In type 1 diabetes (T1D), preservation of β-cell function is correlated with improved long-term clinical outcomes, such as better glycemic control, fewer microvascular complications, and lower hypoglycemia risk. However,...In type 1 diabetes (T1D), preservation of β-cell function is correlated with improved long-term clinical outcomes, such as better glycemic control, fewer microvascular complications, and lower hypoglycemia risk. However, current interventions thus far are unable to stop the destruction of β-cells after clinical onset of T1D. Disease-modifying therapies must follow a long, complex regulatory path requiring clinical end points for full regulatory approval. To facilitate the development of new therapies, regulatory bodies should reinstate C-peptide, the most reliable and feasible measure of endogenous insulin secretion, as an end point for full, unconditional approval. T1D organizations and networks have accepted C-peptide as a primary efficacy end point for years, as did the U.S. Food and Drug Administration (FDA) from 2008 to 2023, followed by its failure to appear on the Surrogate Endpoint Table by the FDA, for unclear reasons. A C-peptide-based policy would substantially decrease the time for disease-modifying therapies to become available and increase investment in them, improving clinical outcomes and easing burden in those living with T1D.
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects the majority of individuals with diabetes and severe obesity, and is one of the most common indications for liver transplantation in the U.S. Emerg...Metabolic dysfunction-associated steatotic liver disease (MASLD) affects the majority of individuals with diabetes and severe obesity, and is one of the most common indications for liver transplantation in the U.S. Emerging evidence underscores the synergistic and detrimental impact of alcohol and metabolic disease on liver and overall health. In 2023, the nomenclature for steatotic liver disease was revised to include a new subcategory known as MetALD (metabolic dysfunction- and alcohol-associated liver disease), which acknowledges alcohol use as a cofactor in liver injury alongside metabolic risk factors. This review offers key insights into the role of alcohol use as both a direct hepatotoxin and an indirect contributor to insulin resistance, dyslipidemia, and obesity. Notably, even light-to-moderate alcohol intake may hasten MASLD progression to cirrhosis and hepatocellular carcinoma, especially in individuals with existing metabolic disease, and can worsen cardiovascular disease risk. MetALD is associated with increased all-cause, cancer-related, and liver-related mortality in comparison with MASLD, reinforcing the importance of accurate alcohol assessment in managing diabetes and obesity. Diagnosis now requires stratifying alcohol use and integrating tools such as the Alcohol Use Disorders Identification Test (AUDIT) questionnaire and phosphatidylethanol testing. The caveats and use of these tools in clinical practice are discussed. Management strategies for MASLD focus on lifestyle changes, weight loss, and medications such as glucagon-like peptide 1 receptor agonists, with emerging evidence suggesting that these agents may also reduce alcohol consumption. However, treatment data on MetALD are limited. This review offers practical guidance for health care professionals on how to integrate alcohol use into existing, recommended MASLD care pathways.
Hitt TA, Kelly A, Stefanovski D
… +9 more, Zemel BS, McCarter R, Yanek L, Zandieh G, Özdemir I, Kamel IR, Hui SCN, Barker P, Magge SN
Diabetes Care
· 2026 Jun · PMID 42008009
