Sodium-Glucose Transporter Inhibition in Adult and Pediatric Patients with Type 1 Diabetes Mellitus.
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ABSTRACT:
SUBMITTER: Vitale RJ
PROVIDER: S-EPMC8849139 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The incidence of renal-related adverse events (AEs) with canagliflozin in patients with type 2 diabetes mellitus from a pooled population of patients in 7 active- and placebo-controlled trials (N?=?5598) and in a 104-week study vs glimepiride (N?=?1450) was low and similar in canagliflozin and non-canagliflozin groups. In the study vs glimepiride, canagliflozin was associated with an initial acute decrease in estimated glomerular filtration rate (eGFR) that attenuated over time, while eGFR declined progressively over 104?weeks with glimepiride. The incidence of renal-related AEs with canagliflozin was generally stable over time, while the incidence with glimepiride increased over 104?weeks. In the present analysis, based on postmarketing reports from the US Food and Drug Administration Adverse Event Reporting System, a potential signal was identified for acute kidney injury with all approved sodium glucose co-transporter 2 (SGLT2) inhibitors (ie, canagliflozin, dapagliflozin and empagliflozin). The early onset of acute kidney injury events with SGLT2 inhibitors in postmarketing reports probably reflects the acute changes in eGFR attibutable to the known renal haemodynamic effects of SGLT2 inhibition.
| S-EPMC5485046 | biostudies-literature
Project description:BackgroundThe treatment duration of insulin-sodium-glucose co-transporter inhibitors (SGLTis) co-treatment of type 1 diabetes mellitus (T1DM) patients in randomized controlled trials (RCTs) varies by 1-52 weeks. Henceforth, treatment duration-wise, we compared the following insulin-treatment adjuncts- mega- versus low-dose SGLTis, SGLTis versus placebo, and different SGLTi dosages.MethodDouble-blinded RCTs reporting the above were searched (using terms like insulin-dependent, "juvenile-onset diabetes," and "sodium glucose cotransport*") in the PubMed, Embase, and Scopus databases and appraised using a Cochrane tool. The risks across different SGLTi-dosages were compared using network meta-analysis. Random-effect pairwise meta-analysis was performed for the remaining harm juxtapositions. Meta-analyses were performed for the following treatment durations- < 4 weeks, 4 to < 24 weeks, and ≥ 24 weeks. For meta-analysis and certainty of evidence assessment, we used the Stata statistical software and the GRADE method, respectively.ResultsA total of 15 (low risks of bias) studies sourcing data from about 7,330 T1DM patients were reviewed. Meta-analysis findings of ≥ 24 weeks long trials were- a. SGLTi-insulin co-treatment increased the genital infection (GI) (RR: 3.51; 95% CI: 2.59, 4.77), diabetic ketoacidosis (DKA) and (RR: 3.25; 95% CI:1.29, 8.16), and serious side effects (RR: 1.43; 95% CI: 1.05, 1.94) risk. b. SGLT2i-insulin increased the GI risk (RR: 3.77; 95% CI: 2.31, 6.16; high-quality evidence). c. Sotagliflozin-insulin increased the GI (RR: 3.36; 95% CI: 2.28, 4.96) and DKA (RR: 6.69; 95% CI: 2.75, 16.32) risk (both high-quality evidence). Compared to low-dose, megadose SGLTi treatment for 4 to < 24 weeks increased the GI risk. The remaining analyses were not statistically significantly different.ConclusionOn moderate to long-term treatment (24-52 weeks) of T1DM patients, insulin-SGLT2i co-treatment was associated with GI risk, and insulin-sotagliflozin co-treatment was associated with DKA and GI risk.Supplementary informationThe online version contains supplementary material available at 10.1007/s40200-023-01192-7.
