Review: Does hypoglycaemia cause cardiovascular events?

The British Journal of Diabetes & Vascular Disease http://dvd.sagepub.com/ Review: Does hypoglycaemia cause cardiovascular events? Alex J Graveling and Brian M Frier British Journal of Diabetes & Vascular Disease 2010 10: 5 DOI: 10.1177/1474651409355113 The online version of this article can be found at: http://dvd.sagepub.com/content/10/1/5 Published by: http://www.sagepublications.com Additional services and information for The British Journal of Diabetes & Vascular Disease can be found at: Email Alerts: http://dvd.sagepub.com/cgi/alerts Subscriptions: http://dvd.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Citations: http://dvd.sagepub.com/content/10/1/5.refs.html >> Version of Record - Feb 17, 2010 What is This? Downloaded from dvd.sagepub.com by guest on October 11, 2013 REVIEW Does hypoglycaemia cause cardiovascular events? ALEX J GRAVELING, BRIAN M FRIER Abstract S trict glycaemic control is strongly advocated in people with type 2 diabetes to prevent vascular disease. However, the outcomes of two large clinical trials have indicated the potential dangers of pursuing this policy in those at high risk of cardiovascular disease, with an excess of fatal vascular events being associated with a higher frequency of severe hypoglycaemia. Hypoglycaemia secondary to insulin and sulphonylurea therapy is often associated with serious morbidity; anecdotal evidence has long implicated hypoglycaemia as a potential cause of myocardial ischaemia or a cardiac arrhythmia. Hypoglycaemia provokes sympatho-adrenal activation and counterregulatory hormone secretion, which exert pronounced cardiovascular effects. Although well tolerated in healthy people, the superimposition of these profound physiological effects on a diseased coronary vasculature and a dysfunctional cardiac conductive system may induce serious or even fatal cardiovascular events. These risks should influence therapeutic targets and the approach to diabetes management in people with diabetes with established vascular disease in whom exposure to severe hypoglycaemia could be dangerous. Br J Diabetes Vasc Dis 2010;10:5–13 Key words: cardiac arrhythmia; cardiovascular event; diabetes mellitus; hypoglycaemia; myocardial ischaemia Introduction Diabetes and cardiovascular mortality Diabetes is a major risk factor for cardiovascular disease and is the principal cause of death in people with type 2 diabetes mellitus.1 Up to 80% of people with diabetes die from a major cardiovascular event, principally myocardial infarction but also stroke.2 Diabetes per se doubles the risk of cardiovascular events, which is equivalent to that of people without diabetes Department of Diabetes, Royal Infirmary of Edinburgh, Edinburgh, Scotland, UK. Correspondence to: Professor Brian M Frier Department of Diabetes, Royal Infirmary of Edinburgh, Edinburgh, EH16 4SA, UK. Tel: +44 (0)131 242 1475; Fax: +44 (0)131 242 1485 E-mail: brian.frier@luht.scot.nhs.uk Abbreviations and acronyms ACCORD ACS ADA ADVANCE DIGAMI ECG HbA1C ICU VADT Action to Control Cardiovascular Risk in Diabetes acute coronary syndrome American Diabetes Association Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction electrocardiogram glycated haemoglobin A1C intensive care unit Veterans Affairs Diabetes Trial who have already suffered a myocardial infarction.3,4 Microvascular disease is considered to be principally a risk of people with type 1 diabetes mellitus while those with type 2 diabetes are thought to be mostly at risk of developing premature macrovascular disease.5 However, although patients with type 2 diabetes undoubtedly have an increased risk of developing premature cardiovascular disease, patients with type 1 diabetes have a similar level of risk for cardiovascular disease when matched for age.6,7 Conversely, around 65% of patients admitted with a myocardial infarction, who have no history of diabetes, are found subsequently to have either impaired glucose tolerance or frank type 2 diabetes.8 Effect of HbA1C on cardiovascular mortality An elevated HbA1C is associated with an increased risk of sustaining a cardiovascular event.9 While good glycaemic control limits the risk; these benefits appear to persist for several years after glycaemic control has been relaxed both in type 1 and type 2 diabetes,10,11 suggesting the existence of a metabolic (glycaemic) memory. However, three large clinical trials, ACCORD, ADVANCE and VADT, have failed to show that intensive treatment to obtain strict glycaemic control (HbA1C < 7.0%) will lower the frequency of major cardiovascular events.12-14 While a subsequent metaanalysis indicated a benefit in selected outcomes, including death from cardiovascular events, no beneficial effect was observed on all cause mortality (see figure 1).15 The DIGAMI study showed that the use of insulin to treat and prevent hyperglycaemia in people © The Author(s), 2010. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav 10.1177/1474651409355113 5 REVIEW Figure 1. Composite forest plot of clinical outcomes of intensive glucose control on cardiovascular outcomes in a meta-analysis of randomised controlled trials Reprinted with permission.15 ©2009 Elsevier. with diabetes who presented with an ACS, resulted in fewer deaths.16 A subsequent study of patients who had better baseline glycaemic control did not show the same mortality benefit.17 Putative mechanisms of myocardial dysfunction in diabetes Diabetes, and hyperglycaemia in particular, can affect the coronary vasculature in several ways.18 Although the risk of coronary heart disease is higher in people with type 2 diabetes, the magnitude of risk varies widely between individuals and is not fully explained by traditional risk factors.2,19 In addition, the risk for women with diabetes is disproportionately raised, to the extent that they lose the protective effect of their sex and exhibit a risk equivalent to that of men with diabetes.20 The incidence of heart failure in people with diabetes is also substantially increased compared with matched non-diabetic controls (11.8% versus 3.2%).21 The putative disease process responsible is erroneously referred to as diabetic cardiomyopathy, although a more accurate term would be ‘specific heart disease of diabetes’.22 The aetiology of this complication is likely to be complex and multifactorial but a microvascular basis has been suggested as it is associated with a higher incidence of retinopathy23 and evidence of various pathological changes in the heart.24 6 Endothelial dysfunction is an early pathological feature in the development of atherosclerosis25 but the degree of impairment does not always correlate with the extent of coronary arterial disease.26 Severe endothelial dysfunction, even in the absence of obstructive coronary artery disease, is associated with an increase in cardiac events.27 People with diabetes develop arterial stiffness prematurely, with a significant increase being observed in young adults with type 1 diabetes of long duration (> 15 years), as compared with age-matched non-diabetic volunteers and those with a shorter duration of type 1 diabetes (< 5 years).28 This arterial stiffness has important implications for coronary vascular flow. Coronary artery filling mostly occurs during diastole. Normal elasticity of the arterial wall ensures that the reflected pressure wave from the high-pressure arterioles, generated during each myocardial contraction, returns to the heart during early diastole so increasing diastolic pressure and thereby enhancing coronary arterial perfusion.29 Progressive stiffening of the arterial wall results in the earlier arrival of the reflected wave during late systole, which may interfere with coronary arterial perfusion.30 The increased vascular stiffness that occurs in people with type 2 diabetes has been shown to predict cardiovascular mortality.31 VOLUME 10 ISSUE 1 . JANUARY/FEBRUARY 2010 REVIEW Haemodynamic changes during hypoglycaemia36-38 Table 1. • Increased heart rate • Increased peripheral systolic blood pressure • Decreased central blood pressure • Increased myocardial contractility with an increased ejection fraction • Decreased peripheral resistance (resulting in a widened pulse pressure) 75 240 70 220 65 200 60 180 55 160 50 140 45 120 40 100 0 Cardiac output (% of basal) Leftventricular ejection fraction (%) Figure 2. Cardiac function during hypoglycaemia. R corresponds with the acute autonomic reaction observed at the glucose nadir (mean 1.0 ± 0.2 mmol/L) R + 90 R + 60 R + 30 R Time from autonomic reaction (R) in minutes Leftventricular ejection fraction Cardiac output Composite of figures 2 and 3 from Fisher et al.39 Hypoglycaemia not important for counterregulation, such as the spleen and the skin. By contrast it is increased to the myocardium, splanchnic circulation (carrying 3-carbon precursors to the liver) and the brain. Autonomic activation, principally of the sympathoadrenal system, results in end-organ stimulation and a profuse release of epinephrine (adrenaline), which provokes haemodynamic changes (see table 1 and figure 2).35-39 The increased activity of the sympathetic nervous system and secretion of other hormones and peptides such as the potent vasoconstrictor, endothelin, have pronounced effects on intravascular haemorheology, coagulability and viscosity. 