Management of diabetes-related hypoglycemia.

Abstract: Iatrogenic hypoglycemia is the main factor limiting aggressive and optimal diabetes management. Rather than being an inevitable consequence of optimal glycemic control, however, hypoglycemia is avoidable and generally straightforward to manage when it occurs. Professional caregivers, patients, and their families are often fearful of hypoglycemia, even though most episodes are minor and easily self-treated. Understanding the factors contributing to hypoglycemia risk and how to minimize its occurrence is an essential part of diabetes care. Building on the physiologic fundamentals presented in the accompanying review, the incidence, mortality/morbidity, clinical symptoms, severity classification, and psychosocial impact of hypoglycemia are described here. Appropriate selection and titration of therapeutic agents, including insulin analogs with more predictable time-action profiles than human insulin formulations, can reduce hypoglycemia risk. Patient education about hypoglycemia prevention, including symptom recognition and necessity of rapid treatment, behavioral modification, and the importance of frequent blood glucose monitoring should accompany all therapeutic interventions.

Key Words: hypoglycemia, diabetes, insulin, oral hypoglycemic agents, symptoms, primary care

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Hypoglycemia commonly occurs in patients with Type 1 diabetes mellitus (T1DM) and advanced Type 2 diabetes mellitus (T2DM), a function of impaired glycemic feedback control and the use of exogenous insulin or long-acting sulfonylureas. (1) Tight glycemic control is essential for delaying the serious micro- and macrovascular consequences of diabetes. (2-4) Iatrogenic hypoglycemia is a risk of intensive therapy particularly if the time-action profiles of resultant insulin secretion or action do not precisely mimic physiologic demand. Other oral medications (metformin, thiazolidinediones, [alpha]1-glucosidase inhibitors), as well the GLP-1 analog exenatide, pose little hypoglycemic risk when used alone. (5,6) However, the majority of patients with T2DM will eventually require insulin because of progressive [beta]-cell failure.

Unrecognized or left untreated, mild or moderate hypoglycemia can become severe, leading to seizures or unconsciousness that require emergency care. (1,7,8) Hypoglycemic symptoms and individual perception of them vary greatly; autonomic activation induced by hypoglycemia can trigger behavioral changes and diminish cognitive functions that limit self-treatment. (9) Even though mild-to-moderate hypoglycemia is easily self-treated, fear of hypoglycemia and its potential consequences can limit optimal glycemic control. (10,11)

Avoidance of hypoglycemia in exchange for suboptimal glycemic control averts short-term risks, but the risk of chronic complications increases substantially. (2,4) Given that most conventional therapies cannot perfectly restore glucose homeostasis, hypoglycemia can result when therapy is not well-matched to individual needs or lifestyle, or if dosing is incorrect or ill-timed. The balance between tight glycemic control and risk of hypoglycemia needs to be managed on an individual basis and strategies for prevention and treatment integrated into any diabetes management plan. Insulin analogs and premixed insulin analogs, for example, have time-action profiles that are more physiologic than conventional human insulins. When selected, administered, and dosed appropriately, they have the potential to reduce the frequency of hypoglycemia. (12,13)

Definition and Symptoms of Hypoglycemia

Hypoglycemia cannot be precisely defined using plasma glucose criteria alone because thresholds for symptoms are unpredictable. Moreover, symptoms comprise a spectrum, with physical, neurologic, and behavioral manifestations (Table 1). To overcome the inconsistency in the literature and confusion among practitioners, the American Diabetes Association (ADA) Workgroup on Hypoglycemia outlined a 5-category system (Table 2) in 2005 to classify hypoglycemic events. (11)

Hypoglycemic severity ranges from asymptomatic or biochemical, to mild-to-moderate symptomatic, to serious (major or severe), (14) with moderate being differentiated from major or severe by the individual's ability to self-treat. Symptoms of mild hypoglycemia generally activate sympathoadrenal responses, (15) and at plasma glucose levels of approximately 55 mg/dL, sweating, tremor, pallor, palpitations, headache, and tachycardia may occur. (15,16) Normalization of plasma glucose usually resolves symptoms. If plasma glucose falls below 45 mg/dL, neuroglycopenic symptoms resulting from cerebral glucose depletion arise, including confusion, slurred speech, blurred vision, or odd behavior, which can limit the individual's ability to self-treat. In severe cases, seizure and coma may ensue. (15)

Incidence of Hypoglycemia

Hypoglycemia occurs approximately twice per week in patients with T1DM. (1) Although less frequent in T2DM, hypoglycemia may be more common than currently recognized, increasing in incidence as [beta]-cell deterioration progresses, as counterregulatory systems become dysfunctional, and as more aggressive therapy is required. (1,5,17) Given the variability in symptom type, severity, perception, and reporting, the true incidence of mild-to-moderate hypoglycemia is difficult to estimate, regardless of disease classification. Therefore, it is not surprising that population statistics on incidence and prevalence are lacking.

