Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors With All-Cause Mortality in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis

Abstract

Importance: The comparative clinical efficacy of sodium-glucose cotransporter 2 (SGLT-2) inhibitors, glucagon-like peptide 1 (GLP-1) agonists, and dipeptidyl peptidase 4 (DPP-4) inhibitors for treatment of type 2 diabetes is unknown.

Objective: To compare the efficacies of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors on mortality and cardiovascular end points using network meta-analysis.

Data sources: MEDLINE, Embase, Cochrane Library Central Register of Controlled Trials, and published meta-analyses from inception through October 11, 2017.

Study selection: Randomized clinical trials enrolling participants with type 2 diabetes and a follow-up of at least 12 weeks were included, for which SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors were compared with either each other or placebo or no treatment.

Data extraction and synthesis: Data were screened by 1 investigator and extracted in duplicate by 2 investigators. A Bayesian hierarchical network meta-analysis was performed.

Main outcomes and measures: The primary outcome: all-cause mortality; secondary outcomes: cardiovascular (CV) mortality, heart failure (HF) events, myocardial infarction (MI), unstable angina, and stroke; safety end points: adverse events and hypoglycemia.

Results: This network meta-analysis of 236 trials randomizing 176 310 participants found SGLT-2 inhibitors (absolute risk difference [RD], -1.0%; hazard ratio [HR], 0.80 [95% credible interval {CrI}, 0.71 to 0.89]) and GLP-1 agonists (absolute RD, -0.6%; HR, 0.88 [95% CrI, 0.81 to 0.94]) were associated with significantly lower all-cause mortality than the control groups. SGLT-2 inhibitors (absolute RD, -0.9%; HR, 0.78 [95% CrI, 0.68 to 0.90]) and GLP-1 agonists (absolute RD, -0.5%; HR, 0.86 [95% CrI, 0.77 to 0.96]) were associated with lower mortality than were DPP-4 inhibitors. DPP-4 inhibitors were not significantly associated with lower all-cause mortality (absolute RD, 0.1%; HR, 1.02 [95% CrI, 0.94 to 1.11]) than were the control groups. SGLT-2 inhibitors (absolute RD, -0.8%; HR, 0.79 [95% CrI, 0.69 to 0.91]) and GLP-1 agonists (absolute RD, -0.5%; HR, 0.85 [95% CrI, 0.77 to 0.94]) were significantly associated with lower CV mortality than were the control groups. SGLT-2 inhibitors were significantly associated with lower rates of HF events (absolute RD, -1.1%; HR, 0.62 [95% CrI, 0.54 to 0.72]) and MI (absolute RD, -0.6%; HR, 0.86 [95% CrI, 0.77 to 0.97]) than were the control groups. GLP-1 agonists were associated with a higher risk of adverse events leading to trial withdrawal than were SGLT-2 inhibitors (absolute RD, 5.8%; HR, 1.80 [95% CrI, 1.44 to 2.25]) and DPP-4 inhibitors (absolute RD, 3.1%; HR, 1.93 [95% CrI, 1.59 to 2.35]).

Conclusions and relevance: In this network meta-analysis, the use of SGLT-2 inhibitors or GLP-1 agonists was associated with lower mortality than DPP-4 inhibitors or placebo or no treatment. Use of DPP-4 inhibitors was not associated with lower mortality than placebo or no treatment.

Figure 1.. Summary of Study Retrieval and Identification for Network Meta-analysis

DPP-4 indicates dipeptidyl peptidase 4; GLP-1, glucagon-like peptide 1; and SGLT-2, sodium-glucose cotransporter 2.

Figure 2.. Network Plot for All Studies

Graphical representation of network for all included trials. Connecting lines represent head-to-head comparisons between drugs, indicated by nodes. Multigroup trials contribute multiple comparisons, resulting in 258 comparisons from 236 trials. The thickness of lines between nodes is proportional to the number of trials comparing the treatments. The sizes of the nodes are proportional to the number of patients in each treatment. Patients may be included in multiple comparisons: for example, in a study of 3 groups consisting of control and 2 different drug classes, the control group is compared with each drug class. This is accounted for within the network model and does not constitute duplication of participants. DPP-4 indicates dipeptidyl peptidase 4; GLP-1, glucagon-like peptide 1; k, the number of comparisons; n, the number of patients per comparison; and SGLT-2, sodium-glucose cotransporter 2.

Figure 3.. Forest Plots for All-Cause Mortality, Cardiovascular Mortality, and Heart Failure

All outcomes are reported in hazard ratios (HRs) for treatment vs the comparator and 95% credible intervals (CrIs). Absolute risk differences (RDs) were calculated by multiplying the RD by the event rate in the comparator group. The 95% CrIs for absolute RDs are calculated by multiplying the 95% CrIs by the event rate in the comparator group. Heterogeneity was assessed using the I² statistic; low heterogeneity was determined by an I² of 25% or less. The x-axis scale shown in blue indicates the range of the HR from 0.5 to 2.0. Tables below the forest plots show, for each drug class, the number of trials, number of participants with events, and the total number of randomized participants. For example, for all-cause mortality, 88 trials randomized 57 022 participants to the control treatment with 2955 participants having events, and 49 trials randomized 30 178 participants to DPP-4 inhibitors with 1171 participants having events. Control represents either placebo or no treatment; DPP-4, dipeptidyl peptidase 4; GLP-1, glucagon-like peptide 1; and SGLT-2, sodium-glucose cotransporter 2.

Figure 4.. Forest Plots for Myocardial Infarction, Unstable Angina, and Stroke

All outcomes are reported in hazard ratios (HRs) for treatment vs the comparator and 95% credible intervals (CrIs). Absolute risk differences (RDs) were calculated by multiplying the RD by the event rate in the comparator group. The 95% CrIs for absolute RDs are calculated by multiplying the 95% CrIs by the event rate in the comparator group. Heterogeneity was assessed using the I² statistic; low heterogeneity was determined by an I² of 25% or less. The x-axis scale shown in blue indicates the range of the HR from 0.5 to 2.0. Tables below the forest plots show for each drug class, the number of trials, number of participants with events, and the total number of randomized participants. For example, for all myocardial infarction, 87 trials randomized 53 099 participants to the control treatment with 2133 participants having events, and 50 trials randomized 27 462 participants to DPP-4 inhibitors with 616 participants having events. Control represents either placebo or no treatment; DPP-4, dipeptidyl peptidase 4; GLP-1, glucagon-like peptide 1; and SGLT-2, sodium-glucose cotransporter 2.

Figure 5.. Ranking Plots

Drug ranking plots for primary and secondary outcomes are stratified by treatment. Each line represents 1 drug class and shows the probability of its ranking from best to worst. The peak of the line represents the rank that the drug is most likely to be for each given outcome. For example, for all-cause mortality, sodium-glucose cotransporter 2 (SGLT-2) inhibitors are most likely to rank best; glucagon-like peptide 1 (GLP-1) agonists, second best; control, third best; and dipeptidyl peptidase 4 (DPP-4) inhibitors, worst. Control includes placebo and no treatment.