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Cotadutide is a glucagon-like peptide-1 (GLP-1) and glucagon receptor agonist that may improve kidney function in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). In this phase 2b study, patients with T2D and CKD (estimated glomerular filtration rate [eGFR] of 20 or more and under 90 mL/min per 1.73 m 2 and urinary albumin-to-creatinine ratio [UACR] over 50 mg/g) were randomized 1:1:1:1:1 to 26 weeks' treatment with standard of care plus subcutaneous cotadutide uptitrated to 100, 300, or 600 μg, or placebo daily (double-blind), or the GLP-1 agonist semaglutide 1 mg once weekly (open-label).The co-primary endpoints were absolute and percentage change versus placebo in UACR from baseline to the end of week 14. Among 248 randomized patients, mean age 67.1 years, 19% were female, mean eGFR was 55.3 mL/min per 1.73 m 2 , geometric mean was UACR 205.5 mg/g (coefficient of variation 270.0), and 46.8% were receiving concomitant sodium-glucose co-transporter 2 inhibitors. Cotadutide dose-dependently reduced UACR from baseline to the end of week 14, reaching significance at 300 μg (-43.9% [95% confidence interval -54.7 to -30.6]) and 600 μg (-49.9% [-59.3 to -38.4]) versus placebo; with effects sustained at week 26. Serious adverse events were balanced across arms. Safety and tolerability of cotadutide 600 μg were comparable to semaglutide. Thus, our study shows that in patients with T2D and CKD, cotadutide significantly reduced UACR on top of standard of care with an acceptable tolerability profile, suggesting kidney protective benefits that need confirmation in a larger study., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Aim: Hypertension and diabetes mellitus (DM) are major causes of morbidity and mortality, with growing burdens in low-income countries where they are underdiagnosed and undertreated. Advances in machine learning may provide opportunities to enhance diagnostics in settings with limited medical infrastructure., Materials and Methods: A non-interventional study was conducted to develop and validate a machine learning algorithm to estimate cardiovascular clinical and laboratory parameters. At two sites in Kenya, digital retinal fundus photographs were collected alongside blood pressure (BP), laboratory measures and medical history. The performance of machine learning models, originally trained using data from the UK Biobank, were evaluated for their ability to estimate BP, glycated haemoglobin, estimated glomerular filtration rate and diagnoses from fundus images., Results: In total, 301 participants were enrolled. Compared with the UK Biobank population used for algorithm development, participants from Kenya were younger and would probably report Black/African ethnicity, with a higher body mass index and prevalence of DM and hypertension. The mean absolute error was comparable or slightly greater for systolic BP, diastolic BP, glycated haemoglobin and estimated glomerular filtration rate. The model trained to identify DM had an area under the receiver operating curve of 0.762 (0.818 in the UK Biobank) and the hypertension model had an area under the receiver operating curve of 0.765 (0.738 in the UK Biobank)., Conclusions: In a Kenyan population, machine learning models estimated cardiovascular parameters with comparable or slightly lower accuracy than in the population where they were trained, suggesting model recalibration may be appropriate. This study represents an incremental step toward leveraging machine learning to make early cardiovascular screening more accessible, particularly in resource-limited settings., (© 2024 AstraZeneca. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Cotadutide is a dual glucagon-like peptide 1 and glucagon receptor agonist under development for the treatment of non-alcoholic steatohepatitis and type 2 diabetes mellitus (T2DM) and chronic kidney disease. Non-alcoholic steatohepatitis is a complex disease with no approved pharmacotherapies, arising from an underlying state of systemic metabolic dysfunction in association with T2DM and obesity. Cotadutide has been shown to improve glycaemic control, body weight, lipids, liver fat, inflammation and fibrosis. We conducted a two-part, randomized phase 2a trial in men and women with overweight or obesity diagnosed with T2DM to evaluate the efficacy and safety of cotadutide compared with placebo and liraglutide. The primary endpoints were change from baseline to day 28 of treatment in postprandial hepatic glycogen (part A) and to day 35 of treatment in fasting hepatic glycogen (part B) with cotadutide versus placebo. Secondary endpoints in part B were changes in fasting hepatic glycogen with cotadutide versus the mono glucagon-like peptide 1 receptor agonist, liraglutide, and change in hepatic fat fraction. The trial met its primary endpoint. We showed that cotadutide promotes greater reductions in liver glycogen and fat compared with placebo and liraglutide. Safety and tolerability findings with cotadutide were comparable to those of previous reports. Thus, this work provides evidence of additional benefits of cotadutide that could be attributed to glucagon receptor engagement. Our results suggest that cotadutide acts on the glucagon receptor in the human liver to promote glycogenolysis and improve the metabolic health of the liver. ClinicalTrials.gov registration: NCT03555994 ., (© 2023. The Author(s).)

