SGLT-2

Effects of Dapagliflozin on EChOcardiographic Measures of CarDiac StructurE and Function in Patients with CKD

tor.biering@gmail.com — Sun, 18 Dec 2022 08:41:27 GMT-08:00

Background: SGLT2 inhibitors, originally developed as glucose-lowering agents for treatment of type 2 diabetes, have been shown to have cardio- and kidney protective effects among chronic kidney disease (CKD) patients with and without diabetes. However, the mechanisms remain largely unknown. Methods: DECODE-CKD is an investigator-initiated, prospective, single-center, randomized, placebo-controlled trial evaluating the effects of 6 months of treatment with 10 mg of dapagliflozin compared with placebo on cardiac structure and function in 222 adults with CKD. The primary objective is to assess whether dapagliflozin improves LV mass index. Secondary and exploratory endpoints include changes in cardiac- and kidney markers, quality of life, depressive symptoms, and cognitive function. Conclusions: This is the first study to address the effects of SGLT2 inhibitors on cardiac structure and function in patients with CKD. The results will provide valuable insights into the mechanisms underlying the cardioprotective benefits of SGLT2 inhibitors in patients with CKD.

A Blueprint for Assessing Affordability of SGLT2 Inhibitors in the United States

Khine, Annika — Wed, 02 Nov 2022 07:07:07 GMT-07:00

Estimated Lifetime Benefit of Combined RAAS and SGLT2 Inhibitor Therapy in Patients with Albuminuric CKD without Diabetes

Vart, Priya — Tue, 22 Nov 2022 05:49:08 GMT-08:00

Toward Guideline-Directed Medical Therapy in Nephrology

Zeitler, Evan M. — Tue, 22 Nov 2022 07:10:33 GMT-08:00

Cost-Effectiveness of Dapagliflozin as a Treatment for Chronic Kidney Disease

McEwan, Phil — Wed, 02 Nov 2022 06:03:30 GMT-07:00

Sodium-Glucose Cotransporter 2 Inhibitors and Urinary Tract Infection: Is There Room for Real Concern?

Wiegley, Nasim — Mon, 12 Sep 2022 11:24:13 GMT-07:00

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have revolutionized our armamentarium for kidney and heart protection in patients with or without diabetes. Based on early reports of a limited number of cases, a concern for increased risk of urinary tract infections arose, which has become one of the main areas of concern for some clinicians. However, data from large randomized clinical trials and real-world population-based studies have not shown a significantly increased risk of UTI in patients on SGLT2 inhibitors. The goal of this brief review article is to review the literature and provide reassurance to patients and prescribers for the broader use of these agents.

Treatment Effect of the SGLT2 Inhibitor Empagliflozin on Chronic Syndrome of Inappropriate Antidiuresis: Results of a Randomized, Double-Blind, Placebo-Controlled, Crossover Trial

Refardt, Julie — Thu, 17 Nov 2022 05:40:59 GMT-08:00

Effects of Dapagliflozin in People without Diabetes and with Microalbuminuria

Heerspink, Hiddo J.L. — Fri, 09 Sep 2022 01:31:57 GMT-07:00

Correlates and Consequences of an Acute Change in eGFR in Response to the SGLT2 Inhibitor Dapagliflozin in Patients with CKD

Jongs, Niels — Wed, 17 Aug 2022 09:37:29 GMT-07:00

Kidney-Protective Effects of SGLT2 Inhibitors

Palmer, Biff F. — Tue, 11 Oct 2022 09:23:53 GMT-07:00

The sodium-glucose cotransporter 2 (SGLT2) inhibitors have become an integral part of clinical practice guidelines to slow the progression of CKD in patients with and without diabetes mellitus. Although initially developed as antihyperglycemic drugs, their effect on the kidney is multifactorial resulting from profuse glycosuria and natriuresis consequent to their primary site of action. Hemodynamic and metabolic changes ensue that mediate kidney-protective effects, including (1) decreased workload of proximal tubular cells and prevention of aberrant increases in glycolysis, contributing to a decreased risk of AKI; (2) lowering of intraglomerular pressure by activating tubular glomerular feedback and reductions in BP and tissue sodium content; (3) initiation of nutrient-sensing pathways reminiscent of starvation activating ketogenesis, increased autophagy, and restoration of carbon flow through the mitochondria without production of reactive oxygen species; (4) body weight loss without a reduction in basal metabolic rate due to increases in nonshivering thermogenesis; and (5) favorable changes in quantity and characteristics of perirenal fat leading to decreased release of adipokines, which adversely affect the glomerular capillary and signal increased sympathetic outflow. Additionally, these drugs stimulate phosphate and magnesium reabsorption and increase uric acid excretion. Familiarity with kidney-specific mechanisms of action, potential changes in kidney function, and/or alterations in electrolytes and volume status, which are induced by these widely prescribed drugs, will facilitate usage in the patients for whom they are indicated.

