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1.
Evaluating the effects of sodium glucose co-transporter -2 inhibitors from a renin-angiotensin-aldosterone system perspective in patients infected with COVID-19: contextualizing findings from the dapagliflozin in respiratory failure in patients with COVID-19 study.
Moustafa, DA, Imran, Z, Ismail, R, Rayan, M, Gadeau, AP, Eldassouki, H, Abdulrahman, N, Mraiche, F
Molecular biology reports. 2022;(3):2321-2324
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Abstract
Numerous studies demonstrate parallels between CVD, type 2 diabetes mellitus (T2DM) and COVID-19 pathology, which accentuate pre-existing complications in patients infected with COVID-19 and potentially exacerbate the infection course. Antidiabetic drugs such as sodium-glucose transporter-2 (SGLT-2) inhibitors have garnered substantial attention recently due to their efficacy in reducing the severity of cardiorenal disease. The effect of SGLT-2 inhibitors in patients with COVID-19 remains unclear particularly since SGLT-2 inhibitors contribute to altering the RAAS cascade activity, which includes ACE-2, the major cell entry receptor for SARS-CoV2. A study, DARE-19, was carried out to unveil the effects of SGLT-2 inhibitor treatment on comorbid disease complications and concomitant COVID-19 outcomes and demonstrated no statistical significance. However, the need for further studies is essential to provide conclusive clinical findings.
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Severe euglycemic diabetic ketoacidosis of multifactorial etiology in a type 2 diabetic patient treated with empagliflozin: case report and literature review.
Sampani, E, Sarafidis, P, Dimitriadis, C, Kasimatis, E, Daikidou, D, Bantis, K, Papanikolaou, A, Papagianni, A
BMC nephrology. 2020;(1):276
Abstract
BACKGROUND Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are a relatively novel class of oral medications for the treatment of Type 2 DM with a generally acceptable safety profile. However, these agents have been associated with rare events of a serious and potentially life-threatening complication named euglycemic diabetic ketoacidosis (euDKA). euDKA is not identical with the typical diabetic ketoacidosis, as it often presents with serious metabolic acidosis but only mild to moderate glucose and anion gap elevation. CASE PRESENTATION We report a case of a 51-year old female with Type 2 DM treated with an SGLT-2 inhibitor, developing severe metabolic acidosis with only mild blood glucose elevation after a routine surgery. A careful evaluation of involved factors led to the diagnosis of euDKA, followed by cautious application of simple therapeutic measures that resulted in complete restoration of acidosis and glycemic control in less than 48-h. CONCLUSIONS Euglycemic ketoacidosis is a rare but rather serious complication of SGLT-2 inhibitors use, often with a multifactorial etiology. Its atypical presentation requires a high level of awareness by physicians as early recognition of this complication can quickly and safely restore acid-base balance.
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United States Pharmacopeia Safety Review of Willow Bark.
Oketch-Rabah, HA, Marles, RJ, Jordan, SA, Low Dog, T
Planta medica. 2019;(16):1192-1202
Abstract
Willow bark (Salix spp.) is an ingredient in some dietary supplements. No serious adverse effects were reported from trials of willow bark extracts delivering 120 - 240 mg salicin (the purported active constituent) daily for up to 8 weeks. All studies involved adults only; none involved special subpopulations such as pregnant or breastfeeding women, or children. The most common adverse effects associated with willow bark are gastrointestinal; a few allergic reactions were also reported. Some publications advise caution when taking willow bark. There is a risk of increased bleeding in vulnerable individuals, salicylates cross the placenta and are eliminated slowly in newborns, some persons are sensitive or allergic to aspirin, and children are at risk of Reye syndrome. Concurrent use with other salicylate-containing medicines increases these risks. Metabolism of 240 mg salicin from willow bark could yield 113 mg of salicylic acid, yet dietary supplement products are not required to be labeled with warnings. In contrast, over-the-counter low-dose aspirin (81 mg strength), which delivers 62 mg salicylic acid, is required by law to include cautions, warnings, and contraindications related to its use in pregnant and nursing women, children, and other vulnerable subpopulations, e.g., those using anticoagulants. In the interest of protecting public health, the United States Pharmacopeia has included a cautionary labeling statement in the United States Pharmacopeia Salix Species monograph as follows: "Dosage forms prepared with this article should bear the following statement: 'Not for use in children, women who are pregnant or nursing, or by persons with known sensitivity to aspirin.'".
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Effect of empagliflozin beyond glycemic control: Cardiovascular benefit in patients with type 2 diabetes and established cardiovascular disease.
