This review examines recent randomized controlled cardiovascular (CV) outcome trials of
glucose-lowering
therapies in
type 2 diabetes and their impact on the treatment of patients with
type 2 diabetes. The trials were designed to comply with regulatory requirements to confirm that
major adverse cardiac events (
MACE) are not detrimentally affected by such
therapies. Trials involving dipeptidyl peptidase-4 (DPP-4) inhibitors did not alter a composite
MACE outcome comprising CV deaths, non-fatal
myocardial infarction and non-fatal
stroke; however, the possibility that some members of this class might incur a small increased risk or worsening of
heart failure cannot be excluded. Some studies on
glucagon-like peptide-1 receptor agonists (
liraglutide: LEADER trial;
semaglutide: SUSTAIN-6 trial) found significant benefits for
MACE, while treatment with
sodium-
glucose co-transporter-2 inhibitors (
empagliflozin: EMPA-REG OUTCOME trial;
canagliflozin: CANVAS trial) also significantly reduced
MACE and reduced hospitalization for
heart failure. Comparisons among trials are complicated by variance in the populations recruited, particularly CV status at randomization, and differences in trial design, data collection and analyses. A large proportion of patients recruited into these trials have previously experienced adverse CV events; thus, the
therapies are mostly assessing
secondary prevention of a further event. This contrasts with the overall
type 2 diabetes population receiving
glucose-lowering
therapies, of whom the majority will not have had
MACE and will be regarded as primary prevention. Overall, the trials provide reassuring evidence that new
glucose-lowering medications do not adversely affect CV events and some of these agents may offer CV protection.