CME INDIA Presentation by Dr. Amit Kumar Dey, Dr. Partha Biswas, Dr. M. H. Sanwarwala, Dr. Agnik Pal, Dr. Moloy Das, Dr. Shamo Samrat Majumdar, Dr. Bijay Patni, Kolkata.
Based on a DRWA (Diabetes Research and Welfare Association) Symposium on Hypoglycemia, held at Vadodara on 15/07.2023 under agis of ICDM (Indian Diabetes and Cardiometabolic Diseases Association), METACON-2023.
Definition & Classification
Dr. Moloy Das:
- Hypoglycaemia, defined as blood glucose levels below 70 mg/dL, is a common complication in diabetes.
- In India, smaller studies indicate a prevalence of over 50% in Type 2 Diabetes Mellitus (T2DM) and over 20% in Type 1 Diabetes Mellitus (T1DM) cases.
- International studies suggest an overall prevalence of 45% for mild/moderate hypoglycaemia and 6% for severe cases. Incidence rates vary, with 19 episodes per person-year for mild/moderate and 0.80 for severe cases.
- These estimates are higher than previously suggested.
- Hypoglycaemia leads to increased costs and poorer quality of life in patients.
Classification: International Hypoglycaemia Study Group (IHSG)
The IHSG proposed three definition levels be adopted universally:
| Level 1 | Glucose ≤3.9 mmol/L(<70mg/dl) ALERT LEVEL |
| Level 2 | Glucose <3.0 mmol/L (54mg/dl) CLINICALLY IMPORTANT |
| Level 3 | Severe events requiring third-party intervention independent of a defined glucose value |
Clinical features
Dr. Partha Biswas:
HAAF (unaware hypoglycemia)
Dr. Agnik Pal:
Patients with diabetes mellitus who experience recurring episodes of hypoglycemia induced by insulin may develop a condition known as hypoglycemia-associated autonomic failure (HAAF). This condition is characterized by a diminished counterregulatory response (CRR), which refers to the body’s ability to respond effectively to hypoglycemia through the release of appropriate hormones, as well as hypoglycemia unawareness. HAAF significantly impacts the management of blood glucose levels, posing a substantial obstacle to achieving optimal regulation and frequently leading to increased morbidity among individuals with diabetes.
Courtesy: Philip E. Cryer, https://www.researchgate.net/publication/26780468_Exercise-Related_Hypoglycemia-Associated_Autonomic_Failure_in_Diabetes
Hypoglycemia & physical exercises
Dr. M. H. Sanwarwalla:
- Exercise is defined as every physical movement produced by skeletal muscles, resulting in energy consumption. It is aerobic and anaerobic.
- Hypoglycaemia is common during exercise, especially in type 1 diabetics and type 2 diabetics on insulin and long-acting oral hypoglycaemic agents.
- Safe exercise tips to prevent hypoglycaemia
- Adequate metabolic control.
- Self- monitoring is essential.
- If blood glucose<100mgdl or>300mgdl, avoid exercise.
- 10-15g carbohydrate 1 hour before exercise.
- Hypoglycaemia may occur 3-15 hours after exercise.
- Decrease insulin dose if prolonged exercise anticipated.
- Injection site should be away from exercising part.
- Fluid consumption is important.
- Carry id card and carbohydrate containing food.
OAD in hypoglycemia
Dr. Shambo Samrat Majumdar:
Personalized Approach to Treatment Based on Individual Characteristics and Comorbidities: Recommended Process for Glucose-Lowering Medication Selection.
