1. Changing Technology: Redefining the
Natural History of Type 2 Diabetes
Professor Roger Mazze

7. 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

8. The Natural History of Type 2 Diabetes
Pre-diabetes
Deterioration of
Glucose Control
Normal
•Insulin
Resistance
•Insulin
Deficiency
•Incretin
Dysfunction
Normal

9. SDM: Applications to Type 2
Diabetes Management

10. Classifying Diabetes: Underlying Defects
Type 1 GDM Type 2
 Genetic predisposition:
Genetic predisposition:  Genetic predisposition: 80-90% concordance in
identical twins
50% concordance in high  Environmental factor:
identical twins obesity, inactivity
 Environmental factor:
 Excessive hepatic glucose
 Environmental factor: obesity output
 insulin resistance/Insulin
virus  Prior exposure to deficiency/Impaired
incretin effect
 Auto-immune hyperglycemia in
destruction of the pregnancy
pancreatic beta cells  Human Placental Lactogen
 Insulin deficiency
 Insulin resistance/Insulin
deficiency

11. Priorities of Care for Adults with Diabetes
Diagnosis–Prevention
Dx Fasting Glucose > 126 Casual > 200 + Symptoms
Prevent Pre-diabetes (IFG-IGT) & Metabolic Syndrome
Self-Management Knowledge and Skill
Monitoring Medication Problem solving Food plan & nutrition
Risk reduction Living & coping Physical activity
Microvascular Other essentials
Glucose Lipids Hypertension
complications of care
CVD Risk
ASA, tobacco, ACEI/ARB, statin
Hemoglobin A1C Annual Lipid Profile Blood Pressure Annual Screening
Target < 7.0% LDL < 100 (every visit) Nephropathy
HDL > 40 Dx and Rx < 130/80 Microalbumin screening Hospital care
SMBG Calculated GFR
Pre 70-120 mg/dL Trigs < 150 Foot care
Retinopathy
2 hr. post < 160 mg/dL Dilated retinal exam Dental care
(~ 50% of readings) DM + CVD Neuropathy Immunizations
Neuro and foot exam
LDL < 70
Sexual health
International Diabetes Center.

12. SDM: Focusing on Type 2
Diabetes Management

13. Diagnosis of Type 2 Diabetes
Blood Glucose and HbA1c Levels
New
Fasting OGTT HbA1c
Diabetes Diabetes Diabetes
>126 mg/dL >200 mg/dL >6.5%
Impaired fasting Impaired glucose High risk for
glucose Pre-diabetes tolerance diabetes
(54 million)
100-125 mg/dL 140-199 mg/dL 6.0-6.4%
Normal Normal Normal
70-99 <140 mg/dL <6.0%
mg/dL
ADA Standards of Care. Diabetes Care, Suppl.1, 2010; ADA , EASD, IDF International
Expert Committee Report on HbA1c for Diagnosis of Diabetes.

14. 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
NORMAL PREDIABETES IFG or IGT DIABETES
FPG < 100 FPG > 100 – 125 (IFG) FPG > 126
2-h PG < 140 2-h PG 140 – 199 (IGT) 2-h PG > 200
A1c < 5.7% A1c 5.7 – 6.4% A1c > 6.5%
American Diabetes Association. Diabetes Care 323(Suppl 1), 2009

15. Confirming the Diagnosis with Repeat
Testing

16. 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

17. 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 Center

18. 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)

19. Redefining Pathophysiology of Type 2
Diabetes?
Impaired
Incretin Action
Insulin Relative Insulin
Resistance Deficiency
Pre-diabetes and
Type 2 Diabetes

20. Natural History of Type 2 Diabetes
350
(mg/dL)
Post-meal glucose
300
250
Fasting glucose
Glucose
200
150
100
50
Relative Function
250
200 Insulin resistance
150
100
Insulin level
50 β cell function
Incretin action
0
-15 -10 -5 0 5 10 15 20 25 30
Pre-diabetes Onset
Years
metabolic syndrome Diabetes
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.

