The antidiabetic SGLT2 inhibitor canagliflozin reduces mitochondrial metabolism in a model of skeletal muscle insulin resistance.

AIMS: Sodium-glucose cotransporter 2 (SGLT2) inhibitors such as canagliflozin (CANA) have emerged as an effective adjuvant therapy in the management of diabetes, however, past observations suggest CANA may alter skeletal muscle mass and function. The purpose of this work was to investigate the effects of CANA on skeletal muscle metabolism both with and without insulin resistance. METHODS: C2C12 myotubes were treated with CANA with or without insulin resistance. Western blot and qRT-PCR were used to assess protein and gene expression, respectively. Cell metabolism was assessed via oxygen consumption and extracellular acidification rate. Mitochondrial, nuclei and lipid content were measured using fluorescent staining and microscopy. RESULTS: CANA decreased mitochondrial function and glycolytic metabolism as did insulin resistance, however, these changes occurred without significant alterations in gene expression associated with each pathway. Additionally, while insulin resistance reduced insulin-stimulated pAkt expression, CANA had no significant effect on insulin sensitivity. CONCLUSIONS: CANA appears to reduce mitochondrial and glycolytic metabolism without altering gene expression governing these pathways, suggesting a reduction in substrate may be responsible for lower metabolism.

Safety and Efficacy of Dapagliflozin in Recurrent Ascites: A Pilot Study.

BACKGROUND: In cirrhosis, activation of renin-angiotensin-aldosterone system leads to sodium and water retention causing ascites. Dapagliflozin, a sodium glucose linked transporter-2 inhibitor, induces natriuresis in patients with heart failure. A similar natriuretic effect may improve ascites in patients with cirrhosis. In this pilot study, we evaluated the safety and efficacy of dapagliflozin in patients with cirrhosis and recurrent ascites. METHODS: Forty patients with recurrent ascites and cirrhosis were randomized to 1:1 in a double blinded fashion to receive either dapagliflozin (10 mg/day) with standard medical therapy (Group A) or placebo with standard medical therapy (Group B). The primary outcome was control of ascites at 6 months. Secondary outcomes were urine output, 24-h urinary sodium, Child Turcotte Pugh (CTP), model for end-stage liver disease (MELD) scores, survival at 6 months, incidence of acute kidney injury (AKI) and infections. RESULTS: The 2 groups were comparable at baseline. Control of ascites at 6 months was significantly better in group A than that in Group B (p = 0.04). Change in urinary sodium was significantly higher in Group A (p < 0.001]. However, there was no difference in change in urine output, CTP or MELD scores and survival (65% vs 72.2%, p = 0.75) between the groups at 6 months. Incidence of AKI (50% vs 15%, p = 0.04) and infections (55% vs 20%, p = 0.04) were significantly higher in Group A. CONCLUSION: Significantly better control of ascites and higher natriuresis are observed with dapagliflozin. However, it does not improve disease severity scores or survival, and is associated with increased AKI and infections (NCT05014594).

Sodium-glucose transport protein 2 inhibitor use in the management of insulin dysregulation in ponies and horses.

Laminitis is a common and painful condition of the equine foot and approximately 90% of cases are associated with insulin dysregulation (ID) that is a central feature of the common endocrine disorder equine metabolic syndrome (EMS) and occurs in a subset of animals with pituitary pars intermedia dysfunction. Additional features of EMS include obesity, altered circulating concentrations of adipokines (particularly adiponectin and leptin) and hypertriglyceridaemia. Obesity, ID, hypoadiponectinaemia, hyperleptinaemia and an altered plasma lipid profile are also features of human metabolic syndrome (HMS) alongside hyperglycaemia. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a novel class of oral hypoglycaemic agents used in combination with lifestyle changes in the management of HMS. SGLT2 receptors are responsible for 90% of the renal glucose reabsorption that occurs in the proximal convoluted tubule. Thus, these drugs increase urinary glucose excretion by suppressing glucose reabsorption from the glomerular filtrate resulting in urinary calorie loss with consequent weight loss and improvements in ID, hyperglycemia, hypoadiponectinaemia and hyperleptinaemia. There are no licenced veterinary drugs available for treating ID and preventing insulin-associated laminitis in horses. Thus, the use of SGLT2i for the control of equine hyperinsulinaemia with the goal of improving recovery from associated active laminitis or preventing future laminitis has recently been advocated. There are a small number of published studies reporting the use of the SGLT2i canagliflozin, ertugliflozin and velagliflozin to aid the management of equine ID. However, the doses used are largely extrapolated from human studies with limited consideration of species-specific variations. In addition, there is limited evaluation of the fundamental differences between ID in horses and humans, particularly the fact that most horses with ID remain hyperinsulinaemic but normoglycaemic such that increased urinary loss of glucose may not explain the beneficial effects of these drugs. Further study of the potential deleterious effects of treatment-associated hypertriglyceridaemia is required together with the effect of SGLT2i therapy on circulating concentrations of adipokines in horses.

