Review Article

The Short and Sweet on Sodium–Glucose Cotransporter Inhibitors and Glucagon-like Peptide-1 Receptor Agonists in Heart Failure

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Abstract

Heart failure (HF) affects 6 million people in the US, and type 2 diabetes (T2D) is a significant risk factor for HF. Since 2008, regulatory agencies have required cardiovascular safety trials for new T2D therapies, and these have consistently demonstrated the cardiovascular benefits of glucose-lowering drugs. Sodium–glucose cotransporter inhibitors (SGLTi) and glucagon-like peptide-1 (GLP-1) receptor agonists (RAs)/glucosedependent insulinotropic polypeptide (GIP) reduce major adverse cardiovascular events and deaths, regardless of diabetes status, and improve cardiorespiratory fitness. SGLTis, such as dapagliflozin and empagliflozin, benefit patients with reduced and preserved ejection fraction, significantly reducing HF hospitalizations and cardiovascular deaths. The DAPA-HF and EMPEROR-Reduced trials showed dapagliflozin and empagliflozin reduce worsening HF or cardiovascular death by 26%. GLP-1 RAs such as semaglutide and the dual GLP-1/GIP receptor agonist tirzepatide improve clinical symptoms, HF hospitalizations, major adverse cardiovascular events, exercise capacity, and quality of life in patients with HF. However, these agents have side effects that must be considered. This review examines the role and efficacy of SGLTis and GLP-1 RAs in established HF.

Keywords

Cardiovascular death, glucagon-like peptide-1 receptor agonists, heart failure, major adverse cardiovascular events, sodium–glucose cotransporter inhibitors, type 2 diabetes,

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Published online:

DOI: https://doi.org/10.15420/usc.2024.44

Disclosure: SC has received speaking honoraria from Baxter. All other authors have no conflicts of interest to declare.

Acknowledgements: JL and TM are co-first authors and contributed equally to this work.

Correspondence: Jose Lopez, University of Miami/JFK Hospital, 5301 South Congress Ave, Atlantis, FL 33462. E: jll296@med.miami.edu

Copyright:

© The Author(s). This work is open access and is licensed under CC-BY-NC 4.0. Users may copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Heart failure (HF) affects approximately 6 million people in the US, with projections estimating a 46% increase in prevalence from 2012 to 2030.1 As the incidence of HF increases with age, the expected doubling in the number of people in the US aged 65 and older over the next decade will only exacerbate this burden.2,3 Concurrently, type 2 diabetes (T2D) is a significant global health problem. T2D is a strong independent risk factor for the development of HF, which is one of its earliest and most common cardiovascular complications.4,5,6

Since 2008, the Food and Drug Administration (FDA) and European Medicines Agency have required that new T2D pharmacotherapies undergo rigorous cardiovascular safety clinical trials using hard cardiovascular endpoints and more stringent statistical review.6 This shift was in response to previously approved T2D medications subsequently demonstrating neutral or harmful cardiovascular effects.7–9 However, the FDA revised its guidance in 2020, moving toward a risk-based approach in which the need for a cardiovascular outcome trial is determined based on the drug’s characteristics, safety profile, and existing cardiovascular risk data.10 Nonetheless, any new diabetes drug must still demonstrate safety concerning cardiovascular outcomes, and many new agents continue to undergo cardiovascular outcomes trials to meet these standards.

Beginning with the EMPA-REG OUTCOME trial in 2015, multiple glucose-lowering therapies have demonstrated a reduction in cardiovascular outcomes in people both with and without T2D.11−13 Two drug classes that significantly reduce major adverse cardiovascular events (MACE) and death, regardless of the presence of T2D, are sodium–glucose co-transporter inhibitors (SGLTis) and glucagon-like peptide-1 (GLP-1) receptor agonists (RAs).13 In this review, we will examine their pharmacology, evidence supporting their use in HF, mechanisms of cardiovascular protection, safety profile, and current guidelines and recommendations.

Sodium–Glucose Cotransporter Inhibitors

Function of Sodium–Glucose Cotransporters in the Human Body

Sodium–glucose cotransporter-2 (SGLT2) is a high-capacity, low-affinity transporter located solely in the luminal membrane of the S1 and S2 segments of the proximal convoluted tubule of nephrons, and they are responsible for about 90% of renal glucose reabsorption.14 Sodium–glucose cotransporter-1 (SGLT1), a lower capacity but higher affinity transporter in the S3 segment, handles the remaining 10%. Both glucose and sodium ions bind to the cotransport protein, with the Na+ electrochemical gradient, maintained by the basolateral sodium–potassium adenosine triphosphatase, driving glucose uptake across the luminal membrane (Figure 1). Subsequently, glucose exits into the bloodstream via the facilitated glucose transporter 2 on the basolateral membrane. SGLT1 is predominantly located in the small intestine, mediating dietary glucose absorption.15

