Metabolic effects of SGLT2i and metformin on 3-hydroxybutyric acid and lactate in db/db mice.

Combining a Sodium-Glucose-Cotransporter-2-inhibitor (SGLT2i) with metformin is recommended for managing hyperglycemia in patients with type 2 diabetes (T2D) who have cardio-renal complications. Our study aimed to investigate the metabolic effects of SGLT2i and metformin, both individually and synergistically. We treated leptin receptor-deficient (db/db) mice with these drugs for two weeks and conducted metabolite profiling, identifying 861 metabolites across kidney, liver, muscle, fat, and plasma. Using linear regression and mixed-effects models, we identified two SGLT2i-specific metabolites, X-12465 and 3-hydroxybutyric acid (3HBA), a ketone body, across all examined tissues. The levels of 3HBA were significantly higher under SGLT2i monotherapy compared to controls and were attenuated when combined with metformin. We observed similar modulatory effects on metabolites involved in protein catabolism (e.g., branched-chain amino acids) and gluconeogenesis. Moreover, combination therapy significantly raised pipecolate levels, which may enhance mTOR1 activity, while modulating GSK3, a common target of SGLT2i and 3HBA inhibition. The combination therapy also led to significant reductions in body weight and lactate levels, contrasted with monotherapies. Our findings advocate for the combined approach to better manage muscle loss, and the risks of DKA and lactic acidosis, presenting a more effective strategy for T2D treatment.

Rationale and design of a randomised phase III registration trial investigating finerenone in participants with type 1 diabetes and chronic kidney disease: The FINE-ONE trial.

AIMS: Despite guideline-recommended treatments, including renin angiotensin system inhibition, up to 40 % of individuals with type 1 diabetes develop chronic kidney disease (CKD) putting them at risk of kidney failure. Finerenone is approved to reduce the risk of kidney failure in individuals with type 2 diabetes. We postulate that finerenone will demonstrate benefits on kidney outcomes in people with type 1 diabetes. METHODS: FINE-ONE (NCT05901831) is a randomised, placebo-controlled, double-blind phase III trial of 7.5 months' duration in ∼220 adults with type 1 diabetes, urine albumin/creatinine ratio (UACR) of ≥ 200-< 5000 mg/g (≥ 22.6-< 565 mg/mmol) and eGFR of ≥ 25-< 90 ml/min/1.73 m2. RESULTS: The primary endpoint is relative change in UACR from baseline over 6 months. UACR is used as a bridging biomarker (BB), since the treatment effect of finerenone on UACR was associated with its efficacy on kidney outcomes in the type 2 diabetes trials. Based on regulatory authority feedback, UACR can be used as a BB for kidney outcomes to support registration of finerenone in type 1 diabetes, provided necessary criteria are met. Secondary outcomes include incidences of treatment-emergent adverse events, treatment-emergent serious adverse events and hyperkalaemia. CONCLUSIONS: FINE-ONE will evaluate the efficacy and safety of finerenone in type 1 diabetes and CKD. Finerenone could become the first registered treatment for CKD associated with type 1 diabetes in almost 30 years. TRIAL REGISTRATION: ClinicalTrials.gov NCT05901831.

Kidney outcomes with finerenone: an analysis from the FIGARO-DKD study.

BACKGROUND: In FIGARO-DKD, finerenone reduced the risk of cardiovascular events in patients with type 2 diabetes (T2D) and stage 1-4 chronic kidney disease (CKD). In FIDELIO-DKD, finerenone improved kidney and cardiovascular outcomes in patients with advanced CKD. This analysis further explores kidney outcomes in FIGARO-DKD. METHODS: FIGARO-DKD (NCT02545049) included patients with urine albumin-to-creatinine ratio (UACR) 30-<300 mg/g and estimated glomerular filtration rate (eGFR) 25-90 mL/min/1.73 m2 or UACR 300-5000 mg/g and eGFR ≥60 mL/min/1.73 m2. Outcomes included two composite kidney endpoints, a composite of ≥40% decrease in eGFR from baseline sustained over ≥4 weeks, kidney failure or renal death, and a composite of ≥57% decrease in eGFR from baseline sustained over ≥4 weeks, kidney failure or renal death. Changes in albuminuria and eGFR slope were also analyzed. Kidney and CV outcomes were evaluated by baseline UACR. RESULTS: A lower incidence rate for the eGFR ≥40% kidney composite endpoint was observed with finerenone compared with placebo, but the between-group difference was not significant [hazard ratio (HR) = 0.87; 95% confidence interval (CI): 0.76-1.01; P = .069]. A greater treatment effect was observed on the eGFR ≥57% kidney composite endpoint (HR = 0.77; 95% CI: 0.60-0.99; P = 0.041) with a 36% relative risk reduction for end-stage kidney disease. A larger magnitude of effect on kidney outcomes was observed with finerenone versus placebo for patients with severely increased albuminuria than with moderately increased albuminuria. Improvements in UACR, eGFR slope and cardiovascular risk were evident in both subgroups with finerenone. CONCLUSIONS: The present analyses suggest that finerenone protects against kidney disease progression and cardiovascular events in patients with T2D and early- or late-stage CKD.

