Cimetidine reduces weight and improves metabolic control in ... - Nature

International Journal of Obesity (1998) 22, 1041±1045 ß 1998 Stockton Press All rights reserved 0307±0565/98 $12.00 http://www.stockton-press.co.uk/ijo

Cimetidine reduces weight and improves metabolic control in overweight patients with Type 2 diabetes G Stùa-Birketvedt*1, PN Paus3, R Ganss3, OC Ingebretsen2 and J Florholmen1 1

Laboratory of Gastroenterology, Institute of Clinical Medicine, University of Tromsù, Tromsù; 2Biochemical Department, University Hospital of Tromsù, Tromsù; and 3Medical Department, Central Hospital of Akershus, Nordbyhagen, Norway

OBJECTIVE: To investigate the weight-reducing effect of cimetidine in overweight patients with Type 2 diabetes. DESIGN: A 12-week clinical intervention study of 400 mg cimetidine prescribed three times daily in a randomised, double-blind, placebo-controlled design. SUBJECTS: Forty-three overweight patients with Type 2 diabetes (age 18 ± 65 y, body mass index (BMI) 27.2 ± 48.2 kg=m2). MEASUREMENTS: Body weight, BMI, body fat, waist and hip circumference, waist=hip ratio, blood pressure, fasting blood glucose, HbA1c, plasma concentrations of insulin, insulin=glucose ratio and lipids at the start and after 12 weeks, and daily recordings of appetite. RESULTS: Subjects given cimetidine (n 19) and placebo (n 24) lost 5.0 2.2 kg (mean s.d.) and 1.3 1.1 kg, respectively. Signi®cant reductions were observed in appetite, body fat (29.9 6.6% to 25.3 7.4%), waist circumference (111.5 10.3 cm to 107.4 10.6 cm), waist=hip ratio (0.96 0.08 to 0.94 0.08), and systolic and diastolic blood pressure (reductions of 6.9 11.4 mm Hg and 6.0 6.6 mm Hg, respectively) in cimetidine group only. Signi®cant decreases in fasting concentrations of blood glucose, HbA1c, plasma insulin, insulin=glucose ratio, plasma triglycerides and a signi®cant increase in plasma high-density lipoprotein cholesterol were observed in the cimetidine group only. CONCLUSIONS: Cimetidine reduces appetite and body weight, and improves metabolic control in overweight subjects with Type 2 diabetes. Keywords: H2-receptor antagonist; hyperlipidemia; insulin resistance; obesity; weight reduction

Introduction According to previous reports, there is a high prevalence of Type 2 diabetes among obese subjects.1,2 Hyperinsulinism and insulin resistance are characteristic features of both Type 2 diabetes and obesity (for review, see Ref. 3). In obese subjects the insulin resistance is highly correlated to the mass of visceral fat.4,5 However, it remains controversial whether obesity is the major and=or an independent contributor to the insulin resistance in Type 2 diabetes.6,7 It is well recognized that weight reduction is associated with bene®cial effects on metabolic control.8 A modest weight reduction may strongly improve the metabolic pro®le.9 Weight reduction induces improved glycemic control, reduced hepatic glucose output, increased insulin action in the liver and the peripheral tissue, and improved insulin secretion.10 However, a weight reduction to normalcy elicits a complete normalization of the peripheral insulin action in only few patients.10 This implies a

* Correspondence: Dr Grethe Stùa-Birketvedt, University of Pennsylvania, 3600 Market Street, Suite 732, 19104 PA, USA. Received 11 September 1997; revised 21 May 1998; accepted 26 May 1998

heterogeneous pathogenesis, with interactions at least between visceral obesity and genetic factors.11 We have previously reported that the H2-receptor antagonist, cimetidine, reduces weight in healthy overweight subjects.12 The mechanism of this effect is unknown. In rats, H2-receptor antagonists reduce appetite and weight gain by a non-gastric acid related mechanism.13 We have shown that cholecystokinin (CCK) is a candidate mediator of this effect on satiety.14 The objective of this study was to investigate the effect of cimetidine on body weight and metabolic pro®le in overweight patients with Type 2 diabetes in a randomized, double blind, placebo-controlled study.

Materials and methods Subjects

Sixty-two patients with Type 2 diabetes were recruited from the outpatient ®les of two Norwegian hospitals. The inclusion criteria were age 18±65 y and body mass index (BMI) > 25 kg=m2. Patients with serious cardial, renal or hepatic diseases were excluded. Patients treated with antacids, gastric acid

Cimetidine reduces weight G Stùa-Birketvedt et al

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antisecretory agents, insulin or corticosteroids were also excluded.

