Guideline sources The following summarized guidelines for the evaluation and management of hypoglycemia are prepared by our editorial team based on guidelines from the American Diabetes Association (ADA 2023), the Endocrine Society (ES 2022; 2016; 2013; 2009), the American Heart Association (AHA/ASA 2022; 2019), the United Kingdom Kidney Association (UKKA 2020), the Kidney Disease: Improving Global Outcomes Foundation (KDIGO 2020; 2013), the American Society of Anesthesiologists (ASA/ACE/OS/AACE/ASMBS/OMA 2020), the Dumping Syndrome Consensus Group (DS-CG 2020), the Japanese Society of Nephrology (JSN 2019), the Diabetes Canada Guidelines (Diabetes Canada 2018), the European Association for the Study of Obesity (EASO 2017), the American Society for Metabolic and Bariatric Surgery (ASMBS 2017), the Pediatric Endocrine Society (PES 2015), the The Scottish Intercollegiate Guidelines Network (SIGN 2015), and the Guidelines and Audit Implementation Network (GAIN 2014). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Guidelines https://web.pathway.md/diseases/recz7ExdKlJXV9SlO 1/10 6/24/23, 12:47 PM Hypoglycemia Pathway 1. Diagnostic investigations Initial evaluation, patients with diabetes: As per ADA 2023 guidelines, review occurrence and risk for hypoglycemia at every encounter and investigate as indicated. Consider assessing for awareness of hypoglycemia using validated tools. B As per Diabetes Canada 2018 guidelines, review the patient's experience with hypoglycemia at each visit, including an estimate of cause, frequency, symptoms, recognition, severity, and treatment, as well as the risk of driving with hypoglycemia. B As per ES 2009 guidelines: Evaluate hypoglycemia only in patients presenting with Whipple's triad: symptoms, signs, or both consistent with hypoglycemia, a low plasma glucose concentration, and resolution of those symptoms or signs after the plasma glucose concentration is raised. A Assess conventional risk factors and those indicative of compromised defenses against hypoglycemia in patients with recurrent treatment-induced hypoglycemia. A Initial evaluation (patients without diabetes): Adopt the following strategy in patients with hypoglycemia without diabetes mellitus: review the history, physical findings, and all available laboratory data seeking clues to specific disorders (drugs, critical illnesses, hormone deficiencies, non-islet cell tumors) measure plasma glucose, insulin, C-peptide, proinsulin, -hydroxybutyrate, and insulin antibodies and screen for oral hypoglycemic agents during an episode of spontaneous hypoglycemia when the cause of the hypoglycemic disorder is not evident (seemingly well individual), and observe the plasma glucose response to IV injection of 1 mg glucagon recreate the circumstances in which symptomatic hypoglycemia is likely to occur (such as during a fast of up to 72 hours or after a mixed meal) when a spontaneous hypoglycemic episode cannot be observed document endogenous hyperinsulinism based on the findings of symptoms, signs, or both with plasma concentrations of glucose < 55 mg/dL (< 3 mmol/L), insulin 3 U/mL (18 pmol/L), C- peptide of 0.6 ng/mL ( 0.2 nmol/L), and proinsulin 5.0 pmol/L document hypoglycemia as induced by insulin (or insulin-like growth factor) based on the findings of symptoms, signs, or both with plasma concentrations of -hydroxybutyrate 2.7 mmol/L and glucose 25 mg/dL (1.4 mmol/L) after IV glucagon administration obtain diagnostic investigations, such as CT or MRI, transabdominal and EUS, and, if necessary, perform selective pancreatic arterial calcium injections with measurements of hepatic venous insulin levels, to localize an insulinoma in patients with documented fasting or postprandial endogenous hyperinsulinemic hypoglycemia, negative screening for oral hypoglycemic agents, and no circulating insulin antibodies tailor treatment to the specific hypoglycemic disorder taking into account the burden of hypoglycemia on patient wellbeing and patient preferences. B Screening for anxiety: https://web.pathway.md/diseases/recz7ExdKlJXV9SlO 2/10 6/24/23, 12:47 PM Hypoglycemia