Treatment with orforglipron, an oral glucagon like peptide-1 receptor agonist, is associated with improvements of CV risk biomarkers in participants with type 2 diabetes or obesity without diabetes
- Design
- Randomized trial · 361 participants · Mixed outcome
- Match to healthy normal-weight adults aged 55–75
- Different population[Auto] Participants had obesity/overweight without diabetes (mean age 59; mean BMI 35.3); effects may be mediated by weight loss.
- Could weight loss explain it?
- Possibly[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.
- Study tier
- Study tier 2[Auto] Randomized trial of moderate size; outcome type and follow-up limit certainty (auto-provisional).
- Assessment
- Version 1 · automatic, not yet reviewed by a person · Sep 13, 2026
Study facts come from the paper. Population match, weight-loss explanation and study tier are our judgments, made against the reference group of healthy normal-weight adults aged 55–75.
[Auto, unreviewed; quoted from abstract conclusions] Orforglipron treatment was associated with beneficial changes in CV risk markers in participants with T2D and in participants with overweight/obesity without T2D. (Clinicaltrials.gov: NCT05048719, NCT05051579).
01Findings
What the study reported
- Drugs
- Dulaglutide, Orforglipron
- Dose
- 45 mg
- Route
- subcutaneous
- Comparator
- placebo
- Primary outcome
- Not extracted
- Effect
- Not extracted
- 95% confidence interval
- Not extracted
- Follow-up
- 59 years
- Adverse events
- Not extracted
- Limitations
- Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.
Who was studied
- Mean age
- 59
- Bmi mean
- 35.3
- Bmi min
- 35.3
- Obesity status
- obesity/overweight present (all or most)
- Diabetes status
- excluded (no diabetes)
- Sample size
- 361
Study quality details
- Study design
- Randomized controlled trial
- Sample size
- 361
- Randomization
- yes
- Blinding
- not stated
- Comparator
- placebo
- Follow up duration
- 59 years
- Outcome type
- mixed
- Replication
- not assessed (auto)
- Consistency with other evidence
- not assessed (auto)
- Population applicability
- INDIRECT
- Statistical precision
- not extracted
- Funding conflicts
- unclear
- Peer review status
- yes
01bRisk of bias
How much the result can be relied on
Risk of bias is judged per result, not per paper: the same study can report one marker at low risk and another at high. Two reviewers assess each result independently against a written guide, and every domain judgment below carries its reasoning and the sentences it rests on.
These words are not quality scores. On the RoB 2 scale, High risk of bias is the worst rating a result can receive and Low risk of bias is the best — the opposite of how the same words read on some other scales. Levels are always written out in full here for that reason.
Assessed, not settled (4)
Recorded rather than omitted. Leaving these out would make the appraisal look cleaner than it is, and a disagreement between two careful readers is itself worth knowing.
hsCRP, percent change from baseline, orforglipron vs placebo · week 36
Assessed, not settled · RoB 2 · Two reviewers reached different judgments and nothing has settled it
This result has no overall judgment, because the two independent reviews did not reach one. Both readings are shown. The domains they did agree on are below.
| Where they differ | The two readings |
|---|---|
| D3 · Missing outcome data | One reviewer: Low risk of bias The other: Some concerns about risk of bias |
| D5 · Selection of the reported result | One reviewer: Some concerns about risk of bias The other: High risk of bias |
| Overall | One reviewer: Some concerns about risk of bias The other: High risk of bias |
| Domain | Judgment and reasoning |
|---|---|
| D1 · Randomisation process Low risk of bias | Parent trial identified by registration number (NCT05051579) and by its primary publication (ref 25, Wharton et al., NEJM 2023); random assignment and stratification are described and baseline characteristics are balanced. The concealment mechanism is described in no retrieved source; under v1.2 item 6 it is PRESUMED (not verified) from the parent trial's character as a multicentre industry (Eli Lilly) phase 2 registration trial, identified in the Methods section by NCT number and reference. Baseline age differs somewhat across dose groups (49.6 to 57.7 years) but the paper states balance and this is within chance for five small arms; not treated as rebutting.Participants were randomly assigned to receive once daily orforglipron (12, 24, 36, or 45 mg) or placebo for 36 weeks as an adjunct to lifestyle intervention ... Randomization was stratified by baseline BMI (above or below 35 kg/m 2 at the screening visit and by sex. A second trial was conducted in adults with obesity (body mass index (BMI) ≥ 30 kg/m 2 ), or with overweight (BMI 27 to 30 kg/m 2 ) plus at least one weight-related complication, excluding diabetes ( NCT05051579 ). |
