the reliability and credibility of current glycemia guidelines in type 2 diabetes

Reliability and Credibility of Current Glycemia

Guidelines in Type 2 Diabetes Mellitus:

With focus on role of 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

• Sulfonylureas Up

Mortality Risk in Diabetes

• By Charles Bankhead, Staff Writer,

MedPage Today

• Published: June 24, 2012

• Reviewed by Robert Jasmer, MD;

Associate Clinical Professor of Medicine,

University of California, San Francisco

• Take Posttest

• Action Points

http://www.medpagetoday.com/reviewer.cfm?reviewerid=55



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My disclosure

No financial relationships

with any commercial interests

Aim of talk

• 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

Conflicts of interest policies—when they exist—they should be:

Strong

Consistent

Adequately administered and enforced

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

Authorship of publications prepared by others

Expert witness for a plaintiff or a defendant

Other payments or financial relationships

Candidate List of Categories of Financial Relationships with Industry to Be Disclosed

Physician relationships withthe industry

The antidoteis for physicians who are involved in drugs

prescribing not to accept money for promoting drugs

The answer is : No

Is disclosure of researcher (s) is

the antidote here?

http://www.addthis.com/bookmark.php?v=250&username=xa-4bc749c249b0232c

http://www.addthis.com/bookmark.php?v=250&username=xa-4bc749c249b0232c

http://health.yahoo.net/videos/rodale/prevention/YHealth_KatzFoodCures

• Lifestyle interventions to improve glucose, blood pressure and lipid levels, and to promote weight loss or at least to avoid weight gain remain the underlying strategy throughout the management of diabetes even when additional medications are needed.

• Metabolic variables, such as HbA 1c , post - prandial blood glucose concentrations, serum triglyceride and low density lipoprotein cholesterol levels, can be used to suggest the most appropriate intakes of carbohydrate - containing foods.

• Vegetables, legumes, fruits and wholegrain cereal - based foods should be part of the diet because they are rich in dietary fi ber, low in glycemic index or load and provide a range of micronutrients.

• In those treated with insulin or oral hypoglycemic agents, the timing and dosage of medication should match the quantity and nature of carbohydrate to avoid hyperglycemia or hypoglycemia. Blood glucose self - monitoring may help to make appropriate choices.

Lifestyle Issues: Diet

Keypoints

Saturated, trans - unsaturated fatty acids and dietary cholesterol should be restricted to reduce the risk for vascular disease, whereas oils rich in monounsaturated fatty acids as well as oily fish rich in n - 3 polyunsaturated fatty acids are useful fat sources. In patients with type 1 or 2 diabetes without evidence of nephropathy, usual protein intake (up to 20% of the total energy intake) need not be modified. In those with established nephropathy, protein restriction to 0.8 g/kg normal body weight per day may be beneficial. Alcohol intake should be moderate. Foods naturally rich in dietary antioxidants, trace elements and other vitamins are encouraged. Routine supplementation and the use of so - called special diabetic foods are not recommended. Individual dietary advice by physicians and dietitians and structured nutritional training are an essential part in the continuing treatment and education process of people with type 1 and 2 diabetes.

Lifestyle Issues: Diet

Keypoints

Lifestyle Issues: Exercise

Keypoints

• Regular exercise increases insulin sensitivity in both individuals with and without diabetes.• In individuals without diabetes, plasma insulin levels decrease during low to moderate intensity exercise to compensate for increases ininsulin sensitivity. Glucose production and glucose disposal increase inparallel in order to maintain blood glucose homeostasis.• In individuals with type 1 diabetes (T1DM), low to moderate intensity exercise can result in hypoglycemia, as insulin levels cannot beregulated physiologically.• During and after high intensity exercise, glucose production can exceed glucose disposal, causing hyperglycemia in individuals both with and without diabetes. In T1DM, hyperglycemia can be more marked andprolonged, as insulin cannot increase in response.• It is recommended that individuals with T1DM adjust their insulin dose and carbohydrate consumption prior to, during and/or after exercise to accommodate the type, intensity and duration of exercise performed.

