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Background: In the DAPA-HF trial, the SGLT2 inhibitor dapagliflozin reduced the risk of worsening heart failure and death in patients with heart failure and reduced ejection fraction. We examined efficacy and tolerability of dapagliflozin in relation to background diuretic treatment and change in diuretic therapy following randomization to dapaglif...
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Context 1
... mean (SD) furosemide-equivalent dose in patients taking any diuretic was 57.0 (94.4) mg; in patients taking a loop diuretic, it was 59.9 (95.9) mg, with no statistically significant difference between treatment groups (Table 2). There was no change in the loop diuretic dose in most patients at 2 weeks and at 2, 6, 12, and 18 months (97.1%, 91.4%, 83.3%, 77.2%, and 73.6%, respectively); this was the case in patients randomized to placebo or dapagliflozin. ...Context 2
... mean (SD) furosemide-equivalent dose in patients taking any diuretic was 57.0 (94.4) mg; in patients taking a loop diuretic, it was 59.9 (95.9) mg, with no statistically significant difference between treatment groups (Table 2). There was no change in the loop diuretic dose in most patients at 2 weeks and at 2, 6, 12, and 18 months (97.1%, 91.4%, 83.3%, 77.2%, and 73.6%, respectively); this was the case in patients randomized to placebo or dapagliflozin. ...Similar publications
Aims:
Concern about hypotension often leads to withholding of beneficial therapy in patients with heart failure and reduced ejection fraction (HFrEF). We evaluated the efficacy and safety of dapagliflozin, which lowers systolic blood pressure (SBP),according to baseline SBP in Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial...
Aims
We examined the efficacy and safety of dapagliflozin, compared with placebo, according to aetiology in patients with heart failure (HF) with reduced ejection fraction (HFrEF) enrolled in the Dapagliflozin And Prevention of Adverse‐outcomes in Heart Failure trial (DAPA‐HF).
Methods and results
Aetiology was investigator‐reported and categorize...
Citations
... This is better than the findings from the DAPA-HF trial, where dapagliflozin was only administered to patients after their treatment had already been optimized and only 10.4% of patients had their diuretic dose reduced at six months. [5] Dapagliflozin decreased cardiovascular mortality or deterioration in individuals with HF and had a modestly reduced or preserved ejection fraction. These are significant benefits as ACEI are used only to relieve congestion symptoms and improve exercise capacity without reducing mortality. ...
Background: The prevalence of heart failure with mildly reduced or preserved ejection fraction (HFpEF) markedly increases with age, with older individuals disproportionately facing excess risk for mortality and hospitalization. To determine the efficacy and safety of dapagliflozin across the age spectrum among Indian population in patients with heart failure with preserved ejection fraction (LVEf >40%). Materials and Methods: This was an Observational study involving 100 patients with HFpEF initiated on dapagliflozin in both the inpatient and outpatient settings for a period of 1 year at NSCB medical college, Jabalpur (M.P.) and were divided according to age. Data were collected, managed and analysed and critically reviewed to ensure accuracy and completeness of the data analysis. All patients were required to have an echocardiogram for assessment of left ventricular ejection fraction (LVEF) ≤40%, or confirmed HFpEF (LVEF >40%), and initiated on dapagliflozin for the management of HFpEF in either the inpatient or outpatient setting along with other guideline directed medical therapy (GDMT). No patients with type 1 diabetes mellitus were included in this study and hospitalized participants were enrolled in the study. Result: Dapagliflozin consistently reduced the risk of the primary outcome across all age categories. Older patient were more frequently females and systolic blood pressure and in patients with atrial fibrillation were higher, and history of atrial fibrillation or flutter, hypertension, chronic obstructive pulmonary disease, and prior stroke were more common with higher age. Type 2 diabetes was more common among patients in the age categories 55 to 64 and 65 to 74 than in patients <55 and ≥75 years of age. Conclusion: In clinical practice, early initiation of dapagliflozin is safe, well-tolerated and resulted in earlier discontinuation or dose reduction in medications, providing opportunities to further optimise other HF medicines.
... The current study showed that renin, aldosterone, and epinephrine levels were similar regardless of conventional diuretic use, which may contribute to long-term cardiorenal protection even in patients receiving combination therapy [19] ( Figure 5B). On the other hand, a subgroup analysis of the DAPA-HF trial and other real-world data showed that volume depletion events were significantly more common with dapagliflozin at higherdose diuretics (furosemide or furosemide equivalent more than 40 mg) [64,65]. Therefore, lower-dose diuretics (furosemide equivalents less than 40 mg) may be an important safeguard against hypovolemia, which prevents the activation of the RAAS and SNS. ...
