REVIEWARTICLE

Management of chronic constipation in patientswith diabetes mellitus

V. G. M. Prasad1& Philip Abraham2

Received: 26 July 2016 /Accepted: 27 November 2016# Indian Society of Gastroenterology 2016

AbstractAim The aim of this review is to provide an overview of theclinical assessment and evidence-based treatment options formanaging diabetes-associated chronic constipation.Methods A literature search of published medical reports inEnglish language was performed using the OVID Portal, fromPUBMED and the Cochrane Database of SystematicReviews, from inception to October 2015. A total of 145 ab-stracts were identified; duplicate publications were removedand 95 relevant full-text articles were retrieved for potentialinclusion.Results Chronic constipation is one of the most common gas-trointestinal symptoms in patients with diabetes, and occursmore frequently than in healthy individuals. Treatment goalsinclude improving symptoms and restoring bowel function byaccelerating colonic transit and facilitating defecation. Basedon guidelines and data from published literature, food anddietary change with exercise and lifestyle change should bethe first step in management. For patients recalcitrant to thesechanges, laxatives should be the next step of treatment.Treatment should begin with bulking agents such as psyllium,bran or methylcellulose followed by osmotic laxatives if re-sponse is poor. Lactulose, polyethylene glycol and lactitol arethe most frequently prescribed osmotic agents. Lactulose has aprebiotic effect and a carry-over effect (continued laxativeeffect for at least 6 to 7 days, post cessation of treatment).Stimulants such as bisacodyl, sodium picosulphate and senna

are indicated if osmotic laxatives are not effective. Neweragents such as chloride-channel activators and 5-HT4 agonistcan be considered for severe or resistant cases.Conclusion The primary aim of intervention in diabetic pa-tients with chronic constipation is to better manage the diabe-tes along with management of constipation. The physicianshould explain the rationale for prescribing laxatives and ed-ucate patients about the potential drawbacks of long-term useof laxatives. They should contact their physician if short-termuse of prescribed laxative fails to provide relief.

Keywords Chronic constipation . Diabetesmellitus .

Laxatives

Introduction

The prevalence of diabetes mellitus has reached epidemic pro-portions in both developed and developing countries, affect-ing more than 366 million people worldwide [1]. This numberis likely to increase in the coming years as a result of an ageingglobal population, urbanization, rising prevalence of obesityand sedentary lifestyles [2]. Diabetes is on the verge of gainingthe status of an epidemic in India. As per the 2011 estimate,India is home to 62 million diabetics, with an increase ofnearly two million each year. India is expected to cross the100 million mark by 2030 [3].

Several gastrointestinal (GI) symptoms such as diarrhea,chronic constipation and fecal incontinence are often observedin patients with diabetes mellitus [4–6]; among these, chronicconstipation is the most commonly reported [7]. The preva-lence of chronic constipation in the general population is re-ported as around 14% [8]. A recent cross-sectional study with372 diabetic patients treated at an outpatient clinic reportedthat about 31% of patients had chronic constipation.

* V. G. M. Prasaddrvgm@rediffmail.com

1 VGM Hospital, 2100, Trichy Road, Coimbatore 641 005, India2 P D Hinduja National Hospital and Medical Research Centre, Veer

Savarkar Marg, Mahim, Mumbai 400 016, India

Indian J GastroenterolDOI 10.1007/s12664-016-0724-2

Prevalence studies conducted in the US, Europe and HongKong report the rate of chronic constipation in diabetic pa-tients to be 10%, 13% to 22% and 27.5%, respectively, indi-cating that chronic constipation is a very common GI symp-tom in diabetics [9–12]. In another cross-sectional study,13.9% of 224 Indian patients with functional constipationhad diabetes [13].

Poor dietary habits, less fluid intake and low physical ac-tivity are significant factors leading to chronic constipation.The prevalence of chronic constipation has been reported to behigher in women than in men, in older patients (≥50 years), inthose with longer (≥10 years) duration of diabetes mellitus andin those who take concomitant medications such as calcium-channel blockers that promote chronic constipation [14]. Theoccurrence of chronic constipation is significantly higher indiabetic patients with autonomic neuropathy compared tothose without neuropathy (22% vs. 9.2%, p < 0.04) [15].

Measures of general health, social functioning and mentalhealth are significantly impaired in patients suffering fromchronic constipation and are comparable with those in otherconditions such as osteoarthritis, rheumatoid arthritis andchronic allergies [16]. Given the growing prevalence ofdiabetes-associated chronic constipation, it is important to fo-cus attention on early identification and appropriate manage-ment of these complications for improving both diabetic careand quality of life of the affected patient.

