Culler 1994

Culler et al.¹⁴² looked at the use of glipizide in patients with CF with IGT. Treatment was not randomised and numbers were few – six patients aged from 12 to 25 years, with elevated BG level 2 hours after oral administration of 1.75 g/kg of glucose and normal fasting BG. It was a case series with no control group and it is not clear how these patients were selected for treatment. The size of the clinic population was not given, so the proportion, and hence representativeness, cannot be assessed.

Results were measured before treatment, and again at 3 and 6 months (for height, weight and BMI) after treatment. Outcome measures used were HbA_1c level, 24-hour urine glucose level, insulin sensitivity, first-phase insulin response (FPIR), and changes in growth assessed as height, weight and BMI. Results showed significant improvements in HbA_1c level, 24-hour urine glucose level and FPIR, but not in insulin sensitivity or weight gain. Three months after glipizide administration, the mean FPIR was raised by 60% (from 287 to 459 pmol/l; p < 0.05), although it was just below the lowest range of normal FPIR (466 pmol/l); glycosuria and HbA_1c both decreased significantly in all patients from 57.5 g/day to 23.2 g/day (p < 0.01) and 6.3% to 5.8% (p < 0.05) over the same period, respectively. The insulin sensitivity values in these subjects were within normal range before treatment and an increase in four of the six patients was observed, although it was not statistically significant in the group as a whole. No changes were found in either weight or BMIs at 3 and 6 months after treatment. Apart from occasional mild symptomatic hypoglycaemia, no other adverse effects were described. The authors suggested that ‘glipizide can be used in the treatment of patients with CF with IGT, especially if a patient has elevated postprandial glucose levels but normal fasting BG levels; and if persistent hyperglycaemia or significant elevation of HbA_1c occurs, then insulin therapy should be instituted’.

The small numbers and short duration, and the lack of a control group, reduce the value of the study. It shows that glipizide can be effective in the short term, but, ideally, we would have a RCT against other agents, such as a meglitinide analogue or a short-acting insulin.

Lanng 1994

Lanng et al.¹³⁴ studied the effect of insulin therapy in patients with CF. Treatment was not randomised and numbers were few: 18 patients aged from 3 to 28 years, from a total clinic population of 240 patients with CF, of whom 41 patients with CFRD had received insulin therapy for at least 2 years. Under half (18 of these with at least 2 years of follow-up on insulin) took part in the study. They had a comparison group of 18 non-diabetic patients with CF who were matched with age, sex and presence of chronic lung infection at the time of diagnosis of diabetes in the diabetic patients.

Data on body weight, BMI, FEV₁, FVC, microscopy, and culture of sputum and precipitins against different bacteria were collected 6 years before and 2 years after the onset of insulin therapy. For data on lung function, only those from patients > 6 years of age were included.

Results before and after insulin were similar to other studies: a decline in BMI, FEV₁ and FVC in the months leading up to the start of insulin therapy (e.g. BMI: patients with CFRD 16.9 ± 0.7 kg/m² vs control subjects 19.2 ± 0.6 kg/m²). At the time at onset of insulin therapy, the patients with CFRD differed significantly to non-diabetic control subjects in BMI, FEV₁ and FVC, but not body weight. After 2 years on insulin therapy the diabetic and non-diabetic groups had similar body weight and BMI. Also the per cent differences in FEV₁ and FVC between the two groups were similar to those found 6 years before insulin therapy.

The study also collected data on lung infections and carriage of organisms. Chronic P. aeruginosa lung infection was present in (diabetic patients vs control subjects) 14 patients compared with 13 at entry, 15 compared with 15 at onset of treatment, and 15 compared with 17 at the end of the study. Precipitins against P. aeruginosa increased in both groups, with no difference between levels at any time during the study. The number of weeks of intravenous anti-Pseudomonas treatment did not differ between the groups before and after insulin treatment. This seems disappointing.

However, the per cent of sputum examinations positive for H. influenzae and Streptococcus pneumoniae decreased significantly (from 11.6% to 7.1% and from 2.4% to 0.3%, respectively) after insulin therapy; these were unchanged in the control subjects; parameters of lung infections with P. aeruginosa and S. aureus remained unchanged.

The authors conclude that insulin improves lung function after the insidious decline resulting from the pre-diabetic condition in patients with CF and recommended its commencement when diagnosis of CFRD is made.

Bertele-Harms 1996 (abstract only)

Bertele-Harms and Harms¹⁴³ studied the effect of glibenclamide in patients with CFRD. Treatment was not randomised and numbers were small. Twenty patients were selected from an original 26 patients with CFRD, aged from 12.8 to 26.5 years when CFRD became manifest, with fasting glucose level > 140 mg/dl, marked glycosuria, dehydration and elevated HbA_1c level.The size of the clinic population was not given, so the proportion, and hence representativeness, cannot be assessed. There was no control group and patients were selected based on the availability of data on HbA_1c.

Results were obtained before and after treatment over a period of 15 years. The initial mean HbA_1c value at onset of CFRD was 5.34% (3.6–7.8%) (normal range 4.2–6.3%). All patients improved on glibenclamide; for instance, glycosuria disappeared in 85% after 6–8 weeks of treatment and the HbA_1c value returned to normal range in 65% of patients, although it remained elevated (6.4–7.5%) in 20% patients. The other 15% (three) patients, who had the most elevated initial HbA_1c values, were switched to insulin after a mean of 8 months owing to insufficient response with the sulfonylurea. Further increases in sulfonylurea doses were ineffective. The mean duration of glibenclamide effectiveness was 2.4 years (range 0.6–5.5 years), but patients considered afterwards that delaying insulin treatment had been worthwhile.

