Oral orforglipron meets cardiovascular safety in diabetes with CVD or CKD

Design

Phase 3, event-driven, randomised, open-label, non-inferiority

Population

2,749 adults with type 2 diabetes and CVD or CKD (37.6% CKD)

Primary outcome

Four-point MACE

Effect

4.2% vs 5.0%; HR 0.84 (95% CI 0.59–1.20); non-inferior

ACHIEVE-4, an open-label phase 3 trial in The Lancet, randomised 2,749 adults with type 2 diabetes, BMI 25 or more and established cardiovascular disease or CKD to once-daily oral orforglipron, a non-peptide GLP-1 receptor agonist, or titrated insulin glargine. 37.6% had CKD. Background therapy could include metformin, a sulfonylurea and an SGLT2 inhibitor.

Over a median two years, the four-point MACE outcome occurred in 4.2% on orforglipron and 5.0% on glargine (HR 0.84), meeting the non-inferiority margin. Gastrointestinal adverse events were far more common (62.1% vs 14.2%) and the main reason for stopping; clinically significant hypoglycaemia was much less common (6.8% vs 19.2%). Deaths were 1.4% versus 3.2%. The trial was funded by the manufacturer.

For nephrologists, the relevance is a high-risk population with substantial CKD, and an oral option that avoids the hypoglycaemia of insulin. The trial was designed to show safety, not benefit, and kidney outcomes are not reported in the abstract.

Check orforglipron's regulatory status locally before considering it; its availability in India is not stated in this report. It may suit patients who need an incretin but will not inject, but GLP-1 receptor agonists with proven kidney outcomes remain the choice in diabetic CKD.

• Keep to GLP-1 receptor agonists with proven kidney and cardiovascular outcomes in diabetic CKD for now
• Note that orforglipron met a cardiovascular safety margin, not a benefit endpoint
• Expect high rates of gastrointestinal effects with oral incretin therapy
• Weigh the lower hypoglycaemia risk against insulin when such options become available

Why it matters

An oral incretin may extend GLP-1 treatment to patients with CKD who will not inject.

Don't overread it

Non-inferiority for safety is not proof of cardiovascular or kidney benefit.

The statistics, in plain English

Non-inferiority was declared because the upper limit of the HR interval (1.20) was below the pre-set 1.8 margin. An HR of 0.84 with an interval crossing 1 does not show that orforglipron reduces events.

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