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Hypoglycemia During Therapy of Diabetes

Page history last edited by Philip E. Cryer, M.D. 10 years, 2 months ago

 

The Web diabetesmanager

 

 

Hypoglycemia During Therapy of Diabetes

Philip E Cryer, MD 

 

Last Author Revision: August 2011

 

 


 

 

The Clinical Problem of Hypoglycemia in Diabetes.

The problem of iatrogenic hypoglycemia in diabetes has been summarized [1] and reviewed in detail [2].

 

 

Glycemic Control.

     In the context of comprehensive treatment, including weight, blood pressure and blood cholesterol control among other measures, glycemic control makes a difference for people with diabetes [3][4][5][6][7][8][9][10]. Partial glycemic control reduces microvascular complications (retinopathy, nephropathy, and neuropathy) in both type 1 diabetes mellitus (T1DM) [11] and type 2 diabetes mellitus (T2DM) [12][13]. Complete glycemic control might eliminate those complications [14]. Follow-up of patients with T1DM [15] and T2DM [16] suggests that an earlier period of partial glycemic control may also reduce macrovascular complications. Clearly, maintenance of euglycemia over a lifetime of diabetes would be in the best interest of people with diabetes if that could be accomplished safely.

 

 

The Limiting Factor.

     Iatrogenic hypoglycemia, fundamentally but not exclusively the result of treatment with an insulin secretagogue or insulin, is the limiting factor in the glycemic management of diabetes [17][18]. Iatrogenic hypoglycemia causes recurrent morbidity in most people with T1DM and many with advanced T2DM, and is sometimes fatal [19][20]. It impairs defenses against subsequent falling plasma glucose concentrations and thus causes a vicious cycle of recurrent hypoglycemia [21][22]. It precludes maintenance of euglycemia over a lifetime of diabetes and, thus, full realization of the benefits of glycemic control [23][24][25][26][27][28][29][30].

 

 

Type 1 and Type 2 Diabetes.

     Iatrogenic hypoglycemia is a fact of life for most people with T1DM who must, of course, be treated with insulin. Most have untold numbers of episodes of asymptomatic hypoglycemia which are not benign since they impair defenses against subsequent hypoglycemia [31][32]. They suffer an average of two episodes of symptomatic hypoglycemia per week – thousands of such episodes over a lifetime of diabetes – and of one episode of severe, at least temporarily disabling, hypoglycemia per year. Hypoglycemia causes brain fuel deprivation that, if unchecked, results in functional brain failure that is typically corrected after the plasma glucose concentration is raised [33][34][35]. Rarely, it causes sudden, presumably cardiac arrhythmic, death or, if it is profound and prolonged, brain death [36][37][38]. Early reports suggested that 2 to 4% of deaths of people with diabetes, largely T1DM, were the result of hypoglycemia [39][40]. More recent reports suggest that 6 to 10% of deaths of people with T1DM are the result of hypoglycemia [41][42][43]. Regardless of the actual rate, the fact that there is an iatrogenic hypoglycemia mortality rate is alarming.

 

 

     Overall, iatrogenic hypoglycemia is less frequent in T2DM [44][45][46][47]. Drugs that can cause unregulated endogenous (sulfonylureas or glinides) or exogenous (insulin) hyperinsulinemia can cause hypoglycemia [48][49]. On the other hand, insulin sensitizers (metformin or a thiazolidinedione), α-glucosidase inhibitors and even those drugs that cause glucose-dependent hyperinsulinemia (glucagon-like peptide-1 receptor agonists or dipeptidyl peptidase-IV inhibitors) among other actions should not, and probably do not, cause hypoglycemia. They do, however, increase the risk of hypoglycemia if used with an insulin secretagogue or with insulin [50][51]. Even during treatment of T2DM with insulin, hypoglycemia event rates are about one-third of those in T1DM overall [52]. However, for reasons discussed shortly (see Glucose Counterregulatory Physiology and its Pathophysiology in Diabetes), the incidence of iatrogenic hypoglycemia increases over time, approaching that in T1DM, as people approach the insulin deficient end of the spectrum of T2DM [53][54][55]. Because T2DM is roughly 20-fold more prevalent than T1DM and many, perhaps most, people with T2DM ultimately require treatment with insulin, most episodes of hypoglycemia, including those of severe hypoglycemia, occur in individuals with T2DM. Insulin secretagogue and insulin induced hypoglycemia can be fatal in T2DM although precise hypoglycemic mortality rates are as yet unknown [56][57]. As many as 10% of patients with severe sulfonylurea-induced hypoglycemia die [58][59].

 

 

Definition and Classification of Hypoglycemia.

