Consultant Physician; Consultant Physician;

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

Conflict of interest (COI) pharmaceutical promotion The relationship between exposure to information from pharmaceutical companies and physicians' prescribing can have serious effects on

the quality, quantity, and cost of drugs. 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

?



?

The answer is : No



?

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.”


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– Physician –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– Physician –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

SECTION 2 : STUDY INFORMATION Paula A Rochon, MD, MPH, is senior scientist at Women’s College Research Institute at Women’s College Hospital, Toronto

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 SECTION 3 : PERSONAL FINANCIAL INFORMATION Paula A Rochon, MD, MPH, is senior scientist MODULE E: FINANCIAL PROFILE at Women’s College Research Institute at Women’s College Hospital, Toronto

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 $3 $3B for Sales,, Safety Violations Sales (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/ Copyright restrictions may apply. American Heart Association

Conflicts (Dualities) of interest in American Association of Clinical Endocrinologists (AACE) Algorithm Author

Research Honoraria/ grants Speakers bureau

Stock/Other Ownership

Consultant/ Advisory boards

1

4

8

0

9

2

0

6

0

3

3

5

6

0

15

4

4

0

2

5

5

8

4

0

0

6

3

8

0

7

7

4

6

0

7

8

2

0

0

13

9

0

1

2

13

10

(6)*

(10)*

0

0

11

0

3

0

3

12

0

5

0

5

#Episodes = 12 8 (75%)

10 (88%)

2 (16%)

*Declared in Subsequent Publication Table Source: Rodbard, H,et al. Endocr Pract 2009;15:541 ; www.ProPublica.Org

10 (88%)

Conflicts (Dualities) of interest in American Association of Clinical Endocrinologists (AACE) Algorithm Auther

Research grants

Honoraria/Speakers bureau

1

4

8

0

9

$ 48,382

2

0

6

0

3

$ 5,945

3

5

6

0

15

$ 44,044

4

4

0

2

5

$ 20,347

5

8

4

0

0

$ 178,600

6

3

8

0

7

$ 99,097

7

4

6

0

7

$ 222,375

8

2

0

0

13

$ 4,400

9

0

1

2

13

$ 125,221

10

(6)*

(10)*

0

0

$ 222,838

11

0

3

0

3

$ 5,800

12

0

5

0

5

$ 99,239

#Episodes = 12

8 (75%)

10 (88%)

*Declared in Subsequent Publication Table Source: Rodbard, H,et al. Endocr Pract 2009;15:541

Stock/Other Ownership

2 (16%)

Consultant / Advisory

10 (88%)

www.ProPublica.Org

Total $ amount

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

12

12 (100%)

8 (75%)

10 (88%)

2 (16%)

10 (88%)

ADA/EASD

7

7 (100%)

6 (84%)

3 (42%)

0

6 (84%)

Canadian

93

78 (84%)

48 (60%)

64 (82%)

3 (4%)

56 (72%)

NICE

13

7 (54%)

1 (8%)

5 (39%)

0

4 (31%)

SIGN

11

6 (55%)

2 (33%)

4 (66%)

0

4 (66%)

VA/DoD

14

0

0

0

0

0

84%

60%

82%

ACCE (American Association of Clinical Endocrinologists)

(ADA= American Association of Clinical Endocrinologists EASD= European Association for the Study of Diabetes)

(National Institute For Health and Clinical Excellence)

(Scottish Intercollegiate Guidelines Network)

(Veterans Administration/Departm ent of Defense)

Median

*Declared in Subsequent Publication Table Source: Rodbard, H,et al. Endocr Pract 2009;15:541

www.ProPublica.Org

72%

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)

6 (1-11)

1.8 (1-4)

Equity

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

1

0

Received nonpharmaceutical industry support

0

9

Received pharmaceutical industry support

1

11

* Column values total more than 44 because 2 guidelines received funding from both industry and government. 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

Nature and author perceptions of relationship with pharmaceutical manufacturers* No. of authors (%) [95% confidence interval] Had relationship with companies whose drugs were considered in the guideline process

