Clinical Guidelines for Treatment of Type 2 Diabetes
Transcript of Clinical Guidelines for Treatment of Type 2 Diabetes
Clinical Guidelines for Treatment of Type 2 Diabetes
Carol H. Wysham, MDClinical Associate Professor of Medicine
University of WashingtonSection Head, Rockwood Center for Diabetes and Endocrinology
Disclosure Information
• Consultant: Amylin Pharmaceuticals, Boerhinger Ingelheim, Eli Lilly & Co, Johnson and Johnson, Sanofi U.S.
• Research funding (paid to institution): Amylin Pharmaceuticals, Boerhinger Ingelheim, Eli Lilly & Co, Intarcia, Johnson and Johnson, Merck, NovoNordisk, Sanofi U.S.
• Speakers Bureau: Amylin Pharmaceuticals, Boerhinger Ingelheim, Eli Lilly & Co, Johnson and Johnson, Merck, NovoNordisk, Sanofi U.S.
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%
2009
2009
CDC Diabetes Data & Trends. National Surveillance Date. http://www.cdc.gov/diabetes/statistics. Accessed 2/8/12.
The Diabetes Epidemic: Global Projections, 2010–2030
IDF. Diabetes Atlas 5th Ed. 2011
ADA/EASD Revised Consensus Statement (2009)
David Nathan et al. Diabetes Care 2009; 32:193-203
Tier 1 : Well-validated core therapies
At diagnosis:
Lifestyle+
Metformin
Step 1
Lifestyle + Metformin+
Intensive Insulin
Step 3
Lifestyle + Metformin+
PioglitazoneNo hypglycemiaOedema/CHF
Bone loss
Lifestyle + Metformin+
GLP-1 agonistb
No hypglycemiaWeight loss
Nausea/Vomitting
Lifestyle + Metformin+
Pioglitazone+
Sulphonylureas
Lifestyle + Metformin+
Basal insulin
Tier 2 : Less well-validated core therapies
Lifestyle + Metformin+
Basal Insulin
Lifestyle + Metformin+
Sulphonlyureasa
Step 2
a A Sulphonylurea other than Glibenclamide or Chlorpropamide b Insufficient clinical use to be confident regarding safety.
Critical Question following the „ADA-EASD- Consensus“
• Should all patients be treated following an identical algorythm irrespective of their age, co-morbidity, beta- cell function, insulin-resistant state, and risk for hypoglycemia?
• Most likely not, since type 2 diabetes is a rather hereogenous disease
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;35:1364–1379Diabetologia 2012;55:1577–1596
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
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, AustraliaHenk Bilo, Isala Clinics, Zwolle, NetherlandsJohn Boltri, Wayne State University, Detroit, MIThomas Buchanan, Univ of So California, LA, CAPaul Callaway, University of Kansas,Wichita, KSBernard Charbonnel, University of Nantes, France Stephen Colagiuri, The University of Sydney, AustraliaSamuel Dagogo-Jack, Univ of Tenn, Memphis, TNMargo 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, Austr
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, Greece
Andrew Wolf, Univ of Virginia Charlottesville, VA
Bernard Zinman, University of Toronto, Ontario, Canada
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
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;35:1364–1379Diabetologia 2012;55:1577–1596
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 2012;35:1364–1379Diabetologia 2012;55:1577–1596
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 lie with the patient.
Diabetes Care 2012;35:1364–1379Diabetologia 2012;55:1577–1596
Informed Medical Decision
22% of U.S. patients take less of the medication than is prescribed
American Heart Association: Statistics you need to know. http://www.americanheart.org/presenter.jhtml?identifier=107
Accessed November 21, 2007.
Medication Adherence
Why Don’t Patients Adhere to Their Medication Therapy?
