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The nephrological perspective on SGLT-2 inhibitors in type 1 diabetes.
Gillard, P, Schnell, O, Groop, PH
Diabetes research and clinical practice. 2020;:108462
Abstract
Prevalence of type 1 diabetes mellitus (T1DM) is globally continuously increasing. T1DM is accompanied by a high risk of developing cardiovascular and renal comorbidities and is one of the leading causes of end-stage renal disease (ESRD). However, current therapeutic approaches for chronic and/or diabetic kidney disease (CKD/DKD) existed for a long time, and offer room for improvement, particularly in T1DM. In 2019, the European Medicines Agency (EMA) approved a first sodium/glucose co-transporter 2 inhibitor (SGLT-2i) and a first dual SGLT-1/-2i to improve glycaemic control, as an adjunctive treatment to insulin in persons with T1DM and a body mass index ≥27 kg/m2. Of note, SGLT-1/2is and SGLT-2is are not approved by the Food and Drug Administration (FDA) as an adjunct treatment in T1DM, nor approved for the treatment of CKD or DKD by EMA and FDA. SGLT is have shown to mediate different renoprotective effects in type 2 diabetes mellitus in corresponding cardiovascular and renal outcome trials. First efficacy trials offer insights into potential positive effects on renal function and kidney disease of SGLTis in T1DM. This review summarizes and discusses latest available data on SGLT inhibition and provides an update on the nephrological perspective on SGLTis, specifically in T1DM.
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Insulin resistance and heart failure during treatment with sodium glucose cotransporter 2 inhibitors: proposed role of ketone utilization.
Hattori, Y
Heart failure reviews. 2020;(3):403-408
Abstract
Sodium glucose cotransporter 2 (SGLT2) inhibitors reduce the rate of hospitalization for heart failure in individuals with type 2 diabetes, but the underlying mechanisms remain elusive. Modestly elevated circulating β-hydroxybutyrate (βOHB) during treatment with SGLT2 inhibitors causes different beneficial effects on organs and cells, depending on succinyl-CoA:3-ketoacid CoA transferase (SCOT) levels. In the heart, in which SCOT is highly expressed/up-regulated, βOHB may be an alternative energy source apart from fat and glucose oxidation. The type 2 diabetic failing heart may be energy inefficient. In skeletal muscle, in which SCOT is not highly expressed/down-regulated, βOHB may cause antioxidant effects, resulting in amelioration of insulin resistance, which could lead to improvement in cardiac insulin resistance with metabolic, endocrine, and cytokine alterations. Although various mechanisms have been suggested, we postulate that the potential impact of SGLT2 inhibitors on heart failure lies in fuel energetics and amelioration of insulin resistance with ketone utilization depending upon SCOT levels.
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Sodium-glucose cotransporter-2 inhibitors for diabetic kidney disease: Targeting Warburg effects in proximal tubular cells.
Morita, M, Kanasaki, K
Diabetes & metabolism. 2020;(5):353-361
Abstract
Inhibitors of sodium-glucose cotransporter 2 (SGLT2) have undoubtedly shifted the paradigm for diabetes medicine and research and, especially, diabetic kidney disease (DKD). The pharmacological action of SGLT2 inhibitors is simply the release of glucose into urine; however, precisely how SGLT2 inhibitors contribute to the health of those with diabetes has still not been completely elucidated. Towards this end, the present review provides a novel insight into the action of SGLT2 inhibitors by highlighting a neglected fuel-burning system found in proximal tubular cells-'glycolysis'. In addition, exploring the details of the molecular mechanisms and clinical biomarkers of the organ protection conferred by SGLT2 inhibitors is now required to prepare for the next stage of clinical diabetes medicine-the 'post-SGLT2 inhibitor era'.
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Long-term efficacy of gliflozins versus gliptins for Type 2 Diabetes after metformin failure: a systematic review and network meta-analysis.
Zilli, RW, Rached, CDA, Silva, FPD, Baena, RC
Revista da Associacao Medica Brasileira (1992). 2020;(4):458-465
Abstract
After metformin failure in treatment for diabetes type 2, there is no trivial option for adjuvant medication. The last two oral class medications, gliflozins and gliptins, have different mechanisms of action but have never been compared in long run studies. The aim of the present meta-analysis is to assess the overall long-term efficacy of these drugs after metformin failure. A systematic review and meta-analysis were performed, including all trials with a duration of over 2 years, comparing gliflozins or gliptins after metformin failure in type 2 diabetes. Data Sources: Pubmed (Medline), Embase, Lilacs, and the Cochrane Library from inception through July 2016 without language restrictions. The longest study period found in the literature was 4 years. We selected 1 article on empagliflozin, 1 on dapagliflozin, and 1 on saxagliptin with missing data. After one year of treatment, over 50% of the patients presented HbA1c > 7%. Efficacy rate after 4 years of empagliflozin (23%) was better than dapagliflozin (5%) and saxagliptin (7%); however, it presented statistically non-significant values for HbA1c (7.4 and 7.3% between gliflozins), and missing data for saxaglifozin. Nonetheless, empagliflozin performed better than glimepiride in the 4-year period (standardized mean difference SMD 0.4, confidence interval CI 95% 0.23 to 0.56). The failure of the secondary treatment using gliflozins occurs in less than one year of treatment (less than 50% of the patients presenting HbA1c > 7 %). Empagliflozin offered better glycemic control compared to sulfonylureas but was similar to dapagliflozin.
