Objective: To evaluate whether the efficacy and safety of finerenone varied by baseline hemoglobin A1c (HbA1c) levels, a proxy of glycemic control, and diabetes duration in people with type 1 diabetes and chronic kidney disease (CKD). Research Design and Methods: Adults with type 1 diabetes, urinary albumin-to-creatinine ratio (UACR) 200−<5000 mg/g and estimated glomerular filtration rate (eGFR) 25−<90 mL/min/1.73 m2 were randomized (1:1) to finerenone or placebo. UACR change from baseline over 6 months by baseline HbA1c and diabetes duration was analyzed. Results: Baseline HbA1c was available for 240/242 participants; mean (SD) HbA1c, diabetes duration, and eGFR were 7.6% (1.1; 60 [12] mmol/mol), 32.0 (14.2) years, and 58.9 (19.2) mL/min/1.73 m2, respectively. At 6 months, HbA1c (95% CI) remained unchanged (finerenone: +0.03% [–0.14, 0.20]; placebo: 0.00% [–0.12, 0.11]; between-group difference +0.04% [–0.17, 0.24]; P=0.74). Over 6 months, median UACR decreased from 574.6 to 373.5 mg/g with finerenone and from 506.4 to 475.6 mg/g with placebo, corresponding to a –25% placebo-corrected change (95% CI –35, –13; P=0.0001). Treatment effects were consistent across HbA1c tertiles (<7.1%, ≥7.1%−≤8.1%, and >8.1%), with placebo-corrected UACR changes (95% CI) of –17% (–40, 13), –18% (–39, 10), and –37% (–55, –13), respectively (P interaction=0.41). Effects were similarly consistent across diabetes duration tertiles (P interaction=0.70). Overall safety and incidence of hyperkalemia were similar across HbA1c tertiles. Conclusions: In adults with type 1 diabetes and CKD, finerenone reduced UACR and was well-tolerated irrespective of HbA1c levels or diabetes duration.

In the SELECT trial, once-weekly subcutaneous semaglutide reduced major adverse cardiovascular events (MACE) by 20% versus placebo in patients with atherosclerotic cardiovascular disease and obesity but without diabetes. We examined semaglutide in SELECT patients at high risk for substantial liver fibrosis in a prespecified secondary analysis. Liver biochemical tests and steatosis risk according to fatty liver index were assessed over 104 weeks. Subgroup analyses of the primary MACE (a composite endpoint including cardiovascular death, nonfatal myocardial infarction or nonfatal stroke) outcome used baseline Fibrosis-4 scores ≥ 1.3, age-specific (≥1.3 (<65 years) or ≥2.0 (≥65 years)) and any age with Fibrosis-4 > 2.67. MACE was reduced by 26% (hazard ratio (HR) 0.74; 95% confidence interval (CI) 0.63-0.88; P = 0.0004), 21% (HR 0.79; 95% CI 0.63-0.98; P = 0.035) and 34% (HR 0.66; 95% CI 0.39-1.10; P = 0.11), respectively. Semaglutide led to a 28% greater decrease in fatty liver index versus placebo (HR 0.72; 95% CI 0.71-0.73; P < 0.0001). In conclusion, semaglutide reduced MACE versus placebo in patients at risk for substantial liver fibrosis, as seen in the overall SELECT population. ClinicalTrials.gov registration no. NCT03574597.