[Normoglycaemic ketoacidosis induced by the use of sglt2 inhibitors : impact of intense physiological stress and fasting]. / Acidocétose normoglycémique induite par la prise de gliflozines en cas de stress physiologique intense et de jeûne.

Ketoacidosis is a serious complication of diabetes that only occurs in cases of absolute or severe relative insulin deficiency. This condition is rare in type 2 diabetes. The use of gliflozin during intense physiological stress associated with fasting can lead to the development of ketoacidosis without severe hyperglycaemia. The diagnosis of this normoglycaemic or euglycaemic diabetic ketoacidosis in the context of type 2 diabetes may be challenging. The treatment of metabolic acidosis cannot rely solely on symptomatic measures such as bicarbonate infusion. The demonstration of metabolic acidosis necessitates the search for an etiological diagnosis. The calculation of the anion gap is the cornerstone of the pathophysiological diagnosis of metabolic acidosis. In the context of diabetes, the occurrence of metabolic acidosis of unknown etiology requires its calculation and systematic measurement of ketones, even in the absence of severe hyperglycaemia. Only the etiological treatment of diabetic ketoacidosis, which is insulin therapy, allows for the lasting restoration of acid-base balance. Normoglycaemic ketoacidosis induced by the use of gliflozin during intense physiological stress associated with fasting should therefore be a recognized situation by healthcare providers.

L'acidocétose est une complication grave du diabète qui ne survient qu'en cas de déficit en insuline, absolu ou relatif sévère. Cette condition est rare dans le diabète de type 2. La prise de gliflozines en cas de stress physiologique intense, notamment associé à un jeûne, peut induire la survenue d'une acidocétose sans hyperglycémie sévère. Cette acidocétose diabétique dite normoglycémique ou euglycémique dans le cadre d'un diabète de type 2 est source d'errance diagnostique. Le traitement d'une acidose métabolique ne peut pas se satisfaire de l'instauration de mesures symptomatiques comme la perfusion de bicarbonates. La démonstration d'une acidose métabolique impose la recherche d'un diagnostic étiologique. Le calcul du trou anionique est la pierre angulaire du diagnostic physiopathologique d'une acidose métabolique. Dans le cadre du diabète, la survenue d'une acidose métabolique d'étiologie inconnue impose son calcul et le dosage systématique de la cétonémie, même en l'absence d'hyperglycémie sévère, a fortiori en cas de traitement par gliflozine. Seul le traitement étiologique d'une acidocétose diabétique, l'insulinothérapie, permet la restitution durable de l'équilibre acido-basique. L'acidocétose normoglycémique induite par la prise de gliflozines en cas de stress physiologique intense associé à un jeûne doit donc être une situation connue.

[Patient with type 2 diabetes and coronary heart disease developing heart failure]. / Vignette thérapeutique de l'étudiant. Patient avec un diabète de type 2, une coronaropathie et une insuffisance cardiaque.

Patients with type 2 diabetes (T2D) are frequently exposed to comorbidities, mainly cardiovascular complications. Thus, a polypharmacy is often mandatory, targeting not only T2D but also comorbidities such as coronary artery disease and heart failure. Interestingly, some drugs improve glucose control, cardiovascular prognosis and heart failure outcome. This versatility may cause trouble regarding prescriptions by practitioners, especially because of the restricted conditions for the reimbursement in Belgium. This clinical vignette aims at discussing the path of pharmacotherapy for a patient with T2D who suffers from a myocardial infarction and subsequently develops a heart failure. It will mainly focus on the place of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporters 2 (gliflozins) as well as the potential of their combination in this context, considering the current restrictions for the reimbursement.

Le patient avec un diabète de type 2 (DT2) est souvent exposé à diverses comorbidités, notamment cardiovasculaires. Dès lors, une polymédication est souvent nécessaire, ciblant le DT2 lui-même, mais aussi les comorbidités comme une coronaropathie et une insuffisance cardiaque. De façon intéressante, certaines médications améliorent à la fois le contrôle glycémique, le pronostic cardiovasculaire et le devenir de l'insuffisance cardiaque. Cette polyvalence peut jeter le trouble en ce qui concerne les prescriptions chez les praticiens, notamment en lien avec les conditions restrictives de remboursement en Belgique. Cette vignette clinique a pour but d'illustrer le cheminement de la pharmacothérapie d'un patient avec un DT2 qui présente un infarctus du myocarde puis, secondairement, une insuffisance cardiaque. Elle ciblera surtout la place des agonistes des récepteurs du glucagon-like peptide-1 et des inhibiteurs des cotransporteurs sodium-glucose de type 2 (gliflozines), et expliquera l'intérêt de leur combinaison dans ce contexte en tenant compte des conditions actuelles de remboursement.

Novel perspectives regarding the physiologic mechanisms by which gliflozins induce reticulocytosis and erythrocytosis.

