Impact of Medication Discontinuation on Increased Intestinal FDG Accumulation in Diabetic Patients Treated With Metformin
Abstract
OBJECTIVE. We evaluated the impact of stopping medication for 2 days on reductions in the high intestinal FDG uptake induced by metformin.
SUBJECTS AND METHODS. One hundred thirty-eight diabetic patients were divided into two groups: one in which the antihyperglycemic drug regimen included metformin (group A; n = 107) and one in which the regimen did not include metformin (group B; n = 31). Fifty-two patients without diabetes mellitus served as the control group (group C). Group A was divided into two subgroups: 77 patients (group A1) were taking metformin at the time of FDG PET/CT scans, whereas the remaining 30 patients (group A2) were asked to stop taking metformin for 2 days before PET/CT scans. In addition, 10 diabetic patients underwent two consecutive PET/CT scans before and after the discontinuation of metformin. The intestinal FDG uptake and blood glucose levels were compared among the four groups, as well as before and after the discontinuation of metformin.
RESULTS. The high intestinal FDG uptake in group A1 was significantly reduced after the discontinuation of metformin (p < 0.001 vs group A2); thus, there were no significant differences among group A2, group B, and group C (p = 0.581–0.872). There were also no statistically significant differences in the blood glucose levels among the three groups of diabetic patients (p > 0.9). In 10 patients who underwent serial PET/CT scans, mean intestinal FDG uptake decreased by 64% without significant changes in the blood glucose level. Hidden colorectal malignancies were revealed in two patients after the discontinuation of medication.
CONCLUSION. The discontinuation of metformin for 2 days is feasible for reducing the high intestinal FDG uptake induced by metformin.
Introduction
PET using FDG has become an integral part of the treatment of patients with cancer. FDG is an analog of glucose and presents enhanced specific utilization in most tumors. However, there are numerous false-positive uptakes of FDG that may limit the diagnostic accuracy of FDG PET, including physiologic variants and pathologic uptake unrelated to malignancy (e.g., infection, autoimmune disease, or granulomatous disease) [1–3]. Physiologic FDG uptake in the gastrointestinal tract is also frequently seen, but its mechanism is not fully understood. On the basis of current knowledge, possible causes of physiologic FDG uptake in the intestine include activated smooth muscle and mucosal uptake, FDG secretion, or microbial overgrowth [2–5].
Metformin is a well-established first-line antihyperglycemic drug used in the treatment of patients with type 2 diabetes mellitus (DM) [6–8]. Recently, emerging evidence that metformin influences FDG uptake in the intestine has been reported [9, 10]. Gontier et al. [9] reported that the intestinal FDG uptake induced by metformin is typically intense and diffuse, so it can mask an actual malignant lesion and can lead to false-negative results. For reducing this unwanted intestinal FDG uptake, Ozulker et al. [11] investigated the effect of stopping medication. The increased FDG uptake in the intestines during metformin treatment was significantly decreased after stopping medication for 3 days. Considering the relatively short plasma half-life of metformin after oral administration (range, 4.0–8.7 hours) [12], we investigated the feasibility of medication discontinuation for 2 days on reducing the increased intestinal FDG uptake induced by metformin. In addition, we also investigated changes in blood glucose level after the discontinuation of medication for 2 days with intrasubject (study 1) and intersubject (study 2) analysis.
Subjects and Methods
Patients
This study was approved by the institutional review board of our hospital, and informed written consent was obtained from all patients, who temporarily discontinued antihyperglycemic drug treatment.
