|Year : 2016 | Volume
| Issue : 3 | Page : 223-228
Utilization study of antidiabetic agents in a teaching hospital of Sikkim and adherence to current standard treatment guidelines
Sushrut Varun Satpathy1, Supratim Datta1, Binu Upreti2
1 Department of Pharmacology, Sikkim Manipal Institute of Medical Sciences, Sikkim Manipal University, 5th Mile, Tadong, Gangtok, East Sikkim, India
2 Department of Community Medicine, Sikkim Manipal Institute of Medical Sciences, Sikkim Manipal University, 5th Mile, Tadong, Gangtok, East Sikkim, India
|Date of Submission||01-Sep-2015|
|Date of Decision||22-Dec-2015|
|Date of Acceptance||27-Dec-2015|
|Date of Web Publication||22-Jun-2016|
Department of Pharmacology, Sikkim Manipal Institute of Medical Sciences, Sikkim Manipal University, 5th Mile, Tadong, Gangtok, East Sikkim
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Objective: Diabetes has gradually emerged as one of the most serious public health problems in our country. This underlines the need for timely disease detection and decisive therapeutic intervention. This prospective cross-sectional observational study aims at analyzing the utilization pattern of antidiabetic agents in a remote North-East Indian tertiary care teaching hospital in the perspective of current standard treatment guidelines. Materials and Methods: Diabetic patients receiving antidiabetic medication, both as outpatients and inpatients in our hospital over a period of 12 months (May 2013–May 2014), were included in this study. The data obtained were sorted and analyzed on the basis of gender, type of therapy, and hospital setting. Results: A total of 310 patients were included in the study. Metformin was the single most frequently prescribed antidiabetic agent (66.8%) followed by the sulfonylureas group (37.4%). Insulin was prescribed in 23.2% of the patients. Combination antidiabetic drug therapy (65.1%) was used more frequently than monotherapy (34.8%). The use of biguanides (P < 0.0001) and sulfonylureas (P = 0.02) in combination was significant as compared to their use as monotherapy. A total of 48% of all antidiabetic combinations used, comprised metformin and sulfonylureas (n = 96). Insulin use was significantly higher as monotherapy and in inpatients (P< 0.0001). The utilization of drugs from the National List of Essential Medicines was 51.2%, while 11% of antidiabetics were prescribed by generic name. Conclusion: The pattern of utilization largely conforms to the current standard treatment guidelines. Increased use of generic drugs is an area with scope for improvement.
Keywords: Antidiabetics, antidiabetic drug utilization, pharmacoepidemiology, prescription pattern study
|How to cite this article:|
Satpathy SV, Datta S, Upreti B. Utilization study of antidiabetic agents in a teaching hospital of Sikkim and adherence to current standard treatment guidelines. J Pharm Bioall Sci 2016;8:223-8
|How to cite this URL:|
Satpathy SV, Datta S, Upreti B. Utilization study of antidiabetic agents in a teaching hospital of Sikkim and adherence to current standard treatment guidelines. J Pharm Bioall Sci [serial online] 2016 [cited 2020 Aug 8];8:223-8. Available from: http://www.jpbsonline.org/text.asp?2016/8/3/223/175975
According to the International Diabetes Federation, 387 million people globally suffer from diabetes which is estimated to rise to 592 million by 2035. The prevalence of diabetes in India, which was 31.7 million in 2000, has since climbed to 65.1 million in 2013 and is projected to reach 79.4 million by 2030. India has the dubious distinction of being the diabetes capital of the world with the number of diabetics far exceeding that of China and America. India is also the largest contributor of diabetes-related mortality in South East Asia accounting for 1.1 million deaths in 2013. Diabetes is thus a major health problem worldwide and even more so in India. Diabetes remains a major risk factor for macrovascular and microvascular complications such as retinopathy, nephropathy, neuropathy, atherosclerosis, ischemic heart disease (IHD), stroke, and peripheral vascular diseases. With a plethora of complications associated with the disease, it is no wonder that diabetes has major implications on the quality of life and life expectancy. Diabetes-related complications and disease progression can only be impeded by timely detection, lifestyle modification, and optimal glycemic control, by making the best use of currently available therapeutic options.