Kentrup 1999

Kentrup et al.¹⁴⁴ studied the efficacy and safety of acarbose in patients with CF with IGT, in a double-blind, randomised crossover trial. There were 12 patients, all inpatients for treatment of Pseudomonas infection, aged from 8 to 22 years. Patients were selected based on their BG response being abnormal after a standard test meal.

The trial lasted only 14 days. Patients were randomised to either acarbose or placebo for 5 days (day 4–8), then had a day of washout (day 9) before receiving the other drug for another 5 days (days 10–14). On day 2 (before the start of study medication) and on the last day of both study periods (days 8 and 14), a standardised nutritional load (a carbohydrate content of 1.75 g/kg body weight) was given, and blood samples were taken before and at 30, 60, 90, 120 and 180 minutes after the test load. A baseline measurement was also taken after a 10-hour overnight fast in resting patients. There were significant reductions in PG, insulin and C-peptide with acarbose treatment compared with baseline values. This was also true with acarbose treatment compared with placebo in mean BG level (6.12 ± 0.82 mmol/l vs 7.54 ± 1.42 mmol/l; p < 0.05) and mean peak BG level (8.01 ± 1.79 mmol/l vs 11.56 ± 2.65 mmol/l; p < 0.01).

Gastrointestinal disturbances, such as diarrhoea, flatulence, loss of appetite, nausea and abdominal cramps, were recorded in 67% of patients during therapy with acarbose. The authors concluded that acarbose has a beneficial therapeutic effect on glucose tolerance in patients with CF, but its side effects are likely to prevent patients from accepting it as a long-term therapy.

Moran 2001

Moran et al.¹⁴⁵ studied the use of preprandial insulin and repaglinide in patients with CFRD without FH. There were seven patients aged 24 ± 5 years. The size of the clinic population was not clearly given, so the proportion, and hence representativeness, cannot be assessed. Seven healthy, non-athletic normal control patients, matched for age, sex and BMI, were recruited by poster advertisement, acting as a reference to the outcome measures. Patients were studied on three separate occasions over a 1- to 2-month period, receiving a test meal in the morning after a night fasting with treatment in a random order: (1) no preprandial diabetes medication (baseline meal); (2) insulin lispro, 10 minutes preprandial; and (3) repaglinide, 10 minutes preprandial. Control subjects received the test meal under the same conditions on a single occasion with no preprandial medication.

Plasma glucose and insulin levels were recorded at the beginning of the meal and after the meal at 20-minute intervals for 5 hours.

After the test meal without medication, postprandial glucose excursion was elevated, with a peak glucose level of 228 ± 30 mg/dl (12.6 mmol/l) at 74 ± 7 minutes after the beginning of meal. The peak insulin levels (53 ± 11 μU/ml) were delayed and blunted at 117 ± 11 minutes post meal.

After the meal with preprandial lispro, there was a significant decrease in the peak glucose level (172 ± 9 mg/dl; p = 0.0004), the 2-hour glucose area under the curve (AUC) (p = 0.001) and the 5-hour glucose AUC (p < 0.0001) compared with the untreated baseline meal. However, glucose excursion was not completely controlled.

After the meal with preprandial repaglinide, the 5-hour glucose AUC was significantly less than baseline (p = 0.03), but there were no differences seen in the 2-hour glucose AUC (p = 0.39) or the peak glucose level (p = 0.17).

Comparing insulin lispro with repaglinide in CFRD, insulin lispro seemed to be better than repaglinide on postprandial glucose excursion, with significant differences observed between the two drugs in the peak glucose level (172 ± 9 vs 208 ± 18 mg/dl; p = 0.02), the 2-hour glucose AUC (p = 0.02) and the 5-hour glucose AUC (p = 0.01). Curiously, neither drug, at the doses used in the study, significantly changed the peak insulin level or the 2-hour insulin AUC compared with baseline. Four episodes of hypoglycaemia (glucose level 48–54 mg/dl, 2.7–3.0 mmol/l) occurred in patients with CF during the study: one after the test meal without medication, two after administration of insulin lispro and one after administration of repaglinide. Hence, both lispro and repaglinide reduced PPH, but insulin was more effective. The authors commented that although based on standard practice recommendations, the doses of insulin and repaglinide seemed to be too low (as instanced by the non-significant difference in peak insulin levels); therefore, higher doses of these drugs may have had greater therapeutic effect.

Nousia-Arvanitakis 2001

Nouisa-Arvanitakis et al.⁵⁴ studied the effect of biphasic (rapid and intermediate) insulin on nutrition, lung function and clinical status in a small case series of six patients, aged 15–22 years, who developed CFRD in a 5-year follow-up of 30 patients with CF, and were thought to require insulin treatment. A control group of non-diabetic patients with CF, matched with the diabetic group for age, sex, pubertal stage, BMI, FEV₁ and SS at the onset of the study, was selected for the comparison of FPIR, BMI, FEV₁ and SS (maximum score of 100) among non-diabetic patients and patients with CF.

The outcome measures used were BMI, FEV₁, SS, intravenous glucose tolerance test and FPIR, at time of diagnosis of CFRD and 6 months after starting insulin. There was significant improvement in BMI (16.36 ± 1.34 kg/m² vs 19.07 ± 1.06 kg/m²; p = 0.0018), FEV₁ (50.66 ± 6.68 l vs 70.83 ± 5.40 l; p = 0.0062) and SS (66.00 ± 3.84 vs 84.50 ± 4.41; p = 0.0006) in all six patients following insulin treatment. A significant difference was found in FPIR (p < 0.0001), BMI (p = 0.0003), FEV₁ (p = 0.0071) and SS (p = 0.0009) when comparing the six patients with CFRD to the control subjects at the time of diagnosis of diabetes mellitus.