Courtsey:https://professional.diabetes.org/content-page/management-hyperglycemia-type-2-diabetes-ada-easd-consensus-report-2022
Hypoglycemia & alcohol
Dr. Moloy Das:
- Alcohol metabolism affects the body’s ability to maintain normal blood glucose levels, particularly in the context of fasting. Here are two key points regarding the relationship between alcohol consumption, fasting, and hypoglycaemia:
- Alcohol metabolism and inhibition of gluconeogenesis: When alcohol is consumed, it undergoes oxidation in the liver. This process leads to an increase in the hepatic cytosolic NADH-to-NAD+ ratio. As a result, key enzymes involved in gluconeogenesis, the process by which the liver produces glucose, become inhibited. This inhibition prevents the release of glucose from the liver into the bloodstream, leading to a decrease in blood glucose levels. The reduced ability of the liver to produce glucose contributes to the development of hypoglycaemia.
- Hypoglycaemia during fasting and alcohol consumption-When alcohol is consumed while fasting, it further exacerbates the decrease in hepatic glucose production caused by the inhibition of gluconeogenesis. Without a dietary source of glucose and with impaired glucose production, blood glucose levels can drop to hypoglycaemic levels.
- It is important for individuals who consume alcohol, particularly while fasting, to be aware of the potential for hypoglycaemia. Monitoring blood glucose levels, consuming appropriate amounts of carbohydrates, and avoiding excessive alcohol intake can help mitigate the risk of hypoglycaemia in these situations
Hypoglycemia in Elderly
Dr. Partha Biswas:
- Recurrent hypoglycemia is common in older people with diabetes and is likely to be less recognized and under reported by patients and health care professionals.
- Hypoglycemia in this age group is associated with significant morbidities leading to both physical and cognitive dysfunction.
- Repeated hospital admissions due to frequent hypoglycemia are also associated with further deterioration in patients’ general health.
- This negative impact of hypoglycemia is likely to eventually lead to frailty, disability and poor outcomes.
- The relationship between hypoglycemia and frailty is bidirectional and mediated through a series of influences including under nutrition
- The brain is highly dependent on glucose for its metabolism and is particularly vulnerable to hypoglycemia especially in the older people.
- After each hypoglycemic episode major cognitive changes occur leading to post-hypoglycaemic encephalopathy.
- Therefore, recurrent hypoglycemia may be associated with impaired cognitive function and development of dementia.
- They are more likely to experience anxiety and panic attacks that in turn can further increase the number of episodes and may result in social isolation and negative emotional states
Nocturnal Hypoglycemia
Dr. Agnik Pal:
- Inadequate self-management of diabetes significantly raises the risk of hypoglycaemia and the development of long-term complications due to poor glycaemic control. Hypoglycaemia not only incurs increased healthcare costs and resources for treatment but also imposes personal financial burdens and hampers productivity at school or work. Moreover, the fear, anxiety, and distress associated with experiencing hypoglycaemic episodes have a negative impact on patients’ overall quality of life.
- Nocturnal hypoglycaemia, specifically, can result in immediate clinical consequences such as seizures, coma, and even fatality. Prolonged exposure to recurrent nocturnal hypoglycaemia can dull the body’s natural mechanisms that regulate glucose levels, leading to diminished cognitive function, impaired awareness of hypoglycaemia, and the development of hypoglycaemia-associated autonomic failure.
- Healthcare professionals need to recognize the significance of hypoglycaemia, particularly nocturnal episodes, in order to prescribe appropriate glucose-lowering therapies and provide education to patients on preventing and managing hypoglycaemic events. By doing so, they can alleviate anxiety, enhance the quality of life for individuals with diabetes, and reduce the adverse consequences associated with hypoglycaemia
Newer Insulins in Hypoglycemia
Dr. Shambo Samrat Majumdar:
| Insulin analogues |
| Ultra-short acting/ Rapid acting- Lispro, Aspart, Glulicine |
| Long acting- Glargine, Detemir, Degludec |
| Better control of PPG, Decreased risk of late PP hypoglycaemia. |
| Glargine prevents night time hypoglycaemia in elderly patients over the age of 70 years. |
| Analogues are preferred in unexpected exercise |
| Critical patients in ICU and chronic renal disease do better with analogues. |
| Action profile of analogues is independent of dose or site or exercise. |
| Greater flexibility of short acting analogues as they can be given even with or after meals. |
| Real world evidence, bright RCT & addition 1-3 RCT |
Relative Hypoglycemia
Dr. Moloy Das:
- Relative hypoglycemia is a glucose reduction more than or equal to 30% below prehospital admission levels (estimated by hemoglobin A1C) but not absolute hypoglycemia levels.
