Keywords
bariatric surgery - dumping syndrome - guidelines - hypoglycemia - obesity - PBH -
postbariatric
Introduction
Bariatric surgery or metabolic surgery has been increasingly accepted and accomplished
as a very effective long-term treatment for morbid obesity or obesity with various
related comorbidities, including type 2 diabetes mellitus, cardiovascular disease,
and fatty liver disease.[1]
[2] Among the bariatric procedures, Roux-en-Y gastric bypass (RYGB) has particularly
shown robust outcomes, with a benefit scale from improvement to complete resolution
of the metabolic-related comorbidities. However, being a major surgery, it has also
been associated with absorptive and metabolic consequences, notably vitamin or mineral
malabsorption and postbariatric hypoglycemia (PBH).[3] PBH is characterized by an exaggerated insulin response to carbohydrate intake,
leading to postprandial hypoglycemia.[4]
[5] Over the past decade, several guidelines have been published to guide health care
providers to properly manage PBH, with the latest updates presented in the years 2017,[6] 2022,[7] and 2024.[8] The first consensus was released from the American Society for Metabolic and Bariatric
Surgery (ASMBS) in 2017 but not updated afterward. The consensus statement in 2022
was released by the Obesity Group of the Spanish Society of Endocrinology and Nutrition,
and the latest guideline is from the Society of Endocrinology in 2024. These guidelines
have evolved based on the advancement in understanding PBH's pathophysiology, the
limitations of previously used dynamic testing like oral glucose tolerance test (OGTT)
and mixed meal tolerance test (MMTT) as diagnostic tools, and more emerging data for
various therapeutic interventions. This review aims to provide an in-depth comparison
of the latest three international guidelines on the management of PBH, focusing on
the key differences and the evidence supporting these recommendations. By examining
the trajectory of PBH management, we highlight the critical importance of individualized
care, the use of advanced glucose monitoring technologies, and targeted pharmacological
therapies as the latest updates on PBH management.
In this document, we shall refer to the 2017, 2022, and 2024 guidelines.
Pathophysiological Insights into Postbariatric Hypoglycemia
Pathophysiological Insights into Postbariatric Hypoglycemia
The pathophysiology of PBH involves a complex interplay of factors that remain incompletely
understood.[4]
[5] A key contributor is the anatomical restructuring of the gastrointestinal tract,
which accelerates nutrient absorption and triggers an exaggerated release of glucagon-like
peptide-1 (GLP-1), a potent insulinotropic hormone.[9] This response often leads to excessive insulin secretion and subsequent hypoglycemia,
typically occurring 1 to 3 hours after eating.[5]
[10] RYGB surgery introduces further metabolic changes through bypassing the pylorus
and proximal small intestine, leading to heightened glycemic variability characterized
by rapid glucose spikes and profound troughs. One prevailing hypothesis suggests that
some individuals exhibit an amplified incretin and insulin response, resulting in
hypoglycemia from insulin “overshooting.”[11] The support for this idea comes from the efficacy of GLP-1 receptor antagonists,
such as exendin 9-39, in mitigating hypoglycemic episodes in PBH patients.[12]
Additionally, non-insulin-dependent glucose disposal, insulin sensitivity modulation,
inflammatory cytokines, and inadequate counterregulatory mechanisms are thought to
exacerbate PBH. Furthermore, RYGB appears to modify β-cell and α-cell responses, with
studies showing enhanced postprandial glucagon secretion alongside reduced glucagon
release during hypoglycemia, potentially contributing to recurrent episodes of hypoglycemia
and diminished hypoglycemia awareness.[13]
Other proposed mechanisms include impaired suppression of basal insulin secretion
during hypoglycemia, excessive insulin release after meals, dysregulated glucagon
secretion by α-cells, and altered bile acid (BA) dynamics, which may lead to elevated
fibroblast growth factor-19 (FGF-19) levels and influence glucose metabolism.[14]
[15] The role of BAs in this process is particularly intriguing, given their impact on
glucose metabolism through mechanisms such as farnesoid X receptor activation and
G protein-coupled bile acid receptor-mediated GLP-1 secretion.[15]
Having a larger B-cell mass after weight loss, excessive GLP-1 receptor expression
in the pancreas, and greater sensitivity of the pancreatic B cells have been denied
in the 2022 guidelines since there was no robust evidence supporting those phenomena.[7] The latest guidelines of 2024 have proposed only the hormonal (GLP-1) and the BA
hypothesis for the pathophysiology of PBH.[8] A comparison of the three guidelines' explanations of pathophysiology is illustrated
in [Table 1].
