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When hypoglycemia is not obvious: Diagnosing and treating under-recognized and undisclosed hypoglycemia

Open AccessPublished:October 07, 2013DOI:https://doi.org/10.1016/j.pcd.2013.09.002

      Abstract

      Hypoglycemia continues to be a significant problem for patients with diabetes. The incidence remains high but patients may also be under-reporting hypoglycemic events for various reasons, including hypoglycemia unawareness and deliberate non-reporting. This restricts the ability of healthcare professionals to manage treatment effectively.
      The aim of this article is to focus specifically on the issues associated with hypoglycemia unawareness and undisclosed hypoglycemia. The article provides general practice teams with an overview of these problems and, through patient narratives, suggests ways to mitigate them.

      Keywords

      1. Introduction

      In real-life clinical practice, hypoglycemia is a significant problem for patients with either type 1 or type 2 diabetes. The incidence remains high and hypoglycemia can often go unrecognized in primary care. Unfortunately, healthcare providers are faced with the dilemma that improving glycemic control through intensive diabetes treatment, to reduce the risk of developing complications in patients with diabetes, is confounded by the risk of hypoglycemia [
      • UK Prospective Diabetes Study (UKPDS) Group
      Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
      ,
      • ADVANCE Collaborative Group
      • Patel A.
      • MacMahon S.
      • Chalmers J.
      • et al.
      Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
      ,
      • The Action to Control Cardiovascular Risk in Diabetes Study Group (ACCORD)
      Effects of intensive glucose lowering in type 2 diabetes.
      ,
      • Duckworth W.
      • Abraira C.
      • Moritz T.
      • et al.
      VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes.
      ]. Hypoglycemia can have a significant negative impact on patients’ well-being, daily routine and lifestyle, preventing them from leading a fulfilling life, and imposing significant burdens on patients as well as the community [
      • Fidler C.
      • Elmelund C.T.
      • Gillard S.
      Hypoglycemia: an overview of fear of hypoglycemia, quality-of-life, and impact on costs.
      ]. However, patient under-reporting – due to hypoglycemia unawareness and possibly deliberate under-reporting – restricts the ability of healthcare professionals to improve treatment regimens and refine management of the disease [
      • Briscoe V.J.
      • Davis S.N.
      Hypoglycemia in type 1 and type 2 diabetes: physiology, pathophysiology, and management.
      ]. The aim of this article is to highlight the issues associated with hypoglycemia unawareness and undisclosed hypoglycemia, the scale of these problems and what can be done to mitigate them.