- This can trigger a hypoglycemic stress response (increased glucagon and adrenaline secretion) in patients without diabetes.
- Patients with relative hypoglycemia had a high risk of mortality.
- How can we prevent relative Hypoglycemia?
- Adjust medication dosage to achieve balanced blood glucose control and prevent relative hypoglycemia.
- Monitor blood glucose regularly to identify fluctuations and take appropriate action.
- Following a consistent meal plan to maintain stable blood glucose levels.
Hypoglycemia in Pregnancy
Dr. Partha Biswas:
- Diabetes in pregnancy has significant adverse effects on both pregnant women and neonates.
- Pregnant women with diabetes are at risk of complications such as polyhydramnios, gestational hypertension, abortion, and an increased future risk of T2DM.
- Neonates born to diabetic mothers may experience perinatal death, macrosomia, congenital cardiac abnormalities, shoulder dystocia, hypoglycaemia, hypocalcaemia, and infection.
- There are chances of increased insulin sensitivity during the early trimester than prior to or in the late pregnancy
- Obesity in pregnant women is associated with an increased risk of non-elective C-sections and elevated rates of neonatal hypoglycaemia.
- Improving glucose control through CGM during the second and third trimesters has been shown to reduce the risk of neonatal hypoglycaemia.
- Dietary interventions such as taking a protein-rich low carbohydrate snack at bedtime could also stabilize blood glucose levels in those prone to episodes of hypoglycaemia.
Technology (CGMS)
Dr. Agnik Pal:
- Continuous glucose monitoring (CGM) proves to be an invaluable tool in identifying individuals who are susceptible to hypoglycaemia-related issues and in preventing both mild and severe hypoglycaemic episodes.
- The use of CGM does not compromise glycaemic control nor does it increase the risk of complications. However, there is a need for further research to enhance our understanding of CGM result interpretation and the underlying mechanisms by which CGM aids in preventing hypoglycaemia. Such knowledge will contribute to the optimization of CGM usage and its effectiveness in hypoglycaemia prevention.
Special Situations:
Non-anti-diabetic drugs
Dr. Shambo Samrat Majumdar:
Drugs with low to moderate quality of evidence supporting association with hypoglycemia
- The available evidence supporting the association between various drugs and hypoglycaemia is of very low quality. However, it is important to note that drug-induced hypoglycaemia can be severe and lead to considerable morbidity.
- Prescribers should make efforts to prevent these adverse events, especially in specific patient populations such as the elderly, patients with sepsis, renal or hepatic disease, and those who are taking insulin or sulfonylurea medications.
- By exercising caution and considering alternative medications or adjusting dosages, healthcare professionals can minimize the risk of hypoglycaemia-related complications in these vulnerable patients
Courtsey: Murad, Met al. (2009). Drug-Induced Hypoglycaemia: A Systematic Review. The Journal of clinical endocrinology and metabolism. 94. 741-5. 10.1210/jc.2008-1416.
Non-Diabetic Hypoglycemia
Dr. M. H. Sanwarwalla:
- This refers to low blood sugar levels in individuals who do not have diabetes.
- Numerous factors need to be considered, including prescription drugs, serious diseases, infections, malnutrition, hormone deficiency, and non-islet cell tumors that secrete IGF-II.
- When sickness or medicine is ruled out, tests done during hypoglycaemia can determine the reason.
- Testing should be done at the time of spontaneous development of symptoms.