Finerenone in Patients With Chronic Kidney Disease and Type 2 Diabetes by Sodium-Glucose Cotransporter 2 Inhibitor Treatment: The FIDELITY Analysis.

OBJECTIVE: Finerenone reduced the risk of kidney and cardiovascular events in people with chronic kidney disease (CKD) and type 2 diabetes in the FIDELIO-DKD and FIGARO-DKD phase 3 studies. Effects of finerenone on outcomes in patients taking sodium-glucose cotransporter 2 inhibitors (SGLT2is) were evaluated in a prespecified pooled analysis of these studies. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes and urine albumin-to-creatinine ratio (UACR) ≥30 to ≤5,000 mg/g and estimated glomerular filtration rate (eGFR) ≥25 mL/min/1.73 m2 were randomly assigned to finerenone or placebo; SGLT2is were permitted at any time. Outcomes included cardiovascular composite (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and kidney composite (kidney failure, sustained ≥57% eGFR decline, or renal death) end points, changes in UACR and eGFR, and safety outcomes. RESULTS: Among 13,026 patients, 877 (6.7%) received an SGLT2i at baseline and 1,113 (8.5%) initiated one during the trial. For the cardiovascular composite, the hazard ratios (HRs) were 0.87 (95% CI 0.79-0.96) without SGLT2i and 0.67 (95% CI 0.42-1.07) with SGLT2i. For the kidney composite, the HRs were 0.80 (95% CI 0.69-0.92) without SGLT2i and 0.42 (95% CI 0.16-1.08) with SGLT2i. Baseline SGLT2i use did not affect risk reduction for the cardiovascular or kidney composites with finerenone (Pinteraction = 0.46 and 0.29, respectively); neither did SGLT2i use concomitant with study treatment. CONCLUSIONS: Benefits of finerenone compared with placebo on cardiorenal outcomes in patients with CKD and type 2 diabetes were observed irrespective of SGLT2i use.

Finerenone in Predominantly Advanced CKD and Type 2 Diabetes With or Without Sodium-Glucose Cotransporter-2 Inhibitor Therapy.

INTRODUCTION: FIDELIO-DKD (FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease) investigated the nonsteroidal, selective mineralocorticoid receptor (MR) antagonist finerenone in patients with CKD and type 2 diabetes (T2D). This analysis explores the impact of use of sodium-glucose cotransporter-2 inhibitor (SGLT-2i) on the treatment effect of finerenone. METHODS: Patients (N = 5674) with T2D, urine albumin-to-creatinine ratio (UACR) of 30 to 5000 mg/g and estimated glomerular filtration rate (eGFR) of 25 to <75 ml/min per 1.73 m2 receiving optimized renin-angiotensin system (RAS) blockade were randomized to finerenone or placebo. Endpoints were change in UACR and a composite kidney outcome (time to kidney failure, sustained decrease in eGFR ≥40% from baseline, or renal death) and key secondary cardiovascular outcomes (time to cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) (ClinicalTrials.gov, NCT02540993). RESULTS: Of 5674 patients, 259 (4.6%) received an SGLT-2i at baseline. Reduction in UACR with finerenone was found with or without use of SGLT-2i at baseline, with ratio of least-squares means of 0.69 (95% CI = 0.66-0.71) and 0.75 (95% CI -= 0.62-0.90), respectively (P interaction = 0.31). Finerenone also significantly reduced the kidney and key secondary cardiovascular outcomes versus placebo; there was no clear difference in the results by SGLT-2i use at baseline (P interaction = 0.21 and 0.46, respectively) or at any time during the trial. Safety was balanced with or without SGLT-2i use at baseline, with fewer hyperkalemia events with finerenone in the SGLT-2i group (8.1% vs. 18.7% without). CONCLUSION: UACR improvement was observed with finerenone in patients with CKD and T2D already receiving SGLT-2is at baseline, and benefits on kidney and cardiovascular outcomes appear consistent irrespective of use of SGLT-2i.

Effects of canagliflozin versus finerenone on cardiorenal outcomes: exploratory post hoc analyses from FIDELIO-DKD compared to reported CREDENCE results.