In the landmark Diabetes Control and Complications Trial (DCCT), severe hypoglycemia was uncommon, occurring once per year in 10 to 30% of patients with T1DM, (18) an incidence of 62 episodes per 100 patient years. (2) Severe hypoglycemia in patients with T2DM is estimated to occur 1/10th as frequently as in T1DM, even in those treated aggressively with insulin, (1) possibly because counterregulation is preserved. (1,5) However, one study where 25% of hypoglycemia episodes were severe (ie, requiring emergency room visits) found that patients with either T1DM or T2DM using insulin had similar rates--11.5 and 11.8 events per 100 patient years, respectively. (19) In patients with T2DM, of whom 85% received oral agents (20) or used only sulfonylureas, (19) rates were 0.9 events per 100 patient years compared with 0.05 per 100 patient years in those managed with metformin or diet alone. (19)

Recognition of Hypoglycemia

Patients recognizing early hypoglycemic symptoms can take appropriate countermeasures. Unfortunately, those experiencing recurrent hypoglycemia may not sense early-warning autonomic symptoms or may remain asymptomatic, even when plasma glucose is very low. (1) This phenomenon, hypoglycemia unawareness, increases the chance of any episode becoming severe before detection. In the DCCT, 60% of severe hypoglycemic episodes occurred without warning. (21) Hypoglycemia unawareness can be alleviated by careful avoidance of further episodes. (22) However, even when symptoms are recognized, physiologic, psychological, and behavioral factors may dampen perceptions of impending hypoglycemia, the risk it poses, and the need to self-treat. (23)

Mortality and Morbidity of Severe Hypoglycemia

Although statistics on prevalence and incidence of mortality and morbidity from hypoglycemia are lacking, the likelihood of fatality appears low, (24) especially compared with deaths associated with diabetes. For example, the United Kingdom Prospective Diabetes Study in T2DM (4) found that each 1% reduction in A1c reduced risk of death, myocardial infarction, and microvascular complications (primarily retinopathy) by 21%, 14%, and 37%, respectively. Death due to hypoglycemia appears to be rare. When reported, it is usually associated with the use of long-acting sulfonylureas by elderly patients, alcohol intake, unusual drug interactions, (25-27) or with the "dead-in-bed" syndrome, which has been anecdotally linked to nocturnal hypoglycemia. (28)

When hypoglycemia is severe, convulsions and coma can occur; autonomic stimulation resulting from hypoglycemia can also have negative cardiac implications such as changes in heart rate, stroke volume, cardiac output, and myocardial contractility. (29) The neuroglycopenic symptoms of hypoglycemia may interfere with driving or other tasks requiring complex motor skills. Eye-hand coordination and decision-making can be compromised even with moderate hypoglycemia. (30,31) Blood glucose should be tested before driving and carbohydrates for self-treatment kept in vehicles. Because the effects of alcohol and hypoglycemia can be cumulative (32) and could combine with a loss of sensation from diabetes-related neuropathy, alcohol consumption represents a particular risk for individuals with diabetes who drive.

Psychosocial Implications of Hypoglycemia

Recurrent hypoglycemia can cause patients and their families to experience feelings of powerlessness, depression, and anxiety, thereby compromising quality of life. (33-36) Anxiety and depression are prevalent in patients with diabetes, in part because of emotional consequences associated with wide blood glucose fluctuations. (37) Acute hypoglycemic episodes can cause mood swings including irritability, stubbornness, or sadness, to feeling giddy or uninhibited. (29,38) Studies of emotional instability during experimentally induced hypoglycemia suggest that as autonomic activation occurs, neurophysiological function deteriorates and feelings of anger and tension increase, whereas positive mood states (eg, energy) decrease. (39) Nocturnal hypoglycemia may precede morning "hangover" and affect well-being and energy levels the next day. (29)

Patients may conceal symptoms for fear of shame and social stigma, (40) and fear of hypoglycemia itself can become phobic and prevent patients from attempting good glycemic control despite knowledge about self-care. (41,42) Spouses, parents, and children of individuals with diabetes may worry more about hypoglycemia than the patient, leading to attempts to control the patient's behavior and to arguments about diet, blood glucose monitoring, and other aspects of diabetes treatment. Marital conflicts stemming from disagreements about diabetes management and sleep disturbances caused by anxiety about hypoglycemia are common. (43)

