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Evaluation of carbohydrate restriction as primary treatment for post-gastric bypass hypoglycemia
Surgery for Obesity and Related Diseases ] (2016) 00–00
Original article
Evaluation of carbohydrate restriction as primary treatment for post-gastric bypass hypoglycemia Jorick van Meijeren, BSca,⁎, Ilse Timmer, BSca, Hans Brandts, MScb, Ignace Janssen, MDc, Hans de Boer, MD, PhDa a
Department of Internal Medicine, Rijnstate Hospital, Arnhem, the Netherlands Department of Clinical Nutrition, Rijnstate Hospital, Arnhem, the Netherlands c Department of Surgery, Rijnstate Hospital, Arnhem, the Netherlands Received September 6, 2016; accepted November 2, 2016
b
Abstract
Background: Up to 15% of patients who have undergone Roux-en-Y gastric bypass (RYGB) surgery may eventually develop symptoms of hypoglycemia. Objectives: To evaluate the daily life efficacy of a carbohydrate (carb)-restricted dietary advice (CRD) of 6 meals per day with a 30 g carb maximum per meal in patients with documented postRYGB hypoglycemia. Setting: Teaching hospital, the Netherlands. Methods: Frequency and severity of hypoglycemic events before and after CRD were assessed retrospectively in 41 patients with documented post-RYGB hypoglycemia, based on medical records and telephone questionnaires. Hypoglycemia was defined as a blood glucose level o3.0 mmol/L. Results are expressed as mean values ⫾ standard error or median and range. Results: CRD decreased the number of hypoglycemic events per month from 17.1 (1.5–180) to 2.5 (0–180), i.e., a decline of 85% (P o .001). The lowest blood glucose measured during a hypoglycemic event increased from 2.1 ⫾ .4 to 2.6 ⫾ .2 mmol/L (P ¼ .004). The number of patients who had required outside help in the treatment of hypoglycemia, decreased from 23 to 6 (P o .001). In 14 patients (34.1%) the diet-induced reduction of hypoglycemia was insufficient and required the start of insulin suppressive therapy. Conclusion: A CRD, consisting of 6 meals per day with up to 30 g carbs each, is an effective treatment of post-RYGB hypoglycemia in the majority of patients. Additional medication is needed in about a third of patients. (Surg Obes Relat Dis 2016;]:00–00.) r 2016 American Society for Metabolic and Bariatric Surgery. All rights reserved.
Keywords:
Roux-en-Y gastric bypass; Hypoglycemia; Carbohydrate restriction; Daily life efficacy
Bariatric surgery is a very successful treatment for morbid obesity, with sustained weight loss in the large majority of patients [1]. Roux-en-Y gastric bypass (RYGB) surgery is the most commonly performed procedure, accounting for about 45% of all bariatric procedures [2]. * Correspondence: Jorick van Meijeren, Department of Internal Medicine, Rijnstate Hospital, Wagnerlaan 55, 6800 TA Arnhem, the Netherlands. E-mail: [email protected]
Despite its well-established clinical benefits, RYGB may also have adverse effects. Post-RYGB hypoglycemia, also known as “late dumping,” is one of the late complications that has been recognized increasingly in recent years [3]. Symptoms include attacks of dizziness, perspiration, confusion, and even collapse [4]. The prevalence of postRYGB hypoglycemia is not exactly known. Initial research, based on hospitalization rates, led to an estimated prevalence of .1%–.2% [5]. However, an analysis based on the
http://dx.doi.org/10.1016/j.soard.2016.11.004 1550-7289/r 2016 American Society for Metabolic and Bariatric Surgery. All rights reserved.
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J. van Meijeren et al. / Surgery for Obesity and Related Diseases ] (2016) 00–00
presence of Whipple’s triad, i.e., clinical signs of hypoglycemia in combination with a blood glucose level o3.0 mmol/L and resolution of the symptoms after glucose administration, found an incidence of 18% in a cohort of 351 patients [6,7]. In a questionnaire-based study, 34% of patients (n = 450) reported symptoms of hypoglycemia [8]. The most commonly proposed mechanism of post-RYGB hypoglycemia is hyperinsulinism, caused by pancreatic ß-cell hypertrophy and/or hyperplasia (nesidioblastosis) or by excessive glucagon-like peptide 1 (GLP-1) mediated ß-cell stimulation. Although nesidioblastosis has been shown to play a role in some cases it is generally considered to be very rare [9,10]. Nesidioblastosis is characterized by autonomic hypersecretion of insulin and should be considered in patients with fasting hyperinsulinemia [7]. Usually, however, patients present with symptoms of postprandial hypoglycemia. This has been attributed to food activated GLP-1 release, stimulating insulin secretion by its binding to specific ß-cell receptors [11]. It has been established that postprandial hypoglycemia in patients after RYGB can be prevented by administration of a GLP-1 receptor antagonist [12]. Other medical options are the use of Acarbose, Octreotide or Diazoxide. Reversal of RYGB and partial pancreas resection have been suggested as last resort options; with these procedures, hypoglycemia disappeared in 13/17 (76%) and 34/51 (67%) of cases, respectively [13]. Carbohydrate (carb) restriction appears to be a logical first step in the treatment of postprandial hypoglycemia after RYGB because it is likely to reduce postprandial insulin release [7]. The efficacy of extreme carb-restricted meals (0 and 2 g per meal) has been successfully demonstrated in clinical settings [14,15]. However, in daily life such diets are hardly feasible. Botros et al. evaluated the effects of a more moderate 30 g carb-restricted meal [16]. During a 6-hour in-hospital observation period under resting conditions, none of the patients developed hypoglycemic symptoms or glucose levels o3.0 mmol/L. Based on these findings, we developed a carb-restricted dietary advice (CRD) consisting of 6 meals per day with a 30 g carb maximum per meal. In the present study, the daily life efficacy of this CRD has been evaluated as a first-line treatment for patients with documented post-RYGB hypoglycemia.
Methods This is a single center, retrospective, per protocol analysis of the efficacy of a CRD for the treatment of patients presenting with symptoms of hypoglycemia after RYGB. Our hospital is a referral center for bariatric surgery where 4 surgeons perform about 1200 bariatric procedures per year. Postoperatively, all patients are advised to eat small, frequent meals throughout the day and to eat slowly and thoroughly. The study was performed according to the regulations of the local ethical committee.
