Optimization of heart failure with reduced ejection fraction prognosis-modifying drugs: A 2021 heart failure expert consensus paper

Heart failure (HF) with reduced ejection fraction (HFrEF) is associated with high rates of hospitalization and death. It also has a negative impact on patients’ functional capacity and quality of life, as well as on healthcare costs. In recent years, new HFrEF prognosis-modifying drugs have emerged, leading to intense debate within the international scientific community toward a paradigm shift for the management of HFrEF. In this article, we report the contribution of a Portuguese HF expert panel to the ongoing debate.Based on the most recently published clinical evidence, and the panel members’ clinical judgment, three key principles are highlighted: (i) sacubitril/valsartan should be preferred as first-line therapy for HFrEF, instead of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker; (ii) the four foundation HFrEF drugs are the angiotensin receptor/neprilysin inhibitor, beta-adrenergic blocking agents, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter 2 inhibitors, regardless of the presence of type-2 diabetes mellitus; (iii) these four HFrEF drug classes should be introduced over a short-term period of four to six weeks, guided by a safety protocol, followed by a dose up-titration period of 8 weeks.     

Foundational drugs for HFrEF: the growing evidence for a rapid sequencing strategy

In randomised, placebo- or active-controlled trials in patients with heart failure with reduced ejection fraction (HFrEF), each of the combination of a neprilysin inhibitor and an angiotensin-receptor blocker (i.e. sacubitril/valsartan), a beta blocker, a mineralocorticoidreceptor antagonist and a sodium-glucose co-transporter 2 (SGLT2) inhibitor have been shown to reduce morbidity and mortality, firmly establishing the role of these five agents, prescribed as four pills, as foundational therapy for HFrEF. Traditionally, the guideline-advocated strategy for the initiation of these therapies was based on the historical order in which the landmark clinical trials were performed, and the requirement to uptitrate each individual drug to the target dose (or maximally tolerated dose below this) prior to initiation of another therapy. This process could take six months or more to complete, during which time patients would not be taking one or more of these life-saving drugs. Recently an alternative, evidence-based, rapid three-step sequencing strategy has been proposed with the aim of establishing HFrEF patients on low-doses of all four foundational treatments within four weeks. This strategy is based on the premise that the benefits of each of these therapies are independent and additive to the others, the benefits are apparent at low doses early following initiation, and a specific ordering of therapies may increase likelihood of tolerance of others. This article will outline this novel rapid-sequencing strategy and provide an evidence-based framework to support its adoption into clinical practice.Key words: angiotensin-receptor blocker/neprilysin inhibitor, beta blocker, clinical trials, heart failure with reduced ejection fraction (HFrEF), mineralocorticoid-receptor antagonist, sodium-glucose co-transporter 2 (SGLT2) inhibitor     

Management of heart failure and type 2 diabetes mellitus: Maximizing complementary drug therapy

Type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease and occurs in ~25% of patients with heart failure (HF). Patients with co-morbid HF and T2DM are at elevated risk of adverse outcomes, making optimization of complementary drug therapies essential. While research is ongoing, recent advances in drug therapy, including the introduction of sacubitril/valsartan for HF with reduced ejection fraction and the finding of positive cardiovascular effects of glucose-lowering agents (particularly sodium-glucose co-transporter-2 [SGLT2] inhibitors) have the potential to transform pharmacologic management of co-morbid HF and T2DM. In this review, we provide a comprehensive overview of cardiovascular clinical trials of therapies for HF and diabetes mellitus to date and identify areas requiring further investigation. We also discuss the pathophysiologic overlap of the two diseases and explore the complementary therapeutic effects of HF and T2DM drugs, with a particular focus on sacubitril/valsartan and SGLT2 inhibitors.     

