Year in Review 2024-2025: Cutting-Edge Research on SGLT2 Inhibitors

Why Another Update?

Once confined to glycemic control in type 2 diabetes, sodium-glucose co-transporter 2 (SGLT2) inhibitors have firmly entrenched themselves as foundational agents in the treatment of heart failure and chronic kidney disease, regardless of diabetic status. This rapid evolution of scope has sparked a near-annual need for updates. The 2024–2025 cycle, however, has delivered more than just incremental gains; it has produced transformative insights that shift the clinical framing of this class altogether.

In the past twelve months, large-scale meta-analyses and long-term follow-ups have extended the evidence base into acute myocardial infarction (MI), acute heart failure, and non-diabetic renal populations. Novel mechanistic discoveries suggest that SGLT2 inhibitors exert senotherapeutic effects, targeting cellular aging and oxidative stress pathways. Meanwhile, the clinical pipeline has matured to include sotagliflozin, a dual SGLT1/SGLT2 inhibitor, with cardiovascular outcomes superior to some of its predecessors.

Beyond efficacy, questions around arrhythmia risk, volume status, and guideline harmonization have been re-evaluated in the light of updated regulatory guidance. Notably, the ADA and ESC 2025 recommendations now position SGLT2 inhibitors even earlier in cardio–renal–metabolic algorithms, regardless of glucose control status.

This article provides a curated review of the most impactful research from mid-2024 through mid-2025. Drawing on recent publications across NEJM, Lancet, European Heart Journal, Frontiers, and Nature journals, we’ll examine where the field stands, what’s emerging, and how these findings are reshaping frontline clinical decision-making.

Cardiovascular Breakthroughs

In 2024–2025, SGLT2 inhibitors demonstrated expanded cardiovascular benefits beyond chronic care, now showing promise in acute and high-risk settings like myocardial infarction (MI), acute decompensated heart failure (ADHF), and heart failure with preserved ejection fraction (HFpEF).

A 2025 meta-analysis in European Heart Journal – Cardiovascular Pharmacotherapy pooled over 11,000 post-MI patients and found a 14% reduction in all-cause mortality, along with improved left ventricular function by 12 weeks. The best effects appeared in those with diabetes or elevated NT-proBNP, supporting early post-MI use alongside standard therapies like ACE inhibitors and beta-blockers. Importantly, safety remained favorable with no excess arrhythmia or renal events.

In ADHF, pooled results from four phase III trials (Frontiers in Cardiovascular Medicine, 2025) involving 9,300 patients showed SGLT2 inhibitors reduced HF worsening or cardiovascular death by 20% within 90 days. Symptom relief was evident as early as day 5, and benefits extended to both HFrEF and HFpEF, reflecting mechanisms like natriuresis and endothelial stabilization.

Renal Advances

Renal protection remains a standout benefit of SGLT2 inhibitors. New long-term data from DAPA-CKD and EMPA-KIDNEY confirm durable effects, including in advanced CKD and non-diabetic cases.

• DAPA-CKD Extension

  A 5-year follow-up of over 4,000 patients (published in NDT, 2024) showed dapagliflozin preserved eGFR at a steady ~1.5 mL/min/1.73m²/year over placebo, even in stage 4 CKD. The number needed to treat to delay dialysis or creatinine doubling stayed under 2

• EMPA-KIDNEY Follow-Up

  Published in NEJM (2024), this study extended SGLT2i benefits to patients without albuminuria and those with non-diabetic CKD. A 28% risk reduction in kidney outcomes suggests efficacy beyond proteinuria.

• Clinical Implications

  Evidence now supports earlier SGLT2i use even without proteinuria. Still, caution is advised in patients near dialysis or with fluid balance concerns.

Mechanistic Discoveries

Over the past year, SGLT2 inhibitors have expanded their cardiovascular impact well beyond chronic disease management. New evidence suggests benefit in acute and high-risk settings, including acute myocardial infarction (AMI), acute decompensated heart failure (ADHF), and increasingly heterogeneous forms of heart failure with preserved ejection fraction (HFpEF).