BACKGROUND: The nonsteroidal mineralocorticoid receptor antagonist finerenone and the sodium-glucose cotransporter-2 inhibitor (SGLT-2i) canagliflozin reduce cardiorenal risk in albuminuric patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). At first glance, the results of Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) (ClinicalTrials.gov, NCT02540993) and Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) appear disparate. In FIDELIO-DKD, the primary endpoint had an 18% [95% confidence interval (CI) 7-27] relative risk reduction; in CREDENCE, the primary endpoint had a 30% (95% CI 18-41) relative risk reduction. Unlike CREDENCE, the FIDELIO-DKD trial included patients with high albuminuria but excluded patients with symptomatic heart failure with reduced ejection fraction. The primary endpoint in the FIDELIO-DKD trial was kidney specific and included a sustained decline in the estimated glomerular filtration rate (eGFR) of ≥40% from baseline. In contrast, the primary endpoint in the CREDENCE trial included a sustained decline in eGFR of ≥57% from baseline and cardiovascular (CV) death. This post hoc exploratory analysis investigated how differences in trial design-inclusion/exclusion criteria and definition of primary outcomes-influenced observed treatment effects. METHODS: Patients from FIDELIO-DKD who met the CKD inclusion criteria of the CREDENCE study (urine albumin: creatinine ratio >300-5000 mg/g and an eGFR of 30-<90 mL/min/1.73 m2 at screening) were included in this analysis. The primary endpoint was a cardiorenal composite (CV death, kidney failure, eGFR decrease of ≥57% sustained for ≥4 weeks or renal death). Patients with symptomatic heart failure with reduced ejection fraction were excluded from FIDELIO-DKD. Therefore, in a sensitivity analysis, we further adjusted for the baseline prevalence of heart failure. RESULTS: Of 4619/5674 (81.4%) patients who met the subgroup inclusion criteria, 49.6% were treated with finerenone and 50.4% received placebo. The rate of the cardiorenal composite endpoint was 43.9/1000 patient-years with finerenone compared with 59.5/1000 patient-years with placebo. The relative risk was significantly reduced by 26% with finerenone versus placebo [hazard ratio (HR) 0.74 (95% CI 0.63-0.87)]. In CREDENCE, the rate of the cardiorenal composite endpoint was 43.2/1000 patient-years with canagliflozin compared with 61.2/1000 patient-years with placebo; a 30% risk reduction was observed with canagliflozin [HR 0.70 (95% CI 0.59-0.82)]. CONCLUSIONS: This analysis highlights the pitfalls of direct comparisons between trials. When key differences in trial design are considered, FIDELIO-DKD and CREDENCE demonstrate cardiorenal benefits of a similar magnitude.

Validation of Candidate Phospholipid Biomarkers of Chronic Kidney Disease in Hyperglycemic Individuals and Their Organ-Specific Exploration in Leptin Receptor-Deficient db/db Mouse.

Biological exploration of early biomarkers for chronic kidney disease (CKD) in (pre)diabetic individuals is crucial for personalized management of diabetes. Here, we evaluated two candidate biomarkers of incident CKD (sphingomyelin (SM) C18:1 and phosphatidylcholine diacyl (PC aa) C38:0) concerning kidney function in hyperglycemic participants of the Cooperative Health Research in the Region of Augsburg (KORA) cohort, and in two biofluids and six organs of leptin receptor-deficient (db/db) mice and wild type controls. Higher serum concentrations of SM C18:1 and PC aa C38:0 in hyperglycemic individuals were found to be associated with lower estimated glomerular filtration rate (eGFR) and higher odds of CKD. In db/db mice, both metabolites had a significantly lower concentration in urine and adipose tissue, but higher in the lungs. Additionally, db/db mice had significantly higher SM C18:1 levels in plasma and liver, and PC aa C38:0 in adrenal glands. This cross-sectional human study confirms that SM C18:1 and PC aa C38:0 associate with kidney dysfunction in pre(diabetic) individuals, and the animal study suggests a potential implication of liver, lungs, adrenal glands, and visceral fat in their systemic regulation. Our results support further validation of the two phospholipids as early biomarkers of renal disease in patients with (pre)diabetes.

Long-term efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes: pooled 52-week outcomes from the DEPICT-1 and -2 studies.

AIM: To evaluate the efficacy and safety of adjunct dapagliflozin therapy in patients with type 1 diabetes (T1D). MATERIALS AND METHODS: DEPICT-1 and -2 were randomized, double-blind, parallel-group, 24-week studies, with 28-week extension periods. Adults with T1D and HbA1c 7.5%-10.5% were randomized (1:1:1) to receive dapagliflozin 5 mg, 10 mg or placebo. The short- and long-term efficacy and safety of dapagliflozin were examined in an exploratory pooled analysis of both studies. RESULTS: Efficacy analyses included 530, 529 and 532 and safety analysis included 548, 566 and 532 patients in the dapagliflozin 5 mg, 10 mg and placebo groups, respectively. Baseline characteristics were similar between treatment groups. At week 24, reductions were seen with dapagliflozin 5 and 10 mg compared with placebo in HbA1c (-0.40%, -0.43% vs. 0.00%) and body weight (-2.45, -2.91 vs. 0.11 kg). HbA1c and body weight reductions versus placebo were also seen after 52 weeks of treatment. There was no imbalance in occurrence of severe hypoglycaemic events between groups. The proportion of patients experiencing definite diabetic ketoacidosis (DKA) was higher with dapagliflozin 5 mg (4.0%) and 10 mg (3.5%) compared with placebo (1.1%) over 52 weeks; most events were of mild or moderate severity, and all resolved with treatment. CONCLUSIONS: Over 52 weeks, dapagliflozin provided glycaemic and weight benefits, with no increased frequency of severe hypoglycaemia compared with placebo. More DKA events were reported with dapagliflozin than placebo, highlighting the importance of appropriate patient selection, education and risk-mitigation strategies.