Impact of Hypoglycemia on Cognitive Function

The speed of information processing and visual and auditory attention levels may be temporarily impaired during hypoglycemic episodes. Electroencephalographic changes in brain electrical transmission found when blood glucose falls below 36 mg/dL (2 mmol/L) sometimes persist long after blood glucose returns to normal, but do not always correlate with symptoms. (44) Intellectual performance in adults experiencing frequent, severe hypoglycemic episodes (ie, more than 5 since diagnosis) can be modestly compromised. (45-47) Male gender, hypoglycemia unawareness, and high IQ are reportedly associated with a greater hypoglycemia-related cognitive impairment. (44) Children and individuals with long-standing diabetes, especially with comorbid neuropathy, appear more vulnerable to cognitive effects of hypoglycemia. (9,48)

Treatment of Hypoglycemia

Ingestion of fast-acting carbohydrates is the initial treatment for mild or moderate hypoglycemia. Five grams of carbohydrate increases plasma glucose concentration by about 15 mg/dL. (8) Twenty-five grams of carbohydrate is usually needed to correct a typical episode of hypoglycemia. Appropriate oral carbohydrates include glucose tablets, fruit juices, and high sugar drinks. If plasma glucose levels remain below 70 mg/dL 15 minutes later, the patient should eat another carbohydrate-rich snack. If hypoglycemia is more severe and neuroglycopenic symptoms limit carbohydrate consumption, IV administration of glucose (25 g) may be required. Since responses to infused glucose last only 1 to 2 hours, repeated glucose infusions or feedings may be required to completely correct severe, prolonged hypoglycemia, particularly for patients with T2DM who experience sulfonylurea-induced hypoglycemia.

When medical personnel are not immediately available or equipped to infuse glucose, glucagon emergency kits (Gluca-Gen HypoKit from Novo Nordisk or Glucagon Emergency Kit from Eli Lilly) can be used by anyone with minimal training. The kits contain a syringe prefilled with sterile diluent, a vial of recombinant glucagon, and instructions for mixing and administration. Glucagon, which is recommended when patients are unable to take oral glucose as a result of altered or lost consciousness, helps restore consciousness if given soon after the onset of hypoglycemic coma. (49) Glucagon stimulates both gluconeogenesis and glycogenolysis, and is ineffective if glycogen stores are depleted; for example, after prolonged fasting. In some people, nausea and vomiting may result from injecting glucagon; therefore, patients should be positioned upright or seated to avoid aspiration risk. (50)

Detecting nocturnal hypoglycemia can be challenging because during sleep patients will be unaware of symptoms if not awakened, and thus unable to self-treat. Prevention is the key to management of nocturnal hypoglycemia, and includes choosing an insulin regimen that does not peak during sleep. (8)

Reducing the Risks of Hypoglycemia

Hypoglycemia risk increases as more aggressive glycemic goals are targeted. (1,11,51,52) However, even patients with poor glycemic control can experience clinically significant hypoglycemia. (53) Hypoglycemia unawareness, missed meals or reduced food intake, strenuous or unplanned exercise, excess alcohol intake, age, stress, individual susceptibility, comorbid disease, history of prior hypoglycemic episodes, and sleep (ie, nocturnal hypoglycemia) can independently increase hypoglycemia risk. (11,21) Steps to prevent hypoglycemia include appropriate goal setting, behavior modification, glucose monitoring, and patient/family education (Table 3).

Behavioral Modifications

Lifestyle changes are inevitable for patients diagnosed with diabetes. Dealing with all disease aspects, treatment, and potential morbidities imposes a significant burden and stress on patients and their families. The clinician can improve the patient's outlook by encouraging active participation in selfcare (54)--eg, by emphasizing balanced food intake, limited alcohol consumption, planned exercise, and taking medication as prescribed. Patients who are empowered to manage their disease more likely feel in charge (54) and experience better quality of life. Blood Glucose Awareness Training (BGAT) is a structured program for people using insulin that focuses on interpreting internal cues (physical symptoms, moods, and thinking) and external cues (food, exercise, insulin dose and action, and last blood glucose readings) to estimate blood glucose levels. (55) BGAT has been scientifically validated and proven to improve recognition and anticipation of low blood glucose levels. (56)

Glucose Monitoring

Verifying hypoglycemia can be difficult because many patients fail to report mild episodes unless they are questioned or they awaken during a nocturnal episode. Patients should record symptoms, time, and circumstances of all hypoglycemic episodes. The degree of autonomic symptom awareness should also be noted in patient records. All patients receiving intensive therapy should check their blood glucose before breakfast to detect nocturnal hypoglycemia. (57) Use of a Holter-type monitoring device or continuous glucose monitoring system can more fully characterize hypoglycemia, at least based on glucose thresholds, and can be particularly useful for patients not recognizing symptoms or those at high risk of nocturnal hypoglycemia. (58) Glycemic excursions detected during sleep with a continuous glucose monitoring system can be downloaded and transmitted to clinicians, providing insight about level of glycemic control as well as frequency and severity of hypoglycemic episodes that might otherwise go undetected. (59) Such monitoring may also be helpful when designing and implementing strategies for improving glycemic control.

