scholarly journals Sympatholytic Mechanisms for the Beneficial Cardiovascular Effects of SGLT2 Inhibitors: A Research Hypothesis for Dapagliflozin’s Effects in the Adrenal Gland

2021 ◽  
Vol 22 (14) ◽  
pp. 7684
Author(s):  
Anastasios Lymperopoulos ◽  
Jordana I. Borges ◽  
Natalie Cora ◽  
Anastasiya Sizova
Keyword(s):  
Blood Glucose ◽  
Adrenal Medulla ◽  
Blood Glucose Control ◽  
Sglt2 Inhibitor ◽  
Cardiovascular Effects ◽  
Sglt2 Inhibitors ◽  
Current Evidence ◽  
Western World ◽  
Reduced Ejection Fraction ◽  
Therapeutic Modalities

Heart failure (HF) remains the leading cause of morbidity and death in the western world, and new therapeutic modalities are urgently needed to improve the lifespan and quality of life of HF patients. The sodium-glucose co-transporter-2 (SGLT2) inhibitors, originally developed and mainly indicated for diabetes mellitus treatment, have been increasingly shown to ameliorate heart disease, and specifically HF, in humans, regardless of diabetes co-existence. Indeed, dapagliflozin has been reported to reduce cardiovascular mortality and hospitalizations in patients with HF and reduced ejection fraction (HFrEF). This SGLT2 inhibitor demonstrates these benefits also in non-diabetic subjects, indicating that dapagliflozin’s efficacy in HF is independent of blood glucose control. Evidence for the effectiveness of various SGLT2 inhibitors in providing cardiovascular benefits irrespective of their effects on blood glucose regulation have spurred the use of these agents in HFrEF treatment and resulted in FDA approvals for cardiovascular indications. The obvious question arising from all these studies is, of course, which molecular/pharmacological mechanisms underlie these cardiovascular benefits of the drugs in diabetics and non-diabetics alike. The fact that SGLT2 is not significantly expressed in cardiac myocytes (SGLT1 appears to be the dominant isoform) adds even greater perplexity to this answer. A variety of mechanisms have been proposed over the past few years and tested in cell and animal models and prominent among those is the potential for sympatholysis, i.e., reduction in sympathetic nervous system activity. The latter is known to be high in HF patients, contributing significantly to the morbidity and mortality of the disease. The present minireview first summarizes the current evidence in the literature supporting the notion that SGLT2 inhibitors, such as dapagliflozin and empagliflozin, exert sympatholysis, and also outlines the main putative underlying mechanisms for these sympatholytic effects. Then, we propose a novel hypothesis, centered on the adrenal medulla, for the sympatholytic effects specifically of dapagliflozin. Adrenal medulla is responsible for the production and secretion of almost the entire amount of circulating epinephrine and of a significant percentage of circulating norepinephrine in the human body. If proven true experimentally, this hypothesis, along with other emerging experimental evidence for sympatholytic effects in neurons, will shed new light on the pharmacological effects that mediate the cardiovascular benefits of SGLT2 inhibitor drugs, independently of their blood glucose-lowering effects.

scholarly journals EMPEROR-Preserved: SGLT2 inhibitors breakthrough in the management of heart failure with preserved ejection fraction

2021 ◽  
Vol 2021 (3) ◽  
Author(s):  
Kerolos Wagdy ◽  
Sherif Nagy
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Complex Disease ◽  
Hospital Admissions ◽  
Sglt2 Inhibitor ◽  
Cardiovascular Death ◽  
Sglt2 Inhibitors ◽  
Preserved Ejection Fraction ◽  
Reduced Ejection Fraction ◽  
Sglt2 Inhibition

