Sodium-dependent Glucose Transporter 2 Inhibitor Research Articles

Pharmacological Research Progress of Novel Antihypertensive Drugs.

Cardiovascular disease stands as the leading cause of death globally, with hypertension emerging as an independent risk factor for its development. The worldwide prevalence of hypertension hovers around 30%, encompassing a staggering 1.2 billion patients, and continues to escalate annually. Medication plays a pivotal role in managing hypertension, not only effectively regulating blood pressure (BP) but also substantially mitigating the occurrence of cardiovascular and cerebrovascular diseases. This review comprehensively outlines the categories, mechanisms, clinical applications, and drawbacks of conventional antihypertensive drugs. It delves into the five primary pharmacological classifications, namely β-receptor blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and diuretics. The emphasis is placed on elucidating the mechanisms, advantages, and research progress of novel antihypertensive drugs targeting emerging areas. These include mineralocorticoid receptor antagonists (MRAs), atrial natriuretic peptides (ANPs), neutral endopeptidase inhibitors (NEPIs), sodium-dependent glucose transporter 2 inhibitors (SGLT-2Is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), endothelin receptor antagonists (ERAs), soluble guanylate cyclase (sGC) agonists, brain aminopeptidase A inhibitors (APAIs), and small interfering ribonucleic acids (siRNAs) targeting hepatic angiotensinogen. Compared to conventional antihypertensive drugs, these novel alternatives exhibit favorable antihypertensive effects with minimal adverse reactions. This review serves as a valuable reference for future research and the clinical application of antihypertensive drugs.

The SGLT2 inhibitor empagliflozin attenuates atherosclerosis progression by inducing autophagy.

Cardiovascular disease due to atherosclerosis is one of the leading causes of death worldwide; however, the underlying mechanism has yet to be defined. The sodium-dependent glucose transporter 2 inhibitor (SGLT2i) empagliflozin is a new type of hypoglycemic drug. Recent studies have shown that empagliflozin not only reduces high glucose levels but also exerts cardiovascular-protective effects and slows the process of atherosclerosis. The purpose of this study was to elucidate the mechanism by which empagliflozin ameliorates atherosclerosis. Male apolipoprotein E-deficient (ApoE-/-) mice were fed a high-fat Western diet to establish an atherosclerosis model. The area and size of atherosclerotic lesions in ApoE-/- mice were then assessed by performing hematoxylin-eosin (HE) staining after empagliflozin treatment. Concurrently, oxidized low-density lipoprotein (oxLDL) was used to mimic atherosclerosis in three different types of cells. Then, following empagliflozin treatment of macrophage cells (RAW264.7), human aortic smooth muscle cells (HASMCs), and human umbilical vein endothelial cells (HUVECs), western blotting was applied to measure the levels of autophagy-related proteins and proinflammatory cytokines, and green fluorescent protein (GFP)-light chain 3 (LC3) puncta were detected using confocal microscopy to confirm autophagosome formation. Oil Red O staining was performed to detect the foaming of macrophages and HASMCs, and flow cytometry was used for the cell cycle analysis. 5-ethynyl-2'-deoxyuridine (EdU), cell counting kit-8 (CCK-8), and scratch assays were also performed to examine the proliferation and migration of HASMCs. Empagliflozin suppressed the progression of atherosclerotic lesions in ApoE-/- mice. Empagliflozin also induced autophagy in RAW246.7 cells, HASMCs, and HUVECs via the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, and it significantly increased the levels of the Beclin1 protein, the LC3B-II/I ratio, and p-AMPK protein. In addition, empagliflozin decreased the expression of P62 and the protein levels of inflammatory cytokines, and it inhibited the foaming of RAW246.7 cells and HASMCs, as well as the expression of inflammatory factors by inducing autophagy. Empagliflozin activated autophagy through the AMPK signaling pathway to delay the progression of atherosclerosis. Furthermore, the results of flow cytometry, EdU assays, CCK-8 cell viability assays, and scratch assays indicated that empagliflozin blocked HASMCs proliferation and migration. Empagliflozin activates autophagy through the AMPK signaling pathway to delay the evolution of atherosclerosis, indicating that it may represent a new and effective drug for the clinical treatment of atherosclerosis.

SGLT2 inhibitor-pretreated macrophage transplantation improves adverse ventricular remodeling after acute myocardial infarction.