      2. Background to hypoglycemia

      2.1 Definition

      Circulating glucose is the primary source of energy for the brain, which is therefore vulnerable to low blood glucose levels. In order to protect the brain, a number of physiological mechanisms are activated to minimize the effects of hypoglycemia (Fig. 1) [
      • Mitrakou A.
      • Ryan C.
      • Veneman T.
      • et al.
      Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction.
      ,
      • Frier B.M.
      • Fisher B.M.
      Impaired hypoglycaemia awareness.
      ]. The initial response is the cessation of insulin secretion at a blood glucose threshold of ∼4.6 mmol/L (∼83 mg/dL) [
      • Zammitt N.N.
      • Frier B.M.
      Hypoglycemia in type 2 diabetes: pathophysiology, frequency, and effects of different treatment modalities.
      ]. This is followed by counter-regulatory hormone responses (starting at 3.8 mmol/L (68.4 mg/dL)), primarily the release of the fast-acting glucagon and epinephrine (adrenaline) hormones, and cognitive and symptomatic changes [
      • Briscoe V.J.
      • Davis S.N.
      Hypoglycemia in type 1 and type 2 diabetes: physiology, pathophysiology, and management.
      ,
      • Zammitt N.N.
      • Frier B.M.
      Hypoglycemia in type 2 diabetes: pathophysiology, frequency, and effects of different treatment modalities.
      ,
      • Cryer P.E.
      • Davis S.N.
      • Shamoon H.
      Hypoglycemia in diabetes.
      ,
      • Graveling A.J.
      • Frier B.M.
      Hypoglycaemia: an overview.
      ].
      Figure thumbnail gr1
      Fig. 1Physiological response to hypoglycemia
      [
      • Frier B.M.
      • Fisher B.M.
      Impaired hypoglycaemia awareness.
      ]
      . (Reproduced with permission of John Wiley & Sons Ltd.).
      In people with type 1 diabetes, an absolute insulin deficiency precludes the first-line defense against falling blood glucose levels. In addition, with the loss of the pancreatic α-cell glucagon secretory response, the last remaining defenses are the release of epinephrine and autonomic warning symptoms, which also become attenuated in these patients [
      • Cryer P.E.
      Hypoglycaemia: the limiting factor in the glycaemic management of type I and type II diabetes.
      ]. In people with type 2 diabetes, the residual β-cell function initially preserves the insulin first-line defense. However, with the progressive loss of β-cell function and repeated hypoglycemic events, the endogenous glucose counter-regulatory response is lost [
      • De Galan B.E.
      • Schouwenberg B.J.
      • Tack C.J.
      • Smits P.
      Pathophysiology and management of recurrent hypoglycaemia and hypoglycaemia unawareness in diabetes.
      ,
      • Segel S.A.
      • Paramore D.S.
      • Cryer P.E.
      Hypoglycemia-associated autonomic failure in advanced type 2 diabetes.
      ].
      The exact biochemical definition of hypoglycemia also varies between associations, with glycemic thresholds defined as follows:
      • European Medicines Agency (EMA), 3.9 mmol/L (70 mg/dL) [
        • EMA
        CPMP/EWP/1080/00. Rev. 1.
        ].
      • American Diabetes Association (ADA), 3.9 mmol/L (70 mg/dL) [
        • Seaquist E.R.
        • Anderson J.
        • Childs B.
        • et al.
        Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and The Endocrine Society.
        ].
      • Canadian Diabetes Association (CDA), 4.0 mmol/L (72 mg/dL) [
        • Yale J.F.
        • Begg I.
        • Gerstein H.
        • et al.
        2001 Canadian Diabetes Association clinical practice guidelines for the prevention and management of hypoglycemia in diabetes.
        ].
      The recent update to the ADA hypoglycemia guidance has not altered the proposed value, but does state that a single threshold value for hypoglycemia cannot be assigned because the threshold for physiological responses may shift up or down.
      The EMA's definition is a very recent change (originally 3.1 mmol/L (56 mg/dL)), which has met with broad resistance from the medical community in Europe due to the burden it places on people living with diabetes and their carers. This is due to the fact that counter-regulatory responses and symptoms are not activated until blood glucose levels fall below 3.8 mmol/L (68.4 mg/dL), with the most important cognitive functional changes not occurring until levels reach 2.8 mmol/L (50.4 mg/dL) [
      • Zammitt N.N.
      • Frier B.M.
      Hypoglycemia in type 2 diabetes: pathophysiology, frequency, and effects of different treatment modalities.
      ]. Thus, the recent change to the EMA's hypoglycemia definition may lead to a higher number of episodes being recorded that are not a true reflection of a hypoglycemic state. This will have wide-reaching consequences for the patient, especially with regard to permission to drive.
      Standard classifications of hypoglycemia include confirmed, severe and nocturnal hypoglycemic events; these classifications are often used as outcomes in clinical trials [
      • Briscoe V.J.
      • Davis S.N.
      Hypoglycemia in type 1 and type 2 diabetes: physiology, pathophysiology, and management.
      ,
      • Seaquist E.R.
      • Anderson J.
      • Childs B.
      • et al.
      Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and The Endocrine Society.
      ], although the definitions used to classify hypoglycemic events in clinical trials have varied quite widely. Confirmed hypoglycemia is an event where a blood glucose measurement below the defined threshold is available, whilst a severe event is one where the assistance of another person is necessary. A nocturnal event is one that occurs during the night, regardless of whether the individual is awake or asleep, and ‘nocturnal’ is generally considered as the period from bedtime until wake-up [
      • Wentholt I.M.
      • Maran A.
      • Masurel N.
      • et al.
      Nocturnal hypoglycaemia in type 1 diabetic patients, assessed with continuous glucose monitoring: frequency, duration and associations.
      ,
      • The D.C.C.T.
      • research group
      Epidemiology of severe hypoglycemia in the diabetes control and complications trial.
      ].

      2.2 Symptoms

      Hypoglycemia can cause a variety of symptoms that can be classified as either neurogenic (autonomic) or neuroglycopenic (Table 1). Neurogenic symptoms are caused by physiological responses to low glucose concentrations; neuroglycopenic symptoms, due to glucose deprivation in the central nervous system, are more distressing and severe [
      • Briscoe V.J.
      • Davis S.N.
      Hypoglycemia in type 1 and type 2 diabetes: physiology, pathophysiology, and management.
      ,
      • Cryer P.E.
      • Davis S.N.
      • Shamoon H.
      Hypoglycemia in diabetes.
      ,
      • Graveling A.J.
      • Frier B.M.
      Hypoglycaemia: an overview.
      ].
      Table 1Symptoms of hypoglycemia
      • Briscoe V.J.
      • Davis S.N.
      Hypoglycemia in type 1 and type 2 diabetes: physiology, pathophysiology, and management.
      ,
      • Cryer P.E.
      • Davis S.N.
      • Shamoon H.
      Hypoglycemia in diabetes.
      ,
      • Graveling A.J.
      • Frier B.M.
      Hypoglycaemia: an overview.
      .
      ClassificationTypical symptoms
      NeurogenicTrembling, sweating, anxiety, hunger
      NeuroglycopenicCognitive impairment, confusion, behavioral changes
      Loss of consciousness (even death) in severe cases