There is no universally accepted definition of constipation.In a real-world clinical setting, constipation tends to be a sub-jective diagnosis. Frequency of bowel movement is an impor-tant factor in the assessment of constipation, yet there is noconsensus on how often the ‘normal’ bowel opens. There iswide variation between individuals in ‘normal’ frequency ofbowel movements, ranging from three times per day to threetimes per week, but many patients have expectations of a dailybowel movement. In addition to frequency of stools, consis-tency of the stool is also important. The Bristol Stool FormScale is a useful visual aid that was designed to assist in theevaluation of patients with self-reported constipation who donot have infrequent bowel movements, to establish that hardor lumpy stools are indeed present [17].

Based on definition, the prevalence of constipation variesbetween different populations across the world. The Romeclassification is widely recognized as a standardizedsymptom-based classification of functional GI disorders, in-cluding functional constipation (Table 1) [18]. Other defini-tions of constipation are consistent with the Rome criteria butare less quantitative and more subjective [19]. The Romecriteria are however used principally for research purposesand are not widely applied in clinical practice [20]. The re-cently developed Rome IV classification defines functionalconstipation as a functional bowel disorder in which symp-toms of difficult, infrequent or incomplete defecation predom-inate. Patients with functional constipation should not meet

the criteria for irritable bowel syndrome, although abdominalpain and/or bloating may be present but are not predominantsymptoms. Symptom onset should occur at least 6 monthsbefore diagnosis, and symptoms should be present duringthe last 3 months [21].

Functional constipation is divided into two subtypes: slow-transit constipation or colonic inertia is characterized by aprolonged length of time for stool to pass through the entirecolon [22]; obstructive defecation (also called pelvic floordyssynergia, dyssynergic defecation, anismus, or outlet ob-struction) is characterized by difficulty in evacuation or asense of incomplete evacuation after defecation.

Pathophysiology

The exact pathogenesis of chronic constipation in diabetesis not well understood. The autonomic nervous system isintimately involved in the control of GI motility and sensi-tivity, and a disturbance of this system may be involved inthe pathophysiology of constipation [15]. Autonomic dys-function with a lack of synchronicity between the gut mus-culature and the sphincters is thought to be the major con-tributing factor [23]. Battle et al. [24] in their study of co-lonic myoelectric and motor activity, demonstrated that di-abetic patients with chronic constipation had absent gastro-colonic response to feeding, resulting in mild to moderateconstipation. High blood sugar levels in both types 1 and 2diabetes can lead to loss of interstitial cells of cajal (ICC)and diabetic neuropathy. Damage to the nerves controllingthe digestive tract motility can lead to chronic constipationand sometimes alternating bouts of diarrhea [25–28]. Formany patients, this condition is chronic, with symptomspersisting 3 months or more [29].

Table 1 Rome IV diagnostic criteria for functional constipation

Following criteria should be present for at least 3 months with symptomonset at least 6 months prior to diagnosis

1 Presence of ≥2 of the following symptomsa:•Lumpy or hard stools (Bristol stool form scale 1–2) in >25% of

defecations•Straining during >25% of defecations•Sensation of incomplete evacuation for >25% of defecations•Sensation of anorectal obstruction/blockage for >25% of defecations•Manual maneuvers to facilitate >25% of defecations (digital

manipulations, pelvic floor support)•<3 spontaneous bowel movements per week

2 Loose stools rarely present without the use of laxatives

3 Insufficient criteria for irritable bowel syndrome

a In research studies, the patients with symptoms of opioid-induced con-stipation should not be diagnosed as FC, since it is difficult to distinguishbetween opioid side-effects and other causes of constipation. However,clinicians recognize that symptoms of the two conditions might overlap

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Clinical evaluation

A complete history and physical examination is needed toelicit the cause of constipation. It is imperative to rule outmalignancy or other organic causes prior to making the diag-nosis of chronic constipation. Evaluation includes recordingexhaustive medical and social history including the patient’spsychological status, blood sugar levels, obstetric history (forwomen) and a complete list of medications that can be asso-ciated with constipation. It is important to determine the du-ration of symptoms to distinguish chronic from transient con-stipation, the amount of fiber the patient has as part of diet andlaxatives or other self-prescribed over-the-counter constipa-tion treatments the patient has indulged in, if any. A completephysical examination with emphasis on the abdomen and per-ineum is imperative.

The aim of clinical assessment should be to establish asymptom profile, in order to plan individualized bowel care.Evidence-based guidelines suggest that a structured approachis required when assessing a patient with chronic constipation.Routine extensive diagnostic and physiological testing is notrecommended for chronic constipation [30, 31]. However, inpatients not responding to initial treatment, physiological testscan be used to assess anorectal disorders [32–35].

