Diabetes Management in the Future: A Whiff and a Long Shot?

Jennifer B. Marks, MD

Subcutaneous injection of insulin, introduced in the early 1920s, revolutionized the care of individuals with diabetes. For the first time, they had a chance to live a meaningful life rather than suffering a certain early death.

Today, our diabetes care practices have evolved far beyond simply crude administration of insulin. But with those advances, it has become obvious that, while suboptimal insulin replacement with inadequate blood glucose control keeps people with diabetes alive, there is considerable risk for developing chronic, severe complications as a result of that inadequate blood glucose control. We have also come to realize, through re-search studies such as the Diabetes Control and Complications Trial,¹ that aggressive control of hyperglycemia will prevent the development and progression of such complications.

For a large number of diabetic individuals, however, achievement of normo- or near-normoglycemia requires multiple insulin injections and frequent blood samplings. So, despite its clear benefits, intensive diabetes management has been slow to gain acceptance and remains unpopular in the minds of many people. Thus, the development of less invasive techniques both for monitoring blood glucose and for replacement of insulin remains a priority for today’s researchers.

It is good news, therefore, that a number of pharmaceutical companies and investigators are involved in ongoing research studying the efficacy and acceptability of new modes of achieving glucose control—insulin analogs with protracted action profiles and inhaled (intrapulmonary) insulin delivery systems for use with both short- and long-acting insulins. This report focuses on the recent findings of a number of clinical studies in these two areas of insulin delivery, both of which appear to hold promise for application to diabetes management in the future.

Efficacy of Inhaled Insulin
It has long been appreciated that the pulmonary alveolar epithelium is a surface that is highly permeable to a number of drugs and hormones and can serve as an effective delivery site for such. Several studies have documented the efficacy of intrapulmonary insulin delivery.

One study included 11 healthy volunteers who underwent euglycemic insulin-glucose clamp procedures to study the time-action profiles of insulin administration by subcutaneous and intrapulmonary routes.² Onset of insulin action was considerably more rapid, maximal metabolic response was reached significantly earlier, and the glucose infusion rates during the 60 minutes after inhalation were significantly greater after inhaled insulin than after subcutaneous injection.

Inhaled Insulin Delivery Systems
While it has long been known that the alveolar epithelium can serve as an effective delivery site for insulin absorption, attempts at actual diabetes management using the intrapulmonary route had to await the development of practical, tolerable, and effective delivery systems. Several groups have tested such systems with short-acting insulins and report interesting results.

A dry powder insulin formulation and an aerosol delivery device (Pfizer Inc. & Inhale Therapeutic Systems) gives reproducible intrapulmonary delivery of rapid-acting insulin in therapeutic amounts with 1–2 inhalations per dose and has been shown to be comparable in terms of efficacy and safety to a conventional subcutaneous insulin regimen.³ In one study, the results of Sustacal challenge tests in 16 non-insulin-treated type 2 diabetic volunteers showed that inhaled short-acting insulin administered before the challenge produced glycemic control indistinguishable from that of subcutaneous insulin administration.

In two 3-month, multicenter trials^4,5 involving 70 type 1 and 51 insulin-treated type 2 diabetic individuals using this system, glycemic control was comparable between the two groups, and the number of hypoglycemic events did not differ significantly. Inhaled insulin was well tolerated, and pulmonary function tests (spirometry, lung volumes, diffusion capacity) showed no changes over the duration of the studies. Satisfaction questionnaires showed that study participants definitely favored inhaled insulin over subcutaneous, with 80% of the type 1 and 92% of the type 2 individuals opting to continue on a 1-year extension of the inhaled insulin treatment.

Another group used a different pulmonary insulin delivery system, the AERx™ system (Aradigm Corp.) to compare the pharmacokinetics and pharmacodynamics of inhaled insulin administered in different strengths to healthy volunteers.⁶ In this study, 11 participants received regular U100 insulin administered subcutaneously. Pharmacokinetic parameters with either U250 insulin (n = 7) or U500 insulin (n = 4) administered by intrapulmonary inhalation were compared. Both inhaled formulations of insulin provided much more rapid insulin absorption (7 ± 6 minutes and 16 ± 7 minutes, respectively) than that achieved after subcutaneous injections of regular insulin (55 ± 18 minutes). The investigators suggest that the administration of insulin to the large pulmonary surface may negate the concentration-dependent (i.e., delayed) absorption that sometimes occurs after subcutaneous insulin injection.

Long-Acting Insulin Analogs
New subcutaneous insulin formulations offer the exciting advantage of a greatly prolonged action profile. For example, the long-acting insulin analog HOE 901 (Hoechst Marion Roussel, Inc.) is produced by substituting the amino acid Gly for Asp at position 21 of the A chain, and the addition of two amino acids (Arg) to the carboxy-terminus of the B chain (B31, B32), creating a change in the isoelectric point, which causes changes in association behavior and absorption characteristics, and results in a longer duration of action.^7-9

It has been demonstrated that HOE 901 has the same receptor-binding characteristics^7,8,10-12 and safety profile^7-9 as human insulin and has at least 2–3 times the duration of effectiveness as NPH insulin.^9,13 Several clinical studies in human participants, in fact, have shown that it has an extended plateau profile of action, making it suitable for effective, once-a-day administration.^9,13,14

Side Effects of Long-Acting
Insulin Analogs
The potential of increased growth-promoting effects of long-acting analogs is a recent concern and has been studied in relation to HOE 901. In experiments testing ability to stimulate DNA synthesis in cardiac myocytes, HOE 901 was equipotent to native insulin, and both were significantly less potent than either IGF-1 or the supermitogenic insulin analog ASP(B10).7,8 It has been suggested that the differential interaction of some analogs with IGF-1 receptors significantly contributes to the growth-promoting activity of those formulations.^7,8

Concern about excessive mitogenic effects with HOE 901 are apparently not warranted. There has also been no evidence of increased immunogenicity with HOE 901.⁹

This analog also can be effectively used in an insulin-pen system,¹⁴ further increasing the convenience associated with its use.

