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AIM: The decline in estimated glomerular filtration rate (eGFR), a significant predictor of cardiovascular disease (CVD), occurs heterogeneously in people with diabetes because of various risk factors. We investigated the role of eGFR decline in predicting CVD events in people with type 2 diabetes in both primary and secondary CVD prevention settings. MATERIALS AND METHODS: Bayesian joint modelling of repeated measures of eGFR and time to CVD event was applied to the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial to examine the association between the eGFR slope and the incidence of major adverse CV event/hospitalization for heart failure (MACE/hHF) (non-fatal myocardial infarction, non-fatal stroke, CV death, or hospitalization for heart failure). The analysis was adjusted for age, sex, smoking, systolic blood pressure, baseline eGFR, antihypertensive and lipid-lowering medication, diabetes duration, atrial fibrillation, high-density cholesterol, total cholesterol, HbA1c and treatment allocation (once-weekly exenatide or placebo). RESULTS: Data from 11 101 trial participants with (n = 7942) and without (n = 3159) previous history of CVD were analysed. The mean ± SD eGFR slope per year in participants without and with previous CVD was -0.68 ± 1.67 and -1.03 ± 2.13 mL/min/1.73 m2, respectively. The 5-year MACE/hHF incidences were 7.5% (95% CI 6.2, 8.8) and 20% (95% CI 19, 22), respectively. The 1-SD decrease in the eGFR slope was associated with increased MACE/hHF risks of 48% (HR 1.48, 95% CI 1.12, 1.98, p = 0.007) and 33% (HR 1.33, 95% CI 1.18,1.51, p < 0.001) in participants without and with previous CVD, respectively. CONCLUSIONS: eGFR trajectories over time significantly predict incident MACE/hHF events in people with type 2 diabetes with and without existing CVD, with a higher hazard ratio for MACE/hHF in the latter group.
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INTRODUCTION: Even with recent treatment advances, type 2 diabetes (T2D) remains poorly controlled for many patients, despite the best efforts to adhere to therapies and lifestyle modifications. Although estimates vary, studies indicate that in >10% of individuals with difficult-to-control T2D, hypercortisolism may be an underlying contributing cause. To better understand the prevalence of hypercortisolism and the impact of its treatment on T2D and associated comorbidities, we describe the two-part Hyper c ortisolism in P at ients with Difficult to Control Type 2 Di a betes Despite Receiving Standard-of-Care Therapies: Preva l ence and Treatment with Korl y m® (Mifepri st one) (CATALYST) trial. METHODS AND ANALYSIS: In part 1, approximately 1000 participants with difficult-to-control T2D (haemoglobin A1c (HbA1c) 7.5%-11.5% despite multiple therapies) are screened with a 1 mg dexamethasone suppression test (DST). Those with post-DST cortisol >1.8 µg/dL and dexamethasone level ≥140 ng/dL are identified to have hypercortisolism (part 1 primary endpoint), have morning adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS) measured and undergo a non-contrast adrenal CT scan. Those requiring evaluation for elevated ACTH are referred for care outside the study; those with ACTH and DHEAS in the range may advance to part 2, a randomised, double-blind, placebo-controlled trial to evaluate the impact of treating hypercortisolism with the competitive glucocorticoid receptor antagonist mifepristone (Korlym®). Participants are randomised 2:1 to mifepristone or placebo for 24 weeks, stratified by the presence/absence of an abnormal adrenal CT scan. Mifepristone is dosed at 300 mg once daily for 4 weeks, then 600 mg daily based on tolerability and clinical improvement, with an option to increase to 900 mg. The primary endpoint of part 2 assesses changes in HbA1c in participants with hypercortisolism with or without abnormal adrenal CT scan. Secondary endpoints include changes in antidiabetes medications, cortisol-related comorbidities and quality of life. ETHICS AND DISSEMINATION: The study has been approved by Cleveland Clinic IRB (Cleveland, Ohio, USA) and Advarra IRB (Columbia, Maryland, USA). Findings will be presented at scientific meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05772169.
