Dose-Response Relation Between Sulfonylurea Drugs and Mortality in Type 2 Diabetes Mellitus: A Population-Based Cohort Study
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BACKGROUND: Over the past 30 years, the relation between use of sulfonylureas to treat type 2 diabetes and the risk of cardiovascular events has been vigorously debated. The purpose of this study was to determine if the risk of death changes with level of exposure to sulfonylurea drugs. METHODS: This was a retrospective, inception cohort study using administrative data from Saskatchewan Health (1991-1999). The 5795 subjects, identified by their first-ever dispensation for an oral antidiabetic agent, were grouped according to their use of such agents during follow-up. Potential subjects using insulin or combination therapy were excluded. Exposure level was defined by daily dose and degree of adherence. Separate multivariate Cox proportional-hazard models were constructed for each monotherapy group and used to calculate the risk of death associated with higher versus lower exposure category. Disease severity indicators were identified among the administrative data and entered as covariates in each model. The main outcomes were all-cause mortality and death from an acute ischemic event. RESULTS: The mean age of the cohort members was 66.3 (standard deviation [SD] 13.4) years; 43.4% were female; and their mean duration of follow-up was 4.6 (SD 2.1) years. First-generation sulfonylureas were used exclusively by 120 subjects; glyburide, by 4138; and metformin, by 1537. A greater risk of death was associated with higher daily doses of the first-generation sulfonylureas (adjusted hazard ratio [HR] 2.1, 95% confidence interval [CI] 1.0-4.7) and glyburide (HR 1.3, 95% CI 1.2-1.4), but not metformin (HR 0.8, 95% CI 0.7-1.1). Similar associations were observed for death caused by an acute ischemic event. INTERPRETATION: Higher exposure to sulfonylureas was associated with increased mortality among patients newly treated for type 2 diabetes. The same relation was not observed with metformin. This implies that the manner in which blood glucose concentration is lowered may be as important as achieving recommended glucose targets.
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The lower survival rate of the sulfonylurea-treated group might reflect a negative effect of sulfonylurea drugs on mortality.
“However, the lower survival rate of those in the sulfonylurea-treated group might reflect a negative effect of sulfonylurea drugs on mortality as has been reported in subsequent studies (162).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [162]
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BackgroundIntensive Glucose Lowering and Cardiovascular Disease Prevention in Diabetes
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Morgan, C. L., Mukherjee, J., Jenkins‐Jones, S., Holden, S. E., & Currie, C. J. (2014) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12306 · Cited by 75 · see citing works
“of intensive blood-glucose management using SUs in patients with type 2 diabetes [9,10].”
Morgan, C. L., Mukherjee, J., Jenkins‐Jones, S., Holden, S. E., & Currie, C. J. (2014) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12302 · Cited by 71 · see citing works
Cardiovascular Protection in People With Diabetes
Stone, J. A., Houlden, R. L., Lin, P., Udell, J. A., & Verma, S. (2018) · Canadian Journal of Diabetes · doi:10.1016/j.jcjd.2017.10.024 · Cited by 71 · see citing works
Kim, H. J., Kang, E. S., Kim, D. J., Kim, S. H., Ahn, C. W., Soo, B., Nam, M., Chung, C. H., Lee, K. W., Nam, C. M., et al. (2007) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2006.02723.x · Cited by 71 · see citing works
Schernthaner, G., Brand, K. M. G., & Bailey, C. J. (2022) · Metabolism · doi:10.1016/j.metabol.2022.155160 · Cited by 70 · see citing works
Type 2 diabetes mellitus—current therapies and the emergence of surgical options
Lebovitz, H. E. (2011) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2011.10 · Cited by 69 · see citing works
Recent HbA1c Values and Mortality Risk in Type 2 Diabetes. Population-Based Case-Control Study
Nicholas, J. M., Charlton, J., Dregan, A., & Gulliford, M. C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0068008 · Cited by 68 · see citing works
Ajjan, R., & Grant, P. J. (2006) · Diabetes and Vascular Disease Research · doi:10.3132/dvdr.2006.023 · Cited by 64 · see citing works
Wu, Q., Wu, S., Yang, C., Zhang, Z., Mao, G., Li, S., Yang, Y., Zhang, X., Wu, M., & Tong, H. (2021) · Food & Function · doi:10.1039/d0fo03329d · Cited by 66 · see citing works
Do sulfonylurea drugs increase the risk of cardiac events?