Pathway Consider screening patients with diabetes for symptoms or diabetes-related worries. Consider discussing diabetes-related worries and referring to a qualified mental health professional for further assessment and treatment if anxiety symptoms indicate interference with diabetes self- management behaviors or quality of life. C Refer patients with hypoglycemia unawareness, which can co-occur with fear of hypoglycemia, to a trained professional to receive evidence-based intervention to help re-establish awareness of symptoms of hypoglycemia and reduce fear of hypoglycemia. A Screening for cognitive impairment: Monitor cognitive capacity throughout the life span in all patients with diabetes, particularly in patients experiencing severe hypoglycemia episodes. B Consider obtaining an ongoing assessment of cognitive function with increased vigilance for hypoglycemia by the clinician, patient, and caregivers in patients with impaired or declining cognition. C 2. Medical management Oral carbohydrates: As per ADA 2023 guidelines: Administer glucose (approximately 15-20 g) as the preferred treatment in conscious patients with blood glucose < 70 mg/dL (3.9 mmol/L), although any form of carbohydrate-containing glucose may be used. Repeat treatment if blood glucose monitoring shows continued hypoglycemia 15 minutes after treatment. B Avoid using carbohydrate sources high in protein for the treatment or prevention of hypoglycemia as ingested protein appears to increase insulin response without increasing plasma glucose concentrations in patients with T2DM. D As per Diabetes Canada 2018 guidelines, administer oral carbohydrates (15 g; preferably as glucose or sucrose tablets or solution rather than orange juice or glucose gels) for the treatment of mild-to-moderate hypoglycemia in patients with diabetes. B Show 2 more As per ES 2009 guidelines, administer oral carbohydrates, if feasible, for urgent treatment of hypoglycemia. A IV carbohydrates and glucagon: As per ADA 2023 guidelines, prescribe glucagon in all patients at increased risk of level 2 or 3 hypoglycemia, so that it is available should it be needed. Ensure that caregivers, school personnel, or family members providing support to these patients know where it is and when and how to administer it as glucagon administration is not limited to healthcare professionals. B As per ES 2022 guidelines, use glucagon preparations not requiring reconstitution in outpatients with severe hypoglycemia. B As per Diabetes Canada 2018 guidelines: https://web.pathway.md/diseases/recz7ExdKlJXV9SlO 3/10 6/24/23, 12:47 PM Hypoglycemia Pathway Administer SC or intramuscularly glucagon (1 mg) for the treatment of severe hypoglycemia in unconscious patients with diabetes with no IV access. Administer IV glucose (10-25 g; 20-50 mL of 50% dextrose solution) over 1-3 minutes in patients with IV access. B Educate support persons of patients with diabetes at risk of severe hypoglycemia on glucagon administration techniques. B As per ES 2009 guidelines, administer parenteral glucagon or glucose for urgent treatment of hypoglycemia, if oral carbohydrate administration is not feasible. A 3. Specific circumstances Neonatal patients: consider evaluating neonates suspected to be at high risk of having a persistent hypoglycemia disorder when the infant is 48 hours of age so that the period of transitional glucose regulation has passed and persistent hypoglycemia may be excluded before discharge home. B Show 4 more Pediatric patients (evaluation): evaluate and manage pediatric patients able to communicate their symptoms only in the presence of Whipple's triad. A Show 2 more Pediatric patients (glycemic targets, T1DM): individualize Hgb A1C goals and reassess over time, recognizing that an Hgb A1C level of < 7% (53 mmol/mol) is appropriate for many pediatric and adolescent patients. B Show 3 more Pediatric patients (glycemic targets, T2DM): set < 7% (53 mmol/mol) as a reasonable Hgb A1C target in most pediatric and adolescent patients with T2DM. Consider setting more stringent Hgb A1C targets (such as < 6.5%; 48 mmol/mol) in