Monteiro, P, Aguiar, C, Matos, P, Silva-Nunes, J, Birne, R, Branco, P, Calado, J, Melo, M, Polónia, J
Revista portuguesa de cardiologia. 2019;(10):721-735
Abstract
The prevalence of type 2 diabetes (T2D) continues to increase, and its association with cardiovascular (CV) disease has led to the inclusion of CV endpoints in clinical trials on the treatment of T2D. This article explores the various trials already performed and under development in this field, with particular focus on the EMPA-REG OUTCOME trial. In this trial, empagliflozin, a sodium-glucose co-transporter 2 inhibitor, demonstrated a reduction in CV risk in patients with T2D and established CV disease, in addition to CV safety and a decrease in glycated hemoglobin. This represents a paradigm shift that has led to changes in the international guidelines for the treatment of T2D. These results were maintained in subsequent subgroup analysis for heart failure, chronic kidney disease and peripheral arterial disease, although there are many questions concerning the mechanisms involved in these effects, including whether they are hemodynamic, metabolic or due to decreased myocardial cytoplasmic sodium concentrations. With this reduction in risk for major CV events in patients with T2D, the EMPA-REG OUTCOME trial demonstrated CV protection from a hypoglycemic drug for the first time, and opened a new era in the treatment and management of T2D. This study has led to the development of ongoing trials that will establish which patients will benefit most from this therapy, particularly with regard to comorbidities.
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Sodium-glucose cotransporter-2 inhibitors induced eu-glycemic diabetic ketoacidosis: The first report in a type 2 diabetic (T2D) Taiwanese and literature review of possible pathophysiology and contributing factors.
Lin, YH
Journal of the Formosan Medical Association = Taiwan yi zhi. 2018;(9):849-854
Abstract
Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are the newest class of oral antidiabetic drugs (OADs), approved to be a second-line OAD for type 2 diabetes in Taiwan since 2016. The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) had both released statements associating the use of SGLT-2 inhibitors may increase the risk of eu-glycemic diabetic ketoacidosis (euDKA). This review reveals the possible pathophysiology with a chain of metabolic adaptions to decrease plasma glucose and increase plasma ketone bodies through pancreas, kidney, liver and adipose tissue. Moreover, euDKA is a potential and rare complication of treatment with SGLT-2 inhibitors when coexisting with triggering factors. It is an emerging challenge for clinical physicians and patients treated with SGLT-2 inhibitors. Therefore, first report of SGLT-2 inhibitor induced euDKA in a T2D Taiwanese and literature review of possible pathophysiology and contributing factors are presented in order to make more attentions in public.
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A systemic review and meta-analysis of the clinical efficacy and safety of total glucosides of peony combined with methotrexate in rheumatoid arthritis.
Feng, ZT, Xu, J, He, GC, Cai, SJ, Li, J, Mei, ZG
Clinical rheumatology. 2018;(1):35-42
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Abstract
To assess the efficacy and safety of the combination of total glucoside of peony (TGP) and methotrexate (MTX) for the treatment of rheumatoid arthritis (RA). Randomized controlled trial (RCT) data on the traditional Chinese active component TGP combined with MTX vs. MTX alone for the treatment of RA was collected by searching the Pubmed, Embase, Cochrane Library, CNKI, VIP Journals database, and Wanfang database up to February 2017. Study selection, data extraction, data synthesis, and data analyses were performed according to the Cochrane standards. A total of eight RCTs involving 522 participants were included in this meta-analysis. Compared with MTX alone, the use of TGP combined with MTX exhibited better therapeutic effects for the treatment of RA (P = 0.004). In addition, TGP combined with MTX caused a more significant decrease in erythrocyte sedimentation rate (ESR) (P < 0.0001) and swollen joint count (SJC) (P < 0.00001). However, no significant differences were found in C-reactive protein (CRP) (P = 0.19), duration of morning stiffness (DMS) (P = 0.32), or tender joint count (TJC) (P = 0.23) between the two groups. In addition, adverse events were more frequently reported in the MTX monotherapy group than in the TGP and MTX combination group (P = 0.0007). Our study demonstrates that TGP combined with MTX is more effective than MTX alone for the treatment of RA. Nevertheless, the adverse effects of the combination of TGP and MTX need to be further assessed. Due to the poor methodological quality of included trials, well-designed, multi-center, and large-scale RCTs are necessary to draw a more definitive conclusion.
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Dapagliflozin in patients with type 2 diabetes mellitus: A pooled analysis of safety data from phase IIb/III clinical trials.
