Comparative efficacy of sodium glucose cotransporter-2 inhibitors in the management of type 2 diabetes mellitus:A real-world experience

BACKGROUND Sodium glucose cotransporter-2 inhibitors(SGLT-2i)are a class of drugs with modest antidiabetic efficacy,weight loss effect,and cardiovascular benefits as proven by multiple randomised controlled trials(RCTs).However,real-world data on the comparative efficacy and safety of individual SGLT-2i medications is sparse.AIM To study the comparative efficacy and safety of SGLT-2i using real-world clinical data.METHODS We evaluated the comparative efficacy data of 3 SGLT-2i drugs(dapagliflozin,canagliflozin,and empagliflozin)used for treating patients with type 2 diabetes mellitus.Data on the reduction of glycated hemoglobin(HbA1c),body weight,blood pressure(BP),urine albumin creatinine ratio(ACR),and adverse effects were recorded retrospectively.RESULTS Data from 467 patients with a median age of 64(14.8)years,294(62.96%)males and 375(80.5%)Caucasians were analysed.Median diabetes duration was 16.0(9.0)years,and the duration of SGLT-2i use was 3.6(2.1)years.SGLT-2i molecules used were dapagliflozin 10 mg(n=227;48.6%),canagliflozin 300 mg(n=160;34.3%),and empagliflozin 25 mg(n=80;17.1).Baseline median(interquartile range)HbA1c in mmol/mol were:dapagliflozin-78.0(25.3),canagliflozin-80.0(25.5),and empagliflozin-75.0(23.5)respectively.The respective median HbA1c reduction at 12 months and the latest review(just prior to the study)were:66.5(22.8)&69.0(24.0),67.0(16.3)&66.0(28.0),and 67.0(22.5)&66.5(25.8)respectively(P<0.001 for all comparisons from baseline).Significant improvements in body weight(in kilograms)from baseline to study end were noticed with dapagliflozin-101(29.5)to 92.2(25.6),and canagliflozin 100(28.3)to 95.3(27.5)only.Significant reductions in median systolic and diastolic BP,from 144(21)mmHg to 139(23)mmHg;(P=0.015),and from 82(16)mmHg to 78(19)mmHg;(P<0.001)respectively were also observed.A significant reduction of microalbuminuria was observed with canagliflozin only[ACR 14.6(42.6)at baseline to 8.9(23.7)at the study end;P=0.043].Adverse effects of SGLT-2i were as follows:genital thrush and urinary infection-20(8.8%)&17(7.5%)with dapagliflozin;9(5.6%)&5(3.13%)with canagliflozin;and 4(5%)&4(5%)with empagliflozin.Diabetic ketoacidosis was observed in 4(1.8%)with dapagliflozin and 1(0.63%)with canagliflozin.CONCLUSION Treatment of patients with SGLT-2i is associated with statistically significant reductions in HbA1c,body weight,and better than those reported in RCTs,with low side effect profiles.A review of large-scale real-world data is needed to inform better clinical practice decision making.

Elucidating the cardioprotective mechanisms of sodium-glucose cotransporter-2 inhibitors beyond glycemic control

Sodium-glucose cotransporter-2(SGLT2)inhibitors have emerged as a pivotal intervention in diabetes management,offering significant cardiovascular benefits.Empagliflozin,in particular,has demonstrated cardioprotective effects beyond its glucose-lowering action,reducing heart failure hospitalizations and improving cardiac function.Of note,the cardioprotective mechanisms appear to be independent of glucose lowering,possibly mediated through several mechanisms involving shifts in cardiac metabolism and anti-fibrotic,anti-inflammatory,and anti-oxidative pathways.This editorial summarizes the multifaceted cardiovascular advantages of SGLT2 inhibitors,highlighting the need for further research to elucidate their full therapeutic potential in cardiac care.

Sodium-glucose cotransporter-2 inhibitors protect tissues via cellular and mitochondrial pathways:Experimental and clinical evidence

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.

Sodium-glucose Cotransporter-2 Inhibitors induced euglycemic diabetic ketoacidosis:A meta summary of case reports

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.

