Tirzepatide In Patients with Heart Failure with Preserved Ejection Fraction, Obesity, and Chronic Kidney Disease: The Summit Trial
Speaker: Dr. Milton Packer
Key Highlights
Introduction:
Heart failure with preserved ejection fraction (HFpEF), obesity, and chronic kidney disease (CKD) are frequently found to coexist, forming a high-risk clinical triad that affects millions. Poor outcomes, including frequent heart failure events and accelerated renal decline, are experienced by patients with this "cardiorenal metabolic" phenotype. The efficacy of tirzepatide (a dual GLP-1/GIP agonist) in improving cardiovascular and renal outcomes in this population was investigated in the SUMMIT trial.
Aim:
The efficacy of tirzepatide in reducing cardiovascular death and worsening heart failure events was evaluated in patients with HFpEF, obesity, and CKD, while its impact on kidney function was assessed using both creatinine- and cystatin C-based eGFR measurements.
Methods:
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Design: A randomized, placebo-controlled trial was conducted.
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Population: Patients with HFpEF (EF ≥50%), BMI ≥30 kg/m², and eGFR <70 mL/min/1.73m² were enrolled to enrich for events.
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Intervention: Tirzepatide (up to 15 mg/week) was compared with placebo over a median follow-up of 104 weeks.
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Primary Endpoint: A composite of cardiovascular death and worsening HF events was used.
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Secondary Analyses:
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Kidney function was assessed via creatinine- and cystatin C-based eGFR.
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Subgroup comparisons were performed based on CKD status.
Results:
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Clinical Outcomes:
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Cardiovascular death and HF events were reduced by tirzepatide consistently across CKD subgroups. Greater absolute risk reduction was observed in CKD patients due to their higher baseline risk.
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Renal Function:
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An improvement in cystatin C-based eGFR was seen in all patients, likely attributed to reduced adipocyte-derived cystatin C. Creatinine-based eGFR was improved only in CKD patients, suggesting a true renal benefit independent of weight loss. CKD prevalence was found to vary by biomarker: 54% (creatinine-based eGFR <60) vs. 61% (cystatin C-based eGFR <60).
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Mechanistic Insights:
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The benefits were not fully explained by reduced diuretic use, supporting the possibility of direct renal effects of tirzepatide. No safety concerns were identified, though caution was advised in HF with reduced EF (HFrEF) due to theoretical risks.
Conclusion:
Significant cardiovascular and renal benefits were demonstrated by tirzepatide in patients with HFpEF, obesity, and CKD. However, the interpretation of kidney function must account for obesity-related biases in eGFR measurements. While cystatin C was found to overestimate CKD prevalence in obesity, improvements in creatinine-based eGFR in CKD patients suggest a true renal protective effect. These findings highlight the need for tailored biomarker use and further research in HFrEF populations. Tirzepatide is considered a promising therapy for high-risk HFpEF with obesity and CKD, but renal assessment requires nuanced interpretation based on adiposity and biomarker selection.
Effect Of Colchicine on Progression of Known Coronary Atherosclerosis in Patients with Stable Coronary Artery Disease Compared to Placebo - Ekstrom Trial
Speaker: Dr. Matthew J. Budoff
Key Highlights
Introduction:
The role of anti-inflammatory therapy in atherosclerosis has been debated, with previous trials showing mixed results for colchicine. The XTRM trial was conducted to evaluate the effect of colchicine 0.5 mg/day on coronary plaque progression in patients with stable coronary artery disease (CAD) using CT angiography (CTA).
Aim:
The efficacy of colchicine in reducing low attenuation plaque (LAP) volume and total plaque atheroma volume (PAV) was assessed over one year in patients with stable CAD, with additional evaluation of its impact on inflammatory markers and plaque composition.
Methods:
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Design: A randomized, placebo-controlled, double-blind study was performed.
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Population: 84 patients with angiographically confirmed stable CAD were enrolled (42 per arm).
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Inclusion Criteria: Stable CAD on optimal medical therapy, no recent acute coronary syndrome (ACS).
