Dataset Information

Effect of Dapagliflozin on Urine Metabolome in Patients with Type 2 Diabetes.

ABSTRACT:

Context

Inhibitors of sodium-glucose cotransporters-2 have cardio- and renoprotective properties. However, the underlying mechanisms remain indeterminate.

Objective

To evaluate the effect of dapagliflozin on renal metabolism assessed by urine metabolome analysis in patients with type 2 diabetes.

Design

Prospective cohort study.

Setting

Outpatient diabetes clinic of a tertiary academic center.

Patients

Eighty patients with hemoglobin A1c > 7% on metformin monotherapy were prospectively enrolled.

Intervention

Fifty patients were treated with dapagliflozin for 3 months. To exclude that the changes observed in urine metabolome were merely the result of the improvement in glycemia, 30 patients treated with insulin degludec were used for comparison.

Main outcome measure

Changes in urine metabolic profile before and after the administration of dapagliflozin and insulin degludec were assessed by proton-nuclear magnetic resonance spectroscopy.

Results

In multivariate analysis urine metabolome was significantly altered by dapagliflozin (R2X = 0.819, R2Y = 0.627, Q2Y = 0.362, and coefficient of variation analysis of variance, P < 0.001) but not insulin. After dapagliflozin, the urine concentrations of ketone bodies, lactate, branched chain amino acids (P < 0.001), betaine, myo-inositol (P < 0001), and N-methylhydantoin (P < 0.005) were significantly increased. Additionally, the urine levels of alanine, creatine, sarcosine, and citrate were also increased (P < 0001, P <0.0001, and P <0.0005, respectively) whereas anserine decreased (P < 0005).

Conclusions

Dapagliflozin significantly affects urine metabolome in patients with type 2 diabetes in a glucose lowering-independent way. Most of the observed changes can be considered beneficial and may contribute to the renoprotective properties of dapagliflozin.

SUBMITTER: Bletsa E

PROVIDER: S-EPMC8063232 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:IntroductionHyperkalemia risk is increased in diabetes, particularly in patients with renal impairment or those receiving angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) or potassium-sparing diuretics. Conversely, other diuretics can increase hypokalemia risk. We assessed the effects of the sodium glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin on serum potassium levels in a pooled analysis of clinical trials in patients with type 2 diabetes mellitus (T2DM).MethodsFourteen randomized, placebo-controlled, double-blind T2DM studies were analyzed: pooled data from 13 studies of ≤24 weeks' duration (dapagliflozin 10 mg, N = 2360; placebo, N = 2295); and one 52-week moderate renal impairment study in patients with baseline eGFR ≥30 to <60 mL/min/1.73 m(2) (dapagliflozin 10 mg, N = 85; placebo, N = 84). Central laboratory serum potassium levels were determined at each study visit.ResultsNo clinically relevant mean changes from baseline in serum potassium ≤24 weeks were reported for dapagliflozin 10 mg [-0.05 mmol/L; 95% confidence interval (CI) -0.07, -0.03] versus placebo (-0.02 mmol/L; 95% CI -0.04, 0.00) in the pooled population or in the renal impairment study (-0.03 mmol/L; 95% CI -0.14, 0.08 vs. -0.02 mmol/L; 95% CI -0.13, 0.09, respectively). The incidence rate ratio for serum potassium ≥5.5 mmol/L over 24 weeks for dapagliflozin 10 mg versus placebo was 0.90 (95% CI 0.74, 1.10) in the pooled population; with no increased risk in patients receiving ARBs/ACE inhibitors, or potassium-sparing diuretics, or in those with moderate renal impairment. Slightly more patients receiving dapagliflozin 10 mg had serum potassium ≤3.5 mmol/L versus placebo (5.2% vs. 3.6%); however, no instances of serum potassium ≤2.5 mmol/L were reported.ConclusionDapagliflozin is not associated with an increased risk of hyperkalemia or severe hypokalemia in patients with T2DM.FundingBristol-Myers Squibb and AstraZeneca.

Project description:Dapagliflozin is a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor approved as a treatment for type 2 diabetes mellitus (T2DM) in the United States, the European Union and other countries. Dapagliflozin increases renal glucose excretion in an insulin-independent manner, and its mechanism of action is complementary to those of other antidiabetes medications. When used as monotherapy or in combination with other oral antidiabetes medications or insulin, dapagliflozin improves glycemic measures in patients with T2DM. Dapagliflozin treatment is also associated with weight reduction and a decrease in blood pressure, both of which may be beneficial in patients with T2DM. Because of its mechanism of action, dapagliflozin has a low intrinsic propensity to cause hypoglycemia. Overall, dapagliflozin is well tolerated, with the frequency of most adverse events similar to that seen with placebo. Cases of genital infections and, in some studies, urinary tract infections have been more frequent in dapagliflozin-treated groups compared with placebo groups. In the clinical development program, more cases of newly diagnosed bladder cancer were reported for patients treated with dapagliflozin (0.17%) compared with placebo or comparator (0.03%). Although there were not enough cases to determine causality, dapagliflozin should not be used in patients with bladder cancer and should be used with caution in patients with a history of bladder cancer. Dapagliflozin may decrease glomerular filtration rate (GFR), especially in elderly patients and patients with impaired renal function. Renal function should be monitored before initiation of dapagliflozin. Dapagliflozin should not be used in patients with an estimated GFR <60 ml/min/1.73 m(2). No cardiovascular safety signals have been detected for dapagliflozin, and a long-term cardiovascular outcomes study is ongoing. Evidence from clinical trials suggests that dapagliflozin is a promising new treatment option for T2DM.

Project description:AimTo evaluate the effect of an inhibitor of sodium-glucose cotransporter 2 (SGLT-2 inhibitor, dapagliflozin) on glycemic variability in type 2 diabetes mellitus (T2D) under insulin glargine combined with oral hypoglycemic drugs, using a continuous glucose monitoring system (CGMS).MethodsThis prospective, self-controlled, single-center clinical trial recruited 36 patients with T2D under combined insulin glargine and oral hypoglycemic drugs. General clinical data were collected. Fasting blood glucose (FBG), postprandial blood glucose (PBG), glycosylated hemoglobin (HbA1c), and C-peptide levels were assessed before and four weeks of dapagliflozin (10 mg per day) treatment. Blood glucose was monitored for 72 hours before and after treatment using CGMS.ResultsAfter treatment with dapagliflozin, FBG decreased from 6.74 ± 1.78 to 5.95 ± 1.13 mmol/L (p < 0.05); PBG decreased from 13.04 ± 2.99 to 10.92 ± 3.26 mmol/L (p < 0.05); HbA1c decreased from 7.37 ± 0.96% to 6.94 ± 0.80%. The proportion of patients with HbA1c < 7% increased from 27.8% to 58.3%, and the proportion of patients with HbA1c < 7% and without level 2 hypoglycemia increased from 27.8% to 55.6% (p < 0.05). CGMS data showed reduction of the 24 h MBG, MAGE, time-above-range (TAR, >10 mmol/L), high blood glucose index (HBGI), glucose management indicator (GMI), and incremental area under the curve of the glucose level more than 10 mmol/L (AUC > 10) and an increase of time-in-range (TIR, 3.9-10 mmol/L) with treatment. Homeostasis model assessment for pancreatic beta-cell function (HOMA-beta) increased significantly with treatment (p < 0.05), and fewer insulin doses were required after the treatment, without increasing in hypoglycemia and urinary tract infection. Further, a stratified analysis showed that patients with higher pretreatment HbA1c and waist-to-hip ratio (WHR) had greater improvement in glycemic control.ConclusionDapagliflozin may reduce blood glucose levels, ameliorate glycemic variability, and improve pancreatic beta-cell function in patients with T2D under insulin glargine combined with other oral hypoglycemic drugs, especially in those with poor glucose control and abdominal obesity.

Project description:A pre-specified meta-analysis of cardiovascular (CV) events from 21 phase 2b/3 dapagliflozin clinical trials was undertaken to characterise the CV profile of dapagliflozin. This showed no increase in CV risk with dapagliflozin compared with control (placebo or comparator treatment) with or without background glucose-lowering therapies. The analysis reported here aimed to characterise the CV profile of dapagliflozin in subgroups of patients in these 21 studies grouped by degree of CV risk, based on both baseline and in-study risk factors (including hypoglycaemic events), with a focus on major adverse CV events (MACE).Patients with type 2 diabetes, both overall and with different levels of CV risk, including CV disease (CVD) history, age and other CV risk factors, were analysed. A further analysis compared CV risk in patients who experienced a hypoglycaemic event prior to MACE and those who did not. Analyses were based on time to first event using a Cox proportional hazards model stratified by study comparing dapagliflozin versus control.In total, 9339 patients were included in this meta-analysis; 5936 patients received dapagliflozin 2.5-10 mg (6668 patient-years) and 3403 received control (3882 patient-years). Dapagliflozin is not associated with increased CV risk and results further suggest the potential for a beneficial effect both in the overall population [Hazard Ratio (HR) 0.77; 95 % CI (0.54, 1.10) for MACE] and in those with a history of CVD [HR 0.80 (0.53, 1.22)]. These findings were consistent in patients with varying degrees of CV risk, including age, number and type of CVD events in medical history and number of CV risk factors present. Furthermore, there was no increased risk of MACE in patients who experienced a hypoglycaemic event compared with those who did not.There was no suggestion of increased risk for MACE with dapagliflozin compared with control in any of the populations investigated. In addition, the results suggest the potential for a beneficial CV effect which is consistent with the multifactorial benefits on CV risk factors associated with sodium-glucose cotransporter-2 (SGLT2) inhibitors.