      2.3 Frequency

      As patients with type 1 diabetes depend on exogenous insulin, they are unable to down-regulate insulin secretion as a first-line response, so they experience a higher frequency of hypoglycemic events than those patients with type 2 diabetes [
      • Donnelly L.A.
      • Morris A.D.
      • Frier B.M.
      Frequency and predictors of hypoglycaemia in Type 1 and insulin-treated Type 2 diabetes: a population-based study.
      ]. These hypoglycemic rates are >15-fold lower in orally treated and approximately 6-fold lower in insulin-treated patients with type 2 diabetes than in patients with type 1 diabetes [
      • De Galan B.E.
      • Schouwenberg B.J.
      • Tack C.J.
      • Smits P.
      Pathophysiology and management of recurrent hypoglycaemia and hypoglycaemia unawareness in diabetes.
      ]. Interestingly, the frequency of severe hypoglycemia increases over time in patients with type 2 diabetes [
      • UK Hypoglycaemia Study Group
      Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration.
      ]. The frequencies of hypoglycemic events reported in some representative studies, chosen to include key clinical trials and large database analyses, are listed in Table 2 [
      • UK Prospective Diabetes Study (UKPDS) Group
      Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
      ,
      • The D.C.C.T.
      • research group
      Epidemiology of severe hypoglycemia in the diabetes control and complications trial.
      ,
      • Donnelly L.A.
      • Morris A.D.
      • Frier B.M.
      Frequency and predictors of hypoglycaemia in Type 1 and insulin-treated Type 2 diabetes: a population-based study.
      ,
      • UK Hypoglycaemia Study Group
      Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration.
      ,
      • Leiter L.A.
      • Yale J.F.
      • Chiasson J.L.
      • et al.
      Assessment of the impact of fear of hypoglycemic eipsodes on glycemic and hypoglycemia management.
      ,
      • Abraira C.
      • Colwell J.A.
      • Nuttall F.Q.
      • et al.
      Veterans Affairs Cooperative Study on glycemic control and complications in type II diabetes (VA CSDM): results of the feasibility trial.
      ,
      • Miller C.D.
      • Phillips L.S.
      • Ziemer D.C.
      • et al.
      Hypoglycemia in patients with type 2 diabetes mellitus.
      ,
      • Henderson J.N.
      • Allen K.V.
      • Deary I.J.
      • Frier B.M.
      Hypoglycaemia in insulin-treated type 2 diabetes: frequency, symptoms and impaired awareness.
      ]. It is worth noting that reporting rates may be lower in clinical practice than in trials, where endpoints such as hypoglycemia are carefully monitored.
      Table 2Incidence and prevalence of hypoglycemia in insulin-treated patients from selected clinical trials and analyses
      • UK Prospective Diabetes Study (UKPDS) Group
      Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
      ,
      • The D.C.C.T.
      • research group
      Epidemiology of severe hypoglycemia in the diabetes control and complications trial.
      ,
      • Donnelly L.A.
      • Morris A.D.
      • Frier B.M.
      Frequency and predictors of hypoglycaemia in Type 1 and insulin-treated Type 2 diabetes: a population-based study.
      ,
      • UK Hypoglycaemia Study Group
      Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration.
      ,
      • Leiter L.A.
      • Yale J.F.
      • Chiasson J.L.
      • et al.
      Assessment of the impact of fear of hypoglycemic eipsodes on glycemic and hypoglycemia management.
      ,
      • Abraira C.
      • Colwell J.A.
      • Nuttall F.Q.
      • et al.
      Veterans Affairs Cooperative Study on glycemic control and complications in type II diabetes (VA CSDM): results of the feasibility trial.
      ,
      • Miller C.D.
      • Phillips L.S.
      • Ziemer D.C.
      • et al.
      Hypoglycemia in patients with type 2 diabetes mellitus.
      ,
      • Henderson J.N.
      • Allen K.V.
      • Deary I.J.
      • Frier B.M.
      Hypoglycaemia in insulin-treated type 2 diabetes: frequency, symptoms and impaired awareness.
      .
      T1DDesignNAll hypoglycemiaSevere hypoglycemia
      Incidence (episodes/PYE)Prevalence (%)Incidence (episodes/PYE)Prevalence (%)
      DCCT
      • The D.C.C.T.
      • research group
      Epidemiology of severe hypoglycemia in the diabetes control and complications trial.
      1991Prospective randomized817NANA0.19 (standard)8.6
      0.62 (intensive)17.9
      Donnelly et al.
      • Donnelly L.A.
      • Morris A.D.
      • Frier B.M.
      Frequency and predictors of hypoglycaemia in Type 1 and insulin-treated Type 2 diabetes: a population-based study.
      2005Prospective9442.8982.01.154.0
      Leiter et al.
      • Leiter L.A.
      • Yale J.F.
      • Chiasson J.L.
      • et al.
      Assessment of the impact of fear of hypoglycemic eipsodes on glycemic and hypoglycemia management.
      2005Retrospective202102.095.52.627.2
      UK Hypo Study Group
      Patients were classified by duration of their diabetes. NA: not applicable; PYE: patient-year of exposure; T1D: type 1 diabetes; T2D: type 2 diabetes.
      • UK Hypoglycaemia Study Group
      Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration.
      2007Retrospective<2 years: 4635.5NA1.1NA
      >5 years: 5429.0NA3.2NA
      T2DDesignNAll hypoglycemiaSevere hypoglycemia
      Incidence (episodes/PYE)Prevalence (%)Incidence (episodes/PYE)Prevalence (%)
      VA CSDM
      • Abraira C.
      • Colwell J.A.
      • Nuttall F.Q.
      • et al.
      Veterans Affairs Cooperative Study on glycemic control and complications in type II diabetes (VA CSDM): results of the feasibility trial.
      1995Prospective randomized1531.5 (standard)56.0 (standard)0.01 (standard)NA
      16.5 (intensive)93.0 (intensive)0.03 (intensive)NA
      UKPDS
      • UK Prospective Diabetes Study (UKPDS) Group
      Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
      1998Prospective randomized3935NA36.5NA2.3
      Miller et al.
      • Miller C.D.
      • Phillips L.S.
      • Ziemer D.C.
      • et al.
      Hypoglycemia in patients with type 2 diabetes mellitus.
      2001Retrospective1055NA30.5NA0.5
      Henderson et al.
      • Henderson J.N.
      • Allen K.V.
      • Deary I.J.
      • Frier B.M.
      Hypoglycaemia in insulin-treated type 2 diabetes: frequency, symptoms and impaired awareness.
      2003Retrospective215NA73.00.2815.0
      Donnelly et al.
      • Donnelly L.A.
      • Morris A.D.
      • Frier B.M.
      Frequency and predictors of hypoglycaemia in Type 1 and insulin-treated Type 2 diabetes: a population-based study.
      2005Prospective17316.3645.00.353.0
      Leiter et al.
      • Leiter L.A.
      • Yale J.F.
      • Chiasson J.L.
      • et al.
      Assessment of the impact of fear of hypoglycemic eipsodes on glycemic and hypoglycemia management.
      2005Retrospective13366.072.95.914.3
      UK Hypo Study Group
      Patients were classified by duration of their diabetes. NA: not applicable; PYE: patient-year of exposure; T1D: type 1 diabetes; T2D: type 2 diabetes.
      • UK Hypoglycaemia Study Group
      Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration.
      2007Retrospective<2 years: 854.08NA0.1NA
      >5 years: 7510.2NA0.7NA
      a Patients were classified by duration of their diabetes. NA: not applicable; PYE: patient-year of exposure; T1D: type 1 diabetes; T2D: type 2 diabetes.

