Is insulin the most effective injectable antihyperglycaemic therapy?
Open accessAbstract
Aims: The recent type 2 diabetes American Diabetes Association/European Association for the Study of Diabetes ( ADA / EASD ) position statement suggested insulin is the most effective glucose‐lowering therapy, especially when glycated haemoglobin ( HbA1c ) is very high. However, randomized studies comparing glucagon‐like peptide‐1 receptor agonists ( GLP‐1RAs ) exenatide once‐weekly [ OW ; DURATION ‐3 (Diabetes therapy Utilization: Researching changes in A1c, weight, and other factors Through Intervention with exenatide ONce‐Weekly)] and liraglutide once‐daily [ OD ; LEAD ‐5 (Liraglutide Effect and Action in Diabetes)] with insulin glargine documented greater HbA1c reduction with GLP‐1RAs , from baseline HbA1c ∼8.3% (67 mmol/mol). This post hoc analysis of DURATION ‐3 and LEAD ‐5 examined changes in HbA1c , fasting glucose and weight with exenatide OW or liraglutide and glargine, by baseline HbA1c quartile. Methods: Descriptive statistics were provided for change in HbA1c , fasting glucose, weight, and insulin dose, and subjects (%) achieving HbA1c <7.0%, by baseline HbA1c quartile. Inferential statistical analysis on the effect of baseline HbA1c quartile was performed for change in HbA1c . An analysis of covariance ( ANCOVA ) model was used to evaluate similarity in change in HbA1c across HbA1c quartiles. Results: At 26 weeks, in both studies, HbA1c reduction, and proportion of subjects reaching HbA1c <7.0%, were similar or numerically greater with the GLP‐1RAs than glargine for all baseline HbA1c quartiles. Fasting glucose reduction was similar or numerically greater with glargine. Weight decreased with both GLP‐1RAs across all quartiles; subjects taking glargine gained weight, more at higher baseline HbA1c . Adverse events were uncommon although gastrointestinal events occurred more frequently with GLP‐1RAs . Conclusions: HbA1c reduction with the GLP‐1RAs appears at least equivalent to that with basal insulin, irrespective of baseline HbA1c . This suggests that liraglutide and exenatide OW may be appropriate alternatives to basal insulin in type 2 diabetes, including when baseline HbA1c is very high (≥9.0%).
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There is evidence that people with type 2 diabetes and severe hyperglycemia can also be effectively treated with a sulfonylurea, a GLP-1 RA, or dual GIP and GLP-1 RA, though evidence is scarce for individuals with baseline A1C above 10-12%.
“Additionally, there is evidence that people with type 2 diabetes and severe hyperglycemia can also be effectively treated with a sulfonylurea, a GLP-1 RA, or dual GIP and GLP-1 RA, though evidence is scarce for individuals with baseline A1C above 10-12% (104,109-111).”
From 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2025 (2025) · cites this paper as [110]
The Conclusion (p. 6) supports GLP-1 receptor agonists as a possible treatment for selected people with type 2 diabetes and HbA1c above 9%. The limitations discussion (p. 5) cautions that results may differ above 11%, consistent with limited evidence at very high baseline HbA1c. The paper treats sulphonylurea as background therapy, not as an alternative tested here, and does not address dual GIP/GLP-1 receptor agonists. (LLM, conf=0.90)
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Cites
Handelsman, Y., Mechanick, J. I., Blonde, L., Grunberger, G., Bloomgarden, Z. T., Bray, G. A., Dagogo-Jack, S., Davidson, J. A., Einhorn, D., Ganda, O., et al. (2011) · Endocrine Practice · doi:10.4158/ep.17.s2.1 · Cited by 513 · cited 1× · see citing works
“0% who fail to achieve glycaemic control using other agents [1,5].”
BackgroundInitiate Insulin by Aggressive Titration and Education (INITIATE)
Yki-Järvinen, H., Juurinen, L., Alvarsson, M., Bystedt, T., Caldwell, I., Davies, M., Lahdenperä, S., Nijpels, G., & Vähätalo, M. (2007) · Diabetes Care · doi:10.2337/dc06-1357 · Cited by 139 · see citing works
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Research works printed but not linked: 5
- [1]1. Inzucchi SE, Bergenstal RM, Buse JB et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2012; 55 : 1577-1596.
