SGLT2 inhibitors as adjunctive therapy for type 1 diabetes: balancing benefits and risks.
ABSTRACT: 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.
Project description:<h4>Background</h4>Sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been demonstrated to be able to improve the cardiovascular and renal prognosis in patients with type 2 diabetes (T2D). However, the relative efficacy of various SGLT2 inhibitors and GLP-1 RAs on cardiorenal outcomes is unestablished.<h4>Methods</h4>We searched PubMed and Embase for relevant cardiovascular or renal outcome trials (CVOTs). Endpoints of interest were major adverse cardiovascular events (MACE), stroke, myocardial infarction (MI), cardiovascular death (CVD), all-cause death (ACD), kidney function progression (KFP), and hospitalization for heart failure (HHF). Bayesian network meta-analysis was conducted to produce pooled hazard ratio (HR) and 95% confidence interval (CI). We calculated the probability values of surface under the cumulative ranking curve to rank active and placebo interventions.<h4>Results</h4>Fourteen COVTs were included in analysis. Sotagliflozin (HR 0.76, 95% CI 0.61-0.94), subcutaneous semaglutide, and albiglutide lowered MACE versus lixisenatide among others. Sotagliflozin (HR 0.59, 95% CI 0.40-0.89), canagliflozin, and empagliflozin lowered HHF versus subcutaneous semaglutide among others. Dapagliflozin and empagliflozin lowered KFP versus exenatide among others. Empagliflozin and oral semaglutide lowered CVD versus dapagliflozin among others. Sotagliflozin (HR 0.65, 95% CI 0.47-0.91) and albiglutide lowered MI versus ertugliflozin among others. Sotagliflozin (HR 0.56, 95% CI 0.37-0.85) and subcutaneous semaglutide lowered stroke versus empagliflozin among others. Oral semaglutide and empagliflozin lowered ACD versus subcutaneous semaglutide among others. The maximum surface under the cumulative ranking curve values followed sotagliflozin, subcutaneous semaglutide, and albiglutide in lowering MACE; sotagliflozin, canagliflozin, and empagliflozin in lowering HHF; dapagliflozin and empagliflozin in lowering KFP; empagliflozin and oral semaglutide in lowering CVD; sotagliflozin and albiglutide in lowering MI; sotagliflozin and subcutaneous semaglutide in lowering stroke; and oral semaglutide and empagliflozin in lowering ACD.<h4>Conclusions</h4>This updated network meta-analysis reproduced the findings in the first network meta-analysis, and moreover revealed that sotagliflozin was one of the most effective drugs as for lowering MI, stroke, MACE, and HHF, whereas ertugliflozin was not. These findings will provide the according evidence regarding the usage of specific SGLT2 inhibitors and GLP-1 RAs in T2D patients for prevention of specific cardiorenal endpoints.