Ethics

The study was conducted according to the Helsinki declarations and with the approval of the Ethical Committee of The Health Region V, Norway.

Study design

The patients were randomized into two groups according to BMI: the ®rst group, cimetidine (400 mg): (Nycomed, Oslo, Norway) and the second group placebo (identical in taste and appearance as cimetidine) (Pharmaceutical Department, University Hospital of Tromsù, Tromsù, Norway), prescribed three times daily, 30 min before meals. Patients were told to follow their own diet or eat less if not hungry, to perform their regular exercise program and not change their smoking habits during the study. The cimetidine dose was twice as high as that used in the former study12 as it seemed to induce a stronger feeling of satiety (unpublished observation). This dose also increases the postprandial CCK response.14 At the start, a physical examination was performed, including sitting blood pressure, height, weight, abdominal circumference (umbilical level), and hip circumference (tuberculum majus). BMI was calculated as kg=m2. Body fat % was measured with near infrared technique (Futrex 5000: Futrex Corp., Gaithersburg, MA) as previously described.15 These procedures were repeated at the end of the study. Duration of the study was 12 weeks, with clinic visits scheduled at the same time each week. Subjects were weighed each week, side effects were recorded and the average degree of hunger before breakfast, lunch and supper during the previous week was recorded on a 10 cm visual analogue scale. Compliance with the drug treatment was checked by the returned dose packets; 80% compliance was considered acceptable.

Laboratory tests

Blood samples were drawn after an overnight fast at the start and after 12 weeks. The blood samples were withdrawn into vacutainer tubes containing EDTA (1 mg=ml, ®nal concentration), and centrifuged at 1000 g for 10 min at 4 C. Blood glucose was measured by a glucose analyzer (Model 2300 STAT, Yellow Springs Instrument Co., Inc., Yellow Springs, OH). The rest of the plasma was immediately frozen (727 C) and stored for later measurements. HbA1c was measured by the Diamat TM system from Bio-Rad Laboratories GmbH (Munich, Germany). Insulin was measured by a radioimmunoassay (RIA) method.16 Plasma concentrations of cholesterol and triglycerides were measured using Hitachi 917 Automatic Analyzer from Boehringer Mannheim (Mannheim, Germany). Reagents, calibrators and controls were purchased from the manufacturer. High-density lipoprotein (HDL) cholesterol concentrations in plasma were measured after preparation of HDL according to the method described by Burstein et al.17

Statistical analysis

Statistical analysis was performed in those patients who ful®lled the study according to the protocol. Differences in consecutive weight changes between the cimetidine and placebo group were evaluated using repeated measures multivariate analysis of variance (RM MANOVA). Loss in appetite was de®ned as a decrease of > 10% in the mean visual analogue scale (VAS) during treatment of an individual patient. Signi®cance between the treatment groups was tested by comparing the fraction of patients with loss in appetite in each group by using Fisher-Irwin exact test. In the remaining parameters, the signi®cance was tested for within-group comparison by paired Student's t test, and for between-group comparison by unpaired t tests. The signi®cance level was set at P < 0.05.

Results Subjects

Of the 62 subjects (31 in each group) randomized to active and placebo treatment, 60 subjects (31=29, in the cimetidine and placebo group, respectively) entered the study, that is, two patients were lost at inclusion due to reasons unknown (Table 1). Five of the patients were not included due to sudden events between the randomization and the start. Twelve subjects were excluded, four subjects due to side effects (one placebo subject with diarrhoea and three cimetidine subjects, one each with arthralgia, abdominal pain and vomiting). After termination of the treatment all subjects recovered completely. In the remaining patients the medication was well tolerated. The remaining 43 subjects (19=24), 14 women and 29 men, completed the study according to the protocol. Table 1 Patients included and excluded Cimetidine Placebo Total Randomized Failed to initiate the study Lack of ful®lling the inclusion criteria Initiated the study Excluded due to Side effects Withdrawals not related to treatment Changes in smoking habits Immobilization (bone fracture) Use of antacids Start of peroral antidiabetic agents Total of excluded patients Total of evaluable patients

