Long-term cisapride treatment improves diabetic gastroparesis but not glycaemic control

Authors


Dr B. Braden, Department of Internal Medicine II, Johann Wolfgang Goethe University, Theodor Stern-Kai 7, D-60590 Frankfurt/Main, Germany. E-mail: Braden@em-uni.frankfurt.de

Abstract

Background:

In patients with diabetic gastroparesis, delayed food delivery to the intestine may become a major obstacle to post-prandial glycaemic control.

Aim:

To investigate whether cisapride accelerates gastric emptying in the long term or improves diabetes control in patients with diabetic gastroparesis.

Methods:

Eighty-five patients with long-standing insulin-dependent diabetes mellitus (glycosylated haemoglobin (HbA1c) > 7.0%), dyspepsia and diabetic neuropathy were tested for impaired gastric emptying of solids by the 13C-octanoate breath test. Nineteen of these patients with severe diabetic gastroparesis (i.e. t1/2 > 170 min) were randomly treated with 10 mg cisapride t.d.s. (n=9) or placebo (n=10) for 12 months. Thereafter, the breath test, dyspeptic symptoms and HbA1c values were reassessed.

Results:

Half emptying times in nine patients with diabetic gastroparesis were significantly shortened by cisapride (175 ± 46 min vs. 227 ± 40 min; P < 0.03). Half emptying times in the 10 patients taking placebo did not change (205 ± 37 min vs. 211 ± 36 min, P=0.54). Cisapride significantly reduced dyspepsia (score: 4.1 ± 1.6 vs. 2.0 ± 0.5, P=0.002). HbA1c values after 12 months of treatment were not different (cisapride: 7.7 ± 0.4% vs. 7.6 ± 0.9%, P=0.76; placebo: 7.5 ± 0.6% vs. 7.6 ± 1.5%, P=0.89).

Conclusions:

Prokinetic treatment with cisapride accelerates gastric emptying of solids and improves dyspeptic symptoms in diabetic gastroparesis. Glycaemic control, however, is not affected by cisapride.

INTRODUCTION

In patients with long-standing diabetes mellitus, gastric emptying disorders are relatively common, but under-recognized in the setting of other diabetic complications.1 The pathogenesis of diabetic gastroparesis is poorly understood, but autonomic neuropathy, hyperglycaemia, hyperinsulinaemia and obesity are considered to be contributory.23 About 50% of patients with insulin- or non-insulin-dependent diabetes have delayed gastric emptying.4 The majority of these patients are asymptomatic, some patients complain of epigastric pain, nausea, early satiety, vomiting or post-prandial fullness, and a few patients are severely symptomatic. However, diabetic gastroparesis is clinically relevant not only by virtue of symptoms, but also by the sequel of inadequate glycaemic control and impaired pharmacodynamics of orally administered drugs. Delayed gastric emptying might render an otherwise timely insulin application unpredictable. Relevant hyperglycaemia induces delayed gastric emptying even in normal controls, i.e. works as a feedback mechanism. The influence of an improvement in gastric emptying in diabetic gastroparesis on glycaemic control has not been investigated.

Diabetic gastroparesis can be quantitatively and sensitively assessed by measuring the gastric emptying of labelled physiological solids by scintigraphy or, more recently, by the 13C-octanoate breath test.56 These methods have contributed current evidence that gastrokinetic drugs (i.e. erythromycin or propantheline) may be helpful in the treatment of gastroparesis and symptoms.7

The aim of this study was to investigate the influence of long-term (12 months) cisapride treatment on: (i) gastric emptying in patients with diabetic gastroparesis; (ii) dyspeptic symptoms in these patients; and (iii) changes in glycaemic control over 1 year.

METHODS

Patients

After obtaining informed consent, 85 patients (35 male, 50 female; age, 50 ± 8 years) with insulin-dependent diabetes mellitus type 1, diabetic neuropathy and dyspeptic symptoms were tested for gastroparesis using the 13C-octanoate breath test. Patients with a history of gastrointestinal surgery, peptic ulcer or cirrhosis of the liver and those taking medication affecting gastric emptying were excluded. Finally, 19 patients with proven gastroparesis, i.e. a delay of gastric emptying of solids with t1/2 > 170 min, were included in this study.

All patients (five male, 14 female; age, 64 ± 11 years) had been treated for more than 10 years with insulin. In all of them, glycosylated haemoglobin (HbA1c) was > 7.0%. In all patients, diabetic autonomic and peripheral neuropathy was proven by testing the heart rate variability, the systolic blood pressure response to orthostasis, thermal discrimination and the perception of vibration.

