Outcome trial data on sodium glucose cotransporter-2 inhibitors: Putting clinical benefits and risks in perspective

2021 ◽  
Author(s):  
B. Chiang ◽  
D.P. Chew ◽  
C.G. De Pasquale
Keyword(s):  
Trial Data ◽  
Sodium Glucose Cotransporter ◽  
Clinical Benefits ◽  
Outcome Trial

Role of Radiation Therapy and Fluoropyrimidines in the Treatment of Gastrointestinal Malignancies

1996 ◽  
Vol 3 (4) ◽  
pp. 319-328
Author(s):  
William W. Wong ◽  
Steven E. Schild ◽  
James A. Martenson
Keyword(s):  
Clinical Trial ◽  
Clinical Trial Data ◽  
Trial Data ◽  
Combined Chemotherapy ◽  
Gastrointestinal Malignancies ◽  
Treatment Regimens ◽  
Improved Outcomes ◽  
Clinical Benefits ◽  
Positive Results

Background The use of combined chemotherapy and radiation for gastrointestinal malignancies has several theoretical advantages, and clinical trials to determine the type and extent of clinical benefits have been performed. Methods The basic science and clinical trial data evaluating such combinations are reviewed, with an emphasis on the interactions between fluoropyrimidines and radiation. Results Improved outcomes from chemoradiotherapy have been demonstrated in patients with selected stages of anal, esophageal, rectal, and pancreatic cancer. Conclusion Despite these positive results, further work is needed to demonstrate even more effective and less toxic treatment regimens.

scholarly journals MECHANISMS IN ENDOCRINOLOGY: SGLT2 inhibitors: clinical benefits by restoration of normal diurnal metabolism?

2018 ◽  
Vol 178 (4) ◽  
pp. R113-R125 ◽  
Author(s):  
Russell L Esterline ◽  
Allan Vaag ◽  
Jan Oscarsson ◽  
Jiten Vora
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Mitochondrial Morphology ◽  
Lysosomal Degradation ◽  
Therapeutic Implications ◽  
Disease States ◽  
Sodium Glucose Cotransporter ◽  
Clinical Benefits ◽  
Key Steps ◽  
Ability To Drive

Type 2 diabetes (T2D) is associated with inhibition of autophagic and lysosomal housekeeping processes that detrimentally affect key organ functioning; a process likely to be exacerbated by conventional insulin-driven anabolic therapies. We propose that the cardio-renal benefits demonstrated with sodium–glucose cotransporter-2 inhibitor (SGLT2i) treatment in T2D partly may be explained by their ability to drive consistent, overnight periods of increased catabolism brought about by constant glucosuria. Key steps driving this catabolic mechanism include: a raised glucagon/insulin ratio initially depleting glycogen in the liver and ultimately activating gluconeogenesis utilizing circulating amino acids (AAs); a general fuel switch from glucose to free fatty acids (accompanied by a change in mitochondrial morphology from a fission to a sustained fusion state driven by a decrease in AA levels); a decrease in circulating AAs and insulin driving inhibition of mammalian target of rapamycin complex 1 (mTORC1), which enhances autophagy/lysosomal degradation of dysfunctional organelles, eventually causing a change in mitochondrial morphology from a fission to a sustained fusion state. Resumption of eating in the morning restores anabolic biogenesis of new and fully functional organelles and proteins. Restoration of diurnal metabolic rhythms and flexibility by SGLT2is may have therapeutic implications beyond those already demonstrated for the cardio-renal axis and may therefore affect other non-diabetes disease states.

scholarly journals Effect of Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors on Left Ventricular Remodelling and Longitudinal Strain: A Prospective Observational Study

2021 ◽  
Author(s):  
Sergio Gamaza-Chulian ◽  
Enrique Díaz-Retamino ◽  
Fátima González-Testón ◽  
José Carlos Gaitero ◽  
María José Castillo ◽  
...  
Keyword(s):  
Speckle Tracking ◽  
Longitudinal Strain ◽  
Speckle Tracking Echocardiography ◽  
Global Longitudinal Strain ◽  
Left Ventricular ◽  
Control Group ◽  
Ventricular Remodelling ◽  
Left Ventricular Remodelling ◽  
Sodium Glucose Cotransporter ◽  
Clinical Benefits

