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Intensive glucose control and hypoglycaemia: a new cardiovascular risk factor?
  1. Omar A Rana1,
  2. Christopher D Byrne2,
  3. Kim Greaves3
  1. 1Department of Cardiology, University of Southampton and Southampton University Hospitals NHS Foundation Trust, Southampton, Hampshire, UK
  2. 2Nutrition & Metabolism Unit, Faculty of Medicine, Institute for Developmental Sciences, University of Southampton and Southampton University Hospitals NHS Foundation Trust, Southampton General Hospital, Southampton, Hampshire, UK
  3. 3Department of Cardiology, Poole Hospital NHS Foundation Trust and Bournemouth University, Poole, Dorset, UK
  1. Correspondence to Professor Kim Greaves, Department of Cardiology, Poole Hospital NHS Foundation Trust, Longfleet Road, Poole, Dorset BH15 2JB, UK; kimickc{at}yahoo.co.uk

Abstract

Intensive glucose control is widely practiced in patients with diabetes mellitus and patients acutely admitted to hospitals with concomitant stress-induced hyperglycaemia. Such a strategy increases the risk of hypoglycaemia by several-fold. Hypoglycaemia leads to a surge in catecholamine levels with a profound haemodynamic response. In patients with a decreased cardiac reserve, such significant changes can culminate in serious or even fatal cardiovascular outcomes. This review is aimed at discussing in depth the evidence to date that links hypoglycaemia with cardiovascular mortality, reviewing the likely mechanisms underlying this association, as well as summarising these from a cardiologist's perspective.

  • MYOCARDIAL ISCHAEMIA AND INFARCTION (IHD)

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Introduction

Several studies have associated hypoglycaemia (plasma glucose ≤3.9 mmol/l) with an increase in cardiovascular (CV) mortality.1–16 These data have emerged from epidemiological studies including healthy individuals and patients with diabetes mellitus (DM).1–10 In addition, hypoglycaemia has also been linked with elevated mortality in patients following an acute coronary syndrome or admission to intensive care units (ICU).11–16 Although this association is complex and poorly understood, recent evidence has helped further the understanding of potential mechanisms.17–19 Indeed, this link has been highlighted in guidelines to increase awareness of this potentially fatal complication.20 ,21

Clinical hypoglycaemia is a plasma glucose concentration low enough to cause symptoms and/or signs, with impairment of brain function.22 Severe hypoglycaemia is recognised as a glucose level below which a patient requires the help of another individual.23 It is not possible to state a single plasma glucose concentration that categorically defines hypoglycaemia. There are several reasons for this. Glycaemic thresholds for the development symptoms shift to lower plasma glucose concentrations in different patient groups, for example in those who suffer recurrent hypoglycaemia.24 Venous plasma glucose levels may not always accurately reflect arterial values as they are highly dependent on the fasting state.25 Despite this, some have felt it useful to recommend a biochemical threshold which allows a more pragmatic approach in the identification and management of individuals at risk of hypoglycaemia.23 These biochemical thresholds are also more readily applicable to studies although ideally clinical symptoms/signs should always be included. As a rough guide, values quoted for clinical hypoglycaemia range below 3.9 mmol/l and for severe hypoglycaemia below 2.2–2.8 mmol/l.14 ,16 ,23 ,26 ,27–37

Hypoglycaemia, diabetes and cardiovascular mortality

Intensive glucose control (IGC) and rates of hypoglycaemia

Poor glycaemic control has been shown to be associated with worse outcome with patients with DM at a high risk of developing premature coronary artery disease (CAD).38 Several trials have been undertaken to examine the effect of intensive glucose control (IGC) on long-term clinical outcomes in patients with DM.27–30 These trials demonstrated for the first time that IGC was associated with a reduction in long-term CV complications in patients with DM.28 ,30 However, such a strategy led to a threefold increased risk of severe hypoglycaemia.39 Subsequently, when further trials were conducted with an even more aggressive regimen of glycaemic control, the positive results of earlier trials were negated.2–4 Although, the cause of these results has been much debated, it was noted that there was a markedly high rate of hypoglycaemic events.17 ,19 ,40

Hypoglycaemia is an extremely common occurrence among the day-to-day routine of patients with DM.41–43 It imposes a significant financial burden on hospitals and adversely affects the quality of life of patients.44 One study reported that patients with type 1 DM had an estimated frequency of two severe hypoglycaemic episodes per patient per year with up to 7% experiencing hypoglycaemic coma in 1 year.41

