Daily Endocrinology Research Analysis
Analyzed 147 papers and selected 3 impactful papers.
Summary
Three high-impact endocrinology papers advance prevention and cardiometabolic care: a long-term follow-up of the Diabetes Prevention Program links intensive lifestyle intervention to reduced multimorbidity; the SAFEHEART pediatric FH cohort shows earlier lipid-lowering from childhood markedly lowers lifetime LDL burden with near-zero early CV events; and a large UK real-world comparative cohort finds once-weekly semaglutide achieves greater HbA1c and weight reductions than dulaglutide with comparable safety.
Research Themes
- Lifestyle intervention and long-term multimorbidity prevention
- Early-life lipid lowering in familial hypercholesterolemia
- Real-world comparative effectiveness of GLP-1 receptor agonists
Selected Articles
1. Cholesterol-lowering therapy from childhood/adolescence and long-term outcomes in familial hypercholesterolaemia: the SAFEHEART study.
In this 12.4-year prospective FH cohort, initiating lipid-lowering therapy during adolescence halved lifetime LDL-C burden compared with parental cohorts treated later and was associated with near-zero cardiovascular events by age 39. On-treatment LDL-C in adolescents approached levels of non-FH peers, supporting FH as a pediatric condition requiring early detection and intervention.
Impact: This is among the most compelling long-term real-world datasets showing pediatric initiation of lipid-lowering therapy translates into substantially reduced lifetime LDL burden and extremely low early cardiovascular event rates.
Clinical Implications: Prioritize early genetic diagnosis and initiation of lipid-lowering therapy (e.g., statins ± ezetimibe/PCSK9i as indicated) during adolescence in FH to reduce lifetime LDL burden and early CV risk; integrate family cascade screening and transition-of-care pathways.
Key Findings
- Adolescents with FH started therapy at median age 14.5 years versus 36.1 years in affected parents.
- On-treatment LDL-C was 3.00 mmol/L in FH adolescents (−47.4%) vs 2.44 mmol/L in FH parents (−67.6%).
- Lifetime LDL-C burden by age 30–40 was 5909 vs 10206 mg/dL*years (FH-Ch vs FH-P).
- By age 39, cardiovascular event rates were 0.3% in FH adolescents vs 5.2% in FH parents; 0% in non-FH relatives.
Methodological Strengths
- Prospective national registry cohort with long median follow-up (12.4 years).
- Genetically confirmed heterozygous FH and inclusion of family-based comparison groups.
Limitations
- Observational design limits causal inference.
- Therapy intensity and adherence not randomized and may differ across generations.
Future Directions: Evaluate optimal age thresholds, therapy intensification sequences (statin–ezetimibe–PCSK9i), and health-economic impacts of universal pediatric FH screening and early treatment.
BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) leads to life-long exposure to high low-density lipoprotein cholesterol (LDL-C) and increased risk of premature atherosclerotic cardiovascular disease. Evidence supporting initiation of cholesterol-lowering medication (CLM) in childhood to lower this cumulative cholesterol burden and cardiovascular sequelae is sparse. This study assessed the long-term impact of contemporary management of FH on LDL-C and cardiovascular events. METHODS: Observational prospective cohort study (SAFEHEART) including children/adolescents (age <18 years) with genetically confirmed heterozygous FH (FH-Ch), their non-affected children and adolescents' relatives (non-FH-Ch), and FH parents (FH-P). Impact of CLM, LDL-C burden, and cardiovascular events were assessed. RESULTS: Overall, 348 FH-Ch, 165 non-FH-Ch and 288 FH-P were included (49.8% female; median untreated LDL-C: 5.46, 2.63, and 7.19 mmol/L, respectively). Median follow-up was 12.4 years (interquartile range 9.6-15.3). At follow-up, 84.5% FH-Ch, 4.2% non-FH-Ch, and 95.1% FH-P were receiving CLM. FH-Ch started therapy at a median age of 14.5, vs. 36.1 years in their FH-P. Latest on-treatment LDL-C was 3.00 mmol/L in FH-Ch (median change: -2.60 mmol/L, -47.4%) and 2.44 mmol/L in FH-P (-4.72 mmol/L, -67.6%); LDL-C among non-FH-Ch (not on CLM) was 2.72 mmol/L. By age 30-40 years, median LDL-C burden over life was 5909.0 and 10 206.8 mg/dL*years among FH-Ch and FH-P, respectively. By age 39 years, rate of cardiovascular events was 0.0%, 0.3% and 5.2% among non-FH-Ch, FH-Ch, and FH-P, respectively. CONCLUSIONS: Treatment of FH from childhood/adolescence reduces the cumulative LDL-C burden compared with later onset treatment from adulthood in affected parents and permits attainment of LDL-C levels close to non-FH individuals; this finding was associated with the observation of a reduction in the cardiovascular risk of young FH patients. These findings support FH as a paediatric condition requiring early-life detection and treatment. STUDY REGISTRATION NUMBER: ClinicalTrials.gov, NCT02693548.
