Administration Of Sodium-glucose Cotransporter 2 Inhibitors Research Articles

Renoprotective effect of additional sodium-glucose cotransporter 2 inhibitor therapy in type 2 diabetes patients with rapid decline and preserved renal function.

Aims/IntroductionThe slope of estimated glomerular filtration rate (eGFR) decline (eGFR slope) in early‐stage type 2 diabetes patients might predict the future risk of end‐stage renal disease. Type 2 diabetes patients who show rapid progressive eGFR decline are termed rapid decliners. Several studies of rapid decliners have investigated the efficacy of sodium–glucose cotransporter 2 inhibitors (SGLT2i) in patients with advanced renal dysfunction; however, no studies, to our knowledge, have focused on patients with preserved renal function. Therefore, we investigated the efficacy of SGLT2i in rapid decliners with preserved renal function.Materials and MethodsThis study enrolled type 2 diabetes patients with baseline eGFR ≥60 mL/min/1.73 m2 who had been treated with SGLT2i for ≥3 years. Among these individuals, we defined those with annual eGFR declines ≥5 mL/min/1.73 m2 per year before SGLT2i administration as rapid decliners. The primary end‐point was the change in eGFR slope after SGLT2i administration.ResultsAmong 165 patients treated with SGLT2i for ≥3 years, 21 patients were rapid decliners with preserved renal function. The mean age and eGFR at SGLT2i administration were 58.6 years and 87.1 mL/min/1.73 m2, respectively. The mean annual eGFR slope improved significantly in those administered SGLT2i compared with the control group (−1.00 and −4.36 mL/min/1.73 m2 per year, respectively; P < 0.001). Notably, the steeper the eGFR slope before starting SGLT2i administration, the larger the improvement of eGFR slope, which was independent of the reduction of albuminuria.ConclusionsEarly intervention with SGLT2i may have renoprotective effects in type 2 diabetes patients with rapid decline and preserved renal function.

Sodium-glucose Co-transporter 2 Inhibitors in Acute Heart Failure: A Review of the Available Evidence and Practical Guidance on Clinical Use.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors were initially conceived as glucose-lowering agents. However, striking renal and cardiovascular benefits were observed in type 2 diabetes trials. This led to evaluate it in dedicated studies in chronic heart failure (HF) and chronic kidney disease, which also showed remarkable clinical results. Given this findings, and taking into account the multiple mechanisms of action, the use of SGLT2 inhibitors in acute heart failure seemed promising. Sotagliflozin was the first SGLT2 inhibitor to reduce heart failure hospitalizations within the acute setting in the SOLOIST-WHF trial. Only type 2 diabetes patients were included, with a preserved and reduced ejection fraction. In slightly less than half of the cohort, this medication was started when the diuretic therapy was transitioned from intravenous to oral, during the hospital admission. In the rest of the patients, sotagliflozin was started early after discharge. Empagliflozin proved to be safe, well-tolerated, increased diuresis, and reduced a combined clinical endpoint (worsening HF, rehospitalization for HF, or death at 60 days) when administered within the first 24 hours of an acute heart failure hospitalization in the EMPA-RESPONSE-AHF trial. More recently, empagliflozin showed a reduction in a composite primary endpoint of death, heart failure events, and quality of life compared to placebo in the EMPULSE trial. Empagliflozin was started after the initial stabilization phase, but while patients were still admitted and receiving intravenous loop diuretics. Less than half of the patients were diabetic and two-thirds had a left ventricular ejection fraction below 40%. Dapagliflozin is currently being tested in the DAPA ACT HF-TIMI 68 trial, which plans to enroll 2400 patients admitted with acute heart failure and reduced ejection fraction. We envision SGLT2 inhibitors as a useful tool in acute heart failure syndrome given the additive diuretic effect, and minimal impact on blood pressure, kidney function, and electrolytes. Its dosage schedule is simple and can help initiation and tolerance of other medical therapy. However, there is an increased risk of genital infections and euglycaemic ketoacidosis. Notwithstanding, once critically ill and fasting patients are excluded, early administration of SGLT2 inhibitors is safe. This review summarizes the development of SGLT2 inhibitors and the available evidence supporting their use during an acute heart failure admission. We also propose a practical guideline for in-hospital initiation and monitoring.

