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Efficacy and Safety of Tradipitant in Patients With Diabetic and Idiopathic Gastroparesis in a Randomized, Placebo-Controlled Trial.
Carlin, JL, Lieberman, VR, Dahal, A, Keefe, MS, Xiao, C, Birznieks, G, Abell, TL, Lembo, A, Parkman, HP, Polymeropoulos, MH
Gastroenterology. 2021;(1):76-87.e4
Abstract
BACKGROUND & AIMS Treatments are needed for gastroparesis; antagonists of tachykinin receptor 1 (TACR1, also called NK1R) can reduce symptoms of nausea and vomiting. We investigated the safety and efficacy of tradipitant, an antagonist of NK1R, in patients with idiopathic or diabetic gastroparesis. METHODS We performed a double-blind trial of 152 adults with gastroparesis at 47 sites in the United States from November 2016 through December 2018. Participants were randomly assigned to groups given oral tradipitant 85 mg (n = 77) or placebo (n = 75) twice daily for 4 weeks. Symptoms were assessed by a daily symptom dairy, Gastroparesis Cardinal Symptom Index scores, and other patient-reported questionnaires. The primary outcome from the intent-to-treat analysis was change from baseline to week 4 in average nausea severity, measured by the Gastroparesis Core Symptom Daily Diary. RESULTS Patients receiving tradipitant had a significant decrease in nausea score (reduction of 1.2) at week 4 compared with placebo (reduction of 0.7) (P = .0099) and a significant increase in of nausea-free days at week 4 (28.8% increase on tradipitant vs 15.0% on placebo; P = .0160). Patients with nausea and vomiting at baseline (n = 101) had an even greater decrease in nausea in when given tradipitant (reduction of 1.4) compared with those given placebo (reduction of 0.4) (P < .0001), as well as an increase in nausea-free days at week 4 (32.3% improvement on tradipitant vs 7.6% on placebo; P = .0003). The average nausea score was 1 or less at week 4 in 32.9% of patients given tradipitant compared with 11.8% of patients given placebo (P = .0013). A greater than 1-point improvement in Gastroparesis Cardinal Symptom Index score was observed in 46.6% of patients given tradipitant compared with 23.5% of patients given placebo (P = .0053). CONCLUSIONS Tradipitant resulted in statistically and clinically meaningful improvements in nausea and reduced vomiting, compared with placebo, in patients with idiopathic or diabetic gastroparesis. ClinicalTrials.gov, Number: NCT02970968.
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Effect of CETP inhibition with evacetrapib in patients with diabetes mellitus enrolled in the ACCELERATE trial.
Menon, V, Kumar, A, Patel, DR, St John, J, Riesmeyer, J, Weerakkody, G, Ruotolo, G, Wolski, KE, McErlean, E, Cremer, PC, et al
BMJ open diabetes research & care. 2020;(1)
Abstract
BACKGROUND High-density lipoprotein (HDL) levels are inversely associated with cardiovascular risk. Cholesteryl ester transfer protein inhibition with evacetrapib results in a marked increase in HDL and reduction in low-density lipoprotein (LDL) levels. We evaluated the impact of treatment with evacetrapib versus placebo in the subset of 8236 patients with diabetes mellitus (DM) enrolled in the Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes trial. METHODS AND RESULTS Time to first occurrence of any component of the primary composite endpoint of cardiovascular death, myocardial infarction, stroke, revascularization, and hospitalization for unstable angina was compared among patients with DM randomized to treatment with evacetrapib (n=4127) or placebo (n=4109) over a median of 26 months of follow-up. The mean baseline LDL at initiation was 80 mg/dL with a mean baseline HDL of 44 mg/dL. In patients with DM, evacetrapib resulted in a 131% mean increase in HDL levels and a 32% mean decrease in LDL at 3 months that was sustained during the course of the trial. At 6 months, hemoglobin A1c (HbA1c) levels were lower with evacetrapib than placebo (7.08% vs 7.15%, p=0.023). Composite event rates were higher in patients with DM than without DM (Kaplan-Meier estimates: 15.2% vs 10.6%, HR 1.46, 95% CI 1.30 to 1.64, p<0.001). In the DM group, event rates for the composite endpoint (14.5% evacetrapib vs 16% placebo, HR 0.95, 95% CI 0.85 to 1.07, p=0.38) and individual components of the composite were similar for both evacetrapib and placebo groups. No significant treatment interaction between treatment assignment and diabetes status was noted. CONCLUSION Despite a favorable increase in HDL, and decreases in LDL and HbA1c levels in patients with DM, we observed no benefits of treatment with evacetrapib on prespecified clinical outcomes in this high-risk population.