      2.4 Causes and risk factors

      Table 3 lists some of the antidiabetic and other drugs that are most commonly associated with a risk of hypoglycemia. It is important to note that, aside from the particular drug used, dosage levels are important in determining the risk of hypoglycemia, with higher circulating doses increasing the risk.
      Table 3Drugs (antidiabetic and others) that are or are not associated with a risk of hypoglycemia.
      Associated with a risk of hypoglycemia
      OADsSulfonylureas, meglitinides (nateglinide, repaglinide), glimepiride
      InsulinAll insulins
      Other drugsAlcohol, aspirin, warfarin, allopurinol or probenecid when in combination with antidiabetic medications
      Not usually associated with a risk of hypoglycemia on their own
      OADsAlpha-glucosidase inhibitors, biguanides (metformin), thiazolidinediones, GLP-1 agonists, DPP-4 inhibitors, SGLT2 inhibitors
      DPP-4 inhibitors: dipeptidyl peptidase-4 inhibitors; GLP-1: glucagon-like peptide 1; OADs: oral antidiabetic drugs; SGLT2: sodium–glucose linked transporter 2
      Variability in the glucose-lowering action of insulin therapy can be a driver for hypoglycemia [
      • Vora J.
      • Heise T.
      Variability of glucose-lowering effect as a limiting factor in optimizing basal insulin therapy: a review.
      ]. Patients can vary in the rate at which they absorb injected insulin (inter-patient variability) and even variations in the absorption profile can occur from day to day within the same patient (intra-patient variability) [
      • Vora J.
      • Heise T.
      Variability of glucose-lowering effect as a limiting factor in optimizing basal insulin therapy: a review.
      ]. Modern basal insulin analogs have been formulated to reduce this variability, thus lowering the risk of hypoglycemia compared with human insulin or neutral protamine Hagedorn (NPH) insulin, although there is still room for further improvement [
      • Vora J.
      • Heise T.
      Variability of glucose-lowering effect as a limiting factor in optimizing basal insulin therapy: a review.
      ].
      In addition to antidiabetic treatment, there are other causes of hypoglycemia including inadequate, delayed or missed meals; exercise; hot weather; the use of recreational drugs or excessive alcohol consumption; and age-related impairment of the counter-regulatory hormone responses [
      • Zammitt N.N.
      • Frier B.M.
      Hypoglycemia in type 2 diabetes: pathophysiology, frequency, and effects of different treatment modalities.
      ,
      • Graveling A.J.
      • Frier B.M.
      Hypoglycaemia: an overview.
      ,
      • Raz I.
      • Weiss R.
      • Yegorchikov Y.
      • et al.
      Effect of a local heating device on insulin and glucose pharmacokinetic profiles in an open-label, randomized, two-period, one-way crossover study in patients with type 1 diabetes using continuous subcutaneous insulin infusion.
      ]. More long-term factors that can influence the risk include change in weight, renal or liver dysfunction and concomitant medications [
      • Cryer P.E.
      Hypoglycaemia: the limiting factor in the glycaemic management of type I and type II diabetes.
      ,
      • Davis T.M.
      • Brown S.G.
      • Jacobs I.G.
      • et al.
      Determinants of severe hypoglycemia complicating type 2 diabetes: the Fremantle diabetes study.
      ,
      • Amiel S.A.
      • Dixon T.
      • Mann R.
      • Jameson K.
      Hypoglycaemia in type 2 diabetes.
      ]. In addition, depression, which many people with diabetes suffer from, has been found to be associated with the risk of severe hypoglycemia [
      • Katon W.J.
      • Young B.A.
      • Russo J.
      • et al.
      Association of depression with increased risk of severe hypoglycemic episodes in patients with diabetes.
      ].
      Box: Hypothetical case study 1: An elderly patient with a high risk of hypoglycemia
      Jean is an 84-year-old widow who has had type 2 diabetes for 16 years. She lives in a warden-controlled dwelling and has her medication prepared in a ‘dosette’ box each week. She is currently taking sustained-release metformin 1 g daily and gliclazide 160 mg twice daily, as well as a statin drug and two anti-hypertensive agents.
      She attends a diabetes review where she states that she is well, although her diet seems to be restricted, but she states that she has no symptoms. You note she had a fall 3 months previously and fractured her wrist. Her current HbA1c is 6.4% (46 mmol/mol), which has been reduced over the past year.
      You are concerned that Jean is a vulnerable adult as she lives on her own with minimal supervision and her eating habits may be erratic. You note that she has a low HbA1c. Her sulfonylurea medication and erratic eating habits leave her vulnerable to hypoglycemia, which may go under-recognized.
      You decide to stop the gliclazide as you feel that her current diabetes control is too tight to be safe. You check her renal function to ensure that she can use metformin safely. You adjust her ‘dosette’ box with the dispensing chemist and ensure that she has a suitable diet, and has meals provided as appropriate.
      Sulfonylureas can also cause hypoglycemia related to absolute/relative insulin excess and may pose the greatest risk of hypoglycemia to patients with renal or hepatic dysfunction and to elderly adults [
      • Zammitt N.N.
      • Frier B.M.
      Hypoglycemia in type 2 diabetes: pathophysiology, frequency, and effects of different treatment modalities.
      ]. Sulfonylurea-induced severe hypoglycemia can be long-lasting, requiring hospitalization and long-term glucose infusion [
      • Zammitt N.N.
      • Frier B.M.
      Hypoglycemia in type 2 diabetes: pathophysiology, frequency, and effects of different treatment modalities.
      ]. The risk of hypoglycemia is related to the pharmacokinetic properties of the drug. Therefore, the longer-acting sulfonylureas are associated with a greater risk compared with their shorter-acting counterparts and should be avoided in contemporary primary care [
      • Zammitt N.N.
      • Frier B.M.
      Hypoglycemia in type 2 diabetes: pathophysiology, frequency, and effects of different treatment modalities.
      ].
      As patients will vary in their exposure and susceptibility to the different triggers of hypoglycemia, it is essential for the physician to constantly refine the treatment strategy for each patient, using an individualized approach to achieve glycemic targets.