Study design

Nineteen patients with delayed gastric emptying of solids were randomized by lot to cisapride therapy (10 mg t.d.s.) or placebo. Nine patients received oral cisapride therapy and 10 patients received placebo. All study participants with diabetic gastroparesis were instructed to avoid the intake of any other prokinetic drugs and macrolide antibiotics. All patients were told not to change the time interval between insulin injection and meals.

After 12 months, the measurement of gastric emptying by means of the 13C-octanoate breath test was repeated, and the parameters of glycaemic control (post-prandial blood glucose and HbA1c), as well as dyspeptic symptoms, were re-evaluated. Dyspeptic symptoms were documented according to a standardized questionnaire8 as epigastric pain, fullness/early satiety, nausea, upper abdominal discomfort or distension, vomiting and anorexia. The intensity of symptoms for these six items was classified by a sum score with: 0, asymptomatic; 1, mild symptoms (symptoms could be ignored if the patient did not think of them); 2, moderate symptoms (symptoms could not be ignored, but did not influence daily activities); 3, strong symptoms (symptoms influenced daily activities). Thus, the highest possible total score was 18 points.

Laboratory methods

Venous blood (2 mL) was taken before and 30, 60, 90, 120, 150, 180 and 240 min after ingestion of the test meal during the 13C-octanoate breath test for the analysis of blood glucose by the hexokinase method. HbA1c was analysed by high-performance liquid chromatography. The normal range with this method is below 6.0%.

13C-Octanoate breath test

The 13C-octanoate breath test was performed in a standardized way as described previously.5 After an overnight fast, the study medication was taken 30 min before ingestion of the test meal. The test meal consisted of a scrambled egg with the yolk labelled with 100 mg sodium 13C-octanoate (1-13C, 99% atom per cent excess). Egg white and yolk were baked separately. The scrambled egg was served with two slices of white bread, 5 g of margarine and 150 mL of water. Thirty minutes after subcutaneous injection of the usual insulin, the test meal (approximately 250 kcal: 42% carbohydrates, 18% protein, 40% fat) was consumed within 10 min. Breath samples were collected at baseline and at 10-min intervals thereafter for 4 h. During the 4-h test period, the subjects remained in a sitting position. Breath samples were analysed for 13CO2/12CO2 enrichment using isotope ratio mass spectrometry (Tracermass, Europa Scientific, UK). The results were related to PeeDeeBelmnite as international standard and were expressed as delta over baseline. Endogenous CO2 production was assumed to be 5 mmol per square metre of body surface area per minute.9 From the 13CO2 exhalation in breath, the percentage of 13C recovery per minute and the cumulative recovery were calculated. Mathematical curve fitting of the cumulative recovery to the function, Y=m(1 − ekt)β, using non-linear regression analysis determined the half emptying times, t1/2=(− 1/k)ln(1 − 2−1/β), and lag phases, tlag=ln(β/k). The normal range of half emptying times in the 13C-octanoate breath test in healthy controls is below 150 min in our isotope ratio mass spectrometry laboratory.

Statistics

Results are given as medians and ranges. Half emptying times of the 13C-octanoate breath tests and HbA1c levels before and after cisapride treatment were compared using the Wilcoxon matched pairs signed rank test. Differences between both groups were tested using the Mann–Whitney U-test. P < 0.05 was considered to be significant.

RESULTS

The clinical characteristics of both groups are given in Table 1. At study entry, there were no significant differences in HbA1c values or fasting blood glucose levels, gastric emptying times or lag times and scores of dyspepsia between both groups.

Table 1.  . Characteristics of patients Thumbnail image of

Over a period of 12 months, 10 mg cisapride t.d.s. accelerated the gastric emptying half time in patients with diabetic gastroparesis (Figure 1). Half emptying times decreased from 216 min (193–267 min) to 179 min (141–201 min) (P < 0.03). The half emptying times in the 10 patients with diabetic gastroparesis taking placebo did not change after 12 months [210 min (181–244 min) vs. 204 min (174–228 min), P=0.38].

Figure 1.

. Half emptying times of the 13 C-octanoate breath test in patients with diabetic gastroparesis before and 12 months after placebo or cisapride treatment. The median (•) and the bars for the first and third quartile are marked.

The lag phase of gastric emptying was also significantly shorter in patients taking cisapride [105 min (77–139 min) vs. 136 min (106–172 min), P=0.03]. Patients on placebo did not show any alteration of the lag times after a period of 12 months [122 min (101–145 min) vs. 125 min (100–147 min), P=0.71].