Table 1
Key differences in diagnostic recommendations across guidelines
|
Aspect
|
2017
|
2022
|
2024
|
|
Definition
|
Whipple's triad in 1–3 hours post-meal
|
Whipple's triad in 1–3 hours post-meal
|
Whipple's triad in 2–4 hours post-meal
|
|
Blood glucose cutoff
|
- No solid cutoff (<60 or <50 mg/dL) spontaneously or after provocation tests
- <50 is more reliable after provocation
|
- <60 mg/dL after provocation test
Or
- <50 mg/dL spontaneously
|
- <54 mg/dL (serum is preferrable)
|
|
Pathophysiology
|
- Rapid nutrients passage
- Exaggerated GLP-1 response to nutrients
- Impaired glucagon response
- To hypoglycemia
- Enhanced sensitivity of B cells to GLP-1
- Hyperplasia of B cells
- Improvement in insulin sensitivity after weight loss
|
- Rapid nutrients passage
- Exaggerated GLP-1 response to nutrients
- Impaired glucagon response
- Altered bile acid metabolism and function
|
- Exaggerated GLP-1 response to nutrients
- Impaired B-cells response to hypoglycemia (continues insulin release despite hypoglycemia)
- Impaired bile acid metabolism and function
|
|
Provocation test
|
- MMT is needed
- Consider CGM for 3 days
- Avoid OGTT
|
- MMTT is highly needed (positive if BG dropped <60 mg/dL)
- In case of BG <50 mg/dL, insulin >3–5 mIU/L, and C-peptide >0.6 ng/mL confirms diagnosis
- CGM is not very reliable
- Avoid OGTT
|
- Pragmatic approach (Whipple's triad, 1 hour after meal, postbariatric)
- CGM is promising (needs further data)
- Avoid MMT (not standardized)
- Avoid OGTT (not reproducible)
|
|
Use of CGM
|
- Useful (use for 3 days)
|
Supplementary tool
|
It is recommended to use as a tool to alter the dietary behavior
|
Abbreviations: CGM, continuous glucose monitoring; GLP-1, glucagon-like peptide-1;
MMTT, mixed meal tolerance test; OGTT, oral glucose tolerance test.
Prevalence and Diagnostic Considerations
Prevalence and Diagnostic Considerations
The precise prevalence of PBH remains unclear, largely due to inconsistent diagnostic
criteria and the use of different reference ranges across all the studies. Differentiating
early dumping syndrome from PBH, which is often referred to as late dumping syndrome,
is crucial in patients presenting with adrenergic symptoms following bariatric surgery.
Early dumping syndrome manifests through a combination of gastrointestinal symptoms
such as abdominal discomfort, bloating, nausea, diarrhea, along with vasomotor responses
like fatigue, flushing, palpitations, tachycardia, hypotension, and syncope, notably
without hypoglycemia. These reactions are attributed to the rapid entry of hyperosmolar
food into the small intestine, prompting fluid shifts, intestinal swelling, reduced
vascular volume, and activation of the autonomic and enteroendocrine systems. However,
the boundary between early and late dumping syndromes is not always well-defined,
with evidence suggesting that both conditions may coexist and share underlying mechanisms.[16]
The diagnostic approach to PBH has significantly evolved over the years. To enhance
diagnostic accuracy in distinguishing PBH from other conditions, a more stringent
definition of hypoglycemia is recommended for postbariatric patients. This includes
neuroglycopenic symptoms such as altered behavior, confusion, cognitive dysfunction,
seizures, or unconsciousness accompanied by plasma glucose levels below 54 mg/dL,
with symptoms promptly resolving upon glucose administration.[17]
While this approach effectively identified cases of hypoglycemia, for some cases,
the yield is limited in capturing the dynamic nature of postprandial glucose fluctuations
that characterize PBH or, in the presence of hypoglycemia, unawareness.
