | ‐0.98 [‐1.18, ‐0.79] |
| 17.1 First‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 17.2 Second‐generation SU | 4 | 121 | Mean Difference (IV, Random, 95% CI) | 1.00 [‐1.20, ‐0.80] |
| 17.3 Third‐generation SU | 3 | 411 | Mean Difference (IV, Random, 95% CI) | ‐0.75 [‐1.58, 0.08] |
| 18 Change in weight from baseline (kg) Show forest plot | 11 | 5948 | Mean Difference (IV, Random, 95% CI) | ‐1.86 [‐2.50, ‐1.21] |
| 18.1 First‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 18.2 Second‐generation SU | 10 | 5779 | Mean Difference (IV, Random, 95% CI) | ‐1.90 [‐2.56, ‐1.25] |
| 18.3 Third‐generation SU | 1 | 169 | Mean Difference (IV, Random, 95% CI) | 0.20 [‐3.75, 4.15] |
| 19 Adverse events Show forest plot | 13 | 7001 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.94, 1.01] |
| 19.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 19.2 Second‐generation SU | 10 | 6491 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.97, 1.01] |
| 19.3 Third‐generation SU | 3 | 510 | Risk Ratio (M‐H, Random, 95% CI) | 0.88 [0.78, 0.99] |
| 20 Serious adverse events Show forest plot | 11 | 5605 | Risk Ratio (M‐H, Random, 95% CI) | 0.90 [0.80, 1.01] |
| 20.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 20.2 Second‐generation SU | 8 | 4979 | Risk Ratio (M‐H, Random, 95% CI) | 0.90 [0.80, 1.01] |
| 20.3 Third‐generation SU | 3 | 626 | Risk Ratio (M‐H, Random, 95% CI) | 0.61 [0.21, 1.83] |
| 21 Drop‐outs due to adverse events Show forest plot | 17 | 7856 | Risk Ratio (M‐H, Random, 95% CI) | 1.16 [1.00, 1.34] |
| 21.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 21.2 Second‐generation SU | 15 | 7433 | Risk Ratio (M‐H, Random, 95% CI) | 1.15 [0.98, 1.36] |
| 21.3 Third‐generation SU | 2 | 423 | Risk Ratio (M‐H, Random, 95% CI) | 0.54 [0.15, 1.97] |
| 22 Mild hypoglycaemia Show forest plot | 9 | 6556 | Risk Ratio (M‐H, Random, 95% CI) | 3.95 [3.08, 5.06] |
| 22.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 22.2 Second‐generation SU | 8 | 6365 | Risk Ratio (M‐H, Random, 95% CI) | 4.05 [3.28, 5.00] |
| 22.3 Third‐generation SU | 1 | 191 | Risk Ratio (M‐H, Random, 95% CI) | 1.41 [0.47, 4.30] |
| 23 Moderate hypoglycaemia Show forest plot | 1 | 35 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 23.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 23.2 Second‐generation SU | 1 | 35 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 23.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 24 Severe hypoglycaemia Show forest plot | 8 | 6030 | Risk Ratio (M‐H, Random, 95% CI) | 6.11 [1.57, 23.79] |
| 24.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 24.2 Second‐generation SU | 6 | 5660 | Risk Ratio (M‐H, Random, 95% CI) | 6.11 [1.57, 23.79] |
| 24.3 Third‐generation SU | 2 | 370 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 25 Cancer Show forest plot | 6 | 4912 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.72, 1.45] |
| 25.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 25.2 Second‐generation SU | 6 | 4912 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.72, 1.45] |
| 25.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 26 Intervention failure Show forest plot | 10 | 6757 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.65, 1.45] |
| 26.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 26.2 Second‐generation SU | 8 | 6438 | Risk Ratio (M‐H, Random, 95% CI) | 1.10 [0.73, 1.65] |
| 26.3 Third‐generation SU | 2 | 319 | Risk Ratio (M‐H, Random, 95% CI) | 0.24 [0.08, 0.75] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 5 | 3586 | Risk Ratio (M‐H, Random, 95% CI) | 1.05 [0.92, 1.21] |
| 1.1 First‐generation SU | 2 | 1944 | Risk Ratio (M‐H, Random, 95% CI) | 1.18 [0.88, 1.59] |
| 1.2 Second‐generation SU | 4 | 1642 | Risk Ratio (M‐H, Random, 95% CI) | 0.96 [0.79, 1.18] |
| 1.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 2 All‐cause mortality; best‐worst case scenario Show forest plot | 2 | 80 | Risk Ratio (M‐H, Random, 95% CI) | 0.13 [0.02, 0.95] |
| 2.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 2.2 Second‐generation SU | 2 | 80 | Risk Ratio (M‐H, Random, 95% CI) | 0.13 [0.02, 0.95] |
| 2.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 3 All‐cause mortality; worst‐best case scenario Show forest plot | 2 | 80 | Risk Ratio (M‐H, Random, 95% CI) | 3.54 [0.83, 15.00] |
| 3.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 3.2 Second‐generation SU | 2 | 80 | Risk Ratio (M‐H, Random, 95% CI) | 3.54 [0.83, 15.00] |
| 3.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 4 Cardiovascular mortality Show forest plot | 5 | 3586 | Risk Ratio (M‐H, Random, 95% CI) | 1.09 [0.82, 1.44] |
| 4.1 First‐generation SU | 2 | 1944 | Risk Ratio (M‐H, Random, 95% CI) | 1.36 [0.68, 2.71] |
| 4.2 Second‐generation SU | 4 | 1642 | Risk Ratio (M‐H, Random, 95% CI) | 0.96 [0.73, 1.28] |
