presentation - university of montana · type 2 diabetes and obesity: evolving treatment stragies...

3/27/2013

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Type 2 Diabetes and Obesity:Evolving Treatment Stragies

Christopher Sorli, MD/PhD, FACEChair, Department of Diabetes, Endocrinology and Metabolism

Billings ClinicBillings, MT

Pathogenesis of Type 2 Diabetes

HGP=hepatic glucose production.

Islet -cell

ImpairedInsulin Secretion

IncreasedHGP

Decreased GlucoseUptake

Metformin

SUsInsulin

Insulin

NHANES1988-1994

Advances in Therapy, but Falling Short of Goals

5

6

7

8

9

10

1980s 1990s 2000s

Hb

A1c

(%)

SU / Insulin Metformin (1995) TZDs (1999) Incretins (2004)

Pre-DCCT9.0%

7.7

NHANES1999-2000

7.8

NHANES2001-2002

7.5

NHANES2003-2004

7.2

Future6.0% ?

1997: ADA lowered T2DM diagnosis from FPG ≥140

mg/dLto ≥126 mg/dL

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

General ADA Target: <7%

1998: UKPDS results published

2008: ACCORD, ADVANCE, VADT, and UKPDS 80 published

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Type 2 Diabetes Evolving Treatment Strategies

Mortality

intensive

standard

HR = 1.22(95% CI =1.01-1.46)

p = 0.04

NHANES1988-1994

Advances in Therapy, but Falling Short of Goals

5

6

7

8

9

10

1980s 1990s 2000s

Hb

A1c

(%)

SU / Insulin Metformin (1995) TZDs (1999) Incretins (2004)

Pre-DCCT9.0%

7.7

NHANES1999-2000

7.8

NHANES2001-2002

7.5

NHANES2003-2004

7.2

Future6.0% ?

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%

2009: ADA added “less stringent” HbA1c goal for patients with significant comorbidities or risk of hypoglycemia, or short

life expectancy

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GroupA1C

Targets

Intensification ThresholdsA1C > 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

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Pathogenesis of Type 2 Diabetes

HGP=hepatic glucose production.

Islet -cell


IncreasedHGP


The Ominous Octet

Islet -cell


NeurotransmitterDysfunction


Islet -cell

IncreasedGlucagon Secretion

IncreasedLipolysis

Increased GlucoseReabsorption

IncreasedHGP

DecreasedIncretin Effect

Metabolic syndrome Hyperglycemia

Failing -cellFunctional -cell

Heine RJ, Spijkerman AM. 2006.

Insulin resistance Insulin resistance

Type 2 Diabetes: A HeterogeneousDisorder

CVD

Cancer

Retinopathy

Neuropathy

Nephropathy

70-80% of

population

20-30% of

population

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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 ApproachPosition Statement of the American Diabetes Association (ADA) and

the European Association for the Study of Diabetes (EASD)

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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]

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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


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

Leptin

Amylin

InsulinGLP-1

GlicentinOxyntomodulin

Ghrelin

GIP

Adiponectin

Visfatin

Resistin

Glucagon

CCK

Adapted from Badman MK and Flier JS; Science 2006: 307, 1909-1914

PYY3-36

Incretins (injectables)

Exenatide – Bydureon, ByettaLiraglutide - Victoza

DPP-IV Inhibitors(orals)

Sitagliptin – JanuviaLinagliptin – TradjentaSaxagliptin - Onglyza

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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 Strategies

Islet -cell




Islet -cell


IncreasedLipolysis


IncreasedHGP

DecreasedIncretin 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

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T2DM – Treatment Strategies

Islet -cell




Islet -cell


IncreasedLipolysis


IncreasedHGP



GLP-1(weight loss)

GLP-1 > DPP-IV

Incretin TherapyEffect on Energy Homeostasis

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T2DM– Treatment Strategies

Islet -cell




Islet -cell


IncreasedLipolysis


IncreasedHGP



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)

Incretins:Expanding Role in Treatment Strategies

Pediatric Type 1 Diabetics (n=8)

Insulin dose reduced 20%with exenatide dosing – mixed meal

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Incretins (DPP-IV inhibitors):Special Populations: Geriatrics

