Obesity and overweight are becoming increasingly common in both developed and developing nations globally. These conditions represent an important risk factor for mortality and morbidity from CVD, diabetes, cancers and musculoskeletal disorders, causing nearly three million annual deaths worldwide(Reference Stevens, Singh and Lu1). Despite clinical recommendations to prioritise lifestyle modification, a significant proportion of patients seeking therapies for weight loss will attain only modest weight loss from lifestyle modification(Reference Terranova, Brakenridge and Lawler2). This could be due to the development of the leptin resistance commonly found in overweight and obese individuals(Reference Izquierdo, Crujeiras and Casanueva3). Thus, for individuals where conventional therapies such as diet and exercise have failed, pharmacotherapy may be seen as an additional option(Reference Patel4). Examples of weight loss medications which are approved by the US FDA and available in the market include phentermine, orlistat, phentermine/topiramate extended release, lorcaserin, naltrexone sustained release/bupropion sustained release and liraglutide(Reference Srivastava and Apovian5).
Satiation refers to physiological responses to food intake during the consumption of food which leads to a cessation of eating, whereas satiety refers to physiological responses which delay the taking of the next meal. The actions of digestive peptides form a key feature of the energy regulation system in humans(Reference Cummings and Overduin6) and their function in this system includes a major role in satiation and satiety signalling after the ingestion of a meal(Reference Benelam7). No relationship has been established between the number of eating episodes and body weight(Reference Bellisle, McDevitt and Prentice8,Reference Whybrow, Mayer and Kirk9) ; therefore, any potential dysfunction in the human energy regulation system in the contemporary food environment, should it exist, is more likely to be found within the biological processes which govern the regulation of meal size, that is, satiation(Reference Blundell, Burley and Cotton10).
Cholecystokinin (CCK) was one of the first digestive peptides to be discovered(Reference Rehfeld11) and was subsequently shown to play an important role in the appetite control in animal models(Reference Gibbs, Young and Smith12). CCK is produced in the small intestine with the highest tissue concentration in the proximal section(Reference Gilliam-Vigh, Jorsal and Rehfeld13) and its release is mediated by the presence of protein and fat in the digestive tract(Reference Rehfeld11). CCK receptors are located in the pancreatic nerves, the gallbladder muscularis, the nerves and muscle along the gastrointestinal tract and several areas of the brain(Reference Noble, Wank and Crawley14).
At physiological levels, the release of CCK into the blood stream acts on CCK receptors causing gastric emptying to slow(Reference Schwizer, Borovicka and Kunz15) and increasing sensations of fullness(Reference Lieverse, Jansen and Van de Zwan16). Although CCK is released very quickly into the blood stream (15 min post-prandially)(Reference Liddle, Goldfine and Rosen17), it is also relatively quickly removed. The elimination half-life of the octapeptide variant of CCK is 18 min(Reference Koulischer, Moroder and Deschodt-Lanckman18); however, a multitude of variants and concentrations of bioactive CCK variants with larger molecules may remain elevated in the blood plasma for several hours after a meal in healthy human volunteers(Reference Rehfeld, Sennels and Jørgensen19). Due to its rapid entrance into the blood plasma and short period of action, any effect of CCK on eating behaviour is more likely to be found within a meal rather than between meals and is therefore known as the digestive peptide most associated with satiation.
CCK and a selection of its analogues have been proposed as a weight loss medication(Reference Moran and Dailey20). It is important to distinguish between research focusing on the use of CCK or analogues of CCK at pharmacological doses as a potential weight loss agent and research investigating the role of CCK at lower doses in the physiology produced by the enteroendocrine system. The present systematic review therefore aims to examine (1) the ability of CCK or analogues of CCK to influence satiation and changes in body weight generally and (2) the efficacy of CCK in influencing satiation and eating behaviour specifically at physiological levels as found in the blood plasma.
Materials and methods
This systematic review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines(Reference Moher, Liberati and Tetzlaff21). The search strategy and criteria for inclusion and exclusion were specified in advance and documented in the priori review protocol registered with the International Prospective Register of Systematic Reviews PROSPERO (University of York), registration number CRD42020210963.