Dapagliflozin Prevents Kidney Glycogen Accumulation and Improves Renal Proximal Tubule Cell Functions in a Mouse Model of Glycogen Storage Disease Type 1b

D’Acierno, Mariavittoria — Tue, 12 Jul 2022 11:22:38 GMT-07:00

The Sweet Science of Glucose Transport

Sridhar, Vikas S. — Fri, 09 Sep 2022 08:51:00 GMT-07:00

Albuminuria-Lowering Effect of Dapagliflozin, Eplerenone, and Their Combination in Patients with Chronic Kidney Disease: A Randomized Crossover Clinical Trial

Provenzano, Michele — Tue, 19 Apr 2022 09:24:58 GMT-07:00

Moving from Evidence to Implementation of Breakthrough Therapies for Diabetic Kidney Disease

Tuttle, Katherine R. — Wed, 01 Jun 2022 11:56:25 GMT-07:00

Diabetic kidney disease is the most frequent cause of kidney failure, accounting for half of all cases worldwide. Moreover, deaths from diabetic kidney disease increased 106% between 1990 and 2013, with most attributed to cardiovascular disease. Recommended screening and monitoring for diabetic kidney disease are conducted in less than half of patients with diabetes. Standard-of-care treatment with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker is correspondingly low. Sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, and a nonsteroidal mineralocorticoid antagonist are highly effective therapies to reduce kidney and cardiovascular risks in diabetic kidney disease. However, <20% of eligible patients are receiving these agents. Critical barriers are high out-of-pocket drug costs and low reimbursement rates. Data demonstrating clinical and cost-effectiveness of diabetic kidney disease care are needed to garner payer and health care system support. The pharmaceutical industry should collaborate on value-based care by increasing access through affordable drug prices. Additionally, multidisciplinary models and communication technologies tailored to individual health care systems are needed to support optimal diabetic kidney disease care. Community outreach efforts are also central to make care accessible and equitable. Finally, it is imperative that patient preferences and priorities shape implementation strategies. Access to care and implementation of breakthrough therapies for diabetic kidney disease can save millions of lives by preventing kidney failure, cardiovascular events, and premature death. Coalitions composed of patients, families, community groups, health care professionals, health care systems, federal agencies, and payers are essential to develop collaborative models that successfully address this major public health challenge.

Safety of SGLT2 Inhibitors in CKD

Dobre, Mirela — Thu, 26 May 2022 07:04:51 GMT-07:00

Fracture Risk of Sodium-Glucose Cotransporter-2 Inhibitors in Chronic Kidney Disease

Cowan, Andrea — Thu, 26 May 2022 07:04:52 GMT-07:00

Empagliflozin Changes Urine Supersaturation by Decreasing pH and Increasing Citrate

Harmacek, Dusan — Wed, 06 Apr 2022 08:47:59 GMT-07:00

Clinical Trial registry name and registration number: Empagliflozin and Renal Oxygenation in Healthy Volunteers (EMPA-REIN), NCT03093103

A Call for Implementation Science: Achieving Equitable Access to SGLT2 Inhibitors

Claudel, Sophie E. — Wed, 02 Mar 2022 12:39:24 GMT-08:00

Changing the Trajectory of Heart Failure and Kidney Disease

Rangaswami, Janani — Tue, 01 Mar 2022 07:47:45 GMT-08:00

Learnings from Throwing Paint at the Wall for COVID-19 with an SGLT2 Inhibitor

Tuttle, Katherine R. — Thu, 28 Apr 2022 05:35:08 GMT-07:00

SGLT2 Inhibition and Uric Acid Excretion in Patients with Type 2 Diabetes and Normal Kidney Function

Suijk, Danii L.S. — Wed, 23 Mar 2022 08:31:11 GMT-07:00

Prescribing Patterns of Sodium-Glucose Cotransporter-2 Inhibitors in Patients with CKD: A Cross-Sectional Registry Analysis

Zhuo, Min — Wed, 19 Jan 2022 01:30:01 GMT-08:00

Drug-Induced Osmotic Nephropathy: Add SGLT2-Inhibitors to the List?

