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Effect of Empagliflozin on Left Ventricular Volumes in Patients With Type 2 Diabetes, or Prediabetes, and Heart Failure With Reduced Ejection Fraction (SUGAR-DM-HF).
Lee, MMY, Brooksbank, KJM, Wetherall, K, Mangion, K, Roditi, G, Campbell, RT, Berry, C, Chong, V, Coyle, L, Docherty, KF, et al
Circulation. 2021;(6):516-525
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BACKGROUND Sodium-glucose cotransporter 2 inhibitors reduce the risk of heart failure hospitalization and cardiovascular death in patients with heart failure and reduced ejection fraction (HFrEF). However, their effects on cardiac structure and function in HFrEF are uncertain. METHODS We designed a multicenter, randomized, double-blind, placebo-controlled trial (the SUGAR-DM-HF trial [Studies of Empagliflozin and Its Cardiovascular, Renal and Metabolic Effects in Patients With Diabetes Mellitus, or Prediabetes, and Heart Failure]) to investigate the cardiac effects of empagliflozin in patients in New York Heart Association functional class II to IV with a left ventricular (LV) ejection fraction ≤40% and type 2 diabetes or prediabetes. Patients were randomly assigned 1:1 to empagliflozin 10 mg once daily or placebo, stratified by age (<65 and ≥65 years) and glycemic status (diabetes or prediabetes). The coprimary outcomes were change from baseline to 36 weeks in LV end-systolic volume indexed to body surface area and LV global longitudinal strain both measured using cardiovascular magnetic resonance. Secondary efficacy outcomes included other cardiovascular magnetic resonance measures (LV end-diastolic volume index, LV ejection fraction), diuretic intensification, symptoms (Kansas City Cardiomyopathy Questionnaire Total Symptom Score, 6-minute walk distance, B-lines on lung ultrasound, and biomarkers (including N-terminal pro-B-type natriuretic peptide). RESULTS From April 2018 to August 2019, 105 patients were randomly assigned: mean age 68.7 (SD, 11.1) years, 77 (73.3%) male, 82 (78.1%) diabetes and 23 (21.9%) prediabetes, mean LV ejection fraction 32.5% (9.8%), and 81 (77.1%) New York Heart Association II and 24 (22.9%) New York Heart Association III. Patients received standard treatment for HFrEF. In comparison with placebo, empagliflozin reduced LV end-systolic volume index by 6.0 (95% CI, -10.8 to -1.2) mL/m2 (P=0.015). There was no difference in LV global longitudinal strain. Empagliflozin reduced LV end-diastolic volume index by 8.2 (95% CI, -13.7 to -2.6) mL/m2 (P=0.0042) and reduced N-terminal pro-B-type natriuretic peptide by 28% (2%-47%), P=0.038. There were no between-group differences in other cardiovascular magnetic resonance measures, diuretic intensification, Kansas City Cardiomyopathy Questionnaire Total Symptom Score, 6-minute walk distance, or B-lines. CONCLUSIONS The sodium-glucose cotransporter 2 inhibitor empagliflozin reduced LV volumes in patients with HFrEF and type 2 diabetes or prediabetes. Favorable reverse LV remodeling may be a mechanism by which sodium-glucose cotransporter 2 inhibitors reduce heart failure hospitalization and mortality in HFrEF. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03485092.
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Vitamin D supplementation for prevention of cancer: The D2d cancer outcomes (D2dCA) study.
