2.1 bioavailability (ba) and bioequivalence...

Chapter 2 Literature Review

Dept. of Pharmaceutical Medicine 4 Jamia Hamdard

2.0 LITERATURE REVIEW

2.1 BIOAVAILABILITY (BA) AND BIOEQUIVALENCE (BE)

The importance of generic drugs in health care has increased globally during the last

three decades due to the new drug discovery (brand-name drugs) as well as generic

drug production Thus, it is imperative that the pharmaceutical quality, safety, and

efficacy of generics should be reliably compared with the corresponding innovator

drugs (brand-name drugs). Bioavailability (BA) and bioequivalence (BE) studies

provide important information in the overall set of data that ensure the availability of

safe and effective medicines to patients and practitioners. BA and BE measures are

frequently expressed in systemic exposure measures, such as area under the plasma

concentration-time curve (AUC) and maximum concentration (Cmax).

2.1.1 A Historical Perspective

The concepts of BA and BE have gained considerable importance during the last three

decades and have become the cornerstones for the approval of brand-name and

generic drugs globally. Consequently regulatory authorities also started developing

and formulating regulatory requirements for approval of generic drug products. Using

the BE as the basis for approving generic drugs was established by the Drug Price

Competition and Patent Restoration Act of 1984 (Hatch-Waxman Act). Subsequently

various criteria and approaches for conducting and reporting BE studies for generic

products from various regulatory authorities have been progressing.

2.1.2 Hatch-Waxman Act

The Hatch-Waxman Act (Melethil 2005 ) was an attempt to resolve two major issues:

1) regulatory delays in marketing of pharmaceutical products faced by innovator (also

called pioneer or research) drug companies and 2) difficulties generic drug companies

had at that time in marketing generic versions of pioneer products following expiry of

pertinent patent(s) (Levitt 2002; Beers 1999). In practical terms, this Act made the

following three important provisions: 1) it provided for the extension of the term of

one existing patent for innovator drugs; 2) it made provisions for the marketing of

generic versions of patented drugs on the day after patent expiry; and 3) it provided

opportunities to challenge the validity of patents issued to innovator drug companies.



2.1.3 Regulatory Authorities

Every country now has its own individual regulatory authority as well as regulatory

guidance for BA/BE studies, and the magnitude of assessment of BE of drug product

is influenced by the regulatory environment of the respective country of marketing.

The regulatory authorities of various countries and international organizations are

listed and briefly described (Table 1.1A). In the United States, the FDA approves and

grants marketing authorization of generic drugs by applying the regulatory

requirements provided in the Code of Federal Regulations (CFR). Some of the

relevant sections in the CFR related to BA/BE are listed (Table 1.1B).

2.1.4 Assessment of Bioequivalence

The assessment of BE of different drug products is based on the fundamental

assumption that two products are equivalent when the rate and extent of absorption of

the test/generic drug does not show a significant difference from the rate and extent of

absorption of the reference/brand drug under similar experimental conditions as

defined. As per the different regulatory authorities, BE studies are generally classified

as: 1. Pharmacokinetic endpoint studies, 2. Pharmacodynamic endpoint studies,

3. Clinical endpoint studies and 4. In vitro endpoint studies.

The general descending order of preference of these studies includes pharmacokinetic,

pharmacodynamic, clinical, and in vitro studies (Chen et al. 2001).

2.1.5 Pharmacokinetic Endpoint Studies

Regulatory guidance recommends that measures of systemic exposure be used to

reflect clinically important differences between test and reference products in BA and

BE studies (Chen et al. 2001). These measures include; i) total exposure (AUC0-t or

AUC0-∞ for single-dose studies and AUC0-τ for steady-state studies), ii) peak exposure

(Cmax), and iii) early exposure (partial AUC to peak time of the reference product for

an immediate- release drug product).

Single dose studies to document BE were preferred because they are generally more

sensitive in assessing in vivo release of the drug substance from the drug product

when compared to multiple dose studies. General pharmacokinetic parameters



(primary and secondary) for single-dose, multiple-dose, and urinary data are described

(Table 1.2). The following are the circumstances that demand multiple -dose

study/steady state pharmacokinetics (CDSCO 2005, TGA 2002, CHPB 1992 EMEA

2010, KSAFDD 2005; KFDA 2008).

Dose- or time-dependent pharmacokinetics.

For modified-release products for which the fluctuation in plasma

concentration over a dosage interval at steady state needs to be assessed.

If problems of sensitivity preclude sufficiently precise plasma concentration

measurements after single-dose administration.

If the intra -individual variability in the plasma concentration or disposition

precludes the possibility of demonstrating BE in a reasonably sized single-

dose study and this variability is reduced at steady state.

When a single-dose study cannot be conducted in healthy volunteers due to

tolerability reasons and a single-dose study is not feasible in patients.

If the medicine has a long terminal elimination half-life and blood

concentrations after a single dose cannot be followed for a sufficient time.

For those medicines that induce their own metabolism or show large intra-

individual variability.

For combination products for which the ratio of plasma concentration of the

individual substances is important.

If the medicine is likely to accumulate in the body.

For enteric coated preparations in which the coating is innovative.

Under normal circumstances, blood should be the biological fluid sampled to measure

drug concentrations. Most drugs may be measured in serum or plasma; however, in

some drugs, whole blood (eg: tacrolimus) may be more appropriate for analysis. If the

blood concentrations are too minute to be detected and a substantial amount (40%) of

the drug is eliminated unchanged in the urine, the urine may serve as the biological

fluid to be sampled (eg: alendronic acid) (MCC 2010, EMEA 2007; NZRGM 2001).



Table 1.1A: A Brief Description of Regulatory Authorities of Various Countries and

International Organizations

Country Regulatory Authority Website

India Central Drugs Standard Control Organization (CDSCO)

http://cdsco.nic.in/

Unites States US Food and Drug Administration (FDA) http://www.fda.gov/

Europe European Medicines Agency (EMEA) http://www.ema.europa.eu/

United Kingdom Medicines and Health care products Regulatory Agency (MHRA)

http://www.mhra.gov.uk/

Canada Health Canada http://www.hc-sc.gc.ca/

South Africa Medicines Control Council (MCC) http://www.mccza.com/

Australia Therapeutic Goods Administration (TGA) http://www.tga.gov.au/

Korea Korea Food and Drug Administration (K-FDA) http://www.kfda.go.kr/

Mexico Ministry of Health http://www.salud.gob.mx/

Japan Pharmaceuticals and Medical Devices Agency

(PMDA) http://www.pmda.go.jp/

People’s Republic of China National institute for the Control of Pharmaceutical

and Biological Products http://www.nicpbp.org.cn/cmsweb/

New Zealand Medicines and Medical Devices Safety Authority

(MEDSAFE) http://www.medsafe.govt.nz/

Malaysia National Pharmaceutical Control Bureau http://portal.bpfk.gov.my/

Hong Kong Department of Health http://www.dh.gov.hk/

Fiji Ministry of Health http://www.health.gov.fj/

indonesia Ministry of Health http://www.depkes.go.id/

Singapore Health Sciences Authority (HAS) http://www.hsa.gov.sg

Sri Lanka Ministry of Health http://www.health.gov.lk/

Armenia Scientific Center of Drug and Medical Technologies

Expertise (SCDMTE) http://www.pharm.am/

Taiwan Department of Health (DOH) http://www.doh.gov.tw/

Belgium Pharmaceutical inspectorate http://afigp.fgov.be/

Bulgaria Drug Agency http://www.bda.bg/

Czech Republic State institute for Drug Control http://www.sukl.cz/

Finland National Agency for Medicines http://www.nam.fi/

France Agence Francaise de Securite Sanitaire des Produits

de Sante (AFSSAPS) http://www.afssaps.fr/

Germany Federal institute for Drugs and Medical Devices http://www.bfarm.de/

Greece National Organization for Medicines http://www.eof.gr/

iceland Icelandic Medicines Agency (IMA) http://www.imca.is/

ireland Medicines Board http://www.imb.ie/

italy National institute of Health http://www.iss.it/

Netherlands Medicines Evaluation Board http://www.cbg-meb.nl/

Norway Norwegian Medicines Agency http://www.legemiddelverket.no/

Poland Drug institute

Spain Spanish Drug Agency http://www.msc.es/

Sweden Medical Products Agency

Switzerland Swiss Agency for Therapeutic Products http://www.swissmedic.ch/

Saudi Arabia Ministry of Health http://www.moh.gov.sa/

United Arab Emirates Federal Department of Pharmacies http://www.uae.gov.ae/

Kenya Ministry of Health



Namibia Ministry of Health and Social Services http://www.healthforall.net/grnmhss/

Tanzania Ministry of Health http://www.tanzania.go.tz/

Zimbabwe Ministry of Health and Child welfare http://www.gta.gov.zw/health.html

Brazil National Health Surveillance Agency (ANVISA) http://www.anvisa.gov.br/

Colombia instituto Nacional de vigilancia de Medicamentos Y

Alimentos (INVIMA) http://web.invima.gov.co/

International Organizations

International Conference on Harmonisation (ICH) http://www.ich.org/

World Health Organization (WHO) http://www.who.int/

Global GMP Harmonization by Japan http://www.nihs.go.jp/drug/section3/h

iyama070518-3.pdf

European Union (European Commission and EMEA) http://www.ema.europa.eu/

Global Harmonization Task Force (GHTF) http://www.ghtf.org/

Association of Southeast Asian Nations Consultative Committee for Standards and

Quality ASEAN http://www.aseansec.org/

Table 1.1B: Some of Relevant Sections in the Code of Federal Regulations Related to

BA/BE Studies

21CFR Section Type of Provision/Information

21CFR 314.94(a)(9) Chemistry, manufacturing, and controls; permitted changes in inactive

ingredients for parenteral, otic, ophthalmic, and topical drug products

21CFR 320.1 Definitions of bioavailability, pharmaceutical equivalents, pharmaceutical

alternatives, and bioequivalence

21CFR 320.21 Regulatory requirements related to submission of in vivo bioavailability and

bioequivalence data

21CFR 320.22 Criteria for waiver of evidence of in vivo bioavailability or bioequivalence data

21CFR 320.23 Basis for measuring in vivo bioavailability or demonstrating bioequivalence

21CFR 320.24 Types of evidence to measure bioavailability or establish bioequivalence

