Objective:

The purpose of this study was to examine the possible effects of a gastrointestinal lipase inhibitor "Orlistat (Xenical)" on the intestinal absorption of oxalate and thereby on the urinary levels of oxalate excretion in overweight patients.

Methods and Procedures:

Long-term follow-up data of 95 cases (57 men, 38 women; M/W= 1.5) were documented. Patients were randomly assigned into two groups. While the patients in group I (n = 55) were treated with orlistat (Xenical) for 6 months, patients in group II (n = 40) received no specific medication. Calcium, oxalate, and citrate levels were determined in a 24-h urine collection from each patient. To evaluate the significance in the groups as well as the differences between the two groups, ANOVA test was performed and the results were given as mean s.d.

Results:

Comparative evaluation of urinary oxalate levels during 3-month follow-up clearly showed that urinary oxalate excretion significantly increased in 34/55 patients (61.8%) in the first group (P < 0.05). Of these 34 patients, 30 (88.2%) continued to have increased urinary oxalate excretion during 6-month follow-up (P = 0.001). However, our data did not show any significant effect of this medication on urinary citrate and calcium levels during 3- and 6-month follow-up evaluation (P = 0.05).

Discussion:

Our results suggest that increased intestinal absorption of dietary oxalate due to this type of medication in obese patients could make a substantial contribution to urinary oxalate excretion and may increase the risk of stone formation.

Introduction

Several studies have pointed out that hyperoxaluria is an important risk factor in the formation of calcium oxalate (CaOx) stones (1,2). Among the possible causes of hyperoxaluria in stone-forming patients, dietary oxalate is being considered to be an important contributor to urinary oxalate excretion in most individuals (3,4,5). Again, studies focusing on enteric hyperoxaluria have shown that nutrition is a highly important additional risk factor in patients who are prone to develop stones due to some specific underlying diseases (6,7,8).

Moreover, obesity is a common health problem in developed countries as well as in developing part of the world, and pharmacotherapy is currently regarded as the second line of treatment for weight loss. Although the first step for body weight reduction is diet and exercise, most algorithms for the treatment of obesity suggest that the next step might be the addition of a weight loss drug (9,10). Several articles have reported that obese patients are prone to have an increased risk of stone formation (11,12,13,14) and depending on the limited data reported in the literature, receiving such drugs may further place these individuals at even higher risk. Although this specific effect of orlistat has been evaluated in the rat model (15), no clinical prospective study evaluating the stone-forming risk factors in obese people taking this drug has been reported to date.

Orlistat (Xenical) is an agent that acts locally in the gastrointestinal tract and inhibits gastric, carboxyl ester, and pancreatic lipases: i.e., the enzymes that are essential for digestion of long chain triglycerides. This in turn results in failure to hydrolyze dietary fat (triglycerides) into absorbable free fatty acids and monoacylglycerols (16,17,18). In this way, orlistat may inhibit the dietary fat absorption of fat calories ingested up to 30%, thus reducing calorie and fat intake. As Ferraz et al. stated in their original study "unabsorbed fat and bile acids may react with calcium in the intestinal lumen and limit the amount of free calcium binding with oxalate which may eventually raise intestinal oxalate absorption resulting in hyperoxaluria" (15). Having been found to cause hyperoxaluria in rats (15), increased absorption of the oxalate ions from the colonic mucosa following the use of such medication might be an explanation of mild-to-moderate hyperoxaluria in stone formers (17,18). Thus, decreased absorption of fatty acids may result in increased free luminal oxalate levels due to the binding of luminal calcium by the action of fatty acids in patients receiving gastrointestinal lipase inhibitor (1). In addition to causing hyperoxaluria, enteric hyperoxaluria may, on the other hand, lead to supersaturation of urine with respect to CaOx, in conjunction with low volume, hypocitraturia, and hypomagnesuria (7,8). As a result of all these specific changes in the gut lumen, increased absorption and eventually urinary excretion of oxalate might be anticipated during long-term application of such drugs.

