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“img class=”responsive ” sizes=”(min-width: 320px) 320px, 100vw” src=”https://mmbiz.qpic.cn/mmbiz_png/x5F5KAyDKw19I4VvcibrfNia7lD1fial5KribXqZxjxMxtoc3ichKKz6ib3w5kJias8QNRBYGn80MM0AxEgOvRLib>p>width=”6400″ >Recently, the journal Circulation published a mechanistic study (BETWEEN study) evaluating the effect of SGLT2i (empagliflozin 25 mg QD) in combination with ACEI (ramipril 10 mg QD) on patients with potential renal hypertension Cardiorenal effects of filtration characteristics in patients with type 1 diabetes mellitus. Let’s take a look together.
Background
Sodium-glucose cotransporter-2 inhibitor (SGLT2i) A finding that reduces the risk of cardiovascular and renal disease in patients with type 2 diabetes mellitus (T2DM) has major implications for clinical practice. SGLT2i reduced the composite of major adverse cardiac events, heart failure hospitalizations and renal endpoints in patients with T2D, and cardiorenal endpoints in patients with proteinuric chronic kidney disease. SGLT2i reduced glycated hemoglobin (HbA1c) by 0.7% to 1.0%, systolic blood pressure (SBP) by 3 to 5 mmHg, and body weight by 2 to 4 kg.
Previous studies have demonstrated that SGLT2i monotherapy is effective in uncomplicated type 1 diabetes (T1DM) Patients had similar effects on glycemic control, body weight and blood pressure, and also significantly reduced renal hyperfiltration. Given the poor prognosis associated with renal hyperfiltration and the renoprotective effect of SGLT2i in experimental models of T1D,SGLT2i may contribute to a protective reduction in intraglomerular hypertension, even in The use of SGLT2i before the onset of clinical chronic kidney disease may also benefit..
Although the mechanistic basis of diabetic glomerular hypertension is very complex, hyperglycemia plays a role in the activation of neurohormones and the effects on renal tubular function. played an important role. First, the hyperfiltered neurohormonal hypothesis suggests that activation of the renin-angiotensin-aldosterone system (RAAS) during hyperglycemia triggers vasoconstriction of output renal arterioles. Furthermore, according to the tubular hypothesis, hyperglycemia-induced overexpression of SGLT2 in the proximal tubule 15 increases sodium (Na+) reabsorption and leads to a decrease in distal Na+ delivery to the densified plaques. This signal is erroneously perceived as a reduction in effective circulating volume, leading to vasodilation of the renal arterioles, resulting in the characteristic hyperfiltration of diabetes.
In an 8-week study of insulin plus adjunctive agents in young patients with uncomplicated T1DM and hyperfiltration , empagliflozin caused a reduction in renal hyperfiltration to a degree comparable to that reported for angiotensin-converting enzyme inhibition (ACEI) in a separate hyperfiltration T1DM cohort. Like monotherapy with a renin-angiotensin-aldosterone system (RAAS) inhibitor (RAASi), SGLT2i did not eliminate hyperfiltration, suggesting potential for these therapies when combined to exploit the neurohormonal and tubular pathways. kidney benefit. Although T1DM is a good model for uncomplicated renal hemodynamic changes attributable to diabetes, this mechanism can also be applied to similar renal hemodynamic changes observed in other settings, such as T2DM disease or obesity disease.
This BETWEEN study was designed to investigate the role of clinical renal or cardiovascular complications in uncomplicated patients with T1DM, T2DM, or obesity Mechanistic model of early cardiorenal physiological changes before development), additional cardiorenal hemodynamic effects of SGLT2i+ACEI combination therapy, in particular neurohormonal inhibition (with ACEi) and tubular activation (SGLT2i) factors.
This trial intends to determine 4 weeks of SGLT2i (empagliflozin 25 mg QD) versus placebo, and ACEi (ramipril 10 mg QD or maximally tolerated dose) on the glomerular filtration rate (GFR).
A secondary objective of this trial was to investigate the effect of adding empagliflozin to ramipril therapy on distal sodium delivery and systemic hemodynamics.
This study hypothesizes that the addition of empagliflozin therapy in the context of ramipril reduces GFR, reduces cardiac output and arterial stiffness, which in turn leads to a decrease in SBP.