Sikkim is a small land-locked hilly state in the Eastern Himalayas having a population of approximately 6 lakhs. Unpublished comprehensive annual and total health check-up for healthy Sikkim reports released by the State Health Department indicate a higher prevalence of diabetes in Sikkim. Studies pertaining to utilization of anti-diabetic drugs have not been undertaken yet in the North-Eastern regions of India in general and Sikkim in particular. This study was thus conducted to study the demographic profile of diabetic patients, analyze the utilization of antidiabetic agents, and observe adherence to current standard treatment guidelines in this tertiary care teaching hospital.
| Materials And Methods|| |
This prospective cross-sectional observational study was conducted in the Department of Pharmacology and Department of Medicine over a period of 12 months (May 2013–May 2014). Prior to initiation of the study, approval of the Research Protocol Evaluation Committee and the Institutional Ethics Committee was obtained. A predesigned pretested schedule was employed to collect data. The schedule contained information on demographic variables along with a format for assessing the utilization of anti-diabetic drugs. Patients included in this study were conclusively diagnosed to be diabetics and were receiving antidiabetic medication. Patients with gestational diabetes and those below 18 years of age were excluded from the study. Data were obtained twice a week at the medicine OPD, and all diabetic patients admitted in the in-patient facility were screened at least once a week. Patients were explained about the purpose of the study and strict confidentiality was ensured. Written informed consent was taken from each participant. Patients unwilling to participate in the study were excluded.
All the anti-diabetic agents were classified into six major groups and one miscellaneous group. These included the biguanides (anatomical-therapeutic-chemical classification code-A10BA), sulfonylureas (ATC code-A10BB), alpha-glucosidase inhibitor (ATC code-A10BF), dipeptidyl peptidase 4 inhibitor (DPP-4) – (ATC code-A10BH), thiazolidinediones (ATC Code-A10BG), insulin and analogues (ATC code-A10A), and other blood glucose lowering drugs (e.g., nateglinide, exenatide, repaglinide, etc.) excluding insulins (ATC code-A10BX). The generic names of drugs prescribed by brand names were obtained from the recent editions of current index of medical specialty and Indian drug review. The data thus obtained were sorted and categorized on the basis of demographic characteristics (male vs. female), hospital setting (outpatient vs. inpatient), and number of drugs prescribed (monotherapy vs. combination therapy). The National List of Essential Medicines of India (NLEM), 2011 which is published by the Ministry of Health and Family Welfare, Government of India, was referred. The data collected were analyzed for frequency, percentage, mean, and standard deviation. Statistical software used was Microsoft Office Excel 2007 and IBM SPSS Statistics version 20 (Statistical Package for the Social Sciences IBM Corporation). Chi-square test was used where applicable and P < 0.05 was considered significant.
| Results|| |
A total of 310 diabetic patients were included in this study, out of which 307 were suffering from Type 2 diabetes mellitus (T2DM), while three patients had T1DM. [Table 1] gives an overview of the demographic characteristics of the study subjects. Diabetes was found to be more common in females (52.3%) than in males (47.7%). The mean age of the study population was 59.85 ± 13.8. Patients were observed to be mostly in the 61–70 years age range (27.1%) followed by 51–60 years (22.9%). As a whole, 71.3% of the patients were above the age of 50 years. The mean duration of diabetes was 9.52 ± 6.5 years.
Utilization of antidiabetic drugs
A total of 560 antidiabetic agents were prescribed during the study period (1.84/prescription) [Table 2]. The mean number of drugs per prescription was 4.92 ± 2.5. Metformin (biguanide antidiabetic class) was the single most prescribed antidiabetic agent (66.8% of patients). It was followed by the sulfonylureas group, which was used in 37.4% patients. Glimepiride (32.9%) was the sulfonylureas used most commonly, while glibenclamide was used in 2.6% of the patients. Insulin was prescribed in 23.2% of the patients. Association between the duration of diabetes and insulin usage was found to be significant (P < 0.05). The utilization of voglibose and sitagliptin was similar (21.6% and 21.9%, respectively). In terms of total number of antidiabetic units prescribed (n = 560) [Figure 1], the drug share of metformin (37%) was more than that of the sulfonylureas (20.7%). Human insulin comprised 12.8% of the total drug share. The utilization of drugs from the NLEMs was 51.2%, while 11% of antidiabetics were prescribed by their generic name.