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Síndrome de Cushing , Diabetes Mellitus Tipo 2 , Mifepristona , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndrome de Cushing/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Método Doble Ciego , Hemoglobina Glucada/análisis , Hemoglobina Glucada/metabolismo , Antagonistas de Hormonas/uso terapéutico , Hidrocortisona/sangre , Mifepristona/uso terapéutico , Estudios Multicéntricos como Asunto , Prevalencia , Estudios ProspectivosRESUMEN
OBJECTIVE: To compare postprandial glucose excursions following a bolus with inhaled technosphere insulin (TI) or subcutaneous rapid-acting analog (RAA) insulin. RESEARCH DESIGN AND METHODS: A meal challenge was completed by 122 adults with type 1 diabetes who were using multiple daily injections (MDI), a nonautomated pump, or automated insulin delivery (AID) and who were randomized to bolus with their usual RAA insulin (n = 61) or TI (n = 61). RESULTS: The primary outcome, the treatment group difference in area under the curve for glucose >180 mg/dL over 2 h, was less with TI versus RAA (adjusted difference -12 mg/dL, 95% CI -22 to -2, P = 0.02). With TI, the glucose excursion was smaller (P = 0.01), peak glucose lower (P = 0.01), and time to peak glucose shorter (P = 0.006). Blood glucose <70 mg/dL occurred in one participant in each group. CONCLUSIONS: Postmeal glucose excursion was smaller with TI than with RAA insulin in a cohort that included both AID and MDI users.
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RATIONALE: While recent evidence suggested glucagon-like peptide 1 receptor agonists (GLP1RA) may reduce the risk of asthma exacerbations, it remains unclear which subpopulations might derive the most benefit from GLP1RA treatment. OBJECTIVE: To identify characteristics of patients with asthma that predict who might benefit the most from GLP1RA treatment using real-world data. METHODS: We implemented an active-comparator, new-user design analysis using commercially insured patients ages 18-65 from Marketscan data 2007-2019 and identified two cohorts: GLP1RA vs thiazolidinediones and GLP1RA vs sulfonylureas. The outcome was acute exacerbation of asthma (hospital admission or emergency department (ED) visit for asthma) within 180 days after initiation. We applied iterative causal forest (iCF), a novel causal machine learning subgrouping algorithm, to assess HTE. In identified subgroups, we predicted propensity score, conducted propensity score trimming, and then estimated adjusted risk differences (aRD) for the effect of GLP1RA relative to comparators on asthma exacerbation using inverse probability treatment weighting in propensity score trimmed subpopulation. RESULTS: Among 10,989 patients initiating GLP1RA or thiazolidinediones and 17,088 patients initiating GLP1RA vs sulfonylurea, GLP1RA initiators had fewer exacerbations with an aRD of -0.5% (95% CI -1.1% to 0.1%) and -1.6% (95% CI -2.2% to -1.1%), respectively. In the GLP1RAvsSUcohort where we observed beneficial effect, our iCF analysis identified 5 subgroups with different treatment effects, defined by number of ED visits, number of prescriptions of short-acting beta2-agonsit (SABA), number of prescriptions of inhaled steroid (ICS) and long-acting beta-agonists (LABA) (either combination therapy or concurrent use), and aged 50+. Among these, patients with 2+ ED visits during 12-month baseline period had the largest absolute exacerbation risk reduction, with a decrease of 2.8% for GLP1RA (95% CI: -4.8% to -0.9%). CONCLUSIONS: GLP1RA demonstrated beneficial effect on reducing asthma exacerbation relative to sulfonylureas. Asthma patients with 2+ ED visits (a proxy for disease severity) benefit most from GLP1RA. ED visit frequency, and number of maintenance and reliever inhalers, and age may help individualize prediction of the short-term benefit from GLP1RA on asthma exacerbation.
