Cardiorenal Protection: Potential of SGLT2
Inhibitors and GLP-1 Receptor Agonists in the Treatment of Type 2
Diabetes

Nagahisa, Taichi; Saisho, Yoshifumi

doi:10.1007/s13300-019-00680-5

Cited by 54 publications

(55 citation statements)

References 104 publications

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“…Proposed mechanisms for GLP-1 RA include an anti-atherothrombotic effect, as well as amelioration of inflammatory markers, resulting in the enhanced retardation of atherosclerosis [ 59 , 60 ], together with an antihypertensive effect [ 61 ]. This may occur via antiproliferative actions on vascular smooth muscle cells and endothelial cells, reductions in oxidative stress, and increases in nitric oxide generation, microvascular recruitment and microvascular blood flow [ 61 ].…”

Section: Out Of Step With the Evidence: The Cvot-shaped Hole In Diabementioning

confidence: 99%

Worldwide inertia to the use of cardiorenal protective glucose-lowering drugs (SGLT2i and GLP-1 RA) in high-risk patients with type 2 diabetes

Schernthaner

Shehadeh

Аметов

et al. 2020

Cardiovasc Diabetol

115

108

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The disclosure of proven cardiorenal benefits with certain antidiabetic agents was supposed to herald a new era in the management of type 2 diabetes (T2D), especially for the many patients with T2D who are at high risk for cardiovascular and renal events. However, as the evidence in favour of various sodium–glucose transporter-2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) accumulates, prescriptions of these agents continue to stagnate, even among eligible, at-risk patients. By contrast, dipeptidyl peptidase-4 inhibitors (DPP-4i) DPP-4i remain more widely used than SGLT2i and GLP-1 RA in these patients, despite a similar cost to SGLT2i and a large body of evidence showing no clear benefit on cardiorenal outcomes. We are a group of diabetologists united by a shared concern that clinical inertia is preventing these patients from receiving life-saving treatments, as well as placing them at greater risk of hospitalisation for heart failure and progression of renal disease. We propose a manifesto for change, in order to increase uptake of SGLT2i and GLP-1 RA in appropriate patients as a matter of urgency, especially those who could be readily switched from an agent without proven cardiorenal benefit. Central to our manifesto is a shift from linear treatment algorithms based on HbA1c target setting to parallel, independent considerations of atherosclerotic cardiovascular disease, heart failure and renal risks, in accordance with newly updated guidelines. Finally, we call upon all colleagues to play their part in implementing our manifesto at a local level, ensuring that patients do not pay a heavy price for continued clinical inertia in T2D.

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Section: Out Of Step With the Evidence: The Cvot-shaped Hole In Diabementioning

confidence: 99%

Worldwide inertia to the use of cardiorenal protective glucose-lowering drugs (SGLT2i and GLP-1 RA) in high-risk patients with type 2 diabetes

Schernthaner

Shehadeh

Аметов

et al. 2020

Cardiovasc Diabetol

115

108

View full text Add to dashboard Cite

show abstract

“…Meanwhile SGLT2 inhibitors manifested clinical supremacy regarding hyperglycemia, visceral adiposity, and body weight. In addition, they ameliorate other metabolic problems come in line with high blood pressure, risky lipid profile, or uric acid level [ 73 ]. Cardiovascular outcome trials (CVOTs) of SGLT2 inhibitors showed better outcomes in diabetic or even nondiabetic patients [ 74 , 75 ].…”

Section: Resultsmentioning

confidence: 99%

Repurposing of Omarigliptin as a Neuroprotective Agent Based on Docking with A2A Adenosine and AChE Receptors, Brain GLP-1 Response and Its Brain/Plasma Concentration Ratio after 28 Days Multiple Doses in Rats Using LC-MS/MS

