Effects of Empagliflozin on Myocardial Flow Reserve in Patients With Type 2 Diabetes Mellitus: The SIMPLE Trial.
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SUBMITTER: Jurgens M
PROVIDER: S-EPMC8475664 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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 registrationThe 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 .
| S-EPMC7519555 | biostudies-literature
Project description:AimsAlthough the reno-protective effects of sodium-glucose cotransporter 2 inhibitors are known in patients with heart failure or type 2 diabetes mellitus (T2DM), this effect has not been confirmed in patients with acute myocardial infarction (AMI).Methods and resultsThe prospective, multicentre, randomized, double-blind, placebo-controlled EMBODY trial investigated patients with AMI and T2DM in Japan. The eligible patients included adults aged 20 years or older, diagnosed with AMI and T2DM, and who could be discharged within 2-12 weeks after the onset of AMI. One hundred and five patients were randomized (1:1) to receive once daily 10 mg empagliflozin or placebo within 2 weeks of AMI onset. In this sub-analysis, we investigated the time course of renal functional parameters such as serum creatinine levels and estimated glomerular filtration rate (eGFR) from baseline to Weeks 4, 12, and 24. Ninety-six patients (64 ± 11 years, 78 male) were included in the full analysis (n = 46 and 50 in the empagliflozin and placebo groups, respectively). We used serum creatinine and eGFR as indicators of renal function. In the placebo group, eGFR decreased from 66.14 mL/min/1.73 m2 at baseline to 62.77 mL/min/1.73 m2 by Week 24 (P = 0.023) but remained unchanged in the empagliflozin group (from 64.60 to 64.36 mL/min/1.73 m2 , P = 0.843). In the latter group, uric acid improved from 5.8 mg/dL at baseline to 4.9 mg/dL at Week 24 (P < 0.001). In the earlier analysis of 56 patients with eGFR ≥ 60 mL/min/1.73 m2 , the eGFR decreased and the serum creatinine increased from baseline to 24 weeks in the placebo group, significantly different to the empagliflozin group (-6.61 vs. +0.22 mL/min/1.73 m2 , P = 0.008 and +0.063 vs. -0.001 mg/dL, P = 0.030, respectively). The changes in serum creatinine and eGFR from baseline to Week 24 were significantly correlated with those in uric acid in the placebo group (r = 0.664, P < 0.001 and r = -0.675, P < 0.001, respectively) but not in the empagliflozin group.ConclusionsEmpagliflozin prevented the kidney functional decline in patients with AMI and T2DM, especially those with baseline eGFR ≥ 60 mL/min/1.73 m2 . Early administration of sodium-glucose cotransporter 2 inhibitors in these patients is considered desirable for renal protection.
| S-EPMC8497324 | biostudies-literature
Project description:ObjectiveCardiovascular (CV) outcome trials have shown that in patients with type 2 diabetes (T2D), treatment with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) reduces CV mortality and hospital admission rates for heart failure (HF). However, the mechanisms behind these benefits are not fully understood. This study was performed to investigate the effects of the SGLT-2i dapagliflozin on myocardial perfusion and glucose metabolism in patients with T2D and stable coronary artery disease (coronary stenosis ≥ 30% and < 80%), with or without previous percutaneous coronary intervention (> 6 months) but no HF.MethodsThis was a single-center, prospective, randomized, double-blind, controlled clinical trial including 16 patients with T2D randomized to SGLT-2i dapagliflozin (10 mg daily) or placebo. The primary outcome was to detect changes in myocardial glucose uptake (MGU) from baseline to 4 weeks after treatment initiation by [(18)F]2-deoxy-2-fluoro-D-glucose (FDG) PET/CT during hyperinsulinemic euglycemic clamp. The main secondary outcome was to assess whether the hypothetical changes in MGU were associated with changes in myocardial blood flow (MBF) and myocardial flow reserve (MFR) measured by 13N-ammonia PET/CT. The study was registered at eudract.ema.europa.eu (EudraCT No. 2016-003614-27) and ClinicalTrials.gov (NCT03313752).Results16 patients were randomized to dapagliflozin (n = 8) or placebo (n = 8). The groups were well-matched for baseline characteristics (age, diabetes duration, HbA1c, renal and heart function). There was no significant change in MGU during euglycemic hyperinsulinemic clamp in the dapagliflozin group (2.22 ± 0.59 vs 1.92 ± 0.42 μmol/100 g/min, p = 0.41) compared with the placebo group (2.00 ± 0.55 vs 1.60 ± 0.45 μmol/100 g/min, p = 0.5). Dapagliflozin significantly improved MFR (2.56 ± 0.26 vs 3.59 ± 0.35 p = 0.006 compared with the placebo group 2.34 ± 0.21 vs 2.38 ± 0.24 p = 0.81; pint = 0.001) associated with a reduction in resting MBF corrected for cardiac workload (p = 0.005; pint = 0.045). A trend toward an increase in stress MBF was also detected (p = 0.054).ConclusionsSGLT-2 inhibition increases MFR in T2D patients. We provide new insight into SGLT-2i CV benefits, as our data show that patients on SGLT-2i are more resistant to the detrimental effects of obstructive coronary atherosclerosis due to increased MFR, probably caused by an improvement in coronary microvascular dysfunction. Trial registration EudraCT No. 2016-003614-27; ClinicalTrials.gov Identifier: NCT03313752.