|Figure 1: Overall utilization of antidiabetics on the basis of total number of units prescribed (n = 560)|
Click here to view
Utilization of antidiabetic drugs on the basis of gender
[Table 3] depicts the pattern of antidiabetic drug use on the basis of gender. Biguanides were prescribed more commonly in males than in females (χ2 = 2.93; P = 0.08). Sulfonylureas (χ2 = 0.34; P = 0.55), insulin (χ2 = 0.002; P = 0.95), and thiazolidinediones (χ2 = 2.79; P = 0.09) were prescribed more commonly in females than in males. However, gender-based differences in the use of the antidiabetic agents were not significant (P > 0.05 for all groups).
Utilization of antidiabetic drugs on the basis of type of therapy
Combination antidiabetic drug therapy (65.1%) was used more frequently than monotherapy (34.8%). A combination of 2 drugs was used in 75.7% of the patients whereas three drug combinations were used in 24.2% of all the patients receiving combination therapy. The most commonly used two drug combinations were metformin + glimepiride (n = 74) and metformin + pioglitazone (n = 47). The three drug combination of metformin + voglibose + sitagliptin was used in 21 patients, followed by metformin + voglibose + glimepiride, which was used in 13 patients [Figure 2]. Metformin was a component of 94.7% of all two drug combinations and 100% of all three drug combinations. A total of 48% of all antidiabetic combinations used, comprised both metformin and a sulfonylureas (n = 96). Insulin has been used in combination with metformin and/or a sulfonylureas in eight patients. The use of biguanides (χ2 = 35.68; P < 0.0001), sulfonylureas (χ2 = 4.89; P = 0.02), and DPP-4 inhibitors (χ2 = 8.1; P = 0.004) in combination therapy was significant as compared to their use as monotherapy. Insulin, on the other hand, was predominantly used as monotherapy in comparison to combination therapy (χ2 = 257.1; P < 0.0001) [Table 4].
|Figure 2: Relative frequency of anti-diabetic drug combinations used (n = 202)|
Click here to view
|Table 4: Pattern of antidiabetic drug use on the basis of type of therapy|
Click here to view
Utilization of antidiabetic drugs on the basis of hospital setting
[Table 5] depicts the relative use of antidiabetics in outpatients (55.5%) and inpatients (44.5%). The use of the thiazolidinedione (pioglitazone) was more in outpatients in comparison to that in inpatients, and this difference was highly significant (P < 0.0001; χ2 = 29.25). The biguanides (P = 0.65; χ2 = 0.2) and sulfonylureas (P = 0.08; χ2 = 2.9) group of antidiabetics were also predominantly used in outpatients as compared to that of inpatients. The difference in their use was however not significant (P > 0.05). Insulin use was more in inpatients as compared to that of outpatients (χ2 = 44.08; P< 0.0001) and the difference was highly significant.
|Table 5: Pattern of antidiabetic drug use on the basis of hospital setting|
Click here to view
A total of 278 patients had associated comorbidities, the single most common one being hypertension (34.5%). Hypertension alone and comorbid with other conditions/complications such as nephropathy, cerebrovascular accident (CVA), and IHD were seen in 74% of the diabetic patients. CVA and IHDs were seen in 9% and 5.2% of the patients, respectively. Other less frequent comorbidities included dyslipidemia, CCF, and COPD.
| Discussion|| |
The WHO defines drug utilization studies as “The marketing, distribution, prescription, and the use of drugs in a society, with special emphasis on the resulting medical, social, and economic consequences.” Prescription pattern surveys are an important methodological instrument of drug utilization research, which help to provide an in-depth insight into the disease profile of patients and prescribing behavior of clinicians. Such studies can contribute to the promotion of rational, evidence-based drug therapy that can in turn help to improve patient care and treatment.
