ASSOCIATION OF SIMVASTATIN USE WITH GLYCEMIC CONTROL IN TYPE 2 DIABETES PATIENTS RECEIVING ORAL ANTIHYPERGLYCEMIC THERAPY AND IN NON-DIABETIC SUBJECTS

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(1)M. al. ay. a. ASSOCIATION OF SIMVASTATIN USE WITH GLYCEMIC CONTROL IN TYPE 2 DIABETES PATIENTS RECEIVING ORAL ANTIHYPERGLYCEMIC THERAPY AND IN NON-DIABETIC SUBJECTS. U. ni. ve r. si. ty. of. NOR RAZIDA BINTI RAZALI. FACULTY OF MEDICINE UNIVERSITY OF MALAYA KUALA LUMPUR 2018.

(2) M. al. ay. a. ASSOCIATION OF SIMVASTATIN USE WITH GLYCEMIC CONTROL IN TYPE 2 DIABETES PATIENTS RECEIVING ORAL ANTIHYPERGLYCEMIC THERAPY AND IN NON-DIABETIC SUBJECTS. si. ty. of. NOR RAZIDA BINTI RAZALI. U. ni. ve r. DISSERTATION SUBMITTED IN FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF MEDICAL SCIENCE. FACULTY OF MEDICINE UNIVERSITY OF MALAYA KUALA LUMPUR. 2018.

(3) UNIVERSITY OF MALAYA ORIGINAL LITERARY WORK DECLARATION. Name of Candidate: Nor Razida binti Razali Matric No: MGN140009 Name of Degree: Master of Medical Science Title of Dissertation: Association of Simvastatin Use with Glycemic Control in Type 2 Diabetes Patients Receiving Oral Antihyperglycemic Therapy and in Non-diabetic. a. Subjects. I do solemnly and sincerely declare that:. al. ay. Field of Study: Clinical Pharmacy. U. ni. ve r. si. ty. of. M. (1) I am the sole author/writer of this Work; (2) This Work is original; (3) Any use of any work in which copyright exists was done by way of fair dealing and for permitted purposes and any excerpt or extract from, or reference to or reproduction of any copyright work has been disclosed expressly and sufficiently and the title of the Work and its authorship have been acknowledged in this Work; (4) I do not have any actual knowledge nor do I ought reasonably to know that the making of this work constitutes an infringement of any copyright work; (5) I hereby assign all and every rights in the copyright to this Work to the University of Malaya (“UM”), who henceforth shall be owner of the copyright in this Work and that any reproduction or use in any form or by any means whatsoever is prohibited without the written consent of UM having been first had and obtained; (6) I am fully aware that if in the course of making this Work I have infringed any copyright whether intentionally or otherwise, I may be subject to legal action or any other action as may be determined by UM. Candidate’s Signature. Date:. Subscribed and solemnly declared before, Witness’s Signature. Date:. Name: Designation:. ii.

(4) ASSOCIATION OF SIMVASTATIN USE WITH GLYCEMIC CONTROL IN TYPE 2 DIABETES PATIENTS RECEIVING ORAL ANTIHYPERGLYCEMIC THERAPY AND IN NON-DIABETIC SUBJECTS ABSTRACT Previous evidence shows the conflicting effect of simvastatin on glycemic control on type 2 diabetes (T2D) patients. Although the lipid-lowering benefits of simvastatin have been. a. shown to outweigh the risks, its potential impact on glycemic control in T2D is a major. ay. concern. Moreover, the effects of statins on glycemic control in T2D patients with multiple co-morbidities and other concomitant drugs have not been fully elucidated. The. al. purpose of this study is to evaluate the association of simvastatin use on glycemic control. M. in T2D patients receiving oral antihyperglycemic drugs (OADs) and compared it with simvastatin users without diabetes. This retrospective cross-sectional study was. of. conducted at University Malaya Medical Centre (UMMC) Kuala Lumpur. The glycemic. ty. control was indicated by fasting plasma glucose (FPG) and glycated hemoglobin (A1C).. si. A total of 418 eligible patients were included in this study with 209 patients in the diabetic and the non-diabetic groups respectively. The mean duration of simvastatin use in diabetic. ve r. was 11.3 ± 6.54 months whilst the non-diabetic group was 11.7 ± 7.03 months. This study found that T2D patients did not experience the impairment of glycemic control whilst on. ni. statins, compared to the non-diabetes patients. In the diabetic group, the FPG levels had. U. significantly decreased from 7.10 ± 1.49 mmol/L to 6.87 ± 1.41 mmol/L post simvastatin therapy (p = 0.041). The same trends were observed in A1C levels with a reduction from 7.18 ± 1.04% at the pre-simvastatin therapy to 6.98 ± 1.05% after the simvastatin therapy (p < 0.001). In contrast, the glycemic control in the non-diabetic group was significantly impaired with an increase in the FPG levels from 5.40 ± 0.66 mmol/L at the presimvastatin therapy to 5.51 ± 0.68 mmol/L post-therapy (p = 0.026) respectively. Besides that, the A1C levels at post simvastatin therapy 5.76 ± 0.5% was significantly higher. iii.

(5) compared to pre-therapy 5.69 ± 0.46% (p = 0.014). Furthermore, in the diabetic group, the results showed a positive correlation between the changes in the triglyceride levels and FPG (r = 0.219, p = 0.014); triglyceride levels and A1C (r = 0.242, p = 0.007) and a negative correlation between the changes in high density lipoprotein (HDL) cholesterol and A1C levels (r = - 0.189, p = 0.030). The correlate model indicated that the decreasing of triglyceride levels in the diabetic group was associated with the decreasing levels in. a. FPG (β = 0.22, t = 2.37, p = 0.019) and A1C (β = 0.24, t = 2.64, p = 0.009). This study. ay. proposed that the reduction of triglyceride levels in T2D patients on oral antihyperglycemic therapy after commencing simvastatin therapy was associated with the. al. improvement in glycemic control. The correlates models suggested that in the T2D. M. patients the decrease in triglyceride levels may be associated with the improvement of glucose parameters, indicating that the management treatments for both glycemic control. of. and lipid profile may play a crucial role to achieve the targeted glycemic levels following. ty. statins initiation.. si. Keywords: Simvastatin, Glycemic control, Diabetes, Oral antihyperglycemic therapy,. U. ni. ve r. Concurrent medication.. iv.

(6) HUBUNGAN PENGGUNAAN SIMVASTATIN DENGAN KAWALAN GLISEMIK DI KALANGAN PESAKIT DIABETES JENIS 2 YANG MENERIMA TERAPI ORAL ANTIHIPERGLISEMIK DAN DI KALANGAN SUBJEK TANPA DIABETES ABSTRAK. Bukti kajian lepas menunjukkan kesan terapi statin terhadap kawalan glisemik adalah. a. bercanggah di kalangan pesakit diabetes jenis 2. Kesan statin terhadap kawalan glisemik. ay. masih menjadi kebimbangan utama walaupun manfaat statin dalam menurunkan lipid. al. mengatasi risikonya. Selain itu, kesan statin terhadap kawalan glisemik pesakit diabetes. M. jenis 2 dengan pelbagai penyakit lain dan pengunaan ubat-ubatan serentak belum dapat dijelaskan sepenuhnya. Tujuan kajian ini adalah untuk menilai hubungan penggunaan. of. simvastatin terhadap kawalan glisemik pada pesakit diabetes jenis 2 yang mengambil terapi oral antihiperglisemik dan membandingkannya dengan pengguna simvastatin tanpa. ty. diabetes. Kajian keratan rentas retrospektif ini dijalankan di Pusat Perubatan Universiti. si. Malaya (PPUM) Kuala Lumpur. Bacaan kawalan glisemik adalah berdasarkan glukosa. ve r. plasma berpuasa dan hemoglobin glikasi (A1C). Sejumlah 418 pesakit yang memenuhi kriteria terlibat dalam kajian ini, dengan masing-masing 209 pesakit bagi kumpulan. ni. diabetes jenis 2 dan bukan diabetes. Tempoh min penggunaan simvastatin di kalangan. U. pesakit diabetes adalah 11.3 ± 6.54 bulan manakala kumpulan bukan diabetes adalah 11.7 ± 7.03 bulan. Selepas pengambilan terapi statin, kajian ini mendapati bahawa pesakit diabetes tidak mengalami penurunan glisemik berbanding pesakit bukan diabetes. Tahap glukosa plasma berpuasa berkurangan bagi kumpulan diabetes iaitu daripada 7.10 ± 1.49 mmol/L menurun kepada 6.87 ± 1.41 mmol/L pasca terapi simvastatin (p = 0.041). Trend yang sama dapat diperhatikan dalam tahap A1C dengan penurunan daripada 7.18 ± 1.04% kepada 6.98 ± 1.05% pasca terapi simvastatin (p <0.001). Sebaliknya, kawalan glisemik dalam kumpulan bukan diabetes terjejas dengan peningkatan paras glukosa plasma. v.