Lifestyle Issues: Exercise

Keypoints

• While regular exercise has not conclusively been found to improve glycemic control in T1DM, it is associated with decreased long –term morbidity and mortality in this population.• Structured supervised diet and exercise interventions can reduce the risk of developing type 2 diabetes mellitus (T2DM) by about 60% inindividuals with impaired glucose tolerance.• Regular exercise improves glycemic control significantly in T2DM.• Individuals with T1DM and T2DM with moderate or high aerobic fi tness have long - term mortality that is 50 – 60% lower than individuals with diabetes and low cardiorespiratory fitness.• Resistance training is a safe and effective means of improving glycemic control in individuals with T2DM of all ages. To maximize the impact of lifestyle measures on glycemic control, combined aerobic and resistance exercise is more effective than either type of exercise alone.

Transparency Conflicts of interest Harm to:

Physician relationships with the industry

Professional reputations (prescribing and professional behavior )

Scientific research Guideline credibility Patients (patient care)

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


Therefore

“Conflicts of interest are not universally

bad, but they’re not universally good.”

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


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.‖

* Policies regarding IRB members' industry relationships often lacking.

Drug surveillance and a real world approach for drugs

Six Guidelines for Type 2 DM Management

in the Last 3 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

website * National Guideline Clearinghouse

Copyright restrictions may apply.

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

Number of Episodes Reported for Types of Conflicts of Interest in Each GuidelineNumber of Episodes Reported for Types of Conflicts of interest in cardiovascular clinical practice guidelines*

17 most recent Clinical Practice Guedelines‘s of the American College of Cardiology/ American Heart Association

Consultant/ Advisory boards

Stock/Other Ownership

Honoraria/Speakers bureau

Researchgrants

Author

90841

30602

150653

52044

00485

70836

70647

130028

132109

00(10)*(6)*10

303011

505012

10 (88%)2 (16%)10 (88%)8 (75%)#Episodes = 12

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

Conflicts (Dualities) of interest in AACE Algorithm

Total $ amountConsultant/ Advisory



Researchgrants

Auther

$ 48,38290841

$ 5,94530602

$ 44,044150653

$ 20,34752044

$ 178,60000485

$ 99,09770836

$ 222,37570647

$ 4,400130028

$ 125,221132109

$ 222,83800(10)*(6)*10

$ 5,800303011

$ 99,239505012

Mean = $ 89,691Median = $ 44,044

10 (88%)2 (16%)10 (88%)8 (75%)#Episodes = 12

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

Conflicts (Dualities) of interest in AACE Algorithm

Consultant/ Advisoryboard



Research grants

Total episodes

AuthorsOrganization

10 (88%)

2 (16%)

10 (88%)

8 (75%)

12 (100%)

12ACCE

6 (84%)03 (42%)

6 (84%)

7 (100%)

7ADA/EASD

56 (72%)

3 (4%)

64 (82%)

48 (60%)

78 (84%)

93Canadian

4 (31%)05 (39%)1 (8%)

7 (54%)

13NICE

4 (66%)04 (66%)2 (33%)

6(55%)

11SIGN

0000014VA/DoD

72%82%60%84%Median

Conflicts (Dualities) of interest among organizations with diabetes algorithms

Hierarchy of evidence-based medicine

Meta-

analysis

Systematic

review

Randomized

controlled trial

Cohort studies

Case control studies

Case series/Case reports

Animal research/Labroratory studies

Why do we talk about systematic reviews so much? There are more than 30,000 medical and

health journals. More than 60 are published every day. This

is why we need systematic reviews to sort out the wheat from the chaff for us.

Researchers look for all the trials and analyse them to see what treatments might really work.

But even keeping up with these is getting harder.

There are four new systematic reviews every day, too.

Meta-analysis may not consider COI‘s

Few meta-analysis in high-impact journals report RCT funding sources

29(RCTs)

272

NOYes

Roseman M. JAMA 305:1008-1017, 2011

?

509 RCT‘s in 29 MA‘s

191318

NOYes

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

Reported funding source

Industry funded

219 (69%)

99 (31%)NO

Yes

Funding sources of RCT‘s*

509 RCT‘s in 29 MA‘s

377132

NOYes

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

Reported author Financial disclosures

Authors with

≥ 1 COI

91

41NO

Yes

Financial disclosures in RCT‘s*

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.

