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Type 2 Diabetes Update Prevention and Treatment
Bruce W. Bode, MD, FACE
Atlanta Diabetes Associates
Atlanta, Georgia
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Causes of Death in People With Diabetes
Geiss LS, et al. In: Diabetes in America, 2nd ed. 1995. Bethesda, MD: National Institutes of Health; 1995:chap 11.
00
1010
2020
3030
4040
5050
%%of Deathsof Deaths
Ischemic Ischemic Heart DiseaseHeart Disease
Other Other Heart Heart
DiseaseDisease
DiabetesDiabetes CancerCancer StrokeStroke InfectionInfection OtherOther
55
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Type 2 Diabetes: Two Principal Defects
Reaven GM. Physiol Rev. 1995;75:473-486Reaven GM. Diabetes/Metabol Rev. 1993;9(Suppl 1):5S-12S;Polonsky KS. Exp Clin Endocrinol Diabetes. 1999;107 Suppl 4:S124-S127.
Insulin resistance-cell dysfunction/
failure
± Environment ± Environment
IGT IGT
GenesGenes
Type 2 diabetesGlucose
Toxicity
Glucose
Toxicity
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Role of Free Fatty Acids in HyperglycemiaRole of Free Fatty Acids in Hyperglycemia
Boden G. Proc Assoc Am Physicians. 1999;111:241-248.
MUSCLEMUSCLELIVERLIVER
FFA oxidation FFA oxidation
Gluconeogenesis Glucose utilization
Hyperglycemia
ADIPOSE TISSUEADIPOSE TISSUE
Lipolysis
FFA mobilization
Liver insulin resistance
Adipose tissue insulin resistance
Muscleinsulin resistance
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HbA1c in the UKPDS
06
7
8
9
0 3 6 9 12 15
HbA
1c (
%)
Years from randomisation
Conventional
Intensive
6.2% upper limit of normal range
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UKPDS: -Cell Function for the Patients Remaining on Diet for 6 Years
0
20
40
60
80
100
-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6
Years After Diagnosis
-C
ell F
un
ctio
n (
%
)
Adapted from UKPDS Group. Diabetes. 1995; 44:1249-1258.
N=376
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Multiple factors may drive progressive decline of -cell function
-cell(genetic background)
Hyperglycaemia(glucose toxicity)
Proteinglycation
Amyloiddeposition
Insulin resistance
“lipotoxicity”elevated FFA,TG
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*Percent risk reduction per 0.9% decrease in HbA1C; UKPDS. Lancet. 1998;352:837-853.
Lowering HbALowering HbA1C1C Reduces Risk Reduces Risk of Complicationsof ComplicationsR
ed
ucti
on
in
ris
k (
%)*
p=0.029
p=0.0099
p=0.052
p=0.015
p=0.000054
0
-10
-20
-30
-40
-50
-12
-25
-16
-34
-21
Any diabetes-related endpoint
Microvascular endpoint
MI
Retinopathy
Albuminuria at 12 years
United Kingdom Prospective Diabetes Study United Kingdom Prospective Diabetes Study (UKPDS)(UKPDS)
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Metformin Prevents Heart Attacks and Reduces Deaths in Type 2 Diabetes
0
5
10
15
20
0
2
4
6
8
10
Inci
den
ce(p
er 1
,00
0 p
atie
nt y
ears
)
39%Reduction
P=0.01
50%Reduction
P=0.02
Heart Attacks Coronary Deaths
Conventional MetforminTherapy
Conventioal Metformin Therapy
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Diabetes Prevention Program
3234 obese patients with IGT
BMI average 34; A1C 5.9%, 55% Caucasion
4 year study to compare diet and exercise to metformin, troglitazone or control
Troglitazone stopped at 8 months
Study ended after 3 years
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Diabetes Prevention Program
58% prevention with diet (low fat) and exercise (2.5 hours per week)
31% prevention with metformin (more effective if < 60 years old and obese)
Troglitazone patients equal to metformin group at three years and equal to the diet and exercise group at 8 months.