- Treatment is dependent on the cause of hypoglycaemia
Post metabolic surgeries
Dr. Shambo Samrat Majumdar:
- The significance of severe hypoglycaemia accompanied by neuroglycopenia cannot be overlooked, as it has a profound impact on patient safety, nutrition, cognitive function, and overall quality of life. Despite this recognition, we currently lack knowledge regarding the long-term health outcomes of individuals who experience severe hypoglycaemia following Roux-en-Y gastric bypass (RYGB) surgery.
Suggested approach to possible hypoglycaemia in a post bariatric patient. glc, glucose.
Courtesy: Salehi M, Vella A, McLaughlin T, Patti ME. Hypoglycaemia After Gastric Bypass Surgery: Current Concepts and Controversies. J Clin Endocrinol Metab. 2018 Aug 1;103(8):2815-2826.
Courtesy: Salehi M, Vella A, McLaughlin T, Patti ME. Hypoglycaemia After Gastric Bypass Surgery: Current Concepts and Controversies. J Clin Endocrinol Metab. 2018 Aug 1;103(8):2815-2826.
Hypoglycemia in Hospital
Dr. Moloy Das:
- Monitor anti-hyperglycemic therapy when calorie intake is reduced or stopped.
- Avoid sliding scale insulin.
- Avoid overly aggressive attempts with intensive insulin therapy.
- Arrythmias and other cardiac events are common when blood glucose falls below 54mgdl.
- Patients receiving total parental nutrition (TPN) and enteric food, have to be controlled with multiple daily insulin injections.
- Chronic Kidney Disease patients especially on dialysis therapy have to be monitored closely.
Cardiovascular Diseases
Dr. Agnik Pal:
- Proposed mechanisms of spontaneous hypoglycaemia-induced arrhythmias differ between daytime and night-time occurrences in patients with type 2 diabetes who have cardiovascular disease or two cardiovascular risk factors. Hypoglycaemia is associated with increased ventricular premature beats during both daytime and night-time, but they are more frequent during nocturnal hypoglycaemia.
- During the day, the predominant response to hypoglycaemia is a sympathetic activation, leading to QT segment prolongation and an increase in heart rate. This sympathetic response is associated with cardio accelerations.
- During nocturnal hypoglycaemia, different phases of heart rate variability indicate a sequential response. Initially, there is a sympathetic response followed by a subsequent parasympathetic (vagal) response. This shift in autonomic activity may explain the occurrence of bradycardia and atrial ectopic arrhythmias, which are eightfold and fourfold more common, respectively, during night-time hypoglycaemia. These arrhythmias are likely attributed to a blunted sympathoadrenal response during the night and a relatively increased parasympathetic activity.
- It is important to note that hypoglycaemia, despite its frequency in patients with type 2 diabetes, can trigger arrhythmias.
- Considering the relatively high occurrence of hypoglycaemia and its associated cardiac arrhythmias, as observed in the referenced study, and the increased mortality demonstrated in the ACCORD study, it is crucial for both patients and healthcare providers to recognize the importance of individualizing target glycaemic goals. By tailoring these goals and making adjustments, the aim is to prevent severe hypoglycaemia and potentially fatal hypoglycaemia-induced arrhythmias.
- This take-home message emphasizes the need for personalized diabetes management, taking into account each patient’s unique characteristics, comorbidities, and cardiovascular risk factors. Striking the right balance in glycaemic control to avoid hypoglycaemia-related complications, including cardiac arrhythmias, is of paramount importance. Healthcare providers should work closely with patients to establish realistic and safe glycaemic targets, considering their overall health status and risk profile.
Courtesy: Clark EvenSH, Even Silent Hypoglycemia Induces Cardiac Arrhythmias Diabetes 2014;63(5):1457–1459
CKD & CLD
Dr. Shambo Samrat Majumdar:
- Renal impairment is considered an independent risk factor of severe hypoglycemia.
