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Shikamura M, Takayama A, Yokogawa K, Kawakami K. Temporal risk patterns of severe hypovolemia associated with sodium-glucose cotransporter-2 inhibitors in patients with type 2 diabetes mellitus: A self-controlled case series study. Diabetes Obes Metab 2025; 27:2584-2592. [PMID: 39966098 DOI: 10.1111/dom.16259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 01/29/2025] [Accepted: 01/31/2025] [Indexed: 02/20/2025]
Abstract
AIMS We aimed to investigate the temporal risk patterns of severe hypovolemia induced by sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus. MATERIALS AND METHODS We conducted a self-controlled case series using claims data from Japan. Patients who were prescribed SGLT2i for treating type 2 diabetes mellitus and experienced severe hypovolemia were enrolled. The primary analysis evaluated the adjusted incidence rate ratios (IRRs) of exposure risk periods (Days 1 to 30, Days 31 to 90, Days 91 to 180 and Days ≥181) with their corresponding 95% confidence intervals (CIs), calculated using a multivariable conditional Poisson regression model, relative to that of the unexposed control period. RESULTS A total of 1200 new users of SGLT2i with 1334 severe hypovolemia events were included. The median follow-up and treatment periods were 3.66 and 2.53 years, respectively. The cohort was predominantly male (78.4%) with a median age of 54.1 years. A higher risk of severe hypovolemia associated with SGLT2i was observed particularly in the first 30 days (adjusted IRR 7.39, 95% CI 6.09-8.96) of treatment initiation. Secondary analyses highlighted the first 22 to 28 days (adjusted IRR 15.24, 95% CI 11.92-19.48) of treatment as the highest risk period for severe hypovolemia. CONCLUSIONS SGLT2i use in patients with type 2 diabetes mellitus was associated with a higher risk of severe hypovolemia, particularly within the first 30 days of treatment initiation, with the highest risk observed during 22 to 28 days.
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Affiliation(s)
- Mitsuhiro Shikamura
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan
- Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Osaka, Japan
| | - Atsushi Takayama
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan
| | - Kasumi Yokogawa
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan
| | - Koji Kawakami
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan
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Hill TG, Briant LJB, Kim A, Wu Y, Rorsman P, Wernstedt Asterholm I, Benrick A. Dehydration-induced AVP stimulates glucagon release and ketogenesis. Am J Physiol Endocrinol Metab 2025; 328:E633-E644. [PMID: 40099572 DOI: 10.1152/ajpendo.00505.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 02/04/2025] [Accepted: 03/11/2025] [Indexed: 03/20/2025]
Abstract
Gliflozins, such as dapagliflozin, belong to a class of drugs that inhibit the sodium-glucose cotransporter 2. Gliflozins have been found to raise glucagon levels, a hormone secreted from pancreatic islet α-cells, which can trigger ketosis. However, the precise mechanisms through which gliflozins increase glucagon secretion remain poorly understood. In addition, gliflozins induce osmotic diuresis, resulting in increased urine volume and plasma osmolality. In this study, we investigated the hypothesis that a compensatory increase in arginine-vasopressin (AVP) mediates dapagliflozin-induced increases in glucagon in vivo. We show that dapagliflozin does not increase glucagon secretion in the perfused mouse pancreas, neither at clinical nor at supra-clinical doses. In contrast, AVP potently increases glucagon secretion. In vivo, dapagliflozin increased plasma glucagon, osmolality, and AVP. An oral load with hypertonic saline amplified dapagliflozin-induced glucagon secretion. Notably, a similar increase in glucagon could also be elicited by dehydration, evoked by 24-h water restriction. Conversely, blockade of vasopressin 1b receptor signaling, with either pharmacological antagonism or knockout of the receptor, resulted in reduced dapagliflozin-induced glucagon secretion in response to both dapagliflozin and dehydration. Finally, blocking vasopressin 1b receptor signaling in a mouse model of type 1 diabetes diminished the glucagon-promoting and ketogenic effects of dapagliflozin. Collectively, our data suggest that AVP is an important regulator of glucagon release during both drug-induced and physiological dehydration.NEW & NOTEWORTHY Gliflozin-induced ketogenic effects partly result from increased glucagon levels. This study shows that dapagliflozin-triggered glucagon secretion is not directly mediated by the pancreas but rather linked to arginine-vasopressin (AVP). Dehydration, common in diabetic ketoacidosis, elevates AVP, potentially explaining the increased ketoacidosis risk in gliflozin-treated patients. Thus, our results highlight AVP as a potential therapeutic target to mitigate the risk of ketoacidosis associated with gliflozin treatments in patients with diabetes.
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Affiliation(s)
- Thomas G Hill
- Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
| | - Linford J B Briant
- Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
- Department of Computer Science, University of Oxford, Oxford, United Kingdom
| | - Angela Kim
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
- Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, United States
| | - Yanling Wu
- Institute of Neuroscience and Physiology, Metabolic Research Unit, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Patrik Rorsman
- Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
- Institute of Neuroscience and Physiology, Metabolic Research Unit, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ingrid Wernstedt Asterholm
- Institute of Neuroscience and Physiology, Metabolic Research Unit, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Anna Benrick
- Institute of Neuroscience and Physiology, Metabolic Research Unit, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- School of Health Sciences, University of Skövde, Skövde, Sweden
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Rolski F, Mączewski M. Cardiac Fibrosis: Mechanistic Discoveries Linked to SGLT2 Inhibitors. Pharmaceuticals (Basel) 2025; 18:313. [PMID: 40143092 PMCID: PMC11944955 DOI: 10.3390/ph18030313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2025] [Revised: 02/17/2025] [Accepted: 02/19/2025] [Indexed: 03/28/2025] Open
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2is), commonly known as flozins, have garnered attention not only for their glucose-lowering effects in type 2 diabetes mellitus (T2DM) but also for their cardioprotective properties. This review examines the mechanisms underlying the anti-fibrotic effects of SGLT2is, with a focus on key clinical trials and preclinical models. SGLT2is, mainly empagliflozin and dapagliflozin, have demonstrated significant reductions in heart failure-related hospitalizations, cardiovascular death, and fibrosis markers, independent of their glucose-lowering effects. The cardioprotective benefits appear to stem from direct actions on cardiac tissues, modulation of inflammatory responses, and improvements in metabolic parameters. In animal models of heart failure, SGLT2is were demonstrated to reduce cardiac fibrosis through mechanisms involving AMPK activation, reduced oxidative stress, and inhibition of pro-fibrotic pathways, not only through the inhibition of SGLT2 present on cardiac cells but also by targeting several other molecular targets. These findings confirm their efficacy in the treatment of heart failure and align with evidence from human trials, supporting the potential involvement of multiple pathways in mediating cardiac fibrosis. These results also provide a promising basis for clinical trials specifically targeting pathways shared with SGLT2is.
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Affiliation(s)
| | - Michał Mączewski
- Department of Clinical Physiology, Centre of Postgraduate Medical Education, 99/103 Marymoncka Str., 01-813 Warsaw, Poland;
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Gronda E, Iacoviello M, Arduini A, Benvenuto M, Gabrielli D, Bonomini M, Tavazzi L. Gliflozines use in heart failure patients. Focus on renal actions and overview of clinical experience. Eur J Intern Med 2025; 132:1-8. [PMID: 39307625 DOI: 10.1016/j.ejim.2024.09.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 08/10/2024] [Accepted: 09/04/2024] [Indexed: 02/07/2025]
Abstract
Use of type 2 sodium-glucose cotransporter inhibitors (SGLT2i) gliflozines have first been applied to treatment of diabetic patients. In this setting, unexpected benefits on concomitant heart failure (HF) were seen in large trials. This clinical benefit was initially traced back to their natriuretic properties and as such they were also included in the therapeutic armamentarium of HF treatment. However, further insight into their mechanism of action has clarified their complex interaction with kidney function which better explains their prompt effectiveness in ameliorating HF outcome in the long-term, independent of left ventricular ejection fraction (LVEF) phenotype and concomitant presence of diabetes and/or chronic renal disease. This mainly results from the ability of SGLT2i to counteract the HF-associated hyperactivity of the sympathetic system and neurohormonal activation by modifying the pattern of renal tubular sodium and glucose reabsorption which results in curbing the overall sodium reabsorption. Their action results in decreased kidney workload and related oxygen consumption thus indirectly reducing sympathetic activity. The complex renal functional changes associated with HF and their modifications during SGLT2i administration will be reviewed.
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Affiliation(s)
- Edoardo Gronda
- Medicine and Medicine Sub-Specialties Department, Cardio Renal Program, U.O.C. Nephrology, Dialysis and Adult Renal Transplant Program, IRCCS Ca' Granda Foundation, Ospedale Maggiore Policlinico, Milano, Italy.
| | - Massimo Iacoviello
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
| | | | - Manuela Benvenuto
- Unità Operativa Complessa Cardiologia-UTIC-Emodinamica, PO Giuseppe Mazzini, Teramo, Italy
| | - Domenico Gabrielli
- Unità Operativa Complessa Cardiologia-UTIC, Azienda Ospedaliera San Camillo Forlanini, Roma, Italy
| | - Mario Bonomini
- Department of Medicine and Aging Sciences, University G. D'Annunzio, Chieti-Pescara, Chieti, Italy.
| | - Luigi Tavazzi
- GVM Care & Research, Maria Cecilia Hospital, Cotignola Ravenna, Italy.
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Elliott J, Oyama MA. Sodium glucose transporter 2 inhibitors: Will these drugs benefit non-diabetic veterinary patients with cardiac and kidney diseases? J Vet Pharmacol Ther 2025; 48 Suppl 1:1-18. [PMID: 39001645 PMCID: PMC11737021 DOI: 10.1111/jvp.13472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 06/14/2024] [Accepted: 07/03/2024] [Indexed: 01/18/2025]
Abstract
Sodium glucose transporter type 2 (SGLT2) inhibitors have been introduced into human medicine where their beneficial effects go beyond the expected improvement in blood glucose control. These drugs appear to prevent progression of both cardiovascular and kidney diseases, not only in diabetic but also in non-diabetic human patients. As these drugs have received conditional approval for use in diabetic cats and are being used in other veterinary species, the intriguing question as to whether they will have similar cardioprotective and nephroprotective effects in dogs and cats is being asked. The primary mechanism(s) by which SGLT2 inhibitors are cardio- and nephroprotective remain to be fully characterized. This paper reviews these suggested mechanisms in the context of the pathophysiology of progressive cardiovascular and kidney diseases in dogs and cats with the goal of predicting which categories of non-diabetic veterinary patients these drugs might be of most benefit.
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Affiliation(s)
- Jonathan Elliott
- Department of Comparative Biomedical SciencesRoyal Veterinary College, University of LondonLondonUK
| | - Mark A. Oyama
- Department of Clinical Sciences & Advanced MedicineUniversity of Pennsylvania School of Veterinary MedicinePhiladelphiaPennsylvaniaUSA
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Grubić Rotkvić P, Rotkvić L, Đuzel Čokljat A, Cigrovski Berković M. Sodium-dependent glucose transporter 2 inhibitors effects on myocardial function in patients with type 2 diabetes and asymptomatic heart failure. World J Cardiol 2024; 16:448-457. [PMID: 39221192 PMCID: PMC11362810 DOI: 10.4330/wjc.v16.i8.448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 07/17/2024] [Accepted: 07/23/2024] [Indexed: 08/26/2024] Open
Abstract
BACKGROUND Sodium-dependent glucose transporter 2 inhibitors (SGLT2i) have shown efficacy in reducing heart failure (HF) burden in a very heterogeneous groups of patients, raising doubts about some contemporary assumptions of their mechanism of action. We previously published a prospective observational study that evaluated mechanisms of action of SGLT2i in patients with type 2 diabetes who were in HF stages A and B on dual hypoglycemic therapy. Two groups of patients were included in the study: the ones receiving SGLT2i as an add-on agent to metformin and the others on dipeptidyl peptidase-4 inhibitors as an add-on to metformin due to suboptimal glycemic control. AIM To evaluate the outcomes regarding natriuretic peptide, oxidative stress, inflammation, blood pressure, heart rate, cardiac function, and body weight. METHODS The study outcomes were examined by dividing each treatment arm into two subgroups according to baseline parameters of global longitudinal strain (GLS), N-terminal pro-brain natriuretic peptide, myeloperoxidase (MPO), high-sensitivity C-reactive protein (hsCRP), and systolic and diastolic blood pressure. To evaluate the possible predictors of observed changes in the SGLT2i arm during follow-up, a rise in stroke volume index, body mass index (BMI) decrease, and lack of heart rate increase, linear regression analysis was performed. RESULTS There was a greater reduction of MPO, hsCRP, GLS, and blood pressure in the groups with higher baseline values of mentioned parameters irrespective of the therapeutic arm after 6 months of follow-up. Significant independent predictors of heart rate decrease were a reduction in early mitral inflow velocity to early diastolic mitral annular velocity at the interventricular septal annulus ratio and BMI, while the predictor of stroke volume index increase was SGLT2i therapy itself. CONCLUSION SGLT2i affect body composition, reduce cardiac load, improve diastolic/systolic function, and attenuate the sympathetic response. Glycemic control contributes to the improvement of heart function, blood pressure control, oxidative stress, and reduction in inflammation.
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Affiliation(s)
- Petra Grubić Rotkvić
- Department of Cardiology, University Hospital Centre Zagreb, Zagreb 10000, Croatia.
| | - Luka Rotkvić
- Department of Cardiology, Magdalena Clinic for Cardiovascular Disease, Krapinske Toplice 49217, Croatia
| | - Ana Đuzel Čokljat
- Department of Internal Medicine, General Hospital Dubrovnik, Dubrovnik 20000, Croatia
| | - Maja Cigrovski Berković
- Department for Sport and Exercise Medicine, University of Zagreb Faculty of Kinesiology, Zagreb 10000, Croatia
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Asakura-Kinoshita M, Masuda T, Oka K, Ohara K, Miura M, Morinari M, Misawa K, Miyazawa Y, Akimoto T, Shimada K, Nagata D. Sodium-Glucose Cotransporter 2 Inhibitor Combined with Conventional Diuretics Ameliorate Body Fluid Retention without Excessive Plasma Volume Reduction. Diagnostics (Basel) 2024; 14:1194. [PMID: 38893720 PMCID: PMC11171863 DOI: 10.3390/diagnostics14111194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 05/28/2024] [Accepted: 06/04/2024] [Indexed: 06/21/2024] Open
Abstract
We previously reported that sodium-glucose cotransporter 2 (SGLT2) inhibitors exert sustained fluid homeostatic actions through compensatory increases in osmotic diuresis-induced vasopressin secretion and fluid intake. However, SGLT2 inhibitors alone do not produce durable amelioration of fluid retention. In this study, we examined the comparative effects of the SGLT2 inhibitor dapagliflozin (SGLT2i group, n = 53) and the combined use of dapagliflozin and conventional diuretics, including loop diuretics and/or thiazides (SGLT2i + diuretic group, n = 23), on serum copeptin, a stable, sensitive, and simple surrogate marker of vasopressin release and body fluid status. After six months of treatment, the change in copeptin was significantly lower in the SGLT2i + diuretic group than in the SGLT2i group (-1.4 ± 31.5% vs. 31.5 ± 56.3%, p = 0.0153). The change in the estimated plasma volume calculated using the Strauss formula was not significantly different between the two groups. Contrastingly, changes in interstitial fluid, extracellular water, intracellular water, and total body water were significantly lower in the SGLT2i + diuretic group than in the SGLT2i group. Changes in renin, aldosterone, and absolute epinephrine levels were not significantly different between the two groups. In conclusion, the combined use of the SGLT2 inhibitor dapagliflozin and conventional diuretics inhibited the increase in copeptin levels and remarkably ameliorated fluid retention without excessively reducing plasma volume and activating the renin-angiotensin-aldosterone and sympathetic nervous systems.
