DIABETES MANAGEMENT 2006: INTEGRATING NEW MEDICINES AND NEW DEVICES Robert B. Baron MD MS Professor...
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Transcript of DIABETES MANAGEMENT 2006: INTEGRATING NEW MEDICINES AND NEW DEVICES Robert B. Baron MD MS Professor...
DIABETES MANAGEMENT 2006:DIABETES MANAGEMENT 2006:INTEGRATING NEW MEDICINES INTEGRATING NEW MEDICINES
AND NEW DEVICESAND NEW DEVICES
Robert B. Baron MD MSRobert B. Baron MD MS
Professor and Associate Dean Professor and Associate Dean
UCSF School of MedicineUCSF School of Medicine
Declaration of full disclosure: No conflict of interest
Diabetes Mellitus in the US: Diabetes Mellitus in the US: Health Impact of the DiseaseHealth Impact of the Disease
DiabetesDiabetesBlindnessBlindness**
Renal Renal failure* failure*
Amputation*Amputation*
Life expectancy Life expectancy
-5-5to 10 yrto 10 yr
CardiovascularCardiovasculardisease 2x to 4xdisease 2x to 4x
**Diabetes is the no. 1 cause of renal failure, new blindness, and nontraumatic amputationsDiabetes is the no. 1 cause of renal failure, new blindness, and nontraumatic amputations
Nerve damage in Nerve damage in 60% to 70% of patients60% to 70% of patients
6th leading cause of 6th leading cause of death death
Diabetes Mellitus: U.S. Impact
DIABETES
IFG
~1 Million Type 1
~16 Million Type 2
2/3 Diagnosed
1/3 Undiagnosed(4.9 Million)
16.7 Million (8.3%) 12.3
Million
(6.3%)
29 Million
(14.4%)
TOTAL:
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
DPP: % Developing DM After 3 YearsDPP: % Developing DM After 3 Years
14.4
21.7
28.9
0
5
10
15
20
25
30
35
Lifestyle Metformin Placebo
%
deve
lop
ing
Dia
bete
s
Prevention of Type 2 DM: RCTs
Trial Description Results (RR)
Da Qing1 Diet &/or exercise 31 to 46%
Finnish PreventionStudy (FPS)2 Intensive lifestyle 58 %
Diabetes Prevention Meformin 31 % Program (DPP)3 Lifestyle 58 %
STOP- NIDDM4 Acarbose 25 %
TRIPOD5 Troglitazone 55 %
ADA Diabetes Care 2006
Recommendations for Adults
Glycemic ControlA1C: <7.0Preprandial: 90-130 mg/dlPostprandial: <180 mg/dl
Blood Pressure: <130/80 mmHg
LipidsLDL: <100 mg/dlTG: <150 mg/dlHDL: >40 mg/dl
Treatment of Type 2 Diabetes
Step 1: Lifestyle Changes
Step 2: Oral Monotherapy
Step 3: Combination Oral Therapy
Step 4: Oral Therapy plus Insulin
Step 5: Insulin Alone
Step 6: Insulin plus Thiazolidinedione/Metformin
Target metabolic values need to be individualized
Attaining Glycemic Goals Using Monotherapy in Obese Patients With Type 2 Diabetes
Turner RC et al. JAMA. 1999;281:2005-2012.
0
10
20
30
40
50
60
3 Years 6 Years 9 Years
Diet Alone
Sulfonylurea
Metformin
Insulin
Pro
porti
on o
f Pat
ient
s W
ithH
bA1c
<7%
(%)
Treatment of Type 2 Diabetes
Improved Glycemic Control
DecreaseDecreaseHepatic Hepatic GlucoseGlucose OutputOutput
IncreaseIncreaseInsulinInsulin
SecretionSecretion
Metformin SFUs/Insulin
Acarbose/
Miglitol
ThiazolidinedionesDecrease Decrease
insulininsulinresistanceresistance
DelayDelay digestion ofdigestion of
carbohydratescarbohydrates
Generic Oral Hypoglycemic Slide
HgA1c
Time
Change from Drug A to B, C, or D
Add Drug A to B, or B to A
Add Drug C
Add Drug D
Adding Instead of Switching
DeFronzo, et al. N Engl J Med. 1995;333:541-549,
Ch
ang
e in
Mea
n H
bA
1c (
%)
0–3
–2
–1
0
1
Continue glyburide
Switch to metformin
Glyburide+ metformin
9 13 17Treatment (wk)
21 25 29
** * *
+0.2%
–0.4%
–1.7%
5-2
Oral Agent “Failure”Why does this occur?
