Module i type 2 dm

Changing Technology: Redefining the Natural History of Type 2 Diabetes

Professor Roger Mazze

What characterizes the natural history of type 2

diabetes?

Normal

Pre-diabetes By HbA1c

By Diurnal Glucose Pattern

Impaired Glucose Tolerance

Overt Type 2 Diabetes Insulin Resistance

Insulin Deficiency

Impaired Incretin Function

Pre-diabetes

The Natural History of Type 2 Diabetes

Deterioration of Glucose Control

•Insulin Resistance•Insulin Deficiency•Incretin Dysfunction

Normal

Normal

SDM: Applications to Type 2 Diabetes Management

Classifying Diabetes: Underlying Defects

Type 2 Genetic predisposition:

80-90% concordance in identical twins

Environmental factor: obesity, inactivity

Excessive hepatic glucose output

insulin resistance/Insulin deficiency/Impaired incretin effect

GDM Genetic predisposition:

high

Environmental factor:

obesity

Prior exposure to

hyperglycemia in

pregnancy

Human Placental Lactogen

Insulin resistance/Insulin

deficiency

Type 1 Genetic predisposition:

50% concordance in

identical twins

Environmental factor:

virus

Auto-immune

destruction of the

pancreatic beta cells

Insulin deficiency

Priorities of Care for Adults with Diabetes

CVD Risk

ASA, tobacco, ACEI/ARB, statin

CVD Risk

ASA, tobacco, ACEI/ARB, statin

International Diabetes Center.

Diagnosis–PreventionDx Fasting Glucose > 126 Casual > 200 + Symptoms

Prevent Pre-diabetes (IFG-IGT) & Metabolic Syndrome

Diagnosis–PreventionDx Fasting Glucose > 126 Casual > 200 + Symptoms

Prevent Pre-diabetes (IFG-IGT) & Metabolic Syndrome

Self-Management Knowledge and SkillMonitoring Medication Problem solving Food plan & nutritionRisk reduction Living & coping Physical activity

Hemoglobin A1C Target < 7.0%

SMBGPre 70-120 mg/dL

2 hr. post < 160 mg/dL(~ 50% of readings)

Blood Pressure (every visit)

Dx and Rx < 130/80

Annual Lipid ProfileLDL < 100HDL > 40

Trigs < 150

DM + CVD LDL < 70

Annual ScreeningNephropathy

Microalbumin screeningCalculated GFR

RetinopathyDilated retinal exam

NeuropathyNeuro and foot exam

Sexual health

Hospital careFoot care

Dental careImmunizations

GlucoseGlucose Hypertension HypertensionLipidsLipids MicrovascularcomplicationsMicrovascularcomplications

Other essentialsof care

Other essentialsof care

SDM: Focusing on Type 2 Diabetes Management

Diagnosis of Type 2 DiabetesBlood Glucose and HbA1c Levels

Fasting

Diabetes >126 mg/dL

Normal 70-99 mg/dL

Impaired fasting glucose

100-125 mg/dL

Diabetes >200 mg/dL

Normal <140 mg/dL

Impaired glucosetolerance

140-199 mg/dL

OGTT

ADA Standards of Care. Diabetes Care, Suppl.1, 2010; ADA , EASD, IDF International

Expert Committee Report on HbA1c for Diagnosis of Diabetes.

Pre-diabetes(54 million)

Diabetes >6.5%

Normal <6.0%

High risk for diabetes 6.0-6.4%

HbA1c

New

ADA Clinical Practice Recommendations Diagnosis of Diabetes

A1C 6.5%– Test performed NGSP certified and standardized to DCCT*

FPG 126 mg/dl – No caloric intake for at least 8 hours

2 hour glucose 200 mg/dl during an OGTT– Test performed as per WHO (75 g glucose)

If classic symptoms of hyperglycemia = random glucose 200 mg/dl

PREDIABETES IFG or IGT

2-h PG > 2002-h PG 140 – 199 (IGT)2-h PG < 140

FPG > 126

FPG > 100 – 125 (IFG)FPG < 100

DIABETESNORMAL

A1c > 6.5%A1c 5.7 – 6.4%A1c < 5.7%

American Diabetes Association. Diabetes Care 323(Suppl 1), 2009

Confirming the Diagnosis with Repeat Testing

Risk Factors for Type 2 Diabetes (screening for asymptomatic patients)

Age > 45 years

Family history of type 2 diabetes in parents or siblings

Overweight or Obesity (BMI >25 kg/m²)

Habitual physical inactivity

Race/ethnicity e.g. Native American, African American, Hispanic, Asian American and Pacific Islanders

Previously identified pre-diabetes (IFG or IGT)

Hypertension >140/90 mmHg in adults

HDL <35 mg/dL and triglycerides >250 mg/dL

History of GDM or delivery of baby weighing >9 lbs.

Polycystic Ovary Syndrome/Acanthosis Nigricans

History of vascular disease

Source: American Diabetes Association, 2010

Treat to Target

HbA1c < 7%

Fasting and Pre meal glucose 70-120 mg/dL

(50% of the time)

Postprandial glucose <160 mg/dL

(Two hours after the start of a meal the BG should

be no more than 20 to 40 mg/dL above the pre-meal BG)

Bedtime glucose 100-160 mg/dL

International Diabetes CenterInternational Diabetes Center

Blood Glucose Monitoring

To improve clinical decision-making

To adjust therapy

To evaluate efficacy of the therapy

To pin point problems

To support adherence to regimen

Feedback for the patient

Use glucose meter with verified data (memory with date/time)

Redefining Pathophysiology of Type 2 Diabetes?

Relative InsulinDeficiency


InsulinResistance

InsulinResistance

ImpairedIncretin Action


Pre-diabetes and Type 2 Diabetes


Natural History of Type 2 Diabetes

Years

Glu

cose

(m

g/d

L)

Rel

ativ

e F

un

ctio

n

-10 -5 0 5 10 15 20 25 30

50

100

150

200

250

300

350

Insulin resistance

Insulin level

Fasting glucose

Post-meal glucose

OnsetDiabetes

OnsetDiabetes

Pre-diabetesmetabolic syndrome

0

50

100

150

200

250

-15

Incretin action cell function

Adapted from: UKPDS 33: Lancet 1998; 352, 837-853 ; DeFronzo RA. Diabetes. 37:667, 1988; Saltiel J. Diabetes. 45:1661-1669, 1996. Robertson RP. Diabetes. 43:1085, 1994; Tokuyama Y. Diabetes 44:1447, 1995. Polonsky KS. N Engl J Med 1996;334:777.

What is the relationship between gaining weight and developing insulin resistance?

Role of Obesity in Development of Insulin Resistance

Central obesity is critical factor:

Waist to hip ratio >1

Waist >40 inches in men

Waist >35 inches in women

Abdominal adipose tissue is more metabolically active than subcutaneous fat.

Increased release of FFA, TNF- leading to insulin resistance.

FFA TNF- Resistin

Elevated FFAs Play Key Role in Insulin Resistance

↓Gluconeogenesis

↓ Glucose Uptake

FFA↓ Glucose Uptake

Impaired Glucose-StimulatedInsulin Secretion

*HOMA = homeostasis model assessment; IGT = impaired glucose tolerance.Dashed line shows extrapolation forward and backward from years 0 to 6 based on HOMA data from UKPDS.Lebovitz. Diabetes Rev. 1999, 7:139-53.UKPDS Group. UKPDS 16 Diabetes 1995, 44:1249-58.

Loss of first-phase insulin secretion

-CellFunction*

(%)

Postprandialhyperglycemia

IGT Type 2diabetesphase I Type 2

diabetesphase II

Type 2 diabetesphase III25

100

75

0

50

-12 -10 -6 -2 0 2 6 10 14

Years from Diagnosis

Relative Insulin DeficiencyDecline In -Cell Function

0 2 4 6 8 10 12 14 16

Time (hours)

Se

cre

ted

Insu

lin

(ng/

ml/i

sle

t)

18

0.5

1.0

1.5

2.0

2.5

Insulin Deficiency: Impaired -Cell FunctionNormal versus Type 2 Diabetes

200 mg/dL Glucose

Normal

Diabetes

Diabetes 1989; 38:673; DeFronzo et al. Diabetes Care. 1992;15:318-368

Butler AE et al. Diabetes. 2003;52:102–110.

Glycemic status:

Body weight:

ß-c

ell v

olum

e (%

)

0

1

2

3

4

Normal Diabetes

Lean

Normal Impaired Diabetes

Obese

-40%

-41%*-63%

cell Volume in HumansImpact of Obesity and Glucose Intolerance

* % Difference between Normal and Diabetes

-cells exposed to even mild chronic hyperglycemia develop changes characterized by dysfunctional insulin secretion associated with altered gene and protein expression.

Glucotoxicity Hypothesis .

What is the role of incretins?

A substance released by the gut in response to food that stimulates insulin secretion

Intestine Secretion Insulin = Incretin

Possible candidates: amino acids, lipids, hormones, peptides (proteins)

Currently two well-described incretins– Glucagon-like peptide-1 (GLP-1)

– Glucose-dependent insulinotropic peptide (GIP)

L L L

GLP-1 GLP-1 GLP-1

InsulinInsulin

glucagonglucagon

Slowed gastric Slowed gastric emptyingemptying

Early Early

SatietySatiety

©2008 International Diabetes Center. All rights reserved

GLP-1 Levels in Impaired Glucose Tolerance (IGT) and Type 2 Diabetes

Toft-Nielsen M, et al., J Clin Endocrinol Metab 2001; 86:3717–3723.

* P <0.05 between T2DM and NGT group.

20

15

10

5

00 60 120 180 240

Time (min)

MeanGLP-1 (pmol/L)

* * * **

**

*

NGT subjectsIGT subjects

T2DM patients

Meal

Nauck MA, et al., J Clin Endocrinol Metab 1986; 63:492–498.

Incretin EffectBeta-cell response to isoglycemic glucose challenge

Pla

sm

a g

luc

os

e (m

g/d

L)

0 60 120 180

Time (min)

Incretin effect200200

100100

00

**

**

**

**

****

**

Oral glucose (50 g)or isoglycemic infusion

IV glucoseOral glucose

C-p

ep

tid

e (

nm

ol/L

)

0 60 120 180

0.0

0.5

1.0

1.5

2.0

Time (min)

Time, min

IR In

sulin

, mU

/L nm

ol/L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 1200

Incretin Effect in Subjects without and with Type 2 Diabetes Given Glucose by IV and Orally

Control Subjects (n=8)

Patients with Type 2 Diabetes (n=14)

Time, min

IR In

sulin

, mU

/L nm

ol / L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 120 0

Oral glucose load Intravenous (IV) glucose infusion

Incretin Effect

Nauck M et al., Diabetologia 1986; 29:46–52.

Incretin Action: Role of Glucagon Like Incretin Action: Role of Glucagon Like Peptide -1 (GLP-1)Peptide -1 (GLP-1)Incretin Action: Role of Glucagon Like Incretin Action: Role of Glucagon Like Peptide -1 (GLP-1)Peptide -1 (GLP-1)

Ahren B Curr Diab Rep 2003; 3:365-372.Baggio LL and Drucker DJ. Gastroenterology 2007; 132:2131-2157.

STOMACH Slows gastric emptying

CNS Effects: Promotes satiety and reduction of appetite

LIVER Less glucagon = less

hepatic glucose output

ALPHA CELLDecreases post-meal

glucagon secretion

BETA CELLIncreases insulin secretion

How GLP-1 is Rapidly Degraded by DPP-4

His Ala Glu Gly Thr ThrPhe SerAspVal Ser Ser Tyr LeuGlu Gly Gln Ala Ala Lys GluPheIle

AlaTrpLeuValLysGlyArg

Active GLP-1

His Ala

Glu Gly Thr ThrPhe SerAspVal Ser Ser Tyr LeuGlu Gly Gln Ala Ala Lys GluPheIle

AlaTrpLeuValLysGlyArg

+

Inactive GLP-1(can’t bind to GLP-1 receptor)

Meier et al., Diabetes Metab Res Rev 2005; 21:91–117.

DPP-4

DPP-4 Cleaves Here

(Half-life = 60-90 seconds)

DPP-4 is a ubiquitous(present everywhere) serine protease High levels in lumen of intestine, liver,

lung, kidney

Membrane-bound and free-circulating form

Multiple Substrates Incretins (GLP-1, GIP)

Hormones (prolactin, IGF-1, luteinizing hormone)

Neuropeptides (substance P, neuropeptide Y)

Chemokines (CCL22)

Expressed on surface of T-cells T-cell activation and other immunological responses

What is the role of Dipeptidyl-Peptidase 4 (DPP-4)?

Idris and Donnelly, Diabetes,Obesity and Metab. 2007; 9:153–165.

Are type 2 diabetes and pre-diabetes part of a larger syndrome that contains a constellation of additional metabolic abnormalities?

National Cholesterol Education Program Definition of Metabolic Syndrome

Risk Factor Defining Level

Abdominal obesity Waist circumference

Men: > 40 in (>102 cm)

Women: > 35 in (>88 cm)

Triglycerides > 150 mg/dL

HDL-C Men: < 40 mg/dL

Women: < 50 mg/dL

Blood pressure > 135/85 mm/Hg

Fasting glucose > 100 mg/dL

Any three of the following:

NCEP ATP III. JAMA 2001, 285:2486.

Treatment Options for Type 2 Diabetes: Matching therapy to defect

Targeting Therapies to the Natural History of Type 2 Diabetes

Metformin

Secretagogues

Exercise

Medical Nutrition

Therapy

Thiazolidinediones (TZD)

Insulin

GLP-1 Agonist

DPP-4 Inhibitors

©2010 International Diabetes Center. All rights reserved

Glucosidase Inhibitors

YearsYears-10-10 -5-5 00 55 1010 1515 2020 2525 3030

Insulin Resistance

Insulin LevelPre DiabetesMetabolic Syndrome

-15-15

Impaired Incretin Action

OnsetDiabetes

OnsetDiabetes

ClinicalDiagnosisClinical

Diagnosis

From Staged Diabetes Management Quick Guide 5th Edition, 2009

Insulin Sensitizer: Metformin

Action– Decreases liver glucose

production

Clinical indicators

– Effective at any BMI

– A1C <9% as monotherapy

– High fasting blood glucose (160-250 mg/dL)

– Dyslipidemia

Side effects

– GI distress (affecting weight loss?)

– Metallic taste

Precautions and contraindications

• Kidney disease: serum creatinine >1.4 F, >1.5 M (eGFR <60 ?)(<30???????)

• Liver disease: if present or if excessive alcohol intake, metabolic acidosis

• Heart disease: Active cardiac or pulmonary disease

• Surgical procedures: Hold metformin at time of, or prior to, iodinated contrast dye

Blonde et al. The Endocrinologist 1996:6:431-438.Ong et al. Diabetes Care 29:2361-2364, 2006

Metformin is 1st line therapy

UKPDS 35: Lancet. 1998;352:837-853UKPDS 38: BMJ 317, 703-713, 1998UKPDS 32: BMJ 316:823-8, 1998

Dose Effect: Metformin

-19

- 31

- 41

- 78

- 62

-80

-60

-40

-20

0

500 mg 1000 mg 1500 mg 2000 mg 2500 mg

Ch

ang

e in

FP

G (

mg

/dL

)

Metformin Dose

Garber et al., Am J Med, 1997.

YearsYears-10-10 -5-5 00 55 1010 1515 2020 2525 3030

Insulin Resistance


-15-15


OnsetDiabetes

OnsetDiabetes


Diagnosis

Metformin

SecretagoguesThiazolidinediones (TZD)

Insulin

GLP-1 Agonist

DPP-4 Inhibitors Alphaglucosidase inhibitors

Medical Nutrition

Therapy


Insulin Sensitizer: Thiazolidinedione Pioglitazone (Actos®) and Rosiglitazone (Avandia®)

Action

Improves insulin sensitivity

Clinical indicators

Insulin resistance

Overweight/obese

High fasting blood glucose

Metabolic syndrome

Side effects

Edema (concern with CHF)

Weight gain

Precautions and Contraindications

Kidney Disease: monitor volume status

Liver Disease: don’t initiate therapy if ALT>2.5X upper limit of normal, more monitoring for mildly elevated ALTs

Heart Disease: Evidence of NYHA class III or IV cardiac status

Pregnancy

Thiazolidinediones (TZDs)Adverse Effects and Safety

Black box warning for CHF

Observe patient for rapid weight gain, edema, dyspnea

Peripheral edema

2-7% of subjects in clinical trials

Increased risk of bone fracture in women and men

Hand, wrist, and hip

Hepatic safety

Pio/rosiglitazone - no increased risk of abnormal liver function studies; interval monitoring of ALT still advised

Grey et al. J Clin Endocrinol Metab 2007; 92:1305–1310; Meier et al. Arch Intern Med 2008; 168:820-825.

Effect of ThiazolidinedionesPeroxisome Proliferator-Activated Receptor (PPAR) Agonists

Liver Decrease glucose production

PPAR

Activate Gene Expression

Cell Signaling

Nucleus Inside Cell

Pancreas Improve Beta-cell function

Adipose Tissue Shift from visceral to subcutaneous fat Lower FFA levels (reducing insulin resistance)

Muscle Increase glucose uptake & disposal

Blood Vessel Lower BP Reduce inflammation

TZD

Lipid Profile Pioglitazone: Triglyceride, HDL Rosiglitazone: LDL, HDL

Simonson and Kendall Curr Opin Endocrinol Diabetes 2006; 13:162–170.

YearsYears-10-10 -5-5 00 55 1010 1515 2020 2525 3030

Insulin Resistance


-15-15


OnsetDiabetes

OnsetDiabetes


Diagnosis

Metformin

SecretagoguesThiazolidinediones (TZD)

Insulin

GLP-1 Agonist


Medical Nutrition

Therapy


Diabetes 1989; 38:673.

Insulin Secretion: Normal vs.Type 2 Diabetes

0 2 4 6 8 10 12 14 16Time (hours)

Se

cre

ted

Ins

ulin

(n

g/m

l/is

let)

18

0.5

1.0

1.5

2.0

2.5

200 mg/dL Glucose

Normal

Diabetes

Insulin SecretagoguesGlipizide (Glucotrol®), Glyburide (Diabeta®), Glimepiride

(Amaryl®), Repaglinide (Prandin®), and Nateglinide (Starlix®)

Action• Releases insulin from

pancreas in response to a glucose challenge

• Repaglinide and Nateglinide have a short half-life

Clinical Indicators• Insulin deficiency

• Leaner patients

• High postprandial BG 200-300 mg/dL

Side effects• Weight gain

Hypoglycemia

Precautions and contraindications• Kidney disease: use with

caution

• Liver disease

• Pregnancy

Monotherapy Failure at 5 YearsADOPT Study; FPG >180 mg/dL

Kahn et al., NEJM 2006; 355:2427-2443.

Dipeptidyl Peptidase-4 Inhibitor Sitagliptin (Januvia) and Saxagliptin (Onglyza)

Action

Selective inhibitor of dipeptidyl peptidase -4 (DPP-4)

Increases GLP-1 levels 2-3 fold

Enhances insulin secretion, reduces glucagon levels

DPP-4

Side effects

Very well tolerated; very low risk of hypoglycemia

Weight neutral


Kidney disease; adjust dosage

Pregnancy (Category B)

His Ala Glu Gly Thr ThrPhe Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe

Ile

Ala

TrpLeuValLysGlyArg

X

DPP-4 Inh.

Sitagliptin and MetforminMonotherapy and Combination

-2.5

-2

-1.5

-1

-0.5

0

Mea

n A

1C R

educ

tion

(%)

Sita100 mg

qd

Goldstein et al. Diab Care 2007; 30:1979-1987.

Duration 24 weeks; Baseline A1C = 8.8%

Met500 mg

bid Met1000 mg

bid Sita 50 mg+ Met

500 mgbid Sita 50 mg

+ Met1000 mg

bid

n=175 n=178 n=178n=177 n=183

(-0.8)

(-1.0)

(-1.3)

(-1.6)

(-2.1)

DPP-4 Inhibitor vs. Sulfonylurea

Change in A1C Depending on baseline A1C Change in Weight

DPP-4

SU

Summary of Available DPP-4 Inhibitors

Medication Indications Dose HbA1c ↓

Sitagliptin (Januvia®) Monotherapy, metformin, TZD, sulfonylurea

100 mg daily*

0.6-0.9%

Vildagliptin (Galvus®)**(not available in US)

Metformin, TZD 50 mg 2x/day

0.6-1.0%

Sulfonylurea 50 mg daily

Saxagliptin (Onglyza®) Monotherapy, metformin, TZD, sulfonylurea

2.5 or 5 mg daily***

0.6-0.9%

*Dose adjustment for renal disease: CrCl ≥30-49 mL/min: 50 mg daily; CrCl <30 mL/min: 25 mg daily** Contraindicated for patients with liver impairment***Dose adjustment for renal disease: CrCl<50 mL/min: 2.5 mg daily

New

YearsYears-10-10 -5-5 00 55 1010 1515 2020 2525 3030

Insulin Resistance


-15-15


OnsetDiabetes

OnsetDiabetes


Diagnosis

Metformin

Secretagogues


Insulin

GLP-1 Agonist


Medical Nutrition

Therapy


Alpha-Glucosidase Inhibitor Acarbose (Precose®) and Miglitol (Glyset®)

Action

– Delays carbohydrates absorption by interfering with their breakdown

Clinical indicators

– Insulin deficiency/insulin resistance

– A1C<8% as monotherapy

– High post-prandial blood glucose

Side effects

– Flatulence, abdominal pain, and diarrhea

– Generally poorly tolerated


Kidney disease: Serum creatinine >2.0 mg/dL

Liver disease: Evidence of severe disease

Heart disease: none

Inflammatory bowel disease

Pregnancy

YearsYears-10-10 -5-5 00 55 1010 1515 2020 2525 3030

Insulin Resistance


-15-15


OnsetDiabetes

OnsetDiabetes


Diagnosis

Metformin

Secretagogues


Insulin

GLP-1 Agonist

DPP-4 Inhibitors

Alphaglucosidase inhibitors

Medical Nutrition

Therapy


Incretin Mimetic (GLP-1 Analog) Exenatide (Byetta®)

Action– Enhances glucose-dependent insulin secretion– Slows gastric emptying– Reduce food intake

Clinical Indicators– Elevated postmeal BG– In combination with metformin, sulfonylurea, thiazolidinedione or

metformin/sulfonylurea Side effects

– Nausea (~40% patients) vomiting (13%) and diarrhea (13%) – Hypoglycemia with sulfonylurea

Precautions and Contraindications– Kidney Disease: Creatine Clearance <30 ml/min– Gastrointestinal disease– Pregnancy (Category C)

Effect of Exenatide in Combination with Oral Therapies

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

Ch

ange

in A

1C (

%)

from

Bas

elin

e

Exenatide+ Metformin

Buse JB, Diabetes Care 2004; 27:2628–2635.Defronzo RA, Diabetes Care 2005; 28:1092–1100.Kendall DM, Diabetes Care 2005; 28:1083–1091.

Baseline A1C 8.7%

Baseline A1C 8.5%

Baseline A1C 8.6%

Exenatide +Sulfonylurea

Exenatide +Met and SU

5 g BID 10 g BID Placebo

P<0.001

P<0.001

P<0.0001

P<0.0001

P<0.0001

P<0.0001

Baseline vs. 30 weeks

When to Inject Exenatide

150

200

250

100

50

-60 0 60 120 180 240 300 360

Placebo

-60 minutes

-15 minutes

0 minutes

+30 minutes

+60 minutes

Time after meal (minutes)

Pla

sma

glu

cose

(m

g/d

L)

Linnebjerg et al., Diab Med 2006; 23:240–245.

N=18, randomized, six way crossover study, with fixed breakfast

Meal

Liraglutide (Victoza®)

GLP-1 analog Half-life 13 hours, resistant to DPP-4 degradation Daily injection (weekly titration 0.6 mg to 1.2 mg to 1.8 mg) G.I. Side effects common (~15-30% report nausea; 10-15%

report diarrhea) and transient in nature Approved January, 2010, not recommended as first-line therapy,

rather in combination with Met, SU, TZDs

His Ala Glu Gly Thr ThrPhe Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu PheIle

Ala

Trp

LeuVal

ArgGly

Arg

Gly

Albumin

Gly

Liraglutide (Victoza®) Precautions and Contraindications

Not for treatment of type 1 DM Has not been studied in combination with insulin Not studied in patients with history of pancreatitis

7 cases pancreatitis vs. 1 in comparator (2.2 vs. 0.6 cases /1000 pts years)