Background and Objective: Zibotentan, a selective endothelin A receptor antagonist, is in development for chronic liver and kidney disease. The pharmacokinetics (PK) of zibotentan were previously investigated in patients with either renal impairment or hepatic impairment, but the impact of both pathologies on PK was not evaluated. This study evaluated the PK and tolerability of a single oral dose of zibotentan in participants with concurrent moderate renal impairment and moderate hepatic impairment versus control participants., Methods: Twelve participants with moderate renal and hepatic impairment and 11 healthy matched control participants with no clinically significant liver or kidney disease were enrolled in an open-label, parallel-group study design. After administration of a single oral dose of zibotentan 5 mg, blood and urine sampling was performed. Pharmacokinetic parameters were determined for each of the two cohorts and compared. Comparisons between the cohorts were based on the geometric least squares mean ratio for the primary endpoints, which were area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC ∞ ) and from time zero to the time of the last measurable concentration (AUC last ), and maximum plasma drug concentration (C max ) on Day 1 through 120 h post-dose. Secondary endpoints included apparent total body clearance (CL/F) on Day 1 through 120 h post-dose. Safety endpoints were assessed up to discharge., Results: In total, 11 participants with concurrent moderate renal and hepatic impairment, and 11 controls, completed the study. Zibotentan was generally well tolerated, and no new clinically significant safety findings were observed. Total exposure (AUC ∞ and AUC last ) was approximately 2.10-fold higher in participants with concurrent moderate renal and hepatic impairment versus controls, while C max and total nonrenal body clearance were similar among all groups. A regression-based post hoc analysis, comparing exposure and CL/F in patients with concurrent impairment to patients with either renal or hepatic impairment alone, showed that CL/F with concurrent impairment was approximately half of that in controls and was positively correlated with reduction of renal function. Inclusion of the data on concurrent moderate renal and hepatic impairment in the regression analysis led to a narrower confidence interval for the predicted mean CL/F in participants with moderate hepatic impairment., Conclusion: The presented findings advance the understanding of the PK of zibotentan in both renal impairment and hepatic impairment, with and without overlapping pathologies, and will thus increase the confidence of dose selection in future studies, particularly in vulnerable patient populations with concurrent renal and hepatic impairment., Trial Registration: ClinicalTrials.gov identifier: NCT05112419., (© 2023. The Author(s).)

