Euglycemic diabetic ketoacidosis(EDKA)is a well-known complication of sodium-glucose co-transporter 2 inhibitors,and many cases with variable onset following the initiation of these agents are reported before,with a m...Euglycemic diabetic ketoacidosis(EDKA)is a well-known complication of sodium-glucose co-transporter 2 inhibitors,and many cases with variable onset following the initiation of these agents are reported before,with a median onset of approximately 2 wk.This letter discusses a 45-year-old lady who initially presented with ischemic stroke but developed EDKA 4 d after starting empagliflozin,a rare occurrence.The patient had severe metabolic acidosis that necessitated admission into the intensive care unit.Prompt discontinuation of empagliflozin and DKA management resulted in clinical recovery.展开更多
Sodium-glucose co-transporter 2(SGLT2)inhibitors are an insulin-independent class of oral antihyperglycemic medication and from recently established therapy in chronic heart failure patients.A rare,but potentially lif...Sodium-glucose co-transporter 2(SGLT2)inhibitors are an insulin-independent class of oral antihyperglycemic medication and from recently established therapy in chronic heart failure patients.A rare,but potentially life-threatening complication of SGLT2 inhibitor use is euglycemic diabetic ketoacidosis.We described a case of a middle-aged male patient with type 2 diabetes who developed metabolic ketoacidosis after a few days of empagliflozin administration.SGLT2 inhibitor related ketoacidosis presents with euglycemia or only modestly elevated glucose blood concentrations,which causes delayed detection and treatment of ketoacidosis.There are multiple possible risk factors and mechanism that might contribute to the pathogenesis of ketoacidosis.It is implied that SGLT2 inhibitor use and prescription by non-diabetologists(cardiologists,nephrologists,family physicians,etc.)will continue to grow in the future.It is important to inform the general cardiac public about this rare but serious side effect of SGLT2 inhibitors.展开更多
Sodium-glucose cotransporter-2 inhibitors (SGLT-2 inhibitors) have transformed diabetes management by targeting renal glucose reabsorption. Designed initially as antidiabetic agents, their ability to lower blood gluco...Sodium-glucose cotransporter-2 inhibitors (SGLT-2 inhibitors) have transformed diabetes management by targeting renal glucose reabsorption. Designed initially as antidiabetic agents, their ability to lower blood glucose levels independently of insulin is well-documented. Beyond glycemic control, emerging research has unveiled their profound cardiorenal benefits. By inhibiting SGLT-2 protein, these drugs enhance glucose excretion in urine, reducing blood glucose levels. This mechanism has translated into significant cardiovascular and renal protection, establishing SGLT-2 inhibitors as pivotal in managing not only diabetes but also cardiovascular and renal diseases. Recent studies have illuminated the broader therapeutic potential of SGLT-2 inhibitors beyond diabetes. Evidence indicates their efficacy in managing heart failure, chronic kidney disease (CKD), and cardiovascular complications in individuals with or without diabetes. This expanded therapeutic landscape has catalyzed a paradigm shift in SGLT-2 inhibitor use, positioning them as key agents in the cardiorenal metabolic continuum. Moreover, their role in the secondary prevention of cardiovascular events and slowing CKD progression in T2DM patients has garnered considerable attention. This consensus-based review aims to offer practical guidance in an algorithmic approach to primary care healthcare professionals to optimize SGLT-2 inhibitors utilization and maximize their benefits. The review seeks to empower clinicians to effectively manage patients who may benefit from SGLT-2 inhibitor therapy by addressing common initiation barriers and optimizing treatment strategies. Additionally, it aims to raise awareness among primary care physicians regarding the multifaceted benefits of these medications and overcome clinical inertia in their adoption into routine clinical practice.展开更多
Mitochondrial dysfunction is a key driver of cardiovascular disease(CVD)in metabolic syndrome and diabetes.This dysfunction promotes the production of reactive oxygen species(ROS),which cause oxidative stress and infl...Mitochondrial dysfunction is a key driver of cardiovascular disease(CVD)in metabolic syndrome and diabetes.This dysfunction promotes the production of reactive oxygen species(ROS),which cause oxidative stress and inflammation.Angiotensin II,the main mediator of the renin-angiotensin-aldosterone system,also contributes to CVD by promoting ROS production.Reduced activity of sirtuins(SIRTs),a family of proteins that regulate cellular metabolism,also worsens oxidative stress.Reduction of energy production by mitochondria is a common feature of all metabolic disorders.High SIRT levels and 5’adenosine monophosphate-activated protein kinase signaling stimulate hypoxia-inducible factor 1 beta,which promotes ketosis.Ketosis,in turn,increases autophagy and mitophagy,processes that clear cells of debris and protect against damage.Sodiumglucose cotransporter-2 inhibitors(SGLT2i),a class of drugs used to treat type 2 diabetes,have a beneficial effect on these mechanisms.Randomized clinical trials have shown that SGLT2i improves cardiac function and reduces the rate of cardiovascular and renal events.SGLT2i also increase mitochondrial efficiency,reduce oxidative stress and inflammation,and strengthen tissues.These findings suggest that SGLT2i hold great potential for the treatment of CVD.Furthermore,they are proposed as anti-aging drugs;however,rigorous research is needed to validate these preliminary findings.展开更多
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent cause of chronic liver disease worldwide. NAFLD is considerably more frequent in patients with type 2 diabetes mellitus (T2DM) than in the general populat...Nonalcoholic fatty liver disease (NAFLD) is the most prevalent cause of chronic liver disease worldwide. NAFLD is considerably more frequent in patients with type 2 diabetes mellitus (T2DM) than in the general population and is also more severe histologically in this group. Sodium-glucose co-transporter-2 (SGLT2) inhibitors, the newest class of antidiabetic agents, appear to represent a promising option for the management of NAFLD in patients with T2DM. In a number of studies, treatment with SGLT2 inhibitors resulted in a reduction in hepatic steatosis and in transaminase levels. However, existing studies are small, their follow-up period was short and none evaluated the effects of SGLT2 inhibitors on liver histology. Accordingly, larger studies are needed to verify these preliminary results and define the role of SGLT2 inhibitors in the treatment of NAFLD in patients with T2DM.展开更多
Heart failure(HF)is a major complication of diabetes mellitus(DM).Patients with DM have considerably higher risk for HF than non-diabetic subjects and HF is also more severe in the former.Given the rising prevalence o...Heart failure(HF)is a major complication of diabetes mellitus(DM).Patients with DM have considerably higher risk for HF than non-diabetic subjects and HF is also more severe in the former.Given the rising prevalence of DM,the management of HF in diabetic patients has become the focus of increased attention.In this context,the findings of several randomized,placebo-controlled trials that evaluated the effects of sodium-glucose co-transporter-2 inhibitors on the risk of hospitalization for HF in patients with type 2 DM represent a paradigm shift in the management of HF.These agents consistently reduced the risk of hospitalization for HF both in patients with and in those without HF.These benefits appear to be partly independent from glucose-lowering and have also been reported in patients without DM.However,there are more limited data regarding the benefit of sodium-glucose co-transporter-2 inhibitors in patients with HF and preserved left ventricular ejection fraction,which is the commonest type of HF in diabetic patients.展开更多
Fulminant type 1 diabetes mellitus(FT1DM)is a subtype of type 1 diabetes mellitus characterized by an abrupt onset and a rapid and complete functional loss of isletβcells.It is a very rare disease generally associate...Fulminant type 1 diabetes mellitus(FT1DM)is a subtype of type 1 diabetes mellitus characterized by an abrupt onset and a rapid and complete functional loss of isletβcells.It is a very rare disease generally associated with ketoacidosis and the absence of circulating pancreatic islet-related autoantibodies.Diabetic ketoacidosis with normal blood glucose levels has been reported during sodiumglucose co-transporter 2(SGLT2)inhibitor therapy.CASE SUMMARY The patient was a 43-year-old woman that consulted a medical practitioner for malaise,thirst,and vomiting.Blood analysis showed high blood glucose levels(428 mg/dL),a mild increase of hemoglobin A1c(6.6%),and increased ketone bodies in urine.The patient was diagnosed with type 2 diabetes mellitus.The patient was initially treated with insulin,which was subsequently changed to an oral SGLT2 inhibitor.Antibodies to glutamic acid decarboxylase were negative.Four days after receiving oral SGLT2 inhibitor,she consulted at Mie University Hospital,complaining of fatigue and vomiting.Laboratory analysis revealed diabetic ketoacidosis with almost normal blood glucose levels.The endogenous insulin secretion was markedly low,and the serum levels of islet-related autoantibodies were undetectable.We made the diagnosis of FT1DM with concurrent SGLT2 inhibitor-associated euglycemic diabetic ketoacidosis.The patient's general condition improved after therapy with intravenous insulin and withdrawal of oral medication.She was discharged on day 14 with an indication of multiple daily insulin therapy.CONCLUSION This patient is a rare case of FT1DM that developed SGLT2 inhibitor-associated diabetic ketoacidosis with almost normal blood glucose levels.This case report underscores the importance of considering the diagnosis of FT1DM in patients with negative circulating autoantibodies and a history of hyperglycemia that subsequently develop euglycemic diabetic ketoacidosis following treatment with a SGLT2 inhibitor.展开更多
