sodium glucose cotransporter-2 (SGLT2) inhibitors

Overview

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a class of oral glucose-lowering drugs, developed for type 2 diabetes and now used more broadly as cardiorenal protective therapy. They act on SGLT2, the transporter responsible for the majority of filtered glucose reabsorption in the proximal tubule of the nephron. Blocking this transporter lowers the renal threshold for glucose, producing glycosuria and an insulin-independent fall in plasma glucose. Because the mechanism does not depend on beta-cell secretion, the class carries little intrinsic hypoglycaemia risk when used without Insulin Therapy or sulfonylureas. Accompanying natriuresis and osmotic diuresis contribute to reductions in blood pressure, plasma volume, and body weight, and the same tubular effects restore tubuloglomerular feedback, causing an expected early dip in glomerular filtration rate that precedes longer-term preservation of kidney function. empagliflozin, dapagliflozin, and canagliflozin are the agents most often studied as representatives of the class.

Clinically, SGLT2 inhibitors occupy a place in cardiometabolic care that extends past glycaemic control, with established roles in heart failure and in chronic kidney disease, including diabetic kidney disease, whether or not diabetes is present. They are commonly considered alongside metformin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists such as semaglutide, the non-steroidal mineralocorticoid receptor antagonist finerenone, and statins, and combination use with these agents is an active area of investigation. The principal class-specific safety considerations follow directly from the mechanism: glycosuria predisposes to genital mycotic infections and urinary tract infections, and volume depletion and euglycaemic ketoacidosis are recognised risks, concerns that carry particular weight in older adults and in patients with chronic renal insufficiency and substantial polypharmacy.

Recent Publications Summary (latest 30 papers)

Recent publications on sodium-glucose cotransporter-2 (SGLT2) inhibitors were dominated by real-world comparative effectiveness studies in type 2 diabetes and related cardio-renal populations. In Indonesian patients with type 2 diabetes, a 12-month multicenter retrospective cohort found that SGLT2 inhibitor use was associated with significant improvements in HbA1c, fasting plasma glucose, body weight, BMI, systolic and diastolic blood pressure, lipid profile, and ASCVD risk in paired analyses 42467634Jul. In older adults aged ≥65 years, SGLT2 inhibitor use was associated with renoprotective effects, including lower risk of 30% and 50% eGFR decline after propensity score matching 42439602Jul. Similar kidney-focused questions were addressed in patients with preserved kidney function, where individual SGLT2 inhibitors were compared for prevention of new-onset proteinuria 41804189Mar, and in Japanese patients with type 2 diabetes and obesity, where renal outcomes were compared between SGLT2 inhibitors and GLP-1 receptor agonists 41838277Mar.

Several studies examined cardiovascular and heart failure-related applications, including precision prescribing and combination therapy. A model development and validation study aimed to predict individual-level heart failure benefit from SGLT2 inhibitors in people with type 2 diabetes without ASCVD, heart failure, or CKD 42160591May. Another study evaluated SGLT2 inhibitor initiation among older sacubitril-valsartan users with heart failure in routine practice 42098937May, while a randomized trial protocol proposed empagliflozin after transcatheter aortic valve implantation to improve left ventricular diastolic function in patients with preserved LVEF 42082222May. Additional work assessed early SGLT2 inhibitor use after acute myocardial infarction in diabetes 41392024Dec, cardiovascular outcomes in patients undergoing peripheral artery revascularization 42055167Apr, QTc interval and ventricular arrhythmia in diabetes with hypertension and coronary artery disease 41879409Mar, and comparative cardiovascular effectiveness versus GLP-1 receptor agonists in diabetes and in metabolic dysfunction-associated steatotic liver disease (MASLD) with type 2 diabetes 41984016Apr41802676Mar. A randomized controlled trial also explored combined statin and dapagliflozin therapy in ischemic heart disease with heart failure 42133048May.

Other publications focused on safety, comorbidity-specific use, and broader real-world outcomes. In India, investigators examined urinary tract and genital tract infections with SGLT2 inhibitors alone or combined with dipeptidyl peptidase-4 inhibitors 42163184May, while a population-based target trial emulation evaluated SGLT2 inhibitor safety and efficacy in patients with psoriasis and comorbid type 2 diabetes 41655841Feb. In chronic kidney disease, one study assessed nephrotoxic medication burden, drug-related problems, kidney failure risk, and patient-reported outcomes among patients receiving SGLT2 inhibitors in a nephrology outpatient clinic 42336367Jun. In end-stage kidney disease with type 2 diabetes, a target trial emulation compared SGLT2 inhibitors with DPP-4 inhibitors for mortality and other clinical outcomes 42086691May. Additional real-world studies examined outcomes in elderly patients 42439602Jul, in type 1 diabetes after dialysis-requiring acute kidney injury 42049097Apr, and in adults with type 1 diabetes and chronic kidney disease receiving cardio-kidney-metabolic therapies 41816887Mar. Beyond cardio-renal disease, SGLT2 inhibitors were also studied in bladder cancer survival 42224918Jun, advanced non-small cell lung cancer with diabetes 42049990Apr, persistent pulmonary nodules 41797126Mar, and mild cognitive impairment through proteomics and molecular docking approaches 41587770Jan.

What Changes, What Holds

1. Real-world data mostly reinforce the class’s metabolic and renal profile, with some comparative questions still unsettled
REINFORCES Recent observational work is broadly consistent with the Overview’s account of glucose lowering, weight loss, blood-pressure reduction, and kidney protection, and it extends those effects into routine care and older adults 42467634Jul42439602Jul. The new comparisons on proteinuria prevention and on SGLT2 inhibitors versus GLP-1 receptor agonists do not overturn the established role; they mainly suggest that relative renal advantages may vary by population and comparator, so head-to-head effectiveness remains incompletely settled 41804189Mar41838277Mar.

2. New studies refine who benefits from cardiovascular use, but they do not displace the established heart-failure role
REINFORCES Work on individualized prediction, post-valve intervention use, post-infarction initiation, arrhythmia-related outcomes, and combination therapy mainly sharpens implementation questions around the already accepted cardiorenal benefits of the class 42160591May42098937May. Comparative studies against GLP-1 receptor agonists and the statin-plus-dapagliflozin trial add nuance about where SGLT2 inhibitors fit in multimorbidity, but they do not challenge the Overview’s statement that heart failure is a core indication 41984016Apr42133048May.

3. safety and special-population studies add caution, while broader off-label outcome signals remain exploratory
NEW DIRECTION The new infection analyses and nephrology-clinic data deepen the adverse-effect and polypharmacy concerns already noted in the Overview, but they do not contradict it 42163184May42336367Jun. What is more novel is the spread into settings the baseline does not cover, including end-stage kidney disease, type 1 diabetes after dialysis-requiring acute kidney injury, and several cancer- or cognition-related outcomes; these are exploratory extensions rather than established uses, and they leave the core cardiorenal account intact 42086691May42049097Apr.

Overview update candidates: none.