A Systematic Review and Meta-Analysis of Hypoglycemia and Cardiovascular Events
Open accessAbstract
OBJECTIVE—Glyburide is the most widely used sulfonylurea but has unique pharmacodynamic properties that may increase harm. We hypothesized that glyburide causes more hypoglycemia and cardiovascular events than other secretagogues or insulin. RESEARCH DESIGN AND METHODS—Data sources were Medline, Embase, Cochrane, and three other web-based clinical trial registers (1966–2005). Parallel, randomized, controlled trials in people with type 2 diabetes comparing glyburide monotherapy with monotherapy using secretagogues or insulin were selected. Outcomes were hypoglycemia, glycemic control, cardiovascular events, body weight, and death. Titles and abstracts of 1,806 publications were reviewed in duplicate and 21 relevant articles identified. Data on patient characteristics, interventions, outcomes, and validity were extracted in duplicate using predefined criteria. RESULTS—Glyburide was associated with a 52% greater risk of experiencing at least one episode of hypoglycemia compared with other secretagogues (relative risk 1.52 [95% CI 1.21–1.92]) and with 83% greater risk compared with other sulfonylureas (1.83 [1.35–2.49]). Glyburide was not associated with an increased risk of cardiovascular events (0.84 [0.56–1.26]), death (0.87 [0.70–1.07]), or end-of-trial weight (weighted mean difference 1.69 kg [95% CI −0.41 to 3.80]) compared with other secretagogues. Limitations included suboptimal reporting of original trials. Loss to follow-up exceeded 20% in some studies, and major hypoglycemia was infrequently reported. CONCLUSIONS—Glyburide caused more hypoglycemia than other secretagogues and other sulfonylureas. Glyburide was not associated with an increased risk of cardiovascular events, death, or weight gain.
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Main side effect of SUs is hypoglycemia due to excess circulating insulin and glucose-independent insulin secretion.
“In addition to the weight gain attributed to the anabolic effects of increased insulin secretion, the main side effect of SUs is hypoglycemia307, 308 due to excess circulating insulin levels and due to the fact that SUs evoke insulin secretion in a glucose-independent manner.309”
From Pancreatic regulation of glucose homeostasis. (2016) · cites this paper as [307]
A 3 mg intranasal glucagon dose (containing 1 mg glucagon per 10 mg powder) seems to produce the maximum effect.
“Three mg of intranasal glucagon (1 mg glucagon per 10 mg dry powder) appears to have maximal effect.1231–1235”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [1235]
The Hypoglycemia and glycemic control section reports outcomes for glyburide versus other diabetes drugs, not intranasal glucagon. Searches for the 3 mg dose, powder formulation, and maximal effect found no passage addressing the claim. The indexed passages provide no page number. (LLM, conf=0.76)
Experimental — accuracy not yet measuredChlorpropamide and glibenclamide are associated with a substantially greater risk of hypoglycemia than other second-generation sulfonylureas (gliclazide, glimepiride, glipizide, and their extended formulations), which are preferable.
“Chlorpropamide and glibenclamide (known as glyburide in the U.S. and Canada), are associated with a substantially greater risk of hypoglycemia than other second-generation sulfonylureas (gliclazide, glimepiride, glipizide, and their extended formulations), which are preferable (Table 1) (53,54).”
From Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy (2009) · cites this paper as [54]
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Cites
Wild, S., Roglic, G., Green, A., Sicree, R., & King, H. (2004) · Diabetes Care · doi:10.2337/diacare.27.5.1047 · Cited by 15,297 · see citing works
Moher, D., Cook, D. J., Eastwood, S., Olkin, I., Rennie, D., & Stroup, D. F. (1999) · The Lancet · doi:10.1016/s0140-6736(99)04149-5 · Cited by 4,826 · see citing works
Gluud, L. L., Villumsen, J., & Gluud, C. N. (2001) · Annals of Internal Medicine · doi:10.7326/0003-4819-135-11-200112040-00010 · Cited by 2,262 · see citing works
Cloning of the β Cell High-Affinity Sulfonylurea Receptor: a Regulator of Insulin Secretion
Aguilar-Bryan, L., Nichols, C. G., Wechsler, S. W., Clement, J. P., Boyd, A. E., González, G., Herrera-Sosa, H., Nguy, K., Bryan, J., & Nelson, D. A. (1995) · Science · doi:10.1126/science.7716547 · Cited by 1,315 · see citing works
Egger, M., Jüni, P., Bartlett, C., Holenstein, F., & Sterne, J. (2003) · Health Technology Assessment · doi:10.3310/hta7010 · Cited by 1,181 · see citing works
Oral Antihyperglycemic Therapy for Type 2 Diabetes
Inzucchi, S. E. (2002) · JAMA · doi:10.1001/jama.287.3.360 · Cited by 1,057 · see citing works
Direction and impact of language bias in meta-analyses of controlled trials: empirical study
Jüni, P., Holenstein, F., Sterne, J., Bartlett, C., & Egger, M. (2002) · International Journal of Epidemiology · doi:10.1093/ije/31.1.115 · Cited by 892 · see citing works
Robinson, K. A., & Dickersin, K. (2002) · International Journal of Epidemiology · doi:10.1093/ije/31.1.150 · Cited by 833 · see citing works
(1995) · BMJ · doi:10.1136/bmj.310.6972.83 · Cited by 478 · see citing works
Diverse causes of hypoglycemia-associated autonomic failure in diabetes.
