Regression of Established Coronary Artery Calcification via a Specialized High-Viscosity Rectal Formulation of 2-Hydroxypropyl-β-Cyclodextrin (Cavadex): A Multi-Center Longitudinal Analysis Challenging the Paradigm of Irreversible Atherosclerosis

• Statin-Intolerant or Statin-Naive Status: Patients were clinically verified as statin-intolerant or statin-naive. Zero new lipid-lowering pharmacotherapies (statins, ezetimibe, PCSK9 inhibitors) were initiated, modified, or escalated during active treatment windows, confirming Cavadex as the sole active therapeutic variable.
• Static Lifestyle Controls: Subjects maintained stable baseline dietary, exercise, and supplementary habits during their treatment courses.

Therapeutic Formulation and Administration Protocols

Patients self-administered Cavadex (Cholrem Pty Ltd), formulated as a high-viscosity rectal micro-enema. The formulation contains pharmaceutical-grade HP-β-CD engineered into a supramolecular clustered matrix. The primary protocol involved nightly administration at bedtime:

• Single-Dose Regimen: 8 grams of active HP-β-CD per nightly unit dose.
• Double-Dose / High-Viscosity Regimen: Highconcentration (“Quad Strength”) formulation delivering enhanced active payloads with increased mucosal residence time to maximize systemic bioavailability.

Radiological Standardization and PACS Traceability

All cardiac CT imaging was performed at independent, accredited diagnostic centers with complete Picture Archiving and Communication System (PACS) audit traceability:

• Hardware & Facility Continuity: Sequential scans for each patient were conducted within the same imaging facility network using standardized cardiac CT hardware (Borg & Ide Imaging, NY; South East Radiology, NSW; Northside Alpharetta Imaging, GA; Qscan Radiology Clinics, QLD).
• Standardized Acquisition Protocols: ECG-gated noncontrast acquisitions timed to end-diastole, utilizing 120 kVp tube potential, automated exposure control (AEC), and slice collimation ranging from 0.6 mm to 2.5 mm [7].
• Agatston Density Thresholding: Calcium scoring was executed using the standard attenuation threshold of >130 Hounsfield Units (HU) covering a lesion area ≥1.0 mm².
• Independent Specialist Interpretations: All CAC scores and 3D volumes were calculated, verified, and electronically signed by independent, board-certified radiologists who were unblinded to the experimental protocol.

Quantitative Trajectory and Divergence Models

Therapeutic outcomes and plaque kinetics were evaluated using three mathematical models:

1. Direct Baseline Delta and Relative Percentage Change

• Absolute Change (ΔCAC):

ΔCAC= CACFollow-up  – CACBaseline

• Percentage Change (%ΔCAC):

2. Annualized Decalcification Velocity Models

To normalize rate changes across varying observation windows, annualized velocities were calculated across both total inter-scan and active dosing intervals:

• Conservative Inter-Scan Velocity (AU/year): Inter-Scan Velocity = (ΔCAC /Total Inter-scan Days) ×365.25
• Active On-Drug Velocity (AU/year): Active On-Drug Velocity = (ΔCAC/Active Dosing Days) × 365.25

3. Projected Natural Trajectory Benchmark (+20% Annual Progression)

Untreated coronary calcification advances at an established clinical rate of +15% to +25% per annum (standardized conservative literature benchmark: +20% /year). The counterfactual projected score (CAC _Projected) and Net Therapeutic Divergence were calculated as:

• Projected Natural Follow-up Score:

CAC _Projected = CAC _Baseline × [1+0.20× (Total Inter-scan Days /365.25)]

• Net Therapeutic Divergence (%):

Detailed Cohort Analyses

1. Ultra-Short-Term Decalcification Velocity (Patient H.J.)

Patient H.J. presented on March 3, 2023, with a baseline Agatston score of 594.00 AU (75th–90th percentile), indicating extensive plaque burden. Following a 64-day protocol (64 daily unit doses of Cavadex), follow-up CT scanning on May 17, 2023, demonstrated a reduction to 521.00 AU.

• Absolute Reduction: -73.00 Agatston units in 75 days (-12.29%).
• Annualized Velocity: -355.3 Agatston units/year, inverting the expected natural disease velocity of +100 to +150 AU/year.

2. 1:1 Software-Matched Vessel Regression (Patient S.D.)

Patient S.D. underwent serial CT scanning at Northside Alpharetta Imaging, with pre-treatment (Nov 18, 2024) and post-treatment (Jan 12, 2026) examinations quantified on identical Siemens platform software.

