One in nine people worldwide has diabetes, with 90% affected by type 2 diabetes, writes endocrinologist Aikaterini Theodoraki in The BMJ, and yet despite ongoing advances in therapy and management, diabetes care continues to face major challenges, including variation in access to care, inconsistent adherence to best practices, and persistent health inequities.
The living rapid recommendations guideline by Agarwal and colleagues provides recommendations for adults with type 2 diabetes on medications that offer cardiovascular or renal benefits – specifically sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, tirzepatide and finerenone – taking into account individual cardiovascular and kidney disease risk, the likelihood of treatment-related harm, quality of the supporting evidence and patient preferences.
This is the first version of a living systematic review. It is linked to a living BMJ Rapid Recommendation and other living clinical practice guidelines, presenting risk stratified recommendations for patients with type 2 diabetes at lower, moderate and higher risk of cardiovascular and kidney complications.
The latest evidence will be made available via the BMJ Rapid Recommendation and via an interactive GRADE evidence summary (MATCH-IT: https://matchit.magicevidence.org/250709dist-diabetes/#!/).
Their research
In their paper, titled Medications for adults with type 2 diabetes: a living systematic review and network meta-analysis, Agarwal et al write that type 2 diabetes affects more than 400m people worldwide and is associated with significant cardiovascular and kidney-related morbidity and mortality, that novel effective medications, including sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs), are shifting management from a glucocentric approach to one more focused on reducing these complications.
Evidence on the weight-lowering effects of GLP-1RAs and other emerging medications like tirzepatide are also attracting global attention. However, questions persist regarding long term effects and rare but serious harms. Variability in access to medications and related costs also impact decision-making internationally.
To make fully informed decisions, policymakers, payers, clinicians and patients require reliable evidence summaries, health technology assessments (HTA) and trustworthy clinical practice guidelines reflecting emerging evidence of benefits and harms, capturing relevant alternatives across available drug classes in type 2 diabetes.
This underscores the need for systematic reviews with network meta-analyses (NMA) to evaluate the comparative effectiveness of multiple treatment options, including indirect comparisons of medications not tested head-to-head.
Benefits of medications on cardiovascular and kidney outcomes vary substantially based on the patient’s individual risk of such complications.
Whereas traditional systematic reviews provide a static cross-sectional summary of available evidence, living systematic reviews involve dynamic updates to include the latest available evidence. For type 2 diabetes, there is an “infodemic” of new publications on a plethora of medicines.
Living systematic reviews and NMAs providing timely updated evidence are thus necessary.
Through the Alliance for Living Evidence (ALIVE) consortium (https://www.aliveevidence.org/), this living review aims to represent the key up-to-date repository of trial evidence to inform clinical practice guidelines and HTA.
Study details
Medications for adults with type 2 diabetes: a living systematic review and network meta-analysis
Kailei Nong, Britta Tendal Jeppesen, Qingyang Shi, Arnav Agarwal, et al.
Published in The BMJ on 14 August 2025
Abstract
Objective
To provide up-to-date evidence on key benefits, harms, and uncertainties regarding medications for adults with type 2 diabetes.
Design
Living systematic review and network meta-analysis (NMA), using frequentist random effects and GRADE (grading of recommendations, assessment, development and evaluation) approaches. Updates are planned at least two times a year.
Data sources
Medline and Embase, searched up to 31 July 2024 for the current iteration.
Study selection
Randomised controlled trials of at least 24 weeks comparing one or more medications with standard treatment, placebo, or each other.