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OBJECTIVE: South Asian individuals are at elevated diabetes risk attributed to insulin resistance, insulin deficiency, and ectopic fat. The CHARISMA study compared metabolic mechanisms in South Asian, White, and African...OBJECTIVE: South Asian individuals are at elevated diabetes risk attributed to insulin resistance, insulin deficiency, and ectopic fat. The CHARISMA study compared metabolic mechanisms in South Asian, White, and African American adolescents and young adults (AYAs) to investigate early diabetes risk in South Asian individuals. RESEARCH DESIGN AND METHODS: AYAs aged 12-21 years with a BMI ≥23 kg/m2 or ≥80 percentile underwent MRI/MRS to quantify fat; OGTT with minimal modeling to calculate insulin sensitivity (Si), AUC insulin secretory rate (ISR), and disposition index (DI); DXA; and glucose-potentiated arginine stimulation test. RESULTS: South Asian AYAs (n = 53, median [interquartile range] age 20.3 [18.9, 21.4] years) compared with White (n = 53, 19.1 [17.6, 20.8] years) and African American (n = 49, 18.8 [17.7, 20.5] years) AYAs (P = 0.02) of similar sex, pubertal stage, and BMI-Z had higher visceral fat on MRI (P < 0.001 vs. White; P = 0.009 vs. African American) and liver fat on MRS (P < 0.001 vs. both). South Asian AYAs had lower Si (P = 0.006) and higher dynamic AUC-ISR (P = 0.003) vs. White AYAs, higher total and static AUC-ISR vs. both White and African American AYAs (P < 0.001), and lower dynamic DI vs. African American AYAs (P = 0.039). South Asian AYAs had lower insulin clearance than White (P = 0.027) and African American (P = 0.007) AYAs. First-pass hepatic insulin extraction was lower in African American than South Asian (P < 0.0001) and White (P = 0.027) AYAs. Group differences in Si, dynamic AUC-ISR, and dynamic DI lost significance when visceral or liver fat was added to models, but higher total and static AUC-ISR in South Asian AYAs persisted. CONCLUSIONS: Compared with White and African American AYAs, South Asian AYAs have higher visceral and liver fat. These findings, along with lower Si and dynamic DI, suggest elevated metabolic risk in South Asian individuals, even at young ages. Higher total and static phase insulin secretion in South Asian AYAs may precede insulin deficiency, reported in adults.
Zupa M, Wormwood J, Qian S
… +1 more, Vimalananda V
Diabetes Care
· 2026 Jun · PMID 41996132
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OBJECTIVE: This study examined the association of consult modality (i.e., electronic consultation [e-consult], synchronous telemedicine, or in person) with 6-month HbA1c improvement to <8% (64 mmol/mol) among adults with...OBJECTIVE: This study examined the association of consult modality (i.e., electronic consultation [e-consult], synchronous telemedicine, or in person) with 6-month HbA1c improvement to <8% (64 mmol/mol) among adults with uncontrolled type 2 diabetes. The impact of factors that affect diabetes management complexity on this association was also explored. RESEARCH DESIGN AND METHODS: This retrospective cohort study included adults with type 2 diabetes and HbA1c ≥8% seen for initial outpatient endocrinology consultation from 31 January 2021 to 1 April 2023 within the Veterans Health Administration. We used mixed-effects logistic regression to assess the association of consultation modality with 6-month HbA1c < 8%, adjusted for relevant patient-level variables. RESULTS: In total, 21,847 patients were included: 93.1% were men; mean age was 64 years; 54.7% were White; 5,180 received e-consults; 4,377 participated in synchronous telemedicine; and 12,290 had in-person visits. Almost half (49.5%) achieved 6-month HbA1c <8%. Compared with in-person care, patients who received e-consults (adjusted odds ratio [aOR] 0.77; 95% CI 0.71-0.83) and synchronous telemedicine (aOR 0.86; 95% CI 0.80-0.93) were less likely to have 6-month HbA1c < 8%. In sensitivity analysis, audio-only telemedicine was associated with lower odds of 6-month HbA1c < 8% (aOR 0.78; 95% CI 0.71-0.86), whereas video-based telemedicine was not (aOR 0.98; 95% CI 0.88-1.09). There were no significant differences in the associations of patient-level characteristics with glycemic outcomes across care modalities. CONCLUSIONS: e-Consult and audio-only telemedicine for initial endocrinology consultations were associated with inferior 6-month glycemic outcomes compared with in-person care among adults with uncontrolled type 2 diabetes, and video telemedicine had similar glycemic outcomes. e-Consult and audio-only telemedicine care protocols may need to incorporate additional support for patients to achieve glycemic outcomes equivalent to in-person consultation.
