Efecto terapéutico de los inhibidores del cotransportador sodio-glucosa tipo 2 en la insuficiencia cardiaca aguda / Therapeutic effect of sodium-glucose cotransporter type 2 inhibitors in acute heart failure

Resumen La insuficiencia cardiaca aguda es una emergencia que aumenta la mortalidad cardiovascular debido a los síntomas y signos de congestión e hipoperfusión vascular. El manejo actual con diuréticos, inotrópicos y vasopresores mejora el estado clínico; sin embargo, la morbimortalidad asociada a esta patología sigue siendo altamente significativa. Por otra parte, los inhibidores del cotransportador sodio-glucosa tipo 2 (iSGLT2) han demostrado una reducción en la hospitalización y mortalidad cardiovascular en los pacientes con insuficiencia cardiaca crónica. Por ende, el objetivo de este artículo es analizar los efectos clínicos de este grupo farmacológico en la insuficiencia cardiaca aguda, con base en investigaciones científicas. Los hallazgos de estas investigaciones demostraron un beneficio clínico de los iSGLT2 sobre esta patología, con base a parámetros como mortalidad, hospitalización, eventos clínicos, función renal, efecto diurético y concentraciones del biomarcador NT-proBnp, los cuales se detallarán en el presente artículo. Por consiguiente, se concluyó que estos fármacos son seguros sobre la evolución clínica de la insuficiencia cardiaca aguda.

Abstract Acute heart failure is an emergency that increases cardiovascular mortality due to symptoms and signs of vascular congestion and hypoperfusion. Current management with diuretics, inotropes, and vasopressors improves the clinical status; However, the morbidity and mortality associated with this pathology remains highly significant. On the other hand, sodium-glucose cotransporter 2 (SGLT2i) inhibitors have shown a reduction in hospitalization and cardiovascular mortality in patients with chronic heart failure. Therefore, the objective of this article is to analyze the clinical effects of this pharmacological group in acute heart failure, based on scientific research. The findings of these investigations demonstrated a clinical benefit of SGLT2i on this pathology, based on parameters such as mortality, hospitalization, clinical events, renal function, diuretic effect and concentrations of the NTproBnp biomarker, which will be detailed in this article. Therefore, it was concluded that these drugs are safe on the clinical course of acute heart failure.

Comprehensive review of SGLT2 inhibitors' efficacy through their diuretic mode of action in diabetic patients.

SGLT2 inhibitors (SGLT2i) are now the mainstay therapy for both diabetes and heart failure. Post-hoc publications, meta-analysis, and conference presentations of the eight SGLT2i Cardiovascular Outcomes trials (CVOTS) done in diabetic patients constantly echo that this class of drug decreases mortality, reduces cardiovascular events, and prevents heart failure and kidney disease. This review of medical agencies' SGLT2i analysis (FDA and EMA) helps to understand the reality of SGLT2i results in those trials, avoiding to consider observational and statistically undemonstrated endpoints as validated. They also confirmed the unique diuretic mode of action of SGLT2i, promoting osmotic diuresis, and its potential adverse events secondary to hypovolemia and hematocrit increase. They also support the understanding that the beliefs in SGLT2i morbi-mortality benefits are largely overstated mostly based on undemonstrated endpoints. Finally, it is clear that SGLT2i's antidiabetic action, secondary to its renal mode of action, plateaued after a few months and decreased strongly over time, questioning its long-term goal of maintaining diabetic patients' HbA1c below 7%. Also, this effect in patients with renal impairment is quasi null. We think that this review would be very helpful to every physician treating diabetic patients to better balance belief and reality of SGLT2i prescription effects.

