Post on 31-Dec-2015
Redefining the Treatment Algorithm for Type 2
Diabetes – 2009
Robert J. Rushakoff, MDProfessor of Medicine
University of California, San Francisco
robert.rushakoff@ucsf.edu
Welcome to Today’s Medical Education Program!
• I am pleased to be here with you on behalf of Merck & Co., Inc. who is sponsoring this medical education program.
• The program you are participating in is not an accredited Continuing Medical Education program.
• The information presented throughout the program will be consistent with FDA guidelines.
What do you think of when told:
2-2.5 fold increased risk of CHF
2-3 fold increase in risk for initial MI
3 fold increase in risk for pancreatitis
Decreased leukocyte function
Risk for lactic acidosis
Increased risk for renal failure, retinopathy, neuropathy
Type 2 Diabetes
Hyperglycemia
β
hepatic glucose output
Insulin secretion
Glucose uptake glucose utilization
Hyperglycemia
β α Postprandial glucagonsecretion
Hyperglycemia
β α
FFA Lipotoxicity
Hyperglycemia
β α
Incretins
Hyperglycemia
β α Altered glucose reabsorption
Hyperglycemia
β α
Altered Hypothalamic
Appetite Control
Hyperglycemia
β α
Ominous Octet
Fundamental Questions Just because a drug may work at
one or more of the sites of defect in Type 2 DM - what about:
Efficacy Side effects Actually improve outcomes or
make them worse Decrease mortality or kill people
Fundamental Questions Is there anything wrong with the
current group of medications? Do the newer medications fix what is
wrong with the older medications? Does it really matter what medication
is used first, second, third? Does it really matter what medication
is used?
New Drug Truthiness Often no clinically relevant literature
published before medication is released
Studies performed to obtain FDA approval are useful for FDA approval
Clinically useful studies may lag release to market by 5 years, or are never done
Today What are the goals? What differentiates the
medications? Does it really matter what
medication is used? Put it all together – ADA way, AACE
way and of course, MY WAY
Diabetes Care 31:1473–1478, 2008
Relationship Between Plasma Glucose and HgA1c
Hemoglobin A1c
50% of level determined in previous month
25% by month before 12.5% by month before 12.5% by month before
Hemoglobin A1c
False High Levels Thalassemia (Hgb F) Lead poisoning Large amount of
ASA High alcohol, Tg
bilirubin levels Hemoglobinopathies
J,K,I,H, Bart’s, Raleigh, Long Island and South Florida
False Low Levels Hemoglobinopathi
es S,D,C,E,G, Lepore and O-Arab.
Hemolytic anemia, bleeding
Large ingestions of Vitamin C and E
The relationship between baseline A1C group and observed reduction from baseline in A1C
and in FPG
Baseline A1C (%)
n enrolled in clinical trials
Change in A1C (%)
Change in FPG (mmol/l)
6.0–6.9 410 –0.2 –0.5
7.0–7.9 1,620 –0.1 –0.8
8.0–8.9 5,269 –0.6 –1.6
9.0–0.9.9 1,228 –1.0 –2.3
10.0–11.8 266 –1.2 –3.4
Diabetes Care 29:2137-2139, 2006
The ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-2572
ADVANCE: Relative Effects of Glucose-Control Strategy on All Prespecified Primary and Secondary Outcomes
ACCORD: Hazard Ratios for the Primary Outcome and Death from Any Cause in Prespecified Subgroups
The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-2559
VADT - Veterans Administration Diabetes Trial
•1742 Enrollees•97% male•Mean age 60.4
•BMI 31.3•Majority had multiple CV risk factors
•72% HTN•40% macrovascular dx•62% retinopathy•43% neuropathy
VADT - Veterans Administration Diabetes Trial
Primary Endpoint: NO DIFFERENCE IN CARDIOVASCULAR DISEASE OUTCOMES Standard: 29.3% (predicted –
40%) Intensive: 27.4% (predicted –
31.6%)
VADT - Veterans Administration Diabetes Trial Baseline Predictor of CVD:
Age and prior CVD event On-trial hypoglycemia – low
glucose and altered consciousness in the three months prior to an event was predictive of CVD outcome
VADT - Veterans Administration Diabetes Trial When duration of DM factored
in: Intensive glycemic control
showed benefit Benefit declines until about 12-15
years of disease
UKPDS: 10 year follow-up Glucose Control
Between-group differences in HgA1c gone after 1 year
In the sulfonylurea–insulin group, relative reductions in risk persisted at 10 years for:
any diabetes-related end point (9%, P=0.04) microvascular disease (24%, P=0.001) risk reductions for myocardial infarction (15%, P=0.01) death from any cause (13%, P=0.007)
In the metformin group: any diabetes-related end point (21%, P=0.01) myocardial infarction (33%, P=0.005) and death from any cause (27%, P=0.002).