Figure 1: Mechanism of Glucose Reabsorption in the Proximal Convoluted Tubule of the Nephron

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Under normal physiological conditions, a decrease in Na+ delivery to the macula densa – due to either hypotension or hypovolemia – reduces adenosine production. This reduction causes afferent arteriole vasodilation, increasing the glomerular filtration rate. This tubuloglomerular feedback mechanism is crucial for preserving renal blood flow and preventing kidney injury.16

Discovery of SGLTis

Phlorizin is a plant glucoside first isolated from the root bark of apple trees in 1835. In 1933, phlorizin was found to completely inhibit renal glucose reabsorption, highlighting its potential to regulate blood glucose.17 In 1987, phlorizin was found to alleviate hyperglycemia and restore insulin sensitivity in rats with diabetes, indicating its potential for T2D treatment.18 However, its rapid hydrolysis by intestinal lactase and SGLT1 inhibition causing diarrhea limited its clinical use.

To avoid intestinal degradation and diarrhea, pharmaceutical companies sought to develop an oral SGLTi to specifically target renal glucose reabsorption. From 1987 to 1992, significant progress was made in cloning and characterizing the intestinal and renal SGLTs, leading to the development of selective SGLTis, known as gliflozins.19 This research culminated in the development of dapagliflozin, canagliflozin, and empagliflozin, which were approved by the FDA between 2013 and 2014 for the treatment of T2D.19 This was followed by the approval of ertugliflozin in 2017, and of sotagliflozin and bexagliflozin in 2023.20−22 The major difference between these agents lies in canagliflozin, which is less selective for SGLT2 over SGLT1 and is metabolized primarily in the liver (compared to kidneys), and sotagliflozin, which inhibits both SGLT1 and SGLT2.19

Cardiovascular Outcome Trials of SGLTis in Patients with Type 2 Diabetes

SGLTis have emerged as potent agents for the reduction in MACE risk, hospitalizations for HF (HFH), and the progression of chronic kidney disease. They have demonstrated a consistent reduction in the risk of mortality in patients with T2D and established heart disease, and in patients with HF with reduced ejection fraction (HFrEF).13

The first four trials were designed primarily to assess cardiovascular safety in patients with T2D and yielded unexpected beneficial results.11,23–25 EMPA-REG OUTCOME was a randomized, double-blind, placebo-controlled trial involving 7,020 patients with T2D and established cardiovascular disease (CVD).11 In this trial, empagliflozin significantly reduced cardiovascular death by 38% (HR 0.62; 95% CI [0.49–0.77]; p<0.001), HFH by 35% (HR 0.65; 95% CI [0.50–0.85]; p=0.002), and all-cause mortality by 32% (HR 0.68; 95% CI [0.57–0.82]; p<0.001) after a median follow-up of 3.1 years. This trial was followed by three other pivotal diabetes trials, CANVAS, DECLARE-TIMI 58, and CREDENCE.23−25 Overall, these trials demonstrated the class effect and benefits of SGLTis in patients with T2D and with established or a high risk of CVD, with even greater benefits observed in those with higher risk (Table 1). Figure 2 summarizes the results of all major clinical trials for SGLTi.

Table 1: Overview of the Key Sodium–Glucose Cotransporter Inhibitors Cardiovascular and Kidney Outcomes Trials in Patients with Type 2 Diabetes

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Figure 2: Summary of Major Clinical Trials of Sodium–Glucose Co-transporter Inhibitors and Glucagon-like Peptide-1 Receptor Agonists with Their Proven Clinical Benefits

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Cardiovascular Outcome Trials of SGLTis in Patients with HFrEF

The suggestion of benefits to HF-related outcomes led to two landmark trials of SGLTis in patients with HFrEF with and without T2D.26,27 DAPA-HF was a randomized, double-blind, placebo-controlled trial of dapagliflozin in 4,744 patients with symptomatic HFrEF (68% were New York Heart Association [NYHA] class II) and had a left ventricular ejection fraction (LVEF) ≤40% (mean LVEF 31%).26 Background use of contemporary medical therapy for HFrEF was robust, with over 90% of patients on renin-angiotensin–aldosterone system inhibitors (RAASi) and β-blockers, and 71% on mineralocorticoid receptor antagonists (MRA). Importantly, 58% of participants did not have T2D at baseline. The mean estimated glomerular filtration rate (eGFR) was 66 ml/min/1.73 m². Dapagliflozin significantly reduced the composite primary outcome of worsening HF (defined by HFH or urgent visit resulting in IV therapy for HF) or cardiovascular death by 26% (HR 0.74; 95% CI [0.65–0.85]; p<0.001), representing a marked 4.9% absolute risk reduction (ARR). Additionally, there was also a 2.3% ARR in all-cause mortality. Of landmark significance, the pre-specified subgroup analyses demonstrated similar benefits independent of diabetes status.