Objective: Cirrhosis describes the end-stage of chronic liver disease. Irreversible changes in the liver cause portal hypertension, which can progress to serious complications and death. Only a few studies with small sample sizes have investigated the prognosis of cirrhosis with portal hypertension. We used electronic healthcare records to examine liver-related outcomes in patients with diagnosed/suspected portal hypertension., Design: This retrospective observational cohort study used secondary health data between 1 January 2017 and 3 December 2020 from the TriNetX Network, a federated electronic healthcare records platform. Three patient groups with cirrhosis and diagnosed/suspected portal hypertension were identified ('most severe', 'moderate severity' and 'least severe'). Outcomes studied individually and as a composite were variceal haemorrhage, hepatic encephalopathy, complications of ascites and recorded mortality up to 24 months., Results: There were 13 444, 23 299, and 23 836 patients in the most severe, moderate severity and least severe groups, respectively. Mean age was similar across groups; most participants were white. The most common individual outcomes at 24 months were variceal haemorrhage in the most severe group, recorded mortality and hepatic encephalopathy in the moderate severity group, and recorded mortality in the least severe group. Recorded mortality rate was similar across groups. For the composite outcome, cumulative incidence was 59% in the most severe group at 6 months. Alcohol-associated liver disease and metabolic-associated steatohepatitis were significantly associated with the composite outcome across groups., Conclusion: Our analysis of a large dataset from electronic healthcare records illustrates the poor prognosis of patients with diagnosed/suspected portal hypertension., Competing Interests: Competing interests: NHCL was employed by AstraZeneca during the majority of her contributions. SJK is an employee of and owns shares in AstraZeneca. SC is an employee of ZS and worked as a contractor for AstraZeneca. SA is an employee of ZS and worked as a contractor for AstraZeneca. DMB is an employee of and owns shares in AstraZeneca. PRH was employed by AstraZeneca during the majority of his contributions and owned shares in AstraZeneca at the time the work was conducted. VERP is an employee of and owns shares in AstraZeneca. PJG is an employee of and owns shares in AstraZeneca. PA is an employee of and owns shares in AstraZeneca., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: To assess the efficacy, safety and tolerability of cotadutide in patients with type 2 diabetes mellitus and chronic kidney disease., Materials and Methods: In this phase 2a study (NCT03550378), patients with body mass index 25-45 kg/m 2 , estimated glomerular filtration rate 30-59 ml/min/1.73 m 2 and type 2 diabetes [glycated haemoglobin 6.5-10.5% (48-91 mmol/mol)] controlled with insulin and/or oral therapy combination, were randomized 1:1 to once-daily subcutaneous cotadutide (50-300 μg) or placebo for 32 days. The primary endpoint was plasma glucose concentration assessed using a mixed-meal tolerance test., Results: Participants receiving cotadutide (n = 21) had significant reductions in the mixed-meal tolerance test area under the glucose concentration-time curve (-26.71% vs. +3.68%, p < .001), more time in target glucose range on continuous glucose monitoring (+14.79% vs. -21.23%, p = .001) and significant reductions in absolute bodyweight (-3.41 kg vs. -0.13 kg, p < .001) versus placebo (n = 20). In patients with baseline micro- or macroalbuminuria (n = 18), urinary albumin-to-creatinine ratios decreased by 51% at day 32 with cotadutide versus placebo (p = .0504). No statistically significant difference was observed in mean change in estimated glomerular filtration rate between treatments. Mild/moderate adverse events occurred in 71.4% of participants receiving cotadutide and 35.0% receiving placebo., Conclusions: We established the efficacy of cotadutide in this patient population, with significantly improved postprandial glucose control and reduced bodyweight versus placebo. Reductions in urinary albumin-to-creatinine ratios suggest potential benefits of cotadutide on kidney function, supporting further evaluation in larger, longer-term clinical trials., (© 2022 AstraZeneca. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Purpose: PIK3CA pathogenic variants in the PIK3CA-related overgrowth spectrum (PROS) activate phosphoinositide 3-kinase signaling, providing a rationale for targeted therapy, but no drug has proven efficacy and safety in this population. Our aim was to establish the six-month tolerability and efficacy of low-dose taselisib, a selective class I PI3K inhibitor, in PROS patients., Methods: Patients over 16 years with PROS and PIK3CA pathogenic variants were included in a phase IB/IIA multicenter, open-label single-arm trial (six patients at 1 mg/day of taselisib, then 24 at 2 mg/day). The primary outcome was the occurrence of dose limiting toxicity (DLT). Efficacy outcomes were the relative changes after treatment of (1) tissue volume at affected and unaffected sites, both clinically and on imaging; (2) cutaneous vascular outcomes when relevant; (3) biologic parameters; (4) quality of life; and (5) patient-reported outcomes., Results: Among 19 enrolled patients, 2 experienced a DLT (enteritis and pachymeningitis) leading to early trial termination (17 treated, 10 completed the study). No serious adverse reaction occurred in the 1 mg cohort (n = 6). No significant reduction in affected tissue volume was observed (mean -4.2%; p = 0.81; SD 14.01). Thirteen (76.4%) participants reported clinical improvement (pain reduction, chronic bleeding resolution, functional improvement)., Conclusion: Despite functional improvement, the safety profile of low-dose taselisib precludes its long-term use., (© 2021. The Author(s).)