Project description:OBJECTIVE:Evaluate the efficacy and safety of the dual sodium-glucose cotransporter 1 (SGLT1) and SGLT2 inhibitor sotagliflozin in combination with optimized insulin in type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS:The inTandem1 trial, a double-blind, 52-week phase 3 trial, randomized North American adults with T1D to placebo (n = 268), sotagliflozin 200 mg (n = 263), or sotagliflozin 400 mg (n = 262) after 6 weeks of insulin optimization. The primary end point was HbA1c change from baseline at 24 weeks. HbA1c, weight, and safety were also assessed through 52 weeks. RESULTS:From a mean baseline of 7.57%, placebo-adjusted HbA1c reductions were 0.36% and 0.41% with sotagliflozin 200 and 400 mg, respectively, at 24 weeks and 0.25% and 0.31% at 52 weeks (all P < 0.001). Among patients with a baseline HbA1c ?7.0%, an HbA1c <7% was achieved by 15.7%, 27.2%, and 40.3% of patients receiving placebo, sotagliflozin 200 mg, and sotagliflozin 400 mg, respectively (P ? 0.003 vs. placebo) at 24 weeks. At 52 weeks, mean treatment differences between sotagliflozin 400 mg and placebo were -1.08 mmol/L for fasting plasma glucose, -4.32 kg for weight, and -15.63% for bolus insulin dose and -11.87% for basal insulin dose (all P < 0.001). Diabetes Treatment Satisfaction Questionnaire scores increased significantly by 2.5 points with sotagliflozin versus placebo (P < 0.001) at 24 weeks. Genital mycotic infections and diarrhea occurred more frequently with sotagliflozin. Adjudicated diabetic ketoacidosis (DKA) occurred in 9 (3.4%) and 11 (4.2%) patients receiving sotagliflozin 200 and 400 mg, respectively, and in 1 (0.4%) receiving placebo. Severe hypoglycemia occurred in 17 (6.5%) patients from each sotagliflozin group and 26 (9.7%) patients receiving placebo. CONCLUSIONS:In a 1-year T1D study, sotagliflozin combined with optimized insulin therapy was associated with sustained HbA1c reduction, weight loss, lower insulin dose, fewer episodes of severe hypoglycemia, improved patient-reported outcomes, and more DKA relative to placebo (ClinicalTrials.gov, NCT02384941).
Project description:<h4>Introduction</h4>Sodium glucose co-transporter 2 (SGLT2) inhibitors increase urinary glucose excretion (UGE) by reducing the renal threshold for glucose excretion, which results in decreased serum glucose concentrations in patients with type 2 diabetes mellitus (T2D). However, no study to date has determined whether larger increases in UGE after SGLT2 inhibitor treatment correspond to larger reductions in glycated hemoglobin (HbA<sub>1C</sub>).<h4>Methods</h4>We enrolled participants who were newly prescribed an SGLT2 inhibitor (dapagliflozin 10 mg or ipragliflozin 50 mg, once daily) as an add-on therapy. Patients were tested for HbA<sub>1C</sub> and first morning spot urinary-creatinine and -glucose concentrations immediately prior to administration of the SGLT2 inhibitor and at a 12-week follow-up appointment. We investigated the relationship between increases in morning spot UGE and decreases in HbA<sub>1C</sub>.<h4>Results</h4>A total of 101 participants with T2D were enrolled. The median age and diabetes duration were 61.0 and 12.8 years, respectively, and the median HbA<sub>1C</sub> was 8.10%. SGLT2 inhibitors significantly lowered the HbA<sub>1C</sub> level, with a median change from baseline to week 12 of -0.60% (p < 0.001). Robust increases from baseline were seen for the morning spot urinary glucose-to-creatinine ratio (UGCR), with a median change at week 12 of 47.3 mg/mg. In the correlation analysis, the ∆HbA<sub>1C</sub> level showed a significant positive correlation with ∆morning spot UGCR (r = 0.395, p < 0.001). In other words, a greater reduction in HbA<sub>1C</sub> was correlated with a smaller increase in UGE. After adjusting for confounding variables, ∆HbA<sub>1C</sub> was significantly associated with ∆morning spot UGCR.<h4>Conclusions</h4>Although SGLT2 inhibitor treatment leads to a reduced HbA<sub>1C</sub> level by augmenting UGE, larger increases in UGE do not correlate to larger reductions in HbA<sub>1C</sub>. This suggests that the increase in UGE might not be an indicator of the degree of reductions in blood glucose.
