Daily Endocrinology Research Analysis
Across endocrinology, a large meta-analysis clarifies the relative benefits and risks of anti-obesity medications, highlighting tirzepatide as top for weight loss and cardiometabolic improvements. A population-based study challenges routine albumin-adjustment of calcium, showing unadjusted total calcium aligns best with ionized calcium and reduces misclassification. A nationwide target trial emulation finds empagliflozin and dapagliflozin yield comparable long-term kidney outcomes in type 2 diab
Summary
Across endocrinology, a large meta-analysis clarifies the relative benefits and risks of anti-obesity medications, highlighting tirzepatide as top for weight loss and cardiometabolic improvements. A population-based study challenges routine albumin-adjustment of calcium, showing unadjusted total calcium aligns best with ionized calcium and reduces misclassification. A nationwide target trial emulation finds empagliflozin and dapagliflozin yield comparable long-term kidney outcomes in type 2 diabetes.
Research Themes
- Pharmacotherapy for obesity and cardiometabolic risk
- Laboratory diagnostics and calcium assessment
- Comparative effectiveness of SGLT2 inhibitors in diabetic kidney outcomes
Selected Articles
1. Safety and effects of anti-obesity medications on weight loss, cardiometabolic, and psychological outcomes in people living with overweight or obesity: a systematic review and meta-analysis.
Synthesizing 154 RCTs (n=112,515), this meta-analysis ranks anti-obesity medications: tirzepatide delivers the greatest weight loss and strong blood pressure/glucose reductions; semaglutide and liraglutide lower major adverse cardiovascular events. Naltrexone/bupropion may raise blood pressure, and phentermine/topiramate carries higher psychological adverse event risk.
Impact: Provides high-certainty comparative evidence across modern anti-obesity agents, informing drug selection beyond weight loss toward cardiometabolic and psychological profiles.
Clinical Implications: Prioritize tirzepatide for maximal weight loss and broad cardiometabolic benefit; consider semaglutide/liraglutide for MACE risk reduction. Monitor BP with naltrexone/bupropion and psychological side effects with phentermine/topiramate; tailor choices to comorbidities and tolerability.
Key Findings
- Among 154 RCTs (n=112,515), tirzepatide showed the greatest weight-loss effect (WMD -11.69 kg; 95% CI -19.22 to -4.15).
- Tirzepatide provided the strongest blood pressure and glucose-lowering benefits among agents evaluated.
- Semaglutide and liraglutide reduced major adverse cardiovascular events (MACEs).
- Naltrexone/bupropion was associated with increased blood pressure risk.
- Phentermine/topiramate had a higher risk of psychological adverse effects.
Methodological Strengths
- Comprehensive PRISMA-based search across major databases with PROSPERO registration
- Random-effects meta-analysis with GRADE assessment for certainty of evidence
- Large aggregate sample size (112,515) enabling robust comparative estimates
Limitations
- Heterogeneity across trials and populations may affect pooled estimates
- Reliance on summary-level data limits exploration of individual patient modifiers
Future Directions: Head-to-head RCTs and IPD meta-analyses to refine comparative effectiveness and safety by patient subgroups and comorbidities; longer-term outcomes (maintenance, MACE, renal) and real-world adherence studies.
BACKGROUND: Overweight and obesity pose serious health challenges for individuals and societies. This study aims to facilitate personalised treatment of obesity by summarising recent research on weight-loss pharmacotherapies, with a focus on their effects on weight reduction, cardiometabolic health, psychological outcomes, and adverse events. METHODS: This systematic review and meta-analysis included searches of Web of Science, PubMed, and Cochrane Central Register of Controlled Trials from inception to June 8, 2024. Randomised controlled trials evaluating weight-loss pharmacotherapies approved by the Food and Drug Administration (FDA) or European Medicines Agency (EMA) for treating overweight or obesity were included. Primary outcomes included changes in body weight, cardiometabolic indicators, psychological outcomes, and adverse events. Summary data was extracted from published reports. Random-effects meta-analyses were used to calculate weighted mean differences (WMDs), risk ratios (RRs), and 95% confidence intervals (CI). The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system was used to assess the certainty of evidence for each pooled analysis. PROSPERO registration: CRD42024547905. FINDINGS: A total of 154 randomised controlled trials (n = 112,515 participants) were included. Tirzepatide had the greatest weight-loss effect (WMD -11.69, 95% CI -19.22 to -4.15; INTERPRETATION: For weight reduction, tirzepatide is the top choice, followed by semaglutide. Considering cardiometabolic risk factors, tirzepatide shows the best blood pressure- and glucose-lowering benefits, while semaglutide and liraglutide reduce the risk of MACEs. Naltrexone/bupropion carries a risk of increased blood pressure. Phentermine/topiramate should be used with caution due to its higher risk of psychological side effects. Despite limitations related to study heterogeneity, these findings provide valuable insights for weight management strategies across diverse individuals. FUNDING: National Natural Science Foundation of China, Leading Talents Program of Hunan Province, and Fundamental Research Funds for the Central Universities of Central South University.
