Browsing by Subject "Hypoglycemic Agents"
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Item Open Access A clinician's guide to the ABCs of cardiovascular disease prevention: the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease and American College of Cardiology Cardiosource Approach to the Million Hearts Initiative.(Clinical cardiology, 2013-07) Hsu, Steven; Ton, Van-Khue; Dominique Ashen, M; Martin, Seth S; Gluckman, Ty J; Kohli, Payal; Sisson, Stephen D; Blumenthal, Roger S; Blaha, Michael JAtherosclerotic cardiovascular disease (CVD) is the leading cause of death in the United States and worldwide. Fortunately, it is often preventable with early adoption of lifestyle modification, prevention of risk factor onset, and aggressive treatment of existing risk factors. The Million Hearts Initiative is an effort by the Centers for Disease Control that aims to prevent 1 million myocardial infarctions and strokes over the next 5 years. As part of this initiative, we present a simply organized "ABCDE" approach for guiding a consistent comprehensive approach to managing cardiovascular risk in daily clinical practice. ABCDE stands for assessment of risk, antiplatelet therapy, blood pressure management, cholesterol management, cigarette/tobacco cessation, diet and weight management, diabetes prevention and treatment, and exercise, interventions regularly used to reduce cardiovascular (CV) risk. Throughout this article we summarize recommendations related to each topic and reference landmark trials and data that support our approach. We believe that the ABCDE approach will be the core framework for addressing CV risk in our effort to prevent CVD.Item Open Access Adherence to diabetes guidelines for screening, physical activity and medication and onset of complications and death.(J Diabetes Complications, 2015-11) Chen, Yiqun; Sloan, Frank A; Yashkin, Arseniy PAIMS: Analyze relationships between adherence to guidelines for diabetes care - regular screening; physical activity; and medication - and diabetes complications and mortality. METHODS: Outcomes were onset of congestive heart failure (CHF), stroke, renal failure, moderate complications of lower extremities, lower-limb amputation, proliferative diabetic retinopathy (PDR), and mortality during follow-up. Participants were persons aged 65+ in the Health and Retirement Study (HRS) 2003 Diabetes Study and had Medicare claims in follow-up period (2004-8). RESULTS: Adherence to screening recommendations decreased risks of developing CHF (odds ratio (OR)=0.83; 95% confidence interval (CI): 0.72-0.96), stroke (OR=0.80; 95% CI: 0.68-0.94); renal failure (OR=0. 82; 95% CI: 0.71-0.95); and death (OR=0.86; 95% CI: 0.74-0.99). Adherence to physical activity recommendation reduced risks of stroke (OR=0.64; 95% CI: 0.45-0.90), renal failure (OR=0.71; 95% CI: 0.52-0.97), moderate lower-extremity complications (OR=0.71; 95% CI: 0.51-0.99), having a lower limb amputation (OR=0.31, 95% CI: 0.11-0.85), and death (OR=0.56, 95% CI: 0.41-0.77). Medication adherence was associated with lower risks of PDR (OR=0.35, 95% CI: 0.13-0.93). CONCLUSIONS: Adherence to screening, physical activity and medication guidelines was associated with lower risks of diabetes complications and death. Relative importance of adherence differed among outcome measures.Item Open Access Effect of Once-Weekly Exenatide on Clinical Outcomes According to Baseline Risk in Patients With Type 2 Diabetes Mellitus: Insights From the EXSCEL Trial.(Journal of the American Heart Association, 2018-10) Mentz, Robert J; Bethel, M Angelyn; Merrill, Peter; Lokhnygina, Yuliya; Buse, John B; Chan, Juliana C; Felício, João S; Goodman, Shaun G; Choi, Jasmine; Gustavson, Stephanie M; Iqbal, Nayyar; Lopes, Renato D; Maggioni, Aldo P; Öhman, Peter; Pagidipati, Neha J; Poulter, Neil R; Ramachandran, Ambady; Reicher, Barry; Holman, Rury R; Hernandez, Adrian F; EXSCEL Study GroupBackground In the EXSCEL (Exenatide Study of Cardiovascular Event Lowering), exenatide once-weekly resulted in a nonsignificant reduction in major adverse cardiovascular events ( MACEs ) and a nominal 14% reduction in all-cause mortality in 14 752 patients with type 2 