Side effects
Dosing frequency
Complex regimen
Failure to explain benefits and side effects of medications
Failure of the provider to understand cost of treatment
Having a poor therapeutic relationshipwith patient
Benner JS, Glynn RJ, Mogun H, Neumann PJ, Weinstein MC, Avorn J. Long‐term persistence in use of statin
therapy in elderly patients. JAMA 2002;288:455‐461
Osterberg L, et al. N Engl J Med. 2005;353:487‐497.
Patient satisfaction with their health care provider
ADA‐EASD Position Statement: Management of Hyperglycemia in T2DM
2. BACKGROUND
• Relationship of glycemic control to outcomes
Diabetes Care 2012;35:1364–1379Diabetologia 2012;55:1577–1596
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. Kendall DM, Bergenstal RM. ©© International Diabetes Center 2009International Diabetes Center 2009UK 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)
++
Peripheralglucose uptake Hepatic
glucose production
Pancreatic Insulin/amylinsecretion
Pancreatic glucagonsecretion
Main Pathophysiological Defects in Type 2 Diabetes
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 hypoglycemia
PG = plasma glucose Diabetes Care 2012;35:1364–1379Diabetologia 2012;55:1577–1596
Figure 1Diabetes Care 2012;35:1364–1379
Diabetologia 2012;55:1577–1596(Adapted with permission from: Ismail-Beigi et al. Ann Intern Med 2011;154:554)
3. ANTI‐HYPERGLYCEMIC THERAPY
• Therapeutic options: Lifestyle
‐ Weight optimization
‐ Healthy diet
‐ Increased activity level
Diabetes Care 2012;35:1364–1379Diabetologia 2012;55:1577–1596
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 2012;35:1364–1379Diabetologia 2012;55:1577–1596
ADA‐EASD Position Statement: Management of Hyperglycemia in T2DM
ClassClass MechanismMechanism AdvantagesAdvantages DisadvantagesDisadvantages CostCostBiguanides(Metformin)
• Activates AMP‐ kinase• Hepatic glucose production
• Extensive experience• No hypoglycemia• Weight neutral• ? CVD events
• Gastrointestinal• Lactic acidosis• B‐12 deficiency• Contraindications
Low
SUs / Meglitinides
• Closes KATP channels• Insulin secretion
• Extensive experience• Microvascular risk
• Hypoglycemia• Weight gain• Low durability• ? Ischemic preconditioning
Low
TZDs • Activates PPAR‐• Insulin sensitivity
• No hypoglycemia• Durability• TGs, HDL‐C • ? CVD events (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.
Diabetes Care 2012;35:1364–1379Diabetologia 2012;55:1577–1596
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 receptor• 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• Post‐prandial glucose
• GI• Modest A1c • Injectable• Hypo w/ insulin• Dosing frequency
High
Bile acid sequestrant s
• Binds bile acids• Hepatic glucose production
• No hypoglycemia• Nonsystemic• LDL‐C
• GI• Modest A1c• TGs• Dosing frequency
High
Dopamine‐2agonists
• Activates DA receptor• Modulates hypothalamic control of metabolism• Insulin sensitivity
• No hypoglycemia• ? CVD events
• Modest A1c• Dizziness/syncope• Nausea• Fatigue
High
ClassClass MechanismMechanism AdvantagesAdvantages DisadvantagesDisadvantages CostCostInsulin • Activates insulin
receptor• Glucose disposal• Hepatic glucose production
• Universally effective• Unlimited efficacy• Microvascular risk
• Hypoglycemia• Weight gain• ? Mitogenicity• Injectable• Training requirements• “Stigma”
Variabl e
Table 1. Properties of anti‐hyperglycemic agentsDiabetes Care 2012;35:1364–1379
Diabetologia 2012;55:1577–1596
3. ANTI‐HYPERGLYCEMIC THERAPY
• Therapeutic options: Insulin
‐ Human Neutral protamine Hagedorn (NPH)
‐ Human Regular
‐ Basal analogues (glargine, detemir)
‐ Rapid analogues (lispro, aspart, glulisine)
‐ Pre‐mixed varieties
Diabetes Care 2012;35:1364–1379Diabetologia 2012;55:1577–1596