We previously reported that sodium–glucose cotransporter 2 (SGLT2) inhibitors exert sustained fluid homeostatic actions through compensatory increases in osmotic diuresis-induced vasopressin secretion and fluid intake. However, SGLT2 inhibitors alone do not produce durable amelioration of fluid retention. In this study, we examined the comparative effects of the SGLT2 inhibitor dapagliflozin (SGLT2i group, n = 53) and the combined use of dapagliflozin and conventional diuretics, including loop diuretics and/or thiazides (SGLT2i + diuretic group, n = 23), on serum copeptin, a stable, sensitive, and simple surrogate marker of vasopressin release and body fluid status. After six months of treatment, the change in copeptin was significantly lower in the SGLT2i + diuretic group than in the SGLT2i group (−1.4 ± 31.5% vs. 31.5 ± 56.3%, p = 0.0153). The change in the estimated plasma volume calculated using the Strauss formula was not significantly different between the two groups. Contrastingly, changes in interstitial fluid, extracellular water, intracellular water, and total body water were significantly lower in the SGLT2i + diuretic group than in the SGLT2i group. Changes in renin, aldosterone, and absolute epinephrine levels were not significantly different between the two groups. In conclusion, the combined use of the SGLT2 inhibitor dapagliflozin and conventional diuretics inhibited the increase in copeptin levels and remarkably ameliorated fluid retention without excessively reducing plasma volume and activating the renin–angiotensin–aldosterone and sympathetic nervous systems.
... Older participants (aged > 65 years) included in the CVOT studies typically demonstrated higher rates of volume depletion, compared with younger subgroups, although the overall rates were similar across the treatment and placebo arms in the DECLARE-TIMI (dapagliflozin) and EMPA-REG (empagliflozin) trials [18,53,102]. On the other hand, the CREDENCE and DAPA-CKD studies did not encounter any issues relating to concomitant use of SGLT2is and loop diuretics and some participants in the T2DM subgroups for HF trials (DAPA-HF and EMPEROR-reduced) were taking high-dose diuretics, and no dose reduction was necessary [20,21,28,75,[103][104][105]. ...
A substantial evidence base supports the use of sodium-glucose cotransporter-2 inhibitors (SGLT2is) in the treatment of type 2 diabetes mellitus (T2DM). This class of medicines has demonstrated important benefits that extend beyond glucose-lowering efficacy to protective mechanisms capable of slowing or preventing the onset of long-term cardiovascular, renal and metabolic (CVRM) complications, making their use highly applicable for organ protection and the maintenance of long-term health outcomes. SGLT2is have shown cost-effectiveness in T2DM management and economic savings over other glucose-lowering therapies due to reduced incidence of cardiovascular and renal events. National and international guidelines advocate SGLT2i use early in the T2DM management pathway, based upon a plethora of supporting data from large-scale cardiovascular outcome trials, renal outcomes trials and real-world studies. While most people with T2DM would benefit from CVRM protection through SGLT2i use, prescribing hesitancy remains, potentially due to confusion concerning their place in the complex therapeutic paradigm, variation in licensed indications or safety perceptions/misunderstandings associated with historical data that have since been superseded by robust clinical evidence and long-term pharmacovigilance reporting. This latest narrative review developed by the Improving Diabetes Steering Committee (IDSC) outlines the place of SGLT2is within current evidence-informed guidelines, examines their potential as the standard of care for the majority of newly diagnosed people with T2DM and sets into context the perceived risks and proven advantages of SGLT2is in terms of sustained health outcomes. The authors discuss the cost-effectiveness case for SGLT2is and provide user-friendly tools to support healthcare professionals in the correct application of these medicines in T2DM management. The previously published IDSC SGLT2i Prescribing Tool for T2DM Management has undergone updates and reformatting and is now available as a Decision Tool in an interactive pdf format as well as an abbreviated printable A4 poster/wall chart.
... [28,29] However, in patients with HF and a reduced ejection fraction (HeFREF), neither the use of loop diuretics nor the mean dose of loop diuretic differed between SGLT2I and placebo groups. [30]. ...