47/80 (59) [48-70]

Relationship predated guideline process

45/47 (96) [92-100]

Relationship postdated guideline process

25/47 (53) [39-67]

Believed that relationships influenced personal recommendations Believed that relationships influenced personal recommendations of colleagues

5/68 (7) [1-9]+ 13/67 (19) [8-30]¶

+ 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

Guideline VA/DoD clinical practice guideline Canadian Task Force on Preventive Health Care‡ American Association of Clinical Endocrinologists Canadian Diabetes § US Preventive Services Task Force Institute for Clinical Systems Improvement American Diabetes Association Total

COI No of declaration Year panel publicly issued Organisation type† members available? 2003 2005

Government Government

Chair with conflicts?

Conflicts Declared identified by conflicts search

Total conflicts

23 15

No Yes

No Yes

Unknown 1 (7)

0 2 (13)

0 3 (20)

2007 Medical specialty society

12

Yes

Yes

9 (75)

1 (8)

10 (83)

2008

93

Yes

Yes

72 (77)

1 (1)

73 (78)

2008

Professional association Government

16

No

No

Unknown

1 (6)

1 (6)

2010

Non-profit

15

Yes

Yes

6 (40)

0

6 (40)

2010

Professional association

15

Yes

NA

13 (87)

0 (0)

13 (87)

101 (53%)

5 (3%)

106 (56%)

189

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 No of Organisation panel type† members Medical specialty 9

Year Guideline issued American Association of Clinical 2002 Endocrinologists¶ Expert Panel on 2004 Government Government Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults American Heart 2005 Medical specialty Association** society VA/DoD clinical 2006 Government practice guideline US Preventive 2008 Government ServicesTask Force†† Canadian 2009 Medical specialty Cardiovascular society Society‡ Institute for Clinical 2009 Non-profit Systems Improvement Total

COI declaration publicly Chair with Declared available? conflicts? conflicts No No No Unknown

9

Yes

Yes

17

Yes

Yes

8 (89)

Conflicts identified by Total search conflicts 1 (11) 1 (11)

0

8 (89)

0

7 (41)

1 (7)

1 (7)

13

No

No

7 (41) Unknown

16

No

No

1 (6)

1 (6)

2 (13)

23

Yes

NA

20 (87)

3 (13)

23 (100)

12

Yes

No

1 (8)

1 (8)

2 (17)

37 (37)

7 (7)

44 (44)

99

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

Level 2 Level 3 Level 4

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 Meets criterion a) above, plus 3 of the other 4 criteria Meets criterion a) above, plus 2 of the other criteria 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 Grade A Grade B Grade C Grade D

Criteria The best evidence was at Level 1 The best evidence was at Level 2 The best evidence was at Level 3 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 Roseman M. JAMA 305:1008-1017, 2011

27

Funding sources of RCT’s*

509 RCT’s in 29 MA’s Reported funding source Yes

NO

318

191 Yes

219 (69%)

NO

99 (31%)

Industry funded

* 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 Yes

Authors with ≥ 1 COI

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.

HbA1c

BG

13 12

350

11

310

10 9 8

275 240 205

7

170

6

135

5

100

4

65

Nice (later: 7.5%)

ADA , SIGN and DoD/VA (7%) EASD , AACE and,NICE (6.5%) ADA (individual patient) (< 6%)

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

345

In the USA 43% have A1c ≥ 7% (56% if African American; 63% if Hispanic)

HBA1C targets suggested by different organizations

Optimal target AACE EASD ADA SIGN NICE

HBA1C equal or more than 6% (normal target) HBA1C HBA1C HBA1C HBA1C HBA1C HBA1c

< 6.5 % < 6.5% < 7% (general) < 6%* (individual patient) 10 years of life expectancy

< 7%

< 8%

8-9%*

Present (e) 5-10 years of life Expectancy

< 8%

< 8%

8-9%*

Marked (f) < 5 years of life expectancy

8-9%*

8-9%*

8-9%*

(c)

Consensus (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 decisions1,2 frequently vary widely in quality2,3.  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. 2.

3.

