Diabetes Trial Research Articles

Protocol for a randomized controlled trial comparing a very low-carbohydrate diet or moderate-carbohydrate plate-method diet for type 2 diabetes: the LEGEND (Lifestyle Education about Nutrition for Diabetes) trial

BackgroundOptimal carbohydrate intake is an important and controversial area in the nutritional management of type 2 diabetes. Some evidence indicates that reducing overall carbohydrate intake with a low- or very low-carbohydrate eating plan can improve glycemic control compared to following eating plans that involve greater carbohydrate intake. However, critical knowledge gaps currently prevent clear recommendations about carbohydrate intake levels.MethodsThe LEGEND (Lifestyle Education about Nutrition for Diabetes) Trial aims to compare a very low-carbohydrate diet to a moderate-carbohydrate plate-method diet for glycemic control in adults with type 2 diabetes. This two-site trial plans to recruit 180 adults with type 2 diabetes. We will randomize participants to either a 20-session group-based diet and lifestyle intervention that teaches either a very low-carbohydrate diet or a moderate-carbohydrate plate-method diet. We will assess participants at study entry and 4 and 12 months later. The primary outcome is HbA1c, and secondary outcomes include inflammation (high sensitivity C-reactive protein), body weight, changes in diabetes medications, lipids (small particle LDL, HDL, triglycerides), skeletal metabolism (bone mineral density from dual-energy x-ray absorptiometry and bone turnover markers serum procollagen type I N propeptide and serum C-terminal telopeptide of type I collagen), and body composition (percent body fat, percent lean body mass).DiscussionThe LEGEND trial is a randomized controlled trial to assess optimal carbohydrate intake in type 2 diabetes by evaluating the effects of a very low-carbohydrate diet vs. a moderate-carbohydrate plate-method diet over a year-long period. The research addresses important gaps in the evidence base for the nutritional management of type 2 diabetes by providing data on potential benefits and adverse effects of different levels of carbohydrate intake.Trial registrationClinicalTrials.gov NCT05237128. Registered on February 11, 2022

Racial and Ethnic Distribution in Diabetic Macular Edema Clinical Trials in the United States (2002–2021)

Diabetic macular edema (DME), the leading cause of vision loss among patients with diabetes mellitus, disproportionately affects Black and Hispanic patients. Currently, non-White racial and ethnic subgroups are frequently underrepresented in clinical trials, limiting the application of results to the most pertinent patient populations. Thus, we aimed to characterize the trajectory of racial reporting as well as changes and disparities in racial and ethnic distribution among participants of DME clinical trials. This is a cross-sectional retrospective study. Patients enrolled in United States (US)-based clinical trials for DME. We examined the racial and ethnic demographic distribution of participants in clinical trials related to DME across a 20-year period from 2002 to 2021. Clinical trials were screened from ClinicalTrials.gov for DME, US trial location, study completion, and > 50 patient enrollment. Descriptive statistics, proportions, odds ratios (ORs), and chi-square tests were reported and compared with 2021 US Census demographic data and diagnosed patients with diabetes demographic data. Change in racial reporting and race/ethnicity across 2 decades and comparison of racial/ethnic distribution with 2021 US Census demographics and diagnosed patients with diabetes. There was an increase in race reporting from January 2002 to December 2011 (8 trials [40%]) versus January 2012 to December 2021 (20 trials [87%]; OR, 10.00; 95% confidence interval [CI], 2.21-45.16; P= 0.0032). Across the 2 decades, the proportion of Asian patients enrolled increased from 2.4% to 8.0% (OR, 3.47; 95% CI, 2.64-4.56; P < 0.0001). Similarly, the proportion of enrolled Hispanic patients increased from 13.4% to 19.5% (OR, 1.56; 95% CI, 1.37-1.78; P < 0.0001). Compared with diabetes prevalence, many minority groups are underrepresented in the total enrollment of DME clinical trial patients (Black [z=-18.51, P < 0.001]; Asian [z=-5.11, P< 0.0001]; Hispanic [chi-square= 274.7, df= 1, P < 0.0001]). In the past 2 decades, there has been a trend of increased racial reporting and minority patient enrollment in DME clinical trials. However, Black, Asian, and Hispanic patients remain significantly underrepresented among the DME clinical trial patient population based on diabetes prevalence. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Metformin in Gestational Diabetes The Offspring Follow Up (MiGTOFU): Associations between maternal characteristics and size and adiposity of boys and girls at nine years.

