ArticleLiterature Review
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Abstract

Diabetes, characterized by high glucose levels, has been listed to be one of the world's major causes of death. Around 1.6 million deaths are attributed to this disease each year. Persistent hyperglycemic conditions in diabetic patients affect various organs of the body leading to diabetic complications and worsen the disease condition. Current treatment strategies for diabetes include biguanides, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, insulin and its analogs, DPP-4(dipeptidyl peptidase-4) and GLP-1 (glucagon-like peptide) analogs. However, many side effects contributing to the devastation of the disease are associated with them. Sodium glucose co-tranporter-2 (SGLT2) inhibition has been reported to be new insulin-independent approach to diabetes therapy. It blocks glucose uptake in the kidneys by inhibiting SGLT2 transporters, thereby promoting glycosuria. Dapagliflozin, empagliflozin and canagliflozin are the most widely used SGLT2 inhibitors. They are effective in controlling blood glucose and HbA1c levels with no side effects including hypoglycemia or weight gain which makes them preferable to other anti-diabetic drugs. However, treatment is found to be associated with inter-individual drug response to SGLT2 inhibitors and adverse drug reactions which are also affected by genetic variations. There have been very few pharmacogenetics trials of these drugs. This review discusses the various SGLT2 inhibitors, their pharmacokinetics, pharmacodynamics and genetic variation influencing the inter-individual drug response.

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... SGLT2-i bekerja dengan menghambat reabsorpsi glukosa pada tubulus kontortus proksimal dan terjadi ekskresi glukosa (gambar 2) melalui urin hingga 80gr/hari. [7,8] Peningkatan eksresi glukosa urin ini menyebabkan penurunan glukosa plasma darah. [9] Mekanisme obat ini membantu untuk mengontrol kadar gula darah termasuk penurunan HbA1c melalui mekanisme glukosuria pada pasien. ...
... Gambar 2. Reabsorbsi Glukosa melalui SGLT2 pada kondisi normal dan Kondisi adanya SGLT-2 inhibitor.[8] Penggunaan SGLT2-i Sebagai Inovasi Terapi Preventif Stroke Pada Pasien Diabetes Mellitus Tipe 2 ...
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Diabetes merupakan faktor resiko stroke iskemik sebesar 2,5 kali dan 1,5 kali lipat menderita stroke hemoragik. Hal ini memicu meningkatnya angka mortalitas baik yang disebabkan oleh diabetes, stroke maupun diabetes yang berkomplikasi pada stroke. Sodium Glucose cotransporter 2 inhibitor (SGLT2-i) diketahui dapat mengurangi permasalahan kardiovaskular pada diabetes sehingga penulis akan menelaah lebih lanjut mengenai mekanisme SGLT2-i terhadap vaskular yang dihubungkan terhadap stroke. Literature Review ini dilakukan dengan menelusuri artikel penelitian yang terdapat pada mesin pencarian. Mesin pencarian jurnal yang digunakan berupa PubMed dan Science Direct. Dari 551 artikel diidentifikasi berdasarkan judul, duplikasi, abstrak dan kesesuaian dengan kriteria inklusi dan dilaksanakan review untuk artikel terpilih. SGLT2-i memiliki mekanisme untuk menghambat progresivitas atheroma. Mekanisme yang terjadi berupa penurunan reaksi inflamasi sistemik, penurunan stress oksidatif, pengurangan ukuran ateroma hingga menjaga kestabilan plak ateroma. Oleh karena itu SGLT2-i merupakan kandidat terapi yang potensial dalam mengurangi risiko stroke pada pasien DMT2. SGLT2-i dapat digunakan sebagai inovasi terapi preventif untuk stroke pada pasien DMT2.
... Дослідження на тваринних моделях з ЦД показали підвищення вироблення матричними РНК НЗКТГ2 на 38 -56 %, пов'язане з посиленою експресією у гепатоцитах ядерного транскрипційного фактора-1 [24,25]. Нещодавнє дослідження показало, що рівень глюкози в плазмі регулює як утворення, так і вплив цього фактора транскрипції на експресію НЗКТГ2 [26]. Відомо, що пацієнти з ЦД мають вищий поріг екскреції глюкози із сечею та вищий ступінь реабсорбції глюкози, ніж здорові особи [27,28]. ...
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В огляді літератури розглядається нова універсальна молекула емпагліфлозину, якій вдалося змінити глюкозоцентричний підхід в ендокринології на органопротекторний. Результати базових клінічних досліджень, проведених з емпагліфлозином (EMPA‑REG‑OUTCOME, EMPEROR‑REDUCED, EMPEROR‑PRESERVED та EMPULSE), дають підстави стверджувати про здатність емпагліфлозину знижувати випадки серцево‑судинної смерті або госпіталізацію з приводу серцевої недостатності та уповільнювати прогресування хронічної хвороби нирок. Серед підтверджених і потенційно сприятливих метаболічних наслідків прийому емпагліфлозину слід зазначити такі: вибірковий антигіперглікемічний ефект лише в умовах гіперглікемії/глюкозурії, що не залежить ані від продукції інсуліну, ані від чутливості периферичних тканин до інсуліну, а лімітований лише швидкістю клубочкової фільтрації. Цей ефект дає змогу уникати гіпоглікемії навіть у пацієнтів без діабету. Препарат є одним з найбільш довговічних серед пероральних цукрознижувальних засобів і дає змогу протягом 6 — 8 років утримувати досягнуті значення глікозильованого гемоглобіну, відтерміновуючи ініціацію інсулінотерапії у пацієнтів із цукровим діабетом 2 типу. Емпагліфлозин у пацієнтів із цукровим діабетом 2 типу переважав плацебо щодо запобігання смертності внаслідок серцево‑судинних захворювань, нелетального інфаркту міокарда або нелетального інсульту. Ефект спричинений значним зниженням ризику серцево‑судинної смертності без суттєвих змін щодо нелетального інфаркту міокарда або нелетального інсульту. Можливе поєднання з іншими пероральними та ін’єкційними цукрознижувальними препаратами. У разі поєднання з препаратами сульфонілсечовини або інсуліном, останні потребують корекції дози у бік її зменшення. Втрата 2 — 3 кг маси тіла на тлі емпагліфлозину є очікуваним явищем, яке може модифікувати показники артеріального тиску та резистентність до інсуліну. Емпагліфлозин має здатність знижувати стеатоз та поліпшувати показники фіброзу печінки у пацієнтів з неалкогольною жировою хворобою печінки без цукрового діабету 2 типу.
... Investigations in animal models of diabetes reported an increase in SGLT2 mRNA levels by 38-56% associated with an enhanced expression of the hepatocyte nuclear transcription factor-1α (HNF-1α) [72,73]. A recent study has suggested that plasma glucose levels regulate both expression and function of this transcription factor which specifically would rule the expression of SGLT2 [74]. Consequently, diabetic patients have a higher threshold for urinary glucose excretion and higher glucose reabsorption than healthy humans [75,76]. ...
Article
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Sodium-glucose co-transporter 2 (SGLT2) inhibitors block glucose reabsorption in the renal proximal tubule, an insulin-independent mechanism that plays a critical role in glycemic regulation in diabetes. In addition to their glucose-lowering effects, SGLT2 inhibitors prevent both renal damage and the onset of chronic kidney disease and cardiovascular events, in particular heart failure with both reduced and preserved ejection fraction. These unexpected benefits prompted changes in treatment guidelines and scientific interest in the underlying mechanisms. Aside from the target effects of SGLT2 inhibition, a wide spectrum of beneficial actions is described for the kidney and the heart, even though the cardiac tissue does not express SGLT2 channels. Correction of cardiorenal risk factors, metabolic adjustments ameliorating myocardial substrate utilization, and optimization of ventricular loading conditions through effects on diuresis, natriuresis, and vascular function appear to be the main underlying mechanisms for the observed cardiorenal protection. Additional clinical advantages associated with using SGLT2 inhibitors are antifibrotic effects due to correction of inflammation and oxidative stress, modulation of mitochondrial function, and autophagy. Much research is required to understand the numerous and complex pathways involved in SGLT2 inhibition. This review summarizes the current known mechanisms of SGLT2-mediated cardiorenal protection.
... When the diabetic cells were treated with coumarin (!10 lM), the production of AGE and RAGE decreased significantly. Thiazolidinediones, an antidiabetic drug 59 , can inhibit bone resorption of osteoclasts regardless of its lipid-forming effect, so these drugs have obvious shortcomings. Coumarins can improve bone turnover and bone remodelling in diabetic patients. ...
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Diabetes is a group of metabolic diseases characterised by chronic hyperglycaemia caused by multiple causes, which is caused by insulin secretion and/or utilisation defects. It is characterised by increased fasting and postprandial blood glucose levels due to insulin deficiency or insulin resistance. It is reported that the harm of diabetes mainly comes from its complications, and the cardiovascular disease caused by diabetes is the primary cause of its harm. China has the largest number of diabetic patients in the world, and the prevention and control of diabetes are facing great challenges. In recent years, many kinds of literature have been published abroad, which have proved that coumarin and its derivatives are effective in the treatment of diabetic complications such as nephropathy and cardiovascular disease. In this paper, the types of antidiabetic drugs and the anti-diabetic mechanism of coumarins were reviewed. © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
... • понижената реабсорбция на натрий би имала положителен ефект върху контрола на артериалното кръвно налягане (16). ...