Introduction and Objective: We investigated the 70-protein risk score for subsequent atherosclerotic cardiovascular disease (ASCVD), reported in the primary prevention deCODE cohort, on subsequent major adverse CV events (MACE) in SELECT, a trial of semaglutide 2.4 mg vs placebo in patients (pts) with ASCVD, obesity (BMI≥27 kg/m²) but not diabetes. These data were used to consider how semaglutide might alter CV risk independently of weight loss. Methods: Proteins were measured using SomaScan 7K in 10,878 SELECT pts (CVD, BMI ≥27 kg/m², no diabetes) at baseline (BL), 20, and 104 weeks. Cox regression assessed association between 70 proteins BL levels and MACE. Effect of semaglutide vs placebo at 20 and 104 weeks (on-treatment) was tested with univariate linear models adjusted for body weight change. Results: At BL, 8 of the 70 proteins tested (NPPB, WFDC2, GDF15, TREM1, CCL15, MCTS1, TNFRSF11B, MANEA) were prognostic for MACE (HR 1.2-1.6, p<0.05). After 104 weeks of treatment, 5 of those were reduced significantly (Fig): cardiac stress markers (NPPB), matrix remodeling enzymes (TNFRSF11B), growth factors (GDF15) and immune/inflammatory mediators (TREM1, CCL15). Two (NPPB, TNFRSF11B) were reduced after 20 weeks. Conclusion: Semaglutide treatment was associated with changes in ASCVD risk proteins that also predict MACE, suggesting potential mechanisms of semaglutide’s weight-independent effect on MACE. Disclosure M. Dermit: None. A. Aguayo Orozco: Employee; Current; Novo Nordisk. A. Bjerregaard: Employee; Current; Novo Nordisk. F. Capelluto: Employee; Current; Novo Nordisk. H.M. Colhoun: Research Support; Current; Diabetes UK, IQVIA Inc., Sanofi, JDRF, Chief Scientist Office. Research Support; Ended; Medical Research Council (UKRI). Other - Personal payment for consultancy (ENDED);Research support (ongoing); Current; Sanofi. Other - Advisory board member (ongoing); Support for attendance at meetings /conferences and travel; Current; Novo Nordisk. Other - Advisory panel member (ongoing);Stockholder (up to January 2025- ENDED); Current; Bayer AG. Other - Stockholder (ongoing);Institutional payment for consultancy (ongoing); Current; Roche Pharmaceuticals. B. Follin: Employee; Current; Novo Nordisk A/S. K.B. Hessellund: Employee; Current; Novo Nordisk A/S. A.M. Lincoff: Consultant; Current; Novo Nordisk, Eli Lilly and Company. Stock/Shareholder; Current; Canary Cure. Research Support; Current; Novartis AG. Consultant; Ended; Alnylam Pharmaceuticals, Inc., Amgen Inc., Ardelyx, Brainstom Cell, Capricor, Johnson & Johnson. I. Lingvay: Consultant; Current; Aadvarak Therapeutics, Abbvie, Alveus Therapeutics, Amgen, Antag Therapeutics, Arrowhead Pharmaceuticals, Astra Zeneca, Baim Institute, Bain Capital, Bayer, Betagenon AB, Bioio Inc., Biomea, Boehringe. Research Support; Current; Novo Nordisk A/S, Dexcom, Inc., Boehringer Ingelheim International GmbH. Consultant; Current; Eli Lilly, Genentech, Janssen/J&J, Juvena, Keros Therapeutic, Inc, Mediflix, Metsera, Neurocrine, Novo Nordisk, Penguin Bio, Pfizer, Regeneron, Response Pharmaceutical, Roche, Sanofi, Shionogi, Skye B, Tenvie, TERNS Pharma, Verdiva Bio, Viking Therapeutics, and Zealand Pharma. J. Plutzky: Consultant; Current; Amgen Inc., Boehringer Ingelheim International GmbH, Corcept Therapeutics, Merck & Co., Inc., Novo Nordisk Foundation. J.A. Sibbesen: Employee; Current; Novo Nordisk A/S. S. Stensen: Employee; Current; Novo Nordisk A/S. P.E. Weeke: Employee; Current; Novo Nordisk. T.N. Wistisen: Employee; Current; Novo Nordisk. L. Bjerre Knudsen: Employee; Current; Novo Nordisk. S. Kahn: Advisory Panel; Current; AltPep, Amgen Inc., Congruence Therapeutics, Eli Lilly and Company, General Medicines, Kayothera, Merck & Co., Inc., Neurimmune, Novo Nordisk, Roche Pharmaceuticals.

