module i type 2 dm
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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
Relative InsulinDeficiency
InsulinResistance
InsulinResistance
ImpairedIncretin Action
ImpairedIncretin Action
Pre-diabetes and Type 2 Diabetes
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
Insulin LevelPre DiabetesMetabolic Syndrome
-15-15
Impaired Incretin Action
OnsetDiabetes
OnsetDiabetes
ClinicalDiagnosisClinical
Diagnosis
Metformin
SecretagoguesThiazolidinediones (TZD)
Insulin
GLP-1 Agonist
DPP-4 Inhibitors Alphaglucosidase inhibitors
Medical Nutrition
Therapy
Targeting Therapies to the Natural History of Type 2 Diabetes
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
Insulin LevelPre DiabetesMetabolic Syndrome
-15-15
Impaired Incretin Action
OnsetDiabetes
OnsetDiabetes
ClinicalDiagnosisClinical
Diagnosis
Metformin
SecretagoguesThiazolidinediones (TZD)
Insulin
GLP-1 Agonist
DPP-4 Inhibitors Alphaglucosidase inhibitors
Medical Nutrition
Therapy
Targeting Therapies to the Natural History of Type 2 Diabetes
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
Precautions and contraindications
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
Insulin LevelPre DiabetesMetabolic Syndrome
-15-15
Impaired Incretin Action
OnsetDiabetes
OnsetDiabetes
ClinicalDiagnosisClinical
Diagnosis
Metformin
Secretagogues
Thiazolidinediones (TZD)
Insulin
GLP-1 Agonist
DPP-4 Inhibitors Alphaglucosidase inhibitors
Medical Nutrition
Therapy
Targeting Therapies to the Natural History of Type 2 Diabetes
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
Precautions and contraindications
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
Insulin LevelPre DiabetesMetabolic Syndrome
-15-15
Impaired Incretin Action
OnsetDiabetes
OnsetDiabetes
ClinicalDiagnosisClinical
Diagnosis
Metformin
Secretagogues
Thiazolidinediones (TZD)
Insulin
GLP-1 Agonist
DPP-4 Inhibitors
Alphaglucosidase inhibitors
Medical Nutrition
Therapy
Targeting Therapies to the Natural History of Type 2 Diabetes
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
Insulin LevelPre DiabetesMetabolic Syndrome
-15-15
Impaired Incretin Action
OnsetDiabetes
OnsetDiabetes
ClinicalDiagnosisClinical
Diagnosis
Metformin
Secretagogues
Thiazolidinediones (TZD)
Insulin
GLP-1 Agonist
DPP-4 Inhibitors
Alphaglucosidase inhibitors
Medical Nutrition
Therapy
Targeting Therapies to the Natural History of Type 2 Diabetes
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
Relative InsulinDeficiency
Relative InsulinDeficiency
Pre-diabetes and Type 2 Diabetes
Pre-diabetes and Type 2 Diabetes
InsulinResistance
InsulinResistance
ImpairedIncretin Action
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
Impaired Incretin Action
OnsetDiabetes
OnsetDiabetes
ClinicalDiagnosisClinical
Diagnosis
Metformin
Secretagogues
Thiazolidinediones (TZD)
Insulin
GLP-1 AgonistDPP-4 Inhibitors
Alphaglucosidase inhibitors
Medical Nutrition
Therapy
Targeting Therapies to the Natural History of Type 2 Diabetes
From Staged Diabetes Management Quick Guide 5th Edition, 2009