Transcript Document

Prediabetes
Management
1
AACE Prediabetes Consensus
Statement: Summary
• Untreated individuals with prediabetes are at
increased risk for diabetes as well as for micro- and
macrovascular complications
• Treatment goals are to prevent deterioration in
glucose levels and modify other risk factors such as
obesity, hypertension, and dyslipidemia
– The same blood pressure and lipid goals are suggested for
prediabetes and diabetes
• Intensive lifestyle management is the cornerstone of
all prevention efforts; pharmacotherapy targeted at
glucose may be considered in high-risk patients
2
Handelsman Y, et al. Endocr Pract. 2011;17(Suppl 2):1-53.
Garber AJ, et al. Endocr Pract. 2008;14:933-946.
Prediabetes
• Epidemiologic evidence suggests that the
complications of T2DM begin early in the progression
from NGT to frank diabetes
• Prediabetes and diabetes are conditions in which
early detection is appropriate, because
– Duration of hyperglycemia is a predictor of adverse
outcomes
– There are effective interventions to prevent disease
progression and to reduce complications
3
NGT, normal glucose tolerance ; T2DM , type 2 diabetes mellitus.
Garber AJ, et al. Endocr Pract. 2008;14:933-946.
Policy Paradigm Shifts Needed to
Stem Global Tide of T2DM
• Integrating primary and secondary prevention along a
clinical continuum
• Early detection of prediabetes and undiagnosed
diabetes
• Implementing cost-effective prevention and control by
integrating community and clinical
expertise/resources within affordable service delivery
systems
• Sharing and adopting evidence-based policies at the
global level
4
T2DM , type 2 diabetes mellitus.
Narayan KM, et al. Health Aff (Millwood). 2012;31:84-92.
Road Map to Prevent Type 2 Diabetes
Intervention
Early
Identification
Age 30 or above for
populations at high risk:
•
•
•
•
•
•
•
•
•
•
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Family history of diabetes
Cardiovascular disease
Overweight
Sedentary lifestyle
Latino/Hispanic, African
American, Asian American,
Native American, or
Pacific Islander
Previously identified IGT
or IFG
Hypertension
Elevated triglycerides,
low HDL, or both
History of gestational
diabetes
Delivery of a baby weighing
>9 lbs
Severe psychiatric illness
FPG or 2-h OGTT is the
recommended screening procedure
5
Therapeutic
Lifestyle
Management
• Medical nutrition
therapy (MNT)
• Physical fitness
Program
• Weight loss
• 5%-7% reduction in body
weight (if overweight)
• 30 minutes exercise, 5
times per week at the
equivalence of brisk
walking
Access Roadmap at:
www.aace.com/pub
Pharmacologic
Non-FDA approved*
• TZD**
• Metformin
• Orlistat
• AGI
Persistent
Monitoring of
Glucose and
Risk Reduction
Measures
•
•
•
•
Hypertension
Dyslipidemia
Physical fitness
Weight control
* Shown to be effective in delaying the
onset of type 2 diabetes in clinical studies
** A recent report (NEJM; 6/14/07) suggests
ACE/AACE Diabetes Road Map
a possible link of rosiglitazone to
cardiovascular events that requires further Task Force
evaluation
Paul S. Jellinger, MD, MACE, Co-Chair
Jaime A. Davidson, MD, FACE, Co-Chair
Lawrence Blonde, MD, FACP, FACE
Daniel Einhorn, MD, FACP, FACE
George Grunberger, MD, FACP, FACE
Yehuda Handelsman, MD, FACP, FACE
Richard Hellman, MD, FACP, FACE
Revision March 2008
Harold Lebovitz, MD, FACE
© 2007 AACE. All rights reserved. No
portion of the Roadmap may be altered,
Philip Levy, MD, FACE
reproduced or distributed in any form
Victor L. Roberts, MD, MBA, FACP, FACE
without the express permission of AACE.
AGI, alpha-glucosidase inhibitors; FDA , Food and Drug Administration; FPG, fasting plasma
glucose; HDL ,high-density lipoprotein; IFG, impaired fasting glucose; IGT, impaired glucose
tolerance; OGTT, oral glucose tolerance test; TZD, thiazolidinedione.