Introduction and Objective: The nonsteroidal mineralocorticoid receptor antagonist finerenone has been reported to improve UACR in people with T1D and CKD. This prespecified analysis evaluated whether safety and efficacy of finerenone varied by baseline HbA1c levels and diabetes duration. Methods: In total, 242 adults with T1D, CKD (eGFR ≥25 to <90 mL/min/1.73 m2; UACR ≥200 to <5000 mg/g), and on stable ACEi/ARB therapy were randomized 1:1 to receive finerenone (10 or 20 mg per day) or matching placebo. The primary outcome was the relative change in UACR from baseline over 6 months. Results: Baseline HbA1c (mean ± SD: 7.6 ± 1.1%) was available for 240 (99%) FINE-ONE participants. At 6 months, HbA1c was unchanged in both treatment arms (change from baseline [95% CI]: finerenone 0.03% [-0.14, 0.20]; placebo 0% [-0.12, 0.11]; between-group difference 0.04% [-0.17, 0.24]; p=0.74). Participants were stratified by HbA1c tertiles: 1 (HbA1c <7.1%), 2 (HbA1c ≥7.1 to ≤8.1%), and 3 (HbA1c >8.1%). Across the 6-month trial duration, median UACR decreased from 574.6 to 373.5 mg/g with finerenone and from 506.4 to 475.6 mg/g with placebo, corresponding to a 25% (95% CI 35, 13) UACR reduction (p=0.0001). There was no heterogeneity in the treatment effect of finerenone on UACR across HbA1c tertiles 1, 2, and 3 (geometric mean [95% CI]: -17% [-40, 13], -18% [-39, 10], and -37% [-55, -13], respectively; p interaction = 0.41). When analyzed by diabetes duration, the reduction in UACR with finerenone vs placebo was also consistent across tertiles (<25 years, ≥25 to ≤38 years, and >38 years; p interaction = 0.70). Hyperkalemia was the most common adverse event. Safety was comparable across tertiles of HbA1c and diabetes duration. Conclusion: In adults with T1D and CKD, finerenone reduced UACR compared with placebo irrespective of baseline HbA1c levels or diabetes duration, and it was well tolerated. Disclosure P. Rossing: Advisory Panel; Ended; Abbott Diagnostics. Advisory Panel; Current; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Eli Lilly and Company. Consultant; Current; Lexicon Pharmaceuticals, Inc., Roche Pharmaceuticals. Consultant; Ended; Amgen Inc. H. Heerspink: Consultant; Current; AstraZeneca, Alnylam Pharmaceuticals, Inc., Amgen Inc., Bayer AG, Boehringer Ingelheim International GmbH, Dimerix, Eli Lilly and Company, Novo Nordisk, Novartis AG, Roche Pharmaceuticals. A.J. Amor: Speaker's Bureau; Ended; Lilly. Research Support; Ended; Novo Nordisk. A.L. Birkenfeld: None. L. Caramori: Consultant; Current; Bayer AG. Research Support; Ended; Bayer AG, Eli Lilly and Company. Research Support; Current; Boehringer Ingelheim International GmbH. Consultant; Current; Novo Nordisk. Other - Content reviewer; Current; UpToDate. D. Cherney: Consultant; Current; Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, AMGEN, Bayer, Prometic, BMS, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon, Inversago, GSK,. Research Support; Current; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring, Lexicon, Novo-Nordisk, Bayer. H.M. Colhoun: Research Support; Current; Diabetes UK, IQVIA Inc., Sanofi, JDRF, Chief Scientist Office. Research Support; Ended; Medical Research Council (UKRI). Other - Personal payment for consultancy (ENDED);Research support (ongoing); Current; Sanofi. Other - Advisory board member (ongoing); Support for attendance at meetings /conferences and travel; Current; Novo Nordisk. Other - Advisory panel member (ongoing);Stockholder (up to January 2025- ENDED); Current; Bayer AG. Other - Stockholder (ongoing);Institutional payment for consultancy (ongoing); Current; Roche Pharmaceuticals. P. Henrick Groop: Other - Lecture Fees; Current; Astellas Pharma Inc., AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim, Eli Lilly and Company, Elo Water, Medscape, MSD, Mundipharma, Nestlé, Novartis AG, Novo Nordisk, Sanofi. P. Fiorina: Board Member; Ended; A. Menarini Diagnostics, Novo Nordisk, AstraZeneca, Bristol-Myers Squibb Company. L. Ji: None. N. Jongs: Other - Travel Support; Current; AstraZeneca. C. Mathieu: Advisory Panel; Current; Abbott Diagnostics, Dexcom, Inc. Board Member; Current; European Association for the Study of Diabetes. Advisory Panel; Current; Novo Nordisk, Eli Lilly and Company, Sanofi, Vertex Pharmaceuticals Incorporated, Medtronic. U. Pagotto: Advisory Panel; Ended; Eli Lilly and Company. Speaker's Bureau; Ended; Eli Lilly and Company. Advisory Panel; Ended; Novo Nordisk. Speaker's Bureau; Ended; Novo Nordisk. Advisory Panel; Ended; Boehringer Ingelheim International GmbH. Speaker's Bureau; Ended; Rhythm Pharmaceuticals, Inc. Research Support; Current; Novo Nordisk. S. Rosas: Advisory Panel; Current; Bayer AG. Research Support; Ended; Bayer AG. Advisory Panel; Current; Novo Nordisk. Advisory Panel; Ended; Travere. E. Setola: Speaker's Bureau; Ended; Sanofi, Eli Lilly and Company. Advisory Panel; Ended; Novo Nordisk, Boehringer Ingelheim International GmbH. J. Skyler: Advisory Panel; Ended; AbbVie Inc. Consultant; Current; ADOCIA. Board Member; Current; Applied Therapeutics. Advisory Panel; Current; Avotres Inc., Bayer AG. Consultant; Current; Eli Lilly and Company. Advisory Panel; Current; Kriya Therapeutics. Consultant; Current; Novo Nordisk. Board Member; Current; SAB Biotherapeutics, Inc. Consultant; Current; Sanofi, Vertex Pharmaceuticals Incorporated. K. Tuttle: Consultant; Ended; Alnylam Pharmaceuticals, Inc. Consultant; Current; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, GlaxoSmithKline plc., Novo Nordisk, Lilly, ProKidney. Consultant; Ended; Roche Diabetes Care. Research Support; Ended; Travere. R. Lawatscheck: Employee; Current; Bayer AG. M. Brinker: Employee; Current; Bayer AG. Other - pending patent for finerenone for treatment of patients with CKD and T1D; Current; Bayer AG. Stock/Shareholder; Current; Bayer AG. J. jRussell: Employee; Current; Bayer PLC. P. Schloemerk: Employee; Current; Bayer AG. J.B. McGill: Consultant; Current; Bayer AG. Advisory Panel; Current; MannKind Corporation. Advisory Panel; Ended; Novo Nordisk, Abbott Diagnostics. Consultant; Ended; Pfizer Inc. Research Support; Ended; Lexicon Pharmaceuticals, Inc. Research Support; Current; Novo Nordisk A/S, Lilly, Viking Therapeutics, Diamyd, Cour Pharmaceutical. Funding Funding Bayer. FINE-ONE Trial registration number: NCT05901831

