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.
5
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
6
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
7
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.
8
Garber AJ, et al. Endocr Pract. 2008;14:933-946.
Primary Care-Based Counseling
for T2DM Prevention: ADAPT
9
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
10
CDC. MMWR Morb Mortal Wkly Rep. 2008;57:1203-1205.
Interventions Proven to Delay or
Prevent T2DM Development
Intervention
11
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:
Selected Lifestyle Modification Trials
12
Study
Country
N
Baseline
BMI
(kg/m2)
Intervention
period
(years)
RRR
(%)
NNT
Diabetes
Prevention
Program
USA
3234
34.0
2.8
58
21
Diabetes
Prevention
Study
Finland
523
31
4
39
22
Da Qing
China
577
25.8
6
51
30
BMI, body mass index; NNT, number needed to treat; RRR, relative risk reduction; T2DM, type 2 diabetes mellitus.
DPP Research Group. N Engl J Med. 2002;346:393-403. Eriksson J, et al. Diabetologia. 1999;42:793-801.
Li G, et al. Lancet. 2008;371:1783-1789. Lindstrom J, et al. Lancet. 2006;368:1673-1679.
T2DM Incidence in the
Diabetes Prevention Program
T2DM incidence
per 100 person-years
12
11
31%
10
8
6
7.8
58%
4.8
4
2
0
Intensive lifestyle
intervention*
(n=1079)
Metformin
850mg BID
(n=1073)
Placebo
(n=1082)
*Goal: 7% reduction in baseline body weight through low-calorie, low-fat diet and ≥150 min/week moderate intensity exercise.
13
IGT, impaired glucose tolerance; T2DM, type 2 diabetes mellitus.
DPP Research Group. N Engl J Med. 2002;346:393-403.
Effect of Age on Incidence of
T2DM in the DPP
T2DM incidence
per 100 person-years
14
12
11.6
10.8
10.8
9.6
10
8
48%
6.7
6
6.2
7.6
Placebo
59%
71%
4.7
4
3.1
Metformin
Lifestyle
2
0
25-44
45-59
Age (years)
≥60
*Goal: 7% reduction in baseline body weight through low-calorie, low-fat diet
and ≥150 min/week moderate intensity exercise.
14
DPP, Diabetes Prevention Program;.
DPP Research Group. N Engl J Med. 2002;346:393-403.
Effect of Weight on T2DM
Incidence in the DPP
T2DM incidence
per 100 person-years
16
14.3
14
12
10
9
51%
8.9
8.8
7.6
8
6
4
7.0
65%
61%
3.3
3.7
7.3
Placebo
Metformin
Lifestyle
2
0
22 to <30
30 to <35
BMI (kg/m2)
≥35
*Goal: 7% reduction in baseline body weight through low-calorie, low-fat diet
and ≥150 min/week moderate intensity exercise.
15
DPP, Diabetes Prevention Program.
DPP Research Group. N Engl J Med. 2002;346:393-403.
10-Year Weight Loss in
the DPP Outcomes Study
0
1
2
3
4
5
6
7
8
9
10
Years
16
DPP, Diabetes Prevention Program; T2DM, type 2 diabetes mellitus.
DPP Research Group. Lancet. 2009;374:1677-1686.
10-Year Incidence of T2DM in the
DPP Outcomes Study
Placebo
Metformin
Lifestyle
0
1
2
3
4
5
6
Years
7
8
9
10
17
DPP, Diabetes Prevention Program; T2DM, type 2 diabetes mellitus.
DPP Research Group. Lancet. 2009;374:1677-1686.
10-Year Incidence of T2DM in
the DPP Outcomes Study
18
DPP, Diabetes Prevention Program; DPPOS, Diabetes Prevention
Program Outcomes Study; T2DM, type 2 diabetes mellitus.
DPP Research Group. Lancet. 2009;374:1677-1686.
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
19
IGT, impaired glucose tolerance; RRR, relative risk reduction.
Yang W, et al. Chin J Endocrinol Metab. 2001;17:131-136.
Cumulative T2DM Incidence During
Follow-up in the Chinese Da Qing
Diabetes Prevention Study
20
CI, confidence interval; DPP, Diabetes Prevention Program; T2DM, type 2 diabetes mellitus.
Li G, et al. Lancet. 2008;371:1783-1789.
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
21
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
22
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
23
IGT, impaired glucose tolerance; NGT, normal glucose tolerance.
Chiasson JL, et al. Lancet. 2002;359:2072-2077.
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%
24
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
25
•
-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
26
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
27
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
28
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
29
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
30
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
31
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)
32
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
33
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
34
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
35
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
36
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
37
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
38
DPP, Diabetes Prevention Program.
Ratner R, et al. Diabetes Care. 2005;28:888-894.
CVD Outcomes in Type 2
Diabetes Prevention Trials
Study
39
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
40
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
41
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
Control
Intervention
42
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
43
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.