Project description:Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that improve glycemic control by inhibiting reabsorption of glucose filtered through the renal glomerulus. Use of drugs in this class has increased because of their effect of decreasing body weight and a low risk for hypoglycemia, in addition to a relatively strong glucose-lowering effect. SGLT2 inhibitors such as canagliflozin and sotagliflozin (a SGLT1/SGLT2 dual inhibitor) also have a mild or moderate intestinal and renal SGLT1 inhibitory effect because of their relatively weak selectivity for SGLT2 over SGLT1. Recent evidence shows that these SGLT2 inhibitors with low SGLT2/SGLT1 selectivity elevate the level of circulating glucagon like peptide-1 (GLP-1), an incretin hormone that promotes insulin secretion in pancreatic β cells. This effect probably occurs partly via inhibition of intestinal SGLT1, and the elevation of active GLP-1 levels is especially apparent when these drugs are co-administered with dipeptidyl peptidase 4 (DPP4) inhibitors. These findings suggest that a combination of canagliflozin or sotagliflozin and a DPP4 inhibitor can provide a beneficial effect associated with elevation of circulating active GLP-1 and may serve as a treatment for patients with type 2 diabetes.
Project description:In a healthy person, the kidney filters nearly 200 g of glucose per day, almost all of which is reabsorbed. The primary transporter responsible for renal glucose reabsorption is sodium-glucose cotransporter-2 (SGLT2). Based on the impact of SGLT2 to prevent renal glucose wasting, SGLT2 inhibitors have been developed to treat diabetes and are the newest class of glucose-lowering agents approved in the United States. By inhibiting glucose reabsorption in the proximal tubule, these agents promote glycosuria, thereby reducing blood glucose concentrations and often resulting in modest weight loss. Recent work in humans and rodents has demonstrated that the clinical utility of these agents may not be limited to diabetes management: SGLT2 inhibitors have also shown therapeutic promise in improving outcomes in heart failure, atrial fibrillation, and, in preclinical studies, certain cancers. Unfortunately, these benefits are not without risk: SGLT2 inhibitors predispose to euglycemic ketoacidosis in those with type 2 diabetes and, largely for this reason, are not approved to treat type 1 diabetes. The mechanism for each of the beneficial and harmful effects of SGLT2 inhibitors-with the exception of their effect to lower plasma glucose concentrations-is an area of active investigation. In this review, we discuss the mechanisms by which these drugs cause euglycemic ketoacidosis and hyperglucagonemia and stimulate hepatic gluconeogenesis as well as their beneficial effects in cardiovascular disease and cancer. In so doing, we aim to highlight the crucial role for selecting patients for SGLT2 inhibitor therapy and highlight several crucial questions that remain unanswered.
Project description:OBJECTIVE:To assess the safety and efficacy of dual sodium-glucose cotransporter (SGLT) 1 and SGLT2 inhibition with sotagliflozin as adjunct therapy to insulin in type 1 diabetes. RESEARCH DESIGN AND METHODS:We treated 33 patients with sotagliflozin, an oral dual SGLT1 and SGLT2 inhibitor, or placebo in a randomized, double-blind trial assessing safety, insulin dose, glycemic control, and other metabolic parameters over 29 days of treatment. RESULTS:In the sotagliflozin-treated group, the percent reduction from baseline in the primary end point of bolus insulin dose was 32.1% (P = 0.007), accompanied by lower mean daily glucose measured by continuous glucose monitoring (CGM) of 148.8 mg/dL (8.3 mmol/L) (P = 0.010) and a reduction of 0.55% (5.9 mmol/mol) (P = 0.002) in HbA1c compared with the placebo group that showed 6.4% reduction in bolus insulin dose, a mean daily glucose of 170.3 mg/dL (9.5 mmol/L), and a decrease of 0.06% (0.65 mmol/mol) in HbA1c. The percentage of time in target glucose range 70-180 mg/dL (3.9-10.0 mmol/L) increased from baseline with sotagliflozin compared with placebo, to 68.2% vs. 54.0% (P = 0.003), while the percentage of time in hyperglycemic range >180 mg/dL (10.0 mmol/L) decreased from baseline, to 25.0% vs. 40.2% (P = 0.002), for sotagliflozin and placebo, respectively. Body weight decreased (1.7 kg) with sotagliflozin compared with a 0.5 kg gain (P = 0.005) in the placebo group. CONCLUSIONS:As adjunct to insulin, dual SGLT1 and SGLT2 inhibition with sotagliflozin improved glycemic control and the CGM profile with bolus insulin dose reduction, weight loss, and no increased hypoglycemia in type 1 diabetes.
