Daily Cardiology Research Analysis
Three impactful studies span prevention, precision, and policy. A health-economic analysis from EMPA-KIDNEY shows empagliflozin improves QALYs and likely reduces healthcare costs in chronic kidney disease. A large U.S. cohort indicates “weekend warrior” activity lowers cardiovascular and all-cause mortality in adults with diabetes. Mendelian randomization in South Asians identifies protein targets for dyslipidemia/CVD and suggests a weaker PCSK9–LDL-C relationship than in Europeans, informing an
Summary
Three impactful studies span prevention, precision, and policy. A health-economic analysis from EMPA-KIDNEY shows empagliflozin improves QALYs and likely reduces healthcare costs in chronic kidney disease. A large U.S. cohort indicates “weekend warrior” activity lowers cardiovascular and all-cause mortality in adults with diabetes. Mendelian randomization in South Asians identifies protein targets for dyslipidemia/CVD and suggests a weaker PCSK9–LDL-C relationship than in Europeans, informing ancestry-tailored prevention.
Research Themes
- Cost-effectiveness and QALY impact of SGLT2 inhibitors in CKD
- Physical activity patterns and mortality risk in diabetes
- Ancestry-specific protein targets for dyslipidemia/CVD via Mendelian randomization
Selected Articles
1. Effects of empagliflozin on quality of life and healthcare use and costs in chronic kidney disease: a health economic analysis of the EMPA-KIDNEY trial.
Using randomized trial data with post-trial follow-up, empagliflozin improved QALYs by 0.012 over 2 years and reduced hospital, concomitant medication, and ESKD costs, yielding net healthcare savings over 4 years. The probability of cost-effectiveness at a £20K/QALY threshold rose to 91% by 4 years, with consistent effects across eGFR, albuminuria, and diabetes subgroups.
Impact: Trial-based economic evidence can accelerate implementation of SGLT2 inhibitors in CKD by demonstrating QALY gains and budget impact, directly informing payers and guideline bodies.
Clinical Implications: Supports broader, earlier use of empagliflozin in CKD for both clinical benefit and cost-effectiveness; payers may anticipate reduced hospitalization and ESKD expenditures within 2–4 years.
Key Findings
- QALYs increased by 0.012 per participant over 2 years with empagliflozin versus placebo.
- Healthcare costs decreased for admissions (−£239), concomitant medications (−£130), and ESKD management (−£208) over 2 years.
- Additional ESKD cost savings (−£842) accrued during 2-year post-trial follow-up, with net 4-year healthcare cost −£593.
- Probability of cost-effectiveness at £20K/QALY was 43% over 2 years and 91% over 4 years.
Methodological Strengths
- Randomized, double-blind, placebo-controlled base trial with large, multinational sample
- Detailed micro-costing and post-trial follow-up capturing downstream ESKD costs
Limitations
- Relatively short active treatment and overall follow-up may underestimate long-term cost-effectiveness
- Costs are UK-specific; generalizability to other health systems requires adaptation
Future Directions: Model longer horizons, country-specific costing, and broader CKD phenotypes; evaluate integration with heart failure prevention and health equity impacts.
BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) slow progression of chronic kidney disease (CKD) but there is no randomised evidence of their effects on health-related quality of life (QoL) and healthcare use. We explored the effects of empagliflozin on health-related QoL, healthcare use and UK healthcare costs in the EMPA-KIDNEY trial. METHODS: EMPA-KIDNEY, a randomised, double blind, placebo-controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA), and included participants aged 18 years or older with an estimated glomerular filtration rate (eGFR) of 20 to <45 mL/min/1.73 m FINDINGS: Between May 15, 2019 and April 16, 2021, 6609 participants were randomly assigned to empagliflozin (3304 participants) or matching placebo (3305 participants) in the active-trial which lasted for a median of 2.0 years. Among them, 4891 (74%) were enrolled in the post-trial follow-up. Per participant allocated to empagliflozin over 2 years, total empagliflozin cost was £826 (95% confidence interval: 818 to 835), QALYs were 0.012 higher (0.001 to 0.022), with less cost for hospital admission (-£239, -449 to -29), concomitant medications (-£130, -214 to -47), and management of ESKD (-£208, -414 to -2) compared to placebo. Over a further 2 years of post-trial follow-up off study treatment, there were additional per participant ESKD cost savings (-£842, -1441 to -242), resulting in net total healthcare cost of -£593 (-1384 to 198) over 4 years. The probability of 2 years of empagliflozin treatment being cost-effective at £20 K threshold in the UK was 43% over 2 years of follow-up and 91% over 4 years. The relative effects of empagliflozin on each cost component were similar across categories by baseline levels of eGFR, uACR and diabetes status, with larger reductions in healthcare costs estimated in categories at higher risk of CKD progression. INTERPRETATION: In EMPA-KIDNEY, 2 years treatment with empagliflozin improved QALYs, and reduced use and cost of other healthcare, resulting in high likelihood of cost-effectiveness across a broad range of patients with CKD. The study's key limitation is its relatively short active treatment period and follow-up duration, which may lead to underestimation of the cost-effectiveness of long-term SGLT2i treatment in CKD. FUNDING: Boehringer Ingelheim, Germany; Eli Lilly, USA; Medical Research Council, UK; British Heart Foundation, UK; Health Data Research, UK; National Institute for Health and Care Research, UK.
