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Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce heart failure events by direct action on the failing heart that is independent of changes in renal tubular function. In the failing heart, nutrient transport into cardiomyocytes is increased, but nutrient utilization is impaired, leading to deficient ATP production and the cytosolic accumulation of deleterious glucose and lipid by-products. These by-products trigger downregulation of cytoprotective nutrient-deprivation pathways, thereby promoting cellular stress and undermining cellular survival. SGLT2 inhibitors restore cellular homeostasis through three complementary mechanisms: they might bind directly to nutrient-deprivation and nutrient-surplus sensors to promote their cytoprotective actions; they can increase the synthesis of ATP by promoting mitochondrial health (mediated by increasing autophagic flux) and potentially by alleviating the cytosolic deficiency in ferrous iron; and they might directly inhibit glucose transporter type 1, thereby diminishing the cytosolic accumulation of toxic metabolic by-products and promoting the oxidation of long-chain fatty acids. The increase in autophagic flux mediated by SGLT2 inhibitors also promotes the clearance of harmful glucose and lipid by-products and the disposal of dysfunctional mitochondria, allowing for mitochondrial renewal through mitochondrial biogenesis. This Review describes the orchestrated interplay between nutrient transport and metabolism and nutrient-deprivation and nutrient-surplus signalling, to explain how SGLT2 inhibitors reverse the profound nutrient, metabolic and cellular abnormalities observed in heart failure, thereby restoring the myocardium to a healthy molecular and cellular phenotype.In this Review, Packer summarizes the latest advances in our understanding of the mechanisms that underlie the benefits of sodium–glucose cotransporter 2 (SGLT2) inhibitors in heart failure, identifies specific pathways that are likely to mediate a direct effect of SGLT2 inhibitors on cardiomyocytes and proposes a novel conceptual framework that explains the findings from experimental studies and clinical trials.

Autophagy is a lysosome-dependent intracellular degradative pathway, which mediates the cellular adaptation to nutrient and oxygen depletion as well as to oxidative and endoplasmic reticulum stress. The molecular mechanisms that stimulate autophagy include the activation of energy deprivation sensors, sirtuin-1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK). These enzymes not only promote organellar integrity directly, but they also enhance autophagic flux, which leads to the removal of dysfunctional mitochondria and peroxisomes. Type 2 diabetes is characterized by suppression of SIRT1 and AMPK signaling as well as an impairment of autophagy; these derangements contribute to an increase in oxidative stress and the development of cardiomyopathy. Antihyperglycemic drugs that signal through insulin may further suppress autophagy and worsen heart failure. In contrast, metformin and SGLT2 inhibitors activate SIRT1 and/or AMPK and promote autophagic flux to varying degrees in cardiomyocytes, which may explain their benefits in experimental cardiomyopathy. However, metformin and SGLT2 inhibitors differ meaningfully in the molecular mechanisms that underlie their effects on the heart. Whereas metformin primarily acts as an agonist of AMPK, SGLT2 inhibitors induce a fasting-like state that is accompanied by ketogenesis, a biomarker of enhanced SIRT1 signaling. Preferential SIRT1 activation may also explain the ability of SGLT2 inhibitors to stimulate erythropoiesis and reduce uric acid (a biomarker of oxidative stress)—effects that are not seen with metformin. Changes in both hematocrit and serum urate are the most important predictors of the ability of SGLT2 inhibitors to reduce the risk of cardiovascular death and hospitalization for heart failure in large-scale trials. Metformin and SGLT2 inhibitors may also differ in their ability to mitigate diabetes-related increases in intracellular sodium concentration and its adverse effects on mitochondrial functional integrity. Differences in the actions of SGLT2 inhibitors and metformin may reflect the distinctive molecular pathways that explain differences in the cardioprotective effects of these drugs.