A positive correlation between FPIR and BMI was detected in the 30 patients with CF (Pearson's correlation coefficient r = 0.759). The authors considered that there was an association between insulin hyposecretion and an overall deterioration in the clinical status of the patients with CF involving nutrition, lung function and clinical scores, which were improved significantly after the institution of insulin. They believed it is important to identify patients with CF who are at risk of developing diabetes, so that early insulin therapy can be given.

Rolon 2001

Rolon et al.¹⁴⁶ assessed the impact of hyperglycaemia preceding diabetes (pre-diabetes) on nutritional status and respiratory function in patients with CF, and to describe the clinical characteristics of CFRD at the start of insulin treatment, insulin regimens and effects of insulin therapy. Of a total of 220 patients receiving follow-up at their clinic, 21 (aged 10–21 years) had insulin-treated diabetes mellitus, with no lung transplantation or immunosuppressive therapy. Of these patients, 14 were selected based on the completeness of clinical data. There were 14 non-diabetic patients matched for age, sex and chronic lung infection by P. aeruginosa. They had normal fasting glucose and normal OGTT.

Results were reported 5 years before and after insulin treatment. Outcome measures used were BMI, BMI z-score, FVC, FEV₁, insulin regimen, mean insulin dosage, hypoglycaemic events and mean HbA_1c value. However, these data were available for 12 patients during the first year, eight during the second year and seven during the third, fourth and fifth years, as seven died during the study period. Hence, only seven patients had 5 years of follow-up at the time of study. Insulin treatment was started either on the basis of symptoms of hyperglycaemia (n = 7) or on the basis of the presence of diabetes mellitus diagnosed by a systematic screening and a nutritional status (n = 7). Results showed no differences in BMI z-score between the CFRD patients and the non-diabetic control subjects during the 4 years prior to insulin treatment but it was significantly lower in the cases (−1.66 ± 1.5 vs −0.3 ± 0.95; p = 0.03) 6 months prior to the treatment; so were BMI (15.9 ± 1.8 kg/m² vs 17.3 ± 1.3 kg/m²; p = 0.04) and lung function (FVC 52% ± 20% vs 79% ± 20%; p = 0.01; FEV₁ 37% ± 19% vs 72% ± 23%; p = 0.01).

After insulin treatment was started, respiratory function improved and the BMI returned to normal (compared with the French population) within 2 years. A decreased rate of FVC decline was seen in five of the seven patients 5 years post insulin (p = 0.1) and FEV₁ improved in all seven patients after the start of treatment (p = 0.02). The mean insulin dose increased from 0.62 units/kg/day during the first year to 1.25 units/kg/day during the fifth year.

Mean HbA_1c value was 8.8% at the start of treatment, fell to 6.6% during the first year of insulin treatment, but rose to 7.8% during the fifth year. Two episodes of severe hypoglycaemia (symptomatic and BG level of < 50 mg/dl) were reported over the total follow-up of 42 patient-years (4.8 episodes per 100 patient-years). Mild hypoglycaemia (BG level of < 60 mg/dl) occurred with a frequency of 10.3 episodes per patient-year. It was concluded that the clinical status of pre-diabetic patients with CF deteriorates before the start of insulin therapy, and that insulin treatment improves anabolism and provides good glycaemic control with few hypoglycaemic events in patients with CFRD with or without FH.

Rosenecker 2001

Rosenecker et al.¹²⁰ compared the effects of insulin with glibenclamide on patients with CFRD. Patients were not randomly allocated to either treatment, so, in effect, this study present data from two case series. There were 45 patients, with 34 on insulin (mean age of 24.0 ± 4.7 years) and 11 on glibenclamide (mean age of 27.7 ± 5.4 years). Five centres participated in this study but the size of the centre populations was not given, so the proportion, and hence representativeness, cannot be assessed. There was no control group. Patients who had been seen regularly in one of the centres and had received a prior CFRD diagnosis of at least 1 year were included.

Results were obtained by questionnaire surveys. Outcome measures used were FEV₁, FVC, weight for height and SS. Of the 34 insulin-treated patients, 13 had been treated initially with glibenclamide, which failed after a mean time interval of 18.2 ± 14.5 months. The diagnosis of CFRD was earlier in the insulin-treated group than in the sulfonylurea group (16.4 ± 3.6 years vs 24.2 ± 4.8 years; p < 0.001) and the durations of treatment with insulin and glibenclamide were 7.6 ± 4.6 years and 3.5 ± 2.0 years, respectively. At the start of the study, the mean HbA_1c levels and mean BG values in the insulin-treated group were 8.3 ± 2.8% and 11.8 ± 8.0 mmol/l, respectively; in the glibenclamide group the levels were 7.0 ± 1.1% and 7.9 ± 4.3 mmol/l, respectively. At the end of the study, no significant differences were found between the two groups in the most recent FEV₁, FVC, SS or BMI measurements. There were no severe hypoglycaemic events in patients treated with insulin or glibenclamide. The authors concluded that ‘CFRD can be treated orally with glibenclamide in some patients with CF, at least in a subgroup with a late onset of diabetes. FEV₁, FVC, SS and BMI were maintained equally well by both treatments’. However, there are problems with comparisons between treatments from a non-randomised study.

Dobson 2002

Dobson et al.¹³⁸ studied the effect of insulin on lung function and weight in four patients aged 15–23 years with long-standing CF, who had weight loss and deteriorating lung function without a clear cause, and had high random glucose values but normal OGTT. The paper mentions that some of these high results were postprandial, implying that they would fall into our non-IGT PPH group.

Weight and spirometry (FEV₁/FVC) were recorded before and 3 months after insulin treatment. Insulin treatment was accompanied by increases in both weight and spirometry in all four patients.

