Background: Cardiovascular-kidney-metabolic (CKM) syndrome has emerged as a major clinical challenge, yet longitudinal evidence characterizing stage-specific adverse outcomes in Asian populations remains scarce.

Objectives: To evaluate the associations between CKM stage and the risks of metabolic, cardiovascular, renal, hepatic, and mortality outcomes.

Methods: We conducted a retrospective cohort study using individually linked data from the Taiwan Biobank and the National Health Insurance Research Database (2009–2021). CKM stages (0–4) were defined per the American Heart Association advisory, and incident outcomes spanned three domains: metabolic progression (hypertension, chronic kidney disease [CKD], diabetes, hyperlipidemia); major clinical events (three-point major adverse cardiovascular events [3P-MACE], heart failure, renal and hepatic endpoints); and all-cause mortality. Multivariable Cox proportional hazards models estimated hazard ratios (HRs), referenced to stage 0, with adjustment for demographics, comorbidity burden, and established risk factors. In addition, Fine–Gray subdistribution hazard models addressed the competing risk of death.

Results: Among 153,591 participants, 28,191 (18.4%) were stage 0, 35,882 (23.4%) stage 1, 61,980 (40.4%) stage 2, 20,859 (13.6%) stage 3, and 6,679 (4.3%) stage 4. Mean age rose progressively from 43.1 years at stage 0 to 59.1 years at stage 4. Higher stage was consistently associated with graded increases in risk. Relative to stage 0, stage 2 conferred elevated risks of hypertension (HR 6.53, 95% CI 6.07–7.02), diabetes (HR 7.41, 6.60–8.32), and hyperlipidemia (HR 2.39, 2.29–2.54). At stage 4, risks were markedly higher for 3P-MACE (HR 4.66, 3.31–6.56), acute myocardial infarction (HR 7.56, 4.26–13.41), advanced CKD (HR 11.42, 6.85–19.03), fatty liver disease (HR 4.04, 3.45–4.73), and all-cause mortality (HR 2.07, 1.62–2.65). Competing-risk analyses yielded consistent estimates.

Conclusions: Advancing CKM stage was associated with graded increases in metabolic, cardiovascular, renal, hepatic, and mortality risks. CKM staging may therefore facilitate risk stratification and stage-targeted intervention.

Introduction:
Hospitalization for acute decompensated heart failure (ADHF) identifies a vulnerable period characterized by high risks of mortality and heart failure (HF) readmission. Although guideline-directed medical therapies improve outcomes, many real-world patients lack foundational renin–angiotensin system inhibitors (RASi) and beta-blockers. Whether early sodium-glucose cotransporter-2 inhibitor (SGLT2i) initiation improves outcomes among ADHF patients lacking sustained dual therapy remains uncertain.

Aims:
This study emulated a target trial to evaluate the clinical impact of early post-discharge SGLT2i initiation versus non-use among ADHF patients lacking prior sustained dual RASi and beta-blocker therapy.

Methods:
Using a nationwide healthcare database (2018-2021), we identified patients newly hospitalized for ADHF with ischemic, hypertensive, or cardiomyopathic etiologies. We excluded patients with acute cardiovascular events within 90 days prior, confounding cardiac conditions, end-stage renal disease, type 1 diabetes, prior SGLT2i exposure, or at least 6 months of concomitant RASi and beta-blocker use before admission. Early SGLT2i initiation was defined as prescription within 90 days post-discharge with continued exposure at the 91-day landmark. Propensity score matching was used to balance baseline demographics, medications, comorbidities, healthcare utilization and frailty index. All-cause mortality was analyzed using Cox models and HF rehospitalization using Fine-Gray models.

Results:
Among 28,797 eligible patients, 1,036 SGLT2i initiators were matched to 4,026 non-users. Over a median follow-up of 36 months, SGLT2i initiation in the per-protocol analysis was significantly associated with a lower risk of all-cause mortality (HR=0.73, 95% CI: 0.60–0.89) and a lower risk of HF rehospitalization (subdistribution HR [sHR]=0.80, 95% CI: 0.67–0.97).

Conclusions:
In hospitalized ADHF patients lacking prior sustained dual RASi and beta-blocker therapy, early post-discharge SGLT2i initiation was significantly associated with lower mortality and reduced HF rehospitalization. These real-world findings support prioritizating SGLT2i during the high-risk post-ADHF period, even in the absence of foundational dual therapy.