| 4.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 5 Non‐fatal myocardial infarction Show forest plot | 2 | 3470 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.79, 1.23] |
| 5.1 First‐generation SU | 2 | 1944 | Risk Ratio (M‐H, Random, 95% CI) | 1.08 [0.81, 1.45] |
| 5.2 Second‐generation SU | 1 | 1526 | Risk Ratio (M‐H, Random, 95% CI) | 0.86 [0.61, 1.22] |
| 5.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 6 Non‐fatal stroke Show forest plot | 2 | 3470 | Risk Ratio (M‐H, Random, 95% CI) | 1.45 [1.02, 2.06] |
| 6.1 First‐generation SU | 2 | 1944 | Risk Ratio (M‐H, Random, 95% CI) | 1.23 [0.74, 2.05] |
| 6.2 Second‐generation SU | 1 | 1526 | Risk Ratio (M‐H, Random, 95% CI) | 1.68 [1.04, 2.71] |
| 6.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 7 Amputation of lower extremity Show forest plot | 2 | 3470 | Risk Ratio (M‐H, Random, 95% CI) | 0.49 [0.24, 1.00] |
| 7.1 First‐generation SU | 2 | 1944 | Risk Ratio (M‐H, Random, 95% CI) | 0.49 [0.18, 1.34] |
| 7.2 Second‐generation SU | 1 | 1526 | Risk Ratio (M‐H, Random, 95% CI) | 0.49 [0.18, 1.35] |
| 7.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 8 Microvascular outcomes Show forest plot | 1 | 3056 | Risk Ratio (M‐H, Random, 95% CI) | 1.12 [0.82, 1.53] |
| 8.1 First‐generation SU | 1 | 1530 | Risk Ratio (M‐H, Random, 95% CI) | 1.30 [0.95, 1.77] |
| 8.2 Second‐generation SU | 1 | 1526 | Risk Ratio (M‐H, Random, 95% CI) | 0.94 [0.67, 1.33] |
| 8.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 9 Nephropathy Show forest plot | 1 | 414 | Risk Ratio (M‐H, Random, 95% CI) | 11.32 [0.63, 203.45] |
| 9.1 First‐generation SU | 1 | 414 | Risk Ratio (M‐H, Random, 95% CI) | 11.32 [0.63, 203.45] |
| 9.2 Second‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 9.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 10 Retinopathy Show forest plot | 1 | 414 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.71, 1.39] |
| 10.1 First‐generation SU | 1 | 414 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.71, 1.39] |
| 10.2 Second‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 10.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 11 Retinal photocoagulation Show forest plot | 1 | 3056 | Risk Ratio (M‐H, Random, 95% CI) | 1.03 [0.80, 1.31] |
| 11.1 First‐generation SU | 1 | 1530 | Risk Ratio (M‐H, Random, 95% CI) | 1.12 [0.80, 1.57] |
| 11.2 Second‐generation SU | 1 | 1526 | Risk Ratio (M‐H, Random, 95% CI) | 0.93 [0.65, 1.32] |
| 11.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 12 Change in fasting blood glucose from baseline (mmol/L) Show forest plot | 5 | 2423 | Mean Difference (IV, Random, 95% CI) | 0.12 [‐0.37, 0.61] |
| 12.1 First‐generation SU | 1 | 1122 | Mean Difference (IV, Random, 95% CI) | ‐0.40 [‐0.69, ‐0.11] |
| 12.2 Second‐generation SU | 5 | 1301 | Mean Difference (IV, Random, 95% CI) | 0.29 [‐0.02, 0.61] |
| 12.3 Third‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 13 Change in HbA1c from baseline (%) Show forest plot | 6 | 2566 | Mean Difference (IV, Random, 95% CI) | ‐0.09 [‐0.20, 0.03] |
| 13.1 First‐generation SU | 1 | 1122 | Mean Difference (IV, Random, 95% CI) | ‐0.20 [‐0.38, ‐0.02] |
| 13.2 Second‐generation SU | 6 | 1444 | Mean Difference (IV, Random, 95% CI) | ‐0.03 [‐0.17, 0.10] |
| 13.3 Third‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 14 Change in BMI from baseline (kg/m2) Show forest plot | 1 | 34 | Mean Difference (IV, Random, 95% CI) | ‐1.70 [‐4.10, 0.70] |
| 14.1 First‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 14.2 Second‐generation SU | 1 | 34 | Mean Difference (IV, Random, 95% CI) | ‐1.70 [‐4.10, 0.70] |
| 14.3 Third‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 15 Change in weight from baseline (kg) Show forest plot | 5 | 2514 | Mean Difference (IV, Random, 95% CI) | 1.00 [‐2.82, 0.83] |
| 15.1 First‐generation SU | 1 | 1122 | Mean Difference (IV, Random, 95% CI) | ‐2.30 [‐4.11, ‐0.49] |
| 15.2 Second‐generation SU | 5 | 1392 | Mean Difference (IV, Random, 95% CI) | ‐0.37 [‐2.39, 1.65] |
| 15.3 Third‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 16 Adverse events Show forest plot | 1 | 143 | Risk Ratio (M‐H, Random, 95% CI) | 1.06 [0.68, 1.65] |
| 16.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 16.2 Second‐generation SU | 1 | 143 | Risk Ratio (M‐H, Random, 95% CI) | 1.06 [0.68, 1.65] |
| 16.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 17 Drop‐outs due to adverse events Show forest plot | 2 | 192 | Risk Ratio (M‐H, Random, 95% CI) | 3.54 [0.43, 29.43] |
| 17.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 17.2 Second‐generation SU | 2 | 192 | Risk Ratio (M‐H, Random, 95% CI) | 3.54 [0.43, 29.43] |
| 17.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 18 Mild hypoglycaemia Show forest plot | 2 | 3105 | Risk Ratio (M‐H, Random, 95% CI) | 0.94 [0.45, 1.95] |
