Daily Endocrinology Research Analysis

RATIONALE: Malnutrition affects 35% to 64% of hospitalised older people, and is associated with adverse health outcomes such as disease complications and hospital readmission. Identifying effective nutritional interventions is essential to improve clinical outcomes and reduce healthcare costs in this population. OBJECTIVES: To evaluate the effects of various nutritional interventions, compared with either a control group (standard care or placebo) or each other, on patient-relevant outcomes in hospitalised older people at risk of or with established malnutrition, and to rank the effects of these different interventions using network meta-analysis (NMA) based on individual participant data (IPD). SEARCH METHODS: We searched CENTRAL, MEDLINE, five other databases, and two trial registries to 2 July 2024, and checked the reference lists of included studies and relevant systematic reviews. ELIGIBILITY CRITERIA: We included older people (≥ 65 years) hospitalised for different acute conditions at risk of or with malnutrition enrolled in randomised controlled trials (RCTs) comparing oral nutritional interventions with control or each other. For RCTs that met our inclusion criteria, either fully or partially, we requested IPD from the study authors. If we did not receive a response or IPD were unavailable, we used published aggregated data. We excluded RCTs that only partially met the eligibility criteria if neither IPD nor sufficient aggregated data were obtainable. OUTCOMES: Critical outcomes were all-cause mortality, serious adverse events (SAEs), and functional status (e.g. activities of daily living). Important outcomes were health-related quality of life (HRQoL), length of hospital stay (LOS), body weight, and fat-free mass. The main outcome assessment time point was at hospital discharge or 30 days after randomisation. RISK OF BIAS: We used the Cochrane risk of bias 2 (RoB 2) tool. SYNTHESIS METHODS: For each outcome, we first analysed IPD within each study. Second, we pooled results in an NMA which also included the aggregated data from RCTs without available IPD. We performed random-effects NMAs based on the frequentist approach and ranked treatments by P-scores. We rated the certainty of evidence using the GRADE approach. INCLUDED STUDIES: We included 21 RCTs (72 reports; 12 RCTs with IPD) with 3309 older participants (mean age ranged from 75 to 85 years; 1863 participants with IPD) with different acute conditions. Interventions included the provision of additional protein (three studies), energy supplements (two studies), oral nutritional supplements (ONS; eight studies), individualised feeding support (two studies), and comprehensive individualised nutritional care (eight studies). In all but two RCTs, interventions were compared to control (standard care with or without a placebo). We judged 16.1% of outcome assessments to be at low risk of bias and 16.8% at high risk. SYNTHESIS OF RESULTS: ONS may reduce all-cause mortality (risk ratio (RR) 0.46, 95% confidence interval (CI) 0.25 to 0.84; absolute risk difference 57 fewer deaths per 1000 people, 95% CI 79 fewer to 17 fewer; low-certainty evidence) compared to control, while comprehensive individualised nutritional care may show little to no effect (RR 0.98, 95% CI 0.55 to 1.73; 1 fewer per 1000 people, 95% CI 26 fewer to 46 more; low-certainty evidence). For all other treatment comparisons, the evidence is very uncertain (NMA with 13 RCTs, 2728 participants; Q between designs: not applicable (NA)). ONS may reduce SAEs compared to control (RR 0.56, 95% CI 0.32 to 0.95; 84 fewer SAEs per 1000 people, 95% CI 131 fewer to 10 fewer; Q between designs: Q 1.95, df 2, P = 0.3772; low-certainty evidence). For all other treatment comparisons, the evidence is very uncertain (NMA with 14 RCTs, 2184 participants). Comprehensive individualised nutritional care may make little to no difference in activities of daily living compared to control (standardised mean difference (SMD) 0.06, 95% CI -0.08 to 0.20; low-certainty evidence) and ONS compared to energy supplements (SMD -0.15, 95% CI -0.53 to 0.23; low-certainty