Study results suggest that long-acting insulin analogs appears to cut risk of severe hypoglycemia in Medicare patients with type 2 diabetes.

Medicare beneficiaries with type 2 diabetes appeared to have a lower risk of emergency department (ED) visits or hospitalization for severe hypoglycemia when they were on long-acting insulin analogs versus neutral prota-mine Hagedorn insulin, researchers reported.

Among 575,008 patients who took long-acting insulin analogs glargine (n=407,018) or detemir (n=141,588), or NPH insulin (n=26,402) alone, there were 7,347 ED visits or hospitalizations during the 12-year study, reported Marie C. Bradley, PhD, Mpharm, MScPH, of the FDA’s Office of Surveillance and Epidemiology, and colleagues. Patients taking long-acting insulin analogs had a lower incidence of ED visits or hospitalizations for hypoglycemia versus patients using NPH insulin (hazard ratio [HR], 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 Impacts of Age & Prandial Insulin

The authors also found that the association of hypoglycemia with insulin analogs may vary by patient age, with the observed protective associa-tion of long-acting analogs compared with NPH insulin being stronger at age 69-87 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 com-pared 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 insu-lin for a year to prevent one excess case of severe hypoglycemia.”


1l 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.

2l 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.

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,” Dr. Bradley and colleagues cautioned, noting that nearly one-third of basal insulin users available for the pri-mary 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, and Kasla J. Lipska, MD, MHS, of the Yale School of Medicine, 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 Dr. 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,” Drs. Huang and Lipska explained.

A Closer Look at the Study

Dr. 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, and the NPH insulin initiators contributed 14,994.

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, the study team 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.”