Abstract Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) lower cardiovascular events in type 2 diabetes mellitus (T2DM) patients, although the mechanisms underlying these benefits are not clearly understood. Our aim was to study the effects of SGLT2i on left ventricular remodelling and longitudinal strain.Methods: Between November 2019 and April 2020, we included 52 patients with T2DM ≥18 years old, with HbA1c between 6.5% and 10.0%, and estimated glomerular filtration ≥45 ml/min/1.73 m2. Patients were classified into SGLT2i group and control group, according to prescribed treatment by their referring physician. Conventional and speckle tracking echocardiography were performed by blinded sonographers, at baseline and after 6 months of treatment.Results: Among the 52 included patients (44% females, mean age 66.8±8.6 years, mean HbA1c was 7.40±0.7%), 30 patients were prescribed SGLT2i and 22 patients were classified as control group. Mean change in indexed left ventricular mass (LVM) was -10.85±3.31 g/m2 (p=0.003) in the SGLT2i group, and +2.34±4.13 g/m2 (p=0.58) in the control group. Absolute value of Global Longitudinal Strain (GLS) increased by a mean of 1.29±0.47 (p=0.011) in the SGLT2i group, and 0.40±0.62 (p=0.34) in the control group. We did not find correlations between changes in LVM and GLS, and other variables like change in HbA1c.Conclusions: Among patients with T2DM, SGLT2i were associated with a significant reduction in indexed LVM and a significant increment in longitudinal strain measured by speckle tracking echocardiography, which may explain in part the clinical benefits found in clinical trials.

scholarly journals Multi-Organ Protective Effects of Sodium Glucose Cotransporter 2 Inhibitors

2021 ◽  
Vol 22 (9) ◽  
pp. 4416
Author(s):  
Hidekatsu Yanai ◽  
Mariko Hakoshima ◽  
Hiroki Adachi ◽  
Hisayuki Katsuyama
Keyword(s):  
Insulin Resistance ◽  
Hepatic Fibrosis ◽  
Tubuloglomerular Feedback ◽  
Liver Fat ◽  
Diabetic Patients ◽  
Protective Effects ◽  
Organ Protection ◽  
Sodium Glucose Cotransporter ◽  
Outcome Trial ◽  
Hepatic Protection

Sodium glucose cotransporter 2 inhibitors (SGLT2i) block the reabsorption of glucose by inhibiting SGLT2, thus improving glucose control by promoting the renal excretion of glucose, without requiring insulin secretion. This pharmacological property of SGLT2i reduces body weight and improves insulin resistance in diabetic patients. Such beneficial metabolic changes caused by SGLT2i are expected to be useful not only for glucose metabolism, but also for the protection for various organs. Recent randomized controlled trials (RCTs) on cardiovascular diseases (EMPA-REG OUTCOME trial and CANVAS program) showed that SGLT2i prevented cardiovascular death and the development of heart failure. RCTs on renal events (EMPA-REG OUTCOME trial, CANVAS program, and CREDENCE trial) showed that SGLT2i suppressed the progression of kidney disease. Furthermore, SGLT2i effectively lowered the liver fat content, and our study demonstrated that SGLT2i reduced the degree of hepatic fibrosis in patients at high-risk of hepatic fibrosis. Such promising properties of SGLT2i for cardiovascular, renal, and hepatic protection provide us the chance to think about the underlying mechanisms for SGLT2i-induced improvement of multiple organs. SGLT2i have various mechanisms for organ protection beyond glucose-lowering effects, such as an increase in fatty acids utilization for hepatic protection, osmotic diuresis for cardiac protection, an improvement of insulin resistance for anti-atherogenesis, and an improvement of tubuloglomerular feedback for renal protection.