Study 1—A total of 138 patients with a history of DM and 52 control subjects without DM were enrolled for the first study. The 138 diabetic patients were divided into two groups: one in which the antihyperglycemic drug regimen included metformin (group A; n = 107) and one in which the regimen did not include metformin (group B; n = 31). Among the metformin-treated patients (group A), 77 patients (group A1) were taking metformin at the time of PET/CT, and 30 patients (group A2) were prospectively asked to stop antihyperglycemic drug treatment including metformin for 2 days just before PET/CT (Fig. 1). Patients receiving insulin treatment (including type 1 DM), patients with an intraabdominal or pelvic malignancy present, patients with a history of inflammatory or infectious bowel disease, and patients with active gastrointestinal symptoms, such as diarrhea or abdominal pain, were excluded.
Study 2—The second study was also prospectively performed in the same patients referred for the investigation of intestinal malignancy. Ten diabetic patients (two men and eight women; mean [± SD] age, 63.0 ± 12.1 years) underwent two consecutive PET/CT scans before and after the discontinuation of antihyperglycemic drug including metformin for 2 days. Six patients were referred for restaging of intraabdominal malignancies, two for evaluating metastasis, and two for screening of occult primary malignancy. The first FDG PET/CT images were acquired during metformin treatment, and the second PET/CT images were acquired just after the discontinuation of metformin for 2 days. The interval between two PET/CT studies was a mean of 5 ± 4 days (range, 2–13 days).
PET/CT
All patients fasted for at least 6 hours before the IV administration of FDG. Patients in groups A1 and B and the patients undergoing the first PET/CT scan in study 2 were asked to stop taking antihyperglycemic drug treatment on the day of the examination. The blood glucose level was measured with a glucometer (Accu-Chek, Roche Diagnostics) before the injection of FDG. Image acquisitions for torso scanning were started at 60 minutes after the injection of 7.4 MBq/kg of body weight. No IV iodinated contrast was administered. Imaging was performed on a PET/CT system (Discovery STE, GE Healthcare). CT images were acquired from the skull base to the upper thigh using the following parameters: peak voltage, 120 kV; tube current, 200 mAs; rotation time, 0.7 second; field of view, 50 cm; length of scan, 40–50 seconds; and slice thickness, 3.75 mm. Immediately after the CT acquisition, the PET data were acquired in the same anatomic locations, with a 15.7-cm axial field of view in the 3D mode at 150 s/bed position. The CT data were used for attenuation correction, and the images were reconstructed using a conventional iterative algorithm (ordered-subsets expectation-maximization). A workstation (Xeleris, GE Healthcare) providing multiplanar reformatted images was used for image display and analysis.
Measurements of Intestinal FDG Uptake
The intestinal FDG uptake was measured using the maximum standardized uptake value (SUVmax) calculated according to the injected dose and the patient's body weight. We recorded the highest SUVmax in each segment of the intestine using the modified method of Gontier et al. [9]. FDG uptake in the duodenum was measured in the third portion of the duodenum, located below the pancreas. FDG uptake in the jejunum was measured in the left central abdomen, close to the midheight of the descending colon. The distal ileal loop connecting to the cecum represented the ileum. The segments from the cecum to the ascending colon, from the hepatic flexure to the transverse colon, from the splenic flexure to the descending colon, and from the sigmoid colon to the rectosigmoid junction represent the ascending colon, transverse colon, descending colon, and sigmoid colon, respectively.
Statistical Analyses
Data analysis was performed using SPSS 12 (SPSS) for Microsoft Windows. In study 1, descriptive statistics and one-way analysis of variance with posthoc analysis, using the Scheffe test, Dunnett's T3 test, or both, were performed to compare the parameters among the four groups, including age, sex, body weight, body mass index, injected FDG activity, period of medication, daily dose of metformin, intestinal FDG uptake, and blood glucose level. In study 2, differences in the intestinal FDG uptake and blood glucose levels of the 10 diabetic patients before and after medication discontinuation were tested with the paired t test, Wilcoxon's signed rank test, or both. A p value less than 0.05 was considered statistically significant.
