SynthesisJournal of the American College of Cardiology2025

Effects of Tirzepatide in Type 2 Diabetes: Individual Variation and Relationship to Cardiometabolic Outcomes.

Arya Aminorroaya, Evangelos K Oikonomou, Dhruva Biswas, Ania M Jastreboff, Rohan Khera

Abstract readMeta-Analysis
In one paragraph

Synthesis in Journal of the American College of Cardiology, 2025. The graph read 3 numbers from its abstract, feeding 2 cells of the map: it supports the treatment in 1, finds no clear difference in 1. Cited by 8 papers.

3numbers the graph read from it
2cells of the map it votes in
8citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

← favours the comparatorfavours the treatment →
0.10.250.51 · no effect
Decreased high-density lipoprotein cholesteroltirzepatide vs placebo or standard antihyperglycemic agentsfavours the comparator · t2d, obesityfeeds one cell of the map
OR 0.660.52 to 0.84
Over a weighted median treatment duration of 41.0 weeks, tirzepatide reduced the odds of all cardiometabolic abnormalities, ranging from 34% reduction for the odds of decreased high-density lipoprotein cholesterol (OR: 0.66 [95% CI: 0.52-0.84]) to 96% reduction in the odds of elevated body mass index (OR: 0.04 [95% CI:0.02-0.08]), and 72% reduction for the odds of MetS (OR: 0.28 [95% CI: 0.24-0.33]).
MetS (≥3 cardiometabolic abnormalities)tirzepatide vs placebo or standard antihyperglycemic agentsfavours the treatment · t2d, obesityfeeds one cell of the map
OR 0.280.24 to 0.33
Over a weighted median treatment duration of 41.0 weeks, tirzepatide reduced the odds of all cardiometabolic abnormalities, ranging from 34% reduction for the odds of decreased high-density lipoprotein cholesterol (OR: 0.66 [95% CI: 0.52-0.84]) to 96% reduction in the odds of elevated body mass index (OR: 0.04 [95% CI:0.02-0.08]), and 72% reduction for the odds of MetS (OR: 0.28 [95% CI: 0.24-0.33]).
Elevated body mass indextirzepatide vs placebo or standard antihyperglycemic agentsfavours the treatment · t2d, obesityfeeds one cell of the map
OR 0.040.02 to 0.08
Over a weighted median treatment duration of 41.0 weeks, tirzepatide reduced the odds of all cardiometabolic abnormalities, ranging from 34% reduction for the odds of decreased high-density lipoprotein cholesterol (OR: 0.66 [95% CI: 0.52-0.84]) to 96% reduction in the odds of elevated body mass index (OR: 0.04 [95% CI:0.02-0.08]), and 72% reduction for the odds of MetS (OR: 0.28 [95% CI: 0.24-0.33]).

clause the extractor read what became the number

2 · Its place on the map

Where it lands on the map

Rows are treatments, columns are outcomes. The coloured squares are the cells this paper feeds, coloured by the vote it casts there. Click one to jump to what this paper adds to it.

supports the treatmentfavours the comparatorno clear differenceread, but no usable result
3 · What it changes

What it adds to each cell

For every cell the paper feeds: the belief in the claim with and without this paper, and this paper's estimate drawn against every other readable study in the cell. The ringed dot is this paper.

GIP/GLP-1 & amylin agonists×lipids

InconclusiveOpen on the map →What to test next →

8 readable studies in this cell: 6 favour the treatment, 1 find no difference, 1 favour the comparator.

Belief with this paper
0.86established · 6 families support, 1 contradict · against placebo
Without itNot a counted family in this claim, so removing it changes nothing.
← favours the comparatorfavours the treatment →
0 · no effect
NCT041846222,539 enrolled · 2019
Δ 7.655.85 to 9.49
NCT04657003938 enrolled · 2021
Δ -4.61-7.11 to -2.03
NCT04660643783 enrolled · 2021
Δ -7.02-9.27 to -4.72
NCT04657016579 enrolled · 2021
Δ -7.79-10.4 to -5.10
NCT03131687318 enrolled · 2017
Δ 0.00-0.10 to 0.00
NCT04844918267 enrolled · 2021
Δ -40.7-50.0 to -29.7
NCT05024032210 enrolled · 2021
Δ -0.31-0.51 to -0.11
NCT0408133755 enrolled · 2020
Δ -1.83-2.60 to -1.06

This paper's own estimate is on a different scale from the rest of the cell, so it is not drawn here.