Search terminology
The search terms included the keywords: (‘cholecystokinin’ OR ‘CCK’) AND ‘(‘infusion’ OR ‘agonist’ OR ‘analog’ or ‘analogue’) AND (‘energy intake’ OR ‘weight loss’ OR ‘satiation’ OR ‘satiety’). Where databases allowed searching by Medical Subject Headings (MeSH), the terms ‘Cholecystokinin’ (MeSH) AND ‘Energy Intake’ (MeSH) OR ‘Satiation’ (MeSH) were also included.
Search strategy
The CINAHL, Cochrane Central Register of Controlled Trails, MEDLINE, Scopus and Web of Science databases were searched for all relevant publications (data cut off – July 2020, exclusion of non-human studies), using a combination of keywords and Medical Subject Headings to increase the sensitivity and inclusiveness of searches. The search architecture was designed by an expert systematic review librarian (M.T.). Search strategies are presented in the Appendix (online Supplementary material). The search strategy was validated by checking that pre-selected relevant studies were indeed retrieved by at least one of the database searches. The titles and abstracts of all retrieved studies were exported to Covidence (Covidence systematic review software, Veritas Health Innovation, Melbourne, Australia) for the study selection process.
Study selection
Randomised controlled trials on adult individuals that examined the effect of an intervention involving CCK or any pharmaceutical agent which mimics the actions of CCK on energy intake and/or change in body weight were included. Randomised crossover trials with a washout period of less than 1 d; diet studies; studies where subjects suffered from any metabolic disorder such as diabetes, studies on bariatric patients and patients taking a weight loss drug; studies where the primary focus was psychological; studies where the primary focus was exercise; studies with participants taking a psychiatric medication and studies where participants were taking a pharmaceutical other than CCK or a CCK agonist which may affect hunger; and non-human studies were all excluded. The abstracts of articles deemed relevant by the lead author (A.W) were independently reviewed by a further investigator (N.N.). If consensus was not reached, the article was moved on to the next stage for a review of the full text. The full texts of the remaining eligible studies were independently reviewed by the investigators (A.W. and N.N.) against the inclusion and exclusion criteria. Any final discrepancies were resolved by referral to a third researcher (S.S.). Disagreements were discussed until consensus was reached in all cases.
Data extraction
Data were extracted from each study to be included and placed on spreadsheets. Information such as study title, study type, number of subjects, randomisation, degree of blinding, energy intake, appetite responses on a Visual Analogue Scale (VAS) and change to hormone levels was inputted into the spreadsheets.
Data synthesis
The primary means of data synthesis was the extraction of study data and extraction into pre-defined spreadsheets. The results were synthesised narratively for interpretation in the ‘Discussion’ section.
Data analysis
The review software (Review Manager (RevMan) (Computer program). Version 5.4.1, The Cochrane Collaboration) was used for the meta-analysis. The outcome to be assessed in the meta-analysis was the difference in mean between those treatments using CCK or CCK analogues and placebo. Data were qualitatively compared across the various methodological approaches of included studies to assess the efficacy of CCK to enhance satiation, reduce energy intake and facilitate weight loss.
Risk of bias and quality assessment
The Physiotherapy Evidence Database (PEDro) scale(Reference Maher, Sherrington and Herbert22) was used to assess the quality of the methodology used in each of the studies included in this review. The PEDro scale is an eleven-item scale used to assess the eligibility criteria, randomisation process, allocation processes, similarity of baseline groups, the blinding process, completeness of data used, between group statistics and measures of variability of a study. Each study is allocated one point on the condition that it complies with one of the eleven items. One author assessed each study for bias (A.W.). The risk of bias for each of the studies was evaluated using criteria suggested by the Cochrane Collaboration(Reference Higgins, Altman and Gøtzsche23) which equates to calculating the total score of PEDro items two to four and seven to nine. A score of five to six is considered to indicate a low risk of bias, a score of three to four moderate and one or two high.
