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1.
Basic Res Cardiol ; 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38922408

RESUMO

Combined [18F]FDG PET-cardiac MRI imaging (PET/CMR) is a useful tool to assess myocardial viability and cardiac function in patients with acute myocardial infarction (AMI). Here, we evaluated the prognostic value of PET/CMR in a porcine closed-chest reperfused AMI (rAMI) model. Late gadolinium enhancement by PET/CMR imaging displayed tracer uptake defect at the infarction site by 3 days after the rAMI in the majority of the animals (group Match, n = 28). Increased [18F]FDG uptake at the infarcted area (metabolism/contractility mismatch) with reduced tracer uptake in the remote viable myocardium (group Mismatch, n = 12) 3 days after rAMI was observed in the animals with larger infarct size and worse left ventricular ejection fraction (LVEF) (34 ± 8.7 vs 42.0 ± 5.2%), with lower LVEF also at the 1-month follow-up (35.8 ± 9.5 vs 43.0 ± 6.3%). Transcriptome analyses by bulk and single-nuclei RNA sequencing of the infarcted myocardium and border zones (n = 3 of each group, and 3 sham-operated controls) revealed a strong inflammatory response with infiltration of monocytes and macrophages in the infarcted and border areas in Mismatch animals. Our data indicate a high prognostic relevance of combined PET/MRI in the subacute phase of rAMI for subsequent impairment of heart function and underline the adverse effects of an excessive activation of the innate immune system in the initial phase after rAMI.

2.
Artigo em Inglês | MEDLINE | ID: mdl-38824910

RESUMO

CONTEXT: People with clinically diagnosed type 2 diabetes (T2D) but positive anti-glutamic acid decarboxylase autoantibodies (GADA), referred to here as latent autoimmune diabetes in adults (LADA), may experience more rapid glycemic deterioration than those with T2D and may benefit from effective diabetes treatment with additional metabolic benefits. OBJECTIVE: Assess glycated hemoglobin (HbA1c) and body weight (BW) changes associated with tirzepatide in GADA-positive versus GADA-negative participants with clinical T2D diagnosis. DESIGN: Post hoc analyses based on pooled data from SURPASS 2-5, using mixed-model repeated measures from the efficacy analysis set, adjusting for study and baseline covariates including age, sex, baseline values, body mass index (BMI), and GADA status. SETTING: N/A. PATIENTS: N = 3791. INTERVENTION: Tirzepatide (5, 10, 15 mg). MAIN OUTCOME MEASURE(S): Change from baseline in HbA1c at Weeks 40 (SURPASS-2, -3, -5) and 42 (SURPASS-4)by GADA status. RESULTS: In participants with confirmed GADA status, 3671 (96.8%) were GADA-negative and 120 (3.2%) were GADA-positive (76 [63.3%] with low and 44 [36.7%] with high GADA levels). Baseline characteristics were similar between groups, except for slightly lower BMI in GADA-positive versus GADA-negative participants (mean [SD] BMI 32.2 [6.1] versus 33.6 [6.3] kg/m2). At Week 40/42, both groups achieved robust reductions in HbA1c (-2.11% versus -2.32%) and BW (9.2 kg versus -9.6 kg) (p < 0.001, both groups). HbA1c reductions were greater in GADA-negative participants (estimated difference [95% CI]: 0.21% [0.03, 0.39]; p = 0.024) and BW reductions did not differ between groups (0.38 kg [-0.99, 1.75]; p = 0.588). CONCLUSIONS: In this post hoc analysis, tirzepatide was associated with substantial reductions in HbA1c and BW irrespective of GADA status in adults diagnosed with T2D, suggesting that tirzepatide may improve glycemic control in individuals with LADA.

3.
Artigo em Inglês | MEDLINE | ID: mdl-38686701

RESUMO

CONTEXT: The role of glucagon-like peptide-1(GLP-1) in Type 2 diabetes (T2D) and obesity is not fully understood. OBJECTIVE: We investigate the association of cardiometabolic, diet and lifestyle parameters on fasting and postprandial GLP-1 in people at risk of, or living with, T2D. METHOD: We analysed cross-sectional data from the two Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) cohorts, cohort 1(n=2127) individuals at risk of diabetes; cohort 2 (n=789) individuals with new-onset of T2D. RESULTS: Our multiple regression analysis reveals that fasting total GLP-1 is associated with an insulin resistant phenotype and observe a strong independent relationship with male sex, increased adiposity and liver fat particularly in the prediabetes population. In contrast, we showed that incremental GLP-1 decreases with worsening glycaemia, higher adiposity, liver fat, male sex and reduced insulin sensitivity in the prediabetes cohort. Higher fasting total GLP-1 was associated with a low intake of wholegrain, fruit and vegetables inpeople with prediabetes, and with a high intake of red meat and alcohol in people with diabetes. CONCLUSION: These studies provide novel insights into the association between fasting and incremental GLP-1, metabolic traits of diabetes and obesity, and dietary intake and raise intriguing questions regarding the relevance of fasting GLP-1 in the pathophysiology T2D.