Frequent self-monitoring of blood glucose is critical for guiding treatment. Because self-monitoring has psychological implications, proper education and encouragement about its benefits are essential. Otherwise, self-monitoring may be considered a punishment, an unpleasant reminder of diabetes, a misunderstood collection of numbers, or an anxiety-provoking "pass-fail" test. (60)

Patient Education

Changing patient perceptions and modifying behavior while providing support and encouragement are major challenges. Teaching patients how to recognize, treat and prevent hypoglycemia is one of the most important educational tasks for Certified Diabetes Educators. (61) The importance of consistent support from the entire healthcare team and need for educational interventions at frequent intervals cannot be overemphasized. (54) Although it may be unrealistic to expect 100% avoidance of hypoglycemia, recognizing risk-precipitating factors can reduce its incidence and severity, as well as associated fears. Educational programs can produce significant sustained reductions in moderate to severe hypoglycemia incidence. (62,63)

Patients should be educated about hypoglycemia symptoms and risk factors, counseled regarding content and timing of meals, especially in relation to medication administration, and advised to carry carbohydrates at all times. Information regarding onset and duration of action of all insulin preparations or oral hypoglycemic agents should be provided in an understandable manner. Spouses, companions, and coworkers can be taught to recognize early signs and symptoms of hypoglycemia and take appropriate corrective actions, including glucagon administration. All hypoglycemic episodes should be investigated to determine the likely precipitating event to help prevent future recurrence. In the event no behavioral cause is determined, current medications should be reviewed.

Therapeutic Considerations for Reducing the Risk of Hypoglycemia

The primary challenge of correcting glucose homeostatic deficits in diabetes involves customizing therapy to minimize plasma glucose excursions from the set point while aggressively targeting A1c goals (<7% or [less than or equal to]6.5%) as recommended by the ADA (64) and American College of Endocrinology/American Association of Clinical Endocrinologists, (65) respectively.

Although excess insulin is the most common cause of iatrogenic hypoglycemia, hypoglycemia can also arise from taking oral agents that potentiate insulin secretion (secretagogues) or insulin action (sensitizers). In particular, long-acting sulfonylureas can cause hypoglycemia when given in larger than necessary doses or in intervals too frequent such that the half-lives overlap. (66) Rapid-acting prandial secretagogues such as meglitinides (repaglinide or nateglinide) are alternatives to long-acting sulfonylureas. Several trials have shown a lower incidence of hypoglycemia when these meglitinides have been compared with long-acting sulfonylureas. (67,68)

Once exogenous insulin is administered, its plasma concentration is largely determined by the imperfect pharmacokinetic properties of the type of insulin or oral agent used, in addition to insulin sensitivity and clearance. (11,64) Other considerations include more subtle endocrine defects in diabetes not compensated for by exogenous insulin and/or oral agents alone. Mediators such as GIP, GLP-1, amylin and their analogs might help shape the prandial glucose/insulin profile in ways that only further research can clarify.

The closer the pattern of insulin supplementation matches physiologic secretion, the lower the risk of hypoglycemia. Insulin analogs and premixed insulin analogs, flexible insulin regimens, continuous subcutaneous insulin infusion with an insulin pump, and the recently approved agents that mimic amylin and GLP activity can provide the means for more closely replicating the normal physiologic profile of insulin secretion. Insulin analogs significantly reduce the frequency of hypoglycemic episodes compared with older human insulin formulations. (69)

Type 1 Diabetes and Insulin Therapy

Before insulin analogs (aspart, lispro, glulisine, glargine, and detemir) were available, conventional human insulins were the mainstay of therapy for T1DM. The time-action profiles of older human insulins (eg, regular and NPH) are less able than insulin analogs to simulate normal basal and prandial insulin requirements. Moreover, conventional insulins have considerable variability in their onset, peak, and duration of action (Table 4). (70) Recognizing that the margin of error is smaller with aggressive glycemic management, insulin analogs have more predictable time-action profiles and may be used with more confidence, in that there is less concern about interindividual variability of absorption from tissue injection sites.

