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Published online May 29, 2007
Diabetes Care 30:2508-2510, 2007
DOI: 10.2337/dc06-2083
© 2007 by the American Diabetes Association
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Clinical Care/Education/Nutrition/Psychosocial Research
Original Article

Body Weight Changes Associated With Insulin Therapy

A retrospective pooled analysis of inhaled human insulin (Exubera) versus subcutaneous insulin in five controlled Phase III trials

Priscilla A. Hollander, MD, PHD1, Alan Krasner, MD2, Sol Klioze, PHD2, Pamela Schwartz, PHD2 and William Duggan, PHD2

1 Baylor Endocrine Center, Baylor University Medical Center, Dallas, Texas
2 Pfizer Global Research, New London, Connecticut

Address correspondence and reprint requests to Priscilla A. Hollander, Baylor University Medical Center, 3600 Gaston Ave., Wadley Tower, Suite 656, Dallas, TX 75246. E-mail: priscilh{at}baylorhealth.edu

Abbreviations: SC, subcutaneous


   INTRODUCTION
TOP
 INTRODUCTION
RESEARCH, DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 
Weight gain is commonly seen when patients are started on subcutaneous (SC) insulin. In the UK Prospective Diabetes Study, those assigned insulin gained 4 kg more than those assigned conventional therapy at 10 years (1). Given that the majority of patients with type 2 diabetes are overweight or obese (2,3), additional weight gain is clearly a concern. Furthermore, while patients with type 1 diabetes were historically often underweight, the greater use of an intensified treatment approach to achieve the benefits of improved glycemic control is associated with greater weight gain than conventional treatment (4). Fear of weight gain, along with factors such as reluctance to self-inject and fear of hypoglycemia, is a frequent deterrent to initiating insulin therapy and has been linked to reduced treatment adherence in patients with both type 1 and type 2 diabetes (5).

In type 2 diabetes, the ß-cell dysfunction that leads to impaired insulin secretion is progressive, and eventually patients will require a treatment strategy that includes insulin either alone or with oral agents (6). The aim of this pooled analysis was to compare weight changes in a large population of adult patients with type 1 or type 2 diabetes receiving a regimen involving inhaled human insulin (Exubera [rDNA origin] Inhalation Powder) versus an SC insulin–only regimen.


   RESEARCH, DESIGN AND METHODS—
TOP
 INTRODUCTION
 RESEARCH, DESIGN AND METHODS--
RESULTS--
 CONCLUSIONS--
 References
 
This was a retrospective analysis of pooled 6-month data from five controlled Phase III clinical trials conducted in North and South America to compare the effect of regimens involving Exubera (Exubera administered in combination with intermediate- or long-acting SC insulin) versus those involving only SC insulin on body weight in adult patients with type 1 or type 2 diabetes. The trials included studies from the Exubera clinical program of 6 months’ duration or longer in patients with type 1 or type 2 diabetes in which SC insulin was used as the comparator regimen. The detailed study designs, clinical measurements, end point definitions, power calculations, and results of the studies used in the retrospective analysis have previously been published (7–11).

In summary, the trials had an open-label design. In general, target blood glucose values were 80–140 mg/dl (4.4–7.8 mmol/l) (premeal) and 100–160 mg/dl (5.6–8.9 mmol/l) (bedtime), with dose adjustments based on home-monitored blood glucose results. The primary outcome measure was change in A1C; secondary outcomes included fasting and postprandial glucose response, insulin dose, insulin antibodies, body weight, hypoglycemia, pulmonary function tests, and patient-reported outcomes. Patients who were smoking or had moderate to severe underlying lung disease (e.g., asthma or chronic obstructive pulmonary disease) were excluded. Data from the five trials were pooled, and statistical methods repeated those used in the original trials, namely an ANCOVA model with model terms for baseline values, study, and treatment group.


