6

2. Literature Review

2.1 Diabetes Mellitus (DM):

The word diabetes (the Greek word for siphon) was coined by Greek

physician Aretaeus the Cappadocian around 2 AD. Aretaeus noticed that

patients with diabetes had a disease caused by siphoning of structural

components of the body into the urine. Although it was known for centuries

that the urine of patients with diabetes was sweet, it was not until 1674 that a

physician named Thomas Willis coined the term diabetes mellitus (from the

Greek word for honey)[18].

It is a group of metabolic disorders characterized by hyperglycemia, which is

associated with abnormalities in carbohydrate, fat and protein metabolism,

and results in chronic complications including microvascular, macrovascular,

and neuropathic disorders. Type 2 DM is characterized by impaired insulin

secretion, insulin resistance, excessive hepatic glucose production, and

abnormal fat metabolism. Type 2 DM has a strong genetic component. The

concordance of type 2 DM in identical twins is between 70 and 90%.

Individuals with a parent with type 2 DM have an increased risk of diabetes; if

both parents have type 2 DM, the risk approaches 40%[19].

2.2 Epidemiology

2.2.1 Global Epidemiology:

As per IDF (International diabetes federation) diabetes Atlas, 5th edition, 2011,

globally there are 366 million people have diabetes in 2011; by 2030 this will

have risen to 552 million. The number of people with type 2 diabetes is

increasing in every country. 80% of people with diabetes live in low and

middle income countries. The greatest numbers of people with diabetes are

between 40-59 years of age. 183 million people (50%) with diabetes are

undiagnosed. Diabetes caused 4.6million deaths in 2011. Diabetes caused at

least 465 billion dollars in healthcare expenditures in 2011; 11% of total

healthcare expenditures in adults (20-79 years). 78,000 children had

type1diabetes every year [20].

7

The greatest increases will be seen in India (195%, from 19 million to 57

million), Middle Eastern crescent (193%, from 18 million to 54 million), and

Sub- Saharan Africa (185%, from 3 million to 8 million). The increase will be

over 150% in Other Asia and Islands (from 12 million to 32 million) and Latin

America and Caribbean (from 15 million to 39 million). In China there will be a

134% increase (from 16 million to 38 million). The smallest increase will occur

in Former Socialist Economies of Europe (33%, from 17 million to 22 million

and Established Market Economies (46%, from 34 million to 50 million). The

three countries with the largest number of people with diabetes are India,

China, and the U.S[21].

2.2.2 Epidemiology of Diabetes in India:

Type2diabetes is more prevalent (more than 90% of all diabetic cases) and

the main driver of the diabetes epidemic, now affects 5.9% of the world’s adult

population with almost 80% of the total in developing countries. Nowhere is

the diabetes epidemic more pronounced than in India as the World Health

Organization (WHO) reports show that 32 million people had diabetes in the

year 2000. The international diabetes federation (IDF) estimates India had

about 61.3 million diabetic patients in 2011, estimated to reach 101.2 million

in 2030(International Diabetic Federation, 2011). In a population based study

National Urban Diabetes Survey (NUDS) was conducted in six large cities

from different regions of India in 2001. This study was done on 11,216

subjects aged over 20 years from all socio-economic strata. The study

showed that the age standardized prevalence of type 2 diabetes was 12.1%.

The prevalence was the highest in Hyderabad (16.6%), followed by Chennai

(13.5%), Bangalore (12.4%), Kolkata (11.7%), New Delhi (11.6%) and

Mumbai (9.3%). Recently national non communicable diseases (NCD) risk

factor surveillance was conducted in six different geographical locations (East,

South, North, and West/Central India) in India. There was a geographical

difference in the overall prevalence of self- reported diabetes, with the centres

in southern states having a higher prevalence of self- reported

diabetes,[Trivandrum (9.2%); Chennai (6.4%) ] compared with north [ Delhi

(6.0%); Ballabgarh (2.7%)], east [Dibrugarh (2.4%)] and west/central India

[ Nagpur (1.5%)]. Similar trends were observed even when categorized based

8

on residential areas as urban, periurban/slum and rural areas, except for

urban areas where Delhi had higher rates (10.3%) than Chennai (8.7%) and

Dibrugarh (5.5%). This study showed that the lowest prevalence of self-

reported diabetes was recorded in rural (3.1%) followed by peri-urban slum

with 3.2% and the highest prevalence were observed in urban areas (7.3%).

From these national reports, it is evident that till the 1970s, the prevalence of

diabetes was less than 3.0% even in urban areas. The prevalence of diabetes

in India is showing a sharp upswing as is evident from secular trends from

different parts of the subcontinent, both in the urban and rural areas with a

rough urban-rural divide of 2:1 or 3:1 being maintained through the last 2-3

decades with the exception of Kerala where rural prevalence rates have

caught up with or even overtaken urban prevalence rates[22].

2.3 Management of Type 2 Diabetes Mellitus:

Treatment of diabetes includes both non pharmacologic therapy (lifestyle

changes) and drug therapy. Lifestyle changes include diet, physical activity,

weight loss and smoking cessation. Drug therapy may include various classes

of oral hypoglycemic agents and insulin.

2.3.1 Non-Pharmacological therapy:

Change in lifestyle is the cornerstone of any diabetes treatment plan. Healthy

diet, regular exercise, management of stress and avoidance of tobacco plays

an important role in diabetes management.

Carbohydrates should constitute 55-60% of the calorie intake. Obesity is the

one of the risk factor for type 2 diabetes, it was recommended to control fat

intake. Mono-unsaturated fats have a lower atherogenic potential and are

therefore recommended as the main source of dietary fat. Intake of fat should

be less than 35% of total energy consumption, with saturated and trans

unsaturated fats accounting for less than 10% of energy intake and

monounsaturated fats providing 10-20%. Protein intake should be 10-20% of

total energy intake. Food should contain fiber rich items like whole pulses,

green leafy vegetables[23].

9

2.3.2 Pharmacological therapy

Oral anti-diabetic drugs:

Oral anti-diabetic drugs are the important agents for the treatment of type 2

diabetes mellitus. Blood glucose levels are determined by absorption from

gut, uptake of glucose from peripheral tissues (muscle, adipose tissue),

hepatic glucose output and insulin secretion from pancreas. Various oral anti-

diabetic drugs act by modifying the factors aiding in control of hyperglycemia.

Various agents available for the treatment of type 2 diabetes mellitus in India

are presented in the Table 1[24,18].

Table.1. Oral agents for the management of type 2 diabetes mellitus

Class Drug

Sulfonylureas Glipizide

Glibenclamide

Glimipride

Gliclazide

Short acting insulin secretogogues Nateglinide

Repaglinide

Biguanides Metformin

Thizolidinediones Pioglitazones

Rosiglitazones

Alpha Glucosidase inhibitor Acarbose

Miglitol

DPP-IV inhibitors Sitagliptin

In addition various fixed dose combinations of oral anti-diabetics are also

available for enhanced control of blood glucose

Insulin:

As per the algorithm of treatment for type 2 diabetes, when oral hypoglycemic

fail to control blood glucose level, then one can add insulin preparation for the

therapy. Insulin is an anabolic and anticatabolic hormone. It plays major roles

in protein, carbohydrate and fat metabolism. There are U-100 and U-500,

10

100units/ml and 500units/ml, respectively are the strength of insulin available

in the market.