Published at www.nejm.org September 10, 2008 Published at www.nejm.org September 10, 2008
Effect of Metformin-Containing Antidiabetic Regimens on All-cause Mortality in Veterans With Type 2 Diabetes Mellitus
Decreased Hazard Ratio for all cause mortality for patients on metformin
vs no metformin – 0.77 (p<0.01)
Increased Hazard Ratio for all cause mortality for patients on insulin:
1.62 (p<0.001)
Decreased Hazard Ratio for all cause mortality for patients on metformin and insulin vs insulin
0.62 (p<0.04)
Am J Med Sci 2008; 336:241-247Am J Med Sci 2008; 336:241-247
ADA Targets for Glycemic Control
Preprandial plasma glucose Preprandial plasma glucose 80–130 mg/dl (5-7.2 mmol/l)80–130 mg/dl (5-7.2 mmol/l)
Peak postprandial plasma glucosePeak postprandial plasma glucose <180 mg/dl (<10 mmol/l)<180 mg/dl (<10 mmol/l)
Hemoglobin AHemoglobin A1c1c <7 (%) <7 (%)
Biochemical IndexBiochemical Index GoalGoal
ADA Targets for Glycemic Control
Key concepts in setting glycemic goals: A1C is the primary target for glycemic control.
Goals should be individualized based on: duration of diabetesage/life expectancycomorbid conditionsknown CVD or advanced microvascular complicationshypoglycemia unawarenessindividual patient considerations
More or less stringent glycemic goals may be appropriate for individual patients.
Postprandial glucose may be targeted if A1C goals are not met despite reaching preprandial glucose goals.
ClassGeneric Name(Brand Name)
Mechanism of Action
Dosage Relative
Effective-ness
Major Side Effects / Interactions / Uses
Weight Effects
(average)
Cost
Sulfonylureas
Glyburide(Micronase)
Glipizide(Glucotrol)
glimepiride(Amaryl)
Stimulate insulin release from beta cells of the pancreas
2.5-10 mg bid
5-20 mg bid
0.5-4 mg qd
1
1
1
HypoglycemiaGain 2 lbs $
ClassGeneric Name(Brand Name)
Mechanism of Action
Dosage Relative
Effective-ness
Major Side Effects / Interactions / Uses
Weight Effects
(average)
Cost
Sulfonylureas Stimulate insulin release
1 Hypoglycemia Gain 2 lbs
$
Meglitinides
repaglinide(Prandin)
nateglinide(Starlix)
Stimulate insulin release from beta cells of the pancreas
0.5-2 mg tid(before meals)
60-360 mg tid(before meals)
1
.8
HypoglycemiaUseful in pts on glucocorticoids and in pts with renal failure who often have good FBS and high BS over the course of the dayPrandin is short-acting. Starlix is very short-acting
Gain 1 lb
$$$
ClassGeneric Name(Brand Name)
Mechanism of Action
Dosage Relative
Effective-ness
Major Side Effects / Interactions / Uses
Weight Effects
(average)
Cost
Sulfonylureas Stimulate insulin release
1 Hypoglycemia Gain 2 lbs
$
Meglitinides Stimulate insulin
.8-1 Hypoglycemiashort-acting Gain 1 lb $$$
Biguanidemetformin(Glucophage)
Primarily inhibits hepatic gluconeogen-esis.