The objective of this manuscript is to provide an overviewof the clinical assessment and evidence-based treatment op-tions for managing diabetes-associated chronic constipation.

Methods

A literature search of published medical reports in Englishlanguage was performed using the OVID portal, fromPUBMED and the Cochrane Database of SystematicReviews, from inception to October 2015. Abstracts were ini-tially obtained using the following keywords: chronic consti-pation’, type 1 diabetes’, type 2 diabetes’, treatment’ andtrials’. Manual searches of references and review articles sup-plemented the computerized search, and only full-length arti-cles were considered. The literature search was done by VGMPrasad along with an independent external agency. They thenselected studies that satisfied the following inclusion criteria:(1) involving human subjects over the age of 18 years and (2)describing at least one form of treatment for chronic constipa-tion and chronic constipation in diabetes mellitus. Selectedstudies were evaluated by each reviewer for their quality andevidence according to the Strength of RecommendationsTaxonomy (SORT), with levels of evidence from I to III andrecommendations from A to C (Tables 2 and 3) [36].

A total of 145 abstracts were identified; duplicate publica-tions were removed and 95 relevant full-text articles wereretrieved for potential inclusion. Based on the findings, a

practical approach to managing chronic constipation is sum-marized in Fig. 1.

Evidence-based management

Non-pharmacological treatment

It is imperative to understand the patient’s views and defini-tions of chronic constipation, which may often differ frommedical criteria. Treatment aims to improve symptoms andrestore bowel function by accelerating colonic transit and fa-cilitating defecation [37].

Many patients’ symptoms can be relieved with life-style and dietary modification, both of which should beimplemented before opting for unnecessary tests or pre-scription medications. The patient should be encouragedto follow a healthy lifestyle, which includes a high-fiberdiet, increased water intake and physical activity [38]. Aformal evaluation of dietary fiber and fluid intakeshould be carried out, before recommending further in-crease in dietary fiber [39].

Food and dietary changes

Dietary fiber can be defined as a plant-derived materialthat is resistant to digestion by human alimentary en-zymes [40, 41]. There are two main types of fiber,insoluble and soluble. Insoluble fiber is not acted onby colonic bacteria and does not create colon gas. Itis an important fiber because it retains water withinthe colon, promoting a large, bulky stool and improvedregularity. Soluble fiber is fermented by colonic bacte-ria. Taken together and in adequate quantities, solubleand insoluble fibers help improve constipation and min-eral absorption.

The American Diabetes Association (ADA) guide-lines recommend lifestyle changes involving dietaryand physical activity as first-line therapy for most indi-viduals with diabetes [42]. These are also first-line ther-apy for patients who suffer from chronic constipation.Dietary fiber has a role to play in increasing stoolweight and improving bowel movement [43]. However,before recommending changes or increase in dietary fi-ber, a formal evaluation of dietary fiber and fluid intakeneeds to be conducted as excessive fiber intake canaggravate bloating and flatulence and lead to abdominalcramps. The generally recommended daily dietary fiberintake in adults is 20–30 g [39]. Vegetarianism is asso-ciated with high dietary fiber intake. Therefore, thor-ough evaluation of type of dietary fiber and recom-mended dose should be conducted [44].

Although there is some evidence from controlled trialsconfirming the efficacy of high-fiber diets, this treatment fails

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to normalize bowel movements in up to 40% of patients, es-pecially in those with slow transit or impaired defecation[45–47]. Voderholzer et al. [48] conducted an observationalstudy among 149 patients with chronic constipation whentreated with dietary fiber (plantago ovate seeds); 85% of

patients without a pathological finding became symptom-free while 80% of patients with slow transit did not respond.

Health practitioners regularly recommend increasedfluid intake to alleviate chronic constipation, althoughevidence suggesting benefit is limited.

Table 2 Laxatives used in management of chronic constipation and their level of recommendations

Category Drugs Mechanismof action

Benefits Side effects Contraindications Level ofrecommendation

Comments

Bulk-forming laxatives

Wheat bran,psylliumseed husk,methylcellu-lose

Luminalwaterbindingincreasesstool bulkandreducesconsistency

Useful treatmentfor small hardstools. Benefitirritable bowelsyndromepatients, andcolostomy andileostomypatients

Flatulence andabdominaldistension, GIobstruction orimpaction

Difficulty inswallowing,intestinalobstruction,colonic atony,and fecalimpaction

Psyllium[108–111] : A

At least 3well-designedRCTs showingbenefits overplacebo

Bran [112, 113] :B

Two controlledtrials showedbenefits inreducing use oflaxatives

Methylcellulose[114] : B

Only onecontrolled trialof mediumquality

Osmotic laxatives

Undigestibledisaccharides

Lactulose [62,115]

