Sodium Glucose Co-transporter Type 2 (SGLT2) Inhibitors: Targeting the Kidney to Improve Glycemic Control in Diabetes Mellitus.
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ABSTRACT:
SUBMITTER: Bays H
PROVIDER: S-EPMC3889318 | biostudies-literature | 2013 Dec
REPOSITORIES: biostudies-literature
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Sodium Glucose Co-transporter Type 2 (SGLT2) Inhibitors: Targeting the Kidney to Improve Glycemic Control in Diabetes Mellitus.
Diabetes therapy : research, treatment and education of diabetes and related disorders 20131019 2
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 ...[more]
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Project description:Although several treatment options are available to reduce hyperglycemia, only about half of individuals with diagnosed diabetes mellitus (DM) achieve recommended glycemic targets. New agents that reduce blood glucose concentrations by novel mechanisms and have acceptable safety profiles are needed to improve glycemic control and reduce the complications associated with type 2 diabetes mellitus (T2DM). The renal sodium-glucose co-transporter 2 (SGLT2) is responsible for reabsorption of most of the glucose filtered by the kidney. Inhibitors of SGLT2 lower blood glucose independent of the secretion and action of insulin by inhibiting renal reabsorption of glucose, thereby promoting the increased urinary excretion of excess glucose. Canagliflozin, dapagliflozin, and empagliflozin are SGLT2 inhibitors approved as treatments for T2DM in the United States, Europe, and other countries. Canagliflozin, dapagliflozin, and empagliflozin increase renal excretion of glucose and improve glycemic parameters in patients with T2DM when used as monotherapy or in combination with other antihyperglycemic agents. Treatment with SGLT2 inhibitors is associated with weight reduction, lowered blood pressure, and a low intrinsic propensity to cause hypoglycemia. Overall, canagliflozin, dapagliflozin, and empagliflozin are well tolerated. Cases of genital infections and, in some studies, urinary tract infections have been more frequent in canagliflozin-, dapagliflozin-, and empagliflozin-treated patients compared with those receiving placebo. Evidence from clinical trials suggests that SGLT2 inhibitors are a promising new treatment option for T2DM.
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Project description:Hospital admissions and mortality from the Coronavirus disease 2019 (COVID-19) pandemic are spreading throughout the world, and second and third waves are thought to be likely. Risk factors for severe COVID-19 include diabetes, chronic kidney disease and cardiovascular disease. Currently, there is no vaccine and no approved therapy. Therapeutic approaches are aimed at preventing viral replication and spread, limiting the impact of the inflammatory overdrive (cytokine storm), preventing thromboembolic complications and replacing or supporting organ function. However, despite organ support, mortality is currently 65% for those receiving advanced respiratory support and 78% for those requiring renal replacement therapies. Thus, efforts should be made to provide adjuvant organ protection therapy. This may imply novel therapies in clinical development (e.g., the Fas ligand trap asunercept), but uptake of repurposed drugs already in clinical use may be faster. In this regard, sodium glucose co-transporter-2 (SGLT2) inhibitors were recently shown to protect the heart and kidney both within and outside of a diabetic milieu context. Further, preclinical data support a beneficial effect for the lung. We now discuss the potential benefits and risks of SGLT2 inhibitors in COVID-19 and an ongoing clinical trial testing the impact of dapagliflozin on outcomes in COVID-19 patients with respiratory failure.