2. Lifestyle and Metformin Interventions and Risk of Multimorbidity in Adults With Prediabetes.
In a long-term follow-up of DPP participants with CMS linkages, intensive lifestyle intervention was associated with a 21% lower hazard of multimorbidity versus placebo, whereas metformin showed no significant difference. Benefits persisted even when excluding diabetes from the outcome and were stronger for dyads of costliest conditions.
Impact: This work reframes diabetes prevention as multimorbidity prevention, providing rare long-horizon evidence that lifestyle programs reduce the accumulation of multiple chronic conditions in aging adults.
Clinical Implications: Health systems should scale intensive lifestyle programs for prediabetes, emphasizing durability and adherence, to curb long-term multimorbidity beyond glycemic endpoints.
Key Findings
- Lifestyle intervention lowered multimorbidity risk vs placebo (adjusted HR 0.79; 95% CI 0.68–0.93).
- Metformin did not differ from placebo (HR 0.91; 95% CI 0.78–1.07).
- Effect persisted when diabetes was excluded from the multimorbidity definition.
- For the costliest condition dyads, lifestyle vs placebo HR was 0.57 (95% CI 0.38–0.85).
Methodological Strengths
- Decades-long follow-up linking DPP/DPPOS to CMS morbidity data.
- Time-to-event modeling with covariate adjustment; robustness checks excluding diabetes.
Limitations
- Only 1173 participants had CMS-linked data, raising selection concerns.
- Observational follow-up; potential residual confounding despite adjustments.
Future Directions: Identify which lifestyle components drive multimorbidity reduction, optimize implementation for sustained adherence, and evaluate cost-effectiveness in diverse health systems.
IMPORTANCE: Studying how to prevent or delay not just 1 disease but multiple chronic conditions is of great importance for public health; however, few interventions have demonstrated success during long-term follow-up. OBJECTIVE: To examine the association of lifestyle or metformin compared with placebo on long-term multimorbidity in adults with prediabetes. DESIGN, SETTING, AND PARTICIPANTS: Observational follow-up cohort study of a randomized clinical trial conducted at 27 sites in the United States from June 1, 1996, to December 31, 2021. From June 1, 1996, through May 28, 1999, 3234 adults at high risk of diabetes enrolled in the 3-year Diabetes Prevention Program (DPP). They were subsequently enrolled in the DPP Outcomes Study (DPPOS). Of this cohort, Centers for Medicare & Medicaid Services (CMS) morbidity data were available through 2021 for 1173 participants who provided consent. Data were analyzed from June 5, 2024, to November 7, 2025. EXPOSURES: Participants in DPP were randomly assigned to intensive lifestyle intervention, metformin, or placebo. During DPPOS, medications were unmasked with discontinuation of placebo; metformin was continued. Group booster classes were offered to the lifestyle group semiannually and all participants were offered lifestyle classes quarterly until 2014. MAIN OUTCOMES AND MEASURES: The primary outcome was multimorbidity (presence of ≥2 of 15 prevalent conditions, defined in CMS' Chronic Condition Data Warehouse and adapted for Medicare Advantage encounters). Cox proportional hazard models were applied to estimate associations between randomized treatment groups and time to development of outcomes. RESULTS: Of the 1173 participants (median age, 74 years [IQR, 70-80]; 795 [68%] were female), 997 (85%) experienced greater than or equal to 2 conditions (median, 5 [IQR, 3-7]) by the end of follow-up (316 of 385 [82%], 327 of 385 [85%], and 350 of 403 [87%], respectively, among lifestyle, metformin, and placebo groups). The risk of multimorbidity was lower among lifestyle compared with placebo participants (hazard ratio [HR], 0.79; 95% CI, 0.68-0.93) after adjustment for relevant covariates. There was no difference between participants in the metformin and placebo groups (HR, 0.91; 95% CI, 0.78-1.07). These relationships persisted when diabetes was excluded from the multimorbidity definition. When restricted to dyads of the costliest conditions, the association with lifestyle vs placebo yielded an HR of 0.57 (95% CI, 0.38-0.85). CONCLUSIONS AND RELEVANCE: Among adults with prediabetes at baseline, lifestyle intervention, but not metformin, was associated with a lower burden of multimorbidity. Lifestyle programs may persistently lower the development of chronic conditions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: DPP, NCT00004992; DPPOS, NCT00038727.