Faruqi N, et al. Aust Fam Physician 2000, 29:173-176. 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. 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. 2. 3. 4. 5. 6. 7. 8. 9.

Grimshaw JM, et al. Health Technol Assess 2004, 8 Larme AC, Pugh JA. Diabetes Care 1998, 21:1391-1396. Wang L. Med Princ Pract 2004, 13:282-285. Nagelkerk J. J Adv Nurs 2006, 54:151-158. Kedward J, Dakin L. Br J Gen Pract 2003, 53:684-689. Nakar S, et al. J Diabetes Complications 2007, 21:220-226. Alberti H, et al. BMC Fam Pract 2007, 8:63. Chin MH, et al. Diabetes Care 2001, 24:268274. Haque M, et al. S Afr Med J 2005, 95:798802.

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 3step 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.) 1.

Relative risk No. of Follow-up reduction Pan XR, et al. Diabetes Care20 Interventions (years) (%) :537 –544,1997 subjects

2. Tuomilehto J, et al. N Engl J Lifestyle modifications Med344 :1343 –1350,2001 3.

Knowler WC, et al. N Engl J

4.

Chiasson JL, et al.the STOPNIDDM randomised trial. Lancet359 :2072 –2077,2002 Buchanan TA, et al. Diabetes49 :782 –788,2000

Da Qing (1997) Med346 (1) :393 –403,2002577 DPS (2001) (2) 5. DPP (2002) (3)

522

2,161

Diet and/or exercise Diet and exercise Diet and exercise

6,0

39

3,2

58

2,8

58

Metformin Troglitazone Acarbose

2,8 2,5 3,3

31 59 36

Drug interventions DPP (2002) (3) TRIPOD (2002) (5) STOP-NIDDM (2002) (4)

2,151 236 1429

Six Guidelines (Algorithms (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 4. Other considerations •

• • •

insulin


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 therapy NO more waste of time and money

- Transitions

to and titrations of insulin

4. Other considerations •

• • •


Hypertension and diabetes: Drug classes in U.S. Over Past Half-Century Dopamine agonists

Renin inhibitors

Number of medication classes

11

Angiotensin II receptor blockers

10 9

Ca+ channel blockers

8

Central α-2 agonist

5 Adrenergic Neuronal blockers

2 1

DPP-4 inhibitors Amylinomimetics

GLP-1 receptoragonists

ß-blockers

6 4 3

ACE inhibitors

Peripheral α-1 agonist

7

Bile acid squestrants

Glinides Thiazoloidenediones α- glucosidase inhibitors

Diuretics

Biguanides

Sulfonylureas Vasodilators

1950

INSULIN

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; HbA1c, glycosylated hemoglobin; MET, metformin; PPG, postprandial glucose; SU, sulfonylurea; TZD, thiazolidinedione. Adapted with permission from Rodbard HW, et al.4 aFor patients with diabetes mellitus and HbA1c 8.5%, combination pharmacologic treatment with agents that cause hypoglycemia should be used with caution. kGLP1 not approved for initial combination pharmacologic treatment. lIf HbA1c >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; HbA1c, glycosylated hemoglobin; MET, metformin; PPG, postprandial glucose; SU, sulfonylurea; TZD, thiazolidinedione. Adapted with permission from Rodbard HW, et al.4 aFor patients with diabetes mellitus and HbA1c 8.5%, combination pharmacologic treatment with agents that cause hypoglycemia should be used with caution. kGLP1 not approved for initial combination pharmacologic treatment. lIf HbA1c >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%** Lifestyle modification

“Stratified by A1Cs and documented evidence of efficacy” A1C 6.5 – 7.5%

A1C 7.6 - 9.0%

A1C > 9.0%

Drug Naive

Under treatment

Monotherapy MET

TZD

DPP-4

Dual Therapy

AGI

2-3 MOs Dual Therapy

GLP-1 or DPP-4

MET

+

GLP-1 or DPP-4 or TZD

SU or Glinides

TZD

+

Glinides or SU MET

2-3 MOs

GLP-1 or DPP-4

+

Triple Therapy

Colesevelam

+

AGI

MET

2-3 MOs Triple Therapy MET +

GLP-1 or DPP-4

+

TZD Glinides or SU

2-3 MOs

Insulin

and other agent (s)