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Захарният диабет се характеризира основно с хипергликемия, но при определени обстоятелства са възможни и хипогликемични състояния. Реабсорбцията на филтрираните през бъбречната базална мембрана разтворени вещества – захари, аниони, витамини, късо-верижни мастни киселини, се дължи на 12-членно семейство транспортни протеини (solute carrier family 5, SLС5), инкорпорирани в тубулните мембрани. Целта на статията е да открои позитивните ефекти на SGLT-инхибиторите в клиничната практика. Ключови думи: захарен диабет, хипергликемия, патогенеза, SGLT-инхибитори
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Introduction: Systemic lupus erythematosus (SLE) is a chronic autoimmune rheumatologic disorder. The kidneys are frequently affected organs. The usual treatment of lupus nephritis includes nephroprotective drugs, immunosuppressants, and immunomodulators. SGLT-2 inhibitors are drugs that initially arrived as antidiabetics. Important cardio and nephroprotective effects have been found even in nondiabetic patients. Experimental studies of lupus nephritis mentioned the expression of SGLT-2; therefore, this article aims to make an updated review of the evidence on the use of SGLT-2 inhibitors in patients with nephritis. Extensive clinical trials with SGLT-2 inhibitors have generally excluded these patients. The current evidence of the use of iSGLT-2 in lupus nephritis is quite limited and carries from small observational studies and case series, where there are benefits in reducing proteinuria. More trials are required to establish its long-term effects.
Article
Potentially beneficial metabolic effects of empagliflozin remain "overshadowed" by the undeniable benefits of this drug in terms of cardio- and renoprotection. Today, there is a large data array (meta-analyses, systematic reviews and separate cohort studies with empagliflozin) that confirm the beneficial effect of this drug on various metabolic processes, which was systematized in this scientific review. It is emphasized that the antihyperglycemic effect of the drug does not depend on the secretion of insulin by β-cells of the pancreas and insulin resistance, it is manifested only in conditions of glucosuria and limited by eGFR. Empagliflozin combines well with all oral and parenteral hypoglycemic drugs; combination with drugs that have a potential risk of hypoglycemia (insulin and sulfonylurea drugs) requires a dose reduction of the latter. The durability of empagliflozin allows to maintain the achieved levels of glycated hemoglobin for a long time and postpone the start of insulin therapy. Weight loss by drug using corrects blood pressure and insulin resistance. In addition to the ability to reduce the level of uric acid and postpone the appointment of antigout drugs, empagliflozin can be considered a drug that has a multi-vector effect on various component of the metabolic syndrome. Promising areas of the drug using are reducing the risk of nephrolithiasis, steatosis and slowing down the progression of liver fibrosis.
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Precision medicine is a scientific and medical practice for personalized therapy based on patients' individual genetic, environmental, and lifestyle characteristics. Pharmacogenetics and pharmacogenomics are also rapidly developing and expanding as a key element of precision medicine, in which the association between individual genetic variabilities and drug disposition and therapeutic responses are investigated. Type 2 diabetes (T2D) is a chronic metabolic disorder characterized by hyperglycemia mainly associated with insulin resistance, with the risk of clinically important cardiovascular, neurological, and renal complications. The latest consensus report from the American Diabetes Association and European Association for the Study of Diabetes (ADA-EASD) on the management of T2D recommends preferential use of glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and some dipeptidyl peptidase-4 (DPP-4) inhibitors after initial metformin monotherapy for diabetic patients with established atherosclerotic cardiovascular or chronic kidney disease, and with risk of hypoglycemia or body weight-related problems. In this review article, we summarized current progress on pharmacogenetics of newer second-line antidiabetic medications in clinical practices and discussed their therapeutic implications for precision medicine in T2D management. Several biomarkers associated with drug responses have been identified from extensive clinical pharmacogenetic studies, and functional variations in these genes have been shown to significantly affect drug-related glycemic control, adverse reactions, and risk of diabetic complications. More comprehensive pharmacogenetic research in various clinical settings will clarify the therapeutic implications of these genes, which may be useful tools for precision medicine in the treatment and prevention of T2D and its complications.
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In contemporary clinical practice, there are numerous glucose-lowering agents available for the treatment of type 2 diabetes mellitus (T2DM): from older drugs such as metformin and sulfonylureas to newer agents such as dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors. In the past decade, large-scale randomized controlled trials (RCTs) of glucose-lowering agents have shown varying benefits on cardiovascular and kidney outcomes among patients with T2DM.1 In particular, SGLT2 inhibitors are being prescribed increasingly by physicians in a wide range of specialties2 because of cardiovascular and kidney benefits reported in large RCTs, the findings of which are reflected in several major guideline updates in the past 18 months. We review the mechanism of action of SGLT2 inhibitors, summarizing data from major cardiovascular and kidney outcome trials underpinning current treatment recommendations, and discuss the use of these agents in clinical practice, including important safety issues.
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Abstract Sotagliflozin is a dual sodium–glucose co-transporter-2 and 1 (SGLT2/1) inhibitor for the treatment of both type 1 (T1D) and type 2 diabetes (T2D). Sotagliflozin inhibits renal sodium–glucose co-transporter 2 (determining significant excretion of glucose in the urine, in the same way as other, already available SGLT-2 selective inhibitors) and intestinal SGLT-1, delaying glucose absorption and therefore reducing post prandial glucose. Well-designed clinical trials, have shown that sotagliflozin (as monotherapy or add-on therapy to other anti-hyperglycemic agents) improves glycated hemoglobin in adults with T2D, with beneficial effects on bodyweight and blood pressure. Similar results have been obtained in adults with T1D treated with either continuous subcutaneous insulin infusion or multiple daily insulin injections, even after insulin optimization. A still ongoing phase 3 study is currently evaluating the effect of sotagliflozin on cardiovascular outcomes (ClinicalTrials.gov NCT03315143). In this review we illustrate the advantages and disadvantages of dual SGLT 2/1 inhibition, in order to better characterize and investigate its mechanisms of action and potentialities.
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Sodium-dependent glucose transporters (SGLTs) exploit sodium gradients to transport sugars across the plasma membrane. Due to their role in renal sugar reabsorption, SGLTs are targets for the treatment of type 2 diabetes. Current therapeutics are phlorizin derivatives that contain a sugar moiety bound to an aromatic aglycon tail. Here, we develop structural models of human SGLT1/2 in complex with inhibitors by combining computational and functional studies. Inhibitors bind with the sugar moiety in the sugar pocket and the aglycon tail in the extracellular vestibule. The binding poses corroborate mutagenesis studies and suggest a partial closure of the outer gate upon binding. The models also reveal a putative Na⁺ binding site in hSGLT1 whose disruption reduces the transport stoichiometry to the value observed in hSGLT2 and increases inhibition by aglycon tails. Our work demonstrates that subtype selectivity arises from Na⁺-regulated outer gate closure and a variable region in extracellular loop EL5.
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Ertugliflozin, an inhibitor of sodium‐glucose cotransporter 2, is approved in the United States and European Union for the treatment of type 2 diabetes in adults, both as monotherapy and as part of fixed‐dose combination (FDC) therapies with either sitagliptin or immediate‐release metformin. The effect of a standard, high‐fat breakfast on the pharmacokinetics of the highest strengths of ertugliflozin monotherapy (15 mg), ertugliflozin/sitagliptin FDC (15‐/100‐mg), and ertugliflozin/metformin FDC (7.5‐/1000‐mg) tablets was evaluated. In 3 separate open‐label, 2‐period, 2‐sequence, single‐dose, crossover studies, 14 healthy subjects per study were randomized to receive either ertugliflozin monotherapy or FDC tablets comprising ertugliflozin and sitagliptin or ertugliflozin and metformin under fasted and fed (or vice versa) conditions. Food did not meaningfully affect the pharmacokinetics of ertugliflozin, sitagliptin, or metformin. For FDCs, the effect of food was consistent with that described for individual components. All treatments were well tolerated. Ertugliflozin and ertugliflozin/sitagliptin FDC tablets can be administered without regard to meals. As metformin is administered with meals because of its gastrointestinal side effects, the ertugliflozin/metformin FDC should also be administered with meals.
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Aims/hypothesis: The EFFECT-II study aimed to investigate the effects of dapagliflozin and omega-3 (n-3) carboxylic acids (OM-3CA), individually or combined, on liver fat content in individuals with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Methods: This randomised placebo-controlled double-blind parallel-group study was performed at five clinical research centres at university hospitals in Sweden. 84 participants with type 2 diabetes and NAFLD were randomly assigned 1:1:1:1 to four treatments by a centralised randomisation system, and all participants as well as investigators and staff involved in the study conduct and analyses were blinded to treatments. Each group received oral doses of one of the following: 10 mg dapagliflozin (n = 21), 4 g OM-3CA (n = 20), a combination of both (n = 22) or placebo (n = 21). The primary endpoint was liver fat content assessed by MRI (proton density fat fraction [PDFF]) and, in addition, total liver volume and markers of glucose and lipid metabolism as well as of hepatocyte injury and oxidative stress were assessed at baseline and after 12 weeks of treatment (completion of the trial). Results: Participants had a mean age of 65.5 years (SD 5.9), BMI 31.2 kg/m2 (3.5) and liver PDFF 18% (9.3). All active treatments significantly reduced liver PDFF from baseline, relative changes: OM-3CA, -15%; dapagliflozin, -13%; OM-3CA + dapagliflozin, -21%. Only the combination treatment reduced liver PDFF (p = 0.046) and total liver fat volume (relative change, -24%, p = 0.037) in comparison with placebo. There was an interaction between the PNPLA3 I148M polymorphism and change in liver PDFF in the active treatment groups (p = 0.03). Dapagliflozin monotherapy, but not the combination with OM-3CA, reduced the levels of hepatocyte injury biomarkers, including alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase (γ-GT), cytokeratin (CK) 18-M30 and CK 18-M65 and plasma fibroblast growth factor 21 (FGF21). Changes in γ-GT correlated with changes in liver PDFF (ρ = 0.53, p = 0.02). Dapagliflozin alone and in combination with OM-3CA improved glucose control and reduced body weight and abdominal fat volumes. Fatty acid oxidative stress biomarkers were not affected by treatments. There were no new or unexpected adverse events compared with previous studies with these treatments. Conclusions/interpretation: Combined treatment with dapagliflozin and OM-3CA significantly reduced liver fat content. Dapagliflozin monotherapy reduced all measured hepatocyte injury biomarkers and FGF21, suggesting a disease-modifying effect in NAFLD. Trial registration: ClinicalTrials.gov NCT02279407 FUNDING: The study was funded by AstraZeneca.