The EMPEROR-Reduced trial was also a randomized double-blind, placebo-controlled trial of 3,730 patients with HFrEF, with or without T2D. Similar to DAPA-HF, the background use of contemporary medical therapy was high (>90% on RAASi and β-blockers, and 70% on MRA), and 50% of participants had T2D.27 The mean eGFR was 62 ml/min/1.73 m², and 76% of patients had NYHA class II symptoms. The trial demonstrated a significant reduction of 25% in the primary composite outcome of cardiovascular death and first HFH (19.4% versus 24.7% [HR 0.75; 95% CI [0.65–0.86]; p<0.001]).27 Compared to DAPA-HF, the EMPEROR-Reduced trial included a study population with more advanced heart failure or patients with a greater severity of left ventricular systolic dysfunction as evidenced by a lower LVEF (mean LVEF 31% in DAPA-HF versus 28% in EMPEROR-Reduced) and higher median levels of NT-proBNP (1,887 pg/ml in EMPEROR-Reduced versus 1,428 pg/ml in DAPA-HF).26,27 While DAPA-HF showed significant reductions in cardiovascular and all-cause mortality, EMPEROR-Reduced did not. This contrasted with the findings of EMPA-REG OUTCOME and DECLARE-TIMI 58, where statistically significant reductions were observed. This difference could be attributed to EMPEROR-Reduced having lower statistical power, a shorter follow-up duration, and a less sensitive primary outcome due to the focus on HF-related events. A summary of these trials can be found in Table 2.

Table 2: Overview of the Sodium–Glucose Cotransporter Inhibitors and Glucagonlike Peptide-1 Receptor Agonists Clinical Trials in Patients with Heart Failure

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In the SOLOIST-WHF trial, sotagliflozin, an SGLT1/2 inhibitor, effectively reduced events in patients with T2D hospitalized for HF with an elevated BNP (≥150 or ≥450 pg/ml for those with AF) or NT-proBNP (≥600 or ≥1,800 pg/ml for those with AF).28 This trial included 1,222 participants predominantly with HFrEF (82.2%) and an average LVEF of 35%. Sotagliflozin led to a 33% relative reduction in the primary composite outcome of incidence of worsening HF, HFH, or cardiovascular death (HR 0.67, 95% CI [0.52–0.85]; p=0.0009) over an average follow-up period of 18 months.28 However, these results were driven by a reduction in hospitalization events as cardiovascular death alone was not statistically significant, and the trial was stopped early due to suboptimal enrollment during the COVID-19 pandemic. Furthermore, there are no major trials comparing selective SGLTi to the non-selective sotagliflozin.

Cardiovascular Outcome Trials of SGLTis in Patients with Heart Failure with Preserved Ejection Fraction

The impact of SGLTis was studied in HF with preserved ejection fraction (HFpEF) in the EMPEROR-Preserved and DELIVER trials.29,30 EMPEROR-Preserved was the first outcomes trial of patients with HF and an LVEF >40% to meet its primary endpoint, addressing a prominent and longstanding therapeutic challenge, since HFpEF constitutes about half of patients with chronic HF and historically has lacked therapies that modify cardiovascular outcomes.31–34

The EMPEROR-Preserved trial studied empagliflozin in 5,988 patients with symptomatic HF, 81% of whom had NYHA class II symptoms, with an LVEF >40% (mean LVEF 54%) and elevated NT-proBNP levels (>300 or >900 pg/ml for those with AF) with a mean of 974 pg/ml, regardless of diabetes status (50% had T2D).29 The mean eGFR was 61 ml/min/1.73 m². Over a follow-up period of 26.2 months, empagliflozin significantly reduced the composite risk of HFH or cardiovascular death by 21% (13.8% versus 17.1%; HR 0.79; 95% CI [0.69–0.90]).29 This reduction was driven primarily by a decrease in HFH events.

The DELIVER trial randomized 6,263 patients with symptomatic HF, 74% of whom had NYHA class II symptoms, either with HF with moderately reduced ejection fraction (HFmrEF; 34% of patients) or HFpEF to dapagliflozin or placebo.30 Patients had a mean LVEF 54% and elevated N-terminal Pro-B-type natriuretic peptide (NT-proBNP) levels (>300 pg/ml, or ≥600 if they had AF), with a mean of 1,399 pg/ml. The trial found a reduction in HFH, urgent HF visits, or cardiovascular death with dapagliflozin compared to placebo (16.4% versus 19.5%; HR 0.82; 95% CI [0.73–0.92]) over a follow-up period of 2.3 years.30 Notably, 18% of patients had a prior LVEF <40%, and outcomes were similar regardless of prior LVEF. Thus, this trial confirmed the benefit of SGLTi in HFmrEF and HFpEF.