Results
The systematic review and NMA includes 493 168 participants from 869 trials (adding 53 trials since October 2022) reporting data for 13 drug classes (63 drugs) and 26 outcomes of interest. Regarding benefits, moderate to high certainty evidence confirms the well established cardiovascular and kidney benefits of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and finerenone (the last for patients with established chronic kidney disease). The most effective drugs in reducing body weight were tirzepatide (mean difference (MD) −8.63 kg (95% confidence interval −9.34 to −7.93); moderate certainty) and orforglipron (MD −7.87 kg (−10.24 to −5.50); low certainty), followed by eight other GLP-1RAs (high to moderate certainty). Absolute benefits of medications vary substantially depending on the baseline risk of cardiovascular and kidney outcomes; risk-stratified absolute effects of medications are summarised using an interactive multiple comparisons tool (https://matchit.magicevidence.org/250709dist-diabetes/#!/). Regarding medication-specific harms, SGLT-2 inhibitors increase genital infections (odds ratio (OR) 3.29 (95% CI 2.88 to 3.77); high certainty) and ketoacidosis due to diabetes (OR 2.08 (1.45 to 2.99); high certainty), and probably increase amputations (OR 1.27 (1.01 to 1.61); moderate certainty); tirzepatide and GLP-1RAs probably increase severe gastrointestinal events (most increased risk with tirzepatide (OR 4.21 (1.87 to 9.49); moderate certainty)); finerenone increases severe hyperkalaemia (OR 5.92 (3.02 to 11.62); high certainty); and thiazolidinediones increase major osteoporotic fractures and probably increase hospitalisation for heart failure. Sulfonylureas, insulin, and dipeptidyl peptidase-4 inhibitors probably increase the risk of severe hypoglycaemia. There is low to very low certainty evidence for effects on other diabetes-related complications, including neuropathy and visual impairment. Despite interest in the issue, there is uncertainty about whether GLP-1RAs may reduce dementia (OR 0.92 (0.83 to 1.02); low certainty).
Conclusions
This living systematic review provides a comprehensive summary of the cardiovascular, kidney, and weight loss benefits, as well as medication-specific harms of medications for adults with type 2 diabetes, including effects of SGLT-2 inhibitors, GLP-1RAs, finerenone and tirzepatide.
Methods
This living systematic review and NMA is developed in collaboration with three international multidisciplinary teams: (i) a living guideline (BMJ Rapid Recommendation) from the MAGIC Evidence Ecosystem Foundation, incorporating input from patient partners living with type 2 diabetes, general practitioners, internists, endocrinologists, nephrologists, cardiologists, and guideline methodologists; (ii) the Australian Evidence-Based Clinical Guidelines for Diabetes developed by the Living Evidence for Diabetes Consortium, a collaboration of multiple diabetes societies in Australia supported by the Australian Living Evidence Collaboration; and (iii) the Cardiovascular Outcome Trial (CVOT) Taskforce with representation from multiple national and international professional societies across endocrinology, cardiology, and nephrology.
Eligibility criteria
Eligible parallel arm randomised controlled trials (RCTs) compare medications for type 2 diabetes with each other, placebo, or standard treatment (typically representing the treatment regimens that patients received in practice before consideration of adding a new candidate medication).
This NMA considers both glucose-lowering and emerging disease-modifying medications including SGLT-2 inhibitors, GLP-1RAs, dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonists (tirzepatide), non-steroidal mineralocorticoid receptor antagonists (finerenone), dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones, sulfonylureas, metformin, alpha-glucosidase inhibitors, meglitinides, and insulins.
We limit eligibility to trials with a follow-up duration of 24 weeks or longer and exclude trials with a systematic difference of two medication classes or more between the intervention and the control. We exclude non-English language studies.
Study selection and study characteristics
To date, the living systematic review and NMA includes 869 trials enrolling 493 168 participants. The average age of study participants was 57.8 years, 56.9% were male, and 55.5% had a cardiovascular history. The median follow-up duration was six months (ranging from 5.5 to 128 months).
In 240 of the 869 trials, there was at least one domain with high risk of bias. Of these studies at high risk of bias, 63.3% had inadequate blinding, 25.0% had serious missing outcome data, and 23.8% had inadequate allocation concealment.
The number and characteristics of studies and participants for each outcome vary from the different included trials.
What is already known on this topic
• Sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), finerenone, and tirzepatide provide risk-dependent and differential benefits in reducing death, cardiovascular diseases, chronic kidney diseases, and body weight while demonstrating drug-specific harms
• Rapidly accumulating new evidence from ongoing trials of existing and new medications, combined with changes in patents and pricing of medications, warrant living systematic reviews
What this study adds
• This network meta-analysis provides the best current evidence on 26 outcomes identified as important to patients regarding 13 drug classes (63 medications) for adults with type 2 diabetes
• Our findings demonstrate differential benefits and drug-specific harms of SGLT-2 inhibitors, GLP-1RAs, finerenone, and tirzepatide
• Major uncertainties remain for complications such as neuropathy and visual impairment
Principal findings
The current iteration of this living systematic review includes 869 randomised controlled trials enrolling nearly half a million people with type 2 diabetes, adding 53 trials since October 2022.