Macrophages play an important role in the progression of acute myocardial infarction (AMI). Studies have shown that sodium-dependent glucose transporter 2 inhibitor (SGLT2i) after AMI could increase the proportion of M2 type/M1 macrophages and reduces adverse ventricular remodeling (AVR) post AMI. This study aimed to investigate whether SGLT2i-pretreated macrophage transplantation could reduce AVR after AMI and the underlying mechanisms. C57BL/6 mice were used to establish an AMI model by ligating the coronary arteries. Dynamic observation of transplanted bone marrow-derived macrophages (BMDMs) was performed using an in vivo imaging system (IVIS). Cardiac function was assessed using echocardiography. The fibrosis ratio was measured using Masson's trichrome staining. Cardiomyocyte apoptosis was measured using the TUNEL assay. Macrophage subtypes were measured using flow cytometry. We detected the expression of inflammatory factors in the myocardium and serum using enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR). IVIS revealed that transplanted SGLT2i-pretreated BMDMs were present in the infarcted myocardium for 7 d. Flow cytometry revealed that SGLT2i-pretreated BMDMs promoted the conversion of native-derived macrophages to the M2-type. SGLT2i-pretreated BMDMs also reduced inflammatory factors (IL-6, TNFα, and IL-1β) in the infarcted myocardium and serum. At 28 d post-AMI, SGLT2i-pretreated BMDMs increased cardiac function and vascular density, but reduced cardiomyocyte hypertrophy. SGLT2i-pretreated BMDMs could reduce cardiomyocyte apoptosis and fibrotic area ratio. In conclusion, transplanted SGLT2i-pretreated BMDMs were present in the infarcted myocardium for 7 d and improved AVR by reducing inflammation and modulating the conversion of native mice-derived macrophages to M2-type macrophages.

Analysis of acute pancreatitis associated with SGLT-2 inhibitors and predictive factors of the death risk: Based on food and drug administration adverse event report system database.

Background and objectives: The US FDA and Health Canada have successively published potential red flags for acute pancreatitis caused by sodium-dependent glucose transporter 2 inhibitors (SGLT-2i). However, existing studies have focused on case reports. We aimed to assess the possible association of SGLT-2i with acute pancreatitis by analyzing postmarketing adverse events reported in the FDA adverse event reporting system (FAERS), to explore risk factors for SGLT-2i-related acute pancreatitis death, and to build a nomogram. Methods and Results: We used a disproportionality analysis of suspected acute pancreatitis-related reports in the FAERS database of patients from the use of SGLT-2i from the first quarter of 2013 to the fourth quarter of 2021. Single-factor and multi-factor logistic regression analyses were performed using the relevant clinical information of patients, and risk factors were combined with the age of patients to construct a SGLT-2i risk prediction model for acute pancreatitis-related death. A total of 757 reports were retrieved. The largest number of acute pancreatitis-related cases were caused by canagliflozin (317 reports), which was also the strongest agent associated with acute pancreatitis, with the information component (IC 2.41, lower 95% one-sided confidence interval 2.16), the reporting odds ratio (ROR 5.37, 95% two-sided confidence interval 4.8-5.99), and the empirical Bayesian geometric mean (EBGM 5.32, lower 90% one-sided confidence interval 4.85). The median time to acute pancreatitis was 54 (interquartile range [IQR] 14-131) days, and approximately 83% of adverse events occurred within 6 months. Odds ratio(OR) adjusted by acute pancreatitis and the coadministration of SGLT-2i with dipeptidyl peptidase 4 inhibitor (DPP-4i), glucagon-like peptide 1 analog (GLP-1RA), and angiotensin converting enzyme inhibitor (ACEIs) was 1.39, 1.97, and 1.34, respectively, all of which were statistically significant. Logistic regression analysis showed that different SGLT-2i type and their combinations with statins were independent risk factors for acute pancreatitis mortality in the patients (p < 0.05). The mortality risk prediction model showed good discrimination and clinical applicability in both the training set (AUC 0.708) and the validation set (AUC 0.732). Conclusion: SGLT-2i may increase the risk of acute pancreatitis especially within the first 6 months of drug administration. Combination with DPP-4i, GLP-1RA or ACEIs significantly increases the risk of acute pancreatitis. In addition, different SGLT-2i type and their combination with statins are risk factors that can predict the risk of death following acute pancreatitis.

Meta-analysis of the effect of sodium-dependent glucose transporter 2 inhibitors on C-reactive protein in type 2 diabetes.