Cryer, P. E. (2004) · New England Journal of Medicine · doi:10.1056/nejmra031354 · Cited by 411 · see citing works
Hypoglycemia: The Limiting Factor in the Management of IDDM
Cryer, P. E. (1994) · Diabetes · doi:10.2337/diab.43.11.1378 · Cited by 307 · see citing works
Drug-Induced Hypoglycemia: A Review of 1418 Cases
Seltzer, H. S. (1989) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/s0889-8529(18)30395-5 · Cited by 266 · see citing works
Holstein, A., Plaschke, A., & Egberts, E. (2001) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.235 · Cited by 264 · see citing works
Glibenclamide-associated hypoglycaemia: A report on 57 cases
Asplund, K., Wiholm, B. ‐., & Lithner, F. (1983) · Diabetologia · doi:10.1007/bf00257338 · Cited by 258 · see citing works
Klepzig, H. (1999) · European Heart Journal · doi:10.1053/euhj.1998.1242 · Cited by 224 · see citing works
Repaglinide versus glyburide: a one-year comparison trial
Marbury, T. C., Huang, W., Strange, P., & Lebovitz, H. E. (1999) · Diabetes Research and Clinical Practice · doi:10.1016/s0168-8227(99)00002-9 · Cited by 183 · see citing works
Draeger, K., Wernicke-Panten, K., Lomp, H.-J., Schüler, E., & Roßkamp, R. (1996) · Hormone and Metabolic Research · doi:10.1055/s-2007-979830 · Cited by 161 · see citing works
Cryer, P. E., Fisher, J. N., & Shamoon, H. (1994) · Diabetes Care · doi:10.2337/diacare.17.7.734 · Cited by 159 · see citing works
Clinical Evaluation of Glimepiride versus Glyburide in NIDDM in a Double-Blind Comparative Study
Dills, D. G., & Schneider, J. (1996) · Hormone and Metabolic Research · doi:10.1055/s-2007-979831 · Cited by 133 · see citing works
Importance of Early Insulin Secretion
Hollander, P. A., Schwartz, S. L., Gatlin, M. R., Haas, S. J., Zheng, H., Foley, J. E., & Dunning, B. E. (2001) · Diabetes Care · doi:10.2337/diacare.24.6.983 · Cited by 131 · see citing works
Wolffenbuttel, B. H. R., & Landgraf, R. (1999) · Diabetes Care · doi:10.2337/diacare.22.3.463 · Cited by 129 · see citing works
Comparison of efficacy, secondary failure rate, and complications of sulfonylureas
Harrower, A. D. B. (1994) · Journal of Diabetes and its Complications · doi:10.1016/1056-8727(94)90044-2 · Cited by 114 · see citing works
Comparative Tolerability of Sulphonylureas in Diabetes Mellitus
Harrower, A. D. B. (2000) · Drug Safety · doi:10.2165/00002018-200022040-00004 · Cited by 92 · see citing works
Landgraf, R., Bilo, H. J. G., & Müller, P. G. (1999) · European Journal of Clinical Pharmacology · doi:10.1007/s002280050613 · Cited by 89 · see citing works
Repaglinide versus glibenclamide treatment of Type 2 diabetes during Ramadan fasting
Mafauzy, M. (2002) · Diabetes Research and Clinical Practice · doi:10.1016/s0168-8227(02)00104-3 · Cited by 87 · see citing works
Kovatchev, B. P., Cox, D. J., Farhy, L. S., Straume, M., Gonder-Frederick, L. A., & Clarke, W. L. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.11.6999 · Cited by 76 · see citing works
Banting Lecture. Hypoglycemia: the limiting factor in the management of IDDM
Cryer, P. E. (1994) · Diabetes · doi:10.2337/diabetes.43.11.1378 · Cited by 63 · see citing works