Pharmacology Recommendations•Metformin – still first line for most

• Less effective in many• GFR - <30 – no, 30-50 reduce dose

•Glyburide – never•DPP-IV inhibitors - recommended



• Comorbidities

‐ Coronary Disease

‐ Heart Failure

‐ Renal disease

‐ Liver dysfunction

‐ Hypoglycemia

Metformin: CVD benefit (UKPDS)

Avoid hypoglycemia

? SUs & ischemic preconditioning

? Pioglitazone & CVD events

? Effects of incretin‐based therapies


Stomach

Islet

GI Tract

Brain



Visceral Fat Cell

Vagal Afferents

Leptin

Amylin

InsulinGLP-1


Ghrelin

GIP

Adiponectin

Visfatin

Resistin

Glucagon

CCK


PYY3-36

Cardiovascular

IncretinsExenatide – Bydureon, Byetta

Liraglutide - Victoza

DPP-IV InhibitorsSitagliptin – Januvia

Linagliptin – TradjentaSaxagliptin - Onglyza

Cardiovascular Outcome TrialsTECOS - sitagliptin

EXSCEL – weekly exenatideLEADER – liraglutideELIXA – lixisenitideSAVOR - saxagliptin

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ACCORD:Mortality Hazard Ratios for Post-Randomization Prescription of Glycemia Medications

Adjusted for Baseline Participant CharacteristicsACCORD Study Group. Presented at the ADA Scientific Sessions, San Francisco, June 2008

RR


Exenatide vs. Non-Exenatide – Cardiovascular Events



• Comorbidities


‐ Heart Failure

‐ Renal disease


‐ Hypoglycemia

Metformin: CVD benefit (UKPDS)

Avoid hypoglycemia

? SUs & ischemic preconditioning

? Pioglitazone & CVD events

? Effects of incretin‐based therapies


Glyburide (and older) – Should never be usedGlimepiride or Glipizide if any SU

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• Comorbidities


‐ Heart Failure

‐ Renal disease


‐ Hypoglycemia Emerging concerns regarding

association with increasedmortality

Proper drug selection in the hypoglycemia prone


Adapted Recommendations: When Goal is to Avoid HypoglycemiaDiabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

T2DM– Treatment Strategies

Islet -cell




Islet -cell


IncreasedLipolysis


IncreasedHGP


TZDs

TZDs

TZDs

TZDsTZDs

TZDs

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Slide Source:Lipids Online Slide Librarywww.lipidsonline.org

Time to Fatal/Nonfatal MI(Excluding Silent MI)

Kapl

an-M

eier

Eve

nt R

ate

Prespecified Analysis

0 6 12 18 24 30 36

Time from Randomization (Months)

Time to Acute Coronary Syndrome

Kapl

an-M

eier

Eve

nt R

ate

Post Hoc Exploratory Analysis

0 6 12 18 24 30 36

Time from Randomization (Months)

–28% –37%

Reprinted with permission from Erdmann E et al. J Am Coll Cardiol. 2007;49:1772-1780.Copyright © 2007 American College of Cardiology Foundation. All rights reserved.

Pioglitazone (65/1230)Placebo (88/1215)

Pioglitazone (35/1230)Placebo (54/1215)

PROactive: Pioglitazone Reduced “Hard”Coronary Heart Disease Endpoints

Pioglitazone vs Placebo:HR 0.72 (95% CI 0.52–0.99);

p=0.045

Pioglitazone vs Placebo:HR 0.63 (95% CI 0.41–0.97);

p=0.035

Type 2 Diabetes: Benefits vs Risks of TZDs

Type 2 Diabetes: Benefits vs Risks of TZDs

But????Actos causes Bladder Cancer!!!...Right?

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T2DM Anti‐hyperglycemic Therapy: General RecommendationsDiabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

The Ominous Octet – Treatment Strategies

Islet -cell




Islet -cell


IncreasedLipolysis


IncreasedHGP


Insulin

Insulin

Insulin

InsulinInsulin

Insulin

New Basal Insulins: insulin degludec molecular structure

DesB30 LysB29(Nε-γ-glu-hexadecandioyl) human insulinDegludec

(Tresiba)

s

s

s

F V N Q H L C G S H L V E A L Y L V C G E R G F F Y T P

G I V E Q C T S I C S L Y Q L E N Y C NC

s

s s

A chain

B chainK

Hexadecandioyl

L-g-Glu

desB30 Insulin

T

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Multi-hexamer formation after injection

Insulin degludec in pen

Long multi-hexamer chains assemble

[ Phenol; Zn2+]

Injection site

Jonassen I et al. Diabetes. 2010;59(suppl 1):A11

Insulin degludec multi-hexamers

Main picture shows elongated IDeg structures in absence of phenol; inset (white box) shows absence of elongated IDeg structures in presence of phenol.