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Cost-effectiveness of ranibizumab and aflibercept to treat diabetic macular edema from a US perspective: analysis of 2-year Protocol T data.
Holekamp, N, Duff, SB, Rajput, Y, Garmo, V
Journal of medical economics. 2020;(3):287-296
Abstract
Aims: Protocol T (NCT01627249) was a head-to-head study conducted by the Diabetic Retinopathy Clinical Research Network that compared intravitreal aflibercept, bevacizumab, and ranibizumab for the treatment of diabetic macular edema (DME). A cost-effectiveness analysis accompanying the 1-year data of Protocol T revealed that aflibercept was not cost-effective vs ranibizumab for all patients, but could have been cost-effective in certain patient sub-groups if the 1-year results were extrapolated out to 10 years. The present study evaluated the cost-effectiveness of US Food and Drug Administration-approved anti-vascular endothelial growth factor agents (ranibizumab, aflibercept) for treatment of DME using the 2-year data from Protocol T.Methods: Costs of aflibercept 2.0 mg or ranibizumab 0.3 mg, visual acuity (VA)-related medical costs, and quality-adjusted life-years (QALYs) were simulated for eight VA health states. Treatment, adverse event management, and VA-related healthcare resource costs (2016 US dollars) were based on Medicare reimbursement and published literature. VA-related health utilities were determined using a published algorithm. Patients were stratified by baseline VA: 20/40 or better; 20/50 or worse.Results: Total 2-year costs were higher, and QALYs similar, for aflibercept vs ranibizumab in the full cohort ($44,423 vs $34,529; 1.476 vs 1.466), 20/40 or better VA sub-group ($40,854 vs $31,897; 1.517 vs 1.519), and 20/50 or worse VA sub-group ($48,214 vs $37,246; 1.433 vs 1.412), respectively. Incremental cost-effectiveness ratios in the full cohort and 20/50 or worse VA sub-group were $986,159/QALY and $523,377/QALY, respectively. These decreased to $711,301 and $246,978 when analyses were extrapolated to 10 years.Limitations: Key potential limitations include the fact that VA was the only QALY parameter analyzed and the uncertainty surrounding the role of better- and worse-seeing eye VA in overall functional impairment.Conclusions: This analysis suggests that aflibercept is not cost-effective vs ranibizumab for patients with DME, regardless of baseline vision.
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Serum apolipoproteins and apolipoprotein-defined lipoprotein subclasses: a hypothesis-generating prospective study of cardiovascular events in T1D.