Modifying chronic kidney disease progression with the mineralocorticoid receptor antagonist finerenone in patients with type 2 diabetes

In patients with type 2 diabetes, chronic kidney disease (CKD) is the most common cause of kidney failure. With its increasing prevalence and limited treatment options, CKD is a major contributor to the global burden of disease. Although recent guidelines for the control of hypertension and hyperglycaemia, as well as the use of renin-angiotensin system inhibitors and, more recently, sodium-glucose co-transporter-2 inhibitors, have improved outcomes for patients with CKD and diabetes, there is still a high residual risk of CKD progression and adverse cardiovascular events. In this review, we discuss the recently published FIDELIO-DKD and FIGARO-DKD studies and FIDELITY prespecified individual patient analysis. Together, these studies have established finerenone, a novel non-steroidal mineralocorticoid receptor antagonist, as an effective treatment for kidney and cardiovascular protection and welcome addition to the pillars of treatment to slow CKD progression in patients with type 2 diabetes.     

CCS/CHFS Heart Failure Guidelines Update: Defining a New Pharmacologic Standard of Care for Heart Failure With Reduced Ejection Fraction

In this update of the Canadian Cardiovascular Society heart failure (HF) guidelines, we provide comprehensive recommendations and practical tips for the pharmacologic management of patients with HF with reduced ejection fraction (HFrEF). Since the 2017 comprehensive update of the Canadian Cardiovascular Society guidelines for the management of HF, substantial new evidence has emerged that has informed the care of these patients. In particular, we focus on the role of novel pharmacologic therapies for HFrEF including angiotensin receptor-neprilysin inhibitors, sinus node inhibitors, sodium glucose transport 2 inhibitors, and soluble guanylate cyclase stimulators in conjunction with other long established HFrEF therapies. Updated recommendations are also provided in the context of the clinical setting for which each of these agents might be prescribed; the potential value of each therapy is reviewed, where relevant, for chronic HF, new onset HF, and for HF hospitalization. We define a new standard of pharmacologic care for HFrEF that incorporates 4 key therapeutic drug classes as standard therapy for most patients: an angiotensin receptor-neprilysin inhibitor (as first-line therapy or after angiotensin converting enzyme inhibitor/angiotensin receptor blocker titration); a β-blocker; a mineralocorticoid receptor antagonist; and a sodium glucose transport 2 inhibitor. Additionally, many patients with HFrEF will have clinical characteristics for which we recommended other key therapies to improve HF outcomes, including sinus node inhibitors, soluble guanylate cyclase stimulators, hydralazine/nitrates in combination, and/or digoxin. Finally, an approach to management that integrates prioritized pharmacologic with nonpharmacologic and invasive therapies after a diagnosis of HFrEF is highlighted.     

中国成人2型糖尿病患者糖化血红蛋白控制目标及达标策略专家共识

糖化血红蛋白(HbA1C)控制目标应遵循患者为中心的个体化原则,即根据患者的年龄、病程、健康状况、药物不良反应风险等因素实施分层管理。本共识建议一般成人2型糖尿病(T2DM)患者的HbA1C控制目标为<7.0%,并对其他情况下的HbA1C目标值作出推荐。本共识建议将二甲双胍作为T2DM患者单药治疗的首选,α-糖苷酶抑制剂(AGI)或胰岛素促泌剂作为单药治疗的备选。进行联合治疗时,建议根据患者是否合并动脉粥样硬化性心血管疾病(ASCVD)、心力衰竭(HF)或慢性肾脏疾病(CKD)进行分层。如患者合并ASCVD,建议在具备条件的情况下联合有心血管获益证据的胰升糖素样肽-1受体激动剂(GLP-1RA)或钠-葡萄糖共转运蛋白2抑制剂(SGLT2i)。如患者合并CKD,建议联合用药时在条件允许的情况下首选有肾脏获益证据的SGLT2i,在患者不能使用SGLT2i时可选择有肾脏获益证据的GLP-1RA。如患者合并HF,建议在条件允许时选择SGLT2i。如患者未合并ASCVD、HF或CKD时,可根据基线HbA1C水平、低血糖风险、体重、经济状况、药物可及性等因素选择联合的药物。     

Influence of background medical therapy on efficacy and safety of dapagliflozin in patients with heart failure with improved ejection fraction in the DELIVER trial

Aims

The Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial demonstrated the sodium–glucose cotransporter 2 inhibitor dapagliflozin to be beneficial in patients with symptomatic heart failure (HF) with improved ejection fraction (HFimpEF; those with prior left ventricular ejection fraction ≤40% that had improved to >40% by enrolment). Whether this benefit differs by background medical therapy is unclear. The current study aims to determine the efficacy and safety of dapagliflozin among patients with HFimpEF by background medical therapy.