(7) berpuasa berbanding sebelum penggunaan terapi statin iaitu daripada 5.40 ± 0.66 mmol/L kepada 5.51 ± 0.68 mmol/L (p = 0.026). Selain itu, tahap A1C pasca terapi simvastatin 5.76 ± 0.5% jauh lebih tinggi daripada pra-terapi 5.69 ± 0.46% (p = 0.014). Tambahan pula, hasil kajian menunjukkan kumpulan diabetes mempunyai korelasi positif antara perubahan dalam kadar trigliserida dan glukosa plasma berpuasa (r = 0.219, p = 0.014); kadar trigliserida dan A1C (r = 0.242, p = 0.007), dan korelasi negatif antara perubahan. a. kolesterol lipoprotein ketumpatan tinggi dan tahap A1C (r = - 0.189, p = 0.030). Model. ay. korelasi menunjukkan kumpulan diabetes yang mengalami penurunan tahap trigliserida dikaitkan dengan penurunan dalam glukosa plasma berpuasa (β = 0.22, t = 2.37,. al. p = 0.019) dan A1C (β = 0.24, t = 2.64, p = 0.009). Kajian ini mencadangkan pengurangan. antihiperglisemik. selepas. M. tahap trigliserida dalam pesakit diabetes jenis 2 yang mengambil terapi oral dimulakan. terapi. simvastatin. dikaitkan. dengan. of. penambahbaikan kawalan glisemik. Model kaitan menunjukkan pesakit diabetes jenis 2. ty. mengalami penurunan tahap trigliserida yang dikaitkan dengan penambahbaikan. si. parameter glukosa. Keadaan ini menunjukkan selepas penggunaan terapi statin, pengurusan rawatan untuk kedua-dua kawalan glisemik dan profil lipid memainkan. ve r. peranan penting untuk mencapai sasaran tahap glisemik.. ni. Kata kunci: Simvastatin, Kawalan glisemik, Diabetes, Terapi oral antihiperglisemik,. U. Ubat-ubatan serentak.. vi.

(8) ACKNOWLEDGEMENTS. First and foremost, I would like to express my deepest gratitude to my respected supervisor, Prof. Dr. Hasniza Zaman Huri for her continuous guidance, patience, and enthusiasm. Her encouragement and kindness will always be remembered. I would like to extend my thanks to my co-supervisor, Dr. Luqman Ibrahim for providing me insightful suggestions and supports especially during the data collection process.. a. I would like to express my deepest appreciation to all the staff from the Department. ay. of Patients Information and Department of Information Technology, University of. al. Malaya Medical Centre (UMMC) especially Kak Su, Madam Akmam and Madam Alia. M. for helping me during the data collection process. Besides that, I would also like to extend my thanks to Dr. Ashraf (Research Medical Centre), Prof. Dr. Ananda Kumar (Faculty of. of. Education), Miss Ranita (T.J Danaraj Library), Dr. Nany and Madam Syazana Umar (former staff from Clinical Investigation Centre of UMMC) for their assistance and. ty. immense knowledge during the accomplishment of this study. Furthermore, thank you to. si. all my friends; Bahirah, Geetha, Miza, Kak Mas, Kak Rif, Kak Vee, Kak Effy and Kak. ve r. Zaini for their constant support and assistance in ensuring that this dissertation is completed with ease.. ni. Finally, my deepest gratitude goes to my family members for their unflagging love. U. and support throughout my life. I am indebted to my parents, Mr. Razali bin Abd. Rahaman and Madam Che Meryam binti Yusof for their love, prayers, financial support and motivational towards my higher achievements in academic. Thank you to all my family members; Razima Razali, Badrol Othman, Razimi Razali, Nor Ziehan Salleh, Ahmad Razuan Razali, Mohd Razizul Azim Razali and all my lovely nephews and niece; Rayyan, Adam, Ammar, Qaleesya, Akif, Adib and Danial for their understanding and. moral support.. vii.

(9) TABLE OF CONTENTS. Abstract ...........................................................................................................................iii Abstrak ............................................................................................................................. v Acknowledgements ......................................................................................................... vii Table of Contents ...........................................................................................................viii List of Figures ................................................................................................................ xiv. a. List of Tables.................................................................................................................. xvi. ay. List of Symbols and Abbreviations ..............................................................................xviii. al. List of Appendices ......................................................................................................... xxi. M. CHAPTER 1: INTRODUCTION .................................................................................. 1 Background of the Study ......................................................................................... 1. 1.2. Problem Statement ................................................................................................... 2. 1.3. Scope of the Study ................................................................................................... 4. ty. of. 1.1. Aim ............................................................................................................. 4. 1.3.2. Objectives ................................................................................................... 4. ve r. si. 1.3.1. 1.3.3. Significance of the Study ......................................................................................... 5. ni. 1.4. Hypothesis .................................................................................................. 5. U. CHAPTER 2: LITERATURE REVIEW ...................................................................... 6 2.1. Type 2 Diabetes ....................................................................................................... 6. 2.2. Statins.. .................................................................................................................... 7 2.2.1. Simvastatin ................................................................................................. 8. 2.3. Mechanism Action of Statins................................................................................. 11. 2.4. Diabetogenic Effect of Statins ............................................................................... 12 2.4.1. New-onset Diabetes .................................................................................. 12. viii.

(10) Effect of Simvastatin on Glycemic Control Parameters .......................... 17. 2.4.3. Mechanism Effect of Statins on Glucose Metabolism ............................. 22. 2.4.4. The Effect of Simvastatin on Glucose Metabolism .................................. 23. Potential Factors Associated with Glycemic Control ............................................ 25 Demographic Characteristics ................................................................... 25. 2.5.2. Doses & Duration of Statins Treatment ................................................... 26. 2.5.3. Oral Antihyperglycemic Therapy ............................................................. 27. 2.5.4. Other Concurrent Medications ................................................................. 30. 2.5.5. Lipid-Lowering Effects ............................................................................ 32. ay. a. 2.5.1. al. 2.5. 2.4.2. M. CHAPTER 3: RESEARCH METHODOLOGY ....................................................... 33 Study Design and Setting ...................................................................................... 33. 3.2. Ethical Approval .................................................................................................... 33. 3.3. Study Population .................................................................................................... 33. 3.4. Sample Size Calculation ........................................................................................ 34. 3.5. Study Procedures ................................................................................................... 34. si. ty. of. 3.1. Inclusion Criteria ...................................................................................... 35. 3.5.2. Exclusion Criteria ..................................................................................... 36. 3.5.3. Adherence to Simvastatin Therapy .......................................................... 39. 3.5.4. Data Extraction ......................................................................................... 41. U. ni. ve r. 3.5.1. 3.5.4.1 Descriptive Information ............................................................ 42 3.5.4.2 Glycemic Control Parameters and Others Clinical Laboratory Results ....................................................................................... 42 3.5.4.3 Oral Antihyperglycemic Drugs (OADs) ................................... 43. 3.6. Statistical Procedure .............................................................................................. 43 3.6.1. Demographic Characteristics ................................................................... 44. 3.6.2. Clinical Parameters at Baseline ................................................................ 44 ix.

(11) 3.6.3. The Changes in Clinical Parameters after Simvastatin Therapy .............. 44. 3.6.4. Factors Associated with the Glycemic Control Changes ......................... 45. CHAPTER 4: RESULTS.............................................................................................. 47 Disposition of Study Subjects ................................................................................ 47. 4.2. Demographic Characteristics ................................................................................. 49. 4.3. Baseline Laboratory Parameters ............................................................................ 52. 4.4. Comorbidities ........................................................................................................ 54. 4.5. The Use of Simvastatin .......................................................................................... 56. 4.6. Oral Antihyperglycemic Drugs in the Diabetic Group .......................................... 58. 4.7. Concurrent Medications Other than OADs ........................................................... 62. 4.8. Glycemic Control after Simvastatin Therapy ........................................................ 64. M. al. ay. a. 4.1. Diabetic Group ......................................................................................... 64. 4.8.2. Non-diabetic Group .................................................................................. 64. 4.8.3. Changes in Glycemic Control Parameters between Groups..................... 65. 4.8.4. Association of Oral Antihyperglycemic Therapy on Glycemic Control in. si. ty. of. 4.8.1. ve r. Diabetic Group ......................................................................................... 67 4.8.4.1 Fasting plasma glucose (FPG)................................................... 67. U. ni. 4.8.4.2 Glycated hemoglobin (A1C) ..................................................... 67. 4.9. 4.8.4.3 The changes in FPG and A1C ................................................... 68. Association between Doses and Duration of Simvastatin Therapy with Glycemic Control. .................................................................................................................. 70. 4.9.1. Simvastatin Doses .................................................................................... 70 4.9.1.1 Fasting plasma glucose (FPG)................................................... 70 4.9.1.2 Glycated hemoglobin (A1C) ..................................................... 70 4.9.1.3 Changes in FPG and A1C ......................................................... 72. 4.9.2. Duration of Simvastatin Therapy ............................................................. 74 x.