Purpose of Review
Fluid retention or congestion is a major cause of symptoms, poor quality of life, and adverse outcome in patients with heart failure (HF). Despite advances in disease-modifying therapy, the mainstay of treatment for congestion—loop diuretics—has remained largely unchanged for 50 years. In these two articles (part I: loop diuretics and part II: combination therapy), we will review the history of diuretic treatment and current trial evidence for different diuretic strategies and explore potential future directions of research.
Recent Findings
We will assess recent trials, including DOSE, TRANSFORM, ADVOR, CLOROTIC, OSPREY-AHF, and PUSH-AHF, and assess how these may influence current practice and future research.
Summary
There are few data on which to base diuretic therapy in clinical practice. The most robust evidence is for high-dose loop diuretic treatment over low-dose treatment for patients admitted to hospital with HF, yet this is not reflected in guidelines. There is an urgent need for more and better research on different diuretic strategies in patients with HF.
... observed that use of dapagliflozin in patients with HF with reduced ejection fraction, on top of mainstay diuretic medication, was safe and did not increase the risk of hypovolaemia and renal adverse events.53 Another less common limitation of diuretics in patients with ascites is the development of reduced sensitivity to atrial natriuretic peptide (ANP) as well as the resistance to loop diuretics in the distal tubular segments.54,55 ...
Type 2 diabetes mellitus (T2DM) and liver cirrhosis are clinical entities that frequently coexist, but glucose‐lowering medication options are limited in cirrhotic patients. Sodium–glucose linked transporter 2 (SGLT2) inhibitors are a class of glucose‐lowering medication that act independently of insulin, by causing glycosuria in the proximal convoluted tubule. In this review, we aimed to briefly present the main data and to provide insight into the pathophysiology and potential usefulness of SGLT2 inhibitors in cirrhotic patients with or without T2DM. SGLT2 inhibitors have been proven useful as antidiabetic treatment in patients with metabolic liver disease, with most robust data from patients with metabolic dysfunction‐associated steatotic liver disease (MASLD), where they also showed improvement in liver function parameters. Moreover, it has been suggested that SGLT2 inhibitors may have effects beyond their antidiabetic action. Accordingly, they have exhibited cardioprotective effects, expanding their indication in patients with heart failure without T2DM. Since decompensated liver cirrhosis and congestive heart failure share common pathophysiological features, namely renin–angiotensin–aldosterone axis and sympathetic nervous system activation as well as vasopressin secretion, SGLT2 inhibitors could also be beneficial in patients with decompensated cirrhosis, even in the absence of T2DM.
... Furosemide is commonly used as a loop diuretic for patients with heart failure. Therefore, our results reflect that patients with severe cardiac outcomes (such as low LVEF) requiring a high dose of furosemide may have a poor prognosis 41 . The same may also be implied in patients receiving high doses of aldosterone within 24 h of their admission, as shown in Fig. 3D. ...
The relationships between acute coronary syndromes (ACS) adverse events and the associated risk factors are typically complicated and nonlinear, which poses significant challenges to clinicians' attempts at risk stratification. Here, we aim to explore the implementation of modern risk stratification tools to untangle how these complex factors shape the risk of adverse events in patients with ACS. We used an interpretable multi-algorithm machine learning (ML) approach and clinical features to fit predictive models to 1,976 patients with ACS in Kuwait. We demonstrated that random forest (RF) and extreme gradient boosting (XGB) algorithms, remarkably outperform traditional logistic regression model (AUCs = 0.84 & 0.79 for RF and XGB, respectively). Our in-hospital adverse events model identified left ventricular ejection fraction as the most important predictor with the highest interaction strength with other factors. However, using the 30-days adverse events model, we found that performing an urgent coronary artery bypass graft was the most important predictor, with creatinine levels having the strongest overall interaction with other related factors. Our ML models not only untangled the non-linear relationships that shape the clinical epidemiology of ACS adverse events but also elucidated their risk in individual patients based on their unique features.
... and HR 0.78; 95% CI, 0.63-0.97, respectively, P for interaction = 0.61) [63]. Another study analyzed whether the benefits of dapagliflozin were consistent in relation to background HF therapy (yes/no): mineralocorticoid receptor antagonist, sacubitril/valsartan, ivabradine, diuretic, digoxin, implanted cardioverter-defibrillating device, and cardiac resynchronization therapy and also according to the dose (≥50% and <50% of target dose): ACEi/ARB, beta blocker, mineralocorticoid receptor antagonist, showing that the benefit of dapagliflozin was independent of background HF therapy [64]. ...
