Digging deep into cells to find mechanisms of kidney protection by SGLT2 inhibitors

Tuttle, Katherine R.

doi:10.1172/jci167700

Cited by 12 publications

(12 citation statements)

References 25 publications

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“…They decrease Na + reabsorption in the proximal tubule by decreasing Na + -coupled glucose transport and reducing sodium–hydrogen exchanger (NHE) 3 activity, thereby regulating the glomerular filtration rate and preventing harmful hyperfiltration. SGLT2i also regulate renal oxygen consumption and maintain renal mitochondrial homeostasis, thereby lowering the urinary albumin to creatinine ratio. − There are four main mechanisms that explain the cardioprotective effect of SGLT2i. First, SGLT2i inhibit NHE1 in cardiomyocytes, which lowers the intracellular sodium level and prevents calcium overload.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Sodium-Glucose Cotransporter 2 Inhibitors in Patients with Acute Coronary Syndrome

Song,

Liu,

et al. 2024

ACS Pharmacol. Transl. Sci.

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The evidence for sodium-glucose cotransporter 2 inhibitors (SGLT2i) in the treatment of type 2 diabetes or chronic heart failure was sufficient but lacking in acute coronary syndrome (ACS). Our aim was to investigate the effects of SGLT2i on cardiovascular outcomes in ACS patients. Studies of SGLT2i selection in ACS patients were searched and pooled. Outcomes included all-cause death, adverse cardiovascular events, cardiac remodeling as measured by the left ventricular end-diastolic dimension (LVEDD) and left ventricular end-systolic dimension (LVESD), cardiac function as assessed by the left ventricular ejection fraction (LVEF) and NT-proBNP, and glycemic control. Twenty-four studies with 12,413 patients were identified. Compared to the group without SGLT2i, SGLT2i showed benefits in reducing all-cause death (OR 0.72, 95% CI [0.61, 0.85]), major adverse cardiovascular events (MACE) (OR 0.44, 95% CI [0.30, 0.64]), cardiovascular death (OR 0.66, 95% CI [0.54, 0.81]), heart failure (OR 0.52, 95% CI [0.44, 0.62]), myocardial infarction (OR 0.68, 95% CI [0.56, 0.83]), angina pectoris (OR 0.37, 95% CI [0.17, 0.78]), and stroke (OR 0.48, 95% CI [0.24, 0.96]). Results favored SGLT2i for LVEDD (MD −2.03, 95% CI [−3.29, −0.77]), LVEF (MD 3.22, 95% CI [1.71, 4.72]), and NT-proBNP (MD −171.53, 95% CI [−260.98, −82.08]). Thus, SGLT2i treatment reduces the risk of all-cause death and MACE and improves cardiac remodeling and function in ACS patients.

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Section: Discussionmentioning

confidence: 99%

Efficacy of Sodium-Glucose Cotransporter 2 Inhibitors in Patients with Acute Coronary Syndrome

Song,

Liu,

et al. 2024

ACS Pharmacol. Transl. Sci.

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“…Previous studies suggest that combining treatments with ACE inhibitors, ARBs, MRAs, and/or SGLT2 inhibitors may provide additive benefits [28][29][30]. Since AS inhibitors may counter the activities of aldosterone more fully than MRAs, their use has the potential to enhance favorable glomerular hemodynamic effects as well as direct cellular metabolic and anti-inflammatory actions of SGLT2 inhibitors [22,23,[31][32][33]. Thus, due to their complementary mechanisms of action, the potentially additive kidney protective activity of BI 690517 and empagliflozin warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

Methods Article for a Study Protocol: Study Design and Baseline Characteristics for Aldosterone Synthase Inhibition in Chronic Kidney Disease

