# DKDComboMiner — top 10 unexplored cells

> Research-use only. Synthetic mock data. Not for clinical decision-making. IRB review required.

- Total cells scored: 235872
- Combo size up to: 2
- Weights: {'gap': 0.2, 'trend': 0.1, 'trial_gap': 0.1, 'kdigo': 0.15, 'mech': 0.2, 'feasibility': 0.2, 'faers_penalty': 0.15}

## Ranked hypothesis cards

## #1 (score 0.816)

### Hypothesis: Empagliflozin (EMPA), Liraglutide (LIRA) | KDIGO G2A1 | UACRV | T2DM_ASCVD

- Drug combo: Empagliflozin (EMPA), Liraglutide (LIRA)
- Class signature: GLP1RA + SGLT2i
- KDIGO stage: G2A1
- Primary biomarker: UACRV
- Target population: T2DM_ASCVD
- Composite score: **0.816**
- Synthetic literature gap (pubmed_n / trend_5y%): 1 / +55%
- Synthetic KR active trials: 0
- KDIGO 2024 strength avg: 0.925 | Mechanism: 0.88 | FAERS caution: 0.45 | KR IIS feasibility: 0.88
- Rationale: Synthetic PubMed n=1 (gap=0.99), 5y trend +55% / Active KR trials (synthetic) = 0; KDIGO 2024 strength avg = 0.93 / Mechanism plausibility prior = 0.88; FAERS caution = 0.45 / Best matching KR cohort: KDA-REG (feasibility 0.88)


## #2 (score 0.803)

### Hypothesis: Dapagliflozin (DAPA), Dulaglutide (DULA) | KDIGO G3aA3 | UACR | T2DM_ASCVD

- Drug combo: Dapagliflozin (DAPA), Dulaglutide (DULA)
- Class signature: GLP1RA + SGLT2i
- KDIGO stage: G3aA3
- Primary biomarker: UACR
- Target population: T2DM_ASCVD
- Composite score: **0.803**
- Synthetic literature gap (pubmed_n / trend_5y%): 9 / +51%
- Synthetic KR active trials: 0
- KDIGO 2024 strength avg: 0.925 | Mechanism: 0.88 | FAERS caution: 0.45 | KR IIS feasibility: 0.88
- Rationale: Synthetic PubMed n=9 (gap=0.95), 5y trend +51% / Active KR trials (synthetic) = 0; KDIGO 2024 strength avg = 0.93 / Mechanism plausibility prior = 0.88; FAERS caution = 0.45 / Best matching KR cohort: KDA-REG (feasibility 0.88)


## #3 (score 0.8029)

### Hypothesis: Finerenone (FINE), Semaglutide (SEMA) | KDIGO G1A1 | UACRV | T2DM_ASCVD

- Drug combo: Finerenone (FINE), Semaglutide (SEMA)
- Class signature: GLP1RA + MRA
- KDIGO stage: G1A1
- Primary biomarker: UACRV
- Target population: T2DM_ASCVD
- Composite score: **0.8029**
- Synthetic literature gap (pubmed_n / trend_5y%): 0 / +49%
- Synthetic KR active trials: 0
- KDIGO 2024 strength avg: 0.925 | Mechanism: 0.8 | FAERS caution: 0.388 | KR IIS feasibility: 0.88
- Rationale: Synthetic PubMed n=0 (gap=1.00), 5y trend +49% / Active KR trials (synthetic) = 0; KDIGO 2024 strength avg = 0.93 / Mechanism plausibility prior = 0.80; FAERS caution = 0.39 / Best matching KR cohort: KDA-REG (feasibility 0.88)