Luminalwaterbinding bycreatingosmoticgradient

Gentle andeffectivelaxative action,prebiotic effect;does not increaseblood sugar

Bloating,flatulence,diarrhea (withlarge doses)BToo sweettaste^ can bemasked bydiluting inwater

Galactosemia,intestinalobstruction

A Two systematicreviews ofRCTs withbenefits overplacebos

Syntheticmacromolecule

Polyethyleneglycol (PEG)[62, 116,117]

Luminalwaterbinding

Does not increasecolonic gas

Abdominaldistensionand pain,nausea,excessivediarrhea (canbe controlledwith doseadjustment)

Intestinalperforation orobstruction,paralytic ileus,severeinflammatoryconditions ofthe GI tract

A At least 3 RCTsshowingbenefits overplacebo

Stimulant laxatives

Diphenylmethanederivatives

Bisacodyl,sodiumpicosulfate

Act locally tostimulatecolonicmotility,decreasewaterabsorptionfrom largeintestine

Patientsunresponsive orintolerant to fiber

Abdominalcramp,hypokalemia

Intestinalobstruction

Senna[118–120] : A

At least 3controlled trialsshowingbenefits overplacebo

Anthraquinones Senna, aloe,cascara

A Strength of Recommendation Taxonomy (SORT) scale was used to grade the available evidence based on the quality, quantity, and consistency of availableevidence. The SORT grading system emphasizes the use of patient-oriented outcomes that matter to patients, such as morbidity, symptom improvement, costreduction, changes in quality of life, and mortality. A grade A recommendation is based on consistent (studies with similar or coherent conclusions) and goodquality patient-oriented evidence (systematic review/meta-analysis of randomized controlled trials (RCTs) or individual high quality RCTs); Grade Brecommendation is based on inconsistent and limited quality patient-oriented evidence (systematic review/meta-analysis of lower quality clinical trials or ofstudies with inconsistent findings, lower quality clinical trial, cohort or case-control study); and grade C recommendation is based on consensus guidelines,extrapolations from usual practice, expert opinions, disease-oriented evidence, or case series for diagnosis, treatment, prevention or screening

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Exercise and lifestyle changes

Regular physical exercise helps not only in the digestionprocess but is also recommended in the ADA guidelinesas a key feature in managing diabetes, which in turn canimprove GI complications by reducing diabetic neuropa-thy [49]. The ADA recommends moderate-intensity exer-cise for ≥150 min per week over ≥3 times per week withno more than two consecutive days’ gap without exercise,for diabetes patients. The guidelines also recommend re-ducing sedentary time (break up >90 min spent sitting). Anumber of studies across different populations haveshown that lifestyle changes can reduce the incidence oftype 2 diabetes by 28 to 59%, with the effects seen manyyears after the intervention [50–56].

As chronic constipation can be caused by a host oflifestyle factors, such as change in routine, lack of reg-ular exercise, or ignoring the urge to defecate, lifestylemodification incorporating appropriate amount of exer-cise is generally recommended as an initial managementtool for treating mild to moderate symptoms of chronicconstipation in diabetes mellitus patients [42].

Medical management

If adequate relief is not obtained with dietary and life-style changes, a range of pharmacological agents can beconsidered. The most recognized and acceptable treat-ment is the use of laxatives (Tables 2 and 3). Thereare no studies assessing a stepwise approach to laxative

therapy. The Asian Neurogastroenterology and MotilityAssociation and Rome IV recommend that therapyshould begin with a bulk-forming agent, followed bytreatment with an osmotic laxative and stimulant laxa-tive in patients with inadequate response to bulk-forming agents [39].

Laxatives aid defecation by decreasing stool consis-tency (softening) and/or artificially or indirectly stimu-lating colon motility via one or more mechanism(Table 2) [20]. These formulations can be taken bymouth (liquids, tablets, capsules), or can be given viathe rectum (e.g. suppositories, enemas) [20]. Well-de-signed, placebo-controlled, blinded, clinical trials ofolder laxatives are sparse; similarly, there is a lack ofhead-to-head comparisons.

