Daily Endocrinology Research Analysis
Analyzed 70 papers and selected 3 impactful papers.
Summary
Three impactful endocrinology papers stand out today: a secondary analysis of the SOUL randomized trial shows oral semaglutide reduces heart failure events in people with type 2 diabetes who already have heart failure, especially HFpEF. A large meta-analysis finds a U-shaped link between dietary carbohydrate percentage and risks of cardiovascular disease and type 2 diabetes. An integrated meta-analysis and drug-target Mendelian randomization supports the fetal safety of metformin regarding congenital malformations.
Research Themes
- Incretin-based therapy and cardiovascular outcomes in type 2 diabetes
- Dietary macronutrient composition and chronic disease risk
- Medication safety in pregnancy: metformin and congenital malformations
Selected Articles
1. Oral Semaglutide and Heart Failure Outcomes in Persons With Type 2 Diabetes: A Secondary Analysis of the SOUL Randomized Clinical Trial.
In a prespecified secondary analysis of SOUL, oral semaglutide reduced the composite heart failure outcome in participants with baseline HF, especially those with preserved ejection fraction, without increasing serious adverse events. MACE reduction was similar irrespective of HF history.
Impact: This analysis provides high-quality randomized evidence that a GLP-1受容体作動薬 in oral form can reduce HF events in T2D patients with HF, informing cardiometabolic therapy selection. The HFpEF-specific signal addresses a major unmet need.
Clinical Implications: Consider oral semaglutide for T2D patients with established HF—particularly HFpEF—to reduce HF events, alongside standard HF therapies. Safety profile appears acceptable without increased serious adverse events.
Key Findings
- In participants with baseline HF, oral semaglutide reduced the composite HF outcome vs placebo (HR 0.78, 95% CI 0.63-0.96).
- HFpEF subgroup showed HR 0.59 (95% CI 0.39-0.86) while HFrEF showed HR 0.98 (95% CI 0.70-1.38).
- MACE risk reduction with oral semaglutide was consistent regardless of HF history (P for interaction = .77).
- Serious adverse events were similar between oral semaglutide and placebo among HF patients (53.8% vs 57.1%).
Methodological Strengths
- Double-blind, placebo-controlled, event-driven randomized clinical trial with prespecified HF composite outcome.
- Large, multinational cohort (n=9650) with long follow-up and HF subtype stratification.
Limitations
- Secondary analysis; the trial was not primarily powered for heart failure outcomes.
- HF subtype was unknown in a subset, and interaction P value for baseline HF was borderline (0.06).
Future Directions: Dedicated HF outcomes trials with oral semaglutide, mechanistic studies in HFpEF vs HFrEF, and comparative effectiveness versus SGLT2 inhibitors and other GLP-1 RAs.
IMPORTANCE: Heart failure (HF) is a common complication of type 2 diabetes (T2D). Oral semaglutide reduced the risk of major adverse cardiovascular (CV) events (MACE; comprising CV death, nonfatal myocardial infarction, or nonfatal stroke) in people with T2D in the SOUL trial, but the impact on HF outcomes in these participants is unknown. OBJECTIVE: To evaluate the effect of oral semaglutide on HF events, MACE, and safety among participants with or without HF at baseline. DESIGN, SETTING, AND PARTICIPANTS: This is a secondary analysis of the double-blind, placebo-controlled, event-driven, phase 3b SOUL randomized clinical trial, which was conducted at 444 centers in 33 countries. Participants were enrolled from June 17, 2019, to March 24, 2021, and had T2D and atherosclerotic CV disease and/or chronic kidney disease, stratified according to the presence or absence of HF history at baseline. Data were analyzed from December 2024 to August 2025. INTERVENTION: Once-daily oral semaglutide or placebo in addition to standard of care. MAIN OUTCOMES AND MEASURES: Prespecified composite HF outcome (time to first occurrence of HF hospitalization, urgent HF visit, or CV death). RESULTS: Overall, 9650 participants (median [IQR] age, 66.0 [61.0-72.0] years; 2790 [28.9%] female) were randomized, with a mean (SD) follow-up of 47.5 (10.9) months. Of these participants, 2229 (23.1%) had HF history (991 [10.3%] with preserved ejection fraction, 592 [6.1%] with reduced ejection fraction, and 646 [6.7%] with unknown subtype). For participants with HF at baseline, the hazard ratio (HR) for risk of the composite HF outcome with oral semaglutide vs placebo was 0.78 (95% CI, 0.63-0.96) and was 1.01 (95% CI, 0.84-1.20) in those without HF at baseline (P for interaction = .06). Among participants with HF, the HR was 0.59 (95% CI, 0.39-0.86) in those with preserved ejection fraction and 0.98 (95% CI, 0.70-1.38) in those with reduced ejection fraction. There was no heterogeneity in the risk reduction of MACE with oral semaglutide in participants with HF history (HR, 0.83; 95% CI, 0.68-1.01) or without HF history (HR, 0.86; 95% CI, 0.75-0.98) (P for interaction = .77). Serious adverse event occurrence among participants with HF was similar with oral semaglutide (594 [53.8%]) and placebo (642 [57.1%]). CONCLUSIONS AND RELEVANCE: In this secondary analysis of the SOUL randomized clinical trial, among individuals with T2D, atherosclerotic CV disease, and/or chronic kidney disease, a reduction of HF events was observed with use of oral semaglutide compared with placebo in those with a history of HF, without increasing the risk of serious adverse events. These data support the potential benefit of oral semaglutide in reducing HF events in people with T2D and HF. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03914326.
2. Impact of metformin use during pregnancy on fetal congenital malformations across 11 organ systems: a meta-analysis and Drug-Target Mendelian Randomization study.
Combining meta-analysis and drug-target Mendelian randomization, the study supports the overall safety of prenatal metformin exposure with respect to congenital malformations and identifies target genes potentially mediating protective effects, validated with placental eQTLs.
Impact: By integrating clinical and genetic instruments, this work addresses long-standing safety concerns and informs guideline-level decision-making for GDM therapy.
Clinical Implications: Metformin can be considered a clinically safe alternative to insulin for GDM regarding congenital malformations, while individualized risk-benefit assessment remains essential.
Key Findings
- Meta-analysis showed lower overall congenital malformations with metformin vs insulin (RR 0.83, 95% CI 0.71-0.99).
- Drug-target Mendelian randomization identified 7 of 92 target genes with significant associations, largely protective for circulatory and musculoskeletal systems.
- Placental eQTL validation corroborated 17 gene–outcome pairs, supporting robustness of safety signals.
Methodological Strengths
- Integrates meta-analysis of clinical studies with drug-target Mendelian randomization for triangulation.
- Multiple sensitivity controls including Bonferroni correction, adjustment for maternal confounders, and placental eQTL validation.
Limitations
- MR reflects lifelong target perturbation and may not precisely mirror pharmacologic dosing and timing in pregnancy.
- Potential residual confounding and publication bias in included observational studies.
Future Directions: Prospective pregnancy registries with standardized congenital anomaly adjudication, dose–timing analyses, and mechanistic studies of implicated mitochondrial targets.
AIMS: Metformin is a cost-effective alternative to insulin for gestational diabetes mellitus (GDM), yet concerns regarding potential teratogenicity persist. This study aimed to evaluate the association between prenatal metformin exposure and multisystem congenital malformations (CMs), and to explore biologically relevant pathways. METHODS: This study first conducted a meta-analysis of RCTs and cohort studies assessing maternal metformin use and fetal CMs. Subsequently, Drug-Target Mendelian Randomization (DTMR) examined genetically proxied associations between metformin pharmacodynamic targets (eQTLs) and 64 CMs (FinnGen), reflecting lifelong target perturbation, adjusting for maternal confounders and validating with placental eQTL data. RESULTS: Meta-analysis showed a protective effect of metformin versus insulin on overall CMs (RR = 0.83, 95% CI 0.71-0.99). In DTMR, following Bonferroni correction and covariate adjustment, seven of 92 target genes (e.g., NDUFS5, NDUFA2) showed significant associations, primarily exhibiting protective effects against circulatory and musculoskeletal system. Validation in placental eQTLs corroborated the direction of effects for 17 gene-outcome pairs, reinforcing the robustness of key safety signals. CONCLUSION: By integrating clinical and genetic evidence, this study is consistent with the overall clinical safety of metformin use during pregnancy with respect to congenital malformations and provides hypothesis-generating insights into relevant biological pathways.