Data from 98 women recruited in the Metformin in Gestational Diabetes trial and dual-energy X-ray absorptiometry studies of their children at nine years were analysed to investigate associations between maternal measures during pregnancy and their children's size and adiposity. Mothers of boys (n = 56) and girls (n = 42) had been randomised to metformin or insulin treatment at 30.1 ± 2.8 and 29.3 ± 4.1 weeks gestation, respectively. In boys, fat-free mass indexed to height squared was associated with maternal weight, body mass index, maternal glycaemia and metformin treatment. In boys and girls, fat mass indexed to height squared was associated with maternal glycaemia measures before gestational diabetes treatment.

Retatrutide as a Novel Treatment for Obesity and Type 2 Diabetes

Retatrutide is a triple hormone agonist of the receptors of glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide (GIP) and glucagon that can be administered subcutaneously once a week. Different doses and escalation schedules of retatrutide were evaluated in 2 phase 2 American trials of subjects with obesity (n=338) and type 2 diabetes (n=281). In the obesity trial of 48 week-duration, percentage change in body weight from baseline after 24 weeks and 48 weeks were the primary and secondary outcomes respectively. At 24 weeks, the mean percentage decrease in weight ranged from 7.2% to 17.5% across retatrutide groups versus 1.6% with placebo. At 48 weeks, the decrease was 8.7% to 24.2% versus 2.1% with placebo. In the diabetes trial, the primary endpoint was a change in glycated hemoglobin (HbA1c) values from baseline to week 24. This trial included an active treatment group receiving dulaglutide 1.5mg once weekly. Secondary endpoints included change in HbA1c and body weight at 36 weeks. At 24 weeks, mean HbA1c reductions were 0.43% to 2.02% with retatrutide, 1.4% with dulaglutide and 0.01% with placebo. At 36 weeks, mean percentage weight reductions were 3.2% to 16.9% with retatrutide, 2.0% with dulaglutide and 3.0% with placebo. While the decrease in HbA1c levels reached a plateau at 24 weeks, weight loss in the 2 studies was progressive without evidence of attenuation effect up to the end of follow-up at 36-48 weeks. The most common adverse effects of retatrutide were gastrointestinal (GI) such as nausea, diarrhea, vomiting and constipation reported by 13-50% in the retatrutide groups compared with 35% in the dulaglutide group, and 13% in the placebo group. Discontinuation rates due to adverse effects were also higher with retatrutide being 16-17% compared with 2% with dulaglutide and 0-4% with placebo. In summary, retatrutide is highly effective drug in causing substantial weight loss and HbA1c reduction. Yet, tolerance to this drug seems sub-optimal. Phase 3 trials are urgently needed to clarify efficacy and safety of retatrutide.

50-OR: First-Trimester Dietary Phenolic Compounds and Lipids Are Associated with Hyperinsulinism at Birth in Type 1 Diabetes Pregnancy

Objective: Type 1 diabetes in pregnancy is associated with perinatal complications attributed to offspring hyperinsulinism. Conventional management prioritises glycaemia in mid/late pregnancy to reduce hyperinsulinism, but the timing and pathophysiology of hyperinsulinism remains unclear. We assessed if hyperinsulinism, quantified by cord C-peptide at birth, was associated with early pregnancy metabolism. Methods and Outcomes: 111 women in the Continuous Glucose Monitoring (CGM) in Pregnant women with Type 1 diabetes Trial (CONCEPTT) had a livebirth with measurement of cord C-peptide. Liquid chromatography-mass spectrometry of maternal serum (12, 24, 34 wks; n=101) and cord blood (n=93) measured 2105 metabolites. Statistical analysis: linear regression of Cord C-peptide and metabolites with adjustment for maternal age, BMI, parity, ethnicity, education, intervention and glycemia (and birth gestation for offspring metabolites). Significance limit was p=0.001. Results: In maternal blood at 12 weeks, positive associations were noted between nine metabolites and cord C-peptide, including lipids (monoglycerides, triglycerides and phospholipids), saccharin and three other dietary phenolic compounds. At 24 weeks, two dietary phenols and several lipids maintained positive associations. At 34 weeks, 124 species in maternal blood showed positive associations with cord C-peptide, including saccharin, free fatty acids, monoglycerides, diglycerides, triglycerides, phospholipids. The profile was distinct from that of large-for-gestational age and neonatal hypoglycemia, despite the perceived pathophysiological overlap in these conditions. In cord blood, carnitines and betonicine were associated with C-peptide. Conclusions: Lipids, saccharin and other dietary phenols in early pregnancy warrant further investigation as potentially modifiable contributors to offspring hyperinsulinism in type 1 diabetes pregnancy. Disclosure C.L.Meek: Research Support; Dexcom, Inc. Z.A.Stewart: None. D.Feig: Advisory Panel; Novo Nordisk Canada Inc., Speaker's Bureau; Sanofi, Novo Nordisk Canada Inc. A.Koulman: None. H.R.Murphy: Advisory Panel; Medtronic, Research Support; Dexcom, Inc. Funding Diabetes UK; JDRF

