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Rate of post-bariatric hypoglycemia using continuous glucose monitoring: A meta-analysis of literature studies

Published:September 25, 2021DOI:https://doi.org/10.1016/j.numecd.2021.08.047

      Abstract

      Aims

      Hypoglycemia is a serious complication of bariatric surgery. The aim of the present meta-analysis was to evaluate the rate and the timing of post-bariatric hypoglycemia (PBH) with different bariatric procedures using reliable data from continuous glucose monitoring (CGM).

      Data synthesis

      Studies were systematically searched in the Web of Science, Scopus and PubMed databases according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The prevalence of PBH was expressed as weighted mean prevalence (WMP) with pertinent 95% confidence intervals (95%CI). A total of 8 studies (16 datasets) enrolling 280 bariatric subjects were identified. The total WMP of PBH was 54.3% (95%CI: 44.5%–63.8%) while the WMP of nocturnal PBH was 16.4% (95%CI: 7.0%–34%). We found a comparable rate of PBH after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) (OR 1.62, 95%CI: 0.71–3.7; P = 0.248); likewise, the percent time spent in hypoglycemia was similar with the two procedures (mean difference 5.3%, 95%CI: −1.4%–12.0%; P = 0.122); however, RYGB was characterized by a higher glycemic variability than SG. Regression models showed that the time elapsed from surgical intervention was positively associated with a higher rate of both total PBH (Z-value: 3.32, P < 0.001) and nocturnal PBH (Z-value: 2.15, P = 0.013).

      Conclusions

      PBH, both post-prandial and nocturnal, is more prevalent than currently believed. The rate of PBH increases at increasing time from surgery and is comparable after RYGB and SG with a higher glucose variability after RYGB.

      Keywords

      Introduction

      Bariatric surgery (BS) represents a valid therapeutic choice for the management of severe obesity since it provides durable weight loss and improvement/remission of obesity-related comorbidities [
      • Fruhbeck G.
      Bariatric and metabolic surgery: a shift in eligibility and success criteria.
      ]. Despite its efficacy in reducing total and cardiovascular mortality and in improving metabolic control [
      • Vest A.R.
      • Heneghan H.M.
      • Schauer P.R.
      • Young J.B.
      Surgical management of obesity and the relationship to cardiovascular disease.
      ,
      • Flum D.R.
      • Dellinger E.P.
      Impact of gastric bypass operation on survival: a population-based analysis.
      ,
      • Adams T.D.
      • Gress R.E.
      • Smith S.C.
      • Halverson R.C.
      • Simper S.C.
      • Rosamond W.D.
      • et al.
      Long-term mortality after gastric bypass surgery.
      ], increasing evidence has shown the occurrence of long-term complications in nutritional status [
      • Lupoli R.
      • Lembo E.
      • Saldalamacchia G.
      • Avola C.K.
      • Angrisani L.
      • Capaldo B.
      Bariatric surgery and long-term nutritional issues.
      ], glucose regulation [
      • Nosso G.
      • Lupoli R.
      • Saldalamacchia G.
      • Griffo E.
      • Cotugno M.
      • Costabile G.
      • et al.
      Diabetes remission after bariatric surgery is characterized by high glycemic variability and high oxidative stress.
      ], and bone health [
      • Gagnon C.
      • Schafer A.L.
      Bone health after bariatric surgery.
      ].
      Post-bariatric hypoglycemia (PBH) is a challenging complication of BS characterized by low blood glucose levels, typically occurring 1–3 h after a meal with autonomic and neuroglycopenic symptoms with relief after glucose ingestion [
      • Eisenberg D.
      • Azagury D.E.
      • Ghiassi S.
      • Grover B.T.
      • Kim J.J.
      ASMBS position statement on postprandial hyperinsulinemic hypoglycemia after bariatric surgery.
      ]. This complication is most often associated with Roux-en-Y gastric bypass (RYGB) although it has been reported also after sleeve gastrectomy (SG) [
      • Belligoli A.
      • Sanna M.
      • Serra R.
      • Fabris R.
      • Pra’ C.D.
      • Conci S.
      • et al.
      Incidence and predictors of hypoglycemia 1 Year after laparoscopic sleeve gastrectomy.
      ,
      • Salehi M.
      • Vella A.
      • McLaughlin T.
      • Patti M.E.
      Hypoglycemia after gastric bypass surgery: current concepts and controversies.
      ]. PBH can be managed through appropriate nutritional measures including multiple small meal, high consumption of dietary fibers and protein, and low intake of rapidly absorbable carbohydrates [
      • Schiavo L.
      • Pilone V.
      • Rossetti G.
      • Iannelli A.
      The role of the nutritionist in a multidisciplinary bariatric surgery team.
      ,
      • Lembo E.
      • Lupoli R.
      • Ciciola P.
      • Silvestri E.
      • Saldalamacchia G.
      • Capaldo B.
      Implementation of low glycemic index diet together with cornstarch in post-gastric bypass hypoglycemia: two case reports.
      ]. In patients with severe symptoms, a pharmacological approach can be required [
      • Eisenberg D.
      • Azagury D.E.
      • Ghiassi S.
      • Grover B.T.
      • Kim J.J.
      ASMBS position statement on postprandial hyperinsulinemic hypoglycemia after bariatric surgery.
      ].
      The prevalence of PBH is uncertain mostly because of a poor consensus on diagnostic criteria. The estimated rates range from 1% if we consider hospitalization data for severe episodes [
      • Marsk R.
      • Jonas E.
      • Rasmussen F.
      • Näslund E.
      Nationwide cohort study of post-gastric bypass hypoglycemia including 5,040 patients undergoing surgery for obesity in 1986-2006 in Sweden.
      ] to ∼30% using specific questionnaires [
      • Lee C.J.
      • Clark J.M.
      • Schweitzer M.
      • Magnuson T.
      • Steele K.
      • Koerner O.
      • et al.
      Prevalence of and risk factors for hypoglycemic symptoms after gastric bypass and sleeve gastrectomy.
      ] and to ∼50% based on provocative tests, namely the mixed meal tolerance test (MMT) [
      • Lobato C.B.
      • Pereira S.S.
      • Guimarães M.
      • Hartmann B.
      • Wewer Albrechtsen N.J.
      • Hilsted L.
      • et al.
      A potential role for endogenous glucagon in preventing post-bariatric hypoglycemia.
      ,
      • Emous M.
      • van den Broek M.
      • Wijma R.B.
      • de Heide L.J.M.
      • van Dijk G.
      • Laskewitz A.
      • et al.
      Prevalence of hypoglycaemia in a random population after Roux-en-Y gastric bypass after a meal test.
      ] and the oral glucose tolerance test (OGTT) [
      • Roslin M.S.
      • Oren J.H.
      • Polan B.N.
      • Damani T.
      • Brauner R.
      • Shah P.C.
      Abnormal glucose tolerance testing after gastric bypass.
      ]. However, the real prevalence is probably underestimated because of several undiagnosed cases due to hypoglycemia unawareness [
      • Salehi M.
      • Vella A.
      • McLaughlin T.
      • Patti M.E.
      Hypoglycemia after gastric bypass surgery: current concepts and controversies.
      ]. More recently, continuous glucose monitoring (CGM), routinely applied to diabetic patients, has been employed in populations suffering from hypoglycemic syndromes since it provides a picture of fluctuations in blood glucose levels over days or weeks, thus unmasking possible episodes of asymptomatic or nocturnal hypoglycemia [
      • Kubota T.
      • Shoda K.
      • Ushigome E.
      • Kosuga T.
      • Konishi H.
      • Shiozaki A.
      • et al.
      Utility of continuous glucose monitoring following gastrectomy.
      ,
      • Saxon D.R.
      • McDermott M.T.
      • Michels A.W.
      Novel management of insulin autoimmune syndrome with rituximab and continuous glucose monitoring.
      ,
      • Philippon M.
      • Sejil S.
      • Mugnier M.
      • Rocher L.
      • Guibergia C.
      • Vialettes B.
      • et al.
      Use of the continuous glucose monitoring system to treat insulin autoimmune syndrome: quantification of glucose excursions and evaluation of treatment efficacy.
      ,
      • Lee D.
      • Dreyfuss J.M.
      • Sheehan A.
      • Puleio A.
      • Mulla C.M.
      • Patti M.E.
      Glycemic patterns are distinct in post-bariatric hypoglycemia after gastric bypass (PBH-RYGB).
      ].
      We here provide a meta-analysis of the literature studies with the aim of determining the rate of PBH assessed by CGM in different bariatric settings.