     The American Diabetes Association (ADA) Workgroup on Hypoglycemia [60] defined hypoglycemia in diabetes as “all episodes of abnormally low plasma glucose concentration that expose the individual to potential harm.” Notably, that includes asymptomatic hypoglycemia which impairs defenses against subsequent hypoglycemia [61][62]. Because the glycemic thresholds for symptoms of hypoglycemia, among other responses, are dynamic, it is not possible to identify a specific plasma glucose concentration that defines hypoglycemia. However, the ADA Workgroup recommended that people with insulin secretagogue or insulin treated diabetes become concerned about the possibility of developing hypoglycemia at a self-monitored (or device estimated) plasma glucose concentration of 70 mg/dL ( 3.9 mmol/L). Within the error of these measurements, that level approximates the lower limit of the postabsorptive plasma glucose concentration range, the glycemic threshold for activation of glucose counterregulatory systems and the highest low level reported to reduce counterregulatory responses to subsequent hypoglycemia in nondiabetic individuals [63]. That does not mean that an individual with diabetes should invariably self-treat for hypoglycemia at a glucose level of 70 mg/dL ( 3.9 mmol). Options include repeating the measurement in the near-term, avoiding a critical task such as driving, ingesting carbohydrates and using the information for subsequent therapeutic regimen adjustments. Although some have suggested a slightly lower cut-off value of 63 mg/dL (3.5 mmol/L), there is really rather little disagreement about this ostensibly contentious issue [64].

 

 

     The ADA Workgroup also suggested a classification of hypoglycemia in diabetes [65] (Table 1).

 

 

Table 1. ADA classification of hypoglycemia in diabetes [66].

Severe hypoglycemia

An event requiring assistance of another person to actively administer carbohydrate, glucagon or other resuscitation actions. Plasma glucose measurements may not be available during such an event, but neurological recovery attributable to the restoration of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration.

 

Documented severe hypoglycemia 

 An event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration  70 mg/dL ( 3.9 mmol/L).

Asymptomatic hypoglycemia 

An event not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose concentration 70 mg/dL ( 3.9 mmol/L).

Probable symptomatic hypoglycemia 

 

An event during which symptoms typical of hypoglycemia are not accompanied by a plasma glucose determination but that was presumably caused by a plasma glucose concentration 70 mg/dL ( 3.9 mmol/L).

Relative hypoglycemia 

An event during which the person with diabetes reports any of the typical symptoms of hypoglycemia and interprets those as indicative of hypoglycemia with a measured plasma glucose concentration >70 mg/dL (>3.9 mmol/L) but approaching that level. 

 

 

Glucose Counterregulatory Physiology and its Pathophysiology in Diabetes

 

 

Red Flags

     Increased mortality has been observed in randomized controlled trials during more aggressive compared with less aggressive glucose-lowering therapy in patients with T2DM [67] and in patients with hyperglycemia in intensive care units [68]. Given the associations between increased  hypoglycemia and increased mortality during aggressive glycemic therapy in these and other [69][70] trials, it is likely that hypoglycemic events caused deaths, presumably by triggering a ventricular arrhythmia. Since plasma glucose concentrations were not measured at the time of the deaths, it is conceivable that the increased frequency of hypoglycemia was a marker of more lethal underlying disease. However, the latter interpretation is not supported by the finding of excess mortality among patients with T2DM with HbA1C levels in the lower, as well as in the higher, deciles [71]. The nadir all cause mortality rates were at HbA1C levels of 7.5% in both the sulfonylurea and the insulin treatment groups in that study. The clinical implication of these findings is that overly aggressive glucose-lowering therapy of diabetes, with currently available methods, may cause excess mortality.

 

 

Physiology.

     The physiological defenses against falling plasma glucose concentrations, in nondiabetic individuals, include decrements in insulin secretion, which occur as glucose levels decline within the physiological range and signal increased hepatic (and renal) glucose production, and increments in glucagon and epinephrine secretion, which occur as glucose levels fall just below the physiological range and stimulate hepatic glucose production [72][73][74][75] (Figure 1). Increased epinephrine levels also normally mobilize gluconeogenic precursors from muscle and fat, stimulate renal glucose production, limit glucose utilization by muscle and fat and limit insulin secretion [76]. The behavioral defense against falling plasma glucose concentrations is carbohydrate ingestion prompted largely by the perception of neurogenic (autonomic) symptoms (e.g., palpitations, tremor and anxiety/arousal which are catecholamine-mediated or adrenergic and sweating, hunger and paresthesias which are acetylcholine-mediated or cholinergic) [77][78] (Figure 1). These are largely sympathetic neural, rather than adrenomedullary, in origin [79]. The extent to which mild neuroglycopenic symptoms such as altered mentation or psychomotor changes contribute to the patient’s recognition of hypoglycemia is unclear; awareness of hypoglycemia is largely prevented by pharmacological antagonism of neurogenic symptoms [80]. Severe neuroglycopenic symptoms include frank confusion, seizure and loss of consciousness [81][82][83]. All of these defenses, not just insulin secretion, are compromised in T1DM and advanced T2DM [84][85][86][87][88].