et al. 2021

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The authors in the current work suggested the potential repurposing of omarigliptin (OMR) for neurodegenerative diseases based on three new findings that support the preliminary finding of crossing BBB after a single dose study in the literature. The first finding is the positive results of the docking study with the crystal structures of A2A adenosine (A2AAR) and acetylcholine esterase (AChE) receptors. A2AAR is a member of non-dopaminergic GPCR superfamily receptor proteins and has essential role in regulation of glutamate and dopamine release in Parkinson’s disease while AChE plays a major role in Alzheimer’s disease as the primary enzyme responsible for the hydrolytic metabolism of the neurotransmitter acetylcholine into choline and acetate. Docking showed that OMR perfectly fits into A2AAR binding pocket forming a distinctive hydrogen bond with Threonine 256. Besides other non-polar interactions inside the pocket suggesting the future of the marketed anti-diabetic drug (that cross BBB) as a potential antiparkinsonian agent while OMR showed perfect fit inside AChE receptor binding site smoothly because of its optimum length and the two fluorine atoms that enables quite lean fitting. Moreover, a computational comparative study of OMR docking, other 12 DPP-4 inhibitors and 11 SGLT-2 inhibitors was carried out. Secondly, glucagon-like peptide-1 (GLP-1) concentration in rats’ brain tissue was determined by the authors using sandwich GLP-1 ELISA kit bio-analysis to ensure the effect of OMR after the multiple doses’ study. Brain GLP-1 concentration was elevated by 1.9-fold following oral multiple doses of OMR (5 mg/kg/day, p.o. for 28 days) as compared to the control group. The third finding is the enhanced BBB crossing of OMR after 28 days of multiple doses that had been studied using LC-MS/MS method with enhanced liquid–liquid extraction. A modified LC-MS/MS method was established for bioassay of OMR in rats’ plasma (10–3100 ng/mL) and rats’ brain tissue (15–2900 ng/mL) using liquid–liquid extraction. Alogliptin (ALP) was chosen as an internal standard (IS) due to its LogP value of 1.1, which is very close to the LogP of OMR. Extraction of OMR from samples of both rats’ plasma and rats’ brain tissue was effectively achieved with ethyl acetate as the extracting solvent after adding 1N sodium carbonate to enhance the drug migration, while choosing acetonitrile to be the diluent solvent for the IS to effectively decrease any emulsion between the layers in the stated method of extraction. Validation results were all pleasing including good stability studies with bias of value below 20%. Concentration of OMR in rats’ plasma were determined after 2 h of the latest dose from 28 days multiple doses, p.o, 5 mg/kg/day. It was found to be 1295.66 ± 684.63 ng/mL estimated from the bio-analysis regression equation. OMR passed through the BBB following oral administration and exhibited concentration of 543.56 ± 344.15 ng/g in brain tissue, taking in consideration the dilution factor of 10. The brain/plasma concentration ratio of 0.42 (543.56/1295.66) was used to illustrate the penetration power through the BBB after the multiple doses for 28 days. Results showed that OMR passed through the BBB more effectively in the multiple dose study as compared to the previously published single dose study by the authors. Thus, the present study suggests potential repositioning of OMR as antiparkinsonian agent that will be of interest for researchers interested in neurodegenerative diseases.

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“…1,3 Evidence and Representation The 2 clinical pathways for persons with ASCVD or either CKD or HF are supported by a number of placebo-controlled trials for individual SGLT2 and GLP-1 medications. 4,5,6 By contrast, the literature guiding treatment of persons with type 2 diabetes without ASCVD, CKD, or HF is relatively weak. Most studies comparing drug classes to one another are of short duration, rely on surrogate outcomes, and are industry funded.…”

Section: Recommendations and Pathwaysmentioning

confidence: 99%

Should Clinical Guidelines Incorporate Cost Pathways for Persons With Financial Hardship?

2021

AMA Journal of Ethics

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The American Diabetes Association 2020 Standards of Care for the treatment of hyperglycemia in type 2 diabetes includes a treatment pathway when "cost is a major issue." This pathway recommends use of 2 generic drug classes, thereby codifying differential treatment for those with financial hardship. This article explores 4 implications of incorporating the cost pathway into clinical recommendations: (1) the presence of a cost pathway might create the appearance of an evidencebased quality difference through activation of implicit bias; (2) screening for financial hardship to guide therapy has potential harms for patients; (3) concern that financial hardship warrants differing care might impact overall quality of care and patient-clinician relationships; and (4) applying the guidelines when caring for patients with financial hardship might demoralize clinicians. To claim one AMA PRA Category 1 Credit TM for the CME activity associated with this article, you must do the following: (1) read this article in its entirety, (2) answer at least 80 percent of the quiz questions correctly, and (3) complete an evaluation. The quiz, evaluation, and form for claiming AMA PRA Category 1 Credit TM are available through the AMA Ed Hub TM .

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Cardiorenal Protection: Potential of SGLT2 Inhibitors and GLP-1 Receptor Agonists in the Treatment of Type 2 Diabetes

Cited by 54 publications

References 104 publications

Worldwide inertia to the use of cardiorenal protective glucose-lowering drugs (SGLT2i and GLP-1 RA) in high-risk patients with type 2 diabetes

Worldwide inertia to the use of cardiorenal protective glucose-lowering drugs (SGLT2i and GLP-1 RA) in high-risk patients with type 2 diabetes

Repurposing of Omarigliptin as a Neuroprotective Agent Based on Docking with A2A Adenosine and AChE Receptors, Brain GLP-1 Response and Its Brain/Plasma Concentration Ratio after 28 Days Multiple Doses in Rats Using LC-MS/MS

Should Clinical Guidelines Incorporate Cost Pathways for Persons With Financial Hardship?

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