Switching from long-acting insulin (LAI), such as glargine or detemir, to intermediate-acting isophane (NPH) insulin could save the average older patient in the United States using 1 vial per month over $2000 annually with no loss in glycemic control. So why not switch? The LAI preparations have been pushed as having less hypoglycemic side effects. Recently, researchers at the US Food and Drug Administration analyzed Medicare claims data to show a difference between the rate of hypoglycemia in people who initiate LAIs compared with those who initiate therapy with NPH—but how meaningful is this difference?

Researchers examined Medicare insurance claims for patients 65 years or older with diabetes but without end-stage renal failure who initiated either an LAI or NPH insulin (but not combination NPH/prandial insulin products) between 2007 and 2019. Over 558,000 patients were initiated on LAI and approximately 26,000 were started on NPH during the study timeframe.

At baseline, those receiving their first NPH prescription were more likely to have lower socioeconomic status, less likely to be prescribed statins, and had fewer office visits prior to insulin initiation compared with those started on LAI. The investigators used propensity score matching based on income and other potential confounders and followed patients to examine subsequent rates of emergency department visits or hospitalizations for hypoglycemia. They also included prescription discontinuation as well as the addition of short-acting (prandial) insulin either at initiation or later during therapy.

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Treatment with glargine or detemir was associated with decreased risk of hypoglycemia compared with NPH alone (hazard ratio [HR] 0.7; 95% CI, 0.6-0.8). On the other hand, when short-acting insulin was prescribed along with the NPH or LAI and when people had been maintained on the insulins after the initiation period the rates of hypoglycemia equalized.

This study builds on recent research indicating that prescribing NPH insulin may be reasonable for older patients with concerns about the cost of their medications, particularly when it is used in combination with prandial insulin. The authors calculated that over 150 NPH prescriptions would need to be written to cause a single additional episode of hypoglycemia per year compared with writing prescriptions for an LAI.

The apparent advantage of the LAIs goes away completely when prandial insulin is added or if NPH is used for maintenance after the initial period. We should not underestimate the significance of a hypoglycemic episode in this population and those prescribed NPH should have closer monitoring in the initial phase of prescribing. If LAIs were reasonably priced, this wouldn’t be an issue.

Alan Ehrlich, MD, is a deputy editor for DynaMed, Ipswich, Massachusetts, and assistant clinical professor in family medicine, University of Massachusetts Medical School, Worcester.

DynaMed is a database that provides evidence-based information on more than 3000 clinical topics and is updated daily through systematic surveillance covering more than 500 journals.


Bradley MC, Chillarige Y, Lee H, et al. Severe hypoglycemia risk with long-acting insulin analogs vs neutral protamine hagedorn insulin. JAMA Intern Med. 2021;181(5):598-607. doi:10.1001/jamainternmed.2020.9176