Background: Heart failure with preserved ejection fraction (HFpEF) is a complex disease which accounts for more than half of all HF hospital admissions with high prevalence and lack of effective evidence-based management. Sodium-glucose cotransporter 2 (SGLT2) inhibitor is a new antidiabetic drug that recently gained a new role in the management of heart failure with reduced ejection fraction but its role in HFpEF had yet to be studied.Study and results: EMPEROR-Preserved trial set out to evaluate the effects of SGLT2 inhibition with empagliflozin on major heart failure outcomes in patients with HFpEF. The patients were randomized in a 1:1 fashion into two groups; to receive either empagliflozin 10 mg per day (n = 2,997) or placebo (n = 2,991) in addition to usual therapy. Empagliflozin led to a 21% risk reduction of the composite of cardiovascular death or hospitalization for heart failure, which was mainly related to a 29% lower risk of hospitalization for heart failure rather than effect on cardiovascular death empagliflozin. The effects SGLT2 inhibitors were consistent in all patients.

Effects of Concomitant Administration of Sodium Glucose Co-transporter 2 Inhibitor with Insulin on Hemoglobin A1c, Body Mass Index and Serum Lipid Profile in Japanese Type 2 Diabetic Patients

Drug Research ◽  
2018 ◽  
Vol 68 (12) ◽  
pp. 669-672
Author(s):  
Masataka Kusunoki ◽  
Yukie Natsume ◽  
Tetsuro Miyata ◽  
Kazuhiko Tsutsumi ◽  
Yoshiharu Oshida
Keyword(s):  
Diabetes Mellitus ◽  
Blood Glucose ◽  
Hemoglobin A1c ◽  
Blood Glucose Control ◽  
Sglt2 Inhibitor ◽  
Serum Triglyceride ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Type 2 Diabetic

AbstractIn patients with type 2 diabetes mellitus who show suboptimal blood glucose control under insulin therapy alone, concomitant treatment with an additional hypoglycemic agent that differs in its mechanism of action from insulin may be considered. We conducted this clinical trial to explore whether further control of increased blood glucose level can be achieved with concomitant use of sodium glucose co-transporter 2 (SGLT2) inhibitor as concomitant with other hypoglycemic therapy, as compared to SGLT2 inhibitor monotherapy, in patients with type 2 diabetes mellitus showing decrease in blood glucose level but less than the effect of insulin monotherapy and there was no significant differences. In the SGLT2 inhibitor monotherapy group, decreases of the serum hemoglobin A1c (HbA1c) level, body weight, body mass index (BMI) and serum triglyceride, and elevation of the serum high density lipoprotein cholesterol concentration were observed as compared to the baseline values. In the type 2 diabetic patients under insulin therapy who received combined insulin plus SGLT2 inhibitor therapy, however decreases in the body weight and BMI, with only a tendency towards decrease of the serum HbA1c value, not reaching statistical significance, were observed. The combined therapy group also showed no appreciable changes of the serum triglyceride level, while the serum adiponectin level increased. The present study data indicate that combined insulin plus SGLT2 inhibitor treatment failed to afford any further improvement of the blood glucose control, as compared to SGLT2 monotherapy, in Japanese type 2 diabetic patients.

scholarly journals Focusing on Sodium Glucose Cotransporter-2 and the Sympathetic Nervous System: Potential Impact in Diabetic Retinopathy

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Lakshini Y. Herat ◽  
Vance B. Matthews ◽  
P. Elizabeth Rakoczy ◽  
Revathy Carnagarin ◽  
Markus Schlaich
Keyword(s):  
Diabetic Retinopathy ◽  
Vision Loss ◽  
Microvascular Complications ◽  
Sglt2 Inhibitor ◽  
Sglt2 Inhibitors ◽  
Current Evidence ◽  
Therapeutic Approaches ◽  
Novel Therapy ◽  
Sodium Glucose Cotransporter ◽  
Major Treatment