Hypoglycemia provocation tests were addressed in the 2017 guidelines, and the authors
stated that the OGTT showed a significant proportion of false-positive cases.[18] Therefore, it was less favored as a provocative test for PBH. The MMTT (a meal containing
carbohydrates, proteins, and fats that better simulates typical food to provoke hypoglycemia)
has been suggested as the primary diagnostic tool.[19] The MMTT is considered positive for PBH when the blood glucose is <55 mg/dL, and
the detectable insulin level is more than 3 μU/mL. On a larger scale, the 2017 guidelines
consider the PBH when the symptoms appear after at least 1 year from surgery, normal
fasting glucose and insulin levels, symptomatic hypoglycemia that resolved spontaneously,
and a positive provocation test. In 2022, the guidelines focused on the MMTT and considered
it to be the preferred diagnostic tool as the evidence supported a better detection
of PBH by providing a more physiological simulation and tending to capture postprandial
glucose excursions more accurately.[7] In the latest guidelines of 2024, for the first time, it has been proposed to diagnose
PBH pragmatically with the presence of Whipple's triad, >1 hour after a meal, and
history of bypass surgery. They recommended against the provocation tests.[8]
Continuous glucose monitoring (CGM) is a helpful tool with variable data on accuracy,
sensitivity, and cost-effectiveness.[20] This technology facilitates the timely and frequent correlation of symptoms with
the hypoglycemic episodes, as well as the relation to different additional variables
like physical activity and meal timing, offering a broader view of a patient's glycemic
patterns than intermittent glucose testing or the MMTT.[21] Studies have shown that CGM can detect hypoglycemia that might go unnoticed with
traditional testing methods, making it a possible diagnostic tool in a subset of patients
with hypoglycemia unawareness.[22]
[23] Any CGM could be used (e.g., Dexcom sensor system or Medtronic's Guardian system)
or the intermittent scanning system (Abbott FreeStyle Libre sensor). The latest guidelines
do not currently recommend CGM for diagnosing PBH due to several limitations, including
insufficient accuracy of CGM devices in the hypoglycemic range.[8] There is a lack of clarity on the expected glycemic response following bariatric
surgery; potential oversensitivity of CGM, detecting asymptomatic interstitial hypoglycemia
postsurgery with unclear clinical relevance[24]; incidental detection of hypoglycemia <3.9 mmol/L (70 mg/dL) in healthy individuals;
and absence of standardized metrics for PBH identification via CGM.[25] Further research is needed to evaluate the diagnostic accuracy and cost-effectiveness
of CGM for PBH.
Dietary Management: From General Recommendations to Personalized Nutrition
Dietary modifications have always been the fundamental tool for managing PBH; the
vast majority of patients may respond to it with no pharmacological intervention.
In the 2017 guidelines, the primary recommendation was to have a small, frequent meal
rich in complex carbohydrates and proteins to slow down the rapid absorption. This
will prevent large postprandial glycemic spikes, which are believed to trigger the
exaggerated insulin response leading to hypoglycemia. The 2022 guidelines elaborated
on a more nuanced nutritional approach, recommending low glycemic index (GI) diets
emphasizing the consumption of complex carbohydrates and high protein foods, which
will avoid the postprandial glucose spike and, consequently, the hyperglycemia pathway.