| S-EPMC9440459 | biostudies-literature
Project description:INTRODUCTION:A diagnosis of type 2 diabetes (T2D) more than doubles the risk of cardiovascular disease (CVD), with heart failure (HF) being one of the most common complications with a severe prognosis. The landmark Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Paitients (EMPA-REG OUTCOME) study demonstrated that treatment with the sodium glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin rapidly and significantly reduces CVD mortality and admission rates for HF. However, the mechanisms behind this reduction in clinical events are unknown.This study was designed to investigate the effects of the SGLT-2 inhibitor empagliflozin on myocardial perfusion and function in patients with T2D and high CVD risk. METHODS AND ANALYSIS:In this investigator-initiated, randomised, double-blind controlled clinical trial, 92 patients with T2D and established CVD or high CVD risk will be randomised to treatment with empagliflozin 25 mg or a matching placebo for 13 weeks. The primary outcome measure is change in myocardial flow reserve measured quantitatively by Rubidium-82 position emission tomography. In a substudy, invasive haemodynamics at rest and during exercise will be measured at baseline and following the intervention, using right heart catheterisation. ETHICS AND DISSEMINATION:The study protocol (v7, 02/08/2018) has been approved by the Ethics Committee of the Capital Region, Danish Data Protection Board and the Danish Medicines Agency, and it will be monitored according to the Good Clinical Practice regulations from the International Conference on Harmonization. The results be submitted to international peer-reviewed journals and be presented at conferences. The data will be made available to the public via EudraCT and www.clinicaltrials.gov. TRIAL REGISTRATION NUMBER:NCT03151343.
| S-EPMC6887087 | biostudies-literature
Project description:OBJECTIVE:To update clinicians with an overview of empagliflozin for the treatment of type 2 diabetes mellitus (T2DM), with focus on use in combination regimens. METHODS:Keyword searches were conducted in the Medline database to identify literature reporting clinical trials of at least 12 weeks' duration using empagliflozin treatment in patients with T2DM. RESULTS:When given as monotherapy or in combination therapy (as add-on or single-pill therapy) with metformin, pioglitazone, sulfonylurea, linagliptin, and insulin, empagliflozin produced clinically meaningful reductions in glycated hemoglobin levels, plasma glucose concentrations, bodyweight, and blood pressure. These changes were sustained during long-term treatment. In a dedicated cardiovascular event trial, empagliflozin on top of standard of care demonstrated a significant reduction in the risk of cardiovascular mortality and all-cause mortality. Across the clinical trials, empagliflozin combination therapies were well tolerated, and empagliflozin used alone was not associated with increased risk of hypoglycemia versus placebo. Indeed, the combination of empagliflozin and metformin had a significantly reduced rate of hypoglycemia compared with the combination of metformin and a sulfonylurea. On the other hand, empagliflozin treatment did have increased risk of genital infections compared with placebo. In clinical trials to date, diabetic ketoacidosis was not seen more frequently with empagliflozin than with placebo, but physicians should be alert to the possibility of this rare event. CONCLUSION:Empagliflozin has the potential to make an important contribution to the treatment of patients with T2DM. In some patients, empagliflozin may be used as monotherapy, but it is most likely to be used in combination with other therapies. Given the reduced risk of mortality seen when empagliflozin was added to standard care in patients at high cardiovascular risk, as well as the lack of alternative options for patients at lower cardiovascular risk, empagliflozin may be added to ongoing regimens for a significant proportion of patients.