BACKGROUND Sodium-glucose cotransporter-2 inhibitors(SGLT2i)are commonly prescribed to manage patients with diabetes mellitus.These agents may rarely lead to the development of euglycemic diabetic ketoacidosis(EDKA),w...BACKGROUND Sodium-glucose cotransporter-2 inhibitors(SGLT2i)are commonly prescribed to manage patients with diabetes mellitus.These agents may rarely lead to the development of euglycemic diabetic ketoacidosis(EDKA),which may complicate the disease course of these patients.AIM To analyze the demographic profile,predisposing factors,symptomology,clinical interventions and outcomes of patients presenting with EDKA secondary to SGLT2i use by reviewing the published case reports and series.METHODS We performed a systematic search of PubMed,Science Direct,Google Scholar and Reference Citation Analysis databases using the terms“canagliflozin”OR“empagliflozin”OR“dapagliflozin”OR“SGLT2 inhibitors”OR“Sodium-glucose cotransporter-2”AND“euglycemia”OR“euglycemic diabetic ketoacidosis”OR“metabolic acidosis”.The inclusion criteria were:(1)Case reports or case series with individual patient details;and(2)Reported EDKA secondary to SGLT2i.Furthermore,the data were filtered from the literature published in the English language and on adults(>18 years).We excluded:(1)Conference abstracts;and(2)Case reports or series which did not have individual biochemical data.All the case reports and case series were evaluated.The data extracted included patient demographics,clinical symptomatology,clinical interventions,intensive care unit course,need for organ support and outcomes.RESULTS Overall,108 case reports and 17 cases series with 169 unique patients that met all the inclusion criteria were included.The majority of patients were females(54.4%,n=92),and the commonly reported symptoms were gastrointestinal(nausea/vomiting 65.1%,abdominal pain 37.3%)and respiratory(breathlessness 30.8%).One hundred and forty-nine(88.2%)patients had underlying type II diabetes,and the most commonly involved SGLT-2 inhibitor reported was empagliflozin(46.8%).A triggering factor was reported in most patients(78.7%),the commonest being acute severe infection(37.9%),which included patients with sepsis,coronavirus disease 2019,other viral illnesses,and acute pancreatitis.61.5%were reported to require intensive unit care,but only a minority of patients required organ support in the form of invasive mechanical ventilation(13%),vasopressors(6.5%)or renal replacement therapy(5.9%).The overall mortality rate was only 2.4%.CONCLUSION Patients on SGLT2i may rarely develop EDKA,especially in the presence of certain predisposing factors,including severe acute infections and following major surgery.The signs and symptoms of EDKA may be similar to that of DKA but with normal blood sugar levels,which may make the diagnosis challenging.Outcomes of EDKA are good if recognized early and corrective actions are taken.Hence,physicians managing such patients must be aware of this potential complication and must educate their patients accordingly to ensure early diagnosis and management.展开更多
BACKGROUND Diabetic ketoacidosis(DKA)manifests as hyperglycemia,metabolic acidosis,and ketosis.However,euglycemic DKA(eu-DKA)conceals severe DKA with glucose levels below 200 mg/dL.Sodium-glucose cotransporter-2(SGLT2...BACKGROUND Diabetic ketoacidosis(DKA)manifests as hyperglycemia,metabolic acidosis,and ketosis.However,euglycemic DKA(eu-DKA)conceals severe DKA with glucose levels below 200 mg/dL.Sodium-glucose cotransporter-2(SGLT2)inhibitors can induce eu-DKA in diabetic patients.Notably,coronavirus disease 2019(COVID-19)-infected individuals with diabetes using SGLT2 inhibitors face an augmented risk of eu-DKA due to the direct toxic impact of the virus on pancreatic islets.This study aims to comprehensively investigate the association between SGLT2 inhibitors and eu-DKA in COVID-19 patients through meticulous case report analysis.Additionally,we endeavor to examine the outcomes and treatment approaches for COVID-19-infected diabetics receiving SGLT2 inhibitors,providing indispensable insights for healthcare professionals managing this specific patient population.AIM To investigate the connection between SGLT2 inhibitors and euglycemic DKA in COVID-19 patients through a meticulous analysis of case reports.METHODS We conducted an exhaustive search across prominent electronic databases,including PubMed,SCOPUS,Web of Science,and Google Scholar.This search encompassed the period from December 2019 to May 2022,incorporating published studies and pre-prints.The search terms employed encompassed“SGLT2 inhibitors”,“euglycemic DKA”,“COVID-19”,and related variations.By incorporating these diverse sources,our objective was to ensure a thorough exploration of the existing literature on this subject,thereby augmenting the validity and robustness of our findings.RESULTS Our search yielded a total of seven case reports and one case series,collectively comprising a cohort of twelve patients.These reports detailed instances of eu-DKA in individuals with COVID-19.Crucially,all twelve patients were utilizing SGLT2 as their primary anti-diabetic medication.Upon admission,all oral medications were promptly discontinued,and the patients were initiated on intravenous insulin therapy to effectively manage the DKA.Encouragingly,eleven patients demonstrated a favorable outcome,while regrettably,one patient succumbed to the condition.Subsequently,SGLT2 were discontinued for all patients upon their discharge from the hospital.These findings provide valuable insights into the clinical management and outcomes of eu-DKA cases associated with COVID-19 and SGLT2,underscoring the critical importance of prompt intervention and vigilant medication adjustments.CONCLUSION Our study sheds light on the possibility of diabetic patients developing both drug-related and unrelated DKA,as well as encountering adverse outcomes in the context of COVID-19,despite maintaining satisfactory glycemic control.The relationship between glycemic control and clinical outcomes in COVID-19 remains ambiguous.Consequently,this systematic review proposes that COVID-19-infected diabetic patients using SGLT2 should contemplate alternative treatment protocols until their recovery from the disease.展开更多
According to recent epidemiological data, chronic kidney diseases (CKDs) affect approximately 10% of the global population. Like many countries, CKD is a significant public health issue in Saudi Arabia. The prevalence...According to recent epidemiological data, chronic kidney diseases (CKDs) affect approximately 10% of the global population. Like many countries, CKD is a significant public health issue in Saudi Arabia. The prevalence of CKD in Saudi Arabia is estimated to be around 4.5% of the adult population, with a higher prevalence in older age groups. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a class of oral medications used to treat type 2 diabetes mellitus (T2DM). In addition to their glucose-lowering effects, SGLT2i have been shown to have beneficial effects on kidney function in patients with or without T2DM. Therefore, a Saudi task force gathered to develop an explicit, evidence-based consensus on SGLT2i use in CKD Saudi patients. A panel of 14 experts made up a task force. An initial concept proposal was obtained. The proposal was divided into several topics discussed on 24 May 2023. A literature review was carried out. The literature search was completed on 3<sup>rd</sup> June 2023. A drafted report was distributed to the entire panel. Approval of the recommendations required consensus, defined as a majority approval (i.e. above 75%). The recommendations were revised to accommodate any differences of opinion until a consensus was reached. Recommendations were finally formulated on 21<sup>st</sup> June 2023. Subsequently, the panel reviewed and discussed the supporting rationale of the revised recommendations. This article presents these practical recommendations.展开更多
BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1RA)and sodium-glucose co-transporter-2 inhibitors(SGLT-2I)are associated with significant cardiovascular benefit in type 2 diabetes(T2D).However,GLP-1RA or SGL...BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1RA)and sodium-glucose co-transporter-2 inhibitors(SGLT-2I)are associated with significant cardiovascular benefit in type 2 diabetes(T2D).However,GLP-1RA or SGLT-2I alone may not improve some cardiovascular outcomes in patients with prior cardiovascular co-morbidities.AIM To explore whether combining GLP-1RA and SGLT-2I can achieve additional benefit in preventing cardiovascular diseases in T2D.METHODS The systematic review was conducted according to PRISMA recommendations.The protocol was registered on PROSPERO(ID:42022385007).A total of 107049 participants from eligible cardiovascular outcomes trials of GLP-1RA and SGLT-2I were included in network meta-regressions to estimate cardiovascular benefit of the combination treatment.Effect modification of prior myocardial infarction(MI)and heart failure(HF)was also explored to provide clinical insight as to when the INTRODUCTION The macro-and micro-vascular benefits of glucagon-like peptide-1 receptor agonists(GLP-1RA)and sodium-glucose co-transporter-2 inhibitors(SGLT-2I)are independent of their glucose-lowering effects[1].In patients with type 2 diabetes(T2D),the major cardiovascular outcome trials(CVOT)showed that dipeptidyl peptidase-4 inhibitors(DPP-4I)did not improve cardiovascular outcomes[2],whereas cardiovascular benefit of GLP-1RA or SGLT-2I was significant[3,4].Further subgroup analyses indicated that the background cardiovascular risk should be considered when examining the cardiovascular outcomes of these newer glucose-lowering medications.For instance,prevention of major adverse cardiovascular events(MACE)was only seen in those patients with baseline atherosclerotic cardiovascular disease[3,4].Moreover,a series of CVOT conducted in patients with heart failure(HF)have demonstrated that(compared with placebo)SGLT-2I significantly reduced risk of hospitalization for HF or cardiovascular death,irrespective of their history of T2D[5-8].However,similar cardiovascular benefits were not observed in those with myocardial infarction(MI)[9,10].Cardiovascular co-morbidities are not only approximately twice as common but are also associated with dispropor-tionately worse cardiovascular outcomes in patients with T2D,compared to the general population[11].Therefore,it is of clinical importance to investigate whether the combination treatment of GLP-1RA and SGLT-2I could achieve greater cardiovascular benefit,particularly when considering patients with cardiovascular co-morbidities who may not gain sufficient cardiovascular protection from the monotherapies.This systematic review with multiple network meta-regressions was mainly aimed to explore whether combining GLP-1RA and SGLT-2I can provide additional cardiovascular benefit in T2D.Cardiovascular outcomes of these newer antidiabetic medications were also estimated under effect modification of prior cardiovascular diseases.This was to provide clinical insight as to when the combination treatment might be prioritized.展开更多
Three major cardiovascular outcome trials(CVOTs)with a new class of antidiabetic drugs-sodium-glucose cotransporter 2(SGLT2)inhibitors(EMPAREG OUTCOME trial with empagliflozin,CANVAS Program with canagliflozin,DECLARE...Three major cardiovascular outcome trials(CVOTs)with a new class of antidiabetic drugs-sodium-glucose cotransporter 2(SGLT2)inhibitors(EMPAREG OUTCOME trial with empagliflozin,CANVAS Program with canagliflozin,DECLARE-TIMI 58 with dapagliflozin)unexpectedly showed that cardiovascular outcomes could be improved possibly due to a reduction in heart failure risk,which seems to be the most sensitive outcome of SGLT2 inhibition.No other CVOT to date has shown any significant benefit on heart failure events.Even more impressive findings came recently from the DAPA-HF trial in patients with confirmed and well-treated heart failure:Dapagliflozin was shown to reduce heart failure risk for patients with heart failure with reduced ejection fraction regardless of diabetes status.Nevertheless,despite their possible wide clinical implications,there is much doubt about the mechanisms of action and a lot of questions to unravel,especially now when their benefits translated to nondiabetic patients,rising doubts about the validity of some current mechanistic assumptions.The time frame of their cardiovascular benefits excludes glucoselowering and antiatherosclerotic-mediated effects and multiple other mechanisms,direct cardiac as well as systemic,are suggested to explain their early cardiorenal benefits.These are:Anti-inflammatory,antifibrotic,antioxidative,antiapoptotic properties,then renoprotective and hemodynamic effects,attenuation of glucotoxicity,reduction of uric acid levels and epicardial adipose tissue,modification of neurohumoral system and cardiac fuel energetics,sodiumhydrogen exchange inhibition.The most logic explanation seems that SGLT2 inhibitors timely target various mechanisms underpinning heart failure pathogenesis.All the proposed mechanisms of their action could interfere with evolution of heart failure and are discussed separately within the main text.展开更多
Sodium-glucose cotransporter 2(SGLT2) inhibition induces glucosuria and decreases blood glucose levels in diabetic patients and lowers hypoglycemic risk. SGLT1 is expressed in the kidney and intestine; SGLT1 inhibitio...Sodium-glucose cotransporter 2(SGLT2) inhibition induces glucosuria and decreases blood glucose levels in diabetic patients and lowers hypoglycemic risk. SGLT1 is expressed in the kidney and intestine; SGLT1 inhibition causes abdominal symptoms such as diarrhea and reduces incretin secretion. Therefore, SGLT2 selectivity is important. Ipragliflozin is highly selective for SGLT2. In type 2 diabetes mellitus(T2DM), urinaryglucose excretion increased to 90 g/24 h after 28 d of treatment with ipragliflozin 300 mg/d. Twelve weeks of ipragliflozin 50 mg/d vs placebo reduced glycated hemoglobin and body weight by 0.65% and 0.66 kg, respectively, in Western T2 DM patients, and by 1.3% and 1.89 kg, respectively, in Japanese patients. Ipragliflozin(highly selective SGLT2 inhibitor) improves glycemic control and reduces body weight and lowers hypoglycemic risk and abdominal symptoms. Ipragliflozin can be a novel anti-diabetic and antiobesity agent.展开更多
BACKGROUND Landmark trials have established the benefits of sodium-glucose cotransporter-2 inhibitors(SGLT2-Is)in cardiovascular disease including heart failure with reduced and preserved ejection fraction and renal d...BACKGROUND Landmark trials have established the benefits of sodium-glucose cotransporter-2 inhibitors(SGLT2-Is)in cardiovascular disease including heart failure with reduced and preserved ejection fraction and renal diseases regardless of the presence of diabetes mellitus.However,studies evaluating the role of SGLT2-Is in metabolic syndrome(MetS)are limited.AIM This study primarily aimed to evaluate the impact of SGLT2-Is on the components of MetS.METHODS Two independent reviewers and an experienced librarian searched Medline,Scopus and the Cochrane central from inception to December 9,2021 to identify placebo controlled randomized controlled trials that evaluated the impact of SGLT2-Is on the components of MetS as an endpoint.Pre-and post-treatment data of each component were obtained.A meta-analysis was performed using the RevMan(version 5.3;Copenhagen:The Nordic Cochrane Center,The Cochrane Collaboration).RESULTS Treatment with SGLT2-Is resulted in a decrease in fasting plasma glucose(–18.07 mg/dL;95%CI:-25.32 to–10.82),systolic blood pressure(–1.37 mmHg;95%CI:-2.08 to–0.65),and waist circumference(–1.28 cm;95%CI:-1.39 to–1.18)compared to placebo.The impact on highdensity lipoprotein cholesterol was similar to placebo(0.01 mg/dL;95%CI:-0.05 to 0.07).CONCLUSION SGLT2-Is have a promising role in the management of MetS.展开更多
Solid organ transplantation offers life-saving treatment for patients with endorgan dysfunction.Patient survival and quality of life have improved over the past few decades as a result of pharmacological development,e...Solid organ transplantation offers life-saving treatment for patients with endorgan dysfunction.Patient survival and quality of life have improved over the past few decades as a result of pharmacological development,expansion of the donor pool,technological advances and standardization of practices related to transplantation.Still,transplantation is associated with cardiovascular complications,of which post-transplant diabetes mellitus(PTDM)is one of the most important.PTDM increases mortality,which is best documented in patients who have received kidney and heart transplants.PTDM results from traditional risk factors seen in patients with type 2 diabetes mellitus,but also from specific posttransplant risk factors such as metabolic side effects of immunosuppressive drugs,post-transplant viral infections and hypomagnesemia.Oral hypoglycaemic agents are the first choice for the treatment of type 2 diabetes mellitus in non-transplanted patients.However,the evidence on the safety and efficacy of oral hypoglycaemic agents in transplant recipients is limited.The favourable risk/benefit ratio,which is suggested by large-scale and long-term studies on new glucoselowering drug classes such as glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors,makes studies warranted to assess the potential role of these agents in the management of PTDM.展开更多