Patients Eighty patients with symptoms suggestive of post-RYGB hypoglycemia (i.e., postprandial attacks of lightheadedness, perspiration, trembling, confusion, and even collapse, disappearing after ingestion of carbohydrates) were referred to the dietician for CRD, either by a surgeon or an internist. For inclusion in this study, additional criteria were set: 1) symptoms of hypoglycemia developed after RYGB in the absence of antidiabetic medication; 2) documented home glucose levels o3.0 mmol/L during an event with symptoms suggestive of hypoglycemia; 3) postoperative remission of diabetes mellitus (fasting glucose o6.0 mmol/L, and HbA1C o42 mmol/mol) with all previous antidiabetic medication discontinued for at least 6 months; 4) baseline screening performed by an endocrinologist; 5) understanding of the Dutch language; and 6) implementation of CRD for a period of at least 1 month without concomitant use of Acarbose, insulin suppressive medication, GLP-1 antagonists, or any other medication known to have an effect on blood glucose levels. Methods Patients reporting hypoglycemic symptoms were usually referred to the internist for evaluation and treatment. This consultation included recording of gender, age, medical history, medication, body mass index (BMI), lowest measured home glucose level, frequency at which hypoglycemic symptoms occurred, and the number of times outside help was required for treatment. A fasting blood sample was obtained as part of standard procedures for measurement of plasma glucose, HbA1C, insulin, C-peptide, glucagon, and cortisol levels. Patients with documented blood glucose levels o3.0 mmol/L received oral instructions for CRD by the dietician, in person or by telephone and additionally in print or by email. Patients were instructed to use a diet consisting of 6 small meals per day with a 30 g carb maximum per meal. Continuous glucose monitoring for 5 consecutive days (CGM, Freestyle Navigator II, Abbott, Hoofddorp, the Netherlands) was used to evaluate the efficacy of CRD in a subset of patients, usually those who still reported hypoglycemic events after CRD. The results of CGM were reviewed by the dietician and endocrinologist, and discussed with the patients. If diet-induced reduction of hypoglycemia was insufficient, medical treatment was added, either Diazoxide or Octreotide or a combination of both. Data collection Medical records were examined to collect the data about frequency and severity of hypoglycemia before CRD. The actual situation after CRD was assessed by telephone questionnaire. Frequency of hypoglycemia was recorded
Carb-restricted diet for post-RYGB-hypoglycemia / Surgery for Obesity and Related Diseases ] (2016) 00–00
as the number of times per month patients subjectively experienced symptoms of hypoglycemia that disappeared after carb ingestion. Severity of hypoglycemia was evaluated by the lowest measured blood glucose during a hypoglycemic event, and by the number of patients that needed outside help for the treatment of hypoglycemia [17]. Patients were also asked to rate their quality of life (QoL) in relation to hypoglycemic symptoms on a 1 to 10 scale, before and after starting CRD. Dietary adherence was quantified by a self-reported measure on a 1 to 10 scale to assess the extent to which implementation of the CRD corresponded with the dietician’s recommendations. Dichotomous questions were asked about whether the patients experienced hypoglycemia postprandially, postexercise, and nocturnally, before and after CRD. Patient understanding about hypoglycemia was addressed by inquiring whether they could point out the precipitating factor that led to a hypoglycemic event and whether this insight had improved after implementation of the CRD. Statistical analysis Results are expressed as mean ⫾ standard error for normally distributed data and as median and range if data were not normally distributed. Testing for significant differences was performed by paired t tests, or by Wilcoxon matched-pairs signed-ranks test, when appropriate. Furthermore, Pearson correlation coefficient was used to examine the relation between frequency and severity of hypoglycemia and self-reported dietary adherence. Finally, CRD induced changes of the various types of hypoglycemia were tested for significance with a McNemar’s χ2 test. Differences were considered to be statistically significant if P o .05. For calculations, software package SPSS version 23 for Macintosh was used (IBM Corp., Armonk, NY). Results
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Patient characteristics Patient baseline characteristics are summarized in Table 1. The patient population included 7 males and 34 females, 45.7 ⫾ 1.5 years old. Their mean preoperative weight was 128.4 ⫾ 3.2 kg with a BMI of 43.7 ⫾ .9 kg/m2. The first hypoglycemic symptoms occurred 19.8 ⫾ 2.8 months after surgery. At that time weight had decreased to 84.5 ⫾ 3.3 kg, a total weight loss of 34.2 ⫾ 1.8%, and BMI to 28.9 ⫾ 1.0 kg/m2. Excess weight loss was 74.1 ⫾ 4.4%. Eight patients had type 2 diabetes (T2D) at time of surgery. Antidiabetic medication had been discontinued in all patients within 6 months after surgery (mean 1.9 ⫾ .9 months). All patients had a complete remission of T2D, confirmed by a normalization of their fasting glucose and HbA1C levels. Fasting blood glucose was 4.8 ⫾ .1 mmol/L (range 3.9–5.8 mmol/L) and mean HbA1C was 33.6 ⫾ .7 mmol/mol (range 25–40 mmol/mol) in absence of antidiabetic medication. In patients with prior T2D, the first hypoglycemic symptoms occurred 15.1 ⫾ 4.2 months after the discontinuation of antidiabetic medication (range 3–41 months). The interval between the day of surgery and the onset of hypoglycemic symptoms was comparable for patients with and without a history of T2D (P ¼ .29). The diagnostic delay, i.e., the mean time elapsing between the onset of symptoms and the first internal medicine consultation was 7.4 ⫾ 1.4 months. Laboratory results generally fell within the normal range (Table 1). Only C-peptide tended to be slightly higher than normal (P ¼ .007). Patients started receiving dietary instructions for CRD, 16.9 ⫾ 1.6 months before the current evaluation (range 3–40 months). In this period between the first dietary instruction and the current evaluation, weight increased by 2.9 ⫾ 1.4 kg, with a rise in BMI to 29.9 ⫾ .8 kg/m2 (P ¼ .023). Impact of dietary advice
Patient selection Patient selection is illustrated in Fig. 1. After a first selection based on predefined inclusion and exclusion criteria, 37 out of 80 patients were excluded. An additional 2 patients were excluded because they could not be contacted by telephone, despite repeated efforts. None of the included patients declined answering the questionnaire.
Changes in frequency, timing, and severity of hypoglycemic events after start of the CRD are summarized in Table 2. CRD decreased the frequency of hypoglycemia by 85% (P o .001). At baseline, patients reported a median of 17.1 (1.5–180) hypoglycemic events per month and this decreased to 2.5 (0–180) times per month after dietary instruction. The decline in hypoglycemic events was not
Fig. 1. Patient selection procedure.