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OBJECTIVE: A new generation of basal insulin analogs enabling once-weekly administration is currently under development. Weekly basal insulins have the potential to overcome limitations exhibited by current daily basal insulins. The pharmacokinetic and glucodynamic characteristics differ significantly between weekly and daily basal insulins and will require paradigm shifts in how basal insulins are dosed. METHODS: An overview of pharmacokinetic and glucodynamic principles of basal insulins is presented. Specifically, the pharmacokinetic and glucodynamic properties of daily basal insulins and how these differ for the new weekly basal insulins are discussed. Finally, models and simulations are used to describe the impact of weekly insulin properties on dosing. RESULTS: Two approaches have been used to extend the half-lives of these insulins, creating fusion proteins with reduced clearance and reduced receptor-mediated degradation of the insulin. The resulting prolonged exposure-response profiles affect dosing and the impact of dosing errors. Specifically, the impact of loading doses, missed doses, and double doses, and the effect on glycemic variability of a once weekly basal insulin option are demonstrated using pharmacokinetic/glucodynamic models and simulations. CONCLUSIONS: The transition from daily to weekly basal insulin dosing requires an understanding of the implications of the prolonged exposure-response profiles to effectively and confidently incorporate these weekly basal insulins into clinical practice. By reviewing the application of pharmacokinetic and glucodynamic principles to daily basal insulin analogs, the differences with weekly basal insulins, and the impact of these properties on dosing, this review intends to explain the principles behind weekly basal insulin dosing.
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INTRODUCTION: Skeletal muscle density (SMD) measurements from imaging scans identify myosteatosis and could screen patients for geriatric assessment. We assessed SMD performance as a screening tool to identify older adults with cancer likely to be frail and who could benefit from in-depth assessment; we compared performance by sex and diabetes status. MATERIALS AND METHODS: We analyzed patients in the Cancer & Aging Resilience Evaluation (CARE) Registry. Frailty and diabetes were captured using a patient-reported geriatric assessment (CARE tool). Frailty was defined using CARE frailty index (CARE-FI) based on principles of deficit accumulation. SMD was calculated from computed tomography scans (L3 vertebrae). Analyses were conducted by sex and diabetes status. Scatterplots and linear regression described crude associations between SMD and frailty score. Classification performance (frail vs. non-frail) was analyzed with (1) area under the receiver operating characteristic curves (AUC) and confidence intervals (CIs); and (2) sensitivity/specificity for sex-specific SMD quartile cut-offs (Q1, median, Q3). Performance was compared between patients with and without diabetes using differences and estimated CIs (2000 bootstrap replicates). We additionally calculated positive and negative likelihood ratios (LR+, LR-). RESULTS: The analytic cohort included 872 patients (39% female, median age 68 years, 27% with diabetes) with predominately stage III/IV gastrointestinal cancer; >60% planning to initiate first-line chemotherapy. SMD was negatively associated with frailty score; models were best fit in male patients with diabetes. AUC estimates for female (range: 0.58-0.62) and male (0.58-0.68) patients were low. Q3 cut-offs had high sensitivity (range: 0.76-0.89), but poor specificity (0.25-0.34). Diabetes did not impact estimates for female patients. Male patients with diabetes had greater sensitivity estimates compared to those without (sensitivity differences: 0.23 [0.07, 0.38], 0.08 [-0.07, 0.24], and 0.11 [0.00, 0.22] for Q1, median, Q3, respectively). LR estimates were most notable for male patients with diabetes (LR+ = 2.92, Q1 cut-off; LR- = 0.46, Q3 cut-off). DISCUSSION: Using SMD alone to screen older patients for geriatric assessment requires improvement. High-sensitivity cut-off points could miss 11-24% of patients with frailty, and many non-frail patients may be flagged. Screening with SMD is practical but work is needed to understand clinical andresource impacts of different cut-off points. Future research should evaluate performance with additional clinical data and in subgroups.