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

22. 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-α
leading to insulin resistance.
FFA TNF-α Resistin

23. Elevated FFAs Play Key Role in Insulin
Resistance
Impaired Glucose-Stimulated
Insulin Secretion
↓Gluconeogenesis
↓ Glucose Uptake
FFA
↓ Glucose Uptake

24. Relative Insulin Deficiency
Decline In β -Cell Function
100
Loss of first-phase insulin secretion
75
β-Cell
Function* 50
(%)
IGT Postprandial Type 2 Type 2 diabetes
25 hyperglycemia diabetes phase III
phase I Type 2
diabetes
phase II
0
-12 -10 -6 -2 0 2 6 10 14
Years from Diagnosis
*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.

25. Insulin Deficiency: Impaired β-Cell Function
Normal versus Type 2 Diabetes
200 mg/dL Glucose
Secreted Insulin (ng/
2.5
Normal
2.0
1.5
Diabetes
ml/islet)
1.0
0.5
0 2 4 6 8 10 12 14 16 18
Time (hours)
Diabetes 1989; 38:673; DeFronzo et al. Diabetes Care. 1992;15:318-368

26. β cell Volume in Humans
Impact of Obesity and Glucose Intolerance
4
3
ß-cell volume (%)
-40%
2
-41%*
-63%
1
0
Body weight: Lean Obese
Glycemic status: Normal Diabetes Normal Impaired Diabetes
* % Difference between Normal and Diabetes
Butler AE et al. Diabetes. 2003;52:102–110.

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

28. 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)

29. Early
Slowed gastric Satiety
emptying
glucagon
Insulin
GLP-1 GLP-1 GLP-1
L L L
©2008 International Diabetes Center. All rights reserved

30. GLP-1 Levels in Impaired Glucose
Tolerance (IGT) and Type 2 Diabetes
Meal
20
* * * * NGT subjects
* IGT subjects
15 * T2DM patients
*
Mean
10
GLP-1 (pmol/L)
*
5
0
0 60 120 180 240
Time (min)
* P <0.05 between T2DM and NGT group.
Toft-Nielsen M, et al., J Clin Endocrinol Metab 2001; 86:3717–3723.

31. Incretin Effect
Beta-cell response to isoglycemic glucose challenge
Oral glucose (50 g)
or isoglycemic infusion
2.0
Plasma glucose (mg/dL)
IV glucose *
Oral glucose
C-peptide (nmol/L)
200
*
1.5
* Incretin effect
*
*
1.0 *
100
*
0.5
0 0.0
0 60 120 180 0 60 120 180
Time (min) Time (min)
Nauck MA, et al., J Clin Endocrinol Metab 1986; 63:492–498.

32. Incretin Effect in Subjects without and with Type 2
Diabetes Given Glucose by IV and Orally
Control Subjects Patients with Type 2 Diabetes
(n=8) (n=14)
0.6 0.6
80 80
Incretin
Effect 0.5 0.5
60 60
IR Insulin, mU/L
IR Insulin, mU/L
0.4 0.4
nmol/L
nmol / L
40 0.3 40 0.3
0.2 0.2
20 20
0.1 0.1
0 0 0 0
0 60 120 180 0 60 120 180
Time, min Time, min
Oral glucose load Intravenous (IV) glucose infusion
Nauck M et al., Diabetologia 1986; 29:46–52.

33. Incretin Action: Role of Glucagon Like
Peptide -1 (GLP-1)
CNS Effects: Promotes
satiety and reduction
of appetite
LIVER
Less glucagon = less
hepatic glucose output
BETA CELL
Increases insulin
secretion
ALPHA CELL STOMACH
Decreases post-meal Slows gastric
glucagon secretion emptying
Ahren B Curr Diab Rep 2003; 3:365-372.
Baggio LL and Drucker DJ. Gastroenterology 2007; 132:2131-2157.