Results
Study selection
Initially, a total of 1054 studies were identified, and after removal of 464 duplicates 590 abstracts remained. By screening based on a reading of study abstracts, a further 545 studies were excluded. The remaining forty-five studies were then independently reviewed by two researchers (A.W., N.N.) and following discussion a further thirty studies were removed to arrive at a final figure of fifteen studies for inclusion reached by consensus (see Fig. 1).
Fig. 1. Flow chart of study selection.
Study characteristics
The characteristics of the included studies are summarised in Table 1.
Table 1. Studies used in the systematic review
CCK, cholecystokinin.
Participants
A total of 938 participants (404 male, 534 female) were used in the studies included in this review. All participants used in these studies were healthy and three studies utilised overweight or obese subjects(Reference Jordan, Greenway and Leiter24–Reference Lieverse, Jansen and Masclee26).
Study designs
All of the studies included in this review were randomised controlled trials(Reference Lieverse, Jansen and Van de Zwan16,Reference Jordan, Greenway and Leiter24–Reference Stacher, Steinringer and Schmierer37) . Two of the included studies were of a parallel design(Reference Jordan, Greenway and Leiter24,Reference Stacher, Bauer and Steinringer36) , while the remainder were crossover(Reference Lieverse, Jansen and Van de Zwan16,Reference Lieverse, Jansen and Masclee25–Reference Brennan, Little and Feltrin29,Reference Greenough, Cole and Lewis31–Reference Gutzwiller, Degen and Matzinger33,Reference Stacher, Steinringer and Schmierer37) or utilised a counterbalanced design(Reference Geary, Kissileff and Pi-Sunyer30,Reference Kissileff, Pi-Sunyer and Thornton34,Reference Kissileff, Gordon and Thornton35) . All of the studies in this review were acute studies excepting one(Reference Jordan, Greenway and Leiter24) which had a duration of 24 weeks. The primary aim of the studies included in this review was to investigate the effect on satiation occurring in response to exogenous CCK or an analogue of CCK. Interventions predominantly involved the use of an intravenous infusion of CCK(Reference Lieverse, Jansen and Van de Zwan16,Reference Lieverse, Jansen and Masclee25–Reference Stacher, Steinringer and Schmierer37) with a saline infusion as a control. One study(Reference Gutzwiller, Drewe and Ketterer32) used a CCK receptor antagonist, loxiglumide, to negate the effect of CCK. Four studies compared the effects of CCK with another peptide such as GLP-1(Reference Brennan, Feltrin and Horowitz28,Reference Gutzwiller, Degen and Matzinger33) or glucagon(Reference Geary, Kissileff and Pi-Sunyer30). Two forms of CCK were utilised in infusions: CCK-8 and CCK-33. CCK-8 was used in nine of the studies(Reference Ballinger, McLoughlin and Medbak27–Reference Gutzwiller, Drewe and Ketterer32,Reference Kissileff, Pi-Sunyer and Thornton34,Reference Kissileff, Gordon and Thornton35,Reference Stacher, Steinringer and Schmierer37) and CCK-33 in five studies(Reference Lieverse, Jansen and Van de Zwan16,Reference Lieverse, Jansen and Masclee25,Reference Lieverse, Jansen and Masclee26,Reference Gutzwiller, Degen and Matzinger33,Reference Stacher, Bauer and Steinringer36) . One study(Reference Jordan, Greenway and Leiter24) involved the use of an analogue of CCK (GI181771X) taken as a 0·25 mg, 0·5 mg, 1·0 or 1·5 mg dose in an oral solution three times daily.