Bell, D. S. H. (2006) · Canadian Medical Association Journal · doi:10.1503/cmaj.051237 · Cited by 64 · see citing works
Abdul-Ghani, M. A., & DeFronzo, R. A. (2017) · Diabetes Care · doi:10.2337/dc16-2368 · Cited by 64 · see citing works
“, sulfonylureas (51,52), DPP-4 inhibitors (53–55), and insulin (56) (Fig.”
BackgroundLi, Y., Hu, Y., Ley, S. H., Rajpathak, S. N., & Hu, F. B. (2014) · Diabetes Care · doi:10.2337/dc14-1306 · Cited by 62 · see citing works
“(19) using administrative data from Saskatchewan Health observed a doseresponse relationship between sulfonylurea drugs andmortality in type 2 diabetic patients.”
BackgroundMethodStephan, D., Winkler, M., Kühner, P., Russ, U., & Quast, U. (2006) · Diabetologia · doi:10.1007/s00125-006-0307-3 · Cited by 62 · see citing works
“A recent Canadian study [23], however, again casts doubt.”
BackgroundZhong, J., Wu, S., Chen, W., Huang, Y., Lei, Q., Mishra, S., Bhatt, P., & Chen, S. (2023) · Chemosphere · doi:10.1016/j.chemosphere.2023.138390 · Cited by 61 · see citing works
GENUTH, S. M. (2014) · Diabetes Care · doi:10.2337/dc14-0565 · Cited by 61 · see citing works
“(69,70), and a dose–response relationship between glyburide use and mortality was not seen with metformin (71).”
BackgroundCardiovascular safety profile of currently available diabetic drugs.
Azimova, K., Juan, Z. T. S., & Mukherjee, D. (2014) · PubMed Central · Cited by 58 · see citing works
Cardiovascular safety of non-insulin pharmacotherapy for type 2 diabetes
Xu, J., & Rajaratnam, R. (2017) · Cardiovascular Diabetology · doi:10.1186/s12933-017-0499-5 · Cited by 58 · see citing works
Wheeler, S., Moore, K. P., Forsberg, C. W., Riley, K., Floyd, J. S., Smith, N. L., & Boyko, E. J. (2013) · Diabetologia · doi:10.1007/s00125-013-2958-1 · Cited by 56 · see citing works
VersorgungsLeitlinie, N. (2011) · Cited by 58 · see citing works
Şahin, İ., Bakıner, O., Demir, T., Sari, R., & Atmaca, A. A. (2024) · Diabetes Therapy · doi:10.1007/s13300-024-01612-8 · Cited by 64 · see citing works
“Gliclazide, as a newer-generation pancreatic β cell-specific SU, seems to be advantageous in this regard, by not increasing the cardiovascular risk, not impairing the protective ischemic cardiac preconditioning, and having a low risk of hypoglycemia [8, 20, 39, 78, 93].”
BackgroundEffect of glucose-lowering therapies on heart failure
Nassif, M. E., & Kosiborod, M. (2018) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2017.211 · Cited by 54 · see citing works
Shah, N. K., Deeb, W., Choksi, R. R., & Epstein, B. J. (2012) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1002/phar.1010 · Cited by 53 · see citing works
Pioglitazone and sulfonylureas: effectively treating type 2 diabetes
Markolf Hanefeld, E. (2007) · International Journal of Clinical Practice · doi:10.1111/j.1742-1241.2007.01361.x · Cited by 50 · see citing works
Lamb, D. A., Eurich, D. T., McAlister, F. A., Tsuyuki, R. T., Semchuk, W., Wilson, T. W., & Blackburn, D. F. (2009) · Circulation Cardiovascular Quality and Outcomes · doi:10.1161/circoutcomes.108.813600 · Cited by 48 · see citing works
Complex of nicosulfuron with human serum albumin: A biophysical study
Ding, F., Liu, W., Li, N., Zhang, L., & Sun, Y. (2010) · Journal of Molecular Structure · doi:10.1016/j.molstruc.2010.04.033 · Cited by 46 · see citing works
Nakamura, I., Oyama, J., Komoda, H., Shiraki, A., Sakamoto, Y., Taguchi, I., Atsushi, H., Komatsu, A., Takeuchi, M., Yamagishi, S., et al. (2014) · Cardiovascular Diabetology · doi:10.1186/1475-2840-13-15 · Cited by 44 · see citing works
“Sulfonylureas may increase the risk of cardiovascular events in patients with type 2 diabetes [14].”