## #4 (score 0.8011)

### Hypothesis: Dulaglutide (DULA), Finerenone (FINE) | KDIGO G3aA2 | UACR | T2DM_ASCVD

- Drug combo: Dulaglutide (DULA), Finerenone (FINE)
- Class signature: GLP1RA + MRA
- KDIGO stage: G3aA2
- Primary biomarker: UACR
- Target population: T2DM_ASCVD
- Composite score: **0.8011**
- Synthetic literature gap (pubmed_n / trend_5y%): 8 / +54%
- Synthetic KR active trials: 0
- KDIGO 2024 strength avg: 0.925 | Mechanism: 0.8 | FAERS caution: 0.388 | KR IIS feasibility: 0.88
- Rationale: Synthetic PubMed n=8 (gap=0.96), 5y trend +54% / Active KR trials (synthetic) = 0; KDIGO 2024 strength avg = 0.93 / Mechanism plausibility prior = 0.80; FAERS caution = 0.39 / Best matching KR cohort: KDA-REG (feasibility 0.88)


## #5 (score 0.801)

### Hypothesis: Dulaglutide (DULA), Empagliflozin (EMPA) | KDIGO G3aA1 | EGFRSLOPE | T2DM_ASCVD

- Drug combo: Dulaglutide (DULA), Empagliflozin (EMPA)
- Class signature: GLP1RA + SGLT2i
- KDIGO stage: G3aA1
- Primary biomarker: EGFRSLOPE
- Target population: T2DM_ASCVD
- Composite score: **0.801**
- Synthetic literature gap (pubmed_n / trend_5y%): 6 / +57%
- Synthetic KR active trials: 1
- KDIGO 2024 strength avg: 0.925 | Mechanism: 0.88 | FAERS caution: 0.45 | KR IIS feasibility: 0.88
- Rationale: Synthetic PubMed n=6 (gap=0.97), 5y trend +57% / Active KR trials (synthetic) = 1; KDIGO 2024 strength avg = 0.93 / Mechanism plausibility prior = 0.88; FAERS caution = 0.45 / Best matching KR cohort: KDA-REG (feasibility 0.88)


## #6 (score 0.7995)

### Hypothesis: Canagliflozin (CANA), Perindopril (PERI) | KDIGO G2A1 | UACRV | T2DM_ASCVD

- Drug combo: Canagliflozin (CANA), Perindopril (PERI)
- Class signature: RAS + SGLT2i
- KDIGO stage: G2A1
- Primary biomarker: UACRV
- Target population: T2DM_ASCVD
- Composite score: **0.7995**
- Synthetic literature gap (pubmed_n / trend_5y%): 8 / +46%
- Synthetic KR active trials: 0
- KDIGO 2024 strength avg: 1.0 | Mechanism: 0.72 | FAERS caution: 0.3 | KR IIS feasibility: 0.88
- Rationale: Synthetic PubMed n=8 (gap=0.96), 5y trend +46% / Active KR trials (synthetic) = 0; KDIGO 2024 strength avg = 1.00 / Mechanism plausibility prior = 0.72; FAERS caution = 0.30 / Best matching KR cohort: KDA-REG (feasibility 0.88)


## #7 (score 0.7978)

### Hypothesis: Dapagliflozin (DAPA), Telmisartan (TELM) | KDIGO G3aA3 | EGFRSLOPE | T2DM_ASCVD

- Drug combo: Dapagliflozin (DAPA), Telmisartan (TELM)
- Class signature: RAS + SGLT2i
- KDIGO stage: G3aA3
- Primary biomarker: EGFRSLOPE
- Target population: T2DM_ASCVD
- Composite score: **0.7978**
- Synthetic literature gap (pubmed_n / trend_5y%): 1 / +49%
- Synthetic KR active trials: 1
- KDIGO 2024 strength avg: 1.0 | Mechanism: 0.72 | FAERS caution: 0.3 | KR IIS feasibility: 0.88
- Rationale: Synthetic PubMed n=1 (gap=0.99), 5y trend +49% / Active KR trials (synthetic) = 1; KDIGO 2024 strength avg = 1.00 / Mechanism plausibility prior = 0.72; FAERS caution = 0.30 / Best matching KR cohort: KDA-REG (feasibility 0.88)