... The relative benefits of dapagliflozin vs. placebo on the primary outcome in the DAPA-HF trial were independent of demographics, comorbidities, physical examination and background therapies. CI: confidence interval; COPD: chronic obstructive pulmonary disease; CV: cardiovascular; HF: heart failure; LVEF: left ventricular ejection fraction; MRA: mineralocorticoid receptor antagonist; HR: Hazard Ratio. Figure performed with data from references[42,48,[51][52][53][54][55][56][57][58][60][61][62][63][64][65][66]68]. ...
Heart failure (HF) is associated with a high morbidity and mortality burden. In light of more recent evidence, SGLT2 inhibitors are currently recommended as first-line therapy in managing patients with HF, regardless of ejection fraction, to reduce HF burden. The DAPA-HF and DELIVER trials, and particularly, the pooled analysis of both studies, have shown that dapagliflozin significantly reduces the risk of cardiovascular death, all-cause death, total HF hospitalizations, and MACE in the whole spectrum of HF, with sustained benefits over time. Recent data have shown that the full implementation of dapagliflozin in clinical practice would translate into a robust reduction in hospitalizations for HF and death in real-life populations. Many pathophysiological mechanisms have been involved in these benefits, particularly the positive effects of dapagliflozin on reversing cardiac (atrial and ventricular) remodeling, reducing cardiac fibrosis and inflammation, and improving endothelial dysfunction. In this manuscript, we reviewed from a practical point of view the role of dapagliflozin in the management of the whole spectrum of patients with HF.
... SGLT2 inhibitors cause natriuresis by inhibition of glucose transport, which is driven by concurrent sodium transport in the proximal convoluted tubule in the kidney [13]. The diuretic/natriuretic properties of SGLT2 inhibitors may offer benefits in reducing congestion and may allow a reduction in loop diuretic requirement [2,80]. HFrEF pre-clinical studies have shown that SGLT2 inhibitors treatment may attenuate edema formation not only through the stimulation of natriuretic and osmotic/diuretic effects, but also through improvement in overall cardiac function, and the suppression of maladaptive cardiac remodeling, chronic inflammation, oxidative stress, and endothelial dysfunction [81]. ...
Heart failure (HF) is a leading cause of morbidity and mortality and a major public health problem. Both overhydration and dehydration are non-physiological states of the body that can adversely affect human health. Congestion and residual congestion are common in patients hospitalized for HF and are associated with poor prognosis and high rates of rehospitalization. However, the clinical problem of dehydration is also prevalent in healthcare and community settings and is associated with increased morbidity and mortality. This article provides a comprehensive review of the issue of congestion and dehydration in HF, including HF guidelines, possible causes of dehydration in HF, confirmed and potential new diagnostic methods. In particular, a full database search on the relationship between dehydration and HF was performed and all available evidence in the literature was reviewed. The novel hypothesis of chronic subclinical hypohydration as a modifiable risk factor for HF is also discussed. It is concluded that maintaining euvolemia is the cornerstone of HF management. Physicians have to find a balance between decongestion therapy and the risk of dehydration.
... Among patients taking a loop diuretic, a total daily dose equivalent to 80 mg of oral furosemide was calculated using the following equivalency: bumetanide 1 mg, torsemide 20 mg, azosemide 60 mg, and ethacrynic acid 100 mg were considered equivalent to 80 mg of oral furosemide. 12,13 When there were missing or insufficient diuretic dose data, patients were excluded at that specific time point and included again at the next available time point. ...
Background: Hospitalization is recognized as a sentinel event in the disease trajectory of patients with heart failure (HF), but not all patients experiencing clinical decompensation are ultimately hospitalized. Outpatient intensification of diuretics is common in response to symptoms of worsening HF, yet its prognostic and clinical relevance, specifically in patient with HF with mildly reduced or preserved ejection fraction is uncertain.
Methods: In this prespecified analysis of the DELIVER trial, we assessed the association between various non-fatal worsening HF events (those requiring hospitalization, urgent outpatient visits requiring intravenous HF therapies, and outpatient oral diuretic intensification) and rates of subsequent mortality. We further examined the treatment effect of dapagliflozin on an expanded composite endpoint of CV death, HF hospitalization, urgent HF visit, or outpatient oral diuretic intensification.