The prevalence of diabetes is at pandemic levels in today’s society. Microvascular complications in organs including the eye are commonly observed in human diabetic subjects. Diabetic retinopathy (DR) is a prominent microvascular complication observed in many diabetics and is particularly debilitating as it may result in impaired or complete vision loss. In addition, DR is extremely costly for the patient and financially impacts the economy as a range of drug-related therapies and laser treatment may be essential. Prevention of microvascular complications is the major treatment goal of current therapeutic approaches; however, these therapies appear insufficient. Presently, sodium glucose cotransporter-2 (SGLT2) inhibitors may offer a novel therapy beyond simple glucose lowering. Excitingly, the EMPA-REG clinical trial, which focuses on the clinically used SGLT2 inhibitor empagliflozin, has been extremely fruitful and has highlighted beneficial cardiovascular and renal outcomes. The effects of SGLT2 inhibitors on DR are currently a topic of much research as outlined in the current review, but future studies are urgently needed to fully gain mechanistic insights. Here, we summarize current evidence and identify gaps that need to be addressed.

scholarly journals Effects of SGLT2 inhibitor dapagliflozin in patients with heart failure with reduced ejection fraction

2020 ◽  
Vol 25 (8) ◽  
pp. 4049
Author(s):  
N. R. Khasanov
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Drug Class ◽  
Sglt2 Inhibitor ◽  
Cardiovascular Death ◽  
Sglt2 Inhibitors ◽  
Reduced Ejection Fraction ◽  
Patients With Heart Failure ◽  
Recommended Therapy

SGLT2 inhibitors have been shown to reduce the risk of cardiovascular events and the development and decompensation of heart failure (HF) in patients with type 2 diabetes (T2D). The improved prognosis in HF may be related not only to the hypoglycemic effect of this drug class. The DAPA-HF study, which included patients with HF with reduced ejection fraction, demonstrated the benefit of dapagliflozin in reducing the risk of cardiovascular death and worsening HF, as well as improving HF symptoms compared to placebo, regardless of the presence of T2D and the recommended therapy for HF.

scholarly journals Estimated Population Prevalence of Heart Failure with Reduced Ejection Fraction in Spain, According to DAPA-HF Study Criteria

2020 ◽  
Vol 9 (7) ◽  
pp. 2089
Author(s):  
Anna Camps-Vilaró ◽  
Juan F. Delgado-Jiménez ◽  
Núria Farré ◽  
Helena Tizón-Marcos ◽  
Jesús Álvarez-García ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Sglt2 Inhibitor ◽  
Heart Association ◽  
Cardiovascular Effects ◽  
Functional Class ◽  
Adverse Outcomes ◽  
Reduced Ejection Fraction ◽  
Patient Profile ◽  
Number Of Patients

Heart failure (HF) is one of the main causes of morbidity, mortality, and high healthcare costs. Dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, reduced cardiovascular mortality and hospitalization for HF compared to placebo in patients with chronic HF, and reduced ejection fraction (EF) in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study. Our aim was to estimate the number of patients with DAPA-HF characteristics in Spain. Our literature review identified epidemiological studies whose objective was to quantify the prevalence of HF and its comorbidities in Spain. We estimated the prevalence of HF with reduced EF, of New York Heart Association (NYHA) functional class II–IV, and with a glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m². In this population, we analysed the prevalence of diabetes using data from the REDINSCOR (Spanish Network for Heart Failure) registry. Our estimations indicate there are 594,684 patients ≥45 years old with HF in Spain (2.6% of this population age group), of which 52.4%, 84.0%, and 93.9% have reduced EF, are NYHA II–IV, and have a GFR ≥ 30 mL/min/1.73 m², respectively. By our calculations, approximately 245,789 Spanish patients would meet the DAPA-HF patient profile, and therefore could benefit from the protective cardiovascular effects of dapagliflozin.

scholarly journals Severe intoxication caused by sodium-glucose cotransporter 2 inhibitor overdose: a case report

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Miho Nakamura ◽  
Junya Nakade ◽  
Tadashi Toyama ◽  
Masaki Okajima ◽  
Takumi Taniguchi
Keyword(s):  
Renal Function ◽  
Blood Glucose ◽  
Blood Glucose Level ◽  
Glucose Level ◽  
Sglt2 Inhibitor ◽  
Severe Hypoglycemia ◽  
Olmesartan Medoxomil ◽  
Sglt2 Inhibitors ◽  
Glucose Levels ◽  
Sodium Glucose Cotransporter

