Consultant Physician

abdulameera
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Credibility and Evidence Based Nature of

Current Glycemia Guidelines

in Type 2 Diabetes Mellitus:

With Focus on Conflicts of Interest

Dr. Abdulameer Abdullah Al-ashbal

Consultant Physician;

Associate professor of medicine at

Al Mustansiriya medical college ,

Department of Medicine ;

Alyermouk Teaching Hospital


My disclosure

No financial relationships

with any commercial interests


Aim of presentation

• How far the conflicts of interest might

undermine the reliability and credibility of

present guidelines for treatment of type 2

diabetes.

• The need for guidelines as being something

important.

• The importance of clinical judgment and

individualization of treatment of type 2

diabetes


Conflict of interest (COI)

occurs when

an individual

or

organization

is involved in multiple interests,

one of which could possibly

corrupt

the motivation for an act in the other


The relationship between exposure to

information from pharmaceutical companies

and physicians' prescribing can have serious

effects on

of drugs.

Conflict of interest (COI)

pharmaceutical promotion

the quality,

quantity,

and

cost

Spurling GK, Mansfield PR, Montgomery BD, Lexchin J, Doust J, et al. PLoS Med 7(10): e1000352. doi:10.1371/journal.pmed.1000352.


Conflicts of interest policies

As an ethical issue, conflict of

interest involves competing

interests as well as raises

questions related to an

individual's integrity.

Therefore when the policies exist—

they should be:


Strong

and


enforced


Conflict of interest (COI)

The traditional medical approach is that

stated in the Declaration of Geneva

(World Medical Association*):

'The health of my patient will be my

first consideration.'7**

* September 1948

August 1968

October 1983

September 1994

May 2005

May 2006

** http://www.wma.net/en/30publications/10policies/g1/


Types of relationships with industry (RWI)

and other potential conflicts of interest (COI)

[RWI/COI]

Consultant. Includes honoraria for consulting, serving on advisory boards,

speaking at non-ACCME approved meetings or other such meetings supported by

industry. Donation of such honoraria to charity or nonprofit 502 C3 organizations is

still counted as a RWI/COI.

• Speakers Bureau. Compensation for speaking or being listed as member of an

industry sponsored speakers bureau.

• Equity ownership. Ownership or option to acquire ownership or other equity

position, stock, stock options industry.

• Personal Research. Investigator, co-investigator, or steering committee

member in industry supported research or institutional direct decision-making

responsibility for such funds (e.g research or other grants that provide support for

fellowship, faculty or other clinical personnel).

• Expert Witness. Court cases or other legal activity where service was rendered


as an expert witness of industry.


Candidate List of Categories of Financial Relationships

with Industry (Relationships with Industry [RWI]) to Be

Disclosed

Research grants and contracts

Consulting agreements

Participation in speakers bureaus

Honoraria

Intellectual property, including patents, royalties, licensing fees

Stock, options, warrants, and other ownership (excepting

general mutual funds)

Position with a company

Company governing boards

Technical advisory committees, scientific advisory

boards, and marketing panels

Company employee or officer, full or part time

Other payments or financial relationships


Conflict of interest (COI) and

Relationships with Industry (RWI)

is an ethical issue not only for

business leaders,

government officials, and

researchers, but also for

academicians.


Actual or reasonably perceived conflicts of

interest as reported on one of the

Disclosure Questionnaires (circ.ahajournals)

A relationship is considered to be “significant” if :


The person receives $10 000 or more during any

12-month period, or 5% or more of the person’s

gross income; or


The person owns 5% or more of the voting stock

or share of the entity, or owns $10 000 or more

of the fair market value of the entity.

A relationship is considered to be “modest” if it is

less than “significant” under the preceding

definition.

http://circ.ahajournals.org/ by guest on March 20, 2013.


Physician relationships with the industry

Is disclosure of researcher (s) is

the antidote here?


Physician relationships with the industry

Is disclosure of researcher (s) is

the antidote here?

The answer is : No


Physician relationships with the industry

Is disclosure of researcher (s) is

the antidote here?

The antidote

is for physicians who are involved in drugs

prescribing not to accept money for

promoting drugs


Physician Relationships With The Industry

Clinical practice guidelines are increasingly

used in medical malpractice cases and are

forming the basis of many of the

pay-for-performance initiatives

These relationships affect the prescribing and

professional behavior of physicians.

Continuing medical education programs

sponsored by a drug company were more likely

to highlight the drug company’s product.

A Journal of the American Medical Association review published by Wazana and colleagues in 2000


Professional behavior and the industry

The credentialing arm of

American Dietitian Association ,

the commission on dietetic

registration,

offers continuing professional

courses sponsored by

Coca-Cola


Physician Relationships With The Industry

What we have to be careful about is that

many trials are not designed to answer

a scientific question,

but rather to answer

a marketing question

Therefore

“Conflicts of interest are not universally

bad, but they’re not universally good.”


Physician relationships with the industry

However,

conflicts

cannot be completely avoided,

but

should be

recognized and disclosed


Concerns Regarding Physician

Relationships With The Industry

Transparency

Conflicts of interest

Harm to:

• Professional reputations (prescribing and

professional behavior )

• Scientific research

• Guideline credibility

• Patients (patient care ).


Ethics And Compliance

Collaborations between physicians or medical

researchers and biopharmaceutical companies

must benefit society by promoting the

discovery and development of new

medications that improve individual and

public health.

The relationships may create conflicts of

interest due to the risk of undue influence on

professional judgments thereby potentially

jeopardizing the integrity of scientific

investigations and the quality of patient care.


Ethics And Compliance

Payments to health care providers must

be for legitimate, reasonable, and

necessary services.

Biopharmaceutical companies

appropriately compensates healthcare

providers conducting sponsored or

supported medical research for

performing study procedures and

collecting relevant data.


Ethics And Compliance

Drug companies choose providers who are not

well suited to perform the services.

Drug companies preferentially select service

providers who are customers for their products

and condition any service provider's selection

upon the purchase of their products.

Biopharmaceutical companies make payments to

healthcare providers for the purpose of

rewarding past or altering current/future

prescribing practices.


Ethics And Compliance

Biopharmaceutical companies pay healthcare

providers to gain experience with its products

or to learn about its products.

Biopharmaceutical companies‘ policies restrict

the ability of innovators from engaging directly

with medical professionals and are an

impediment to advancing medical knowledge

and patient care.


Relations Between

Professional Medical Associations

And The Health-Care Industry




The costs of continuing medical education

(CME) are insufficiently supported from

governments and employers; however, medical

associations have been criticized for accepting

alternative financial support from industry

There is some risk of bias in any form of

scientific communication including intellectual,

professional, and financial

it is recommended how to minimize bias in

scientific communications and CME and how to

ensure proper ethical standards and

transparency in relations between the medical

profession and industry.


Guidelines For

Physician–Pharmaceutical Pharmaceutical Industry Relations:

The Politics Of Policy Formation

Consumer-driven health care, direct-to-consumer

advertising, and broader access to health information

via the Internet may be changing the way medications

are prescribed and dispensed.

Doctors write more than 2.2 billion prescriptions each

year, and it’s critical that they have knowledge of and

access to the latest information on what will best meet

their patients’ health needs.


Guidelines For

Physician–Pharmaceutical Pharmaceutical Industry Relations:

The Politics Of Policy Formation

But how can patients be assured that drug

manufacturers—whose ultimate goal, after all, is to

increase product sales—do not unduly influence their

doctors?

When physicians are paid to learn about new

products, and detailers share selective clinical trial

results, patients’ interests are compromised.

Who determines what protections are necessary and

how much influence is too much?


Financial Conflicts of Interest Checklist (FCIC) for

investigator (s)*

(For funders, journal editors and other stakeholders

with a standardized tool)

The FCIC is designed to be completed by each investigator in

the context of a specific clinical research study

To be completed also by other study team members, such as

study coordinators, research assistants and study nurses.

FCIC contains four sections:

1) administrative information,

2) study information,

3) personal financial information, and

4) authorship information.

* Rochon PA, et al . Medicine, Vol 4, No 1 (2010)•

Paula A Rochon, MD, MPH, is senior scientist at Women’s College Research Institute at Women’s

College Hospital, Toronto


BOX 3-1 Model of Steps Used to Identify and

Respond to a Conflict of Interest

Step 1 Obtain the disclosure of information about financial and other relationships that

could constitute a conflict of interest.

No relationships reported: stop. Relationships disclosed: go to Step 2.

Step 2 Evaluate the disclosures—in light of the individual’s responsibilities or specific

activities (e.g., research, teaching, and patient care)—to determine whether a conflict of

interest exists. If necessary, collect additional information to assess the likelihood of

undue influence and the seriousness of possible harms.

No conflict exists: stop. Conflict exists: go to Step 3.

Step 3 Determine whether the relationship is one prohibited under institutional or other

policies or whether the risks of the relationship are so serious that the individual

should either eliminate it or forgo participation in the activity put at risk by the

relationship.

Conflict elimination necessary: go to Step 5. Elimination not necessary: go to Step 4.

Step 4 If management is appropriate, devise and implement a plan to manage the

conflict. Go to Step 5.

Step 5 Monitor conflict elimination or management plan and assess adherence.

Plan followed. Plan not followed: go to Step 6.

Step 6 Determine the nature of the noncompliance and the appropriate response (e.g.,

education, penalty, or revision of the plan) and implement the response.


Financial Conflicts of Interest Checklist 2010

For funders, journal editors and other stakeholders with a standardized tool

Paula A Rochon, MD,

MPH, is senior scientist

at Women’s College

Research Institute at

Women’s College

Hospital, Toronto

SECTION 1 : ADMINSTRATIVE INFORMATION

MODULE A: ADMINSTRATIVE PROFILE


Financial Conflicts of Interest Checklist 2010

For funders, journal editors and other stakeholders with a standardized tool

Paula A Rochon, MD, MPH,

is senior scientist at Women’s

College Research Institute at

Women’s College Hospital,

Toronto

SECTION 2 : STUDY INFORMATION

MODULE B: FUNDER PROFILE

MODULE C: CONTRACT PROFILE

MODULE D: STUDY TEAM AND FUNDER RELATIONSHIP PROFILE


Financial Conflicts of Interest Checklist 2010

For funders, journal editors and other stakeholders with a standardized tool

Paula A Rochon, MD,

MPH, is senior scientist

at Women’s College

Research Institute at

Women’s College

Hospital, Toronto

SECTION 3 : PERSONAL FINANCIAL INFORMATION

MODULE E: FINANCIAL PROFILE


Checklist 2010 for clinical research studies

For funders, journal editors and other stakeholders with a standardized tool

Paula A Rochon, MD,

MPH, is senior scientist

at Women’s College

Research Institute at

Women’s College

Hospital, Toronto

SECTION 4 : AUTHORSHIP INFORMATION

MODULE F: AUTHORSHIP PROFILE


Drug surveillance and a real world

approach for drugs*

Many side effects, drug interactions, and

effectiveness can not be detected when drugs are

approved. They may be found only after drugs have

been used by millions of people and for a long time.

In addition, available reports were sponsored by

pharmaceutical companies and arguably have a

limited capacity to detect adverse outcomes*.

Drug regulatory agencies are unlikely to receive

data on drug safety (i.e. an administrative,

healthcare database.) that are independent of

industry ties.

* Dore DD, et al. Curr Med Res Opin 2009;25:1019–1027.

Williams-Herman D, et al. BMC Endocr Disord 2008;8:14.


Drug surveillance and a real world

approach for drugs*

Moreover, university-based medicine institutions

have not viewed the problem of drug surveillance

as a worthy academic pursuit.

In 2009 a study found that "a number of academic

institutions" do not have clear guidelines for

relationships between Institutional Review Boards

and industry**.

Until surveillance tools devoid of

industry influence have been established to provide

more robust data, such

dilemmas of uncertainty regarding adverse effects

will remain unsolved.”

* Dore DD, et al. Curr Med Res Opin 2009;25:1019–1027.

Williams-Herman D, et al. BMC Endocr Disord 2008;8:14.

**Policies regarding IRB members' industry relationships often lacking.


Systems for assessment of postmarketing

adverse events



Spontaneous reports

Computerized claims or

medical record databases,


Formal postmarketing studies.


Systems for assessment of postmarketing

adverse events


Spontaneous reports

The limitations of spontaneous reports

include substantial and unquantifiable

underreporting (thus, such systems do

not produce accurate estimates of

incidence for a given adverse event) as

well as lack of verification of important

clinical details.


Systems for assessment of postmarketing

adverse events

Computerized claims or medical record

databases.

The resources proposed—for example, for the

creation of the very large claims database—

are likely to be inadequate and may require

public–private partnerships. Such

partnerships should fully engage all

stakeholders—especially industry, academic,

and regulatory scientists—in methodological

discussions.


Systems for assessment of

postmarketing adverse events

Formal postmarketing studies.

premarketing studies, may not adequately reflect the profile

that will emerge with widespread use after approval, for

several reasons:

(1) study participants may represent a somewhat healthier

and select subset of all participants,

(2) they may receive better care than “real-life” patients,

(3) study drugs will (of necessity) be given for shorter

durations in studies than in postmarketing use, and

(4) neither concomitant medications administered in clinical

trials nor comorbidities of study participants will

represent all those possible outside the trial setting.


Exposures to information from

pharmaceutical companies

(promotional or otherwise)*.

Exposures included:







pharmaceutical sales representative visits,

journal advertisements,

attendance at pharmaceutical sponsored

meetings,

mailed information,

prescribing software, and

participation in sponsored clinical trials.

*Spurling GK,, et al. PLoS Med 7(10): e1000352. doi:10.1371/journal.pmed.1000352.


Why we as prescribers still meet

pharmaceutical representatives (PRs)?

Studies show that marketing strategies used by

pharmaceutical representatives (PRs) such as

education,

samples,

office support, and

patient resources

can increase brand recognition and influence

prescribing *.

* Peay MY, Peay ER. Soc Sci Med. 1988;26(12):1183–9.

Avorn J, Chen M, Hartley R. Am J Med. 1982;73(1):4–8.

Wazana A. JAMA. 2000;283(3):373–80.

Banks JW 3rd, Mainous AG 3rd. Acad Med. 1992;67(9):610–2.

Steinman M, et al. Am J Med. 2001;110(7):551–7.