34. How GLP-1 is Rapidly Degraded by DPP-4
Active GLP-1
His Ala Glu Gly Thr Phe Thr SerAsp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe
Ile
Ala
DPP-4
Arg Gly Lys Val Leu Trp
DPP-4 Cleaves Here
(Half-life = 60-90 seconds)
Inactive GLP-1
(can’t bind to GLP-1 receptor)
Glu Gly Thr Phe Thr SerAsp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe
Ile
+ Ala
Arg Gly Lys Val Leu Trp
His Ala
Meier et al., Diabetes Metab Res Rev 2005; 21:91–117.

35. What is the role of Dipeptidyl-Peptidase 4
(DPP-4)?
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
Idris and Donnelly, Diabetes,Obesity and Metab. 2007; 9:153–165.

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

37. National Cholesterol Education Program
Definition of Metabolic Syndrome
Any three of the following:
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
NCEP ATP III. JAMA 2001, 285:2486.

38. Treatment Options for Type 2
Diabetes: Matching therapy to
defect

39. Targeting Therapies to the Natural
History of Type 2 Diabetes
Exercise Thiazolidinediones (TZD)
Medical Metformin Insulin
Nutrition
Therapy Secretagogues
GLP-1 Agonist
DPP-4 Inhibitors
α Glucosidase Inhibitors
Insulin Resistance
Insulin Level
Pre Diabetes
Metabolic Syndrome Impaired Incretin Action
-15 -10 -5 0 5 10 15 20 25 30
Onset
Diabetes
Clinical
Diagnosis
Years
©2010 International Diabetes Center. All rights reserved

40. From Staged Diabetes Management Quick Guide 5th Edition, 2009

44. Insulin Sensitizer: Metformin
 Action  Precautions and
– Decreases liver glucose contraindications
production • Kidney disease: serum
creatinine >1.4 F, >1.5 M
 Clinical indicators (eGFR <60 ?)(<30???????)
– Effective at any BMI • Liver disease: if present or if
– A1C <9% as monotherapy excessive alcohol intake,
– High fasting blood glucose metabolic acidosis
(160-250 mg/dL) • Heart disease: Active cardiac
– Dyslipidemia or pulmonary disease
• Surgical procedures: Hold
 Side effects metformin at time of, or prior to,
– GI distress (affecting weight iodinated contrast dye
loss?)
– Metallic taste
Blonde et al. The Endocrinologist 1996:6:431-438.
Ong et al. Diabetes Care 29:2361-2364, 2006

45. Metformin is 1st line therapy
UKPDS 35: Lancet. 1998;352:837-853
UKPDS 38: BMJ 317, 703-713, 1998
UKPDS 32: BMJ 316:823-8, 1998

46. Dose Effect: Metformin
Metformin Dose
500 mg 1000 mg 1500 mg 2000 mg 2500 mg
Change in FPG (mg/dL)
0
-20
-19
- 31
-40
- 41
-60
- 62
-80
- 78
Garber et al., Am J Med, 1997.

47. Targeting Therapies to the Natural
History of Type 2 Diabetes
Metformin Insulin
Thiazolidinediones (TZD)
GLP-1 Agonist Secretagogues
DPP-4 Inhibitors Alphaglucosidase inhibitors
Medical
Nutrition
Therapy Insulin Resistance
Insulin Level
Pre Diabetes
Metabolic Syndrome Impaired Incretin Action
-15 -10 -5 0 5 10 15 20 25 30
Onset
Diabetes
Clinical
Diagnosis
Years

48. Insulin Sensitizer: Thiazolidinedione
Pioglitazone (Actos®) and Rosiglitazone (Avandia®)
 Action  Precautions and
Contraindications
Improves insulin sensitivity
Kidney Disease: monitor
 Clinical indicators volume status
Insulin resistance Liver Disease: don’t
Overweight/obese initiate therapy if ALT>2.5X
upper limit of normal, more
High fasting blood glucose
monitoring for mildly
Metabolic syndrome elevated ALTs
 Side effects Heart Disease: Evidence
of NYHA class III or IV
Edema (concern with CHF)
cardiac status
Weight gain
Pregnancy

49. 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.