Toki R, Sakamoto M, Yuki M
… +7 more, Iida M, Yamazaki M, Ichikawa S, Horiuchi R, Maegawa H, Okamura T, Takebayashi T
Diabetes Care
· 2026 Jun · PMID 41980087
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OBJECTIVE: Body weight variability is linked to cardiometabolic outcomes, but its renal impact in type 2 diabetes remains uncertain. We tested whether the magnitude of seasonal BMI fluctuation is independently associated...OBJECTIVE: Body weight variability is linked to cardiometabolic outcomes, but its renal impact in type 2 diabetes remains uncertain. We tested whether the magnitude of seasonal BMI fluctuation is independently associated with kidney function decline. RESEARCH DESIGN AND METHODS: We analyzed a nationwide, multicenter Japanese cohort (2014-2020). Monthly BMI was modeled using seasonal-trend locally estimated scatterplot smoothing to quantify each participant's within-year peak-to-trough difference. The primary outcome was ≥40% decline in estimated glomerular filtration rate (eGFR). Secondary outcomes were ≥30% eGFR decline, creatinine doubling, incident chronic kidney disease (CKD) stage ≥3, and kidney failure. Associations were estimated using multivariable Cox models with clinic as a random effect. RESULTS: Among 6,700 outpatients (median follow-up: 6.8 years), 779 reached the primary end point. Each 1-SD increase in BMI fluctuation was associated with higher risk of ≥40% eGFR decline (hazard ratio [HR] 1.23, 95% CI 1.16-1.31). The highest versus lowest tertile showed a 1.7-fold increased risk (HR 1.72, 95% CI 1.42-2.09). Patterns were consistent for ≥30% eGFR decline (HR 1.18, 95% CI 1.13-1.23), creatinine doubling (HR 1.30, 95% CI 1.17-1.45), and incident CKD stage ≥3 (HR 1.11, 95% CI 1.07-1.16). Longitudinal analyses showed steeper eGFR decline in the highest-fluctuation group. Results were robust across sensitivity analyses, including models for time-varying medication exposure. CONCLUSIONS: In type 2 diabetes, larger intra-annual BMI fluctuations were independently and dose-dependently associated with kidney function decline. Seasonal BMI amplitude may identify higher-risk individuals; whether reducing seasonal BMI fluctuations improves kidney outcomes warrants prospective evaluation.
Parente EB, Jansson Sigfrids F, Groop PH
… +4 more, Thorn LM, Sandholm N, Harjutsalo V, FinnDiane Study Group*
Diabetes Care
· 2026 Jun · PMID 41980064
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Obesity, kidney disease, and coronary artery disease (CAD) are interconnected. Here, the relationship between central obesity and CAD across albuminuria categories in type 1 diabetes was investigated. Data on 4,349 indiv...Obesity, kidney disease, and coronary artery disease (CAD) are interconnected. Here, the relationship between central obesity and CAD across albuminuria categories in type 1 diabetes was investigated. Data on 4,349 individuals without prior CAD from the Finnish Diabetic Nephropathy Study were analyzed. Central obesity was defined as waist-to-height ratio (WHtR) ≥0.5. Outcomes included acute myocardial infarction, coronary revascularizations, and CAD-related death. Associations were assessed with Cox regression adjusted for baseline covariates. Over a median 19-year follow-up, 664 CAD events (15.3%) occurred. The 10- and 20-year cumulative CAD incidences were 11.6% and 25.3%, respectively, in those with central obesity versus 4.4% and 9.9% without, respectively. In multivariable analysis, the hazard ratio for CAD per 0.1-unit WHtR increase was 1.21 (95% CI, 1.06-1.38; P = 0.006) overall and 1.26 (95% CI, 1.02-1.56; P = 0.03) among those without albuminuria. In conclusion, WHtR is associated with increased CAD risk in type 1 diabetes, particularly among those without albuminuria.
Incretin-based pharmacology has revolutionized the medical treatment of type 2 diabetes and obesity. The most effective drug to date is tirzepatide, a dual incretin receptor agonist that engages both the glucagon-like pe...Incretin-based pharmacology has revolutionized the medical treatment of type 2 diabetes and obesity. The most effective drug to date is tirzepatide, a dual incretin receptor agonist that engages both the glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR). While the relative contributions of GIPR and GLP-1R actions to the clinical effects of tirzepatide have not been established, the potency of this agent has reignited interest in the clinical potential of GIPR agonism. Here, we discuss incretin biology as it relates to metabolic pharmacology and contextualize the mechanisms by which GIPR activity could contribute to the development of new and effective drugs. We explore current and future applications of GIPR agonists and antagonists, to underscore the potential that this signaling system could add to treatment of type 2 diabetes and obesity.