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Diabetes Mellitus , Fragilidad , Evaluación Geriátrica , Músculo Esquelético , Neoplasias , Sistema de Registros , Humanos , Masculino , Femenino , Anciano , Fragilidad/diagnóstico , Neoplasias/complicaciones , Músculo Esquelético/diagnóstico por imagen , Evaluación Geriátrica/métodos , Anciano de 80 o más Años , Diabetes Mellitus/epidemiología , Anciano Frágil/estadística & datos numéricos , Tomografía Computarizada por Rayos X , Sarcopenia/epidemiología , Sarcopenia/diagnóstico , Factores SexualesRESUMEN
Background: Observed activity of metformin in reducing the risk of severe COVID-19 suggests a potential use of the anti-hyperglycemic in the prevention of post-acute sequelae of SARS-CoV-2 infection (PASC). We assessed the 3-month and 6-month risk of PASC among patients with type 2 diabetes mellitus (T2DM) comparing metformin users to sulfonylureas (SU) or dipeptidyl peptidase-4 inhibitors (DPP4i) users. Methods: We used de-identified patient level electronic health record data from the National Covid Cohort Collaborative (N3C) between October 2021 and April 2023. Participants were adults ≥ 18 years with T2DM who had at least one outpatient healthcare encounter in health institutions in the United States prior to COVID-19 diagnosis. The outcome of PASC was defined based on the presence of a diagnosis code for the illness or using a predicted probability based on a machine learning algorithm. We estimated the 3-month and 6-month risk of PASC and calculated crude and weighted risk ratios (RR), risk differences (RD), and differences in mean predicted probability. Results: We identified 5596 (mean age: 61.1 years; SD: 12.6) and 1451 (mean age: 64.9 years; SD 12.5) eligible prevalent users of metformin and SU/DPP4i respectively. We did not find a significant difference in risk of PASC at 3 months (RR = 0.86 [0.56; 1.32], RD = -3.06 per 1000 [-12.14; 6.01]), or at 6 months (RR = 0.81 [0.55; 1.20], RD = -4.91 per 1000 [-14.75, 4.93]) comparing prevalent users of metformin to prevalent users of SU/ DPP4i. Similar observations were made for the outcome definition using the ML algorithm. Conclusion: The observed estimates in our study are consistent with a reduced risk of PASC among prevalent users of metformin, however the uncertainty of our confidence intervals warrants cautious interpretations of the results. A standardized clinical definition of PASC is warranted for thorough evaluation of the effectiveness of therapies under assessment for the prevention of PASC.
Previous research suggests that metformin, due to its anti-viral, anti-inflammatory, and anti-thrombotic properties may reduce the risk of severe COVID-19. Given the shared etiology of COVID-19 and the post-acute sequelae of SARS-CoV-2 (PASC), and the proposed inflammatory processes of PASC, metformin may also be a beneficial preventive option. We investigated the benefit of metformin for PASC prevention in a population of type 2 diabetes mellitus patients with a COVID-19 diagnosis who were on metformin or two other anti-hyperglycemic medications prior to infection with SARS-CoV-2. Our results were consistent with a reduction in the risk of PASC with the use of metformin, however, the imprecise confidence intervals obtained warrants further investigation of this association of the potential beneficial effect of metformin for preventing PASC in patients with medication-managed diabetes.
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INTRODUCTION: We previously identified a genetic subtype (C4) of type 2 diabetes (T2D), benefitting from intensive glycemia treatment in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Here, we characterized the population of patients that met the C4 criteria in the UKBiobank cohort. RESEARCH DESIGN AND METHODS: Using our polygenic score (PS), we identified C4 individuals in the UKBiobank and tested C4 status with risk of developing T2D, cardiovascular disease (CVD) outcomes, and differences in T2D medications. RESULTS: C4 individuals were less likely to develop T2D, were slightly older at T2D diagnosis, had lower HbA1c values, and were less likely to be prescribed T2D medications (P < .05). Genetic variants in MAS1 and IGF2R, major components of the C4 PS, were associated with fewer overall T2D prescriptions. CONCLUSION: We have confirmed C4 individuals are a lower risk subpopulation of patients with T2D.