• Overall Score Regression: Agatston score decreased from 207.30 to 89.10 (-57.02%; -118.20 AU).
• Targeted LCX Clearance: Baseline calcification was isolated primarily to the Left Circumflex (LCX) artery (205.1 AU). Following double-dose Cavadex therapy, the LCX score dropped to 70.6 AU, reflecting an absolute clearance of -134.5 AU (-65.58% vessel-specific regression).
• Population Percentile Normalization: MESA risk percentiles shifted from an elevated 50th–75th percentile range down into the 25th–50th percentile (normal age-matched baseline).

3. Severe-Burden 3D Volumetric Plaque Resorption (Patient M.M.)

Patient M.M. presented on August 21, 2024, with severe 99thpercentile disease burden (Agatston score: 2,726.00 AU; total plaque volume: 2,113 mm³). Follow-up CT imaging on matched Siemens Somatom hardware at 13.1 months demonstrated significant volumetric demineralization:

• Agatston Score Reduction: Dropped by -320.00 AU to 2,406.00 AU (-11.74%; -294.4 AU/year velocity).
• Total Plaque Volume Clearance: Total calcified plaque volume dropped from 2,113 mm³ to 755 mm³—an absolute resorption of 1,358.00 mm³ of calcified atheroma (-64.27% volumetric reduction).
• RCA Debulking: In the heavily diseased Right Coronary Artery (baseline: 2,226 AU; 1,684 mm³), calcified volume fell by 1,150.00 mm³ (-68.29%) down to 534 mm³, while the RCA Agatston score decreased by -449.00 AU (-20.17%).

Vessel-specific analysis revealed a dual response: while total 3D calcified volume decreased markedly across all four anatomical branches (LM: -55.1%, LAD: -55.2%, LCX: -32.8%, RCA: -68.3%), 2D Agatston scores in smaller left-sided vessels exhibited mild numeric increases. Because the Agatston score incorporates an attenuation multiplier (1–4 based on peak Hounsfield units), this pattern reflects calcific lesion compaction—where the extraction of surrounding lipid scaffolding collapses diffuse lowdensity microcalcifications into smaller, denser, structurally stable nodules. In the dominant Right Coronary Artery (representing 81.7% of initial disease), both volume (-68.3%) and Agatston score (-20.2%) regressed substantially, driving a net coronary clearance of 1,358 mm³ (-64.3%) and -320 Agatston units (Table 4 and Table 5).

Table 4: Longitudinal 3D Volumetric Plaque Resorption & Vessel-Specific Clearance (Patient M.M.)

Table 5: Multi-Vessel Agatston and Volumetric Plaque Breakdown (Patient M.M.)

4. Multi-Year Longitudinal Tracking & A-B-A On-OffOn Proof (Patient T.A.)

Patient T.A. underwent continuous scanning from 2019 to 2026 at Borg & Ide Imaging (Rochester, NY):

• Phase 1 (Untreated Natural Progression, 2019–2023): Score increased linearly from 29.00 to 53.00 (+82.8%) and peaked at 77.09 (+45.5%), exhibiting an average progression velocity of +12.0 AU/year (+165.8% overall increase).
• Phase 2 (Active Cavadex Protocol, Jan–Apr 2024): Following 96 days of daily double-dose Cavadex, the score regressed to 67.75 AU on May 22, 2024 (-12.11%; -9.34 AU).
• Phase 3 (Post-Cessation Rebound, Apr 2024–Feb 2026): Following drug cessation due to supply exhaustion, calcification surged to 113.00 AU on February 24, 2026 (+66.79% increase).

This Progression (A) → Regression (B) → Rebound (A) sequence provides pharmacological proof that decalcification was directly dependent on active Cavadex administration.

Discussion

Challenging the Dogma of Irreversible Arterial Calcification

For decades, cardiovascular medicine has treated calcified coronary plaque as an irreversible, permanent marker of arterial disease. While lipid-lowering therapies (such as statins and PCSK9 inhibitors) reduce acute clinical events by promoting plaque stability, they systematically accelerate mineral densification (+8% to +15% per annum) rather than plaque regression [9].

The clinical datasets presented in this study directly challenge this paradigm. Across diverse disease stages—ranging from focal, early lesions to massive 99th-percentile disease burden—targeted Cavadex administration produced verifiable regression in Agatston scores and substantial clearance of 3D calcified plaque volumes [Table 4 and Table 5]. The inter-scan noise floor for repeat Agatston scoring is established at ±5% to ±10%. The relative reductions documented here (up to -57.02% in Agatston score and -64.27% in total calcified volume) exceed technical variability by orders of magnitude (Table 6).