Cardiovascular benefits from SGLT2 inhibition in type 2 diabetes mellitus patients is not impaired with phosphate flux related to pharmacotherapy.

The beneficial cardiorenal outcomes of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM) have been substantiated by multiple clinical trials, resulting in increased interest in the multifarious pathways by which their mechanisms act. The principal effect of SGLT2i (-flozin drugs) can be appreciated in their ability to block the SGLT2 protein within the kidneys, inhibiting glucose reabsorption, and causing an associated osmotic diuresis. This ameliorates plasma glucose elevations and the negative cardiorenal sequelae associated with the latter. These include aberrant mitochondrial metabolism and oxidative stress burden, endothelial cell dysfunction, pernicious neurohormonal activation, and the development of inimical hemodynamics. Positive outcomes within these domains have been validated with SGLT2i administration. However, by modulating the sodium-glucose cotransporter in the proximal tubule (PT), SGLT2i consequently promotes sodium-phosphate cotransporter activity with phosphate retention. Phosphatemia, even at physiologic levels, poses a risk in cardiovascular disease burden, more so in patients with type 2 diabetes mellitus (T2DM). There also exists an association between phosphatemia and renal impairment, the latter hampering cardiovascular function through an array of physiologic roles, such as fluid regulation, hormonal tone, and neuromodulation. Moreover, increased phosphate flux is associated with an associated increase in fibroblast growth factor 23 levels, also detrimental to homeostatic cardiometabolic function. A contemporary commentary concerning this notion unifying cardiovascular outcome trial data with the translational biology of phosphate is scant within the literature. Given the apparent beneficial outcomes associated with SGLT2i administration notwithstanding negative effects of phosphatemia, we discuss in this review the effects of phosphate on the cardiometabolic status in patients with T2DM and cardiorenal disease, as well as the mechanisms by which SGLT2i counteract or overcome them to achieve their net effects. Content drawn to develop this conversation begins with proceedings in the basic sciences and works towards clinical trial data.

Relationship Between HbA1c Level and Effectiveness of SGLT2 Inhibitors in Decompensated Heart Failure Patients with Type 2 Diabetes Mellitus.

The DAPA-HF trial demonstrated that sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduced worsening heart failure (HF) events in chronic HF patients with or without type 2 diabetic mellitus (T2DM). However, it remains unclear whether the effectiveness of SGLT2i is also observed in patients with decompensated HF irrespective of HbA1c level. Eighty-one T2DM patients hospitalized due to decompensated HF were enrolled and divided into 2 groups according to their HbA1c levels (group H, HbA1c 6.9-13.0%, n = 41; group L, HbA1c < 6.9%, n = 40). After the initial management of HF, one of the SGLT2i (canagliflozin 100 mg/day or dapagliflozin 5 mg/day or empagliflozin 10 mg/day) was non-randomly administered, and clinical parameters associating with HF and T2DM were followed for 7 days. No symptomatic hypoglycemia was observed in any patient. In both groups, urine glucose excretion was increased significantly after the administration of SGLT2i. However, its amount was greater in group H than group L. Urine volume was increased significantly at day 1 in both groups. Urine volume returned to the baseline after one week in group L. In contrast, the increase in urine volume persisted at least for one week in group H. Of note, a decrease in B-type natriuretic peptide levels after the initiation of SGLT2i was observed in both groups similarly despite differences in urine output and excretion of urine glucose. In conclusion, SGLT2i can improve decompensated HF in patients with T2DM irrespective of the HbA1c level.

Effect of Empagliflozin Versus Placebo on Plasma Volume Status in Patients with Acute Myocardial Infarction and Type 2 Diabetes Mellitus.