diabetes mellitus (T2 DM ) with and without cardiovascular disease. Whether patients at increased risk for events experienced a comparatively greater treatment benefit with exenatide is unknown. Methods and Results In the EXSCEL population, we created risk scores for MACEs and all-cause mortality using step-wise selection of baseline characteristics. A risk score was calculated for each patient, and a time-to-event model for each end point was developed including the risk score, treatment assignment, and risk-treatment interaction. Interaction P values evaluating for a differential treatment effect by baseline risk were reported. Over a median follow-up of 3.2 years (interquartile range, 2.2, 4.4), 1091 (7.4%) patients died and 1744 (11.8%) experienced a MACE . Independent predictors of MACEs and all-cause mortality included age, sex, comorbidities (eg, previous cardiovascular event), body mass index, blood pressure, hemoglobin A1c, and estimated glomerular filtration rate. The all-cause mortality and MACE risk models had modest discrimination with optimism-corrected c-indices of 0.73 and 0.71, respectively. No interaction was observed between treatment effect and risk profile for either end point (both interactions, P>0.1). Conclusions Baseline characteristics (eg, age, previous cardiovascular events) and routine laboratory values (eg, hemoglobin A1c, estimated glomerular filtration rate) provided modest prognostic value for mortality and MACEs in a broad population of patients with type 2 diabetes mellitus. Exenatide's effects on mortality and MACEs were consistent across the spectrum of baseline risk. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT 01144338.Item Open Access Effects of Linagliptin on Cardiovascular and Kidney Outcomes in People With Normal and Reduced Kidney Function: Secondary Analysis of the CARMELINA Randomized Trial.(Diabetes care, 2020-08) Perkovic, Vlado; Toto, Robert; Cooper, Mark E; Mann, Johannes FE; Rosenstock, Julio; McGuire, Darren K; Kahn, Steven E; Marx, Nikolaus; Alexander, John H; Zinman, Bernard; Pfarr, Egon; Schnaidt, Sven; Meinicke, Thomas; von Eynatten, Maximillian; George, Jyothis T; Johansen, Odd Erik; Wanner, Christoph; CARMELINA investigatorsObjective
Type 2 diabetes is a leading cause of kidney failure, but few outcome trials proactively enrolled individuals with chronic kidney disease (CKD). We performed secondary analyses of cardiovascular (CV) and kidney outcomes across baseline estimated glomerular filtration rate (eGFR) categories (≥60, 45 to <60, 30 to <45, and <30 mL/min/1.73 m2) in Cardiovascular and Renal Microvascular Outcome Study With Linagliptin (CARMELINA), a cardiorenal placebo-controlled outcome trial of the dipeptidyl peptidase 4 inhibitor linagliptin (NCT01897532).Research design and methods
Participants with CV disease and/or CKD were included. The primary outcome was time to first occurrence of CV death, nonfatal myocardial infarction, or nonfatal stroke (three-point major adverse CV event [3P-MACE]), with a secondary outcome of renal death, end-stage kidney disease, or sustained ≥40% decrease in eGFR from baseline. Other end points included progression of albuminuria, change in HbA1c, and adverse events (AEs) including hypoglycemia.Results
A total of 6,979 subjects (mean age 65.9 years; eGFR 54.6 mL/min/1.73 m2; 80.1% albuminuria) were followed for 2.2 years. Across eGFR categories, linagliptin as compared with placebo did not affect the risk for 3P-MACE (hazard ratio 1.02 [95% CI 0.89, 1.17]) or the secondary kidney outcome (1.04 [0.89, 1.22]) (interaction P values >0.05). Regardless of eGFR, albuminuria progression was reduced with linagliptin, as was HbA1c, without increasing risk for hypoglycemia. AEs were balanced among groups overall and across eGFR categories.Conclusions
Across all GFR categories, in participants with type 2 diabetes and CKD and/or CV disease, there was no difference in risk for linagliptin versus placebo on CV and kidney events. Significant reductions in risk for albuminuria progression and HbA1c and no difference in AEs were observed.Item Open Access Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.(The New England journal of medicine, 2017-09) Holman, Rury R; Bethel, M Angelyn; Mentz, Robert J; Thompson, Vivian P; Lokhnygina, Yuliya; Buse, John B; Chan, Juliana C; Choi, Jasmine; Gustavson, Stephanie M; Iqbal, Nayyar; Maggioni, Aldo P; Marso, Steven P; Öhman, Peter; Pagidipati, Neha J; Poulter, Neil; Ramachandran, Ambady; Zinman, Bernard; Hernandez, Adrian F; EXSCEL Study GroupBackground
