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Liraglutide 3·0 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes. In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3·0 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219. The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2·7 times longer with liraglutide than with placebo (95% CI 1·9 to 3·9, p<0·0001), corresponding with a hazard ratio of 0·21 (95% CI 0·13–0·34). Liraglutide induced greater weight loss than placebo at week 160 (–6·1 [SD 7·3] vs −1·9% [6·3]; estimated treatment difference −4·3%, 95% CI −4·9 to −3·7, p<0·0001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group. In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3·0 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes. Novo Nordisk, Denmark.

OBJECTIVE: The Diabetes Prevention Program (DPP) and its Outcomes Study (DPPOS) demonstrated that either intensive lifestyle intervention or metformin could prevent type 2 diabetes in high-risk adults for at least 10 years after randomization. We report the 10-year within-trial cost-effectiveness of the interventions. RESEARCH DESIGN AND METHODS: Data on resource utilization, cost, and quality of life were collected prospectively. Economic analyses were performed from health system and societal perspectives. RESULTS: Over 10 years, the cumulative, undiscounted per capita direct medical costs of the interventions, as implemented during the DPP, were greater for lifestyle ($4,601) than metformin ($2,300) or placebo ($769). The cumulative direct medical costs of care outside the DPP/DPPOS were least for lifestyle ($24,563 lifestyle vs. $25,616 metformin vs. $27,468 placebo). The cumulative, combined total direct medical costs were greatest for lifestyle and least for metformin ($29,164 lifestyle vs. $27,915 metformin vs. $28,236 placebo). The cumulative quality-adjusted life-years (QALYs) accrued over 10 years were greater for lifestyle (6.81) than metformin (6.69) or placebo (6.67). When costs and outcomes were discounted at 3%, lifestyle cost $10,037 per QALY, and metformin had slightly lower costs and nearly the same QALYs as placebo. CONCLUSIONS: Over 10 years, from a payer perspective, lifestyle was cost-effective and metformin was marginally cost-saving compared with placebo. Investment in lifestyle and metformin interventions for diabetes prevention in high-risk adults provides good value for the money spent.

Limited evidence is available about the association between serum uric acid and sub-stages of the spectrum from normoglycaemia to type 2 diabetes mellitus. We aimed to investigate the association between serum uric acid and risk of prediabetes and type 2 diabetes mellitus. Eligible participants of the Rotterdam Study (n = 8,367) were classified into mutually exclusive subgroups of normoglycaemia (n = 7,030) and prediabetes (n = 1,337) at baseline. These subgroups were followed up for incident prediabetes (n = 1,071) and incident type 2 diabetes mellitus (n = 407), respectively. We used Cox proportional hazard models to determine hazard ratios (HRs) for incident prediabetes among individuals with normoglycaemia and incident type 2 diabetes mellitus among individuals with prediabetes. The mean duration of follow-up was 7.5 years for incident prediabetes and 7.2 years for incident type 2 diabetes mellitus. A standard deviation increment in serum uric acid was significantly associated with incident prediabetes among individuals with normoglycaemia (HR 1.10, 95% confidence interval (CI) 1.01; 1.18), but not with incident type 2 diabetes mellitus among individuals with prediabetes (HR 1.07, 95% CI 0.94; 1.21). Exclusion of individuals who used diuretics or individuals with hypertension did not change our results. Serum uric acid was significantly associated with incident prediabetes among normoglycaemic women (HR 1.13, 95% CI 1.02; 1.25) but not among normoglycaemic men (HR 1.08, 95% CI 0.96; 1.21). In contrast, serum uric acid was significantly associated with incident type 2 diabetes mellitus among prediabetic men (HR 1.23, 95% CI 1.01; 1.48) but not among prediabetic women (HR 1.00, 95% CI 0.84; 1.19). Our findings agree with the notion that serum uric acid is more closely related to early-phase mechanisms in the development of type 2 diabetes mellitus than late-phase mechanisms.

