Editorial Article

Newly Diagnosed Diabetes in Patients with Acute Coronary Syndrome

Marija Vavlukis
Professor, Ss’ Cyril and Methodius University, Medical Faculty, University Clinic of Cardiology, Republic of Macedonia
*Corresponding author:

Marija Vavlukis, Cyril and Methodius University, Medical Faculty, University Clinic of Cardiology, Vodnjanska st. no.17, 1000, Skopje, Republic of Macedonia, E-mail: marija.vavlukis@gmail.com, Tel: 0038972231131, Fax: 0038923113116

Keywords:

Acute coronary syndrome, Diabetes mellitus, Newly diagnosed diabetes, Prognosis, Stress glycaemia

Abbreviations:

ACS: Acute Coronary Syndrome, ADA: American Diabetes Association, AMI: Acute Myocardial Infarction, BG: Blood Glycose, CAD: Coronary Artery Disease, CVD: Cardiovascular Disease, DM: Diabetes Mellitus, ESC: European Society of Cardiology, FBG: Fasting Plasma Glycose, HbA1c: Glycosylated Hemoglobin, NDDM- Newly Diagnosed Diabetes Mellitus, NSTEMI: Non-ST Segment Elevation Myocardial Infarction, PCI: Percutany Coronary Intervention, SG: Stress Glycaemia, STEMI: ST Segment Elevation Myocardial Infar

Diabetes mellitus is increasing on a global level with an estimated prevalence of around 12-14%, with the increasing trend over the years to come, especially in the Middle East, India and China [1]. Saudi Arabia and Middle Eastern countries are among those with the highest prevalence of diabetes (23.7% in Saudi Arabia), and in the same time the highest prevalence of diabetes in the ACS population. According to the Saudi Project for Acute Coronary Events (SPACE) registry, 57.9% of ACS patient in this Registry were diabetic (92.8% known diabetics and 7.2% newly diagnosed). This is the highest DM prevalence ever reported in an ACS population [2]. The Study of Abdullatef et al. performed on Qatar population with ACS, also refers a very high prevalence of NDDM in 21%, pre-diabetes in 14%, and stress hyperglycemia in 10% of the patients, predominantly males and elderly [1]. As reported by Lugg et al., patients of South Asian ethnicity are at highest risk of developing Type 2 diabetes, even in the living settings of Europe. These findings are in accordance with other studies demonstrating that Asian Indians, without prior diagnosed diabetes, show a high prevalence of hyperglycemia following ACS. HbA1c concentrations also, have been shown to be higher in some ethnic groups (Afro-Caribbean, Hispanic, Asian) compared to Caucasian patients with similar plasma glucose levels. Caucasians have significantly lower incidence rates. Lugg et al. report a prevalence of pre-diabetes of 14.3% and Type 2 diabetes of 10.8% in ACS treated patients in England. Similar data are reported by Arnold et al. (10% prevalence of Type 2 diabetes in AMI patients without known diabetes on admission) [3]. Maybe the lowest prevalence of new-DM is reported in an Australian cohort of ACS patients, about 5%, as reported by Chih. In the study of the author, the prevalence of NDDM was 5%, and pre-DM (IGT) 25% among Macedonian cohort of patients with ACS [1]. While a significant influence of racial affiliation on the prevalence of diabetes in the general population and in the cohort of patients with ACS is observed, the severity and type of ACS does not affect the incidence of pre-diabetes and diabetes [3].