50. Effect of Thiazolidinediones
Peroxisome Proliferator-Activated Receptor (PPAR) Agonists
Muscle
Adipose Tissue  Increase glucose uptake &
 Shift from visceral to disposal
subcutaneous fat
 Lower FFA levels (reducing
insulin resistance) TZD Liver
PPARγ  Decrease glucose
production
Activate Gene
Blood Vessel Expression
 Lower BP Cell Signaling
Pancreas
 Reduce inflammation  Improve Beta-cell
function
Nucleus Inside Cell
Lipid Profile
 Pioglitazone: Triglyceride, HDL
 Rosiglitazone: LDL, HDL
Simonson and Kendall Curr Opin Endocrinol Diabetes 2006; 13:162–170.

51. Targeting Therapies to the Natural
History of Type 2 Diabetes
Insulin
Thiazolidinediones (TZD)
GLP-1 Agonist Secretagogues
DPP-4 Inhibitors Alphaglucosidase inhibitors
Medical
Nutrition
Metformin
Therapy Insulin Resistance
Insulin Level
Pre Diabetes
Metabolic Syndrome Impaired Incretin Action
-15 -10 -5 0 5 10 15 20 25 30
Onset
Diabetes
Clinical
Diagnosis
Years

52. Insulin Secretion: Normal vs.
Type 2 Diabetes
200 mg/dL Glucose
2.5
Secreted Insulin
Normal
(ng/ml/islet)
2.0
1.5
Diabetes
1.0
0.5
0 2 4 6 8 10 12 14 16 18
Time (hours)
Diabetes 1989; 38:673.

53. Insulin Secretagogues
Glipizide (Glucotrol®), Glyburide (Diabeta®), Glimepiride
(Amaryl®), Repaglinide (Prandin®), and Nateglinide (Starlix®)
 Action  Side effects
• Releases insulin from • Weight gain
pancreas in response to a Hypoglycemia
glucose challenge
 Precautions and
• Repaglinide and
Nateglinide have a short
contraindications
half-life • Kidney disease: use with
caution
 Clinical Indicators
• Liver disease
• Insulin deficiency
• Pregnancy
• Leaner patients
• High postprandial
BG 200-300 mg/dL

54. Monotherapy Failure at 5 Years
ADOPT Study; FPG >180 mg/dL
Kahn et al., NEJM 2006; 355:2427-2443.

55. Dipeptidyl Peptidase-4 Inhibitor
Sitagliptin (Januvia) and Saxagliptin (Onglyza)
 Action DPP-4 Inh.
Selective inhibitor of dipeptidyl peptidase -4 (DPP-4)
Increases GLP-1 levels 2-3 fold
Enhances insulin secretion, reduces glucagon levels
DPP-4 X His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu
Phe
Ile
Ala
Trp
Gly Lys Val Leu
 Side effects
Arg
Very well tolerated; very low risk of hypoglycemia
Weight neutral
 Precautions and contraindications
Kidney disease; adjust dosage
Pregnancy (Category B)

56. Sitagliptin and Metformin
Monotherapy and Combination
Duration 24 weeks; Baseline A1C = 8.8%
n=175 n=178 n=177 n=183 n=178
0
Mean A1C Reduction (%)
-0.5
(-0.8)
(-1.0)
-1 Sita
100 mg Met (-1.3)
qd 500 mg
-1.5 bid Met (-1.6)
1000 mg
bid Sita 50 mg
-2 + Met (-2.1)
500 mg
bid Sita 50 mg
-2.5 + Met
1000 mg
bid
Goldstein et al. Diab Care 2007; 30:1979-1987.