Table 6: Tripartite Molecular Mechanism of HP-β-CD-Mediated Decalcification

Tripartite Biological Mechanism of Action

The biological plausibility of Cavadex-mediated decalcification is supported by three coordinated molecular pathways:

1. Host-Guest Solubilization of Cholesterol Crystals: Vascular calcification is nucleated upon cholesterol crystals embedded within the necrotic core. HP-β-CD complexes free unesterified cholesterol and crystal deposits into soluble inclusion compounds, removing the physical nidus that drives mineral deposition.
2. LXR-Mediated Macrophage Reprogramming: HPβ-CD-mediated cholesterol mobilization generates intracellular oxysterols, which act as natural ligands for Liver X Receptors (LXR). LXR upregulation activates ABCA1 and ABCG1 efflux transporters, clearing lipid-engorged foam cells and suppressing the pro-inflammatory NLRP3 inflammasome.
3. 3. Microenvironmental Demineralization (Organic De-Scaffolding): Mineralized hydroxyapatite plates require an underlying organic extracellular lipid matrix to maintain structural integrity. By stripping the surrounding lipid core, Cavadex destabilizes this calcific scaffold, allowing endogenous phagocytic pathways to resorb and clear the mineralized deposits. This explains the massive -64.27% volumetric clearance (1,358 mm³) documented in the Patient M.M. series.

Methodological Consideration on Treatment Window vs. Inter-Scan Interval (Patient T.A.):

The total inter-scan interval for Patient T.A. spanned 426 days (March 23, 2023 to May 22, 2024), during which active Cavadex therapy was administered for a discrete 96-day window (January 10 to April 15, 2024), followed by a 37-day pre-scan washout. When calculated conservatively across the entire 426-day interscan period, the annualized decalcification velocity was -8.0 AU/ year. When annualized specifically across the 96 days of active pharmacological exposure, the decalcification velocity was -35.5 AU/year. Because the patient was untreated for approximately 293 days prior to initiating Cavadex—a period during which his historical untreated progression would predict a rise from 77.09 to ~93.9 AU—utilizing the March 2023 scan as the baseline provides a highly conservative estimate of therapeutic decalcification [9].

Pharmacokinetic Significance of the Cavadex Clustered Enema Formulation

Generic cyclodextrin molecules cannot be effectively delivered via oral administration due to minimal mucosal absorption (<3%). The clinical results in this series were achieved utilizing Cavadex, where the manufacturing process induces supramolecular molecular clustering within a high-viscosity rectal micro-enema.

This high-viscosity matrix improves mucosal retention, allowing the product to remain in contact with the rectal epithelium overnight (6–8 hours). This prolonged contact establishes a steep concentration gradient that drives transmucosal absorption directly into the systemic circulation, avoiding first-pass hepatic metabolism and eliminating the need for daily intravenous infusions [4,6].

Clinical Significance of Divergence from Natural Trajectories

Evaluating therapeutic efficacy solely against pre-treatment baselines underestimates the true clinical impact of Cavadex. In clinical cardiology, established coronary calcium progresses at an annual rate of +15% to +25%. Therefore, maintaining a static CAC score over 12 months represents disease stabilization.

When compared against the standard +20%/year progression benchmark, Cavadex achieved a Net Therapeutic Divergence of -15.75% to -65.06% below expected disease trajectories. In highburden patients, annualized decalcification velocities (-102.8 to -355.3 AU/year) represent an inversion of the natural course of coronary disease.

Methodological   Strengths and Cross-Sectional Representativeness

Representativeness Across the ASCVD Disease Continuum

A primary strength of this multi-center analysis is the deliberate stratification of evaluated cases across the clinical spectrum of coronary atherosclerosis. Rather than restricting observation to a narrow disease bracket, the evaluated cohort spans baseline Agatston loads from 77 AU up to 2,726 AU, and encompasses diverse anatomical distributions (including Left Circumflex predominance, multi-vessel left-sided disease, and massive Right Coronary Artery atheroma).

The consistency of quantitative decalcification observed across these distinct archetypes—ranging from acute velocity shifts (-355.3” AU/year” ) to sustained multi-vessel volumetric demineralization (-64.3%)—indicates that the pharmacological action of HP-β-CD is operative across early, intermediate, and advanced calcified plaque architectures. Furthermore, the presence of the A-B-A withdrawal rebound in Patient T.A. provides direct pharmacological evidence that regression was actively driven by HP-β-CD exposure rather than measurement artifact or spontaneous regression.

Clinical Safety and Tolerability Profile

Across all longitudinal treatment periods, Cavadex demonstrated a favorable safety profile. Systemic administration via the rectal micro-enema route produced zero reported cases of ototoxicity or hearing loss on serial audiometry, avoiding the auditory adverse events historically reported with high-dose intrathecal cyclodextrin in Niemann-Pick Type C trials. Adverse events were limited to mild, transient gastrointestinal effects (e.g., loose stools) associated with osmotic clearance.

Study Limitations

This study is limited by its retrospective observational design and small cohort size. While intra-facility hardware continuity and independent specialist sign-offs were maintained, larger prospective randomized controlled trials (RCTs) are needed to establish optimal dosing schedules, assess long-term decalcification durability, and measure direct reductions in clinical MACE endpoints.