The authors concluded that insulin can result in a significant clinical improvement in patients with CF with normal OGTT results or HbA_1c value, although they all had multiple random blood glucose (RBG) levels above 11.1 mmol/l. They also commented that the benefit seen in these patients was unlikely to result from improved glucose concentrations, as HbA_1c values were normal before insulin treatment and not altered significantly by it. However, the improvement might have been only in PPH. They proposed that in patients with CF clinically significant insulin deficiency may precede the development of diabetes as defined by OGTT.

This study is very small, but its value may be in the implication that treatment is worthwhile even at the isolated PPH stage. The four patients gained weight, with increases ranging from 0.7−5.7 kg, on 6–12 units of insulin daily.

Ballmann 2003 (abstract only)

Ballmann et al.¹⁴⁷ studied the use of glibenclamide in patients with CFRD. Treatment was not randomised and numbers were small: 19 patients aged [mean ± standard deviation (SD)] 13.7 ± 3.7 years (out of a total of 41 patients with CFRD) were initially treated with glibenclamide and had completed follow-up for 2 years. Six patients changed to insulin (group 1) after 14–24 months owing to hyperglycaemia in all, systemic steroids in one and nocturnal percutaneous endoscopic gastrostomy feeding in three patients; the rest remained on glibenclamide after 2 years (group 2). The mean time until starting insulin treatment was 4.5 years in those treated initially with glibenclamide. There was no control group and it is not clear how these patients were selected for treatment.

Results at the start of glibenclamide treatment were given for both groups. Final results for group 1 were when they changed to insulin, and for group 2 were after 2 years of glibenclamide treatment. Outcome measures used were nutritional status (BMI z-score), lung function [per cent predicted forced expiratory volume in 1 second (%FEV₁)] and metabolic control (HbA_1c), as shown in Table 5. The authors commented that ‘more than 68% of those on glibenclamide were in a stable clinical condition (BMI z-score and %FEV₁) and good metabolic control after 2 years’.

TABLE 5

Results before and after treatment with glibenclamide (reproduced from Ballman 2003).

So those who remained on glibenclamide appeared to do well. The authors did emphasise the need for controlled randomised prospective studies comparing insulin with oral antidiabetic treatment of CFRD.

Boyle 2004 (abstract only)

Boyle et al.¹⁴⁸ studied the effects of early insulin treatment in 30 patients with CF, who were drawn from a clinic with 155 patients. The average age of the included patients was 26.9 years: 13 had CFRD, 10 had IGT and 7 had NGT. Treatment was not randomised. There was no control group and patients were selected because they were insulin treated.

Outcome measures used were weight gain and FEV₁ changes, before and after a year of insulin treatment. Weight (% change year before, then year after) seemed to improve in all patients: pre-insulin −3.14% versus 0.59% post insulin (CFRD), 1.1% versus 1.56% (IGT) and −2.1% versus 0.45% (NGT). The results for FEV₁ were: −0.28% versus −1.47% (CFRD), −7.08% versus +1.46% (IGT) and −2.68% versus +1.47% (NGT). However, statistical significance of the results is unclear, as p-values were not given. The authors concluded that insulin treatment prior to the development of diabetes appears to have positive effect on lung function and body weight.

Franzese 2005

This study¹⁴⁹ was reported only in a letter. Franzese et al.¹⁴⁹ studied the use of glargine in patients with CFRD. Treatment was not randomised and numbers were small: eight patients aged from 10 to 29 years, four with chronic CFRD who were treated with rapid insulin in the previous 1–3 years (group A) and another four patients with intermittent CFRD requiring insulin only during infections (group B). The size of the clinic population was not given, so the proportion, and hence representativeness, cannot be assessed. There was a control group (non-glargine treated) comprising six patients (aged 14–18 years) with intermittent CFRD. It is not clear how these patients were selected.

Results were before and 6 months after glargine treatment (plus preprandial rapid insulin in group A). The outcome measures used were BMI, FEV₁, HbA_1c and the number of lung infections. There was a significant decrease in the number of lung infections in both group A and group B, from 3.75 ± 0.5 to 1.75 ± 0.9 (p < 0.01) and from 2.75 ± 0.5 to 1.25 ± 0.5 (p < 0.001), respectively; no change was seen in the control group (3.3 ± 1.2 vs 3.1 ± 0.4). There were no positive changes in HbA_1c value or BMI, and no hypoglycaemic events were recorded. This was attributed to the short period of observation. The conclusion was that basal insulin may play a role in reducing the number of lung infections in both overt CFRD and pre-patients with CFRD.

Minicucci 2005 (abstract only)

Minicucci et al.¹⁵⁰ looked at the efficacy and safety of insulin glargine in a case series of 12 CFRD and three CF IGT patients aged from 14 to 34 years: six had CFRD treated with insulin (group A); six appeared to have CFRD but without FH, diagnosed on the basis of OGTT (group B), and three had CFRIGT (group C). Group A had been on insulin regular or rapid analogue before meals. It is not clear whether they were also on neutral protamine Hagedorn (NPH) but the abstract says that glargine took the place of intermediate insulin, which implies that the short-acting insulin was continued. Neither group B nor group C had ever been treated with insulin. The size of the clinic population was not given, so the proportion, and hence representativeness, cannot be assessed. There was no control group and it is not clear how these patients were selected for treatment.

Results were collected at the start of, and 3 months after, glargine treatment. Outcome measures used were HbA_1c value, BMI, frequency of hypoglycaemia, and compliance with the therapy. The results showed no significant difference in HbA_1c value in any group (group A: 9.6% vs 9.2% – no difference, indicating that glargine had similar effects to NPH; group B: 7% vs 7.47%; group C: 6.76% vs 6.74%). The failure to reduce HbA_1c value in groups B and C is odd; the authors suggest this could be due to small numbers and short follow-up. BMI changed little (group A: 21 vs 21.5 kg/m²; group B: 16.68 vs 17.2 kg/m²; group C: 18.17 vs 18.55 kg/m²) in all groups. The frequency of hypoglycaemia did not change in group A. No hypoglycaemia events were observed in groups B and C. The authors state that glargine seemed to be safe and well accepted. A larger multicentre study in Italy is under way, but there is no mention of a RCT.