Based on time activity profile, insulins are categorized into rapid acting, short

acting, intermediate –acting and long-acting insulin. Rapid acting insulin

include the insulin analogs lispro, aspart and glulisine. The short acting

insulins include semilente, regular and regular buffered insulins. Regular and

buffered insulin formulations are clear and contain solubilized crystalline

insulin. Regular insulin and the rapid –acting analogs are the only insulins that

can be safely given intravenously. Intermediate –acting insulins include

neutral protamine Hagedorn (NPH) and lenteinsulins. NPH insulin

preparations contain a suspension of zinc-insulin crystals and protamine, a

protein derived from fish sperm. Lente insulin is composed of a 30: 70 mixture

of semilente and ultralente. The lenteinsulins are produced from various forms

of the zinc-insulin complex and are particularly useful in patients sensitive to

protamine. The available long-acting insulins include ultralente and the insulin

analogue glargine. Insulin detemir is another long-acting insulin that recently

approved by FDA. The most common adverse reaction of insulin is

hypoglycemia. Other side effects are liphypertrophy and lioatrophy [27].

In addition non-insulin injectable like Glucagon-Like Peptide 1 Agonists (GLP-

1) and Amylinomimetics are also available for the treatment of type 2 diabetes

mellitus [27].

2.4 Management of hypertension in diabetes mellitus:

Diabetes mellitus and hypertension are both major public health problems that

co-exist frequently, associated with a significant morbidity and mortality. Both

occur in increasing frequency with increasing age and they have a common

predisposing factor, i.e. insulin resistance. In type II diabetes, hypertension

may be present before the diagnosis of diabetes or at the time of diagnosis.

Importantly, hypertension is common in the setting of insulin resistance; 70%

of patients with type II diabetes have a blood pressure greater than or equal to

140/90 mmHg. Hypertension is a critical determinant of the development and

11

progression of both the macrovascular and micro vascular complications of

diabetes. Multiple clinical trials have demonstrated a close correlation

between blood pressure and cardiovascular events and mortality,

development and progression of nephropathy, and progression of retinopathy

and development of blindness in DM patients. In the United Kingdom

Prospective Diabetes Study (UKPDS), every 10 mmHg decrease in mean

systolic pressure was associated with reduced risk by 12% for any diabetic

complication, 15% for diabetes-related deaths, 11% for myocardial infarction,

13% for macrovascular complications, and a no risk threshold was found for

any end-point studies.

Compared to the general population, people with diabetes face a two-to

fourfold increased risk of cardiovascular disease (CVD). Concomitant

hypertension triples the already high risk of coronary artery disease (CAD),

doubles total mortality and stroke risk, and may be responsible for up to 75%

of all CVD events in people with diabetes. Similarly, hypertension significantly

accelerates the progression of diabetic nephropathy, retinopathy, and

neuropathy. Of particular importance, systolic blood pressure is a stronger

predictor than diastolic blood pressure for both CVD and renal

complications[25-28].

Based on results of clinical trials, the American Diabetes Association (ADA)

and the National Kidney Foundation (NKF) and the Joint National Committee

VII (JNC VII), recommend a goal blood pressure of 130/80 mmHg or less in

hypertensive patient with diabetes[29].

For patients with isolated systolic hypertension, which the ADA defines as a

systolic blood pressure greater than or equal to 180 mmHg with a normal

diastolic blood pressure, the treatment goal is to reduce systolic pressure to

below to 160 mmHg. The NFK and Joint National Committee VII(JNCVII) also

recommended that in patients with evidence of renal disease,

microalbuminuria or proteinuria, blood pressure goal should be targeted at

125/75 mmHg or less . The average number of antihypertensive agents

needed to reach this treatment goal is 3.4. Therefore, increased

12

understanding of the mechanisms contributing to hypertension in insulin

resistance and the pathophysiology of diabetic vascular complications, as well

as awareness of the results of antihypertensive trials in patients with diabetes

is important to develop a logical, evidence-based treatment strategy[30].

Hypertension and diabetes mellitus are interrelated diseases, which, if

untreated, strongly predispose to atherosclerotic cardiovascular disease.

Lifestyle and genetic factors are important in the genesis of both

conditions[31]. Over the last decade, there has been an increasing interest in

the clinical association between hypertension and diabetes[32]. Diabetes and

its attendant co morbidities like hypertension pose a significant and increasing

health burden, with the potential to become a huge health care crisis in the

near future.

2.5 Epidemiology of Diabetes- Hypertension combination in India:

Nearly one-third of the Indian population is in danger of being afflicted by two

major killer diseases, namely, hypertension and diabetes, by the year 2015,

according to the Hypertension Society of India (HSI).Management of

hypertension in diabetics demands special attention, more so in Indian

scenario. Higher prevalence of hypertension (HTN) amongst diabetics in India

has been reported since 1985 [33, 34].

The frequency of hypertension (HTN) in diabetic population is almost twice as

compared to non-diabetic general population. In India about 50% of diabetics

have HTN[35]. The current studies in India indicate that there is alarming rise

in prevalence of diabetes which has gone beyond epidemic form to a

pandemic one.

2.6 Guidelines for treatment of hypertension in diabetic patients

2.6.1 Current Treatment of Hypertensive Diabetic Patients: A Report

from the ADA 2004 and JNC-VII 2003

Hypertension is an extremely common comorbidity of diabetes, affecting 20–

60% of people with diabetes, and it is also a major risk factor for

cardiovascular events as well as for diabetic microvascular complications,

13

such as retinopathy nephropathy, and possibly neuropathy. Thus, the

occurrence of hypertension in association with type 2 diabetes mellitus

constitutes one of the most rapidly increasing disorders in the world. Recently,

the results of adequate evidence-based studies support an aggressive

approach to the diagnosis and treatment of hypertension in reducing the

incidence of both diabetic macrovascular and microvascular complications.

Unfortunately, outside of research settings, control of vascular risk factors is

inadequate in people with diabetes. Only 4–10% of diabetic patients meet the

combined American Diabetes Association goals for blood pressure(< 130/80

mmHg), LDL cholesterol (< 100 mg/dl), and hemoglobinA1c (< 7.0%)[36].

There is strong evidence that pharmacologic therapy of hypertension in

patients with diabetes is effective in producing substantial decrease in

cardiovascular and microvascular diseases. Patients with confirmed

hypertension(systolic BP ≧140 mmHg or diastolic BP≧90 mmHg) should

receive immediate pharmacological treatment in addition to

lifestyle/behavioral therapy. JNC VII suggests the use of both therapies

simultaneously and immediately when systolic BP ≧130 mmHg or diastolic

BP≧80 mmHg, and in order to achieve such goal, usually a combination of 2

or more drugs are required[29].

Five classes of drugs are considered to be effective for monotherapy.

Diuretics, beta blocker, calcium channel blocker, alpha 1 adrenergic blocker,

Angiotensin converting enzyme inhibitor and likely Angiotensin receptor

antagonist are the armamentarium for first line drugs available for use in India.

Many studies of combination of the antihypertensive agents have been

published. The superiority of one combination regime over another in diabetes

has not been documented. Diuretic agents in combination with adrenergic

blockers have been used in UKPDS, SHEP and several nephropathy studies.

ACE inhibitors have been used in combination with diuretics and calcium

channel blockers (CCB).CCBs in combination with diuretics or ACE inhibitors

have been reported. Recently, studies have also been published that compare

“older” antihypertensive agents such as thiazide diuretics and beta blockers,

14

which have been available for the past 3 to 4 decades, to “newer” agents,

such as ACE inhibitors and CCBs in STOP-2, INSIGHT,NORDIL and ARIC are

4 major, new trials with such comparisons[37-41].

