Optimal glucose, HbA1c, glucose-HbA1c ratio and stress-hyperglycaemia ratio cut-off values for predicting 1-year mortality in diabetic and non-diabetic acute myocardial infarction patients

Stress-induced hyperglycaemia (SH) refers to the transient rise in blood glucose levels that occurs during an acute illness and has been linked to a worse prognosis in acute myocardial infarction (AMI) patients [1]. Despite its potential role as a predictor for patient outcomes, guidelines are not consistent on the choice of optimal glucose level to define SH as the thresholds have been arbitrarily selected due to lack of scientific evidence. As such, the prognostic relevance of the blood glucose levels for defining SH are not clear and need to be better defined. The European Society of Cardiology and the American Heart Association recommend an admission blood glucose of > 11 mmol/L and > 10 mmol/L as cut-off values for defining SH, respectively, regardless of diabetic or chronic glycaemic status of patients [2, 3]. Previous therapeutic trials for improving acute glucose control in AMI patients have been inconsistent in their definitions of glucose level that constitutes SH, which might account, in part, for the inconclusive results of these studies in terms of clinical outcomes [4‐6].

This uncertainty in optimal cut-off values for glucose in AMI patients in predicting adverse events, may also differ between ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) patients, and there is also a need to account for the diabetic status of patients to avoid incorrect estimation of real prevalence of stress hyperglycaemia. Roberts et al. [7] have devised a Stress Hyperglycaemia Ratio (SHR) index to normalise the acute increase in glucose values in relation to background glycaemic status, but the optimal SHR cut-off level for defining SH are not known. Similarly, hemoglobin a1c (HbA1c) and glucose-HbA1c-ratio (GHR) were reported as predictors of clinical outcomes in AMI and other pathological processes, but their relative performance to other predictors and optimal values were not clarified [8, 9].

As such, in this study, we evaluated and compared the optimal blood glucose and SHR cut-off values in both diabetic and non-diabetic STEMI and NSTEMI patients and their utility in predicting 1-year all-cause mortality as compared to other potential predictors, such as glucose, HbA1c, and GHR.

This study utilised the Singapore Myocardial Infarction Registry (SMIR), a national registry managed by the ministry-funded National Registry of Diseases Office. The local institutional review board granted an exemption for written consent from the participants for this study (SingHealth CIRB Reference No: 2016/2480) as this study utilised de-identified data. The research was conducted in accordance with the Declaration of Helsinki. The statistician had access to anonymised individual data, while the co-authors had access to analysed, aggregated data. The SMIR collects clinical data of all AMI patients in all hospitals in Singapore [10‐14]. Notification of AMI to the registry is mandated by law. The International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code 410 was used to obtain AMI cases diagnosed prior to 2012, while ICD-10 (Australian Modification) codes I21 and I22 were used for those cases diagnosed in 2012. Patients’ data was extracted from medical claims listings, hospital discharge summaries, and medical records by dedicated registry coordinators. Annual audit was performed on the SMIR data for accuracy and inter-rater reliability, with outliers and illogical data flagged for review. The multinational monitoring of trends and determinants in cardiovascular disease criteria were used to define episodes. STEMI was defined by: (1) Typical chest pain of 20 min, (2) Significant ST segment elevation (0.1 or 0.2 mV on 2 adjacent limb or precordial leads, respectively, or new left bundle-branch block) and (3) Confirmed later by a rise in biomarkers. Medication use was based on documentation in the medical records. The SMIR data was subsequently merged with data from the national death registry, which captures all deaths in Singapore to obtain the outcome of interest—1-year all-cause mortality.

This study utilised STEMI and NSTEMI cases reported to the SMIR from January 2008 to December 2015 who received percutaneous coronary intervention [15]. We excluded patients with a blood glucose level of < 3.9 mmol/L, a first glucose level measured more than 24 h after admission, patients with fasting glucose levels, patients managed outside the hospital and patients with missing glucose or HbA1c results (Fig. 1). The glucose values referred henceforth throughout the manuscript implies the admission random glucose within the first 24 h. Diabetics were defined as patients with a previously documented history of diabetes or those with no documented history of diabetes but a HbA1c value of > 6.5% [16]. Non-diabetics were defined as those without a history of diabetes and with a HbA1c value of ≤ 6.5%.

The main findings of our study were: glucose, GHR, and SHR were independent predictors of 1-year all-cause mortality in STEMI patients, whereas glucose and HbA1c were independent predictors in NSTEMI patients. AUC analysis showed GHR and SHR performed better than glucose in predicting 1-year all-cause mortality in diabetic STEMI patients, whereas glucose, GHR, and SHR performed equally well in non-diabetic STEMI patients. Furthermore, AUC analysis revealed that glucose performed better than HbA1c in predicting 1-year all-cause mortality in both diabetic and non-diabetic NSTEMI patients. The optimal values for glucose, GHR, and SHR in STEMI patients were 15.0 mmol/L, 2.11, and 1.68 in diabetic patients and 10.6 mmol/L, 1.72, and 1.51 in non-diabetic patients with a negative predictive value of > 94%. Similarly, the optimal values for glucose were 10.87 mmol/L and 8.1 mmol/L in diabetic and non-diabetic NSTEMI patients respectively.

It is postulated that hyperglycaemia leads to poorer outcomes after AMI events due to an acute increase in cortisol and catecholamine levels secondary to activation of the sympathetic nervous system as a physiological response to stress [23]. Catecholamines suppress insulin release from the pancreatic β-cells and promote hepatic and muscular glycogenolysis. This decreases glucose uptake into the heart and causes hyperglycaemia. Cortisol reduces glucose transporter translocation in the peripheral tissues and increases liver gluconeogenesis and hence hyperglycaemia [24‐26]. It is speculated that the hyperglycaemia causes a poor outcome as it induces oxidative stress [27], increases endothelial dysfunction [28] and reduces the cardioprotective effect of ischaemic preconditioning [29].

In summary, in this national registry of AMI patients treated by PCI, glucose, GHR, and SHR were independent predictors of 1-year all-cause mortality in STEMI with acceptable negative and positive predictive values, whereas glucose was the only reliable predictor in NSTEMI patients. Our findings need to be validated in future studies.