 

 

Pathophysiology.

     Episodes of therapeutic hyperinsulinemia, the result of unregulated delivery of endogenous (insulin secretagogue therapy) or exogenous (insulin therapy) insulin into the circulation, initiate the sequence that may, or may not, culminate in an episode of hypoglycemia [89][90]. Absolute therapeutic insulin excess of sufficient magnitude can cause isolated episodes of hypoglycemia despite intact glucose counterregulatory defenses against hypoglycemia [91][92] (Figure 2). But, that is an uncommon event. Iatrogenic hypoglycemia is typically the result of the interplay of mild-moderate absolute or relative (to low glucose availability) therapeutic insulin excess and compromised physiological and behavioral defenses against falling plasma glucose concentrations in T1DM [93][94][95] and T2DM [96][97][98].

 

     In T1DM, because of β-cell failure insulin levels do not decline as glucose levels fall; the first physiological defense is lost. Furthermore, glucagon levels do not increase as glucose levels fall [99]; the second physiological defense is lost. That, too, is plausibly attributable to β-cell failure since a decrease in β-cell secretion, coupled with a low α-cell glucose concentration, normally signals α-cell glucagon secretion [100][101]. Finally, the increase in epinephrine levels as glucose levels fall is attenuated [102][103][104]; the third physiological defense is compromised. 

Figure 1. Physiological and behavioral defenses against hypoglycemia in humans. ACH, acetylcholine; NE, norepinephrine; PNS, parasympathetic nervous system; SNS, sympathetic nervous system. From reference [105].

 
     Although it is often caused by recent antecedent hypoglycemia [106] or by prior exercise or sleep [107][108], the mechanism of the attenuated sympathoadrenal response to falling glucose levels is unknown. Nonetheless, the attenuated epinephrine response is a marker of an attenuated sympathetic neural response [109] and the latter largely results in reduction of the symptoms of hypoglycemia causing hypoglycemia unawareness (or impaired awareness of hypoglycemia) and thus loss of the behavioral defense, carbohydrate ingestion. In the setting of therapeutic hyperinsulinemia, falling plasma glucose concentrations, absent decrements in insulin and absent increments in glucagon, attenuated increments in epinephrine cause the clinical syndrome of defective glucose counterregulation [110][111][112] which is associated with a 25-fold [113] or greater [114] increased risk of iatrogenic hypoglycemia. The attenuated sympathoadrenal, particularly the attenuated sympathetic neural, response causes the clinical syndrome of hypoglycemia unawareness [115][116][117] which is associated with a 6-fold increased risk of iatrogenic hypoglycemia [118].

 

     The pathophysiology of glucose counterregulation is the same in T1DM and T2DM albeit with different time courses [119][120][121][122][123]. β-cell failure, and therefore loss of the insulin and glucagon responses to falling plasma glucose concentrations, develops early in T1DM but more gradually in T2DM. Thus, the setting of defective glucose counterregulation – absent decrements in insulin and absent increments in glucagon – develops early in T1DM and later in T2DM and that and hypoglycemia unawareness, and thus iatrogenic hypoglycemia, become a common problem early in T1DM and later in T2DM.

 

 

     The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes [124][125][126][127] (Figure 2) posits that recent antecedent hypoglycemia, as well as prior exercise or sleep, causes both defective glucose counterregulation (by reducing increments in epinephrine in the setting of absent decrements in insulin and absent increments in glucagon during subsequent hypoglycemia) and hypoglycemia unawareness (by reducing sympathoadrenal and resulting neurogenic symptom responses during subsequent hypoglycemia) and, therefore, a vicious cycle of recurrent hypoglycemia. Perhaps the most compelling support for the concept of HAAF is the finding, initially in three independent laboratories [128][129][130][131], that as little as 2-3 weeks of scrupulous avoidance of hypoglycemia reverses hypoglycemia unawareness and improves the attenuated epinephrine component of defective glucose counterregulation in most affected patients.

 

 

     The mechanism(s) of the attenuated sympathoadrenal response to falling glucose levels, the key feature of HAAF, is not known. It must involve the central nervous system or the afferent of efferent components of the sympathoadrenal system. Theories include increased blood-to-brain transport of a metabolic fuel, effects of a systemic mediator such as cortisol on the brain, altered hypothalamic mechanisms and activation of an inhibitory cerebral network mediated through the thalamus [132][133][134].