The rapid-acting insulin analogs (aspart, lispro, and glulisine) and premixed insulin analogs (biphasic insulin aspart 70/30 and insulin lispro 75/25, used primarily for T2DM) offer the convenience and flexibility of dosing around meals (within 15 min as opposed to 30-45 min for regular human insulin or premixed human insulin). (70) Following subcutaneous administration, these analogs dissociate rapidly into monomeric insulin, resulting in faster onsets, shorter times to peak activity, and shorter durations of action compared with conventional insulins. (70) Because of this more physiologic pharmacokinetic profile (Fig.), normal pancreatic insulin action is faithfully reproduced (71)--ie, insulin is available and handles the glucose challenge immediately after a meal but does not persist long enough in the circulation to cause hypoglycemia between meals. (72) Use of rapid-acting or premixed insulin analogs has allowed patients with either T1DM or T2DM greater flexibility with regard to meals, while at the same time minimizing postprandial glucose excursions. (73-76)

Two long-acting insulin analogs are available: insulin glargine and insulin detemir. Following subcutaneous injection, insulin glargine undergoes self-aggregation, forming microprecipitates that slowly dissociate once in the circulation. (77) Insulin detemir has a unique dual mechanism of protraction. First, unlike insulin glargine, insulin detemir is soluble at neutral pH and undergoes self-association into hexamers at the injection site without forming microprecipitates. (78) A fatty-acid moiety on the insulin detemir B-chain enables the molecule to bind to albumin after subcutaneous absorption. (70) Like the normal pancreatic basal secretory response, both insulin glargine and insulin detemir produce a relatively flat plasma level of insulin (Fig.), similar to the pattern seen during continuous subcutaneous insulin infusion and in contrast to the definitive peak seen with NPH insulin. (79) Both long-acting insulin analogs have been shown to improve glycemic control with less hypoglycemia risk compared with NPH. (71) In clinical trials in patients with T1DM or T2DM, once-daily insulin glargine at bedtime produced better glycemic control and fewer incidents of hypoglycemia than onceor twice-daily NPH insulin. (80,81) Twice-daily insulin detemir provided better control of fasting plasma glucose and A1c than twice-daily NPH (both were combined with insulin aspart at meal time). Hypoglycemia (overall and nocturnal) was reported less frequently in insulin detemir-treated patients. (82) Combining a rapid-acting meal time insulin analog with a long-acting basal insulin analog better mimics the prandial and basal insulin profiles of healthy individuals; thereby lowering hypoglycemia risk without compromising overall glycemic control.

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Type 2 Diabetes and Therapy Options

In early T2DM, clinicians have more options for reinstating glucose homeostasis. Oral agents (sulfonylureas, meglitinides, [alpha]-glucosidase inhibitors, thiazolidinediones, and metformin, a biguanide) are commonly chosen as initial pharmacotherapy for convenience and because [beta]-cells still produce insulin. (83,84) The risk of hypoglycemia varies considerably among the classes and also within each class (eg, lowest with metformin and highest with long-acting sulfonylureas). Hypoglycemic episodes with long-acting sulfonylureas can be prolonged, particularly in elderly patients with insufficient food intake or comorbidities such as hepatic or renal insufficiency. (10,25,85)

Oral agents alone seldom achieve the desired glycemic control over the long term, (86,87) and combining an oral agent with insulin is a rational approach to maintain glycemic control, potentially providing a better safety profile than maximally titrated single-agent therapy. (88) Insulin analogs may be a safer alternative to conventional insulins for combination therapy with regard to hypoglycemia risk. (75,89)

Premixed insulin formulations, consisting of mixtures of rapid- and intermediate-acting insulin analogs, provide a convenient way for patients with T2DM to cover basal and prandial insulin requirements in one injection. (12) Premixed insulin aspart 70/30 or premixed insulin lispro 75/25 contain a soluble fraction of a rapid-acting insulin analog and a crystallized fraction that releases the active insulin over a prolonged period. (90-92) The benefits of premixed insulin formulations are primarily related to the reduced number of daily injections, meal time dosing, and the resultant convenience. As with insulin analogs, pharmacokinetic studies suggest the premixed insulin analogs have the potential to cause hypoglycemia less frequently than premixed human insulin formulations. (12)

In patients with T2DM transitioning to insulin, a premixed formulation or basal insulin is commonly used with or without an oral agent. Insulin glargine, insulin detemir, and NPH insulin provide basal coverage only, whereas premixed insulins cover both basal and postprandial glucose excursions. In patients treated with a basal insulin, a short-acting oral agent may provide sufficient prandial coverage (93); this should be confirmed by self-monitoring of blood glucose.