Abstract Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors inhibit SGLT2, which is expressed in the proximal renal tubule, and thus reduce blood glucose levels by enabling the urinary excretion of excess glucose. SGLT2 inhibitors have been reported to suppress the complications of diabetes and reduce overall mortality. However, little is known about the types of symptoms that may occur in response to an overdose of an SGLT2 inhibitor. Here, we describe a case of intoxication caused by an overdose of an SGLT2 inhibitor. Case presentation An otherwise physically healthy adult woman ingested an overdose of ipragliflozin, an SGLT2 inhibitor, and a polypill of olmesartan medoxomil, and azelnidipine in a suicide attempt. Although her blood ipragliflozin concentration was very high (9516.3 ng/mL) upon hospital arrival, her initial blood glucose level was normal, and she did not exhibit symptoms such as hypoglycemia or polyuria. Moderate renal dysfunction associated with an estimated glomerular filtration rate of 42.3 mL/min/1.73 m2 was observed. Thirty-six hours after ingestion, her blood ipragliflozin concentration decreased to a level equivalent to that observed after a therapeutic dose and her renal function improved almost simultaneously. After improvement in her renal function, the osmotic diuretic effect of the drug progressed. Her blood glucose level declined slightly but was in the normal range due to glucose administration. During the clinical course, fatal hypoglycemia was not observed. Conclusions Our case showed that an overdose of an SGLT2 inhibitor caused toxic effects on renal function, but severe hypoglycemia was not observed. Additional cases of intoxication from SGLT2 inhibitors alone would be helpful to clarify the mechanism of intoxication.

scholarly journals SGLT2 inhibitors in heart failure with reduced ejection fraction

2021 ◽  
Vol 73 (1) ◽  
Author(s):  
Uday Sankar Das ◽  
Aritra Paul ◽  
Suvro Banerjee
Keyword(s):  
Heart Failure ◽  
Cardiovascular Disease ◽  
Renal Failure ◽  
Blood Glucose ◽  
High Risk ◽  
Ejection Fraction ◽  
Sglt2 Inhibitors ◽  
Renal Tubules ◽  
Reduced Ejection Fraction ◽  
Patients With Heart Failure

AbstractSodium – glucose co-transporter 2 (SGLT2) inhibitors reduce blood glucose by inhibiting reabsorption of glucose from the proximal renal tubules. Initial studies showed that apart from reducing blood glucose they also reduce the combined endpoint of myocardial infarction, stroke, and cardiovascular death, hospitalization from heart failure, and occurrence of renal failure in patients with known cardiovascular disease or at high risk of developing cardiovascular disease. Recent studies have shown that these drugs also could be used in patients to treat heart failure or to slow the progression of renal failure, irrespective of whether the patients have diabetes or not. In this review, we discuss the clinical trial evidence for the use of SGLT2 inhibitors for the treatment of patients with heart failure with reduced ejection fraction and for the prevention of heart failure in patients with diabetes who are at high risk of cardiovascular events. We also discuss the plausible mechanisms of action for the cardiovascular beneficial effects of SGLT2 inhibitors. EMPA-REG OUTCOME TRIAL, DECLARE-TIMI 58, CANVAS, VERTIS-CV studies have shown that SGLT2 inhibitors namely empagliflozin, dapagliflozin, canagliflozin and ertugliflozin reduce the chances of hospitalisation in patients who have cardiovascular disease or at high risk of cardiovascular disease. The DAPA-HF study and the EMPEROR-REDUCED TRIAL have further shown that Dapagliflozin and Empagliflozin could be used to treat patients with heart failure, with or without diabetes. SGLT2 inhibitors provide us with a new armamentarium for treatment of patients with a triad of diabetes, heart or renal disease. Their mechanism of action in prevention or treatment of patients with heart failure however still remains speculative.