The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown.Methods
We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy.Results
In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups.Conclusions
Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .).Item Open Access Glucose control in hospitalized patients.(American family physician, 2010-05) Sawin, Gregory; Shaughnessy, Allen FEvidence indicates that hospitalized patients with hyperglycemia do not benefit from tight blood glucose control. Maintaining a blood glucose level of less than 180 mg per dL (9.99 mmol per L) will minimize symptoms of hyperglycemia and hypoglycemia without adversely affecting patient-oriented health outcomes. In the absence of modifying factors, physicians should continue patients' at-home diabetes mellitus medications and randomly check glucose levels once daily. Sulfonylureas should be withheld to avoid hypoglycemia in patients with limited caloric intake. Patients with cardiovascular conditions may benefit from temporarily stopping treatment with thiazolidinediones to avoid precipitating heart failure. Metformin should be temporarily withheld in patients who have worsening renal function or who will undergo an imaging study that uses contrast. When patients need to be treated with insulin in the short term, using a long-acting basal insulin combined with a short-acting insulin before meals (with the goal of keeping blood glucose less than 180 mg per dL) better approximates normal physiology and uses fewer nursing resources than sliding-scale insulin approaches. Most studies have found that infusion with glucose, insulin, and potassium does not improve mortality in patients with acute myocardial infarction. Patients admitted with acute myocardial infarction should have moderate control of blood glucose using home regimens or basal insulin with correctional doses.Item Open Access Improving blood pressure control through a clinical pharmacist outreach program in patients with diabetes mellitus in 2 high-performing health systems: the adherence and intensification of medications cluster randomized, controlled pragmatic trial.(Circulation, 2012-06) Heisler, Michele; Hofer, Timothy P; Schmittdiel, Julie A; Selby, Joe V; Klamerus, Mandi L; Bosworth, Hayden B; Bermann, Martin; Kerr, Eve ABackground
Even in high-performing health systems, some patients with diabetes mellitus have poor blood pressure (BP) control because of poor medication adherence and lack of medication intensification. We examined whether the Adherence and Intensification of Medications intervention, a pharmacist-led intervention combining elements found in efficacy studies to lower BP, improved BP among patients with diabetes mellitus with persistent hypertension and poor refill adherence or insufficient medication intensification in 2 high-performing health systems.Methods and results
We conducted a prospective, multisite cluster randomized pragmatic trial with randomization of 16 primary care teams at 5 medical centers (3 Veterans Affairs and 2 Kaiser Permanente) to the Adherence and Intensification of Medications intervention or usual care. The primary outcome was relative change in systolic BP (SBP), comparing 1797 intervention with 2303 control team patients, from 6 months preceding to 6 months after the 14-month intervention period. We examined shorter-term changes in SBP as a secondary outcome. The mean SBP decrease from 6 months before to 6 months after the intervention period was ≈9 mm Hg in both arms. Mean SBPs of eligible intervention patients were 2.4 mm Hg lower (95% CI: -3.4 to -1.5; P<0.001) immediately after the intervention than those achieved by control patients.Conclusions
