Treatment of Diabetes

1
Treatment of Diabetes

• Sunder Mudaliar, M.D.
• Staff Physician
• VA Medical Center, San Diego
• Associate Clinical Professor of Medicine
• University of California, San Diego
• Co-Investigator, Diabetes Prevention Program

2
Types of Diabetes

• Type 2 Diabetes 90
• Type 1 Diabetes 10
• Diabetes secondary to Chronic Pancreatitis
• Gestational Diabetes

3
What is Diabetes ????
4
Criteria for the Diagnosis of Diabetes Mellitus

• Diagnosis of diabetes FPG ? 126 mg/dL
• or
• Symptoms (polyuria, polydipsia, unexplained
  weight loss) plus casual plasma glucose ? 200
  mg/dL
• or
• 2-hour plasma glucose ? 200 mg/dL during 75 g OGTT

ADA. Diabetes Care. 1997201183-1197.
5
Prevalence of Retinopathy by Deciles
NHANES III
HbA1c
15
FPG (mg/dl)
2-h plasma glucose (2hPG) (mg/dl)
10
Retinopathy ()
5
0
5.1
5.2
5.4
5.5
5.6
5.7
5.9
6.2
HbA1c
FPG (mg/dl)
90
93
96
98
101
104
109
120
2hPG (mg/dl)
86
94
102
112
120
133
154
195
Adapted from The Expert Committee on the
Diagnosis and Classification of Diabetes
Mellitus. Diabetes Care. 1997
6
Mortality and Glycemic ControlA Continuum, Not
a Threshold
EPIC-Norfolk Study
7
A1C ()
6
lt5
5
5-5.4
4
Mortality ()
5.5-6.9
3
³7
2
Diabetes
1
0
All cause
Ischemic heart
disease
Khaw et al. BMJ. 20012221.
7
Stages of Glucose Tolerance

• Fasting plasma OGTT
  2-hr plasma
• glucose (mg/dl)
  glucose (mg/dl)
• Normal lt 100 lt 140
• Impaired lt 100-125 140-199
• Diabetes gt 126 gt 200

ADA. Diabetes Care. 2003201183-1197.
8
Causes of Hyperglycemia in Type 2 Diabetes
FFAs, IL-6, TNF? Adiponectin
9
Progression to Type 2 Diabetes
Acquired Obesity Sedentary lifestyle Aging
Genetics
Insulin Resistance
Hyperinsulinemia
Compensated Insulin ResistanceNormal Glucose
Tolerance
Impaired Glucose Tolerance
Acquired Glucotoxicity FFA levels Other
Genetics
?-Cell Failure
Increased Hepatic Glucose Output
Type 2 Diabetes
Kruszynska Y, Olefsky JM. J Invest Med.
199644413428.
10
Insulin Resistance Syndrome(Cardiovascular
Metabolic Syndrome)
EnvironmentalInfluences
GeneticInfluences
InsulinResistance
Hyperinsulinemia
GlucoseIntolerance
IncreasedTriglyceride
DecreasedHDL Cholesterol
Small DenseLDL
Increased Blood Pressure
Procoagulant State
CardiovascularDisease
Modified from G Reaven. Diabetes Mellitus A
Fundamental and Clinical Text, 1996.
11
Mortality in Subjects With and Without Diabetes
BARI 7-Year Follow-up
44.3
7-Yearmortality ()
23.6
13.6
13.2
CABG PTCA CABG PTCA
No diabetes Diabetes
The BARI Investigators. J Am Coll Cardiol.
2000351122-1129.
12
Alternative Definition of Diabetes
Diabetes .. Is a state of premature
cardiovascular death which is associated with
chronic hyperglycemia, and may also be associated
with blindness and renal failure.
BM Fisher
Diabet Med 15275, 1998
13
Multiple Assaults on the Vascular SystemDeadly
H Quartet
Insulin Resistance Hyperinsulinemia
Hyperglycemia
Hyperlipidemia
HbA1C lt 7 FPG 90-130 mg/dl PPPG lt 180 mg/dl
LDL goal lt 100 mg/dl (lt 70 mg/dl) HDL goal gt 40
in men and 50 in women Triglycerides lt 150 mg/dl
Low dose Aspirin daily
Hypercoagulable/ Inflammatory State
Hypertension
lt 130/80 mm Hg
14
Type 2 DiabetesThe Present
15
Available oral hypoglycemic agents
Non-Insulin Secretagogues
InsulinSecretagogues