IntroductionPlasma volume status (PVS), a parameter of the discrepancy between actual plasma volume (PV) and ideal PV, has been recently evaluated as a prognostic marker in patients with heart failure. This subgroup analysis of the EMBODY trial was designed to determine whether a sodium-glucose cotransporter 2 (SGLT2) inhibitor affects the alleviation of heart failure and improvement of PVS in patients after acute myocardial infarction (AMI) with congestive heart failure (CHF).MethodsThe EMBODY trial was a prospective, multicenter, randomized, double-blind, placebo-controlled trial to identify the effect of an SGLT2 inhibitor on cardiac sympathetic hyperactivity in patients with AMI and type 2 diabetes mellitus (T2DM) in Japan. In total, 105 patients were randomized (1:1) to receive 10 mg empagliflozin or a placebo (once daily), 2 weeks after the onset of AMI. In this subanalysis, we investigated the time-course of PVS at baseline and weeks 4, 12, and 24.ResultsOverall, 96 patients were included in the subgroup analysis set (age 64.3 ± 10.9 years, 80.2% men; 46 in the empagliflozin group and 50 in the placebo group). Body weight and PVS decreased in the empagliflozin group compared with the placebo group at 24 weeks (− 2.2 vs. + 0.1 kg, P < 0.001, and − 5.1 vs. − 0.3%, P < 0.001, respectively). Decreased PVS, defined as a change in PVS of < − 4.5%, was associated with the administration of empagliflozin (odds ratio 2.61, 95% confidence interval 1.11–6.15, P = 0.028). N-terminal pro b-type natriuretic peptide levels decreased in both the empagliflozin and placebo groups (1028.7–370.3 pg/mL, P < 0.001, and 1270.6–673.7 pg/mL, P < 0.01, respectively).ConclusionEmpagliflozin reduced the body weight and PVS. Early SGLT2 inhibitor administration in patients with AMI, CHF, and T2DM can therefore be effective in reducing the body weight and PVS.Trial RegistrationUMIN 000030158.

Perspectives on Sarcopenia and Protein Intake in Aged and Diabetic Patients

Perspectives on Sarcopenia and Protein Intake in Aged and Diabetic Patients

Effects of sodium-glucose cotransporter 2 inhibitors on cardiovascular outcomes in elderly patients with comorbid coronary heart disease and diabetes mellitus.

OBJECTIVETo investigate the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on cardiovascular outcomes in elderly Chinese patients with comorbid coronary heart disease (CHD) and type 2 diabetes mellitus (T2DM).METHODSA retrospective cohort study was conducted on 501 elderly inpatients (≥ 60 years) with comorbid CHD/T2DM in Department of Cardiovascular Medicine and Endocrinology, Chinese PLA General Hospital from January 2018 to December 2019. These patients were divided into two groups according to the administration of SGLT2i. All the demographic characteristics and clinical data were collected. Cardiovascular outcomes, including all-cause mortality, major adverse cardiovascular events (MACE), and hospitalization for heart failure (HHF), were followed up.RESULTSIn the cohort, there were 167 patients in the SGLT2i group and 334 patients in the control group. In the efficacy analyses, the incidence of MACE was lower in the SGLT2i group than in the control group: 3.6% vs. 9.3% (P = 0.022). A lower risk of MACE was observed in the SGLT2i group [hazard ratio (HR) = 0.40, 95% CI: 0.17–0.95]. There was no significant difference in the incidence of all-cause mortality or HHF between the two groups. No significant difference of HR was observed for all-cause mortality (HR = 0.41, 95% CI: 0.12–1.41) or HHF (HR = 0.58, 95% CI: 0.12–2.81). CONCLUSIONSSGLT2i treatment exhibited benefits for elderly patients with comorbid CHD/T2DM with a lower risk for MACE.

Two-year administration of sodium-glucose co-transporter 2 inhibitor brought about marked reduction of body fat independent of skeletal muscle amount or glycemic improvement in Japanese patients with type 2 diabetes.

To investigate long-term effects of sodium-glucose co-transporter 2 inhibitor (SGLT2i) on anthropometric and metabolic factors in Japanese patients with type 2 diabetes (T2DM). This is a retrospective observation study. Forty-six outpatients with T2DM (32 men and 14 women, 51 ± 13years old, BMI 27.9 ± 4.8, means ± S.D.) who had been treated by SGLT2i for 2years were selected and their metabolic and anthropometric data were retrieved from medical records retrospectively. Regular instruction for diet and exercise had been performed throughout the administration of SGLT2i in outpatient clinic basis. By the administration of SGLT2i for 2years, body weight and body fat amount were significantly reduced (P < 0.0001) in spite of no change in skeletal muscle mass. HbA1c (P < 0.0001), liver function and lipid profile (P < 0.01) were ameliorated and eGFR was reduced significantly (P < 0.0001). It is of note that the reduction of body weight was strongly correlated to that of body fat (r = 0.951, P < 0.0001) with no correlation to the change of skeletal muscle mass. The reduction of HbA1c was strongly correlated to the baseline HbA1c (r = - 0.922, P < 0.0001) and modestly correlated to the baseline eGFR (r = - 0.449, P < 0.01). Multivariate analysis revealed a weak relationship between the amelioration of HbA1c and the reduction of body weight. SGLT2i can effectively reduce body weight and body fat mass independent of the blood glucose improvement or the renal function. Under the periodical instruction for nutrition and exercise this oral hypoglycemic agent can be safely administered for a long term without a risk for sarcopenia.