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Resistant SensitiveInsulin Sensitivity
Preventing Diabetes after GDMThe Strategy
Workload Reductionfor the Pancreas
1
2
Insu
lin S
ecre
tion
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Troglitazone In the Prevention Of DiabetesTRIPOD: A Test of “Workload Reduction” for B-cells
Subjects Non-pregnant, non-diabetic Hispanic women Recent gestational diabetes (< 4 years) 5-year diabetes risk = 70% (oGTT glucose sum)
Procedures Placebo vs 400 mg troglitazone daily Fasting glucose every three months oGTT every year ivGTT at 0, 3, 24 months, Dx of diabetes and study end
Main Outcome Variables Diabetes incidence rates
Azen et al: Contr Clin Trials, 1998
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Preventing Diabetes: The “TRIPOD” Study
Months on Study
Peo
ple
with
Dia
bete
s 53%
19%
RR=0.44Placebo12.3%/yr
Troglitazone5.4%/yr
60%
40%
20%
0%0 10 20 30 40 50 60
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Randomization
Placebo Troglitazone
Small Change Large Changein S
Iin S
I
Small Fall in Large Fall inInsulin Levels Insulin Levels
DM Rate
DM Rate DM Rate
9.8%/yr
5.8%/yr 0%/yr
DM Rate12.3%/yr
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Baseline 3 Months
Troglitazone Group
DM Rate: 9.8% per year DM Rate: 5.8% per year DM Rate: 0% per year
31% 32% 26%
20% 14% 0%
0.30 0.04 0.008
Fraction with Diabetes
Expected:
Observed:
p-value:
Non-Responders
IVG
TT
In
suli
n A
rea
Minimal Model SI
Responders
Small Fall in Insulin
Minimal Model SI
Responders
Large Fall in Insulin
Minimal Model SI
Early Changes in Insulin Sensitivity and Insulin Secretion and Subsequent Diabetes Rates
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On Trial Off Trial
Placebo
Troglitazone(Protected)
TRIPOD Off-Trial Follow-up Study
Months after Randomization
Fra
ctio
n w
ith
Dia
bete
s
DiabetesMasking
Prevention
Observed=2.4%
37%Predicted
9%Predicted
40%
30%
20%
10%
0%
0 10 20 30 40
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TRIPOD: Conclusion
Reducing secretory demands placed on pancreatic B-cells by chronic insulin resistance can delay or prevent the onset of type 2 diabetes.
“B-cell rest = B-cell protection”
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Management of Type 2 DMStep Therapy
Diet
Exercise
Sulfonylurea or Metformin
Add Alternate Agent
Add hs NPH vs TZD
Switch to Mixed Insulin bid
Switch to Multiple Dose Insulin
Prone to Failure from Negative ReinforcementMisscheduling, Mismanagement
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Management of Type 2 DM Stumble Therapy
WAG Diet
Golf Cart Exercise
Sample of the Week Medication
– Interrupted
– Not Combined
Poor Understanding of Goals
Poor Monitoring
HbA1c >8% (If Seen)
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Consider A New Treatment Paradigm
Treatment designed to correct the dual impairments
Vigorous effort to meet glycemic targets
Simultaneous rather than sequential therapy
Combination therapy from the outset
Early step-wise titrations to meet glycemic targets
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ACE / AACE Targets for Glycemic Control
HbA1c < 6.5 %
Fasting/preprandial glucose < 110 mg/dL
Postprandial glucose < 140 mg/dL
ACE / AACE Consensus Conference, Washington DC August 2001
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Goals in Management of Type 2 Diabetes
Fasting BG < 110 mg/dL
Post-meal < 140 mg/dL
HbA1c < 6.5%
Blood Pressure < 130/80
LDL < 100 mg/dl
HDL > 45 mg/dl
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Sulfonylureas
Repaglinide
LiverMetformin
Rosiglitazone
Pioglitazone
Pancreas
Acarbose
Miglitol
Gut
MuscleRosiglitazone
Pioglitazone
Metformin
Hyperglycemia
Adiposetissue
Glucoseuptake
FFA output
RosiglitazonePioglitazone
Avandia® (rosiglitazone maleate) PI. GlaxoSmithKline, February 2001.Actos® (pioglitazone HCl) PI. Takeda Pharmaceuticals, May 2001.Prandin® (repaglinide) PI. Novo Nordisk, August 2000. Precose® (acarbose) PI. Bayer Corporation, October 1999.GlysetTM (miglitol tablets) PI. Pharmacia/Upjohn, September 1999.Glucophage® (metformin HCl) PI. Bristol-Myers Squibb, June 2001.
Insulin secretion
Glucose absorption
Hepatic glucose output
Glucose uptake
Oral Therapy for Type 2 Diabetes Target Sites of Action
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Normal Type 2 Diabetes
Courtesy of Wilfred Y. Fujimoto, MD.