GIP/GLP-1 & amylin agonists×body weight & composition

SupportsOpen on the map →What to test next →

28 readable studies in this cell: 27 favour the treatment, 1 find no difference, 0 favour the comparator.

Belief with this paper
1.00replicated · 19 families support, 0 contradict · against placebo
Without itNot a counted family in this claim, so removing it changes nothing.
← favours the treatmentfavours the comparator →
0 · no effect
Δ -17.3-18.1 to -16.6
NCT041846222,539 enrolled · 2019
Δ -13.5-14.6 to -12.5
NCT037306622,002 enrolled · 2018
Δ -9.00-9.80 to -8.30
NCT039879191,879 enrolled · 2019
Δ -1.70-2.60 to -0.70
NCT038829701,444 enrolled · 2019
Δ -9.80-10.8 to -8.80
NCT045379231,428 enrolled · 2020
Δ -10.7-11.5 to -9.90
Δ -10.4-11.2 to -9.50
NCT04657003938 enrolled · 2021
Δ -10.1-11.5 to -8.80
NCT04093752917 enrolled · 2019
Δ -6.50-7.40 to -5.60
NCT04660643783 enrolled · 2021
Δ -21.4-22.9 to -20.0
NCT05822830751 enrolled · 2023
Δ -6.50-8.10 to -4.90
NCT04847557731 enrolled · 2021
Δ -11.6-12.8 to -10.4

This paper's own estimate is on a different scale from the rest of the cell, so it is not drawn here.

4 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

5 · Its place in the literature

Who cites it

8 citing papers in PubMed.

  1. Trial
  2. Article
  3. Article
  4. Review
  5. The Bounce-back Effect: What Happens After Cessation of Low-dose Semaglutide in People With HIV.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2026
    Article
  6. Review
  7. Review
  8. Article
6 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

7 · Who and what money

Authors and funding

5 authors.

Arya AminorroayaSection of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA; Cardiovascular Data Science (CarDS) Lab, Yale School of Medicine, New Haven, Connecticut, USA.
Evangelos K OikonomouSection of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA; Cardiovascular Data Science (CarDS) Lab, Yale School of Medicine, New Haven, Connecticut, USA.
Dhruva BiswasSection of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA; Cardiovascular Data Science (CarDS) Lab, Yale School of Medicine, New Haven, Connecticut, USA.
Ania M JastreboffSection of Endocrinology and Metabolism, Department of Medicine, Yale School of Medicine, New Haven, Connecticut, USA; Section of Pediatric Endocrinology, Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA; Yale Obesity Research Center (Y-Weight) Yale School of Medicine, New Haven, Connecticut, USA.
Rohan KheraSection of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA; Cardiovascular Data Science (CarDS) Lab, Yale School of Medicine, New Haven, Connecticut, USA; Center for Outcomes Research and Evaluation (CORE), Yale New Haven Hospital, New Haven, Connecticut, USA; Section of Biomedical Informatics and Data Science, Yale School of Medicine, New Haven, Connecticut, USA; Section of Health Informatics, Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut, USA. Electronic address: rohan.khera@yale.edu.