Brennan T, Rothman D, Blank L, et al. JAMA. 2006;294(4):429–33.

Minnigan H, Chisholm CD. E Med Clin N Amer. 2006;4(3):671–85.

Campo K, et al. Health Mark Quar. 2005;2(4):73–107.

Vainiomaki M, et al. Med Teach. 2004;6(7):630–4.

Adair RF, Holmgren LR. A randomized trial. Am J Med. 2005;118(8):881–4.

Crigger NJ. J Am Acad NP. 2005;17(6):207–12.


Why we as prescribers still meet

pharmaceutical representatives (PRs) ?

In response,

national organizations,

medical societies,

politicians and

academic medical centers

are responding with increasingly stringent

recommendations governing trainee and

clinician interactions with PRs*

* Revised external funds policy - update from SGIM President Barbara Turner. 2006 Jan 26. http://www.sgim.org/index.cfm?section = site&pageId = 367. Accessed April 7, 2009.

Kuehn B. JAMA. 2005;293:1572–80.

Academic Medical Centers Increasingly Ban Gifts from Pharmaceutical Industry. Medical News Today. http://www.medicalnewstoday.com/articles/62478.php. Accessed April 7, 2009.

AMA Opinion of the Council on Ethical and Judicial Affairs, E-8.061. http://www.mcg.edu/SOM/medicine/documents/AMAGuidelinesforIndustry.pdf. Accessed April 7, 2009.

American College of PhysiciansAmerican Society of Internal Medicine. Position Paper. Pharmacist scope of practice. Ann Intern Med. 2002;136:79–85.

Stanford School of Medicine. News Release: New Stanford Medical Center Policy Limits Drug Company Access and Gifts. 9/12/06. http://med.stanford.edu/news_releases/2006/september/coi.html.

Accessed April 7, 2009.

Kowalczyk L.UMass Policy Limits Doctor, Drug Maker Ties. The Boston Globe. December 24, 2007.

www.boston.com/business/healthcare/articles/2007/12/24/umass_policy_limits_doctor_drug_maker_ties/. Accessed April 7, 2009.

Yale University Policy on Conflict of Interest and Conflict of Commitment. www.yale.edu/provost/html/conflict.pdf. Accessed April 7, 2009.


Drug Companies Retain Tight Control of

Physicians’ Presentations*

Whistleblower lawsuits in recent years have accused the firms

of using doctors to push their pills for unapproved uses during

dinner talks.

All told, at least 10 firms have settled such cases for nearly $7

billion in the past three years and have pledged reforms

under threat of further punishment.



All seven companies whose payments are listed in

ProPublica’s Dollars for Docs database say that

physicians must use the slides they provide.

Adhering to the drug company rules, however, can put

speakers in violation of their universities’ policies.

* http://www.propublica.org/article/drug-companies-retain-tight-control-of-physicians-presentations

by Charles Ornstein and Tracy Weber

ProPublica, Dec. 19, 2010, 10:08 p.m.


This is how each of the companies listed in

ProPublica’s databases responded to questions

about its speaker requirements*:

The companies are leaving little to the speakers’

control.

The companies say that physicians must use the

slides they provide.

All companies claim that they provides content

which is in compliance with FDA regulations and

approved product labeling

* by Charles Ornstein and Tracy Weber

ProPublica, Dec. 19, 2010, 10:08 p.m.

http://www.propublica.org/article/drug-companies-retain-tight-control-of-physicians-presentations


This is how each of the companies listed in

ProPublica’s databases responded to

questions about its speaker requirements*:

Merck , GlaxoSmithKline (GSK), Eli Lilly and

Company, AstraZeneca, Pfizer, Johnson &

Johnson, Cephalon

Example: GSK chooses the speaker, topic and

program content. All information presented must

be consistent with the approved U.S. label for the

product (s) discussed. GSK prepares the slides.

* by Charles Ornstein and Tracy Weber

ProPublica, Dec. 19, 2010, 10:08 p.m.

http://www.propublica.org/article/drug-companies-retain-tight-control-of-physicians-presentations


After two decades of decimation, only a few large

pharmaceutical companies remain capable of conducting

multiple parallel phase-3 drug trials (boldface indicates

companies that are currently still in operation)*.

* Tschöp M H , and DiMarchi R D Diabetes 2012;61:1309-1314


Piercing the Veil, More Drug Companies in the

USA Reveal Payments to Doctors

Company 2010 Speaker Payments 2010 U.S. Sales

Lilly $61,477,547 $14.3 billion

GlaxoSmithKline $52,755,793 $13.6 billion

Pfizer $34,382,574 $26.2 billion

AstraZeneca $31,647,101 $18.3 billion

Merck $20,365,446 $18.8 billion

Johnson & Johnson $11,712,900 $12.9 billion

Cephalon $4,241,080 $2.1 billion

ViiV Healthcare $3,975,102 Unavailable

Several companies began reporting the information publicly under

pressure from lawmakers or as a condition of settling federal

whistle-blower lawsuits.

http://www.propublica.org/article/piercing-the-veil-more-drug-companies-reveal-payments-to-doctors

by Charles Ornstein, Tracy Weber and Dan Nguyen ProPublica, Sept. 7, 2011, 4:31 p.m.


Incretin Drugs Contribute Heavily to

the Bottom Line

The oral incretin drugs are the most profitable.

In 2013 Januvia was Merck's number one selling drug.

Januvia and Janumet combined achieved sales of $5.75 billion

and represented 14% of Merck's total pharmaceutical sales for

the year.

Onglyza and Kombiglyze earned $709 million dollars for Bristol

Myers Squibb in 2012 which was 26% of their total

pharmaceutical sales.

It earned another $323 million for AstraZenaca (Byetta and

Bydureon), which was 4% of its total annual drug sales.


Patent protection and drug industry

The most lucrative drugs are those

still protected by patent and

deemed worthy of selection despite

high expense because of clear

advantages over cheaper drugs no

longer covered by

patent protection


A Clouded Future For Big Pharma's

Blockbuster Diabetes Drugs

Apr 3 2013, 10:04 by: Psycho Analyst

The injectable incretin drugs include:

Byetta and Bydureon, sold by a partnership of

Bristol-Myers Squibb (BMY) and AstraZeneca

(AZN), and

Victoza, from Novo Nordisk (NVO).


GlaxoSmithKline (GSK) to Pay $3B for

Sales, Safety Violations

(The largest health fraud settlement in U.S. history)

July 02, 2012 GlaxoSmithKline has agreed

to plead guilty and pay $3 billion in civil

and criminal penalties in a deal with

federal prosecutors of US Justice

Department

over its marketing of different drugs

and


for failing to report safety problems

with rosiglitazone (Avandia).

http://www.medpagetoday.com/PublicHealthPolicy/FDAGeneral/33587.


The largest health fraud settlement in U.S. history

GlaxoSmithKline ‘s civil and criminal offences

has been described by the prosecutors as:

Cheaters

health care fraud

False and misleading labeling

sponsored dinner programs, lunch programs, spa programs,

and similar activities to promote the use of its drugs.

paid millions to doctors to promote the drug off-label during

meetings sometimes held at swanky resorts.


relied on pharmaceutical sales reps, "sham advisory

boards," and continuing medical education programs that

appeared independent but were not.

reported false drug prices under Medicaid, making it appear

that its drugs were cheaper than what they actually were.

http://www.medpagetoday.com/PublicHealthPolicy/FDAGeneral/33587.


The largest health fraud settlement in U.S. history

GSK CEO described these offences as

mistakes:

"On behalf of GSK, I want to express our regret

and that we have learnt from

the mistakes that were made,".*

The company said at the time that its total legal

charges for 2010 totalled roughly $6.5 billion**.

* http://www.medpagetoday.com/PublicHealthPolicy/FDAGeneral/33587.

** http://www.medpagetoday.com/Cardiology/Diabetes/29432.


Use of drugs and its budgetary implications

for health systems*

Increased use of newer, more expensive

drugs, along with the rising incidence of

Type 2 Diabetes Mellitus

The growth in the worldwide diabetes

pharmaceutical market is

from US$ 3.8 billion in 1995

to US$ 17.8 billion in 2005

to US$ 975 billion in 2013

• Hauber Alexandra, Gale Edwin A M. The market in diabetes. Diabetologia. 2006;49(2):247–252. doi: 10.1007/s00125-005-0108-0.

http://www.dailyfinance.com/2009/10/08/a-slightly-healthier-forecast-for-global-pharmaceutical-sales-in/


Drug regulation

People and Governments willing to spend money on

drugs for many reasons so, it must be safe, effective

and good quality and used appropriately.

Development, production, importation, exportation

and subsequent distribution of drugs must be

regulated to ensure that they meet prescribed

standards.


Therefore, effective drug regulation is required to

ensure the safety, efficacy and quality of drugs as

well as accuracy and appropriateness of the drug

information available to the public.


Key functions of

drug regulatory agency

Product registration (drug evaluation and

authorization, and monitoring of drug efficacy and

safety);

Regulation of drug manufacturing, importation,

and distribution;

Regulation & Control of drug promotion and

information.

Adverse drug reaction (ADR) monitoring.

Licensing of premises, persons and practices.

Main goal of drug regulation is to guarantee the

safety, efficacy and quality of drugs available to

public.


Relationships Between Authors of Clinical Practice

Guidelines and the Pharmaceutical Industry

JAMA. 2002;287(5):612-617. doi:10.1001/jama.287.5.612


Relationships Between Authors of Clinical Practice

Guidelines and the Pharmaceutical Industry

JAMA. 2002;287(5):612-617. doi:10.1001/jama.287.5.612


Number of Episodes Reported for Types of Conflicts of interest in

Number of Episodes Reported for Types of Conflicts of Interest in Each Guideline

cardiovascular clinical practice guidelines*

* Mendelson, T. B. et al. Arch Intern Med 2011;171:577-584.

17 most recent Clinical Practice Guedelines’s of the American College of Cardiology/

American Copyright restrictions Heart may apply. Association


Conflicts (Dualities) of interest in American Association of Clinical

Endocrinologists (AACE) Algorithm

Author

1

2

3

4

5

6

7

8

9

10

11

12

#Episodes = 12

Research

grants

4

0

5

4

8

3

4

2

0

(6)*

0

0

8 (75%)

Honoraria/

Speakers

bureau

8

6

6

0

4

8

6

0

1

(10)*

3

5

10 (88%)

Stock/Other

Ownership

0

0

0

2

0

0

0

0

2

0

0

0

2 (16%)

*Declared in Subsequent Publication

Table Source: Rodbard, H,et al. Endocr Pract 2009;15:541 ; www.ProPublica.Org

Consultant/

Advisory

boards

9

3

15

5

0

7

7

13

13

0

3

5

10 (88%)


Conflicts (Dualities) of interest in American Association of Clinical

Endocrinologists (AACE) Algorithm

Auther

Research

grants

Honoraria/Speakers

bureau

Stock/Other

Ownership

Consultant

/ Advisory

Total $ amount

1

2

3

4

5

6

7

8

9

10

11

12

#Episodes = 12

4

0

5

4

8

3

4

2

0

(6)*

0

0

8 (75%)

10 (88%)

8

6

6

0

4

8

6

0

1

(10)*

*Declared in Subsequent Publication

Table Source: Rodbard, H,et al. Endocr Pract 2009;15:541

3

5

0

9

0

3

0

15

2

5

0

0

0

7

0

7

0

13

2

13

0

0

0

3

0

5

2 (16%) 10 (88%)

www.ProPublica.Org

$ 48,382

$ 5,945

$ 44,044

$ 20,347

$ 178,600

$ 99,097

$ 222,375

$ 4,400

$ 125,221

$ 222,838

$ 5,800

$ 99,239

Mean = $ 89,691

Median = $ 44,044


Conflicts (Dualities) of interest among organizations

with diabetes algorithms

Organization

Authors

Total

episodes

Research

grants

Honoraria/

Speakers

bureau

Stock/

Other

Ownership

Consultant/

Advisory

board

ACCE

(American Association of

Clinical Endocrinologists)

12

12 (100%)

8 (75%)

10 (88%)

2 (16%)

10 (88%)

ADA/EASD

(ADA= American

Association of Clinical

Endocrinologists

EASD= European

Association for the

Study of Diabetes)

7

7 (100%)

6 (84%)

3 (42%)

0

6 (84%)

Canadian

93

78 (84%)

48 (60%)

64 (82%)

3 (4%)

56 (72%)

NICE

(National Institute For

Health and Clinical

Excellence)

13

7 (54%)

1 (8%)

5 (39%)

0

4 (31%)

SIGN

(Scottish Intercollegiate

Guidelines Network)

11

6 (55%)

2 (33%)

4 (66%)

0

4 (66%)

VA/DoD

(Veterans

Administration/Departm

ent of Defense)

14

0

0

0

0

0

Median

84%

60%

82%

72%

*Declared in Subsequent Publication

Table Source: Rodbard, H,et al. Endocr Pract 2009;15:541

www.ProPublica.Org


Cross-sectional survey of 192 authors of 44 CPGs endorsed by

North American and European societies on common adult

diseases published between 1991 and July 1999.

Relationship with pharmaceutical manufactures and no. of

companies with which authors had relationships*

Relationships

% of Authors

(95% Confidence Interval)

(N:100)

Mean No. of

Companies

(Range)

(N= 87)

Any relationship 87 (80-94) 10.5 (1-37)

Trade funding/honorarium 53 (43-63) 5.4 (1-16)

Speaker honorarium 64(54-74) 7.3 (1-20)

Educational program support 51 (41-61) 4.7 (1-36)

Research support 58 (48-68) 6.7 (1-26)

Employee/Consultant 38 (28-48) 5.7 (1-21)

Equity 6 (1-11) 1.8 (1-4)

From: Relationships Between Authors of Clinical Practice Guidelines and the Pharmaceutical

Industry

* JAMA. 2002;287(5):612-617. doi:10.1001/jama.287.5.612


Cross-sectional survey of 192 authors of 44 CPGs endorsed by

North American and European societies on common adult

diseases published between 1991 and July 1999.