Background:As novel hypoglycemic drugs, the effects of sodium-dependent glucose transporter 2 inhibitors (SGLT-2I) on inflammatory factors such as C-reactive protein (CRP) remain unclear.Methods:We conducted a meta-analysis of studies on SGLT-2I in the treatment of type 2 diabetes (T2DM) to observe the changes of CRP in patients with T2DM. We searched 4 electronic databases (CNKI, PubMed, EMBASE, and Cochrane Library) for articles published up to December 31, 2021. Studies were analyzed using a random-effects model to obtain standard deviation mean differences (SMDs) and 95% confidence intervals (CIs). Sensitivity and subgroup analyses were performed. Publication bias was evaluated using funnel plots and Egger test.Results:We included data from 927 patients in 13 confirmatory trials that showed a significant decrease in CRP among patients with T2DM treated with SGLT-2I. The decrease was more significant with than without SGLT-2I. In subgroup analysis according to nationality, medication, and comorbidities, CRP reduction was associated with nationality, SGLT-2I type, and the presence of comorbidities. Sensitivity analysis showed that our results were reliable and found no evidence of substantial publication bias.Conclusions:SGLT-2I could reduce CRP levels in patients with T2DM.Registration:International Prospective Register for Systematic Reviews (PROSPERO) number CRD42021268079.

Evaluation of Pharmacokinetic Interactions Between the New SGLT2 Inhibitor SHR3824 and Valsartan in Healthy Chinese Volunteers

Hypertension is often observed in patients with diabetes, and the progression of diabetic nephropathy is closely related to blood pressure elevation. Thus, the effects of hypoglycemic drugs on kidney function and pharmacokinetic interactions in combination with antihypertensive and hypoglycemic drugs are of great clinical value. The purpose of this study was to evaluate the pharmacokinetic interactions between henagliflozin (SHR3824), a new sodium-dependent glucose transporter 2 (SGLT2) inhibitor class drug, and valsartan, an angiotensin II receptor blocker. A single-center, single-arm, open-label, self-controlled study was conducted in healthy Chinese volunteers. The pharmacokinetic parameters were calculated with Phoenix WinNonlin version 7.0, and the statistical analysis was performed with SAS version 9.4. Data on pharmacokinetic parameters (single and/or steady-state) were collected and tabulated for different analytes (valsartan and SHR3824) according to the sampling time specified in the protocol. Continuous attention was paid to the safety of all subjects. The aim of the study was to evaluate the effect of a single dose of valsartan on the pharmacokinetic behavior of SHR3824 after multiple doses of SHR3824 (Cmax,ss and AUCτ,ss) and the effect of multiple doses of SHR3824 on the pharmacokinetic behavior of valsartan (Cmax, AUC0-24h, and AUC0-∞). A mixed effect model was used to estimate the point estimation and 90% CI of the geometric mean ratio of the corresponding pharmacokinetic indices at the combined-medication stage (SHR3824+valsartan) and the single-medication stage (SHR3824 or valsartan). Twelve volunteers were screened into this experiment and underwent blood sampling. The pharmacokinetic properties of SHR3824 were evaluated after its administration alone or in combination with valsartan. Point estimates and 90% CIs of the geometric mean ratio of SHR3824 Cmax,ss and AUCτ,ss were within the conventional bioequivalence range of 80% to 125%. The pharmacokinetic properties of valsartan were evaluated after its administration alone or in combination with SHR3824. The geometric mean ratios and 90% CIs of the valsartan Cmax, AUC0-24h, and AUC0-∞ were also within the range of 80% to 125%. Thirty-four mild adverse events were reported, with no serious adverse events or suspected unexpected serious adverse reactions. This study provides basis for the clinical co-administration of SHR3824 with angiotensin II receptor blockers represented by valsartan. Based on these findings, co-administration of SHR3824 and valsartan seemed to have no effect on the pharmacokinetic properties of either drug. Chinadrugtrials.org.cn Identifier: CTR20180002.

Effects of GLP-1RA and SGLT2i, Alone or in Combination, on Mouse Models of Type 2 Diabetes Representing Different Disease Stages.

Glucagon-like peptide-1 receptor agonist (GLP-1RA) and sodium-dependent glucose transporter 2 inhibitor (SGLT2i), in addition to lowering glucose, have pleiotropic effects on the heart, kidneys, and liver. These drugs have thus come into widespread use for treating type 2 diabetes (T2DM). However, mechanistic comparisons and effects of combining these drugs have not been adequately studied. Employing diet-induced obese (DIO) mice and db/db mice as models of the early and advanced stages of T2DM, we evaluated effects of single or combined use of liraglutide (a GLP-1RA) and ipragliflozin (a SGLT2i). Treatments with liraglutide and/or ipragliflozin for 28 days improved glycemic control and reduced hepatic lipid accumulation similarly in DIO mice. In contrast, in db/db mice, despite similar favorable effects on fatty liver, liraglutide exerted no beneficial effects on glycemic control. Improved glycemic control in db/db mice treated with ipragliflozin was accompanied by increased pancreatic β-cell area and insulin content, both of which tended to rise further when ipragliflozin was combined with liraglutide. Our data suggest that liraglutide is more efficient at an earlier stage and ipragliflozin can be effective in both stages. In addition, their combined use is a potential option for treating advanced stage diabetes with fatty liver disease.

