Download DRUG THERAPY OF OBESITY: METFORMIN (UKPDS)

DIABETES MANAGEMENT 2006:
INTEGRATING NEW MEDICINES
AND NEW DEVICES
Robert B. Baron MD MS
Professor and Associate Dean
UCSF School of Medicine
Declaration of full disclosure: No conflict of interest
Diabetes Mellitus in the US:
Health Impact of the Disease
6th leading cause of
death
Renal
failure*
Blindness*
Amputation*
Life expectancy
-5 to 10 yr
Diabetes
Cardiovascular
disease 2x to 4x
Nerve damage in
60% to 70% of patients
*Diabetes is the no. 1 cause of renal failure, new blindness, and nontraumatic amputations
Diabetes Mellitus: U.S. Impact
DIABETES
16.7
Million
(8.3%)
IFG
12.3 Million
(6.3%)
~1
Million
Type 1
~16
Million
Type 2
2/3
Diagnosed
1/3
Undiagnosed
(4.9 Million)
TOTAL:
29 Million
(14.4%)
Screening for Diabetes
 ADA: >45, especially if BMI >25. <45 if
overweight and have risk factor for DM (inactive,
FH, high risk ethnicity, baby >9 lb, HTN, low HDL
or high TG, PCOS, vascular disease). Screen with
FPG or 2-h OGTT
Diabetes Care, 2006
 USPSTF: Insufficient evidence to recommend for
or against. However, recommend screening in
adults with hypertension and lipid disorders
Ann Intern Med, 2003
Diagnosis of Diabetes
Two measures of any of the following:
 Random glucose: 200 mg/dl with symptoms
(poly’s, weight loss)
 Fasting glucose: 126 mg/dl
 2-hr glucose: 200 mg/dl during OGTT
Diabetes Care 2006
HbA1C for Screening ?
• HbA1c 2SD above mean has sensitivity of 66 %
and specificity of 98 % and compares favorably to
FPG
• Different nondiabetic reference ranges due to
different glycated hemoglobin fractions
• Precision and accuracy may not be sufficient in
all labs
• Affected by hemoglobinopathies, anemia,
transfusions, uremia, pregnancy
Diagnosis of Pre-Diabetes
Two measures of any of the following:
 Fasting glucose 100 - 125 mg/dl
 2-hr glucose 140 - 199 mg/dl during
OGTT
% developing Diabetes
DPP: % Developing DM After 3 Years
35
28.9
30
25
21.7
20
15
14.4
10
5
0
Lifestyle
Metformin
Placebo
Prevention of Type 2 DM: RCTs
Trial
Description
Results (RR)
Da Qing1
Diet &/or exercise
31 to 46%
Finnish Prevention
Study (FPS)2
Intensive lifestyle
58 %
Diabetes Prevention
Program (DPP)3
Meformin
Lifestyle
31 %
58 %
STOP- NIDDM4
Acarbose
25 %
TRIPOD5
Troglitazone
55 %
Recommendations for Adults
 Glycemic Control
A1C: <7.0
Preprandial: 90-130 mg/dl
Postprandial: <180 mg/dl
 Blood Pressure: <130/80 mmHg
 Lipids
LDL: <100 mg/dl
TG: <150 mg/dl
HDL: >40 mg/dl
ADA Diabetes Care 2006
Treatment of Type 2 Diabetes
Step 1:
Step 2:
Step 3:
Step 4:
Step 5:
Step 6:
Lifestyle Changes
Oral Monotherapy
Combination Oral Therapy
Oral Therapy plus Insulin
Insulin Alone
Insulin plus
Thiazolidinedione/Metformin
Target metabolic values need to be
individualized
Attaining Glycemic Goals Using Monotherapy
in Obese Patients With Type 2 Diabetes
Diet Alone
Sulfonylurea
Metformin
Insulin
Proportion of Patients With
HbA1c <7% (%)
60
50
40
30
20
10
0
3 Years
Turner RC et al. JAMA. 1999;281:2005-2012.
6 Years
9 Years
Treatment of Type 2 Diabetes
Acarbose/
Miglitol
Delay
digestion of
carbohydrates
SFUs/Insulin
Metformin
Decrease
Hepatic
Glucose
Output
Improved
Glycemic
Control
Increase
Insulin
Secretion
Decrease
insulin
Thiazolidinediones
resistance
Generic Oral Hypoglycemic Slide
Change from Drug A to B, C, or D
Add Drug A to B, or B to A
HgA1c
Add Drug C
Add Drug D
Time
Adding Instead of Switching
Continue glyburide
Switch to metformin
Change in Mean HbA1c (%)
1
Glyburide+ metformin
+0.2%
0
*
–1
–0.4%
*
*
*
–1.7%
–2
–3
0
9
13
17
21
Treatment (wk)
25
29
DeFronzo, et al. N Engl J Med. 1995;333:541-549,
5-2
Oral Agent “Failure”
Why does this occur?
