Inhaled Formoterol Prevents Hypoglycemia in Diabetes Study

Miriam E Tucker

July 10, 2015

A treatment currently approved for asthma, the beta-2 adrenergic receptor (AR) agonist formoterol, could help prevent hypoglycemia in patients with type 1 diabetes without causing hyperglycemia, a small pilot study suggests.

Hypoglycemia is one of the major factors limiting implementation of tight glycemic control in patients with type 1 diabetes and is associated with increased morbidity and mortality during intensive insulin treatment, explain Renata D Belfort-DeAguiar, MD, an endocrinologist at Yale University, New Haven, Connecticut, and colleagues in their paper, published online July 7, 2015 in Diabetes Care

Inhaled beta-2 AR agonists have previously been investigated for prevention of nocturnal hypoglycemia — for example, terbutaline — but this latter agent was found to cause morning hyperglycemia.

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, the authors explain.

And 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, Dr Belfort-DeAguiar and colleagues note.

Although more studies will be needed to determine formoterol's long-term effect on glycemic control, "due to the limited options for prevention of hypoglycemia, formoterol treatment may be useful for a subgroup of patients with type 1 diabetes at high risk for severe and frequent episodes of hypoglycemia," the authors write.

No Effects of Formoterol on Counterregulatory Hormones

The small study comprised two protocols, one involving seven patients with type 1 diabetes and seven healthy controls, the other with five type 1 patients.

In the first protocol, 48 mg of inhaled formoterol or placebo was given just prior to the start of a hyperinsulinemic-hypoglycemia clamp. Insulin was continuously infused intravenously and dextrose 20% given at the same time and adjusted to maintain glucose levels within the range of 95 to 100 mg/dL for 30 minutes. After that, glucose levels were allowed to fall into the hypoglycemic range (50–58 mg/dL) for the next hour.

During the clamp, inhaled formoterol decreased the glucose infusion rate required to maintain plasma glucose at the target levels significantly in both the type 1 diabetes patients (P < .02) and the controls (P = .05).

At the end of the euglycemic phase, formoterol or placebo had no effect on glucose in the control group, but among those with type 1 diabetes, formoterol raised plasma glucose levels compared with placebo (106 vs 91 mg/dL, P = .02).

Subsequently, when glucose levels were allowed to fall, formoterol delayed the time to hypoglycemia by 10 to 15 minutes in both the controls and type 1 diabetes subjects, although both groups did hit the 55–58-mg/dL-hypoglycemia threshold during the last 30 minutes.

The formoterol had no significant effects on levels of counterregulatory hormones (epinephrine, glucagon, cortisol, or growth hormone), and it did not affect blood pressure, although it did increase pulse rate during the euglycemic phase.

In the second protocol, the five type 1 patients were given 48 mg of inhaled formoterol or placebo, and then their basal insulin infusion was doubled for an hour. Glucose levels dropped to 58 mg/dL at 1 hour in the placebo group, whereas they remained stable in the formoterol group and were twice as high as the levels in the placebo group at the end of the study (P < .05).

None of the formoterol patients required a rescue of 20% dextrose infusion, whereas three control subjects required dextrose following placebo to avoid dropping glucose below 55 mg/dL.

At the end of the study, epinephrine levels were significantly lower with formoterol vs placebo (P = .05), but no significant differences were seen in norepinephrine or glucagon levels.

"Inhalation of…formoterol may be useful in the prevention or treatment of acute hypoglycemia and thus may help patients with type 1 diabetes achieve optimal glucose control more safely," the authors conclude.

This study was funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases and the Juvenile Diabetes Research Foundation. Dr Belfort-DeAguiar has no relevant financial relationships. Disclosures for the coauthors are listed in the article.

Diabetes Care. Published online July 7, 2015. Abstract

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