Keywords: SGLT2 inhibitor, Target trial emulation, Acute Heart failure

Introduction: Many patients with atherosclerotic cardiovascular disease (ASCVD) require treatment intensification beyond moderate-intensity statin (MIS) monotherapy to achieve guideline-recommended low-density lipoprotein cholesterol (LDL-C) targets. However, real-world patterns and comparative effectiveness of alternative intensification strategies remain underdetermined.

Aims: To characterize patients undergoing treatment intensification with high-intensity statin (HIS) versus ezetimibe add-on therapy (MIS+EZE) and emulate a target trial comparing their risk of major adverse cardiovascular events (MACE).

Methods: Using a national claims database (2014-2024), we identified adults aged 18 to 80 years with ASCVD who intensified treatment with HIS or MIS+EZE after at least 4 weeks of newly initiated MIS monotherapy. The primary outcome was MACE, defined as all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke. Follow-up began 30 days after intensification to mitigate protopathic bias. Inverse probability of treatment weighting (IPTW) was used to balance baseline characteristics and weighted Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: Among 166,230 patients with ASCVD who initiated MIS monotherapy, 22,727 (14.2%) subsequently underwent intensification. The mean age was 63 years, and 62.9% were male. Compared with HIS users (43.5%), MIS+EZE users (56.5%) had a longer median time to intensification (887 vs. 831 days) and a lower burden of cardiovascular, metabolic, and renal comorbidities (all p<0.001). After IPTW adjustment, MIS+EZE was associated with a lower risk of MACE than HIS during a median follow-up of 3.2 years (HR 0.72, 95% CI 0.65-0.79).

Conclusions: Treatment intensification was uncommon among patients with ASCVD receiving MIS monotherapy, suggesting potential clinical inertia in lipid management. Compared with switching to HIS, intensification with MIS+EZE was associated with a lower risk of MACE. Further studies incorporating LDL-C measurements are needed to assess whether differences in lipid control or residual confounding contributed to this association.

Keywords: Atherosclerotic cardiovascular disease; Major adverse cardiovascular events; Treatment intensification

Background
Despite their widespread use and efficacy in cardiovascular prevention, statins show considerable inter-individual variability in LDL-C response. CPIC-justified PGx variants may explain part of this variability through pharmacokinetic and pharmacodynamic mechanisms, but longitudinal real-world evidence is limited.

Objectives
To examine associations between 14 CPIC-justified PGx variants and absolute on-statin LDL-C, statin LDL-C lowering response, and SNP × statin-type interactions in a large UK primary care longitudinal cohort.

Methods
20,808 statin users in UK Biobank primary care were included with median age 62 years and 58% male. Three lmer model families: (a) = absolute on-statin log(LDL-C); (b) = per-visit delta LDL-C from pre-statin baseline; (c) = SNP × statin-type interaction were constructed. All adjusted for age, sex, BMI, smoking, deprivation, diabetes, hypertension, chip, PC1–10. FDR correction was done within each model.

Results
Nine SNPs predict absolute on-statin LDL-C (a): APOE rs7412 (+23.4% per allele), PCSK9 rs11591147 (+15.8%), LPA rs10455872 (−7.3%), SORT1 rs646776 (+5.6%), HMGCR rs3846662, PCSK9 rs11206510, CETP rs708272, CYP7A1 rs2073547, and SLCO1B1*5 rs4149056. These are dominantly pharmacodynamic variants influencing ambient LDL-C rather than statin response per se.
Four SNPs predict the LDL-C lowering response itself (b): APOE rs7412, LPA rs10455872, CYP3A5*3 rs776746, and CYP3A4*22 rs35599367. Notably, the two CYP variants are pharmacokinetic, and their appearance here but not in (a) is mechanistically coherent.
No interaction survived FDR in (c), though directional patterns in the focus pairs (SLCO1B1*5 × simvastatin, CYP3A4*22 × atorvastatin) are consistent with CPIC predictions. The limited rosuvastatin sample (n = 285) constrained power for that arm.

