Medications for adults with type 2 diabetes: a living systematic review and network meta-analysis.
In a living systematic review and network meta-analysis of 869 randomised trials and 493,168 adults with type 2 diabetes, SGLT-2 inhibitors, GLP-1 receptor agonists and finerenone showed moderate-to-high certainty cardiovascular and kidney benefits, with tirzepatide producing the largest weight loss; each class carried distinct, well-characterised harms.
Background
Adults with type 2 diabetes now have many drug classes available, and the balance of cardiovascular, kidney, weight and safety effects across them is difficult to keep current. This work was designed to provide up-to-date evidence on the key benefits, harms and remaining uncertainties of medications for adults with type 2 diabetes, and is maintained as a living review with updates planned at least twice a year.
Study design
Living systematic review and network meta-analysis using frequentist random-effects methods and the GRADE approach, with Medline and Embase searched to 31 July 2024 for this iteration. Eligible studies were randomised controlled trials of at least 24 weeks comparing one or more medications with standard treatment, placebo, or each other. The current iteration includes 493,168 participants from 869 trials (53 trials added since October 2022), covering 13 drug classes (63 drugs) and 26 outcomes of interest. Registered on PROSPERO (CRD42022325948).
Key findings
Moderate to high certainty evidence confirms the established cardiovascular and kidney benefits of SGLT-2 inhibitors, GLP-1 receptor agonists and finerenone — the last in patients with established chronic kidney disease. The most effective drugs for weight reduction were tirzepatide (mean difference -8.63 kg, 95% CI -9.34 to -7.93; moderate certainty) and orforglipron (-7.87 kg, -10.24 to -5.50; low certainty), followed by eight other GLP-1 receptor agonists (high to moderate certainty). Absolute benefits varied substantially with baseline cardiovascular and kidney risk, and are presented as risk-stratified effects through an interactive comparison tool. Evidence for other diabetes-related complications, including neuropathy and visual impairment, was low to very low certainty, and whether GLP-1 receptor agonists reduce dementia remains uncertain (odds ratio 0.92, 0.83 to 1.02; low certainty).
Safety
Harms were medication-specific. SGLT-2 inhibitors increased genital infections (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 increased amputations (OR 1.27, 1.01 to 1.61; moderate certainty). Tirzepatide and GLP-1 receptor agonists probably increased severe gastrointestinal events, with the greatest risk for tirzepatide (OR 4.21, 1.87 to 9.49; moderate certainty). Finerenone increased severe hyperkalaemia (OR 5.92, 3.02 to 11.62; high certainty). Thiazolidinediones increased major osteoporotic fractures and probably increased hospitalisation for heart failure, while sulfonylureas, insulin and DPP-4 inhibitors probably increased severe hypoglycaemia.
Clinical implications
For nephrology practice, the review reinforces SGLT-2 inhibitors, GLP-1 receptor agonists and finerenone as the agents with the strongest cardiovascular and kidney evidence, with finerenone's benefit anchored in established chronic kidney disease. Because absolute benefit depends heavily on baseline cardiovascular and kidney risk, drug selection should be risk-stratified rather than uniform, and weighed against each class's characteristic harms — genital infection and ketoacidosis with SGLT-2 inhibitors, severe gastrointestinal events with tirzepatide and GLP-1 receptor agonists, and severe hyperkalaemia with finerenone, which requires potassium monitoring. The living format means recommendations linked to this review are expected to change as new trials are incorporated.
Category
Guidelines
Source
BMJ
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