4.
Cardiovasc Diabetol ; 23(1): 63, 2024 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-38341541

RESUMO

BACKGROUND: Metabolic syndrome is characterized as the co-occurrence of interrelated cardiovascular risk factors, including insulin resistance, hyperinsulinemia, abdominal obesity, dyslipidemia and hypertension. Once weekly tirzepatide is approved in the US and EU for the treatment of type 2 diabetes (T2D) and obesity. In the SURPASS clinical trial program for T2D, tirzepatide demonstrated greater improvements in glycemic control, body weight reduction and other cardiometabolic risk factors versus placebo, subcutaneous semaglutide 1 mg, insulin degludec, and insulin glargine. This post hoc analysis assessed the effect of tirzepatide use on the prevalence of patients meeting the criteria for metabolic syndrome across SURPASS 1-5. METHODS: Metabolic syndrome was defined as having ≥ 3 of 5 criteria according to the US National Cholesterol Education Program: Adult Treatment Panel III. Analyses were based on on-treatment data at the primary endpoint from patients adherent to treatment (taking ≥ 75% study drug). A logistic regression model with metabolic syndrome status as the response variable, metabolic syndrome status at the baseline visit as an adjustment, and randomized treatment as fixed explanatory effect was used. The effect of tirzepatide use on the prevalence of patients meeting the criteria for metabolic syndrome by categorical weight loss, background medication and gender were assessed. RESULTS: In SURPASS, the prevalence of patients meeting the criteria for metabolic syndrome at baseline was 67-88% across treatment groups with reductions at the primary endpoint to 38-64% with tirzepatide versus 64-82% with comparators. Reductions in the prevalence of patients meeting the criteria for metabolic syndrome was significantly greater with all tirzepatide doses versus placebo, semaglutide 1 mg, insulin glargine, and insulin degludec (p < 0.001). Individual components of metabolic syndrome were also reduced to a greater extent with tirzepatide vs comparators. Greater reductions in body weight were associated with greater reductions in the prevalence of patients meeting the criteria for metabolic syndrome and its individual components. Background SGLT2i or sulfonylurea use or gender did not impact the change in prevalence of patients meeting the criteria for metabolic syndrome. CONCLUSIONS: In this post hoc analysis, tirzepatide at all doses studied was associated with a greater reduction in the prevalence of patients meeting the criteria for metabolic syndrome compared to placebo, semaglutide 1 mg, insulin degludec, and insulin glargine. Although more evidence is needed, these data would support greater potential improvement in cardiovascular risk factor profile with tirzepatide treatment in people across the continuum of T2D.


Assuntos
Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 2 , Síndrome Metabólica , Adulto , Humanos , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/epidemiologia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Prevalência , Insulina Glargina , Polipeptídeo Inibidor Gástrico , Obesidade , Peso Corporal , Hipoglicemiantes/efeitos adversos
5.
Am Heart J ; 267: 1-11, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37758044

RESUMO

BACKGROUND: Tirzepatide, a once-weekly GIP/GLP-1 receptor agonist, reduces blood glucose and body weight in people with type 2 diabetes. The cardiovascular (CV) safety and efficacy of tirzepatide have not been definitively assessed in a cardiovascular outcomes trial. METHODS: Tirzepatide is being studied in a randomized, double-blind, active-controlled CV outcomes trial. People with type 2 diabetes aged ≥40 years, with established atherosclerotic CV disease, HbA1c ≥7% to ≤10.5%, and body mass index ≥25 kg/m2 were randomized 1:1 to once weekly subcutaneous injection of either tirzepatide up to 15 mg or dulaglutide 1.5 mg. The primary outcome is time to first occurrence of any major adverse cardiovascular event (MACE), defined as CV death, myocardial infarction, or stroke. The trial is event-driven and planned to continue until ≥1,615 participants experience an adjudication-confirmed component of MACE. The primary analysis is noninferiority for time to first MACE of tirzepatide vs dulaglutide by demonstrating an upper confidence limit <1.05, which will also confirm superiority vs a putative placebo, and also to determine whether tirzepatide produces a greater CV benefit than dulaglutide (superiority analysis). RESULTS: Over 2 years, 13,299 people at 640 sites in 30 countries across all world regions were randomized. The mean age of randomized participants at baseline was 64.1 years, diabetes duration 14.7 years, HbA1c 8.4%, and BMI 32.6 kg/m2. Overall, 65.0% had coronary disease, of whom 47.3% reported prior myocardial infarction and 57.4% had prior coronary revascularization. 19.1% of participants had a prior stroke and 25.3% had peripheral artery disease. The trial is fully recruited and ongoing. CONCLUSION: SURPASS-CVOT will provide definitive evidence as to the CV safety and efficacy of tirzepatide as compared with dulaglutide, a GLP-1 receptor agonist with established CV benefit.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Infarto do Miocárdio , Acidente Vascular Cerebral , Humanos , Pessoa de Meia-Idade , Aterosclerose/complicações , Aterosclerose/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon , Hemoglobinas Glicadas , Hipoglicemiantes , Infarto do Miocárdio/tratamento farmacológico , Acidente Vascular Cerebral/induzido quimicamente , Resultado do Tratamento , Método Duplo-Cego
6.
Diabetes Res Clin Pract ; 202: 110770, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37279858