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Diabetes Mellitus Tipo 2 , Herencia Multifactorial , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Reino Unido/epidemiología , Herencia Multifactorial/genética , Anciano , Fenotipo , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/epidemiología , Predisposición Genética a la Enfermedad , Hemoglobina Glucada/metabolismo , Hemoglobina Glucada/genética , Bancos de Muestras Biológicas , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Diabetes complications occur at higher rates in individuals of African ancestry. Glucose-6-phosphate dehydrogenase deficiency (G6PDdef), common in some African populations, confers malaria resistance, and reduces hemoglobin A1c (HbA1c) levels by shortening erythrocyte lifespan. In a combined-ancestry genome-wide association study of diabetic retinopathy, we identified nine loci including a G6PDdef causal variant, rs1050828 -T (Val98Met), which was also associated with increased risk of other diabetes complications. The effect of rs1050828 -T on retinopathy was fully mediated by glucose levels. In the years preceding diabetes diagnosis and insulin prescription, glucose levels were significantly higher and HbA1c significantly lower in those with versus without G6PDdef. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, participants with G6PDdef had significantly higher hazards of incident retinopathy and neuropathy. At the same HbA1c levels, G6PDdef participants in both ACCORD and the Million Veteran Program had significantly increased risk of retinopathy. We estimate that 12% and 9% of diabetic retinopathy and neuropathy cases, respectively, in participants of African ancestry are due to this exposure. Across continentally defined ancestral populations, the differences in frequency of rs1050828 -T and other G6PDdef alleles contribute to disparities in diabetes complications. Diabetes management guided by glucose or potentially genotype-adjusted HbA1c levels could lead to more timely diagnoses and appropriate intensification of therapy, decreasing the risk of diabetes complications in patients with G6PDdef alleles.
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Insulin replacement therapy is indispensable in the treatment of type 1 and advanced type 2 diabetes. However, insulin's clinical application is challenging due to its narrow therapeutic index. To mitigate acute and chronic risks of glucose excursions, glucose-responsive insulin (GRI) has long been pursued for clinical application. By integrating GRI with glucose-sensitive elements, GRI is capable of releasing or activating insulin in response to plasma or interstitial glucose levels without external monitoring, thereby improving glycemic control and reducing hypoglycemic risk. In this Perspective, we first introduce the history of GRI development and then review major glucose-responsive components that can be leveraged to control insulin delivery. Subsequently, we highlight the recent advances in GRI delivery carriers and insulin analogs. Finally, we provide a look to the future and the challenges of clinical application of GRI.
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Glucemia , Hipoglucemiantes , Insulina , Humanos , Insulina/metabolismo , Insulina/uso terapéutico , Hipoglucemiantes/uso terapéutico , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , AnimalesRESUMEN
BACKGROUND & AIMS: Glucagon-like peptide-1-receptor agonists (GLP1-RAs) have been associated with greater retention of gastric contents, however, there is minimal controlled, population-based data evaluating the potential adverse effects of GLP1-RA in the periprocedural setting. We aimed to determine if there is increased risk of aspiration and aspiration-related complications after upper endoscopy in patients using GLP1-RAs. METHODS: We used a nationwide commercial administrative claims database to conduct a retrospective cohort study of patients aged 18 to 64 with type 2 diabetes who underwent outpatient upper endoscopy from 2005 to 2021. We identified 6,806,046 unique upper endoscopy procedures. We compared claims for aspiration and associated pulmonary adverse events in the 14 days after upper endoscopy between users of GLP1-RAs, dipeptidyl peptidase 4 inhibitors (DPP4is), and chronic opioids. We adjusted for age, sex, Charlson Comorbidity score, underlying respiratory disease, and gastroparesis. RESULTS: We found that pulmonary adverse events after upper endoscopy are rare, ranging from 6 to 25 events per 10,000 procedures. When comparing GLP1-RAs with DPP4i, crude relative risks of aspiration (0.67; 95% CI, 0.25-1.75), aspiration pneumonia (0.95; 95% CI, 0.40-2.29), pneumonia (1.07; 95% CI, 0.62-1.86), or respiratory failure (0.75; 95% CI, 0.38-1.48) were not higher in patients prescribed a GLP1-RA. When comparing GLP1-RAs with opioids, crude relative risks were 0.42 (95% CI, 0.15-1.16) for aspiration, 0.60 (95% CI, 0.24-1.52) for aspiration pneumonia, 0.30 (95% CI, 0.19-0.49) for pneumonia, and 0.24 (95% CI, 0.13-0.45) for respiratory failure. These results were consistent across several sensitivity analyses. CONCLUSIONS: GLP1-RA use is not associated with an increased risk of pulmonary complications after upper endoscopy compared with DPP4i use in patients with type 2 diabetes.