The Role of SGLT2 Inhibitor on the Treatment of Diabetic Retinopathy.

Diabetic retinopathy (DR) is one of the most serious complications of diabetic microangiopathy. DR has an early onset and is not easy to detect. When visual impairment occurs, the optimal period for therapy is often missed. Therefore, the prevention and treatment of DR should start from the early stage of diabetes. Sodium-dependent glucose transporter 2 inhibitor (SGLT2i) is a new antidiabetic drug which is mainly used in clinical practice to control blood glucose of patients with type 2 diabetes prone to develop chronic heart failure. Recent studies have found that SGLT2 is also expressed in the human retina. Now, the prevention and treatment of diabetic retinopathy with SGLT2i while reducing blood sugar has become a new research field. Hence, this article reviewed the recent therapeutic and research progress of SGLT2 in the treatment of diabetic retinopathy.

Abstract A46: A novel patient-derived approach for preclinical evaluation of predictive imaging biomarkers in early lung cancer

Abstract Background: Lung cancer is the number one cause of cancer-related death, and lung adenocarcinoma (LUAD) is the most frequent type. Lung screening with computed tomography has allowed detection of early nodules that need diagnostic definition. We have identified the sodium-dependent glucose transporter 2 (SGLT2) as a novel diagnostic and therapeutic target that may aid the identification and the treatment of early LUAD. However, a limitation of these studies is the lack of experimental models of early cancer. Patient-derived xenografts (PDXs) are a reliable tool of translational oncology. However, the establishment of PDXs from early-stage, low-grade LUAD is characterized by low efficiency and extremely long experimental times. To study the predictive value of SGLT2 activity in early LUAD, we have established an alternative model based on a double culture system: 1) implantation of tumor tissue on the chorioallantoic membrane (CAM) of the chicken egg (in ovo system), which can be imaged only 1 week after the patient surgery; 2) growth of tumor spheroids in 3D in vitro culture, to test response to treatments. Methods: Each PDX of LUAD is divided in two specimens: one for in ovo growth in the CAM assay and one for the 3D culture as tumor spheroids. The CAM xenografts are imaged with two different tracers to characterize glucose uptake: [18F] fluorodeoxyglucose (FDG), to measure GLUT activity, and 4-[18F] fluorodeoxyglucose (Me4FDG), to assess sodium-dependent glucose transport (SGLT). The PD-tumor spheroids are cultured in 96-well plates and used for treatment with SGLT2 inhibitors as well as other drugs. Results: PET imaging of LUADs with FDG and Me4FDG revealed the presence of both glucose transporters, GLUT1 and SGLT2. Treatment of the tumor spheroids with SGLT2 inhibitors reduced cell viability and caused integrity loss in a dose-dependent manner. Conclusion: The CAM xenograft model is a useful model for implanting PD tumor fragments and studying glucose metabolism in ovo by PET imaging with very short experimental times. Tumor fragments connect to the chicken embryo vasculature within 3-5 days, so that PD material can be analyzed soon after surgery. The Me4FDG uptake in the CAM system predicts the treatment response of tumor spheroids cultured in vitro from the same PD samples. Citation Format: Eva J. Koziolek, Desiree Martin, Jie Liu, Jorge R. Barrio, W. Dean Wallace, David B. Shackelford, Jane Yanagawa, Steven Dubinett, Claudio Scafoglio. A novel patient-derived approach for preclinical evaluation of predictive imaging biomarkers in early lung cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A46.