Changing HbA1c goals
Compliance, side effects
Wrong diagnosis (LADA--latent
autoimmune diabetes in adults 10%)
Stress, diabetogenic medications
Natural progression of the disease
Natural History of Type 2 Diabetes
Obesity
Glucose
(mg/dL)
IFG*
Diabetes
350
300
250
200
150
100
50
Uncontrolled hyperglycemia
Post-meal
Glucose
Fasting
Glucose
250
200
Relative
150
Function
100
(%)
50
0
Insulin Resistance
Insulin Level`
Beta-cell failure
-10
*IFG = impaired fasting glucose
-5
0
5
10
Years of
Diabetes
15
20
25
30
Natural History of Type 2 Diabetes
Thiazolidinedione - Biguanide
Lifestyle
Glucose
(mg/dL)
Relative
Function
(%)
350
300
250
200
150
100
50
250
200
150
100
50
0
Insulin
SU
Post-meal
Glucose
Fasting Glucose
Insulin Resistance
Insulin Level
Beta-cell failure
-10
-5
0
5
10
15
Years of Diabetes
20
25
30
Insulin Plus Oral Agents
Introduction of insulin
– Bedtime
– Intermediate/Long-acting insulins
• NPH, UL, glargine
• 10 units
– Self-monitoring of blood glucose (hypoglycemia
education)
Insulin plus other oral agent combinations (maintain
effect on insulin sensitivity)
When to go to > 1 shot per day
 HgA1c >7
 Glucose in AM at goal but g lucose before
dinner >140
Options
 Add premeal lispro/aspart
 Add bid premixed insulin – 70/30, 75/25
Questions
 Continue metformin
 ? Sulfonylurea, ? Thiazolidinedione
Function of Insulin in Regimens
Meal coverage (carbohydrates)
Basal insulin
Correction of high blood sugar
More Options
Insulins
– Insulin Lispro (Humalog®)
‘96
– Insulin Aspart (Novolog®)
9/00
– Humalog ® Mix 75/25
1/00
– Insulin Glargine (Lantus®)
4/00
– Novolog ® Mix 70/30
5/02
– Insulin Glulisine (Apidra®)
4/04
– Insulin Detemir (Levemir®)
6/05
– Insulin delivery devices and glucose meters
Insulin Pharmacokinetics
Type of Insulin
Short-acting
Regular
Lispro/Aspart/
Glulisine
Onset
Peak
½-1hr
2-4hr
<15 min 1-2 hr
Duration Appearance
6-8hr
3-5hr
clear
clear
Intermediate-acting
NPH/Lente*
1-2hr
6-10hr 12+hr
cloudy
Long-acting
Ultralente*
Detemir
Glargine
4-6hr
1 hr
1.5hr
18hr
flat
flat
cloudy
clear
clear
24+hr
12-24hr
24hr
On July 6, 2005 Lilly announced Lente and Ultralente
will no longer be available in 2006.
Short-acting Insulin Analogues: Lispro and Aspart
Plasma Insulin (pmol/L)
400
Lispro
350
300
250
200
150
100
50
0
0
glulisine
Regular
Human
30
Meal
SC injection
60
90 120 150 180 210 240
Time (min)
Plasma Insulin (pmol/L)
Plasma Insulin Profiles
500 Aspart
450
400
350
300
250
200
150
Regular
100
Human
50
0
0
50 100
150 200
Time (min)
250
300
Meal
SC injection
Heinemann, et al. Diabet Med. 1996;13:625-629; Mudaliar, et al. Diabetes Care.
1999;22:1501-1506.
6-28
Rapid-Acting Insulins
Advantages
Disadvantages
• Flexibility--given
immediately before or after
meals
• Caution with adequate CHO
intake (if < than predicted,
susceptible to hypoglycemia
• Postprandial control-better
match with glucose peak
• Cost/insurance coverage
• Limited duration so less
overlap with subsequent
injections
Activity Profile in Type 1 Diabetes
Glucose
Utilization Rate
(mg/kg/min)
Lepore et al. Diabetes 1999;48(suppl 1):A97. Abst 416; Study 1015
(Hourly Mean Values)
6
5
Insulin Glargine
4
3
2
1
0
0
10
Time (h) after sc injection
20
30
= End of observation
period
Type 2 Diabetes: Unanswered
Questions
When should insulin be started?
What insulin should you use in Type
2? What insulin regimen is best?
Which, if any, oral agents should be
continued?
Insulin tactics
Minimize weight gain – metformin
Minimize risk of hypoglycemia – insulin
analogs, optimize self management skills
Minimize insulin resistance –
thiazolidinediones and metformin
Use oral agents to limit number of
injections
More Options
Incretin mimetics
Exenatide (Byetta ®)
4/05
Amylinomimetics (amylin analog)
Pramlintide (Symlin ®)
3/05
Incretins in Type 2 DM
Gut hormones released postprandially
Oral glucose elicits greater insulin response than IV
glucose; “incretin effect” accounts for 50-70% of
insulin response to oral glucose
2 main gut incretins
– Glucose-dependent insulinotropic polypeptide
(GIP)
• Released by K cells in duodenum
– Glucagon-like peptide-1 (GLP-1)
• Released by L cells in small intestines
• Levels are diminished in type 2 DM post-meal
Incretins in Type 2 DM (cont)
Rapidly degraded by dipeptidyl peptidase
IV (DPP-IV)
• GLP-1 analogs; “incretin mimetics”
– Liraglutide (free fatty acid added to
bind to albumin; injected daily)
– Exenatide
• DPP-IV inhibitors (oral)
Actions of GLP-1
Insulin secretion (Insulinotropic effects)
–
–
–
–
–
–
Potentiates glucose-induced insulin secretion
Enhances all steps of insulin biosynthesis
Upregulates insulin gene expression
Upregulates genes needed for beta-cell function (
Stimulates beta cell proliferation
Promotes differentiation of beta cells from progenitor
cells
Inhibits glucagon secretion (Glucostatic effect)
Slows gastric emptying
Inhibits appetite and food intake
Exenatide (Byetta)
Synthetic Exendin-4, or exenatide
Exendin-4 originally isolated from Gila monster’s
(Heloderma suspectum) saliva; lizard in Arizona
Analog of GLP-1
– 39 amino acid peptide
– >50% overlap with human GLP-1
Resistant to DPP-IV degradation
Similar binding affinity at GLP-1 receptors
Exenatide (Byetta)
Indications: adults with type 2 DM who are taking
metformin, sulfonylurea or combination
Peak concentration post injection achieved in 2.1
hr (injected SQ twice daily within 60 minutes
of meal)
Metabolized primarily by kidneys
Not recommended in Clcr <30 ml/min
OK in hepatic impairment
Exenatide: BG Effects
Lowers post-prandial BG
– Restores first-phase insulin response
– Slows gastric emptying
– Lowers post-prandial glucagon ( hepatic
glucose output)
–  food intake
Lowers A1C
Clinical Data: Exenatide
3 large, 30 week clinical trials (randomized, doubleblind, placebo-controlled) in patients with type 2 DM
• On SFU: Buse et al. Diabetes Care. 2004;27:2628-35
• On SFU & metformin: Kendall DM et al. Diabetes Care.
2005;28:1083-91.
• On metformin: DeFronzo RA et al. Diabetes Care.
2005;28:1092-1100
Placebo BID
5 mcg exenatide BID
10 mcg exenatide BID
ITT
483
480
483
Age (y)
55
55
55
BMI
34
33
34
A1C
8.5
8.4
8.5
8
8
7
Duration of DM
A1C (%) Effect (change from baseline)
Placebo BID
5 mcg exenatide BID
10 mcg exenatide BID
MET
0.1
-0.4
-0.8
SFU
0.1
-0.5
-0.9
MET+SFU
0.2
-0.6
-0.8
Changes in A1C from baseline vs placebo statistically significant
Effect on FBG less pronounced:  6-9 mg/dl (5 mcg dose);
10 mg/dl (10 mcg dose)
PPG 60% (5 mcg dose) & 90% (10 mcg dose)
Weight (change from baseline) & Hypoglycemia
Placebo
BID
5 mcg exenatide BID
10 mcg exenatide BID
Weight (kg)
-1.4
-3.1
-4.2
Hypoglycemia (%)
MET
SFU
MET + SFU
5.3
3.3
1.26
4.5
14.4
19.2
5.3
35.7
27.8
Open-label extension study to 90 weeks: persistence in weight loss and A1C
Exenatide Dosing
Start 5 mcg SQ BID before morning and
evening meal
When added to SFU, lower dose of SFU
After 1 month, can increase to 10 mcg SQ BID
Available in prefilled pen
Must be continuously stored refrigerated at
36-46°F
For oral medications dependent on threshold
concentrations or rapid onset, take them 1