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Exclusion Criteria: Advanced renal disease (due to contrast requirements).
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Intervention: Colchicine 0.5 mg/day or placebo was administered for one year.
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Imaging: CTA was performed at baseline and one year to assess plaque changes.
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Primary Endpoint: Change in LAP volume.
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Secondary Endpoints: Change in total PAV, plaque subtypes, and hs-CRP levels.
Results:
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Plaque Volume Changes: No significant difference in LAP volume was observed, likely due to low baseline levels in this stable cohort. Total plaque volume progression was reduced by 1.1% with colchicine compared to placebo.
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Plaque Composition: Non-calcified, fibrofatty, and fibrous plaques trended towards regression, though not statistically significant. Dense calcified plaque progression was attenuated, suggesting plaque stabilisation.
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Inflammatory Markers: hs-CRP levels were significantly reduced with colchicine. Plaque reduction was independent of CRP changes, indicating possible alternative mechanisms.
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Background Therapy: Nearly all patients were on high-intensity statins, with no significant LDL differences between groups. Colchicine’s benefits appeared additive to statin therapy.
Conclusion:
A significant reduction in total plaque volume progression was demonstrated with colchicine in stable CAD patients despite no change in LAP. The attenuation of dense calcified plaque and reduction in hs-CRP suggest anti-inflammatory and plaque-stabilising effects. These benefits were observed independently of statin therapy, supporting colchicine’s potential role in atherosclerosis management. Further studies in higher-risk or inflamed populations are needed to confirm these findings. Colchicine may slow atherosclerosis progression in stable CAD, but its impact on vulnerable plaque requires investigation in higher-risk cohorts.
Effects of Dapagliflozin on Echocardiographic Measures of Cardiac Structure and Function in Patients with Chronic Kidney Disease: The DECODE-CKD
Speaker: Dr. Katja Vu Bartholdy
Key Highlights
Introduction:
Cardiac remodeling, particularly left ventricular hypertrophy (LVH), is commonly observed in chronic kidney disease (CKD) and is associated with adverse cardiovascular outcomes. While SGLT2 inhibitors like dapagliflozin have demonstrated cardiovascular and renal benefits in CKD populations, their specific effects on cardiac structure and function remain unclear. The DECODE-CKD trial was conducted to evaluate the impact of dapagliflozin on echocardiographic parameters in patients with CKD.
Aim:
The primary objective was to assess whether dapagliflozin could improve cardiac remodeling by reducing left ventricular mass index (LVMI) over six months in CKD patients, while secondary objectives included the evaluation of cardiac function, biomarkers, and renal parameters.
Methods:
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Design: A double-blind, randomized, placebo-controlled, single-center study
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Participants: 222 adults with CKD (eGFR 20-60 mL/min/1.73m² or eGFR >60 with UACR ≥200 mg/g)
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Intervention: Dapagliflozin 10 mg daily versus placebo for six months
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Assessments: Echocardiography (LVMI, ejection fraction, global longitudinal strain), Biomarkers (NT-proBNP, troponin), Renal function (eGFR, UACR), Hematologic parameters (hemoglobin)
Results:
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Cardiac Structure: Significant reduction in LVMI observed with dapagliflozin (-8.44 g/m² vs placebo). Absolute left ventricular mass decreased by 17.5 g in the treatment group. Benefits are consistent across all subgroups regardless of baseline characteristics
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Cardiac Function: No significant changes in ejection fraction or global longitudinal strain. NT-proBNP and troponin levels remained unchanged.
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Renal and Hematologic Effects: Expected initial eGFR dip observed. Hemoglobin levels significantly increased. No significant change in UACR
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Mechanistic Findings: Greater eGFR reductions correlated with greater LVMI improvements. Effects independent of albuminuria status or baseline cardiac function
Conclusion:
A significant reduction in left ventricular mass was observed with dapagliflozin treatment in CKD patients over six months, demonstrating that beneficial effects on cardiac remodeling were achieved. These structural improvements were noted without significant changes in systolic function or cardiac biomarkers. The cardioprotective potential of SGLT2 inhibitors in CKD, even in patients without overt heart failure, was supported by the results. A possible hemodynamic mechanism underlying these benefits was suggested by the correlation between early eGFR changes and LVMI reduction. The value of early intervention in CKD patients to mitigate cardiovascular risk through structural cardiac improvements was reinforced by these findings.
