Daily Endocrinology Research Analysis
Three papers stand out today in endocrinology and metabolism: a large RCT-based meta-analysis shows GLP-1 receptor agonists reduce serious and total infections; metabolic and bariatric surgery is associated with improved survival in adults ≥69 years; and a Ghanaian case-control study reveals substantial residual C-peptide in clinically diagnosed long-term type 1 diabetes, challenging classification in resource-limited settings.
Summary
Three papers stand out today in endocrinology and metabolism: a large RCT-based meta-analysis shows GLP-1 receptor agonists reduce serious and total infections; metabolic and bariatric surgery is associated with improved survival in adults ≥69 years; and a Ghanaian case-control study reveals substantial residual C-peptide in clinically diagnosed long-term type 1 diabetes, challenging classification in resource-limited settings.
Research Themes
- Pleiotropic effects of incretin therapies on infection risk
- Surgical obesity treatment and survival in older adults
- Diabetes phenotyping using C-peptide and immunogenetics in sub-Saharan Africa
Selected Articles
1. Association of glucagon-like peptide-1 receptor agonist use with risk of infections: A systematic review and meta-analysis.
Across 136 RCTs with 164,322 participants, GLP-1 receptor agonists reduced serious, non-serious, and total infections, including respiratory, skin/subcutaneous, musculoskeletal, vascular infections and COVID-19. Risk reductions correlated with greater weight loss, HbA1c reduction, and higher GLP-1 RA doses.
Impact: This is the most comprehensive RCT-based synthesis linking GLP-1 RAs to lower infection risk across organ systems and COVID-19, suggesting pleiotropic benefits beyond glycemic control.
Clinical Implications: In patients at high infection risk, choosing a GLP-1 RA may confer incremental protection while improving weight and glycemia. Guideline committees may consider infection outcomes in benefit–risk assessments, though causality and mechanisms warrant confirmation.
Key Findings
- Reduced serious infections: RR 0.89 (95% CI 0.86–0.93); absolute risk difference −30 per 10,000 persons/year; I² = 0%
- Lower serious respiratory (RR 0.84), skin/subcutaneous (RR 0.77), musculoskeletal (RR 0.79), vascular (RR 0.65), and COVID-19 infections (RR 0.82), all with I² = 0%
- Dose–response signals: greater weight loss (β = −0.011), HbA1c reduction (β = −0.229), and higher GLP-1 RA dose (RR 0.87) associated with lower infection risk
Methodological Strengths
- Large-scale meta-analysis of 136 RCTs with 164,322 participants and PRISMA-adherent methods
- Consistent effects with zero heterogeneity for serious infections and organ-specific serious infections
Limitations
- Infections were not primary endpoints in many trials, raising potential reporting bias
- Trial-level meta-regression cannot confirm individual-level mediation; high heterogeneity for non-serious/total infections
Future Directions: Pursue individual participant data meta-analyses and pragmatic trials with prespecified infection endpoints to confirm causality and elucidate immunometabolic mechanisms.
OBJECTIVE: To assess whether GLP-1 RA treatment influences infection risk in randomized clinical trials (RCTs). METHODS: Systematic searches were conducted across PubMed, EMBASE, Cochrane Library, and Web of Science (inception to September 24, 2024), and reference lists of eligible articles. RCTs comparing GLP-1 RA treatment with placebo or non-GLP-1 RA treatments were included. Dual reviewer resolved disagreements by consensus. Two reviewers independently extracted data following PRISMA recommendations and assessed risk of bias via Cochrane tool. RESULTS: A total of 136 RCTs (n = 164,322) were included. GLP-1 RA treatment was associated with a significant reduction in serious infections (RR, 0.89; 95% CI, 0.86-0.93; absolute risk difference, -30 per 10,000 persons/year; I² = 0%), non-serious (RR, 0.90; 95% CI, 0.85-0.97; I² = 77%), and total infections (RR, 0.89; 95% CI, 0.84-0.94; I² = 77%). Reductions were observed for serious respiratory (RR, 0.84; 95% CI, 0.79-0.90), skin and subcutaneous (RR, 0.77; 95% CI, 0.68-0.87), musculoskeletal (RR, 0.79; 95% CI, 0.65-0.97), vascular (RR, 0.65; 95% CI, 0.47-0.90), and COVID-19 infections (RR, 0.82; 95% CI, 0.72-0.92), all with I² = 0%. Meta-regression showed greater weight loss (β = -0.011; P =.045), hemoglobin A1c reduction (β = -0.229; P =.026), and higher GLP-1 RA doses (RR, 0.87; 95% CI, 0.83-0.92) were associated with lower risk. CONCLUSION: GLP-1 RA use was associated with reduced risk of serious infections, particularly in respiratory, skin, musculoskeletal, vascular systems and COVID-19, partially explained by weight loss and improved glycemic control.