Methods and results

Treatment effects on the primary endpoint (worsening HF or cardiovascular death) were assessed by number of background HF medical therapies (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor–neprilysin inhibitor, evidence-based beta-blocker, and mineralocorticoid receptor antagonist). Among the 6263 patients randomized in DELIVER, 1151 (18%) had HFimpEF. Of those, 21% of patients were on 0–1 therapies, 44% were on two therapies, and 35% were on three therapies. During 2.3 years of median follow-up, the incidence rate of the primary outcome was 9.7, 8.8, and 8.4 per 100 person-years for patients on 0–1, 2 and 3 HF medications at baseline, respectively. Treatment effects with dapagliflozin on the primary outcome may be greater in patients with HFimpEF on 0–1 therapies at baseline (p_interaction = 0.09), driven mostly by a significant interaction for HF hospitalization (p_interaction = 0.023) with no evidence of effect modification for cardiovascular death (p_interaction = 0.65). Treatment effects of dapagliflozin on the primary outcome were, however, consistent when assessed across the modified Heart Failure Collaboratory Medical Therapy Score integrating both therapeutic use and dosing (p_interaction = 0.39). The use of dapagliflozin was not associated with changes in use or doses of background HF therapies, and among patients on three HF medications at baseline, the addition of dapagliflozin did not lead to higher adverse events.

Conclusions

In patients with HFimpEF, the safety and efficacy of dapagliflozin were largely similar by background use and dosing of HF medical therapies. The benefit of dapagliflozin in reducing HF events tended to be greater in those patients on 0-1 medications at baseline. Among patients already on three HF medical therapies, the addition of dapagliflozin was safe without requiring de-escalation of other therapies.     

Impact of empagliflozin in patients with diabetes and heart failure

Heart failure (HF) is a common disease with increased risk for mortality and morbidity among patients with type 2 diabetes mellitus (T2DM). Optimal glycemic control in this patient population is challenging as many available therapies can potentially exacerbate symptoms of HF. Empagliflozin is one in a novel class of agents, the sodium glucose co-transporter 2 (SGLT2) inhibitors, that lowers blood glucose by increasing urinary glucose excretion and improves glycemic control and lowers body weight and blood pressure. In the recent EMPA-REG OUTCOME trial, empagliflozin was shown to improve cardiovascular outcomes in patients with T2DM and established cardiovascular risk where it reduced HF hospitalizations and cardiovascular death, with a consistent benefit among patients both with and without baseline HF. Here, we review the empagliflozin data on HF outcomes and discuss potential mechanisms for its benefits in HF with a focus on the potentially significant impact that empagliflozin may have on the care of patients with T2DM and HF in the future.     

Sodium-glucose co-transporter inhibitors,their role in type 1 diabetes treatment and a risk mitigation strategy for preventing diabetic ketoacidosis: The STOP DKA Protocol

Recent phase 3 clinical trials have evaluated the impact of adding sodium-glucose co-transporter (SGLT) inhibitors to the type 1 diabetes armamentarium. These trials studied SGLT2 inhibitors (dapagliflozin and empagliflozin) and a dual SGLT1 and SGLT2 inhibitor (sotagliflozin), and demonstrated that these oral non-insulin antihyperglycaemic medications are able not only to improve glycaemic control, but also to reduce body weight and extend time in range without increasing rates of hypoglycaemia in type 1 diabetes. Diabetic ketoacidosis (DKA) is a feature of type 1 diabetes and the risk is increased when SGLT inhibitors are used in type 1 diabetes. To minimize the risk of DKA and still gain the multiple benefits, we developed the “STOP DKA Protocol “, an easily accessible and practical tool, that provides a risk mitigation strategy for reducing DKA in patients with type 1 diabetes being treated with SGLT inhibitors.     