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Table 1 General patient characteristics Mean ⫾ SE Range Male/female ratio Age (years) BMI before RYGB (kg/m2) BMI at first hypoglycemic event (kg/m2) BMI at start of present study (kg/m2) Excess weight loss (%) First symptoms after surgery (months) Diagnostic delay (months) Instruction of CRD (months before study) Preexistent T2D (number of patients) HbA1C (mmol/mol) Fasting glucose (mmol/L) Fasting insulin (mU/L) Fasting C-peptide (mmol/L) Fasting glucagon (pmol/L) Cortisol (pmol/L)
Normal range
7/34 45.7 ⫾ 1.5 43.7 ⫾ .9 28.9 ⫾ 1.0
27–62 24.5–58.1 21.5–41
29.9 ⫾ .8
22.2–45.2
74.1 ⫾ 4.4 19.8 ⫾ 2.8
0–127 3–90
7.4 ⫾ 1.4 16.9 ⫾ 1.6
0–30 3–40
9 33.6 ⫾ .7 4.8 ⫾ .1 8.1 ⫾ 1.0 0.93 ⫾ .12 33.6 ⫾ 3.2 458 ⫾ 41
25–40 3.9–5.8 2–28 0.30–4.30 7.5–59.7 209–1096
20–42 3.5–6.0 0–29 0.26–0.62 o 60 171–536
BMI ¼ body mass index; C-peptide ¼ connecting peptide; CRD ¼ carbohydrate restricted dietary advice; HbA1C ¼ hemoglobin A1c; RYGB ¼ Roux-en-Y gastric bypass; SE ¼ standard error; T2D ¼ type 2 diabetes.
related to the duration of CRD implementation (r ¼ -0.25, P ¼ .12). Fig. 2 illustrates the response to CRD in individual patients. CRD decreased the number of hypoglycemic events to 0 in 6 patients (14.6%), and to less than once per week in 25 patients (61.0%). In contrast, 9 patients (22.0%) did not experience any benefit at all. None of the patients experienced an increase in hypoglycemic events after the start of CRD. The lowest blood glucose measured before start of the CRD was 2.1 ⫾ .4 mmol/L (n ¼ 41). After CRD, the lowest blood glucose was 2.6 ⫾ .2 mmol/L (n ¼ 18), i.e., an improvement of .5 ⫾ .2 mmol/L (P ¼ .004). The number of patients needing outside help for the
Fig. 2. Number of hypoglycemic events per month, before and after the carbohydrate restricted dietary advice (CRD). Results of patients who remained on CRD-only are shown as solid lines. The dashed lines represent the patients who were later put on insulin-suppressive treatment because of lack of response to CRD-only. Results of insulin-suppressive treatment are not shown in this figure.
treatment of hypoglycemia decreased by 73.9% (P o .001). Before start of the CRD, 23 patients (56%) reported to have needed help at least once. After CRD this number decreased to 6 patients (15%). Before starting CRD, mean QoL, measured on a scale of 1 to 10, was rated 5.4 ⫾ .3 and this increased to 7.4 ⫾ .3 after CRD, i.e., a 2.0 ⫾ .3 point increase (P o .001).
Table 2 Frequency, severity, and timing of hypoglycemic episodes, and quality of life before and after carbohydrate restricted dietary advice. Before
After
Difference
P value
Frequency of hypoglycemia (events/month) Lowest measured blood glucose (mmol/L) Patients needing outside help (n)
17.1 (1.5–180) 2.1 ⫾ .4 23
2.5 (0–180) 2.6 ⫾ .2 6
-14.6 þ0.5 ⫾ .2 -17
o .001 .004 o .001
Timing of hypoglycemia Postprandial* Postexercise* Nocturnal* Quality of Life (1 to 10 scale)
85% 73% 83% 5.4 ⫾ .3
68% 68% 61% 7.4 ⫾ .3
-17% -5% -22% þ2.0 ⫾ .3
.020 .41 .007 o .001
Frequency of hypoglycemia was recorded as the number of times per month patients subjectively experienced symptoms of hypoglycemia that disappeared after carb ingestion. * Percentage of patients reporting the specified timing of hypoglycemia.
Carb-restricted diet for post-RYGB-hypoglycemia / Surgery for Obesity and Related Diseases ] (2016) 00–00
Patient self-reported dietary adherence was 7.7 ⫾ .3 on a 1 to 10 scale. Five patients rated dietary adherence lower than 6, while 26 patients (64%) scored dietary adherence with an 8 or higher. No correlation was found between selfreported dietary adherence and the change in frequency of hypoglycemia (r ¼ .02, P ¼ .92), the lowest blood glucose (r ¼ -0.28, P ¼ .26), or the change in QoL (r ¼ -0.06, P ¼ .71). Nine patients, who did not experience a decline in frequency of hypoglycemia, reported a self-rated dietary adherence of 8.3 ⫾ .7. This was not significantly different from that reported by the patients experiencing benefit (P ¼ .14). Finally, the timing of hypoglycemia was assessed. Before the start of CRD, 34 patients occasionally experienced nocturnal hypoglycemia. After CRD, the number of patients reporting hypoglycemia at night decreased to 25 (P ¼ .007). The number of patients who reported postprandial hypoglycemia decreased from 35 to 28 (P ¼ .02). There was no significant difference in number of patients who reported postexercise hypoglycemia (30 versus 28, P ¼ .41). The majority of patients (81%) indicated that understanding of the causes of hypoglycemia improved after CRD instruction. Most patients could identify the cause of a hypoglycemic event in retrospect. Continuous glucose monitoring A subset of patients (n ¼ 19), mainly those with symptoms suggesting persisting hypoglycemia despite CRD, underwent 5-day CGM testing at home, about 64.1 ⫾ 14.2 days after CRD implementation. CGM recorded daytime hypoglycemia in 58% of these patients, nocturnal hypoglycemia in 79%. Glucose levels o3.0 mmol/L were observed 1.1 ⫾ .3 times during daytime and 1.5 ⫾ .3 times during the night (P ¼ .14). Extrapolated to one month, this group of patients had CGM-documented hypoglycemic events 20.5 ⫾ 3.8 times/month. During the telephone interview, these same patients reported to experience 23.2 ⫾ 7.4 hypoglycemic events per month. The results of CGM did not differ from the self-reported frequency (P ¼ .31). Effect of insulin suppression In 14 patients (34%), the diet-induced decrease in frequency and severity of hypoglycemia was insufficient and required medical treatment in addition to CRD. They had been on CRD for 7.0 ⫾ 1.6 months before medication was started (range 2.8-24.6 months). Twelve patients received Diazoxide monotherapy, with doses ranging from 50 to 300 mg per day. One patient received Octreotide and another patient received a combination of Diazoxide and Octreotide. After the start of medication, the median number of hypoglycemic events decreased from 15.0 (8.6–180) to 3.0 (0.5–15) times per month (P ¼ .008).