Add-on therapy with dapagliflozin under full closed loop control improves time in range in adolescents and young adults with type 1 diabetes: The DAPADream study.

AIM: To investigate the effect of the sodium-glucose co-transporter-2 inhibitor dapagliflozin on glucose levels overnight and during the following day after two unannounced meals under full closed loop (FCL) conditions. MATERIALS AND METHODS: For this single-centre, double-blind, randomized, placebo-controlled, cross-over trial, non-obese persons with type 1 diabetes (T1D) were studied twice (10 mg dapagliflozin bid vs. placebo) for 24 hours with two unannounced mixed meal tests 6 hours apart under FCL conditions. Primary outcome was sensor glucose time in range (TIR; 3.9-10 mmol/L). For safety evaluation, ß-hydroxybutyrate (BHB), glucagon, insulin and gastric inhibitory polypeptide were measured. RESULTS: Fifteen adolescents (aged 15.4 ± 1.6 years, diabetes duration 10.0 ± 3.4 years, HbA1c 8.4% ± 0.9% [67.7 ± 10.1 mmol/mol]) and 15 young adults (aged 18.7 ± 0.8 years; diabetes duration 12.5 ± 3.6 years; HbA1c 8.3% ± 0.9% [68.5 ± 11.2 mmol/mol]) completed the trial. TIR was significantly higher in the intervention group compared with placebo (68% ± 6% vs. 50% ± 13%; P < .001); nocturnal glucose was significantly lower with dapagliflozin (6.2 ± 0.7 vs. 7.3 ± 1.7 mmol/L; P = .003) without an increase in time at less than 3.9 mmol/L (3.3% ± 6.0% vs 3.1% ± 5.2%; P = .75). Urinary glucose excretion was increased 3-fold using dapagliflozin (149 ± 42 vs. 49 ± 23 g/24 hours) with a total insulin reduction of 22% (39.7 ± 12.7 vs. 30.6 ± 10.4 U; P = .004). No abnormal elevated BHB values were observed. CONCLUSIONS: In adolescents and adults with T1D, dapagliflozin significantly increased TIR on average by 259 minutes/day while reducing glycaemic variability during FCL control without any signs of hypoglycaemia or ketosis.

Dapagliflozin effects on haematocrit, red blood cell count and reticulocytes in insulin-treated patients with type 2 diabetes.

Recent studies have shown that high-risk patients with type 2 diabetes mellitus (T2DM) treated with sodium glucose cotransporter 2 (SGLT2) inhibitors have improved cardiovascular (CV) outcomes. In an exploratory analysis of data from the EMPA-REG study, elevations in haematocrit were shown to be strongly associated with beneficial CV effects. As insulin treatment has been shown to be antinatriuretic, with an associated increase in extracellular fluid volume, it is important to confirm whether haematocrit increase is maintained with concomitant insulin therapy. Here, we investigate the effect of the SGLT2 inhibitor dapagliflozin on haematocrit, red blood cell (RBC) counts and reticulocyte levels in high-risk patients with T2DM receiving insulin. A 24-week, double-blinded, randomised, placebo-controlled trial (ClinicalTrials.gov: NCT00673231) was reported previously with extension periods of 24 and 56 weeks (total of 104 weeks). Patients receiving insulin were randomised 1:1:1:1 to placebo or dapagliflozin at 2.5, 5 or 10 mg. Haematocrit, RBC and reticulocyte measurements were conducted during this study, and a longitudinal repeated-measures analysis was performed here to examine change from baseline during treatment. Dapagliflozin treatment in combination with insulin resulted in a dose-dependent increase in haematocrit levels and RBCs over a 104 week period. There was a short-term increase in reticulocyte levels at the start of treatment, which dropped to below baseline after 8 weeks. SGLT2 inhibition with dapagliflozin leads to a sustained increase in haematocrit in patients receiving chronic insulin treatment.

Machine Learning Approaches Reveal Metabolic Signatures of Incident Chronic Kidney Disease in Individuals With Prediabetes and Type 2 Diabetes.

