Optimising the Benefits of SGLT2 Inhibitors for Type 1 Diabetes.
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SUBMITTER: Evans M
PROVIDER: S-EPMC6965597 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
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Optimising the Benefits of SGLT2 Inhibitors for Type 1 Diabetes.
Evans Marc M Hicks Debbie D Patel Dipesh D Patel Vinod V McEwan Phil P Dashora Umesh U
Diabetes therapy : research, treatment and education of diabetes and related disorders 20191207 1
Sodium-glucose cotransporter 2 (SGLT2) inhibitor clinical studies in type 1 diabetes mellitus (T1DM) have demonstrated reduced HbA1c and lower glucose variability with increased time in optimal glucose range as well as additional benefits of reductions in weight and insulin dose without increasing the incidence of hypoglycaemia. However, the appropriate use of SGLT2 inhibitor therapies within clinical practise to treat people with T1DM remains unclear. In this article we have used consensus expe ...[more]
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Project description:Sodium-glucose co-transporter-2 (SGLT2) inhibitors have several beneficial effects in patients with type 2 diabetes, including glucose lowering, weight loss, blood pressure lowering, and a reduced risk of major adverse cardiovascular events. To address high unmet medical need via improved glycaemic control, several clinical trials have been done to assess the efficacy and safety of SGLT2 inhibitors in combination with insulin therapy in patients with type 1 diabetes. In this Personal View, we summarise data from eight clinical trials of canagliflozin, dapagliflozin, empagliflozin, and sotagliflozin in patients with type 1 diabetes. HbA1c-lowering efficacy was greatest at 8-12 weeks of therapy, but the magnitude of HbA1c lowering waned with longer duration of treatment (up to 52 weeks). Data are not yet available to establish for how long glycaemic efficacy could be sustained during long-term therapy in patients with type 1 diabetes. Moreover, SGLT2 inhibitor therapy induces serious adverse events, including a roughly six-times increased risk of diabetic ketoacidosis. The US Food and Drug Administration estimated that one additional case of ketoacidosis will occur for every 26 patient-years of exposure of patients with type 1 diabetes to sotagliflozin therapy. Assuming a case mortality of 0·4%, this estimate translates into 16 additional deaths per year per 100 000 patients with type 1 diabetes undergoing treatment. These considerations raise important questions about the risk-to-benefit profile of SGLT2 inhibitors when used as adjunctive therapy in patients with type 1 diabetes.
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Project description:SGLT2 inhibitors are plausible second-line drugs that provide powerful additional A1c-lowering effects while inducing weight loss without hypoglycemia.
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Project description:Some studies have shown that sodium-glucose cotransporter (SGLT) 2 inhibitors can definitively attenuate the occurrence of cardiovascular diseases such as heart failure (HF), dilated cardiomyopathy (DCM), and myocardial infarction. With the development of research, SGLT2 inhibitors can also reduce the risk of arrhythmias. So in this review, how SGLT2 inhibitors play a role in reducing the risk of arrhythmia from the perspective of electrical remodeling and structural remodeling are explored and then the possible mechanisms are discussed. Specifically, we focus on the role of SGLT2 inhibitors in Na+ and Ca2 + homeostasis and the transients of Na+ and Ca2 +, which could affect electrical remodeling and then lead to arrythmia. We also discuss the protective role of SGLT2 inhibitors in structural remodeling from the perspective of fibrosis, inflammation, oxidative stress, and apoptosis. Ultimately, it is clear that SGLT2 inhibitors have significant benefits on cardiovascular diseases such as HF, myocardial hypertrophy and myocardial infarction. It can be expected that SGLT2 inhibitors can reduce the risk of arrhythmia.
