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Study · Randomized controlled trial · n = 2,726 · 2026

5 results

Cardiovascular safety of orforglipron versus insulin glargine in adults with type 2 diabetes at increased cardiovascular risk (ACHIEVE-4): a phase 3, event-driven, randomised, open-label, non-inferiority, active comparator trial.

Klein KR, Wysham C, Tuttle KR, Davies MJ, Cox D, Chen J, Wu WS, Denning M, Liu R, Ludwig L, Meskimen ER

Lancet (London, England)30 Sept 2026

PMID42815506 (opens in a new tab)DOI10.1016/s0140-6736(26)01865-9 (opens in a new tab)PepBankPUB-42815506
Publisher pagePubMedAsk about this study
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Summary

The text of this summary is not shown here, because the article license does not allow reuse. Read it at the source (opens in a new tab)

Text rights: Publisher copyright. Results still quote short attributed sentences.

Results from this study5

5 results from studies that gave the peptide. 5 results from people.

  1. 01HumanRandomized controlled trialSafety outcome

    In adults with diabetes at increased cardiovascular risk, orforglipron was non-inferior to insulin glargine for four-component major adverse cardiovascular events.

    In plain wordsIn adults with diabetes at increased cardiovascular risk, orforglipron met the non-inferiority criterion versus insulin glargine for major cardiovascular events.

    Peptide
    Orforglipron
    Outcome
    No significant changeFour-component major adverse cardiovascular events
    Study

    n = 2,701

    Comparator
    Insulin glargine
    Analysis
    Primary
    Outcome group
    Cardiovascular events · Cardiovascular
    Studied dose
    Maximum tolerated dose up to 36 mg capsule, equivalent to 17.2 mg tablet, once daily · oral · Median follow-up of 2 yearsAs given in this study (human).

    Measurements

    MACE-4
    4.2%
    orforglipron
    MACE-4
    5%
    insulin glargine
    Hazard ratio
    0.84 ratio
    orforglipron versus insulin glargine
    MACE-4 events
    57 participants
    orforglipron
    MACE-4 events
    67 participants
    insulin glargine
    Hazard ratio 95% CI
    0.59 to 1.2 ratio
    orforglipron versus insulin glargine
    P value
    < 0.0001 P
    non-inferiority
    Participants analysed for MACE-4
    1358 participants
    orforglipron

    1 more measurement in the study.

    Source sentences

    Summary
    Over a median follow-up of 2 years, the primary outcome occurred in 57 (4·2%) of 1358 orforglipron participants and 67 (5·0%) of 1343 insulin glargine participants, showing non-inferiority to insulin glargine for MACE-4 (HR 0·84; 95% CI 0·59-1·20; p<0·0001 for non-inferiority).
    2 context sentences
    Summary · context
    This event-driven, phase 3, multicentre, randomised, open-label, active comparator, parallel-group study was conducted in 317 sites across 16 countries and territories.
    Summary · context
    All participants had established cardiovascular or chronic kidney disease.
  2. 02HumanRandomized controlled trialSafety outcome

    In adults with diabetes at increased cardiovascular risk, gastrointestinal adverse events were 62.1% with orforglipron versus 14.2% with insulin glargine.

    In plain wordsIn adults with diabetes at increased cardiovascular risk, gastrointestinal adverse events were more frequent with orforglipron than insulin glargine.

    Peptide
    Orforglipron
    Outcome
    IncreaseGastrointestinal adverse events
    Study

    n = 2,726

    Comparator
    Insulin glargine
    Outcome group
    Gastrointestinal adverse events · Gastrointestinal
    Studied dose
    Maximum tolerated dose up to 36 mg capsule, equivalent to 17.2 mg tablet, once daily · oral · Median follow-up of 2 yearsAs given in this study (human).

    Measurements

    Gastrointestinal adverse events
    62.1%
    orforglipron
    Gastrointestinal adverse events
    14.2%
    insulin glargine
    Gastrointestinal adverse events
    851 participants
    orforglipron
    Gastrointestinal adverse events
    193 participants
    insulin glargine
    Participants assessed for gastrointestinal adverse events
    1371 participants
    orforglipron
    Participants assessed for gastrointestinal adverse events
    1355 participants
    insulin glargine

    Source sentences

    Summary
    Gastrointestinal adverse events were reported in 851 (62·1%) of 1371 orforglipron participants and 193 (14·2%) of 1355 insulin glargine participants;
    2 context sentences
    Summary · context
    This event-driven, phase 3, multicentre, randomised, open-label, active comparator, parallel-group study was conducted in 317 sites across 16 countries and territories.
    Summary · context
    All participants had established cardiovascular or chronic kidney disease.
  3. 03HumanRandomized controlled trialSafety outcome

    In adults with diabetes at increased cardiovascular risk, significant or severe hypoglycaemia was 6.8% with orforglipron versus 19.2% with insulin glargine.

    In plain wordsIn adults with diabetes at increased cardiovascular risk, significant or severe hypoglycaemia occurred less frequently with orforglipron than insulin glargine.