| D2 · Deviations from intended interventions Some concerns about risk of bias | Same non-ITT handling: data after permanent discontinuation of study drug are excluded, over a longer (36-week) exposure, in a trial where GI adverse events were the most common adverse effect with active drug. Per-arm discontinuation numbers are not reported in any retrieved source, so balance cannot be checked.This analysis set included all randomized participants with at least one dose of study drug, excluding data after the initiation of glycemic rescue medication (T2D study) or after permanent discontinuation of the study drug (both studies). in these trials gastrointestinal events were the most common adverse effects in patients receiving orforglipron, consistent with the GLP-1 receptor agonist class |
| D3 · Missing outcome data Low risk of bias | 234 of 272 randomized (86%) had evaluable data, i.e. ~14% without the outcome — below the 20% threshold. Per-arm missingness is not reported so the 5-point prong cannot be evaluated; under v1.1 ruling 2 the thresholds are decisive in both directions and neither trips on the evidence available, so D3 is Low. The unreported arm split at 14% overall missingness is recorded in limitations as the point where a second reviewer could reasonably diverge.Between September 2021 and late November 2022, 272 participants were randomized in the obesity study; 234 (86%) had evaluable data. |
| D4 · Measurement of the outcome Low risk of bias | Central-laboratory hsCRP (Roche) run at Lilly Research Laboratories for both trials, identical across arms; objective measure, no reported assay change.For both trials, hsCRP (Roche, Indianapolis, IN) and IL-6 (MesoScalse Discovery, Rockville, MD) were measured at Lilly Research Laboratories. |
| D5 · Selection of the reported result Some concerns about risk of bias | Explicitly exploratory added-biomarker analysis, no multiplicity adjustment across many biomarkers and four active doses, and a dose-inconsistent significance pattern reported (significant vs placebo at 12, 24 and 45 mg but not 36 mg), which is the shape multiplicity produces. The parent protocol and SAP are not retrievable (Vivli-gated), so prespecification is unverifiable rather than affirmatively absent; domain floor Some concerns, not ruling-3 High.In the obesity trial, significant decreases in hsCRP were observed for all doses of orforglipron with effects ranging from − 27.1 to − 41.9%, statistically different from placebo (− 2.2%) at 12, 24, and 45 mg As these were exploratory analyses, no adjustments for multiple comparisons were made. |
hsCRP, percent change from baseline, orforglipron vs placebo · week 26
Assessed, not settled · RoB 2 · Two reviewers reached different judgments and nothing has settled it
This result has no overall judgment, because the two independent reviews did not reach one. Both readings are shown. The domains they did agree on are below.
| Where they differ | The two readings |
|---|---|
| D3 · Missing outcome data | One reviewer: Low risk of bias The other: Some concerns about risk of bias |
| D5 · Selection of the reported result | One reviewer: Some concerns about risk of bias The other: High risk of bias |
| Overall | One reviewer: Some concerns about risk of bias The other: High risk of bias |
| Domain | Judgment and reasoning |
|---|---|
| D1 · Randomisation process Low risk of bias | Randomized parent trial identified by registration number (NCT05048719) and by its primary publication (ref 26, Frias et al., Lancet 2023); randomization and its stratification are described, and baseline characteristics are balanced across arms. The allocation-concealment MECHANISM is not described in any retrieved source; under v1.2 item 6 concealment is PRESUMED (not verified) from the parent trial's character as a large multicentre industry (Eli Lilly) phase 2 registration trial, the parent being identified by the NCT number and reference 25/26 cited in the Methods. Nothing in the retrieved sources rebuts the presumption.The T2D study was a randomized clinical trial (RCT) in which participants were assigned to placebo, once weekly dulaglutide 1.5 mg, or once daily orforglipron (3, 12, 24, 36, or 45 mg) for 26 weeks ( NCT05048719 ). Randomization was stratified by country and HbA 1c stratum (above or below 8.0%) at their screening visit. Baseline demographics and characteristics were well balanced across the treatment groups for the evaluable subgroups from both trials as shown in Tables 1 and 2 . |