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Diazoxide had to be discontinued in 3 patients because of side effects such as palpitations, edema, and gastrointestinal intolerance. Discussion This study shows that CRD is an effective first line treatment for post-gastric bypass hypoglycemia. It produced a large decrease in hypoglycemia frequency and severity in the majority of patients and led to a substantial improvement in QoL. The dietary advice, consisting of 3 main meals with a maximum of 30 g carbs each and 3 smaller meals with a maximum of 15–30 g carbs reduced the number of hypoglycemic events by a median of 85% (range 0–100). In 15% of patients the number of events was reduced to zero, and in 61% to less than once a week. However, in contrast to in-hospital testing where a standardized 30 g carb-restricted meal did not provoke any symptoms at all [16], CRD was reported to be ineffective in a home setting in 22% of patients. None of these patients experienced a decrease in frequency or severity of hypoglycemia after the implementation of CRD (Fig. 2). In total, 14 patients (34%), 9 with a lack of response and 5 with a partial response, were started on insulin suppressive medication to achieve a clinically meaningful improvement. The lacking or limited effect of CRD in a home setting in 34% of patients needs further explanation. We hypothesize that at least 2 factors might contribute. The first is dietary adherence. Many patients who have undergone RYGB have a history of eating disorders and of multiple failed dietary attempts to lose weight. They are at increased risk to lose control over eating [18,19]. Nevertheless, all patients included in this study reported high dietary adherence, and patients with no improvement in CRD tended to report an even higher dietary adherence than patients who experienced benefit (8.3 ⫾ .7 versus 7.5 ⫾ .4, P = .14). However, the accuracy of self-reported dietary adherence is known to be limited and it is possible that socially desirable responses were given. In addition, each patient responds according to his own reference frame, and patients with identical performance may therefore rate it differently. Unfortunately, objective instruments to evaluate implementation of CRD in a home situation are not available. Other instruments, such as food diaries, are also biased, because patients can unintentionally make mistakes by weighing errors or misinterpretation of food labels [20,21]. A second factor that may play a role is exercise. During clinical testing of the 30 g carb meal, physical activity was limited, in contrast to the situation at home where activities usually start after a meal. A substantial number of patients (73%) reported to experience hypoglycemia during, or shortly after physical activity. The cause of this exerciseinduced hypoglycemia remains incompletely understood. In healthy people, exercise leads to increased muscle glucose uptake but does not lead to hypoglycemia because the
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increment in muscle glucose uptake is matched by the increments in hepatic glycogenolysis and gluconeogenesis [22]. A possible explanation for the occurrence of hypoglycemia during exercise is that liver glucose production is suppressed to some extent, possibly caused by persisting hyperinsulinemia. Standardized exercise testing with glucose and insulin monitoring may be helpful to elucidate the mechanisms behind this post-RYGB exercise-induced hypoglycemia. A rather surprising result in this study was the high prevalence of nocturnal hypoglycemia, during the CGM at home, in a subset of patients with persisting symptoms of hypoglycemia despite CRD instruction. In as many as 15 out of 19 (79%) patients, nocturnal hypoglycemia with a corresponding glucose level o3.0 mmol/L, was observed at least once in the 5-day CGM-testing period. A recent CGMstudy reported nocturnal events in 39% of patients (n ¼ 40) [23]. It is unlikely that these hypoglycemic events are related to (nocturnal) carbohydrate ingestion. Which mechanisms do play a role remains to be established. To our knowledge, this is the first study to show the efficacy of CRD in the treatment of postprandial hypoglycemia, as a primary treatment option. In a clinical setting, it has been observed that post-RYGB patients with documented hypoglycemia did not develop any hypoglycemic symptoms or blood glucose levels o3.0 mmol/L after test meals containing up to 30 g carbs maximal [14,16]. In a 5-day CGM study of 13 post-RYGB patients with confirmed postprandial hypoglycemia and specific instructions to use 6 carb-restricted meals during 1 out of 5 days with a maximum of 10 g carbs per meal none developed symptoms of hypoglycemia or blood glucose levels o3.6 mmol/L during the low-carb day [24]. In contrast, during the other 4 days on a free diet, 7 patients had hypoglycemic symptoms, with blood glucose levels o3.6 mmol/L. Data about the impact of exercise on blood glucose levels were not evaluated in that study. It would be of interest to know whether exercise-related hypoglycemia worsens or improves at a 10 g carb restriction. If suppression of liver glucose output is the main cause of exerciseinduced hypoglycemia, a 10 g carb restriction is unlikely to reduce the exercise-related symptoms. Excessive carb restriction may even have adverse effects because it can lead to muscle and liver glycogen depletion and stimulation of proteolysis to provide the amino acids for gluconeogenesis. The most important limitation of the present study is its retrospective design. In some cases, this implied that patients had to respond to questions relating to their medical situation up to 3 years ago. However, the risks of recall bias were minimized by the examination of medical records. If ambiguous data arose, those from the medical record data were used for the evaluation. In 15/41 cases (37%), we had to rely on numbers reported during the telephone interview exclusively.
Another factor that may affect the results of this study is reporting bias. Assessment of frequency and severity of hypoglycemia was primarily based on self-report, based on symptoms. It is well known that patients may experience symptoms mimicking hypoglycemia despite blood glucose levels 43.0 mmol/L and thus overreport. In contrast, patients who frequently experience a state of hypoglycemia may develop “hypoglycemia unawareness,” which will lead to underreporting. This phenomenon is well known in patients with diabetes mellitus and a too tight control of blood glucose levels [25]. It has also been described in patients with post-RYGB hypoglycemia [26]. Despite the potential lack of symptom specificity, reporting bias must have been low since CGM recorded hypoglycemic events did not differ significantly from the self-reported frequency of hypoglycemia. Another limitation is that we were not able to verify whether reported hypoglycemic events were due to nonadherence or to CRD failure. This may have led to an underestimation of CRD efficacy in some patients. With perfect implementation of CRD, an even greater decrease in hypoglycemia might be expected. In some patients a further refinement of the CRD in terms of a personalized carbrestriction protocol may also help to improve efficacy and/or dietary adherence. This aspect needs further investigation. Finally, the lack of a control group not receiving CRD may have led to an overestimation of the efficacy of the dietary regimen because improvement may also have occurred spontaneously over time, at least to some extent. However, as we did not observe a greater decrease in hypoglycemia frequency or severity in patients who received instructions longer ago, a major effect seems unlikely.
Conclusions We conclude that a CRD, consisting of 6 meals with up to 30 g of carbs each, is effective as a first line treatment of post-gastric bypass hypoglycemia in the majority of patients. Additional insulin suppressive medication was needed in about a third of patients. More research will be needed to further elucidate the mechanisms of postexercise and nocturnal hypoglycemia and to develop effective treatment strategies for these types of hypoglycemia. Based on our current experience we recommend the use of CGM to document the severity of post-RYGB hypoglycemia before as well as after the start of treatment. If not, nocturnal hypoglycemia is likely to go undetected.
