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Heart failure in diabetes: From an increased risk to a treatment target

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Abstract


Heart failure (HF) is one of the most common comorbidities of type 2 diabetes mellitus (T2DM) and poor glycaemic control can worsen the HF outcomes and increase the risk of hospitalisations. With the entry of several antihyperglycaemic agents for the management of T2DM over the last decade, there has been an increasing concern regarding the cardiovascular (CV) safety profile of these agents. In view of this, FDA mandated the demonstration of cardiovascular risk-benefit profile of these agents through specifically designed CV outcome trials. Although we have several findings from these trials, none of them included HF as a primary endpoint indicating the need of trials focusing on HF. Here, we briefly discuss the results of the CV outcome trials in the context of HF.


Heart failure (HF) and type 2 diabetes mellitus (T2DM) are clinical conditions that coexist frequently with an alarmingly increasing prevalence and economic burden. While HF is defined as a global pandemic affecting 26 million people worldwide [1], T2DM is expected to affect 642 million people by 2040 [2].

Poor glycaemic control in patients with T2DM doubles the risk of HF [3–5], and for every 1% increase in glycated haemoglobin (HbA1c), the risk of HF increases by 15% [6] and hospitalisations due to HF (hHF) by 36% [7, 8]. According to the data from REACH registry, in patients with T2DM, HF increases cardiovascular (CV) death by about 250% and hHF by about 500% [9]. Furthermore, HF in patients with T2DM is associated with poor prognosis, with a median survival of about 4 years from the time of diagnosis [10]. This indicates an urgent need for treatment strategies that prevent worsening of HF outcomes in patients with T2DM.

HEART FAILURE: SIGNS, SYMPTOMS, DIAGNOSIS AND TREATMENT STRATEGIES

Heart failure is a clinical syndrome typically characterised by symptoms and signs that result from the structural and functional abnormalities of the heart. The classic symptoms are “breathlessness (dyspnea e.g. on exertion or even at rest)”, ankle swelling and fatigue that may be accompanied by signs like elevated jugular venous pressure, hepato-jugular reflux, pulmonary crackles and peripheral oedema culminating in a reduced cardiac output and/or elevated intracardiac pressures either at rest or during stress [11].

Heart failure is categorised based on ejection fraction as, patients with normal left ventricular ejection fraction (LVEF) [typically considered as ≥50% HF with preserved EF (HFpEF)], reduced LVEF [typically considered as <40%; HF with reduced EF (HFrEF)], and intermediate range of 40%–49% LVEF which is HF with a mid-range EF (HFmrEF) [11].

Heart failure can be due to any abnormality of the structure, mechanical function or electrical activity of the heart and is characterised by a trajectory of deteriorating cardiac output and declining renal function leading to fluid retention, peripheral oedema and pulmonary congestion, which may result in hospitalisation and treatment with an intravenous diuretic. Factors related to T2DM, including cardioneuropathy, cardiomyopathy, microangiopathy, renal hyperfiltration, and intravascular fluid expansion, in addition to hypertension, ischaemic heart disease and sympathetic nervous system (SNS)-overdrive, all contribute to the worsening of HF [12, 13] (Figure 1).

 

Fig. 1. The ominous octet: Contributors to a failing heart in diabetes mellitus.

Notes: CV, cardiovascular; DM, diabetes mellitus. Adapted from [13].

 

As the symptoms of HF are often non-specific it may be difficult to differentiate them with other conditions. Signs such as the elevated jugular venous pressure, hepato-jugular reflux, and laterally displaced apical impulse are more specific; however, they may be difficult to detect and have poor reproducibility and thus need careful clinical examination. Once the signs have been determined by evaluating the clinical history and physical examination, the clinician needs to perform further diagnostic tests. The plasma concentration of natriuretic peptides (NPs) and electrocardiogram (ECG) are the preliminary tests recommended to rule out HF, but not for conclusive diagnosis. Echocardiography is the most effective and widely used test in patients with suspected HF to establish the diagnosis and proceed with the plan of treatment [11].