selected patients (such as patients with a short duration of diabetes and lesser degrees of -cell dysfunction and patients treated with lifestyle or metformin only and achieved significant weight improvement) if they can be achieved without significant hypoglycemia or other adverse effects of treatment. B Show 2 more Pediatric patients (glucose monitoring, T1DM): advise all young patients with T1DM to monitor glucose levels multiple times daily (up to 6-10 times/day by blood glucose meter or continuous glucose monitoring), including before meals and snacks, at bedtime, and as needed for safety in specific situations, such as exercise, driving, or the presence of symptoms of hypoglycemia. B Show 6 more Pediatric patients (glucose monitoring, T2DM): Individualize blood glucose monitoring taking into consideration the pharmacologic treatment of the patient. B Obtain real-time continuous glucose monitoring or intermittently scanned continuous glucose monitoring for diabetes management in young patients with T2DM on multiple daily injections or continuous SC insulin infusion capable of using the device safely (either by themselves or with a https://web.pathway.md/diseases/recz7ExdKlJXV9SlO 4/10 6/24/23, 12:47 PM Hypoglycemia Pathway caregiver). Decide on the choice of the device based on patient circumstances, desires, and needs. B Pregnant patients: As per ADA 2023 guidelines, obtain fasting and postprandial blood glucose monitoring in both gestational diabetes mellitus and preexisting diabetes in pregnancy, to achieve optimal glucose levels. Set the following glucose targets: fasting plasma glucose < 95 mg/dL (5.3 mmol/L) and either 1-hour postprandial glucose < 140 mg/dL (7.8 mmol/L) or 2-hour postprandial glucose < 120 mg/dL (6.7 mmol/L). Obtain blood glucose preprandially in some patients with preexisting diabetes. B Show 4 more As per ES 2013 guidelines, consider targeting blood glucose and Hgb A1C levels as close to normal as possible in female patients with diabetes seeking to conceive, without causing undue hypoglycemia. C Show 2 more Elderly patients: prefer medication classes with a low risk of hypoglycemia in older patients with T2DM at increased risk of hypoglycemia. B Show 8 more Patients with chronic kidney disease (glycemic targets): Do not treat to a target Hgb A1c of < 7.0% (< 53 mmol/mol) in patients at risk of hypoglycemia. D Consider setting a target Hgb A1c of > 7.0% (> 53 mmol/mol) in patients with comorbidities or limited life expectancy and risk of hypoglycemia. C Patients with chronic kidney disease (considerations for pharmacotherapy): Recognize that the risk of hypoglycemia is generally low with GLP-1 receptor agonists when used alone, but the risk is increased when GLP-1 receptor agonists are used concomitantly with other medications, such as sulfonylureas or insulin. Consider reducing the doses of sulfonylurea and/or insulin. B Consider discontinuing or reducing the dose of an antihyperglycemic drug other than metformin to facilitate the addition of an SGLT-2 inhibitor when additional glucose-lowering may increase the risk for hypoglycemia (such as treated with insulin or sulfonylureas and currently meeting glycemic targets). C Patients with chronic kidney disease (continuous glucose monitoring): Consider obtaining daily glycemic monitoring with continuous glucose monitoring or self- monitoring of blood glucose to help prevent hypoglycemia and improve glycemic control when antihyperglycemic therapies associated with the risk of hypoglycemia are used. C Prefer antihyperglycemic agents posing a lower risk of hypoglycemia and administer in doses appropriate for the level of estimated GFR in patients with T2DM and CKD refusing daily glycemic monitoring by continuous glucose monitoring or self-monitoring of blood glucose. B Patients with chronic kidney disease (elderly patients): consider deciding the target for glycemic control in 75 years old patients with CKD and diabetes mellitus individually depending https://web.pathway.md/diseases/recz7ExdKlJXV9SlO 5/10 6/24/23, 12:47 PM Hypoglycemia Pathway on the patient's health condition (age, cognitive function, physical function, comorbidity, risk of hypoglycemia, and time to live) as they are at risk of severe hypoglycemia. C Patients with post-bariatric hypoglycemia, general principles: As per ADA 2023 guidelines: Exclude other potential disorders contributing to hypoglycemia in patients with suspected postbariatric hypoglycemia. Provide education, medical nutrition therapy with a dietitian experienced in postbariatric hypoglycemia, and medication treatment as needed for the management of patients with postbariatric hypoglycemia. A Consider obtaining continuous glucose monitoring as an important adjunct to improve safety by alerting patients to hypoglycemia, especially in patients with severe hypoglycemia or hypoglycemia unawareness. C As per ASA/OMA/ASMBS/OS/ACE/AACE 2020 guidelines, discontinue all insulin secretagogues (sulfonylureas and meglitinides), SGLT-2 inhibitors, and thiazolidinediones and adjust insulin doses (due to low-calorie intake) to minimize the risk of hypoglycemia in the immediate postoperative period in patients with T2DM. B Show 3 more As per EASO 2017 guidelines, direct treatment in the first 7-10 days after surgery toward fasting glucose values and instruct patients to test blood glucose at least BID - fast in the morning (target values: 100-120 mg/dL) and during the day (< 180 mg/dL 2 hours after a meal). B Show 3 more Patients with post-bariatric hypoglycemia, postprandial hyperinsulinemic hypoglycemia: As per ASA/OMA/ASMBS/OS/ACE/AACE 2020 guidelines: Evaluate patients undergone Roux-en-Y gastric bypass, biliopancreatic diversion with duodenal switch, or sleeve gastrectomy and presenting with postprandial hypoglycemic symptoms not responding to nutritional manipulation, to differentiate non-insulinoma pancreatogenous hypoglycemia syndrome from factitious or iatrogenic causes, dumping syndrome, and insulinoma. B Offer dietary changes (low-carbohydrate diet), octreotide, diazoxide, acarbose, calcium- channel antagonists, gastric restriction, and/or reversal procedures (with partial or total pancreatectomy reserved for the rare recalcitrant cases) in patients with non-insulinoma pancreatogenous hypoglycemia. B As per ASMBS 2017 guidelines, recognize that postprandial hyperinsulinemic hypoglycemia after bariatric surgery is rare and most commonly associated with Roux-en-Y gastric bypass. Screen for, educate, and counsel to recognize the signs and symptoms of hypoglycemia. E Show 5 more Patients with post-bariatric hypoglycemia (late dumping syndrome): recognize that hypoglycemia is the main symptom of late dumping syndrome and is driven by a hyperinsulinemic response and GLP-1 release. B Show 2 more Patients with acute stroke: https://web.pathway.md/diseases/recz7ExdKlJXV9SlO 6/10 6/24/23, 12:47 PM Hypoglycemia Pathway As per ASA 2022 guidelines: Monitor serum glucose to reduce the risk of hyperglycemia and hypoglycemia in patients with spontaneous intracerebral hemorrhage. B Treat hypoglycemia (< 40-60 mg/dL; < 2.2-3.3 mmol/L) to reduce mortality in patients with spontaneous intracerebral hemorrhage. B As per AHA 2019 guidelines, assess blood glucose levels before administering IV alteplase since hypoglycemia may mimic acute stroke presentations. B Show 2 more Patients with hyperkalemia: As per UKKA 2020 guidelines, consider administering a preemptive infusion of 10% glucose at 50 mL/hour for 5 hours (25 g) following insulin/glucose treatment for hyperkalemia in patients with a pre-treatment blood glucose < 7.0 mmol/L, to avoid hypoglycemia (target blood glucose 4-7 mmol/L). C As per GAIN 2014 guidelines, monitor blood glucose 15 and 30 minutes after starting insulin/glucose infusion for hyperkalemia, and then hourly up to 6 hours after completion of the infusion, as delayed hypoglycemia is commonly reported when < 30 g of glucose is administered with insulin. E Patients with status epilepticus: administer IV glucose (50 mL of 50% solution) in patients with status epilepticus if there is any suggestion of hypoglycemia. B 4. Preventative measures General principles: As per ADA 2023 guidelines, assess