2.6.2 ACE inhibitors in diabetes mellitus hypertensive patients

These drugs are useful in the management of hypertension in diabetic

patients with or without diabetic nephropathy. ACE inhibitors have been

extensively studied in the treatment of diabetic nephropathy and are effective

in preventing progression of retinopathy. The recent HOPE (Heart Outcomes

Prevention Evaluation) trial that documented decreased cardiovascular end

points despite quite minor changes in BP raises the possibility that ACE

inhibitors have benefits for diabetic patients that are independent of their

antihypertensive effect. Postulated mechanisms include effects on the

endothelium as a result of decreased vascular smooth muscle growth,

decreased release of endothelin, increased fibrinolysis, and release of the

vasodilating substances nitric oxide and prostacyclin mediated by bradykinin.

The most common side effects of ACE inhibitors include coughand,

occasionally, acute decreases in renal function. Hyperkalemia can be seen,

especially in patients with renal insufficiency, bilateral renal artery stenosis,

and hyporeninemic hypoaldosteronism[42].

Benefits of ACE inhibitors in Diabetes

Many trials have demonstrated the CV and renal protective benefits of ACE

inhibitors in diabetic patients compared with other antihypertensives. The

UKPDS showed that tight BP control with an ACE inhibitor or a beta-blocker

compared with less tight control produced a significant reduction in the

number of deaths related to diabetes, diabetic complications, and progression

of diabetic retinopathy. The ABCD trial demonstrated a higher incidence of

fatal and nonfatal MI among those assigned to the calcium channel blocker

than to the ACE inhibitor. In the CAPPP trial, ACE inhibitor therapy in patients

with diabetes reduced the combined outcome of fatal and nonfatal MI, stroke,

and CV deaths when compared with a diuretic and/or beta-blocker therapy[26,

43, and 44].

15

The HOPE study and the Microalbuminuria, Cardiovascular, and Renal

Outcomes (MICRO) substudy of the HOPE study showed that ACE inhibition

therapy reduced the incidence of death, MI, and stroke and reduced the

progression of proteinuria compared with placebo. And in the FACET study,

patients randomized to ACE inhibition had a significantly lower risk of major

CV events than those assigned to calcium channel blockade[45, 46].

2.6.3 Role of dual RAAS blockade with combination therapy:

The renin-angiotensin-aldosterone (RAA) axis is a multi-organendocrine

system that regulates electrolytes, blood volume, and blood pressure. The

pharmacological targets in this system include inhibitors of the production of

angiotensin II (ACEinhibitors), inhibitors of angiotensin II action (ARBs), and

the aldosterone receptor antagonists spironolactone and eplerenone. A recent

meta-analysis of 14 randomized trials evaluated the benefits of combination

therapy with an ACE inhibitor and an ARB compared with either agent alone.

Results showed that combination therapy significantly reduced the incidence

of proteinuria, but the modest reduction in BP with the combination compared

with monotherapy did not reach statistical significance. However, most of the

studies included in the meta-analysis did not use the maximum allowed doses

of the ACE inhibitors. They also failed to compare the ACE inhibitor/ARB

combination therapy with other non– RAAS blocking drug combinations (eg,

ACE inhibitor plus thiazide diuretic), leading the authors of the meta-analysis

to conclude that better designed studies are needed before recommendations

can be made[47]. The recently published RENAAL (Reduction of Endpoints in

NIDDM with the Angiotensin II Antagonist Losartan) and PRIME (Program for

Irbesartan Mortality and Morbidity Evaluations) showed that ARBs are able to

retard the progression of albuminuria and the development and progressionof

nephropathy in Type 2 DM. However, long-term data on cardiovascular

outcomes using this class of drugs are limited[48-50].

2.6.4 Combinations of antihypertensive agents:

In general, combination therapy may help to improve compliance, as one drug

may antagonize the adverse effects of another. The superiority of one

combination regime over another has not been documented. However, it is

16

clear that intensive treatment of hypertension, with goals recommended by

the ADA’s and JNC VII’s new target of ＜130/80 mmHg, will require more than

two drugs in most patients and three or more in many. Combination therapy

with 2 or more antihypertensive drugs is typically required to achieve BP goals

in most hypertensives with diabetes. Many studies have shown that patients

with diabetes who have lower BP levels have lower rates of CV events and

better preservation of renal function than those with higher BP levels[47].

2.7 Lipid lowering therapy in diabetic patients:

2.7.1 Diabetic dyslipidemia:

Diabetic dyslipidemia is characterized by hypertriglyceridemia, low HDL, and

LDL that is minimally elevated. To prevent CHD risk in diabetes, the primary

target is LDL with a goal of treatment being to lower LDL-C ≤100mg/dl. When

LDL is ≥130 mg/dl, most patients will require simultaneous therapeutic

lifestyle changes and drug therapy. When LDL_C is between 100 and 129

mg/dL, intensifying glycemic control, adding drugs for the atherogenic

dyslipidemia (fibric acid derivatives, niacin) and intensifying LDL-C lowering

therapy are options. Because the primary target is LDL-C in diabetic

dyslipidemia, statins are considered by many to be initial drugs of choice. It

shown relative risk reduction for CHD in diabetes versus non-diabetic is

greater in the West of Scotland, AFCAPS/texCAPS, CARE and 4S trials[51-

53].

All statins are more or less similar in triglyceride lowering and because statins

differ in potency for LDL reduction, a ratio of LDL reduction to triglyceride

reduction can be applied. The most recent trial LDL-lowering in type 2

diabetes mellitus is the Collaborative Atorvastatin Diabetes Study[54]. The

primary end point of this study was, a composite of acute CHD death, nonfatal

MI, hospitalized unstable angina, resuscitated cardiac arrest, and coronary

revascularization or stroke was reduced by 37%. This study suggests that all

diabetics should have a LDL much lower than 100 mg/dl and these results are

consistent with the Heart Protection Study analysis of diabetic patients.

According to FIELD (The Fenofibrate Intervention and Event Lowering in

17

Diabetes) study, Fenofibrate reduced the angiographic progression of CAD in

type 2 diabetes. Fibric acids principally lower VLDL and triglycerides while

increasing HDL with only modest lowering of total and LDL cholesterol. Fibric

acid derivatives tend to improve glucose tolerance, in contrast to niacin; the

greatest effect has been seen with bezafibrate. The Helsinki Heart Study

found gemfibrozil to be most effective in diabetic dyslipidemia[55].Although

the effect of statins on triglycerides and HDL abnormalities commonly seen in

diabetes is less than with fibric acids, the subgroup analysis cited earlier

suggest that they reduce CHD risk significantly. In the Action to Control

Cardiovascular Risk in Diabetes[56], the combination of statin and fenofibrate

in patients with type 2 diabetes did not reduce the rate of fatal cardiovascular

events, nonfatal myocardial infarction, or nonfatal stroke compared to

simvastatin alone[57].

2.8 Role of aspirin in diabetic patients:

Aspirin has been shown to reduce the risk of myocardial infarction and other

vascular adverse events (stroke, transient ischemic attack) through its

inhibition of thromboxane A2. Thromboxane A2 is a potent platelet aggregator

and vasoconstrictor. The use of enteric-coated aspirin (81-325 mg) is

recommended in patients with diabetes who have evidence of large vessel

disease (e.g., history of myocardial infarction, stroke, angina) and in those

with a family history of coronary heart disease, cigarette smoking,

hypertension, hyperlipidemia, obesity or albuminuria. Contraindications to

aspirin therapy include aspirin allergy, bleeding disorder, history of

gastrointestinal bleeding and active hepatic disease[18].

2.9 Drug utilization research:

Drug utilization research was defined by WHO in 1977 as “the marketing,

distribution, prescription and use of drugs in a society, with special emphasis

on the resulting medical, social and economic consequences”. The principle

aim of drug utilization research is to assess whether drug therapy is rational or

not and the ultimate goal is to facilitate rational use of drugs in populations.

