Introduction
Compared with individuals without diabetes, individuals with diabetes have a higher rate, extent and severity of obstructive coronary artery disease [
1]. Individuals with diabetes and multi-vessel coronary artery disease derive greater benefit from coronary artery bypass graft (CABG) surgery than percutaneous coronary intervention (PCI) [
2], and CABG is regarded as a preferred strategy in these individuals [
3]. However, despite advances in surgical techniques, perioperative management and pharmacotherapy, there remains considerable residual cardiovascular risk in individuals with diabetes after CABG. The 5 year event rate of major adverse cardiovascular events (MACE) after CABG in participants with diabetes was 19% in the FREEDOM trial and 29% in the SYNTAX trial [
4,
5]. In addition to residual ischaemic cardiovascular risk, there remains a substantial risk of heart failure after CABG, with 2 year rates of heart failure hospitalisation ranging from 12.9% (in participants with ejection fraction ≥50%) to 36.9% (in those with ejection fraction <25%) [
6].
Following Food and Drug Administration (FDA) guidance [
7], results are available from large trials evaluating the cardiovascular effects of glucose-lowering agents in participants with type 2 diabetes. One such trial was the EMPA-REG OUTCOME® trial (
ClinicalTrials.gov NCT01131676), in which participants with type 2 diabetes and established cardiovascular disease were randomised to receive the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin or placebo in addition to standard of care [
8]. The EMPA-REG OUTCOME® trial was the first placebo-controlled trial to report a benefit of a glucose-lowering agent on major cardiovascular outcomes, with risk reductions in cardiovascular and all-cause mortality of 38% and 32%, respectively [
8]. Data from this trial led to the FDA approval of an indication for empagliflozin to include reducing the risk of cardiovascular death in participants with type 2 diabetes and established cardiovascular disease—the first such approval for a glucose-lowering agent [
9]. These data have also led to recommendations in clinical practice guidelines that empagliflozin should be considered in the treatment of individuals with type 2 diabetes and cardiovascular disease [
10,
11].
There remains controversy regarding pharmacological cardiovascular risk reduction approaches in individuals following surgical revascularisation, with very limited data on this group available from large randomised clinical trials [
12,
13]. Approximately one quarter of the 7020 participants enrolled in the EMPA-REG OUTCOME® trial had a self-reported history of CABG at baseline. We investigated the effect of empagliflozin on cardiovascular outcomes and mortality in this subgroup.
Discussion
In this post hoc subanalysis of data from the EMPA-REG OUTCOME® trial, we report findings in participants with type 2 diabetes and a history of CABG that are consistent with those in the overall trial population [
8,
14]. In participants with a history of CABG, cardiovascular death was reduced by 48%, all-cause mortality by 43%, hospitalisation for heart failure by 50% and incident or worsening nephropathy by 35% with empagliflozin vs placebo.
In addition to a greater burden of atherosclerosis, diabetes predisposes individuals to diffuse coronary lesions that are more vulnerable and often not amenable to complete revascularisation [
15]. People with diabetes also have specific myocardial defects and are known to exhibit high rates of diastolic dysfunction, placing them at high risk of heart failure [
6,
16,
17]. Although much attention has focused on reducing macrovascular events through antiplatelet, antithrombotic and cholesterol-lowering approaches, limited success has been achieved in the prevention of heart failure and mortality following CABG in individuals with type 2 diabetes. Our analyses illuminate the benefits of empagliflozin in individuals with type 2 diabetes and a history of CABG, demonstrating clinically important reductions in important adverse cardiovascular and renal outcomes in this high-risk population when empagliflozin was given in addition to standard of care.
Several mechanisms have been suggested to underlie the beneficial effects of empagliflozin on heart failure and cardiovascular death [
18,
19]. As an SGLT2 inhibitor, empagliflozin promotes renal glycosuria and natriuresis [
20,
21]. Whereas glycosuria leads to an improvement in glycaemic control, it has been proposed that the ensuing natriuresis and osmotic diuresis reduces preload and ventricular stress [
18,
22]. Individuals with type 2 diabetes and cardiovascular disease have a higher body sodium content and, in many instances, are in pre-clinical heart failure or volume overload; thus, recalibration of sodium/volume balance may improve outcomes. In a cohort of ten post-CABG participants with type 2 diabetes, empagliflozin reduced indices of diastolic dysfunction within a 3 month period [
23]. In non-clinical models, empagliflozin has been shown to prevent worsening of cardiac failure [
24,
25]. Empagliflozin may also improve myocardial energetics through increasing ketone production, yielding ATP at a more efficient rate than other substrates, although this concept remains to be proven [
26]. Further, empagliflozin may have SGLT2-independent effects that attenuate myocardial sodium-hydrogen exchange, promoting calcium efflux through cardiomyocytes [
27]. The renal benefits of empagliflozin appear to stem from natriuresis-induced tubuloglomerular feedback, which is believed to cause afferent arteriolar vasoconstriction, reducing intraglomerular hypertension [
28‐
30]. Large clinical studies will examine the role of empagliflozin in the treatment of cardiac failure both in participants with reduced and preserved ejection fraction (NCT03057977, NCT03057951) and in the treatment of participants with chronic kidney disease [
31].