We aimed to explore whether changes in circulating levels of miRNAs according to type 2 diabetes mellitus (T2DM) or prediabetes status could be used as biomarkers to evaluate the risk of developing the disease. The study included 462 patients without T2DM at baseline from the CORDIOPREV trial. After a median follow-up of 60 months, 107 of the subjects developed T2DM, 30 developed prediabetes, 223 maintained prediabetes and 78 remained disease-free. Plasma levels of four miRNAs related to insulin signaling and beta-cell function were measured by RT-PCR. We analyzed the relationship between miRNAs levels and insulin signaling and release indexes at baseline and after the follow-up period. The risk of developing disease based on tertiles (T1-T2-T3) of baseline miRNAs levels was evaluated by COX analysis. Thus, we observed higher miR-150 and miR-30a-5p and lower miR-15a and miR-375 baseline levels in subjects with T2DM than in disease-free subjects. Patients with high miR-150 and miR-30a-5p baseline levels had lower disposition index ( p  = 0.047 and p  = 0.007, respectively). The higher risk of disease was associated with high levels (T3) of miR-150 and miR-30a-5p ( HR T3-T1  = 4.218 and HR T3-T1  = 2.527, respectively) and low levels (T1) of miR-15a and miR-375 ( HR T1-T3  = 3.269 and HR T1-T3  = 1.604, respectively). In conclusion, our study showed that deregulated plasma levels of miR-150 , miR-30a-5p , miR-15a , and miR-375 were observed years before the onset of T2DM and pre-DM and could be used to evaluate the risk of developing the disease, which may improve prediction and prevention among individuals at high risk for T2DM. Metabolic disease: a red flag for diabetes risk Tiny RNA molecules circulating in the blood could give early warning of type 2 diabetes risk. MicroRNAs help regulate the expression of other genes, and recent research has linked irregularities in these molecules to many different diseases. Researchers led by José López Miranda of the University of Córdoba in Spain monitored a cohort of 462 patients for several years to assess how plasma levels of certain microRNAs are deregulated before the onset and progression of diabetes. They observed a striking ‘signature’ of altered expression in four microRNAs for patients who developed diabetes over the course of the study. Intriguingly, patients with markedly elevated blood sugar—state known as prediabetes—exhibited a similar signature, but with more modest alteration in the gene expression levels, indicating that these microRNAs could help clinicians track and prevent disease onset.

Background Maintaining optimal glucose control is critical for postoperative care cardiac surgery patients. Continuous glucose monitoring (CGM) in this setting remains understudied. We evaluated the efficacy of CGM with a specialized titration protocol in cardiac surgery patients with type 2 diabetes (T2D) and prediabetes. Methods In this randomized-controlled trial, 54 cardiac surgery patients were randomized one day post-surgery, with 27 CGM and 25 point-of-care (POC) patients completing the study. The CGM group used Dexcom G6 with a CGM-specialized titration protocol, while the POC group used standard monitoring with blinded CGM. The primary outcome was time-in-range (TIR) 100–180 mg/dL for 7 days post-surgery. Secondary outcomes included various glycemic metrics and surgical outcomes. Multiple comparison adjustments were performed using false-discovery-rate (FDR). Results Thirty-one (59.6%) had diabetes and 21 (40.4%) had prediabetes. While TIR 100–180 mg/dL showed no difference (74.7% vs. 71.6%, FDR-adjusted p  = 0.376), the CGM group demonstrated improvements in TIR 70–180 mg/dL (83.8% vs. 75.8%, FDR-adjusted p  = 0.026), time-in-tight-range (TITR) 100–140 mg/dL (46.3% vs. 36.3%, FDR-adjusted p  = 0.018), and TITR 70–140 mg/dL (55.3% vs. 40.5%, FDR-adjusted p  = 0.003). Both groups maintained very low rates of time below range (< 70 mg/dL: 0.03% vs. 0.18%, FDR-adjusted p  = 0.109). The CGM group showed lower postoperative atrial fibrillation (AF) (18.8% vs. 55.6%, FDR-adjusted p  = 0.04999). Conclusion While the primary outcome was not achieved, CGM with a specialized titration protocol demonstrated safe glycemic control with improvements in TIR 70–180 mg/dL and TITRs in cardiac surgery patients with T2D and prediabetes. The observed reduction in postoperative AF warrants further investigation. Trial Registration ClinicalTrials.gov NCT06275971 Graphical Abstract

