Algoritmo Slide Set Diabetes 2012

Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach
Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)
Click to edit Master subtitle style
Diabetes Care 2012;35:13641379 Diabetologia 2012;55:15771596
Writing Group
American Diabetes Association Richard M. Bergenstal MD
Intl Diabetes Center, Minneapolis, MN
European Assoc. for the Study of Diabetes Michaela Diamant MD, PhD
VU University, Amsterdam, The Netherlands
John B. Buse MD, PhD
University of North Carolina, Chapel Hill, NC
Ele Ferrannini MD
University of Pisa, Pisa, Italy
Anne L. Peters MD
Michael Nauck MD
Univ. of Southern California, Los Angeles, CA
Diabeteszentrum, Bad Lauterberg, Germany
Richard Wender MD
Apostolos Tsapas MD, PhD
Thomas Jefferson University, Philadelphia, PA
Aristotle University, Thessaloniki, Greece
Silvio E. Inzucchi MD (co-chair) 10/20/12

Yale University, New Haven, CT
David R. Matthews MD, DPhil (cochair) 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
10/20/12 - Oral agents & non-insulin injectables - Insulin
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM: A Patient-Centered Approach
3. ANTIHYPERGLYCEMIC THERAPY
Implementation Strategies - Initial drug therapy

- Advancing to dual combination therapy - Advancing to triple combination therapy - Transitions to and titrations of insulin
4. OTHER CONSIDERATIONS
Age Weight Sex/racial/ethnic/genetic differences Comorbidities (Coronary artery disease, Heart failure,
Chronic kidney disease, Liver dysfunction,

Hypoglycemia)
10/20/12
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 patients preferred level of involvement.
Explore, where possible, therapeutic

choices.
Utilize decision aids.

lifestyle 10/20/12 patient.
Shared decision making final decisions re:
choices ultimately lie with the Diabetes Care 2012;35:13641379

Diabetologia 2012;55:15771596
2. BACKGROUND
Epidemiology and health care impact
10/20/12
Age-adjusted Percentage of U.S. Obesity (BMI 30 Adults with Obesity or Diagnosed kg/m2) 1994 2000 2009 O Diabetes
B E S I T Y Diabetes D I A B E T E S
No Data
<14.0%
14.0-17.9%
18.0-21.9%
22.0-25.9%
>26.0%
1994
2000
2009
No Data
<4.5%
4.5-5.9%
6.0-7.4%
7.5-8.9%
>9.0%
CDCs Division of Diabetes Translation. National Diabetes Surveillance System available
at http://www.cdc.gov/diabetes/statistics
The Diabetes Epidemic: Global Projections, 20102030
IDF. Diabetes Atlas 5th Ed. 2011
2. BACKGROUND
Relationship of glycemic control to outcomes
10/20/12
Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials

Study
UKPDS DCCT / EDIC* ACCORD ADVANCE VADT
Microvasc
CVD
Mortality
Initial Trial Long Term Followup * in
Kendall DM, Bergenstal RM. International Diabetes Center 2009
2. BACKGROUND
T2DM
Overview of the pathogenesis of

- Insulin secretory dysfunction - Insulin resistance (muscle, fat, liver) - Increased endogenous glucose
production
- Deranged adipocyte biology - Decreased incretin effect

10/20/12
Main Pathophysiological Defects in T2DM pancrea

increti n effect tic insulin secretio pancrea tic n
glucago n secretio n
gut carbohydr ate delivery & absorption
HYPERGLYCEM IA
+
hepatic glucose producti peripher al glucose Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011 uptake
Glycemic targets
- HbA1c < 7.0% (mean PG 150-160 mg/dl [8.38.9 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,
10/20/12 PG = plasma
comorbidities,
hypoglycemia prone, Care 2012;35:13641379 Diabetes etc.

Figur
Diabetes Care 2012;35:13641379 Diabetologia 2012;55:15771596 (Adapted with permission from: Ismail-Beigi et al. Ann Intern Med 2011;154:554)
Therapeutic options: Lifestyle
- Weight optimization - Healthy diet

- Increased activity level
10/20/12
Therapeutic options: Oral agents & non-insulin injectables
- Metformin - Sulfonylureas - Thiazolidinediones - DPP-4 inhibitors - GLP-1 receptor agonists

