Dataset Information

Safety and Effectiveness of Bexagliflozin in Patients With Type 2 Diabetes Mellitus and Stage 3a/3b CKD.

ABSTRACT:

Rationale & objective

Hyperglycemia exacerbates the progression of chronic kidney disease (CKD), but most glucose-lowering therapies do not address morbidities associated with CKD. Sodium/glucose cotransporter 2 (SGLT2) inhibitors offer potential benefits to patients with diabetes and CKD, but their effectiveness may be diminished with decreased kidney function. We aimed to evaluate the safety and effectiveness of bexagliflozin, a novel SGLT2 inhibitor, in patients with type 2 diabetes and CKD.

Study design

Phase 3, double-blind, placebo-controlled, multicenter, multinational, randomized trial.

Setting & participants

54 sites across 4 countries. Patients with CKD stage 3a or 3b, type 2 diabetes mellitus, and hemoglobin A_1c level of 7.0% to 10.5% and estimated glomerular filtration rate (eGFR) of 30 to 59mL/min/1.73m² who were taking oral hypoglycemic agents for 8 weeks.

Interventions

Bexagliflozin, 20mg, daily versus placebo for 24 weeks.

Outcomes

Primary outcome was change in percent hemoglobin A_1c from baseline to week 24. Secondary end points included changes in body weight, systolic blood pressure, albuminuria, and hemoglobin A_1c level stratified by CKD stage.

Results

312 patients across 54 sites were analyzed. Bexagliflozin lowered hemoglobin A_1c levels by 0.37% (95% CI, 0.20%-0.54%); P<0.001 compared to placebo. Patients with CKD stages 3a (eGFR, 45-<60mL/min/1.73m²) and 3b (eGFR, 30-<45mL/min/1.73m²) experienced reductions in hemoglobin A_1c levels of 0.31% (P=0.007) and 0.43% (P=0.002), respectively. Bexagliflozin decreased body weight (1.61kg; P<0.001), systolic blood pressure (3.8mm Hg; P=0.02), fasting plasma glucose level (0.76mmol/L; P=0.003), and albuminuria (geometric mean ratio reduction of 20.1%; P=0.03). Urinary tract infection and genital mycotic infections were more common in the bexagliflozin group; otherwise, frequencies of adverse events were comparable between groups.

Limitations

Not designed to evaluate the impact of treatment on long-term kidney disease and cardiovascular outcomes.

Conclusions

Bexagliflozin reduces hemoglobin A_1c levels in patients with diabetes and stage 3a/3b CKD and appears to be well tolerated. Additional observed benefits included reductions in body weight, systolic blood pressure, and albuminuria.

Funding

Trial was sponsored by Theracos Sub, LLC.

SUBMITTER: Allegretti AS

PROVIDER: S-EPMC10077840 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Safety and Effectiveness of Bexagliflozin in Patients With Type 2 Diabetes Mellitus and Stage 3a/3b CKD.

Allegretti Andrew S AS Zhang Wenbin W Zhou Wenjiong W Thurber Tara K TK Rigby Scott P SP Bowman-Stroud Cynthia C Trescoli Carlos C Serusclat Pierre P Freeman Mason W MW Halvorsen Yuan-Di C YC

American journal of kidney diseases : the official journal of the National Kidney Foundation 20190514 3

<h4>Rationale & objective</h4>Hyperglycemia exacerbates the progression of chronic kidney disease (CKD), but most glucose-lowering therapies do not address morbidities associated with CKD. Sodium/glucose cotransporter 2 (SGLT2) inhibitors offer potential benefits to patients with diabetes and CKD, but their effectiveness may be diminished with decreased kidney function. We aimed to evaluate the safety and effectiveness of bexagliflozin, a novel SGLT2 inhibitor, in patients with type 2 diabetes a ...[more]

PMID: 31101403

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Project description:BackgroundRecent studies reported that sodium glucose cotransporter 2 (SGLT2) inhibitors can potentially reduce the risk of cardiovascular mortality in patients with type 2 diabetes mellitus (T2DM). However, there is little or no information on the therapeutic effects of SGLT2 inhibitors on the progression of atherosclerosis. This dapagliflozin effectiveness on vascular endothelial function and glycemic control (DEFENCE) study was designed to determine the effects of dapagliflozin, a SGLT2 inhibitor, on endothelial function in patients with early-stage T2DM.MethodsDEFENCE is a prospective, randomized, open-label, blinded-endpoint, parallel-group, comparative clinical trial. Between October 2015 and August 2016, 80 T2DM patients treated with 750 mg of metformin (hemoglobin A1c ≥6.0 and <8.0%, n = 80) were enrolled and randomized to receive either 1500 mg/day metformin (the metformin group, n = 40), or 750 mg/day metformin supplemented with 5 mg/day dapagliflozin (the dapagliflozin group, n = 40), for 16 weeks. The primary endpoint was a change in flow-mediated dilation (FMD) from baseline to the end of the 16-week treatment period. The secondary outcomes include changes in indexes of glycemic control, lipid metabolism, and oxidative stress, body composition, and safety evaluation.ResultsAlthough FMD tended to improve only in the dapagliflozin group, ΔFMD was comparable between the two groups. Analysis of patients with HbA1c >7.0% showed significant improvement of FMD in the dapagliflozin group than metformin group (P < 0.05). HbA1c, fasting plasma glucose, plasma glucagon, and body weight significantly decreased in both groups. Interestingly, urine 8-hydroxy-2'-deoxyguanosin, a biomarker of oxidative stress, was significantly lower in the dapagliflozin group than metformin group at 16 weeks (P < 0.001).ConclusionsDapagliflozin add-on therapy to metformin for 16 weeks improved endothelial function, as assessed by FMD, in patients with inadequately controlled early-stage T2DM. Improvement in oxidative stress may contribute to the improvement in FMD. Trial registration University Hospital Medical Information Network Clinical Trial Registry (UMIN000018754).

Project description:Rationale & objectiveWe aimed to test interventions to improve physical activity in persons with advanced chronic kidney disease not yet receiving dialysis.Study designRandomized controlled trial with parallel-group design.Setting & participantsWe embedded a pragmatic referral to exercise programming in high-volume kidney clinics servicing diverse populations in San Jose, CA, and Atlanta, GA. We recruited 56 participants with estimated glomerular filtration rates < 45 mL/min/1.73 m2.InterventionsWe randomly assigned participants to a mobile health (mHealth) group-wearable activity trackers and fitness professional counseling, or an Exercise is Medicine intervention framework (EIM) group-mHealth components plus twice-weekly small-group directed exercise sessions customized to persons with kidney disease. We performed assessments at baseline, 8 weeks at the end of active intervention, and 16 weeks after passive follow-up and used multilevel mixed models to assess between-group differences.OutcomesActivity tracker total daily step count.ResultsOf 56 participants, 86% belonged to a racial/ethnic minority group; randomly assigned groups were well balanced on baseline step count. In intention-to-treat analyses, the EIM and mHealth groups both experienced declines in daily step counts, but there was an attenuated reduction in light intensity physical activity (standard error 0.2 [5.8] vs -8.5 [5.4] min/d; P = 0.08) in the EIM compared with the mHealth group at 8 weeks. In as-treated analyses, total daily step count, distance covered, and light and moderate-vigorous activity minutes per day improved in the EIM group and declined in the mHealth group at 8 weeks (standard error +335 [506] vs -884 [340] steps per day; P = 0.05; P < 0.05 for secondary measures), but group differences faded at 16 weeks. There were no differences in quality-of-life and mental health measures during the study.LimitationsSmall sample size, limited duration of study, assessment of intermediate outcomes (steps per day).ConclusionsA clinic-integrated referral to small-group exercise sessions is feasible, safe, and moderately effective in improving physical activity in an underserved population with high comorbid conditions.FundingNormon S Coplon Applied Pragmatic Clinical Research program.Trial registrationNCT03311763.

Dataset Information

Safety and Effectiveness of Bexagliflozin in Patients With Type 2 Diabetes Mellitus and Stage 3a/3b CKD.

Rationale & objective

Study design

Setting & participants

Interventions

Outcomes

Results

Limitations

Conclusions

Funding

Publications

Safety and Effectiveness of Bexagliflozin in Patients With Type 2 Diabetes Mellitus and Stage 3a/3b CKD.

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