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Affiliation(s)
- Maki Asakura-Kinoshita
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke 3290498, Japan; (M.A.-K.); (K.O.); (K.O.); (K.M.); (T.A.); (D.N.)
| | - Takahiro Masuda
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke 3290498, Japan; (M.A.-K.); (K.O.); (K.O.); (K.M.); (T.A.); (D.N.)
- Department of Nephrology, Shin-Oyama City Hospital, Oyama 3230827, Japan;
| | - Kentaro Oka
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke 3290498, Japan; (M.A.-K.); (K.O.); (K.O.); (K.M.); (T.A.); (D.N.)
- Department of Nephrology, Shin-Oyama City Hospital, Oyama 3230827, Japan;
| | - Ken Ohara
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke 3290498, Japan; (M.A.-K.); (K.O.); (K.O.); (K.M.); (T.A.); (D.N.)
| | - Marina Miura
- Department of Nephrology, Shin-Oyama City Hospital, Oyama 3230827, Japan;
| | - Masato Morinari
- Department of Internal Medicine, Nasu Minami Hospital, Nasu-Karasuyama 3210621, Japan; (M.M.); (Y.M.)
| | - Kyohei Misawa
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke 3290498, Japan; (M.A.-K.); (K.O.); (K.O.); (K.M.); (T.A.); (D.N.)
- Department of Nephrology, Shin-Oyama City Hospital, Oyama 3230827, Japan;
| | - Yasuharu Miyazawa
- Department of Internal Medicine, Nasu Minami Hospital, Nasu-Karasuyama 3210621, Japan; (M.M.); (Y.M.)
| | - Tetsu Akimoto
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke 3290498, Japan; (M.A.-K.); (K.O.); (K.O.); (K.M.); (T.A.); (D.N.)
| | - Kazuyuki Shimada
- Department of Cardiology, Shin-Oyama City Hospital, Oyama 3230827, Japan;
| | - Daisuke Nagata
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke 3290498, Japan; (M.A.-K.); (K.O.); (K.O.); (K.M.); (T.A.); (D.N.)
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Hullon D, Taherifard E, Al-Saraireh TH. The effect of the four pharmacological pillars of heart failure on haemoglobin level. Ann Med Surg (Lond) 2024; 86:1575-1583. [PMID: 38463117 PMCID: PMC10923357 DOI: 10.1097/ms9.0000000000001773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 01/21/2024] [Indexed: 03/12/2024] Open
Abstract
Anaemia, a condition characterized by low levels of haemoglobin, is frequently observed in patients with heart failure (HF). Guideline-directed medical therapy improves HF outcomes by using medications like beta blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers, along with mineralocorticoid receptor antagonists and sodium-glucose cotransporter 2 inhibitors. In this study, we aimed to review the pathophysiology of anaemia in patients with HF and present the current evidence regarding the relationship between the main recommended medications for these patients and haemoglobin levels. The authors conducted a comprehensive search in the medical literature for relevant original clinical articles in which the four pharmacological pillars of HF were given to the patients; we, then, assessed whether the association of use of these medications and haemoglobin level or development of anaemia was provided. These common medications have been shown in the literature that may exacerbate or ameliorate anaemia. Besides, it has been shown that even in the case that they result in the development of anaemia, their use is associated with positive effects that outweigh this potential harm. The literature also suggests that among patients receiving medications with negative effects on the level of haemoglobin, there was no difference in the rate of mortality between anaemic and non-anaemic patients when both were on treatment for anaemia; this point highlights the importance of the detection and treatment of anaemia in these patients. Further research is needed to explore these relationships and identify additional strategies to mitigate the risk of anaemia in this population.
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Affiliation(s)
| | - Erfan Taherifard
- Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Cases A, Cigarrán S, Luis Górriz J, Nuñez J. Effect of SGLT2 inhibitors on anemia and their possible clinical implications. Nefrologia 2024; 44:165-172. [PMID: 38604895 DOI: 10.1016/j.nefroe.2024.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 11/11/2023] [Indexed: 04/13/2024] Open
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated cardiovascular and renal benefits in patients with type 2 diabetes mellitus, heart failure, or chronic kidney disease. Since the first studies with these drugs, an initial increase in hemoglobin/hematocrit levels was observed, which was attributed to an increase in hemoconcentration associated with its diuretic effect, although it was early appearent that these drugs increased erythropoietin levels and erythropoiesis, and improved iron metabolism. Mediation studies found that the increase in hemoglobin was strongly associated with the cardiorenal benefits of these drugs. In this review, we discuss the mechanisms for improving erythropoiesis and the implication of the increase in hemoglobin on the cardiorenal prognostic benefit of these drugs.
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Affiliation(s)
- Aleix Cases
- Servei de Nefrología, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain; Grupo de Anemia de la S.E.N., Spain
| | | | - José Luis Górriz
- Grupo de Anemia de la S.E.N., Spain; Servicio de Nefrología, Hospital Clínico Universitario, INCLIVA, Universitat de València, Valencia, Spain.
| | - Julio Nuñez
- Servicio de Cardiología, Hospital Clínico Universitario, INCLIVA, Universitat de València, CIBER Cardiovascular, Spain
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Schork A, Eberbach ML, Bohnert BN, Wörn M, Heister DJ, Eisinger F, Vogel E, Heyne N, Birkenfeld AL, Artunc F. SGLT2 Inhibitors Decrease Overhydration and Proteasuria in Patients with Chronic Kidney Disease: A Longitudinal Observational Study. Kidney Blood Press Res 2024; 49:124-134. [PMID: 38228104 PMCID: PMC10885839 DOI: 10.1159/000535643] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 11/29/2023] [Indexed: 01/18/2024] Open
Abstract
INTRODUCTION SGLT2 inhibitors are used to reduce the risk of progression of chronic kidney disease (CKD). In patients with type 2 diabetes, they have been found to reduce extracellular volume. Given the high prevalence of extracellular volume expansion and overhydration (OH) in CKD, we investigated whether SGLT2 inhibitors might correct these disturbances in CKD patients. METHODS CKD patients who started treatment with an SGLT2 inhibitor were investigated in this prospective observational study for 6 months. Body composition and fluid status were measured by bioimpedance spectroscopy. In addition, spot urine samples were analyzed for albuminuria, glucosuria, and urinary aprotinin-sensitive serine protease activity. RESULTS Forty-two patients (29% with diabetic/hypertensive CKD, 31% with IgA nephropathy; 88% dapagliflozin 10 mg, 10% dapagliflozin 5 mg, 2% empagliflozin 20 mg; median eGFR 46 mL/min/1.73 m2 and albuminuria 1,911 mg/g creatinine) participated in the study. Median glucosuria increased to 14 (10-19) g/g creatinine. At baseline, patients displayed OH with +0.4 (-0.2 to 2.2) L/1.73 m2, which decreased by 0.5 (0.1-1.2) L/1.73 m2 after 6 months. Decrease of OH correlated with higher OH at BL, decrease of albuminuria, glucosuria, and urinary aprotinin-sensitive protease activity. Adipose tissue mass was not significantly reduced after 6 months. CONCLUSION SGLT2 inhibitors reduce OH in patients with CKD, which is pronounced in the presence of high albuminuria, glucosuria, and urinary aprotinin-sensitive protease activity.
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Affiliation(s)
- Anja Schork
- Division of Endocrinology, Diabetology and Nephrology, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany
- Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
| | - Marie-Luise Eberbach
- Division of Endocrinology, Diabetology and Nephrology, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany
| | - Bernhard N Bohnert
- Division of Endocrinology, Diabetology and Nephrology, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany
- Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
| | - Matthias Wörn
- Division of Endocrinology, Diabetology and Nephrology, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany
- Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
| | - David J Heister
- Division of Endocrinology, Diabetology and Nephrology, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany
- Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
| | - Felix Eisinger
- Division of Endocrinology, Diabetology and Nephrology, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany
- Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
| | - Elisabeth Vogel
- Division of Endocrinology, Diabetology and Nephrology, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany
- Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
| | - Nils Heyne
- Division of Endocrinology, Diabetology and Nephrology, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany
- Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
| | - Andreas L Birkenfeld
- Division of Endocrinology, Diabetology and Nephrology, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany
- Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
| | - Ferruh Artunc
- Division of Endocrinology, Diabetology and Nephrology, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany
- Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
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11
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Oka K, Masuda T, Ohara K, Miura M, Morinari M, Misawa K, Miyazawa Y, Akimoto T, Shimada K, Nagata D. Fluid homeostatic action of dapagliflozin in patients with chronic kidney disease: the DAPA-BODY Trial. Front Med (Lausanne) 2023; 10:1287066. [PMID: 38155663 PMCID: PMC10753517 DOI: 10.3389/fmed.2023.1287066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 11/30/2023] [Indexed: 12/30/2023] Open
Abstract
Sodium glucose cotransporter 2 (SGLT2) inhibitors have both glucose-lowering and diuretic effects. We recently reported that the SGLT2 inhibitor dapagliflozin exerts short-term fluid homeostatic action in patients with chronic kidney disease (CKD). However, the long-term effects of SGLT2 inhibitors on body fluid status in patients with CKD remain unclear. This was a prospective, non-randomized, open-label study that included a dapagliflozin treatment group (n = 73) and a control group (n = 24) who were followed for 6 months. Body fluid volume was measured using a bioimpedance analysis device. The extracellular water-to-total body water ratio (ECW/TBW), a predictor of renal outcomes, was used as a parameter for body fluid status (fluid retention, 0.400 ≤ ECW/TBW). Six-month treatment with dapagliflozin significantly decreased ECW/TBW compared with the control group (-0.65% ± 2.03% vs. 0.97% ± 2.49%, p = 0.0018). Furthermore, dapagliflozin decreased the ECW/TBW in patients with baseline fluid retention, but not in patients without baseline fluid retention (-1.47% ± 1.93% vs. -0.01% ± 1.88%, p = 0.0017). Vasopressin surrogate marker copeptin levels were similar between the control and dapagliflozin groups at 6 months (32.3 ± 33.4 vs. 30.6 ± 30.1 pmol/L, p = 0.8227). However, dapagliflozin significantly increased the change in copeptin levels at 1 week (39.0% ± 41.6%, p = 0.0010), suggesting a compensatory increase in vasopressin secretion to prevent hypovolemia. Renin and aldosterone levels were similar between the control and dapagliflozin groups at 6 months, while epinephrine and norepinephrine (markers of sympathetic nervous system activity) were significantly lower in the dapagliflozin group than in the control group. In conclusion, the SGLT2 inhibitor dapagliflozin ameliorated fluid retention and maintained euvolemic fluid status in patients with CKD, suggesting that SGLT2 inhibitors exert sustained fluid homeostatic actions in patients with various fluid backgrounds. Clinical trial registration: https://www.umin.ac.jp/ctr/, identifier [UMIN000048568].
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Affiliation(s)
- Kentaro Oka
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
- Department of Nephrology, Shin-Oyama City Hospital, Oyama, Tochigi, Japan
| | - Takahiro Masuda
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
- Department of Nephrology, Shin-Oyama City Hospital, Oyama, Tochigi, Japan
| | - Ken Ohara
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Marina Miura
- Department of Nephrology, Shin-Oyama City Hospital, Oyama, Tochigi, Japan
| | - Masato Morinari
- Department of Internal Medicine, Nasu Minami Hospital, Nasukarasuyama, Tochigi, Japan
| | - Kyohei Misawa
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
- Department of Nephrology, Shin-Oyama City Hospital, Oyama, Tochigi, Japan
| | - Yasuharu Miyazawa
- Department of Internal Medicine, Nasu Minami Hospital, Nasukarasuyama, Tochigi, Japan
| | - Tetsu Akimoto
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Kazuyuki Shimada
- Department of Cardiology, Shin-Oyama City Hospital, Oyama, Tochigi, Japan
| | - Daisuke Nagata
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
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12
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Guan X, Zhang J, Chen G, Zhang G, Chang S, Nie Z, Liu W, Guo T, Zhao Y, Li B. MRAs may have lost their cornerstone position for heart failure treatment in the age of SGLT-2 inhibitors: A meta-analysis of randomized controlled trials. Heart Fail Rev 2023; 28:1427-1436. [PMID: 37369935 DOI: 10.1007/s10741-023-10330-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/14/2023] [Indexed: 06/29/2023]
Abstract
Mineralocorticoid receptor antagonists (MRAs) are a cornerstone drug class for heart failure therapy. Several clinical studies have demonstrated its role in heart failure therapy. However, due to the recommendation of sodium-glucose cotransporter-2 (SGLT-2) inhibitors for the treatment of heart failure, there is a lack of sufficient evidence regarding whether MRAs can continue to play a cornerstone role in heart failure treatment. A meta-analysis was performed on subgroups of the DAPA-HF and EMPEROR-Reduced trials. Using trial-level data, we performed a meta-analysis to assess the effects of SGLT-2 inhibitors and MRAs on various clinical endpoints of heart failure. The incidence of cardiovascular-related death or heart failure hospitalization was the primary outcome. In addition, we assessed cardiovascular death, all-cause death, heart failure hospitalization, renal outcomes, and hyperkalemia. This study has already been registered with PROSPERO, CRD42022385023. Compared with SGLT-2 inhibitor monotherapy, combined treatment did not demonstrate more significant advantages in terms of heart failure or cardiovascular death (RR = 1.00; 95% CI: 0.78-1.28), cardiovascular death (RR = 0.96; 95% CI: 0.61-1.52), heart failure hospitalization (RR = 0.92; 95% CI: 0.79-1.07), all-cause death (RR = 1.00; 95% CI: 0.63-1.59) and composite kidney endpoint (RR = 0.85; 95% CI: 0.49-1.46). Moreover, in comparison to SGLT-2 inhibitors, combined therapy increased the risk of moderate-severe hyperkalemia (blood potassium > 6.0 mmol/l) (RR = 4.13; 95% CI: 2.23-7.65). In patients with HFrEF who have started MRAs treatment, the addition of an SGLT-2 inhibitor provides significant clinical benefit. However, the addition of MRAs to SGLT-2 inhibitors to treat heart failure is not essential.
