ACHIEVE-4 Foundayo Trial: What It Tested and What It Found

Foundayo ACHIEVE-4: What This Trial Search Refers To

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ACHIEVE-4 is a phase 3 clinical trial of Foundayo, the brand name of orforglipron, in adults with type 2 diabetes and obesity or overweight who were at increased risk of cardiovascular events. Its main purpose was to show that orforglipron was no worse than insulin glargine, a long acting insulin, for the risk of major cardiovascular events, and it met that goal. It randomised 2,749 people across 15 countries, ran for up to 104 weeks, and ran for longer than any other phase 3 study of orforglipron reported so far. Topline results were announced on 16 April 2026, and the trial forms part of the ACHIEVE programme that supports Foundayo's UK licence for type 2 diabetes, which the MHRA granted on 10 August 2026.

People who search for ACHIEVE-4 have usually seen it in a headline about heart safety or a lower death rate and want to know what was tested, what was found, and what it means for someone taking or considering the medicine. This guide from the EveryDayMeds pharmacy team explains the trial's design, its results with the numbers, what it did and did not show, how it fits with the other ACHIEVE and ATTAIN trials, and what a UK patient should and should not read into it.

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What is the ACHIEVE-4 trial?

ACHIEVE-4 is a randomised, open label, event driven, phase 3 trial of orforglipron against insulin glargine in adults with type 2 diabetes who also had obesity or overweight and an increased risk of cardiovascular events. Each of those terms matters.

Term	What it means in ACHIEVE-4
Phase 3	A large late-stage clinical trial designed to evaluate efficacy and safety in the intended patient population and provide evidence for regulatory review.
Randomised	Participants were assigned to orforglipron or insulin glargine by chance, so the groups were comparable
Open label	Participants and investigators knew which treatment was assigned. The trial compared an oral tablet with once-daily injectable insulin.
Event driven	The trial ran until enough cardiovascular events had occurred to answer the question, rather than for a fixed time
Comparator: insulin glargine	A long acting insulin injected once daily, a standard treatment when oral diabetes medicines are not enough
Participants	2,749 adults with type 2 diabetes, a BMI of 25 or above, and increased cardiovascular risk from conditions such as heart disease affecting the heart's own arteries, cerebrovascular disease or heart failure, taking one to three oral diabetes medicines
Duration	Participants were followed for up to 104 weeks. HbA1c and body-weight comparisons were reported at 52 weeks, with effects maintained through 104 weeks; the cardiovascular endpoint was assessed over the event-driven study period.

Key things to know

ACHIEVE-4 tested cardiovascular safety. Its primary question was whether orforglipron was non inferior to insulin glargine for major adverse cardiovascular events, and the answer was yes.
In ACHIEVE-4, orforglipron produced greater reductions in HbA1c and body weight than insulin glargine at 52 weeks, with these differences reported as maintained through 104 weeks.
A lower rate of death from any cause was observed with orforglipron, but this analysis was not controlled for multiple testing and is described as hypothesis generating, not proven.
Side effects were the GLP-1 class effects, mainly nausea, vomiting, diarrhoea, reduced appetite and constipation, and 10.6% of people on orforglipron stopped because of side effects.
The trial was in people with type 2 diabetes at high cardiovascular risk. Its results do not automatically apply to people using Foundayo for weight management without diabetes.
ACHIEVE-4 is one of several ACHIEVE trials in type 2 diabetes. The ATTAIN trials cover weight management.
Treatment suitability depends on an individual clinical assessment, and your prescriber will determine the appropriate treatment.

Why compare a GLP-1 tablet with insulin?

Insulin glargine is an established glucose-lowering treatment used in type 2 diabetes, including when additional treatment is needed despite other medicines. ACHIEVE-4 therefore compared orforglipron with an active treatment rather than placebo.

What did ACHIEVE-4 find?