| S-EPMC9631490 | biostudies-literature
Project description:BackgroundSodium-glucose cotransporter-2 inhibitors (SGLT2i) have proven cardiovascular benefits in patients with type 2 diabetes (T2D). This self-controlled case series study aims to evaluate whether metformin use and SGLT2i-associated erythrocytosis influence its cardiovascular benefits.MethodsT2D patients with metformin and/or SGLT2i prescriptions between 2015 and 2020 were identified from the Hong Kong population. Study outcomes were composite cardiovascular diseases (CVD), coronary heart disease (CHD), hospitalisation for heart failure (HHF), stroke, and erythrocytosis. Risk periods were patient-time divided into four mutually exclusive windows: (i) 'baseline period' of metformin use without SGLT2i; (ii) pre-SGLT2i period; (iii) exposure to SGLT2i without metformin; and (iv) exposure to the drug combination. Another SCCS model was applied to evaluate the association between erythrocytosis and cardiovascular outcomes regarding SGLT2i exposure. Four mutually exclusive risk periods included (i) SGLT2i exposure with erythrocytosis; (ii) SGLT2i exposure without erythrocytosis; (iii) absence of SGLT2i exposure with erythrocytosis; and (iv) absence of SGLT2i exposure without erythrocytosis. Incidence rate ratios (IRR) of events at different risk periods were estimated using conditional Poisson regression model.ResultsAmong 20,861 patients with metformin and/or SGLT2i prescriptions, 2575 and 1700 patients with events of composite CVD and erythrocytosis were identified, respectively. Compared to metformin use without SGLT2i, SGLT2i initiation was associated with lower risks of composite CVD, CHD, and HHF-regardless of the presence (CVD: IRR = 0.43, 95% CI 0.37-0.51; CHD: IRR = 0.44, 95% CI 0.37-0.53; HHF: IRR = 0.29, 95% CI 0.22-0.40; all p < 0.001) and absence of concomitant metformin (CVD: IRR = 0.31, 95% CI 0.20-0.48; CHD: IRR = 0.38, 95% CI 0.25-0.59; HHF: IRR = 0.17, 95% CI 0.09-0.31; all p < 0.001); while SGLT2i was neutral on stroke risk. Compared to metformin-SGLT2i combination, exposure to SGLT2i alone was associated with comparable risks of all cardiovascular outcomes (all p > 0.05). Incidence rates of erythrocytosis at baseline, SGLT2i without and with metformin use periods were 0.75, 3.06 and 3.27 per 100 person-years, respectively. SGLT2i users who developed erythrocytosis had lower risk of HHF (IRR = 0.38, 95% CI 0.14-0.99, p = 0.049) than those who did not.ConclusionsOur real-world data suggested that SGLT2i-associated cardiovascular benefits were not attenuated by metformin use. Further studies will delineate the role of erythrocytosis as a surrogate marker of SGLT2i-associated cardiovascular benefit in reducing HHF.
| S-EPMC9166572 | biostudies-literature
Project description:Diabetic kidney disease (DKD) is a topic of increasing concern among clinicians involved in the management of type 2 diabetes mellitus (T2DM). It is a progressive and costly complication associated with increased risk of adverse cardiovascular (CV) and renal outcomes and mortality. Ongoing monitoring of the estimated glomerular filtration (eGFR) rate alongside the urine albumin:creatinine ratio (ACR) is recommended during regular T2DM reviews to enable a prompt DKD diagnosis or to assess disease progression, providing an understanding of adverse risk for each individual. Many people with DKD will progress to end-stage kidney disease (ESKD), requiring renal replacement therapy (RRT), typically haemodialysis or kidney transplantation. A range of lifestyle and pharmacological interventions is recommended to help lower CV risk, slow the advancement of DKD and prevent or delay the need for RRT. Emerging evidence concerning sodium-glucose co-transporter-2 inhibitor (SGLT2i) agents suggests a role for these medicines in slowing eGFR decline, enabling regression of albuminuria and reducing progression to ESKD. Improvements in renal end points observed in SGLT2i CV outcome trials (CVOTs) highlighted the possible impact of these agents in the management of DKD. Data from the canagliflozin CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) have since demonstrated the effectiveness of this medicine in reducing the risk of kidney failure and CV events in a population comprising individuals with T2DM and renal disease. CREDENCE was the first SGLT2i study to examine renal outcomes as the primary end point. Real-world studies have reaffirmed these outcomes in routine clinical practice. This article summarises the evidence regarding the use of SGLT2i medicines in slowing the progression of DKD and examines the possible mechanisms underpinning the renoprotective effects of these agents. The relevant national and international guidance for monitoring and treatment of DKD is also highlighted to help clinicians working to support this vulnerable group.
| S-EPMC7524028 | biostudies-literature
Project description:Cardiovascular disease (CVD), including heart failure (HF), is a leading cause of morbidity and mortality in people with type 2 diabetes mellitus (T2DM). CVD and T2DM share common risk factors for development and progression, and there is significant overlap between the conditions in terms of worsening outcomes. In assessing the cardiovascular (CV) safety profiles of anti-diabetic drugs, sodium-glucose co-transporter-2 inhibitor (SGLT2i) therapies have emerged with robust evidence for reducing the risk of adverse CVD outcomes in people with T2DM who have either established CVD or are at risk of developing CVD. A previous consensus document from the Improving Diabetes Steering Committee has examined the potential role of SGLT2is in T2DM management and considered the risk-benefit profile of the class and the appropriate place for these medicines within the T2DM pathway. This paper builds on these findings and presents practical guidance for maximising the pleiotropic benefits of this class of medicines in people with T2DM in terms of reducing adverse CVD outcomes. The Improving Diabetes Steering Committee aims to offer evidence-based practical guidance for the use of SGLT2i therapies in people with T2DM stratified by CVD risk. This is of particular importance currently because some treatment guidelines have not been updated to reflect recent evidence from cardiovascular outcomes trials (CVOTs) and real-world studies that complement the CVOTs. The Improving Diabetes Steering Committee seeks to support healthcare professionals (HCPs) in appropriate treatment selection for people with T2DM who are at risk of developing or have established CVD and examines the role of SGLT2i therapy for these people.Funding: Napp Pharmaceuticals Limited.