1331-P: Association of Short-Term and Long-Term Glycemic Variability and the Renal Complications in the ACCORD Trial

Recent studies have shown that long-term and short-term glycemic variability (measured by low concentrations of the biomarker 1,5-anhydroglucitol (1,5-AG)) were associated with incident diabetes complications; yet, none have assessed their relative importance. Using the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, we measured 1,5-AG 12 months from randomization (when HbA1c was stable) in 4,000 randomly selected samples and assessed the risk of short-term and long-term glycemic variability for incident renal complications. The coefficient of variation of fasting glucose (CV-FG) was used to measure long-term variability. Primary outcomes were time (after 12 months) to 1) microalbuminuria and 2) macroalbuminuria. Risks were estimated using Cox proportional hazard models. Both CV-FG and lower 1,5-AG were independently associated with microalbuminuria even after adjusting for other risk factors (Table). Only CV-FG was a significant risk factor for macroalbuminuria. After adjusting for average glycemic control, the CV-FG association remained. Subgroup analysis indicated that CV-FG and 1,5 AG were more harmful in those receiving less intensive glucose control. The secondary outcome analysis supported the main conclusion (Table). This post hoc analysis indicates that long-term and short-term glucose variability may play a role in developing renal diseases in T2D. Disclosure T.Okuno: None. P.Reaven: Research Support; Dexcom, Inc. J.Zhou: None. Funding National Institutes of Health (R01HG006139, DMS-2054253, IIS-2205441, R21HL150374)

1350-P: Risk Models for the Development of Cardiovascular and Microvascular Events in Adults with Type 2 Diabetes in the FIELD Study

Background: There are a few prediction models for chronic complications in people with type 2 diabetes (T2D). This study developed such risk models. Methods: Data from 9795 adults with T2D in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial were used to develop risk prediction models for total CVD events, cardiovascular mortality, amputations and new microvascular events using 27 candidate traditional risk factors and additional novel biomarkers (incl. vascular and systemic inflammation, oxidative stress; n=26) using exhaustive search methods. Results: There were 1295 total first CVD events, 267 CVD deaths, 115 amputations and 1530 new microvascular events. A total of 19 and 18 traditional risk factors were selected in the clinical risk models for total CVD events and CVD mortality, with AUC of 0.723 and 0.821 respectively. For individual microvascular complications, the AUC of their models ranged from 0.656 to 0.895. The addition of novel biomarkers to the clinical risk models only resulted in modestly higher AUC (Table below). Conclusion: New clinical risk models can be implemented as risk prediction tools for chronic complications in adults with T2D, including for sight-threatening retinopathy and amputations. Novel biomarkers may guide future research on disease mechanisms, but had limited predictive value over clinical variables. Disclosure K.Ong: None. M.Taskinen: Board Member; Novo Nordisk, Consultant; Eli Lilly and Company, Novartis, Akcea, Research Support; Novo Nordisk. R.J.Simes: None. A.Jenkins: Advisory Panel; Insulet Corporation, Board Member; Insulin for Life, Research Support; Abbott Diabetes, Medtronic, Hemsley Charitable Trust, Juvenile Diabetes Research Foundation (JDRF), National Institutes of Health. A.C.Keech: None. On behalf of the field study investigators: n/a. R.L.O'connell: None. A.S.Januszewski: None. M.W.Donoghoe: None. V.Gebski: None. D.Sullivan: None. K.Rye: None. R.S.Scott: None. J.D.Best: None. Funding Laboratories Fournier; National Health and Medical Research Council of Australia (457103, 1024105, 1037786)