While developing treatment strategies, it is importantto recognize that patients with diabetes have composi-tional changes in the intestinal microbiota compared tonon-diabetic patients. Gut microbiota are essential forthe digestion and production of organic acids to main-tain an appropriate pH environment in the gut [57]. Indiabetes patients, there is a loss of gut microbial diver-sity with an increase in opportunistic pathogens. In astudy of 36 men, the relative abundance of Firmicutes(specifically Bacteroides vulgatus, Faecalibacteriumprauznitzii) and the Bifidobacterium and Roseburia ge-nuses were observed to be significantly lower, while theproportion of Bacteroidetes and Proteobacteria wasfound to be somewhat higher in diabetic persons com-pared to their non-diabetic counterparts [58].

Table 3 Evidence-basedrecommendations of non-pharmacological treatments forchronic constipation

Treatment Level ofrecommendation

Comments

Non-pharmacological

Increasing dietaryfiber [121–127]

C No RCTs, data from multiple observational studies, resultsconflicting. More likely to be beneficial in people with fibersdeficiency

Increasing exercise[123, 128–130]

B Two small RCTs with opposite results and two other cohortsshowing benefits. More likely to be beneficial in people withlack of exercise

Increasing fluids[131, 132]

C One observational study and one controlled trial, the latter showingbenefits of increased fluids only in the presence of sufficientfiber intake

A Strength of Recommendation Taxanomy (SORT) scale was used to grade the available evidence based on thequality, quantity, and consistency of available evidence. The SORT grading system emphasizes the use of patient-oriented outcomes that matter to patients, such as morbidity, symptom improvement, cost reduction, changes inquality of life, and mortality. A grade A recommendation is based on consistent (studies with similar or coherentconclusions) and good quality patient-oriented evidence (systematic review/meta-analysis of RCTS or individualhigh quality RCTs); Grade B recommendation is based on inconsistent and limited quality patient-orientedevidence (systematic review/meta-analysis of lower quality clinical trials or of studies with inconsistent findings;lower quality clinical trial, cohort or case-control study); and grade C recommendation is based on consensusguidelines, extrapolations from usual practice, expert opinions, disease-oriented evidence, or case series fordiagnosis, treatment, prevention or screening

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Probiotics and prebiotics can eradicate gut dysbiosis andameliorate inflammatory, metabolic and molecular imbal-ances, thus preventing or treating diabetes and developmentof neurodegenerative disease. Probiotic therapies increase in-sulin sensitivity, inflammation, oxidative stress and GI dis-tress. Prebiotics were shown to increase the level of speciesin the Bifidobacterium genus, an effect that positively corre-lates with improved glucose tolerance and glucose-inducedinsulin secretion and reduced inflammatory markers [59, 60].

Bulk-forming laxatives

Bulk-forming laxatives, also known as fiber laxatives, addsoluble fiber to the stool. This helps in retaining fluid in thestool, thus making stool soft and easier to pass. Commonlyprescribed bulk-forming laxatives include ispaghula/psylliumhusk, bran and methylcellulose [61]. A systematic review by

Tramonte et al. (1997) listed six trials on treatment with fiberlaxatives, which resulted in increase of 1.4 bowel movementper week [62]. A double-blind trial reported that fiber laxa-tives gave significant symptom improvement, improved stoolconsistency and resulted in fewer complaints of abdominalpain [63–65].

Psyllium husk is reported from well-designed, randomized,placebo-controlled studies to improve symptoms and providenatural constipation relief by improving colonic transit timeand stool consistency [66–68]. This is an edible soluble fiberand a prebiotic. Psyllium husk swells when combined withwater or another liquid, and produces more bulk, which stim-ulates the intestines to contract. It is also known to have pos-itive effects on heart health, blood pressure and cholesterollevels. It is safe, well-tolerated and improves glycemic controlin people with diabetes. In adults with chronic idiopathic con-stipation, psyllium increased the mean number of stools per

History and diabetes examination(A1C >6.5% / FPG >126 mg/dL / 2-hour

plasma glucose >200 mg/dL duringOGTT)

Fulfilling Rome IV criteria forchronic constipation?

No

Consider otherdiagnoses

Yes

Investigations forcolonic transit time

Normalcolonictransit

Tests for pelvic floordysfunction (PFD)

No PFDPFD confirmed

Slow colonic transit

Adequate intake ofdietary fiber, fluids orexercise

Partial divisionof puborectalis

Biofeedback

Start with bulk-forming agents likepsyllium or bran

Consider osmotic agents likelactulose, polyethylene glycol

Consider stimulants like bisacodyl and senna

Consider chloride channel activators, 5-HT4

antagonist, and guanylate cyclase-creceptor agonist

Yes

Inadequateresponse

Inadequate response

Inadequateresponse

Inadequateresponse

Fig. 1 Flow-chart formanagement of chronicconstipation in diabetes patients[20, 39]

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week by 0.9, compared to no change in the placebo group(p < 0.05), in one 8-week trial [68]. Another trial found thatadults with chronic constipation who received 2 weeks ofpsyllium were more likely to report normalization of bowelfunction than those who received placebo (87% vs. 30%,p<0.001) [64]. A third, 2-week study found that 87% of pa-tients allocated to psyllium reported improvement in symp-toms compared to 47% of those who received placebo [63].One study found that psyllium not only improved blood sugarin type 2 diabetic patients but also reduced the risk of coronaryheart disease, suggesting that it can be considered as an effi-cacious option for diabetes patients with chronic constipation[69].

