Applied Evidence

Diabetes drug update: How 4 new options stack up

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

References

1. Narayan KM, Boyle JP, Thompson TJ, Sorensen SW, Williamson DF. Lifetime risk for diabetes mellitis in the United States. JAMA 2003;290:1884-1890.

2. Quattrin T, Belanger A, Bohannon NJV, Schwartz SL. for the Exubera phase III Study Group. Efficacy and safety of inhaled insulin (Exubera) compared to subcuatenous insulin therapy in patients with type 1 diabetes: results of a 6-month, randomized, comparative trial. Diabetes Care 2004;27:2622-2627.

3. Skyler JS, Cefalu WT, Kourides IA, Landschulz WH, Balagtas CC, Cheng S-L, et al. for the Inhaled Insulin Phase II Study Group. Efficacy of inhaled human insulin in type 1 diabetes mellitus: a randomized proof-of-concept study. Lancet 2001;357:331-335.

4. Weiss SR, Cheng S-L, Kourides IA, Gelfand RA, Land-Schulz WH. for the Inhaled Insulin Phase II Study Group. Inhaled insulin provides improved glycemic control in patients with type 2 diabetes mellitus inadequately controlled with oral agents:a randomized controlled trial. Arch Intern Med 2003;163:2277-2282.

5. Hollander PA, Blonde L, Rowe R, Mehta ME, Milburn JL, Hershon KS. for the Exubera Phase III Study Group. Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulint eharpy in patients with type 2 diabetes: results of a 6-month, randomized comparative trial. Diabetes Care 2004;27:2356-2362.

6. Rosenstock J, Bolinder B, Cappeleri JC, Gerber R. Patient satisfaction and glycemic control after 1 year with inhaled insulin (Exubera) in patients with type 1 or type 2 diabetes. Diabetes Care 2004;27:1318-1323.

7. DeFronzo RA, Bergenstal RM, Cefalu WT, Pullman J, Lerman S, Bode BW, et al. for the Exubera Phase III Study Group. Efficacy of inhaled insulin in patients with type 2 diabetes not controlled with diet and exercise. Diabetes Care 2005;28:1922-1928.

8. Rosenstock J, Zinman B, Murphy LJ, Clement SC, Moore P, Bowering K, Hendler R, Lan S-P, Cefalu WT. Inhaled insulin improves glycemic control when substituted for or added to oral combination therapy in type 2 diabetes. Ann Intern Med 2005;143:549-558.

9. Gerber RA, Cappalleri JC, Kourides IA, Gelfand RA. Treatment satisfaction with inhaled insulin in patients with type 1 diabetes: a randomized controlled trial. Diabetes Care 2001;24:1556-1559.

10. Cappalerri JC, Cefalu WT, Rosenstock J, Kourides IA, Gerber RA. Treatment satisfaction in type 2 diabetes: a comparison between an inhaled insulin regimen and a subcutaneous insulin regimen. Clin Ther 2002;24:552-564.

11. Odegard PS, Capoccia KL. Inhaled insulin: exubera. Ann Pharmacother 2005;39:843-853.

12. Fineberg SE, Schatz D, Krasner A. Results of insulin antibody monitoring during phase II and phase III clinical studies of inhaled insulin (Exubera) in patients with type 1 or type 2 diabetes (abstract 46). Diabetes 2002;51(suppl):A17.-

13. Himmelman A, Jende J, Mellen A, Petersen AH, Dahl UL, Wollmer P. The impact of smoking on inhaled insulin. Diabetes Care 2003;26:677-682.

14. Pfizer. Exubera (insulin human inhalation opwder) package insert. New York, NY; 2006.

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.-

17. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 2004;27:2628-2635.

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.

21. Gallwitz B. Glucagon-like peptide-1 as a treatment option for type 2 diabetes and its role in restoring beta-cell mass. Diabetes Technol Ther 2005;7:651-657.

22. Triplitt C, Wright A, Chiquette E. Incretin mimetics and dipeptidyl peptidase-IV inhibitors: potential new therapies for type 2 diabetes mellitus. Pharmacotherapy 2006;26:360-374.

23. Willms B, Ruge D. Comparison of acarbose and metformin in patients with type 2 diabetes mellitus insufficiently controlled with diet and sulphonylureas: a randomized, placebo-controlled study. Diabetes Med 1999;16:755-761.

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.

26. Herman G, Hanefeld M, Wu M, Chen X, Zhao P, Stein P. Effect of MK-0431, a dipeptidyl peptidase IV (DPP-IV) inhibitor, on glycemic control after 12 weeks in patients with T2DM (abstract 541-P). Diabetes 2005;54(suppl 1):A134.-

27. Whitehouse F, Kruger DF, Fineman M, Shen L, Ruggles JA, Maggs DG, et al. A randomized study and open-label extension evaluating the long-term efficacy of pramlintide as an adjunct to insulin therapy in type 1 diabetes. Diabetes Care 2002;25:724-730.

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.

29. Hollander PA, Levy P, Fineman MS, Maggs DG, Shen LZ, Strobel SA, et al. Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes. Diabetes Care 2003;26:784-790.

30. Fineman M, Bahner A, Gottlieb A, Kolterman OG. Effects of six months administration of pramlintide as anadjunct to insulin therapy on metabolic control in people with type 1 diabetes (abstract). Diabetes 1999;48(suppl 1):A113.-

31. Gottlieb A, Fineman M, Bahner A, Parker J, Waite G, Kolterman O. Pramlintide therapy in addition to insulin in type 2 diabetes: effect on metabolic control after 6 months (abstract). Diabetologia 1999;42(suppl 1):A232.-

32. Nyholm B, Orskov L, Hove K, Gravholt CH, Moller N, Alberti GMN, et al. The amylin analog pramlintide improves glycemic control and reduces postprandial glucagons concentrations in patients wih type 1 diabetes mellitus. Metabolism 1999;48:935-941.

33. Levetan C, Want LL, Weyer C, Strobel SA, Crean J, Wang Y, et al. Impact of pramlintide on glucose fluctuations and postprandial glucose, glucagons, and triglyceride excursions among patients with type 1 diabetes intensively treated with insulin pumps. Diabetes Care 2003;26:1-8.

34. Ratner RE, Dickey R, Fineman M, et al. Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in type 1 diabetes mellitus: a 1-year, randomized controlled trial. Diabet Med 2004;21:1204-1212.

35. Lillioja S, Mott DM, Spraul M, Ferraro R, Foley JE, Ravussin E. Insulin resistance and insulin and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. N Engl J Med 1993;329:1988-1992.

36. Ferrannini E. Insulin resistance versus insulin deficiency in non-insulin-dependent diabetes mellitus: problems and prospects. Endocr Rev 1998;19:477-490.

37. Jawa AA, Fonseca VA. Role of insulin secretagogues and insulin sensitizing agents in the prevention of cardiovascular disease in patients who have diabetes. Cardiol Clin 2005;23:119-138.

38. Mazzone T, Meyer PM, Feinstein SB, et al. Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes:a randomized trial. JAMA 2006;296:2572-2581.

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.