Front Cover

Patients with type 2 diabetes are at an increased risk of developing heart failure and chronic kidney disease. The presence of these co-morbidities substantially increases the risk of morbidity as well as mortality in patients with diabetes. The clinical focus has historically centred around reducing the risk of cardiovascular disease by targeting hyperglycaemia, hyperlipidaemia and hypertension. Nonetheless, patients with type 2 diabetes who have well-controlled blood glucose, blood pressure and lipid levels may still go on to develop heart failure, kidney disease or both. Major diabetes and cardiovascular societies are now recommending the use of treatments such as sodium-glucose co-transporter-2 inhibitors and non-steroidal mineralocorticoid receptor antagonists, in addition to currently recommended therapies, to promote cardiorenal protection through alternative pathways as early as possible in individuals with diabetes and cardiorenal manifestations. This review examines the most recent recommendations for managing the risk of cardiorenal progression in patients with type 2 diabetes.     

Heart failure and diabetes: Clinical significance and epidemiology of this two-way association

People with type 2 diabetes (T2DM) and those with prediabetes have an increased risk of heart failure (HF). Longer duration of T2DM correlates with a greater risk of HF, but HF is also seen in patients with recent-onset diabetes. Insulin resistance is more likely to be present in patients with HF. The risk of HF persists even in the face of standard-of-care preventive treatments for atherosclerotic cardiovascular (CV) disease. HF is commonly the presenting symptom of CV disease in people with diabetes and is the most expensive complication of diabetes because of the high cost of hospitalizations. Recently hospitalization for HF has been included in CV outcome trials (CVOTs), including for medications that are used to treat T2DM, which has led to new therapies for all HF patients. In addition, these CVOTs have shown that many drugs used in the therapy of diabetes are either neutral or detrimental in the HF patient and should be used with caution in patients with existing HF or those at high risk of HF. Most recently, sodium-glucose cotransporter-2 receptor blockers have shown efficacy in both HF with reduced ejection fraction (EF) and HF with preserved EF. The only other oral or injectable diabetes agent shown to improve outcomes in both is metformin.     

2022 Canadian Cardiovascular Society Guideline for Use of GLP-1 Receptor Agonists and SGLT2 Inhibitors for Cardiorenal Risk Reduction in Adults

This guideline synthesizes clinical trial data supporting the role of glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors (SGLT2i) for treatment of heart failure (HF), chronic kidney disease, and for optimizing prevention of cardiorenal morbidity and mortality in patients with type 2 diabetes. It is on the basis of a companion systematic review and meta-analysis guided by a focused set of population, intervention, control, and outcomes (PICO) questions that address priority cardiorenal end points. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system and a modified Delphi process were used. We encourage comprehensive assessment of cardiovascular (CV) patients with routine measurement of estimated glomerular filtration rate, urinary albumin-creatinine ratio, glycosylated hemoglobin (A1c), and documentation of left ventricular ejection fraction (LVEF) when evaluating symptoms of HF. For patients with HF, we recommend integration of SGLT2i with other guideline-directed pharmacotherapy for the reduction of hospitalization for HF when LVEF is > 40% and for the reduction of all-cause and CV mortality, hospitalization for HF, and renal protection when LVEF is ≤ 40%. In patients with albuminuric chronic kidney disease, we recommend integration of SGLT2i with other guideline-directed pharmacotherapy to reduce all-cause and CV mortality, nonfatal myocardial infarction, and hospitalization for HF. We provide recommendations and algorithms for the selection of glucagon-like peptide-1 receptor agonists and SGLT2i for patients with type 2 diabetes and either established atherosclerotic CV disease or risk factors for atherosclerotic CV disease to reduce all-cause and CV mortality, nonfatal stroke, and for the prevention of hospitalization for HF and decline in renal function. We offer practical advice for safe use of these diabetes-associated agents with profound cardiorenal benefits.     