| 18.1 First‐generation SU | 1 | 1530 | Risk Ratio (M‐H, Random, 95% CI) | 0.57 [0.42, 0.78] |
| 18.2 Second‐generation SU | 2 | 1575 | Risk Ratio (M‐H, Random, 95% CI) | 1.41 [1.13, 1.76] |
| 18.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 19 Severe hypoglycaemia Show forest plot | 4 | 3172 | Risk Ratio (M‐H, Random, 95% CI) | 1.27 [0.38, 4.24] |
| 19.1 First‐generation SU | 1 | 1530 | Risk Ratio (M‐H, Random, 95% CI) | 0.59 [0.11, 3.02] |
| 19.2 Second‐generation SU | 4 | 1642 | Risk Ratio (M‐H, Random, 95% CI) | 2.07 [0.66, 6.50] |
| 19.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 20 Cancer Show forest plot | 3 | 3519 | Risk Ratio (M‐H, Random, 95% CI) | 1.01 [0.75, 1.36] |
| 20.1 First‐generation SU | 2 | 1944 | Risk Ratio (M‐H, Random, 95% CI) | 0.81 [0.29, 2.27] |
| 20.2 Second‐generation SU | 2 | 1575 | Risk Ratio (M‐H, Random, 95% CI) | 0.95 [0.61, 1.49] |
| 20.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 21 Intervention failure Show forest plot | 4 | 3200 | Risk Ratio (M‐H, Random, 95% CI) | 1.24 [0.67, 2.27] |
| 21.1 First‐generation SU | 1 | 1530 | Risk Ratio (M‐H, Random, 95% CI) | 0.62 [0.44, 0.89] |
| 21.2 Second‐generation SU | 4 | 1670 | Risk Ratio (M‐H, Random, 95% CI) | 1.96 [0.80, 4.76] |
| 21.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 6 | 714 | Risk Ratio (M‐H, Random, 95% CI) | 2.25 [0.43, 11.84] |
| 1.1 First‐generation SU | 2 | 246 | Risk Ratio (M‐H, Random, 95% CI) | 3.16 [0.13, 76.44] |
| 1.2 Second‐generation SU | 4 | 468 | Risk Ratio (M‐H, Random, 95% CI) | 1.98 [0.28, 13.86] |
| 1.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 2 All‐cause mortality; best‐worst case scenario Show forest plot | 2 | 90 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 2.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 2.2 Second‐generation SU | 2 | 90 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 2.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 3 All‐cause mortality; worst‐best case scenario Show forest plot | 2 | 90 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 3.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 3.2 Second‐generation SU | 2 | 90 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 3.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 4 Cardiovascular mortality Show forest plot | 6 | 708 | Risk Ratio (M‐H, Random, 95% CI) | 2.39 [0.30, 19.28] |
| 4.1 First‐generation SU | 2 | 242 | Risk Ratio (M‐H, Random, 95% CI) | 3.0 [0.12, 72.44] |
| 4.2 Second‐generation SU | 4 | 466 | Risk Ratio (M‐H, Random, 95% CI) | 2.02 [0.13, 31.96] |
| 4.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 5 Non‐fatal macrovascular outcomes Show forest plot | 2 | 345 | Risk Ratio (M‐H, Random, 95% CI) | 1.61 [1.06, 2.44] |
| 5.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 5.2 Second‐generation SU | 2 | 345 | Risk Ratio (M‐H, Random, 95% CI) | 1.61 [1.06, 2.44] |
| 5.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 6 Non‐fatal myocardial infarction Show forest plot | 2 | 133 | Risk Ratio (M‐H, Random, 95% CI) | 0.96 [0.06, 14.92] |
| 6.1 First‐generation SU | 1 | 98 | Risk Ratio (M‐H, Random, 95% CI) | 0.96 [0.06, 14.92] |
| 6.2 Second‐generation SU | 1 | 35 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 6.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 7 Non‐fatal stroke Show forest plot | 1 | 35 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 7.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 7.2 Second‐generation SU | 1 | 35 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 7.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 8 Amputation of lower extremity Show forest plot | 1 | 35 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 8.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 8.2 Second‐generation SU | 1 | 35 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 8.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 9 Cardial revascularisation Show forest plot | 1 | 35 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 9.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 9.2 Second‐generation SU | 1 | 35 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 9.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 10 Peripheral revascularisation Show forest plot | 1 | 35 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 10.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 10.2 Second‐generation SU | 1 | 35 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 10.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 11 Microvascular outcomes Show forest plot | 1 | 35 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 11.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 11.2 Second‐generation SU | 1 | 35 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 11.