Cardiometabolic multiple long-term conditions (MLTC) arise from the complex interplay of biological, sociodemographic, environmental, and behavioural factors across the life course. Shared risk factors and mechanisms, in...Cardiometabolic multiple long-term conditions (MLTC) arise from the complex interplay of biological, sociodemographic, environmental, and behavioural factors across the life course. Shared risk factors and mechanisms, including insulin resistance, adiposity, and chronic inflammation, underpin its development. Growing evidence also implicates that even low-level, long-term exposure to fine particulate matter, nitrogen dioxide, and related pollutants can accelerate the trajectory of cardiometabolic MLTC. Early-life exposures, including undernutrition and overnutrition, altered gut microbiome, and endocrine-disrupting chemicals, interact with social determinants of health to aggravate inflammatory and metabolic dysregulation. These mechanisms, together with genetic susceptibility, epigenetic modifications, and multiomics perturbations, shape disease progression, heterogeneity, and the clustering of cardiometabolic MLTC. Yet, fundamental gaps persist, whereby most mechanistic insights are derived from single-disease studies, leaving the temporal hierarchy, causal pathways, and population-level heterogeneity largely unresolved. Addressing these challenges will require life-course research, integrative systems approaches, and translational studies that link mechanistic insights to precision prevention and therapeutic strategies. By bridging discovery with actions, such efforts can enhance care for cardiometabolic MLTC and promote equitable health outcomes globally.
Cardiometabolic multiple long-term conditions (MLTC), defined as the coexistence of two or more cardiometabolic diseases such as diabetes, cardiovascular disease, and chronic kidney disease, are increasingly prevalent an...Cardiometabolic multiple long-term conditions (MLTC), defined as the coexistence of two or more cardiometabolic diseases such as diabetes, cardiovascular disease, and chronic kidney disease, are increasingly prevalent and represent a growing challenge for health systems worldwide. Despite rising interest, progress in understanding cardiometabolic MLTC has been limited by substantial heterogeneity in definitions, measurements, and analytical approaches, restricting comparability across studies and limiting translation into clinical and public health practice. Reported prevalence estimates vary across populations, largely reflecting differences in study design and conditions included. The prevalence of cardiometabolic MLTC increases with age but is not confined to older populations, with these conditions often emerging in early adulthood, particularly among socioeconomically disadvantaged and minority ethnic populations, for whom these conditions also progress more rapidly. Longitudinal studies demonstrate disease accumulation and accelerating transitions following development of a cardiometabolic condition leading to premature mortality. These trajectories are shaped by interacting genetic, metabolic, behavioural, and psychosocial factors, while deprivation and structural inequities substantially amplify risk and earlier onset. Advancing research and improving care will require harmonised definitions, greater use of longitudinal data, and scalable analytical approaches that explicitly capture disease sequencing and transitions. To improve consistency and comparability, the definition of cardiometabolic MLTC should be standardised.