Stress hyperglycemia is present in one of four hospitalized patients. Gardner reported that admission hyperglycemia was found in 41% of the elderly patients with acute coronary syndrome. There are three possible causes for hyperglycemia in hospitalized patients: existing known diabetes, existing but unknown diabetes and stress hyperglycemia. Stress hyperglycemia is defined by ADA as an elevation of fasting glucose ≥ 7 mmol/L, or 2-hour postprandial glucose ≥ 11 mmol/L, in a patient without evidence of previous diabetes. Glycosylated hemoglobin (HbA1c) value has been recommended to distinguish between patients with stress hyperglycemia and those with previously undiagnosed diabetes. HbA1c value ≥ 6.5% indicates pre-existing unrecognized diabetes, whereas HbA1c value < 6.5% indicates stress-induced hyperglycemia. Stress hyperglycemia has several means. Stress conditions such as surgery, trauma and acute illness (ACS) increase the circulatory level of counter regulatory hormones (glucagon, cortisol, catecholamines) and pro-inflammatory cytokines and they alter the effect of insulin on the liver and on the skeletal muscles by increasing hepatic glucose production and decreasing the peripheral utilization of glucose. Pro-inflammatory cytokines also increase the hepatic release of glucose and increase the insulin resistance in the liver and in the skeletal muscles. Stress hyperglycemia in patients with diabetes type 2 includes a combination of insulin resistance and beta cell secretory defect [1].

With respect to the disease, it is a well known fact that diabetic patients have more severe risk profile, are more likely to present with NSTEMI, multi-vessel disease (more diffuse atherosclerotic disease) and are at higher risk of complications (repeat revascularization after PCI, heart failure and death), nearly doubled in comparison to non-diabetics (OR 1.83 (95% CI, 1.02-3.30, p= 0.042) [2]. Compared with individuals without diabetes mellitus, patients with DM have about a two-fold higher risk of short-term mortality after acute myocardial infarction (AMI). In the reperfusion era, DM patients who survive ACS are prone to significantly increased mortality after 6 months [4]. Diabetes modulates the course of the disease in terms of delayed treatment initiation due to atypical chest pain. Diabetic patients receive the same reperfusion and antithrombotic therapy as non-diabetics. In terms of type of antiplatelet drugs, the more potent oral P2Y12 receptor inhibitors (prasugrel or ticagrelor) have shown increased relative benefits with higher absolute risk reductions compared with clopidogrel in DM patients [5].

However, less established, is the fact that stress hyperglycemia carries an increased risk of complications, not only in diabetic but also in patients with previously unknown diabetes.Patients with stress hyperglycemia with no previous history of diabetes have worse clinical outcomes compared to those with pre-existing diabetes with a comparable degree of hyperglycemia. Hyperglycemia is an even more significant predictor of complications in comparison to diabetes per se. Patients with stress hyperglycemia has a higher mortality rate and longer hospitalization time in comparison with patients with known diabetes but with normoglycaemia. Their risk of death after AMI is 3.9 fold higher in comparison with normoglycaemic non-DM patients. Simon and co-workers reported a positive linear association between the degree of hyperglycemia and the mortality in patients with acute coronary syndrome, independently of the presence of confirmed diabetes. The author of this article reports that stress hyperglycemia is more pronounced in newly diagnosed diabetics, as compared to patients with in-control DM. The occurrence of complications is associated with stress hyperglycemia and failure to achieve good glycemic control during hospitalization, not with the presence of diabetes. The impact of hyperglycemia on the clinical outcome depends of several factors such as the intensity of hyperglycemic response, the underlying disease, the co-morbidities, the caloric intake and risk of infection [1].

Elevated plasma glucose levels on admission are very common in patients with MI, and are associated with a high incidence of adverse clinical outcomes. Hyperglycemic patients without a previous diagnosis of DM have higher short-term morality risk in comparison to hyperglycemic patients with known DM.The prognostic effect of NDDM and IGT in post-MI patients is an important issue. Both conditions are associated with increased long-term cardiovascular events in patients with acute myocardial infarction. More importantly, there is no difference in the MACE rates between the NDDM/IGM and DM groups during long-term follow-up after AMI. The lowest rate of MACE is observed in the group with normal glycemic control [4].

The Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe study demonstrated that fasting glucose concentrations alone do not identify individuals at increased risk of death and CVD associated with hyperglycemia; the oral glucose tolerance test provides additional prognostic information. Post-challenge hyperglycemia is associated with an increased risk of CAD. The Funagata Diabetes Study, using a Japanese cohort of ACS population, demonstrated that IGT, but not IFG, was a risk factor for CV events. Tamita also reported that an abnormal OGTT is a better risk predictor for future adverse CV events than IFG in AMI patients. [4] The study of George et al., demonstrated that NDDM/IGT detected by OGTT, independently adversely affects prognosis after MI, irrespective of the underlying pathophysiology. In this study event-free survival was lower in IGT and non-DM groups (HR 1.54, 95% CI: 1.06–2.24, p = 0.024) as compared with the NDDM (HR 2.15, 95% CI: 1.42–3.24, p = 0.003) group. Non-target vessel revascularization was a predominate MACE in post-MI patients with NDDM/IGT. The revascularization rate was similar to the one reported by the GRACE registry. Compared to the EHS-ACS II survey, PCI rates were lower in STEMI, as most patients were thrombolysed, but similar in NSTEMI patients. It is important to mention that this data is from the thrombolytic era for STEMI, as PCI era results vary significantly in terms of type of MACE [6].

The most recent ESC guidelines in collaboration with the European Association for the Studyof Diabetes recommend that all ACS patients bescreened for Type 2 diabetes. Using FPG or OGTT has limitations in acute settings [3].

The FPG is usually acutely elevated in the first 2 days after anMI (and therefore unreliable in screening purposes). [3]But, elevated plasma glucose levels on admission can be the first indication of glucose intolerance, and, as previously mentioned, are an important prognostic marker [4]. OGTT is a powerful test to assess the presence of previously undiagnosed DM or impaired glucose regulation in hyperglycemic patients with AMI, with a high predictive role (as aforementioned).Tamita reported a high prevalence (72%) of impaired glucometabolic status, with 31% previous DM, and 41% NDDM in AMI patients among Japanese population. In this study, the FPG test alone identified only 10% of the patients with IGT and 37% with NDDM, while 90% of patients with IGT and 63% of those with NDDM would remain undiagnosed by using FPG alone. Similar data was reported by Hashimoto et al. Taken together these findings suggest better diagnostic performance of OGTT in comparison to FPG. [4]The percentage of normal glucose tolerance by FPG was decreased to 43% when OGTT was used in the study of George et al. In the DECODE study 37% of NDDM patients with OGTT were normal on FPG criteria, similar to the GAMI population, where 10% had NDDM on FPG criteria compared to 31% on OGTT criteria [6]. However, it should be emphasized that the OGTT results influence factors such as timing of performance in relation to ACS index day and severity of the cardiac event. [3, 6]It is suggested that the optimal timing for its performance is at, or after 5 days of ACS. Pre-discharge OGTT based classification of ACS patients independently predicts prognosis in post-MI patients [6].

In 2012, the WHO approved the use of HbA1c as the preferred screening test in the diagnosis and targeted screeningfor Type 2 diabetes. Lugg et al.tested the effectiveness of a screening program based on HbA1c levels alone to identify glucose intolerance and diabetes among non-diabetes patients presenting with ACS.Relying on HbA1c alone, around 8% of patients with undetected diabetes can be missed [3]. When using HbA1C measurements, we have to be aware of the variations of this measurement among patients of different ethnicities and its’ unreliability in patients with hematologic conditions such as hemolytic anemia and hemoglobinopathies, as well as in those with mechanical heart valves, hypothyroidism, or patients taking certain medications that influence the red cell survival. Any condition that shortens the erythrocyte survival or decreases mean erythrocyte age may falsely lower HbA1c test results regardless of the assay method used [3,7,8].

In terms of screening, the 2017 ESC STEMI Guidelines recommend identification of patients with hyperglycemia after ACS, who are at high risk of developing diabetes, by measuring HbA1c and FBG no earlier than 4 days after ACS onset. Patients with HbA1c and FBG levels within the normal range are advised on annual monitoring of HbA1c and FBG, as they are at increased risk of developing type 2 diabetes [9].

