Drug-class and individual-agent evidence: GLP-1 receptor agonists, SGLT2 inhibitors, and the major trials behind semaglutide, tirzepatide, and related therapies.
The LEADER trial demonstrated that liraglutide significantly reduced 3-point MACE and cardiovascular mortality in patients with type 2 diabetes and high cardiovascular risk, becoming the first GLP-1 receptor agonist CVOT to demonstrate superiority and characterising an atherosclerotic rather than heart failure protection profile distinct from SGLT2 inhibitors.
DAPA-CKD demonstrated that dapagliflozin reduced the composite of a sustained 50% or greater eGFR decline, end-stage kidney disease, or renal or cardiovascular death by 39% in patients with albuminuric CKD with or without type 2 diabetes, extending nephroprotective SGLT2 inhibition beyond diabetic nephropathy to a broad CKD population for the first time.
EMPEROR-Reduced confirmed that empagliflozin reduces cardiovascular death or hospitalisation for heart failure by 25% in patients with HFrEF irrespective of diabetes status, while also demonstrating a 50% reduction in a renal composite outcome and a markedly slower rate of eGFR decline, adding critical confirmatory evidence for SGLT2 inhibitors as standard-of-care in HFrEF.
The DAPA-HF trial demonstrated that dapagliflozin reduced the composite of worsening heart failure or cardiovascular death by 26% in patients with heart failure and reduced ejection fraction, with consistent benefit observed in both those with and without type 2 diabetes, establishing SGLT2 inhibition as a core therapy for HFrEF independent of glycaemic status.
A biomarker substudy finds empagliflozin modulates sirtuins and microRNAs after myocardial infarction, with a panel predicting recovery. PICO summary and expert commentary.
A 20-week RCT finds empagliflozin improves nerve conduction velocity in diabetic neuropathy but not clinical exam scores, with glycaemic confounding. PICO summary and commentary.
The CREDENCE trial demonstrated that canagliflozin reduced the composite of end-stage kidney disease, doubling of serum creatinine, or renal or cardiovascular death by 30% in patients with type 2 diabetes and albuminuric chronic kidney disease, becoming the first dedicated renal outcomes trial to demonstrate that an SGLT2 inhibitor could substantially slow the progression of diabetic nephropathy.
The DECLARE-TIMI 58 trial demonstrated that dapagliflozin did not reduce 3-point MACE compared with placebo but significantly reduced the composite of cardiovascular death or hospitalisation for heart failure, driven entirely by a 27% reduction in heart failure hospitalisation, in the largest and most broadly representative SGLT2 inhibitor cardiovascular outcomes trial conducted to date.
The CANVAS Programme demonstrated that canagliflozin reduced major adverse cardiovascular events by 14% in patients with type 2 diabetes at high cardiovascular risk, but identified an approximately twofold increase in lower-extremity amputation risk, primarily at the toe or metatarsal level, requiring careful patient selection and monitoring.
The EMPA-REG OUTCOME trial demonstrated that empagliflozin reduced cardiovascular death by 38% and heart failure hospitalisation by 35% in patients with type 2 diabetes and established cardiovascular disease — the first glucose-lowering agent to show a mortality benefit in a cardiovascular outcomes trial.
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