evidence). For all other treatment comparisons, the evidence is very uncertain (NMA with 5 RCTs, 1128 participants; Q between designs: NA). Energy supplements probably make little to no difference in HRQoL compared with ONS (mean difference (MD) 0.01, 95% CI -0.06 to 0.08; Q between designs: NA; moderate-certainty evidence). All other comparisons of different nutritional interventions may make little to no difference to HRQoL (NMA with 3 RCTs, 1513 participants). The provision of additional protein, energy supplements, ONS, and comprehensive individualised nutritional care may make little to no difference in LOS compared to control (18 RCTs, 3013 participants; Q between designs: Q 2.86, df 3, P = 0.4145). Body weight (16 RCTs, 2114 participants; Q between designs: Q 2.03, df 3, P = 0.5655) may increase with ONS when compared to control (MD 0.9 kg, 95% CI 0.37 to 1.42) or comprehensive individualised nutritional care (MD 1.00 kg, 95% CI 0.12 to 1.87), but the evidence is very uncertain. Energy supplements and ONS probably have similar effects on body weight (MD 0.11 kg, 95% CI -0.85 to 0.63; moderate-certainty evidence). For fat-free mass, no meta-analysis was possible. One RCT (102 participants) compared ONS with energy supplements and found little or no difference between groups (MD 0.13 kg, 95% CI -0.63 to 0.90; low-certainty evidence), while evidence regarding the effects of additional protein compared with control was very uncertain (1 RCT, 19 participants). Rankings of treatments by P-scores were not consistent across outcomes. AUTHORS' CONCLUSIONS: In older hospitalised people at risk of or with malnutrition, oral nutritional supplements may reduce mortality and SAEs compared to control 30 days after randomisation. For other outcomes, there may be little or no differences in results. Overall, the evidence was of low to very low certainty, primarily due to a limited number of studies and participants per comparison. The comparison of treatment effects across outcomes was constrained by variations in network structure. When interpreting the results, the heterogeneity of the population in terms of acute and chronic conditions needs to be considered. To improve certainty, adequately powered studies with robust methodologies should compare interventions with controls as well as against each other. FUNDING: The German Federal Ministry of Education and Research funded this work (grant number: 01KG2102). REGISTRATION: Protocol (2022) doi.org/10.1002/14651858.CD015468.

OBJECTIVE: To compare the glycemic response and pharmacokinetics (PK) of Lyumjev versus Humalog during manual basal rate reductions (BRRs) before exercise with conventional continuous subcutaneous insulin infusion (CSII) in active adults with type 1 diabetes. RESEARCH DESIGN AND METHODS: This study was a double-blind, four-period, crossover, randomized controlled trial. Exercise (60 min walking at 45-55% VO2max) was performed 4 h after a standardized meal, with either a 50% (-60 min) or 100% (-15 min) BRR before exercise using Lyumjev or Humalog. The primary endpoint was the change in glucose during exercise, and insulin lispro PK was the secondary endpoint. RESULTS: Twenty-five participants (mean ± SD age 36.7 ± 10.3 years; mean ± SD HbA1c 50.4 ± 8.5 mmol/mol [6.76 ± 0.8%]; 48% female) completed the study. Lyumjev significantly attenuated the reduction in glucose level compared with Humalog during both the 50% BRR (-26.8 ± 37 vs. -39.0 ± 39 mg/dL; P < 0.05) and the 100% BRR (-46.9 ± 32 vs. -60.5 ± 39 mg/dL; P < 0.01). Circulating insulin lispro concentrations rose in the first 15 min of exercise, but maximum concentration was lower with Lyumjev versus Humalog within each BRR strategy. Numerically less hypoglycemia was observed during exercise with Lyumjev (6%) compared with Humalog (16%). Following a postexercise meal, faster insulin absorption of Lyumjev resulted in an earlier postprandial glucose lowering compared with Humalog. CONCLUSIONS: Using Lyumjev in conventional CSII pump therapy provides more effective BRRs prior to exercise compared with Humalog, with fewer hypoglycemic events in active adults with type 1 diabetes.

