A collaborative physician/clinical pharmacist-led intervention for monitoring patients at a high risk for iatrogenic hypoglycemia significantly reduced the risk for severe diabetes medication-caused hypoglycemia without compromising glycemic control, according to new research.

“Many studies have looked at clinical interventions that use team-based care,” first author Lisa K. Gilliam, MD, an endocrinologist and researcher at the Kaiser Permanente South San Francisco in San Francisco, told Medscape Medical News. “But to our knowledge, this is the first study to demonstrate that proactive outreach by a clinical pharmacist, applying a standardized hypoglycemia protocol, resulted in safer diabetes regimens in patients at high risk for hypoglycemia.”

The study was published in JAMA Network Open.

Iatrogenic hypoglycemia is common among patients with type 2 diabetes taking certain medications, such as insulin and sulfonylureas. More than half report at least one hypoglycemic event in the prior 3-6 months, Gilliam noted. Risk is particularly higher in older adults, patients taking multiple medications, and those with comorbidities such as heart failure or kidney disease.

“These factors combine to make fixed diabetes medication doses unsafe,” she said.

Severe hypoglycemia can be life-threatening and increases the risk for falls, cardiovascular events, and mortality. Prior research has shown that de-escalating hypoglycemia-prone medications can reduce risk without necessarily compromising glucose control.

Randomized Trial of Pharmacist Outreach

To evaluate an approach of using a clinical pharmacist to help monitor at-risk patients, Gilliam and colleagues conducted a randomized trial of patients in the Kaiser Permanente Northern California system.

Between July 2023 and January 2024, Gilliam and colleagues enrolled 200 patients with type 2 diabetes who were at a high risk for hypoglycemia. Patients were randomly assigned in a 1:1 ratio to receive either the evidence-based Hypoglycemia on a Page (HOAP) protocol — a clinical pharmacist-led outreach intervention — or usual care. Baseline characteristics were similar in terms of race, ethnicity, sex, mean A1c, and treatments.

In the intention-to-treat cohort of 191 patients (96 intervention and 95 usual care; mean age, 71.3 years; 52.4% female), those in the intervention arm were significantly more likely to be prescribed a safer diabetes regimen at 6 months than those in the control arm (28.1% vs 15.8%; risk difference, 12.3%).

In an age-stratified sub-analysis, the benefit was even more pronounced among those aged 75 years or older (39.1% vs 12.5%).

Patients in the intervention group also experienced significantly fewer hypoglycemia-related emergency department or inpatient encounters (0 vs 5 events). Importantly, glycemic control was maintained in both groups, with 61.8% of intervention patients and 63.6% of usual-care patients having A1c levels < 8%.

Of note, 26% of patients had medications deprescribed prior to randomization, yet the intervention still demonstrated benefit.

Discontinued medications most commonly included bolus insulin (73.8%), followed by sulfonylureas (28.6%) and mixed insulin (7.1%), with some patients discontinuing more than one therapy.

At 12 months, hypoglycemia-related emergency department or inpatient utilization remained lower in the intervention group, although the difference between groups was no longer statistically significant.

Intervention Based on Hypoglycemia Prevention Guidance

The HOAP intervention is based on an algorithm from the International Geriatric Diabetes Society for deprescribing hypoglycemia-prone diabetes medications in older adults.

“The HOAP algorithm provides guidance on medication regimen changes, glycemic target resetting, use of continuous glucose monitoring, glucagon prescribing, tailoring patient education, and adding hypoglycemia to the patient’s problem list,” the authors wrote.

As part of the intervention, pharmacists with clinical diabetes expertise reviewed medical records, with the approval of the patient’s primary care team, and then provided proactive management to prevent hypoglycemia. Shared decision-making was used to individualize medication adjustments based on comorbidities, treatment goals, patient preferences, and readiness for change.

Persistent Use of Higher-Risk Medications

Nearly half of the study participants had experienced a hypoglycemia-related emergency department or inpatient encounter in the 12 months before enrollment, far higher than the approximately 0.5% typically observed in the general type 2 diabetes population. However, only 16.2% had hypoglycemia documented on the problem list at baseline.

Although 91% of participants were designated as high-risk using a validated hypoglycemia risk stratification tool, as many as 74% in both groups were still using at least one higher-risk medication, such as basal insulin (82.2%), bolus insulin (56.0%), sulfonylureas (24.1%), and mixed insulin (6.3%).

Not all medications could be deprescribed, with barriers including continued need for intensive glycemic control (such as due to symptomatic hyperglycemia), patient preference, and clinical judgment.

“These findings highlight the challenges of implementing a uniform deprescribing algorithm,” the authors wrote.

Need for Proactive Outreach

The authors noted that simply sharing guidelines may not change practice. In an earlier unpublished study, they found that disseminating the new HOAP guideline across the Kaiser Permanent of Northern California system did not significantly reduce hypoglycemia-related emergency department visits or hospitalizations over a year.

“Dissemination of a guideline, without proactive identification and outreach to patients at risk, may not change prescribing patterns of diabetes physicians,” they wrote.

Gilliam emphasized that the pharmacist-led intervention can in fact be less burdensome than conventional approaches, which often require multiple visits to titrate medications safely.

“Emergency department visits for hypoglycemia are very costly,” she said. “The time a pharmacist spends to reduce that risk is well worthwhile.”

Gilliam added that at Kaiser Permanente, the team-based care approach has been “fully embraced,” with diabetes specialist pharmacists practicing under treatment protocols and involving the physicians when needed.

Expert Perspective

Commenting on the study, Cecilia C. Low Wang, MD, professor of medicine in the Division of Endocrinology, Diabetes and Metabolism at CU Anschutz, University of Colorado Anschutz, Aurora, Colorado, said the findings “suggest that clinical pharmacists, especially in diabetology, can play an important role in helping to prevent or manage iatrogenic hypoglycemia.”

Low Wang noted that “such physician/pharmacist collaboration models are more common in the hospital setting, with various existing models for diabetes care.”

The high rate of hypoglycemia-prone medication use was not surprising, she added.

“Cost and access are still major issues in optimal diabetes care, and sulfonylureas are often prescribed because of their low cost and familiarity.”

She also noted that the incomplete documentation of hypoglycemia is common and underscores the need for greater awareness and education regarding appropriate deprescribing.

Further recommendations for the prevention of iatrogenic hypoglycemia are outlined in guidelines from the Endocrine Society.

Gilliam and Low Wang reported having no disclosures.