Results
Intestinal FDG Uptake During Metformin Treatment
The age, sex, body weight, body mass index, injected FDG activity, period of medication, and daily dose of metformin were not significantly different among the groups (p = 0.122–1.000; Table 1). Metformin-treated patients (group A1) had significantly higher FDG uptake in almost all segments of the small and large intestines, except the duodenum, compared with patients who were treated with other antihyperglycemic drugs (group B) and also with patients without DM (group C; Table 2). Comparisons of the mean FDG uptake in the small and large intestines are presented in Figures 2A and 2B. The mean FDG uptake in the small and large intestines was higher in the patients taking antihyperglycemic drugs including metformin (group A1) than in the patients taking other antihyperglycemic drugs (group B) (SUVmax in the small intestine, 3.56 ± 1.94 vs 2.53 ± 0.54 [p < 0.001]; SUVmax in the large intestine, 5.62 ± 3.67 vs 2.96 ± 0.75 [p < 0.001]).
| Characteristic | Group A1: Continued Metformin Therapy | Group A2: Stopped Metformin Therapy | Group B: Not Receiving Metformin Therapy | Group C: Control Subjects | p |
|---|---|---|---|---|---|
| No. of patients | 77 | 30 | 31 | 52 | |
| Age (y) | 63.6 ± 8.2 | 63.1 ± 10.0 | 62.7 ± 11.7 | 58.9 ± 9.9 | NSa |
| Sex (no. of men/no. of women) | 44/33 | 12/18 | 17/14 | 26/26 | NSa |
| Weight (kg) | 62.1 ± 11.0 | 61.1 ± 10.1 | 62.4 ± 9.5 | 62.8 ± 8.2 | NSa |
| Body mass index (kg/m2) | 24.1 ± 3.6 | 24.3 ± 3.1 | 24.1 ± 3.2 | 23.4 ± 2.8 | NSa |
| Injected FDG activity (MBq) | 487 ± 76 | 452 ± 65 | 489 ± 64 | 462 ± 62 | NSa |
| Period of medication (y) | 7.3 ± 6.9 | 5.6 ± 6.6 | 5.7 ± 5.7 | NA | NSb |
| Daily dose of metformin (mg) | 1,080 ± 549 | 1,184 ± 483 | NA | NA | NSc |
Note—Except where noted, data are mean ± SD. NS = not significant, NA = not applicable.
a
Group A1 vs A2 vs B vs C, one-way analysis of variance test with posthoc analysis using Dunnett's T3 test.
b
Group A1 vs A2 vs B, one-way analysis of variance test with posthoc analysis using Dunnett's T3 test.
c
Group A1 vs A2, independent test.
| Group A1: Continued Metformin Therapy | Group A2: Stopped Metformin Therapy | Group B: Not Receiving Metformin Therapy | Group C: Control Subjects | pa | |||
|---|---|---|---|---|---|---|---|
| Intestinal Segment | Group A1 vs Group B | Group A1 vs Group A2 | Group A2 vs Group B | ||||
| Duodenum | 2.12 ± 0.39 | 2.09 ± 0.89 | 2.14 ± 0.29 | 2.00 ± 0.27 | 0.995 | 0.984 | 0.984 |
| Jejunum | 3.95 ± 2.77 | 2.64 ± 0.89 | 2.66 ± 0.80 | 2.14 ± 0.39 | 0.014b | 0.013b | 1.000 |
| Ileum | 4.59 ± 3.63 | 2.64 ± 0.89 | 2.78 ± 0.94 | 2.25 ± 0.48 | 0.006b | 0.001b | 0.976 |
| Ascending colon | 5.28 ± 4.62 | 2.50 ± 0.72 | 2.97 ± 1.14 | 2.48 ± 0.74 | 0.006b | 0.001b | 0.947 |
| Transverse colon | 4.86 ± 3.64 | 2.65 ± 0.90 | 2.61 ± 0.77 | 2.29 ± 0.50 | < 0.001b | < 0.001b | 1.000 |
| Descending colon | 5.57 ± 3.55 | 3.02 ± 1.84 | 2.92 ± 1.15 | 2.39 ± 0.57 | < 0.001b | < 0.001b | 0.999 |
| Sigmoid colon | 6.75 ± 4.15 | 3.54 ± 1.75 | 3.32 ± 1.16 | 2.79 ± 0.66 | < 0.001b | < 0.001b | 0.992 |
Note—Except for p values, data are mean ± SD maximum standardized uptake values.
a
One-way analysis of variance test with posthoc analysis using Scheffe test.
b
A p value of < 0.05 was considered as significant.
Impact of Discontinuing Metformin for 2 Days on Intestinal FDG Uptake
Intestinal FDG uptake was significantly reduced in almost of all segments of the intestines, except for the duodenum, among the patients who stopped taking medication for 2 days (group A2) compared with patients who continued taking metformin (group A1) (Table 2). The distribution and degree of intestinal FDG uptake after metformin discontinuation is very similar to that of the patients taking other antihyperglycemic drugs (group B), as presented in Table 2. Consequently, the mean intestinal FDG uptake in group A2 was markedly lower than that in the patients taking metformin (group A1) (group A1 vs A2: SUVmax in the small intestine, 3.56 ± 1.94 vs 2.40 ± 0.43 [p = 0.003]; SUVmax in the large intestine, 5.62 ± 3.67 vs 2.93 ± 1.04 [p < 0.001]). Also, there were no statistically significant differences in the mean intestinal FDG uptake among groups A2, B, and C (p = 0.581–0.872; Figs. 2A and 2B).
In another prospective study, high intestinal FDG uptake during metformin treatment was significantly diminished after medication discontinuation for 2 days in all patients who underwent two consecutive PET/CT studies (Figs. 3A and 3B). The mean FDG uptake (SUVmax) decreased from 4.86 ± 3.40 to 2.31 ± 0.40 (p = 0.011) in the small intestine and from 10.42 ± 6.45 to 3.30 ± 1.47 (p = 0.001) in the large intestine. Among the 10 enrolled diabetic patients, two patients were successfully diagnosed with colorectal malignancies (one patient had rectal cancer, and another patient had descending colon cancer) on the second PET/CT image performed after stopping metformin treatment for 2 days; the malignancies had previously been obscured by high intestinal FDG uptake during metformin treatment (Table 3).
| Daily Metformin Dose (mg) | Interval Between Scans (d) | PET/CT Findings in Intestine | ||||||
|---|---|---|---|---|---|---|---|---|
| Patient No. | Age (y) | Sex | Period of Medication (y) | Reason for PET/CT | Before Metformin Discontinuation | After Metformin Discontinuation | ||
| 1 | 69 | F | 10 | 2,000 | Restaging gastric cancer | 6 | Diffuse and intense uptake | No significant localized uptake |
| 2 | 62 | M | 15 | 2,000 | Suspicious metastatic lung nodules | 2 | Diffuse and moderate uptake | No significant localized uptake |
| 3 | 45 | F | 3 | 500 | Restaging thyroid cancer | 2 | Diffuse and moderate uptake | No significant localized uptake |
| 4 | 38 | F | 1 | 1,000 | Restaging thyroid cancer | 2 | Diffuse and moderate uptake | No significant localized uptake |
| 5 | 66 | F | 4 | 2,500 | Restaging colon cancer | 3 | Segmental and moderate uptake | No significant localized uptake |
| 6 | 67 | F | 5 | 1,500 | Suspicious rectal cancer | 8 | Diffuse and intense uptake | Localized FDG uptake in rectuma |
| 7 | 76 | F | 8 | 500 | Metastatic adenocarcinoma in left axillary lymph node | 7 | Diffuse and moderate uptake | No significant localized uptake |
| 8 | 71 | F | 6 | 1,000 | Suspicious colon cancer | 13 | Segmental and intense uptake | Localized FDG uptake in descending colona |
| 9 | 64 | F | 1 | 1,500 | Restaging colon cancer | 3 | Diffuse and intense uptake | No significant localized uptake |
| 10 | 72 | M | 5 | 500 | Restaging rectal cancer | 5 | Segmental and intense uptake | No significant localized uptake |
Note—F = female, M = male.
a
Confirmed with histopathology findings after surgery.