Rosen Vollmar AK, Hedderson MM, Ngo AL
… +7 more, Chehab RF, Peterson AK, Greenberg MB, Liao LD, Ames JL, Ferrara A, Zhu Y
Diabetes Care
· 2026 Jun · PMID 41973635
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OBJECTIVE: Despite limitations in using BMI to assess obesity, little is known about central obesity's role in pregnancy and postpartum cardiometabolic conditions. We investigated associations of central obesity with per...OBJECTIVE: Despite limitations in using BMI to assess obesity, little is known about central obesity's role in pregnancy and postpartum cardiometabolic conditions. We investigated associations of central obesity with perinatal cardiometabolic conditions, independently and jointly with BMI. RESEARCH DESIGN AND METHODS: We examined associations of early pregnancy central obesity measures (waist circumference, waist-to-hip ratio, waist-to-height ratio, and body roundness index) with gestational diabetes mellitus, hypertensive disorders of pregnancy, postpartum prediabetes/diabetes, and postpartum chronic hypertension using modified Poisson (prenatal outcomes) and Cox (postpartum outcomes) regression. RESULTS: Among the 3,055 individuals in the study, there was a dose-response relationship between increasing central obesity and all outcomes, even after adjusting for BMI. Among individuals with healthy prepregnancy BMI, central obesity was associated with a higher risk of gestational diabetes mellitus (relative risks 1.92-2.42), postpartum prediabetes/diabetes (hazard ratios [HRs] 1.50-2.16), and postpartum chronic hypertension (HRs 2.04-3.63). CONCLUSIONS: Early pregnancy central obesity measures may enhance perinatal cardiometabolic risk assessment, helping identify at-risk individuals who could be missed using BMI alone.
Diabetes-related disparities among U.S. racial and ethnic minority groups persist, despite decades of research on their causes and interventions in an attempt to reduce them. Research demonstrates a strong relationship b...Diabetes-related disparities among U.S. racial and ethnic minority groups persist, despite decades of research on their causes and interventions in an attempt to reduce them. Research demonstrates a strong relationship between diabetes disparities and social determinants of health, the conditions where people are born, live, work, play, worship, and age. While these upstream factors strongly shape health outcomes, they are largely influenced by policy and community-level interventions with limited influence by clinicians or health systems. By contrast, health-related social needs (HRSN) are downstream consequences of adverse social and structural conditions that directly affect individuals and families. These immediate, actionable needs, such as food, housing, and transportation, can be addressed within health care settings. HRSN disproportionately affect racial and ethnic minority communities, with higher prevalence of diabetes, worse outcomes, and greater acute care use. These observations highlight the importance of addressing HRSN in diabetes care given the potential to improve outcomes and achieve diabetes equity. This narrative review summarizes current evidence on identifying and addressing HRSN in health care settings. Recently, significant progress has been made integrating medical and social care for adults with diabetes and HRSN. Specific examples of these efforts with reporting of diabetes outcomes are reviewed here. However, existing research has not yet demonstrated that HRSN interventions consistently reduce diabetes disparities. Additional infrastructure is needed to scale and sustain interventions, enhancing their feasibility, effectiveness, and long-term impact. We conclude with recommendations for research and practice to optimize social care integration for adults with diabetes and achieve diabetes equity.
