Long-acting insulin analogs appeared to cut risk of severe hypoglycemia in Medicare patients

Medicare beneficiaries with type 2 diabetes seemed to have a lower risk of landing in the emergency department (ED) or the hospital for severe hypoglycemia when they were on long-acting insulin analogs versus NPH neutral insulin, researchers reported.

Among 575,008 patients who took long-acting insulin analogs glargine (n=407,018) or detemir (n=141,588), or protamine Hagedorn (NPH) insulin (n=26,402) alone, there were 7,347 ED visits or hospitalizations during the 12-year study time frame, reported Marie C. Bradley, PhD, Mpharm, MScPH, of the Office of Surveillance and Epidemiology at the FDA in Silver Spring, Maryland, and co-authors.

Patients taking long-acting insulin analogs had a lower incidence of ED visits or hospitalizations for hypoglycemia versus patients using NPH insulin (hazard ratio 0.71 for glargine vs NPH insulin, 95% CI 0.63 to 0.80; HR 0.72 for detemir vs NPH insulin, 95% CI 0.63 to 0.82), they reported in JAMA Internal Medicine.

The authors also found that the association of hypoglycemia with insulin analogs may vary by patient age, with the observed protective association of long-acting analogs compared with NPH insulin being stronger at ages 69 to 87 versus other ages.

“In this new-user, active comparator cohort study, which included more than 575,000 insulin users, initiation of glargine and detemir use was associated with a nearly 30% lower risk of ED visits or hospitalizations for hypoglycemia compared with initiation of NPH insulin use, which translated to 9.3 fewer hypoglycemia events with glargine and 8.4 fewer with detemir per 1,000 patient-years of treatment,” they explained.

“In terms of number needed to harm, one would need to treat 154 patients with glargine or 167 with detemir rather than with NPH insulin for a year to prevent one excess case of severe hypoglycemia,” the authors added.

However, an exploratory analysis of the time-varying use of concomitant prandial insulin use did not show a protective association with long-acting analogs versus NPH insulin as seen in the primary analysis.

“This is an important finding and suggests that the advantages of long-acting analogs on hypoglycemia, observed in the main analysis, at least in certain age groups may not be seen if the patient initiates concomitant prandial insulin,” Bradley and co-authors cautioned, pointing out that nearly one-third of basal insulin users available for the primary analysis had concomitant use of prandial insulin during follow-up, and were excluded from the primary analysis by study criteria. Patients who took NPH insulin combination products also were excluded.

In an invited commentary accompanying the study, Elbert S. Huang, MD, MPH, of the Center for Chronic Disease Research and Policy at the University of Chicago in Chicago, and Kasla J. Lipska, MD, MHS, of the Yale School of Medicine in New Haven, Connecticut, highlighted that the patient mean-age of 75 was vital, and differed from prior research that mostly included younger individuals, such as a 2014 “natural history study” by Huang and colleagues.

“This difference by age group is important because the risk of hypoglycemia increases with advancing age and is known to be particularly high among octogenarians… the findings suggest a need for caution for the use of insulin isophane suspension [NPH insulin] among Medicare beneficiaries, particularly those who may be at greatest risk for hypoglycemia,” Huang and Lipska explained.

Bradley’s group evaluated Medicare beneficiaries (mean age 74.9; 53% female; majority white) who started long-acting insulin analogs glargine or detemir (141,588), or NPH insulin alone, from January 2007 through January 2019. The primary outcome was the ICD-identified time to first ED visit or hospitalization.

The authors reported 5,194 ED or hospital events for glargine patients, 1,693 for detemir patients, and 460 for NPH insulin patients at a median follow-up of 0.37 years across the three cohorts. Overall, the glargine initiators contributed 299,098 person-years of follow-up, the detemir initiators contributed 101,426 person-years of follow-up, and the NPH insulin initiators contributed 14,994 person years of follow-up.

A propensity score-weighted Cox proportional hazards regression model that calculated inverse probability of treatment weights (IPTWs) for each comparison was used to account for potential confounding at baseline and time-varying concomitant use of other pharmaceuticals, such as noninsulin antidiabetic drugs, during follow-up, they explained.

“Before the IPTW adjustment, no substantial differences were found in demographic or clinical characteristics between the glargine and detemir cohorts,” they wrote. “However, when the NPH insulin cohort was compared with each long-acting analog cohort, slight differences were noted, including a higher proportion of NPH insulin users who were Black (13% for NPH insulin vs 9% for analogs), fewer physician visits and glycated hemoglobin tests before the index date in NPH insulin users than analog users, and a smaller proportion of NPH insulin users who used oral diabetes medications and statins compared with analog users.”

Study limitations included its observational nature, and the potential for residual confounding, such as unmeasured aspects of socioeconomic status, insulin dose, and glycated hemoglobin levels. However, the propensity score model mitigated any potential confounding, Bradley’s group noted.

Huang and Lipska noted that the lack of lab data was another limitation because the authors could not adjust for baseline glycemic control. “Adjusting for the baseline glycemic control would help to account for some of the practice variation related to initiation of insulin use…[i]t is critical to step back from the decision to initiate insulin use and ask whether this will improve patient-centered goals of care.”

  1. Long-acting insulin analogs were linked with a lower risk of emergency department visits or hospitalizations for hypoglycemia compared with NPH insulin in a Medicare population.

  2. Long-acting insulin analogs may reduce the risk of severe hypoglycemia versus NPH insulin in older patients, although the main study finding was not seen with concomitant use of prandial insulin.

Shalmali Pal, Contributing Writer, BreakingMED™

The study was supported by the FDA and CMS.

Bradley reported no relationships relevant to the contents of this paper to disclose. Co-authors reported employment with Acumen.

Huang reported support from the NIH. Lipska reported support from the NIH and CMS.

Cat ID: 13

Topic ID: 76,13,282,494,730,13,187,255,669,918