      Methods

      The search strategy was determined a priori and included: reporting the specific objectives, the inclusion and exclusion criteria for study selection, the approach for quality assessment, the outcomes and the statistical methods.

      Search strategy, selection criteria and quality assessment

      In order to identify all available studies reporting the PBH rate assessed by CGM, we conducted a systematic research of the literature in Web of Science, Scopus and PubMed according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      • Group P.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ]. The last search was carried out on May, 2021 with no language or publication year restriction, using the following terms in all possible combinations: bariatric, sleeve gastrectomy, gastric bypass, diversion, banding, band, duodenal switch, single anastomosis duodeno–ileal, SADI-S, mini gastric bypass, one anastomosis gastric bypass, weight loss surgery, continuous glucose monitoring, glucose variability, glycemic variability, glycaemic variability, CGM, hypoglycaemia, hypoglycemia, hypoglycaemic, hypoglycemic. In addition, the lists of the bibliographic references of all retrieved articles were manually consulted to find other relevant articles. In case of missing data, the Authors were contacted by e-mail to claim the original data. Two independent Authors (EL and CR) analysed each article and separately performed the data extraction. In case of disagreement, a third investigator was consulted (RL). Discrepancies were resolved by consensus. Overall, selection results showed a high inter-reader agreement (κ = 0.98) and were reported according to PRISMA flow-chart (Supplemental Figure S1).
      According to a pre-specified protocol, all studies reporting data on the rate of PBH assessed by real time CGM were included. Case reports, reviews and articles on animal models were excluded. Overall, we included in the analysis all studies performed in individuals undergoing bariatric surgery that provided the number of patients with hypoglycemia assessed by CGM. Given the unstable health conditions occurring during the first year after surgery (i.e. rapid and massive weight loss, changes in nutritional and metabolic status, etc.), studies considering a time from bariatric procedure <1 year were excluded from the analysis. In each study, data regarding sample size, major clinical and demographic characteristics of the study population were extracted.
      The evaluation of methodological quality of each study was performed with the Newcastle–Ottawa Scale (NOS) [
      • Ga Wells B.S.
      • O'Connell D.
      • Peterson J.
      • Welch V.
      • Losos M.
      • Tugwell P.
      The Newcastle-Ottawa Scale (NOS) for assessing the quality of non-randomized studies in meta-analyses.
      ]. The scoring system encompasses three major domains (selection, exposure, outcome) and a resulting score range between 0 and 5, a higher score representing a better methodological quality. Results of the NOS quality assessment are reported in Supplemental Table S1.

      Data synthesis and statistics

      Data synthesis and analyses were carried out using Comprehensive Meta-analysis (Version 3, Biostat, Englewood NJ, 2006). The prevalence of PBH was expressed as weighted mean prevalence (WMP) with 95% confidence intervals (95%CI). Differences in the percent time spent in hypoglycemia between RYGB and SG subjects were expressed as weighted mean difference (MD) with 95%CI.
      The primary outcome was the rate of PBH assessed by CGM at least 1 year from weight loss surgery. Secondary outcomes were the comparative assessment of PBH prevalence and differences in CGM parameters in RYGB subjects as compared to SG subjects. The overall effect was tested by Z-scores, with P < 0.05 being considered statistically significant. We evaluated statistical heterogeneity among studies with chi-squared Cochran's Q test and with I2 statistic, which measure the inconsistency across study results and describe the proportion of total variation in study estimates due to heterogeneity rather than sampling error. In detail, an I2 value of 25% corresponds to low, 25–50% to moderate, and 50% to high heterogeneity [
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      ]. Publication bias was assessed by the Egger's test and funnel plots of the logit event rate vs the standard error were used as graphical representation. To assess small-study effect, funnel plots were visually inspected for asymmetry and the Egger's test was used to assess publication bias, over and above any subjective evaluation, with P < 0.10 being considered statistically significant [
      • Sterne J.A.
      • Egger M.
      • Smith G.D.
      Systematic reviews in health care: investigating and dealing with publication and other biases in meta-analysis.
      ]. In case of a significant publication bias, the Duval and Tweedie's trim and fill method with the random-effect model was used to allow for the estimation of an adjusted effect size [
      • Duval S.
      • Tweedie R.
      Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis.
      ].
      In order to be as conservative as possible, the random-effect method was used for all analyses to take into account the variability among studies.

      Subgroup analyses

      We performed separate sub-group analyses on the prevalence of PBH according to a) different bariatric procedures; b) type of CGM device; c) glucose thresholds used to define hypoglycemia. Moreover, we performed a separate analysis on the prevalence of nocturnal hypoglycemia.

      Meta-regression analyses

      In order to assess whether the rate of PBH observed in different studies could be affected by demographic data (mean age, male gender) and clinical variables (time elapsed from surgery, current body mass index (BMI), pre-operative BMI, excess weight loss [percentage of excess body weight lost after surgery], pre-operative diabetes mellitus, hypoglycemia symptoms, CGM duration), we performed meta-regression analyses after implementing regression models with the rate of PBH as dependent variable (y) and the above mentioned co-variates as independent variables (x). Comprehensive Meta-analysis software (Version 3, Biostat, Englewood NJ, 2006) was used for the multivariate approach.

      Results

      After excluding duplicates, the search detected 372 articles. Of these studies, 272 were excluded because they were off the topic after scanning the title and/or the abstract. Other 92 studies were excluded after full-length paper evaluation (Supplemental Figure S1). Studies by Abrahamsson et al. [
      • Abrahamsson N.
      • Edén Engström B.
      • Sundbom M.
      • Karlsson F.A.
      Hypoglycemia in everyday life after gastric bypass and duodenal switch.
      ], Lazar et al. [
      • Lazar L.O.
      • Sapojnikov S.
      • Pines G.
      • Mavor E.
      • Ostrovsky V.
      • Schiller T.
      • et al.
      Symptomatic and asymptomatic hypoglycemia post three different bariatric procedures: a common and severe complication.
      ], Capristo et al. [
      • Capristo E.
      • Panunzi S.
      • De Gaetano A.
      • Spuntarelli V.
      • Bellantone R.
      • Giustacchini P.
      • et al.
      Incidence of hypoglycemia after gastric bypass vs sleeve gastrectomy: a randomized trial.
      ], Jimenez et al. [
      • Jiménez A.
      • Ceriello A.
      • Casamitjana R.
      • Flores L.
      • Viaplana-Masclans J.
      • Vidal J.
      Remission of type 2 diabetes after Roux-en-Y gastric bypass or sleeve gastrectomy is associated with a distinct glycemic profile.
      ], and Lupoli et al. [
      • Lupoli R.
      • Lembo E.
      • Ciciola P.
      • Schiavo L.
      • Pilone V.
      • Capaldo B.
      Continuous glucose monitoring in subjects undergoing bariatric surgery: diurnal and nocturnal glycemic patterns.
      ] provided separate data for patients undergoing different bariatric procedures. The study by Halperin et al. [
      • Halperin F.
      • Patti M.E.
      • Skow M.
      • Bajwa M.
      • Goldfine A.B.
      Continuous glucose monitoring for evaluation of glycemic excursions after gastric bypass.
      ] provided separate data for patients with and without hypoglycemia symptoms and the study by Vaurs et al. [
      • Vaurs C.
      • Brun J.F.
      • Bertrand M.
      • Burcelin R.
      • du Rieu M.C.
      • Anduze Y.
      • et al.
      Post-prandial hypoglycemia results from a non-glucose-dependent inappropriate insulin secretion in Roux-en-Y gastric bypassed patients.
      ] provided separate data for patients reporting plasma glucose levels <50 mg/dl during a 75-g OGTT. In all these cases, the different populations were analyzed as separate datasets.
      A total of 8 studies (16 datasets) [
      • Abrahamsson N.
      • Edén Engström B.
      • Sundbom M.
      • Karlsson F.A.
      Hypoglycemia in everyday life after gastric bypass and duodenal switch.
      ,
      • Lazar L.O.
      • Sapojnikov S.
      • Pines G.
      • Mavor E.
      • Ostrovsky V.
      • Schiller T.
      • et al.
      Symptomatic and asymptomatic hypoglycemia post three different bariatric procedures: a common and severe complication.
      ,
      • Capristo E.
      • Panunzi S.
      • De Gaetano A.
      • Spuntarelli V.
      • Bellantone R.
      • Giustacchini P.
      • et al.
      Incidence of hypoglycemia after gastric bypass vs sleeve gastrectomy: a randomized trial.
      ,
      • Jiménez A.
      • Ceriello A.
      • Casamitjana R.
      • Flores L.
      • Viaplana-Masclans J.
      • Vidal J.
      Remission of type 2 diabetes after Roux-en-Y gastric bypass or sleeve gastrectomy is associated with a distinct glycemic profile.
      ,
      • Lupoli R.
      • Lembo E.
      • Ciciola P.
      • Schiavo L.
      • Pilone V.
      • Capaldo B.
      Continuous glucose monitoring in subjects undergoing bariatric surgery: diurnal and nocturnal glycemic patterns.
      ,
      • Halperin F.
      • Patti M.E.
      • Skow M.
      • Bajwa M.
      • Goldfine A.B.
      Continuous glucose monitoring for evaluation of glycemic excursions after gastric bypass.
      ,
      • Vaurs C.
      • Brun J.F.
      • Bertrand M.
      • Burcelin R.
      • du Rieu M.C.
      • Anduze Y.
      • et al.
      Post-prandial hypoglycemia results from a non-glucose-dependent inappropriate insulin secretion in Roux-en-Y gastric bypassed patients.
      ,
      • Kefurt R.
      • Langer F.B.
      • Schindler K.
      • Shakeri-Leidenmühler S.
      • Ludvik B.
      • Prager G.
      Hypoglycemia after Roux-En-Y gastric bypass: detection rates of continuous glucose monitoring (CGM) versus mixed meal test.
      ] enrolling 280 bariatric subjects were included in the meta-analysis.

      Study characteristics

      The major characteristics of the included studies are shown in Table 1. The number of enrolled patients ranged from 16 to 51 with a mean age of 46.3 year (range: 39.6–52.0 years). Eight studies [
      • Abrahamsson N.
      • Edén Engström B.
      • Sundbom M.
      • Karlsson F.A.
      Hypoglycemia in everyday life after gastric bypass and duodenal switch.
      ,
      • Lazar L.O.
      • Sapojnikov S.
      • Pines G.
      • Mavor E.
      • Ostrovsky V.
      • Schiller T.
      • et al.
      Symptomatic and asymptomatic hypoglycemia post three different bariatric procedures: a common and severe complication.