Aim: The EMPA-REG OUTCOME study reported that the sodium-glucose cotransporter 2 inhibitor (SGLT2-i) suppressed cardiovascular (CV) events in patients with type 2 diabetes;we recently suggested that increase of the se...Aim: The EMPA-REG OUTCOME study reported that the sodium-glucose cotransporter 2 inhibitor (SGLT2-i) suppressed cardiovascular (CV) events in patients with type 2 diabetes;we recently suggested that increase of the serum magnesium (Mg) by SGLT2-i’s can, in part, explain this reduction. The objective of this study was to elucidate the mechanism underlying the elevation of the serum Mg level induced by treatment with SGLT2-i’s. Methods: We analyzed the data of 37 patients with type 2 diabetes who underwent clinical evaluation and laboratory assessment at baseline and the end of 3 months. To investigate the relationship between the changes in the serum Mg concentrations during 3 months’ treatment (ΔMg) and other variables, we carried out simple linear regression analysis and multiple linear regression analysis. Results: Three months’ treatment with the SGLT2-i resulted in a significant improvement of the body weight (BW), BMI, hemoglobin A1c (HbA1c), and fasting plasma glucose levels. The serum Mg increased significantly. Simple linear regression analysis revealed an association between the ΔMg and the serum triglyceride, serum Mg at baseline, change of the BW (ΔBW), and change of the HbA1c. Multiple linear regression analysis revealed a significant association between the ΔMg and the serum Mg level at the baseline (r = -0.55, P Conclusion: Our study revealed that a lower serum Mg level at the baseline and BW reduction were significantly associated with an increase in the serum Mg following 3 months’ treatment with SGLT2-i’s.展开更多
BACKGROUND Type 1 diabetes(T1D) is associated with major chronic microvascular complications which contribute significantly to diabetes associated morbidity.The protein primarily responsible for glucose reabsorption i...BACKGROUND Type 1 diabetes(T1D) is associated with major chronic microvascular complications which contribute significantly to diabetes associated morbidity.The protein primarily responsible for glucose reabsorption in the kidney is sodium glucose co-transporter 2(SGLT2). Presently, SGLT2 inhibitors are widely used in diabetic patients to improve blood glucose levels and prevent cardiovascular and renal complications. Given the broad therapeutic application of SGLT2 inhibitors, we hypothesised that SGLT2 inhibition may exert its protective effects via alterations of the gut microbiome and tested this in a type 1 diabetic mouse model of diabetic retinopathy.AIM To determine whether the treatment with two independent SGLT2 inhibitors affects gut health in a type 1 diabetic mouse model.METHODS The SGLT2 inhibitors empagliflozin or dapagliflozin(25 mg/kg/d) or vehicle dimethylsulfoxide(DMSO) were administered to C57 BL/6 J, Akita, Kimba and Akimba mice at 10 wk of age for 8 wk via their drinking water. Serum samples were collected and the concentration of succinate and the short chain fatty acid(SCFA) butyric acid was measured using gas chromatography-mass spectrometry. Enzyme-linked immunosorbent assay(ELISA) was performed to determine the concentration of insulin and leptin. Furthermore, the norepinephrine content in kidney tissue was determined using ELISA. Pancreatic tissue was collected and stained with haematoxylin and eosin and analysed using brightfield microscopy.RESULTS Due to the presence of the Akita allele, both Akita and Akimba mice showed a reduction in insulin production compared to C57 BL/6 J and Kimba mice.Furthermore, Akita mice also showed the presence of apoptotic bodies within the pancreatic islets. The acinar cells of Akita and Akimba mice showed swelling which is indicative of acute injury or pancreatitis. After 8 wk of SGLT2 inhibition with dapagliflozin, the intermediate metabolite of gut metabolism known as succinate was significantly reduced in Akimba mice when compared to DMSO treated mice. In addition, empagliflozin resulted in suppression of succinate levels in Akimba mice. The beneficial SCFA known as butyric acid was significantly increased in Akita mice after treatment with dapagliflozin when compared to vehicle treated mice. The norepinephrine content in the kidney was significantly reduced with both dapagliflozin and empagliflozin therapy in Akita mice and was significantly reduced in Akimba mice treated with empagliflozin.In non-diabetic C57 BL/6 J and Kimba mice, serum leptin levels were significantly reduced after dapagliflozin therapy.CONCLUSION The inhibition of SGLT2 reduces the intermediate metabolite succinate, increases SCFA butyric acid levels and reduces norepinephrine content in mouse models of T1 D. Collectively, these improvements may represent an important mechanism underlying the potential benefits of SGLT2 inhibition in T1 D and its complications.展开更多
An increasing body of evidence shows that new antidiabetic drugs—particularly sodium-glucose cotransporter 2(SGLT2)inhibitors and glucagon-like peptide 1(GLP-1)receptor agonists—have a beneficial effect on cardiovas...An increasing body of evidence shows that new antidiabetic drugs—particularly sodium-glucose cotransporter 2(SGLT2)inhibitors and glucagon-like peptide 1(GLP-1)receptor agonists—have a beneficial effect on cardiovascular outcome.The majority of these studies have been performed in patients with heart failure and the results have shown first positive effect on blood pressure(BP)reduction.These effects are more pronounced with SGLT2 inhibitors than with GLP-1 receptor agonists.However,the reasons and mechanisms of action inducing BP reduction are still not sufficiently clear.Proposed mechanisms of SGLT2 inhibitors involve the natriuretic effect,modification of the renin-angiotensin-aldosterone system,and/or the reduction in the sympathetic nervous system.GLP-1 receptor agonists have several mechanisms that are related to glycemic,weight,and BP control.Current data show that SGLT2 inhibitors have a stronger antihypertensive effect than GLP-1 receptor agonists,which is mainly related to their renal effect.Briefly,SGLT2 inhibitors increase the response to diuretics and decrease the meal-related antinatriuretic pressure by lowering post-prandial hyperglycemia and hyperinsulinemia and prevent proximal sodium reabsorption.SGLT2 inhibitors can be used as second-line therapy in patients with diabetes mellitus or heart disease and concomitant hypertension.This article aims to summarize current knowledge regarding the antihypertensive effect of SGLT2 inhibitors and GLP-1 receptor agonists.展开更多
In recent years, the progress of NAFLD has become an important health problem, and the prevention or delay of progress in NAFLD is a major key point. Whether or not to combine T2MD, people are interested in the mechan...In recent years, the progress of NAFLD has become an important health problem, and the prevention or delay of progress in NAFLD is a major key point. Whether or not to combine T2MD, people are interested in the mechanisms and efficacy of SGLT2i for NAFLD. In this review, we summarized the current clinical research on SGLT2i for the combination of T2MD’s NAFLD patients, and the latest evidence of external or animal experiments. These evidences will help us to more accurately understand the protective effects of SGLT2i in NAFLD. Lifestyle changes are still essential to prevent and treat NAFLD, and for all kinds of drugs that treat NAFLD in clinical trials, SGLT2i may be one of the promising treatments.展开更多
Canagliflozin(CANA)is a sodium-glucose co-transporter 2 inhibitor.One of the important mechanisms of CANA is the inhibitory effect on the glucose uptake in the proximal tubule of the nephron,and the other mechanism ca...Canagliflozin(CANA)is a sodium-glucose co-transporter 2 inhibitor.One of the important mechanisms of CANA is the inhibitory effect on the glucose uptake in the proximal tubule of the nephron,and the other mechanism can be the reduction of inflammatory cytokine expression monocytes and macrophages.It is proved by FDA for the management of type 2 diabetes.In the present work,we summarized the publication and clinical evidence of the CANA on healthy individuals and those with related metabolic diseases,such as type 1 and 2 diabetes,obesity,or cardiovascular and kidney diseases.This drug has been reported to offer potential advantages in regulating body weight and reducing heart failure,hypoglycemia,and stroke risk in patients with type 2 diabetes.Some in vitro and animal experiments also show that this drug has good effects on cancer treatment.However,some case reports and experiments also show the side effect of CANA,such as amputation,fracture,and pancreatitis,while the mechanism is still unknown.Overall,CANA has a good effect on the management of type 2 diabetes by reducing the risk of kidney failure,cardiovascular diseases,and stroke.However,as a new drug,more clinical trials and experiments of CANA should be carried out in the future.展开更多
文摘Euglycemic diabetic ketoacidosis(EDKA)is a well-known complication of sodium-glucose co-transporter 2 inhibitors,and many cases with variable onset following the initiation of these agents are reported before,with a median onset of approximately 2 wk.This letter discusses a 45-year-old lady who initially presented with ischemic stroke but developed EDKA 4 d after starting empagliflozin,a rare occurrence.The patient had severe metabolic acidosis that necessitated admission into the intensive care unit.Prompt discontinuation of empagliflozin and DKA management resulted in clinical recovery.
文摘Sodium-glucose co-transporter 2(SGLT2)inhibitors are an insulin-independent class of oral antihyperglycemic medication and from recently established therapy in chronic heart failure patients.A rare,but potentially life-threatening complication of SGLT2 inhibitor use is euglycemic diabetic ketoacidosis.We described a case of a middle-aged male patient with type 2 diabetes who developed metabolic ketoacidosis after a few days of empagliflozin administration.SGLT2 inhibitor related ketoacidosis presents with euglycemia or only modestly elevated glucose blood concentrations,which causes delayed detection and treatment of ketoacidosis.There are multiple possible risk factors and mechanism that might contribute to the pathogenesis of ketoacidosis.It is implied that SGLT2 inhibitor use and prescription by non-diabetologists(cardiologists,nephrologists,family physicians,etc.)will continue to grow in the future.It is important to inform the general cardiac public about this rare but serious side effect of SGLT2 inhibitors.
文摘Sodium-glucose cotransporter-2 inhibitors (SGLT-2 inhibitors) have transformed diabetes management by targeting renal glucose reabsorption. Designed initially as antidiabetic agents, their ability to lower blood glucose levels independently of insulin is well-documented. Beyond glycemic control, emerging research has unveiled their profound cardiorenal benefits. By inhibiting SGLT-2 protein, these drugs enhance glucose excretion in urine, reducing blood glucose levels. This mechanism has translated into significant cardiovascular and renal protection, establishing SGLT-2 inhibitors as pivotal in managing not only diabetes but also cardiovascular and renal diseases. Recent studies have illuminated the broader therapeutic potential of SGLT-2 inhibitors beyond diabetes. Evidence indicates their efficacy in managing heart failure, chronic kidney disease (CKD), and cardiovascular complications in individuals with or without diabetes. This expanded therapeutic landscape has catalyzed a paradigm shift in SGLT-2 inhibitor use, positioning them as key agents in the cardiorenal metabolic continuum. Moreover, their role in the secondary prevention of cardiovascular events and slowing CKD progression in T2DM patients has garnered considerable attention. This consensus-based review aims to offer practical guidance in an algorithmic approach to primary care healthcare professionals to optimize SGLT-2 inhibitors utilization and maximize their benefits. The review seeks to empower clinicians to effectively manage patients who may benefit from SGLT-2 inhibitor therapy by addressing common initiation barriers and optimizing treatment strategies. Additionally, it aims to raise awareness among primary care physicians regarding the multifaceted benefits of these medications and overcome clinical inertia in their adoption into routine clinical practice.
文摘Mitochondrial dysfunction is a key driver of cardiovascular disease(CVD)in metabolic syndrome and diabetes.This dysfunction promotes the production of reactive oxygen species(ROS),which cause oxidative stress and inflammation.Angiotensin II,the main mediator of the renin-angiotensin-aldosterone system,also contributes to CVD by promoting ROS production.Reduced activity of sirtuins(SIRTs),a family of proteins that regulate cellular metabolism,also worsens oxidative stress.Reduction of energy production by mitochondria is a common feature of all metabolic disorders.High SIRT levels and 5’adenosine monophosphate-activated protein kinase signaling stimulate hypoxia-inducible factor 1 beta,which promotes ketosis.Ketosis,in turn,increases autophagy and mitophagy,processes that clear cells of debris and protect against damage.Sodiumglucose cotransporter-2 inhibitors(SGLT2i),a class of drugs used to treat type 2 diabetes,have a beneficial effect on these mechanisms.Randomized clinical trials have shown that SGLT2i improves cardiac function and reduces the rate of cardiovascular and renal events.SGLT2i also increase mitochondrial efficiency,reduce oxidative stress and inflammation,and strengthen tissues.These findings suggest that SGLT2i hold great potential for the treatment of CVD.Furthermore,they are proposed as anti-aging drugs;however,rigorous research is needed to validate these preliminary findings.
文摘Nonalcoholic fatty liver disease (NAFLD) is the most prevalent cause of chronic liver disease worldwide. NAFLD is considerably more frequent in patients with type 2 diabetes mellitus (T2DM) than in the general population and is also more severe histologically in this group. Sodium-glucose co-transporter-2 (SGLT2) inhibitors, the newest class of antidiabetic agents, appear to represent a promising option for the management of NAFLD in patients with T2DM. In a number of studies, treatment with SGLT2 inhibitors resulted in a reduction in hepatic steatosis and in transaminase levels. However, existing studies are small, their follow-up period was short and none evaluated the effects of SGLT2 inhibitors on liver histology. Accordingly, larger studies are needed to verify these preliminary results and define the role of SGLT2 inhibitors in the treatment of NAFLD in patients with T2DM.
文摘Heart failure(HF)is a major complication of diabetes mellitus(DM).Patients with DM have considerably higher risk for HF than non-diabetic subjects and HF is also more severe in the former.Given the rising prevalence of DM,the management of HF in diabetic patients has become the focus of increased attention.In this context,the findings of several randomized,placebo-controlled trials that evaluated the effects of sodium-glucose co-transporter-2 inhibitors on the risk of hospitalization for HF in patients with type 2 DM represent a paradigm shift in the management of HF.These agents consistently reduced the risk of hospitalization for HF both in patients with and in those without HF.These benefits appear to be partly independent from glucose-lowering and have also been reported in patients without DM.However,there are more limited data regarding the benefit of sodium-glucose co-transporter-2 inhibitors in patients with HF and preserved left ventricular ejection fraction,which is the commonest type of HF in diabetic patients.
文摘Fulminant type 1 diabetes mellitus(FT1DM)is a subtype of type 1 diabetes mellitus characterized by an abrupt onset and a rapid and complete functional loss of isletβcells.It is a very rare disease generally associated with ketoacidosis and the absence of circulating pancreatic islet-related autoantibodies.Diabetic ketoacidosis with normal blood glucose levels has been reported during sodiumglucose co-transporter 2(SGLT2)inhibitor therapy.CASE SUMMARY The patient was a 43-year-old woman that consulted a medical practitioner for malaise,thirst,and vomiting.Blood analysis showed high blood glucose levels(428 mg/dL),a mild increase of hemoglobin A1c(6.6%),and increased ketone bodies in urine.The patient was diagnosed with type 2 diabetes mellitus.The patient was initially treated with insulin,which was subsequently changed to an oral SGLT2 inhibitor.Antibodies to glutamic acid decarboxylase were negative.Four days after receiving oral SGLT2 inhibitor,she consulted at Mie University Hospital,complaining of fatigue and vomiting.Laboratory analysis revealed diabetic ketoacidosis with almost normal blood glucose levels.The endogenous insulin secretion was markedly low,and the serum levels of islet-related autoantibodies were undetectable.We made the diagnosis of FT1DM with concurrent SGLT2 inhibitor-associated euglycemic diabetic ketoacidosis.The patient's general condition improved after therapy with intravenous insulin and withdrawal of oral medication.She was discharged on day 14 with an indication of multiple daily insulin therapy.CONCLUSION This patient is a rare case of FT1DM that developed SGLT2 inhibitor-associated diabetic ketoacidosis with almost normal blood glucose levels.This case report underscores the importance of considering the diagnosis of FT1DM in patients with negative circulating autoantibodies and a history of hyperglycemia that subsequently develop euglycemic diabetic ketoacidosis following treatment with a SGLT2 inhibitor.
文摘BACKGROUND Sodium-glucose cotransporter-2 inhibitors(SGLT2i)are commonly prescribed to manage patients with diabetes mellitus.These agents may rarely lead to the development of euglycemic diabetic ketoacidosis(EDKA),which may complicate the disease course of these patients.AIM To analyze the demographic profile,predisposing factors,symptomology,clinical interventions and outcomes of patients presenting with EDKA secondary to SGLT2i use by reviewing the published case reports and series.METHODS We performed a systematic search of PubMed,Science Direct,Google Scholar and Reference Citation Analysis databases using the terms“canagliflozin”OR“empagliflozin”OR“dapagliflozin”OR“SGLT2 inhibitors”OR“Sodium-glucose cotransporter-2”AND“euglycemia”OR“euglycemic diabetic ketoacidosis”OR“metabolic acidosis”.The inclusion criteria were:(1)Case reports or case series with individual patient details;and(2)Reported EDKA secondary to SGLT2i.Furthermore,the data were filtered from the literature published in the English language and on adults(>18 years).We excluded:(1)Conference abstracts;and(2)Case reports or series which did not have individual biochemical data.All the case reports and case series were evaluated.The data extracted included patient demographics,clinical symptomatology,clinical interventions,intensive care unit course,need for organ support and outcomes.RESULTS Overall,108 case reports and 17 cases series with 169 unique patients that met all the inclusion criteria were included.The majority of patients were females(54.4%,n=92),and the commonly reported symptoms were gastrointestinal(nausea/vomiting 65.1%,abdominal pain 37.3%)and respiratory(breathlessness 30.8%).One hundred and forty-nine(88.2%)patients had underlying type II diabetes,and the most commonly involved SGLT-2 inhibitor reported was empagliflozin(46.8%).A triggering factor was reported in most patients(78.7%),the commonest being acute severe infection(37.9%),which included patients with sepsis,coronavirus disease 2019,other viral illnesses,and acute pancreatitis.61.5%were reported to require intensive unit care,but only a minority of patients required organ support in the form of invasive mechanical ventilation(13%),vasopressors(6.5%)or renal replacement therapy(5.9%).The overall mortality rate was only 2.4%.CONCLUSION Patients on SGLT2i may rarely develop EDKA,especially in the presence of certain predisposing factors,including severe acute infections and following major surgery.The signs and symptoms of EDKA may be similar to that of DKA but with normal blood sugar levels,which may make the diagnosis challenging.Outcomes of EDKA are good if recognized early and corrective actions are taken.Hence,physicians managing such patients must be aware of this potential complication and must educate their patients accordingly to ensure early diagnosis and management.
文摘BACKGROUND Diabetic ketoacidosis(DKA)manifests as hyperglycemia,metabolic acidosis,and ketosis.However,euglycemic DKA(eu-DKA)conceals severe DKA with glucose levels below 200 mg/dL.Sodium-glucose cotransporter-2(SGLT2)inhibitors can induce eu-DKA in diabetic patients.Notably,coronavirus disease 2019(COVID-19)-infected individuals with diabetes using SGLT2 inhibitors face an augmented risk of eu-DKA due to the direct toxic impact of the virus on pancreatic islets.This study aims to comprehensively investigate the association between SGLT2 inhibitors and eu-DKA in COVID-19 patients through meticulous case report analysis.Additionally,we endeavor to examine the outcomes and treatment approaches for COVID-19-infected diabetics receiving SGLT2 inhibitors,providing indispensable insights for healthcare professionals managing this specific patient population.AIM To investigate the connection between SGLT2 inhibitors and euglycemic DKA in COVID-19 patients through a meticulous analysis of case reports.METHODS We conducted an exhaustive search across prominent electronic databases,including PubMed,SCOPUS,Web of Science,and Google Scholar.This search encompassed the period from December 2019 to May 2022,incorporating published studies and pre-prints.The search terms employed encompassed“SGLT2 inhibitors”,“euglycemic DKA”,“COVID-19”,and related variations.By incorporating these diverse sources,our objective was to ensure a thorough exploration of the existing literature on this subject,thereby augmenting the validity and robustness of our findings.RESULTS Our search yielded a total of seven case reports and one case series,collectively comprising a cohort of twelve patients.These reports detailed instances of eu-DKA in individuals with COVID-19.Crucially,all twelve patients were utilizing SGLT2 as their primary anti-diabetic medication.Upon admission,all oral medications were promptly discontinued,and the patients were initiated on intravenous insulin therapy to effectively manage the DKA.Encouragingly,eleven patients demonstrated a favorable outcome,while regrettably,one patient succumbed to the condition.Subsequently,SGLT2 were discontinued for all patients upon their discharge from the hospital.These findings provide valuable insights into the clinical management and outcomes of eu-DKA cases associated with COVID-19 and SGLT2,underscoring the critical importance of prompt intervention and vigilant medication adjustments.CONCLUSION Our study sheds light on the possibility of diabetic patients developing both drug-related and unrelated DKA,as well as encountering adverse outcomes in the context of COVID-19,despite maintaining satisfactory glycemic control.The relationship between glycemic control and clinical outcomes in COVID-19 remains ambiguous.Consequently,this systematic review proposes that COVID-19-infected diabetic patients using SGLT2 should contemplate alternative treatment protocols until their recovery from the disease.
文摘According to recent epidemiological data, chronic kidney diseases (CKDs) affect approximately 10% of the global population. Like many countries, CKD is a significant public health issue in Saudi Arabia. The prevalence of CKD in Saudi Arabia is estimated to be around 4.5% of the adult population, with a higher prevalence in older age groups. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a class of oral medications used to treat type 2 diabetes mellitus (T2DM). In addition to their glucose-lowering effects, SGLT2i have been shown to have beneficial effects on kidney function in patients with or without T2DM. Therefore, a Saudi task force gathered to develop an explicit, evidence-based consensus on SGLT2i use in CKD Saudi patients. A panel of 14 experts made up a task force. An initial concept proposal was obtained. The proposal was divided into several topics discussed on 24 May 2023. A literature review was carried out. The literature search was completed on 3<sup>rd</sup> June 2023. A drafted report was distributed to the entire panel. Approval of the recommendations required consensus, defined as a majority approval (i.e. above 75%). The recommendations were revised to accommodate any differences of opinion until a consensus was reached. Recommendations were finally formulated on 21<sup>st</sup> June 2023. Subsequently, the panel reviewed and discussed the supporting rationale of the revised recommendations. This article presents these practical recommendations.
基金Supported by China Scholarship Council,No.202006920018Key Talent Program for Medical Applications of Nuclear Technology,No.XKTJ-HRC2021007+2 种基金the Second Affiliated Hospital of Soochow University,No.SDFEYBS1815 and No.SDFEYBS2008National Natural Science Foundation of China,No.82170831The Jiangsu Innovation&Career Fund for PhD 2019.
文摘BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1RA)and sodium-glucose co-transporter-2 inhibitors(SGLT-2I)are associated with significant cardiovascular benefit in type 2 diabetes(T2D).However,GLP-1RA or SGLT-2I alone may not improve some cardiovascular outcomes in patients with prior cardiovascular co-morbidities.AIM To explore whether combining GLP-1RA and SGLT-2I can achieve additional benefit in preventing cardiovascular diseases in T2D.METHODS The systematic review was conducted according to PRISMA recommendations.The protocol was registered on PROSPERO(ID:42022385007).A total of 107049 participants from eligible cardiovascular outcomes trials of GLP-1RA and SGLT-2I were included in network meta-regressions to estimate cardiovascular benefit of the combination treatment.Effect modification of prior myocardial infarction(MI)and heart failure(HF)was also explored to provide clinical insight as to when the INTRODUCTION The macro-and micro-vascular benefits of glucagon-like peptide-1 receptor agonists(GLP-1RA)and sodium-glucose co-transporter-2 inhibitors(SGLT-2I)are independent of their glucose-lowering effects[1].In patients with type 2 diabetes(T2D),the major cardiovascular outcome trials(CVOT)showed that dipeptidyl peptidase-4 inhibitors(DPP-4I)did not improve cardiovascular outcomes[2],whereas cardiovascular benefit of GLP-1RA or SGLT-2I was significant[3,4].Further subgroup analyses indicated that the background cardiovascular risk should be considered when examining the cardiovascular outcomes of these newer glucose-lowering medications.For instance,prevention of major adverse cardiovascular events(MACE)was only seen in those patients with baseline atherosclerotic cardiovascular disease[3,4].Moreover,a series of CVOT conducted in patients with heart failure(HF)have demonstrated that(compared with placebo)SGLT-2I significantly reduced risk of hospitalization for HF or cardiovascular death,irrespective of their history of T2D[5-8].However,similar cardiovascular benefits were not observed in those with myocardial infarction(MI)[9,10].Cardiovascular co-morbidities are not only approximately twice as common but are also associated with dispropor-tionately worse cardiovascular outcomes in patients with T2D,compared to the general population[11].Therefore,it is of clinical importance to investigate whether the combination treatment of GLP-1RA and SGLT-2I could achieve greater cardiovascular benefit,particularly when considering patients with cardiovascular co-morbidities who may not gain sufficient cardiovascular protection from the monotherapies.This systematic review with multiple network meta-regressions was mainly aimed to explore whether combining GLP-1RA and SGLT-2I can provide additional cardiovascular benefit in T2D.Cardiovascular outcomes of these newer antidiabetic medications were also estimated under effect modification of prior cardiovascular diseases.This was to provide clinical insight as to when the combination treatment might be prioritized.
文摘Three major cardiovascular outcome trials(CVOTs)with a new class of antidiabetic drugs-sodium-glucose cotransporter 2(SGLT2)inhibitors(EMPAREG OUTCOME trial with empagliflozin,CANVAS Program with canagliflozin,DECLARE-TIMI 58 with dapagliflozin)unexpectedly showed that cardiovascular outcomes could be improved possibly due to a reduction in heart failure risk,which seems to be the most sensitive outcome of SGLT2 inhibition.No other CVOT to date has shown any significant benefit on heart failure events.Even more impressive findings came recently from the DAPA-HF trial in patients with confirmed and well-treated heart failure:Dapagliflozin was shown to reduce heart failure risk for patients with heart failure with reduced ejection fraction regardless of diabetes status.Nevertheless,despite their possible wide clinical implications,there is much doubt about the mechanisms of action and a lot of questions to unravel,especially now when their benefits translated to nondiabetic patients,rising doubts about the validity of some current mechanistic assumptions.The time frame of their cardiovascular benefits excludes glucoselowering and antiatherosclerotic-mediated effects and multiple other mechanisms,direct cardiac as well as systemic,are suggested to explain their early cardiorenal benefits.These are:Anti-inflammatory,antifibrotic,antioxidative,antiapoptotic properties,then renoprotective and hemodynamic effects,attenuation of glucotoxicity,reduction of uric acid levels and epicardial adipose tissue,modification of neurohumoral system and cardiac fuel energetics,sodiumhydrogen exchange inhibition.The most logic explanation seems that SGLT2 inhibitors timely target various mechanisms underpinning heart failure pathogenesis.All the proposed mechanisms of their action could interfere with evolution of heart failure and are discussed separately within the main text.
文摘Sodium-glucose cotransporter 2(SGLT2) inhibition induces glucosuria and decreases blood glucose levels in diabetic patients and lowers hypoglycemic risk. SGLT1 is expressed in the kidney and intestine; SGLT1 inhibition causes abdominal symptoms such as diarrhea and reduces incretin secretion. Therefore, SGLT2 selectivity is important. Ipragliflozin is highly selective for SGLT2. In type 2 diabetes mellitus(T2DM), urinaryglucose excretion increased to 90 g/24 h after 28 d of treatment with ipragliflozin 300 mg/d. Twelve weeks of ipragliflozin 50 mg/d vs placebo reduced glycated hemoglobin and body weight by 0.65% and 0.66 kg, respectively, in Western T2 DM patients, and by 1.3% and 1.89 kg, respectively, in Japanese patients. Ipragliflozin(highly selective SGLT2 inhibitor) improves glycemic control and reduces body weight and lowers hypoglycemic risk and abdominal symptoms. Ipragliflozin can be a novel anti-diabetic and antiobesity agent.
文摘BACKGROUND Landmark trials have established the benefits of sodium-glucose cotransporter-2 inhibitors(SGLT2-Is)in cardiovascular disease including heart failure with reduced and preserved ejection fraction and renal diseases regardless of the presence of diabetes mellitus.However,studies evaluating the role of SGLT2-Is in metabolic syndrome(MetS)are limited.AIM This study primarily aimed to evaluate the impact of SGLT2-Is on the components of MetS.METHODS Two independent reviewers and an experienced librarian searched Medline,Scopus and the Cochrane central from inception to December 9,2021 to identify placebo controlled randomized controlled trials that evaluated the impact of SGLT2-Is on the components of MetS as an endpoint.Pre-and post-treatment data of each component were obtained.A meta-analysis was performed using the RevMan(version 5.3;Copenhagen:The Nordic Cochrane Center,The Cochrane Collaboration).RESULTS Treatment with SGLT2-Is resulted in a decrease in fasting plasma glucose(–18.07 mg/dL;95%CI:-25.32 to–10.82),systolic blood pressure(–1.37 mmHg;95%CI:-2.08 to–0.65),and waist circumference(–1.28 cm;95%CI:-1.39 to–1.18)compared to placebo.The impact on highdensity lipoprotein cholesterol was similar to placebo(0.01 mg/dL;95%CI:-0.05 to 0.07).CONCLUSION SGLT2-Is have a promising role in the management of MetS.
文摘Solid organ transplantation offers life-saving treatment for patients with endorgan dysfunction.Patient survival and quality of life have improved over the past few decades as a result of pharmacological development,expansion of the donor pool,technological advances and standardization of practices related to transplantation.Still,transplantation is associated with cardiovascular complications,of which post-transplant diabetes mellitus(PTDM)is one of the most important.PTDM increases mortality,which is best documented in patients who have received kidney and heart transplants.PTDM results from traditional risk factors seen in patients with type 2 diabetes mellitus,but also from specific posttransplant risk factors such as metabolic side effects of immunosuppressive drugs,post-transplant viral infections and hypomagnesemia.Oral hypoglycaemic agents are the first choice for the treatment of type 2 diabetes mellitus in non-transplanted patients.However,the evidence on the safety and efficacy of oral hypoglycaemic agents in transplant recipients is limited.The favourable risk/benefit ratio,which is suggested by large-scale and long-term studies on new glucoselowering drug classes such as glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors,makes studies warranted to assess the potential role of these agents in the management of PTDM.