Methods
30 patients (out of 31 randomized) completed This double-blind, placebo-controlled crossover trial.
Recruitment was stopped early because the proportion of ultrafiltration patients was much lower than expected.
Measurements were made in each of 6 treatment periods over 19 weeks:
(1) Baseline measurement without treatment;
(2) 4 weeks of ramipril alone;
(3) Empagliflozin-ramipril combination therapy for 4 weeks;
(4) 4-week washout period;
(5) Placebo-ramipril combination therapy for 4 weeks;
(6) 1-week follow-up period.
Primary endpoint:
Compared with placebo-ramipril, en Glomerular filtration rate (GFR) following combination therapy with glipizin-ramipril.
GFR was adjusted for ramipril alone before randomization.
At the end of the study period, the following results were measured under clamp normoglycemia (4-6mmol/L): p>
Inulin (GFR) and p-aminothiopurine (effective renal plasma flow) clearance, renal tubular sodium handling, ambulatory blood pressure, arterial stiffness, heart rate variability, noninvasive cardiac output monitoring, plasma and urine biochemical markers, renin-angiotensin-aldehydeSterone system and markers of oxidative stress.
Figure 1
normal physiological and Hyperfiltration in early stages of renal disease and putative mechanisms following combined inhibition of SGLT2 and RAAS.
Results
Compared with placebo-ramipril treatment,< /span>
empagliflozin-ramipril combination treatment resulted in an 8 mL/min/1.73 reduction in GFRm2 (P=0.0061),
, but there was no significant change in effective renal plasma flow.
Compared with placebo-ramipril combination therapy,
At the same time as GFR decreased,
the absolute value of proximal fluid reabsorption rate decreased by 21.3mL/min (P=0.0092), p>
The absolute value of proximal sodium reabsorption rate decreased by 3.1mmol/min (P=0.0056),
urine 8-isoprostaglandin Levels decreased by 194ng/mmol (P=0.0084).
SGLT2i/ACEI combination therapy produced additional antihypertensive effects: span>
systolic blood pressure decreased by 4mmHg [P=0.0112];
diastolic blood pressure decreased by 3mmHg [P=0.0032],
At the same time, total peripheral resistance decreased by 94.5 dynes×sex/cm5 (P=0.0368).
No significant changes in ambulatory blood pressure, arterial stiffness, heart rate variability, or cardiac output were observed with empagliflozin.
Conclusions
Adding SGLT2i to ACEI would lead to expected A decrease in GFR, inhibition of markers of oxidative stress, a further decrease in blood pressure and a decrease in total peripheral resistance.
When SGLT2i was added to conservative treatment, these changes were consistent with a protective physiology characterized by a reduction in intraglomerular pressure and associated cardiorenal risk.
Review highlights
Innovation< /strong>
This study demonstrates that the addition of Engelatin to ramipril Net 4 weeks improves surrogate markers of renal protection and preserves renal function in uncomplicated type 1 diabetic patients.
The physiological mechanism by which SGLT2i modulates tubular feedback and reduces glomerular hypertension is hypothesized to be ameliorated by the addition of empagliflozin, It is manifested by a decrease in proximal tubular sodium reabsorption and an expected decrease in glomerular filtration rate.
Ramipril combined with empagliflozin treatment reduced blood pressure and total peripheral resistance, but did not affect arterial stiffness, heart rate variability or cardiac output, suggesting a novel SGLT2i-mediated antihypertensive mechanism.
clinical significance strong>
This is the first mechanistic test to evaluate the physiological effects of adding SGLT2i to ACEI , including acute effects on glomerular filtration rate, which were consistent with cardiorenal protection in clinical trials to date that included only patients with type 2 diabetes or non-diabetic nephropathy.
Given the consistency of physiologic effects in different cohorts, including patients with type 1 diabetes, future clinical trials should continue to evaluate whether long-term SGLT2i therapy can Reduce the risk of cardio-renal complications in people at high risk for renal failure or cardiovascular disease.
Source:
Renal and Vascular Effects of Combined SGLT2 and Angiotensin-Converting Enzyme Inhibition. Circulation. 2022;146:00–00. DOI: 10.1161/CIRCULATIONAHA.122.059150
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