THE NEED FOR NEW TREATMENT STRATEGIES FOR HF IN PATIENTS WITH T2DM

Beginning of a new era in diabetes research: cardiovascular outcome trials

Currently, metformin is being recommended as first-line therapy for patients with T2DM and HF who have preserved or moderately reduced renal function (i.e. estimated glomerular filtration rate >30 mL/min) whereas, sulphonylureas (SUs) and insulin could be used as a second- or third-line treatment, although their safety in HF is still inconclusive [13, 14]. These recommendations are based on the limited evidence available, as there have been no randomised controlled trials (RCTs) performed to evaluate CV safety for these traditional drugs such as metformin, insulin and SUs. A large observational study in HF demonstrated that metformin was associated with lower mortality and hHF rates compared to SUs and insulin [15]. Findings from ORIGIN study, the only RCT of insulin versus standard of care, revealed that insulin was not associated with higher rates of hHF as compared to the control group [16]. Overall, the information on these drugs is limited with regard to HF.

Following guidance by the US Food and Drug Administration (FDA) for a routinely required mandatory exclusion of CV risk of all new glucose-lowering therapies prompted by an unexpected elevated CV and HF risk seen with rosiglitazone and the dual peroxisome proliferator-activated receptor α/γ agonist muraglitazar [17, 18], a plethora of CV outcome trials (CVOTs) have emerged over the last decade. Although these studies have evaluated the effects of AHAs on HF outcomes, the data is limited to the study populations, hence more studies on HF are required to enable the clinicians to make appropriate treatment decisions.

Dipeptidyl peptidase-4 inhibitors

Three large CVOTs of dipeptidyl peptidase-4 (DPP-4) inhibitors (SAVOR-TIMI53, TECOS and EXAMINE) met the safety primary endpoint [3-point major adverse cardiac events (MACE) comprising CV disease mortality, nonfatal myocardial infarction (MI), and nonfatal stroke] of noninferiority versus placebo [19–21]. Unexpectedly, however, findings from the SAVOR-TIMI53 trial showed an increased risk of hHF in patients using saxagliptin [19], raising doubts regarding the use of these drugs in patients with HF, as the EXAMINE trial (alogliptin) disclosed a similar numerical, but nonsignificant trend [22]. However, findings from the TECOS (sitagliptin) and VIVIDD study (vildagliptin) demonstrated no increased risk of hHF [21, 23, 24]. Further, findings from several observational trials and meta-analyses conducted on hHF demonstrated a neutral effect of DPP-4 inhibitors on the risk of HF, underpinning their safety. Two large ongoing CVOTs with linagliptin, CAROLINA (https://clinicaltrials.gov/show/NCT01243424) and CARMELINA (https://clinicaltrials.gov/ct2/show/NCT01897532, publication expected in September 2018), will shed further light on the safety of DPP-4 inhibitors in HF.

Glucagon like peptide-1 receptor agonists

Findings from the ELIXA trial demonstrated that the use of lixisenatide in patients with diabetes with acute coronary syndrome showed a neutral effect on CV disease outcomes with no increase in the risk of hHF [25]. Liraglutide (LEADER trial) significantly reduced the occurrence of 3-point MACE by 13%, CV death by 22% and all-cause mortality by 15%, with no significant effect on nonfatal MI, stroke and hHF [26]. Similarly, SUSTAIN-6 (semaglutide) and EXSCEL (exenatide once a week) showed no adverse HF signal, though the trials differed in the primary outcome, with semaglutide demonstrating CV benefit for the primary 3-point MACE outcome [27], whereas exenatide once a week falling short of achieving that endpoint [28].

Sodium glucose co-transporter-2 inhibitors

Two large trials of sodium glucose co-transporter-2 (SGLT-2) inhibitors with empagliflozin (EMPA-REG OUTCOME trial) and canagliflozin (CANVAS) showed a significant reduction in hHF [29, 30]. The primary outcome of the EMPA-REG OUTCOME trial of 3-point MACE (composite of death from CV causes, nonfatal MI, and nonfatal stroke) showed superiority versus placebo and noninferiority for 4-point MACE (including hospitalisation for unstable angina). Empagliflozin significantly reduced the risk of hHF by 35%, risk of CV death by 38%, and risk for all-cause mortality by 32% [29].