RESUMO

Tirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist (GIP/GLP-1 RA) improves glycemic control. Besides improvement of glycemic control, tirzepatide treatment is associated with significantly more weight loss as compared to potent selective GLP-1 receptor agonists as well as other beneficial changes in cardio-metabolic parameters, such as reduced fat mass, blood pressure, improved insulin sensitivity, lipoprotein concentrations, and circulating metabolic profile in individuals with type 2 diabetes (T2D). Some of these changes are partially associated with weight reduction. We review here the putative mechanisms of GIP receptor agonism contributing to GLP-1 receptor agonism-induced weight loss and respective findings with GIP/GLP-1 RAs, including tirzepatide in T2D preclinical models and clinical studies. Subsequently, we summarize the clinical data on weight loss and related non-glycemic metabolic changes of tirzepatide in T2D. These findings suggest that the robust weight loss and associated changes are important contributors to the clinical profile of tirzepatide for the treatment of T2D diabetes and serve as the basis for further investigations including clinical outcomes.


Assuntos
Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1 , Polipeptídeo Inibidor Gástrico , Peptídeo 1 Semelhante ao Glucagon , Redução de Peso , Hipoglicemiantes/uso terapêutico
7.
Paediatr Drugs ; 25(4): 467-481, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37269500

RESUMO

BACKGROUND: Pulmonary hypertension (PH) is a severe hemodynamic condition with high morbidity and mortality. Approved targeted therapies are limited for pediatric subjects, and treatments are widely adopted from adult algorithms. Macitentan is a safe and effective drug used for adult PH, but data on pediatric patients are limited. In this prospective single-center study, we investigated mid- and long-term effects of macitentan in children with advanced pulmonary hypertensive vascular disease. METHODS: Twenty-four patients were enrolled in the study for treatment with macitentan. Efficacy was determined by echo parameters and brain natriuretic peptide levels (BNP) at 3 months and 1 year. For detailed analysis, the entire cohort was subgrouped into patients with congenital heart disease-related PH (CHD-PH) and non-CHD-PH patients, respectively. RESULTS: Mean age of the patients was 10.7 ± 7.6 years; median observation period was 36 months. Twenty of 24 patients were on additional sildenafil and/or prostacyclins. Two of 24 patients discontinued because of peripheral edema. Within the entire cohort, BNP levels and all echo measures such as right ventricular systolic pressure (RVSP), right ventricular end-diastolic diameter (RVED), tricuspid annular plane systolic excursion (TAPSE), pulmonary velocity time integral (VTI), and pulmonary artery acceleration time (PAAT) improved significantly after 3 months (p ≤ 0.01), whereas in the long term significant improvement persisted for BNP levels (-16%), VTI (+14%) and PAAT (+11%) (p < 0.05). By subgroup analysis, non-CHD PH patients showed significant improvements in BNP levels (-57%) and all echo measures (TAPSE +21%, VTI +13%, PAAT +37%, RVSP -24%, RVED -12%) at 3 months (p ≤ 0.01), whereas at 12 months, improvements persisted (p < 0.05) except for RVSP and RVED (nonsignificant). In CHD-PH patients, none of the measures changed (nonsignificant). 6-MWD (distance walked in 6 minutes) slightly increased but was not statistically evaluated. CONCLUSION: Data presented herein account for the largest cohort of severely affected pediatric patients receiving macitentan. Overall, macitentan was safe and associated with significant beneficial effects and sustained positive signals after 1 year, albeit in the long term disease progression remains a major concern. Our data suggest limited efficacy in CHD-related PH, whereas favorable outcomes were mainly driven by improvements in patients with PH not related to CHD. Larger studies are needed to verify these preliminary results and to prove efficacy of this drug in different pediatric PH entities.


