NON-SEVERE HYPOGLYCEMIA RISK DIFFERENCE BETWEEN SULFONYLUREA AND SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS (SGLT2-I) AS AN ADD-ON TO METFORMIN IN RANDOMIZED CONTROLLED TRIALS
Main Article Content
Keywords
diabetes, sulfonylurea, SGLT2-I, hypoglycemia, risk
Abstract
Background
Non-severe hypoglycemia reduces well-being, lowers quality of life, reduces productivity and increases treatment costs. The non-severe hypoglycemia rate, attributable to sulfonylurea (SU) utilization compared with newer classes such as SGLT2-I, could be of clinical significance.
Objective
To explore the non-severe hypoglycemia risk difference (RD) for SU use compared with SGLT2-I in randomized controlled trials (RCTs) as an add on to metformin.
Methods
A search was conducted for RCTs of SGLT2-I. The PubMed database was utilized for this search. The search was limited to RCTs reported in English language for canagliflozin, dapagliflozin, and empagliflozin. SU dose comparison was utilized to convert the dose of SUs to glimepiride equivalent doses.
Results
In total, 118 RCTs were reviewed; 6 articles had an arm for a SU as add on to metformin. Six articles belong to 3 RCTs, which reported results for 52 weeks and 104 weeks. Average non-severe hypoglycemia rate for SU arm was 30% (5.5%) [Mean (SD)] for 52 weeks and 35.6% (6.1%) for 104 weeks. RD for non-severe hypoglycemia events for SU compared to SGLT2-I was 26.7% (4.9%) for 52 weeks ( p-value less than 0.001) and 30.6% (5.5%) for 104 weeks (p-value less than 0.001). There was a significant correlation between dose of SU and hypoglycemia rate (Pearson correlation 0.995; R-square 99%).
Conclusion
This study illustrated that a large proportion of patients who had exposure to SU in RCTs of SGLT2-I experienced non-severe hypoglycemia compared to SGLT2-I. There was a close relation between SU dose and increased probability of non-severe hypoglycemia events.
Non-severe hypoglycemia reduces well-being, lowers quality of life, reduces productivity and increases treatment costs. The non-severe hypoglycemia rate, attributable to sulfonylurea (SU) utilization compared with newer classes such as SGLT2-I, could be of clinical significance.
Objective
To explore the non-severe hypoglycemia risk difference (RD) for SU use compared with SGLT2-I in randomized controlled trials (RCTs) as an add on to metformin.
Methods
A search was conducted for RCTs of SGLT2-I. The PubMed database was utilized for this search. The search was limited to RCTs reported in English language for canagliflozin, dapagliflozin, and empagliflozin. SU dose comparison was utilized to convert the dose of SUs to glimepiride equivalent doses.
Results
In total, 118 RCTs were reviewed; 6 articles had an arm for a SU as add on to metformin. Six articles belong to 3 RCTs, which reported results for 52 weeks and 104 weeks. Average non-severe hypoglycemia rate for SU arm was 30% (5.5%) [Mean (SD)] for 52 weeks and 35.6% (6.1%) for 104 weeks. RD for non-severe hypoglycemia events for SU compared to SGLT2-I was 26.7% (4.9%) for 52 weeks ( p-value less than 0.001) and 30.6% (5.5%) for 104 weeks (p-value less than 0.001). There was a significant correlation between dose of SU and hypoglycemia rate (Pearson correlation 0.995; R-square 99%).
Conclusion
This study illustrated that a large proportion of patients who had exposure to SU in RCTs of SGLT2-I experienced non-severe hypoglycemia compared to SGLT2-I. There was a close relation between SU dose and increased probability of non-severe hypoglycemia events.
References
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2. Kalra S, Mukherjee JJ, Venkataraman S et al. Hypoglycemia: The neglected complication. Indian J Endocrinol Metab 2013;17:819–34.
3. Williams SA, Shi L, Brenneman SK, Johnson JC, Wegner JC, Fonseca V. The burden of hypoglycemia on healthcare utilization, costs, and quality of life among type 2 diabetes mellitus patients. J Diabetes Complicat 2012;26:399–406.
4. Fidler C, Elmelund CT, Gillard S. Hypoglycemia: an overview of fear of hypoglycemia, quality-of-life, and impact on costs. J Med Econ 2011;14:646–55.
5. Harris S, Mamdani M, Galbo-Jorgensen CB, Bogelund M, Gundgaard J, Groleau D. The effect of hypoglycemia on health-related quality of life: Canadian results from a multinational time trade-off survey. Can J Diabetes 2014;38:45–52.
