scholarly journals Treatment Response to SGLT2 Inhibitors: From Clinical Characteristics to Genetic Variations

2021 ◽  
Vol 22 (18) ◽  
pp. 9800
Author(s):  
Jasna Klen ◽  
Vita Dolžan
Keyword(s):  
Treatment Response ◽  
Genetic Factors ◽  
Sglt2 Inhibitors ◽  
Response To Treatment ◽  
Comorbid Conditions ◽  
Everyday Clinical Practice ◽  
New Class ◽  
Sodium Glucose Cotransporter ◽  
Antihyperglycaemic Drugs

SGLT2 (sodium-glucose cotransporter 2) inhibitors are a new class of antihyperglycaemic drugs that act on the proximal tubules of the kidney. They have shown efficacy in the management of diabetes mellitus type 2 and their cardiovascular and renal safety have been extensively investigated and confirmed in clinical trials. However, inter-individual differences in response to treatment with SGLT2 inhibitors may present in everyday clinical practice, and good predictors of glycemic response and the risk for adverse events in an individual patient are lacking. As genetic variability of SGLT2 may influence the treatment response, pharmacogenetic information could support the choice of the most beneficial treatment strategy in an individual patient. This review focuses on the clinical and genetic factors that may influence the treatment response to SGLT2 inhibitors in type 2 diabetes patients with comorbid conditions.

scholarly journals Is cancer incidence modified by SGLT2 inhibitors?

2019 ◽  
Vol 22 (4) ◽  
pp. 399-402
Author(s):  
Lev M. Berstein
Keyword(s):  
Type 2 Diabetes ◽  
Clinical Practice ◽  
Sglt2 Inhibitors ◽  
Antitumor Therapy ◽  
Glucose Lowering ◽  
New Class ◽  
Sodium Glucose Cotransporter ◽  
Main Pathway ◽  
Organ Specific

One of the most important achievements of diabetology in the second decade of the 21st century is undoubtedly the introduction of sodium-glucose cotransporter (SGLT2) inhibitors into clinical practice as a new class of glucose-lowering agents for type 2 diabetes. In addition to the glucosuria induced by these agents, which is their main pathway for achieving antidiabetic recovery, other consequences accompany the intake of SGLT2 inhibitors. These pathways, particularly in oncology, have not been extensively studied. Considering the analysis of the previous studies, this report demonstrates, although not significantly, that cancer morbidity in patients with T2DM treated with SGLT2 inhibitors may be organ-specific. In addition, agents within the class of SGLT-2 inhibitors may be useful in several variants of antitumor therapy, but this theory requires further study.

Mechanisms of Protective Effects of SGLT2 Inhibitors in Cardiovascular Disease and Renal Dysfunction

2019 ◽  
Vol 19 (20) ◽  
pp. 1818-1849 ◽  
Author(s):  
Ban Liu ◽  
Yuliang Wang ◽  
Yangyang Zhang ◽  
Biao Yan
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Renal Dysfunction ◽  
Sglt2 Inhibitors ◽  
Sodium Glucose Cotransporter ◽  
Glucose Reabsorption ◽  
Renal Glucose Reabsorption

: Type 2 diabetes mellitus is one of the most common forms of the disease worldwide. Hyperglycemia and insulin resistance play key roles in type 2 diabetes mellitus. Renal glucose reabsorption is an essential feature in glycaemic control. Kidneys filter 160 g of glucose daily in healthy subjects under euglycaemic conditions. The expanding epidemic of diabetes leads to a prevalence of diabetes-related cardiovascular disorders, in particular, heart failure and renal dysfunction. Cellular glucose uptake is a fundamental process for homeostasis, growth, and metabolism. In humans, three families of glucose transporters have been identified, including the glucose facilitators GLUTs, the sodium-glucose cotransporter SGLTs, and the recently identified SWEETs. Structures of the major isoforms of all three families were studied. Sodium-glucose cotransporter (SGLT2) provides most of the capacity for renal glucose reabsorption in the early proximal tubule. A number of cardiovascular outcome trials in patients with type 2 diabetes have been studied with SGLT2 inhibitors reducing cardiovascular morbidity and mortality. : The current review article summarises these aspects and discusses possible mechanisms with SGLT2 inhibitors in protecting heart failure and renal dysfunction in diabetic patients. Through glucosuria, SGLT2 inhibitors reduce body weight and body fat, and shift substrate utilisation from carbohydrates to lipids and, possibly, ketone bodies. These pleiotropic effects of SGLT2 inhibitors are likely to have contributed to the results of the EMPA-REG OUTCOME trial in which the SGLT2 inhibitor, empagliflozin, slowed down the progression of chronic kidney disease and reduced major adverse cardiovascular events in high-risk individuals with type 2 diabetes. This review discusses the role of SGLT2 in the physiology and pathophysiology of renal glucose reabsorption and outlines the unexpected logic of inhibiting SGLT2 in the diabetic kidney.

