scholarly journals Natriuretic Effect of Two Weeks of Dapagliflozin Treatment in Patients With Type 2 Diabetes and Preserved Kidney Function During Standardized Sodium Intake: Results of the DAPASALT Trial

2020 ◽  
Author(s):  
Rosalie A. Scholtes ◽  
Marcel H.A. Muskiet ◽  
Michiel .J.B. van Baar ◽  
Anne C. Hesp ◽  
Peter J. Greasley ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Type 2 Diabetes ◽  
Kidney Function ◽  
Plasma Volume ◽  
Sodium Excretion ◽  
Sodium Intake ◽  
Extracellular Volume ◽  
Treatment Change ◽  
Urinary Glucose

<b>Background: </b> <p>Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce risk for heart failure hospitalization, potentially by inducing sodium excretion, osmotic diuresis and plasma volume contraction. Few studies have investigated this hypothesis, but none have assessed cumulative sodium excretion with SGLT2 inhibition during standardized sodium intake in patients with type 2 diabetes. </p> <p><b>Methods: </b></p> <p>DAPASALT (NCT03152084) was a mechanistic, non-randomized, open-label study in patients with type 2 diabetes with preserved kidney function, on a controlled standardized sodium diet (150 mmol/day). It evaluated the effects of dapagliflozin on sodium excretion, 24-hour blood pressure, and extracellular, intracellular and plasma volumes at start of treatment (ST; days 2-4), end of treatment (ET; days_12-14) and at follow-up (FU; days_15-18). </p> <p><b>Results:</b> </p> <p>Fourteen patients were included in the efficacy analysis. Mean [SD] baseline sodium excretion (150 [32] mmol/24-hours), did not significantly change during treatment (change at ST: -7.0 mmol/24-hours [95%CI: -22.4, 8.4]; change at ET 2.1 mmol/24-hours [95%CI: -28.8, 33.0]). Mean (SD) baseline 24-hour systolic blood pressure was 128 (10) mmHg and significantly reduced at ST (-6.1 mmHg [95%CI: -9.1, -3.1]; p<0.001) and ET (-7.2 mmHg [95%CI: -10.0, -4.3]; p<0.001). Dapagliflozin did not significantly alter plasma volume or intracellular volume, while extracellular volume changed at ST (-0.7 L [95%CI: -1.3, 0.1]; p=0.02). As expected, 24-hour urinary glucose excretion significantly increased during dapagliflozin treatment and reversed during FU. </p> <p><b>Conclusions:</b></p> <p>During standardized sodium intake, dapagliflozin reduced blood pressure without clear changes in urinary sodium excretion, suggesting that factors other than natriuresis and volume changes may contribute to the blood-pressure lowering effects. </p>

scholarly journals Natriuretic Effect of Two Weeks of Dapagliflozin Treatment in Patients With Type 2 Diabetes and Preserved Kidney Function During Standardized Sodium Intake: Results of the DAPASALT Trial

2020 ◽  
Author(s):  
Rosalie A. Scholtes ◽  
Marcel H.A. Muskiet ◽  
Michiel .J.B. van Baar ◽  
Anne C. Hesp ◽  
Peter J. Greasley ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Type 2 Diabetes ◽  
Kidney Function ◽  
Plasma Volume ◽  
Sodium Excretion ◽  
Sodium Intake ◽  
Extracellular Volume ◽  
Treatment Change ◽  
Urinary Glucose

<b>Background: </b> <p>Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce risk for heart failure hospitalization, potentially by inducing sodium excretion, osmotic diuresis and plasma volume contraction. Few studies have investigated this hypothesis, but none have assessed cumulative sodium excretion with SGLT2 inhibition during standardized sodium intake in patients with type 2 diabetes. </p> <p><b>Methods: </b></p> <p>DAPASALT (NCT03152084) was a mechanistic, non-randomized, open-label study in patients with type 2 diabetes with preserved kidney function, on a controlled standardized sodium diet (150 mmol/day). It evaluated the effects of dapagliflozin on sodium excretion, 24-hour blood pressure, and extracellular, intracellular and plasma volumes at start of treatment (ST; days 2-4), end of treatment (ET; days_12-14) and at follow-up (FU; days_15-18). </p> <p><b>Results:</b> </p> <p>Fourteen patients were included in the efficacy analysis. Mean [SD] baseline sodium excretion (150 [32] mmol/24-hours), did not significantly change during treatment (change at ST: -7.0 mmol/24-hours [95%CI: -22.4, 8.4]; change at ET 2.1 mmol/24-hours [95%CI: -28.8, 33.0]). Mean (SD) baseline 24-hour systolic blood pressure was 128 (10) mmHg and significantly reduced at ST (-6.1 mmHg [95%CI: -9.1, -3.1]; p<0.001) and ET (-7.2 mmHg [95%CI: -10.0, -4.3]; p<0.001). Dapagliflozin did not significantly alter plasma volume or intracellular volume, while extracellular volume changed at ST (-0.7 L [95%CI: -1.3, 0.1]; p=0.02). As expected, 24-hour urinary glucose excretion significantly increased during dapagliflozin treatment and reversed during FU. </p> <p><b>Conclusions:</b></p> <p>During standardized sodium intake, dapagliflozin reduced blood pressure without clear changes in urinary sodium excretion, suggesting that factors other than natriuresis and volume changes may contribute to the blood-pressure lowering effects. </p>