Central administration of sodium-glucose cotransporter-2 inhibitors increases food intake involving adenosine monophosphate-activated protein kinase phosphorylation in the lateral hypothalamus in healthy rats

IntroductionSodium glucose cotransporter-2 (SGLT2) inhibitors are widely used for diabetes treatment. Although SGLT2 inhibitors have been clinically observed to increase food intake, roles or even the presence of SGLT2 in...

Sodium-glucose cotransporter2 inhibitors in type2 diabetes patients with renal function impairment slow the annual renal function decline, in a real clinical practice.

Aims/IntroductionThe aim of this study was to elucidate whether sodium–glucose cotransporter 2 inhibitors (SGLT2is) treatment has any renoprotective effect for type 2 diabetes mellitus patients with an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2 in clinical practice.Materials and MethodsWe evaluated the annual eGFR slope in 85 type 2 diabetes mellitus patients with renal impairment, treated with SGLT2is ≥2 years. Each patient's eGFR was <60 mL/min/1.73 m2 at the start of SGLT2is therapy. The calculation of the annual change in eGFR for each patient was obtained by acquired eGFR data before and after 2 years of the initial SGLT2is administration, followed by analysis of the changes in the mean eGFR slope.ResultsThe participants' mean age was 72.0 ± 9.4 years, and the mean eGFR was 47.1 ± 9.7 mL/min/1.73 m2 at the start of additional treatment with SGLT2is. The mean annual eGFR slope after SGLT2is administration (−0.11 ± 0.20 mL/min/1.73 m2/year) was significantly slower than before SGLT2is administration (−2.93 ± 0.59 mL/min/1.73 m2/year; P < 0.0001). Additionally, SGLT2is treatment slowed the annual decline of eGFR, independent of the levels of both the initial eGFR and albuminuria levels before SGLT2is therapy was started. In the patient groups who showed an annual eGFR decline of ≥3 and 1–3 mL/min/1.73 m2, there was a significant slowing of the decline after SGLT2is therapy, compared with before the treatment (P < 0.001, respectively).ConclusionsSGLT2is administration slows the decline observed in the annual renal function in type 2 diabetes mellitus patients with eGFR of <60 mL/min/1.73 m2 in clinical practice.

A decrease in plasma glucose levels is required for increased endogenous glucose production with a single administration of a sodium-glucose co-transporter-2 inhibitor tofogliflozin.

To investigate whether changes in endogenous glucose production (EGP) and insulin and glucagon levels are elicited by the decrease in plasma glucose (PG) levels induced by the sodium-glucose co-transporter-2 (SGLT2) inhibitor tofogliflozin. We evaluated EGP in 12 Japanese patients with type 2 diabetes under the conditions of no drugs administered (CON), single administration of the SGLT2 inhibitor tofogliflozin (TOF), and single administration of TOF with adjustment of PG levels with exogenous glucose infusion to mimic changes in PG levels observed with CON (TOF + G). We evaluated changes in EGP and levels of C-peptide and glucagon from baseline to 180 minutes after drug administration. Endogenous glucose production decreased in the CON (-0.22 ± 0.11 mg/kg·min) and TOF + G experiments (-0.31 ± 0.24 mg/kg·min), but not in the TOF experiment (+0.08 ± 0.19 mg/kg·min). The decrease in C-peptide was significantly greater in the TOF experiment (-0.11 ± 0.06 nmol/L) than in the CON (-0.03 ± 0.06 nmol/L) and the TOF + G experiments (-0.01 ± 0.11 nmol/L), while the increase in glucagon was significantly greater in the TOF experiment (+11.1 ± 6.3 pmol/L), but not in the TOF + G experiment (+8.6 ± 7.6 pmol/L) compared to the CON experiment (+5.1 ± 4.3 pmol/L). These results indicate that the decrease in PG levels induced by SGLT2 inhibitor administration is required for the increase in EGP and decrease in insulin secretion.