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 12 Nephropathy Show forest plot | 1 | 35 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 12.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 12.2 Second‐generation SU | 1 | 35 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 12.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 13 Retinopathy Show forest plot | 1 | 35 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 13.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 13.2 Second‐generation SU | 1 | 35 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 13.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 14 Retinal photocoagulation Show forest plot | 1 | 35 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 14.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 14.2 Second‐generation SU | 1 | 35 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 14.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 15 Change in fasting blood glucose from baseline (mmol/L) Show forest plot | 11 | 915 | Mean Difference (IV, Random, 95% CI) | ‐0.46 [‐0.80, ‐0.11] |
| 15.1 First‐generation SU | 2 | 208 | Mean Difference (IV, Random, 95% CI) | ‐1.16 [‐1.92, ‐0.41] |
| 15.2 Second‐generation SU | 8 | 488 | Mean Difference (IV, Random, 95% CI) | ‐0.16 [‐0.42, 0.11] |
| 15.3 Third‐generation SU | 1 | 219 | Mean Difference (IV, Random, 95% CI) | ‐1.20 [‐1.92, ‐0.48] |
| 16 Change in HbA1c from baseline (%) Show forest plot | 13 | 968 | Mean Difference (IV, Random, 95% CI) | ‐0.20 [‐0.46, 0.06] |
| 16.1 First‐generation SU | 2 | 208 | Mean Difference (IV, Random, 95% CI) | ‐0.50 [‐0.79, ‐0.20] |
| 16.2 Second‐generation SU | 10 | 541 | Mean Difference (IV, Random, 95% CI) | ‐0.06 [‐0.36, 0.24] |
| 16.3 Third‐generation SU | 1 | 219 | Mean Difference (IV, Random, 95% CI) | ‐0.7 [‐1.28, ‐0.12] |
| 17 Change in BMI from baseline (kg/m2) Show forest plot | 5 | 232 | Mean Difference (IV, Random, 95% CI) | ‐0.02 [‐0.20, 0.16] |
| 17.1 First‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 17.2 Second‐generation SU | 5 | 232 | Mean Difference (IV, Random, 95% CI) | ‐0.02 [‐0.20, 0.16] |
| 17.3 Third‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 18 Change in weight from baseline (kg) Show forest plot | 7 | 689 | Mean Difference (IV, Random, 95% CI) | 0.81 [‐0.61, 2.23] |
| 18.1 First‐generation SU | 1 | 132 | Mean Difference (IV, Random, 95% CI) | 3.2 [2.29, 4.11] |
| 18.2 Second‐generation SU | 5 | 338 | Mean Difference (IV, Random, 95% CI) | ‐0.22 [‐0.47, 0.03] |
| 18.3 Third‐generation SU | 1 | 219 | Mean Difference (IV, Random, 95% CI) | 1.5 [0.28, 2.72] |
| 19 Adverse events Show forest plot | 11 | 1111 | Risk Ratio (M‐H, Random, 95% CI) | 0.65 [0.51, 0.82] |
| 19.1 First‐generation SU | 2 | 246 | Risk Ratio (M‐H, Random, 95% CI) | 0.63 [0.52, 0.76] |
| 19.2 Second‐generation SU | 8 | 646 | Risk Ratio (M‐H, Random, 95% CI) | 0.64 [0.39, 1.03] |
| 19.3 Third‐generation SU | 1 | 219 | Risk Ratio (M‐H, Random, 95% CI) | 0.64 [0.53, 0.78] |
| 20 Serious adverse events Show forest plot | 3 | 229 | Risk Ratio (M‐H, Random, 95% CI) | 0.52 [0.09, 3.03] |
| 20.1 First‐generation SU | 1 | 98 | Risk Ratio (M‐H, Random, 95% CI) | 0.96 [0.14, 6.55] |
| 20.2 Second‐generation SU | 2 | 131 | Risk Ratio (M‐H, Random, 95% CI) | 0.15 [0.01, 2.81] |
| 20.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 21 Drop‐outs due to adverse events Show forest plot | 12 | 1335 | Risk Ratio (M‐H, Random, 95% CI) | 0.37 [0.22, 0.63] |
| 21.1 First‐generation SU | 2 | 246 | Risk Ratio (M‐H, Random, 95% CI) | 0.28 [0.12, 0.67] |
| 21.2 Second‐generation SU | 9 | 870 | Risk Ratio (M‐H, Random, 95% CI) | 0.48 [0.24, 0.96] |
| 21.3 Third‐generation SU | 1 | 219 | Risk Ratio (M‐H, Random, 95% CI) | 0.19 [0.02, 1.64] |
| 22 Mild hypoglycaemia Show forest plot | 6 | 636 | Risk Ratio (M‐H, Random, 95% CI) | 8.59 [2.62, 28.12] |
| 22.1 First‐generation SU | 1 | 98 | Risk Ratio (M‐H, Random, 95% CI) | 2.88 [0.12, 69.07] |
| 22.2 Second‐generation SU | 4 | 319 | Risk Ratio (M‐H, Random, 95% CI) | 12.63 [0.73, 219.86] |
| 22.3 Third‐generation SU | 1 | 219 | Risk Ratio (M‐H, Random, 95% CI) | 9.73 [2.33, 40.63] |
| 23 Moderate hypoglycaemia Show forest plot | 3 | 183 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 23.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 23.2 Second‐generation SU | 3 | 183 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 23.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 24 Severe hypoglycaemia Show forest plot | 5 | 500 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 24.1 First‐generation SU | 1 | 98 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 24.2 Second‐generation SU | 3 | 183 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 24.3 Third‐generation SU | 1 | 219 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 25 Cancer Show forest plot | 3 | 443 | Risk Ratio (M‐H, Random, 95% CI) | 0.90 [0.11, 7.27] |