Methodological Considerations

The divergence between volumetric plaque resorption and 2D Agatston density weighting in focal coronary branches underscores the limitation of relying solely on Agatston area-density scoring. In early or moderate lesions, lipid de-bulking can lead to densification of residual mineral deposits, artificially elevating the Agatston multiplier even as total physical plaque volume contracts by >50%.

True multi-vessel regression is thus most accurately demonstrated by combining 3D volumetric analysis with total calcium load.

Conclusion

This multi-center study provides quantitative, radiologically verified evidence that Cavadex (2-hydroxypropyl-β-cyclodextrin formulated as a high-viscosity rectal micro-enema) induces rapid, multi-vessel regression of established Coronary Artery Calcium (CAC) and substantial reductions in total calcified plaque volume in humans. By achieving annualized decalcification velocities up to -355.3 AU/year and net therapeutic divergences exceeding -65% below expected natural trajectories, Cavadex demonstrates true disease-modifying potential where conventional pharmaceutical therapies currently offer no solutions. These real-world findings establish a formal record that coronary calcification is biologically reversible and provide a compelling mandate for confirmatory randomized clinical trials.

Declarations

Competing Interests: Kyle Hodgetts is the Founder, CEO, and shareholder of Cholrem Pty Ltd, which manufactures and distributes Cavadex.

Funding: This research received no external public or commercial grant funding. All study expenses and analysis were funded by Cholrem Pty Ltd.

Author Contributions: K.H. conceived the study, designed the analytical framework, aggregated and evaluated the radiological data, performed trajectory modeling, and drafted the manuscript.

Data Availability Statement: De-identified PACS accession records, DICOM parameters, and certified radiology reports supporting the findings of this study are available from the corresponding author upon reasonable request.

References

1. Hodgetts K, Howes L, Fang YY, Song ZM (2024) 2-Hydroxypropylβ-Cyclodextrin Induces Rapid Regression of Atherosclerotic plaque and Reduces Hyperlipidaemia in Adult with Cardiovascular Disease. Cardiol Res Cardiovasc Med. 9:261.
2. Hodgetts K, Demian M, Fang YY, Song ZM (2024) 2-Hydroxypropylβ-Cyclodextrin Reduces Atherosclerotic Plaques in Human Coronary Artery. Cardiol Res Cardiovasc Med. 9:262.
3. Zimmer S, Grebe A, Bakke SS, Bode N, Halvorsen B, et al. (2016) Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming. Sci Transl Med. 8:333ra50.
4. Hodgetts K, Roberts JC, Howes LG (2025) Cyclodextrin Therapy for Atherosclerotic Cardiovascular Disease: A Case Series on Plaque Regression and Symptomatic Improvement. Cardiol Res Cardiovasc Med. 10:284.
5. Hodgetts K (2025) Symptomatic Improvement and Enhanced Quality of Life in Individuals with Atherosclerotic Cardiovascular Disease Following a 12-Week Self-Monitored Regimen of Rectally Administered 2-Hydroxypropyl-β-Cyclodextrin (Cavadex): An Observational Study. Cardiol Res Cardiovasc Med. 10:287.
6. Hodgetts K, Roberts J (2026) Regression of Atherosclerotic Plaque Via High-Viscosity 2-Hydroxypropyl-β-Cyclodextrin (Cavadex): A Multi-Center Retrospective Case Series. Cardiol Res Cardiovasc Med. 11:292.
7. Hecht HS, Blaha MJ, Kazerooni EA, Cury RC, Budoff M, et al. (2018) CAC-DRS: Coronary Artery Calcium Data and Reporting System. An expert consensus document of the Society of Cardiovascular Computed Tomography (SCCT). J Cardiovasc Comput Tomogr. 12:185-191.
8. McClelland RL,  Jorgensen NW,  Budoff M, Blaha MJ,  Post WS, et al. (2015) Ten-Year Coronary Heart Disease Risk Prediction Using Coronary Artery Calcium and Traditional Risk Factors: Derivation in the Multi-Ethnic Study of Atherosclerosis with Validation in the Heinz Nixdorf Recall Study and the Dallas Heart Study. J Am Coll Cardiol. 66:1643–1653.
9. van Rosendael AR, van den Hoogen IJ, Gianni U, Ma X, Tantawy SW, et al. (2021) Association of Statin Treatment With Progression of Coronary Atherosclerotic Plaque Composition. JAMA Cardiol. 6:12571266.
10. Budoff MJ, Young R, Burke G, Carr JJ, Detrano RC, et al. (2018) Ten-year association of coronary artery calcium with atherosclerotic cardiovascular disease (ASCVD) events: the multi-ethnic study of atherosclerosis (MESA). Eur Heart J. 39:2401-2408.