The Adherence and Intensification of Medications program more rapidly lowered SBPs among intervention patients, but usual-care patients achieved equally low SBP levels by 6 months after the intervention period. These findings show the importance of evaluating in different real-life clinical settings programs found in efficacy trials to be effective before urging their widespread adoption in all settings.Clinical trial registration
URL: http://clinicaltrials.gov. Unique identifier: NCT00495794.Item Open Access International variation in characteristics and clinical outcomes of patients with type 2 diabetes and heart failure: Insights from TECOS.(American heart journal, 2019-12) Bhatt, Ankeet S; Luo, Nancy; Solomon, Nicole; Pagidipati, Neha J; Ambrosio, Giuseppe; Green, Jennifer B; McGuire, Darren K; Standl, Eberhard; Cornel, Jan H; Halvorsen, Sigrun; Lopes, Renato D; White, Harvey D; Holman, Rury R; Peterson, Eric D; Mentz, Robert J; TECOS Study GroupInternational differences in management/outcomes among patients with type 2 diabetes and heart failure (HF) are not well characterized. We sought to evaluate geographic variation in treatment and outcomes among these patients. METHODS AND RESULTS: Among 14,671 participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), those with HF at baseline and a documented ejection fraction (EF) (N = 1591; 10.8%) were categorized by enrollment region (North America, Latin America, Western Europe, Eastern Europe, and Asia Pacific). Cox models were used to examine the association between geographic region and the primary outcome of all-cause mortality (ACM) or hospitalization for HF (hHF) in addition to ACM alone. Analyses were stratified by those with EF <40% or EF ≥40%. The majority of participants with HF were enrolled in Eastern Europe (53%). Overall, 1,267 (79.6%) had EF ≥40%. β-Blocker (83%) and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (86%) use was high across all regions in patients with EF <40%. During a median follow-up of 2.9 years, Eastern European participants had lower rates of ACM/hHF compared with North Americans (adjusted hazard ratio: 0.45; 95% CI: 0.32-0.64). These differences were seen only in the EF ≥40% subgroup and not the EF <40% subgroup. ACM was similar among Eastern European and North American participants (adjusted hazard ratio: 0.79; 95% CI: 0.44-1.45). CONCLUSIONS: Significant variation exists in the clinical features and outcomes of HF patients across regions in TECOS. Patients from Eastern Europe had lower risk-adjusted ACM/hHF than those in North America, driven by those with EF ≥40%. These data may inform the design of future international trials.Item Open Access Kidney and Cardiovascular Effectiveness of SGLT2 Inhibitors vs GLP-1 Receptor Agonists in Type 2 Diabetes.(Journal of the American College of Cardiology, 2024-08) Edmonston, Daniel; Mulder, Hillary; Lydon, Elizabeth; Chiswell, Karen; Lampron, Zachary; Shay, Christina; Marsolo, Keith; Shah, Raj C; Jones, W Schuyler; Gordon, Howard; Hwang, Wenke; Ayoub, Isabella; Ford, Daniel; Chamberlain, Alanna; Rao, Ajaykumar; Fonseca, Vivian; Chang, Alexander; Ahmad, Faraz; Hung, Adriana; Hunt, Kelly; Butler, Javed; Bosworth, Hayden B; Pagidipati, NehaBackground
Emerging data suggest that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve kidney outcomes for people with type 2 diabetes (T2D). Direct comparisons of the kidney and cardiovascular effectiveness of GLP-1 RA with sodium-glucose cotransporter 2 inhibitors (SGLT2i), a first-line therapy for this population, are needed.Objectives
The authors compared kidney and cardiovascular outcomes for new users of SGLT2i and GLP-1 RAs with T2D.Methods
Using propensity score overlap weighting, we analyzed electronic health record data from 20 U.S. health systems contributing to PCORnet between 2015 and 2020. The primary kidney outcome was a composite of sustained 40% estimated glomerular filtration rate (eGFR) decline, incident end-stage kidney disease, or all-cause mortality over 2 years or until censoring. In addition, we examined cardiovascular and safety outcomes.Results