A relative preponderance of diabetes was observed in females, a finding similar to that of studies conducted in Nepal  and Chennai. A relative male preponderance was however noted in other studies., The mean age of patients in this study was 59.85 ± 13.8 years. A study in Mysore reported the mean age of diabetics as 56.5 ± 13.2 years, while another study in Spain reported it to be 60.5 ± 12.8 years in type 2 diabetics. Patients in our study were observed to be mostly in the 61–70 years age range (27.1%) followed by 51–60 years (22.9%). In a study done in Nepal, most of the patients belonged to the 51–60 years age group (37.9%) whereas 21.9% of the patients belonged to the 61–70 years age range. All together, the population of diabetics above 50 years of age was 73.63% which was similar to that seen in our study (71.3%). The findings support the fact that the risk of diabetes tends to increase with age.
The mean duration of diabetes was observed to be 9.52 ± 6.5 years which is comparable to the findings of a study done in Spain in which the mean duration of diabetes was 11.8 ± 8.0 years. In another study done by John et al., the mean duration of diabetes was 4.3 ± 4.2 years which was much less than that reported in our study. In the same study, the average number of drugs per prescription was 3.2 ± 1.3 as compared to 4.92 ± 2.5 observed in our study. The duration of diabetes has a probable association with the number of drugs prescribed. Other factors, such as high number of inpatients and comorbid hypertension, are likely to have had an impact on number of drugs prescribed. It is recognized that patients with DM are generally prescribed more drugs as compared to other patients.
Metformin monotherapy and combination therapy was used in 66.8% of the patients and was additionally the single most frequently prescribed anti-diabetic drug. This finding is in line with that of Upadhyay et al., where biguanides accounted for 51.2% of the total antidiabetic medications. A study by Johnson et al. in Canada, similarly observed that 65% of the patients received metformin, alone or in combination. Another study in Nepal also noted metformin to be the most frequently prescribed antidiabetic agent. However, in some studies conducted in India ,, and abroad,, the sulfonylureas group of antidiabetics were observed to be the most commonly prescribed drug class. The fact that metformin was the most frequently prescribed drug in this study is in accordance with its endorsement as the preferred anti-diabetic agent by current clinical guidelines., It has even been recommended as the first choice oral medication in the large subset of elderly diabetics (<65 years). Advantages of metformin that make it the preferred antidiabetic agent include its efficacy in blood sugar reduction without risk of hypoglycemia, greater general tolerability, and relatively lower cost. In obese diabetic patients, it has also been found to significantly reduce glycosylated hemoglobin and all-cause mortality as compared to sulfonylureas and insulin. Among the sulfonylureas, glibenclamide was used sparingly (2.6% patients) despite being included in the NLEM, whereas glipizide and glimepiride together were prescribed in 34.8% of the patients. This could be due to the fact that glibenclamide is more likely to cause hypoglycemia, particularly in the elderly, consequent to its longer duration of action. On the contrary, other second generation sulfonylureas such as gliclazide, glipizide, and glimepiride are safer than glibenclamide and are preferred.,
The use of combination antidiabetic therapy (65.1%) was more frequent than that of monotherapy (34.8%), a finding also observed in a study by Rajeshwari et al., in which polytherapy was used in 71.8% and monotherapy in 28.1% patients. A total of 48% of all combinations used, comprised metformin and sulfonylurea. This was also the most frequently used two drug combination. Several other studies have also reported the combination of metformin and a sulfonylurea to be used most widely., A combination of metformin and glimepiride, in particular, was the most commonly used drug combination in a study conducted in Gujarat where it was prescribed in 76.2% of the patients. Clinical studies have shown that a combination of sulfonylureas with metformin can achieve optimal glycemic control even in advanced NIDDM. Broadly speaking, antidiabetics with different mechanisms of action show the greatest synergy, which in turn forms the basis of the guideline recommendation of adding either insulin or sulfonylurea to metformin when the target glycosylated hemoglobin is not achieved. Insulin has been used in 23% of the patients, which is similar to the frequency of insulin use in a study by Rajeshwari et al. The use of insulin has been observed to be more frequent in inpatients than in outpatients and monotherapy as compared to combination therapy (P < 0.0001 for both parameters). A similar pattern of insulin use was also observed in a study done in Mysore. This may suggest that in patients with advanced diabetes and concomitant complications are more likely to require an insulin-based treatment regimen. Insulin is mostly indicated when optimal doses of oral hypoglycemic agents do not achieve target glycemic control, and deterioration of glycemic status is associated with substantial weight loss. Because of the progressive nature of type 2 diabetes, a substantial proportion of patients are eventually going to require insulin therapy., Many studies suggest that T2DM patients who are intensively being treated with insulin, the combination of insulin and metformin results in superior glycemic control as compared to insulin therapy alone while insulin requirement and weight gain are less. Use of metformin in combination with an insulin-based treatment regimen has however been minimal. The use of thiazolidinedione, pioglitazone, and the DPP-4 inhibitor, sitagliptin, has been used mostly in an outpatient hospital setting and in combination with other hypoglycemic agents. A similar pattern of use for these agents has been noted in other studies., The newer oral hypoglycemic agents are likely to be used in combination with the first-line hypoglycemic agents to achieve optimal glycemic control.
