Orforglipron hemicalcium

What is orforglipron hemicalcium?

Orforglipron hemicalcium is a chemically synthesised, small-molecule substance under investigation as a glucagon-like peptide 1 receptor agonist (GLP-1RA).^[14] It appears in the CTIS product records under the name ORFORGLIPRON HEMICALCIUM and the product names Orforglipron and ORFORGLIPRON. The substance is supplied by Eli Lilly and Company Limited. In the trial records, it has no marketing authorisation and is described as an investigational substance. Its development code is LY3502970.^[10]

How does orforglipron work?

Orforglipron is a small-molecule agonist of the glucagon-like peptide 1 receptor. Activating this receptor is the same mechanism used by injectable GLP-1 receptor agonists. A systematic review of randomised controlled trials describes orforglipron and a related substance, danuglipron, as novel, orally administered, small-molecule GLP-1RAs studied for type 2 diabetes and obesity.^[14] By stimulating the GLP-1 receptor, the substance is expected to influence blood glucose control and body weight.

Which conditions is orforglipron being studied for?

The phase 3 programme covers several conditions:

• Obesity and overweight — studied in adults and adolescents, with and without type 2 diabetes.^[2][3][5]
• Type 2 diabetes — studied in adults and in paediatric participants, including comparisons with dapagliflozin, insulin glargine, and dulaglutide.^[1][4][12]
• Atherosclerotic cardiovascular disease and chronic kidney disease — studied in the large ATTAIN-Outcomes trial.^[10]
• Peripheral arterial disease — studied for its effect on walking distance.^[11]
• Hypertension — studied in participants with obesity or overweight.^[6]
• Osteoarthritis of the knee — studied for pain in people with obesity or overweight.^[9]
• Stress urinary incontinence — studied in female participants with obesity or overweight.^[8]

How is orforglipron given?

Orforglipron is given by mouth. The CTIS product records list the pharmaceutical forms as tablet and capsule, with the route of administration recorded as oral use or oral.^[10] The trial records describe once-daily oral dosing, and one trial refers to doses of 6 mg, 12 mg and 36 mg given once daily.^[3] A paediatric trial specifies a 36 mg oral dose.^[12]

What do the clinical trials show so far?

All 12 trials in the CTIS records are phase 3 interventional studies. Three are listed as completed and nine as authorised. The table below summarises the trials. The largest is ATTAIN-Outcomes with 7,140 participants, and the smallest is a platform trial for adolescents with 125 participants. The trials investigate orforglipron as a test substance; the records state it appears as the test substance in 49 trials overall.^[10]

Which conditions are being studied?

The phase 3 programme spans metabolic, cardiovascular and urogenital conditions. Obesity and overweight are the most frequently studied conditions, appearing in seven of the twelve trials, including two dedicated adult weight-management trials (ATTAIN-1 and ATTAIN-2), a master protocol for obesity with and without type 2 diabetes, and a platform trial for adolescents.^[2][3][7]Type 2 diabetes appears in five trials, including comparisons against dapagliflozin, insulin glargine and dulaglutide.^[1][4][12]

What phases and statuses do the trials have?

All twelve trials are phase 3. Three trials are completed: the comparison with insulin glargine in type 2 diabetes, ATTAIN-2 in obesity with type 2 diabetes, and ACHIEVE-2 comparing orforglipron with dapagliflozin.^[1][2][4] The remaining nine trials are authorised, meaning they have received regulatory approval to proceed in the EU.

What are the trials measuring?

The primary outcomes vary by condition. In obesity trials, the main measure is the percent change in body weight from baseline to week 72, or in adolescents, the percent change in body mass index (BMI).^[2][3][5] In type 2 diabetes trials, the primary measure is the change in haemoglobin A1c (HbA1c), a marker of average blood glucose over about three months.^[1][4][12] The ATTAIN-Outcomes trial measures the time to the first occurrence of a composite of major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, hospitalisation or urgent visit for heart failure, coronary revascularisation, or all-cause death.^[10] The peripheral artery disease trial measures the percent change in maximum walking distance on a treadmill test.^[11] The osteoarthritis trial measures change in the WOMAC pain subscale score, a standard questionnaire for knee pain.^[9] The stress urinary incontinence trial measures the change in weekly incontinence episode frequency.^[8] The hypertension master protocol measures the change in office systolic blood pressure.^[6]

Who can take part in these trials?

Eligibility varies by trial. Adult trials enrol participants with obesity or overweight, with or without type 2 diabetes, and in some cases with additional conditions such as hypertension, osteoarthritis of the knee, peripheral arterial disease, or stress urinary incontinence in women.^[6][8][11]Two trials include paediatric or adolescent participants: a platform trial for adolescents with obesity or overweight, and a trial comparing orforglipron with dulaglutide in paediatric participants with type 2 diabetes.^[5][12]

What side effects are known?

A systematic review and meta-analysis of randomised controlled trials reported that novel oral GLP-1 receptor agonists, including orforglipron and danuglipron, showed a neutral effect on the odds of severe hypoglycaemia and serious adverse events compared to controls.^[14] The analysis found no significant increase in the odds of serious adverse events (odds ratio 0.95) or severe hypoglycaemia (odds ratio 0.34).^[14] The source does not provide a detailed breakdown of individual side effects.

What ongoing research is there?

The phase 3 programme is extensive. Nine of the twelve trials in the CTIS records are authorised and ongoing, including the large cardiovascular outcomes trial ATTAIN-Outcomes, the peripheral artery disease trial ATTAIN-PAD, and trials in hypertension, osteoarthritis of the knee, and stress urinary incontinence.^[6][8][11]A systematic review published in 2024 pooled data from randomised controlled trials and found that once-daily oral orforglipron reduced body weight and improved metabolic markers.^[13]