Results: In DELIVER, 4,532 (72%) patients experienced no worsening HF event, while 789 (13%) had outpatient oral diuretic intensification, 86 (1%) required an urgent HF visit, 585 (9%) had a HF hospitalization, and 271 (4%) died of CV causes as a first presentation. Patients with a first presentation manifesting as outpatient oral diuretic intensification experienced rates of subsequent mortality that were higher (10[8-12] per 100py) than those without a worsening HF event (4[3-4] per 100py) but similar to rates of subsequent death following urgent HF visit (10[6-18] per 100py). Patients with a HF hospitalization as a first presentation of worsening HF had the highest rates of subsequent death (35[31-40] per 100py). The addition of outpatient diuretic intensification to the adjudicated DELIVER primary endpoint (CV death, HF hospitalization, or urgent HF visit) increased the overall number of patients experiencing an event from 1,122 to 1,731 (a 54% increase). Dapagliflozin reduced the need for outpatient diuretic intensification alone (HR 0.72; 95% CI: 0.64-0.82) and when analyzed as a part of an expanded composite endpoint of worsening HF or CV death (HR 0.76; 95% CI: 0.69-0.84).
Conclusions: In patients with HF with mildly reduced or preserved ejection fraction, worsening HF requiring oral diuretic intensification in ambulatory care was frequent, adversely prognostic, and significantly reduced by dapagliflozin.
... Short-term outcomes after sodium-glucose cotransporter-2 inhibitor initiation in a cohort of heart failure patients 3 ESC Heart Failure (2023) DOI: 10.1002/ehf2.14489 initiation, 6 the mean diuretic dose in this study was higher. This highlights the need to determine whether patients on higher furosemide equivalent diuretic doses should have their loop diuretic doses reduced prior to SGLT2i initiation. ...
Aims:
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) decrease mortality and risk of hospitalization in patients with heart failure with reduced ejection fraction (HFrEF). SGLT2i have a natriuretic effect shortly after initiation, followed by a lasting osmotic diuretic effect. We sought to evaluate rates of acute kidney injury (AKI) and therapy discontinuation with SGLT2i initiation in a real-world cohort of HFrEF patients.
Methods and results:
We abstracted data on 200 patients with HFrEF initiated on a SGLT2i in the outpatient setting at the University of Michigan (between 1 July 2016 and 2 July 2022). Our co-primary endpoints were rate of AKI and discontinuation of SGLT2i. A total of 200 patients were included. The majority of patients were male (64%) with a mean left ventricular ejection fraction (LVEF) of 27%. One hundred and four (52%) patients had diabetes mellitus. Most patients exhibited New York Heart Association class II (51.5%) or III (33.5%) symptoms. The majority of patients (54%) were taking an angiotensin-receptor neprilysin inhibitor. The mean daily furosemide equivalent diuretic dose was 93.3 mg. AKI occurred in 22 patients and 18 patients discontinued their SGLT2i. Yeast infection (n = 6), hypotension (n = 5), and AKI (n = 4) were the most common reasons for discontinuation. Using receiver operating characteristic curve analysis, the strongest models for AKI were A1C [area underneath its curve (AUC) = 75.8, empirical confidence interval (ECI) 66.5-83.5]; baseline serum creatinine (SCr) (AUC = 72.0, ECI 65.7-78.7); LVEF (AUC = 67.6, ECI 58.4-75.8); and furosemide equivalent diuretic dose (AUC = 66.0, ECI 57.5-74.6). Similarly, the strongest positive models for SGLT2i discontinuation were A1C (AUC = 81.1, ECI 74.8-87.2); baseline SCr (AUC = 67.4, ECI 58.7-75.5); LVEF (AUC = 68.7, ECI 58.9-76.5); and furosemide equivalent diuretic dose (AUC = 67.2, ECI 58.2-76.0).
Conclusions:
A1C was the strongest model of AKI, and SGLT2i discontinuation in HFrEF patients started on SGLT2i. Glucosuria may be related to this effect. Patients with higher baseline SCr on higher doses of loop diuretics may be at greater risk of these outcomes. Future prospective studies will be needed to further evaluate these findings and other models of AKI and SGLT2i discontinuation to guide clinical use of SGLT2 inhibitors.