Background: Genome-wide association studies (GWASs) have identified thousands of genomic regions in which common variants affect blood pressure, but have yielded limited mechanistic insight. This study used a novel method of genetic analysis based on identifying core genes on which the _trans_-effects of common variants coalesce to influence blood pressure. Methods: We undertook GWASs of mean arterial pressure (MAP) and body mass index (BMI) in 373,882 individuals aged less than 60 years in the Our Future Health study. We used summary statistics from GWASs of proteins on the SomaScan and Olink platforms to compute genome-wide aggregated trans-effects (GATE) scores for each protein, and tested for association of MAP with these scores. Results: The strongest GATE score association with MAP was for lipoprotein lipase (LpL, encoded by LPL_. Genetic up-regulation of circulating levels of LpL was associated with lower MAP but higher BMI. Associations of MAP and BMI with GATE scores for circulating levels of proteins encoded by three other genes involved in lipid handling -- CD300LG, ADIPOQ, TIMP4 -- were similar to those with LpL. GATE scores for all four of these proteins were inversely associated with measurements by NMR spectroscopy of plasma triglyceride in chylomicrons and extremely large VLDL particles. Conclusions: These results point to a key role in hypertension for proteins that regulate post-prandial clearance of triglyceride-rich lipoproteins, independently of adiposity. This is consistent with experimental studies showing that accumulation of lipids in endothelial cells impairs endothelial function.

Introduction and Objective: The SELECT trial of patients with BMI ≥27 kg/m2 and CVD without diabetes found a 20% reduction in major adverse CV events (MACE) with semaglutide. Proteomic analysis in the STEP 1 trial yielded proteins modulated by semaglutide. For six of these proteins with genetic evidence for causal effects on cardiovascular disease (CVD), we conducted a mediation analysis in SELECT. Methods: Thrombospondin 2 (THBS2), N-terminal pro-BNP (NPPB), macrophage scavenger receptor 1 (MSR1), angiopoietin-2 (ANGPT2), complement component C1q receptor (CD93), and tenascin-C (TNC) were measured in 9461/17,604 patients with available samples at baseline and week 20. Mediation analysis of MACE effect at 3 years, with/without adjustment for weight loss at week 20, used the Vansteelandt method. Results: Baseline protein levels were associated with MACE, and semaglutide modulated levels of these proteins in SELECT (Figure). Combined mediation was estimated at 44.0% (95% CI 7.6, >100) and 65.8% (19.7, >100), with and without weight adjustment, respectively (Figure). Weight-adjusted protein-specific estimates were significant for THBS2 (11.1%), NPPB (32.6%), ANGPT2 (19.3%), and CD93 (35.8%). Conclusion: Four prespecified proteins were altered by semaglutide and were significant in weight-adjusted mediation analysis, suggesting additional potential mechanisms of semaglutide’s effect on MACE beyond weight loss. Disclosure H.M. Colhoun: Research Support; Current; Diabetes UK, IQVIA Inc., Sanofi, JDRF, Chief Scientist Office. Research Support; Ended; Medical Research Council (UKRI). Other - Personal payment for consultancy (ENDED);Research support (ongoing); Current; Sanofi. Other - Advisory board member (ongoing); Support for attendance at meetings /conferences and travel; Current; Novo Nordisk. Other - Advisory panel member (ongoing);Stockholder (up to January 2025- ENDED); Current; Bayer AG. Other - Stockholder (ongoing);Institutional payment for consultancy (ongoing); Current; Roche Pharmaceuticals. J. Deanfield: Other - Received CME honoraria; Ended; Amgen Inc., Aegerion. Consultant; Current; AstraZeneca. Other - Member of Study Steering Committee for SOUL and SELECT; Current; Novo Nordisk. Other - Received CME honoraria; Ended; Bayer AG, Boehringer Ingelheim International GmbH. Other - Received CME honoraria; Current; Novo Nordisk. Research Support; Ended; British Heart Foundation, Alzheimer's Research UK, Pfizer, Colgate, Roche, Pfizer, Aegerion. Other - Advisory agreement.; Current; Caristo Diagnostics, eMed Healthcare, Floe Oral Care Ltd, Friede-Springer Cardiovascular Prevention Center, iOWNA, PMI Harm Reduction Group, Smarter Cardiovascular Outcomes By Research And Education L. S. Kahn: Advisory Panel; Current; AltPep, Amgen Inc., Congruence Therapeutics, Eli Lilly and Company, General Medicines, Kayothera, Merck & Co., Inc., Neurimmune, Novo Nordisk, Roche Pharmaceuticals. A.M. Lincoff: Consultant; Current; Novo Nordisk, Eli Lilly and Company. Stock/Shareholder; Current; Canary Cure. Research Support; Current; Novartis AG. Consultant; Ended; Alnylam Pharmaceuticals, Inc., Amgen Inc., Ardelyx, Brainstom Cell, Capricor, Johnson & Johnson. I. Lingvay: Consultant; Current; Aadvarak Therapeutics, Abbvie, Alveus Therapeutics, Amgen, Antag Therapeutics, Arrowhead Pharmaceuticals, Astra Zeneca, Baim Institute, Bain Capital, Bayer, Betagenon AB, Bioio Inc., Biomea, Boehringe. Research Support; Current; Novo Nordisk A/S, Dexcom, Inc., Boehringer Ingelheim International GmbH. Consultant; Current; Eli Lilly, Genentech, Janssen/J&J, Juvena, Keros Therapeutic, Inc, Mediflix, Metsera, Neurocrine, Novo Nordisk, Penguin Bio, Pfizer, Regeneron, Response Pharmaceutical, Roche, Sanofi, Shionogi, Skye B, Tenvie, TERNS Pharma, Verdiva Bio, Viking Therapeutics, and Zealand Pharma. J. Plutzky: Consultant; Current; Amgen Inc., Boehringer Ingelheim International GmbH, Corcept Therapeutics, Merck & Co., Inc., Novo Nordisk Foundation. K.B. Hessellund: Employee; Current; Novo Nordisk A/S. G.G. Hovingh: Employee; Current; Novo Nordisk A/S. K.J. Kolnes: Employee; Current; Novo Nordisk. Stock/Shareholder; Current; Novo Nordisk. P.E. Weeke: Employee; Current; Novo Nordisk. L. Bjerre Knudsen: Employee; Current; Novo Nordisk. J. Refsgaard: Employee; Current; Novo Nordisk A/S.