Patients with heart failure have increased cardiac filling pressures, circulating natriuretic peptides, and physical signs of fluid retention, which are related to sodium retention by the kidneys and are alleviated by conventional diuretics. Sodium-glucose cotransporter 2 (SGLT2) inhibitors interfere with sodium and glucose reabsorption in the proximal renal tubule, but they evoke a marked counterregulatory activation of sodium and water reabsorption in distal nephron segments, which opposes and negates any diuretic effect. Nevertheless, it has been postulated that SGLT2 inhibitors modulate the volume set point, leading selectively to decongestion in patients with fluid overload. This hypothesis was tested in a review of 15 randomized controlled trials of SGLT2 inhibitors in patients with heart failure, with 7 trials focusing on urinary volume within the first week, and 8 trials focusing on objective decongestion at 12 weeks. In trials < 1 week, SGLT2 inhibition increased urine volume in the first 24 h, but typically without a change in urinary sodium excretion, and this diuresis was not sustained. In 8 trials of 12 weeks’ duration, none reported alleviation of edema, ascites or pulmonary rales. The 2 trials that evaluated changes in left ventricular filling pressure noted no or small changes (1–2 mm Hg); the two trials that measured interstitial lung water or total blood volume found no effect; and 6 of the 7 trials found no decrease in circulating natriuretic peptides. Therefore, randomized controlled trials do not indicate that SGLT2 inhibitors produce a durable natriuresis or objective decongestion in patients with heart failure.

Four large-scale trials in type 2 diabetes have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors prevent the occurrence of serious heart failure events. Additionally, the DAPA-HF trial demonstrated a benefit of dapagliflozin to reduce major adverse outcomes in patients with established heart failure with a reduced ejection fraction. The trial sheds light on potential mechanisms. In DAPA-HF, the benefits of dapagliflozin on heart failure were seen to a similar extent in both patients with or without diabetes, thus undermining the hypothesis that these drugs mitigate glycemia-related cardiotoxicity. The action of SGLT2 inhibitors to promote ketogenesis is also primarily a feature of the action of these drugs in patients with diabetes, raising doubts that enhanced ketogenesis contributes to the benefit on heart failure. Also, dapagliflozin does not have a meaningful effect to decrease circulating natriuretic peptides, and it did not potentiate the actions of diuretics in DAPA-HF; moreover, intensification of diuretics therapy does not reduce cardiovascular death, questioning a benefit of SGLT2 inhibitors that is mediated by an action on renal sodium excretion. Finally, although hematocrit increases with SGLT2 inhibitors might favorably affect patients with coronary artery disease, in DAPA-HF, the benefit of dapagliflozin was similar in patients with or without an ischemic cardiomyopathy; furthermore, increases in hematocrit do not favorably affect the clinical course of patients with heart failure. Therefore, the results of DAPA-HF do not support many currently-held hypotheses about the mechanism of action of SGLT2 inhibitors in heart failure. Ongoing trials are likely to provide further insights.

Both obesity and type 2 diabetes are important risk factors for atrial fibrillation (AF), possibly because they both cause an expansion of epicardial adipose tissue, which is the source of proinflammatory adipocytokines that can lead to microvascular dysfunction and fibrosis of the underlying myocardium. If the derangement of epicardial fat adjoins the left atrium, the result is an atrial myopathy, which is clinically manifest as AF. In patients with AF, there is a close relationship between epicardial fat volume and the severity of electrophysiological abnormalities in the adjacent myocardial tissues, and epicardial fat mass predicts AF in the general population. The expansion of epicardial adipose tissue in obesity and type 2 diabetes may also affect the left ventricle, impairing its distensibility and leading to heart failure with a preserved ejection fraction (HFpEF). Patients with obesity or type 2 diabetes with AF often have HFpEF, but the diagnosis may be missed, if dyspnea is attributed to increased body mass or to the arrhythmia. The expected response to the treatment for obesity, diabetes or AF may be influenced by their effects on epicardial inflammation and the underlying atrial and ventricular myopathy. Bariatric surgery and metformin reduce epicardial fat mass and ameliorate AF, whereas insulin promotes adipogenesis and cardiac fibrosis, and its use is accompanied by an increased risk of AF. Rate control strategies for AF may impair exercise tolerance, because they allow for greater time for ventricular filling in patients who cannot tolerate volume loading because of cardiac fibrosis and HFpEF. At the same time, both obesity and diabetes decrease the expected success rate of rhythm control strategies for AF (e.g., electrical cardioversion or catheter ablation), because increased epicardial adipose tissue volumes and cardiac fibrosis are important determinants of AF recurrence following these procedures.