Declarations contained within published guidelines*

Type of Declaration

No. of guidelins

Making declarations

regarding authers’

financial interactions

(n=44)

No. of guidelines

Making declarations

regarding guideline

Creation process

(n=44)

No Declaration made 42 26

Declared that no

sponsorship received

Received

nonpharmaceutical

industry support

Received pharmaceutical

industry support

* JAMA. 2002;287(5):612-617. doi:10.1001/jama.287.5.612

1 0

0 9

1 11

* Column values total more than 44 because 2 guidelines received funding from both

From: industry Relationships and government.

Between Authors of Clinical Practice Guidelines and the Pharmaceutical Industry


Nature and author perceptions of relationship

with pharmaceutical manufacturers*

No. of authors (%)

[95% confidence interval]

Had relationship with companies 47/80 (59) [48-70]

whose drugs were considered

in the guideline process

Relationship predated guideline process 45/47 (96) [92-100]

Relationship postdated guideline process 25/47 (53) [39-67]

Believed that relationships influenced 5/68 (7) [1-9] +

personal recommendations

Believed that relationships influenced 13/67 (19) [8-30]

personal recommendations of colleagues

+ Only 68 of the 80 respondents provided answers to the questions.

Only 67 of the 80 respondents provided answers to the questions.

* JAMA. 2002;287(5):612-617. doi:10.1001/jama.287.5.612


Clinical practice guidelines for diabetes : panel members’ conflicts of interest (COI)*. Values are numbers

(percentages) unless stated otherwise

No of

panel

members

COI

declaration

publicly

available?

Conflicts

identified by

search

Guideline

Year

issued Organisation type†

Chair with

conflicts?

Declared

conflicts

Total

conflicts

VA/DoD clinical

practice guideline 2003 Government 23 No No Unknown 0 0

2005 Government 15 Yes Yes 1 (7) 2 (13) 3 (20)

Canadian Task Force

on Preventive

Health Care‡

American

Association of

Clinical

Endocrinologists

Canadian Diabetes

§

US Preventive

Services Task Force

Institute for Clinical

Systems

Improvement

2007 Medical specialty

society

12 Yes Yes 9 (75) 1 (8) 10 (83)

2008 Professional 93 Yes Yes 72 (77) 1 (1) 73 (78)

association

2008 Government 16 No No Unknown 1 (6) 1 (6)

2010 Non-profit 15 Yes Yes 6 (40) 0 6 (40)

American Diabetes 2010 Professional 15 Yes NA 13 (87) 0 (0) 13 (87)

Association

association

Total 189 101 (53%) 5 (3%) 106 (56%)

NA=no panel chair identified; VA/DoD=Veterans Administration/Department of Defense.

*Defined as direct compensation of guideline author by drug company in form of grants, speakers’ fees, honorariums, consultant/adviser/employee

compensation, and stock ownership 2 years before and including year of guideline release.†Classified exactly as listed on National Guidelines

Clearinghouse website, except for Canadian Diabetes Association and Canadian Cardiovascular Association, which were not included on website;

designations of US organisations most similar to them used—American Diabetes Association and American Heart Association.‡Canadian

guidelines.§Drug company sponsors included GlaxoSmithKline, Novo, Sanofi, Servier Canada, Astra Zeneca, Bayer, Eli Lilly, Merck, Pfizer, and

Hoffman-LaRoche, although document states that none of the authors was compensated in any way.

*BMJ 2011;343:d5621 doi: 10.1136/bmj.d5621


Clinical practice guidelines for Hyperlipidaemia: panel members’ conflicts of interest (COI)*. Values

are numbers (percentages) unless stated otherwise

Year

Guideline

issued

American Association

of Clinical

2002

Endocrinologists

Expert Panel on

Government

Detection, Evaluation,

and Treatment of High

Blood Cholesterol in

Adults

American Heart

Association**

VA/DoD clinical

practice guideline

US Preventive

ServicesTask Force††

Canadian

Cardiovascular

Society‡

Organisation

type†

No of

panel

members

COI declaration

publicly

available?

Chair with

conflicts?

Declared

conflicts

Conflicts

identified by

search

Total

conflicts

Medical specialty 9 No No No Unknown 1 (11) 1 (11)

2004 Government 9 Yes Yes 8 (89) 0 8 (89)

2005 Medical specialty 17 Yes Yes

0 7 (41)

society

7 (41)

2006 Government 13 No No Unknown 1 (7) 1 (7)

2008 Government 16 No No 1 (6) 1 (6) 2 (13)

2009 Medical specialty

society

23 Yes NA 20 (87) 3 (13) 23 (100)

Institute for Clinical 2009 Non-profit 12 Yes No 1 (8) 1 (8) 2 (17)

Systems Improvement

Total 99 37 (37) 7 (7) 44 (44)

NA=no panel chair identified; VA/DoD=Veterans Administration/Department of Defense.

Drug company sponsors included Abbott Laboratories, Bayer, Bristol-Myers Squibb, KOS Pharmaceuticals, Merck, Parke-Davis Pharmaceuticals,

and Sankyo Parke-Davis.**Other sponsoring organisations included councils on cardiovascular nursing, arteriosclerosis, thrombosis, vascular biology,

basic cardiovascular sciences, cardiovascular disease in the young, clinical cardiology epidemiology and prevention, nutrition, physical activity and

metabolism, and stroke and Preventive Cardiovascular Nurses Association.††No official COI document in guideline, but one author was noted to have

been excused from voting because of his employment at Merck Pharmaceuticals.

*BMJ 2011;343:d5621 doi: 10.1136/bmj.d5621


Hierarchy of evidence-based medicine*

* http://library.downstate.edu/EBM2/2700.htm


Hierarchy of evidence-based medicine

Even meta-analysis

has recently been

strongly criticized.

Because a metaanalysis

may be

conducted on a group

of studies chosen in an

incomplete or biased

manner.


Criteria for assigning levels of evidence to the published studies

Studies of diagnosis

Level

Criteria

Level 1

Level 2

Level 3

Level 4

a) Independent interpretation of test results (without

knowledge of the result of the diagnostic or gold standard)

b) Independent interpretation of the diagnostic standard

(without knowledge of the test result)

c) Selection of people suspected (but not known) to have

the disorder

d) Reproducible description of both the test and diagnostic

standard

e) At least 50 patients with and 50 patients without the

disorder

Meets 4 of the Level 1 criteria

Meets 3 of the Level 1 criteria

Meets 1 or 2 of the Level 1 criteria


Criteria for assigning levels of evidence to the

published studies

Studies of prognosis

Level 1

a) Inception cohort of patients with the condition of

interest but free of the outcome of interest

b) Reproducible inclusion/exclusion criteria

c) Follow-up of at least 80% of subjects

d) Statistical adjustment for extraneous prognostic

factors (confounders)

e) Reproducible description of outcome measures

Level 2 Meets criterion a) above, plus 3 of the other 4

criteria

Level 3

Meets criterion a) above, plus 2 of the other criteria

Level 4

Meets criterion a) above, plus 1 of the other criteria

RCT, randomized, controlled trial.

*In cases where such blinding was not possible or was impractical (e.g. intensive

vs. conventional insulin therapy), the blinding of individuals who assessed and

adjudicated study outcomes was felt to be sufficient.


Criteria for assigning grades of recommendations

for clinical practice

Grade

Criteria

Grade A The best evidence was at Level 1

Grade B The best evidence was at Level 2

Grade C The best evidence was at Level 3

Grade D

The best evidence was at Level 4 or consensus


Criteria for assigning levels of evidence to

the published studies

Studies of treatment and prevention

Level 1A Systematic overview or meta-analysis

of high quality RCTs

a) Comprehensive search for evidence

b) Authors avoided bias in selecting articles for

inclusion

c) Authors assessed each article for validity

d) Reports clear conclusions that are supported

by the data and appropriate analyses


Criteria for assigning levels of evidence to the

published studies

Studies of treatment and prevention

OR

Level 1A

Appropriately designed RCT with adequate

power to answer the question posed by the investigators

a) Patients were randomly allocated to treatment

groups

b) Follow-up at least 80% complete

c) Patients and investigators were blinded to the

treatment

d) Patients were analyzed in the treatment groups to

which they were assigned

e) The sample size was large enough to detect the

outcome of interest


Criteria for assigning levels of evidence to

the published studies

Studies of treatment and prevention

Level 1B

Nonrandomized clinical trial or cohort

study with indisputable results

Level 2

Level 3

Level 4

RCT or systematic overview that does not

meet Level 1 criteria

Nonrandomized clinical trial or cohort

study; systematic overview or meta-analysis

of level 3 studies

Other


Meta-analysis may not consider COI’s

Few meta-analysis in high-impact journals

report RCT funding sources

29

(RCTs)

?

Yes

NO

2

27

Roseman M. JAMA 305:1008-1017, 2011


Funding sources of RCT’s*

509 RCT’s in 29 MA’s

Yes

Reported funding source

NO

318

191

Industry

funded

Yes

NO

219 (69%)

99 (31%)

* Roseman M. JAMA 305:1008-1017, 2011


Financial disclosures in RCT’s*

509 RCT’s in 29 MA’s

Reported author Financial disclosures

Yes

NO

132

377

Authors

with

≥ 1 COI

Yes

NO

91

41

* Roseman M. JAMA 305:1008-1017, 2011


Glycemic Goals

The goal of glycemic treatment of

persons with T2DM is to

achieve clinical and biochemical

targets with as few adverse

consequences as possible.

Early enthusiasm for tight control

for all is now waning and

individualization of goals seems

most appropriate.


Large trials that compared clinical outcomes among

patients with type 2 diabetes who were randomly

assigned to tight versus less tight glycemic targets

1. ADVANCE

2. VADT

3. UKPDS 34

4. UKPDS 33

5. ACCORD

1. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl

J Med. 2008;358:2560-72.

2. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD; et al. VADT Investigators. Glucose control and vascular

complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129-39.

3. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS

34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-65.

4. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications

in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-53.

5. Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group. Effects of intensive glucose lowering in type 2

diabetes. N Engl J Med. 2008;358:2545-59.


Nice

(later: 7.5%)

ADA , SIGN

and DoD/VA

(7%)

EASD , AACE

and,NICE

(6.5%)

HbA1c

13

12

11

10

9

8

7

6

5

4

BG

350

345

310

275

240

205

170

135

100

65

In the

USA

43% have A1c

≥ 7%

(56% if

African

American;

63% if

Hispanic)

ADA (individual patient)

(< 6%)

Hoeger TJ. Diab Care 31:81-86, 2008


HBA1C targets suggested by different organizations

Optimal

target

AACE

EASD

ADA

SIGN

NICE

HBA1C equal or more than 6%

(normal target)

HBA1C < 6.5 %

HBA1C < 6.5%

HBA1C < 7% (general)

HBA1C < 6%* (individual patient)

HBA1C


Factor Increased A1C Decreased A1C Variable

Change in A1C

Erythropoiesis

Altered hemoglobin

Altered

glycation

Erythrocyte

destruction

Assays

Factors that can affect A1C

Iron deficiency

B12 deficiency

Decreased erythropoiesis

Alcoholism

Chronic renal failure

Decreased erythrocyte pH

Increased erythrocyte

lifespan:

Splenectomy

Hyperbilirubinemia

Carbamylated hemoglobin

Alcoholism

Large doses of aspirin

Chronic opiate use

Use of erythropoietin, iron or

B12

Reticulocytosis

Chronic liver disease

Ingestion of aspirin, vitamin C

or vitamin E

Hemoglobinopathies

Increased erythrocyte pH

Decreased erythrocyte lifespan:

Chronic renal failure

Hemoglobinopathies

Splenomegaly

Rheumatoid arthritis

Antiretrovirals, Ribavirin

Dapsone

Hypertriglyceridemia

Hemoglobinopathies


The goal for A1c may not be safely achieved with current

therapy

ACCORD ADVANCE VADT (VA diabetes)

Number

10,251

11,400

1791

Age (Yrs)

62.2

66

60.4

BMI (Kg/m)

32.2

28.5

31.3

Duration of DM (Yrs)

10

8

11.5

Previous CV events (%)

35.2

32.2

31.3

Mean A1C level

8.3

7.5

9.4

Median A1C level achieved

Intensive control

6.4

6.4

6.9

Conventional control

7.5

7.3

8.6

Drugs

Metformin

Gliclazide XR

Glimepiride

Drugs

Glimepiride

Metformin

Roseglitazone

Drugs

Roseglitazone

Insulin

Insulin

Drugs

Insulin

Acarbose/

Roseglitazone

Results

Higher mortality

No difference

No difference


Impact of Intensive Therapy for Diabetes:

Summary of Major Clinical Trials

Study Microvasc CVD Mortality

UKPDS/PSM


DCCT /


EDIC*

ACCORD

ADVANCE

VADT

Kendall )

DM, Bergenstal RM. © International Diabetes Center 2009

UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854.

Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977.

Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545.

Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum:

Moritz T. N Engl J Med 2009;361:1024




Initial Trial

Long Term

Follow-up

* in T1DM


A Patient- Centered Approach to Type 2 Diabetes


Treatment strategies should be made taking

into consideration

the needs ,

preferences, and

tolerances

of each patient.


Currently 13 classes of FDA-approved

antidiabetic agents for type 2 diabetes


Managing cardiovascular risk factors is a

major focus of therapy

Iamail-Beigi F, et al. Ann Intern Med 2011;154:554-559.

Inzucchi SE, et al.Diabetes Care . 2012;35:1364-1379.

Inzucchi SE, et al. Diabetologia. 2012;55:1577-1596.


What have we learned

Hypoglycemia is bad

Tight glycemic control is associated

with decrease risk for nephropathy*

and retinopathy**

* ADVANCE Colaborative Group, et al. N Engl J Med. 2008; 358:2560-2572

UKPDF Group. Lancet. 1998;352:837-853

** ACCORD Study Group, et al. N Engl J Med 2008;358:2545-2559


According to subset analyses from all three

studies (ACCORD,ADVANCE, VADT),

patients most likely to benefit from intensive

glycemic control were:

Those with a shorter duration of

diabetes

Those with a lower HbA1c at the start of

the study,

As well as patients without active CVD.