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Introduction: The sodium-glucose cotransporter 2 inhibitor dapagliflozin and the glucagon-like peptide-1 (GLP-1) receptor agonist exenatide reduce bodyweight via differing and complementary mechanisms. This post hoc analysis investigated the metabolic effects and baseline associations with bodyweight loss on coadministration of dapagliflozin and exenatide once weekly (QW) among adults with obesity and without diabetes. Methods: In the primary trial, adults with obesity and without diabetes [n = 50; 18-70 years; body mass index (BMI) 30-45 kg/m2] were randomized to double-blind oral dapagliflozin 10 mg (DAPA) once daily plus subcutaneous long-acting exenatide 2 mg QW (ExQW) or placebo over 24 weeks, followed by an open-label extension from 24-52 weeks during which all participants received active treatment. Primary results have been published previously. This analysis evaluated: (1) the effects of DAPA + ExQW on changes in substrates [free fatty acids (FFAs), glycerol, beta-OH-butyrate, and glucose], hormones (glucagon and insulin), and insulin secretion [insulinogenic index (IGI)] via an oral glucose tolerance test (OGTT) and (2) associations between bodyweight loss and baseline characteristics (e.g., BMI), single-nucleotide polymorphisms (SNPs) associated with the GLP-1 pathway, and markers of glucose regulation. Results: Compared with placebo at 24 weeks, 2-h FFAs post-OGTT increased (mean difference, +20.4 μmol/l; P < 0.05), and fasting glucose, 2-h glucose post-OGTT, and glucose area under the concentration-time curve (AUC) decreased with DAPA + ExQW [mean differences, -0.68 mmol/l [P < 0.001], -2.20 mmol/l (P < 0.01), and -306 mmol/l min (P < 0.001), respectively]. Glucagon, glycerol, beta-OH-butyrate, and IGI did not differ by treatment group at 24 weeks. Over 52 weeks, DAPA + ExQW decreased fasting insulin, 2-h post-OGTT insulin, and insulin AUC. Among DAPA + ExQW-treated participants, for each copy of the SNP variant rs10010131 A allele (gene WFS1), bodyweight decreased by 2.4 kg (P < 0.05). Lower BMI and a lower IGI were also associated with greater bodyweight loss with DAPA + ExQW. Conclusions: Metabolic effects with DAPA + ExQW included less FFA suppression versus placebo during the OGTT, suggesting compensatory lipid mobilization for energy production when glucose availability was reduced because of glucosuria. The expected increase in glucagon with DAPA did not occur with DAPA + ExQW coadministration. Bodyweight loss with DAPA + ExQW was associated with the SNP variant rs10010131 A allele, lower baseline adiposity (BMI), and lower baseline insulin secretion (IGI). These findings require further validation. Funding: AstraZeneca.
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Aims/introduction: While sodium glucose cotransporter 2 inhibitors are a promising treatment for type 2 diabetes mellitus, they are associated with concerns about specific adverse drug reactions. We conducted a 1-year post-marketing study of tofogliflozin, a novel agent in this class, in Japanese elderly patients with type 2 diabetes mellitus. Materials and methods: This was a prospective, observational, and multicenter post-marketing study conducted in the context of routine clinical practice. The study included all type 2 diabetic patients aged ≥65 years who started treatment with tofogliflozin during the first three months following its launch on 23 May 2014. Results: Of 1535 patients registered, 1507 patients whose electronic case report forms were collected and who had at least one follow-up visit were included in the safety analysis. A total of 270 of 1507 patients (17.92%) had at least one adverse drug reaction to tofogliflozin. The incidences of adverse drug reactions of special interest, namely, polyuria/pollakiuria, volume depletion-related events, urinary tract infection, genital infection, hypoglycaemia, and skin disorders, were 2.92%, 3.85%, 2.06%, 1.33%, 1.06% and 2.39%, respectively. Among those patients evaluable for clinical effectiveness, the mean change in glycated hemoglobin and body weight from baseline to last visit was -0.46% (p < 0.0001) and -2.71 kg (p < 0.0001), respectively. Conclusions: This study revealed that the incidence of adverse drug reactions to tofogliflozin in this study in elderly patients aged ≥65 years was little different from the incidence in the preapproval clinical trials. It was demonstrated that tofogliflozin significantly decreased glycated hemoglobin levels. This article is protected by copyright. All rights reserved.
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Healthy kidneys filter ∼160 g/day of glucose (∼30% of daily energy intake) under euglycaemic conditions. To prevent valuable energy from being lost in the urine, the proximal tubule avidly reabsorbs filtered glucose up to a limit of ∼450 g/day. When blood glucose levels increase to the point that the filtered load exceeds this limit, the surplus is excreted in the urine. Thus, the kidney provides a safety valve that can prevent extreme hyperglycaemia as long as glomerular filtration is maintained. Most of the capacity for renal glucose reabsorption is provided by sodium glucose cotransporter (SGLT) 2 in the early proximal tubule. In the absence or with inhibition of SGLT2, the renal reabsorptive capacity for glucose declines to ∼80 g/day (the residual capacity of SGLT1), i.e. the safety valve opens at a lower threshold, which makes it relevant to glucose homeostasis from day-to-day. Several SGLT2 inhibitors are now approved glucose lowering agents for individuals with type 2 diabetes and preserved kidney function. By inducing glucosuria, these drugs improve glycaemic control in all stages of type 2 diabetes, while their risk of causing hypoglycaemia is low because they naturally stop working when the filtered glucose load falls below ∼80 g/day and they do not otherwise interfere with metabolic counterregulation. Through glucosuria, SGLT2 inhibitors reduce body weight and body fat, and shift substrate utilisation from carbohydrates to lipids and, possibly, ketone bodies. Because SGLT2 reabsorbs sodium along with glucose, SGLT2 blockers are natriuretic and antihypertensive. Also, because they work in the proximal tubule, SGLT2 inhibitors increase delivery of fluid and electrolytes to the macula densa, thereby activating tubuloglomerular feedback and increasing tubular back pressure. This mitigates glomerular hyperfiltration, reduces the kidney's demand for oxygen and lessens albuminuria. For reasons that are less well understood, SGLT2 inhibitors are also uricosuric. 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 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.
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With rates of obesity and diabetes rising across the world, effective therapies to treat hyperglycemia and its associated comorbidities continue to be in demand. Empagliflozin is a highly selective sodium glucose transporter-2 inhibitor that improves serum glucose levels by inducing glucosuria. Taken orally, it is rapidly absorbed with linear pharmacokinetics consistent in Asian and Caucasian populations. Empagliflozin treatment demonstrates consistent reductions in hemoglobin A1c, fasting plasma glucose, body weight, and blood pressure in individuals with type 2 diabetes. Improvements in glycemic control and metabolic end points are evident with empagliflozin monotherapy, as add-on to oral hypoglycemics or add-on to insulin. The nonglycemic effects of empagliflozin with consistent improvements in blood pressure, body weight, and waist circumference provide additional rationale for use in patients with type 2 diabetes. Moreover, treatment with empagliflozin has recently shown significant reductions in both microvascular and macrovascular complications of diabetes.
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Purpose: Luseogliflozin, a sodium-glucose cotransporter-2 inhibitor, may be beneficial in obese diabetic patients based on its potential to decrease blood glucose and body weight, but there is limited proof. This analysis aimed to investigate the efficacy and safety of luseogliflozin in patients with varying levels of obesity. Methods: A pooled analysis of four 52-week Phase III trials of luseogliflozin 2.5 mg daily (or up to 5 mg daily) in Japanese patients with type 2 diabetes mellitus stratified according to baseline body mass index (BMI) was conducted. Efficacy end points included changes in glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), and body weight. Findings: In total, 1031 patients were included and stratified into 5 BMI (kg/m(2)) groups: low-to-medium (<22.5, n = 222); medium (≥22.5 to <25, n = 270); high-level 1 (≥25 to <27.5, n = 262); high-level 2 (≥27.5 to <30, n = 142); and very-high (≥30, n = 135). HbA1c decreased significantly compared with baseline until week 52 in all groups, and a similar trend was observed with FPG and body weight. The reduction in glycemic parameters tended to be slightly smaller in patients with BMI <22.5 kg/m(2), and the reduction in body weight tended to be greater in patients with higher BMI, especially those with BMI ≥30 kg/m(2). Levels of fasting insulin, C-peptide immunoreactivity, triglyceride, blood pressure, aspartate aminotransferase, alanine aminotransferase, and uric acid decreased significantly at week 52 in all groups (except for aspartate aminotransferase in patients with BMI <22.5 kg/m(2)). Levels of these parameters tended to be higher at baseline and these enhanced levels resulted in a greater decrease in patients with higher BMI. In safety, the incidence of adverse events was similar between groups, and most of them were mild in severity. Implications: HbA1c and body weight decreased significantly in all groups. Decrease in glycemic parameters tended to be smaller in patients with BMI <22.5 kg/m(2), while that of body weight was larger in patients with higher BMI. Furthermore, luseogliflozin was especially beneficial in patients with higher BMI in terms of metabolic abnormalities, including insulin secretion and hypertension. Luseogliflozin exhibited a favorable and similar safety profile over 52 weeks in all groups. This agent can be an effective and well-tolerated therapeutic option in patients with a wide range of BMI levels, and it may be more beneficial in patients with higher BMI.