31 0 4 27

31 2 1 28

62 2 5 55

3 3

1 1

4 4

1 1 8 19

1 1 4 24

1 1 1 1 12 43


Characteristics of patients

Characteristics of the patients are shown in Table 2. At the start of the study there were no signi®cant differences between age, gender, duration of Type 2 diabetes, patients on peroral antidiabetic medication, body weight, BMI, fat %, waist and hip circumferences or waist=hip ratio (WHR). During the ®rst week of treatment, appetite measured by VAS was signi®cantly reduced in the cimetidine group and remained so throughout the study. No changes in appetite were observed in the placebo group (Figure 1). There was a signi®cant weight loss in the cimetidine group (5.0 2.1 kg (mean s.d.)) and in the placebo group (1.3 1.1 kg) (Table 3). The weight loss was signi®cantly greater in the cimetidine group than in the placebo group (Figure 2). BMI, fat %, waist circumference and WHR were reduced in the cimetidine group. In the placebo group, these variables were only signi®cantly changed for BMI (Table 3). The weight loss consisted of 89% fat in the cimetidine group and 85% fat in the placebo group. There was a signi®cant reduction in the systolic (6.9 11.4 mm Hg) and diastolic (6.0 6.6 mm Hg) blood pressure in the cimetidine group only (Table 3).

plasma concentrations of insulin and insulin=glucose ratio (Table 4). In the cimetidine group there were signi®cant reductions in the levels of HbA1c, insulin and insulin=glucose ratio, but no signi®cant changes in the placebo group were observed. There were no signi®cant differences in baseline plasma levels of cholesterol, triglycerides and HDL cholesterol between the two groups (Table 4). During treatment there were signi®cant reductions in the plasma levels of triglycerides and signi®cant increases in the plasma levels of HDL cholesterol in the cimetidine group, but no signi®cant changes in these variables in the placebo group were observed. Signi®cant changes in the plasma concentrations of cholesterol were not seen in any group.

Biochemical parameters

There were no signi®cant differences between groups in baseline values of fasting blood glucose and HbA1c,

Table 2 Characteristics of patients ful®lling the inclusion and exclusion criteria

Female=male ratio Age (y) Duration of the disease (y) Patients on peroral antidiabetics Body weight BMI (kg=m2) Fat % Waist circumference (cm) Hip circumference (cm) Waist=hip ratio

Cimetidine

Placebo

6=13 46.3 8.0 2.5 1.8 7 103.9 13.8 33.8 3.4 29.9 6.6 111.5 10.3 116.2 8.1 0.96 0.08

8=16 49.1 7.2 4.0 3.5 14 102.0 18.3 34.0 4.2 30.6 7.2 112.7 12.0 116.3 11.9 0.98 0.08

Mean s.d. or actual number. BMI body mass index.

Figure 1 Appetite registrations (recorded on a 10 cm visual analogue scale (VAS)) during a 12 week treatment with cimetidine (n 19) and placebo (n 24) in overweight patients with Type 2 diabetes. Statistical analysis by Fisher-Irvine exact test. The changes from initial values were signi®cant (P < 0.05) in the cimetidine group. For further details, see text.

Table 3 Characteristics of patients Cimetidine

Weight (kg) BMI (kg=m2) Fat % Waist circumference (cm) Hip circumference (cm) Waist=hip ratio Systolic BP (mm Hg) Diastolic BP (mm Hg)

Placebo

Start

End

Start

End

103.9 13.8 33.8 3.4 29.9 6.6 111.5 10.3 116.2 8.1 0.96 0.08 149 13 94 6

98.9 13.0* 32.2 3.2* 25.3 7.2* 107.4 10.6* 114.0 8.6 0.94 0.08* 142 11* 88 8*

102.0 18.3 34.0 4.2 30.6 7.2 112.7 12.0 116.3 11.9 0.98 0.08 148 21 90 8

100.7 18.7* 33.6 4.0* 29.8 6.7 111.2 13.0 112.5 11.8 0.99 0.08 141 12 87 7

Mean s.d. Statistical analysis by paired t test. * indicates signi®cant difference from start (P < 0.05). BMI body mass index; BP blood pressure.