Individualizing Glycemic Targets

in Type 2 Diabetes Mellitus

Goals should be individualized based on :







duration of diabetes

age/life expectancy

comorbid conditions

known CVD or advanced microvascular

complications

hypoglycemia unawareness

individual patient considerations


Approach to management of hyperglycaemia:

More stringent

Less stringent

Patient attitude and

expected treatment

efforts

Risks potentially

associated with

hypoglycaemia, other

adverse events

Highly motivated, adherent,

excellent self-care capacities

Low

Less motivated, non-adherent,

poor self-care capacities

Newly diagnosed Long-standing

Disease duration

High

Life expectancy

Long

Short

Important

comorbidities

Absent

Few / mild

Severe

Established vascular

complications

Resources,

support system

Absent

Readily available

Few / mild

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print](Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554)

Severe

Limited


Recommended targets for glycemic control


VA/DoD Clinical Practice Guideline for the Management of

Diabetes Mellitus – 2011

Determination of target HBA1c level* (upper normal range is 6%)

Major comorbidity (d)

or physiolgical age

Absent

> 10 years of life

expectancy

Present (e)

5-10 years of life

Expectancy

Marked (f)

< 5 years of life

expectancy

Microvascular complications

Absent or mild (a) Moderate (b) Advanced (c)

< 7%

< 8%

8-9%*

< 8%

8-9%*

Consensus

< 8%

8-9%*

8-9%*

8-9%*

(a) Mild microvascular disease is defined by early background retinopathy, and/or microalbuminuria, and/or

mild neuropathy. (b) Moderate microvascular disease is defined by pre-proliferative (without severe hemorrhage, intra-retinalanomalies

[IRMA], or venous bleeding) retinopathy or persistent, fixed proteinuria

(macroalbuminuria) and/or demonstrable peripheral neuropathy (sensory loss). (c) Advanced microvascular disease is defined by

severe non-proliferative (with severe hemorrhage, IRMA, or venous bleeding) or proliferative retinopathy and/or renal insufficiency

(serum creatinine level > 2.0 mg/dL) and/or insensate extremities or autonomic neuropathy (e.g., gastroparesis, impaired sweating, or

orthostatic hypotension).

(d) Major comorbidity includes, but is not limited to, any or several of the following conditions: cardiovascular disease, chronic

obstructive pulmonary disease, chronic liver disease, stroke, and malignancy. (e) Moderate degree of major comorbid condition. (f)

Severe degree or end-stage major comorbid condition.


Clinical practice guidelines (CPGs)

CPGs are systematically developed statements

aimed at helping people make clinical, policyrelated

and system-related decisions 1,2

frequently vary widely in quality 2,3 .

CPGs are intended to present a synthesis of

current evidence and recommendations

preformed by expert clinicians and may affect

the practice of large numbers of physicians.

1. Committee to Advise the Public Health Service on Clinical Practice Guidelines, Institute of Medicine In: Field MJ, Lohr KN, editors. , editors. Clinical practice

guidelines: directions for a new program. Washington (DC): National Academy Press; 1990.

2. Browman GP, Brouwers M, Fervers B, et al. Population-based cancer control and the role of guidelines-towards a “systems” approach. In: Elwood JM,

Sutcliffe SB, editors. , editors. Cancer control. Oxford (UK): Oxford University Press; 2010.

3. Shaneyfelt TM, Mayo-Smith MF, Rothwangl J. Are guidelines following guidelines? The methodological quality of clinical practice guidelines in the peerreviewed

medical literature [see comments]. JAMA 1999;281:1900–5.

4. Vigna-Taglianti F, Vineis P, Liberati A, et al. Quality of systematic reviews used in guidelines for oncology practice. Ann Oncol 2006;17:691–701.


What is Algorithm (in guidelines)?

It is

a flow chart of the

clinical decision pathway

described in the Clinical practice

guidelines (CPGs) , where decision

points are represented by boxes,

linked with arrows


The AGREE II Instrument*

(International consortium of guideline developers )

The aim of this instrument to assess

methodological rigour and

transparency of how a clinical

practice guideline was developed.

* National Collaborating Centre for Methods and Tools (2011). Critically appraising practice guidelines: The AGREE II instrument. Hamilton, ON: McMaster

University. (Updated 28 November, 2011). Retrieved from

http://www.nccmt.ca/registry/view/eng/100.html.


Types of medical practice setting






Academic practice

Public health practice

Outpatient private practice

Outpatient group practice

Hospital-based practice


Why clinical practice guidelines and

recommendations for Type 2 diabetes

To provide a user-friendly, clinical, evidence-based

guideline for all healthcare professionals :

offers best clinical advice

is based on best published clinical and economic

evidence, alongside expert consensus

takes into account patient choice and informed decision

making

defines the major components of care provision

details areas of uncertainty or controversy

provides a choice of guideline versions for differing

audiences.


In summary

why we need clinical practice guidelines

we need them to provide a

considered,

unbiased,


evidence-based,

accessible,


transparent and


easy-to-use

evaluation of what provides benefit and harm.


Barriers to diabetes ( and hypertension ) guideline

implementation*

insufficient resources and time,



overcrowded clinics,

poor patient records,

lack of medical officers education on guidelines,

decreasing staff numbers,

few opportunities for continuing medical

education (CME)

poor patient compliance

* Bernard AM, et al Diabetes Care 1999; 22: 661-666.

Greaves CJ, et al. J Adv Nurs 2003;42: 487-496.

Chin MH, et al. Diabetes Care 2001; 24: 268-274.

Dalewitz J, et al. Am J Med Qual 2000; 15: 16-25.


Dissemination and implementation

and Type 2 diabetic patients’ care gap

Despite the strength of the evidence

supporting the multifactorial treatment of

people with diabetes to reduce

complications, only 13% of patients with

type 2 diabetes achieve all 3 metabolic

targets (glycemia, lipids and blood

pressure)*.

* Leiter LA, et al. Type 2 diabetes mellitus management in Canada: Is it improving? Can J Diabetes 2013: in press.


Dissemination and implementation

and Type 2 diabetic patients’ care gap

Therefore, a care gap remains and the effective

dissemination and implementation of clinical

practice guidelines is critical.

Strategies must be developed to increase

practitioner implementation.

Development of a strategic plan to be

implemented at the launch of the guidelines and

to continue for years thereafter.

* Leiter LA, et al. Type 2 diabetes mellitus management in Canada: Is it improving? Can J Diabetes 2013: in press.


Clinical Practice Guidelines (CPGs)

and Knowledge-Action Gap in Diabetes

Especially for General Physicians (GPs)

CPGs are potentially useful for health

services and health workforce planning,

but would be more valuable for this purpose

if they contained more detail about care

protocols and specific skills and

competencies especially for General

Physicians (GPs) who would be expected to

have reduced capacity for effective highquality

care.

To be followed


Clinical Practice Guidelines (CPGs)

and Knowledge-Action Gap in Diabetes

Especially for General Physicians (GPs)

The GPs lack the needed and reliable

knowledge in deciding exactly to which patient

and when to give and best example are

incretin-based medications

(i.e. Januvia)

and what are the precautions, warnings and

potential adverse effects that they them self be

aware of it and must be explained to the patient.

To be followed


Clinical Practice Guidelines (CPGs)

and Knowledge-Action Gap in Diabetes

Especially for General Physicians (GPs)

In addition, many of these GPs are not ready to

detect and to deal properly and timely with the

potential serious adverse effects.

Subsequently, many patients will not receive

such level of care despite the availability of

international treatment guidelines describing the

supposed optimal management of patients with

diabetes*.

* Bowman BA, Vinicor F. Nutr Clin Care 2003, 6:49-50.

To be followed


Clinical Practice Guidelines (CPGs)

and Knowledge-Action Gap in Diabetes

Especially for General Physicians (GPs)

A clear understanding on how to overcome this

knowledge-action gap in diabetes seems to be

lacking 1-3 , despite previous studies which

outlined the obstacles that prevent GPs from

following the CPGs 1-9 1. Faruqi N, et al. Aust Fam Physician 2000,

29:173-176.

2. McDonald K, Sundaram V, Bravavata DM,

.

Lewis R, Lin N, Kraft S, McKinnon M,

Paguntalan H, Owens DK: Closing the Quality

Gap: A Critical Analysis of Quality

Improvement Strategies Volume 7-Care

Coordination (Technical Review 9 (Prepared

by the Stanford University-UCSF Evidencebased

Practice Center under contract

2007;.290-02-0017). 2007.

3. Shojania KG, Ranji SR, Shaw LK, Charo LN,

Lai JC, Rushakoff RJ, McDonald KM, Owens

DK: Closing the Quality Gap: A Critical

Analysis of Quality Improvement Strategies

Volume 2-Diabetes Mellitus Care, Technical

review 9 (Contract No. 290-02-0017 to the

Stanford University-UCSF Evidence-based

Practice Center). 2004.

1. Grimshaw JM, et al. Health Technol Assess

2004, 8

2. Larme AC, Pugh JA. Diabetes Care 1998,

21:1391-1396.

3. Wang L. Med Princ Pract 2004, 13:282-285.

4. Nagelkerk J. J Adv Nurs 2006, 54:151-158.

5. Kedward J, Dakin L. Br J Gen Pract 2003,

53:684-689.

6. Nakar S, et al. J Diabetes Complications

2007, 21:220-226.

7. Alberti H, et al. BMC Fam Pract 2007, 8:63.

8. Chin MH, et al. Diabetes Care 2001, 24:268-

274.

9. Haque M, et al. S Afr Med J 2005, 95:798-

802.


Clinical Practice Guidelines (CPGs)

and Knowledge-Action Gap in Diabetes

Especially for General Physicians (GPs)

So the only winner in such

battle field

is the pharmaceutical

companies


Personalized medicine


Personalized medicine for diabetes is a

potential method to specifically identify

people who are at high risk of developing

type 2 diabetes based on a combination of

Personal history,

Family history,

Physical examination,

Circulating biomarkers, and

Genome.

High-risk individuals can then be referred to

lifestyle programs for risk

Klonoff DC, et al. J Diabetes Sci Technol. 2009 July; 3(4): 677–679.


Personalized medicine

Using a personalized medicine approach,

a patient with already-diagnosed type 2

diabetes can be treated individually based

on information specific to that individual.

Klonoff DC, et al. J Diabetes Sci Technol. 2009 July; 3(4): 677–679.


Template care vs. personalized medicine

Template care

is increasingly at odds with the emergence of

personalized medicine,

a new discipline driven by the exploding

knowledge of the human genome that guides

treatment tailored to the individual patient.

And this is what today's medical students

will be practicing


Delaying the Onset of Type 2 Diabetes

Among those at high risk, the proposed 3-

step approach was to

A) identify those who may be at higher risk,

B) measure the risk, and

C) intervene to delay/prevent the onset of

type 2 diabetes using predominantly

health behaviour strategies to affect the

modifiable risk factors for type 2

diabetes.


Delaying the Onset of Type 2 Diabetes

There remains an urgent and

increasing need for governments to

invest in research to define effective

strategies and programs to prevent

and treat obesity and to encourage

physical activity


Intervention studies on the prevention of

type 2 diabetes 1-5

Studies (ref. no.)

Lifestyle modifications

No. of

subjects

1. Pan XR, et al. Diabetes Care20

:537 –544,1997

2. Tuomilehto J, et al. N Engl J

Med344 :1343 –1350,2001

3. Knowler WC, et al. N Engl J

Interventions

Da Qing (1997) Med346 (1) :393 –403,2002577 Diet and/or

4. Chiasson JL, et al.the STOPexercise

NIDDM randomised trial.

DPS (2001) (2) Lancet359 :2072 –2077,2002

522 Diet and

5. Buchanan TA, et al. Diabetes49

:782 –788,2000

exercise

DPP (2002) (3) 2,161 Diet and

exercise

Follow-up

(years)

Relative

risk

reduction

(%)

6,0 39

3,2 58

2,8 58

Drug interventions

DPP (2002) (3) 2,151 Metformin 2,8 31

TRIPOD (2002) (5) 236 Troglitazone 2,5 59

STOP-NIDDM (2002) (4) 1429 Acarbose 3,3 36


Six Guidelines (Algorithms) for Type 2 DM

Management in the Last 5 Years*

1.ADA/EASD (American Diabetes Association/European

Association for the Study of Diabetes ) – 2009

2.ADA-EASD Position Statement: Management of

Hyperglycemia in T2DM: A Patient-Centered Approach

- 2012

3.AACE (American Association of Clinical

Endocrinologists) - 2011

4.NICE (National Institute For Health and Clinical

Excellence)- 2009

5. VA (Veterans Health Affairs) - 2011

6. SIGN (Scottish Intercollegiate Guidelines Network)–

2010

* National Guideline Clearinghouse website


Management of hyperglycaemia in type 2 diabetes:

a patient-centered approach.

Key points


Glycaemic targets and glucose-lowering

therapies must be individualised


Diet, exercise and education remain the

foundation of any type 2 diabetes treatment

programme


Unless there are prevalent contraindications,

metformin is the optimal first-line drug

After metformin, there are limited data

to guide us.


Management of hyperglycaemia in type 2 diabetes:

a patient-centered approach.

Key points


Combination therapy with an additional 1–2 oral or

injectable agents is reasonable, aiming to minimise

side effects where possible




Ultimately, many patients will require

insulin therapy alone or in combination with

other agents to maintain glucose control (mainly

metformin)

All treatment decisions, where possible, should be

made in conjunction with the patient, focusing on

his/her preferences, needs and values

Comprehensive cardiovascular risk reduction must

be a major focus of therapy


General recommendations for management of

type 2 diabetes


Lifestyle modifications: healthy eating including

eating slowly, weight control, increased physical

activity


If no contraindications and if tolerated, metformin

is the preferred first agent


Glycemic targets and therapies must be

individualized


Treatment decisions should be in conjunction with

the patients.


Self-management education (SME)


Dissemination and Implementation

Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.

Inzucchi SE, et al. Diabetes Care.2012;55:1577-1596.


Self-management education (SME)

Self-management education (SME) is defined as



a systematic intervention that involves active

patient participation in selfmonitoring

(physiological processes) and/or decision

making (managing) (1) .

It recognizes that patient-provider

collaboration and the enablement of problemsolving

skills are crucial to the individual’s

ability for sustained self-care (2) .

1. Bennett WL, Odelola OA, Wilson LM, et al.. Ann Intern Med 2012;156:27e36.

2. International Diabetes Federation. IDF Diabetes Atlas. 5th ed. Brussels: International Diabetes Federation,

www.idf.org/diabetesatlas; 2012. Accessed February 21, 2013.