The purpose of this investigation was to evaluate the possible effects of orlistat, a gastrointestinal lipase inhibitor, on the urinary levels of oxalate excretion in patients receiving this medication for overweight problems.

Methods and Procedures

Of the 110 patients being managed for weight loss in our hospital, detailed documented data of 95 cases (57 men, 38 women, M/W = 1.5) were gathered during long-term follow-up. The initial study protocol was approved by the ethical committee of the hospital. Patients with anatomical abnormalities, previous stone surgery, urinary tract infection, renal tubular acidosis, renal functional disorders, cystinuria, and other evident metabolic abnormalities (primary or secondary hyperoxaluria, hyperparathyroidism, etc.) or patients receiving any medication which may alter renal tubular function were excluded from this study program. A standard weight reduction diet of 1,600 cal/day was initiated in both group patients aiming 5% weight loss in 3-month period. Concomitant diseases associated with the obesity problem in both groups of patients are being given in Table 1.

Table 1 - Patient characteristics in both groups (n = 95).

Full table (38K)

Of the 110 patients evaluated, based on the follow-up protocol, 95 cases were independently randomized into two groups as follows:

Group I (study group, n = 55). Overweight patients receiving orlistat for 6-month period in conjunction with a weight reduction diet. Patients' age ranged from 28 to 36 years (mean 32.4 years) and the mean BMI, (kg/m², defined by World Health Organization) value in this group patients was 27.95 2.50 (27.66–28.24).

Group II (control group, n = 40). Age and weight-matched overweight patients under the same weight reduction diet without any specific medication. Mean age value was 34.6 years (30–42) and mean BMI was 28.12 2.62 (27.52–29.02) in these patients (Table 1). A weight reduction diet of 1,600 kcal/day (reduced caloric intake under close monitoring) was initiated in both groups patients aiming to lose 5% of body weight in 3 months. There was no positive family history of urolithiasis in the patients and no concomitant medication was taken. Again, the distribution of male and female patients in both groups (M/W was 1.5 in group I, 33 men, 22 women and 1.5 in group II, 24 men and 16 women) were similar.

In addition to urinalysis and culture sensitivity tests, renal functional markers of biochemical parameters (creatinine, Jaffe reaction) and stone-forming risk factors in both serum and urine have been assessed in 24-h collected urine of each patient which were repeated at least two times (three 24-h urine specimen were collected in the majority of the patients i.e., in 86 of 95 patients, 90.5%) in specially prepared bottles given from the laboratory. Urine collections were preserved with thymol in isopropanol and kept refrigerated at 4 °C during collection. Urine samples were acidified with hydrochloric acid and the samples were kept below –20 °C until subsequent evaluation. The analysis of the urine specimen included the assessment of the urinary risk factors namely, oxalate, calcium, uric acid, and citrate. Urinary citrate and uric acid levels were assessed enzymatically (citrate lyase and uricase respectively); urinary oxalate was determined by ion chromatography; and calcium using atomic absorption method. Urinary magnesium levels were detected by atomic absorption spectrophotometry and sodium was detected by flame emission spectrophotometry. To ensure complete urine collection in an individual base, daily urine collection was based on the normal range of creatinine contents of urines in men and women. Urine samples were acidified during sample collection to ensure complete dissolution of any CaOx crystals formed and to prevent spontaneous conversion of ascorbate into oxalate. The 24-h urine output values were recorded in each patient. Additionally, to determine the level of CaOx supersaturation, CaOx ion-activity product values (AP (CaOx) index) were calculated using the risk index formula defined by Tiselius (16).

Urinary oxalate, citrate, and calcium excretion were evaluated for all patients before the initiation of the therapy, as well as 3 and 6 months afterward, in group I. The baseline data obtained before medication have been comparatively evaluated with the results noted during the same follow-up visits in group II. To evaluate the significance in each group as well as the differences between groups, ANOVA test was performed and the results were given as mean s.d.