Perazella, Mark A. — Tue, 21 Dec 2021 01:32:50 GMT-08:00

Comparative Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Serum Electrolyte Levels in Patients with Type 2 Diabetes: A Pairwise and Network Meta-Analysis of Randomized Controlled Trials

Zhang, Jingjing — Wed, 19 Jan 2022 11:33:25 GMT-08:00

Assessment of Proximal Tubular Function by Tubular Maximum Phosphate Reabsorption Capacity in Heart Failure

Emmens, Johanna E. — Mon, 07 Feb 2022 10:00:33 GMT-08:00

SGLT2 Inhibitors: Physiology and Pharmacology

Wright, Ernest M. — Fri, 17 Sep 2021 09:47:50 GMT-07:00

SGLTs are sodium glucose transporters found on the luminal membrane of the proximal tubule, where they reabsorb some 180 g (1 mol) of glucose from the glomerular filtrate each day. The natural glucoside phlorizin completely blocks glucose reabsorption. Oral SGLT2 inhibitors are rapidly absorbed into the blood stream, where theyremain in the circulation for hours. On glomerular filtration, they bind specifically to SGLT2 in the luminal membrane of the early proximal tubule to reduce glucose reabsorption by 50%–60%. Because of glucose excretion, these drugs lower plasma glucose and glycosylated hemoglobin levels in patients with type 2 diabetes mellitus. The drugs also protect against heart and renal failure. The aim of this review is to summarize what is known about the physiology of renal SGLTs and the pharmacology of SGLT drugs.

Transforming the Care of Patients with Diabetic Kidney Disease

Brosius, Frank C. — Tue, 08 Jun 2021 06:52:50 GMT-07:00

Diabetes and its associated complications pose an immediate threat to humankind. Diabetic kidney disease is one of the most devastating complications, increasing the risk of death more than ten-fold over the general population. Until very recently, the only drugs proven and recommended to slow the progression of diabetic kidney disease were angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers, which act by inhibiting the renin-angiotensin system. Despite their efficacy as kidney and cardiovascular protective therapies and as antihypertensive agents, renin-angiotensin system inhibitors have been grossly underutilized. Moreover, even when renin-angiotensin system inhibitors are used, patients still have a high residual risk of diabetic kidney disease progression. Finally, the kidney-protective effect of renin-angiotensin system inhibitors has been categorically demonstrated only in patients with macroalbuminuria included in the Irbesartan Diabetic Nephropathy Trial (IDNT) and Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trials, not in other individuals. The lack of new therapies to treat diabetic kidney disease over the past 2 decades has therefore represented a tremendous challenge for patients and health care providers alike. In recent years, a number of powerful new therapies have emerged that promise to transform care of patients with diabetes and kidney disease. The challenge to the community is to ensure rapid implementation of these treatments. This white paper highlights advances in treatment, opportunities for patients, challenges, and possible solutions to advance kidney health, and introduces the launch of the Diabetic Kidney Disease Collaborative at the American Society of Nephrology, to aid in accomplishing these goals.

Are All SGLT2 Inhibitors Created Equal?