In a trial in overweight patients with T2DM, 60% of those using either insulin glargine or NPH insulin achieved an A1c of <7% while remaining on metformin and a sulfonylurea; however, the hypoglycemia risk was 21 to 48% lower with insulin glargine. (94) Similarly, insulin detemir added to oral agents resulted in 1 versus 8 major hypoglycemic events compared with NPH, as well as significantly fewer overall and nocturnal hypoglycemic events (47% and 55%, respectively) versus NPH. (95) A recent meta-analysis comparing insulin glargine with NPH insulin in patients with T2DM showed an 11% risk reduction for symptomatic hypoglycemia, 26% reduction in nocturnal hypoglycemia, 46% reduction in severe hypoglycemia, and 59% reduction in severe nocturnal hypoglycemia with no difference in A1c. (13)

Compared with once-daily insulin glargine, a twice-daily premixed analog regimen was approximately 50% more effective for controlling postprandial glucose excursions and achieving overall glycemic control in patients with T2DM. (96) However, minor episodes of hypoglycemia were more frequent with the premixed formulation. (97,98) Only one major hypoglycemic event occurred in the insulin glargine arm during these three trials. (96-98) Further studies comparing premixed insulin analogs to conventional insulin mixes, basal insulins, or to multiple daily injection regimens are awaited to assess the balance of benefits (glycemic control and convenience) with hypoglycemia risk in T2DM patients.

Advances in pharmacologic therapies aimed at improving glycemic control and at establishing more finely-tuned and physiologic plasma glucose excursions include the Amylin analog pramlintide and the incretin (GLP-1) mimetic exenatide, as well as agents in development that inhibit the enzymatic breakdown of GLP-1 by dipeptidyl peptidase IV (DPP IV). Recently approved by the US Food and Drug Administration (FDA), pramlintide works via a centrally mediated mechanism (99) and is indicated as adjunctive therapy to insulin in patients with T1DM or T2DM. Patients treated in the phase 3 trials had a twofold higher risk of developing severe hypoglycemia when pramlintide was added to their insulin regimen. (99) Subsequent studies performed at the FDA's request showed that hypoglycemic risk was reduced with appropriate reductions in insulin dosage during pramlintide titration. (100)

GLP-1-mimetics exhibit glucose-dependent activity and are therefore thought to have a lower risk of hypoglycemia. (101) Exenatide, derived from the saliva of Gila monster lizards, (101,102) was recently FDA-approved for patients with T2DM who fail to achieve glycemic control with a sulfonylurea and/or metformin. Liraglutide, a long-acting GLP-1 analog still in development, improves glycemic control without causing weight gain or increasing hypoglycemia risk. (103) DPP IV inhibitors protect endogenous and exogenous forms of GLP-1. These agents also have the potential to improve glucose tolerance in T2DM (104) without increasing the risk of hypoglycemia. (105) The first DPP IV inhibitor, sitagliptin, was recently approved for use in T2DM as monotherapy or combined with metformin or a thiazolidinedione.

Continuous Subcutaneous Insulin Injection

Cutaneous subcutaneous insulin injection (CSII), especially with modern pump technology and rapid-acting insulin analogs, can improve glycemic control while minimizing the risk of hypoglycemia. (106-108) Most clinical trials have been observational (109-116) rather than randomized and conducted primarily in T1DM, with only two recent trials for T2DM. (117,118) Compared with multiple daily injections of insulin, continuous subcutaneous insulin infusion has the potential to reduce the risk of hypoglycemia by minimizing glucose excursions in motivated patients who receive proper training on how to program basal rates and adjust prandial boluses for carbohydrate content of foods. Pump insulin delivery also enables subtle adjustments for activity, skipping meals or adding snacks. Thus, it is not surprising that recent reviews and a meta-analysis on continuous subcutaneous insulin infusion therapy (72,107,119-122) suggest overall clinical and quality-of-life benefits in addition to potential cost-effectiveness of continuous subcutaneous insulin infusion therapy, especially in patients who experience recurrent hypoglycemia.

Summary and Conclusions

Tight glycemic control is necessary for maximal reduction of diabetes complications but fear of hypoglycemia can present a major impediment. Although hypoglycemia is not benign and carries risks, the complications of diabetes pose a larger threat. The goal of health care providers should be to balance the long-term benefit of glycemic control while minimizing all health-related risks, including those of hypoglycemia. Understanding the risks of uncontrolled diabetes and the therapeutic options available to lower those risks is the first step. Realistic blood glucose targets established with patient input, aggressive patient and caregiver education about hypoglycemia, and emotional support are necessary. In addition, diligent monitoring of blood glucose, behavioral modification, and new pharmacotherapies that maintain glycemic control with less risk of hypoglycemia should reduce hypoglycemia incidence and alter the perception that hypoglycemia is an inevitable consequence of tight glycemic control.