BACKGROUND: Type 2 diabetes is a complex metabolic disorder often requiring combination therapy for optimal glycaemic control. This study assessed the efficacy and safety of orforglipron, an oral, non-peptide GLP-1 recep...BACKGROUND: Type 2 diabetes is a complex metabolic disorder often requiring combination therapy for optimal glycaemic control. This study assessed the efficacy and safety of orforglipron, an oral, non-peptide GLP-1 receptor agonist, versus dapagliflozin, an oral SGLT2 inhibitor, in participants with type 2 diabetes and inadequate glycaemic control with metformin. METHODS: This 40-week, phase 3, multicentre, open-label (orforglipron dose-blinded), randomised study was conducted in 73 sites across six countries. The study included adults with type 2 diabetes using metformin (≥1500 mg/day) with glycated haemoglobin (HbA) concentrations between 7·0% and 10·5% (53-91 mmol/mol), stable bodyweight (±5%), and a BMI of 23·0 kg/m or more. Participants were randomly assigned in a 1:1:1:1 ratio to receive once-daily oral orforglipron (3 mg, 12 mg, or 36 mg) or dapagliflozin 10 mg. The primary endpoint was change from baseline in HbA at week 40, using a non-inferiority margin of 0·3% for orforglipron versus dapagliflozin; analysis was based on the treatment-regimen estimand (data obtained regardless of study intervention discontinuation or initiation of additional glucose-lowering agents). The treatment regimen estimand was the primary estimand, with the efficacy estimand considered supportive. Safety was assessed in all randomised participants who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov (NCT06192108, completed). FINDINGS: From Jan 10, 2024, to Sept 26, 2025, 1404 adults were assessed and 962 participants were randomly assigned to orforglipron 3 mg (n=240), 12 mg (n=241), or 36 mg (n=241), or dapagliflozin 10 mg (n=240). The baseline population included 474 (49%) females and had a mean age of 56·1 years (SD 11·5), HbAof 8·14% (1·04), type 2 diabetes duration of 8·0 years (6·7), and BMI of 32·6 kg/m (6·6). At week 40, for the treatment regimen estimand, all orforglipron doses were non-inferior to dapagliflozin in reducing HbA. Change from baseline in mean HbA was -1·23% (SE 0·08), -1·50% (0·08), and -1·56% (0·09) with orforglipron 3 mg, 12 mg, and 36 mg, respectively, versus -0·81% (0·07) with dapagliflozin 10 mg; estimated treatment difference versus dapagliflozin was -0·42% (95% CI -0·62 to -0·23), -0·70% (-0·90 to -0·49), and -0·75% (-0·96 to -0·55) with orforglipron 3 mg, 12 mg, and 36 mg, respectively (all p<0·0001). The most frequent adverse events associated with orforglipron were mild-to-moderate gastrointestinal events, observed in 112 (47%) of 240 participants receiving orforglipron 3 mg, 112 (46%) of 241 receiving 12 mg, and 130 (54%) of 241 receiving 36 mg, versus 29 (12%) of 240 receiving dapagliflozin. More study intervention discontinuations were observed with orforglipron 3 mg (35 [15%] of 240), 12 mg (44 [18%] of 241), and 36 mg (47 [20%] of 241) than with dapagliflozin (14 [6%] of 240). No severe episode of hypoglycaemia was reported. INTERPRETATION: Orforglipron demonstrated superior glycaemic control compared with dapagliflozin, with a tolerability profile consistent with the GLP-1 receptor agonist class, including increased rates of discontinuation due to adverse events, positioning it as a potential effective oral treatment option for type 2 diabetes. FUNDING: Eli Lilly and Company.
BACKGROUND: Elecoglipron (AZD5004) is an oral small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist administered once daily without food or fluid restriction, in development for weight management in people livi...BACKGROUND: Elecoglipron (AZD5004) is an oral small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist administered once daily without food or fluid restriction, in development for weight management in people living with obesity or overweight and type 2 diabetes. We assessed the efficacy, safety, and tolerability of elecoglipron versus placebo in participants with obesity or overweight and at least one weight-related condition without diabetes. METHODS: In this double-blind, randomised, controlled, phase 2 dose-ranging study with a total treatment duration of 36 weeks, adult participants were recruited from medical research centres and hospitals in Australia, Canada, Germany, Japan, Taiwan, the UK, and the USA. Participants were aged 18 years or older living with obesity (BMI ≥30 kg/m) or with overweight (BMI ≥27 kg/m) with at least one weight-related condition and without type 2 diabetes. Eligible participants were randomly assigned in a 2:3:3:3:3:5 