      3. Hypoglycemia unawareness and undisclosed hypoglycemia: the scale of the problem and the consequences

      3.1 Hypoglycemia unawareness

      3.1.1 Definition

      Hypoglycemia unawareness (also called ‘impaired awareness of hypoglycemia’) is defined as the onset of hypoglycemia before the appearance of autonomic warning symptoms, and presents clinically as the patient's inability to perceive hypoglycemic symptoms [
      • De Galan B.E.
      • Schouwenberg B.J.
      • Tack C.J.
      • Smits P.
      Pathophysiology and management of recurrent hypoglycaemia and hypoglycaemia unawareness in diabetes.
      ,
      • Graveling A.J.
      • Frier B.M.
      Impaired awareness of hypoglycaemia: a review.
      ,
      • White Jr., J.R.
      The contribution of medications to hypoglycemia unawareness.
      ].
      As noted above, when glucagon responses to hypoglycemia become deficient, epinephrine and autonomic warning symptoms develop into the critical defenses for glucose counter-regulation. However, repeated hypoglycemic events (including those that are non-severe, asymptomatic or nocturnal) can reduce the magnitude of these responses to subsequent hypoglycemic episodes. Consequently, the counter-response is initiated at increasingly lower glucose concentrations and the perception of hypoglycemia becomes impaired, all resulting in an increased risk of future hypoglycemic events, particularly severe events [
      • De Galan B.E.
      • Schouwenberg B.J.
      • Tack C.J.
      • Smits P.
      Pathophysiology and management of recurrent hypoglycaemia and hypoglycaemia unawareness in diabetes.
      ,
      • Davis M.R.
      • Shamoon H.
      Counterregulatory adaptation to recurrent hypoglycemia in normal humans.
      ,
      • Bolli G.B.
      • De Feo P.
      • De Cosmo S.
      • et al.
      A reliable and reproducible test for adequate glucose counterregulation in type I diabetes mellitus.
      ].
      Aside from repeated hypoglycemic events, other risk factors for the impairment of hypoglycemia awareness include physiological (e.g. overly strict glycemic control), psychological (e.g. denial) and educational factors (e.g. little knowledge about treatments), and concomitant drugs (e.g. unselective β-blockers due to changes to sympatho-adrenal stimulation) [
      • Graveling A.J.
      • Frier B.M.
      Impaired awareness of hypoglycaemia: a review.
      ,
      • White Jr., J.R.
      The contribution of medications to hypoglycemia unawareness.
      ].