3. The Relationship of Digestible Carbohydrate Intake Level and Cardiovascular Disease and Type 2 Diabetes: A Systematic Review and Meta-analysis.
Across 30 cohort studies (>1.7 million participants), digestible carbohydrate percentage showed a nonlinear (U-shaped) association with CVD and T2D risk. CVD risk was lowest at ~50% of energy from carbohydrates, with risk increasing >65%; T2D risk was lowest around 45–55% before rising at higher levels.
Impact: Defines plausible intake ranges for carbohydrate percentage associated with lower CVD and T2D risk using dose-response modeling, informing dietary guidance while highlighting evidence gaps.
Clinical Implications: Dietary counseling for cardiometabolic prevention may target ~45–55% of energy from digestible carbohydrates while avoiding very high (>65%) levels, pending confirmation from better-controlled studies.
Key Findings
- Included 30 prospective cohort studies with >1.7 million participants.
- Nonlinear (U-shaped) associations observed for both CVD and T2D with carbohydrate percentage.
- CVD risk lowest at ~50% energy from carbohydrates; risk increased beyond 65%.
- T2D risk decreased up to ~45%, plateaued at 45–55%, then increased at higher intake levels.
- Overall serious risk of bias due to inadequate confounding adjustment in many studies.
Methodological Strengths
- Large-scale synthesis with predefined registration (PROSPERO) and explicit isolation of carbohydrate effects from other macronutrients.
- Dose–response and nonlinearity modeling across sex and geography.
Limitations
- Predominantly observational cohorts with serious residual confounding and dietary measurement error.
- No eligible studies in children <18 years; heterogeneous intake assessment methods.
Future Directions: Well-controlled prospective cohorts and randomized feeding trials manipulating carbohydrate percentage while holding other macronutrients constant; improved dietary assessment and mediation analyses.
OBJECTIVES: To evaluate the association between the dietary digestible carbohydrate intake level and the incidence of cardiovascular disease (CVD) and type 2 diabetes (T2D). METHODS: We searched Embase, MEDLINE, and Cochrane Central from January 1, 2000, to July 19, 2024, to find randomized controlled trials and prospective cohort studies evaluating healthy individuals over 2 years of age, isolating for the effect of the digestible carbohydrate intake level from other macronutrients. RESULTS: Thirty prospective cohort studies with more than 1.7 million participants were included. Most of the studies reported inadequate confounding adjustment and were deemed to have serious risks of bias. No eligible studies evaluated children under 18 years. The association between the digestible carbohydrate intake level and CVD and T2D was nonlinear, which was supported by a low strength of evidence. The risk of CVD was the lowest at a carbohydrate intake level of 50% of total energy intake. The risk of CVD significantly increased when the carbohydrate intake level exceeded 65% of total energy intake. The risk of incident T2D gradually reduced with increasing carbohydrate intake levels up to 45% of total energy intake, then plateaued between 45% and 55% of total energy intake, before rising with higher carbohydrate intake levels. The nonlinear relationships were overall similar based on sex or geographic location but with variable intake range associated with the lowest risk. CONCLUSION: A U-shaped relationship was observed between the intake level of digestible carbohydrates and CVD and T2D. The findings have important implications on the incidence and morbidity of chronic conditions and public health. REGISTRATION: clinicaltrials.gov: PROSPERO #CRD42024494567 and CRD42024496101.