2. Metabolic and bariatric surgery in adults aged 69 years and older in England: a matched survival retrospective cohort study.
In a matched retrospective cohort from a UK tertiary center, metabolic and bariatric surgery in adults ≥69 years was independently associated with improved survival with acceptable perioperative risk. The study used Mahalanobis distance matching and Cox regression to mitigate confounding.
Impact: This study challenges age-based exclusion for MBS by demonstrating a survival advantage in older adults, informing surgical candidacy discussions as populations age.
Clinical Implications: Chronological age alone should not preclude MBS referral; comprehensive risk stratification can identify older candidates who may gain survival benefits. Shared decision-making should incorporate functional status and comorbidities rather than age cutoffs.
Key Findings
- Retrospective matched cohort (n=186; 44 underwent MBS) with median age 71 years (IQR 70–74) and median BMI 41 kg/m²
- MBS was independently associated with improved overall survival after 1:1 Mahalanobis matching and Cox regression
- Perioperative risk deemed acceptable in the specialist setting; results support reconsidering age-based exclusions
Methodological Strengths
- Mahalanobis distance matching on key clinical covariates to reduce confounding
- Cox proportional hazards modelling for survival with real-world electronic health records
Limitations
- Single-center retrospective design with a relatively small surgical cohort (n=44)
- Residual confounding and selection bias cannot be excluded; detailed follow-up duration and hazard ratios are not reported in the abstract
Future Directions: Prospective multicenter studies and pragmatic trials assessing survival, complications, and quality of life in older adults undergoing MBS with standardized geriatric assessments.
BACKGROUND: The prevalence of obesity is rising alongside population ageing, yet the long-term benefits of metabolic and bariatric surgery (MBS) in older adults is unclear. We aimed to evaluate the impact of MBS on survival in individuals aged 69 years and older with obesity. METHODS: We conducted a retrospective cohort study of patients aged 69 years and older managed in a UK tertiary bariatric centre between Jan 1, 2015, and Dec 31, 2024. Patients were eligible for inclusion if they had complete clinical data. Patients who underwent MBS were compared with matched controls who did not undergo MBS. Mahalanobis distance matching was performed (1:1) using age, BMI, American Society of Anesthesiologists grade, type 2 diabetes, and cardiovascular disease. Data were retrieved from electronic health records. The primary outcome was all-cause mortality after matching. Cox regression was used to assess survival. FINDINGS: Of the 186 patients, 44 (24%) underwent MBS. The median age was 71 years (IQR 70-74), 114 (61%) of 186 patients were women, 72 (39%) were men, median BMI was 41 kg/m INTERPRETATION: In a specialist setting, MBS was independently associated with improved survival in individuals aged 69 years and older, with acceptable perioperative risk. Chronological age alone should not preclude consideration for MBS. These findings support further evaluation of surgical options in well selected older adults with obesity. FUNDING: National Institute for Health and Care Research.
3. Heterogeneity in clinically diagnosed type 1 diabetes: characterising a unique cohort with maintained C-peptide secretion in Ghana.