Bizzarri 2006

Bizzarri et al.¹⁵¹ studied the effects of insulin glargine in patients with CFRIGT. Treatment was not randomised and numbers were small: six patients aged from 9.2 to 27.8 years, who were identified with normal fasting glucose and IGT (FPG < 110 mg/dl and 2-hour PG 140–199 mg/dl) out of a total of 113 patients with CF. There was no control group.

Results were before and after glargine treatment over median follow-up of 1.4 years (range 1.0–1.8 years). Outcome measures used were HbA_1c value, BMI z-score, FEV₁ and number of hospitalisations for clinical exacerbation. There were significant improvements in both median BMI z-scores (− 0.95 vs − 0.5; p = 0.026) and median FEV₁ (72.7% vs 76.7%; p = 0.027). No significant difference was observed in the median HbA_1c value (5.9% vs 6.1%; p = 0.496) or the median number of hospitalisations for clinical exacerbation (1.95 patients/year vs 2.0 patients/year; p = 0.715). Hypoglycaemia was not a problem. The authors concluded that ‘early insulin glargine is well tolerated and safe, and that it seemed to slow down the deterioration of the clinical status (particularly nutritional condition and lung function) seen in the years before treatment in some patients’.

Drummond 2006 (abstract only)

Another study¹⁵² from the Glasgow group, as in the Boyle abstract, which may include some of the same patients, gives data for 5 years before and after insulin treatment.

Drummond et al.¹⁵² studied the effect of insulin treatment in patients with CF. Treatment was not randomised. The study included 54 patients aged from 16 to 52 years (mean age 27.6 years), not all of whom had CFRD: some had IGT and some had NGT, but numbers were not given. The size of the clinic population was not given, so the proportion, and hence representativeness, cannot be assessed. There was no control group and it is not clear how these patients were selected for treatment.

The outcome measures used were lung function and weight gain, 5 years before and 5 years after insulin initiation. FEV₁ declined from 2.6 ± 0.14 l to 1.78 ± 0.12 l (p < 0.001) 5 years prior to insulin treatment and the mean 5-year post-insulin FEV₁ was 1.74 ± 0.20 l (p = 0.15). So decline seemed to be arrested after insulin initiation. But when stratified according to the OGTT at initiation, the rate of FEV₁ decline in patients with IGT changed significantly from 0.51 ± 0.31 l pre-insulin to 0.04 ± 0.12 l post insulin (p = 0.02); changes were not significant in those with NGT (p = 0.86) or with CFRD (p = 0.70). Numbers of patients are not given. Weight increased significantly with insulin therapy from 53.08 ± 1.53 kg to 56.22 ± 2.08 kg (p = 0.05). The authors concluded that insulin therapy reduced the decline in lung function in patients with CF and recommended its commencement at the IGT stage.

Hardy 2006 (abstract only)

Hardy et al.¹⁵³ reported the effect of insulin treatment on growth and lung function in children with CF with abnormal OGTT but normal fasting glucose. Treatment was not randomised and numbers were small: 27 children (age not given), with 14 on insulin glargine (group A) owing to clinical deterioration and 13 not given insulin (group B). The size of the clinic population was not given, so the proportion, and hence representativeness, cannot be assessed. There was a control group of 55 patients with CF with normal OGTT. It is not clear how these patients were selected.

Height, weight, BMI and best %FEV₁ were measured 12 months before and after either treatment with glargine (group A) or without (group B). Group A had higher 2-hour PG levels (11.9 vs 9.5 mmol/l; p = 0.01), lower BMI and a significant decline in weight in the preceding 12 months (p = 0.02) compared with group B, so the two groups were not matched. Compared with the control subjects, groups A and B had lower height (p = 0.03), FEV₁ (p < 0.001) and FEV₁ 12 months before treatment (group A p = 0.03, group B p = 0.01). FEV₁ declined significantly (> 5%) before treatment in eight patients from group A but improved in six of these eight after insulin treatment. FEV₁ also declined in seven patients from group B, but improved in five of these seven patients without insulin treatment. It was concluded that glargine arrested the progressive decline in lung function in patients with more severe undernutrition and hyperglycaemia, but it also improved in patients who were not given insulin (group B), suggesting that spontaneous improvement also occurs.

McGinnity 2006 (abstract only)

McGinnity et al.¹⁵⁴ examined the effect of once-daily long-acting insulin (detemir or glargine) in a case series of five patients with CFRD aged from 11 to 18 years. The size of the clinic population was not given, so the proportion, and hence representativeness, cannot be assessed. It is not clear how patients were selected. All patients had received treatment with once-daily long-acting human insulin analogues for more than 12 months prior to the study, so were presumed to have reached a stable state after titration against blood glucose monitoring. Insulin had been started because of CFRD, PPH, weight loss or declining lung function; the implication is that it was started earlier rather than later.

Blood glucose was measured over a 3-day period using a subcutaneous continuous glucose monitor. BG levels in the five patients were within normal limits 65%, 93%, 94%, 96% and 99% of the time. Mean glucose levels (range) were 7.6 mmol/l (2.2–17.2 mmol/l), 6.6 mmol/l (3.8–13.7 mmol/l), 5.3 mmol/l (2.2–9.0 mmol/l), 5.9 mmol/l (3.4–12.9 mmol/l), 6.4 mmol/l (4.1–11.8 mmol/l). Hyperglycaemia seems to have been commonest round midday. Symptomatic hypoglycaemia did not occur, which seems odd, given the low end of two of the ranges. The authors conclude that these preliminary data indicate that good control is achievable with the early use of long-acting insulins for CFRD. CBGM was well tolerated. HbA_1c value was not reported.

