Hypoglycemia Poses Risk for All Blood Glucose Levels in Diabetes

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By Annette M. Boyle

Candis Morello, PharmD

SAN DIEGO — For the more than one million veterans with diabetes, recent research raises new concerns about the risks of severe low blood glucose levels or hypoglycemia.

In clinical trials, hypoglycemia occurs most often in patients with tightly controlled HbA1c levels. A large study published in Diabetes Care, however, found that hypoglycemia plagues patients across all blood glucose levels in clinical practice. A second study, published in JAMA Internal Medicine, found a two-way association between dementia and hypoglycemia.1, 2

At the Diabetes Intense Medical Management Clinic, Veterans Affairs San Diego Healthcare System, Director Candis Morello, PharmD, strives to achieve patient-specific HbA1c goals without triggering any hypoglycemia.

“We know that our veterans are older, mostly over age 65, and particularly sensitive to cognitive effects of hypoglycemia and the associated increased risk of cardiovascular disease and dementia,” Morello told U.S. Medicine.

In the Diabetes Care study, researchers surveyed 9,094 patients with type 2 diabetes on medications to reduce blood glucose levels. Nearly 11% (985) of patients reported experiencing a severe hypoglycemic event that required assistance from others in the previous year.

Researchers established five categories of HbA1c (less than 6, 6-6.9, 7-7.9, 8-8.9, and over 9) and calculated the prevalence of severe hypoglycemia for each category. While there was little difference in prevalence across the ranges, the relative risk was somewhat higher for patients who had HbA1c levels of less than 6 (1.25) and more than 9 (1.16), compared to those with blood glucose levels of 7-7.9.

Rural veterans from northeastern North Carolina and southeastern Virginia attend a diabetes education program held by the Hampton, VA, VAMC. Managing hypoglycemia is a special challenge for older diabetes patients.

“Hypoglycemia is the most common acute complication of diabetes therapy and is associated with poor health outcomes,” according to lead author Kasia Lipska, MD, of the Yale University School of Medicine. “While aggressive treatment of high blood sugar was once considered a hallmark of better care, recent clinical trials have raised concerns about the risks of tight control, particularly in the frail and elderly.”

“It is important to note that it’s not the HbA1c that directly causes hypoglycemia, it’s the therapies we use to lower it,” Lipska said.

VA clinicians are constantly aware of the threat of hypoglycemia and do everything possible to mitigate it, according to Morello.

“We strive to avoid hypoglycemia at all costs. We do that by employing the right medication for each person, finding the right combination that works specifically for them, with a focus on using the smallest number of medications that can cause hypoglycemia possible,” she pointed out.

For patients with type 2 diabetes, sulfonylureas pose the greatest risk for hypoglycemia and “substitution with other classes of oral agents or even glucagon-like peptide 1 (GLP-1) analogs should be considered in the event of troublesome hypoglycemia,” according to a recent report by a workgroup of the American Diabetes Association and The Endocrine Society. 3

“A number of newer agents, even metformin, can help patients achieve their personal blood glucose goals without risking hypoglycemia. Even long-acting insulin analogs started at very low doses and slowly titrated can be beneficial in reducing hypoglycemic events,” Morello said.

Because of their glucose-dependent mechanism of action – the drugs stimulate insulin secretion only during hyperglycemia — incretin-based therapies such as dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1 analogs have a low hypoglycemia risk, according to the American Diabetes Association.

Association with Dementia

In the JAMA Internal Medicine study, researchers found that a having a hypoglycemic event doubled the risk of dementia. At the same time, a dementia diagnosis more than doubled the risk of experiencing a hypoglycemic event (14.2% vs. 6.3%).

Researchers from the San Francisco Veterans Affairs Medical Center and the University of California San Francisco tracked 783 older adults with diabetes mellitus (DM) for 12 years. All participants were participants in the prospective Health, Aging, and Body Composition Study that started in 1997, and all had baseline Modified Mini-Mental State Examination scores above 79. During the study period, 7.8% or 61 study participants reported experiencing hypoglycemia and nearly 19% (148) developed dementia.

“The association (between hypoglycemia and dementia) remained even after adjustment for age, sex, educational level, race/ethnicity, comorbidities and other covariates. These results provide evidence for a reciprocal association between hypoglycemia and dementia among older adults with DM,” wrote the authors.

The researchers noted that low blood glucose levels impair cognitive function and at severely low levels may damage the neurons. On the flip side, cognitive impairment can make management of DM more difficult and increase the risk of hypoglycemia.

Even without a diagnosis of dementia, the cognitive effects of hypoglycemia can pose significant danger to patients.

“We particularly notice that with older veterans, the cognitive symptoms associated with hypoglycemia last longer. Recovery doesn’t take just a day or two; it’s more like a week or two or longer,” Morello said.

“We tell them not to drive a car unless they’ve checked their glucose. If they’ve had a hypoglycemic event in the last few days, their glucose levels may be OK, but they may still be confused,” she said. “If they’re behind the wheel, they’re dangerous, not just to themselves, but everyone else on the road.”

Patients who frequently experience hypoglycemia may not even know they have severely low blood glucose levels, noted Morello. “Patients who have been diabetic for a long time or had multiple hypoglycemic events often develop hypoglycemic unawareness. They lose the first symptoms of low blood sugar such as palpitations, sweating, tremors and hunger. They may not realize they are in danger until they experience central nervous system symptoms such as forgetfulness and confusion, and at that point, they may need help from other people to reverse the hypoglycemia.”

For clinicians, that level of unawareness poses a problem as “a patient may report just one event, but if they are asymptomatic, was it only one?” Morello said.

1 Lipska K, Warton EM, Huang ES, Moffet HH, Inzucchi SE, et al. “HbA1c and the Risk of Severe Hypoglycemia in Type 2 Diabetes,” Diabetes Care, online before print July 30, 2013.

2 Yaffe K, Falvey CM, Hamilton N, Harris TB, Simonsick EM, et al. “Association between hypoglycemia and dementia in a biracial cohort of older adults with diabetes mellitus,” JAMA Internal Medicine. July 2013;173(14)1300-1306.

3 Sequist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. “Hypoglycemia and Diabetes: a Report of a Workgroup of the American Diabetes Association and The Endocrine Society,” Diabetes Care, May 2013. 36(5):1384-95.

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