Background: Due to several limitations in the study designs of sulfonylurea pharmacogenomics studies, we investigated the clinical and genetic predictors of secondary sulfonylurea failure in Type 2 diabetes patients. Materials & methods: Patients receiving the maximum sulfonylurea and metformin doses for >1 year were enrolled. Secondary sulfonylurea failure was defined as HbA1c >7.0% (>53 mmol/mol) after a 12-month follow-up. Results: By multivariate analysis, increased insulin resistance (HOMA2-IR), baseline HbA1c >7.0%, residing in eastern Peninsular Malaysia, and the CC genotype of rs757110 ABCC8 gene polymorphism were independent predictors of secondary sulfonylurea failure (p < 0.05) while sulfonylurea-induced hypoglycemia was protective against such failure (p < 0.05). Conclusion: Sulfonylurea does not benefit patients with an increased risk of secondary sulfonylurea failure.

Keywords:

Papers of special note have been highlighted as: •• of considerable interest

References

1. Cho NH, Shaw JE, Karuranga S et al. IDF Diabetes Atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res. Clin. Pract. 138, 271–281 (2018).
Medline CASGoogle Scholar
2. American Diabetes Association. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes – 2020. Diabetes Care 43(Suppl. 1), S98–S110 (2020).
MedlineGoogle Scholar
3. Khunti K, Chatterjee S, Gerstein HC, Zoungas S, Davies MJ. Do sulphonylureas still have a place in clinical practice? Lancet Diabetes Endocrinol. 6, 821–832 (2018).
Medline CASGoogle Scholar
4. Song J, Yang Y, Mauvais-Jarvis F, Wang Y-P, Niu T. KCNJ11, ABCC8 and TCF7L2 polymorphisms and the response to sulfonylurea treatment in patients with Type 2 diabetes: a bioinformatics assessment. BMC Med. Genet. 18(1), 64 (2017). •• Shows association between sulphonylurea and CYP2C9*2 and CYP2C9*3 gene polymorphisms
MedlineGoogle Scholar
5. Zhou K, Donnelly L, Burch L et al. Loss-of-function CYP2C9 variants improve therapeutic response to sulfonylureas in Type 2 diabetes: a Go-DARTS study. Clin. Pharmacol. Ther. 87(1), 52–56 (2010). •• Shows association between sulphonylurea and rs7756992 CDKAL1 gene polymorphism
Medline CASGoogle Scholar
6. Schroner Z, Javorsky M, Haluskova J et al. Variation in CDKAL1 gene is associated with therapeutic response to sulphonylureas. Physiol. Res. 61(2), 177–183 (2012). •• Paper that shows association between sulphonylurea and rs2237892 KCNQ1 gene polymorphism
Medline CASGoogle Scholar
7. Li Q, Tang T-T, Jiang F et al. Polymorphisms of the KCNQ1 gene are associated with the therapeutic responses of sulfonylureas in Chinese patients with Type 2 diabetes. Acta Pharmacol. Sin. 38(1), 80–89 (2017).
Medline CASGoogle Scholar
8. Halban PA, Polonsky KS, Bowden DW et al. β-cell failure in Type 2 diabetes: postulated mechanisms and prospects for prevention and treatment. Diabetes Care 37(6), 1751–1758 (2014).
MedlineGoogle Scholar
9. Maedler K, Carr RD, Bosco D, Zuellig RA, Berney T, Donath MY. Sulfonylurea induced β-cell apoptosis in cultured human islets. J. Clin. Endocrinol. Metab. 90(1), 501–506 (2005).
Medline CASGoogle Scholar
10. Efanova IB, Zaitsev SV, Zhivotovsky B et al. Glucose and tolbutamide induce apoptosis in pancreatic β-cells: a process dependent on intracellular Ca²⁺ concentration. J. Biol. Chem. 273(50), 33501–33507 (1998).
Medline CASGoogle Scholar
11. Takahashi A, Nagashima K, Hamasaki A et al. Sulfonylurea and glinide reduce insulin content, functional expression of K_ATP channels and accelerate apoptotic β-cell death in the chronic phase. Diabetes Res. Clin. Pract. 77(3), 343–350 (2007).
Medline CASGoogle Scholar
12. Matthews DR, Cull CA, Stratton IM, Holman RR, Turner RC. UKPDS 26: sulphonylurea failure in non-insulin-dependent diabetic patients over six years. Diabet. Med. 15(4), 297–303 (1998).
Medline CASGoogle Scholar