Jellinger PS, et al. Endocr Pract. 2007;13:260-268.
2-Track Approach to Reduce Risk
Associated With Prediabetes
(1) Lower glucose
to prevent
microvascular
complications and
progression to
diabetes
• Therapeutic lifestyle
management
• Pharmacotherapy in highrisk patients
• Therapeutic lifestyle
management
(2) Address
• Blood pressure goals:
cardiovascular
<130/80 mm Hg
disease risk factors
• LDL goal: <100 mg/dL
6
LDL , low-density lipoprotein; mm Hg, millimeters of mercury.
Garber AJ, et al. Endocr Pract. 2008;14:933-946.
Feasibility of Preventing T2DM
• There is a long period of glucose intolerance that
precedes the development of diabetes
• Screening tests can identify persons at high risk
• There are safe, potentially effective interventions
that can address modifiable risk factors:
–
–
–
–
Obesity
Body fat distribution
Physical inactivity
High blood glucose
7
T2DM, type 2 diabetes mellitus.
Garber AJ, et al. Endocr Pract. 2008;14:933-946.
Interventions to Reduce Risks
Associated With Prediabetes
• Therapeutic lifestyle management is the
cornerstone of all prevention efforts
• No pharmacologic agents are currently
approved for the management of prediabetes
– Pharmacotherapy targeted at glucose may be
considered in high-risk patients after individual
risk-benefit analysis
8
Garber AJ, et al. Endocr Pract. 2008;14:933-946.
Lifestyle Intervention in
Prediabetes
Persons with prediabetes should reduce weight by
5% to 10%, with long-term maintenance at this
level
• A program of regular moderate-intensity physical activity for
30-60 minutes daily, at least 5 days a week, is recommended
A diet that includes caloric restriction, increased
fiber intake, and (in some cases) carbohydrate
intake limitations is advised.
9
Garber AJ, et al. Endocr Pract. 2008;14:933-946.
Primary Care-Based Counseling
for T2DM Prevention: ADAPT
10
ADAPT, Avoiding Diabetes Thru Action Plan Targeting;
T2DM , type 2 diabetes mellitus.
Mann DM, Lin JJ. Implement Sci. 2012;23:6.
Self-Reported Risk Reduction Activities
in Patients With Prediabetes
(National Health and Nutrition Examination Survey Data)
Percent of Patients
80%
70%
60%
50%
40%
30%
20%
10%
0%
68%
60%
55%
42%
Tried to lose or Reduced dietary
Increased
control weight fat or calories physical activity
or exercise
All 3
11
CDC. MMWR Morb Mortal Wkly Rep. 2008;57:1203-1205.
Interventions Proven to Delay or
Prevent T2DM Development
Intervention
12
Rate of Conversion to
Normal Glucose Tolerance
Lifestyle (3 trials)
52%-58%
Metformin (2 trials)
26%-31%
Acarbose (1 trial)
25%
Pioglitazone (1 trial)
48%
T2DM, type 2 diabetes mellitus.
Sherwin RS, et al. Diabetes Care. 2004;27,(Suppl 1): S47-S54.
Eriksson K-F, Lindgärde F. Diabetologia. 1991;34:891-898.
Ramachandran A, et al. Diabetologia 2006;49:289-297.
Knowler WC, et al. N Engl J Med. 2002;346:393-403.
Defronzo RA, et al. N Engl J Med. 2011;364:1104-15.
Prevention of T2DM:
Lifestyle Modification Trials
13
Study
N
BMI
kg/m2
Time
(years)
RRR
%
ARR %
NNT
Malmö
217
26.6
5
63
18
28
DPS
523
31.0
3
58
12
22
DPP
2161
34.0
3
58
15
21
Da Qing
259
25.8
6
46
27
25
ARR, absolute risk reduction; DPP, Diabetes Prevention Program; DPS, Diabetes Prevention Study; NNT,
number needed to treat; RRR, relative risk reduction; T2DM, type 2 diabetes mellitus.
Regensteiner JG, et al, eds. Diabetes and Exercise. New York: Humana Press, 2009.