Gregg, L. Parker — Wed, 08 Sep 2021 05:37:36 GMT-07:00

Effects of Dapagliflozin in Stage 4 Chronic Kidney Disease

Chertow, Glenn M. — Fri, 16 Jul 2021 10:14:04 GMT-07:00

Euglycemic Ketoacidosis as a Complication of SGLT2 Inhibitor Therapy

Palmer, Biff F. — Tue, 09 Feb 2021 06:53:45 GMT-08:00

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are drugs designed to lower plasma glucose concentration by inhibiting Na+-glucose–coupled transport in the proximal tubule. Clinical trials demonstrate these drugs have favorable effects on cardiovascular outcomes to include slowing the progression of CKD. Although most patients tolerate these drugs, a potential complication is development of ketoacidosis, often with a normal or only a minimally elevated plasma glucose concentration. Inhibition of sodium-glucose cotransporter-2 in the proximal tubule alters kidney ATP turnover so that filtered ketoacids are preferentially excreted as Na+ or K+ salts, leading to indirect loss of bicarbonate from the body and systemic acidosis under conditions of increased ketogenesis. Risk factors include reductions in insulin dose, increased insulin demand, metabolic stress, low carbohydrate intake, women, and latent autoimmune diabetes of adulthood. The lack of hyperglycemia and nonspecific symptoms of ketoacidosis can lead to delays in diagnosis. Treatment strategies and various precautions are discussed that can decrease the likelihood of this complication.

Clinical Implications of an Acute Dip in eGFR after SGLT2 Inhibitor Initiation

Heerspink, Hiddo J. L. — Tue, 20 Apr 2021 11:01:49 GMT-07:00

Sodium-Glucose Cotransporter 2 Inhibitors and Kidney Transplantation: What Are We Waiting For?

Patel, Niralee — Thu, 22 Apr 2021 01:34:55 GMT-07:00

eGFR Decline after SGLT2 Inhibitor Initiation: The Tortoise and the Hare Reimagined

Meraz-Muñoz, Alejandro Y. — Fri, 26 Mar 2021 07:32:10 GMT-07:00

Payment, Coverage, and Health Economics of SGLT2 Inhibitors

Pham, Ngoc-Yen T. — Thu, 18 Mar 2021 09:25:01 GMT-07:00

Empagliflozin Inhibits Proximal Tubule NHE3 Activity, Preserves GFR, and Restores Euvolemia in Nondiabetic Rats with Induced Heart Failure

Borges-Júnior, Flávio A. — Mon, 12 Apr 2021 08:29:15 GMT-07:00

Are the Protective Effects of SGLT2 Inhibitors a “Class-Effect” or Are There Differences between Agents?

Schmidt, Darren W. — Fri, 05 Feb 2021 09:45:50 GMT-08:00

Real-Life Prescribing of SGLT2 Inhibitors: How to Handle the Other Medications, Including Glucose-Lowering Drugs and Diuretics

Lam, David — Mon, 01 Feb 2021 12:07:36 GMT-08:00

Lower Urinary Tract Symptoms Should Be Queried When Initiating Sodium Glucose Co-Transporter 2 Inhibitors

Krepostman, Nicolas — Wed, 03 Feb 2021 09:27:12 GMT-08:00

SGLT2 Inhibitors in Diabetic Kidney Disease

Zoungas, Sophia — Wed, 03 Feb 2021 11:29:56 GMT-08:00

Kidney, Cardiovascular, and Safety Outcomes of Canagliflozin according to Baseline Albuminuria

Jardine, Meg — Mon, 22 Feb 2021 07:19:34 GMT-08:00

Network Meta-Analysis of Novel Glucose-Lowering Drugs on Risk of Acute Kidney Injury

Zhao, Min — Tue, 29 Dec 2020 08:13:40 GMT-08:00

Early Change in Albuminuria with Canagliflozin Predicts Kidney and Cardiovascular Outcomes: A Post Hoc Analysis from the CREDENCE Trial

Oshima, Megumi — Wed, 30 Sep 2020 10:43:47 GMT-07:00

Effects of Canagliflozin in Patients with Baseline eGFR <30 ml/min per 1.73 m2

Bakris, George — Thu, 19 Nov 2020 06:44:08 GMT-08:00

Are SGLT2 Inhibitors Safe and Effective in Advanced Diabetic Kidney Disease?