Acknowledgments

The authors would like to thank Novo Nordisk for funding that helped support preparation of this manuscript and Kathryn J. Lucchesi, PhD, RPh for writing and editorial support.

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Patrick J. Boyle, MD, and John Zrebiec, MSW, CDE 

From the Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM; and the Joslin Diabetes Center, Harvard Medical School, Boston, MA.

Corresponding Author: Patrick J. Boyle, MD, Professor of Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131. Email: [e-mail]

Novo Nordisk of Princeton, NJ provided funding that helped support the preparation of this manuscript. The authors have received grant support/honoraria for speaking/consulting fees from Novo Nordisk. The authors have no financial interest in any drug, device, or equipment mentioned in this review.

Accepted July 11, 2006.

RELATED ARTICLE: Key Points

* The health benefits of tight glycemic control are well established and should not be compromised because of fear of hypoglycemia.

* Symptoms and plasma glucose thresholds for hypoglycemia vary from individual to individual, but common risk factors apply and can be minimized.

* Although more frequent in patients with Type 1 diabetes treated with insulin, hypoglycemia is also common in patients with Type 2 diabetes whose [beta]-cell function has deteriorated and are using insulin, or in those treated with long-acting sulfonylurea drugs.

* Most episodes of hypoglycemia are mild or moderate and can easily be self-treated if symptoms are recognized. Family members can be trained to recognize and respond to severe episodes.

* Education, behavioral modification, and new pharmacotherapies, including rapid- and long-acting insulin analogs, premixed insulin analogs, and GLP-1 analogs, are strategies to reduce hypoglycemia risk and still maintain optimal glycemic control.

RELATED ARTICLE

Causes of increased hypoglycemia risk:

 1. Hypoglycemia unawareness
 2. Missed meals or reduced food intake
 3. Strenuous or unplanned exercise
 4. Excess alcohol intake
 5. Age (very young to older age)
 6. Stress
 7. Individual susceptibility
 8. Comorbid disease
 9. History of prior hypoglycemic episodes
10. Sleep (nocturnal hypoglycemia)

The clinician can empower the patient by encouraging active participation in self-care:

1. Emphasize balanced food intake.

2. Encourage limited alcohol consumption.

3. Discuss the importance of routine exercise.

4. Encourage medication compliance.

Table 1. Signs and symptoms of hypoglycemia

Physical                Neuroglycopenic        Behavioral or mood

Pallor                  Difficulty             Emotional lability
                          concentrating
Diaphoresis             Hypothermia            Giddiness
Increased heart rate    Weakness               Tenseness
Tremulousness           Warmth                 Anger
Acute diplopia/blurred  Hunger                 Anxiety
  vision
Increased blood         Fatigue                Arousal
  pressure
Palpitations            Motor impairment       Low frustration tolerance
Paresthesias            Difficulty             Irritability
                          concentrating
                        Clumsiness             Feeling down
                        Difficulty speaking    Tearfulness
                        Slurred speech
                        Seizures
                        Hemiparesis
                        Brain damage
                        Loss of consciousness

Table 2. American Diabetes Association classification of hypoglycemic
events (11)

Severe hypoglycemia     Requiring assistance of another person to
                          actively administer carbohydrate, glucagon, or
                          other resuscitative actions. May be associated
                          with sufficient neuroglycopenia to induce
                          seizure or coma. Neurological recovery
                          attributable to restoration of plasma glucose
                          is sufficient evidence that low plasma glucose
                          concentration induced the event.
Documented symptomatic  Typical symptoms of hypoglycemia are accompanied
  hypoglycemia            by plasma glucose concentration
                          [less than or equal to]70 mg/dL (3.9 mmol/L).
Asymptomatic            Not accompanied by typical symptoms but with
  hypoglycemia            plasma glucose concentration
                          [less than or equal to]70 mg/dL (3.9 mmol/L).
Probable symptomatic    Symptoms not accompanied by a plasma glucose
  hypoglycemia            determination, but probably caused by plasma
                          glucose concentration
                          [less than or equal to]70 mg/dL (3.9 mmol/L).
Relative hypoglycemia   Person with diabetes reports any of the typical
                          symptoms of hypoglycemia, and interprets those
                          as hypoglycemia, but with plasma glucose
                          concentration >70 mg/dL (3.9 mmol/L).

Copyright [c] 2005 American Diabetes Association. Reprinted with
permission from The American Diabetes Association from Diabetes Care
2005;28:1245-1249.