Early and precise identification of individuals with prediabetes and type 2 diabetes (T2D) at risk for progressing to chronic kidney disease (CKD) is essential to prevent complications of diabetes. Here, we identify and evaluate prospective metabolite biomarkers and the best set of predictors of CKD in the longitudinal, population-based Cooperative Health Research in the Region of Augsburg (KORA) cohort by targeted metabolomics and machine learning approaches. Out of 125 targeted metabolites, sphingomyelin C18:1 and phosphatidylcholine diacyl C38:0 were identified as candidate metabolite biomarkers of incident CKD specifically in hyperglycemic individuals followed during 6.5 years. Sets of predictors for incident CKD developed from 125 metabolites and 14 clinical variables showed highly stable performances in all three machine learning approaches and outperformed the currently established clinical algorithm for CKD. The two metabolites in combination with five clinical variables were identified as the best set of predictors, and their predictive performance yielded a mean area value under the receiver operating characteristic curve of 0.857. The inclusion of metabolite variables in the clinical prediction of future CKD may thus improve the risk prediction in people with prediabetes and T2D. The metabolite link with hyperglycemia-related early kidney dysfunction warrants further investigation.

Effect of dapagliflozin as an adjunct to insulin over 52 weeks in individuals with type 1 diabetes: post-hoc renal analysis of the DEPICT randomised controlled trials.

BACKGROUND: The DEPICT-1 and DEPICT-2 studies showed that dapagliflozin as an adjunct to insulin in individuals with inadequately controlled type 1 diabetes improved glycaemic control and bodyweight, without increase in risk of hypoglycaemia. We aimed to determine the effect of dapagliflozin on urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) using pooled data from the DEPICT studies. METHODS: In this post-hoc analysis, we used data pooled from both DEPICT studies (DEPICT-1 ran from Nov 11, 2014, to Aug 25, 2017; DEPICT-2 ran from July 8, 2015, to April 18, 2018), in which participants were aged 18-75 years, with inadequately controlled type 1 diabetes and with a baseline UACR of at least 30 mg/g. In the DEPICT studies, participants were randomly assigned (1:1:1) to receive dapagliflozin (5 mg or 10 mg) or placebo all plus insulin, for 24 weeks, with a 28-week long-term extension (ie, 52 weeks in total). In this post-hoc analysis, we assessed the percentage change from baseline in UACR and in eGFR, up to 52 weeks. UACR, eGFR, and safety were assessed in all eligible participants who had received at least one dose of study drug. HbA1c, bodyweight, and systolic blood pressure were assessed in all participants who received at least one dose of study drug during the first 24-week period, and who had a baseline and any post-baseline assessment for that parameter. The DEPICT trials were registered with ClinicalTrials.gov, NCT02268214 (DEPICT-1), NCT02460978 (DEPICT-2), and are now complete. RESULTS: 251 participants with albuminuria at baseline were included in this post-hoc analysis; of whom 80 (32%) had been randomly assigned to dapagliflozin 5 mg, 84 (33%) to dapagliflozin 10 mg, and 87 (35%) to placebo. Compared with placebo, treatment with both dapagliflozin doses improved UACR over 52 weeks. At week 52, mean difference in change from baseline versus placebo in UACR was -13·3% (95% CI -37·2 to 19·8) for dapagliflozin 5 mg and -31·1% (-49·9 to -5·2) for dapagliflozin 10 mg. No notable change from baseline was seen in eGFR, with a mean difference in change from baseline versus placebo of 3·27 mL/min per 1·73 m2 (95% CI -0·92 to 7·45) for dapagliflozin 5 mg and 2·12 mL/min per 1·73 m2 (-2·03 to 6·27) for dapagliflozin 10 mg. Similar proportions of participants in each treatment group had adverse events and serious adverse events, including hypoglycaemia and diabetic ketoacidosis; no new safety signals were identified in this population. INTERPRETATION: Treatment with dapagliflozin resulted in UACR reduction, which might provide renoprotective benefits in individuals with type 1 diabetes and albuminuria. Dedicated prospective studies are needed to confirm these findings as prespecified endpoints. FUNDING: AstraZeneca.

Benefit/risk profile of dapagliflozin 5 mg in the DEPICT-1 and -2 trials in individuals with type 1 diabetes and body mass index ≥27 kg/m2.