ADA‐EASD Position Statement: Management of Hyperglycemia in T2DM
3. ANTI‐HYPERGLYCEMIC THERAPY
• Therapeutic options: Insulin
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
Insulin
level
Intermediate (NPH)
ADA‐EASD Position Statement: Management of Hyperglycemia in T2DM
Fig. 3. Sequential Insulin Strategies in T2DM Diabetes Care 2012;35:1364–1379Diabetologia 2012;55:1577–1596
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 2012;35:1364–1379Diabetologia 2012;55:1577–1596
ADA‐EASD Position Statement: Management of Hyperglycemia in T2DM
SulfonylureasSulfonylureas GlinidesGlinides
Liver
Pancreas
aa‐‐Glucosidase InhibitorsGlucosidase Inhibitors
Bile acid sequestrantsBile acid sequestrants
Gut
Muscle
HyperglycemiaHyperglycemia
AdiposeTissue
Therapy for Type 2 Diabetes: Sites of Action
DPPDPP--IV IV inhibitors inhibitors
Insulin
Insulin Insulin
GLP-1Ra
GLP-1Ra
GLP-1Ra
GlitazonesGlitazones
GlitazonesGlitazones
GlitazonesGlitazonesBiguanidesBiguanides
Biguanides
Glu
cose
(mg/
dL)
Bod
y W
eigh
t
Diabetesdiagnosis
50
100
150
200
250
300
350
Fasting glucose
Years
Rel
ativ
e A
mou
nt
-10 -5 0 5 10 15 20 25 30
Insulin resistance
Insulin level
Onset
High risk for diabetes
0
50
100
150
200
250
-15
Natural History of Type 2 Diabetes
Postmeal glucose
Incretin effectβ-cell function
Body weight
Kendall DM, et al. Am J Med. 2009;122(suppl 6):S37-S50. Simonson G, et al. Diabetes Manage. 2011;1:175-189.
Diabetes Care, Diabetologia. 19 April 2012 .[Epub ahead of print]
Initial drug monotherapy
Efficacy ( HbA1c) Hypoglycemia Weight Side effects Costs
Healthy eating, weight control, increased physical activity
Metformin high low risk neutral/loss GI / lactic acidosis low
If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (order not meant to denote any specific preference):
Metformin +
Metformin +
Metformin +
Metformin +
Metformin +
Efficacy ( HbA1c) Hypoglycemia Weight Major side effect(s) Costs
high low risk gain edema, HF, fx’s‡ high
Thiazolidine- dione
intermediate low risk neutral rare‡
high
DPP-4 Inhibitor
highest high risk gain hypoglycemia‡
variable
Insulin (usually basal)
Two drug combinations*
Sulfonylurea† +
Thiazolidine-dione +
DPP-4 Inhibitor +
GLP-1 receptor agonist +
Insulin (usually basal) +
Metformin +
Metformin +
Metformin +
Metformin +
Metformin +
TZD
DPP-4-i
GLP-1-RA
Insulin§
SU†
DPP-4-i
GLP-1-RA
Insulin§
SU† SU†
TZD TZD
TZD
DPP-4-i
Insulin§ Insulin§
If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months, proceed to a more complex insulin strategy, usually in combination with 1-2 non-insulin agents:
Insulin#
Three drug combinations
More complex insulin strategies
or
or
or
or
or
or
or
or
or
or
or
or GLP-1-RA
high low risk loss GI‡ high
GLP-1 receptor agonist
Sulfonylurea†
high moderate risk gain hypoglycemia‡ low
If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination (order not meant to denote any specific preference):
T2DM Antihyperglycemic Therapy: General RecommendationsDiabetes Care, Diabetologia. 19 April 201[Epub ahead of print]
A1c Reduction of Oral Therapies Added onto Metformin (compared to placebo)
Phung O, Scholle J, Talwar M et al. JAMA 2010;303:1410‐1418
Comparison of Therapies Added onto Metformin (compared to placebo)
Phung O, Scholle J, Talwar M et al. JAMA 2010;303:1410‐1418
Hanefeld (n=500)
Charbonnel (n=630)
CHICAGO (n=462)
ADOPT (n=2897)
UKPDS (n=1573)
-2
-1
0
1
Cha
nge
in A
1C (%
)
Time (yrs)0 1 2 3 4 5 6 10
GlimepirideGlyburide
Glyburide
Glyburide
Gliclazide
Mazzone T. JAMA. 2006;296:2572-2581. Hanefeldd M. Cur Med Res Opin. 2006;22:1211-1215. Nissen SE. JAMA. 2008;299:1567-1573. UKPDS Study Group. Lancet.1998;352:837-853Charbonnel B. Diabetoogia. 2005;48(6):1093-1104.
Durability of Glycemic Control with Sulfonylurea Therapy
Glycemic control deteriorates with standard therapies
Cook MN et al. Diabetes Care. 2005;28:995‐1000.
N = 2220 with T2DM treated with SU + MET
≥109.0‐9.98.0‐8.94.0‐7.9
~85% of patients had A1C ≥8% after 4 years
Patients with
A1C ≥8%(%)
SU = sulfonylurea, MET = metformin
Pre‐SU A1C levels (%)100
80
60
40
20
00 1 2 3 4
Time from sulfonylurea initiation (years)
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
•Hypoglycemia
• Emerging concerns regarding association with increased mortality
• Associated with prolonged QT and arrhythmias
• Hypoglycemia due to Insulin and sulfonylureas represents at least 10% of ER visits for adverse drug reactions
• Proper drug selection in the hypoglycemia prone
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Diabetes Care, Diabetologia. 19 April 2012 .[Epub ahead of print]
When Goal is to Avoid Hypoglycemia
Concerns about Weight in Diabetes
• From 2007-2008 NHANES data, 32% of men and 36% of women are obese1
• Incidence of diabetes has doubled over the past 3 decades, primarily amongst obese individuals2
• In the NHANES data, the gains in life expectancy from smoking cessation are beginning to be outweighed by loss of life expectancy from obesity3
• Recent report: Increase of BMI by ≥ 1 kg/m2 after diagnosis: 63% increase CV death over 4.6 yrs4
1.
Flegal KM et al. JAMA 2010;303;235‐412.
Fox CS et al Circulation 2006;113:2914‐8
3.
Stewart ST et al. N Engl J Med 2009;361:2252‐604.
Bodegard J et al. Presented at EASD 2012
Initial drug monotherapy
Efficacy ( HbA1c) Hypoglycemia Weight Side effects Costs
Healthy eating, weight control, increased physical activity
Metformin high low risk neutral/loss GI / lactic acidosis low
Metformin +
Metformin +
Metformin +
Metformin +
Metformin +
Efficacy ( HbA1c) Hypoglycemia Weight Major side effect(s) Costs
high low risk gain edema, HF, fx’s‡ high
Thiazolidine- dione
intermediate low risk neutral rare‡
high
DPP-4 Inhibitor
highest high risk gain hypoglycemia‡
variable
Insulin (usually basal)
Two drug combinations*
Sulfonylurea† +
Thiazolidine-dione +
DPP-4 Inhibitor +
GLP-1 receptor agonist +
Insulin (usually basal) +
Metformin +
Metformin +
Metformin +
Metformin +
Metformin +
TZD
DPP-4-i
GLP-1-RA
Insulin§
SU†
DPP-4-i
GLP-1-RA
Insulin§
SU† SU†
TZD TZD
TZD
DPP-4-i
Insulin§ Insulin§
Insulin# (multiple daily doses)
Three drug combinations
More complex insulin strategies
or
or
or
or
or
or
or
or
or
or
or
or GLP-1-RA
high low risk loss GI‡ high
GLP-1 receptor agonist
Sulfonylurea†
high moderate risk gain hypoglycemia‡ low
If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (order not meant to denote any specific preference):
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
When Goal is to Avoid Weight Gain
Initial drug monotherapy
Efficacy ( HbA1c) Hypoglycemia Weight Side effects Costs
Healthy eating, weight control, increased physical activity
Metformin high low risk neutral/loss GI / lactic acidosis low
Metformin +
Metformin +
Metformin +
Metformin +
Metformin +
Efficacy ( HbA1c) Hypoglycemia Weight Major side effect(s) Costs
high low risk gain edema, HF, fx’s‡ high
Thiazolidine- dione
intermediate low risk neutral rare‡
high
DPP-4 Inhibitor
highest high risk gain hypoglycemia‡
variable
Insulin (usually basal)
Two drug combinations*
Sulfonylurea† +
Thiazolidine-dione +
DPP-4 Inhibitor +
GLP-1 receptor agonist +
Insulin (usually basal) +
Metformin +
Metformin +
Metformin +
Metformin +
Metformin +
TZD
DPP-4-i
GLP-1-RA
Insulin§
SU†
DPP-4-i
GLP-1-RA
Insulin§
SU† SU†
TZD TZD
TZD
DPP-4-i
Insulin§ Insulin§
If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months, proceed to a more complex insulin strategy, usually in combination with 1-2 non-insulin agents:
Insulin# (multiple daily doses)
Three drug combinations
More complex insulin strategies
or
or
or
or
or
or
or
or
or
or
or
or GLP-1-RA
high low risk loss GI‡ high
GLP-1 receptor agonist
Sulfonylurea†
high moderate risk gain hypoglycemia‡ low
If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (order not meant to denote any specific preference):
If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination (order not meant to denote any specific preference):
When Goal is to Minimize Costs
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Features to Include in a Cost AnalysisOral Agents GLP‐1RA Insulin
Drug Cost $ to $$$ $$$$ $ to $$$$
Hypoglycemia 0 to 0 to SMBG Need + + +++
Weight Gain None to some Loss Some
Training + ++ +++
Follow‐up + + +++
Reduction in other
Medications
Usually None Some None
Beta‐Cell Preservation
TZD’s=YesOthers=No/unk
nown
Unknown Maybe
Diabetes Care, Diabetologia. 19 April 2012 .[Epub ahead of print]
Comparison of 3 Insulin Regimens: 4-T Study
Enrollment and Year 11 Receiving OAD or dual OAD (A1c 7%-10%), N=708
Biphasic BID, n=235
Prandial TID, n=239
Basal QD (or BID), n=234
If unacceptable A1c in Year 1, sulfonylurea replaced with second insulin type
Prandial at midday, n=159 (67.7%)2
+ +Basal at bedtime,
n=176 (73.6%)
+Prandial TID, n=191 (81.6%)
n=201 (86%) n=188 (79%) n=189 (81%)
Year 3: Completion
4-T, Treating to Target in Type 2 Diabetes; A1c, glycosylated hemoglobin; OAD, oral antidiabetic drug. 1.Holman RR et al. N Engl J Med. 2007;357(17):1716-1730. 2.Holman RR et al. N Engl J Med. 2009;361(18):1736-1747.
Patie
nts
With
A1c
≤6.
5%, %
4-T Study Outcomes: A1C Goal Achieved
Baseline A1C, 8.5%. 4-T, Treating to Target in Type 2 Diabetes; A1C, glycosylated hemoglobin.1. Holman RR et al. N Engl J Med. 2007;357(17):1716-1730. 2. Holman RR et al. N Engl J Med. 2009;361(18):1736-1747.
Biphasic Prandial Basal
17.0
31.9
23.9
44.8
8.1
43.2
0
10
20
30
40
50
Year 11 Year 32
P<.001
P=.001
P=.006
P=.03
4-T Study Outcomes: Insulin Doses
4-T, Treating to Target in Type 2 Diabetes.1. Holman RR et al. N Engl J Med. 2007;357(17):1716-1730. 2. Holman RR et al. N Engl J Med. 2009;361(18):1736-1747.
Year 11 Year 32
Insu
lin D
ose,
IU/d
0
20
40
60
80
100
BiphasicPrandialBasal
4-T Study Outcomes: Weight Change
4-T, Treating to Target in Type 2 Diabetes.1. Holman RR et al. N Engl J Med. 2007;357(17):1716-1730. 2. Holman RR et al. N Engl J Med. 2009;361(18):1736-1747.
Wei
ght C
hang
e Fr
om B
asel
ine,
kg
4.7
5.75.76.4
1.9
3.6
0
1
2
3
4
5
6
7
Year 11 Year 32
P<.001
P<.001
P<.001
P=.005P=.005
Biphasic Prandial Basal
Diabetes Care, Diabetologia. 19 April 2012 .[Epub ahead of print]
Adding Exenatide BID to Optimized Glargine in T2DM Improves Glycemic Control Without Increasing Hypoglycemia
Incidence of hypoglycemia was similar in both groups; 1 patient in GLAR + PBO group had severe hypoglycemia
a P < .001 between-group difference.b P < .01 between-group difference.Results from 30-week RCT in 259 patients with T2DM. Buse J, et al. Ann Intern Med. 2011;154:103-112.
Parameter GLAR + EXN BID vs
GLAR + PBO
P
A1C, % −0.69 < .001
Weight, kg −2.74 < .001
b
aa
a
aa
234
216
198
180
144
126
Fasti
ng
Glucose Level (m
g/dL)
162
108
Mor
ning 2
‐h PP
G
Midd
ay pr
emea
l
Midd
ay 2‐
h PPG
Even
ing pr
emea
l
Even
ing 2‐
h PPG
0300
hour
s
GLAR + EXN BID, baselineGLAR + PBO, baselineGLAR + EXN BID, 30 wkGLAR + PBO, 30 wk
Liraglutide QD With Detemir QD Improves Glycemic Control in T2DM Over 38 Weeks
Incidence of hypoglycemia was similar in both groups; no major hypoglycemia occurred in either group
No major hypoglycemia occurred in any group during weeks 12to 38.Transient nausea occurred in 21% of patients during weeks 0 to 12, 4% of patients during weeks 12 to 38.
DeVries JH, et al. Diabetes Care. 2012 May 18. [Epub ahead of print];Rosenstock J, et al. Diabetes. 2011;60(suppl 1):A76 [abstr 276-OR].
Parameter LIRA + DET + MET vs LIRA + MET
P
A1C, % −0.52 < .0001
Weight, kg 0.79 .03
LIRA + DET + MET (n = 162)
LIRA + MET (n = 161)
234
198
180
162
108
90
Self‐Measured Plasma
Glucose (m
g/dL)
126
Befo
re di
nner
Bedt
ime
90 m
in af
ter
dinne
r
90 m
in af
ter
lunch
Befo
re lu
nch
90 m
in af
ter
brea
kfast
Befo
re br
eakfa
st
144
216
P = .0003
P = .0244
P = .0141
Decision Points for Choosing Drug Therapy
• Efficacy – BG and A1c lowering• Safety:
– Hypoglycemia risk– Side effects
• Effect on weight• CV risk factors:
– Outcome studies• Patient acceptance:
– Oral versus injected– Frequency of administration– Cost
• Desirable mechanism of action
Guidelines for Glycemic, Blood Pressure and Lipid Control
HDL = high-density lipoprotein; LDL = low-density lipoprotein; PG = plasma glucose; TG = triglycerides.
ADA. Diabetes Care. 2012;35:S11-63.
American Diabetes Association Goals
A1c < 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)