BackgroundBo, S., Castiglione, A., Ghigo, E., Gentile, L., Durazzo, M., Cavallo‐Perin, P., & Ciccone, G. (2013) · European Journal of Endocrinology · doi:10.1530/eje-13-0299 · Cited by 43 · see citing works
West, T. M., Wang, Q., Deng, B., Zhang, Y., Barbagallo, F., Reddy, G. R., Chen, D., Phan, K. S., Xu, B. Y., Isidori, A. M., et al. (2019) · Journal of the American Heart Association · doi:10.1161/jaha.119.012273 · Cited by 43 · see citing works
ROLE OF ADENOSINE TRIPHOSPHATE-SENSITIVE POTASSIUM CHANNEL INHIBITION IN SHOCK STATES
Lange, M., Morelli, A., Ertmer, C., Bröking, K., Rehberg, S. W., Aken, H. V., Traber, D. L., & Westphal, M. (2007) · Shock · doi:10.1097/shk.0b013e318050c836 · Cited by 40 · see citing works
Ridderstråle, M., Svärd, R., Zeller, C., Kim, G., Woerle, H. J., & Broedl, U. C. (2013) · Cardiovascular Diabetology · doi:10.1186/1475-2840-12-129 · Cited by 38 · see citing works
“4, respectively) [25].”
Martono, D. P., Lub, R., Heerspink, H. J. L., Hak, E., Wilffert, B., & Denig, P. (2015) · Diabetic Medicine · doi:10.1111/dme.12688 · Cited by 38 · see citing works
Lang, V., Fatehi, M., & Light, P. E. (2011) · Pharmacogenetics and Genomics · doi:10.1097/fpc.0b013e32835001e7 · Cited by 37 · see citing works
Alhadramy, M. S. (2016) · Journal of Taibah University Medical Sciences · doi:10.1016/j.jtumed.2016.02.001 · Cited by 38 · see citing works
The Management of Type 2 Diabetic Patients with Hypoglycaemic Agents
Tsang, M.-W. (2012) · ISRN Endocrinology · doi:10.5402/2012/478120 · Cited by 35 · see citing works
“Recent population studies [15, 16] reported increased coronary heart event and mortality with increased dose of SU exposure, and plausible mechanisms have been related to blockage of SUR2 receptor in myocardium and impaired the preischemic precondition of myocardium [17].”
BackgroundPandarekandy, S. T., Sreejesh, P. G., Thampi, B. S. H., & Sreekumaran, E. (2017) · Indian Journal of Pharmaceutical Sciences · doi:10.4172/pharmaceutical-sciences.1000290 · Cited by 35 · see citing works
Pladevall, M., Riera‐Guàrdia, N., Margulis, A. V., Varas‐Lorenzo, C., Calingaert, B., & Perez‐Gutthann, S. (2016) · BMC Cardiovascular Disorders · doi:10.1186/s12872-016-0187-5 · Cited by 34 · see citing works
The Effect of Sulphonylureas on the Microvascular and Macrovascular Complications of Diabetes
Kar, P. S., & Holt, R. I. G. (2008) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-008-6090-2 · Cited by 34 · see citing works
“conducted a retrospective cohort study using data from Saskatchewan Health (1991–1999) in an effort to determine the dose–response relation between sulphonylurea and mortality in type 2 diabetes [21].”
MethodThiazolidinediones in patients with type 2 diabetes mellitus and heart failure
Granberry, M. C., Hawkins, J. B., & Franks, A. M. (2007) · American Journal of Health-System Pharmacy · doi:10.2146/ajhp060446 · Cited by 34 · see citing works
Qushawy, M. K. E., Nasr, A. M., Swidan, S. A., & Mortagi, Y. I. (2020) · Scientia Pharmaceutica · doi:10.3390/scipharm88040052 · Cited by 33 · see citing works
Pfützner, A., Standl, E., Strotmann, H.-J., Schulze, J., Hohberg, C., Lübben, G., Pahler, S., Schöndorf, T., & Forst, T. M. (2006) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm.2006.108 · Cited by 32 · see citing works
“These results support the hypothesis that cardiovascular disease risk may be associated with sulfonylurea treatment, as suspected decades ago (25, 26) and reported again recently (27).”