| D2 · Deviations from intended interventions Some concerns about risk of bias | The analysis is not by assignment as randomized: the analysis set censors data after glycemic rescue medication or after permanent study-drug discontinuation, which is an on-treatment rather than an ITT handling of the assigned effect. Because GI adverse events are the commonest adverse effect with orforglipron and are drug-related, this censoring can be differential by arm; no per-arm discontinuation or rescue counts are reported in any retrieved source, so imbalance can be neither confirmed nor excluded. Per the domain rule, D2 is judged on discontinuation imbalance and ITT handling, not unblinding. Deviation from intended intervention beyond that is not reported.This analysis set included all randomized participants with at least one dose of study drug, excluding data after the initiation of glycemic rescue medication (T2D study) or after permanent discontinuation of the study drug (both studies). As previously reported, in these trials gastrointestinal events were the most common adverse effects in patients receiving orforglipron, consistent with the GLP-1 receptor agonist class [ 25 , 26 ]. |
| D3 · Missing outcome data Low risk of bias | 361 of 383 randomized participants (94%) had evaluable biomarker data, i.e. ~5.7% without the outcome, below the 20% threshold. Per-arm missingness is not reported, so the 5-point arm-difference prong cannot be evaluated directly, but the overall 6% ceiling bounds any arm difference to a small value. Under v1.1 ruling 2 the thresholds are decisive: neither prong trips and no specific contrary evidence of value-dependent missingness is presented, so D3 is Low. The absence of an MNAR sensitivity analysis is recorded in limitations, not as a downgrade.From September 2021 through September 2022, 383 participants were enrolled and randomly assigned to a treatment group in the T2D study; 361 (94%) participants had evaluable biomarker data for the current analyses. |
| D4 · Measurement of the outcome Low risk of bias | hsCRP is an objective biomarker measured by a single central laboratory (Lilly Research Laboratories, Roche assay) identically in all arms; no indication of an assay change partway through or of arm-differential measurement. Per the domain rule, central-lab hs-CRP is Low.For both trials, hsCRP (Roche, Indianapolis, IN) and IL-6 (MesoScalse Discovery, Rockville, MD) were measured at Lilly Research Laboratories. |
| D5 · Selection of the reported result Some concerns about risk of bias | The paper states its analyses are exploratory and that the inflammatory biomarkers were ADDED to previously reported outcomes; no prespecification of the hsCRP analysis in the parent protocol or SAP is claimed, and no adjustment for multiple comparisons was made across many biomarkers and six treatment arms. The protocol and SAP were not retrieved (available only on request via Vivli), so prespecification is unverifiable rather than affirmatively absent; v1.1 ruling 3 (High) therefore does not apply, and the domain rule floor of "at least Some concerns" governs. The paper reports percent change only, without an alternative transformation being shown and one selected for emphasis.In order to assess treatment effects on cardiovascular risk, the current analyses expanded upon the evaluation of changes in blood pressure and lipid parameters that have been previously reported [ 25 , 26 ], and added evaluation of additional biomarkers of CV risk (ApoB, ApoC3, NT-pro-BNP, hsCRP and IL-6) As these were exploratory analyses, no adjustments for multiple comparisons were made. |
IL-6, percent change from baseline, orforglipron vs placebo (36 mg dose significant vs placebo; other doses not) · week 36
Assessed, not settled · RoB 2 · Two reviewers reached different judgments and nothing has settled it
This result has no overall judgment, because the two independent reviews did not reach one. Both readings are shown. The domains they did agree on are below.
| Where they differ | The two readings |
|---|---|
| D3 · Missing outcome data | One reviewer: Low risk of bias The other: Some concerns about risk of bias |
| D5 · Selection of the reported result | One reviewer: Some concerns about risk of bias The other: High risk of bias |
| Overall | One reviewer: Some concerns about risk of bias The other: High risk of bias |
| Domain | Judgment and reasoning |
|---|---|
| D1 · Randomisation process Low risk of bias | Same randomization as O1_obesity; parent trial identified by NCT05051579 and ref 25. Concealment PRESUMED (not verified) under v1.2 item 6 from the parent trial's character as a multicentre industry registration trial, identified in the Methods section; baseline balance is stated and does not rebut it.Participants were randomly assigned to receive once daily orforglipron (12, 24, 36, or 45 mg) or placebo for 36 weeks as an adjunct to lifestyle intervention Baseline demographics and characteristics were well balanced across the treatment groups for the evaluable subgroups from both trials as shown in Tables 1 and 2 . |
