treatment strategies for diabetes and obesity: update 2013 christopher sorli, md/phd, face chair,...

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


7.8


7.5


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


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


7.8


7.5


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




The Ominous OctetThe Ominous Octet

Islet -cell


NeurotransmitterNeurotransmitterDysfunctionDysfunction


Islet -cell

IncreasedIncreasedGlucagon SecretionGlucagon SecretionIncreasedIncreasedGlucagon SecretionGlucagon Secretion

IncreasedIncreasedLipolysisLipolysisIncreasedIncreasedLipolysisLipolysis

Increased GlucoseIncreased GlucoseReabsorptionReabsorptionIncreased GlucoseIncreased GlucoseReabsorptionReabsorption


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




Islet -cell






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




Islet -cell








GLP-1(weight loss)

GLP-1 > DPP-IV

Incretin TherapyIncretin TherapyEffect on Energy HomeostasisEffect on Energy Homeostasis

T2DM– Treatment StrategiesT2DM– Treatment Strategies

Islet -cell




Islet -cell








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)

treatment strategies for diabetes and obesity: update 2013 christopher sorli, md/phd, face chair,...

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