Hypoglycemia: Risks and Prevention

Simon Heller, MD
Sheffield, England, UK

Let’s start with the pathophysiology of hypoglycemia. As you probably see in your own practice, severe hypoglycemia is rare when patients are first diagnosed with diabetes; the risk rises as the disease progresses and/or insulin therapy intensifies.1

The most important defense against hypoglycemia—and the first to become impaired in diabetes—is the release of glucagon from the alpha cells of pancreatic islets. This, in turn, triggers a strong release of glucose from the liver through glycogenolysis. In type 1 diabetes, this response is reduced within a year or two of diagnosis, generally disappearing entirely within 5 years. It takes longer in type 2, but eventually it, too, fails.2

Those who lose their glucagon response become dependent on a sympathoadrenal response that not only leads to increased release of glucose from the liver due to glycogenolysis, but also clinical symptoms, including sweating, tremor, and palpitations. Repeated episodes of hypoglycemia may result in a diminished sympathetic response with attenuation of symptoms.3 When this happens, patients often learn to rely on more non-specific symptoms such as confusion and loss of concentration. These are less reliable, however, occurring only once when blood glucose falls below 3 mmol/L (around 55 mg/dL), by which time cognitive impairment occurs.4

Risk factors for hypoglycemia include increasing age, duration of diabetes, and comorbidities, including impaired renal function, cardiovascular disease, cognitive impairment, depression, and heart failure. One of the strongest predictors of hypoglycemia is a history of hypoglycemia. Tools are available that can help you assess patient risk.1

Prevention starts with some relatively simple clinical approaches. 

  • Identify patients at high risk for hypoglycemia and talk with them about opportunities to reduce their risk.
  • Inquire about frequency of hypoglycemia (even mild).
  • Ask about blood glucose levels when patients develop symptoms.
  • Consider switching T2DM patients on sulphonylureas or insulin to other therapies, such as GLP-1 analogues or SGLT-2 inhibitors.  One study found a 2-fold increased risk of severe hypoglycemia with sulfonylureas and a 4.5-fold increased risk with insulin.5
  • Consider alternatives to prandial insulin such as GLP-1 analogues as an add-on to basal insulin is needed.
  • Check all medication dosages.
  • Adjust insulin dosing: 
    • Regular/soluble insulin → rapid-acting insulin
    • NPH/isophane → insulin analogues
    • Adjusting insulin in relation to exercise
  • Modify glucose targets upwards for those with co-morbidities, renal impairment, cognitive impairment, and dementia.

Do you have questions about the pathophysiology, definition, management, and prevention of hypoglycemia? Please leave a comment below.  

1 Tourkmani AM, Alharbi TJ, Rsheed AMB, et al. Hypoglycemia in Type 2 Diabetes Mellitus patients: A review article. Diabetes Metab Syndr. 2018;12(5):791-794.
2 Segel SA, Paramore DS, Cryer PE: Hypoglycemia-associated autonomic failure in advanced type 2 diabetes. Diabetes. 2002;51:724-733.
3 Heller SR, Cryer PE: Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after one episode of hypoglycemia in nondiabetic humans. Diabetes. 1991;40:223-226.
4 Cranston I, Lomas J, Maran A, Macdonald I, Amiel SA: Restoration of hypoglycaemia awareness in patients with long-duration insulin-dependent diabetes. Lancet. 1994;344:283-287.
5 ORIGIN Investigators. Predictors of nonsevere and severe hypoglycemia during glucose-lowering treatment with insulin glargine or standard drugs in the ORIGIN trial. Diabetes Care. 2015;38(1):22–8.



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