Ada 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)
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
Univ. of Southern California, Los Angeles, CA
Michael Nauck MD
Diabeteszentrum, Bad Lauterberg, Germany
Richard Wender MD
Thomas Jefferson University, Philadelphia, PA
Apostolos Tsapas MD, PhD

Aristotle University, Thessaloniki, Greece
Silvio E. Inzucchi MD (co-chair)

Yale University, New Haven, CT
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
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)
5. FUTURE DIRECTIONS / RESEARCH NEEDS

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 patients 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) 1994 O 2000 2009
B E S I T Y
Diabetes
No Data
<14.0%
14.0-17.9%
18.0-21.9%
22.0-25.9%
>26.0%
D I A B E T E S
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
Diabetes Care 2012;35:1364 1379
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 Follow-up * 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
Main Pathophysiological Defects in T2DM

incretin effect
pancreatic insulin secretion
pancreatic glucagon secretion
gut carbohydrate delivery & absorption
HYPERGLYCEMIA
hepatic glucose production
Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 20
+
peripheral glucose uptake
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 hypoglycemia PG = plasma glucose
Figure 1
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
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
Biguanides (Metformin )
Mechanism
Activates AMPkinase Hepatic glucose production
Advantages
Extensive experience No hypoglycemia Weight neutral ? CVD events Extensive experience Microvascular risk
Disadvantages
Gastrointestinal Lactic acidosis B-12 deficiency Contraindications Hypoglycemia Weight gain Low durability ? Ischemic preconditioning Weight gain Edema / heart failure Bone fractures ? MI (rosi) ? Bladder ca (pio) Gastrointestinal Dosing frequency Modest A1c
Cost
Low
SUs / Closes KATP Meglitinide channels s Insulin secretion
Low
TZDs
Activates PPAR-g Insulin sensitivity
No hypoglycemia Durability TGs, HDL-C ? CVD events (pio)
High
a-GIs
Inhibits aglucosidase Slows carbohydrate absorption
Table 1. Properties of anti-hyperglycemic agents
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 Activates GLP-1 receptor Insulin, glucagon gastric emptying satiety Activates amylin receptor glucagon gastric emptying satiety Binds bile acids Hepatic glucose production
Advantages
No hypoglycemia Well tolerated Weight loss No hypoglycemia ? Beta cell mass ? CV protection Weight loss Post-prandial glucose
Disadvantages Cost
Modest A1c ? Pancreatitis Urticaria GI ? Pancreatitis Medullary ca Injectable GI Modest A1c Injectable Hypo w/ insulin Dosing frequency GI Modest A1c TGs Dosing frequency High
High
Amylin mimetics
High
Bile acid sequestrant s
No hypoglycemia Nonsystemic LDL-C
High
Dopamine-2 Activates DA receptor agonists Modulates
No hypoglycemia ? CVD events
High Modest A1c Diabetes Care 2012;35:13641379

Diabetologia 2012;55:15771596
Class
Insulin
Mechanism
Activates insulin receptor Glucose disposal Hepatic glucose production
Advantages
Universally effective Unlimited efficacy Microvascular risk
Disadvantages
Hypoglycemia Weight gain ? Mitogenicity Injectable Training requirements Stigma
Cost
Variable
Therapeutic options: Insulin

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

Rapid (Lispro, Aspart, Glulisine) Insulin level Short (Regular)
Intermediate (NPH)
Long (Detemir)
Long (Glargine) 0 24 2 4 6 8 10 12 14 16 Hours after injection
Hours
18
20
22
Implementation strategies:
- Initial therapy
- Advancing to dual combination therapy