21CFR 320.25 Guidelines for the conduct of an in vivo bioavailability study

21CFR 320.26 Guidelines on the design of a single dose in vivo bioavailability or

bioequivalence study

21CFR 320.27 Guidelines on the design of a multiple-dose in vivo bioavailability study

21CFR 320.28 Correlation of bioavailability with an acute pharmacological effect or clinical

evidence

21CFR 320.29 Analytical methods for an in vivo bioavailability or bioequivalence study

21CFR 320.30 inquiries regarding bioavailability and bioequivalence requirements and review

of protocols by the FDA

21CFR 320.32 Procedures for establishing or amending a bioequivalence requirement

21CFR 320.33 Criteria and evidence to assess actual or potential bioequivalence problems

21CFR 320.36 Requirements for maintenance of records of bioequivalence testing

21CFR 320.38 Retention of bioavailability samples

21CFR 320.63 Retention of bioequivalence samples

http://www.nihs.go.jp/drug/section3/hiyama070518-3.pdf

http://www.nihs.go.jp/drug/section3/hiyama070518-3.pdf



Table 1.2: Brief Description of Pharmacokinetic Parameters Used for BA/BE Studies

Study Type Primary Pharmacokinetic

Parameters

Secondary Pharmacokinetic

Parameters

Single Dose Cmax, AUC0-t, AUC0-∞ Tmax, AUC % extrapolation, MRT,

Kel, and T1/2

Steady State Cmax(ss), Cmin(ss), AUC0-τ Tmin(ss), Tmax(ss), Cavg, % swing,

% fluctuation

Urinary

Based Ae(0-t), Ae(0-∞), Rmax Tlag

Notes: Cmax, Maximum plasma concentration; Cmin, Minimum plasma concentration; Cmax(ss), Maximum plasma concentration at steady-state; Cmin(ss), Minimum plasma concentration at steady-state; Cavg, Average plasma concentration;

Tmax, Time to Cmax, AUC0-t, Area under the plasma/serum/blood concentration-time curve from time zero to time t, where t is

the last time point with measurable concentration; AUC0-∞, Area under the plasma/serum/blood concentration-time curve from time zero to time infinity; AUC0-τ, AUC during a dosage interval at steady state; MRT, Mean residence time; Ae(0-t),

Cumulative urinary excretion from pharmaceutical product administration until time t; Ae(0-∞), Amount of unchanged API

excreted in the urine at infinite time (7-10 half-lives); T1/2, Plasma concentration elimination half-life;

% fluctuation, (Cmax(ss) - Cmin(ss))/Cavg⋅100; % swing, (Cmax(ss) - Cmin(ss))/Cmin⋅100.

2.1.6 General Regulatory Considerations For BA/BE Studies

The processes of study design and workflow of BA/BE studies are presented in brief

(Figures 1.1 and 1.2). The general considerations for the advancement of conducting

BA/BE studies are:

Study Design and Protocol.

Bioanalysis.

Selection of Appropriate Analyte(s).

Be Metrics and Data Treatment.

Statistical Approaches and Analysis.

Acceptance Criteria For Be

2.1.6.1 Study Design and Protocol

Successfully determining the BE of generic drugs to their respective reference drugs

depends mostly on design and managing the conduct of study such that the highest

quality samples are obtained. Some regulatory authorities (US: http:// www.access

data.fda.gov/scripts/cder/drugsatfda/index.cfm; Europe: http://www.medicines.org.uk/

EMC/browsedocuments. aspx; Canada: http://webprod.hc-sc.gc.ca/dpd-bdpp/index-

eng.jsp; Australia: https://www.ebs.tga.gov.au/) are providing specific information

about Reference Listed Drug (RLD)/ reference product information on their websites,



which makes it easy for investigators to proceed with BA/BE study design. Generally

the study design and number of studies (single- dose and/or multiple-dose and/or

fasting and/or fed) depend on the RLD or reference product, physicochemical

properties of the drug, its pharmacokinetic properties, and proportionality in

composition with justification along with respective regulatory guidance and

specifications. Various study designs generally used for BA/BE studies (Table 1.3).

Figure 1.1: Brief Process of Bioequivalence Study Design and Protocol Approval



Figure 1.2: Brief Work Flow of Bioavailability/Bioequivalence Study

The regulatory specifications on demographics, sample size, sampling and washout

period, regulatory acceptance criteria for bioequivalence and regulatory acceptance

criteria for special class drugs are briefly described (Tables 1.4, 1.5, 1.6, 1.7 and 1.8).



2.1.6.2 Bioanalysis

In a general prospective of BA/BE studies, bioanalysis should be the subsequent step

following clinical operations of the study (Figure 1.2), and it should be executed with

strict adherence to good laboratory practices, standard operating procedures, and

specific regulatory requirements. Bioanalysis is a term generally used to describe the

quantitative measurement of a compound (drug) or its metabolite in biological

fluids, primarily blood, plasma, serum, urine, or tissue extracts (James et al. 2004).

Bioanalysis typically consists of two important components 1) sample preparation and

2) detection of the desired compound using a validated method.

2.1.6.3 Selection of Appropriate Analyte(s)

2.1.6.3.1 Parent Drug vs Metabolite(s)

BE based on test/reference comparisons of pharmacokinetic measures serves two

purposes 1) to act as a surrogate for therapeutic equivalence, 2) to provide in vivo

evidence of pharmaceutical quality. Traditional BE studies have been carried out on

the basis of measurement of only the parent drug in body fluids such as plasma or

serum. In some cases, however, monitoring a metabolite, or the parent and

metabolite(s), may be more appropriate. A number of reasons for use of metabolite

data have been put forward (Midha et al. 2004), such as i) the parent is an inactive

prodrug, ii) plasma concentrations of the parent drug are too low to monitor because

of inadequate assay sensitivity, iii) the parent drug is metabolized rapidly to an active

metabolite, and iv) the parent drug and a metabolite both have therapeutic activities

but the metabolite is present in higher concentrations when the parent drug is rapidly

and extensively metabolized such that only metabolite(s) data are available (Chen et

al. 2001 ).

2.1.6.4 BE Metrics and Data Treatment

The most frequent data treatment involves analysis of variance using a suitable

program such as SAS® (Statistical Analysis System, SAS Institute, Cary, NC) or

WinNonlin® (Pharsight Corporation, St. Louis, MO) so that contributions from

subject, period, product/formulation, and interactions between these can be examined.

Geometric mean ratios and log transformed data are examined to test the hypothesis



that the 90% confidence interval of extent (AUC0-t and AUC0-∞) and the maximum

concentration (Cmax) fall within the acceptance limits of 80% to 125%. More recently,

other data treatments have been popular, which include partial area measurements and

exposure metrics including Cmax/ AUC, especially with highly variable drugs (HVDs),

and with drugs having a long terminal t1/2, specialized dosage forms, and/or whose

time to Cmax is considered important (e.g., certain analgesics).

2.1.6.5 Statistical Approaches

The various pharmacokinetic parameters derived from the plasma concentration-time

curve are subjected to ANOVA in which the variance is partitioned into components

due to subjects, periods, and treatments. The FDA therefore recognized that a finding

of no statistical signifycance in the first case was not necessarily evidence of BE and

consequently asked for a retrospective examination of the power of the test of null

hypothesis (Rani et al. 2004).

Adequate statistical approaches should be considered to establish the BE of generic

product to that of reference product. Much worldwide discussion and interaction has

focused on facilitating the appropriate statistical approaches to establish

interchangeability between generic drug and reference drug. The pertinent statistical

approaches include i) study power; ii) 75/75 rule; and iii) 90% confidence interval

(Midha1 2009).



Table 1.3: Brief Description About Various Study Designs Used in BA/BE Studies

Design Significance Advantages Disadvantages

Crossover

When intra-subject CV (approx. 15%) is

usually substantially smaller than that inter-

subject CV (approx. 30%)

Generally recommended by all regulatory

authorities

Since the treatments are compared on the same subject, the inter-

subject variability does not contribute to the error variability

Subject randomization causes unbiased determination of

treatment effects

Large information based on minimum sample size

Straightforward statistical analysis

Carryover effects and period effects are possible due to

inappropriate wash-out period

Long duration

Possibility of more drop outs leads to insufficient

power

Not suitable for long half-life drugs

Not optimal for studies in patients and highly variable

drugs

Parallel

If the drug has a very long terminal

elimination half-life

Duration of the washout time for the two-

period crossover study is so long (if >1 month)

If the intra-subject CV is higher with crossover

design

Design is simple and robust

Drop outs will be comparatively less

Duration of the study is less than crossover study

Study with patients is possible

Straightforward statistical analysis

Subjects cannot serve as their own controls for intra-

subject comparisons

Large sample size is required

Lower statistical power than crossover

Phenotyping mandatory for drugs showing

polymorphism

Replicate Useful for the highly variable drugs (intra-

subject CV ≥30%)

Allows comparisons of within-subject variances for the test and

reference products

Indicates whether a test product exhibits higher or lower within-

subject variability in the bioavailability measures when

compared to the reference product

Provides more information about the intrinsic factors underlying

formulation performance

Reduces the number of subjects needed in the BE study

The number of subjects required to demonstrate bioequivalence

can be reduced by up to about 50%

Design increases the power of the study when the variability in

the systemic exposure of the test drug and formulation is high

Involves larger volume of blood withdrawn from each

subject

Longer duration of the entire study

Increased possibility of subject drop outs

Expensive

Variance

Balanced

Design

For more than two formulations

Desirable to estimate the pair wise effects with

the same degree of precision

Allows to choose between two more candidate test formulations

Comparison of test formulation with several reference

formulations

Standard design for the establishment of dose proportionality

Statistical analysis is more complicated (especially

when dropout rate is high)

May need measures against multiplicity (increasing the

sample size)



2.1.6.5.1 Study Power

The conduct of a BE study should require some prior knowledge of the performance

of the products (generic and brand drugs) in the human body so that an appropriate

number of test subjects can be enrolled and provide adequate power to test the

hypothesis with a reasonable likelihood (ie, at least 80%) that the two products are

indeed bioequivalent. The two criteria considered most important to understand are

the inherent variability of the drug and the geometric mean ratio between the test and

reference product. Both of these parameters can be determined through the conduct of

a pilot study (n = 6-12) to determine the proper sample size required for the pivotal

study to establish BE as well as to minimize the possibility of undersizing the study

(Midha1 2009).

