*For medical professionals only
“img class=”responsive ” sizes=”(min-width: 320px) 320px, 100vw” src=”https://mmbiz.qpic.cn/mmbiz_png/x5F5KAyDKw19I4VvcibrfNia7lD1fial5KribXqZxjxMxtoc3ichKKz6ib3w5kJias8QNRBYGn80MM0AxEgOvRLibqE2uw/640″ width=”6400″ >Sodium-glucose cotransporter-2 inhibitor (SGLT2i) blocks the reabsorption of glucose in the proximal renal tubules and promotes the production of glucosuria; studies have demonstrated its effect on reducing type 2 diabetes mellitus (T2DM) Patient-specific cardiovascular (CV) events and progression of renal disease were effective.
In several large CV outcome trials in T2DM patient populations, SGLT2i reduced overall CV death or hospitalization for heart The effect is often better than CV death and also prevents the development of kidney disease.
Because of various CV and renal comorbidities in patients with T2DM, commonly used drugs include angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEI/ARBs) , beta-blockers, diuretics, and aldosterone receptor antagonists (MRAs), which also have an impact on HF or kidney disease progression. In addition, since SGLT2i is known to have diuretic and hypotensive effects, there is a theoretical concern that the use of SGLT2i may cause harm when drugs with similar effects are used concurrently.
However, in the large CV outcome trial in patients with T2DM, the study data on any potential treatment interactions between these CV drugs and the risk of efficacy and safety outcomes of SGLT2i limited.
Recently, JAMA Cardiology published the results of a prespecified secondary analysis of the DECLARETIMI 58 trial, which aimed to evaluate the cardio-renal efficacy and safety of dapagliflozin and whether it is related to T2DM. Patient backgrounds were consistent with CV medications commonly used for HF and renal disease.
Study Design
This study is a prespecified secondary analysis of DECLARE-TIMI 58 .
The study was a randomized trial of dapagliflozin versus placebo in 17,160 patients with type 2 diabetes, atherosclerotic disease, or CV disease. Risk factors were studied.
Patients were stratified by baseline using the following CV medications:
Angiotensin conversion Enzyme inhibitors or angiotensin receptor blockers (ACEI/ARBs),
β-blockers,
Diuretics,
aldosterone receptor antagonists (MRAs).
The study was conducted from May 2013 to September 2018, and data were assessed from February 2021 to May 2022 for use in this analysis.
Interventions: Dapagliflozin vs Placebo.
Primary endpoint: CV death or hospitalization for HF (HHF), HHF alone, and a kidney-specific composite endpoint (sustained decline in estimated glomerular filtration rate [eGFR] ≥40%) %, end-stage renal disease, or kidney-related death).
Results
In 17,160 patients, at baseline< /p>
13,950 (81%) were using ACEI/ARBs,
9,030 (53%) were using beta-blockers, < /span>
6205 (36%) used diuretics and
762 (4%) used MRAs.
Dapagliflozin compared with placebo at 48 months of follow-up< /strong>
Changes in blood pressure and eGFR, and concomitant treatments did not differ between groups< /p>
(placebo-adjusted change, -1.6mmHg [95%CI -4.2 – 1.0] to -2.6mmHg [95%CI -3.3 – -2.9]; P>0.05 for each interaction ).
Regardless of background use of the selected drug, p>
Dapagliflozin consistently reduced the risk of the composite of CV death/HHF, HHF alone, and kidney-specific endpoints p>
(hazard ratio [HR] range: 0.50; 95%CI 0.39-0.63; to 0.82; 95%CI 0.72-0.95; P>0.05 for each interaction).
Figure 1 The effect of dapagliflozin on cardiovascular ( CV) death or heart failure (HHF) hospitalization, and its effect on HHF itself, specific renal composite endpoints
In patients receiving ACEI/ARBs + beta-blockers + diuretics (n=4243),
span>
Dapagliflozin reduced the risk of CV death/HF and kidney-specific outcomes by 24% and 38%, respectively.
CV death/HF: 24% (HR 0.76; 95% CI 0.62-0.93);
< p> Kidney-specific results: 38% (HR 0.62; 95% CI 0.44-0.87).
