Diabetes drug update: How 4 new options stack up

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Applied Evidence

Diabetes drug update: How 4 new options stack up

J Fam Pract. 2007 March;56(3):207-215

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References

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15. Barnett AH. for the Exubera Phase III Study group. Efficacy and one-year pulmonary safety of inhaled insulin (Exubera) as adjunctive therapy with metformin or glibenclamide in type 2 diabetes patients poorly controlled on oral agent monotherapy (abstract 454-P). Diabetes 2004;53:A107.-

16. Skyler J. for the Exubera Phase II Study Group. Sustained long-term efficacy and safety of inhaled insulin during 4 years continuous therapy (abstract 486-P). Diabetes 2004;53:A115.-

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18. DeFronzo RA, Ratner R, Han J, Kim D, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes mellitus. Diabetes Care 2005;28:1092-1100.

19. Kendall DM, Riddle MC, Rosenstock J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes mellitus treated with metformin and a sulfonylurea. Diabetes Care 2005;28:1083-1091.

20. Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG. for the GWAA Study group. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes. Ann Intern Med 2005;143:559-569.

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24. Rosenstock J, Sugimoto D, Strange P, Stewart JA, Soltesrak E, Dailey J. Triple therapy in type 2 diabetes: insulin glargine or rosiglitazone added to combination therapy of sulfonylurea plus metformin in insulin-naïve patients. Diabetes Care 2006;29:554-559.

25. Miller SA, St. Onge EL. Sitagliptin: a dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Ann Pharmacother 2006;40:1336-1343.

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28. Ratner RE, Want LL, Fineman MS, Velte MJ, Ruggles JA, Gottlieb A, et al. Adjunctive therapy with the amylin analogue pramlintide leads to a combined improvement in glycemic and weight control in insulin-treated subjects with type 2 diabetes. Diabetes Technol Ther 2002;4:51-61.

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TABLE 2
Inhaled insulin studies

STUDY	TYPE	DESIGN	A_1C CHANGE FROM BASELINE (%)
Skyler (2001) ³	Type 1	RCT, 12 weeks	-0.6 (INH); -0.8 (INJ)
Weiss (2003) ⁴	Type 2	RCT, 12 weeks INH + preexisting OHA vs preexisting OHA	-2.3 (INH+OHA) -0.1 (OHA)*
Quattrin (2004) ²	Type 1	RCT, 6 months INH + U vs R + NPH	-0.2 (INH + U) -0.4 (R + NPH)
Hollander (2004) ⁵	Type 2	RCT, 6 months INH + U vs R + NPH	-0.7 (INH + U) -0.6 (R + NPH)
Rosenstock (2004) ⁶	Type 1 or type 2	RCT, 12 weeks INH + U vs conventional split/mixed regimen	Type 1 diabetes: -0.69 (INH + U) -0.85 (split/mixed) Type 2 diabetes: -0.61 (INH + U) -0.79 (split/mixed)
DeFronzo (2005) ⁷	Type 2	RCT, 3 months INH vs rosiglitazone	-2.3 (INH) -1.4 (rosiglitazone)
Rosenstock (2005) ⁸	Type 2	RCT, 12 weeks INH alone, INH + OHA, or OHA alone (all after OHA failure)	-1.4 (INH alone) -1.9 (INH + OHA) -0.2 (OHA alone)
A_1c, glycosylated hemoglobin; RCT, randomized controlled trial; INH, inhaled insulin; INJ, injected insulin; OHA, oral hypoglycemic agent; U, ultralente; R, regular insulin; NPH, NPH insulin
*P<.05

Not an option for smokers or those with pulmonary disease

The most common side effects of inhaled insulin include hypoglycemia, weight gain, cough, and bitter taste. The risk of hypoglycemia appears to be about the same or less than that seen with subcutaneous insulin.² The same is true for weight gain, based on limited data.¹¹ Other potential concerns include the formation of insulin antibodies. Antibody formation is higher with inhaled insulin than with subcutaneous insulin, but the clinical significance at this point is not clear.¹²

FAST TRACK

With inhaled insulin, the risk of hypoglycemia is the same or less than that of subcutaneous insulin

The drug's effect on lung function is also an issue. Inhaled insulin powder should not be used in patients who smoke (or those who have quit within the past 6 months) or who have underlying pulmonary disease. Smoking increases the drug's absorption and can lead to hypoglycemia.¹³ The safety and efficacy of inhaled insulin in patients with underlying pulmonary disease remains unclear. Some short-term studies in those without underlying pulmonary disease found no effects on pulmonary function, while others showed a decline in lung function.^2-5

The manufacturer reports that in trials lasting less than 2 years, both individual patients on inhaled insulin or a comparative agent experienced a decrease in pulmonary function.¹⁴ Forced expiratory volume in 1 second (FEV₁) declined by =20% in 1.5% of inhaled insulin treated patients and in 1.3% of those on another agent. Carbon monoxide diffusing capacity (DL_CO) decreased by =20% in 5.1% of those on inhaled insulin and 3.6% of those on a comparative agent. Thus, the manufacturer recommends a baseline spirometry (FEV₁) and possibly DL_CO. The manufacturer does not recommend the use of inhaled insulin if FEV₁ or DL_CO is <70% predicted.

FAST TRACK

Should FEV₁ decline by =20% from baseline or pulmonary symptoms develop, you'll need to stop inhaled insulin

A patient's pulmonary function should be assessed after 6 months on the drug and then annually thereafter. Should FEV₁ decline by =20% from baseline or pulmonary symptoms develop while on therapy, you'll need to discontinue the inhaled insulin. Two longer-term trials of up to 4 years in duration did not show any significant effect on pulmonary function.^15,16

A convenience with a price tag

Inhaled insulin powder is available in single-dose 1-mg and 3-mg blister packs and should be used no more than 10 minutes before meals. To administer the insulin, the patient breathes out, inhales the dose, and then holds his breath for 5 seconds. The patient will, however, need to load each dose.

FAST TRACK

Because of pulmonary function concerns, injectable insulins may be a safer alternative to inhaled insulin

Each milligram of the inhaled insulin is equivalent to 2 to 3 units of regular subcutaneous insulin. Inhaled insulin powder is a bolus insulin that targets postprandial glucose and thus can be used in place of rapid- or short-acting injectable insulins.

Patients with type 1 diabetes will require an injectable basal insulin (intermediate or long acting) in conjunction with the inhaled insulin. In type 2 diabetes, inhaled insulin can be used in conjunction with a basal insulin or oral therapy. In patients who are currently using an injectable bolus insulin, the package insert contains a dose conversion table. Initial doses can also be estimated based on weight.

Inhaled insulin may reduce the number of daily insulin injections to 1 to 2 times a day, and that could translate into improved patient compliance, although this has not been directly evaluated. The cost of Exubera is significantly higher than traditional subcutaneous insulin. An Exubera kit costs $180, which includes an inhaler and 270 1 mg and 3 mg doses.