Impact of antidiabetic agents on dementia risk: A Bayesian network meta-analysis

BackgroundDementia is more prevalent among people with type 2 diabetes, but little is known regarding the influence of antidiabetic agents on this association. ObjectiveThis study assessed the impact of various antidiabetic agents on the risk of dementia among patients with Type 2 diabetes mellitus. MethodsRelevant studies were retrieved from the PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov databases. Nine antidiabetic agents were included in the search. Data were pooled via network meta-analysis and meta-analysis. ResultsNine studies were selected for the network meta-analysis with 530,355 individuals and 17 studies for the meta-analysis with 1,258,879 individuals. The analysis excluded glucagon-like peptide 1 (GLP-1) analogs and sodium-dependent glucose transporter 2 (SGLT-2) inhibitors due to the absence of relevant data. The use of dipeptidyl peptidase-4 (DPP-4) inhibitors, metformin, thiazolidinedione, and sulfonylurea was associated with a decreased risk of dementia in comparison to no treatment with antidiabetic agents (hazard ratio [HR] for DPP-4 inhibitors, 0.54; 95% confidence interval [CI], 0.38–0.74, HR for metformin, 0.75; 95% CI, 0.63–0.86; HR for sulfonylurea, 0.85; 95%CI, 0.73–0.98 and HR for thiazolidinedione, 0.70; 95% CI, 0.55–0.89, respectively). However, the node-splitting analysis showed the inconsistency of direct and indirect estimates in sulfonylurea (P = 0.042). DPP-4 inhibitors, metformin, thiazolidinedione, and sulfonylurea exhibited a significant impact on the risk of dementia in diabetics compared with insulin (HR, 0.35; 95%CI, 0.20–0.59, HR, 0.48; 95% CI, 0.30–0.77, HR, 0.45; 95% CI, 0.29–0.73 and HR, 0.55; 95% CI, 0.34–0.88, respectively). DPP-4 inhibitors also exhibited a protective effect on the risk of Alzheimer's dementia compared with the no treatment with antidiabetic agents (HR, 0.48; 95% CI, 0.25–0.92). The meta-analysis demonstrated a protective effect of using metformin and DPP-4 inhibitors on the risk of dementia (HR, 0.86; 95% CI, 0.74–1.00 and HR, 0.65; 95% CI, 0.55–0.76, respectively). Further analysis showed insulin was associated with an increased risk of Alzheimer's dementia (HR, 1.60; 95% CI, 1.13–2.26). Only two case-control studies mentioned GLP-1 analogs and SGLT-2 inhibitors, and the pooled ORs showed no evidence of an association with dementia (GLP-1 analogs: 0.71; 95% CI, 0.46–1.10 and SGLT-2 inhibitors: 0.74; 95% CI, 0.47–1.15). ConclusionThis analysis indicated that patients with type 2 diabetes under treatment with DPP-4 inhibitors presented with the lowest risk of dementia, followed by those treated with metformin and thiazolidinedione, while treatment with insulin was associated with the highest risk. For the increasing focus on the protective effect on dementia, further specific clinical studies are needed to evaluate the impact of GLP-1 analogs and SGLT-2 inhibitors on the risk of dementia.

Comparing the effects of ipragliflozin versus metformin on visceral fat reduction and metabolic dysfunction in Japanese patients with type 2 diabetes treated with sitagliptin: A prospective, multicentre, open-label, blinded-endpoint, randomized controlled study (PRIME-V study).

A prospective, multicentre, open‐label, blinded‐endpoint, randomized controlled study was conducted to evaluate the efficacy of treatment with ipragliflozin (sodium‐dependent glucose transporter‐2 inhibitor) versus metformin for visceral fat reduction and glycaemic control among Japanese patients with type 2 diabetes treated with sitagliptin, HbA1c levels of 7%‐10%, and body mass index (BMI) ≥ 22 kg/m2. Patients were randomly assigned (1:1) to receive ipragliflozin 50 mg or metformin 1000‐1500 mg daily. The primary outcome was change in visceral fat area as measured by computed tomography after 24 weeks of therapy. The secondary outcomes were effects on glucose metabolism and lipid metabolism. Mean percentage reduction in visceral fat area was significantly greater in the ipragliflozin group than in the metformin group (−12.06% vs. −3.65%, P = 0.040). Ipragliflozin also significantly reduced BMI, subcutaneous fat area, waist circumference, fasting insulin, and homeostatic model assessment (HOMA)‐resistance, and increased HDL‐cholesterol levels. Metformin significantly reduced HbA1c and LDL‐cholesterol levels and increased HOMA‐beta. There were no severe adverse events. The use of ipragliflozin or metformin in combination with dipeptidyl peptidase‐4 inhibitors, widely used in Japan, may have beneficial effects in ameliorating multiple cardiovascular risk factors.

Dypeptidylpeptidase-4 inhibitors and the cardiovascular system: How to manage the fil rouge

Dypeptidylpeptidase-4 (DPP-4) inhibitors are a therapeutic option for improving glucose control in patients with type 2 diabetes. They can be prescribed at different stages of the natural history of the disease because of their low risk for hypoglycemia and associated weight gain. For all new drugs for diabetes, the US Food and Drug Administration requires the demonstration of the cardiovascular (CV) safety profile through pooled analyses of phase 3 studies or specifically designed trials.A significant superiority over placebo has been observed with a sodium-dependent glucose transporter-2 inhibitor, empagliflozin, and two glucagon-like peptide-1 receptor agonists, liraglutide and semaglutide, thus suggesting cardioprotective effects for some antidiabetic drugs.The neutral results of CV safety trials on DPP-4 inhibitors have been disappointing, appearing to contradict the data from pooled analyses and meta-analyses of early trials. The main aim of this review is to find a possible interpretation for the differences between the results of these early trials and the CV safety studies with DPP-4 inhibitors. We conclude that the hypothesis of additional beneficial effects by DPP-4 inhibitors (beyond the improvement of glucose control), on the CV system in low-risk patients in primary prevention, needs to be verified with specifically designed studies.