 

 

Figure 2. Schematic diagram of HAAF in diabetes. From references [135][136]. 

 

 

Risk Factors for Hypoglycemia in Diabetes 

 

 

Conventional Risk Factors.

The conventional risk factors are based on the premise that relative (to low rates of glucose delivery into the circulation, high rates of glucose efflux out of the circulation, or both) or absolute therapeutic hyperinsulinemia is the sole determinant of risk. They include:

 

 

  1. Insulin (or insulin secretagogue) doses are excessive, ill-timed or of the wrong type.   
  2. Exogenous glucose delivery is decreased (as following missed meals and during the overnight fast, with gastroparesis or celiac disease).  
  3. Glucose utilization is increased (as during and shortly after exercise). 
  4. Endogenous glucose production is decreased (as following alcohol ingestion).  
  5. Sensitivity to insulin is increased (as in the middle of the night or following weight loss, improved fitness or improved glycemic control). 
  6. Insulin clearance is decreased (as in renal failure).

 

     Patients with diabetes and their caregivers must consider each of these risk factors carefully whenever hypoglycemia is a problem. Nonetheless, aside from the first they explain only a minority of episodes of hypoglycemia [137].

 

 

Risk Factors Indicative of Hypoglycemia-Associated Autonomic Failure (HAAF).

These risk factors stem directly from the pathophysiology of glucose counterregulation and the concept of HAAF in diabetes [138][139][140][141]. They include:

 

 

  1. The degree of absolute endogenous insulin deficiency. This determines the extent to which insulin levels will not decrease and glucagon levels will not increase as plasma glucose concentrations fall in response to therapeutic hyperinsulinemia.  

 

  1. A history of severe hypoglycemia, hypoglycemia unawareness, or both as well as recent antecedent hypoglycemia, prior exercise or sleep. A history of severe hypoglycemia indicates, and that of hypoglycemia unawareness implies, recent antecedent hypoglycemia which, like prior exercise and sleep, causes attenuated sympathoadrenal and symptomatic responses to subsequent hypoglycemia, the key feature of HAAF. 

 

  1. Aggressive glycemic therapy per se (lower HbA1C levels, lower glycemic goals). Studies with a control group treated to higher mean glycemia consistently document higher rates of hypoglycemia in the group treated to lower mean glycemia (e.g. [142][143][144][145]). Mean glycemia is a risk factor for hypoglycemia. However, hypoglycemia can occur in individuals with any HbA1C level, and the fact that mean glycemia is a risk factor does not mean that one cannot both lower mean glycemia and reduce the risk of hypoglycemia in individual patients [146][147][148].

 

 

Prevention of Hypoglycemia in Diabetes.

     Obviously, it is preferable to prevent, rather than treat, hypoglycemia in people with diabetes. The prevention of hypoglycemia requires the practice of hypoglycemia risk reduction [149][150][151]. That involves four steps: 1) Acknowledge the problem. 2) Apply the principles of aggressive glycemic therapy. 3) Consider the conventional risk factors in diabetes. 4) Consider the risk factors indicative of HAAF in diabetes.

 

 

Acknowledge the Problem.

     The issue of hypoglycemia should be addressed at every contact with a patient treated with an insulin secretagogue or with insulin [152][153]. In addition to the patient’s comments and review of the individual’s self monitoring of blood glucose (SMBG) data (as well as any continuous glucose monitoring [CGM] data), it is often helpful to question close associates of the patient since they may have observed clues to episodes of hypoglycemia. Patient concerns about the reality, or even the possibility, of hypoglycemia can be a barrier to glycemic control [154][155]. Their concerns need to be discussed and addressed if hypoglycemia is a real or perceived problem.

 

 

Apply the Principles of Aggressive Glycemic Therapy.

     These have been reviewed [156][157][158][159][160][161][162]. They include: 1) Patient education and empowerment. 2) Frequent SMBG (and in some instances CGM). 3) Flexible and appropriate insulin (and other) regimens. 4) Individualized glycemic goals. 5) Ongoing professional guidance and support.