350

345

310

275

240

205

170

135

100

65

13

12

11

10

9

8

7

6

5

4

HbA1c

Nice (later: 7.5%)

ADA/EASD and SIGN and DoD/VA

(7%)

BG

AACE and NICE(6.5%)

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

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

In the

USA

HBA1C equal or more than 6%(normal target)

Optimal target

HBA1C < 6.5 %AACE

HBA1C < 6.5%EASD

HBA1C < 7% (general)HBA1C < 6%* (individual patient)

ADA

HBA1C <7% (or individualised as agreed)SIGN

HBA1c < 6.5% (or individualised as agreed)NICE

As close to normal (< 6%) without significant hypoglycemia.

HBA1C targets suggested by different organizations

Retinopathy

Nephropathy

Neuropathy

Microalbuminuria

Rela

tive r

isk

HBA1c%

6 7 8 9 10 11 12

1

3 5

7 9

11

1

3 1

5

* N Engl J Med. 1993;329:978-986.

Microvascular disease reduction in DCCT*

Improved control of blood glucose

reduces the risk of clinically

meaningful:

Retinopathy 76% (P 0.002)

Nephropathy 54% (P 0.04)

Neuropathy 60% (P 0.002)

* N Engl J Med. 1993;329:978-986.

DCCT*: Results Summary

Conventionaltreatment

Intensivetreatment

Conventionaltreatment

Intensivetreatment

The Diabetes Control and Complication Trial/Epidemiology ofDiabetes interventional and Complications (DCCT/EDIC) Study Research Group.* NEJM, 353:2643-2653, 2005

Observational study

Macrovascular disease reduction in DCCT/EDIC* – Legacy effect

* Holman R, et al.N Engl J Med 2008;359:1577-1589

Observational study

Any diabetes-related end point (Panels A and B),

myocardial infarction (Panels C and D), or

microvascular disease (Panels E and F) or

Death from any cause(Panels G and H)

The overall values at the end of the study, in 1997, are shown (red squares),

Values during the 10-year post-trial monitoring period (blue diamonds).

The vertical bars represent 95% confidence intervals.

UKPDS study: 10-Year follow-up of intensive glucose control in Type 2 diabetes* Hazard ratios for four pre-specified aggregate clinical outcomes

Glycemic Goals

- Early enthusiasm for tight control for all is now waning and individualization of goals seems most appropriate

VA diabetesADVANCEACCORD

179111,40010,251Number

60.46662.2Age (Yrs)

31.328.532.2BMI (Kg/m)

11.5810Duration of DM (Yrs)

31.332.235.2Previous CV events (%)

9.47.58.3Mean A1C level

Median A1C level achieved

6.96.46.4Intensive control

8.67.37.5Conventional control

GlimepirideGliclazide XRMetforminDrugs

RoseglitazoneMetforminGlimepirideDrugs

InsulinInsulinRoseglitazoneDrugs

Acarbose/roseglitazone

InsulinDrugs

No differenceNo differenceHigher mortalityResults

The goal for A1c may not be safely achieved with current therapy

Impact of Intensive Therapy for Diabetes: Summary

of Major Clinical Trials

Study Microvasc CVD Mortality

UKPDS

DCCT / EDIC*

ACCORD

ADVANCE

VADT

Long Term Follow-up

Initial Trial

* in T1DM

Kendall DM, Bergenstal RM. © International Diabetes Center 2009UK 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)

Percentage of non-responders

Drug efficacy is questioned..

Drugs costs are escalating..

The priorities for fitting personalized medicine should be like fitting a belt for your trousers:

The first priority is ensuring that it does not harm you.

Ensuring that it holds your trousers is second priority.

The priority - reducing drug toxicity!

