CRD summary

The authors of this reasonably well-conducted review concluded that inhaled insulin offers an alternative noninvasive option, with comparable glycaemic efficacy and increased patient acceptability, when compared with subcutaneous regular insulin for patients with diabetes. However, they emphasised the need for further research to determine the role of inhaled insulin in diabetes treatment.

Authors' objectives

To investigate the efficacy, safety and patient acceptability of inhaled insulin therapy in adults with diabetes.

Searching

MEDLINE(1966 to June 2006) and the Cochrane Controlled Trials Register(from Issue 2, 2006) were searched; the search terms were reported. The authors also searched for additional publications in reference lists. Unpublished studies were sought through a briefing document on Exubera. Only articles reported in the English language were eligible.

Study selection

Assessment of study quality

The following were used to assess study quality: allocation generation, intention-to-treat analysis, drop-out rate, and whether the trial was designed to test glycaemic efficacy noninferiority or superiority. The authors did not state how many reviewers performed the validity assessment.

Data extraction

Two reviewers independently extracted data, with any differences resolved by consensus. The safety data extracted related to severe hypoglycaemia, pulmonary symptoms, change in pulmonary function and level of circulating insulin antibodies. Data were gathered on the total number of patients per treatment group who reported at least one episode of severe hypoglycaemia. The Food and Drug Administration's definition of hypoglycaemia was used (patient had a blood glucose level less than or equal to 2 mmol/L (i.e. 36 mg/dL) or required assistance).

For continuous variables, the weighted mean difference (WMD) and its associated 95% confidence interval (CI) were calculated, based on the change from baseline in the inhaled insulin group versus the comparison group. For dichotomous variables, the risk ratio (RR) and its associated CI were calculated. Publicly available information was used to supplement published reports.

Methods of synthesis

Results of the review

Sixteen open-label RCTs (4,023 patients) were included.

No trials reported attempts to blind the outcome assessors, and none used a double dummy technique to blind patient and physician. All trials comparing inhaled insulin with subcutaneous insulin were designed to test 'noninferiority', whereas those comparing inhaled insulin with oral agents were designed to show 'superiority' of inhaled insulin. Seven of 12 trials used intention-to-treat analysis.

Glycaemic outcomes.

Inhaled insulin versus subcutaneous insulin.

Based on 11 studies in patients with type 1 or type 2 diabetes, there was a statistically significant difference in the decrease in haemoglobin levels from baseline favouring subcutaneous insulin (WMD 0.08%, 95% CI: 0.03, 0.14). Two studies of 104 weeks' duration gave a WMD of 0.18% (95% CI: 0.09, 0.27), but studies of less than 24 weeks' duration demonstrated no difference between treatments. Trials of patients with type 1 diabetes had a WMD of 0.09% (95% CI: 0.03, 0.16), whereas those of patients with type 2 diabetes showed no statistically significant difference between treatments. There was no heterogeneity between trials. Based on 5 trials, there was no difference between the proportion of patients who achieved HbA1c levels of less than 7%.

Inhaled insulin versus oral hypoglycaemic agents.

Based on 6 trials in patients with type 2 diabetes, inhaled insulin lowered HbA1c levels more than oral agents (WMD -1.04%, 95% CI: -1.59, -0.49); there was some heterogeneity between trials. The larger 2 trials, which had a duration of 24 weeks and titrated the dose of therapy in both groups to achieve glycaemic targets, had a smaller, although still statistically significant, mean difference than the other trials. Patients taking inhaled insulin were more likely than those taking oral agents to achieve HbA1c levels of less than 7% (RR 1.87%, 95% CI: 1.07, 3.25).

Safety.

Severe hypoglycaemia was more likely in patients taking inhaled insulin than in those taking oral agents (RR 3.06, 95% CI: 1.03, 9.07). There was no difference between inhaled insulin and subcutaneous insulin. There was an increased incidence of mild to moderate nonprogressive dry cough in patients taking inhaled insulin compared with oral agents or subcutaneous insulin (RR 3.52, 95% CI: 2.23, 5.56). Two per cent of patients with type 1 diabetes and 2.3% with type 2 diabetes discontinued inhaled insulin treatment due to respiratory events compared with 0% and 0.1%, respectively, taking either subcutaneous insulin or oral agents.

Patient-reported outcomes.

Based on 4 trials of patients with either type 1 or type 2 diabetes, there was a statistically significant increase in overall patient satisfaction with inhaled insulin over subcutaneous insulin. Two studies reported statistically significant improvements in overall quality of life with inhaled insulin, and in 2 further studies patients randomly assigned to inhaled insulin were more likely to continue with it than to switch back to subcutaneous insulin.

Authors' conclusions

Inhaled insulin offered an alternative, noninvasive option with slightly less glycaemic efficacy to subcutaneous regular insulin and increased patient acceptability. However, the authors emphasised the need for further research to determine the role of inhaled insulin in diabetes treatment.

CRD commentary

The review addressed a clear question with defined inclusion criteria for the participants, interventions, outcomes and study designs. The search was appropriate, but some unpublished studies might have been missed and the review was limited to English language articles only. Two reviewers were involved in the selection of studies and data extraction, thus helping to minimise bias. The validity of the included studies was assessed and discussed in the context of the results.

The meta-analysis appeared to have been conducted appropriately, with results also being presented for subgroup analysis based on diabetes type and length of study. It should be noted that the studies comparing inhaled insulin with subcutaneous insulin were designed as equivalence trials, not as superiority trials, and so might have underestimated the effects of inhaled insulin. The review appeared to be a reliable synthesis of the trials in this area and appropriately pointed to the need for further research on inhaled insulin.

Implications of the review for practice and research

Practice: The authors concluded that until long-term safety data become available, inhaled insulin should be reserved for non-pregnant adults without pulmonary conditions who are opposed to injections and who would otherwise delay taking their insulin.

Research: The authors stated that studies of longer duration are needed to assess the effects of inhaled insulin on lung function.

Bibliographic details

Ceglia L, Lau J, Pittas A G. Meta-analysis: efficacy and safety of inhaled insulin therapy in adults with diabetes mellitus. Annals of Internal Medicine 2006; 145(9): 665-675. [PubMed: 17088580]

Original Paper URL

http://www.annals.org/cgi/content/full/145/9/665

Indexing Status

Subject indexing assigned by NLM

MeSH

Administration, Inhalation; Administration, Oral; Adult; Diabetes Mellitus, Type 1 /blood /drug therapy; Diabetes Mellitus, Type 2 /blood /drug therapy; Hemoglobin A, Glycosylated /metabolism; Humans; Hypoglycemic Agents /administration & dosage /adverse effects; Injections, Subcutaneous; Insulin /administration & dosage /adverse effects; Insulin Antibodies /blood; Lung Diseases /chemically induced; Patient Satisfaction; Treatment Outcome; Weight Gain /drug effects

AccessionNumber

12006008434

Database entry date

31/07/2007

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.