Mechanism of Action and Potential Cardiovascular Benefits

Natriuresis and Osmotic Diuresis

Inhibition of SGLT2 results in a 1:1 stoichiometric inhibition of sodium and glucose uptake in the proximal convoluted tubule of nephrons, leading to natriuresis and glucosuria.14 The degree of inhibition and glucosuria correlates with hyperglycemia, where euglycemia results in minimal glucosuria, thereby reducing the risk of hypoglycemia in patients without diabetes. SGLTis increase glucosuria by as much as 80–100 g/day, improving glycemic control and inducing weight loss. In patients with normal renal function, SGLTis lower HbA1c by 0.6–1.0% and reduce weight by 2–3 kg, primarily through adipose tissue reduction.35,36 They also enhance uricosuria through the exchange of filtered glucose, reducing plasma uric acid levels by 10–15%, ultimately reducing the risk for gout and gout flares.37–39 This reduction in uric acid has been linked with better cardiovascular outcomes in HF, likely due to a reduction in oxidative stress and inflammation.40

SGLTi-induced natriuresis leads to an approximate 7% contraction in plasma volume, as measured by radiolabeled albumin studies.41 However, the increase in urinary sodium excretion is transient, lasting only 3–5 days before returning to baseline.12 This temporary increase in sodium excretion reduces interstitial sodium content, as shown by skin sodium content studies using MRI, decreasing plasma volume.42 Overall, inhibition of SGLT results in a statistically significant – but not necessarily clinically relevant – reduction in systolic (3–5 mmHg) and diastolic (1–2 mmHg) blood pressure without significant sympathetic activation.35,37,43 A more significant reduction was not seen in SGLTi clinical trials because baseline blood pressure was well controlled.

Another important effect of SGLTis is their ability to reduce insulin secretion by lowering hyperglycemia. Insulin use is associated with an increased risk of HF progression and adverse outcomes in patients with established HF, despite achieving better glycemic control.44–46 People with T2D experience excess heart disease and cardiovascular deaths, even when controlled for HbA1c, LDL cholesterol, and blood pressure in population-based cohort analyses.47 Elevated insulin levels are indicators of adverse ventricular remodeling and unfavorable outcomes after an acute MI in patients without T2D.48 Hyperinsulinemia, rather than hyperglycemia, drives the pathogenesis of HF in patients with T2D (but not type 1 diabetes).48 Finally, taking empagliflozin has been shown to reverse cardiac abnormalities by improving left ventricular hypertrophy and diastolic dysfunction in humans within 3 months, which suggests there are direct cardiac benefits of these agents.49

Pathophysiological Mechanisms in Patients without Diabetes

Two sodium–hydrogen exchanger (NHE) isoforms, NHE1 and NHE3, are crucial in the pathogenesis of HF and T2D. NHE1 regulates intracellular pH in the heart, while NHE3 mediates sodium reabsorption in renal and gastrointestinal cells.50 Both are stimulated by insulin and angiotensin II and are upregulated in HF and T2D, leading to harmful intracellular sodium and calcium overload in cardiac cells.50,51 Excessive intracellular calcium then leads to the activation of multiple enzymes that damage different cellular structures, leading to necrosis or apoptosis and impairing contractile function.51–53

Therefore, even though there are no SGLT2 receptors in the heart, SGLTis can bind and inhibit NHE1 and NHE3.50,54 SGLTi inhibit NHE1 and reduce sodium and calcium load in cardiac myocytes and even decrease infarct size.51 It has been hypothesized that at least part of the beneficial effects of SGLTis are mediated by the blockade of NHE.51 This hypothesis is supported by preclinical studies indicating that NHE1 is essential for T2D’s adverse effects on the heart and liver, and its deletion improves cardiac health in mice fed a high-fat diet.55

Another important proposed mechanism is the improvement on myocardial and whole-body metabolism, which improves metabolic flexibility.56,57 T2D and HF impair the heart’s metabolic flexibility, leading to an over-reliance on non-esterified fatty acids for adenosine triphosphate generation, which results in lipotoxicity and promotes diastolic dysfunction.58 SGLTis increase the release of free fatty acids and β-hydroxybutyrate (a ketone body) production, possibly providing a more efficient myocardial fuel source that not only improves cardiac function but mechanical efficiency as well, though definitive evidence is limited.57,59,60