(12) 4.9.2.1 Fasting plasma glucose (FPG)................................................... 74 4.9.2.2 Glycated hemoglobin (A1C) ..................................................... 74 4.9.2.3 Changes in FPG and A1C ......................................................... 76 4.10 Trends of Glycemic Control Parameters during Simvastatin Therapy .................. 77 4.10.1 Fasting plasma glucose (FPG) .................................................................. 77 4.10.2 Glycated hemoglobin (A1C) .................................................................... 77. a. 4.11 Association of Lipid Lowering Effect with Changes in Glycemic Control .......... 79. ay. 4.11.1 Lipid-Lowering Effect after Simvastatin Therapy ................................... 79 4.11.1.1 Diabetic Group .......................................................................... 79. al. 4.11.1.2 Non-diabetic Group ................................................................... 79. M. 4.11.1.3 Comparison of the Changes in Lipid Profile between Groups .. 80 4.11.2 Association of Oral Antihyperglycemic Drugs on Lipid Profile ............. 82. of. 4.12 Correlation of Lipid Profile with Changes in Glycemic Control .......................... 84. ty. 4.12.1 Diabetic Group ......................................................................................... 84. si. 4.12.2 Non-diabetic Group .................................................................................. 87 4.13 Factors Associated with the Change in Glycemic Control Parameters among. ve r. Simvastatin Users .................................................................................................. 90. 4.13.1 Diabetic Group ......................................................................................... 90. ni. 4.13.2 Non-diabetic Group .................................................................................. 93. U. 4.14 Correlate Model of Factors Associated with the Changes in Glycemic Control among Simvastatin Users ...................................................................................... 95. 4.14.1 Correlate Model for Diabetic Group ........................................................ 95 4.14.1.1 Correlate Model for FPG ........................................................... 95 4.14.1.2 Correlate Model for A1C .......................................................... 97 4.14.2 Correlate Model for Non-diabetic Group ................................................. 98. xi.

(13) CHAPTER 5: DISCUSSION ....................................................................................... 99 Demographic Characteristics ................................................................................. 99. 5.2. Baseline Laboratory Parameters .......................................................................... 101. 5.3. Comorbidities ...................................................................................................... 102. 5.4. Use of Simvastatin ............................................................................................... 103. 5.5. Oral Antihyperglycemic Drugs............................................................................ 103. 5.6. Concurrent Medications....................................................................................... 105. 5.7. Glycemic Control Parameters after the Simvastatin Therapy ............................. 105 5.7.1. ay. a. 5.1. Association of Oral Antihyperglycemic Therapy with Glycemic. Association between Doses and Duration of Simvastatin Therapy on the Glycemic. M. 5.8. al. Control….. .............................................................................................. 108. Control…………………………………………………………………………..110. 5.8.2. Duration of Simvastatin Therapy ........................................................... 111. ty. of. Simvastatin Doses .................................................................................. 110. Trends in Glycemic Control Parameters during Simvastatin Therapy ................ 112. si. 5.9. 5.8.1. 5.10 Association of Lipid Lowering Effect with Changes in Glycemic Control ........ 112. ve r. 5.10.1 Lipid-Lowering Effect after Simvastatin Therapy ................................. 112. ni. 5.10.1.1 Association of Oral Antihyperglycemic Drugs on Lipid Profile…… .............................................................................. 114. U. 5.10.2 Correlation of Lipid Lowering Effect with Changes in Glycemic Control….. .............................................................................................. 115. 5.11 Factors Associated with Changes in Glycemic Control among Simvastatin Users….. .............................................................................................................. 116 5.11.1 Demographic Characteristics ................................................................. 116 5.11.2 Concurrent Medications ......................................................................... 117 5.11.3 Lipid Profile ........................................................................................... 118. xii.

(14) CHAPTER 6: CONCLUSION ................................................................................... 122 6.1. Study Strength ..................................................................................................... 122. 6.2. Limitation of Study .............................................................................................. 123. 6.3. Recommendation for Future Work ...................................................................... 124. References ..................................................................................................................... 125 List of Publications and Papers Presented .................................................................... 145. U. ni. ve r. si. ty. of. M. al. ay. a. Appendix ....................................................................................................................... 146. xiii.

(15) LIST OF FIGURES. Figure 2.1: Intracellular action of lipophilic and hydrophilic statins .............................. 10 Figure 2.2: Inhibition of the cholesterol synthesis pathway by statins ........................... 11 Figure 2.3: Paradigm of hypothetical for statins-induce glucose impairment ................ 23 Figure 2.4: Laboratory finding on the effect of simvastatin on glucose-insulin secretion ........................................................................................................................ 24. a. Figure 3.1: Overview summary of study flow ................................................................ 35. ay. Figure 3.2: Overview of data extraction ......................................................................... 41. al. Figure 4.1: Flowchart of disposition study subjects ....................................................... 47. M. Figure 4.2: Comorbidities in diabetic and non-diabetic groups ...................................... 55. of. Figure 4.3: Percentage of patients prescribed with simvastatin according to the dosages ...................................................................................................................... 57 Figure 4.4: Percentage of patients based on duration of simvastatin therapy ................. 57. ty. Figure 4.5: Intensification of oral antihyperglycemic drugs in the diabetic group ......... 58. ve r. si. Figure 4.6: The use of oral antihyperglycemic regimens pre and post simvastatin therapy among T2D patients ..................................................................................... 59 Figure 4.7: The use of oral antihyperglycemic therapy among T2D patients based on OADs classes pre and post simvastatin therapy ........................................... 60. U. ni. Figure 4.8: The dosing regimen of biguanides pre and post simvastatin therapy received by T2D patients ............................................................................................ 61 Figure 4.9: The dosing regimen of sulphonylureas class pre and post simvastatin therapy received by T2D patients.............................................................................. 61 Figure 4.10: Comparison of concurrent medication among patients in diabetic and nondiabetic groups ............................................................................................. 63 Figure 4.11: The comparison of FPG (a-b) and A1C levels (c-d) in diabetic and nondiabetic groups for different types of simvastatin doses between pre and post simvastatin therapy....................................................................................... 71 Figure 4.12: The changes in FPG levels between different types of simvastatin doses in diabetic and non-diabetic groups.................................................................. 73 xiv.

(16) Figure 4.13: The changes in A1C levels between different types of simvastatin doses in diabetic and non-diabetic groups ............................................................... 73 Figure 4.14: The comparison of FPG (a-b) and A1C levels (c-d) in diabetic and nondiabetic groups for different duration of simvastatin between pre and post simvastatin therapy .................................................................................... 75 Figure 4.15: The changes in FPG values between duration of simvastatin therapy in diabetic and non-diabetic groups ............................................................... 76. a. Figure 4.16: The changes in A1C levels between duration of simvastatin therapy in diabetic and non-diabetic group ................................................................. 76. ay. Figure 4.17 (a-b): Comparison of FPG and A1C level between pre and post simvastatin therapy in diabetic and non-diabetic groups ....................................... 78. M. al. Figure 4.18 (a-d): Correlation between the changes in lipid profile and FPG pre and post simvastatin therapy in the diabetic group ........................................... 85. of. Figure 4.19 (a-d): Correlation between the changes in lipid profile and A1C pre and post simvastatin therapy in the diabetic group ........................................... 86. ty. Figure 4.20 (a-d): Correlation between the changes in lipid profile and FPG pre and post simvastatin therapy in non-diabetic group .......................................... 88. U. ni. ve r. si. Figure 4.21 (a-d): Correlation between the changes in lipid profile and A1C pre and post simvastatin therapy in non-diabetic group .......................................... 89. xv.