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Type 2 diabetes is increasing in prevalence worldwide, and hyperglycemia is often poorly controlled despite a number of therapeutic options. Unlike previously available agents, sodium-glucose co-transporter 2 (SGLT2) inhibitors offer an insulin-independent mechanism for improving blood glucose levels, since they promote urinary glucose excretion (UGE) by inhibiting glucose reabsorption in the kidney. In addition to glucose control, SGLT2 inhibitors are associated with weight loss and blood pressure reductions, and do not increase the risk of hypoglycemia. Empagliflozin is a selective inhibitor of SGLT2, providing dose-dependent UGE increases in healthy volunteers, with up to 90 g of glucose excreted per day. It can be administered orally, and studies of people with renal or hepatic impairment indicated empagliflozin needed no dose adjustment based on pharmacokinetics. In Phase II trials in patients with type 2 diabetes, empagliflozin provided improvements in glycosylated hemoglobin (HbA1c) and other measures of glycemic control when given as monotherapy or add-on to metformin, as well as reductions in weight and systolic blood pressure. As add-on to basal insulin, empagliflozin not only improved HbA1c levels but also reduced insulin doses. Across studies, empagliflozin was generally well tolerated with a similar rate of hypoglycemia to placebo; however, patients had a slightly increased frequency of genital infections, but not urinary tract infections, versus placebo. Phase III studies have also reported a good safety profile along with significant improvements in HbA1c, weight and blood pressure, with no increased risk of hypoglycemia versus placebo. Based on available data, it appears that empagliflozin may be a useful option in a range of patients; however, clinical decisions will be better informed by the results of ongoing studies, in particular, a large cardiovascular outcome study (EMPA-REG OUTCOME™).
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Our previous work has shown that gene-knockout of the sodium-glucose cotransporter SGLT2 modestly lowered blood glucose in streptozotocin-diabetic mice (BG; from 470 to 300mg/dl) and prevented glomerular hyperfiltration, but did not attenuate albuminuria or renal growth and inflammation. Here we determined effects of the SGLT2 inhibitor empagliflozin (300mg/kg of diet for 15 weeks; corresponding to 60-80mg/kg/d) in type 1 diabetic Akita mice that, opposite to streptozotocin-diabetes, upregulate renal SGLT2 expression. Akita-diabetes, empagliflozin, and Akita+empagliflozin similarly increased renal membrane SGLT2 expression (by 38-56%) and reduced the expression of SGLT1 (by 33-37%) vs. vehicle-treated wild-type controls (WT). The diabetes-induced changes in SGLT2/SGLT1 protein expression are expected to enhance the BG lowering potential of SGLT2 inhibition, and empagliflozin strongly lowered BG in Akita (means of 187-237 vs. 517-535mg/dl in vehicle group; 100-140mg/dl in WT). Empagliflozin modestly reduced GFR in WT (250 vs. 306µl/min), and completely prevented the diabetes-induced increase in GFR (255 vs. 397µl/min). Empagliflozin attenuated increases in kidney weight and urinary albumin/creatinine ratio in Akita in proportion to hyperglycemia. Empagliflozin did not increase urinary glucose/creatinine ratios in Akita, indicating the reduction in filtered glucose balanced the inhibition of glucose reabsorption. Empagliflozin attenuated/prevented the increase in systolic blood pressure, glomerular size, and molecular markers of kidney growth, inflammation, and gluconeogenesis in Akita. We propose that SGLT2 inhibition can lower GFR independent of reducing BG (consistent with the tubular hypothesis of diabetic glomerular hyperfiltration), while attenuation of albuminuria, kidney growth, and inflammation in the early diabetic kidney may mostly be secondary to lower BG.
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Sotagliflozin (Zynquista™) is the first dual inhibitor of sodium-glucose co-transporter-1 and -2 (SGLT1 and 2). In the phase 3, inTANDEM 1–3 trials, adjunctive use of oral sotagliflozin (200 mg or 400 mg once daily) improved glycaemic control and reduced bodyweight and insulin requirements relative to placebo over 24 weeks of treatment in adults whose type 1 diabetes (T1D) was inadequately controlled by insulin therapy. Similar benefits were seen with the drug in patients who were overweight/obese [i.e. body mass index (BMI) ≥ 27 kg/m²] in inTANDEM 1 and 2 (pooled). The benefits of sotagliflozin were largely maintained over 52 weeks of treatment. Overall, use of sotagliflozin in this setting is generally well tolerated and reduces, or at least does not increase, the likelihood of hypoglycaemia; however, as with other SGLT inhibitors, sotagliflozin carries a risk of diabetic ketoacidosis (DKA). On the basis of its risk/benefit profile, sotagliflozin is indicated in the EU as an adjunct to insulin in adults with T1D with a BMI ≥ 27 kg/m² who have failed to achieve adequate glycaemic control despite optimal insulin therapy, thus expanding the currently limited adjunctive oral treatment options available for use in this population.
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Diabetes is a major health problem worldwide. Glycemic control is the main goal in the management of type 2 diabetes. While many anti-diabetic drugs and guidelines are available, almost half of diabetic patients do not reach their treatment goal and develop complications. The glucose-lowering response to anti-diabetic drug differs significantly between individuals. Relatively little is known about the factors that might underlie this response. The identification of predictors of response to anti-diabetic drugs is essential for treatment personalization. Unfortunately, the evidence on predictors of drugs response in type 2 diabetes is scarce. Only a few trials were designed for specific groups of patients (e.g. patients with renal impairment or older patients), while subgroup analyses of larger trials are frequently unreported. Physicians need help in picking the drug which provides the maximal benefit, with minimal side effects, in the right dose, for a specific patient, using an omics-based approach besides the phenotypic characteristics.
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BACKGROUND & AIMS: Genetic factors may impact nonalcoholic fatty liver disease (NAFLD) severity. We aimed to assess the prevalence of patatin-like phospholipase domain-containing 3 protein (PNPLA3) gene rs738409 C > G polymorphism in Brazilian individuals with type 2 diabetes and to investigate its association with liver disease severity, diabetic chronic degenerative complications, and metabolic control. METHODS AND RESULTS: PNPLA3 genotyping was performed and classified as CC, CG, and GG. Clinical and laboratory data were obtained, including chronic degenerative diabetes complications. Liver stiffness and steatosis were evaluated by transient hepatic elastography with CAP using FibroScan®. Multiple logistic regression was performed to investigate the association of PNPLA3 G allele with clinical and laboratory variables and with hepatic fibrosis/steatosis. Three hundred three patients were included (118 male, mean age 59 ± 9.5 years). The G allele frequency was 32.5% (CC 47%, CG 41%, and GG 12%). Significant liver fibrosis and severe steatosis were diagnosed in 26% and 43% of patients, respectively. The variables independently associated with the G allele were coronary artery disease (OR: 2.25; 95% CI: 1.03-4.88; p = 0.04), better glycemic control (OR for having an HbA1c ≥ 8% [64 mmol/mol]: 0.53; 95% CI: 0.31-0.89; p = 0.01), and significant liver fibrosis (OR: 1.82; 95% CI: 1.04-3.17; p = 0.03). CONCLUSION: In individuals with diabetes and NAFLD, PNPLA3 gene rs738409 C > G polymorphism is a marker for the risk of significant liver fibrosis and cardiovascular disease and may be associated with better glycemic control.
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Sotagliflozin (Zynquista™) is a dual inhibitor of sodium-glucose co-transporters (SGLT) 1 and 2 being developed by Lexicon Pharmaceuticals and Sanofi as a treatment for type 1 (T1DM) and type 2 diabetes mellitus (T2DM). The drug has a dual action, blunting and delaying absorption of glucose from the gastrointestinal tract and the reabsorption of glucose in the proximal tubule of the kidney, respectively. In the phase III inTandem clinical trial program in patients with T1DM, sotagliflozin as an adjunct to optimised insulin therapy produced a clinically meaningful reduction in HbA1c levels, but was associated with a higher incidence of diabetic ketoacidosis than placebo. Sotagliflozin was recently approved for use as an adjunct to insulin in T1DM in the EU. However, the FDA Endocrinologic and Metabolic Drugs Advisory Committee was divided, citing concerns regarding diabetic ketoacidosis, leading the FDA to issue an Complete Response Letter for this indication in the USA. This article summarizes the milestones in the development of sotagliflozin leading to this first approval in the EU as an adjunct to insulin in patients with T1DM with a body mass index ≥ 27 kg/m2 who have failed to achieve adequate glycaemic control despite optimal insulin therapy.