Tuttle,

Rossing,

Hauske

et al. 2023

Am J Nephrol

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Introduction: Aldosterone synthase (AS) inhibition may overcome increased aldosterone production in response to renin–angiotensin system inhibition. BI 690517 is an AS inhibitor under investigation for chronic kidney disease (CKD). Methods: This multinational, Phase II, double-blind study (NCT05182840) investigated the efficacy and safety of daily oral BI 690517, with or without empagliflozin 10 mg, in participants with CKD. The primary endpoint was change from baseline in urine albumin:creatinine ratio (UACR) at week 14. Between February 18, 2022, and December 30, 2022, 714 adults already treated by angiotensin-converting enzyme inhibitor (30.5%) or angiotensin receptor blocker (69.8%) were randomized (1:1) to an 8-week run-in to assign background empagliflozin (n = 356) or placebo (n = 358). Participants in each group were then randomized (1:1:1:1) to a 14-week treatment period with BI 690517 (3 mg, 10 mg, or 20 mg) or placebo. Of the 714 participants who entered run-in, 586 were randomized to the treatment period. They were predominantly men (66.6%) of White race (58.4%) with a mean (standard deviation [SD]) age of 63.8 (11.3) years. Type 2 diabetes was present in 414 participants (70.6%). The baseline mean (SD) estimated glomerular filtration rate was 51.9 (17.7) mL/min/1.73 m2 and median (interquartile range) UACR was 426.3 mg/g (205.3–888.5). Conclusion: This study will inform dose selection for further clinical development and determine whether BI 690517, with or without background empagliflozin, has a favorable safety profile and potential for additive kidney protection in participants with CKD already treated with a renin–angiotensin system inhibitor.

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“…52 In recent years, there is an emerging understanding that SGLT2 inhibitors activate autophagy by favorably influencing mammalian target of rapamycin (mTOR), 59adenosine monophosphate-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and hypoxia-inducible factor (HIF) signaling pathways (Figure 5). [54][55][56] mTOR protein complex 1 (mTORC1) is a serinethreonine kinase protein complex that integrates nutrient signals, including from glucose and amino acid, to stimulate anabolism and suppress autophagy in a state of calorie excess. 59 Proximal tubular mTORC1 is believed to play a significant role in DKD.…”

Section: Regulation Of Autophagy and Maintenance Of Cellular Homeostasismentioning

confidence: 99%

“…SGLT2 inhibitors create negative energy balance which stimulates nutrient deprivation sensors in tissues 53. Tissues respond to nutrient deficiency by inducing pathways that inhibit mTORC1 and stimulate AMPK and SIRT1 [54][55][56]. SIRT1 stimulates AMPK and HIF-2a and suppresses HIF-1a 53,57,58.…”

mentioning

confidence: 99%

SGLT2 Inhibitors and Kidney Protection: Mechanisms Beyond Tubuloglomerular Feedback

Upadhyay

2024

Kidney360

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Sodium-glucose cotransporter 2 (SGLT2)-inhibitors reduce the risk for kidney failure and are a key component of guideline-directed therapy for chronic kidney disease. While SGLT2-inhibitors’ ability to activate tubulo-glomerular feedback and reduce hyperfiltration-mediated kidney injury is considered to be the central mechanism for kidney protection, recent data from experimental studies raises questions on the primacy of this mechanism. This review examines SGLT2-inhibitors’ role in tubulo-glomerular feedback and summarizes emerging evidence on following of SGLT2-inhibitors’ other putative mechanisms for kidney protection: optimization of kidney’s energy substrate utilization and delivery, regulation of autophagy and maintenance of cellular homeostasis, attenuation of sympathetic hyperactivity, and improvement in vascular health and microvascular function. It is imperative to examine the impact of SGLT2 inhibition on these different physiologic processes to help our understanding of mechanisms underpinning kidney protection with this important class of drugs.

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Digging deep into cells to find mechanisms of kidney protection by SGLT2 inhibitors

Cited by 12 publications

References 25 publications

Efficacy of Sodium-Glucose Cotransporter 2 Inhibitors in Patients with Acute Coronary Syndrome

Efficacy of Sodium-Glucose Cotransporter 2 Inhibitors in Patients with Acute Coronary Syndrome

Methods Article for a Study Protocol: Study Design and Baseline Characteristics for Aldosterone Synthase Inhibition in Chronic Kidney Disease

SGLT2 Inhibitors and Kidney Protection: Mechanisms Beyond Tubuloglomerular Feedback

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