Results

Of the 110 patients being managed for weight loss in our hospital, detailed documented data of 95 cases (57 men, 38 women, M/W = 1.5) were gathered during long-term follow-up. Of these patients, while 40 cases were followed with sole conservative measures for the overweight problem, the remaining 70 patients were treated with orlistat and the medication was well tolerated by 55 of these patients. Fifteen patients (21.4%) however stopped the medication because of some certain side effects (oily spotting in 9 patients, increased bowel movements in 4 and inability to control bowel movements in 2 patients).

Under specific medication, patients in group I lost weight significantly compared with the baseline values. Mean bodyweight was 84.2 11.6 kg before the medication and the values were noted as 81.9 10.8 kg at 3 months and 78.1 10.4 kg at 6 months. In group II, however, the percent change in body weight at 6-month follow-up was not significant as noted in group I. Mean values were 82.8 11.4, 81.6 10.7, and 80.4 10.7 kg, respectively. Urinary creatinine levels were within normal limits in all patients with a mean value of 0.95 mg/dl (0.75–1.20 mg/dl) in the whole group. Although comparative evaluation of baseline urinary oxalate levels with 3-month follow-up findings demonstrated an increase in all group I patients, this change was significant in 34 of the 55 patients (61.8%) during this period. Of these patients, 30/34 (88.2%) continued to show increased urinary oxalate excretion during 6-month follow-up (P < 0.05). Mean urinary oxalate excretion increased from 0.48 0.16 to 0.96 0.22 mmol/24 h during 3-month period (P = 0.001) and remained at higher level during 6-month follow-up, with a mean value of 0.47 0.09 mmol/24 h. (P = 0.001) (Table 2). The relatively higher baseline level of oxalate detected in group I patients was due to the higher excretion of oxalate detected in 12 of these patients (7 men, 5 women). Although the exact etiology of hyperoxaluria in these patients is not clear, dietary habits have been accepted as the main possible underlying cause in at least some of these cases.

Table 2 - Median (95% CL) excretion of urinary risk factors before and during medication with the gastrointestinal lipase inhibitor orlistat (Xenical) (study group, n = 55).

Full table (31K)

Despite a profound effect of the medication on urinary oxalate excretion, evaluation of the urinary citrate as well as calcium levels during the same follow-up period, however, showed an increase to a slight extent which was not found to be statistically significant as demonstrated in Table 2. These findings suggested an association between the use of gastrointestinal lipase inhibitor (orlistat) and the urinary oxalate excretion possibly originating from the changed absorption rate of oxalate ion at the intestinal level due to the specific effect of such medication.

Patients were carefully followed for possible formation of new stones and despite the significant rise in oxalate excretion detected in a considerable percentage of the patients in group I, none of them revealed new stone formation during short- and long-term follow-ups. On the other hand, comparative evaluation of the urinary excretion of oxalate as well as other risk factors did not reveal any significant alteration in group II (control group) as summarized in Table 3. Urinary levels of the stone-forming risk factors, including the excretion of oxalate levels remained within normal limits during 3- and 6-month follow-up control. Moreover, the evaluation of the AP (CaOx) values showed a significant rise in patients receiving this medication during 3-month follow-up, but not in group II patients (Tables 2 and 3). In addition to the evaluation of the differences noted in both groups during 3- and 6-month follow-up, the changes between both groups were compared in an attempt to assess their significance, as shown in Table 4.

Table 3 - Median (95% CL) excretion of urinary risk factors in patients receiving no specific medication (control group, n = 40).

Full table (30K)

Table 4 - Comparative evaluation of urinary stone forming risk factors and AP (CaOx) values in both groups.

Full table (51K)

Discussion

Studies have demonstrated that hyperoxaluria leads to an increased CaOx supersaturation and kidney stones due to the low solubility of CaOx salts (1,2). Oxalate ions as well as the CaOx crystals have been shown to exhibit harmful effects on renal tubular cells which promote new stone formation, until the levels of oxalate in urine normalize by specific measures (19,20,21,22). Concerning the etiology of hyperoxaluria, dietary oxalate is currently believed to make a strong contribution to urinary oxalate excretion (2). In normal subjects, intestinal oxalate absorption is <20% of an administered dose; when the test dose of oxalate is administered with food, absorption is usually under 10% (1,8). In addition to some specific bowel pathologies, which leads to the hyperabsorption of the oxalate available in gut lumen resulting in intestinal hyperoxaluria, authors have focused on the unestimated hyperoxaluric effect of some certain antiobesity drugs.

