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

Scholtes, Rosalie A.; Muskiet, Marcel H.A.; Baar, Michiel J. B. van; Hesp, Anne C.; Greasley, Peter J.; Karlsson, Cecilia; Hammarstedt, Ann; Arya, Niki; Raalte, Daniël H. van; Heerspink, Hiddo J.L.

doi:10.2337/dc20-2604

Cited by 82 publications

(98 citation statements)

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“…It is also of interest that dapagliflozin did not induce a significant diuretic effect, as reflected in 24-h urinary volumes. The lack of persistent natriuretic and diuretic effects of SGLT2 inhibitors has been documented before, 4,10 including in a study with controlled sodium intake, 11 There is also the possibility that patients consumed less salt after 12 weeks of treatment because of the new sodium balance achieved.…”

Section: *# *#mentioning

confidence: 90%

“…SGLT2 inhibitors also induce natriuresis by inhibiting transport of one sodium ion for every molecule of glucose excreted. However, this effect is also transient, owing to compensatory mechanisms that increase sodium reabsorption at other nephron sites 3–6 . Clearly, therefore, we have to investigate other avenues to explain the antihypertensive action of these drugs, which might contribute to the beneficial effects of these drugs on cardiovascular outcomes.…”

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confidence: 99%

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Dapagliflozin reduces systolic blood pressure and modulates vasoactive factors

Ghanim

Batra

Green

et al. 2021

Diabetes Obesity Metabolism

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Aim: To investigate the mechanisms underlying improvements in blood pressure (BP) and congestive heart failure outcomes following treatment with dapagliflozin, a sodium-glucose co-transporter-2 inhibitor.Research Design and Methods: A total of 52 patients with type 2 diabetes (T2D) with an HbA1c of less than 8% participated in this prospective, double-blind and placebo-controlled study. Patients were randomized (1:1) to either dapagliflozin 10 mg daily or placebo for 12 weeks. Half the patients were also monitored for 6 h following their first dose for acute effects on BP. Blood and urine samples were collected and levels of angiotensinogen, angiotensin II, renin, aldosterone, endothelin-1, atrial natriuretic peptide (ANP), brain natriuretic peptide, cyclic adenosine monophosphate, cyclic guanosine monophosphate (cGMP) and neprilysin were measured. The expression of angiotensin-converting enzyme, guanylate cyclase and phosphodiesterase 5 (PDE5) was measured in circulating mononuclear cells (MNC).Results: A total of 24 and 23 patients receiving dapagliflozin and placebo, respectively, completed the 12-week study. Systolic BP decreased significantly, compared with placebo, both after single-dose (by 7 ± 3 mmHg) and 12-week (by 7 ± 2 mmHg) treatment with dapagliflozin. Dapagliflozin suppressed angiotensin II and angiotensinogen (by 10.5 ± 2.1 and 1.45 ± 0.42 μg/mL, respectively) and increased ANP and cGMP (by 34 ± 11 and 29 ± 11 pmol/mL, respectively) compared with the placebo group. cGMP levels also increased acutely following a single dose of dapagliflozin. Dapagliflozin also suppressed PDE5 expression by 26% ± 11% in MNC. There were no changes observed in the other vasoactive mediators investigated.Conclusions: Dapagliflozin administration in T2D resulted in both acute and chronic reduction in systolic BP, a reduction in vasoconstrictors and an increase in vasodilators. These changes may potentially contribute to its antihypertensive effects and its benefits in congestive cardiac failure.

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confidence: 90%

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confidence: 99%

Dapagliflozin reduces systolic blood pressure and modulates vasoactive factors

Ghanim

Batra

Green

et al. 2021

Diabetes Obesity Metabolism

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“…Activation of tubuloglomerular feedback is a result of SGLT2 inhibitor ability to block sodium and glucose reabsorption in the proximal tubules resulting in a modest diuresis 26,27 . Glucosuria is sustained and appears to account for the increase in urine volume observed, whereas natriuresis is inconsistently observed and when present is modest and unsustained 28–30 . The reduction in plasma volume and resultant hemoconcentration have been suggested to be the most important mediator of CV risk reduction seen in the EMPA‐REG OUTCOME trial 31 .…”