Highly motivated, adherent,excellent self-care capacities

Less motivated, non-adherent,poor self-care capacities

Approach to management of hyperglycaemia:More stringent Less stringent

Patient attitude andexpected treatment efforts

Risks potentially associated with hypoglycaemia, otheradverse events

Low High

Disease duration Newly diagnosed Long-standing

LongLife expectancy Short

Important comorbidities Few / mildAbsent Severe

Established vascularcomplications

Few / mildAbsent Severe

LimitedReadily availableResources, support system

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)

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

Microvascular complicationMajor comorbidity (d)

or physiolgical ageAdvanced (c)Moderate (b)Absent or mild (a)

8-9%*8%7%Absent> 10 years of life expectancy

8-9%*8%8%Present (e)

5-10 years of lifeExpectancy

8-9%*8-9%*8-9%*Marked (f)

< 5 years of life expectancy

Consensus

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

VA/DoD Clinical Practice Guideline for the Management of Diabetes Mellitus – 2011

Existing Algorithms

What is Algorithm (in guidelines)?

It is a flow chart of the

clinical decision pathway

described in the guideline, where decision points are represented by boxes, linked with arrows

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 <6.5%, pharmacologic treatment may be considered. bDPP-4 if PPG and FPG or GLP-1 if PPG. cTZD if metabolic syndrome and/or nonalcoholic fatty liver disease. dHbA1c if PPG. eIfHbA1c goal not achieved safely. fLow-dose secretagogue recommended. gGlinide if PPG or SU if FPG. hDecrease secretagogue by 50% when added to GLP-1 or DPP-4. ia) Discontinue insulin secretagogue with multidose insulin; b) can use pramlintide with prandial insulin. jIf HbA1c >8.5%, combination pharmacologic treatment with agents that cause hypoglycemia should be used with caution. kGLP-1 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 : A1C Goal ≤ 6.5%**

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

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

http://www.jaoa.org/cgi/content/full/111/7_suppl_5/S20



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

3.Q6.2. Anti-hyperglycemic PharmacotherapyThe 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….)

Efficacy of monotherapy

A1CReduction (%)

Fasting Plasma GlucoseReduction (mg/dl)

Drug

0.5-2.035-40Thiazolidinedione

1.0-2.060-70Sulphonylura

1.0-2.060-70Biguanide

1.0-2.060-70Glinides

0.5-1.020-30Α-glucosidaseinhib (AGI)

0.5-0.812-19Exenatide

0.617-20Sitagliptin

0.615-21Saxagliptin

0.523Bromocriptine



A1CReduction (%)

Cost per monthDrug

0.5-2.0$ 199-223Thiazolidinedione

1.0-2.0$ 8-50Sulphonylura

1.0-2.0$ 44Biguanide

1.0-2.0$ 147-155Glinides

0.5-1.0$ 85-100Α-glucosidaseinhib (AGI)

0.5-0.9$ 204-240Exenatide

0.6-0.8$ 182Sitagliptin

0.6$ 171Saxagliptin

0.5$ 299Bromocriptine




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

Conclusion

When added to maximal metformin therapy, all noninsulin

antidiabetic drugs were associated with similar HbA1c

reductions but differed in their associations with weight

gain and risk of hypoglycemia.

• Olivia J. Phung; Jennifer M. Scholle; Mehak Talwar, BS; Craig I. Coleman. JAMA. 2010;303(14):1410-1418.Evid Based Med2011;16:39-40 doi:10.1136/ebm1116

Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes*

Competing interests :

Drs Phung and Coleman reported previously receiving research support from Takeda Pharmaceuticals North America, a manufacturer of antidiabetic drugs.

Dr Scholle and Ms Talwarreported no disclosures.

From: Effect of Noninsulin Antidiabetic Drugs Added to Metformin Therapy on Glycemic Control, Weight Gain,

and Hypoglycemia in Type 2 Diabetes

Table 2. Results of Traditional Meta-analysis Comparing Noninsulin Antidiabetic Drugs With Placebo on Change in HbA1c, HbA1c Goal Achieved, Change in Body Weight, and Overall Hypoglycemia

Competing interests :

Drs Phung and Coleman reported previously receiving research support from Takeda Pharmaceuticals North America, a manufacturer of antidiabetic drugs. Dr Scholle and Ms Talwarreported no disclosures.