Disclosures The authors have no commercial associations that might be a conflict of interest in relation to this article.
Carb-restricted diet for post-RYGB-hypoglycemia / Surgery for Obesity and Related Diseases ] (2016) 00–00
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Original article
Evaluation of carbohydrate restriction as primary treatment for post-gastric bypass hypoglycemia Jorick van Meijeren, BSca,⁎, Ilse Timmer, BSca, Hans Brandts, MScb, Ignace Janssen, MDc, Hans de Boer, MD, PhDa a
Department of Internal Medicine, Rijnstate Hospital, Arnhem, the Netherlands Department of Clinical Nutrition, Rijnstate Hospital, Arnhem, the Netherlands c Department of Surgery, Rijnstate Hospital, Arnhem, the Netherlands Received September 6, 2016; accepted November 2, 2016
b
Abstract
Background: Up to 15% of patients who have undergone Roux-en-Y gastric bypass (RYGB) surgery may eventually develop symptoms of hypoglycemia. Objectives: To evaluate the daily life efficacy of a carbohydrate (carb)-restricted dietary advice (CRD) of 6 meals per day with a 30 g carb maximum per meal in patients with documented postRYGB hypoglycemia. Setting: Teaching hospital, the Netherlands. Methods: Frequency and severity of hypoglycemic events before and after CRD were assessed retrospectively in 41 patients with documented post-RYGB hypoglycemia, based on medical records and telephone questionnaires. Hypoglycemia was defined as a blood glucose level o3.0 mmol/L. Results are expressed as mean values ⫾ standard error or median and range. Results: CRD decreased the number of hypoglycemic events per month from 17.1 (1.5–180) to 2.5 (0–180), i.e., a decline of 85% (P o .001). The lowest blood glucose measured during a hypoglycemic event increased from 2.1 ⫾ .4 to 2.6 ⫾ .2 mmol/L (P ¼ .004). The number of patients who had required outside help in the treatment of hypoglycemia, decreased from 23 to 6 (P o .001). In 14 patients (34.1%) the diet-induced reduction of hypoglycemia was insufficient and required the start of insulin suppressive therapy. Conclusion: A CRD, consisting of 6 meals per day with up to 30 g carbs each, is an effective treatment of post-RYGB hypoglycemia in the majority of patients. Additional medication is needed in about a third of patients. (Surg Obes Relat Dis 2016;]:00–00.) r 2016 American Society for Metabolic and Bariatric Surgery. All rights reserved.
Keywords:
Roux-en-Y gastric bypass; Hypoglycemia; Carbohydrate restriction; Daily life efficacy
Bariatric surgery is a very successful treatment for morbid obesity, with sustained weight loss in the large majority of patients [1]. Roux-en-Y gastric bypass (RYGB) surgery is the most commonly performed procedure, accounting for about 45% of all bariatric procedures [2]. * Correspondence: Jorick van Meijeren, Department of Internal Medicine, Rijnstate Hospital, Wagnerlaan 55, 6800 TA Arnhem, the Netherlands. E-mail: [email protected]
Despite its well-established clinical benefits, RYGB may also have adverse effects. Post-RYGB hypoglycemia, also known as “late dumping,” is one of the late complications that has been recognized increasingly in recent years [3]. Symptoms include attacks of dizziness, perspiration, confusion, and even collapse [4]. The prevalence of postRYGB hypoglycemia is not exactly known. Initial research, based on hospitalization rates, led to an estimated prevalence of .1%–.2% [5]. However, an analysis based on the
http://dx.doi.org/10.1016/j.soard.2016.11.004 1550-7289/r 2016 American Society for Metabolic and Bariatric Surgery. All rights reserved.
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presence of Whipple’s triad, i.e., clinical signs of hypoglycemia in combination with a blood glucose level o3.0 mmol/L and resolution of the symptoms after glucose administration, found an incidence of 18% in a cohort of 351 patients [6,7]. In a questionnaire-based study, 34% of patients (n = 450) reported symptoms of hypoglycemia [8]. The most commonly proposed mechanism of post-RYGB hypoglycemia is hyperinsulinism, caused by pancreatic ß-cell hypertrophy and/or hyperplasia (nesidioblastosis) or by excessive glucagon-like peptide 1 (GLP-1) mediated ß-cell stimulation. Although nesidioblastosis has been shown to play a role in some cases it is generally considered to be very rare [9,10]. Nesidioblastosis is characterized by autonomic hypersecretion of insulin and should be considered in patients with fasting hyperinsulinemia [7]. Usually, however, patients present with symptoms of postprandial hypoglycemia. This has been attributed to food activated GLP-1 release, stimulating insulin secretion by its binding to specific ß-cell receptors [11]. It has been established that postprandial hypoglycemia in patients after RYGB can be prevented by administration of a GLP-1 receptor antagonist [12]. Other medical options are the use of Acarbose, Octreotide or Diazoxide. Reversal of RYGB and partial pancreas resection have been suggested as last resort options; with these procedures, hypoglycemia disappeared in 13/17 (76%) and 34/51 (67%) of cases, respectively [13]. Carbohydrate (carb) restriction appears to be a logical first step in the treatment of postprandial hypoglycemia after RYGB because it is likely to reduce postprandial insulin release [7]. The efficacy of extreme carb-restricted meals (0 and 2 g per meal) has been successfully demonstrated in clinical settings [14,15]. However, in daily life such diets are hardly feasible. Botros et al. evaluated the effects of a more moderate 30 g carb-restricted meal [16]. During a 6-hour in-hospital observation period under resting conditions, none of the patients developed hypoglycemic symptoms or glucose levels o3.0 mmol/L. Based on these findings, we developed a carb-restricted dietary advice (CRD) consisting of 6 meals per day with a 30 g carb maximum per meal. In the present study, the daily life efficacy of this CRD has been evaluated as a first-line treatment for patients with documented post-RYGB hypoglycemia.
Methods This is a single center, retrospective, per protocol analysis of the efficacy of a CRD for the treatment of patients presenting with symptoms of hypoglycemia after RYGB. Our hospital is a referral center for bariatric surgery where 4 surgeons perform about 1200 bariatric procedures per year. Postoperatively, all patients are advised to eat small, frequent meals throughout the day and to eat slowly and thoroughly. The study was performed according to the regulations of the local ethical committee.