| D2 · Deviations from intended interventions Some concerns about risk of bias | Identical non-ITT censoring after permanent study-drug discontinuation, with no per-arm discontinuation figures available to assess imbalance.excluding data after the initiation of glycemic rescue medication (T2D study) or after permanent discontinuation of the study drug (both studies) |
| D3 · Missing outcome data Low risk of bias | Same 86% evaluable accounting as O1_obesity (~14% missing), under the 20% threshold; no separate IL-6 missingness reported. Thresholds decisive.272 participants were randomized in the obesity study; 234 (86%) had evaluable data. |
| D4 · Measurement of the outcome Low risk of bias | Central-laboratory IL-6 (MesoScale Discovery) measured at Lilly Research Laboratories identically across arms; objective assay, no reported change.For both trials, hsCRP (Roche, Indianapolis, IN) and IL-6 (MesoScalse Discovery, Rockville, MD) were measured at Lilly Research Laboratories. |
| D5 · Selection of the reported result Some concerns about risk of bias | Exploratory added biomarker, no multiplicity adjustment, and the reported result is a single significant dose (36 mg) out of four, against a placebo change of the same order (− 7.1%) — an isolated significant cell among many unadjusted comparisons. Protocol/SAP not retrievable, so prespecification is unverifiable; domain floor Some concerns applies rather than High.IL-6 changes ranged from − 8.6 to − 12.6% but only the effect of 36 mg orforglipron (− 12.6%) was statistically different from placebo (− 7.1%) As these were exploratory analyses, no adjustments for multiple comparisons were made. |
IL-6, percent change from baseline, orforglipron vs placebo (reported as not significantly changed from baseline at any dose) · week 26
Assessed, not settled · RoB 2 · Two reviewers reached different judgments and nothing has settled it
This result has no overall judgment, because the two independent reviews did not reach one. Both readings are shown. The domains they did agree on are below.
| Where they differ | The two readings |
|---|---|
| D3 · Missing outcome data | One reviewer: Low risk of bias The other: Some concerns about risk of bias |
| D5 · Selection of the reported result | One reviewer: Some concerns about risk of bias The other: High risk of bias |
| Overall | One reviewer: Some concerns about risk of bias The other: High risk of bias |
| Domain | Judgment and reasoning |
|---|---|
| D1 · Randomisation process Low risk of bias | Same randomization as O1_T2D. Parent trial identified by NCT05048719 and ref 26; concealment is PRESUMED (not verified) from the parent's character as a large multicentre industry registration trial, per v1.2 item 6, with the Methods section as the source identifying the parent. Baseline balance supports rather than rebuts the presumption.The T2D study was a randomized clinical trial (RCT) in which participants were assigned to placebo, once weekly dulaglutide 1.5 mg, or once daily orforglipron (3, 12, 24, 36, or 45 mg) for 26 weeks ( NCT05048719 ). Baseline demographics and characteristics were well balanced across the treatment groups for the evaluable subgroups from both trials as shown in Tables 1 and 2 . |
| D2 · Deviations from intended interventions Some concerns about risk of bias | Identical analysis-set construction to O1_T2D: on-treatment censoring after rescue medication or permanent discontinuation rather than ITT, with no per-arm discontinuation figures reported to show whether the censoring was balanced.This analysis set included all randomized participants with at least one dose of study drug, excluding data after the initiation of glycemic rescue medication (T2D study) or after permanent discontinuation of the study drug (both studies). |
| D3 · Missing outcome data Low risk of bias | Same evaluable-sample accounting as O1_T2D (94% of randomized), below the 20% threshold; IL-6 is not separately reported as having additional missingness in any retrieved source. Thresholds decisive (v1.1 ruling 2).383 participants were enrolled and randomly assigned to a treatment group in the T2D study; 361 (94%) participants had evaluable biomarker data for the current analyses. |
| D4 · Measurement of the outcome Low risk of bias | IL-6 measured by a single central laboratory using one validated platform (MesoScale Discovery) identically in both arms; objective assay, no reported change of method.For both trials, hsCRP (Roche, Indianapolis, IN) and IL-6 (MesoScalse Discovery, Rockville, MD) were measured at Lilly Research Laboratories. |
