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1
Prediabetes
Management
2
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
Handelsman Y, et al. Endocr Pract. 2011;17(Suppl 2):1-53. Garber AJ, et al. Endocr Pract. 2008;14:933-946.
3
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
NGT, normal glucose tolerance ; T2DM , type 2 diabetes mellitus.Garber AJ, et al. Endocr Pract. 2008;14:933-946.
4
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
T2DM , type 2 diabetes mellitus.Narayan KM, et al. Health Aff (Millwood). 2012;31:84-92.
5
6
• 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
T2DM, type 2 diabetes mellitus.Garber AJ, et al. Endocr Pract. 2008;14:933-946.
Feasibility of Preventing T2DM
7
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
Garber AJ, et al. Endocr Pract. 2008;14:933-946.
8
Lifestyle Intervention in Prediabetes
Persons with prediabetes should reduce weight by 5% to 10%, with long-term maintenance at this
level
A diet that includes caloric restriction, increased fiber intake, and (in some cases) carbohydrate
intake limitations is advised.
• A program of regular moderate-intensity physical activity for 30-60 minutes daily, at least 5 days a week, is recommended
Garber AJ, et al. Endocr Pract. 2008;14:933-946.
9
Primary Care-Based Counseling for T2DM Prevention: ADAPT
ADAPT, Avoiding Diabetes Thru Action Plan Targeting; T2DM , type 2 diabetes mellitus.
Mann DM, Lin JJ. Implement Sci. 2012;23:6.
10
Self-Reported Risk Reduction Activities in Patients With Prediabetes
0%20%40%60%80%
100%68% 60% 55%
42%
CDC. MMWR Morb Mortal Wkly Rep. 2008;57:1203-1205.
National Health and Nutrition Examination Survey
Pat
ien
ts
11
PREVENTION OF DIABETES: LIFESTYLE STUDIES
Prediabetes Management
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
StudyFinland 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.
Prevention of T2DM: Selected Lifestyle Modification Trials
13
Series10
2
4
6
8
10
12
4.8
7.8
11
T2DM Incidence in theDiabetes Prevention Program
Intensive lifestyle intervention*
(n=1079)
T2D
M i
nci
de
nce
per
10
0 p
erso
n-y
ear
s
Placebo(n=1082)
Metformin850mg BID(n=1073)
58%
31%
*Goal: 7% reduction in baseline body weight through low-calorie, low-fat diet and ≥150 min/week moderate intensity exercise.
IGT, impaired glucose tolerance; T2DM, type 2 diabetes mellitus.
DPP Research Group. N Engl J Med. 2002;346:393-403.
14
25-44 45-59 ≥600
2
4
6
8
10
12
14
11.610.8 10.8
6.77.6
9.6
6.2
4.7
3.1
PlaceboMetforminLifestyle
Effect of Age on Incidence of T2DM in the DPPT
2DM
in
cid
en
ce
per
10
0 p
erso
n-y
ear
s
48%59%
Age (years)
71%
*Goal: 7% reduction in baseline body weight through low-calorie, low-fat dietand ≥150 min/week moderate intensity exercise.
DPP, Diabetes Prevention Program;.
DPP Research Group. N Engl J Med. 2002;346:393-403.
15
22 to <30 30 to <35 ≥350
2
4
6
8
10
12
14
16
9 8.9
14.3
8.87.6 7.0
3.3 3.7
7.3PlaceboMetforminLifestyle
Effect of Weight on T2DM Incidence in the DPP
T2D
M i
nci
de
nce
per
10
0 p
erso
n-y
ear
s
65%
BMI (kg/m2)
51%
61%
*Goal: 7% reduction in baseline body weight through low-calorie, low-fat dietand ≥150 min/week moderate intensity exercise.
DPP, Diabetes Prevention Program.
DPP Research Group. N Engl J Med. 2002;346:393-403.
16
10-Year Weight Loss inthe DPP Outcomes Study
DPP, Diabetes Prevention Program; T2DM, type 2 diabetes mellitus.DPP Research Group. Lancet. 2009;374:1677-1686.