The CANVAS trial with canagliflozin met the prespecified noninferiority MACE endpoint and in addition demonstrated superiority over standard of care for the primary 3-point MACE outcome (Hazard ratio [HR] 0.86, 95% confidence interval [CI]: 0.75–0.97, p=0.02). In addition, hHF was reduced (HR 0.67, 95% CI: 0.52–0.87), although not rated as statistically significant due to all-cause mortality not reaching a significant difference in the predefined hierarchical statistical analysis [30].

Two ongoing trials will further evaluate the safety and efficacy of empagliflozin versus placebo for the reduction in primary outcomes (CV death or hHF) in patients with HFrEF (EMPEROR-Reduced; https://clinicaltrials.gov/ct2/show/NCT03057977) and HFpEF (EMPEROR-Preserved; https://clinicaltrials.gov/ct2/show/NCT03057951). Two ongoing trials with dapagliflozin, DECLARE-TIMI58 (https://clinicaltrials.gov/ct2/show/NCT01730534) and Dapa-HF (https://clinicaltrials.gov/ct2/show/NCT03036124) will be reported in November 2018 and December 2019, respectively. A list of all completed and ongoing CVOTs are presented in Table 1.

 

Table 1. Cardiovascular outcomes trials with various antihyperglycaemic agents

Drug class

Drug name (trial name)

Primary outcome¶

Hospitalisation due to heart failure

HR (95%CI)

Reference

studies

DPP-4 inhibitors

Completed studies

Saxagliptin (SAVOR-TIMI 53)

3-point MACE

1.00 (0.89–1.12)

1.27 (1.07–1.51)

[19]

 

Sitagliptin (TECOS)

4-point MACE

0.98 (0.89–1.08)

1.00 (0.83–1.20)

[21]

 

Alogliptin (EXAMINE)

3-point MACE

0.96 (95% UL ≤1.16)

1.19 (0.90–1.58)

[22]

Ongoing studies

Linagliptin (CAROLINA); NCT01243424

§Linagliptin (CARMELINA); NCT01897532

GLP-1 receptor agonists

Completed studies

Lixisenatide (ELIXA)

4-point MACE

1.02 (0.89–1.17)

0.96 (0.75–1.23)

[25]

 

Liraglutide (LEADER)

3-point MACE

0.87 (0.78–0.97)

0.87 (0.73–1.05)

[26]

 

Semaglutide (SUSTAIN-6*)

3-point MACE

0.74 (0.58–0.95)

1.11 (0.77–1.61)

[27]

 

Exenatide (EXSCEL)

3-point MACE

0.91 (0.83–1.00)

0.94 (0.78–1.13)

[28]

 

Exenatide (ITCA 650) (FREEDOM-CVO^)

-

-

NCT01455896

Ongoing studies

Albiglutide (HARMONY Outcomes); NCT02465515

Dulaglutide (REWIND); NCT01394952

SGLT-2 inhibitors

Completed studies

Empagliflozin (EMPA-REG OUTCOME)

3-point MACE

0.86 (0.74–0.99)

0.65 (0.50–0.85)

[29]

 

Canagliflozin (CANVAS program)

3-point MACE

0.86 (0.75–0.97)

0.67 (0.52–0.87)

[30]