• Sulfonylureas
• First generation
• eg. Tolbutamide
• Second generation
• eg. Glyburide
• Third generation
• eg. Glimiperide
• Meglitinides
• eg. Repaglinide,
• Nateglinide

a -glucosidase inhibitors eg. Acarbose,
Miglitol Glitazones - PPAR? agonists eg.
Rosiglitazone Pioglitazone
Biguanides eg. Metformin
Sitagliptin
DPP-IV Inhibitors
16
Summary of AvailableNon-oral Agents
NPH neutral protamine hagedorn
17
Conventional Antihyperglycemic AgentsMajor Sites
of Action
18
Incretin TherapiesMajor Sites of Action
Drucker DJ. Diabetes Care. 2003262929-2940
Ahrén B et al. J Clin Endocrinal Metab.
20048920782084.
19
Metabolic Effects of Noninsulin Antihyperglycemics

20
Adverse Effects and Limitations of Noninsulin
Antihyperglycemics
Special populations elderly, renal-impaired,
and CHF patients
Physicians Desk Reference. 61st ed. Montvale,
NJ Thomson PDR 2007.
21
Antihyperglycemic MonotherapyAverage Therapeutic
Effect on A1C
Reduction in A1C ()
Placebo-adjusted absolute percentage of A1C
reduction. Different studies had different
recruitment criteria, particularly baseline
A1C Kimmel B, Inzucchi SE. Clin Diabetes.
20052364-76
22
Sulfonylureas

• Glyburide 2.5 mg QD to 10 mg BID
• Glipizide 5 mg QD to 20 mg BD
• Disadvantages Hypoglycemia
• Weight Gain
• Secondary Failure

23
Repaglinide (Prandin) Nateglinide (Starlix)
Dosage and Administration

• Taken from 0 to 30 minutes before meals
• Repaglinide 0.5 to 4 mg Nateglinide 60-120
  mg
• Patients who skip or add an extra meal
  shouldskip or add an extra dose
• Allow 1-week interval between dose adjustments

24
Metformin Prescribing Considerations

• Dose 500 mg QD to 1000 mg BID
• Reduces hepatic glucose production
• Advantages No weight gain, lipids improved
• Disadvantages GI side effects (titrate slowly)
• Lactic acidosis

25
Metformin Prescribing Considerations

• Metformin is contraindicated in
• renal dysfunction serum creatinine ³1.5 mg/dL
  (men) or ³1.4 (women), or abnormal creatinine
  clearance
• CHF requiring pharmacologic treatment
• use of iodinated contrast materials for
  radiologic studies
• known hypersensitivity to metformin
• acute or chronic metabolic acidosis, including
  diabetic ketoacidosis

Metformin Package Insert. Metformin hydrochloride
Rx List Monograph.
26
Acarbose/Miglitol Dosing Guidelines

• TID dosing at start of each main meal
• Initiate therapy with 25 mg QD
• Increase dosage gradually to minimize GI
  adverse effects
• Maintenance dosage, 50 mg-100 mg tid

27
Disadvantages of Acarbose/Miglitol

• GI side effects
• flatulence (80), diarrhea (27), nausea (8),
• vomiting (7)
• start with low doses (25 mg with each meal),
• titrate slowly to therapeutic range

28
Thiazolidinedione Dosing Guidelines

• Rosiglitazone (Avandia) 4 mg BID/8 mg QD
• Pioglitazone (Actos) 15, 30, 45 mg QD
• Advantages Can be used in renal insufficiency
• Side effects weight gain, pedal edema
• Caution CHF No more regular LFT Monitoring
• Possible increased CAD with Rosiglitazone