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Aims To evaluate the evidence for the novel dual sodium‐glucose co‐transporter‐1 and ‐2 inhibitor, sotagliflozin, which may enhance the efficacy of sodium‐glucose co‐transporter‐2 inhibitors by additionally reducing intestinal glucose absorption. Methods The search terms ‘sotagliflozin’, ‘LX4211′, ‘SGLT’ and ‘diabetes’ were entered into PubMed. Evidence of the pharmacokinetics, pharmacodynamics, safety and efficacy of sotagliflozin in Type 1 and 2 diabetes was extracted from the retrieved literature, critically evaluated, and contextualized in relation to data on existing sodium‐glucose co‐transporter‐2 inhibitors. Results There is convincing evidence from a range of phase II and III clinical trials that sotagliflozin significantly improves glycaemic control in both Type 1 and Type 2 diabetes. Additional benefits, such as smaller postprandial plasma glucose excursions, lower insulin requirements, appetite suppression and weight loss have been documented. While this is encouraging, several safety concerns remain; a dose‐dependent increase in the rate of diabetic ketoacidosis, diarrhoea and genital mycotic infection is apparent, although statistical exploration of the data regarding such events is currently lacking. Speculatively, use of a 200‐mg rather than a 400‐mg dose may help to limit unwanted effects. Conclusions Current evidence for sotagliflozin in diabetes appears promising. Further studies sufficiently powered to assess present and emerging safety concerns, as well as to identify individuals for whom sotagliflozin may be of particular benefit/harm would now be informative for regulatory decision‐making. Direct comparisons with existing SGLT2 inhibitors are also needed to determine relative safety/efficacy profiles for the different indications. This article is protected by copyright. All rights reserved.
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Ertugliflozin (Steglatro™) is an orally active sodium glucose co-transporter type 2 inhibitor being developed by Merck and Pfizer as a treatment for type 2 diabetes mellitus (T2DM). Ertugliflozin as monotherapy and in combination with various other antidiabetic drugs was associated with improvements in glycaemic control and secondary outcome measures in the VERTIS phase III clinical trial program. Ertugliflozin and fixed-dose combinations of ertugliflozin and metformin (Segluromet™) and ertugliflozin and sitagliptin (Steglujan™) have recently been approved by the US FDA as an adjunct to diet and exercise to improve glycaemic control in adults with T2DM. These products have also received a positive opinion from the EU Committee for Medicinal Products for Human Use (CHMP). This article summarizes the milestones in the development of ertugliflozin leading to its first approval for T2DM.
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Canagliflozin (Invokana®) is a sodium-glucose co-transporter-2 (SGLT2) inhibitor indicated in various countries worldwide for the once-daily oral treatment of type 2 diabetes (T2D). Canagliflozin lowers blood glucose levels independently of insulin, with the inhibition of SGLT2 reducing renal reabsorption of glucose and increasing excretion of glucose in the urine. In well-designed clinical trials, canagliflozin (as first-line monotherapy or add-on therapy to other antihyperglycaemic agents) improved glycaemic control in adults with T2D, including those of older age and/or at high cardiovascular (CV) risk, and also had beneficial effects on their bodyweight and blood pressure (BP). CV risk reduction, as well as possible renal benefits, were also seen with canagliflozin in T2D patients at high CV risk in the CANVAS Program, an integrated analysis of two large CV outcomes studies. Canagliflozin was generally well tolerated, had a low risk of hypoglycaemia and was most commonly associated with adverse events such as genital and urinary tract infections and increased urination, consistent with its mechanism of action. Although the amputation and fracture risk observed among recipients of the drug require further investigation, canagliflozin is an important option for T2D management in adults.
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Introduction: Sodium glucose co-transporter-2 (SGLT2) inhibitors have been developed recently as a new class of anti-diabetic drug, and are becoming widely used in the management of type 2 diabetes (T2D). As these agents have a considerably different glucose-lowering mechanism from those of other anti-diabetic drugs, safe use of this drug class needs to be discussed based on data available from preapproval clinical trials as well as real-world studies. The SGLT2 inhibitor luseogliflozin was developed by Taisho Pharmaceutical Co., Ltd. and was approved as an oral anti-diabetic drug for T2D in Japan Areas covered: The overall safety and efficacy of SGLT2 inhibitor luseogliflozin are summarized on the basis of a literature review, with a focus on reported adverse drug reactions in preapproval clinical trials and a post-marketing surveillance. Expert opinion: SGLT2 inhibitor luseogliflozin is well tolerated, significantly improves hyperglycemia in preapproval clinical trials, and has a favorable safety profile in both preapproval clinical trials and post-marketing surveillance in elderly patients. While long-term safety and efficacy remain to be seen, luseogliflozin can benefit T2D patients worldwide. However, healthcare professionals must perform appropriate patient education that includes temporary withdrawal of luseogliflozin during patient a "sick day" and avoidance of strict carbohydrate restriction during luseogliflozin treatment.
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Purpose Tofogliflozin is a selective oral inhibitor of sodium-glucose co-transporter 2 for treatment of type 2 diabetes mellitus. The pharmacokinetics, pharmacodynamics, and safety of tofogliflozin were investigated in healthy male subjects. Methods Three studies were conducted: single-ascending dose study (10–640 mg) in 56 Japanese and 24 Caucasian subjects; multiple-ascending dose study (2.5–80 mg once daily for 7 days) in 24 Japanese subjects; and food-effect study (20–40 mg) in 30 Japanese subjects. Results Tofogliflozin was absorbed rapidly and eliminated from the systemic circulation with a t1/2 of 5–6 h. Exposure increased dose-proportionally up to 320 mg. Body weight-corrected exposure was similar between Japanese and Caucasian subjects. Urinary excretion of tofogliflozin ranged from 17.1 to 27.4% of dose. Tofogliflozin did not accumulate with once daily administration. Food intake decreased Cmax by approximately 30% but did not change AUC0-inf. Tofogliflozin caused dose-dependent daily urinary glucose excretion (UGE0-24h), but food intake condition at administration did not affect it. The exposure-response relationship between plasma average concentration of tofogliflozin (Cavg) and UGE0-24h fitted Emax model well. There were no serious adverse events leading to discontinuation or episodes of hypoglycemia. Conclusions Single and multiple administration of tofogliflozin were generally well tolerated. Exposure to tofogliflozin was dose-proportional up to 320 mg and did not accumulate with multiple once-a-day administration. The model suggests more than 100 ng/mL Cavg corresponding to the dose of between 20 and 40 mg leads to almost maximum effect of tofogliflozin.
Article
Objective: Inhibition of the renal sodium-glucose cotransporter 2 (SGLT2) is a novel concept in the therapy of diabetes mellitus. In this study, we first assessed whether common single nucleotide polymorphisms (SNPs) in the SGLT2-encoding gene SLC5A2 affect diabetes-related metabolic traits in subjects at risk for type 2 diabetes and, second, whether these have pharmacogenetic relevance by interfering with the response to empagliflozin treatment in patients with type 2 diabetes. Patients and methods: Samples from a metabolically well-phenotyped cross-sectional study population (total N=2600) at increased risk for type 2 diabetes and pooled pharmacogenetic samples from patients from four phase III trials of empagliflozin (in total: 603 receiving empagliflozin, 305 receiving placebo) were genotyped for five common SNPs (minor allele frequencies ≥5%) present in the SLC5A2 gene locus. Results: In the cross-sectional study, none of the SLC5A2 SNPs significantly influenced metabolic traits such as body fat, insulin sensitivity/resistance, insulin release, HbA1c, plasma glucose, or systolic blood pressure when multiple testing was taken into account (all P≥0.0083). Further, no relevant effect on response to treatment with empagliflozin on HbA1c, fasting glucose, weight, or systolic blood pressure was observed for the SNPs tested in the pharmacogenetic study. Conclusion: Common genetic variants in the SLC5A2 gene neither affects diabetes-related metabolic traits nor have a clinically relevant impact on response to treatment with the SGLT2 inhibitor empagliflozin.
Article
Diabetes mellitus is a disease that affects millions of people worldwide and its prevalence is estimated to rise in the future. Billions of dollars are spent each year around the world in health expenditure related to diabetes. There are several anti-diabetic drugs in the market for the treatment of non-insulin dependent diabetes mellitus. In this article, we will be talking about a relatively new class of anti-diabetic drugs called sodium glucose co-transporter 2 (SGLT2) inhibitors. This class of drugs has a unique mechanism of action focusing on inhibition of glucose reabsorption that separates it from other classes. This article covers the mechanism of glucose reabsorption in the kidneys, the mechanism of action of SGLT2 inhibitors, several SGLT2 inhibitors currently available in the market as well as those in various phases of development, their individual pharmacokinetics as well as the discussion about the future role of SGLT2 inhibitors, not only for the treatment of diabetes, but also for various other diseases like obesity, hepatic steatosis, and cardiovascular disorders.