scholarly journals Effect of Empagliflozin on Left Ventricular Volumes in Patients with Type 2 Diabetes, or Prediabetes, and Heart Failure with Reduced Ejection Fraction (SUGAR-DM-HF)

Circulation ◽  
2020 ◽  
Author(s):  
Matthew M. Y. Lee ◽  
Katriona J. M. Brooksbank ◽  
Kirsty Wetherall ◽  
Kenneth Mangion ◽  
Giles Roditi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Ejection Fraction ◽  
Global Longitudinal Strain ◽  
Sglt2 Inhibitor ◽  
Left Ventricular ◽  
Sglt2 Inhibitors ◽  
Reduced Ejection Fraction ◽  
B Lines

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of heart failure hospitalization and cardiovascular death in patients with heart failure and reduced ejection fraction (HFrEF). However, their effects on cardiac structure and function in HFrEF are uncertain. Methods: We designed a multicenter randomized, double-blind, placebo-controlled trial to investigate the cardiac effects of empagliflozin in patients in NYHA functional class II to IV with a left ventricular (LV) ejection fraction ≤40% and type 2 diabetes or prediabetes. Patients were randomized 1:1 to empagliflozin 10 milligrams once daily or placebo, stratified by age (<65 and ≥65 years) and glycemic status (diabetes or prediabetes). The co-primary outcomes were change from baseline to 36 weeks in LV end-systolic volume indexed to body surface area (LVESVi) and LV global longitudinal strain (LV GLS) measured using cardiovascular magnetic resonance (CMR). Secondary efficacy outcomes included other CMR measures (LVEDVi, LVEF), diuretic intensification, symptoms (Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS)), 6-minute walk distance (6MWD), B-lines on lung ultrasound and biomarkers (including NT-proBNP). Results: From April 2018 to August 2019, 105 patients were randomized: 77 (73.3%) male, mean age 68.7 [SD 11.1] years, 82 (78.1%) diabetes and 23 (21.9%) prediabetes, mean LVEF 32.5% [9.8%], and 81 (77.1%) NYHA II and 24 (22.9%) NYHA III. Patients received standard treatment for HFrEF. Compared with placebo, empagliflozin reduced LVESVi by 6.0 (-10.8 to -1.2) ml/m 2 (p=0.015). There was no difference in LV GLS. Empagliflozin reduced LVEDVi by 8.2 (-13.7 to -2.6) ml/m 2 (p=0.0042) and reduced NT-proBNP by 28 (2 to 47) %, p=0.038. There were no between-group differences in other CMR measures, KCCQ-TSS, 6MWD or B-lines. Conclusions: The SGLT2 inhibitor empagliflozin reduced LV volumes in patients with HFrEF and type 2 diabetes or prediabetes. Favorable reverse LV remodeling may be a mechanism by which SGLT2 inhibitors reduce HF hospitalization and mortality in HFrEF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov Unique Identifier: NCT03485092.

scholarly journals The dawn of the four-drug era? SGLT2 inhibition in heart failure with reduced ejection fraction

2021 ◽  
Vol 15 ◽  
pp. 175394472110026
Author(s):  
Michael V. Genuardi ◽  
Paul J. Mather
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Controlled Trial ◽  
Sglt2 Inhibitor ◽  
The United States ◽  
Sglt2 Inhibitors ◽  
Current Guideline ◽  
Converting Enzyme Inhibitors ◽  
Reduced Ejection Fraction

Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are a relatively new class of antihyperglycemic drug with salutary effects on glucose control, body weight, and blood pressure. Emerging evidence now indicates that these drugs may have a beneficial effect on outcomes in heart failure with reduced ejection fraction (HFrEF). Post-approval cardiovascular outcomes data for three of these agents (canagliflozin, empagliflozin, and dapagliflozin) showed an unexpected improvement in cardiovascular endpoints, including heart failure hospitalization and mortality, among patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease or risk factors. These studies were followed by a placebo controlled trial of dapagliflozin in patients with HFrEF both with and without T2DM, showing a reduction in all-cause mortality comparable to current guideline-directed HFrEF medical therapies such as angiotensin-converting enzyme inhibitors and beta-blockers. In this review, we discuss the current landscape of evidence, safety and adverse effects, and proposed mechanisms of action for use of these agents for patients with HFrEF. The United States (US) and European guidelines are reviewed, as are the current US federally approved indications for each SGLT2 inhibitor. Use of these agents in clinical practice may be limited by an uncertain insurance environment, especially in patients without T2DM. Finally, we discuss practical considerations for the cardiovascular clinician, including within-class differences of the SGLT2 inhibitors currently available on the US market (217/300).

scholarly journals A Case of Euglycemic Diabetic Ketoacidosis Following Canagliflozin Therapy

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A358-A358
Author(s):  
Kubra M Tuna ◽  
Randa Abdelmasih ◽  
Ramy Abdelmaseih ◽  
Mrhaf Alsamman ◽  
Joseph Robbins
Keyword(s):  
Fatty Acid ◽  
Metabolic Acidosis ◽  
Blood Glucose ◽  
Side Effects ◽  
Diabetic Ketoacidosis ◽  
Sglt2 Inhibitor ◽  
Oral Intake ◽  
Sglt2 Inhibitors ◽  
Anion Gap

Abstract Introduction: Diabetic ketoacidosis (DKA) is a life-threatening complication of diabetes mellitus (DM). In general, DKA characterized by blood sugar over 250 mg/dL, anion-gap metabolic acidosis, and increased plasma or urine ketones. Approximately 2–3% of DKA patients can present with normal blood glucose levels (less than 250 mg/dl) which called euglycemic DKA. Some of the etiologies of euglycemic DKA include recent use of insulin, low caloric intake, alcoholism, chronic liver disease, and pregnancy. Very rarely, SGLT2 inhibitor use may be responsible for euglycemic DKA. Case Presentation: Here we present a case of 44 years old female with a past medical history of DM type 2 who presented with acute onset of nausea and vomiting. Initial laboratory findings were remarkable for anion gap metabolic acidosis with a blood glucose level of 201 mg/dl. The patient was on long-acting insulin along with Canagliflozin and Metformin therapy over years and reported being compliant with medications. She was treated with intravenous insulin therapy which resolved acidosis as well as symptoms. The patient was discharged with recommendations of discontinuation of Canagliflozin. Discussion: SGLT2 inhibitors are the novel class of oral antidiabetic drugs which widely used due to their favorable cardiovascular and renal outcomes independent of glycemic control. However, their side effects remain a concern. DKA is a rare but serious side effect of SGLT2 inhibitors with an incidence rate of 9.4% in type 1 DM and less than 0.2% in type 2 DM. Patients typically present with euglycemia or low-grade hyperglycemia which results in a diagnostic challenge for treating physicians. SGLT2 inhibitors increase urinary glucose excretion with a subsequent decrease in circulating insulin and an increase in glucagon, rendering a metabolic shift from glucose to fatty acid utilization. During times of intercurrent illness (decreased oral intake, sepsis) or metabolic stress (surgery), decreased carbohydrate intake coupled with the aforementioned changes will result in decreased insulin secretion and increased counter-regulatory hormones including adrenaline and cortisol, promoting lipolysis, fatty acid oxidation, and ketone production by the liver which ultimately leading to euglycemic DKA. Conclusion: SGLT2 inhibitors induced euglycemic DKA treatment is identical to classic DKA with consideration of the lack of hyperglycemia. Appropriate patient counseling to ensure safe SGLT2 inhibitor therapy is crucial, including appropriate holding parameters during concomitant volume-depleting illnesses and decreased oral intake. Timely diagnosis of euglycemic DKA, and recognitions of other rare but lethal side effects to decrease overall morbidity and mortality.

Sign in / Sign up

Export Citation Format

Share Document