Two authors independently extracted data and assessed the risk of bias in the included studies. Authors also used GRADE to assess the quality of the evidence.
MAIN RESULTS: The searches identified 29 trials (45 references). Four included trials provide results: one short-term single-center cross-over trial (seven adults) comparing
insulin with oral
repaglinide and no medication in adults with CFRD and normal fasting
glucose; one long-term multicenter trial (61 adults with CFRD) comparing
insulin with oral
repaglinide and placebo; one long-term multicenter trial (67 adults) comparing
insulin with oral
repaglinide; and one 12-week single-center cross-over trial (20 adults) comparing the
long-acting insulin glargine to short-term
neutral protamine Hagedorn insulin. Two ongoing trials of newly approved
incretin mimics have been noted for possible future inclusion. Downgrading of the quality of the evidence was mainly due to risks of bias across all domains, but particularly due to concerns surrounding allocation concealment and selective reporting. There were also some concerns due to imprecision from small sample sizes and low event rates. Finally, there may be some bias due to the amounts of
insulin and
repaglinide given not being comparable. Data from one trial comparing
insulin to placebo (39 participants) did not show any difference between groups for the primary outcomes of
blood glucose levels (very low-quality evidence), lung function (low-quality evidence) or nutritional status (low-quality evidence). Similarly, no differences between groups were seen for the secondary outcomes of number of
hypoglycemic episodes (low-quality evidence),
secondary infection complications or quality of life (QoL). These results were mirrored in the narrative reports for the second trial in this comparison (seven participants). Data from the one-year trial comparing
repaglinide to placebo (38 participants), showed no differences between groups for the primary outcomes of
blood glucose levels (very low-quality evidence), lung function (low-quality evidence) and nutritional status (low-quality evidence). Also, no differences were seen between groups for the secondary outcomes of number of
hypoglycemic episodes (low-quality evidence),
secondary infection complications or QoL. These findings were mirrored in the narrative reports for the second trial (n = 7) in this comparison. Three trials compared
insulin to
repaglinide (119 participants). Data from one trial (n = 67) showed no difference in
blood glucose levels at either 12 months (high-quality evidence) or 24 months; narrative reports from one trial (45 participants) reported no difference between groups, but the second trial (7 participants) reported a beneficial effect of
insulin over
repaglinide. Two trials (112 participants) found no difference between
insulin and
repaglinide in lung function or nutritional status (moderate-quality evidence). Two trials (56 participants) reported no difference in the number of
hypoglycemic episodes (low-quality evidence). One trial (45 participants) reported no difference between groups in
secondary infections and
cystic fibrosis QoL. The single trial comparing
glargine to
neutral protamine Hagedorn insulin did not report directly on the review's primary outcomes, but did report no differences between groups in post-prandial
glucose values and weight; neither group reported infectious complications. There was no difference in episodes of
hypoglycemia (very low-quality evidence) and while there was no difference reported in QoL, all participants opted to continue treatment with
glargine after the trial was completed. Mortality was not reported by any trial in any comparison, but death was not given as a reason for withdrawal in any trial.
AUTHORS' CONCLUSIONS: This review has not found any conclusive evidence that any agent has a distinct advantage over another in controlling
hyperglycemia or the clinical outcomes associated with CFRD. Given the treatment burden already experienced by people with
cystic fibrosis, oral
therapy may be a viable treatment option. 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 and its impact on the course of
pulmonary disease process in
cystic fibrosis continue to be a high priority. Specifically, investigators should evaluate adherence to different
therapies and also whether there is benefit in using additional
hypoglycemic agents as well as the newly approved
incretin mimics. Agents that potentiate
insulin action, especially agents with additional anti-inflammatory potential should also be further investigated as adjuvant
therapy to
insulin.