2.1.6.5.2 75/75 Rule

This approach was the first application wherein individual BE (ABE) was being

tested. The biomedical community felt that unless the change in the biological system

was greater than 20% to 25%, it would really not pose a significant clinical risk of

invalidating the use of one therapeutic strategy versus another. This formed the basis

for the 75/75 rule, which states that two products are equivalent if, and only if, at least

75% of the individuals being tested had ratios (of the various pharmacokinetic

parameters obtained from the individual results) between the 75% and 125% limits,

and the study conducted has the statistical power to detect a 20% difference between

the two products (Midha1 2009). This approach was sound until the arrival of the

90% confidence interval.

2.1.6.5.3 90% Confidence Interval

Westlake38 was the first to suggest the use of confidence intervals as a BE test to

evaluate whether the mean amount of drug absorbed using the test formulation was

close to the mean amount absorbed of the reference product. Subsequently, in July

1992, the guidance on Statistical Procedures for Bioequivalence Studies Using a

Standard Two-treatment Crossover Design was released by the FDA. It was revised

in 2001, and is available as Statistical Approaches to Establishing Bioequivalence

(http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/

Guidances/ucm070244.pdf). This is based primarily on average BE (ABE), wherein



the average values for the pharmacokinetic parameters were determined for the test

and reference products and compared using a 90% confidence interval for the ratio of

the averages using a two one-sided t-tests procedure (Schuirmann 1987).

This concept was really based on the fact that if the ratios of the two pharmacokinetic

parameters of clinical interest (such as AUC, Cmax) are to be compared, each with

their own variability which may or may not be randomly distributed, then such a

comparison can truly be done only through a confidence interval approach. This

concept is well accepted by almost all regulatory authorities to establish the BE.

The general statistical deliverables for a single-dose crossover BE study include

summary statistics, ANOVA, 90% confidence interval, ratio analysis, and intra-

subject variability in addition to sequence, treatment, and period effects.

2.1.6.6 Acceptance Criteria for Bioequivalence

An equivalence approach is generally recommended, which usually relies on i) a

criterion to allow the comparison; ii) a confidence interval for the criterion; and iii) a

BE limit. Log transformation of exposure measures (Cmax and AUC) is generally

recommended by various regulatory authorities. To compare measures in these

studies, data are generally analyzed by using an average BE criterion with some

considerations allowed for special category drugs.

2.1.6.6.1 General

To establish BE, the calculated 90% confidence interval should fall within a BE limit

of 80% to 125% using logarithm transformed data (adopted since the concentration

parameters Cmax and AUC may or may not be normally distributed). Currently, the BE

limits of 80% to 125% have been applied to almost all drug products by regulatory

authorities. More detailed information on acceptance criteria for BE is given (Table

1.7).

2.1.6.6.2 For Highly Variable Drugs

In the context of BE, HVDs are considered to be drugs and drug products exhibiting

intra-subject variability greater than 30% coefficient of variation in the

pharmacokinetic measures, AUC and/or Cmax (Schuirmann 1987; Haidar et al. 2008 ).



Due to this high variability, large sample size may be needed in BE studies to give

adequate statistical power to meet FDA BE limits, and thus designing BE studies for

HVDs is challenging.

Major regulatory agencies also considered different approaches for evaluating BE of

highly variable drugs (NIHS 2010, AGCB 2010, Tamboli et al. 2010). From 2004

onward the FDA started looking for alternative approaches to resolve this issue, and

eventually found that replicate crossover design and scaled average BE provides a

good approach for evaluating the BE of highly variable drugs and drug products as it

would effectively decrease sample size, without increasing patient risk (Haidar1 et al.

2008).

Table 1.4: Regulatory Criteria on Subject Demographics for BA/BE Studies

Regulatory Authority Sex Age

(years) Body Mass Index (BMI) (kg/m2)

India Male or female

Healthy

adult

volunteers

Not specified

Asia Either sex 18-55 18-30; Asians: 18-25

United States Both sexes ≥18 Not specified

Europe Either sex ≥18 18.5-30

Canada Both sexes 18-55

Height/weight ratio for healthy

volunteer subjects should be within

15% of the normal range

Australia Either sex 18-55 Accepted normal BMI

South Africa Either sex 18-55

Accepted normal BMI or within

15% of the ideal body mass or any

other recognized reference

Russia Both sexes 19-45

weight of body does not fall outside

the limits ±15% on Ketle total-

height index

Korea Healthy adult 19-55 Not specified

Japan Healthy adult Not

specified Not specified

People’s Republic of

China Both sexes 18-40 Standard weight range

Mexico

Avoiding pharmacokinetic

differences between sexes is well

documented; volunteers of just one

sex must be included

18-55 weight 10% from the ideal weight

Saudi Arabia

if females are included in the study,

the effects of gender differences and

menstrual cycle (if applicable) are

examined statistically.,

18-50 within 15% of ideal body weight,

height, and body fluid

New Zealand Both sexes

Age range

prior to

the onset

Average weight (eg, within ±15%

of their ideal weight as given in the

current Metropolitan Life Insurance

Company Height and Mass Tables)



2.1.6.6.3 For Narrow Therapeutic Index Drugs (NTIDs)

NTIDs can be defined as drugs that require therapeutic drug concentration or

pharmacodynamic monitoring and/or drugs for which drug product labeling indicates

a narrow therapeutic range designation.

Table 1.5: Regulatory Criteria on Sample Size for BA/BE Studies

Regulatory

Authority Minimum Sample Size Specifications

India

Should not be<16 unless justified for

ethical reasons

The number of subjects required for a study should be statistically significant and should be sufficient to allow for possible withdrawals or removals (drop outs) from the

study

Asia Should not be <12

The number of subjects required is determined by

a) The error variance associated with the primary characteristic to be studied as estimated from a pilot experiment, from previous studies or from published data; b)

The significance level desired; c) The expected deviation from the reference product

compatible with BE (delta, ie, percentage difference from 100%); and d) the required power

United

States 12

A sufficient number of subjects should complete the study to achieve adequate power for a statistical assessment

Europe Should not be <12 The number of subjects to be included in the study should be based on an appropriate sample size calculation

Canada 12

a) Obtain an estimate of the intra-subject CV from the literature or from a pilot study; b) choose one of Figures 3.1 through 3.3 (mentioned in BE guidance document) by

determining which one has the closest rounded-up CV to that estimated in a), above; c)

choose an expected true ratio of test over reference means (usually 100%) and move up the graph to the 0.90 probability of acceptance; d) a linear extrapolation between

given sample sizes is adequate. This sample size calculation must be provided in the

study protocol. More subjects than the sample size calculation required should be recruited into the study. This strategy allows for possible drop-outs and withdrawals

Australia Should not be<16

unless justified Same as that of Asian guidelines

South Africa

Should not be ,12

(general); 20 subjects

(for modified release

oral dosage forms)

The number of subjects should be justified on the basis of providing at least 80%

power of meeting the acceptance criteria; Alternatively, the sample size can be

calculated using appropriate power equations, which should be presented in the

protocol

Russia 18 In quantity sufficient for ensuring statistical importance of study. Thus capacity of the statistical test for BE study must be supported at a level of not less than 80% for

revealing 20% distinctions between comparison parameters

Korea 12

The number of subjects should meet the requirements for statistical validity. The

number of subjects can be determined based on the characteristics of the active component of the pertinent drug products

Japan 20

A sufficient number of subjects for assessing BE should be included. If BE cannot be

demonstrated because of an insufficient number, an add-on subject study can be performed using not less than half the number of subjects in the initial study. A sample

size of 20 (n = 10/group) for the initial study and pooled size of 30 for initial plus add-

on subject study may suffice if test and reference products are equivalent in dissolution and similar in average AUC and Cmax

Saudi

Arabia

A number of ubjects of

less than 24 may be accepted (with a

minimum of 12

subjects) when

statistically justifiable

Generally recommends a number of 24 normal healthy subjects. Should enroll a

number of subjects sufficient to ensure adequate statistical results, which is based on

the power function of the parametric statistical test procedure applied. The number of subjects should be determined using appropriate methods taking into account the error

variance associated with the primary parameters to be studied (as estimated for a pilot

experiment, from previous studies or from published data), the significance level

desired (α = 0.05), and the deviation from the reference product compatible with BE

(±20%) and compatible with safety and efficacy

New

Zealand 12

The number of subjects should provide the study with a sufficient statistical power (usually $80%) to detect the allowed difference (usually 20%) between the test and

reference medicines for AUC and Cmax. This number (n) may, in many cases, be

estimated in advance from published or pilot study data using formula. If the calculated number of subjects appears to be higher than is ethically justifiable, it may

be necessary to accept a statistical power which is less than desirable. Normally it is

not practical to use more than about 40 subjects in a bioavailability study

Brazil The number of healthy volunteers shall all times assure an adequate statistical power to guarantee reliability of BE

study results



A NTIDs list was prepared by the Center for Drug Evaluation and Research and

available in the Scale-Up and Post-Approval Changes for Intermediate Release

Products (more information is available at http:// www.fda.gov/ downloads/ Drugs/

Guidance Compliance Regulatory Information/ Guidances/ ucm070636. pdf). The

regulatory acceptance criterion for NTIDs are presented (Table 1.8).