scholarly journals Mitigation of the Adverse Consequences of Nutrient Excess on the Kidney: A Unified Hypothesis to Explain the Renoprotective Effects of Sodium-Glucose Cotransporter 2 Inhibitors

2020 ◽  
Vol 51 (4) ◽  
pp. 289-293 ◽  
Author(s):  
Milton Packer
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Renin Angiotensin System ◽  
Tissue Expansion ◽  
Adenosine Monophosphate ◽  
Sglt2 Inhibitors ◽  
Sirtuin 1 ◽  
Glomerular Hyperfiltration ◽  
Sodium Glucose Cotransporter

The 2 most common causes of chronic kidney disease worldwide (type 2 diabetes and obesity) are states of nutrient excess, suggesting that fuel overabundance leads to deleterious effects on the structure and function of the kidneys. Three pathophysiological pathways may potentially explain this linkage. First, both obesity and type 2 diabetes are characterized by glomerular hyperfiltration, which may result from increased proximal tubular reabsorption of sodium (due to enhanced glucose and sodium transport) coupled with activation of the renin-angiotensin system. Second, both obesity and type 2 diabetes are characterized by adipose tissue expansion and inflammation, followed by the augmented synthesis and release of lipid intermediates and proinflammatory adipocytokines that can have deleterious effects on the kidney. Third, states of nutrient excess cause a diminution in the activation of the energy sensors, sirtuin-1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK). The result is a suppression of autophagy, a lysosomal degradative pathway that is responsible for the clearance of damaged organelles that are an important source of oxidative and endoplasmic reticulum stress and inflammation. Sodium-glucose cotransporter 2 (SGLT2) inhibitors induces a transcriptional paradigm that mimics fasting, which leads to the amelioration of glomerular hyperfiltration and adipose tissue inflammation as well as augmentation of AMPK/SIRT1 signaling and autophagy, thereby acting to mute organellar and cellular stress in the kidney. Therefore, SGLT2 inhibitors are positioned to antagonize all 3 pathways by which nutrient excess can lead to nephropathy.

scholarly journals Impact of sodium–glucose cotransporter 2 inhibitors on renal function in participants with type 2 diabetes and chronic kidney disease with normoalbuminuria

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Akinobu Nakamura ◽  
Hideaki Miyoshi ◽  
Hiraku Kameda ◽  
Kumiko Yamashita ◽  
Yoshio Kurihara
Keyword(s):  
Type 2 Diabetes ◽  
Chronic Kidney Disease ◽  
Renal Function ◽  
Kidney Disease ◽  
Sglt2 Inhibitor ◽  
Sglt2 Inhibitors ◽  
Creatinine Ratio ◽  
Sodium Glucose Cotransporter ◽  
Clinical Records

Abstract Background We compared the effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors on renal function in participants with type 2 diabetes and chronic kidney disease (CKD) classified by degree of albuminuria. Methods A retrospective review of the clinical records of Japanese participants with type 2 diabetes (age > 20 years; SGLT2 inhibitor treatment > 2 years; estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2) was conducted. Based on the urinary albumin-to-creatinine ratio (UACR) or urinary protein-to-creatinine ratio (UPCR) at the start of SGLT2 inhibitor administration, participants were categorized into three groups: normoalbuminuria (A1; UACR < 30 mg/g Cr or UPCR < 0.15 g/g Cr), microalbuminuria (A2; UACR 30 to < 300 mg/g Cr or UPCR 0.15 to < 0.50 g/g Cr), and macroalbuminuria (A3; UACR ≥ 300 mg/g Cr or UPCR ≥ 0.50 g/g Cr). The study outcome was a comparison of the rates of change in renal function evaluated by eGFR at 2 years after starting SGLT2 inhibitor among the three groups. Results A total of 87 participants (40 females, 47 males) were categorized into three groups: A1 (n = 46), A2 (n = 25), and A3 (n = 16). eGFR was similarly decreased at 2 years before starting SGLT2 inhibitor in all three groups. However, the decline in eGFR was ameliorated at 2 years after starting SGLT2 inhibitor, and eGFR was rather increased in the A1 and A2 groups. Interestingly, the rate of change in eGFR at 2 years after starting SGLT2 inhibitor in the A1 group was significantly higher than that in the A3 group. Conclusions These results demonstrate that more favorable effects of SGLT2 inhibitors on renal function were observed in participants with type 2 diabetes and CKD with normoalbuminuria compared with those with macroalbuminuria. Trial registration UMIN-CTR: UMIN000035263. Registered 15 December 2018

scholarly journals Cohort profile for the MASTERMIND study: using the Clinical Practice Research Datalink (CPRD) to investigate stratification of response to treatment in patients with type 2 diabetes