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BACKGROUND: Metformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism appears to be suppression of protein translation via targeting the host mechanistic target of rapamycin pathway. In the COVID-OUT randomized trial for outpatient coronavirus disease 2019 (COVID-19), metformin reduced the odds of hospitalizations/death through 28 days by 58%, of emergency department visits/hospitalizations/death through 14 days by 42%, and of long COVID through 10 months by 42%. METHODS: COVID-OUT was a 2 × 3 randomized, placebo-controlled, double-blind trial that assessed metformin, fluvoxamine, and ivermectin; 999 participants self-collected anterior nasal swabs on day 1 (n = 945), day 5 (n = 871), and day 10 (n = 775). Viral load was quantified using reverse-transcription quantitative polymerase chain reaction. RESULTS: The mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log10 copies/mL; 95% confidence interval [CI], -1.05 to -.06; P = .027). Those who received metformin were less likely to have a detectable viral load than placebo at day 5 or day 10 (odds ratio [OR], 0.72; 95% CI, .55 to .94). Viral rebound, defined as a higher viral load at day 10 than day 5, was less frequent with metformin (3.28%) than placebo (5.95%; OR, 0.68; 95% CI, .36 to 1.29). The metformin effect was consistent across subgroups and increased over time. Neither ivermectin nor fluvoxamine showed effect over placebo. CONCLUSIONS: In this randomized, placebo-controlled trial of outpatient treatment of SARS-CoV-2, metformin significantly reduced SARS-CoV-2 viral load, which may explain the clinical benefits in this trial. Metformin is pleiotropic with other actions that are relevant to COVID-19 pathophysiology. CLINICAL TRIALS REGISTRATION: NCT04510194.
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Antivirales , Tratamiento Farmacológico de COVID-19 , COVID-19 , Metformina , SARS-CoV-2 , Carga Viral , Humanos , Metformina/uso terapéutico , Metformina/farmacología , Carga Viral/efectos de los fármacos , Masculino , SARS-CoV-2/efectos de los fármacos , Femenino , Persona de Mediana Edad , Método Doble Ciego , Antivirales/uso terapéutico , Antivirales/farmacología , Adulto , COVID-19/virología , Ivermectina/uso terapéutico , Ivermectina/farmacología , Fluvoxamina/uso terapéutico , Fluvoxamina/farmacología , AncianoRESUMEN
INTRODUCTION: After colectomy with ileoanal pouch anastomosis (IPAA), many patients develop high bowel frequency (BF) refractory to antimotility agents, despite normal IPAA morphology. Low circulating levels of glucagon-like protein-1 (GLP-1), a modulator of gastroduodenal motility, have been reported after colectomy. METHODS: Double-blind crossover study of 8 IPAA patients with refractory high BF treated with daily administration of the GLP-1 receptor agonist liraglutide or placebo. RESULTS: Liraglutide, but not placebo, reduced daily BF by more than 35% ( P < 0.03). DISCUSSION: Larger randomized controlled studies are warranted to delineate the treatment potential of GLP-1 receptor agonists in IPAA patients suffering from noninflammatory high BF.