500-2000 mg daily with meals
1Diarrhea, nausea, vomitingIncreased risk of lactic acidosis if impaired renal or hepatic function or heavy EtOH use
Loss2-3 lbs $
Metformin and Lactic Acidosis
• “Metformin may provoke lactic Acidosis which is most likely to occur in patients with renal impairment. It should not be used with even mild renal impairment” 1
• Metformin probably not as unsafe as previously thought. – 25% users have relative contraindication 2
– Patient’s with lactic acidosis usually have acute renal failure 3
1. Joint Formulary Committee British National Formulary. 2006:3532. Diabet Med 2001; 18:483-4883. Diabet Med 2007; 24:494-497
Metformin and eGFR
• 186 x (Creat / 88.4)-1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if black)
• Current Guidelines call for discontinuation of Metformin serum creatinine >150 umol/l (1.7 mg/dl).
• Estimated GFR (eGFR) being introduced as possible better measure of renal function than serum creatinine alone
• eGFR of 36 ml/min per 1.73m2 would be somewhat neutral to current use
ClassGeneric Name(Brand Name)
Mechanism of Action
Dosage Relative
Effective-ness
Major Side Effects / Interactions / Uses
Weight Effects
(average)
Cost
Sulfonylureas Stimulate insulin release
1 Hypoglycemia Gain 2 lbs
$
Meglitinides Stimulate insulin
.8-1 Hypoglycemiashort-acting Gain 1 lb $$$
Biguanide inhibits hepatic gluconeogenesis.
1 Diarrhealactic acidosis
Loss2-3 lbs
$
Alpha-glucosidaseInhibitoracarbose(Precose)
Inhibits enzymes needed to break down complex CHO in the small intestine
50 mg with 1st bite of each meal (start at 12.5 mg and titrate up over weeks)
0.7 Gas/ GI upset Loss1-2 lbs
$$$
Treatment of Hypoglycemia in Patients Treated with Acarbose
• In case of hypoglycemia(due to sulfonylurea or insulin treatment)– Glucose (dextrose) must be administered– Sucrose and complex carbohydrates should
not be administered
Bile Acid Sequestrants• Bile acid sequestrants lower LDL cholesterol
• Colesevelam (Welchol) a bile acid sequestrant, lowers glucose levels and AIC levels in T2D patients
–The bad
–The good
–The very ugly
Thiazolidenediones
TZDs and Liver Disease
• From troglitazone – contraindicated in patients with liver disease
• Diabetes patients frequently have fatty liver (NASH---Non- Alcoholic Steatorrhoeic Hepatosis) with elevated LFT
• TZDs decrease liver fat and improve NASH• TZDs may be best treatment for NASH and
preventing cirrhosis
Rushakoff RJ: Normalization of abnormal liver function tests in Type 2 diabetic patients after administration of Troglitazone. Diabetes 48 supplement 1999
Current TZD Side Effects
• Weight Gain: 5-12 lbs in 1 year– Blunted with metformin– Worse with insulin
• Edema: 4-30%– Unresponsive to diuretics
• BUT:– Increased Cardiac Index– Increased Stroke volume– Decreased systemic resistance– Decreased Blood Pressure
Thiazolidinediones and Risk of Repeat Target Vessel Revascularization Following Percutaneous
Coronary Intervention
Diabetes Care 30:384-388, 2007
Positive Side to TZDs
• Reduction in glucose• Reduces BP• Reduces albuminuria• Reduces CRP• Possible DM
prevention• Reduces NASH• Reduces LFT
• Reduces IMT• Reduces stent failure• Reduces death after
CHF
• Increases adiponectin• Increases HDL
The N E W E N G L A N DJ O U R N A L of M E D I C I N E
ESTABLISHED IN 1812 JUNE 14, 2007 VOL. 356 NO. 24
Effect of Rosiglitazone on the Risk of Myocardial InfarctionAnd Death from Cardiovascular Causes
Steven E. Nissen, M.D., and Kathy Wolski, M.P.H.
Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death…that had borderline significance.
CONCLUSIONS
Meta-analysis of MI and Death risk with rosiglitazone
Nissen SE, Wolski K. N Engl J Med. 2007;356.
n = 15,560 on rosiglitazone; n = 12,283 on comparator drug or placebo
Rosiglitazone group
Control group
Study No. of events/Total no. (%)Odds ratio
(95% CI) P
Myocardial infarction
Small trials combined
DREAM
ADOPT
Overall
44/10,280 (0.43)
15/2635 (0.57)
27/1456 (1.85)
86
22/6105 (0.36)
9/2634 (0.34)
41/2895 (1.44)
72
1.45 (0.88–2.39)
1.65 (0.74–3.68)
1.33 (0.80–2.21)
1.43 (1.03–1.98)
0.15
0.22
0.27
0.03
86/14371 (.60%) 72/11634 (0.62%)Relative Risk = 86/72 = 1.19
Absolute Risk = -.02%
Comparison of RSG to SU or MET MI/CV Death/Stroke
Meta-analysis database (ICT), ADOPT and RECORD
Myocardial Infarction
Overall pooled data (N=26011)
ADOPT (N=4351)
DREAM (N=5269)
Small trials combined(N=16391)
0 1 2 3 4Odds ratio
Uncorrected (Peto)
1.45 (0.88-2.39)
1.43 (1.03-1.98)
0 1 2 3 4Odds ratio
Corrected (MH/CC)
1.16 (0.76-1.78)
1.28 (0.95-1.72)
Rosiglitazone and Cardiovascular Events
Meta-Analytic Subgroups
Rosiglitazone and Cardiovascular Events
Meta-Analytic Subgroups
Center for Drug Evaluation and ResearchCenter for Drug Evaluation and ResearchJoint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory CommitteeDrug Safety and Risk Management Advisory CommitteeJuly 30, 2007July 30, 2007
David Graham, MD MPH
Center for Drug Evaluation and ResearchCenter for Drug Evaluation and ResearchJoint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory CommitteeDrug Safety and Risk Management Advisory CommitteeJuly 30, 2007July 30, 2007
David Graham, MD MPH
PANIC
Rosiglitazone Associated Fractures in Type 2 Diabetes: An Analysis From
ADOPT
Diabetes Care Publish Ahead of Print, published online on February 5, 2008
Changes in BMD during pioglitazone or placebo treatment in patients with PCOS
J Clin Endocrinol Metab. 2008 Feb 19 [Epub ahead of print]
ClassGeneric Name(Brand Name)
Mechanism of Action
Dosage Relative
Effective-ness
Major Side Effects / Interactions / Uses
Weight Effects
(average)
Cost
Sulfonylureas Stimulate insulin release
1 Hypoglycemia Gain 2 lbs
$
Meglitinides Stimulate insulin
1 Hypoglycemiashort-acting Gain 1 lb $$$
Biguanide inhibits hepatic gluconeogenesis.
1 Diarrhealactic acidosis
Loss2-3 lbs
$
Alpha-glucosidaseInhibitor
Decreased CHO absorption
0.7Gas/ GI upset Loss
1-2 lbs$$$
Thiazolidine-diones
rosiglitazone(Avandia)
pioglitazone(Actos)
Insulin sensitizers—Activate receptor molecules inside cell nuclei to decrease insulin resistance
4-8 mg daily
15-45 mg daily
1
1
Weight gain, edema which is resistant to diuretic therapy, CHF.
Associated with bone loss and fractures.
Gain 12 lbs $$
$
Comparison of metabolic effects of pioglitazone, metformin, and glimepiride over 1 year in Japanese patients with newly diagnosed Type 2 diabetes
114 drug naïve patients Initial HgA1c Duration DM about 3 years Initial Hga1c 10% Body mass index 25
Diabetes Medicine 2005; 22:980-985
Time course of reduction in glycated haemoglobin (HbA1c) in patients receiving pioglitazone (O), metformin (●), or glimepiride (). Data are mean ±sd. *P < 0.05; **P < 0.01; ***P < 0.005 vs. baseline.
