Management of Hyperglycemia in Type 2_1.

7/31/2019 Management of Hyperglycemia in Type 2_1.

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Management of Hyperglycemia in Type 2Diabetes: A Patient-Centered Approach

Position Statement of the American Diabetes Association (ADA) and

the European Association for the Study of Diabetes (EASD)


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Writing Group

American Diabetes Association

Richard M. Bergenstal MDIntl Diabetes Center, Minneapolis, MN

John B. Buse MD, PhDUniversity of North Carolina, Chapel Hill, NC

Anne L. Peters MDUniv. of Southern California, Los Angeles, CA

Richard Wender MD

Thomas Jefferson University, Philadelphia, PA

Silvio E. Inzucchi MD (co-chair)Yale University, New Haven, CT

European Assoc. for the Study of Diabetes

Michaela Diamant MD, PhDVU University, Amsterdam, The Netherlands

Ele Ferrannini MDUniversity of Pisa, Pisa, Italy

Michael Nauck MDDiabeteszentrum, Bad Lauterberg, Germany

Apostolos Tsapas MD, PhD

Aristotle University, Thessaloniki, Greece

David R. Matthews MD, DPhil (co-chair)Oxford University, Oxford, UK


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ADA-EASD Position Statement: Management of

Hyperglycemia in T2DM: A Patient-Centered Approach

1. PATIENT-CENTERED APPROACH

2. BACKGROUND

Epidemiology and health care impact

Relationship of glycemic control to outcomes Overview of the pathogenesis of Type 2 diabetes

3. ANTI-HYPERGLYCEMIC THERAPY

Glycemic targets Therapeutic options

- Lifestyle

- Oral agents & non-insulin injectables

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


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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


Hyperglycemia in T2DM: A Patient-Centered Approach

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


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Hyperglycemia in T2DM

1. Patient-Centered Approach

...providing care that is respectful of and responsive to

individual patient preferences, needs, and values - ensuringthat patient values guide all clinical decisions.

Gauge patients preferred level of involvement.

Explore, where possible, therapeutic choices.

Utilize decision aids.

Shared decision making final decisions re: lifestyle choicesultimately lies with the patient.



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2. BACKGROUND

Epidemiology and health care impact



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Age-adjusted Percentage of U.S. Adults with

Obesity or Diagnosed DiabetesObesity (BMI 30 kg/m2)

Diabetes

1994

1994

2000

2000

No Data 26.0%

No Data 9.0%

CDCs Division of Diabetes Translation. National Diabetes Surveillance System available

at http://www.cdc.gov/diabetes/statistics

2009

2009

OBE

SITY

OOBBEE

SSIITTYY

DIAB

ETES

DDIIAABB

EETTEESS


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The Diabetes Epidemic: Global Projections,

20102030

IDF. Diabetes Atlas 5th Ed. 2011


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2. BACKGROUND

Relationship of glycemic control to outcomes



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Impact of Intensive Therapy for Diabetes:

Summary of Major Clinical TrialsStudy Microvasc CVD Mortality

UKPDS

DCCT / EDIC*

ACCORD ADVANCE

VADT

Long Term Follow-up

Initial Trial

* in T1DM

Kendall DM,Kendall DM, BergenstalBergenstal RM.RM. International Diabetes Center 2009International Diabetes Center 2009

UK Prospective Diabetes Study (UKPDS) Group.Lancet1998;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 Med2009;361:1024)


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2. BACKGROUND

Overview of the pathogenesis of T2DM- Insulin secretory dysfunction

-Insulin resistance (muscle, fat, liver)

-Increased endogenous glucose production

-Deranged adipocyte biology

-Decreased incretin effect



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++++++++

peripheralglucoseuptake

hepatic

glucoseproduction

pancreaticinsulinsecretion

pancreatic

glucagonsecretion

Main Pathophysiological Defects in T2DM

gutcarbohydratedelivery &

absorption

incretineffect

HYPERGLYCEMIAHYPERGLYCEMIAHYPERGLYCEMIAHYPERGLYCEMIAHYPERGLYCEMIAHYPERGLYCEMIAHYPERGLYCEMIAHYPERGLYCEMIA

?

Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011


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Glycemic targets

- HbA1c < 7.0% (mean PG 150-160 mg/dl [8.3-8.9 mmol/l])

- Pre-prandial PG


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Figure 1 Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print](Adapted with permission from: Ismail-Beigi F, et al.Ann Intern Med2011;154:554)


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Therapeutic options: Lifestyle

- Weight optimization

- Healthy diet

- Increased activity level



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Therapeutic options:Oral agents & non-insulin injectables

- Metformin

- Sulfonylureas

- Thiazolidinediones

- DPP-4 inhibitors- GLP-1 receptor agonists

- Meglitinides

- -glucosidase inhibitors

- Bile acid sequestrants

- Dopamine-2 agonists- Amylin mimetics



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ClassClass MechanismMechanism AdvantagesAdvantages DisadvantagesDisadvantages CostCost

Biguanides Activates AMP-kinase

Hepatic glucoseproduction

Extensive experience

No hypoglycemia Weight neutral

? CVD

Gastrointestinal

Lactic acidosis B-12 deficiency

Contraindications

Low

SUs /

Meglitinides

Closes KATP channels

Insulin secretion Extensive experience

Microvasc. risk Hypoglycemia

Weight gain

Low durability

? Ischemic

preconditioning

Low

TZDs PPAR- activator

insulin sensitivity

No hypoglycemia

Durability TGs, HDL-C ? CVD (pio)

Weight gain

Edema / heart failure Bone fractures

? MI (rosi) ? Bladder ca (pio)

High

-GIs Inhibits glucosidase

Slows carbohydrate

absorption

No hypoglycemia

Nonsystemic

Post-prandial glucose ? CVD events

Gastrointestinal

Dosing frequency

Modest A1c

Mod.

Table 1. Properties of anti-hyperglycemic agents Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]


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DPP-4

inhibitors

Inhibits DPP-4

Increases GLP-1, GIP

No hypoglycemia

Well tolerated

Modest A1c

? Pancreatitis Urticaria

High

GLP-1

receptor

agonists

Activates GLP-1 R

Insulin, glucagon gastric emptying satiety

Weight loss

No hypoglycemia

? Beta cell mass

? CV protection

GI

? Pancreatitis

Medullary ca

Injectable

High

Amylin

mimetics

Activates amylin

receptor

glucagon

gastric emptying satiety

Weight loss

PPG GI

Modest A1c Injectable

Hypo w/ insulin Dosing frequency

High

Bile acid

sequestrants

Bind bile acids

Hepatic glucoseproduction

No hypoglycemia

Nonsystemic

Post-prandial glucose CVD events

GI

Modest A1c Dosing frequency

High

Dopamine-2

agonists

Activates DA receptor

Modulates hypothalamic

control of metabolism

insulin sensitivity

No hypoglyemia

? CVD events Modest A1c Dizziness/syncope

Nausea

Fatigue

High



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Insulin Activates insulin

receptor peripheral glucoseuptake

Universally

effective Unlimited efficacy

Microvascularrisk

Hypoglycemia

Weight gain ? Mitogenicity

Injectable

Training

requirements

Stigma

Variable



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Therapeutic options: Insulin

- Neutral protamine Hagedorn (NPH)

- Regular

- Basal analogues (glargine, detemir)

- Rapid analogues (lispro, aspart, glulisine)

- Pre-mixed varieties



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Long (Detemir)

Rapid (Lispro, Aspart, Glulisine)

Hours

Long (Glargine)

0 2 4 6 8 10 12 14 16 18 20 22 24

Short (Regular)

Hours after injection

Insulinl

ev

el


Therapeutic options: Insulin

Intermediate (NPH)


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Implementation strategies:

- Initial therapy

- Advancing to dual combination therapy

- Advancing to triple combination therapy

- Transitions to & titrations of insulin



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T2DM Antihyperglycemic Therapy: General RecommendationsDiabetes Care, Diabetologia. 19 April 2012

[Epub ahead of print]


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T2DM Antihyperglycemic Therapy: General RecommendationsDiabetes Care, Diabetologia. 19 April 2012


T2DM Ant yperg ycem cnt yperg ycem c T erapy: Genera Recommen at onserapy: enera ecommen at ons


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T2DM Ant yperg ycem cnt yperg ycem c T erapy: Genera Recommen at onserapy: enera ecommen at ons

Di bete C reDiabetes Care Di bet l iDiabetolo ia.. 1919 A ril 201A ril 201 E ubE ub ahead of rintahead of rint


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Diabetes Care, Diabetologia.

