Transcript beta cells

Diabetes Rx:
A Primer
Laura Shane-McWhorter, PharmD,
BCPS, FASCP, CDE, BC-ADM
Professor (Clinical)
University of Utah College of Pharmacy
Department of Pharmacotherapy
Objectives
• Describe presentation differences in persons
with Type 1 and Type 2 diabetes
• Explain initial drug therapy choices for persons
with Type 2 diabetes
• Differentiate between the available drug classes
for treatment of Type 2 diabetes, based on dose,
ADRs, pharmacokinetics, and efficacy
• Given a patient with Type 2 diabetes, develop a
monitoring plan, including labs for disease
outcomes and drug-related monitoring
Diabetes Mellitus (DM)
A chronic disorder:
• Characterized by hyperglycemia
• Abnormal CHO, fat, protein metabolism
• Acute complications (hypo/hyperglycemia, secondary
infections)
• Marked propensity to develop chronic complications:
• Renal
Microvascular
• Ophthalmic
• Neurologic
• Cardiovascular disease - Macrovascular
Diabetes: The Statistics
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Persons with diabetes:
• 24 million persons
• 12.2 million in > 60 yrs
1.6 million new cases
• diagnosed in people aged 20 years or
older in 2007
Pre-diabetes: 57 million people
Lifetime risk
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Males: 32.8%
Females: 38.5%
Hispanic women: 52.5%
www.diabetes.org/diabetes-statistics/prevalence.jsp
Prevalence of Diabetes in the USA
Diagnosed Diabetes
17.5 Million
Undiagnosed Diabetes
6.6 Million
Diabetes Costs
• 2007 Costs of diabetes in the US:
• Total: $174 billion
• Medical costs
• $116 billion
• Decreased productivity
(absenteeism,  work productivity,
inability to work due to disability,
and premature mortality)
• $58 billion
Diabetes Care 2008;31:1-20.
Diabetes Costs
• 2008 Costs of diabetes in the US:
• Total: $218 billion (10% of USA
healthcare spending)
• Medical costs - $174.4 billion
• $14.9 billion for T1DM
• $159.5 billion for T2DM
• Cost for undiagnosed DM - $18 billion
• Cost for pre-DM - $25 billion
• Cost for GDM - $636 million
Associated Press
Diabetes Statistics…
• Medications/supplies
• $3.7 billion for insulin
• $1.8 for supplies
• $8.6 billion for oral agents
• $12.7 billion for retail Rxs
Diabetes Care 2008;31:1-20.
BJ
• BJ is a 20 y/o junior in college. She is concerned about
having a lot of UTIs in the last eight months. She is
seen at Student Health for an upper respiratory infection
and random glucose values in the last month have been
> 200 mg/dL. She complains of polyuria and polydipsia.
She has also been losing weight without trying. Her labs
are the following:
•
•
•
•
•
Glucose 340 mg/dL
+ Glutamic Acid Decarboxylase Antibodies
C-peptide 0.5 ng/mL (0.5-5 ng/mL)
+ ketonuria
5’4” tall and 104 lbs (weight was 118 lbs 3 months ago)
RE
• RE is a 45 y/o male seen in clinic for balanitis
and onychomycosis. The patient is 5’10” and
weighs 240 lb. He complains of thirst and
polyuria. His fasting glucose values have been
in the low 120s (mg/dL). He has gained 40 lbs in
the last 2 years.
• Today, random glucose is 359 mg/dL
• BP 148/98 mm Hg
• Fasting lipids total cholesterol 240 mg/dL,
triglycerides 438 mg/dL, HDL of 32 mg/dL
Criteria for Diagnosis
• Fasting plasma glucose (FPG) > 126mg/dL†
• Symptoms of diabetes plus casual plasma glucose
concentration > 200 mg/dL* (3 Ps, wt loss)
• 2 hr PG during Oral Glucose Tolerance Test (75 g
OGTT) is > 200 mg/dL
• A1C > 6.5% (NGSP)
* Casual is defined as any time of day without regard to time
since last meal.
† Fasting is defined as no caloric intake for at least 8 hours.
• In absence of unequivocal hyperglycemia, confirm by
testing on different day (same or different test)
• OGTT not for routine use
Classification
TYPE 1
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< 30 y/o (75% < 18 y/o)
Abrupt onset (wt , 3 Ps)
5-10%
FH – emerging genetic basis
No insulin production
Normal/underweight
Ketosis common
Whites: more common
Etiology: Autoimmune
Initially, no microvascular
complications
Initially, macrovascular
complications rare
TYPE 2
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Any age;  with age
Gradual onset (+ Sx)
90-95%
FH – strong
Insulin resistance, impaired insulin
secretion (may need insulin)
80% overweight
Ketosis rare; HHS may occur
Ethnic minorities: common
Etiology: Obesity? Insulin
resistance?