Effect of Lifestyle and Metformin on the
Progression From Prediabetes to T2DM
Cumulative Incidence
of Diabetes (%)
40
Placebo (N=1082)
Metformin (N=1073,
P<0.001 vs. Placebo)
30
Lifestyle (N=1079,
P<0.001 vs Metformin
P<0.001 vs Placebo)
20
Risk Reduction
31% by metformin
58% by lifestyle
10
0
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
Year
Figure 2. Cumulative Incidence of Diabetes According to Study Group.
The diagnosis of diabetes was based on the criteria of the American
Diabetes Association.11 The incidence of diabetes differed significantly
among the 3 groups (P<0.001 for each comparison).
14
T2DM, type 2 diabetes mellitus.
Knowler WC, et al. N Engl J Med. 2002;346:393-403.
The Chinese Prevention Study
The Effect of Metformin on the Progression
of IGT to Diabetes Mellitus (N=321)
Incidence of Diabetes (%/yr)
14
12
11.6
10
8
RRR=65%
6
4.1
4
2
0
Control
Metformin
15
IGT, impaired glucose tolerance; RRR, relative risk reduction.
Yang W, et al. Chin J Endocrinol Metab. 2001;17:131-136.
Effect of Lifestyle Modification and Metformin
on Cumulative Diabetes Incidence
The Indian DPP (N=531)
60
55.0
RRR (%)
Incidence (%)
50
28.5
P=0.018
26.4
P=0.029
28.2
P=0.022
n=136
n=133
n=133
n=129
Control
LSM
MET
LSM & MET
40
30
20
10
0
16
DPP, Diabetes Prevention Program; LSM, lifestyle modification;
MET, metformin; RRR, relative risk reduction.
Ramachandran A, et al. Diabetologia 2006;49:289-297.
T2DM Prevention in Women
With a History of GDM:
Effect of Metformin and Lifestyle Interventions
• Findings from the DPP:
– Progression to diabetes is more common in
women with a history of GDM vs those without,
despite equivalent degrees of IGT at baseline
• Both intensive lifestyle and metformin are
highly effective in delaying or preventing
diabetes in women with IGT and a history of
GDM
17
DPP, Diabetes Prevention Program; GDM, gestational diabetes mellitus;
IGT, impaired glucose tolerance; T2DM, type 2 diabetes mellitus.
Ratner RE, et al. J Clin Endocrinol Metab. 2008;93:4774-4779.
Effect of Acarbose on
Reversion of IGT to NGT
The Study to Prevent Non-Insulin Dependent
Diabetes Mellitus (STOP-NIDDM)
Number of Patients
250
P<0.0001
240
n=241
(35.3%)
230
220
210
n=212
(30.9%)
200
Placebo
Acarbose
18
IGT, impaired glucose tolerance; NGT, normal glucose tolerance.
Chiasson JL, et al. Lancet. 2002;359:2072-2077.
10-Year Follow-up of T2DM
Incidence and Weight Loss in the
DPP Outcomes Study
19
DPP, Diabetes Prevention Program; T2DM, type 2 diabetes mellitus.
DPP Research Group. Lancet. 2009;374:1677-1686.
10-Year Follow-up of T2DM
Incidence and Weight Loss in the
DPP Outcomes Study
20
DPP, Diabetes Prevention Program; T2DM, type 2 diabetes mellitus.
DPP Research Group. Lancet. 2009;374:1677-1686.
10-Year Follow-up of T2DM
Incidence and Weight Loss in the
DPP Outcomes Study
21
DPP, Diabetes Prevention Program; DPPOS, Diabetes Prevention
Program Outcomes Study; T2DM, type 2 diabetes mellitus.
DPP Research Group. Lancet. 2009;374:1677-1686.
Cumulative T2DM Incidence During
Follow-up in the Chinese Da Qing
Diabetes Prevention Study
22
CI, confidence interval; DPP, Diabetes Prevention Program; T2DM, type 2 diabetes mellitus.
Li G, et al. Lancet. 2008;371:1783-1789.