• Olivia J. Phung; Jennifer M. Scholle; Mehak Talwar, BS; Craig I. Coleman. JAMA. 2010;303(14):1410-1418.Evid Based Med2011;16:39-40 doi:10.1136/ebm1116



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

Problems with initiating triple therapy:There is no evidence that treatment with triple therapy in an a symptomatic is necessaryThere 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 drug-drug 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”.

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

No rush in starting with triple (or even dual) therapy in asymptomatic patients with A1C > 9.0%

At Diagnosis:Lifestyle

+Metformin

Tier 1 : Well-validated core therapies

Lifestyle+Metformin+

Basal Insulin


Sulfonylurea


Intensive Insulin

Lifestyle+Metformin

+Pioglitazone

No hypoglycemiaOedema/CHF, Bone loss

Lifestyle+

Metformin+

No hypoglycemiaWeight loss/Nausea/Vomiting

Lifestyle+Metformin

+Pioglitazone

+Sulfonylurea

Lifestyle+Metformin

+Basal Insulin

Step 1 Step 2 Step 3

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

Tier 2 : Less well-validated therapies

GLP-1 R agonistDDP-4 inhibitors

Medical management of hyperglycemia in type 2 diabetes

ADA\EASD* Consensus Algorithm - 2009**

ADA-EASD Position Statement: Management of Hyperglycemia

in T2DM: A Patient-Centered Approach - 2012*

T2DM Antihyperglycemic Therapy: General Recommendations

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



T2DM Antihyperglycemic Therapy: General Recommendations* Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

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. 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

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

Key points of recent DA/EASD guidelines

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‖

Relevant comments on ADA/EASD algorithm

HbA1c ≥ 6.5% 1 after trial of lifestyle interventions

HbA1c ≥ 6.5% 1

Metformin 2

HbA1c < 6.5% 1

Monitor for deterioration

Metformin +sulfonylurea4

HbA1c ≥ 7.5% 1 HbA1c < 7.5% 1


Add insulin 2, 8 ,particularly if the person ismarkedly hyperglycaemic

Insulin + metformin + sulfonylurea 4

HbA1c < 7.5% 1

Monitor for deterioration HbA1c ≥ 7.5% 1

Consider sulfonylurea4 here if:● not overweight (tailor the assessmentof body-weight-associated riskaccording to ethnic group3), or● metformin is not tolerated or iscontraindicated, or● a rapid therapeutic response isrequired because of hyperglycaemicsymptoms.

Consider a rapid-acting insulinsecretagogue for people with erraticlifestyles.Consider substituting a DPP-4inhibitor9 or a thiazolidinedione10 forthe sulfonylurea if there is a significantrisk of hypoglycaemia (or itsconsequences) or a sulfonylurea iscontraindicated or not tolerated.

Consider adding sitagliptin or athiazolidinedione10 instead of insulin ifinsulin is unacceptable (because ofemployment, social, recreational orother personal issues, or obesity).Consider adding exenatide6 tometformin and a sulfonylurea if:• BMI ≥ 35 kg/m2 in people of Europeandescent7 and there are problemsassociated with high weight, or• BMI < 35 kg/m2 and insulin isunacceptable because of occupationalimplications or weight loss wouldbenefit other comorbidities.

Increase insulin dose and intensifyregimen over time (see page 11).Consider pioglitazone with insulin if:• a thiazolidinedione has previouslyhad a marked glucose-loweringeffect, or• blood glucose control is inadequatewith 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 HbA1cof at least 0.5 percentage points in 6 months.6 Only continue exenatide if reduction in HbA1c of at least 1 percentagepoint 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 withinsulin. Review the use of sulfonylurea if hypoglycaemia occurs.9 DPP-4 inhibitor refers to sitagliptin or vildagliptin.10 Thiazolidinedione refers to pioglitazone.