In Ghana, only 28.9% of clinically diagnosed, insulin-treated long-term type 1 diabetes cases had low C-peptide, whereas 71.1% retained mid-to-high C-peptide with low autoantibodies and protective HLA, resembling controls. Onset ketosis occurred most frequently in the high C-peptide group, underscoring misclassification risks.
Impact: This well-powered case-control study integrates C-peptide, autoantibodies, HLA, and metabolomics to reveal profound heterogeneity in clinically diagnosed type 1 diabetes in sub-Saharan Africa, challenging current diagnostic pathways.
Clinical Implications: Routine C-peptide testing and selective autoimmunity/HLA assessment can improve diabetes classification in resource-limited settings, avoiding misclassification of ketosis-prone or lean type 2 diabetes as type 1 diabetes.
Key Findings
- Among 266 clinically diagnosed long-term type 1 diabetes cases, only 28.9% had low C-peptide (<0.2 nmol/L); 34.6% mid (0.2–0.6) and 36.5% high (>0.6)
- Low C-peptide group: youngest, leanest, enriched for HLA class II risk haplotypes and GAD/ZnT8 autoantibodies
- Mid/high C-peptide groups: low autoantibody titres and a protective HLA class II haplotype; ketosis at onset most prevalent in high C-peptide group
- Aromatic and branched-chain amino acids correlated positively with C-peptide across diabetes subgroups
Methodological Strengths
- Comprehensive phenotyping: C-peptide stratification combined with HLA class II, islet autoantibodies, inflammatory and metabolomic profiling
- Well-sized case-control design (266 cases and 266 controls) in an understudied population
Limitations
- Single random C-peptide measurement may misclassify residual insulin secretion
- Case-control design limits causal inference; external validity beyond Ghana requires caution
Future Directions: Prospective longitudinal studies with standardized mixed-meal tolerance tests and genotyping across African settings to refine diagnostic algorithms.
AIMS/HYPOTHESIS: In sub-Saharan Africa, type 1 diabetes is typically diagnosed clinically, which can be challenging due to atypical diabetes presentations such as ketosis-prone type 2 diabetes or type 2 diabetes in the absence of overweight and obesity. C-peptide, a marker of residual insulin secretion capacity, is crucial for understanding these variations but understudied in the region. Here, we investigated whether C-peptide measurement and concomitant genetic, autoimmune and metabolic characterisation of individuals with clinically diagnosed type 1 diabetes confirm diabetes classification and highlight population-specific features. METHODS: In this case-control study from Ghana, we recruited 266 individuals with clinically diagnosed and insulin-treated long-term type 1 diabetes and 266 healthy control individuals. We compared clinical features, HLA class II haplotypes, autoantibodies, and inflammatory and metabolic serum profiles across control and patient groups classified by random C-peptide levels: low (<0.2 nmol/l), mid (0.2-0.6 nmol/l) and high (>0.6 nmol/l). RESULTS: Only 28.9% of individuals with clinically diagnosed type 1 diabetes had low C-peptide concentrations. They were the youngest and leanest group, with higher frequencies of HLA class II risk haplotypes and GAD and ZnT8 autoantibodies compared with all other groups. By contrast, 34.6% and 36.5% had mid-range or high C-peptide levels, respectively. These subgroups resembled the control group in terms of low autoantibody titres and one protective HLA class II haplotype. Ketosis at onset was most prevalent in individuals with high C-peptide. Serum proinflammatory biomarkers differed between individuals with diabetes and control participants, but not between C-peptide subgroups. Aromatic and branched-chain amino acids varied between diabetes subgroups and positively correlated with C-peptide levels. CONCLUSIONS/INTERPRETATION: Maintained C-peptide levels in two-thirds of individuals with long-term type 1 diabetes in Ghana, combined with the absence of autoantibodies and HLA risk association, highlight the necessity for better differentiation from atypical diabetes presentations to optimise patient care and improve health outcomes in resource-limited settings.