Combination Therapy of Alpha-Glucosidase Inhibitor, Thiazolidinedione and Sodium Glucose Co-Transporter-2 Inhibitor in Japanese Type 2 Diabetes Patients

Background: We additionally administered selective inhibitor of sodium glucose co-transporter-2 (SGLT2) inhibitor to type 2 diabetic patients on alpha-glucosidase inhibitor (alpha-GI) and/or thiazolidinedione (TZD), to determine whether the multi-drug combination therapy including SGLT2 inhibitor further improved the glycemic control in Japanese patients with diabetes mellitus. Methods: The subjects were divided into four groups. Group I was administered an SGLT2 inhibitor in addition to ongoing treatment using hypoglycemic agents other than alpha-GI and SGLT2 inhibitor. Group II was administered an SGLT2 inhibitor in addition to an alpha-GI. Group III was administered an SGLT2 inhibitor in addition to a TZD. Group IV was administered an SGLT2 inhibitor in addition to an alpha-GI and TZD. The body weight and biochemical parameters were measured before and 1, 2 and 3 years after the start of SGLT2 inhibitor treatment. Results: In patients receiving alpha-GI or TZD, additional administration of an SGLT2 inhibitor resulted in a reduction of the body weight, body mass index (BMI) and serum uric acid level, but had little effect on the glucose or lipid metabolism. On the other hand, additional administration of SGLT2 inhibitor in patients receiving both alpha-GI and TZD (three-drug combination therapy) resulted not only in a reduction of the body weight, BMI and serum uric acid, but also in improvement of the glucose and lipid metabolism, with a reduction of the hemoglobin A1c level and increase of the serum high-density lipoprotein cholesterol level. Conclusion: The results suggest that three-drug combination therapy with alpha-GI, TZD and SGLT2 inhibitor, each of which has different mechanism of action, is beneficial for the treatment of type 2 diabetes mellitus. J Endocrinol Metab. 2020;10(6):167-172 doi: https://doi.org/10.14740/jem708

Effect of sodium\u2013glucose cotransporter-2 inhibitors on aldosterone-to-renin ratio in diabetic patients with hypertension: a retrospective observational study

BackgroundPlasma aldosterone-to-renin ratio (ARR) is popularly used for screening primary aldosteronism (PA). Some medications, including diuretics, are known to have an effect on ARR and cause false-negative and false-positive results in PA screening. Currently, there are no studies on the effects of sodium–glucose cotransporter-2 (SGLT2) inhibitors, which are known to have diuretic effects, on ARR. We aimed to investigate the effects of SGLT2 inhibitors on ARR.MethodsWe employed a retrospective design; the study was conducted from April 2016 to December 2018 and carried out in three hospitals. Forty patients with diabetes and hypertension were administered SGLT2 inhibitors. ARR was evaluated before 2 to 6 months after the administration of SGLT2 inhibitors to determine their effects on ARR.ResultsNo significant changes in the levels of ARR (90.9 ± 51.6 vs. 81.4 ± 62.9) were found. Body mass index, diastolic blood pressure, heart rate, fasting plasma glucose, and hemoglobin A1c were significantly decreased by SGLT2 inhibitors. Serum creatinine was significantly increased.ConclusionSGLT2 inhibitor administration yielded minimal effects on ARR and did not increase false-negative results in PA screening in patients with diabetes and hypertension more than 2 months after administration.

Abstract 13625: Effect of Empagliflozin versus Placebo on Plasma Volume Status in Patients With Acute Myocardial Infarction and Type 2 Diabetes Mellitus: Subgroup Analysis of the Embody Trial