Sodium-glucose cotransporter-2 inhibitor use in kidney transplant recipients

Sodium-glucose cotransporter-2 inhibitors(SGLT2i)are novel oral hypoglycemic agents garnering much attention for their substantial benefits.These recent data have positioned SGLT2i at the forefront of diabetic chronic kidney disease(CKD)and heart failure management.SGLT2i use post-kidney transplant is an emerging area of research.Highlights from this mini review include the following:Empagliflozin is the most prescribed SGLT2i in kidney transplant recipients(KTRs),median time from transplant to initiation was 3 years(range:0.88-9.6 years).Median baseline estimated glomerular filtration rate(eGFR)was 66.7 mL/min/1.73 m2(range:50.4-75.8).Median glycohemoglobin(HgbA1c)at initiation was 7.7%(range:6.9-9.3).SGLT2i were demonstrated to be effective short-term impacting HgbA1c,eGFR,hemoglobin/hematocrit,serum uric acid,and serum magnesium levels.They are shown to be safe in KTRs with low rates of infections,hypoglycemia,euglycemic diabetic ketoacidosis,and stable tacrolimus levels.More data is needed to demonstrate long-term outcomes.SGLT2i appear to be safe,effective medications for select KTRs.Our present literature,though limited,is founded on precedent robust research in CKD patients with diabetes.Concurrent research/utilization of SGLT2i is vital to not only identify long-term patient,graft and cardiovascular outcomes of these agents,but also to augment management in KTRs.

Analgesic effect of intrathecal bumetanide is accompanied by changes in spinal sodium-potassium-chloride co-transporter 1 and potassium-chloride co-transporter 2 expression in a rat model of incisional pain

Accumulating evidence has demonstrated that the sodium-potassium-chloride co-transporter 1 and potassium-chloride co-transporter 2 have a role in the modulation of pain transmission at the spinal level through chloride regulation in the pain pathway and by effecting neuronal excitability and pain sensitization. The present study aimed to investigate the analgesic effect of the speciifc sodium-potassium-chloride co-transporter 1 inhibitor bumetanide, and the change in spinal sodium-potassium-chloride co-transporter 1 and potassium-chloride co-transporter 2 expression in a rat model of incisional pain. Results showed that intrathecal bumetanide could decrease cumulative pain scores, and could increase thermal and mechanical pain thresholds in a rat model of incisional pain. Sodium-potassium-chloride co-transporter 1 expression in-creased in neurons from dorsal root ganglion and the deep laminae of the ipsilateral dorsal horn following incision. By contrast, potassium-chloride co-transporter 2 expression decreased in neurons of the deep laminae from the ipsilateral dorsal horn. These ifndings suggest that spinal sodium-potassium-chloride co-transporter 1 expression was up-regulated and spinal potassi-um-chloride co-transporter 2 expression was down-regulated following incision. Intrathecal bumetanide has analgesic effects on incisional pain through inhibition of sodium-potassi-um-chloride co-transporter 1.

Saudi Consensus on the Usage of Sodium-Glucose Cotransporter-2 Inhibitors on the Management of Chronic Kidney Diseases

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 3rd 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 21st June 2023. Subsequently, the panel reviewed and discussed the supporting rationale of the revised recommendations. This article presents these practical recommendations.

Progress in the Study of the Hepatoprotective Effect of SGLT2i on NAFLD Patients with T2DM

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.

Impact of sodium glucose cotransporter-2 inhibitors on liver steatosis/fibrosis/inflammation and redox balance in non-alcoholic fatty liver disease

BACKGROUND Sodium glucose cotransporter-2 inhibitors(SGLT2-I)are the most recently approved drugs for type 2 diabetes(T2D).Recent clinical trials of these compounds reported beneficial cardiovascular(CV)and renal outcomes.A major cause of vascular dysfunction and CV disease in diabetes is hyperglycemia associated with inflammation and oxidative stress.Pre-clinical studies demonstrated that SGLT2-I reduce glucotoxicity and promote anti-inflammatory effects by lowering oxidative stress.AIM To investigate the effects of SGLT2-I on markers of oxidative stress,inflammation,liver steatosis,and fibrosis in patients of T2D with non-alcoholic fatty liver disease(NAFLD).METHODS We referred fifty-two consecutive outpatients treated with metformin monotherapy and exhibiting poor glycemic control to our centre.We introduced the outpatients to an SGLT2-I(dapagliflozin,empagliflozin,or canagliflozin;n=26)or a different hypoglycemic drug[other glucose-lowering drugs(OTHER),n=26].We evaluated circulating interleukins and serum hydroxynonenal(HNE)-or malondialdehyde(MDA)-protein adducts,fatty liver index(FLI),NAFLD fibrosis score,aspartate aminotransferase(AST)/alanine aminotransferase(ALT)ratio,AST-to-platelet-ratio index(APRI),and fibrosis-4 on the day before(T0)and following treatment for six months(T1).We also performed transient elastography at T0 and T1.RESULTS Add-on therapy resulted in improved glycemic control and reduced fasting blood glucose in both groups.Of note,following treatment for six months,a reduction of FLI and APRI,as well as of the FibroScan result,was reported in patients treated with SGLT2-I,but not in the OTHER group;furthermore,in the SGLT2-I group,we reported lower circulating levels of interleukin(IL)-1β,IL-6,tumor necrosis factor,vascular endothelial growth factor,and monocyte chemoattractant protein-1,and higher levels of IL-4 and IL-10.We did not observe any modification in circulating interleukins in the OTHER group.Finally,serum HNE-and MDA-protein adducts decreased significantly in SGLT2-I rather than OTHER patients and correlated with liver steatosis and fibrosis scores.CONCLUSION The present data indicate that treatment with SGLT2-I in patients with T2D and NAFLD is associated with improvement of liver steatosis and fibrosis markers and circulating pro-inflammatory and redox status,more than optimizing glycemic control.