| S-EPMC4888761 | biostudies-literature
Project description:Inflammation is a key determinant of cardiovascular outcomes, but its role in heart failure is uncertain. In patients with cardiometabolic disease enrolled in the prospective, multicenter ancillary study of CIRT (Cardiovascular Inflammation Reduction Trial), CIRT-CFR (Coronary Flow Reserve to Assess Cardiovascular Inflammation), impaired coronary flow reserve was independently associated with increased inflammation and myocardial strain despite well-controlled lipid, glycemic, and hemodynamic profiles. Inflammation modified the relationship between CFR and myocardial strain, disrupting the association between cardiac blood flow and function. Future studies are needed to investigate whether an early inflammation-mediated reduction in CFR capturing microvascular ischemia may lead to heart failure in patients with cardiometabolic disease. (Cardiovascular Inflammation Reduction Trial [CIRT]; NCT01594333; Coronary Flow Reserve to Assess Cardiovascular Inflammation [CIRT-CFR]; NCT02786134).
| S-EPMC9998473 | biostudies-literature
Project description:Empagliflozin is an oral treatment for type 2 diabetes mellitus (T2DM), one of the leading causes of death in the US and around the world. Recently, the EMPA-REG OUTCOME study has shown that empagliflozin added to standard of care treatment reduced the risk of cardiovascular (CV) events in patients with T2DM who were also at increased CV risk. The risk of major adverse CV events (MACE: first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke) was reduced by 14% relative to placebo (HR 0.86; 95.02% CI: 0.74-0.99; P = 0.04 for superiority). The risk of CV death was reduced by 38% relative to the placebo group (HR 0.62; 95% CI: 0.49-0.77; P < 0.001) and the risk of death from any cause by 32% (HR 0.68; 95% CI: 0.57-0.82; P < 0.001). Furthermore, empagliflozin was associated with reduced risk of hospitalization for heart failure and of renal adverse events. As well as EMPA-REG OUTCOME, empagliflozin has been studied in a number of clinical trials in patients with T2DM, in various combinations, including with insulin. Empagliflozin has shown significant improvements in glycemic control, body weight, and blood pressure, albeit improvements are limited in patients with declining renal function (estimated glomerular filtration rate <45 ml/min/1.73 m2). Empagliflozin has been generally well tolerated, with the typical adverse events of genital mycotic infections usually being straightforward to manage. Considering all the data together, empagliflozin appears to be a promising option for many patients with T2DM, but care will still be needed to ensure that use is appropriate for an individual patient's characteristics.
| S-EPMC5306110 | biostudies-literature
Project description:AIMS: Diastolic reserve is the ability of left ventricular filling pressures to remain normal with exercise. Impaired diastolic reserve may be an early sign of diabetic cardiomyopathy. We aimed to determine whether diastolic reserve differs in type 2 diabetes (DM) compared with non-DM, and to identify clinical, anthropological, metabolic and resting echocardiographic correlates of impaired diastolic reserve in patients with DM. METHODS AND RESULTS: 237 patients (aged 53±11 years, 133 DM, ejection fraction 68±9%) underwent rest and exercise echocardiography. Mitral E and septal e' were measured at rest, immediately post, and 10 min into recovery. Analysis of covariance (ANCOVA) and binary regression with continuous outcomes were used to model e' and E/e' changes with exercise to identify impaired diastolic reserve defined as post-exercise E/e' ≥15. After adjusting for baseline differences, patients with DM immediately post-exercise had a lower septal e', a lower Δe' (1.2 vs 2.3 cm/s, p=0.006) and a higher Δ septal E/e' (1.7 vs 0.08, p<0.001) than patients without DM. In patients with normal resting E/e' of ≤8 (n=130), DM had a significantly higher post-exercise septal E/e' and a higher Δseptal E/e' (2.63 vs 0.50, p<0.001). E/e' in patients with DM remained significantly elevated up to 10 min post-exercise. Hypertension, longer duration of insulin therapy, poorer glycaemic control, worse renal function, larger left atrial volume and lower septal e' were independent correlates of impaired diastolic reserve in patients with DM. CONCLUSIONS: Patients with DM have impaired diastolic reserve manifest as a blunted e' response with exercise, persisting into recovery. Clinical, anthropometric, metabolic and echocardiographic correlates of impaired diastolic reserve in patients with DM were identified. An impaired LV diastolic reserve may be the underlying pathophysiological mechanism in patients with DM with unexplained exertional dyspnoea and may allow earlier detection of DM cardiomyopathy.