In the patients with proven diabetic gastroparesis and dyspeptic symptoms, cisapride (10 mg t.d.s.) resulted in a significant reduction of the symptom score after 12 months of therapy [5.0 (2.5–5.5) vs. 2.0 (1.5–2.5), P < 0.02], while in the control group this score remained unchanged after 1 year [5.0 (4.0–5.3) vs. 4.0 (3.0–6.3), P=0.91] (Figure 2).

Figure 2.

. Score of dyspepsia in patients with diabetic gastroparesis before and 12 months after placebo or cisapride treatment (same results in two - - - or three - - - patients). The median (•) and the bars for the first and third quartile are marked.

Fasting blood glucose levels, post-prandial peak blood glucose increments, the area under the curve [blood glucose vs. time (240 min)] during both breath tests and insulin requirements did not differ after the 12-month period in both groups.

HbA1c was not changed by cisapride therapy after 12 months [7.8% (7.6–8.2%) vs. 7.7% (7.1–8.4%), P=0.73]. Also, the HbA1c values in the control group without cisapride therapy remained stable within 12 months [7.4% (7.1–8.1%) vs. 7.6% (6.4–8.7%), P=0.64]. The fasting blood glucose concentrations were unaffected both with and without cisapride therapy 12 months later (Table 2).

Table 2.  . Effect of prokinetic therapy on gastric emptying, dyspeptic symptoms and glycaemic control Thumbnail image of

DISCUSSION

Previous publications have demonstrated a prokinetic effect of cisapride treatment, leading to accelerated gastric emptying rates for both solids and liquids.10–12 Studies from Japan report a positive effect of accelerated gastric emptying on dyspeptic symptoms after 12 weeks, but not on glycaemic control.13 According to the double-blind crossover trial by Stacher et al., cisapride did not affect glycaemic control, but the intake of prokinetics also did not result in a significant acceleration of gastric emptying.14 In a crossover study in patients with insulin-dependent diabetes mellitus and glycaemic instability, Johansson et al. did not observe treatment effects of cisapride with respect to the standard deviation of self-monitored blood glucose, insulin requirements, number of hypoglycaemic episodes and well-being.15 In our study, the influence of accelerating gastric emptying by prokinetic treatment on glycaemic control was investigated. Although the half emptying times of solid meals were shortened with cisapride therapy, the improved gastric emptying did not result in positive effects on glycaemic control.

The 13C-octanoate breath test is a reliable and clinically feasible method for the analysis of the gastric emptying of solids,5 while liquid emptying can be measured by the 13C-acetate breath test.16 Owing to the lack of radiation exposure and their non-invasive nature, breath tests are most appropriate for therapy control and follow-up.5711 Meanwhile, the 13C-octanoate breath test has also been shown to be a reliable diagnostic tool in diabetic patients.17 The gastric emptying breath test can be carried out even in non-specialized institutions because the breath samples can be sent by mail for the analysis of isotopic enrichment to laboratories with experience in isotope ratio mass spectrometry or recently established and less expensive non-dispersive infrared spectroscopy.18–20

Gastroprokinetic agents, such as metoclopramide, cisapride, domperidone and erythromycin, improve the gastric emptying pattern by increasing fundic or antral contractions and/or eradicating gastric dysrhythmias.2122 Diet and blood glucose control are also important factors in the management of diabetic gastropathy. Electrical stimulation (pacemaker) is another therapeutic option, but the results are not yet convincing.

The results of our study demonstrate the positive long-term effect of cisapride on both gastric motility and dyspeptic symptoms. However, no improvement of long-term glycaemic control by accelerating disturbed gastric emptying was observed in our symptomatic group of patients with diabetic gastroparesis given prokinetic therapy.

Cisapride prolongs the QT interval and can cause torsade de pointes and ventricular tachycardia. In particular, in interactions with enzyme-inhibiting drugs (e.g. macrolide antibiotics, human immunodeficiency virus protease inhibitors and antifungal imidazoles), cases of cardiac dysrhythmia and death have occurred. Therefore, cisapride was withdrawn from the market and is now no longer available (shortly after the completion of this study). However, the presence of a positive effect of this prokinetic drug on the symptoms of gastroparesis and the lack of an effect on diabetes control is of general interest, showing that, on a long-term basis, gastric emptying and blood glucose control are not closely related.

In conclusion, the acceleration of gastric emptying by cisapride treatment reduces dyspeptic symptoms, but has no effect on glycaemic control, in patients with long-standing diabetic gastroparesis.

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