Onady 2006

Onady et al.¹⁵⁵ compared the effects of insulin, sulfonylurea, metformin and thiazolidinedione in patients with CFRD.¹⁵⁵ However, treatment was not randomised and numbers were small: 20 patients aged from 13 to 49 years, with eight initially chosen to be on insulin, five on sulfonylureas, four on metformin and three on thiazolidinediones. (There are uncertainties over the numbers in the study. Twenty-four patients were originally diagnosed with CFRD during the 10-year span but four were excluded: three after lung transplantation and one on combination diabetic therapy during the study period. Hence, a total of 20 patients with CFRD over the 10-year period remained for the prospective study. However, the tables of results show a total of 25 patients in both the baseline and final results.)

The size of the clinic population was not given, so the proportion included, and hence representativeness, cannot be assessed. Patients chose their treatment based on risk and benefit information provided for treatment options. Baseline variables varied among groups, for example with HbA_1c value ranging from 7.2% on sulfonylurea to 9.5% on insulin.

Follow-up was for 10 years. There were no statistically significant differences in overall glycaemic control, changes in weight, liver function testing and FEV₁ between oral agents and insulin. All patients tolerated the initial therapy and none had to change treatment because of side effects. Four patients with inadequate HbA_1c control, discontinued insulin and switched to oral agents. No adverse effects from oral agents during the study were reported. Mortality was highest among patients in the sulfonylurea group (60%), followed by the insulin group (37%), with no deaths from the biguanide and thiazolidinedione treatment groups, but these differences were not statistically significant (p = 0.062). Sixty patients with CF had been followed in the centre during the 10-year period, with a mortality rate of 23% observed in those without diabetes and 38% in those with diabetes. One patient who was on a thiazolidinedione had been identified with diabetic nephropathy 18 months after the diagnosis of CFRD (a surprisingly short duration). There were no reports of abnormal urine microalbumin measures or retinal examinations indicating microvascular disease in these patients. The authors concluded that OHAs were effective and safe in treating selected patients with CFRD, and may provide an alternative for patients reluctant to use insulin. However, the groups showed baseline differences, treatment was not allocated randomly and no firm conclusions can be reached.

Drummond 2007 (abstract only)

This is another abstract from the Glasgow group,¹⁵⁶ with data on the incidence, awareness and apparent symptoms of hypoglycaemia experienced by patients with CF who were receiving insulin. Drummond et al.¹⁵⁶ retrospectively estimated the frequency of hypoglycaemia and the associated symptoms experienced in insulin-treated patients. Treatment was not randomised and numbers were small: 24 patients with a mean age of 30.7 ± 9.1 years. Patients had been on insulin treatment for 7.3 years ± 6.4 years and HbA_1c value was 6.56 ± 1.13%.

The frequency of mild hypoglycaemia over a period of 6 months was recorded, along with details of usual symptoms and awareness of hypoglycaemia. Hypoglycaemic events were reported in 13 patients who experienced between one and four episodes: six (25%) had five or more and five patients experienced no hypoglycaemic events (21%). Sweating, hunger, warmness, confusion and trembling were the most common symptoms. Seventy-five of the insulin-treated patients had hypoglycaemic unawareness. So, hypoglycaemia episodes and hypoglycaemic unawareness were common among patients with CF. The frequency may relate in part to the loss of glucagon-producing α-cells.

Sulli 2007

Sulli et al.¹³⁹ described three case reports of insulin pump therapy in patients with CFRD over 2 years of CSII treatment. The patients were two males (aged 5.5 and 21 years) and a female (aged 28 years). All patients were receiving multiple daily injections [(MDIs): four insulin injections per day] in the year prior to CSII use.

During the CSII treatment, all patients experienced a reduction in their annual mean level of HbA_1c. This reduction was more or less steady over the 2 years. At the end of the 2-year period, there were significant reductions (1.7%, 2.7% and 1.2%, respectively) in HbA_1c levels compared with baseline values.

Also, during the CSII treatment, the annual mean level of BMI increased and the insulin requirements decreased. None of the patients experienced episodes of diabetic ketoacidosis (DKA) or hypoglycaemia during the CSII treatment. Only two episodes of lipohypertrophy and a slight local cutaneous inflammation were reported.

Grover 2008

Grover et al.¹⁵⁷ looked at the effect of glargine versus NPH in patients with CFRD with FH. They carried out a randomised, non-blinded, crossover study but the numbers were small: 19 patients aged 34 ± 8 years. All were clinically well and receiving a single dose of bedtime NPH insulin plus rapid-acting insulin before meals. The size of the clinic population was not given so the proportion, and hence representativeness, cannot be assessed. Twenty patients with CFRD with FH were recruited and one dropped out.

Patients received 12 weeks' therapy with bedtime NPH (plus rapid-acting insulin) or bedtime glargine (plus rapid-acting insulin); nine patients received NPH first and the rest received glargine first. Before each study period there was a 1-month insulin adjustment period. Outcome measure used were BG control (HbA_1c, FPG, 2-hour postprandial glucose) and weight change (weight, fat mass, lean mass). There was a significantly greater reduction in FPG with glargine therapy (p = 0.03) but no changes in HbA_1c value and postprandial PG level. More weight gain in patients on glargine was observed, but this did not achieve statistical significance (p = 0.07). No differences in adverse events and QoL were seen between the groups. There were no serious hypoglycaemic episodes, but minor hypoglycaemic episodes occurred with both treatments (NPH: 5 ± 1 times per participant; glargine: 6 ± 1 times; p = 0.3). After the study, all 19 patients chose to continue glargine therapy as they believed that daytime BG levels seemed more consistent and some were less worried about night-time hypoglycaemia.