The Convenience Factor in Future Diabetes Management
With these new developments coming down the pipeline, it doesn’t take much imagination to envision the exciting scenario that could become reality for future diabetes management. Just combine a long-acting insulin analog, which provides basal coverage with only one injection per day, with an inhaled insu-lin formulation, which offers a painless method of rapid-acting insulin delivery, and you have a very tolerable means of achieving good glycemic control.

Ongoing research into convenient modes of insulin delivery is very active, with long-acting analogs and inhaled delivery systems being only a part of the overall efforts. These efforts on the part of today’s scientific investigators and pharmaceutical companies are driven by the desire of diabetic individuals to have improved means of insulin delivery. So don’t hold your breath just yet, but the future seems bright for diabetes management, including the possibility to control blood glucose with just "a whiff and a long shot."

REFERENCES

¹The DCCT Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977-86, 1993.

²Heinemann L, Traut T, Heise T: Time-action profile of inhaled insulin. Diabet Med 14:63-72, 1997.

³Gelfand RA, Schwartz SL, Horton M, Law CG, Pun EF: Pharmacologic reproducibility of inhaled human insulin pre-meal dosing in patients with type 2 diabetes mellitus (NIDDM) (Abstract). Diabetes 47 (Suppl. 1):A99, 1998.

⁴Skyler JS, Gelfand RA, Kourides IA, for the Inhaled Insulin Phase II Study Group: Treatment of type 1 diabetes mellitus with inhaled human insulin: a 3-month, multicenter trial (Abstract). Diabetes 47 (Suppl. 1):A61, 1998.

⁵Cefalu WT, Gelfand RA, Kourides IA, for the Inhaled Insulin Phase II Study Group: Treatment of type 2 diabetes mellitus with inhaled human insulin: a 3-month, multicenter trial (Abstract). Diabetes 47 (Suppl. 1):A61, 1998.

⁶Farr S, McElduff A, Ward E, Okumu F, Mather L, Gonda I, Rubsamen R: A comparison of the pharmacokinetics and pharmacodynamics of inhaled insulin administered as different strength solutions to healthy volunteers (Abstract). Diabetes 47 (Suppl. 1):A61, 1998.

⁷Bahr M, Kolter T, Seipke G, Eckel J: Growth-promoting and metabolic activity of the human insulin analogue [GlyA21, ArgB31, ArgB32]insulin (HOE 901) in muscle cells. Eur J Pharmacol 320:259-65, 1997.

⁸Eckel J, Kolter T, Bahr M, Lammerhirt H, Spelleken M, Seipke G: Growth-promoting and metabolic activity of the insulin HOE 901 in muscle cells (Abstract). Diabetologia 38 (Suppl. 1): A4, 1995.

⁹Seipke G, Berchthold H, Geisen K, Hilgenfeld R, Roskamp R: HOE 901: a new insulin with prolonged action (Abstract). Eur J Endocrinol 132 (Suppl. 1):25, 1995.

¹⁰Berti L, Bossenmaier B, Kellerer M, Seffer E, Seipke G, Haring H: Comparisons of the human insulin analogues HOE 901 and ASP (B10): characteristics of receptor binding, activation and tyrosine phosphorylation of different substrate proteins (Abstract). Diabetologia 38 (Suppl. 1):A191, 1995.

¹¹Liu L, Koenen M, Seipke G, Eckel J: IGF-1 receptor-mediated signaling of the human insulin analogue HOE 901 (Abstract). International Diabetes Federation Abstracts Diabetologia (Suppl.):1395, 1997.

¹²Berti L, Seffer E, Seipke G, Kroder C, Haring H: Human insulin analogue HOE 901: characteristics of receptor binding, activation, and tyrosine kinase activation (Abstract). Diabetes 44 (Suppl. 1):243A, 1995.

¹³Coates PA, Mukherjee S, Luzio S, Srodzinski KA, Kurzhals R, Roskamp R, Owens DR: Pharmacokinetics of a ‘long-acting’ human insulin analogue (HOE901) in healthy subjects (Abstract). Diabetes 44 (Suppl. 1):130A, 1995.

¹⁴Soon PC, Matthews DR, Roskamp R, Herz M, Kurzhals R: 24-h profile of action of biosynthetic long-acting insulin (HOE901) tested in normal volunteers by glucose clamp methodology (Abstract). Diabetes 46 (Suppl. 1):161A, 1997.

Jennifer B. Marks, MD, is an associate professor of medicine at the University of Miami School of Medicine in Miami, Fla.

Note of disclosure: Dr. Marks sits on an advisory panel for Hoechst Marion Roussel and has received consulting fees from Novo Nordisk, Eli Lilly, Hoechst Marion Roussel, and Pfizer, Inc. These companies manufacturer and market insulin and related products.