      ,
      • Capristo E.
      • Panunzi S.
      • De Gaetano A.
      • Spuntarelli V.
      • Bellantone R.
      • Giustacchini P.
      • et al.
      Incidence of hypoglycemia after gastric bypass vs sleeve gastrectomy: a randomized trial.
      ,
      • Jiménez A.
      • Ceriello A.
      • Casamitjana R.
      • Flores L.
      • Viaplana-Masclans J.
      • Vidal J.
      Remission of type 2 diabetes after Roux-en-Y gastric bypass or sleeve gastrectomy is associated with a distinct glycemic profile.
      ,
      • Lupoli R.
      • Lembo E.
      • Ciciola P.
      • Schiavo L.
      • Pilone V.
      • Capaldo B.
      Continuous glucose monitoring in subjects undergoing bariatric surgery: diurnal and nocturnal glycemic patterns.
      ,
      • Halperin F.
      • Patti M.E.
      • Skow M.
      • Bajwa M.
      • Goldfine A.B.
      Continuous glucose monitoring for evaluation of glycemic excursions after gastric bypass.
      ,
      • Vaurs C.
      • Brun J.F.
      • Bertrand M.
      • Burcelin R.
      • du Rieu M.C.
      • Anduze Y.
      • et al.
      Post-prandial hypoglycemia results from a non-glucose-dependent inappropriate insulin secretion in Roux-en-Y gastric bypassed patients.
      ,
      • Kefurt R.
      • Langer F.B.
      • Schindler K.
      • Shakeri-Leidenmühler S.
      • Ludvik B.
      • Prager G.
      Hypoglycemia after Roux-En-Y gastric bypass: detection rates of continuous glucose monitoring (CGM) versus mixed meal test.
      ] enrolled subjects undergoing RYGB, 4 studies [
      • Lazar L.O.
      • Sapojnikov S.
      • Pines G.
      • Mavor E.
      • Ostrovsky V.
      • Schiller T.
      • et al.
      Symptomatic and asymptomatic hypoglycemia post three different bariatric procedures: a common and severe complication.
      ,
      • Capristo E.
      • Panunzi S.
      • De Gaetano A.
      • Spuntarelli V.
      • Bellantone R.
      • Giustacchini P.
      • et al.
      Incidence of hypoglycemia after gastric bypass vs sleeve gastrectomy: a randomized trial.
      ,
      • Jiménez A.
      • Ceriello A.
      • Casamitjana R.
      • Flores L.
      • Viaplana-Masclans J.
      • Vidal J.
      Remission of type 2 diabetes after Roux-en-Y gastric bypass or sleeve gastrectomy is associated with a distinct glycemic profile.
      ,
      • Lupoli R.
      • Lembo E.
      • Ciciola P.
      • Schiavo L.
      • Pilone V.
      • Capaldo B.
      Continuous glucose monitoring in subjects undergoing bariatric surgery: diurnal and nocturnal glycemic patterns.
      ] subjects undergoing SG, 1 study [
      • Abrahamsson N.
      • Edén Engström B.
      • Sundbom M.
      • Karlsson F.A.
      Hypoglycemia in everyday life after gastric bypass and duodenal switch.
      ] subjects undergoing duodenal switch (DS), 1 study [
      • Lazar L.O.
      • Sapojnikov S.
      • Pines G.
      • Mavor E.
      • Ostrovsky V.
      • Schiller T.
      • et al.
      Symptomatic and asymptomatic hypoglycemia post three different bariatric procedures: a common and severe complication.
      ] subjects undergoing omega-loop gastric-bypass (OLGB). The mean preoperative BMI was 45.1 kg/m2 (range: 41.1–55 kg/m2) and the mean BMI at the time of CGM assessment was 29.6 kg/m2 (range: 26.6–31.9 kg/m2). The mean time elapsed from bariatric procedure was 3.1 years (range: 1–8.9 years) with a mean excess weight loss of 82.5% (range: 68.6–104.2%). The percent of diabetic patients before surgery was 25.2% (range: 0–100%), while none of the patients was diabetic at the time of CGM assessment.
      Table 1Characteristics of included studies.
      AuthorOverall Population (N)Type of surgeryTime from surgery (years)Age (years)Male gender (%)Pre-operative BMICurrent BMICGM Subjects (N)CGM DeviceCut-off hypoglycemia CGM (mg/dl)CGM monitoring duration (days)
      Halperin (2011)10RYGB-SX8.951NR50.129.810i-Pro Medtronic703
      6RYGB-ASX5.352NR46.2306
      Kefurt (2015)51RYGB7.248.29.847.231.940i-Pro Medtronic555
      Jiménez (2015)8RYGB2.849.212.5NR28.58Medtronic enlite703
      8SG2.547.237.5NR30.48
      Vaurs (2016)25 HYPORYGB139.6NR42.326.622i-Pro Medtronic604.97
      21 NONHYPO46.8NR43.231214.34
      Capristo (2018)59RYGB1NRNR43.128.325Medtronic enlite555
      58SGNRNR43.43025
      Abrahamsson (2019)15RYGB1.54620422915i-Pro Medtronic603
      15DS24253.3553215
      Lazar (2019)16RYGB>15012.546.2NR11DEXCOM547
      12OLGB4358.339.4NR8
      15SG454041.4NR12
      Lupoli (2020)22RYGB34477432722DEXCOM547
      29SG4362453029
      BMI: Body mass index; CGM: continuous glucose monitoring; RYGB: Roux-en-Y gastric bypass; RYGB-SX: Roux-en-Y gastric bypass with neuroglycopenia symptoms; RYGB-ASX: asymptomatic Roux-en-Y gastric bypass; SG: Sleeve Gastrectomy; HYPO: patients with plasma glucose <50 mg/dl between 90 and 120 min after the oral glucose load; NONHYPO: patients with plasma glucose >50 mg/dl between 90 and 120 min after the oral glucose load; DS: duodenal switch; OLGB: omega loop gastric bypass; NR: not reported.

      Rate of hypoglycemia

      The WMP of PBH in the whole sample (8 studies; 16 datasets) [
      • Abrahamsson N.
      • Edén Engström B.
      • Sundbom M.
      • Karlsson F.A.
      Hypoglycemia in everyday life after gastric bypass and duodenal switch.
      ,
      • Lazar L.O.
      • Sapojnikov S.
      • Pines G.
      • Mavor E.
      • Ostrovsky V.
      • Schiller T.
      • et al.
      Symptomatic and asymptomatic hypoglycemia post three different bariatric procedures: a common and severe complication.
      ,
      • Capristo E.
      • Panunzi S.
      • De Gaetano A.
      • Spuntarelli V.
      • Bellantone R.
      • Giustacchini P.
      • et al.
      Incidence of hypoglycemia after gastric bypass vs sleeve gastrectomy: a randomized trial.
      ,
      • Jiménez A.
      • Ceriello A.
      • Casamitjana R.
      • Flores L.
      • Viaplana-Masclans J.
      • Vidal J.
      Remission of type 2 diabetes after Roux-en-Y gastric bypass or sleeve gastrectomy is associated with a distinct glycemic profile.
      ,
      • Lupoli R.
      • Lembo E.
      • Ciciola P.
      • Schiavo L.
      • Pilone V.
      • Capaldo B.
      Continuous glucose monitoring in subjects undergoing bariatric surgery: diurnal and nocturnal glycemic patterns.
      ,
      • Halperin F.
      • Patti M.E.
      • Skow M.
      • Bajwa M.
      • Goldfine A.B.
      Continuous glucose monitoring for evaluation of glycemic excursions after gastric bypass.
      ,
      • Vaurs C.
      • Brun J.F.
      • Bertrand M.
      • Burcelin R.
      • du Rieu M.C.
      • Anduze Y.
      • et al.
      Post-prandial hypoglycemia results from a non-glucose-dependent inappropriate insulin secretion in Roux-en-Y gastric bypassed patients.
      ,
      • Kefurt R.
      • Langer F.B.
      • Schindler K.
      • Shakeri-Leidenmühler S.
      • Ludvik B.
      • Prager G.
      Hypoglycemia after Roux-En-Y gastric bypass: detection rates of continuous glucose monitoring (CGM) versus mixed meal test.
      ] was 54.3% (95%CI: 44.5%–63.8%, Fig. 1). The heterogeneity among studies was significant (I2: 62.8%, P < 0.001). Results were similar and heterogeneity was not reduced after exclusion of one study at a time. The WMP of PBH was 56.1% (95%CI: 41.2%–69.9%; I2: 68.1%, P = 0.001) in studies specifically examining RYGB patients [
      • Abrahamsson N.
      • Edén Engström B.
      • Sundbom M.
      • Karlsson F.A.
      Hypoglycemia in everyday life after gastric bypass and duodenal switch.
      ,
      • Lazar L.O.
      • Sapojnikov S.
      • Pines G.
      • Mavor E.
      • Ostrovsky V.
      • Schiller T.
      • et al.
      Symptomatic and asymptomatic hypoglycemia post three different bariatric procedures: a common and severe complication.
      ,
      • Capristo E.
      • Panunzi S.
      • De Gaetano A.
      • Spuntarelli V.
      • Bellantone R.
      • Giustacchini P.
      • et al.
      Incidence of hypoglycemia after gastric bypass vs sleeve gastrectomy: a randomized trial.
      ,
      • Jiménez A.
      • Ceriello A.
      • Casamitjana R.
      • Flores L.
      • Viaplana-Masclans J.
      • Vidal J.
      Remission of type 2 diabetes after Roux-en-Y gastric bypass or sleeve gastrectomy is associated with a distinct glycemic profile.
      ,
      • Lupoli R.
      • Lembo E.
      • Ciciola P.
      • Schiavo L.
      • Pilone V.
      • Capaldo B.
      Continuous glucose monitoring in subjects undergoing bariatric surgery: diurnal and nocturnal glycemic patterns.
      ,
      • Halperin F.
      • Patti M.E.
      • Skow M.
      • Bajwa M.
      • Goldfine A.B.
      Continuous glucose monitoring for evaluation of glycemic excursions after gastric bypass.
      ,
      • Vaurs C.
      • Brun J.F.
      • Bertrand M.
      • Burcelin R.
      • du Rieu M.C.
      • Anduze Y.
      • et al.
      Post-prandial hypoglycemia results from a non-glucose-dependent inappropriate insulin secretion in Roux-en-Y gastric bypassed patients.
      ,
      • Kefurt R.
      • Langer F.B.
      • Schindler K.
      • Shakeri-Leidenmühler S.
      • Ludvik B.
      • Prager G.
      Hypoglycemia after Roux-En-Y gastric bypass: detection rates of continuous glucose monitoring (CGM) versus mixed meal test.
      ] and 54.3% (95%CI: 44.5%–63.8%) in those examining SG patients [
      • Lazar L.O.
      • Sapojnikov S.
      • Pines G.
      • Mavor E.
      • Ostrovsky V.
      • Schiller T.
      • et al.
      Symptomatic and asymptomatic hypoglycemia post three different bariatric procedures: a common and severe complication.
      ,
      • Capristo E.
      • Panunzi S.
      • De Gaetano A.
      • Spuntarelli V.
      • Bellantone R.
      • Giustacchini P.
      • et al.
      Incidence of hypoglycemia after gastric bypass vs sleeve gastrectomy: a randomized trial.
      ,
      • Jiménez A.
      • Ceriello A.
      • Casamitjana R.
      • Flores L.
      • Viaplana-Masclans J.
      • Vidal J.
      Remission of type 2 diabetes after Roux-en-Y gastric bypass or sleeve gastrectomy is associated with a distinct glycemic profile.
      ,
      • Lupoli R.
      • Lembo E.
      • Ciciola P.
      • Schiavo L.
      • Pilone V.
      • Capaldo B.
      Continuous glucose monitoring in subjects undergoing bariatric surgery: diurnal and nocturnal glycemic patterns.
      ] with a non-significant heterogeneity among studies (I2: 36.9%, P = 0.190). In studies comparing RYGB and SG [
      • Lazar L.O.
      • Sapojnikov S.
      • Pines G.
      • Mavor E.
      • Ostrovsky V.
      • Schiller T.
      • et al.
      Symptomatic and asymptomatic hypoglycemia post three different bariatric procedures: a common and severe complication.
      ,
      • Capristo E.
      • Panunzi S.
      • De Gaetano A.
      • Spuntarelli V.
      • Bellantone R.
      • Giustacchini P.
      • et al.
      Incidence of hypoglycemia after gastric bypass vs sleeve gastrectomy: a randomized trial.
      ,
      • Jiménez A.
      • Ceriello A.
      • Casamitjana R.
      • Flores L.
      • Viaplana-Masclans J.
      • Vidal J.
      Remission of type 2 diabetes after Roux-en-Y gastric bypass or sleeve gastrectomy is associated with a distinct glycemic profile.
      ,
      • Lupoli R.
      • Lembo E.
      • Ciciola P.
      • Schiavo L.
      • Pilone V.
      • Capaldo B.
      Continuous glucose monitoring in subjects undergoing bariatric surgery: diurnal and nocturnal glycemic patterns.
      ], we found a comparable rate of PBH with the two procedures (OR 1.62, 95%CI: 0.71–3.7; P = 0.248 - I2: 19.1%, P = 0.294, Fig. 2). The percent time spent in hypoglycemia was similar for the two procedures (MD 5.3%, 95%CI: −1.4%–12.0%; P = 0.122 - I2: 73.5%, P = 0.052); however, RYGB was characterized by a higher glycemic variability than SG as shown by the difference in standard deviation of mean glucose concentrations (SD) (MD 12.4, 95%CI: 8.1–16.7%; P = 0.002 - I2: 0%, P = 0.347). Moreover, 3 studies (5 datasets) [
      • Abrahamsson N.
      • Edén Engström B.
      • Sundbom M.
      • Karlsson F.A.
      Hypoglycemia in everyday life after gastric bypass and duodenal switch.
      ,
      • Lupoli R.
      • Lembo E.
      • Ciciola P.
      • Schiavo L.
      • Pilone V.
      • Capaldo B.
      Continuous glucose monitoring in subjects undergoing bariatric surgery: diurnal and nocturnal glycemic patterns.
      ,
      • Kefurt R.
      • Langer F.B.
      • Schindler K.
      • Shakeri-Leidenmühler S.
      • Ludvik B.
      • Prager G.
      Hypoglycemia after Roux-En-Y gastric bypass: detection rates of continuous glucose monitoring (CGM) versus mixed meal test.
      ] reported data on nocturnal hypoglycemia (occurring from 0.00 to 6.00 a.m.) showing a WMP of 16.4% (95%CI: 7.0%–34%; I2: 64.5%, P = 0.024).
      Figure 1
      Figure 1Weighted mean prevalence of post-bariatric hypoglycemia in the included studies. DS: duodenal switch; OLGB: omega loop gastric bypass; RYGB: Roux-en-Y gastric bypass; SG: Sleeve Gastrectomy; RYGB-SX: Roux-en-Y gastric bypass with neuroglycopenia symptoms; RYGB-ASX: asymptomatic Roux-en-Y gastric bypass; RYGB-HYPO: Roux-en-Y gastric bypass with plasma glucose <50 mg/dl between 90 and 120 min after the oral glucose load; RYGB-NONHYPO: Roux-en-Y gastric bypass with plasma glucose >50 mg/dl between 90 and 120 min after the oral glucose load.
      Figure 2
      Figure 2Weighted mean prevalence of post-bariatric hypoglycemia in subjects undergoing Roux-en-Y gastric bypass vs Sleeve Gastrectomy.
      When stratifying the analysis according to different glucose cut-off (70 mg/dl, 60 mg/dl, 55 mg/dl), the rate of PBH was similar at the different thresholds considered: 57.4% (95%CI: 28.8%–81.8%; I2: 52.8%, P = 0.100) in the 4 datasets (2 studies) [
      • Jiménez A.
      • Ceriello A.
      • Casamitjana R.
      • Flores L.
      • Viaplana-Masclans J.
      • Vidal J.
      Remission of type 2 diabetes after Roux-en-Y gastric bypass or sleeve gastrectomy is associated with a distinct glycemic profile.
      ,
      • Halperin F.
      • Patti M.E.
      • Skow M.
      • Bajwa M.
      • Goldfine A.B.
      Continuous glucose monitoring for evaluation of glycemic excursions after gastric bypass.
      ] at 70 mg/dl, 49.8% (95%CI: 30.6%–69.1%; I2: 63.6%, P = 0.040) in the 4 datasets (2 studies) [
      • Abrahamsson N.
      • Edén Engström B.
      • Sundbom M.
      • Karlsson F.A.
      Hypoglycemia in everyday life after gastric bypass and duodenal switch.
      ,
      • Vaurs C.
      • Brun J.F.
      • Bertrand M.
      • Burcelin R.
      • du Rieu M.C.
      • Anduze Y.
      • et al.
      Post-prandial hypoglycemia results from a non-glucose-dependent inappropriate insulin secretion in Roux-en-Y gastric bypassed patients.
      ] at 60 mg/dl and 56.2% (95%CI: 40.2%–71.0%; I2: 72.3%, P = 0.001) in the 8 datasets (4 studies) [
      • Lazar L.O.
      • Sapojnikov S.
      • Pines G.
      • Mavor E.
      • Ostrovsky V.
      • Schiller T.
      • et al.
      Symptomatic and asymptomatic hypoglycemia post three different bariatric procedures: a common and severe complication.
      ,
      • Capristo E.
      • Panunzi S.
      • De Gaetano A.
      • Spuntarelli V.
      • Bellantone R.
      • Giustacchini P.
      • et al.
      Incidence of hypoglycemia after gastric bypass vs sleeve gastrectomy: a randomized trial.
      ,
      • Lupoli R.
      • Lembo E.
      • Ciciola P.
      • Schiavo L.
      • Pilone V.
      • Capaldo B.
      Continuous glucose monitoring in subjects undergoing bariatric surgery: diurnal and nocturnal glycemic patterns.
      ,
      • Kefurt R.
      • Langer F.B.
      • Schindler K.
      • Shakeri-Leidenmühler S.
      • Ludvik B.
      • Prager G.
      Hypoglycemia after Roux-En-Y gastric bypass: detection rates of continuous glucose monitoring (CGM) versus mixed meal test.
      ] at 55 mg/dl. Interestingly, the WMP of PBH reported in studies including consecutive individuals irrespective of the presence of symptoms of hypoglycemia (55.8%; 95%CI: 43.4%–67.5%; I2: 63.2%, P = 0.002) [
      • Abrahamsson N.
      • Edén Engström B.
      • Sundbom M.
      • Karlsson F.A.
      Hypoglycemia in everyday life after gastric bypass and duodenal switch.
      ,
      • Lazar L.O.
      • Sapojnikov S.
      • Pines G.
      • Mavor E.
      • Ostrovsky V.
      • Schiller T.
      • et al.
      Symptomatic and asymptomatic hypoglycemia post three different bariatric procedures: a common and severe complication.
      ,
      • Capristo E.
      • Panunzi S.
      • De Gaetano A.
      • Spuntarelli V.
      • Bellantone R.
      • Giustacchini P.
      • et al.
      Incidence of hypoglycemia after gastric bypass vs sleeve gastrectomy: a randomized trial.
      ,
      • Jiménez A.
      • Ceriello A.
      • Casamitjana R.
      • Flores L.
      • Viaplana-Masclans J.
      • Vidal J.
      Remission of type 2 diabetes after Roux-en-Y gastric bypass or sleeve gastrectomy is associated with a distinct glycemic profile.
      ,
      • Lupoli R.
      • Lembo E.
      • Ciciola P.
      • Schiavo L.
      • Pilone V.
      • Capaldo B.
      Continuous glucose monitoring in subjects undergoing bariatric surgery: diurnal and nocturnal glycemic patterns.
      ,
      • Kefurt R.
      • Langer F.B.
      • Schindler K.
      • Shakeri-Leidenmühler S.
      • Ludvik B.
      • Prager G.
      Hypoglycemia after Roux-En-Y gastric bypass: detection rates of continuous glucose monitoring (CGM) versus mixed meal test.
      ] were comparable to those reported in studies specifically enrolling patients referring symptoms (51.0%; 95%CI: 25.9%–75.7%; I2: 67.5%, P = 0.030) [
      • Halperin F.
      • Patti M.E.
      • Skow M.
      • Bajwa M.
      • Goldfine A.B.
      Continuous glucose monitoring for evaluation of glycemic excursions after gastric bypass.
      ,
      • Vaurs C.
      • Brun J.F.
      • Bertrand M.
      • Burcelin R.
      • du Rieu M.C.
      • Anduze Y.
      • et al.
      Post-prandial hypoglycemia results from a non-glucose-dependent inappropriate insulin secretion in Roux-en-Y gastric bypassed patients.
      ].
      With regard to the type of CGM device, the WMP of PBH was 61.8% (95%CI: 48.8%–73.3%; I2: 19.3%, P = 0.291) in the 2 studies (5 datasets) [
      • Lazar L.O.
      • Sapojnikov S.
      • Pines G.
      • Mavor E.
      • Ostrovsky V.
      • Schiller T.
      • et al.
      Symptomatic and asymptomatic hypoglycemia post three different bariatric procedures: a common and severe complication.
      ,
      • Lupoli R.
      • Lembo E.
      • Ciciola P.
      • Schiavo L.
      • Pilone V.
      • Capaldo B.
      Continuous glucose monitoring in subjects undergoing bariatric surgery: diurnal and nocturnal glycemic patterns.
      ] using Dexcom devices and 50% (95%CI: 35.6%–64.4%; I2: 69.8%, P < 0.001) in the 6 studies (11 datasets) [
      • Abrahamsson N.
      • Edén Engström B.
      • Sundbom M.
      • Karlsson F.A.
      Hypoglycemia in everyday life after gastric bypass and duodenal switch.
      ,
      • Capristo E.
      • Panunzi S.
      • De Gaetano A.
      • Spuntarelli V.
      • Bellantone R.
      • Giustacchini P.
      • et al.
      Incidence of hypoglycemia after gastric bypass vs sleeve gastrectomy: a randomized trial.
      ,
      • Jiménez A.
      • Ceriello A.
      • Casamitjana R.
      • Flores L.
      • Viaplana-Masclans J.
      • Vidal J.
      Remission of type 2 diabetes after Roux-en-Y gastric bypass or sleeve gastrectomy is associated with a distinct glycemic profile.
      ,
      • Halperin F.
      • Patti M.E.
      • Skow M.
      • Bajwa M.
      • Goldfine A.B.
      Continuous glucose monitoring for evaluation of glycemic excursions after gastric bypass.
      ,
      • Vaurs C.
      • Brun J.F.
      • Bertrand M.
      • Burcelin R.
      • du Rieu M.C.
      • Anduze Y.
      • et al.
      Post-prandial hypoglycemia results from a non-glucose-dependent inappropriate insulin secretion in Roux-en-Y gastric bypassed patients.
      ,
      • Kefurt R.
      • Langer F.B.
      • Schindler K.
      • Shakeri-Leidenmühler S.
      • Ludvik B.
      • Prager G.
      Hypoglycemia after Roux-En-Y gastric bypass: detection rates of continuous glucose monitoring (CGM) versus mixed meal test.
      ] using Medtronic devices.
      Sensitivity analysis according to NOS showed that after excluding 3 studies [
      • Lazar L.O.
      • Sapojnikov S.
      • Pines G.
      • Mavor E.
      • Ostrovsky V.
      • Schiller T.
      • et al.
      Symptomatic and asymptomatic hypoglycemia post three different bariatric procedures: a common and severe complication.
      ,
      • Capristo E.
      • Panunzi S.
      • De Gaetano A.
      • Spuntarelli V.
      • Bellantone R.
      • Giustacchini P.
      • et al.
      Incidence of hypoglycemia after gastric bypass vs sleeve gastrectomy: a randomized trial.
      ,
      • Kefurt R.
      • Langer F.B.
      • Schindler K.
      • Shakeri-Leidenmühler S.
      • Ludvik B.
      • Prager G.
      Hypoglycemia after Roux-En-Y gastric bypass: detection rates of continuous glucose monitoring (CGM) versus mixed meal test.
      ] WMP of PBH was 53.2% (95%CI: 40.9%–65.1%)

      Publication bias

      Funnel plot examination (Supplemental Figure S2) suggested the absence of publication bias and of small-study effect, confirmed by the Egger's test for studies reporting the rate of PBH (P = 0.467) in subjects undergoing bariatric surgery.

      Meta-regression analyses

      Regression models showed that an increasing post-surgery time was associated with a higher rate of both total PBH (Z-value: 3.32, P < 0.001, Fig. 3) and nocturnal PBH (Z-value: 2.15, P = 0.013). Apart from a trend toward significance for the presence of hypoglycemic symptoms (Z-value: 1,94, P = 0.052), none of the other evaluated clinical and demographic variables influenced the WMP of PBH (Supplemental Table S2).
      Figure 3
      Figure 3Meta-regression analysis. Impact of time (years) from surgery on weighted mean prevalence of post-bariatric hypoglycemia. The circle size is proportional to individual study weight in the pooled analysis.

      Discussion

      The present meta-analysis reveals a considerable rate of hypoglycemia (∼50%) after BS through the use of the CGM systems, with no difference between RYGB and SG. The rate of PBH obtained in the present study is quite higher than that reported in previous studies in which hypoglycemia was diagnosed with different diagnostic tools, such as self-reported questionnaires, hospitalization records [
      • Marsk R.
      • Jonas E.
      • Rasmussen F.
      • Näslund E.
      Nationwide cohort study of post-gastric bypass hypoglycemia including 5,040 patients undergoing surgery for obesity in 1986-2006 in Sweden.
      ,
      • Lee C.J.
      • Wood G.C.
      • Lazo M.
      • Brown T.T.
      • Clark J.M.
      • Still C.
      • et al.
      Risk of post-gastric bypass surgery hypoglycemia in nondiabetic individuals: a single center experience.
      ], and provocative tests [
      • Emous M.
      • van den Broek M.
      • Wijma R.B.
      • de Heide L.J.M.
      • van Dijk G.
      • Laskewitz A.
      • et al.
      Prevalence of hypoglycaemia in a random population after Roux-en-Y gastric bypass after a meal test.
      ,
      • Capristo E.
      • Panunzi S.
      • De Gaetano A.
      • Spuntarelli V.
      • Bellantone R.
      • Giustacchini P.
      • et al.
      Incidence of hypoglycemia after gastric bypass vs sleeve gastrectomy: a randomized trial.
      ,
      • Halperin F.
      • Patti M.E.
      • Skow M.
      • Bajwa M.
      • Goldfine A.B.
      Continuous glucose monitoring for evaluation of glycemic excursions after gastric bypass.
      ,
      • Kefurt R.
      • Langer F.B.
      • Schindler K.
      • Shakeri-Leidenmühler S.
      • Ludvik B.
      • Prager G.
      Hypoglycemia after Roux-En-Y gastric bypass: detection rates of continuous glucose monitoring (CGM) versus mixed meal test.
      ]. Indeed, in post-RYGB patients, a previous study demonstrated a significantly higher rate of hypoglycemia based on CGM data (75%) than that diagnosed with MMT (29%) [
      • Kefurt R.
      • Langer F.B.
      • Schindler K.
      • Shakeri-Leidenmühler S.
      • Ludvik B.
      • Prager G.
      Hypoglycemia after Roux-En-Y gastric bypass: detection rates of continuous glucose monitoring (CGM) versus mixed meal test.
      ]. Furthermore, a study by Halperin et al. showed higher sensitivity (90%) and specificity (50%) of CGM compared to MMT (33% and 40%, respectively), concluding for a better performance of CGM in detecting hypoglycemic episodes in bariatric patients [
      • Halperin F.
      • Patti M.E.
      • Skow M.
      • Bajwa M.
      • Goldfine A.B.
      Continuous glucose monitoring for evaluation of glycemic excursions after gastric bypass.
      ]. To date, there is no general consensus on the modalities for diagnosis of PBH since each of them has strengths and weaknesses [
      • Emous M.
      • Ubels F.L.
      • van Beek A.P.
      Diagnostic tools for post-gastric bypass hypoglycaemia.
      ]. Moreover, no uniformly established cut-off values exist for diagnosis of PBH [
      • Emous M.
      • Ubels F.L.
      • van Beek A.P.
      Diagnostic tools for post-gastric bypass hypoglycaemia.
      ]. With regard to provocative tests, both OGTT and MMT show a high prevalence of hypoglycemia in post-gastric bypass patients with and without hypoglycemic symptoms as well as in healthy volunteers [
      • Emous M.
      • Ubels F.L.
      • van Beek A.P.
      Diagnostic tools for post-gastric bypass hypoglycaemia.
      ]. As to CGM, although the exact sensitivity and specificity of this method in this specific clinical setting has not been defined yet, it has the advantage to provide a great abundance of glycemic data over a long period of time under real life condition, thus unveiling possible episodes of asymptomatic and/or nocturnal hypoglycemia [
      • Danne T.
      • Nimri R.
      • Battelino T.
      • Bergenstal R.M.
      • Close K.L.
      • DeVries J.H.
      • et al.
      International consensus on use of continuous glucose monitoring.
      ]. This is supported by the present meta-analysis showing that 16.4% of patients experienced nocturnal hypoglycemia. Indeed, although the impact of hypoglycemia symptoms on WMP of PBH evaluated by the meta-regression analysis showed a trend toward significance, sub-group analysis showed that the rate of PBH was similar in studies enrolling consecutive patients regardless of the presence of hypoglycemic symptoms and in studies specifically enrolling subjects with symptomatic hypoglycemia.
      Asymptomatic hypoglycemia is a relevant problem in postbariatric patients since symptoms may be non-specific because of the dumping phenomenon. Furthermore, hypoglycemia unawareness may develop as a consequence of recurrent episodes of hypoglycemia [
      • Abrahamsson N.
      • Edén Engström B.
      • Sundbom M.
      • Karlsson F.A.
      Hypoglycemia in everyday life after gastric bypass and duodenal switch.
      ,
      • Lazar L.O.
      • Sapojnikov S.
      • Pines G.
      • Mavor E.
      • Ostrovsky V.
      • Schiller T.
      • et al.
      Symptomatic and asymptomatic hypoglycemia post three different bariatric procedures: a common and severe complication.
      ,
      • Halperin F.
      • Patti M.E.
      • Skow M.
      • Bajwa M.
      • Goldfine A.B.
      Continuous glucose monitoring for evaluation of glycemic excursions after gastric bypass.
      ]. Indeed, a state of repeated or chronic hypoglycemia is associated with a reduction of glycemic threshold for the counterregulatory response and for cognitive impairment [
      • Boyle P.J.
      • Nagy R.J.
      • O'Connor A.M.
      • Kempers S.F.
      • Yeo R.A.
      • Qualls C.
      Adaptation in brain glucose uptake following recurrent hypoglycemia.
      ,
      • Davis S.N.
      • Mann S.
      • Briscoe V.J.
      • Ertl A.C.
      • Tate D.B.
      Effects of intensive therapy and antecedent hypoglycemia on counterregulatory responses to hypoglycemia in type 2 diabetes.
      ]. The importance to recognize asymptomatic hypoglycemia is also highlighted by the evidence that in diabetic patients this complication is related to severe clinical outcomes such as all-cause mortality and major adverse cardiovascular events [
      • Wei W.
      • Zhao S.
      • Fu S.L.
      • Yi L.
      • Mao H.
      • Tan Q.
      • et al.
      The association of hypoglycemia assessed by continuous glucose monitoring with cardiovascular outcomes and mortality in patients with type 2 diabetes.
      ].
      In the present meta-analysis, we highlighted a significant rate of nocturnal hypoglycemia, suggesting that PBH should not be viewed as an exclusively postprandial phenomenon. While the mechanisms responsible for PBH occurring post-prandially have been extensively studied [
      • Tharakan G.
      • Behary P.
      • Wewer Albrechtsen N.J.
      • Chahal H.
      • Kenkre J.
      • Miras A.D.
      • et al.
      Roles of increased glycaemic variability, GLP-1 and glucagon in hypoglycemia after Roux-en-Y gastric bypass.
      ,
      • Patti M.E.
      • Goldfine A.B.
      The rollercoaster of post-bariatric hypoglycemia.
      ], to date no information is available on nocturnal hypoglycemia in bariatric patients, and further studies are needed to clarify the pathophysiological mechanisms underlying meal-independent hypoglycemia.
      With regard to factors influencing PBH rate, we found that a longer time from surgical intervention was associated with a higher rate of both total and nocturnal PBH. This finding is in line with a longitudinal cohort study showing that a longer duration of postoperative follow-up was associated with an increased risk of incident hypoglycemia [
      • Lee C.J.
      • Wood G.C.
      • Lazo M.
      • Brown T.T.
      • Clark J.M.
      • Still C.
      • et al.
