ADA EASD Management of hyperglycemia in type 2

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)

Writing Group
American Diabetes Association European Assoc. for the Study of Diabetes

Richard M. Bergenstal MD Michaela Diamant MD, PhD
Int’l Diabetes Center, Minneapolis, MN VU University, Amsterdam, The Netherlands

John B. Buse MD, PhD Ele Ferrannini MD
University of North Carolina, Chapel Hill, NC 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) David R. Matthews MD, DPhil (co-chair)
Yale University, New Haven, CT 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]

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

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.



2. BACKGROUND
• Epidemiology and health care impact


Age-adjusted Percentage of U.S. Adults with
Obesity or Diagnosed Diabetes
Obesity (BMI ≥30 kg/m2)
O
O 1994 2000 2009
B
B
E
E
S
S
II
T
T
Y
Y
No Data <14.0% 14.0-17.9% 18.0-21.9% 22.0-25.9% >26.0%

Diabetes
D
D 1994 2000 2009
II
A
A
B
B
E
E
T
T
E
E
S
S
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

The Diabetes Epidemic: Global Projections,
2010–2030

IDF. Diabetes Atlas 5th Ed. 2011


2. BACKGROUND
• Relationship of glycemic control to outcomes


Impact of Intensive Therapy for Diabetes:
Summary of Major Clinical Trials
Study Microvasc CVD Mortality
UKPDS      
DCCT / EDIC*      
ACCORD   
ADVANCE   
VADT   
Initial Trial

Long Term Follow-up

* in T1DM


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


Main Pathophysiological Defects in T2DM
pancreatic
incretin insulin
effect secretion
pancreatic
glucagon

gut
−
− secretion ?
carbohydrate
delivery &
absorption HYPERGLYCEMIA

−
−
+
+
peripheral
hepatic glucose
glucose uptake
production Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011


•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 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)


•Therapeutic options: Lifestyle

-Weight optimization

-Healthy diet

- Increased activity level


• Therapeutic options:
Oral agents & non-insulin injectables

- Metformin - Meglitinides
- Sulfonylureas - α-glucosidase inhibitors
- Thiazolidinediones - Bile acid sequestrants
- DPP-4 inhibitors - Dopamine-2 agonists
- GLP-1 receptor agonists - Amylin mimetics


Class Mechanism Advantages Disadvantages Cost
Biguanides • Activates AMP-kinase • Extensive experience • Gastrointestinal Low
• ↓ Hepatic glucose • No hypoglycemia • Lactic acidosis
production • Weight neutral • B-12 deficiency
• ? ↓ CVD • Contraindications
SUs / • Closes KATP channels • Extensive experience • Hypoglycemia Low
Meglitinides • ↑ Insulin secretion • ↓ Microvasc. risk • Weight gain
• Low durability
• ? Ischemic
preconditioning
TZDs • PPAR-γ activator • No hypoglycemia • Weight gain High
• ↑ insulin sensitivity • Durability • Edema / heart failure
• ↓ TGs, ↑ HDL-C • Bone fractures
• ? ↓ CVD (pio) • ? ↑ MI (rosi)
• ? Bladder ca (pio)

α-GIs • Inhibits • No hypoglycemia • Gastrointestinal Mod.
α−glucosidase • Nonsystemic • Dosing frequency
• Slows carbohydrate • ↓ Post-prandial • Modest ↓ A1c
absorption glucose
• ? ↓ CVD events
Table 1. Properties of anti-hyperglycemic agents Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

DPP-4 • Inhibits DPP-4 • No hypoglycemia • Modest ↓ A1c High
inhibitors • Increases GLP-1, GIP • Well tolerated • ? Pancreatitis
• Urticaria
GLP-1 • Activates GLP-1 R • Weight loss • GI High
receptor • ↑ Insulin, ↓ glucagon • No hypoglycemia • ? Pancreatitis
agonists • ↓ gastric emptying • ? Beta cell mass • Medullary ca
• ↑ satiety • ? CV protection • Injectable
Amylin • Activates amylin • Weight loss • GI High
mimetics receptor • ↓ PPG • Modest ↓ A1c
• ↓ glucagon • Injectable
• ↓ gastric emptying • Hypo w/ insulin
• ↑ satiety • Dosing frequency
Bile acid • Bind bile acids • No hypoglycemia • GI High
sequestrants • ↓ Hepatic glucose • Nonsystemic • Modest ↓ A1c
production • ↓ Post-prandial • Dosing frequency
glucose
• ↓ CVD events
Dopamine-2 • Activates DA receptor • No hypoglyemia • Modest ↓ A1c High
agonists • Modulates hypothalamic • ? ↓ CVD events • Dizziness/syncope
control of metabolism • Nausea
• ↑ of anti-hyperglycemic agents Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Table 1. Propertiesinsulin sensitivity • Fatigue

