Daily Endocrinology Research Analysis
Analyzed 57 papers and selected 3 impactful papers.
Summary
Analyzed 57 papers and selected 3 impactful articles.
Selected Articles
1. Finerenone in Type 1 Diabetes and Chronic Kidney Disease.
In adults with type 1 diabetes and CKD, finerenone reduced urinary albumin-to-creatinine ratio by 25% more than placebo over 6 months, with a geometric mean ratio of 0.75 versus placebo (P<0.001). Hyperkalemia was the most common adverse event (10.1% vs 3.3%); discontinuation due to hyperkalemia was uncommon (1.7%).
Impact: This is the first phase 3 randomized evidence for finerenone in type 1 diabetes with CKD, extending benefits observed in type 2 diabetes to a high-risk population using a clinically relevant surrogate endpoint.
Clinical Implications: Finerenone may be considered to reduce albuminuria in type 1 diabetes with CKD under careful potassium monitoring, supporting broader MR antagonist use beyond type 2 diabetes while awaiting hard renal outcomes.
Key Findings
- Finerenone reduced UACR by 34% from baseline vs 12% with placebo over 6 months.
- Geometric mean ratio for finerenone vs placebo was 0.75 (95% CI, 0.65–0.87; P<0.001).
- Hyperkalemia occurred in 10.1% (finerenone) vs 3.3% (placebo); 1.7% discontinued due to hyperkalemia.
- Randomized sample size was 242 adults with type 1 diabetes and CKD.
Methodological Strengths
- Phase 3 randomized design with placebo control and central laboratory assessment of UACR.
- Registered trial (ClinicalTrials.gov NCT05901831) enabling transparency and reproducibility.
Limitations
- Primary endpoint was a surrogate (albuminuria) over a relatively short 6-month period.
- Moderate sample size; long-term renal and cardiovascular outcomes are not yet reported.
Future Directions: Evaluate long-term effects of finerenone on eGFR decline, ESKD, and cardiovascular events in type 1 diabetes and identify subgroups by albuminuria and baseline potassium risk.
BACKGROUND: The nonsteroidal mineralocorticoid receptor antagonist finerenone has been reported to improve kidney and cardiovascular outcomes in persons with type 2 diabetes and chronic kidney disease (CKD). The efficacy and safety of finerenone in persons with type 1 diabetes and CKD are unknown. METHODS: We conducted a phase 3 trial involving adults who had type 1 diabetes, CKD (estimated glomerular filtration rate [eGFR], 25 to <90 ml per minute per 1.73 m RESULTS: A total of 242 participants underwent randomization. The median urinary albumin-to-creatinine ratio decreased from 574.6 at baseline to 373.5 at 6 months among all the participants assigned to receive finerenone and from 506.4 to 475.6 among those assigned to receive placebo. Over a period of 6 months, the urinary albumin-to-creatinine ratio decreased by 34% with finerenone (geometric mean ratio to baseline, 0.66; 95% confidence interval [CI], 0.60 to 0.73) and 12% with placebo (geometric mean ratio to baseline, 0.88; 95% CI, 0.79 to 0.98), which corresponded to a 25% greater reduction with finerenone than with placebo (geometric mean ratio for finerenone vs. placebo, 0.75; 95% CI, 0.65 to 0.87; P<0.001). The most common adverse event was hyperkalemia (in 12 participants [10.1%] with finerenone and in 4 [3.3%] with placebo); 2 participants (1.7%) discontinued finerenone because of hyperkalemia. At 6 months, the change in the eGFR was -5.6 ml per minute per 1.73 m CONCLUSIONS: In adults with type 1 diabetes and CKD, finerenone resulted in a significantly greater decrease in the urinary albumin-to-creatinine ratio than placebo. (Funded by Bayer; FINE-ONE ClinicalTrials.gov number, NCT05901831.).
2. Semaglutide Effects on Insulin Sensitivity and β-Cell Function in Patients With Schizophrenia, Prediabetes, and Obesity Treated With Second-Generation Antipsychotics: Findings From the HISTORI Trial, a 30-Week Randomized, Placebo-Controlled Trial With Semaglutide 1.0 mg Weekly.
Over 30 weeks, semaglutide 1.0 mg weekly significantly lowered fasting glucose by 0.87 mmol/L, improved insulin sensitivity, reduced insulin resistance, and induced 9.2 kg mean weight loss versus placebo. Mediation analyses indicate weight loss partially explains metabolic improvements, while β-cell function changes were not significant.
Impact: This double-blind randomized trial addresses a high-need population with antipsychotic-induced metabolic dysfunction, demonstrating clinically meaningful glycemic and weight benefits and mechanistic insight via mediation analyses.
Clinical Implications: Semaglutide can be considered to mitigate antipsychotic-associated metabolic risk in patients with schizophrenia and prediabetes, with weight reduction contributing to improved insulin sensitivity and glycemia.
Key Findings
- Fasting glucose decreased by −0.87 mmol/L versus placebo (P<0.001).
- Insulin sensitivity improved (estimate 8.60; P=0.001) and insulin resistance decreased (−0.69; P=0.006).
- Mean weight loss was 9.2 kg; weight loss partially mediated improvements in insulin sensitivity and resistance (P=0.01 for both).
- β-cell function showed a nonsignificant increase (8.10; P=0.19).
Methodological Strengths
- 30-week double-blind, randomized, placebo-controlled design with high completion (91.5%).
- Prespecified metabolic endpoints with mediation analysis linking weight change to insulin sensitivity.
Limitations
- β-cell function changes were not significant, limiting mechanistic conclusions.