Background: Plasma volume status (PVS), a parameter of the discrepancy between actual plasma volume (PV) and ideal PV, has been evaluated recently as a prognostic marker of patients with heart failure. This subgroup analysis of the EMBODY trial was designed to determine whether the sodium-glucose cotransporter 2 (SGLT2) inhibitor affect the improvement of heart failure and PVS in patients after acute myocardial infarction (AMI) with congestive heart failure (CHF). Methods: The EMBODY trial was a prospective, multicenter, randomized, double-blind, placebo-controlled trial to identify the effect of the SGLT2 inhibitor on cardiac sympathetic hyperactivity in patients with AMI and type 2 diabetes mellitus (T2DM) in Japan. A total of one hundred and five patients were randomized (1:1) to receive once-daily 10 mg empagliflozin or placebo 2 weeks after the onset of AMI. In this subanalysis, we investigated the time-course of PVS on baseline, weeks 4, 12 and 24. Results: Overall, 96 patients were included in the subgroup analysis set (64.3±10.9 years, male 80.2%, and 46 in the empagliflozin group and 50 in the placebo group). The empagliflozin group showed significant decreases in body weight, systolic blood pressure, and PVS compared with the placebo group at 24 weeks (-2.2 vs. +0.1 kg, P=0.0007; -6.6 vs. +3.5 mmHg, P=0.003; and -5.1 vs. -0.3%, P=0.0006; respectively). Decreased of PVS, defined as change of PVS &lt; -4.5 % was associated with received empagliflozin (odds ratio, 2.61; 95% confidence interval, 1.11 - 6.15; P=0.028). On the other hand, NT-Pro BNP levels significantly decreased in the empagliflozin group and placebo group (1028.7 to 370.3 pg/ml, P=0.0001 and 1270.6 to 673.7 pg/ml, P=0.006, respectively). Conclusion: Empagliflozin reduced not only body weight but also PVS. These results suggested that early SGLT2 inhibitor administration in patients with AMI, CHF and T2DM could be effective to reduce body weight and PVS.

Analysis of time-dependent alterations of parameters related to erythrocytes after ipragliflozin initiation.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors often increase the hematocrit. It remains unclear whether this increase would be observed in all patients administered SGLT2 inhibitors, however. We therefore used the data from the previous study and investigated time-dependent alterations of various outcomes related to erythrocytes, erythropoiesis, and clinical outcome in type 2 diabetes subjects (n = 89) treated with ipragliflozin for 16weeks. Among a total of 89 participants, 71 subjects (80.0% of total participants) showed the elevation of the hematocrit and 18 subjects (20.0% of total participants) did not at 16weeks. Although the hematocrit levels at baseline were significantly lower in hematocrit-elevated group than non-elevated group, they reached the same levels 4weeks after the onset of treatment. Binomial logistic regression analysis demonstrated that a lower baseline hematocrit level was related to the elevation of hematocrit at 16weeks. Optimal cutoff hematocrit levels at baseline to predict hematocrit elevation were 46.9% (male) and 41.7% (female) in ROC analysis. Random intercept model analysis revealed the serum erythropoietin level increased in both hematocrit-elevated and non-elevated groups, whereas only the former group showed an increase in the percentage of reticulocytes during the first 4weeks. These results suggest that the ipragliflozin-induced increase in hematocrit which is affected by the baseline hematocrit level is attributable to the responsiveness to, but not to the production of, erythropoietin. Collectively, Ht elevation observed in administration of SGLT2 inhibitors can result from erythropoietin-induced erythropoiesis, which is determined by the pre-treatment Ht level. Trial registration: This trial has been registered with University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR no. 000015478).

Effect of empagliflozin versus placebo on body composition in patients with acute myocardial infarction and type 2 diabetes mellitus: subgroup analysis of the EMBODY trial