Diabetes Medicine 2005; 22:980-985
-80-60
-40-20
0
2040
0 7 14 21 28Weeks
Me
an
Ch
an
ge
(m
g/d
l)
Continuedglyburide(n=209)
Switched tometformin(n=210)
Metformin +glyburide(n+213)
Fasting Plasma glucose: Mean Change From Baseline
Diabetes 452:146, 1993
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
3.94
-5.29
7.32
10.84
-6
-4
-2
0
2
4
6
8
10
12
Change in Weight
SulfonylureaMetforminInsulinTZD
Weight Changes Associated with Anti-Hyperglycemic Therapies for Type 2
Diabetes
ADA Scientific Meeting 2005 ABS 13-or
Postprandial Glucose Control
Shin J et al. Abstract 424-P. ADA; 2004: New Orleans, La.
Postprandial Glucose Excursions in Subjects With or Without Diabetes
350
300
250
200
150
100
50
0–1 0 1 2 3 4 5 6 7 8
Time (hours)
Se
rum
Glu
cos
e V
alu
e (
mg
/mL
) Without diabetesType 1 diabetesType 2 diabetes
Meal Event
Subjects
Relative Contribution of FPG and PPG to Overall Hyperglycemia Depending on A1C Quintiles
n=58 n=58 n=58 n=58n=58
Monnier L et al. Diabetes Care. 2003;26:881–885.
0
20
40
60
80
100
<7.3 7.3–8.4 8.5–9.2 9.3–10.2 >10.2
Postprandial glucose Fasting glucose
A1C
Co
ntr
ibu
tio
n,
%
INCRETINS
• Gut factors that promote insulin secretion in response to nutrients
•Major incretins: GLP-1, CCK, GIP
Oral Glucose Promotes More Insulin Release than IV Glucose - Indicating a
Role for Incretins
Non-Diabetic Diabetic
Plasma Insulin Responses to Oral and Intravenous Glucose
J Clin Invest 1967; 46:1954-1962
OralIntravenous
OralIntravenous
60
Insu
lin
(U
/mL
)
30
0
0 60 120 18030 90 150 0 60 120 18030 90 150
90
Insu
lin
(U
/mL
)
60
30
0
90
MinutesMinutes
Glucose-Dependent Effects of GLP-1 on Insulin and Glucagon Levels in Patients With Type 2 Diabetes
Glucose
Glucagon When glucose levels approach normal values, glucagon levels rebound.
When glucose levels approach normal values,insulin levels decreases.
*P <0.05Patients with type 2 diabetes (N=10)
mm
ol/
L
15.012.510.0
7.55.0
25020015010050
mg
/dL*
* * * * * *p
mo
l/L 250
200150100
50
40
30
20
10
0
mU
/L
* ** ** * * *
Infusion
Minutes
pm
ol/
L 20
15
10
5
0 60 120 180 240
* * * *
pm
ol/L
20
15
10
5
Placebo
GLP-1
Insulin
2.50
0
0 0
0
Adapted with permission from Nauck MA et al. Diabetologia. 1993;36:741–744. Copyright © 1993 Springer-Verlag.
–30
GLP-1 and GIP Are Degraded by the DPP-4 Enzyme
Meal
Intestinal GIP and GLP-1 release
GIP and GLP-1 Actions
DPP-4 (Dipeptidyl Peptidase IV)Enzyme
GIP-(1–42)GLP-1(7–36)
Intact
GIP-(3–42)GLP-1(9–36)Metabolites
Rapid Inactivation
Half-life*GLP-1 ~ 2 minutes
GIP ~ 5 minutes
Deacon CF et al. Diabetes. 1995;44:1126–1131.*Meier JJ et al. Diabetes. 2004;53:654–662.
