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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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Impact of Diabetes on Complications, Long Term Mortality and Recurrence in 608,890 Hospitalised Patients with Stroke.
Szlachetka, WA, Pana, TA, Tiamkao, S, Clark, AB, Kongbunkiat, K, Sawanyawisuth, K, Bettencourt-Silva, JH, Kasemap, N, Mamas, MA, Myint, PK
Global heart. 2020;(1):2
Abstract
BACKGROUND Patients with diabetes mellitus (DM) have been found to be at an increased risk of suffering a stroke. However, research on the impact of DM on stroke outcomes is limited. OBJECTIVES We aimed to examine the influence of DM on outcomes in ischaemic (IS) and haemorrhagic stroke (HS) patients. METHODS We included 608,890 consecutive stroke patients from the Thailand national insurance registry. In-hospital mortality, sepsis, pneumonia, acute kidney injury (AKI), urinary tract infection (UTI) and cardiovascular events were evaluated using logistic regressions. Long-term analysis was performed on first-stroke patients with a determined pathology (n = 398,663) using Royston-Parmar models. Median follow-ups were 4.21 and 4.78 years for IS and HS, respectively. All analyses were stratified by stroke sub-type. RESULTS Mean age (SD) was 64.3 (13.7) years, 44.9% were female with 61% IS, 28% HS and 11% undetermined strokes. DM was associated with in-hospital death, pneumonia, sepsis, AKI and cardiovascular events (odds ratios ranging from 1.13-1.78, p < 0.01) in both stroke types. In IS, DM was associated with long-term mortality and recurrence throughout the follow-up: HRmax (99% CI) at t = 4108 days: 1.54 (1.27, 1.86) and HR (99% CI) = 1.27(1.23,1.32), respectively. In HS, HRmax (t = 4108 days) for long-term mortality was 2.10 (1.87, 2.37), significant after day 14 post-discharge. HRmax (t = 455) for long-term recurrence of HS was 1.29 (1.09, 1.53), significant after day 116 post-discharge. CONCLUSIONS Regardless of stroke type, DM was associated with in-hospital death and complications, long-term mortality and stroke recurrence.
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Adverse risk factor trends limit gains in coronary heart disease mortality in Barbados: 1990-2012.
Sobers, NP, Unwin, N, Samuels, TA, Capewell, S, O'Flaherty, M, Critchley, JA
PloS one. 2019;(4):e0215392
Abstract
BACKGROUND Although most countries face increasing population levels of obesity and diabetes their effect on coronary heart disease (CHD) mortality has not been often studied in small island developing states (SIDs) where obesity rates are among the highest in the world. We estimated the relative contributions of treatments and cardiovascular risk factors to the decline in CHD mortality from 1990 to 2012 in the Caribbean island, Barbados. METHODS We used the IMPACT CHD mortality model to estimate the effect of increased coverage of effective medical/surgical treatments and changes in major CHD risk factors on mortality trends in 2012 compared with 1990. We calculated deaths prevented or postponed (DPPs) for each model risk factor and treatment group. We obtained data from WHO Mortality database, population denominators from the Barbados Statistical Service stratified by 10-year age group (ages 25-34 up to 85 plus), population-based risk factor surveys, Global Burden of Disease and Barbados' national myocardial infarction registry. Monte Carlo probabilistic sensitivity analysis was performed. RESULTS In 1990 the age-standardized CHD mortality rate was 109.5 per 100,000 falling to 55.3 in 2012. Implementation of effective treatment accounted for 56% DPPs (95% (Uncertainty Interval (UI) 46%, 68%), mostly due to the introduction of treatments immediately after acute myocardial infarction (AMI) (14%) and unstable angina (14%). Overall, risk factors contributed 19% DPPs (95% UI 6% to 34%) mostly attributed to decline in cholesterol (18% DPPs, 95% UI 12%, 26%). Adverse trends in diabetes: 14% additional deaths(ADs) 95% UI 8% to 21% ADs) and BMI (2% ADs 95%UI 0 to 5% ADs) limited potential for risk factor gains. CONCLUSIONS Given the significant negative impact of obesity/diabetes on mortality in this analysis, research that explores factors affecting implementation of evidenced-based preventive strategies is needed. The fact that most of the decline in CHD mortality in Barbados was due to treatment provides an example for SIDs about the advantages of universal access to care and treatment.
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Fasting glucose variability in young adulthood and incident diabetes, cardiovascular disease and all-cause mortality.