- The kidney has an important role in metabolizing circulating insulin, reabsorbing filtered glucose, contributing to gluconeogenesis, and excreting drugs and their metabolites with blood glucose lowering agents
- Kidney impairment reduces the ability to clear hypoglycaemic agents, the degradation of insulin in peripheral tissues, gluconeogenesis, and insulin metabolism which can predispose a patient with chronic kidney disease (CKD) to hypoglycaemia.
- The counter-regulatory response to hypoglycemia may be defected by impaired gluconeogenesis or a glycogen reserve deficiency caused by uremia-induced anorexia in patients with renal impairment.
Awareness & Prevention
Dr. M. H. Sanwarwalla:
- Structured patient education, counselling, and continuous blood glucose monitoring are critical for preventing hypoglycaemia in diabetes patients. Timely meals and SMBG play important roles in prevention.
- CGM technology and structured education can effectively reduce the time spent below the target range in patients with diabetes.
- Telehealth and community-based intervention programs are recommended for preventing hypoglycaemia and promoting patient education.
- Knowledge about symptoms, consequences, and treatment options is essential for effective prevention through counselling.
- Short-term relaxation of glycaemic targets and the availability of glucagon can benefit patients with occasional hypoglycaemic episodes.
CME INDIA Tail-Piece
References:
- Heller SR, Buse JB, Ratner R, Seaquist E, Bardtrum L, Hansen CT, Tutkunkardas D, Moses AC. Redefining Hypoglycemia in Clinical Trials: Validation of Definitions Recently Adopted by the American Diabetes Association/European Association for the Study of Diabetes. Diabetes Care. 2020 Feb;43(2):398-404. doi: 10.2337/dc18-2361. Epub 2019 Oct 28. PMID: 31658975; PMCID: PMC7411283.
- Rodríguez-Gutiérrez R, Salcido-Montenegro A, González-González JG, McCoy RG. Variation in hypoglycemia ascertainment and report in type 2 diabetes observational studies: a meta-epidemiological study. BMJ Open Diabetes Res Care. 2021 Apr;9(1):e001906. doi: 10.1136/bmjdrc-2020-001906. PMID: 33888541; PMCID: PMC8070868.
- Cryer, Philip. (2009). Exercise-Related Hypoglycemia-Associated Autonomic Failure in Diabetes. Diabetes. 58. 1951-2. 10.2337/db09-0834.
- Clark EvenSH, Even Silent Hypoglycemia Induces Cardiac Arrhythmias Diabetes 2014;63(5):1457–1459.https://doi.org/10.2337/db14-0108
- Hermanns N, Heinemann L, Freckmann G, Waldenmaier D, Ehrmann D. Impact of CGM on the Management of Hypoglycemia Problems: Overview and Secondary Analysis of the HypoDE Study. J Diabetes Sci Technol. 2019 Jul;13(4):636-644. doi: 10.1177/1932296819831695. Epub 2019 Mar 6. PMID: 30841740; PMCID: PMC6610605.
- Murad, M. Hassan & Coto-Yglesias, Fernando & Wang, Amy & Sheidaee, Nasim & Mullan, Rebecca & Mohamed, Benyagoub & Erwin, Patricia & Montori, Victor. (2009). Drug-Induced Hypoglycemia: A Systematic Review. The Journal of clinical endocrinology and metabolism. 94. 741-5. 10.1210/jc.2008-1416.
- Salehi M, Vella A, McLaughlin T, Patti ME. Hypoglycemia After Gastric Bypass Surgery: Current Concepts and Controversies. J Clin Endocrinol Metab. 2018 Aug 1;103(8):2815-2826. doi: 10.1210/jc.2018-00528. PMID: 30101281; PMCID: PMC6692713.
- Edelman SV, Blose JS. The Impact of Nocturnal Hypoglycemia on Clinical and Cost-Related Issues in Patients With Type 1 and Type 2 Diabetes. Diabetes Educ. 2014 May;40(3):269-279. doi: 10.1177/0145721714529608. Epub 2014 Apr 2. PMID: 24695260.
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