Initially microvascular
complications common
Initially, macrovascular
complications common
Pathophysiology of Type 1 DM
• Primary defect is absolute insulin deficiency with
almost total loss of functional beta cell mass in
months before diagnosis
• Beta cell mass loss usually related to
autoimmune destruction of pancreatic beta cells
• Fasting hyperglycemia when 80-90% of beta cell
mass is destroyed
• e.g., no insulin secretion
Pathophysiology of Type 1 DM
• Measurable antibodies due to autoimmune destruction of
beta cells
• Glutamic acid decarboxylase autoantibodies (GAD)
• Insulin autoantibodies (against islet tyrosine phosphatase)
• Islet cell antibodies (not standardized in labs)
• Significant HLA association (DR3, DR4) on Chromosome
6 (40 known genes on Chromosome 6 contribute risk)
• Strong genetic linkage to DQA and B genes
Pathophysiology of Type 1 DM
• Disturbances in lipid and amino acid metabolism in
those that later declare with T1DM
•  succinic acid/phosphatidylcholine at birth
•  TGs/antioxidant ether phospholipids
•  lysophosphatidylcholines (pro-inflammatory) months
before beta cell autoimmunity
• Absolute amylin deficiency (co-stored, co-secreted
with insulin)
• Disrupted compensatory systems of glucose
regulation (glucagon) that  risk for hypoglycemia
and erratic glucose control
Presentation of Type 1 DM
• 20-40% of T1DM present with DKA after
several days of polyuria, polydipsia,
polyphagia, and weight loss
• Some T1DM pts may enter “honeymoon”
phase
• Some residual beta cell function
Islet Cell Dysfunction
Glucagon
(alpha cells)
Pancreas
Glucose output
Liver
Insulin
Amylin
(beta cells)
Blood glucose
Glucose uptake
Muscle
Adipose
tissue
1. Del Prato S,Marchetti P. Horm Metab Res. 2004;36:775–781.
2. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.
Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.
BJ
• BJ is a 20 y/o junior in college. She is concerned about
having a lot of UTIs in the last eight months. She is
seen at Student Health for an upper respiratory infection
and random glucose values in the last month have been
> 200 mg/dL. She complains of polyuria and polydipsia.
She has also been losing weight without trying. Her labs
are the following:
•
•
•
•
•
Glucose 340 mg/dL
+ Glutamic Acid Decarboxylase Antibodies
C-peptide 0.5 ng/mL (0.5-5 ng/mL)
+ ketonuria
5’4” tall and 104 lbs (weight was 118 lbs 3 months ago)
BJ
• How should we confirm the diagnosis of DM
when a glucose is repeated?
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•
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•
Fasting glucose?
Postprandial glucose?
OGTT?
A1C?
BJ
• What tests suggest that BJ has Type 1 DM?
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Glucose 340 mg/dL?
+ Glutamic Acid Decarboxylase Antibodies?
C-peptide 0.5 ng/mL (0.5-5 ng/mL)?
+ ketonuria?
5’4” tall and 104 lbs (weight was 118 lbs 3 months
ago)?
What is A1C and Why is it Important ?
• Glucose attaches to proteins throughout the body
through a reaction called glycosylation
• HbA is the predominant form of Hb contained in RBCs
• This serves as a marker for the extent of protein
glycosylation
• HbA has 3 fractions (1a, 1b, 1c) where 1c is the
predominant form (95%)
• The higher the BG the greater the fraction of A1C that is
glycosylated
• A1C represents average BG over previous 3 months
• Normal A1C is 4-6% (<126 mg/dL)
• Pre-DM: 5.7-6.4%
ADAG Trial
• Average glucose (mg/dL)
• 28.7 x A1C – 46.7
• 28.7 x 6 – 46.7 = 126 mg/dL
A1C
EAG
5%
6%
7%
8%
9%
10%
11%
12%
13%
14%
97 mg/dL (5.4 mmol/L)
126 mg/dL (7 mmol/L)
154 mg/dL (8.5 mmol/L)
183 mg/dL (10.1 mmol/L)
212 mg/dL (11.7 mmol/L)
240 mg/dL (13.3 mmol/L)
269 mg/dL (14.9 mmol/L)
298 mg/dL (16.5 mmol/L)
326 mg/dL (18.1 mmol/L)
355 mg/dL (19.7 mmol/L)
Diabetes Care 2008;31:1473-8
Relationship Between A1C and Average Blood Glucose Over
Past 2-3 Months
>10 Seriously >240 mg/dL
Elevated
8-10
7-8
6-7
<6
Elevated
Slightly Elevated
Good Goal
183-240 mg/dL
155-183 mg/dL
126-154 mg/dL
Non-Diabetes
<126 mg/dL
(Formula: 28.7 X A1C -46.7 = eAG)
ADAG Study. Diabetes Care 2008.
Target A1C Values
• TN is a 42 y/o female with Type 2 diabetes. She
has a 6 y/o child and a 14 y/o child – both have
Type 1 diabetes. Her father is 75 y/o and also
has diabetes. TN would like to know her goal
A1C.
Target A1C Values
• TN is a 42 y/o female with Type 2 diabetes. She
has a 6 y/o child and a 14 y/o child – both have
Type 1 diabetes. Her father is 75 y/o and also
has diabetes. TN would like to know her goal
A1C.
• What is TN’s goal A1C (per ADA)?
• < 6%
• < 7%
• < 8%
Target A1C Values
• What is TN’s goal BG (per ADA)?
• Fasting/preprandial?
• < 100 mg/dL
• < 110 mg/dL
• 70-130 mg/dL
• Postprandial?
• < 130 mg/dL
• < 140 mg/dL
• < 180 mg/dL
Target A1C Values
• TN is a 42 y/o female with Type 2 diabetes. She
has a 6 y/o child and a 14 y/o child – both have
Type 1 diabetes. Her father is 75 y/o and also
has diabetes.
• What is the goal A1C for her 6 y/o?
• Her 14 y/o?
• Her father?
Glycemic Control
(2010 ADA Guidelines)
A1C
Goal
Adults
Children 0-6
<7%
< 8.5% (> 7.5%)
Higher goals due to
hypoglycemia vulnerability
<8%
Age 6-12
Adolescents/
young adults
Elderly
< 7.5%
?
Treatment of Type 1 DM
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Insulin
MNT
Exercise
Other?