hour before
Side Effects
GI
– Nausea (44% vs 18% with placebo); incidence
lessens over time; 3% dropout rate due to
nausea
– Vomiting (13% vs 4%)
– Diarrhea (13% vs 6%)
Headache (9% vs 6%)
Hypoglycemia (see previous slide)
New Options for Insulin Delivery
Durable Insulin Pens
Use replaceable insulin cartridge
Use dial mechanism for dose
NovoPen® 3
– Maximum dosage: 70 units
– 1 unit increment
– metal material
NovoPen ® Junior
– Maximum dosage: 35 units
– ½ unit increment
BD™ Pen and Pen Mini
– 1.5 cc cartridge
– Maximum dosage: 30 or 15
units
Innovo® & InDuo™
InDuo: Integrates two daily activities
combined into one device
– Blood glucose monitoring
(OneTouch® Ultra® meter) and
Insulin Delivery Device (Innovo)
– Supports an acceptance and
understanding of the link between
SMBG and insulin therapy
– Device serves as a constant reminder
to test whenever the patient injects
Memory function stores the time elapsed &
amount of last insulin dose
Uses 3 cc cartridge
Maximum dosage: 70 units; 1 unit increments
OptiClik
FDA approved 8/04
Reusable pen for Lantus & Apidra
1-unit increments; takes only BD pen needles
Supplied to physicians; not available in pharmacies
www.opticlik.com
Disposable/Prefilled Insulin Pens
Hold 3 cc insulin
Discard when finished
Use dial mechanism for dose; need to prime
(“air shot”)
Novolin® InnoLet®
– Clock-like dial (egg timer-like) with
large scale numbers; audible clicks
– large grip and ergonomic shape that
allows alternative grips, easy-to-push
large button and support shoulder
– Maximum dose: 50 units
– 1 unit increments
Regular, NPH and 70/30 insulin only
Disposable/Prefilled Insulin Pens, cont.
Novo Nordisk FlexPen ® (Novolog ®, Novolog ® Mix 70/30): up to 60 units;
1 unit increments
Eli Lilly pens (Humalog ®,Humalog ® Mix 75/25™, NPH, 70/30): up to 60
units; 1 unit increments
Needles
Pen Needles
BD
– 29 G: ½” (12.7mm)
– 31 G: 3/16” (5 mm) or
5/16” (8 mm)
Novo Nordisk
– NovoFine®
– 30 gauge x 1/3” (8mm)
– 31 gauge x ¼” (6mm)
Caution with obese patients if use
shorter needles
Syringes: 1/3, ½, 1 cc
Several times enlarged NovoFine® 30
[30 gauge x 1/3” (8mm)] Disposable Needle
Alternate Testing Sites
Alternative Site Testing: Cons
Lag time of 5-30 minute between forearm & finger
– blood flow to finger is 3-5 x faster than arm
– significant when BG changing rapidly
When not to use (use fingers)
–
–
–
–
BG rapidly changing
suspect low BG
hypoglycemic unawareness
within 1-2 hours after meals
Bruising at site
Other Methods of SMBG
Continuous ambulatory blood glucose monitoring
– CGMS  (Continuous Glucose Monitoring System)
System Gold™
• Medtronic MiniMed
• 72-hour; BG recorded q5min
– 24-hour glucose patterns
– detect unrecognized hypoglycemia
– Requires HCP support
Noninvasive: GlucoWatch G2 Biographer
– Cygnus
– Requires a prescription
Self-Monitoring of Blood Glucose
(SMBG) - ADA Recommendations
 Type 1 Diabetes : 3 x daily
 Type 2 Diabetes: optimal frequency and timing not
known; “sufficient to facilitate reaching glucose
goals”
 Postprandial BG may be necessary to reach A1C
goals and/or reduce risk of hypoglycemia
 Self-management training: how to use the data to
adjust food intake, exercise or pharmacologic
therapy
Diabetes Care 2006
Self-Monitoring:Outcomes
Improve overall control:
Best studies:
HbA1c 0.7% lower in type 1
HbA1c 0.6% lower in type 2
Meta-analysis
HbA1c 0.25% lower
Other Emerging Therapies
Pharmacologic
– PPAR/PPAR dual agonists
• Muraglitazar (Pargluva; Advisory committee met
9/9/05; recommended approval)
• Tesaglitazar (Galida)
– Alternative insulin dosage forms (IH, buccal;
transdermal; nasal)
• Inhaled insulin, Exubera
• Islet cell transplants
– Rimonabant (Acomplia)
Monitoring
– Continous blood glucose monitoring