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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)
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, Diabetologia. 19 April 2012 [Epub ahead of print]
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, Diabetologia. 19 April 2012 [Epub ahead of print]
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 lies with the patient.
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
2. BACKGROUND
• Epidemiology and health care impact
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
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
OOBBEESSIITTYY
OOBBEESSIITTYY
DDIIAABBEETTEESS
DDIIAABBEETTEESS
The Diabetes Epidemic: Global Projections, 2010–2030
IDF. Diabetes Atlas 5th Ed. 2011
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
2. BACKGROUND
• Relationship of glycemic control to outcomes
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
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 2009Kendall 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)
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
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, Diabetologia. 19 April 2012 [Epub ahead of print]
++
peripheralglucose uptake
hepatic glucose production
pancreatic insulinsecretion
pancreatic glucagonsecretion
Main Pathophysiological Defects in T2DM
gutcarbohydratedelivery &absorption
incretineffect
HYPERGLYCEMIAHYPERGLYCEMIA
?
Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
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, Diabetologia. 19 April 2012 [Epub ahead of print]
Figure 1 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)
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
3. ANTI-HYPERGLYCEMIC THERAPY
•Therapeutic options: Lifestyle
-Weight optimization
-Healthy diet
- Increased activity levelDiabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
3. ANTI-HYPERGLYCEMIC THERAPY
• 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
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ClassClass MechanismMechanism AdvantagesAdvantages DisadvantagesDisadvantages CostCostBiguanides • Activates AMP-kinase
• Hepatic glucose production
• 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]
ClassClass MechanismMechanism AdvantagesAdvantages DisadvantagesDisadvantages CostCostDPP-4inhibitors
• 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 glucose production
• No hypoglycemia• Nonsystemic• Post-prandial glucose• CVD events
• GI• Modest A1c• Dosing frequency
High
Dopamine-2agonists
• Activates DA receptor• Modulates hypothalamic control of metabolism• insulin sensitivity
• No hypoglyemia• ? CVD events
• Modest A1c• Dizziness/syncope• Nausea• Fatigue
High
Table 1. Properties of anti-hyperglycemic agents Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ClassClass MechanismMechanism AdvantagesAdvantages DisadvantagesDisadvantages CostCostInsulin • Activates insulin
receptor• peripheral glucose uptake
• Universally effective• Unlimited efficacy• Microvascular risk
• Hypoglycemia• Weight gain• ? Mitogenicity• Injectable• Training requirements• “Stigma”
Variable
Table 1. Properties of anti-hyperglycemic agents Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
3. ANTI-HYPERGLYCEMIC THERAPY
•Therapeutic options: Insulin
- Neutral protamine Hagedorn (NPH)
- Regular
- Basal analogues (glargine, detemir)
- Rapid analogues (lispro, aspart, glulisine)
- Pre-mixed varieties
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
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
3. ANTI-HYPERGLYCEMIC THERAPY
•Therapeutic options: Insulin
Intermediate (NPH)
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
3. ANTI-HYPERGLYCEMIC THERAPY
•Implementation strategies:
-Initial therapy
-Advancing to dual combination therapy
-Advancing to triple combination therapy
-Transitions to & titrations of insulin
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]
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]
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Sequential Insulin Strategies in T2DM Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS•Age•Weight•Sex / racial / ethnic / genetic differences•Comorbidities
-Coronary artery disease-Heart Failure-Chronic kidney disease-Liver dysfunction-Hypoglycemia
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
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 hypoglycemia
Less ambitious targetsHbA1c <7.5–8.0% if tighter
targets not easily achievedFocus on drug safety
Less ambitious targetsHbA1c <7.5–8.0% if tighter
targets not easily achievedFocus on drug safety
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
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
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
T2DM Anti-hyperglycemic Therapy: General RecommendationsDiabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Adapted Recommendations: When Goal is to Avoid Weight GainDiabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
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)
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
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
Metformin: CVD benefit (UKPDS) Avoid hypoglycemia ? SUs & ischemic preconditioning ? Pioglitazone & CVD events ? Effects of incretin-based
therapies
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS•Comorbidities
-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
Metformin: May use unless condition is unstable or severe
Avoid TZDs ? Effects of incretin-based
therapies
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS•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 <45 & stop @GFR <30
Caution with SUs (esp. glyburide) DPP-4-i’s – dose adjust for most Avoid exenatide if GFR <30
Increased risk of hypoglycemia Metformin & lactic acidosis
US: stop @SCr ≥ 1.5 (1.4 women)
UK: dose @GFR <45 & stop @GFR <30
Caution with SUs (esp. glyburide) DPP-4-i’s – dose adjust for most Avoid exenatide if GFR <30
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS•Comorbidities
-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
Most drugs not tested in advanced liver disease
Pioglitazone may help steatosis Insulin best option if disease
severe
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS•Comorbidities
-Coronary Disease
-Heart Failure
-Renal disease
-Liver dysfunction
-Hypoglycemia Emerging concerns regarding
association with increased mortality
Proper drug selection in the hypoglycemia prone
Emerging concerns regarding association with increased mortality
Proper drug selection in the hypoglycemia prone
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
T2DM Anti-hyperglycemic Therapy: General Recommendations Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Adapted Recommendations: When Goal is to Avoid HypoglycemiaDiabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Adapted Recommendations: When Goal is to Minimize Costs Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Guidelines for Glycemic, 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:S11-63HDL = high-density lipoprotein; LDL = low-density lipoprotein; PG = plasma glucose; TG = triglycerides.
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. FUTURE DIRECTIONS / RESEARCH NEEDS
•Comparative effectiveness research Focus on important clinical outcomes
•Contributions of genomic research
•Perpetual need for clinical judgment!
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
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, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
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, AU
Henk Bilo, Isala Clinics, Zwolle, NL
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, 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, Int’l Diabetes Center, Minneapolis, MN
Agathocles Tsatsoulis, University of Ioannina, GR
Andrew Wolf, Univ of Virginia Charlottesville, VA
Bernard Zinman, University of Toronto, CA