Objective To characterize associations of C-peptide measurements with type 1 diabetes complications across long-term clinical follow-up in a large representative population cohort (Scottish Diabetes Research Network Type 1 Bioresource (SDRNT1BIO)). Research Design and Methods SDRNT1BIO includes people with a clinical diagnosis of type 1 diabetes aged 16 or older at enrollment and with a median diabetes duration of 21 years (interquartile range 11-31). C-peptide was measured in an untimed blood sample using the Roche immunoassay with a lower limit of detection of 3 pmol/L. Incident events and continuous outcomes were captured through electronic health record linkage across follow-up. Associations were studied using Poisson generalized linear models and linear mixed models, adjusted for sex, age, time-updated type 1 diabetes duration, year of entry, and age/type 1 diabetes duration interaction. Results Participants (n=5630) were followed for a median of 10.8 years. Inverse associations were found between baseline C-peptide and diabetic ketoacidosis (DKA) (p<0.0001, n[events]=1015), severe hospitalized hypoglycemia (SHH) (p=0.0055, n=539), and incident retinopathy (p<0.0001, n=1172). These associations persisted when adjusted for time-updated glycosylated hemoglobin (HbA1c). No associations were found between baseline C-peptide and cardiovascular disease (p=0.9, n=714) or death (p=0.8, n=566). In a subset of participants (n=407) with serial C-peptide measures, follow-up C-peptide level was inversely associated with risk for DKA (p<0.001, n=92) and there was a borderline association with SHH (p=0.015, n=28). Conclusions These data demonstrate the importance of C-peptide level and its maintenance for glycemic control and avoidance of acute and chronic complications of type 1 diabetes.

Introduction:Variability in estimated glomerular filtration rate (eGFR) has been associated with increased risks of mortality and chronic kidney disease (CKD) progression in people with type 2 diabetes mellitus (T2DM) and impaired kidney function. However, its significance in individuals with preserved kidney function remains unclear. Methods:In this nationwide retrospective population-based study of individuals with T2DM, eGFR variability was calculated by fitting a linear regression model to longitudinal data to estimate both the individual eGFR slope over the 5-year period as well as the variability in model residuals provided by the SD of the model residuals using longitudinal serum creatinine (SCr) measurements obtained during the first 5 years after diagnosis. Cox proportional hazards models were then applied to assess the association between eGFR variability and progression to stage G3b CKD among participants with preserved kidney function. Results:This study included 98,322 participants who had an eGFR > 60 ml/min per 1.73 m2 at diagnosis, remained alive with an eGFR > 60 ml/min per 1.73 m2 5 years after diagnosis, and were subsequently followed for a mean of 5.1 years. Greater eGFR variability was associated with an increased risk of progression to stage G3b CKD- hazard ratios (HRs) for the second, third, and fourth quartiles of variability versus the first quartile were 1.56 (95% confidence interval [CI]: 1.38-1.75), 1.85 (95% CI: 1.65-2.08), and 2.56 (95% CI: 2.29-2.86), respectively. This association persisted after adjustment for multiple variables-HR: 1.57; 95% CI: 1.40-1.77 for the fourth quartiles of variability versus the first quartile. Conclusion:eGFR variability in the absence of acute kidney injury (AKI) is associated with CKD progression in individuals with T2DM and preserved kidney function.

BACKGROUND:In SELECT (Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity), among 17 604 patients with known atherosclerotic cardiovascular disease and overweight or obesity, but not diabetes, randomization to the glucagon-like peptide-1 receptor antagonist semaglutide significantly reduced the primary outcome of major adverse cardiovascular events (MACEs; cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) compared with placebo (mean follow-up, 39.8 months). Inflammation, as indicated by plasma hsCRP (high-sensitivity C-reactive protein) level, is implicated as a biomarker predicting cardiovascular risk in obesity and atherosclerotic cardiovascular disease. SELECT provides a unique opportunity to study the relationship among hsCRP, obesity, weight loss, and MACE outcomes in semaglutide versus placebo groups. METHODS:In this prespecified SELECT substudy, we evaluated whether baseline hsCRP levels predicted MACE risk and examined the relationships between changes in hsCRP levels and time to first MACE, baseline body weight, weight loss, and other clinical measures among treatment groups over time (104-208 weeks) using multiple approaches, including Cox modeling. RESULTS:Baseline hsCRP level, which was similar in the semaglutide (geometric mean 1.96 mg/L) and placebo (geometric mean 1.91 mg/L) groups, was prognostic of future MACEs. The risk of MACEs increased across baseline hsCRP level <2, 2-<10, and ≥10 mg/L subgroups, including significant associations with cardiovascular and all-cause death. Semaglutide reduced hsCRP levels (-37.8% [104 weeks]) and risk of MACEs across all hsCRP subgroups. Greater reductions in ratio-to-baseline hsCRP with semaglutide were associated with greater weight loss, but preceded major weight loss, evident by 4 and 8 weeks, and occurred among those without weight loss. Semaglutide-associated changes in hsCRP were independent of low-density lipoprotein cholesterol levels, statin use, and atherosclerotic cardiovascular disease entry criteria. hsCRP reductions were found to be prognostic of decreased risk of MACEs. Modeling suggests decreased inflammation as contributing in part to the benefits seen with semaglutide in SELECT. CONCLUSIONS:In SELECT, hsCRP data at baseline and in response to treatment with semaglutide support inflammation as a potential prognostic factor associated with cardiovascular risk in these generally well-treated patients with atherosclerotic cardiovascular disease and overweight or obesity but not diabetes. These findings suggest that the MACE reduction observed with semaglutide versus placebo in SELECT may have partially involved a decrease in inflammation. REGISTRATION:URL: https://clinicaltrials.gov; Unique identifier: NCT03574597.