The weighted study cohort included 35,004 SGLT2i and 47,268 GLP-1 RA initiators. Over a median of 1.2 years, the primary outcome did not differ between treatments (HR: 0.91; 95% CI: 0.81-1.02), although SGLT2i were associated with a lower risk of 40% eGFR decline (HR: 0.77; 95% CI: 0.65-0.91). Risks of mortality (HR: 1.08; 95% CI: 0.92-1.27), a composite of stroke, myocardial infarction, or death (HR: 1.03; 95% CI: 0.93-1.14), and heart failure hospitalization (HR: 0.95; 95% CI: 0.80-1.13) did not differ. Genital mycotic infections were more common for SGLT2i initiators, but other safety outcomes did not differ. The results were similar regardless of chronic kidney disease status.Conclusions
SGLT2i and GLP-1 RAs led to similar kidney and cardiovascular outcomes in people with T2D, though SGLT2i initiation was associated with a lower risk of 40% eGFR decline. (Evaluating Comparative Effectiveness of Empagliflozin in Type 2 Diabetes Population With and Without Chronic Kidney Disease; NCT05465317).Item Open Access Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial.(Lancet, 2024-08-24) Deanfield, John; Verma, Subodh; Scirica, Benjamin M; Kahn, Steven E; Emerson, Scott S; Ryan, Donna; Lingvay, Ildiko; Colhoun, Helen M; Plutzky, Jorge; Kosiborod, Mikhail N; Hovingh, G Kees; Hardt-Lindberg, Søren; Frenkel, Ofir; Weeke, Peter E; Rasmussen, Søren; Goudev, Assen; Lang, Chim C; Urina-Triana, Miguel; Pietilä, Mikko; Lincoff, A Michael; SELECT Trial InvestigatorsBACKGROUND: Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure. METHODS: The SELECT trial was a randomised, double-blind, multicentre, placebo-controlled, event-driven phase 3 trial in 41 countries. Adults aged 45 years and older, with a BMI of 27 kg/m2 or greater and established cardiovascular disease were eligible for the study. Patients were randomly assigned (1:1) with a block size of four using an interactive web response system in a double-blind manner to escalating doses of once-weekly subcutaneous semaglutide over 16 weeks to a target dose of 2·4 mg, or placebo. In a prespecified analysis, we examined the effect of semaglutide compared with placebo in patients with and without a history of heart failure at enrolment, subclassified as heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, or unclassified heart failure. Endpoints comprised MACE (a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); a composite heart failure outcome (cardiovascular death or hospitalisation or urgent hospital visit for heart failure); cardiovascular death; and all-cause death. The study is registered with ClinicalTrials.gov, NCT03574597. FINDINGS: Between Oct 31, 2018, and March 31, 2021, 17 604 patients with a mean age of 61·6 years (SD 8·9) and a mean BMI of 33·4 kg/m2 (5·0) were randomly assigned to receive semaglutide (8803 [50·0%] patients) or placebo (8801 [50·0%] patients). 4286 (24·3%) of 17 604 patients had a history of investigator-defined heart failure at enrolment: 2273 (53·0%) of 4286 patients had heart failure with preserved ejection fraction, 1347 (31·4%) had heart failure with reduced ejection fraction, and 666 (15·5%) had unclassified heart failure. Baseline characteristics were similar between patients with and without heart failure. Patients with heart failure had a higher incidence of clinical events. Semaglutide improved all outcome measures in patients with heart failure at random assignment compared with those without heart failure (hazard ratio [HR] 0·72, 95% CI 0·60-0·87 for MACE; 0·79, 0·64-0·98 for the heart failure composite endpoint; 0·76, 0·59-0·97 for cardiovascular death; and 0·81, 0·66-1·00 for all-cause death; all pinteraction>0·19). Treatment with semaglutide resulted in improved outcomes in both the heart failure with reduced ejection fraction (HR 0·65, 95% CI 0·49-0·87 for MACE; 0·79, 0·58-1·08 for the composite heart failure endpoint) and heart failure with preserved ejection fraction groups (0·69, 0·51-0·91 for MACE; 0·75, 0·52-1·07 for the composite heart failure endpoint), although patients with heart failure with reduced ejection fraction had higher absolute event rates than those with heart failure with preserved ejection fraction. For MACE and the heart failure composite, there were no significant differences in benefits across baseline age, sex, BMI, New York Heart Association status, and diuretic use. Serious adverse events were less frequent