Bancks, MP, Carson, AP, Lewis, CE, Gunderson, EP, Reis, JP, Schreiner, PJ, Yano, Y, Carnethon, MR
Diabetologia. 2019;(8):1366-1374
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AIMS/HYPOTHESIS The aim of this study was to determine whether long-term intra-individual variability in fasting glucose (FG) during young adulthood is associated with incident diabetes, cardiovascular disease (CVD) and mortality. METHODS We included participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study, ages 18-30 years at baseline (1985-1986) and followed with eight examinations for up to 30 years. Long-term glucose variability was assessed using the CV (CV-FG) and the absolute difference between successive FG measurements (average real variability; ARV-FG). For participants who developed any event (diabetes, CVD or mortality), FG variability measurement was censored at the examination prior to event ascertainment. We estimated HRs for incident diabetes, CVD and mortality with adjustment for demographics, baseline FG, change in FG (censor - baseline) and time-varying education, smoking, alcohol consumption, BMI, physical activity, systolic BP, BP medications, LDL-cholesterol and cholesterol medications (and incident diabetes and diabetes medications for CVD and mortality outcomes). RESULTS Among 3769 black and white participants, there were 317 incident diabetes cases (102,677 person-years), 159 incident CVD events (110,314 person-years) and 174 deaths (111,390 person-years). After adjustment, HRs per 1 SD higher ARV-FG were 1.64 (95% CI 1.52, 1.78) for diabetes, 1.15 (95% CI 1.01, 1.31) for CVD and 1.25 (95% CI 1.11, 1.40) for mortality. The HRs per 1 SD higher CV-FG were 1.39 (95% CI 1.21, 1.58) for diabetes, 1.32 (95% CI 1.13, 1.54) for CVD and 1.08 (95% CI 0.92, 1.27) for mortality, after adjustment. The cause-specific HRs per 1 SD higher ARV-FG were 1.29 (95% CI 1.14, 1.47) for non-CVD death and 1.05 (95% CI 0.76, 1.45) for CVD death. We did not observe evidence for effect modification of any association by sex or race. CONCLUSIONS/INTERPRETATION Our results suggest that higher intra-individual FG variability during young adulthood before the onset of diabetes is associated with incident diabetes, CVD and mortality.
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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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Prevalence Of Diabetic Complications In Newly Diagnosed Type 2 Diabetes Patients In Pakistan: Findings From National Registry.
Uddin, F, Ali, B, Junaid, N
Journal of Ayub Medical College, Abbottabad : JAMC. 2018;(4):S652-S658
Abstract
BACKGROUND This study was conducted to assess the prevalence of micro- and macrovascular complications in patients with newly diagnosed type 2 diabetes (T2DM) in Pakistan. METHODS In this multicentre, observational, cross-sectional disease registry, patients (aged ≥18 years) who were diagnosed at enrolment with T2DM, defined by fasting blood glucose (FBG) ≥126 mg/dL and/or glycated haemoglobin (HbA1c) ≥6.5%, were enrolled. Microvascular complications were ascertained by objective examination while macrovascular complications were identified from patients' medical history. Descriptive statistics were used for data analysis. RESULTS Data from 891 patients were analysed in the study. Mean [±standard deviation (SD)] HbA1c, FBG, and random blood glucose were 9.9% (±2.2%), 193.4 (±74.0) mg/dL, and 294.3 (±72.7) mg/dL, respectively. Obesity (n=689, 77.3%) and familial history of diabetes (n=575, 64.3%) were the most common risk factors for T2DM. Overall prevalence of micro- and macrovascular complications was 68.6% [n=611, 95% confidence interval (CI): 65.4-71.5] and 9.0% (n=80, 95% CI: 7.3-11.0), respectively. Neuropathy, nephropathy, and retinopathy were reported in 59.6% (95% CI: 56.3-62.8), 24.4% (95% CI: 21.6-27.2), and 15.9% (95% CI: 13.7-18.5) of the patients, respectively. Oral antidiabetic agents and insulin were prescribed to 839 (94.2%) and 140 (15.7%) patients, respectively. All study patients received education on T2DM management, mostly from the investigators, and also from diabetes educators and nurses. CONCLUSION The prevalence of micro- and macrovascular complications of T2DM is high, indicating a delay in diagnosis of disease. In order to counter the burden of diabetic complications, optimum strategies for screening of the general population are required.
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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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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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Add-On Antihypertensive Medications to Angiotensin-Aldosterone System Blockers in Diabetes: A Comparative Effectiveness Study.