      3.1.2 Frequency

      The incidence of hypoglycemia unawareness has been investigated in a number of studies. Overall, a higher proportion of patients with type 1 diabetes are reported with hypoglycemia unawareness compared with patients with type 2 diabetes. One study determined that 25% of patients with type 1 diabetes had “partial” or “absent” awareness [
      • Hepburn D.A.
      • Patrick A.W.
      • Eadington D.W.
      • et al.
      Unawareness of hypoglycaemia in insulin-treated diabetic patients: prevalence and relationship to autonomic neuropathy.
      ], while another found that 19.5% of patients in secondary care had hypoglycemia unawareness [
      • Gerich J.E.
      • Mokan M.
      • Veneman T.
      Hypoglycemia unawareness.
      ]. Among insulin-treated patients with type 2 diabetes, 9.8% had trouble correctly identifying hypoglycemic events [
      • Schopman J.E.
      • Geddes J.
      • Frier B.M.
      Prevalence of impaired awareness of hypoglycaemia and frequency of hypoglycaemia in insulin-treated Type 2 diabetes.
      ].
      As the counter-response is initiated at lower glucose concentrations, the risk of severe hypoglycemic events increases markedly in patients with hypoglycemia unawareness [
      • Unger J.
      • Parkin C.
      Hypoglycemia in insulin-treated diabetes: a case for increased vigilance.
      ]. Schopman et al. showed that those patients with type 2 diabetes and hypoglycemia unawareness had a 17-fold higher incidence of severe hypoglycemic events than patients with normal awareness [
      • Schopman J.E.
      • Geddes J.
      • Frier B.M.
      Prevalence of impaired awareness of hypoglycaemia and frequency of hypoglycaemia in insulin-treated Type 2 diabetes.
      ]. Severe hypoglycemic events are subsequently associated with an increased risk of morbidity and mortality, further emphasizing the need to minimize hypoglycemia [
      • Graveling A.J.
      • Frier B.M.
      Impaired awareness of hypoglycaemia: a review.
      ].
      Box: Hypothetical case study 2: A patient with hypoglycemia unawareness
      Jane is a 27-year-old married schoolteacher who has had type 1 diabetes for 8 years. She is currently controlled on a basal–bolus insulin regimen. She does carbohydrate counting, having successfully completed a Dose Adjustment For Normal Eating (DAFNE) course 6 months ago.
      She attends the clinic, stating that her husband has noticed that on two or three nights during the week she has woken up sweating and uncomfortable. On further questioning you discover that she has increased her exercise regime to include one aerobics class and two spinning classes per week.
      You feel that she may have undiscovered night-time hypoglycemia. You encourage her to monitor her blood sugars before and after exercise. She should not engage in heavy physical activity if sugars are either too high or too low. She will want to take appropriate carbohydrate after exercise. In the short term, she may want to wake between 2 and 3 am to do glucose monitoring.

      3.2 Undisclosed hypoglycemia

      The extent of under-reported and undisclosed hypoglycemia is quite difficult to ascertain. There are observational reports indicating that some patients do not discuss hypoglycemia with their physicians for a number of reasons, including feelings that hypoglycemia is a private issue that they do not feel comfortable sharing with others [
      • Ritholz M.D.
      • Jacobson A.M.
      Living with hypoglycemia.
      ,
      • Rubin R.R.
      • Peyrot M.
      Psychological issues and treatments for people with diabetes.
      ]. Patients may also not understand the importance of hypoglycemia (especially non-severe episodes) or they may be concerned about losing their driving license or job if they report a serious or frequent event(s) [
      • Graveling A.J.
      • Frier B.M.
      Hypoglycaemia: an overview.
      ].
      Indeed, in the UK, a recent update to the Driver and Vehicle Licensing Agency (DVLA) rules indicates that if more than one episode of severe hypoglycemia (requiring the assistance of another person) occurs within 12 months or the individual develops impaired hypoglycemia awareness, this needs to be reported and could lead to revocation of the individual's license [
      DVLA DIAB1 Rev.
      ,
      • Kilpatrick E.S.
      • Rigby A.S.
      • Warren R.E.
      • Atkin S.L.
      Implications of new European Union driving regulations for patients with Type 1 diabetes who participated in the Diabetes Control and Complications Trial.
      ].
      Box: Hypothetical case study 3: A patient with undisclosed hypoglycemia
      Robert is a 43-year-old taxi driver who holds a public service vehicle license. He has had type 2 diabetes for 14 years and has been using insulin for 3 years. He attends an examination to renew his license. He is on twice-daily pre-mixed insulin as well as metformin. His last recorded HbA1c was 8.8% (73 mmol/mol) 10 months ago. You note that he is currently driving long hours and at night. He has not brought his diary with him, and has missed two recent diabetic appointments.
      You are concerned that you have very little evidence on which to assess how safe Robert is driving as he admits to neither hypoglycemic episodes nor daytime sleepiness.
      You take a detailed dietary history, provide him with a meter with a memory, examine his injection technique and advise him of his obligations to maintain satisfactory control. You give him a printout of the Driver and Vehicle Licensing Agency (DVLA) guidance or make sure he has an internet link to it, if he prefers. You record in his clinical record what has been done. The license form is not filled out until better objective evidence of safety is obtained.