Indeed, hypoglycaemia is far from a benign occurrence; each episode is associated with an additional 2.5 days in hospital and a threefold and twofold increase in inhospital and 1-year mortality rates, respectively in patients with DM.45 More worryingly, a large retrospective study suggested that, in young (<30 years) patients with type 1 DM, 18% and 6% of deaths were attributed to hypoglycaemia in men and women, respectively.9 Gandevia observed that one in two patients with a history of DM who suffered a fatal myocardial infarction (MI) had had a preceding episode of severe hypoglycaemia.8 Recently, healthy volunteers suffering fasting hypoglycaemia recorded a twofold to threefold increase in long-term CV mortality.1

Evidence favouring IGC to decrease cardiovascular outcomes in diabetes in the community setting

The Diabetes Control and Complications Trial examined the effect of IGC on 1441 patients with type 1 DM (table 1).27 This study demonstrated for the first time that IGC (aiming for an HbA1c <7.0%) lowered the absolute risk of major CV events by 3.6%.28 In addition, there was a 57% relative risk reduction in the cumulative rates of non-fatal MI, stroke and CV mortality with an independent threefold decrease in CV mortality. Similarly, an extended follow-up of the UK Prospective Diabetes Study demonstrated a 13% reduction in all-cause mortality in patients with type 2 DM receiving IGC.30 Of note, the rate of severe hypoglycaemia was threefold higher in patients receiving IGC in both trials.27 ,30 ,39

Table 1

Studies that showed benefit of IGC in patients in the outpatient setting

Evidence against IGC to decrease cardiovascular events in diabetes in the community setting

More recent trials have attempted an even stricter IGC regimen (HbA1c of ≤6.5%).2–4 These include the Veterans Affairs Diabetes Trial, the Action in Diabetes and Vascular Disease-Preterax and the Diamicron Modified Release Controlled Evaluation and Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies (table 2).2–4 These have been reviewed extensively in a meta-analysis by Ray et al.46

Table 2

Studies that showed no benefit of IGC in patients in the outpatient setting

In brief, the Action in Diabetes and Vascular Disease-Preterax and the Diamicron Modified Release Controlled Evaluation study randomised patients with type 2 DM with either established CV disease or one CV risk factor to IGC (target HbA1c <6.5%) or standard care.3 The results showed that although the risk of developing microvascular complications was reduced by 14%, there was no impact on the rate of CV events. Of note, the rate of severe hypoglycaemia was increased by twofold in the IGC group with a 50% increase in hypoglycaemia-related hospitalisations. A five-year follow-up revealed that the risk of all-cause mortality and CV mortality following severe hypoglycaemia was increased by threefold to fourfold.5

The Veterans Affairs Diabetes Trial randomised patients to either IGC or standard therapy.2 Although there was no difference in the rate of CV events in both the groups, there was a dramatic increase in the rate of sudden death in the IGC group. Twenty-one per cent of patients in the IGC group experienced severe hypoglycaemia in comparison to just 10% of the group receiving standard therapy.

The ACCORD study randomised patients with type 2 DM to even stricter IGC with a target HbA1c level of <6.0%.4 The trial had to be terminated early due to a higher mortality in the IGC group. The rates of severe hypoglycaemia were alarmingly high with 16.2% versus 5.1% in the IGC and standard therapy groups, respectively. A 22% increase in the relative risk of all-cause mortality in the IGC group was observed. Similarly, there was a 1% increase in the absolute risk of CV mortality with IGC. Recently, long-term follow-up analysis of the ACCORD study demonstrated that mortality rates were directly proportional to the frequency of hypoglycaemic episodes.6 ,7

Hypoglycaemia in patients with known coronary artery disease

Several studies have recorded an association between spontaneous hypoglycaemic episodes and an increased risk of mortality in patients with established CAD.11–15 Fisman observed a 69% and 30% increase in the relative risk of all-cause mortality and CV mortality, respectively in patients with CAD experiencing fasting hypoglycaemia.11 a recent meta-analysis examined the association between spontaneous hypoglycaemia on admission and 30-day mortality rates following ST-elevation myocardial infarction.12 Patients experiencing hypoglycaemia on admission had a threefold increased rate of 30-day mortality rates with an alarming 18-fold increased risk in patients with DM. More importantly, high-risk patients experiencing hypoglycaemia had a >11-fold risk of death within 30 days. Subsequently, Kosiborod demonstrated that following a MI, spontaneous hypoglycaemia increased the risk of inhospital mortality by twofold.13