Funding

Yale Diabetes Research CenterP30DK045735 · NIDDK · YALE UNIVERSITY · PI GERALD I SHULMAN · 1993 to 2026
$44.0M
GLP-1 analogue effects on food cues, stress, motivation for highly palatable foods, and weightR01DK099039 · NIDDK · YALE UNIVERSITY · PI JASTREBOFF, ANIA, SINHA, RAJITA · 2013 to 2024
$6.8M
Obesity complicating type 1 diabetes in young people: Physiology and Impact of GLP-1 analogue anti-obesity treatment on cardiometabolic risk factorsR01DK134398 · NIDDK · YALE UNIVERSITY · PI Michelle Van Name · 2023 to 2026
$2.9M
Deep learning enhanced detection and personalized monitoring of aortic stenosis - The DETECT-AS StudyR01AG089981 · NIA · YALE UNIVERSITY · PI Rohan Khera · 2024 to 2026
$2.4M
Translating Personalized Inference from Randomized Clinical Trials to Real-World Cardiovascular CareR01HL167858 · NHLBI · YALE UNIVERSITY · PI Rohan Khera · 2024 to 2026
$2.3M
Connectome-based neurofeedback of the craving network to reduce food cue-reactivityR01DK136623 · NIDDK · YALE UNIVERSITY · PI Kathleen A. GARRISON, Dustin Scheinost · 2024 to 2026
$1.0M
Evaluating and Improving Utilization of Evidence-Based Medical Therapy in Patients with Heart Failure using Automated Tools in the Electronic Health RecordK23HL153775 · NHLBI · YALE UNIVERSITY · PI KHERA, ROHAN · 2021 to 2025
$918k
A multi-modal approach for efficient, point-of-care screening of hypertrophic cardiomyopathyF32HL170592 · NHLBI · YALE UNIVERSITY · PI OIKONOMOU, EVANGELOS · 2023 to 2024
$166k
NHLBI NIH HHS F32 HL170592NHLBI NIH HHS K23 HL153775NHLBI NIH HHS R01 HL167858NIA NIH HHS R01 AG089981NIDDK NIH HHS P30 DK045735NIDDK NIH HHS R01 DK099039NIDDK NIH HHS R01 DK134398NIDDK NIH HHS R01 DK136623
8 · The paper itself

Abstract

The marked sentences are the ones the graph read a number from.

backgroundTirzepatide-a dual GIP/GLP-1 receptor agonist-exerts pleiotropic effects on cardiometabolic health.

objectivesThe authors sought to investigate the efficacy of tirzepatide in improving different cardiometabolic risk factors across individuals and subpopulations.

methodsUsing an independent, global data-sharing and analytics platform, we performed an individual participant data meta-analysis by pooling data from 7 Phase 3 randomized clinical trials that compared tirzepatide with placebo or standard antihyperglycemic agents in individuals with type 2 diabetes. The study outcomes were the presence of a range of cardiometabolic abnormalities, representing components of metabolic syndrome (MetS) (elevated waist circumference, triglycerides, blood pressure, and fasting blood glucose, and decreased high-density lipoprotein cholesterol), as well as elevated body mass index and MetS (≥3 cardiometabolic abnormalities). Outcomes were modeled using mixed-effects models, with inverse probability weighting to account for study design differences.

resultsWe included 7,805 participants with a weighted median age of 59 years (Q1-Q3: 51-66 years) and 43.2% women. Over a weighted median treatment duration of 41.0 weeks, tirzepatide reduced the odds of all cardiometabolic abnormalities, ranging from 34% reduction for the odds of decreased high-density lipoprotein cholesterol (OR: 0.66 [95% CI: 0.52-0.84]) to 96% reduction in the odds of elevated body mass index (OR: 0.04 [95% CI:0.02-0.08]), and 72% reduction for the odds of MetS (OR: 0.28 [95% CI: 0.24-0.33]). Tirzepatide's superior efficacy in resolving MetS was consistent across demographic and clinical subpopulations, with higher efficacy in age <65 years vs ≥65 years, and in individuals without vs with baseline use of sodium-glucose cotransporter 2 inhibitors (P for interaction = 0.008 and 0.009, respectively).

conclusionsThis pooled analysis suggests that tirzepatide may improve cardiometabolic abnormalities and resolve MetS in individuals with type 2 diabetes.

Indexed as

Diabetes Mellitus, Type 2Hypoglycemic AgentsMetabolic SyndromeTirzepatideAgedCardiometabolic Risk FactorsFemaleHumansMaleMiddle AgedRandomized Controlled Trials as TopicTreatment OutcomeHypoglycemic AgentsTirzepatidediabetes mellitus type 2heart disease risk factorsmeta-analysisrandomized controlled trialtirzepatide

Identifiers

PMID40368575
PMCPMC12186526

What OpenQuestion holds

Texttitle and abstract
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.