6. Brod M, Wolden M, Christensen T, Bushnell DM. A 9 country study of the burden of non-severe nocturnal hypoglycemic events on diabetes management and daily function. Diabetes Obes Metab 2013;15:546–57.
7. Brod M, Pohlman B, Wolden M, Christensen T. non-severe nocturnal hypoglycemic events: experience and impacts on patient functioning and well-being. Qual Life Res 2013;22:997–1004.
8. Canadian Diabetes Association. Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2013;37:S1–S212.
9. Inzucchi SE, Bergenstal RM, Buse JB et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2015;58:429–42.
10. No authors listed. Standards of medical care in diabetes--2015: summary of revisions. Diabetes Care 2015;38 Suppl: S4.
11. Pharmacist’s Letter. Sulfonylurea dose comparison. Pharmacist’s Letter/Prescriber’s Letter 2009;25(8):250801 2009.
12. Nauck MA, Del PS, Meier JJ et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care 2011;34:2015–2022.
13. Nauck MA, Del PS, Duran-Garcia S et al. Durability of glycaemic efficacy over 2 years with dapagliflozin versus glipizide as add-on therapies in patients whose type 2 diabetes mellitus is inadequately controlled with metformin. Diabetes Obes Metab 2014;16:1111–20.
14. Cefalu WT, Leiter LA, Yoon KH et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet 2013;382:941–50.
15. Leiter LA, Yoon KH, Arias P et al. Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: a randomized, double-blind, phase 3 study. Diabetes Care 2015;38:355–64.
16. Efficacy and Safety of Empagliflozin (BI 10773) With Metformin in Patients With Type 2 Diabetes. https://clinicaltrials gov/ct2/show/study/NCT01167881?term5NCT01167881&rank51 2016.
17. Ridderstrale M, Andersen KR, Zeller C, et al. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol 2014;2:691–700.
18. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27:1047-1053.
19. Canadian Diabetes Association. An economic tsunami: the cost of diabetes in Canada. http://www diabetes ca/economic report/ [serial online] 2009.
20. Canadian Diabetes Association. The prevalence and costs of diabetes. Available at: http://www diabetes ca/diabetes-and-you/what/prevalence/ [serial online] 2013.
21. Public Health Agency of Canada. Diabetes in Canada: Facts and figures from a public health perspective. Ottawa. Available at: http://www phac-aspc gc ca/cd-mc/publications/diabetes-diabete/facts-figures-faits-chiffres-2011/ [serial online] 2011.
22. Abdelhafiz AH, Rodriguez-Manas L, Morley JE, Sinclair AJ. Hypoglycemia in older people - a less well recognized risk factor for frailty. Aging Dis 2015;6:156–67.
23. Farahani P, Khan S, Oatway M, Dziarmaga A. Exploring the distribution of prescription for sulfonylureas in patients with type 2 diabetes according to cardiovascular risk factors within a Canadian primary care setting. J Popul Ther Clin Pharmacol 2015;22:e228–e236.
24. Greiver M, Williamson T, Barber D et al. Prevalence and epidemiology of diabetes in Canadian primary care practices: a report from the Canadian Primary Care Sentinel Surveillance Network. Can J Diabetes 2014;38:179–85.
25. Ostenson CG, Geelhoed-Duijvestijn P, Lahtela J, et al. Self-reported non-severe hypoglycaemic events in Europe. Diabet Med 2014;31:92–101.
26. Geelhoed-Duijvestijn PH, Pedersen-Bjergaard U, Weit-gasser R, et al. Effects of patient-reported non-severe hypoglycemia on healthcare resource use, work time loss, and wellbeing in insulin-treated patients with diabetes in 7 European countries. J Med Econ 2013;16:1453–61.
27. Brod M, Christensen T, Thomsen TL, Bushnell DM. The impact of non-severe hypoglycemic events on work productivity and diabetes management. Value Health 2011;14:665–71.
28. Jensen MM, Pedersen-Bjergaard U. Self-reported frequency and impact of non-severe hypoglycemic events in insulin-treated diabetic patients in Denmark. Diabetes Management 2015;5:67–78.
29. Kulzer B, Seitz L, Kern W. Real-world patient-reported rates of non-severe hypoglycaemic events in Germany. Exp Clin Endocrinol Diabetes 2014;122:167–72.
30. Weitgasser R, Lopes S. Self-reported frequency and impact of hypoglycaemic events in insulin-treated diabetic patients in Austria. Wien Klin Wochenschr 2015;127:36–44.