| 25.1 First‐generation SU | 1 | 98 | Risk Ratio (M‐H, Random, 95% CI) | 0.32 [0.01, 7.67] |
| 25.2 Second‐generation SU | 2 | 345 | Risk Ratio (M‐H, Random, 95% CI) | 1.98 [0.13, 31.35] |
| 25.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 26 Intervention failure Show forest plot | 5 | 831 | Risk Ratio (M‐H, Random, 95% CI) | 0.32 [0.18, 0.57] |
| 26.1 First‐generation SU | 1 | 98 | Risk Ratio (M‐H, Random, 95% CI) | 0.32 [0.01, 7.67] |
| 26.2 Second‐generation SU | 3 | 514 | Risk Ratio (M‐H, Random, 95% CI) | 0.25 [0.07, 0.92] |
| 26.3 Third‐generation SU | 1 | 219 | Risk Ratio (M‐H, Random, 95% CI) | 0.34 [0.17, 0.65] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 3 | 2249 | Risk Ratio (M‐H, Random, 95% CI) | 1.57 [0.62, 4.00] |
| 1.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 1.2 Second‐generation SU | 2 | 1503 | Risk Ratio (M‐H, Random, 95% CI) | 1.39 [0.52, 3.68] |
| 1.3 Third‐generation SU | 1 | 746 | Risk Ratio (M‐H, Random, 95% CI) | 6.01 [0.25, 147.05] |
| 2 All‐cause mortality; best‐worst case scenario Show forest plot | 1 | 1092 | Risk Ratio (M‐H, Random, 95% CI) | 0.39 [0.18, 0.84] |
| 2.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 2.2 Second‐generation SU | 1 | 1092 | Risk Ratio (M‐H, Random, 95% CI) | 0.39 [0.18, 0.84] |
| 2.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 3 All‐cause mortality; worst‐best case scenario Show forest plot | 1 | 1092 | Risk Ratio (M‐H, Random, 95% CI) | 3.67 [1.50, 8.97] |
| 3.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 3.2 Second‐generation SU | 1 | 1092 | Risk Ratio (M‐H, Random, 95% CI) | 3.67 [1.50, 8.97] |
| 3.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 4 Cardiovascular mortality Show forest plot | 2 | 1157 | Risk Ratio (M‐H, Random, 95% CI) | 6.01 [0.25, 147.05] |
| 4.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 4.2 Second‐generation SU | 1 | 411 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 4.3 Third‐generation SU | 1 | 746 | Risk Ratio (M‐H, Random, 95% CI) | 6.01 [0.25, 147.05] |
| 5 Non‐fatal macrovascular outcomes Show forest plot | 1 | 411 | Risk Ratio (M‐H, Random, 95% CI) | 1.61 [0.82, 3.17] |
| 5.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 5.2 Second‐generation SU | 1 | 411 | Risk Ratio (M‐H, Random, 95% CI) | 1.61 [0.82, 3.17] |
| 5.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 6 Non‐fatal myocardial infarction Show forest plot | 2 | 1157 | Risk Ratio (M‐H, Random, 95% CI) | 0.66 [0.10, 4.19] |
| 6.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 6.2 Second‐generation SU | 1 | 411 | Risk Ratio (M‐H, Random, 95% CI) | 0.65 [0.03, 15.85] |
| 6.3 Third‐generation SU | 1 | 746 | Risk Ratio (M‐H, Random, 95% CI) | 0.67 [0.07, 6.40] |
| 7 Non‐fatal stroke Show forest plot | 1 | 411 | Risk Ratio (M‐H, Random, 95% CI) | 3.91 [0.36, 42.79] |
| 7.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 7.2 Second‐generation SU | 1 | 411 | Risk Ratio (M‐H, Random, 95% CI) | 3.91 [0.36, 42.79] |
| 7.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 8 Amputation of lower extremity Show forest plot | 1 | 411 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 8.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 8.2 Second‐generation SU | 1 | 411 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 8.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 9 Cardial revascularisation Show forest plot | 1 | 411 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 9.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 9.2 Second‐generation SU | 1 | 411 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 9.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 10 Peripheral revascularisation Show forest plot | 1 | 411 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 10.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 10.2 Second‐generation SU | 1 | 411 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 10.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 11 Microvascular outcomes Show forest plot | 1 | 411 | Risk Ratio (M‐H, Random, 95% CI) | 1.09 [0.52, 2.29] |
| 11.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 11.2 Second‐generation SU | 1 | 411 | Risk Ratio (M‐H, Random, 95% CI) | 1.09 [0.52, 2.29] |
| 11.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 12 Nephropathy Show forest plot | 1 | 411 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.09, 10.70] |
| 12.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 12.2 Second‐generation SU | 1 | 411 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.09, 10.70] |
| 12.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 13 Retinopathy Show forest plot | 1 | 411 | Risk Ratio (M‐H, Random, 95% CI) | 1.10 [0.50, 2.43] |
| 13.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 13.2 Second‐generation SU | 1 | 411 | Risk Ratio (M‐H, Random, 95% CI) | 1.10 [0.50, 2.43] |