Background: Type 1 diabetes (T1D) is a chronic autoimmune disease that causes the progressive irreversible loss of pancreatic beta-cell function, leading to glycemic dysregulation. T1D progresses through stages, beginning with a presymptomatic phase marked by multiple islet autoantibodies (stage 1), dysglycemia (stage 2), and ultimately, clinical (stage 3) and established (stage 4) disease. Although stage 3 is characterized by significant loss of beta-cell function, the remaining reserve can be assessed by measuring markers of residual function, such as C-peptide. Residual C-peptide is associated with improved clinical outcomes, including reduced risk for severe hypoglycemia and long-term complications, improved glycemic control, and lower insulin requirements. Summary: Understanding and monitoring the state of the functional residual beta-cell population may yield useful insights for clinical management of T1D throughout its course. Because early beta-cell dysfunction can already be detected with C-peptide-based metrics in stage 1, in the future advanced C-peptide measures could aid in earlier identification of presymptomatic individuals to guide treatment management before irreversible beta-cell damage occurs. Currently, C-peptide measurement is most applicable in individuals with stage 3 and stage 4 T1D, where it serves as a surrogate measure of beta-cell function that can inform differential diagnosis, improve identification of those who may be eligible for disease-modifying therapy, and facilitate dynamic tracking of therapeutic responses. Despite these benefits, C-peptide measurement is not yet a part of routine clinical care and is rarely performed after disease onset. C-peptide assessment continues to be complicated by logistical barriers, individual variance in pancreatic reserve, insulin sensitivity, and other patient-specific factors, along with a lack of standardized, age-specific normative values. Key Messages: In this review, we describe beta-cell function across T1D stages, testing strategies to quantify beta-cell health such as C-peptide, and potential benefits of beta-cell monitoring in clinical practice. When used in the correct context, C-peptide combined with other glycemic monitoring can give clinicians real-time insights into residual beta-cell function throughout T1D progression and therapeutic interventions. .

Obesity and chronic kidney disease (CKD) are complex diseases that are interlinked directly and indirectly. In October 2024, Kidney Disease: Improving Global Outcomes (KDIGO) held a Controversies Conference on the Relationship Between Obesity and CKD: Pathophysiology, Prognosis, and Management. The goals of the conference were to examine the most recent evidence regarding the epidemiology, pathophysiology, and treatment of obesity and CKD as well as to articulate priorities for research. A key conference theme was increasing the awareness of obesity-related CKD. Long-term, early-onset obesity and prolonged exposure to obesity carry the highest risk of developing CKD. Identifying early biomarkers of kidney dysfunction and refining assessment methods in the context of obesity could provide opportunities for preventing loss of kidney function. The foundation for managing obesity in CKD comprises modifications to diet, physical activity level, and behaviors related to both. However, these strategies can be unsuccessful in achieving or maintaining weight loss for a myriad of reasons. Pharmacotherapies, such as those including glucagon-like peptide-1 receptor agonists, are effective in weight reduction and have been shown to have kidney-protective and cardiovascular benefits. Metabolic and bariatric surgery has also demonstrated benefits in reducing obesity-related complications. Appropriateness and choice of management strategies will vary depending on age and comorbidities and may change over time. Patient-led goal setting is a foundation for dietary and physical activity interventions focusing on incremental, achievable changes toward healthy eating and an active lifestyle. Health care professionals require training to deliver these interventions and provide ongoing support with positive messaging using nonjudgmental, stigma-free language. Evaluating the optimal duration of therapy, long-term safety of novel pharmacotherapies, and therapies in the context of early and later stages of CKD is a key priority for research. Multidisciplinary collaboration is important both for optimizing patient care and for advancing research.