Incretin Drugs GLP Agonists
Exenatide Liraglutide CJC-1131 AVE-0010 Albugon Glp-1-transferin Exenatide Lar
DPP IV Inhibitors Vildagliptin Sitagliptin Saxagliptin PSN-931 Takeda-Syrrx
N
ONH2
NN
CF3
F
F
F
N
Sitagliptin
Improvements in HbA1C With Initial Co-administration of Sitagliptin and Metformin
Placebo
Sita 100 mg QD
Sita 50 mg BID + Met 500 mg BID
Sita 50 mg BID + Met 1000 mg BID
Met 1000 mg BID
Met 500 mg BID
* Placebo-subtracted LS mean change form baseline at Week 24. Sita=sitagliptin; Met=metformin.
-2.5
-2.0
-1.5
-1.0
-0.5
Hb
A1C
(%
)* -0.8-1.0
-1.3
-1.6
-2.1
Mean Baseline HbA1C = 8.8%N=1091
Aschner P, et al. Oral presentation at the EASD 42nd Annual Meeting; 14-17 September 2006; Copenhagen.
Proportion of Patients Achieving HbA1C Goals
0
10
20
30
40
50
60
70
Placebo
Sita 100 mg QD
Sita 50 mg BID + Met 500 mg BID
Sita 50 mg BID + Met 1000 mg BID
Met 1000 mg BID
Met 500 mg BID
HbA1C <7.0%HbA1C <6.5%
To
Go
al (
%)
Sita=sitagliptin; Met=metformin.Aschner P, et al. Oral presentation at the EASD 42nd Annual Meeting; 14-17 September 2006; Copenhagen.
79
bid=twice a day; LSM=least-squares mean; qd=once a day. aResults include only randomized patients who agreed to enter the extension study, had not received glycemic rescue therapy through week 54, took at least 1 dose of study medication after week 54, and had at least 1 post-54-week A1C measurement.bValues represented are rounded, actual values 1.15 for Sitagliptin 100 mg qd and 1.06 for Metformin 500 mg bid.Data available on request from Merck & Co., Inc. Please specify 20852883(1)-JAN.
LS
M A
1C C
ha
ng
e F
rom
Bas
elin
e,
%
–2.0
–1.5
–1.0
–0.5
0.0
–1.1 –1.1
–1.3
Initial Combination Therapy With Sitagliptin Plus Metformin Study: A1C Results at 104 Weeks
(Extension Study)a
Sitagliptin 100 mg qd
Metformin 1,000 mg bid
Metformin 500 mg bid
Sitagliptin 50 mg bid + metformin 1,000 mg bid
Sitagliptin 50 mg bid + metformin 500 mg bid
n=50 n=64 n=87
104-week resultsMean baseline A1C = 8.5%–8.7%
–1.4
–1.7
n=96 n=105
b b
DPP-4 Study Summary
Sitagliptin vs glipizide added to metformin
52 weeks, 100 mg/d vs 20 mg/d
Baseline HgA1c 7.5
Both 0.67% reduction in HgA1c
Both about 60% reached HgA1c <7
Hypoglycemia –
• glipizide: 32%
• sitagliptin: 4.9%
ClassGeneric Name(Brand Name)
Mechanism of Action
Dosage Relative
Effective-ness
Major Side Effects / Interactions / Uses
Weight Effects
(average)
Cost
Sulfonylureas Stimulate insulin release
1 Hypoglycemia Gain 2 lbs
$
Meglitinides Stimulate insulin
1 Hypoglycemiashort-acting Gain 1 lb $$$
Biguanide inhibits hepatic gluconeogenesis.
1 Diarrhealactic acidosis
Loss2-3 lbs
$
Alpha-glucosidaseInhibitor
Decreased CHO absorption
0.7Gas/ GI upset Loss
1-2 lbs$$$
Thiazolidinediones
Insulin 1 Weight gain, edema, fractures Gain 12 lbs
$$$
Incretins
exenatide(Byetta)
sitagliptin(Januvia)
Mimics GLP-1 (gut hormone which affects insulin, glucagon, gastric emptying and satiety)DPP-4 inhibitor (enzyme that breaks down GLP-1)
5-10 mcg bid SQ
100, 50, or 25 mg daily (dose by Cr Cl)
1
1
Nausea, Vomiting, constipation, pancreatitis (?)Weight loss achieved through appetite suppression
Side effects are rare. Occ GI side effects. Pancreatitis (?), vasculitis (?)