Passos PRC, Motta R, Oliveira Costa Filho V
… +6 more, Noronha MM, Venâncio RC, Grossi Lopes Cançado G, Adler A, Cobbold JF, Tomlinson JW
Diabetes Care
· 2026 Jun · PMID 41973508
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BACKGROUND: Type 2 diabetes mellitus (T2DM) amplifies liver disease burden, yet the comparative hepatic effects of glucose-lowering drugs remain poorly defined. PURPOSE: To compare associations between glucose-lowering d...BACKGROUND: Type 2 diabetes mellitus (T2DM) amplifies liver disease burden, yet the comparative hepatic effects of glucose-lowering drugs remain poorly defined. PURPOSE: To compare associations between glucose-lowering drug classes and major adverse liver outcomes (MALOs) in adults with T2DM. DATA SOURCES: PubMed, EMBASE, and Cochrane Central Register of Controlled Trials were searched from December 1946 through 23 August 2025. STUDY SELECTION: Studies enrolling adults with T2DM that evaluated associations between glucose-lowering drug classes with regard to MALOs were included. DATA EXTRACTION: Data were extracted on study characteristics, drug exposures, and MALOs. DATA SYNTHESIS: A three-level Bayesian network meta-analysis with study- and database-level random effects was performed. Outcomes are reported as hazard ratios (HRs) and ranked using the surface under the cumulative ranking curve. Forty-six observational studies (N = 7,124,845) were included. Thiazolidinediones were least associated with hepatocellular carcinoma incidence and significantly lower than dipeptidyl peptidase 4 (DPP-4) inhibitors (HR 0.50), glucagon-like peptide 1 receptor agonists (GLP-1RAs) (HR 0.72), insulin (HR 0.20), and sulfonylureas (HR 0.69). For decompensation (composite), GLP-1RAs were associated with the lowest hazard compared with all other classes (HRs 0.16-0.91; all significant). Sodium-glucose cotransporter 2 (SGLT2) inhibitors were least associated with cirrhosis (HR 0.66 vs. DPP-4 inhibitors; HR 0.66 vs. GLP-1RAs). GLP-1RAs were least associated with variceal bleeding and hepatic encephalopathy, whereas SGLT2 inhibitors were least associated with liver-related mortality. LIMITATIONS: All included studies were observational, precluding causal inference. CONCLUSIONS: Liver-specific risk reduction is not uniform across antihyperglycemic drug classes. Randomized trials are needed to determine whether these associations reflect true drug effects.
Dungan KM, Chinchilli VM, Pichardo-Lowden A
… +24 more, Raja-Khan N, Bellin MD, Yadav D, Hart PA, Basina M, Buxbaum JL, Casu A, Evans-Molina C, Conwell DL, Fogel EL, Forsmark CE, Goodarzi MO, Kalyani RR, Layden BT, Lord SM, Papachristou GI, Park WG, Pratley R, Singh VK, Speake C, Trikudanathan G, Laughlin M, Toledo FGS, Type 1 Diabetes in Acute Pancreatitis Consortium (T1DAPC)*
Diabetes Care
· 2026 Jun · PMID 41940812
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OBJECTIVE: Hyperglycemia during acute pancreatitis (HDAP) likely reflects both stress hormone responses and pancreatic islet injury, distinguishing it from typical stress-induced hyperglycemia. The aim of this study was...OBJECTIVE: Hyperglycemia during acute pancreatitis (HDAP) likely reflects both stress hormone responses and pancreatic islet injury, distinguishing it from typical stress-induced hyperglycemia. The aim of this study was to determine the prevalence of HDAP and its prognostic significance for early-onset diabetes following acute pancreatitis (AP). RESEARCH DESIGN AND METHODS: Diabetes Related to Acute Pancreatitis and Its Mechanisms (DREAM) is a prospective multicenter study examining the development of diabetes following AP. This analysis included 395 participants without prior diabetes with an AP episode, focusing on their glucose levels during the event. Two definitions of HDAP were examined: peak glucose >140 mg/dL (HDAP140) and >200 mg/dL (HDAP200). Outpatient glycemic status after recovery (median: 111 days post-AP) was evaluated using fasting glucose, oral glucose tolerance test, and HbA1c. RESULTS: HDAP140 and HDAP200 were present in 37.5% and 7.1% of participants, respectively. Age, race, etiology, and AP severity were significant predictors of HDAP140. Among participants with HDAP140, 14.8% developed early-onset diabetes after AP recovery vs. 1.2% in those without (P = 0.0001). In those with HDAP200, 42.9% developed early-onset diabetes vs. 3.5% in those without (P = 0.0001). The absence of HDAP140 and HDAP200 was associated with negative predictive values of 99% and 97%, respectively, for diabetes. CONCLUSIONS: HDAP can be common in individuals without diabetes and is associated with early-onset diabetes following AP. Individuals without HDAP have a low risk of diabetes short term, while those with HDAP200 are at high risk. Monitoring glycemia during AP can identify individuals best suited for early targeted postdischarge care.