ADA-EASD Position Statement: Management of

Hyperglycemia in T2DM:

A Patient-Centered Approach

3. Antihyperglycemic therapy

• Implementation Strategies

- Initial drug therapy

- Advancing to dual combination therapy

- Advancing to triple combination therapy

- Transitions to and titrations of insulin

4. Other considerations

• Age

• Weight

• Sex/racial/ethnic/genetic differences

• Comorbidities (Coronary artery disease, Heart failure, Chronic

kidney

disease, Liver dysfunction, Hypoglycemia)

5. Future directions / research needs

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]


Management of Hyperglycemia in T2DM: A

Patient-Centered Approach

3. Antihyperglycemic therapy

• Implementation Strategies

- Initial drug therapy (Drug of choice: Metformin)

- Advancing to dual combination therapy

- Advancing to triple combination therapy

- Transitions to and titrations of insulin

4. Other considerations

• Age

• Weight

• Sex/racial/ethnic/genetic differences

• Comorbidities (Coronary artery disease, Heart failure, Chronic kidney

disease, Liver dysfunction, Hypoglycemia)


Management of Hyperglycemia in T2DM:

A Patient-Centered Approach (Alashbal A.)

3. Antihyperglycemic therapy

• Implementation Strategies

- Initial drug therapy(Drug of choice:Metformin)

- Advancing to dual combination therapy

- Advancing to triple combination therapyNO more waste of time and money

- Transitions to and titrations of insulin

4. Other considerations

• Age

• Weight

• Sex/racial/ethnic/genetic differences

• Comorbidities (Coronary artery disease, Heart failure, Chronic kidney

disease, Liver dysfunction, Hypoglycemia)


Number of medication classes

Hypertension and diabetes:

Drug classes in U.S. Over Past Half-Century

11

10

7

9

8

6

5

4

3

2

1

Adrenergic

Neuronal

blockers

Vasodilators

Peripheral

α-1 agonist

ß-blockers

Central

α-2 agonist

Sulfonylureas

Diuretics

Ca + channel

blockers

Angiotensin II

receptor

blockers

Renin inhibitors

ACE

inhibitors

Bile acid

squestrants

DPP-4

inhibitors

Amylinomimetics

GLP-1 receptoragonists

Thiazoloidenediones

α- glucosidase

inhibitors

Biguanides

Dopamine

agonists

Glinides

INSULIN

1950 1960 1970 1980 1990 2000


AACE/ACE* Diabetes Algorithm For Glycemic Control 2010: A1C Goal ≤ 6.5%**

* American Association of Clinical Endocrinologists/American

College of Endocrinology (AACE/ACE)

** Am J Manag Care. 2010;16:S187-S194

The American Association of Clinical Endocrinologists/American College of Endocrinology algorithm for treatment of patients with type 2 diabetes mellitus.

Abbreviations: AGI, alpha-glucosidase inhibitor; DPP-4, dipeptidyl peptidase-4; FPG, fasting plasma glucose; GLP-1, glucagon-like peptide-1; HbA 1c ,

glycosylated hemoglobin; MET, metformin; PPG, postprandial glucose; SU, sulfonylurea; TZD, thiazolidinedione. Adapted with permission from Rodbard HW, et

al. 4 a For patients with diabetes mellitus and HbA 1c 8.5%, combination pharmacologic treatment with agents that cause hypoglycemia should be used with caution. k GLP-

1 not approved for initial combination pharmacologic treatment. l If HbA 1c >8.5%, in patients on dual therapy, insulin should be considered.


AACE/ACE* Diabetes Algorithm For Glycemic Control 2010: A1C Goal ≤ 6.5%**




* American Association of Clinical Endocrinologists/American

College of Endocrinology (AACE/ACE)

** Am J Manag Care. 2010;16:S187-S194

The American Association of Clinical Endocrinologists/American College of Endocrinology algorithm for treatment of patients with type 2 diabetes mellitus.

Abbreviations: AGI, alpha-glucosidase inhibitor; DPP-4, dipeptidyl peptidase-4; FPG, fasting plasma glucose; GLP-1, glucagon-like peptide-1; HbA 1c ,

glycosylated hemoglobin; MET, metformin; PPG, postprandial glucose; SU, sulfonylurea; TZD, thiazolidinedione. Adapted with permission from Rodbard HW, et

al. 4 a For patients with diabetes mellitus and HbA 1c 8.5%, combination pharmacologic treatment with agents that cause hypoglycemia should be used with caution. k GLP-

1 not approved for initial combination pharmacologic treatment. l If HbA 1c >8.5%, in patients on dual therapy, insulin should be considered.


Dr. Alashbal’ s observation regarding the use

of JANUVIA and other DPP-4 inhibitors

Until now, All T2 diabetics who I have seen them

and were victims of using JANUNIA OR its

brothers were severely hyperglycemic and they

have themselves noticed, regardless of their

adverse effects, that these drugs were absolutely

of no benefits and they have been told by other

doctors that they are new ones.

In addition, almost all of them were insulin

requiring T2 diabetics , but unfortunately

insulin was not used as their proper therapy.


AACE/ACE* Diabetes Algorithm For Glycemic Control 2009 : A1C Goal ≤ 6.5%**

Monotherapy

MET TZD DPP-4 AGI

+

Dual Therapy

GLP-1 or DPP-4

TZD

2-3 MOs

Glinides or SU

MET + GLP-1 or DPP-4

MET +

Lifestyle modification

“Stratified by A1Cs and documented evidence of efficacy”

A1C 6.5 – 7.5% A1C 7.6 - 9.0% A1C > 9.0%

+

MET +

GLP-1 or

DPP-4

2-3 MOs

Triple Therapy

+

Insulin

and other

agent (s)

Colesevelam

AGI

TZD

Glinides or SU

2-3 MOs

MET +

Dual Therapy

GLP-1

or DPP-4

or TZD

SU or Glinides

Triple Therapy

GLP-1

or DPP-4

GLP-1

or DPP-4

TZD

Insulin

and other

agent (s)

2-3 MOs

+

TZD

+ SU

2-3 MOs

Drug Naive

Symptoms

Insulin

and other

agent (s)

No symptoms

MET +

GLP-1

or DPP-4

TZD

GLP-1

or DPP-4

TZD:Thiazolidinediones

Met: metformin

AGI: alpha glucosidase inhibitors

SU: sulfonylurea

Under treatment

±

SU

±

TZD

Insulin

and other

agent (s)

* American Association of Clinical Endocrinologists/American

College of Endocrinology (AACE/ACE)

** Rodbard,H. Am J Manag Care. 2010;16:S187-S194


AACE/ACE* Diabetes Algorithm For Glycemic Control 2009 : A1C Goal ≤ 6.5%**

Monotherapy

MET TZD DPP-4 AGI

+

Dual Therapy

GLP-1 or DPP-4

TZD

2-3 MOs

Glinides or SU

MET + GLP-1 or DPP-4

MET +

Lifestyle modification

“Stratified by A1Cs and documented evidence of of efficacy”

A1C 6.5 – 7.5% A1C 7.6 - 9.0% A1C > 9.0%

+

MET +

GLP-1 or

DPP-4

2-3 MOs

Triple Therapy

+

Insulin

and other

agent (s)

Colesevelam

AGI

TZD

Glinides or SU

2-3 MOs

3 broad ranges =3 pathways

MET +

Dual Therapy

GLP-1

or DPP-4

or TZD

SU or Glinides

Triple Therapy

GLP-1

or DPP-4

GLP-1

or DPP-4

TZD

Insulin

and other

agent (s)

2-3 MOs

+

TZD

+ SU

2-3 MOs

Drug Naive

Symptoms

Insulin

and other

agent (s)

No symptoms

MET +

GLP-1

or DPP-4

TZD

GLP-1

or DPP-4

TZD:Thiazolidinediones

Met: metformin

AGI: alpha glucosidase inhibitors

SU: sulfonylurea

Under treatment

±

SU

±

TZD

Insulin

and other

agent (s)

* American Association of Clinical Endocrinologists/American

College of Endocrinology (AACE/ACE)

** Rodbard,H. Am J Manag Care. 2010;16:S187-S194


AACE/ACE* Diabetes Algorithm For Glycemic Control 2009 : A1C Goal ≤ 6.5%**

Monotherapy

MET TZD DPP-4 AGI

+

Dual Therapy

GLP-1 or DPP-4

TZD

2-3 MOs

Glinides or SU

MET + GLP-1 or DPP-4

MET +

Lifestyle modification

“Stratified by A1Cs and documented evidence of of efficacy”

A1C 6.5 – 7.5% A1C 7.6 - 9.0% A1C > 9.0%

+

MET +

GLP-1 or

DPP-4

Colesevelam

AGI

2-3 MOs

Triple Therapy

+ A1C:

6.5% to

7.5%

Insulin

and other

agent (s)

TZD

Glinides or SU

2-3 MOs

3 broad ranges =3 pathways

MET +

Dual Therapy

GLP-1

or DPP-4

or TZD

SU or Glinides

Triple Therapy

GLP-1

or DPP-4

GLP-1

or DPP-4

TZD

Insulin

and other

agent (s)

2-3 MOs

+

TZD

+ SU

2-3 MOs

Drug Naive

Symptoms

Insulin

and other

agent (s)

No symptoms

MET +

GLP-1

or DPP-4

TZD

GLP-1

or DPP-4

TZD:Thiazolidinediones

Met: metformin

AGI: alpha glucosidase inhibitors

SU: sulfonylurea

Under treatment

±

SU

±

TZD

Insulin

and other

agent (s)

* American Association of Clinical Endocrinologists/American

College of Endocrinology (AACE/ACE)

** Rodbard,H. Am J Manag Care. 2010;16:S187-S194


AACE/ACE* Diabetes Algorithm For Glycemic Control 2009 : A1C Goal ≤ 6.5%**

Monotherapy

MET TZD DPP-4 AGI

+

2-3 MOs

Dual Therapy

GLP-1 or DPP-4

TZD

Glinides or SU

MET + GLP-1 or DPP-4

MET +

Lifestyle modification

“Stratified by A1Cs and documented evidence of of efficacy”

A1C 6.5 – 7.5% A1C 7.6 - 9.0% A1C > 9.0%

+

MET +

GLP-1 or

DPP-4

Colesevelam

AGI

2-3 MOs

Triple Therapy

+ A1C:

6.5% to

7.5%

Insulin

and other

agent (s)

TZD

Glinides or SU

2-3 MOs

3 broad ranges =3 pathways

MET +

Dual Therapy

GLP-1

or DPP-4

or TZD

SU or Glinides

Triple Therapy

GLP-1

or DPP-4

GLP-1

or DPP-4

A1C: TZD

7.6% to

9.0%,

Insulin

and other

agent (s)

2-3 MOs

+

TZD

+ SU

2-3 MOs

Drug Naive

Symptoms

Insulin

and other

agent (s)

No symptoms

MET +

GLP-1

or DPP-4

TZD

GLP-1

or DPP-4

TZD:Thiazolidinediones

Met: metformin

AGI: alpha glucosidase inhibitors

SU: sulfonylurea

Under treatment

±

SU

±

TZD

Insulin

and other

agent (s)

* American Association of Clinical Endocrinologists/American

College of Endocrinology (AACE/ACE)

** Rodbard,H. Am J Manag Care. 2010;16:S187-S194


AACE/ACE* Diabetes Algorithm For Glycemic Control 2009 : A1C Goal ≤ 6.5%**

Monotherapy

MET TZD DPP-4 AGI

+

2-3 MOs

Dual Therapy

GLP-1 or DPP-4

TZD

Glinides or SU

MET + GLP-1 or DPP-4

MET +

Lifestyle modification

“Stratified by A1Cs and documented evidence of of efficacy”

A1C 6.5 – 7.5% A1C 7.6 - 9.0% A1C > 9.0%

+

MET +

GLP-1 or

DPP-4

Colesevelam

AGI

2-3 MOs

Triple Therapy

+ A1C:

6.5% to

7.5%

Insulin

and other

agent (s)

TZD

Glinides or SU

2-3 MOs

3 broad ranges =3 pathways

MET +

Dual Therapy

GLP-1

or DPP-4

or TZD

SU or Glinides

Triple Therapy

GLP-1

or DPP-4

GLP-1

or DPP-4

A1C: TZD

7.6% to

9.0%,

Insulin

and other

agent (s)

2-3 MOs

+

TZD

+ SU

2-3 MOs

Drug Naive

Symptoms

Insulin

and other

agent (s)

No symptoms

MET +

GLP-1

or DPP-4

A1C:

>9.0%

TZD

GLP-1

or DPP-4

TZD:Thiazolidinediones

Met: metformin

AGI: alpha glucosidase inhibitors

SU: sulfonylurea

Under treatment

±

SU

±

TZD

Insulin

and other

agent (s)

* American Association of Clinical Endocrinologists/American

College of Endocrinology (AACE/ACE)

** Rodbard,H. Am J Manag Care. 2010;16:S187-S194


AACE/ACE* Diabetes Algorithm For Glycemic Control : A1C Goal ≤ 6.5%**

3.Q6.2. Anti-hyperglycemic

Pharmacotherapy

The choice of the therapeutic agents

should be based on their differing

metabolic actions and adverse effect

profiles as described in the 2009

ACCE/ACE Diabetes Algorithm for

Glycemic Control (Grade D;

BEL4).

Not evidence based

Best Evidence Level 4= No

evidence (theory, opinion,

consensus….)

* American Association of Clinical

Endocrinologists/American College of Endocrinology

(AACE/ACE)

** Am J Manag Care. 2010;16:S187-S194


AACE/ACE* Diabetes Algorithm For Glycemic Control : A1C Goal ≤ 6.5%**

* American Association of Clinical Endocrinologists/American

College of Endocrinology (AACE/ACE)

** Am J Manag Care. 2010;16:S187-S194


AACE/ACE* Diabetes Algorithm For Glycemic Control 2010 : A1C Goal ≤ 6.5%**

Problems with initiating

triple therapy:

There is no evidence that treatment

with triple therapy in an a

symptomatic is necessary

There is no evidence that initiating

treatment with triple therapy in an

a symptomatic patient has better

short- or long –term outcomes.

There is increased risk of drugdrug

interaction and of not being

able to identify which agent caused

a side effect should one occur.