More recently, spontaneous hypoglycaemia was associated with a twofold increase in 2-year mortality in patients with DM presenting with acute coronary syndrome.14 Furthermore, fasting hypoglycaemia was associated with a 33% increase in 3-year mortality rates in elderly patients following MI.15 Patients with DM and those requiring coronary artery bypass grafting (CABG) had a worse outcome with a twofold and threefold increase in 3-year mortality rates, respectively.

Hypoglycaemia in patients admitted to intensive care units (ICU)

Evidence in favour of IGC in ICU patients

The prevention of hyperglycaemia during acute illness with IGC has been shown to improve survival in patients with and without CAD (table 3). The Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction study recorded a 29% relative risk reduction in all-cause mortality with IGC.31 ,47 Subsequently, Van den Berghe observed a 3.7% absolute reduction in inhospital mortality with the use of IGC in surgical patients admitted to ICU.32 This benefit was more pronounced in patients with a prolonged ICU stay (>5 days). More recently, Krinsley observed a 25% relative risk reduction in inhospital mortality rates with the use of IGC.33 However, the inhospital mortality rate was threefold higher in patients experiencing severe hypoglycaemia. In fact, severe hypoglycaemia emerged as an independent predictor of mortality. Finally, in a separate study, perioperative IGC in patients with DM undergoing CABG led to a 57% relative risk reduction in inhospital mortality.34 Although, the exact rates of severe hypoglycaemia were not published, these were said to be very low.34 It is important to note that the mean blood glucose achieved in the aforementioned studies combined was 7.8±1.5 mmol/l. This is well within the range of 7.8–10.0 mmol/l set by current guidelines.21

Table 3

Studies that showed benefit of IGC in patients admitted to hospitals with an acute illness

Evidence against IGC in ICU patients

The aforementioned studies have led to the development of guidelines recommending IGC for inpatient control of hyperglycaemia with a caveat that ‘care should be taken to avoid hypoglycaemia.’21 This is particularly important as several trials have further examined the effect of a more aggressive IGC regimen (4.5–6.0 mmol/l) on patients with acute illnesses, with and without CAD.16 ,35 ,36 These have failed to confirm the beneficial effect of IGC on survival observed in earlier trials (table 4).

Table 4

Studies that did not show benefit of IGC in patients admitted to hospitals with an acute illness

In contrast to the benefit of IGC in postsurgery patients, Van den Berghe did not confirm any benefit of IGC in medical ICU patients.35 One explanation may have been the extremely high rates of severe hypoglycaemia. For example, the medical ICU patients had a much higher rate of hypoglycaemia (19%) in comparison with surgical ICU patients (5%) while receiving IGC. Of note, severe hypoglycaemia emerged as an independent predictor of inhospital mortality. The Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis study was designed to look at the effect of IGC on 28-day mortality rates of patients with sepsis admitted to ICU.36 The study was terminated early due to a sixfold increase in severe hypoglycaemic events. Insulin-induced hypoglycaemia was associated with a threefold increase in the 28-day mortality-rate.

Finally, the Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation study is the largest study to-date which examined the effect of IGC on 90-day mortality rates in 6104 patients admitted to ICU.16 The rates of severe hypoglycaemia were 14-fold higher in patients receiving IGC with a 2.6% absolute increase in the 90-day mortality rates in the IGC group. Importantly, the relative risk of death from CV causes was increased by 16% in the IGC group (number needed to harm=17). A recent analysis of the Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation study has confirmed that moderate (2.3–3.9 mmol/l) and severe (<2.2 mmol/l) hypoglycaemia were associated with elevated 90-day mortality rates.37 In light of these findings, the authors concluded that a more aggressive IGC could not be recommended in clinical practice.

Hypoglycaemia and the cardiovascular system

Physiological effects of acute hypoglycaemia

The haemodynamic effects of acute hypoglycaemia in humans are well reported. In healthy individuals, acute hypoglycaemia leads to an increase in heart rate of approximately 20 beats per minute with a 10% increase in mean systolic blood pressure and a 20 mm Hg decrease in the mean diastolic blood pressure.48 This translates into a 50–100% increase in cardiac output which lasts for up to 1 hour. In conjunction with this there is a sevenfold to eightfold increase in plasma adrenaline levels. Acute hypoglycaemia also increases the work-load on a human heart through an adrenaline surge and subsequent rise in myocardial oxygen demand.49 This may be of particular importance during episodes of acute coronary ischaemia.

