Applied Evidence

Controlling hypoglycemia in type 2 diabetes: Which agent for which patient?

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At each new stage of treatment, choices can be made to reduce risk.



Practice recommendations
  • Advise patients to monitor blood glucose levels frequently and learn to correlate drops in glucose to symptoms, which vary among patients.
  • Ask patients at each visit about awareness of hypoglycemic episodes, their severity and timing, and how events relate to dosing, meals, and activities.
  • When using oral agents, consider insulin sensitizers or newer sulfonylureas or meglitinides to reduce risk of hypoglycemia.
  • If adding basal insulin to an oral regimen, the analog glargine has proven superior to NPH insulin in avoiding hypoglycemia.

Signs and symptoms of hypoglycemia vary considerably among patients with type 2 diabetes, making the condition easy to miss. Moreover, the most common symptoms are not necessarily the first symptoms.

If hypoglycemia occurs repeatedly, it can start a vicious cycle of physiologic reactions that mask or diminish the symptoms that warn patients of an impending episode. This may lead to hypoglycemia unawareness and hypoglycemic episodes of increasing severity. Fear of hypoglycemia, particularly of nocturnal events, may discourage patients from more intensive glycemic control, particularly using insulin. Such fear may even lead them to reduce their antidiabetic medication dosage, resulting in poor glycemic control.1

Breaking this cycle and restoring normal physiologic responses is one focus of this article, as is teaching patients how to monitor their blood glucose levels and how to correlate low blood glucose with the signs and symptoms of hypoglycemia.

Other therapies and strategies that we discuss in this article:

  • Newer insulin analogs and the associated risk of hypoglycemia with each
  • Appropriate combination of insulin with oral antidiabetic medications
  • The long-acting analog insulin glargine used as basal insulin to lower the incidence of hypoglycemia, including nocturnal and severe hypoglycemia
  • Rapid-acting insulin analogs (aspart, glulisine, and lispro) used in basalprandial insulin regimens.

First symptoms vary among individuals

Symptoms of hypoglycemia result primarily from a lowered glucose level in the brain and its effects on the central and autonomic nervous systems (FIGURE 1). A decrease in glucose below physiologic levels has acute consequences for brain function because the brain has an immediate requirement for glucose and little capacity for storage.

Two types of symptoms

Neuroglycopenia and the inhibition of neuronal metabolism causes sensations of warmth, weakness, fatigue, difficulty concentrating, confusion, behavioral changes, and in the most severe cases, a loss of consciousness, seizures, brain damage, and even death.2-4

Neurogenic symptoms are mediated by the hormones and neurotransmitters secreted in response to low brain glucose levels (FIGURE 1). The gluconeogenic actions of the autonomic nervous system produce the classic warning symptoms—tremulousness, pounding heart, anxiety, sweating, hunger, and tingling sensations—that usually precede the symptoms of hypoglycemia.2-4 This is particularly so in iatrogenic hypoglycemia.

These direct symptoms of neuroglycopenia are the ones patients typically identify with hypoglycemia. The most common symptoms of hypoglycemia are therefore not necessarily the first symptoms of hypoglycemia (TABLE 1).5 For example, though most patients experience sweating as a symptom of hypoglycemia, the first symptom might be trembling or anxiety, depending on the individual.5

Signs and symptoms most commonly associated with hypoglycemia are not always the first to appear

Inability to concentrate496
Dry mouth350
Blurred vision343
Difficulty walking213
Pounding heart200
Tingling around mouth206
Difficulty speaking170
Odd behavior131
Adapted from Hepburn DA, MacLeod KM, Pell AC, et al. Diabet Med 1993;10:231–237.5

Factors influencing frequency and severity of hypoglycemia

Aggressive diabetes management commonly causes mild-to-moderate hypoglycemia, defined as a blood glucose value <60 mg/dL, that can be managed by the patient without assistance.

Severe hypoglycemia—a blood glucose value <50 mg/dL—is relatively uncommon in type 2 diabetes and requires the assistance of another person to manage, since neurological impairment may render patients unable to treat themselves.2,6 Severe hypoglycemia, whether in patients with type 1 or type 2 diabetes, can have debilitating consequences, including seizures or coma or even death.7

Long-standing type 2 disease. Hypoglycemia is more common in patients with type 1 diabetes than in those with type 2, but it can occur in type 2 diabetes patients who require insulin or are treated intensively with combinations of oral agents.6 As type 2 diabetes progresses,8 the incidence of hypoglycemic events increases, as endogenously produced insulin declines and is replaced by exogenous insulin.5,9 In fact, the prevalence of severe episodes (eg, requiring assistance of another person to administer glucose or glucagon) in patients with type 2 diabetes was comparable to that exhibited among patients with type 1 diabetes if they had been on insulin therapy for the same length of time.5,10

Nocturnal hypoglycemia. This event poses a special concern because the warning signs of hypoglycemia may be blunted during sleep. It has been reported that as many as 29% to 56% of all adult patients treated with insulin have an overnight glucose profile that indicates hypoglycemia occurs at night.11-13 However, it is important to note that the extent of the problem of nocturnal hypoglycemia is difficult to assess since overnight monitoring of glucose levels is required.


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