Schroeder, EB, Chonchol, M, Shetterly, SM, Powers, JD, Adams, JL, Schmittdiel, JA, Nichols, GA, O'Connor, PJ, Steiner, JF
Clinical journal of the American Society of Nephrology : CJASN. 2018;(5):727-734
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BACKGROUND AND OBJECTIVES In individuals with diabetes, the comparative effectiveness of add-on antihypertensive medications added to an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker on the risk of significant kidney events is unknown. DESIGN, SETTING PARTICIPANTS, & MEASUREMENTS We used an observational, multicenter cohort of 21,897 individuals with diabetes to compare individuals who added β-blockers, dihydropyridine calcium channel blockers, loop diuretics, or thiazide diuretics to angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. We examined the hazard of significant kidney events, cardiovascular events, and death using Cox proportional hazard models with propensity score weighting. The composite significant kidney event end point was defined as the first occurrence of a ≥30% decline in eGFR to an eGFR<60 ml/min per 1.73 m2, initiation of dialysis, or kidney transplant. The composite cardiovascular event end point was defined as the first occurrence of hospitalization for acute myocardial infarction, acute coronary syndrome, stroke, or congestive heart failure; coronary artery bypass grafting; or percutaneous coronary intervention, and it was only examined in those free of cardiovascular disease at baseline. RESULTS Over a maximum of 5 years, there were 4707 significant kidney events, 1498 deaths, and 818 cardiovascular events. Compared with thiazide diuretics, hazard ratios for significant kidney events for β-blockers, calcium channel blockers, and loop diuretics were 0.81 (95% confidence interval, 0.74 to 0.89), 0.67 (95% confidence interval, 0.58 to 0.78), and 1.19 (95% confidence interval, 1.00 to 1.41), respectively. Compared with thiazide diuretics, hazard ratios of mortality for β-blockers, calcium channel blockers, and loop diuretics were 1.19 (95% confidence interval, 0.97 to 1.44), 0.73 (95% confidence interval, 0.52 to 1.03), and 1.67 (95% confidence interval, 1.31 to 2.13), respectively. Compared with thiazide diuretics, hazard ratios of cardiovascular events for β-blockers, calcium channel blockers, and loop diuretics compared with thiazide diuretics were 1.65 (95% confidence interval, 1.39 to 1.96), 1.05 (95% confidence interval, 0.80 to 1.39), and 1.55 (95% confidence interval, 1.05 to 2.27), respectively. CONCLUSIONS Compared with thiazide diuretics, calcium channel blockers were associated with a lower risk of significant kidney events and a similar risk of cardiovascular events.
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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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Type 1 diabetes in older adults: Comparing treatments and chronic complications in the United States T1D Exchange and the German/Austrian DPV registries.
Weinstock, RS, Schütz-Fuhrmann, I, Connor, CG, Hermann, JM, Maahs, DM, Schütt, M, Agarwal, S, Hofer, SE, Beck, RW, Holl, RW, et al
Diabetes research and clinical practice. 2016;:28-37
Abstract
AIMS: Compare characteristics, therapies and clinical outcomes in older adults with type 1 diabetes in the United States T1D Exchange (T1DX) and German/Austrian Diabetes Patienten Verlaufsdokumentation (DPV) registries. METHODS Cross-sectional study of adults ≥60years old with type 1 diabetes seen in 2011-2012 in the T1DX (n=1283) and DPV (n=2014) registries. Wilcoxon rank-sum test was used for continuous variables and chi-square test for categorical variables. Adjusted analyses used generalized linear models. RESULTS Individuals in both registries were similar in body mass index (mean 27kg/m2), percent with obesity (25%) and gender (48% male). In T1DX there was longer diabetes duration (32.3 vs. 28.8years), greater use of antihypertensive medications (including ACE-I and ARBs; 85% vs. 62%), statins (68% vs. 40%), aspirin (77% vs. 21%), insulin pumps (58% vs. 18%), and less smoking (7% vs. 10%); lower adjusted mean LDL-cholesterol (84 vs. 109mg/dL), and lower adjusted mean systolic and diastolic blood pressures (128 vs. 136 and 68 vs. 74mmHg); fewer myocardial infarctions (6% vs. 9% [99% CI of difference, 1% to 5%]), strokes (2% vs. 8% [3% to 7%]), microvascular complications including microalbuminuria (17% vs. 44% [22% to 32%]) but increased depression (16.1% vs. 8.7%). Adjusted mean HbA1c levels were similar (7.5%, 58mmol/mol). CONCLUSIONS Differences between the registries included greater use of antihypertensives, statins and insulin pumps, and fewer chronic complications in the T1DX. Further research is needed to better understand the role of intensive therapy in improving outcomes in older adults with type 1 diabetes.