(17) LIST OF TABLES. Table 2.1: Comparison of risk of new-onset diabetes with statin use............................. 15 Table 2.2: The effect of simvastatin on glucose metabolism markers in human data .... 19 Table 2.3: The association of oral antihyperglycemic therapy use in combination with simvastatin on glycemic control ................................................................... 29. a. Table 2.4: The association of concurrent medications use in combination with simvastatin on glycemic control ........................................................................................ 31. ay. Table 3.1: The exclusion criteria of the study subjects ................................................... 38 Table 4.1: Number and reasons of patients being excluded from the study ................... 48. al. Table 4.2: Demographic characteristics of patients ........................................................ 51. M. Table 4.3: Baseline values of clinical parameters ........................................................... 53. of. Table 4.4: Comparison of glycemic control pre and post simvastatin therapy ............... 66. ty. Table 4.5: Comparison of FPG changes at pre and post simvastatin therapy between OADs subgroups in diabetic group ................................................................ 69. si. Table 4.6: Comparison of A1C changes at pre and post simvastatin therapy between OADs subgroups in diabetic group ................................................................ 69. ve r. Table 4.7: Lipid profile between pre and post simvastatin therapy and comparison of the changes in lipid profile between the diabetic and non-diabetic group ........... 81. ni. Table 4.8: The mean changes in lipid profile between the subgroups of OADs for the diabetic group ................................................................................................. 83. U. Table 4.9: Pearson correlation coefficient (r) of the mean changes in FPG and A1C levels with the mean changes in lipid profile in diabetic group ............................... 84 Table 4.10: Pearson correlation coefficient (r) of the mean changes in FPG and A1C levels with the mean changes in lipid profile in non-diabetic group ...................... 87 Table 4.11: Simple linear regression analysis for the association of potential factors with the changes in FPG levels (diabetic group) .................................................. 91 Table 4.12: Simple linear regression analysis for the association of potential factors with the changes in A1C levels (diabetic group) ................................................. 92. xvi.

(18) Table 4.13: Simple linear regression analysis for the association of potential factors with the changes in FPG levels (non-diabetic group) .......................................... 93 Table 4.14: Simple linear regression analysis for the association of potential factors with the changes in A1C levels (non-diabetic group) .......................................... 94 Table 4.15: Factors associated with the changes in FPG in diabetic group .................... 96. U. ni. ve r. si. ty. of. M. al. ay. a. Table 4.16: Factors associated with the changes in A1C in the diabetic group .............. 98. xvii.

(19) LIST OF SYMBOLS AND ABBREVIATIONS. : Glycated hemoglobin. ACC. : American College of Cardiology. ACEIs. : Angiotensin-converting enzyme inhibitors. ACS. : Acute coronary syndrome. AHA. : American Heart Association. AMPK. : Adenosine-monophosphate-activated protein kinase. ARBs. : Angiotensin receptor blockers. ATP. : Adenosine triphosphate. BMI. : Body mass index. CAMERA. : Carotid Atherosclerosis Metformin for Insulin Resistance. Ca2+. : Calcium. Cav1.2. : Calcium channel 1.2. CCBs. : Calcium channel blockers. CI. : Confidence interval. ay. al M. of. ty. si. : Cholesterol Treatment Trialist’. ve r. CTT. a. A1C. : Cerebrovascular accident. CVD. : Cardiovascular disease. ni. CVA. U. DKA. : Diabetes ketoacidosis. DPP4Is. : Dipeptidyl peptidase – 4 inhibitors. FDA. : Food and Drug Administration. FPG. : Fasting plasma glucose. GDM. : Gestational diabetes mellitus. GLUT 2. : Glucose transporter 2. GLUT 4. : Glucose transporter 4. xviii.

(20) : High-density lipoprotein. HHS. : Hyperosmolar hyperglycemic syndrome. HMG-CoA. : 3-hydroxyl-3 methyl glutaryl coenzyme A. HOMA-B. : Homeostasis Model Assessment For Β Cell Function. HOMA-IR. : Homeostasis Model Assessment Insulin Resistance. HPS. : Heart Protection Study. ICD-10. : International Classification of Disease Tenth Edition. IFG. : Impaired fasting glucose. IGT. : Impaired glucose tolerance. IHD. : Ischemic heart disease. JNC. : Joint National Committee. JUPITER. : Justification For The Use Of Statin In Primary Prevention: An Intervention. M. al. ay. a. HDL. of. Trial Evaluating Rosuvastatin. : ATP-sensitive potassium channel. Kir6.2. : Rectifier potassium channel : Low-density lipoprotein : Metabolic Syndrome in Men. ve r. METSIM. si. LDL. ty. KATP. : Mouse islet beta-cell line. MREC. : Medical Research Ethics Committee. NHMS. : National Health and Morbidity Survey. NIDDM. : Non-insulin dependent diabetes mellitus. OADs. : Oral antihyperglycemic drugs. OGTT. : Oral glucose tolerance test. QUICKI. : Quantitative insulin sensitivity check index. PDC. : Proportion days covered. PDE5. : Phosphodiesterase type 5. U. ni. MIN6. xix.

(21) PQA. : Pharmacy Quality Alliance. RCT. : Randomised controlled trial. SEARCH. : Study of Effectiveness of Additional Reductions in Cholesterol,. : Sodium glucose co-transporter 2. T1DM. : Type 1 diabetes mellitus. T2D. : Type 2 diabetes. TRL-TG. : Triglyceride-rich lipoprotein triglyceride. UMMC. : University Malaya Medical Centre. VLDL. : Very low-density lipoprotein. WHO. : World Health Organization. M. al. ay. SGLT-2. a. Homocysteine. WOSCOPS : West of Scotland Coronary Prevention Study. of. : Scandinavian Simvastatin Survival Study Group. U. ni. ve r. si. ty. 4S. xx.

(22) LIST OF APPENDICES Appendix A: Ethics Approval UMMC…………………………………………... 146. Appendix B: Data Collection Form……………………………………………… 147 Appendix C: Certificate Of Participation Poster Presentation MONASH 152 Science Symposium 2016……………………………………………………....... U. ni. ve r. si. ty. of. M. al. ay. a. Appendix D: Gantt Chart………………………………………………………… 153. xxi.

(23) CHAPTER 1: INTRODUCTION 1.1. Background of the Study. The prevalence of diabetes mellitus is rapidly increasing throughout the world, and it has become a major global issue. The International Diabetes Federation reported that in 2015, 415 million adults had diabetes and it was estimated that by the year of 2040, the number of diabetes patients will increase to 642 million (Ogurtsova et al., 2017). The. a. trends of diabetes prevalence in Malaysia is equally worrying as the number of diabetes. ay. cases continue to increase from 2006 with 11.6% to 15.2% in 2011 (Institute for Public Health, 2011; Letchuman et al., 2010). The National Health and Morbidity Survey. al. (NHMS) 2015 reported that the increase in the prevalence of diabetes among adults, age. M. 18 years and above in Malaysia, was alarming with 17.5% or 3.5 million people (Institute. of. for Public Health, 2015).. Type 2 diabetes (T2D) is usually accompanied by the elevation of low-density. ty. lipoprotein (LDL) cholesterol, triglyceride and lower high-density lipoprotein (HDL). si. cholesterol that increases the risk of cardiovascular events (Gomes, 2013). The United. ve r. States Preventive Service Task Force (2016) recommends the use of statins (from low to moderate dose) for adults aged 40-75 years old without a history of cardiovascular disease. ni. (CVD) who have one or more CVD risk factors (dyslipidemia, diabetes, hypertension or. U. smoking) and calculated 10-year risk of CV event of 10% or greater. Statins are the most common lipid-lowering drug used to treat dyslipidemia patients worldwide over the past 20 years (Carreras & Polk, 2017). Currently, there are six types of statins approved by the United States Food and Drug Administration (FDA) which are simvastatin, atorvastatin, lovastatin, fluvastatin, rosuvastatin and pravastatin (Geyer & Gomez, 2009). The Malaysian Statistics on Medicine 2009 and 2010 reported that the most commonly statin used in Malaysia was simvastatin.. 1.

(24) 1.2. Problem Statement. The numbers of diabetes case is remarkably increasing worldwide. Many studies have proven the effectiveness of statins through the improvement of lipid profile, which further reduces cardiovascular risk (Ceriello, 2002; Pedersen, Kjekshus, Berg, & Haghfelt, 1994; SEARCH Study Collaborative Group, 2010). However, statins have potential to increase the risk of diabetes (Maki, Dicklin, & Baum, 2015) as a result of poorer glycemic control. a. after the statins treatment (Cederberg et al., 2015; Djousse et al., 2017).. ay. The exact mechanism by which statins affects glycemic control is still unknown, but. al. in the animal study have demonstrated that it may be related to the glucose-insulin. M. secretion mechanism (Sampson, Linton, & Fazio, 2011; Yada, Nakata, Shiraishi, & Kakei, 1999; Yoon & Lee, 2013). Besides that, the previous studies have reported that. of. simvastatin can cause an impairment of glucose metabolism markers (Bellia et al., 2012; Kain, Kapadia, Misra, & Saxena, 2015) whilst others have demonstrated that simvastatin. ty. do not have any effect on glycemic control (Heart Protection Study Collaborative Group,. si. 2003; Koh et al., 2015). On the other hand, another study has shown that simvastatin. ve r. improved insulin sensitivity (Paolisso et al., 2000; Silva et al., 2011).. Previous studies on statins therapy have shown differing results on glycemic control,. ni. and this could be associated with several factors such as demographic characteristics. U. (Robinson et al., 2013; Swerdlow et al., 2015), doses and the duration of statins (Zaharan, Williams, & Bennett, 2013), concurrent use of medications including antihypertensives (Sukhija et al., 2009) and the effect of lipid profile on glycemic control such as LDL cholesterol (Sampson et al., 2011; Sattar & Taskinen, 2012), triglyceride (Armato, Ruby, & Reaven, 2015; Waters et al., 2011) and HDL cholesterol (Parhofer, 2015).. 2.