Loss 8 lbs
Neutral
$$$
$$$
Conventional Therapies Do Not Influence -Cell Failure: UKPDS
UKPDS 34. Lancet 1998; 352: 854-865UKPDS 16: Diabetes 1995; 44: 1249-1258
cohort, median values
06
7
8
9
10
-1 0 2 4 6 8 10Years from randomization
ChlorpropamideConventionalGlibenclamideInsulin
Metformin
Hb
A1
c(%
)
0
20
40
60
80
100
0 1 2 3 4 5 6 7
ß c
ell
fu
ncti
on
(%
)0
20
40
60
80
100
0 1 2 3 4 5 6 7
ß c
ell
fu
ncti
on
(%
)
Years from randomizationConventional Sulphonylurea Metformin
OverweightNon-OverweightOverweight
DIGAMI2 (European Heart J. Prepublication Feb
2005)
Group 1 – IV insulin then long term SQ insulinGroup 2 – IV insulin then standard treatmentGroup 3 – Standard treatment
Mortality
Effect of different updated glucose lowering treatments on mortality and morbidity
Mellbin, L. G. et al. Eur Heart J 2008 29:166-176
ClassGeneric Name(Brand Name)
Mechanism of Action
Dosage Relative
Effective-ness
Major Side Effects / Interactions / Uses
Weight Effects
(average)
Cost
Sulfonylureas Stimulate insulin release
1 Hypoglycemia Gain 2 lbs
$
Meglitinides Stimulate insulin
.8-1 Hypoglycemiashort-acting Gain 1 lb $$$
Biguanide inhibits hepatic gluconeogenesis.
1 Diarrhealactic acidosis
Loss2-3 lbs
$
Alpha-glucosidaseInhibitor
Decreased CHO absorption
0.7Gas/ GI upset Loss
1-2 lbs$$$
Thiazolidinediones
Insulin 1 Weight gain, edema, fractures Gain 12 lbs
$$$
Incretins exenatide
sitagliptin
Increase insulin, decrease glucagon
11
NauseaWeight loss
Side effects are rare.
Loss 8 lbs
Neutral
$$$
Insulin Titrated to need
1+ Hypoglycemia Gain 8 lbs
$$
Drug Cost Comparison
Drug and Dose Cost/month
Glucose Strips (2 per day) $60
Sulfonylurea Generic $4-14Brand $50
Rapaglinide 2 mg tid $175Acarbose 100 mg tid $88Metformin 1000 bid Generic $ 4-32
Brand $132Rosiglitazone 8 mg qd $223Pioglitazone 45 mg/d $222Sitagliptin $181Exenatide 5mcg $230
10mcg $255Colesevelam 3750 mg/d $212Glargine, 45 U/d $150
24 hour fitness center $44YMCA $60
No Meds
1 Drug
2 Drugs
3 Drugs
Insulin
added
7
9
10
8
HgA1c
Diabetes Care. Published online Oct 22, 2008
2009 ADA Type 2 Consensus Statement Diabetes Treatment Algorithm
An American Diabetes Association consensus statement represents the authors’ collective analysis, evaluation, and opinion at the time of publication and does not represent official association opinion.
Road Maps to Achieve Glycemic Control
In Type 2 Diabetes Mellitus
ACE/AACE Diabetes Road Map Task Force
ChairpersonsPaul S. Jellinger, MD, MACE, Co-Chair
Jaime A. Davidson, MD, FACE, Co-Chair
Task Force MembersLawrence Blonde, MD, FACP, FACE
Daniel Einhorn, MD, FACP, FACE
George Grunberger, MD, FACP, FACE
Yehuda Handelsman, MD, FACP, FACE
Richard Hellman, MD, FACP, FACE
Harold Lebovitz, MD, FACE
Philip Levy, MD, FACE
Victor L. Roberts, MD, MBA, FACP, FACE
© 2007 AACE. All rights reserved. No portion of the Roadmap may be altered, reproducedor distributed in any form without the express permission of AACE.