From the patient’s perspective, the rational use of drug would imply the

prescription of a well-documented drug in an optimal dose on the right

18

indication, with the correct information and at an affordable price[58].Studies

on the process of drug utilization focus on the factors related to the

prescribing, dispensing, administering, and taking of medication, and its

associated events, covering the medical and non-medical determinants of

drug utilization, the effects of drug utilization, as well as studies of how drug

utilization relates to the effects of drug use, beneficial or adverse effects[59].

Drug utilization studies have been reported from North America initially and in

recent years, number of studies is reported from many other countries[60].

Number of factors is responsible for the development of drug utilization

review, out of which the most important factor is the growth of private health

insurance companies for the coverage of prescription medications[61].

Drug utilization research will enhance the understanding of how drugs are

being used by making estimates of numbers of patients exposed to drugs

within a given time period in a certain area (e.g., country, region, community,

hospital). Drug utilization studies will also help to measure the prescribing

quality using the prescription data.

The observed patterns of drug use can then be compared with

recommendations or guidelines for the treatment of a certain disease. Use of

drug registers following the drug use pattern will give opportunity for carrying

out further pharmaco-epidemiological studies[62].

Moreover, information on patterns of drug usage has increasingly become

indicator of the many processes that cause drugs to be prescribed. In

addition, drug utilization research will also provide early signals of irrational

drug use which can be helpful in designing interventions that improve drug

use so as to have the desired impact[63].

Standardized and validated information on drug use plays a pivotal role in the

auditing of patterns of drug utilization, identification of problems, educational

or other interventions and monitoring of the outcomes of the interventions. For

such information to be meaningful and reliable, adherence to strict

19

methodological standards is essential. In general Drug utilization review

involves comparison of actual behavior to explicit, prospectively established

standards, referred to as criteria. The criteria will normally be decided on the

most rational approach at the time of decision[64].

Different types of drug use information are required depending on the problem

being examined. These include information about the overall use of drugs,

drug groups, individual generic compounds or specific products, information

about the condition being treated, the patient information and prescriber

information. In addition data on drug costs will be useful in evaluating the

economic aspects of drug utilization. Clinically important questions can

usually be answered by evaluating the information involving aggregation of

data on drug use at various levels, information on indications, doses, and

dosage regimen. The level at which data on drug use are aggregated will

depend on the question being asked – the concern may be the relative use of

drug groups, relative scale of use of individual products, information to the

level of dose strength etc. In addition to level of drug use, for drugs with

multiple indications, it will also be necessary to divide data on use according

to indication to allow a correct interpretation of overall trends.

Patient information such as age, gender, ethnicity, co-morbidities, knowledge,

beliefs and perceptions will often serve as useful information in determining

the pattern of drug use. In addition to the patient information demographic

information about the prescriber also plays a critical role in determining drug

use. Interestingly, there have been claims that the differences between

doctors are greater than those between patients and that variation in drug

prescribing behavior often lack rational explanations. Information as to

prescriber’s medical education, whether the prescriber is a specialist or

general practitioner, the age and gender of the prescriber, the locality (rural or

urban) of the prescriber may all have influence on the prescribing behavior of

the physician[58].

Drug utilization studies can be aimed at the systems and structures of drug

use which includes how the drugs are ordered, delivered and administered in

20

a hospital, or it may be aimed at the processes of drug use which asks

questions such as what drugs are used, how they are used and does their use

comply with relevant criteria, guidelines or restrictions, or alternatively it may

be aimed at the outcomes of drug use such as efficacy, adverse drug

reactions, use of laboratory tests and procedures. The studies can be

conducted as cross-sectional, longitudinal and continuous longitudinal

studies.

2.9.1 Cross-sectional studies:

Cross sectional data provide a snapshot of drug use at a particular time.

Cross-sectional studies may be used for making comparisons with similar

data collected over the same period in a different country, hospital, ward, and

could be drug-, problem-, indication-, prescriber- or patient-based.

Alternatively, a cross-sectional study can be carried out before and after an

intervention. Studies could also be criterion-based to assess drug use in

relation to guidelines or restrictions.

2.9.2 Longitudinal studies:

Public health authorities are often interested in trends in drug use, and

longitudinal data are required for this purpose. Drug-based longitudinal data

can be on total drug use as obtained through a claims database, or the data

may be based on a statistically valid sample of pharmacies or medical

practices. Longitudinal data are often obtained from repeated cross-sectional

surveys. Data collection is continuous, but the practitioners surveyed and

therefore the patients, are continually changing. Such data give information

about overall trends, but not about prescribing trends for individual

practitioners or practices

2.9.3 Continuous longitudinal studies:

In some cases continuous longitudinal data at the individual practitioner and

patient level can be obtained. Claims databases are often able to follow

individual patients using unique identifier. These data can provide information

about concordance with treatment based on the period between prescriptions,

co-prescribing, duration of treatment, PDDs and so on. As electronic

21

prescribing becomes more common, databases are being developed to

provide continuous longitudinal data comprising full medical and prescribing

information at the individual patient level. Such databases are very powerful

and can address a range of issues including reasons for changes in therapy,

adverse effects and health outcomes[65-66].

Table.2. Summary of Drug utilization studies in diabetic patients

Author and year Seong, Choi &Jung et al.(2011)[67]

Study design and

site

Observation study using the Health Insurance Review

& Assessment Service(HIRA) database, Korea

Sample size All the elderly (65-99 years) patients visited as out

patients from July 2005-June 2006

Drugs studied Prescription pattern of OHAs specifically use of

thiozolidinedions(TZDs) in diabetes patients with heart

failure

Key findings TZDs were frequently prescribed to diabetic patients

(10.4%) with heart failure, even though the TZDs were

contraindicated in patients with heart failure. This is

highest in primary care settings.

Author and year Kumar et al(2011)[68]

Study design and

site

A prospective observation study at inpatient

department of SRM medical college hospital and

research centre, Tamilnadu, India.

Sample size Data collected from July 2010-February 2011 (142

patients)

Drugs studied Prescription pattern of antdiabetic drugs

Key findings Metformin and human insulin were most frequently

prescribed drugs. Monotherapy was used for 68.9%

patients and 41.1% patients were prescribed with

combination therapy

22

Author and year Tripathi et al(2010)[69]

Study design and

site

Observational study, using questionnaire at outpatient

department at Institute of Technology and

management, Gorakhpur, India.

Sample size 200 diabetic outpatients

Drugs studied The pattern of drug prescription in diabetes

Key findings Prescription pattern shows sulfonylurea and

biguanides were most frequently prescribed followed

by thiazolidediones and alpha glucosidase inhibitors.

Insulin was prescribed in 15.5%patients. 31.97%

diabetic patients had hypertension

Author and year Filion et al(2009)[14]

Study design and

site

Observation study using the General Practice

Research Database(GPRD) in United Kingdom

Sample size Patients with type 2 diabetes from January 2000-

December 2006

Drugs studied Trends in prescribing anti-diabetic medications in type

2diabetic patients

Key findings They found sharp increases in the overall prescription

of anti-diabetic medications between 2000 and 2006.

The greatest increase was observed in metformin and

TZDs. There was also an increase in the prescription

of insulin during this period in type 2 diabetic patients.

The management of type 2 diabetes is consistent with

recent practice guidelines.

Author and year Alexander et al (2008)[70]

Study design and

site

Observational study using National Disease and

Therapeutic Index (Data base) USA.

