Iatrogenic Hypoglycemia: Identification, Troubleshooting, and Precautions
Q: How big of a problem is iatrogenic hypoglycemia?
A: Iatrogenic hypoglycemia, which is most commonly driven by insulin but can be due to other antidiabetic agents, is a common problem for patients with diabetes. For many, hypoglycemic episodes are manageable, but a severe episode can result in confusion, seizure, or arrhythmia, which in turn can lead to falls, motor vehicle accidents, or death. In patients with type 1 diabetes who must frequently balance a low target A1c to prevent long-term complications with the immediate risk of hypoglycemia, the mortality rate associated with hypoglycemia has been estimated as high as 10%.1
Hypoglycemia is often a chronic problem managed by the patients, primary care physicians, or an endocrinologist, but may come to attention suddenly. In 1 study, after warfarin, insulin was the second most frequent cause of emergency hospitalization due to adverse drug events in adults over 65.2 Therefore, hospitalists treating these patients will often have to make quick decisions for the patient’s safety, both during their admission and on discharge.
Q: How do I identify iatrogenic hypoglycemia in my patients?
A: The presentation of hypoglycemia in patients treated for diabetes can vary widely. Many patients will self-report hypoglycemic episodes, while others may be less concerned by the episodes and require more extensive questioning. Some patients (eg, the elderly) may not even identify their episodes of hypoglycemia and may present with falls or confusion. A full review of the patient’s regimen should be done for anyone admitted with diabetes, but extra attention is worthwhile if they report objective hypoglycemia on home checks, symptomatic hypoglycemia (including nocturnal hypoglycemia) that resolves with oral glucose intake, or episodes of otherwise unexplained symptoms.
We should try to find patterns in the timing of hypoglycemic episodes in relation to food, activities, and medications, which can help determine the causative agent. Many patients will be able to identify the blood glucose level at which they start to sense the autonomic symptoms associated with hypoglycemia. Inability to sense hypoglycemia until it reaches potentially dangerous levels is consistent with hypoglycemia unawareness or hypoglycemia associated autonomic failure (HAAF), which is a sign of frequent, recurrent hypoglycemia that blunts the normal autonomic response which helps alert the patient and induces counterregulatory mechanisms to reverse hypoglycemia.3 HAAF places the patient at a higher risk of severe hypoglycemia because they are unable to raise their blood sugar before it can reach levels which deprive the brain of glucose and induce mental changes or seizures. Patients with hypoglycemia unawareness can often restore their symptoms of hypoglycemia if they intentionally permit some hyperglycemia and strictly avoid hypoglycemia for a period of 2 to 3 weeks.4
Q: Which agents most commonly cause hypoglycemia?
A: Insulin, because of its direct effect on blood glucose, is by far the most common cause, but oral agents should be considered as well. Sulfonylureas act directly on the ATP-sensitive potassium channels on the beta cell membrane, inducing depolarization and insulin release. Since this depolarization occurs independently of stimulation of physiologic insulin release by glucose, the insulin released can be inappropriate for the patient’s actual blood glucose level and may induce hypoglycemia. Other classes of noninsulin antidiabetic agents typically work by increasing peripheral sensitivity to insulin (metformin and thiazolidinediones), enhancing pancreatic insulin secretion in response to oral glucose through the incretin pathway (eg, glucagon-like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors), or increasing renal loss of glucose (sodium-glucose cotransporter-2 inhibitors), which makes them less likely to induce hypoglycemia.
When considering insulin regimens, both basal and bolus insulin can induce hypoglycemia, which makes any patterns that can be discerned very helpful. Hypoglycemia due to bolus insulin can induce a rapid onset of symptoms after meals or correction of hyperglycemia. This may be due to misjudging the dose, improper timing of the bolus (too early or too late), or eating less than was intended for the bolus. Since the onset of modern insulin analogues is short, they should only be given when the patient is sure he or she will be able to eat within 15 minutes of administration. In general, patients on more complex insulin regimens receiving more daily injections have higher rates of hypoglycemia.5
Basal insulin is used widely in patients with type 2 diabetes, both with oral medications and in combination with bolus insulin. Many patients who are reluctant to take multiple daily injections of rapid-acting insulin will have their dose of basal insulin gradually titrated up as their A1c rises. However, when basal insulin is dosed to compensate for oral intake, the risk of hypoglycemia with fasting (overnight and if meals are missed) increases. Overnight hypoglycemia (the need to eat a snack before bed due to fear of hypoglycemia), low morning fasting blood glucoses, or fear of skipping meals are all signs of potential excess basal insulin. In these cases, if the A1c is not at goal, treatments that provide more coverage of oral carbohydrate intake, such as bolus insulin, will be more effective in improving control with less risk of hypoglycemia.