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Affiliation(s)
- Xiangfeng Guan
- School of Clinical Medicine, Affiliated Hospital of Weifang Medical University, Weifang Medical University, Weifang, 261053, China
| | - Ju Zhang
- School of Clinical Medicine, Affiliated Hospital of Weifang Medical University, Weifang Medical University, Weifang, 261053, China
| | - Guangxin Chen
- Department of Emergency, Zibo Central Hospital Affiliated to Binzhou Medical College, No. 10, South Shanghai Road, Zibo, 255000, China
| | - Guanzhao Zhang
- Department of Cardiology, Zibo Central Hospital Affiliated to Binzhou Medical College, No. 10, South Shanghai Road, Zibo, 255000, China
| | - Shuting Chang
- School of Clinical Medicine, Affiliated Hospital of Weifang Medical University, Weifang Medical University, Weifang, 261053, China
| | - Zifan Nie
- Department of Cardiology, Zibo Central Hospital Affiliated to Binzhou Medical College, No. 10, South Shanghai Road, Zibo, 255000, China
| | - Wenhao Liu
- Department of Cardiology, Zibo Central Hospital Affiliated to Binzhou Medical College, No. 10, South Shanghai Road, Zibo, 255000, China
| | - Tianlong Guo
- School of Clinical Medicine, Affiliated Hospital of Weifang Medical University, Weifang Medical University, Weifang, 261053, China
| | - Yunhe Zhao
- Department of Cardiology, Zibo Central Hospital Affiliated to Binzhou Medical College, No. 10, South Shanghai Road, Zibo, 255000, China.
| | - Bo Li
- Department of Cardiology, Zibo Central Hospital Affiliated to Binzhou Medical College, No. 10, South Shanghai Road, Zibo, 255000, China.
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Packer M, Butler J. Similarities and distinctions between acetazolamide and sodium-glucose cotransporter 2 inhibitors in patients with acute heart failure: Key insights into ADVOR and EMPULSE. Eur J Heart Fail 2023; 25:1537-1543. [PMID: 37403655 DOI: 10.1002/ejhf.2968] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 06/26/2023] [Accepted: 07/02/2023] [Indexed: 07/06/2023] Open
Abstract
Both acetazolamide and sodium-glucose cotransporter 2 (SGLT2) inhibitors block sodium reabsorption in the proximal renal tubule primarily through inhibition of sodium-hydrogen exchanger isoform 3 (NHE3), but neither SGLT2 inhibitors nor acetazolamide produce a sustained natriuresis due to compensatory upregulation of sodium reabsorption at distal nephron sites. Nevertheless, acetazolamide and SGLT2 inhibitors have been used as adjunctive therapy to loop diuretics in states where NHE3 is upregulated, e.g. acute heart failure. Two randomized controlled trials have been carried out with acetazolamide in acute heart failure (DIURESIS-CHF and ADVOR). In ADVOR, acetazolamide improved physical signs of fluid retention, but this finding could not be explained by the modest observed diuretic effect. Acetazolamide did not produce a natriuresis in the DIURESIS-CHF trial, and in ADVOR, immediate effects on symptoms and body weight were not reported, and the drug had no effect on morbidity or mortality after 90 days. Three randomized controlled trials have been carried out with empagliflozin (EMPAG-HF, EMPA-RESPONSE-AHF and EMPULSE) in acute heart failure. The EMPULSE trial did not report effects on diuresis or in changes in physical signs of congestion during the first week of treatment, but in EMPAG-HF and EMPA-RESPONSE-AHF, empagliflozin had no effect of dyspnoea, urinary sodium excretion or body weight during the first 4 days. In the EMPULSE trial, empagliflozin improved health status at 15 days and reduced the risk of worsening heart failure events at 90 days, but these effects are similar in magnitude and time course to the early statistical significance on the risk of heart failure hospitalizations achieved within 14-30 days in the major trials of SGLT2 inhibitors in patients with chronic heart failure. Neurohormonal inhibitors produce this early effect in the absence of a diuresis. Additionally, in numerous randomized controlled trials, in-hospital diuretic intensification has not reduced the risk of major heart failure events, even when treatment is sustained. These findings, taken collectively, suggest that any immediate diuretic effects of acetazolamide and SGLT2 inhibitors in acute heart failure are not likely to influence the short- or long-term clinical course of patients.
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Affiliation(s)
- Milton Packer
- Baylor University Medical Center, Dallas, TX, USA
- Imperial College, London, UK
| | - Javed Butler
- Baylor Scott and White Research Institute, Dallas, TX, USA
- Department of Medicine, University of Mississippi School of Medicine, Jackson, MS, USA
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14
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Grubić Rotkvić P, Ćelap I, Bralić Lang V, Jug J, Snagić A, Huljev Šipoš I, Cigrovski Berković M. Impact of SGLT2 inhibitors on the mechanisms of myocardial dysfunction in type 2 diabetes: A prospective non-randomized observational study in patients with type 2 diabetes mellitus without overt heart disease. J Diabetes Complications 2023; 37:108541. [PMID: 37329705 DOI: 10.1016/j.jdiacomp.2023.108541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/29/2023] [Accepted: 06/07/2023] [Indexed: 06/19/2023]
Abstract
AIMS This prospective observational study evaluated the possible mechanisms of action of SGLT2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM) without overt heart disease. METHODS The study was designed to verify whether SGLT2i impact biomarkers of: myocardial stress-NT-proBNP, inflammation-high sensitivity C-reactive protein, oxidative stress -myeloperoxidase, functional and structural echocardiographic parameters, in patients with T2DM on metformin (heart failure stages A and B) who needed treatment intensification with a second antidiabetic agent. The patients were divided in two groups - the ones planned to receive SGLT2i or DPP-4 inhibitor (except saxagliptin). At baseline, and after six months of therapy, 64 patients underwent blood analysis, physical and echocardiography examination. RESULTS There were no significant differences between the two groups in terms of biomarkers of myocyte and oxidative stress, inflammation and blood pressure. Body mass index, triglycerides, aspartate aminotransferase, uric acid, E/E', deceleration time and systolic pressure in the pulmonary artery significantly decreased, while stroke volume, indexed stroke volume, high-density lipoprotein, hematocrit and hemoglobin significantly increased in the group on SGLT2i. CONCLUSIONS According to the results, SGLT2i mechanisms of action comprise rapid changes in body composition and metabolic parameters, reduced cardiac load and improvement in diastolic and systolic parameters.
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Affiliation(s)
- Petra Grubić Rotkvić
- The Department of Cardiovascular Diseases, University Hospital Centre Zagreb, Croatia.
| | - Ivana Ćelap
- Department of Clinical Chemistry, Sestre Milosrdnice University Hospital Centre, Zagreb, Croatia; Faculty of Pharmacy and Biochemistry, University of Zagreb, Croatia
| | - Valerija Bralić Lang
- Department of Family Medicine, Andrija Štampar School of Public Health, School of Medicine, University of Zagreb, Croatia
| | - Juraj Jug
- Health Center Zagreb-West, Zagreb, Croatia
| | - Andrea Snagić
- Institute for Cardiovascular Prevention and Rehabilitation, Zagreb, Croatia
| | - Ivana Huljev Šipoš
- Department of Internal Medicine, University Hospital Dubrava, Zagreb, Croatia
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15
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Packer M, Wilcox CS, Testani JM. Critical Analysis of the Effects of SGLT2 Inhibitors on Renal Tubular Sodium, Water and Chloride Homeostasis and Their Role in Influencing Heart Failure Outcomes. Circulation 2023; 148:354-372. [PMID: 37486998 PMCID: PMC10358443 DOI: 10.1161/circulationaha.123.064346] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 05/25/2023] [Indexed: 07/26/2023]
Abstract
SGLT2 (sodium-glucose cotransporter 2) inhibitors interfere with the reabsorption of glucose and sodium in the early proximal renal tubule, but the magnitude and duration of any ensuing natriuretic or diuretic effect are the result of an interplay between the degree of upregulation of SGLT2 and sodium-hydrogen exchanger 3, the extent to which downstream compensatory tubular mechanisms are activated, and (potentially) the volume set point in individual patients. A comprehensive review and synthesis of available studies reveals several renal response patterns with substantial variation across studies and clinical settings. However, the common observation is an absence of a large acute or chronic diuresis or natriuresis with these agents, either when given alone or combined with other diuretics. This limited response results from the fact that renal compensation to these drugs is rapid and nearly complete within a few days or weeks, preventing progressive volume losses. Nevertheless, the finding that fractional excretion of glucose and lithium (the latter being a marker of proximal sodium reabsorption) persists during long-term treatment with SGLT2 inhibitors indicates that pharmacological tolerance to the effects of these drugs at the level of the proximal tubule does not meaningfully occur. This persistent proximal tubular effect of SGLT2 inhibitors can be hypothesized to produce a durable improvement in the internal set point for volume homeostasis, which may become clinically important during times of fluid expansion. However, it is difficult to know whether a treatment-related change in the volume set point actually occurs or contributes to the effect of these drugs to reduce the risk of major heart failure events. SGLT2 inhibitors exert cardioprotective effects by a direct effect on cardiomyocytes that is independent of the presence of or binding to SGLT2 or the actions of these drugs on the proximal renal tubule. Nevertheless, changes in the volume set point mediated by SGLT2 inhibitors might potentially act cooperatively with the direct favorable molecular and cellular effects of these drugs on cardiomyocytes to mediate their benefits on the development and clinical course of heart failure.
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Dallas, TX (M.P.)
- Imperial College London, United Kingdom (M.P.)
| | - Christopher S. Wilcox
- Division of Nephrology and Hypertension, Kidney, and Vascular Research Center, Georgetown University, Washington, DC (C.S.W.)
| | - Jeffrey M. Testani
- Section of Cardiovascular Medicine, Yale University, New Haven, CT (J.M.T.)
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16
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Gronda E, Palazzuoli A, Iacoviello M, Benevenuto M, Gabrielli D, Arduini A. Renal Oxygen Demand and Nephron Function: Is Glucose a Friend or Foe? Int J Mol Sci 2023; 24:9957. [PMID: 37373108 PMCID: PMC10298324 DOI: 10.3390/ijms24129957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 06/02/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
The kidneys and heart work together to balance the body's circulation, and although their physiology is based on strict inter dependence, their performance fulfills different aims. While the heart can rapidly increase its own oxygen consumption to comply with the wide changes in metabolic demand linked to body function, the kidneys physiology are primarily designed to maintain a stable metabolic rate and have a limited capacity to cope with any steep increase in renal metabolism. In the kidneys, glomerular population filters a large amount of blood and the tubular system has been programmed to reabsorb 99% of filtrate by reabsorbing sodium together with other filtered substances, including all glucose molecules. Glucose reabsorption involves the sodium-glucose cotransporters SGLT2 and SGLT1 on the apical membrane in the proximal tubular section; it also enhances bicarbonate formation so as to preserve the acid-base balance. The complex work of reabsorption in the kidney is the main factor in renal oxygen consumption; analysis of the renal glucose transport in disease states provides a better understanding of the renal physiology changes that occur when clinical conditions alter the neurohormonal response leading to an increase in glomerular filtration pressure. In this circumstance, glomerular hyperfiltration occurs, imposing a higher metabolic demand on kidney physiology and causing progressive renal impairment. Albumin urination is the warning signal of renal engagement over exertion and most frequently heralds heart failure development, regardless of disease etiology. The review analyzes the mechanisms linked to renal oxygen consumption, focusing on sodium-glucose management.
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Affiliation(s)
- Edoardo Gronda
- Medicine and Medicine Sub-Specialties Department, Cardio Renal Program, U.O.C. Nephrology, Dialysis and Adult Renal Transplant Program, IRCCS Ca’ Granda Foundation, Ospedale Maggiore Policlinico, 20122 Milano, Italy
| | - Alberto Palazzuoli
- Cardiovascular Diseases Unit, Cardio Thoracic and Vascular Department, S. Maria alle Scotte Hospital University of Siena, 53100 Siena, Italy;
| | - Massimo Iacoviello
- Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy
| | - Manuela Benevenuto
- Unità Operativa Complessa Cardiologia-UTIC-Emodinamica, PO Giuseppe Mazzini, 64100 Teramo, Italy;
| | - Domenico Gabrielli
- Unità Operativa Complessa Cardiologia-UTIC, Azienda Ospedaliera San Camillo Forlanini, 00152 Rome, Italy;
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Jones NK, Costello HM, Monaghan MT, Stewart K, Binnie D, Marks J, Bailey MA, Culshaw GJ. Sodium-glucose cotransporter 2 inhibition does not improve the acute pressure natriuresis response in rats with type 1 diabetes. Exp Physiol 2023; 108:480-490. [PMID: 36644793 PMCID: PMC10103849 DOI: 10.1113/ep090849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 12/19/2022] [Indexed: 01/17/2023]
Abstract
NEW FINDINGS What is the central question of this study? Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular risk in patients with both diabetic and non-diabetic kidney disease: can SGLT2 inhibition improve renal pressure natriuresis (PN), an important mechanism for long-term blood pressure control, which is impaired in type 1 diabetes mellitus (T1DM)? What is the main finding and its importance? The SGLT2 inhibitor dapagliflozin did not enhance the acute in vivo PN response in either healthy or T1DM Sprague-Dawley rats. The data suggest that the mechanism underpinning the clinical benefits of SGLT2 inhibitors on health is unlikely to be due to an enhanced natriuretic response to increased blood pressure. ABSTRACT Type 1 diabetes mellitus (T1DM) leads to serious complications including premature cardiovascular and kidney disease. Hypertension contributes importantly to these adverse outcomes. The renal pressure natriuresis (PN) response, a key regulator of blood pressure (BP), is impaired in rats with T1DM as tubular sodium reabsorption fails to down-regulate with increasing BP. We hypothesised that sodium-glucose cotransporter 2 (SGLT2) inhibitors, which reduce cardiovascular risk in kidney disease, would augment the PN response in T1DM rats. Non-diabetic or T1DM (35-50 mg/kg streptozotocin i.p.) adult male Sprague-Dawley rats were anaesthetised (thiopental 50 mg/kg i.p.) and randomised to receive either dapagliflozin (1 mg/kg i.v.) or vehicle. Baseline sodium excretion was measured and then BP was increased by sequential arterial ligations to induce the PN response. In non-diabetic animals, the natriuretic and diuretic responses to increasing BP were not augmented by dapagliflozin. Dapagliflozin induced glycosuria, but this was not influenced by BP. In T1DM rats the PN response was impaired. Dapagliflozin again increased urinary glucose excretion but did not enhance PN. Inhibition of SGLT2 does not enhance the PN response in rats, either with or without T1DM. SGLT2 makes only a minor contribution to tubular sodium reabsorption and does not contribute to the impaired PN response in T1DM.