20-LB: Impact of Optimal Medical Therapy, Insulin Sensitization, and Revascularization Strategies on Soluble Urokinase Plasminogen Activator Receptor and Its Association with Cardiovascular Outcomes—A BARI-2D Ancillary Study

Chronic inflammation is a hallmark of type 2 diabetes (T2D) and a driver of its complications. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived signaling glycoprotein involved in the pathogenesis of diabetes-related outcomes, notably atherosclerosis and nephropathy. We aimed to determine if optimal medical therapy, insulin sensitization, and revascularization strategy impact suPAR levels and modulate its association with outcomes. We leveraged the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI-2D) trial, a study of patients with T2D and coronary artery disease (CAD) who underwent either revascularization or optimized medical therapy, and were randomized to either insulin-sensitization or insulin-provision therapy. We measured plasma suPAR levels in 2316 patients at baseline and 1-year follow-up and examined the association between suPAR and major adverse cardiovascular events (MACE). The median suPAR level at baseline was 3.02 ng/ml (IQR 2.32-3.95) and 3.15 ng/ml (2.4-4.2) at 1-year. SuPAR levels were notably higher in patients who underwent CABG (2.94 vs 2.70, p&amp;lt;0.001), but were unchanged post-PCI, insulin sensitization or insulin provisioning at 1 year. In multivariable analyses, baseline and 1-years suPAR levels were predictive of MACE, without difference in the strengths of the association between the two time points (HR of 2.18 (95%CI[1.57-3.03]) at baseline and 2.13 (95%CI[1.45-3.13]) at follow-up for the 3rd tertile compared to the first. Our findings suggest that inflammation as measured by suPAR is not reduced by revascularization or T2D treatment strategy, and likely accounts for the residual CV risk in patients with T2D. The advent of anti-suPAR therapies may offer new promise for patients with T2D and co-morbid CAD. Disclosure K. Amadi: None. G. Erne: None. F. Presswalla: None. B. Bitterman: None. M. Nelapudi: None. I. S. Pizzo: None. M. Tripathi: None. A. Tekumulla: None. N. Meyette: None. P. Blakely: None. N. Sulaiman: None. Y. Huang: None. A. Bardwell: None. J. Chen: None. C. R. Tilley: None. A. Ismail: None. S. Hayek: None. A. Vasbinder: None. R. E. Pratley: Other Relationship; Bayer Inc., Corcept Therapeutics, Dexcom, Inc., Gasherbrum Bio, Inc., Hanmi Pharm. Co., Ltd., Hengrui (USA) Ltd., Merck Sharp &amp; Dohme Corp., Novo Nordisk, Pfizer Inc., Rivus Pharmaceuticals Inc., Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. M. Banerjee: None. R. Busui: Board Member; American Diabetes Association, Consultant; Averitas Pharma, Inc., Lexicon Pharmaceuticals, Inc., Nevro Corp., Novo Nordisk, Roche Diagnostics, Procter &amp; Gamble, Research Support; Novo Nordisk, Medtronic, National Institutes of Health. T. C. Catalan: None. Funding National Heart, Lung, and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center

1222-P: An Examination of Frailty as Measured via Deficit Accumulation in African American Adults with Diabetes and Prediabetes

Type 2 diabetes increases the accumulation of health deficits and has been described to be connected to accelerated biological aging. We utilized a frailty index (FI) in African Americans with prediabetes and diabetes modeled after the deficit accumulation index approach used in the Action for Health in Diabetes (Look AHEAD) Trial. This metric of frailty is comprised of 32 functional, behavioral, and clinical characteristics using the Jackson Heart Study (JHS) public access dataset. JSH is a large, community-based, observational study investigating the causes of cardiovascular disease (CVD) in 5301 African-Americans from Jackson, MS. Our study included 1339 adults aged 40-84 with prediabetes and diabetes who had over 12 years of follow-up for incident CVD events. Obese individuals, older individuals, those with poorer diabetes control, and hypertension had significantly higher mean FI scores than those without these characteristics. Approximately 34% of this sample was frail and 66% not frail. Compared with non-frail participants, stroke, heart failure, and coronary heart disease incidence of frail participants were increased. Frailty was an independent predictor of 12-year stroke (adjusted hazard ratio (HR): 6.84; 95% confidence interval (CI): 3.09 to 15.12), heart failure (adjusted HR: 3.00; 95% CI: 1.77 to 5.09), and coronary heart disease (adjusted HR: 2.48; 95% CI: 1.44 to 4.15) after adjusting for age and gender. Frailty is prevalent among African Americans with diabetes and prediabetes and is a predictor cardiovascular outcome. Frail adults with diabetics have an even higher risk of CVD, compared to non-frail adults with diabetes. Disclosure F.Simpson: None. A.Bertoni: None.