A significant number of patients with long-term diabetes are at a higher risk of developing complications. Various comorbidities, including hypertension, hyperlipidemia, and IHD are a major threat. The prevalence of hypertension is 1.5–2 times greater in patients with diabetes mellitus compared with matched non diabetic individuals. Conversely, hypertensives are more predisposed to the development of diabetes than their normotensive counterparts. Hypertension comorbid with other conditions/complications such as nephropathy, CVA, and IHD was seen in 74% of the patients. A high incidence of hypertension comorbid with diabetes was also seen in other studies by Rajeshwari et al. and Upadhyay et al. Since concomitant hypertension increases the risk of development of diabetes-related complications, and vice versa, it is imperative to ensure widespread screening and early detection of both these disorders to impede involvement and progression of end organ damage.
Rational prescribing practices and the safe use of drugs are very important in the management of diabetic patients since they are likely to be on lifelong therapy. The NLEMs is aimed at promoting rational use of medicines by considering their cost, safety, and efficacy, thus prioritizing the availability of affordable quality medicine at all levels of healthcare. In our study, the use of antidiabetic agents from the NLEM was 51.2%. A slightly higher use of drugs from the NLEM was observed in a study by Agarwal et al., in which 67% of patients were prescribed with antidiabetics from the essential drug list. Use of drugs by generic name was observed to be 11%. Prescribing drugs by generic name allows flexibility of stocking and dispensing various brands of a particular drug that are cheaper than and as effective as proprietary brands, and should thus be encouraged.
| Conclusions|| |
The use of antidiabetics in this hospital largely conforms to the recommended treatment guidelines. There is a clear emphasis on the overall use of metformin and sulfonylureas as combination therapy, and insulin as monotherapy, particularly in an inpatient hospital setting. Underutilization of generic drugs is probably an area of concern. Evidence-based medicine should be an essential component of continuing medical education to enable advances in clinical research to be translated into best possible patient care practices.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Global Burden of Diabetes. IDF Diabetes Atlas 6th
ed. Brussels: International Diabetes Federation; 2014. Available from:
. [Last accessed on 2015 Jul 17].
Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27:1047-53.
Das P, Das BP, Rauniar GP, Roy RK, Sharma SK. Drug utilization pattern and effectiveness analysis in diabetes mellitus at a tertiary care centre in eastern Nepal. Indian J Physiol Pharmacol 2011;55:272-80.
Sutharson L, Hariharan RS, Vamsadhara C. Drug utilization study in diabetology outpatient setting of a tertiary hospital. Indian J Pharmacol 2003;35:237-40.
Abdi SA, Churi S, Kumar YS. Study of drug utilization pattern of antihyperglycemic agents in a South Indian tertiary care teaching hospital. Indian J Pharmacol 2012;44:210-4.
Upadhyay DK, Palaian S, Shankar PR, Mishra P, Sah AK. Prescribing pattern in diabetic outpatients in a tertiary care teaching hospital in Nepal. J Clin Diagn Res 2007;3:248-55.
de Pablos-Velasco PL, Martínez-Martín FJ, Molero R, Rodríguez-Perez F, García-Puente I, Caballero A. Patterns of prescription of hypoglycaemic drugs in Gran Canaria (Canary islands, Spain) and estimation of the prevalence of diabetes mellitus. Diabetes Metab 2005;31:457-62.