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1. To understand the clearance mechanism of luseogliflozin, a sodium–glucose cotransporter 2 (SGLT2) inhibitor, we investigated its human metabolite profile and metabolic enzymes responsible for the primary metabolic pathways in human using reaction phenotyping. 2. Sixteen metabolites of luseogliflozin were found in human plasma and/or urine and their structural information indicated that the drug was metabolized via multiple metabolic pathways. The primary metabolic pathways involve (1) O-deethylation to form M2 and subsequent glucuronidation to form M12, (2) ω-hydroxylation at ethoxy group to form M3 followed by oxidation to form the corresponding carboxylic acid metabolite (M17) and (3) direct glucuronidation to form M8. 3. The reaction phenotyping studies indicated that the formation of M2 was mainly mediated by cytochrome P450 (CYP) 3A4/5, and subsequently M12 formation was catalyzed by UGT1A1, UGT1A8 and UGT1A9. The formation of M3 was mediated by CYP4A11, CYP4F2 and CYP4F3B, and the further oxidation of M3 to M17 was mediated by alcohol dehydrogenase and aldehyde dehydrogenase. The formation of M8 was catalyzed by UGT1A1. 4. These results demonstrate that luseogliflozin is metabolized through multiple pathways, including CYP-mediated oxidation and glucuronidation, in human.
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EMPA-REG OUTCOME is an international, prospective, placebo-controlled clinical trial investigating the cardiovascular outcomes of empagliflozin, an inhibitor of sodium-glucose cotransporters type 2 (SGLT2), in patients with type 2 diabetes mellitus and known cardiovascular disease. The trial succeeded in reaching the primary objective of non-inferiority and, in addition, showed, after a median follow up of 3.1 years, a superiority of empagliflozin (10 or 25 mg/day) versus placebo as regards the primary composite cardiovascular endpoint (hasard ratio or HR = 0.86; 95% CI 0.74-0.99; P = 0.04), hospitalisations for heart failure (- 35 %), cardiovascular mortality (- 38 %) and all-cause mortality (- 32 %, each p< 0.001). The reduction in mortality appeared early (< 6 months) and concerned all subgroups, without any obvious heterogeneity. This reduction in mortality does not seem to be fully explained by the concomitant slight reductions in HbA1c, body weight, waist circumference, blood pressure and serum uric acid levels in the empagliflozin groups versus the placebo group. Finally, the tolerance and safety profile of empagliflozin was good, with only a moderate increase in benign mycotic genital infections, a well-known adverse event with SGLT2 inhibitors. The remarkable effects of empagliflozin in the EMPA-REG OUTCOME trial, especially on mortality, should modify the management of patients with type 2 diabetes and a high cardiovascular risk in a near future.
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Canagliflozin is an orally active, reversible, selective sodium-glucose co-transporter-2 inhibitor. A population pharmacokinetic (popPK) model of canagliflozin, including relevant covariates as sources of inter-individual variability, was developed to describe phase I, II, and III data in healthy volunteers and in patients with type 2 diabetes mellitus (T2DM). The final analysis included 9061 pharmacokinetic (PK) samples from 1616 volunteers enrolled in nine phase I, two phase II, and three phase III studies and was performed using NONMEM(®) 7.1. Inter-individual variability was evaluated using an exponential model and the residual error model was additive in the log domain. The first-order conditional estimation method with interaction was applied and the model was parameterized in terms of rate constants. Covariate effects were explored graphically on empirical Bayes estimates of PK parameters, as shrinkage was low. Clinical relevance of statistically significant covariates was evaluated. The predictive properties of the model were illustrated by prediction-corrected visual predictive checks. A two-compartment PK model with lag-time and sequential zero- and first-order absorption and first-order elimination best described the observed data. Sex, age, and weight on apparent volume of distribution of the central compartment, body mass index on first-order absorption rate constant, and body mass index and over-encapsulation on lag-time, and estimated glomerular filtration rate (eGFR, by MDRD equation), dose, and genetic polymorphism (carriers of UGT1A9*3 allele) on elimination rate constant were identified as statistically significant covariates. The prediction-corrected visual predictive checks revealed acceptable predictive performance of the model. The popPK model adequately described canagliflozin PK in healthy volunteers and in patients with T2DM. Because of the small magnitude of statistically significant covariates, they were not considered clinically relevant. However, dosage adjustments are recommended for T2DM patients with renal impairment (eGFR ≥60 mL/min/1.73 m(2): 100 or 300 mg/day; eGFR of 45 to <60 mL/min/1.73 m(2): 100 mg/day).
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Sodium-glucose cotransporters (SGLTs) are important mediators of glucose uptake across apical cell membranes. SGLT1 mediates almost all sodium-dependent glucose uptake in the small intestine, while in the kidney SGLT2, and to a lesser extent SGLT1, account for more than 90% and nearly 3%, respectively, of glucose reabsorption from the glomerular ultrafiltrate. Although the recent availability of SGLT2 inhibitors for the treatment of diabetes mellitus has increased the number of clinical studies, this review has a focus on mechanisms contributing to the cellular regulation of SGLTs. Studies have focused on the regulation of SGLT expression under different physiological/pathophysiological conditions, for example diet, age or diabetes mellitus. Several studies provide evidence of SGLT regulation via cyclic adenosine monophosphate/protein kinase A, protein kinase C, glucagon-like peptide 2, insulin, leptin, signal transducer and activator of transcription-3 (STAT3), phosphoinositide-3 kinase (PI3K)/Akt, mitogen-activated protein kinases (MAPKs), nuclear factor-kappaB (NF-kappaB), with-no-K[Lys] kinases/STE20/SPS1-related proline/alanine-rich kinase (Wnk/SPAK) and regulatory solute carrier protein 1 (RS1) pathways. SGLT inhibitors are important drugs for glycemic control in diabetes mellitus. Although the contribution of SGLT1 for absorption of glucose from the intestine as well as SGLT2/SGLT1 for renal glucose reabsorption has been comprehensively defined, this review provides an up-to-date outline for the mechanistic regulation of SGLT1/SGLT2.
Article
Canagliflozin, an orally active sodium-glucose cotransporter 2 inhibitor, is approved in many countries as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The recommended dose of canagliflozin is 100 or 300 mg once daily. This Phase I study was conducted to evaluate the pharmacokinetics, pharmacodynamics, and safety profile of canagliflozin in healthy Chinese subjects. In this double-blind, single-dose, 3-way crossover study, 15 healthy subjects were randomized (1:1:1) to receive single oral doses of canagliflozin 100 mg, canagliflozin 300 mg, or placebo. Pharmacokinetic, pharmacodynamic, and safety assessments were made at prespecified time points. All participants are healthy Chinese adults. Mean AUC and Cmax of canagliflozin increased in a dose-dependent manner after single-dose administration (AUC0-∞, 10,521 ng · h/mL for 100 mg, 33,583 ng · h/mL for 300 mg; Cmax, 1178 ng/mL for 100 mg, 4113 ng/mL for 300 mg). The mean apparent t½ and the median Tmax of canagliflozin were independent of dose (t½, 16.0 hours for 100 mg, 16.2 hours for 300 mg; Tmax, ~1 hour). Mean CL/F and renal clearance of canagliflozin were comparable between the 2 doses. Mean plasma metabolite to parent molar ratios for Cmax and AUC0-∞ were similar with both doses. Canagliflozin decreased the 24-hour mean renal threshold for glucose, calculated by using measured creatinine clearance to estimate the glomerular filtration rate (67.9 and 60.7 mg/dL for canagliflozin 100 and 300 mg, respectively) and 24-hour increased urinary glucose excretion (33.8 and 42.9 g for canagliflozin 100 and 300 mg, respectively) in a dose-dependent manner; the 24-hour plasma glucose profile remained largely unchanged. No deaths, hypoglycemic events, or discontinuations due to adverse events were observed. Pharmacokinetics (AUC and Cmax) of canagliflozin increased in a dose-dependent manner after single oral doses of canagliflozin (100 and 300 mg) in these healthy Chinese subjects. Tmax and t½ of canagliflozin were independent of the dose. Canagliflozin decreased the 24-hour mean renal threshold for glucose and increased urinary glucose excretion in a dose-dependent manner; these results are consistent with those observed in other patient populations. Canagliflozin was generally safe and well tolerated in these healthy Chinese subjects. ClinicalTrials.gov identifier: NCT01707316. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.
Article
The sodium-glucose co-transporter 2 (SGLT2) inhibitors represent novel therapeutic approaches in the management of type 2 diabetes mellitus; they act on kidneys to decrease the renal threshold for glucose (RTG) and increase urinary glucose excretion (UGE). Canagliflozin is an orally active, reversible, selective SGLT2 inhibitor. Orally administered canagliflozin is rapidly absorbed achieving peak plasma concentrations in 1-2 h. Dose-proportional systemic exposure to canagliflozin has been observed over a wide dose range (50-1600 mg) with an oral bioavailability of 65 %. Canagliflozin is glucuronidated into two inactive metabolites, M7 and M5 by uridine diphosphate-glucuronosyltransferase (UGT) 1A9 and UGT2B4, respectively. Canagliflozin reaches steady state in 4 days, and there is minimal accumulation observed after multiple dosing. Approximately 60 % and 33 % of the administered dose is excreted in the feces and urine, respectively. The half-life of orally administered canagliflozin 100 or 300 mg in healthy participants is 10.6 and 13.1 h, respectively. No clinically relevant differences are observed in canagliflozin exposure with respect to age, race, sex, and body weight. The pharmacokinetics of canagliflozin remains unaffected by mild or moderate hepatic impairment. Systemic exposure to canagliflozin is increased in patients with renal impairment relative to those with normal renal function; however, the efficacy is reduced in patients with renal impairment owing to the reduced filtered glucose load. Canagliflozin did not show clinically relevant drug interactions with metformin, glyburide, simvastatin, warfarin, hydrochlorothiazide, oral contraceptives, probenecid, and cyclosporine, while co-administration with rifampin modestly reduced canagliflozin plasma concentrations and thus may necessitate an appropriate monitoring of glycemic control. Canagliflozin increases UGE and suppresses RTG in a dose-dependent manner, thereby lowering the plasma glucose levels and reducing the glycosylated hemoglobin levels through an insulin-independent mechanism of action. The 300-mg dose provides near-maximal effects on RTG throughout the full 24-h dosing interval, whereas the effect of the 100-mg dose on RTG is near-maximal for approximately 12 h and is modestly attenuated during the overnight period. The observed pharmacokinetic/pharmacodynamic profile of canagliflozin in patients with type 2 diabetes mellitus supports a once-daily dosing regimen.