29
Treatment ConsiderationsNon-insulin
Antihyperglycemic Agents

• Choice of treatment should be based on
• Glucose control
• Glycemic lowering effects (speed, duration)
• Other metabolic effects
• Tolerability
• Contraindications/Drug interactions
• Individual needs of patient
• Below baseline A1C 8.0, all non-insulin drugs
  used as monotherapy yield comparable A1C
  reductions

Bloomgarden ZT et al. Diabetes Care.
2006292137-2139 Kimmel B, Inzucchi SE. Clin
Diabetes. 200523 64-76 Kahn SE et al. N Engl J
Med. 2006 2427-2443
30
Type 2 DiabetesADA Suggested Treatment Algorithm
Years from diagnosis
0
10
5
15
-10
-5
Onset
Diagnosis
Type 2 diabetes
Pre-diabetes
Nathan DM et al, Diavetes Care 2006291963-72
31
Traditional Treatment Algorithm forType 2
Diabetes Mellitus
Diet and Exercise
Nonpharmacologic measures inadequate FPG gt140
mg/dl HbA1cgt7
Alternative First-Line Therapeutics
Usual First-Line Monotherapeutic
Agents Metformin or Sulfonylurea
Acarbose/Miglitol(Postprandial
hyperglycemia) Repalinide/Nateglinide(Erratic
meals renal impairment)
Rosiglitazone Pioglitazone (Insulin
resistance or renal impairment) Insulin(If
very symptomatic)
or
or
32
Traditional Treatment Algorithm forType 2
Diabetes Mellitus
Monotherapy adequateFPG lt120 mg/dl, HbA1c
lt7 Continue
Monotherapy inadequateFPG gt 140 mg/dl, HbA1c
gt7 Initiate combination oral therapy
Most frequently used combination
MetforminSulfonylurea
Other possible combinations
Sulfonylurea ThiazolidinedioneRepaglinide/Nateg
linide MetforminMetformin ThiazolidinedioneS
ulfonylurea Alpha Gluconidase Inhibitor
33
Proposed Treatment Algorithm for Type 2 Diabetes
Mellitus
MonotherapyInadequate FPG gt140 mg/dl HbA1c gt7
Combination Oral TherapyInadequateFPG gt140
mg/dl, HbA1c gt8
Consider (1) Triple oral agent therapy(2)
Adding insulin and/or referral to Endocrinologist
34
Natural History of Type 2 Diabetes
Postmeal glucose
Plasma Glucose
Fasting glucose
126 mg/dL
Insulin resistance
Relative ?-Cell Function
Insulin secretion
?20
?10
0
10
20
30
Years of Diabetes
Adapted from International Diabetes Center (IDC).
Minneapolis, Minnesota.
6-6
35
Progressive Decline of ?-Cell Function in the
UKPDS
100
80
60
?-Cell Function ( ?)
40
20
0
?10
?9
?8
?7
?6
?5
?4
?3
?2
?1
0
1
2
3
4
5
6
Years
Adapted from UK Prospective Diabetes Study
(UKPDS) Group. Diabetes. 1995441249-1258.
36

• Over time,most patients with type 2 diabetes
  will needinsulinto control glucose

6-7
37
Barriers to Insulin Therapy

• Insulin therapy might cause
• Worsening Insulin Resistance
• More Cardiovascular Risk
• Weight Gain
• Hypoglycemia

6-8
38
The Most Severe Insulin Resistance is .The
resistance of medical practitioners to start
Insulin !!!
6-8
39
Initiating Insulin Therapy

• Mimicking Nature
• The Basal/Bolus Insulin Concept

6-16
40
The Basal/Bolus Insulin Concept

• Basal Insulin
• Suppresses glucose production between meals and
  overnight
• Nearly constant levels
• 50 of daily needs
• Bolus Insulin (Mealtime or Prandial)
• Limits hyperglycemia after meals
• Immediate rise and sharp peak at 1 hour
• 10 to 20 of total daily insulin requirement at
  each meal
• Ideally, for insulin replacement therapy, each
  component should come from a different insulin
  with a specific profile