Study Protocol for the Effects of Formula Diet with Dapagliflozin on Metabolic Improvement and Body Composition in Type 2 Diabetes Mellitus.

IntroductionSodium-dependent glucose transporter-2 (SGLT2) inhibitors such as dapagliflozin induce weight loss, but the mechanism is thought to involve loss of both body fat and skeletal muscle mass. The decrease in skeletal muscle mass may lead to worsening of insulin resistance in type 2 diabetes patients. On the other hand, formula diet (FD) is a low-calorie food containing low carbohydrates, low fat, and sufficient protein, vitamins, and minerals to support a healthy and balanced diet, and is used for the treatment of obesity or diabetes. Therefore, we examine whether the protein supplementation is superior to the fat supplementation in metabolic improvement of the poorly controlled type 2 diabetes patients treated with SGLT2 inhibitor. We compare the therapeutic effects using two types of FD; a high protein FD and a high fat FD. Patients are prescribed dapagliflozin and replacement of one of three meals with FD. We compare high protein FD and high fat FD with respect to improvement of glycemic control while maintaining skeletal muscle mass.MethodsWe conduct a prospective, multicenter, double-blinded, randomized, controlled, investigator-initiated clinical trial. Patients who satisfy the eligibility criteria will be randomized to two groups (1:1) and prescribed 5 mg of dapagliflozin once daily together with a high protein FD or high fat FD (same number of calories) to replace one of three meals a day (one meal with FD only and two normal meals). The observation period for both groups is 24 weeks. The primary endpoint is the change in HbA1c.Planned OutcomesThis study is ongoing and scheduled to complete in June 2019. The findings of this study will be disseminated through peer-reviewed publications and conference presentations.Trial RegistrationUniversity Hospital Medical Information Network (UMIN) 000024580.FundingThis study was carried out under contract with the specified nonprofit corporation Hokkaido Institute of Health Sciences, based on a grant from AstraZeneca Co., Ltd. and Ono Pharmaceutical Co., Ltd. for an investigator-initiated clinical trial. The authors funded the journals article processing charges.

Ertugliflozin as a monotherapy for the treatment of type 2 diabetes

ABSTRACTIntroduction: Sodium-dependent glucose transporter 2 (SGLT2) inhibitors are novel, potent oral anti-diabetic agents in a β-cell function-independent manner, inhibiting SGLT2-mediated renal glucose reabsorption and thus increasing urinary glucose excretion. Ertugliflozin (SteglatroTM) is a new oral SGLT2 inhibitor for the treatment of patients with type 2 diabetes mellitus (T2DM) as a monotherapy or in combination with other anti-diabetic agents.Areas covered: This review summarizes the collected data concerning the pharmacokinetics, clinical efficacy, as well as safety and tolerability profiles of ertugliflozin given as a monotherapy for the management of T2DM.Expert opinion: Good glycemic control is crucial to the management of T2DM, and accordingly, anti-diabetic agents with various anti-hyperglycemic mechanisms are developed one after another. Based on the available clinical trials of ertugliflozin as a monotherapy for T2DM, it could be found that ertugliflozin effectively improves the glycemic control, body weight and blood pressure of patients with a low risk of hypoglycemia. It is also found that ertugliflozin moderately reduces their blood pressure, which is beneficial for decreasing the risk of cardiovascular disease. These attributes show the good potential of ertugliflozin as an adjunct treatment to diet and exercise for improving glycemic control in patients with T2DM.

Abstract A16: Sodium-dependent glucose transporter 2 is a novel diagnostic and therapeutic target for early-stage lung adenocarcinoma