    Peptide
    Orforglipron
    Outcome
    DecreaseClinically significant or severe hypoglycaemia
    Study

    n = 2,726

    Comparator
    Insulin glargine
    Outcome group
    Adverse events · Metabolic and weight
    Studied dose
    Maximum tolerated dose up to 36 mg capsule, equivalent to 17.2 mg tablet, once daily · oral · Median follow-up of 2 yearsAs given in this study (human).

    Measurements

    Significant or severe hypoglycaemia
    6.8%
    orforglipron
    Significant or severe hypoglycaemia
    19.2%
    insulin glargine
    Significant or severe hypoglycaemia
    93 participants
    orforglipron
    Significant or severe hypoglycaemia
    260 participants
    insulin glargine
    Participants assessed for clinically significant or severe hypoglycaemia
    1371 participants
    orforglipron
    Participants assessed for clinically significant or severe hypoglycaemia
    1355 participants
    insulin glargine

    Source sentences

    Summary
    clinically significant or severe hypoglycaemia (glucose <3 mmol/L [54 mg/dL]) occurred in 93 (6·8%) of 1371 orforglipron participants and 260 (19·2%) of 1355 insulin glargine participants.
    2 context sentences
    Summary · context
    This event-driven, phase 3, multicentre, randomised, open-label, active comparator, parallel-group study was conducted in 317 sites across 16 countries and territories.
    Summary · context
    All participants had established cardiovascular or chronic kidney disease.
  4. 04HumanRandomized controlled trialSafety outcome

    In adults with diabetes at increased cardiovascular risk, deaths were 1.4% with orforglipron versus 3.2% with insulin glargine.

    In plain wordsIn adults with diabetes at increased cardiovascular risk, fewer deaths occurred with orforglipron than insulin glargine.

    Peptide
    Orforglipron
    Outcome
    DecreaseAll-cause deaths
    Study

    n = 2,726

    Comparator
    Insulin glargine
    Outcome group
    Mortality · Whole body
    Studied dose
    Maximum tolerated dose up to 36 mg capsule, equivalent to 17.2 mg tablet, once daily · oral · Median follow-up of 2 yearsAs given in this study (human).

    Measurements

    Deaths
    19 participants
    orforglipron
    Deaths
    1.4%
    orforglipron
    Deaths
    3.2%
    insulin glargine
    Deaths
    43 participants
    insulin glargine
    Participants assessed for all-cause deaths
    1371 participants
    orforglipron
    Participants assessed for all-cause deaths
    1355 participants
    insulin glargine
    All-cause deaths
    62 deaths
    all study treatment arms

    Source sentences

    Summary
    62 deaths were reported during the study: 19 (1·4%) of 1371 participants receiving orforglipron and 43 (3·2%) of 1355 participants receiving insulin glargine; all deaths except one (in the insulin glargine group) were deemed unrelated to treatment.
    2 context sentences
    Summary · context
    This event-driven, phase 3, multicentre, randomised, open-label, active comparator, parallel-group study was conducted in 317 sites across 16 countries and territories.
    Summary · context
    All participants had established cardiovascular or chronic kidney disease.
  5. 05HumanRandomized controlled trialSafety outcome

    In adults with diabetes at increased cardiovascular risk, all deaths in the orforglipron arm were deemed unrelated to treatment.

    In plain wordsIn adults with diabetes at increased cardiovascular risk, all deaths during orforglipron treatment were deemed unrelated to treatment.

    Peptide
    Orforglipron
    Outcome
    Not applicableDeath treatment relatedness
    Study

    n = 1,371

    Outcome group
    Mortality · Whole body
    Studied dose
    Maximum tolerated dose up to 36 mg capsule, equivalent to 17.2 mg tablet, once daily · oral · Median follow-up of 2 yearsAs given in this study (human).

    Measurements

    Deaths deemed unrelated to treatment
    19 deaths
    orforglipron arm

    Source sentences

    Summary
    62 deaths were reported during the study: 19 (1·4%) of 1371 participants receiving orforglipron and 43 (3·2%) of 1355 participants receiving insulin glargine; all deaths except one (in the insulin glargine group) were deemed unrelated to treatment.
    2 context sentences
    Summary · context
    This event-driven, phase 3, multicentre, randomised, open-label, active comparator, parallel-group study was conducted in 317 sites across 16 countries and territories.
    Summary · context
    All participants had established cardiovascular or chronic kidney disease.

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Registered trials1

Trials this study reports on, or that list this study as a reference. Registry data from ClinicalTrials.gov.

1 trial · 1 completed · source ClinicalTrials.gov (opens in a new tab)

CompletedPhase 3NCT05803421

A Study of Daily Oral Orforglipron (LY3502970) Compared With Insulin Glargine in Participants With Type 2 Diabetes and Obesity or Overweight at Increased Cardiovascular Risk

Eli Lilly and Companyn = 2,7493 Apr 2023 to 16 Mar 2026

Type 2 Diabetes · Obesity · Overweight or Obesity · Overweight · Cardiovascular Diseases · Chronic Kidney Disease

Trial pageClinicalTrials.govUpdated 17 Apr 2026

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

  1. Version 2Current

    14 Oct 2026, 05:02 UTC

    Study results updated

  2. Version 1

    14 Oct 2026, 01:46 UTC

    First added · source update from Europe PMC

Subjects

Terms as the source lists them.

Publication types

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