Daily Endocrinology Research Analysis
Analyzed 83 papers and selected 3 impactful papers.
Summary
Across endocrinology and metabolism, three studies stand out: a massive UK Biobank cohort links steatotic liver disease subtypes and fibrosis severity to cause-specific mortality; a pragmatic randomized trial reveals real-world barriers to initiating dual SGLT2 inhibitor and GLP-1RA therapy; and a multicenter Chinese prospective study shows SGLT2 inhibitors slow kidney function decline compared with other glucose-lowering drugs. Together they refine risk stratification and highlight implementation and renal-protective strategies in diabetes and metabolic liver disease.
Research Themes
- Risk stratification in metabolic dysfunction-associated steatotic liver disease
- Implementation challenges of combination cardiometabolic therapies
- Renal protection with SGLT2 inhibitors in real-world type 2 diabetes care
Selected Articles
1. Unveiling the Burden of Steatotic Liver Disease: Mortality Risks by Subtype and Fibrosis Stage in a Nationwide Cohort.
In nearly half a million UK adults, steatotic liver disease (36.7% prevalence) independently increased all-cause and cause-specific mortality, with heterogeneity by subtype (MASLD, MetALD, ALD) and a strong fibrosis (FIB-4) dose-response. Excess deaths were driven mainly by extrahepatic cancers (42.5%) and cardiovascular disease (24.2%), while liver-related deaths clustered in ALD and higher fibrosis.
Impact: This study delivers robust, population-level risk quantification across SLD subtypes and fibrosis stages, reframing SLD as a systemic condition with major extrahepatic mortality drivers.
Clinical Implications: Integrate oncology and cardiovascular prevention into SLD care, prioritize fibrosis risk stratification (e.g., FIB-4), and target high-risk subgroups (ALD, advanced fibrosis) for intensified surveillance and intervention.
Key Findings
- SLD prevalence was 36.7% (MASLD 73.5%, MetALD 19.0%, ALD 6.4%).
- All-cause mortality increased across subtypes: MASLD HR 1.32 (95% CI 1.29-1.35), MetALD 1.16 (1.12-1.20), ALD 1.36 (1.29-1.44).
- Excess deaths were mainly from extrahepatic cancers (42.5%) and CVD (24.2%); liver-related deaths concentrated in ALD and those with fibrosis.
- FIB-4 showed a strong dose-response with mortality, independent of socioeconomic, lifestyle, and cardiometabolic factors.
Methodological Strengths
- Very large, population-based cohort (n=486,156) with median 13.8 years follow-up
- Multivariable Cox modeling with subtype- and fibrosis-stratified analyses and cause-specific mortality
Limitations
- SLD defined by fatty liver index and fibrosis by FIB-4 (surrogate indices, not imaging/biopsy)
- Observational design cannot infer causality; potential residual confounding and UK Biobank selection bias
Future Directions: Validate findings using imaging/biopsy-based phenotyping, develop integrated risk tools combining metabolic, fibrosis, and cancer risk, and test targeted prevention strategies.
BACKGROUND AND AIMS: We investigated the associations between SLD, fibrosis stage, and all-cause and cause-specific mortality, with a focus on SLD subtypes. METHODS: We analysed 486 156 UK Biobank participants. SLD cases were identified using fatty liver index ≥ 60. Causes of death were confirmed via death registries. Multivariable Cox models estimated associations between SLD, SLD subtypes, FIB4 score and mortality outcomes, including all-cause mortality, mortality from liver-related diseases, cardiovascular disease (CVD) and extrahepatic cancers. RESULTS: SLD was identified in 178 336 participants (36.7%): 73.5% with MASLD, 19.0% with MetALD and 6.4% with ALD. Over a median follow-up of 13.8 years, 20 766 (11.6%) deaths occurred among people with SLD and 21 754 among those without (307 820; 7.1%), suggesting a higher mortality rate in SLD than in non-SLD (8.78 vs. 5.25/1000 person-years). All SLD subtypes were associated with higher all-cause mortality: MASLD (HR (95% CI): 1.32 (1.29-1.35)), MetALD (1.16 (1.12-1.20)) and ALD (1.36 (1.29-1.44)). Excess mortality was primarily driven by extrahepatic cancer (42.5%) and cardiovascular disease (24.2%), while liver-related deaths were concentrated among those with ALD and fibrosis. A strong dose-response relationship was observed between FIB4 stratification and mortality, particularly for liver-related deaths. These associations were independent of socioeconomic status, lifestyle and cardiometabolic risk factors. CONCLUSION: SLD is independently associated with increased all-cause and cause-specific mortality, with substantial variation across subtypes and fibrosis severity. Extrahepatic cancer and cardiovascular disease are the leading contributors to excess mortality. These findings underscore the need for integrated care strategies targeting metabolic risk, fibrosis progression and cancer prevention in the SLD population. In this large population‐based study of nearly half a million adults, 36.7% had SLD, with MASLD being the most common subtype. The leading causes of death in people with SLD were non‐liver cancers and cardiovascular diseases. Having SLD significantly increased the risk of death by 28%, including a 22% higher death risk from cancer, 57% from cardiovascular disease and 136% from liver‐related disease, with risks rising alongside liver fibrosis severity and varying across SLD subtypes.
2. Dual versus monotherapy with SGLT2 inhibitor and GLP-1 receptor agonist:PRECIDENTD pragmatic randomized trial.
In a pragmatic feasibility RCT (n=173) of high-risk T2D patients, prescription fill rates were markedly lower and discontinuation rates higher for dual SGLT2i+GLP-1RA therapy versus monotherapy, with no changes in PROMIS or mKCCQ-12 scores. Side effects were the most common reason for discontinuation.