ratio to receive 5 mg, 15 mg, 50 mg, 75 mg (weekly titration), or 75 mg (every 2-week titration) of elecoglipron or matching placebo. Elecoglipron was administered as oral once-daily tablets without titration (5 mg and 15 mg) and as three different dose-titration regimens. The daily dose of 50 mg was evaluated using an every-4-weeks dose-escalation schedule, while 75 mg was assessed with weekly or every 2-week dose-escalation schedules. Participants, treating physicians, and sponsor were masked to the treatment allocation. The dual primary endpoints were percent change in bodyweight from baseline and the proportion of patients reaching at least 5% weight loss at week 26. Safety and tolerability were assessed in all participants who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT06579092) and is completed. FINDINGS: From Oct 8, 2024, to Feb 18, 2025, 472 individuals were screened for potential study inclusion, 162 did not meet the inclusion criteria, and 310 participants were randomly assigned to the varied elecoglipron groups or placebo. 288 participants (93%) completed the study and 231 (75%) completed the assigned treatment. The mean age of participants was 48·4 years (SD 13·7), 225 (73%) were female, 85 (27%) were male, their mean bodyweight was 106·9 kg (SD 24·1), and their mean BMI was 38·2 kg/m (SD 7·2). At week 26, the estimated mean change from baseline in bodyweight was between -2·6% (5 mg elecoglipron), and -10·5% (75 mg with weekly titration steps) compared with -0·6% with placebo. The estimated proportion of participants reaching weight reductions of at least 5% at week 26 was 40·4-88·8% with elecoglipron versus 15·6% with placebo. Adverse events were reported by 84% (27 of 32) to 98% (48 of 49) of participants across elecoglipron doses compared with 84% (68 of 81) in the placebo group, the most common being nausea, constipation, diarrhoea, headache, and vomiting. INTERPRETATION: Daily oral elecoglipron demonstrated clinically meaningful weight reductions and a safety and tolerability profile consistent with the GLP-1 receptor agonist class in this phase 2 dose-ranging study, supporting phase 3 investigation in people living with obesity or overweight. FUNDING: AstraZeneca.
BACKGROUND: Basal insulin treatment for type 2 diabetes often results in inadequate glycaemic control and is associated with weight gain and increased risk of hypoglycaemia. We aimed to compare the efficacy and safety of...BACKGROUND: Basal insulin treatment for type 2 diabetes often results in inadequate glycaemic control and is associated with weight gain and increased risk of hypoglycaemia. We aimed to compare the efficacy and safety of a once per week combination of cagrilintide with semaglutide (CagriSema) versus placebo as an add-on to basal insulin in individuals with type 2 diabetes. METHODS: This double-blind, parallel-group, randomised, controlled, phase 3a study (REIMAGINE 3) was done at 46 centres (university hospitals, health-care centres, research centres, and other clinical trial sites) in six countries (the USA, China, Japan, Serbia, Slovakia, and South Africa). Adults with type 2 diabetes (glycated haemoglobin [HbA] 7·0-10·5%) receiving stable once per day basal insulin with or without metformin were randomly assigned (2:2:1:1) to once per week subcutaneous cagrilintide 2·4 mg plus semaglutide 2·4 mg (hereafter cagrilintide-semaglutide [2·4 mg each]) or cagrilintide 1·0 mg plus semaglutide 1·0 mg (hereafter cagrilintide-semaglutide [1·0 mg each]) or dose-matched placebo (2·4 mg plus 2·4 mg or 1·0 mg plus 1·0 mg) for 40 weeks. Randomisation was stratified by HbA of less than 8·5% at screening (yes or no) and country (Japan; yes or no). Participants, care providers, investigators, and outcome assessors were masked within each dose level to treatment allocation, with active treatments visually identical to placebo. The primary endpoint was mean HbA change (percentage points) from baseline to week 40 in all participants randomly assigned to treatment; secondary endpoints included change in bodyweight and safety, including hypoglycaemia. This trial was registered with ClinicalTrials.gov (NCT06323161) and is complete. FINDINGS: Between March 26 and Nov 29, 2024, we screened 340 individuals and 274 were included and randomly assigned to cagrilintide-semaglutide (2·4 mg each; n=90), cagrilintide-semaglutide (1·0 mg each; n=93), or placebo (pooled; n=91). Mean baseline HbA was 8·8% (SD 1·0), 159 (58%) participants were male, and 115 (42%) were female. Mean HbA reductions were significantly greater with cagrilintide-semaglutide (2·4 mg each -2·33% [SE 0·08] and 1·0 mg each -2·10% [0·08]) versus placebo (-0·66% [0·11]) at week 40, using the efficacy estimand (estimated treatment difference for cagrilintide-semaglutide [2·4 mg each] vs placebo -1·68 percentage points [95% CI -1·95 to -1·41], p<0·0001; for cagrilintide-semaglutide [1·0 mg each] vs placebo -1·44 percentage points [95% CI -1·71 to -1·17], p<0·0001). Cagrilintide-semaglutide provided bodyweight reductions of 10-12%. Adverse events were reported by 72 (80%) of 90 participants receiving cagrilintide-semaglutide (2·4 mg each), 66 (71%) of 93 receiving cagrilintide-semaglutide (1·0 mg each), and 65 (71%) of 91 receiving placebo, and were mostly mild or moderate gastrointestinal disorders. No severe hypoglycaemia was reported. There was one death in the cagrilintide-semaglutide (1·0 mg each) group not related to treatment (due to malignancy). INTERPRETATION: Cagrilintide-semaglutide at doses of 2·4 mg each and 1·0 mg each met the primary endpoint, with statistically significant and clinically relevant HbA reductions versus placebo when added to basal insulin-treated type 2 diabetes. These reductions were accompanied by robust bodyweight reduction and no additional risk of hypoglycaemia. The safety profile was consistent with that of the GLP-1 receptor agonist class and previous safety data for cagrilintide. Findings support the use of cagrilintide-semaglutide as an add-on to once per day basal insulin to significantly improve glycaemic control. FUNDING: Novo Nordisk.
BACKGROUND: Retatrutide is a GIP, GLP-1, and glucagon triple hormone receptor agonist, under clinical development for type 2 diabetes, obesity, and related complications. We aimed to assess the efficacy and safety of ret...BACKGROUND: Retatrutide is a GIP, GLP-1, and glucagon triple hormone receptor agonist, under clinical development for type 2 diabetes, obesity, and related complications. We aimed to assess the efficacy and safety of retatrutide as a monotherapy in people with type 2 diabetes that is inadequately controlled by diet and exercise alone. METHODS: In this 40-week, phase 3, randomised, double-blind, placebo-controlled trial at 48 sites in the USA, Mexico, and India, we recruited adults (aged ≥18 years) with type 2 diabetes that is inadequately controlled by diet and exercise alone, glycated haemoglobin (HbA) between 7·0% and 9·5% (53-80 mmol/mol), and BMI of at least 23 kg/m. Participants were randomly assigned (1:1:1:1) to receive retatrutide (4 mg, 9 mg, or 12 mg) or placebo by once-weekly subcutaneous injection. The primary endpoint was the change in HbA concentration from baseline to week 40. A key secondary endpoint was the percentage change in bodyweight from baseline to week 40. This trial is registered with ClinicalTrials.gov, NCT06354660, and is completed. FINDINGS: Between April 10, 2024, and April 21, 2025, 930 participants were screened and 537 (296 [55%] female and 241 [45%] male) were randomly assigned: 134 to retatrutide 4 mg, 133 to retatrutide 9 mg, 136 to retatrutide 12 mg, and 134 to placebo. Baseline mean age was 48·8 years (SD 12·1), mean HbA concentration was 7·9% (SD 1·1), mean duration of diabetes was 2·5 years (SD 4·4), and mean BMI was 35·8 kg/m (SD 7·0). 490 (91%) participants completed the treatment period on study drug and 504 (94%) completed the study. For the treatment regimen estimand, the mean change from baseline in HbA concentration was -1·69% (SE 0·11) with retatrutide 4 mg, -1·86% (0·10) with 9 mg, and -1·94% (0·08) with 12 mg, versus -0·81% (0·12) with placebo, resulting in estimated treatment differences versus placebo of -0·88% (95% CI -1·18 to -0·59) with retatrutide 4 mg, -1·04% (-1·32 to -0·76) with 9 mg, and -1·12% (-1·39 to -0·85) with 12 mg (all p<0·0001). The mean percentage change from baseline in bodyweight was -11·5% (SE 0·7) with retatrutide 4 mg, -13·9% (0·8) with 9 mg, and -15·3% (0·8) with 12 mg, versus -2·6% (0·5) with placebo. The most frequent adverse events with retatrutide were generally mild to moderate gastrointestinal events, which subsided over time. Study intervention discontinuations due to adverse events were 2-5% with retatrutide and 0% with placebo. No severe hypoglycaemia was reported. Two deaths occurred during the study, both in the retatrutide 4 mg group and unrelated to the study drug. INTERPRETATION: Retatrutide showed significant improvements in glycaemic control and bodyweight reduction as a monotherapy in adults with type 2 diabetes that is inadequately controlled with diet and exercise alone, with an adverse event profile consistent with molecules with GLP-1 agonist activity, supporting its potential as an effective treatment for type 2 diabetes. FUNDING: Eli Lilly and Company.