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INTRODUCTION: People with type 2 diabetes are at heightened risk for severe outcomes related to COVID-19 infection, including hospitalization, intensive care unit admission, and mortality. This study was designed to examine the impact of premorbid use of glucagon-like peptide-1 receptor agonist (GLP-1RA) monotherapy, sodium-glucose cotransporter-2 inhibitor (SGLT-2i) monotherapy, and concomitant GLP1-RA/SGLT-2i therapy on the severity of outcomes in individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: Utilizing observational data from the National COVID Cohort Collaborative through September 2022, we compared outcomes in 78,806 individuals with a prescription of GLP-1RA and SGLT-2i versus a prescription of dipeptidyl peptidase 4 inhibitors (DPP-4i) within 24 months of a positive SARS-CoV-2 PCR test. We also compared concomitant GLP-1RA/SGLT-2i therapy to GLP-1RA and SGLT-2i monotherapy. The primary outcome was 60-day mortality, measured from the positive test date. Secondary outcomes included emergency room (ER) visits, hospitalization, and mechanical ventilation within 14 days. Using a super learner approach and accounting for baseline characteristics, associations were quantified with odds ratios (OR) estimated with targeted maximum likelihood estimation (TMLE). RESULTS: Use of GLP-1RA (OR 0.64, 95% confidence interval [CI] 0.56-0.72) and SGLT-2i (OR 0.62, 95% CI 0.57-0.68) were associated with lower odds of 60-day mortality compared to DPP-4i use. Additionally, the OR of ER visits and hospitalizations were similarly reduced with GLP1-RA and SGLT-2i use. Concomitant GLP-1RA/SGLT-2i use showed similar odds of 60-day mortality when compared to GLP-1RA or SGLT-2i use alone (OR 0.92, 95% CI 0.81-1.05 and OR 0.88, 95% CI 0.76-1.01, respectively). However, lower OR of all secondary outcomes were associated with concomitant GLP-1RA/SGLT-2i use when compared to SGLT-2i use alone. CONCLUSION: Among adults who tested positive for SARS-CoV-2, premorbid use of either GLP-1RA or SGLT-2i is associated with lower odds of mortality compared to DPP-4i. Furthermore, concomitant use of GLP-1RA and SGLT-2i is linked to lower odds of other severe COVID-19 outcomes, including ER visits, hospitalizations, and mechanical ventilation, compared to SGLT-2i use alone. Graphical abstract available for this article.
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AIMS: Type 2 diabetes (T2D) is a risk factor for cardiovascular and non-cardiovascular mortality. However, global distribution of cause-specific deaths in T2D is poorly understood. We characterized cause-specific deaths by geographic region among individuals with T2D at risk for cardiovascular disease (CVD). METHODS AND RESULTS: The international EXSCEL trial included 14,752 participants with T2D (73% with established CVD). We identified the proportion of deaths over 5-year follow-up attributed to cardiovascular and non-cardiovascular causes, and associated risk factors. During median 3.2-year follow-up, 1,091 (7.4%) participants died. Adjudicated causes of death were 723 cardiovascular (66.3% of deaths), including 252 unknown, and 368 non-cardiovascular (33.7%). Most deaths occurred in North America (N = 356/9.6% across region) and Eastern Europe (N = 326/8.1%), with fewest in Asia/Pacific (N = 68/4.4%). The highest proportional cause-specific deaths by region were sudden cardiac in Asia/Pacific (23/34% of regional deaths) and North America (86/24%); unknown in Eastern Europe (90/28%) and Western Europe (39/21%); and non-malignant non-cardiovascular in Latin America (48/31%). Cox proportional hazards model for adjudicated causes of death showed prognostic risk factors (hazard ratio [95% CI]) for cardiovascular and non-cardiovascular deaths, respectively: heart failure 2.04 (1.72-2.42) and 1.86 (1.46-2.39); peripheral artery disease 1.83 (1.54-2.18) and 1.78 (1.40-2.26); and current smoking status 1.61 (1.29-2.01) and 1.77 (1.31-2.40). CONCLUSIONS: In a contemporary T2D trial population, with and without established CVD, leading causes of death varied by geographic region. Underlying mechanisms leading to variability in cause of death across geographic regions and its impact on clinical trial endpoints warrant future research.