Methods to address selection bias in post-trial studies of legacy effects were evaluated

ObjectivesPost-trial follow-up studies have become increasingly important to investigate the long-term effectiveness of interventions after randomized controlled trials (RCTs). Legacy effects refer to intervention effects that are only observed after the trial has ended and are not the direct effects observed during the trial period. However, limited attention has been given to the potential selection bias in post-trial studies. MethodsUsing directed acyclic graphs, we illustrated potential sources of selection bias in post-trial studies of cardiovascular disease preventative interventions. We constructed scenarios where selection bias was present and undertook simulations to assess the ability of different modeling approaches to correct for this bias: no adjustment, adjustment for trial baseline covariates, adjustment for post-trial covariates and inverse probability weighting (IPW) methods. Using empirical data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and post-trial study, we demonstrated application of different modeling approaches. ResultsIn the presence of selection bias, modeling without adjustment always resulted in biased estimates. Modeling with adjustment and IPW methods were able to correct the selection bias. The ACCORD study also demonstrated that while the direct effects were potentially beneficial, all models attempting to address selection bias revealed larger potential legacy effects when compared to unadjusted estimates. ConclusionPost-trial follow-up studies have the potential to provide valuable information for clinical practice by detecting legacy effects. However, it is important to consider and address selection bias that may arise from the post-trial study. This study highlights the importance of using an appropriate analysis method and identifying the potential bias sources to ensure that the findings are reliable and generalizable to the target population.

Acute Declines in Estimated GFR in Blood Pressure Target Trials and Risk of Adverse Outcomes

Acute decreases in glomerular filtration rate (GFR) occur commonly during intensive blood pressure (BP) lowering. Our objective was to determine the relationship between acute decreases in estimated GFR and patient outcomes. Retrospective observational study. Participants from 4 randomized controlled trials of intensive BP lowering in chronic kidney disease (Modification of Diet in Renal Disease study, African American Study of Kidney Disease and Hypertension, Systolic Blood Pressure Intervention Trial, and Action to Control Cardiovascular Risk in Diabetes trial). A 4-category exposure defined by the level of acute decrease in estimated GFR (defined as>15% vs≤15% between baseline and month 4) and the randomization to intensive versus usual BP control. Risk of kidney replacement therapy (primary outcome), defined as the need for dialysis or transplant except in the Action to Control Cardiovascular Risk in Diabetes trial, which defined its kidney outcome as a composite occurrence of serum creatinine concentration>3.3mg/dL, kidney failure, or kidney replacement therapy. Multivariable Cox models. We included 4,473 individuals randomly assigned to intensive versus usual BP control who had a total of 351 kidney outcomes and 304 deaths during median follow-up durations of 22 and 24 months, respectively. Approximately 14% of participants exhibited an acute decrease in eGFR, 11.0% in the usual BP treatment arm and 17.8% in the intensive BP treatment arm. In adjusted models, compared with a≤15% eGFR decrease in the usual BP arm, a≤15% eGFR decrease in the intensive BP control arm was associated with lower risk of the kidney outcome (HR, 0.75; 95% CI, 0.57-0.98). In contrast, a>15% decrease in eGFR was associated with a higher risk of the kidney outcome in the usual (HR, 2.47; 95% CI, 1.80-3.38) and intensive BP treatment arms (HR, 1.99; 95% CI, 1.45-2.73) compared with a≤15% decrease in the usual BP arm. Observational study, residual confounding. Decreases in eGFR of>15% in the usual and intensive BP treatment arms were associated with a higher risk of kidney outcomes compared with a≤15% decrease in the usual BP arm and may be a harbinger of adverse outcomes.