scholarly journals Natriuretic effect of 2 weeks of dapagliflozin treatment in patients with type 2 diabetes and preserved kidney function: results of the DAPASALT trial

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
R Scholtes ◽  
M.H.A Muskiet ◽  
M.J.B Van Baar ◽  
P.J Greasley ◽  
C Karlsson ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Type 2 Diabetes ◽  
Steady State ◽  
Sodium Excretion ◽  
Sodium Intake ◽  
Sodium Balance ◽  
Funding Source ◽  
Treatment Change ◽  
Glucose Excretion

Abstract Background Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce the risk for heart failure hospitalization, potentially by inducing sodium excretion, osmotic diuresis and plasma volume contraction, leading to more favorable systemic hemodynamic function. However, this hypothesis has never been formally investigated as no studies have assessed cumulative sodium excretion with SGLT2 inhibition during standardized sodium intake. Methods We conducted a mechanistic open label study in patients with type 2 diabetes mellitus (T2D) with preserved kidney function, who were receiving a standardized sodium intake (150 mmol/day) to evaluate the acute effects (average day 2–4), effects at steady state (average day 12–14) and effects during three days wash-out of dapagliflozin on sodium balance and blood pressure. Primary outcome measure was 24-hr sodium excretion during the acute phase. Secondary outcomes included 24-hr glucose excretion and 24-hr blood pressure at each time period and sodium excretion at steady state and during follow-up. Results Seventeen patients with T2D were enrolled (64.7% male, mean ± SD age 64.24±7.33 years, weight 99.54±17.36 kg, eGFR 94.53±10.10 mL/min/1.73m2, HbA1c 7.20±0.63%). Average sodium excretion at baseline was 147±32 mmol/24 hr, which did not significantly change during treatment (Change at day 2–4 [95% CI]: −5.21 [19.54, 9.12] mmol/24 hr; Change at Day 12–14 [95% CI]: 3.69 [−24.82, 32.20] mmol/24 hr). However, sodium excretion was reduced following washout compared to end of treatment (Change at Day 15–17 [95% CI]: −16.72 [−34.11, 0.66] mmol/24 hr). Glucose excretion was significantly increased throughout the study. Systolic blood pressure was 127.0±10.3 mmHg at baseline and significantly reduced at Day 3 [95% CI]: −5.27 [−8.55, −1.99] mmHg and Day 14 [95% CI]: −7.10 [−10.04, −4.16] mmHg compared to baseline and remained lower following washout. Conclusions This study shows that, during a standardized sodium intake, the SGLT-2 inhibitor dapagliflozin acutely reduces blood pressure without altering sodium excretion, indicating possible direct vascular effects independent of sodium balance. Funding Acknowledgement Type of funding source: Other. Main funding source(s): Astra Zeneca

Abstract 16709: Contrasting Influences of Renal Function on Blood Pressure and HbA1c Reductions With Empagliflozin in Patients With Type 2 Diabetes and Hypertension

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
David Cherney ◽  
Mark Cooper ◽  
Ilkka Tikkanen ◽  
Susanne Crowe ◽  
Odd Erik Johansen ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Type 2 Diabetes ◽  
Renal Function ◽  
Controlled Trial ◽  
Phase Iii ◽  
Vascular Effects ◽  
Antihypertensive Medications ◽  
Urinary Glucose ◽  
The Impact