Dosing ranged between infusions of a lower, or physiological dose(Reference Lieverse, Jansen and Van de Zwan16,Reference Lieverse, Jansen and Masclee25–Reference Ballinger, McLoughlin and Medbak27,Reference Brennan, Little and Feltrin29,Reference Gutzwiller, Drewe and Ketterer32,Reference Gutzwiller, Degen and Matzinger33) , or higher, pharmacological doses(Reference Jordan, Greenway and Leiter24,Reference Brennan, Feltrin and Horowitz28,Reference Geary, Kissileff and Pi-Sunyer30,Reference Greenough, Cole and Lewis31,Reference Kissileff, Pi-Sunyer and Thornton34–Reference Stacher, Steinringer and Schmierer37) . Four studies utilised a preload prior to infusion such as banana shake(Reference Lieverse, Jansen and Masclee26,Reference Gutzwiller, Drewe and Ketterer32) , soup(Reference Greenough, Cole and Lewis31) or solid food such as cracker biscuits with topping and juice(Reference Kissileff, Pi-Sunyer and Thornton34). One study employed use of a gastric balloon in order to combine the stimulus of CCK with those of stomach distention(Reference Kissileff, Gordon and Thornton35).
The effect on satiation was measured by the difference in the weight of food consumed by participants(Reference Lieverse, Jansen and Van de Zwan16,Reference Lieverse, Jansen and Masclee25,Reference Lieverse, Jansen and Masclee26,Reference Geary, Kissileff and Pi-Sunyer30,Reference Kissileff, Pi-Sunyer and Thornton34,Reference Kissileff, Gordon and Thornton35) or the effect on energy intake(Reference Ballinger, McLoughlin and Medbak27–Reference Brennan, Little and Feltrin29,Reference Greenough, Cole and Lewis31–Reference Gutzwiller, Degen and Matzinger33) or subjective measures of satiety(Reference Lieverse, Jansen and Van de Zwan16,Reference Lieverse, Jansen and Masclee25,Reference Lieverse, Jansen and Masclee26,Reference Brennan, Feltrin and Horowitz28,Reference Brennan, Little and Feltrin29,Reference Greenough, Cole and Lewis31–Reference Gutzwiller, Degen and Matzinger33,Reference Stacher, Bauer and Steinringer36,Reference Stacher, Steinringer and Schmierer37) . Three of the studies measured changes in hormone levels(Reference Jordan, Greenway and Leiter24,Reference Brennan, Little and Feltrin29,Reference Gutzwiller, Degen and Matzinger33) .
Risk of bias and quality assessment
According to the Cochrane Classification Risk Scale, four of the studies in this review were assessed as having a high risk of bias(Reference Jordan, Greenway and Leiter24,Reference Geary, Kissileff and Pi-Sunyer30,Reference Gutzwiller, Degen and Matzinger33,Reference Kissileff, Gordon and Thornton35) with the remainder of the studies(Reference Lieverse, Jansen and Van de Zwan16,Reference Lieverse, Jansen and Masclee25–Reference Brennan, Little and Feltrin29,Reference Greenough, Cole and Lewis31,Reference Gutzwiller, Drewe and Ketterer32,Reference Kissileff, Pi-Sunyer and Thornton34,Reference Stacher, Bauer and Steinringer36,Reference Stacher, Steinringer and Schmierer37) assessed as having a moderate risk of bias. One study was single blinded(Reference Ballinger, McLoughlin and Medbak27), the remainder of the studies(Reference Lieverse, Jansen and Van de Zwan16,Reference Jordan, Greenway and Leiter24–Reference Lieverse, Jansen and Masclee26,Reference Brennan, Feltrin and Horowitz28–Reference Gutzwiller, Degen and Matzinger33,Reference Stacher, Bauer and Steinringer36,Reference Stacher, Steinringer and Schmierer37) were all reported to be double-blinded. The quality of the methodology used in the studies and risk of bias in studies is summarised in Table 2.
Table 2. Risk of bias table
1. Eligibility criteria were specific.
2. Subjects were randomly allocated to groups (in a crossover study, subjects were randomly allocated an order in which treatments were received).
3. Allocation was concealed.
4. The groups were similar at baseline regarding the most important prognostic indicators.
5. There was blinding of all subjects.
6. There was blinding of all therapists who administered the therapy.
7. There was blinding of all assessors who measured at least one key outcome.
8. Measures of at least one key outcome were obtained from more than 85 % of the subjects initially allocated to groups.
9. All subjects for whom outcome measures were available received the treatment or control condition as allocated or, where this was not the case, data for at least one key outcome were analysed by ‘intention to treat’.