Zoungas, Sophia — Thu, 19 Nov 2020 06:44:08 GMT-08:00

Decision Algorithm for Prescribing SGLT2 Inhibitors and GLP-1 Receptor Agonists for Diabetic Kidney Disease

Li, Jiahua — Tue, 09 Jun 2020 06:29:26 GMT-07:00

Diabetic kidney disease and its comorbid conditions, including atherosclerotic cardiovascular disease, heart failure, diabetes, and obesity, are interconnected conditions that compound the risk of kidney failure and cardiovascular mortality, and exponentiate health care costs. Sodium glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide 1 receptor agonist (GLP-1 RA) are novel diabetes medications that prevent cardiovascular events and kidney failure. Clinical trials exploring the cardiovascular and kidney outcomes of SGLT2i and GLP-1 RA have fundamentally shifted the treatment paradigm of diabetes. Clinical guidelines for diabetes management recommend a more holistic approach beyond glycemic control and emphasize heart and kidney protection of SGLT2i and GLP-1 RA. However, the adoption of prescribing SGLT2i and GLP-1 RA for patients with diabetes and high cardiovascular and kidney risk has been slow. In this review, we provide a decision-making tool to help clinicians determine when to consider SGLT2i and GLP-1 RA for heart and kidney protection. First, we discuss a comprehensive risk assessment for patients with diabetic kidney disease. We compare the effectiveness of SGLT2i and GLP-1 RA for different risk categories. Then, we present a decision algorithm using cardiovascular and kidney failure risk stratification and the strength of current evidence for the use of SGLT2i and GLP-1 RA. Lastly, we review the adverse effects of SGLT2i and GLP-1 RA and propose mitigation strategies.

Different eGFR Decline Thresholds and Renal Effects of Canagliflozin: Data from the CANVAS Program

Oshima, Megumi — Tue, 21 Jul 2020 02:54:18 GMT-07:00

SGLT2 Inhibitors across the Spectrum of Severity of CKD

Ziaolhagh, Ali — Tue, 29 Sep 2020 11:35:11 GMT-07:00

Empagliflozin and Cardiovascular and Kidney Outcomes across KDIGO Risk Categories

Levin, Adeera — Tue, 29 Sep 2020 11:35:12 GMT-07:00

Drug Testing for Residual Progression of Diabetic Kidney Disease in Mice Beyond Therapy with Metformin, Ramipril, and Empagliflozin

Motrapu, Manga — Tue, 23 Jun 2020 08:10:24 GMT-07:00

Renal, Cardiovascular, and Safety Outcomes of Canagliflozin by Baseline Kidney Function: A Secondary Analysis of the CREDENCE Randomized Trial

Jardine, Meg J. — Thu, 30 Apr 2020 10:00:30 GMT-07:00

Role of Impaired Nutrient and Oxygen Deprivation Signaling and Deficient Autophagic Flux in Diabetic CKD Development: Implications for Understanding the Effects of Sodium-Glucose Cotransporter 2-Inhibitors

Packer, Milton — Fri, 10 Apr 2020 07:16:41 GMT-07:00

Growing evidence indicates that oxidative and endoplasmic reticular stress, which trigger changes in ion channels and inflammatory pathways that may undermine cellular homeostasis and survival, are critical determinants of injury in the diabetic kidney. Cells are normally able to mitigate these cellular stresses by maintaining high levels of autophagy, an intracellular lysosome-dependent degradative pathway that clears the cytoplasm of dysfunctional organelles. However, the capacity for autophagy in both podocytes and renal tubular cells is markedly impaired in type 2 diabetes, and this deficiency contributes importantly to the intensity of renal injury. The primary drivers of autophagy in states of nutrient and oxygen deprivation—sirtuin-1 (SIRT1), AMP-activated protein kinase (AMPK), and hypoxia-inducible factors (HIF-1α and HIF-2α)—can exert renoprotective effects by promoting autophagic flux and by exerting direct effects on sodium transport and inflammasome activation. Type 2 diabetes is characterized by marked suppression of SIRT1 and AMPK, leading to a diminution in autophagic flux in glomerular podocytes and renal tubules and markedly increasing their susceptibility to renal injury. Importantly, because insulin acts to depress autophagic flux, these derangements in nutrient deprivation signaling are not ameliorated by antihyperglycemic drugs that enhance insulin secretion or signaling. Metformin is an established AMPK agonist that can promote autophagy, but its effects on the course of CKD have been demonstrated only in the experimental setting. In contrast, the effects of sodium-glucose cotransporter–2 (SGLT2) inhibitors may be related primarily to enhanced SIRT1 and HIF-2α signaling; this can explain the effects of SGLT2 inhibitors to promote ketonemia and erythrocytosis and potentially underlies their actions to increase autophagy and mute inflammation in the diabetic kidney. These distinctions may contribute importantly to the consistent benefit of SGLT2 inhibitors to slow the deterioration in glomerular function and reduce the risk of ESKD in large-scale randomized clinical trials of patients with type 2 diabetes.