Clinical Implications:
A mechanistic rationale for the use of SGLT2 inhibitors in CKD management, particularly for addressing subclinical cardiac remodeling, is provided by the study. Further research is warranted to explore long-term clinical outcomes and potential applications in more advanced CKD populations.
Effect of Solbinsiran, a Small Interfering RNA Targeting ANGPTL3, on Biomarkers of Major Adverse Cardiovascular Events in Adults with Mixed Dyslipidemia: A Randomized Phase 2 Trial
Speaker: Dr. Kausik K. Ray
Key Highlights
Introduction:
Mixed dyslipidemia, characterized by elevated triglycerides and residual non-HDL cholesterol, is considered a therapeutic challenge due to limited treatment options. ANGPTL3 (angiopoietin-like 3), which is known to inhibit lipoprotein lipase and endothelial lipase, has been identified as a potential target, with its loss-of-function mutations being associated with reduced cardiovascular disease risk. Solbinsiran, a GalNAc-conjugated siRNA targeting ANGPTL3, was developed to explore this pathway.
Aim:
The efficacy of solbinsiran was evaluated for reducing atherogenic lipoproteins and biomarkers of cardiovascular risk in adults with mixed dyslipidemia. The assessment of hepatic fat reduction, safety profile, and optimal dosing strategy were included as secondary objectives.
Methods:
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A phase 2, randomized, placebo-controlled, multicenter trial was conducted
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Enrollment of 205 adults with mixed dyslipidemia (TG 150-499 mg/dL, LDL-C >70 mg/dL, non-HDL-C >130 mg/dL) was completed
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Randomization to receive 100 mg, 400 mg, or 800 mg solbinsiran or placebo was performed via subcutaneous injection on day 1 and day 90
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Primary endpoints were assessed at day 180, with extended follow-up being conducted to day 270
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Measurements of lipid parameters, ANGPTL3 levels, hepatic fat content (by MRI-PDFF), and safety outcomes were taken
Results:
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Lipid Effects: Significant reductions in ApoB (-14.3%), triglycerides (-50%), VLDL-C (-50%), LDL-C (-16.8%), and non-HDL-C (-25.5%) were observed with the 400 mg dose. HDL-C was reduced by 16.4%, which was consistent with genetic expectations. The 400 mg dose was identified as optimal, with no additional benefit being shown at higher doses
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ANGPTL3 Suppression: Approximately 70% reduction in ANGPTL3 levels was maintained through day 270
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Hepatic Effects: A 27.6% placebo-corrected reduction in hepatic fat content was demonstrated. This effect was shown to be independent of body weight changes
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Safety: No deaths were reported. Serious adverse events were observed in 11 cases. Discontinuation rates were found to be minimal. No hepatotoxicity signals were detected
Conclusion:
Significant reductions in atherogenic lipoproteins and hepatic fat content were demonstrated by solbinsiran in adults with mixed dyslipidemia, with the 400 mg dose being shown to have optimal efficacy and durability. The treatment was found to be well-tolerated with a favorable safety profile. These results are considered to support the further development of solbinsiran as a potential therapy for residual cardiovascular risk in mixed dyslipidemia, particularly for patients not being adequately controlled by current treatments. A cardiovascular outcomes trial is recommended to confirm these findings in high-risk populations.
Clinical Implications:
A novel therapeutic approach for mixed dyslipidemia is represented by solbinsiran, with both lipid parameters and hepatic fat content being targeted. The observed effects on multiple atherogenic lipoproteins are suggested to have the potential for comprehensive cardiovascular risk reduction beyond what is achieved by current standard therapies.
ACC.25, March 29 - 31, 2025, Chicago