Assuntos
Hipertensão Pulmonar , Sulfonamidas , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Estudos Prospectivos , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Centros de Atenção Terciária , Peptídeo Natriurético Encefálico/sangue
8.
Diabetes Care ; 46(8): 1501-1506, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37267479

RESUMO

OBJECTIVE: Tirzepatide reduces HbA1c and body weight, and creatinine-based estimated glomerular filtration rate (eGFR) decline. Unlike creatine-derived eGFR (eGFR-creatinine), cystatin C-derived eGFR (eGFR-cystatin C) is unaffected by muscle mass changes. We assessed effects of tirzepatide on eGFR-creatinine and eGFR-cystatin C. RESEARCH DESIGN AND METHODS: Our primary outcome was eGFR change from baseline at 52 weeks with pooled tirzepatide (5, 10, and 15 mg) and titrated insulin glargine in adults with type 2 diabetes and high cardiovascular risk (SURPASS-4). RESULTS: Least squares mean (SE) eGFR-creatinine (mL/min/1.73 m2) changes from baseline with tirzepatide and insulin glargine were -2.5 (0.38) and -3.9 (0.38) (between-group difference, 1.4 [95% CI 0.3-2.4]) and -3.5 (0.37) and -5.3 (0.37) (between-group difference, 1.8 [95% CI 0.8-2.8]) for eGFR-cystatin C. Baseline, 1-year, and 1-year change from baseline values significantly correlated between eGFR-cystatin C and eGFR-creatinine. Measures of eGFR changes did not correlate with body weight changes. CONCLUSIONS: Tirzepatide slows the eGFR decline rate, supporting a kidney-protective effect.


Assuntos
Diabetes Mellitus Tipo 2 , Adulto , Humanos , Insulina Glargina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cistatina C/farmacologia , Creatinina , Taxa de Filtração Glomerular/fisiologia , Rim , Peso Corporal
9.
Antioxidants (Basel) ; 12(5)2023 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-37237995

RESUMO

(1) Background: In cardiovascular applications, paclitaxel inhibits smooth muscle cell proliferation and migration and significantly reduces the occurrence of restenosis and target lesion revascularization. However, the cellular effects of paclitaxel in the myocardium are not well understood; (2) Methods: Wistar rats were divided into four groups: control (CTRL), isoproterenol (ISO) treated (1 mg/kg) and two groups treated with paclitaxel (PAC), which was administrated (10 mg/kg/day) for 5 days by gavage/per os alone or in combination (ISO + PAC) 3 weeks after ISO treatment. Ventricular tissue was harvested 24 h later for measurements of heme oxygenase (HO-1), reduced glutathione (GSH), oxidized glutathione (GSSG), superoxide dismutase (SOD), NF-κB, TNF-α and myeloperoxidase (MPO); (3) Results: HO-1 protein concentration, HO-1 activity, SOD protein concentration and total glutathione significantly decreased in response to ISO treatment. When PAC was administered in conjunction with ISO, HO-1, SOD concentration and total glutathione were not different from control levels. MPO activity, NF-κB concentration and TNF-α protein concentration were significantly increased in the ISO-only group, while the levels of these molecules were restored when PAC was co-administered; (4) Conclusions: Oral administration of PAC can maintain the expression of important antioxidants, anti-inflammatory molecules, HO-1, SOD and GSH, and suppress the production of TNF-α, MPO and NF-κB, which are involved in myocardial damage. The principal component of this cellular defense seems to be the expression of HO-1.

10.
Nat Commun ; 14(1): 2533, 2023 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-37137910

RESUMO

We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.


Assuntos
Diabetes Mellitus Tipo 2 , Ilhotas Pancreáticas , Camundongos , Animais , Masculino , Diabetes Mellitus Tipo 2/metabolismo , Glicemia/metabolismo , Ilhotas Pancreáticas/metabolismo , Insulina/metabolismo , Lipídeos , Biomarcadores/metabolismo , Moléculas de Adesão Celular/metabolismo , Proteínas da Matriz Extracelular/metabolismo
12.
Lancet Diabetes Endocrinol ; 11(1): 33-41, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36528349

RESUMO

BACKGROUND: In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1 receptor agonist treatment. METHODS: In this genome-wide analysis we included adults (aged ≥18 years) with type 2 diabetes treated with GLP-1 receptor agonists with baseline HbA1c of 7% or more (53 mmol/mol) from four prospective observational cohorts (DIRECT, PRIBA, PROMASTER, and GoDARTS) and two randomised clinical trials (HARMONY phase 3 and AWARD). The primary endpoint was HbA1c reduction at 6 months after starting GLP-1 receptor agonists. We evaluated variants in GLP1R, then did a genome-wide association study and gene-based burden tests. FINDINGS: 4571 adults were included in our analysis, of these, 3339 (73%) were White European, 449 (10%) Hispanic, 312 (7%) American Indian or Alaskan Native, and 471 (10%) were other, and around 2140 (47%) of the participants were women. Variation in HbA1c reduction with GLP-1 receptor agonists treatment was associated with rs6923761G→A (Gly168Ser) in the GLP1R (0·08% [95% CI 0·04-0·12] or 0·9 mmol/mol lower reduction in HbA1c per serine, p=6·0 × 10-5) and low frequency variants in ARRB1 (optimal sequence kernel association test p=6·7 × 10-8), largely driven by rs140226575G→A (Thr370Met; 0·25% [SE 0·06] or 2·7 mmol/mol  [SE 0·7] greater HbA1c reduction per methionine, p=5·2 × 10-6). A similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian or Alaska Native populations who have a higher frequency of this variant (6-11%) than in White European populations. Combining these two genes identified 4% of the population who had a 30% greater reduction in HbA1c than the 9% of the population with the worse response. INTERPRETATION: This genome-wide pharmacogenomic study of GLP-1 receptor agonists provides novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants might benefit from earlier initiation of GLP-1 receptor agonists. FUNDING: Innovative Medicines Initiative and the Wellcome Trust.