10. The results of between-group statistical comparisons are reported for at least one key outcome.
11. The study provides both point measures and measures of variability for at least one key outcome.
Effect on satiation and body weight
Of the twelve studies(Reference Lieverse, Jansen and Van de Zwan16,Reference Lieverse, Jansen and Masclee26–Reference Kissileff, Gordon and Thornton35,Reference Stacher, Steinringer and Schmierer37) measuring the effect on satiation via either a reduction in energy intake or the weight of food consumed, eleven studies(Reference Lieverse, Jansen and Masclee26–Reference Kissileff, Gordon and Thornton35,Reference Stacher, Steinringer and Schmierer37) showed a significant effect, with only one study(Reference Lieverse, Jansen and Van de Zwan16) showing no effect. Of the ten studies(Reference Lieverse, Jansen and Van de Zwan16,Reference Lieverse, Jansen and Masclee25,Reference Lieverse, Jansen and Masclee26,Reference Brennan, Feltrin and Horowitz28,Reference Brennan, Little and Feltrin29,Reference Greenough, Cole and Lewis31–Reference Gutzwiller, Degen and Matzinger33,Reference Stacher, Bauer and Steinringer36,Reference Stacher, Steinringer and Schmierer37) measuring the effect on satiation via subjective appetite ratings, nine(Reference Lieverse, Jansen and Masclee25,Reference Lieverse, Jansen and Masclee26,Reference Brennan, Feltrin and Horowitz28,Reference Brennan, Little and Feltrin29,Reference Greenough, Cole and Lewis31–Reference Gutzwiller, Degen and Matzinger33,Reference Stacher, Bauer and Steinringer36,Reference Stacher, Steinringer and Schmierer37) showed a significant positive influence on measures of satiety with one(Reference Lieverse, Jansen and Van de Zwan16) showing no effect. One study(Reference Jordan, Greenway and Leiter24), utilising a CCK-A receptor agonist taken as an oral solution (GI181771X), showed no significant effect on body weight at 24 weeks. The effects of CCK on satiation and body weight are summarised in Table 3.
Table 3. Study outcomes
CCK, cholecystokinin.
Meta-analysis
The question as to whether any effect from CCK on satiation is merely the result of pharmacological dosing and whether CCK is truly efficacious at levels in the blood plasma produced by the physiology is controversial(Reference Schick, Schusdziarra and Mössner38). A random effects model meta-analysis was employed to investigate this question. Nine studies in the present review infused CCK at doses facilitating a level of CCK in the blood plasma considered to be physiological(Reference Lieverse, Jansen and Van de Zwan16,Reference Lieverse, Jansen and Masclee25–Reference Brennan, Little and Feltrin29,Reference Gutzwiller, Drewe and Ketterer32,Reference Gutzwiller, Degen and Matzinger33,Reference Stacher, Bauer and Steinringer36) . Dosages used for each of these studies are shown in Table 1. Seven of the nine studies(Reference Lieverse, Jansen and Van de Zwan16,Reference Lieverse, Jansen and Masclee26–Reference Brennan, Little and Feltrin29,Reference Gutzwiller, Drewe and Ketterer32,Reference Gutzwiller, Degen and Matzinger33) measured satiation via the difference in the weight of food ingested or energy intake. Two of the nine studies(Reference Lieverse, Jansen and Masclee25,Reference Stacher, Bauer and Steinringer36) utilised only subjective measures of the effect on satiation using a VAS scale and were excluded from the meta-analysis. Five studies dosed CCK at pharmacological levels(Reference Geary, Kissileff and Pi-Sunyer30,Reference Greenough, Cole and Lewis31,Reference Kissileff, Pi-Sunyer and Thornton34,Reference Kissileff, Gordon and Thornton35,Reference Stacher, Steinringer and Schmierer37) . Data suitable for inclusion into the meta-analysis were available for three of these studies(Reference Greenough, Cole and Lewis31,Reference Kissileff, Pi-Sunyer and Thornton34,Reference Stacher, Steinringer and Schmierer37) which were added to the meta-analysis for comparison. In summary, studies which infused CCK at physiological levels of dosing had a significant effect with a standardised mean difference of 0·57 (95 % CI 0·30, 0·85, P < 0·0001) as did studies which infused CCK at pharmacological levels of dosing which has a standardised mean difference of 0·91 (95 % CI 0·46, 1·36, P < 0·0001). Both results were at a high level of homogeneity (I 2 = 7 % and 0 %, respectively). A sensitivity analysis was conducted excluding any studies originally included in the meta-analysis found to have a potentially high level of bias(Reference Gutzwiller, Degen and Matzinger33) and results remained significant with a standardised mean difference of 0·45 (95 % CI 0·15, 0·74, P = 0·003). The results of the meta-analysis are shown in Fig. 2.