Jabbour, S, Seufert, J, Scheen, A, Bailey, CJ, Karup, C, Langkilde, AM
Diabetes, obesity & metabolism. 2018;(3):620-628
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Abstract
AIM: To evaluate the safety and tolerability of dapagliflozin, a highly selective sodium-glucose co-transporter-2 inhibitor, in patients with type 2 diabetes mellitus (T2DM). METHODS Data were pooled from 13 placebo-controlled trials of up to 24 weeks' duration (dapagliflozin, n = 2360; placebo, n = 2295). Larger placebo-/comparator-controlled pools of 21 (≤208 weeks; dapagliflozin, n = 5936; control, n = 3403) and 30 trials (≥12 weeks; dapagliflozin, n = 9195; control, n = 4629) assessed the rare adverse events (AEs) of diabetic ketoacidosis (DKA) and lower limb amputation, respectively. RESULTS Over 24 weeks, the overall incidence of AEs and serious AEs (SAEs) was similar for dapagliflozin and placebo: 60.0% vs 55.7% and 5.1% vs 5.4%, respectively. Rates of hypoglycaemia, volume depletion AEs, urinary tract infections (UTIs) and fractures were balanced between the groups. Genital infections were more frequent with dapagliflozin (5.5%) vs placebo (0.6%) and renal function AEs occurred in 3.2% vs 1.8% of patients (the most common renal AE was decreased creatinine clearance: 1.1% vs 0.7%). In the 21-study pool, 1 SAE of DKA and 3 AEs of ketonuria/metabolic acidosis occurred with dapagliflozin vs none with control; estimated combined incidence for these events was 0.03% (95% confidence interval 0.010-0.089). In the 30-study pool, lower limb amputation occurred in 8 (0.1%) and 7 (0.2%) patients receiving dapagliflozin and control, respectively. CONCLUSION The overall incidence rates of AEs and SAEs were similar in the dapagliflozin and placebo/control groups, including the incidence of hypoglycaemia, volume depletion, fractures, UTIs, amputations and DKA. Genital infections were more frequent with dapagliflozin than placebo.
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EMPA-REG OUTCOME: The Endocrinologist's Point of View.
Perreault, L
The American journal of cardiology. 2017;(1S):S48-S52
Abstract
For many years, it was widely accepted that control of plasma lipids and blood pressure could lower macrovascular risk in patients with type 2 diabetes mellitus (T2DM), whereas the benefits of lowering plasma glucose were largely limited to improvements in microvascular complications. The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME) study demonstrated for the first time that a glucose-lowering agent, the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin, could reduce major adverse cardiovascular events, cardiovascular mortality, hospitalization for heart failure, and overall mortality when given in addition to standard care in patients with T2DM at high cardiovascular risk. These results were entirely unexpected and have led to much speculation regarding the potential mechanisms underlying cardiovascular benefits. In this review, the results of EMPA-REG OUTCOME are summarized and put into perspective for the endocrinologist who is treating patients with T2DM and cardiovascular disease.
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Cardiovascular Protection by Sodium Glucose Cotransporter 2 Inhibitors: Potential Mechanisms.
Staels, B
The American journal of cardiology. 2017;(1S):S28-S36
Abstract
The mechanism of action of empagliflozin in reducing the risk of adverse cardiovascular outcomes vs placebo in patients with type 2 diabetes mellitus and a high risk of cardiovascular disease in the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME) trial is currently unknown. An antiatherosclerotic effect is considered unlikely given the speed of the observed decrease in cardiovascular mortality. Hemodynamic effects, such as reductions in blood pressure and intravascular volume, and involving osmotic diuresis, may provide a more plausible explanation. Metabolic effects, such as cardiac fuel energetics, and hormonal effects, such as increased glucagon release, may also contribute to the results observed during EMPA-REG OUTCOME. This review discusses the main hypotheses suggested to date.
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EMPA-REG OUTCOME: The Cardiologist's Point of View.
Pham, SV, Chilton, RJ
The American journal of cardiology. 2017;(1S):S53-S58
Abstract
Cardiologists could view empagliflozin as a cardiovascular drug that also has a beneficial effect on reducing hyperglycemia in patients with type 2 diabetes mellitus (T2DM). The effects of empagliflozin in lowering the risk of cardiovascular death and hospitalization for heart failure in T2DM patients with high cardiovascular risk during the recent Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME) trial may be explained principally in terms of changes to cardiovascular physiology; namely, by the potential ability of empagliflozin to reduce cardiac workload and myocardial oxygen consumption by lowering blood pressure, improving aortic compliance, and improving ventricular arterial coupling. These concepts and hypotheses are discussed in this report.