Symptoms

+

GLP-1 or DPP-4

+ TZD

GLP-1 or DPP-4

+ SU

No symptoms

Insulin

and other agent (s)

MET

+

GLP-1 or DPP-4

± SU

TZD

GLP-1 or DPP-4

Insulin

and other agent (s)

± TZD

TZD

2-3 MOs

Insulin

and other agent (s)

TZD:Thiazolidinediones Met: metformin AGI: alpha glucosidase inhibitors SU: sulfonylurea

* American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) ** Rodbard,H. Am J Manag Care. 2010;16:S187-S194


“Stratified “Stratifiedby by A1Cs A1Cs and anddocumented documented evidence evidenceof ofefficacy” efficacy”

3 broad =3 pathways A1C 7.6 ranges - 9.0%

A1C 6.5 – 7.5%

A1C > 9.0%

Drug Naive

Under treatment

Monotherapy MET

TZD

DPP-4

Dual Therapy

AGI


GLP-1 or DPP-4

MET

+


SU or Glinides

TZD

+

Glinides or SU MET

2-3 MOs

GLP-1 or DPP-4

+

Triple Therapy

Colesevelam

+

AGI

MET


GLP-1 or DPP-4

+

TZD Glinides or SU

2-3 MOs

Insulin

and other agent (s)

Symptoms

+

GLP-1 or DPP-4

+ TZD

GLP-1 or DPP-4

+ SU

No symptoms

Insulin

and other agent (s)

MET

+

GLP-1 or DPP-4

± SU

TZD

GLP-1 or DPP-4

Insulin

and other agent (s)

± TZD

TZD

2-3 MOs

Insulin

and other agent (s)






A1C 6.5 – 7.5%

A1C > 9.0%

Drug Naive

Under treatment

Monotherapy MET

TZD

DPP-4

Dual Therapy

AGI


GLP-1 or DPP-4

MET

+


SU or Glinides

TZD

+

Glinides or SU MET

+ +

2-3 MOs

GLP-1 or DPP-4

Triple Therapy

Colesevelam AGI

MET


GLP-1 or DPP-4

TZD

+A1C: Glinides or SU

6.5% to 7.5% 2-3 MOs Insulin

and other agent (s)

Symptoms

+

GLP-1 or DPP-4

+ TZD

GLP-1 or DPP-4

+ SU

No symptoms

Insulin

and other agent (s)

MET

+

GLP-1 or DPP-4

± SU

TZD

GLP-1 or DPP-4

Insulin

and other agent (s)

± TZD

TZD

2-3 MOs

Insulin

and other agent (s)






A1C 6.5 – 7.5%

A1C > 9.0%

Drug Naive

Under treatment

Monotherapy MET

TZD

DPP-4

Dual Therapy

AGI


GLP-1 or DPP-4

MET

+

Glinides or SU MET

+ +

Triple Therapy

Colesevelam AGI

MET

MET +

GLP-1 or DPP-4

TZD



and other agent (s)

or TZD

2-3 MOs

GLP-1 or DPP-4

2-3 MOs Triple Therapy

GLP-1 or DPP-4 SU or Glinides

TZD

+

Symptoms

+

GLP-1 or DPP-4

+ TZD

GLP-1 or DPP-4

+ SU

TZD A1C: 7.6% to2-3 MOs 9.0%, Insulin and other agent (s)

No symptoms

Insulin

and other agent (s)

MET

+

GLP-1 or DPP-4

± SU

TZD

GLP-1 or DPP-4

Insulin

and other agent (s)