Table 1.6: Regulatory Criteria on Sampling and Washout Period for BA/BE Studies

Regulatory

Authority Sampling criteria Washout Criteria

India

Blood sampling : Should be extended to at least 3 elimination half lives;

at least 3 sampling pointsduring absorption phase, 3-4 at the projected

Tmax, and 4 points during elimination phase; sampling should be

continued for a sufficient period to ensure that AUC0-t to AUC0-∞ is

only a small percentage (normally <20%) of the total AUC. Truncated

AUC is undesirable except in the presence of enterohepatic recycling

Urinary sampling: Collect urine samples for 7 or more half-lives

Adequate and ideally

it should be ≥5 half-

lives of the moieties

to be measured

United

States

Blood samples should be drawn at appropriate times to describe the

absorption, distribution, and elimination phases of the drug; 12-18

samples, including a period predose sample, should be collected per

subject per dose; should continue for at least 3 or more terminal half-lives

of the drug

An adequate washout

period (eg, more than

5 half-lives of the

moieties to be

measured)

Europe

Single-dose blood sampling: Sufficient sampling is required; frequent

sampling around predicted Tmax; avoid Cmax be the first point;

accommodate reliable estimate (AUC0-t) covers at least 80% of AUC0-

∞); at least 3-4 points during the terminal log-linear phase; AUC

truncated at 72 h (AUC0-72h) may be used as an alternative to AUC0-t or

comparison of extent of exposure

Multiple-dose blood sampling

Pre-dose sample should be taken immediately before (within 5 min)

dosing and the last sample is recommended to be taken within 10 min of

the nominal time for the dosage interval to ensure an accurate

determination of AUC0-τ

Urinary sampling: Urine should normally be collected over no less than

3 times the terminal elimination half-life

Sufficient washout

period (usually at

least 5 terminal half-

lives)

Australia

Single-dose blood sampling: Should provide adequate estimation of

Cmax; cover plasma concentration time curve long enough to provide a

reliable estimation of the extent of absorption; 3-4 samples during the

terminal log-linear phase. AUC truncated at 72 h is permitted for long

half-life drugs Multiple-dose blood sampling when differences between

morning and evening or nightly dosing are known, sampling should be

carried out over a full 24-h cycle

Adequate washout

period

South

Africa

Blood sampling: Sampling should be sufficient to account for at least

80% of the known AUC0-∞, Cmax; collecting at least 3-4 samples above

the LOQ during the terminal log-linear phase; sampling period is

approximately three terminal half-lives of the drug; AUC truncated at 72

h is permitted for long half-life drugs; 12-18 samples should be collected

per each subject per dose; at least 3-4 samples above LOQ should be

obtained during the terminal log-linear phase.

Urine sampling: Sufficient urine should be collected over an extended

period and generally no less than 7 times the terminal elimination half-

life; for a 24-h study, sampling times of 0-2, 2-4, 4-8, 8-12, and 12-24 h

post dose are usually appropriate

Adequate washout

period

Canada

Blood sampling: Sampling should be sufficient to account for at least

80% of the known AUC0-∞, Cmax and terminal disposition; 3 times the

terminal half-life of the drug; 12-18 samples should be collected per each

subject per dose; 4 or more points be determined during the terminal log-

linear phase

Urine sampling: Urine should be collected over no less than 3 times the

terminal elimination half-life. For a 24-h study, sampling times of 0-2, 2-

4, 4-8, 8-12, and 12-24 h

Normally should be

not less than 10 times

the mean terminal

half-life of the drug.

Normally, the interval

between study days

should not exceed 3-4

weeks



Table 1.7: Regulatory Acceptance Criteria for Bioequivalence

Regulatory

authority

90% Confidence Interval on Log Transformed Data

Single-Dose Study Steady-State Study

Cmax AUC0-t AUC0-∞ Cmax Cmin AUCτ

India 80-125 80-125 80-125 80-125 80-125 80-125

Asia 80-125 80-125 80-125 80-125 80-125 80-125

United States 80-125 80-125 80-125 80-125 80-125 80-125

Europe 80-125 80-125 Not

applicable 80-125 Not applicable 80-125

Canada

Ratio must be 80–125. Need

to pass also on potency

corrected data Add-on studies may be allowed if

intra-CV greater than

expected

80-125 Not

applicable 80-125 80-125 80-125

Australia 80-125 80-125 Not

applicable 80-125 80-125 80-125

South Africa 75-133 80-125 Not

applicable 75-133 75-133

80-125

(including % swing and %

fluctuation)

Russia 75-133 80-125 80-125 75-133 75-133 80-125

Korea 80-125 80-125 80-125 80-125 80-125 80-125

Mexico 80-125 80-125 Not

applicable 80-125 80-125 80-125

Saudi Arabia 80-125 80-125 80-125 80-125 80-125

80-125

(including % swing and %

fluctuation)

New Zealand 80-125 80-125 80-125 80-125 80-125 80-125

Table 1.8: Regulatory BA/BE Acceptance Criteria for Special Class Drugs

Regulatory

Authority

Highly variable drugs 90% confidence interval

Log transformed data

Narrow therapeutic index drugs 90%

confidence interval Log transformed

data

Cmax AUC Cmax AUC0-t

Asia

The interval must be prospectively defined, eg, 0.75-1.33 and justified for

addressing in particular any safety or efficacy concerns for patients switched

between formulations

in rare cases a wider acceptance range may

be acceptable if it is based on sound clinical

justification

Acceptance

interval may need to be

tightened

Acceptance interval

may need to be tightened

United

States

GMR (80-125) 95% upper bound for (µT-µR)/δ2 WR # 0.7976 (using scaled

average approach)

GMR (80-125) 95%

upper bound or (µT-µR)/δ2 wR # 0.7976

(using scaled average

approach)

80-125 80-125

Europe* - - 90.00-111.11 90.00-111.11

Canada GMR (80-125) GMR (80-125)

90% CI (80-125) - -

Saudi

Arabia 75-133

wider acceptance range

may be acceptable and

this should be justified clinically

90-111 -

Japan - - 90.00-111.11 90.00-111.11

Notes: *For highly variable drugs: a wider difference in Cmax is considered relevant based on a sound clinical justification. If

this is the case the acceptance criteria for Cmax can be widened to a maximum of 69.84%-143.19%. For this acceptance BE study must be a replicate design where it has been demonstrated that intra-subject Cv for Cmax of reference drug is .30%. The

applicant should justify the calculated intra-subject Cv is a reliable estimate and that it is not the result of outliers and the request

for widened interval must be prospectively specified in the protocol.



2.2 FIXED DOSE COMBINATION

The development of fixed-dose combinations (FDCs) is becoming increasingly

important from a public health perspective. They are being used in the treatment of a

wide range of conditions and are particularly useful in the management of human

immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), malaria

and tuberculosis, which are considered to be the foremost infectious disease threats in

the world today.

FDCs have advantages when there is an identifiable patient population for whom

treatment with a particular combination of actives in a fixed ratio of doses has been

shown to be safe and effective, and when Additionally, in a situation of limited

resources, the cost of an FDC finished pharmaceutical product (FDC-FPP) may be

less than that of separate products given concurrently, and there are simpler logistics

of distribution. Improved patient adherence and reduced development of resistance in

the case of antimicrobials can be difficult to prove, but may be additional benefits.

Notwithstanding these potential benefits, FDCs must be shown to be safe and

effective for the claimed indications. It should not be assumed that benefits outweigh

risks. As for any new medicine, the risks and benefits should be defined and

compared. The World Health Organization has published a series of guidelines

relating to marketing authorization of finished pharmaceutical products (FPPs)

2.2.1 Scenarios

An application to register an FDC-FPP may fall into any one of the following four

scenarios. These guidelines are intended to address the different requirements for each

scenario.

a) Scenario 1: The new FDC-FPP contains the same actives in the same doses as

an existing FDC-FPP; that is it is a “generic” of the existing FDC-FPP; they

are “multisource” products. The quality, safety and efficacy of the existing

product have been established.

b) Scenario 2: The new FDC-FPP contains the same actives in the same doses as

an established regime of single entity products, and the dosage regimen is the

same. Alternatively the established regime may involve combinations of single



entities and FDCs, for example, a single entity FPP combined with an FDC-

FPP that contains two actives. In all cases, the established regime has a well-

characterized safety and efficacy profile, and all of the FPPs used in obtaining

clinical evidence have been shown to be of good quality.

c) Scenario 3: 1) The new FDC-FPP combines actives that are of established

safety and efficacy but have not previously been used in combination for this

indication.

2) The new FDC-FPP comprises a combination for which safety and efficacy

have been established, but that will be used in a different dosage regimen.

d) Scenario 4: The new FDC-FPP contains one or more new chemical entities.

2.2.2 Balancing the Advantages and Disadvantages of A New Fixed-Dose

Combination

2.2.2.1 In determining whether it is rational to combine actives into a single

product, there are medical, quality and bioavailability considerations.

Quality issues may be addressed by much the same criteria that apply to

single-component products and it is difficult to imagine a case in which

essentially the same standards would not apply.

Medical considerations are more complex and sometimes contradictory, for

example, when increased efficacy is accompanied by increased toxicity. The

decision as to whether to give marketing approval for a new FDC-FPP in

scenarios 3 and 4 is often based on a consideration of the balance of

advantages and disadvantages from the medical perspective.

Interpretation of the results of bioavailability and bioequivalence tests

involves both quality and medical considerations. For example it is not

acceptable that bioavailability is reduced or variable, when compared with that

of single entity products, because of poor formulation, but an interaction

between two actives that leads to an increased bioavailability may be one of

the advantages that is taken into account when balancing advantages and

disadvantages.



Balancing the advantages and disadvantages of a new FDC-FPP should form a major

component of submissions pursuant to this guideline.

2.2.2.2 Submissions for marketing approval of a new FDC in scenarios 2, 3 and 4

should include a section in which the advantages of the new combination

are weighed against the disadvantages. All the possible advantages and

disadvantages of the combination should be listed and discussed. The

discussion should be based on the available data and on scientific and

medical principles. In less well-developed nations, and particularly where

there are difficulties with transport and the logistics of distribution, other

matters may need to be taken into account, such as:

The cost of the combination as compared with the cost of individual

components.

Evidence as to whether the new FDC will improve the reliability of supply as

a result of simplified distribution procedures. Improved patient adherence may

result from more reliable (continuing) availability of the FDC-FPP than of all

of the components as loose combinations of single entity products. However,

issues of cost and procurement alone are not sufficient reason to approve an

FDC if it has not been justified by appropriate data and on scientific and

medical principles.

2.2.2.3 From a scientific or medical perspective, FDCs are more likely to be

useful when several of the following factors apply:

There is a medical rationale for combining the actives.

There is an identifiable patient group for which this combination of actives

and doses is suitable therapy. The larger the patient group in question, the

more significant is this factor. It is not appropriate to combine actives that

separately treat conditions that do not commonly coexist.

The combination has a greater efficacy than any of the component actives

given alone at the same dose.



The incidence of adverse reactions in response to treatment with the

combination is lower than in that response to any of the component actives

given alone, for example as a result of a lower dose of one component or a

protective effect of one component, and particularly when the adverse

reactions are serious.

For antimicrobials, the combination results in a reduced incidence of

resistance.

One drug acts as a booster for another (for example in the case of some

antiviral drugs).

The component actives have compatible pharmacokinetics and/or

pharmacodynamics.

Therapy is simplified, particularly when the existing therapy is complex or

onerous (e.g. because of a “high tablet load”).