• Pramlintide
Role of Insulin
• Suppresses
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Hepatic glucose production
Lipolysis
Proteolyis
Gluconeogenesis
• Promotes
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Transport of glucose into adipocytes/myocytes
Glycogen synthesis
Insulin Secretion
• In adults without DM, the pancreas secretes 2550 units of insulin/day
• Basal insulin secretion 0.5-1 units/hour
• Additional insulin is secreted when BG > 100
mg/dL
• Insulin is secreted in response to CHO intake at
approximately 1 U/10-15 gram of CHO
• In humans without DM, BG:40-160 mg/dL
• BG> 40 mg/dL needed for normal brain function
The Basal/Bolus Insulin Concept
• Basal Insulin (Background insulin)
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Suppresses glucose production between meals and
overnight
•
Nearly constant levels
•
Supplies 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
6-
NORMAL PANCREAS
Insulin Effect
‘Bolus’ Insulin
(Meal Associated)
Basal Insulin
(~0.5-1.0 U/hr)
Insulin is released in response to varying
blood glucose levels and hypoglycemia
does not occur
6-23
Human Insulin
Type
Onset
Peak
Rapid
Lispro/Aspart/Glulisine
(Humalog/Novolog/Apidra)
5-15 min
Regular (Humulin/Novolin)
30-60 min
NPH (Humulin/Novolin)
2-4 hr
4-6 hr
Detemir (Levemir)
2
hr
6-8 hr
Glargine (Lantus)
2-4
hr
Flat
Premix Rapid
Humalog Mix 75/25
Humalog Mix 50/50
Novolog Mix 70/30
Premixed Regular
Humulin 70/30
Novolin 70/30
5-15 min
30-60 min
30-60 min
1-2 hr
2-3 hr
Duration
4-6 hr
6-8 hr
14-18 hr
12 hr (0.2 U/kg)
20 hr (0.4 U/kg)
20-24 hr
Dual 7-12 hr
14-18 hr
Dual 7-12 hr
Dual 7-12 hr
14-18 hr
14-18 hr
Islet Cell Dysfunction
Glucagon
(alpha cells)
Pancreas
Glucose output
Liver
Insulin
Amylin
(beta cells)
Blood glucose
Glucose uptake
Muscle
Adipose
tissue
1. Del Prato S,Marchetti P. Horm Metab Res. 2004;36:775–781.
2. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.
Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.
What is Amylin?
• A 37-AA peptide hormone that is co-stored with
insulin and co-secreted with insulin from the
pancreatic ß cell in response to nutrient stimuli
• Secreted in a pulsatile manner similar to insulin
• Absent in Type 1 DM
• Deficient in Type 2 DM
• Pramlintide (Symlin®) is a synthetic analog of
amylin
Pramlintide (Symlin®) - MOA
• Complements insulin in PPG homeostasis
• Suppresses postprandial glucagon secretion from
pancreatic  cells
• Neuroendocrine hormone – binds to CNS receptors
• Effects mediated through the vagus nerve
• Vagus nerve stimulates the gut
• Slows gastric emptying
• May enhance satiety through CNS activity
• High-affinity binding sites in the area postrema in the hindbrain
Pramlintide
Side Effects
• Nausea, fullness
• Abates with continued use
• ~ 4 weeks
• Hypoglycemia
•  prandial insulin dose by
50%
• Headache
Drug interactions
• Drugs that alter GI
motility
• Anticholinergics
• Drugs that alter nutrient
intake
• AGIs
• May delay absorption of
concomitant meds
• Give analgesics/OCPs
1 hr before/2 hrs after
Type 1 DM
Type 2 DM
Pramlintide – Effects on A1C, BG,
Weight, Insulin Dose
• Overall,  A1C 0.5 to 1%
• BUT…PPG  to near normal levels
•
140-180 mg/dL
•
Possibly due to restoration of first-phase insulin
secretion
• Weight 
•
1 to 1.5 kg
• Allows  in insulin dose
•
Variable effect for each person
SY
• SY is a 28 y/o patient with Type 1 DM and her
insulin regimen consists of Lantus 18 Units at
bedtime and Humalog 6 Units with meals. Her
A1C is 7.8% and she carb counts but she still
has high PPG values. She especially loves to
have cinnamon rolls on Tuesdays and
Thursdays and then again on the weekends.
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Is SY a candidate for pramlintide?
What is the starting dose?
If SY had Type 2 DM, what would be the starting dose
of pramlintide?
Trends in Type 2 Diabetes:
1988 - 2000 NHANES
• Average BMI  from 30.4 to 32.3 kg/m2
Pathophysiology of Type 2 DM
• Two main factors
• Insulin resistance
• Hepatic, skeletal muscle, adipose tissues
• Evident years before diagnosis
• Impaired insulin secretion
• Normal/  fasting plasma insulin
• At diagnosis, ~ 40% of beta cell mass is left (due to
apoptosis)
Pathophysiology of Type 2 DM
• Another main factor
• Patients have
• HTN
• Hyperlipidemia
• HIGH TGs
• Low HDL
•  PAI-1
RE
• RE is a 45 y/o male seen in clinic for balanitis
and onychomycosis. The patient is 5’10” and
weighs 240 lb. He complains of thirst and
polyuria. His fasting glucose values have been
in the low 120s (mg/dL). He has gained 40 lbs in
the last 2 years.
• Today, random glucose is 359 mg/dL
• BP 148/98 mm Hg
• Fasting lipids total cholesterol 240 mg/dL, triglycerides 438
mg/dL, HDL of 32 mg/dL
• Does RE have Type 1 or Type 2 DM?