Targeting Inflammation in Diabetic Kidney Disease: Is There a Role for Pentoxifylline?

Leehey, David J. — Fri, 28 Feb 2020 05:30:09 GMT-08:00

Diabetic kidney disease (DKD) is the most common cause of ESKD in the United States and worldwide. Current treatment for DKD includes strict glycemic control and normalization of BP with renin-angiotensin-aldosterone system (RAAS) blockade. Although RAAS blockers slow progression of disease, they do not generally prevent ESKD and none of the studies with these agents in DKD included patients who were nonproteinuric, which make up an increasingly large percentage of patients with diabetes now seen in clinical practice. Recent studies with glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown beneficial renal effects, and the benefits of SGLT2 inhibitors likely extend to patients who are nonproteinuric. However, there remains a need to develop new therapies for DKD, particularly in those patients with advanced disease. A role of chronic low-grade inflammation in microvascular complications in patients with diabetes has now been widely accepted. Large clinical trials are being carried out with experimental agents such as bardoxolone and selonsertib that target inflammation and oxidative stress. The Food and Drug Administration–approved, nonspecific phosphodiesterase inhibitor pentoxifylline (PTX) has been shown to have anti-inflammatory effects in both animal and human studies by inhibiting the production of proinflammatory cytokines. Small randomized clinical trials and meta-analyses indicate that PTX may have therapeutic benefits in DKD, raising the possibility that a clinically available drug may be able to be repurposed to treat this disease. A large, multicenter, randomized clinical trial to determine whether this agent can decrease time to ESKD or death is currently being conducted, but results will not be available for several years. At this time, the combination of RAAS blockade plus SGLT2 inhibition is considered standard of care for DKD, but it may be reasonable for clinicians to consider addition of PTX in patients whose disease continues to progress despite optimization of current standard-of-care therapies.

Safety of Liraglutide in Type 2 Diabetes and Chronic Kidney Disease

Mann, Johannes F.E. — Wed, 04 Mar 2020 07:23:06 GMT-08:00

A Randomized Trial of Empagliflozin to Increase Plasma Sodium Levels in Patients with the Syndrome of Inappropriate Antidiuresis

Refardt, Julie — Tue, 04 Feb 2020 09:07:32 GMT-08:00

Sodium Glucose Cotransporter 2 Inhibition Heralds a Call-to-Action for Diabetic Kidney Disease

Tuttle, Katherine R. — Mon, 18 Nov 2019 08:35:30 GMT-08:00

How Does CREDENCE Inform Best Use of SGLT2 Inhibitors in CKD?

Neumiller, Joshua J. — Tue, 01 Oct 2019 10:02:18 GMT-07:00

Protection of Cystinotic Mice by Kidney-Specific Megalin Ablation Supports an Endocytosis-Based Mechanism for Nephropathic Cystinosis Progression

Janssens, Virginie — Mon, 23 Sep 2019 08:22:21 GMT-07:00

Effect of Canagliflozin on Renal and Cardiovascular Outcomes across Different Levels of Albuminuria: Data from the CANVAS Program

Neuen, Brendon L. — Tue, 17 Sep 2019 06:24:04 GMT-07:00

Inhibition of Sodium Glucose Cotransporter 2 Attenuates the Dysregulation of Kelch-Like 3 and NaCl Cotransporter in Obese Diabetic Mice