Visceral Fat Distribution Normal versus Type 2 Diabetes
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Type 2 diabetes and glycemic disorders Dyslipidemia- Low HDL- Small, dense LDL particles- Hypertriglyceridemia
Hypertension
Impaired thrombolysis- PAI-1
Endothelial dysfunction/inflammation - CRP, MMP-9
Microalbuminuria
VisceralObesity
InsulinResistance
Free Fatty Acids
Ath
erosclero
sisThe Metabolic Syndrome:A Network of Atherogenic Factors
Brunzell J, Hokanson J. Diabetes Care. 1999;22(Suppl 3):C10-3.McFarlane S, et al. J Clin Endocrinol Metab. 2001;86(2):713-8.Frohlich M, et al. Diabetes Care. 2000 Dec;23(12):1835-9.Kuusisto J, et al. Circulation. 1995;91:831-7.Parulkar AA, et al. Ann Intern Med. 2001;134:61-71.Hseuh WA, et al. Diabetes Care. 2001 Feb;24(2):392-7.Lebovitz H. Clin Chem. 1999;45(8B):1339-45.
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Saltiel & Olefsky. Diabetes 1996;45:1661–9
Thiazolidinediones: Mode of Action
PPAR
– Affects glucose, lipid and protein metabolism
PPAR
– Affects lipoprotein metabolism (some TZDs)
Peroxisome Proliferator-Activated Receptors Peroxisome Proliferator-Activated Receptors
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TZD
PPAR RXR
PPAR RXR
TZD
TF
INSULIN
RECEPTOR
Protein– signaling– downstream events
RNA
DNA
TZD - thiazolidinedionePPAR RXR - nuclear receptorsTF - transcription factors
Saltiel & Olefsky. Diabetes 1996;45:1661–9
Thiazolidinediones: Mechanism of Insulin Sensitization
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Thiazolidinediones:Rationale for Type 2 Diabetes Therapy
Proven characteristics– Target insulin resistance, a core defect– Improve glycemic control– Do not cause hypoglycemia – Improve lipid profile (pioglitazone and troglitazone)
Potential benefits– Preservation of pancreatic b-cell function– Prevention of progression from impaired glucose tolerance to
type 2 diabetes– Improvement in cardiovascular outcomes
Saltiel & Olefsky. Diabetes 1996;45:1661–9Sonnenberg and Kotchen. Curr Opin Nephrol Hypertens 1998;7(5):551–5
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-1.01
-0.54
-1.01
-1.60
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
Changes in HbA1C at Endpoint in All Treated Patients
* p0.05
ACTOSACTOS™™ (pioglitazone HCl) U.S. Clinical Trials (pioglitazone HCl) U.S. Clinical Trials
HbA1C
at week 26(% points)
Daily dose ofACTOS
*
**
-0.27 -0.27
-0.86
0.74
0.20
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
Placebo (n = 79)
7.5 mg (n = 80)
15 mg (n = 79)
30 mg (n = 85)
45 mg (n = 76)
Change from Baseline Difference from Placebo
*
*
*
LOCF
Takeda Pharmaceuticals America, Data on file Study 001
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Change in Lipid Profile at Endpoint: ACTOS Added to Sulfonylurea
10.15
4.07
-0.95
7.02
2.33
12.00
6.57
-15.89-20
-10
0
10
20
SU + Placebo (n = 187)
SU + ACTOS 30 mg from baseline at 16 weeks
HDL cholesterol LDL cholesterolTriglycerides Total cholesterol
*
*
(n = 189)
(%)
Baseline (mg/dL) 258.6 126.5123.741.842.9214.4211.5259.5
Takeda Pharmaceuticals America, Data on file Study 010
LOCF* p 0.05 vs. placebo
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Mean Triglycerides Over Time
Error bars = SE; *Given in divided doses; Study 080, 100-week completer analysis Data on file; GlaxoSmithKline
Me
an
tri
gly
ceri
des
(m
g/d
L)
Treatment week
0 12 28 40 52 64 76 88 1000
50
100
150
200
250
300
350
RSG 8 mg/day* (n=45)Gly (n=35)
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MET, metformin; TRO, troglitazone; *p=0.04; **p=0.01;Kim DD, et al. Diabetes. 2000;49:Abstract 459.