      4. Methods to mitigate the problem

      Improving patient education and empowering the patient to take some control over their disease are often very valuable tactics to improve both treatment outcomes [
      • Naik A.D.
      • Palmer N.
      • Petersen N.J.
      • et al.
      Comparative effectiveness of goal setting in diabetes mellitus group clinics: randomized clinical trial.
      ,
      • Zoffmann V.
      • Lauritzen T.
      Guided self-determination improves life skills with type 1 diabetes and A1C in randomized controlled trial.
      ] and treatment adherence, and therefore reduce the frequency of hypoglycemia [
      • Marrero D.G.
      • Ard J.
      • Delamater A.M.
      • et al.
      Twenty-first century behavioural medicine: a context for empowering clinicians and patients with diabetes. A consensus report.
      ,
      • Ma C.
      • Warren J.
      • Phillips P.
      • Stanek J.
      Empowering patients with essential information and communication support in the context of diabetes.
      ,
      • Anderson R.M.
      • Funnell M.M.
      • Barr P.A.
      • et al.
      Learning to empower patients: results of professional education program for diabetes educators.
      ]. If the doctor can help the patient to clearly understand how their antidiabetic drugs and/or insulin work and impact their glucose levels in relation to their everyday activities, this will go a long way toward improving overall patient care [
      • Briscoe V.J.
      • Davis S.N.
      Hypoglycemia in type 1 and type 2 diabetes: physiology, pathophysiology, and management.
      ,
      • Davis T.M.
      • Brown S.G.
      • Jacobs I.G.
      • et al.
      Determinants of severe hypoglycemia complicating type 2 diabetes: the Fremantle diabetes study.
      ,
      • Rubin R.R.
      • Peyrot M.
      Psychological issues and treatments for people with diabetes.
      ,
      • Fowler M.J.
      Hypoglycemia.
      ,
      • Benroubi M.
      Fear, guilt feelings and misconceptions: barriers to effective insulin treatment in type 2 diabetes.
      ].
      “Patient empowerment” is an approach that emphasizes collaboration with patients in helping them to understand their disease, develop personal goals to manage it, and adapt their management as needed according to circumstances [
      • Marrero D.G.
      • Ard J.
      • Delamater A.M.
      • et al.
      Twenty-first century behavioural medicine: a context for empowering clinicians and patients with diabetes. A consensus report.
      ]. Shared decision making and a collaborative approach to goal setting are central to empowerment [
      • Marrero D.G.
      • Ard J.
      • Delamater A.M.
      • et al.
      Twenty-first century behavioural medicine: a context for empowering clinicians and patients with diabetes. A consensus report.
      ]; the focus is on increasing the patient's autonomy rather than on obtaining increased compliance with the instructions of those in authority [
      • Anderson R.M.
      • Funnell M.M.
      Patient empowerment: myths and misconceptions.
      ].

      4.1 Hypoglycemia unawareness: diagnosis and patient education

      Doctors can help their patients to identify hypoglycemia unawareness by taking a full clinical history, using a structured questionnaire to assess past hypoglycemia experiences, and recommending increased self-monitoring of blood glucose (see Section 4.3 “Use of technology” below). In addition, a Likert scale is available that allows patients to score their own awareness on a scale from 1 to 7, where a low score represents normal awareness and a high score designates loss of awareness [
      • Graveling A.J.
      • Frier B.M.
      Impaired awareness of hypoglycaemia: a review.
      ,
      • Gold A.E.
      • MacLeod L.M.
      • Frier B.M.
      Frequency of severe hypoglycemia in patients with type I diabetes with impaired awareness of hypoglycemia.
      ]. This self-reported failure to perceive hypoglycemic symptoms via a questionnaire setting has been shown to be extremely accurate when compared with a quantitative blood glucose symptom/estimation trial [
      • Clarke W.L.
      • Cox D.J.
      • Gonder-Frederick L.A.
      • et al.
      Reduced awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic frequency and associated symptoms.
      ,
      • Geddes J.
      • Wright R.J.
      • Zammitt N.N.
      • et al.
      An evaluation of methods of assessing impaired awareness of hypoglycemia in type 1 diabetes.
      ], with hypoglycemia unawareness associated with a 9-fold higher risk of severe hypoglycemic events [
      • Henderson J.N.
      • Allen K.V.
      • Deary I.J.
      • Frier B.M.
      Hypoglycaemia in insulin-treated type 2 diabetes: frequency, symptoms and impaired awareness.
      ].
      It is important for healthcare providers to be aware of the possibility that their patients may be experiencing hypoglycemia unawareness, as early recognition may help to slow or even arrest its progression if the necessary steps are taken to minimize the occurrence of hypoglycemic events [
      • Graveling A.J.
      • Frier B.M.
      Impaired awareness of hypoglycaemia: a review.
      ]. A valuable source of information is to interview spouses and family members, as they often recognize hypoglycemic events before the patient with hypoglycemia unawareness perceives them.
      Therefore, the primary objective should be to avoid all hypoglycemic events as much as possible. Table 4 contains some useful treatment strategies that can be used to minimize the occurrence of hypoglycemia. Changing the type of treatment or the regimen to one that has shown a lower risk of associated hypoglycemia may also help to reduce hypoglycemic events; however, this does need to be combined with additional patient education to ensure that improvements from the switch are maximized.
      Table 4Practical treatment strategies for patients with hypoglycemia unawareness
      • Seaquist E.R.
      • Anderson J.
      • Childs B.
      • et al.
      Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and The Endocrine Society.
      . (Reproduced with permission from American Diabetes Association).
      Blood glucose monitoring Frequent blood glucose monitoring, especially before meals, at bedtime and during suggestive symptoms
       Avoid low blood glucose values
       Evaluate blood glucose targets
      Insulin Adjust insulin regimen to achieve and maintain target glucose levels
       Consider using basal insulin analogs to decrease the risk of nocturnal hypoglycemia
       Consider using carefully adjusted, rapid-acting insulin analogs to decrease the risk of interprandial hypoglycemia
       Consider a CSII pump or CGM device as appropriate
      Diet Ensure adequate caloric intake with interprandial and bedtime snacks, as required, strictly based on blood glucose measurements
       Ensure blood glucose measurements are taken before, during and after exercise
       Pre-exercise – additional caloric intake if blood glucose values indicate falling glucose levels
       Ensure access to readily absorbable carbohydrates when embarking on exercise
      Symptoms Identify subtle cues to low blood glucose
      CGM: continuous glucose monitoring; CSII: continuous subcutaneous insulin infusion.