One of the ingredients is intended to minimize abuse of the other ingredient

(e.g. the combination of diphenoxylate with atropine, or buprenorphine with

naloxone).

The active pharmaceutical ingredients are chemically and physicochemically

compatible, or special formulation techniques have been used that adequately

address any incompatibility.

Other potential advantages of FDCs over single entity products given concurrently in

the same dose may include:

Convenience for prescribers and patients.

Better patient adherence (but the evidence for this is largely anecdotal) (1, and

Haynes, RB, personal communication, 2003).

Simplified logistics of procurement and distribution.

Lower cost.



These factors are important, but there may not necessarily be evidence to

support them; they may be more significant when there is specific evidence

available to support a particular case.

2.2.2.4 From a scientific or medical perspective, FDCs are less likely to be useful

when one or more of the following factors apply:

The component actives are normally separately titrated to meet the patient’s

needs. Consequently:

o Either the doses of the components, and/or the ratio of doses, typically

differ from patient to patient, and/or

o Patients are likely to be taking different doses at different stages of

treatment (for example initial treatment compared with long-term

treatment). These two factors are particularly significant when one or

more of the actives has a narrow therapeutic index and/or a steep dose-

response curve in the therapeutic range.

There is a higher incidence or greater severity of adverse reactions to the

combination than with any of the ingredients given alone, or there are adverse

reactions not seen in response to treatment with any of the individual

ingredients.

There are unfavorable pharmacokinetic interactions between the ingredients,

for example when one drug alters the metabolism, absorption or excretion of

another. Dose adjustment is necessary in special populations, such as in people

with renal or hepatic impairment.

The product (tablets or capsules), is so large that patients find it difficult to

swallow.



2.2.3 Bioavailability and Bioequivalence for Fixed Dose Combination Product

2.2.3.1 Data on bioequivalence provide a bridge between two pharmaceutical

equivalents, when safety and efficacy data are available for one of the

FPPs, but not for the other. By demonstrating that the two products lead to

the same profile for plasma concentration over time, available safety and

efficacy data for one of the products can be extrapolated to the other. The

two products being compared may be different brands, or different batches

of the same brand, for example when manufactured by different methods,

at different sites or according to different formulations.

2.2.3.2 Data on bioequivalence may also be important when the same FPP is

administered under different circumstances, for example before or after

food, in different patient populations (such as children versus adults), or by

different routes of administration (such as subcutaneous versus

intramuscular injection).

2.2.3.3 In the context of these guidelines, an additional application of

bioequivalence studies is in scenario 2 in which safety and efficacy data on

single entity products given concurrently may be extrapolated to an FDC-

FPP, provided that all of the conditions described elsewhere in these

guidelines are met. There are two common circumstances in which data on

bioequivalence are likely to be generated for pharmaceutical equivalents:

Pivotal clinical trials were generated on one formulation and another is to be

marketed by the same company (for example because the second formulation

is more stable or more marketable than the first); or

A relevant patent has expired and a multisource pharmaceutical equivalent has

been developed.

2.2.3.4 Evidence as to bioequivalence is required for scenarios 1 and 2, and

sometimes for scenarios 3 and 4, for example when there are major

differences between the formulation and/or method of manufacture of the

product to be registered and that used in pivotal clinical trials.



2.2.3.5 If a study of bioequivalence finds that the two treatments are

bioequivalent, it may be assumed that any pharmacokinetic interactions

between the actives were the same, even if one treatment comprised an

FDC-FPP and the other comprised separate products.

2.2.3.6 Data on absolute bioavailability are usually required in scenario 4, i.e.

comparison of the area under the curve for plasma concentration over time

after an intravenous injection with that after administration of the dosage

form to be marketed, for example a tablet given orally.1

2.2.3.7 A decision as to whether it is necessary to conduct a study of the effect of

food on the bioavailability of an FDC-FPP should be based on what is

known of the effect of food on the individual actives, and any relevant

recommendations in the product information for the single entity products.

The effect of food should normally be studied in scenario 4.

2.2.3.8 Recommendations as to the conduct and analysis of bioequivalence studies

are provided in the WHO guidelines, Multisource (generic) pharmaceutical

products: guidelines on registration requirements to establish

interchangeability (1996, or later updates). Other guidelines may be

relevant depending on the jurisdiction in which the application is

submitted.

2.2.3.9 During analysis of the results of a bioavailability or bioequivalence study

for an FDC-FPP, the parameters to be reported and assessed are those

that would normally be required of each active if it were present as a single

entity and the same statistical confidence intervals and decision criteria

should be applied.

2.2.3.10 An additional scientific consideration that has been elaborated in recent

years is the option for biowaivers based on the Biopharmaceutics

Classification Scheme (BCS). This is an area in which further

developments are expected. The main relevant publication to date is

Waiver of in vivo bioavailability and bioequivalence studies for

immediate-release solid oral dosage forms based on a biopharmaceutics

classification system. US Food and Drug Administration (2000). At



present, and in the absence of clear guidance for FDCs, it is recommended

that biowaivers based on the BCS classification as the sole criterion for a

decision be handled cautiously because there is at present no guidance as

to how to consider the possibility of a chemical or pharmacokinetic

interaction between actives that may affect bioequivalence. However there

are circumstances in which the BCS classification may nevertheless be

relevant to FDCs. In such a case the BCS classification of all the actives in

the FDC should be taken into account.

2.2.3.11 Validation of assays of actives in biological media is crucial in order to

generate a meaningful bioavailability and bioequivalence study. See, for

example, the guidelines Bioanalytical method validation. US Food and

Drug Administration (2001).

2.2.3.12 Selection of a suitable comparator for the purpose of bioequivalence is

described in Guidance on the selection of comparator pharmaceutical

products for equivalence assessment of interchangeable multisource

(generic) products. World Health Organization (2002). Some additional

comments follow.

The comparator should be of known quality, safety and efficacy.

For applications in scenario 1, the decision as to the comparator depends on

whether there is more than one existing brand of the combination whose safety

and efficacy is known to be acceptable. If only one brand is known to have

acceptable safety and efficacy, this should be used as comparator. In other

circumstances, the decision is more difficult and should be justified by cogent

argument and data. The WHO Guidance on the selection of comparator

pharmaceutical products for equivalence assessment of interchangeable

multisource (generic) products (2002) may be of assistance.

For applications in scenario 2, single entity products will have been used in the

majority of pivotal clinical trials. The same brands of those single entity FPPs

should be the comparator and should be given concurrently as was the case in

the pivotal clinical trials.



For applications in scenarios 3 and 4 (with which evidence as to safety and

efficacy will be submitted), the new product should be shown to be

bioequivalent to the product(s) that was (were) used in pivotal clinical trials.

2.2.4 Superiority, Equivalence and Non-Inferiority Trials and Fixed-Dose

Combinations

Regulatory guidelines define superiority, equivalence and non-inferiority trials and

make some general points concerning different types of study. In the context of FDCs,

equivalence trials are largely confined to bioequivalence studies.

2.2.4.1 An FDC-FPP should be shown, directly or indirectly, to be superior to the

component actives given as single entity treatments. Only a superiority

trial can give the necessary statistical confidence. Submissions should

discuss both the statistical significance and clinical relevance of the

results. Any alternative form of evidence that purports to address the

same issues, for example one that concerns a dose-response surface, must

be explained and justified with appropriate statistical confidence.

2.2.4.2 In clinical trials that are intended to test for superiority and/or non-

inferiority, the choice of comparator should be carefully considered and

will depend in part on the medical and ethical circumstances. The

comparator may be:

The treatment whose risk-benefit profile is best supported by evidence or

is at least well established.

One or more of the actives in the FDC given as a single treatment.

A placebo.

2.2.4.3 Depending on the claim, superiority or non-inferiority should be

demonstrated for each specified clinical outcome. For example if the claim

is less bone marrow depression, but similar efficacy, a non-inferiority

outcome should be demonstrated for efficacy and a superiority outcome

for safety.



2.3 DIABETES

Diabetes has become an increasingly prevalent and costly chronic disease state and

presents a significant medical and economic burden to the U.S. health care system.

The increasing prevalence of diabetes has been most pronounced among younger age

groups (Mokdad et al. 2000). Much of the morbidity and cost is attributable to long-

term, diabetes-related complications, particularly cardiovascular disease (CVD).

Prevention of these complications requires a management strategy that addresses

multiple physiologic conditions including hyperglycemia, dyslipidemia, and

hypertension.

2.3.1 Definition

Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia

resulting from defects in insulin secretion, insulin action, or both. The chronic

hyperglycemia of diabetes is associated with long-term damage, dysfunction, and

failure of various organs, especially the eyes, kidneys, nerves, heart, and blood

vessels.

“The growth of knowledge regarding the etiology and pathogenesis of diabetes has

led many individuals and groups in the diabetes community to express the need for a

revision of the nomenclature, diagnostic criteria, and classification of diabetes. As a

consequence, it was deemed essential to develop an appropriate, uniform terminology

and a functional, working classification of diabetes that reflects the current

knowledge about the disease”. (NDDG)

2.3.2 Classification

The current Expert Committee has carefully considered the data and rationale for

what was accepted in 1979, along with research findings of the last 18 years, and we

are now proposing changes to the NDDG/WHO classification scheme (Table 2.1A).

The main features of these changes are as follows:

1. The terms insulin-dependent diabetes mellitus and non–insulin dependent

diabetes mellitus and their acronyms, IDDM and NIDDM, are eliminated.

These terms have been confusing and have frequently resulted in classifying

the patient based on treatment rather than etiology.



2. The terms type-1 and type-2 diabetes are retained, with arabic numerals being

used rather than roman numerals.