Figure 2 The effect of dapagliflozin on safety endpoints under baseline cardiovascular drug use Effects
In terms of adverse events such as volume depletion, acute kidney injury, or hyperkalemia,
No apparent therapeutic interaction with concomitant CV medications
(range: HR 0.12; 95%CI 0.02-0.99; to HR, 1.04; 95%CI 0.83-1.32; P>0.05 for each interaction).
discuss
although HFrEF Randomized clinical trials of patients (with or without diabetes) show benefit ofSGLT2inhibitors and are widely accepted for treatment< There were no prohibitive safety concerns in the /span>HFbaseline drugHFrEF population, but in the broader HFrEF population Efficacy and safety data on interactions mediated with common CV in a trial in a population of patients with type 2 diabetes mellitus /span>2 scarce.
In the EMPA-REG OUTCOME trial and the CANVAS study, subgroup analyses by background CV medication reported their primary outcome, MACE (CV death, non-fatal myocardial infarction or Nonfatal stroke), in general, did not differ between patients with and without these drugs, but no CV death/HHF, HHF alone, or renal outcomes were reported.
In the CANVAS study, the efficacy of canagliflozin on MACE differed only between patients with and without diuretics at baseline. In the VERTIS CV trial, a subgroup analysis of CV death/HHF outcomes by background CV drug use was reported, although itogliflozin did not reduce the risk of CV death/HHF in the overall trial population, therefore, treatment interaction The evaluation of the effect is not reliable. The current analysis, which is dedicated to investigating the effects of dapagliflozin on HF and renal outcomes, and its safety in concomitant use with CV drugs, may help inform clinical practice.
Renin-angiotensin-aldosterone system (RAAS) inhibitors, including ACEIs, ARBs, and MRAs, are the most widely used class of Antihypertensive drugs, with strong effects on major CV events, renal disease progression, and mortality outcomes. Previous studies have shown that the use of ACEI/ARBs in combination with diuretics may increase the risk of acute kidney injury. The results of this study showed that dapagliflozin reduced the overall risk of acute kidney injury in patients with type 2 diabetes, and this reduction was consistent regardless of background CV medications, including RAAS inhibitors and diuretics.
Since SGLT2 absorbs sodium in addition to glucose in the proximal renal tubule, inhibition of SGLT2 results in diuresis, as well as increased urine glucose and concomitant water excretion. Therefore, SGLT2i has diuretic and antihypertensive effects, which raises concerns about the possible harm of concomitant use of diuretics. However, in a sub-study of the DAPA-HF trial, the benefit, tolerability, and safety of dapagliflozin did not differ regardless of background diuretic therapy and within the background dose range of diuretics used in patients with HFrEF, Although there was no difference in diuretic dose between the dapagliflozin and placebo groups after randomization. The results of this study also showed that dapagliflozin had a similar effect on CV outcomes in patients with type 2 diabetes who received and did not receive diuretics. However, the favorable effect of dapagliflozin on kidney-specific composite outcomes appeared to be relatively greater in the subgroup of patients not taking any diuretics (P=0.003 for interaction). Although this may be an accidental finding and should be interpreted with caution, it may be relevant to the patient population taking diuretics. This may be related to the patient population taking diuretics and to the underlying renal protective mechanism of SGLT2 inhibitors.
Study Conclusions
With or without the use of variousCV drugs, dapagliflozinbothsustainably reducedCVand renal span>prognosisrisk without any treatment interaction on critical safety events.
These data demonstrate a clinical benefit and safety profile of dapagliflozin in a broad range of patients with type 2 diabetes, regardless of background therapy.
Review of Key Points
Research Questions< /strong>:Cardiorenal benefit of SGLT2i dapagliflozin in patients with type 2 diabetes, regardless of whether they received cardiovascular (CV) drugs commonly used in heart failure and renal disease Is it consistent with security?
Study Results:Dapagliflozin continued Reduced composite risk of CV death or hospitalization for heart failure (HHF), HHF alone, and progression of renal disease, with or without other CV drugs (including ACEi/ARBs, beta-blockers, diuretics, and MRAs) and without any treatment Interactive critical security events.
Research implications: These data demonstrate a favorable clinical benefit and safety profile of dapagliflozin in a broad range of patients with type 2 diabetes, regardless of background therapy.
Source:
Efficacy and Safety of Dapagliflozin According to Background Use of Cardiovascular Medications in Patients With Type 2 Diabetes: A Prespecified Secondary Analysis of a Randomized Clinical Trial. JAMA Cardiol.2022 Jul 20. DOI: 10.1001/jamacardio.2022.2006.
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