Evolution of sodium-glucose co-transporter 2 inhibitors from a glucose-lowering drug to a pivotal therapeutic agent for cardio-renal-metabolic syndrome

Abstract

Cardio-renal-metabolic (CRM) syndrome, which involves type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), and heart failure (HF), is a serious healthcare issue globally, with high morbidity and mortality. The disorders that comprise CRM syndrome are independent can mutually affect and accelerate the exacerbation of each other, thereby substantially increasing the risk of mortality and impairing quality of life. To manage CRM syndrome by preventing vicious interactions among individual disorders, a holistic treatment approach that can simultaneously address multiple disorders underpinning CRM syndrome is of great importance. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) lower blood glucose levels by inhibiting glucose reabsorption in the renal proximal tubule and were first indicated for the treatment of T2DM. Several cardiovascular outcome trials have demonstrated that SGLT2i not only lower blood glucose but also reduce the risk of hospitalization for HF and worsening renal function in patients with T2DM. Results have also suggested that the observed cardiorenal benefits of SGLT2i may be independent of their blood glucose-lowering effects. Several randomized controlled trials subsequently assessed the efficacy and safety of SGLT2i in patients without T2DM, and revealed considerable benefits of SGLT2i treatment against HF and CKD, regardless of the presence of T2DM. Thus, SGLT2i have become an essential therapeutic option to prevent the onset, slow the progression, and improve the prognosis of CRM syndrome. This review assesses the evolution of SGLT2i from a glucose-lowering drug to a therapeutic agent for CRM syndrome by evaluating epoch-making clinical studies, including randomized control trials and real-world studies.

Glucose Deprivation Promotes Pseudohypoxia and Dedifferentiation in Lung Adenocarcinoma

“…Our work provides evidence that these treatments are effective in reducing the tumor burden, but are also likely to cause an epigenetic adaptation of cancer cells to glucose restriction, leading to an unexpected and unintended dedifferentiation and increased aggressiveness of treated tumors driven by pseudohypoxia. SGLT2 inhibitors are FDA approved for diabetes, heart failure, and chronic kidney disease ( 54 ). Since the first SGLT2 inhibitors were introduced a decade ago, epidemiologic evidence is starting to emerge showing improved cancer outcomes in diabetic patients treated with SGLT2 inhibitors ( 13, 14 ), confirming the beneficial effects of these drugs against cancer.…”

Challenging Clinical Perspectives in Type 2 Diabetes with Tirzepatide, a First-in-Class Twincretin

“…A holistic approach to CRM care that recognises the interconnected nature of these disorders may improve patient outcomes compared with isolated treatment of the individual conditions [ 47 – 50 ]. Although SGLT2i have offered a therapeutic option for CRM syndrome [ 48 ], there remains an unmet need for effective agents in this area.…”

Prospects of using sodium-glucose co-transporter-2 (SGLT-2) inhibitors in patients with metabolic-associated fatty liver disease (MAFLD)

“…На жаль, при дотриманні принципів пацієнт-орієнтованого підходу корекції вуглеводного обміну у коморбідних пацієнтів із МАЖХП (ЦД 2-го типу, АССЗ, СН, НАСГ та ін. ), акцентуючи увагу на кар- Відомо більшість позитивних метаболічних ефектів іНЗКТГ2: втрата ваги (на 2-3 %), позитивні кардіо-та ренопротекторні властивості, покращення показників ліпідного обміну та сечової кислоти [60][61][62][63][64][65]. Доступні дослідження, що оцінюють роль іНЗКТГ2 у лікуванні НАЖХП / НАСГ, обмежені відносно малими розмірами вибірок досліджуваних осіб без ЦД та відсутністю гістологічних результатів пункційної біопсії печінки.…”