Risk for Severe Hypoglycemia Found at All Levels of Glucose Control

Patients with type 2 diabetes who are taking glucose-lowering medications are at risk for severe hypoglycemia regardless of whether their diabetes is poorly or well controlled

Patients with type 2 diabetes who are taking glucose-lowering medications are at risk for severe hypoglycemia regardless of whether their diabetes is poorly or well controlled, according to data from a large retrospective study reported online ahead of print in Diabetes Care.

“Patients reported severe hypoglycemia across all levels of hemoglobin A1C (A1C); in other words, patients who achieved near normal A1C levels, those in the middle, and those who remained poorly controlled all commonly reported experiencing severe hypoglycemia,” said senior author and study principal investigator, Andrew Karter, PhD, of the Kaiser Permanente Northern California Division of Research, Oakland. “This suggests that clinicians should actively ask about symptoms of hypoglycemia of our patients regardless of how well-controlled their diabetes appears to be,” Dr. Karter said.

“It is important to note that it is not the A1C that directly causes hypoglycemia—it is the therapies we use to lower it,” said lead author Kasia J. Lipska, MD, an endocrinologist from the Yale University School of Medicine, New Haven, CT. “Intensifying therapy to reach a lower glycemic target is likely to increase the risk of hypoglycemia for each individual patient,” Dr. Lipska said.

Study Design

The study involved 9,094 patients with type 2 diabetes (ages 30-77 years) who were treated with glucose-lowering therapy. They were asked how many times in the past year they had a severe low blood sugar reaction such as passing out or needing help to treat the reaction. The researchers examined the last A1C level collected in the year preceding the observation period. Overall, 985 patients (10.8%) reported a severe hypoglycemia in the prior year.

“The conventional wisdom that patients with lowest A1C levels are at highest risk of hypoglycemia was not supported by our findings,” the authors noted. In contrast, there was a U-shaped relationship between risk and A1C levels; severe hypoglycemia was reported by 11.5%, 9.3%, 10.6%, 11.5%, and 13.8% of patients in A1C categories <6%, 6%-6.9%, 7%-7.9%, 8%-8.9%, and ≥9%, respectively. The relative risk was not significantly altered by age, disease duration, or type of diabetes medication.

Findings May Affect Treatment Decisions

While striving for near-normal glucose control is associated with reduced risk of long-term clinical complications (neuropathy, retinopathy, nephropathy), seminal studies of type 1 diabetes (ie, Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications trial) and type 2 diabetes (ie, Action to Control Cardiovascular Risk in Diabetes trial) have noted more frequent episodes of severe hypoglycemia in subjects on intensive glucose-lowering therapy, commented Tamara L. Wexler, MD, PhD, endocrinologist, attending physician at Massachusetts General Hospital in Boston, and a spokesperson for The Endocrine Society.  However, the association between glycemic control and type 2 diabetes in usual care settings is less well-characterized.

“It is an important question to consider, and can definitely affect treatment as there may be a fear of tight glucose control in patients whose risk of severe hypoglycemia is deemed higher,” Dr. Wexler said.

“As the study authors note, there are natural limitations to the way this study was designed and conducted, but there also are benefits to a retrospective epidemiologic design such as the ability to assess larger populations,” Dr. Wexler said. “Taking lessons from studies is fine if the study design and limitations are taken into consideration,” she said. One concern is that the findings are based on self-report and not confirmed hypoglycemic episodes. However, “if you only look at people who show up in the hospital with severe hypoglycemia, you may be missing people who have been treating it at home,” she noted.

Dr. Wexler added that “the findings suggest a trend and something we should pay attention to, but don’t reach statistical significance by definition.” In addition, Dr. Wexler said, “the A1C measures a 3-month average so if someone is having a lot of hypoglycemic events the A1C might appear to be low but they might actually have higher blood sugar spikes.” Furthermore, the A1C measurements were not always taken within 3 months of the reporting period, she noted.

Tips for Counseling Patients on Hypoglycemia

“Patients need to be aware of the risk of hypoglycemia with the use of certain glucose-lowering therapies, recognize the symptoms of hypoglycemia, be able to treat hypoglycemia when it occurs, and know when to seek assistance,” Dr. Lipska said.

“How do we prevent it altogether?,” wondered Dr. Lipska. “This is a much tougher question because there are multiple potential reasons or triggers for hypoglycemia, ranging from inappropriately prescribed medications (such as glyburide in the elderly), overly aggressive efforts at glucose-lowering (with the use of multiple medications in high-risk individuals), missed meals, or medication errors,” she said. “Although universal precautions should be taken, honing in on who is at high risk to begin with is the first step toward hypoglycemia prevention. Then we can focus our research efforts on studying interventions to lower the risk in these individuals,” Dr. Lipska noted.

“You should always ask all patients with diabetes about symptoms that you know to be related to hypoglycemia regardless of their A1C levels and the type of medication that they are on,” said Dr. Wexler. “Most important is for patients to document their blood glucose levels; people who think they have low blood sugar may not and, even more concerningly, people who have poor control or who have long-standing diabetes may have a blunted response to hypoglycemia and may not know when their blood glucose is low,” she said.

While recordable glucometers are helpful, “even better is for patients to have a book that they use to record blood glucose with the time and co-incident food and exercise patterns,” Dr. Wexler suggested. “If patients are able to do that, they or their physician can start to analyze the pattern to get a sense of when glucose levels tend to be high or low during the day. Also, patients who have symptoms of hypoglycemia should check their blood sugar or have someone do it for them,” she said.

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