Project description:<h4>Aims/hypothesis</h4>Minimal evidence supports the efficacy of flash monitoring in lowering HbA<sub>1c</sub>. We sought to assess the impact of introducing flash monitoring in our centre.<h4>Methods</h4>We undertook a prospective observational study to assess change in HbA<sub>1c</sub> in 900 individuals with type 1 diabetes following flash monitoring (comparator group of 518 with no flash monitoring). Secondary outcomes included changes in hypoglycaemia, quality of life, flash monitoring data and hospital admissions.<h4>Results</h4>Those with baseline HbA<sub>1c</sub> ?58 mmol/mol (7.5%) achieved a median -7 mmol/mol (interquartile range [IQR] -13 to -1) (0.6% [-1.2 to -0.1]%) change in HbA<sub>1c</sub> (p?<?0.001). The percentage achieving HbA<sub>1c</sub> <58 mmol/mol rose from 34.2% to 50.9% (p?<?0.001). Median follow-up was 245 days (IQR 182 to 330). Individuals not using flash monitoring experienced no change in HbA<sub>1c</sub> across a similar timescale (p?=?0.508). Higher HbA<sub>1c</sub> (p?<?0.001), younger age at diagnosis (p?=?0.003) and lower social deprivation (p?=?0.024) were independently associated with an HbA<sub>1c</sub> fall of ?5 mmol/mol (0.5%). More symptomatic (OR 1.9, p?<?0.001) and asymptomatic (OR 1.4, p?<?0.001) hypoglycaemia was reported after flash monitoring. Following flash monitoring, regimen-related and emotional components of the diabetes distress scale improved although the proportion with elevated anxiety (OR 1.2, p?=?0.028) and depression (OR 2.0, p?<?0.001) scores increased. Blood glucose test strip use fell from 3.8 to 0.6 per day (p?<?0.001). Diabetic ketoacidosis admissions fell significantly following flash monitoring (p?=?0.043).<h4>Conclusions/interpretation</h4>Flash monitoring is associated with significant improvements in HbA<sub>1c</sub> and fewer diabetic ketoacidosis admissions. Higher rates of hypoglycaemia may relate to greater recognition of hitherto unrecognised events. Impact upon quality of life parameters was mixed but overall treatment satisfaction was overwhelmingly positive.
Project description:Although sodium-glucose cotransporter 2 (SGLT2) inhibitors lower serum uric acid, their long-term effect on uric acid metabolism is not well understood. We analyzed pooled data from studies wherein patients with type 2 diabetes mellitus received luseogliflozin, an SGLT2 inhibitor. Upon stratifying patients by baseline glycated hemoglobin (HbA<sub>1c</sub> ) or serum uric acid, lower HbA<sub>1c</sub> or higher serum uric acid level was associated with a greater reduction in serum uric acid after treatment. At week 12 of treatment, significant increases in urinary glucose/creatinine (Cr) ratio and urinary uric acid clearance/Cr clearance ratio (C<sub>UA</sub> /C<sub>Cr</sub> ratio) and a significant reduction in serum uric acid were observed. Comparison of the subgroups of patients with a reduction or an increase in serum uric acid showed that the increase subgroup had a higher estimated glomerular filtration rate (eGFR) at baseline, and the eGFR was significantly reduced, associated with a significant reduction in the C<sub>UA</sub> /C<sub>Cr</sub> ratio. Multiple regression analysis showed that the reduction in serum uric acid in the luseogliflozin group was strongly associated with baseline high serum uric acid, low HbA<sub>1c</sub> levels, and an increase in eGFR. Luseogliflozin was shown to reduce serum uric acid by enhancing urinary uric acid excretion in association with increased urinary glucose. Treatment with luseogliflozin resulted in increased serum uric acid in some patients, which may be due to reduced glomerular filtration of uric acid via the tubuloglomerular feedback. SGLT2 inhibitors reduced serum uric acid desirably in patients with type 2 diabetes mellitus with low HbA<sub>1c</sub> and high serum uric acid.