| S-EPMC6778582 | biostudies-literature
Project description:The importance of the kidney's role in glucose homeostasis has gained wider understanding in recent years. Consequently, the development of a new pharmacological class of anti-diabetes agents targeting the kidney has provided new treatment options for the management of type 2 diabetes mellitus (T2DM). Sodium glucose co-transporter type 2 (SGLT2) inhibitors, such as dapagliflozin, canagliflozin, and empagliflozin, decrease renal glucose reabsorption, which results in enhanced urinary glucose excretion and subsequent reductions in plasma glucose and glycosylated hemoglobin concentrations. Modest reductions in body weight and blood pressure have also been observed following treatment with SGLT2 inhibitors. SGLT2 inhibitors appear to be generally well tolerated, and have been used safely when given as monotherapy or in combination with other oral anti-diabetes agents and insulin. The risk of hypoglycemia is low with SGLT2 inhibitors. Typical adverse events appear to be related to the presence of glucose in the urine, namely genital mycotic infection and lower urinary tract infection, and are more often observed in women than in men. Data from long-term safety studies with SGLT2 inhibitors and from head-to-head SGLT2 inhibitor comparator studies are needed to fully determine their benefit-risk profile, and to identify any differences between individual agents. However, given current safety and efficacy data, SGLT2 inhibitors may present an attractive option for T2DM patients who are failing with metformin monotherapy, especially if weight is part of the underlying treatment consideration.
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Project description:SGLT2 inhibitors have profound benefits on reducing heart failure and cardiovascular mortality in individuals with type 2 diabetes, although the mechanism(s) of this benefit remain poorly understood. Because changes in cardiac bioenergetics play a critical role in the pathophysiology of heart failure, the authors evaluated cardiac energy production and substrate use in diabetic mice treated with the SGTL2 inhibitor, empagliflozin. Empagliflozin treatment of diabetic db/db mice prevented the development of cardiac failure. Glycolysis, and the oxidation of glucose, fatty acids and ketones were measured in the isolated working heart perfused with 5 mmol/l glucose, 0.8 mmol/l palmitate, 0.5 mmol/l ß-hydroxybutyrate (ßOHB), and 500 μU/ml insulin. In vehicle-treated db/db mice, cardiac glucose oxidation rates were decreased by 61%, compared with control mice, but only by 43% in empagliflozin-treated diabetic mice. Interestingly, cardiac ketone oxidation rates in db/db mice decreased to 45% of the rates seen in control mice, whereas a similar decrease (43%) was seen in empagliflozin-treated db/db mice. Overall cardiac adenosine triphosphate (ATP) production rates decreased by 36% in db/db vehicle-treated hearts compared with control mice, with fatty acid oxidation providing 42%, glucose oxidation 26%, ketone oxidation 10%, and glycolysis 22% of ATP production in db/db mouse hearts. In empagliflozin-treated db/db mice, cardiac ATP production rates increased by 31% compared with db/db vehicle-treated mice, primarily due to a 61% increase in the contribution of glucose oxidation to energy production. Cardiac efficiency (cardiac work/O2 consumed) decreased by 28% in db/db vehicle-treated hearts, compared with control hearts, and empagliflozin did not increase cardiac efficiency per se. Because ketone oxidation was impaired in db/db mouse hearts, the authors determined whether this contributed to the decrease in cardiac efficiency seen in the db/db mouse hearts. Addition of 600 μmol/l ßOHB to db/db mouse hearts perfused with 5 mmol/l glucose, 0.8 mmol/l palmitate, and 100 μU/ml insulin increased ketone oxidation rates, but did not decrease either glucose oxidation or fatty acid oxidation rates. The presence of ketones did not increase cardiac efficiency, but did increase ATP production rates, due to the additional contribution of ketone oxidation to energy production. The authors conclude that empagliflozin treatment is associated with an increase in ATP production, resulting in an enhanced energy status of the heart.