Group Lifestyle Balance Program
Intervention
University of Pittsburgh Primary Care Practice and Diabetes Prevention Support Center
•
DPP lifestyle intervention was
adapted to a 12-session
group-based program
•
Implemented in a community
setting in 2 phases using a
nonrandomized prospective
design
•
Significant decreases in
weight, waist circumference,
and BMI were noted in both
phases vs baseline
•
Average combined weight
loss for both groups over the
3-month intervention was 7.4
pounds (3.5% relative
loss, P<0.001)
Weight Loss Achieved
70
60
Percent
50
40
30
20
10
0
Phase 1 Post Phase 2 Post Completers
(n=51)
(n=42)
Both phases
(n=67)
Weight Loss > 3.5%
Weight Loss > 5%
Phase 2
6 mo
Phase 2
12 mo
Weight Loss >7%
23
DPP, Diabetes Prevention Program; mo, month.
Kramer MK, et al. Am J Prev Med. 2009;37:505-511.
Translating the DPP Into
Community Intervention
The DEPLOY Pilot Study
Standard (4-6 months)
DPP (4-6 months)
Standard (12-14 months)
DPP (12-14 months)
 Total Cholesterol (%)
15
10
•
11.8
6
5
0
-5
Pilot, cluster-randomized
trial
Group-based DPP
lifestyle intervention vs
brief counseling alone
(control) among high-risk
adults who attended a
diabetes risk-screening
event at one of two semiurban YMCA facilities
-10
-15
-13.5
P=0.002
-20
-25
24
•
-21.6
P<0.001
DEPLOY, Diabetes Education & Prevention with a Lifestyle Intervention Offered at the
YMCA; DPP, Diabetes Prevention Program; YMCA, Young Men’s Christian Association.
Ackermann RT, et al. Am J Prev Med. 2008;35:357-363.
Montana CVD and DPP
Mean weight and physical activity min/week among participants by lifestyle
intervention session
25
CVD, cardiovascular disease; DPP, Diabetes Prevention Program.
Amundson HA, et al. Diabetes Educ. 2009;35:209-223.
Translation of the DPP’s Lifestyle
Intervention
• Four additional studies utilizing the DPP lifestyle
interventions in community settings provided the
following findings:
– Promising evidence of the prevention of diabetes by
significantly decreasing glucose levels and adiposity
– Statistically significant improvements in many behavioral
outcomes and anthropometrics, particularly at 6 months
– Decreased fasting glucose and weight in at-risk African
Americans
– Approaches that improve recruitment of participants from
underserved communities into research, especially research
related to chronic disease risk factors
26
DPP, Diabetes Prevention Program.
Boltri JM, et al. J Natl Med Assoc. 2011;103:194-202.
Katula JA, et al. Diabetes Care. 2011;34:1451-1457.
Ruggiero L, et al. Diabetes Educ. 2011;37:564-572.
Santoyo-Olsson J, et al. Gerontologist. 2011;51(Suppl 1):S82-93.
Pioglitazone for T2DM
Prevention in IGT: ACT NOW
Kaplan–Meier plot of hazard ratios for time to development of T2DM
27
ACT NOW, Actos NOW for the Prevention of Diabetes;
IGT, impaired glucose tolerance; T2DM, type 2 diabetes mellitus.
Defronzo RA, et al. N Engl J Med. 2011;364:1104-1115.
Effects of Exenatide and Lifestyle Modification on
Body Weight and Glucose Tolerance
in Obese Patients With and Without Prediabetes
• Patients
– N=152, weight 108.6 +/- 23.0 kg, BMI 39.6 +/- 7.0 kg/m2 (IGT
or IFG 25%)
•
Design
– 24-week randomized controlled trial: exenatide or placebo
plus lifestyle intervention
•
Results:
– Exenatide-treated patients lost 5.1 kg from baseline vs 1.6 kg with
placebo (P<0.001)
– Both groups reduced their daily caloric intake
– IGT or IFG normalized at end point in 77% and 56% of exenatide
and placebo subjects, respectively
28
BMI, body mass index; IFG, impaired fasting glucose; IGT, impaired glucose tolerance.