Use of sodium-glucose co-transporter-2 inhibitors in patients with type 2 diabetes mellitus and multiple cardiovascular risk factors: An Asian perspective and expert recommendations

Diabetes mellitus in Asia accounts for more than half of the global prevalence. There is a high prevalence of cardiovascular disease (CVD) in the region among people with type 2 diabetes mellitus (T2DM) and it is often associated with multiple risk factors including hypertension, renal disease and obesity. The early onset of T2DM and the eventual long disease duration portends an increasing proportion of the population to premature CVD. In addition to lowering blood glucose, sodium-glucose co-transporter-2 (SGLT-2) inhibitors exert favourable effects on multiple risk factors (including blood pressure, body weight and renal function) and provide an opportunity to reduce the risk of CVD in patients with T2DM. In this article, we consolidated the existing literature on SGLT-2 inhibitor use in Asian patients with T2DM and established contemporary guidance for clinicians. We extensively reviewed recommendations from international and regional guidelines, published data from clinical trials in the Asian population (dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, luseogliflozin and tofogliflozin), CVD outcomes trials (EMPAREG-OUTCOME, CANVAS and DECLARE-TIMI 58) and real-world evidence studies (CVD-REAL, EASEL, CVD-REAL 2 and OBSERVE-4D). A series of clinical recommendations on the use of SGLT-2 inhibitors in Asian patients with T2DM was deliberated among experts with multiple rounds of review and voting. Based on the available evidence, we conclude that SGLT-2 inhibitors represent an evidence-based therapeutic option for the primary prevention of heart failure hospitalization and secondary prevention of CVD in patients with T2DM, and should be considered early on in the treatment algorithm for patients with multiple risk factors, or those with established CVD.     

New paradigm shift in the pharmacotherapy for heart failure-where are we now and where are we heading?

Over the past 30 years, accumulating evidence has shown that three main therapies including angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, ß-blockers, and mineralocorticoid receptor antagonists are the standard treatment for patients with heart failure (HF) who exhibit reduced ejection fraction (EF). However, lessons learned from recent large-scale clinical trials have added a paradigm shift including angiotensin receptor-neprilysin inhibitor, sodium glucose co-transporter 2 inhibitor, and ivabradine. In addition, soluble guanyl cyclase stimulator and omecamtiv mecarbil are also suggested as next generation therapeutic measures for these patients. From these clinical trials, we learned some patients with preserved EF will benefit from certain agents, which has been one of the largest unmet needs over these decades. This article will review these paradigm shifts over the past 10 years and address a new therapeutic algorithm for patients with HF.     

Heart failure in the patient with diabetes: Epidemiology,aetiology, prognosis,therapy and the effect of glucose-lowering medications

In people with type 2 diabetes the frequency of heart failure (HF) is increased and mortality from HF is higher than with non-diabetic HF. The increased frequency of HF is attributable to the cardiotoxic tetrad of ischaemic heart disease, left ventricular hypertrophy, diabetic cardiomyopathy and an extracellular volume expansion resistant to atrial natriuretic peptides. Activation of the renin-angiotensin-aldosterone system and sympathetic nervous systems results in cardiac remodelling, which worsens cardiac function. Reversal of remodelling can be achieved, and cardiac function improved in people with HF with reduced ejection fraction (HFrEF) by treatment with angiotensin-converting enzyme inhibitors and β-blockers. However, with HF with preserved ejection fraction (HFpEF), only therapy for the underlying risk factors helps. Blockers of mineralocorticoid receptors may be beneficial in both HFrEF and HFpEF. Glucose-lowering drugs can have a negative effect (insulin, sulphonylureas, dipeptidyl peptidase-4 inhibitors and thiazolidinediones), a neutral effect (α-glucosidase inhibitors and glucagon-like peptide-1 receptor agonists) or a positive effect (sodium-glucose co-transporter-2 inhibitors and metformin).     

Type 2 diabetes pharmacotherapy trends in high-risk subgroups

Medication use trends among patients with type 2 diabetes from 2015 to 2019 were investigated in relation to the clinical group-specific recommendations from the 2018 American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) consensus report. Data were drawn from a large health insurance claims database representing Commercial (total patient-year count: 2,379,704) and Medicare (total patient-year count: 845,823) insurance programmes (IBM® MarketScan®). The utilization of sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists increased over time but was lower in the Medicare cohort in every year evaluated. Patients diagnosed with obesity received recommended therapies at higher rates than those without obesity. Differences were more modest between those with versus without atherosclerotic cardiovascular disease (ASCVD) or chronic kidney disease, with greater treatment adoption in those without ASCVD in the Medicare cohort. Utilization of recommended treatments was paradoxically lower in those with versus without heart failure, and worse in the Medicare than in the Commercial cohort. Utilization of sulphonylureas was not different in those with versus without severe hypoglycaemia history. In conclusion, utilization of therapies recommended in the guidelines is increasing overall, which is not preferentially guided by ADA/EASD-defined clinical groups, and there exists a persistent gap in utilization between Commercial and Medicare populations.     

SGLT-2 inhibitors: A step forward in the treatment of heart failure with reduced ejection fraction

Heart failure (HF) is a major health problem with a significant impact on morbidity, mortality, quality of life and healthcare costs. Despite the positive impact of disease-modifying therapies developed over the last four decades, HF mortality and hospitalization remain high.We aim at reviewing the evidence supporting the use of sodium-glucose co-transporter-2 (SGLT-2) inhibitors, as a novel strategy for HF with reduced ejection fraction (HFrEF) treatment.The consistent observation of a reduction in HF hospitalizations in type-2 diabetes cardiovascular safety trials EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58 and VERTIS raised the hypothesis that SGLT-2 inhibitors could have an impact in HF treatment.This hypothesis was first confirmed in 2019 with the DAPA-HF publication showing that dapagliflozin on top of optimized HFrEF therapy, reduced HF-hospitalizations and cardiovascular mortality. This was reinforced by the EMPEROR-Reduced publication in 2020 showing that empagliflozin on top of optimized HFrEF therapy, reduced HF-hospitalizations. Both studies established SGLT-2 inhibitors as a fourth pillar of HFrEF prognosis-modifying therapy, in addition to the gold standard triple neurohormonal modulation/blockade.     

Use of and association between heart failure pharmacological treatments and outcomes in obese versus non-obese patients with heart failure with reduced ejection fraction: data from the Swedish Heart Failure Registry

Aims

To investigate the use of guideline-directed medical therapies (GDMT) and associated outcomes in obese (body mass index ≥30 kg/m²) versus non-obese patients with heart failure (HF) with reduced ejection fraction (HFrEF).

Methods and results

Patients with HFrEF from the Swedish HF Registry were included. Of 16 116 patients, 24% were obese. In obese versus non-obese patients, use of treatments was 91% versus 86% for renin–angiotensin system inhibitors (RASi)/angiotensin receptor–neprilysin inhibitors (ARNi), 94% versus 91% for beta-blockers, 53% versus 43% for mineralocorticoid receptor antagonists. Obesity was shown to be independently associated with more likely use of each treatment, triple combination therapy, and the achievement of target dose by multivariable logistic regressions. Multivariable Cox regressions showed use of RASi/ARNi and beta-blockers being independently associated with lower risk of all-cause/cardiovascular death regardless of obesity, although, when considering competing risks, a lower risk of cardiovascular death with RASi/ARNi in obese versus non-obese patients was observed. RASi/ARNi were associated with lower risk of HF hospitalization in obese but not in non-obese patients, whereas beta-blockers were not associated with the risk of HF hospitalization regardless of obesity. At the competing risk analysis, RASi/ARNi use was associated with higher risk of HF hospitalization regardless of obesity.

Conclusion

Obese patients were more likely to receive optimal treatments after adjustment for factors affecting tolerability, suggesting that perceived beyond actual tolerance issues limit GDMT implementation. RASi/ARNi and beta-blockers were associated with lower mortality regardless of obesity, with a greater association between RASi/ARNi and lower cardiovascular death in obese versus non-obese patients when considering competing risk.