2. Association of Weekend Warrior and Other Physical Activity Patterns With Mortality Among Adults With Diabetes : A Cohort Study.
Among 51,650 U.S. adults with diabetes followed for 9.5 years, meeting MVPA ≥150 min/week as a weekend warrior or via regular sessions was linked to lower all-cause mortality (HR 0.79 and 0.83, respectively) and reduced cardiovascular mortality (HR 0.67 and 0.81). Insufficiently active individuals had modest benefits; cancer mortality differences were smaller.
Impact: Provides robust, diabetes-specific evidence that accumulating MVPA in 1–2 sessions per week confers mortality benefits comparable to regular distribution, improving feasibility for busy patients.
Clinical Implications: Counseling can emphasize flexibility: patients with diabetes may achieve mortality benefits by concentrating MVPA into 1–2 weekly sessions if regular distribution is impractical.
Key Findings
- Weekend warriors (MVPA ≥150 min/week in 1–2 sessions) had HR 0.79 for all-cause mortality versus inactive peers.
- Cardiovascular mortality was markedly reduced in weekend warriors (HR 0.67) and regularly active (HR 0.81) groups.
- Insufficiently active participants showed smaller or nonsignificant cardiovascular mortality benefits (HR 0.98).
- Cancer mortality differences were modest across activity patterns.
Methodological Strengths
- Large, nationally representative cohort with long median follow-up (9.5 years)
- Clear operationalization of activity patterns and multivariable adjustment
Limitations
- Physical activity was self-reported at one time point, risking misclassification
- Residual confounding is possible in observational design
Future Directions: Use device-based activity tracking and repeated measures; test interventions leveraging weekend-focused programs in diabetes care.
BACKGROUND: "Weekend warrior" and regularly active physical activity patterns have been associated with reduced mortality risk in the general population. The association in patients with diabetes is unknown. OBJECTIVE: To examine the associations of different physical activity patterns, particularly weekend warrior and regularly active behavior, with all-cause, cardiovascular, and cancer mortality among adults with diabetes. DESIGN: Prospective cohort study. SETTING: National Health Interview Survey (1997 to 2018) linked to the National Death Index records through 31 December 2019. PARTICIPANTS: 51 650 U.S. adults with self-reported diabetes. MEASUREMENTS: Participants categorized by 4 physical activity groups: inactive (reporting no moderate-to-vigorous physical activity [MVPA]), insufficiently active (MVPA <150 minutes per week), weekend warrior (MVPA ≥150 minutes per week in 1 to 2 sessions), and regularly active (MVPA ≥150 minutes per week in ≥3 sessions). RESULTS: During a median follow-up of 9.5 years, 16 345 deaths (cardiovascular, 5620; cancer, 2883) were documented. Compared with inactive participants, multivariable-adjusted hazard ratios (HRs) for all-cause mortality were significantly lower across physical activity groups: insufficiently active persons (HR, 0.90 [95% CI, 0.85 to 0.95]), weekend warriors (HR, 0.79 [CI, 0.69 to 0.91]), and regularly active persons (HR, 0.83 [CI, 0.78 to 0.87]). These reductions were mostly due to benefits with cardiovascular mortality: insufficiently active persons (HR, 0.98 [CI, 0.89 to 1.07]), weekend warriors (HR, 0.67 [CI, 0.52 to 0.86]), and regularly active persons (HR, 0.81 [CI, 0.74 to 0.88]). There were fewer differences by cancer mortality: insufficiently active persons (HR, 0.88 [CI, 0.78 to 1.00]), weekend warriors (HR, 0.99 [CI, 0.76 to 1.30]), and regularly active persons (HR, 0.85 [CI, 0.75 to 0.96]). LIMITATION: Physical activity was self-reported and assessed at a single time point. CONCLUSION: Weekend warrior and regularly active physical activity patterns meeting current physical activity recommendations (MVPA ≥150 minutes per week) were associated with 21% and 17% lower risks for all-cause mortality and 33% and 19% lower hazards of cardiovascular mortality among adults with diabetes compared with those with diabetes who are physically inactive. PRIMARY FUNDING SOURCE: Capital's Funds for Health Improvement and Research, and National Natural Science Foundation of China.
