Disease-modifying approach to cardiovascular–kidney–metabolic syndrome: The role of combining GLP-1RAs and SGLT-2is

Q: What is the clinical evidence from this study?

Study design: Review. Population: Cardiovascular-kidney-metabolic (CKM) syndrome. Intervention: Combination of GLP-1 receptor agonists (GLP-1RA) and SGLT-2 inhibitors (SGLT-2i) vs. GLP-1RA or SGLT-2i monotherapy.

Q: What does this research mean for the field?

Combining GLP-1 receptor agonists and SGLT-2 inhibitors provides complementary and predominantly additive reductions in body weight, HbA1c, blood pressure, and cardiorenal risk in cardiovascular-kidney-metabolic syndrome. Novelty: ClaimNovelty.SYNTHESIS. Consensus alignment: ConsensusAlignment.NEUTRAL.

Sanja Borozan; Cornelius J Fernandez; ABM Kamrul-Hasan; Joseph M Pappachan

doi:10.17925/ee.2026.22.2.5

October 1, 2026touchREVIEWS in EndocrinologyOpen Access

Disease-modifying approach to cardiovascular–kidney–metabolic syndrome: The role of combining GLP-1RAs and SGLT-2is

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Key result

Combining GLP-1RAs and SGLT2 inhibitors provides additive reductions in weight, HbA1c, and cardiorenal risk in CKM syndrome.

Why the study?

The escalating global prevalence of cardiovascular-kidney-metabolic (CKM) syndrome necessitates a fundamental reframing toward the simultaneous and coordinated management of cardiac, renal, and metabolic health, incorporating therapies such as GLP-1 RAs and SGLT-2is.

Does combining GLP-1 receptor agonists and SGLT-2 inhibitors improve cardiovascular, renal, and metabolic outcomes in patients with cardiovascular-kidney-metabolic (CKM) syndrome?

Key Points

To review the pathophysiological rationale and clinical evidence for combining GLP-1 receptor agonists and SGLT-2 inhibitors to modify cardiovascular-kidney-metabolic syndrome.
Narrative review synthesizing clinical trials, meta-analyses, and mechanistic literature on dual GLP-1RA and SGLT-2i therapy across metabolic, cardiovascular, and renal disease populations.
GLP-1RAs primarily reduce appetite, body weight, visceral adiposity, hepatic steatosis, inflammation, and atherosclerotic cardiovascular disease risk, while SGLT-2is primarily reduce intraglomerular pressure, plasma volume, blood pressure, heart failure risk, and chronic kidney disease progression.
Dual therapy demonstrates predominantly additive rather than synergistic effects in lowering body weight, HbA1c, blood pressure, and albuminuria compared with monotherapy.
In a pooled meta-analysis of randomized controlled trials (n=1,895; 12–104 weeks), combination therapy provided additional reductions in HbA1c of 0.6–0.9%, weight of 1.5–3 kg, and systolic blood pressure of 2–4 mmHg versus monotherapy.

Structured PICO

Does combining GLP-1 receptor agonists and SGLT-2 inhibitors improve cardiovascular, renal, and metabolic outcomes in patients with cardiovascular-kidney-metabolic (CKM) syndrome?

P

Population

Patients with or at risk for cardiovascular-kidney-metabolic (CKM) syndrome, including obesity, type 2 diabetes mellitus, chronic kidney disease, and cardiovascular disease.

I

Intervention

Combination therapy with glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is), alongside lifestyle interventions

C

Comparator

Monotherapy with either GLP-1RAs or SGLT-2is, or traditional fragmented single-diagnosis-centered pharmacological approaches

O

Outcome

Prevention and management of CKM syndrome progression, including reductions in major adverse cardiovascular events (MACE), heart failure hospitalizations, renal disease progression, and mortality

This review highlights that combining GLP-1RAs and SGLT-2is offers complementary pathobiological mechanisms that may provide additive cardiorenal and metabolic benefits in managing cardiovascular-kidney-metabolic (CKM) syndrome, though dedicated large RCTs for hard clinical outcomes are still needed.

Limitations

Lack of dedicated large randomized controlled trials designed to directly compare combination therapy with monotherapy for hard cardiovascular or renal outcomes.
Most cardiovascular and cardiorenal benefits of dual therapy are extrapolated from post hoc analyses, observational cohorts, or trials focused on surrogate metabolic endpoints.
High medication costs, restricted access, adherence challenges, gastrointestinal side effects, euglycemic diabetic ketoacidosis, and potential loss of lean body mass.
Dedicated large RCTs designed to compare the benefits of combination therapy with either monotherapy for hard cardiovascular or renal outcomes are lacking.
Emerging evidence is largely from post hoc analyses of RCTs with relatively short-term interventions, observational cohorts, and studies focused on surrogate metabolic endpoints.
While additive benefits appear plausible, the presence of true synergistic effects remains uncertain.

Implication

CKM syndrome integration may guide coordinated care now; leaves open prospective validation before practice change.

Abstract

ardiovascular-kidney-metabolic (CKM) syndrome represents a recent paradigm shift from a traditional, fragmented, disease-specific approach to an interconnected, holistic one driven by shared pathophysiologic pathways that are crucial to the development of multisystem organ dysfunction.The escalating global prevalence of CKM syndrome, associated with industrialization, the obesity pandemic and aging demographics, necessitates a fundamental reframing toward the simultaneous and coordinated management of cardiac, renal and metabolic health.Core to this integrated approach is the development of novel therapeutic options, such as glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 inhibitors (SGLT-2i), which target these common mechanisms and have the potential to improve long-term prognosis and reverse trends in cardiovascular mortality.In this article, we suggest a strategic roadmap for CKM syndrome to prioritize early, interdisciplinary intervention focused on addressing modifiable risk factors, weight management and tailored treatment protocols, particularly for high-risk populations, to mitigate the detrimental impact of this multiorgan condition.Cardiovascular-kidney-metabolic (CKM) syndrome is a term coined to

Discussion

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Cite This Study

Borozan et al. (2026) conducted a review in Cardiovascular-kidney-metabolic (CKM) syndrome. Combination of GLP-1 receptor agonists (GLP-1RA) and SGLT-2 inhibitors (SGLT-2i) vs. GLP-1RA or SGLT-2i monotherapy was evaluated. Combining GLP-1RAs and SGLT-2is provides complementary, additive reductions in body weight (8-20%), HbA1c (1.5-3%), and cardiorenal risk in CKM syndrome.

synapsesocial.com/papers/6ae28e94cbadf70daf6c4370 https://doi.org/10.17925/ee.2026.22.2.5

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Disease-modifying approach to cardiovascular–kidney–metabolic syndrome: The role of combining GLP-1RAs and SGLT-2is

Key Points

Structured PICO

Limitations

Implication

Abstract

Discussion

Cite This Study

Disease-modifying approach to cardiovascular–kidney–metabolic syndrome: The role of combining GLP-1RAs and SGLT-2is

Key Points

Structured PICO

Limitations

Implication

Abstract

Discussion

Cite This Study

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