19 April 2012 [Epub ahead of print]

I li St t i i T2DMI li St t i i T2DM


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Insulin Strategies in T2DMInsulin Strategies in T2DM

Diabetes Care,Diabetes Care,DiabetologiaDiabetologia.. 1919 April 2012 [April 2012 [EpubEpub ahead of print]ahead of print]

ADA EASD P iti St t t M t f


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4. OTHER CONSIDERATIONS

Age

WeightSex / racial / ethnic / genetic differences

Comorbidities

- Coronary artery disease- Heart Failure

- Chronic kidney disease

- Liver dysfunction- Hypoglycemia


ADA EASD Position Statement: Management of


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Age: Older adults

- Reduced life expectancy- Higher CVD burden

- Reduced GFR

- At risk for adverse events from polypharmacy

- More likely to be compromised from hypoglycemia

Less ambitious targets

HbA1c


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Weight

- Majority of T2DM patients overweight / obese- Intensive lifestyle program

- Metformin

- GLP-1 receptor agonists- ? Bariatric surgery

- Consider LADA in lean patients


T2DM AntiT2DM Anti--hyperglycemic Therapy: General Recommendationshyperglycemic Therapy: General Recommendations


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T2DM AntiT2DM Anti hyperglycemic Therapy: General Recommendationshyperglycemic Therapy: General Recommendations

Diabetes Care,Diabetes Care,DiabetologiaDiabetologia.. 1919 April 2012April 2012

[[EpubEpub ahead of print]ahead of print]

Adapted Recommendations: When Goal is to Avoid Weight GainAdapted Recommendations: When Goal is to Avoid Weight Gain


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Adapted Recommendations: When Goal is to Avoid Weight Gainp g





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Sex/ethnic/racial/genetic differences

- Little is known- MODY & other monogenic forms of diabetes

- Latinos: more insulin resistance

- East Asians: more beta cell dysfunction- Gender may drive concerns about adverse effects (e.g.,

bone loss from TZDs)




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Comorbidities

- Coronary Disease

- Heart Failure

- Renal disease

- Liver dysfunction

- Hypoglycemia

Metformin: CVD benefit (UKPDS)

Avoid hypoglycemia

? SUs & ischemic preconditioning

? Pioglitazone & CVD events

? Effects of incretin-basedtherapies




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g



Comorbidities

- Coronary Disease

- Heart Failure

- Renal disease

- Liver dysfunction

- Hypoglycemia

Metformin: May use unless

condition is unstable or severe

Avoid TZDs

? Effects of incretin-basedtherapies




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g



Comorbidities

- Coronary Disease

- Heart Failure

- Renal disease

- Liver dysfunction

- Hypoglycemia

Increased risk of hypoglycemia

Metformin & lactic acidosis

US: stop @SCr 1.5 (1.4

women)

UK: dose @GFR


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Comorbidities

- Coronary Disease

- Heart Failure

- Renal disease

- Liver dysfunction

- Hypoglycemia

Most drugs not tested in advancedliver disease

Pioglitazone may help steatosis

Insulin best option if disease severe




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Comorbidities

- Coronary Disease

- Heart Failure

- Renal disease

- Liver dysfunction

- Hypoglycemia Emerging concerns regarding

association with increased

mortality Proper drug selection in the

hypoglycemia prone


T2DM AntiT2DM Anti--hyperglycemic Therapy: General Recommendationshyperglycemic Therapy: General Recommendations