13. Pearson ER, Donnelly LA, Kimber C et al. Variation in TCF7L2 influences therapeutic response to sulfonylureas. Diabetes 56(8), 2178–2182 (2007). •• Shows association between sulphonylurea and rs757110 ABCC8 gene polymorphism
Medline CASGoogle Scholar
14. Feng Y, Mao G, Ren X et al. Ser1369Ala variant in sulfonylurea receptor gene ABCC8 is associated with antidiabetic efficacy of gliclazide in Chinese Type 2 diabetic patients. Diabetes Care 31(10), 1939–1944 (2008). •• Shows association between sulphonylurea and rs7903146 TCF7L2 gene polymorphism
Medline CASGoogle Scholar
15. Holstein A, Hahn M, Korner A, Stumvoll M, Kovacs P. TCF7L2 and therapeutic response to sulfonylureas in patients with Type 2 diabetes. BMC Med. Genet. 12, 30 (2011). •• Shows association between sulphonylurea and rs5219 KCNJ11 gene polymorphism
Medline CASGoogle Scholar
16. Sesti G, Laratta E, Cardellini M et al. The E23K variant of KCNJ11 encoding the pancreatic beta-cell adenosine 5′-triphosphate-sensitive potassium channel subunit Kir6.2 is associated with an increased risk of secondary failure to sulfonylurea in patients with Type 2 diabetes. J. Clin. Endocrinol. Metab. 91(6), 2334–2339 (2006).
Medline CASGoogle Scholar
17. El-Sisi AE, Hegazy SK, Metwally SS, Wafa AM, Dawood NA. Effect of genetic polymorphisms on the development of secondary failure to sulfonylurea in Egyptian patients with Type 2 diabetes. Ther. Adv. Endocrinol. Metab. 2(4), 155–164 (2011).
Medline CASGoogle Scholar
18. Shimajiri Y, Yamana A, Morita S, Furuta H, Furuta M, Sanke T. Kir6.2 E23K polymorphism is related to secondary failure of sulfonylureas in non-obese patients with Type 2 diabetes. J. Diabetes Investig. 4(5), 445–449 (2013).
Medline CASGoogle Scholar
19. Loganadan NK, Huri HZ, Vethakkan SR, Hussein Z. Genetic markers predicting sulphonylurea treatment outcomes in Type 2 diabetes patients: current evidence and challenges for clinical implementation. Pharmacogenomics J. 16(3), 209–219 (2016). •• Paper that shows association between sulphonylurea and rs757110 ABCC8 gene polymorphism
Medline CASGoogle Scholar
20. Zhang H, Liu X, Kuang H, Yi R, Xing H. Association of sulfonylurea receptor 1 genotype with therapeutic response to gliclazide in Type 2 diabetes. Diabetes Res. Clin. Pract. 77(1), 58–61 (2007).
Medline CASGoogle Scholar
21. Ministry of Health Malaysia. Clinical practice guidelines management of Type 2 diabetes mellitus (5th edition). (2015). http://www.moh.gov.my/penerbitan/CPG/CPG%20T2DM%202015.pdf
Google Scholar
22. Al-Qazaz HK, Hassali MA, Shafie AA, Sulaiman SaS, Sundram S. The 14-item Michigan Diabetes Knowledge Test: translation and validation study of the Malaysian version. Pract. Diabetes Intl 27(6), 238–241a (2010).
Google Scholar
23. Hasanah CI, Naing L, Rahman AR. World Health Organization quality of life assessment: brief version in Bahasa Malaysia. Med. J. Malaysia 58(1), 79–88 (2003).
Medline CASGoogle Scholar
24. Diabetes Trials Unit. HOMA calculator (1 May 2015). (2013). https://www.dtu.ox.ac.uk/homacalculator/
Google Scholar
25. Khunti S, Khunti K, Seidu S. Therapeutic inertia in Type 2 diabetes: prevalence, causes, consequences and methods to overcome inertia. Ther. Adv. Endocrinol. Metab. 10, 2042018819844694 (2019).
Google Scholar
26. Khunti K, Wolden ML, Thorsted BL andersen M, Davies MJ. Clinical inertia in people with Type 2 diabetes: a retrospective cohort study of more than 80,000 people. Diabetes Care 36(11), 3411–3417 (2013).
Medline CASGoogle Scholar
27. Khunti K, Seidu S. Therapeutic inertia and the legacy of dysglycemia on the microvascular and macrovascular complications of diabetes. Diabetes Care 42(3), 349–351 (2019).
MedlineGoogle Scholar
28. Ng YP, Ahmed R, Ooi GS, Lau CY, Balasubramanian GP, Yap CH. The rate of progression of Type 2 diabetes mellitus to end stage renal disease – a single centred retrospective study from Malaysia. Diabetes Metab. Syndr. 12(6), 1025–1030 (2018).
MedlineGoogle Scholar