Abstract Lung cancer claims approximately 160,000 lives in the United States every year, and lung adenocarcinoma (LADC) is the most frequent type. Early diagnosis is crucial; the National Lung Screening Trial showed a 20% reduction in mortality in high-risk individuals screened by computed tomography (CT). However, CT has low specificity in early-stage LADC. In vivo detection of glucose uptake by FDG PET is a standard tool for lung cancer staging, but has low sensitivity in early-stage LADC. Here, we demonstrate that GLUT transporters, responsible for FDG uptake, are expressed in advanced, poorly differentiated LADC, whereas early LADC utilizes a different glucose transport system, the sodium-dependent glucose transporter 2 (SGLT2), that is not detected by FDG. This can be imaged with the novel tracer Me4FDG. We investigated the expression of two different glucose transporters, GLUT1 and SGLT2, in a cohort of 56 human LADC specimens, in patient-derived xenografts, and in a KrasG12D-driven, p53-null genetically engineered mouse model of LADC. We observed a switch in the modality of glucose transport during lung carcinogenesis: SGLT2 was highly expressed in premalignant lesions and well-differentiated LADC, whereas GLUT1 was upregulated in advanced, poorly differentiated lesions. This pattern was observed both in human samples and in murine models. This observation led us to hypothesize that early-stage LADCs are often negative on FDG PET because this imaging modality does not detect the activity of SGLT2, which is expressed in early lesions. Therefore, we performed PET imaging with the tracer Me4FDG, which measures SGLT2 activity, in our mouse model, and observed that Me4FDG accumulated in small nodules that were negative with FDG. We confirmed the functionality of SGLT2 in human LADC by Me4FDG PET in patient-derived xenografts. Finally, we tested the hypothesis that sodium-dependent glucose transport is a critical metabolic supply strategy in the early stages of lung adenocarcinoma development. We performed therapeutic trials in genetically engineered mouse models with the FDA-approved SGLT2 inhibitor canagliflozin, which slowed down tumor progression and prolonged mouse survival, by specifically reducing the proliferation rate of premalignant lesions. In conclusion, Me4FDG PET is a novel diagnostic test to image lung premalignancy and early-stage LADC. We propose that Me4FDG-PET will identify the patients who are likely to respond to SGLT2 inhibition, as a cancer interception strategy to prevent the progression of premalignancy to invasive disease, by blocking the supply of glucose required for proliferation of premalignant lesions. Citation Format: Claudio Scafoglio, Sean T. Bailey, Gihad Abdelhady, Jie Liu, Jane Yanagawa, Aditya Shirali, Dean W. Wallace, Jorge R. Barrio, Ernest M. Wright, Tonya Walser, Steven M. Dubinett, David B. Shackelford. Sodium-dependent glucose transporter 2 is a novel diagnostic and therapeutic target for early-stage lung adenocarcinoma [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A16.

Comparing the Effects of Ipragliflozin versus Metformin Added to Sitagliptin on Visceral Fat Reduction in Asian Patients with Type 2 Diabetes: A Prospective, Multicenter, Blinded-Endpoint Randomized Controlled Study (PRIME-V Study)

Background: Visceral fat accumulation is associated with insulin resistance and various metabolic complications. We aimed to determine the effect of ipragliflozin (sodium-dependent glucose transporter-2 inhibitor) versus metformin with a dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin) in reducing visceral fat in Asian patients with insufficiently controlled type 2 diabetes. Methods: A prospective, multicenter, blinded-endpoint, randomized controlled study was conducted to evaluate the efficacy of treatment with either ipragliflozin or metformin combined with sitagliptin on visceral fat reduction and glycemic control among Japanese patients with type 2 diabetes, HbA1c 7-10%, and BMI ≥22 kg/m2. Patients who met the eligibility criteria were randomly assigned (1:1) to receive ipragliflozin 50 mg (n=51) or metformin 1000-1500 mg daily (n=52). The primary outcome was rate change in visceral fat area measured by computed tomography at 24 weeks of therapy. Two radiologists, blinded to patients' clinical information and randomized treatment assignment, analyzed the images. Secondary outcomes included effects on blood glucose, fasting insulin level, and lipids. The full analysis set was used for analysis. Findings: Mean percent reduction in visceral fat area was significantly greater in the ipragliflozin group than in the metformin group (-12·06% vs. -3·65%, group difference [95% CI] -8·40%; [-16·4 to -3·38], P=0·040). The ipragliflozin group also showed significant lowering of fasting insulin (-20·73% vs. 0·85%, group difference [95% CI] -21·58%, [2·80 to 34·20], P=0·018), while HbA1c decreased in the metformin group compared with ipragliflozin group. Interpretation: Ipragliflozin significantly reduced the visceral fat area compared with metformin, as the secondary agent used in combination with DPP-4 inhibitor. Since the fasting insulin level decreased, the reduction in visceral fat associated with ipragliflozin administration might have contributed to the improvement in insulin resistance. Trial Registration Number: Trial registration: UMIN 000015170. Funding Statement: To conduct this study, an agreement was signed between Chiba University and Astellas Pharma Inc. (Tokyo, Japan). Astellas Pharma Inc. funded this work. Declaration of Interests: KY received research grants from Astellas Pharma Inc. and MSD K.K. (Tokyo, Japan), and received a lecture fee from Astellas Pharma Inc. and Sumitomo Dainippon Pharma (Tokyo, Japan). No conflicts of interest are declared for other authors. Ethics Approval Statement: The study protocol was approved by the Institutional Review Boards (IRBs), Ethics Review Committees, or Ethics Committees of the following institutions: Chiba University Hospital (ID number: G26009), Asahi General Hospital (ID number: 2014091602), National Hospital Organization Chiba Medical Center, Seirei Sakura Citizen Hospital, Chiba Rosai Hospital (ID number: 26-21), Toho University Sakura Medical Center (ID number: 2014-077), Tokyo Women’s Medical University Yachiyo Medical Center (ID number: 150303), Chiba Aoba Municipal Hospital, Kimitsu Chuo Hospital, Funabashi Central Hospital (ID number: H27-1), and Chiba Kaihin Municipal Hospital. In other facilities, approval was provided at Chiba University Hospital (which had the centralized IRB).