3. Comparative Effectiveness and Safety of Once-Weekly Injectable Semaglutide Versus Dulaglutide in Individuals with Type 2 Diabetes Managed in UK Primary Care: A Population-Based Cohort Study.
In over 6600 UK primary-care initiators, semaglutide produced greater 1-year HbA1c (ETD −0.22%) and weight (ETD −1.92 kg) reductions than dulaglutide with similar safety. Benefits held across the large non–trial-eligible majority, supporting preferential semaglutide use in routine care.
Impact: Provides robust, methodologically advanced real-world comparative effectiveness evidence generalizable beyond RCT eligibility, directly informing agent selection among weekly GLP-1 RAs.
Clinical Implications: When choosing a weekly GLP-1 RA in primary care, semaglutide may be preferred for greater glycemic and weight efficacy with similar safety; monitor adherence given attenuated effects with early discontinuation.
Key Findings
- Semaglutide vs dulaglutide 1-year ETD in HbA1c: −0.22 percentage points (95% CI −0.30, −0.15).
- Semaglutide vs dulaglutide 1-year ETD in weight: −1.92 kg (95% CI −2.91, −0.93).
- Efficacy preserved in 87.7% non–SUSTAIN-7-eligible patients.
- Early discontinuers had attenuated benefits and higher GI event rates (23.5–26.1 vs 10.6–13.8 per 100 person-years).
Methodological Strengths
- New-user, active-comparator design with marginal structural models and IPTW.
- Heterogeneity assessed by trial-eligibility; safety evaluated while-on-treatment.
Limitations
- Residual confounding possible despite advanced adjustment.
- Per-protocol primary analysis may be sensitive to adherence-related selection.
Future Directions: Compare cardiovascular and renal outcomes across GLP-1 RAs in routine care; evaluate persistence strategies to mitigate early discontinuation and GI intolerance.
BACKGROUND: The SUSTAIN-7 trial demonstrated greater HbA1c and bodyweight reductions with once-weekly semaglutide versus dulaglutide in type 2 diabetes, but strict eligibility criteria limit external validity. We evaluated the comparative real-world effectiveness and safety of these agents in UK primary care. METHODS: Using the IQVIA Medical Research Data (IMRD) incorporating data from THIN, a Cegedim Database, we included adults with type 2 diabetes initiating semaglutide or dulaglutide between 01-Jan-2019 and 01-Dec-2022, followed through 30-Jun-2023. Co-primary outcomes were 1-year changes in HbA1c and bodyweight, estimated using a new-user, active-comparator cohort design with marginal structural models and inverse probability of treatment weighting. Treatment heterogeneity was assessed in the primary per-protocol analysis by SUSTAIN-7 trial-eligibility. Safety events were assessed while-on-treatment. FINDINGS: Among 6616 new users, 4636 (70.1%) remained on-treatment and 1980 (29.9%) discontinued early. Semaglutide new users (n = 1901) achieved greater 1-year reductions than dulaglutide new users (n = 2735) in HbA1c (estimated treatment difference [ETD] -0.22 percentage points [95% CI -0.30, -0.15]) and bodyweight (ETD -1.92 kg [95% CI -2.91, -0.93]). While semaglutide's benefits were preserved across the 87.7% (n = 4064) not meeting SUSTAIN-7 trial-eligibility (HbA1c: ETD -0.23 percentage points [95% CI -0.31, -0.15]; bodyweight: ETD -2.01 kg [95% CI -3.07, -0.95]), reductions in HbA1c and bodyweight were greater among trial-eligible individuals (12.3%; n = 572) for both agents (trial-eligible [semaglutide/dulaglutide] versus non-eligible [semaglutide/dulaglutide] individuals, HbA1c: -1.10/-1.02 versus -0.83/-0.60 percentage points; bodyweight: -5.72/-4.18 versus -5.50/-3.49 kg). Early discontinuers showed attenuated treatment effects and higher gastrointestinal event rates than those remaining on-treatment (23.5-26.1 versus 10.6-13.8 per 100 person-years). INTERPRETATION: New users of semaglutide achieved greater reductions in HbA1c and bodyweight than new users of dulaglutide with comparable safety, with benefits preserved across SUSTAIN-7 trial-eligible and non-eligible individuals, supporting preferential use of semaglutide in UK clinical practice. FUNDING: Swiss National Science Foundation.