Oral GLP-1 agonist HRS-7535 lowered HbA1c in Phase II trial in type 2 diabetes

The study

This was a multicentre, randomised, double-blind, placebo-controlled, parallel-group Phase II trial, published in Diabetologia. It tested HRS-7535, an oral small-molecule glucagon-like peptide-1 receptor agonist (GLP-1RA), in Chinese adults with type 2 diabetes.

Participants were aged 18-75 years. They had HbA1c of 58-97 mmol/mol (7.5-11.0%) and BMI of 20.0-35.0 kg/m2. All had been on a stable dose of metformin plus an SGLT2 inhibitor for at least 8 weeks. A total of 155 people were randomised 1:1:1 to HRS-7535 30 mg (n=51), HRS-7535 60 mg (n=53) or matching placebo (n=51), once daily. The primary endpoint was change in HbA1c from baseline to week 16. Mean baseline HbA1c was 69 mmol/mol (8.5%). The trial is registered as NCT06393348 and was funded by Jiangsu Hengrui Pharmaceuticals.

What they found

At week 16, HbA1c fell in all three groups. The percentage figures below are given as the source reports them:

• HRS-7535 30 mg: fell by 16 mmol/mol (95% CI -19, -14), reported as -1.5% (95% CI -1.7, -1.3).
• HRS-7535 60 mg: fell by 20 mmol/mol (95% CI -22, -17), reported as -1.8% (95% CI -2.0, -1.6).
• Placebo: fell by 4 mmol/mol (95% CI -7, -2), reported as -0.4% (95% CI -0.6, -0.2).

Both doses lowered HbA1c significantly more than placebo (p<0.0001).

The share of participants reaching HbA1c below 53 mmol/mol (7.0%) was 51.0% with 30 mg, 66.0% with 60 mg and 9.8% with placebo. For HbA1c of 48 mmol/mol (6.5%) or lower, the shares were 35.3%, 37.7% and 3.9%.

Body weight fell in the 60 mg group (reported as -2.4%) and in the placebo group (reported as -0.7%). The abstract does not report the 30 mg weight result or a test of the weight difference.

Most treatment-emergent adverse events were mild to moderate. Gastrointestinal events were the most common. No severe hypoglycaemia was reported. The only adverse event that led to stopping treatment occurred in the placebo group. The abstract does not report event rates by group.

How much weight to give it

The authors concluded that HRS-7535 gave significant improvements in glycaemic management and had a favourable safety profile. The randomised, double-blind, placebo-controlled design is a strength for the HbA1c result.

Several limits apply. The trial had 155 participants and lasted 16 weeks, so it cannot show longer-term safety, durability of effect or effects on complications. HbA1c and weight are surrogate outcomes. The abstract reports no cardiovascular or kidney outcomes. Only Chinese participants were included, so the results may not apply to other populations. The abstract does not report gastrointestinal event rates, so tolerability is hard to judge from it. There was no active comparator, so this trial says nothing about how HRS-7535 compares with other GLP-1 drugs. The sponsor funded the study.

For your clinic

This result does not change prescribing. The abstract does not state the regulatory status of HRS-7535, and it gives no basis for individual treatment decisions.

The authors state that the study addressed a significant clinical data void by testing HRS-7535 added to background metformin and SGLT2 inhibitor therapy. Larger and longer trials, ideally with gastrointestinal tolerability data, hard outcomes and a comparison with established GLP-1 therapies, are needed before this can be placed in practice. Read the full paper for adverse event rates, the weight results for both doses and the trial's analysis methods before drawing practical conclusions.