Cardiovascular Outcomes Trial (CVOT)
A large clinical trial specifically designed to evaluate a drug's effect on cardiovascular events such as heart attack, stroke, and cardiovascular death. The FDA requires CVOTs for new diabetes drugs. Positive CVOT results for semaglutide and liraglutide demonstrated cardiovascular benefits beyond glucose control.
Technical Context
The FDA mandated CVOTs for new diabetes drugs following the rosiglitazone cardiovascular safety concern (2008 guidance). CVOTs must demonstrate that the drug does not increase cardiovascular risk (upper bound of 95% CI for HR <1.3 for pre-approval; <1.8 post-marketing). Notable peptide CVOTs: LEADER (liraglutide) — HR 0.87 for MACE, first GLP-1 RA to show CV benefit; SUSTAIN-6 (semaglutide 0.5/1.0mg) — HR 0.74 for MACE; SELECT (semaglutide 2.4mg in obesity without diabetes) — HR 0.80 for MACE; SURPASS-CVOT (tirzepatide) — ongoing. These CVOTs transformed GLP-1 RA positioning from glucose-lowering agents to cardioprotective drugs, with treatment guidelines now recommending them for patients with established cardiovascular disease.