Impact: Provides real-world, randomized evidence on implementation barriers to cardiometabolic combination therapy, informing policy, coverage, and stepwise initiation strategies.
Clinical Implications: Anticipate lower uptake and higher discontinuation with dual therapy; consider phased initiation, proactive side-effect management, and payer facilitation to enhance persistence.
Key Findings
- At 4 months, fill rates were 84% for monotherapy vs 53% for dual therapy (P<0.001).
- Overall during 10-month median follow-up, fill rates were 87% (monotherapy) vs 68% (dual) (P=0.004).
- Among those who filled, discontinuation occurred in 22% (monotherapy) vs 49% (dual) (P=0.002), mostly due to side effects.
- No changes were observed in PROMIS physical/mental health or mKCCQ-12 scores.
Methodological Strengths
- Pragmatic randomized allocation across three arms in insured real-world settings
- Prespecified patient-reported outcomes alongside initiation and discontinuation metrics
Limitations
- Feasibility phase not powered for clinical outcomes; primary endpoints were fill/discontinuation
- Use of participants' own insurance may limit generalizability and introduce access-related biases
Future Directions: Evaluate clinical endpoints (CV/renal outcomes), test stepwise initiation and adherence-support interventions, and assess cost-effectiveness and coverage policies.
BACKGROUND: Dual therapy with sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) is frequently recommended. We compared rates of medication initiation and discontinuation between participants assigned to treatment with a single medication class or dual therapy in the feasibility phase of the PREvention of CardIovascular and DiabEtic kidNey disease in Type 2 Diabetes (PRECIDENTD) pragmatic trial. METHODS: PRECIDENTD randomly assigned participants with type 2 diabetes (T2D) and ASCVD or high ASCVD risk to fill prescriptions for SGLT2i, GLP-1RA, or dual therapy (1:1:1) using their own insurance. Analyses compared medication fill and discontinuation rates of assigned medication(s), Patient-Reported Outcomes Measurement Information System (PROMIS) Physical and Mental Health Scores, and Modified Kansas City Cardiomyopathy Questionnaire (mKCCQ)-12 between the combined monotherapy (SGLT2i or GLP-1RA) and dual therapy (SGLT2i and GLP-1RA) groups. RESULTS: This report includes 173 insured participants [median age 67 years (IQR 62, 72), 46% female, 35% non-White, 67% with ASCVD]; 113 assigned to monotherapy and 60 to dual therapy. Monotherapy vs. dual therapy fill rates were 84% vs. 53% (P<0.001) 4 months after randomization and 87% vs. 68% overall (P=0.004) during 10-month median follow-up. Of those who filled medication, 22% in monotherapy and 49% in dual therapy discontinued a study medication (P=0.002), mostly due to side effects. PROMIS and mKCCQ-12 scores showed no change. CONCLUSIONS: Despite efforts to facilitate medication uptake in the feasibility phase of the PRECIDENTD pragmatic trial, barriers to initiation and ongoing use challenge the use of combination SGLT2i and GLP-1RA in T2D. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05390892, https://clinicaltrials.gov/study/NCT05390892.
3. Effects of SGLT2 inhibitors on development and progression of kidney disease in Chinese patients with type 2 diabetes: A multicentre, prospective real-world study.
In a multicenter prospective real-world cohort across 45 Chinese hospitals, SGLT2 inhibitor use was associated with a slower 6-month decline in eGFR compared with other glucose-lowering therapies in adults with T2D. Baseline HbA1c averaged 8.33% and eGFR 114.68 mL/min/1.73 m².
Impact: Extends renal-protective evidence for SGLT2 inhibitors to a large Chinese real-world setting, supporting generalizability across populations and routine care.
Clinical Implications: Prefer SGLT2 inhibitors when aiming to slow kidney function decline in T2D; monitor eGFR trajectory over months to assess treatment effect in routine practice.
Key Findings
- Prospective multicenter real-world design across 45 hospitals in China.
- Primary endpoint: 6-month eGFR slope favored SGLT2 inhibitors over other glucose-lowering drugs.
- Baseline mean HbA1c was 8.33% and mean eGFR 114.68 mL/min/1.73 m².
Methodological Strengths
- Prospective observational design with pre-specified renal endpoint (eGFR slope)
- Real-world multicenter enrollment enhances external validity
Limitations
- Non-randomized design susceptible to confounding by indication
- Short follow-up (6 months) limits assessment of hard renal outcomes
Future Directions: Longer-term follow-up with propensity adjustment or randomized comparative effectiveness, subgroup analyses by CKD stage and albuminuria, and evaluation of combined SGLT2i with other renoprotective agents.
AIMS: We aimed to compare renal outcomes between patients with type 2 diabetes mellitus (T2DM) who were treated with sodium-glucose cotransporter 2 (SGLT2) inhibitors and those on other glucose-lowering drugs under routine clinical practice. MATERIALS AND METHODS: IMPROVE was a multicentric, observational, prospective real-world study conducted across 45 hospitals in China. Eligible patients were adults ≥18 years with T2DM for ≥12 months who were currently taking SGLT2 inhibitors or other glucose-lowering drugs. Blood and urine samples were collected at baseline and 6 months. The primary endpoint was the rate of change of eGFR compared with the baseline level after 6 months. RESULTS: The study took place between September 2021 and September 2023. At baseline, mean glycated haemoglobin was 8.33%, and mean eGFR was 114.68 mL/min/1.73 m CONCLUSIONS: In this Chinese real-world study of patients with T2DM, treatment with SGLT2 inhibitors was associated with a slower decline in kidney function compared with other glucose-lowering drugs.