ACHIEVE-4 met its primary endpoint and its main secondary endpoints, and the numbers are worth reading carefully, with clinically meaningful improvements in HbA1c, body weight, and other cardiometabolic measures supporting the overall safety and efficacy profile. The key question is how Foundayo performed compared with insulin glargine for cardiovascular risk and metabolic outcomes across the trial.

Outcome	Orforglipron	Insulin glargine	What it means
Major adverse cardiovascular events (MACE-4): cardiovascular death, heart attack, stroke, hospitalisation for unstable angina	Hazard ratio 0.84 against insulin glargine, 95% confidence interval 0.59 to 1.20	Reference	Non inferiority met. The risk of major adverse events was not worse, and the point estimate was 16% lower, but the confidence interval crosses 1, so superiority was not shown. This includes events such as sudden chest pain requiring hospital admission
Blood sugar (HbA1c) change at 52 weeks	Around 1.6 percentage points lower	Around 1.0 percentage point lower	A greater reduction with orforglipron, treatment difference around 0.66 points, maintained to 104 weeks
Body weight at 52 weeks	Around 8.8% loss	Weight gain	Treatment difference around 10.4% of body weight in favour of orforglipron, maintained to 104 weeks
Death from any cause	Hazard ratio 0.43, 95% confidence interval 0.25 to 0.75	Reference	An exploratory analysis found a hazard ratio of 0.43 for all-cause death, corresponding to a 57% lower observed hazard compared with insulin glargine. The analysis was not controlled for multiple testing, so it does not establish that orforglipron reduces mortality.
Other cardiometabolic measures	Improvements reported in blood fats, systolic blood pressure and an inflammation marker	Reference	Changes in non-HDL cholesterol, systolic blood pressure, triglycerides and hsCRP were also reported.
Stopping because of side effects	10.6%	Not reported in topline results	The most common adverse events were digestive effects during dose steps, including decreased appetite, and they eased over time
Liver safety	The reported ACHIEVE-4 safety assessment did not identify a drug-induced liver injury signal.	Not applicable	Reported alongside the trial as a safety review, with the hepatic safety signal consistent with prior studies

What does "non inferior" mean?

Non inferior means the trial showed that orforglipron was not meaningfully worse than insulin glargine for cardiovascular events, within a margin set before the trial began. It does not prove a lower risk of MACE, only that major adverse cardiovascular events were not meaningfully worse than with insulin glargine. The point estimate, a 16% lower risk, leaned in orforglipron's favour, but the confidence interval, the range within which the true effect probably lies, ran from a 41% lower risk to a 20% higher risk. A result that includes both possibilities cannot claim superiority. It can, and did, claim non inferiority, a cardiovascular safety result generally consistent with previous trials.

What does the death rate finding mean?

Fewer deaths from any cause occurred in the orforglipron group, with a hazard ratio of 0.43 (95% CI 0.25–0.75). This corresponds to a 57% lower observed hazard, but it should not be interpreted as proof that orforglipron reduces mortality. The analysis was not controlled for multiple testing, so it is considered hypothesis generating. Confirmation would require further evidence from appropriately designed analyses or trials.

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What did ACHIEVE-4 not show?

ACHIEVE-4 did not show cardiovascular superiority, did not prove the death rate finding, did not study people without diabetes, and did not blind participants to their treatment.

Not superiority. The trial was designed and powered to show non inferiority for cardiovascular events, and that is what it showed.
Not proof of lower mortality. The all cause death finding is nominal and awaits confirmation.
Not weight management without diabetes. Every participant had type 2 diabetes and high cardiovascular risk.ATTAIN-1, the key weight-management trial in adults without type 2 diabetes, reported a mean body-weight change of −12.4% at week 72 with the 36 mg capsule dose in the ITT analysis, compared with −0.9% with placebo.
Not a blinded comparison. Open label trials are necessary when a tablet is compared with an injection, but knowing the treatment can influence some outcomes, which is why the hard cardiovascular endpoints were adjudicated.
Not a comparison with other GLP-1 medicines. The comparator was insulin glargine. Other ACHIEVE trials compared orforglipron with other diabetes medicines.