Pharmacology & Pathophysiology
GLP-1
Analogs
Glucose Influx
Sulfonylureas
Glinides
Insulin
Alpha-glucosidase
inhibitors
Pramlintide
Hepatic
Insulin
Glucose
Hyperglycemia
Secretion
Output Biguanides
(TZD)
Insulin
TZD
(Biguanides)
Insulin
Peripheral
Glucose Uptake
Medications for Type 2 Diabetes
• Biguanides – e.g., Metformin
• Sulfonylureas
• Thiazolidinediones (Glitazones)
• Exenatide
• DPP-IV Inhibitors
• Glinides (Meglitinides)
• Alpha glucosidase inhibitors
• Colesevelam
• Insulin
AND…
• Bromocriptine (Cycloset®)
2009 ADA/EASD Consensus Algorithm
Tier 1 (Well-validated therapies)
Step 1
At Diagnosis:
Lifestyle (LS) + Metformin
Step 2
Lifestyle (LS) + Metformin
+
Basal Insulin
Step 3
Lifestyle (LS) + Metformin
+
Intensive Insulin
Diabetes Care 2009;32:193-203
Lifestyle (LS) + Metformin
+
Sulfonylurea
ADA/EASD Tier 2 – Less Validated
Step 1
At Diagnosis:
Lifestyle (LS) + Metformin
Lifestyle (LS) + Metformin
+
Pioglitazone
No hypoglycemia; Edema/HF; Bone 
Lifestyle (LS) + Metformin
+
GLP-1 agonist
No hypoglycemia; Wt ; N/V
Step 2
Lifestyle (LS) + Metformin
+ Pioglitazone
+ Sulfonylurea
Diabetes Care 2009;32:193-203
Step 3
Lifestyle (LS) + Metformin
+
Basal Insulin
Lifestyle (LS) + Metformin
+
Intensive Insulin
RE
• RE is a 45 y/o male seen in clinic for balanitis
and onychomycosis. The patient is 5’10” and
weighs 240 lb. He complains of thirst and
polyuria. His fasting glucose values have been
in the low 120s (mg/dL). He has gained 40 lbs in
the last 2 years.
• Today, random glucose is 359 mg/dL
• BP 148/98 mm Hg
• Fasting lipids total cholesterol 240 mg/dL, triglycerides 438
mg/dL, HDL of 32 mg/dL
• What medication should be started?
Biguanides - Metformin (Glucophage®)
• MOA:  hepatic gluconeogenesis
• Other effects
• Advantages
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Possible weight loss
Rapid effects
CVD benefits
No hypoglycemia
• Limitations
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GI side effects (titrate slowly)
Renal dysfunction (Lactic acidosis risk)
HF (but may use if HF is stable and Cr is normal)
Females of childbearing age – RPh must counsel
• Effects
•  A1C – 1-2%
UKPDS, UKPDS 10-yr Follow-Up (RRR)
UKPDS1 10-yr2
36% 27%
0
UKPDS1 10-yr2
39% 33%
UKPDS1 10-yr2
30% 30%
Meta analysis3
26%
-5
-10
-15
-20
-25
-30
-35
-40
Mortality
(all cause)
P=0.01;0.002
1 Lancet 1998;352:854-65
2 N Engl J Med 2008;359:1577-89
3 Arch Intern Med 2008;168:2070-80
MI
p=0.01;0.005
Macrovascular DM-related
(all endpoints) death
p=0.02
p=0.01
C-V Mortality
95% CI 0.62-0.89
Sulfonylureas
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Glipizide, glimepiride, glyburide
MOA: Stimulate insulin secretion
Monotherapy or combination
Advantages
• Rapid effects
• Limitations
• Weight gain
• Hypoglycemia (Don’t delay/skip meals)
• Elderly/  renal function
• Benefit at half of max doses
• 5-15% yearly secondary failure
• Effects
•  A1C – 1-2%
UKPDS 10-yr Follow-Up (RRR)
0
9%
17%
13%
15%
24%
-5
-10
-15
-20
-25
DM related
endpoints
p=0.04
N Engl J Med 2008;359:1577-89
DM related Mortality
death
(all cause)
p=0.01
p=0.007
MI
p=0.01
Microvascular
disease
p=0.001
Thiazolidinediones
• Pioglitazone (Actos®), Rosiglitazone (Avandia®)
• MOA: Bind PPAR ( insulin sensitivity in muscle, fat,
liver)
• Monotherapy or combination
• Advantages
• Improves lipids
•  visceral fat/PAI-1
• Limitations
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•
•
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Fluid retention/weight gain
HF/cardiac events
 fracture risk
Effect takes several weeks
• Effects
•  A1C – 0.5-1.4%
Alpha Glucosidase Inhibitors
• Acarbose (Precose®), Miglitol (Glyset®)
• MOA: Inhibit intestinal brush border enzymes that break
down saccharides (e.g.,  CHO absorption)
• Monotherapy or combination
• Advantages
• Weight neutral
•  PPG
• Limitations
• TID dosing
• Slow titration
•  GI side effects
• Effects
•  A1C – 0.5-0.8%
Glinides
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•
•
•
Repaglinide (Prandin®), Nateglinide (Starlix®)
MOA: Same as sulfonylurea (release insulin)
Monotherapy or combination
Advantages
• Less hypoglycemia than sulfonylureas
•  PPG
• May use in  renal function
• Limitations
• TID dosing
•  weight
• How to titrate repaglinide
• Effects
•  A1C – 0.5-1.5%
Bile Acid Sequestrant
•
•
•
•
Colesevelam (Welchol®)
MOA: Blocks glucose absorption
Monotherapy or combination
Advantages
• Not absorbed; not metabolized
•  lipids
• Limitations
• Constipation, nausea, dyspepsia
•  TGs
• May bind medications
• Effects
•  A1C – 0.5%
Dopamine Agonist
• Bromocriptine mesylate (Cycloset®)
• MOA: DA boost may re-set biological clock to improve
metabolic problems
• Monotherapy/Combination with SU, metformin/SU
• Advantages
• First “new” drug to follow FDA guidelines: Evaluated for
potential CV adverse events (MI, stroke, other CV events)
• May help lower elevated PPG; may  weight
• Limitations
• Nausea/vomiting, HA, fatigue, orthostasis;  lactation
• “Psychosis;” May  effectiveness of DA antagonists
• May  ergot side effects; CYP3A4 substrate
• Effects
•  A1C ~ 0.5%
HC
•
•
•
•
•
•
•
HC is a 56 y/o male with T2DM x 6 years
On glyburide/metformin 5/500 mg – 2 po BID
H/O CAD, HTN, IBS, NASH (fatty liver)
FBG: 180-220 mg/dL
PPG: 250-320 mg/dL
A1C = 9.6%
Should we?