Section: Discussionmentioning

confidence: 99%

Impact of SGLT2 inhibitors on cardiovascular outcomes in patients with heart failure with reduced ejection fraction

et al. 2021

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Heart failure (HF) impacts more than 6 million Americans with an annual mortality rate approaching 22%. Along with optimizing guideline‐directed management and therapy (GDMT), the development of treatment options to improve mortality and morbidity in patients with HF with reduced ejection fraction (HFrEF) is paramount. Cardiovascular outcome trials in patients with type 2 diabetes have shown that sodium‐glucose cotransporter‐2 (SGLT2) inhibitors improve both cardiovascular (CV) and renal outcomes and have consistently reduced hospitalizations for HF in patients with and without a previous history of HF. A precise mechanism by which SGLT2 inhibitors provide benefits for patients with HFrEF has not been identified, and it is probable that multiple pathways may best explain the outcomes seen in recent clinical trials. The mounting evidence that SGLT2 inhibitors reduce HF‐related hospitalizations in patients with type 2 diabetes led to the publication of two pivotal trials, the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA‐HF) trial and the Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure (EMPEROR‐Reduced) trial. Data from these publications demonstrate significant benefit of dapagliflozin and empagliflozin on a variety of CV and HF quality of life end points in patients with HFrEF independent of the presence of type 2 diabetes. Now, widespread application of the clinical findings from the DAPA‐HF and EMPEROR‐Reduced trials must follow with SGLT2 inhibitors incorporated into GDMT for HFrEF regardless of the presence or absence of diabetes. In this review, we examine key literature surrounding the CV outcome data for SGLT2 inhibitors with a specific focus on patients with HFrEF.

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“…The lower blood pressure was not accompanied by natriuresis but was associated with increased renal expression of HIF-1α and the amelioration of renal inflammation. The recent DAPASALT trial also reported that dapagliflozin produced no significant natriuresis in association with its blood pressure lowering effect [125], which is compatible with the roles of inflammation, oxidative stress, and vascular dysfunction in hypertension [126]. In a rat model of angiotensin IIdependent hypertension, on the other hand, empagliflozin did not affect blood pressure but did prevent the development of renal glomerulosclerosis, tubulointerstitial fibrosis, an increase in inflammatory infiltrates, and the expression of collagen types I and IV [127].…”

Section: Chronic Kidney Diseasementioning

confidence: 99%

Use of Anti-Diabetic Agents in Non-Diabetic Kidney Disease: From Bench to Bedside

Chung

Kim

2021

Life

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New drugs were recently developed to treat hyperglycemia in patients with type 2 diabetes mellitus (T2D). However, metformin remains the first-line anti-diabetic agent because of its cost-effectiveness. It has pleiotropic action that produces cardiovascular benefits, and it can be useful in diabetic nephropathy, although metformin-associated lactic acidosis is a hindrance to its use in patients with kidney failure. New anti-diabetic agents, including glucagon-like peptide-1 receptor (GLP-1R) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose transporter-2 (SGLT-2) inhibitors, also produce cardiovascular or renal benefits in T2D patients. Their glucose-independent beneficial actions can lead to cardiorenal protection via hemodynamic stabilization and inflammatory modulation. Systemic hypertension is relieved by natriuresis and improved vascular dysfunction. Enhanced tubuloglomerular feedback can be restored by SGLT-2 inhibition, reducing glomerular hypertension. Patients with non-diabetic kidney disease might also benefit from those drugs because hypertension, proteinuria, oxidative stress, and inflammation are common factors in the progression of kidney disease, irrespective of the presence of diabetes. In various animal models of non-diabetic kidney disease, metformin, GLP-1R agonists, DPP-4 inhibitors, and SGLT-2 inhibitors were favorable to kidney morphology and function. They strikingly attenuated biomarkers of oxidative stress and inflammatory responses in diseased kidneys. However, whether those animal results translate to patients with non-diabetic kidney disease has yet to be evaluated. Considering the paucity of new agents to treat kidney disease and the minimal adverse effects of metformin, GLP-1R agonists, DPP-4 inhibitors, and SGLT-2 inhibitors, these anti-diabetic agents could be used in patients with non-diabetic kidney disease. This paper provides a rationale for clinical trials that apply metformin, GLP-1R agonists, DPP-4 inhibitors, and SGLT-2 inhibitors to non-diabetic kidney disease.

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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

Cited by 82 publications

References 38 publications

Dapagliflozin reduces systolic blood pressure and modulates vasoactive factors

Dapagliflozin reduces systolic blood pressure and modulates vasoactive factors

Impact of SGLT2 inhibitors on cardiovascular outcomes in patients with heart failure with reduced ejection fraction

Use of Anti-Diabetic Agents in Non-Diabetic Kidney Disease: From Bench to Bedside

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