 

 

Patient education and empowerment are fundamentally important. As the therapeutic regimen becomes progressively more complex, early in T1DM and later in T2DM, successful glycemic management becomes progressively more dependent on the skills and management decisions of a well-informed person with diabetes. In addition to basic training about diabetes, people with insulin secretagogue or insulin treated diabetes need to be taught about [163]

 

 

  • The anticipation, recognition and treatment of hypoglycemia [164]  
  • How their medications can cause hypoglycemia  
  • Their most meaningful symptoms as well as the common symptoms of hypoglycemia  
  • How to treat (and not over-treat) hypoglycemia (Close associates need to be taught how to recognize severe hypoglycemia and to administer parenteral glucagon.)  
  • The conventional risk factors for hypoglycemia, including the effects of the dose and timing of their individual secretagogue or insulin preparation(s) as well as the effects of missed meals and the overnight fast, exercise and alcohol  
  • The fact that increasing episodes of hypoglycemia signal an increased likelihood of future, often more severe, episodes [165]  
  • How to apply SMBG (and CGM) data to adjustment of the subsequent regimen

 

 

Frequent SMBG (and some instances CGM) becomes progressively more important as the treatment regimen becomes progressively more complex, particularly during treatment with insulin [166][167]. Ideally, patients should perform SMBG whenever they suspect hypoglycemia. That would not only confirm or deny hypoglycemia. It would also help the person learn their key symptoms of hypoglycemia and might lead to valuable regimen adjustments. It is particularly important for people with hypoglycemia unawareness to monitor their glucose level before a critical task such as driving. Because it will disclose directional trends in glucose levels, CGM should facilitate glycemic therapy and reduce the risk of hypoglycemia. There appears to be some progress toward that ultimate goal [168][169]. Ultimately, CGM will likely be computer linked to insulin infusion in a closed-loop insulin replacement system.

 

Several aspects of flexible and appropriate insulin (and other) regimens are relevant to the prevention of hypoglycemia in diabetes [170][171]. Those include the selection of glucose-lowering drugs, the issues of nocturnal hypoglycemia, exercise-related hypoglycemia, and hypoglycemia in the elderly, and other causes of hypoglycemia.

 

     Among the commonly used sulfonylureas, glyburide (glibenclamide) is most often associated with hypoglycemia [172][173]. The use of a long-acting basal insulin analogue (e.g., glargine or detemir) rather than NPH insulin in a multiple daily injections (MDI) insulin regimen reduces at least the incidence of nocturnal hypoglycemia, perhaps that of total and symptomatic hypoglycemia, in T1DM and T2DM [174][175][176]. The use of a rapid-acting prandial insulin analogue (e.g., lispro, aspart or glulisine) rather than regular insulin reduces the incidence of nocturnal hypoglycemia at least in T1DM [177][178][179]. In patients with T2DM just failing oral agent therapy, the provision of basal insulin followed by the addition of prandial insulin when needed is a reasonable approach from the standpoint of both improving glycemic control and minimizing the risk of hypoglycemia [180]. Although it is conceptually attractive, the superiority of continuous subcutaneous insulin infusion (CSII) with an insulin analogue over MDI with insulin analogues with respect to the frequency and severity of hypoglycemia at comparable levels of glycemic control remains to be established convincingly [181][182]. A systematic review of randomized controlled trials in pregnant women with diabetes also did not document a significant advantage of CSII over MDI [183].

 

     The three recognized causes of HAAF are recent antecedent hypoglycemia (hypoglycemia-related HAAF), sleep (sleep-related HAAF) and prior exercise (exercise-related HAAF) [184][185]. As discussed earlier, hypoglycemia-related HAAF led to the concept [186][187][188]. Iatrogenic hypoglycemia often occurs at night, specifically during sleep [189][190][191][192][193]. When plasma glucose concentrations were measured every 15 minutes in 21 patients with rather well-controlled T1DM [194], nadir glucose levels were <70 mg/dL (3.9 mmol/L) in twelve (57%), <60 mg/dL (3.3 mmol/L) in nine (43%), <50 mg/dL (2.8 mmol/L) in seven (33%) and <40 mg/dL (2.2 mmol/L) in three (14%). In another study, approximately one quarter of youth with T1DM suffered nocturnal hypoglycemia [195]. Night time is typically the longest period between SMBG and between eating. It is also the time of maximal sensitivity to insulin. Furthermore, sympathoadrenal responses to a given level of hypoglycemia are reduced further during sleep in T1DM [196][197]. Perhaps because of their further reduced sympathoadrenal responses, patients with T1DM are much less likely to be awakened by hypoglycemia [198][199]. Thus, sleeping patients with T1DM have both further reduced epinephrine responses to hypoglycemia, the key feature of defective glucose counterregulation, and reduced arousal from sleep, a form of hypoglycemia unawareness. They have sleep-related HAAF [200][201][202][203][204] and are at high risk for hypoglycemia [205][206][207][208]. In addition to the use of insulin analogues [209][210][211], approaches to the prevention of nocturnal hypoglycemia include attempts to provide sustained delivery of exogenous carbohydrates or to produce sustained endogenous glucose production throughout the night [212][213][214]. With respect to the former approach, a conventional bedtime snack or bedtime administration of uncooked cornstarch has not been found to be effective [215]; they simply shift the episodes of hypoglycemia later into the night. With respect to the latter approach, bedtime administration of the epinephrine simulating β2-adrenergic agonist terbutaline has been shown to prevent nocturnal hypoglycemia in patients with aggressively treated T1DM [216][217] in preliminary studies. However, given in a sufficient dose, the drug can cause hyperglycemia the following morning [218]. An alternative experimental approach is overnight subcutaneous glucagon infusion. These off-label uses of terbutaline and of glucagon have not been subjected to suitably powered randomized controlled trials. Afternoon exercise is another potential cause of nocturnal hypoglycemia [219]. Thus, the key feature of the prevention of nocturnal hypoglycemia would appear to be the avoidance of even relative nocturnal hyperinsulinemia. Indeed, the introduction of closed-loop insulin replacement (continuous insulin infusion directed by online glucose sensing) just during the overnight period has been used to reduce nocturnal hypoglycemia in the inpatient setting [220].