Differential Effects on Insulin SensitivityG
luco
se d
isp
osa
l rat
e
(mg
/kg
/min
)
02468
101214
MET TRO
***
+20% +44%
05
1015202530354045
MET TRO
*
Fas
tin
g p
lasm
a in
sulin
(uU
/mL
)
Baseline16 weeks
+6% -21%
Fas
tin
g p
lasm
a F
FA
(meq
/L)
00.10.20.30.40.50.60.7
MET TRO
*
+9% -24%
Assessed by Glucose Disposal, Plasma Insulin and FFA
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Differential Effects on Endogenous Glucose Production
MET, metformin; TRO, troglitazone; Inzucchi SE, et al. N Engl J Med. 1998;338:867-872.
-25
-20
-15
-10
-5
0MET TRO
Ch
an
ge
in e
nd
og
en
ou
sg
luc
os
e p
rod
uc
tio
n (
%)
p=0.001
p=0.04
p=ns
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Incidence of Edema
1.2 2.1 2.57.06.0
15.3
7.54.8
0
20
40
60
80
100
Placebo
ACTOS
28/373 10/1684/1604/187 58/37913/1873/259 29/606
U.S. Placebo-controlled Studies
ACTOSACTOS™™ (pioglitazone HCl) Summary of Adverse Events (pioglitazone HCl) Summary of Adverse Events
(%)(%)
Monotherapy Combination withsulfonylurea
Combination withmetformin
Combination withinsulin
2 patients from combination therapy trials and 0 from the monotherapy trials discontinued due to edema
Pioglitazone HCl Package Insert July, 1999
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Patient Case 1 Patient JM DOB 11/30/1943
Problem List:
1. Diabetes Mellitus, onset 1981,age 38
a. Insulin therapy, 10/88 through 3/92, A1c 9.0%
C-peptide of 5.1
b. Metformin and Glyburide therapy. A1c 7.7%- 8.9%
c. Troglitazone therapy 400 mg/day, 5/97 through 3/99:A1c 8.9% to 7.1% then to 8.1%
d. Pioglitazone added 12/99:
A1c 8.1% to 6.3-6.5% range.
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Case 1 Cont’d
2.Hypertriglyceridemia
Simvastatin therapy with TG of 402 mg/dL
Pioglitazone added
TG levels fell to 140 mg/dL
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Patient Case 2 Patient CM DOB 11/17/1935
Problem List:
1. Type 2 Diabetes, Onset 1993, age 59
a. Troglitazone added to Metformin and Repaglinide,
3/98: A1c 9.6% to 8.1%
b. Pioglitazone 45 mg added 1/26/00, A1c 8.1% to 7.3%, avg glucose 121 mg/dL
TG decreased from 206 mg/dL to 118 mg/dLTchol 164 mg/dL to 130 mg/dL, LDL 82 mg/dL to 58 mg/dL, HDL 41 to 46.
2. CHD: status post PTCA 1989, 1999.
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Patient Case 3 Patient EM; DOB 9/27/1932
1. Type 2 DM, Onset 1995, age 63
Insulin therapy since onset, post 15 lbs wt loss to 185 lbs
Height 71 inches
Glucose well controlled on NPH and Regular bid until 5/99,
A1c 8.7%
Changed to NPH at am and hs with pre-meal Lispro.
A1c to 7.0% on 54 - 81 units/day. Weight 229 pounds
Desires insulin pump therapy
C-peptide 3.7
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Patient Case 3 Cont’d
Changed to Pioglitazone 30 mg/day,
Glimepiride 4 mg/d, off insulin.
A1c down 6.2%.
TG decreased from 546 to 182 to 79 mg/dL.
LDL 191 to 132 (Atorvastatin 10 mg/day).