the hypoglycemia risk, in addition to the assessments of overall health status, diabetes complications, and cardiovascular risk, to guide the ongoing management of diabetes. B Take the hypoglycemia risk into account to guide the choice of pharmacologic agents in patients with T2DM. B Show 2 more As per Diabetes Canada 2018 guidelines, counsel about the risk, prevention, recognition, and treatment of hypoglycemia in all patients with diabetes currently using or starting therapy with insulin or insulin secretagogues and their support persons. Identify and address risk factors for severe hypoglycemia. B Show 2 more Choice of insulin: As per ADA 2023 guidelines, prescribe multiple daily injections of prandial and basal insulin, or continuous SC insulin infusion in most patients with T1DM. A Show 4 more As per ES 2022 guidelines, consider prescribing long-acting insulin analogs rather than human NPH insulin in adult and pediatric outpatients on basal insulin therapy at high risk for hypoglycemia. C https://web.pathway.md/diseases/recz7ExdKlJXV9SlO 7/10 6/24/23, 12:47 PM Hypoglycemia Pathway Show 2 more As per ES 2016 guidelines, prescribe continuous subcutaneous insulin infusion over analog- based basal-bolus multiple daily injections in patients with T1DM not achieved the Hgb A1C goal, B or achieved the Hgb A1C goal but continuing to experience severe hypoglycemia or high glucose variability, as long as the patient and caregivers are willing and able to use the device. B Show 3 more Continuous glucose monitoring: As per ES 2022 guidelines, obtain continuous glucose monitoring rather than self-monitoring of blood glucose by fingerstick in patients with T1DM receiving multiple daily injections. B Show 5 more As per ES 2022 guidelines, consider obtaining real-time continuous glucose monitoring with confirmatory bedside point-of-care blood glucose monitoring for adjustments in insulin dosing (in hospital settings where resources and training are available) in adult patients with insulin-treated diabetes at high risk of hypoglycemia hospitalized for a non-critical illness. C As per ES 2016 guidelines, obtain real-time continuous glucose monitoring in adult patients with T1DM with Hgb A1C levels above target, if they are willing and able to use continuous glucose monitoring devices on a nearly daily basis. A Show 3 more Counseling on alcohol use: Advise adult patients with diabetes drinking alcohol to do so in moderation ( 1 drink/day for adult females and 2 drinks/day for adult males). B Educate patients with diabetes about the signs, symptoms, and self-management of delayed hypoglycemia after drinking alcohol, especially when using insulin or insulin secretagogues. Emphasize the importance of glucose monitoring after drinking alcoholic beverages to reduce hypoglycemia risk. B 5. Follow-up and surveillance Post-hypoglycemia care: As per ADA 2023 guidelines, advise patients to consume a meal or snack once the blood glucose monitoring or glucose pattern is trending up, to prevent the recurrence of hypoglycemia. B As per Diabetes Canada 2018 guidelines, advise patients to have the usual meal or snack that is due at that time of the day, once the hypoglycemia has been reversed, to prevent repeated hypoglycemia. Advise having a snack (including 15 g carbohydrate and a protein source) if a meal is > 1 hour away. B As per ES 2009 guidelines, obtain a fundamental review of the treatment regimen and the glycemic goals after an episode of severe hypoglycemia, unless the cause is easily remediable. A https://web.pathway.md/diseases/recz7ExdKlJXV9SlO 8/10 6/24/23, 12:47 PM Hypoglycemia Pathway References 1. Steven E. Kahn, Cheryl A.M. Anderson, John B. Buse et al. Standards of Care in Diabetes 2023. Diabetes Care. 2023 Jan;46 Supplement_1 S1 S291. Open 2. Diabetes Canada Clinical Practice Guidelines Expert Committee, Jean-Fran ois Yale, Breay Paty et al. Hypoglycemia. Can J Diabetes. 