Kay Yi Htun1, Thida Tun1, Nu Nu Aye1 The Effect of Amlodipine on Insulin Sensitivity in Prediabetic Hypertensive Patients Kay Yi Htun1, Thida Tun1, Nu Nu Aye1 1. Department of Pharmacology, University of Medicine 1, Yangon

INTRODUCTION Insulin sensitivity describes how sensitive the body is to the effects of insulin Low insulin sensitivity, or insulin resistance, requires larger amounts of insulin to keep blood glucose stable1 Chronic elevations of glucose and insulin levels are symptoms of insulin resistance, which are underlying causes of prediabetes, diabetes and hypertension2 Pearson ER and McCrimmon RJ. Diabetes Mellitus. In Davidson’s Principles and Practice of Medicine, 22nd edition. ED; Walker BR,Colledge NR,Ralston SH and Penman ID. Churchill Livingstone. The Elsevier Limited, printed in China. 2014; 800-826 Kumar, V., Abbas, A. and Aster, J.C. (eds) (2013) Endocrine system; Insulin resistance. In; Robbin Basic Pathology. 9th Edition. Philadelphia; ELSEVIER, pp.741-743.

INTRODUCTION Prediabetes is characterized by impaired fasting glucose (FBS:100-125 mg/dL), or impaired glucose tolerance (2 hr OGTT: 149-199 mg/dL), or HbA1c in the range of 5.7-6.4%3 Prevalence of prediabetes in adults was found to be 37% in the general population, and 51% in subjects older than 65 years of age3 According to the study of Tint-Swe-Latt et al. in 2014, prevalence of prediabetes was 19.7% between the age of 25 and 644 Tint-Swe-Latt, Ko-Ko Zaw, Ko-Ko and Moh-Moh-Hlaing. (2014) Myanmar Diabetes Association. Diabetes in Myanmar and Prevention of Diabetes; National Prevalence of Diabetes and Prediabetes in Myanmar American Diabetes Association, Diagnosis and Classification of Diabetes Mellitus. Diabetes Care; 2014: 37, 81-90.

INTRODUCTION Identification and treatment of prediabetic hypertensive patients is clinically important Amlodipine is one of the calcium channel blockers widely used in Myanmar It was found that amlodipine has beneficial effects on glucose and insulin sensitivity5 Antihypertensive treatment with amlodipine could reduce the risk of advancing into type 2 diabetes and favor regression to euglycemia Vitolina R, Krauze A, Duburs G, and Velena A. Aspects of the Amlodipine Pleotrophy in Biochemistry, Pharmacology and Clinics. International Journal of Pharmaceutical Sciences and Research 2012; 3(5), 1215-1232.

AIM To study the effect of amlodipine on insulin sensitivity in prediabetic hypertensive patients

OBJECTIVES To determine and compare the fasting blood glucose level and fasting serum insulin level before and after treatment with amlodipine for 12 weeks To determine and compare the insulin sensitivity by means of HOMA-IR before and after treatment with amlodipine for 12 weeks

Amlodipine 5 mg manufactured by Windlas Biotech Limited, India MATERIALS AND METHODS Drug Amlodipine 5 mg manufactured by Windlas Biotech Limited, India Mfg. date - June 2016 Exp. Date - May 2018 Batch no. - AMB 024

Before and after drug treatment intervention study Study period MATERIALS AND METHODS Study design Before and after drug treatment intervention study Study period January 2017 to December 2017 Study population 25 prediabetic hypertensive patients form UHC (Pazungdaung and Tharketa) and monasteries (Tharketa and Thingangyun)

age ³ 18 yrs of both males and females with grade 1 hypertension6 and MATERIALS AND METHODS Inclusion criteria age ³ 18 yrs of both males and females with grade 1 hypertension6 and fasting blood glucose level between 100 mg/dL and 125 mg/dL4 Exclusion criteria history of taking drugs which affect insulin sensitivity (such as thiazolindinediones, insulin, metformin, sulphonylurea, diuretics, beta blockers, ARB and ACEI) known case of secondary hypertension, diabetes mellitus, cardiovascular disease, and pregnancy European Society of Hypertension (ESH) and European Society of Cardiology (ESC) (2013) ESH/ESC Guidelines for the management of arterial hypertension. European Heart Journal. 34, pp.2159-2219.