Basu, A, Bebu, I, Jenkins, AJ, Stoner, JA, Zhang, Y, Klein, RL, Lopes-Virella, MF, Garvey, WT, Budoff, MJ, Alaupovic, P, et al
Journal of lipid research. 2019;(8):1432-1439
Abstract
APOB, APOC3, and APOE and apolipoprotein-defined lipoprotein subclasses (ADLSs; based on qualitative apolipoprotein complement) have been associated with dyslipidemia and CVD. Our main objective was to define associations of serum apolipoproteins and ADLSs with "any CVD" and "major atherosclerotic cardiovascular events" (MACEs) in a prospective study of T1D. Serum apolipoproteins and ADLSs (14 biomarkers in total) were measured in sera (obtained between 1997 and 2000) from a subset (n = 465) of the Epidemiology of Diabetes Interventions and Complications cohort. Prospective associations of "any CVD" (myocardial infarction, stroke, confirmed angina, silent myocardial infarction, revascularization, or congestive heart failure) and MACEs (fatal or nonfatal myocardial infarction or stroke), over 5,943 and 6,180 patient-years follow-up, respectively, were investigated using Cox proportional hazards models that were unadjusted and adjusted for risk factors. During 15 years of follow-up, 50 "any CVD" events and 24 MACEs occurred. Nominally significant positive univariate associations with "any CVD" were APOB, APOC3 and its subfractions [heparin precipitate, heparin-soluble (HS)], and ADLS-defined Lp-B. In adjusted analyses, APOC3-HS remained nominally significant. Nominally significant positive univariate associations with MACEs were APOC3 and its subfractions and Lp-B:C; those with total APOC3 and APOC3-HS persisted in adjusted analyses. However, these associations did not reach significance after adjusting for multiple testing. There were no significant associations of APOA1, APOA2, APOE, or other ADLSs with either "any CVD" or MACEs. These hypothesis-generating data suggest that total serum APOC3 and APOC3 in HDL are potentially important predictive biomarkers for any CVD and MACEs in adults with T1D.
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Effects of n-3 Fatty Acid Supplements in Diabetes Mellitus.
, , Bowman, L, Mafham, M, Wallendszus, K, Stevens, W, Buck, G, Barton, J, Murphy, K, Aung, T, Haynes, R, et al
The New England journal of medicine. 2018;(16):1540-1550
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Abstract
BACKGROUND Increased intake of n-3 fatty acids has been associated with a reduced risk of cardiovascular disease in observational studies, but this finding has not been confirmed in randomized trials. It remains unclear whether n-3 (also called omega-3) fatty acid supplementation has cardiovascular benefit in patients with diabetes mellitus. METHODS We randomly assigned 15,480 patients with diabetes but without evidence of atherosclerotic cardiovascular disease to receive 1-g capsules containing either n-3 fatty acids (fatty acid group) or matching placebo (olive oil) daily. The primary outcome was a first serious vascular event (i.e., nonfatal myocardial infarction or stroke, transient ischemic attack, or vascular death, excluding confirmed intracranial hemorrhage). The secondary outcome was a first serious vascular event or any arterial revascularization. RESULTS During a mean follow-up of 7.4 years (adherence rate, 76%), a serious vascular event occurred in 689 patients (8.9%) in the fatty acid group and in 712 (9.2%) in the placebo group (rate ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08; P=0.55). The composite outcome of a serious vascular event or revascularization occurred in 882 patients (11.4%) and 887 patients (11.5%), respectively (rate ratio, 1.00; 95% CI, 0.91 to 1.09). Death from any cause occurred in 752 patients (9.7%) in the fatty acid group and in 788 (10.2%) in the placebo group (rate ratio, 0.95; 95% CI, 0.86 to 1.05). There were no significant between-group differences in the rates of nonfatal serious adverse events. CONCLUSIONS Among patients with diabetes without evidence of cardiovascular disease, there was no significant difference in the risk of serious vascular events between those who were assigned to receive n-3 fatty acid supplementation and those who were assigned to receive placebo. (Funded by the British Heart Foundation and others; Current Controlled Trials number, ISRCTN60635500 ; ClinicalTrials.gov number, NCT00135226 .).
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Reducing cardiovascular disease risk in diabetes: a randomised controlled trial of a quality improvement initiative.