Obesity is a common health problem for developed countries and it is a growing problem in developing countries (9,10) and the pathology is considered to be a certain risk factor for stone formation (11,12,13,14). In their original study, Siener et al. demonstrated a strong association between obesity and increased risk of stone formation due to increased urinary excretion of stone-forming risk actors (13). Among these drugs, orlistat is a noncentrally acting antiobesity agent which at the recommended dose of 120 mg, three times daily inhibits dietary fat absorption by 30%. Owing to its mechanism of action, a possible side effect of this medication might be the increased risk of stone formation due to hyperoxaluria, which may be originated from colonic hyperabsorption (15,17,23,24,25). Hyperoxaluria in patients receiving gastrointestinal lipase inhibitors could be attributed to hyperabsorption of oxalate which may result from two general mechanisms: alteration in mucosal oxalate transport and changes in ionic oxalate concentrations in the gut lumen. These mechanisms may be due to the presence of unabsorbed fat and bile acids, which in turn may react with the calcium in the intestinal lumen. In this way, the amount of calcium in the lumen available for oxalate binding will also be limited, leading to an increase in intestinal oxalate absorption and hyperoxaluria. It is possible that an increase in colonic free fatty acids may both increase the permeability to oxalate and the concentration of soluble oxalate available for absorption (1,8,18,23).

Considering these possible effects of lipase inhibitors as well as the increased risk of stone formation in obese population, in this prospective study, our aim was to evaluate the possible effects of long-term use of an antiobesity drug (orlistat) on the urinary oxalate and citrate levels which may play a certain role in the formation of urinary calculi in such patients.

Although Ferraz et al. were able to demonstrate that gastrointestinal lipase inhibition in rats may lead to a significant increase in urinary oxalate and a slight reduction in urinary calcium which may result in an increase in AP (CaOx) index (15), the authors were not able to find any study in the literature dealing with this potential side effect in patients. Data analysis of this study demonstrated that long-term treatment with gastrointestinal lipase inhibitors (often due to obesity problems) may well cause a statistically significant increase in urinary levels of oxalate, which reflected the hyperoxaluric effect of such drugs. When compared with other risk factors such as hypocitraturia or hypercalciuria, these patients experienced a significant increase in urinary oxalate excretion during short (3 months), and although it was not as significant as early follow-up, there was a continuing increase during long-term application (6 months). Thus, this observation could indicate that the effect of the medication on urinary oxalate excretion might be transient. Although none of the patients in this study demonstrated new stone formation, the increase in oxalate levels suggests that an increased risk of stone formation could be anticipated during long-term use of these drugs. Thus, we recommend that all patients receiving such agents should be closely monitored for increased risk of oxalate excretion and possibly stone formation. Although not shown in this study, it is clear that one certainly needs a long-term prospective study to evaluate new stone formation under this medication. This requirement is especially important in patients with an earlier history of stone disease. Thus, our findings suggest an association between the use of gastrointestinal lipase inhibitor medication and the urinary oxalate excretion. This effect may be best explained by the specific binding effect of this medication with fatty acids in the intestinal lumen which in turn leads to increase in unbound oxalate in intestinal lumen. Although Ferraz et al. (15) reported an increase in urinary calcium levels, the authors were not able to show any significant alteration in this study. On the other hand, no significant effect of this medication has been observed on urinary citrate levels during the same follow-up period.

On the basis of these results and the limited published literature; it is clear that oral intake of gastrointestinal lipase inhibitors could decrease fat absorption and thereby increase calcium fatty acid soap formation and oxalate hyperabsorption during long-term medication. Our results again, suggest that the intestinal absorption of dietary oxalate in such patients, although it might be a transient side effect of the medication, may make a substantial contribution to urinary oxalate excretion and may even further increase the risk of stone formation.

Disclosure

The authors declared no conflict of interest.

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