## #8 (score 0.796)

### Hypothesis: Dulaglutide (DULA) | KDIGO G2A2 | UACR | T2DM_LEAN

- Drug combo: Dulaglutide (DULA)
- Class signature: GLP1RA
- KDIGO stage: G2A2
- Primary biomarker: UACR
- Target population: T2DM_LEAN
- Composite score: **0.796**
- Synthetic literature gap (pubmed_n / trend_5y%): 30 / +58%
- Synthetic KR active trials: 0
- KDIGO 2024 strength avg: 0.85 | Mechanism: 0.7 | FAERS caution: 0.1 | KR IIS feasibility: 0.88
- Rationale: Synthetic PubMed n=30 (gap=0.85), 5y trend +58% / Active KR trials (synthetic) = 0; KDIGO 2024 strength avg = 0.85 / Mechanism plausibility prior = 0.70; FAERS caution = 0.10 / Best matching KR cohort: KDA-REG (feasibility 0.88)


## #9 (score 0.7939)

### Hypothesis: Ramipril (RAMI) | KDIGO G3aA3 | UACRV | T2DM_LEAN

- Drug combo: Ramipril (RAMI)
- Class signature: RAS
- KDIGO stage: G3aA3
- Primary biomarker: UACRV
- Target population: T2DM_LEAN
- Composite score: **0.7939**
- Synthetic literature gap (pubmed_n / trend_5y%): 14 / +50%
- Synthetic KR active trials: 0
- KDIGO 2024 strength avg: 1.0 | Mechanism: 0.65 | FAERS caution: 0.237 | KR IIS feasibility: 0.88
- Rationale: Synthetic PubMed n=14 (gap=0.93), 5y trend +50% / Active KR trials (synthetic) = 0; KDIGO 2024 strength avg = 1.00 / Mechanism plausibility prior = 0.65; FAERS caution = 0.24 / Best matching KR cohort: KDA-REG (feasibility 0.88)


## #10 (score 0.792)

### Hypothesis: Dulaglutide (DULA) | KDIGO G2A1 | UACRV | T2DM_ASCVD

- Drug combo: Dulaglutide (DULA)
- Class signature: GLP1RA
- KDIGO stage: G2A1
- Primary biomarker: UACRV
- Target population: T2DM_ASCVD
- Composite score: **0.792**
- Synthetic literature gap (pubmed_n / trend_5y%): 19 / +46%
- Synthetic KR active trials: 0
- KDIGO 2024 strength avg: 0.85 | Mechanism: 0.7 | FAERS caution: 0.1 | KR IIS feasibility: 0.88
- Rationale: Synthetic PubMed n=19 (gap=0.91), 5y trend +46% / Active KR trials (synthetic) = 0; KDIGO 2024 strength avg = 0.85 / Mechanism plausibility prior = 0.70; FAERS caution = 0.10 / Best matching KR cohort: KDA-REG (feasibility 0.88)


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## Grant-ready specific aims (top-1)

# Grant-Ready Specific Aims: Empagliflozin + Liraglutide in DKD G2A1

> Research-use only. IRB approval and expert review required prior to any clinical application. Synthetic data only.

## Specific Aims
**Aim 1.** Determine the effect of Empagliflozin + Liraglutide on UACRV trajectory in T2DM_ASCVD with KDIGO G2A1 DKD over 52 weeks (synthetic preliminary data: gap-score 0.816; current Korea active trials = 0).

**Aim 2.** Identify mechanistic mediators (mechanism plausibility prior 0.88) using paired plasma + urine multi-omics in a Korean IIS cohort with feasibility 0.88.

**Aim 3.** Build a Korean-cohort-validated risk-stratification tool combining UACRV with KDIGO 2024 (combo strength 0.925) for treatment selection.