Rosenstock J, et al. Diabetes Care. 2010;33:1173-1175.
Special Concerns for
Thiazolidinedione Use in Patients
With Prediabetes
• Because of concerns about long-term safety,
use of thiazolidinediones should be reserved
for higher risk populations and those failing
other, lower-risk strategies
29
Garber AJ, et al. Endocr Pract. 2008;14:933-946.
Medical Weight-Loss Strategies
• Orlistat may prevent progression from prediabetes to diabetes
• Lorcaserin, a selective serotonin 2C agonist, is indicated for use
in obese patients with at least 1 weight-related comorbid
condition (eg, hypertension, dyslipidemia, CVD, glucose
intolerance, sleep apnea)
• Low-dose, immediate-release phentermine and controlledrelease topiramate is recommended for obese or overweight
patients with weight-related comorbidities such as hypertension,
T2DM, dyslipidemia, or central adiposity
30
CVD, cardiovascular disease; obese, BMI ≥30 kg/m2;
overweight, BMI ≥27 kg/m2; T2DM, type 2 diabetes mellitus.
Garber AJ, et al. Endocr Pract. 2008;14:933-946.
Pharmacologic Weight-Loss
Strategies
Drug name
Orlistat
Lorcaserin
Phentermine/
topiramate)
31
Placebosubtracted
mean % body
weight loss
from baseline
Patients (N) in
clinical
program/
patients (n) with
diabetes
% of patients
losing ≥5% of
body weight
Clinical trial
withdrawal rates
2.4% (following 4
years of
treatment with
orlistat 120 mg
TID)
7504/321
35.5%-54.8%
(following 1 year
of treatment with
orlistat 120 mg
TID)
8.8%
3.3% at 52
weeks
6888/510
47.1%
36%-50%
3.5%-6.4%
3678/808
45%-70%
31%-40%
LOCF, last observation carried forward.
Orlistat [package insert]. South San Francisco CA; Genentech USA; 2010.
Belviq [package insert]. Woodcliff Lake, NJ; Eisai Inc.; 2012.
Qsymia [package insert]. Mountain View, CA; VIVUS , Inc; 2012.
DPP Year 1:
Mean Change in Blood Pressure
Systolic
Change in BP
(mm Hg)
Baseline BP
124
124
Diastolic
124
79
0
0
-0.5
-0.5
-1
-0.91
-0.9
-1
-1.5
-1.5
-2
-2
-2.5
-2.5
-3
-3
-3.5
-4
-0.89
-1.3
-3.6
-4
Metformin
78
-3.5
-3.4
Lifestyle
78
Placebo
Lifestyle
Metformin
Placebo
32
BP, blood pressure; DPP, Diabetes Prevention Program.
Ratner R, et al. Diabetes Care. 2005;28:888.
Effects of Metformin, Lifestyle
Modifications, and Placebo on
Hypertension Over 36 Months in DPP
P<0.001
P=0.08
P<0.001
40
*
35
30
25
Baseline
20
12 months
15
24 months
36 months
10
5
0
Placebo
Metformin
Lifestyle
33
DPP, Diabetes Prevention Program; HTN, hypertension.
Ratner R, et al. Diabetes Care. 2005;28:888-894.
STOP NIDDM: Incidence of New Cases
of Hypertension in IGT Patients
18
Hypertension defined as
BP 140/90 mmHg
16
Placebo
14
12
10
Acarbose
8
6
4
RRR = 34%
P=0.0059
2
0
0
34
1
3
2
4
Years After Randomization
5
BP, blood pressure; IGT, impaired glucose tolerance; STOP NIDDM, Study to Prevent Non-Insulin Dependent Diabetes
Mellitus Trial
Chiasson JL, et al. JAMA. 2003;290:486-494.
DPP Study: Mean Change in
Total and LDL Cholesterol
Total Cholesterol
Baseline (mg/dL)
202
127
Change in Lipids (%)
0
0
-0.2
-0.5
-0.3
-0.4
-1
-0.9
-0.6
-1.2
-1.5
-0.7
-0.8
-1
-2
-1.2
-2.3
-2.5
Lifestyle
35
LDL-C
Metformin
-1.3
-1.4
Placebo
Lifestyle
Metformin
Placebo
DPP, Diabetes Prevention Program; LDL-C, low-density lipoprotein.
