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Meta-Analysis: Efficacy and Safety of Inhaled Insulin Therapy in Adults with Diabetes Mellitus

Lisa Ceglia, MD; Joseph Lau, MD; and Anastassios G. Pittas, MD, MSc
[+] Article and Author Information

From Tufts-New England Medical Center, Boston, Massachusetts.


Grant Support: By the National Institutes of Health research grant K23 DK61506 (Dr. Pittas) and by the Dr. Gerald J. and Dorothy R. Friedman New York Foundation for Medical Research Grant (Dr. Ceglia).

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Anastassios G. Pittas, MD, MSc, Division of Endocrinology, Diabetes and Metabolism, Tufts-New England Medical Center, 750 Washington Street, 268, Boston, MA 02111; e-mail, apittas@tufts-nemc.org.

Current Author Addresses: Drs. Ceglia and Pittas: Division of Endocrinology, Diabetes and Metabolism, Tufts-New England Medical Center, 750 Washington Street, 268, Boston, MA 02111.

Dr. Lau: Institute for Clinical Research and Health Policy Studies, Tufts-New England Medical Center, 750 Washington Street, 063, Boston, MA 02111.


Ann Intern Med. 2006;145(9):665-675. doi:10.7326/0003-4819-145-9-200611070-00009
Text Size: A A A

Background: Injection insulin therapy is not readily accepted by patients and many health care providers; therefore, less invasive options for insulin therapy are desirable.

Purpose: To examine the efficacy, safety, and patient acceptability of inhaled insulin therapy in nonpregnant adults with diabetes mellitus.

Data Sources: English-language studies in MEDLINE, the Cochrane Clinical Trials Register (through June 2006), and U.S. Food and Drug Administration review documents of the first formulation of inhaled insulin approved for clinical use.

Study Selection: Randomized, controlled trials of at least 12 weeks' duration that compared inhaled insulin with another active therapy and reported hemoglobin A1c levels in adults with type 1 or type 2 diabetes mellitus.

Data Extraction: Two reviewers independently assessed trials for inclusion and extracted data. Differences were resolved by consensus.

Data Synthesis: Sixteen open-label trials met the inclusion criteria (4023 patients; age range, 18 to 80 years). Among patients with type 1 or type 2 diabetes, there was a small decrease in hemoglobin A1c level from baseline that favored subcutaneous insulin over inhaled insulin (weighted mean difference, 0.08% [95% CI, 0.03% to 0.14%]), although there was no difference in the proportion of participants achieving hemoglobin A1c levels less than 7%. Inhaled insulin lowered hemoglobin A1c levels more (weighted mean difference favoring inhaled insulin, −1.45% [CI, −1.80% to − 1.10%]) compared with fixed doses of oral agents but much less when compared with oral agents titrated to glycemic efficacy (weighted mean difference favoring inhaled insulin, −0.20% [CI, −0.34% to − 0.07%]). Severe hypoglycemia was more likely to occur with inhaled insulin than with oral agents (risk ratio, 3.1 [CI, 1.0 to 9.1]), but there was no increased risk compared with subcutaneous insulin. There was an increased incidence of mild to moderate nonprogressive dry cough in patients treated with inhaled insulin (risk ratio, 3.5 [CI, 2.2 to 5.6]) and a mild decrease in certain pulmonary function testing variables, which did not progress over 2 years. Patients preferred inhaled insulin over subcutaneous insulin.

Limitations: All trials were open label, which may introduce bias. Most of the trials were of 24 weeks' duration or less, limiting assessment of long-term safety.

Conclusions: Inhaled insulin offers an alternative noninvasive option for premeal insulin administration, with glycemic efficacy slightly less than subcutaneous regular insulin and increased patient acceptability. Until long-term safety data are available, inhaled insulin should be reserved for nonpregnant adults with diabetes who are opposed to injections and who would otherwise delay appropriate and timely therapy with insulin.

Figures

Grahic Jump Location
Appendix Figure.
Search results.

FDA = U.S. Food and Drug Administration.

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Figure 1.
Weighted mean difference (error bars indicate 95% CIs) in change in hemoglobin A1c level for inhaled (INH) versus subcutaneous (SC) insulin in adults with type 1 or type 2 diabetes.

The I2 statistic describes the percentage of total variation across studies, which is due to heterogeneity rather than chance (14).

Grahic Jump Location
Grahic Jump Location
Figure 2.
Weighted mean difference (error bars indicate 95% CIs) in change in hemoglobin A1c level for inhaled (INH) versus oral hypoglycemic agents (OHAs) in adults with type 2 diabetes.

The I2 statistic describes the percentage of total variation across studies that is due to heterogeneity rather than chance (14). Rosenstock and colleagues (22) had 2 intervention groups (study A [inhaled insulin alone] and study B [inhaled insulin added to oral hypoglycemic agents]) versus 1 control group (oral hypoglycemic agents).

Grahic Jump Location
Grahic Jump Location
Figure 3.
Weighted mean difference (error bars indicate 95% CIs) in change in FEV1 in liters for inhaled insulin (INH) versus control (subcutaneous insulin [SC] or oral hypoglycemic agents [OHAs]) in adults with type 1 or type 2 diabetes.

The I2 statistic describes the percentage of total variation across studies that is due to heterogeneity rather than chance (14). Rosenstock and colleagues (22) had 2 intervention groups (study A [inhaled insulin alone] and study B [inhaled insulin added to oral hypoglycemic agents]) versus 1 control group (oral hypoglycemic agents).

