Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials
Authors: Shi Qingyang , Nong Kailei , Vandvik Per Olav , Guyatt Gordon H , Schnell Oliver , Rydén Lars , Marx Nikolaus , Brosius Frank C , Mustafa Reem A , Agarwal Arnav , Zou Xinyu , Mao Yunhe , Asadollahifar Aminreza , Chowdhury Saifur Rahman , Zhai Chunjuan , Gupta Sana , Gao Ya , Lima João Pedro , Numata Kenji , Qiao Zhi , Fan Qinlin , Yang Qinbo , Jin Yinghui , Ge Long , Yang Qiuyu , Zhu Hongfei , Yang Fan , Chen Zhe , Lu Xi , He Siyu , Chen Xiangyang , Lyu Xiafei , An Xingxing , Chen Yaolong , Hao Qiukui , Standl Eberhard , Siemieniuk Reed , Agoritsas Thomas , Tian Haoming , Li Sheyu 
Published: April 2023

Abstract

Objective
To compare the benefits and harms of drug treatments for adults with type 2 diabetes, adding non-steroidal mineralocorticoid receptor antagonists (including finerenone) and tirzepatide (a dual glucose dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist) to previously existing treatment options.

Design
Systematic review and network meta-analysis.

Data sources
Ovid Medline, Embase, and Cochrane Central up to 14 October 2022.

Eligibility criteria for selecting studies
Eligible randomised controlled trials compared drugs of interest in adults with type 2 diabetes. Eligible trials had a follow-up of 24 weeks or longer. Trials systematically comparing combinations of more than one drug treatment class with no drug, subgroup analyses of randomised controlled trials, and non-English language studies were deemed ineligible. Certainty of evidence was assessed following the GRADE (grading of recommendations, assessment, development and evaluation) approach.

Results

The analysis identified 816 trials with 471 038 patients, together evaluating 13 different drug classes; all subsequent estimates refer to the comparison with standard treatments. Sodium glucose cotransporter-2 (SGLT-2) inhibitors (odds ratio 0.88, 95% confidence interval 0.83 to 0.94; high certainty) and GLP-1 receptor agonists (0.88, 0.82 to 0.93; high certainty) reduce all cause death; non-steroidal mineralocorticoid receptor antagonists, so far tested only with finerenone in patients with chronic kidney disease, probably reduce mortality (0.89, 0.79 to 1.00; moderate certainty); other drugs may not. The study confirmed the benefits of SGLT-2 inhibitors and GLP-1 receptor agonists in reducing cardiovascular death, non-fatal myocardial infarction, admission to hospital for heart failure, and end stage kidney disease. Finerenone probably reduces admissions to hospital for heart failure and end stage kidney disease, and possibly cardiovascular death. Only GLP-1 receptor agonists reduce non-fatal stroke; SGLT-2 inhibitors are superior to other drugs in reducing end stage kidney disease. GLP-1 receptor agonists and probably SGLT-2 inhibitors and tirzepatide improve quality of life. Reported harms were largely specific to drug class (eg, genital infections with SGLT-2 inhibitors, severe gastrointestinal adverse events with tirzepatide and GLP-1 receptor agonists, hyperkalaemia leading to admission to hospital with finerenone). Tirzepatide probably results in the largest reduction in body weight (mean difference −8.57 kg; moderate certainty). Basal insulin (mean difference 2.15 kg; moderate certainty) and thiazolidinediones (mean difference 2.81 kg; moderate certainty) probably result in the largest increases in body weight. Absolute benefits of SGLT-2 inhibitors, GLP-1 receptor agonists, and finerenone vary in people with type 2 diabetes, depending on baseline risks for cardiovascular and kidney outcomes (
https://matchit.magicevidence.org/230125dist-diabetes
).

Conclusions
This network meta-analysis extends knowledge beyond confirming the substantial benefits with the use of SGLT-2 inhibitors and GLP-1 receptor agonists in reducing adverse cardiovascular and kidney outcomes and death by adding information on finerenone and tirzepatide. These findings highlight the need for continuous assessment of scientific progress to introduce cutting edge updates in clinical practice guidelines for people with type 2 diabetes.

Systematic review registration
PROSPERO CRD42022325948.