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Approach to Combination Oral Therapy
Intensifying of Oral Therapies
m etform in &/or glitazone+
sulfonylurea/repaglinide&/or glucosidase inh
sulfonylurea/repaglinide&/or glucosidase inh
+m etform in &/or glitazone
Continue
FPG < 120 m g/dl HbA1c < 7.0% FPG > 120 m g/dl HbA1c >7.0%
Add Insulin
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Insulin Therapy in Type 2 Diabetes Indications
Significant hyperglycemia at presentation Hyperglycemia on maximal doses of oral agents Decompensation
– Acute injury, stress, infection, myocardial ischemia– Severe hyperglycemia with ketonemia and/or ketonuria– Uncontrolled weight loss– Use of diabetogenic medications (eg, corticosteroids)
Surgery Pregnancy Renal or hepatic disease
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Mimicking Nature
The Basal/Bolus Insulin Concept
6-16
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Treat to Target Study: Glargine vs NPH Added to Oral Therapy of Type 2 Diabetes
Type 2 DM on 1 or 2 oral agents (SU, MET, TZD)
Age 30 to 70
BMI 26 to 40
A1C 7.5 to 10% and FPG > 140 mg/dL
Anti GAD negative
Willing to enter a 24 week randomized, open labeled study
Riddle et al, Diabetes June 2002, Abstract 457-p
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Treat to Target Study: Glargine vs NPH Added to Oral Therapy of Type 2 Diabetes
Add 10 units Basal insulin at bedtime (NPH or Glargine)
Continue current oral agents
Titrate insulin weekly to fasting BG < 100 mg/dL
- if 100-120 mg/dL, increase 2 units
- if 120-140 mg/dL, increase 4 units
- if 140-160 mg/dL, increase 6 units
- if 160-180 mg/dL, increase 8 unitsRiddle et al, Diabetes June 2002, Abstract 457-p
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Treat to Target Study; A1C Decrease
8.6
7.5
7.16.9 7
6.5
7
7.5
8
8.5
9
0 5 10 15 20 25 30
Weeks in Study (N=756)
Mea
n H
bA
1c%
Riddle et al, Diabetes June 2002, Abstract 457-p
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Treat to Target Study: Patients in Target (A1C < 7%)
2.5
32.3
48.8
66.2
57
0
10
20
30
40
50
60
70
Percentage of Patients
Week 0 Week 8 Week 12 Week 18 Week 24
Riddle et al, Diabetes June 2002, Abstract 457-p
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Treat to Target Study: Glargine vs NPH Added to Oral Therapy of Type 2 Diabetes
Nocturnal Hypoglycemia reduced by 40% in the Glargine group (532 events) vs NPH group (886 events)
Riddle et al, Diabetes June 2002, Abstract 457-p
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Advancing Basal/Bolus Insulin
Indicated when FBG acceptable but– HbA1c > 7% or > 6.5%
and/or– SMBG before dinner > 140 mg/dL
Insulin options– To glargine or NPH, add mealtime aspart / lispro– To suppertime 70/30, add morning 70/30– Consider insulin pump therapy
Oral agent options– Usually stop sulfonylurea– Continue metformin for weight control– Continue glitazone for glycemic stability?
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Insulin Monotherapy vs Combination
88 Type 2 patients on insulin monotherapy
Baseline A1C 8.7%
Randomized for 4 months to:
Monotherapy with titration to A1C 5.6%
Metformin 1000 mg BID (no titration)
Troglitazone 600 mg per day (no titration)
Strowig et al, Diabetes Care 25, 10, October 2002
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Insulin Monotherapy vs Combination
Baseline A1C 8.7%
Randomized for 4 months to:
Monotherapy: A1C 7.0% (+ 55 units/day; + 0.5 kg)
Metformin: A1C 7.1% (- 1.4 units/day; + 4.4 kg)
Troglitazone: A1C 6.4% (-12.8 units/day; + 4.4 kg)
Strowig et al, Diabetes Care 25, 10, October 2002
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Multiple Daily Injections
Starting dose 0.2 x wgt. in lbs.
Wgt. 180 lbs which = 36 units
Bolus dose (lispro/aspart) = 20% of starting dose at each meal, which = 7 units ac (tid)
Basal dose (glargine) = 40% of starting dose at HS, which = 14 units at HS
Correction bolus = (BG - 100)/ SF, where SF = 1500/total daily dose = 1500/36 = 40
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Correction Bolus Formula
Example:
–Current BG: 220 mg/dl
– Ideal BG: 100 mg/dl
–Glucose Correction Factor: 40 mg/dl
Current BG - Ideal BGGlucose Correction factor
220 - 100 40
=3.0u
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Strategies to Improve Glycemic Control: Type 2 Diabetes
Monitor glycemic targets – Fasting and postprandial glucose, HbA1c
Self-monitoring of blood glucose is essential
Nutrition and activity are cornerstones of therapy
Combinations of pharmacologic agents are often necessary to achieve glycemic targets
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Conclusion
Intensive therapy is
the best way to treat
patients with diabetes