Hypoglycaemia and myocardial blood flow

Following the early use of insulin, there were several case reports of it being associated with chest pain, angina and MI.8 ,50–56 These concerns meant that some clinicians were reluctant to commence patients on insulin therapy.51 While a direct causal link has not been established, animal studies have demonstrated that hypoglycaemia can increase myocardial infarct size by over 40%.57 Furthermore, in patients with DM and coexisting CAD, hypoglycaemia was associated with a third of all episodes of angina and corresponding ischaemic ECG changes.58

Myocardial blood flow reserve (MBFR) is an important parameter of myocardial perfusion determined by measuring myocardial blood flow (MBF) at rest and under maximal hyperaemia (peak stress).59 The ratio of MBF (peak stress) to MBF (rest) is equal to MBFR.60 In patients with CAD, the extent of the reduction in MBFR is directly related to the severity of epicardial coronary stenosis.61 ,62 However, in patients with unobstructed arteries on coronary angiography, a decreased MBFR is a marker of microvascular dysfunction.63 Patients with DM have been shown to have reduced MBFR even in the absence of flow-limiting CAD.64 ,65

Our group recently examined the effects of acute insulin-induced hypoglycaemia (using hyperinsulinemic clamp studies) on MBFR in 28 patients with type 1 DM and 19 healthy controls.66 All individuals underwent MBFR assessment at baseline, euglycaemia (5.0 mmol/l) and hypoglycaemia (2.8 mmol/l). In comparison with baseline, there was a 19% and 10% reduction in MBFR during hypoglycaemia in the healthy volunteers and patients with type 1 DM, respectively. It is plausible that the reduction in MBFR during hypoglycaemia may contribute to adverse CV outcomes.

Finally, patients with type 1 DM for >15 years’ duration have less elastic arteries in comparison with healthy controls during normal glucose levels and hypoglycaemia.67 In fact, arteries that are less compliant may accelerate the reflection of the arterial pulse back to the heart from arterioles, thereby returning during cardiac systole rather than diastole. The arrival of the arterial wave during diastole augments myocardial perfusion, and a loss of this benefit may subsequently reduce myocardial perfusion and predispose patients to myocardial ischaemia.

Hypoglycaemia and the risk of cardiac arrhythmias

Two decades ago, amidst concerns of increasing number of sudden deaths in the UK, Tattersall and Gill carried out a retrospective analysis of 50 suspected sudden deaths in young patients with type 1 DM.68 In 22 cases, no cause was found on autopsy and this led to the term ‘dead in bed syndrome’. All patients were young (12–43 years), with a history of nocturnal hypoglycaemic attacks.

The relation between hypoglycaemia and cardiac arrhythmias is recognised albeit poorly understood.69 and although it is suggested that these patients may have died secondary to hypoglycaemia-induced arrhythmia, a degree of caution in this interpretation is advised, as this association is theoretical and unproven. Prolonged QT syndrome is a well-recognised condition with an increased risk of sudden cardiac death and has been shown to occur during acute hypoglycaemia.70–72 In an observational study of 697 patients with type 1 DM, prolonged corrected QT interval QTc (>440 ms) emerged as an independent predictor of all-cause mortality.72 Subsequently, the Europe and Diabetes (EURODIAB) Prospective Complications Study showed that one in five patients with type 1 DM developed a persistently prolonged QTc during a 7-year follow-up with an annual incidence of 3%.73

Marques and coworkers investigated the effects of insulin-induced hypoglycaemia on the QTc in patients with type 1 and type 2 DM.74 During hypoglycaemia QTc increased by a similar amount in both groups however, a strong correlation was also demonstrated between the incremental increase in QTc during hypoglycaemia and peak adrenaline concentrations in blood. Following on from this, Lee demonstrated that adrenaline was responsible for QTc prolongation, and that this effect was independent of extracellular potassium levels.75 In addition, a subsequent study demonstrated that β-blockade prevented QTc prolongation during hypoglycaemia strongly suggesting further that an adrenaline rise was responsible for QTc prolongation.76

