The combination of these therapies is mechanistically

The gap

Evidence profile

Sourced from the abstract and future work and conclusions and recommendations of the source papers, classified as general, drawn from work published between 2023 and 2026, spanning 5 journals. Those papers have been cited 4 times in total.

Supporting evidence — 6 representative gaps

• Kidneys in heart failure: Impact of flozins (2023) · Kardiologia Polska · cited 4× · doi

  SGLT2i are clearly cardioprotective in a wide spectrum of estimated GFR although the data for HF patients with respect to urine albumin-creatinine ratio (UACR) are scarce, and for those with significantly reduced estimated GFR are still not available or not convincing, even after completion of large-scale high-quality major cardiovascular outcome trials (CVOT) in type 2 diabetes mellitus (T2DM) or trials with flozins in CKD and HF.

  generalabstractevidence 5/5
  Keywords: estimated trials sglt clearly cardioprotective wide spectrum patients respect urine albumin creatinine ratio uacr scarce
• Predictive value of left atrial diameter and epicardial adipose tissue in sleep apnea and heart failure with preserved ejection fraction (2026) · Frontiers in Cardiovascular Medicine · doi

  With the rising global prevalence of HFpEF, optimizing risk stratification and clinical management has become a top priority in cardiovascular research. To the best of our knowledge, the present study is among the first to systematically evaluate the combined association of LAD and EAT with HFpEF in patients with SA. Our findings highlight that both parameters are independently associated with the condition and closely related to disease severity in this patient population. risk and refine stratification In clinical practice, intensified monitoring of LAD and EAT in SA patients is warranted. When integrated with established biomarkers such as NT-proBNP, these imaging metrics could facilitate personalized help management strategies. From a therapeutic standpoint, emerging agents such as SGLT2 inhibitors and GLP-1 receptor agonists— known for their beneficial effects on cardiac metabolism and for EAT reducing accumulation and adverse LA remodeling (34, 35). Future research investigate whether early pharmacological intervention targeting these pathways can alter the clinical trajectory of patients with both SA and HFpEF.

  generalfuture workevidence 5/5
  Keywords: hfpef clinical patients risk stratification management rising global prevalence optimizing become priority cardiovascular best knowledge
• Emerging metabolic hormone therapeutics for metabolic dysfunction-associated steatohepatitis: incretin-based drugs, fibroblast growth factor analogs, and liver-targeting strategies (2026) · Journal of Pharmaceutical Investigation · doi

  With the recent USA approvals of a THR-β agonist (resmetirom) in 2024 and GLP-1R agonist (semaglutide) in 2025 for adults with MASH and moderate-to-advanced fibrosis, the field is shifting from generalized metabolic control toward multi-mechanism targeting and stage-aware, liverselective interventions. Early multi-mechanism approaches are exemplified by the GLP-1R/GIPR/GCGR triple agonist (retatrutide) (Sanyal et al. 2024) and GLP-1R/GCGR dual agonist (survodutide), which extend metabolic debulking beyond GLP-1 monotherapy. Systematic evaluation of combination and sequencing strategies is now a critical priority. Combination strategies may pair upstream metabolic debulking agents (GLP-1 monotherapy, GLP-1R/GCGR dual agonists, and nextgeneration triple agonists) with liver-directed therapies, including THR-β agonists, FXR agonists, FGF21 analogs, and antifibrotic agents that more directly target fibrosis and intrahepatic pathology. Such an approach may facilitate early improvements in body weight, insulin resistance, and steatosis, while subsequently promoting more durable histologic improvements. In addition, a sequential treatment strategy may offer further advantages, whereby initial metabolic debulking establishes a more favorable hepatic environment before introducing agents specifically designed to target activated HSCs, fibrotic lesions, or other intrahepatic drivers of persistent fibrosis. Early clinical signals support GLP-1 + FGF21 strategies under evaluation, informing rational co-administration or sequence designs with prespecified safety architectures (Harrison et al. 2025). Beyond selecting therapeutic mechanisms and treatment sequences, optimizing the delivery of these agents will also be essential for the long-term management of MASH. Given that MASH requires chronic treatment, and that most incretin- and FGF-based therapies are being developed as repeatedly administered subcutaneous injectable formulations, the development of long-acting drug delivery systems (DDSs) may improve treatment durability, reduce dosing frequency, enhance patient adherence, and stabilize systemic exposure. For GLP-1-based therapies, a rapid increase in peak plasma 1 3Journal of Pharmaceutical Investigationconcentration resulting from excessive initial burst release may contribute to gastrointestinal adverse events, such as nausea and vomiting. Therefore, sustained-release depot formulations require careful optimization of release kinetics to minimize the initial burst and maintain stable systemic exposure (Kim et al. 2024; Maharjan et al. 2024). Stage-specific selection of liver-targeting strategies is also critical in MASH.