Guidelines published by the American Heart Association highlight that the majority of evidence for secondary prevention in individuals who have undergone CABG has been derived and/or extrapolated from studies of broader populations of participants with coronary disease [
32]. Very few subanalyses of large trials examining subgroups of participants after CABG are available to help guide practice. The only Class IIa recommendation (level of evidence B) that exists for people who have had CABG with respect to diabetes is to strive to achieve an HbA
1c of 53 mmol/mol (7%) [
32]. There are no specific recommendations on the type of glucose-lowering agents that should be used. Our data provide additional information to help guide clinicians about the choice of glucose-lowering agent for secondary prevention in individuals with type 2 diabetes after CABG. From a practical point of view, surgeons are to be reminded that SGLT2 inhibitors are not indicated in individuals with type 1 diabetes, although trials are ongoing to establish the benefit:risk in this population. Moreover, although hypoglycaemia does not occur with these agents per se, they may increase hypoglycaemia when combined with a sulfonylurea or insulin. Thus, in certain clinical scenarios, a collaborative approach between surgeons and endocrinologists or primary care clinicians will be required. Empagliflozin was not associated with an increased risk of lower limb amputation in participants with or without a history of CABG, similar to observations in the overall trial population [
33] and in subgroups by peripheral artery disease at baseline [
34].
The EMPA-REG OUTCOME® trial had several strengths. It was a large international trial in which participants received the study drug in addition to standard of care. Cardiovascular events and deaths were adjudicated by blinded committees. Vital status was available for 99% of participants [
8]. Participants were identified as having CABG at baseline based directly on case report forms. However, a few limitations to our findings in CABG subgroups must be acknowledged. These analyses were post hoc. Data specific to surgical revascularisation (e.g. number of grafts, use of arterial or venous grafts, on- or off-pump) are not available, nor are biomarker data (e.g. B-type natriuretic peptide). No echocardiograms were performed and baseline indices of left ventricular systolic or diastolic function are unknown. Our analyses were not adjusted for changes in background glucose-lowering therapy or cardiovascular medications.
Acknowledgements
Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by E. Ng and W. Morris (FleishmanHillard Fishburn, London, UK) during the preparation of this article. The authors were fully responsible for all content and editorial decisions and were involved at all stages of manuscript development and have approved the final version.
Duality of interest
SV has received research grants and/or speaking honoraria from Boehringer Ingelheim, Eli Lilly, AstraZeneca, Janssen, Merck, Amgen, Sanofi, Valeant, Bayer, Pfizer and Valeant, holds a tier 1 Canada Research Chair, is national lead investigator for the DAPA-HF trial (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients with Chronic Heart Failure), the EMPagliflozin outcomE tRial in Patients With chrOnic heaRt failure with Reduced ejection fraction (EMPEROR-Reduced) and the EMPagliflozin outcomE tRial in Patients With chrOnic heaRt failure with Preserved ejection fraction (EMPEROR-Preserved), and is a member of the steering committees of the Cardiovascular Inflammation Reduction Trial (CIRT) and the Behavior of Valve Leaflets (BELIEVE) trial. CDM has received consulting fees from Amgen, Boehringer Ingelheim and OctaPharma. DF reports honoraria from Sanofi, Merck & Co., Amgen, AstraZeneca, Eli Lilly and Company and Boehringer Ingelheim. SEI has consulted for Janssen, vTv Therapeutics and Alere, served on Clinical Trial Steering/Executive Committees for Boehringer Ingelheim, AstraZeneca, Novo Nordisk, Sanofi/Lexicon Pharmaceuticals, Daiichi-Sankyo and Eisai (Thrombolysis in Myocardial Infarction [TIMI]) and served on Data Monitoring Committees for Intarcia Therapeutics, Inc. BZ has received research grants awarded to his institution from Boehringer Ingelheim, AstraZeneca and Novo Nordisk, and honoraria from Janssen, Sanofi, Eli Lilly and Company, Boehringer Ingelheim, Novo Nordisk and Merck. EP and JTG are employees of Boehringer Ingelheim.
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