(25) Despite a considerable number of studies that have linked the use of statins with the diabetogenic effect, contrasting results were also obtained when statins were used in combination with oral antihyperglycemic drugs (OADs). Scattolini et al. (2016) suggested that the effect of simvastatin on the inhibition of insulin secretion can possibly be counteracted by the concomitant use of antihyperglycemic therapy. In addition, a recent animal experimental study had demonstrated that the effect of the combination of. a. simvastatin with OADs had led to the reduction of glucose levels. However, further. ay. studies are needed to confirm these findings (Begum et al., 2016).. al. Most of the studies in T2D were randomised controlled trials (RCT), while real-world. M. evidence studies are lacking (Bellia et al., 2012; Paolisso et al., 1991; Sen, Misra, Kumar, & Pandey, 2002) . Although RCT is the "gold standard" in evaluating the effectiveness. of. of a treatment, the said study design was conducted in a strict and controlled environment which reduced its generalizability (Saturni et al., 2014). Besides that, the previous studies. ty. related to statins and glycemic effects were mainly conducted in retrospective and did not. ve r. al., 2015).. si. take into account the adherence of statins that could affect the clinical outcomes (Cho et. Thus, a clinical observational study is required to identify the possible clinical factors. ni. that may mediate the effects of statins on glycemic control parameters. This study will. U. evaluate the association between simvastatin therapies with glycemic control in type 2 diabetes patients receiving oral antihyperglycemic therapy.. 3.

(26) 1.3. Scope of the Study. 1.3.1. Aim. To evaluate the association of simvastatin use with glycemic control in type 2 diabetes patients receiving OADs and non-diabetic subjects.. 1.3.2. Objectives. 1) To compare the demographic, clinical factors, baseline biochemistry parameters. a. and the use of simvastatin between the type 2 diabetes patients on OADs and non-. ay. diabetic groups.. al. 2) To compare glycemic control parameters among simvastatin users between the. M. type 2 diabetes patients on OADs and non-diabetic groups.. 3) To determine the association between different doses and the duration of. of. simvastatin therapy with glycemic control parameters between the type 2 diabetes patients on OADs and non-diabetic groups.. ty. 4) To describe the trends of glycemic control parameters pre and post simvastatin. si. therapy in the type 2 diabetes patients on OADs and non-diabetic groups.. ve r. 5) To determine the association between the changes of glycemic control parameters with the improvement in lipid-lowering effect between the type 2 diabetes patients. ni. on OADs and non-diabetic groups.. U. 6) To identify factors (clinical factors and biochemistry parameters) that may be associated with the changes of glycemic control parameters in the type 2 diabetes patients on OADs and non-diabetic groups.. 7) To develop correlated models of factors associated with the changes of glycemic control parameters among simvastatin user in the type 2 diabetes patients on OADs and non-diabetic groups.. 4.

(27) 1.3.3. Hypothesis.  Ha: The use of simvastatin impairs the glycemic control parameters in type 2 diabetes patients receiving oral antihyperglycemic drugs and non-diabetic subjects.  Ho: The use of simvastatin does not impair the glycemic control parameters in type 2 diabetes patients receiving oral antihyperglycemic drugs and non-diabetic subjects. 1.4. Significance of the Study. ay. a. T2D is associated with dyslipidemia which leads to an increased risk of CVD. Despite the beneficial effect of statins usage among T2D patients in improving their lipid profile,. al. statins have also been hypothesized to adversely affect their glycemic control. The. M. possibilities of poor glycemic control among T2D patients among statin users could increase the progression of diabetes and lead to more serious microvascular (diabetic. of. nephropathy, neuropathy and retinopathy) and macrovascular (coronary artery disease, peripheral arterial disease and stroke) complications. However, it is proposed that such. ty. effect could be reversed by concurrently using antihyperglycemic therapy. This study was. si. conducted to provide better understanding regarding the association of statins use on. ve r. glycemic control among T2D patients receiving oral antihyperglycemic therapy. Therefore, the study’s finding could enhance the management of the T2D patients. ni. especially for those using the OADs with or without other concurrent medications such. U. as antihypertensive drugs.. 5.

(28) CHAPTER 2: LITERATURE REVIEW 2.1. Type 2 Diabetes. According to the American Diabetes Association (2017b), type 2 diabetes (T2D) is caused by a progressive loss of β-cell insulin secretion usually on the background of insulin resistance. Glycemic control in T2D patients can be controlled with healthy lifestyle modification (Asif, 2014). However, most of the T2D patients are required to use. a. oral antihyperglycemic therapy or insulin to achieve the targeted glycemic control.. ay. Glycemic control is an essential element in diabetes management which can be achieved. M. healthy dietary intake (Saito et al., 2015).. al. in several ways such as proper diabetes self-management, education, physical activity and. The number of people with diabetes is increasing due to several possible factors such. of. as population growth, aging, urbanization, the high prevalence of obesity and physical inactivity (Thibault et al., 2016). Individuals with T2D are predisposed to cardiovascular. ty. disease (CVD) and have a higher rate of cardiovascular morbidity and mortality compared. si. to non-diabetics (Anagnostis, Majeed, Johnston, & Godsland, 2014). In addition, diabetes. ve r. patients tend to have higher triglyceride levels, low levels of high-density lipoprotein (HDL) with smaller and denser LDL particles that promote atherogenesis (Hanefeld,. ni. Traylor, Gao, & Landgraf, 2017) which necessitate T2D patients to use statins as primary. U. or secondary prevention of CVD.. 6.

(29) 2.2. Statins. Following the recommendation by the American College of Cardiology and the American Heart Association (ACC/AHA) 2013 to expand the use of statins in reducing the cardiovascular events (Stone NJ et al., 2014), T2D patients above the age of 40 years old without overt CVD should be treated with statin regardless of their baseline LDL cholesterol, while those with overt CVD should receive high-intensity statin regardless. a. of age (Clinical Practice Guidelines for the Management of Type 2 Diabetes Mellitus,. ay. 2015). Statins or known as 3-hydroxyl-3 methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors are used to treat dyslipidemia patients worldwide and are part of the. al. management for patients with high risk of developing or had cardiovascular disease. M. (Taylor et al., 2013) which are related to diabetes complications or hypertension. The main target of statins therapy is to lower the LDL cholesterol, with a modest effect on. of. decreasing triglyceride and increasing HDL cholesterol levels (Anderson, 2015).. ty. The first statin was lovastatin, marketed as Mevacor® in 1987 after it received the. si. approval from US FDA (Endo, 2010; Goldstein & Brown, 2015). Currently, there are six. ve r. types of statins available in Malaysia namely simvastatin, atorvastatin, lovastatin, fluvastatin, rosuvastatin and pravastatin (Azuana, Syed Mohamed, Saperi, & Faridah. ni. Aryani, 2013). In the United States, the data from the National Health and Nutrition. U. Examination Survey 2011-2012 showed that among adults aged 40 years and above who were using lipid-lowering drugs, 83% were using a statin, 10% a combination of a statin and a non-statin and 7% non-statin. Simvastatin was the most commonly used statin (42%), followed by atorvastatin (20.2%), pravastatin (11.2%), rosuvastatin (8.2%), and lovastatin (7.4%) (Gu, Paulose-Ram, Burt, & Kit, 2015). In Malaysia, the most common statins prescribed is simvastatin (57.6%) followed by lovastatin with overall use of 27.2% (Wan Azman et al., 2014).. 7.