More specifically, ingestion of soluble fibers, like guar gum and pectin, was also
recommended to slow glucose absorption and prevent postprandial hypoglycemia.[26]
[27]
[28]
Further emphasis on the timelines for food intake, frequency, and content was clearly
elaborated in these guidelines, summarized in [Table 2]. In 2024, dietary recommendations emphasized more precisely and in-depth on dietary
modification, reflecting the increased use of CGM to monitor individual patient responses
to different types of foods.[8] The 2024 guidelines focused on more specific carbohydrate and protein targets ([Table 2]).[29] Moreover, it introduced the concept of CGM-assisted individualized dietary intervention,
where the personalization of dietary intervention tackles the various biological variations
between patients.[21]
Table 2
Key differences in dietary management recommendations across guidelines
|
Aspect
|
2017
|
2022
|
2024
|
|
Broad guidance
|
- Rich in complex carbs
|
- Low GI carbs, high protein, soluble fibers
|
- <30 g carbs/meal, CGM-guided
|
|
Meal's timings
|
- Not mentioned
|
- Small meals, five to six times/day
|
- Small frequent meals: six per day
|
|
Eating patterns
|
- Small, frequent meals
- Rich in complex carbs
|
- Slow chewing, rest after meal
- No liquids 30 minutes pre- or post-meals
|
- Slow chewing
- No liquids 30 minutes pre- or post-meals
|
|
Carbs contents
|
–
|
- Complex carbs and whole grains
- 15–30 g/meal
- 5–15 g/snack
- Avoid carbs in snacks
|
- Personalization
- CGM for personalization
- Complex carbs and whole grains
- Avoid sugar and simple carbs
- Technology (Applications)
|
|
Proteins contents
|
–
|
- 60–80 g/day
|
- 60 g/day
|
|
Healthy fat contents
|
–
|
- 15 g/meal
- 5 g/snack
|
–
|
|
Other recommendations
|
–
|
–
|
- Avoid alcohol, avoid water 30 minutes before and after a meal, fast-acting CHO after
exercise
|
Abbreviations: CGM, continuous glucose monitoring; GI, glycemic index; CHO, Carbohydrates.
Pharmacological Interventions
Pharmacological Interventions
Pharmacological interventions have been the most dynamic area of research and evidence
development over the last decade. That would be attributed to a better understanding
of the pathophysiology. In the 2017 guidelines, Acarbose, an α-glucosidase inhibitor,
was classically recommended as the first-line pharmacological therapy for PBH.[6] Acarbose delays the absorption of carbohydrates in the small intestine, thereby
minimizing the postprandial glucose surge and the subsequent insulin response and
hypoglycemia.[30] The 2022 guidelines expanded the pharmacological options, retaining Acarbose as
the first-line therapy and stressing other therapies, such as somatostatin analogs,
adding pasireotide, sodium-glucose cotransporter 2 inhibitors, GLP-1 receptor agonists,
and insulin receptor modulators as potential therapeutic options.[31]
[32]
[33]
[34]
[35] Similar to the earlier guidelines, these therapies were recommended for patients
with suboptimal responses to dietary modifications and Acarbose.[36]
[37] By 2024, pharmacological therapies had become even more targeted, with pasireotide,
a long-acting somatostatin analog, recommended as a second-line therapy for patients
unresponsive to Acarbose.[8] Somatostatin analogs include octreotide, lanreotide, and pasireotide.[38] These analogs vary in somatostatin receptors (SRs) affinity: Octreotide and lanreotide
preferentially target SR subtype 2, whereas pasireotide activates both SR subtypes
2 and 5. Pasireotide's heightened hyperglycemic effect stems from its stronger SR
subtype 5 activation compared with subtype 2. While both pasireotide and octreotide
suppress insulin release, pasireotide is less effective at suppressing glucagon, as
insulin inhibition involves both subtypes, whereas glucagon inhibition depends primarily
on subtype 2.[36]
Diazoxide, an adenosine-triphosphate-dependent potassium channel agonist, has also
been recommended, in addition to calcium channel blockers and somatostatin analogs.[37] Avexitide, a pioneering GLP-1 receptor antagonist, has received FDA Breakthrough
Therapy designation. It has demonstrated robust statistical efficacy and a consistent,
well-tolerated safety profile across multiple clinical trials.[39] GLP-1 receptor antagonists were also suggested as a potential treatment in current
guidelines, although these are still under phase II trials ([Table 3]).[40] The 2024 guidelines also emphasized using CGM to guide the patients in behavioral
and dietary modifications as the first-line step to tailor their carbohydrate intake
based on real-time glucose data.[41] Other new modalities like glucagon, glucagon pumps, and insulin receptor modulators
are currently in trials.[42] However, the highlight was having the pasireotide recommended as the second-line
therapy for Acarbose use. This approach represents a significant and dynamic advancement
in PBH pharmacological management.