- [2]2. Diamant M, Van Gaal L, Stranks S et al. Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial. Lancet 2010; 375 : 2234-2243.
- [3]3. Russell-Jones D, Vaag A, Schmitz O et al., Liraglutide Effect and Action in Diabetes 5 (LEAD-5) met + SU Study Group. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met + SU): a randomised controlled trial. Diabetologia 2009; 52 : 2046-2055.
- [4]4. Qu Y. Issues for stratified randomization based on a factor derived from a continuous baseline variable. Pharm Statist 2011; 10 : 232-235.
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Davies, M. J., D’Alessio, D. A., Fradkin, J., Kernan, W. N., Mathieu, C., Mingrone, G., Rossing, P., Tsapas, A., Wexler, D. J., & Buse, J. B. (2018) · Diabetes Care · doi:10.2337/dci18-0033 · Cited by 3,518 · see citing works
Self-citationGLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art
Nauck, M. A., Quast, D. R., Wefers, J., & Meier, J. J. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101102 · Cited by 1,647 · see citing works
Davies, M. J., D’Alessio, D. A., Fradkin, J., Kernan, W. N., Mathieu, C., Mingrone, G., Rossing, P., Tsapas, A., Wexler, D. J., & Buse, J. B. (2018) · Diabetologia · doi:10.1007/s00125-018-4729-5 · Cited by 1,455 · see citing works
Self-citation9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2025
American Diabetes Association Professional Practice Committee, ElSayed, N. A., McCoy, R. G., Aleppo, G., Bajaj, M., Balapattabi, K., Beverly, E. A., Briggs Early, K., Bruemmer, D., Echouffo-Tcheugui, J. B., et al. (2025) · Diabetes Care · doi:10.2337/dc25-s009 · Cited by 728 · see citing works
User’s guide to mechanism of action and clinical use of GLP-1 receptor agonists
Shaefer, C. F., Kushner, P., & Aguilar, R. (2015) · Postgraduate Medicine · doi:10.1080/00325481.2015.1090295 · Cited by 128 · see citing works
- Authors
- Buse, J. B., Peters, A., Russell‐Jones, D., Furber, S., Donsmark, M., Han, J., MacConell, L., Maggs, D., & Diamant, M.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- University of Southern California (US)
- Endocrinology and Metabolism, Royal Surrey County Hospital Guildford UK
- Novo Nordisk Canada (Canada) (CA)
- Novo Nordisk (Denmark) (DK)
- Amylin Pharmaceuticals LLC San Diego CA USA
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Corresponding author
- Buse, J. B.
- Venue
- Diabetes, Obesity and Metabolism
- Publisher
- Wiley
- Published
- 2014-11-09
- Volume
- 17
- Issue
- 2
- Pages
- 145-151
- ISSN
- 1462-8902 (ISSN-L)
- 1463-1326
- OpenAlex
- W2044374397
- Cited by
- 32
- References
- 2
- Citations by year
- 2025: 5 · 2024: 2 · 2022: 3 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 4 · 2017: 3 · 2016: 6 · 2015: 2 · 2014: 1
- FWCI
- 3.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes Obesity and Metabolism (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- Amylin Pharmaceuticals
- AstraZeneca
- Sanofi
- F. Hoffmann-La Roche
- Osiris Therapeutics
- Intarcia Therapeutics
- Orexigen Therapeutics
- Halozyme
- Quest Diagnostics
- Dexcom
- Vrije Universiteit Amsterdam
- Novo Nordisk
- Abbott Diabetes Care
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- type 2 diabetes, insulin glargine, exenatide once weekly, liraglutide, GLP-1 receptor agonists, HbA1c, HbA1c reduction, fasting blood glucose, weight change, insulin dose, gastrointestinal adverse effects
- MeSH terms
- Insulin Glargine, Liraglutide, Exenatide, Blood Glucose, Body Weight, Diabetes Mellitus, Type 2, Fasting, Female, Glycated Hemoglobin, Humans, Hypoglycemic Agents, Male, Metformin, Middle Aged, Peptides, Venoms, Treatment Outcome, Insulin, Long-Acting, Glucagon-Like Peptide 1
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