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Adapted Recommendations: When Goal is to Avoid HypoglycemiaAdapted Recommendations: When Goal is to Avoid Hypoglycemia


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Adapted Recommendations: When Goal is to Minimize CostsAdapted Recommendations: When Goal is to Minimize Costs


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Diabetes Care, Diabetologia. 19 April 2012


Guidelines for Glycemic BP & Lipid Control


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Guidelines for Glycemic, BP, & Lipid Control

American Diabetes Assoc. Goals

HbA1C < 7.0% (individualization)

Preprandialglucose 70-130 mg/dL (3.9-7.2 mmol/l)

Postprandialglucose

< 180 mg/dL

Blood pressure < 130/80 mmHg

Lipids

LDL: < 100 mg/dL (2.59 mmol/l)

< 70 mg/dL (1.81 mmol/l) (with overt CVD)

HDL: > 40 mg/dL (1.04 mmol/l)

> 50 mg/dL (1.30 mmol/l)

TG: < 150 mg/dL (1.69 mmol/l)

ADA.Diabetes Care. 2012;35:S11-63HDL = high-density lipoprotein; LDL = low-density

lipoprotein; PG = plasma glucose; TG = triglycerides.




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4. FUTURE DIRECTIONS / RESEARCH NEEDS

Comparative effectiveness research

Focus on important clinical outcomes

Contributions of genomic research

Perpetual need for clinical judgment!





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KEY POINTS Glycemic targets & BG-lowering therapies must individualizedindividualized..

Diet, exercise, & educationDiet, exercise, & education: foundation of any T2DM therapy

program

Unless contraindicated, metforminmetformin = optimal 1st-line drug.

After metformin, data are limited.

Combination therapyCombination therapywith 1-2

other oral / injectable agents is reasonable; minimize side effects.

Ultimately, many patients will require insulininsulin therapy alone / in

combination with other agents to maintain BG control.

All treatment decisions should be made in conjunction with theAll treatment decisions should be made in conjunction with the

patientpatient (focus on preferences, needs & values.)

Comprehensive CV risk reductionCV risk reduction - a major focus of therapy.Di bete C reDiabetes Care Di bet l iDiabetolo ia.. 1919 A ril 2012A ril 2012 E ubE ub ahead of rintahead of rint




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Invited Reviewers

Professional Practice Committee, American Diabetes Association

Panel for Overseeing Guidelines and Statements, European Association for the Study of Diabetes

American Association of Diabetes Educators

The Endocrine SocietyAmerican College of Physicians

James Best, The University of Melbourne, AU

Henk Bilo,Isala Clinics, Zwolle, NL

John Boltri, Wayne State University, Detroit, MI

Thomas Buchanan, Univ of So California, LA, CAPaul Callaway, University of Kansas,Wichita, KS

Bernard Charbonnel, University of Nantes, France

Stephen Colagiuri, The University of Sydney, AS

Samuel Dagogo-Jack, Univ of Tenn, Memphis, TN

Margo Farber,Detroit Medical Center, Detroit, MI

Cynthia Fritschi, University of Illinois, Chicago, IL

Rowan Hillson,Hillingdon Hospital, Uxbridge, U.K.

Faramarz Ismail-Beigi, CWR Univ, Cleveland, OH

Devan Kansagara, Oregon H&S Univ, Portland, OR

Ilias Migdalis, NIMTS Hospital,Athens, Greece

Donna Miller, Univ of So California, LA, CA

Robert Ratner,MedStar/Georgetown Univ, DC

Julio Rosenstock,Dallas Diab/Endo Ctr, Dallas, TX

Guntram Schernthaner,Rudolfstiftung Hosp, Vienna, AT

Robert Sherwin, Yale University, New Haven, CT

Jay Skyler, University of Miami, Miami, FL

Geralyn Spollett, Yale University,New Haven, CT

Ellie Strock,Intl Diabetes Center, Minneapolis, MN

Agathocles Tsatsoulis, University of Ioannina, GR

Andrew Wolf, Univ of Virginia Charlottesville, VA

Bernard Zinman, University of Toronto, CA

Management of Hyperglycemia in Type 2_1.

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