| S-EPMC10225433 | biostudies-literature
Project description:INTRODUCTION:Sodium glucose co-transporter-2 inhibitors (SGLT2i) have been on the market for 5 years in Japan. We explored the real-world effectiveness of SGLT2i in Japan. METHODS:We retrospectively analyzed two large Japanese administrative databases from JMDC Inc.: insurance-dataset (I-dataset) and Medical Data Vision Co. Ltd. [hospital-dataset (H-dataset)]. Patients who newly started SGLT2i or other oral antidiabetic drugs (OADs) between 1 April 2014 and 31 March 2016 were selected for this analysis and followed for 1 year from the index date. Changes in glycated hemoglobin (HbA1c), body mass index (BMI), and estimated glomerular filtration rate (eGFR) were evaluated during the 1-year period. RESULTS:A total of 127,961 patients in the H-dataset and 26,436 in the I-dataset were included in this analysis. Baseline HbA1c, BMI, and eGFR levels tended to be higher in SGLT2i users than in other OAD cohorts. After 1 year, 44.3% (I-dataset) and 53.3% (H-dataset) of SGLT2i users and 33.0-44.2% (I-dataset) and 47.0-58.1% (H-dataset) of other users were still on their medications. The mean HbA1c level decreased by - 0.7 to - 0.9% in SGLT2i users versus - 0.4 to - 1.5% in the other cohorts. The mean BMI decreased by - 0.8 kg/m2 in SGLT2i users whereas the change in other cohorts was - 0.5 to 0.4 kg/m2. No clinically relevant changes in eGFR were observed over the period. CONCLUSION:This study showed that around half of the SGLT2i users were still on medication after 1 year from treatment initiation. Initiation of SGLT2i was associated with improvement in HbA1c and BMI, with no abnormal changes in renal function observed in the first year following treatment. These findings support the results from clinical trials and will expand the existing evidence of SGLT2i use in real-life practice in Japan. FUNDING:Astellas Pharma Inc., Tokyo, Japan.
| S-EPMC6848551 | biostudies-literature
Project description:BackgroundEvidence from prospective cardiovascular (CV) outcome trials in type 2 diabetes (T2DM) patients supports the use of sodium-glucose co-transporter-2 inhibitors (SGLT2i) to reduce the risk of CV events. In this study, we compared the risk of several CV outcomes between new users of SGLT2i and other glucose-lowering drugs (oGLDs) in Catalonia, Spain.MethodsCVD-REAL Catalonia was a retrospective cohort study using real-world data routinely collected between 2013 and 2016. The cohorts of new users of SGLT2i and oGLDs were matched by propensity score on a 1:1 ratio. We compared the incidence rates and hazard ratio (HR) for all-cause death, hospitalization for heart failure, chronic kidney disease, and modified major adverse CV event (MACE; all-cause mortality, myocardial infarction, or stroke).ResultsAfter propensity score matching, 12,917 new users were included in each group. About 27% of users had a previous history of CV disease. In the SGLT2i group, the exposure time was 60% for dapagliflozin, 26% for empagliflozin and 14% for canagliflozin. The use of SGLT2i was associated with a lower risk of heart failure (HR: 0.59; 95% confidence interval [CI] 0.47-0.74; p < 0.001), all-cause death (HR = 0.41; 95% CI 0.31-0.54; p < 0.001), all-cause death or heart failure (HR = 0.55; 95% CI 0.47-0.63; p < 0.001), modified MACE (HR = 0.62; 95% CI 0.52-0.74; p < 0.001), and chronic kidney disease (HR = 0.66; 95% CI 0.54-0.80; p < 0.001).ConclusionsIn this large, retrospective observational study of patients with T2DM from a Catalonia, initiation of SGLT-2i was associated with lower risk of mortality, as well as heart failure and CKD.
| S-EPMC8272340 | biostudies-literature
Project description:AIMS:Sodium-glucose co-transporter type 2 (SGLT2) inhibitors are a new class of anti-hyperglycaemic agents in type 2 diabetes mellitus (T2DM). This review examines their mechanism of action and provides an overview of safety and efficacy from the main studies of SGLT2 inhibitors marketed in the United States and Europe, namely, canagliflozin, dapagliflozin and empagliflozin. METHODS:We searched the PubMed database to identify relevant publications on the mechanism of action of SGLT2 inhibitors and clinical trial reports. RESULTS:Clinical trials in patients with T2DM have shown significant improvements in glycaemic control vs placebo with canagliflozin, dapagliflozin and empagliflozin: patients were more likely to reach target glycated haemoglobin levels compared with patients receiving placebo. All SGLT2 inhibitors also led to modest reductions in body weight and blood pressure vs placebo. Generally, all agents were well tolerated, with the most common adverse events with this class being genital mycotic infections and urinary tract infections. Hypoglycaemia was reported at rates similar to those seen with placebo, except when SGLT2 inhibitors were given in combination with insulin or an insulin secretagogue. Long-term outcome data are available only for empagliflozin: in the EMPA-REG OUTCOME study, empagliflozin demonstrated reduced risk of the composite end-point of 3-point major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke), primarily because of a significant reduction in cardiovascular mortality. CONCLUSIONS:SGLT2 inhibitors are an exciting addition to the list of available agents for T2DM, and may be suitable for various types of patients who need additional glycaemic control.