Article
This study (NCT01096667) compared the blood pressure (BP)-lowering effect of ertugliflozin (1, 5, 25 mg), hydrochlorothiazide (HCTZ; 12.5 mg) and placebo in 194 patients with type 2 diabetes mellitus (T2DM) and hypertension for 4 weeks using ambulatory BP monitoring. Endpoints (change from baseline to week 4) were: 24-h mean systolic BP (SBP; primary); daytime, night-time, seated pre-dose SBP, 24-h, daytime, night-time, seated pre-dose diastolic BP, 24-h urinary glucose excretion, fasting plasma glucose (secondary). Safety/tolerability were monitored. Significant decreases in placebo-corrected 24-h mean SBP (-3.0 to -4.0 mmHg) were recorded for all doses of ertugliflozin (HCTZ, -3.2 mmHg). Daytime, but not night-time SBP was consistently reduced. Ertugliflozin produced dose-dependent significant decreases in FPG and increases in UGE. No notable changes in plasma renin activity or urinary aldosterone were seen. The most common adverse events were urinary tract infection, genital fungal infection, upper respiratory tract infection and musculoskeletal pain. This article is protected by copyright. All rights reserved.
Article
O-glucuronidation is the major metabolic elimination pathway for canagliflozin. The objective was to identify enzymes and tissues involved in the formation of two major glucuronidated metabolites (M7 and M5) of canagliflozin and subsequently assess the impact of genetic variations in these uridine diphosphate glucuronosyltransferases (UGTs) on in vivo pharmacokinetics in humans. In vitro incubations with recombinant UGTs revealed involvement of UGT1A9 and UGT2B4 in the formation of M7 and M5, respectively. While M7 and M5 were formed in liver microsomes, only M7 was formed in kidney microsomes. Participants from seven phase 1 studies were pooled for pharmacogenomics analyses. A total of 134 participants (mean age=41 years; men=63%; white=84%) were included in the analysis. In UGT1A9*3 carriers, exposure of plasma canagliflozin (Cmax,ss =11%; AUCτ,ss =45%) increased relative to wild-type. An increase in exposure of plasma canagliflozin (Cmax,ss =21%; AUCt,ss =18%) was observed in participants with UGT2B4*2 genotype compared with UGT2B4*2 noncarriers. Metabolites further delineate the role of both enzymes. The pharmacokinetic findings in participants carrying the UGT1A9*3 and UGT2B4*2 allele implicate that UGT1A9 or UGT2B4 are involved in the metabolism of canagliflozin to M7 and M5, respectively. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Article
Inhibitors of sodium–glucose co-transporter type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus (T2DM). Several compounds are already available in many countries (dapagliflozin, canagliflozin, empagliflozin and ipragliflozin) and some others are in a late phase of development. The available SGLT2 inhibitors share similar pharmacokinetic characteristics, with a rapid oral absorption, a long elimination half-life allowing once-daily administration, an extensive hepatic metabolism mainly via glucuronidation to inactive metabolites, the absence of clinically relevant drug–drug interactions and a low renal elimination as parent drug. SGLT2 co-transporters are responsible for reabsorption of most (90 %) of the glucose filtered by the kidneys. The pharmacological inhibition of SGLT2 co-transporters reduces hyperglycaemia by decreasing renal glucose threshold and thereby increasing urinary glucose excretion. The amount of glucose excreted in the urine depends on both the level of hyperglycaemia and the glomerular filtration rate. Results of numerous placebo-controlled randomised clinical trials of 12–104 weeks duration have shown significant reductions in glycated haemoglobin (HbA1c), resulting in a significant increase in the proportion of patients reaching HbA1c targets, and a significant lowering of fasting plasma glucose when SGLT2 inhibitors were administered as monotherapy or in addition to other glucose-lowering therapies including insulin in patients with T2DM. In head-to-head trials of up to 2 years, SGLT2 inhibitors exerted similar glucose-lowering activity to metformin, sulphonylureas or sitagliptin. The durability of the glucose-lowering effect of SGLT2 inhibitors appears to be better; however, this remains to be more extensively investigated. The risk of hypoglycaemia was much lower with SGLT2 inhibitors than with sulphonylureas and was similarly low as that reported with metformin, pioglitazone or sitagliptin. Increased renal glucose elimination also assists weight loss and could help to reduce blood pressure. Both effects were very consistent across the trials and they represent some advantages for SGLT2 inhibitors when compared with other oral glucose-lowering agents. The pharmacodynamic response to SGLT2 inhibitors declines with increasing severity of renal impairment, and prescribing information for each SGLT2 inhibitor should be consulted regarding dosage adjustments or restrictions in moderate to severe renal dysfunction. Caution is also recommended in the elderly population because of a higher risk of renal impairment, orthostatic hypotension and dehydration, even if the absence of hypoglycaemia represents an obvious advantage in this population. The overall effect of SGLT2 inhibitors on the risk of cardiovascular disease is unknown and will be evaluated in several ongoing prospective placebo-controlled trials with cardiovascular outcomes. The impact of SGLT2 inhibitors on renal function and their potential to influence the course of diabetic nephropathy also deserve more attention. SGLT2 inhibitors are generally well-tolerated. The most frequently reported adverse events are female genital mycotic infections, while urinary tract infections are less commonly observed and generally benign. In conclusion, with their unique mechanism of action that is independent of insulin secretion and action, SGLT2 inhibitors are a useful addition to the therapeutic options available for the management of T2DM at any stage in the natural history of the disease. Although SGLT2 inhibitors have already been extensively investigated, further studies should even better delineate the best place of these new glucose-lowering agents in the already rich armamentarium for the management of T2DM.
Article
Dapagliflozin (Forxiga(®), Farxiga(®)) is an orally administered sodium-glucose co-transporter-2 (SGLT2) inhibitor used in the management of patients with type 2 diabetes. Dapagliflozin reduces renal glucose reabsorption by inhibiting the transporter protein SGLT2 in the renal proximal tubule, thereby increasing urinary glucose excretion and reducing blood glucose levels. Its mechanism of action is independent of insulin secretion or action; therefore, dapagliflozin provides complementary therapy when used in combination with other antihyperglycaemic drugs. This article updates an earlier review of dapagliflozin and focuses on longer-term efficacy and tolerability data (e.g. from extensions of earlier clinical trials), as well as data from studies in special patient populations (e.g. history of cardiovascular disease). Numerous well-designed clinical trials with dapagliflozin, primarily as add-on therapy for 24 weeks (but also as monotherapy or initial combination therapy), have consistently demonstrated reductions in glycosylated haemoglobin, fasting plasma glucose levels and bodyweight. Extensions of these trials show the effects are maintained over longer-term follow-up periods of ≈1-4 years and dapagliflozin is generally well tolerated. Dapagliflozin has a low risk of hypoglycaemia, although the incidence varies depending on background therapy, and genital mycotic infections (particularly in women) are the most common adverse events. Dapagliflozin is not recommended in patients with moderate or severe renal impairment. In view of its unique mechanism of action and now well-established efficacy and tolerability profile, dapagliflozin is a useful treatment option in the management of type 2 diabetes, although its effects on diabetic complications remain to be evaluated.
Article
The kidneys in normoglycemic humans filter 160-180 g of glucose per day (∼30% of daily calorie intake), which is reabsorbed and returned to the systemic circulation by the proximal tubule. Hyperglycemia increases the filtered and reabsorbed glucose up to two- to three-fold. The sodium glucose cotransporter SGLT2 in the early proximal tubule is the major pathway for renal glucose reabsorption. Inhibition of SGLT2 increases urinary glucose and calorie excretion, thereby reducing plasma glucose levels and body weight. The first SGLT2 inhibitors have been approved as a new class of antidiabetic drugs in type 2 diabetes mellitus, and studies are under way to investigate their use in type 1 diabetes mellitus. These compounds work independent of insulin, improve glycemic control in all stages of diabetes mellitus in the absence of clinically relevant hypoglycemia, and can be combined with other antidiabetic agents. By lowering blood pressure and diabetic glomerular hyperfiltration, SGLT2 inhibitors may induce protective effects on the kidney and cardiovascular system beyond blood glucose control. Expected final online publication date for the Annual Review of Medicine Volume 66 is January 14, 2015. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
Article
Ipragliflozin (Suglat(®)) is a potent and selective inhibitor of sodium-glucose cotransporter-2 that was recently launched in Japan. Its mechanism of action involves the suppression of glucose re-absorption in the kidney proximal tubules, causing excretion of glucose in the urine. The aim of this review is to provide a comprehensive overview of currently available pharmacokinetic and pharmacodynamic data on ipragliflozin, including studies in healthy subjects, patients with type 2 diabetes mellitus and special populations. In single- and multiple-dose studies, the maximum plasma concentration and area under the plasma concentration-time curve (AUC) for ipragliflozin increased in a dose-dependent manner. Although urinary excretion of ipragliflozin is low (approximately 1 %), tubular concentration of free ipragliflozin is adequate to provide pharmacological activities. No clinically relevant effects of age, gender or food on the exposure of ipragliflozin were observed. The AUC for ipragliflozin was 20-30 % greater in patients with moderate renal or hepatic impairment than in patients with normal renal or hepatic function. In drug-drug interaction studies, the pharmacokinetics of ipragliflozin and other oral antidiabetic drugs (metformin, sitagliptin, pioglitazone, glimepiride, miglitol and mitiglinide) were not significantly affected by their co-administration. Urinary glucose excretion (UGE) also increased in a dose-dependent manner, approaching a maximum effect at 50-100 mg dosages in Japanese healthy volunteers and patients with type 2 diabetes. The change in UGE from baseline (ΔUGE) tended to be lower in older subjects and female subjects, compared with younger subjects and male subjects, respectively. ΔUGE tended to decrease with decreasing renal function, especially in patients with type 2 diabetes with moderate or severe renal impairment.