Chatterjee, R, Erban, JK, Fuss, P, Dolor, R, LeBlanc, E, Staten, M, Sheehan, P, Pittas, A, ,
Contemporary clinical trials. 2019;:62-70
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Abstract
Evidence on biological plausibility from mechanistic studies and data from observational studies suggest that vitamin D may be linked to risk of several types of cancer. However, evidence from clinical trials evaluating the effect of vitamin D supplementation on cancer risk is limited. The Vitamin D and Type 2 Diabetes (D2d) study is a multi-center, randomized, placebo-controlled clinical trial conducted to examine the causal relationship between oral vitamin D supplementation and development of diabetes among overweight adults with prediabetes. The D2d study provides a unique opportunity to assess the effect of vitamin D supplementation at a higher dose (4000 IU/day) than has been used in other clinical trials with cancer outcomes, in a population at higher than average risk for cancer. This paper provides: Krishnan and Feldman (2011) a) baseline characteristics of the D2d population included in the D2d cancer outcomes secondary study (D2dCA) and comparison to other large trials of vitamin D supplementation and cancer risk; Leyssens et al. (2013) b) description of data that are being collected during the trial and the planned statistical analyses to test whether vitamin D supplementation at a dose of 4000 IU/day has an effect on incident cancer overall, on incidence of certain types of cancer, and on incidence of precancerous lesions. Results of D2dCA will help guide future research and clinical recommendations related to vitamin D and cancer risk.
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Dietary instructions focusing on meal-sequence and nutritional balance for prediabetes subjects: An exploratory, cluster-randomized, prospective, open-label, clinical trial.
Yabe, D, Kuwata, H, Fujiwara, Y, Sakaguchi, M, Moyama, S, Makabe, N, Murotani, K, Asano, H, Ito, S, Mishima, H, et al
Journal of diabetes and its complications. 2019;(12):107450
Abstract
BACKGROUND Although lifestyle modifications are known to be effective in type 2 diabetes (T2D) as well as in prediabetes, adherence to a healthy diet is difficult for some, and interventions of lifestyle modifications need to be revised occasionally. Meal sequence has been gaining attention as a part of a healthy diet among T2D individuals to improve glycemia and body weight. In addition, a dietary instruction program, SMART Washoku®, which can help individuals to consume a more nutritionally balanced diet, has been developed. METHODS The current exploratory trial was designed to examine the effects of dietary instructions focusing on meal sequence and nutritional balance in individuals with prediabetes in the Japanese national health check-up and guidance program. Participants were cluster-randomized into three groups: Group A, receiving a conventional health guidance program (n = 11); Group B, receiving health guidance with dietary instructions focusing on meal sequence (n = 18); and Group C, receiving health guidance with dietary instructions focusing on nutritional balance (n = 13). Participants received health guidance education and various measurements before and 6 months after the instructions. RESULTS Body weight in Group B was significantly reduced compared to that in Group A, with similar adherence, while the effects on glycemia were similar between the two Groups. Body weight reduction was greater in Group C compared to that in Group A, although adherence in Group C was significantly lower than that in Group A. CONCLUSION The group receiving health guidance with dietary instructions focusing on meal sequence exhibited similar adherence and greater reduction in body weight than the group receiving conventional health guidance.
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Effect of Process- and Outcome-Based Financial Incentives on Weight Loss Among Prediabetic New York Medicaid Patients: A Randomized Clinical Trial.
VanEpps, EM, Troxel, AB, Villamil, E, Saulsgiver, KA, Zhu, J, Chin, JY, Matson, J, Anarella, J, Roohan, P, Gesten, F, et al
American journal of health promotion : AJHP. 2019;(3):372-380
Abstract
PURPOSE To determine whether different financial incentives are effective in promoting weight loss among prediabetic Medicaid recipients. DESIGN Four-group, multicenter, randomized clinical trial. SETTING AND PARTICIPANTS Medicaid managed care enrollees residing in New York, aged 18 to 64 years, and diagnosed as prediabetic or high risk for diabetes (N = 703). INTERVENTION In a 16-week program, participants were randomly assigned to one of 4 arms: (1) control (no incentives), (2) process incentives for attending weekly Diabetes Prevention Program sessions, (3) outcome incentives for achieving weekly weight loss goals, and (4) combined process and outcome incentives. MEASURES Weight loss over a 16-week period; proportion who completed educational sessions; proportion who met weight loss goals. ANALYSIS AND RESULTS No intervention arm achieved greater reduction in weight than control (outcome incentive -6.6 lb [-9.1 to -4.1 lb], process incentive -7.3 lb [-9.5 to -5.1 lb], combined incentive -5.8 lb [-8.8 to -2.8 lb], control -7.9 lb [-11.1 to -4.7 lb]; all P > .29). Session attendance in the process incentive arm (50%) was significantly higher than control (31%; P < .0001) and combined incentive arms (28%; P < .0001), but not significantly higher than the outcome incentive arm (38%). CONCLUSION Process incentives increased session attendance, but when combined at half strength with outcome incentives did not achieve that effect. There were no significant effects of either process or outcomes incentives on weight loss.