6-20
41
Comparison of Human Insulins and Analogs

• Insulin Onset of Duration
  ofPreparations Action Peak
  Action
• Lispro/Aspart 5-15 minutes 1-2 hours 4-6 hours
• Human Regular 30-60 minutes 2-4 hours 6-10 hours
• Human NPH/Lente 1-2 hours 4-8 hours 10-20 hours
• Ultralente 2-4 hours
  Unpredictable 16-20 hours
• Glargine 1-2 hours Flat 24 hours
• Levemir 1-2 hours Flat 12-24 hrs

6-22
Courtesy Matt Riddle and J. Rosenstock
42
Starting With Basal Insulin

• BIDS Regime (Bedtime Insulin
• Daytime Sulfonylurea)
• Combination Sulfonylurea
• Evening Basal Insulin

6-39
43
Treating Fasting Hyperglycemia Lowers the Entire
24-Hour Plasma Glucose Profile
400
20
300
15
200
Plasma Glucose (mg/dL)
Hyperglycemia due to increase in fasting glucose
10
Plasma Glucose (mmol/L)
100
5
Normal
Meal
Meal
Meal
0
0
6
6
10
14
18
22
2
Time of Day (h)
Comparison of 24-hour glucose levels in control
subjects vs patients with diabetes
(Plt0.001). Adapted from Polonsky K et al. N Engl
J Med. 19883181231-1239.
44
BIDS Regime Rationale

• Decreases nighttime hepatic glucose production
  (insulin)
• May ameliorate glucose toxicity on ?-cells,
  increasing response to sulfonylurea
• Daytime control mediated by sulfonylureas/insulin
  sensitizers

Riddle, et al. Diabetes Care. 1998211052-1057.
5-11
45
Starting Evening Insulin

• Continue oral agent(s) at same dosage (eventually
  reduce)
• Add single, evening insulin dose (around 10 U)
• NPH (bedtime)
• 70/30 or 75/25 (evening meal)
• Glargine (bedtime or anytime) Detemir
• Adjust dose by fasting SMBG
• Increase insulin dose weekly as needed
• Increase 4 U if FBG gt140 mg/dL
• Increase 2 U if FBG 120 to 140 mg/dL
• Treat to target (usually lt120 mg/dL)

6-59
46
BIDS Regime in Type 2 Diabetes

• 1 injection with no mixing
• Insulin pens for increased acceptance
• Slow, safe, and simple titration
• Low dosage
• Limited weight gain
• Effective improvement in glycemic control

47
Advancing Basal/Bolus Insulin
Indicated when FBG acceptable but


HbA
gt7 or gt7.5
1c
and/or
SMBG before dinner gt180 mg/
dL


Insulin options

To bedtime NPH, add morning NPH and
mealtime Regular or
Lispro

To suppertime 70/30, add morning 70/30

To
Glargine
, add mealtime Regular or
Lispro
Oral agent options


Usually stop
sulfonylurea
Continue
metformin
for weight control?

Continue
glitazone
for
glycemic
stability?

48
Treating Fasting Hyperglycemia Lowers the Entire
24-Hour Plasma Glucose Profile
400
20
300
15
200
Plasma Glucose (mg/dL)
Hyperglycemia due to increase in fasting glucose
10
Plasma Glucose (mmol/L)
100
5
Normal
Meal
Meal
Meal
0
0
6
6
10
14
18
22
2
Time of Day (h)
Comparison of 24-hour glucose levels in control
subjects vs patients with diabetes
(Plt0.001). Adapted from Polonsky K et al. N Engl
J Med. 19883181231-1239.
49
Treating Fasting Hyperglycemia Lowers the Entire
24-Hour Plasma Glucose Profile
400
20
300
15
200
Plasma Glucose (mg/dL)
Hyperglycemia due to increase in daytime glucose
10
Plasma Glucose (mmol/L)
100
5
Normal
Meal
Meal
Meal
0
0
6
6
10
14
18
22
2
Time of Day (h)
Comparison of 24-hour glucose levels in control
subjects vs patients with diabetes
(Plt0.001). Adapted from Polonsky K et al. N Engl
J Med. 19883181231-1239.
50
Limitations of Current Treatment Options for
Type 2 Diabetes