40 Increased plasma viscosity occurs during hypoglycaemia because of an increase in erythrocyte concentration, while coagulation is promoted by platelet activation and an increment in factor VIII and von Willebrand factor. Endothelial function may be compromised during hypoglycaemia because of an increase in C-reactive protein, mobilisation and activation of neutrophils and platelet activation. Figure 3 indicates how these changes could promote vascular occlusion and localised tissue ischaemia. How does hypoglycaemia affect myocardial function? Hypoglycaemia has profound effects on cardiac function but initially these can be difficult to distinguish from the effects of insulin per se. Insulin is a coronary vasodilator and has proinflammatory actions.41,42 The administration of intravenous insulin has a small, immediate effect to promote sympathetic neural activation and to increase left ventricular ejection fraction, before any fall in blood glucose occurs.22 These changes become more pronounced with a progressive decline in blood glucose; the maximal responses coincide with the glucose nadir. Significant increments in stroke volume and cardiac output also occur during hypoglycaemia.36 The haemodynamic changes during hypoglycaemia that are observed in non-diabetic adults are attenuated in some people with type 1 diabetes who have strict glycaemic control, which has been attributed to attenuated sympathetic stimulation.43 Hypoglycaemia is a very common side effect of insulin therapy and to a lesser extent of treatment with sulphonylureas. In type 1 diabetes the requisite for strict glycaemic control using intensive insulin therapy to minimise long-term microvascular complications, is associated with a three-fold increase in the risk of severe hypoglycaemia.32 Risk factors for severe hypoglycaemia include age, duration of diabetes, strict glycaemic control, sleep, impaired awareness of hypoglycaemia, renal impairment, C-peptide negativity and a previous history of severe hypoglycaemia.33,34 Hypoglycaemia results in significant morbidity and in younger patients with type 2 diabetes (aged from 20–49 years), between 6 and 18% of deaths have been attributed to hypoglycaemia.35 Antecedent hypoglycaemia induces a reduction in baroreflex sensitivity and sympathetic response to hypotensive stress, which may predispose susceptible individuals to the development of a cardiac arrhythmia.44,45 Diminished sympatho-adrenal responses also occur in type 2 diabetes following exposure to antecedent hypoglycaemia46 but the possible effects on the autonomic innervation to the heart have not been studied in type 2 diabetes. Impairment of the autonomic neural control of heart rate is associated with an increased risk of mortality.47 Pathophysiology of hypoglycaemia Hypoglycaemia and mortality rate Acute hypoglycaemia provokes pronounced physiological responses, the important consequences of which are to maintain the supply of glucose to the brain and promote the hepatic production of glucose. Blood flow is reduced to organs that are A direct relationship between hypoglycaemia and a fatal cardiovascular event is difficult to demonstrate as blood glucose and cardiac monitoring are seldom performed simultaneously. In 2008 an excess of deaths in the intensive treatment arm of the THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE Does previous exposure to hypoglycaemia modify the risk? 7 REVIEW Figure 3. Haematological and inflammatory processes that may lead to vascular complications Haemodynamic changes ↑Endothelin ↑Plasma viscosity ↑Factor VIII ↓Blood flow Vasoconstriction Capillary closure ↑vWF Platelet activation Neutrophil activation ↑Coagulation Endothelial damage Thrombosis Atherogenesis ↑CRP VASCULAR COMPLICATIONS Adapted with permission.40 ACCORD study led to early