2018 Apr;42 Suppl 1 S104 S108. Open 3. McVeigh G, Maxwell P, O'Donell S et al. Guidelines for the Treatment of Hyperkalaemia in Adults. GAIN Sub-Group on the Treatment of Hyperkalaemia in Adults. Open 4. William J Powers, Alejandro A Rabinstein, Teri Ackerson et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2019 Dec;50 12):e344-e418. Open 5. Busetto L, Dicker D, Azran C et al. Practical Recommendations of the Obesity Management Task Force of the European Association for the Study of Obesity for the Post-Bariatric Surgery Medical Management. Obes Facts. 2017;10 6 597 632. Open 6. Annette Alfonzo, Alexander Harrison, Richard Baines et al. Clinical Practice Guidelines Treatment of Acute Hyperkalaemia in Adults. The Renal Association. 2020 Jun. Open 7. Kidney Disease: Improving Global Outcomes KDIGO Diabetes Work Group. KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int. 2020 Oct;98 4S S1 S115. Open 8. Anthony L McCall, David C Lieb, Roma Gianchandani et al. Management of Individuals With Diabetes at High Risk for Hypoglycemia: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2022 Dec 7;dgac596. Open 9. Anne L Peters, Andrew J Ahmann, Tadej Battelino et al. Diabetes Technology-Continuous Subcutaneous Insulin Infusion Therapy and Continuous Glucose Monitoring in Adults: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016 Nov;101 11 3922 3937. Open 10. Philip E Cryer, Lloyd Axelrod, Ashley B Grossman et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2009 Mar;94 3 709 28. Open 11. KDIGO Executive Committee. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. KDIGO. 2013 Jan;3 1 . Open 12. Japanese Society of Nephrology. Essential points from Evidence-based Clinical Practice Guidelines for Chronic Kidney Disease 2018. Clin Exp Nephrol. 2019 Jan;23 1 1 15. Open 13. Jeffrey I Mechanick, Caroline Apovian, Stacy Brethauer et al. Clinical Practice Guidelines for the Perioperative Nutrition, Metabolic, and Nonsurgical Support of Patients Undergoing Bariatric Procedures 2019 Update: Cosponsored by American Association of Clinical Endocrinologists/American College of Endocrinology, The Obesity Society, American Society for Metabolic and Bariatric Surgery, Obesity Medicine Association, and American Society of Anesthesiologists. Obesity Silver Spring). 2020 Apr;28 4 O1 O58. Open https://web.pathway.md/diseases/recz7ExdKlJXV9SlO 9/10 6/24/23, 12:47 PM Hypoglycemia Pathway 14. Steven M Greenberg, Wendy C Ziai, Charlotte Cordonnier et al. 2022 Guideline for the Management of Patients With Spontaneous Intracerebral Hemorrhage: A Guideline From the American Heart Association/American Stroke Association. Stroke. 2022 May 17;101161STR0000000000000407. Open 15. Paul S Thornton, Charles A Stanley, Diva D De Leon et al. Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children. J Pediatr. 2015 Aug;167 2 238 45. Open 16. Dan Eisenberg, Dan E Azagury, Saber Ghiassi et al. ASMBS Position Statement on Postprandial Hyperinsulinemic Hypoglycemia after Bariatric Surgery. Surg Obes Relat Dis. 2017 Mar;13 3 371 378. Open 17. Mary T Korytkowski, Ranganath Muniyappa, Kellie Antinori-Lent et al. Management of Hyperglycemia in Hospitalized Adult Patients in Non-Critical Care Settings: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2022 Jun 12;dgac278. Open 18. SIGN. SIGN 143 Diagnosis and management of epilepsy in adults. SIGN, 2015. Open 19. Emidio Scarpellini, Joris Arts, George Karamanolis et al. International consensus on the diagnosis and management of dumping syndrome. Nat Rev Endocrinol. 2020 Aug;16 8 448 466. Open 20. Blumer I, Hadar E, Hadden DR et al. Diabetes and pregnancy: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2013 Nov;98 11 4227 49. Open 21. Endocrine Society. Choosing Wisely ES recommendations. Choosing Wisely. 2013. Open 22. B P Kovatchev, D J Cox, L A Gonder-Frederick et al. Assessment of risk for severe hypoglycemia among adults with IDDM validation of the low blood glucose index. Diabetes Care. 1998 Nov;21 11 1870 5. Open 23. William G. Herrington, Andrew H. Frankel, Alexa Wonnacott et al. UK Kidney Association Clinical Practice Guideline: Sodium-Glucose Co-transporter-2 SGLT 2 Inhibition in Adults with Kidney Disease. UKKA. 2021 Oct. Open https://web.pathway.md/diseases/recz7ExdKlJXV9SlO 10/10