31. Canadian Agency for Drugs and Technologies in Health. Optimal Second- and Third-Line Therapy in Type 2 Diabetes. CADTH Report/Project in Briefs [Internet] Ottawa, ON: Author; 2011- 2013 Sep 2011.
32. Wendel CS, Fotieo GG, Shah JH, Felicetta J, Curtis BH, Murata GH. Incidence of non-severe hypoglycaemia and intensity of treatment among veterans with type 2 diabetes in the U.S.A.: a prospective observational study. Diabet Med 2014;31:1524–31.
33. Farahani P. Sulfonylurea and the Heart: Theoretically a compounded question from a pathophysiological perspective. J Popul Ther Clin Pharmacol 2016;23:e193–e195.
34. Simpson SH, Majumdar SR, Tsuyuki RT, Eurich DT, Johnson JA. Dose-response relation between sulfonylurea drugs and mortality in type 2 diabetes mellitus: a population-based cohort study. CMAJ 2006;174:169–74.
35. Yeh JS, Sung SH, Huang HM et al. Hypoglycemia and risk of vascular events and mortality: a systematic review and meta-analysis. Acta Diabetol 2016;53:377–92.
36. Soydan N, Bretzel RG, Fischer B, et al. Reduced capacity of heart rate regulation in response to mild hypoglycemia induced by glibenclamide and physical exercise in type 2 diabetes. Metabolism 2013;62:717–24.
37. Chow E, Bernjak A, Williams S et al. Risk of cardiac arrhythmias during hypoglycemia in patients with type 2 diabetes and cardiovascular risk. Diabetes 2014;63:1738–47.
38. Endocrinenews.org. HYPOGLYCEMIA QUALITY COLLABORATIVE STRATEGIC BLUEPRINT. http://endocrinenews endocrine org/wp-content/uploads/HQC_Strategic_Blueprint_VIEW pdf 2016.
2. Kalra S, Mukherjee JJ, Venkataraman S et al. Hypoglycemia: The neglected complication. Indian J Endocrinol Metab 2013;17:819–34.
3. Williams SA, Shi L, Brenneman SK, Johnson JC, Wegner JC, Fonseca V. The burden of hypoglycemia on healthcare utilization, costs, and quality of life among type 2 diabetes mellitus patients. J Diabetes Complicat 2012;26:399–406.
4. Fidler C, Elmelund CT, Gillard S. Hypoglycemia: an overview of fear of hypoglycemia, quality-of-life, and impact on costs. J Med Econ 2011;14:646–55.
5. Harris S, Mamdani M, Galbo-Jorgensen CB, Bogelund M, Gundgaard J, Groleau D. The effect of hypoglycemia on health-related quality of life: Canadian results from a multinational time trade-off survey. Can J Diabetes 2014;38:45–52.
6. Brod M, Wolden M, Christensen T, Bushnell DM. A 9 country study of the burden of non-severe nocturnal hypoglycemic events on diabetes management and daily function. Diabetes Obes Metab 2013;15:546–57.
7. Brod M, Pohlman B, Wolden M, Christensen T. non-severe nocturnal hypoglycemic events: experience and impacts on patient functioning and well-being. Qual Life Res 2013;22:997–1004.
8. Canadian Diabetes Association. Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2013;37:S1–S212.
9. Inzucchi SE, Bergenstal RM, Buse JB et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2015;58:429–42.
10. No authors listed. Standards of medical care in diabetes--2015: summary of revisions. Diabetes Care 2015;38 Suppl: S4.
11. Pharmacist’s Letter. Sulfonylurea dose comparison. Pharmacist’s Letter/Prescriber’s Letter 2009;25(8):250801 2009.
12. Nauck MA, Del PS, Meier JJ et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care 2011;34:2015–2022.
13. Nauck MA, Del PS, Duran-Garcia S et al. Durability of glycaemic efficacy over 2 years with dapagliflozin versus glipizide as add-on therapies in patients whose type 2 diabetes mellitus is inadequately controlled with metformin. Diabetes Obes Metab 2014;16:1111–20.
14. Cefalu WT, Leiter LA, Yoon KH et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet 2013;382:941–50.
15. Leiter LA, Yoon KH, Arias P et al. Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: a randomized, double-blind, phase 3 study. Diabetes Care 2015;38:355–64.
16. Efficacy and Safety of Empagliflozin (BI 10773) With Metformin in Patients With Type 2 Diabetes. https://clinicaltrials gov/ct2/show/study/NCT01167881?term5NCT01167881&rank51 2016.
17. Ridderstrale M, Andersen KR, Zeller C, et al. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol 2014;2:691–700.
18. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27:1047-1053.