ResultCorrao, G., Romio, S., Zambon, A., Merlino, L. G., Bosi, E., & Scavini, M. (2010) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-010-0939-6 · Cited by 31 · see citing works
Tayek, J. A. (2006) · Diabetologia · doi:10.1007/s00125-006-0404-3 · Cited by 30 · see citing works
“3 with glibenclamide (known as glyburide in the USA and Canada) monotherapy [3], similar to the figure of 1.”
BackgroundPatorno, E., Garry, E. M., Patrick, A. R., Schneeweiß, S., Gillet, V. G., Zorina, O., Bartels, D. B., & Seeger, J. D. (2015) · Drug Safety · doi:10.1007/s40264-015-0280-1 · Cited by 29 · see citing works
“mortality include comorbidities identified post-treatment, such as myocardial infarction and cancer [46, 53], drug utilization during follow-up [20, 22, 24, 27, 32, 34, 45, 46], and metabolic information such as mean body mass index (BMI) and HbA1c that are ascertained after cohort entry (and initiation of treatment)…”
Glycemic Control and Cardiovascular Disease: What’s a Doctor to Do?
Kishore, P., Kim, S. H., & Crandall, J. P. (2012) · Current Diabetes Reports · doi:10.1007/s11892-012-0268-5 · Cited by 28 · see citing works
“Furthermore, a greater risk of death has been reported with increased use of higher doses of first-generation SUs, suggesting a dose-dependent effect [38].”
BackgroundMannucci, E., Monami, M., Candido, R., Pintaudi, B., & Targher, G. (2020) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2020.05.032 · Cited by 27 · see citing works
Vascular Complications of Diabetes Mellitus
Chiong, Y., & Evans‐Molina, C. (2014) · Springer eBooks · doi:10.1007/978-3-642-37078-6_49 · Cited by 27 · see citing works
Impact of Glycemic Treatment Choices on Cardiovascular Complications in Type 2 Diabetes
Weiss, I. A., Valiquette, G., & Schwarcz, M. (2009) · Cardiology in Review · doi:10.1097/crd.0b013e3181a7b34c · Cited by 26 · see citing works
“A more recent study looked retrospectively at CV mortality in a large group of Canadian patients.(19) Patients treated with a first generation sulfonylurea had a mortality of 67.”
BackgroundSulistio, M. S., Carothers, C., Mangat, M., Lujan, M., OLIVEROS, R. A., & CHILTON, R. J. (2009) · Current Atherosclerosis Reports · doi:10.1007/s11883-009-0015-9 · Cited by 26 · see citing works
“However, to impact macrovascular disease, the drug chosen to lower blood glucose concentration may be more important [ 6 ].”
BackgroundKhodadadi, S., Zabihi, N. A., Niazmand, S., Abbasnezhad, A., Mahmoudabady, M., & Rezaee, S. A. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.04.158 · Cited by 25 · see citing works
Thiazolidinedione insulin sensitizers and the heart: a tale of two organs?
Buckingham, R. E., & Hanna, A. (2007) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2006.00700.x · Cited by 26 · see citing works
Sulfonylureas: do we need to introspect safety again?
Sehra, D., Sehra, S., & Sehra, S. T. (2011) · Expert Opinion on Drug Safety · doi:10.1517/14740338.2011.583234 · Cited by 25 · see citing works
Maguire, J., & Dhar, V. (2012) · Health Systems · doi:10.1057/hs.2012.20 · Cited by 23 · see citing works
“…may be associated with higher risk of mortality and with higher risk of developing comorbidities such as cardiovascular disease and cancer risks ( Johnson et al , 2005; Karter et al, 2005; Nichols et al, 2005; Eurich et al , 2005a,b; Bowker et al , 2006, Simpson et al , 2006, Tzoulaki, 2009).”
BackgroundComparative safety of newer oral antidiabetic drugs
Krentz, A. J. (2006) · Expert Opinion on Drug Safety · doi:10.1517/14740338.5.6.827 · Cited by 24 · see citing works
“A recent study used data from Saskatchewan Health (1991 – 1999) on 5795 subjects, mean age 66 years, identified by their first-ever dispensation for an oral antidiabetic agent [9].”