| S-EPMC5518299 | biostudies-literature
Project description:Although hyperglycemia is a key therapeutic focus in the management of patients with type 2 diabetes mellitus (T2DM), many patients experience sub-optimal glycemic control. Current glucose-lowering agents involve the targeting of various body organs. Sodium glucose co-transporter type 2 (SGLT2) inhibitors target the kidney, reduce renal glucose reabsorption, and increase urinary glucose elimination, thus lowering glucose blood levels. This review examines some of the key efficacy and safety data from clinical trials of the main SGLT2 inhibitors approved or currently in development, and provides a rationale for the use of SGLT2 inhibitors in the treatment of T2DM.
| S-EPMC3889318 | biostudies-literature
Project description:Sodium glucose co-transporter 2 (SGLT2) inhibitors are a new class of pharmacologic agents developed for the treatment of type 2 diabetes mellitus (T2DM). Their unique mechanism of action is independent of pancreatic beta-cell function or the degree of insulin resistance, giving these agents the potential for use in combination with any of the existing classes of glucose-lowering agents, including insulin. This makes SGLT2 inhibitors an option for patients with long-standing T2DM, but they also have a promising role for early intervention in T2DM, and that role is explored in this review.A literature search was performed to identify relevant English language articles relating to SGLT2 inhibitors, particularly dapagliflozin, canagliflozin and empagliflozin.Clinical trials of dapagliflozin, canagliflozin and empagliflozin, given as monotherapy or in combination with other glucose-lowering agents, reported clinically significant improvements in glycaemic control, body weight and systolic blood pressure. SGLT2 inhibitors were well tolerated and had a generally favourable safety profile. Few serious adverse events have been reported to date. The frequency of hypoglycaemic events was low, similar to that of placebo, and the choice of co-administered glucose-lowering agent was the major determinant of hypoglycaemic risk. Increased genital and urinary tract infections were consistently reported with SGLT2 inhibitors.SGLT2 inhibitors, with their unique insulin-independent mode of action, could have a significant impact on the early management of T2DM, by addressing some of the specific risk factors associated with this disease. SGLT2 inhibitors induce beneficial changes in a number of cardiovascular risk factors, such as lowering blood pressure and body weight, in addition to improved glycaemic control, although information on clinical cardiovascular outcomes is currently limited.
| S-EPMC4758393 | biostudies-literature
Project description:While patients with type 2 diabetes mellitus (T2DM) are at increased risk to develop atrial fibrillation (AF), the mechanistic link between T2DM and AF-susceptibility remains unclear. Common co-morbidities of T2DM, particularly hypertension, may drive AF in the setting of T2DM. But direct mechanisms may also explain this relation, at least in part. In this regard, recent evidence suggests that mitochondrial dysfunction drives structural, electrical and contractile remodelling of atrial tissue in patients T2DM. Mitochondrial dysfunction may therefore be the mechanistic link between T2DM and AF and could also serve as a therapeutic target. An elegant series of experiments published in Cardiovascular Diabetology provide compelling new evidence to support this hypothesis. Using a model of high fat diet (HFD) and low-dose streptozotocin (STZ) injection, Shao et al. provide data that demonstrate a direct association between mitochondrial dysfunction and the susceptibility to develop AF. But the authors also demonstrated that the sodium-glucose co-transporter 2 inhibitors (SGLT2i) empagliflozin has the capacity to restore mitochondrial function, ameliorate electrical and structural remodelling and prevent AF. These findings provide a new horizon in which mitochondrial targeted therapies could serve as a new class of antiarrhythmic drugs.