 

     Moderate exercise increases glucose utilization (by exercising muscle) but in nondiabetic individuals decrements in insulin, increments in glucagon (and, during intense exercise increments in catecholamines) drive glucose production to match or even exceed glucose utilization and hypoglycemia does not occur [221][222][223]. However, largely because insulin levels are not regulated and therefore do not decline, hypoglycemia occurs commonly during or shortly after exercise in people with T1DM [224][225][226][227]. While that risk is generally recognized, the risk of late post-exercise hypoglycemia [228][229][230][231] is less widely appreciated. That typically occurs 6 to 15 hours after unusually strenuous exercise and is, therefore, often nocturnal [232]. In one study roughly half of young people with T1DM suffered nocturnal hypoglycemia after afternoon exercise while approximately one-quarter of those patients suffered nocturnal hypoglycemia in the absence of afternoon exercise [233]. Davis and colleagues have shown that exercise reduces sympathoadrenal responses to a given level of hypoglycemia several hours later in both nondiabetic individuals [234] and people with T1DM [235]. The latter have absent insulin and glucagon responses and reduced sympathoadrenal and symptomatic responses to hypoglycemia and their sympathoadrenal responses are reduced further late after exercise [236]. They have exercise-related HAAF [237][238][239] and are at high risk of late post-exercise hypoglycemia [240][241][242][243][244]. Its prevention requires consideration of the balance between carbohydrate ingestion and insulin action that is different late after exercise than it is in the absence of prior exercise.

 

     Hypoglycemia is a problem for older people with T2DM [245] but the distinction between effects of age per se and effects of other time-related factors is not always clear. For example, to what extent are reports of less intense symptoms of hypoglycemia [246][247], impaired recovery from hypoglycemia [248][249] and reduced counterregulatory responses at a given level of hypoglycemia [250] in older patients with T2DM the result of advanced age or of longer duration of diabetes? Follow-up of the DCCT patients suggests that recurrent iatrogenic hypoglycemia does not result in cognitive impairments [251]; however, that did not include very young patients with T1DM or elderly patients with T2DM [252][253]. There is evidence of hypoglycemia-associated impairment of cognitive function in the former [254] and of hypoglycemia-associated dementia in the latter in some [255], but not other [256], studies. Older patients are at increased risk of morbidity from hypoglycemic episodes such as fracture and perhaps arrhythmia, stroke and myocardial infarction [257].

 

 

     People with diabetes are not, of course, free from causes of hypoglycemia other than that caused by treatment with an insulin secretagogue or insulin [258]. Those include other drugs and critical illnesses, which are relatively uncommon causes of hypoglycemia, and endocrine deficiency states, nonislet cell tumors, endogenous hyperinsulinism and accidental, factitious or malicious hypoglycemia, which are rare causes of hypoglycemia.

 

Glycemic goals for people with diabetes need to be individualized. The generic goal is a HbA1C level as close to the nondiabetic range as can be accomplished and maintained safely in a given patient at a given stage in his or her diabetes [259][260]. That is often, but not invariably, <7.0% [261][262][263] which is generally in the patients best interest [264][265][266][267][268][269]. Indeed, there is long-term benefit from reducing HbA1C from higher to lower, although still above desirable, levels [270]. Early in the course of T2DM glucose lowering can be accomplished safely by lifestyle changes, such as weight loss, or by drugs that do not cause hypoglycemia. When these approaches are effective without side effects, there is no reason one should not aim for euglycemia. However, when these are no longer sufficient and therapy with an insulin secretagogue is elected or therapy with insulin becomes necessary, euglycemia is not an appropriate goal [271][272]. Nonetheless, as discussed earlier, the frequency of hypoglycemia is relatively low early on [273]. Thus, a glycemic goal of <7.0% is reasonable even if it is not always achievable. Ultimately, in individuals with limited life expectancy or functional capacity in whom glycemic control is unlikely to be beneficial [274][275], a higher glycemic goal becomes appropriate.