± TZD






A1C 6.5 – 7.5%

A1C > 9.0%

Drug Naive

Under treatment

Monotherapy MET

TZD

DPP-4

Dual Therapy

AGI


GLP-1 or DPP-4

MET

+

Glinides or SU MET

+ +

Triple Therapy

Colesevelam AGI

MET

MET +

GLP-1 or DPP-4

TZD



and other agent (s)

or TZD

2-3 MOs

GLP-1 or DPP-4

2-3 MOs Triple Therapy

GLP-1 or DPP-4 SU or Glinides

TZD

+

Symptoms

+

GLP-1 or DPP-4

+ TZD

GLP-1 or DPP-4

+ SU

TZD A1C: 7.6% to2-3 MOs 9.0%, Insulin and other agent (s)

No symptoms

Insulin

and other agent (s)

MET

GLP-1 A1C: or DPP-4 + >9.0% TZD

± SU

GLP-1 or DPP-4

± TZD

Insulin

and other agent (s)



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

Clinical assessment Lifestyle intervention (initiation of nutrition therapy and physical activity) A1C 2% above target

Very symptomatic Severe hyperglycemia Ketosis Unrecognized type 1 DM

Insulin† - Basal insulin - Basal + bolus insulin - Bolus insulin Basal insulin = NPH or long-acting analog Bolus insulin = Regular or rapid-acting analog †+/- oral hypoglycemic agents for type 2 diabetes

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 ( 10 10..0 mmol mmol/L /L [> 180 mg/ mg/dL dL]) ]) is almost inevitable. In the aboveabovementioned ADOPT trial, monotherapy with metformin,, rosiglitazone and glyburide all failed metformin over time, despite differences in the rates of decline. At 5 years, the cumulative incidence of monotherapy failure was:  15 15% % with rosiglitazone rosiglitazone,,  21 21% % with metformin and  34 34% % with glyburide (figure 2). ).4 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--234 222 (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, 10291029-1036 (1986).

twice-daily mixture twiceof regular human insulin and NPH

One month Type 2 diabetes

10

After 6 weeks improvements in fasting glucose production and insulin action

16

improved FPG and a greater insulin response to the OGTT immediately and at 1 year

Diabetes Care 27, 10281028-1032 basal basal--bolus insulin (2004). therapy

2-3 weeks

newly diagnosed Type 2 diabetes

Diabetes Care CSII 27, 25972597-2602 (2004).

2 weeks

newly 138 diagnosed Type 2 diabetic

improved ββ-cell function and restored firstfirst-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 CSII 20, 13531353-1356 (1997).

2 weeks

newly 13 diagnosed Type 2 diabetic

69% were subsequently maintained on diet alone for at least 9 months, and six patients remained controlled without medication for 1.31.3-4.9 years.

long-standing longT2DM (averaging 7.6 years)

reduced glycosylated hemoglobin (HbA1C) levels but was not able to restore the firstfirst-phase insulin response or improve ββ-cell function.

Diabetes Care twicetwice-daily mixture 2004;27: 25852585- of regular human 2589. insulin and NPH

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%

Monotherapy

Frequency of adjustment of regimen, if BG levels not at goal

A1C 7.6 - 9.0%

A1C > 9.0%

Dual Therapy

Dual Therapy Triple Therapy

Triple Therapy

Total: 6-9 MOs

Total: 6-9 MOs

In most cases as initial

Insulin

Insulin

Insulin

alone or with other agent (s)

alone or with other agent(s)

alone or with other agent(s)


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


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


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

Contrasting

express alarm regarding the potential long-term cancer risk associated with use of incretinbased glucose-lowering agents

Adverse outcomes/ Risks !!!

Michael A, Nauck, MD, from the Bad Lauterberg Diabetes Center, in Germany presents the opposing view.

with

Clinical benefits/ improved outcomes ???

A Critical Analysis of the Clinical A Critical Analysis of the Clinical Use of Incretin-Based Therapies Use of Incretin-Based Therapies. Are the GLP-1 therapies safe? The benefits by far outweigh the potential risks Butler PC, et al. Diabetes Care July 2013 vol. 36 no. 7 2118-2125

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

Andthe first, Never be this sin is to assume that: or the last, new drugs are better to use a new drug

Andthe first, Never be or the last, new drugs are better to use a new drug

We control the market for products that this sin ispay to for assume that: we neither nor consume, and 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