Osmotic laxatives

Osmotic laxatives work by creating an osmotic gradient thatincreases the retention of water in the stool, making them softand enhancing their passage. Osmotic laxatives include bothinorganic salts (magnesium compounds) and organic sugarsor alcohols such as lactulose, lactitol and polyethylene glycol(PEG). Their dose can be titrated according to the stool output,and they are used for both chronic and occasional constipation[70]. Lactulose and PEG have been shown to be effective andsafe treatments for chronic constipation and are commonlyused in both pediatric and adult populations. The alternativeosmotic laxatives of magnesium hydroxide or magnesiumsalts are satisfactory for occasional use or where rapid evacu-ation is required but tend not to be used in the long-term [71].Osmotic agents are useful when first-line bulk-forming agentsdo not provide satisfactory outcomes. Abdominal bloating,nausea and flatulence are side effects with some osmotic lax-atives [70].

Lactulose is a synthetic disaccharide that does not getabsorbed in the small intestine nor is it broken down by humanenzymes. It stays as a bolus and causes retention of waterthrough osmosis, leading to soften stool. It has a secondarylaxative effect in the colon, where it is completely fermentedby gut flora, producing metabolites that have osmotic abilitiesand peristalsis-stimulating effect [72]. Fermentation also leadsto production of lactic acid and volatile fatty acids especiallyacetic acids, which may interfere with glucose metabolism bydecreasing glucose hepatic production [73]. A small studyevaluated the effect of purified lactulose (27–33 g/day) onglucose tolerance in seven non-insulin dependent diabetic pa-tients during two randomized 10-day periods. At the end ofthe two periods, blood glucose levels during oral glucose tol-erance test were significantly lower when patients receivedlactulose [72].

In healthy humans, the ingestion of lactulose has beenshown to increase bifidobacterial degradation of primary tosecondary bile acids. Lactulose can therefore be consideredas a prebiotic as it positively affects host health by selectively

stimulating the growth or activity of one or a limited numberof colonic bacteria (bifidogenic effect). This is supported bydata from a prospective, randomized, controlled trial compar-ing the effect of lactulose and PEG-4000 on colonic flora in 65patients with chronic idiopathic constipation; fecalbifidobacterial counts were higher in the lactulose group thanin the PEG group (p = 0.04). The study showed that lactuloseinduced significant changes in the composition of fecal flora,whereas PEG inhibited most of the metabolic activities of theflora [74]. Bifidobacteria result in acidification of the coloniccontent, which is important for the energy metabolism andnormal development of colonic epithelial cells and acts as aprotective factor against colonic disease. In another random-ized controlled study, comprising 12 healthy volunteers pergroup, the effect of lactulose, lactitol and placebo on colonicmicroflora and enzymatic activity was evaluated. Lactuloseprovided a better effect on colonic microflora and thus betterprebiotic effect than lactitol. Lactulose was a better carbonsource for the probiotic intestinal bacteria Bifidobacteriumand Lactobacillus than lactitol, resulting in a reduction in det-rimental species [75].

The clinical efficacy and safety of lactulose in treatingchronic constipation have been established in randomizedcontrolled studies. In a double-blind trial comparing lactulose(60 mL/day) with placebo, lactulose produced significant in-crease in stools per week (4.5 vs. 1.6 stools/week; p<0.05) aswell as stools of a softer consistency. Similarly, in anotherrandomized, double-blind, placebo-controlled trial, lactulose(30 mL of 50% solution) was superior to placebo in improv-ing mean bowel movement frequency per week and reducingseverity of symptoms such as cramping, bloating and flatu-lence [76, 77]. Lactulose has demonstrated superiority toispaghula in terms of mean bowel movement frequency perweek, and a trend of causing less abdominal pain was ob-served [78]. Connolly et al. [79] reported that, after 1-weektreatment with lactulose (15 mL twice daily), consistentlymore patients continued to produce normal stools than whenthey had received stimulant laxatives. Thus, lactulose can beconsidered as an effective osmotic laxative in treating consti-pation, with a possible positive effect on glycemic control indiabetes patients. It has a superior prebiotic effect as com-pared to PEG and lactitol in the context of the growing rec-ognition of gut dysbiosis in the pathogenesis of diabetes andconstipation, along with the added benefit of carry-over ef-fect, thus making it a suitable laxative for managing consti-pation in diabetics.