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Establishing an electronic health record-supported approach for outreach to and recruitment of persons at high risk of type 2 diabetes in clinical trials: The vitamin D and type 2 diabetes (D2d) study experience.
Aroda, VR, Sheehan, PR, Vickery, EM, Staten, MA, LeBlanc, ES, Phillips, LS, Brodsky, IG, Chadha, C, Chatterjee, R, Ouellette, MG, et al
Clinical trials (London, England). 2019;(3):306-315
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AIMS: To establish recruitment approaches that leverage electronic health records in multicenter prediabetes/diabetes clinical trials and compare recruitment outcomes between electronic health record-supported and conventional recruitment methods. METHODS Observational analysis of recruitment approaches in the vitamin D and type 2 diabetes (D2d) study, a multicenter trial in participants with prediabetes. Outcomes were adoption of electronic health record-supported recruitment approaches by sites, number of participants screened, recruitment performance (proportion screened who were randomized), and characteristics of participants from electronic health record-supported versus non-electronic health record methods. RESULTS In total, 2423 participants were randomized: 1920 from electronic health record (mean age of 60 years, 41% women, 68% White) and 503 from non-electronic health record sources (mean age of 56.9 years, 58% women, 61% White). Electronic health record-supported recruitment was adopted by 21 of 22 sites. Electronic health record-supported recruitment was associated with more participants screened versus non-electronic health record methods (4969 vs 2166 participants screened), higher performance (38.6% vs 22.7%), and more randomizations (1918 vs 505). Participants recruited via electronic health record were older, included fewer women and minorities, and reported higher use of dietary supplements. Electronic health record-supported recruitment was incorporated in diverse clinical environments, engaging clinicians either at the individual or the healthcare system level. CONCLUSION Establishing electronic health record-supported recruitment approaches across a multicenter prediabetes/diabetes trial is feasible and can be adopted by diverse clinical environments.
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Demographic and Social-Cognitive Factors Associated with Weight Loss in Overweight, Pre-diabetic Participants of the PREVIEW Study.
Hansen, S, Huttunen-Lenz, M, Sluik, D, Brand-Miller, J, Drummen, M, Fogelholm, M, Handjieva-Darlenska, T, Macdonald, I, Martinez, AJ, Larsen, TM, et al
International journal of behavioral medicine. 2018;(6):682-692
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PURPOSE Weight loss has been demonstrated to be a successful strategy in diabetes prevention. Although weight loss is greatly influenced by dietary behaviors, social-cognitive factors play an important role in behavioral determination. This study aimed to identify demographic and social-cognitive factors (intention, self-efficacy, outcome expectancies, social support, and motivation with regard to dietary behavior and goal adjustment) associated with weight loss in overweight and obese participants from the PREVIEW study who had pre-diabetes. METHOD Prospective correlational data from 1973 adult participants were analyzed. The participants completed psychological questionnaires that assessed social-cognitive variables with regard to dietary behavior. Stepwise multiple regression analyses were performed to identify baseline demographic and social-cognitive factors associated with weight loss. RESULTS Overall, being male, having a higher baseline BMI, having a higher income, perceiving fewer disadvantages of a healthy diet (outcome expectancies), experiencing less discouragement for healthy eating by family and friends (social support), and lower education were independently linked to greater weight loss. When evaluating females and males separately, education was no longer associated with weight loss. CONCLUSION The results indicate that a supportive environment in which family members and friends avoid discouraging healthy eating, with the application of a strategy that uses specific behavior change techniques to emphasize the benefits of outcomes, i.e., the benefits of a healthy diet, may support weight loss efforts. Weight loss programs should therefore always address the social environment of persons who try to lose body weight because family members and friends can be important supporters in reaching a weight loss goal.