Glucagon-like-1 receptor agonists and sodium/glucose cotransporter-2 inhibitors combination—are we exploiting their full potential in a real life setting?

BACKGROUND The sodium/glucose cotransporter-2 inhibitors(SGLT-2i)and glucagon-like-1 receptor agonists(GLP-1RA)are antidiabetic agents effective both in hemoglobin A1c(HbA1c)reduction(with a low risk of hypoglycemia)and cardiovascular event prevention.In patients with type 2 diabetes,the add-on value of combination therapy of GLP-1RA and an SGLT-2i seems promising.AIM To investigate whether the efficacy of GLP-1RA and SGLT-2i combination observed in randomized controlled trials translates into therapeutic benefits in the Croatian population during routine clinical practice and follow-up.METHODS We included 200 type 2 diabetes patients with poor glycemic control and analyzed the effects of treatment intensification with(1)GLP-1RA on top of SGLT-2i,(2)SGLT-2i on top of GLP-1RA compared to(3)simultaneous addition of both agents.The primary study endpoint was the proportion of participants with HbA1c<7.0%and/or 5%bodyweight reduction.Secondary outcomes included changes in fasting plasma glucose(FPG),prandial plasma glucose,lowdensity lipoprotein cholesterol,estimated glomerular filtration rate(eGFR),and cardiovascular(CV)incidents assessment over a follow-up period of 12 mo.RESULTS The majority of patients were over 65-years-old,had diabetes duration for more than 10 years.The initial body mass index was 39.41±5.49 kg/m2 and HbA1c 8.32±1.26%.Around half of the patients in all three groups achieved target HbA1c below 7%.A more pronounced decrease in the HbA1c seen with simultaneous SGLT-2i and GLP-1RA therapy was a result of higher baseline HbA1c and not the effect of initiating combination therapy.The number of patients achieving FPG below 7.0 mmol/L was significantly higher in the SGLT-2i group(P=0.021),and 5%weight loss was dominantly achieved in the simultaneous therapy group(P=0.044).A composite outcome(reduction of HbA1c below 7%(53 mmol/mol)with 5%weight loss)was achieved in 32.3%of total patients included in the study.Only 18.2%of patients attained composite outcome defined as HbA1c below 7%(53 mmol/mol)with 5%weight loss and low-density lipoprotein cholesterol<2.5 mmol/L.There were no significant differences between treatment groups.No differences were observed regarding CV incidents or eGFR according to treatment group over a follow-up period.CONCLUSION Combination therapy with GLP-1RA and SGLT-2i is effective in terms of metabolic control,although it remains to be determined whether simultaneous or sequential intensification is better.

Sodium glucose cotransporter-2 inhibitors: Are we targeting old devil with new problems?

Dear editor,The advent of modern molecular mechanism’s approach to disease treatment is highly advancing to mitigate/normalize the symptoms of disease i.e.hyperglycemia by targeting at least eight different pathophysiological approaches popularly known as omnious octet[1].Importantly,type 2 diabetes is a

Targeting epicardial adipose tissue:A potential therapeutic strategy for heart failure with preserved ejection fraction with type 2 diabetes mellitus