Key findings include the confirmation of cardiovascular and kidney benefits of SGLT-2 inhibitors, GLP-1Ras, and finerenone with moderate to high certainty evidence; some notable harms of established medications (including increased risks of genital infection, amputation, and ketoacidosis due to diabetes for SGLT-2 inhibitors, severe gastrointestinal events for GLP-1RAs and tirzepatide, severe hyperkalaemia for finerenone, heart failure exacerbation and fractures for thiazolidinediones, and severe hypoglycaemia for insulin, sulfonylureas, and DPP-4 inhibitors); and the remaining uncertainty for numerous outcomes of importance to patients.
With absolute benefits determined by baseline risks for cardiovascular and kidney outcomes balanced against relevant harms, our findings underscore the need to provide personalised diabetes care for medications and directly inform the linked guidelines to facilitate shared decision making based on values and preferences.
For weight loss and HbA1c, tirzepatide and orforglipron represent the most effective among many emerging molecules.4 Tirzepatide also carries the highest risk of severe gastrointestinal events, and its cardiovascular and kidney benefits continue to be evaluated in a large ongoing trial.
Orforglipron, an emerging non-peptide oral GLP-1RA, demonstrates potential for significant weight and HbA1c reductions, but evidence is limited to one phase 2 trial providing low certainty evidence.
Although it is fair to assume similar cardiovascular and kidney benefits as observed for GLP-1 RAs as a medication class, orforglipron is now undergoing phase 3 randomised trials and has not yet received marketing approval in any countries.
Major uncertainties for all medications include benefits on complications such as severe visual impairment and neuropathy, which take many years to develop and have not been sufficiently captured in the existing trials.
Similarly, we found low certainty evidence to investigate the hypothesis that GLP-1RAs may reduce dementia, and more trials are needed to investigate this potential benefit.
Strengths and limitations
A key strength of our living systematic review and NMA is the comprehensive summary of best current evidence across benefits and harms for available medications for type 2 diabetes.
Our wide inclusion of 13 medication classes and 26 outcomes was informed by three international teams representing guideline panels in the global perspective, reflecting a harmonised effort to better inform a global target audience and reduce duplication of efforts.
Our study incorporated current and rigorous approaches to NMA and GRADE assessment, wide expert input, as well as risk-stratified evidence summaries in digestible formats for absolute effects across key cardiovascular and kidney outcomes.
This living systematic review also has limitations, some of which reflect limited trial evidence as noted above. Heterogeneity of trial design and baseline characteristics of the participants may amplify the beneficial effects of some therapeutics for specific outcomes.
Our sensitivity and subgroup analyses demonstrate consistent results, supporting the robustness of our findings.
We also recognise limited nuance in our analysis and questions left unanswered in this first iteration of the living review. A recent NMA focusing on 15 different GLP-1RAs demonstrated molecule-specific and dose-dependent benefits and harms for weight loss and gastrointestinal side effects. The extent to which these are credible subgroup effects is uncertain, and we aim to include such extended analyses in future iterations.
A pertinent clinical question concerns the effectiveness of two or more therapeutics used in combination; SGLT-2 inhibitors and GLP-1 receptor agonists demonstrate improvements in cardiovascular outcomes among individuals with type 2 diabetes, and some evidence suggests that there may be additional benefit when they are used in combination.
Finally, we acknowledge methodological limitations for our choices in rating certainty of evidence for imprecision and categorisation of effectiveness of medications using relative estimates of effect in this NMA.
To consistently interpret and rate imprecision of relative effects, we adopted a minimally contextualised approach according to GRADE, and used arbitrary relative effect thresholds for what constitutes important effects versus little or no effect.
Representing the first pilot from the ALIVE consortium, this systematic review will—if funding permits—be iteratively updated to reflect latest evidence in a “living” model.
Conclusions
This living systematic review and NMA provides a comprehensive and up-to-date summary of the comparative effectiveness of available medications for patients with type 2 diabetes. It is designed to allow global collaboration on living evidence synthesis. As such, it holds the potential to facilitate a global living evidence ecosystem, informed decisions by policy-makers, clinicians, and patients, and reduced waste in
Empowering choice in the pharmacological management of type 2 diabetes
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