Patients Eighty patients with symptoms suggestive of post-RYGB hypoglycemia (i.e., postprandial attacks of lightheadedness, perspiration, trembling, confusion, and even collapse, disappearing after ingestion of carbohydrates) were referred to the dietician for CRD, either by a surgeon or an internist. For inclusion in this study, additional criteria were set: 1) symptoms of hypoglycemia developed after RYGB in the absence of antidiabetic medication; 2) documented home glucose levels o3.0 mmol/L during an event with symptoms suggestive of hypoglycemia; 3) postoperative remission of diabetes mellitus (fasting glucose o6.0 mmol/L, and HbA1C o42 mmol/mol) with all previous antidiabetic medication discontinued for at least 6 months; 4) baseline screening performed by an endocrinologist; 5) understanding of the Dutch language; and 6) implementation of CRD for a period of at least 1 month without concomitant use of Acarbose, insulin suppressive medication, GLP-1 antagonists, or any other medication known to have an effect on blood glucose levels. Methods Patients reporting hypoglycemic symptoms were usually referred to the internist for evaluation and treatment. This consultation included recording of gender, age, medical history, medication, body mass index (BMI), lowest measured home glucose level, frequency at which hypoglycemic symptoms occurred, and the number of times outside help was required for treatment. A fasting blood sample was obtained as part of standard procedures for measurement of plasma glucose, HbA1C, insulin, C-peptide, glucagon, and cortisol levels. Patients with documented blood glucose levels o3.0 mmol/L received oral instructions for CRD by the dietician, in person or by telephone and additionally in print or by email. Patients were instructed to use a diet consisting of 6 small meals per day with a 30 g carb maximum per meal. Continuous glucose monitoring for 5 consecutive days (CGM, Freestyle Navigator II, Abbott, Hoofddorp, the Netherlands) was used to evaluate the efficacy of CRD in a subset of patients, usually those who still reported hypoglycemic events after CRD. The results of CGM were reviewed by the dietician and endocrinologist, and discussed with the patients. If diet-induced reduction of hypoglycemia was insufficient, medical treatment was added, either Diazoxide or Octreotide or a combination of both. Data collection Medical records were examined to collect the data about frequency and severity of hypoglycemia before CRD. The actual situation after CRD was assessed by telephone questionnaire. Frequency of hypoglycemia was recorded
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as the number of times per month patients subjectively experienced symptoms of hypoglycemia that disappeared after carb ingestion. Severity of hypoglycemia was evaluated by the lowest measured blood glucose during a hypoglycemic event, and by the number of patients that needed outside help for the treatment of hypoglycemia [17]. Patients were also asked to rate their quality of life (QoL) in relation to hypoglycemic symptoms on a 1 to 10 scale, before and after starting CRD. Dietary adherence was quantified by a self-reported measure on a 1 to 10 scale to assess the extent to which implementation of the CRD corresponded with the dietician’s recommendations. Dichotomous questions were asked about whether the patients experienced hypoglycemia postprandially, postexercise, and nocturnally, before and after CRD. Patient understanding about hypoglycemia was addressed by inquiring whether they could point out the precipitating factor that led to a hypoglycemic event and whether this insight had improved after implementation of the CRD. Statistical analysis Results are expressed as mean ⫾ standard error for normally distributed data and as median and range if data were not normally distributed. Testing for significant differences was performed by paired t tests, or by Wilcoxon matched-pairs signed-ranks test, when appropriate. Furthermore, Pearson correlation coefficient was used to examine the relation between frequency and severity of hypoglycemia and self-reported dietary adherence. Finally, CRD induced changes of the various types of hypoglycemia were tested for significance with a McNemar’s χ2 test. Differences were considered to be statistically significant if P o .05. For calculations, software package SPSS version 23 for Macintosh was used (IBM Corp., Armonk, NY). Results
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Patient characteristics Patient baseline characteristics are summarized in Table 1. The patient population included 7 males and 34 females, 45.7 ⫾ 1.5 years old. Their mean preoperative weight was 128.4 ⫾ 3.2 kg with a BMI of 43.7 ⫾ .9 kg/m2. The first hypoglycemic symptoms occurred 19.8 ⫾ 2.8 months after surgery. At that time weight had decreased to 84.5 ⫾ 3.3 kg, a total weight loss of 34.2 ⫾ 1.8%, and BMI to 28.9 ⫾ 1.0 kg/m2. Excess weight loss was 74.1 ⫾ 4.4%. Eight patients had type 2 diabetes (T2D) at time of surgery. Antidiabetic medication had been discontinued in all patients within 6 months after surgery (mean 1.9 ⫾ .9 months). All patients had a complete remission of T2D, confirmed by a normalization of their fasting glucose and HbA1C levels. Fasting blood glucose was 4.8 ⫾ .1 mmol/L (range 3.9–5.8 mmol/L) and mean HbA1C was 33.6 ⫾ .7 mmol/mol (range 25–40 mmol/mol) in absence of antidiabetic medication. In patients with prior T2D, the first hypoglycemic symptoms occurred 15.1 ⫾ 4.2 months after the discontinuation of antidiabetic medication (range 3–41 months). The interval between the day of surgery and the onset of hypoglycemic symptoms was comparable for patients with and without a history of T2D (P ¼ .29). The diagnostic delay, i.e., the mean time elapsing between the onset of symptoms and the first internal medicine consultation was 7.4 ⫾ 1.4 months. Laboratory results generally fell within the normal range (Table 1). Only C-peptide tended to be slightly higher than normal (P ¼ .007). Patients started receiving dietary instructions for CRD, 16.9 ⫾ 1.6 months before the current evaluation (range 3–40 months). In this period between the first dietary instruction and the current evaluation, weight increased by 2.9 ⫾ 1.4 kg, with a rise in BMI to 29.9 ⫾ .8 kg/m2 (P ¼ .023). Impact of dietary advice
Patient selection Patient selection is illustrated in Fig. 1. After a first selection based on predefined inclusion and exclusion criteria, 37 out of 80 patients were excluded. An additional 2 patients were excluded because they could not be contacted by telephone, despite repeated efforts. None of the included patients declined answering the questionnaire.
Changes in frequency, timing, and severity of hypoglycemic events after start of the CRD are summarized in Table 2. CRD decreased the frequency of hypoglycemia by 85% (P o .001). At baseline, patients reported a median of 17.1 (1.5–180) hypoglycemic events per month and this decreased to 2.5 (0–180) times per month after dietary instruction. The decline in hypoglycemic events was not
Fig. 1. Patient selection procedure.
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Table 1 General patient characteristics Mean ⫾ SE Range Male/female ratio Age (years) BMI before RYGB (kg/m2) BMI at first hypoglycemic event (kg/m2) BMI at start of present study (kg/m2) Excess weight loss (%) First symptoms after surgery (months) Diagnostic delay (months) Instruction of CRD (months before study) Preexistent T2D (number of patients) HbA1C (mmol/mol) Fasting glucose (mmol/L) Fasting insulin (mU/L) Fasting C-peptide (mmol/L) Fasting glucagon (pmol/L) Cortisol (pmol/L)
Normal range
7/34 45.7 ⫾ 1.5 43.7 ⫾ .9 28.9 ⫾ 1.0
27–62 24.5–58.1 21.5–41
29.9 ⫾ .8
22.2–45.2
74.1 ⫾ 4.4 19.8 ⫾ 2.8
0–127 3–90
7.4 ⫾ 1.4 16.9 ⫾ 1.6
0–30 3–40
9 33.6 ⫾ .7 4.8 ⫾ .1 8.1 ⫾ 1.0 0.93 ⫾ .12 33.6 ⫾ 3.2 458 ⫾ 41
25–40 3.9–5.8 2–28 0.30–4.30 7.5–59.7 209–1096
20–42 3.5–6.0 0–29 0.26–0.62 o 60 171–536
BMI ¼ body mass index; C-peptide ¼ connecting peptide; CRD ¼ carbohydrate restricted dietary advice; HbA1C ¼ hemoglobin A1c; RYGB ¼ Roux-en-Y gastric bypass; SE ¼ standard error; T2D ¼ type 2 diabetes.
related to the duration of CRD implementation (r ¼ -0.25, P ¼ .12). Fig. 2 illustrates the response to CRD in individual patients. CRD decreased the number of hypoglycemic events to 0 in 6 patients (14.6%), and to less than once per week in 25 patients (61.0%). In contrast, 9 patients (22.0%) did not experience any benefit at all. None of the patients experienced an increase in hypoglycemic events after the start of CRD. The lowest blood glucose measured before start of the CRD was 2.1 ⫾ .4 mmol/L (n ¼ 41). After CRD, the lowest blood glucose was 2.6 ⫾ .2 mmol/L (n ¼ 18), i.e., an improvement of .5 ⫾ .2 mmol/L (P ¼ .004). The number of patients needing outside help for the
Fig. 2. Number of hypoglycemic events per month, before and after the carbohydrate restricted dietary advice (CRD). Results of patients who remained on CRD-only are shown as solid lines. The dashed lines represent the patients who were later put on insulin-suppressive treatment because of lack of response to CRD-only. Results of insulin-suppressive treatment are not shown in this figure.
treatment of hypoglycemia decreased by 73.9% (P o .001). Before start of the CRD, 23 patients (56%) reported to have needed help at least once. After CRD this number decreased to 6 patients (15%). Before starting CRD, mean QoL, measured on a scale of 1 to 10, was rated 5.4 ⫾ .3 and this increased to 7.4 ⫾ .3 after CRD, i.e., a 2.0 ⫾ .3 point increase (P o .001).
Table 2 Frequency, severity, and timing of hypoglycemic episodes, and quality of life before and after carbohydrate restricted dietary advice. Before
After
Difference
P value
Frequency of hypoglycemia (events/month) Lowest measured blood glucose (mmol/L) Patients needing outside help (n)
17.1 (1.5–180) 2.1 ⫾ .4 23
2.5 (0–180) 2.6 ⫾ .2 6
-14.6 þ0.5 ⫾ .2 -17
o .001 .004 o .001
Timing of hypoglycemia Postprandial* Postexercise* Nocturnal* Quality of Life (1 to 10 scale)
85% 73% 83% 5.4 ⫾ .3
68% 68% 61% 7.4 ⫾ .3
-17% -5% -22% þ2.0 ⫾ .3
.020 .41 .007 o .001
Frequency of hypoglycemia was recorded as the number of times per month patients subjectively experienced symptoms of hypoglycemia that disappeared after carb ingestion. * Percentage of patients reporting the specified timing of hypoglycemia.
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Patient self-reported dietary adherence was 7.7 ⫾ .3 on a 1 to 10 scale. Five patients rated dietary adherence lower than 6, while 26 patients (64%) scored dietary adherence with an 8 or higher. No correlation was found between selfreported dietary adherence and the change in frequency of hypoglycemia (r ¼ .02, P ¼ .92), the lowest blood glucose (r ¼ -0.28, P ¼ .26), or the change in QoL (r ¼ -0.06, P ¼ .71). Nine patients, who did not experience a decline in frequency of hypoglycemia, reported a self-rated dietary adherence of 8.3 ⫾ .7. This was not significantly different from that reported by the patients experiencing benefit (P ¼ .14). Finally, the timing of hypoglycemia was assessed. Before the start of CRD, 34 patients occasionally experienced nocturnal hypoglycemia. After CRD, the number of patients reporting hypoglycemia at night decreased to 25 (P ¼ .007). The number of patients who reported postprandial hypoglycemia decreased from 35 to 28 (P ¼ .02). There was no significant difference in number of patients who reported postexercise hypoglycemia (30 versus 28, P ¼ .41). The majority of patients (81%) indicated that understanding of the causes of hypoglycemia improved after CRD instruction. Most patients could identify the cause of a hypoglycemic event in retrospect. Continuous glucose monitoring A subset of patients (n ¼ 19), mainly those with symptoms suggesting persisting hypoglycemia despite CRD, underwent 5-day CGM testing at home, about 64.1 ⫾ 14.2 days after CRD implementation. CGM recorded daytime hypoglycemia in 58% of these patients, nocturnal hypoglycemia in 79%. Glucose levels o3.0 mmol/L were observed 1.1 ⫾ .3 times during daytime and 1.5 ⫾ .3 times during the night (P ¼ .14). Extrapolated to one month, this group of patients had CGM-documented hypoglycemic events 20.5 ⫾ 3.8 times/month. During the telephone interview, these same patients reported to experience 23.2 ⫾ 7.4 hypoglycemic events per month. The results of CGM did not differ from the self-reported frequency (P ¼ .31). Effect of insulin suppression In 14 patients (34%), the diet-induced decrease in frequency and severity of hypoglycemia was insufficient and required medical treatment in addition to CRD. They had been on CRD for 7.0 ⫾ 1.6 months before medication was started (range 2.8-24.6 months). Twelve patients received Diazoxide monotherapy, with doses ranging from 50 to 300 mg per day. One patient received Octreotide and another patient received a combination of Diazoxide and Octreotide. After the start of medication, the median number of hypoglycemic events decreased from 15.0 (8.6–180) to 3.0 (0.5–15) times per month (P ¼ .008).
