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

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.

Fig 1

Flow diagram for trial screen and selection. MRA=non-steroidal mineralocorticoid receptor antagonists; GIP/GLP-1=glucose dependent insulinotropic polypeptide/glucagon-like peptide-1. *Previous review refers to reference 2

Fig 2

Network plot for all included studies, by drug treatments. Drug treatments were grouped by their drug classes. Network plots consist of the drug nodes with node size being proportional to the sample size and the comparison edges with line thickness being proportional to the number of trials. MRA=non-steroidal mineralocorticoid receptor antagonists; GLP-1=glucagon-like peptide-1; SGLT-2=sodium glucose cotransporter-2; DPP-4=dipeptidyl peptidase-4

Fig 3

Benefits and harms of drug treatments for type 2 diabetes. Figure shows benefits and harms of the drugs for diabetes with the estimates that represent the comparative effects of the drugs compared with standard treatments. The GRADE (grading of recommendations, assessment, development, and evaluations) approach was used with a null effect threshold to rate and categorise drugs from among the most effective to among the most harmful. Any 95% confidence intervals touching but not crossing the decision threshold (ie, the null effect), were not rated down for imprecision. Drugs that were superior to (or inferior to) standard treatments (ie, point estimate exceeding (or falling below) the null effect and the 95% confidence interval not crossing) were first categorised into the most effective group (or the most harmful group). Drugs among the most effective (or most harmful) but inferior to (ie, point estimate falling below and 95% confidence interval not crossing) at least one drug in that group were then categorised into the intermediate effective group (or the intermediate harmful group). Non-steroidal mineralocorticoid receptor antagonists (MRAs) mainly refer to finerenone. *End stage kidney disease was defined as a composite of a long term dialysis, kidney transplantation, sustained estimated glomerular filtration rate <15 mL per min per 1.73 m² for ≥30 days, sustained percent decline in estimated glomerular filtration rate of at least 40% for ≥30 days or a doubling of serum creatinine, or renal death; effects on end stage kidney disease were rated down owing to indirectness. CI=confidence interval; GLP-1=glucagon-like peptide-1; OR=odds ratio; SGLT-2=sodium glucose cotransporter-2

Fig 4

Anticipated absolute effects for patients with type 2 diabetes and chronic kidney disease, by drug treatment. Figure shows absolute benefits and harms of the drugs for patients with type 2 diabetes and chronic kidney disease. Estimates represent risk differences per 1000 patients in five years compared with standard treatments. Absolute effects were anticipated by applying the relative effects to the baseline risks adopted from a previous guideline panel. Figure is restricted to adults with type 2 diabetes and chronic kidney disease as an example, with the full populations in appendix 6 and the online tool (https://qingys.shinyapps.io/data_visualization) or the MATCH-IT tool (https://matchit.magicevidence.org/230125dist-diabetes). Non-steroidal mineralocorticoid receptor antagonists (MRAs) mainly refer to finerenone. GLP-1=glucagon-like peptide-1; SGLT-2=sodium glucose cotransporter-2

Fig 5

Body weight impact of drug treatment for type 2 diabetes by drug treatment. Figure shows body weight changes of the drugs for diabetes with the estimates that represent the comparative effects of the drugs compared with standard treatments. The GRADE (grading of recommendations, assessment, development, and evaluations) approach was used with a null effect threshold to rate and categorise drugs from among the most effective to among the most harmful. Any 95% confidence intervals touching but not crossing the decision threshold (ie, the null effect) were not rated down for imprecision. Drugs that were superior to (or inferior to) standard treatments (ie, point estimate exceeding (or falling below) the null effect and the 95% confidence interval not crossing) were first categorised into the most effective group (or the most harmful group). Drugs among the most effective (or the most harmful) but inferior to (ie, point estimate falling below and 95% confidence interval not crossing) at least one drug in that group were then categorised into the intermediate effective group (or the intermediate harmful group). CI=confidence interval; DPP-4=dipeptidyl peptidase-4; MD=mean difference; SGLT-2=sodium glucose cotransporter-2