How Common is Hypoglycemia After Gastric Bypass?

Bariatric surgery leads to substantial and sustained weight loss, and resolution or improvements in type 2 diabetes, hypertension and dyslipidemia. Cohort studies support improved longer-term mortality. Metabolic health improvements and safety vary with the specific bariatric surgery performed, likely a result of procedure-specific anatomic and physiologic changes.

Recently, increased attention has focused on a syndrome of hypoglycemia with neuroglycopenia observed most commonly following Roux-en-Y gastric bypass (RYGB), which typically first presents more than 1–2 years postoperatively and occurs predominantly in the postprandial state (1, 2). Post-bariatric hypoglycemia can be life-threatening with altered consciousness, seizures, and motor vehicle accidents. Understanding the frequency of this syndrome and identifying which patients may be at risk is highly relevant given the large number of bariatric procedures performed worldwide.

Lee et al. (ref) now provide additional insights into the occurrence of post-RYGB hypoglycemia. The authors performed a retrospective survey of the bariatric registry and electronic medical records of Geisinger Health System, identifying a cohort of over 1200 patients followed for a mean duration of 4.8 years postoperatively. 13.1% of patients without known pre-operative hypoglycemia or diabetes met at least one criterion for hypoglycemia, including clinical diagnosis, laboratory glucose value <60 mg/dL [3.3 mmol/L], or new use of medication associated with treatment of hypoglycemia. Most of these patients met only one of these criteria. Notably, only 0.7% had evidence for more severe hypoglycemia, with documented laboratory glucose below 40 mg/dL [2.2 mmol/L], emergency room visit, or hospitalization for hypoglycemia. Clinical characteristics associated with incident hypoglycemia include modestly lower body mass index and HbA_1c preoperatively, greater excess weight loss at 6 months, and longer duration of postoperative follow-up. Symptoms consistent with hypoglycemia may be even more prevalent, as up to one-third of patients completing a survey report some symptoms potentially consistent with hypoglycemia (3), although hypoglycemic symptoms are non-specific and there can be reporting bias with those perceiving problems more likely to respond.

While these data suggest mild hypoglycemia may be more frequent than recognized clinically, the long-term significance of mild hypoglycemia and accompanying increases in glycemic variability following RYGB remains unknown. Glycemic and hormonal profiles are modified in post-bypass patients, with early peak of glucose and insulin after glucose or mixed meal ingestion, in turn contributing to lower glucose concentrations in the later postprandial period (1, 4). Such metabolic profiles have been associated with dumping syndrome, which may occur in up to 70% of RYGB patients after consuming high glycemic index carbohydrates; these symptoms are often responsive to dietary modification. However, a much smaller percentage of patients may develop severe hypoglycemia with neuroglycopenia. Metabolic studies in these severely affected patients demonstrate both insulin-dependent and insulin-independent mechanisms may contribute to hypoglycemia (5). Notably, these patients are often incompletely responsive to medical nutritional therapy, and require therapies aimed at slowing carbohydrate absorption with medical nutritional therapy or alpha-glucosidase inhibitors such as acarbose, or suppression of insulin production using somatostatin analogues or diazoxide. Estimates of incidence of severe post-RYGB hypoglycemia differ, likely due to differences in definitions of severe hypoglycemia, patient selection criteria, and duration of follow-up, but are consistently <1% (Table 1).

Table 1.

Prevalence of Hypoglycemia after Roux-en-Y Gastric Bypass Surgery

Method of Ascertainment	Prevalence	Reference
Hospitalization	0.1–1%	Marska, Gribsholtb, Leec
Clinical recognition	0.4–7.6%	Gribsholtb, Kelloggd
Severe hypoglycemia requiring assistance (self-report)	11.6%	Leee
Symptoms (survey) OGTT glucose below 50–60 mg/dl	33–38%, or 0.1% 10% to 68%	Gribshallb, Leee,, Sarwarf Pigeyreg, Roslinh
MMTT glucose below 55 mg/dl	22–29%	Kefurti, Goldfinej
CGMS sensor glucose below 55 mg/dl	75%	Kefurti
	Duration
CGMS sensor glucose below 60 mg/dl	29–71 minutes	Kefurti*, Halperinj, Abrahamssonk Hanairel, Ritzm

^*median duration postop 7.4 years;

^**threshold below 55 mg/dl

CGMS=continuous glucose monitoring system; OGTT=oral glucose tolerance test; MMTT=mixed meal tolerance test.