29. Abu Hassan H, Tohid H, Mohd Amin R, Long Bidin MB, Muthupalaniappen L, Omar K. Factors influencing insulin acceptance among Type 2 diabetes mellitus patients in a primary care clinic: a qualitative exploration. BMC Family Pract. 14(1), 164 (2013).
MedlineGoogle Scholar
30. Lee YK, Lee PY, Ng CJ. A qualitative study on healthcare professionals' perceived barriers to insulin initiation in a multi-ethnic population. BMC Family Pract. 13(1), 28 (2012).
MedlineGoogle Scholar
31. Tan WL, Asahar SF, Harun NL. Insulin therapy refusal among type II diabetes mellitus patients in Kubang Pasu district, the state of Kedah, Malaysia. Singapore Med. J. 56(4), 224–227 (2015).
MedlineGoogle Scholar
32. Lee YK, Ng CJ, Lee PY et al. What are the barriers faced by patients using insulin? A qualitative study of Malaysian health care professionals' views. Patient Prefer. Adherence 7, 103–109 (2013).
MedlineGoogle Scholar
33. Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell 148(5), 852–871 (2012).
Medline CASGoogle Scholar
34. Yoon K-H, Lee J-H, Kim J-W et al. Epidemic obesity and Type 2 diabetes in Asia. Lancet 368(9548), 1681–1688 (2006).
MedlineGoogle Scholar
35. Ukpds Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with Type 2 diabetes (UKPDS 33). Lancet 352(9131), 837–853 (1998).
MedlineGoogle Scholar
36. Group TaC. Intensive blood glucose control and vascular outcomes in patients with Type 2 diabetes. N. Engl. J. Med. 358(24), 2560–2572 (2008).
MedlineGoogle Scholar
37. Group TaTCCRIDS. Effects of intensive glucose lowering in Type 2 diabetes. N. Engl. J. Med. 358(24), 2545–2559 (2008).
MedlineGoogle Scholar
38. Hussein Z, Kamaruddin NA, Chan SP, Jain A, Uppal S, Bebakar WMW. Hypoglycemia awareness among insulin-treated patients with diabetes in Malaysia: a cohort subanalysis of the HAT study. Diabetes Res. Clin. Pract. 133, 40–49 (2017). •• Shows association between sulphonylurea and rs757110 ABCC8 gene polymorphism
Medline CASGoogle Scholar
39. Hamming KSC, Soliman D, Matemisz LC et al. Coexpression of the Type 2 diabetes susceptibility gene variants KCNJ11 E23K and ABCC8 S1369A alter the ATP and sulfonylurea sensitivities of the ATP-sensitive K⁺ channel. Diabetes 58(10), 2419–2424 (2009). •• Shows association between sulphonylurea and rs5219 KCNJ11 gene polymorphism
Medline CASGoogle Scholar
40. Villareal DT, Koster JC, Robertson H et al. Kir6.2 variant E23K increases ATP-sensitive K⁺ channel activity and is associated with impaired insulin release and enhanced insulin sensitivity in adults with normal glucose tolerance. Diabetes 58(8), 1869–1878 (2009). •• Shows association between sulphonylurea and rs7756992 CDKAL1 gene polymorphism
Medline CASGoogle Scholar
41. Chistiakov D, Potapov VA, Smetanina SA, Bel'chikova LN, Suplotova LA, Nosikov VV. The carriage of risk variants of CDKAL1 impairs beta-cell function in both diabetic and non-diabetic patients and reduces response to non-sulfonylurea and sulfonylurea agonists of the pancreatic KATP channel. Acta Diabetol. 48(3), 227–235 (2011). •• Shows association between sulphonylurea and rs163184 KCNQ1 gene polymorphism
Medline CASGoogle Scholar
42. Schroner Z, Dobrikova M, Klimcakova L et al. Variation in KCNQ1 is associated with therapeutic response to sulphonylureas. Med. Sci. Monit. 17(7), Cr392–396 (2011).
Medline CASGoogle Scholar
43. Haghverdizadeh P, Sadat Haerian M, Haghverdizadeh P, Sadat Haerian B. ABCC8 genetic variants and risk of diabetes mellitus. Gene 545(2), 198–204 (2014).
Medline CASGoogle Scholar
44. Sokolova EA, Bondar IA, Shabelnikova OY, Pyankova OV, Filipenko ML. Replication of KCNJ11 (p.E23K) and ABCC8 (p.S1369A) association in Russian diabetes mellitus 2 Type cohort and meta-analysis. PLoS ONE 10(5), e0124662 (2015).
MedlineGoogle Scholar
45. Haghvirdizadeh P, Mohamed Z, Abdullah NA, Haghvirdizadeh P, Haerian MS, Haerian BS. KCNJ11: genetic polymorphisms and risk of diabetes mellitus. J. Diabetes Res. 2015, 908152 (2015).
MedlineGoogle Scholar