D-22 | Trajectories of Patients Treated With Beta Blockers and Calcium Channel Blockers for Stable Ischemic Heart Disease and Diabetes Mellitus (from the Bypass Angioplasty Revascularization Investigation 2 Diabetes Trial)

D-22 | Trajectories of Patients Treated With Beta Blockers and Calcium Channel Blockers for Stable Ischemic Heart Disease and Diabetes Mellitus (from the Bypass Angioplasty Revascularization Investigation 2 Diabetes Trial)

Racial/Ethnic Variation in White Matter Hyperintensity Progression in the ACCORDION MIND Study.

White matter hyperintensities (WMHs) are linked to cognitive decline and stroke. We investigate the impact of race on WMH progression in the Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes (ACCORDION MIND) trial. The primary outcome is WMH progression in milliliters, evaluated by fitting linear regression to WMH volume on the month 80 magnetic resonance imaging (MRI) and including the WMH volume on the baseline MRI. The primary predictor is patient race, with the exclusion of patients defined as "other" race. We also derived predicted probabilities of our outcome for systolic blood pressure (SBP) levels. We included 276 patients who completed the baseline and month 80 MRI, of which 207 (75%) were White, 48 (17%) Black, and 21 (8%) Hispanic. During follow-up, the mean number of SBP, low-density lipoprotein (LDL), and A1c measurements per patient was 21, 8, and 15. The median (IQR) WMH progression was 1.5mL (0.5 to 3.9) for Black patients, 1.0mL (0.4 to 4.0) for Hispanics, and 1.3mL (0.5 to 2.7) for Whites (Kruskal-Wallis test, P =0.59). In the multivariate regression model, Black, compared with White, patients had significantly more WMH progression (β Coefficient 1.26, 95% confidence interval 0.45 to 2.06, P =0.002). Hispanic, compared with White, patients neither have significantly different WMH progression ( P =0.392), nor was there a difference when comparing Hispanic to Black patients ( P =0.162). The predicted WMH progression was significantly higher for Black compared with White patients across a mean SBP of 117 to 139mmHg. Black diabetic patients in Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes (ACCORDION MIND) have a higher risk of WMH progression than White patients across a normal range of SBP.

Health care registers can be instrumental for endpoint capture in clinical diabetes trials: example of microvascular complications in Swedish patients with type 2 diabetes.

SMARTEST is a register-based randomized clinical trial (RRCT) that compares dapagliflozin to metformin in early-stage type 2 diabetes. The primary outcome includes progression of microvascular complications based on data from the Swedish National Diabetes Register (NDR). In this sub-study, the aim was to validate microvascular complication variables in the NDR against electronic health records (EHRs). Data were extracted from EHRs of 276 SMARTEST participants with a median observation period of 3years in the Uppsala, Örebro and Sörmland counties and compared with NDR data. Agreement was determined for all corresponding data entries as well as for progression of microvascular complications after randomization. The agreement for all corresponding data entries was 98.9% (Intraclass Correlation Coefficient 0.999) for creatinine and eGFR, 95.1% for albuminuria, 91.6% for foot-at-risk and 98.2% for retinopathy status (Kappa 0.67-0.91). The agreement for progression of microvascular complications was 98.0% for CKD stage, 98.9% for albuminuria grade, 96.3% for foot-at-risk grade and 99.6% for retinopathy grade progression (Gwet's AC1 0.96-1.00). Microvascular complication variables in the NDR show good agreement with EHR data. The use of a well-established national health care registry, exemplified by the NDR, for endpoint collection in RRCTs such as SMARTEST is supported by this study.

Daily intranasal insulin at 40IU does not affect food intake and body composition: A placebo-controlled trial in older adults over a 24-week period with 24-weeks of follow-up