## Innovation
- Class signature GLP1RA + SGLT2i addresses an unexplored cell of the DKD therapeutic ontology.
- Korean lean / non-albuminuric DKD phenotype is underrepresented in pivotal trials (FLOW, EMPA-KIDNEY, FIDELIO/FIGARO).

## Approach
- Design: prospective IIS, parallel-arm, target N derived from KR cohort coverage.
- Outcomes: primary UACRV change at 52w; secondary eGFR slope, hard renal endpoints.
- Safety monitoring informed by synthetic FAERS caution score = 0.45.

## Preliminary Data (synthetic)
- Synthetic PubMed n=1 (gap=0.99), 5y trend +55%
- Active KR trials (synthetic) = 0; KDIGO 2024 strength avg = 0.93
- Mechanism plausibility prior = 0.88; FAERS caution = 0.45
- Best matching KR cohort: KDA-REG (feasibility 0.88)

## Deliverables
- KDA / KSAD abstracts, peer-reviewed manuscript, KR cohort-derived RWE evidence package.


## KDA / KSAD abstract draft (top-1)

# KDA / KSAD Abstract Draft (synthetic preliminary)

> Research-use only. Synthetic mock data; not an actual study result.

## English (target ~250 words)
**Title.** Empagliflozin + Liraglutide for KDIGO G2A1 diabetic kidney disease in T2DM_ASCVD: a Korean investigator-initiated study proposal.

**Background.** Despite SGLT2i, GLP-1RA, and finerenone-class advances, the (drug-combo x stage x biomarker x population) cell defined by Empagliflozin + Liraglutide / G2A1 / UACRV / T2DM_ASCVD remains underexplored (synthetic literature n=1, KR active trials=0).

**Methods.** Using a DKD therapeutic ontology of 23 drugs, 18 KDIGO stages, 7 biomarkers, and 8 populations, we systematically screened ~70,000 cells. We integrated synthetic literature counts, KR cohort feasibility, KDIGO 2024 recommendation strength, mechanism plausibility, and FAERS-style safety priors into a composite score.

**Results.** This cell scored 0.816 (top-tier). KDIGO 2024 strength 0.925, mechanism plausibility 0.88, KR IIS feasibility 0.88, FAERS caution 0.45.

**Conclusion.** A KR IIS evaluating Empagliflozin + Liraglutide on UACRV in T2DM_ASCVD with G2A1 DKD is high-priority; preliminary feasibility supports KDA / KSAD pursuit.

## 한국어 (약 250 단어)
**제목.** T2DM_ASCVD 환자에서 KDIGO G2A1 당뇨병성 신증에 대한 Empagliflozin + Liraglutide 병용 효과: 한국형 연구자 주도 임상시험 제안.

**배경.** SGLT2 억제제·GLP-1 수용체 작용제·non-steroidal MRA의 발전에도 불구하고, Empagliflozin + Liraglutide / G2A1 / UACRV / T2DM_ASCVD 조합은 미탐색 영역으로 남아있다 (합성 문헌 n=1, 한국 활성 시험 0).

**방법.** 23개 약물·18개 KDIGO 단계·7개 바이오마커·8개 인구학을 포함하는 DKD 치료 온톨로지를 구성하고 약 70,000개 cell을 체계적으로 스크리닝하였다. 합성 문헌 수, 한국 코호트 가용성, KDIGO 2024 권고 강도, 기전 타당성, FAERS 유사 안전성 prior를 가중합하여 복합 점수를 산출하였다.

**결과.** 본 cell의 점수 0.816 (상위권). KDIGO 강도 0.925, 기전 타당성 0.88, 한국 IIS 가능성 0.88, FAERS 주의 0.45.

**결론.** T2DM_ASCVD의 G2A1 단계에서 Empagliflozin + Liraglutide 병용이 UACRV에 미치는 영향을 평가하는 한국형 IIS는 우선순위가 높으며, 예비 가용성 평가가 KDA·KSAD 추진을 뒷받침한다.