| S-EPMC4395831 | biostudies-other
Project description:Sodium glucose cotransporter 2 (SGLT2) inhibitors have a unique mechanism of action leading to excretion of glucose in the urine and subsequent lowering of plasma glucose. This mechanism is independent of ?-cell function; thus, these agents are effective treatment for type 2 diabetes mellitus (T2DM) at theoretically any disease stage. This class should not confer an additional risk of hypoglycemia (unless combined with insulin or an insulin secretagogue) and has the potential to be combined with other classes of glucose-lowering agents. Empagliflozin is one of three currently approved SGLT2 inhibitors in the United States, and has shown a favorable benefit-risk ratio in phase 3 clinical trials as monotherapy and as add-on to other glucose-lowering therapy in broad patient populations. In addition to its glucose-lowering effects, empagliflozin has been shown to reduce body weight and blood pressure without a compensatory increase in heart rate. Moreover, on top of standard of care, empagliflozin is the first glucoselowering agent to demonstrate cardiovascular risk reduction in patients at high risk of cardiovascular disease in a prospective outcomes trial: a 14% reduction in risk of the 3-point composite endpoint of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Like other SGLT2 inhibitors, empagliflozin is associated with a higher rate of genital mycotic infections than placebo and has the potential for volume depletion-associated events.This review summarizes the empagliflozin phase 3 clinical trials program and its potential significance in the treatment of patients with T2DM. Evidence from these clinical trials show reductions in glycated hemoglobin (-0.59 to -0.82%) with a low risk of hypoglycemia except when used with insulin or insulin secretagogues, and moderate reductions in body weight (-2.1 to - 2.5 kg) and systolic blood pressure (-2.9 to -5.2 mm Hg), thus supporting the use of empagliflozin as monotherapy or in addition to other glucose-lowering agents. In addition, evidence from the recent EMPA-REG OUTCOME study, which demonstrated relative risk reductions in major adverse cardiac events (14%), cardiovascular mortality (38%) and all-cause mortality (32%), as well as hospitalization for heart failure (36%), supports use of empagliflozin in patients with T2DM and increased cardiovascular risk.
| S-EPMC5543566 | biostudies-literature
Project description:BackgroundType 2 diabetes mellitus (T2DM) is a metabolic disorder in which the patients with high blood sugar develop insufficient insulin secretion or insulin resistance. The solute carrier family, 5 member 2 (SLC5A2) gene is a member of sodium/glucose transporter family which can reduce heart and kidney problems. The current study aims to look into any association between rs11646054 variant in SLC5A2 gene and the anti-diabetic efficacy and safety of empagliflozin.Methods14 T2DM who failed to respond to previous treatments, empagliflozin 10 mg was added for 6 months. Genotyping of the rs11646054 variant of SLC5A2 gene was performed by polymerase chain reaction (PCR) followed by Sanger sequencing.ResultsAlthough hemoglobin A1c (HbA1c) and low-density lipoprotein (LDL) were not significantly different, but the mean fasting blood sugar (FBS), 2-h post prandial (2hpp), albumin-to-creatinine ratio (ACR), and total cholesterol (TC) were significantly decreased after 6 months empagliflozin treatment. There was a significant difference in the mean final reductions in FBS level among genotypes. It's important to mention that those who were GG homozygotes had a tendency to have more decrements.ConclusionsThe study results indicate that effects of variation in SLC5A2 (rs11646054) on the clinical efficacy of empagliflozin were negligible.
| S-EPMC8630276 | biostudies-literature