10/20/12
- Meglitinides - -glucosidase inhibitors - Bile acid sequestrants - Dopamine-2 agonists - Amylin mimetics
Class
Mechanism
Advantages
Extensive experience No hypoglycemia Weight neutral ? CVD events
Disadvantages Cost
Gastrointestinal Lactic acidosis B-12 deficiency Contraindications Low
Biguanides Activates AMP(Metformin) kinase Hepatic glucose production SUs / Closes KATP Meglitinidechannels s Insulin secretion
Extensive Hypoglycemia experience Weight gain Microvascular risk Low durability ? Ischemic preconditioning Weight gain Edema / heart failure Bone fractures ? MI (rosi) ? Bladder ca (pio) Gastrointestinal Dosing frequency Modest A1c
Low
TZDs
No hypoglycemia Activates PPAR- Insulin sensitivity Durability TGs, HDL-C Click to edit Master subtitle style ? CVD events (pio)
High
-GIs
Inhibits glucosidase Slows carbohydrate absorption
Table 1. Properties of anti-
10/20/12
No hypoglycemia Nonsystemic Post-prandial glucose ? CVD events
Mod.
Class
DPP-4 inhibitors GLP-1 receptor agonists
Mechanism
Inhibits DPP-4 Increases GLP-1, GIP
Advantages
No hypoglycemia Well tolerated Weight loss No hypoglycemia ? Beta cell mass ? CV protection
Modest A1c ? Pancreatitis Urticaria GI ? Pancreatitis Medullary ca Injectable
Disadvantag Cost es
High
Activates GLP-1 receptor Insulin, glucagon gastric emptying satiety
High
Amylin mimetics
Activates amylin Weight loss receptor Post-prandial to edit Master subtitle style glucose Click glucagon gastric emptying satiety
GI High Modest A1c Injectable Hypo w/ insulin Dosing frequency GI High Modest A1c TGs Dosing Diabetes frequency Care 2012;35:13641379
Bile acid Binds bile acids sequestran Hepatic glucose ts production
No hypoglycemia Nonsystemic LDL-C
10/20/12
Class
Insulin
Mechanism
Advantages Disadvantages Cost

Hypoglycemia Weight gain ? Mitogenicity Injectable Training requirements Stigma Variable
Activates insulin Universally receptor effective Glucose Unlimited efficacy disposal Microvascular Hepatic glucose risk production
10/20/12
Therapeutic options: Insulin

- Human Regular - Basal analogues (glargine, detemir) - Rapid analogues (lispro, aspart, glulisine) - Pre-mixed varieties
- Human Neutral protamine Hagedorn (NPH)
10/20/12
Therapeutic options: Insulin

Rapid (Lispro, Aspart, Glulisine) Short (Regular) Intermediate (NPH)
Insulin level
Long (Detemir)
Long (Glargine) 22
0 24 10/20/12
10 12 14 s Hours after injection
Hour
16
18
20
Implementation strategies:
- Initial therapy - Advancing to dual combination therapy - Advancing to triple combination therapy - Transitions to & titrations of insulin
10/20/12
Fig. 2. T2DM Antihyperglycemic Therapy: General
Fig. 3. Sequential Insulin Strategies
Age Weight Sex / racial / ethnic / genetic differences Comorbidities
Coronary artery disease Heart Failure Chronic kidney disease Liver dysfunction Hypoglycemia
10/20/12
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 ambitious targets Less
-
10/20/12
HbA1c <7.58.0% if tighter targets not easily achieved Focus on drug safety Diabetes Care 2012;35:13641379
Weight
-
Majority of T2DM patients overweight / obese Intensive lifestyle program Metformin GLP-1 receptor agonists ? Bariatric surgery Consider LADA in lean patients
10/20/12
T2DM Anti-hyperglycemic Therapy: General
Adapted Recommendations: When Goal is to
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)
10/20/12
Comorbidities
-
Coronary Disease (UKPDS) Avoid hypoglycemia Heart Failure ? SUs & ischemic Renal disease preconditioning Liver dysfunction ? Pioglitazone & CVD events Hypoglycemia ? Effects of incretin-based therapies
Metformin: CVD benefit
10/20/12
Comorbidities
-
Coronary Disease Heart Failure
unless condition is unstable or severe Renal disease Avoid TZDs Liver dysfunction ? Effects of incretinbased therapies Hypoglycemia
Metformin: May use
10/20/12
Comorbidities
-
Coronary Disease Heart Failure Renal disease hypoglycemia Metformin & lactic acidosis Liver dysfunction US: stop @SCr 1.5 Hypoglycemia (1.4 women) UK: half-dose @GFR < 45 & stop @GFR < 30 Caution with SUs (esp. glyburide) DPP-4-is doseDiabetes Care 2012;35:13641379 adjust for
Increased risk of
10/20/12
Comorbidities
-
Coronary Disease Heart Failure Renal disease Liver dysfunctionadvanced liver disease Pioglitazone may help Hypoglycemia steatosis Insulin best option if disease severe
Most drugs not tested in
10/20/12
Comorbidities
-
Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia

Emerging concerns
10/20/12
regarding association with increased morbidity / mortality Proper drug selection is key in the hypoglycemia prone Diabetes Care 2012;35:13641379
T2DM Anti-hyperglycemic Therapy: General
Guidelines for Glucose, BP, & Lipid Control American Diabetes Assoc. Goals
HbA1C Preprandial glucose Postprandial glucose Blood pressure
< 7.0% (individualization) 70-130 mg/dL (3.9-7.2 mmol/l) < 180 mg/dL < 130/80 mmHg LDL:
< 100 mg/dL (2.59 mmol/l) < 70 mg/dL (1.81 mmol/l) (with overt CVD) Lipids HDL: > 40 mg/dL (1.04 mmol/l) > 50 mg/dL (1.30 mmol/l) HDL = high-density lipoprotein; LDL = low-density
lipoprotein; PG = plasma glucose; TG = triglycerides. ADA. Diabetes Care 2012;35:S11S63
4. FUTURE DIRECTIONS / RESEARCH NEEDS
Comparative effectiveness research

Focus on important clinical outcomes
Contributions of genomic research Perpetual need for clinical judgment!
10/20/12
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.) Care 2012;35:13641379 Diabetes 10/20/12
Invited Reviewers
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 Geralyn Spollett, Yale University, New Haven, CT Ellie Strock, Intl Diabetes Center, Minneapolis, MN Agathocles Tsatsoulis, University of Ioannina, Greece Andrew Wolf, Univ of Virginia Charlottesville, VA 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
Bernard Zinman, University of Toronto, Ontario, Canada Devan Kansagara, Oregon H&S Univ, Practice Committee, American Diabetes Association Professional Portland, OR Panel for Overseeing Guidelines and Statements, European Association for the Study of Diabetes
10/20/12
American Association of Diabetes Educators

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

Diabetes Care 2012;35:13641379 Diabetologia 2012;55:15771596

John B. Buse MD, PhD

University of North Carolina, Chapel Hill, NC

University of Pisa, Pisa, Italy

Univ. of Southern California, Los Angeles, CA

Diabeteszentrum, Bad Lauterberg, Germany

Apostolos Tsapas MD, PhD

Thomas Jefferson University, Philadelphia, PA

Aristotle University, Thessaloniki, Greece

Silvio E. Inzucchi MD (co-chair) 10/20/12

David R. Matthews MD, DPhil (cochair) Oxford University, Oxford, UK

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

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

Implementation Strategies - Initial drug therapy

Chronic kidney disease, Liver dysfunction,

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

Explore, where possible, therapeutic

Utilize decision aids.

Shared decision making final decisions re:

choices ultimately lie with the Diabetes Care 2012;35:13641379

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

Diabetes Care 2012;35:13641379 Diabetologia 2012;55:15771596

CDCs Division of Diabetes Translation. National Diabetes Surveillance System available

The Diabetes Epidemic: Global Projections, 20102030

IDF. Diabetes Atlas 5th Ed. 2011

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

Diabetes Care 2012;35:13641379 Diabetologia 2012;55:15771596

Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials

Initial Trial Long Term Followup * in

Kendall DM, Bergenstal RM. International Diabetes Center 2009

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

Overview of the pathogenesis of

- Deranged adipocyte biology - Decreased incretin effect

Main Pathophysiological Defects in T2DM pancrea

gut carbohydr ate delivery & absorption

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

- HbA1c < 7.0% (mean PG 150-160 mg/dl [8.38.9 mmol/l])

hypoglycemia prone, Care 2012;35:13641379 Diabetes etc.

Click to edit Master subtitle style

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

Therapeutic options: Lifestyle

- Weight optimization - Healthy diet

Diabetes Care 2012;35:13641379 Diabetologia 2012;55:15771596

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

Therapeutic options: Oral agents & non-insulin injectables

- Metformin - Sulfonylureas - Thiazolidinediones - DPP-4 inhibitors - GLP-1 receptor agonists

Inhibits glucosidase Slows carbohydrate absorption

Table 1. Properties of anti-

No hypoglycemia Nonsystemic Post-prandial glucose ? CVD events

Diabetes Care 2012;35:13641379 Diabetologia 2012;55:15771596

Modest A1c ? Pancreatitis Urticaria GI ? Pancreatitis Medullary ca Injectable

Activates GLP-1 receptor Insulin, glucagon gastric emptying satiety

Bile acid Binds bile acids sequestran Hepatic glucose ts production

No hypoglycemia Nonsystemic LDL-C

Table 1. Properties of anti-

Advantages Disadvantages Cost

Click to edit Master subtitle style

Table 1. Properties of anti-

Diabetes Care 2012;35:13641379 Diabetologia 2012;55:15771596

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

Therapeutic options: Insulin