Sample size Type 2 diabetic patients from 1994-2007(outpatients)

Drugs studied Trends in treatment of type 2 diabetes mellitus.

23

Key findings On evaluation of trend in treatment of type 2 diabetic

patients, monotherapy is declined from 1994 to 2007.

Insulin use decreased from 1994 to 2000 and then

increased. Sulfonylurea use decreased from 1994-

2007. Biguanides and glitazones were leading

therapeutic classes. Increasing use of newer class like

newer insulins, sitagliptin and exenatide also observed.

These newer drugs may effect treatment costs.

Author and year Thiyagu, Arulmani & Narmadha T(2008)[71]

Study design and

site

A prospective cross-sectional study at outpatient

department of Government Head Quarters Hospital,

Ootacamund.

Sample size For three month period (243 diabetic patients)

Drugs studied Drug use pattern of antidaibetics in outpatients

Key findings The incidence of diabetes was 91.36% and 83.95%

patients were receiving more than 2 or more drugs.

Total of 90.12% patients were prescribed II generation

sulphonylureas and remaining 9.88% patients

received with sulphonylureas and biquanides. 38.27%

diabetic patients had hypertension.

Author and year Grant et al(2007)[13]

Study design and

site

Population based survey in US

Sample size 886 physicians are responded for study

Drugs studied Practice of management of diabetes using survey

questionnaire through email

Key findings While choosing medication for the treatment of

diabetes, physicians will consider a range of issues,

such as overall assessment of their patients’ health

and comorbid conditions and patients A1 level,

adherence and motivation to improve and/or avoid

24

insulin. Also they have constrained by medication

costs and formulary restrictions but not expert

guidelines or hospital algorithms.

Author and year Alba JE (2007)[72]

Study design and

site

Observational study Using Database in Colombia(19

cities included)

Sample size 7308 diabetic patients who covered General System

for Social Security in Health(SGSSS)

Drugs studied Prescription pattern of antidiabetic drugs

Key findings 48% of the group had been prescribed one diabetes

medication, while 52% had been prescribed from 2-

4diabetic medication. The drugs prescribed were

biquanides (67.5%), sulphonylureas (64.9%), insulin

(23.5%) and TZDs (0.1%). The common combinations

prescribed were glibenclamide with metformin,

metformin and insulin, glibenclamide and insulin.

Among 74.4% cases received antihypertensives.

Thereare significant differences in oral therapies

prescribed for diabetes across the 19 cities studied, but

overall, prescription patterns are appropriate.

Author and year Boyc, Yugin & Lage (2007)[73]

Study design and

site

Observational study using IMS Disease Analyzer-

Mediplus France Database(IMS health incorporated,

London, United kingdom)

Sample size 14,281 diabetic patients over a period from 2001 to

2003

Drugs studied Trends in the prescription of antidiabetic medications

Key findings Monotherapy with sulfonylurea decreased from

34.98% to 29.47% (p< .0001), monotherapy with

metformin increased from 17.38% to 21.31% (p<

.0001), and monotherapy with insulin increased from

25

1.71% to 2.27% of the population (p= 0.0437) in

France, antidiabetic medication prescribing patterns

changed from 2001 to 2003.In general, the trend has

been away from sulfonylurea monotherapy and

towards metformin monotherapy, insulin monotherapy,

or combination therapy.

Author and year Chiang et al (2006)[7]

Study design and

site

A cross-sectional study using National Health

Insurance Research Database in Taiwan.

Sample size Data collected for over a period of 7 years from 1997-

2003 of diabetic outpatients.

Drugs studied Trends in the use of oral antidiabetic drugs in

outpatients.

Key findings Sulphonylureas (SU) were most commonly used OAD

class, but the propotion of prescription belonging to

this class declined over time. Within SU class the

second generation SUs was prescribed more often

than the first generation SUs. The Biquanides(BG)

was the second most frequently prescribed OAD class.

The largest proportional increase in prescribing rate

was found for acarbose. Also prescribing rates of

maglitinide and TZDs significantly increased within a

short period of time. Combination therapy was a more

widely prescribed regimen than mono-therapy,

accounting for more than 50% of total prescriptions in

study year.

Author and year Ludwig et al (2006)[74]

Study design and

site

Longitudinal cross sectional study using data from

Manitoba’s Drug Programs Information Network and

Manitoba’s Diabetic Database, Canada.

Sample size Data from 1996 to 2001 were collected

26

Drugs studied Drug utilization in diabetic patients from 1996 to 2001

Key findings Treatment with oral antihyperglycemic,

antihypertensive and lipid lowering agents increased

significantly. However prescriptions for all three

therapeutic indications remained low. Specifically, 42%

of patients with diabetes were not prescribed any

antihyperglycemic medications (oral or insulin) and

only 42.4% and 26.5% received antihypertensive

agents or lipid-lowering agents, respectively.

Author and year Al Khaja, Sequeira & Damanhori(2005)[75]

Study design and

site

A retrospective analysis of medical records of patients

from six primary care centres in Bahrain

Sample size 177 from diabetic clinic and 180 from GP-clinic

Drugs studied Anthyperglycemics and antihypertensives

Key findings On evaluation of prescription pattern of antidiabetic,

glibenclaimede, whether alone or in combination with

metformin, was the most commonly prescribed drug.

As regards antihypertensive drug therapy,

monotherapy was prescribed at a rate significantly

higher than that of combination therapy in patients

attending diabetic clinics. Whereas there is no

difference between mono-and combination drug

therapy in GP clinics.

Author and year Cohen et al (2003)[5]

Study design and

site

Cross sectional study using Market Scan Research

Database In U.S.

Sample size Over a period of 1997 to 2000

Drugs studied Antihyperglycemic prescribing trends

Key findings Monotherapy with SUs decreased, but monotherapy

with TZDs anf metformin and other antihyperglycemics

increased. Combinations of SUs and metformin; SUs

27

and TZD; metformin and TZD; and SU, metformin and

thiozolidinedione each increased over the time interval.

Insulin monotherapy decreased, as did insulin

combination therapy with SUs. The combination of

insulin and metformin increased, whereas insulin and

thiazolidinedione was stable.

Table.3. Summary of Drug utilization studies in diabetes with hypertensive patients:

Author and year Chou et al (2012)[76]

Study design and

site

Secondary data analysis of Taiwanese population from

the National Health Insurance,.

Sample size Data from 1997 to 2004

Drugs studies Use of antihypertensives in patient with diabetes,

without diabetes and other comorbidites

Key findings ACEIs, Abs and ARBs were prescribed more

frequently in the DM arm than the non-DM arm. BBs ,

CCBs, Diuretics and other antihypertensive

medications were prescribed more frequently in the

non-DM arm than in the DM arm.

Author and year Swelleh et al (2009)[77]

Study design and

site

An observational retrospective study conducted at Al-

Watani governmental hospital and medical center in

north Palestine

Sample size Data were collected between August 2006 to August

2007 (340 patients)

Drugs studies Use of antihypertensive medication in Diabetic

hypertensive patients

Key findings The most commonly antihypertensive drug classes

utilized by the patients were ACI followed by diuretics

and CCB. Monotherapy was the most common mode

of therapy among the patients.

28

Author and year Greving et al (2007)[78]

Study design and

site

A longitudinal observational Study using data from the

Zwolle Outpatient Diabetes project Integrated Available

care (ZODIAC) –study in the Netherlands

Sample size From 1998-2004

Drugs studies Trends in hyperlipidemia and hypertension management

in type 2 diabetic patients

Key findings Study shows that management of hypertension and

hyperlipidemia in patients with diabetes was improved in

the recent years. But further improvement is required in

the management of controlling blood pressure and lipid

levels.