Kovatchev, B. P. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.85.11.4287 · Cited by 59 · see citing works
Clarke, B. F., & Campbell, I. W. (1975) · The Lancet · doi:10.1016/s0140-6736(75)91141-1 · Cited by 53 · see citing works
Harrower, A. D. B. (1985) · Current Medical Research and Opinion · doi:10.1185/03007998509109650 · Cited by 33 · see citing works
Herz, M., Sun, B., Miličević, Z., et al. (2002) · Clinical Therapeutics · doi:10.1016/s0149-2918(02)85006-8 · Cited by 31 · see citing works
Rosenstock, J., Corrao, P. J., Goldberg, R. B., et al. (1994) · PubMed · Cited by 21 · see citing works
Glycemic control with Humalog® Mix25™ in type 2 diabetes inadequately controlled with glyburide
Roach, P. J., Koledova, E. B., Metcalfe, S., Hultman, C. I., & Miličević, Z. (2001) · Clinical Therapeutics · doi:10.1016/s0149-2918(01)80140-5 · Cited by 21 · see citing works
Comparison of gliclazide and glibenclamide treatment in non-insulin-dependent diabetes.
Baba, S., Nakagawa, S., Takebe, K., GOTOJ, Y., MAEZAWA, H., Takeda, R., Sakamoto, N., & Fukui, I. (1983) · The Tohoku Journal of Experimental Medicine · doi:10.1620/tjem.141.suppl_693 · Cited by 20 · see citing works
Cardiovascular effects of sulphonylureas: role of K ATP channels
Howes, L. G. (2000) · Diabetes Obesity and Metabolism · doi:10.1046/j.1463-1326.2000.00047.x · Cited by 15 · see citing works
Metabolic Effects of Mealtime Insulin Lispro in Comparison to Glibenclamide in Early Type 2 Diabetes
Forst, T. M., Eriksson, J., Strotmann, H.-J., et al. (2003) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/s-2003-39237 · Cited by 14 · see citing works
Role of Protein in Diabetes Control
Malik, R., & Jaspan, J. B. (1989) · Diabetes Care · doi:10.2337/diacare.12.1.39b · Cited by 4 · see citing works
Clinical Comparison of Glipizide and Glyburide
Schmitt, J. K. (1989) · Diabetes Care · doi:10.2337/diacare.12.1.39a · Cited by 4 · see citing works
Ciccarone, A., Cecchetti, P., Orsini, P., et al. (1999) · Current Therapeutic Research · doi:10.1016/s0011-393x(99)80008-3 · Cited by 2 · see citing works
A comparative study of glibenclamide and chlorpropamide. (Preliminary report).
Hamblin, J. J., Ismay, G., Ms, G., et al. (1970) · PubMed · Cited by 1 · see citing works
Comparative study of glibenclamide & chlorpropamide in newly diagnosed maturity onset diabetics.
Haider, Z., Obaidullah, S., & Fayyaz-ud-Din (1976) · PubMed · Cited by 1 · see citing works
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Nathan, D. M., Buse, J. B., Davidson, M. B., Ferrannini, E., Holman, R. R., Sherwin, R., & Zinman, B. (2009) · Diabetes Care · doi:10.2337/dc08-9025 · Cited by 3,834 · 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) · Diabetes Care · doi:10.2337/dci18-0033 · Cited by 3,518 · 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
Cryer, P. E., Axelrod, L., Grossman, A. B., Heller, S. R., Montori, V. M., Seaquist, E. R., & Service, F. J. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-1410 · Cited by 1,277 · see citing works
Pancreatic regulation of glucose homeostasis.