Ongoing studies

¥Dapagliflozin (DECLARE-TIMI 58); NCT01730534

Ertugliflozin (VERTIS CV); NCT01986881

Dapagliflozin (Dapa-HF); NCT03036124

Empagliflozin (EMPEROR-Reduced); NCT03057977

Empagliflozin (EMPEROR-Preserved); NCT03057951

Notes: Outcomes reported as HR (95% CI) unless otherwise noted. ^Pre-approval trial. #Nontruncated integrated data (refer to pooled data from CANVAS, including before 20 November 2012 plus CANVAS-R). *Powered to rule out an HR upper margin ≥1.8; superiority hypothesis not prespecified. 95% UL, upper limit of 95% CI. 3-point MACE includes composite of death from CV causes, nonfatal MI, and nonfatal stroke; 4-point MACE includes hospitalisation for unstable angina in addition to components of 3-point MACE. §CARMELINA met its primary endpoint, defined as time to first occurrence of CV death, nonfatal MI or nonfatal stroke (3-point MACE), with linagliptin demonstrating similar CV safety compared with placebo (full results to be presented at the 54th European Association for the Study of Diabetes Annual Meeting in Berlin). ¥DECLARE-TIMI 58 (co-primary endpoints are the incidence CV death, MI, or ischemic stroke or the incidence of CV death or hHF), results anticipated to be read out at AHA 2018. CI, confidence interval; CV, cardiovascular; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; hHF, hospitalisation due to heart failure; HR, hazard ratio; MACE, major adverse cardiac events; MI, myocardial infarction; SGLT-2, sodium glucose co-transporter-2; UL, upper limit.

 

CONCLUSIONS

HF is one of the most common comorbidities of T2DM and poor glycaemic control can have direct effects on HF outcomes; thus, it is important to have a good glycaemic control to prevent or improve the CV outcomes including HF events, in patients with T2DM. The findings suggest that metformin is associated with a modest and favourable effect on HF events and insulin has a neutral effect. Although nearly all CVOTs including GLP-1 receptor agonists, DPP-4 inhibitors and SGLT-2 inhibitors had hHF as a secondary or an exploratory outcome, several important findings were revealed in these studies. Although, findings from the trials using DPP-4 inhibitors demonstrated noninferiority versus placebo of meeting the safety primary endpoint, it must be noted that an increase in hHF was observed in patients randomised to saxagliptin during first year with no significant difference thereafter. The findings from the ELIXA trial showed neutrality on CV outcomes, whereas LEADER demonstrated positive effect on the CV outcomes; however, none of them demonstrated reduction in hHF. Remarkably, the EMPA-REG OUTCOME and CANVAS trials for SGLT-2 inhibitors demonstrated a positive effect on the CV outcomes and had reduced the risk of heart failure events. Furthermore, trials specifically designed and powered to evaluate the HF outcomes may be helpful in this context as there seems to be a huge potential for undiagnosed HF in patients with diabetes mellitus, it is crucial for every endocrinologist/diabetologist to understand the basics in diagnostics and treatment of HF in cooperation with the cardiologist, in order to design a tailored glucose-lowering therapy to the individual patient (i.e. precision medicine).

ADDITIONAL INFORMATION

Support. The publication of this article was supported by Novartis Pharma AG.

Conflict of interests. E. Standl has received lecturing honoraria and consultation fees from AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Merck Serono, MSD/Merck, Novartis, Novo Nordisk, and Sanofi. This article is the syllabus of the lecture of Eberhard Standl presented on Novartis scientific conference 27th of April 2018 in St.Petersburg and has not been submitted to external peer reviewers but was reviewed by a member of the Editorial Board before publication.

Author involvement. The author meets the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, takes responsibility for the integrity of the work as a whole, and has given final approval to the version to be published.

Acknowledgements. The author acknowledges Ishita Guha Thakurta, PhD and Lakshmi Deepa G, PhD of Novartis Healthcare Private Limited, India for medical writing support, which was funded by Novartis in accordance with good publication practice (GPP3) guidelines (http://www.ismpp.org/gpp3).

Eberhard Standl

Munich Diabetes Research Group e.V. at Helmholtz Center

Author for correspondence.
Email: eberhard.standl@lrz.uni-muenchen.de
ORCID iD: 0000-0002-8667-633X

Germany, Ingolstaedter Land-St 1 85764, Neuherberg

MD, PhD

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Supplementary files

Supplementary Files Action
1. Fig. 1. The ominous octet: Contributors to a failing heart in diabetes mellitus. View (842KB) Indexing metadata

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