The sodium glucose cotransporter 2 inhibitor empagliflozin (EMPA) reduces HbA1c, weight and blood pressure (BP) in patients with type 2 diabetes (T2D). While glucose lowering with EMPA is dependent on renal function, the impact of chronic kidney disease (CKD) on BP reduction with EMPA is less well understood. Our aim was to determine if impaired renal function attenuates antihypertensive effects of EMPA. A Phase III randomized placebo (PBO)-controlled trial (EMPA-REG BP™) investigated the efficacy and safety of EMPA in patients with T2D and hypertension (defined as mean seated office systolic BP [SBP] 130-159 mmHg and diastolic BP [DBP] 80-99 mmHg at screening). Patients (mean [SD] age 60.2 [9.0] years, HbA1c 7.90 [0.74] %, 24-hour SBP 131.4 [12.3] and 24-hour DBP 75.0 [7.8] mmHg) received EMPA 10 mg (n=276), EMPA 25 mg (n=276) or PBO (n=271) once daily for 12 weeks. We assessed changes from baseline in mean ambulatory 24-hour SBP and HbA1c in subgroups by baseline eGFR (MDRD equation), adjusting for differences in baseline mean 24-hour SBP (for SBP analyses only), HbA1c, region, number of antihypertensive medications, treatment, eGFR and treatment by eGFR interaction between groups. In patients with normal renal function, or stage 2 or 3 CKD, EMPA significantly reduced HbA1c and mean 24-hour SBP vs PBO (Table). As expected, PBO-corrected HbA1c reductions with EMPA appeared to decrease with decreasing eGFR (Table). In contrast, PBO-corrected reductions in mean 24-hour SBP with EMPA mostly appeared to increase with decreasing eGFR (Table). Unlike HbA1c, mean 24-hour SBP reductions with EMPA in patients with T2D and hypertension appear to be greater in patients with lower eGFR, indicating that SBP modulation with EMPA may involve pathways other than urinary glucose excretion such as diuretic effects, weight loss, improved glycemic control, reduced arterial stiffness or direct vascular effects.

Effect of Salt Supplementation on Sympathetic Activity and Endothelial Function in Salt-Sensitive Type 2 Diabetes

2019 ◽  
Vol 105 (4) ◽  
pp. e1187-e1200 ◽  
Author(s):  
Sara Baqar ◽  
Yee Wen Kong ◽  
Angela X Chen ◽  
Christopher O’Callaghan ◽  
Richard J MacIsaac ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Type 2 Diabetes ◽  
Endothelial Function ◽  
Augmentation Index ◽  
Sodium Intake ◽  
Blood Pressure Monitoring ◽  
Muscle Sympathetic Nerve Activity ◽  
Burst Frequency ◽  
Low Sodium

Abstract Context Lower sodium intake is paradoxically associated with higher mortality in type 2 diabetes (T2D). Objective To determine whether sympathetic nervous system (SNS) activation and endothelial dysfunction contribute to these observations, we examined the effect of salt supplementation on these systems in people with T2D with habitual low sodium. We hypothesized that salt supplementation would lower SNS activity and improve endothelial function compared to placebo. Design We conducted a randomized, double-blinded, placebo-controlled crossover trial. Setting The study took place in a tertiary referral diabetes outpatient clinic. Participants Twenty-two people with T2D with habitual low sodium intake (24-hour urine sodium &lt;150 mmol/24h) were included. Intervention Salt supplementation (100 mmol NaCl/24h) or placebo for 3 weeks was administered. Main outcome measures The primary outcome of SNS activity and endothelial function was assessed as follows: Microneurography assessed muscle sympathetic nerve activity (MSNA), pulse amplitude tonometry assessed endothelial function via reactive hyperemic index (RHI), and arterial stiffness was assessed via augmentation index (AI). Secondary outcomes included cardiac baroreflex, serum aldosterone, ambulatory blood pressure monitoring (ABPM), heart rate variability (HRV), and salt sensitivity. Results Compared to placebo, salt supplementation increased MSNA (burst frequency P = .047, burst incidence P = .016); however, RHI (P = .24), AI (P = .201), ABPM (systolic P = .09, diastolic P = .14), and HRV were unaffected. Salt supplementation improved baroreflex (slope P = .026) and lowered aldosterone (P = .004), and in salt-resistant individuals there was a trend toward improved RHI (P = .07). Conclusions In people with T2D and low habitual sodium intake, salt supplementation increased SNS activity without altering endothelial function or blood pressure but improved baroreflex function, a predictor of cardiac mortality. Salt-resistant individuals trended toward improved endothelial function with salt supplementation.