Identified genetic loci for C-peptide and age at diagnosis (AAD) in individuals with type 1 diabetes (T1D) explain only a small proportion of their variation. Here, we aimed to perform large metagenome-wide association studies (GWAS) of C-peptide and AAD in T1D; and to identify the HLA allele/haplotypes associated with C-peptide and AAD. 7,252 and 7,923 European individuals with T1D were included in C-peptide and AAD GWAS, respectively. HLA-DQB1*06:02 which is strongly protective against T1D was associated with higher C-peptide. HLA-DQB1*03:02, HLADRB1*03:01 and HLA-A*24:02 which increase T1D risk were independently associated with younger AAD. HLA-DR3-DR4 haplotype combination, the strongest T1D susceptibility factor, was associated with younger AAD. Outside HLA region, rs115673528 on Chr5 (GABRG2) was associated with C-peptide, and an indel, rs111970692, on Chr15 within CTSH, a known T1D locus, was associated with AAD. Genetically predicted CTSH expression, methylation and protein levels were associated with AAD; Mendelian randomization analysis suggested that higher levels of procathepsin H reduce AAD. In conclusion, some HLA allele/haplotypes associated with T1D also contribute to variability of C-peptide and AAD. Outside HLA, T1D loci are generally not associated with C-peptide or AAD. CTSH could be a potential therapeutic target to delay development/progression of type 1 diabetes.

Rationale & objective: Despite a lack of supporting evidence, current guidance recommends against the use of metformin in people with advanced kidney impairment. This observational study compared the outcomes of patients with type 2 diabetes who continued versus stopped metformin after developing stage 4 chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR]<30mL/min/1.73m(2)). Study design: Nationwide observational cohort study. Setting & participants: All adults with type 2 diabetes and incident stage 4 CKD in Scotland who were treated with metformin between January 2010 and April 2019. Exposure: Stopping versus continuing metformin within 6 months following incident stage 4 CKD. Outcome: Primary outcome was all-cause mortality. Secondary outcomes included major adverse cardiovascular events (MACE). Analytical approach: Target trial emulation with clone-censor-weight design and marginal structural models fit for sensitivity analyses. Results: In a population of 371,742 Scottish residents with a diagnosis of type 2 diabetes before April 30, 2019, 4,278 were identified as prevalent metformin users with incident CKD stage 4. Within 6 months of developing CKD stage IV, 1,713 (40.1%) individuals discontinued metformin. Compared with continuing metformin, stopping metformin was associated with a lower 3-year survival (63.7% [95% CI, 60.9-66.6] vs 70.5% [95% CI, 68.0-73.0]; HR, 1.26 [95% CI, 1.10-1.44]), and the incidence of MACE was similar between both strategies (HR, 1.05 [95% CI, 0.88-1.26]). Marginal structural models confirmed the higher risk of all-cause mortality and similar risk of MACE in patients who stopped versus continued metformin (all-cause mortality: HR, 1.34 [95% CI, 1.08-1.67]; MACE: HR, 1.04 [95% CI, 0.81-1.33]). Limitations: Residual confounding. Conclusions: The continued use of metformin may be appropriate when eGFR falls below 30mL/min/1.73m(2). Randomized controlled trials are needed to confirm these findings.

The “omnigenic” hypothesis postulates that polygenic effects of common variants on typical complex traits coalesce via trans-effects on the expression of a relatively sparse set of “core” effector genes and their encoded proteins in relevant tissues. The objective of this study was to identify core proteins for type 1 diabetes. We used summary statistics for SNP associations with plasma levels of 5130 proteins in three large cohorts to compute genome-wide aggregated trans-effects (GATE) scores for protein levels in two type 1 diabetes case-control studies (6828 cases, 416,000 controls). GATE scores for 27 proteins were associated with type 1 diabetes. Fourteen were replicated between datasets, 11 had support in Mendelian randomisation analysis and 9 had experimental support in mouse models of autoimmune diabetes. The strongest associations were for immune checkpoints (PDCD1, CD5, TIGIT, LAG3), chemokines and innate immune system proteins (NCR1, KLRB1). Whilst PDCD1 is a known cause of monogenic autoimmune diabetes, neither it nor most of the core proteins identified here were previously reported as GWAS hits for type 1 diabetes. These results identify possible drug targets with genetic support for causality and suggest that PD-1 agonists under development for other indications should be trialled for type 1 diabetes prevention.