      4.2 Undisclosed hypoglycemia

      As an initial step, it is vital for healthcare professionals to ask their patients about their hypoglycemic experiences in terms of frequency, severity, and the emotional impact these events may be having on the patient [
      • Ritholz M.D.
      • Jacobson A.M.
      Living with hypoglycemia.
      ,
      • Rubin R.R.
      • Peyrot M.
      Psychological issues and treatments for people with diabetes.
      ]. This can help to build a personal relationship and a level of trust, such that the patient feels comfortable sharing with their physician what can be a very personal experience. It can also help to remove any feeling that they need to hide what they may consider a personal failure. Practicing patient empowerment, as described above, may encourage a more open relationship between doctor and patient.
      Case study 3 highlights the ethical dilemma faced by physicians. On the one hand they wish to do beneficence and be the patient's advocate; on the other hand, they must also act within a framework of social justice and perform their duty to public safety by ensuring safety for other road users. If doctors have suspicions about driver safety, they should encourage patient disclosure and, as a last resort, inform the DVLA themselves, having informed the patient accordingly.

      4.3 Use of technology to improve management of hypoglycemia

      Continuous glucose monitoring (CGM) is a useful system that may help individuals to detect nocturnal or otherwise asymptomatic hypoglycemia [
      • Facchinetti A.
      • Sparacino G.
      • Guerra S.
      • et al.
      Real-time improvement of continuous glucose-monitoring accuracy.
      ]. Originally, CGM technology allowed the analysis of glycemic profiles or highlighted certain trends or patterns. However, with technology continually being improved, these systems are now beginning to provide real-time data and alerts for the individual.
      It is important to bear in mind that although the accuracy of these systems is constantly being improved, there is still a high level of inaccuracy, random sources of noise that can alter readings, and delays between actual glucose levels and readings [
      • Facchinetti A.
      • Sparacino G.
      • Guerra S.
      • et al.
      Real-time improvement of continuous glucose-monitoring accuracy.
      ]. There is also a tendency to inaccurately estimate the time spent under hypoglycemic conditions [
      • Chico A.
      • Vidal-Ríos P.
      • Subirà M.
      • Novials A.
      The continuous glucose monitoring system is useful for detecting unrecognized hypoglycemias in patients with type 1 and type 2 diabetes but is not better than frequent capillary glucose measurements for improving metabolic control.
      ,
      • Zijlstra E.
      • Heise T.
      • Nosek L.
      • et al.
      Continuous glucose monitoring: quality of hypoglycaemia detection.
      ].
      Despite these issues, these systems can be useful to both the patient and the physician, not only by providing an early warning system for both hyper- and hypoglycemia, but also by providing long-term data that may reveal particular patterns contributing to recurring and/or asymptomatic hypoglycemic episodes.
      In addition to CGM, there are also continuing improvements in glucose monitors. Many companies are advancing their technology to allow blood glucose readings to be shared with physicians in real time. This is primarily via a mobile phone connection, with the blood glucose data being uploaded to a secure webpage where physicians can access it and provide advice and messages to the patient directly. This interaction helps to create a strong connection between physician and patient, and also allows for useful analyses of the data over the long term. In particular, the technology can provide information to users and physicians on glucose variability. If patterns of variability can be identified, steps can be taken to address the root cause (e.g. possibly incorrect dosing, erratic routines).
      Electronic records of glucose monitoring are very important for people with type 1 diabetes in the UK who want to drive because such records provide important evidence to DVLA medical officials in terms of a person's safety to drive. People with type 1 diabetes who want to obtain a Class 2 vocational driving license will require such an electronic record as evidence of freedom from hypoglycemic episodes over a 6-month period.
      Healthcare professionals may therefore need to wholeheartedly embrace the use of the internet and technology in order to provide the best possible care for their patients.

      5. Summary

      Hypoglycemia is an important and under-recognized aspect of both type 1 and type 2 diabetes treatment and represents a significant barrier to improving diabetes care for patients on multiple levels. Healthcare providers, as much as possible, need to be aware of under-reporting or under-recognized hypoglycemic events to ensure the best possible outcome for their patients.
      Improving patient education, empowering the patient, modifying treatment (bearing in mind variability of drug effect), and incorporating the latest technological advances may all help to reduce the frequency of hypoglycemic episodes, minimize the progression toward impaired awareness, and improve overall patient care.

      Conflicts of interest

      Colin Kenny is a general practitioner in Dromore. He is editor of the Diabetes and Primary Care journal. He has given professional advice to and received travel grants to attend symposia from: GSK; Boehringer Ingelheim; Eli Lilly; Novo Nordisk; Takeda; Novartis; Sanofi; BMS; Pfizer; Janssen; and MSD.

      Acknowledgements

      Dr Kenny suggested the content of this manuscript, and reviewed and provided input to all drafts.
      The author would like to thank Francesca Hemingway and Daria Renshaw, Watermeadow Medical, Witney, UK, for their assistance in the writing, editing and submission of this manuscript. This assistance was funded by Novo Nordisk, which also had a role in the review of the manuscript for scientific accuracy. The author retained complete autonomy as regards content and direction of this work.
      Dr Kenny is the guarantor of this work.
      This full article has not been previously published nor is it currently submitted for consideration for publication elsewhere.

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