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Tubular effects of sodium-glucose cotransporter 2 inhibitors: intended and unintended consequences.
Dominguez Rieg, JA, Xue, J, Rieg, T
Current opinion in nephrology and hypertension. 2020;(5):523-530
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Abstract
PURPOSE OF REVIEW Sodium-glucose cotransporter 2 (SGLT2) inhibitors are antihyperglycemic drugs that act by inhibiting renal sodium-glucose cotransport. Here we present new insights into 'off target', or indirect, effects of SGLT2 inhibitors. RECENT FINDINGS SGLT2 inhibition causes an acute increase in urinary glucose excretion. In addition to lowering blood glucose, there are several other effects that contribute to the overall beneficial renal and cardiovascular effects. Reabsorption of about 66% of sodium is accomplished in the proximal tubule and dependent on the sodium-hydrogen exchanger isoform 3 (NHE3). SGLT2 colocalizes with NHE3, and high glucose levels reduce NHE3 activity. The proximal tubule is also responsible for the majority of phosphate (Pi) reabsorption. SGLT2 inhibition is associated with increases in plasma Pi, fibroblast growth factor 23 and parathyroid hormone levels in nondiabetics and type 2 diabetes mellitus. Studies in humans identified a urate-lowering effect by SGLT2 inhibition which is possibly mediated by urate transporter 1 (URAT1) and/or glucose transporter member 9 in the proximal tubule. Of note, magnesium levels were also found to increase under SGLT2 inhibition, an effect that was preserved in nondiabetic patients with hypomagnesemia. SUMMARY Cardiorenal effects of SGLT2 inhibition might involve, in addition to direct effects on glucose homeostasis, effects on NHE3, phosphate, urate, and magnesium homeostasis.
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Severe euglycemic diabetic ketoacidosis of multifactorial etiology in a type 2 diabetic patient treated with empagliflozin: case report and literature review.
Sampani, E, Sarafidis, P, Dimitriadis, C, Kasimatis, E, Daikidou, D, Bantis, K, Papanikolaou, A, Papagianni, A
BMC nephrology. 2020;(1):276
Abstract
BACKGROUND Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are a relatively novel class of oral medications for the treatment of Type 2 DM with a generally acceptable safety profile. However, these agents have been associated with rare events of a serious and potentially life-threatening complication named euglycemic diabetic ketoacidosis (euDKA). euDKA is not identical with the typical diabetic ketoacidosis, as it often presents with serious metabolic acidosis but only mild to moderate glucose and anion gap elevation. CASE PRESENTATION We report a case of a 51-year old female with Type 2 DM treated with an SGLT-2 inhibitor, developing severe metabolic acidosis with only mild blood glucose elevation after a routine surgery. A careful evaluation of involved factors led to the diagnosis of euDKA, followed by cautious application of simple therapeutic measures that resulted in complete restoration of acidosis and glycemic control in less than 48-h. CONCLUSIONS Euglycemic ketoacidosis is a rare but rather serious complication of SGLT-2 inhibitors use, often with a multifactorial etiology. Its atypical presentation requires a high level of awareness by physicians as early recognition of this complication can quickly and safely restore acid-base balance.
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Diabetic ketoacidosis with SGLT2 inhibitors.
Musso, G, Saba, F, Cassader, M, Gambino, R
BMJ (Clinical research ed.). 2020;:m4147
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Sodium-glucose cotransporter 2 inhibition: which patient with chronic kidney disease should be treated in the future?