BACKGROUND: Overactivation of the mineralocorticoid receptor is a common pathway for chronic kidney disease (CKD) progression across multiple disease aetiologies. Finerenone, a non-steroidal mineralocorticoid receptor an...BACKGROUND: Overactivation of the mineralocorticoid receptor is a common pathway for chronic kidney disease (CKD) progression across multiple disease aetiologies. Finerenone, a non-steroidal mineralocorticoid receptor antagonist, has shown kidney and cardiovascular benefits in CKD due to type 2 diabetes, but its efficacy and safety across disease aetiologies, and levels of glycaemia, estimated glomerular filtration rate (eGFR), and albuminuria have not been evaluated. The aim of this study was to evaluate the efficacy and safety of finerenone across the spectrum of CKD. METHODS: We conducted an individual participant data meta-analysis of three randomised, double-blind, placebo-controlled trials of finerenone in patients with CKD: FIDELIO-DKD (NCT02540993; Sept 17, 2015, to April 14, 2020), FIGARO-DKD (NCT02545049; Sept 17, 2015, to Feb 2, 2021), and FIND-CKD (NCT05047263; Sept 21, 2021, to Feb 2, 2026). We used Cox regression models to evaluate relative effects on kidney and cardiovascular outcomes. The main kidney outcome was kidney failure or sustained 57% or more decline in eGFR; the main cardiovascular outcome was hospitalisation for heart failure or cardiovascular death. This study was registered with PROSPERO, CRD420251269149. FINDINGS: Across the three trials enrolling 14 574 participants, the mean age was 63·7 years (SD 10·6), 4467 (30·7%) were female, 10 107 (69·3%) were male, mean eGFR was 56·4 mL/min per 1·73 m (SD 21·4), and median urinary albumin-to-creatinine ratio was 567·4 mg/g (IQR 233·6-1164·7). Finerenone reduced the risk of the composite kidney outcome by 24% versus placebo (22·3 vs 28·8 events per 1000 patient-years; hazard ratio 0·76 [95% CI 0·68-0·86]) and kidney failure alone (0·85 [0·74-0·99]). Finerenone reduced the risk of the composite cardiovascular outcome versus placebo (19·1 vs 23·9 events per 1000 patient-years; 0·80 [0·70-0·91]), including heart failure hospitalisation (0·78 [0·66-0·92]) and cardiovascular death (0·82 [0·67-0·999]). Finerenone also reduced the risk of all-cause death (0·88 [0·79-0·99]). Treatment effects on the composite kidney outcome were consistent irrespective of glycaemic status, CKD aetiology, baseline eGFR, albuminuria, and use of sodium-glucose co-transporter-2 inhibitors. Hyperkalaemia occurred more frequently with finerenone than with placebo, but the absolute incidence of hyperkalaemia leading to hospitalisation was low. INTERPRETATION: In the studied populations with CKD, finerenone reduced the risk of CKD progression, including kidney failure alone, and reduced heart failure hospitalisation, cardiovascular death, and all-cause death. These findings support finerenone as a foundational therapy for CKD across a broad range of disease aetiologies and levels of glycaemia, eGFR, and albuminuria. FUNDING: Bayer.
