CoChat
Sign Up
Cited by 45Diabetes Management and ResearchDiabetes Treatment and ManagementPatient Safety and Medication Errors

Severe hypoglycemia risk with long-acting insulin analogs vs neutral protamine Hagedorn insulin

Open access
Bradley, Marie C., Chillarige, Yoganand, Lee, Hana, Wu, Xiyuan, Parulekar, Shruti, Muthuri, Stella, Wernecke, Michael, MaCurdy, Thomas E. +2 more·2021·JAMA Internal Medicine
DOI 10.1001/jamainternmed.2020.9176PMC PMC7922234
Open this paper in CoChat — free account

Abstract

Importance: Previous studies have found that the risk of severe hypoglycemia does not differ between long-acting insulin analogs and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes. However, these studies did not focus on patients 65 years or older, who are at an increased risk for hypoglycemia, or did not include patients with concomitant prandial insulin use. Objective: To examine the risk of emergency department (ED) visits or hospitalizations for hypoglycemia among older community-residing patients with type 2 diabetes who initiated long-acting insulin or NPH insulin in real-world settings. Design, Setting, and Participants: This retrospective, new-user cohort study assessed Medicare beneficiaries 65 years or older who initiated insulin glargine (n = 407 018), insulin detemir (n = 141 588), or NPH insulin (n = 26 402) from January 1, 2007, to July 31, 2019. Exposures: Insulin glargine, insulin detemir, and NPH insulin. Main Outcomes and Measures: The primary outcome was time to first ED visit or hospitalization for hypoglycemia, defined using a modified validated algorithm. Propensity score-weighted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs. The risk of recurring hypoglycemia events was estimated using the Andersen-Gill model. Post hoc analyses were conducted investigating possible effect modification by age. Results: Of the 575 008 patients initiating use of insulin (mean [SD] age 74.9 [6.7] years; 53% female), 407 018 used glargine, 141 588 used detemir, and 26 402 used NPH insulin. The study included 7347 ED visits or hospitalizations for hypoglycemia (5194 for glargine, 1693 for detemir, and 460 for NPH insulin, with a median follow-up across the 3 cohorts of 0.37 years (interquartile range, 0.20-0.76 years). Initiation of glargine and detemir use was associated with a reduced risk of hypoglycemia compared with NPH insulin use (HR for glargine vs NPH insulin, 0.71; 95% CI, 0.63-0.80; HR, detemir vs NPH insulin, 0.72; 95% CI, 0.63-0.82). The HRs were similar for the recurrent event analysis. The protective association of long-acting insulin analogs varied by age and was not seen with concomitant prandial insulin use. Conclusions and Relevance: In this cohort study, initiation of long-acting analogs was associated with a lower risk of ED visits or hospitalizations for hypoglycemia compared with NPH insulin in older patients with type 2 diabetes in Medicare. However, this association was not seen with concomitant prandial insulin use.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1001/jamainternmed.2020.9176

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Once-daily basal insulin injection therapy is associated with minimal side effects and may be a reasonable option in many older adults.

    “Once-daily basal insulin injection therapy is associated with minimal side effects and may be a reasonable option in many older adults (119).”

    From 13. Older Adults: <i>Standards of Care in Diabetes—2024</i> (2024) · cites this paper as [119]

    The Results and Discussion report a lower risk of severe hypoglycemia with long-acting insulin analogs than with NPH insulin in older adults with type 2 diabetes, although the association was not seen with concomitant prandial insulin. The paper does not establish that once-daily basal injections have minimal side effects overall or recommend them as a reasonable option for many older adults. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Once-daily basal insulin injection therapy is associated with minimal side effects and may be a reasonable option in many older adults.

    “Once-daily basal insulin injection therapy is associated with minimal side effects and may be a reasonable option in many older adults (134).”

    From 13. Older Adults: Standards of Care in Diabetes—2025 (2025) · cites this paper as [134]

    The Results report that, among Medicare patients aged 65 or older with type 2 diabetes, long-acting insulin analogs were associated with fewer emergency visits or hospitalizations for hypoglycemia than NPH insulin. The paper does not establish that once-daily basal insulin has minimal side effects overall or recommend it as a reasonable option for many older adults; it also notes that the lower hypoglycemia risk was not seen with concomitant prandial insulin. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Long-acting insulin analogs have been associated with a lower risk of emergency department visits and hospitalizations for hypoglycemia than NPH insulin in the Medicare population.