Assuntos
Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 1 , Adulto , Feminino , Humanos , Adolescente , Masculino , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Hipoglicemiantes/uso terapêutico , Estudo de Associação Genômica Ampla , Farmacogenética , Resultado do Tratamento , Glicemia , Ensaios Clínicos Controlados Aleatórios como Assunto
13.
Lancet Diabetes Endocrinol ; 10(11): 774-785, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36152639

RESUMO

BACKGROUND: In the SURPASS-4 trial, the dual GIP and GLP-1 receptor agonist tirzepatide reduced HbA1c concentrations, bodyweight, and blood pressure more than titrated daily insulin glargine in people with type 2 diabetes inadequately controlled on oral diabetes treatments and with high cardiovascular risk. We aimed to compare the effects of tirzepatide and insulin glargine on kidney parameters and outcomes in people with type 2 diabetes. METHODS: We did a post-hoc analysis of data from SURPASS-4, a randomised, open-label, parallel-group, phase 3 study at 187 sites (including private practice, research institutes, and hospitals) in 14 countries. Eligible participants were adults (age ≥18 years), with type 2 diabetes treated with any combination of metformin, sulfonylurea, or SGLT2 inhibitor, and with baseline HbA1c of 7·5-10·5% (58-91 mmol/mol), BMI of 25 kg/m2 or greater, and established cardiovascular disease or a high risk of cardiovascular events. Randomisation via an interactive web-response system was 1:1:1:3 to a once-weekly subcutaneous injection of tirzepatide (5 mg, 10 mg, or 15 mg) or a once-daily subcutaneous injection of titrated insulin glargine (100 U/mL). The study included up to 104 weeks of treatment, with a median treatment duration of 85 weeks. We compared the rates of estimated glomerular filtration rate (eGFR) decline and the urine albumin-creatinine ratio (UACR) between the combined tirzepatide groups and the insulin glargine group in the modified intention-to-treat population. The kidney composite outcome was time to first occurrence of eGFR decline of at least 40% from baseline, end-stage kidney disease, death owing to kidney failure, or new-onset macroalbuminuria. This study is registered with ClinicalTrials.gov, NCT03730662. FINDINGS: Between Nov 20, 2018, and Dec 30, 2019, we screened 3045 people, of whom 1043 (34%) were ineligible, and 2002 (66%) were randomly assigned to a study drug (997 to tirzepatide and 1005 to insulin glargine). 1995 (>99%) of 2002 received at least one dose of tirzepatide (n=995) or insulin glargine (n=1000). At baseline, participants had a mean eGFR of 81·3 (SD 21·11) mL/min per 1·73 m2 and a median UACR of 15·0 mg/g (IQR 5·0-55·8). The mean rate of eGFR decline was -1·4 (SE 0·2) mL/min per 1·73 m2 per year in the combined tirzepatide groups and -3·6 (0·2) mL/min per 1·73 m2 per year in the insulin group (between-group difference 2·2 [95% CI 1·6 to 2·8]). Compared with insulin glargine, the reduction in the annual rate of eGFR decline induced by tirzepatide was more pronounced in participants with eGFR less than 60 mL/min per 1·73 m2 than in those with eGFR 60 mL/min per 1·73 m2 or higher (between-group difference 3·7 [95% CI 2·4 to 5·1]). UACR increased from baseline to follow-up with insulin glargine (36·9% [95% CI 26·0 to 48·7]) but not with tirzepatide (-6·8% [-14·1 to 1·1]; between-group difference -31·9% [-37·7 to -25·7]). Participants who received tirzepatide showed a significantly lower occurrence of the composite kidney endpoint compared with those who received insulin glargine (hazard ratio 0·58 [95% CI 0·43 to 0·80]). INTERPRETATION: Our analysis suggests that in people with type 2 diabetes and high cardiovascular risk, tirzepatide slowed the rate of eGFR decline and reduced UACR in clinically meaningful ways compared with insulin glargine. FUNDING: Eli Lilly and Company.