Who was excluded from ACHIEVE-4?

The trial excluded several groups, including people with type 1 diabetes and certain medical conditions. These eligibility criteria mean the results should be interpreted in the context of the population actually studied.

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How does ACHIEVE-4 fit with the other Foundayo trials?

ACHIEVE-4 is one trial in two programmes: ACHIEVE, in type 2 diabetes, and ATTAIN, in weight management, and its findings were consistent with prior studies in the ACHIEVE programme. Across seven phase 3 studies, more than 11,000 people have taken part.

Trial	Population	Comparator	What it addressed
ACHIEVE-1	Type 2 diabetes	Placebo	Orforglipron on its own for blood sugar control
ACHIEVE-2	Type 2 diabetes not controlled with metformin	Dapagliflozin, an oral diabetes medicine	Orforglipron against another oral option
ACHIEVE-3	Type 2 diabetes	Oral semaglutide	Orforglipron against the other oral GLP-1 tablet. Greater weight loss was reported with orforglipron
ACHIEVE-4	Type 2 diabetes with obesity or overweight and high cardiovascular risk	Insulin glargine	Cardiovascular safety, blood sugar and weight over up to 104 weeks
ACHIEVE-5	Type 2 diabetes already on insulin glargine	Placebo added to insulin glargine	Orforglipron added to insulin
ATTAIN-1	Obesity or overweight with a weight related condition, without diabetes	Placebo	Weight management over 72 weeks. The main evidence for the weight management licence
ATTAIN-2	Obesity or overweight with type 2 diabetes	Placebo	Weight management in people with diabetes

A dedicated cardiovascular outcomes trial is also under way, which is the study designed to answer the questions ACHIEVE-4 could only raise. Across the broader programme, ACHIEVE-4 adds longer-term cardiovascular safety data to the wider orforglipron development programme. The ACHIEVE trials evaluate type 2 diabetes, while the ATTAIN trials provide the main evidence for weight management.

Does ACHIEVE-4 apply to someone using Foundayo for weight loss?

ACHIEVE-4 provides additional safety information about orforglipron, but it studied adults with type 2 diabetes and elevated cardiovascular risk. Its findings should therefore not be assumed to have the same implications for people taking orforglipron solely for weight management without diabetes. The weight-management evidence comes primarily from the ATTAIN programme.

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How should you read a trial like ACHIEVE-4?

Read the design before the headline, the confidence interval before the point estimate, and the population before applying the result to yourself.

Find the primary endpoint. For ACHIEVE-4 it was cardiovascular events, non inferiority. Everything else is secondary or exploratory.
Check the comparator. Insulin glargine, not placebo and not another GLP-1 medicine. A result against one comparator does not transfer to another.
Read the confidence interval. A range that crosses 1 for a hazard ratio means the trial could not rule out no difference.
Ask whether a finding was controlled for multiple testing. The death rate finding was not, which is why it is hypothesis generating.
Check the population. Type 2 diabetes with high cardiovascular risk. Not everyone takes the medicine.
Note the duration. Up to 104 weeks, longer than any other orforglipron trial so far, but still two years.
Look at who stopped and why. 10.6% stopped for side effects, mainly digestive, mainly during dose steps.

What commonly goes wrong when people read trial headlines?

Reading non inferiority as "safer". It means not worse.
Reading a nominal death rate finding as proven.
Applying a diabetes trial to weight management without diabetes.
Ignoring the comparator. A result against insulin says nothing about a result against another GLP-1 medicine.
Treating a trial average as a personal forecast. Results vary between individuals.
Deciding on treatment from a trial rather than an assessment. A prescriber weighs your own history, medicines and risks.

What does ACHIEVE-4 mean for a UK patient?