with semaglutide versus placebo, regardless of heart failure subtype. INTERPRETATION: In patients with atherosclerotic cardiovascular diease and overweight or obesity, treatment with semaglutide 2·4 mg reduced MACE and composite heart failure endpoints compared with placebo in those with and without clinical heart failure, regardless of heart failure subtype. Our findings could facilitate prescribing and result in improved clinical outcomes for this patient group. FUNDING: Novo Nordisk.Item Open Access STAR 3 randomized controlled trial to compare sensor-augmented insulin pump therapy with multiple daily injections in the treatment of type 1 diabetes: research design, methods, and baseline characteristics of enrolled subjects.(Diabetes Technol Ther, 2010-04) Davis, Stephen N; Horton, Edward S; Battelino, Tadej; Rubin, Richard R; Schulman, Kevin A; Tamborlane, William VBACKGROUND: Sensor-augmented pump therapy (SAPT) integrates real-time continuous glucose monitoring (RT-CGM) with continuous subcutaneous insulin infusion (CSII) and offers an alternative to multiple daily injections (MDI). Previous studies provide evidence that SAPT may improve clinical outcomes among people with type 1 diabetes. Sensor-Augmented Pump Therapy for A1c Reduction (STAR) 3 is a multicenter randomized controlled trial comparing the efficacy of SAPT to that of MDI in subjects with type 1 diabetes. METHODS: Subjects were randomized to either continue with MDI or transition to SAPT for 1 year. Subjects in the MDI cohort were allowed to transition to SAPT for 6 months after completion of the study. SAPT subjects who completed the study were also allowed to continue for 6 months. The primary end point was the difference between treatment groups in change in hemoglobin A1c (HbA1c) percentage from baseline to 1 year of treatment. Secondary end points included percentage of subjects with HbA1c < or =7% and without severe hypoglycemia, as well as area under the curve of time spent in normal glycemic ranges. Tertiary end points include percentage of subjects with HbA1c < or =7%, key safety end points, user satisfaction, and responses on standardized assessments. RESULTS: A total of 495 subjects were enrolled, and the baseline characteristics similar between the SAPT and MDI groups. Study completion is anticipated in June 2010. CONCLUSIONS: Results of this randomized controlled trial should help establish whether an integrated RT-CGM and CSII system benefits patients with type 1 diabetes more than MDI.Item Open Access Vanadyl sulfate inhibits NO production via threonine phosphorylation of eNOS.(Environmental health perspectives, 2004-02) Li, Zhuowei; Carter, Jacqueline D; Dailey, Lisa A; Huang, Yuh-Chin TExposure to excessive vanadium occurs in some occupations and with consumption of some dietary regimens for weight reduction and body building. Because vanadium is vasoactive, individuals exposed to excessive vanadium may develop adverse vascular effects. We have previously shown that vanadyl sulfate causes acute pulmonary vasoconstriction, which could be attributed in part to inhibition of nitric oxide production. In the present study we investigated whether NO inhibition was related to phosphorylation of endothelial nitric oxide synthase (eNOS). VOSO4 produced dose-dependent constriction of pulmonary arteries in isolated perfused lungs and pulmonary arterial rings and a right shift of the acetylcholine-dependent vasorelaxation curve. VOSO4 inhibited constitutive as well as A23187-stimulated NO production. Constitutive NO inhibition was accompanied by increased Thr495 (threonine at codon 495) phosphorylation of eNOS, which would inhibit eNOS activity. Thr495 phosphorylation of eNOS and inhibition of NO were partially reversed by pretreatment with calphostin C, a protein kinase C (PKC) inhibitor. There were no changes in Ser1177 (serine at codon 1177) or tyrosine phosphorylation of eNOS. These results indicate that VOSO4 induced acute pulmonary vasoconstriction that was mediated in part by the inhibition of endothelial NO production via PKC-dependent phosphorylation of Thr495 of eNOS. Exposure to excessive vanadium may contribute to pulmonary vascular diseases.