Changing HbA1c goalsCompliance, side effectsWrong diagnosis (LADA--latent
autoimmune diabetes in adults 10%)Stress, diabetogenic medicationsNatural progression of the disease
Natural History of Type 2 Diabetes
050
100150200250
-10 -5 0 5 10 15 20 25 30
Years of Years of DiabetesDiabetes
Glucose(mg/dL)
Relative Function
(%)
Insulin Resistance
Insulin Level`Beta-cell failure
*IFG = impaired fasting glucose
50100150200250300350
Fasting Glucose
Post-meal Glucose
Obesity IFGObesity IFG** Diabetes Uncontrolled hyperglycemia Diabetes Uncontrolled hyperglycemia
Natural History of Type 2 Diabetes
050
100150200250
50100150200250300350
-10 -5 0 5 10 15 20 25 30Years of Diabetes
Glucose(mg/dL)
Relative Function
(%)
LifestyleLifestyle SUSU
Insulin ResistanceInsulin Resistance
Insulin LevelInsulin Level
Fasting GlucoseFasting Glucose
Beta-cell failureBeta-cell failure
Post-meal Post-meal GlucoseGlucose
InsulinInsulin
Thiazolidinedione - Biguanide Thiazolidinedione - Biguanide
Insulin Plus Oral AgentsIntroduction 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 OptionsInsulins
– 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 Onset Peak Duration Appearance
Short-acting Regular Lispro/ Aspart/ Glulisine
½-1hr <15 min
2-4hr 1-2 hr
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
24+hr 12-24hr 24hr
cloudy clear clear
On July 6, 2005 Lilly announced Lente and Ultralente will no longer be available in 2006.
Short-acting Insulin Analogues: Lispro and AspartPlasma Insulin Profiles
400
350
300
250
200
150
100
MealSC injection
50
00 30 60
Time (min)90 120 180 210150 240
Lispro
Regular Human
500450400350300250
150
50
200
100
00 50 100
Time (min)150 200 300250
Aspart
Regular Human
Pla
sma
Insu
lin
(p
mol
/L)
Pla
sma
Insu
lin
(p
mol
/L)
MealSC injection
Heinemann, et al. Diabet Med. 1996;13:625-629; Mudaliar, et al. Diabetes Care. 1999;22:1501-1506.
6-28
glulisine
Rapid-Acting Insulins
Advantages• Flexibility--given immediately before or after meals
• Postprandial control-better match with glucose peak
• Limited duration so less overlap with subsequent injections
Disadvantages• Caution with adequate CHO intake (if < than predicted, susceptible to hypoglycemia
• Cost/insurance coverage
Activity Profile in Type 1 Diabetes Lepore et al. Diabetes 1999;48(suppl 1):A97. Abst 416; Study 1015
30
(Hourly Mean Values)
Time (h) after sc injection = End of observation period
0
1
2
3
4
5
6
0
Glu
cose
U
tiliz
atio
n R
ate
(mg/
kg/m
in)
Insulin Glargine
NPH insulin
2010
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?
Type 2 Diabetes: Unanswered Questions
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 mimeticsExenatide (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/minOK 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, double-blind, 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
Duration of DM 8 8 7
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 SFUAfter 1 month, can increase to 10 mcg SQ BIDAvailable in prefilled penMust be continuously stored refrigerated at
36-46°FFor 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 materialNovoPen ® 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 insulinDiscard when finishedUse 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
NeedlesPen NeedlesBD
– 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 ccSeveral 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 2006Diabetes 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