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Affiliation(s)
- Natalie K. Jones
- British Heart Foundation Centre for Cardiovascular ScienceUniversity of EdinburghEdinburghUK
| | - Hannah M. Costello
- British Heart Foundation Centre for Cardiovascular ScienceUniversity of EdinburghEdinburghUK
| | | | - Kevin Stewart
- British Heart Foundation Centre for Cardiovascular ScienceUniversity of EdinburghEdinburghUK
| | - David Binnie
- British Heart Foundation Centre for Cardiovascular ScienceUniversity of EdinburghEdinburghUK
| | - Joanne Marks
- Department of NeurosciencePhysiology and Pharmacology, Royal Free CampusUniversity College LondonLondonUK
| | - Matthew A. Bailey
- British Heart Foundation Centre for Cardiovascular ScienceUniversity of EdinburghEdinburghUK
| | - Geoffrey J. Culshaw
- British Heart Foundation Centre for Cardiovascular ScienceUniversity of EdinburghEdinburghUK
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18
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van der Aart-van der Beek AB, Apperloo E, Jongs N, Rouw DB, Sjöström CD, Friedli I, Johansson L, van Raalte DH, Hoogenberg K, Heerspink HJL. Albuminuria-lowering effect of dapagliflozin, exenatide, and their combination in patients with type 2 diabetes: A randomized cross-over clinical study. Diabetes Obes Metab 2023; 25:1758-1768. [PMID: 36843215 DOI: 10.1111/dom.15033] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 02/12/2023] [Accepted: 02/24/2023] [Indexed: 02/28/2023]
Abstract
AIM To evaluate the albuminuria-lowering effect of dapagliflozin, exenatide, and the combination of dapagliflozin and exenatide in patients with type 2 diabetes and microalbuminuria or macroalbuminuria. METHODS Participants with type 2 diabetes, an estimated glomerular filtration rate (eGFR) of more than 30 ml/min/1.73m2 and an urinary albumin: creatinine ratio (UACR) of more than 3.5 mg/mmol and 100 mg/mmol or less completed three 6-week treatment periods, during which dapagliflozin 10 mg/d, exenatide 2 mg/wk and both drugs combined were given in random order. The primary outcome was the percentage change in UACR. Secondary outcomes included blood pressure, HbA1c, body weight, extracellular volume, fractional lithium excretion and renal haemodynamic variables as determined by magnetic resonance imaging. RESULTS We enrolled 20 patients, who completed 53 treatment periods in total. Mean percentage change in UACR from baseline was -21.9% (95% CI: -34.8% to -6.4%) during dapagliflozin versus -7.7% (95% CI: -23.5% to 11.2%) during exenatide and -26.0% (95% CI: -38.4% to -11.0%) during dapagliflozin-exenatide treatment. No correlation was observed in albuminuria responses between the different treatments. Numerically greater reductions in systolic blood pressure, body weight and eGFR were observed during dapagliflozin-exenatide treatment compared with dapagliflozin or exenatide alone. Renal blood flow and effective renal plasma flow (ERPF) did not significantly change with either treatment regimen. However, all but four and two patients in the dapagliflozin and dapagliflozin-exenatide groups, respectively, showed reductions in ERPF. The filtration fraction did not change during treatment with dapagliflozin or exenatide, and decreased during dapagliflozin-exenatide treatment (-1.6% [95% CI: -3.2% to -0.01%]; P = .048). CONCLUSIONS In participants with type 2 diabetes and albuminuria, treatment with dapagliflozin, exenatide and dapagliflozin-exenatide reduced albuminuria, with a numerically larger reduction in the combined dapagliflozin-exenatide treatment group.
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Affiliation(s)
- Annemarie B van der Aart-van der Beek
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, The Netherlands
- Department of Clinical Pharmacy, Martini Hospital, Groningen, The Netherlands
| | - Ellen Apperloo
- Department of Internal Medicine, Isala Hospital, Zwolle, The Netherlands
| | - Niels Jongs
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, The Netherlands
| | - Dennis B Rouw
- Department of Radiology, Martini Hospital, Groningen, The Netherlands
| | - C David Sjöström
- Late-Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Iris Friedli
- Antaros Medical AB, BioVenture Hub, Mölndal, Sweden
| | | | | | - Klaas Hoogenberg
- Department of Internal Medicine, Martini Hospital, Groningen, The Netherlands
| | - Hiddo J L Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, The Netherlands
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19
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Kugathasan L, Dubrofsky L, Advani A, Cherney DZI. The anti-hypertensive effects of sodium-glucose cotransporter-2 inhibitors. Expert Rev Cardiovasc Ther 2023; 21:15-34. [PMID: 36524239 DOI: 10.1080/14779072.2023.2159810] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Hypertension is a well-established risk factor for cardiovascular (CV) events in patients with chronic kidney disease (CKD), heart failure, obesity, and diabetes. Despite the usual prescribed antihypertensive therapies, many patients fail to achieve the recommended blood pressure (BP) targets. AREAS COVERED This review summarizes the clinical BP-lowering data presented in major CV and kidney outcome trials for sodium-glucose cotransporter-2 (SGLT2) inhibitors, as well as smaller dedicated BP trials in high-risk individuals with and without diabetes. We have also highlighted potential mechanisms that may contribute to the antihypertensive effects of SGLT2 inhibitors, including natriuresis and hemodynamic changes, a loop diuretic-like effect, and alterations in vascular physiology. EXPERT OPINION The antihypertensive properties of SGLT2 inhibitors are generally modest but may be larger in certain patient populations. SGLT2 inhibitors may have an additional role as an adjunctive BP-lowering therapy in patients with hypertension at high risk of CV disease or kidney disease.
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Affiliation(s)
- Luxcia Kugathasan
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada.,Department of Physiology, University of Toronto, Toronto, Ontario, Canada.,Cardiovascular Sciences Collaborative Specialization, University of Toronto, Toronto, Ontario, Canada
| | - Lisa Dubrofsky
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada.,Division of Nephrology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.,Division of Nephrology, Women's College Hospital, Toronto, Ontario, Canada
| | - Andrew Advani
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada.,Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada.,Department of Physiology, University of Toronto, Toronto, Ontario, Canada.,Cardiovascular Sciences Collaborative Specialization, University of Toronto, Toronto, Ontario, Canada.,Department of Medicine, University of Toronto, Toronto, Ontario, Canada.,Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
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20
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Berton AM, Parasiliti-Caprino M, Prencipe N, Bioletto F, Lopez C, Bona C, Caputo M, Rumbolo F, Ponzetto F, Settanni F, Gasco V, Mengozzi G, Ghigo E, Grottoli S, Maccario M, Benso AS. Copeptin adaptive response to SGLT2 inhibitors in patients with type 2 diabetes mellitus: The GliRACo study. Front Neurosci 2023; 17:1098404. [PMID: 37021137 PMCID: PMC10067557 DOI: 10.3389/fnins.2023.1098404] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 03/03/2023] [Indexed: 04/07/2023] Open
Abstract
Introduction In type 2 diabetes mellitus (T2DM), the antidiuretic system participates in the adaptation to osmotic diuresis further increasing urinary osmolality by reducing the electrolyte-free water clearance. Sodium glucose co-transporter type 2 inhibitors (SGLT2i) emphasize this mechanism, promoting persistent glycosuria and natriuresis, but also induce a greater reduction of interstitial fluids than traditional diuretics. The preservation of osmotic homeostasis is the main task of the antidiuretic system and, in turn, intracellular dehydration the main drive to vasopressin (AVP) secretion. Copeptin is a stable fragment of the AVP precursor co-secreted with AVP in an equimolar amount. Aim To investigate the copeptin adaptive response to SGLT2i, as well as the induced changes in body fluid distribution in T2DM patients. Methods The GliRACo study was a prospective, multicenter, observational research. Twenty-six consecutive adult patients with T2DM were recruited and randomly assigned to empagliflozin or dapagliflozin treatment. Copeptin, plasma renin activity, aldosterone and natriuretic peptides were evaluated at baseline (T0) and then 30 (T30) and 90 days (T90) after SGLT2i starting. Bioelectrical impedance vector analysis (BIVA) and ambulatory blood pressure monitoring were performed at T0 and T90. Results Among endocrine biomarkers, only copeptin increased at T30, showing subsequent stability (7.5 pmol/L at T0, 9.8 pmol/L at T30, 9.5 pmol/L at T90; p = 0.001). BIVA recorded an overall tendency to dehydration at T90 with a stable proportion between extra- and intracellular fluid volumes. Twelve patients (46.1%) had a BIVA overhydration pattern at baseline and 7 of them (58.3%) resolved this condition at T90. Total body water content, extra and intracellular fluid changes were significantly affected by the underlying overhydration condition (p < 0.001), while copeptin did not. Conclusion In patients with T2DM, SGLT2i promote the release of AVP, thus compensating for persistent osmotic diuresis. This mainly occurs because of a proportional dehydration process between intra and extracellular fluid (i.e., intracellular dehydration rather than extracellular dehydration). The extent of fluid reduction, but not the copeptin response, is affected by the patient's baseline volume conditions. Clinical trial registration Clinicaltrials.gov, identifier NCT03917758.
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Affiliation(s)
- Alessandro Maria Berton
- Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
- *Correspondence: Alessandro Maria Berton, ; orcid.org/0000-0002-4745-2624
| | - Mirko Parasiliti-Caprino
- Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
- Mirko Parasiliti-Caprino, ; orcid.org/0000-0002-6930-7073
| | - Nunzia Prencipe
- Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Fabio Bioletto
- Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Chiara Lopez
- Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Chiara Bona
- Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Marina Caputo
- Department of Health Sciences, University of Eastern Piedmont, Novara, Italy
| | - Francesca Rumbolo
- Clinical Biochemistry Laboratory, Department of Laboratory Medicine, AOU Città della Salute e della Scienza di Torino, University Hospital, Turin, Italy
| | - Federico Ponzetto
- Clinical Biochemistry Laboratory, Department of Laboratory Medicine, AOU Città della Salute e della Scienza di Torino, University Hospital, Turin, Italy
| | - Fabio Settanni
- Clinical Biochemistry Laboratory, Department of Laboratory Medicine, AOU Città della Salute e della Scienza di Torino, University Hospital, Turin, Italy
| | - Valentina Gasco
- Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Giulio Mengozzi
- Clinical Biochemistry Laboratory, Department of Laboratory Medicine, AOU Città della Salute e della Scienza di Torino, University Hospital, Turin, Italy
| | - Ezio Ghigo
- Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Silvia Grottoli
- Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Mauro Maccario
- Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Andrea Silvio Benso
- Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
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21
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Shamkhalova MS, Sukhareva OY, Shestakova MV. Sub-analyses of the DAPA-CKD study: new data on the use of sodium-glucose cotransporter type 2 inhibitor in the treatment of chronic kidney disease. TERAPEVT ARKH 2022; 94:1188-1196. [DOI: 10.26442/00403660.2022.10.201883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Indexed: 11/23/2022]
Abstract
Sodium-glucose cotransporter inhibitors updated their position in the therapy of patients with type 2 diabetes mellitus due to proven nephro- and cardioprotective effects. The DAPA-CKD study, performed among individuals with CKD of various etiologies, was also conducted in a mixed population, including patients without type 2 diabetes, showed the ability of dapagliflozin to reduce the risk of the primary combined endpoint (eGFR15 ml/min/1.73 m2, the need for chronic dialysis or kidney transplantation, time to renal or cardiovascular death), and certain secondary endpoints. Due to the inclusion of dapagliflozin into the treatment of the patients with CKD of not only the diabetic origin and the expected subsequent significant expansion of the patient population with indications for the use of this drug, the review of the results of the sub-analyses of DAPA-CKD study may be of interest to the clinicians.
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22
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Curovic VR, Eickhoff MK, Rönkkö T, Frimodt-Møller M, Hansen TW, Mischak H, Rossing P, Ahluwalia TS, Persson F. Dapagliflozin Improves the Urinary Proteomic Kidney-Risk Classifier CKD273 in Type 2 Diabetes with Albuminuria: A Randomized Clinical Trial. Diabetes Care 2022; 45:2662-2668. [PMID: 35998283 DOI: 10.2337/dc22-1157] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 07/19/2022] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To evaluate the effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on the kidney-risk urinary proteomic classifier (CKD273) in persons with type 2 diabetes (T2D) and albuminuria. RESEARCH DESIGN AND METHODS In a double-blind, randomized, controlled, crossover trial, we assigned participants with T2D and urinary albumin to creatinine ratio (UACR) ≥30 mg/g to receive dapagliflozin or matching placebo added to guideline-recommended treatment (ClinicalTrial.gov identifier NCT02914691). Treatment periods lasted 12 weeks, when crossover to the opposing treatment occurred. The primary outcome was change in CKD273 score. Secondary outcomes included regression from high-risk to low-risk CKD273 pattern using the prespecified cutoff score of 0.154. The primary outcome was assessed using paired t test between end-to-end CKD273 scores after dapagliflozin and placebo treatment. The McNemar test was used to assess regression in risk category. RESULTS A total of 40 participants were randomized and 32 completed the trial with intact proteomic measurements. Twenty-eight (88%) were men, the baseline mean (SD) age was 63.0 (8.3) years, mean (SD) diabetes duration was 15.4 (4.5) years, mean HbA1c was 73 (14) mmol/mol (8.8% [1.3%]), and median (interquartile range) UACR was 154 (94, 329) mg/g. Dapagliflozin significantly lowered CKD273 score compared with placebo (-0.221; 95% CI -0.356, -0.087; P = 0.002). Fourteen participants exhibited a high-risk pattern after dapagliflozin treatment compared with 24 after participants placebo (P = 0.021). CONCLUSIONS Dapagliflozin added to renin-angiotensin system inhibition reduced the urinary proteomic classifier CKD273 in persons with T2D and albuminuria, paving the way for the further investigation of CKD273 as a modifiable kidney risk factor.
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Affiliation(s)
| | | | - Teemu Rönkkö
- Steno Diabetes Center Copenhagen, Herlev, Denmark
| | | | | | | | - Peter Rossing
- Steno Diabetes Center Copenhagen, Herlev, Denmark.,Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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23
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Kuzmin OB, Zhezha VV. Refractory Arterial Hypertension: Features of Neurohormonal and Water-salt Imbalanceand Approaches to Antihypertensive Drug Therapy. RATIONAL PHARMACOTHERAPY IN CARDIOLOGY 2022. [DOI: 10.20996/1819-6446-2022-08-14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Refractory arterial hypertension is characterized by a lack of control of target blood pressure, despite the prolonged use >5 antihypertensive drugs with different mechanisms of action, including longacting diuretic chlorthalidone and the mineralcorticoid receptor antagonists (spironolactone or eplerenone). The review presents the results of clinical studies devoted the elucidating peculiarities of the neurohormonal status and water-salt balance in such patients and developing new approaches to antihypertensive drug therapy based on them. According to these studies, individuals with refractory hypertension differ from patients with resistant hypertension with the higher of sympathetic nervous system activity and the absence of an increased of intrathoracic fluid volume, which indirectly indicates a significant decrease in the intravascular fluid volume. In this regard, the review focuses on the data obtained in assessing the clinical efficacy of sympatholytics clonidine and reserpine in patients with resistant and refractory hypertension, as well as renal sodium-glucose co-transporter type 2 inhibitors, which suppress the sympathetic nervous system activity and can be used to overcome refractory hypertension in patients with type 2 diabetes.
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24
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Mogi M, Maruhashi T, Higashi Y, Masuda T, Nagata D, Nagai M, Bokuda K, Ichihara A, Nozato Y, Toba A, Narita K, Hoshide S, Tanaka A, Node K, Yoshida Y, Shibata H, Katsurada K, Kuwabara M, Kodama T, Shinohara K, Kario K. Update on Hypertension Research in 2021. Hypertens Res 2022; 45:1276-1297. [PMID: 35790879 PMCID: PMC9255494 DOI: 10.1038/s41440-022-00967-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 06/03/2022] [Indexed: 12/16/2022]
Abstract
In 2021, 217 excellent manuscripts were published in Hypertension Research. Editorial teams greatly appreciate the authors' contribution to hypertension research progress. Here, our editorial members have summarized twelve topics from published work and discussed current topics in depth. We hope you enjoy our special feature, "Update on Hypertension Research in 2021".