Purpose: Hypomelanosis of Ito (HI) is a skin marker of somatic mosaicism. Mosaic MTOR pathogenic variants have been reported in HI with brain overgrowth. We sought to delineate further the pigmentary skin phenotype and clinical spectrum of neurodevelopmental manifestations of MTOR-related HI., Methods: From two cohorts totaling 71 patients with pigmentary mosaicism, we identified 14 patients with Blaschko-linear and one with flag-like pigmentation abnormalities, psychomotor impairment or seizures, and a postzygotic MTOR variant in skin. Patient records, including brain magnetic resonance image (MRI) were reviewed. Immunostaining (n = 3) for melanocyte markers and ultrastructural studies (n = 2) were performed on skin biopsies., Results: MTOR variants were present in skin, but absent from blood in half of cases. In a patient (p.[Glu2419Lys] variant), phosphorylation of p70S6K was constitutively increased. In hypopigmented skin of two patients, we found a decrease in stage 4 melanosomes in melanocytes and keratinocytes. Most patients (80%) had macrocephaly or (hemi)megalencephaly on MRI., Conclusion: MTOR-related HI is a recognizable neurocutaneous phenotype of patterned dyspigmentation, epilepsy, intellectual deficiency, and brain overgrowth, and a distinct subtype of hypomelanosis related to somatic mosaicism. Hypopigmentation may be due to a defect in melanogenesis, through mTORC1 activation, similar to hypochromic patches in tuberous sclerosis complex., (© 2021. The Author(s).)

Context: Cotadutide is a dual receptor agonist with balanced glucagon-like peptide-1 and glucagon activity., Objective: To evaluate different doses of cotadutide and investigate underlying mechanisms for its glucose-lowering effects., Design/setting: Randomized, double-blind, phase 2a study conducted in 2 cohorts at 5 clinical trial sites., Patients: Participants were 65 adult overweight/obese patients with type 2 diabetes mellitus; 63 completed the study; 2 were withdrawn due to AEs., Intervention: Once-daily subcutaneous cotadutide or placebo for 49 days. Doses (50-300 µg) were uptitrated weekly (cohort 1) or biweekly (cohort 2)., Main Outcome Measures: Co-primary end points (cohort 1) were percentage changes from baseline to end of treatment in glucose (area under the curve from 0 to 4 hours [AUC0-4h]) post-mixed-meal tolerance test (MMTT) and weight. Exploratory measures included postprandial insulin and gastric emptying time (GET; cohort 2)., Results: Patients received cotadutide (cohort 1, n = 26; cohort 2, n = 20) or placebo (cohort 1, n = 13; cohort 2, n = 6). Significant reductions were observed with cotadutide vs placebo in glucose AUC0-4h post MMTT (least squares mean [90% CI], -21.52% [-25.68, -17.37] vs 6.32% [0.45, 12.20]; P < 0.001) and body weight (-3.41% [-4.37, -2.44] vs -0.08% [-1.45, 1.28]; P = 0.002). A significant increase in insulin AUC0-4h post MMTT was observed with cotadutide (19.3 mU.h/L [5.9, 32.6]; P = 0.008) and GET was prolonged on day 43 with cotadutide vs placebo (t½: 117.2 minutes vs -42.9 minutes; P = 0.0392)., Conclusion: These results suggest that the glucose-lowering effects of cotadutide are mediated by enhanced insulin secretion and delayed gastric emptying., Trial Registration: ClinicalTrials.gov, NCT03244800., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: PIK3CA-related overgrowth spectrum (PROS) encompasses a range of debilitating conditions defined by asymmetric overgrowth caused by mosaic activating PIK3CA variants. PIK3CA encodes the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), a critical transducer of growth factor signaling. As mTOR mediates the growth-promoting actions of PI3K, we hypothesized that the mTOR inhibitor sirolimus would slow pathological overgrowth., Methods: Thirty-nine participants with PROS and progressive overgrowth were enrolled into open-label studies across three centers, and results were pooled. For the primary outcome, tissue volumes at affected and unaffected sites were measured by dual energy X-ray absorptiometry during 26 weeks of untreated run-in and 26 weeks of sirolimus therapy., Results: Thirty participants completed the study. Sirolimus led to a change in mean percentage total tissue volume of -7.2% (SD 16.0, p = 0.04) at affected sites, but not at unaffected sites (+1.7%, SD 11.5, p = 0.48) (n = 23 evaluable). Twenty-eight of 39 (72%) participants had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently., Conclusion: This study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk-benefit evaluations for sirolimus treatment in PROS.