Hypoglycaemia and the risk of thrombosis

There is a growing body of evidence suggesting that acute hypoglycaemia alters platelet and clotting factor function thereby inducing a procoagulant and prothrombotic state.77–80

Corrall observed a twofold increase in the serum factor VIII levels within 30 min of acute hypoglycaemia, an effect abolished by β-blockade.77 Furthermore, in patients with DM, there is a twofold to threefold increase in platelet aggregation and a 50% increase in factor VIII concentrations following acute hypoglycaemia.78 The Von Willebrand factor (vWF) is also released from endothelial cells and platelets following episodes of low blood glucose. vWF prolongs the circulation lifetime of the coagulation factor VIII and promotes platelet aggregation. Following hypoglycaemia, the rise in vWF levels was shown to be greater in patients with DM.79 Acute hypoglycaemia has also been shown to promote platelet aggregation by 30%.80

In summary, hypoglycaemia induces several changes in the haemostatic parameters which include an increase in platelet aggregation, activation, degranulation as well as a rise in factor VIII and vWF levels. These effects are exaggerated in patients with DM and are likely to be detrimental to myocardial circulation particularly in patients with an already compromised myocardial perfusion.

Hypoglycaemia and endothelial dysfunction

The endothelium is a biologically active single cell layer responsible for the release of several substances the most important of which are nitric oxide (NO) and endothelin-1 (ET-1).81 NO is produced by the endothelium via an L-arginine pathway through endothelial NO synthase and mediates the vasodilatation of blood vessels.82

ET-1 is a 21-amino acid peptide and the most potent vasoconstrictor yet identified in man with a plasma half-life of 4–7 min.83 ET-1 acts on receptors located on vascular smooth muscle cells and fibroblasts. Direct infusion of ET-1 into the coronary sinus of humans has been shown to decrease coronary blood flow in a dose-related manner by up to 25%.84 ET-1 level has also been shown to be a strong predictor of no-reflow following primary angioplasty.85 Recently, the plasma concentration of ET-1 was shown to increase acutely by 70% in patients with type 1 DM following hypoglycaemia.86 Another study demonstrated that acute hypoglycaemia was associated with a threefold increase in high sensitivity C reactive protein levels in patients with DM (measured 24 h after the episode).87 In addition, acute hypoglycaemia has been shown to increase the circulating levels of interleukins, cytokines, markers of endothelial dysfunction and reactive oxygen species in humans significantly.88 ,89 This effect may last for up to 2 h following normalisation of blood glucose levels. These data suggest that acute hypoglycaemia causes the release of vasoactive substances, proinflammatory cytokines and oxygen-free radicals thereby promoting a milieu of endothelial dysfunction. This is of clinical importance as recent evidence has demonstrated that endothelial dysfunction is a precursor for the development of de novo atherosclerosis.90

Conclusion

Hypoglycaemia is a serious and frequent complication of IGC. Several recent studies have shown increased CV mortality when IGC induces hypoglycaemia in patients with DM in the outpatient setting and those admitted to hospitals. The mechanistic basis underpinning hypoglycaemia-induced CV morbidity and mortality is complex and is summarised in figure 1. This includes a reduction in the stress-induced increase in MBFR, a prothrombotic tendency, endothelial dysfunction and the risk of cardiac arrhythmias. Importantly, healthcare professionals should take meticulous care to avoid this potentially fatal complication.

Figure 1

Putative Pathological Mechanisms Linking Acute Hypoglycaemia with Adverse Cardiovascular Events. Acute Hypoglycaemia induces a prothrombotic milieu and a rise in cytokines, vasoconstrictors, inflammatory markers, interleukins and free oxygen radicals. These are likely to act as intermediary changes leading to a decrease in myocardial blood flow reserve and subsequent myocardial injury with a heightened risk of cardiac arrhythmias and sudden cardiac death. ET-1, Endothelin-1; hs-CRP, High sensitivity C reactive protein; IL-6, Interleukin 6; IL-8, Interleukin 8; MBFR, myocardial blood flow reserve; ROS, reactive oxygen species; QTc, Corrected QT interval.

Acknowledgments

We thank Mrs Nadia Saad for her help with figure 1. CDB is supported in part by the Southampton National Institute for Health Research Biomedical Research Centre.

References

Footnotes

  • Contributors The manuscript has been coauthored by all authors.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.