Flow chart Subject selection and consent taking for screening (n=98) Inclusion criteria (n=28) Exclusion criteria (n=70) Informed consent taking Baseline measurements of FBS, Insulin and HOMA-IR PO Amlodipine 5 mg OD before meal, 2 weekly follow up FBS, Insulin and HOMA-IR measurement after 12wks (n=25) Drop out (n=3) Compare HOMA-IR before and after treatment  

MATERIALS AND METHODS Fasting blood glucose levels were measured by GOD-PAP method with spectrophotometer, using glucose liquicolor kit at Department of Pharmacology, University of Medicine 1, Yangon7 Fasting serum insulin levels were measured by ELISA method using DRG insulin ELISA kit at Department of Physiology, University of Medicine 1, Yangon8 Trinder P. (1969) Glucose GOD/PAP. Ann. Clin. Biochem., 6(24) MacDonald MJ and Gapinski JP. (1989) A rapid ELISA for measuring insulin in a large number of research samples. Metabolism Clinical and Experimental ,38 (5), 450-452

Calculation for HOMA-IR index MATERIALS AND METHODS Calculation for HOMA-IR index HOMA-IR = [fasting insulin (mU/mL) x FBS (mmol/L)]/ 22.59 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentration in man. Diabetologia 1985;28:412–9

MATERIALS AND METHODS Data were represented as the mean ± SD for blood pressures and as median (interquartile range) for fasting glucose, fasting insulin and HOMA-IR Comparison of groups was performed using paired t test and Wilcoxon signed ranks test applying SPSS software version 16 P value < 0.05 was considered as significant

Table 1. Systolic and diastolic blood pressure before and after RESULTS Table 1. Systolic and diastolic blood pressure before and after 12 weeks treatment with amlodipine (n=25) Blood pressure (mmHg) Before treatment (Mean ± SD) After treatment P value (Paired t test) Systolic blood pressure 143.60 ± 5.69 126 ± 6.45 < 0.001 Diastolic blood pressure 91.60 ± 3.74 81.60 ± 3.74

(Wilcoxan Signed Ranks Test) Table 2. Fasting blood glucose, fasting serum insulin and HOMA-IR before and after 12 weeks treatment with amlodipine (n = 25) Parameters Before treatment Median (IQR) After treatment P value (Wilcoxan Signed Ranks Test)   Fasting blood glucose (mmol/L) 6.14 (5.99 - 6.47) 5.02 (4.64 - 5.43) < 0.001 Fasting serum insulin (mU/mL) 15.80 (9.36-20.74) 13.61 (8.82-26.14) 0.861 HOMA-IR 4.01 (2.49-5.72) 3.38 (2.09-5.37) < 0.05 A

DISCUSSION In this study, fasting blood glucose levels were significantly decreased The possible mechanism might be that amlodipine decreases intracellular Ca2+ level leading to vasodilation and increases blood flow to skeletal muscle10,11 This results in enhanced glucose utilization and decreases blood glucose level10,11 Harano Y, Kageyama A, Hirose J, Asakura Y, Yokota T, and Ikebuchi M. Improvement of insulin sensitivity for glucose metabolism with the long-acting Calcium channel blocker amlodipine in essential hypertensive subjects. Metabolism 1995; 44, 315-9. Baron AD, Brechtel GB, Wallace P, and Edelman S. Rates and tissue sites on non-insulin and insulin-mediated glucose uptake in humans. Am J Physiol 1988; 255, E769-E774.

DISCUSSION In this study, fasting serum insulin levels were not significantly decreased after 12 weeks treatment The possible factor might be due to larger individual variations of baseline fasting serum insulin levels (from 6.39 mU/mL to 89.73 mU/mL) According to the findings of Baron and Franzoni, it was found that amlodipine did not have effect on beta cell function and hyperinsulinemia12,13 Baron AD, Brechtel GB, Wallace P, and Edelman S. Rates and tissue sites on non-insulin and insulin-mediated glucose uptake in humans. Am J Physio 1988; 255, E769-E774. Franzoni F, Santoro G, Regoli F, and Plantinga Y. An in vitro study of the peroxyl and hydroxyl radical scavenging capacity of the calcium antagonist amlodipine. Biomed Pharmacother 2004; 58, 423-426.

DISCUSSION HOMA-IR significantly decreased after 12 weeks treatment with amlodipine Insulin sensitivity was determined in terms of HOMA-IR which serve as a surrogate measure of the insulin resistance14 Although hyperinsulinemic euglycemic clamp is referred to as the “gold standard” test, there is good correlation between estimates of insulin sensitivity derived from HOMA and from the euglycemic clamp in normal and diabetic subjects15 Muniyappa R, Lee S, Chen H, and Quon MJ. Current approach for assessing insulin sensitivity and resistance in vivo advantages, limitations and appropriate usage. J Physiol Endocrinol Metab 2008; 294, 15-26. Wallace, T. M., Levy, J. C. and Matthews, D. R. (2004) Use and abuse of HOMA modeling; Diabetes care. 27(6), pp.1487-1495.

CONCLUSION Decrease in HOMA-IR level after 12 weeks treatment indicated that amlodipine can improve insulin sensitivity in prediabetic hypertensive patients This study may provide some evidence that amlodipine exerted a beneficial effect in hypertensive prediabetic patients However, studies on larger group intervention are required for confirmation

RECOMMENDATION To explore the effect of amlodipine on insulin sensitivity in larger population To examine the effect of other CCBs on insulin sensitivity in compared with amlodipine

ACKNOWLEDGEMENT We would like to express special thanks to Medical Research and External Grant Committee, Department of Medical Research, for kind permission to use the grant for our research

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