ada 2012

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)

Diabetes Care 2012;35:1364–1379Diabetologia 2012;55:1577–1596

Writing Group

American Diabetes Association

Richard M. Bergenstal MDInt’l 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 MDThomas 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, PhDAristotle University, Thessaloniki, Greece

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

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- Insulin

Diabetes Care 2012;35:1364–1379

Diabetologia 2012;55:1577–1596

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

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM: A Patient-Centered Approach

Diabetes Care 2012;35:1364–1379


ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

1. Patient-Centered Approach“...providing care that is respectful of and responsive to individual patient preferences, needs, and values - ensuring that patient values guide all clinical decisions.”

• Gauge patient’s preferred level of involvement.

• Explore, where possible, therapeutic choices.

• Utilize decision aids.

• Shared decision making – final decisions re: lifestyle choices ultimately lie with the patient.

Diabetes Care 2012;35:1364–1379



2. BACKGROUND

• Epidemiology and health care impact


Age-adjusted Percentage of U.S. Adults with Obesity or Diagnosed Diabetes

Obesity (BMI ≥30 kg/m2)

Diabetes

1994

1994

2000

2000

No Data <14.0% 14.0-17.9% 18.0-21.9% 22.0-25.9% >26.0%

No Data <4.5% 4.5-5.9% 6.0-7.4% 7.5-8.9% >9.0%

CDC’s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics

2009

2009

O

BESITY

DIABETES

The Diabetes Epidemic: Global Projections, 2010–2030

IDF. Diabetes Atlas 5th Ed. 2011


2. BACKGROUND

• Relationship of glycemic control to outcomes

Diabetes Care 2012;35:1364–1379


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 2009

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

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

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

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

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


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

Diabetes Care 2012;35:1364–1379


+

-

-

peripheralglucose uptake

hepatic glucose production

pancreatic insulinsecretion

pancreatic glucagonsecretion

Main Pathophysiological Defects in T2DM

gutcarbohydratedelivery &absorption

incretineffect

HYPERGLYCEMIA

?

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


3. ANTI-HYPERGLYCEMIC THERAPY• Glycemic targets

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

- Pre-prandial PG <130 mg/dl (7.2 mmol/l)

- Post-prandial PG <180 mg/dl (10.0 mmol/l)

- Individualization is key: Tighter targets (6.0 - 6.5%) - younger, healthier

Looser targets (7.5 - 8.0%+) - older, comorbidities, hypoglycemia prone, etc.

- Avoidance of hypoglycemiaPG = plasma glucose Diabetes Care 2012;35:1364–1379


Figure 1Diabetes Care 2012;35:1364–1379

Diabetologia 2012;55:1577–1596(Adapted with permission from: Ismail-Beigi et al. Ann Intern Med 2011;154:554)


3. ANTI-HYPERGLYCEMIC THERAPY

• Therapeutic options: Lifestyle

- Weight optimization

- Healthy diet

- Increased activity level




• Therapeutic options: Oral agents & non-insulin injectables

- Metformin

- Sulfonylureas

- Thiazolidinediones

- DPP-4 inhibitors

- GLP-1 receptor agonists

- Meglitinides

- a-glucosidase inhibitors

- Bile acid sequestrants

- Dopamine-2 agonists

- Amylin mimetics


Class Mechanism Advantages Disadvantages CostBiguanides(Metformin)

• Activates AMP-kinase• Hepatic glucose production

• Extensive experience• No hypoglycemia• Weight neutral• ? CVD events

• Gastrointestinal• Lactic acidosis• B-12 deficiency• Contraindications

Low

SUs / Meglitinides

• Closes KATP channels• Insulin secretion

• Extensive experience• Microvascular risk

• Hypoglycemia• Weight gain• Low durability• ? Ischemic preconditioning

Low

TZDs • Activates PPAR-g• Insulin sensitivity

• No hypoglycemia• Durability• TGs, HDL-C • ? CVD events (pio)

• Weight gain• Edema / heart failure• Bone fractures• ? MI (rosi)• ? Bladder ca (pio)

High

a-GIs • Inhibits a-glucosidase• Slows carbohydrate absorption

• No hypoglycemia• Nonsystemic• Post-prandial glucose• ? CVD events

• Gastrointestinal• Dosing frequency• Modest A1c

Mod.

Table 1. Properties of anti-hyperglycemic agentsDiabetes Care 2012;35:1364–1379


Class Mechanism Advantages Disadvantages CostDPP-4inhibitors

• Inhibits DPP-4• Increases GLP-1, GIP

• No hypoglycemia• Well tolerated

• Modest A1c • ? Pancreatitis• Urticaria

High

GLP-1 receptor agonists

• Activates GLP-1 receptor• 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• Post-prandial glucose

• GI• Modest A1c • Injectable• Hypo w/ insulin• Dosing frequency

High

Bile acid sequestrants

• Binds bile acids• Hepatic glucose production

• No hypoglycemia• Nonsystemic• LDL-C

• GI• Modest A1c• TGs• Dosing frequency

High

Dopamine-2agonists

• Activates DA receptor• Modulates hypothalamic control of metabolism• Insulin sensitivity

• No hypoglycemia• ? CVD events

• Modest A1c• Dizziness/syncope• Nausea• Fatigue

High



Class Mechanism Advantages Disadvantages CostInsulin • Activates insulin

receptor• Glucose disposal• Hepatic glucose production

• Universally effective• Unlimited efficacy• Microvascular risk

• Hypoglycemia• Weight gain• ? Mitogenicity• Injectable• Training requirements• “Stigma”