Heart failure with preserved ejection fraction(HFpEF)is a heterogeneous syndrome with various comorbidities,multiple cardiac and extracardiac pathophysiologic abnormalities,and diverse phenotypic presentations.Since HFpEF is a heterogeneous disease with different phenotypes,individualized treatment is required.HFpEF with type 2 diabetes mellitus(T2DM)represents a specific phenotype of HFpEF,with about 45%-50% of HFpEF patients suffering from T2DM.Systemic inflammation associated with dysregulated glucose metabolism is a critical pathological mechanism of HFpEF with T2DM,which is intimately related to the expansion and dysfunction(inflammation and hypermetabolic activity)of epicardial adipose tissue(EAT).EAT is well established as a very active endocrine organ that can regulate the pathophysiological processes of HFpEF with T2DM through the paracrine and endocrine mechanisms.Therefore,suppressing abnormal EAT expansion may be a promising therapeutic strategy for HFpEF with T2DM.Although there is no treatment specifically for EAT,lifestyle management,bariatric surgery,and some pharmaceutical interventions(anti-cytokine drugs,statins,proprotein convertase subtilisin/kexin type 9 inhibitors,metformin,glucagon-like peptide-1 receptor agonists,and especially sodium-glucose cotransporter-2 inhibitors)have been shown to attenuate the inflammatory response or expansion of EAT.Importantly,these treatments may be beneficial in improving the clinical symptoms or prognosis of patients with HFpEF.Accordingly,well-designed randomized controlled trials are needed to validate the efficacy of current therapies.In addition,more novel and effective therapies targeting EAT are needed in the future.

Effects of High Frequency Repetitive Transcranial Magnetic Stimulation on KCC2 Expression in Rats with Spasticity Following Spinal Cord Injury

The effect of high-frequency repetitive transcranial magnetic stimulation（r TMS） on potassium-chloride cotransporter-2（KCC2） protein expression following spinal cord injury（SCI） and the action mechanism were investigated. SCI models were established in SD rats. Five groups were set up randomly： normal control group, SCI 7-day（7 D） model group, SCI 14-day（14 D） model group, SCI-7 DrTMS group and SCI-14 DrTMS group（n=5 each）. The rats in SCI rTMS groups were treated with 10 Hz rTMS from 8 th day and 15 th day after SCI respectively, once every day, 5 days every week, a total of 4 weeks. After the model establishment, motor recovery and spasticity alleviation were evaluated with BBB scale once a week till the end of treatment. Finally, different parts of tissues were dissected out for detection of variations of KCC2 protein using Western blotting and polymerase chain reaction（PCR） technique. The results showed that the BBS scores after treatment were significantly higher in SCI-7 DrTMS group than in SCI-14 DrTMS group（P〈0.05）. As compared with normal control groups, The KCC2 protein in SCI model groups was down-regulated after SCI, and the decrease was much more significant in SCI-14 D model group than in SCI-7 D group（P〈0.05）. As compared with SCI model groups, KCC2 protein in rTMS groups was up-regulated after the treatment（P〈0.05）. The up-regulation of KCC2 protein content and expression was more obvious in SCI-7 DrTMS group than in SCI-14 DrTMS group（P〈0.05）. It was concluded that 10 Hz rTMS can alleviate spasticity in rats with SCI, which might be attributed to the up-regulation of KCC2 protein. It was also suggested that the high-frequency rTMS treatment after SCI at early stage might achieve more satisfactory curative effectiveness.

Effect of dapagliflozin on uric acid in patients with chronic heart failure and hyperuricemia

BACKGROUND Patients with chronic heart failure(CHF)frequently develop hyperuricemia,an elevated serum uric acid level,associated with adverse outcomes.Dapagliflozin,a sodium-glucose cotransporter-2 inhibitor,demonstrates reduction in cardiovascular mortality and hospitalization in patients with CHF and ejection fraction(HFrEF),irrespective of diabetes.However,dapagliflozin’s effect on the uric acid levels in patients with CHF and hyperuricemia remain unclear.AIM To investigate the effects of dapagliflozin on uric acid levels in CHF patients with hyperuricemia.METHODS We conducted a randomized,double-blind,placebo-controlled trial in 200 patients with CHF and hyperuricemia,with HFrEF and serum uric acid levels≥7 mg/dL(≥416μmol/L).The participants were randomly assigned to receive a daily dose of 10 mg dapagliflozin or placebo for 24 months.The primary endpoint was the change in serum uric acid level from baseline to 24 months.Secondary endpoints included changes in left ventricular ejection fraction(LVEF),Nterminal pro-B-type natriuretic peptide(NT-proBNP),and quality of life(QoL)scores,as well as the incidence of cardiovascular death and hospitalization for heart failure.RESULTS At 24 months,dapagliflozin significantly reduced serum uric acid levels by 1.2 mg/dL(71μmol/L)compared with placebo(95%CI:-1.5 to-0.9;P<0.001).Dapagliflozin also significantly improved LVEF by 3.5%(95%CI:2.1-4.9;P<0.001),NT-proBNP by 25%(95%CI:18-32;P<0.001),and QoL scores by 10 points(95%CI:7-13;P<0.001)and reduced the risk of cardiovascular death and hospitalization for heart failure by 35%(95%CI:15–50;P=0.002)compared with the placebo.Adverse events were similar between the two groups,except for a higher rate of genital infections in the dapagliflozin group(10%vs 2%,P=0.01).CONCLUSION Dapagliflozin significantly lowered serum uric acid levels and improved the clinical outcomes in patients with CHF and hyperuricemia.Therefore,dapagliflozin may be a useful therapeutic option for this high-risk population.

Prevention of macrovascular complications in patients with type 2 diabetes mellitus: Review of cardiovascular safety and efficacy of newer diabetes medications

Lack of conclusive beneficial effects of strict glycemic control on macrovascular complications has been very frustrating for clinicians involved in care of patients with diabetes mellitus (DM). Highly publicized controversy surrounding cardiovascular (CV) safety of rosiglitazone resulted in major changes in United States Food and Drug Administration policy in 2008 regarding approval process of new antidiabetic medications, which has resulted in revolutionary data from several large CV outcome trials over the last few years. All drugs in glucagon-like peptide-1 receptor agonist (GLP-1 RA) and sodium-glucose cotransporter-2 (SGLT-2) inhibitor classes have shown to be CV safe with heterogeneous results on CV efficacy. Given twofold higher CV disease mortality in patients with DM than without DM, GLP-1 RAs and SGLT-2-inhibitors are important additions to clinician’s armamentarium and should be second line-therapy particularly in patients with T2DM and established atherosclerotic CV disease or high risks for CV disease. Abundance of data and heterogeneity in CV outcome trials results can make it difficult for clinicians, particularly primary care physicians, to stay updated with all the recent evidence. The scope of this comprehensive review will focus on all major CV outcome studies evaluating CV safety and efficacy of GLP-1 RAs and SGLT-2 inhibitors.

Novel pharmacological therapy in type 2 diabetes mellitus with established cardiovascular disease: Current evidence

Cardiovascular diseases(CVDs) remain the leading cause of death in the world and in most developed countries. Patients with type 2 diabetes mellitus(T2DM)suffer from both microvascular and macrovascular diseases and therefore have higher rates of morbidity and mortality compared to those without T2DM. If current trends continue, the Center for Disease Control and Prevention estimates that 1 in 3 Americans will have T2DM by year 2050. As a consequence of the controversy surrounding rosiglitazone and the increasing prevalence of diabetes and CVDs, in 2008 the Food and Drug Administration(FDA) established new expectations for the evaluation of new antidiabetic agents, advising for pre and,in some cases, post-marketing data on major cardiovascular events. As a direct consequence, there has been a paradigm shift in new antidiabetic agents that has given birth to the recently published American Diabetes Association/European Association for the Study of Diabetes consensus statement recommending sodium-glucose cotransporter-2 inhibitors(SGLT2i) and glucagon like peptide-1 receptor agonists(GLP-1RA) in patients with T2DM and established CVD. As a result of over a decade of randomized placebo controlled cardiovascular outcome trials, the aforementioned drugs have received FDA approval for risk reduction of cardiovascular(CV) events in patients with T2DM and established CV disease.SGLT2i have been shown to have a stronger benefit in patients with congestiveheart failure and diabetic kidney disease when compared to their GLP-1RA counterparts. These benefits are not withstanding additional considerations such as cost and the multiple FDA Black Box warnings. This topic is currently an emerging research area and this mini-review paper examines the role of these two novel classes of drugs in patients with T2DM with both confirmed, and at risk for, CVD.