(30) 2.2.1. Simvastatin. Simvastatin is one of the most common statins used because of its effectiveness in reducing LDL cholesterol levels, its ability to produce fewer adverse effects, and is more affordable compared with other statins (Heintjes et al., 2012; Wilke et al., 2012). Simvastatin is a semi-synthetic lovastatin derivative which was derived from a fermentation product of Aspergillus terreus (Manzoni & Rollini, 2002). Most patients. a. have been prescribed simvastatin at the dosage of 10 mg/day, 20 mg/day, or 40 mg/day.. ay. However, the use of simvastatin at 80 mg/day is restricted because of a high risk of muscle. al. injury (Food Drug Administration, 2013).. M. The efficacy of simvastatin in reducing the risk, morbidity, and mortality of cardiovascular events has been reported in various studies, such as the Scandinavian. of. Simvastatin Survival Study (Pedersen et al., 1998), the Heart Protection Study (2003), the Study of the Effectiveness of Additional Reduction in Cholesterol and Homocysteine. ty. (SEARCH) Collaborative Group (2010) and others (Ceriello, 2002; Dobs et al., 2008;. si. Foody, Joyce, Rudolph, Liu, & Benner, 2008). In spite of its beneficial effects, statins. ve r. therapy has a potential to increase the risk of diabetes (Maki et al., 2015).. Previous studies had reported that statins had been associated with the deteriorating. ni. level of glycemic control. However, studies on the effects of simvastatin on glycemic. U. control had shown conflicting outcomes, ranging from adverse, neutral, to beneficial effects. In diabetics, simvastatin has been shown to worsen their glycemic control and insulin secretion (Bellia et al., 2012), improve insulin resistance (Paolisso et al., 2000) or have no effect on glucose levels (Krysiak & Okopien, 2013b; Szendroedi et al., 2009).. 8.

(31) The solubility of statins can be classified as hydrophilic (water-soluble) and lipophilic statins (lipid soluble). Lipophilic statins include atorvastatin, fluvastatin, lovastatin, and simvastatin; while rosuvastatin and pravastatin categorized as hydrophilic statins (Ling & Tejada-Simon, 2016).. As shown Figure 2.1, lipophilic statins can be diffused effectively through the cell membranes of extra-hepatic cells, for example, β-cells, adipocytes, and skeletal muscle. a. cells compared to hydrophilic statins (Brault, Ray, Gomez, Mantzoros, & Daskalopoulou,. ay. 2014). Nevertheless, lipophilic statins at the same time could lead to more adverse effects. al. such as the diabetogenic effect (Aiman, Najmi, & Khan, 2014; Liao, 2002; Schachter,. M. 2005). Previous studies have suggested that simvastatin as lipophilic statins has a. U. ni. ve r. si. ty. of. potential to reduce insulin secretion and sensitivity (Koh et al., 2009; Yada et al., 1999).. 9.

(32) a ay. al. Figure 2.1: Intracellular action of lipophilic and hydrophilic statins. M. Reprinted from “Statin treatment and new-onset diabetes: a review of proposed mechanism” by M. Brault, J. Ray, Y.H. Gomez, C.S. Mantzoros and S.S. Daskalopoulou,. of. 2014, Mechanism, 63 (6), p 739. Copyright 2014 with permission from Elsevier. Lipophilic statins penetrate the cell membrane easier those which are hydrophilic, and at. ty. the same time most likely to have more extrahepatic effects. Statins have been shown to. si. decrease membrane IR phosphorylation or expression, resulting in insulin resistance.. ve r. Within the cell, insulin signaling and GLUT4 transport can be altered by changes in IRS1, Akt, Rab4, Ras, IR-β, or membrane fraction of RhoA, all of which have been shown to. ni. be inhibited by statin therapy. Different statins shown to affect different factors, as. U. illustrated in this figure. Abbreviations: A (atorvastatin); C (cerivastatin), L (lovastatin); S (simvastatin); Cav1 (caveolin1); FFP (farnesyl pyrophosphate); GGPP (geranylgeranyl pyrophosphate); GLUT4 (glucose transporter); GTP (guanosine triphosphate); IGF (insulin-like growth factor); IR (insulin receptor); IRS-1 (insulin receptor substrate); PI3K (phosphatidylinositol 3-kinase).. 10.

(33) 2.3. Mechanism Action of Statins. Cholesterol is a water-insoluble molecule, which is important for the formation of the cell membrane and the synthesis of steroid hormone and bile acids (Singleton et al., 2014). The major source of cholesterol is de-novo synthesis, which starts with acetyl CoA (Ronner, 2016). HMG-CoA reductase is the first rate-determining enzyme in cholesterol biosynthesis, converting the HMG-CoA into mevalonate. Subsequently, the conversion. a. pathway leads to cholesterol synthesis (Singh, Saxena, Srinivas, Pande, &. ay. Chattopadhyay, 2013). The key action of statins is by inhibiting the HMG-CoA reductase enzyme, reducing the mevalonate synthesis which subsequently prevents several another. al. isoprenoid pathway and consequently leads to limiting cholesterol biosynthesis and. U. ni. ve r. si. ty. of. M. lowering cholesterol concentration in the liver as shown in Figure 2.2 (Sirtori, 2014).. Figure 2.2: Inhibition of the cholesterol synthesis pathway by statins Reproduced from “Glycemic effects of simvastatin: where do we stand?” by Nor Razida, Hasniza, Luqman, Shireene Ratna & Bashar Mudhaffar, 2018, Brazilian Journal of Pharmaceutical Sciences. 54(1), p.2.. 11.

(34) 2.4. Diabetogenic Effect of Statins. Despite the beneficial use of statins to improve the lipid profile, previous studies reported that statins have an effect in increasing the risk of diabetes and impairing the glycemic control. On February 28, 2012, the US FDA changed the labeling of statins by including new information to indicate that statins may increase blood glucose and A1C levels (Food Drug Administration, 2012).. New-onset Diabetes. a. 2.4.1. ay. As shown in Table 2.1, the post-hoc-analysis of the West of Scotland Coronary. al. Prevention Study (WOSCOPS) in 2001 reports that the use of pravastatin is associated. M. with a 30% reduction in the incidence of diabetes (Freeman et al., 2001; The WOSCOPS Study Group, 1995). However, several studies had demonstrated that statins-induce. of. diabetes could occur as a result of the elevation of FPG and A1C levels. The first indication of an increased risk of diabetes with statin therapy is reported in the. ty. Justification for the Use of Statin in Primary Prevention: an Intervention Trial Evaluating. si. Rosuvastatin (JUPITER) study, where there is an increase in incidences of diabetes in. ve r. patients receiving rosuvastatin 20 mg/day compared to those who were given a placebo (Mora et al., 2010; Ridker et al., 2008). However, a re-analysis of the JUPITER study. ni. shows that the risk of new-onset diabetes is small, and limited to patients who are already. U. at high risk of developing diabetes such as impaired fasting glucose with FPG ≥ 5.6 mmol/L, A1C ≥ 6%, multiple metabolic syndromes, and BMI ≥ 30 kg/m² (Ridker, Pradhan, MacFadyen, Libby, & Glynn, 2012).. 12.

(35) The Metabolic Syndrome in Men (METSIM) cohort study shows that statin therapy is associated with an increased risk of T2D by 46% after the adjustment of confounders which leads to the deterioration of glycemic and decrease in insulin sensitivity and insulin secretion (Cederberg et al., 2015). Besides that, a population-based retrospective cohort study demonstrates that there are 10% to 22% increased risks of new-onset diabetes linked to the use of simvastatin, rosuvastatin, and atorvastatin compared to pravastatin.. a. Nevertheless, the use of fluvastatin and lovastatin are not associated with increased risk. ay. of diabetes (Carter et al., 2013).. al. A recent study involving the Asian population shows that statins are associated with. M. the increase of new-onset diabetes but at the same time lowers the rates of major adverse cerebral-cardiovascular events compared to non-statins group (Rha et al., 2016).. of. Furthermore, in a retrospective cohort study, it is reported that the incidence of diabetes occurrence is found to be 3.2% higher among statin users compared to just 1.2% among. ty. non-statin users. After controlling the demographic and clinical covariates, the use of. si. statins is associated with an increased risk of diabetes incidence and the highest risk is. ve r. associated with the use of atorvastatin, lovastatin, simvastatin, and fluvastatin whilst the risk is found to be lower in pravastatin and rosuvastatin (Olotu et al., 2016).. ni. Meanwhile, the Heart Protection Study (HPS) has suggested that there is no. U. association between simvastatin therapy and new-onset diabetes. During the study entry, 14, 573 subjects without diabetes are examined and the results show that there is no significant difference in the number of new-onset diabetes between the simvastatin and placebo groups (4.6% and 4.0% respectively) (p = 0.10). It is found that among the 1, 087 subjects who had diabetes at the study entry, there is no significant difference in the increase of A1C levels in the treatment groups after follow-ups are conducted for 4.6 years (Heart Protection Study Collaborative Group, 2003). However, in the Study of. 13.

(36) Effectiveness of Additional Reductions in Cholesterol, Homocysteine (SEARCH) trial, the findings show that there is a slight increase in new-onset diabetes with a high dose of simvastatin 80 mg/day compared to a low dose of simvastatin 20 mg/day (11.6% and. U. ni. ve r. si. ty. of. M. al. ay. a. 10.9% respectively) (SEARCH Study Collaborative Group, 2010).. 14.