ACCE/ACE consensus Statement,

P. 544: “ The ACCORD study also

suggested that excessively rapid

or aggressive adjustment of

therapy may be associated with

increased risk of mortality”.

* American Association of Clinical

Endocrinologists/American College of Endocrinology

(AACE/ACE)

** Am J Manag Care. 2010;16:S187-S194


Relevant comments on AACE algorithm

Specifies duration of therapy for each stage

A1C target is inappropriate for many patients and the rationale

for its use fails to account for recent RCT results

No clearly stated reason for stratification of A1Cs

- Most studies use different cut points for analysis

Scientifically unjustified prominence of newer, more expensive,

and non-superior drugs

- None of the recent drugs have long-term outcomes data

- Levels of evidence are not provided to justify selections

DPP-4 inhibitors are new agent (unknown long-term safety) are

less potent

No rush in starting with triple (or even dual) therapy in

asymptomatic patients with A1C > 9.0%


Management of hyperglycemia in type 2 diabetes - 2008: Canadian Diabetes Association

L

I

F

E

S

T

Y

L

E

A1C


Medical management of hyperglycemia in type 2 diabetes

ADA\EASD* Consensus Algorithm - 2009**

Tier 1 : Well-validated core therapies

At Diagnosis:

Lifestyle

+

Metformin

Lifestyle+Metformin

+

Basal Insulin

Lifestyle+Metformin

+

Sulfonylurea

Lifestyle+Metformin

+

Intensive Insulin

Step 1 Step 2 Step 3

Tier 2 : Less well-validated therapies

DDP-4 inhibitors

Lifestyle+

Metformin

+

Pioglitazone

No hypoglycemia

Oedema/CHF, Bone loss

Lifestyle

+

Metformin

+

GLP-1 R agonist

No hypoglycemia

Weight loss/Nausea/Vomiting

Lifestyle+

Metformin

+

Pioglitazone

+

Sulfonylurea

Lifestyle+

Metformin

+

Basal Insulin

* ADA: American diabetes association; EASD: European association for the study of diabetes ; * *Nathan DM, et al. Diabetes Care. 2009;32:193-203.


Relevant comments on ADA/EASD algorithm

No Evidence grading

Admitted paucity of high-quality evidence

No explicit individualization of A1C goals

Clinical judgment – collective knowledge

and clinical experience

One of the authors has said, ‘I would never

prescribe a sulfonylurea… but this was a

consensus”


ADA-EASD Position Statement: Management of Hyperglycemia

in T2DM: A Patient-Centered Approach - 2012*

T2DM Antihyperglycemic Therapy: General Recommendations

* Inzucchi SE, et al . Diabetologia. 2012;55:1577-1596.


ADA-EASD Position Statement: Management of Hyperglycemia

in T2DM: A Patient-Centered Approach - 2012*

T2DM Antihyperglycemic Therapy: General Recommendations

* Inzucchi SE, et al . Diabetologia. 2012;55:1577-1596.


ADA-EASD Position Statement: Management of Hyperglycemia in T2DM:

A Patient-Centered Approach - 2012*

Alashbal A. opinion

T2DM Antihyperglycemic Therapy: General Recommendations

* Inzucchi SE, et al . Diabetologia. 2012;55:1577-1596.


ADA-EASD Position Statement: Management of Hyperglycemia

in T2DM: A Patient-Centered Approach - 2012*


T2DM Antihyperglycemic Therapy: General Recommendations

* Inzucchi SE, et al . Diabetologia. 2012;55:1577-1596.


ADA-EASD Position Statement: Management of Hyperglycemia

in T2DM: A Patient-Centered Approach - 2012*

T2DM Antihyperglycemic Therapy: General Recommendations

Inzucchi SE, et al . Diabetologia. 2012;55:1577-1596.


ADA-EASD Position Statement: Management of Hyperglycemia

in T2DM: A Patient-Centered Approach - 2012*

(Alashbal A.’ opinion)

NO more waste of time and money



T2DM Antihyperglycemic Therapy: General Recommendations

Inzucchi SE, et al . Diabetologia. 2012;55:1577-1596.


2012


Sequential insulin strategies in type 2 diabetes

Accordind to ADA-EASD Position Statement - 2012*

Non-insulin regimens

Basal insulin only

(usually with oral agents)

Number of

injections

1

Regimen

complexity

Low

Basal insulin

+ 1 (mealtime)

rapid-acting

insulin injection

Pre-mixed insulin

twice daily

2

Mod.

Basal insulin

+ ≥ 2 (mealtime)

rapid-acting insulin

injections

+3

High

More flexible

Less flexible

Flexible

* Inzucchi SE, et al . Diabetologia. 2012;55:1577-1596.


ADA-EASD Position Statement: Management of Hyperglycemia

in T2DM: A Patient-Centered Approach - 2012*

Antidiabetic

agents

Efficacy ↓

HbA1c%

Hypoglycemia Weight Side effect

(s)

Metformin (Met) high Low risk Neutral/

loss

Antidiabetic

agents

Met

+Sulphonylurea

Met+

Thiazolidinedione

Met+

DPP-4 inhibitor

Met+

GLP-1 receptor

agonist

Met+

Insulin (usually

basal)

Efficacy ↓

HbA1c%

GI/lactic

acidosis

Hypoglycemia Weight Major side

effect (s)

high moderate risk gain hypoglycemia

high low risk gain edema, HF,

fractures

Costs

low

Costs

low

high

intermediate low risk neutral rare high

high low risk loss GI high

highest high risk gain hypoglycemia

Inzucchi SE, et al. Diabetologia. 2012;55:1577-1596.

variable


ADA/EASD position statement 2012

Inzucchi SE, et al. Diabetologia. 2012;55:1577-1596.


ADA/EASD position statement 2012

L I F E S T Y L E

Inzucchi SE, et al. Diabetologia. 2012;55:1577-1596.


ADA/EASD position statement 2012

L I F E S T Y L E

Inzucchi SE, et al. Diabetologia. 2012;55:1577-1596.


ADA-EASD Position Statement: Management of

Hyperglycemia in T2DM: A Patient-Centered

Approach - 2012*

Glycaemic targets and glucose-lowering therapies must be

individualized

Diet, exercise and education remain the foundation of any type 2

diabetes treatment programme

Unless there are prevalent contraindications, metformin is the

optimal first-line drug

After metformin, there are limited data to guide us.

Combination therapy with an additional 1–2 oral or

injectable agents is reasonable, aiming to minimize side

effects where possible

All treatment decisions, where possible, should be made

in conjunction with the patient, focusing on his/her

preferences, needs and values.

Comprehensive cardiovascular risk reduction must be a

major focus of therapy

* Inzucchi SE, et al . Diabetologia. 2012;55:1577-1596.


Individualization of therapy ADA/EASD algorithm






Much individualization is based on adverse

effects

Sulfonylureas and insulin not ideal for patients

at high risk of hypoglycemia

TZDs not optimal for those with baseline edema

or in women with osteoporosis

Avoid GLP-1 agonists in patients who can’t

tolerate GI effects

DPP-4 inhibitors are new agent (unknown longterm

safety) are less potent

* Inzucchi SE, et al . Diabetologia. 2012;55:1577-1596.


NICE Type 2 diabetes algorithm for glycemic control - 2009 : A1C goal ≤ 6.5%

HbA1c ≥ 6.5% 1 after trial of lifestyle interventions

HbA1c ≥ 6.5% 1 Metformin 2 HbA1c < 6.5% 1

Monitor for deterioration

Metformin +

sulfonylurea 4

HbA1c ≥ 7.5% 1 HbA1c < 7.5% 1

Monitor for deterioration

Add insulin 2, 8 ,

particularly if the person is

markedly hyperglycaemic

Insulin + metformin + sulfonylurea 4

HbA1c ≥ 7.5% 1

HbA1c < 7.5% 1

Monitor for deterioration

Consider sulfonylurea4 here if:

● not overweight (tailor the

assessment

of body-weight-associated risk

according to ethnic group3), or

● metformin is not tolerated or is

contraindicated, or

● a rapid therapeutic response is

required because of

hyperglycaemic

symptoms.

Consider a rapid-acting insulin

secretagogue for people with

erratic

lifestyles.

Consider substituting a DPP-4

inhibitor9 or a thiazolidinedione10

for

the sulfonylurea if there is a

significant

risk of hypoglycaemia (or its

consequences) or a sulfonylurea

is

contraindicated or not tolerated.

Consider adding sitagliptin or a

thiazolidinedione10 instead of

insulin if

insulin is unacceptable (because

of

employment, social, recreational

or

other personal issues, or obesity).

Consider adding exenatide6 to

metformin and a sulfonylurea if:

• BMI ≥ 35 kg/m2 in people of

European

descent7 and there are problems

associated with high weight, or

• BMI < 35 kg/m2 and insulin is

unacceptable because of

occupational

implications or weight loss would

benefit other comorbidities.

Sulfonylurea 4

HbA1c ≥ 6.5%

1 HbA1c < 6.5%

1

Monitor for deterioration

Metformin 2 + DPP-4 inhibitor 5, 9

or a thiazolidinedione 5,10

Consider adding a DPP-4 inhibitor 9 or a

thiazolidinedione 10 if metformin is

contraindicated or not tolerated

Sulfonylurea 4

+ DPP-4 inhibitor 5, 9 or a

Thiazolidinedione 5,10

HbA1c ≥

HbA1c < 7.5% 7.5% 1 1

Monitor for HbA1c ≥ HbA1c < 7.5% 1

deterioration 7.5% 1 Monitor for

deterioration

1 Or individually agreed target.

2 With active dose titration.

3 See the NICE clinical guideline on obesity (www.nice.org.uk/CG43).

4 Offer once-daily sulfonylurea if adherence is a problem.

5 Only continue DPP-4 inhibitor or thiazolidinedione if reduction in HbA1c

of at least 0.5 percentage points in 6 months.

6 Only continue exenatide if reduction in HbA1c of at least 1 percentage

point and weight loss of at least 3% of initial body weight at 6 months.

7 With adjustment for other ethnic groups.

8 Continue with metformin and sulfonylurea (and acarbose, if used), but only continue other drugs that are licensed for use with

insulin. Review the use of sulfonylurea if hypoglycaemiaoccurs.

9 DPP-4 inhibitor refers to sitagliptin or vildagliptin.

10 Thiazolidinedione refers to pioglitazone.

Increase insulin dose and

intensify

regimen over time (see page 11).

Consider pioglitazone with insulin

if:

• a thiazolidinedione has

previously

had a marked glucose-lowering

effect, or

• blood glucose control is

inadequate

with high-dose insulin.

Metformin 2 + sulfonylurea 4 +

sitagliptin 5 , or

Metformin 2 + sulfonylurea 4 + a

Thiazolidinedione 5, 10, or

Metformin 2 + sulfonylurea 4 +

exenatide 6 HbA1c ≥ 7.5% 1

HbA1c < 7.5% 1

Monitor for

deterioration

Start insulin 2, 8

HbA1c ≥ 7.5% 1 HbA1c ≥ 7.5% 1


NICE Type 2 diabetes algorithm for glycemic control - 2009 : A1C goal ≤ 6.5%

HbA1c ≥ 6.5% 1 after trial of lifestyle interventions

HbA1c ≥ 6.5% 1 Metformin 2 HbA1c < 6.5% 1

Monitor for deterioration

Metformin +

sulfonylurea 4

Consider sulfonylurea 4 here if:

● not overweight (tailor the assessment of body-weight-associated risk according

to ethnic group 3 ), or

● metformin is not tolerated or is contraindicated, or

● a rapid therapeutic response is required because of hyperglycaemic symptoms.

Consider a rapid-acting insulin secretagogue for people with erratic

lifestyles.Consider substituting a DPP-4 inhibitor 9 or a thiazolidinedione 10 for the

sulfonylurea if there is a significant risk of hypoglycaemia (or its consequences) or

a sulfonylurea is contraindicated or not tolerated.

HbA1c ≥ 7.5% 1 HbA1c < 7.5% 1

Monitor for deterioration

Add insulin 2, 8 ,

particularly if the person is

markedly hyperglycaemic

Insulin + metformin + sulfonylurea 4

HbA1c ≥ 7.5% 1

HbA1c < 7.5% 1

Monitor for deterioration

Consider adding sitagliptin or a thiazolidinedione 10 instead of insulin if insulin is

unacceptable (because of employment, social, recreational or other personal

issues, or obesity). Consider adding exenatide 6 to metformin and a sulfonylurea if:

• BMI ≥ 35 kg/m2 in people of European descent7 and there are problems

associated with high weight, or

• BMI < 35 kg/m2 and insulin is unacceptable because of occupational implications

or weight loss would benefit other comorbidities.

Increase insulin dose and intensify regimen over time.

Consider pioglitazone with insulin if:

• a thiazolidinedione has previously had a marked glucose-lowering effect, or

• blood glucose control is inadequate with high-dose insulin.

1 Or individually agreed target

2 With active dose titration.

3 See the NICE clinical guideline on obesity (www.nice.org.uk/CG43).

4 Offer once-daily sulfonylurea if adherence is a problem.

5 Only continue DPP-4 inhibitor or thiazolidinedione if reduction in HbA1c of at least 0.5 percentage points in 6 months.

6 Only continue exenatide if reduction in HbA1c of at least 1 percentage point and weight loss of at least 3% of initial body weight at 6 months.

7 With adjustment for other ethnic groups.

8 Continue with metformin and sulfonylurea (and acarbose, if used), but only continue other drugs that are licensed for use with insulin. Review the use of

sulfonylurea if hypoglycaemia occurs.


NICE Type 2 diabetes algorithm for glycemic control - 2009 : A1C goal ≤ 6.5%

entions

1

ration

5% 1

rioration

1

ration

y

e is a

Consider sulfonylurea4 here if:

● not overweight (tailor the assessment of body-weightassociated

risk according to ethnic group 3 ), or

● metformin is not tolerated or is contraindicated, or

● a rapid therapeutic response is required because of

hyperglycaemic symptoms.

Consider a rapid-acting insulin secretagogue for people

with erratic lifestyles.Consider substituting a DPP-4

inhibitor 9 or a thiazolidinedione 10 for the sulfonylurea if

there is a significant risk of hypoglycaemia (or its

consequences) or a sulfonylurea is contraindicated or not

tolerated.