Gliflozins provide a breakthrough in the management of type-2 diabetes. In addition to facilitating normoglycemia, these sodium-glucose cotransporter type 2 (SGLT2) inhibitors attenuate obesity, hypertension, dyslipidemia, and fluid retention, reduce cardiovascular morbidity, retard the progression of renal dysfunction, and improve survival. The administration of gliflozins also triggers erythropoietin (EPO) production, with the consequent induction of reticulocytosis and erythrocytosis. The mechanism(s) by which gliflozins induce erythropoiesis is a matter of debate. Whereas the canonical pathway of triggering EPO synthesis is through renal tissue hypoxia, it has been suggested that improved renal oxygenation may facilitate EPO synthesis via noncanonical trails. The latter proposes that recovery of peritubular interstitial fibroblasts producing erythropoietin (EPO) is responsible for enhanced erythropoiesis. According to this hypothesis, enhanced glucose/sodium reuptake by proximal tubules in uncontrolled diabetes generates cortical hypoxia, with injury to these cells. Once transport workload declines with the use of SGLT2i, they recover and regain their capacity to produce EPO. In this short communication, we argue that this hypothesis is incorrect. First, there is no evidence for interstitial cell injury related to hypoxia in the diabetic kidney. Tubular, rather than interstitial cells are prone to hypoxic injury in the diabetic kidney. Moreover, hypoxia, not normoxia, stimulates EPO synthesis by hypoxia-inducible factors (HIFs). Hypoxia regulates EPO synthesis as it blocks HIF prolyl hydroxylases (that initiate HIF alpha degradation), hence stabilizing HIF signals, inducing HIF-dependent genes, including EPO located in the deep cortex, and its production is initiated by the apocrinic formation of HIF-2, colocalized in these same cells.

Vascular and metabolic effects of SGLT2i and GLP-1 in heart failure patients.

Alterations of endothelial function, inflammatory activation, and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway are involved in the pathophysiology of heart failure. Metabolic alterations have been studied in the myocardium of heart failure (HF) patients; alterations in ketone body and amino acid/protein metabolism have been described in patients affected by HF, as well as mitochondrial dysfunction and other modified metabolic signaling. However, their possible contributions toward cardiac function impairment in HF patients are not completely known. Recently, sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have emerged as a new class of drugs designed to treat patients with type 2 diabetes (T2D), but have also been shown to be protective against HF-related events and CV mortality. To date, the protective cardiovascular effects of these drugs in patients with and without T2D are not completely understood and several mechanisms have been proposed. In this review, we discuss on vascular and metabolic effects of SGLT2i and GLP-1 in HF patients.

SGLT2 Inhibition in Heart Failure with Preserved Ejection Fraction - The New Frontier.

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome with high morbidity and increasing socio-economic burden, compounded by the lack of effective treatment options available to treat this disease. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have previously been shown to improve cardiovascular and renal outcomes in patients with type 2 diabetes and patients with heart failure with reduced ejection fraction (HFrEF). Recent major clinical trials with SGLT2 inhibitors, both empagliflozin and dapagliflozin, have now demonstrated improved cardiovascular outcomes in patients with HFpEF and a significant reduction in heart failure hospitalization. Current evidence shows a potential for cardiovascular benefits with SGLT2 inhibition that is consistent across the spectrum of ejection fraction, age, New York Heart Association (NYHA) functional class, natriuretic peptide levels and diabetes status. Although the cardioprotective mechanisms behind SGLT2 inhibition remain unclear, ongoing clinical studies aim to clarify the role of SGLT2 inhibitors on biomarkers of cardiac metabolism, diastolic function and exercise capacity in HFpEF. This article analyzes current clinical evidence from randomized controlled trials and meta-analyses and explores the potential cardioprotective mechanisms of SGLT2 inhibitors, while also looking towards the future of SGLT2 inhibition in HFpEF.

UK Kidney Association Clinical Practice Guideline: Sodium-Glucose Co-transporter-2 (SGLT-2) Inhibition in Adults with Kidney Disease 2023 UPDATE.

Large placebo-controlled trials have demonstrated kidney and cardiovascular clinical benefits of SGLT-2 inhibitors. Data from the EMPA-KIDNEY and DELIVER trials and associated meta-analyses triggered an update to the UK Kidney Association Clinical Practice Guideline on Sodium-Glucose Co-transporter-2 (SGLT-2) Inhibition in Adults with Kidney Disease. We provide a summary of the full guideline and highlight the rationale for recent updates. The use of SGLT-2 inhibitors in people with specific medical conditions, including type 1 diabetes, kidney transplants, and people admitted to hospital with heart failure is also considered, along with Recommendations for future research and Recommendations for implementation. A full "lay" summary of the guidelines is provided as an appendix to ensure that these guidelines are accessible and understandable to people who are not medical professionals.

[EMPA-KIDNEY: empagliflozin in chronic kidney disease]. / EMPA-KIDNEY : l'empagliflozine dans la maladie rénale chronique.