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Affiliation(s)
- Masaki Mogi
- Department of Pharmacology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Tohon, Ehime, 791-0295, Japan.
| | - Tatsuya Maruhashi
- Department of Regenerative Medicine, Division of Radiation Medical Science, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
| | - Yukihito Higashi
- Department of Regenerative Medicine, Division of Radiation Medical Science, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
- Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Takahiro Masuda
- Division of Nephrology, Department of Medicine, Jichi Medical University School of Medicine, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
| | - Daisuke Nagata
- Division of Nephrology, Department of Medicine, Jichi Medical University School of Medicine, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
| | - Michiaki Nagai
- Department of Cardiology, Hiroshima City Asa Hospital, 1-2-1 Kameyamaminami Asakita-ku, Hiroshima, 731-0293, Japan
| | - Kanako Bokuda
- Department of Endocrinology and Hypertension, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Atsuhiro Ichihara
- Department of Endocrinology and Hypertension, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Yoichi Nozato
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2, Yamada-oka, Suita, Osaka, 565-0871, Japan
| | - Ayumi Toba
- Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Sakaecho, Itabashi-ku, Tokyo, 173-0015, Japan
| | - Keisuke Narita
- Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
| | - Satoshi Hoshide
- Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
| | - Atsushi Tanaka
- Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga, 849-8501, Japan
| | - Koichi Node
- Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga, 849-8501, Japan
| | - Yuichi Yoshida
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, 1-1, 1-1 Idaigaoka, Hasama-machi, Yufu city, Oita, 879-5593, Japan
| | - Hirotaka Shibata
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, 1-1, 1-1 Idaigaoka, Hasama-machi, Yufu city, Oita, 879-5593, Japan
| | - Kenichi Katsurada
- Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
- Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University School of Medicine, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
| | - Masanari Kuwabara
- Department of Cardiology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Takahide Kodama
- Department of Cardiology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Keisuke Shinohara
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kazuomi Kario
- Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
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25
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Escudero VJ, Mercadal J, Molina-Andújar A, Piñeiro GJ, Cucchiari D, Jacas A, Carramiñana A, Poch E. New Insights Into Diuretic Use to Treat Congestion in the ICU: Beyond Furosemide. FRONTIERS IN NEPHROLOGY 2022; 2:879766. [PMID: 37675009 PMCID: PMC10479653 DOI: 10.3389/fneph.2022.879766] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 05/30/2022] [Indexed: 09/08/2023]
Abstract
Diuretics are commonly used in critically ill patients with acute kidney injury (AKI) and fluid overload in intensive care units (ICU), furosemide being the diuretic of choice in more than 90% of the cases. Current evidence shows that other diuretics with distinct mechanisms of action could be used with good results in patients with selected profiles. From acetazolamide to tolvaptan, we will discuss recent studies and highlight how specific diuretic mechanisms could help to manage different ICU problems, such as loop diuretic resistance, hypernatremia, hyponatremia, or metabolic alkalosis. The current review tries to shed some light on the potential use of non-loop diuretics based on patient profile and give recommendations for loop diuretic treatment performance focused on what the intensivist and critical care nephrologist need to know based on the current evidence.
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Affiliation(s)
- Victor Joaquin Escudero
- Nephrology and Kidney Transplantation Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Jordi Mercadal
- Surgical Intensive Care Unit, Anesthesiology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Univesitat de Barcelona, Barcelona, Spain
| | - Alícia Molina-Andújar
- Nephrology and Kidney Transplantation Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Gaston J. Piñeiro
- Nephrology and Kidney Transplantation Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - David Cucchiari
- Nephrology and Kidney Transplantation Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Adriana Jacas
- Surgical Intensive Care Unit, Anesthesiology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Univesitat de Barcelona, Barcelona, Spain
| | - Albert Carramiñana
- Surgical Intensive Care Unit, Anesthesiology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Univesitat de Barcelona, Barcelona, Spain
| | - Esteban Poch
- Nephrology and Kidney Transplantation Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
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26
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Lin H, Geurts F, Hassler L, Batlle D, Mirabito Colafella KM, Denton KM, Zhuo JL, Li XC, Ramkumar N, Koizumi M, Matsusaka T, Nishiyama A, Hoogduijn MJ, Hoorn EJ, Danser AHJ. Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting. Pharmacol Rev 2022; 74:462-505. [PMID: 35710133 PMCID: PMC9553117 DOI: 10.1124/pharmrev.120.000236] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The concept of local formation of angiotensin II in the kidney has changed over the last 10-15 years. Local synthesis of angiotensinogen in the proximal tubule has been proposed, combined with prorenin synthesis in the collecting duct. Binding of prorenin via the so-called (pro)renin receptor has been introduced, as well as megalin-mediated uptake of filtered plasma-derived renin-angiotensin system (RAS) components. Moreover, angiotensin metabolites other than angiotensin II [notably angiotensin-(1-7)] exist, and angiotensins exert their effects via three different receptors, of which angiotensin II type 2 and Mas receptors are considered renoprotective, possibly in a sex-specific manner, whereas angiotensin II type 1 (AT1) receptors are believed to be deleterious. Additionally, internalized angiotensin II may stimulate intracellular receptors. Angiotensin-converting enzyme 2 (ACE2) not only generates angiotensin-(1-7) but also acts as coronavirus receptor. Multiple, if not all, cardiovascular diseases involve the kidney RAS, with renal AT1 receptors often being claimed to exert a crucial role. Urinary RAS component levels, depending on filtration, reabsorption, and local release, are believed to reflect renal RAS activity. Finally, both existing drugs (RAS inhibitors, cyclooxygenase inhibitors) and novel drugs (angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter-2 inhibitors, soluble ACE2) affect renal angiotensin formation, thereby displaying cardiovascular efficacy. Particular in the case of the latter three, an important question is to what degree they induce renoprotection (e.g., in a renal RAS-dependent manner). This review provides a unifying view, explaining not only how kidney angiotensin formation occurs and how it is affected by drugs but also why drugs are renoprotective when altering the renal RAS. SIGNIFICANCE STATEMENT: Angiotensin formation in the kidney is widely accepted but little understood, and multiple, often contrasting concepts have been put forward over the last two decades. This paper offers a unifying view, simultaneously explaining how existing and novel drugs exert renoprotection by interfering with kidney angiotensin formation.
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Affiliation(s)
- Hui Lin
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Frank Geurts
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Luise Hassler
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Daniel Batlle
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Katrina M Mirabito Colafella
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Kate M Denton
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Jia L Zhuo
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Xiao C Li
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Nirupama Ramkumar
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Masahiro Koizumi
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Taiji Matsusaka
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Akira Nishiyama
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Martin J Hoogduijn
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Ewout J Hoorn
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - A H Jan Danser
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
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van Ruiten CC, Hesp AC, van Raalte DH. Sodium glucose cotransporter-2 inhibitors protect the cardiorenal axis: Update on recent mechanistic insights related to kidney physiology. Eur J Intern Med 2022; 100:13-20. [PMID: 35414444 DOI: 10.1016/j.ejim.2022.03.031] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 03/23/2022] [Accepted: 03/29/2022] [Indexed: 12/11/2022]
Abstract
Sodium glucose cotransporter-2 (SGLT2) inhibitors have acquired a central role in the treatment of type 2 diabetes, chronic kidney disease including diabetic kidney disease, and heart failure with reduced ejection fraction. SGLT2 inhibitors lower glucose levels by inducing glycosuria. In addition, SGLT2 inhibitors improve cardiovascular outcomes (3-point MACE), end-stage kidney disease, hospitalization for heart failure, and cardiovascular mortality in people with and without diabetes. The mechanisms underlying these benefits have been extensively investigated, but remain poorly understood. In this review, we first summarize recent trial evidence and subsequently focus on (1) the mechanisms by which SGLT2 inhibitors improve kidney outcomes and (2) the potential role of the kidneys in mediating the cardioprotective effects of SGLT2 inhibitors.
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Affiliation(s)
- Charlotte C van Ruiten
- Amsterdam Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers (Amsterdam UMC), location VU University Medical Center, De Boelelaan 1117 (room ZH 4A63), Amsterdam 1081 HV, the Netherland.
| | - Anne C Hesp
- Amsterdam Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers (Amsterdam UMC), location VU University Medical Center, De Boelelaan 1117 (room ZH 4A63), Amsterdam 1081 HV, the Netherland
| | - Daniël H van Raalte
- Amsterdam Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers (Amsterdam UMC), location VU University Medical Center, De Boelelaan 1117 (room ZH 4A63), Amsterdam 1081 HV, the Netherland; Department of Vascular Medicine Amsterdam University Medical Center, Location VU University Medical Center, Amsterdam, the Netherland
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28
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Groothof D, Post A, Gans ROB, Bakker SJL. Ertugliflozin, renoprotection and potential confounding by muscle wasting. Diabetologia 2022; 65:906-907. [PMID: 34940888 DOI: 10.1007/s00125-021-05614-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 10/08/2021] [Indexed: 11/28/2022]
Affiliation(s)
- Dion Groothof
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
| | - Adrian Post
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Reinold O B Gans
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Stephan J L Bakker
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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29
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Granata A, Pesce F, Iacoviello M, Anzaldi M, Amico F, Catalano M, Leonardi G, Gatta C, Costanza G, Corrao S, Gesualdo L. SGLT2 Inhibitors: A Broad Impact Therapeutic Option for the Nephrologist. FRONTIERS IN NEPHROLOGY 2022; 2:867075. [PMID: 37674992 PMCID: PMC10479658 DOI: 10.3389/fneph.2022.867075] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/17/2022] [Indexed: 09/08/2023]
Abstract
Since their introduction as antidiabetic drugs, SGLT2 inhibitors (SGLT2i) have come a long way, proving to be beneficial on cardiovascular and renal outcomes independently of diabetes status. The benefits go far beyond glycemic control, and both the cardio- and nephroprotection are underpinned by diverse mechanisms. From the activation of tubule glomerular feedback and the consequent reduction in hyperfiltration to the improvement of hypoxia and oxidative stress in the renal cortex, SGLT2i have also been shown to inhibit hepcidin and limit podocyte damage. Likewise, they improve cardiac metabolism and bioenergetics, and reduce necrosis and cardiac fibrosis and the production of adipokines, cytokines, and epicardial adipose tissue mass. In terms of outcomes, the efficacy has been demonstrated on blood pressure control, BMI, albuminuria, stroke, heart disease, and mortality rate due to cardiovascular events. Patients with chronic kidney disease and proteinuria, with or without diabetes, treated with some SGLT2i have a reduced risk of progression. The analysis of subgroups of individuals with specific diseases such as IgA nephropathy has confirmed this solid effect on renal outcomes. Given these overarching activities on such a broad pathophysiological background and the favorable safety profile that goes with the use of SGLT2i, it is now certain that they are changing our approach to clinical interventions for important outcomes with an impressive impact.
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Affiliation(s)
- Antonio Granata
- Nephrology and Dialysis Unit, “Cannizzaro” Emergency Hospital, Catania, Italy
| | - Francesco Pesce
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Massimo Iacoviello
- Cardiology Unit, Department of Medical and Surgical Science, University of Foggia, Foggia, Italy
| | | | - Francesco Amico
- Cardiology Unit, “Cannizzaro” Emergency Hospital, Catania, Italy
| | - Maria Catalano
- Cardiology Unit, “Cannizzaro” Emergency Hospital, Catania, Italy
| | - Giuseppe Leonardi
- Cardiology Unit, Azienda Ospedaliera Universitaria (A.O.U.) “Policlinico-San Marco”, Catania, Italy
| | - Carmela Gatta
- Internal Medicine Unit, Azienda Ospedaliera Universitaria (A.O.U.) “Policlinico-San Marco”, Catania, Italy
| | - Giusy Costanza
- Nephrology and Dialysis, “Vittorio Emanuele” Hospital, Gela, Italy
| | - Salvatore Corrao
- Department of Internal Medicine, “Azienda di Rilievo Nazionale ed Alta Specializzazione (ARNAS) Civico, Di Cristina e Benfratelli”, Palermo, Italy
| | - Loreto Gesualdo
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
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Hernandez M, Sullivan RD, McCune ME, Reed GL, Gladysheva IP. Sodium-Glucose Cotransporter-2 Inhibitors Improve Heart Failure with Reduced Ejection Fraction Outcomes by Reducing Edema and Congestion. Diagnostics (Basel) 2022; 12:989. [PMID: 35454037 PMCID: PMC9024630 DOI: 10.3390/diagnostics12040989] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 03/30/2022] [Accepted: 04/12/2022] [Indexed: 02/07/2023] Open
Abstract
Pathological sodium-water retention or edema/congestion is a primary cause of heart failure (HF) decompensation, clinical symptoms, hospitalization, reduced quality of life, and premature mortality. Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) based therapies reduce hospitalization due to HF, improve functional status, quality, and duration of life in patients with HF with reduced ejection fraction (HFrEF) independently of their glycemic status. The pathophysiologic mechanisms and molecular pathways responsible for the benefits of SGLT-2i in HFrEF remain inconclusive, but SGLT-2i may help HFrEF by normalizing salt-water homeostasis to prevent clinical edema/congestion. In HFrEF, edema and congestion are related to compromised cardiac function. Edema and congestion are further aggravated by renal and pulmonary abnormalities. Treatment of HFrEF patients with SGLT-2i enhances natriuresis/diuresis, improves cardiac function, and reduces natriuretic peptide plasma levels. In this review, we summarize current clinical research studies related to outcomes of SGLT-2i treatment in HFrEF with a specific focus on their contribution to relieving or preventing edema and congestion, slowing HF progression, and decreasing the rate of rehospitalization and cardiovascular mortality.
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Affiliation(s)
- Michelle Hernandez
- Department of Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ 85004, USA; (M.H.); (R.D.S.); (M.E.M.); (G.L.R.)
- School of Medicine, Universidad Autónoma de Guadalajara, Zapopan 45129, Mexico
| | - Ryan D. Sullivan
- Department of Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ 85004, USA; (M.H.); (R.D.S.); (M.E.M.); (G.L.R.)
| | - Mariana E. McCune
- Department of Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ 85004, USA; (M.H.); (R.D.S.); (M.E.M.); (G.L.R.)
| | - Guy L. Reed
- Department of Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ 85004, USA; (M.H.); (R.D.S.); (M.E.M.); (G.L.R.)
| | - Inna P. Gladysheva
- Department of Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ 85004, USA; (M.H.); (R.D.S.); (M.E.M.); (G.L.R.)
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Zanchi A, Pruijm M, Muller ME, Ghajarzadeh-Wurzner A, Maillard M, Dufour N, Bonny O, Wuerzner G, Burnier M. Twenty-Four Hour Blood Pressure Response to Empagliflozin and Its Determinants in Normotensive Non-diabetic Subjects. Front Cardiovasc Med 2022; 9:854230. [PMID: 35391843 PMCID: PMC8981729 DOI: 10.3389/fcvm.2022.854230] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 02/21/2022] [Indexed: 01/10/2023] Open
Abstract
Background Sodium–glucose co-transport 2 inhibitors (SGLT2i) lower blood pressure (BP) in normotensive subjects and in hypertensive and normotensive diabetic and non-diabetic patients. However, the mechanisms of these BP changes are not fully understood. Therefore, we examined the clinical and biochemical determinants of the BP response to empagliflozin based on 24-h ambulatory BP monitoring. Methods In this post-hoc analysis of a double-blind, randomized, placebo-controlled study examining the renal effects of empagliflozin 10 mg vs. placebo in untreated normotensive non-diabetic subjects, the 1-month changes in 24 h ambulatory BP were analyzed in 39 subjects (13 placebo/26 empagliflozin) in regard to changes in biochemical and hormonal parameters. Results At 1 month, empagliflozin 10 mg decreased 24-h systolic (SBP) and diastolic (DBP) BP significantly by −5 ± 7 mmHg (p < 0.001) and −2 ± 6 mmHg (p = 0.03). The effect on SBP and DBP was more pronounced during nighttime (resp. −6 ± 11 mmHg, p = 0.004; −4 ± 7 mmHg, p = 0.007). The main determinants of daytime and nighttime SBP and DBP responses were baseline BP levels (for daytime SBP: coefficient −0.5; adj. R2: 0.36; p = 0.0007; for night-time SBP: coefficient −0.6; adj. R2: 0.33; p = 0.001). Although empaglifozin induced significant biochemical changes, none correlated with blood pressure changes including urinary sodium, lithium, glucose and urate excretion and free water clearance. Plasma renin activity and plasma aldosterone levels increased significantly at 1 month suggesting plasma volume contraction, while plasma metanephrine and copeptin levels remained the same. Renal resistive indexes did not change with empagliflozin. Conclusion SGLT2 inhibition lowers daytime and nighttime ambulatory systolic and diastolic BP in normotensive non-diabetic subjects. Twenty-four jour changes are pronounced and comparable to those described in diabetic or hypertensive subjects. Baseline ambulatory BP was the only identified determinant of systolic and diastolic BP response. This suggests that still other factors than sustained glycosuria or proximal sodium excretion may contribute to the resetting to lower blood pressure levels with SGLT2 inhibition. Clinical Trial Registration: [https://www.clinicaltrials.gov], identifier [NCT03093103].