Assuntos
Diabetes Mellitus Tipo 2 , Adulto , Humanos , Adolescente , Insulina Glargina/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Rim , Resultado do Tratamento , Hemoglobinas Glicadas/análise
14.
Cardiovasc Diabetol ; 21(1): 163, 2022 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-36002856

RESUMO

Cardiovascular (CV) outcome trials (CVOTs) of type 2 diabetes mellitus (T2DM) therapies have mostly used randomized comparison with placebo to demonstrate non-inferiority to establish that the investigational drug does not increase CV risk. Recently, several glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium glucose cotransporter 2 inhibitors (SGLT-2i) demonstrated reduced CV risk. Consequently, future T2DM therapy trials could face new ethical and clinical challenges if CVOTs continue with the traditional, placebo-controlled design. To address this challenge, here we review the methodologic considerations in transitioning to active-controlled CVOTs and describe the statistical design of a CVOT to assess non-inferiority versus an active comparator and if non-inferiority is proven, using novel methods to assess for superiority versus an imputed placebo. Specifically, as an example of such methodology, we introduce the statistical considerations used for the design of the "Effect of Tirzepatide versus Dulaglutide on Major Adverse Cardiovascular Events (MACE) in Patients with Type 2 Diabetes" trial (SURPASS CVOT). It is the first active-controlled CVOT assessing antihyperglycemic therapy in patients with T2DM designed to demonstrate CV efficacy of the investigational drug, tirzepatide, a dual glucose-dependent insulinotropic polypeptide and GLP-1 RA, by establishing non-inferiority to an active comparator with proven CV efficacy, dulaglutide. To determine the efficacy margin for the hazard ratio, tirzepatide versus dulaglutide, for the composite CV outcome of death, myocardial infarction, or stroke (MACE-3), which is required to claim superiority versus an imputed placebo, the lower bound of efficacy of dulaglutide compared with placebo was estimated using a hierarchical Bayesian meta-analysis of placebo-controlled CVOTs of GLP-1 RAs. SURPASS CVOT was designed so that when the observed upper bound of the 95% confidence interval of the hazard ratio is less than the lower bound of efficacy of dulaglutide, it demonstrates non-inferiority to dulaglutide by preserving at least 50% of the CV benefit of dulaglutide as well as statistical superiority of tirzepatide to a theoretical placebo (imputed placebo analysis). The presented methods adding imputed placebo comparison for efficacy assessment may serve as a model for the statistical design of future active-controlled CVOTs.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Hipoglicemiantes , Teorema de Bayes , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Drogas em Investigação/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/efeitos adversos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Hipoglicemiantes/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Resultado do Tratamento
15.
Bone ; 162: 116478, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35779845

RESUMO

Postmenopausal osteoporosis (PMOP) therapies are frequently evaluated by bone mineral density (BMD) gains against patients receiving placebo (calcium and vitamin D supplementation, a mild bone turnover-suppressing intervention), which is not equivalent to either healthy or treatment-naive PMOP. The aim of the present observational study was to assess the effects of TPTD treatment in PMOP (20 µg, once daily) at 6 (TPTD 6m; n = 28, age 65 ± 7.3 years), and 24 (TPTD 24m; n = 32, age 67.4 ± 6.15 years) months on bone quality indices at actively forming trabecular surfaces (with fluorescent double labels). Data from the TPTD-treated PMOP patients were compared with those in healthy adult premenopausal women (HC; n = 62, age 40.5 ± 10.6 years), and PMOP receiving placebo (PMOP-PLC; n = 94, age 70.6 ± 4.5 years). Iliac crest biopsies were analyzed by Raman microspectroscopy at three distinct tissue ages: mid-distance between the second label and the bone surface, mid-distance between the two labels, and 1 µm behind the first label. Mineral to matrix ratio (MM), mineral maturity/crystallinity (MMC), tissue water (TW), glycosaminoglycan (GAGs), and pyridinoline (Pyd) content were determined. Outcomes were compared by ANCOVA with subject age and tissue age as covariates, and health status as a fixed factor, followed by Sidak's post-hoc testing (significance assigned to p < 0.05). Both TPTD groups increased MM compared to PMOP-PLC. While TPTD 6m had values similar to HC, TPTD 24m had higher values compared to either HC or TPTD 6m. Both TPTD groups had lower MMC values compared to PMOP-PLC and similar to HC. TPTD 6m patients had higher TW content compared to HC, while TPTD 24m had values similar to HC and lower than either PMOP-PLC or TPTD 6m. Both TPTD groups had lower GAG content compared to HC group, while TPTD 6m had higher values compared to PMOP-PLC. Finally, TPTD 6m patients had higher Pyd content compared to HC and lower compared to PMOP-PLC, while TPTD 24m had lower values compared to PMOP-PLC and TPTD 6m, and similar to HC group. The results of the present study indicate that effects of TPTD on forming trabecular bone quality indices depend on treatment duration. At the recommended length of 24 m, TPTD restores bone mineral and organic matrix quality indices (MMC, TW, Pyd content) to premenopausal healthy (HC) levels.


Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Adulto , Idoso , Densidade Óssea , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Feminino , Humanos , Ílio/patologia , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/patologia , Teriparatida/farmacologia , Teriparatida/uso terapêutico
16.
J Clin Med ; 11(11)2022 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-35683592

RESUMO

Individual patient data (IPD)-based meta-analysis (ACCRUE, meta-analysis of cell-based cardiac studies, NCT01098591) revealed an insufficient effect of intracoronary cell-based therapy in acute myocardial infarction. Patients with ischemic heart failure (iHF) have been treated with reparative cells using percutaneous endocardial, surgical, transvenous or intracoronary cell delivery methods, with variable effects in small randomized or cohort studies. The objective of this meta-analysis was to investigate the safety and efficacy of percutaneous transendocardial cell therapy in patients with iHF. Two investigators extracted the data. Individual patient data (IPD) (n = 8 studies) and publication-based (n = 10 studies) aggregate data were combined for the meta-analysis, including patients (n = 1715) with chronic iHF. The data are reported in accordance with PRISMA guidelines. The primary safety and efficacy endpoints were all-cause mortality and changes in global ejection fraction. The secondary safety and efficacy endpoints were major adverse events, hospitalization and changes in end-diastolic and end-systolic volumes. Post hoc analyses were performed using the IPD of eight studies to find predictive factors for treatment safety and efficacy. Cell therapy was significantly (p < 0.001) in favor of survival, major adverse events and hospitalization during follow-up. A forest plot analysis showed that cell therapy presents a significant benefit of increasing ejection fraction with a mean change of 2.51% (95% CI: 0.48; 4.54) between groups and of significantly decreasing end-systolic volume. The analysis of IPD data showed an improvement in the NYHA and CCS classes. Cell therapy significantly decreased the end-systolic volume in male patients; in patients with diabetes mellitus, hypertension or hyperlipidemia; and in those with previous myocardial infarction and baseline ejection fraction ≤ 45%. The catheter-based transendocardial delivery of regenerative cells proved to be safe and effective for improving mortality and cardiac performance. The greatest benefit was observed in male patients with significant atherosclerotic co-morbidities.

17.
Nat Med ; 28(3): 591-598, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35210595

RESUMO

Tirzepatide is a novel, once weekly, dual GIP/GLP-1 receptor agonist and is under development for the treatment of type 2 diabetes (T2D) and obesity. Its association with cardiovascular outcomes requires evaluation. This pre-specified cardiovascular meta-analysis included all seven randomized controlled trials with a duration of at least 26 weeks from the tirzepatide T2D clinical development program, SURPASS. The pre-specified primary objective of this meta-analysis was the comparison of the time to first occurrence of confirmed four-component major adverse cardiovascular events (MACE-4; cardiovascular death, myocardial infarction, stroke and hospitalized unstable angina) between pooled tirzepatide groups and control groups. A stratified Cox proportional hazards model, with treatment as a fixed effect and trial-level cardiovascular risk as the stratification factor, was used for the estimation of hazard ratios (HRs) and confidence intervals (CIs) comparing tirzepatide to control. Data from 4,887 participants treated with tirzepatide and 2,328 control participants were analyzed. Overall, 142 participants, 109 from the trial with high cardiovascular risk and 33 from the six trials with lower cardiovascular risk, had at least one MACE-4 event. The HRs comparing tirzepatide versus controls were 0.80 (95% CI, 0.57-1.11) for MACE-4; 0.90 (95% CI, 0.50-1.61) for cardiovascular death; and 0.80 (95% CI, 0.51-1.25) for all-cause death. No evidence of effect modifications was observed for any subgroups, although the evidence was stronger for participants with high cardiovascular risk. Tirzepatide did not increase the risk of major cardiovascular events in participants with T2D versus controls.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Doenças Cardiovasculares/complicações , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Polipeptídeo Inibidor Gástrico/efeitos adversos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Hipoglicemiantes/uso terapêutico
18.
Calcif Tissue Int ; 110(1): 74-86, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34415388

RESUMO

The Asian and Latin America Fracture Observational Study (ALAFOS) is a prospective, observational, single-arm study conducted in 20 countries across Asia, Latin America and the Middle East. ALAFOS evaluated new clinical vertebral and non-vertebral fragility fractures in relation to time on teriparatide, in postmenopausal women with osteoporosis in real-life clinical practice. Clinical fragility fractures, back pain, and health-related quality of life (HRQoL) were recorded in 6-month intervals for ≤ 24 months during teriparatide treatment and up to 12-months post-treatment. Data were analysed with piecewise exponential regression with inverse probability weighting for time to event outcomes and mixed-model repeated measures for back pain and HRQoL. 3054 postmenopausal women started teriparatide and attended ≥ one follow-up visit (mean [SD] age 72.5 [10.4] years). The median (95% CI) time to treatment discontinuation was 22.0 months (21.2, 22.8). During the treatment period, 111 patients (3.6%) sustained 126 clinical fractures (2.98 fractures/100 patient-years). Rates of new clinical fragility fractures were significantly decreased during the > 6-12, > 12-18, and > 18-24-month periods, as compared with the first 6 months of treatment (hazard ratio [HR] 0.57; 95% CI 0.37, 0.88; p = 0.012; HR 0.35; 95% CI 0.19, 0.62; p < 0.001; HR 0.43; 95% CI 0.23, 0.83; p = 0.011; respectively). Patients also reported an improvement in back pain and HRQoL (p < 0.001). These results provide data on the real-world effectiveness of teriparatide in the ALAFOS regions and are consistent with other studies showing reduction of fractures after 6 months of teriparatide treatment. These results should be interpreted in the context of the noncontrolled design of this observational study.


Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Osteoporose , Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Idoso , Conservadores da Densidade Óssea/uso terapêutico , Feminino , Humanos , América Latina , Osteoporose Pós-Menopausa/complicações , Osteoporose Pós-Menopausa/tratamento farmacológico , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/prevenção & controle , Pós-Menopausa , Estudos Prospectivos , Qualidade de Vida , Fraturas da Coluna Vertebral/epidemiologia , Fraturas da Coluna Vertebral/prevenção & controle , Teriparatida/uso terapêutico
19.
J Bone Miner Res ; 37(1): 29-35, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34490915

RESUMO

The surrogate threshold effect (STE) is defined as the minimum treatment effect on a surrogate that is reliably predictive of a treatment effect on the clinical outcome. It provides a framework for implementing a clinical trial with a surrogate endpoint. The aim of this study was to update our previous analysis by validating the STE for change in total hip (TH) BMD as a surrogate for fracture risk reduction; the novelty of this study was this validation. To do so, we used individual patient data from 61,415 participants in 16 RCTs that evaluated bisphosphonates (nine trials), selective estrogen receptor modulators (four trials), denosumab (one trial), odanacatib (one trial), and teriparatide (one trial) to estimate trial-specific treatment effects on TH BMD and all, vertebral, hip, and nonvertebral fractures. We then conducted a random effects meta-regression of the log relative fracture risk reduction against 24-month change in TH BMD, and computed the STE as the intersection of the upper 95% prediction limit of this regression with the line of no fracture reduction. We validated the STE by checking whether the number of fractures in each trial provided 80% power and determining what proportion of trials with BMD changes ≥ STE reported significant reductions in fracture risk. We applied this analysis to (i) the trials on which we estimated the STE; and (ii) trials on which we did not estimate the STE. We found that the STEs for all, vertebral, hip, and nonvertebral fractures were 1.83%, 1.42%, 3.18%, and 2.13%, respectively. Among trials used to estimate STE, 27 of 28 were adequately powered, showed BMD effects exceeding the STE, and showed significant reductions in fracture risk. Among the validation set of 11 trials, 10 met these criteria. Thus STE differs by fracture type and has been validated in trials not used to develop the approach. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Assuntos
Conservadores da Densidade Óssea , Fraturas Ósseas , Biomarcadores , Densidade Óssea , Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Fraturas Ósseas/tratamento farmacológico , Humanos
20.
Front Med (Lausanne) ; 9: 1092688, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36777159

RESUMO

Objective: Patients with psoriasis have an increased prevalence of type 2 diabetes when compared to the general population. Research suggests that type 2 diabetes (T2D) as well as obesity may have an impact on patients' response to treatment. This post-hoc analysis reports the efficacy of ixekizumab in treating moderate-to-severe psoriasis in patients with prediabetes or T2D. Method and materials: UNCOVER-1, UNCOVER-2, and UNCOVER-3 were three Phase 3, multicenter, randomized, double-blind, placebo-controlled trials that evaluated the efficacy and safety of ixekizumab in adult patients with moderate-to-severe psoriasis. Patients were aged ≥18 years with chronic moderate-to-severe psoriasis (defined as ≥10% body surface area affected, static Physician Global Assessment ≥3, and Psoriasis Area and Severity Index [PASI] ≥12 at screening and baseline) who were candidates for phototherapy or systemic therapy. UNCOVER-1, UNCOVER-2, and UNCOVER-3 participants received ixekizumab as per label (that is, an initial dose of two subcutaneous injections [160 mg in total] at Week 0, followed by 80 mg every 2 weeks through Week 12 and 80 mg every 4 weeks thereafter through Week 60). Results: The proportions of patients with prediabetes, T2D and normoglycemia that achieved PASI75, PASI90, and PASI100 at Week 60 were similar. Results suggest that patients with T2D were slower to achieve PASI100 than patients with prediabetes or those with normoglycemia. Ixekizumab had no effect on any metabolic markers in patients receiving the treatment. Conclusions: Despite the higher rate of obesity and extreme obesity in patients with prediabetes and T2D, ixekizumab was an efficacious treatment in treating patients with psoriasis.

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