 

Finally, because the glycemic management of diabetes is empirical, caregivers should work with the individual patient over time to find the best methods of glycemic control at a given time in the course of that patient’s diabetes. Ongoing professional guidance and support is best accomplished by a team that includes, in addition to a physician, professionals trained in, and dedicated to, translating the standards of care [276] into care of individual patients.

 

 

Consider the Conventional Risk Factors in Diabetes.

     Each of the risk factors that result in relative or absolute therapeutic hyperinsulinemia, detailed earlier, should be considered carefully in any patient with iatrogenic hypoglycemia [277][278]. Those include the dose, timing and type of the insulin secretagogue or insulin preparation(s) used, and conditions in which exogenous glucose delivery or endogenous glucose production is decreased, glucose utilization or insulin sensitivity is increased or insulin clearance is decreased.

 

 

Consider the Risk Factors Indicative of HAAF in Diabetes.

     As detailed earlier, the risk factors indicative of HAAF include the degree of absolute endogenous insulin deficiency, a history of severe hypoglycemia, hypoglycemia unawareness, or both as well as any relationship between iatrogenic hypoglycemia and recent antecedent hypoglycemia, prior exercise or sleep, and lower glycemic goals. A history of severe hypoglycemia is a clinical red flag. Absent a fundamental adjustment of the treatment regimen, the likelihood of another episode is high [279][280].  Indeed, an episode of severe hypoglycemia was a significant predictor of death in the ACCORD and VA Diabetes Trials. Given a history of hypoglycemia unawareness, a 2- to 3-week period of scrupulous avoidance of hypoglycemia – which may require acceptance of somewhat higher glycemic goals in the short-term – is advisable, since that can be expected to restore awareness [281][282][283][284]. When incorporated into a structured education program that produced a decline in HbA1C of 0.3% and a substantial reduction in severe hypoglycemia (from 780 to 220 episodes per 100 patient years), roughly half of the patients reported restoration of awareness one year later [285]. A history of late post-exercise hypoglycemia, nocturnal hypoglycemia, or both should prompt regimen adjustments that increase carbohydrate availability, reduce insulin action, or both at the appropriate time.

 

 

Treatment of Hypoglycemia in Diabetes

 

     Most episodes of asymptomatic hypoglycemia, detected by routine SMBG or CGM, or of mild-moderate symptomatic hypoglycemia are effectively self-treated by ingestion of glucose tablets or carbohydrate containing juice, soft drinks, candy, other snacks or a meal [286][287][288]. A reasonable dose is 20 g of carbohydrate [289]. The dose can be repeated in 15 to 20 minutes, if necessary. Since the glycemic response to oral glucose is transient – roughly two hours in the setting of ongoing hyperinsulinemia [290] – the ingestion of a more substantial snack or meal shortly after the plasma glucose level is raised is generally advisable.

  

     When a hypoglycemic patient is unwilling (because of neuroglycopenia) or unable to take carbohydrate orally parenteral therapy is required. That is often glucagon injected subcutaneously or intramuscularly by an associate of the patient who has been trained to recognize and treat severe hypoglycemia. The usual glucagon dose is 1.0 mg; that can be life-saving although it causes substantial, albeit transient, hyperglycemia [291] and can cause nausea, and even vomiting. Smaller doses (e.g., 150 mcg), repeated if necessary, have been found to be effective without side effects in adolescents [292]. Because it also stimulates insulin secretion, glucagon might be less effective in patients with early T2DM. In a medical setting intravenous glucose, 25 g initially, is the standard parenteral therapy [293][294]. The glycemic response to intravenous glucose is, of course, transient. A subsequent glucose infusion is generally needed, and food should be provided as soon as the patient is able to ingest it safely. 

 

     The duration of a hypoglycemic episode is a function of its cause. While that caused by a short-acting insulin secretagogue or a rapid-acting insulin can be measured in hours, that caused by a long-acting insulin secretagogue or a slow-acting insulin can last for days requiring hospitalization for prolonged therapy. The duration of secretagogue-induced hypoglycemia can be shortened by administration of octreotide [295][296].

 

 

Mechanisms of Hypoglycemic Mortality

 

     There is clear evidence that administration of insulin or of an insulin secretagogue can cause fatal hypoglycemia [297]. Prolonged, profound hypoglycemia can cause brain death, but most fatal episodes are probably the result of ventricular arrhythmias [298]. The mechanisms of the latter include reduced baroreflex sensitivity [299] and an increased risk of an intense sympathoadrenal discharge triggered by an episode of hypoglycemia, both of which can be caused by recent antecedent hypoglycemia [300].