| 13.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 14 Retinal photocoagulation Show forest plot | 1 | 411 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 14.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 14.2 Second‐generation SU | 1 | 411 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 14.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 15 Change in fasting blood glucose from baseline (mmol/L) Show forest plot | 3 | 1948 | Mean Difference (IV, Random, 95% CI) | 0.34 [‐0.44, 1.13] |
| 15.1 First‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 15.2 Second‐generation SU | 2 | 1202 | Mean Difference (IV, Random, 95% CI) | 0.11 [‐1.07, 1.28] |
| 15.3 Third‐generation SU | 1 | 746 | Mean Difference (IV, Random, 95% CI) | 0.8 [0.34, 1.26] |
| 16 Change in HbA1c from baseline (%) Show forest plot | 3 | 1950 | Mean Difference (IV, Random, 95% CI) | 0.35 [0.05, 0.64] |
| 16.1 First‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 16.2 Second‐generation SU | 2 | 1204 | Mean Difference (IV, Random, 95% CI) | 0.26 [‐0.23, 0.75] |
| 16.3 Third‐generation SU | 1 | 746 | Mean Difference (IV, Random, 95% CI) | 0.5 [0.32, 0.68] |
| 17 Change in BMI from baseline (kg/m2) Show forest plot | 1 | 400 | Mean Difference (IV, Random, 95% CI) | 0.7 [0.52, 0.88] |
| 17.1 First‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 17.2 Second‐generation SU | 1 | 400 | Mean Difference (IV, Random, 95% CI) | 0.7 [0.52, 0.88] |
| 17.3 Third‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 18 Change in weight from baseline (kg) Show forest plot | 3 | 1952 | Mean Difference (IV, Random, 95% CI) | 1.96 [0.63, 3.28] |
| 18.1 First‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 18.2 Second‐generation SU | 2 | 1206 | Mean Difference (IV, Random, 95% CI) | 1.31 [0.33, 2.29] |
| 18.3 Third‐generation SU | 1 | 746 | Mean Difference (IV, Random, 95% CI) | 3.30 [2.64, 3.96] |
| 19 Adverse events Show forest plot | 2 | 1157 | Risk Ratio (M‐H, Random, 95% CI) | 0.89 [0.74, 1.08] |
| 19.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 19.2 Second‐generation SU | 1 | 411 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.90, 1.04] |
| 19.3 Third‐generation SU | 1 | 746 | Risk Ratio (M‐H, Random, 95% CI) | 0.82 [0.73, 0.92] |
| 20 Serious adverse events Show forest plot | 2 | 1157 | Risk Ratio (M‐H, Random, 95% CI) | 1.22 [0.77, 1.94] |
| 20.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 20.2 Second‐generation SU | 1 | 411 | Risk Ratio (M‐H, Random, 95% CI) | 1.37 [0.71, 2.63] |
| 20.3 Third‐generation SU | 1 | 746 | Risk Ratio (M‐H, Random, 95% CI) | 1.09 [0.56, 2.10] |
| 21 Drop‐outs due to adverse events Show forest plot | 3 | 2249 | Risk Ratio (M‐H, Random, 95% CI) | 0.89 [0.64, 1.24] |
| 21.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 21.2 Second‐generation SU | 2 | 1503 | Risk Ratio (M‐H, Random, 95% CI) | 1.00 [0.67, 1.50] |
| 21.3 Third‐generation SU | 1 | 746 | Risk Ratio (M‐H, Random, 95% CI) | 0.70 [0.40, 1.24] |
| 22 Mild hypoglycaemia Show forest plot | 3 | 2249 | Risk Ratio (M‐H, Random, 95% CI) | 2.07 [1.44, 2.97] |
| 22.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 22.2 Second‐generation SU | 2 | 1503 | Risk Ratio (M‐H, Random, 95% CI) | 1.99 [1.02, 3.87] |
| 22.3 Third‐generation SU | 1 | 746 | Risk Ratio (M‐H, Random, 95% CI) | 2.41 [1.71, 3.40] |
| 23 Severe hypoglycaemia Show forest plot | 3 | 2249 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 23.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 23.2 Second‐generation SU | 2 | 1503 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 23.3 Third‐generation SU | 1 | 746 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 24 Intervention failure Show forest plot | 3 | 2249 | Risk Ratio (M‐H, Random, 95% CI) | 1.31 [0.56, 3.05] |
| 24.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 24.2 Second‐generation SU | 2 | 1503 | Risk Ratio (M‐H, Random, 95% CI) | 1.00 [0.41, 2.43] |
| 24.3 Third‐generation SU | 1 | 746 | Risk Ratio (M‐H, Random, 95% CI) | 2.09 [1.22, 3.59] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 7 | 2038 | Risk Ratio (M‐H, Random, 95% CI) | 1.44 [0.47, 4.42] |
| 1.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 1.2 Second‐generation SU | 7 | 2038 | Risk Ratio (M‐H, Random, 95% CI) | 1.44 [0.47, 4.42] |
| 1.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 2 All‐cause mortality; best‐worst case scenario Show forest plot | 2 | 209 | Risk Ratio (M‐H, Random, 95% CI) | 0.07 [0.00, 1.16] |
| 2.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 2.2 Second‐generation SU | 2 | 209 | Risk Ratio (M‐H, Random, 95% CI) | 0.07 [0.00, 1.16] |
| 2.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 3 All‐cause mortality; worst‐best case scenario Show forest plot | 2 | 209 | Risk Ratio (M‐H, Random, 95% CI) | 15.17 [0.88, 261.61] |