Cardiac fibrosis and inflammation are key pathways leading to HF. Experimental data suggest that SGLTis have antifibrotic effects by means of reducing collagen synthesis, myofibroblast differentiation, fibroblast activation, and extracellular matrix remodeling, thus preventing remodeling.61,62 Furthermore, canagliflozin delayed the rise in NT-proBNP and high sensitivity troponin I in older adults with T2D, indicating the potential effects of reducing cardiac fibrosis, inflammation, and preventing adverse remodeling.63

It has also been postulated that SGLTis may in part exert their beneficial effects by modulating adipokinetics (the equilibrium between pro- and anti-inflammatory adipokines) and reducing epicardial fat.44,64,65 Canagliflozin was shown to lower serum leptin levels by 25% and increase the levels of the anti-inflammatory adipokine adiponectin by 17%, compared to glimepiride; however, it is unknown whether these benefits are a result of weight loss induced by canagliflozin or by its direct effects on adipose tissue functionality.66

SGLTis have also been shown to reduce the risk of atrial arrhythmias by reducing atrial dilation, inflammation, oxidative stress, and sympathetic overdrive.67 AF has a strong relationship with HF and might be a causal pathway for improving outcomes in HF.68 Finally, the beneficial effects of SGLTis on renal function by slowing diabetic kidney disease progression may be a major contributor to improved outcomes in patients with HF.12 Additionally, these SGLTis have also been shown to improve cardiorespiratory fitness.69

While these mechanisms provide several potential explanations, it is challenging to account for the dramatic reduction in HF-related outcomes observed with SGLTis, especially considering the lack of specific receptors for gliflozins in the heart other than NHE1. Notably, these benefits appear independent of glucose-lowering effects, blood pressure, and cholesterol levels.13 Therefore, the exact mechanisms by which SGLTis produce significant reductions in cardiovascular outcomes remain uncertain.

Safety Profile

SGLTis are linked to a higher risk of genital infections, more so in women, particularly in patients with poor hygiene and severe hyperglycemia. SGLTis are generally not associated with an elevated risk of urinary tract infections (UTIs), including pyelonephritis, despite diabetes being a risk factor for UTIs, particularly in patients with poor glycemic control.70 For example, in the EMPA-REG OUTCOME trial, empagliflozin significantly reduced the risk of UTIs in women (placebo 40.6%, 10 mg empagliflozin 35.5%). However, it is important to note that SGLTis are associated with a higher incidence of genital mycotic infections rather than UTIs.71 Additionally, while the risk of UTIs has been low across both randomized controlled trials and observational studies, there is some evidence indicating that 10 mg dapagliflozin may have an association with UTIs.71 SGLTis can also increase the risk of volume depletion, leading to pre-renal acute kidney injury, but they do not cause direct kidney injury.72 This risk decreases with better glycemic control and is minimal in people who do not have diabetes.

As SGLTi urinary glucose excretion is dependent on the filtered load, the risk of hypoglycemia is low unless other diabetes drugs are administered concurrently. However, SGLTis have been consistently associated with a very small but increased risk of diabetic ketoacidosis (DKA) in patients with T2D.73 Across several trials, including EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58, and CREDENCE, 74 DKA events were reported among 38,702 patients, with an overall incidence of 0.2%.25,74 Notably, the incidence was 0.18% in the placebo group (24 events out of 13,099) and 0.28% in the treatment group (42 events out of 15,461). Therefore, although the incidence was higher in the treatment group, the overall incidence and absolute risk increase are extremely low. Further, there were clear precipitants shown in these trials, such as severe infection, major surgery, and inadvertent reduction in insulin dosage. Nonetheless, this elevated risk, although low, is significant given the potentially severe consequences of DKA. The rate of DKA in patients who do not have diabetes approaches zero.26,27,29 Concerns about Fournier’s gangrene have been discredited in all relevant trials.72

In the CANVAS trial, canagliflozin was associated with an increased risk of lower-limb amputations (HR 1.97), but no other trials confirmed this, leading the FDA to remove the amputation warning.23,75,76

The non-selective SGLTi, sotagliflozin, was associated with a significantly increased risk of diarrhea compared to placebo (6.1% versus 3.4%) in the SOLOIST-WHF trial due to SGLT1 inhibition in the gastrointestinal tract.28