Chalasani, S, Peiris, DP, Usherwood, T, Redfern, J, Neal, BC, Sullivan, DR, Colagiuri, S, Zwar, NA, Li, Q, Patel, A
The Medical journal of Australia. 2017;(10):436-441
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OBJECTIVES To describe the management of cardiovascular disease (CVD) risk in Australian patients with diabetes; to compare the effectiveness of a quality improvement initiative for people with and without diabetes. RESEARCH DESIGN AND METHODS Subgroup analyses of patients with and without diabetes participating in a cluster randomised trial. SETTING AND PARTICIPANTS Indigenous people (≥ 35 years old) and non-Indigenous people (≥ 45 years old) who had attended one of 60 Australian primary health care services at least three times during the preceding 24 months and at least once during the past 6 months. INTERVENTION Quality improvement initiative comprising point-of-care electronic decision support with audit and feedback tools. MAIN OUTCOME MEASURES Adherence to CVD risk screening and prescribing guidelines. RESULTS Baseline rates of guideline-recommended screening were higher for 8829 patients with diabetes than for 44 335 without diabetes (62.0% v 39.5%; P < 0.001). Baseline rates of guideline-recommended prescribing were greater for patients with diabetes than for other patients at high risk of CVD (55.5% v 39.6%; P < 0.001). The proportions of patients with diabetes not attaining recommended treatment targets for blood pressure, low-density lipoprotein-cholesterol or HbA1c levels who were not prescribed the corresponding therapy at baseline were 28%, 44% and 24% respectively. The intervention was associated with improved screening rates, but the effect was smaller for patients with diabetes than for those without diabetes (rate ratio [RR], 1.14 v 1.28; P = 0.01). It was associated with improved guideline-recommended prescribing only for undertreated individuals at high risk; the effect size was similar for those with and without diabetes (RR, 1.63 v 1.53; P = 0.28). CONCLUSIONS Adherence to CVD risk management guidelines was better for people with diabetes, but there is room for improvement. The intervention was modestly effective in people with diabetes, but further strategies are needed to close evidence-practice gaps.Australian and New Zealand Clinical Trials Registry number: ACTRN12611000478910.
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A Traditional Mouthwash (Punica granatum var pleniflora) for Controlling Gingivitis of Diabetic Patients: A Double-Blind Randomized Controlled Clinical Trial.
Sedigh-Rahimabadi, M, Fani, M, Rostami-Chijan, M, Zarshenas, MM, Shams, M
Journal of evidence-based complementary & alternative medicine. 2017;(1):59-67
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This study evaluates the safety and efficacy of Punica granatum var pleniflora mouthwash in treatment of diabetic gingivitis. In a double-blind randomized clinical trial 80 patients with diabetes mellitus and gingivitis were assigned to Golnaar and chlorhexidine 0.2% groups. After using mouthwashes for 2 weeks; participants underwent tooth scaling and the last visit was 2 weeks after scaling. The primary outcome measures were plaque, modified gingival and gingival bleeding indices, and pocket depth. Both interventions had significant improvement on all of the gingival and plaque indices (P < .001 for all indices). There were no significant differences between Golnaar and chlorhexidine in primary outcome measures except for modified gingival index for which Golnaar mouthwash had a superiority after 2 weeks when comparing with chlorhexidine (P = .039). Meanwhile, Golnaar mouthwash had no staining effect. Golnaar mouthwash is safe and effective in treatment of gingivitis in diabetic patients although further studies are recommended.
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Quality Control Measures over 30 Years in a Multicenter Clinical Study: Results from the Diabetes Control and Complications Trial / Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study.
Lorenzi, GM, Braffett, BH, Arends, VL, Danis, RP, Diminick, L, Klumpp, KA, Morrison, AD, Soliman, EZ, Steffes, MW, Cleary, PA, et al
PloS one. 2015;(11):e0141286
Abstract
Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented.
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[Effect of lifestyle interventions on reduction of cardiovascular disease events and its mortality in pre-diabetic patients:long-term follow-up of Da Qing Diabetes Prevention Study].