   RESULTS—
TOP
 INTRODUCTION
 RESEARCH, DESIGN AND METHODS--
 RESULTS--
CONCLUSIONS--
 References
 
This analysis included 1,048 patients with type 1 diabetes (Exubera, n = 527; SC insulin, n = 521) and 912 patients with type 2 diabetes (Exubera, 460; SC insulin, 452). Baseline body weight and A1C levels were similar between the Exubera and comparator groups (Table 1).


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  		Table 1— Body weight and glycated A1C levels at baseline and mean adjusted change from baseline and insulin dose in patients with type 1 or type 2 diabetes randomized to inhaled human insulin (Exubera) or SC insulin for 6 months

 
Less weight gain was observed with Exubera regimens compared with SC insulin regimens in adult patients with type 1 or type 2 diabetes. The differences in the treatment effect on body weight were consistent across sex. In patients with type 1 diabetes, a 0.2-kg increase was noted with Exubera, compared with a 1.1-kg increase with SC insulin. Patients with type 2 diabetes gained only one-half as much weight on a regimen including Exubera than on regimens that only included SC insulin (0.7 vs. 1.6 kg, respectively). The adjusted mean change in weight was statistically different in patients treated with a regimen including Exubera versus an SC insulin–only regimen for both type 1 (–0.87 kg [95% CI –1.24 to –0.50]) and type 2 (–0.93 kg [–1.39 to –0.48]) diabetic subjects.

Despite differences in weight changes, reductions in A1C were comparable in both treatment groups (Table 1) for both type 1 and type 2 diabetes. Similarly, rates of overall hypoglycemia (type 1 diabetes [n = 1,048]: Exubera 7.0 vs. SC insulin 6.8 events/subject-month; type 2 diabetes [n = 912]: Exubera 1.8 vs. SC insulin 2.1 events/subject-month) and severe hypoglycemia (type 1 diabetes: Exubera 5.8 vs. SC insulin 5.2 events/100 subject-months; type 2 diabetes: Exubera 0.8 vs. SC insulin 1.1 events/100 subject-months) were also comparable.


   CONCLUSIONS—
TOP
 INTRODUCTION
 RESEARCH, DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
References
 
Significantly less weight gain was observed at 6 months with regimens including Exubera therapy compared with SC insulin–only regimens in adult patients with type 1 or type 2 diabetes. Long-term data have confirmed that these differences in weight gain are sustained at 2 years (Table 1) (9,11). Compared with SC insulin, patients with type 1 diabetes receiving Exubera only gained a modest amount of weight; patients with type 2 diabetes gained one-half as much weight.

Comparable mean changes from baseline A1C were observed with Exubera and SC insulin–only regimens in both the type 1 and type 2 diabetes groups; thus, less weight gain with Exubera is not explained by differences in glycemic control. The incidence of hypoglycemia with Exubera regimens was consistent with that associated with SC insulin use. Both the frequency and nature of hypoglycemia with Exubera are comparable to those with SC insulin, with most events mild to moderate in severity (12).

The authors acknowledge that this was an analysis of 6-month data only, a relatively short time period given the life-long need for insulin in patients with diabetes. However, in well-controlled animal studies comparing inhaled and matched intravenous insulin administration, inhalation of insulin was associated with markedly increased peripheral and decreased hepatic glucose uptake (13). Pending confirmation in humans, this finding may point to significant differences between routes of insulin administration potentially affecting metabolic energy balances.

For the patient, the clinical significance of less weight gain is important from a psychological standpoint and may also influence the likelihood of diabetes- and obesity-related complications. While there is no direct evidence that less weight gain reduces cardiovascular events or mortality, studies have shown beneficial effects of moderate weight loss on the cardiovascular risk factors associated with obesity (14,15). While speculative, any reduction in the amount of weight a patient gains with an insulin therapy may, therefore, have long-term benefits in reducing diabetes complications.


   Acknowledgments
 
This study was funded by Pfizer, manufacturer of Exubera.

Editorial support was provided by J. Grice of PAREXEL.


   Footnotes
 
Published ahead of print at http://care.diabetesjournals.org on 29 May 2007. DOI: 10.2337/dc06-2083.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received for publication October 9, 2006. Accepted for publication May 18, 2007.