Author and year Bunnag et al(2006)[79]

Study design and

site

A cross-sectional study using multi-center, hospital

based diabetes registry, Thailand.

Sample size 8,884 patients from 11 tertiary centers

Drugs studies Treatment of hypertension in type 2 diabetic patients.

Key findings The prevalence of hypertension in adult Thailand type 2

diabetic patients was 78.4%. Antihypertensive drugs

were prescribed in 84.4% of all hypertensive patients.

The percentage of patients receiving 1,2,3,4, and 5

drugs were 45%., 33.4%, 16.8%, 4.4%, and 0.4%

respectively. Angiotensin-converting enzyme inhibitors

were the most commonly prescribed antihypertensive

agents (54.6%) followed by diuretics (43.8%) and

calcium channel blockers(34.6%)

Author and year McAlister et al(2006)[80]

Study design and

site

Cross linked the Ontario Diabetes Database and four

administrative databases in Ontario, Canada

Sample size 27,822 elderly diabetic with hypertensive patients(1995-

29

2001)

Drugs studies Pattern of antdiabetic and anthypertensive medications

Key findings Among 27,822 elderly diabetic with hypertensive

patients, 62% were treated with oral hypoglycemic

agents alone. 8% with insulin alone, 8% with both OHAs

and insulin and 22% diet alone. Among them 73%

received monotherapy with antihypertensive drugs, 22%

received 2 antihypertensive drugs and 5% received

three or more drugs. The most frequently chosen

antihypertensive drugs were ACE inhibitors, thiazides

and calcium channel blockers.

Author and year Gulliford, Charlton and Latinovic(2005)[8]

Study design and

site

Analysis of data from the General Practice Research

database (GPRD), London.

Sample size Patients from 1993-2001(4519 DM patients with

hypertension0

Drugs studies Antihypertensive and lipid lowering therapy in type II

diabetes

Key findings Among 9365 DM patients, 4519(48%) had hypertension.

The main changes in prescribing to diabetic subjects

with hypertension during this period were consistent with

the accumulating evidence for the efficacy of ACEIs,

diuretics and statins in the management of subjects with

type 2 diabetes

Author and year Johnson & Singh (2005)[9]

Study design and

site

Retrospective cohort study using database of Veterans

Affairs Medical center, USA

Sample size 9,975 patients from 1998 to 2001.

Drugs studies Pattern of antihypertensive therapy in diabetic patients

Key findings Over 60% of patients were received ACEIs or ARBs

followed by diuretics and calcium Channel blockers and

30

beta blockers. 19.1% patients were untreated. The

majority (70.7%) of treated patients on multiple drug

therapy. And it was according to JNC VI guideline

which was introduced during that time.

Author and year Chan (2005)[81]

Study design and

site

A cross sectional study, primary healthcare level in

Malaysia

Sample size 517 DM patients from August to October 2003.

Drugs studies Management of hypertension in type 2 diabetic patients

Key findings Out of 517 DM patients, 350(67.7%) patients had

hypertension. Among them 38.6% patients on

monotherapy and 21.8 % were on two or more

antihypertensive drugs. Metoprolol was the most

commonly prescribed drug(22.4%), followed by

nifedifine(16.2%) and Prazocin (13.5%).Only 18.3% DM

patients with hypertension were prescribed with ACEIs

and 0.3% with ARBs.

Author and year Cheng et al (2004)[82]

Study design and

site

Observational study using computer prescription data

base used for BNHI reimbursement purposes.

Sample size January 2001 data (4week)- 5015 patients data

Drugs studies Antihypertensive pattern in diabetic patients

Key findings Calcium channel blockers were most commonly

prescribed antihypertensive drugs. Inappropriate use of

immediate release of nifedipine also observed. The

combination of hydrochlorothiazide and atenolol were

extensively used. Among combination therapy CCBs

and ACEIs were most commonly used drugs.

31

Table.4. Summary of Drug utilization studies in diabetes with hyperlipidemia

Author and year Berthold et al (2009)[83]

Study design and

site

An observational study using German diabetes registry.

Sample size 51,640 patients with type 2 diabetes

Drugs studies Use of statin in diabetic patients

Key findings The majority of patients with type 2 diabetes were not

receiving statins. The predominant factors determining

statin prescription were the patient’s prevention status

and in primary prevention, estimated cardiovascular risk.

The results suggest that although physicians are aware

of the general concept of cardiovascular risk, they fail to

consistently implement guidelines.

Author and year Thomas and Nestel(2007)[84]

Study design and

site

Used Data from the NEFRON study( the National

Evaluation of the Frequency of Renal Impairment Co-

existing with NIDDM) in Australia Sample size 3893 patients with DM( April to September 2005)

Drugs studies Management of dyslipidemia in Type 2 diabetic patients

Key findings 63.9% patients with DM in NEFRON study received lipid

lowering medication. Among them 61.3% received

statins, 2.5% patients received fibrate and 1.5%

received cholesterol absorption inhibitor. Target for total

cholesterol was achieved in 31% patients, target for LDA

was achieved in 63% patients, 35% achieved target

levels for triglycerides and 84% for HDL cholesterol

among treated patients.

2.10 Pharmacoeconomic studies

2.10.1 Introduction:

Increased cost of health care has led to interest in the evaluation of health

care systems and programs in terms of economic value, this is more so in

case of drugs and pharmaceuticals. Pharmacoeconomics is a field of study

that evaluates the behavior or welfare of individuals, firms, and markets

32

relevant to the use of pharmaceutical products, services, and programs[85].

Pharmaco-economics, as well as outcomes research, have become part of

the background and expertise of many health care professionals, including

pharmacists. Health care technology has grown rapidly, leading to more

expensive pharmaceutical tools to treat a variety of illnesses. At the same

time health care professionals are dealing with limited resources. This forces

society to decide on the services and products it is able to afford for patient

care. In this context, drugs represent an easily identifiable part of healthcare

expenditures, both in the inpatient and outpatient settings[86].

Pharmacoeconomic tools are important in analyzing the potential value for

individual patients and the public. These methods compliment the traditional

market place value as measured by the prices that patient or their care givers

willing to pay[87].

The demand for and hence the cost of healthcare are growing in all countries

in the world as the improvement and sophistication of health technologies

increase. Many governments are focusing their activities on promoting the

effective and economic use of resources allocated to healthcare. The

increased use of evidence-based programmes not only concentrates on

optimizing health outcomes but also utilizes health economic evaluations.

Medicines form a small but significant proportion of total healthcare costs and

one that has been increasing consistently as new medicines are marketed[3].

2.10.2 Methodology of pharmacoeconomics

Pharmacoeconomic evaluations primarily consider the costs and

consequences of a pharmacological intervention and are often applied among

various alternatives. Costs are defined as the input resources utilized by the

therapeutic strategy and/or intervention under study; consequences (or

outcomes) are the outputs. Costs are broadly classified as direct, indirect and

intangible costs.

Direct costs: This includes the cost of goods and services that can be

purchased in the marketplace. Direct costs are further classified into medical

33

and non-medical costs. Examples of direct medical costs are inpatient costs

(e.g., laboratory tests, drugs, hospitalization, etc.). In the case of

pharmacological treatments, these include not only the cost of the drugs, but

also cost of their administration, clinical monitoring, costs for treatment of

adverse events, etc. an example of a direct non-medical cost is transportation

cost.

Indirect cost: These costs which result from changes in production capacity

brought about by the intervention or illness. Examples of indirect costs are

days lost from work, and reduction or loss of productivity.

Intangible cost: These are costs or savings associated with additional or

lessened pain or suffering. These costs are very important but difficult to

quantify [86, 88].