- Population limited to schizophrenia with prediabetes; generalizability to other groups requires study.
Future Directions: Assess durability of benefits, psychiatric symptom interplay, and optimal integration with antipsychotic regimens; evaluate cardiovascular and renal outcomes.
OBJECTIVE: To examine the effects of semaglutide on insulin sensitivity, insulin resistance, and β-cell function and explore whether these changes were mediated by weight loss in overweight or obese individuals with schizophrenia and prediabetes receiving second-generation antipsychotics. RESEARCH DESIGN AND METHODS: In this 30-week, double-blind trial, 154 participants were randomized to semaglutide (n = 77) or placebo (n = 77); 141 (91.5%) completed the study. Baseline and end-of-study assessments included fasting glucose, insulin, C-peptide, HOMA2 of β-cell function, HOMA2 of insulin sensitivity, HOMA of insulin resistance, and body weight. RESULTS: Participants (56% women, mean age 38.3 years) provided complete insulin data in 131 cases. Compared with placebo, semaglutide significantly reduced fasting glucose (-0.87 mmol/L [95% CI -1.15, -0.59]; P < 0.001), improved insulin sensitivity (8.60 [5.82, 13.65]; P = 0.001), and lowered insulin resistance (-0.69 [-1.00, -0.20]; P = 0.006). Mean weight loss was 9.2 kg and mediated improvements in insulin sensitivity (estimate 7.82; P = 0.01) and insulin resistance (estimate -0.75; P = 0.01). Nonsignificant trends were observed toward reduced fasting insulin (-52.3 pmol/L; P = 0.11) and C-peptide (-182.9 pmol/L; P = 0.096), with a modest, nonsignificant increase in β-cell function (8.10; P = 0.19). CONCLUSIONS: Semaglutide significantly improved insulin sensitivity, reduced insulin resistance, lowered fasting glucose, and promoted substantial weight loss in patients with antipsychotic-induced metabolic disturbances. Weight loss partly mediated the metabolic improvements, while β-cell function remained largely unchanged. These findings support semaglutide as a potential strategy for mitigating metabolic dysfunction in this high-risk population.
3. A meta-analysis of smoking and fracture risk to update the FRAX® tool.
Across 58 prospective cohorts (N=1,691,024), current smoking increased risk of clinical, osteoporotic, major osteoporotic, and hip fractures in both sexes, with stronger effects in men (e.g., hip fracture HR 1.78 in men vs 1.64 in women). Lower BMD explained only part (≈19–54%) of excess risk, and past smokers had substantially lower risk than current smokers.
Impact: This analysis provides precise, sex-specific, BMD-adjusted risk estimates for smoking that will directly inform future FRAX iterations, improving global fracture risk prediction.
Clinical Implications: Clinicians should incorporate the elevated fracture risk of current smoking beyond BMD into counseling and risk assessments; cessation likely confers rapid risk reduction, supporting smoking cessation as part of fracture prevention.
Key Findings
- Current smoking increased risk across fracture categories in both sexes; hip fracture HR 1.78 (1.58–2.00) in men and 1.64 (1.50–1.78) in women.
- Low BMD accounted for approximately 19–54% of the smoking-associated risk increase.
- Past smokers had significantly lower fracture risk than current smokers (e.g., men: hip fracture HR 1.08 vs 1.73).
- Analysis pooled 58 prospective cohorts totaling 1,691,024 participants using extended Poisson models.
Methodological Strengths
- Very large pooled sample from 58 prospective cohorts with sex-stratified analyses.
- Use of extended Poisson models with BMD adjustment to quantify BMD-independent risk.
Limitations
- Observational data subject to residual confounding and heterogeneity across cohorts.
- Smoking exposure and changes over time may be misclassified when based on baseline status.
Future Directions: Integrate refined smoking coefficients into FRAX and evaluate calibration across regions; assess interactions with cessation timing and other risk modifiers.
UNLABELLED: In this meta-analysis of international cohorts, current smoking is confirmed as a significant BMD-independent predictor of future fracture with a stronger relationship in men than in women. A causative and reversible effect of smoking on fracture risk is suggested by past smoking having a significantly lower risk than current smoking. PURPOSE: In this meta-analysis of international cohorts, the aim was to examine the relationship of current and past smoking with fracture risk to provide an update for future iterations of the FRAX tool. METHODS: The risk of fracture associated with current and past smoking was estimated using an extended Poisson model applied separately to each of 58 prospective international cohort studies. Covariates included current time since start of follow up, current age, and in an additional model, BMD at the femoral neck. The results of the different studies were merged by using inverse-variance weighted β-coefficients. RESULTS: This analysis included a total of 1,691,024 participants (61.2% women, overall mean age 58.8 years). Current smoking, documented in 12.1% of all participants (15.2% and 10.1% respectively in men and women), was associated with a significantly increased risk of any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and particularly hip fracture in both sexes. The hazard ratio (HR) for fracture was greater in men than in women for all fracture categories [e.g. hip fracture HR (95% confidence interval): 1.78 (1.58-2.00) vs. 1.64 (1.50-1.78)]. Low BMD explained about 19-54% of the increase in risk. When compared with never smoking, past smoking was associated with a significantly lower risk than current smoking [e.g. hip fractures for men, HR in past smokers: 1.08 (1.05-1.12) vs. 1.73, 95%CI (1.46-2.05) in current smokers]. CONCLUSIONS: Our results confirm the association between current smoking and increased fracture risk that is partly independent of BMD; these data will be used to inform future iterations of FRAX.