Neuen, BL, Jardine, MJ, Perkovic, V
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2020;(Suppl 1):i48-i55
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Abstract
The advent of sodium-glucose cotransporter 2 (SGLT2) inhibitors represents a major advance for people with type 2 diabetes (T2DM) and chronic kidney disease (CKD). The results of the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial have clearly demonstrated that canagliflozin prevents kidney failure and cardiovascular events. The results from three other large-scale randomized trials, collectively enrolling >30 000 participants, have provided further evidence that the effects of SGLT2 inhibition on major kidney outcomes in people with T2DM may be present across the class, although this will only be known for certain when Dapagliflozin and Renal Outcomes and Cardiovascular Mortality in Patients with CKD (DAPA-CKD) (NCT03036150) and The Study of Heart and Kidney Protection with Empagliflozin (EMPA-KIDNEY) (NCT03594110) are reported over coming years. Importantly, the benefits of SGLT2 inhibition have been achieved in addition to the current standard of care. This review summarizes evidence for SGLT2 inhibition in people with T2DM and CKD, evaluates key patient characteristics and concomitant drug use that may influence the use of these drugs in people with CKD, discusses current guideline recommendations and explores how these drugs may be used in people with CKD in the future, including in combination with other treatments.
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Glucagon-Like Peptide 1 Receptor Agonists and Heart Failure: The Need for Further Evidence Generation and Practice Guidelines Optimization.
Khan, MS, Fonarow, GC, McGuire, DK, Hernandez, AF, Vaduganathan, M, Rosenstock, J, Handelsman, Y, Verma, S, Anker, SD, McMurray, JJV, et al
Circulation. 2020;(12):1205-1218
Abstract
With worsening epidemiological trends for both the incidence and prevalence of type 2 diabetes mellitus (T2DM) and heart failure (HF) worldwide, it is critical to implement optimal prevention and treatment strategies for patients with these comorbidities, either alone or concomitantly. Several guidelines and consensus statements have recommended glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter type 2 inhibitors as add-ons to lifestyle interventions with or without metformin in those at high atherosclerotic cardiovascular disease risk. However, these recommendations are either silent about HF or fail to differentiate between the prevention of HF in those at risk versus the treatment of individuals with manifest HF. Furthermore, these documents do not differentiate among those with different HF phenotypes. This distinction, even though important, may not be critical for sodium-glucose cotransporter type 2 inhibitors in view of the consistent data for benefit for both atherosclerotic cardiovascular disease- and HF-related outcomes that have emerged from the regulatory-mandated cardiovascular outcome trials for all sodium-glucose cotransporter type 2 inhibitors and the recent DAPA-HF trial (Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction)demonstrating the benefit of dapagliflozin on HF-related outcomes in patients with HF with reduced ejection fraction with or without T2DM. However, the distinction may be crucial for glucagon-like peptide-1 receptor agonists and other antihyperglycemic agents. Indeed, in several of the new statements, glucagon-like peptide-1 receptor agonists are suggested treatment not only for patients with T2DM and atherosclerotic cardiovascular disease, but also in those with manifest HF, despite a lack of evidence for the latter recommendation. Although glucagon-like peptide-1 receptor agonists may be appropriate to use in patients at risk for HF, mechanistic insights and observations from randomized trials suggest no clear benefit on HF-related outcomes and even uncertainty regarding the safety in those with HF with reduced ejection fraction. Conversely, theoretical rationales suggest that these agents may benefit patients with HF with preserved ejection fraction. Considering that millions of patients with T2DM have HF, these concerns have public health implications that necessitate the thoughtful use of these therapies. Achieving this aim will require dedicated trials with these drugs in both patients who have HF with reduced ejection fraction and HF with preserved ejection fraction with T2DM to assess their efficacy, safety, and risk-benefit profile.
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Translating the statistical benefits of SGLT-2 inhibitors on cardio-renal outcomes into clinical practice.
Ghosal, S, Sinha, B
Expert review of clinical pharmacology. 2020;(5):545-551
Abstract
BACKGROUND/OBJECTIVES This study aims to analyze the positive outcomes observed in cardiovascular outcomes trials conducted with sodium-glucose co-transporter inhibitors and determine their statistical and clinical significance. METHODS A literature search conducted using the Cochrane library resulted in five citations - randomized controlled trials (RCTs), identified for analysis. Positive cardio-renal outcomes from the five RCTs were analyzed in accordance with a pre-defined strategy which included the hierarchical flow chart, presence of a persuasive p-value (p < 0.001), and number needed to treat (NNT) estimation calculated from the absolute risk reduction (ARR) reported. RESULTS Only four instances fulfilled these stringent criteria - reduction of cardiovascular (CV) death with empagliflozin in T2DM patients with established atherosclerotic cardiovascular disease (eASCVD) (p < 0.001; NNT 45), reduction in cardiorenal outcomes with canagliflozin in a pooled T2DM population with macroalbuminuria (p < 0.00001; NNT 22), as well as reduction in the composite of CV death or hospitalization for heart failure (hHF) (p < 0.001; NNT 30) and also reduction in hHF or CV death with dapagliflozin in T2DM with heart failure with reduced ejection fraction (HFrEF) (p < 0.001; NNT 21). CONCLUSIONS Statistically positive outcome results must be interpreted in the context of associated clinical benefits and not in isolation.