For most of the past 3000 years, physicians believed that all patients with heart failure had acute heart failure. Heart failure was viewed as an episodic disorder — that is, patients were considered to have heart failure when they presented with fluid retention, and they no longer had heart failure after diuresis. 1 The chronicity of heart failure was recognized only when invasive and noninvasive measurements showed severe ongoing structural and functional abnormalities between episodes. 2 To develop approaches to preventing hospitalizations and minimizing the functional and prognostic consequences of heart failure, clinical investigators needed to focus on the underlying disease process. . . .

Drugs that inhibit dipeptidyl peptidase-4 (DPP-4) are conventionally regarded as incretin-based agents that signal through the glucagon-like peptide-1 (GLP-1) receptor. However, inhibition of DPP-4 also potentiates the stem cell chemokine, stromal cell-derived factor-1 (SDF-1), which can promote inflammation, proliferative responses and neovascularization. In large-scale cardiovascular outcome trials, enhanced GLP-1 signaling has reduced the risk of atherosclerotic ischemic events, potentially because GLP-1 retards the growth and increases the stability of atherosclerotic plaques. However, DPP-4 inhibitors have not reduced the risk of major adverse cardiovascular events, possibly because potentiation of SDF-1 enhances plaque growth and instability, activates deleterious neurohormonal mechanisms, and promotes cardiac inflammation and fibrosis. Similarly, trials with GLP-1 agonists and sodium-glucose cotransporter 2 inhibitors have reported favorable effects on renal function, even after only 3–4 years of treatment. In contrast, no benefits on the rate of decline in glomerular filtration rate have been seen in trials of DPP-4 inhibitors, perhaps because the renal actions of DPP-4 inhibitors are primarily mediated by potentiation of SDF-1, not GLP-1. Experimentally, SDF-1 can promote podocyte injury and glomerulosclerosis. Furthermore, the natriuretic action of SDF-1 occurs primarily in the distal tubules, where it cannot utilize tubuloglomerular feedback to modulate the deleterious effects of glomerular hyperfiltration. Potentiation of SDF-1 in experimental models may also exacerbate both retinopathy and neuropathy. Therefore, although DPP-4 inhibitors have attractive clinical features, the benefits that might be expected from GLP-1 signaling may be undermined by their actions to enhance SDF-1.