    “long-acting insulin analogs have been associated with a lower risk of emergency department visits and hospitalizations for hypoglycemia than NPH insulin in the Medicare population”

    From 13. Older Adults: Standards of Care in Diabetes—2026 (2026) · cites this paper as [148]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 22

  1. [1]Feldman WB, Rome BN, Lehmann LS, Kesselheim AS. Estimation of Medicare Part D spending on insulin for patients with diabetes using negotiated prices and a defined formulary. JAMA Intern Med. 2020;180(4):597-601. doi: 10.1001/jamainternmed.2019.7018 [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  2. [2]Herkert D, Vijayakumar P, Luo J, et al. Cost-related insulin underuse among patients with diabetes. JAMA Intern Med. 2019;179(1):112-114. doi: 10.1001/jamainternmed.2018.5008 [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  3. [3]Horvath K, Jeitler K, Berghold A, et al. Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2007;(2):CD005613. doi: 10.1002/14651858.CD005613.pub3 [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  4. [4]Eliaschewitz FG, Calvo C, Valbuena H, et al. ; HOE 901/4013 LA Study Group . Therapy in type 2 diabetes: insulin glargine vs. NPH insulin both in combination with glimepiride. Arch Med Res. 2006;37(4):495-501. doi: 10.1016/j.arcmed.2005.10.015 [DOI] [PubMed] [Google Scholar] · DOI
  5. [5]Fritsche A, Schweitzer MA, Häring HU, 4001 Study Group . Glimepiride combined with morning insulin glargine, bedtime neutral protamine hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med. 2003;138(12):952-959. doi: 10.7326/0003-4819-138-12-200306170-00006 [DOI] [PubMed] [Google Scholar] · DOI
  6. [6]Haak T, Tiengo A, Draeger E, Suntum M, Waldhäusl W. Lower within-subject variability of fasting blood glucose and reduced weight gain with insulin detemir compared to NPH insulin in patients with type 2 diabetes. Diabetes Obes Metab. 2005;7(1):56-64. doi: 10.1111/j.1463-1326.2004.00373.x [DOI] [PubMed] [Google Scholar] · DOI
  7. [7]Hermansen K, Davies M, Derezinski T, Martinez Ravn G, Clauson P, Home P. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naïve people with type 2 diabetes. Diabetes Care. 2006;29(6):1269-1274. doi: 10.2337/dc05-1365 [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  8. [8]Riddle MC, Rosenstock J, Gerich J; Insulin Glargine 4002 Study Investigators . The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26(11):3080-3086. doi: 10.2337/diacare.26.11.3080 [DOI] [PubMed] [Google Scholar] · DOI
  9. [9]Rosenstock J, Schwartz SL, Clark CM Jr, Park GD, Donley DW, Edwards MB. Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin. Diabetes Care. 2001;24(4):631-636. doi: 10.2337/diacare.24.4.631 [DOI] [PubMed] [Google Scholar] · DOI
  10. [10]Lipska KJ, Parker MM, Moffet HH, Huang ES, Karter AJ. Association of initiation of basal insulin analogs vs neutral protamine hagedorn insulin with hypoglycemia-related emergency department visits or hospital admissions and with glycemic control in patients with type 2 diabetes. JAMA. 2018;320(1):53-62. doi: 10.1001/jama.2018.7993 [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  11. [11]Singh SR, Ahmad F, Lal A, Yu C, Bai Z, Bennett H. Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis. CMAJ. 2009;180(4):385-397. doi: 10.1503/cmaj.081041 [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  12. [12]Kong AP, Yang X, Luk A, et al. Severe hypoglycemia identifies vulnerable patients with type 2 diabetes at risk for premature death and all-site cancer: the Hong Kong diabetes registry. Diabetes Care. 2014;37(4):1024-1031. doi: 10.2337/dc13-2507 [DOI] [PubMed] [Google Scholar] · DOI
  13. [13]Yun JS, Ko SH. Risk factors and adverse outcomes of severe hypoglycemia in type 2 diabetes mellitus. Diabetes Metab J. 2016;40(6):423-432. doi: 10.4093/dmj.2016.40.6.423 [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  14. [14]Ray WA. Evaluating medication effects outside of clinical trials: new-user designs. Am J Epidemiol. 2003;158(9):915-920. doi: 10.1093/aje/kwg231 [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  15. [15]Ginde AA, Blanc PG, Lieberman RM, Camargo CA Jr. Validation of ICD-9-CM coding algorithm for improved identification of hypoglycemia visits. BMC Endocr Disord. 2008;8:4. doi: 10.1186/1472-6823-8-4 [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  16. [16]Chang HY, Weiner JP, Richards TM, Bleich SN, Segal JB. Validating the adapted Diabetes Complications Severity Index in claims data. Am J Manag Care. 2012;18(11):721-726. [PubMed] [Google Scholar]
  17. [19]Roshani D, Ghaderi E. Comparing smoothing techniques for fitting the nonlinear effect of covariate in Cox models. Acta Inform Med. 2016;24(1):38-41. doi: 10.5455/aim.2016.24.38-41 [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  18. [20]Altman DG, Andersen PK. Calculating the number needed to treat for trials where the outcome is time to an event. BMJ. 1999;319(7223):1492-1495. doi: 10.1136/bmj.319.7223.1492 [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  19. [21]Luo J, Khan NF, Manetti T, et al. Implementation of a health plan program for switching from analogue to human insulin and glycemic control among Medicare beneficiaries with type 2 diabetes. JAMA. 2019;321(4):374-384. doi: 10.1001/jama.2018.21364 [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  20. [22]Freemantle N, Chou E, Frois C, et al. Safety and efficacy of insulin glargine 300 u/mL compared with other basal insulin therapies in patients with type 2 diabetes mellitus: a network meta-analysis. BMJ Open. 2016;6(2):e009421. doi: 10.1136/bmjopen-2015-009421 [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  21. [23]American Diabetes Association . Older adults: standards of medical care in diabetes-2020. Diabetes Care. 2020;43(suppl 1):S152-S162. doi: 10.2337/dc20-S012 [DOI] [PubMed] [Google Scholar] · DOI
  22. [24]Karter AJ, Moffet HH, Liu JY, Lipska KJ. Surveillance of hypoglycemia-limitations of emergency department and hospital utilization data. JAMA Intern Med. 2018;178(7):987-988. doi: 10.1001/jamainternmed.2018.1014 [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page