Insulin • Activates insulin • Universally • Hypoglycemia Variable
receptor effective • Weight gain
• ↑ peripheral glucose • Unlimited efficacy • ? Mitogenicity
uptake • ↓ Microvascular • Injectable
risk • Training
requirements
• “Stigma”

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


•Therapeutic options: Insulin
- Neutral protamine Hagedorn (NPH)
- 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 2 4 6 8
Hours
10 12 14 16 18 20 22 24
Hours after injection


•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
T2DM Antihyperglycemic Therapy: General Recommendations [Epub ahead of print]

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

equential Insulin Strategies in T2DM Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]


•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
Less ambitious
HbA1c <7.5–8.0% if tighter
HbA1c <7.5–8.0% if tighter
targets not easily achieved
targets not achieved
Focus on drug safety
Focus on


•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 [Epub ahead of print]

Adapted Recommendations: When Goal is to Avoid Weight Gain [Epub ahead of print]


•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  Metformin: CVD benefit (UKPDS)
 Metformin: CVD benefit (UKPDS)
-Coronary Disease  Avoid hypoglycemia
 Avoid hypoglycemia
-Heart Failure  ? SUs & ischemic
 ? SUs & ischemic
preconditioning
preconditioning
-Renal disease
 ? Pioglitazone & ↓ CVD events
 ? Pioglitazone & ↓ CVD events
-Liver dysfunction  ? Effects of incretin-based
 ? Effects of incretin-based
-Hypoglycemia therapies
therapies



•Comorbidities
-Coronary Disease  Metformin: May use unless
 Metformin: May use unless
-Heart Failure condition is unstable or severe
condition is unstable or severe
 Avoid TZDs
 Avoid TZDs
-Renal disease
-Liver dysfunction therapies
therapies
-Hypoglycemia



•Comorbidities
-Coronary Disease
-Heart Failure  Increased risk of hypoglycemia
 Increased risk of hypoglycemia
-Renal disease  Metformin & lactic acidosis
 Metformin & lactic acidosis
US: stop @SCr ≥ 1.5 (1.4
US: stop @SCr ≥ 1.5 (1.4
-Liver dysfunction
women)
women)
-Hypoglycemia UK: ↓ dose @GFR <45 &
UK: ↓ dose @GFR <45 &
stop @GFR <30
stop @GFR <30
 Caution with SUs (esp. glyburide)
 Caution with SUs (esp. glyburide)
 DPP-4-i’s – dose adjust for most
 DPP-4-i’s – dose adjust for most
 Avoid exenatide if GFR <30
 Avoid exenatide if GFR <30


•Comorbidities
-Coronary Disease
-Heart Failure
-Renal disease
 Most drugs not tested in
 Most drugs not tested in
-Liver dysfunction advanced liver disease
advanced liver disease
-Hypoglycemia  Pioglitazone may help steatosis
 Pioglitazone may help steatosis
 Insulin best option if disease
 Insulin best option if disease
severe
severe



•Comorbidities
-Coronary Disease
-Heart Failure
-Renal disease
-Liver dysfunction
 Emerging concerns regarding
 Emerging concerns regarding
-Hypoglycemia association with increased
association with increased
mortality
mortality
 Proper drug selection in the
 Proper drug selection in the
hypoglycemia prone
hypoglycemia prone


Adapted Recommendations: When Goal is to Avoid Hypoglycemia[Epub ahead of print]

Adapted Recommendations: When Goal is to Minimize Costs [Epub ahead of print]

Guidelines for Glycemic, BP, & Lipid Control
American Diabetes Assoc. Goals
HbA1C < 7.0% (individualization)
Preprandial
70-130 mg/dL (3.9-7.2 mmol/l)
glucose
Postprandial
< 180 mg/dL
glucose
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
ADA. Diabetes Care. 2012;35:S11-63
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.)


Invited Reviewers
James Best, The University of Melbourne, AU Ilias Migdalis, NIMTS Hospital, Athens, Greece
Henk Bilo, Isala Clinics, Zwolle, NL Donna Miller, Univ of So California, LA, CA
John Boltri, Wayne State University, Detroit, MI Robert Ratner, MedStar/Georgetown Univ, DC
Thomas Buchanan, Univ of So California, LA, CA Julio Rosenstock, Dallas Diab/Endo Ctr, Dallas, TX
Paul Callaway, University of Kansas,Wichita, KS
Guntram Schernthaner, Rudolfstiftung Hosp, Vienna, AT
Bernard Charbonnel, University of Nantes, France
Robert Sherwin, Yale University, New Haven, CT
Stephen Colagiuri, The University of Sydney, AS
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, Int’l Diabetes Center, Minneapolis, MN
Cynthia Fritschi, University of Illinois, Chicago, IL
Rowan Hillson, Hillingdon Hospital, Uxbridge, U.K. Agathocles Tsatsoulis, University of Ioannina, GR

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, CA
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 EASD Management of hyperglycemia in type 2

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