•
•
•
•
Intensify lifestyle?
Add TZD?
Add exenatide?
Start insulin?
Progressive Decline of -Cell Function-UKPDS
100
-Cell Function (% )
80
60
40
20
0
-10 -9
-8
-7
-6
-5
-4
-3
-2 -1
Years
0
1
2
3
4
5
6
Adapted from UK Prospective Diabetes Study (UKPDS) Group. Diabetes. 1995; 44:1249-1258.
Adding Insulin
• If patient on 2-4 oral agents and A1C still
elevated, time to add insulin
• Typical delay when 2 oral meds fail?
Adding Insulin
• Add glargine 10 Units hs?
• Advantage – can titrate every few days or weekly; less
weight gain/hypoglycemia but expensive
• Add NPH 10 Units hs?
• Advantage –  cost but must have good technique and
patient may have hypoglycemia
• Add levemir 10 Units hs or 5 units bid?
• Advantage – can titrate; less weight gain/hypoglycemia
• BUT…half of all patients eventually need prandial insulin
Bottom line: Must talk to patient and individualize
treatment
Adding Insulin
• When to add prandial insulin in Type 2 DM?
• One opinion:
• When basal insulin dose is > 40 to 50 Units and A1C > 7%
• When basal dose approaches 1 Unit/kg and A1C > 7%
• Add lispro 75/25 or aspart 70/30 twice/day?
• Advantage – starting bolus and basal insulin; but more
weight gain/hypoglycemia
Bottom line: Must talk to patient and individualize
treatment
Islet Cell Dysfunction & Insulin Resistance
Glucagon
(alpha cells)
Pancreas
Glucose output
Liver
Gut
GLP-1
Insulin
Amylin
(beta cells)
Blood glucose
Glucose uptake
Muscle
Adipose
tissue
1. Del Prato S,Marchetti P. Horm Metab Res. 2004;36:775–781.
2. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.
Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.
The Incretin Effect
GLP-1 restores first
phase insulin secretion
What Are The Incretins?
•
•
•
Gastrointestinal tract-derived hormones that are
released in response to nutrient ingestion
Approximately 60% of insulin secreted in response
to a meal is due to the incretin effect
2 major incretins identified to date
•
Glucagon-like peptide 1 (GLP-1)
• Released from L cells in ileum
•
Glucose-dependent insulinotropic peptide (GIP)
• Released from K cells in jejunum
What Are The Incretins?
• Common actions of 2 major incretins
• Exert effects on ß-cells to stimulate glucosedependent insulin secretion
• Regulate ß-cell proliferation and cytoprotection
• GLP-1 and GIP produce similar insulin
release effects up to BG of 108 mg/dL
• GIP has little effect at BG > 140 mg/dL
Exenatide (Byetta®)
• Synthetic GLP-1 analog
• Synthetic version of exendin-4 (from Gila
monster saliva)
• Injectable
• Side effects
•
•
•
•
Nausea
Hypoglycemia
Pancreatitis
Altered renal function
Exenatide – Drug Interactions
• May see hypoglycemia if given with SU
•
•
Consider  dose of SU before starting
Dose reduction is a clinical judgment (~ ½)
• May slow rate of absorption of concomitant
orally-administered drugs
•
Take OCPs, antibiotics 1 hr before exenatide
• If a concomitant med must be given with
food, consider administering with a snack
other than when exenatide is injected
• Don’t use: Type 1 DM (or on insulin), ESRD,
gastroparesis
Exenatide (Byetta®)
• Dose: Start out at 5 mcg bid (breakfast,
supper) then increase to 10 mcg bid after at
least one month if tolerated
Exenatide (Byetta®)
• Effects on A1C, BG, Weight
•
•
•
•
A1C  0.5% to 1%
FBG  ~ 8 mg/dL
PPG  60-70 mg/dL
Weight  is variable
• In studies, up to 2.8 kg
• May be greater in individual patients
On The Horizon?
• Exenatide Once Weekly
• Advantage – once/week
• 1.9%  in A1C for 2 mg vs 1.7%  for qd (10 mcg)
• Disadvantage – unknown long-term side effects
• Liraglutide (Victoza®)
• Advantage - Once/day dosing
• Disadvantage – a few patients developed small
thyroid papillary carcinomas
Glucagon Like Peptide 1 pathophysiology
Mixed
meal
Long-term GLP-1 Actions:
•Increase insulin synthesis
•Promote ß-cell differentiation
Intestinal
GLP-1
release
Active
GLP-1
Acute GLP-1 Actions:
•Augment glucose-induced
insulin secretion
•Inhibit glucagon secretion and
hepatic glucose production
•Slow gastric emptying
•Increase glucose disposal
Adapted from Rothenberg P. Diabetes. 2000;49(suppl 1):A39
Drucker DJ. Diabetes Care 2003;26:2929-2940.