Conclusions
PGx variants: APOE, LPA, PCSK9, and SORT1 robustly predict on-statin LDL-C, and CYP3A5 and CYP3A4 predict statin LDL-C response in longitudinal primary care data. Larger statin-stratified studies are required to confirm pharmacogenomic interactions, particularly for rosuvastatin and pravastatin.

Keywords
pharmacogenomics; statins; LDL cholesterol;

Introduction: The prevalence of and risk factors for suboptimal low-density lipoprotein cholesterol (LDL-C) response to proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) remain unclear.
Aims: To determine the prevalence of and risk factors for suboptimal LDL-C response to PCSK9i.
Methods: We conducted a cohort study using electronic health records from the Hong Kong Hospital Authority. A total of 2899 patients initiating alirocumab, evolocumab, or inclisiran between 1 August 2016 and 31 December 2024 were followed through to 31 December 2025. The primary outcome was the prevalence of one-year suboptimal response, defined as <30% LDL-C reduction from baseline. Risk factors were identified using multivariable logistic regression, and population attributable fractions (PAFs) were estimated to quantify their contribution to suboptimal response.
Results: Overall, 33.4% (95% CI, 31.7–35.1) of PCSK9i users experienced suboptimal LDL-C response. Female sex (odds ratio [OR], 1.37; 95% CI, 1.12–1.67), ischemic stroke (OR, 1.53; 95% CI, 1.12–2.07), and familial hypercholesterolemia were associated with higher odds of suboptimal response. Older age (OR per year, 0.99; 95% CI, 0.98–1.00), higher baseline LDL‑C (OR per mmol/L, 0.49; 95% CI, 0.45–0.53), hypertension (OR, 0.65; 95% CI, 0.50–0.84), liver disease (OR, 0.65; 95% CI, 0.46–0.91), adherent statin and ezetimibe use (OR, 0.54; 95% CI, 0.41–0.70), and adherent statin use (OR, 0.57; 95% CI, 0.43–0.74) were associated with lower odds. A significant interaction was observed between PCSK9i type and adherence trajectory. The largest PAFs were joint non-evolocumab use and partial adherence (23.96%; 95% CI, 18.64–28.82), absence of adherent statin use (21.42%; 95% CI, 13.98–28.23) and partial adherence to PCSK9i alone (16.78%; 95% CI, 14.46–19.32).
Conclusions: Suboptimal LDL-C response to PCSK9i is common in clinical practice, with poor PCSK9i adherence and the absence of statin use being the primary modifiable contributors.
Keywords: PCSK9i; Interindividual response; Medication adherence

Introduction: Gabapentinoids are prescribed for neuropathic pain and other chronic conditions, particularly among older adults. Concerns remain regarding cardiovascular safety, including fluid retention and worsening heart failure. Evidence on the acute association between gabapentinoid use and heart failure is limited. Within-person designs can help account for time-invariant confounding.

Aims: To assess whether gabapentinoid use is associated with increased risk of heart failure. We further examined robustness across sensitivity analyses and clinically relevant subgroups.

Methods: We conducted case-crossover and case-case-time-control analyses using UK CPRD database linked to hospitalisation and mortality records. Adults aged ≥18 years with a first-ever heart failure event were included and patients with cancer were excluded. Gabapentinoid exposure during a 30-day hazard window before the event was compared with exposure during a randomly selected 30-day reference window between days -180 and -61. In the case-case-time-control analysis, current cases were matched 1:1 with future cases by sex, age, ethnicity and socioeconomic status, and conditional logistic regression estimated odds ratios adjusted for time-varying co-medications.

Results: The case-crossover analysis included 31,794 heart failure events and showed an increased odds of gabapentinoid exposure before heart failure (OR, 1.71; 95% CI, 1.60–1.82). In the case-case-time-control analysis, 18,838 current cases were matched to future cases. Gabapentinoid use remained associated with increased risk of heart failure (1.29, 1.14–1.46). Results of subgroup analyses are generally consistent with the main analysis. Estimates were also similar after alternative co-medication adjustment and remained elevated in analyses using different windows, washout periods, lag periods and future-case definitions.

Conclusions: Gabapentinoid use was associated with increased risk of heart failure across complementary within-person designs. Baseline cardiovascular vulnerability should be considered when initiating gabapentinoids, particularly in older adults and patients with hypertension.

Keywords: Gabapentinoids; heart failure; within individual study