Variable





• Therapeutic options: Insulin

- Human Neutral protamine Hagedorn (NPH)

- Human Regular

- Basal analogues (glargine, detemir)

- Rapid analogues (lispro, aspart, glulisine)

- Pre-mixed varieties



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

Insu

lin le

vel


• Therapeutic options: Insulin

Intermediate (NPH)



• Implementation strategies:

- Initial therapy

- Advancing to dual combination therapy

- Advancing to triple combination therapy

- Transitions to & titrations of insulin


Fig. 2. T2DM Antihyperglycemic Therapy: General RecommendationsDiabetes Care 2012;35:1364–1379Diabetologia 2012;55:1577–1596

Fig. 3. Sequential Insulin Strategies in T2DM Diabetes Care 2012;35:1364–1379Diabetologia 2012;55:1577–1596


4. OTHER CONSIDERATIONS• Age• Weight• Sex / racial / ethnic / genetic differences• Comorbidities

- Coronary artery disease- Heart Failure- Chronic kidney disease- Liver dysfunction- Hypoglycemia



4. OTHER CONSIDERATIONS• Age: Older adults

-Reduced life expectancy-Higher CVD burden-Reduced GFR-At risk for adverse events from polypharmacy-More likely to be compromised from

hypoglycemiaLess ambitious targetsHbA1c <7.5–8.0% if tighter

targets not easily achievedFocus on drug safety



4. OTHER CONSIDERATIONS• Weight

- Majority of T2DM patients overweight / obese- Intensive lifestyle program- Metformin- GLP-1 receptor agonists- ? Bariatric surgery- Consider LADA in lean patients


T2DM Anti-hyperglycemic Therapy: General Recommendations Diabetes Care 2012;35:1364–1379Diabetologia 2012;55:1577–1596

Adapted Recommendations: When Goal is to Avoid Weight GainDiabetes Care 2012;35:1364–1379Diabetologia 2012;55:1577–1596


4. OTHER CONSIDERATIONS• 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)



4. OTHER CONSIDERATIONS• 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-based

therapies




- Coronary Disease

- Heart Failure

- Renal disease

- Liver dysfunction

- Hypoglycemia


Metformin: May use unless condition is unstable or

severe Avoid TZDs ? Effects of incretin-based therapies



- 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: half-dose @GFR < 45 & stop @GFR < 30

Caution with SUs (esp. glyburide)

DPP-4-i’s – dose adjust for most Avoid exenatide if GFR < 30



- Coronary Disease

- Heart Failure

- Renal disease

- Liver dysfunction

- Hypoglycemia


Most drugs not tested in advanced liver disease

Pioglitazone may help steatosis

Insulin best option if disease severe



- Coronary Disease

- Heart Failure

- Renal disease

- Liver dysfunction

- Hypoglycemia


Emerging concerns regarding association with increased morbidity / mortality

Proper drug selection is key in the hypoglycemia prone

T2DM Anti-hyperglycemic Therapy: General Recommendations Diabetes Care 2012;35:1364–1379Diabetologia 2012;55:1577–1596

Adapted Recommendations: When Goal is to Avoid HypoglycemiaDiabetes Care 2012;35:1364–1379Diabetologia 2012;55:1577–1596

Adapted Recommendations: When Goal is to Minimize Costs Diabetes Care 2012;35:1364–1379Diabetologia 2012;55:1577–1596

Guidelines for Glucose, BP, & Lipid Control American Diabetes Assoc. Goals

HbA1C < 7.0% (individualization)

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

Postprandial glucose < 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–S63HDL = high-density lipoprotein; LDL = low-density lipoprotein; PG = plasma glucose; TG = triglycerides.


4. FUTURE DIRECTIONS / RESEARCH NEEDS

• Comparative effectiveness research Focus on important clinical outcomes

• Contributions of genomic research

• Perpetual need for clinical judgment!



KEY POINTS

• Glycemic targets & BG-lowering therapies must be individualized.

• Diet, exercise, & education: foundation of any T2DM therapy program

• Unless contraindicated, metformin = optimal 1st-line drug.

• After metformin, data are limited. Combination therapy with 1-2 other oral / injectable agents is reasonable; minimize side effects.

• Ultimately, many patients will require insulin therapy alone / in combination with other agents to maintain BG control.

• All treatment decisions should be made in conjunction with the patient (focus on preferences, needs & values.)

• Comprehensive CV risk reduction - a major focus of therapy.Diabetes Care 2012;35:1364–1379



Invited Reviewers

Professional Practice Committee, American Diabetes AssociationPanel for Overseeing Guidelines and Statements, European Association for the Study of Diabetes

American Association of Diabetes EducatorsThe Endocrine Society

American College of Physicians

James Best, The University of Melbourne, Australia

Henk Bilo, Isala Clinics, Zwolle, Netherlands

John Boltri, Wayne State University, Detroit, MI

Thomas Buchanan, Univ of So California, LA, CA

Paul Callaway, University of Kansas,Wichita, KS

Bernard Charbonnel, University of Nantes, France

Stephen Colagiuri, The University of Sydney, Australia

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, Austria

Robert Sherwin, Yale University, New Haven, CT

Jay Skyler, University of Miami, Miami, FL

Geralyn Spollett, Yale University, New Haven, CT

Ellie Strock, Int’l Diabetes Center, Minneapolis, MN

Agathocles Tsatsoulis, University of Ioannina, Greece

Andrew Wolf, Univ of Virginia Charlottesville, VA

Bernard Zinman, University of Toronto, Ontario, Canada

ada 2012

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