Liraglutide vs. Sulfonylurea (LEAD-3)Effects on A1C and Weight at 52 Weeks

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

-6

-4

-2

0

2

4

6

Ch

ange

in A

1C (

%)

from

Bas

elin

e

Ch

ange

in W

eigh

t (l

bs)

fro

m B

asel

ine

1.2 mgn=251

Glimepiriden=248

Garber et al. Lancet 2009; 373:438-449

1.8 mgn=247

1.2 mgn=251

Glimepiriden=248

1.8 mgn=247

Baseline A1C 8.3% Baseline Weight ~205 lbs

YearsYears-10-10 -5-5 00 55 1010 1515 2020 2525 3030

Insulin Resistance


-15-15


OnsetDiabetes

OnsetDiabetes


Diagnosis

Metformin

Secretagogues


Insulin

GLP-1 Agonist

DPP-4 Inhibitors


Medical Nutrition

Therapy


The Burden of Type 2 Diabetes Treatment Failure

*Adapted from: Brown JB et al. Diabetes Care. 2004;27:1535-1540.

Mea

n A

1C a

t Las

t Vis

it*

(%)

8.2 Years8.2 Years

ADA GoalADA Goal

Diet and ExerciseDiet and Exercise

Years Elapsed Since Initial Diagnosis

Initiation of

insulin therapy

Initiation of

insulin therapy

SU or metformin

SU or metformin

Combination oral agents

Combination oral agents8.6%

8.9%

9.6%

7

8

9

10

2.5 Years 2.9 Years 2.8 Years





InsulinResistance

InsulinResistance


ImpairedIncretin ActionInsulin

DeficiencyInsulin

Deficiency

Type 1 DiabetesType 1 Diabetes

The Role of Insulin Therapy

Critical role in both Type 1 and Type 2 diabetes Greatest potency of available therapies

Demonstrated benefit – multiple clinical trials

Clinical Indicators for Insulin in Type 2 Diabetes

Staged Diabetes Management Quick Guide 5th Edition, 2009

Initiate if: A1C >7% for 3 months and on maximum effective dose of

2 or more glucose-lowering agents

Symptomatic and glucose >300 mg/dL

If clinically stable and high intake of sweetened Beverages (>36 oz or 3 cans/day), eliminate sweetenedBeverages and re-evaluate need for insulin in 1-2 weeks

Normal Insulin Secretion

Mealtime (bolus) insulin needs ~ 50%

Re

lati

ve

Ins

ulin

Eff

ec

tR

ela

tiv

e In

su

lin E

ffe

ct

Time (Hours)Time (Hours)

0 2 4 6 8 10 12 14 16

Long-Acting: Glargine, Detemir

18 20

Intermediate: NPH

Short-Acting: Regular

Rapid-Acting: Lispro, Aspart, Glulisine

Insulin Time Action Curves

Bergenstal, Effective insulin therapy. International Textbook of Diabetes Mellitus Vol 1. 3rd Ed Chichester NY, John Wiley and Sons, Inc. 2004:995-1015.

Background (Basal) Insulin+ Oral Agent(s)

•Elevated FPG•Stable daytime BG

•Overwhelmed•Desire single injection

Premixed Insulin Sensitizer(s)

• Elevated PPG• Increasing daytime BG

•Decreased dexterity or visual acuity•Regular schedule

Background andMealtime Insulin

Sensitizer(s)

•Elevated fasting and/or post-meal•Intensive control

•More flexibility•Erratic schedule

Selecting an Insulin Regimen

Glycemic Factors

Patient Factors

Type 2 Insulin Guidelines © 2007 International Diabetes Center, Park Nicollet Institute

Basal (Background) Insulin in Type 2 Diabetes

TZD or Metformin

SU

(LA 0.1 – 0.2 U/kg)

Basal (Background) and Bolus (Mealtime) Insulin Regimen

Metformin

Premixed with Rapid Acting Insulin Regimen

Humalog Mix 75/25 or NovoLog Mix 70/30

Metformin

YearsYears-10-10 -5-5 00 55 1010 1515 2020 2525 3030

Insulin Resistance

Pre DiabetesMetabolic Syndrome

-15-15


OnsetDiabetes

OnsetDiabetes


Diagnosis

Metformin

Secretagogues


Insulin

GLP-1 AgonistDPP-4 Inhibitors


Medical Nutrition

Therapy


From Staged Diabetes Management Quick Guide 5th Edition, 2009

Health & Medicine

Module i type 2 dm