Large trials have shown that sodium glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of adverse kidney and cardiovascular outcomes in patients with heart failure or chronic kidney disease, or with type 2 diabetes and high risk of atherosclerotic cardiovascular disease. None of the trials recruiting patients with and without diabetes were designed to assess outcomes separately in patients without diabetes. We did a systematic review and meta-analysis of SGLT2 inhibitor trials. We searched the MEDLINE and Embase databases for trials published from database inception to Sept 5, 2022. SGLT2 inhibitor trials that were double-blind, placebo-controlled, performed in adults (age ≥18 years), large (≥500 participants per group), and at least 6 months in duration were included. Summary-level data used for analysis were extracted from published reports or provided by trial investigators, and inverse-variance-weighted meta-analyses were conducted to estimate treatment effects. The main efficacy outcomes were kidney disease progression (standardised to a definition of a sustained ≥50% decrease in estimated glomerular filtration rate [eGFR] from randomisation, a sustained low eGFR, end-stage kidney disease, or death from kidney failure), acute kidney injury, and a composite of cardiovascular death or hospitalisation for heart failure. Other outcomes were death from cardiovascular and non-cardiovascular disease considered separately, and the main safety outcomes were ketoacidosis and lower limb amputation. This study is registered with PROSPERO, CRD42022351618. We identified 13 trials involving 90 413 participants. After exclusion of four participants with uncertain diabetes status, we analysed 90 409 participants (74 804 [82·7%] participants with diabetes [>99% with type 2 diabetes] and 15 605 [17·3%] without diabetes; trial-level mean baseline eGFR range 37–85 mL/min per 1·73 m2). Compared with placebo, allocation to an SGLT2 inhibitor reduced the risk of kidney disease progression by 37% (relative risk [RR] 0·63, 95% CI 0·58–0·69) with similar RRs in patients with and without diabetes. In the four chronic kidney disease trials, RRs were similar irrespective of primary kidney diagnosis. SGLT2 inhibitors reduced the risk of acute kidney injury by 23% (0·77, 0·70–0·84) and the risk of cardiovascular death or hospitalisation for heart failure by 23% (0·77, 0·74–0·81), again with similar effects in those with and without diabetes. SGLT2 inhibitors also reduced the risk of cardiovascular death (0·86, 0·81–0·92) but did not significantly reduce the risk of non-cardiovascular death (0·94, 0·88–1·02). For these mortality outcomes, RRs were similar in patients with and without diabetes. For all outcomes, results were broadly similar irrespective of trial mean baseline eGFR. Based on estimates of absolute effects, the absolute benefits of SGLT2 inhibition outweighed any serious hazards of ketoacidosis or amputation. In addition to the established cardiovascular benefits of SGLT2 inhibitors, the randomised data support their use for modifying risk of kidney disease progression and acute kidney injury, not only in patients with type 2 diabetes at high cardiovascular risk, but also in patients with chronic kidney disease or heart failure irrespective of diabetes status, primary kidney disease, or kidney function. UK Medical Research Council and Kidney Research UK.

The magnitude of the clinical benefits produced by inhibitors of the renin-angiotensin system in heart failure has been modest, possibly because of the ability of renin-angiotensin activity to escape from suppression during long-term treatment. Efforts to intensify pharmacological blockade by use of dual inhibitors that interfere with the renin-angiotensin system at multiple sites have not yielded consistent incremental clinical benefits, but have been associated with serious adverse reactions. By contrast, potentiation of endogenous compensatory vasoactive peptides can act to enhance the survival effects of inhibitors of the renin-angiotensin system, as evidenced by trials that have compared angiotensin-converting enzyme inhibitors with drugs that inhibit both the renin-angiotensin system and neprilysin. Several endogenous vasoactive peptides act as adaptive mechanisms, and their augmentation could help to broaden the benefits of renin-angiotensin system inhibitors for patients with heart failure.

Abstract Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been used to reduce body weight in overweight or people with obesity and to improve glycemic control and cardiovascular outcomes among people with type 2 diabetes (T2D) and a high cardiovascular risk. However, the effects of GLP-1 RAs may be modified by the presence of heart failure (HF). In this review, we summarize the evidence for the use of GLP-1 RA across a patient's risk with a particular focus on HF. After a careful review of the literature, we challenge the current views about the use of GLP-1 RAs and suggest performing active HF screening (with directed clinical history, physical examination, an echocardiogram, and natriuretic peptides) before initiating a GLP-1 RA. After HF screening, we suggest GLP-1 RA treatment decisions as follows: (1) in people with T2D without HF, GLP-1 RAs should be used for reducing the risk of myocardial infarction and stroke, with a possible effect to reduce the risk of HF hospitalizations; (2) in patients with HF and preserved ejection fraction, GLP-1 RAs do not reduce HF hospitalizations but may reduce atherosclerotic events, and their use may be considered in an individualized manner; and (3) in patients with HF and reduced ejection fraction, the use of GLP-1 RAs warrants caution due to potential risk of worsening HF events and arrhythmias, pending risk–benefit data from further studies.