2. Use of Albumin-Adjusted Calcium Measurements in Clinical Practice.
In 22,658 adults with simultaneous testing, unadjusted total calcium correlated better with ionized calcium than common albumin-adjustment formulas and yielded the highest agreement in classifying hypo-, normo-, or hypercalcemia. Adjustment formulas increased misclassification, especially with hypoalbuminemia.
Impact: Challenges entrenched laboratory practice by showing albumin-adjustment offers no advantage and may worsen classification, prompting a shift toward unadjusted total calcium or direct ionized calcium.
Clinical Implications: Prefer unadjusted total calcium for routine assessment and avoid automatic albumin-adjustment, particularly in hypoalbuminemia. When clinical stakes are high or results discordant, measure ionized calcium directly.
Key Findings
- Unadjusted total calcium showed higher correlation with ionized calcium (R2=71.7%) than the simplified Payne formula (R2=68.9%).
- Overall classification agreement with ionized calcium was best for unadjusted total calcium (74.5%) versus Payne formulas (63.0% and 58.7%).
- Albumin-adjustment formulas performed worse in hypoalbuminemia (albumin <30 g/L), increasing misclassification risk.
Methodological Strengths
- Large, population-based cohort with 22,658 simultaneous total and ionized calcium measurements
- Compared 10 adjustment formulas with ionized calcium reference and assessed clinical classification agreement
Limitations
- Cross-sectional observational design limits causal inference
- Single-province health system may limit generalizability
Future Directions: Prospective validation across diverse settings and exploration of decision-support rules for when to obtain ionized calcium versus relying on unadjusted total calcium.
IMPORTANCE: Using albumin-adjusted calcium is commonly recommended for for measuring calcium, but with little empirical evidence to support the practice. OBJECTIVE: To assess the correlation between total calcium measurements (with or without adjustment) vs the ionized calcium level as a reference standard. DESIGN, SETTING, AND PARTICIPANTS: This was a population-based cross-sectional study in the province of Alberta, Canada, including adults tested for serum total calcium and ionized calcium simultaneously between January 1, 2013, and October 31, 2019. Statistical analysis was performed from March 2023 to October 2024. MAIN MEASURES AND OUTCOMES: The correlation between unadjusted and adjusted total calcium measurements (using 10 formulas) and the ionized calcium level was evaluated, along with the potential association with the classification of calcium status. RESULTS: Among 22 658 patients included, 11 889 (52.5%) were female and 10 769 (47.5%) were male; the median (IQR) age was 60 (47-72) years. The unadjusted total calcium (R2 = 71.7%; 95% CI, 71.1%-72.2%) had a stronger correlation with ionized calcium than the commonly used simplified Payne formula (ie, total calcium [mmol/L] + 0.02 [40 - albumin (g/L)]) (R2 = 68.9%; 95% CI, 68.0%-69.6%) and correlated similarly to other formulas (Payne: lowest R2 = 60.3%; 95% CI, 59.3%-61.3%; and James: highest R2 = 76.7%; 95% CI, 76.1%-77.3%). When classifying patients into categories of hypocalcemia, normocalcemia, or hypercalcemia, unadjusted total calcium had the best overall agreement (74.5%) with ionized calcium compared with albumin-adjusted calcium using the original Payne and simplified Payne formulas (agreement 63.0% and 58.7%, respectively). Misclassification using the adjustment formulas was worse in the presence of hypoalbuminemia (albumin level <30 g/L). CONCLUSIONS AND RELEVANCE: In this cross-sectional study drawn from a contemporaneous population, there appeared to be heavy reliance on adjustment formulas for calcium in clinical practice with little gain but considerable risk of misclassification of true calcium status, especially in the presence of hypoalbuminemia. These results suggest that unadjusted total calcium was the best and most practical alternative to ionized calcium.