The inhibition of the renin-angiotensin system represents the first preventive treatment of the chronic kidney disease (CKD), especially in presence of albuminuria. Recently, sodium-glucose cotransporter type 2 inhibitors (SGLT2i, gliflozins) demonstrated a nephroprotective effect, first in patients with type 2 diabetes at cardiovascular risk, then in diabetic patients with CKD assessed by a reduction of the glomerular filtration rate (GFR) and albuminuria (CREDENCE with canagliflozin), and finally in patients with CKD and albuminuria, with or without diabetes (DAPA-CKD with dapagliflozin). EMPA-KIDNEY study compared the effects of empagliflozin 10 mg/day versus placebo in patients with CKD, with or without diabetes. In comparison with the two previous renal studies, this clinical trial randomised patients with a lower GFR (78 % of patients with GFR inferior to 45 mL/min/1.73 m²) and a lower level of albuminuria (20 % of patients without pathological albuminuria). EMPA-KIDNEY demonstrated a reduction by 28 % (p inferior to 0.001) of the primary composite outcome (progression of CKD or cardiovascular death) and of several renal endpoints, including the shift to terminal CKD (-33 %), independently of the presence of diabetes, and with a tolerance profile comparable to what is already known. EMPA-KIDNEY results reinforce the use of SGLT2is, in general, and of empagliflozin, in particular, in a broader population with CKD and, thus, the indication of this pharmacological class in nephrology in combination with inhibitors of the renin-angiotensin system.

L'inhibition du système rénine-angiotensine représente le premier traitement de prévention de la maladie rénale chronique (MRC), en particulier chez les patients avec albuminurie. Récemment, les inhibiteurs des cotransporteurs sodium-glucose de type 2 (iSGLT2, gliflozines) ont démontré une néphroprotection, d'abord chez les patients avec un diabète de type 2 à risque cardiovasculaire, puis chez des patients avec MRC avec diminution du débit de filtration glomérulaire (DFG) et albuminurie (CREDENCE avec la canagliflozine), puis chez des patients avec MRC albuminurique, avec ou sans diabète (DAPA-CKD avec la dapagliflozine). L'étude EMPA-KIDNEY a comparé les effets de l'empagliflozine 10 mg/jour à un placebo chez des patients avec MRC, avec ou sans diabète. Par comparaison aux deux études précédentes, cet essai a recruté des patients avec un DFG plus bas (78 % de patients avec un DFG inf�rieur a 45 mL/min/1,73 m²) et avec un niveau d'albuminurie plus faible (dont 20 % de patients sans albuminurie pathologique). EMPA-KIDNEY a démontré une réduction de 28 % (p inf�rieur a 0,001) du critère primaire composite (progression de la MRC ou mort cardiovasculaire) et de divers critères rénaux secondaires, dont l'évolution vers la MRC terminale (-33 %), indépendamment de la présence d'un diabète, et avec un profil de tolérance de l'empagliflozine comparable à celui déjà connu. EMPA-KIDNEY consolide l'utilisation des iSGLT2, en général, et de l'empagliflozine, en particulier, dans une population plus diversifiée en ce qui concerne la MRC et, donc, l'indication de cette classe pharmacologique en néphrologie en combinaison avec les inhibiteurs du système rénine-angiotensine.e.

[Dapagliflozin in DELIVER : confirmation of the benefit with SGLT2 inhibitors in heart failure with preserved ejection fraction]. / Dapagliflozine dans l'étude DELIVER : confirmation du bénéfice des inhibiteurs des SGLT2 dans l'insuffisance cardiaque à fraction d'éjection préservée.

Gliflozins (sodium-glucose cotransporter type 2 inhibitors or SGLT2is) first demonstrated a reduction in hospitalisation for heart failure (hHF) in patients with type 2 diabetes (T2DM) at high cardiovascular risk. Then, a reduction in hHF (also combined with cardiovascular mortality) was reported in patients with heart failure, independently of the presence of T2DM. These placebo-controlled trials first concerned patients with heart failure and reduced left ventricular ejection fraction (LVEF) in DAPA-HF with dapagliflozin and EMPEROR-Reduced with empagliflozin. Afterwards, the benefit was observed in patients with preserved LVEF in EMPEROR-Preserved with empagliflozin, yet some doubt persisted in patients with LVEF > 60 %. The DELIVER study recently confirmed a significant reduction in the composite outcome hHF plus cardiovascular mortality (- 27 %) and in hHF (- 21 %) in patients (with or without T2DM) with heart failure and mildly reduced or preserved LVEF treated with dapagliflozin compared with placebo. The protection was noticed whatever the level of LVEF. These results reinforce the place of SGLT2is in international guidelines for the prevention or treatment of heart failure independently of the level of LVEF. SGLT2is represent the first pharmacological class that has proven its efficacy in patients with heart failure and preserved LVEF.