BMJ Open ◽  
2017 ◽  
Vol 7 (10) ◽  
pp. e017989 ◽  
Author(s):  
Lauren R Rodgers ◽  
Michael N Weedon ◽  
William E Henley ◽  
Andrew T Hattersley ◽  
Beverley M Shields
Keyword(s):  
Type 2 Diabetes ◽  
Clinical Practice ◽  
Treatment Response ◽  
Response To Treatment ◽  
Practice Research ◽  
Clinical Practice Research Datalink ◽  
Data Quality Control ◽  
Data Set ◽  
The Impact

PurposeThis is a retrospective cohort study using observational data from anonymised primary care records. We identify and extract all patients with type 2 diabetes and associated clinical data from the Clinical Practice Research Datalink (CPRD) to inform models of disease progression and stratification of treatment.ParticipantsData were extracted from CPRD on 8 August 2016. The initial data set contained all patients (n=313 485) in the database who had received a type 2 diabetes medication. Criteria were applied to identify and exclude those with type 1 diabetes, polycystic ovarian syndrome or other forms of diabetes (n=40 204), and for data quality control (n=12). We identified 251 338 patients for inclusion in future analyses of diabetes progression and treatment response.Findings to dateFor 6-month response to treatment, measured by change in glycated haemoglobin (HbA1c), we have 91 765 patients with 119 785 treatment response episodes. The greatest impact on reduction of HbA1c occurs with first-line and second-line treatments, metformin and sulfonylurea. Patients moving to third-line treatments tend to have greater weights and higher body mass index. We have investigated the impact of non-adherence to commonly used glucose-lowering medications on HbA1c. For baseline-adjusted HbA1c change over 1 year, non-adherent patients had lower HbA1c reductions than adherent patients, with mean and 95% CI of −4.4 (−4.7 to −4.0) mmol/mol (−0.40 (−0.43 to −0.37) %).Future plansFindings from studies using these data will help inform future treatment plans and guidelines. Additional data are added with updates from CPRD. This will increase the numbers of patients on newer medications and add more data on those already receiving treatment. There are several ongoing studies investigating different hypotheses regarding differential response to treatment and progression of diabetes. For side effects, links to Hospital Episode Statistics data, where severe events such as hypoglycaemia will be recorded, will also be explored.

scholarly journals Effects of SGLT2 Inhibitors on Circulating Stem and Progenitor Cells in Patients With Type 2 Diabetes

2018 ◽  
Vol 103 (10) ◽  
pp. 3773-3782 ◽  
Author(s):  
Benedetta Maria Bonora ◽  
Roberta Cappellari ◽  
Mattia Albiero ◽  
Angelo Avogaro ◽  
Gian Paolo Fadini
Keyword(s):  
Type 2 Diabetes ◽  
Placebo Group ◽  
Progenitor Cells ◽  
Sglt2 Inhibitors ◽  
Open Label ◽  
Sodium Glucose Cotransporter ◽  
Open Label Extension ◽  
Stem And Progenitor Cells ◽  
Extension Period

Abstract Context Reduction in the levels of circulating stem cells (CSCs) and endothelial progenitor cells (EPCs) predicts development or progression of microangiopathy and macroangiopathy in patients with type 2 diabetes (T2D). Objective We tested whether treatment with sodium glucose cotransporter-2 (SGLT2) inhibitors affected the levels of CSCs and EPCs. Design A randomized trial of dapagliflozin vs placebo with open-label extension, and an open-label observational study of empagliflozin treatment. Setting Tertiary referral diabetes outpatient clinic. Patients Patients with T2D aged 18 to 75 years. Intervention Dapagliflozin at 10 mg vs placebo (n = 31); empagliflozin at 10 mg (n = 15). Main Outcome Measures We measured CSCs (CD34+) and EPCs (CD34+KDR+) by flow cytometry at baseline, at 12 weeks, and after the extension period. Results After 12 weeks, CSCs declined nonsignificantly in the dapagliflozin group, remained stable in the placebo group, and the change from baseline was not significantly different between the two groups. EPCs declined nonsignificantly in the dapagliflozin group, increased nonsignificantly in the placebo group, and the change from baseline was significantly different between the two groups. After an open-label extension period of about 1.5 years, CSCs remained stable over time, whereas EPCs significantly increased in patients who received dapagliflozin. In all patients, irrespectively of treatment, EPCs increased significantly from baseline to the end of observation, concomitantly with improvement in HbA1c. In a cohort of 15 patients who received open-label empagliflozin for 12 weeks, CSCs declined nonsignificantly, whereas EPCs remained stable. Conclusion SGLT2 inhibitors do not significantly increase CSCs or EPCs. Thus, cardiovascular protection by SGLT2 inhibitors may not directly involve stem/progenitor cells.