• Durability of effect - ß-cell function
  declines regardless of treatment
• Treatment is more difficult for patients with
  hypoglycemic risks or obesity

Saydah SH, et al. JAMA. 2004291335-342 Turner
RC, et al. JAMA. 19992812005-2012.
51
Newer Drugs for Type 2 Diabetes Drugs Which
Could Improve ?-cell function

• GLP1 Analog Exenatide Byetta
• DPP-IV Inhibitors Sitagliptin - Januvia

52
GLP-1 Modulates Numerous Functions in Humans
GLP-1 Secreted upon the ingestion of food
Promotes satiety and reduces appetite
Alpha cells ? Postprandialglucagon secretion
Liver ? Glucagon reduces hepatic glucose output
Beta cellsEnhances glucose-dependent insulin
secretion
Stomach Helps regulate gastric emptying
Data from Flint A, et al. J Clin Invest.
1998101515-520 Data from Larsson H, et al.
Acta Physiol Scand. 1997160413-422Data from
Nauck MA, et al. Diabetologia. 1996391546-1553
Data from Drucker DJ. Diabetes. 199847159-169
53
Exenatide Reduced A1C and Weight Large Phase 3
Clinical Studies Combined
Placebo BID 5 µg Exenatide BID10 µg Exenatide
BID
0.5
-0.5
0.1
0
0
-0.5
? A1C ()
? Weight (kg)
-0.5
-1
-0.6
-1
-0.9
-1.5
-1.5
-2
ITT 30-wk data N 1446 Mean (SE) Plt0.005
Weight was a secondary endpointData on file,
Amylin Pharmaceuticals, Inc.
54
Nausea Large Phase 3 Clinical Studies Combined

• Most episodes mild to moderate in intensity
• Episodes were generally
• Intermittent
• More frequent at initiation of treatment
• Decreased over time
• Low incidence of severe nausea (placebo 1,
  exenatide 4)
• Low dropout rate due to nausea (placebo lt1,
  exenatide 3)

ITT 30-wk data N 1446 Exenatide Prescribing
Information, 2005 Data on file, Amylin
Pharmaceuticals, Inc.
55
Exenatide Indication

• Exenatide is indicated as adjunctive therapy to
  improve glycemic control in patients with type 2
  diabetes mellituswho are taking
• MET/SFU/TZD
• A combination of MET and SFU
• But have not achieved adequate glycemic control

Exenatide Prescribing Information, 2005
56
GLP-1 Secretion and MetabolismDPP-IV Inhibitors
Mixed meal
GLP-1 (9-36) inactive
X
Intestinal GLP-1 release
DPP-IV
GLP-1 (7-36) active
Rapid inactivation (gt80 of pool)
Plasma
GLP-1 actions
Renal clearance
Kieffer TJ, Habener JF. Endocr Rev.
199920876-913Deacon CF et al. Diabetes.
1995441126-1131
57
Sitagliptin

• Clinical Use
• Approved for use as monotherapy and in
  combination with metformin or glitazone
• Mechanism of Action
• Inhibits DPP-IV and prolongs GLP-1 levels
• Increase insulin secretion
• Reduces glucagon secretion
• Benefits
• No weight gain (possible wt loss)
• Favorable side effect profile

58
Beta Cell Deficiency in DiabetesInsulin and
Amylin

• Amylin
• Reported in 1987
• 37-amino acid peptide
• Co-located and co-secreted with insulin from
  pancreatic ß-cells

amylin
insulin
Unger and Foster. Williams Textbook of
Endocrinology, 1992.
59
Effects from Pramlintide (Symlin)