BackgroundMany Diabetes Prevention Program (DPP) translation efforts have been less effective for underresourced populations. In the cluster-randomized Prediabetes Informed Decision and Education (PRIDE) trial, which evaluated a shared decision-making (SDM) intervention for diabetes prevention, Hispanic and non-Hispanic Black participants lost less weight than non-Hispanic White participants at 12-month follow-up.ObjectiveTo explore perspectives about weight loss from PRIDE participants of different racial and ethnic groups.ParticipantsSample of participants with prediabetes who were randomized to the PRIDE intervention arm (n=24).ApproachWe conducted semi-structured interviews within three groups stratified by DPP participation and % weight loss at 12 months: (DPP+/WL+, enrolled in DPP and lost >5% weight; DPP+/WL−, enrolled in DPP and lost <3% weight; DPP−/WL−, did not enroll in DPP and lost <3% weight). Each group was further subdivided on race and ethnicity (non-Hispanic Black (NHB), non-Hispanic White (NHW), Hispanic). Interviews were conducted on Zoom and transcripts were coded and analyzed with Dedoose.Key ResultsCompared to NHW participants, Hispanic and NHB participants more often endorsed weight loss barriers of limited time to make lifestyle changes due to long work and commute hours, inconvenient DPP class locations and offerings, and limited disposable income for extra weight loss activities. Conversely, facilitators of weight loss regardless of race and ethnicity included retirement or having flexible work schedules; being able to identify convenient DPP classes; having a strong, positive support system; and purchasing supplementary resources to support lifestyle change (e.g., gym memberships, one-on-one activity classes).ConclusionsWe found that NHB and Hispanic SDM participants report certain barriers to weight loss more commonly than NHW participants, particularly barriers related to limited disposable income and/or time constraints. Our findings suggest that increased lifestyle change support and flexible program delivery options may be needed to ensure equity in DPP reach, participant engagement, and outcomes.

Hemoglobin A1c (HbA1c) is recommended for diagnosing and monitoring diabetes. However, in people with sickle cell disease (SCD), sickle cell trait (SCT), α-thalassemia or glucose-6-phosphate dehydrogenase (G6PD) deficiency, HbA1c may underestimate the prevalence of diabetes. There are no data on the extent of this problem in sub-Saharan Africa despite having high prevalence of these red blood cell disorders. Blood samples from 431 adults in northwestern Tanzania, randomly selected from the prospective cohort study, Chronic Infections, Comorbidities and Diabetes in Africa (CICADA), were analysed for SCT/SCD, α-thalassemia and G6PD deficiency and tested for associations with the combined prevalence of prediabetes and diabetes (PD/DM) by HbA1c, using the HemoCue 501 HbA1c instrument, and by 2-hour oral glucose tolerance test (OGTT). The mean age of the participants was 40.5 (SD11.6) years; 61% were females and 71% were HIV-infected. Among 431 participants, 110 (25.5%) had SCT and none had SCD. Heterozygous α-thalassemia (heterozygous α+ AT) was present in 186 (43%) of the participants, while 52 participants (12%) had homozygous α-thalassemia (homozygous α+ AT). Furthermore, 40 (9.3%) participants, all females, had heterozygous G6PD deficiency while 24 (5.6%) males and 4 (0.9%) females had hemizygous and homozygous G6PD deficiency, respectively. In adjusted analysis, participants with SCT were 85% less likely to be diagnosed with PD/DM by HbA1c compared to those without SCT (OR = 0.15, 95% CI: 0.08, 0.26, P < 0.001). When using OGTT, in adjusted analysis, SCT was not associated with diagnosis of PD/DM while participants with homozygous α+ AT and hemizygous G6PD deficiency were more likely to be diagnosed with PD/DM. HbA1c underestimates the prevalence of PD/DM among Tanzanian adults with SCT. Further research using other HbA1c instruments is needed to optimize HbA1c use among populations with high prevalence of hemoglobinopathies or G6PD deficiency.

Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cardiovascular risk (CV) factor. Interleukin-1β (IL-1β), a cytokine involved in the pathogenesis of obesity-associated inflammation and type 2 diabetes (T2D), promotes hepatic steatosis. The Canakinumab Anti-inflammatory Thrombosis Outcome (CANTOS) trial showed that the inhibition of the IL-1β pathway was associated with a reduction of CV events in high-risk patients. The present study was designed to determine: (i) whether an equal degree of weight loss by liraglutide or lifestyle changes has a different impact on MASLD extent and IL-1β expression in peripheral blood mononuclear cells from obese subjects with prediabetes or early T2D; (ii) whether baseline IL-1β levels may predict the extent of weight loss and related metabolic changes. Methods Thirty-two obese subjects with prediabetes (n = 16) or newly diagnosed T2D (n = 16), were randomized to the glucagon-like peptide receptor agonist (GLP1-RA) liraglutide or lifestyle counselling until achieving a comparable weight loss. Visceral adipose tissue (VAT) and gene expression of IL-1β in peripheral blood mononuclear cells were assessed by magnetic resonance and real time PCR, respectively. Results At baseline, IL-1β was positively correlated to body mass index (BMI), fasting plasma glucose, HbA1c, VAT, MASLD extent, platelet count, chemerin and interleukin-1 receptor antagonist (IL1-RA). After achievement of the weight loss target in the two groups, a significant but comparable reduction of IL-1β (p for difference = 0.56) was observed in both arms, in parallel with a comparable improvement in glycaemic control, C reactive protein (CRP), BMI and MASLD. Furthermore, basal IL-1β levels independently predicted the extent of MASLD decrease (p = 0.030); subjects in the highest tertile showed a median decrease of − 8.0 (95% CI − 12.3 to − 4.8) compared with − 23.0 (95% CI − 39.5 to − 16.3) in the lowest tertile. Conclusion In patients with obesity with initial impairment of glucose metabolism successful weight loss is associated with a reduction of both IL-1β levels and MASLD degree. Of interest, basal levels of IL-1β predict the extent of MASLD improvement, regardless of the intervention. Our results may set the stage for ad-hoc studies investigating the usefulness of baseline IL-1β a level as a drug-response biomarker. Graphical abstract

This three-arm, randomized, controlled study aimed to determine the differences in the effects of general advice (GA) on lifestyle change, intensive lifestyle modification programme (ILMP) and GA + metformin (GA + Met) in reducing the prevalence of full metabolic syndrome (MetS) in subjects with prediabetes; 294 Saudis with prediabetes (fasting glucose 5.6–6.9 mmol/L) were initially randomized, 263 completed 6 months and 237 completed 12 months. They were allocated into three groups: GA group which received a standard lifestyle change education; ILMP which followed a rigorous lifestyle modification support on diet and physical activity; and a GA + Met group. Anthropometric and biochemical estimations were measured. Full MetS (primary endpoint) and its components (secondary endpoint) were screened at baseline, 6 and 12 months. Full MetS in the ILMP group decreased by 26% (p < 0.001); in GA + Met group by 22.4% (p = 0.01) and in GA group by 8.2% (p = 0.28). The number of MetS components decreased significantly in the ILMP and GA + Met groups (mean change 0.81, p < 0.001 and 0.35, p = 0.05, respectively). Between-group comparison revealed a clinically significant decrease in MetS components in favor of the ILMP group (−0.58 (−0.88–0.28), p < 0.001). This study highlights the clinical potency of ILMP versus other diabetes prevention options in reducing MetS in Saudi adults with elevated fasting glucose.

Background There is conflicting evidence whether prediabetes is associated with adverse clinical outcomes in patients with chronic coronary syndrome. We aimed to assess the effect of prediabetes in patients with chronic coronary syndrome on clinical outcomes. Methods This is a secondary analysis of data from the ISCHEMIA and ISCHEMIA-CKD trials, including patients with chronic coronary syndrome determined by coronary computed tomography angiography or exercise-stress testing. Participants were assigned to the normoglycemia group (HbA1c < 5.7% [< 39 mmol/mol]), prediabetes group (HbA1c 5.7–6.4% [40–47 mmol/mol]), or diabetes group (HbA1c ≥ 6.5% [≥ 48 mmol/mol]). The primary end point of this study was all-cause mortality. Secondary endpoints included major adverse cardiovascular events and composites thereof. Results Overall, the primary endpoint all-cause mortality occurred in 330 (8.4%) of 3910 patients over a median follow-up time of 3.1 years (IQR 2.1–4.1). The primary endpoint all-cause mortality occurred in 37 (5.2%) of 716 patients in the normoglycemia group, in 63 (6.9%) of 911 in the prediabetes group, and in 230 (10.1%) of 2283 in the diabetes group. In the covariate-adjusted Cox model analysis, the estimated adjusted HR (aHR) in the prediabetes group as compared with the normoglycemia group was 1.45 (95%CI, 0.95–2.20). The aHR in the diabetes group as compared with the normoglycemia group was 1.84 (95%CI, 1.29–2.65). Prediabetes, compared with normoglycemia, was associated with an increased risk of stroke (aHR, 3.44, 95%CI, 1.15–10.25). Subgroup analyses suggested an increased risk of all-cause death associated with prediabetes in males and patients under 65 years. Conclusions In patients with chronic coronary syndrome, diabetes but not prediabetes was associated with significantly increased risk of all-cause death within a median follow-up period of 3.1 years. Trial Registration NCT01471522, BioLINCC ID 13936.