MethodLange, M., Szabó, C., Aken, H. V., Williams, W., Traber, D. L., Daudel, F., Bröking, K., Salzman, A. L., Bone, H.-G., & Westphal, M. (2006) · Shock · doi:10.1097/01.shk.0000228795.33421.45 · Cited by 23 · see citing works
“Furthermore, recent investigations provide evidence that administration of sulfonylureas is associated with an increased risk of cardiovascular death in patients with cardiovascular diseases (34, 35) but not in patients without (36).”
BackgroundThe Infamous, Famous Sulfonylureas and Cardiovascular Safety: Much Ado About Nothing?
Pop, L. M., & Lingvay, I. (2017) · Current Diabetes Reports · doi:10.1007/s11892-017-0954-4 · Cited by 23 · see citing works
Is There Evidence That Oral Hypoglycemic Agents Reduce Cardiovascular Morbidity or Mortality? No
Kassem, S., & Raz, I. (2009) · Diabetes Care · doi:10.2337/dc09-s335 · Cited by 21 · see citing works
“However, this change did not reach statistical significance (17).”
BackgroundTreating the elderly diabetic patient: special considerations
Barski, L., Kezerle, L., & Shalev, L. (2014) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s48898 · Cited by 21 · see citing works
Simard, P., Presse, N., Roy, L. F., Dorais, M., White‐Guay, B., Räkel, A., & Perreault, S. (2017) · Annals of Pharmacotherapy · doi:10.1177/1060028017743517 · Cited by 21 · see citing works
“In fact, only 1 study, primarily focused on sulfonylurea, reported incidental data on metformin, suggesting no significant association between adherence and all-cause mortality.(9) In the past 10 years, a number of observational studies reported lower mortality rates after 1.”
Abdelmoneim, A. S., Eurich, D. T., Senthilselvan, A., Qiu, W., & Simpson, S. H. (2016) · Pharmacoepidemiology and Drug Safety · doi:10.1002/pds.4014 · Cited by 20 · see citing works
Mata‐Cases, M. (2014) · Journal of Diabetes & Metabolism · doi:10.4172/2155-6156.1000338 · Cited by 20 · see citing works
Santamarina, M. L., & Carlson, C. J. (2019) · BMC Cardiovascular Disorders · doi:10.1186/s12872-019-1036-0 · Cited by 20 · see citing works
Oral Glyburide, But Not Glimepiride, Blocks the Infarct-Size Limiting Effects of Pioglitazone
Ye, Y., Lin, Y., Perez-Polo, J. R., & Birnbaum, Y. (2008) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-008-6138-3 · Cited by 20 · see citing works
“reported that use of high-doses of Glyb was associated with higher risk of death among patients newly treated for type 2 DM [68].”
BackgroundSULLIVAN, D. R., Forder, P., Simes, J. R., Whiting, M. J., Kritharides, L., Merrifield, A., Donoghoe, M. W., Colman, P. G., Graham, N. M. H., Haapamäki, H., et al. (2011) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2011.07.028 · Cited by 19 · see citing works
“[22] Simpson S, Majumdar S, Tsuyuki R, Eurich D, Johnson J.”
Background
- Authors
- Simpson, S. H.
- Affiliations
- University of Alberta (CA)
- Corresponding author
- Simpson, S. H.
- ORCID
- Simpson, S. H.
- Venue
- Canadian Medical Association Journal
- Publisher
- CMA Joule Inc.
- Published
- 2006-01-17
- Volume
- 174
- Issue
- 2
- Pages
- 169-174
- ISSN
- 0820-3946 (ISSN-L)
- 1488-2329
- PMC
- PMC1329454
- OpenAlex
- W2090414284
- Cited by
- 235
- References
- 45
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 8 · 2023: 3 · 2022: 4 · 2021: 5 · 2020: 5 · 2019: 5 · 2018: 7 · 2017: 16 · 2016: 11 · 2015: 17 · 2014: 16 · 2013: 15 · 2012: 16
- FWCI
- 16.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Canadian Medical Association Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Alberta
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- sulfonylureas, type 2 diabetes, all-cause mortality, dose-response relationship, glibenclamide, metformin, acute ischemic events, oral antidiabetic drugs, drug safety, blood glucose reduction
- MeSH terms
- Aged, Blood Glucose, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Retrospective Studies, Sulfonylurea Compounds, Cohort Studies
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