      Risk of post-gastric bypass surgery hypoglycemia in nondiabetic individuals: a single center experience.
      ]. Based on these observations, a periodical screening for PBH should be included in the frame of long-term surveillance of bariatric patients.
      Although PBH rate was reported to be higher following purely malabsorptive interventions, such as DS and OLGB [
      • Abrahamsson N.
      • Edén Engström B.
      • Sundbom M.
      • Karlsson F.A.
      Hypoglycemia in everyday life after gastric bypass and duodenal switch.
      ,
      • Lazar L.O.
      • Sapojnikov S.
      • Pines G.
      • Mavor E.
      • Ostrovsky V.
      • Schiller T.
      • et al.
      Symptomatic and asymptomatic hypoglycemia post three different bariatric procedures: a common and severe complication.
      ], our data show that the degree of surgically induced malabsorption is not critical for the occurrence of PBH. In fact, the rate of PBH and the percent time spent in hypoglycemia were similar after RYGB (a mixed restrictive and malabsorptive procedure) and SG (a restrictive procedure), questioning the belief that PBH is less frequent with the latter. However, we found a higher glycemic variability after RYGB compared to SG, suggesting that the two surgical procedures are characterized by different patterns of glycemic excursions. This is in line with a recent observation by our group [
      • Lupoli R.
      • Lembo E.
      • Ciciola P.
      • Schiavo L.
      • Pilone V.
      • Capaldo B.
      Continuous glucose monitoring in subjects undergoing bariatric surgery: diurnal and nocturnal glycemic patterns.
      ] demonstrating that hypoglycemia is frequently post-prandial and symptomatic after RYGB and it is mostly nocturnal and asymptomatic after SG. Of note, Capristo et al. [
      • Capristo E.
      • Panunzi S.
      • De Gaetano A.
      • Spuntarelli V.
      • Bellantone R.
      • Giustacchini P.
      • et al.
      Incidence of hypoglycemia after gastric bypass vs sleeve gastrectomy: a randomized trial.
      ] found a similar PBH rate with the two types of interventions, with more severe hypoglycemic events leading to hospitalization after RYGB. In the present meta-analysis glycemic variability was estimated by means of SD of mean glucose concentrations due to the lack of more accurate metrics in all but one [
      • Lupoli R.
      • Lembo E.
      • Ciciola P.
      • Schiavo L.
      • Pilone V.
      • Capaldo B.
      Continuous glucose monitoring in subjects undergoing bariatric surgery: diurnal and nocturnal glycemic patterns.
      ] of the included articles.
      Overall, the present data have relevant clinical implications. First, SG should no longer be considered a safer option than RYGB in terms of hypoglycemia risk. Second, the conversion from RYGB to SG, used as a treatment strategy for the management of severe RYGB-related hypoglycemia [
      • Lakdawala M.
      • Limas P.
      • Dhar S.
      • Remedios C.
      • Dhulla N.
      • Sood A.
      • et al.
      Laparoscopic revision of Roux-en-Y gastric bypass to sleeve gastrectomy: a ray of hope for failed Roux-en-Y gastric bypass.
      ,
      • Carter C.O.
      • Fernandez A.Z.
      • McNatt S.S.
      • Powell M.S.
      Conversion from gastric bypass to sleeve gastrectomy for complications of gastric bypass.
      ], should be considered with caution, also considering that it often does not resolve the hypoglycemic manifestations and is associated with an increased risk of peri-operative complications [
      • Carter C.O.
      • Fernandez A.Z.
      • McNatt S.S.
      • Powell M.S.
      Conversion from gastric bypass to sleeve gastrectomy for complications of gastric bypass.
      ,
      • van Beek A.P.
      • Emous M.
      • Laville M.
      • Tack J.
      Dumping syndrome after esophageal, gastric or bariatric surgery: pathophysiology, diagnosis, and management.
      ].
      A strength of the present meta-analysis is that it provides an insight into the PBH rate in real life evaluating factors potentially affecting this complication, and evaluating differences between the two most commonly performed bariatric procedures.
      Our study has some limitations. Inclusion and exclusion criteria of the studies included in our analysis are quite heterogeneous. To overcome this limitation, we used a meta-regression approach adjusting the results for relevant clinical and demographic covariates. However, because of some missing information in each study, the multivariate approach allowed adjustment for some, but not all, potential confounders. Moreover, the studies analysed presented some variability as to a) the type of bariatric procedure, b) the type of CGM device, c) glucose thresholds to define hypoglycemia. We, therefore, performed subgroup analyses stratifying for these variables in order to limit the impact of these sources of variability on the results. In detail, in our analysis we took into account the type of the bariatric procedure and directly compared RYGB and SG. As to CGM systems, all assessments were performed using Medtronic or Dexcom devices. In this regard, we found a slightly higher rate of PBH with a low heterogeneity in studies using Dexcom compared to Medtronic devices. Interestingly, the rate of PBH was similar when stratifying analysis according to different glucose cut-offs (70 mg/dl, 60 mg/dl, 55 mg/dl), suggesting that our results are reliable and repeatable. Although the analytical performance of the CGM devices is progressively improving, as shown by a mean absolute relative difference (MARD) between CGM readings and paired blood glucose values <10%, it cannot be excluded that their accuracy may be lower in the hypoglycemic range. Whereas this could potentially impact the absolute rate of PBH, the comparative analysis between RYGB and SG is likely not to be biased. A further point to be discussed is the heterogeneity of the cut-off values for the definition of hypoglycemia [
      • Heller S.R.
      • Buse J.B.
      • Ratner R.
      • Seaquist E.
      • Bardtrum L.
      • Hansen C.T.
      • et al.
      Redefining hypoglycemia in clinical Trials: validation of definitions recently adopted by the American diabetes association/European association for the study of diabetes.
      ]. According to a joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes, hypoglycemia is defined as glucose levels <54 mg/dl (<3.0 mmol/L) detected by self-monitoring of capillary glucose, continuous glucose monitoring or a laboratory measurement since this level does not occur under physiological conditions in nondiabetic individuals [
      International Hypoglycaemia Study Group
      Glucose concentrations of less than 3.0 mmol/L (54 mg/dL) should Be reported in clinical trials: a joint position statement of the American diabetes association and the European association for the study of diabetes.
      ]. Indeed, a recent study performed in healthy non diabetic individuals wearing CGM for 10 days recommends sensor glucose values <54 mg/dl as a cut-off to define clinical important hypoglycemia since only 1% of participants spent ≥2% of time below <54 mg/dl [
      • Shah V.N.
      • DuBose S.N.
      • Li Z.
      • Beck R.W.
      • Peters A.L.
      • Weinstock R.S.
      • et al.
      Continuous glucose monitoring profiles in healthy nondiabetic participants: a multicenter prospective study.
      ]. In this light, we performed a subgroup analysis considering different glycemic cut-off and found a similar rate to that observed in the overall analysis. Unfortunately, none of the included studies paired interstitial glucose measurements by CGM with blood glucose levels or confirmed nocturnal episodes of hypoglycemia with serial plasma glucose, insulin and C-peptide measurements during a prolonged fast. For this reason, it cannot be excluded that the rate of PBH reported by the included studies could have been overestimated. Given the increasing use of CGM, further studies evaluating the diagnostic performance of this tool in patients with PBH would be desirable.
      In conclusion, the present meta-analysis shows that PBH, detected by means of real-time CGM, is a frequent complication of bariatric procedures with both post-prandial and nocturnal events. The rate of PBH increases with increasing time from surgery and is comparable after RYGB and SG, with a higher glucose variability after RYGB. Further studies are needed to extend these results and to assess the diagnostic accuracy of different CGM devices in this specific clinical setting.

      Declaration of competing interest

      The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.

      Appendix A. Supplementary data

      The following is the supplementary data to this article:

      Funding

      No financial support was received for this study.

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