Fig. 2. Forest plot of standardised mean difference in effect of cholecystokinin on satiation at both physiological and pharmacological levels of dosing.
Discussion
Early research into the use of CCK produced conflicting evidence on satiation with some studies demonstrating efficacy(Reference Kissileff, Pi-Sunyer and Thornton34,Reference Stacher, Bauer and Steinringer36,Reference Stacher, Steinringer and Schmierer37) while others indicated no effect(Reference Lieverse, Jansen and Van de Zwan16,Reference Greenway and Bray39) . The present review found evidence indicating that exposure to exogenous CCK results in an increase in satiation. This was demonstrated in studies measuring satiation via reduction in food or energy intake or via an increase in subjective satiety measures and was the case for both the CCK-8 and CCK-33 variants of the peptide. Where observed, the reduction in food intake appears to result from earlier meal termination as opposed to a reduction in the rate of food intake(Reference Greenough, Cole and Lewis31,Reference Kissileff, Pi-Sunyer and Thornton34) . These results were further supported by a finding of increased satiation in nine of the ten studies assessing satiation by subjective measures.
Attempts have been made to utilise CCK’s effects on satiation by development of a viable pharmaceutical product for weight loss. One study(Reference Jordan, Greenway and Leiter24) in this review involved the use of such a drug – the CCK-A receptor agonist GI181771X – which is available in an oral solution form. Use of GI181771X over a 24-week period failed to produce any effect on body weight(Reference Jordan, Greenway and Leiter24). The study’s authors discounted CCK’s use as a monotherapy for weight loss yet acknowledged a potential role for CCK in regulating energy intake. There may be multiple explanations for GI181771X’s failure to facilitate weight loss. This study utilised overweight and obese patients, and it is possible that some other weight regulation pathways, such as the development of leptin resistance in participants, could have become involved and negated the effect of CCK agonist use. Tachyphylaxis could provide a further explanation. Another still may be an acute effect which is not sustained whether due to the short half-life of the molecule or a lower within-meal energy intake resulting in an increase in meal frequency. CCK-8 has been shown to significantly reduce pre-meal hunger and reduced energy intake at a subsequent ad libitum test meal(Reference Greenough, Cole and Lewis31); however, the smaller meal resulted in a faster return of hunger if compared with placebo. It should be noted that the present review identified only one study which assessed the potential of a CCK analogue for weight loss and thus a broader review including more such studies on this topic is likely warranted before drawing any conclusions. In any case, another drug in the same class as GI181771X (CCK-1 receptor agonist) has been found to produce abnormal effects on the exocrine pancreas(Reference Nyborg, Kirk and de Boer40) which would limit the future use of drugs in this class and GI181771X’s proposed use as a potential weight loss drug has itself been discontinued by the developer(Reference Fong41).
The effects of CCK are known to be dose dependent(Reference Brennan, Little and Feltrin29). As evidenced in the meta-analysis contained in the present review, at higher or pharmacological doses the weight of evidence clearly supports the case for an effect by CCK on satiation. Until now the case for an effect at physiological doses, however, has been less clear. This point is of relevance as any findings in relation to CCK’s role in eating behaviour would apply to biological mechanisms only to the extent that dosing of CCK was similar to those levels found physiologically in the blood plasma.