Kurtzhals P et al. ADA 2011;32-LB (MoP + NN1250-1993)Kurtzhals P. EASD 2011; 092-P #1049 (MoP + NN1250-1993)

Following injection

[Zn2+ ]

Insulin degludec multi-hexamers

Subcutaneous depot

Monomers are absorbed from the depot into the circulation

- zinc

As zinc slowly diffuses out of the multi-hexamers, insulin degludec

monomers are formed

Jonassen I et al. Diabetes. 2010;59(suppl 1):A11

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Clamp profile in type 2 diabetes: ultra-long, flat and consistent

Glu

cose

infu

sion

rat

e (m

g/(k

g*m

in))

5

4

3

2

1

0

Treatment

IDeg 100 U/mL 0.4 U/kg

IDeg 100 U/mL 0.8 U/kgIDeg 100 U/mL 0.6 U/kg

Nosek L et al. ADA 2011;49-LB (NN1250-1987)Nosek L. EASD 2011; 093-P #1055 (NN1250-1987)

Consistently lower within-subject variability over time for insulin degludec

Heise et al. Diabetes 2011;60(Suppl. 1):A263c

IDeg

Consistently lower within-subject variability over time for insulin degludec

IDegIGlar

Heise et al. Diabetes 2011;60(Suppl. 1):A263c

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IDeg OD+ metformin ±DPP-4 (n=773)

IGlar OD + metformin ±DPP-4 (n=257)

Insulin-naïve patients with type

2 diabetes(n=1030)

0 52 weeksInclusion criteria• Type 2 diabetes ≥6 months• Insulin naïve treated with

metformin ± SU, DPP-4 or acarbose for ≥3 months

• HbA1C 7.0–10.0%• BMI ≤40 kg/m2

• Age ≥18 years

Study designONCE LONG (3579)

Randomized 3:1 (IDeg OD:IGlar OD)Open label

NN1250-3579; IDeg OD vs IGlar OD in T2DM.

DPP-4: dipeptidyl peptidase-4 inhibitorSU: sulphonylureaOD: once-daily

Nocturnal confirmed hypoglycemiaONCE LONG (3579)

36% lower ratewith IDeg OD

p<0.05

NN1250-3579; IDeg OD vs IGlar OD in T2DM.

IDeg OD (n=766)IGlar OD (n=257)

SAS Comparisons: Estimates adjusted for multiple covariates

JM2

Reduction in confirmed hypoglycemia with

degludec (all IDeg vs. IGlar studies,

maintenance period)

*statistically significant improvement

Overall

NocturnalT1 and T2 32%*

T2 basal only 49%*

16%*T1 and T228%*T2 basal only

http://www.novonordisk.com/images/investors/investor_presentations/2011/CMD2011/04_Diabetes_treatment_tomorrow_CMD2011.pdf’

Maintenance period

Pre-specified hypoglycemia meta-analyses Type 1 & type 2 diabetes

JM2 Graph is picture. SDM will source slide with graph as graph.Jackson, Meryn, 2/23/2012

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Treatment Strategies for Type 2 Diabetes (My Approach – T2DM + Metabolic Syndrome)

Islet -cell




Islet -cell


IncreasedLipolysis


IncreasedHGP


GLP-1

GLP-1

GLP-1

GLP-1

GLP-1

Insulin

Insulin

Insulin

Insulin

Insulin

Insulin

Metformin

Exercise

Exercise

Exercise

Exercise Exercise

TZDs

TZDs

TZDs

TZDs TZDs

TZDs



• Weight

- Majority of T2DM patients overweight / obese

- Intensive lifestyle program

- Metformin

- GLP‐1 receptor agonists

- ? Bariatric surgery

- Consider LADA in lean patients


Energy Balance and Body Weight:Simple Right?