discontinuation of the study.12 This has prompted much speculation about the likely reasons and potential underlying mechanisms that could be responsible for the greater number of deaths in people with strict glycaemic control. In ACCORD hypoglycaemia was three times more common in the intensively treated group, with an annual prevalence of severe hypoglycaemia of 3.3% compared to 1.1% in the group receiving standard treatment. Mortality in the 93% of patients who had no episodes of severe hypoglycaemia during the study was 1.2% compared with 3.1% in those with a history of one or more episodes of severe hypoglycaemia.48 Although the authors of the ACCORD study have persistently maintained that the cardiovascular deaths were not caused by hypoglycaemia (ADA meeting, New Orleans, 2009), this assertion cannot be proven as neither continuous blood glucose nor Holter monitoring was used in the study. A panel of cardiologists, that adjudicated the cause of death in the fatal cases, decided that none of these had been caused by hypoglycaemia. As concomitant blood glucose data were not available in these fatal cases it is unclear how the potential predisposing effects of hypoglycaemia could be discounted in this situation. In the smaller study of veterans with type 2 diabetes, VADT,14 severe hypoglycaemia was found to increase the risks of adverse events and death. In both treatment groups combined, those who had experienced hypoglycaemic coma had an 88% increase in primary cardiovascular events and a threefold higher rate of cardiovascular death (ADA meeting, New Orleans, 2009). Information from other clinical studies support the premise that exposure to hypoglycaemia has inherent cardiovascular risks, particularly in people who are seriously ill. Patients with 8 diabetes, who were admitted to hospital with ACS and who experienced severe hypoglycaemia at some point during their hospital stay, exhibited double the mortality rate compared with those who had no hypoglycaemia. This effect persisted despite adjustment for potential confounders.49,50 The cardiovascular causes of death in patients who had a history of recent hypoglycaemia suggested that the susceptibility of those patients to cardiac arrhythmia may have been increased by preceding exposure to low blood glucose. A possible mechanism may involve the demonstrated effect of antecedent hypoglycaemia to diminish the cardiac vagal baroreflex sensitivity and the sympathetic response to drug-induced hypotension, and thereby attenuating the autonomic responses to cardiovascular stress for up to 16 hours.44 Extremes of blood glucose on admission to hospital in patients with ST-elevation ACS, were associated with a greater 30-day mortality (figure 4).51 In a different study, patients who did not have diabetes but who developed spontaneous hypoglycaemia during their hospital stay had a significantly poorer outcome than those with insulintreated diabetes who developed iatrogenic hypoglycaemia.50,52 In this situation the development of hypoglycaemia may be a surrogate marker for severity of illness, but it may also contribute directly to a fatal outcome. Hypoglycaemia in the ICU In hospitalised patients with critical illness, hyperglycaemia is associated with poorer clinical outcomes but the degree to which glucose should be lowered during the management of these patients has provoked debate.53,54 Despite various observational studies that have shown a direct linear relationship between VOLUME 10 ISSUE 1 . JANUARY/FEBRUARY 2010 REVIEW Figure 4. Association of admission blood glucose level with mortality at 30 days 12.0% 10.4% Mortally (%) 10.0% 8.0% 6.3% 5.2% 6.0% 4.0% 3.1% 2.6% 2.3% 4.5–5.5 5.6–6.9 2.0% 0.0% <4.5 7.0–8.3 8.4–11.1 >11.1 Blood glucose level (mmol/L) Reprinted with permission51©2008 Elsevier. Table 2. Trial name Summary data from randomised clinical trials of intensive insulin therapy in critically ill patients55 No. of Type of Blood glucose level patients ICU targeted Blood glucose level achieved Primary outcome Intensive Conventional Intensive Conventional glucose glucose glucose glucose control control control control mmol/L Rate of outcome Odds ratio Intensive Conventional glucose glucose control control mmol/L % Leuven 1 1548 Surgical 4.4–6.1 10.0–11.1 5.7 8.5 Death in ICU 4.6 8.0 0.58 (0.38–0.78) Leuven 2 1200 Medical 4.4–6.1 10.0–11.1 6.2 8.5 Death in hospital 37.3 40.0 