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#202 Sulfonylureas in Diabetes: Sweet on the Heart or Surrogate Charlatan?

Does treating type 2 diabetes with sulfonylureas affect mortality or cardiovascular events?

There is a lack of convincing evidence that sulfonylureas reduce cardiovascular events or mortality in type 2 diabetic patients. If anything, sulfonylureas potentially increase cardiovascular harm. 

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Sulfonylurea versus placebo: 
  • Most Randomized Controlled Trials (RCTs) investigate HbA1c, not patient-oriented outcomes.1-5 
  • Largest RCT for patient outcomes (n=409), ~5 years, tolbutamide versus placebo:6,7 
    • Non-significant: All-cause mortality (14.7% versus 10.2%), myocardial infarction (13.7% versus 10.7%). 
    • Significant increase: Cardiovascular (CV) mortality (12.7% versus 4.9%), Number Needed to Harm (NNH)=13. 
    • Limitations: Possible randomization imbalance, smoking not included in baseline demographics, first generation sulfonylurea. 
Sulfonylurea versus metformin: 
  • RCT (n=304) five years, patients with coronary artery disease, mean HbA1c 7.6%, glipizide versus metformin:8 
    • Sulfonylureas increased composite CV events: 35% versus 25%, NNH=10. 
  • RCT (n=2,895), four years, mean HbA1c 7.4%, glyburide versus metformin:9
    • Non-significant: All-cause mortality (2.2% versus 2.1%), total CV events (2.9% versus 4.0%). 
    • Limitations: ~40% withdrew after randomization. 
  • Systematic review: No other RCTs with more than one death.10 
Sulfonylurea added to metformin:  
  • RCT (n=3028), ~5 years, sulfonylurea versus pioglitazone: 
    • No difference in CV events.11 
  • Other studies reported CV events or mortality as adverse events:  
    • Sulfonylurea versus DPP-4 inhibitors:  
      • No difference in death:12 0.5% versus 0.4%. 
      • Major CV events:13 3.4% versus 1.5%, NNH=53. 
    • Versus other drugs:  
      • Studies underpowered to find a difference in patient outcomes compared to GLP-1 agonists, SGLT2 inhibitors, or insulin.14,15,16    
  • Two systematic reviews of observational studies report increased CV risk with sulfonylureas, however multiple confounders limit conclusions.17,18   
  • UKPDS is frequently cited to support sulfonylureas, but confounded by use of insulin.19 
  • CV disease causes ~50% of diabetes type 2 deaths.20 
  • Sulfonylureas increase risk of severe hypoglycemia (<1% overall) and weight gain (~2.1kg).21 
  • We need to think critically about the use of sulfonylureas beyond HbA1C reduction (~0.8%) and low cost.21

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  • Christina Korownyk MD CCFP
  • Joey Ton PharmD
  • Kirstin Bester BSc

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2. Hoffman J, Spengler M. Diabetes Care. 1994; 17(6):561-6.

3. Kovacevic I, Profozic V, Skrabalo Z, et al. Diabetologia Croatica. 1997; 26(2):83-9.

4. Roberts V, Stewart J, Issa M, et al. Clin Ther. 2005; 27(10):1535-47.

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6. The University Group Diabetes Program. Diabetes. 1970; 19(2):747-830.

7. The University Group Diabetes Program. Diabetes. 1976; 25:1129-53.

8. Hong J, Zhang Y, Lai S, et al. Diabetes Care. 2013; 36(5):1304-11.

9. Kahn SE, Haffner SM, Heise MA, et al. N Engl J Med. 2006; 355(23):2427-43.

10. Hemmingsen B, Schroll JB, Wetterslev J, et al. CMAJ Open. 2014; 2(3):E162-75.

11. Vaccaro O, Masulli M, Nicolucci A, et al. Lancet Diabetes Endocrinol. 2017; S2213-8587(17)30317-0. [Epub ahead of print].

12. Karagiannis T, Paschos P, Paletas K, et al. BMJ. 2012; 12(344):e1369.

13. Gallwitz B, Rosenstock J, Rauch T, et al. Lancet. 2012; 380:475-83.

14. Gallwitz B, Guzman J, Dotta F, et al. Lancet. 2012; 379:2270-8.

15. Leiter LA, Yoon KH, Arias P, et al. Diabetes Care. 2015; 38(3):355-64.

16. Moon J, Ha K, Yoon J, et al. Acta Diabetol. 2014; 51(2):277-85.

17. Forst T, Hanefeld M, Jacob S, et al. Diab Vasc Dis Res. 2013; 10(4):302-14.

18. Phung OJ, Schwartzman E, Allen RW, et al. Diabet Med. 2013; 30(10):1160-71.

19. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998; 352:837-53.

20. Bruno G, Ferrero S, Biggeri A, et al. Diabetes Care. 2003; 26:2353-8.

21. The Institute for Clinical and Economic Review. Controversies in the Management of Patients with Type 2 Diabetes. Available at: Last Accessed: July 1, 2017.

Authors do not have any conflicts of interest to declare.