scholarly journals Cardiovascular benefits of sodium-glucose cotransporter 2 inhibitors in diabetic and nondiabetic patients

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Boyang Xiang ◽  
Xiaoya Zhao ◽  
Xiang Zhou
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Glycemic Control ◽  
Large Scale ◽  
Protective Effects ◽  
Beneficial Effects ◽  
Sodium Glucose Cotransporter ◽  
Outcome Trial

AbstractSodium-glucose cotransporter 2 inhibitors (SGLT2i) were developed as antidiabetic agents, but accumulating evidence has shown their beneficial effects on the cardiovascular system. Analyses of the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) suggested that these benefits are independent of glycemic control. Several large-scale outcome trials of SGLT2i also showed cardiovascular benefits in nondiabetic patients, strengthening this perspective. Extensive animal and clinical studies have likewise shown that mechanisms other than the antihyperglycemic effect underlie the cardiovascular benefits. Recent clinical guidelines recommend the use of SGLT2i in patients with type 2 diabetes mellitus and cardiovascular diseases because of the proven cardiovascular protective effects. Since the cardiovascular benefits are independent of glycemic control, the therapeutic spectrum of SGLT2i will likely be extended to nondiabetic patients.

scholarly journals Antihyperglycemic agents as novel natriuretic therapies in diabetic kidney disease

2018 ◽  
Vol 315 (5) ◽  
pp. F1406-F1415 ◽  
Author(s):  
David León Jiménez ◽  
David Z. I. Cherney ◽  
Petter Bjornstad ◽  
Luis Castilla-Guerra ◽  
José Pablo Miramontes González
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Kidney Disease ◽  
Sglt2 Inhibitors ◽  
Tubuloglomerular Feedback ◽  
Protective Effects ◽  
Sodium Glucose Cotransporter ◽  
Sglt2 Inhibition ◽  
Clinical Benefits ◽  
Intraglomerular Pressure

While sodium-glucose cotransporter-2 (SGLT2) inhibitors have been used for the routine management of type 2 diabetes for several years, it is perhaps their natriuretic effects that are most important clinically. This natriuresis activates tubuloglomerular feedback, resulting in reduced glomerular hypertension and proteinuria, leading to renal protective effects in the EMPA-REG OUTCOME and CANVAS Program trials. In the cardiovascular system, it is likely that plasma volume contraction due to natriuresis in response to SGLT2 inhibition is at least in part responsible for the reduction in the risk of heart failure observed in these trials. We compare this mechanism of action with other antidiabetics. Importantly, other diuretic classes, including thiazide and loop diuretics, have not resulted in such robust clinical benefits in patients with type 2 diabetes, possibly because these older agents do not influence intraglomerular pressure directly. In contrast, SGLT2 inhibitors do have important physiological similarities with carbonic anhydrase inhibitors, which also act proximally, and have been shown to activate tubuloglomerular feedback.

scholarly journals Perspective of the β-blockers for the patients with diabetes and heart failure 

2020 ◽  
Vol 8 (4) ◽  
pp. 97-99
Author(s):  
Hiroshi BANDO
Keyword(s):  
Heart Failure ◽  
Adverse Outcomes ◽  
Control Group ◽  
Sodium Glucose Cotransporter ◽  
Strict Glycemic Control ◽  
Cardiovascular Assessment ◽  
Patients With Diabetes ◽  
Outcome Trial ◽  
Β Blockers

Patients with diabetes and heart failure have been increasing due to Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) study. β-blockers showed significantly suppressed cardiovascular events in the strict glycemic control group. Sodium-glucose Cotransporter-2 Inhibitors (SGLT2i) seem to be beneficial for diabetes and heart failure. Clinical efficacy of β-blockers would be suggested from three studies including Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME) trial, Canagliflozin cardioVascular Assessment Study (CANVAS) and Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study. Further discussion will be expected with research in detail.

scholarly journals Sodium glucose cotransporter 2 inhibitors: mechanisms of action in heart failure

