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. Author manuscript; available in PMC: 2023 Feb 22.
Published in final edited form as: Surg Obes Relat Dis. 2021 May 19;17(10):1787–1798. doi: 10.1016/j.soard.2021.04.021

Postbariatric hypoglycemia: symptom patterns and associated risk factors in the Longitudinal Assessment of Bariatric Surgery study

Laura E Fischer a,*, Bruce M Wolfe b, Nora Fino b, Miriam R Elman c, David R Flum d, James E Mitchell e, Alfons Pomp f, Walter J Pories g, Jonathan Q Purnell b, Mary-Elizabeth Patti h; LABS Investigators
PMCID: PMC9944569  NIHMSID: NIHMS1871833  PMID: 34294589

Abstract

Background:

Postbariatric hypoglycemia (PBH) can be a devastating complication for which current therapies are often incompletely effective. More information is needed regarding frequency, incidence, and risk factors for PBH.

Objectives:

To examine hypoglycemia symptoms following Roux-en-Y gastric bypass (RYGB) and laparoscopic adjustable gastric banding (LAGB) and baseline and in-study risk factors.

Setting:

Multicenter, at 10 US hospitals in 6 geographically diverse clinical centers.

Methods:

A prospective, longitudinal cohort study of adults undergoing RYGB or LAGB as part of clinical care between 2006 and 2009 were recruited and followed until January 31, 2015, with baseline and annual postoperative research assessments. We analyzed baseline prevalence and postoperative incidence and frequency of self-reported hypoglycemia symptoms as well as potential preoperative risk factors.

Results:

In all groups, postoperative prevalence of hypoglycemia symptoms was 38.5%. Symptom prevalence increased postoperatively from 2.8%–36.4% after RYGB in patients without preoperative diabetes (T2D), with similar patterns in prediabetes (4.9%–29.1%). Individuals with T2D had higher baseline hypoglycemia symptoms (28.9%), increasing after RYGB (57.9%). Hypoglycemia symptoms were lower after LAGB, with 39.1% reported hypoglycemia symptoms at only 1 postoperative visit with few (4.0%) having persistent symptoms at 6 or more annual visits. Timing of symptoms was not restricted to the postprandial state. Symptoms of severe hypoglycemia were reported in 2.6–3.6% after RYGB. The dominant risk factor for postoperative symptoms was preoperative symptoms; additionally, baseline selective serotonin (SSRI) and serotonin-norepinephrine (SNRI) reuptake inhibitor use was also associated with increased risk in multivariable analysis. Weight loss and regain were not related to hypoglycemia symptom reporting.

Conclusion:

Hypoglycemia symptoms increase over time after RYGB, particularly in patients without diabetes. In a small percentage, symptoms can be persistent or severe and require hospitalization. Preoperative hypoglycemia symptoms and SSRI/SNRI use in RYGB patients without diabetes is associated with increased risk of symptoms.

Keywords: Bariatric surgery, Roux-en-Y gastric bypass, Laparoscopic adjustable gastric band, Hypoglycemia, SSRI, SNRI, Diabetes

Postbariatric hypoglycemia (PBH) is a poorly understood complication of bariatric-metabolic surgery [1]. Differences in diagnostic criteria have led to a range of prevalence estimates. Up to one third of patients report hypoglycemia symptoms on self-reported surveys and oral glucose tolerance tests (OGTT) [2-4], while 50% of asymptomatic Roux-en-Y gastric bypass (RYGB) patients have glucose levels <70 mg/dL on continuous glucose monitoring (CGM) [5]. While most hypoglycemia is treated in the outpatient setting, .1–1% of patients have hypoglycemia severe enough to require hospitalization [6-8].

Hypoglycemia can have severe, disabling effects. Acute hypoglycemia causes autonomic and neuroglycopenic symptoms, such as impaired cognition, falls, loss of consciousness, and seizures [9]. Recurrent hypoglycemia can lead to hypoglycemia unawareness [10,11] further impairing safety and quality of life. Hypoglycemia in patients with diabetes is associated with increased risk of cardiovascular disease and mortality [12-14]. Moreover, postbariatric hypoglycemia (PBH) has been proposed as a mediator of weight regain due to increased oral intake and potential anabolic effects of post-prandial insulin secretion [15-18].