André E, Ssengooba W, Berner-Rodoreda A
… +16 more, Bahizire E, Skordis J, Ngabonziza JS, Fröschl G, Yazdanpanah Y, Liesenborghs L, Bassat Q, Ismail K, Vlieghe E, de Waroux OLP, Schreijer A, Simonian G, Grais R, Fall IS, Piot P, Mbala-Kingebeni P
Heerspink HJL, Jardine MJ, Kohan DE
… +20 more, Lafayette R, Levin A, Liew A, Zhang H, Noronha IL, Mastroianni-Kirsztajn G, Chow S, Choi DE, Lv J, Trimarchi H, Fu P, Guenther S, Yang S, Liu J, Rahalkar S, Lodha A, Dahlke M, Kollins D, Barratt J, ALIGN study group
BACKGROUND: Atrasentan, a selective endothelin A receptor antagonist, reduced proteinuria in the prespecified interim analysis (week 36) of the ALIGN trial in adults with IgA nephropathy. We assessed whether atrasentan s...BACKGROUND: Atrasentan, a selective endothelin A receptor antagonist, reduced proteinuria in the prespecified interim analysis (week 36) of the ALIGN trial in adults with IgA nephropathy. We assessed whether atrasentan slowed estimated glomerular filtration rate (eGFR) decline after 2·5 years' treatment. METHODS: We performed a randomised, double-blind, placebo-controlled, phase 3 trial (133 sites, 20 countries). Adults with biopsy-proven IgA nephropathy, eGFR of at least 30 mL/min per 1·73 m, and urinary protein excretion of at least 1·0 g/day while receiving renin-angiotensin system inhibition were enrolled (main stratum). An exploratory stratum enrolled participants also receiving an SGLT2 inhibitor. Participants were randomly assigned (1:1) to oral atrasentan 0·75 mg once daily or placebo for 132 weeks, followed by a 4-week off-treatment follow-up. The key secondary endpoint was change from baseline to week 136 in eGFR in the main stratum, assessed in all randomised patients (excluding data after intercurrent events, defined as initiation of restricted or alternative IgA nephropathy medications or kidney replacement therapy). Safety was assessed in all randomised patients who received at least one dose of study treatment. ALIGN is registered with ClinicalTrials.gov, NCT04573478; the double-blind section is complete, and the open-label extension is ongoing. FINDINGS: Between March 15, 2021, and April 28, 2023, 404 participants were randomly assigned (main stratum: 340; SGLT2 inhibitor stratum: 64). In the main stratum, change from baseline in eGFR at week 136 was -7·5 mL/min per 1·73 m (95% CI -9·2 to -5·8) with atrasentan and -9·9 mL/min per 1·73 m (-11·7 to -8·1) with placebo (between-group difference 2·4 mL/min per 1·73 m; 95% CI -0·1 to 4·8; p=0·057). The between-group difference in eGFR change from baseline at end of treatment (week 132) was 2·6 mL/min per 1·73 m (95% CI 0·1-5·0), and the difference in total eGFR slope (baseline to week 136) was 1·4 mL/min per 1·73 m per year (95% CI 0·5-2·3). In the SGLT2 inhibitor stratum, the difference in eGFR change from baseline at week 136 between atrasentan and placebo was 9·1 mL/min per 1·73 m (95% CI 3·0-15·2). Treatment-emergent adverse events were well balanced between atrasentan and placebo, with no new safety signals. In the main stratum, fluid retention adverse events occurred in 24 (14%) of 169 patients receiving atrasentan and 20 (12%) of 170 receiving placebo. INTERPRETATION: Atrasentan reduced proteinuria and preserved kidney function after 2·5 years. This effect was present with or without concomitant SGLT2 inhibitor use. Atrasentan was well tolerated. FUNDING: Novartis.