Ishizawa, Kenichi — Tue, 26 Mar 2019 06:34:53 GMT-07:00

Good Guys, Bad Guys, Guesses, and Near Misses in Nephrology

Edmonston, Daniel — Mon, 17 Dec 2018 07:27:02 GMT-08:00

SGLT2 Inhibition in the Diabetic Kidney—From Mechanisms to Clinical Outcome

van Bommel, Erik J.M. — Thu, 02 Mar 2017 09:14:16 GMT-08:00

Diabetic kidney disease not only has become the leading cause for ESRD worldwide but also, highly contributes to increased cardiovascular morbidity and mortality in type 2 diabetes. Despite increased efforts to optimize renal and cardiovascular risk factors, like hyperglycemia, hypertension, obesity, and dyslipidemia, they are often insufficiently controlled in clinical practice. Although current drug interventions mostly target a single risk factor, more substantial improvements of renal and cardiovascular outcomes can be expected when multiple factors are improved simultaneously. Sodium-glucose cotransporter type 2 in the renal proximal tubule reabsorbs approximately 90% of filtered glucose. In type 2 diabetes, the maladaptive upregulation of sodium-glucose cotransporter type 2 contributes to the maintenance of hyperglycemia. Inhibiting these transporters has been shown to effectively improve glycemic control through inducing glycosuria and is generally well tolerated, although patients experience more genital infections. In addition, sodium-glucose cotransporter type 2 inhibitors favorably affect body weight, BP, serum uric acid, and glomerular hyperfiltration. Interestingly, in the recently reported first cardiovascular safety trial with a sodium-glucose cotransporter type 2 inhibitor, empagliflozin improved both renal and cardiovascular outcomes in patients with type 2 diabetes and established cardiovascular disease. Because the benefits were seen rapidly after initiation of therapy and other glucose-lowering agents, with the exception of liraglutide and semaglutide, have not been able to improve cardiovascular outcome, these observations are most likely explained by effects beyond glucose lowering. In this mini review, we present the drug class of sodium-glucose cotransporter type 2 inhibitors, elaborate on currently available renal and cardiovascular outcome data, and discuss how the effects of these agents on renal physiology may explain the data.

Macula Densa SGLT1-NOS1-Tubuloglomerular Feedback Pathway, a New Mechanism for Glomerular Hyperfiltration during Hyperglycemia

Zhang, Jie — Wed, 13 Mar 2019 08:05:06 GMT-07:00

The Other Glucose Transporter, SGLT1 – Also a Potential Trouble Maker in Diabetes?

Carlström, Mattias — Wed, 13 Mar 2019 08:05:05 GMT-07:00

Effects of Dapagliflozin on Circulating Markers of Phosphate Homeostasis

de Jong, Maarten A. — Mon, 17 Dec 2018 07:27:02 GMT-08:00

Mapping Progress in Reducing Cardiovascular Risk with Kidney Disease

Bansal, Nisha — Wed, 15 Aug 2018 07:23:59 GMT-07:00

Are SGLT2 Inhibitors Ready for Prime Time for CKD?

Pecoits-Filho, Roberto — Mon, 11 Sep 2017 07:49:29 GMT-07:00

Dapagliflozin Binds Specifically to Sodium-Glucose Cotransporter 2 in the Proximal Renal Tubule

Ghezzi, Chiara — Mon, 12 Sep 2016 09:51:38 GMT-07:00

Kidneys contribute to glucose homeostasis by reabsorbing filtered glucose in the proximal tubules via sodium-glucose cotransporters (SGLTs). Reabsorption is primarily handled by SGLT2, and SGLT2-specific inhibitors, including dapagliflozin, canagliflozin, and empagliflozin, increase glucose excretion and lower blood glucose levels. To resolve unanswered questions about these inhibitors, we developed a novel approach to map the distribution of functional SGLT2 proteins in rodents using positron emission tomography with 4-[18F]fluoro-dapagliflozin (F-Dapa). We detected prominent binding of intravenously injected F-Dapa in the kidney cortexes of rats and wild-type and Sglt1-knockout mice but not Sglt2-knockout mice, and injection of SGLT2 inhibitors prevented this binding. Furthermore, imaging revealed only low levels of F-Dapa in the urinary bladder, even after displacement of kidney binding with dapagliflozin. Microscopic ex vitro autoradiography of kidney showed F-Dapa binding to the apical surface of early proximal tubules. Notably, in vivo imaging did not show measureable specific binding of F-Dapa in heart, muscle, salivary glands, liver, or brain. We propose that F-Dapa is freely filtered by the kidney, binds to SGLT2 in the apical membranes of the early proximal tubule, and is subsequently reabsorbed into blood. The high density of functional SGLT2 transporters detected in the apical membrane of the proximal tubule but not detected in other organs likely accounts for the high kidney specificity of SGLT2 inhibitors. Overall, these data are consistent with data from clinical studies on SGLT2 inhibitors and provide a rationale for the mode of action of these drugs.