IMPORTANCE: Given the common use of weight-inducing (WI) medications, it is crucial to understand the potential association of these medications with the effectiveness of obesity treatments. OBJECTIVE: To assess the association between tirzepatide and weight reduction among participants with overweight or obesity who initiated WI medications during the SURMOUNT-1, -3, and -4 trials. DESIGN, SETTING, AND PARTICIPANTS: This post hoc analysis of the phase 3 randomized clinical trials SURMOUNT-1 (December 4, 2019, to April 1, 2022), SURMOUNT-3 (March 29, 2021, to May 12, 2023), and SURMOUNT-4 (March 29, 2021, to May 18, 2023) assessed the association between tirzepatide and weight reduction among participants taking concomitant WI medications. Randomized participants (lead-in and randomized treatment period data) who started taking 1 or more WI medications for 3 or more months (≥1 week for oral corticosteroids) during the trial were included in the analysis. Statistical analysis was performed from July to December 2025 in the modified intent-to-treat population. MAIN OUTCOMES AND MEASURES: WI medication use was summarized for all treatment arms from weeks 0 to 72 (SURMOUNT-1 and SURMOUNT-3) or weeks 0 to 88 (SURMOUNT-4). A mixed model of repeated measures was used to assess percentage change in weight from week 0 to week 72 or week 88 in the efficacy analysis sets (excluding off-treatment data), with 1 or more postbaseline weight measures. RESULTS: This post hoc analysis comprised the WI medication subgroups of SURMOUNT-1 participants (N = 442; mean [SD] age, 48.0 [12.5] years; 325 women [73.5%]; mean [SD] body weight, 105.9 [22.4] kg), SURMOUNT-3 participants (N = 100; mean [SD] age, 49.5 [12.0] years; 75 women [75.0%]; mean [SD] body weight, 102.7 [23.5] kg), and SURMOUNT-4 participants (N = 134; mean [SD] age, 51.8 [11.9] years; 91 women [67.9%]; mean [SD] body weight, 111.8 [23.7] kg). Approximately one-fifth of participants used 1 or more WI medications (SURMOUNT-1, 17.4% [442 of 2539]; SURMOUNT-3, 17.3% [100 of 579]; and SURMOUNT-4, 20.0% [134 of 670]). Among them, 72.9% in SURMOUNT-1 (322 of 442), 68.0% in SURMOUNT-3 (68 of 100), and 64.9% in SURMOUNT-4 (87 of 134) were taking 1 nonsteroid WI medication, with 2.0% in SURMOUNT-1 (9 of 442), 3.0% in SURMOUNT-3 (3 of 100), and 2.2% in SURMOUNT-4 (3 of 134) using 3 or more medications. The mean (SD) duration of treatment with nonsteroid WI medications was 50.9 (28.8) weeks in SURMOUNT-1, 50.9 (29.3) weeks in SURMOUNT-3, and 58.1 (34.9) weeks in SURMOUNT-4. The mean percentage weight change compared with placebo from randomization to 72 weeks for those treated with tirzepatide and using WI medication was -13.3% (95% CI, -16.0% to -10.7%) for 5 mg to -21.3% (95% CI, -23.9% to -18.7%) for 15 mg in SURMOUNT-1 and -26.1% (95% CI, -30.0% to -22.3%) for the maximum tolerated dose in SURMOUNT-3, and from randomization to 88 weeks, it was -18.6% (95% CI, -20.9% to -16.3%) for the maximum tolerated dose in SURMOUNT-4. CONCLUSIONS AND RELEVANCE: In this post hoc analysis of 3 randomized clinical trials for participants taking at least 1 concomitant WI medication, tirzepatide treatment was associated with weight loss comparable with the primary study results. These findings suggest that people with overweight or obesity who require treatment with WI medications may be able to achieve clinically meaningful weight reduction with tirzepatide. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04184622, NCT04657016, NCT04660643.