Hespanhol LC, Agarwal S, Carvalhal G
… +4 more, de Mendonça Bisneto OI, Chagas GCL, Galindo RJ, Abreu M
Diabetes Care
· 2026 Jun · PMID 41940799
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BACKGROUND: Automated insulin delivery (AID) systems are the standard of care in type 1 diabetes. Recent studies suggest benefits of these systems for people with type 2 diabetes, as well. PURPOSE: To evaluate the effect...BACKGROUND: Automated insulin delivery (AID) systems are the standard of care in type 1 diabetes. Recent studies suggest benefits of these systems for people with type 2 diabetes, as well. PURPOSE: To evaluate the effects of AID systems on glycemic outcomes in people with type 2 diabetes requiring insulin. DATA SOURCES: The PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched through 10 March 2025. This study was registered with PROSPERO (CRD420251036184). STUDY SELECTION: Nine studies (n = 1,530 participants) were included that evaluated AID systems in people with type 2 diabetes reporting continuous glucose monitoring outcomes. DATA EXTRACTION: Data were collected on study characteristics and outcomes including time in range (TIR) (3.9-10.0 mmol/L [70-180 mg/dL]), time above range (TAR) (>10.0 mmol/L [>180 mg/dL]), time below range (TBR) (<3.9 mmol/L [<70 mg/dL]), mean glucose, and HbA1c. We performed a single-arm meta-analysis using a random-effects model. DATA SYNTHESIS: AID systems significantly increased TIR by 16.06% (95% CI 10.48-21.65), changed TAR by -15.90% (95% CI -21.44 to -10.36), changed HbA1c by -1.27% (95% CI -2.06 to -0.48), and changed mean glucose by -21.34 mg/dL (95% CI -32.06 to -10.62) or 1.19 mmol/L (95% CI -1.78 to -0.59). There was a modest yet significant reduction in TBR. There were no changes in body weight or BMI. LIMITATIONS: Heterogeneous study designs, including only three randomized controlled trials, and imputed missing data. CONCLUSIONS: AID systems improved glucose control in a diverse population of individuals with type 2 diabetes requiring insulin therapy with reduction in hypoglycemia. These findings support recommendations for AID systems use in future type 2 diabetes management guidelines.
OBJECTIVE: In prespecified analyses, the treatment effect for MACE of tirzepatide compared with imputed placebo was estimated using SURPASS-CVOT and REWIND data. RESEARCH DESIGN AND METHODS: The indirect comparison with...OBJECTIVE: In prespecified analyses, the treatment effect for MACE of tirzepatide compared with imputed placebo was estimated using SURPASS-CVOT and REWIND data. RESEARCH DESIGN AND METHODS: The indirect comparison with placebo was conducted for primary (MACE-3) and secondary outcomes of SURPASS-CVOT. The analysis included data from REWIND participants who would have been eligible for SURPASS-CVOT and all participants from SURPASS-CVOT. Propensity score estimation was used to adjust for differences in participant characteristics between studies. The indirect analysis of the treatment effect was derived by multiplying the hazard ratio (HR) for MACE-3 between tirzepatide and dulaglutide in SURPASS-CVOT by the HR for dulaglutide versus placebo in REWIND. Sensitivity analyses were performed using unadjusted analyses, including both the selected REWIND and the entire REWIND populations, and adjusted analysis in the entire REWIND population. Post hoc sensitivity analyses used data from a recent GLP-1RA meta-analysis that included REWIND. RESULTS: Analyses included 2,055 of 9,901 participants from REWIND and all 13,165 participants from SURPASS-CVOT. In indirect treatment effect comparisons, tirzepatide versus placebo was associated with lower MACE-3 (HR 0.72; 95% CI 0.55, 0.94), death from CV cause or heart failure events (HR 0.70; 95% CI 0.51, 0.96), and all-cause death (HR 0.61; 95% CI 0.45, 0.82). Sensitivity analyses, including nonadjusted or the entire REWIND cohort data or meta-analysis data for GLP-1RAs, were generally consistent. CONCLUSIONS: In this indirect prespecified exploratory comparison, tirzepatide compared with imputed placebo was associated with reduced CV outcomes and all-cause mortality in participants with type 2 diabetes and established atherosclerotic CV disease.