文摘Aim: The EMPA-REG OUTCOME study reported that the sodium-glucose cotransporter 2 inhibitor (SGLT2-i) suppressed cardiovascular (CV) events in patients with type 2 diabetes;we recently suggested that increase of the serum magnesium (Mg) by SGLT2-i’s can, in part, explain this reduction. The objective of this study was to elucidate the mechanism underlying the elevation of the serum Mg level induced by treatment with SGLT2-i’s. Methods: We analyzed the data of 37 patients with type 2 diabetes who underwent clinical evaluation and laboratory assessment at baseline and the end of 3 months. To investigate the relationship between the changes in the serum Mg concentrations during 3 months’ treatment (ΔMg) and other variables, we carried out simple linear regression analysis and multiple linear regression analysis. Results: Three months’ treatment with the SGLT2-i resulted in a significant improvement of the body weight (BW), BMI, hemoglobin A1c (HbA1c), and fasting plasma glucose levels. The serum Mg increased significantly. Simple linear regression analysis revealed an association between the ΔMg and the serum triglyceride, serum Mg at baseline, change of the BW (ΔBW), and change of the HbA1c. Multiple linear regression analysis revealed a significant association between the ΔMg and the serum Mg level at the baseline (r = -0.55, P Conclusion: Our study revealed that a lower serum Mg level at the baseline and BW reduction were significantly associated with an increase in the serum Mg following 3 months’ treatment with SGLT2-i’s.
基金Supported by the Royal Perth Hospital Medical Research Foundation,No.VMMRF2018。
文摘BACKGROUND Type 1 diabetes(T1D) is associated with major chronic microvascular complications which contribute significantly to diabetes associated morbidity.The protein primarily responsible for glucose reabsorption in the kidney is sodium glucose co-transporter 2(SGLT2). Presently, SGLT2 inhibitors are widely used in diabetic patients to improve blood glucose levels and prevent cardiovascular and renal complications. Given the broad therapeutic application of SGLT2 inhibitors, we hypothesised that SGLT2 inhibition may exert its protective effects via alterations of the gut microbiome and tested this in a type 1 diabetic mouse model of diabetic retinopathy.AIM To determine whether the treatment with two independent SGLT2 inhibitors affects gut health in a type 1 diabetic mouse model.METHODS The SGLT2 inhibitors empagliflozin or dapagliflozin(25 mg/kg/d) or vehicle dimethylsulfoxide(DMSO) were administered to C57 BL/6 J, Akita, Kimba and Akimba mice at 10 wk of age for 8 wk via their drinking water. Serum samples were collected and the concentration of succinate and the short chain fatty acid(SCFA) butyric acid was measured using gas chromatography-mass spectrometry. Enzyme-linked immunosorbent assay(ELISA) was performed to determine the concentration of insulin and leptin. Furthermore, the norepinephrine content in kidney tissue was determined using ELISA. Pancreatic tissue was collected and stained with haematoxylin and eosin and analysed using brightfield microscopy.RESULTS Due to the presence of the Akita allele, both Akita and Akimba mice showed a reduction in insulin production compared to C57 BL/6 J and Kimba mice.Furthermore, Akita mice also showed the presence of apoptotic bodies within the pancreatic islets. The acinar cells of Akita and Akimba mice showed swelling which is indicative of acute injury or pancreatitis. After 8 wk of SGLT2 inhibition with dapagliflozin, the intermediate metabolite of gut metabolism known as succinate was significantly reduced in Akimba mice when compared to DMSO treated mice. In addition, empagliflozin resulted in suppression of succinate levels in Akimba mice. The beneficial SCFA known as butyric acid was significantly increased in Akita mice after treatment with dapagliflozin when compared to vehicle treated mice. The norepinephrine content in the kidney was significantly reduced with both dapagliflozin and empagliflozin therapy in Akita mice and was significantly reduced in Akimba mice treated with empagliflozin.In non-diabetic C57 BL/6 J and Kimba mice, serum leptin levels were significantly reduced after dapagliflozin therapy.CONCLUSION The inhibition of SGLT2 reduces the intermediate metabolite succinate, increases SCFA butyric acid levels and reduces norepinephrine content in mouse models of T1 D. Collectively, these improvements may represent an important mechanism underlying the potential benefits of SGLT2 inhibition in T1 D and its complications.
文摘An increasing body of evidence shows that new antidiabetic drugs—particularly sodium-glucose cotransporter 2(SGLT2)inhibitors and glucagon-like peptide 1(GLP-1)receptor agonists—have a beneficial effect on cardiovascular outcome.The majority of these studies have been performed in patients with heart failure and the results have shown first positive effect on blood pressure(BP)reduction.These effects are more pronounced with SGLT2 inhibitors than with GLP-1 receptor agonists.However,the reasons and mechanisms of action inducing BP reduction are still not sufficiently clear.Proposed mechanisms of SGLT2 inhibitors involve the natriuretic effect,modification of the renin-angiotensin-aldosterone system,and/or the reduction in the sympathetic nervous system.GLP-1 receptor agonists have several mechanisms that are related to glycemic,weight,and BP control.Current data show that SGLT2 inhibitors have a stronger antihypertensive effect than GLP-1 receptor agonists,which is mainly related to their renal effect.Briefly,SGLT2 inhibitors increase the response to diuretics and decrease the meal-related antinatriuretic pressure by lowering post-prandial hyperglycemia and hyperinsulinemia and prevent proximal sodium reabsorption.SGLT2 inhibitors can be used as second-line therapy in patients with diabetes mellitus or heart disease and concomitant hypertension.This article aims to summarize current knowledge regarding the antihypertensive effect of SGLT2 inhibitors and GLP-1 receptor agonists.
文摘In recent years, the progress of NAFLD has become an important health problem, and the prevention or delay of progress in NAFLD is a major key point. Whether or not to combine T2MD, people are interested in the mechanisms and efficacy of SGLT2i for NAFLD. In this review, we summarized the current clinical research on SGLT2i for the combination of T2MD’s NAFLD patients, and the latest evidence of external or animal experiments. These evidences will help us to more accurately understand the protective effects of SGLT2i in NAFLD. Lifestyle changes are still essential to prevent and treat NAFLD, and for all kinds of drugs that treat NAFLD in clinical trials, SGLT2i may be one of the promising treatments.
基金Beijing Excellent Talents Training Assistance(Grant No.2017000082595G244)the Health and Research Bureau of Tongzhou District(Grant No.TWKY-2016-QN-01-58)。
文摘Canagliflozin(CANA)is a sodium-glucose co-transporter 2 inhibitor.One of the important mechanisms of CANA is the inhibitory effect on the glucose uptake in the proximal tubule of the nephron,and the other mechanism can be the reduction of inflammatory cytokine expression monocytes and macrophages.It is proved by FDA for the management of type 2 diabetes.In the present work,we summarized the publication and clinical evidence of the CANA on healthy individuals and those with related metabolic diseases,such as type 1 and 2 diabetes,obesity,or cardiovascular and kidney diseases.This drug has been reported to offer potential advantages in regulating body weight and reducing heart failure,hypoglycemia,and stroke risk in patients with type 2 diabetes.Some in vitro and animal experiments also show that this drug has good effects on cancer treatment.However,some case reports and experiments also show the side effect of CANA,such as amputation,fracture,and pancreatitis,while the mechanism is still unknown.Overall,CANA has a good effect on the management of type 2 diabetes by reducing the risk of kidney failure,cardiovascular diseases,and stroke.However,as a new drug,more clinical trials and experiments of CANA should be carried out in the future.