Vol. 21, No. 9

Supplemental Materials

Metrics

Downloaded 155 times

History

Received 18 November 2019

Accepted 23 March 2020

Published online 29 May 2020

Published in print June 2020

Information

Keywords

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/pgs-2019-0171

Author contributions

NK Loganadan designed and conducted the study, analyzed the data and wrote the manuscript. HZ Huri, SR Vethakkan and Z Hussein provided advice regarding study design and manuscript revisions. All authors reviewed and approved the final manuscript. HZ Huri assumed the final responsibility of submitting the manuscript for publication.

Acknowledgments

The authors would like to thank K Chinna from the University of Malaya for his assistance in the statistical analysis. We also appreciate the cooperation of the heads of the out-patient clinics where patients were recruited, in addition to the patients, study nurses and laboratory officers.

Financial & competing interests disclosure

This research was funded by the University of Malaya through the University of Malaya Research Grant (no. RP024-14HTM) and Postgraduate Research Grant (no. PG056-2014A). The funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. NK Loganadan, HZ Huri and SR Vethakkan received grants from the University of Malaya during the performance of this study. NK Loganadan also received the Doctor of Philosophy scholarship from Ministry of Health, Malaysia. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

This study was approved by the Medical Research Ethics Committee of the Ministry of Health, Malaysia (approval reference no. (13)KKM/NIHSEC/P14-1055) and the Medical Ethics Committee of University of Malaya Medical Centre (approval reference no. 1059.6). The study was conducted following the principles outlined in the Declaration of Helsinki for all human investigations. In addition, informed consent has been obtained from the participants involved in the investigations involving human subjects.

PDF download