Chen, Y, Wang, J, An, Y, Gong, Q, He, Y, Zhang, B, Li, H, Shuai, Y, Tang, X, Jiang, Y, et al
Zhonghua nei ke za zhi. 2015;(1):13-7
Abstract
OBJECTIVE To investigate if a six-year intensive lifestyle intervention in people with pre-diabetes lead to reduction of cardiovascular events and cardiovascular disease (CVD) mortality in subsequent 23 years. METHODS Five hundreds and nineteen subjects with normal glucose tolerance (NGT) and 577 subjects with impaired glucose tolerance (IGT) in Da Qing city were recruited in the study in 1986. The IGT subjects randomly assigned to either the no-intervention group or one of three lifestyle intervention groups (diet, exercise, or diet plus exercise) to receive a 6-year lifestyle intervention. In 2009, the participants were followed up to assess the primary outcomes of cardiovascular events and CVD mortality by a questionnaire and medical records. RESULTS Subjects in IGT no-intervention group had the highest incidences of cardiovascular events (44.44%) and CVD mortality (20.00%), while those in NGT group had the lowest incidences of cardiovascular events (29.59%) and CVD mortality (7.52%) after 23-year follow-up. The incidences of cardiovascular events and CVD mortality in IGT intervention subjects were 37.84% and 12.53%, respectively. The multivariable analyses showed that, after controlling of age, gender, BMI smoking, blood pressure and cardiovascular event at baseline, the CVD mortality and incidence of cardiovascular events in IGT no-intervention group was 1.89 (HR = 1.89, 95%CI 1.11-3.22, P = 0.02) and 1.38 (HR = 1.38, 95%CI 1.01-1.90, P = 0.04) times of those in NGT group. However, the CVD mortality and incidence of cardiovascular events were not different in the IGT intervention group compared with those in the NGT group (HR = 1.39, 95%CI 0.89-2.18, P = 0.15 and HR = 1.25, 95%CI 0.98-1.59, P = 0.07, respectively). CONCLUSIONS Subjects with IGT were at high risk for cardiovascular events and mortality. A six-year lifestyle intervention in this population can reduce both the incidence of cardiovascular event and CVD mortality.
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Relationship between intervention dose and outcomes in living well with diabetes--a randomized trial of a telephone-delivered lifestyle-based weight loss intervention.
Goode, AD, Winkler, EA, Reeves, MM, Eakin, EG
American journal of health promotion : AJHP. 2015;(2):120-9
Abstract
PURPOSE To examine associations of intervention dose with weight, physical activity, glycemic control, and diet outcomes in a randomized trial of a telephone counseling intervention. DESIGN Study design was a secondary analysis of intervention group. SETTING Study setting was primary care practices in a disadvantaged community in Australia. SUBJECTS Participants were adult patients with type 2 diabetes (n = 151). INTERVENTION Up to 27 telephone counseling calls were made during 18 months. MEASURES Intervention dose was assessed as the number of calls completed (in tertile categories). Primary outcomes were weight and HbA1c, and moderate to vigorous intensity physical activity via accelerometer. Secondary outcomes were dietary energy intake and diet quality via a validated questionnaire. ANALYSIS Analyses employed were bivariate associations of call completion with sociodemographics, and confounder-adjusted linear mixed models for associations of call completion with outcomes (multiple imputation of missing data). RESULTS Only previous diagnosis of depression/anxiety had a statistically significant (p = .008) association with call completion. Call completion was significantly associated with weight loss (p < .001) but not the other outcomes (p > .05). Relative to low call completion, mean weight loss (as a percentage of baseline weight) was greater in the high-call completion group by -3.3% (95% confidence interval, -5.0% to -1.5%). CONCLUSION Increased dose of intervention was associated with greater weight loss. More needs to be done to retain patients for the duration of weight loss and behavior change interventions, particularly those with diabetes and comorbid depression, who were the most difficult to engage.