 

 

Acknowledgments and Disclosures

 

     The author’s original work cited has been supported, in part, by U.S. Public Health Service, National Institutes of Health grants R37 DK27085, MO1 RR00036 (now UL1 RR24992), P60 DK20579 and T32 DK07120 and a fellowship award from the American Diabetes Association. The author is grateful for the contributions of postdoctoral fellows and the skilled nursing, technical, dietary and data management/statistical assistance of the staff of the Washington University General Clinical Research Center. Ms. Janet Dedeke prepared this manuscript.

 

     This chapter was written shortly after the publication of the author’s book Hypoglycemia in Diabetes: Pathophysiology, Prevalence and Prevention, American Diabetes Association, Alexandria, Virginia, 2009 [301]. Therefore, much of the factual and interpretive content here is the same, as is no small part of the phraseology.

 

     The author has served as a consultant to several pharmaceutical or device firms including Amgen Inc., Bristol-Myers Squibb/Astra Zeneca, Johnson & Johnson, MannKind Corp., Marcadia Biotech, Medtronic MiniMed Inc., Merck and Co., Novo Nordisk A/S, Takeda Pharmaceuticals North America and TolerRx Inc. in recent years. He does not receive research funding from, hold stock in or speak for any of these firms.

 

 

Footnotes

  1. Cryer PE 2008 The barrier of hypoglycemia in diabetes. Diabetes 57:3169-3176
  2. Cryer PE 2009 Hypoglycemia in Diabetes: Pathophysiology, Prevalence and Prevention. American Diabetes Association, Alexandria, VA
  3. Cryer PE 2008 The barrier of hypoglycemia in diabetes. Diabetes 57:3169-3176
  4. Cryer PE 2009 Hypoglycemia in Diabetes: Pathophysiology, Prevalence and Prevention. American Diabetes Association, Alexandria, VA
  5. The Diabetes Control and Complications Trial Research Group 1993 The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977-986
  6. U.K. Prospective Diabetes Study (UKPDS) Group 1998 Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837-853
  7. U.K. Prospective Diabetes Study (UKPDS) Group 1998 Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854-865
  8. The Diabetes Control and Complications Trial Research Group 1995 The relationship of glycemic exposure (HbA1C) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial. Diabetes 44:968-983
  9. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group 2005 Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 353:2643-2653
  10. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA 2008 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 359:1577-1589
  11. The Diabetes Control and Complications Trial Research Group 1993 The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977-986
  12. U.K. Prospective Diabetes Study (UKPDS) Group 1998 Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837-853
  13. U.K. Prospective Diabetes Study (UKPDS) Group 1998 Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854-865
  14. The Diabetes Control and Complications Trial Research Group 1995 The relationship of glycemic exposure (HbA1C) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial. Diabetes 44:968-983
  15. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group 2005 Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 353:2643-2653
  16. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA 2008 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 359:1577-1589
  17. Cryer PE 2008 The barrier of hypoglycemia in diabetes. Diabetes 57:3169-3176
  18. Cryer PE 2009 Hypoglycemia in Diabetes: Pathophysiology, Prevalence and Prevention. American Diabetes Association, Alexandria, VA
  19. Cryer PE 2008 The barrier of hypoglycemia in diabetes. Diabetes 57:3169-3176
  20. Cryer PE 2009 Hypoglycemia in Diabetes: Pathophysiology, Prevalence and Prevention. American Diabetes Association, Alexandria, VA
  21. Cryer PE 2008 The barrier of hypoglycemia in diabetes. Diabetes 57:3169-3176
  22. Cryer PE 2009 Hypoglycemia in Diabetes: Pathophysiology, Prevalence and Prevention. American Diabetes Association, Alexandria, VA
  23. Cryer PE 2008 The barrier of hypoglycemia in diabetes. Diabetes 57:3169-3176
  24. Cryer PE 2009 Hypoglycemia in Diabetes: Pathophysiology, Prevalence and Prevention. American Diabetes Association, Alexandria, VA
  25. The Diabetes Control and Complications Trial Research Group 1993 The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977-986
  26. U.K. Prospective Diabetes Study (UKPDS) Group 1998 Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837-853
  27. U.K. Prospective Diabetes Study (UKPDS) Group 1998 Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854-865
  28. The Diabetes Control and Complications Trial Research Group 1995 The relationship of glycemic exposure (HbA1C) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial. Diabetes 44:968-983
  29. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group 2005 Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 353:2643-2653
  30. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA 2008 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 359:1577-1589
  31. Cryer PE 2008 The barrier of hypoglycemia in diabetes. Diabetes 57:3169-3176
  32. Cryer PE 2009 Hypoglycemia in Diabetes: Pathophysiology, Prevalence and Prevention. American Diabetes Association, Alexandria, VA
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