Table 2.1A: Etiologic Classification of Diabetes Mellitus

I. Type-1 diabetes* (β-cell

destruction, usually leading to

absolute insulin deficiency)

A. Immune mediated

B. Idiopathic

II. Type-2 diabetes* (may range

from predominantly insulin

resistance with relative insulin

deficiency to a predominantly

secretory defect with insulin

resistance)

III. Other specific types

A. Genetic defects of β-cell function

1. Chromosome 12, HNF-1α

(MODY3)

2. Chromosome 7, glucokinase

(MODY2)

3. Chromosome 20, HNF-4α

(MODY1)

4. Mitochondrial DNA

5. Others

B. Genetic defects in insulin action

1. Type A insulin resistance

2. Leprechaunism

3. Rabson-Mendenhall syndrome

4. Lipoatrophic diabetes

5. Others

C. Diseases of the exocrine pancreas

1. Pancreatitis

2. Trauma/pancreatectomy

3. Neoplasia

4. Cystic fibrosis

5. Hemochromatosis

6. Fibrocalculous pancreatopathy

7. Others

D. Endocrinopathies

1. Acromegaly

2. Cushing’s syndrome

3. Glucagonoma

4. Pheochromocytoma

5. Hyperthyroidism

6. Somatostatinoma

7. Aldosteronoma

8. Others

E. Drug- or chemical-induced

1. Vacor

2. Pentamidine

3. Nicotinic acid

4. Glucocorticoids

5. Thyroid hormone

6. Diazoxide

7. β-adrenergic agonists

8. Thiazides

9. Dilantin

10. α -Interferon

11. Others

F. Infections

1. Congenital rubella

2. Cytomegalovirus

3. Others

G. Uncommon forms of immune-

mediated diabetes

1. “Stiff-man” syndrome

2. Anti-insulin receptor antibodies

3. Others

H. Other genetic syndromes

sometimes associated with diabetes

1. Down’s syndrome

2. Klinefelter’s syndrome

3. Turner’s syndrome

4. Wolfram’s syndrome

5. Friedreich’s ataxia

6. Huntington’s chorea

7. Laurence-Moon-Biedl syndrome

8. Myotonic dystrophy

9. Porphyria

10. Prader-Willi syndrome

11. Others

IV. Gestational diabetes mellitus

(GDM)

*Patients with any form of diabetes may require insulin treatment at some stage of

their disease. Such use of insulin does not, of itself, classify the patient.



The degree of hyperglycemia (if any) may change over time, depending on the extent

of the underlying disease process (Figure 2.1).

*Even after presenting in ketoacidosis, these patients can briefly return to

normoglycemia without requiring continuous therapy (i.e., “honeymoon” remission);

**in rare instances, patients in these categories (e.g., Vacor toxicity, type-1 diabetes

presenting in pregnancy) may require insulin for survival.

Figure 2.1: Disorders of Glycemia: Etiologic Types and Stages

Type-1 diabetes, β-cell destruction, usually leading to absolute insulin deficiency,

Immune-mediated diabetes. This form of diabetes, previously encompassed by the

terms insulin-dependent diabetes, type-1 diabetes, or juvenile-onset diabetes, results

from a cellular-mediated autoimmune destruction of the β-cells of the pancreas

(Atkinson & Maclaren 1994). Markers of the immune destruction of the β-cell,

include islet cell auto antibodies (ICAs), auto antibodies to insulin (IAAs), auto

antibodies to glutamic acid decarboxylase (GAD65), and auto antibodies to the

tyrosine phosphatases IA-2 and IA-2β (Baekkeskov et al. 1982, Atkinson et al. 1986,

Kaufman et al. 1992, Christie et al. 1992, Schott et al. 1994, Schmidli et al. 1994

Myers et al. 1995 Lan et al. 1996; Lu et al. 1996).

Type-2 diabetes (ranging from predominantly insulin resistance with relative insulin

deficiency to predominantly an insulin secretory defect with insulin resistance) this

form of diabetes, previously referred to as non-insulin-dependent diabetes, type-2

diabetes, or adult-onset diabetes, is a term used for individuals who have insulin



resistance and usually have relative (rather than absolute) insulin deficiency (Reaven

et al. 1976, Olefsky et al. 1982, DeFronzo et al. 1979; Turner et al. 1978). Insulin

resistance may improve with weight reduction and/or pharmacological treatment of

hyperglycemia but is seldom restored to normal (Scarlett et al. 1982, Firth et al. 1986,

Simonson et al. 1984, Henry et al. 1986; Wing et al. 1994).Other specific types of

diabetes are 1) Genetic defects of the β-cell. They are referred to as maturity onset

diabetes of the young (MODY) and are characterized by impaired insulin secretion

with minimal or no defects in insulin action (Herman et al. 1994, Byrne et al. 1996;

Clement et al. 1996). 2) Genetic defects in insulin action. There are unusual causes of

diabetes that result from genetically determined abnormalities of insulin action.

Endocrinopathies. Several hormones (e.g., growth hormone, cortisol, glucagon,

epinephrine) antagonize insulin action. Excess amounts of these hormones (e.g.,

acromegaly, Cushing’s syndrome,glucagonoma, pheochromocytoma) can cause

diabetes (Soffer et al. 1961, Jadresic et al. 1982, Stenstrom et al. 1988; Berelowitz et

al. 1996).

2.3.3 Incidence and Prevalence

According to the most recent data from the Centers for Disease Control and

Prevention (CDC 2005), nearly 15 million people in the United States, or 5% of the

population, have been diagnosed with diabetes, with an additional 6 million cases, as

yet, undiagnosed. Diabetes is particularly prevalent among older adults and is present

in approximately 6 million individuals aged ≥ 65 years. However, the prevalence of

type-2 diabetes is increasing in younger adults (CDC 2007). The increasing rate of

diabetes is expected to continue, with projections of 29 million total diagnosed cases

by 2020 and 48 million cases by 2050 (Narayan et al. 2006).

2.3.4 Burden of Illness

Annual expenditures for diabetes in the United States have been conservatively

estimated at $132 billion in direct and indirect costs (Figure 2.2), with costs only

expected to increase as the prevalence of diabetes continues to rise (ADA2003).

Cumulative costs of diabetes-related complications, particularly macrovascular

complications, rise substantially as time elapses since the original diagnosis (Figure

3.1) (Caro et al. 2002).



2.3.5 Diagnostic Criteria for Diabetes Mellitus

The diagnostic criteria for diabetes mellitus have been modified from those previously

recommended by the NDDG or WHO. The revised criteria for the diagnosis of

diabetes are shown (Table 2.1B). Three ways to diagnose diabetes are possible, and

each must be confirmed, on a subsequent day, by any one of the three methods given

(Table 2.1B). For example, one instance of symptoms with casual plasma glucose ≥

200 mg/dl (11.1 mmol/ l), confirmed on a subsequent day by

1) FPG ≥ 126 mg/dl (7.0 mmol/l),

2) An OGTT with the 2-h postload value ≥ 200 mg/dl (11.1 mmol/l), or

3) Symptoms with a casual plasma glucose≥ 200 mg/dl (11.1 mmol/l),

warrants the diagnosis of diabetes.

Patients with undiagnosed type-2 diabetes are at significantly increased risk for

coronary heart disease, stroke, and peripheral vascular disease. In addition, they have

a greater likelihood of having dyslipidemia, hypertension, and obesity (Klein 1995).

Suggested criteria for testing are given (Table 2.2).

The Expert Committee recognizes an intermediate group of subjects whose glucose

levels, although not meeting criteria for diabetes, are nevertheless too high to be

considered altogether normal. This group is defined as having FPG levels ≥ 110 mg/dl

(6.1 mmol/l) but < 126 mg/dl (7.0 mmol/l) or 2-h values in the OGTT of ≥ 140 mg/dl

Figure 2.2 Figure 3.1



(7.8 mmol/l) but < 200 mg/dl (11.1 mmol/l). Thus, the categories of FPG values are as

follows:

FPG <110 mg/dl (6.1 mmol/l) = normal fasting glucose;

FPG ≥ 110 (6.1 mmol/l) and <126 mg/dl (7.0 mmol/l) = IFG;

FPG ≥126 mg/dl (7.0 mmol/l) = provisional diagnosis of diabetes (the

diagnosis must be confirmed, as described above).

The corresponding categories when the OGTT is used are the following:

2-h postload glucose (2-h PG) < 140 mg/dl (7.8 mmol/l) = normal glucose

tolerance;

2-h PG ≥140 (7.8 mmol/l) and < 200 mg/dl (11.1 mmol/l) = IGT;

2-h PG ≥ 200 mg/dl (11.1 mmol/l) = provisional diagnosis of diabetes (the

diagnosis must be confirmed, as described above).

Because the 2-h OGTT cutoff of 140 mg/dl (7.8 mmol/l) will identify more people as

having impaired glucose homeostasis than will the fasting cutoff of 110 mg/d (6.1

mmol/l), it is essential that investigator always report which test was used.

Table 2.1B—Criteria for the Diagnosis of Diabetes Mellitus

1. Symptoms of diabetes plus casual plasma glucose concentration ≥ 200 mg/dl

(11.1 mmol/l). Casual is defined as any time of day without regard to time

since last meal. The classic symptoms of diabetes include polyuria, polydipsia

and unexplained weight loss. Or

2. FPG ≥ 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at

least 8 h. Or

3. 2-h PG ≥ 200 mg/dl (11.1 mmol/l) during an OGTT. The test should be

performed as described by WHO (2), using a glucose load containing the

equivalent of 75 g anhydrous glucose dissolved in water.

In the absence of unequivocal hyperglycemia with acute metabolic decompensation,

these criteria should be confirmed by repeat testing on a different day. The third

measure (OGTT) is not recommended for routine clinical use.



Table 2.2: Testing for Diabetes in Asymptomatic, Undiagnosed Individuals

1. Testing for diabetes should be considered in individuals at age 45 years and

above, particularly in those with a BMI ≥ 25 kg/m2*; if normal, it should be

repeated at 3-year intervals.

2. Testing should be considered at a younger age or be carried out more frequently in

individuals who are overweight (BMI ≥ 25 kg/m2*) and have additional risk

factors:

have a first-degree relative with diabetes

are habitually physically inactive

are members of a high-risk ethnic population (e.g., African-American,

Hispanic American, Native American, Asian American, Pacific Islander)

have delivered a baby weighing > 9 lb or have been diagnosed with GDM

are hypertensive (≥140/90)

have an HDL cholesterol level ≤ 35 mg/dl (0.90 mmol/l) and/or a triglyceride

level ≥ 250 mg/dl (2.82 mmol/l)

have PCOS

on previous testing, had IGT or IFG

have a history of vascular disease

The OGTT or FPG test may be used to diagnose diabetes; however, in clinical

settings the FPG test is greatly preferred because of ease of administration,

convenience, acceptability to patients, and lower cost. *May not be correct for all

ethnic groups.

2.3.6 Value of Aggressive Management

Adequate glycemic control is a critical component in preventing microvascular

complications associated with type-2 diabetes. The United Kingdom Prospective

Diabetes Study (UKPDS) demonstrated a 25% reduction in the risk of microvascular

endpoints in patients with type-2 diabetes who were treated using an intensive

glucose-lowering strategy compared with a conventional approach (UKPDS 33).