Les gliflozines (inhibiteurs des cotransporteurs sodium-glucose de type 2 ou iSGLT2) ont d'abord montré une réduction des hospitalisations pour insuffisance cardiaque (hHF) chez des patients avec un diabète de type 2 (DT2) à haut risque cardiovasculaire. Ensuite, une réduction des hHF (également combinée à la mortalité cardiovasculaire) a été démontrée dans des études chez des patients avec insuffisance cardiaque, indépendamment de la présence d'un DT2. Ces essais contrôlés versus placebo ont d'abord concerné des patients avec insuffisance cardiaque à fraction d'éjection du ventricule gauche (FEVG) réduite (DAPA-HF avec la dapagliflozine, EMPEROR-Reduced avec l'empagliflozine). Ensuite, le bénéfice a été démontré chez des patients avec FEVG préservée dans EMPEROR-Preserved avec l'empagliflozine, mais avec un doute chez les patients avec FEVG > 60 %. L'étude DELIVER a récemment confirmé une réduction significative du critère combiné hHF plus mortalité cardiovasculaire (- 27 %) et des hHF (- 21 %) chez des patients (avec ou sans DT2) avec insuffisance cardiaque et FEVG modérément réduite ou préservée traités par la dapagliflozine par rapport à ceux sous placebo. La protection a été observée quelle que soit la valeur de la FEVG. Ces résultats confortent la place accordée dans les recommandations internationales aux iSGLT2 dans la prévention et le traitement de l'insuffisance cardiaque, que la FEVG soit réduite ou préservée. Les iSGLT2 représentent la première classe pharmacologique qui ait montré une efficacité chez les patients avec insuffisance cardiaque et FEVG préservée.

[SGLT2 inhibitors : on the borders of diabetology, cardiology, nephrology and primary care]. / Inhibiteurs des SGLT2 (gliflozines) : aux confins de la diabétologie, la cardiologie, la néphrologie et la médecine générale.

Sodium-glucose cotransporter type 2 inhibitors (SGLT2is or gliflozins) are now considered as a therapeutic breakthrough in clinical practice, not only for the management of type 2 diabetes (T2D), but also for the treatment of heart failure and chronic renal disease. Patients with T2D are exposed to a higher risk of atheromatic lesions, heart failure and renal insufficiency, all complications that can be reduced by a gliflozin as shown in several placebo- controlled randomised trials in at high risk patients. Unexpectedly, such cardio-renal protection has also been observed among non-diabetic patients with heart failure (both with reduced and preserved ejection fraction) or with chronic kidney disease (especially with albuminuria). Because of these properties, SGLT2is now occupy a privileged place in diabetology, cardiology and nephrology. However, they are still slow to settle in primary care practice, even in high risk patients who should benefit, an underuse possibly due at least partially to quite complex reimbursement criteria in Belgium.

Les inhibiteurs des sodium-glucose cotransporteurs type 2 (iSGLT2 ou gliflozines) ont réalisé une percée remarquable dans la pratique clinique, non seulement pour le traitement du diabète de type 2 (DT2), mais aussi pour celui de l'insuffisance cardiaque et de la maladie rénale chronique. Le patient avec DT2 est exposé à des lésions athéromateuses, une insuffisance cardiaque et une insuffisance rénale, toutes complications freinées par la prise d'une gliflozine comme démontré dans plusieurs essais cliniques contrôlés versus placebo chez des patients à haut risque. De façon a priori inattendue, cette protection cardio-rénale a également été prouvée chez des patients non diabétiques présentant une insuffisance cardiaque (avec fraction d'éjection réduite ou préservée) ou une maladie rénale chronique (notamment avec albuminurie). Au vu de ces propriétés, les iSGLT2 occupent maintenant une place privilégiée en diabétologie, en cardiologie et en néphrologie. Cependant, ils tardent encore à s'implanter en médecine de première ligne, y compris chez des patients à haut risque qui devraient pourtant en bénéficier et ce, probablement en partie à cause de critères de remboursement relativement complexes en Belgique.

Paradigm shift in heart failure treatment: are cardiologists ready to use gliflozins?

Despite recent advances in chronic heart failure (HF) therapy, the prognosis of HF patients remains poor, with high rates of HF rehospitalizations and death in the early months after discharge. This emphasizes the need for incorporating novel HF drugs, beyond the current approach (that of modulating the neurohumoral response). Recently, new antidiabetic oral medications (sodium-glucose cotransporter 2 inhibitors (SGLT2i)) have been shown to improve prognosis in diabetic patients with previous cardiovascular (CV) events or high CV risk profile. Data from DAPA-HF study showed that dapaglifozin is associated with a significant reduction in mortality and HF hospitalization as compared with placebo regardless of diabetes status. Recently, results from EMPEROR-Reduced HF trial were consistent with DAPA-HF trial findings, showing significant beneficial effect associated with empagliflozin use in a high-risk HF population with markedly reduced ejection fraction. Results from the HF with preserved ejection fraction trials using these same agents are eagerly awaited. This review summarizes the evidence for the use of gliflozins in HF treatment.

Cardiorenal Impact of SGLT-2 Inhibitors: A Conceptual Revolution in The Management of Type 2 Diabetes, Heart Failure and Chronic Kidney Disease.

Type 2 Diabetes Mellitus (T2DM) is associated with an elevated incidence of cardiovascular and renal diseases, responsible for mortality rates significantly higher than in the general population. The management of both cardiovascular risk and progression of kidney disease thus seem crucial in the treatment of the diabetic patient. The availability of new classes of drugs which positively affect both cardiovascular and renal risk, regardless of the glycemic control, represents a revolution in the treatment of T2DM and shifts the attention from the intensive glycemic control to a holistic management of the diabetic patient. Among these, sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been associated with a remarkable reduction of cardiovascular and renal mortality, lower hospitalization rates for heart failure and lower progression of renal damage and albuminuria. Thus, their use in selected subpopulations seems mandatory. Aim of this review was the assessment of the current evidence on SGLT2i and their related impact on the cardiovascular and renal profiles.