Cited by

Sorted by citations

Authors
Bradley, M. C., Chillarige, Y., Lee, H., Wu, X., Parulekar, S., Muthuri, S., Wernecke, M., MaCurdy, T. E., Kelman, J. A., & Graham, D. J.
Affiliations
  • United States Food and Drug Administration (US)
  • Acumen (United States) (US)
  • Centers for Medicare and Medicaid Services (US)
Corresponding author
Bradley, Marie C.
ORCID
Venue
JAMA Internal Medicine
Publisher
American Medical Association (AMA)
Published
2021-05-01
Volume
181
Issue
5
Pages
598
ISSN
2168-6106 (ISSN-L)
DOI
10.1001/jamainternmed.2020.9176
PMC
PMC7922234
OpenAlex
W3133553555
Cited by
45
References
2
Citations by year
2026: 3 · 2025: 9 · 2024: 9 · 2023: 10 · 2022: 8 · 2021: 6
FWCI
6.16
Type
journal article
Language
en
Open access
Locations
  • JAMA Internal Medicine (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Health Professions › Emergency Medical Services › Patient Safety and Medication Errors
Keywords
long-acting insulin analogues, insulin glargine, insulin detemir, neutral protamine Hagedorn insulin, type 2 diabetes, older adults, emergency department visits, hospitalization, prandial insulin, insulin initiation, real-world evidence, Medicare beneficiaries, glycemic control
MeSH terms
Aged, Aged, 80 and over, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Female, Humans, Hypoglycemia, Insulin, Isophane, Male, Retrospective Studies, Cohort Studies, Proportional Hazards Models, Insulin, Long-Acting

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review