(37) Table 2.1: Comparison of risk of new-onset diabetes with statin use. Mean follow up. Method. WOSCOPS (Freeman et al., 2001; The WOSCOPS Study Group, 1995). Male, 5, 977 out of 6, 595 had ≥ 2 post-randomisation blood glucose measurement, with no self-reported of diabetes and no elevated of FPG at baseline (all < 7 mmol/L). 5 years. Randomised, double-blind, placebo-controlled trial. Patients randomly receiving either pravastatin 40 mg/day or placebo. JUPITER (Mora et al., 2010; Ridker et al., 2008; Ridker et al., 2012). 17, 802 healthy men and women with LDL cholesterol levels < 3.7 mmol/L & high sensitivity protein levels ≥ 2 mg/L. 5 years. METSIM cohort study (Cederberg et al., 2015). 8, 749 men non-diabetic, aged 45-73 years old. Population study in Ontario, Canada (Carter et al., 2013). Patients aged ≥ 66 years, started statin therapy from 1 August 1997-31 March 2010. 471, 250 patients on statin therapy found had no history of diabetes. 14 years. al ay. Pravastatin associated with ↓ risk of diabetes development compared to placebo with HR 0.70 (95% CI 0.50-0.98). Rosuvastatin was associated with the ↑ incidence of diabetes versus placebo with HR 1.49 (95% CI 1.11-2.01) & HR 1.14 (95% CI 0.91-1.43) respectively. Reanalysis: patients with ≥ one risk of diabetes had associated with small ↑ incident of diabetes with 28%. Participants randomly selected from the population register of Kuopio, Eastern Finland, performed between 20052010. After adjustment for confounding factors, statin therapy associated with 46% ↑ risk of diabetes 46% HR 1.46 (95% CI 1.22-1.74). Retrospective cohort study. After the adjustment of confounding factors, atorvastatin (HR 1.22; 95% CI 1.15-1.29), rosuvastatin (HR 1.18; 95% CI 1.10-1.26) and simvastatin (HR 1.10; 95% CI 1.04-1.17) associated with ↑ risk of diabetes compared with pravastatin. M. Randomised, double-blind. Patients randomly receiving either rosuvastatin 20 mg/day placebo. of 6 years. rs i ve. ni. U. Findings. a. Subjects. ty. Study. Abbreviations: CI (confidence interval) HR (hazard ratio); IGT (impaired glucose tolerance); JUPITER (Justification for the Use of Statin in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin); METSIM (Metabolic Syndrome in Men); NOD (New-onset diabetes); WOSCOPS (West of Scotland Coronary Prevention Study); ↑ (increase); ↓(decrease). 15.

(38) Table 2.1(continue): Comparison of risk of new-onset diabetes with statin use. Subjects. Mean follow up. Method. Findings. a. Study. Patients who visited the cardiovascular centre of Korea University Guro Hospital from January 2004 to February 2010. 6 years. Retrospective study 10, 944 patients without diabetes and IGT were identified. NOD incident higher in statin users compared to non-statin users (4.7% & 2.4% respectively) HR 1.99 (95% CI 1.36-2.92). United States population study (Olotu et al., 2016). New statin users aged 20-63 years without history of diabetes and compared with non-statin users, from 2003-2004. App. 1 year. Retrospective cohort study. Higher incident diabetes in statin users (3.4%) compared to the non-statin users (1.2%). After controlling the demographic and other clinical covariates, statin use was associated with ↑ risk of diabetes HR 2.01 (99% CI 1.74-2.33). HPS (2003). Patients with diabetes (5, 963) and patient occlusive arterial disease with non-diabetes (14, 573). SEARCH (2010). 12, 064 patients with a history of myocardial infarction. of. M. al ay. Asian population study –Korean (Rha et al., 2016). ty. 4.6 years. ve. rs i. 6.7 years. Patients randomised to receive either simvastatin 40 mg/day or matching placebo. Simvastatin versus placebo HR 1.14 (0.98-1.33). Patients randomised to receive either low dose, simvastatin 20 mg (6, 033 patients) or high dose 80 mg (6, 031 patients) daily. High dose verses low dose HR 1.07 (0.95-1.19). U. ni. Abbreviations: App (approximately); CI (confidence interval); HPS (Heart Protection Study); HR (hazard ratio); IGT (impaired glucose tolerance); NOD (New-onset diabetes);; SEARCH (Study of Effectiveness of Additional Reductions in Cholesterol and Homocysteine); ↑ (increase); ↓(decrease),. 16.

(39) 2.4.2. Effect of Simvastatin on Glycemic Control Parameters. Several randomised control studies have measured the effect of simvastatin therapy on glucose-insulin homeostasis as presented in Table 2.2. The first study that indicates a reduction of plasma glucose after simvastatin therapy was reported by Paolisso et al. (1991). In a small double-blind cross-over randomised study among 12 elderly with T2D, after 3 weeks of simvastatin administration, there was a significant decrease in glucose. ay. a. levels besides the lipid-lowering effects of simvastatin (Paolisso et al., 1991).. Nevertheless, simvastatin has been reported to increase plasma glucose levels and. al. reduce insulin sensitivity. A previous study has indicated that patients on simvastatin had. M. a higher glucose level during oral glucose tolerance test (OGTT) and impaired insulin sensitivity compared to the control group (Larsen et al., 2013). Moreover, Koh et al.. of. (2008) reported that simvastatin improves flow-mediated dilation, but reduces adiponectin levels and insulin sensitivity in hypercholesterolemia patients. After 2. ty. months of simvastatin therapy, patients on 80 mg/day have a 7% increase in mean plasma. si. glucose levels. Patients on simvastatin at the doses of 10, 20, 40 or 80 mg/day have. ve r. increased insulin secretion compared to baseline, indicative of deterioration in insulin sensitivity. This study also demonstrates that there is a slight reduction in insulin. ni. sensitivity as measured using the quantitative insulin sensitivity check index (QUICKI),. U. in the simvastatin group (Koh et al., 2008). Another study by Koh et al. (2015), illustrates significant reductions in insulin sensitivity and plasma adiponectin levels among hypercholesterolemia patients receiving 20 mg/day simvastatin after 2 months, even. though there are no significant differences in plasma insulin or glucose levels compared with the baseline.. 17.

(40) In another argument, Bellia et al. (2010) show that after patients randomly received simvastatin 20 mg or rosuvastatin 20 mg daily for 4 weeks, there is no effect of simvastatin therapy on insulin sensitivity and no significant change in glycemic control between the baseline and at the end of the study. However, another study by the same authors reports that both simvastatin and rosuvastatin therapy worsen FPG and A1C levels after 12 months without affecting insulin sensitivity (Bellia et al., 2012).. a. Furthermore, Sen et al. (2002) study shows that simvastatin therapy is associated with the. ay. increase in A1C levels at follow-up 90 and 180 days compared to day 1.. al. On the other hand, some studies have shown a lack of association between simvastatin. M. therapy and glucose levels. After 90 days of simvastatin therapy, homeostasis model assessment insulin resistance (HOMA-IR) and FPG levels remain unchanged in patients. of. with isolated hypercholesterolemia even though there are improvements in plasma lipid levels (Krysiak & Okopien, 2013b). Szendroedi et al. (2009), report no effect in the. ty. simvastatin group in relation to insulin sensitivity and no difference in either fasting. si. insulin or homeostasis model assessment of β-cell function (HOMA-B). In addition,. ve r. Hydrie et al. (2007) find no significant difference in HOMA-IR values with the use of simvastatin. Whereas, in 20 patients T2D with insulin resistance at the study entry as. ni. indicated by the HOMA-IR value, more than 2.8 have demonstrated an improvement in. U. insulin sensitivity after the simvastatin therapy (p = 0.001).. 18.