| D5 · Selection of the reported result Some concerns about risk of bias | IL-6 is one of the biomarkers explicitly added to this exploratory analysis, with no multiplicity adjustment and no retrievable protocol or SAP to confirm prespecification. Prespecification is unverifiable, not affirmatively absent, so the domain floor (Some concerns) applies rather than ruling 3's High. Note the result assessed here is null, which reduces but does not remove the concern about selective emphasis.added evaluation of additional biomarkers of CV risk (ApoB, ApoC3, NT-pro-BNP, hsCRP and IL-6) in participants who received placebo, dulaglutide, or orforglipron during the T2D and obesity trials As these were exploratory analyses, no adjustments for multiple comparisons were made. |
02Funding
Funding and conflicts
- Funding
- not reported in abstract
- Industry funded
- Unclear
- Manufacturer
- Novo Nordisk, Eli Lilly, Lilly, Sanofi, Boehringer Ingelheim, Pfizer, Hanmi
- Sponsor role
- not reported in abstract
- Author conflicts
- Declarations. Ethical approval and informed consent: The trials adhered to the principles of the Declaration of Helsinki and received approval from an independent ethics committee or institutional review board at each participating site. Participants provided informed consent for study participation. Conflict of interest: SW reports receiving grants from Novo Nordisk, speaking engagement fees from Bausch and Lomb, Eli Lilly and Company, Novo Nordisk, advisory board fees from Biohaven Pharmaceuticals, Inc., Boehringer Ingelheim, Eli Lilly and Company, Novo Nordisk; JR reports receiving grants from Applied Therapeutics, Boehringer Ingelheim, Eli Lilly and Company, Hanmi Pharmaceutical Co. Ltd, Intarcia, Novartis, Novo Nordisk, Oramed, Pfizer, Sanofi US Services Inc, travel support from applied therapeutics, Boehringer Ingelheim, Intarcia, Novo Nordisk, Oramed, Sanofi US Services Inc, serves on scientific advisory boards for applied therapeutics, Boehringer Ingelheim, Eli Lilly and Company, Intarcia, Novo Nordisk, Oramed, Sanofi US Services Inc, Zealand, speaker fees honoraria from Boehringer Ingelheim, Novo Nordisk, Sanofi US Services Inc, and consulting fees for Hanmi Pharmaceutical Co. MK was an employee at Eli Lilly, during which she contributed to this article. MK is currently employed at Pfizer Inc. which provided no review of, or other support for, this article. KM, YL, KD, JW, HB, VP, and CK are employees and shareholders of Eli Lilly and Company.
- Independent replication
- unknown
- Notes
- Authors declare relationships with the drug's manufacturer: Eli Lilly, Eli Lilly
Funding is shown on every study and never used to score it.
04Source
The source, as retrieved
Abstract
[BACKGROUND] Orforglipron, a novel oral, non-peptide glucagon like peptide-1 (GLP-1) receptor agonist, has demonstrated efficacy in improving body weight reduction and glycemic control. However, its potential benefits in improving cardiovascular (CV) risk factors have yet to be determined. We assessed the effect of orforglipron in participants with type 2 diabetes (T2D) and/or overweight or obesity on blood pressure, lipid, and inflammatory biomarkers associated with risk for major adverse cardiovascular events. [METHODS] Using data from participants with available samples from Phase 2 trials of orforglipron in participants with T2D (N = 361) or with overweight or obesity without diabetes mellitus (N = 234), we performed an exploratory analysis of changes in CV risk markers. For the T2D study, participants mean age 59 years, 40% were assigned female at birth with a mean HbA1c of 8.1% and mean BMI of 35.3 kg/m2; they received once daily orforglipron doses (3, 12, 24, 36, or 45 mg) or once weekly subcutaneous dulaglutide 1.5 mg, or placebo. In the obesity study, participants had a mean age 54 years, 60% were assigned female at birth, and mean BMI was 37.9 kg/m2; they received once daily orforglipron (12, 24, 36, or 45 mg) or placebo. The change from baseline at 26 weeks (T2D study) or 36 weeks (obesity study) in blood pressure, lipids (cholesterol, triglycerides, Apolipoprotein B (ApoB), Apolipoprotein C3 (ApoC3), N-terminal pro-b-type natriuretic peptide (NT-pro-BNP), and inflammatory biomarkers (high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6)) were assessed. [RESULTS] Significant placebo-adjusted decreases from baseline in blood pressure, low-density lipoprotein (LDL) cholesterol, triglycerides, ApoB, ApoC3, and hsCRP were observed following orforglipron treatment in participants with T2D and/or overweight or obesity. In both studies, improvements in blood pressure, lipid parameters, and most of the evaluated biomarkers were of similar magnitude after treatment with 12 mg orforglipron as with 24, 36, and 45 mg. [CONCLUSION] Orforglipron treatment was associated with beneficial changes in CV risk markers in participants with T2D and in participants with overweight/obesity without T2D. (Clinicaltrials.gov: NCT05048719, NCT05051579).
Where this record came from
| Source | Retrieved | Identifier |
|---|---|---|
| pubmed | Sep 13, 2026 | 40481478 first ingestion |