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Affiliation(s)
- Anne Zanchi
- Service of Nephrology and Hypertension, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.,Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital, Lausanne, Switzerland
| | - Menno Pruijm
- Service of Nephrology and Hypertension, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Marie-Eve Muller
- Service of Nephrology and Hypertension, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Arlène Ghajarzadeh-Wurzner
- Service of Nephrology and Hypertension, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Marc Maillard
- Service of Nephrology and Hypertension, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Nathalie Dufour
- Service of Nephrology and Hypertension, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Olivier Bonny
- Service of Nephrology and Hypertension, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Grégoire Wuerzner
- Service of Nephrology and Hypertension, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Michel Burnier
- Service of Nephrology and Hypertension, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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Scholtes RA, Muskiet MH, van Baar MJ, Hesp AC, Greasley PJ, Hammarstedt A, Karlsson C, Hallow KM, Danser AJ, Heerspink HJ, van Raalte DH. The adaptive renal response for volume homeostasis during two weeks of dapagliflozin treatment in people with type 2 diabetes and preserved renal function on a sodium-controlled diet. Kidney Int Rep 2022; 7:1084-1092. [PMID: 35570989 PMCID: PMC9091605 DOI: 10.1016/j.ekir.2022.02.023] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/11/2022] [Accepted: 02/15/2022] [Indexed: 12/20/2022] Open
Abstract
Introduction Proximal tubule sodium uptake is diminished following sodium glucose cotransporter 2 (SGLT2) inhibition. We previously showed that during SGLT2 inhibition, the kidneys adapt by increasing sodium uptake at distal tubular segments, thereby maintaining body sodium balance. Despite continuous glycosuria, we detected no increased urine volumes. We therefore assessed the adaptive renal responses to prevent excessive fluid loss. Methods We conducted a mechanistic open-label study in people with type 2 diabetes mellitus with preserved kidney function, who received a standardized sodium intake (150 mmol/d) to evaluate the effects of dapagliflozin on renin-angiotensin-aldosterone system (RAAS) hormones, volume-related biomarkers, urinary albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR), at start of treatment (day 4), end of treatment (day 14), and follow-up (day 18). Results A total of 14 people were enrolled. Plasma renin and angiotensin II and urinary aldosterone and angiotensinogen were acutely and persistently increased during treatment with dapagliflozin. Plasma copeptin level was numerically increased after 4 days (21%). Similarly, fractional urea excretion was significantly decreased at start of treatment (−17%). Free water clearance was significantly decreased after 4 days (−74%) and 14 days (−41%). All changes reversed after dapagliflozin discontinuation. Conclusion Dapagliflozin-induced osmotic diuresis triggers kidney adaptive mechanisms to maintain volume and sodium balance in people with type 2 diabetes and preserved kidney function. ClinicalTrials.gov (identification: NCT03152084).
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Swapnasrita S, Carlier A, Layton AT. Sex-Specific Computational Models of Kidney Function in Patients With Diabetes. Front Physiol 2022; 13:741121. [PMID: 35153824 PMCID: PMC8827383 DOI: 10.3389/fphys.2022.741121] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 01/04/2022] [Indexed: 12/25/2022] Open
Abstract
The kidney plays an essential role in homeostasis, accomplished through the regulation of pH, electrolytes and fluids, by the building blocks of the kidney, the nephrons. One of the important markers of the proper functioning of a kidney is the glomerular filtration rate. Diabetes is characterized by an enlargement of the glomerular and tubular size of the kidney, affecting the afferent and efferent arteriole resistance and hemodynamics, ultimately leading to chronic kidney disease. We postulate that the diabetes-induced changes in kidney may exhibit significant sex differences as the distribution of renal transporters along the nephron may be markedly different between women and men, as recently shown in rodents. The goals of this study are to (i) analyze how kidney function is altered in male and female patients with diabetes, and (ii) assess the renal effects, in women and men, of an anti-hyperglycemic therapy that inhibits the sodium-glucose cotransporter 2 (SGLT2) in the proximal convoluted tubules. To accomplish these goals, we have developed computational models of kidney function, separate for male and female patients with diabetes. The simulation results indicate that diabetes enhances Na+ transport, especially along the proximal tubules and thick ascending limbs, to similar extents in male and female patients, which can be explained by the diabetes-induced increase in glomerular filtration rate. Additionally, we conducted simulations to study the effects of diabetes and SGLT2 inhibition on solute and water transport along the nephrons. Model simulations also suggest that SGLT2 inhibition raises luminal [Cl-] at the macula densa, twice as much in males as in females, and could indicate activation of the tubuloglomerular feedback signal. By inducing osmotic diuresis in the proximal tubules, SGLT2 inhibition reduces paracellular transport, eventually leading to diuresis and natriuresis. Those effects on urinary excretion are blunted in women, in part due to their higher distal transport capacity.
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Affiliation(s)
- Sangita Swapnasrita
- Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, Netherlands
| | - Aurélie Carlier
- Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, Netherlands
| | - Anita T. Layton
- Department of Applied Mathematics, University of Waterloo, Waterloo, ON, Canada
- Department of Biology, Cheriton School of Computer Science, School of Pharmacology, University of Waterloo, Waterloo, ON, Canada
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Empagliflozin Alleviates Left Ventricle Hypertrophy in High-Fat-Fed Mice by Modulating Renin Angiotensin Pathway. J Renin Angiotensin Aldosterone Syst 2022; 2022:8861911. [PMID: 35111238 PMCID: PMC8789460 DOI: 10.1155/2022/8861911] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 11/30/2021] [Accepted: 12/08/2021] [Indexed: 12/13/2022] Open
Abstract
Aims. The cardiobenefits of empagliflozin are multidimensional, and some mechanisms are still unclear. The aim of the present study was to evaluate the effect of treatment with empagliflozin on biometric parameters and gene expression in the local cardiac RAS, oxidative stress, and endoplasmic reticulum pathways in a mouse model. Main Methods. Forty male C57BL/6 mice were fed with control (C) or high-fat (HF) diets for 10 weeks. After that, the groups were redistributed according to the treatment with empagliflozin—CE or HFE. The empagliflozin was administered via food for 5 weeks (10 mg/kg/day). We performed biochemical analyses, blood pressure monitoring, oral glucose tolerance test, left ventricle (LV) stereology, RT-qPCR for genes related to classical and counterregulatory local RAS, oxidative stress, and endoplasmic reticulum stress. Key Findings. In comparison to HF, HFE decreased body mass and improved glucose intolerance and insulin resistance. The cardiac parameters were enhanced after treatment as expressed by decrease in plasma cholesterol, plasma uric acid, and systolic blood pressure. In addition, LV analysis showed that empagliflozin reduces cardiomyocyte area and LV thickness. The local RAS had less activity of the classical pathway and positive effects on the counterregulatory pathway. Empagliflozin treatment also decreased oxidative stress and endoplasmic reticulum stress-related genes. Significance. Our results suggests that empagliflozin modulates the local RAS pathway towards alleviation of oxidative stress and ER stress in the LV, which may be a route to its effects on improved cardiac remodeling.
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Liu H, Sridhar VS, Boulet J, Dharia A, Khan A, Lawler PR, Cherney DZI. Cardiorenal protection with SGLT2 inhibitors in patients with diabetes mellitus: from biomarkers to clinical outcomes in heart failure and diabetic kidney disease. Metabolism 2022; 126:154918. [PMID: 34699838 DOI: 10.1016/j.metabol.2021.154918] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 10/14/2021] [Accepted: 10/19/2021] [Indexed: 12/23/2022]
Abstract
Type 2 diabetes (T2D) is one of the most common causes of chronic kidney disease (CKD) and cardiovascular (CV) disease. Until recently, glycemic and BP control were the cornerstones for preventing progression of CKD and CV disease associated with T2D. However, there has been a paradigm shift in treatment since the publication of the first clinical trial demonstrating benefits of sodium glucose cotransporter 2 (SGLT2) inhibitors in 2015. SGLT2 inhibitors have been shown to reduce the risk of major adverse CV events and progression of kidney disease in the setting of T2D. However, the elucidation of mechanisms of underlying these clinical benefits is the subject of ongoing investigation. Experimental studies have shown that SGLT2 inhibitors have diverse pleiotropic effects such as modulation of neurohormones such as the renin-angiotensin-aldosterone system, increasing hematocrit, altering energy substrate use, and attenuating systemic inflammation and oxidative stress, all of which have been implicated in the CV and kidney protective effects of SGLT2 inhibitors. In this review, we highlight biomarkers linked with diabetic kidney disease and heart failure and discuss how SGLT2 inhibitor-associated changes potentially mediate the cardiorenal protection observed with these therapies.
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Affiliation(s)
- Hongyan Liu
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
| | - Vikas S Sridhar
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Jacinthe Boulet
- Department of Medicine, Division of Cardiology, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada
| | - Atit Dharia
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada
| | - Abid Khan
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada
| | - Patrick R Lawler
- Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada; Ted Rogers Centre for Heart Research, University of Toronto, Toronto, ON, Canada; Division of Cardiology and Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
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Vallon V, Nakagawa T. Renal Tubular Handling of Glucose and Fructose in Health and Disease. Compr Physiol 2021; 12:2995-3044. [PMID: 34964123 PMCID: PMC9832976 DOI: 10.1002/cphy.c210030] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The proximal tubule of the kidney is programmed to reabsorb all filtered glucose and fructose. Glucose is taken up by apical sodium-glucose cotransporters SGLT2 and SGLT1 whereas SGLT5 and potentially SGLT4 and GLUT5 have been implicated in apical fructose uptake. The glucose taken up by the proximal tubule is typically not metabolized but leaves via the basolateral facilitative glucose transporter GLUT2 and is returned to the systemic circulation or used as an energy source by distal tubular segments after basolateral uptake via GLUT1. The proximal tubule generates new glucose in metabolic acidosis and the postabsorptive phase, and fructose serves as an important substrate. In fact, under physiological conditions and intake, fructose taken up by proximal tubules is primarily utilized for gluconeogenesis. In the diabetic kidney, glucose is retained and gluconeogenesis enhanced, the latter in part driven by fructose. This is maladaptive as it sustains hyperglycemia. Moreover, renal glucose retention is coupled to sodium retention through SGLT2 and SGLT1, which induces secondary deleterious effects. SGLT2 inhibitors are new anti-hyperglycemic drugs that can protect the kidneys and heart from failing independent of kidney function and diabetes. Dietary excess of fructose also induces tubular injury. This can be magnified by kidney formation of fructose under pathological conditions. Fructose metabolism is linked to urate formation, which partially accounts for fructose-induced tubular injury, inflammation, and hemodynamic alterations. Fructose metabolism favors glycolysis over mitochondrial respiration as urate suppresses aconitase in the tricarboxylic acid cycle, and has been linked to potentially detrimental aerobic glycolysis (Warburg effect). © 2022 American Physiological Society. Compr Physiol 12:2995-3044, 2022.
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Affiliation(s)
- Volker Vallon
- Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego, La Jolla, California, USA,Department of Pharmacology, University of California San Diego, La Jolla, California, USA,VA San Diego Healthcare System, San Diego, California, USA,Correspondence to and
| | - Takahiko Nakagawa
- Division of Nephrology, Rakuwakai-Otowa Hospital, Kyoto, Japan,Correspondence to and
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Delanaye P, Scheen AJ. The diuretic effects of SGLT2 inhibitors: A comprehensive review of their specificities and their role in renal protection. DIABETES & METABOLISM 2021; 47:101285. [PMID: 34597788 DOI: 10.1016/j.diabet.2021.101285] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 09/16/2021] [Indexed: 02/08/2023]
Abstract
Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) are new oral glucose-lowering agents that provide cardiovascular and renal protection in both patients with and without type 2 diabetes. Because of their unique mechanism of action, increased glucosuria is associated with osmotic diuresis and some natriuresis, yet the latter seems mostly transient. The potential role of the diuretic effect in overall cardiovascular and renal protection by SGLT2is remains a matter of debate. Precise evaluation of the diuretic effect is not so easy and most studies relied upon indirect estimations that led to divergent results, presumably also explained by different study designs and population characteristics. Everybody agrees upon the fact that SGLT2is are different from other classical diuretics (thiazides and loop diuretics) as they present some favourable properties, i.e. reduced sympathetic activity, preserved potassium balance, lower risk of acute renal injury, decrease of serum uric acid level. The potential role of the diuretic effect of SGLT2is on renal outcomes is still unclear, yet their ability to reduce albuminuria and dampen the risk of heart failure may contribute to improve renal prognosis besides other complex underlying mechanisms. In this comprehensive review we first critically analyse the results obtained with indirect methods that assess a diuretic effect of SGLT2is, second we describe the specificities of the diuretic activity of SGLT2is compared with other classical diuretics, and third we discuss the potential mechanisms by which the diuretic effect of SGLT2is could contribute to the improvement of renal outcomes consistently reported with this innovative amazing pharmacological class.
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Affiliation(s)
- Pierre Delanaye
- Department of Nephrology-Dialysis-Transplantation, University of Liège (ULg CHU), CHU Sart Tilman, Liège, Belgium; Department of Nephrology-Dialysis-Apheresis, Hôpital Universitaire Carémeau, Nimes, France
| | - Andre J Scheen
- Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium; Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège, Belgium.
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Persson F, Rossing P, Vart P, Chertow GM, Hou FF, Jongs N, McMurray JJV, Correa-Rotter R, Bajaj HS, Stefansson BV, Toto RD, Langkilde AM, Wheeler DC, Heerspink HJL. Efficacy and Safety of Dapagliflozin by Baseline Glycemic Status: A Prespecified Analysis From the DAPA-CKD Trial. Diabetes Care 2021; 44:1894-1897. [PMID: 34183431 PMCID: PMC8385469 DOI: 10.2337/dc21-0300] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 04/18/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) study demonstrated risk reduction for kidney and cardiovascular outcomes with dapagliflozin versus placebo in participants with chronic kidney disease (CKD) with and without diabetes. We compared outcomes according to baseline glycemic status. RESEARCH DESIGN AND METHODS We enrolled participants with CKD, estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2, and urinary albumin-to-creatinine ratio 200-5,000 mg/g. The primary composite end point was sustained eGFR decline ≥50%, end-stage kidney disease, or kidney or cardiovascular death. RESULTS Of 4,304 participants, 738 had normoglycemia, 660 had prediabetes, and 2,906 had type 2 diabetes. The effect of dapagliflozin on the primary outcome was consistent (P for interaction = 0.19) in normoglycemia (hazard ratio [HR] 0.62 [95% CI 0.39, 1.01]), prediabetes (HR 0.37 [0.21, 0.66]), and type 2 diabetes (HR 0.64 [0.52, 0.79]). We found no evidence for effect modification on any outcome. Adverse events were similar, with no major hypoglycemia or ketoacidosis in participants with normoglycemia or prediabetes. CONCLUSIONS Dapagliflozin safely reduced kidney and cardiovascular events independent of baseline glycemic status.