3. Effectiveness of Empagliflozin vs Dapagliflozin for Kidney Outcomes in Type 2 Diabetes.
In a nationwide target trial emulation (n=50,283), empagliflozin and dapagliflozin produced comparable 6-year risks of acute kidney injury, incident CKD (G3–G5 or A2/A3), and CKD progression, with balanced covariates after weighting and consistent per-protocol results.
Impact: Offers high-quality real-world comparative effectiveness evidence where no head-to-head RCT exists, guiding SGLT2 inhibitor selection for renal protection in type 2 diabetes.
Clinical Implications: Empagliflozin and dapagliflozin can be considered interchangeable for long-term kidney outcomes; selection may be based on patient-specific factors (CV history, tolerability, cost/access) and extra-renal evidence.
Key Findings
- After weighting 56 confounders, covariates were well balanced between empagliflozin (n=32,819) and dapagliflozin (n=17,464) initiators.
- Six-year risks were comparable for acute kidney injury (18.2% vs 18.5%; RR 0.98, 95% CI 0.91-1.06) and incident CKD stages G3–G5 (11.8% vs 12.1%; RR 0.97, 95% CI 0.89-1.05).
- Albuminuria (A2/A3) incidence (14.8% vs 14.3%; RR 1.04, 95% CI 0.93-1.15) and CKD progression (≥40% eGFR decline: 5.3% vs 5.7%; RR 0.94, 95% CI 0.56-1.58) were also similar.
- Per-protocol analyses corroborated intention-to-treat results.
Methodological Strengths
- Target trial emulation with nationwide, routinely collected data and competing risk methods (Aalen-Johansen)
- Extensive confounder adjustment (56 variables) with weighting achieving good covariate balance
Limitations
- Observational emulation cannot fully eliminate residual confounding and channeling bias
- Findings from a Danish healthcare setting may limit generalizability to other systems
Future Directions: Head-to-head randomized trials or advanced emulations incorporating additional outcomes (e.g., cardiovascular events) and subgroup analyses by baseline CKD and albuminuria.
IMPORTANCE: No large randomized clinical trial has directly compared empagliflozin with dapagliflozin, leaving their comparative effectiveness regarding kidney outcomes unknown. OBJECTIVE: To compare kidney outcomes between initiation of empagliflozin vs dapagliflozin in adults with type 2 diabetes who were receiving antihyperglycemic treatment. DESIGN, SETTING, AND PARTICIPANTS: This target trial emulation used nationwide, population-based routinely collected Danish health care data to compare initiation of empagliflozin vs dapagliflozin in adults with type 2 diabetes who received antihyperglycemic treatment between June 1, 2014, and October 31, 2020. Data were analyzed from October 2023 to August 2024. Persons were followed up until an outcome, emigration, death, 6 years, or December 31, 2021, whichever occurred first. EXPOSURE: Initiation of empagliflozin vs dapagliflozin. MAIN OUTCOMES AND MEASURES: Outcomes included acute kidney injury, incident chronic kidney disease (stages G3 to G5 or stage A2 or A3), and progression of chronic kidney disease (≥40% decrease in estimated glomerular filtration rate from baseline). Risks of kidney outcomes were estimated in intention-to-treat and per-protocol analyses using an Aalen-Johansen estimator that adjusted for 56 potential confounders and considered death as a competing event. RESULTS: A total of 32 819 individuals who initiated treatment with empagliflozin and 17 464 with dapagliflozin were included (median [IQR] age, 63 [54-71] years; 18 872 female individuals [37.5%]; median [IQR] estimated glomerular filtration rate, 88 [73-104] mL/min/1.73 m2). After weighting, all measured covariates were well balanced between the groups. In intention-to-treat analyses, people who initiated treatment with empagliflozin and dapagliflozin exhibited comparable 6-year risks of acute kidney injury (18.2% vs 18.5%; risk ratio, 0.98; 95% CI, 0.91-1.06), chronic kidney disease stages G3 to G5 (11.8% vs 12.1%; risk ratio, 0.97; 95% CI, 0.89-1.05), chronic kidney disease stage A2 or A3 (14.8% vs 14.3%; risk ratio, 1.04; 95% CI, 0.93-1.15), and progression of chronic kidney disease (5.3% vs 5.7%; risk ratio, 0.94; 95% CI, 0.56-1.58). The primary analyses were supported by corresponding per-protocol analyses. CONCLUSIONS AND RELEVANCE: The results of this cohort study suggest that people with type 2 diabetes who initiated treatment with empagliflozin and dapagliflozin had comparable long-term kidney outcomes.