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)
OO 1994 2000 2009
BB
EE
SS
II
TT
YY
No Data <14.0% 14.0-17.9% 18.0-21.9% 22.0-25.9% >26.0%
Diabetes
DD 1994 2000 2009
II
AA
BB
EE
TT
EE
SS
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
secretion

gut
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 (Adapted with permission from: IsmailBeigi 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 - -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- activator • No hypoglycemia • Weight gain High

•  insulin sensitivity • Durability • Edema / heart failure
•  TGs,  HDL-C • Bone fractures
• ?  CVD (pio) • ?  MI (rosi)
• ? Bladder ca (pio)
-GIs • Inhibits • No hypoglycemia • Gastrointestinal Mod.

glucosidase • Nonsystemic • Dosing frequency
• Slows carbohydrate •  Post-prandial glucose • Modest  A1c
absorption • ?  CVD events
Table 1. Properties of anti-hyperglycemic agents
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
• ? CV protection • Injectable
•  satiety
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 glucose • Dosing frequency
•  CVD events
Dopamine-2 • Activates DA receptor • No hypoglyemia • Modest  A1c High
agonists • Modulates hypothalamic • ?  CVD events • Dizziness/syncope
control of metabolism • Nausea
•  insulin sensitivity • Fatigue
Insulin • Activates insulin • Universally • Hypoglycemia Variable
receptor effective • Weight gain
•  peripheral glucose • Unlimited efficacy • ? Mitogenicity
uptake •  Microvascular • Injectable
risk • Training
requirements
• “Stigma”
•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]
quential 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
targets

HbA1c
HbA1c <7.5–8.0%
<7.5–8.0% if tighter
targets
targets not
not easily achieved
achieved

Focus
Focus on drug
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 [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:
 Metformin: CVD
CVD benefit
benefit (UKPDS)
(UKPDS)
-Coronary Disease  Avoid
 Avoid hypoglycemia
hypoglycemia
-Heart Failure  ?? SUs
 SUs &
& ischemic
ischemic preconditioning
preconditioning
-Renal disease  ?? Pioglitazone
 &  CVD
Pioglitazone & CVD events
events
 ?? Effects
 Effects of
of incretin-based
incretin-based
-Liver dysfunction therapies
therapies
-Hypoglycemia
•Comorbidities
-Coronary Disease
 Metformin:
 Metformin: May
May use
use unless
unless
-Heart Failure condition
condition isis unstable
unstable oror severe
severe
-Renal disease  Avoid
 Avoid TZDs
TZDs
 ?? Effects
 Effects of
of incretin-based
incretin-based
-Liver dysfunction
therapies
therapies
-Hypoglycemia
•Comorbidities
-Coronary Disease
-Heart Failure  Increased
 Increased risk
risk of
of hypoglycemia
hypoglycemia
-Renal disease  Metformin
 Metformin & & lactic
lactic acidosis
acidosis
US:
US: stop
stop @SCr
@SCr ≥≥ 1.5
1.5 (1.4
(1.4
-Liver dysfunction
women)
women)
-Hypoglycemia
UK:  dose
UK: dose @GFR
@GFR <45<45 & &
stop
stop @GFR
@GFR <30<30
 Caution
 Caution with
with SUs
SUs (esp.
(esp. glyburide)
glyburide)
 DPP-4-i’s
 DPP-4-i’s –– dose
dose adjust
adjust for
for most
most
 Avoid
 Avoid exenatide
exenatide ifif GFR
GFR <30
<30
•Comorbidities
-Coronary Disease
-Heart Failure
-Renal disease
 Most
 Most drugs
drugs not
not tested
tested in
in
-Liver dysfunction advanced
advanced liver
liver disease
disease
-Hypoglycemia  Pioglitazone
 Pioglitazone may
may help
help steatosis
steatosis
 Insulin
 Insulin best
best option
option ifif disease
disease
severe
severe
•Comorbidities
-Coronary Disease
-Heart Failure
-Renal disease
-Liver dysfunction
 Emerging
 Emerging concerns
concerns regarding
regarding
-Hypoglycemia association
association with
with increased
increased
mortality
mortality
 Proper
 Proper drug
drug selection
selection in
in the
the
hypoglycemia
hypoglycemia prone
prone
T2DM Anti-hyperglycemic Therapy: General Recommendations [Epub ahead of print]
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:S1163
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 DagogoJack, 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 IsmailBeigi, 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

Management of Hyperglycemia in Type 2

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Management of Hyperglycemia in Type 2

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Management of Hyperglycemia in Type 2

Diabetes: A Patient-Centered Approach

Richard M. Bergenstal MD Michaela Diamant MD, PhD

John B. Buse MD, PhD Ele Ferrannini MD

Anne L. Peters MD Michael Nauck MD

Richard Wender MD Apostolos Tsapas MD, PhD

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

5. FUTURE DIRECTIONS / RESEARCH NEEDS

• Gauge patient’s preferred level of involvement.

Long Term Follow-up

- Increased activity level

SUs / • Closes KATP channels • Extensive experience • Hypoglycemia Low

TZDs • PPAR- activator • No hypoglycemia • Weight gain High

-GIs • Inhibits • No hypoglycemia • Gastrointestinal Mod.

Bile acid • Bind bile acids • No hypoglycemia • GI High

Rapid (Lispro, Aspart, Glulisine)

4. FUTURE DIRECTIONS / RESEARCH NEEDS

•Comparative effectiveness research

•Contributions of genomic research

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

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