Grahic Jump Location
Grahic Jump Location
Figure 4.
Weighted mean difference (error bars indicate 95% CIs) in change in diffusing capacity of carbon monoxide (DLCO in mL/min per mm Hg) for inhaled insulin (INH) versus control (subcutaneous insulin [SC] or oral hypoglycemic agents [OHAs]) in adults with type 1 or type 2 diabetes.

The I2 statistic describes the percentage of total variation across studies that is due to heterogeneity rather than chance (14). Rosenstock and colleagues (22) had 2 intervention groups (study A [inhaled insulin alone] and study B [inhaled insulin added to oral hypoglycemic agents]) versus 1 control group (oral hypoglycemic agents).

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Comments

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Effect of inhaled insulin on fasting and postprandial plasma glucose
Posted on November 20, 2006
Nasser E Mikhail
Endocrinology department, Olive View-UCLA Medical Center, Sylmar, CA 91342
Conflict of Interest: None Declared

We read with interest the meta-analysis of Dr. Ceglia and colleagues (1) regarding the efficacy and safety of inhaled insulin. This analysis provides a valuable appraisal of this new form of insulin delivery because it represents one of the very few studies of inhaled insulin not sponsored by the manufacturer and therefore is less likely to be associated with bias. However, we disagree with the authors (1) in not collecting data on fasting or postprandial glucose values because they "were self-reported and therefore were less reliable than hemoglobin A1c levels". In fact, in at least 7 of the 16 trials included in the meta-analysis (1), both fasting and postprandial glucose values were obtained from plasma in the laboratory setting and considered as secondary efficacy endpoints. These 7 trials correspond to reference numbers 15, 17, 19, 20, 21, 22, and 23 of the meta-analysis (1). Results from these trials were mixed, with some studies showing superior (reference numbers 17,19,20,22,23), whereas others reporting similar (reference numbers 15,21) effects of inhaled insulin in improving one or both glucose parameters versus the comparison groups. It would be interesting if the authors (1) can analyze the levels of fasting and postprandial plasma glucose from all trials reporting these parameters to give an estimate of the global effect. The postprandial plasma glucose values are particularly important since inhaled insulin has a short duration of action designed to control postprandial hyperglycemia.

Reference

1. Ceglia L, Lau J, Pittas AG. Meta-analysis: Efficacy and safety of inhaled insulin therapy in adults with diabetes mellitus. Ann Intern Med 2006; 145: 665-675.

Conflict of Interest:

None declared

The Authors Reply
Posted on January 4, 2007
Anastassios G Pittas
Tufts-New England Medical Center
Conflict of Interest: None Declared

The authors reply:

We would like to thank Drs. Mikhail, Wali and Cope for their comments and we appreciate the opportunity to respond. In our analysis (1), we chose not to present data on fasting plasma glucose, because this measure reflects the effectiveness of a long-acting basal insulin regimen or oral medication rather than inhaled insulin therapy, which has a short time of action. Furthermore, fasting blood glucose is a less reliable measure of glycemia in open label trials because it can be affected by short-term changes in a variety of factors. After combining data for fasting blood glucose available from 8 out of the 16 trials included in our meta-analysis (original references 9, 17, 19-24), we found statistically significant differences in fasting blood glucose levels from baseline favoring the inhaled insulin arm (weighted mean difference -25.8 mg/dl [95% CI -41.9, -9.7] vs. subcutaneous insulin and -22.1 mg/dl [95% CI -44.0, -0.3] vs. oral agents) but with significant heterogeneity among studies.

We agree with Dr. Mikhail and colleagues that the effect of inhaled insulin on postprandial hyperglycemia is of interest given the pre-meal indication for inhaled insulin therapy. In our meta-analysis, only 5 of the 16 trials (original references 19-23) reported postprandial blood glucose levels using the same standard meal "“ 16 oz. Boost liquid meal. None of the trials specified if insulin (inhaled or subcutaneous) was administered shortly prior to the liquid meal. When we combined the data from these trials, we found no significant differences in postprandial blood glucose levels (weighted mean difference -14.8 mg/dl [95% CI -33.2, 3.6] vs. subcutaneous insulin and -44.9 mg/dl [95% CI -92.2, 2.3] vs. oral agents).

The results of the fasting and post-prandial glucose concentrations, which tend to favor inhaled insulin over subcutaneous insulin, are in contrast with the hemoglobin A1c results, which slightly favored subcutaneous insulin. In our analysis (1), we elected to present only the change in hemoglobin A1c concentration because it is a measure that captures both fasting and postprandial glycemia, and it is the most reliable and least biased glycemic measure (2). Hemoglobin A1c is also the best predictor of diabetic complications. Hemoglobin A1c is, therefore, the preferred outcome when evaluating the glycemic efficacy of new diabetes therapies (3).

Lisa Ceglia, MD Joseph Lau, MD Anastassios G. Pittas, MD MSc

Potential Financial Conflicts of Interest: None disclosed.

References 1. Ceglia L, Lau J and Pittas AG. Meta-analysis: Efficacy and safety of inhaled insulin therapy in adults with diabetes mellitus. Ann Intern Med 2006; 145:665-675. 2. Goldstein DE, Little RR, Lorenz RA, Malone JI, Nathan D, Peterson CM et al. Tests of glycemic in diabetes. Diabetes Care 2005: 27:7:1761-1773. 3. Nathan DM. Thiazolidinediones for Initial Treatment of Type 2 Diabetes? N Eng J Med 2006; 355:2477-2480.

Conflict of Interest:

None declared

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