Article
Type 2 diabetes mellitus is a prevalent, progressive disease with a need for innovative therapeutic agents to continue to advance disease management. Dapagliflozin is the second agent in a new class of oral antihyperglycemic drugs: sodium-glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 is responsible for the majority of renal glucose reuptake; inhibition of the cotransporter allows for increased renal glucose excretion that consequently leads to reduced plasma glucose levels. Because this mechanism does not require the action of insulin, dapagliflozin rarely causes hypoglycemia and is effective in patients both early and late in the course of their disease. Studies of dapagliflozin have demonstrated efficacy both as monotherapy and in combination with oral antihyperglycemic agents and insulin. Dapagliflozin has been shown to decrease hemoglobin A1c (HbA1c) values 6 mmol/mol (0.5%) to 8 mmol/mol (0.7%). The most common adverse reactions observed with dapagliflozin in clinical trials were female genital mycotic infections, urinary tract infections, and nasopharyngitis. Dapagliflozin is a new oral agent for type 2 diabetes with short-term efficacy similar to dipeptidyl peptidase 4 inhibitors; its long-term safety and efficacy are unknown.
Article
Objectives: Luseogliflozin is a selective sodium glucose cotransporter 2 inhibitor under development for the treatment of type 2 diabetes mellitus (T2DM). This phase II study was conducted to confirm the efficacy and safety of luseogliflozin monotherapy at doses of up to 10 mg in Japanese patients with T2DM. Patients and methods: Patients with hemoglobin A1c (HbA1c) of 6.9-10.5% on diet therapy were randomized in a double-blind manner to treatment with 1, 2.5, 5, or 10 mg luseogliflozin or placebo for 12 weeks (n = 56, 56, 54, 58, and 58, respectively). Trial registration: Japan Pharmaceutical Information Center (identifier: Japic CTI-101191). Main outcome measures: The primary endpoint was the change in HbA1c from baseline to the end of treatment. Other endpoints included fasting plasma glucose (FPG), postprandial plasma glucose (PPG) and body weight. Adverse events were recorded throughout the study. Results: HbA1c decreased significantly at the end of treatment in the 1, 2.5, 5, and 10 mg luseogliflozin groups compared with placebo (-0.29, -0.39, -0.46, and -0.43%, respectively, versus +0.22%; all P < 0.001), as did FPG and PPG (all P < 0.001). Body weight also decreased significantly in all luseogliflozin groups compared with placebo (all P < 0.001). The incidence rates of adverse events (40.0-50.0%) were not significantly different among the five groups. The overall incidence of hypoglycemia was low. Limitations of this study include the short study duration and the relatively small sample size. Conclusions: In Japanese patients with T2DM, luseogliflozin was well tolerated, improved glycemic control, and reduced body weight over 12 weeks of treatment at all tested doses. Doses of ≥2.5 mg achieved similar improvements in glycemic control.
Article
Ipragliflozin (Suglat(®) [Japan]), an orally active, next-generation sodium-glucose transporter 2 (SGLT2) inhibitor, has been developed by Astellas Pharma and Kotobuki Pharmaceutical for the treatment of type 2 diabetes mellitus. Ipragliflozin has received its first global approval in this indication in Japan, for use as monotherapy or in combination with another antihyperglycaemic agent (metformin, pioglitazone, a sulfonylurea, an α-glucosidase inhibitor, a dipeptidylpeptidase-4 inhibitor or nateglinide). Ipragliflozin is the first SGLT2 inhibitor to be approved in Japan. This article summarizes the milestones in the development of ipragliflozin leading to this first approval for the treatment of type 2 diabetes mellitus.
Article
Luseogliflozin, a sodium glucose cotransporter 2 inhibitor, inhibits reabsorption of glucose in the proximal renal tubule. It was developed for the treatment of type 2 diabetes mellitus. For this first human study of luseogliflozin, randomized, single-blind, placebo-controlled, single ascending dose (1-25 mg) and multiple ascending dose (5 or 10 mg/day, 7 days) trials were conducted in healthy male Japanese subjects to investigate safety, pharmacokinetics, and pharmacodynamics. There were no serious adverse events, adverse events leading to discontinuation, or episodes of hypoglycemia. After administration of a single oral dose of luseogliflozin, its maximum plasma level (C max) and area under the concentration-time curve increased in a dose-dependent manner, and no food effects were observed on pharmacokinetics. The mean time taken to reach C max (T max) ranged from 0.667 to 2.25 h. The mean plasma half-life of luseogliflozin (T 1/2) after multiple dosing for 7 days ranged from 9.14 to 10.7 h, and no detectable accumulation of luseogliflozin was observed. Urinary glucose excretion increased in a dose-dependent manner, ranging from 18.9 to 70.9 g (single-dose study). Luseogliflozin was well tolerated and showed favorable pharmacokinetic and pharmacodynamic profiles in healthy male Japanese subjects.
Article
Background Empagliflozin is a potent, oral, selective inhibitor of sodium glucose cotransporter 2 in development for the treatment of type 2 diabetes mellitus. Objective The goal of these studies was to investigate potential drug–drug interactions between empagliflozin and gemfibrozil (an organic anion-transporting polypeptide 1B1 [OATP1B1]/1B3 and organic anion transporter 3 [OAT3] inhibitor), rifampicin (an OATP1B1/1B3 inhibitor), or probenecid (an OAT3 and uridine diphosphate glucuronosyltransferase inhibitor). Methods Two open-label, randomized, crossover studies were undertaken in healthy subjects. In the first study, 18 subjects received the following in 1 of 2 randomized treatment sequences: a single dose of empagliflozin 25 mg alone and gemfibrozil 600 mg BID for 5 days with a single dose of empagliflozin 25 mg on the third day. In the second study, 18 subjects received a single dose of empagliflozin 10 mg, a single dose of empagliflozin 10 mg coadministered with a single dose of rifampicin 600 mg, and probenecid 500 mg BID for 4 days with a single dose of empagliflozin 10 mg on the second day in 1 of 6 randomized treatment sequences. Results In the gemfibrozil study, 11 subjects were male, mean age was 35.1 years and mean body mass index (BMI) was 23.47 kg/m2. In the rifampicin/probenecid study, 10 subjects were male, mean age was 32.7 years and mean BMI was 23.03 kg/m2. Exposure to empagliflozin was increased by coadministration with gemfibrozil (AUC0–∞: geometric mean ratio [GMR], 158.50% [90% CI, 151.77–165.53]; Cmax: GMR, 115.00% [90% CI, 106.15–124.59]), rifampicin (AUC0–∞: GMR, 135.20% [90% CI, 129.58–141.06]; Cmax: GMR, 175.14% [90% CI, 160.14–191.56]), and probenecid (AUC0–∞: GMR, 153.47% [90% CI, 146.41–160.88]; Cmax: GMR, 125.60% [90% CI, 113.67–138.78]). All treatments were well tolerated. Conclusions Increases in empagliflozin exposure were <2-fold, indicating that the inhibition of the OATP1B1/1B3, OAT3 transporter, and uridine diphosphate glucuronosyltransferases did not have a clinically relevant effect on empagliflozin exposure. No dose adjustments of empagliflozin were necessary when it was coadministered with gemfibrozil, rifampicin, or probenecid. ClinicalTrials.gov identifiers: NCT01301742 and NCT01634100.
Article
Sodium-glucose co-transporter 2 (SGLT2) is predominantly expressed in the S1 segment of the proximal tubule of the kidney and is the major transporter responsible for mediating renal glucose reabsorption. Dapagliflozin is an orally active, highly selective SGLT2 inhibitor that improves glycemic control in patients with type 2 diabetes mellitus (T2DM) by reducing renal glucose reabsorption leading to urinary glucose excretion (glucuresis). Orally administered dapagliflozin is rapidly absorbed generally achieving peak plasma concentrations within 2 h. Dose-proportional systemic exposure to dapagliflozin has been observed over a wide dose range (0.1–500 mg) with an oral bioavailability of 78 %. Dapagliflozin has extensive extravascular distribution (mean volume of distribution of 118 L). Dapagliflozin metabolism occurs predominantly in the liver and kidneys by uridine diphosphate-glucuronosyltransferase-1A9 to the major metabolite dapagliflozin 3-O-glucuronide (this metabolite is not an SGLT2 inhibitor at clinically relevant exposures). Dapagliflozin is not appreciably cleared by renal excretion (