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Discussion This study shows that cimetidine reduces body weight and appetite in overweight patients with Type 2 diabetes. This agrees with previous reports in healthy overweight subjects12 and in rats.13 The mechanism of this effect of the H2-receptor antagonist is not known, although we have previously reported that cimetidine increases the basal and postprandial plasma level of CCK,14 and CCK may mediate satiety signals from the gut to the brain.18 The cimetidine-induced weight reduction during the 12 week period was 5.1 kg, which represents a 5% reduction in body weight. In the previous study of healthy overweight subjects,12 the weight reduction was 9.5 kg, which represents a 12% weight reduction during an eight week combined treatment of cimetidine and diet. Patients in the present study were already restricted to a diabetic diet, which may

explain their smaller weight loss. In this study, the weight reduction was 0.4 kg=week and consisted of 89% body fat, a rate considered optimal in preserving the lean body mass19 and to prevent an undesirable weight cycling.20 Finally, in this and in the previously reported study,12 the reduction of appetite and weight was not attenuated during the observation period. Therefore, cimetidine appears to be a promising supplement to diet and exercise, in the long term treatment of obesity. The cimetidine-induced weight reduction was associated with improved glycemic control, that is, reduction of fasting concentrations of blood glucose and HbA1c, plasma insulin and the insulin=glucose ratio. This improvement was obtained with only a 5% reduction in body weight and without achieving the ideal body weight. This is in agreement with other studies where only a modest weight reduction improved glycemic control and insulin sensitivity.8,21 Moreover, the plasma concentrations of triglycerides and HDL cholesterol were both elevated (out of the normal range) at the start of the study. Obesity and Type 2 diabetes are both part of the metabolic syndrome where hypertriglyceridemia, low HDL cholesterol and increased free fatty acids are the characteristic metabolic pro®le.3 In this study, the plasma concentrations of triglyceride and HDL cholesterol changed towards normalcy. This agrees with other reports where a modest weight reduction also improved the blood lipid pro®le.8 The plasma concentration of cholesterol, however, was in the normal range at the start of the study and no signi®cant change in this variable was observed during the weight reduction.

Conclusion

Figure 2 Weight loss during a 12 week treatment with active (n 19) and placebo (n 24) in overweight patients with Type 2 diabetes. Statistical analysis by repeated measures multivariate analysis of variance. * Indicates signi®cant difference between the two groups (P < 0.05). For further details, see text.

During the study, there were reductions in the waist circumference and the WHR suggesting a reduction in visceral fat22 and in blood pressure. Altogether, our study shows that cimetidine reduces appetite and body weight, and improves metabolic control in overweight patients with Type 2 diabetes. This should indeed reduce the risk of cardiovascular disease and contri-

Table 4 Responses to biochemical parameters Cimetidine

Blood glucose (mmol=l) HbA1c (%) Insuln (mU=ml) Insuliin=glucose ratio Plasma cholesterol (mmol=l) Plasma triglycerides (mmol=l) Plasma HDL cholesterol (mmol=l)

Placebo

Start

End

Start

End

9.0 2.9 7.2 1.2 14.4 9.1 1.7 1.0 6.1 0.9 2.8 1.4 0.84 0.3

7.7 1.6* 6.7 1.0* 5.2 3.4* 0.7 0.4* 6.0 1.0 2.3 1.2* 0.94 0.2*

9.5 2.9 7.6 1.5 12.7 9.8 1.3 1.1 6.2 1.1 2.9 2.4 0.94 0.3

9.0 2.4 7.3 1.3 16.0 8.7 2.2 2.4 5.9 1.0 2.9 2.6 0.88 0.2

Mean s.d. Statistical analysis by paired t test. * indicates signi®cant difference from start (P < 0.05). HDL high-density lipoprotein.


bute to positive health bene®ts. However, it remains to be proved that the H2-receptor antagonist has long term effects beyond three months. As reported by others,8 modest weight reduction caused substantial improvements in diabetic control, in spite of the fact that most of the patients remained obese. Fasting plasma concentrations of insulin and plasma insulin=blood glucose ratio were normalized in almost all the patients in the cimetidine group. The insulin resistance appears at a BMI > 32 kg=m2.23 In the cimetidine group, the improvement in the insulin sensitivity, measured indirectly as the plasma insulin= blood glucose ratio, is probably at least partly due to weight reduction. In conclusion, cimetidine induces reductions in appetite and body weight and improves diabetic control, insulin sensitivity and blood lipids in overweight subjects with Type 2 diabetes. These effects are probably a result of weight reduction. Acknowledgements

We appreciate the superb technical assistance of Tone IndergaÊrd, Astrid Augdal, Ingrid Christiansen and The Clinical Research Laboratorium, University Hospital of Tromsù. The present work was supported by The Norwegian Research Council for Science and the Humanities, Norsk RaÊd til Bekjempelse av Fordùyelsessykdommer, The Helga Sembs Fund, The Novo Nordic Foundation and The Norwegian Diabetes Association. References

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