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Project description:ObjectiveTo estimate the association between the use of sodium glucose co-transporter-2 (SGLT2) inhibitors and postmarket harms as identified by drug regulatory agencies.DesignWe conducted a systematic review and meta-analysis of randomised controlled trials (RCT). Six large databases were searched from inception to May 2018. Random effects models were used to estimate pooled relative risks (RRs).InterventionSGLT2 inhibitors, compared with placebo or active comparators.Primary outcomesAcute kidney injury (AKI), diabetic ketoacidosis (DKA), urinary tract infections (UTI), bone fractures and lower limb amputations.ResultsWe screened 2418 citations of which 109 were included. Most studies included one of four SGLT2 inhibitors, dapagliflozin, canagliflozin, empagliflozin and ipragliflozin. When compared with placebo, SGLT2 inhibitors were found to be significantly protective against AKI (RR=0.59; 95% CI 0.39 to 0.89; I2=0.0%), while no difference was found for DKA (RR 0.66; 95% CI 0.30 to 1.45, I2=0.0%), UTI (RR 1.02; 95% CI 0.95 to 1.09, I2=0.0%) or bone fracture (RR 0.87; 95% CI 0.69 to 1.09, I2=1.3%). Three studies reported on amputation, with one finding a significant increase risk. No increased risk for either outcome was found when compared with active controls. Subgroup analysis did show an increased risk of UTI with dapagliflozin only (RR 1.21; 95% CI 1.02 to 1.43, I2=0.0%), but no other analysis supported an increased risk of AKI, DKA, UTI or fracture.ConclusionsCurrent evidence from RCTs does not suggest an increased risk of harm with SGLT2 inhibitors as a class over placebo or active comparators with respect to AKI, DKA, UTI or fracture. However, wide CIs for many comparisons suggest limited precision, and therefore clinically important adverse events cannot be ruled out. Dapagliflozin, appears to independently increase the risk of UTI, although the mechanism for this intraclass variation in risk is unclear.Prospero registration numberCRD42016038715.
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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.
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Project description:Patients with type 2 diabetes mellitus (T2DM) appear to have increased risk for fractures. In this context, the finding that canagliflozin, a sodium-glucose co-transporter-2 (SGLT) inhibitor, increased the risk for fracture compared with placebo in the Canagliflozin Cardiovascular Assessment Study (CANVAS), a large randomized controlled trial (RCT) in patients with established cardiovascular disease or multiple cardiovascular risk factors, created concern. In the present review, we summarize the data regarding the association between SGLT2 inhibitors and fracture risk in patients with T2DM. In contrast to the findings reported in CANVAS, canagliflozin did not affect the risk of fracture in a more recent, large RCT in patients with diabetic nephropathy. In addition, empagliflozin and dapagliflozin, other members of this class, also do not appear to affect the incidence of fracture. Moreover, there is no clear pathogenetic mechanism through which SGLT2 inhibitors increase the risk for fractures. Therefore, available data are inconclusive to attribute to these drugs a direct responsibility for bone fractures.
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Project description:IntroductionThe first cardiovascular safety trial in the sodium-glucose co-transporter-2 (SGLT2) inhibitor drug class, the Empagliflozin Cardiovascular Outcomes and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) trial, demonstrated significant cardiovascular risk reduction with empagliflozin. It is currently not clear what proportions of people with type 2 diabetes (T2DM) have the same high cardiovascular risk as those included in the trial, and will therefore be likely to experience the same cardiovascular benefit. We aimed to identify and describe the proportion of people with T2DM from a representative English national population who have the comparable high cardiovascular risk to those included in the EMPA-REG trial.MethodA cross-sectional analysis of cardiovascular risk in people with T2DM and a subgroup prescribed SGLT2 inhibitors. Patients were identified from the Royal College of General Practitioners Research and Surveillance Centre database. Cardiovascular risk factors were identified from electronic patient records.ResultsFrom 1,238,909 patients at 128 GP practices, we identified 60,327 adults with T2DM (mean age 66.1 years, SD 13.9) of whom 55.6% were male. From these 1642 (2.7%) people had been initiated on an SGLT2 inhibitor (mean age 58.1 years, SD 10.4; 58.8% male). In the complete T2DM group only 15.7% (95% CI 15.5-16.0%) had the same high cardiovascular risk as those included in the EMPA-REG trial. In those already initiated on SGLT2 inhibitors this proportion was 11.1% (95% CI 9.8-12.4%). Whilst the proportion was higher in the oldest age groups, in those 70+ years old less than a quarter met the EMPA-REG trial high cardiovascular risk criteria.ConclusionsThe EMPA-REG trial results are applicable only to a small proportion of people with T2DM and a smaller proportion of those currently treated with SGLT2 inhibitors. Additional data are required to identify any cardiovascular benefit in people with lower cardiovascular risk.FundingAstraZeneca.
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