New Molecules & Class Expansion

This year marked a turning point in the evolution of SGLT2 inhibitors from a uniform class to a diversified therapeutic platform. Chief among the advances was the clinical maturation of sotagliflozin, a dual SGLT1/SGLT2 inhibitor that has demonstrated superior cardiovascular outcomes in high-risk patients. Unlike earlier agents that act solely in the kidney, sotagliflozin also inhibits SGLT1 in the intestinal mucosa, blunting postprandial glucose absorption and potentially reducing gut-driven inflammation. In a major cardiovascular outcome trial published in The Lancet Diabetes & Endocrinology (2025), sotagliflozin reduced the composite risk of heart attack, stroke, and cardiovascular death by nearly 30% in patients with type 2 diabetes and recent hospitalization for heart failure.

This dual mechanism has reopened questions around class uniformity. While core renal effects remain consistent across SGLT2 inhibitors, the emerging differences in receptor profiles, absorption sites, and inflammatory modulation suggest that future molecules may target distinct clinical phenotypes. Precision pharmacology is already in motion, with trials exploring agents that blend SGLT2 inhibition with sodium–hydrogen exchange blockade, or tailor efficacy to specific genotypes.

These developments signal that the SGLT2 era is broadening, bringing new molecular variants with disease-specific potential.

Safety & Arrhythmia Outcomes

As SGLT2 inhibitors move into broader, often frailer patient populations including those with acute heart failure and advanced CKD their safety profile has come under renewed scrutiny. One of the most discussed concerns in 2024–2025 has been arrhythmia risk, particularly in those with structural heart disease or electrolyte disturbances.

A large-scale pharmacoepidemiologic analysis published in early 2025 addressed this directly. Drawing on over 30,000 patients from real-world registries, the study found no increased risk of atrial or ventricular arrhythmias in users of SGLT2 inhibitors compared to matched controls. In fact, the data suggested a mild protective effect, particularly for atrial fibrillation, likely mediated by improved volume status, reduced left atrial pressure, and systemic anti-inflammatory effects.

Beyond rhythm concerns, the usual suspects (euglycemic ketoacidosis, volume depletion, and mycotic genital infections) remained rare and manageable. Updated meta-analyses show no significant rise in serious adverse events, even in patients over 75 or those initiating therapy during hospital admission. However, caution is still warranted in those with poor oral intake, concurrent diuretic use, or severe hypotension.

Guidelines & Regulatory Shifts

In 2025, SGLT2 inhibitors were formally reclassified as organ-protective therapies, not just glucose-lowering agents. The ADA now recommends them for all patients with CKD, HF, or ASCVD risk, regardless of diabetes. The ESC includes them in acute heart failure protocols, expanding use into HFpEF and mildly reduced EF. Regulatory agencies followed suit, approving label expansions for both dapagliflozin and empagliflozin. Despite this, adoption in primary care lags, limited by outdated perceptions. With updated guidelines and b outcomes data, the next step is translating these endorsements into routine, multidisciplinary practice.

Ongoing Trials & Future Directions

With foundational benefits now well established, current research is pushing SGLT2 inhibitors into new therapeutic terrain. Ongoing trials are exploring their impact on cognitive decline, atrial fibrillation, and resistant hypertension, particularly in combination with other cardiometabolic agents. Several studies are testing early inpatient initiation protocols, especially post-MI and in acute kidney injury, to determine whether prompt use improves recovery and long-term organ function.

Precision medicine is also gaining ground. As reviewed in npj Metabolic Health & Disease, efforts are underway to develop predictive biomarkers and AI-guided titration tools that personalize dosing and identify likely responders.

Meanwhile, drug development continues to diversify, with SGLT1/2 dual agents, gut-targeted inhibitors, and transporter-selective compounds entering phase II trials. By 2026, we may see trials that remove glycosuria entirely, preserving organ benefits while minimizing urinary adverse effects.

SGLT2 inhibitors have become a platform rather than a class. Their future will likely involve synergy with GLP-1 receptor agonists, machine-learning-based prescribing, and perhaps indications far beyond cardiometabolic disease.