SGLT-2 inhibitors in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus: A systematic review

BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is a common comorbidity with type 2 diabetes.The existing therapeutic options for NAFLD are not adequate.Hypocaloric diet and exercise is the cornerstone of therapy in NAFLD.Pioglitazone is the only drug recommended in diabetes patients with biopsy proven non-alcoholic steatohepatitis.The frequent coexistence of NAFLD and type 2 diabetes with their combined adverse health consequences and inadequate therapeutic options makes it necessary to search for newer alternatives.AIM To assess the effect of sodium glucose cotransporter-2(SGLT-2)inhibitors on liver enzymes in type 2 diabetes patients with NAFLD.METHODS We searched PubMed/MEDLINE,Cochrane library,Google scholar,and Clinicaltrials.gov for the relevant articles to be included in this systematic review.Human studies done in type 2 diabetes patients with NAFLD treated with SGLT-2 inhibitors for at least 12 wk were included.Data from eight studies(four randomised controlled trials and four observational studies)were extracted and a narrative synthesis was done.A total of 214 patients were treated with SGLT-2 inhibitors in these studies(94 in randomised controlled trials and 120 in observational studies).RESULTS The primary outcome measure was change in serum alanine aminotransferase level.Out of eight studies,seven studies showed a significant decrease in serum alanine aminotransferase level.Most of the studies revealed reduction in serum level of other liver enzymes like aspartate aminotransferase and gamma glutamyl transferase.Five studies that reported a change in hepatic fat exhibited a significant reduction in hepatic fat content in those treated with SGLT-2 inhibitors.Likewise,among the three studies that evaluated a change in indices of hepatic fibrosis,two studies revealed a significant improvement in liver fibrosis.Moreover,there was an improvement in obesity,insulin resistance,glycaemia,and lipid parameters in those subjects taking SGLT-2 inhibitors.The studies disclosed that about 17%(30/176)of the subjects taking SGLT-2 inhibitors developed adverse events and more than 40%(10/23)of them had genitourinary tract infections.CONCLUSION Based on low to moderate quality of evidence,SGLT-2 inhibitors improve the serum level of liver enzymes,decrease liver fat,and fibrosis with additional beneficial effects on various metabolic parameters in type 2 diabetes patients with NAFLD.

Sodium-Glucose Cotransporter-2 Inhibitors: Who, When & How? Guidance for Use from a Multidisciplinary Practical Approach

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.

Evolution of care in cirrhosis: Preventing hepatic decompensation through pharmacotherapy

Cirrhosis is a leading cause of morbidity and mortality,impacting more than 120 million people worldwide.Although geographic differences exist,etiologic factors such as alcohol use disorder,chronic viral hepatitis infections,and non-alcoholic fatty liver disease are prevalent in nearly every region.Historically,significant effort has been devoted to modifying these risks to prevent disease progression.Nevertheless,more than 11%of patients with compensated cirrhosis experience hepatic decompensation each year.This transition signifies the most important prognostic factor in the natural history of the disease,corresponding to a decline in median survival to below 2 years.Over the past decade,the need for pharmacotherapies aimed at reducing the risk for hepatic decompensation has been emphasized,and non-selective beta-blockers have emerged as the most effective option to date.However,a critical therapeutic gap still exists,and additional therapies have been proposed,including statins,rifaximin,and sodium-glucose cotransporter-2 inhibitors.Based on the results of innovative retrospective analyses and small-scale prospective trials,these pharmacotherapies represent promising options,but further studies,including randomized controlled trials,are necessary before they can be incorporated into clinical use.This report highlights the potential impact of these agents and others in preventing hepatic decompensation and discusses how this paradigm shift may pave the way for guideline-directed medical therapy in cirrhosis.

Multifaceted relationship between diabetes and kidney diseases:Beyond diabete

Diabetes mellitus is one of the most common causes of chronic kidney disease.Kidney involvement in patients with diabetes has a wide spectrum of clinical presentations ranging from asymptomatic to overt proteinuria and kidney failure.The development of kidney disease in diabetes is associated with structural changes in multiple kidney compartments,such as the vascular system and glomeruli.Glomerular alterations include thickening of the glomerular basement membrane,loss of podocytes,and segmental mesangiolysis,which may lead to microaneurysms and the development of pathognomonic Kimmelstiel-Wilson nodules.Beyond lesions directly related to diabetes,awareness of the possible coexistence of nondiabetic kidney disease in patients with diabetes is increasing.These nondiabetic lesions include focal segmental glomerulosclerosis,IgA nephropathy,and other primary or secondary renal disorders.Differential diagnosis of these conditions is crucial in guiding clinical management and therapeutic approaches.However,the relationship between diabetes and the kidney is bidirectional;thus,new-onset diabetes may also occur as a complication of the treatment in patients with renal diseases.Here,we review the complex and multifaceted correlation between diabetes and kidney diseases and discuss clinical presentation and course,differential diagnosis,and therapeutic opportunities offered by novel drugs.