The comparative clinical and cost effectiveness of the three classes of glucose-lowering agents have not been explored, leading to clinical uncertainty about the optimal treatment pathway and a potential negative cost effect. Similarly, no cardiovascular outcome trials have directly compared the efficacy of these classes. When no head-to-head trial exists, network meta-analysis can be used to estimate the effect.
The purpose of this network meta-analysis was to compare the efficacy of SGLT-2 inhibitors, DPP-4 inhibitors, and GLP-1 agonists in reducing mortality and cardiovascular outcomes in participants with type 2 diabetes and their relative safety profiles. Even though these classes of drugs have been proven efficacious in improving glycemic control in patients with type 2 diabetes (T2D), they have not been in a head-to-head study as to their abilities in extending life.
Sean L. Zheng, BM BCh, MA, MRCP, of the Department of Endocrinology at Imperial College Healthcare NHS Foundation Trust, in London, UK, and colleagues in a meta-analysis of 236 clinical trials, including 176,310 participants with T2D, looked at comparisons of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors against each other or placebo. All trials included had a follow-up period of at least 12 weeks.
Trials were considered eligible if they (1) were a randomized clinical trial; (2) enrolled participants with type 2 diabetes mellitus; (3) compared SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors at market-approved doses with each other or with a control group (defined as placebo or no treatment), (4) had a follow-up of at least 12 weeks; (5) provided information on any of the prespecified primary, secondary, and safety end points; and (6) were published in the English language.
The primary outcome was all-cause mortality. Secondary outcomes included cardiovascular mortality, heart failure events, myocardial infarction (MI) (all and nonfatal), unstable angina, and stroke (all and nonfatal). Safety end points were adverse events (any, serious, and leading to study withdrawal), and hypoglycemia (minor and major). A composite cardiovascular outcome consisting of cardiovascular mortality, nonfatal MI, and nonfatal stroke was extracted and analyzed for the cardiovascular outcome trials alone.
Additional drug class–specific safety end points for SGLT-2 inhibitors were lower-limb amputation, urinary tract infection, and genital infection, for GLP-1 agonists were acute pancreatitis, and retinopathy, and for DPP-4 inhibitors was acute pancreatitis.
In all, there were 6035 deaths: 714 (3.6%) of 19 587 participants treated with SGLT-2 inhibitors, 1171 (3.9%) of 30 178 treated with DPP-4 inhibitors, 1195 (4.4%) of 27 373 treated with GLP-1 agonists, and 2955 (5.2%) of 57 022 in the control groups.
Compared with the control groups, both SGLT-2 inhibitors and GLP-1 agonists were associated with reductions in all-cause mortality. Dipeptidyl peptidase 4 inhibitors were not associated with a difference in mortality compared with the control groups absolute Risk Reduction (RD). Both SGLT-2 inhibitors and GLP-1 agonists were associated with reduced all-cause mortality when compared with DPP-4 inhibitors. There was no significant difference between SGLT-2 inhibitors and GLP-1 agonists (HR, 0.91 [95% CrI, 0.79 to 1.04]; absolute RD, −0.4% [95% CrI, −0.9% to 0.2%]).
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.
From the results it was concluded that this network meta-analysis of 236 trials randomizing 176 310 participants found SGLT-2 inhibitors and GLP-1 were associated with significantly lower all-cause mortality than the control groups. SGLT-2 inhibitors and GLP-1 agonists were associated with lower mortality than were DPP-4 inhibitors. DPP-4 inhibitors were not significantly associated with lower all-cause mortality than were the control groups. SGLT-2 inhibitors and GLP-1 agonists were significantly associated with lower CV mortality than were the control groups. SGLT-2 inhibitors were significantly associated with lower rates of HF and MI 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 and DPP-4 inhibitors.
Zheng and colleagues wrote. “Of the 3 classes tested, SGLT-2 inhibition may be preferred over the incretin-based therapies based on their association with lower mortality and their favorable adverse event profile.”
The SGLT-2 inhibitors were associated with additional cardiovascular benefits for heart failure events compared with incretin-based therapies and control groups and for [myocardial infarction] events compared with control groups.
- 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.
- There were additional cardiovascular benefits with the SGLT-2 inhibitors as reduced MI’s
- Use of DPP-4 inhibitors was not associated with lower mortality than placebo or no treatment.
JAMA. 2018;319(15):1580-1591. doi:10.1001/jama.2018.3024