Project description:BACKGROUND:Regulatory agencies have concluded that sodium glucose cotransporter 2 (SGLT2) inhibitors lead to ketoacidosis, but published literature on this point remains controversial. METHODS:We searched the FDA Adverse Event Reporting System (FAERS) for reports of acidosis in patients treated with canagliflozin, dapagliflozin, or empagliflozin (from the date of each drug's FDA approval until May 15, 2015). We compared the number of SGLT2 inhibitor-related reports to reports of acidosis in patients treated with the 2 most commonly used DPP4 inhibitors: sitagliptin and saxagliptin. We estimated relative risks of acidosis by relating the number of reports to cumulative drug sales (a surrogate for patient exposure). RESULTS:FAERS contained 259 reports of acidosis (including 192 reports of ketoacidosis) for SGLT2 inhibitors compared with 477 reports of acidosis for DPP4 inhibitors (including 71 reports of ketoacidosis). Based on estimated patient exposure, the overall risk of developing acidosis was ~14-fold higher for SGLT2 inhibitors. Among 51 SGLT2 inhibitor-related reports with quantifiable metabolic information, 20 cases occurred in patients with type 1 diabetes (T1D), 25 in type 2 diabetes (T2D), and 6 in patients with unspecified type of diabetes. After excluding patients with T1D and focusing on patients identified as having T2D, we estimate that SGLT2 inhibitors were associated with ~7-fold increase in developing acidosis. Seventy-one percent had euglycemic ketoacidosis. CONCLUSIONS:Our results support the FDA's warning that SGLT2 inhibitors lead to ketoacidosis, as evidenced by an increased reporting rate for acidosis above that in a comparator population treated with DPP4 inhibitors.
Project description:<h4>Objective</h4>To evaluate the incidence and risk factors for diabetic ketoacidosis (DKA) and related adverse events (AEs) in adults with type 1 diabetes treated with sotagliflozin adjunctive to insulin.<h4>Research design and methods</h4>Data from two identically designed, 52-week, randomized studies were pooled and analyzed for DKA, changes in β-hydroxybutyrate (BHB), and percentage of patients with BHB >0.6 and >1.5 mmol/L. The patients were administered placebo, sotagliflozin 200 mg, or sotagliflozin 400 mg once daily.<h4>Results</h4>A total of 191 ketosis-related AEs were reported, and 98 underwent adjudication. Of these, 37 events (36 patients) were adjudicated as DKA, with an exposure-adjusted incidence rate of 0.2, 3.1, and 4.2 events per 100 patient-years for placebo, sotagliflozin 200 mg, and sotagliflozin 400 mg, respectively. No patient died of a DKA event. From a baseline BHB of ∼0.13 mmol/L, sotagliflozin treatment led to a small median increase over 52 weeks (≤0.05 mmol/L at all time points). Of sotagliflozin-treated patients, approximately 47% and 7% had ≥1 BHB measurement >0.6 mmol/L and >1.5 mmol/L, respectively (vs. 20% and 2%, respectively, of placebo-treated patients). Subsequent to the implementation of a risk mitigation plan, annualized DKA incidence was lower versus preimplementation in both the sotagliflozin 200 and 400 mg groups.<h4>Conclusions</h4>In patients with type 1 diabetes, confirmed DKA incidence increased when sotagliflozin was added to insulin compared with insulin alone. A lower incidence of DKA was observed following the implementation of an enhanced risk mitigation plan, suggesting that this risk can be managed with patient education.