Röder, P. V., Wu, B., Liu, Y., & Han, W. (2016) · Experimental & Molecular Medicine · doi:10.1038/emm.2016.6 · Cited by 985 · see citing works
Cryer, P. E., Davis, S. N., & Shamoon, H. (2003) · Diabetes Care · doi:10.2337/diacare.26.6.1902 · Cited by 1,160 · see citing works
Nathan, D. M., Buse, J. B., Davidson, M. B., Ferrannini, E., Holman, R. R., Sherwin, R., & Zinman, B. (2009) · Diabetologia · doi:10.1007/s00125-008-1157-y · Cited by 712 · see citing works
Update on the treatment of type 2 diabetes mellitus
Marín-Peñalver, J. J., Martín-Timón, I., Sevillano-Collantes, C., & Cañizo-Gómez, F. J. D. (2016) · World Journal of Diabetes · doi:10.4239/wjd.v7.i17.354 · Cited by 647 · see citing works
Handelsman, Y., Bloomgarden, Z. T., Grunberger, G., Umpierrez, G., Zimmerman, R. S., Bailey, T. S., Blonde, L., Bray, G. A., Cohen, A. J., Dagogo-Jack, S., et al. (2015) · Endocrine Practice · doi:10.4158/ep15672.glsuppl · Cited by 559 · see citing works
Blonde, L., Umpierrez, G. E., Reddy, S. S., McGill, J. B., Berga, S. L., Bush, M., Chandrasekaran, S., DeFronzo, R. A., Einhorn, D., Galindo, R. J., et al. (2022) · Endocrine Practice · doi:10.1016/j.eprac.2022.08.002 · Cited by 507 · see citing works
Hypoglycemia: The neglected complication
Kalra, S., Mukherjee, J. J., Venkataraman, S., Bantwal, G., Shaikh, S., Saboo, B., Das, A. K., & Ramachandran, A. (2013) · Indian Journal of Endocrinology and Metabolism · doi:10.4103/2230-8210.117219 · Cited by 255 · see citing works
Rados, D. V., Pinto, L. C., Remonti, L. R., Leitão, C. B., & Gross, J. L. (2016) · PLOS Medicine · doi:10.1371/journal.pmed.1001992 · Cited by 143 · see citing works
Do sulphonylureas still have a place in clinical practice?
Khunti, K., Chatterjee, S., Gerstein, H. C., Zoungas, S., & Davies, M. J. (2018) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(18)30025-1 · Cited by 116 · see citing works
Self-citationPharmacokinetics, efficacy and safety of glyburide for treatment of gestational diabetes mellitus
Malek, R., & Davis, S. N. (2016) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2016.1187131 · Cited by 54 · see citing works
Lega, I. C., Campitelli, M. A., Austin, P. C., Na, Y., Zahedi, A., Leung, F., Yu, C., Bronskill, S. E., Rochon, P. A., & Lipscombe, L. L. (2021) · Diabetologia · doi:10.1007/s00125-020-05370-7 · Cited by 40 · see citing works
Cardiovascular events in individuals treated with sulfonylureas or dipeptidyl peptidase 4 inhibitors
Turchin, A., Petito, L. C., Hegermiller, E., Carnahan, R., DeVries, A., Goel, S., Lansang, M. C., McDonnell, M. E., Nair, V., Priest, E., et al. (2025) · JAMA Network Open · doi:10.1001/jamanetworkopen.2025.23067 · Cited by 14 · see citing works
Tschöpe, D., Bramlage, P., Schneider, S., & Gitt, A. K. (2016) · Diabetes and Vascular Disease Research · doi:10.1177/1479164115610470 · Cited by 12 · see citing works
- Authors
- Gangji, A. S., Cukierman, T., Gerstein, H. C., Goldsmith, C. H., & Clase, C. M.
- Affiliations
- St. Joseph’s Healthcare Hamilton (CA)
- Population Health Research Institute (CA)
- McMaster University (CA)
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 2007-02-01
- Volume
- 30
- Issue
- 2
- Pages
- 389-394
- ISSN
- 0149-5992 (ISSN-L)
- 1935-5548
- OpenAlex
- W2133236380
- Cited by
- 308
- References
- 42
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 9 · 2023: 7 · 2022: 16 · 2021: 10 · 2020: 11 · 2019: 14 · 2018: 12 · 2017: 15 · 2016: 26 · 2015: 35 · 2014: 22 · 2013: 28 · 2012: 21
- FWCI
- 2.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes Care (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Society of Nephrology
- Kidney Foundation of Canada
- 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
- glibenclamide, sulfonylureas, hypoglycemia, cardiovascular events, type 2 diabetes, secretagogues, insulin, glycemic control, body weight, mortality, drug safety
- MeSH terms
- Cardiovascular Diseases, Diabetic Angiopathies, Glyburide, Humans, Hypoglycemia, Hypoglycemic Agents, Insulin
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