   References
TOP
 INTRODUCTION
 RESEARCH, DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 

  1. UK Prospective Diabetes Study (UKPDS) Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853, 1998[Medline]
  2. Daousi C, Casson IF, Gill GV, MacFarlane IA, Wilding JPH, Pinkney JH: Prevalence of obesity in type 2 diabetes in secondary care: association with cardiovascular risk factors. Postgrad Med J 82:280–284, 2006[Abstract/Free Full Text]
  3. International Obesity Task Force: Diabetes atlas [article online], 2003. 2nd ed. International Diabetes Federation, Brussels. Available from http://www.eatlas.idf.org/Obesity_and_type_2_diabetes. Accessed 9 October 2006
  4. Purnell JO, Hokanson JE, Marcovina SM, Steffes MW, Cleary PA, Brunzell JD: Effect of excessive weight gain with intensive therapy of type 1 diabetes on lipid levels and blood pressure: results from the Diabetes Control and Complications Trial. JAMA 280:140–146, 1998[Abstract/Free Full Text]
  5. Korytkowski M: When oral agents fail: practical barriers to starting insulin. Int J Obes 26 (Suppl. 3):S18–S24, 2002
  6. Wright A, Burden ACF, Paisey RB, Cull CA, Holman RR, the UK Prospective Diabetes Study Group: Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the UK Prospective Diabetes Study. Diabetes Care 25:330–336, 2002[Abstract/Free Full Text]
  7. Quattrin T, Belanger A, Bohannon NJV, Schwartz SL, the Exubera Phase III Study Group: Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulin therapy in patients with type 1 diabetes. Diabetes Care 27:2622–2627, 2004[Abstract/Free Full Text]
  8. Skyler JS, Weinstock RS, Raskin P, Yale JF, Barrett E, Gerich JE, Gerstein HC, the Inhaled Insulin Phase III Type 1 Diabetes Study Group: Use of inhaled insulin in a basal/bolus insulin regimen in type 1 diabetic subjects. Diabetes Care 28:1630–1635, 2005[Abstract/Free Full Text]
  9. Skyler JS, Jovanovic L, Klioze S, Reis J, Duggan W, the Inhaled Human Insulin Type 1 Diabetes Study Group: Two-year safety and efficacy of inhaled human insulin (Exubera) in adult patients with type 1 diabetes. Diabetes Care 30:579–585, 2007[Abstract/Free Full Text]
  10. Hollander PA, Blonde L, Rowe R, Mehta AE, Milburn JL, Hershon KS, Chiasson J-L, Levin SR, the Exubera Phase III Study Group: Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulin therapy in patients with type 2 diabetes. Diabetes Care 27:2356–2362, 2004[Abstract/Free Full Text]
  11. Rosenstock J, Foyt H, Klioze S, Ogawa M, St Aubin L, Duggan W: Inhaled human insulin (Exubera®) therapy shows sustained efficacy and is well tolerated over a 2-year period in patients with type 2 diabetes (T2DM) (Abstract). Diabetes 55 (Suppl. 1):A26, 2006
  12. Odegard PS, Capoccia KL: Inhaled insulin: Exubera. Ann Pharmacother 39:843–853, 2005[Abstract/Free Full Text]
  13. Edgerton DS, Neal DW, Scott M, Glass D, Bowen L, Wilson W, Hobbs CH, Leach C, Sivakumaran S, Strack TR, Cherrington AD: Inhalation of insulin (Exubera) is associated with augmented disposal of portally infused glucose in dogs. Diabetes 54:1164–1170, 2005[Abstract/Free Full Text]
  14. Van Gaal LF, Wauters MA, De Leeuw IH: The beneficial effects of modest weight loss on cardiovascular risk factors. Int J Obes Relat Metab Disord 21 (Suppl. 1):S5–S9, 1997
  15. Jung R: Obesity as a disease. Br Med Bull 53:307–321, 1997[Abstract/Free Full Text]

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This Article
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