57. DPP-4 Inhibitor vs. Sulfonylurea
Change in A1C
Depending on baseline A1C Change in Weight
S
U
DPP-
4

58. New
Summary of Available DPP-4 Inhibitors
Medication Indications Dose HbA1c ↓
Sitagliptin (Januvia®) Monotherapy, metformin, 100 mg 0.6-0.9%
TZD, sulfonylurea daily*
Vildagliptin (Galvus®)** Metformin, TZD 50 mg 2x/ 0.6-1.0%
(not available in US) day
Sulfonylurea 50 mg daily
Saxagliptin (Onglyza®) Monotherapy, metformin, 2.5 or 5 mg 0.6-0.9%
TZD, sulfonylurea daily***
*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

59. Targeting Therapies to the Natural
History of Type 2 Diabetes
Insulin
GLP-1 Agonist
DPP-4 Inhibitors Alphaglucosidase inhibitors
Medical
Nutrition Metformin Thiazolidinediones (TZD)
Therapy Insulin Resistance
Secretagogues
Insulin Level
Pre Diabetes
Metabolic Syndrome Impaired Incretin Action
-15 -10 -5 0 5 10 15 20 25 30
Onset
Diabetes
Clinical
Diagnosis
Years

60. Alpha-Glucosidase Inhibitor
Acarbose (Precose®) and Miglitol (Glyset®)
 Action  Precautions and
– Delays carbohydrates contraindications
absorption by interfering Kidney disease: Serum
with their breakdown creatinine >2.0 mg/dL
 Clinical indicators Liver disease: Evidence of
– Insulin deficiency/ severe disease
insulin resistance Heart disease: none
– A1C<8% as monotherapy Inflammatory bowel
– High post-prandial disease
blood glucose Pregnancy
 Side effects
– Flatulence, abdominal pain,
and diarrhea
– Generally poorly tolerated

61. Targeting Therapies to the Natural
History of Type 2 Diabetes
Insulin
GLP-1 Agonist
Alphaglucosidase inhibitors
Medical
Nutrition Metformin Thiazolidinediones (TZD)
Therapy Insulin Resistance
Secretagogues
DPP-4 Inhibitors Insulin Level
Pre Diabetes
Metabolic Syndrome Impaired Incretin Action
-15 -10 -5 0 5 10 15 20 25 30
Onset
Diabetes
Clinical
Diagnosis
Years

62. 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)

63. Effect of Exenatide in Combination
with Oral Therapies
Baseline vs. 30 weeks
5 µg BID 10 µg BID Placebo
0.4
Change in A1C (%) from Baseline
Baseline Baseline Baseline
A1C 8.7% A1C 8.5% A1C 8.6%
0.2
0
-0.2
-0.4 P<0.001
-0.6
P<0.0001
P<0.0001
-0.8 P<0.001 P<0.0001
P<0.0001
-1
Exenatide Exenatide + Exenatide +
+ Metformin Sulfonylurea Met and SU
Buse JB, Diabetes Care 2004; 27:2628–2635.
Defronzo RA, Diabetes Care 2005; 28:1092–1100.
Kendall DM, Diabetes Care 2005; 28:1083–1091.

64. When to Inject Exenatide
Placebo
-60 minutes
Plasma glucose (mg/dL)
Meal -15 minutes
250 0 minutes
+30 minutes
200
+60 minutes
150
100
50
-60 0 60 120 180 240 300 360
Time after meal (minutes)
N=18, randomized, six way crossover study, with fixed breakfast
Linnebjerg et al., Diab Med 2006; 23:240–245.