Mutations in PIK3CA are very frequent in cancer and lead to sustained PI3K pathway activation. The impact of acute expression of mutant PIK3CA during early stages of malignancy is unknown. Using a mouse model to activate the Pik3ca H1047R hotspot mutation in the heterozygous state from its endogenous locus, we here report that mutant Pik3ca induces centrosome amplification in cultured cells (through a pathway involving AKT, ROCK and CDK2/Cyclin E-nucleophosmin) and in mouse tissues, and increased in vitro cellular tolerance to spontaneous genome doubling. We also present evidence that the majority of PIK3CA H1047R mutations in the TCGA breast cancer cohort precede genome doubling. These previously unappreciated roles of PIK3CA mutation show that PI3K signalling can contribute to the generation of irreversible genomic changes in cancer. While this can limit the impact of PI3K-targeted therapies, these findings also open the opportunity for therapeutic approaches aimed at limiting tumour heterogeneity and evolution.

Neurofibromatosis type 1 (NF1; OMIM 162200), a dominantly inherited multitumor syndrome, results from mutations in the Neurofibromin 1 (NF1) gene. We present the case of a Hungarian woman with the clinical phenotype of NF1 over her whole body and the clinical features of unilateral overgrowth involving her entire left leg. This unusual phenotype suggested either the atypical form of NF1 or the coexistence of NF1 and overgrowth syndrome. Direct sequencing of the genomic DNA isolated from peripheral blood revealed a novel frameshift mutation (c.5727insT, p.V1909fsX1912) in the NF1 gene. Next-generation sequencing of 50 oncogenes and tumour suppressor genes, performed on the genomic DNAs isolated from tissue samples and peripheral blood, detected only wild-type sequences. Based on these results, we concluded that the patient is affected by an unusual phenotype of NF1, and that the observed unilateral overgrowth of the left leg might be a rare consequence of the identified c.5727insT mutation., (© 2017 British Association of Dermatologists.)

Objective: Genetic activation of the insulin signal-transducing kinase AKT2 causes syndromic hypoketotic hypoglycaemia without elevated insulin. Mosaic activating mutations in class 1A phospatidylinositol-3-kinase (PI3K), upstream from AKT2 in insulin signalling, are known to cause segmental overgrowth, but the metabolic consequences have not been systematically reported. We assess the metabolic phenotype of 22 patients with mosaic activating mutations affecting PI3K, thereby providing new insight into the metabolic function of this complex node in insulin signal transduction., Methods: Three patients with megalencephaly, diffuse asymmetric overgrowth, hypoketotic, hypoinsulinaemic hypoglycaemia and no AKT2 mutation underwent further genetic, clinical and metabolic investigation. Signalling in dermal fibroblasts from one patient and efficacy of the mTOR inhibitor Sirolimus on pathway activation were examined. Finally, the metabolic profile of a cohort of 19 further patients with mosaic activating mutations in PI3K was assessed., Results: In the first three patients, mosaic mutations in PIK3CA (p.Gly118Asp or p.Glu726Lys) or PIK3R2 (p.Gly373Arg) were found. In different tissue samples available from one patient, the PIK3CA p.Glu726Lys mutation was present at burdens from 24% to 42%, with the highest level in the liver. Dermal fibroblasts showed increased basal AKT phosphorylation which was potently suppressed by Sirolimus. Nineteen further patients with mosaic mutations in PIK3CA had neither clinical nor biochemical evidence of hypoglycaemia., Conclusions: Mosaic mutations activating class 1A PI3K cause severe non-ketotic hypoglycaemia in a subset of patients, with the metabolic phenotype presumably related to the extent of mosaicism within the liver. mTOR or PI3K inhibitors offer the prospect for future therapy., (© 2017 The authors.)