2.10.3 Types of pharmacoeconomic evaluations:

The discipline of pharmacoeconomics is defined as the science of measuring

the costs and outcomes associated with the use of pharmaceuticals in health

care delivery. The basic purpose of pharmacoeconomic evaluation is to

compare the costs and consequences of therapeutic alternatives.

There are five types of pharmacoeconomic evaluation: cost of illness (COI),

cost-minimization(CMA), cost-effectiveness(CEA), cost utility (CUA), and cost

benefit analysis(CBA). All the methods compare treatment alternatives except

COI, which is concerned with the identification and estimation of the overall

cost of a particular disease on a defined population [86, 88].

Cost of illness (COI): This method involves the computation of direct and

indirect costs attributable to a specific disease. Thus, COI does not compare

competing treatment alternatives, but provides an estimation of the financial

burden of a disease.

Cost minimization analysis (CMA): is used to define the most economical

treatment among different alternatives with equal efficacy/effectiveness and

34

safety profiles. CMA is frequently employed in formulary decision making

where often the available evidence for a new product appears to be no better

than for existing products.

Cost effectiveness analysis (CEA): compares treatment alternatives with

different efficacy/effectiveness and safety profiles. While costs are calculated

in monetary value, outcomes are valued in clinical terms (e.g., drop in value of

HbA1c, blood pressure, number of cases cured). Moreover, in the so-called

lifetime CEA, outcomes are measured as years of life gained with the new

treatment as compared with the standard care treatment.

Cost utility analysis(CUA): in this method cost is measured in monetary

value and outcomes in clinical terms incorporating patient preferences (e.g.,

quality of life measures). Often the utility measure used is a “Quality Adjusted

Life Year” (QALY) gained. QALY incorporates both quantity and quality of life.

The use of QALY as a measure of outcomes, allows a direct comparison

among cost-utility ratios from different pharmacoeconomic analysis. The

preferred treatment alternatives are that with the lowest cost per QALY.

Possible alternative measures are healthy-year equivalents (HYE) or saved

young life equivalents. The first measure is very difficult to compute, while the

latter is not as broadly known and used as QALYs.

Cost –benefit analysis(CBA): in this method, both costs and benefits of a

treatment are measured in monetary values. Future costs and benefits are

discounted to their current value. Although considered the best economic

analysis, its application in pharmacoeconomics and health care in general is

limited, due to the difficulties in assigning a monetary value to health

outcomes and a patient’s life.

2.11 Cost of Illness

2.11.1 Introduction:

Cost–of-illness (COI) analysis measures the economic burden of disease and

illness on society. It is often called burden-of-illness (BOI). The components of

a pharmacoeconomic or cost-effectiveness analysis include costs and

35

consequences. Cost can be divided into direct and indirect costs. Direct

medical costs are those related to providing medical services, such as a

hospital stay, physician fees for outpatient visits, and drug costs (including the

cost of the medication itself and any downstream adverse events that may

arise as a result of drug administration). Direct nonmedical costs are those

related to expenses, such as transportation costs, that are a direct result of

the illness. Direct costs are most frequently included in a COI study, whereas

indirect cost, those associated with changes of individual productivity, are

often not included in a COI study, because they are difficult to obtain.

Examples of indirect costs are lost time from work (absenteeism) and unpaid

assistance from a family member. In addition, intangible costs, such as pain

and suffering, may be included in the analysis. Analysis can be done from one

or several perspectives, which will help in determining the distribution of

disease costs across multiple stakeholders. The societal perspective typically

includes indirect, as well as direct, medical costs because these are costs to

society, that is, as previously mentioned, lost time from work. The payer

perspective typically includes only direct costs.

COI analyses are used to aid in policy making resource allocation –that is,

prioritizing resource use for disease treatment and prevention and as baseline

research from which to determine the potential benefit of new therapies [88a].

2.11.2 Approaches

There are two approaches to conducting COI analyses, the prevalence–based

approach and incidence-based approach. The prevalence–based approach

considers the cost of disease within a specified time period. The prevalence–

based approach is most appropriate for diseases or illnesses that are

measured within the time period of analysis and that do not change much

over time(e.g., migraine) or acute diseases (e.g., asthma, eczema).

This is in contrast to the incidence–based approach, which calculates the life-

time costs of disease. This approach is most appropriate for chronic diseases,

such as hypertension, or diseases that take a long time to progress, such as

diabetes. This approach considers disease progression and survival

36

probability. The disease is first defined using existing disease definitions or

classification systems, such as International classification of diseases-ninth

revision (ICD-9-CM) codes. To accurately capture the disease COI over the

appropriate timeframe, depending on the aforementioned approaches, one

must take into consideration the epidemiology of the disease under study and

the demographic profiles of the typical patient population.

2.11.3 Methods:

A micro-costing method has been used in many studies to examine COI. The

direct costs included in this method typically comprise out-of-pocket expenses

for noninsured items(over-the –counter medications, visit to out-of plan health

practitioners, laundry/clothing, and specialty items) and co-payments for

prescription medications and clinic visits determined from insurance claims

databases as well as the usual direct cost items previously outlined[88a].

Table 5.Summary of Cost of Illness Studies in Diabetes

Author and year Javanbakht M, Baradaran HR, and Mashayekhi A et al

.(2011)[89]

Study design and

site

Prevalence based Cost of Illness study, Iran.

Sample size 2009 data were collected from national registry in Iran

Cost assessed Direct and indirect cost for type 2 diabetic patients

Key findings The total national cost of diagnosed Type 2 DM in 2009 is

estimated at 3.78 billion US dollars (USD) including direct

and indirect costs. Average direct and indirect cost per

capita was 842.6±102 and 864.8 USD respectively.

Complications and drugs were main components of direct

cost. The largest components of medical expenditures

attributed to diabetes complications are cardiovascular

disease, nephropathy and ophthalmic complications.

Indirect costs include temporarily disability, permanent

disability and reduced productivity due to premature

mortality.

37

Author and year Bahia LR, Araujo DV, Schaan BD et al (2011)[90]

Study design and

site

A retrospective study based on data collected from

different levels of care in eight Brazilian cities.

Sample size 1000 out patients during the year 2007

Cost assessed Direct and indirect cost involved in type 2 diabetes

mellitus care

Key findings Total annual cost for outpatient care was US$ 2108 per

patient, out of which US$ 1335 per patient of direct costs

(63.3%0 and US$ 773 per patient of indirect costs

(36.7%). Costs escalated as duration of diabetes and level

of health care increased. Patients with both microvascular

and macrovascular complications had higher costs

(US$3199 per patient) than macrovascular (US$ 2517 per

patient) complications only. The greatest portion of direct

costs was attributed to medication (48.2%).

Author and year Solli O, Jenssen T, and Kristiansen IS. ( 2010)[91]

Study design and

site

The study based on prevalence approach using register

data for the entire Norwegian population and responses to

survey of 584 patients with diabetes.

Sample size 2005 data

Cost assessed Direct and indirect cost for type diabetic patient care

Key findings When hospital stays with diabetes as a secondary

diagnosis were excluded, the total costs were €293million,

which represents about 1.4% of the total health care

expenditure. Pharmaceuticals accounted for €95 million

(32%), disability pensions €48 million (16%), medical

devices €40 million (14%) and hospital admissions €21

million (7%). Patient expenditures for acupuncture,

physiotherapy and foot therapy were many times higher

than expenditure for nutritional guidance. Indirect costs

accounted for€70.1 million (24% of the €293million) and

38

included sick leave (€16.7million), disability support and

disability pensions (€48.2 million) and other indirect costs

(€5.3 million). If all diabetes related hospital stays are

included total costs amounts to €535 million, about 2.6%

of the total health care expenditure in Norway.