Abstract 16107: Combined HbA1c and Systolic Blood Pressure Reduction With Dapagliflozin in Patients With Both Inadequately Controlled Type 2 Diabetes Mellitus and Hypertension

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Michael A Weber ◽  
James List ◽  
Traci A Mansfield ◽  
Shamik J Parikh ◽  
Agata Ptaszynska
Keyword(s):  
Diabetes Mellitus ◽  
Blood Pressure ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Systolic Blood Pressure ◽  
Enzyme Inhibitor ◽  
Blood Pressure Reduction ◽  
Glucose Lowering ◽  
Urinary Glucose

Background: Hypertension is a common comorbidity in patients with type 2 diabetes mellitus (T2DM). Initial treatment is usually with an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), with other antihypertensive therapies (AHTs) added if needed. Dapagliflozin (DAPA) increases urinary glucose excretion accompanied by diuresis and weight loss, which contributes to blood pressure (BP) reduction. Here we evaluate the proportions of patients achieving combined HbA1c and systolic blood pressure (SBP) reduction with DAPA in two studies of patients with both inadequately controlled T2DM and hypertension. Methods: Patients with both inadequately controlled T2DM (HbA1c 7.0-10.5%) and hypertension (seated SBP / diastolic BP: 140-164 / 85-104 mmHg) despite receiving glucose-lowering drugs and an ACEi or ARB (Study 1) plus a 2nd AHT agent (Study 2) were randomized to receive double-blind DAPA 10 mg or placebo for 12 weeks. Primary results have been presented previously; here we present proportions of patients achieving combined changes from baseline (Δ) in HbA1c and SBP. Results: In Study 2, additional AHT drugs were thiazide/thiazide-like diuretics (~44%), calcium channel blockers (~27%), and beta blockers (~27%). Across both studies, 520 and 522 patients had available paired ΔHbA1c and ΔSBP values in the DAPA and placebo groups, respectively. More patients achieved combined ΔHbA1c and ΔSBP reduction with DAPA (n=325; 62.5%) vs placebo (n=190; 36.4%) (Figure - dotted boxes). Considering more stringent thresholds, more patients achieved combined reductions in ΔHbA1c of ≥0.5% and ΔSBP of ≥5 mmHg with DAPA (n=194; 37.3%) vs placebo (n=86; 16.5%) (Figure - solid boxes). Conclusions: In T2DM patients with hypertension on glucose-lowering therapies and an ACEi or ARB ± 1 additional AHT, adding dapagliflozin achieved clinically significant combined HbA1c and SBP reductions over 12 weeks in greater numbers of patients than placebo.

scholarly journals Comparison of endothelial function and sympathetic nervous system activity along the glucose continuum in individuals with differing metabolic risk profiles and low dietary sodium intake

2019 ◽  
Vol 7 (1) ◽  
pp. e000606 ◽  
Author(s):  
Sara Baqar ◽  
Nora E Straznicky ◽  
Gavin Lambert ◽  
Yee Wen Kong ◽  
John B Dixon ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Type 2 Diabetes ◽  
Heart Rate ◽  
Glucose Tolerance ◽  
Endothelial Function ◽  
Sodium Intake ◽  
Metabolic Risk ◽  
Low Sodium ◽  
Sympathetic Nervous

Objective: Low sodium intake may trigger sympathetic nervous system (SNS) activation and endothelial dysfunction. Studies have not explored these associations along the glucose continuum. Accordingly, we compared endothelial function and SNS activity in individuals with low sodium intake and differing categories of metabolic risk along the glucose continuum. We hypothesized that low sodium intake is associated with (1) impairment of endothelial function and (2) higher SNS activity in individuals with higher metabolic risk. Research Design and Methods: In this prospective observational study, participants (n=54) with low sodium intake (single 24 hours urine sodium excretion <150 mmol/24 hours) were categorized based on oral glucose tolerance testing as: normal glucose tolerance (NGT, n=10), impaired glucose tolerance (IGT, n=15), treatment naive type 2 diabetes (T2D−) (n=12) or treated type 2 diabetes (T2D+) (n=17). We assessed endothelial function using pulse amplitude tonometry (PAT) derived reactive hyperemic index and PAT ratio; arterial stiffness via augmentation index; muscle sympathetic nerve activity (MSNA) using microneurography; cardiac baroreflex; heart rate; blood pressure; glycosylated hemoglobin A1c (HbA1c) and lipid profile. Results: Mean (SD) sodium excretion was 110.6 (26) mmol/24 hours. Compared with NGT, IGT and T2D−, the T2D+ group had lower MSNA (p=0.005), PAT ratio (p=0.04) and baroreflex sensitivity (p=0.0002) and an augmented heart rate (p=0.02). The T2D+ group had appropriate mean (SD) glycemic (HbA1c 7.2 (1.72)%), total cholesterol (4.2 (1.0) mmol/L), low-density lipoprotein (2.2 (1.0) mmol/L) and blood pressure (systolic 136 (13), diastolic 78 (12)) (mm Hg) control. Conclusions: Individuals with T2D+ have impaired endothelial and baroreflex function, despite low sodium intake, appropriately managed cardiometabolic risk factors and lower SNS activity, compared with others along the glucose continuum. Whether low sodium intake is associated with modulation of the sympathovascular profile in T2D requires further investigation.

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