Sodium–glucose cotransporter 2 inhibitor‐induced euglycaemic diabetic ketoacidosis in heart failure with preserved ejection fraction

Cavka, Luka; Ferko, Urska Bencak; Pitz, Natasa; Trpkovski, Zoranco; Lainščak, Mitja

doi:10.1002/ehf2.13452

Cited by 5 publications

(3 citation statements)

References 36 publications

(105 reference statements)

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“…insulin, glucose if serum glucose is less than 180 mg/dL, and sodium bicarbonate in case of severe acidosis. [29] Valsartan/sacubitril in AHF…”

Section: Sglt 2 Inhibitor Trialsmentioning

confidence: 99%

Earlier is Better. New Options for Acute Heart Failure: When, Who, How Much?

Nechita

2022

Romanian Journal of Cardiology

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Heart failure (HF) is a major public health problem characterised by a high rate of hospitalisation and death. The risk is maximal for patients admitted with acute heart failure (AHF). New therapies with solid proof of mortality reduction in both groups of patients with reduced and preserved ejection fraction (EF) are now available (valsartan/sacubitril and SGLT2 inhibitors). The purpose of this article is to review the main data available and to clarify the role of these new therapies in AHF. The precise moment of initiating these therapies is still a matter of debate. This paper presents the recommended criteria for clinical stability that the clinician could use in deciding to initiate therapy. There is a growing amount of evidence that initiating these therapies sooner provides more benefits to patients.

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“…insulin, glucose if serum glucose is less than 180 mg/dL, and sodium bicarbonate in case of severe acidosis. [29] Valsartan/sacubitril in AHF…”

Section: Sglt 2 Inhibitor Trialsmentioning

confidence: 99%

Earlier is Better. New Options for Acute Heart Failure: When, Who, How Much?

Nechita

2022

Romanian Journal of Cardiology

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“…Heart failure (HF), a global public health problem, has an estimated prevalence of 64.3 million patients worldwide, and the mortality remains high despite the advances in treatments. 4 As HF represents the end stage of various cardiac conditions requiring multiple medications for the disease and complications, close follow-up, nutritional, and psychosocial support, 5,6 it is possible that SES-related mortality differences may also be present in patients with HF. However, it is still unclear whether such an association exists due to the paucity of evidence and conflicting results.…”

Section: Introductionmentioning

confidence: 99%

Socio‐economic status and 1 year mortality among patients hospitalized for heart failure in China

Zhang

Gao

et al. 2022

ESC Heart Failure

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AimsThis study explored the association between socio-economic status (SES) and mortality among patients hospitalized for heart failure (HF) in China. Methods and resultsWe used data from the China Patient-centred Evaluative Assessment of Cardiac Events-Prospective Heart Failure Study (China PEACE 5p-HF Study), which enrolled patients hospitalized primarily for HF from 52 hospitals between 2016 and 2018. SES was measured using the income, employment status, educational attainment, and partner status. Individual socio-economic risk factor (SERF) scores were assigned based on the number of coexisting SERFs, including low income, unemployed status, low education, and unpartnered status. We assessed the effects of SES on 1 year all-cause mortality using Cox models. We used the Harrell c statistic to investigate whether SES added incremental prognostic information for mortality prediction. A total of 4725 patients were included in the analysis. The median (interquartile range) age was 67 (57-76) years; 37.6% were women. In risk-adjusted analyses, patients with low/middle income [low income: hazard ratio (

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“…26 Furthermore, very few patients in the dapagliflozin arm (2.5%) experienced ketosis, which is of clinical relevance, and consistent with the observation that SGLT2i in HFrEF have thus far not been associated with euglycemic diabetic ketoacidosis in clinical trials. 36 Regardless, ketone body cardiac oxidation is unregulated and proportional to serum concentrations, suggesting that even small increases may augment cardiac oxidation. 28,37 In addition, the relevance of SGLT2i-induced ketosis to clinical benefit may not be captured completely by circulating levels, as SGLT2i also upregulate enzymatic machinery fundamental to ketone body oxidation.…”

Section: Discussionmentioning

confidence: 99%

Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF

Selvaraj

Jones

et al. 2022

Circulation

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Background: Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are foundational therapy in patients with heart failure with reduced ejection fraction (HFrEF), yet underlying mechanisms of benefit are not well defined. We sought to investigate the relationships between SGLT2i treatment, changes in metabolic pathways, and outcomes using targeted metabolomics. Methods: Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction (DEFINE-HF) was a placebo-controlled trial of dapagliflozin in HFrEF. We performed targeted mass spectrometry-based profiling of 63 metabolites (45 acylcarnitines [markers of fatty acid oxidation], 15 amino acids, and 3 conventional metabolites) in plasma samples at randomization and 12 weeks. Using mixed models, we identified principal components analysis (PCA)-defined metabolite clusters that changed differentially with treatment, and also examined the relationship between change in metabolite clusters with change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Scores and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Models were adjusted for relevant clinical covariates, and nominal p<0.05 with FDR-adjusted p-value<0.10 were used to determine statistical significance. Results: Among the 234 DEFINE-HF participants with targeted metabolomic data, the mean age was 62.0±11.1 years, 25% were women, 38% were Black, and mean ejection fraction was 27±8%. Dapagliflozin increased ketone-related and short/medium-chain acylcarnitine PCA metabolite clusters compared with placebo (nominal p=0.01, FDR-adjusted p-value=0.08 for both clusters). However, ketosis (Β-hydroxybutyrate levels > 500 μM), was infrequently achieved (3 [2.5%] in dapagliflozin arm vs. 1 [0.9%] in placebo arm), and supraphysiologic levels were not observed. Conversely, increases in long-chain acylcarnitine, long-chain dicarboxylacylcarnitine, and aromatic amino acid metabolite clusters were associated with decreases in KCCQ scores (i.e. worse quality of life) and increases in NT-proBNP levels, without interaction by treatment group. Conclusions: In this study of targeted metabolomics in a placebo-controlled trial of SGLT2i in HFrEF, we observed effects of dapagliflozin on key metabolic pathways, supporting a role for altered ketone and fatty acid biology with SGLT2i in patients with HFrEF. Reassuringly, only physiologic levels of ketosis were observed. Additionally, we identified several metabolic biomarkers associated with adverse HFrEF outcomes.

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Sodium–glucose cotransporter 2 inhibitor‐induced euglycaemic diabetic ketoacidosis in heart failure with preserved ejection fraction

Cited by 5 publications

References 36 publications

Earlier is Better. New Options for Acute Heart Failure: When, Who, How Much?

Earlier is Better. New Options for Acute Heart Failure: When, Who, How Much?

Socio‐economic status and 1 year mortality among patients hospitalized for heart failure in China

Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF

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