Centrally administered insulin stimulates the reward system to reduce appetite in response to food intake in animal studies. In humans, studies have shown conflicting results, with some studies suggesting that intranasal insulin (INI) in relatively high doses may decrease appetite, body fat, and weight in various populations. These hypotheses have not been tested in a large longitudinal placebo-controlled study. Participants in the Memory Advancement with Intranasal Insulin in Type 2 Diabetes (MemAID) trial were enrolled in this study. This study on energy homeostasis enrolled 89 participants who completed baseline and at least 1 intervention visit (42 women; age 65±9 years; 46 INI, 38 with type 2 diabetes) and 76 completed treatment (16 women, age 64±9; 38 INI, 34 with type 2 diabetes). The primary outcome was the INI effect on food intake. Secondary outcomes included the effect of INI on appetite and anthropometric measures, including body weight and body composition. In exploratory analyses, we tested the interaction of treatment with gender, body mass index (BMI), and diagnosis of type 2 diabetes. There was no INI effect on food intake or any of the secondary outcomes. INI also showed no differential effect on primary and secondary outcomes when considering gender, BMI, and type 2 diabetes. INI did not alter appetite or hunger nor cause weight loss when used at 40 I.U. intranasally daily for 24 weeks in older adults with and without type 2 diabetes.

Intensive glucose control and recurrent cardiovascular events: 14-year follow-up investigation of the ACCORDION study.

While cardiovascular disease in patients with type 2 diabetes commonly progresses with the occurrence of repeated events, most trials consider the effect of glucose-lowering strategies only on the first event. We examined the Action to Control Cardiovascular Risk in Diabetes trial and its observational follow-up study (ACCORDION) to investigate the effect of intensive glucose control on multiple events and further identify any subgroup effects. A recurrent events analysis, using a negative binomial regression model, was applied to estimate the treatment effect on different consecutive cardiovascular disease events, including non-fatal myocardial infarction, non-fatal stroke, hospitalisation from heart failure, and cardiovascular death. Interaction terms were used to identify potential effect modifiers. The robustness of the results was confirmed in sensitivity analyses using alternative models. The median duration of follow-up was 7.7years. Of the 5128 participants in the intensive and 5123 in the standard glucose control arm, respectively, 822 (16.0%) and 840 (16.4%) participants experienced a single event; 189 (3.7%) and 214 (4.2%) participants experienced two events; 52 (1.0%) and 40 (0.8%) experienced three events; and 1 (0.02%) and 1 (0.02%) experienced four events. There was no evidence of a treatment effect, with a rate difference of 0.0 (-0.3, 0.3) per 100 person-years comparing intensive versus standard intervention, although with non-significantly lower event rates in younger patients with HbA1c < 7% and higher event rates in older patients with HbA1c≥9%. Intensive glucose control may not affect cardiovascular disease progression except in select subgroups. Since time-to-first event analysis may miss beneficial or harmful effects of glucose control on the risk of cardiovascular disease, recurrent events analysis should be routinely analysed in cardiovascular outcome trials, particularly when investigating long-term treatment effects. NCT00000620, clinicaltrials.gov.

The influence of triglycerides on small dense low-density lipoprotein cholesterol levels is attenuated in low low-density lipoprotein-cholesterol range: Implications for the negative results of the PROMINENT trial.

The Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) trial failed to show the preventive effects of pemafibrate, a triglyceride (TG)-lowering drug, on atherosclerotic cardiovascular disease in patients with type 2 diabetes and dyslipidemia. We recently reported that TG-lowering with pemafibrate did not decrease the calculated small dense (sd) low-density lipoprotein cholesterol (LDL-C), and speculated that the effect of TG on sdLDL-C is attenuated in low LDL-C levels. This report examined this possibility in 1,508 patients with type 2 diabetes and 670 healthy controls. LDL-C ranges were classified as ≤69, 70-99, 100-139 and 140≤ mg/dL. The slope of the regression curve between sdLDL-C and TG was found to flatten as LDL-C decreased; 0.18, 0.13, 0.10 and 0.04 for controls, and 0.18, 0.13, 0.09 and 0.07 for diabetes patients. Correspondingly, the lower the LDL-C range, the lower the sdLDL-C/TG ratio. These results suggest that when LDL-C is tightly controlled, TG-lowering has only a weak inhibitory effect on sdLDL-C.

Optimised plasma sample preparation and LC-MS analysis to support large-scale proteomic analysis of clinical trial specimens: Application to the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial.