Efficacy and safety of ipragliflozin and metformin for visceral fat reduction in patients with type 2 diabetes receiving treatment with dipeptidyl peptidase-4 inhibitors in Japan: a study protocol for a prospective, multicentre, blinded-endpoint phase IV randomised controlled trial (PRIME-V study)

IntroductionIn Japan, dipeptidyl peptidase-4 (DPP-4) inhibitors are frequently used as the treatment of choice for patients with type 2 diabetes. In some cases, however, poor glycaemic and body weight control...

New Antihyperglycemic Drugs and Heart Failure: Synopsis of Basic and Clinical Data.

The assessment of the cardiovascular safety profile of any newly developed antihyperglycemic drug is mandatory before registration, as a meta-analysis raised alarm describing a significant increase in myocardial infarction with the thiazolidinedione rosiglitazone. The first results from completed cardiovascular outcome trials are already available: TECOS, SAVOR-TIMI, and EXAMINE investigated dipeptidyl peptidase 4 (DPP-4) inhibitors, ELIXA, LEADER, and SUSTAIN-6 investigated glucagon-like peptide 1 (GLP-1) receptor agonists, and EMPA-REG OUTCOME and CANVAS investigated sodium-dependent glucose transporter 2 (SGLT-2) inhibitors. LEADER, SUSTAIN-6, EMPA-REG OUTCOME, and CANVAS showed potential beneficial results, while the SAVOR-TIMI trial had an increased rate of hospitalization for heart failure. Meanwhile, the same drugs are investigated in preclinical experiments mainly using various animal models, which aim to find interactions and elucidate the underlying downstream mechanisms between the antihyperglycemic drugs and the cardiovascular system. Yet the direct link for observed effects, especially for DPP-4 and SGLT-2 inhibitors, is still unknown. Further inquiry into these mechanisms is crucial for the interpretation of the clinical trials' outcome and, vice versa, the clinical trials provide hints for an involvement of the cardiovascular system. The synopsis of preclinical and clinical data is essential for a detailed understanding of benefits and risks of new antihyperglycemic drugs.

Diabetes Drug Effects on the Skeleton.

Diabetes be it type 1 or type 2 is associated with an increased risk of fragility fractures. The mechanisms underlying this increased risk are just being elucidated. Anti-diabetes medications are crucial for maintaining glucose control and for preventing micro- and macrovascular complications in diabetes. However, they may modulate fracture risk in diabetes in different ways. Thiazolidinediones have demonstrated an unfavorable effect on the skeleton, while metformin and sulfonylureas may have a neutral if not beneficial effect on bone. The use of insulin has been associated with an increased risk of fragility fractures though it is not clear whether it is due to direct influence of insulin or whether it is mediated through hypoglycemia and increased falls risk. The overall effect of incretin mimetics appears to be beneficial; however, this has to be elucidated further. The bone effects of pramlintide, a synthetic analog of amylin, have not been explored fully. Finally, issues regarding bone safety of SGLT2 (sodium-dependent glucose transporter 2) inhibitors, the newest anti-diabetic medications on the market are of concern. The purpose of this review is to provide a comprehensive overview of the effect of these medications on bone metabolism and the studies exploring the risk or lack thereof of these medications on bone loss and fragility fractures.

A new and improved process for C-aryl glucoside SGLT2 inhibitors

A practical and scalable synthesis of C-glycosides identified as highly potent sodium-dependent glucose transporter 2 (SGLT2) inhibitors is described. Highlights of the synthetic process are a concise, ten-step synthesis of a structurally complex active pharmaceutical ingredient from a known intermediate via a selective and quantitative addition of an aryl species to the Weinreb amide, and the isomers of undesired ortho-products were avoided during the preparation. The chemistry developed has been applied to prepare SGLT2 inhibitors without recourse to chromatography.