We reviewed the evidence about how good pancreatic enzyme replacement therapy (PERT) is in overcoming the enzyme deficiency in people with cystic fibrosis (CF) and if there are any side effects.
Between 80% and 90% of people with CF take PERT because their pancreas can not make the enzymes needed to digest food. As a result, children may fail to gain weight and thrive; while adults may lose weight and become malnourished as they do not absorb vitamins properly. In people with CF, malnutrition is linked to poorer general health, more severe lung disease and shorter life expectancy. If their pancreas is not making enough enzymes, people with CF can also experience painful, frequent, bulky, offensive bowel movements. PERT is needed to help gain weight, prevent malnutrition and avoid some vitamin deficiencies, as well as to control bowel symptoms. This is an updated version of the review.
We last searched for evidence: 26 December 2019.
We assessed 14 trials (641 adults and children with CF); 13 trials gave treatment for four weeks and one for seven weeks. Trials compared different formulations of PERT, some were treated to delay the release of the medication until they passed from the stomach into the intestine, while others were not. In 12 trials participants took both types of supplement for four weeks each, although the order in which they took them was random. These factors made it difficult to analyse trial results. Most of the trials were old; the most recent was from 2017, but the oldest was from 1986.
We are uncertain whether any PERT formulation is better than another for improving any of our most important outcomes (weight, height or body mass index). In two trials (41 participants) those taking delayed-release microspheres (miniature drug capsules) had less fat in their poo than those taking delayed-release tablets (normal size); they also had less abdominal pain and did not need to go to the toilet as often. In a different trial (12 participants), those taking the delayed-release microspheres also had less fat in their poo than those taking delayed-release supplements. We also found that in a large trial (128 participants), people taking PERT not made from animal enzymes had less fat in their poo than those taking PERT made from pigs' enzymes. We found no difference between any of the different PERT formulations for any other bowel symptoms (e.g. abdominal pain, flatulence, constipation), quality of life, side effects or for any measure of lung disease. None of the trials reported the number of days in hospital or the incidence of vitamin deficiency.
We did not find any evidence on different dose levels of PERT needed for people who produce different levels of pancreatic enzymes, on the best time to start treatment or for the amounts of supplements based on differences in type of food eaten and meal sizes. A properly designed trial is needed to answer these questions.
Quality of the evidence
We found the quality of the evidence for the different outcomes to be moderate at best, but mostly very low. We are not sure that the participants had equal chances of being put into the different treatment groups as the trials gave no details about how the decisions were made. In several trials large numbers of participants dropped out and reasons for this were often not given. In most trials, people took one treatment for four weeks and then swapped to the alternative treatment. This design means that the results may appear more consistent than they really are when we analyse them. The only results we could combine were from two such trials. Finally, several trials did not completely report their findings in a way we could analyse in this review. We are not sure how these factors affect our confidence in the results we found.
There is limited evidence of benefit from enteric-coated microspheres when compared to non-enteric coated pancreatic enzyme preparations up to one month. In the only comparison where we could combine any data, the fact that these were cross-over trials is likely to underestimate the level of inconsistency between the results of the trials due to over-inflation of CIs from the individual trials.There is no evidence on the long-term effectiveness and risks associated with PERT. There is also no evidence on the relative dosages of enzymes needed for people with different levels of severity of pancreatic insufficiency, optimum time to start treatment and variations based on differences in meals and meal sizes. There is a need for a properly designed trial that can answer these questions.
Most people with cystic fibrosis (CF) (80% to 90%) need pancreatic enzyme replacement therapy (PERT) to prevent malnutrition. Enzyme preparations need to be taken whenever food is taken, and the dose needs to be adjusted according to the food consumed. A systematic review on the efficacy and safety of PERT is needed to guide clinical practice, as there is variability between centres with respect to assessment of pancreatic function, time of commencing treatment, dose and choice of supplements. This is an updated version of a published review.
To evaluate the efficacy and safety of PERT in children and adults with CF and to compare the efficacy and safety of different formulations of PERT and their appropriateness in different age groups. Also, to compare the effects of PERT in CF according to different diagnostic subgroups (e.g. different ages at introduction of therapy and different categories of pancreatic function).
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search: 07 November 2019.
We also searched an ongoing trials website and the websites of the pharmaceutical companies who manufacture pancreatic enzyme replacements for any additional trials. Most recent search: 26 December 2019.
Randomised and quasi-randomised controlled trials in people of any age, with CF and receiving PERT, at any dosage and in any formulation, for a period of not less than four weeks, compared to placebo or other PERT preparations.
Two authors independently assessed trials and extracted outcome data. They also assessed the risk of bias and quality of the evidence (GRADE) of the trials included in the review.
14 trials were included in the review (641 children and adults with CF), two of these were parallel trials and 12 were cross-over trials. Interventions included different enteric and non-enteric-coated preparations of varying formulations in comparison to each other. The number of participants in each trial varied between 14 and 129. 13 trials were for a duration of four weeks and one trial lasted seven weeks. The majority of the trials had an unclear risk of bias from the randomisation process as the details of this were not given; they also had a high risk of attrition bias and reporting bias. The quality of the evidence ranged from moderate to very low.
We mostly could not combine data from the trials as they compared different formulations and the findings from individual trials provided insufficient evidence to determine the size and precision of the effects of different formulations.