Abstract Background Prevention of heart failure is one of the most important challenges after acute myocardial infarction (AMI). The development of heart failure is closely associated with fluid balance which can be evaluated by the measurement of body composition such as total body water (TBW), extracellular water (ECW), and intracellular water (ICW). This subgroup analysis of the EMBODY trial was designed to determine whether the Sodium–glucose cotransporter 2 (SGLT2) inhibitor affect fluid balance and improve heart failure in patients after AMI. Methods The EMBODY trial was a prospective, multicenter, randomized, double-blind, placebo-controlled trial in patients with AMI and type 2 diabetes in Japan. A total of 105 patients were randomized (1:1) to receive once-daily 10 mg empagliflozin, an SGLT2 inhibitor or placebo 2 weeks after the onset of AMI. In this subanalysis, we investigated the time-course of body composition measured by a bioelectrical impedance analyzer “InBody®”. The primary endpoints were changes in every particular parameter of body composition at week 0, 4, 12, and 24. Secondary endpoints were changes in blood pressure (BP), body weight and N-terminal pro b-type natriuretic peptide (NT-proBNP). Results Overall, 55 patients were included in the full analysis set (67.2±10.0 years, male 78.2%, and n=30 in empagliflozin group and 25 in placebo group). Baseline characteristics were not significantly different between the two groups. The change between at baseline and 24 weeks in TBW was −0.44 L (P=0.19) in the empagliflozin group and +1.14 L (P=0.0002) in the placebo group, adjusted difference −1.58 L, 95% confidence interval (CI) −2.46 to −0.70 L (P=0.0006). The empagliflozin group showed significant decreases in the body weight, ECW, ICW and systolic BP compared with the placebo group (−2.2 kg vs, +0.01 kg, P=0.004, −0.21 L vs, +0.40 L, P=0.001, −0.23 L vs, +0.74 L, P=0.0007, and −11.0 mmHg vs, +5.0 mmHg, P&amp;lt;0.0001, respectively). On the other hand, NT-Pro BNP levels significantly decreased in the empagliflozin group and placebo group (1028.7 pg/mL to 370.3 pg/ml, p=0.0001 and 1270.6 pg/mL to 673.7 pg/ml, p=0.006, respectively). In the multiple regression analysis of the change in TBW and ICW for the empagliflozin group, systolic BP was identified as a significant factor (P=0.001, and 0.003, respectively). In stratified analysis of BMI 25 kg/m2 or more, the empagliflozin group showed significant decreases in body weight, TBW, ECW and ICW compared with the placebo group, but not below BMI 25 kg/m2 group. Conclusion Empagliflozin reduced not only body weight, but also TBW, ECW and ICW. Interestingly, this tendency was remarkable at BMI 25 or more. This study suggested that early SGLT2 inhibitor administration in obesity patients with AMI and DM might be effective to reduce body weight and TBW. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Boehringer Ingelheim

Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial

BackgroundProtection from lethal ventricular arrhythmias leading to sudden cardiac death (SCD) is a crucial challenge after acute myocardial infarction (AMI). Cardiac sympathetic and parasympathetic activity can be noninvasively assessed using heart rate variability (HRV) and heart rate turbulence (HRT). The EMBODY trial was designed to determine whether the Sodium–glucose cotransporter 2 (SGLT2) inhibitor improves cardiac nerve activity.MethodsThis prospective, multicenter, randomized, double-blind, placebo-controlled trial included patients with AMI and type 2 diabetes mellitus (T2DM) in Japan; 105 patients were randomized (1:1) to receive once-daily 10-mg empagliflozin or placebo. The primary endpoints were changes in HRV, e.g., the standard deviation of all 5-min mean normal RR intervals (SDANN) and the low-frequency–to–high-frequency (LF/HF) ratio from baseline to 24 weeks. Secondary endpoints were changes in other sudden cardiac death (SCD) surrogate markers such as HRT.ResultsOverall, 96 patients were included (46, empagliflozin group; 50, placebo group). The changes in SDANN were + 11.6 and + 9.1 ms in the empagliflozin (P = 0.02) and placebo groups (P = 0.06), respectively. Change in LF/HF ratio was – 0.57 and – 0.17 in the empagliflozin (P = 0.01) and placebo groups (P = 0.43), respectively. Significant improvement was noted in HRT only in the empagliflozin group (P = 0.01). Whereas intergroup comparison on HRV and HRT showed no significant difference between the empagliflozin and placebo groups. Compared with the placebo group, the empagliflozin group showed significant decreases in body weight, systolic blood pressure, and uric acid. In the empagliflozin group, no adverse events were observed.ConclusionsThis is the first randomized clinical data to evaluate the effect of empagliflozin on cardiac sympathetic and parasympathetic activity in patients with T2DM and AMI. Early SGLT2 inhibitor administration in AMI patients with T2DM might be effective in improving cardiac nerve activity without any adverse events.Trial Registration: The EMBODY trial was registered by the UMIN in November 2017 (ID: 000030158). UMIN000030158; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034442.

