Pleiotropic Effects of Sodium-Glucose Cotransporter-2 Inhibitors in Cardiovascular Disease and Chronic Kidney Disease

Cardiovascular disease (CVD), chronic kidney disease (CKD), and type 2 diabetes (T2D) frequently coexist along a cardiorenal continuum and collectively contribute to substantial morbidity and mortality. T2D increases the risk of both macrovascular and microvascular complications, is an independent risk factor for heart failure (HF), and is the most common cause of CKD. Over the past decade, sodium-glucose cotransporter-2 inhibitors (SGLT2is), originally developed as glucose-lowering agents, have demonstrated robust cardiovascular and renal benefits in randomized outcome trials among patients with and without T2D, across the spectrum of HF phenotypes and CKD stages. Despite consistent clinical benefits, the precise mechanisms underpinning these effects—beyond glucose lowering—remain incompletely defined. This narrative review aims to summarize the glucose-independent mechanisms that may explain the observed cardiovascular and renal protection with SGLT2is.

This narrative review synthesizes evidence from cardiovascular outcomes trials (CVOTs), renal outcomes studies, and HF trials evaluating SGLT2 inhibitors across diverse populations (T2D with established CVD or multiple risk factors, CKD, HFrEF, HFmrEF, and HFpEF). It integrates mechanistic data from clinical and preclinical studies on renal hemodynamics (tubuloglomerular feedback), natriuresis/diuresis, sympathetic nervous system modulation, hematologic changes, uric acid metabolism, intracellular sodium handling (NHE), anti-inflammatory/antioxidant and antiplatelet effects, and metabolic reprogramming (ketone bodies and fatty acid utilization). The review contextualizes guideline recommendations (AHA/ACC/HFSA, ESC, ADA/EASD, UK Kidney Association) endorsing SGLT2is for reducing HF events, major adverse cardiovascular events (MACE), cardiovascular death, and CKD progression in patients with and without T2D.

Targeted PubMed search of English-language publications (July 2015–December 2022) using terms related to SGLT2 inhibitors and specific agents (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, sotagliflozin), conditions (heart failure, chronic kidney disease, type 2 diabetes mellitus), and mechanisms (mechanism of action, glomerular pressure, sympathetic nervous system, hematocrit, uric acid, electrolytes, preload/afterload). Clinical studies and meta-analyses were included; additional relevant studies were identified from reference lists of retrieved articles. This is a narrative (not systematic) review.