2020 ◽  
Author(s):  
Mieczysław Dutka ◽  
Rafał Bobiński ◽  
Izabela Ulman-Włodarz ◽  
Maciej Hajduga ◽  
Jan Bujok ◽  
...  
Keyword(s):  
Heart Failure ◽  
Glycaemic Control ◽  
Experimental Studies ◽  
Mechanisms Of Action ◽  
New Class ◽  
Current State ◽  
Sodium Glucose Cotransporter ◽  
Patients With Diabetes ◽  
Clinical Benefits ◽  
Treatment Of Diabetes

Abstract Diabetes is a key independent risk factor in the development of heart failure (HF) and a strong, adverse prognostic factor in HF patients. HF remains the primary cause of hospitalisation for diabetics and, as previous studies have shown, when HF occurs in these patients, intensive glycaemic control does not directly improve the prognosis. Recent clinical studies assessing a new class of antidiabetic drugs, sodium-glucose cotransporter 2 inhibitors (SGLT2is) showed some unexpected beneficial results. Patients treated with SGLT2is had a significant decrease in both cardiovascular (CV) and all-cause mortality and less hospitalisations due to HF compared to those given a placebo. These significant clinical benefits occurred quickly after the drugs were administered and were not solely due to improved glycaemic control. These groundbreaking clinical trials’ results have already changed clinical practice in the management of patients with diabetes at high CV risk. These trials have triggered numerous experimental studies aimed at explaining the mechanisms of action of this unique group of drugs. This article presents the current state of knowledge about the mechanisms of action of SGLT2is developed for the treatment of diabetes and which, thanks to their cardioprotective effects, may, in the future, become a treatment for patients with HF.

scholarly journals Effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on left ventricular remodelling and longitudinal strain: a prospective observational study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Sergio Gamaza-Chulián ◽  
Enrique Díaz-Retamino ◽  
Fátima González-Testón ◽  
José Carlos Gaitero ◽  
María José Castillo ◽  
...  
Keyword(s):  
Speckle Tracking ◽  
Longitudinal Strain ◽  
Speckle Tracking Echocardiography ◽  
Global Longitudinal Strain ◽  
Left Ventricular ◽  
Control Group ◽  
Ventricular Remodelling ◽  
Left Ventricular Remodelling ◽  
Sodium Glucose Cotransporter ◽  
Clinical Benefits

Abstract Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) lower cardiovascular events in type 2 diabetes mellitus (T2DM) patients, although the mechanisms underlying these benefits are not clearly understood. Our aim was to study the effects of SGLT2i on left ventricular remodelling and longitudinal strain. Methods Between November 2019 and April 2020, we included 52 patients with T2DM ≥ 18 years old, with HbA1c between 6.5 and 10.0%, and estimated glomerular filtration ≥ 45 ml/min/1.73 m2. Patients were classified into SGLT2i group and control group, according to prescribed treatment by their referring physician. Conventional and speckle tracking echocardiography were performed by blinded sonographers, at baseline and after 6 months of treatment. Results Among the 52 included patients (44% females, mean age 66.8 ± 8.6 years, mean HbA1c was 7.40 ± 0.7%), 30 patients were prescribed SGLT2i and 22 patients were classified as control group. Mean change in indexed left ventricular mass (LVM) was − 0.85 ± 3.31 g/m2 (p = 0.003) in the SGLT2i group, and + 2.34 ± 4.13 g/m2 (p = 0.58) in the control group. Absolute value of Global Longitudinal Strain (GLS) increased by a mean of 1.29 ± 0.47 (p = 0.011) in the SGLT2i group, and 0.40 ± 0.62 (p = 0.34) in the control group. We did not find correlations between changes in LVM and GLS, and other variables like change in HbA1c. Conclusions Among patients with T2DM, SGLT2i were associated with a significant reduction in indexed LVM and a significant increment in longitudinal strain measured by speckle tracking echocardiography, which may explain in part the clinical benefits found in clinical trials.

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