Subsequent observational analyses from the UKPDS trial showed reductions in

mortality and other diabetes related complications, including cardiovascular

complications (Stratton et al. 2000). For example, a 1% decrease in glycated

hemoglobin (HbA1c) was associated with a 14% reduction in the incidence of MI



(Table 2.3). Reductions in HBA1C have also been shown to decrease medical costs

and health care utilization (Shetty et al. 2005, Gilmer et al. 2005, Menzin et al. 2001;

Wagner et al. 2001).

a

Result are based on an observational analysis of the association between glycemic

exposure and diabetes complications.

2.3.7 Pathophysiology and the Rationale for Aggressive Management

Techniques

Four intrinsic defects are present in individuals with type-2 diabetes:

(1) insulin resistance in muscle and adipose tissue, (2) decreased insulin production

by pancreatic beta cells, (3) increased production of glucose by the liver (Figure 3.2),

(DeFronzo 1988, Ramlo-Halsted 2000; Bays et al. 2004) and (4) decreased glucagon-

like peptide-1 (GLP-1) levels(Toft-Nielsen et al. 2001).

Some data suggest that chronic insulin resistance places increased secretory demands

on beta cells, resulting in progressive beta-cell dysfunction (Buchanan et al. 2002,

Xiang et al. 2006). Loss of beta-cell function is gradual, and individuals generally

have < 20% of normal beta-cell function by the time they are diagnosed with diabetes

(Gastaldelli et al. 2004). The ideal treatment strategy would address all 4 defects

resulting in type-2 diabetes: reduced disposal of glucose by muscle and other tissues,

impaired function of pancreatic beta cells, increased hepatic glucose production, and

reduced GLP-1 levels.

2.3



2.3.8 Currently Recommended Treatments

The ADA and the European Association for the Study of Diabetes (EASD) have

published consensus guidelines for the management of hyperglycemia in type-2

diabetes (Figure 3.3) (Nathan et al. 2006).

Initial management of both IGT and diabetes should always include lifestyle

modifications, such as exercise and weight loss; however, long-term efficacy of

lifestyle modification alone is limited, often requiring the addition of drug therapy to

reach or maintain the goal HBA1C of < 7%. The benefits of intensive lifestyle

modification of 5%-10% weight loss and 150 minutes of exercise/week were well

demonstrated in the Diabetes Prevention Program (DPP) study of patients with IGT.

Current ADA guidelines recommend that individuals with IGT or IFG lose 5%-10%

of their body weight and increase their physical activity to at least 150 minutes per

week of moderate activity (such as walking) to prevent or delay the onset of type-2

diabetes(ADA 2008).

In addition to promoting lifestyle modifications, the ADAEASD guidelines

recommend use of Metformin for initial pharmacotherapy. A comparison of available

glucose-lowering agents is presented (Table 2.4).

Figure 3.2



2.3.9 Cardiovascular (CV) Risk In Diabetes

Although mortality due to CVD is declining in non-diabetic populations, patients with

T2DM are at a high risk of CV morbidity and mortality (Kannel and McGee 1979;

Schernthaner 1996). Some studies have reported that almost 75% of patients with

T2DM die of macrovascular events, such as acute myocardial infarction (MI) and

stroke (Laakso 1995). In a mortality study of more than 3000 patients, 4-year survival

was 92% for patients with Diabetes duration ≤5 years, and 84% if diabetes duration

was >5 years (Bo et al. 2006). Most deaths were due to CVD (36% and 41% for

diabetes duration≤ 5 years and >5 years, respectively) (Bo et al. 2006).

A 7-year Finnish study suggested that the CV event rate for patients with diabetes

without prior MI was as high as the event rate in patients without diabetes with prior

MI (Haffner et al. 1998). CVDs common in T2DM include coronary artery disease,

stroke, peripheral vascular disease, cardiomyopathy and congestive heart failure.

Several of these pathologies are usually present in a majority of patients; therefore

most patients require multiple interventions (Kannel 2000).

Figure 3.3



Table 2.4: Comparison of Available Glucose-Lowering Agents



At the 2007 annual meeting of the American Diabetes Association, the authors of a

3.3 million population- based study proposed that patients with T2DM should be

treated with antiplatelet drugs, statins, ACE inhibitors, or angiotensin receptor

blockers, because they carry the same CV risk as patients with a history of MI

(Schramm et al. 2007).

Although CVD accounts for a high proportion of deaths, patient awareness remains

low (CDC 2003), and opportunities to intervene and modify the risks are missed. The

high risk of morbidity and mortality in patients with diabetes indicates that it is vital

to implement timely interventions in order to minimize CV complications (Stolar et

al. 2003).

2.3.10 Factors Contributing To Increased CV Risk In Diabetes

Patients with T2DM usually present various factors contributing to the risk of CV

problems. These include hyperglycemia and fluctuation of blood glucose, central

(visceral) obesity, hypertension, lipid abnormalities, hyperinsulinemia, and

endothelial dysfunction (Stolar et al. 2003).

The increased risk of CV morbidity and mortality associated with diabetes has led to

the concept that hyperglycemia may be one of the risk factors for CVD (Haffner et

al. 2003). A prospective study of CVD in patients with T2DM reported that CVD

episodes at 6.3 years were related to baseline HbA1c (Rius et al. 2003). A significant

increase in the risk for CV events and mortality has been reported in patients with

HbA1c 7% compared with those who had lower HbA1c values (Kuusisto et al. 1994).

The UK Prospec- tive Diabetes Study (UKPDS) showed a more than 2-fold increase

in incidence of MI over a range of HbA1c values from 6% to 10%; each 1% reduction

in HbA1c was associated with a reduction in risk of 21% for any diabetes endpoint

and death, and 14% for MI (Stratton et al. 2000).

PPG control also plays a significant role in overall glycemic control and becomes

even more important than fasting plasma glucose (FPG) when better control (eg,

HbA1c level < 8.4%) is achieved (Monnier et al. 2003). Excessive postprandial

hyperglycemia may also be an important independent contribu- tor to the risk of CV

complications and mortality in T2DM (Massi-Benedetti and Federici 1999; Ceriello et

al. 2006). Interestingly, the deterioration of glucose homeostasis in the evolution of



T2DM progresses from postprandial to fasting hyperglycemia (Monnier et al. 2007).

The Diabetes Interven- tion Study showed that PPG level can be used to predict the

risk of MI (Hanefeld et al. 1996). In a more recent, 5-year prospective study, PPG was

an independent CVD risk factor in patients with T2DM, particularly women (Cavalot

et al. 2006). Thus, attaining glycemic control, and reducing CVD risk, may be

difficult without adequate control of PPG levels.

Lipid abnormalities such as elevated levels of triglycerides (TG), small dense LDL

cholesterol and decreased levels of HDL cholesterol have been consistently reported

in diabetes, and these abnormalities dramatically increase the risk of macrovascular

disease (Reaven 1995). In the Diabetes Control and Complications Trial (DCCT),

treating T1DM subjects intensively for a mean of 6.5 years showed that high total

cholesterol, high LDL cholesterol, high HbA1c at baseline were associated with the

development of CVD during the 17 years of follow-up (Nathan et al. 2005). In a 7-

year study of patients with T2DM, a previous history of MI, low HDL cholesterol,

high LDL cholesterol, high TG, and high FPG was associated with a 2-fold increase

in the risk of CVD morbidity and mortality (Lehto et al. 1997). In T2DM, high

postprandial TG responses have been associated with MI (Carstensen et al. 2004).



2.4 DYSLIPIDEMIA

Lipid metabolism can be disturbed in different ways, leading to changes in plasma

lipoprotein function and/or levels. This by itself and through interaction with other

cardiovascular (CV) risk factors may affect the development of atherosclerosis.

Therefore, dyslipidemias cover a broad spectrum of lipid abnormalities, some of

which are of great importance in CVD prevention. Dyslipidemias may be related to

other diseases (secondary dyslipidemias) or to the interaction between genetic

predisposition and environmental factors. Elevation of total cholesterol (TC) and low-

density lipoprotein-cholesterol (LDL-C) has received most attention, particularly

because it can be modified by lifestyle changes and drug therapies. The evidence

showing that reducing TC and LDL-C can prevent CVD is strong and compelling,

based on results from multiple randomized controlled trials (RCTs). TC and LDL-C

levels continue therefore to constitute the primary targets of therapy.

Coronary heart disease (CHD) remains the leading cause of death in both men and

women in the US (AHA). In 2006, 18 million of the estimated 81 million adults in the

US with cardiovascular disease (CVD) had CHD, and more than 400,000 Americans

died of CHD. CHD is the cause of one in every six deaths in the US (AHA). Although

these statistics are sobering, the age-adjusted death rates for CVD and CHD decreased

substantially from 1996 to 2006 by 30% and 36%, respectively (AHA). Population

studies using validated statistical models have provided compelling evidence that the

decrease in CHD-related mortality rates is attributable to reductions in modifiable

CHD risk factors and improvements in evidenced-based medical therapies (Ford et al.

2007; Wijeysundera et al. 2010). Smoking, hypertension, obesity, type-2 diabetes, and

dyslipidemia have long been established as important risk factors for CHD (Wilson et

al. 1998). The contribution of dyslipidemia to cardiovascular risk was illustrated in a

multicenter, case-control study conducted in 52 countries showing that abnormal lipid

levels accounted for approximately 50% of the attributable risk for myocardial

infarction (MI) in the population (Yusuf et al. 2004 ).

Another important factor contributing to this positive trend has been the availability of

powerful lipid-lowering therapies, particularly statins. The lipid lowering potency of

statins and their clinical benefit in terms of CHD risk reduction have been established

in numerous randomized controlled trials (Mills et al. 2008). Atherosclerosis typically



starts in early adulthood or even youth (in high-risk individuals) and may progress

silently for decades before CHD symptoms manifest (McGill et al. 2008). The

importance of dyslipidemia as a likely CHD risk factor is related to the central role of

specific lipoprotein particles, especially low-density lipoprotein (LDL), in the

development and progression of atherosclerosis (Toth 2009).