Table 3. Behavioral and educational steps for preventing hypoglycemia

Step                         Comment

 1. Set realistic blood      The goal of any management program is to
    glucose goals              achieve maximum therapeutic benefit with
                               minimal adjustment of lifestyle.
 2. Correct misconceptions   Educate patients about how self-monitoring
    about blood glucose        of blood glucose can be used to
    results                    objectively guide treatment decisions;
                               avoid pass or fail, good or bad
                               judgments.
 3. Teach patients to        Prevention is based upon a sophisticated
    anticipate and avoid       understanding of how insulin, food, and
    hypoglycemia               activity levels interact and match.
                               Patients who suspect they might have low
                               blood glucose can be coached to ask
                               themselves:
                               1. Was more insulin injected or was the
                                  dose taken at a different time than
                                  usual?
                               2. Were meals different, delayed, or
                                  missed?
                               3. Was physical activity increased?
 4. Teach patients to        A. Physical symptoms -- focus on physical
    recognize symptoms          cues from their own body.
                             B. Mood symptoms -- ask themselves two
                                questions:
                                1. Are my feelings stronger or weaker
                                   than they should be?
                                2. Do my feelings match the situation?
                             C. Neuroglycopenic symptoms
                                1. Thinking can be affected when blood
                                   glucose is <70 mg/dL.
                                2. Recognize the very earliest signs of
                                   low blood glucose in the brain, ie,
                                   more time and effort than usual to
                                   perform routine tasks, forgetfulness,
                                   problems with concentration slower
                                   reaction time.
 5. Teach patients to        A. Always carry fast-acting carbohydrate.
    follows steps for safe   B. Check blood glucose if they suspect it
    treatment                   is low.
                             C. Check blood glucose if others think it
                                is low (even if the patient does not).
                             D. Treat low blood glucose immediately and
                                with appropriate amount of fast-acting
                                carbohydrate.
                             E. Recheck blood glucose again in 15
                                minutes and treat again if it is low.
 6. Teach patients the       A. Check blood glucose before driving or if
    steps for safe driving      a second party thinks that your blood
                                glucose is low.
                             B. Stop the car immediately if hypoglycemia
                                is suspected while driving.
                             C. Treat immediately.
                             D. Do not resume driving until blood
                                glucose has normalized.
 7. Help patients to         A. Educate patients about when to check
    improve decision making     blood glucose and about whether, when,
                                and how much to treat hypoglycemia.
                             B. Help patients understand their beliefs,
                                attitudes, and "personal rules" that
                                lead to denial, delay, or resistance to
                                taking these steps.
                             C. Encourage patients to make logical
                                behavioral changes that will not be
                                undermined by the emotion of the moment.
 8. Teach families how to    A. Know types of food/drink to use for
    deal with hypoglycemia      treatment.
                             B. Understand and recognize the mood and
                                behavioral changes that occur when blood
                                glucose is low.
                             C. Provide support without becoming the
                                "diabetes police."
                             D. Know how to administer glucagon in an
                                emergency.
 9. Develop strategies for   A. Provide counseling about the risks and
    improving control,          prevention of hypoglycemia.
    increasing awareness,    B. Increase frequency of self-monitoring of
    and reducing risk           blood glucose.
                             C. Review the patient's experience with
                                hypoglycemia since the last visit,
                                including an estimate of cause,
                                frequency, symptoms, recognition,
                                severity, and treatment
10. Attend blood glucose     Behavioral educational programs improve
    awareness training         detection of both hypo- and
                               hyperglycemia, improve management of
                               blood glucose, reduce motor vehicle
                               accidents, reduce the incidence of severe
                               hypoglycemia, reduce fears associated
                               with hypoglycemia, and improve quality of
                               life and diabetes knowledge. (56)

Table 4. Selected insulin preparations in common clinical use (22)

Type of insulin      Classification  Onset      Peak       Duration

Insulin analogs
  Aspart, lispro,    Rapid acting    5-15 min   30-90 min   4-6 hrs
    glulisine (a)
  Glargine, detemir  Long acting     2-4 hrs    No peak    20-24 hrs
Conventional human
  insulins
  Regular            Short acting    30-60 min  2-3 hrs     8-10 hrs
  NPH                Intermediate    2-4 hrs    4-10 hrs   12-18 hrs

(a) The precise onset of glulisine action has not yet been published;
however, [T.sub.max] (time to maximum concentration in plasma) = 0.93
hours following a dose of 0.3 U/kg administered subcutaneously qualifies
this agent to belong to the rapid-acting category of insulin
analogs. (71) All other data adapted from Hirsch (72) and Oiknine et
al. (70)