John LJ, Arifulla M, Sreedharan J, Muttappallymyalil J, Das R, John J, et al
. Age and gender-based utilization pattern of antidiabetic drugs in Ajman, UAE. Malays J Pharm Sci 2012;10:79-85.
Good CB. Polypharmacy in elderly patients with diabetes. Diabetes Spectr 2002;15:240-8.
Johnson JA, Pohar SL, Secnik K, Yurgin N, Hirji Z. Utilization of diabetes medication and cost of testing supplies in Saskatchewan, 2001. BMC Health Serv Res 2006;6:159.
Xavier D, Nagarani MA, Srishyla MV. Drug utilization study of antihypertensives and antidiabetics in an Indian referral hospital. Indian J Pharmacol 1999;31:241-2.
Agarwal AA, Jadhav PR, Deshmukh YA. Prescribing pattern and efficacy of anti-diabetic drugs in maintaining optimal glycemic levels in diabetic patients. J Basic Clin Pharm 2014;5:79-83.
Al Khaja KA, Sequeira RP, Mathur VS. Prescribing patterns and therapeutic implications for diabetic hypertension in Bahrain. Ann Pharmacother 2001;35:1350-9.
Lau GS, Chan JC, Chu PL, Tse DC, Critchely JA. Use of antidiabetic and antihypertensive drugs in hospital and outpatient settings in Hong Kong. Ann Pharmacother 1996;30:232-7.
Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al
. Medical management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: A consensus statement from the American Diabetes Association and the European Association for the study of diabetes. Diabetes Care 2009;32:193-203.
National Collaborating Centre for Chronic Conditions. Type 2 Diabetes: National Clinical Guideline for Management in Primary and Secondary Care (Update). London: Royal College of Physicians; 2008.
Baruah MP, Kalra S, Unnikrishnan AG, Raza SA, Somasundaram N, John M, et al
. Management of hyperglycemia in geriatric patients with diabetes mellitus: South Asian consensus guidelines. Indian J Endocrinol Metab 2011;15:75-90.
Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854-65.
Chelliah A, Burge MR. Hypoglycaemia in elderly patients with diabetes mellitus: Causes and strategies for prevention. Drugs Aging 2004;21:511-30.
Holstein A, Plaschke A, Egberts EH. Lower incidence of severe hypoglycaemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide. Diabetes Metab Res Rev 2001;17:467-73.
Rajeshwari S, Adhikari P, Pai MR. Drug utilisation study in geriatric type 2 diabetic patients. J Clin Diagn Res 2007;1:440-3.
Vengurlekar S, Shukla P, Patidar P, Bafna R, Jain S. Prescribing pattern of antidiabetic drugs in indore city hospital. Indian J Pharm Sci 2008;70:637-40.
Hermann LS, Scherstén B, Bitzén PO, Kjellström T, Lindgärde F, Melander A. Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. A double-blind controlled study. Diabetes Care 1994;17:1100-9.
Acharya KG, Shah KN, Solanki ND, Rana DA. Evaluation of antidiabetic prescriptions, cost and adherence to treatment guidelines: A prospective, cross-sectional study at a tertiary care teaching hospital. J Basic Clin Pharm 2013;4:82-7.
Wulffelé MG, Kooy A, Lehert P, Bets D, Ogterop JC, Borger van der Burg B, et al
. Combination of insulin and metformin in the treatment of type 2 diabetes. Diabetes Care 2002;25:2133-40.
Sultana G, Kapur P, Aqil M, Alam MS, Pillai KK. Drug utilization of oral hypoglycemic agents in a university teaching hospital in India. J Clin Pharm Ther 2010;35:267-77.
Simonson DC. Etiology and prevalence of hypertension in diabetic patients. Diabetes Care 1988;11:821-7.
Gress TW, Nieto FJ, Shahar E, Wofford MR, Brancati FL. Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. Atherosclerosis risk in communities study. N Engl J Med 2000;342:905-12.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]