Cardiovascular and renal outcomes of dual combination therapies with glucagon-like peptide-1 receptor agonists and sodium-glucose transport protein 2 inhibitors: a systematic review and meta-analysis
Bibliographic record
Abstract
Abstract Background Combination therapy with glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose co-transporter 2 inhibitors (SGLT2i), and/or finerenone offers a strategy to reduce the risk of adverse cardiovascular and renal outcomes. This study aimed to quantify the cardiorenal benefits of combination regimens with GLP-1RA, SGLT2i, and/or finerenone versus corresponding monotherapies. Methods MEDLINE and Embase were systematically searched, yielding four post hoc analyses of randomized controlled trials (RCTs) and ten observational studies that met prespecified inclusion criteria. Among RCTs, a random-effects meta-regression was performed to assess whether the effect of GLP-1RAs on cardiorenal outcomes differed based on baseline SGLT2i use. Additionally, for observational studies, random-effects meta-analyses were performed to estimate the effect of combination therapy versus monotherapy on the risk of cardiorenal outcomes. Results Across RCTs, p for interaction was > 0.05 for major adverse cardiac events (MACE) (p = 0.730), cardiovascular (CV) mortality (p = 0.889), non-fatal myocardial infarction (MI) (p = 0.237), non-fatal stroke (p = 0.696), all-cause mortality (p = 0.682), heart failure (HF) hospitalization (p = 0.257), and renal composite outcome (p = 0.890), supporting that GLP-1RAs result in a consistent reduction in outcomes irrespective of baseline SGLT2i use. In observational trials, compared to SGLT2i monotherapy, GLP-1RA and SGLT2i combination therapy significantly reduced MACE (HR 0.59, 95% CI 0.47–0.75), MI (HR 0.73, 95% CI 0.61–0.88), stroke (HR 0.72, 95% CI 0.53–0.97), all-cause mortality (HR 0.57, 95% CI 0.48–0.67), and HF hospitalization/events (HR 0.71, 95% CI 0.59–0.86). Compared to GLP-1RA monotherapy, SGLT2i and GLP-1RA combination therapy significantly reduced CV mortality (HR 0.35, 95% CI 0.15–0.81), MI (HR 0.93, 95% CI 0.88–0.97), stroke (HR 0.92, 95% CI 0.88–0.96), all-cause mortality (HR 0.59, 95% 0.49–0.70), HF hospitalization/events (HR 0.84, 95% CI 0.81–0.88), and serious renal events (HR 0.43, 95% CI 0.23–0.80). Compared to either SGLT2i or finerenone monotherapy, SGLT2i and finerenone combination therapy significantly reduced all-cause mortality and major adverse kidney events. Conclusion Combination therapy with GLP-1RA, SGLT2i, or finerenone confers cardiorenal protection beyond monotherapy in T2D, as supported by concordant evidence from RCTs and large real-world cohorts. These findings support broader clinical adoption of dual-agent strategies but also underscore the need for dedicated prospective trials powered to assess hard clinical outcomes with dual-agent strategies.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.004 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.024 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".