| S-EPMC6945755 | biostudies-literature
Project description:Purpose of reviewSodium-glucose co-transporter-2 (SGLT2) inhibitors are the newest class of oral antihyperglycemic agents that have been approved for the treatment of diabetes mellitus. Over the past year, there have been significant developments in both the safety and efficacy of this class of medications that are presented in this review.Recent findingsApart from data on the glucose-lowering effect of SGLT2 inhibitors, other metabolic benefits have been demonstrated for this class of medications. Moreover, there have been three Food and Drug Administration Drug Safety Communications issued in 2015 that have led to additional drug labeling. The basic mechanism of action, indications, glucose-lowering benefits, other metabolic benefits, and adverse side-effects of SGLT2 inhibitors are presented in this review.SummarySGLT2 inhibitors are medications that have a unique mechanism of action and that lower glucose independent of insulin. Given the recent findings on efficacy and benefits, these agents are rapidly establishing their role in the treatment of diabetes. Especially in patients with type 2 diabetes not willing or not ready to start insulin, SGLT2 inhibitors may be another option in those patients requiring additional glucose lowering and in those with acceptable risk factor profiles. Although there appears to be some positive benefits in cardiovascular endpoints, more research on the long-term outcomes in people taking SGLT2 inhibitors is warranted.
| S-EPMC6028052 | biostudies-literature
Project description:Cardiovascular and renal impairment are the most common complications of type 2 diabetes mellitus (T2DM). As an emerging class of glucose-lowing agents sodium glucose co-transporter 2 (SGLT2), possesses beneficial effects on cardiovascular and renal outcomes in patients with T2DM. The aim of this study is to assess the efficacy of different SGLT2 inhibitors for cardiovascular and renal outcomes for patients with T2DM when compared with placebo. We performed a systematic search of PubMed, Embase, and the Cochrane library from inception through November 2021. Randomized clinical trials enrolling participants with T2DM were included, in which SGLT2 inhibitors were compared with each other or placebo. The primary outcomes including all-caused mortality, Cardiovascular outcomes (cardiovascular mortality, hospitalization for heart failure), and the renal composite outcomes (worsening persistent microalbuminuria or macroalbuminuria, new or worsening chronic kidney disease, doubling of serum creatinine, end-stage renal disease, renal transplant, or renal death). The data for the outcomes were pooled and recorded as Hazard rations (HRs) with 95% confidence intervals (CLs). Two researcher independently screened the trials and drawn the data. Ten trials enrolling 68,723 patients were included. Compared with placebo groups, Canagliflozin [HR, 0.85 (95%CI, 0.75-0.98)], ertugliflozin [HR, 0.93 (95%CI, 0.78-1.11)], and sotagliflozin [HR, 0.94 (95%CI, 0.79-1.12)] were associated with a reduction in all-cause mortality. Canagliflozin [HR, 0.84 (95%CI, 0.72-0.97)], dapagliflozin [HR, 0.88 (95%CI, 0.79-0.99)], empagliflozin [HR, 0.62 (95%CI, 0.49-0.78)], ertugliflozin [HR, 0.92 (95%CI, 0.77-1.10)], and sotagliflozin [HR, 0.88 (95%CI, 0.73-1.06)] were associated with a reduction in cardiovascular mortality; Canagliflozin [HR, 0.64 (95%CI, 0.53-0.77)], dapagliflozin [HR, 0.71 (95%CI, 0.63-0.81)], empagliflozin [HR, 0.65 (95%CI, 0.50-0.85)], ertugliflozin [HR, 0.70 (95%CI, 0.54-0.90)], and sotagliflozin [HR, 0.66 (95%CI, 0.56-0.77)] were associated with a reduction in hospitalization for heart failure. Dapagliflozin [HR, 0.55 (95%CI, 0.47-0.63)], Empagliflozin [HR, 0.54 (95%CI, 0.39-0.74)], canagliflozin [HR, 0.64 (95%CI, 0.54-0.75)], sotagliflozin [HR, 0.71 (95%CI, 0.46-1.09)], and ertugliflozin [HR, 0.81 (95%CI, 0.63-1.04)] were associated with a reduction in the renal composite outcome. All SGLT2 inhibitors showed a reduction in cardiovascular mortality, hospitalization for heart failure, renal composite outcomes and all-cause mortality. Canagliflozin and empagliflozin seemed to have the same efficacy in reducing hospitalization for heart failure, but empagliflozin had advantage in reducing cardiovascular mortality, whereas dapagliflozin most likely showed the best renal composite outcomes.
| S-EPMC9731650 | biostudies-literature