10 32 54 76 8 109
Years
17DPP, Diabetes Prevention Program; T2DM, type 2 diabetes mellitus.
DPP Research Group. Lancet. 2009;374:1677-1686.
10 32 54 76 8 109
PlaceboMetforminLifestyle
Years
10-Year Incidence of T2DM in the DPP Outcomes Study
18DPP, Diabetes Prevention Program; DPPOS, Diabetes Prevention
Program Outcomes Study; T2DM, type 2 diabetes mellitus.
DPP Research Group. Lancet. 2009;374:1677-1686.
10-Year Incidence of T2DM in the DPP Outcomes Study
19
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
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.
20
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
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.
21
The Finnish Diabetes PreventionStudy: Lifestyle Modifications
DBP, diastolic blood pressure; SBP, systolic blood pressure.
Tuomilehto J, et al. N Engl J Med. 2001;344:1343-1350.
Ch
ang
e f
rom
bas
elin
e
Weight (kg) Waist (cm) SBP (mm Hg) DBP (mm Hg)
-6
-5
-4
-3
-2
-1
0
Control (n=250) Diet intervention (n=256)
P<0.001 P<0.001P=0.007 P=0.02
22
The Finnish Diabetes Prevention Study: Lifestyle Modifications
FPG 2-h PG Fasting insulin 2-h insulin-40
-30
-20
-10
0
10
Control (n=250) Diet intervention (n=256)
Ch
ang
e f
rom
bas
elin
e
P<0.001
P=0.003
P=0.001
(mg/dL) (mg/dL) (mg/mL) (g/mL)
DBP, diastolic blood pressure; SBP, systolic blood pressure.
Tuomilehto J, et al. N Engl J Med. 2001;344:1343-1350.
23
The Finnish Diabetes Prevention Study: Cumulative Incidence of Diabetes Over 4 Years
0
20
40
60
80 78
32
Control (n=250) Diet intervention (n=256)
Inci
den
ce
of
dia
bet
es(c
ases
/100
0 p
ers
on
-yea
rs)
DBP, diastolic blood pressure; SBP, systolic blood pressure.
Tuomilehto J, et al. N Engl J Med. 2001;344:1343-1350.
58%
24
Da Qing: Cumulative Incidence of Diabetes at 6-Year Evaluation
Pat
ien
ts w
ith
T2D
M a
t Y
ear
6 (%
)
IGT, impaired glucose tolerance.
Pan XR, et al. Diabetes Care. 1997;20:537-544.
Control Diet Exercise Diet + Exercise0
10
20
30
40
50
60
70
80
90
100
65.9
47.1 44.2 44.6
60
38.2
26.3
34.8
72.3
48 51.2 52.5
Total Lean Overweight
Patients with IGT (N=577)
25CI, confidence interval; DPP, Diabetes Prevention Program; T2DM, type 2 diabetes mellitus.
Li G, et al. Lancet. 2008;371:1783-1789.
Cumulative T2DM Incidence During Follow-up in the Chinese Da Qing
Diabetes Prevention Study
26
Group Lifestyle Balance Program Intervention
• 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)
University of Pittsburgh Primary Care Practice and Diabetes Prevention Support Center
Phase 1 Post(n=51)
Phase 2 Post(n=42)
CompletersBoth phases
(n=67)
Phase 2 6 mo
Phase 2 12 mo
0
10
20
30
40
50
60
70
Weight Loss Achieved
Weight Loss > 3.5% Weight Loss > 5% Weight Loss >7%
Pe
rce
nt
DPP, Diabetes Prevention Program; mo, month.Kramer MK, et al. Am J Prev Med. 2009;37:505-511.
27
-25
-20
-15
-10
-5
0
5
10
15
6
-21.6
11.8
-13.5
Standard (4-6 months) DPP (4-6 months)Standard (12-14 months) DPP (12-14 months)
T
ota
l C
ho
lest
ero
l (%
)
• 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 semi-urban YMCA facilities
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.