DPP-4
DPP-4
inhibitor
Inactive GLP-1
DPP-IV Inhibitors
• Sitagliptin (Januvia®)
• Saxagliptin (Onglyza®)
• Mechanism of action
•
•
•
Inhibit breakdown of GLP-1 and GIP
Hence, levels of GLP-1 and GIP rise, especially
in response to meals
• This inhibits glucagon
• Stimulates endogenous insulin secretion
when glucose is highest
Since these agents increase only glucosestimulated insulin secretion, there is little risk of
hypoglycemia
Gliptins
• Side effects
•
•
•
•
•
Pancreatitis (within 30 days of start; metformin is
protective)
Headache
Nasopharyngitis
URIs (UTI with saxagliptin)
Other concerns?
• Thus far, no problems but theoretical
concerns regarding the immune system since
other DPP-IV substrates include growth
factors and cytokines
• DPP-IV may affect T-cell activity
Gliptins
• Sitagliptin dose adjustment in renal
impairment
• Cr Cl > 30 to < 50 mL/min is 50 mg daily
• Males: Cr > 1.7 to < 3 mg/dL
• Females: Cr > 1.5 to < 2.5 mg/dL
• Cr Cl < 30 mL/min is 25 mg daily
• Males: Cr > 3 mg/dL
• Females: Cr > 2.5 mg/dL
• On dialysis
• Not studied in hepatic impairment
• Saxagliptin 2.5 to 5 mg daily
• 2.5 mg daily for CrCl < 50 mL/min
DPP-IV Inhibitors
• Gliptins:
• If A1C is ~ 8-9%
• A1C  0.5 to 0.8%
• If A1C is 9-10%
• A1C  1.4%
• FBG  ~16 to 22 mg/dL (sitagliptin); 10-15 mg/dL (saxagliptin)
• PPG  ~ 50-60 mg/dL (sitagliptin); 43-45 mg/dL (saxagliptin)
• Weight neutral
• Will help if close to A1C goals
• Will help with decreasing PPG
• Not evaluated in persons on insulin
Monitoring?
Drug
Dose
ADRs
Cautions
A1C
Metformin
2000 mg/day
GI; lactic
acidosis
Cr < 1.4 mg/dL
Cr < 1.5 mg/dL
1-2%
Sulfonylureas
½ of max dose;
glyburide,glipizide
(10 mg)
glimepiride (4 mg)
Hypoglycemia,
weight gain,
photosensitivity
Do not skip or
delay meals;
weight,
sunscreen
1-2%
TZDs
Pio – 45 mg/day
Rosi – 8 mg/day
Weight gain,
fluid retention,
HF, fractures
LFTs, weight;
baseline cardiac
evaluation
0.5-1.4%
Glinides
Repaglinide – 16
mg/day
Nateglinide – 120
mg/day
Hypoglycemia,
weight gain
Weight, PPG
0.5-1.5%
-glucosidase
Inhibitors
Acarbose/miglitol
50 mg tid
GI;
hypoglycemia
Treat
hypoglycemia
with glucose
0.5-0.8%
GLP-1 Agonists
Exenatide
5 to 10 mcg bid
GI;  BG;
pancreatitis
Cut dose of SU
by 1/2
0.5-1%
DPP-IV
Inhibitors
Sita:50-100 mg/d
Saxa:2.5-5 mg/d
Nausea,
infections
pancreatitis
Renal function;
infections
0.5-0.8%
Pramlintide
60 mcg/120 mcg
Nausea,  BG
 Dose of
prandial insulin
0.5-1%
Drug Class
Insulin
Biguanides
% A1C 
Treat to target
1-2
Sulfonylureas
TZDs
Glinides
Alpha-glucosidase Inhibitors
1-2
0.5-1.4
0.5-1.5
0.5-0.8
GLP-1 Agonists
DPP-IV Inhibitors
Pramlintide
0.5-1.0
0.5-0.8
0.5-1
Bile Acid Sequestrant
Bromocriptine
~0.5
Monitoring Insulin
•
•
•
•
•
Blood glucose (fasting/postprandial)
A1C
Hypoglycemia
Weight gain
The dose that gets a person to target blood
glucose/A1C (safely) is the right dose
DM Control: How Intensive?
Type 1 DM: Risk of Retinopathy
JAMA 2002;287:2563-9
A1C Distribution After DCCT
And Each Year During EDIC
JAMA 2002;287:2563-9
Retinopathy:Cumulative Incidence
EDIC Trial (JAMA 2002;287;2563-9)
7-Yr Incidence of Fatal/Nonfatal MI in Finland
7-Year incidence
rate of MI (%)
No diabetes
(n=1,373)
50
45
40
35
30
25
20
15
10
5
0
Diabetes
(n=1,059)
45
P<0.001
P<0.001
20
19
4
No previous MI*
Previous MI
No previous MI*
*No previous myocardial infarction (MI) at baseline.
Haffner SM et al. N Engl J Med. 1998;339:229-234.
Previous MI
Macrovascular Complications Treatment
•
Control of BG  macrovascular complications in post
active-intervention:
•
Type 1 DM: EDIC (at 17 years)1
• 42%  in CVD outcomes (p=0.02)
• 57%  in risk of nonfatal MI, stroke, or CVD death (p=0.02)
•
Type 2 DM: UKPDS 10-year F/U2*
SU + insulin:
15% RRR in MI (p=0.01)
17% RRR in DM-related death (p=0.01)
13% RRR in mortality (p=0.007)
Metformin:
33% RRR in MI (p=0.005)
30% RRR in DM-related death (p=0.01)
27% RRR in mortality (p=0.002)
*Criticized because of loss to F/U (selection bias?)
1 N Engl J Med 2005;353:2643-53
2 N Engl J Med 2008;359:1577-89
ACCORD
ADVANCE
VADT
ACCORD
• In T2DM pts with CVD or CVD risk, does
intensive glucose control prevent CV events
more than standard glucose control?
• Goal A1C < 6% in intensive control group vs 77.9% in standard control
• More CV mortality in intensive rather than
standard control (trial stopped early)
N Engl J Med 2008;358:2545-59
ACCORD
• N=10,251
• Multiple drugs used to achieve goal (including
91% on rosiglitazone in intensive group)
• Median BL A1C – 8.1%
• Achieved A1C – 6.4% vs 7.5%
N Engl J Med 2008;358:2545-59
ACCORD
•
Primary outcome 
•
•
•
•
Mortality 
•
•
•
Nonfatal MI or stroke, CVD death
HR 0.9 (95% CI 0.78-1.04)
Significant?
HR 1.22 (95% CI 1.01-1.46) (all-cause mortality)
257 vs 203 deaths
Mortality higher if severe hypoglycemia, weight gain,
on intensive insulin
•
Reason – Fast glucose lowering?
N Engl J Med 2008;358:2545-59
ADVANCE
• In T2DM pts does intensive glucose control
prevent adverse events (microvascular +
macrovascular) more than standard glucose
control?
• Goal A1C < 6.5% vs “based on local guidelines”
• No difference in CV mortality between intensive
and standard groups
N Engl J Med 2008;358:2560-72
ADVANCE
• N=11,140
• Compared gliclazide + multiple drugs (intensive) vs no
gliclazide + multiple drugs (standard control)
• < 20% received a TZD
• Median BL A1C – 7.2%
• Achieved A1C – 6.3% vs 7%
N Engl J Med 2008;358:2560-72
ADVANCE
• Primary outcome 
•
•
•
•
•
Microvascular (nephropathy, retinopathy) +
macrovascular disease (nonfatal MI or stroke, CVD
death)
Decreased mostly because of  microvascular
disease (specifically, nephropathy)
HR 0.9 (95% CI 0.82-0.98) (microvascular disease)
HR 0.94 (95% CI 0.84-1.06) (macrovascular
disease)
HR 0.93 (95% CI 0.83-1.06) (mortality)
N Engl J Med 2008;358:2560-72
ADVANCE vs ACCORD
• Comparison between the two studies
•
•
•
•
•
BL A1C lower than ACCORD (7.2% vs 8.1%)
Duration of DM (2 yrs less)
Less severe hypoglycemia in intensive gp (2.7% vs
16.2%) for ADVANCE
BL BMI lower (28 vs 32) for ADVANCE
Fewer on insulin in intensive gp (40% vs 77% at the
end) for ADVANCE
• ADVANCE verified  risk with lower albuminuria
if A1C  to 6.3%
VADT
• In pts with long-standing T2DM (not wellcontrolled with insulin or max dose oral
agents):
•
•
Does intensive glucose control prevent CV events
more than standard glucose control?
Goal A1C < 6% (action if A1C > 6.5%) vs standard
(target of 1.5%  in intensive vs standard)
• Results:
•
Intensive control had no effect on death, CV events,
or microvascular complications
N Engl J Med 2008;358:DOI:10.1056/NEJMoa0808431
VADT
• N=1,791
•
•
•
•
Non-obese: rosiglitazone + glimepiride
Obese: rosiglitazone + metformin
Insulin if needed to reach goal
42% to 53% on TZD
• Median BL A1C – 9.4%
• Achieved A1C – 6.9% vs 8.5%
N Engl J Med 2008;358:DOI:10.1056/NEJMoa0808431
VADT
• Primary outcome 
• Nonfatal MI or stroke, CVD death, HF hospitalization,
vascular disease surgery, inoperable CHD, ischemic
gangrene amputation:
• HR 0.88 (95% CI 0.74-1.05)
• Mortality
• HR 1.07 (95% CI 0.81-1.42)
N Engl J Med 2008;358:DOI:10.1056/NEJMoa0808431
VADT vs ACCORD
• Comparison between the two studies
• Mortality increase NS in VADT
• Endpoint A1C higher for VADT than ACCORD (6.9%
vs 6.4%)
• In VADT more hypoglycemia, weight gain, insulin use
than in ACCORD
• No difference in microvascular complications
ACCORD F/U Information
• Hypoglycemia was not a cause of death
• Rate of glucose lowering not responsible for excess deaths
• 3 BL factors emerged as predictors of increased mortality risk:
• Higher BL A1C (> 8.5%) was associated with increased
mortality
• Reason? Possibly a surrogate for greater DM severity
• H/O neuropathy
• Reason? Surrogate for significant microvascular disease
• ASA use
• Reason? Surrogate for known/suspected CVD
• Persons who got to goal did better in intensive group than those
in standard group
ADVANCE F/U Information
• Risks/benefits of glucose lowering was
uniform across different sub-groups
• Intensive group had major reductions in
microvascular disease without increased
cardiovascular mortality
• Those with greatest benefit attained optimal
glucose and BP measures
VADT F/U Information
• Risk factors for primary CV event or total
mortality:
•
•
•
•
Hypoglycemia
Previous CV event
Older age
Impaired renal function
ACCORD, ADVANCE, VADT
• Take home messages
•
•
CVD Risk Management Critical
• Manage BP, lipids, risk reduction (ASA,
smoking cessation)
Less stringent goals for glucose (A1C <7% not
<6%) if:
• H/O severe hypoglycemia
• Limited life expectancy
• Have micro or macrovascular complications
• Long-standing DM where goals haven’t been
achieved
Macrovascular Complications Treatment
• BP Management (per ADA)
• Goal is < 130/80 mm Hg
• Lifestyle (3 mo):
• SBP 130-139 mm Hg
• DBP is 80-89 mm Hg
• Meds if BP > 140/90 mm Hg
• ACE Is, ARBs, non dihydropyridine CCBs (if fail or
can’t tolerate ACE Is or ARBs)
Diabetes Care 2009 32(Suppl 1):S13-61
CARDS: Major CVD Events
Cumulative hazard (%)
20
Placebo (n=1,410)
Atorvastatin 10 mg/d (n=1,428)
Primary prevention study in persons
With DM and at least 1 risk factor
15
37% reduction
P=0.001
10
5
0
0
1
2
Years
CARDS=Collaborative Atorvastatin
Diabetes Study
3
4
4.7
5
Lancet. 2004;364:685-696.