In terms of diabetes monitoring and treatment in ACS patients,Guidelines recommend evaluation of the glycemic status in all patients with or without a history of diabetes or hyperglycemia, and frequent glycemic monitoring in diabetic patients and patients with hyperglycemia (Gl level ≥11.1mmol/L) (Class I, LOE C). However, due to higher risk of hypoglycemia - related events when using intensive insulin therapy, a close but not too strict glycose control is considered the best approach. In the acute phase, maintaining a blood glycose concentration ≤11.0 mmol/L, and avoiding hypoglycemia (≤3,9mmol/L), with glycose-lowering therapy threshold set at Gl >10mmol/L (Class IIa, LOE C) is recommended. [5]In addition to that, the 2011 NICE Guidelines recommend treatment with dose-adjusted glycose-insulin infusion (in cases of glycose level >11.1 mmol/L), with regular monitoring of blood glycose levels [9]. Less stringent glycose control is recommended for ACS patients with more advanced CVD, older age, longer diabetes duration and more comorbidities (Class IIa, LOE C) [5]. Because of the increased risk of renal insufficiency, in the setting of performed coronary angiography, in diabetic patients on metformin and/or sodium-glycose co-transporter-2 (SGLT2) inhibitors, it is recommended to measure eGFR for at least 3 days after coronary angiography/PCI (Class I, LOE C) [5].

Just recently, Krinsly et al. reported significant data on glycemic control in critically ill patients. With respect to glycol-metabolic state, hyperglycemia, hypoglycemia, and increased glucose variability are independently associated with mortality. The relationship between glycose control and outcome is different in patients with and without DM, with intensive glycose control offering greater benefits among patients without diabetes. In a cohort of critically ill DM patients, those with HbA1c levels ≥7%, have a higher probability of death when lower mean BG levels predominate, while patients with HbA1c levels <7% have better outcome with lower blood glycose levels while in the intensive care unit.Thus, the strongest relationship between hypoglycemia and mortality was observed among those with the highest HbA1c, during comparison between patients with and without DM. This, apparently paradoxical finding has a biological explanation. Hyperglycemia is ubiquitous in critically ill patients due to a number of endogenous factors, mentioned previously. However, chronic hyperglycemia induces cellular conditioning that attenuates the deleterious impact of acute hyperglycemia. This is also true for hypoglycemia and glycose variability, which can induce a similar inflammatory response as seen with hyperglycemia. Therefore, a single glycemic target is not suitable for all critically ill patients.

This was confirmed by recently published data from a large interventional trial conducted by Krinsly et al.This trial proposes a two target-based BG control, based on DM status and HbA1c in a cohort of critically ill patients. These data support a BG target of 4.4 to 7.8 mmol/L for patients without DM, and perhaps for patients with DM and excellent pre-admission glycemic control, reflected by a low HbA1c. The appropriate BG target for DM patients, especially those with HbA1c levels ≥7%, is less clear. Data suggest the need for a higher BG target in these patients, probably in range of 6.1 to 8.9 mmol/L or 7.8 to 10.0mmol/L. The second target in the study of Krinsley et al. was chosen, as reported by authors, with the intent to avoid glycose excursions >10 mmol/L (the threshold for glycosuria), associated with increased risk of nosocomial infection and increased risk of death. Considering outcome, the authors reported a nonsignificantly lower mortality rate when less tight glycemic control was introduced for DM patients with HbA1c ≥7% [7].

Can we expect, in near future, prospective interventional trials, in the cohort of patients treated for acute coronary syndrome that will assess the clinical outcome in patients randomized to personalized glucose targets as a function of glucometabolic status before the index event?

There is no conflict of interest for this manuscript.

The contribution to the manuscript is by author only.

None.

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Citation: Vavlukis M (2017) Newly Diagnosed Diabetes in Patients with Acute Coronary Syndrome. J Diabetes Care Endocrinol 1:e003

Published: 20 November 2017

Copyright:

© 2017 Vavlukis M . This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.