Abstract: The searches identified 22 trials (34 references). Four trials (200 participants) are included: one short-term single-center trial (n = 7) comparing insulin with oral repaglinide and no medication in people with cystic fibrosis-related diabetes and normal fasting glucose; one long-term multicenter trial (n = 100, 74 of whom had cystic fibrosis-related diabetes) comparing insulin with oral repaglinide and placebo; one long-term multicenter trial (n = 73) comparing insulin with oral repaglinide; and one 12-week single-center trial (n = 20) comparing the long-acting insulin glargine to short-term neutral protamine Hagedorn insulin. Two trials with data for the comparison of insulin to placebo did not report any significant differences between groups for the primary outcomes of blood glucose levels, lung function and nutritional status. This was also true for the single trial with data for the comparison of repaglinide to placebo. Two trials (one lasting one year and one lasting two years) contributed data for the comparison of insulin versus repaglinide. There were no significant differences for the primary outcomes at any time point, except at one year (in the two-year trial) when the insulin group had significant improvement in z score for body mass index compared to the repaglinide group. The single trial comparing glargine to neutral protamine Hagedorn insulin also did not report any significant differences in the review's primary outcomes. A few cases of hypoglycemia were seen in three out of the four trials (none in the longest trial), but these events resolved without further treatment. There was an unclear risk of bias from randomization and allocation concealment in two of the four included trials as the authors did not report any details; in the remaining two studies details for randomization led to a low risk of bias, but only one had sufficient details on allocation concealment to allow a low risk judgement, the second was unclear. There was a high risk from blinding for all trials (except for the comparison of oral repaglinide versus placebo) due to the nature of the interventions. Complete data for all outcomes were not available from any trial leading to a high risk of reporting bias. The amounts of insulin and repaglinide administered were not comparable and this may lead to bias in the results. None of the included trials were powered to show a significant improvement in lung function. This review has not found any significant conclusive evidence that long-acting insulins, short-acting insulins or oral hypoglycemic agents have a distinct advantage over one another in controlling hyperglycemia or clinical outcomes associated with cystic fibrosis-related diabetes. While some cystic fibrosis centers use oral medications to help control diabetes, the Cystic Fibrosis Foundation (USA) clinical practice guidelines support the use of insulin therapy and this remains the most widely-used treatment method. Randomized controlled trials specifically related to controlling diabetes with this impact on the course of pulmonary disease process in cystic fibrosis continue to be a high priority. There is no demonstrated advantage yet established for using oral hypoglycemic agents over insulin, and further trials need to be evaluated to establish whether there is clear benefit for using hypoglycemic agents. Agents that potentiate insulin action, especially agents with additional anti-inflammatory potential should be further investigated to see if there may be a clinical advantage to adding these medications to insulin as adjuvant therapy.

Plain-language summary: We included four randomized trials with a total of 200 participants. The trials' duration ranged from single doses to 24 months of treatment. Three trials compared insulin (given via a syringe) to repaglinide tablets and recruited 180 people between them. Trial participants had an average age of 25 years and mild to severe diabetes. One of these trials (73 people) compared the two treatment groups directly over a two-year period; the remaining two trials each had a third treatment arm - one (seven people) compared single doses of insulin to repaglinide and to no treatment and the other (100 people) compared insulin to repaglinide and to a placebo (a dummy tablet with no active medication) for 12 months. The fourth trial recruited 20 participants with an average age of 34 years and compared the long-acting insulin glargine to short-term neutral protamine Hagedorn insulin over a 12-week period. We were not able to show that any of the treatments were better than the others. Only a few cases of hypoglycemia (low blood sugar) were seen in three out of the four trials (none in the longest trial), but these events resolved without further treatment. Longer-term studies are still needed to see how controlling cystic fibrosis-related diabetes affects lung function. There also needs to be research into the use of agents used together with insulin to enhance its action, especially those agents with additional anti-inflammatory potential. The participants would have been mostly able to tell which treatment they were receiving (e.g. insulin via a syringe or repaglinide as a tablet), so we thought there was a high risk from blinding in all trials (except when comparing repaglinide tablets to placebo (dummy) tablets). In two trials we are satisfied that participants were put into the different treatment groups completely at random; however, the other two trial reports were not clear on how it was decided which group the participants were put into. In only one trial was it clear that no one knew in advance which group a participant would be put into, in the other three trials there were no details given. There could be some bias if it was known in advance which group the next participant would be in, e.g. healthier participants might be put into one group to show better results for that treatment. There were also many results which were not fully reported in the publications. Finally, there may be bias in the results as the amounts of insulin and repaglinide given were not comparable.