For a UK patient it means three things. Foundayo's UK licence for insufficiently controlled type 2 diabetes, granted by the MHRA on 10 August 2026, rests partly on the ACHIEVE programme, of which ACHIEVE-4 enrolled more people and ran for longer than any other study. The cardiovascular safety result provides evidence that orforglipron was not inferior to insulin glargine for MACE-4 in the studied population. And the side effect profile, with about one in ten stopping for adverse events, is a realistic picture of what dose steps involve. None of it replaces an individual assessment, and a prescriber decides whether the medicine suits you.

The MHRA continues to monitor the safety of orforglipron after authorisation. Suspected adverse reactions can be reported through the Yellow Card scheme.

How can EveryDayMeds help?

If you are considering treatment for type 2 diabetes or weight management, an appropriately qualified prescriber can assess your medical history, current medicines and treatment goals and explain which licensed options may be appropriate. EveryDayMeds states that its online service uses UK-registered prescribers and that its pharmacy is registered with the GPhC under reference 9012878.

Medically supervised weight loss treatment is available to adults living with obesity, subject to an individual clinical assessment.

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Medical Disclaimer

This article is for general information only and does not replace advice from a doctor, pharmacist or other qualified healthcare professional. It summarises published topline trial results and does not recommend any specific medicine or dose. Foundayo is a prescription only medicine that should only be used under the supervision of an appropriately qualified prescriber, within its UK licence. Always read the patient information leaflet. If you have severe abdominal pain, cannot keep fluids down, or notice yellowing of the skin or eyes, seek urgent medical attention.

Frequently Asked Questions

What is ACHIEVE-4?

In the reported 52-week analyses, orforglipron produced greater reductions in HbA1c and body weight than insulin glargine. The estimated treatment difference was −0.66 percentage points for HbA1c and −10.42 percentage points for body weight, with effects reported as maintained through 104 weeks.

What did ACHIEVE-4 show?

That orforglipron was non inferior compared to insulin glargine for the risk of major adverse cardiovascular events, with a hazard ratio of 0.84 and a confidence interval of 0.59 to 1.20, and that the trial showed superior improvements in blood sugar and body weight compared with insulin glargine at 52 weeks, maintained to 104 weeks. A lower rate of death from any cause was observed but is not yet proven.

Did ACHIEVE-4 prove Foundayo reduces deaths?

No. Fewer deaths from any cause were observed with orforglipron, hazard ratio 0.43, but the analysis was not controlled for multiple testing and the trial was not designed to prove it. It is described as hypothesis generating and awaits confirmation in a dedicated trial.

Does ACHIEVE-4 apply to people using Foundayo for weight loss?

ATTAIN-1 reported a mean body-weight change of −12.4% at week 72 with the 36 mg capsule dose in the ITT analysis, compared with −0.9% with placebo.

What were the side effects in ACHIEVE-4?

The most common adverse events were GLP-1 class effects: nausea, vomiting, diarrhoea, decreased appetite, and constipation, mainly during dose steps and easing over time; some participants discontinued treatment because of these adverse events, and ACHIEVE-4 confirmed no hepatic safety signal for Foundayo, with the hepatic safety signal consistent with prior studies.

How does ACHIEVE-4 relate to Foundayo's UK licence?

Foundayo's UK licence, granted by the MHRA on 10 August 2026, covers weight management and insufficiently controlled type 2 diabetes. The ACHIEVE programme, including ACHIEVE-4, supports the diabetes licence, and the ATTAIN programme supports the weight management licence, reflecting the wider lilly cardiometabolic health development focus.

What is the difference between ACHIEVE and ATTAIN?

ACHIEVE is the trial programme in type 2 diabetes, and ATTAIN is the programme in weight management. ACHIEVE-4 is the cardiovascular safety trial within ACHIEVE. ATTAIN-1 is the main weight management trial in people without diabetes.