65. 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 Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe
Gly Ile
Ala
Trp
eu
Albumin A rg V
al L
Gly
Arg
Gly

66. 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)

67. Liraglutide vs. Sulfonylurea (LEAD-3)
Effects on A1C and Weight at 52 Weeks
Change in A1C (%) from Baseline
Baseline A1C 8.3% Baseline Weight ~205 lbs
0 6
Change in Weight (lbs) from Baseline
-0.2 4
-0.4 2
-0.6 0
-0.8 -2
-1 -4
-1.2 -6
1.2 mg 1.8 mg Glimepiride 1.2 mg 1.8 mg Glimepiride
n=251 n=247 n=248 n=251 n=247 n=248
Garber et al. Lancet 2009; 373:438-449

68. Targeting Therapies to the Natural
History of Type 2 Diabetes
Insulin
GLP-1 Agonist
Medical
Nutrition Metformin Thiazolidinediones (TZD)
Therapy Insulin Resistance
Secretagogues Alphaglucosidase inhibitors
DPP-4 Inhibitors Insulin Level
Pre Diabetes
Metabolic Syndrome Impaired Incretin Action
-15 -10 -5 0 5 10 15 20 25 30
Onset
Diabetes
Clinical
Diagnosis
Years

69. The Burden of Type 2 Diabetes
Treatment Failure
Mean A1C at Last Visit*
10 9.6%
8.9% Combination
(%)
9 8.6% oral agents
SU or
Diet and metformin
8 Exercise
7
ADA Goal 2.5 Years 2.9 Years 2.8 Years Initiation
8.2 Years of
insulin therapy
Years Elapsed Since Initial Diagnosis
*Adapted from: Brown JB et al. Diabetes Care. 2004;27:1535-1540.

70. 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
Impaired
Insulin Incretin Action
Deficiency Insulin Relative Insulin
Resistance Deficiency
Type 1 Diabetes Pre-diabetes and
Type 2 Diabetes

71. Clinical Indicators for Insulin
in Type 2 Diabetes
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 sweetened
Beverages and re-evaluate need for insulin in 1-2 weeks
Staged Diabetes Management Quick Guide 5th Edition, 2009

72. Normal Insulin Secretion
Mealtime (bolus)
insulin needs ~ 50%

73. Insulin Time Action Curves
Rapid-Acting: Lispro, Aspart, Glulisine
Relative Insulin Effect
Short-Acting: Regular
Intermediate: NPH
Long-Acting: Glargine, Detemir
0 2 4 6 8 10 12 14 16 18 20
Time (Hours)
Bergenstal, Effective insulin therapy. International Textbook of
Diabetes Mellitus Vol 1. 3rd Ed Chichester NY, John Wiley and
Sons, Inc. 2004:995-1015.

74. Selecting an Insulin Regimen
Background Background and
Premixed Insulin
(Basal) Insulin Mealtime Insulin ± Sensitizer(s)
+ Oral Agent(s) ± Sensitizer(s)
Glycemic •Elevated fasting • Elevated PPG
•Elevated FPG
Factors and/or post-meal • Increasing daytime BG
•Stable daytime BG
•Intensive control
Patient •More flexibility •Decreased dexterity
•Overwhelmed
Factors •Erratic schedule or visual acuity
•Desire single injection •Regular schedule
Type 2 Insulin Guidelines © 2007
International Diabetes Center, Park Nicollet Institute

75. Basal (Background) Insulin in
Type 2 Diabetes
TZD or Metformin
SU
(LA 0.1 – 0.2 U/kg)

76. Basal (Background) and
Bolus (Mealtime) Insulin Regimen
Metformin

77. Premixed with
Rapid Acting Insulin Regimen
Humalog Mix 75/25 or NovoLog Mix 70/30
Metformin

78. Targeting Therapies to the Natural
History of Type 2 Diabetes
Insulin
Medical
Nutrition Metformin Thiazolidinediones (TZD)
Therapy Insulin Resistance
Secretagogues Alphaglucosidase inhibitors
DPP-4 Inhibitors GLP-1 Agonist
Pre Diabetes
Metabolic Syndrome Impaired Incretin Action
-15 -10 -5 0 5 10 15 20 25 30
Onset
Diabetes
Clinical
Diagnosis
Years

79. From Staged Diabetes Management Quick Guide 5th Edition, 2009