Another group of osmotic laxatives that is commonly usedis formulations containing polyethylene glycol. High doses ofPEG-based formulations were originally used primarily forcolon cleansing prior to colonoscopy. They have also beenshown to be useful for fecal disimpaction in both childrenand the elderly [67, 80, 81]. These formulations are now usedto treat chronic constipation. Daily doses of 17 g have been

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given for up to 6 months in adults [82, 83]. These are also safefor use in children, pregnant women and the elderly. The mostcommon side effect is diarrhea with liquid stools, which ap-pears to be a function of the dose, occurring in up to 17% withsingle dose and up to 36% with double dose; thus patientshave to be taught to titrate the dose according to their response[71]. Some formulations contain sodium and potassium; it isnot known whether the small quantities present give rise tohypernatremia and hyperkalemia in the elderly and those withimpaired renal functions [84].

PEG provides well-tolerated and effective relief in consti-pated patients [85, 86]. In a 6-month placebo-controlled study,304 patients with chronic constipation received either 17 g perday PEG or placebo. Fifty-two percent of PEG-treated pa-tients compared with 11% of placebo-treated patients(p < 0.001) were successfully relieved for more than 50% oftheir treatment weeks. No treatment-related safety differenceswere observed, with the exception of abdominal distension,diarrhea, loose stools, flatulence and nausea (39.7% of PEG-treated patients vs. 25% of placebo-treated patients; p=0.015),which are considered usual effects of laxative use [87]. Aretrospective study of institutionalized patients with chronicconstipation reported good long-term results for up to12 months [82], and for up to 5 months in randomized pro-spective studies in adult [88] and pediatric patients [89].

Most comparative data suggest that lactulose and PEGhave similar efficacy in treating patients with chronic consti-pation [85, 90]. A randomized, triple-crossover study of 57patients comparing PEGwith lactulose showed that the agentshave equal effect and were better than having nothing or pla-cebo, in improving stool frequency and ease of defecation[91]. A multicenter, randomized, controlled study conductedamong 65 patients reported the same results [74]. There are nodata on the efficacy and safety of PEG in diabetes patients.

Milk of magnesia (magnesium hydroxide) is an osmoticlaxative where the poorly absorbable magnesium ions causewater to be retained in the intestinal lumen; stimulation ofcholecystokin in release and activation of constitutive nitricoxide synthase might contribute to its laxative actions [92,93]. Evidence for its efficacy from randomized controlled trialsis limited. One crossover study in 64 chronic constipated pa-tients aged 65 years or older revealed that magnesium hydrox-ide at mean dose of 25 mL daily for 8 weeks produced signif-icantly more normal stool consistency, more frequent bowelmovements and reduced requirement for bisacodyl treatmentcompared with bulk laxative [94]. Reporting of adverse eventsis limited. In view of the risk of hypermagnesemia, it should notbe used in patients with renal impairment.

Stimulant laxatives

If the stool is soft but there is still difficulty in passing it,stimulant laxatives can be prescribed. These laxatives

stimulate the muscles in the digestive tract through their directstimulant/irritant properties. They are usually used on a short-term basis and start working between 6 and 12 h [95]. Themost commonly prescribed stimulant laxatives are senna,bisacodyl and sodium picosulphate. They are hydrolyzed inthe gut by enterocyte enzymes or colonic flora, stimulate peri-stalsis and sensory nerve endings, and possibly interfere withelectrolyte flux to inhibit water absorption [66].

Newer agents

Prucalopride is a highly selective 5-HT4 agonist stimulatingprokinetic activity of the colon with minimal activity on 5-HT3 and hERG receptors. It is reported to accelerate transitand stool output in volunteers and patients [96, 97]. Threelarge studies in the USA and Europe [19, 98, 99], havingidentical inclusion criteria (laxative-refractory patients, with80% having less than one spontaneous complete bowel move-ment per week), reported that prucalopride was associatedwith increase in bowel frequency to more than 3 per week in24% of patients compared with 11% in the placebo group.Prucalopride is approved in Europe for the treatment of chron-ic constipation [20].