Effect of Metformin Discontinuation on Blood Glucose Levels
Even after stopping an antihyperglycemic drug regimen that included metformin for 2 days, blood glucose levels were not significantly changed. In the first study, the mean blood glucose level in group A2 was not significantly different from those in group A1 and group B (group A2, 6.95 mmol/L; group A1, 6.76 mmol/L; and group B, 6.55 mmol/L; p > 0.9). In the second study, the mean blood glucose level was not changed before and after medication discontinuation in the patients who underwent two serial PET/CT scans (6.19 vs 7.01 mmol/L; p = 0.283; Fig. 3C). The blood glucose level in one patient notably increased from 5.44 to 10.89 mmol/L, but a localized hypermetabolic lesion suggesting malignancy in the splenic flexure of the colon was successfully identified on the second FDG PET/CT image (Fig. 4A, 4B, 4C, 4D, 4E, 4F, 4G, 4H).
Discussion
Our study shows that metformin significantly induces high intestinal FDG uptake in diabetic patients and that the transient discontinuation of metformin therapy for 2 days just before a FDG PET/CT scan markedly reduces the increased intestinal FDG uptake without causing an increase in the blood glucose level. Another recent study showed that discontinuing metformin for 3 days is effective in reducing increased FDG uptake in the intestines [11]. Considering the relatively short half-life of metformin (4.0–8.7 hours) [12], we hypothesized that the shorter period (2 days) of medication discontinuation would be effective for reducing increased intestinal FDG activity, and the results were dramatic, as described previously in this article. In our experience, discontinuing medication for 1 or 1.5 days does not sufficiently reduce the increased intestinal FDG uptake associated with metformin treatment in a fair number of patients.
Discontinuing antihyperglycemic drug treatment is a challenge, because optimal glycemic control in diabetic patients is crucial for the performance of FDG PET. A previous study did not address the change in blood glucose level, because those researchers used insulin injection to control hyperglycemia [11]. However, because many institutions do not yet prefer to use insulin to control hyperglycemia before FDG PET/CT scans, we also investigated the feasibility of medication discontinuation in terms of blood glucose level. There have been remarkably few reports on the short-term glycemic control of metformin. Eriksson et al. [13] reported that fasting plasma glucose levels began to decrease after treatment for 14 days. Our study also revealed that transient discontinuation of medication for 2 days did not lead to hyperglycemia or withdrawal symptoms. The discontinuation of medication for 2 days was appropriate and feasible for reducing high intestinal FDG uptake, in consideration of the biologic half-life and antihyperglycemic effects of metformin.
High intestinal FDG uptake during metformin treatment was observed in almost of all the intestinal segments, with predominance in the large intestine, a lesser presence in the small intestine, and no presence in the duodenum in the present study. These results are comparable to those of previous studies [9, 11]. Variable patterns of intestinal FDG uptake were present in the patients receiving antihyperglycemic drugs including metformin, with particularly diffuse, multifocal, or nodular variations in the segments of the intestine, as shown in Figure 4A. According to previous studies, nodular or focal FDG uptake is highly associated with cancerous or precancerous lesions, and segmental high FDG uptake may imply inflammation, whereas diffuse FDG uptake is often associated with normal colonoscopy findings [5, 14–18]. Because of the variably increased FDG intestinal uptake induced by metformin, these findings can lead to possible false-positive or false-negative results in the evaluation of colorectal cancer.