3. Identification of protein targets for dyslipidaemia and cardiovascular diseases among people with South Asian ancestry: a mendelian randomisation study.
Two-sample MR and colocalization across 2,800 plasma proteins identified several causal targets for lipid traits and CVD in South Asians, including CELSR2, ANGPTL3, LPA, and PCSK9. PCSK9’s genetic effect on LDL-C was substantially weaker in South Asians (β 0.16) than Europeans (β 0.37), highlighting ancestry-specific biology relevant to lipid-lowering strategies.
Impact: Defines ancestry-specific therapeutic targets and cautions against extrapolating European-derived pharmacogenetic expectations (e.g., PCSK9 inhibition magnitude) to South Asians.
Clinical Implications: Precision prevention and lipid-lowering strategies in South Asians may require tailored choices (e.g., prioritizing ANGPTL3/LPA pathways or combined approaches) and careful evaluation of PCSK9 inhibitor benefit.
Key Findings
- Identified 29 proteins with putative causal effects on lipid traits; 12 had strong colocalization/GMR support (e.g., ANGPTL3, PCSK9, CELSR2).
- PCSK9 effect on LDL-C: Europeans β=0.37 (95% CI 0.36–0.38) vs South Asians β=0.16 (0.11–0.21), with significant interaction.
- CELSR2 implicated in coronary artery disease in South Asians.
- Findings support ancestry-specific targets for dyslipidaemia and CVD prevention.
Methodological Strengths
- Robust two-sample MR with sensitivity analyses (MR-Egger, weighted median) and colocalization
- Ancestry-stratified comparisons between South Asian and European datasets
Limitations
- Limited South Asian GWAS sample sizes may reduce instrument strength
- MR assumptions (e.g., no horizontal pleiotropy) may not fully hold despite sensitivity analyses
Future Directions: Larger South Asian proteomic/GWAS datasets; pharmacogenetic studies testing PCSK9 and ANGPTL3 modulation; clinical trials powered for ancestry-specific efficacy.
BACKGROUND: South Asians are considered to be at higher risk of dyslipidaemia, a modifiable risk factor for cardiovascular diseases (CVDs). We aimed to identify protein targets for dyslipidaemia and CVDs among people with South Asian ancestry. METHODS: We used a two-sample mendelian randomisation (MR) approach, supplemented with MR-Egger, weighted median, colocalisation, and generalised MR (GMR), to evaluate the effect of 2800 plasma proteins on high/low/non-high-density lipoprotein cholesterol (HDL-C/LDL-C/non-HDL-C), total cholesterol, and triglycerides. Observational analyses were conducted on MR findings with strong colocalisation (posterior probability ≥ 80%) and GMR evidence. Univariate MR assessed lipid-associated proteins' effect on CVDs. Finally, we compared the effects of plasma proteins on lipids between South Asian and European populations. FINDINGS: We identified 29 genetically proxied proteins potentially causal to at least one lipid measure, 12 of which showed strong colocalisation and GMR evidence, including angiopoietin-related protein 3 (ANGPTL3), proprotein convertase subtilisin/kexin type 9 (PCSK9), and cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2). Notably, PCSK9 demonstrated a stronger association with LDL-C in Europeans compared to South Asians (βEuropean = 0.37; 95% CI 0.36, 0.38, βSouth Asian = 0.16; 95% CI 0.11, 0.21). Observational analysis suggested statistically significant interaction between PCSK9 levels with LDL-C levels in South Asians with South Asians having a significantly lower effect compared to other ethnicities (PCSK9∗South Asian; β = -0.14; 95% CI -0.174, -0.107). Additionally, we showed that CELSR2 is also linked with coronary artery disease in South Asians. INTERPRETATION: Our study highlighted potential causal links between plasma proteins, dyslipidaemia, and CVDs in South Asians and highlighted protein targets, including CELSR2, PCSK9, ANGPTL3, and Apolipoprotein(a) (LPA). Notably, our study indicated that PCSK9 has a significantly weaker effect on LDL-C in South Asians than Europeans. FUNDING: This work is supported by the British Heart Foundation Research Excellence Award (4) (RE/24/130023). IT and AR are supported by NIHR01 HL162300-02.