Consider adding sitagliptin or a thiazolidinedione 10 instead

of insulin if insulin is unacceptable (because of

employment, social, recreational or other personal issues,

or obesity). Consider adding exenatide6 to metformin and a

sulfonylurea if:

• BMI ≥ 35 kg/m2 in people of European descent 7 and there

are problems associated with high weight, or

• BMI < 35 kg/m2 and insulin is unacceptable because of

occupational implications or weight loss would benefit

other comorbidities.

Increase insulin dose and intensify regimen over time.

Consider pioglitazone with insulin if:

• a thiazolidinedione has previously had a marked glucoselowering

effect, or

• blood glucose control is inadequate with high-dose

insulin.

HbA1c ≥ 6.5%

Metformin 2 + DPP-4 inhibitor 5, 9

or a thiazolidinedione 5,10

Sulfonylurea 4

1 HbA1c < 6.5%

1

Monitor for deterioration

Consider adding a DPP-4 inhibitor 9 or a

thiazolidinedione 10 if metformin is

contraindicated or not tolerated

Sulfonylurea 4

+ DPP-4 inhibitor 5, 9 or a

Thiazolidinedione 5,10

HbA1c ≥

HbA1c < 7.5% 1

7.5% 1 Monitor for HbA1c ≥ HbA1c < 7.5% 1

deterioration 7.5% 1 Monitor for

deterioration

Metformin 2 + sulfonylurea 4 + sitagliptin 5 , or

Metformin 2 + sulfonylurea 4 + a

Thiazolidinedione 5, 10, or

Metformin 2 + sulfonylurea 4 + exenatide 6

HbA1c < 7.5% 1

Monitor for

deterioration

HbA1c ≥ 7.5% 1

9 DPP-4 inhibitor refers to sitagliptin or vildagliptin.; 10 Thiazolidinedione refers to pioglitazone.

Start insulin 2, 8

HbA1c ≥ 7.5% 1 HbA1c ≥ 7.5% 1


Relevant comments on NICE algorithm


A1C target is inappropriate for many patients

and no individual guidance is given

Discrepancy between A1C goals for 1-2

agents (< 6.5%) vs. 3 agents (< 7.5%)



No evidence grading given in the guideline

Declaration of Interest” are not in Guideline

and difficult to obtain


Algorithm for glucose-lowering in people with type 2 diabetes ; Scottish Intercollegiate Guidelines

Network (SIGN) – 2010: REVIEW AND SET GLYCAEMIC TARGET: HBA1C 30 kg/m2

• If a desire to lose weight

• Usually 0.5% (5.5 mmol/mol) in 3-6 months


Relevant comments on SIGN algorithm

A1C target is individualized

Clearly presented recommendation

and evidence levels

Algorithm synthesizes all the data yet

is simple to follow

“Declaration of interest” are not in

guideline and difficult to obtain (only

through File of Information ‘FOI’

request)


VA/DoD Clinical Practice Guideline for the Management of

Diabetes Mellitus - 2011

Establish A1C goals*


Very symptomatic

Nonpharmacologic Therapy


Severe hyperglycemia

-Diet


Ketosis

-Exercise


Unrecognized type 1 DM

Glycemic goals not achieved

Recommended Monotherapy

-Biguanide

Insulin†

-Sulfonylurea

- Basal insulin

-Insulin

- Basal + bolus insulin

Oral agent not

- Bolus insulin

-Alpha-glucosidase inhibitors

tolerable or A1c >

Basal insulin = NPH or long-acting analog

-DPP-4 inhibitors

2% above target

Bolus insulin = Regular or rapid-acting analog

-GLP-1 agonist

†+/- oral hypoglycemic agents for type 2

-Meglitinides

diabetes

-Thiazolidinediones

Glycemic goals not achieved

Recommended Combination Therapy

-Biguanide+ Sulfonylurea

-Biguanide + Insulin

-Sulfonylurea + Insulin

-Alpha-glucosidase inhibitors

-DPP-4 inhibitors

-GLP-1 agonists

-Meglitinides

-Thiazolidinediones

Glycemic goals not

achieved

*Listed alphabetically; not in order of preference

guidance/criteria for further recommendations on use of these agents

DoD


Relevant comments on DoD/VA algorithm





Establishes A1C goals through

shared decision making at the onset

Clearly shows evidence tables

Fails to provide clear guidance on

alternative drug preferences

3 and 4 oral therapy are only rare

options


Risk factors for severe hypoglycemia


Prior episode of severe hypoglycemia

Current low A1C (


Comparison of the ADA/EASD algorithm – 2009, the AACE/ACE

Algorithm – 2009 and the ADA/EASD position statement- 2012

ADA-EASD-2009 AACE/ACE-2009 ADA-EASD-2012

Nature of document algorithm algorithm Position statement

Target levels of HbA1c

Frequency of adjustment of

regimen, if not at goal

Lifestyle, diet, exercise,

weight loss

Insulin therapy: basal,

premixed, basal-bolus, with or

without other agents

7% (53 mmol/L) or, “as

low as possible without

hypoglycemia”

2-3 months (6-9 months

reach insulin therapy if

not at goal)

6.5% (48mmol/L) ,

with caveats

2-3 months (6-9

months reach

insulin therapy if

not at goal)

Same Same Same

Same Same Same

< 7% (53 mmol/L) a

6.0-6.5% b

7.5-8% c

2-6 months (6-18

months reach

insulin therapy if

not at goal)

Metformin as preferred agent

for monotherapy

Summary of risks and benefits

for different classes of therapy

Same Same Same

Same Same Same

AACE = American Association of Clinical Endocrinologists ; ACE = American Clinical Endocrinologists

ADA= American Association of Clinical Endocrinologists

EASD= European Association for the Study of Diabetes


Comparison of the ADA/EASD algorithm – 2009, the AACE/ACE

Algorithm – 2009 and the ADA/EASD position statement- 2012

Specificity for advice

for different agents

Priority for

sulfonylureas

Priority for

thiazolidinidiones

Priority for incretinbased

therapies: DPP-

4 inhibitors or GLP-1

receptor agonists

ADA-EASD-2009 AACE/ACE-2009 ADA-EASD-2012

High: algorithm with

specified order for

selection of agents and

regimens

High (used in dual and

triple therapy)

High (second of five

options)

DPP-4 inhibitors:

‘ insuffecient experience’

GLP-1 receptor agonists

: ‘ Tier 2: less well –

validated’

High: algorithm with

specified order for

selection of agents and

regimens, with rationale

Low (because of

hypoglycemia, weight

gain, short duration of

effectiveness); not

recommended for

monotherapy

Low (because of weight

gain, CHF, fractures)

High (high efficacy and

excellent safety, low risk

of hypoglycemia)

Low: Fig. 2 states

‘order not meant to

specify any preference’

No specific preferences

(first option listed for

dual and triple therapy)

No specific preferences

(second option listed for

dual and triple therapy

in fig. 2)

No specific preferences

AACE = American Association of Clinical Endocrinologists ; ACE = American Clinical Endocrinologists

ADA= American Association of Clinical Endocrinologists

EASD= European Association for the Study of Diabetes


Comparison of the ADA/EASD algorithm – 2009, the AACE/ACE

Algorithm – 2009 and the ADA/EASD position statement- 2012

ADA-EASD-

2009

Priority for basal insulin ‘ Tier 2: less well –

validated’

Preferences for insulin

analogues (rapid and longacting)

relative to regular and

NPH insulins

None : no discussion of

rapid- and long-acting

insulin analogues

AACE/ACE-

2009

High

High: regular and

NPH insulins are

not recommended

ADA-EASD-

2012

High

Ambiguous, no

preference stated

Colesevelam Not recommended Included Mentioned briefly

Bromocriptine Not available Internationally

excluded

Included, low

priority

a- glucosidase inhibitors Not considered Included Mentioned briefly

Sensitivity to cost of

medication

High Low High

Sensitivity to total cost of care Not discussed High Not discussed

AACE = American Association of Clinical Endocrinologists

ADA= American Association of Clinical Endocrinologists

EASD= European Association for the Study of Diabetes


Pharmacotherapy of Type 2 Diabetes

Sulphonylureas (SUs) and metformin

are the current mainstays in the

treatment of T2DM and represent the

most commonly used oral

hypoglycaemic agents (OHAs)*.

* Smith NL, et al. Diabetes Care 1999; 22: 736-42.

Costa B, Hernández JM. Med Clin (Barc) 1993; 100: 571-5.

Cohen FJ, et al. Diabetes Care 2003; 26: 1847-51.


Pharmacotherapy of Type 2 Diabetes

Anti-hyperglycemic therapy

Glycemic targets

Therapeutic options

- Lifestyle

- Oral agents & non-insulin injectables

- Insulin


Time (months) to event of all-cause mortality (A), any

cardiovascular disease (CVD) (B) and any acidosis/serious

infection (C) in each treatment group, unadjusted

Metformin only

Metformin + OHA

Metformin + Insulin

Metformin + Insulin+ OHA

Other OHA only

Insulin only

Insulin + other OHA.

Ekström N et al. BMJ Open 2012;2:e001076 doi:10.1136/bmjopen-2012-001076


Maximum blood glucose lowering effects of

Sulphonyureas (SUs) 1-10

Various manufacturers

Maximum manufacturer's

recommended dose.

Various investigators

Approximately half that of the

maximum manufacturer's

recommended dose.

Various

investigators

If no blood glucose lowering effect is observed with half

(Glibenclamide 7.5-10 mg/d) of the maximally recommended

dose, further dose increases may not have a clinically significant

effect on blood glucose regulation.

There may be a narrow range of plasma concentration below

which SUs are ineffective and above which there is little

additional pharmacological benefit.


Maximum blood glucose lowering effects of

Sulphonyureas (SUs) 1-10

Various manufacturers

Maximum manufacturer's

recommended dose.

Various investigators

Approximately half that of the

maximum manufacturer's

recommended dose.

Various investigators

1. Krentz AJ, Bailey CJ. Drugs

2005;65:385-411.

2. Wahlin-Boll E, et al. Clin

Pharmacokinet 1982;7:363-372.

3. Shaw KM, et al. Diabet Med

1985;2:484-490.

4. Jackson L, Robertson L. S Afr Med

J 1989;76:286-289.

5. Stenman S, et al? Ann Intern Med

1993;118:169-172.

6. Simonson DC, et al. Diabetes Care

1997;20:597-606.

7. DeFronzo RA. Ann Intern Med

1999;131:281-303.

8. Jonsson A, et al. Diabetes Obes

Metab 2001;3:403-409.

9. Melander A. Diabetes

2004;53:151-155.

10. Rambiritch V. Dissertation.

University of KwaZulu-Natal,

South Africa. 2004.

Various

investigators

If no blood glucose lowering effect is observed with half

(Glibenclamide 7.5-10 mg/d) of the maximally recommended

dose, further dose increases may not have a clinically significant

effect on blood glucose regulation.

There may be a narrow range of plasma concentration below

which SUs are ineffective and above which there is little

additional pharmacological benefit.


Dose-response relationships of

sulphonyureas 1-17

Sulphonyureas

Glibenclamide

Glimepiride

Gliclazide

Glipizide

maximum

manufacturer's

recommended

dose

15-20 mg

8 mg

320 mg

40 mg

maximum dose

of Therapeutic

efficacy

7.5 (5 to 10 mg)

4-6 mg

80-160 mg

10 mg

If no blood glucose lowering effect is observed with half

of the maximally recommended dose, further dose

increases may not have a clinically significant effect on

blood glucose regulation.


Dose-response relationships of

sulphonyureas 1-17

Sulphonyureas

Glibenclamide

Glimepiride

Gliclazide

Glipizide

maximum

manufacturer's

recommended

dose

15-20 mg

8 mg

320 mg

40 mg

maximum dose

of Therapeutic

efficacy

7.5 (5 to 10 mg)

4-6 mg

80-160 mg

10 mg

If no blood glucose lowering effect is observed with half

of the maximally recommended dose, further dose

increases may not have a clinically significant effect on

blood glucose regulation.


Hazard ratios (95% CI) for different endpoints in relation to

monotherapies with different glucose-lowering agents

according to previous myocardial infarction

Schramm T K et al. Eur Heart J 2011;32:1900-1908


Schematic representation of the effect of sulphonylurea

medications on pancreatic β-cells and cardiac myocytes

Impaired ischaemic pre-conditioning in cardiac myocytes.

Gore M O , and McGuire D K Eur Heart J 2011;eurheartj.ehr019


"metformin,

sulfonylureas,



and


insulin,


the regular old stuff."•


Efficacy of monotherapy

Drug

Thiazolidinedione

Sulphonylura

Efficacy of monotherapy

Biguanide

Glinides

Α-glucosidase inhib

(AGI)

Exenatide

Sitagliptin

Saxagliptin

Bromocriptine

Fasting Plasma

Glucose

Reduction (mg/dl)

35-40

60-70

60-70

60-70

20-30

12-19

17-20

15-21

23

A1C

Reduction

(%)

0.5-2.0

1.0-2.0

1.0-2.0

1.0-2.0

0.5-1.0

0.5-0.8

0.6

0.6

0.5


Efficacy of monotherapy

Drug

Thiazolidinedione

Sulphonylura

Efficacy of monotherapy

Biguanide

Glinides

Α-glucosidase inhib

(AGI)

Exenatide

Sitagliptin

Saxagliptin

Bromocriptine

Cost per month

$ 199-223

$ 8-50

$ 44

$ 147-155

$ 85-100

$ 204-240

$ 182

$ 171

$ 299

A1C

Reduction

(%)

0.5-2.0

1.0-2.0

1.0-2.0

1.0-2.0

0.5-1.0

0.5-0.9

0.6-0.8

0.6

0.5


Monotherapy failure

As β-cell function continues to decline, monotherapy

failure (in ADOPT defined as FPG > 10.0 mmol/L [>

180 mg/dL

dL]) is almost inevitable. In the above-

mentioned ADOPT trial, monotherapy with

metformin, rosiglitazone and glyburide all failed

over time, despite differences in the rates of decline.

At 5 years, the cumulative incidence of monotherapy

failure was:

15% with rosiglitazone,

21

21% with metformin and

34

34% with glyburide (figure 2).

).4

Kahn SE, et al. For the ADOPT Study Group. N Engl J Med2006;355:2427–43.


