Title: Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials

Name: NMA_Diabetes

Identifier: FOI 264321

Identifier: PROSPERO CRD42022325948

Brief Description: What is already known on this topic Sodium glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists have proven benefits in cardiovascular and kidney outcomes, with some notable differences in outcomes such as heart failure and stroke Recent randomised trials report both cardiovascular and kidney benefits with finerenone, a novel non-steroidal mineralocorticoid receptor antagonist, and improvements in quality of life and weight loss with tirzepatide, a dual glucose dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist What this study adds Compared with standard treatments, adding finerenone probably reduces all cause mortality, admission to hospital for heart failure, and end stage kidney disease, while adding tirzepatide could reduce body weight Compared with standard treatments, findings indicate that adding SGLT-2 inhibitors or GLP-1 receptor agonists reduces all cause mortality, cardiovascular death, non-fatal myocardial infarction, admission to hospital for heart failure, and end stage kidney disease, while adding only GLP-1 receptor agonists reduces non-fatal stroke Compared with standard treatments, adding metformin possibly reduces all cause mortality and non-fatal myocardial infarction, adding sulfonylureas possibly increases all cause mortality, and adding thiazolidinediones probably increases admission to hospital due to heart failure

Description: 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.

Purpose Type: Treatment (coded as: treatment from http://hl7.org/fhir/research-study-prim-purp-type)

Study Design: Quantitative analysis (coded as: SEVCO:01086 from https://fevir.net/sevco)

Study Design: combined direct plus indirect network meta-analysis (coded as: combined-NMA from http://terminology.hl7.org/CodeSystem/synthesis-type)

Related Item (derived-from): Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials [Journal Article]. Contributors: Shi Q, Nong K, Vandvik PO, Guyatt GH, Schnell O, Rydén L, Marx N, Brosius FC, Mustafa RA, Agarwal A, Zou X, Mao Y, Asadollahifar A, Chowdhury SR, Zhai C, Gupta S, Gao Y, Lima JP, Numata K, Qiao Z, Fan Q, Yang Q, Jin Y, Ge L, Yang Q, Zhu H, Yang F, Chen Z, Lu X, He S, Chen X, Lyu X, An X, Chen Y, Hao Q, Standl E, Siemieniuk R, Agoritsas T, Tian H, Li S. In: BMJ (Clinical research ed.), PMID 37024129. Published April 06, 2023. Available at: https://pubmed.ncbi.nlm.nih.gov/37024129/. 37024129 Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials.

Associated Party: Sichuan Science and Technology Programme (grant 2022YFH0114) (funding-source (coded as: funding-source from http://hl7.org/fhir/research-study-party-role))

Comparison Group: SGLT2 inhibitors (Experimental (coded as: experimental from http://hl7.org/fhir/research-study-arm-type))

Comparison Group: GLP-1 receptor agonists (Experimental (coded as: experimental from http://hl7.org/fhir/research-study-arm-type))

Comparison Group: (Active Comparator (coded as: active-comparator from http://hl7.org/fhir/research-study-arm-type))

Comparison Group: Standard treatment (Other Arm Type (coded as: other-arm-type from http://hl7.org/fhir/research-study-arm-type))

Objective: All-cause death () Number of patients who died due to any reason within follow-ups. The measure should be odds ratio.

Result: Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials.