Assessment of dapagliflozin effect on diabetic endothelial dysfunction of brachial artery (ADDENDA-BHS2 trial): rationale, design, and baseline characteristics of a randomized controlled trial

Cintra, Riobaldo M.R.; Soares, Ana Flávia; Breder, Íkaro; Munhoz, Daniel; Barreto, Joaquim; Kimura-Medorima, Sheila T.; Cavalcante, Pamela; Zanchetta, Renata; Breder, Jéssica Cunha; Moreira, Camila; Virginio, Vitor W.M.; Bonilha, Isabella; Lima-Júnior, José Carlos de; Coelho‐Filho, Otávio R.; Wolf, Vaneza Lira Waldow; Guerra‐Júnior, Gil; Oliveira, Dayane Carvalho Ramos Salles de; Haeitmann, Rodrigo; Fernandes, Vicente; Nadruz, Wilson; Chaves, Fernando Rodrigo Pedreira; Arieta, Carlos Eduardo Leite; Quinaglia, Thiago; Spósito, Andrei C.; investigators, Addenda-Bhs trial

doi:10.1186/s13098-019-0457-3

Cited by 9 publications

(9 citation statements)

References 57 publications

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“…The Assessment of Dapagliflozin Effect on Diabetic Endothelial Dysfunction of Brachial Artery-Brazilian Heart Study 2 (ADDENDA-BHS2) was a randomized, open-label, single-center study comparing equipotent glucose-lowering regimens of glibenclamide combined with metformin versus dapagliflozin combined with metformin in patients with T2DM and subclinical carotid atherosclerotic disease. Full details regarding the study selection criteria, procedures, and assessment of brachial artery function are published elsewhere [ 18 ] and described in depth in the Additional file 1 . Briefly, eligible patients were 40–70 years of age.…”

Section: Methodsmentioning

confidence: 99%

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Dapagliflozin effect on endothelial dysfunction in diabetic patients with atherosclerotic disease: a randomized active-controlled trial

Sposito

Breder

Soares

et al. 2021

Cardiovasc Diabetol

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Background The glucose-lowering independent effect of sodium glucose cotransporter-2 inhibitors (SGLT2i) on arterial wall function has not yet been clarified. This study aims to assess whether SGLT2i treatment can attenuate endothelial dysfunction related to type 2 diabetes mellitus (T2D) compared with glucose-lowering equivalent therapy. Methods In a prospective, open-label, single-center, randomized clinical trial, 98 patients with T2DM and carotid intima-media thickness above the 75th percentile were randomized 1:1 to 12 weeks of therapy with dapagliflozin or glibenclamide in addition to metformin in glucose-lowering equivalent regimens. The coprimary endpoints were 1-min flow-mediated dilation (FMD) at rest and 1-min FMD after 15 min of ischemia followed by 15 min of reperfusion time (I/R). Results Ninety-seven patients (61% males, 57 ± 7 years) completed the study. The median HbA1c decreased by − 0.8 (0.7)% and -0.7 (0.95)% following dapagliflozin and glibenclamide, respectively. The first coprimary endpoint, i.e., rest FMD changed by + 3.3(8.2)% and − 1.2(7.5)% for the dapagliflozin and glibenclamide arms, respectively (p = 0.0001). Differences between study arms in the second coprimary endpoint were not significant. Plasma nitrite 1 min after rest FMD was higher for dapagliflozin [308(220) nmol/L] than for glibenclamide (258[110] nmol/L; p = 0.028). The resistive indices at 1 min [0.90 (0.11) vs. 0.93 (0.07); p = 0.03] and 5 min [0.93 (0.07) vs. 0.95 (0.05); p = 0.02] were higher for the glibenclamide group than for the dapagliflozin group. Plasma biomarkers for inflammation and oxidative stress did not differ between the treatments. Conclusions Dapagliflozin improved micro- and macrovascular endothelial function compared to glibenclamide, regardless of glycemic control in patients with T2DM and subclinical carotid atherosclerotic disease.

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Section: Methodsmentioning

confidence: 99%

“…Sample size calculations have been published elsewhere [ 18 ]. Briefly, the two study endpoints equally split an alpha level at the bilateral α = 0.025.…”

Section: Methodsmentioning

confidence: 99%

Dapagliflozin effect on endothelial dysfunction in diabetic patients with atherosclerotic disease: a randomized active-controlled trial

Sposito

Breder

Soares

et al. 2021

Cardiovasc Diabetol

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“…This study is a pre-specified analysis of the ADDENDA-BHS2 trial (ClinicalTrials.gov, NCT 02919345). Methods and baseline characteristics have been published elsewhere [ 11 ]. Briefly, ADDENDA-BHS2 was a randomized, single-center, open, active-controlled, phase-4 trial that compared dapagliflozin versus glibenclamide for 12 weeks.…”

Section: Methodsmentioning

confidence: 99%

“…Randomization was performed in a 1:1 ratio for dapagliflozin 10 mg/day or glibenclamide 5 mg/day on top of metformin for 12 weeks of intervention. Eligible volunteers received a 30-day supply of medications according to a previously published protocol [ 11 ]. Anthropometric evaluation performed by the investigators was performed within 2 weeks prior to the randomization visit and up to 2 weeks after the last visit.…”

Section: Methodsmentioning

confidence: 99%

Dapagliflozin increases the lean-to total mass ratio in type 2 diabetes mellitus

et al. 2021

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We compared the effect of dapagliflozin versus glibenclamide on the ratio of lean-to total mass in patients with type 2 diabetes mellitus, carotid subclinical atherosclerosis, HbA1c 7.0–9.0% and 40–70 years-old. Ninety-eight patients (61% male; mean age 57 ± 7 years) were randomized into dapagliflozin 10 mg/day or glibenclamide 5 mg/day on top of metformin. Body composition was measured by Dual Energy X-Ray at randomization and after 12 weeks of treatment. Glycemic control was equivalent in both groups. Dapagliflozin decreased total body mass (−2741 g [95% CI: −3360 to 1945]; p < 0.001) and lean mass (−347 g [95% CI: −761 to −106]; p < 0.001), while glibenclamide increased total body mass (1060 g [95% CI: 140 to 1836]; p < 0.001) and lean mass (929 g [95% CI: 575 to 1283]; p < 0.001) for the differences between arms. The lean-to-total mass ratio increased by 1.2% in the dapagliflozin group and 0,018% in the glibenclamide group (p < 0.001). Dapagliflozin reduced the risk of a negative balance in the lean-to total mass ratio [OR: 0.16 (95% CI: 0.05 to 0.45); p < 0.001] even after adjustment for baseline lean-to total mass ratio, waist circumference, HOMAIR, HbA1c, mean of the two hands handgrip strength and gait speed [OR: 0.13 (95% CI: 0.03–0.57); p < 0.007]. In conclusion, under equivalent glycemic control, dapagliflozin reduced total body mass but increased the ratio of lean-to-total mass when compared with glibenclamide.

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“…In the latter, surrogate markers of endothelial dysfunction and inflammation, such as adhesion molecule 1, endothelial nitric oxide synthase and high-sensitivity CRP, decreased with dapagliflozin therapy, and FMD correlated negatively with HbA1c[ 75 ]. Assessment of the Dapagliflozin Effect on Diabetic Endothelial Dysfunction of the Brachial Artery (ADDENDABHS2) trial, in which patients with poor glycemic control were randomized to receive either dapagliflozin or glibenclamide, shed more light on the effect of this agent[ 76 ].…”

Section: Functional Markersmentioning

confidence: 99%

Effect of glycemic control on markers of subclinical atherosclerosis in patients with type 2 diabetes mellitus: A review

Antoniou¹,

Naka²,

Papadakis³

et al. 2021

WJD

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Cardiovascular disease is the predominant cause of death in type 2 diabetes mellitus (T2DM). Evidence suggests a strong association between duration and degree of hyperglycemia and vascular disease. However, large trials failed to show cardiovascular benefit after intensive glycemic control, especially in patients with longer diabetes duration. Atherosclerosis is a chronic and progressive disease, with a long asymptomatic phase. Subclinical atherosclerosis, which is impaired in T2DM, includes impaired vasodilation, increased coronary artery calcification (CAC), carotid intima media thickness, arterial stiffness, and reduced arterial elasticity. Each of these alterations is represented by a marker of subclinical atherosclerosis, offering a cost-effective alternative compared to classic cardiac imaging. Their additional use on top of traditional risk assessment strengthens the predictive risk for developing coronary artery disease (CAD). We, herein, review the existing literature on the effect of glycemic control on each of these markers separately. Effective glycemic control, especially in earlier stages of the disease, attenuates progression of structural markers like intima-media thickness and CAC. Functional markers are improved after use of newer anti-diabetic agents, such as incretin-based treatments or sodium-glucose co-transporter-2 inhibitors, especially in T2DM patients with shorter disease duration. Larger prospective trials are needed to enhance causal inferences of glycemic control on clinical endpoints of CAD.

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Assessment of dapagliflozin effect on diabetic endothelial dysfunction of brachial artery (ADDENDA-BHS2 trial): rationale, design, and baseline characteristics of a randomized controlled trial

Cited by 9 publications

References 57 publications

Dapagliflozin effect on endothelial dysfunction in diabetic patients with atherosclerotic disease: a randomized active-controlled trial

Dapagliflozin effect on endothelial dysfunction in diabetic patients with atherosclerotic disease: a randomized active-controlled trial

Dapagliflozin increases the lean-to total mass ratio in type 2 diabetes mellitus

Effect of glycemic control on markers of subclinical atherosclerosis in patients with type 2 diabetes mellitus: A review

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