(41) Table 2.2: The effect of simvastatin on glucose metabolism markers in human data. Country. Subjects. N. Mean follow up. Method. Outcome. a. Study design. Insulin sensitivity. Double-blind, randomised, crossover study (Paolisso et al., 1991). Italy. Moderately obese, hypercholesterolemia, T2D. 12. 3 weeks. Patients randomly received either placebo and SIM 30 mg/day. -. SIM ↓ glucoseOGTT. N.S.. ↑ insulin sensitivity. -. Prospective study (Larsen et al., 2013). Denmark. Men with hypercholesterolemia (case group) and healthy subjects (control group). 19. 12 months. For the case group, the subject received 1 dose of SIM and control subjects do not receive any medication. -. ↑ glucoseOGTT in SIM. Insulin level similar in both groups. ↓ insulin sensitivity in SIM compared to control. -. Randomised, doubleblind, placebocontrolled parallel study (Koh et al., 2008). Korea. Hypercholesterolemia. 156. 2 months. Each 32 patients given either placebo, SIM 10, 20, 40 or 80mg daily. -. SIM 80 mg ↑ glucose level. SIM 10, 20, 40 & 80 mg ↑ insulin level. SIM 10,20, 40 & 80mg ↓insulin sensitivity. SIM 10, 20, 40 &80mg ↓ plasma adiponectin. Randomised, singleblind, placebocontrolled, parallel study (Koh et al., 2015). Korea. Hypercholesterolemia. 203. For SIM 20 mg N.S. compared to baseline. For SIM 20 mg N.S compared to baseline. SIM 20 mg group N.S. compared to baseline. SIM 20 mg group ↓ insulin sensitivity. SIM 20 mg group ↓ adiponectin level. M. of. ty. Each 51 patients receives either placebo, EZE 10mg + SIM 10 mg (Vyto10), EZE 10 mg + SIM 20 mg (Vyto20) or SIM 20 mg alone once daily. ve. rs i. 2 months. Glucose. al ay. A1C. Insulin. Adiponectin. U. ni. Abbreviations: EZE (ezetimibe); FPG (fasting plasma glucose); N.S.(not significant); OGTT (oral glucose tolerance test); ROS (rosuvastatin); SIM (simvastatin); T2D (type 2 diabetes); ↑(increase); ↓(decrease): - (not measured) Significant value p < 0.05. 19.

(42) Table 2.2 (continued): The effect of simvastatin on glucose metabolism markers in human data. N. Mean follow up. Method A1C. Glucose. Italy. Patients with middle-aged with T2D and mildly treated dyslipidemia. 29. 4 weeks. Patients receive either ROS 20 mg/day or SIM 20 mg/day. Randomised, single-blind with two periods (Bellia et al., 2012). Italy. Well controlled T2D patients. 27. 12 months. Patients receive either ROS 20 mg/day or SIM 20 mg/day for 6 months and switch the treatment for following next 6 months. Double blind randomised placebo-controlled study (Sen et al., 2002). India. Diabetes mellitus Type 1 and 2 with diabetic retinopathy. 50. 180 days. Patients receive either SIM 20 mg/day or placebo. Randomised study (Tsutamoto et al., 2009). Japan. Non-ischemic chronic heart failure. 71. Insulin. Insulin sensitivity. Adiponectin. -. No effect of SIM & ROS. No effect of SIM & ROS. No effect of SIM & ROS. No effect of SIM & ROS. Both group ↑ A1C. Both group ↑ FPG (p < 0.001). N.S.. N.S.. N.S.. In SIM group ↑ at 90 & 180 days. N.S.. N.S.. -. -. Slightly ↑in SIM & ↓in ROS group. -. -. -. N.S. in SIM group but ↑in ROS group. rs i. ty. of. Randomised, single-blind, parallel intervention study (Bellia et al., 2010). Outcome. a. Subjects. al ay. Country. M. Study design. ve. 2.2 ± 0.15 years. Patients receive either SIM 5 mg/day (n = 35) or ROS 2.5 mg/day (n = 36). U. ni. Abbreviations: FPG (fasting plasma glucose); N.S.(not significant); ROS (rosuvastatin); SIM (simvastatin); T2D (type 2 diabetes); ↑(increase); ↓(decrease); - (not measured) Significant value p < 0.05. 20.

(43) Table 2.2 (continued): The effect of simvastatin on glucose metabolism markers in human data. Subjects. N. Mean follow up. Method. Outcome A1C. a. Country. Glucose. al ay. Study design. Insulin. Insulin sensitivity. Adiponectin. Poland. Isolated hypertriglyceridemia. 39. 3 months. Patients receive placebo or SIM 40 mg/day. -. N.S. in both group. -. N.S. in both group. -. Randomised, double-blind, placebo-controlled, single centre study (Szendroedi et al., 2009). German. Non-obese T2D patients. 30. 2 months. Patients were given placebo or SIM 80 mg/day. N.S.. -. N.S.. N.S.. -. Randomised, casecontrol study (Hydrie et al., 2007). Pakistan. Patient with T2D. 100. -. N.S.. N.S.. N.S.. -. of. M. Randomised, casecontrol study (Krysiak & Okopien, 2013b). rs i. ty. 3 months. 50 patients received either SIM 40 mg/day (case) and 50 patients as control. U. ni. ve. Abbreviations: N.S.(not significant); SIM (simvastatin); T2D (type 2 diabetes); ↑(increase); ↓(decrease); - (not measured) Significant value p < 0.05. 21.

(44) 2.4.3. Mechanism Effect of Statins on Glucose Metabolism. The exact mechanisms underlying the effect of statins on glycemia are still unknown. However, previous studies have implicated the inhibition of glucose-stimulated insulin secretion. Glucose transported into the pancreatic β-cells is mediated by glucose transporter 2 (GLUT2). Once it is within the pancreatic β-cell, glucose is phosphorylated by glucokinase, which leads to the adenosine triphosphate (ATP) production. ATP-. a. sensitive potassium channel (KATP) closure causes cell membrane depolarization, which. ay. leads to the calcium channel opening, allowing calcium influx which ultimately results in. al. insulin efflux (Szablewski, 2011).. M. As shown in Figure 2.3, the presence of statins inhibits the cascade of the closure of ATP-dependent potassium channel, subsequently preventing depolarization and. of. inhibiting calcium influx that leads to insulin secretion. The abundance of plasma cholesterol causes the inhibition of glucokinase and leads to a statin-induced inhibition. ty. of de-novo cholesterol synthesis by increasing the uptake of plasma LDL (Sattar &. si. Taskinen, 2012). Besides that, statins restrained ubiquinone syntheses, the essential. ve r. substance in the electron transfer system of mitochondrial lead to the decrease of insulin secretion because the production of ATP diminish (Mabuchi et al., 2005). Furthermore,. ni. statins inhibit HMG-CoA reductase and prevent the synthesis of isoprenoid which leads. U. to the down-regulation of GLUT 4 expression in adipocytes and prevents glucose uptake (Nakata et al., 2006). The inhibition of HMG-CoA reductase by statins causes the upregulation of LDL receptor which leads to the higher uptake of LDL cholesterol. The oxidation of LDL cholesterol may initiate an inflammatory cascade. In addition, the cytokine-inducing excess nitric oxide production leads to induced β-cells apoptosis via the activation of calpain (Sampson et al., 2011; Sattar & Taskinen, 2012).. 22.

(45) a ay al. M. Figure 2.3: Paradigm of hypothetical for statins-induce glucose impairment. of. Reprinted from “Statin are diabetogenic-myth or reality?” by N. Sattar and M.R. Taskinen, 2012, Atherosclerosis Supplements, 13(1), p.6. Copyright 2012 with. The Effect of Simvastatin on Glucose Metabolism. ve r. 2.4.4. si. ty. permission from Elsevier.. Several experimental studies have indicated how simvastatin affects glucose. ni. metabolism (Figure 2.4). The effect of statins (simvastatin, simvastatin acids and. U. pravastatin) on β-cell function has been tested on rodent β-cells. The concentration of. cytosolic calcium (Ca2+) is an important component in β-cell regulation (De Marchi,. Thevenet, Hermant, Dioum, & Wiederkehr, 2014) where the reduction of the concentration in cytosolic Ca2+ leads to the impairment of insulin secretion. In a study by Yada et al. (1999), it showed that simvastatin reduced insulin secretion and inhibited the β-cell L-type Ca2+channels but not in pravastatin.. 23.

(46) Besides that, the effect of simvastatin on glucose metabolism could be elucidated using rodent β-cell line, MIN6. Compared to normal control cells, simvastatin inhibited insulin secretion in a dose-dependent manner. Inhibition of insulin secretion was indirectly caused by the reduction of GLUT2. Simvastatin reduced the ATP levels in MIN6 cells, increased the KATP channel current and reduced the L-type - Ca2+ current (Zhou et al., 2014). This study also suggested that simvastatin may reduce insulin secretion by. a. increasing rectifier potassium channel (Kir6.2) current while at the same time decreasing. ay. the voltage-dependent calcium channel 1.2 (Cav1.2) current, which could lead to the inhibition of membrane cell depolarization and inhibition of calcium influx (Zhou et al.,. U. ni. ve r. si. ty. of. M. al. 2014).. Figure 2.4: Laboratory finding on the effect of simvastatin on glucose-insulin secretion Reproduced from “Glycemic effects of simvastatin: where do we stand?” by Nor Razida, Hasniza, Luqman, Shireene Ratna & Bashar Mudhaffar, 2018, Brazilian Journal of Pharmaceutical Sciences. 54(1), p.3.. 24.