[SGLT2 inhibitors and RAAS blockers : similarities, differences and complementarity]. / Inhibiteurs des SGLT2 et bloqueurs du système rénine-angiotensine. Similitudes, différences et complémentarité.

Both renin-angiotensin-aldosterone system inhibitors (RAASi) and sodium-glucose cotransporter type 2 inhibitors (SGLT2i, gliflozins) reduce the risk of heart failure and of progressing towards end-stage renal disease, especially in patients with type 2 diabetes (T2D). Positive results reported in patients with T2D have been confirmed in people without diabetes. These two pharmacological classes now occupy a privileged place in international guidelines, in diabetology, cardiology and nephrology. The present article describes similarities and differences between these two types of medications. It emphasizes the importance of combining both approaches in order to optimize the cardiovascular and renal prognosis, while maintaining a good safety profile.

Les inhibiteurs du système rénine-angiotensine-aldostérone (iSRAA) et les inhibiteurs des cotransporteurs sodium-glucose de type 2 (iSGLT2, gliflozines) réduisent le risque d'insuffisance cardiaque et de progression vers l'insuffisance rénale terminale, notamment chez les patients avec un diabète de type 2 (DT2). Les effets positifs rapportés chez les patients DT2 ont été confirmés chez les personnes non diabétiques. Ces deux classes pharmacologiques occupent maintenant une place de choix dans les recommandations internationales, en diabétologie, en cardiologie et en néphrologie. Cet article fait le point sur les similitudes et les différences entre ces deux familles médicamenteuses. Il insiste sur l'importance de les combiner pour optimiser le pronostic cardiovasculaire et rénal, tout en maintenant un bon niveau de sécurité.

[Prescribing a SGLT2 inhibitor for treating heart failure without inducing hypoglycaemia]. / Vignette thérapeutique de l'étudiant. Prescrire un inhibiteur des SGLT2 pour une insuffisance cardiaque sans risquer une hypoglycémie.

Sodium-glucose cotransporter type 2 inhibitors (SGLT2i or gliflozins) improve the prognosis of patients with heart failure, independently of the presence of diabetes. They are now recommended for the treatment of heart failure in international guidelines. The addition of a gliflozin driven by such a cardiological indication may require some adjustment of the antidiabetic therapy. The aim of this concise article is to discuss the potential risk of hypoglycaemia, highly deleterious in fragile patients at risk, following the prescription of a gliflozin in patients with heart failure. Different clinical situations will be considered, both in nondiabetic patients and in patients with type 2 diabetes already treated with a variety of antihyperglycaemic agents, metformin, sulphonylureas, gliptins, GLP-1 receptor agonists and insulin.

Les inhibiteurs des cotransporteurs sodium-glucose de type 2 (iSGLT2 ou gliflozines) améliorent le pronostic des patients avec insuffisance cardiaque, qu'ils présentent un diabète de type 2 ou non. Ils sont maintenant recommandés pour le traitement de l'insuffisance cardiaque dans les guidelines internationales. L'ajout d'une gliflozine pour cette indication cardiologique peut nécessiter d'ajuster le traitement antidiabétique. Le but de cette vignette est de discuter le risque éventuel de survenue d'une hypoglycémie, très délétère chez des patients fragiles à risque, suite à l'ajout d'un iSGLT2 chez des patients avec insuffisance cardiaque. Différentes situations cliniques seront considérées, chez le patient non diabétique mais aussi chez le patient avec un diabète de type 2 recevant déjà divers traitements, allant de la metformine à l'insuline, en passant par les sulfamides, les gliptines et les agonistes des récepteurs du glucagon-like peptide-1.

[About the safety profile of SGLT2 inhibitors]. / À propos de la sécurité d'emploi des inhibiteurs des SGLT2 (gliflozines).

Since their launch, sodium-glucose cotransporter type 2 inhibitors (SGLT2is) were suspected to be associated with various adverse events. They contributed to delay, as in France, or to restrict the use of this new pharmacological class in clinical practice, despite remarkable results reported in large cardiovascular or renal clinical trials. This article is devoted to three major adverse events that were imputed to SGLT2is : lower-limb extremity amputations, euglycaemic ketoacidosis and acute kidney injuries. In contrast to pharmacovigilance reports that raised suspicion, analysis of all data from the literature, either placebo-controlled trials or retrospective observational cohort studies, led to rather reassuring conclusions. The incidence of amputations does not appear to be increased while cases of acute kidney injury are reduced instead of increased as suspected earlier. Ketoacidosis events are almost doubled with SGLT2is versus comparators, yet their incidence remains extremely low among patients with type 2 diabetes. Of note, this potentially severe complication contributes to the denial of marketing authorization and reimbursement of SGLT2is in the population with type 1 diabetes.