^aMarsk R, Jonas E, Rasmussen F, Naslund E. Nationwide cohort study of post-gastric bypass hypoglycaemia including 5,040 patients undergoing surgery for obesity in 1986–2006 in Sweden. Diabetologia 2010;53: 2307–2311.

^bGribsholt SB, Pedersen AM, Svensson E, Thomsen RW, Richelsen B. Prevalence of Self-reported Symptoms After Gastric Bypass Surgery for Obesity. JAMA surgery 2016: 1–9.

^cLee-Obesity in press

^dKellogg TA, Bantle JP, Leslie DB, Redmond JB, Slusarek B, Swan T, et al. Postgastric bypass hyperinsulinemic hypoglycemia syndrome: characterization and response to a modified diet. Surgery for Obesity and Related Diseases 2008;4: 492–499.

^eLee CJ, Clark JM, Schweitzer M, Magnuson T, Steele K, Koerner O, et al. Prevalence of and risk factors for hypoglycemic symptoms after gastric bypass and sleeve gastrectomy. Obesity 2015;23: 1079–1084.

^fSarwar H, Chapman WH, 3rd, Pender JR, Ivanescu A, Drake AJ, 3rd, Pories WJ, et al. Hypoglycemia after Roux-en-Y gastric bypass: the BOLD experience. Obesity Surgery 2014;24: 1120–1124.

^gPigeyre M, Vaurs C, Raverdy V, Hanaire H, Ritz P, Pattou F. Increased risk of OGTT-induced hypoglycemia after gastric bypass in severely obese patients with normal glucose tolerance. Surgery for Obesity and Related Diseases 2015;11: 573–577.

^hRoslin MS, Oren JH, Polan BN, Damani T, Brauner R, Shah PC. Abnormal glucose tolerance testing after gastric bypass. Surgery for Obesity and Related Diseases 2013;9:26–31.

ⁱKefurt R, Langer FB, Schindler K, Shakeri-Leidenmuhler S, Ludvik B, Prager G. Hypoglycemia after Roux-En-Y gastric bypass: detection rates of continuous glucose monitoring (CGM) versus mixed meal test. Surgery for Obesity and Related Diseases 2015;11: 564–569.

^jGoldfine AB, Mun EC, Devine E, Bernier R, Baz-Hecht M, Jones DB, et al. Patients with neuroglycopenia after gastric bypass surgery have exaggerated incretin and insulin secretory responses to a mixed meal. The Journal of Clinical Endocrinology and Metabolism 2007;92: 4678–4685.

^jHalperin F, Patti ME, Skow M, Bajwa M, Goldfine AB. Continuous glucose monitoring for evaluation of glycemic excursions after gastric bypass. Journal of Obesity 2011;2011: 1–7.

^kAbrahamsson N, Eden Engstrom B, Sundbom M, Karlsson FA. Hypoglycemia in everyday life after gastric bypass and duodenal switch. European Journal of Endocrinology 2015;173: 91–100.

^lHanaire H, Bertrand M, Guerci B, Anduze Y, Guillaume E, Ritz P. High glycemic variability assessed by continuous glucose monitoring after surgical treatment of obesity by gastric bypass. Diabetes Technology Therapeutics 2011;13:625–30.

^mRitz P, Vaurs C, Bertrand M, Anduze Y, Guillaume E, Hanaire H. Usefulness of acarbose and dietary modifications to limit glycemic variability following Roux-en-Y gastric bypass as assessed by continuous glucose monitoring. Diabetes Technology Therapeutics 2012;14:736–40

Studies utilizing continuous glucose monitoring suggest substantial hypoglycemia occurs even in completely asymptomatic patients post-RYGB, ranging from 29–71 minutes-per-day of sensor glucose values <60 mg/dL [3.3 mmol/L]; in one study, 75% of 40 unselected RYGB patients had a sensor glucose <55 mg/dl [3.1 mmol/L] (Table 1) compared to none in nonsurgical controls. Hypoglycemia during glucose or meal tolerance testing is also common (10–29%), and can be observed after sleeve gastrectomy, but the physiologic relevance of asymptomatic hypoglycemia remains uncertain.

The clinical relevance of severe hypoglycemia with neuroglycopenia is undeniable, as patient safety, cognition, and quality of life can be compromised. It remains plausible these individuals represent a spectrum of metabolic response, or underlying susceptibility profiles not yet identified. Further understanding of the importance of glycemic variability or asymptomatic hypoglycemia in the post-bariatric surgery setting, and novel approaches to prevent severe hypoglycemia continue to merit further investigation.