It was commented that glargine was a newer agent and patients' perception could had been influenced by the health-care team. Variability in glucose levels appeared to be similar between the groups, as the within-patient SD of fasting glucose levels (NPH 50 ± 10 mg/dl, glargine 40 ± 6 mg/dl; p = 0.18) and 2-hour postprandial glucose levels (NPH 91 ± 7 mg/dl, glargine 83 ± 6 mg/dl; p = 0.28) were not significantly different.

The conclusion was that ‘long-term studies are needed to determine the metabolic and nutritional impact of glargine in CFRD, but the initial data suggested that it is a promising therapy’. The trial was sponsored by the manufacturer of glargine.

Mohan 2008

Mohan et al.¹⁵⁸ looked at the long-term impact of insulin therapy in 42 patients with CFRD aged from 16 to 39 years. There was a total of 215 patients in their unit, of whom 65 (30.2%) had CFRD. There was no control group in the study. Forty-two out of the 65 patients were selected based on the completeness of data required for the study, hence possible selection bias.

Results were 5 years before and 3 years after insulin therapy. Outcome measures included FEV₁, FVC, BMI and the number of pulmonary exacerbations requiring hospital admissions. At 3 months following institution of insulin therapy, there was significant improvement compared with baseline in mean FEV₁ (51.6% vs 58.2%; p < 0.0001), mean FVC (66.4% vs 75.5%; p < 0.0001) and mean BMI (19.5 vs 20.5 kg/m²; p < 0.0001). This improvement over baseline was maintained at 1 year for FEV₁ (mean 55.1%; p < 0.002), 2 years for FVC (mean 72.1%; p < 0.01) and at 3 years for BMI (mean 20.43 kg/m²; p < 0.002). However, the mean rate of FEV₁ decline from 3 months to 3 years after treatment was comparable with that of the pre-treatment period (−3.2% vs −3.1% per year; p = 0.77); and the mean post-insulin FEV₁ value returned to baseline at 34 months. The annual rate of FVC decline was also similar to the pre-insulin values during the same period (−2.6% vs −2.5% per year; p = 0.96). There was no difference in the number of hospital admissions for pulmonary exacerbations before and after insulin treatment (1.8 vs 2.1 per year; p = 0.19). HbA_1c values were available in 32 patients, but no significant change was found at the end of the follow-up period (mean 6.8% vs 6.7%). Seventeen of the 32 had elevated values (mean 8.1%) at diagnosis that improved significantly during the 3 years following insulin treatment (mean HbA_1c value: first year, 6.9%, p = 0.004; second year, 7.1%, p = 0.04; third year, 7.0%, p = 0.02).

The conclusion was that insulin treatment is associated with temporary improvement in lung function and BMI in symptomatic patients with CFRD, with FEV₁ decline delayed by an average of 34 months.

Hardin 2009

A before-and-after study by Hardin et al.¹⁵⁹ evaluated the safety, efficacy and metabolic benefits of CSII via an insulin pump in nine patients with CFRD over 6 months.

To be eligible for inclusion, patients had to be between 18 and 32 years old and to be treated with a minimum of three subcutaneous injections per day, based on a basal bolus regimen, for a minimum of 6 months, and be recording blood sugar readings at least four times daily. Patients were converted to CSII therapy in a single visit, and asked to report results of self-BG monitoring (measured before all major meals and bed) and a minimum of four postprandial BG levels a week. Baseline measurements were taken of each patient's HbA_1c level, body weight, lean body mass, and whole-body protein turnover (using a stable isotope of leucine).

The mean age of the nine patients (five males and four females) was 27 years. After 6 months of CSII therapy, body weight increased significantly from 55.6 kg (SD 3.5 kg) at baseline to 59.2 kg (SD 3.3 kg) (p = 0.01). HbA_1c level decreased from 8.2% (SD 1.9%) to 7.1% (SD 1.5%) (p = 0.05). In addition, there were significant improvements in fasting and postprandial BG levels and lean body mass. Protein catabolism was significantly decreased. No patient had an episode of hypoglycaemia, whereas prior to CSII the patients reported several hypoglycaemic episodes per month. All patients but one wanted to continue pump therapy.

Hence, in this study of patients with CFRD, the use of CSII over 6 months led to improved glycaemic control and safety compared with multiple daily subcutaneous insulin injections. In addition, metabolic benefits were shown.

Mozillo 2009

Mozillo et al.¹⁶⁰ reported preliminary data from a study designed to evaluate the effect of glargine treatment on lung function, BMI, lung infections and HbA_1c level in patients with CF with early glucose derangements.

A total of 98 of 220 patients with CF who attended the CF unit at a Department of Pediatrics in Naples were screened for glucose abnormalities on the basis of an OGTT and/or continuous glucose monitoring system (CGMS), and 65 patients had been enrolled in this ongoing open trial. There was no control group. The data of the first 22 patients who completed 12 months of glargine were presented. Their mean age was 12.4 years. Four had abnormal glucose tolerance on a CGMS, nine had IGT, seven had diabetes mellitus without FH and two had diabetes mellitus with FH. After 12 months of glargine therapy there was an 8.8% increase in per cent predicted FEV₁ (%FEV₁) (p = 0.01) and a 42% decrease in the number of lung infections (p = 0.003). The BMI z-score and HbA_1c level did not show any significant difference for the whole group. However, a significant (p = 0.017) improvement was found in those patients (n = 8) with the worst BMI z-scores, i.e. baseline BMI z-score of < −1.