| S-EPMC6234616 | biostudies-literature
Project description:BackgroundIn patients with type 2 diabetes (T2D) and a history of heart failure (HF), sodium-glucose cotransporter-2 inhibitors (SGLT2is) have demonstrated cardiovascular (CV) benefits. However, the comparative efficacy of individual SGLT2is remains uncertain. This network meta-analysis (NMA) compared the efficacy and safety of five SGLT2is (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and sotagliflozin) on CV outcomes in these patients.Materials and methodsPubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched up to September 23, 2022, to identify all randomized controlled trials (RCTs) comparing SGLT2is to placebo in T2D patients with HF. The main outcomes included composite CV death/heart failure hospitalization (HFH), HFH, CV death, all-cause mortality, and adverse events. Pairwise and NMA approaches were applied.ResultsOur analysis included 11 RCTs with a total of 20,438 patients with T2D and HF. All SGLT2is significantly reduced HFH compared to standard of care (SoC) alone. "Add-on" SGLT2is, except ertugliflozin, significantly reduced composite CV death/HFH relative to SoC alone. Moreover, canagliflozin had lower composite CV death/HFH compared to dapagliflozin. Based on the surface under the cumulative ranking curve (SUCRA), the top-ranked SGLT2is for reducing HFH were canagliflozin (95.5%), sotagliflozin (66.0%), and empagliflozin (57.2%). Head-to-head comparisons found no significant differences between individual SGLT2is in reducing CV death. "Add-on" SGLT2is reduced all-cause mortality compared with SoC alone, although only dapagliflozin was statistically significant. No SGLT2is were significantly associated with serious adverse events. A sensitivity analysis focusing on HF-specific trials found that dapagliflozin, empagliflozin, and sotagliflozin significantly reduced composite CV death/HFH, consistent with the main analysis. However, no significant differences were identified from their head-to-head comparisons in the NMA. The SUCRA indicated that sotagliflozin had the highest probability of reducing composite CV death/HFH (97.6%), followed by empagliflozin (58.4%) and dapagliflozin (44.0%).ConclusionSGLT2is significantly reduce the composite CV death/HFH outcome. Among them, canagliflozin may be considered the preferred treatment for patients with diabetes and a history of heart failure, but it may also be associated with an increased risk of any adverse events compared to other SGLT2is. However, a sensitivity analysis focusing on HF-specific trials identified sotagliflozin as the most likely agent to reduce CV death/HFH, followed by empagliflozin and dapagliflozin.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022353754.
| S-EPMC10765518 | biostudies-literature
Project description:ImportanceCardiovascular disease (CVD) can be recurrent during type 2 diabetes (T2D) progression in this aging population. The effectiveness of sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy on total (ie, first and subsequent) CVD among patients with T2D in clinical practice remains uncertain.ObjectiveTo analyze the comparative association of SGLT2i vs dipeptidyl peptidase 4 inhibitor (DPP4i) therapy with total CVD among patients with T2D in clinical practice.Design, setting, and participantsThis retrospective cohort study used electronic medical records at the National Cheng Kung University Hospital, a leading medical center in Taiwan, from 2015 through 2021. Adult patients with T2D who initiated first use of the study drugs from 2016 through 2019, with up to 6 years of follow-up, were identified.Main outcomes and measuresThe primary outcomes included total composite CVD events and individual CVD subtypes (ie, atrial fibrillation, coronary heart disease, heart failure, stroke, myocardial infarction, and transient ischemic attack). A shared frailty model analysis was used to assess the association of treatment with repeat CVD events. Data from patients at high risk for CVD recurrence were further analyzed. Data were analyzed from September 1, 2022, to December 31, 2023.ResultsOverall, 8384 patients with T2D were identified (mean [SD] age, 63.7 [12.4] years; 4645 [55.4%] male). A total of 1632 propensity score-matched pairs of SGLT2i (mean [SD] age, 57.8 [12.0] years; 673 [41.2%] female and 959 [58.8%] male) and DPP4i (mean [SD] age, 58.2 [12.9] years; 655 [40.1%] female and 977 [59.9%] male) users were included. SGLT2i was associated with reduced total CVD risk vs DPP4i therapy (hazard ratio [HR], 0.82 [95% CI, 0.69-0.98]) but not the first CVD event (with the use of SGLT2i therapy were more prominent for patients at high risk of CVD (ie, HR, 0.70 [95% CI, 0.62-0.80] for individuals with estimated glomerular filtration rate lower than 60 mL/min/1.73 m2; HR, 0.70 [95% CI, 0.64-0.78]; for individuals having any diabetes-related complications; and HR, 0.72 [95% CI, 0.65-0.80] for individuals with a history of CVD) compared with the overall cohort. Among patients at high risk of CVD, greater reduced total CVD burden associated with SGLT2i therapy was observed for women vs men (eg, HR, 0.59 [95% CI, 0.49-0.72] in the subgroup with CVD history).Conclusions and relevanceIn this cohort study of patients with T2D, the use of SGLT2is vs DPP4is was associated with reduced total cardiovascular burden, suggesting that long-term use of this therapy may optimize treatment benefit among patients with chronic CVD. The SGLT2i-associated benefit among patients with high risk of CVD encourages the prioritization of SGLT2i use for these vulnerable individuals.
| S-EPMC11525605 | biostudies-literature