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Enfermedades Cardiovasculares , Causas de Muerte , Diabetes Mellitus Tipo 2 , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/epidemiología , Causas de Muerte/tendencias , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etiología , Diabetes Mellitus Tipo 2/mortalidad , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Europa (Continente)/epidemiología , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/epidemiología , América del Norte/epidemiología , Enfermedad Arterial Periférica/mortalidad , Enfermedad Arterial Periférica/epidemiología , Factores de Riesgo , Método Doble CiegoRESUMEN
OBJECTIVE: We report mortality outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) among people with type 2 diabetes diagnosed within 10 years and no recent history of cardiovascular events or cancer. RESEARCH DESIGN AND METHODS: Overall mortality rates and major causes of death were assessed over an average of 5 years of follow-up. Cause of death was adjudicated centrally by a committee masked to treatment assignment. We examined baseline covariates and the 10-year Framingham Risk Score for associations. RESULTS: Mortality rate was low (0.59 per 100 participant-years). Participants who died during follow-up were likely to be older, be male, have a history of hypertension, have a history of smoking, and have moderate albuminuria. The two most common underlying causes of death were "cardiovascular-cause" (a composite of underlying causes) (38.6%) and cancer (26.8%). There were no differences by treatment group. CONCLUSIONS: Among people with diabetes of relatively short duration, cause of death was varied. Attention to health risks beyond cardiovascular diseases is warranted.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Hipertensión , Neoplasias , Humanos , Masculino , Factores de RiesgoRESUMEN
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.
Asunto(s)
Aterosclerosis , Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Infarto del Miocardio , Accidente Cerebrovascular , Humanos , Persona de Mediana Edad , Aterosclerosis/complicaciones , Aterosclerosis/tratamiento farmacológico , Enfermedades Cardiovasculares/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Agonistas Receptor de Péptidos Similares al Glucagón , Hemoglobina Glucada , Hipoglucemiantes , Infarto del Miocardio/tratamiento farmacológico , Accidente Cerebrovascular/inducido químicamente , Resultado del Tratamiento , Método Doble CiegoRESUMEN
BACKGROUND: Many older adults with cancer have ≥2 impairments on geriatric assessment which impacts present and future frailty status, treatment tolerability, and outcomes. Our objective was to identify and describe distinct geriatric assessment impairment classes using latent class analysis (LCA) in older patients with gastrointestinal malignancies and assess 1-year mortality. METHODS: We used the Cancer & Aging Resilience Evaluation (CARE) Study, a registry of older adults (≥60 years) at University of Alabama at Birmingham. The analytic cohort included patients with gastrointestinal malignancies who completed a self-administered geriatric assessment (CARE tool) before chemotherapy and had ≥1 geriatric assessment impairment. Thirteen geriatric assessment impairments were used as indicators in LCA. Resultant classes were described, mortality was estimated, and risk contrasts (differences, hazard ratios) were calculated with 95% confidence intervals. For comparison, estimates were provided for frailty categories (robust, pre-frail, frail) determined from 44 items in the CARE tool. Stratified analyses included high-risk (pancreatic, hepatobiliary, esophageal) vs. low-risk gastrointestinal cancers, and stage (IV vs. I-III). RESULTS: Six geriatric assessment impairment classes were identified: Mild impairment (LC1); Social support impairment (LC2); Weight loss alone (LC3); Impaired, low anxiety/depression (LC4); Impaired with anxiety/depression (LC5); Global impairment (LC6). One-year mortality was 14%, 22%, 29%, 34%, 50% and 50% for LC1-LC6, respectively. For frailty categories, estimates ranged from 18% (robust) to 40% (frail). In stratified analyses, LC4-LC6 consistently had higher mortality estimates compared to LC1. CONCLUSIONS: The 6 geriatric assessment impairment classes showed a wider spread of mortality estimates compared to frailty categories and could be used to identify vulnerable patients and to plan interventions.