DPP Research Group. Diabetes Care. 2005;28:2472–2479.
Ratner R, et al. Diabetes Care. 2005;28:888-894.
DPP Study: Mean Change in Triglycerides
and HDL Cholesterol
Triglycerides
Change in Lipids (mg/dL)
Baseline (mg/dL)
HDL-C
172
40
0
1.2
-5
1
0.8
-7.4
-10
-11.9
-15
0.6
0.4
-20
0.3
0.2
-25
0
-25.4
-30
-0.1
-0.2
Lifestyle
36
1
Metformin
Placebo
Lifestyle
Metformin
Placebo
DPP, Diabetes Prevention Program.
DPP Research Group. Diabetes Care. 2005;28:2472–2479.
Ratner R, et al. Diabetes Care. 2005;28:888-894.
DPP Study: Effects of Metformin, Lifestyle
Modifications, and Placebo on Lipids:
3-year Timeframe
37
DPP, Diabetes Prevention Program.
Ratner R, et al. Diabetes Care. 2005;28:888-894.
CVD Outcomes in Type 2
Diabetes Prevention Trials
Study
38
Outcome
DPP
64 of 3234 patients (89 total events)
DREAM
0.5 events/100 patient-years
STOP NIDDM
1.4 events/100 patient-years
CVD, cardiovascular disease; DPP, Diabetes Prevention Program; DREAM,
Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication;
STOP NIDDM, Study to Prevent Non-Insulin Dependent Diabetes Mellitus Trial.
Ratner R, et al. Diabetes Care. 2005;28:888-894.
DREAM Investigators. Diabetes Care. 2008;31:1007-1014.
Chiasson JL, et al. JAMA. 2003;290:486-494.
STOP-NIDDM Study: Effect of Acarbose
on Cardiovascular Event Incidence in
Patients With IGT
Cumulative Incidence (%)
5
4
Placebo
RRR = 49% P=.03
3
2
Acarbose
1
0
39
47 subjects with CVD events
32 placebo
15 acarbose
0
1
2
3
4
Years After Randomization
5
CVD, cardiovascular disease; IGT, impaired glucose tolerance; RRR, relative risk
reduction; STOP NIDDM, Study to Prevent Non-Insulin Dependent Diabetes Mellitus Trial.
Chiasson JL, et al. JAMA. 2003;290:486-494.
STOP NIDDM CVD Events
Acarbose
(N=682)
Placebo
(N=686)
Hazard Rate
Myocardial Infarction
1
12
0.09*
Angina
5
12
0.45
Revascularization
11
20
0.61
CVD Death
1
2
0.55
Cerebrovascular Event
or Stroke
2
4
0.56
Peripheral Vascular
Disease
1
1
1.14
Any CVD Event
15
32
0.51*
*P<0.05
40
CVD, cardiovascular disease; STOP NIDDM, Study to Prevent Non-Insulin Dependent.
Chiasson JL, et al. JAMA. 2003;290:486-494.
Cumulative Incidence of CVD Death
During Follow-up in China Da Qing
Diabetes Prevention Study
41
CVD, cardiovascular disease.
Li G, et al. Lancet. 2008;371:1783-1789.
Pharmacotherapy for
Cardiovascular Risk Factors
Target
LDL
Blood
pressure
First-Line
Agents
Comments
<100 mg/dL
Statins
Additional use of fibrates, bile acid
sequestrants, ezetimibe, etc,
should be considered as
appropriate
<130/80 mm/Hg
ACE inhibitors,
Angiotensin
receptor
blockers
Calcium channel blockers are
appropriate second-line treatment
approaches
Goal
Low-dose aspirin is recommended for all persons with prediabetes for whom there is
no identified excess in risk for gastrointestinal, intracranial, or other hemorrhagic
condition
42
ACE, angiotensin converting enzyme; LDL, low-density lipoprotein.
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
Garber AJ, et al. Endocr Pract. 2008;14:933-946.