CFDB - Cystic Fibrosis DataBase

Cochrane Database of Systematic Reviews - Cochrane Review

Drug treatments for managing cystic fibrosis‐related diabetes

Study design (if review, criteria of inclusion for studies)

Randomized controlled trials comparing all methods of diabetes therapy in people with diagnosed cystic fibrosis-related diabetes

List of included studies (4)

Ballmann; Grover 2008; Moran 2001; Moran 2009

Participants

Participants of all ages with CF (a positive diagnostic test for CF that may include sweat, nasal epithelial and genotype testing) associated with pulmonary or gastrointestinal disease or both. Diabetes from this cohort will be further established by oral glucose tolerance testing, A1C data, two fasting or random blood sugars as defined by ADA standards (ADA 2004). The CF Foundation Guidelines (USA) related to a diagnosis during pulmonary exacerbations and in those with CF requiring feeding tubes may also be additionally used in establishing diagnostic criteria for CFRD.

Interventions

Different insulin regimens and regimens of oral diabetic medications. Studies where insulin regimens plus either an oral medication or placebo are compared. Different classes of these therapeutic agents, as well as strategies to reduce side effects and harm in using these agents. Insulin preparations: 1. short-acting insulin (with duration of action typically lasting two to four hours); 2. intermediate-acting insulin (action to 12 hours); 3. long-acting insulin (duration of actions approaching 24 hours). Post hoc change Oral anti-diabetic agents: 1. sulphonyureas and related agents; 2. biguanides and related agents; 3. glitazones and related agents; 4. other agents that specifically manage hyperglycaemia

Outcome measures

Primary outcomes 1. Biochemical measures of glycaemic control, ie HbA1c, fasting and two-hour post-meal serum blood sugar values 2. Pulmonary function (eg forced expiratory volume (FEV1) and forced vital capacity (FVC)) 3. Assessment of nutritional status (eg body mass index (BMI)) Secondary outcomes: Prevalence of microvascular and macrovascular disease; Rate of pulmonary exacerbations; Complications of therapeutic management (hypoglycemia, liver toxicity, metabolic effects on acid-base status); Clinical status: six-minute walk test, health-related quality of life (HRQoL) instrument (eg the Cystic Fibrosis Questionnaire-Revised (CFQ-R) (Quittner 2009)), mortality

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.

Keywords: Diabetes Mellitus; Gastrointestinal Diseases; Hypoglycemic Agents; Insulin; Oral; Pancreatic Diseases; pharmacological_intervention;