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Affiliation(s)
| | - Peter Rossing
- Steno Diabetes Center Copenhagen, Gentofte, Denmark.,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Priya Vart
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Glenn M Chertow
- Departments of Medicine and Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA
| | - Fan Fan Hou
- Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, Guangzhou, China
| | - Niels Jongs
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - John J V McMurray
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, U.K
| | - Ricardo Correa-Rotter
- National Medical Science and Nutrition Institute Salvador Zubirán, Mexico City, Mexico
| | | | - Bergur V Stefansson
- Late-stage Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals Research and Development, AstraZeneca, Gothenburg, Sweden
| | - Robert D Toto
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Anna Maria Langkilde
- Late-stage Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals Research and Development, AstraZeneca, Gothenburg, Sweden
| | - David C Wheeler
- Department of Renal Medicine, University College London, London, U.K.,The George Institute for Global Health, Sydney, Australia
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The Potential Roles of Osmotic and Nonosmotic Sodium Handling in Mediating the Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Heart Failure. J Card Fail 2021; 27:1447-1455. [PMID: 34289398 PMCID: PMC8759453 DOI: 10.1016/j.cardfail.2021.07.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 06/08/2021] [Accepted: 07/02/2021] [Indexed: 11/24/2022]
Abstract
Concomitant type 2 diabetes and chronic kidney disease increases the risk of heart failure. Recent studies demonstrate beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on chronic kidney disease progression and heart failure hospitalization in patients with and without diabetes. In addition to inhibiting glucose reabsorption, SGLT2 inhibitors decrease proximal tubular sodium reabsorption, possibly leading to transient natriuresis. We review the hypothesis that SGLT2 inhibitor’s natriuretic and osmotic diuretic effects mediate their cardioprotective effects. The degree to which these benefits are related to changes in sodium, independent of the kidney, is currently unknown. Aside from effects on osmotically active sodium, we explore the intriguing possibility that SGLT2 inhibitors could also modulate nonosmotic sodium storage. This alternative hypothesis is based on emerging literature that challenges the traditional 2-compartment model of sodium balance to provide support for a 3-compartment model that includes the binding of sodium to glycosaminoglycans, such as those in muscles and skin. This recent research on nonosmotic sodium storage, as well as direct cardiac effects of SGLT2 inhibitors, provides possibilities for other ways in which SGLT2 inhibitors might mitigate heart failure risk. Overall, we review the effects of SGLT2 inhibitors on sodium balance and sensitivity, cardiac tissue, interstitial fluid and plasma volume, and nonosmotic sodium storage. SGLT2 inhibitors have cardiovascular benefits that include HF outcomes in patients with and without diabetes. Because the underlying mechanisms are only partly explained by improvements in BP, body weight, or glucose control, other mechanisms have been proposed. We focus here on a central role for effects on sodium as underlying the positive benefits of SGLT2 inhibitors in HF. We explore the new (although still unconfirmed) idea that SGLT2 inhibitors exert some of their positive effects by affecting nonosmotic sodium (ie, sodium bound to muscles and skin and not dissolved in the blood).
SGLT2 inhibitors have emerged as a class of drugs, previously prescribed for patients with T2D, that have in more recent years been shown to have substantial heart and kidney clinical benefits in patients with and without T2D. The degree to which these benefits are related to kidney-independent changes in sodium homeostasis is currently unknown. A better understanding of the nonosmotic mechanisms underpinning the benefits of SGLT2 inhibition on HF (with reduced or preserved left ventricular ejection fraction) may allow researchers to assess the effects of SGLT2 inhibitors in combination with other treatments that affect sodium balance.
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Trujillo H, Caravaca-Fontán F, Caro J, Morales E, Praga M. The Forgotten Antiproteinuric Properties of Diuretics. Am J Nephrol 2021; 52:435-449. [PMID: 34233330 DOI: 10.1159/000517020] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 04/30/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND Although diuretics are one of the most widely used drugs by nephrologists, their antiproteinuric properties are not generally taken into consideration. SUMMARY Thiazide diuretics have been shown to reduce proteinuria by >35% in several prospective controlled studies, and these values are markedly increased when combined with a low-salt diet. Thiazide-like diuretics (indapamide and chlorthalidone) have shown similar effectiveness. The antiproteinuric effect of mineralocorticoid receptor antagonists (spironolactone, eplerenone, and finerenone) has been clearly established through prospective and controlled studies, and treatment with finerenone reduces the risk of chronic kidney disease progression in type-2 diabetic patients. The efficacy of other diuretics such as amiloride, triamterene, acetazolamide, or loop diuretics has been less explored, but different investigations suggest that they might share the same antiproteinuric properties of other diuretics that should be evaluated through controlled studies. Although the inclusion of sodium-glucose cotransporter-2 inhibitors (SGLT2i) among diuretics is a controversial issue, their renoprotective and cardioprotective properties, confirmed in various landmark trials, constitute a true revolution in the treatment of patients with kidney disease. Recent subanalyses of these trials have shown that the early antiproteinuric effect induced by SGLT2i predicts long-term preservation of kidney function. Key Message: Whether the early reduction in proteinuria induced by diuretics other than finerenone and SGLT2i, as summarized in this review, also translates into long-term renoprotection requires further prospective and observational studies. In any case, it is important for the clinician to be aware of the antiproteinuric properties of drugs so often used in daily clinical practice.
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Affiliation(s)
- Hernando Trujillo
- Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain,
| | | | - Jara Caro
- Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain
- Instituto de Investigación Hospital Universitario 12 de Octubre (imas12), Madrid, Spain
| | - Enrique Morales
- Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain
- Instituto de Investigación Hospital Universitario 12 de Octubre (imas12), Madrid, Spain
- Department of Medicine, Universidad Complutense de Madrid, Madrid, Spain
| | - Manuel Praga
- Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain
- Instituto de Investigación Hospital Universitario 12 de Octubre (imas12), Madrid, Spain
- Department of Medicine, Universidad Complutense de Madrid, Madrid, Spain
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Ghanim H, Batra M, Green K, Hejna J, Abuaysheh S, Makdissi A, Chaudhuri A, Dandona P. Dapagliflozin reduces systolic blood pressure and modulates vasoactive factors. Diabetes Obes Metab 2021; 23:1614-1623. [PMID: 33729664 DOI: 10.1111/dom.14377] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 03/04/2021] [Accepted: 03/14/2021] [Indexed: 11/30/2022]
Abstract
AIM To investigate the mechanisms underlying improvements in blood pressure (BP) and congestive heart failure outcomes following treatment with dapagliflozin, a sodium-glucose co-transporter-2 inhibitor. RESEARCH DESIGN AND METHODS A total of 52 patients with type 2 diabetes (T2D) with an HbA1c of less than 8% participated in this prospective, double-blind and placebo-controlled study. Patients were randomized (1:1) to either dapagliflozin 10 mg daily or placebo for 12 weeks. Half the patients were also monitored for 6 h following their first dose for acute effects on BP. Blood and urine samples were collected and levels of angiotensinogen, angiotensin II, renin, aldosterone, endothelin-1, atrial natriuretic peptide (ANP), brain natriuretic peptide, cyclic adenosine monophosphate, cyclic guanosine monophosphate (cGMP) and neprilysin were measured. The expression of angiotensin-converting enzyme, guanylate cyclase and phosphodiesterase 5 (PDE5) was measured in circulating mononuclear cells (MNC). RESULTS A total of 24 and 23 patients receiving dapagliflozin and placebo, respectively, completed the 12-week study. Systolic BP decreased significantly, compared with placebo, both after single-dose (by 7 ± 3 mmHg) and 12-week (by 7 ± 2 mmHg) treatment with dapagliflozin. Dapagliflozin suppressed angiotensin II and angiotensinogen (by 10.5 ± 2.1 and 1.45 ± 0.42 μg/mL, respectively) and increased ANP and cGMP (by 34 ± 11 and 29 ± 11 pmol/mL, respectively) compared with the placebo group. cGMP levels also increased acutely following a single dose of dapagliflozin. Dapagliflozin also suppressed PDE5 expression by 26% ± 11% in MNC. There were no changes observed in the other vasoactive mediators investigated. CONCLUSIONS Dapagliflozin administration in T2D resulted in both acute and chronic reduction in systolic BP, a reduction in vasoconstrictors and an increase in vasodilators. These changes may potentially contribute to its antihypertensive effects and its benefits in congestive cardiac failure.
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Affiliation(s)
- Husam Ghanim
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Williamsville, New York, USA
| | - Manav Batra
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Williamsville, New York, USA
| | - Kelly Green
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Williamsville, New York, USA
| | - Jeanne Hejna
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Williamsville, New York, USA
| | - Sanaa Abuaysheh
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Williamsville, New York, USA
| | - Antione Makdissi
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Williamsville, New York, USA
| | - Ajay Chaudhuri
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Williamsville, New York, USA
| | - Paresh Dandona
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Williamsville, New York, USA
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The Mystery of Diabetic Cardiomyopathy: From Early Concepts and Underlying Mechanisms to Novel Therapeutic Possibilities. Int J Mol Sci 2021; 22:ijms22115973. [PMID: 34205870 PMCID: PMC8198766 DOI: 10.3390/ijms22115973] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 05/26/2021] [Accepted: 05/30/2021] [Indexed: 02/07/2023] Open
Abstract
Diabetic patients are predisposed to diabetic cardiomyopathy, a specific form of cardiomyopathy which is characterized by the development of myocardial fibrosis, cardiomyocyte hypertrophy, and apoptosis that develops independently of concomitant macrovascular and microvascular diabetic complications. Its pathophysiology is multifactorial and poorly understood and no specific therapeutic guideline has yet been established. Diabetic cardiomyopathy is a challenging diagnosis, made after excluding other potential entities, treated with different pharmacotherapeutic agents targeting various pathophysiological pathways that need yet to be unraveled. It has great clinical importance as diabetes is a disease with pandemic proportions. This review focuses on the potential mechanisms contributing to this entity, diagnostic options, as well as on potential therapeutic interventions taking in consideration their clinical feasibility and limitations in everyday practice. Besides conventional therapies, we discuss novel therapeutic possibilities that have not yet been translated into clinical practice.
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Empagliflozin therapy and insulin resistance-associated disorders: effects and promises beyond a diabetic state. ACTA ACUST UNITED AC 2021; 6:e57-e78. [PMID: 34027215 PMCID: PMC8117073 DOI: 10.5114/amsad.2021.105314] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Accepted: 03/21/2021] [Indexed: 12/21/2022]
Abstract
Empagliflozin is a SGLT2 inhibitor that has shown remarkable cardiovascular and renal activities in patients with type 2 diabetes (T2D). Preclinical and clinical studies of empagliflozin in T2D population have demonstrated significant improvements in body weight, waist circumference, insulin sensitivity, and blood pressure – effects beyond its antihyperglycaemic control. Moreover, several studies suggested that this drug possesses significant anti-inflammatory and antioxidative stress properties. This paper explores extensively the main preclinical and clinical evidence of empagliflozin administration in insulin resistance-related disorders beyond a diabetic state. It also discusses its future perspectives, as a therapeutic approach, in this high cardiovascular-risk population.
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Scholtes RA, Muskiet MHA, van Baar MJB, Hesp AC, Greasley PJ, Karlsson C, Hammarstedt A, Arya N, van Raalte DH, Heerspink HJL. Natriuretic Effect of Two Weeks of Dapagliflozin Treatment in Patients With Type 2 Diabetes and Preserved Kidney Function During Standardized Sodium Intake: Results of the DAPASALT Trial. Diabetes Care 2021; 44:440-447. [PMID: 33318125 PMCID: PMC7818331 DOI: 10.2337/dc20-2604] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 11/08/2020] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk for heart failure hospitalization potentially by inducing sodium excretion, osmotic diuresis, and plasma volume contraction. Few studies have investigated this hypothesis, but none have assessed cumulative sodium excretion with SGLT2 inhibition during standardized sodium intake in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS The DAPASALT trial was a mechanistic, nonrandomized, open-label study in patients with type 2 diabetes with preserved kidney function on a controlled standardized sodium diet (150 mmol/day). It evaluated the effects of dapagliflozin on sodium excretion, 24-h blood pressure, and extracellular, intracellular, and plasma volumes at the start of treatment (ST) (days 2-4), end of treatment (ET) (days 12-14), and follow-up (FU) (days 15-18). RESULTS Fourteen patients were included in the efficacy analysis. Mean (SD) baseline sodium excretion (150 [32] mmol/24-h) did not significantly change during treatment (change at ST: -7.0 mmol/24-h [95% CI -22.4, 8.4]; change at ET: 2.1 mmol/24-h [-28.8, 33.0]). Mean baseline 24-h systolic blood pressure was 128 (10) mmHg and significantly reduced at ST (-6.1 mmHg [-9.1, -3.1]; P < 0.001) and ET (-7.2 mmHg [-10.0, -4.3]; P < 0.001). Dapagliflozin did not significantly alter plasma volume or intracellular volume, while extracellular volume changed at ST (-0.7 L [-1.3, -0.1]; P = 0.02). As expected, 24-h urinary glucose excretion significantly increased during dapagliflozin treatment and reversed during FU. CONCLUSIONS During standardized sodium intake, dapagliflozin reduced blood pressure without clear changes in urinary sodium excretion, suggesting that factors other than natriuresis and volume changes may contribute to the blood pressure-lowering effects.