2.4.1 Lipid Goals

The National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP) III

guidelines (available at http: //www. nhlbi.nih.gov/guidelines/cholesterol/)

recommend specific lipid goals based on a person’s global risk for CHD: the higher

the risk, the lower the goal (Table 2.5). For example, an LDL cholesterol (LDL-C)

goal of < 100 mg/dl was recommended for high-risk persons – i.e., those with CHD

or CHD risk equivalents – while an LDL-C goal of < 130 mg/dl was recommended

for moderate-risk persons who had ≥ 2 risk factors but no CHD or CHD risk

equivalents (Grundy et al. 2004). Based on a 2003 survey, 67% of adults at risk of

CHD achieved the ATP III–recommended LDL-C goals (Davidson et al. 2005). This

number increased to 76% in a more recent survey conducted in 2006 and 2007

(Waters et al. 2009).

Table 2.5: ATP III–Recommended LDL-C Targets Based on Risk for CHD



2.4.2 Therapeutic Lifestyle Changes For All At-Risk Persons

Therapeutic lifestyle changes – increased physical activity, weight loss, smoking

cessation, and adoption of a healthier diet – effectively reduce cardiovascular risk in

primary (Wister et al. 2007, Maruthur et al. 2009; Fujii et al. 2010) and secondary

prevention (Maron et al. 2010; Decewicz et al. 2009).

2.4.3 Treatment for Dyslipidemia (Statin Therapy)

The Heart Protection Study was a placebo-controlled primary prevention study of

simvastatin conducted in the UK in more than 20,000 adults at high risk of a

cardiovascular event. The study results revealed a 13% lower all-cause mortality rate

(P = 0.0003) and a 24% lower rate in major vascular events (P < 0.0001) for

simvastatin vs placebo (HPS 2002). Diabetic individuals who benefited from

simvastatin therapy included those without occlusive arterial disease and those with

LDL-C, 116 mg/dl at baseline (Collins et al. 2003). Thus, the findings from the Heart

Protection Study strongly suggested that lipid lowering therapy with statins can

provide primary prevention benefits for high-risk individuals, even in the absence of

hyperlipidemia.

The efficacy of statin therapy in elderly patients with or at high risk of stroke or CVD

was demonstrated in the Prospective Study of Pravastatin in the Elderly at Risk

(PROSPER). In this study, pravastatin was associated with a modest but significant

reduction in the risk for the composite end point of CHD mortality, stroke, and

nonfatal MI, compared with placebo (hazard ratio [HR]: 0.85; P = 0.014) (Shepherd et

al. 2002).

The results of the Pravastatin or Atorvastatin Evaluation and Infection Therapy–

Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) study provided

evidence that in patients who have acute coronary syndrome (ACS), an intensive

lipid-lowering statin regimen may be warranted. In this comparative study, intensive

therapy with Atorvastatin 80 mg was significantly more effective than standard

therapy with pravastatin 40 mg in reducing LDL-C levels well below the 100-mg/dl

goal for high-risk patients (62 mg/dl with intensive therapy vs 95 mg/dl with standard

therapy).



Importantly, the more effective LDL-C reduction with intensive therapy was

accompanied by a significantly greater reduction in the risk of the composite primary

end point of death from any cause, MI, unstable angina requiring re-hospitalization,

revascularization, and stroke (relative risk [RR] reduction: 16%; P = 0.005) (Cannon

et al. 2004).

Two primary prevention studies evaluated the clinical benefits of statin therapy in

hypertensive and moderately hypercholesterolemic patients at moderately high risk

for CHD. In the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm

(ASCOT–LLA), the addition of Atorvastatin to antihypertensive therapy decreased

LDL-C to 87 mg/dl (placebo, 133 mg/dl) – a level substantially below the goal of 130

mg/dl for moderate-risk patients – and significantly reduced the incidence of nonfatal

MI and fatal CHD (HR: 0.64; P = 0.0005) (Sever et al. 2003). In contrast, the

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

(ALLHAT–LLT) found no significant reduction in the risk of all-cause mortality

(primary end point) or in the risk of CHD events with pravastatin vs usual care in this

patient population.

A possible explanation for this negative result is the modest difference observed

between the mean LDL-C values achieved with pravastatin (111 mg/dl) and usual

care (135 mg/dl) after 2 years of treatment (ALLHAT). The results of a prospective

meta-analysis of data from 90,056 participants in 14 randomized statin trials

suggested that the absolute benefits of treatment in terms of risk reduction largely

depend on the risk at baseline and the absolute reduction in LDL-C achieved (Baigent

et al. 2005). The benefits of statin therapy were co firmed recently by the results of a

large network meta-analysis of 76 randomized controlled trials with a total of more

than 170,000 participants (Mills et al. 2011).

2.4.4 Secondary Prevention

The meta-analysis by Mills et al. included 42 studies of patients with CHD as the

primary study population. In these patients, statin therapy vs control was associated

with a RR reduction of 18% for cardiovascular death (Mills et al. 2011). Meta-

analysis of nine placebo-controlled trials of statins that included previously

unpublished data demonstrated a 22% reduction in all-cause mortality among elderly

patients (aged 65–82 years) with CHD (Afilalo et al. 2008) (Table 2.6).



In addition, two meta-analyses of data from patients with ACS suggested that more

intensive lipid-lowering therapy is associated with greater benefits in this population.

In the first meta-analysis, data from 13 randomized controlled trials in patients with

ACS showed that intensive statin therapy, compared with standard statin therapy,

reduced the incidence of adverse cardiovascular outcomes when started within 14

days of hospitalization for ACS (Hulten et al. 2006) (Table 2.6).

Similarly, in the second meta-analysis, data from patients with ACS or stable CHD

who participated in the Treating to New Targets (TNT), Incremental Decrease in End

Points Through Aggressive Lipid-Lowering (IDEAL), PROVE IT–TIMI 22, or

Aggrastat-to-Zocor (A-to-Z) studies showed significantly greater efficacy of high-

dose vs standard-dose statin therapy in reducing the risk of cardiovascular events,

including coronary death (Table 2.6) (Cannon et al. 2006).

Rosuvastatin significantly effect on hospitalization for cardiovascular causes, with

placebo, and on the primary end point of death or hospitalization for cardiovascular

reasons in patients with chronic heart failure (Table 2.6) (Kjekshus et al. 2007; GISSI

2008). Lipid-lowering therapy with statins also has not been shown to provide

significant benefits in patients with end stage kidney disease requiring maintenance

hemodialysis (Wanner et al. 2005; Fellstrom et al. 2009).

2.4.5 Primary Prevention

The updated ATP III guidelines emphasize that lipid-lowering therapy can provide

benefits for high-risk individuals, including those with diabetes, even if they have no

obvious signs of hyperlipidemia. The results of the Collaborative Atorvastatin

Diabetes Study (CARDS) confirmed the primary prevention benefit of statin therapy

in diabetic patients without high LDL- C (Colhoun et al. 2004). CARDS showed that

Atorvastatin 10 mg daily reduced the rate of first major cardiovascular events,

including ACS, coronary revascularization, and stroke, by 37% (P = 0.001) compared

with placebo (Table 2.7).



Table 2.6: Clinical Effects of Statins in Secondary Prevention: Recent Meta-Analyses and Randomized Controlled Clinical Outcomes

Trials



Table 2.7: Clinical Effects of Statins on Cardiovascular Events in Primary Prevention: Randomized Controlled Clinical Outcomes

Trials



Patients with diabetes generally have higher triglycerides and lower high-density

lipoprotein cholesterol (HDL-C) levels, which are associated with an increased risk

for cardiovascular events (Ballantyne et al. 2001). Findings from the recent

Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating

Rosuvastatin (JUPITER) (Table 2.7) demonstrated that statin therapy may provide

cardiovascular benefits, for healthy individuals who do not meet the current ATP III

criteria for high CVD risk (Ridker et al. 2008).

JUPITER was a large, double-blind, placebo-controlled study that evaluated the

efficacy of rosuvastatin in the primary prevention of cardiovascular death and

vascular events in 17,802 men (aged ≥ 50 years) and women (aged ≥ 60 years) from

26 countries who had LDL-C < 130 mg/dl but plasma concentrations of high

sensitivity C-reactive protein ≥ 2 mg/L. Although many meta-analyses of primary

prevention trials clearly demonstrated that statin therapy may provide important

cardiovascular benefits in individuals without CHD, findings for all-cause mortality

have been mixed in terms of the statistical significance of statin-related benefit (Table

2.8) (Ray et al. 2010, Taylor et al. 2011, Thavendiranathan et al. 2006; Brugts et al.

2009).

Table 2.8 Clinical Effects of Statins on All-Cause Mortality in Primary

Prevention



2.4.6 Effect of Lipid-Lowering Therapy on Atherosclerotic Disease Progression

Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial

showed that intensive therapy with high dose Atorvastatin reduced the progression of

coronary atherosclerosis compared with standard-dose pravastatin (Nissen et al.

2004).

A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived

Coronary Atheroma Burden (ASTEROID) further demonstrated that intensive lipid

lowering with high-dose rosuvastatin, achieving average LDL-C levels of 61 mg/dl

(53% reduction) and HDL-C increases of 6 mg/dl (15%), resulted in significant

regression of coronary atherosclerosis (Nissen et al. 2006).

Similarly, the Stop Atherosclerosis in Native Diabetics Study (SANDS) showed that

intensive therapy lowering LDL-C to ≤ 70 mg/dl resulted in the regression of carotid

intima-media thickness (CIMT) in patients with type-2 diabetes and no prior

cardiovascular event (Fleg et al. 2008). Finally the findings from these studies are

consistent with the clinical benefits of intensive lipid-lowering therapy observed in

trials with clinical end points and suggest that the aggressive LDL-C goal of , 70

mg/dl may be beneficial for specific patient groups, such as high-risk patients with

established CHD or type-2 diabetes. In addition, some findings suggest that statins

may slow the progression of atherosclerosis in asymptomatic low-risk patients, for

whom the ATP III guidelines currently do not recommend the use of statins.

Statin therapy may benefit high-risk individuals with diverse demographic and

clinical characteristics, including women, the elderly, patients with type-2 diabetes,

and high-risk individuals without hyperlipidemia. Moreover, recent results suggest

that the treatment benefits of statins may extend to individuals traditionally not

considered at high risk for CHD, such as those with elevated C-reactive protein but

normal lipid levels. The demonstrated efficacy of statins in primary prevention

together with their potential to slow atherosclerotic disease progression provides a

strong argument in favor of starting lipid-lowering therapy as early as possible.

2.1 bioavailability (ba) and bioequivalence...

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