AIM: The DEPICT-1 and -2 studies (NCT02268214, NCT02460978) evaluated the efficacy and safety of dapagliflozin in individuals with type 1 diabetes who were receiving intensive insulin therapy. The DEPICT-1 and -2 studies (NCT02268214, NCT02460978) evaluated the efficacy and safety of dapagliflozin in individuals with type 1 diabetes. This post-hoc study investigated the safety and efficacy of dapagliflozin in individuals with BMI ≥27 kg/m2 to assess if the benefit/risk ratio associated with dapagliflozin treatment can be further improved than that observed in the overall DEPICT population. METHODS: Changes in glycated haemoglobin (HbA1c) and body weight, percentage change in daily insulin dose and proportion of participants achieving HbA1c reduction ≥0.5% without severe hypoglycaemia were evaluated at weeks 24 and 52. Changes in mean interstitial glucose, mean amplitude of glycaemic excursions and time in target glycaemic range were evaluated at week 24. Safety was assessed until week 56. RESULTS: Week-52 adjusted mean (SE) change from baseline for HbA1c was -0.26% (0.05) with dapagliflozin versus +0.08% (0.05) with placebo and for body weight was -2.74 kg (0.25) with dapagliflozin versus +0.81 kg (0.26) with placebo. Mean (SE) percentage change in daily insulin dose was -10.5% (1.23) with dapagliflozin versus -1.4% (1.36) with placebo. Time spent in target glycaemic range increased by 2.2 h/day versus placebo. Dapagliflozin was well tolerated, with fewer participants experiencing diabetic ketoacidosis (dapagliflozin, 1.7%; placebo, 1.0%) than dapagliflozin 5 mg receiving participants in the pooled DEPICT populations. CONCLUSIONS: Compared with the pooled DEPICT population, the benefit/risk profile of adjunct dapagliflozin therapy was more favourable in individuals with type 1 diabetes with body mass index ≥27 kg/m2 because of the reduced risk of diabetic ketoacidosis in this population.

Long-term efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (the DEPICT-2 study): 52-week results from a randomized controlled trial.

AIM: To investigate the long-term efficacy and safety of dapagliflozin as an adjunct to adjustable insulin in adults with type 1 diabetes (T1D) and inadequate glycaemic control. MATERIALS AND METHODS: Dapagliflozin Evaluation in Patients with Inadequately Controlled Type 1 Diabetes (DEPICT-2) was a placebo-controlled, double-blind, multicentre, phase III study of adults with T1D (HbA1c 7.5%-10.5%) randomized (1:1:1) to receive dapagliflozin 5, 10 mg, or placebo. The efficacy and safety of dapagliflozin over 52 weeks were exploratory endpoints in this extension to DEPICT-2. RESULTS: Of 813 participants randomized, 88.2% completed the study. From baseline to 52 weeks, dapagliflozin 5 and 10 mg were associated with reduction in HbA1c (difference [95% CI] vs. placebo: -0.20% [-0.34, -0.06] and -0.25% [-0.38, -0.11], respectively) and adjusted mean percentage change in body weight (difference [95% CI] vs. placebo: -4.42% [-5.19, -3.64] and -4.86% [-5.63, -4.08], respectively). Serious adverse events were reported in the dapagliflozin 5, 10 mg, and placebo groups (32 [11.8%], 19 [7.0%] and 16 [5.9%], respectively). The proportion of hypoglycaemic events was similar across groups; severe hypoglycaemia was uncommon. More participants with events adjudicated as definite diabetic ketoacidosis (DKA) were in the dapagliflozin 5 and 10 mg groups versus placebo (11 [4.1%], 10 [3.7%] and 1 [0.4%], respectively); the majority of events were mild or moderate in severity and all were resolved with treatment. CONCLUSIONS: Dapagliflozin led to long-term reductions in HbA1c and body weight in adults with T1D, but increased DKA risk compared with placebo.

Adverse Changes in HbA1c, Body Weight and Insulin Use in People with Type 1 Diabetes Mellitus Following Dapagliflozin Discontinuation in the DEPICT Clinical Trial Programme.

INTRODUCTION: Dapagliflozin is an orally active inhibitor of sodium-glucose co-transporter 2 (SGLT2) that is indicated for use in adults with type 1 diabetes (T1DM) (with a body mass index (BMI) of at least 27 kg/m2 in Europe, no such BMI limit in Japan), when insulin alone does not provide adequate glycaemic control. The aim of this study was to evaluate changes in glycated haemoglobin (HbA1c), body weight and insulin dose following discontinuation of dapagliflozin for the management of T1DM in the DEPICT clinical trial programme. METHODS: The interrelationship between treatment discontinuation, insulin requirement and outcomes post-discontinuation was evaluated using descriptive summary statistics and linear regression modelling. Data were analysed from individuals with T1DM discontinuing dapagliflozin in DEPICT-1 or DEPICT-2 (unplanned or end of study). HbA1c and body weight were measured over the 56-week study period (consisting of a 52-week treatment period and a 4-week follow-up period) at 4-8 weekly intervals. Following discontinuation of dapagliflozin, 1-year change in HbA1c (%) and weight (kg) following discontinuation of dapagliflozin was estimated; total daily insulin doses were descriptively summarised. RESULTS: Of the 1059 individuals that received dapagliflozin during the DEPICT trials 91 met the eligibility criteria and were included in the analyses of HbA1c and body weight. The mean duration of follow-up was 209 days in both analyses. Following dapagliflozin discontinuation, estimated annualised changes in HbA1c and body weight were + 0.99% (95% CI 0.39, 1.59) and + 3.75 kg (1.65, 5.86), respectively. An increase in insulin dose was observed around the time of discontinuation; insulin dose in the 2-week post-discontinuation was + 3.6 IU and + 4.4 IU higher with dapagliflozin 5 mg and 10 mg than 2 weeks pre-discontinuation, respectively. CONCLUSION: Discontinuation of dapagliflozin is predicted to lead to clinically meaningful increases in HbA1c and body weight, in addition to higher insulin doses. These findings are important in the management of people with T1DM among whom insulin is the only existing pharmacological treatment option.