  generalfuture workevidence 5/5
  Keywords: agonist mash strategies agents agonists treatment metabolic targeting liver early gcgr debulking therapies initial release
• Concomitant use of SGLT2 inhibitors and GLP-1 receptor agonists in patients with heart failure (2026) · Cardiovascular Diabetology – Endocrinology Reports · doi

  The combination of these therapies is mechanistically appealing and may offer incremental benefit in selected patients with overlapping metabolic, renal, and cardio- vascular risk; however, current evidence remains limited, heterogeneous, and derived largely from secondary anal- yses or observational studies rather than dedicated ran- domized heart failure trials.

  generalconclusionsevidence 5/5
  Keywords: combination therapies mechanistically appealing offer incremental benefit selected patients overlapping metabolic renal cardio vascular risk
• Concomitant use of SGLT2 inhibitors and GLP-1 receptor agonists in patients with heart failure (2026) · Cardiovascular Diabetology – Endocrinology Reports · doi

  In patients with T2DM and established heart failure, SGLT2 inhibitors currently have the strongest evidence base for improving HF outcomes and should be priori- tized when not contraindicated [8, 11, 45]. Their ben- efits extend across the ejection fraction spectrum and are observed irrespective of diabetes status [8, 10, 11, 46]. GLP-1 receptor agonists may be considered when additional treatment goals include weight reduction, improved glycemic control, chronic kidney disease risk reduction, or lowering atherosclerotic cardiovascular risk, particularly in patients with obesity or established Atherosclerotic Cardiovascular Disease (ASCVD) [7, 16, 47]. However, they should not be viewed as substitutes for evidence-based HF therapies, and their role in estab- lished HFrEF remains less certain [18, 19, 22, 48]. Altogether, combination therapy may be reasonable in selected high-risk patients who would benefit from both HF-directed treatment and broader cardiometabolic risk reduction. Decisions should be individualized according to comorbidity burden, renal function, tolerability, cost, route of administration, and patient preference. At pres- ent, routine use of dual therapy specifically to improve HF outcomes cannot be recommended because dedi- cated randomized HF trials are lacking. Authors’ perspective and future directions Current evidence supports SGLT2 inhibitors as a core component of contemporary heart failure manage- ment because of their consistent reductions in HF hos- pitalization and cardiovascular death across a broad range of patient populations [8–13, 45, 49]. In contrast, GLP-1 receptor agonists appear to offer important Khademi and Shoar Cardiovascular Diabetology – Endocrinology Reports (2026) 12:47 Page 6 of 8 complementary benefits related to weight reduction, glycemic control, renal protection, and atherosclerotic cardiovascular risk reduction, although their direct role in established HF remains less certain [16, 20, 22, 47]. The potential value of combining these therapies lies in addressing overlapping cardiorenal and metabolic risk pathways as available evidence for dual therapy in HF populations remains limited and is derived largely from subgroup analyses, observational studies, and extrapola- tion from diabetes or obesity trials rather than dedicated HF randomized trials [24, 25, 27, 30, 50]. Future research should prioritize adequately pow- ered randomized controlled trials evaluating combined SGLT2 inhibitor and GLP-1 receptor agonist therapy in patients with HF. Key objectives include determin- ing long-term safety, identifying patient subgroups most likely to benefit, clarifying effects across HF phenotypes, and assessing patient-centered outcomes such as quality of life, functional status, and hospitalization burden.

  generalrecommendationsevidence 5/5
  Keywords: risk reduction cardiovascular patients evidence therapy patient trials established sglt outcomes across receptor atherosclerotic remains
• EFFICACY OF GLP-1 RECEPTOR AGONISTS ON GLYCAEMIC CONTROL AND WEIGHT REDUCTION IN TYPE 2 DIABETES MELLITUS: A SYSTEMATIC REVIEW OF RANDOMIZED CONTROLLED TRIALS (2026) · The Indonesian Journal of General Medicine · doi

  For clinicians ● Consider a GLP-1 receptor agonist as second-line intensification in patients with T2DM and overweight or obesity who have not attained target on metformin, particularly where weight reduction is a co-equal therapeutic goal. ● In patients with atherosclerotic cardiovascular disease or chronic kidney disease, consider a GLP-1 receptor agonist on cardiorenal grounds irrespective of the degree of hyperglycaemia. ● In patients already receiving basal insulin but not at target, prioritise addition of a GLP-1 receptor agonist over intensification toward a basal-bolus regimen. ● Reduce the sulphonylurea dose when initiating a GLP-1 receptor agonist to prevent an increase in hypoglycaemia risk. ● Apply gradual dose escalation with anticipatory education about the transient nature of gastrointestinal symptoms to maximise tolerability and adherence. ● Calibrate expectations of absolute weight reduction to the patient's baseline body weight, since absolute magnitudes are smaller in patients with lower baseline weight. ● Consider temporary withholding before elective anaesthetic procedures and assess residual gastric content where clinically indicated.

  generalrecommendationsevidence 5/5
  Keywords: receptor agonist patients weight consider intensification target reduction disease basal dose absolute baseline clinicians second

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