Author and year Tharkar S, devarajan A, Kumpatla S and Viswanathan

V.(2010) [92]

Study design and

site

Population based Cost of Illness study, conducted at MV

Hospital for diabetes and diabetes Centre, Chennai.

Sample size 718 diabetes patients are participated in survey

Cost assessed Direct and indirect cost involved in the diabetes care.

Key findings The median annual direct and indirect cost associated

with diabetes care was 25,391 INR and 4970 INR

respectively. Extrapolating the direct and indirect costs to

Indian population, the annual costs for diabetes would be

1541.4 billion INR in 2010.

Author and year Clarke PM, Glasziou P, patel A, Chalmers J, Woodward

M, et al.(2010)[93]

Study design and

site

Data from type 2 diabetic patients participating in the

Action in Diabetes and Vascular Disease (ADVANCE)

study. A multicountry comparative analysis

Sample size 11,140 patients from 20 countries.

Cost assessed Costs associated with major complications of diabetes.

Key findings Overall estimated annual hospital costs for patients with

none of the specified events or event histories ranged

from I$ 76 in Asia to I$ 296 in Established Market

Economics. All complications included in this analysis led

to significant increases in hospital costs; coronary events,

cerebrovascular events, and heart failure were the most

costly, at more than I$ 800, I$ 3000 and I$4,000 in Asia.

Eastern Europe, and Established Market Economics,

respectively.

39

Author and year Al-Maskari F, El-Sadig M and Nagelkerke N.(2010)[94]

Study design and

site

A cross sectional survey conducted in Al-Ain District, UAE

Sample size 150 DM patients during 2004-2005

Cost assessed Direct medical costs

Key findings The total annual direct treatment costs of DM among

patients without complications was US$ 1,605 which is

3.2times higher than per capita expenditure for health

care in the UAE (US$497) during 2004. However, this cost

increased 2.2 times with the presence of DM related

complications for patients with microvascular

complications, by 6.4times for patients with macrovascular

complications and 9.4 times for patients with both micro

and macrovascular complications. Likewise, the annual

direct hospitalization costs of DM patients increased by

3.7 times for patients with microvascular complications, by

6.6 times for patients with macrovascular complications

and by 5 times for patients with both micro and

macrovascular complications. Overall, costs increased

with age, diabetes duration and were higher for patients

treated with insulin compared to those treated with oral

hypoglycemic agents or with diet control only.

Author and year Wang W, Fu CW, Pan CY and et al. (2009)[16]

Study design and

site

A cross- sectional study of prevalent type 2 diabetes

carried out in four major cities of China.

Sample size 1530 outpatients and 524 inpatients

Cost assessed Direct medical cost in type2 diabetic patients

Key findings The annual direct medical cost per patient was estimated

to be 4800 Chinese Yuan (CNY) in median or 10,164 CNY

in mean. There is a difference between annual direct

costs for patients with or without complications (6056 vs.

40

3583 CNY; P< 0.001). The direct medical cost varied

significantly among the four cities (p< 0.001). Patients who

simultaneously suffered microvascular and macrovascular

diseases had higher direct medical cost (7600) than those

with macrovascular (6000) (p=0.012) and microvascular

disease (5364) (p< 0.001), and those without both (36000

(p< 0.001).

Author and year Kapur A. (2007)[95]

Study design and

site

The cost of diabetes in India (CODI) study- a large

community based survey of diabetes costs

Sample size A total of 5516 persons with diabetes in the towns and

cities constituting a representative sample of Indian

population.

Cost assessed Direct and indirect cost involved in the management of

type 2 diabetes

Key findings In this study they found that the mean direct annual cost

for outpatient care for all patients with diabetes was INR

4724/-, those without complications had an 18% lower

cost while those with three or more complications had a

48 per cent higher cost. Indirect cost was estimated to be

INR 12,756/- of this productivity loss accounted for INR

9166. The mean annual cost for the entire study

population was INR 19914/-.

Author and year Ramachandran A, Ramachandran S, Snehalatha C and et

al .(2007)[96]

Study design and

site

Using Questionnaire (24 Items). Conducted in India

Sample size 566 diabetic subjects from various urban and rural regions

of seven Indian states

Cost assessed Direct cost involved in the diabetic treatment

Key findings Total median expenditure on health care was Rs 10,000 in

41

urban and Rs 6,260 in rural (P< 0.001) subjects.

Treatment costs increased with duration of diabetes,

presence of complications, hospitalization, surgery, insulin

therapy, and urban setting. Urban and rural diabetic

subjects spend a large percentage of income on diabetic

management. The economic burden on urnan families in

developing countries is rising, and the total direct cost has

doubled from 1998 to 2005.

Author and year Burke M, Chittleborough C, Taylor A, Gill T and Philips P.

(2007)[97]

Study design and

site

Population research and outcome studies, The south

Australian Department of Health , Australia

Sample size COI for the year 2000

Cost assessed Direct and indirect cost involved in diabetes treatment

Key findings The average cost per person with diabetes in 2000 was $

4059. Medical costs made up 48.2% of the direct costs, at

an average of $1732 per person. Non- medical costs

made up 51.8% of the direct costs with additional costs of

physical activity and special diets making up 87.6% of

these nonmedical direct costs. The total direct cost of

diabetes in 2000 was $218 million. This value increased to

over $246 million when indirect costs were also included.

Author and year Suleiman IA, Fadeke OF, and Okubanjo OO.(2006)[98]

Study design and

site

A retrospective study at OlabisiOnabanjo University

Teaching Hospital Sagamu. Ogun State, Nigeria

Sample size 277 prescriptions from 37 patients( July 2003-June 2004)

Cost assessed Direct cost

Key findings The total cost of drugs in all the patients is $ 8,713.81;

total cost of illness (COI) for one year for the 37 patients is

$ 9716.93; average cost of illness per patient/year is $

262.22; 84% of annual per capital income.

42

Author and year Grover S, Avasthi A, Bhansali A, Chakrabarti S and

Kulhara P. (2005)[99]

Study design and

site

COI analysed using Questionnaire. A study from north

India

Sample size 50 out patients with diabetes from Post graduate Institute

of Medical Education and Research (PGIMER),

Chandigarh

Cost assessed Cost of Illness for type 2 diabetic with direct, indirect and

providers cost.

Key findings Total treatment cost was 7254.05 rupees for the six month

period. It includes 68.4% of the direct cost, 28.76% of

indirect cost and 2.8% providers cost. The direct

treatment cost was INR 4966.42/-. an the mean indirect

treatment cost was 2086.74 rupees and 205.55 rupees

contribute for total providers cost for diabetes mellitus .

Author and year Brandle M, Burke R, Zhou H and et al.(2003)[100]

Study design and

site

A patient survey and computer –assisted telephone

interview or in writing – Michigan health maintenance

organization.

Sample size Random sampling of 364 type 2 DM patients

Cost assessed Direct Medical Cost

Key findings The median annual medical costs for subjects with diet –

controlled type2 diabetes, BMI 30 kg/m2, and no

microvascular, neuropathic or cardiovascular

complications were $ 1,700 for white men and $ 2,100 for

white women. A 10kg/m2 increase in BMI , treatment with

oral antidiabetic or antihypertensive agents, diabetic

kidney disease, cerebrovascular disease, and peripheral

vascular disease were each associated with 10-30%

increases in cost. Insulin treatment, angina and MI were

each associated with 60-90% increases in cost. Dialysis

was associated with an 11- fold increase in cost.