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Prediabetes in pregnancy, can early intervention improve outcomes? A feasibility study for a parallel randomised clinical trial.
Hughes, RCE, Rowan, J, Williman, J
BMJ open. 2018;(3):e018493
Abstract
OBJECTIVE Measurement of glycated haemoglobin (HbA1c) in early pregnancy is routine in New Zealand to identify women with diabetes and prediabetes. However, the benefit of early intervention in women with prediabetes is inconclusive. Our aim was to test the feasibility of a two-arm parallel randomised controlled trial of standard care versus early intervention in pregnancies complicated by prediabetes. SETTING Two tertiary referral centres in New Zealand. PARTICIPANTS Women <14 weeks' gestation and HbA1c ≥5.9%-6.4% (41-46 mmol/mol) measured at booking, without pre-existing diabetes. INTERVENTIONS Randomisation was done by remote web-based allocation into one of two groups. Women in the early intervention group attended an antenatal diabetes clinic, commenced daily home blood glucose monitoring, and medication was prescribed if lifestyle measures failed to maintain target blood glucose levels. Controls received lifestyle education, continued standard care with their midwife and/or obstetrician, and were asked to perform a 75 g oral glucose tolerance test at 24 weeks' gestation with a referral to clinic if this test was positive. Both groups received lifestyle questionnaires at recruitment and in late pregnancy. OUTCOME MEASURES Recruitment rate, adherence to protocol and validation of potential primary outcomes. RESULTS Recruitment rates were lower than expected, especially in Māori and Pacific women. Non-adherence to allocated treatment protocol was significant, 42% (95% CI 24% to 61%) in the early intervention group and 30% (95% CI 16% to 51%) in controls. Caesarean section and pre-eclampsia were signalled as potential primary outcomes, due to both the high observed incidence in the control group and ease of measurement. CONCLUSIONS For a future definitive trial, extending the gestation of eligibility and stepped-wedge cluster randomisation may overcome the identified feasibility issues. Consistent with published observational data, pre-eclampsia and emergency caesarean section could be included as primary outcome measures, both of which have a significant impact on maternal and neonatal morbidity and healthcare costs. TRIAL REGISTRATION NUMBER ACTRN12615000904572; Pre-results.
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Causal Effects of Intensive Lifestyle and Metformin Interventions on Cardiovascular Disease Risk Factors in Pre-Diabetic People: An Application of G-Estimation.
Salimi, Y, Fotouhi, A, Mohammad, K, Mansournia, N, Mansournia, MA
Archives of Iranian medicine. 2017;(1):55-59
Abstract
BACKGROUND In the presence of non-adherence, intention-to-treat analysis preserves randomization, but does not lead to a valid comparison of outcome between the assigned groups. Using a reanalysis of Diabetes Prevention Program, this study aimed to estimate the causal effect of treatment with intensive lifestyle intervention or metformin vs. placebo on blood pressure and lipid profile using G-estimation after accounting for non-adherence. METHODS The Diabetes Prevention Program randomized 3,052 pre-diabetic individuals to metformin (N = 1015), placebo (N = 1014), or an intensive lifestyle intervention (N = 1023). G-estimation was used to estimate the causal effect of intensive lifestyle intervention or metformin vs. placebo on blood pressure and lipid profile in 2,973 patients who had adherence data. For comparison, we also performed the standard intention-to-treat analysis. RESULTS The G-estimation results showed that intensive lifestyle substantially improves systolic and diastolic blood pressure and lipid profile. The G-estimates of the effects of metformin vs. placebo as well as intensive lifestyle intervention vs. metformin on blood pressure and lipid profile were also stronger than the intention-to-treat effect estimates. CONCLUSION G-estimation suggests that intensive lifestyle modification improves known risk factors for cardiovascular disease, including systolic blood pressure, diastolic blood pressure, triglyceride, and HDL levels more than what standard ITT analysis suggests. Adherence to the assigned treatment should be measured in all randomized trials, and G-estimation should be the standard analysis of randomized trials with substantial non-adherence.