scholarly journals Effects of SGLT2 Inhibitors beyond Glycemic Control—Focus on Myocardial SGLT1

2021 ◽  
Vol 22 (18) ◽  
pp. 9852
Author(s):  
Alex Ali Sayour ◽  
Mihály Ruppert ◽  
Attila Oláh ◽  
Kálmán Benke ◽  
Bálint András Barta ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Large Scale ◽  
Sglt2 Inhibitor ◽  
Basic Research ◽  
Additional Benefit ◽  
Sglt2 Inhibitors ◽  
Preclinical Studies ◽  
Sodium Glucose Cotransporter

Selective sodium–glucose cotransporter 2 (SGLT2) inhibitors reduced the risk of hospitalization for heart failure in patients with or without type 2 diabetes (T2DM) in large-scale clinical trials. The exact mechanism of action is currently unclear. The dual SGLT1/2 inhibitor sotagliflozin not only reduced hospitalization for HF in patients with T2DM, but also lowered the risk of myocardial infarction and stroke, suggesting a possible additional benefit related to SGLT1 inhibition. In fact, several preclinical studies suggest that SGLT1 plays an important role in cardiac pathophysiological processes. In this review, our aim is to establish the clinical significance of myocardial SGLT1 inhibition through reviewing basic research studies in the context of SGLT2 inhibitor trials.

scholarly journals Pharmacoeconomic evaluation of ipragliflozin in combination with metformin in comparison with other regimens of therapy for type 2 diabetes mellitus

2021 ◽  
pp. 50-63
Author(s):  
A. S. Kolbin ◽  
A. A. Kurylev ◽  
Yu. E. Balykina ◽  
M. A. Proskurin
Keyword(s):  
Type 2 Diabetes ◽  
Cost Effectiveness ◽  
Weighted Average ◽  
Sglt2 Inhibitors ◽  
Cost Effectiveness Ratio ◽  
Glucose Lowering ◽  
Lowering Therapy ◽  
Sodium Glucose Cotransporter ◽  
Glucose Lowering Therapy

Ipragliflozin is a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor that reduce plasma glucose concentrations by inhibiting glucose reabsorption by the kidney through inhibiting SGLT2 sodium-glucose cotransporter and induce glycosuria. SGLT2 inhibitors are a new class of glucose lowering drugs most recently approved for treatment of type 2 diabetes mellitus (T2DM). Unlike other antidiabetic agents, SGLT2 inhibitors improve glycemic control (by HbA1c) and provide multiple additional benefits, including decreased body weight, blood pressure, and other multiple pleiotropic effects. The completed clinical trials and real world data have provided evidence that including of SGLT2 inhibitors in the treatment of T2DM has benefits of reduction of cardiovascular and renal outcomes. Goal. The aim of the study was to conduct a clinical and economic examination of ipragliflozin in comparison with other regimens of glucose-lowering therapy with other SGLT2 inhibitors. Methods. In carrying out the pharmacoeconomic analysis itself, a cost-effectiveness analysis (CEA) was applied with the calculation of the corresponding cost-effectiveness ratio (CER), incremental cost-effectiveness ratio (ICER) according to the formula, as well as an a «budget impact analysis». Multiple one-way sensitivity analysis, check the robustness of the results of the main scenario results to changes in key parameters such as the cost of drugs and complications of diabetes. The time horizon for analyzing the dynamics of economic consequences when using ipragliflozin as a glucose-lowering therapy for T2DM was 5 years. Results. The weighted average cost per patient per year when using the ipragliflozin treatment strategy is 31,182 rubles. The costs of the empagliflozin strategy are 61,291 rubles per patient. In the case of using dapagliflozin, the weighted average costs are 30,032 rubles per patient per year, the total direct medical costs for the current drug therapy option, calculated on the initial number of target practice in 72,143 patients with type 2 diabetes, amounted to 3,068,642,442 rubles. Analysis of the trend of changes in weighted average costs showed that the broader use of ipragliflozin for the treatment of T2DM in the target population leads to reducing in diabetes related direct medical costs by 6.7 %, while the total economic effect of ipragliflozin introduction over five years will be 501,539,327 rubles. Conclusions. Use of ipragliflozin + metformin in T2DM treatment is a cost-effective strategy compared to empagliflozin + metformin. The combination of ipragliflozin with metformin versus dapagliflozin + metformin is economically feasible in terms of cost-effectiveness.

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