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Diazoxide had to be discontinued in 3 patients because of side effects such as palpitations, edema, and gastrointestinal intolerance. Discussion This study shows that CRD is an effective first line treatment for post-gastric bypass hypoglycemia. It produced a large decrease in hypoglycemia frequency and severity in the majority of patients and led to a substantial improvement in QoL. The dietary advice, consisting of 3 main meals with a maximum of 30 g carbs each and 3 smaller meals with a maximum of 15–30 g carbs reduced the number of hypoglycemic events by a median of 85% (range 0–100). In 15% of patients the number of events was reduced to zero, and in 61% to less than once a week. However, in contrast to in-hospital testing where a standardized 30 g carb-restricted meal did not provoke any symptoms at all [16], CRD was reported to be ineffective in a home setting in 22% of patients. None of these patients experienced a decrease in frequency or severity of hypoglycemia after the implementation of CRD (Fig. 2). In total, 14 patients (34%), 9 with a lack of response and 5 with a partial response, were started on insulin suppressive medication to achieve a clinically meaningful improvement. The lacking or limited effect of CRD in a home setting in 34% of patients needs further explanation. We hypothesize that at least 2 factors might contribute. The first is dietary adherence. Many patients who have undergone RYGB have a history of eating disorders and of multiple failed dietary attempts to lose weight. They are at increased risk to lose control over eating [18,19]. Nevertheless, all patients included in this study reported high dietary adherence, and patients with no improvement in CRD tended to report an even higher dietary adherence than patients who experienced benefit (8.3 ⫾ .7 versus 7.5 ⫾ .4, P = .14). However, the accuracy of self-reported dietary adherence is known to be limited and it is possible that socially desirable responses were given. In addition, each patient responds according to his own reference frame, and patients with identical performance may therefore rate it differently. Unfortunately, objective instruments to evaluate implementation of CRD in a home situation are not available. Other instruments, such as food diaries, are also biased, because patients can unintentionally make mistakes by weighing errors or misinterpretation of food labels [20,21]. A second factor that may play a role is exercise. During clinical testing of the 30 g carb meal, physical activity was limited, in contrast to the situation at home where activities usually start after a meal. A substantial number of patients (73%) reported to experience hypoglycemia during, or shortly after physical activity. The cause of this exerciseinduced hypoglycemia remains incompletely understood. In healthy people, exercise leads to increased muscle glucose uptake but does not lead to hypoglycemia because the
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increment in muscle glucose uptake is matched by the increments in hepatic glycogenolysis and gluconeogenesis [22]. A possible explanation for the occurrence of hypoglycemia during exercise is that liver glucose production is suppressed to some extent, possibly caused by persisting hyperinsulinemia. Standardized exercise testing with glucose and insulin monitoring may be helpful to elucidate the mechanisms behind this post-RYGB exercise-induced hypoglycemia. A rather surprising result in this study was the high prevalence of nocturnal hypoglycemia, during the CGM at home, in a subset of patients with persisting symptoms of hypoglycemia despite CRD instruction. In as many as 15 out of 19 (79%) patients, nocturnal hypoglycemia with a corresponding glucose level o3.0 mmol/L, was observed at least once in the 5-day CGM-testing period. A recent CGMstudy reported nocturnal events in 39% of patients (n ¼ 40) [23]. It is unlikely that these hypoglycemic events are related to (nocturnal) carbohydrate ingestion. Which mechanisms do play a role remains to be established. To our knowledge, this is the first study to show the efficacy of CRD in the treatment of postprandial hypoglycemia, as a primary treatment option. In a clinical setting, it has been observed that post-RYGB patients with documented hypoglycemia did not develop any hypoglycemic symptoms or blood glucose levels o3.0 mmol/L after test meals containing up to 30 g carbs maximal [14,16]. In a 5-day CGM study of 13 post-RYGB patients with confirmed postprandial hypoglycemia and specific instructions to use 6 carb-restricted meals during 1 out of 5 days with a maximum of 10 g carbs per meal none developed symptoms of hypoglycemia or blood glucose levels o3.6 mmol/L during the low-carb day [24]. In contrast, during the other 4 days on a free diet, 7 patients had hypoglycemic symptoms, with blood glucose levels o3.6 mmol/L. Data about the impact of exercise on blood glucose levels were not evaluated in that study. It would be of interest to know whether exercise-related hypoglycemia worsens or improves at a 10 g carb restriction. If suppression of liver glucose output is the main cause of exerciseinduced hypoglycemia, a 10 g carb restriction is unlikely to reduce the exercise-related symptoms. Excessive carb restriction may even have adverse effects because it can lead to muscle and liver glycogen depletion and stimulation of proteolysis to provide the amino acids for gluconeogenesis. The most important limitation of the present study is its retrospective design. In some cases, this implied that patients had to respond to questions relating to their medical situation up to 3 years ago. However, the risks of recall bias were minimized by the examination of medical records. If ambiguous data arose, those from the medical record data were used for the evaluation. In 15/41 cases (37%), we had to rely on numbers reported during the telephone interview exclusively.
Another factor that may affect the results of this study is reporting bias. Assessment of frequency and severity of hypoglycemia was primarily based on self-report, based on symptoms. It is well known that patients may experience symptoms mimicking hypoglycemia despite blood glucose levels 43.0 mmol/L and thus overreport. In contrast, patients who frequently experience a state of hypoglycemia may develop “hypoglycemia unawareness,” which will lead to underreporting. This phenomenon is well known in patients with diabetes mellitus and a too tight control of blood glucose levels [25]. It has also been described in patients with post-RYGB hypoglycemia [26]. Despite the potential lack of symptom specificity, reporting bias must have been low since CGM recorded hypoglycemic events did not differ significantly from the self-reported frequency of hypoglycemia. Another limitation is that we were not able to verify whether reported hypoglycemic events were due to nonadherence or to CRD failure. This may have led to an underestimation of CRD efficacy in some patients. With perfect implementation of CRD, an even greater decrease in hypoglycemia might be expected. In some patients a further refinement of the CRD in terms of a personalized carbrestriction protocol may also help to improve efficacy and/or dietary adherence. This aspect needs further investigation. Finally, the lack of a control group not receiving CRD may have led to an overestimation of the efficacy of the dietary regimen because improvement may also have occurred spontaneously over time, at least to some extent. However, as we did not observe a greater decrease in hypoglycemia frequency or severity in patients who received instructions longer ago, a major effect seems unlikely.
Conclusions We conclude that a CRD, consisting of 6 meals with up to 30 g of carbs each, is effective as a first line treatment of post-gastric bypass hypoglycemia in the majority of patients. Additional insulin suppressive medication was needed in about a third of patients. More research will be needed to further elucidate the mechanisms of postexercise and nocturnal hypoglycemia and to develop effective treatment strategies for these types of hypoglycemia. Based on our current experience we recommend the use of CGM to document the severity of post-RYGB hypoglycemia before as well as after the start of treatment. If not, nocturnal hypoglycemia is likely to go undetected.
Disclosures The authors have no commercial associations that might be a conflict of interest in relation to this article.
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