Comparison of pharmacokinetics and the exposure-response relationship of dapagliflozin between adolescent/young adult and adult patients with type 1 diabetes mellitus.

AIMS: To quantitatively compare pharmacokinetics (PK) and the exposure-response (ER) relationship of the sodium-glucose cotransporter-2 inhibitor, dapagliflozin, between adolescents/young adults and adults with type 1 diabetes mellitus (T1DM). METHODS: Data from 2 clinical studies for dapagliflozin were analysed using a non-linear mixed-effects approach. The PK and the relationship between dapagliflozin exposure and response (24-hour urinary glucose excretion) were characterized. PK was evaluated using a 2-compartment model with first-order absorption while the exposure response-relationship was analysed using a sigmoidal maximal-effect model. The 24-hour median blood glucose, estimated glomerular filtration rate (eGFR), sex, age and body weight were evaluated as covariates. RESULTS: A 2-compartment model with first order absorption provided a reasonable fit to the dapagliflozin PK data. Body weight was found to be a significant covariate on dapagliflozin exposure. The ER relationship was best described by a sigmoidal maximal effect model with 24-hour median blood glucose and eGFR as significant covariates on maximal effect. In accordance with the observed data, model-predicted urinary glucose excretion response following 10 mg dapagliflozin dose was higher in the study in adolescents/young adults (138.0 g/24 h) compared to adults (70.5 g/24 h) with T1DM. This is linked to higher eGFR and 24-hour median blood glucose in this trial. CONCLUSIONS: Dapagliflozin PK and ER relationship were similar in the 2 analysed studies after accounting for covariate effects. These results suggest that no dose adjustment is required for adolescent patients with T1DM.

Changes in patient characteristics, glucose lowering treatment, glycemic control and complications in type 2 diabetes in general practices (Disease Analyzer, Germany: 2008-2016).

OBJECTIVES: The objectives were to examine long-term changes in type 2 diabetes patient characteristics, diabetes treatment, control and complications in general practices. METHODS: All type 2 diabetes patients were identified in a representative general practice database (Disease Analyser, Germany) in three periods (01/2008-12/2008: n = 90.866, 818 practices, mean age (SD): 67.6 (12.1) years, 51% males; 01/2012-12/2012: n = 179.923, 1.158 practices, 68.3 (12.6) years, 51% males; 10/2015-09/2016: n = 201.667, 1.184 practices, 68.2 (12.9) years, 52% males). Chi-square and Wilcoxon rank-sum tests were used for testing differences (2008 vs. 2015/16). RESULTS: The mean number of type 2 patients per practice increased (2008: 111; 2015/16: 170). The proportion of retirees declined (74% vs. 61%) and patients in the working population increased (18% vs. 28%) (all p < 0.001). There were no relevant changes in mean HbA1c (7.1% vs. 7.2%), fasting blood glucose (141 mg/dl vs. 144 mg/dl) and BMI (31 kg/m2 vs. 32 kg/m2), whereas total cholesterol (204 mg/dl vs. 196 mg/dl) and triglycerides (159 mg/dl vs. 153 mg/dl) slightly declined (all p < 0.001). Prescription use of metformin, dipeptidyl peptidase-4 (DPP-4) and sodium dependent glucose transporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists enlarged (dual or triple combinations) while sulfonylurea use decreased. Prevalence of polyneuropathy (6.2% vs. 8.6%), nephropathy (1.9% vs. 3.2%) and depression (7.6% vs. 10.0%) rised (all p < 0.001). CONCLUSIONS: General practitioners play a key role in diabetes care, increasingly treating type 2 diabetes patients in the working population. There was no change in glycemic control over the study period (2008-2016). The use of glucose-lowering drug combinations increased and microvascular complications were more often recorded.

Effects of dapagliflozin on insulin-requirement, glucose excretion and ß-hydroxybutyrate levels are not related to baseline HbA1c in youth with type 1 diabetes.