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

Sulfonylurea 4

Sulfonylurea 4

+ DPP-4 inhibitor 5, 9 or aThiazolidinedione 5,10

Consider adding a DPP-4 inhibitor 9 or a thiazolidinedione10 if metformin is contraindicated or not tolerated

HbA1c ≥ 6.5% 1 HbA1c < 6.5% 1


Metformin 2 + DPP-4 inhibitor 5, 9

or a thiazolidinedione 5,10

HbA1c < 7.5% 1

Monitor fordeterioration

HbA1c ≥ 7.5% 1 HbA1c < 7.5% 1


HbA1c ≥ 7.5% 1

Metformin 2 + sulfonylurea 4 + sitagliptin 5, orMetformin 2 + sulfonylurea 4 + aThiazolidinedione 5, 10, orMetformin 2 + sulfonylurea 4 + exenatide 6

HbA1c ≥ 7.5% 1HbA1c < 7.5% 1


Start insulin 2, 8

HbA1c ≥ 7.5% 1 HbA1c ≥ 7.5% 1

HbA1c ≥ 6.5% 1 after trial of lifestyle interventions

HbA1c ≥ 6.5% 1

Metformin 2

HbA1c < 6.5% 1


Metformin +sulfonylurea4

HbA1c ≥ 7.5% 1 HbA1c < 7.5% 1


Add insulin 2, 8 ,particularly if the person ismarkedly hyperglycaemic

Insulin + metformin + sulfonylurea 4

HbA1c < 7.5% 1

Monitor for deterioration HbA1c ≥ 7.5% 1

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 hyperglycaemicsymptoms.

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.

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 target2 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.



daily sulfonylurea if adherence is a


Sulfonylurea 4

Sulfonylurea 4

+ DPP-4 inhibitor 5, 9 or aThiazolidinedione 5,10

Consider adding a DPP-4 inhibitor 9 or a thiazolidinedione10 if metformin is contraindicated or not tolerated

HbA1c ≥ 6.5% 1 HbA1c < 6.5% 1


Metformin 2 + DPP-4 inhibitor 5, 9

or a thiazolidinedione 5,10

HbA1c < 7.5% 1


HbA1c ≥ 7.5% 1 HbA1c < 7.5% 1


HbA1c ≥ 7.5% 1

Metformin 2 + sulfonylurea 4 + sitagliptin 5, orMetformin 2 + sulfonylurea 4 + aThiazolidinedione 5, 10, orMetformin 2 + sulfonylurea 4 + exenatide 6

HbA1c ≥ 7.5% 1HbA1c < 7.5% 1


Start insulin 2, 8

HbA1c ≥ 7.5% 1 HbA1c ≥ 7.5% 1

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.

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.

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

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

Relevant comments on NICE algorithm

Metformin (MF)

Review and ifnot reaching

target move to2nd line

DPP-IV inhibitor*• If hypos a concern (eg driving, occupational

hazards, at risk of falls)• If weight gain a concern

2nd LINE OPTIONS in addition to lifestyle measures, adherence to medication and dose optimisation; ADD ONE OF

Sulphonylurea* (SU)

1st LINE OPTIONS in addition to lifestyle measures; START ONE OF

Thiazolidinedione* (In the EU only pioglitazone is licensed)• If hypos a concern (eg driving, occupational hazards, at risk of falls) and• If no congestive heart failure

Review and ifnot reaching

target move to3rd line

3rd LINE OPTIONS in addition to lifestyle measures, adherence to medication and dose optimization; ADD OR SUBSTITUTE WITH ONE OF

INJECTABLE (if willing to self inject; continue MF/SU if tolerated)ORAL (continue MF/SU if tolerated)

Thiazolidinedione* (In the EUonly pioglitazone is licensed)If no congestive heart failure

DPP-IV inhibitor*If weight gain a concern

Insulin* (inject before bed)• If osmotic symptoms/rising HbA1c; NPH insulin initially• If hypos a concern, use basal analogue insulin as an

alternative• Add prandial insulin with time if required

GLP-1 agonists*• If BMI >30 kg/m2• If a desire to lose weight• Usually <10 years from diagnosis

Sulphonylurea* (SU)• If intolerant of metformin or• If weight loss/osmotic symptoms

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

Guidelines Network (SIGN) – 2010: REVIEW AND SET GLYCAEMIC TARGET: HBA1C <7% (53

mmol/mol) OR INDIVIDUALISED AS AGREED

Usual approach

Alternative approach. Special considerations

Continue medication if EITHER individualised target achieved OR HbA1c falls >0.5% (5.5 mmol/mol) in 3-6 months*

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)