- Advancing to triple combination therapy - Transitions to & titrations of insulin
Diabetes Fig. 2. T2DM Antihyperglycemic Therapy: General Recommendations Care 2012;35:13641379 Diabetologia 2012;55:15771596
Fig. 3. Sequential Insulin Strategies in T2DM
Age Weight Sex / racial / ethnic / genetic differences Comorbidities
Coronary artery disease Heart Failure Chronic kidney disease Liver dysfunction Hypoglycemia
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 <7.58.0% if tighter targets not easily achieved Focus on drug safety
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
Adapted Recommendations: When Goal is to Avoid Weight Gain Diabetes Care 2012;35:13641379 Diabetologia 2012;55:15771596
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)
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
Comorbidities
Metformin: May use unless
condition is unstable or severe Avoid TZDs ? Effects of incretin-based therapies
Comorbidities
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-is dose adjust for most Avoid exenatide if GFR < 30
Comorbidities
Most drugs not tested in
advanced liver disease Pioglitazone may help steatosis Insulin best option if disease severe
Comorbidities
Emerging concerns regarding
association with increased morbidity / mortality Proper drug selection is key in the hypoglycemia prone
T2DM Anti-hyperglycemic Therapy: General Recommendations
Adapted Recommendations: When Goal is to Avoid Hypoglycemia Diabetologia 2012;55:15771596
Diabetes Care 2012;35:13641379
Adapted Recommendations: When Goal is to Minimize Costs
Guidelines for Glucose, BP, & Lipid Control

American Diabetes Assoc. Goals
HbA1C Preprandial glucose Postprandial glucose
< 7.0% (individualization)
70-130 mg/dL (3.9-7.2 mmol/l)

< 180 mg/dL
Blood pressure < 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) TG: < 150 mg/dL (1.69 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!
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.
Invited Reviewers
James Best, The University of Melbourne, Australia Ilias Migdalis, NIMTS Hospital, Athens, Greece 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 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, Aus
Robert Sherwin, Yale University, New Haven, CT Stephen Colagiuri, The University of Sydney, Australia Jay Skyler, University of Miami, Miami, FL Samuel Dagogo-Jack, Univ of Tenn, Memphis, TN Geralyn Spollett, Yale University, New Haven, CT Margo Farber, Detroit Medical Center, Detroit, MI Ellie Strock, Intl Diabetes Center, Minneapolis, MN Cynthia Fritschi, University of Illinois, Chicago, IL Rowan Hillson, Hillingdon Hospital, Uxbridge, U.K. Agathocles Tsatsoulis, University of Ioannina, Greece Faramarz Ismail-Beigi, CWR Univ, Cleveland, OH Andrew Wolf, Univ of Virginia Charlottesville, VA
Devan Kansagara, Oregon H&S Univ, Portland, OR Bernard Zinman, University of Toronto, Ontario, Canada 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 Society American College of Physicians

Ada 2012

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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

Apostolos Tsapas MD, PhD

Silvio E. Inzucchi MD (co-chair)

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

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

5. FUTURE DIRECTIONS / RESEARCH NEEDS

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

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

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

The Diabetes Epidemic: Global Projections, 20102030

IDF. Diabetes Atlas 5th Ed. 2011

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

Diabetes Care 2012;35:1364 1379

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

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

Overview of the pathogenesis of T2DM

Diabetes Care 2012;35:1364 1379

Main Pathophysiological Defects in T2DM

gut carbohydrate delivery & absorption

hepatic glucose production

Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 20

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

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

hypoglycemia prone, etc.

- Avoidance of hypoglycemia PG = plasma glucose

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

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

Therapeutic options: Lifestyle

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

SUs / Closes KATP Meglitinide channels s Insulin secretion

Activates PPAR-g Insulin sensitivity

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

Inhibits aglucosidase Slows carbohydrate absorption

Table 1. Properties of anti-hyperglycemic agents

No hypoglycemia Nonsystemic Post-prandial glucose ? CVD events

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

Bile acid sequestrant s

No hypoglycemia Nonsystemic LDL-C

Table 1. Properties of anti-hyperglycemic agents

Dopamine-2 Activates DA receptor agonists Modulates

No hypoglycemia ? CVD events

High Modest A1c Diabetes Care 2012;35:13641379

Table 1. Properties of anti-hyperglycemic agents

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

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

Therapeutic options: Insulin

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

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

Therapeutic options: Insulin

Long (Glargine) 0 24 2 4 6 8 10 12 14 16 Hours after injection

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

- Advancing to dual combination therapy

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

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

Fig. 3. Sequential Insulin Strategies in T2DM

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

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM