treatment strategies for diabetes and obesity: update 2013 christopher sorli, md/phd, face chair,...
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Treatment Strategies for Diabetes and Obesity:Treatment Strategies for Diabetes and Obesity:Update 2013Update 2013
Christopher Sorli, MD/PhD, FACEChair, Department of Diabetes,
Endocrinology and MetabolismBillings ClinicBillings, MT
Pathogenesis of Type 2 DiabetesPathogenesis of Type 2 Diabetes
HGP=hepatic glucose production.
Islet -cell
ImpairedImpairedInsulin SecretionInsulin SecretionImpairedImpairedInsulin SecretionInsulin Secretion
IncreasedIncreasedHGPHGPIncreasedIncreasedHGPHGP
Decreased GlucoseDecreased GlucoseUptakeUptakeDecreased GlucoseDecreased GlucoseUptakeUptake
Metformin
SUsInsulin
Insulin
NHANESNHANES1988-19941988-1994
Advances in Therapy, Advances in Therapy, but Falling Short of Goalsbut Falling Short of Goals
5
6
7
8
9
10
1980s1980s 1990s1990s 2000s 2000s
Hb
AH
bA
1c1c (
%)
(%
)
SU / InsulinSU / InsulinSU / InsulinSU / Insulin Metformin (1995)Metformin (1995)Metformin (1995)Metformin (1995) TZDs (1999)TZDs (1999)TZDs (1999)TZDs (1999) Incretins (2004)Incretins (2004)Incretins (2004)Incretins (2004)
Pre-DCCTPre-DCCT9.0%9.0%
7.7
NHANESNHANES1999-20001999-2000
7.8
NHANESNHANES2001-20022001-2002
7.5
NHANESNHANES2003-20042003-2004
7.2
FutureFuture6.0% ?6.0% ?
1997: ADA lowered T2DM diagnosis from FPG ≥140
mg/dLto ≥126 mg/dL
1997: ADA lowered T2DM diagnosis from FPG ≥140
mg/dLto ≥126 mg/dL
2003: ADA eliminated HbA1c “action point” of <8% from
guidelines
2003: ADA eliminated HbA1c “action point” of <8% from
guidelines
SU=sulfonylurea; TZDs=thiazolidinediones; T2DM=type 2 diabetes.
Koro CE, et al. Diabetes Care. 2004;27:17-20; Hoerger TJ, et al. Diabetes Care. 2008;31:81-86.
2005: ADA added HbA1c goal of <6% for “individual patients” to guidelines
2005: ADA added HbA1c goal of <6% for “individual patients” to guidelines
General ADA Target: <7%General ADA Target: <7%
1998: UKPDS results published
1998: UKPDS results published
2008: ACCORD, ADVANCE, VADT, and UKPDS 80 published
2008: ACCORD, ADVANCE, VADT, and UKPDS 80 published
Type 2 Diabetes Evolving Treatment Strategies
Mortality
intensive
standard
HR = 1.22(95% CI =1.01-1.46)
p = 0.04
NHANESNHANES1988-19941988-1994
Advances in Therapy, Advances in Therapy, but Falling Short of Goalsbut Falling Short of Goals
5
6
7
8
9
10
1980s1980s 1990s1990s 2000s 2000s
Hb
AH
bA
1c1c (
%)
(%
)
SU / InsulinSU / InsulinSU / InsulinSU / Insulin Metformin (1995)Metformin (1995)Metformin (1995)Metformin (1995) TZDs (1999)TZDs (1999)TZDs (1999)TZDs (1999) Incretins (2004)Incretins (2004)Incretins (2004)Incretins (2004)
Pre-DCCTPre-DCCT9.0%9.0%
7.7
NHANESNHANES1999-20001999-2000
7.8
NHANESNHANES2001-20022001-2002
7.5
NHANESNHANES2003-20042003-2004
7.2
FutureFuture6.0% ?6.0% ?
SU=sulfonylurea; TZDs=thiazolidinediones; T2DM=type 2 diabetes.
Koro CE, et al. Diabetes Care. 2004;27:17-20; Hoerger TJ, et al. Diabetes Care. 2008;31:81-86.
General ADA Target: <7%General ADA Target: <7%
2009: ADA added “less stringent” HbA1c goal for patients with significant comorbidities or risk of hypoglycemia, or short
life expectancy
2009: ADA added “less stringent” HbA1c goal for patients with significant comorbidities or risk of hypoglycemia, or short
life expectancy
GroupA1C
Targets
Intensification Thresholds
A1C> 50% of SMBG Results/4
Days
Intensive
< 6% > 5.9%Fasting > 100 (5.6)
OR2 Hr PP > 140 (7.8)Even if the A1C is
<6.0Rx was reduced in the presence of significant hypoglycemia.
Mortality Primary outcome (composite nonfatal MI,
nonfatal stroke, CVD death)
Diabetes Management StrategiesMaking Sense of ACCORD
Mortality vs Treatment A1c
10 x less
10 x more
Death Rate vs Drop in A1c
No drop in A1c = higher death rate
Pathogenesis of Type 2 DiabetesPathogenesis of Type 2 Diabetes
HGP=hepatic glucose production.
Islet -cell
ImpairedImpairedInsulin SecretionInsulin SecretionImpairedImpairedInsulin SecretionInsulin Secretion
IncreasedIncreasedHGPHGPIncreasedIncreasedHGPHGP
Decreased GlucoseDecreased GlucoseUptakeUptakeDecreased GlucoseDecreased GlucoseUptakeUptake
The Ominous OctetThe Ominous Octet
Islet -cell
ImpairedImpairedInsulin SecretionInsulin SecretionImpairedImpairedInsulin SecretionInsulin Secretion
NeurotransmitterNeurotransmitterDysfunctionDysfunction
Decreased GlucoseDecreased GlucoseUptakeUptakeDecreased GlucoseDecreased GlucoseUptakeUptake
Islet -cell
IncreasedIncreasedGlucagon SecretionGlucagon SecretionIncreasedIncreasedGlucagon SecretionGlucagon Secretion
IncreasedIncreasedLipolysisLipolysisIncreasedIncreasedLipolysisLipolysis
Increased GlucoseIncreased GlucoseReabsorptionReabsorptionIncreased GlucoseIncreased GlucoseReabsorptionReabsorption
IncreasedIncreasedHGPHGPIncreasedIncreasedHGPHGP
DecreasedDecreasedIncretin EffectIncretin Effect
DecreasedDecreasedIncretin EffectIncretin Effect
Metabolic syndrome Hyperglycemia
Failing -cellFunctional -cell
Heine RJ, Spijkerman AM. 2006.
Insulin resistance Insulin resistance
Type 2 Diabetes: A HeterogeneousType 2 Diabetes: A HeterogeneousDisorderDisorder
CVD
Cancer
Retinopathy
Neuropathy
Nephropathy
70-80% of
population
20-30% of
population
DIABETES/OBESITYManagement Strategies
Insulin ResistanceMetabolic Syndrome
Energy Storage
Insulin SupplyBeta Cell Dysfunction
Hyperglycemia
Insulin Resistance
β cell function
Years of Diabetes/Metabolic Syndrome
RelativeFunction 100 (%)
-20 -10 0 10 20 30
β cell mass
Adapted from IDC, Minneapolis, MN
Macrovascular Risk/ Cancer Risk
Prevention!Intensive managment of
Insulin resistanceβ cell dysfunction
CVD risks
Damage Control!Less intensive glycemic goals
Avoid hypoglycemia
History of Diabetes Therapy:What More Could We Possibly Want?
Animal Insulin
1922 1950’s 1982-85 1995 1996 2001 2003 2005 2007 2009
Sulfonylurea
Human Insulin
Metformin
Lispro
Glitazones
Glinides
Aspart
Exenatide
Pramlintide
Detemir
Sitagliptin
Bromocriptine
Saxagliptin
2013
Liraglutide
SGLT-2 inhib
11-β-HSD1 inhib
The End of Protocol Driven Therapy
Weekly Exenatide
DegludecGlucagon R antangonists
Management of Hyperglycemia in Type 2Diabetes: A Patient-Centered Approach
Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)
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, 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)
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS•Weight
-Majority of T2DM patients overweight / obese-Intensive lifestyle program-Metformin-GLP-1 receptor agonists-? Bariatric surgery-Consider LADA in lean patients
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Adapted Recommendations: When Goal is to Avoid Weight GainDiabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Stomach
Islet
GI Tract
Brain
HypothalmusHind Brain
Peptide Therapeutics:Incretins (GLP-1 and GIP)
Visceral Fat Cell
Vagal Afferents
LeptinLeptin
AmylinAmylin
InsulinInsulinGLP-1GLP-1
GlicentinGlicentinOxyntomodulinOxyntomodulin
GhrelinGhrelin
GIPGIP
AdiponectinAdiponectin
VisfatinVisfatin
ResistinResistin
GlucagonGlucagon
CCKCCK
Adapted from Badman MK and Flier JS; Science 2006: 307, 1909-1914
PYY3-36PYY3-36
Incretins (injectables)
Exenatide – Bydureon, Byetta Liraglutide - Victoza
DPP-IV Inhibitors(orals)
Sitagliptin – JanuviaLinagliptin – TradjentaSaxagliptin - Onglyza
Incretins (injectables)
Exenatide – Bydureon, Byetta Liraglutide - Victoza
DPP-IV Inhibitors(orals)
Sitagliptin – JanuviaLinagliptin – TradjentaSaxagliptin - Onglyza
Incretins:GLP-1 Agonists vs. DPP-IV Inhibitors
Pharmacology vs PhysiologyDPP-IV – increases endogenous
GLP-1GLP-1 agonist – super physiologic
effect
…Not quite that simple
Differential Effects:Glycemic ControlEnergy Balance
T2DM – Treatment StrategiesT2DM – Treatment Strategies
Islet -cell
ImpairedImpairedInsulin SecretionInsulin SecretionImpairedImpairedInsulin SecretionInsulin Secretion
NeurotransmitterNeurotransmitterDysfunctionDysfunction
Decreased GlucoseDecreased GlucoseUptakeUptakeDecreased GlucoseDecreased GlucoseUptakeUptake
Islet -cell
IncreasedIncreasedGlucagon SecretionGlucagon SecretionIncreasedIncreasedGlucagon SecretionGlucagon Secretion
IncreasedIncreasedLipolysisLipolysisIncreasedIncreasedLipolysisLipolysis
Increased GlucoseIncreased GlucoseReabsorptionReabsorptionIncreased GlucoseIncreased GlucoseReabsorptionReabsorption
IncreasedIncreasedHGPHGPIncreasedIncreasedHGPHGP
DecreasedDecreasedIncretin EffectIncretin Effect
DecreasedDecreasedIncretin EffectIncretin EffectGLP-1 > DPP IV
(A1c, FPG, -cell function)
GLP-1 > DPP-IV
Incretins (Exenatide):Sustained Efficacy- Improved Beta Cell Function
Buse et.al., Oct 2012, EASD, Berlin
T2DM – Treatment StrategiesT2DM – Treatment Strategies
Islet -cell
ImpairedImpairedInsulin SecretionInsulin SecretionImpairedImpairedInsulin SecretionInsulin Secretion
NeurotransmitterNeurotransmitterDysfunctionDysfunction
Decreased GlucoseDecreased GlucoseUptakeUptakeDecreased GlucoseDecreased GlucoseUptakeUptake
Islet -cell
IncreasedIncreasedGlucagon SecretionGlucagon SecretionIncreasedIncreasedGlucagon SecretionGlucagon Secretion
IncreasedIncreasedLipolysisLipolysisIncreasedIncreasedLipolysisLipolysis
Increased GlucoseIncreased GlucoseReabsorptionReabsorptionIncreased GlucoseIncreased GlucoseReabsorptionReabsorption
IncreasedIncreasedHGPHGPIncreasedIncreasedHGPHGP
DecreasedDecreasedIncretin EffectIncretin Effect
DecreasedDecreasedIncretin EffectIncretin EffectGLP-1 > DPP IV
(A1c, FPG, -cell function)
GLP-1(weight loss)
GLP-1 > DPP-IV
Incretin TherapyIncretin TherapyEffect on Energy HomeostasisEffect on Energy Homeostasis
T2DM– Treatment StrategiesT2DM– Treatment Strategies
Islet -cell
ImpairedImpairedInsulin SecretionInsulin SecretionImpairedImpairedInsulin SecretionInsulin Secretion
NeurotransmitterNeurotransmitterDysfunctionDysfunction
Decreased GlucoseDecreased GlucoseUptakeUptakeDecreased GlucoseDecreased GlucoseUptakeUptake
Islet -cell
IncreasedIncreasedGlucagon SecretionGlucagon SecretionIncreasedIncreasedGlucagon SecretionGlucagon Secretion
IncreasedIncreasedLipolysisLipolysisIncreasedIncreasedLipolysisLipolysis
Increased GlucoseIncreased GlucoseReabsorptionReabsorptionIncreased GlucoseIncreased GlucoseReabsorptionReabsorption
IncreasedIncreasedHGPHGPIncreasedIncreasedHGPHGP
DecreasedDecreasedIncretin EffectIncretin Effect
DecreasedDecreasedIncretin EffectIncretin EffectGLP-1 > DPP IV
(A1c, FPG, -cell function)
GLP-1(weight loss)
GLP-1 > DPP-IV
GLP-1 > DPP IV(glucagon inhibition, FPG,
Prandial control)
GLP-1 > DPP IV(Glucagon inhibition, FPG,
Prandial control)
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