Relevant comments on SIGN algorithm

Establish A1C goals*

Nonpharmacologic Therapy-Diet-Exercise

Very symptomatic Severe hyperglycemia Ketosis Unrecognized type 1 DM

Recommended Monotherapy-Biguanide-Sulfonylurea-InsulinAlternative Agents*‡-Alpha-glucosidase inhibitors-DPP-4 inhibitors-GLP-1 agonist-Meglitinides-Thiazolidinediones

Glycemic goals not achieved


Recommended Combination Therapy-Biguanide+ Sulfonylurea-Biguanide + Insulin-Sulfonylurea + InsulinAlternative Combination Therapy*‡-Alpha-glucosidase inhibitors-DPP-4 inhibitors-GLP-1 agonists-Meglitinides-Thiazolidinediones


Oral agent not tolerable or A1c > 2% above target

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

*Listed alphabetically; not in order of preference‡If applicable, refer to VA www.pbm.va.gov or http://vaww.pbm.va.gov or DoDguidance/criteria for further recommendations on use of these agents

VA/DoD Clinical Practice Guideline for the Management of Diabetes Mellitus - 2011

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

Relevant comments on DoD/VA algorithm

Cochrane Database of Systematic Reviews 2008 on

DPP-4 inhibitors for type 2 diabetes mellitus*

Dpp-4 inhibitors have some theoretical advantages over

existing therapies with oral antidiabetic compounds but should currently be restricted to individual patients.

Long-term data especially on cardiovascular outcomes and safety are

Urgently needed before widespread use of these agents.

More information on the benefit-risk ratio of dpp-4 inhibitor treatment is necessary especially analysingadverse effects on parameters of immune function.

Also, long-term data are needed investigating patient-oriented parameters like health related quality of life, diabetic complications and all cause mortality.

* Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch C. Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus.

Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD006739. DOI: 10.1002/14651858.CD006739.pub2

Example of conflicts of interest or

Competing interestsSafety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes

Debora Williams-Herman ; Samuel S Engel ; Elizabeth Round ; Jeremy Johnson; Gregory T Golm; Hua Guo ; Bret J Musser ; Michael J Davies ; Keith D Kaufman: ; Barry J Goldstein Received February 10, 2010; Accepted April 22, 2010.

Conclusions : In this updated pooled safety analysis of

data from 10,246 patients with type 2 diabetes, sitagliptin 100

mg/day was generally well tolerated in clinical

trials of up to 2 years in duration.

BMC Endocr Disord. 2010; 10: 7. Published online 2010 April 22. doi: 10.1186/1472-6823-10-7

Disclosures All authors are employed by

Merck Sharp & Dohme, Corp.,a subsidiary of Merck & Co., Inc.,the manufacturer of sitagliptin

and may have company stock or

stock options.

A Systematic Assessment of Cardiovascular Outcomes in the Saxagliptin Drug Development Program for Type 2 DiabetesDOI: 10.3810/pgm.2010.05.2138Robert Frederich; John H. Alexander; Fred T. Fiedorek, MD; Mark Donovan; Niklas Berglind; Susan Harris; Roland Chen; Robert Wolf; and Kenneth W. Mahaffey.Postgraduate Medicine: Volume: 122 No.3

Conclusion:

No increased risk of CV

death/MI/stroke was observed in patients randomly assigned saxagliptin across a broad drug development program.Although this systematic overview has inherent and important limitations, the data support a potential reduction in CV events with saxagliptin. The hypothesis of CV protection with saxagliptinwill be tested prospectively in a large randomized clinical outcome trial evaluating saxagliptincompared with standard of care in patients with type 2 diabetes at increased risk for CV events.