| 3.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 3.2 Second‐generation SU | 2 | 209 | Risk Ratio (M‐H, Random, 95% CI) | 15.17 [0.88, 261.61] |
| 3.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 4 Cardiovascular mortality Show forest plot | 7 | 2038 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.27, 3.53] |
| 4.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 4.2 Second‐generation SU | 7 | 2038 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.27, 3.53] |
| 4.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 5 Non‐fatal macrovascular outcomes Show forest plot | 3 | 866 | Risk Ratio (M‐H, Random, 95% CI) | 0.50 [0.20, 1.20] |
| 5.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 5.2 Second‐generation SU | 3 | 866 | Risk Ratio (M‐H, Random, 95% CI) | 0.50 [0.20, 1.20] |
| 5.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 6 Non‐fatal myocardial infarction Show forest plot | 3 | 726 | Risk Ratio (M‐H, Random, 95% CI) | 1.03 [0.26, 4.08] |
| 6.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 6.2 Second‐generation SU | 3 | 726 | Risk Ratio (M‐H, Random, 95% CI) | 1.03 [0.26, 4.08] |
| 6.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 7 Non‐fatal stroke Show forest plot | 1 | 34 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 7.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 7.2 Second‐generation SU | 1 | 34 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 7.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 8 Amputation of lower extremity Show forest plot | 1 | 34 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 8.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 8.2 Second‐generation SU | 1 | 34 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 8.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 9 Cardial revascularisation Show forest plot | 1 | 34 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 9.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 9.2 Second‐generation SU | 1 | 34 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 9.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 10 Peripheral revascularisation Show forest plot | 1 | 34 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 10.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 10.2 Second‐generation SU | 1 | 34 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 10.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 11 Microvascular outcomes Show forest plot | 1 | 34 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 11.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 11.2 Second‐generation SU | 1 | 34 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 11.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 12 Nephropathy Show forest plot | 1 | 34 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 12.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 12.2 Second‐generation SU | 1 | 34 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 12.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 13 Retinopathy Show forest plot | 1 | 34 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 13.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 13.2 Second‐generation SU | 1 | 34 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 13.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 14 Retinal photocoagulation Show forest plot | 1 | 34 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 14.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 14.2 Second‐generation SU | 1 | 34 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 14.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 15 Change in fasting blood glucose from baseline (mmol/L) Show forest plot | 10 | 2329 | Mean Difference (IV, Random, 95% CI) | ‐0.21 [‐0.45, 0.03] |
| 15.1 First‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 15.2 Second‐generation SU | 9 | 2205 | Mean Difference (IV, Random, 95% CI) | ‐0.27 [‐0.51, ‐0.02] |
| 15.3 Third‐generation SU | 1 | 124 | Mean Difference (IV, Random, 95% CI) | 0.20 [‐0.22, 0.62] |
| 16 Change in HbA1c from baseline (%) Show forest plot | 10 | 2345 | Mean Difference (IV, Random, 95% CI) | 0.05 [‐0.09, 0.19] |
| 16.1 First‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 16.2 Second‐generation SU | 9 | 2221 | Mean Difference (IV, Random, 95% CI) | 0.07 [‐0.08, 0.22] |
| 16.3 Third‐generation SU | 1 | 124 | Mean Difference (IV, Random, 95% CI) | ‐0.10 [‐0.40, 0.20] |
| 17 Change in BMI from baseline (kg/m2) Show forest plot | 3 | 333 | Mean Difference (IV, Random, 95% CI) | ‐0.05 [‐0.25, 0.14] |
| 17.1 First‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 17.2 Second‐generation SU | 2 | 209 | Mean Difference (IV, Random, 95% CI) | 0.00 [‐0.19, 0.20] |
| 17.3 Third‐generation SU | 1 | 124 | Mean Difference (IV, Random, 95% CI) | ‐0.30 [‐0.66, 0.06] |
| 18 Change in weight from baseline (kg) Show forest plot | 5 | 1176 | Mean Difference (IV, Random, 95% CI) | 0.05 [‐0.40, 0.51] |
| 18.1 First‐generation SU | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 18.2 Second‐generation SU | 4 | 1052 | Mean Difference (IV, Random, 95% CI) | 0.13 [‐0.50, 0.76] |
| 18.3 Third‐generation SU | 1 | 124 | Mean Difference (IV, Random, 95% CI) | 0.10 [‐1.77, 1.97] |
| 19 Adverse events Show forest plot | 5 | 1829 | Risk Ratio (M‐H, Random, 95% CI) | 1.00 [0.95, 1.06] |
| 19.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 19.2 Second‐generation SU | 5 | 1829 | Risk Ratio (M‐H, Random, 95% CI) | 1.00 [0.95, 1.06] |
| 19.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 20 Drop‐outs due to adverse events Show forest plot | 8 | 2151 | Risk Ratio (M‐H, Random, 95% CI) | 1.03 [0.79, 1.33] |
| 20.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 20.2 Second‐generation SU | 7 | 2019 | Risk Ratio (M‐H, Random, 95% CI) | 1.01 [0.78, 1.32] |
| 20.3 Third‐generation SU | 1 | 132 | Risk Ratio (M‐H, Random, 95% CI) | 5.0 [0.24, 102.19] |
| 21 Serious adverse events Show forest plot | 5 | 1829 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.74, 1.39] |
| 21.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 21.2 Second‐generation SU | 5 | 1829 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.74, 1.39] |
| 21.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 22 Mild hypoglycaemia Show forest plot | 6 | 1863 | Risk Ratio (M‐H, Random, 95% CI) | 1.20 [0.96, 1.49] |
| 22.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 22.2 Second‐generation SU | 6 | 1863 | Risk Ratio (M‐H, Random, 95% CI) | 1.20 [0.96, 1.49] |
| 22.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 23 Moderate hypoglycaemia Show forest plot | 1 | 34 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 23.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 23.2 Second‐generation SU | 1 | 34 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 23.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 24 Severe hypoglycaemia Show forest plot | 6 | 1863 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.87 [0.91, 8.99] |
| 24.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 24.2 Second‐generation SU | 6 | 1863 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.87 [0.91, 8.99] |
| 24.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 25 Cancer Show forest plot | 2 | 290 | Risk Ratio (M‐H, Random, 95% CI) | 6.44 [0.27, 156.37] |
| 25.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 25.2 Second‐generation SU | 2 | 290 | Risk Ratio (M‐H, Random, 95% CI) | 6.44 [0.27, 156.37] |
| 25.3 Third‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 26 Intervention failure Show forest plot | 5 | 1656 | Risk Ratio (M‐H, Random, 95% CI) | 0.96 [0.69, 1.35] |
| 26.1 First‐generation SU | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 26.2 Second‐generation SU | 4 | 1524 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.69, 1.38] |
| 26.3 Third‐generation SU | 1 | 132 | Risk Ratio (M‐H, Random, 95% CI) | 0.67 [0.12, 3.86] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 1 | 1234 | Risk Ratio (M‐H, Random, 95% CI) | 0.90 [0.72, 1.11] |
| 2 Cardiovascular mortality Show forest plot | 1 | 1234 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.72, 1.34] |
| 3 Non‐fatal myocardial infarction Show forest plot | 1 | 1234 | Risk Ratio (M‐H, Random, 95% CI) | 0.80 [0.55, 1.16] |
| 4 Non‐fatal stroke Show forest plot | 1 | 1234 | Risk Ratio (M‐H, Random, 95% CI) | 1.32 [0.80, 2.17] |
| 5 Amputation of lower extremity Show forest plot | 1 | 1234 | Risk Ratio (M‐H, Random, 95% CI) | 1.01 [0.29, 3.46] |
| 6 Microvascular outcomes Show forest plot | 1 | 1234 | Odds Ratio (M‐H, Random, 95% CI) | 0.70 [0.48, 1.03] |
| 7 Retinal photocoagulation Show forest plot | 1 | 1234 | Risk Ratio (M‐H, Random, 95% CI) | 0.82 [0.56, 1.20] |
| 8 Change in fasting blood glucose from baseline (mmol/L) Show forest plot | 2 | 936 | Mean Difference (IV, Random, 95% CI) | 0.62 [0.31, 0.94] |
| 9 Change in HbA1c from baseline (%) Show forest plot | 2 | 1014 | Mean Difference (IV, Random, 95% CI) | ‐1.44 [‐4.48, 1.60] |
| 10 Change in weight from baseline (kg) Show forest plot | 2 | 1014 | Mean Difference (IV, Random, 95% CI) | 1.80 [‐0.63, 4.23] |
| 11 Mild hypoglycaemia Show forest plot | 1 | 1234 | Risk Ratio (M‐H, Random, 95% CI) | 2.51 [1.83, 3.42] |
| 12 Severe hypoglycaemia Show forest plot | 1 | 1234 | Risk Ratio (M‐H, Random, 95% CI) | 3.52 [0.73, 16.89] |
| 13 Cancer Show forest plot | 1 | 1234 | Risk Ratio (M‐H, Random, 95% CI) | 0.81 [0.50, 1.31] |
| 14 Intervention failure Show forest plot | 3 | 1364 | Risk Ratio (M‐H, Random, 95% CI) | 1.96 [0.67, 5.75] |