19. Canadian Diabetes Association. An economic tsunami: the cost of diabetes in Canada. http://www diabetes ca/economic report/ [serial online] 2009.
20. Canadian Diabetes Association. The prevalence and costs of diabetes. Available at: http://www diabetes ca/diabetes-and-you/what/prevalence/ [serial online] 2013.
21. Public Health Agency of Canada. Diabetes in Canada: Facts and figures from a public health perspective. Ottawa. Available at: http://www phac-aspc gc ca/cd-mc/publications/diabetes-diabete/facts-figures-faits-chiffres-2011/ [serial online] 2011.
22. Abdelhafiz AH, Rodriguez-Manas L, Morley JE, Sinclair AJ. Hypoglycemia in older people - a less well recognized risk factor for frailty. Aging Dis 2015;6:156–67.
23. Farahani P, Khan S, Oatway M, Dziarmaga A. Exploring the distribution of prescription for sulfonylureas in patients with type 2 diabetes according to cardiovascular risk factors within a Canadian primary care setting. J Popul Ther Clin Pharmacol 2015;22:e228–e236.
24. Greiver M, Williamson T, Barber D et al. Prevalence and epidemiology of diabetes in Canadian primary care practices: a report from the Canadian Primary Care Sentinel Surveillance Network. Can J Diabetes 2014;38:179–85.
25. Ostenson CG, Geelhoed-Duijvestijn P, Lahtela J, et al. Self-reported non-severe hypoglycaemic events in Europe. Diabet Med 2014;31:92–101.
26. Geelhoed-Duijvestijn PH, Pedersen-Bjergaard U, Weit-gasser R, et al. Effects of patient-reported non-severe hypoglycemia on healthcare resource use, work time loss, and wellbeing in insulin-treated patients with diabetes in 7 European countries. J Med Econ 2013;16:1453–61.
27. Brod M, Christensen T, Thomsen TL, Bushnell DM. The impact of non-severe hypoglycemic events on work productivity and diabetes management. Value Health 2011;14:665–71.
28. Jensen MM, Pedersen-Bjergaard U. Self-reported frequency and impact of non-severe hypoglycemic events in insulin-treated diabetic patients in Denmark. Diabetes Management 2015;5:67–78.
29. Kulzer B, Seitz L, Kern W. Real-world patient-reported rates of non-severe hypoglycaemic events in Germany. Exp Clin Endocrinol Diabetes 2014;122:167–72.
30. Weitgasser R, Lopes S. Self-reported frequency and impact of hypoglycaemic events in insulin-treated diabetic patients in Austria. Wien Klin Wochenschr 2015;127:36–44.
31. Canadian Agency for Drugs and Technologies in Health. Optimal Second- and Third-Line Therapy in Type 2 Diabetes. CADTH Report/Project in Briefs [Internet] Ottawa, ON: Author; 2011- 2013 Sep 2011.
32. Wendel CS, Fotieo GG, Shah JH, Felicetta J, Curtis BH, Murata GH. Incidence of non-severe hypoglycaemia and intensity of treatment among veterans with type 2 diabetes in the U.S.A.: a prospective observational study. Diabet Med 2014;31:1524–31.
33. Farahani P. Sulfonylurea and the Heart: Theoretically a compounded question from a pathophysiological perspective. J Popul Ther Clin Pharmacol 2016;23:e193–e195.
34. Simpson SH, Majumdar SR, Tsuyuki RT, Eurich DT, Johnson JA. Dose-response relation between sulfonylurea drugs and mortality in type 2 diabetes mellitus: a population-based cohort study. CMAJ 2006;174:169–74.
35. Yeh JS, Sung SH, Huang HM et al. Hypoglycemia and risk of vascular events and mortality: a systematic review and meta-analysis. Acta Diabetol 2016;53:377–92.
36. Soydan N, Bretzel RG, Fischer B, et al. Reduced capacity of heart rate regulation in response to mild hypoglycemia induced by glibenclamide and physical exercise in type 2 diabetes. Metabolism 2013;62:717–24.
37. Chow E, Bernjak A, Williams S et al. Risk of cardiac arrhythmias during hypoglycemia in patients with type 2 diabetes and cardiovascular risk. Diabetes 2014;63:1738–47.
38. Endocrinenews.org. HYPOGLYCEMIA QUALITY COLLABORATIVE STRATEGIC BLUEPRINT. http://endocrinenews endocrine org/wp-content/uploads/HQC_Strategic_Blueprint_VIEW pdf 2016.