The known mechanisms of metformin in the intestine are a decrease in glucose absorption [19–23] and an increase in glucose utilization, mainly in the small intestine [24–28]. FDG reaches the intestines possibly through swallowing [2] and through the bloodstream. The intestinal FDG uptake induced by metformin is mainly from the bloodstream, because swallowed FDG could not easily reach the colon within an hour after FDG injection. Intestinal glucose transport from the intestinal lumen to the bloodstream via the enterocyte is performed both actively, by sodium glucose cotransporter 1, glucose transporter (GLUT) 2, and GLUT5, and passively, through the dilated paracellular tight junctions [29, 30]. However, intestinal glucose transport directed in the opposite manner, from the circulation to the intestinal epithelium, is not well known yet. Wright et al. [30] suggested that the reversibility of GLUT2 in the basolateral membrane would account for the ability of the enterocyte to be fueled by the blood glucose.
Metformin also activates adenosine monophosphate–activated kinase, an intracellular energy sensor, resulting in the up-regulation of nonenergy requiring glucose uptake by GLUT2 in the enterocyte [31]. These results were observed in the small intestine, but not in the large intestine, in animal studies [26–28]. In our human study, however, the intestinal FDG uptake during metformin treatment is predominantly found in the large intestine, rather than in the small intestine. These results were in agreement with those from another human study using FDG PET [9, 11]. These data suggest the possibility that the large intestine as well as the small intestine could be activated sites induced by metformin treatment in humans.
Another possible mechanism of colonic FDG uptake was also postulated by Kim et al. [5]. They found that 18F radioactivity in the stool was 3.8–54.3% of that in the plasma, suggesting that FDG excretion or leakage into the lumen could be the source of FDG accumulation in the intestine. For this reason, metformin could not be excluded as a factor that enhances the excretion of FDG from the bloodstream into the intestinal lumen. Further research is needed to elucidate the mechanisms of enhanced glucose utilization or transportation in the intestines induced by metformin.
The first limitation of this study is the combined use of antihyperglycemic drugs. A total of 70 (65%) of 108 diabetic patients taking various antihyperglycemic drugs and 61 (79%) of 77 patients taking metformin were prescribed a combination of antihyperglycemic drugs. Ideally, the effect of discontinuing medication would have been evaluated under the selective discontinuation of metformin. Because almost all of the patients could not recognize metformin from their medications, they were asked to stop taking all antihyperglycemic drugs, including metformin. Although the blood glucose levels were not elevated after the cessation of all antihyperglycemic drugs, if possible, a selective discontinuation of metformin would be a more proper preparation for these patients.
The second limitation is the side effects associated with metformin. Among the major adverse effects of metformin are gastrointestinal symptoms, such as anorexia, nausea, abdominal pain, and diarrhea [24]. The probable causes of gastrointestinal intolerance are a high concentration of metformin in the upper gastrointestinal tract, which leads to local irritation in the enterocyte and bile salt malabsorption, which increases fluid retention in the large intestine [7]. Although patients with active gastrointestinal symptoms were excluded from our study, this could also be a cause of the increased intestinal FDG uptake in patients with subclinical gastrointestinal symptoms during metformin treatment.
The last limitation is that the repetitive PET scans were performed in a small subset of patients. Although the diagnosis changed for 20% of the patients in this group, further studies of larger series of patients are needed to establish the diagnostic impact of this method.
Metformin, an antihyperglycemic drug that is widely used to treat patients with type 2 DM, is considered as a significant factor influencing increased FDG uptake in the intestine, predominantly in the colon. Discontinuing metformin therapy for 2 days markedly reduced the increased intestinal FDG uptake induced by metformin but did not lead to a significant increase in blood glucose levels. This is an effective and feasible preparation for more accurate FDG PET/CT studies for the investigation of intestinal malignancies in diabetic patients treated with metformin.
Footnote
Address correspondence to H. C. Song ([email protected]).
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Submitted: March 23, 2010
Accepted: May 20, 2010
First published: November 23, 2012
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