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Affiliation(s)
- Rosalie A Scholtes
- Amsterdam Diabetes Center, Department of Internal Medicine, Academic Medical Center, VU University Medical Center, Amsterdam, the Netherlands
| | - Marcel H A Muskiet
- Amsterdam Diabetes Center, Department of Internal Medicine, Academic Medical Center, VU University Medical Center, Amsterdam, the Netherlands
| | - Michiel J B van Baar
- Amsterdam Diabetes Center, Department of Internal Medicine, Academic Medical Center, VU University Medical Center, Amsterdam, the Netherlands
| | - Anne C Hesp
- Amsterdam Diabetes Center, Department of Internal Medicine, Academic Medical Center, VU University Medical Center, Amsterdam, the Netherlands
| | | | | | | | - Niki Arya
- BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD
| | - Daniël H van Raalte
- Amsterdam Diabetes Center, Department of Internal Medicine, Academic Medical Center, VU University Medical Center, Amsterdam, the Netherlands
| | - Hiddo J L Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
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Boorsma EM, Beusekamp JC, ter Maaten JM, Figarska SM, Danser AJ, van Veldhuisen DJ, van der Meer P, Heerspink HJ, Damman K, Voors AA. Effects of empagliflozin on renal sodium and glucose handling in patients with acute heart failure. Eur J Heart Fail 2020; 23:68-78. [PMID: 33251643 PMCID: PMC8048437 DOI: 10.1002/ejhf.2066] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 11/01/2020] [Accepted: 11/23/2020] [Indexed: 12/18/2022] Open
Abstract
AIMS Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve clinical outcome in patients with heart failure (HF), but the mechanisms behind their beneficial effects are not yet fully understood. We examined the effects of empagliflozin on renal sodium and glucose handling in patients with acute HF. METHODS AND RESULTS This study was a pre-defined sub-study of a double-blind, randomized, placebo-controlled, multicentre study (EMPA-RESPONSE-AHF). Patients were allocated within 24 h of an acute HF admission to either empagliflozin 10 mg/day (n = 40) or placebo (n = 39) for 30 days. Markers of glucose and sodium handling were measured daily during the first 96 h and at day 30. Patients were 76 (range 38-89) years old and 33% had diabetes. The use of loop diuretics during the first 96 h was similar in both groups. Empagliflozin increased fractional glucose excretion with a peak after 24 h (21.8% vs. 0.1%; P < 0.001), without affecting plasma glucose concentration, while fractional sodium and chloride excretion and urinary osmolality remained unchanged (P >0.3 for all). However, empagliflozin increased plasma osmolality (delta osmolality at 72 h: 5 ± 8 vs. 2 ± 5 mOsm/kg; P = 0.049). Finally, there was an early decline in estimated glomerular filtration rate with empagliflozin vs. placebo (-10 ± 12 vs. -2 ± 12 mL/min/1.73 m2 ; P = 0.009), which recovered within 30 days. CONCLUSION In patients with acute HF, empagliflozin increased fractional glucose excretion and plasma osmolality, without affecting fractional sodium excretion or urine osmolality and caused a temporary decline in estimated glomerular filtration rate. This suggests that empagliflozin stimulates osmotic diuresis through increased glycosuria rather than natriuresis in patients with acute HF.
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Affiliation(s)
- Eva M. Boorsma
- University of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - Joost C. Beusekamp
- University of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - Jozine M. ter Maaten
- University of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - Sylwia M. Figarska
- University of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - A.H. Jan Danser
- Department of Internal Medicine, Division of PharmacologyErasmus University Medical Center RotterdamRotterdamThe Netherlands
| | | | - Peter van der Meer
- University of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - Hiddo J.L. Heerspink
- University of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - Kevin Damman
- University of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - Adriaan A. Voors
- University of Groningen, University Medical Center GroningenGroningenThe Netherlands
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Stefánsson BV, Heerspink HJL, Wheeler DC, Sjöström CD, Greasley PJ, Sartipy P, Cain V, Correa-Rotter R. Correction of anemia by dapagliflozin in patients with type 2 diabetes. J Diabetes Complications 2020; 34:107729. [PMID: 32948397 DOI: 10.1016/j.jdiacomp.2020.107729] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 08/26/2020] [Accepted: 08/27/2020] [Indexed: 12/22/2022]
Abstract
AIMS Anemia is common in type 2 diabetes (T2D), particularly in patients with kidney impairment, and often goes unrecognized. Dapagliflozin treatment increases hemoglobin and serum erythropoietin levels. We investigated the effect of dapagliflozin 10-mg/day on hemoglobin in T2D patients with and without anemia. METHODS Data from 5325 patients from 14 placebo-controlled, dapagliflozin-treatment studies of at least 24-weeks duration were pooled. Dapagliflozin's effects (vs. placebo) on hemoglobin, serum albumin, estimated glomerular filtration rate (eGFR), systolic blood pressure, body weight, and safety in patients with and without anemia were evaluated. RESULTS At baseline, 13% of all T2D patients and 28% of those with chronic kidney disease (eGFR <60 mL/min/1.73 m2) had anemia. Hemoglobin increased continuously to at least week 8 and was sustained throughout 24-weeks follow-up in dapagliflozin-treated patients. Serum albumin increased in dapagliflozin-treated patients at week 4 and remained stable thereafter. Dapagliflozin was well tolerated and corrected anemia in 52% of patients with anemia at baseline (placebo: 26%). Incidences of new-onset anemia were lower in dapagliflozin-treated (2.3%) versus placebo-treated (6.5%) patients. CONCLUSIONS Treatment with dapagliflozin can correct and prevent anemia in T2D patients. A gradual increase in hemoglobin beyond week 4 may indicate an erythropoiesis-stimulating effect of sodium-glucose cotransporter 2 inhibition.
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Affiliation(s)
- Bergur V Stefánsson
- Late-stage Development Cardiovascular Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Hiddo J L Heerspink
- Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, the Netherlands; George Institute for Global Health, Sydney, Australia
| | - David C Wheeler
- George Institute for Global Health, Sydney, Australia; Department of Renal Medicine, University College London, London, United Kingdom
| | - C David Sjöström
- Late-stage Development Cardiovascular Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Peter J Greasley
- Research and Early Development, Cardiovascular Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Peter Sartipy
- Late-stage Development Cardiovascular Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, Sweden
| | - Valerie Cain
- Bogier Clinical and IT Solutions, Raleigh, NC, United States
| | - Ricardo Correa-Rotter
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
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Grubić Rotkvić P, Cigrovski Berković M, Bulj N, Rotkvić L. Minireview: are SGLT2 inhibitors heart savers in diabetes? Heart Fail Rev 2020; 25:899-905. [PMID: 31410757 DOI: 10.1007/s10741-019-09849-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a class of drugs that promote urinary glucose excretion in the treatment of diabetes, have provoked large interest of scientific and professional community due to their positive and, somehow, unexpected results in the three major cardiovascular outcome trials (EMPA-REG OUTCOME trial with empagliflozin, CANVAS Program with canagliflozin, and DECLARE-TIMI 58 with dapagliflozin). In fact, along with the reduction of major adverse cardiovascular events, SGLT2 inhibitors reduced significantly hospitalization for heart failure regardless of existing atherosclerotic cardiovascular disease or a history of heart failure. The latter have reminded us of the frequent but neglected entity of diabetic cardiomyopathy which is currently poorly understood despite its great clinical importance. Physiological mechanisms responsible for the benefits of SGLT2 inhibitors are complex and multifactorial and still not well defined. Interestingly, the time frame of their effect excludes a glucose- and antiatherosclerotic-mediated effect. It would be of great importance to better understand SGLT2 inhibitor mechanisms of action since they could have a potential to be used in early stages of diabetes as cardioprotective agents. There are widely available biomarkers as well as echocardiography that are used in everyday clinical practice and could elucidate physiological mechanisms in the heart protection with SGLT2 inhibitors treatment but studies are still lacking. The purpose of this minireview is to summarize the latest concepts about SGLT2 inhibitors and its benefits regarding diabetic cardiomyopathy especially on its early stage development and to discuss controversies and potential future developments in the field.
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Affiliation(s)
| | - Maja Cigrovski Berković
- Department of Endocrinology, Diabetes, and Metabolism, University Hospital Centre "Sestre milosrdnice", Zagreb, Croatia
- Department for Medicine of Sports and Exercise, Faculty of Kinesiology, University of Zagreb, Zagreb, Croatia
| | - Nikola Bulj
- Department of Cardiology, University Hospital Centre "Sestre milosrdnice", Zagreb, Croatia
| | - Luka Rotkvić
- Department of Cardiology, Magdalena Clinic for Cardiovascular Disease, Krapinske Toplice, Croatia
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48
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Oshima M, Neuen BL, Jardine MJ, Bakris G, Edwards R, Levin A, Mahaffey KW, Neal B, Pollock C, Rosenthal N, Wada T, Wheeler DC, Perkovic V, Heerspink HJL. Effects of canagliflozin on anaemia in patients with type 2 diabetes and chronic kidney disease: a post-hoc analysis from the CREDENCE trial. Lancet Diabetes Endocrinol 2020; 8:903-914. [PMID: 33065060 DOI: 10.1016/s2213-8587(20)30300-4] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 08/14/2020] [Accepted: 08/17/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Sodium-glucose co-transporter 2 inhibitors might enhance erythropoiesis and increase red blood cell mass. We assessed the long-term effects of canagliflozin on anaemia-related outcomes. METHODS In a post-hoc analysis of the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, we included patients with type 2 diabetes and chronic kidney disease who were randomly assigned to treatment with canagliflozin or placebo at 690 sites in 34 countries. We assessed the effects of canagliflozin versus matched placebo on haemoglobin and haematocrit using linear mixed-effects models. The primary outcome of this post-hoc analysis was a composite outcome of investigator-reported anaemia or treatment for anaemia, which was assessed using Kaplan-Meier analysis and Cox regression models. All analyses were done by intention to treat. FINDINGS Between March 24, 2014, and May 5, 2017, 4401 participants were randomly assigned to receive canagliflozin (100 mg; n=2202) or placebo (n=2199). At baseline, mean haemoglobin concentration was 132·0 g/L (SD 17·7), 1599 (36%) of 4401 participants had anaemia (defined as haemoglobin <130 g/L in men or <120 g/L in women), and 33 (<1%) of 4401 participants used erythropoiesis-stimulating agents. During a median follow-up period of 2·6 years (IQR 2·1-3·1), mean haemoglobin concentration was 7·1 g/L (95% CI 6·4-7·8) higher and haematocrit was 2·4% (2·2-2·6) higher in the canagliflozin group than the placebo group. Overall, 573 of 4401 participants had either an investigator-reported anaemia event or initiation of treatment for anaemia: 358 (8%) of 4401 participants reported anaemia events, 343 (8%) initiated iron preparations, 141 (3%) initiated erythropoiesis-stimulating agents, and 114 (2%) received blood transfusion. The risk of the composite outcome of anaemia events or initiation of treatment for anaemia was lower in the canagliflozin group than the placebo group (hazard ratio 0·65, 95% CI 0·55-0·77; p<0·0001). Compared with the placebo group, participants in the canagliflozin group also had lower risks of anaemia events alone (0·58, 0·47-0·72; p<0·0001), initiation of iron preparations (0·64, 0·52-0·80; p<0·0001), and need for erythropoiesis-stimulating agents (0·65, 0·46-0·91; p=0·012). INTERPRETATION These data suggest that canagliflozin reduces the risk of anaemia-associated outcomes, including the need for erythropoiesis-stimulating agents, among patients with type 2 diabetes and chronic kidney disease. FUNDING Janssen Research and Development.
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Affiliation(s)
- Megumi Oshima
- Renal and Metabolic Division, The George Institute for Global Health, UNSW Sydney, Sydney, NSW, Australia; Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Brendon L Neuen
- Renal and Metabolic Division, The George Institute for Global Health, UNSW Sydney, Sydney, NSW, Australia
| | - Meg J Jardine
- Renal and Metabolic Division, The George Institute for Global Health, UNSW Sydney, Sydney, NSW, Australia; Concord Repatriation General Hospital, Sydney, NSW, Australia
| | - George Bakris
- Department of Medicine, University of Chicago, Chicago, IL, USA
| | | | - Adeera Levin
- Division of Nephrology, University of British Columbia, Vancouver, BC, Canada
| | | | - Bruce Neal
- Renal and Metabolic Division, The George Institute for Global Health, UNSW Sydney, Sydney, NSW, Australia; The Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia; Imperial College London, London, UK
| | - Carol Pollock
- Kolling Institute of Medical Research, Sydney Medical School, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia
| | | | - Takashi Wada
- Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - David C Wheeler
- Renal and Metabolic Division, The George Institute for Global Health, UNSW Sydney, Sydney, NSW, Australia; Department of Renal Medicine, University College London, London, UK
| | - Vlado Perkovic
- Renal and Metabolic Division, The George Institute for Global Health, UNSW Sydney, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia
| | - Hiddo J L Heerspink
- Renal and Metabolic Division, The George Institute for Global Health, UNSW Sydney, Sydney, NSW, Australia; Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
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Scheen AJ. Sodium-glucose cotransporter type 2 inhibitors for the treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 2020; 16:556-577. [PMID: 32855502 DOI: 10.1038/s41574-020-0392-2] [Citation(s) in RCA: 168] [Impact Index Per Article: 33.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/03/2020] [Indexed: 02/07/2023]
Abstract
The management of type 2 diabetes mellitus (T2DM) is becoming increasingly complex. Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) are the newest antidiabetic agents for T2DM. By targeting the kidney, they have a unique mechanism of action, which results in enhanced glucosuria, osmotic diuresis and natriuresis, thereby improving glucose control with a limited risk of hypoglycaemia and exerting additional positive effects such as weight loss and the lowering of blood pressure. Several outcome studies with canagliflozin, dapagliflozin or empagliflozin reported a statistically significant reduction in major cardiovascular events, hospitalization for heart failure and progression to advanced renal disease in patients with T2DM who have established atherosclerotic cardiovascular disease, several cardiovascular risk factors, albuminuric mild to moderate chronic kidney disease or heart failure. Current guidelines proposed a new paradigm in the management of T2DM, with a preferential place for SGLT2is, after metformin, in patients with atherosclerotic cardiovascular disease, heart failure and progressive kidney disease. Ongoing trials might extend the therapeutic potential of SGLT2is in patients with, but also without, T2DM. This Review provides an update of the current knowledge on SGLT2is, moving from their use as glucose-lowering medications to their new positioning as cardiovascular and renal protective agents.
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Affiliation(s)
- André J Scheen
- Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège, Belgium.
- Division of Clinical Pharmacology, Center for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium.
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50
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Marton A, Kaneko T, Kovalik JP, Yasui A, Nishiyama A, Kitada K, Titze J. Organ protection by SGLT2 inhibitors: role of metabolic energy and water conservation. Nat Rev Nephrol 2020; 17:65-77. [PMID: 33005037 DOI: 10.1038/s41581-020-00350-x] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/18/2020] [Indexed: 12/17/2022]
Abstract
Therapeutic inhibition of the sodium-glucose co-transporter 2 (SGLT2) leads to substantial loss of energy (in the form of glucose) and additional solutes (in the form of Na+ and its accompanying anions) in urine. However, despite the continuously elevated solute excretion, long-term osmotic diuresis does not occur in humans with SGLT2 inhibition. Rather, patients on SGLT2 inhibitor therapy adjust to the reduction in energy availability and conserve water. The metabolic adaptations that are induced by SGLT2 inhibition are similar to those observed in aestivation - an evolutionarily conserved survival strategy that enables physiological adaptation to energy and water shortage. Aestivators exploit amino acids from muscle to produce glucose and fatty acid fuels. This endogenous energy supply chain is coupled with nitrogen transfer for organic osmolyte production, which allows parallel water conservation. Moreover, this process is often accompanied by a reduction in metabolic rate. By comparing aestivation metabolism with the fuel switches that occur during therapeutic SGLT2 inhibition, we suggest that SGLT2 inhibitors induce aestivation-like metabolic patterns, which may contribute to the improvements in cardiac and renal function observed with this class of therapeutics.
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Affiliation(s)
- Adriana Marton
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore
| | - Tatsuroh Kaneko
- Medicine Division, Nippon Boehringer Ingelheim Co., Ltd, Tokyo, Japan
| | - Jean-Paul Kovalik
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore
| | - Atsutaka Yasui
- Medicine Division, Nippon Boehringer Ingelheim Co., Ltd, Tokyo, Japan
| | - Akira Nishiyama
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Kento Kitada
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore.,Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Jens Titze
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore. .,Division of Nephrology and Hypertension, University Clinic Erlangen, Erlangen, Germany. .,Division of Nephrology, Duke University Medical Center, Durham, NC, USA.
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