• Modulate gastric emptying and delay the
  absorption of carbohydrates (improved post meal
  glucose values)
• Anti-glucagon effects
• Suppresses the appetite and leads to weight loss
• For type 1 and insulin using type 2 DM
• Side effects Nausea, anorexia, hypoglycemia

60
Pramlintide Therapy Offers A Unique Combination
of Effects in Type 2 Diabetes
All Patients, Recommended Dose
Change in HbA1c
Change in Weight (lb)
Change in Insulin Use ()
Baseline 9.3 9.1
Week 4
Week 13
Week 26
Week 4
Week 13
Week 26
Week 4
Week 13
Week 26
0
6
2
-0.1
5
-0.2
1
4
-0.3
3
0
2
-0.4
-1
1
-0.5
0
-0.6
-2
-1
-0.7
-3
-2
-0.8
-3
-4
Placebo Insulin (N284)
Pramlintide Recommended Dose Insulin (N292)
Data on file, Amylin Pharmaceuticals, Inc.
61
Insulin Use in Type 1 Diabetes

• Insulin Requirements 0.5 units/Kg/day
• Basal Requirements 50
• Prandial Requirements 50
• In a 70 Kg (154 lbs individual) 70 X 0.5 35
  units
• 18 units NPH/Glargine/Detemir
• 18 units Prandial based on calories
• 30 calories at breakfast 5 units
• 30 of calories at lunch 5 units
• 40 of calories at dinner 6-7 units

62
Insulin Use in Type 1 Diabetes

• Patient education extremely important
• Frequent SMBG
• Difference between prandial and basal insulins
  and correction factor
• Understand differences between lispro and regular
• Understand when regular may be better than lispro
• Prandial insulin doses need to be initially
  estimated with carbohydrate or calorie estimation

63
Type 2 DiabetesGoal-Oriented Treatment Paradigm
A1C Below 7
Years from diagnosis
15
5
10
20
-5
-0
Pramlintide Insulin
Onset and Diagnosis
Metformin
A1Cgt7? Add on
Prediabetes therapy?
Preferred for most patients
Type 2 diabetes
Pre-diabetes
64
Other Insulin Delivery Systems
65
Inhaled Insulin
66
Pulmonary Insulin Delivery System Alkermes AIR /
Lilly Prototype

Large, Porous Particles
67

Mannkind Pulmonary Insulin Delivery System
68
Pulmonary Inhaled Insulin Issues.

• Absorption 10-20
• Safety .. Lung function
• Insulin antibodies
• Patients with COPD/Asthma
• Absorption in smokers

Alternative routes of insulin delivery. Diabet
Med. 2003 Nov20(11)886-98.
69
Oral Delivery of Insulin

• The conjugated drug-polymer is not degraded as
  readily by enzymes in the body compared with the
  drug in its native form
• The conjugated drug is absorbed more
  efficiently across the GI wall due to enhanced
  diffusion

70
Buccal Delivery of Insulin
Oral Inhaler - Spary Mist
71
Dermal Delivery of Insulin

• Altea Therapeutics Micropore Technology rapidly
  and painlessly causes tiny openings or
  'micropores', that are tens of microns in
  diameter, to form through the stratum corneum,
  the dead outer layer of the skin
• No mechanical probes or skin puncturing devices
  are used
• Insulin diffuses through these micropores. The
  'skin microporation' technology can be configured
  to achieve a variety of drug delivery profiles
  including sustained, pulsatile, rapid and
  on-demand dosing.

72
Natural History of Type 2 Diabetes Mellitus
Onset of Diabetes
Complications
Disability
Death
IGT
Ongoing Hyperglycemia
Insulin resistanceHyperinsulinemiaDyslipidemia
Atherosclerosis Hypertension
RetinopathyNephropathy Neuropathy
BlindnessRenal Failure CAD Amputations
73
Diabetes Prevention Program
Average follow-up of 2.8 years
? 31
? 58
Cases / 100 person-years
Intensive Lifestyle
Placebo
Metformin
All pair-wise comparisons significantly
different by group sequential log-rank test
The Diabetes Prevention Program Research Group.
New Engl J Med 2002346393-403.