GLP-1 Receptor Agonists

Discovery of GLP-1 RAs

The impact of gastrointestinal hormones on insulin secretion has been the subject of scientific investigation for decades and in 1986 the amino acid sequence of the biologically active GLP-1 hormone was discovered.77–79 The first randomized, placebo-controlled study to show the physiological impacts of GLP-1 on appetite control and energy uptake in humans was with synthetic, human GLP-1 (7–36 amide). The study randomized 20 healthy young men to an infusion of GLP-1 while eating breakfast versus placebo.77,80 Using visual analogue scales, the authors found that GLP-1 increased satiety and weight loss, and decreased gastric emptying and the amount of food individuals ate at their next meal by 12%.77,80

Subsequent trials in this period had mixed results due to lack of statistical power with smaller sample sizes, but pooled data analysis proved the dose-dependent effects of GLP-1 on caloric intake.77 Collaboration with the pharmaceutical industry yielded the first long-acting GLP-1 RA, the once-daily injected liraglutide, which was first produced in 1996.77 Since then, multiple GLP-1 analogues have been developed and changed the paradigm on the management of T2D and obesity, but the cardiovascular outcomes of GLP-1 RAs on patients with T2D have yet to be proven.77

Cardiovascular Outcome Trials of GLP-1 RAsin Patients with T2D

While GLP-1 has been effective in treating T2D by lowering blood glucose levels, weight, and blood pressure, the cardiovascular effects of GLP-1 remained unknown until the LEADER trial, which examined the long-term effects of liraglutide on cardiovascular outcomes.81 The double-blinded trial randomized 9,340 patients with T2D and a high cardiovascular risk to either liraglutide (1.8 mg or the maximum tolerated dose) or placebo. In this trial, liraglutide reduced deaths from cardiovascular causes (HR 0.78; 95% CI [0.66–0.93]; p=0.007) and all-cause death (HR 0.85; 95% CI [0.74–0.97]; p=0.02) after a median follow-up of 3.8 years.81 In contrast, the dose of liraglutide used for weight loss is 3.0 mg, and whether similar cardiovascular benefits can be achieved at this higher dose is not yet established. The subsequent cardiovascular outcome trials SUSTAIN-6 (1.0 mg semaglutide), HARMONY, REWIND, and AMPLITUDE-O demonstrated that GLP-1 RA use was superior to placebo in reducing MACE (Table 3 and Figure 2).82−85

Table 3: Overview of the Key Glucagon-like Peptide-1 Receptor Agonists Cardiovascular Outcomes Trials Meeting the Primary Endpoints in Patients with Type 2 Diabetes

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Therefore, while GLP-1 RA use shows cardiovascular protection and suggests a reduction in the risk of HFH in patients who are overweight, have obesity or have T2D without HF, the benefits in patients with HF remain unclear.86–88 A meta-analysis of GLP-1 RAs across clinical trials showed a reduction in MACE by 14%, all-cause mortality by 12%, and HFH by 11%.89 Given these cardioprotective effects and their role on diabetes management, we reviewed the clinical impact of GLP-1 RAs in patients with HF.

Cardiovascular Outcome Trials of GLP-1RA in Patients with HFrEF

In patients with T2D, semaglutide has been shown to improve cardiovascular outcomes.86 The SELECT trial investigated whether the clinical benefits of semaglutide extend to patients without diabetes but with a history of CVD and a BMI ≥27 kg/m2. A total of 17,604 patients received once weekly semaglutide compared to placebo and followed for a mean duration of 33 months. The primary endpoint was a MACE composite – cardiovascular death, non-fatal MI, or non-fatal stroke. About 25% had chronic HF, and nearly 75% had a prior MI. Semaglutide reduced MACE by 20% among patients without diabetes (HR 0.80; 95% CI [0.72–0.90]; p<0.001), with reductions in the HF composite endpoint (first occurrence of death from cardiovascular causes, hospitalization, or an urgent medical visit for HF; HR 0.82; 95% CI [0.71–0.96]), significant weight loss (difference 8.51%; 95% CI [8.75–8.27]), and waist circumference reduction (difference −6.53 cm; 95% CI [−6.79, 6.27]).86 Additionally, secondary endpoints, such as HFH or urgent medical visits for HF (HR 0.79 95% CI [0.60–1.03]), were numerically lower but did not reach statistical significance. However, in patients with established HF, the effect of GLP-1 RAs on clinical outcomes might be modified by LVEF.