Q: What other factors should be considered?
A: Renal failure, either acute or chronic, places the patient at higher risk for iatrogenic hypoglycemia. The kidneys metabolize most sulfonylureas, many of which have active metabolites that can be retained beyond the expected half-life of the drug.6 Glyburide, in particular, is not recommended in renal insufficiency with a glomerular filtration rate (GFR) <50-60 mL/min/1.73 m2. Glipizide tends to be safer in renal insufficiency but may still require dose reductions. The kidneys also play a direct role in insulin metabolism and gluconeogenesis in response to hypoglycemia, both of which are blunted in renal failure. As most oral and noninsulin agents require caution or dose reduction as a patient’s GFR falls, option are quickly limited and most patients in advanced renal failure will require reduced doses of insulin.
Patients being admitted to the hospital may be ill with a poor appetite, nothing by mouth (NPO) for procedures, or receiving less food than they would typically eat at home. In all cases, their home doses of insulin may be excessive and place the patient at risk of hypoglycemia. In general, a reduction in home doses by about 20% with attention to compliance and the balance between basal and bolus insulin should provide a margin of safety. Admitted patients who are hyperglycemic and require rising doses of insulin often benefit from receiving a portion of their insulin as rapid-acting with meals rather than as sliding scale and basal alone. Again, patterns can be helpful and a consistent downtrend from the bedtime blood glucose to the next morning’s blood glucose is a sign of excessive basal insulin, which places the patient at risk of hypoglycemia if they are unable to eat or made NPO.
Rarely, patients with type 1 diabetes as part of a polyglandular autoimmune syndrome can develop new or worsening hypoglycemia as an early symptom of adrenal insufficiency. A cosyntropin stimulation test may be considered in patients with compatible symptoms, such as nausea, vomiting, weight loss, hyperpigmentation, or hyperkalemia.
Q: What safety precautions can my patient with hypoglycemia take?
A: Patients at risk for hypoglycemia should be evaluated by a diabetes educator to ensure they are aware of the symptoms and safety precautions. They should have a source of rapidly absorbable glucose on hand at all times and a medical alert bracelet if the hypoglycemia is frequent. Glucagon kits can be kept at home, work, or other places where the patient spends time and may be administered by friends or family if the patient is unconscious or too confused due to hypoglycemia to eat. Since glucagon is unstable in solution, it is dispensed as a powder and needs to be reconstituted before injection. Most family members need some training by a diabetes educator to feel comfortable performing the injection.
All patients should check their blood glucose before driving and eat a snack if there is any concern for hypoglycemia. Some states impose restrictions on driving licenses for patients with documented hypoglycemia that is unable to be explained by an acute condition unlikely to recur.7 In rare cases, a patient who is unsafe to drive can be reported to the Department of Public Safety; the rules regarding reporting also vary by state.
Dr. Carmichael is on the speaker’s bureaus for Merck and Janssen.
Conor Best, MD, is a clinical fellow in the department of internal medicine, division of endocrinology, diabetes, and lipid research at Washington University School of Medicine in St. Louis, MO.
Kim A. Carmichael, MD, is an associate professor of medicine in the department of internal medicine, division of endocrinology, diabetes, and lipid research at Washington University School of Medicine in St. Louis, MO.
References:
- Skrivarhuag T, Bangstad HJ, Stene LC, et al. Long-term mortality in a nationwide cohort of childhood-onset type 1 diabetic patients in Norway. Diabetologica. 2006;
- 49(2):298-305.
- Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med. 2011;365(21):
- 2002-2012.
- Cryer PE. Glycemic goals in diabetes: trade-off between glycemic control and iatrogenic hypoglycemia. Diabetes. 2014;
- 63(7):2188-2195.
- Fanelli CG, Epifano L, Rambotti AM, et al. Meticulous prevention of hypoglycemia normalizes the glycemic thresholds and magnitude of most of neuroendocrine responses to, symptoms of, and cognitive function during hypoglycemia in intensively treated patients with short-term IDDM. Diabetes. 1993;42(11):1683-1689.
- Holman RR, Farmer AJ, Davies MJ, et al. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med. 2009;361(18):1736-1747.
- Mazen A, Gerich JE. Hypoglycemia, chronic kidney disease, and diabetes mellitus. Mayo Clin Proc. 2014;89(11):1564-1571.
- American Diabetes Association. Diabetes and driving. Diabetes Care. 2014;37:S97-S102.