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Inhaled Formoterol May Be Useful in Preventing Hypoglycemia

Study finds that beta 2 adrenergic receptor (AR) agonist formoterol may prevent hypoglycemia by reducing the effect of insulin….

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Hypoglycemia is a common phenomenon seen in type 1 diabetes patients or those who are on insulin for glycemic control. Hypoglycemia is often associated with increased morbidity and mortality among these patients. Dr. Renata Belfort-DeAnguiar and her colleagues at Yale University investigated the effectiveness of AR in preventing hypoglycemia in type 1 diabetes patients.

Previous studies on terbutaline, an inhaled beta 2-AR agonist, showed that it may be effective in preventing nocturnal hypoglycemia. However, it appeared to cause hyperglycemia in the morning. According to researchers at Yale University, “Formoterol is a more specific beta-2 AR agonist than terbutaline and appears to reduce the inhibitory effect of insulin on glucose production via a direct effect on the liver and possibly also through activation of beta-2 receptors in the ventral medial hypothalamus.” Dr. Belfort-DeAnguiar further noted, “Because formoterol is already approved for the acute treatment of asthma and comes in an inhaled formulation, it could provide direct access to the arterial circulation with rapid onset of action.”

The team conducted a small study that consisted of two sets of protocols. In the first set of the study, 7 type 1 diabetes patients and 7 healthy control subjects were selected to receive either inhaled formoterol (48 μg) or placebo during a hyperinsulinemic-hypoglycemic clamp (insulin and dextrose 20% were given at the same time to maintain glucose levels within the 95-100 mg/dl range for 30 minutes then decreased to 50-58mg/dl for the next hour). The results showed that inhaled formoterol decreased the glucose infusion rate required to maintain plasma glucose at a target level by 45–50% (P < 0.05) and delayed the time to hypoglycemia by 10-15 minutes in both the control and type 1 diabetes subjects. At the end of the euglycemic phase, formoterol raised blood glucose in type 1 diabetes patients, but had no effect on blood glucose of the control group. Furthermore, there was no significant effect on glucagon, epinephrine, cortisol, or growth hormone release.

In the second set of the study, five subjects with type 1 diabetes received either inhaled formoterol or a placebo to evaluate the preventative effect of formoterol for insulin-induced hypoglycemia. According to the results of the study, glucose levels dropped to 58 mg/dL at the 1-hour mark in the placebo group, but remained stable in the formoterol group when the insulin levels of all participants doubled. However, at the end of the study, the blood glucose levels of the formoterol group were two times higher than the blood glucose levels of the placebo group.

The effectiveness of the formoterol in preventing hypoglycemia has yet to be confirmed. A larger study is needed to adequately determine the usefulness of formoterol in preventing hypoglycemia. However, due to the limited options for preventing hypoglycemia, the authors suggested that, “Formoterol treatment may be useful for a subgroup of patients with type 1 diabetes at high risk for severe and frequent episodes of hypoglycemia.”

Practice Pearls:

  • Formoterol is a specific beta-2 AR agonist and appears to affect the liver directly or possibly through activation of beta- 2 receptors in the ventral medial hypothalamus to attenuate the effect of insulin.
  • Inhaled formoterol decreased the glucose infusion rate required to maintain plasma glucose at target levels by 45–50% (P < 0.05) and delayed the time to hypoglycemia by 10-15 minutes in both the control and type 1 diabetes subjects.
  • Glucose levels dropped in the placebo group, but remained stable in the formoterol group when insulin level was doubled in tested subjects.

Belfort-DeAguiar RD, Naik S, Hwang J, Szepietowska B, Sherwin RS. “Inhaled Formoterol Diminishes Insulin-Induced Hypoglycemia in Type 1 Diabetes.” Diabetes Care. 2015 Jul 7. pii: dc142472.