In patients with HFrEF, the effects of GLP-1 RAs have been the subject of few clinical trials. The FIGHT study was the first multicenter trial investigating GLP-1 agonism in patients with reduced LVEF. This study enrolled patients recently hospitalized for acute HF, with significant functional limitations (NYHA class II–IV) and an LVEF ≤40%, regardless of diabetes status.90 Patients were assigned to either liraglutide 1.8 mg daily (n=154) or placebo (n=146) and followed for 180 days. Overall, this was a high-risk study population with a median age of 61 years, a median LVEF of 25%, and the majority had NYHA class III–IV symptoms with an elevated NT-proBNP level (median = 2,049 pg/ml). The primary endpoint was the global rank score, which refers to a hierarchical composite measure that ranks patients based on a combination of clinical events (such as death and HFH), and changes in NT-proBNP levels. The study found no significant difference in the global rank score, number of deaths, HFH, or changes in NT-proBNP levels. Additionally, the use of liraglutide did not improve cardiac function, 6-minute-walk test, or quality of life as measured by Kansas City Cardiomyopathy Questionnaire (KCCQ) score.90 In a subgroup analysis of patients with diabetes there was no significant difference; however, liraglutide was associated with increased risk of HF-related events in patients with HFrEF and diabetes, a concerning signal for safety events with liraglutide.

An ad hoc analysis of the FIGHT trial examined first and recurrent events of HFH or all-cause death, revealing a positive trend towards increased total HFH or all-cause death (HR 1.53, 95% CI [1.02–2.31]; p=0.040), use of IV diuretic therapy, and total arrhythmias reported by investigators in the liraglutide cohort.87

A subsequent multicenter, double-blind, randomized trial, the LIVE Study, enrolled 241 patients with reduced LVEF ≤45% and NYHA class I–III. Patients were assigned to liraglutide or placebo and followed for 24 weeks, with the primary endpoint of change in LVEF.91 Unlike the FIGHT trial, these patients were less sick, mostly NYHA class II–III in the liraglutide group, with a lower median NT-proBNP (413 pg/ml) and mean LVEF of 34%.91 The results also showed no difference in the change in LVEF. However, liraglutide use was associated with increased weight loss (mean difference: −2.2; p<0.0001), increased heart rate (mean difference: 7 BPM; p<0.0001), and a non-significant reduction in blood pressure.91

The EXSCEL trial evaluated the cardiovascular effects of exenatide among patients with diabetes, showing a net neutral effect on HFH risk.92 To delineate the impact of exenatide among patients with pre-existing HF, a pre-specified analysis was performed in 2,389 patients (16.2%) who had baseline HF at time of study initiation, with n=1,161 treated with exenatide versus placebo (n=1,228). Overall, patients with pre-existing HF were older white men and the majority had NYHA functional class I-II symptoms. In this group, 13% had reduced LVEF, 46% had LVEF >40, and 42% had undocumented LVEF.92 The analysis showed no difference in all-cause mortality among those with baseline HF when compared to placebo (HR 1.05; 95% CI [0.85–1.29]).92 In the subgroup analysis by preserved versus reduced LVEF, there was no difference between treatment and placebo.92

Cardiovascular Outcome Trials of GLP-1RAs in Patients with HFpEF

In contrast to its use in patients with HFrEF, GLP-1 RA use in patients with HFpEF is associated with significant improvements in symptoms, weight loss and enhanced quality of life.93 In the randomized clinical trial STEP-HFpEF, patients who did not have T2D were assigned to either semaglutide 2.4 mg once weekly or placebo and followed for 52 weeks. Most patients had LVEF >50% and functional NYHA class II symptoms. The use of semaglutide was associated with improved clinical symptoms, physical activity, exercise function, quality of life, and more significant weight loss than the placebo group. However, the trial lacked power to detect differences in urgent hospital visits or HFH.

The STEP-HFpEF DM trial investigated whether the changes in glucose levels in HFpEF patients with obesity moderates the treatment benefits of GLP-1 RAs. Patients were assigned to a group that took semaglutide 2.4 mg once weekly or placebo and they were followed up for 52 weeks. The study population was mostly white (83%), with a median BMI of 37 kg/m2 and a median NT-proBNP level of 493 pg/ml, and 33% of the patients had concomitant SGLTi use. The primary endpoints were changes in patient-reported quality of life using the KCCQ clinical summary score and changes in body weight. The results showed improvement in patient-reported quality of life (estimated difference: 7.3 points; 95% CI [4.1–10.4]; p<0.001), greater improvement in 6-minute-walk distance (estimated difference: 14.3 m; 95% CI [3.7–24.9]; p=0.008), and greater weight loss (estimated difference: −6.4%; 95% CI [−7.6, −5.2]; p<0.001) among patients treated with semaglutide. While also underpowered to detect clinical events, there was a signal noted towards reduction of the first HF event (HR 0.40; 95% CI [0.15–0.92]).93 Fewer adverse cardiovascular events were noted in the semaglutide group. Additionally, the results showed that while semaglutide may result in lower overall weight loss among patients with diabetes than among those who did not have diabetes, there were consistent benefits in symptom reduction and improved quality of life. These benefits were further supported by the results of the SUMMIT trial, which investigated tirzepatide, a dual GLP-1/glucose-dependent insulinotropic polypeptide receptor agonist, in patients with HFpEF with or without T2D. While the complete results of the study have not yet been published, an initial press release in 2024 indicated that tirzepatide reduced the relative risk for the composite endpoint (HF urgent visit or hospitalization, oral diuretic intensification, or cardiovascular death) by 38%.94 Additionally, improvements were noted in body weight, quality of life, and functional capacity.

Mechanism of Action and Potential Cardiovascular Benefits

Enteroendocrine cells in the gastrointestinal system regulate energy balance and glucose metabolism by secreting various peptides, such as GLP-1. GLP-1s are integral in maintaining energy homeostasis and controlling glucose levels, particularly in individuals with T2D. Food intake, particularly ingestion of carbohydrate-rich food, increases GLP-1 secretion, which promotes post-prandial insulin secretion, β-cell proliferation, and glucose homeostasis, contributing to reducing glucose levels and aiding weight loss.95–97

Peripheral activation of GLP-1 receptors triggers a cascade of metabolic effects, including slowed gastric emptying, reduced appetite, lower hepatic glucose production, enhanced insulin synthesis and sensitivity, and improved cardiovascular functions such as vasodilation and cardiac output.95,96 Pharmacological agents such as GLP-1 RAs mimic endogenous GLP-1 regulatory activities, aiding in T2D management by increasing the incretin effect, postprandial insulin release, increased satiety, and decreased glucagon secretion, thus improving glycemic control.98

Although located in the sinoatrial node, GLP-1 RAs influence the cardiovascular system through several other mechanisms, including the use of myocardial glucose, improvement of left ventricular function, myocardial ischaemic protection, increased heart rate, vasodilation, anti-atherosclerotic effects, and blood pressure reduction.97 Finally, these medications have shown to improve cardiorespiratory fitness.69,99

Safety Profile

In patients with obesity who do not have diabetes, semaglutide treatment is safe, with fewer serious adverse events compared to placebo (p<0.001), though it is associated with higher discontinuation rates due to gastrointestinal side effects (10% versus 2%, p<0.001).86 In patients with T2D and high cardiovascular risk, semaglutide use has resulted in fewer serious cardiac and kidney disorders compared to placebo but is linked to worsening diabetic retinopathy, likely due to rapid glucose reduction.82

For patients with obesity and HFpEF, GLP-1 RAs, such as semaglutide, are safe, with fewer serious cardiovascular events reported.93,100 However, the evidence does not support the use of GLP-1 RA in patients with HFrEF. In the FIGHT study, the use of liraglutide was associated with an increased risk for rehospitalization for other cardiovascular reasons (HR 1.33; p=0.09), emergency visits (HR 1.41; p=0.16), and rehospitalization for HF or death (HR 1.36; p=0.05).90 An ad hoc analysis revealed increased use of antiarrhythmic drugs and worse outcomes in patients with NYHA class III–IV symptoms and diabetes.87 The LIVE study further noted more adverse events in the liraglutide group, including increased ventricular tachycardia, AF, worsening underlying ischaemic heart disease, and worsening HF.91 It is unclear whether the heart rate increase associated with GLP-1 RAs, which may pose a safety concern in patients with HFrEF, can be mitigated by the concurrent use of β-blockers, which are typically prescribed for HFrEF. Overall, these findings raise concerns about GLP-1 RA use in patients with reduced LVEF.

Albiglutide use in patients with HFrEF and diabetes was well tolerated, with subjects mainly reporting gastrointestinal events. Ventricular tachycardia and AF were reported in two subjects in the placebo group, while hypotension and UTIs were reported in two subjects in the treatment group.99

Until more robust trials confirm their safety specifically in patients with reduced LVEF, GLP-1 RAs should be used cautiously in this population.

Guideline Recommendations

Figure 3 includes the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America HF guidelines and the 2023 European Society of Cardiology guidelines for the diagnosis and treatment of acute and chronic heart failure. Figure 3 is a summarized version of the recommendations from both guidelines.

Figure 3: Guideline Recommendations for the Use of Sodium–Glucose Co-transporter Inhibitors and Glucagon-like Peptide-1 Receptor Agonists in HF

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Conclusion

The use of SGLTis and GLP-1 RAs represents a paradigm shift in the management of HF, moving beyond their traditional role as drugs for diabetes. These therapies have demonstrated significant reductions in MACE, HFH, and mortality, irrespective of diabetes status. Current societal guidelines recommend incorporating SGLTi for all patients with symptomatic HF.13 As our understanding of their mechanisms continues to evolve, these agents offer promising new avenues for improving outcomes in HF patients.

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