SGLT2 inhibitors, sodium and off-target effects: an overview.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a relatively new class of antidiabetic drugs that in addition to emerging as an effective antihyperglycemic treatment have been shown to improve, in several trials, both renal and cardiovascular outcomes. In consideration of the renal site of action and the associated osmotic diuresis, a negative sodium balance has been postulated during SGLT2i administration. Actually, sodium and water depletion may contribute to some positive actions of SGLT2i but evidence is far from being conclusive and the real physiologic effects of SGLT2i on sodium remain largely unknown. Indeed, no study has yet investigated how SGLT2i change sodium balance in the long term and especially the pathways through which the natriuretic effect is expressed. Furthermore, several experimental studies have recently identified different pathways, not directly linked to tubular sodium handling, which could contribute to the renal and cardiovascular benefits associated with SGLT2i. This paper will review the evidence of SGLT2i action on sodium transporters, their off-target effects and their potential role on kidney protection.

Effect of Sodium-Glucose Cotransporter-2 Inhibitors on Endothelial Function: A Systematic Review of Preclinical Studies

IntroductionWhile the beneficial effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on cardiovascular and renal outcomes are recognized, their direct effects on endothelial function remain unclear. We, therefore, undertook a systematic review to evaluate the current literature in this area. MethodsElectronic databases (PubMed, EMBASE, and Medline) were systematically searched using PRISMA guidelines for studies involving the in vitro, in vivo, or ex vivo administration of SGLT-2 inhibitors to animals, vascular tissue, or vascular endothelial cells. ResultsOf 144 retrieved publications, 24 experimental studies met the inclusion criteria. Reporting of possible sources of bias were poor, making the overall risk of bias difficult to assess. Within the 24 studies, the SGLT-2 inhibitors canagliflozin, ipragliflozin, empagliflozin, dapagliflozin, tofogliflozin, and luseogliflozin were assessed as interventions. Animal model studies (n = 17) demonstrated that all SGLT-2 inhibitors prevented endothelial dysfunction and enhanced endothelium-dependent vasorelaxation in diabetic and non-diabetic models. In vitro studies (n = 9) using human endothelial cells indicated a direct anti-inflammatory effect of dapagliflozin (1–100 nM) and canagliflozin, (10 µM), while empagliflozin (1 and 10 µM) improved viability of hyperglycemic cells. Potential mechanisms of action of the SGLT-2 inhibitors include a reduction in oxidative stress, modulation of adhesion molecules and reductions in pro-inflammatory cytokines.ConclusionsPreclinical studies indicate that SGLT-2 inhibitors attenuate vascular dysfunction in preclinical models via a combination of mechanisms that appear to act independently of glucose-lowering benefits.Electronic Supplementary MaterialThe online version of this article (10.1007/s13300-020-00885-z) contains supplementary material, which is available to authorized users.

Blood pressure after treatment with sodium-glucose cotransporter2 inhibitors influences renal composite outcome: Analysis using propensity score-matched models.

Aims/IntroductionSodium–glucose cotransporter 2 inhibitors (SGLT2i) improve renal outcome in patients with type 2 diabetes mellitus, but the mechanism is not fully understood. The aim of this retrospective study was to assess the association of achieved blood pressure with renal outcomes in Japanese type 2 diabetes mellitus patients with chronic kidney disease.Materials and MethodsWe assessed 624 Japanese type 2 diabetes mellitus patients with chronic kidney disease taking SGLT2i for >1 year. The patients were classified as those with post‐treatment mean arterial pressure (MAP) of ≥92 mmHg (n = 344) and those with MAP of <92 mmHg (n = 280) for propensity score matching (1:1 nearest neighbor match with 0.04 of caliper value and no replacement). The end‐point was a composite of progression of albuminuria or a decrease in the estimated glomerular filtration rate by ≥15% per year.ResultsBy propensity score matching, a matched cohort model was constructed, including 201 patients in each group. The incidence of renal composite outcome was significantly lower among patients with MAP of <92 mmHg than among patients with MAP of ≥92 mmHg (n = 11 [6%] vs n = 26 [13%], respectively, P = 0.001). The change in estimated glomerular filtration rate was similar in the two groups; however, the change in the albumin‐to‐creatinine ratio was significantly larger in patients with MAP of <92 mmHg.ConclusionsIn Japanese type 2 diabetes mellitus patients with chronic kidney disease, blood pressure after SGLT2i administration influences the renal composite outcome. Blood pressure management is important, even during treatment with SGLT2i.