Example of conflicts of interest or Competing interests

Conflict of Interests Statements

Robert Frederich, MD, PhD, Fred Fiedorek, MD, Mark Donovan, PhD, Niklas

Berglind, BSc, Roland Chen, MD, and Robert Wolf, MD are employed by

Bristol-Myers SquibbSusan Harris MS is employed by AstraZeneca

John H. Alexander, MD, MHS, FACC provided consulting or other services, and received

honoraria from, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Duke Private Diagnostic Clinic, Duke Health System, and Regado Biosciences

John H. Alexander also received research grant or contract funding from Bristol-Myers Squibb, Duke Health System, Medtronic Japan, Merck and Company, National Institutes of

Health, Pfizer, and Regado Biosciences

Kenneth W. Mahaffey, MD provided consulting or other services, received honoraria, or

received research grant or contract funding from, or provided educational activities or lectures for,

Adolor Corp, Alexion, Amgen Inc., Amylin Inc., Argolyn, AstraZeneca, Bayer HealthCare, Boehringer Ingelheim, Brigham & Women’s Hospital, Bristol-Myers Squibb, CardioKinetix Inc., Cierra, Cordis, Daiichi Sankyo, Duke University School of Medicine, Edwards Lifesciences, Eli Lilly, Elsevier (AHJ), Forest Laboratories, Genentech, GlaxoSmithKline, Guidant Corporation, Innocoll Pharmaceuticals, Johnson & Johnson, KCI Medical, Luitpold Pharmaceutical,

Medtronic Inc., Merck and Company, Momenta Pharmaceutical, Novartis, Pfizer, Portola Pharmaceutical, Proctor and Gamble, Pozen, Regado Biosciences, sanofi-aventis, Schering-Plough Corp., Scios Inc., The Medicines Company, WebMD, and William Beaumont Hospital

Sitagliptin: review of preclinical and clinical data regarding incidence of pancreatitisS S Engel, D E Williams-Herman, G T Golm, R J Clay, S V Machotka, K D Kaufman, and B J Goldstein

Int J Clin Pract. 2010 June; 64(7): 984–990.

ConclusionsPreclinical and clinical trial data with sitagliptin to date

do not indicate an increased risk of pancreatitis in

patients with T2DM treated with sitagliptin.

Disclosures All authors are

employees of Merck & Co., Inc., the manufacturer of sitagliptin and

may have stock or stock optionsin the company.

Received February 2010; Accepted February 2010.


Dore DD, et alCurrent Medical Research and Opinion. 2009;25 :1019-1027.Curr Med Res Opin. 2009 Apr;25(4):1019-27.

CONCLUSIONS:

These data do not provide evidence for an

association of acute pancreatitis among initiators of exenatide or sitagliptin compared to met/gly initiators. These results are limited by the data available in an administrative, healthcare database.

Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide.

Declaration of interest:Funding for this research was

provided to i3 Drug safety by AmylinPharmaceuticals, , Inc., which has a global agreement with Eli Lilly and

Company to collaborate on the development and commercialization

of exentide. D.D.D., J. D.S. and K.A.C. are employees of i3 Drug

Safety.


Acute Pancreatitis in Type 2 Diabetes Treated With Exenatide or Sitagliptin: A retrospective observational pharmacy claims analysis

Rajesh Garg, MDWilliam Chen, PHD, MPH and Merri Pendergrass, MD, PHD2

Garg R, et al. Diabetes Care November 2010 vol 33 :2349-2354

CONCLUSIONS Our study demonstrated increased incidence of acute pancreatitis in diabetic versus nondiabetic patients but

did not find an association between the use of exenatide or

sitagliptin and acute pancreatitis. The limitations of this observational claims-based analysis cannot exclude the possibility of an increased risk. Despite these limitations, these data provide valuable information for practicing

clinicians weighing potential reported benefits versus risks, including the FDA

warning of increased pancreatitis.

Declaration of interest:

No potential conflicts ofinterest relevant to

this article were reported.


* Butler PC, et al. Diabetologia (2010) 53:1–6.Animal studies:

** Nachnani JS, et al. Diabetologia 2009; doi:10.1007/s00125-009Matveyenko AV, et al .Diabetes 2009;58:1604–1615

Although, the GLP-1–based therapies arrived in clinical practice with

much fanfare and anticipation*

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

The pendulum is swinging toward the individualization of A1c goals

Algorithms for diabetes care are mostly consensus documents since few head-to-head, long-term trials exist to inform us about best practices

Clinical judgment sometimes trumps ―evidence-based‖ guidelines

Conclusions

the reliability and credibility of current glycemia guidelines in type 2 diabetes

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