Background GLP-1 receptor agonists reduce the risk of major adverse cardiovascular events (MACE) and can also have kidney benefits. However, whether GLP-1 receptor agonists improve clinically important kidney outcomes remains uncertain. We aimed to comprehensively assess the effects of GLP-1 receptor agonists on kidney and cardiovascular disease outcomes by performing a meta-analysis of randomised controlled trials. Methods For this meta-analysis, we searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for randomised controlled trials that included at least 500 participants with type 2 diabetes, compared a GLP-1 receptor agonist with placebo with at least 12 months of follow-up, and reported a primary clinical kidney or cardiovascular outcome, from database inception to March 26, 2024. Post hoc, we included the SELECT trial (NCT03574597), which enrolled participants with cardiovascular disease and a BMI of 27 kg/m(2) or more without diabetes. Study-level summary data were extracted independently by two authors for inclusion in this random-effects analysis. The main kidney outcome was a composite outcome, consisting of kidney failure (kidney replacement therapy or a persistent estimated glomerular filtration rate [eGFR] <15 mL/min per 173 m(2)), a sustained reduction in eGFR by at least 50% or the nearest equivalent, or death from kidney failure. The main cardiovascular outcome was MACE, consisting of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. This study is registered with PROSPERO, CRD42024528864. Findings Of the 5140 records identified through the literature search, 11 trials, involving 85 373 participants (29 386 female, 55 987 male), were included in the meta-analysis. In participants with type 2 diabetes (67 769), GLP-1 receptor agonists reduced the composite kidney outcome by 18% compared with placebo (hazard ratio [HR] 082, 95% CI 073-093; I-2 =2641%), kidney failure by 16% (HR 084, 072-099; I-2 =0%), MACE by 13% (HR 087, 081-093; I-2 =4975%), and all-cause death by 12% (HR 088, 083-093; I-2 =0%). The effect on the composite kidney outcome (HR 081, 95% CI 072-092; I-2 =2311%), kidney failure (HR 084, 072-098; I-2 =0%), MACE (HR 086, 080-092; I-2 =489%), and all-cause death (HR 087, 082-091; I-2 =0%) was similar when the SELECT trial was included, with no evidence of heterogeneity between this trial and those including participants with type 2 diabetes (p(heterogeneity) >005). There was no difference in the risk of serious adverse events, including acute pancreatitis and severe hypoglycaemia, between the GLP-1 receptor agonist and placebo groups (risk ratio [RR] 095, 95% CI 090-101; I-2 =885%). However, treatment discontinuation due to adverse events occurred more frequently in the GLP-1 receptor agonist groups (RR 151, 95% CI 118-194; I-2 =963%). Interpretation We found evidence that GLP-1 receptor agonists significantly reduce clinically important kidney events, kidney failure, and cardiovascular events. Funding None. Copyright (c) 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

BACKGROUND:The SELECT trial found semaglutide reduced major adverse cardiovascular events (MACE) in patients with overweight or obesity with cardiovascular disease but without diabetes. We report a prespecified analysis of the SELECT trial on the relationships between baseline adiposity measures, treatment-induced adiposity changes, and subsequent MACE risk. METHODS:Patients aged at least 45 years, with a BMI of at least 27 kg/m2 were enrolled in 41 countries (804 sites) and randomised 1:1 to once-weekly semaglutide 2·4 mg or placebo. The primary outcome was time to first MACE (composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke). Adiposity measures included weight and waist circumference. In this analysis, risk of MACE occurring after 20 weeks was assessed between patients by adiposity changes in the first 20 weeks and, in a separate analysis, all in-trial MACE were assessed between patients by adiposity changes over 104 weeks. This trial is registered with ClinicalTrials.gov, NCT03574597. FINDINGS:Semaglutide significantly reduced MACE incidence compared with placebo among 17 604 patients enrolled in SELECT, with consistent benefits across all baseline weight and waist circumference categories. In the semaglutide group, analyses for linear trends showed lower baseline bodyweight and waist circumference were associated with lower incidence of MACE-an average 4% reduction in risk per 5 kg lower bodyweight (hazard ratio [HR] 0·96 [95% CI 0·94-0·99]; p=0·001) and per 5 cm smaller waist circumference (0·96 [0·93-0·99]; p=0·004). In the placebo group, lower baseline waist circumference (0·96 [0·94-0·99]; p=0·007), but not bodyweight (0·99 [0·97-1·01]; p=0·28), was associated with a lower MACE risk and weight loss was paradoxically associated with increased MACE risk. In those receiving semaglutide there was no linear trend linking weight loss at week 20 to subsequent MACE risk, but greater waist circumference reduction at week 20 was associated with lower subsequent MACE risk, and waist circumference reduction by week 104 was associated with lower in-trial risk of MACE. An estimated 33% of the observed benefit on MACE was mediated through waist circumference reduction (HR 0·86 [95% CI 0·77-0·97] after adjustment for time-varying changes in waist circumference). INTERPRETATION:The cardioprotective effects of semaglutide were independent of baseline adiposity and weight loss and had only a small association with waist circumference, suggesting some mechanisms for benefit beyond adiposity reduction. FUNDING:Novo Nordisk.

BACKGROUND:Genome-wide association studies of inflammatory bowel disease have identified hundreds of common genetic variants that are associated with inflammatory bowel disease, but few promising therapeutic targets. The "omnigenic" sparse effector hypothesis postulates that the polygenic effects of common SNPs on a typical complex trait are mediated by trans-effects that coalesce on the expression of a sparse set of core genes. The objective of this study was to identify core genes for inflammatory bowel disease. METHODS:Using summary statistics from studies of transcript levels in whole blood or proteins in plasma, we constructed genome-wide aggregated trans-effects (GATE) scores for predicted gene expression in the UK Biobank cohort and tested these scores for association with inflammatory bowel disease (7949 cases, 452 790 noncases). RESULTS:Inflammatory bowel disease was inversely associated with GATE scores for 5 interferon-stimulated genes-IFIT1, IFI44, HERC5, MX1, IFI44L-regulated by the same trans-expression quantitative trait locus, and with the GATE score for IFNL1. For 6 other genes, GATE score associations with inflammatory bowel disease were supported by other criteria: reported associations with nearby genetic variants, perturbation in experimental models, association with measured protein levels, or drug effects. CONCLUSIONS:These results implicate down-regulation of Type III interferon signaling as a core pathway in the etiology of inflammatory bowel disease, supported by reports of monogenic inflammatory bowel disease caused by rare loss-of-function variants and by perturbation in experimental models of colitis. Deficient Type III interferon signaling may be amenable to therapeutic intervention.