Road Map to Achieve Glycemic Goals: Naïve to Therapy (Type 2)
Initial
A1C%
Achieve ACEGlycemic Goals†
( FPG, PPG, and A1C ) Intervention
ContinuousTitration of Rx( 2 - 3 months )
If ≤ 6.5% A1C GoalNot Achieved
Assess FPG
and PPG
Initial Therapy
Monitor / adjust Rx to
maximal effective dose to meet ACE
Glycemic Goals
Intensify Lifestyle Modification
Intensify or combine Rx
including incretin mimetic*1
Target: PPG
and FPG
Monitor / adjust Rx to
maximal effective dose to meet ACE
Glycemic Goals
Combine Therapies 6,7Intensify Lifestyle
Modification
Intensify or combine Rx, including incretin mimetic
with SU, TZD, and/or metformin
6 - 7
7 - 8
Lifestyle
Mo
dificatio
n
Lifestyle
Mo
dificatio
n
If ≤ 6.5% A1C GoalNot Achieved
Alternatives• Glinides• SU (low dose)• Prandial insulin5,8
Preferred:• Metformin4
• TZD10,11
• AGI• DPP-4 Inhibitor
Alternatives• Prandial insulin5,8
• Premixed insulinpreparations8
• Basal insulinanalog9
• Metformin• Glinides• AGI• TZD• SU• DPP-4 Inhibitor
© 2007 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE.
ACE/AACE Diabetes Road Map Task Force
Paul S. Jellinger, MD, MACE, Co-ChairJaime A. Davidson, MD, FACE, Co-ChairLawrence Blonde, MD, FACP, FACEDaniel Einhorn, MD, FACP, FACE George Grunberger, MD, FACP, FACEYehuda Handelsman, MD, FACP, FACERichard Hellman, MD, FACP, FACEHarold Lebovitz, MD, FACEPhilip Levy, MD, FACEVictor L. Roberts, MD, MBA, FACP, FACE
Endocr Pract. 2007;13:260-268
†ACE Glycemic Goals ≤ 6.5% A1C< 110 mg/dL FPG < 110 mg/dL Preprandial< 140 mg/dL 2-hr PPG
Access Roadmap at: www.aace.com/pub
* Available as exenatide 1 Indicated for patients not at goal despite SU and/or
metformin or TZD therapy; incretin mimetic is notindicated for insulin-using patients
4 Preferred first agent in most patients 5 Rapid-acting insulin analog (available as lispro, aspart and
glulisine), inhaled insulin, or regular insulin 6 Appropriate for most patients 7 2 or more agents may be required 8 Analog preparations preferred 9 Available as glargine and detemir10 A recent report (NEJM; 6/14/07) suggests a possible link of rosiglitazone to cardiovascular events that requires further evaluation.11 Cannot be used in NYHA CHF Class 3 or 4
Start onsulfonylurea or insulin
TYPE 2 DIABETES
SYMPTOMATICAnd very highNO YES
Referral for:•Diet•HGM•Exercise•Foot Care
Goal Met
Start Metformin
Referral for:•Diet•HGM•Sick Day Rules•Exercise (+/- EST)•Foot Care
NO
Continue Current TreatmentAdd
Medication
YESConsidertransitionto metformin
TYPE 2 DIABETES
Metformin
OBESE THIN
Exenatide Sulfonylurea
Add Sulfonylurea(consider TZD)
•Start insulin – use pens•Add detemir, glargine or PM NPH (isolated fasting hyperglycemia or insurance)
•? of which existing meds to continue, generally all •Change to bid premixed insulin
•? of which existing meds to continue, generally just metformin•Change to basal and with premeal insulin
•? of which existing meds to continue, generally just metformin
Goal Not Met
Sitagliptin
Thin or no injection
Sitagliptin(consider TZD)
Goal Not Met
Add Sulfonylurea(consider TZD)
Goal Not Met
Goal Not Met