0.94 (0.84–1.06) 1.10 (0.84–1.44) Glucontrol 1101 General 4.4–6.1 7.8–10.0 6.6 8.0 Death in ICU 16.7 15.2 VISEP 537 General 4.4–6.1 10.0–11.1 6.2 8.4 Death at 28 days 24.7 26.0 Not reported NICE- 6104 General 4.4–6.1 8.0–10.0 6.6 8.1 Death at 90 days 27.5 24.9 1.14 (1.02–1.28) SUGAR decrements in blood glucose and an increase in mortality rates, it is unclear whether hypoglycaemia per se is responsible for these outcomes or whether it is simply a surrogate marker indicating the sickest patients who are at the greatest risk of dying.55 A seminal study from Belgium showed that mortality was lower in patients who were treated with an intensive insulin regimen in the setting of an ICU;56 only 13% of these patients were known to have diabetes. Subsequent studies have failed to replicate these findings in other inpatient populations (table 2), which has challenged how much these results can be generalised. THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE The relationship of glycaemic control to outcome was examined in a large, multi-centre, randomised controlled trial of patients treated in ICUs in Australia.57 Strict control of blood glucose (4.5–6.0 mmol/L) was compared with standard control (<10.0 mmol/L). The mortality was higher in those who received strict glycaemic control, in whom severe hypoglycaemia (defined as blood glucose < 2.2mmol/L) was much more common (6.8% vs. 0.5%). A subgroup analysis suggested that no difference existed between those with diabetes (~20%) and those without diabetes (~80%). A potential criticism is that 9 REVIEW Figure 5. ECG alterations during hypoglycaemia, ECG recorded at the glucose nadir when maximal ST depression was observed Hypoglycaemia and adverse cardiac outcomes Wright and Frier have suggested that while a young healthy individual can tolerate the profound physiological effects of acute hypoglycaemia on the cardiovascular system, when these acute changes are superimposed on a diseased coronary vasculature, they may provoke myocardial ischaemia or an arrhythmia.40 It would now be considered potentially dangerous and unethical to subject patients with established coronary heart disease to experimental hypoglycaemia, but anecdotal case reports have demonstrated a relationship between hypoglycaemia and acute vascular events63 and sudden death.64,65 Can hypoglycaemia cause myocardial ischaemia? Reprinted with permission.68 ©1960 Elsevier. when blood glucose was considered to be ‘stable’, the protocol moved blood glucose measurement to 4-hourly testing, which most commentators would consider to be insufficient to assess glycaemic control in an intensive care setting. Neuroglycopenia may be much more difficult to detect in an unconscious patient under sedation, and may therefore be missed in this situation. In comparison with the earlier Belgian studies, the conventionally treated group had stricter glycaemic control (blood glucose of 8.0–10.0 mmol/L vs. 10.0–11.1 mmol/L) with a predominance of enteral rather than parenteral nutrition. Two metaanalyses have shown that strict glycaemic control in seriously ill patients does not improve overall survival or reduce the need for dialysis.58,59 It reduced the risk of septicaemia, but only in surgical ICUs and at the expense of a five-fold higher incidence of hypoglycaemia (13.7% vs. 2.5%). Hypoglycaemia in the hospital setting Outside the critical care environment, glycaemic management in the hospital setting has received less attention. A large retrospective cohort study of patients admitted with diabetes found that one or more episodes of hypoglycaemia (blood glucose < 2.8 mmol/L) was associated with an increased length of stay, while inpatient deaths increased by 85% and 1-year mortality was increased by 66%,60 Glycaemic targets were reached more often when a basal-bolus subcutaneous insulin regimen was used compared with an intravenous sliding scale (66% vs. 38%), with no increase in the incidence of hypoglycaemia.61 No differences in glycaemic control or in the incidence of hypoglycaemia were observed when comparing insulin regimens using human or analogue insulins.62 10 An early case report described a 58-year-old patient who experienced angina in association with ‘insulin shock’ (hypoglycaemia),66 while in a modern case, typical ECG and enzyme changes were associated with an ACS that followed a massive insulin overdose and subsequent severe hypoglycaemia.67 Angiography demonstrated normal coronary vasculature; therefore dynamic changes in the coronary blood vessels may have caused the myocardial ischaemia. Anecdotal case studies such as these have prompted researchers to examine the association between hypoglycaemia and cardiovascular events. Egeli (1960) conducted a study of the effects of insulin and hypoglycaemia on ECG changes (figure 5).68 Patients with diabetes were made hypoglycaemic with insulin (the lowest blood glucose was around 2.5 mmol/L) and ECG changes involving the ST segments and T waves were noted. These changes could be partly ameliorated with betablockade or administration of serum potassium.69 Ischaemic changes were noted in the ECGs of five out of six patients with type 2 diabetes when they were rendered hypoglycaemic, with a bradyarrhythmia occurring in one patient that resulted in loss of consciousness.70 Continuous blood glucose monitoring and Holter ECG monitoring were performed simultaneously in patients with type 2 diabetes and known ischaemic heart disease;71 54 episodes of hypoglycaemia (blood glucose < 3.9 mmol/L) were identified, 10 of which were accompanied by chest pain. ST segment abnormalities were observed in four of the symptomatic episodes and in two episodes of asymptomatic biochemical hypoglycaemia. By contrast, one solitary episode of chest pain occurred during hyperglycaemia (blood glucose > 11.1 mmol/L) and none occurred during euglycaemia. Can hypoglycaemia cause a clinically significant arrhythmia? Ventricular tachycardia and atrial fibrillation have been reported during hypoglycaemia.72,73 Hypoglycaemia has long been known to affect the ECG74 and it also causes hypokalaemia secondary to the increase in plasma catecholamines. Although the finding of a lengthened QTc (corrected QT) interval has not been invariable, hypoglycaemia consistently reduces the T wave amplitude.69,75 These ECG changes may increase the risk of arrhythmia.76 VOLUME 10 ISSUE 1 . JANUARY/FEBRUARY 2010 REVIEW Key messages particularly at night. This may permit more rational adjustment of insulin regimens to avoid hypoglycaemia and reduce the potential risk of inducing a cardiac arrhythmia. References People with type 1 and type 2 diabetes are at major risk of developing cardiovascular disease ● Hypoglycaemia provokes profound physiological changes that may result in cardiovascular events ● Hypoglycaemia as a result of insulin or sulphonylurea therapy can be associated with substantial morbidity and mortality ● Several large trials have not shown the anticipated mortality benefits of strict glycaemic control (HbA1C < 7.0%) but have reported a higher frequency of severe hypoglycaemia in the intensive treatment arms with an excess of cardiovascular deaths ● Sudden death during sleep has been described in patients with type 1 diabetes, the putative mechanism being a significant cardiac arrhythmia induced by nocturnal hypoglycaemia.77,78 Many of these patients had no evidence of severe hypoglycaemia-induced neuronal damage at autopsy, implying that a cardiac arrhythmia had been triggered by hypoglycaemia, resulting in sudden death.79 Cardiac arrhythmias have been recorded during spontaneous episodes of nocturnal hypoglycaemia.80 It is reassuring that despite the high frequency of nocturnal hypoglycaemia in young people with type 1 diabetes, sudden nocturnal death (‘dead in bed’ syndrome) is rare. However, it is possible that the presence of a genetic mutation (e.g. in a cardiac ion channel) or predisposition may be necessary for a cardiac arrhythmia to occur.81 A German study of 16 adolescents with type 1 diabetes observed lengthening of QTc during hypoglycaemia in all subjects with the greatest increase recorded in the sibling of a patient who had died previously with the ‘dead in bed’ syndrome.82 Routine ECG screening appears to be of limited use in detecting those at risk as no correlation was shown between QTc prolongation during euglycaemia and QTc prolongation during hypoglycaemia. Conclusions Evidence is accumulating that severe hypoglycaemia can provoke adverse cardiovascular outcomes such as myocardial ischaemia or cardiac arrhythmia. This may explain why some clinical trials in the critical care setting have failed to show a benefit of strict glycaemic control to reduce mortality. 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