Body WeightEnergy In(Caloric Intake)

Energy Out(Metabolism)

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Stomach

Islet

GI Tract

Brain


Evolving Treatment Strategies:The Complexity of Energy Homeostasis

Visceral Fat Cell

Vagal Afferents

Leptin

Amylin

InsulinGLP-1


Ghrelin

GIP

Adiponectin

Visfatin

Resistin

Glucagon

CCK


PYY3-36

The Science ofWillpower

Energy Homeostasis - Metabolic Syndrome Set Point Theory

Genetics, Age, Activity Level, Health, Stress

Evolving Treatment Strategies:The Complexity of Energy Homeostasis

Artificial sweetners lead to weight gain?

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Energy Balance and Body Weight:What is Metabolism?



Energy Homeostasis:The Quick Fix?

The Diet StrategyFailure Rate of Diet Alone 90-98%

Weight

Baseline

Counter-Regulation

New Set Point

↓ 5-10%

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Weight ManagementCounter-Regulation and the Failure of the “Diet” – HCG Diet

Weight LossCounter-Regulation and the Failure of the “Diet” –

Ideal Protein

295

Ideal Protein Diet↓ 28%

211

308

Fatigue, Depression, Fibromyalgia,Sleep Disorder,

“Must be something hormonal”

Energy Balance and Body Weight:What is Metabolism?



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Low MetabolismHow Do I Fix It? – “Get Your Ducks in a Row”

• Sleep Problems – Sleep Apnea

• Vitamin D Deficiency

• Thyroid

• Vitamin B12

• Low Testosterone (male)

• Medications (centrally acting)

Energy Homeostasis:The Miracle Pill?

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Energy Homeostasis:The Search for the Magic Pill?

SubstratesGlucose

AminoacidsFree Fatty Acids

Lipids

HormonesInsulinLeptinGhrelin

PYYCCK

Adiponectin

MechanicalGastric Distension

NeuralVagal Afferents

PsychologicalPleasureRewardVisual

OlfactoryTaste

Hypothalmus

Dopamine, CannabanoidsNorepinephrine, NPY

Serotonin, POMC,GABA etc…

Sibutramine(Meridia)

Topiramate(Topomax)

Phentermine

Rimonobant

Qsymia(phentermine +

topiramate)

Contrave(bupropion + naltrexone)

Energy Balance CenterBelviqLorcaserin (5HT2C)

BelviqLorcaserin (5HT2C)

Weight Loss Pills

Empatic(bupropion + zonisamide)

Tesofensine(NS2330) 4-8% Total body weight loss

Not sustainable20-30% Non-response rate

BelviqN=8,000 52-104 weeks

Weight Loss: 3-3.7% over placebo

47% loss >5%

Dosing: 10mg BID

QsymiaN=3,700 52-104 weeks

Weight Loss: 6.7-8.9% over placebo

70% loss >5%

Dosing: 3.75/23mg, 7.5/46mg, 11.25/69mg, 15/92mg

The Ominous Octet – Treatment Strategies

Islet -cell




Islet -cell


IncreasedLipolysis


IncreasedHGP


Surgery?

ADA Clinical Practice Recommendations 2011:Changing Treatment Paradigms

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Energy Homeostasis:A Role for Surgery?

Lap BandRestriction of caloric intake

Gastric Bypass (Roux-En-Y)Restriction of caloric intakeMalabsorption of nutrients

X

Gastric Bypass: Five Operations

CONFIDENTIAL


1. Isolation of gastric cardia

CONFIDENTIAL

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2. Exclusion of distal stomach

CONFIDENTIAL


3. Exclusion of duodenum and proximal jejunum

CONFIDENTIAL


4. Exposure of distal jejunum to undigested nutrients

CONFIDENTIAL

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5. Partial vagotomy

CONFIDENTIAL

Energy Homeostasis:A Role for Surgery?

Sleeve GastrectomyStomach becomes a “sleeve”Alters signaling mechanismsIndependent glycemic effect

Metabolic Surgery: The STAMPEDE Trial

Type 2 DM, A1c > 7.0%, BMI 27 - 43

N = 150, single center, one surgeon

Intensive Medical Therapy

No Surgery

Sleeve Gastrectomy

Gastric Bypass

Primary Outcome: Proportion with A1c < 6.0% at 12 months

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THE END

Metabolic Surgery: The STAMPEDE Trial -Results

presentation - university of montana · type 2 diabetes and obesity: evolving treatment stragies...

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