Short Report
Heart failure hospitalisation relative to major atherosclerotic events in type 2 diabetes with versus without chronic kidney disease: A meta-analysis of cardiovascular outcomes trials

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Abstract

Aim

We examined whether chronic kidney disease (CKD) modifies the frequency of heart failure hospitalisation (HHF) relative to atherosclerotic major adverse cardiovascular events (MACE; composite of cardiovascular death, myocardial infarction [MI], or stroke) in people with type 2 diabetes.

Methods

Of 16 cardiovascular outcomes trials in type 2 diabetes since 2013, seven reported outcomes stratified by estimated glomerular filtration rate (eGFR) category (<60 vs. ≥60 mL/min/1.73 m2), and five by albuminuria status. Placebo-arm incidence rates of HHF, MACE, MI and stroke were extracted for each eGFR and albuminuria subgroup.

Results

CKD coincided with higher rates of all events, but the greatest increase was observed for HHF (2.66 times higher rate in subgroups with reduced eGFR [95% CI 2.23–3.18]; 2.69 times higher in those with albuminuria [95% CI 2.30–3.13]). By contrast, the rate of MACE was 1.78 (1.67–1.91) and 1.80 (1.57–2.07) times higher in those with reduced eGFR and albuminuria, respectively. In people with CKD, HHF occurred at a similar rate to MI (ratio of HHF:MI = 0.92 with eGFR <60, 0.94 with albuminuria), while in those without CKD, MI was significantly more common (HHF:MI = 0.58 with eGFR 60+ and 0.60 with normoalbuminuria). HHF rates exceeded stroke in people with CKD, but these events otherwise occurred at a similar rate. While reduced eGFR was associated with older age, no such differences between people with/without albuminuria explained their different event profile.

Conclusion

CKD is associated with a shift in the profile of cardiovascular events in people with type 2 diabetes, marked by a disproportionate increase in HHF relative to MACE.

Introduction

Atherosclerotic major adverse cardiovascular (CV) events (MACE) are collectively the most common CV events in people with type 2 diabetes, as demonstrated in our recent meta-analysis of contemporary CV outcomes trials [1]. However, this work also showed that in trials enriched with people with chronic kidney disease (CKD; i.e. CARMELINA [2] and CREDENCE [3]), hospitalisation for heart failure (HHF) occurred as often, or more often, than nonfatal MACE events. In the current era of diabetes treatment, selection between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter-2 (SGLT2) inhibitors to treat type 2 diabetes is partly dictated by which CV outcomes may be considered the “gravest threat” [4]. Knowing whether CKD materially shifts the relative appearance of HHF versus MACE may help to inform treatment decisions. In this analysis, we compared placebo-arm incidence rates of HHF, MACE, myocardial infarction (MI), and stroke in CV outcome trial subgroups with and without baseline CKD (manifest as reduced eGFR or micro-/macro-albuminuria).

Section snippets

Data sources

Since regulatory authorities mandated in 2008 that new diabetes therapies demonstrate CV safety [5], 16 placebo-controlled CV outcomes trials have been published in type 2 diabetes covering the three new classes of GLP-1RAs, SGLT2 inhibitors, and dipeptidyl-peptidase-4 (DPP4) inhibitors. As part of data sourcing/extraction for a preceding meta-analysis [1], we identified seven trials with reports of CV outcomes stratified by baseline eGFR categories, and five stratified by levels of baseline

Results

Subgroups with eGFR <60 were older (pooled mean age 68 vs. 63 years with normal eGFR), had a lower proportion of men (61% vs. 67%), and a higher proportion with prior heart failure (19% vs. 12%); however, subgroups with reduced vs. normal eGFR were similar in terms of haemoglobin A1c (8.0% vs. 8.1%) and prior CV disease history (86% vs. 82%). Albuminuria subgroups were characterised by a small increase in mean age (65 vs. 64 years with normoalbuminuria), a higher proportion of men (70% vs.

Discussion

CKD was associated with higher incidence of all CV outcomes in type 2 diabetes, irrespective of its manifestation as kidney dysfunction (eGFR < 60) or kidney damage (albuminuria). However, the magnitude of increase was significantly greater for HHF than for MACE. This translated to a shift in the relative frequencies of HHF and MACE events, so that HHF appeared at a similar frequency to MI – and was more common than stroke – in the setting of CKD.

Although the relatively small number of trials

Conclusion

With the advent of glucose-lowering therapies with differential efficacy for HHF and MACE outcomes, CKD markers – particularly albuminuria – may be useful in identifying people with type 2 diabetes at higher/lower risk of specific CV events.

Conflicts of interests

JWS and DJM declare no competing interests relevant to this paper. Dr Jonathan Shaw reports receiving honoraria for lectures and advisory boards from: Astra Zeneca; Sanofi; Novo Nordisk; MSD; Eli Lilly; Abbott; Mylan; Boehringer Ingelheim; and Pfizer.

Acknowledgements

This work was supported by the National Health and Medical Research Council of Australia (NHMRC; APP1107361 to DJM and APP1173952 to JES) and the Victorian Government’s Operational Infrastructure Support Program. Neither funding organisation had any role in study design/conduct, collection/interpretation of data, preparation/review of the manuscript, nor in the final decision to submit for publication.

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