Although first reported 20 years ago [19-22], the natural history and pathophysiology of PBH remain incompletely understood [1]. Symptomatic hypoglycemia typically occurs in the postprandial state and emerges 1–3 years after surgery [1], however, nonspecific symptoms overlapping with dumping syndrome and other conditions make it challenging to diagnose [23]. Previously reported risk factors include preoperative hypoglycemia symptoms, female sex, longer interval from surgery, and the absence of diabetes [2]. Potential pathophysiologic mechanisms include increased postprandial secretion of incretin hormones including GLP1 [24], insulin-independent glucose uptake [25], increases in the intestinal hormone fibroblast growth factor 19 (FGF19) [26], impaired counter-regulatory hormone secretion in response to hypoglycemia [27], and micronutrient deficiencies [22]. Medications are an over-looked contributor, particularly in year 1 when glycemic control improves rapidly [28,29]. Rarely, postsurgical weight loss will unmask an insulinoma [30,31]. Ideally, the diagnosis of PBH requires exclusion of these other potential contributors [1].

The Longitudinal Assessment of Bariatric Surgery 2 (LABS-2) study was a multicenter, prospective, longitudinal study that evaluated the long-term safety and efficacy of bariatric surgery, acquiring clinical and biologic data for >2000 patients over 7 years [32]. LABS data provide a unique opportunity to assess the long-term clinical characteristics of postbariatric hypoglycemia symptoms in a large patient cohort to gain further insight into this potentially serious complication. We analyzed data collected prospectively during annual visits from specific questionnaires regarding hypoglycemia symptoms. Moreover, we analyzed data from both RYGB and laparoscopic adjustable gastric banding (LAGB) in order to allow comparison of symptom prevalence between a surgical procedure with altered gastrointestinal anatomy and nutrient flow (RYGB) versus a restrictive procedure without alteration in nutrient flow (LAGB).

Methods

Participants

LABS-2 enrolled and completed baseline studies in 2458 adult participants between 2006 and 2009 at 10 centers in 6 geographically diverse U.S. centers, and over 85% of the original study participants completed 7-year follow-up [33]. Individuals (n = 111) who did not undergo RYGB (RYGB, n = 1,738) or LAGB (LAGB, n = 609) were excluded (Supplemental Fig. 1). In total, 285 RYGB and 98 LAGB participants were excluded for not completing the preoperative hypoglycemia questionnaire. Five RYGB participants were excluded for having no identifiable diabetes status at preoperative appointment. The final analytic sample included 1448 RYGB and 511 LAGB participants. The institutional review board at each center approved the protocol and all participants provided informed consent. This trial was registered at clinicaltrials.gov (NCT00465829).

Stratification by baseline diabetes status

Patients were stratified by baseline diabetes status into 3 groups: (1) no diabetes (T2D); (2) prediabetes; and (3) diabetes. The T2D subgroup included patients who met ≥1 of the following criteria: self-reported T2D diagnosis, presence of T2D medication on medication inventory, elevated baseline hemoglobin A1C (HbA1C) >6.5%, or fasting plasma glucose ≥126 mg/dL. Metformin alone was not considered an anti-T2D medication if the patient reported polycystic ovary syndrome but not T2D. Prediabetes (preT2D) was defined as a baseline HbA1C 5.7–6.4% or fasting plasma glucose 100–125 mg/dL without anti-diabetes medication. The remaining participants were classified as having “no diabetes” (NoT2D).

Hypoglycemia

At preoperative visit (“baseline”) and each of 7 annual postoperative visits, participants were asked about hypoglycemia symptoms by a trained research professional using a validated questionnaire (Supplemental Fig. 2). “I don’t know” responses were considered equivalent to “no.” Participants were asked to describe the timing of symptoms with regard to eating. Episodes of severe hypoglycemia symptoms were defined as those requiring assistance (visit to emergency department or hospitalization) within the past 3 months.

Risk factors for hypoglycemia symptoms

Baseline physiologic, laboratory, and self-reported survey data points [33] were considered as potential risk factors for postoperative hypoglycemia symptoms. Fasting insulin and glucose levels were used to calculate homeostatic model of insulin resistance (HOMA2) [34]. Depression was assessed using the Beck Depression Inventory (BDI) [35]. A comprehensive medication inventory was performed by the authors to categorize 2471 unique medications into groups for diabetes (including insulin and noninsulin), hypertension, and depression to analyze medication effects on hypoglycemia symptoms. Within antidepressant medications, the selective serotonin (SSRI) and serotonin-norepinephrine (SNRI) reuptake inhibitors were analyzed in a separate group based on previously reported data regarding hypoglycemia symptoms [36,37].

Statistical methods

The primary outcome for association analyses was whether the participant self-reported any hypoglycemia symptoms at >1 of the annual postoperative visits to a research staff member using the questionnaire. Baseline characteristics of the analytic sample were described according to surgical procedure and diabetes status. Continuous variables were summarized using means and standard deviations (SD), while nominal variables were summarized using frequencies and percentages. The frequency of hypoglycemia symptoms over the study period was calculated using person-months of observation as the denominator. Logistic regression was used to calculate odds ratios for any hypoglycemia symptoms during follow-up in association with each potential risk factor. Variables with an association of P<.2 in bivariate models and ≥20 observations in the exposure group, as well as age, sex, and BMI (regardless of P value) were included in multivariable models. All analysis was performed in SAS Version 9.4 (Cary, NC).

Results

At baseline, average (SD) age was 46.1 (11.4) years, body mass index (BMI) 46.9 (7.2) kg/m2, and female sex 78.7%. Compared with LAGB, RYGB patients were younger (P < 001), more obese (P < .01), with greater waist circumference (P<.01), and higher hs-C-reactive protein (hs-CRP) (P < .01) (Supplemental Table 1). Leptin, T2D duration, HbA1C, frequency of insulin and noninsulin T2D medication use, and insulin resistance were not different between surgical groups.

Hypoglycemia symptom characteristics

Overall, baseline (preoperative) hypoglycemia symptoms were reported in 12.7% of participants (12.7% RYGB, 12.9% LAGB). In the RYGB group, the prevalence of baseline hypoglycemia symptoms according to diabetes status was 2.8% RYGB-noT2D, 4.9% RYGB-preT2D, and 28.9% RYGB-T2D (Fig. 1). Similarly, the LAGB group reported preoperative symptom prevalence according to diabetes status of 5.2% LAGB-noT2D, 5.8% LAGB-preT2D, and 29.8% LAGB-T2D. At baseline, 50.9% RYGB and 63.3% LAGB patients were on diabetes medication, with 28.6% and 27.9% on insulin.

Fig. 1.

Fig. 1.

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Baseline and any reported postoperative hypoglycemia (%) in patients undergoing Roux-en-Y gastric bypass (RYGB) or laparoscopic adjustable gastric band (LAGB), stratified by preoperative diabetes status.

Over 6–7 annual follow-up visits, 38.5% of all patients reported hypoglycemia symptoms postoperatively (43.2% RYGB, 25.4% LABG). Hypoglycemia symptoms increased significantly in all RYGB groups, with similar trends in the LAGB-T2D group (Fig. 1, Supplemental Table 2). The largest percent increase in symptom prevalence at any time during follow-up occurred in RYGB-noT2D group, increasing from 2.8%–36.4% (P < .0001). More moderate increases were seen in other groups: from 4.9%–29.1% in RYGB-preT2D (P < .0001), and 5.2%–12.7% in LAGB-no T2D (P = .0037). The highest prevalence of both preoperative and postoperative hypoglycemia symptoms was seen in both groups with diabetes, RYGB-T2D (28.9%–57.9%, P <.0001) and LAGB-DM (29.8%–55.1%, P <.0001), suggesting that the administration of insulin and insulin secretagogue medications may be a substantial contributor to symptoms in this patient cohort.

The timing of the first reported postoperative hypoglycemia symptoms was similar in both diabetes groups, with 48.7% of RYGB-T2D and 55.2% of LAGB-T2D reporting their first hypoglycemia symptoms in year 1. A similar, but less dramatic, pattern was seen in both surgical groups with prediabetes. With the exception of LAGB-noT2D, which had no discernible pattern, all other groups had the highest frequency of first-reported symptoms in the first 2 postoperative years with subsequent reductions in frequency of new-onset symptoms over time (Supplemental Table 2, Supplemental Fig. 3).

The annual prevalence of hypoglycemia symptoms over time differed between groups (Fig. 2). In RYGB-T2D, annual symptom prevalence ranged from 17.1%–28.8% with a slight decrease over time. In contrast, other RYGB groups experienced an increasing prevalence of symptoms over time: 8.3% at year 1 to a peak prevalence of 18.1% at year 5 in RYGB-noT2D and 9.7% to a peak of 14.1% in year 5 in RYGB-preT2D. In LAGB-T2D, prevalence ranged from 10.1%–30.4% with decreasing symptoms over time. LAGB-noT2D and LAGB-preT2D showed a stable, low prevalence, ranging from 2.4%–6.7%, with no particular pattern.

Fig. 2.

Fig. 2.

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Percentage of patients who reported any postoperative hypoglycemia at each follow-up visit, stratified by preoperative diabetes status following Roux-en-Y gastric bypass (RYGB, upper graph) or laparoscopic adjustable gastric band (LAGB, lower graph).

We also analyzed hypoglycemia symptom persistence over time. Of patients who had any postoperative hypoglycemia symptoms, the most often reported frequency was at a single postoperative visit (39.1%). The percent reporting symptoms at a single visit by diabetes status was as follows: RYGB-noT2D 39.8%, RYGB-preT2D 45.5%, RYGB-T2D 33.8%, LAGB-noDM 44.1%, LAGB-preDM 55.6%, and LAGB-DM 47.1%. Very few patients reported hypoglycemia symptoms at 6 or more annual postoperative visits (4.0%), with a higher percentage of high-frequency hypoglycemia symptoms seen in the RYGB group (4.5%) compared with the LAGB group (1.5%). When analyzing only patients with symptoms, the breakdown by diabetes status for persistent (6+ annual visits) hypoglycemia symptoms was as follows: RYGB-noT2D 3.2%, RYGB-preT2D 6.0%, RYGB-DM 5.2%, LAGB-noT2D 0%, LAGB-preT2D 0%, and LAGB-T2D 2.3%. When analyzing persistent (6+ annual visists) hypoglycemia symptoms for all patients in the study: RYGB-noT2D 1.2%, RYGB-preT2D 1.8%, RYGB-T2D 3.0%, LAGB-noT2D 0%, LAGB-preT2D 0%, and LAGB-T2D 1.3%.

Symptoms of severe hypoglycemia requiring hospitalization or emergency room (ER) visits increased markedly during follow-up in all 3 RYGB groups, reaching 2.6–3.6% at 5 years (P < .01 baseline versus 60 months post-RYGB, Fig. 3). Severe symptoms in LAGB occurred too infrequently for testing, with only a single participant reporting 1 ER visit over 7-year follow-up.

Fig. 3.

Fig. 3.

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Percentage of Roux-en-Y gastric bypass (RYGB) patients who reported a hospital or emergency room (ER) visit for low blood sugar in the 3 months prior to survey, stratified by preoperative diabetes status.

We assessed the timing of hypoglycemia symptoms in relationship to meals. The majority of individuals in RYGB-noT2D and RYGB-preT2D groups reported symptoms occurred within 4 hours of eating (Fig. 4). This pattern increased over time in both groups and peaked at 8.6% and 6.6% at 5-year follow-up, respectively. Interestingly, all RYGB groups also reported significant increases in symptoms that occurred without relationship to meals; these similarly peaked at 5-year follow-up. In LAGB-noT2D and LAGB-preT2D, no clear temporal relationship to meals was observed. By contrast, in LAGB-T2D, symptoms occurring >4 hours after eating or without relation to meals mirrored that of RYGB-T2D, ranging from 8%-13% in both groups.

Fig. 4.

Fig. 4.

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Percentage of Roux-en-Y gastric bypass (RYGB) patients reporting timing of low blood sugar with regard to meals (<4 hr, >4 hr, or unrelated), stratified by preoperative diabetes status.

In all groups, “shakiness”, “sweating”, “dizziness” and “trouble concentrating” were the most reported symptoms, while “blacking out” was least common (Supplemental Fig. 4).

Predictors of hypoglycemia symptoms

We next performed univariate and multivariable analyses to identify baseline factors associated with postoperative hypoglycemia symptoms, stratified by procedure and diabetes status. LAGB-preT2D was excluded from the analysis due to small sample size. In all groups, the strongest baseline variable associated with postoperative hypoglycemia symptoms was preoperative symptoms (Fig. 5). The predictive strength of baseline symptoms remained strong in multivariable models for groups with diabetes (RYGB-T2D, OR 5.42 [95%CI 3.12–9.42], P < .0001; and LAGB-T2D, OR 5.71 [95% CI 1.59–8.00], P = .008). Because the effect size was so large, we excluded it in multivariable analysis of the remaining variables to avoid confounding error (Supplemental Tables 3 and 4).

Fig. 5.

Fig. 5.

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Multivariable models for postoperative hypoglycemia after Roux-en-Y gastric bypass (RYGB) (A) or laparoscopic adjustable gastric band (LAGB) (B).

In RYGB-noT2DM, increasing age was associated with a lower risk of hypoglycemia symptoms (OR .81 [95%CI .69–.96], P = .016) whereas higher baseline leptin level was associated with increased risk (OR 1.12 [95%CI 1.02–1.23], P = .013) (Supplemental Table 3). For both RYGB-noT2D and RYGB-preT2D, baseline SSRI/SNRI use was significantly associated with postoperative hypoglycemia symptoms (OR 1.54 [95%CI 1.04–2.28], P = .030, and 2.30 [95%CI 1.17–4.52], P=.016, respectively) (Fig. 5A, Supplemental Table 3); this association was not seen in RYGB-T2D. The depression score was a modest, but significant predictor in RYGB-T2D (OR 1.05 [95%CI 1.00–1.09], P = .035) (Supplemental Table 3). Interestingly, a subgroup analysis of RYGB-T2D patients not taking diabetes medications revealed that SSRI/SNRI use again emerged as a significant predictor (OR 2.22 [95%CI 1.13–4.34], P = .020).

Depression score was a risk factor in multivariable analysis of LAGB-noT2D (OR 1.07 [95%CI 1.01–1.12], P = .019), but SSRI/SNRI use was not (Fig. 5B, Supplemental Table 4). In LAGB-T2D, hemoglobin A1C and smoking were both significant risk factors (OR 1.06 [95%CI 1.01–1.12), P = .032 and OR 5.15 [95%CI 1.63–8.00], P = .005, respectively).

Baseline characteristics not associated with postoperative hypoglycemia symptoms included BMI, total body weight lost (%TWBL) at 1 year, systolic or diastolic blood pressure, hypertension medications, fasting insulin or glucose levels, and HOMA2 IR. While tramadol use has been associated with hypoglycemia [38], the number of patients taking tramadol was too small to be included as an independent risk factor in this model.

Weight loss

We next examined the relationship between hypoglycemia symptoms and weight loss. Total weight loss did not differ regardless of hypoglycemia symptoms (Supplemental Fig. 5). For example, RYGB-noT2D patients with symptoms lost 29.2% total body weight as compared with 29.6% in those without symptoms. Weight loss after LAGB was less robust and more variable [39], ranging from 5.2%–19.3% without any relationship to symptoms. Likewise, there was no relationship between weight regain from postoperative nadir and hypoglycemia symptoms.

Discussion

We undertook the present analysis to address several important questions regarding the prevalence, frequency, timing, and associated risk factors for hypoglycemia symptoms after bariatric surgery in a unique longitudinal patient cohort spanning 7 years. We found that hypoglycemia symptoms increased after surgery, particularly in RYGB-noT2D and RYGB-preT2D groups. Additionally, preoperative hypoglycemia symptoms and SSRI/SNRI use were the factors most associated with postoperative hypoglycemia symptoms. There was no correlation with weight loss or weight regain and hypoglycemia symptoms.

As others have shown, the prevalence of hypoglycemia symptoms increases after weight loss surgery, most significantly after RYGB. Overall prevalence rates of postoperative hypoglycemia symptoms was 38.5%, with the highest increase from baseline to postoperative (33.6%) seen in the RYGB-noT2D group, from 2.8% baseline to 36.4% postoperative. The RYGB-preT2D group also increased significantly (24.2%) from 4.9% to 29.1% postoperatively. These results were similar to a prior report from a cross-sectional survey analysis, in which 29% of post-RYGB reported new hypoglycemia symptom onset after RYGB [2]. In our study, the highest absolute prevalence of postoperative hypoglycemia symptoms was in those with diabetes at baseline; in this group, symptoms were common both before and after bariatric surgery, occurring in up to 58% of subjects, and risk was especially high for those taking insulin and insulin secretagogues, as expected.

Over time, the RYGB-T2D group saw decreasing annual prevalence with the highest percentage of symptoms seen at postoperative year 1 (28.9%) and the lowest at postoperative year 6 (17.1%). Improved insulin sensitivity with weight loss, and in RYGB, rapid onset of additional weight-independent mechanisms which increase insulin secretion and lower serum glucose levels, allowing reduction in diabetes medication use, likely contributed to decreasing symptom prevalence in patients with T2D. In participants who did not have T2D at baseline, annual prevalence of hypoglycemia symptoms was low at baseline, but tripled (from 4.8% to 14.1%) in the RYGB-preT2D group and increased by a factor of 6 (from 2.8% to 18.1%) in the RYGB-noT2D group. In both RYGB-noT2D and RYGB-preT2D groups, peak annual prevalence occurred in the fifth postoperative year before declining slightly. After LAGB-noT2D and LAGB-preT2D, the annual prevalence of symptoms remained low (~5% or less), potentially due to the restrictive mechanism, maintenance of normal nutrient flow, and lack of excessive incretin hormone secretion. The absence of symptoms in the LAGB cohort without diabetes suggests that there are physiologic mechanisms specific to RYGB which lead to the development of hypoglycemia symptoms.

The overall frequency of hypoglycemia symptoms was rare with 39.1% reporting symptoms at only 1 postoperative visit. Among those with symptoms, only 4.0% reported persistent hypoglycemia symptoms at 6 or more annual postoperative visits, with the majority of these patients being in the RYGB groups. Fortunately, severe episodes of hypoglycemia symptoms were uncommon (2.6%–3.6% at 5 years), similar to previous reports [7].

Analysis of the timing of hypoglycemia symptoms in relationship to meals revealed both expected and unexpected findings after RYGB. As predicted, the majority of patients reported that these symptoms occurred in the post-prandial state. Because of the small stomach pouch and bypass of the pyloric valve, nutrient transit into the intestine is rapid and may produce vasomotor symptoms characteristic of “early dumping” syndrome. Hypoglycemia can be a substantial component of dumping, and both dumping and hypoglycemia share some elements of common pathophysiology, such as postprandial surges of both glucose and GLP1. In some individuals this pattern can also promote excessive insulin secretion and yield subsequent hypoglycemia. We acknowledge that there may be substantial overlap between symptoms of early dumping and later-onset hypoglycemia, and our survey-based queries are unable to fully distinguish these.

However, by year 5, participants in our study also reported hypoglycemia symptoms at times of the day and night that were unrelated to meals. In a recent study using CGM after RYGB and sleeve gastrectomy, over half (55%) of sensor glucose levels <55 mg/dL (3.1 mmol/L) occurred nocturnally [40]. Additionally, patients often report that activity precipitates hypoglycemia, suggesting additional factors, such as increases in levels of FGF19 [26] and increased insulin-independent glucose uptake, may be contributors [25]. These data underscore that PBH is not limited to the postprandial state, and also highlight the importance of careful assessment of symptom timing and corresponding glucose levels during clinical evaluation. Symptoms occurring upon arising (after an overnight fast), or severe, treatment-refractory hypoglycemia should prompt additional hormonal and micronutrient evaluation to rule out autonomous insulin secretion potentially related to insulinoma.

We examined a large number of baseline clinical and laboratory variables identified as potential risk factors for postoperative hypoglycemia symptoms. One of our key findings is that regardless of the surgical treatment and diabetes status, the greatest risk factor for postoperative hypoglycemia symptoms was preoperative hypoglycemia symptoms. The magnitude of this effect on the postoperative risk was so large that it needed to be excluded from subsequent analyses to detect other significant baseline variables. This suggests that the contributors to an individual’s experience of hypoglycemia symptoms following either RYGB or LAGB are likely present prior to surgery. While hypoglycemia symptoms are nonspecific, making definitive preoperative diagnosis challenging, these data are consistent with findings of lower glucose and higher insulin levels in patients who subsequently develop symptomatic PBH during OGTT [41]. While we do not fully understand mechanisms underlying these interesting findings, we suggest that patients should be queried preoperatively for symptoms of hypoglycemia; if present, additional evaluation could be considered, and these factors should be included in risk/benefit analysis and decision-making about the type of surgical procedure planned.

Once the presence of baseline hypoglycemia symptoms was removed from the multivariable analysis, we found that older age was associated with fewer hypoglycemia symptoms. It is possible that older adults have reduced capacity for postprandial insulin secretion, reducing hypoglycemia risk. Interestingly, higher baseline leptin levels were associated with increased risk. Sex, baseline BMI, or postoperative weight loss were not identified as risk factors. Moreover, we could detect no impact of symptom frequency or severity on either weight loss or regain 5–7 years after surgery. Our data contrast to the study of Varma et al [15], which reported hypoglycemia symptoms were associated with increased odds of weight regain of >10%. These differences are likely attributable to the cross-sectional survey design with single time point, low response rates, and much smaller sample size (428), all of which may have introduced bias into the observed relationships.

A key new finding in our study was the significant association between SSRI/SNRI medication use and postoperative hypoglycemia symptoms following RYGB. This was especially apparent in the RYGB-noT2D and RYGB-preT2D groups, and in the RYGB-T2D subgroup not taking a diabetes medication. Diabetes is an established risk factor for depression with prevalence ranging from 8.5%–27.3% [42,43]. SSRIs are considered the preferred initial therapy for treatment in patients with diabetes due to their effect on lowering blood glucose, increasing insulin sensitivity, decreasing appetite, promoting weight loss, and reducing depression recurrence [42,44,45]. It is hypothesized that SSRIs can suppress basal sympathetic nervous system activity [46], predisposing patients to hypoglycemia. Although animal studies have not shown a decrease in counter-regulatory responses to hypoglycemia with SSRIs [47], significant reductions in serum glucose have been demonstrated [48]. Nonsurgical patients with diabetes and depression treated with SSRIs are at increased risk of symptomatic hypoglycemia and decreased hypoglycemia awareness [36,37]. We believe this is the first report linking hypoglycemia symptoms in post-RYGB patients with use of SSRI/SNRI antidepressant medications. Future clinical studies will be required to directly test the metabolic impact of these medications on glucose metabolism in the population of patients with PBH.

Strengths of this study include data collection from a unique prospective, longitudinal study with multiple (10) institutions across the United States, which was adequately powered (sample size of >2000 participants), with >85% retention at 7 years. This robust database allowed us to define the incidence of postoperative hypoglycemia symptoms and to identify factors which were associated with increased risk of postoperative symptoms. Our study integrated clinical information that is difficult to collect outside of a multi-institutional, nationally funded study. Moreover, our analysis of both RYGB and LAGB allowed comparison of frequency and patterns of symptoms in those with weight loss due to dietary restriction of intake with a restrictive procedure (LAGB) as compared with individuals who experience both weight loss and complex changes in endocrine hormonal secretion as a consequence of altered gastrointestinal anatomy and nutrient flow (RYGB).

Study limitations include the self-report of hypoglycemia symptoms to research staff using a validated survey device which is subject to recall bias. We acknowledge limitations of assessment using symptoms, as symptoms of hypoglycemia are nonspecific and could reflect other diagnoses including “dumping syndrome”, which has broad symptom overlap and shares some elements of pathophysiology with PBH. Confirming a diagnosis of hypoglycemia with laboratory data is challenging even in clinical practice, as few patients are hospitalized for severe hypoglycemia and many that do present for treatment have already self-medicated with oral carbohydrates prior to assessment of plasma glucose. Additionally, the use of continuous glucose monitoring (CGM) for diagnosis is not recommended due to reduced sensor accuracy at low glucose levels [49]. Masked CGM was not widely available at the time of the LABS study initiation, would have been cost prohibitive, and would not allow conclusion about symptomatic hypoglycemia, which would be required for diagnosis and management. Despite these limitations, our longitudinal assessment of symptoms in a large surgical cohort is a key step toward understanding the prevalence of symptoms and identifying risk factors for this symptom complex. Other limitations include the fact that our data do not address postoperative treatment of diabetes, including medication changes that typically accompany weight loss. Therefore, the observed postoperative hypoglycemia symptoms in individuals with diabetes may have been medication-induced, especially at early time points. Physicians may be slow to adjust antidiabetes medications leading to over-medication and episodes of hypoglycemia. However, observed increases in hypoglycemia symptoms from baseline to 5 years in patients without diabetes were striking and unlikely to be confounded by diabetes medications. Finally, our data do not allow us to assess the relationship between dietary macronutrients or quantity and hypoglycemia symptoms; it is possible that differences in diet may contribute to differences in severity or frequency between groups (e.g., diabetes versus non-diabetes groups).

Future studies will be required to further investigate patient-specific risk factors potentially contributing to the presence and/or emergence of hypoglycemia symptoms in the postbariatric population, such as genetic background, diet, microbiome, and alterations in postprandial bile acid kinetics, recently linked to low glucose levels in asymptomatic postbariatric patients [50]. Moreover, studies of the potential role of cholecystectomy as a risk factor for symptoms of dumping syndrome in RYGB and of hypoglycemia after sleeve gastrectomy [51] will be valuable.

Conclusion

In summary, hypoglycemia symptoms increase after bariatric surgery, with the most profound increases seen in RYGB patients without diabetes and with prediabetes. In multivariable analysis, the presence of preoperative hypoglycemia symptoms is the strongest risk factor for postoperative hypoglycemia symptoms. Additionally, SSRI/SNRI use in RYGB patients without diabetes is a significant risk factor. The timing of hypoglycemia symptoms changes as time from surgery increases and is often unrelated to meals. Approximately 1.2–3.6% of RYGB have persistent or severe hypoglycemia symptoms after bariatric surgery. We suggest that preoperative evaluation include questions about hypoglycemia symptoms, guiding evaluation and decision-making. Moreover, the role of SSRI/SNRI as a potential risk factor for hypoglycemia symptoms should be evaluated in individual patients.

Supplementary Material

Supplementary Material

Acknowledgments

We gratefully acknowledge the statistical analysis contributions of Carrie M. Nielson, M.P.H., Ph.D. This clinical study was a cooperative agreement funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Grant number: DCC -U01 DK066557; Columbia - U01-DK66667 (in collaboration with Cornell University Medical Center CTRC, Grant UL1-RR024996); University of Washington - U01-DK66568 (in collaboration with CTRC, Grant M01RR-00037); Neuropsychiatric Research Institute - U01-DK66471; East Carolina University – U01-DK66526; University of Pittsburgh Medical Center – U01-DK66585 (in collaboration with CTRC, Grant UL1-RR024153); Oregon Health & Science University – U01-DK66555. Additional funding support came from NIH R01 DK106193, U01 DK114156, and P30 DK036836 (DRC, Joslin Diabetes Center) and R01 DK103842 (JQP).

LABS personnel contributing to the study include:

Columbia University Medical Center, New York, NY: Paul D. Berk, M.D., Marc Bessler, M.D., Amna Daud, Harrison Lobdell IV, Jemela Mwelu, Beth Schrope, M.D., Ph.D., Akuezunkpa Ude, M.D. Cornell University Medical Center, New York, NY: Jamie Honohan B.A., Michelle Capasso, B.A., Ricardo Costa, B.S., Greg Dakin, M.D., Faith Ebel R.D., M.P.H., Michel Gagner, M.D., Jane Hsieh B.S., Alfons Pomp, M.D., Gladys Strain, Ph.D. East Carolina Medical Center, Greenville, NC: Rita Bowden, R.N., William Chapman, M.D., FACS, Blair Cundiff, B.S., Mallory Ball, B.S., Emily Cunningham, B.A., Lynis Dohm, Ph.D., John Pender, M.D., Walter Pories, M.D., FACS Neuropsychiatric Research Institute, Fargo, ND: Jennifer Barker, M.B.A., Michael Howell, M.D., Luis Garcia, M.D., FACS, M.B.A., Kathy Lancaster, B.A., Erika Lovaas, B.S., James E. Mitchell, M.D., Tim Monson, M.D., Oregon Health & Science University: Chelsea Cassady, B.S., Emily Coburn, M.P.H., Emily Moher, M.P.H., Clifford Deveney, M.D., Katherine Elder, Ph.D., Stefanie Greene, Jonathan Purnell, M.D., Robert O’Rourke, M.D., Chad Sorenson, Bruce M. Wolfe, M.D., Legacy Good Samaritan Hospital, Portland, OR: Emma Patterson, M.D., William Raum, M.D., Lisa VanDerWerff, P.A.C., Jason Kwiatkowski, P.A.C., University of Pittsburgh Medical Center, Pittsburgh, PA: Anita P. Courcoulas, M.D., M.P.H., FACS, William Gourash, M.S.N., C.R.N.P., Carol A. McCloskey, M.D., Ramesh Ramanathan, M.D., Melissa Kalarchian, Ph.D., Marsha Marcus, Ph.D., Eleanor Shirley, M.A., Angela Turo, B.S., University of Washington, Seattle, WA: David R. Flum, M.D., M.P.H., E. Patchen Dellinger, M.D., Saurabh Khandelwal, M.D., Skye D. Stewart, M.S., CCRC, Morgan M. Cooley, Rebecca Blissell, Megan J. Miller, MEd Virginia Mason Medical Center, Seattle, WA: Richard Thirlby, M.D., Lily Chang, M.D., Jeffrey Hunter, M.D., Ravi Moonka, M.D., Debbie Ng, M.P.H., M.A. Data Coordinating Center, Graduate School of Public Health at the University of Pittsburgh, Pittsburgh, PA: Steven H. Belle, Ph.D., M.Sc.Hyg., Wendy C. King, Ph.D., Debbie Martin, B.A., Rocco Mercurio, M.B.A., Abdus Wahed, Ph.D., Frani Averbach, M.P.H., R.D.N. National Institute of Diabetes and Digestive and Kidney Diseases: Mary Horlick, M.D., Carolyn W. Miles, Ph.D., Myrlene A. Staten, M.D., Susan Z. Yanovski, M.D. National Cancer Institute: David E. Kleiner, M.D., Ph.D.

Footnotes

Disclosures

Dr. Patti reports grants from National Institutes of Health during the conduct of the study; grants from Helmsley Trust, other from Xeris Pharmaceuticals, grants from Dexcom, grants from Chan Zuckerberg Initiative, personal fees from DRG, personal fees from Avolynt, personal fees from Eiger, personal fees from Poxel, personal fees from Fractyl, personal fees from Premier Research, personal fees from Decision Resources, personal fees from Globe Life Sciences, personal fees from Cello Health Advantage, personal fees from Springer Publishing, personal fees from Obesity Medicine Association, personal fees from Endocrine Society, personal fees from American Diabetes Association, personal fees from American Society for Metabolic and Bariatric Surgery personal fees from American Association for Clinical Endocrinologists, personal fees from Academy of Nutrition and Dietetics, outside the submitted work. In addition, Dr. Patti has a patent Treatment of Post-Bariatric Hypoglycemia Using Mini-Dose Stable Glucagon pending, and a patent Methods and Composition for Treating Hypoglycemia pending.

None of the remaining authors have any financial disclosure related to the content of this manuscript.

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.1016/j.soard.2021.04.021.

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Supplementary Material
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