Macrovascular Complications Treatment
• Hyperlipidemia Treatment (per ADA)
• If person doesn’t reach goal on max statin dose,
lowering LDL by 30-40% from BL is alternative
goal
• May need concomitant meds to  TGs or  HDL
• TGs do decrease if elevated A1C is decreased to
goal
Diabetes Care 2009 32(Suppl 1):S13-61
Macrovascular Complications Treatment
• Hyperlipidemia Treatment (per ADA)
• IF TGs are > 200 mg/dL:
• Non HDL goal (TC – HDL) is 30 mg/dL higher than
goal LDL
• 2008 ACC/ADA guidelines: Measure Apo B
• Represents most atherogenic lipoprotein particles
• In children screen lipids at age 2 if FH positive or
unknown; otherwise screen at puberty (> 10 years)
Diabetes Care 2009 32(Suppl 1):S13-61
Macrovascular Complications Treatment
• Risk Reduction
•
•
•
•
ASA or other antiplatelets
Smoking cessation
(Immunizations)
Lifestyle
• Medical Nutrition Therapy
• Physical activity
Diabetes Care 2009 32(Suppl 1):S13-61
60
 cardiovascular and microvascular events by 50%
50
P = 0.007
20
30
40
Conventional Therapy
10
Intensive Therapy
0
Primary Composite End Point (%)
Multifactorial Intervention
in Type 2 DM
0
12
24
36
48
60
Months of Follow-up
N Engl J Med 2003;348:383-93.
72
84
96
HC
•
•
•
•
•
•
•
HC is a 56 y/o male with T2DM x 6 years
On glyburide/metformin 5/500 mg – 2 po BID
H/O CAD, HTN, IBS, NASH (fatty liver)
FBG: 180-220 mg/dL;PPG: 250-320 mg/dL
Wt 220 lb; BMI – 30kg/m2; A1C = 9.6%
BP 142/85 mm Hg on lisinopril/HCTZ (40/25); HR - 90
Lipids: LDL only abnormal value (80 mg/dL) on Lipitor 20
mg
• Should we?
•
•
•
•
Intensify lifestyle?
Add TZD?
Add exenatide?
Start insulin?
HC - Plan
• Should we?
• Intensify lifestyle
• Yes; send to a dietitian
• Add TZD
• No; h/o of CAD
• Add exenatide?
• Possibly; but pt has IBS and this is Tier 2 per ADA algorithm
• Start insulin?
• Yes; start with basal; titrate/treat to target (A1C: 3 mo)
• Stop glyburide?
• Prandial insulin when basal dose is ~ 50 Units/day (A1C: 3 mo)
• Treat intensively to A1C < 6.5%?
• No; goal is < 7%; monitor for hypoglycemia/weight gain
• Intensify treatment of co-morbidities?
• Yes; LDL goal is < 70 mg/dL;  dose of Lipitor to 40 mg/day (recheck LDL and Apo-B in 4-6 weeks); monitor for ADRs
• Yes; lifestyle for BP; add diltiazem 120 mg/day (re-check in 2
weeks); monitor BP and HR
Role of the Clinician
• Provide education
• What is DM?
• Target BG, A1C, BP, LDL
• Information during pregnancy
• Assess patient needs and provide MI
• Provide information on how to recognize both
hyperglycemia and hypoglycemia
• Provide information on possible complications and
how to avoid them (checklist)
Role of the Clinician
• Diabetes care checklist
•
•
•
•
How to use a BG monitor; check pt’s technique
Review BG log regularly, A1C goals
Information on optimal medication use
Remind pt of risk reduction (immunizations,
smoking cessation, ASA use)
• How to recognize hyperglycemia and a
management plan
• Sick day management instructions
Management of Diabetes
Goals
A1C
Plasma glucose (mg/dL)
Preprandial
Peak PPG
BP
Lipids
TC
LDL
TG
HDL
Males
Females
< 7%
70-130 mg/dL
< 180 mg/dL
< 130/80 mm Hg
<200 mg/dL
<100 mg/dL (<70 mg/dL)
<150 mg/dL
>40 mg/dL
>40 mg/dL
>50 mg/dL
Pre-Diabetes And Risk for DM?
•
•
•
•
•
•
•
My wt is > 20% of my IBW for ht (5 pts)
I am < 65 y/o and do little/no exercise (5 pts)
I am between 45-65 y/o (5 pts)
I am > 65 y/o (9 pts)
I am a woman who has had a baby weighing > 9 lb (1 pt)
I have a sister/brother with DM (1 pt)
I have a parent with DM (1 pt)
Total # of pts scored:
3-9 pts: low risk, but note if in high-risk gp (wt, BP, ethnicity, etc.)
> 10 pts: high risk; see HCP for further eval
Pre-DM: Target values for BP and LDL same as DM