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Walking Away from Type 2 diabetes: a cluster randomized controlled trial.
Yates, T, Edwardson, CL, Henson, J, Gray, LJ, Ashra, NB, Troughton, J, Khunti, K, Davies, MJ
Diabetic medicine : a journal of the British Diabetic Association. 2017;(5):698-707
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AIMS: This study aimed to investigate whether an established behavioural intervention, Walking Away from Type 2 Diabetes, is effective at promoting and sustaining increased walking activity when delivered within primary care. METHODS Cluster randomized controlled trial involving 10 general practices recruited from Leicestershire, UK, in 2009-2010. Eight hundred and eight (36% female) individuals with a high risk of Type 2 diabetes mellitus, identified through a validated risk score, were included. Participants in five practices were randomized to Walking Away from Type 2 Diabetes, a pragmatic 3-h group-based structured education programme incorporating pedometer use with annual follow-on refresher sessions. The primary outcome was accelerometer assessed ambulatory activity (steps/day) at 12 months. Longer term maintenance was assessed at 24 and 36 months. Results were analysed using generalized estimating equation models, accounting for clustering. RESULTS Complete accelerometer data for the primary outcome were available for 571 (71%) participants. Increases in ambulatory activity of 411 steps/day [95% confidence interval (CI): 117, 704] and self-reported vigorous-intensity physical activity of 218 metabolic equivalent min/week (95% CI: 6, 425) at 12 months were observed in the intervention group compared with control; differences between groups were not sustained at 36 months. No differences between groups were observed for markers of cardiometabolic health. Replacing missing data with multiple imputation did not affect the results. CONCLUSIONS A pragmatic low-resource group-based structured education programme with pedometer use resulted in modest increases in ambulatory activity compared with control conditions after 12 months when implemented within a primary care setting to those at high risk of Type 2 diabetes mellitus; however, the results were not maintained over 36 months.
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Rationale and design of Diabetes Prevention with active Vitamin D (DPVD): a randomised, double-blind, placebo-controlled study.
Kawahara, T, Suzuki, G, Inazu, T, Mizuno, S, Kasagi, F, Okada, Y, Tanaka, Y
BMJ open. 2016;(7):e011183
Abstract
INTRODUCTION Recent research suggests that vitamin D deficiency may cause both bone diseases and a range of non-skeletal diseases. However, most of these data come from observational studies, and clinical trial data on the effects of vitamin D supplementation on individuals with pre-diabetes are scarce and inconsistent. The aim of the Diabetes Prevention with active Vitamin D (DPVD) study is to assess the effect of eldecalcitol, active vitamin D analogue, on the incidence of type 2 diabetes among individuals with pre-diabetes. METHODS AND ANALYSIS DPVD is an ongoing, prospective, multicentre, randomised, double-blind and placebo-controlled outcome study in individuals with impaired glucose tolerance. Participants, men and women aged ≥30 years, will be randomised to receive eldecalcitol or placebo. They will also be given a brief (5-10 min long) talk about appropriate calorie intake from diet and exercise at each 12-week visit. The primary end point is the cumulative incidence of type 2 diabetes. Secondary endpoint is the number of participants who achieve normoglycaemia at 48, 96 and 144 weeks. Follow-up is estimated to span 144 weeks. ETHICS AND DISSEMINATION All protocols and an informed consent form comply with the Ethics Guideline for Clinical Research (Japan Ministry of Health, Labour and Welfare). The study protocol has been approved by the Institutional Review Board at Kokura Medical Association and University of Occupational and Environmental Health. The study will be implemented in line with the CONSORT statement. TRIAL REGISTRATION NUMBER UMIN000010758; Pre-results.