Originally it was thought that the mechanism underlying CCK’s effect on satiation was due to CCK’s influence on gastric emptying. Subsequently, it was shown that CCK’s effect on food intake was greater than that on gastric emptying(Reference Muurahainen, Kissileff and Lachaussee42) suggesting the existence of another mechanism. In rats, it was found that an infusion of CCK prior to the delivery of a gastric load significantly magnifies the response from fibres in the afferent vagus(Reference Schwartz, McHugh and Moran43). Other studies, both animal and human, have shown that gastric distention increases the reduction of food intake produced by CCK infusions(Reference Muurahainen, Kissileff and Lachaussee42,Reference Schwartz, Netterville and McHugh44) . The relationship between CCK dosage, gastric distension and the resulting level of food intake appears to be linear. A potential synergistic interaction between the effects of CCK and gastric distention has been studied, but this was not found to be significant(Reference Kissileff, Gordon and Thornton35). Eight of the ten studies included in the meta-analysis(Reference Lieverse, Jansen and Masclee26–Reference Brennan, Little and Feltrin29,Reference Greenough, Cole and Lewis31–Reference Kissileff, Pi-Sunyer and Thornton34) utilised some means to facilitate stomach distension. The one study which failed to find an effect of CCK on satiation(Reference Lieverse, Jansen and Van de Zwan16) did not employ any means to increase stomach distention such as a preload. CCK has been found to both reduce food/energy intake and increase subjective satiety measures at physiological levels when combined with a preload or gastric distension mediated by the use of a gastric balloon(Reference Kissileff, Gordon and Thornton35). Four studies in the meta-analysis utilised a preload(Reference Lieverse, Jansen and Masclee26,Reference Greenough, Cole and Lewis31,Reference Gutzwiller, Drewe and Ketterer32,Reference Kissileff, Pi-Sunyer and Thornton34) . CCK has also been shown to reduce energy intake when accompanied by intragastric load of saline(Reference Moran and McHugh45) and thus it was notable that studies which did not utilise a preload tended to incorporate a sizeable fluid intake into the test meal. Five studies allowed free intake of fluid together with the test meal(Reference Brennan, Feltrin and Horowitz28,Reference Brennan, Little and Feltrin29,Reference Greenough, Cole and Lewis31–Reference Gutzwiller, Degen and Matzinger33) . A sixth(Reference Ballinger, McLoughlin and Medbak27) incorporated 200 ml of water intake 5 min prior to the test meal and a further 200 ml of water to be consumed together with the test meal.
The results of these studies suggest separate feedback systems working in unison to mediate satiation. A proper understanding of the function and efficacy of biochemical signalling from the consumption of food cannot be realised without considering input from multiple feedback systems(Reference Powley and Phillips46) and, specifically in the present review, CCK in combination with stimulus from mechanical receptors in the stomach. Eating behaviour is governed by the body estimating energy intake based on input from multiple systems. Combining CCK or CCK analogues with stimulus from other feedback systems to better regulate energy intake may present a road for future research. However, the greatest value of these findings is their potential in further elucidating the complex systems which regulate energy intake.
Conclusion
The findings of this systematic literature review indicate that the exposure to either the CCK-8 or CCK-33 variants of CCK may result in an increase in satiation in healthy participants. This effect also appears to result from earlier meal termination rather than a reduction in the rate of food intake. An analogue of CCK which can be administered orally failed to produce any long-term weight loss at 24 weeks. The meta-analysis found that CCK has a significant effect on satiation at both physiological and pharmacological levels in the blood plasma.
Supplementary material
For supplementary material/s referred to in this article, please visit https://doi.org/10.1017/S0007114522000381
Acknowledgements
No financial assistance was received in support of this study by any of the authors.
A.W. conceptualised the review, contributed to the development of the methodology and the study selection, conducted the analysis and completed the draft of the paper; M.T. designed the methodology and conducted the search; N.N. contributed to the development of the methodology, participated in the study selection and assisted with writing and editing the paper; S.S. contributed to the development of the methodology, assisted with writing and editing the paper and provided overall supervision.
All authors declare no conflict of interest.