Table 3
Key differences in pharmacological management recommendations across guidelines
|
Aspect
|
2017
|
2022
|
2024
|
|
Pharmacological management
|
Acarbose first-line, GLP-1 antagonist
|
- Acarbose, then Ca-channel blockers
- Then octreotide LAR or lanreotide
- Keep paseriotide or diazoxide for refractory cases
|
- Acarbose, pasireotide, diazoxide
- Future options include (AVEXITIDE)
Glucagon pump, Xoma 358 (insulin receptor modulator), IL-1β blocker
|
|
Surgical management
|
- Gastrostomy tube
- Gastric outlet restriction
- Conversion of RYGB to SG
- Pancreatectomy
|
- Transoral outlet reduction endoscopy
- Gastrostomy tube
- Conversion of RYGB to SG
|
Gastrostomy tube in remnant stomach
|
Abbreviations: CGM, continuous glucose monitoring; GLP-1, glucagon-like peptide-1;
IL-1, interleukin-1; LAR, long-acting release; RYGB, Roux-en-Y gastric bypass; SG,
sleeve gastrectomy.
Surgical Management
Surgical interventions for PBH have classically been reserved for the most severe
cases, where dietary and pharmacological therapies have failed to provide adequate
control.
The 2017 guidelines recommended reversal of RYGB or, perhaps, partial pancreatectomy
for patients with refractory PBH. However, these procedures carried significant risks,
including weight regain and long-term morbidity, and were therefore considered last-resort
options.[43] The 2021 guidelines made few changes to the surgical recommendations, continuing
to endorse RYGB reversal and pancreatectomy in extreme cases.[44] However, the lack of long-term data on these procedures' efficacy and safety limited
their widespread use.[45]
[46] By 2024, the guidelines introduced a less invasive surgical option, such as gastrostomy
tube placement in the remnant stomach, allowing for controlled feeding into the remnant
stomach, bypassing the hyperactive jejunal response to food that characterizes PBH.[47] Gastrostomy tube placement may offer a less invasive approach than RYGB reversal
or pancreatectomy, providing symptomatic relief without requiring complete surgical
reversal.[48] Studies have shown that gastrostomy tube placement can effectively reduce the frequency
and severity of hypoglycemic episodes in patients with refractory PBH.[48]
Summary of the Evolution of the Guidelines
Summary of the Evolution of the Guidelines
The management of PBH has been evolving over the past decade following the progressive
advancements in our understanding of PBH's pathophysiology and the tools available
for its diagnosis and treatment. From early reliance on dietary modifications and
intermittent glucose testing, the field has shifted toward individualized, technology-driven
care, with CGM playing an important role in the early identification of hypoglycemia,
response to nutrition adjustment, and subsequent adherence to those behavioral modifications
by response monitoring.
Though there is no approved pharmacological therapy yet, the role of interventions
have expanded to include therapeutic options, targeting the hormonal mechanisms of
PBH, particularly SR blockade and GLP-1 antagonist. In contrast, surgical interventions
have become less favored in clinical practice and are reserved for highly refractory
cases.