Canagliflozin reduces the contractile response of isolated heart of normal adult rats / Canagliflozin reduce la respuesta contráctil del corazón aislado de ratas adultas normales

SUMMARY: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) represent a unique class of glucose-declining renal-targeted drugs. The SGLT2i Canagliflozin (CANA) is an anti-hyperglycemic drug that reduces various cardiovascular and renal outcomes in patients with type 2 diabetes mellitus. This study aimed to explore the potential effects of CANA on the isolated healthy adult rat hearts to show if CANA has positive inotropic or cardiac depressant effects via analyzing the amplitude and frequency of cardiac contractions. In isolated normal adult rat hearts, the effects of CANA on cardiac contractility were examined. In a dose-response curve, CANA led to a significant cardiac depressant effect in a dose-dependent manner. This cardiac depressant effect of CANA (10-6 M) was not prevented by atropine. However, this cardiac depressant effect was partially antagonized by both Isoproterenol (10-5 M) and Calcium chloride (10-6 M), suggesting beta-adrenoceptor and calcium channel blocking actions. In addition, the cardiac depressant effect of CANA (10-6 M) was mitigated in part by Nitric oxide synthase inhibitor, L-NAME, suggesting that its action probably depends to some extent on the accumulation of nitric oxide, which decreases the rise of intracellular Calcium. Data from this study demonstrate that CANA has a significant cardiac relaxant effect in isolated hearts of healthy adult rats by different possible mechanisms. This inhibitory effect on cardiac contractility may help improve the diastolic ventricular filling providing a therapeutic potential to help the other cardioprotective mechanisms of CANA in the prevention and treatment of heart failure.

RESUMEN: Los inhibidores del cotransportador de sodio- glucosa 2 (SGLT2i) representan una clase única de fármacos dirigidos a los riñones que disminuyen la glucosa. El SGLT2i Canagliflozin (CANA) es un fármaco antihiperglucémico que reduce varios resultados cardiovasculares y renales en pacientes con diabetes mellitus tipo 2. Este estudio tuvo como objetivo explorar los efectos potenciales de CANA en corazones aislados de ratas adultas sanas para indicar si CANA tiene efectos inotrópicos o depresores cardíacos positivos mediante el análisis de la amplitud y la frecuencia de las contracciones cardíacas. En corazones aislados de ratas adultas normales, se examinaron los efectos de CANA sobre la contractilidad cardíaca. En una curva de dosis-respuesta, CANA condujo a un efecto depresor cardíaco significativo de manera dependiente de la dosis. Este efecto depresor cardíaco de CANA (10-6 M) no fue impedido por la atropina. Sin embargo, este efecto depresor cardíaco fue parcialmente antagonizado tanto por el isoproterenol (10-5 M) como por el cloruro de calcio (10-6 M), lo que sugiere acciones bloqueadoras de los receptores beta adrenérgicos y de los canales de calcio. Además, el efecto depresor cardíaco de CANA (10-6 M) fue mitigado en parte por el inhibidor de la sintasa de óxido nítrico, L-NAME, lo que sugiere que su acción probablemente depende en cierta medida de la acumulación de óxido nítrico, lo que disminuye el aumento de calcio intracelular. Los datos de este estudio demuestran que CANA tiene un efecto relajante cardíaco significativo en corazones aislados de ratas adultas sanas por diferentes mecanismos posibles. Este efecto inhibitorio sobre la contractilidad cardíaca puede ayudar a mejorar el llenado ventricular diastólico proporcionando un potencial terapéutico para ayudar a los otros mecanismos cardioprotectores de CANA en la prevención y tratamiento de la insuficiencia cardíaca.

External validity of type 2 diabetes clinical trials on cardiovascular outcomes for a multimorbid population.

AIM: To investigate the external validity of recent antihyperglycaemic trials evaluating cardiovascular outcomes in a multimorbid population. MATERIALS AND METHODS: Selection criteria of 15 randomized controlled trials from the 2020 American Diabetes Association Standard of Care statement were applied in a stepwise manner to tertiary care patients with type 2 diabetes. Primary outcomes were the number of patients eligible per individual trial and for the aggregate of trials. Secondary outcomes included patient predictors of trial eligibility. RESULTS: Of 1059 patients, the mean (SD) age was 66 (10.74) years, the median (IQR) Charlson index was 2 (2, 3) and 458 (43%) had documented cardiovascular disease. The median (IQR) number of patients included in individual trials was 263 (174.25-308.75) and 795 (75.1%) of them were eligible for at least one trial. Among those 264 ineligible, 127 (48.1%) had an HbA1c level of 7% or less and no cardiovascular disease; 53.5% and 34.4% of the patients were eligible for two and three different classes of drugs, respectively. The strongest predictor of trial eligibility was cardiovascular disease (risk ratio 2.17, 95% CI 2.01-2.35). CONCLUSIONS: A considerable proportion of multimorbid patients would be eligible for recent antihyperglycaemic trials. This positive finding can be attributed to development guidance in diabetes trials and the different approach we took, in which we evaluated inclusion by trials as an aggregate.