Depuis leur mise sur le marché, les inhibiteurs des cotransporteurs sodium-glucose de type 2 (iSGLT2) ont été incriminés dans diverses manifestations indésirables. Celles-ci ont contribué à retarder, comme en France, ou à limiter la prescription de cette nouvelle classe pharmacologique en pratique clinique, malgré les résultats remarquables rapportés dans de grands essais à visée cardiovasculaire ou rénale. Cet article fait le point sur trois effets secondaires délétères importants imputés aux iSGLT2 : les amputations des extrémités des membres inférieurs, les acidocétoses dites euglycémiques et les insuffisances rénales aiguës. Malgré des données de pharmacovigilance qui avaient soulevé la suspicion, l'analyse de l'ensemble des données de la littérature, que ce soit les essais prospectifs contrôlés versus placebo ou les études observationnelles rétrospectives de cohorte versus des comparateurs actifs, aboutit à des conclusions assez rassurantes. Les amputations ne semblent pas être augmentées tandis que les cas d'insuffisance rénale aiguë sont plutôt en diminution au lieu de présenter une incidence accrue. Les cas d'acidocétose sont environ doublés sous iSGLT2 par rapport aux comparateurs, mais leur incidence reste extrêmement basse chez les patients diabétiques de type 2. Rappelons, néanmoins, que c'est cette complication potentiellement grave qui a entraîné le refus d'autorisation de mise sur le marché et du remboursement des iSGLT2 dans la population diabétique de type 1.

[From the discovery of phlorizin (a Belgian story) to SGLT2 inhibitors]. / De la découverte de la phlorizine (une histoire belge) aux inhibiteurs des SGLT2.

Most physicians do not know, or do not remember, the name of phlorizin. Hence this molecule has a major historical importance because it was the precursor of gliflozins, a new class of oral antidiabetic drugs with recent therapeutic perspectives beyond diabetes. This article recalls the history of phlorizin: its discovery in the 19th century by De Koninck and Stas, the demonstration of its ability to induce glucosuria and reduce hyperglycaemia by von Mering, its use to demonstrate the concept of glucose toxicity by the team of DeFronzo and finally the development of selective (phlorizin being not selective) sodium-glucose cotransporter type 2 inhibitors (gliflozins) which block glucose reabsorption in renal tubules. Gliflozins have increasing therapeutic indications, not only in type 2 diabetes, but also in cardiology and nephrology among non-diabetic people with heart failure or renal insufficiency.

La plupart des médecins ne connaissent pas, ou ne se souviennent plus, de la phlorizine. Pourtant, cette molécule a une grande importance historique car elle a été le précurseur des gliflozines, une nouvelle classe d'antidiabétiques oraux ouvrant maintenant de nouvelles perspectives thérapeutiques au-delà du diabète. Cet article retrace l'histoire de la phlorizine : sa découverte au 19ème siècle par De Koninck et Stas, la démonstration de l'induction d'une glucosurie abaissant la glycémie par von Mering, son utilisation pour conceptualiser la notion de glucotoxicité par l'équipe de DeFronzo et, enfin, le développement d'inhibiteurs sélectifs (la phlorizine étant non sélective) des cotransporteurs sodium-glucose de type 2 (SGLT2, gliflozines),dans les tubules rénaux, bloquant la réabsorption du glucose. Les gliflozines ont, maintenant, des indications thérapeutiques de plus en plus larges, non seulement dans le diabète de type 2, mais aussi en cardiologie et en néphrologie chez des personnes non diabétiques avec insuffisance cardiaque ou insuffisance rénale.

[SGLT2 inhibitors in patients with chronic kidney disease : from clinical trials to guidelines and new prospects for clinical practice]. / Inhibiteurs des SGLT2 chez les patients avec insuffisance rénale chronique : des essais contrôlés aux recommandations internationales et perspectives en pratique clinique.

Sodium-glucose cotransporter type 2 inhibitors (iSGLT2 or gliflozins) exert their antidiabetic action through a specific renal mechanism, by inhibiting tubular glucose reabsorption. These agents have proven their efficacy to reduce major cardiovascular events and hospitalisation for heart failure, but also the progression of chronic kidney disease (CKD), in patients with type 2 diabetes (T2DM) at high risk, independently of glucose control. While the glucose-lowering effect of iSGLT2 is decreasing with the decline of estimated glomerular filtration rate (eGFR), both cardiovascular and renal protections remain present until an eGFR as low as 30 ml/min/1,73 m². These effects were demonstrated in several meta-analyses and in two trials specifically dedicated to renal outcomes in patients with CKD and macroalbuminuria : CREDENCE with canagliflozin and Dapa-CKD with dapagliflozin. In addition, Dapa-CKD showed similar positive results whatever the presence or absence of T2DM. Safety profile of SGLT2is among patients with CKD is good and similar to that of patients with normal renal function. These favourable findings led to a privileged place of SGLT2i in recent international guidelines promoted by diabetologists, cardiologists and nephrologists. Current restrictive criteria for the prescription and reimbursement of SGLT2i in Belgium according to eGFR level (initiation only if eGFR superior to 60 and interruption if eGFR inferior to 45 ml/min/1.73 m²) should be enlarged very soon owing to convincing results of published controlled trials.