Lubiprostone, a derivative of prostaglandin E1, is achloride-channel activator that stimulates intestinal fluid se-cretion. It acts on the enterocytes from the luminal side and isnot systemically absorbed, accelerating colonic transit andsoftening stool consistency [100]. Three double-blind, ran-domized, placebo-controlled trials have shown the efficacyof lubiprostone in increasing spontaneous bowel movementsand improving self-reported symptoms of chronic constipa-tion [101–103]. The long-term use of lubiprostone is reportedto be safe [12]. Lubiprostone has been approved by the USFDA for treatment of chronic idiopathic constipation, consti-pation caused by irritable bowel syndrome and opioid-induced constipation in adults with chronic, non-cancer pain[104].

Linaclotide

Linaclotide is a guanylate cyclase-C agonist that stimulatesintestinal fluid secretion and transit. It has been approved bythe US FDA for treatment of irritable bowel syndrome withconstipation and chronic idiopathic constipation, though it iscurrently not licensed in the EU. Results from two phase IIIstudies conducted among 1272 patients with chronic consti-pation reported linaclotide to improve bowel function in 20%of the patients. Abdominal symptoms, global measures ofconstipation and quality of life were also seen to be signifi-cantly improved with no evidence of rebound constipation[105, 106]. Common adverse events were GI-related withdiarrhea being the most common [107].

Indian J Gastroenterol

Conclusion

Chronic constipation is one of the most common GI symp-toms in patients with diabetes, and occurs more frequentlythan in healthy individuals [7, 8]. For some, this conditioncan be chronic, where symptoms can be severe and can sig-nificantly affect a patient’s quality of life. As clinical manage-ment of diabetes improves and enables better glycemic controlto be achieved, prevention and clinical improvement of asso-ciated GI complications may be realized. This improvement inglycemic control could be particularly relevant to diabetes-associated changes in the ICC, which are considered to be amajor underlying cause of many GI complications. The prev-alence of chronic constipation is higher in older adults, wom-en than men and among patients with diabetes who are takingmedications that can promote chronic constipation (e.g.calcium-channel blockers) [9, 14]. Although it is not wellunderstood, chronic constipation in this patient populationmost likely results from slow transit caused by loss of ICCfunction and smooth muscle myopathy. Moreover, autonomicneuropathy and neuroendocrine imbalances may also play arole [15]. Anorectal dysfunction, either because of anorectalsensory or motor abnormalities, should be considered, be-cause these patients can benefit from biofeedback training.

As there is no specific treatment for diabetes-associatedchronic constipation, these patients are generally treated inthe same way as those with chronic constipation. A step-wise approach is recommended while handling these pa-tients, given the multiple risk factors, coexisting morbidconditions and medication-induced causes. Managementof medication-induced causes, lifestyle modification andnon-pharmacologic therapies should be the first step, inorder to avoid unnecessary drug therapy.

There is limited evidence to guide the order in which ther-apeutic agents should be used, but detailed patient historyalong with an understanding of the patient’s glycemic control,an understanding of slow or normal transit and absence ofdefecatory dysfunction, can assist in developing patient-specific treatment pathways. These usually comprise initiatingtherapy with a bulk-forming agent, except in those who arebedridden, are cognitively impaired, or have other contraindi-cations. For patients with a contraindication or lack of re-sponse to a bulking agent, an osmotic agent, such as lactuloseor PEG 3500 is indicated, followed by stimulants (bisacodyl,picosulfate, or senna), and finally the newer agents (chloride-channel activators or 5-HT4 agonist) for severe or resistantcases.

Educational interventions and self-management programsdirected at medication management and counseling have thepotential to improve clinical, humanistic, adherence and costoutcomes. The underlying objective of these interventionsshould be to assist patients better manage their diabetes alongwith existing comorbid conditions such as chronic

constipation and associated complex medication regimens,reduce complications and improve adherence and relatedcosts. Patient preferences such as cost, convenience and toler-ance should be considered while selecting treatment regimens.

Lastly, patients who report frequent use of laxatives need tobe educated about the potential complications that can resultfrom their long-term use. When prescribing laxatives to treatchronic constipation, especially in the diabetic patient, theprimary healthcare provider should explain the rationale forthe prescription to the patient. As a means of increasing com-pliance to prescribed medications, physicians should addressand alleviate probable concerns of diabetic patients byhighlighting the benefits of taking the prescribed agent, forexample, describing the prebiotic effect and safety of lactulosein patients of diabetes with constipation. The patient shouldalso be instructed to contact the provider if short-term use ofthe prescribed laxative fails to restore the patient’s regularbowel routine. This will discourage the patient fromattempting self-treatment with one or more of the many laxa-tives that are available over the counter.

Acknowledgements The assistance for conducting literature searchand writing was provided by Shalaka Marfatia of pharmEDGE and herteam.

Compliance with ethical standards

Conflicts of interest VGMP, and PA declare that they have no conflictsof interest.

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