The sodium-glucose cotransporter-2 (SGLT2) inhibitors synergize with nitric oxide and prostacyclin to reduce human platelet activation.

Gliflozins (canagliflozin, dapagliflozin and empagliflozin) are the newest anti-hyperglycemic class and have offered cardiovascular and renal benefits. Because platelets are involved in the atherothrombosis process, this study is aimed to evaluate the direct effect of gliflozins on platelet reactivity. Platelet-rich plasma (PRP) or washed platelets (WP) were obtained from healthy volunteers. Aggregation, flow cytometry for glycoprotein IIb/IIIa, cyclic nucleotides and intracellular calcium levels, Western blot, thromboxane B2 (TXB2) measurement and COX-1 activity were performed in the presence of gliflozins (1-30 µM) alone or in combination with sodium nitroprusside (SNP, 10 or 100 nM) + iloprost (ILO, 0.1 or 1 nM). SGLT2 protein is not expressed on human platelets. Gliflozins produced little inhibitory effect in agonists-induced aggregation and this effect was greatly potentiated by ~10-fold in the presence of SNP + ILO, accompanied by lower levels of TXB2 (58.1 ± 5.1%, 47.1 ± 7.2% and 43.4 ± 9.2% inhibition for canagliflozin, dapagliflozin and empagliflozin, respectively). The activity of COX-1 was not affected by gliflozins. Collagen increased Ca2+ levels and α(IIb)ß(3) activation, both of which were significantly reduced by gliflozins + SNP + ILO. The intracellular levels of cAMP and cGMP and the protein expression of p-VASPSer157 and p-VASPSer239 were not increased by gliflozins while the expression of the serine-threonine kinase, AktSer473 was markedly reduced. Our results showed that the antiplatelet activity of gliflozins were greatly enhanced by nitric oxide and prostacyclin, thus suggesting that the cardiovascular protection seen by this class of drugs could be in part due to platelet inhibition.

SGLT2 Inhibitors for Treatment of Refractory Hypomagnesemia: A Case Report of 3 Patients.

In patients with urinary magnesium wasting, oral and intravenous supplementation often fail to adequately improve serum magnesium levels. Glucose intolerance and diabetes mellitus frequently accompany hypomagnesemia. Clinical trials examining inhibitors of the type 2 sodium glucose cotransporter (SGLT2) show small but significant increases in serum magnesium levels in diabetic patients. This report describes dramatic improvement in serum magnesium levels and associated symptoms after initiating SGLT2 inhibitor therapy in 3 patients with refractory hypomagnesemia and diabetes. Each patient received a different SGLT2 inhibitor: canagliflozin, empagliflozin, or dapagliflozin. One patient discontinued daily intravenous magnesium supplements and exhibited higher serum magnesium levels than had been achieved by magnesium infusion. 2 of the 3 patients exhibited reduced urinary fractional excretion of magnesium, suggesting enhanced tubular reabsorption of magnesium. These observations demonstrate that SGLT2 inhibitors can improve the management of patients with otherwise intractable hypomagnesemia, representing a new tool in this challenging clinical disorder.