Insulin is the most effective

diabetes agent,

only limited by hypoglycemia;

however, when used

inappropriately in

nonphysiological and

nonoptimized regimens,

many patients treated with insulin

remain poorly controlled


There seems to be a unanimous consensus

that more severe hyperglycemic

derangement at diagnosis of type 2 diabetes

is at best “first line” handled by aggressive

insulin therapy for 4–7 days to eliminate

glucose toxicity, after which the further

therapeutic approach may be reconsidered.


Burdens of insulin therapy as a first-line

approach in type 2 diabetes

Weight gain

Hypoglycemia

Low success rate in reaching A1C targets


Nonsignificant improvement in

cardiovascular outcome

No preventive effect on β-cell deterioration


Experimental studies in humans with T2DM have demonstrated that

intensive insulin therapy can improve β-cell function

Diabetes 34,

222-234234

(1985).

continuous

subcutaneous

insulin infusion

(CSII)

3 weeks Type 2

diabetes

14 improved peripheral insulin action, decreased

hepatic glucose output and enhanced insulin

secretion compared to baseline

Metabolism

35, 1029-10361036

(1986).

twice-daily mixture

of regular human

insulin and NPH

One month Type 2

diabetes

10 After 6 weeks improvements in fasting glucose

production and insulin action

Diabetes Care

27, 1028-1032

1032

(2004).

basal-bolus bolus insulin

therapy

2-3 weeks

newly

diagnosed

Type 2

diabetes

16 improved FPG and a greater insulin response to

the OGTT immediately and at 1 year

Diabetes Care

27, 2597-26022602

(2004).

CSII

2 weeks newly

diagnosed

Type 2 diabetic

138 improved β-cell function and restored first-phase

insulin response. Remission rates were 72.6% at

month 3, 67.0% at month 6, 47.1% at month 12

and 42.3% at month 24

Diabetes Care

20, 1353-13561356

(1997).

CSII

2 weeks newly

diagnosed

Type 2 diabetic

13 69% were subsequently maintained on diet alone

for at least 9 months, and six patients remained

controlled without medication for 1.3-4.9 years.

Diabetes Care

2004;27: 2585-

2589.

twice-daily mixture

of regular human

insulin and NPH

long-standing

T2DM

(averaging 7.6

years)

reduced glycosylated hemoglobin (HbA 1C ) levels

but was not able to restore the first-phase insulin

response or improve β-cell function.


Why health care providers and patients are often

reluctant to initiate insulin therapy.

Many people with diabetes eventually require insulin therapy to

maintain glycemic control because of progressive β-cell

dysfunction.

However, health care providers and patients are often reluctant

to initiate insulin therapy.

Some reasons for this may include

clinical inertia,


personal preferences or


inadequate resources.

This reluctance may reflect suboptimal quality of care and can be

modified*.

Other reasons, such as the risk of harms of insulin therapy, may

reflect rational treatment decisions for individual patients. Studies

of the rates and determinants of the initiation of insulin therapy

that can differentiate between appropriate and inappropriate use

are needed to guide health policy and clinical practice.

* Peyrot M, Rubin RR, Lauritzen T, et al.. Diabetes Care 2005;28:2673–9.


AACE/ACE* Diabetes Algorithm For Glycemic Control 2010 : A1C Goal ≤ 6.5%**

A1C 6.5 – 7.5% A1C 7.6 - 9.0% A1C > 9.0%

Monotherapy

Dual Therapy

Frequency

of

adjustment

of regimen,

if BG levels

not at goal

Dual Therapy

Triple Therapy

Total:

6-9 MOs

Triple Therapy

Total:

6-9 MOs

In most

cases as

initial

Insulin

alone or with

other agent (s)

Insulin

alone or with

other agent(s)

Insulin

alone or with

other agent(s)

* American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE)

** Rodbard,H. Am J Manag Care. 2010;16:S187-S194


ADA-EASD Position Statement: Management of

Hyperglycemia in T2DM: A Patient-Centered

Approach - 2012*

Frequency of adjustment of regimen, if not at goal: 3-6 months

Monotherapy: Metformin;

3 months

Dual

Therapy: Metformin + other

oral agents or

basal insulin;

3

months

Triple Therapy :Metformin+other oral agents or basal insulin;3-6 months

Total : 9-12 MOs

Insulin

Multiple daily doses

* Inzucchi SE, et al . Diabetologia. 2012;55:1577-1596.


The maximum period

after which we must use insulin

if BG levels not at goal

according to most guidelines

Will be

6month or 9months or 12months


The maximum period

after which we must use insulin

if BG levels not at goal according to most guidelines will be

6month or 9months or 12months

In real practice this is rarely followed

in particular when diabetic

patients are treated by GPs

which is the usual way

in most communities


Doctor, patient, and system barriers to

initiating insulin therapy in patients

with type 2 DM

Doctors’ barriers:

• lack of knowledge,

• lack of experience with use of

guidelines related to insulin therapy,

• fear of hypoglycaemia.


Doctor, patient, and system barriers to

initiating insulin therapy in patients with

type 2 DM

Patients’ barriers:

• mistaken beliefs about insulin,

• noncompliance ,

• lack of understanding of diabetes,

• use of traditional herbs,

• fear of injections, and

• poor socioeconomic conditions.


Doctor, patient, and system barriers to

initiating insulin therapy in patients with type

2 DM

System’ barriers:

• inadequate time,

• lack of continuity of care and

• financial constraints.


Painful truth and big question

why human insulin

is increasingly replaced by

insulin analogues


regardless

in vitro characteristics,

immunogenicity,

safety and adverse effects


Report of Institute for Quality and Efficiency in

Health Care*

Final report [Assignment No. A05-04]

12 April 2006

For patient-relevant outcomes, there is no

convincing evidence of a superiority of

rapid-acting insulin analogues compared with

regular human insulin in diabetes mellitus type 2

therapy.


Rapid-acting insulin analogues have not been

sufficiently investigated with regard to their potential

long term beneficial and harmful effect

* https://www.iqwig.de/download/A05-04_Final_Report_Rapid

acting_insulin_analogues_for_the_treatment_of_diabetes_mellitus_type_2.pdf


Report of Institute for Quality and Efficiency in

Health Care

Executive summary of final report A08-01 Version 1.0 ; 24.09.2009

Rapid-acting insulin analogues (RAIs) in children

and adolescents

There is no proof of additional benefit of RAIs

compared to human insulin or in direct

comparisons with each other.

In addition, there is no proof of greater or lesser

harm from RAIs compared to human insulin or in

direct comparisons with each other.

https://www.iqwig.de/en/projects_results/projects/drug_assessment/a08_01_rapid_acting_insulin_analogues_in_children_and_ado

lescents_with_diabetes_mellitus_type_1_follow_up_commission.1112.html


Report of Institute for Quality and Efficiency in

Health Care

Executive summary of final report A08-01 Version 1.0 ; 24.09.2009

Rapid-acting insulin analogues (RAIs) in children and

adolescents

Only trials with a maximum treatment period of 1 year

were available on the treatment of children and

adolescents with RAIs. In all trials the RAIs were

investigated in a basal bolus regimen; no relevant trials

on their use in pump therapy were identified.

https://www.iqwig.de/en/projects_results/projects/drug_assessment/a08_01_rapid_acting_insulin_analogues_in_children_and_adolescents

_with_diabetes_mellitus_type_1_follow_up_commission.1112.html


Report of Institute for Quality and Efficiency in

Health Care

Executive summary of final report A08-01 Version 1.0 ; 24.09.2009

Rapid-acting insulin analogues (RAIs) in children and

adolescents

There were no long term trials identified that

investigated micro- and macrovascular late

complications or physical or psychosocial development

disorders.

Moreover, there is a lack of valid data on health-related

quality of life and patient satisfaction.

https://www.iqwig.de/en/projects_results/projects/drug_assessment/a08_01_rapid_acting_insulin_analogues_in_children_and_adolescents

_with_diabetes_mellitus_type_1_follow_up_commission.1112.html


Examples of short-acting insulin

analogue’ s side effects

Early onset side effects include rash, disturbances

in walking and general fatigue. These symptoms

appeared 2–3 days after the use of short-acting insulin

analogue and disappeared several hours after

switching short-acting human regular insulin.

The late onset side effect is bilateral leg edema,

which appeared 1–2 months after the induction of

short-acting insulin analogue and disappeared after

several hours by changing to short-acting human

regular insulin.

Kuroe A, et al . Diabetes Research and Clinical Practice . 2007;77: 412-413.


Insulin glargine vs. NPH insulin

Institute for Quality and Efficiency in Health Care

Executive summary of final report A05-03, Version 1.1

Created: February 26, 2009.

For treatment within the framework of intensified insulin

therapy, there is no proof of an additional benefit of insulin

glargine vs. NPH insulin.

For treatment within the framework of a treatment scheme with

basal insulin in combination with OADs, there is also no proof of

an additional benefit of insulin glargine vs. NPH insulin when

the use of NPH insulin is optimized.

For treatment within the framework of conventional insulin

therapy, there is no proof of an additional benefit of insulin

glargine vs. NPH insulin, due to a lack of data.

http://www.ncbi.nlm.nih.gov/books/NBK84172/


Insulin detemir vs. NPH insulin

Institute for Quality and Efficiency in Health Care

Executive summary of final report A05-03, Version 1.1;February 26, 2009.

For treatment within the framework of intensified

insulin therapy, the data do not provide proof of an

additional benefit of insulin detemir vs. NPH insulin.

For treatment within the framework of a treatment

scheme with basal insulin in combination with OADs,

there is no proof of an additional benefit of insulin

detemir compared with NPH insulin.

For treatment within the framework of conventional

insulin therapy, there is no proof of an additional

benefit of insulin detemir vs. NPH insulin, due to a lack

of data.

http://www.ncbi.nlm.nih.gov/books/NBK84172/


Safety of

Incretin-Based Therapies

(a, GLP-1 receptor agonists; b, inhibitors of DPP-4)

Hotly Debated


A Clouded Future For Big Pharma's

Blockbuster Diabetes Drugs

Apr 3 2013, 10:04 by: Psycho Analyst |

More recent oral incretin drugs are even more

popular:

Januvia and Janumet, from Merck (MRK),

Onglyza and Kombiglyze from Bristol-Myers

Squibb and AstraZeneca, and

Trajenta and Jentadueto (also sold as

Tradjenta) from a partnership of Boehringer

Ingelheim and Eli Lilly (LLY).

(The second drug in each pair is a pill combining both the patented incretin drug and the generic

drug metformin.)


The use of incretin-based glucose-lowering medications

(a, GLP-1 receptor agonists; b, inhibitors of DPP-4)

Peter C. Butler, MD,

from the University of

California, Los Angeles, and

colleagues

express alarm regarding the

potential long-term cancer risk

associated with use of incretinbased

glucose-lowering agents

Adverse outcomes/

Risks !!!

Contrasting

with

Michael A, Nauck, MD,

from the Bad

Lauterberg Diabetes

Center, in Germany

presents the opposing

view.

Clinical benefits/

improved outcomes ???

A Critical Analysis of the Clinical

Use of Incretin-Based Therapies

Are the GLP-1 therapies safe?

Butler PC, et al. Diabetes Care July 2013 vol. 36 no. 7 2118-2125

A Critical Analysis of the Clinical

Use of Incretin-Based Therapies.

The benefits by far outweigh the

potential risks

Nauck MA. Diabetes Care July 2013 vol. 36 no. 7 2126-2132


Dipeptidyl peptidase-4 (DPP-4) inhibitors for

type 2 diabetes mellitus

Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch C

Published Online: July 8, 2009

Editorial Group: Cochrane Metabolic and Endocrine Disorders Group

Published Online: 23 APR 2008 Assessed as up-to-date: 30 JAN 2008

DOI: 10.1002/14651858.CD006739.pub2

Since the new DPP-4 inhibitors may influence immune

function additional long-term data on the safety of

these drugs are necessary.

Also, cardiovascular outcomes like heart attacks and

strokes should not be increased with any antidiabetic

therapy but data so far are lacking.

Until new information arrives, DPP-4 inhibitors should

only be used under controlled conditions and in

individual patients.

http://summaries.cochrane.org/CD006739/dipeptidyl-peptidase-4-dpp-4-inhibitors-for-type-2-diabetes-mellitus


Dr. Alashbal’ s observation regarding the use

of JANUVIA and other DPP-4 inhibitors

Until now, All T2 diabetics who I have seen them

and were victims of using JANUNIA OR its

brothers were severely hyperglycemic and they

have themselves noticed, regardless of their

adverse effects, that these drugs were absolutely

of no benefits and they have been told by other

doctors that they are new ones.

In addition, almost all of them were insulin

requiring T2 diabetics , but unfortunately

insulin was not used as their proper therapy.


Conclusions

Diabetes guideline are powerful

documents which are challenging to

develop and need near-continual

updating given the pace of new

developments

Transparency is a critical element in

guideline development

- Conflict (Duality) of interest are nearly

ubiquitous among experts in this field


Conclusions

The pendulum is swinging toward the

individualization of A1c goals

Algorithms for diabetes care are mostly

consensus documents since few head-tohead,

long-term trials exist to inform us

about best practices

Clinical judgment sometimes trumps

“evidence- based” guidelines


The

takeaway

message


Suggested seven deadly sins of

drug prescription

1. to assume that new drugs are better (‘Never be

the first, or the last, to use a new drug.’ )

2. to use pharmaceuticals to treat a non-pharmaceutical

problem;

3. to repeat prescriptions that serve no rational purpose;

4. to use one drug to counter the side effects produced by

another;

5. to overestimate the benefits of your intervention;

6. to pursue the mirage of longevity beyond the realms of

common sense; and

7. to reduce the quality of the life you are trying to improve.


And

this sin is to assume that:

new drugs are better


Never be And

the first,

this sin is to assume that:

or the last,

new drugs are better

to use a new drug


And

Never be the first,

We control the market for products that

we this neither sin is pay to for assume nor consume,

that:

or the last,

new drugs and

are better

to use a new drug

whose unwanted consequences are

experienced by other people


hank you

Dr. Abdulameer Abdullah Al-ashbal

Consultant Physician; Diabetologist

Associate professor of medicine at

Al Mustansiriya medical college ,

Department of Medicine ;

Alyermouk Teaching Hospital

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