- Clinical outcome benefits across populations: SGLT2is reduce HF hospitalization and improve renal outcomes in patients with and without T2D, across EF spectrum and CKD stages. - CVOT highlights: CANVAS (canagliflozin) reduced MACE HR 0.86 and CV death or HHF HR 0.78; DECLARE-TIMI 58 (dapagliflozin) reduced CV death or HHF HR 0.83 and HHF HR 0.73; EMPA-REG OUTCOME (empagliflozin) reduced MACE HR 0.86, CV death HR 0.62, HHF HR 0.65; VERTIS-CV (ertugliflozin) reduced HHF HR 0.70; all showed favorable renal signals with composite renal HRs typically ~0.5–0.8 depending on definition. - Renal protection: SGLT2is restore tubuloglomerular feedback, lower intraglomerular pressure, and mitigate hyperfiltration, leading to long-term preservation of eGFR. An initial eGFR dip (~5 mL/min/1.73 m2 within 2–6 weeks) is hemodynamic, stabilizes, and is not associated with worse long-term decline. - Albuminuria: Significant reductions in UACR across T2D and CKD populations, including with baseline micro- and macroalbuminuria; effects reverse upon discontinuation, supporting hemodynamic mechanisms. - AKI: Meta-analysis of CVOTs shows 34% reduced AKI risk versus placebo; DAPA-CKD and DAPA-HF showed 32–44% reductions in abrupt kidney function decline. - Hemodynamics/volume: Early diuretic and natriuretic effects produce ~1–2 kg decrease in total body water, ~6% sodium loss, and plasma volume contraction; associated sustained BP reductions ~5/2 mmHg without tachycardia or orthostatic hypotension. - Congestion and diuretics: Preferential interstitial fluid reduction; synergy with loop diuretics in HFrEF enabling dose reductions. - Afterload surrogates: Reductions in central SBP, pulse pressure, MAP, double product, and aortic pulse wave velocity indicate reduced arterial stiffness; potential vasodilation via PKG and Kv channels. - Potassium: Lower risk of moderate hyperkalemia across T2D/CKD and HF (HFrEF/HFpEF) without increased hypokalemia, including in patients on RAAS blockers and MRAs. - Cardiac structure/function: Reductions in LV mass index and end-diastolic volumes; improved diastolic parameters and global longitudinal strain in HFpEF; reductions in atrial and ventricular volumes in HFrEF. - Arrhythmias: In DAPA-HF, dapagliflozin reduced risk of any ventricular arrhythmia, resuscitated cardiac arrest, or sudden death by 21% versus placebo. - Sympathetic nervous system: Evidence of sympathoinhibition from animal models and small clinical studies (reduced MSNA, improved HRV metrics), potentially contributing to cardiorenal benefits. - Hematologic effects: Increases in erythropoietin, reticulocytes, hemoglobin, hematocrit, and red cell mass sustained long-term; reduced anemia risk and need for iron/ESA; mechanisms may involve hepcidin suppression and improved renal cortical oxygenation. - Uric acid: Sustained reductions in serum uric acid with fewer hyperuricemic events; effect attenuated with lower eGFR. - Intracellular sodium/NHE: Mixed evidence; some preclinical data suggest NHE inhibition and reduced intracellular Na+/Ca2+ in cardiomyocytes/endothelium, whereas other studies do not confirm direct NHE inhibition. - Anti-inflammatory, antiplatelet, antioxidant: Reductions in inflammatory markers (e.g., IL-6, TNF-α, hsCRP), platelet reactivity, oxidative stress; increases in antioxidant capacity. - Metabolic reprogramming: Fasting-like state with increased fatty acid and ketone utilization and potential mTOR attenuation/mitochondrial benefits; rare risk of euglycemic DKA noted across trials.

The review consolidates clinical and mechanistic evidence showing that SGLT2 inhibitors provide cardiovascular and renal protection beyond glucose lowering. Central to renal benefit is restoration of tubuloglomerular feedback, reducing intraglomerular pressure and albuminuria and slowing eGFR decline. Hemodynamic effects—modest plasma volume contraction, reduced preload and afterload, and arterial stiffness improvements—likely underlie rapid reductions in HF hospitalization. Additional mechanisms—including sympathoinhibition, mitigation of hyperkalemia risk, improvements in LV remodeling, increased oxygen delivery via hematologic effects, uric acid lowering, and potential anti-inflammatory/antioxidant actions—contribute to broad benefits observed across T2D and non-T2D populations. While natriuresis/diuresis initiates early changes, sustained outcomes appear multifactorial and independent of mean BP reduction or glycemia. These insights support contemporary guideline recommendations endorsing SGLT2is across the HF spectrum and in CKD irrespective of diabetes status.

SGLT2 inhibitors confer robust cardiovascular and renal benefits across patients with and without type 2 diabetes, heart failure across the EF spectrum, and chronic kidney disease. Benefits arise from integrated mechanisms: restoration of tubuloglomerular feedback and reduced intraglomerular pressure, favorable hemodynamic shifts (reduced preload/afterload), sympathoinhibition, mitigation of hyperkalemia, improved cardiac remodeling, hematologic enhancements, uric acid lowering, and anti-inflammatory/antioxidant effects. Initially developed as antihyperglycemics, SGLT2is now represent foundational therapy in HF and CKD. Future research should further delineate causal pathways linking mechanistic changes to clinical outcomes, clarify the role of NHE modulation, and identify biomarkers to personalize therapy and predict responders.

- Narrative (not systematic) review with a targeted search; potential selection bias and incomplete capture of all relevant studies. - Mechanistic inferences are partly based on small clinical studies or preclinical models; causal links to outcomes remain partly speculative. - Heterogeneity across trials in populations, endpoints, and renal composite definitions limits direct comparisons of effect sizes. - Some safety observations (e.g., AKI, euglycemic DKA) derive from post-marketing reports or trial subgroup analyses and may be underpowered for rare events. - Funding support from industry (AstraZeneca) may introduce potential bias, although the article declares conflicts of interest and uses peer-reviewed sources.