Análise crítica dos estudos que mudaram a prática clínica recente: diabetes mellitus e doenças cardiovasculares / Critical analysis of studies that changed recent clinical practice: diabetes mellitus and cardiovascular disease

Já é bem conhecida a importância da terapêutica para os pacientes com diabetes mellitus (DM) no que diz respeito à redução dos eventos cardiovasculares e, por isso, existe interesse em comprovar a segurança cardiovascular das diferentes terapias anti-hiperglicêmicas disponíveis no mercado. O objetivo desta revisão consiste em discutir três grandes estudos publicados recentemente, LEADER, CANVAS e DECLARE ­ TIME 58, que avaliaram o efeito sobre morbidade e mortalidade cardiovascular das medicações em questão em comparação com placebo

The importance of therapy for patients with diabetes mellitus (DM) in reducing cardiovascular events is well-known and, therefore, there is interest in confirming the cardiovascular safety of the different antihyperglycemic therapies available on the market. The objective of this review is to discuss three large recently-published studies, LEADER, CANVAS and DECLARE ­ TIME 58, which evaluated the effect of the medications in question on morbidity and cardiovascular mortality as compared to a placebo

Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus from Latin America.

OBJECTIVE: This post hoc analysis evaluated the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) from Latin America. RESEARCH DESIGN AND METHODS: Analyses were performed in subgroups of patients from Latin America based on data from three individual, 26-week, placebo-controlled studies of canagliflozin (monotherapy [n = 116/584], add-on to metformin [n = 199/918], and add-on to metformin plus sulfonylurea [n = 76/469]) and three individual, 52-week, active-controlled studies of canagliflozin (add-on to metformin versus sitagliptin [n = 240/1101], add-on to metformin versus glimepiride [n = 155/1450], and add-on to metformin plus sulfonylurea versus sitagliptin [n = 156/755]). MAIN OUTCOME MEASURES: Changes from baseline in HbA1c, body weight, and systolic blood pressure (BP) with canagliflozin 100 and 300 mg versus placebo or active comparator (i.e., sitagliptin or glimepiride) were evaluated in the overall study populations and Latin American subgroups. Safety was assessed based on adverse event (AE) reports. RESULTS: Canagliflozin 100 and 300 mg provided reductions in HbA1c, body weight, and systolic BP across studies in patients from Latin America that were generally similar to those seen in the overall populations of patients with T2DM. The AE profile in patients from Latin America was equivalent to that in the overall populations; higher rates of genital mycotic infections and osmotic diuresis-related AEs were seen with canagliflozin versus comparators. Limitations of this study include the post hoc analysis of data and the small sample size of patients from Latin America. CONCLUSION: Canagliflozin improved glycemic control, reduced body weight and systolic BP, and was generally well tolerated in patients with T2DM from Latin America. CLINICAL TRIAL REGISTRATION: NCT01081834; NCT01106677; NCT01106625; NCT00968812; NCT01137812.

Effect of canagliflozin on the pharmacokinetics of glyburide, metformin, and simvastatin in healthy participants.

Drug-drug interactions between canagliflozin, a sodium glucose co-transporter 2 inhibitor, and glyburide, metformin, and simvastatin were evaluated in three phase-1 studies in healthy participants. In these open-label, fixed sequence studies, participants received: Study 1-glyburide 1.25 mg/day (Day 1), canagliflozin 200 mg/day (Days 4-8), canagliflozin with glyburide (Day 9); Study 2-metformin 2,000 mg/day (Day 1), canagliflozin 300 mg/day (Days 4-7), metformin with canagliflozin (Day 8); Study 3-simvastatin 40 mg/day (Day 1), canagliflozin 300 mg/day (Days 2-6), simvastatin with canagliflozin (Day 7). Pharmacokinetic parameters were assessed at prespecified intervals. Co-administration of canagliflozin and glyburide did not affect the overall exposure (maximum plasma concentration [Cmax ] and area under the plasma concentration-time curve [AUC]) of glyburide and its metabolites (4-trans-hydroxy-glyburide and 3-cis-hydroxy-glyburide). Canagliflozin did not affect the peak concentration of metformin; however, AUC increased by 20%. Though Cmax and AUC were slightly increased for simvastatin (9% and 12%) and simvastatin acid (26% and 18%) following coadministration with canagliflozin, compared with simvastatin administration alone; however, no effect on active 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitory activity was observed. There were no serious adverse events or hypoglycemic episodes. No drug-drug interactions were observed between canagliflozin and glyburide, metformin, or simvastatin. All treatments were well-tolerated in healthy participants.