These data suggest that glargine could benefit patients with CF with early glucose derangements. However, RCTs with more patients and longer follow-up are needed to confirm this.

Moran 2009: Cystic Fibrosis-Related Diabetes Therapy trial

The aim of the Cystic Fibrosis-Related Diabetes Therapy (CFRDT) trial¹⁴¹ was to determine whether or not diabetes therapy improves BMI in patients with CFRD without FH (CFRD FH−). The trial was a three-arm multicentre trial comparing preprandial insulin aspart, repaglinide and oral placebo. Patients were randomised to receive insulin aspart 0.5 units per 15 g of dietary carbohydrate, repaglinide 2.0 mg orally or oral placebo three times a day before meals. Ongoing diabetes education was also provided.

Measurements on the patients' BMI and lung function 12 months prior to the study were retrospectively obtained from chart reviews and then measured prospectively for 12 months after randomisation. BMI was the primary study end point. Measures of DEXA (dual-energy X-ray absorptiometry), NIH prognostic score, Cystic Fibrosis Quality-of-Life questionnaire (CFQoL), 3-day dietary histories, and HbA_1c level were measured at baseline and after 1 year in the study.

One hundred adult patients were enrolled: 74 CFRD patients without FH and 26 with severe IGT. ‘CFRD FH−’ was defined as FPG level of < 126 mg/dl (7.0 mmol/l) and a 2-hour glucose level of ≥ 200 mg/dl (11.1 mmol/l) and severe IGT was defined as a glucose level of ≥ 200 mg/dl (11.1 mmol/l) during the OGTT and a 2-hour glucose level of 180–199 mg/dl (10.0–11.1 mmol/l). The mean age of the patients was 27 years (SD 8 years) and mean HbA_1c value was 6.0% (SD 0.7%) and the ratio of males to females was 53 : 47.

Results were presented for the 81 patients (61 CFRD FH− and 20 with IGT) who completed the trial. The absolute change in BMI during the study year did not differ significantly between the groups for the CFRD patients without FH. However, in the IGT group, the BMI change was significantly worse for the repaglinide-treated patients than in those on placebo.

The results for the change in BMI for the 12 months prior to the study compared with the change during the study year showed a significant improvement for the CFRD patients without FH on insulin. For the 12 months prior to baseline, the change in BMI was −0.30 kg/m² (SE 0.21 kg/m²) and after 12 months on insulin the decline was reversed, and there was an increase of 0.39 kg/m² (SD 0.21 kg/m²) (p = 0.02). The CFRD FH– repaglinide and placebo groups did not show a significant change, i.e. changes in BMI 12 months prior to the study were −0.14 kg/m² (SD 0.21 kg/m²) and −0.29 kg/m² (SD 0.25 kg/m²), respectively, and 12 months after the study the changes in BMI were +0.15 kg/m² (SD 0.21 kg/m²) and −0.02 kg/m² (SD 0.25 kg/m²).

All study arms for the CFRD patients without FH showed a decline in FVC during the study when compared with 12 months prior to study, and the insulin and repaglinide arms showed a reduction in decline in FEV₁. The patients with IGT in the insulin and repaglinide arms showed no significant change in rate of BMI decline compared with the previous year, although, surprisingly, the placebo-treated patients showed a significant improvement (p = 0.02).

After 1 year on therapy, there was no significant change in HbA_1c level in any group and no difference in fasting glucose levels within or between groups compared with baseline. During the study year there were no differences in the number of episodes of acute illness between treatment groups or between CFRD patients without FH and IGT patients. Also, NIH and CFQoL scores showed no differences between or within groups during the 1-year treatment period. There were no serious adverse events related to the study medication.

In conclusion, the CFRDT trial showed that preprandial rapid-acting insulin given for 1 year significantly reversed the chronic weight loss in CFRD patients without FH, without any adverse effects. However, it had no significant effect on lung function or acute illnesses.

Hameed 2011

This before-and-after study¹⁶¹ looked at the effect of a single daily dose of insulin detemir on weight change and lung function in six patients with CFRD and 12 with ‘early insulin deficiency’, defined by peak BG level during OGTT but with a 2-hour level of < 11.1 mmol/l. The median age of the patients was 12.5 years, and all but one had exocrine pancreatic insufficiency. Changes in mean weight SD score (WtSDS), mean change in per cent predicted FVC (%FVC) and %FEV₁ were measured.

The values at 1 year before treatment versus those after a median of 42 weeks of insulin treatment showed improvements of 0.22 in WtSDS (p = 0.003), 5.3% in %FEV₁ (p = 0.004) and 5.8% in FVC (p = 0.024). No episodes of severe hypoglycaemia were reported.

Minicucci 2011 (Pediatric Diabetes 2011 online)

Minicucci et al.¹⁶² reported a randomised controlled study of the effect of insulin glargine in patients with CF with IGT. Patients were selected because BMI was under the 10th percentile or had fallen by one percentile over the previous year, or if there were similar findings for FEV. All were aged > 10 years. The study initially recruited 45 patients but, after dropouts, 34 remained for analysis at 18 months. They were randomised to low-dose insulin glargine, starting with a dose of 0.1 units/kg/day, increasing to 0.15 units/kg/day if no hypoglycaemia occurred. The dose could be increased to 0.2 units/kg/day at the physician's discretion. The primary end point was BMI, with HbA_1c level and FEV being secondary end points. At 18 months, there were no significant differences between the groups in BMI or FEV, but some difference in HbA_1c level, with a reduction of 0.11% in the insulin group compared with a rise of 0.26% in the control subjects (p = 0.04). There was a bigger reduction of 0.52% in four patients who had received 0.2 units/kg/day.

The authors suggest that the lack of effect might be due to the low dose of glargine used or to the trial duration being too short.

Summary of main findings