Youth with type 1 diabetes (T1D) infrequently achieve HbA1c targets. Therefore, this placebo-controlled, randomized, crossover study was set up to assess the safety, effect and pharmacokinetics of a single dose of 10 mg dapagliflozin (DAPA) as add-on to insulin in relationship to HbA1c in youth. A total of 33 youths (14 males, median age 16 years, diabetes duration 8 years) were included and stratified into 3 baseline HbA1c categories (<7.5%, 7.5%-9.0% or >9.0; n = 11 each). During the study period of 24 hours, intravenous insulin administration and glucose-infusion kept blood glucose levels at 160 to 220 mg/dL. DAPA reduced mean insulin dose by 13.6% ( P < .0001 by ANOVA) and increased urinary glucose excretion by 610% (143.4 vs 22.4 g/24 h; P < .0001), both irrespective of baseline HbA1c. Six independent episodes in 6 patients with plasma ß-hydroxybutyrate levels between ≥0.6 and <1.0 mmol/L were observed after liquid meal challenges, 5 episodes in the DAPA group and 1 in the placebo group. This study provides a proof-of-concept, irrespective of preexisting HbA1c levels, for adjunct SGLT2-inhibitor therapy in the paediatric age group by lowering insulin dose and increasing glucose excretion.

Changes in Glycemic Control and Body Weight After Initiation of Dapagliflozin or Basal Insulin Supported Oral Therapy in Type 2 Diabetes: A Primary Care Database Study.

BACKGROUND: The aim was to compare changes in HbA1c and body weight after initiation of dapagliflozin or basal insulin supported oral therapy (BOT) in type 2 diabetes patients in primary care practices. METHODS: Patients from 983 primary care practices who started dapagliflozin or BOT between December 2012 and July 2015 (index date, ID) were retrospectively analyzed (Disease Analyzer; Germany). Changes in HbA1c (%) and body weight (kg) were evaluated 90-270 days after ID. Propensity score (PS) matching (1:1) was used to adjust for differences in baseline clinical characteristics (180-0 days before ID: age, sex, health insurance, diabetologist care, glucose lowering therapy, HbA1c, body mass index) and duration (days) between start of therapies and last HbA1c or weight documentation after ID. RESULTS: After PS matching, 766 dapagliflozin (mean ± SD; age: 63 ± 10 years; HbA1c: 8.9 ± 1.2%) and 766 BOT (age: 63 ± 10 years; HbA1c: 8.7 ± 1.1%) patients were included. HbA1c decreased by mean (SD) of 1.0% (1.3) in dapagliflozin and by 1.0% (1.4) in BOT patients after 90-270 days (HbA1c reduction; dapagliflozin vs BOT: -0.01%; P = .79). In 440 dapagliflozin users with available data, body weight (97.4 ± 19.9 kg) decreased by 3.1 (5.8) kg after 90-270 days, whereas no significant weight change was observed in 440 matched BOT patients (97.5 ± 19.9 kg) (weight reduction; dapagliflozin vs BOT: -3.0 kg; P < .05). CONCLUSIONS: Initiation of dapagliflozin therapy reduced HbA1c similar to basal insulin with the additional benefit of weight reduction in type 2 diabetes patients treated in general practices.

Changes in HbA1c, body weight, and systolic blood pressure in type 2 diabetes patients initiating dapagliflozin therapy: a primary care database study.

AIMS: To investigate changes in glycated hemoglobin (HbA1c), body weight (BW), and systolic blood pressure (SBP) in type 2 diabetes (T2D) primary care patients initiating dapagliflozin treatment. METHODS: T2D patients who started dapagliflozin in 985 general and 32 diabetologist practices (Disease Analyzer, Germany: December 2012-October 2014) were analyzed (3- and 6-month follow-up). Multivariate linear regression analyses were used to identify clinical characteristics and comorbidity associated with changes in HbA1c, BW, and SBP. RESULTS: The study included 1,169 T2D patients (age: 62.5 years; men: 59.3%; diabetologist care: 23%) with newly initiated dapagliflozin therapy. At the 3-month stage, dapagliflozin significantly reduced HbA1c (-0.8%±1.4%) compared to the baseline (8.5%±1.5%) (P<0.001). Changes were maintained after 6 months (-0.8%±1.5%) (P<0.001). Patients with high baseline HbA1c values (>9%) showed greater reductions in HbA1c than the overall sample (3 months -1.8%, 6 months -1.8%; both P<0.05). BW and SBP also showed statistically significant reductions with dapagliflozin over 3 and 6 months (-2.2 kg, P<0.001; -2.2 mmHg, P=0.003 and -2.5 kg, P<0.001; -2.3 mmHg, P=0.011, respectively). After 3 months, 53% of patients achieved a reduction in both HbA1c and BW; the same holds true for 45% of patients at the 6-month mark. Similar results were observed both in general and diabetologist practices. In multivariate analyses, baseline HbA1c (parameter estimate: -0.6479) and diabetologist care (-0.2553) were independent predictors of HbA1c change (6 months) (all P<0.05). CONCLUSION: T2D patients treated with dapagliflozin therapy achieved statistically significant reductions in HbA1c, BW, and SBP in a real-world primary and diabetologist care setting. The changes were comparable to the results of the dapagliflozin clinical trial program.