Translating the DPP Into Community Intervention
The DEPLOY Pilot Study
P<0.001
P=0.002
28
Mean weight and physical activity min/week among participants by lifestyle intervention session
CVD, cardiovascular disease; DPP, Diabetes Prevention Program.Amundson HA, et al. Diabetes Educ. 2009;35:209-223.
Montana CVD and DPP
29
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
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.
30
PREVENTION OF DIABETES: PHARMACOTHERAPY STUDIES
Prediabetes Management
31
Pharmacologic Interventions Proven to Delay or Prevent T2DM Development
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.
InterventionRate of Conversion to
Normal Glucose Tolerance
Metformin (2 trials) 26%-31%
Acarbose (1 trial) 25%
Pioglitazone (1 trial) 48%
32
The Chinese Prevention Study
Series10
2
4
6
8
10
12
14
11.6
4.1
Inci
den
ce
of
Dia
bet
es (
%/y
r)
Control Metformin
The Effect of Metformin on the Progressionof IGT to Diabetes Mellitus (N=321)
IGT, impaired glucose tolerance; RRR, relative risk reduction.
Yang W, et al. Chin J Endocrinol Metab. 2001;17:131-136.
65%
33
Series10
10
20
30
40
50
6055.0
Effect of Lifestyle Modification and Metformin on Cumulative Diabetes Incidence
The Indian DPP (N=531)
n=136 n=133
Inci
den
ce (
%)
RRR (%)
Control LSM MET LSM & MET
28.5P=0.018
26.4P=0.029
28.2P=0.022
n=133 n=129
DPP, Diabetes Prevention Program; LSM, lifestyle modification; MET, metformin; RRR, relative risk reduction.
Ramachandran A, et al. Diabetologia 2006;49:289-297.
34
Effect of Acarbose on Reversion of IGT to NGT
P<0.0001
Placebo Acarbose
Nu
mb
er
of
Pa
tien
ts
200
210
220
230
240
250
n=241(35.3%)
n=212(30.9%)
IGT, impaired glucose tolerance; NGT, normal glucose tolerance.Chiasson JL, et al. Lancet. 2002;359:2072-2077.
The Study to Prevent Non-Insulin Dependent Diabetes Mellitus (STOP-NIDDM)
35
DREAM: Rosiglitazone and New-Onset Diabetes or Death
DREAM Trial Investigators. Lancet. 2006;368:1096-1105.
No. at riskPlaceboRosiglitazone
26342635
24702538
21502414
11481310
177217
0.6
0.5
0 1 2 3 4
Follow-up (years)
0.4
0.3
0.2
0.1
0.0
Placebo
Cu
mu
lati
ve
haz
ard
ra
te
Rosiglitazone
60%
36
Pioglitazone for T2DM Prevention in IGT: ACT NOW
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.
Kaplan–Meier plot of hazard ratios for time to development of T2DM
37
Garber AJ, et al. Endocr Pract. 2008;14:933-946.
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
38
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
BMI, body mass index; IFG, impaired fasting glucose; IGT, impaired glucose tolerance.Rosenstock J, et al. Diabetes Care. 2010;33:1173-1175.
39
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 controlled-release topiramate is recommended for obese or overweight patients with weight-related comorbidities such as hypertension, T2DM, dyslipidemia, or central adiposity
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.
40
Pharmacologic Weight-Loss Strategies
Drug name
Placebo-subtracted
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
Orlistat
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%
Lorcaserin3.3% at 52
weeks6888/510 47.1% 36%-50%
Phentermine/ topiramate)
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.
41
Phentermine/Topiramate and Prevention of Type 2 Diabetes
Garvey TW, et al. Diabetes Care. 2014;37:912-921.
Prediabetes Metabolic syndrome0
1
2
3
4
5
6
7
3.5
6.4
1.81.5
0.4
1.3
Placebo Phen/TPM 7.5/46 Phen/TPM 15/92
An
nu
aliz
ed i
nc
iden
ce
of
T2D
M
88.6%
48.6% 79.7%76.6%