Les gliflozines (inhibiteurs des cotransporteurs sodium-glucose de type 2 ou iSGLT2) ont un mécanisme d'action antidiabétique spécifiquement rénal, en inhibant la réabsorption tubulaire du glucose. Indépendamment du contrôle glycémique, ces médicaments ont prouvé leur efficacité pour réduire les événements cardiovasculaires majeurs et les hospitalisations pour insuffisance cardiaque, mais aussi la progression vers l'insuffisance rénale chronique (IRC) terminale chez des patients diabétiques de type 2 (DT2) à haut risque. Si l'effet anti-hyperglycémiant des iSGLT2 diminue avec le déclin du débit de filtration glomérulaire (DFG), les effets protecteurs cardiovasculaires et rénaux persistent au moins jusqu'à un DFG de 30 ml/min/1,73 m². Ces effets ont été démontrés dans plusieurs méta-analyses des essais cardiovasculaires et dans deux essais spécifiquement à visée rénale chez des patients avec IRC et macroalbuminurie, CREDENCE avec la canagliflozine et Dapa-CKD avec la dapagliflozine. En outre, Dapa-CKD a montré les mêmes effets positifs en cas d'IRC non diabétique. Par ailleurs, le profil de sécurité des gliflozines chez les patients avec IRC est bon et comparable à celui des patients avec fonction rénale normale. Ces résultats favorables ont donné aux iSGLT2 une place privilégiée dans les dernières recommandations internationales diabétologiques, cardiologiques et néphrologiques. Les critères restrictifs actuels de prescription et de remboursement en Belgique des iSGLT2 en fonction du niveau de DFG (instauration si DFG sup�rieur a 60 et interruption si DFG inf�rieur a 45 ml/min/1,73 m²) devraient être élargis prochainement au vu des résultats convaincants des essais cliniques disponibles.

[SGLT2 inhibitors, new option to prevent or treat heart failure]. / Inhibiteurs des SGLT2 : nouvelle option pour prévenir ou traiter l'insuffisance cardiaque.

Gliflozins (sodium-glucose cotransporter type 2 inhibitors or SGLT2is) are the only glucose-lowering agents that have proven their ability to reduce major cardiovascular events, hospitalisations for heart failure and the progression to end-stage kidney disease in at risk patients with type 2 diabetes (T2D). One of the most marked and reproducible effects is the reduction in hospitalisations for heart failure. This protective effect was observed in all large prospective cardiovascular outcome trials, independently of the presence of heart failure at inclusion, and was confirmed in two dedicated trials that specifically targeted patients with heart failure and reduced left ventricular ejection fraction, with or without diabetes : DAPA-HF with dapagliflozin and EMPEROR-reduced with empagliflozin. The reduction in hospitalisations for heart failure appeared more marked when baseline renal function was impaired, including when estimated glomerular filtration rate (eGFR) was inferior to 45 ml/min/1.73 m². These favourable results contribute to give a privileged position to SGLT2is in more recent international guidelines produced by diabetologists, cardiologists and nephrologists. According to these guidelines, the prescription of SGLT2is should be extended to patients with an eGFR between 30 and 60 ml/min/1.73 m² as well to non-diabetic patients with heart failure and reduced ejection fraction. For other patients with preserved ejection fraction, one has to wait for further results from ongoing large prospective trials.

Les gliflozines (inhibiteurs des cotransporteurs sodium-glucose de type 2 ou iSGLT2), sont les seuls antidiabétiques oraux qui ont prouvé leur efficacité pour réduire les événements cardiovasculaires majeurs, les hospitalisations pour insuffisance cardiaque et la progression vers l'insuffisance rénale chronique terminale chez des patients diabétiques de type 2 (DT2) à haut risque. Un des effets les plus marqués et les plus reproductibles est la réduction des hospitalisations pour insuffisance cardiaque. Cet effet protecteur a été observé dans tous les grands essais prospectifs, que les patients présentent ou non une insuffisance cardiaque à l'inclusion. Les effets ont été confirmés dans deux essais ciblant spécifiquement les patients avec insuffisance cardiaque à fraction d'éjection réduite, qu'ils soient diabétiques ou non : DAPA-HF avec la dapagliflozine et EMPEROR-reduced avec l'empagliflozine. L'effet favorable sur les hospitalisations pour insuffisance cardiaque apparaît d'autant plus marqué que la fonction rénale initiale est altérée, y compris lorsque le débit de filtration glomérulaire (DFG) est inf�rieur a 45 ml/min/1,73 m². Ces résultats favorables ont donné aux iSGLT2 une place privilégiée dans les dernières recommandations internationales de diabétologie, de cardiologie et de néphrologie. Selon elles, la prescription des iSGLT2 devrait être étendue aux patients avec un DFG entre 30 et 60 ml/min/1,73 m² ainsi qu'aux patients non diabétiques avec insuffisance cardiaque à fraction d'éjection réduite. Pour les patients à fraction d'éjection préservée, il conviendra d'attendre les résultats d'autres grandes études en cours.