Robust, affordable plasma proteomic biomarker workflows are needed for large-scale clinical studies. We evaluated aspects of sample preparation to allow liquid chromatography-mass spectrometry (LC-MS) analysis of more than 1500 samples from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial of adults with type 2 diabetes. Using LC-MS with data-independent acquisition we evaluated four variables: plasma protein depletion, EDTA or citrated anti-coagulant blood collection tubes, plasma lipid depletion strategies and plasma freeze-thaw cycles. Optimised methods were applied in a pilot study of FIELD participants. LC-MS of undepleted plasma conducted over a 45min gradient yielded 172 proteins after excluding immunoglobulin isoforms. Cibachrome-blue-based depletion yielded additional proteins but with cost and time expenses, while immunodepleting albumin and IgG provided few additional identifications. Only minor variations were associated with blood collection tube type, delipidation methods and freeze-thaw cycles. From 65 batches involving over 1500 injections, the median intra-batch quantitative differences in the top 100 proteins of the plasma external standard were less than 2%. Fenofibrate altered seven plasma proteins. A robust plasma handling and LC-MS proteomics workflow for abundant plasma proteins has been developed for large-scale biomarker studies that balance proteomic depth with time and resource costs.

Factors associated with fragility fractures in type 2 diabetes: An analysis of the randomised controlled Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.

Fracture risk is elevated in some type 2 diabetes patients. Bone fragility may be associated with more clinically severe type 2 diabetes, although prospective studies are lacking. It is unknown which diabetes-related characteristics are independently associated with fracture risk. In this post-hoc analysis of fracture data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial (ISRCTN#64783481), we hypothesised that diabetic microvascular complications are associated with bone fragility. The FIELD trial randomly assigned 9795 type 2 diabetes participants (aged 50-75years) to receive oral co-micronised fenofibrate 200mg (n=4895) or placebo (n=4900) daily for a median of 5years. We used Cox proportional hazards models to identify baseline sex-specific diabetes-related parameters independently associated with incident fractures. Over 49,470 person-years, 137/6138 men experienced 141 fractures and 143/3657 women experienced 145 fractures; incidence rates for the first fracture of 4∙4 (95% CI 3∙8-5∙2) and 7∙7 per 1000 person-years (95% CI 6∙5-9∙1), respectively. Fenofibrate had no effect on fracture outcomes. In men, baseline macrovascular disease (HR 1∙52, 95% CI 1∙05-2∙21, p=0∙03), insulin use (HR 1∙62, HR 1∙03-2∙55, p=0∙03), and HDL-cholesterol (HR 2∙20, 95% CI 1∙11-4∙36, p=0∙02) were independently associated with fracture. In women, independent risk factors included baseline peripheral neuropathy (HR 2∙04, 95% CI 1∙16-3∙59, p=0∙01) and insulin use (HR 1∙55, 95% CI 1∙02-2∙33, p=0∙04). Insulin use and sex-specific complications (in men, macrovascular disease; in women, neuropathy) are independently associated with fragility fractures in adults with type 2 diabetes.

The Association of Total Knee Arthroplasty With Weight Loss in the Look AHEAD (Action for Health in Diabetes) Clinical Trial

BackgroundPatients who have obesity seldom lose weight after total knee arthroplasty (TKA). The Look AHEAD (Action for Health in Diabetes) trial randomized patients with type 2 diabetes who were overweight or had obesity to a 10-year intensive lifestyle intervention (ILI) or diabetes support and education (DSE). MethodsOf the total 5,145 participants enrolled who had a median 14-year follow-up, a subset of 4,624 met inclusion criteria. The ILI aimed at achieving and maintaining a 7% weight loss and included weekly counseling the first 6 months, with decreasing frequency thereafter. This secondary analysis was undertaken to determine what effects a TKA had on patients participating in a known successful weight loss program and specifically if there was a negative impact on weight loss or their Physical Component Score. ResultsThe analysis suggests that the ILI remained effective for maintaining or losing weight after TKA. Participants in ILI had significantly greater percent weight loss than those in DSE both before and after TKA (ILI-DSE before TKA: −3.6% (−5.0, −2.3); after TKA: −3.7% (−4.1, −3.3); both P < .0001). When comparing percent weight loss before to after TKA, there was no significant difference within either the DSE or ILI group (least square means ± standard error ILI: −0.36% ± 0.3, P = .21; DSE: −0.41% ± 0.29, P = .16). Physical Component Scores improved after TKA (P < .001), but no difference was found between TKA ILI and DSE groups before or after surgery. ConclusionParticipants who had a TKA did not have an altered ability to adhere to intervention goals to maintain weight loss or obtain further weight loss. The data suggest patients who have obesity can lose weight after TKA on a weight loss program.