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NIDDK Diabetes Research
Judith Fradkin, M.D.
Director, Division of Diabetes, Endocrinology and Metabolic
Diseases, NIDDK
AANHPI/NCAPIP August 27, 2016
Clinical Studies: Diabetes
Normal
Prediabetes
Type 2
Diabetes
Type 1
Diabetes
Complications
The DPP Study
3234 participants (45% minority) with IGT
who were overweight or obese
Compared 3 approaches to diabetes
prevention for 3 years:
Placebo
Metformin
Lifestyle
DPP Study Population
Caucasian
1768
African-American
645
Hispanic-American
508
Asian-American &
Pacific Islander
142
American Indian
171
Asian/Pacific Islander
4%
American
Indian
Hispanic
5%
American
16%
African
American
20%
Caucasian
55%
~67% women
20% older than age 60
Mean age 50, BMI-34
History of GDM 16%
DPP Diabetes Rates
Placebo
Metformin
Lifestyle
Cases/100 person-yr
12
8
4
0
Caucasian
(n=1768)
African
American
(n=645)
Hispanic
(n=508)
American
Indian
(n=171)
Asian
(n=142)
Vitamin D for Prevention of Type 2 Diabetes
 4000 units Vitamin D daily vs placebo
 2500 Participants with prediabetes
 BMI >22.5 for Asian/PI participants
 Recruitment ongoing; Asian/PI currently constitute 5.5%
of participants
GRADE Goals
• To provide an unbiased comparison of the
most commonly used drugs to treat
diabetes in metformin-treated patients with
relatively recent-onset type 2 diabetes.
• To determine patient characteristics and
mechanisms associated with differential responses
to medications to facilitate individualization of
diabetes care.
GRADE Goals
• Practical and generalizable with
potential for immediate translation
• Capture characteristics important to
patient and society
• Capture majority of drugs in common use
• Compare drugs over a clinically meaningful
period of time (> 4 years)
• Use meds based on labeling and usual use
• Fair, balanced comparison
Study Population
•
•
•
•
•
Type 2 diabetes
Age >30 years (>20 for Am. Indians)
Duration diagnosed diabetes < 10 years
HbA1c 6.8-8.5% at end of run-in
Must be able to tolerate at least 1000 mg
metformin daily (Goal 1000 mg BID)
Meant to represent relatively
new-onset Type 2 diabetes.
Screening
Type 2 diabetes
Treated with metformin alone
HbA1c >6.8% at screening
<10 years duration of diagnosed diabetes at Screening
Metformin run-in
Titrate metformin to 1000 (min) – 2000 (goal) mg/day
HbA1c 6.8-8.5% at final run-in visit
Randomization
n=5000 eligible subjects
Sulfonylurea
(glimepiride)
n=1250
DPP-4 inhibitor
(sitagliptin)
n=1250
GLP-1 analog
(liraglutide)
n=1250
Insulin
(glargine)
n=1250
Design
Glimepiride +
Metformin
n=1250
Sitagliptin +
Metformin
n=1250
Liraglutide +
Metformin
n=1250
Glargine +
Metformin
n=1250
Primary outcome
HbA1c >7%, confirmed, on maximally tolerated dose of assigned regimen
Observe on assigned therapy
Secondary metabolic outcome
HbA1c >7.5%, confirmed, on maximally tolerated dose of assigned regimen
Add basal insulin (per glargine protocol)
Continue Metformin, continue second agent
Tertiary metabolic outcome
HbA1c >7.5%, confirmed, on glargine, assigned agent and metformin
Intensify insulin (add rapid-acting insulin to basal glargine),
continue metformin, and discontinue second agent
State of the Union Address
January 20, 2015
“Tonight, I’m launching a new Precision Medicine Initiative to bring us closer to curing diseases
like cancer and diabetes — and to give all of us access to the personalized information we need
to keep ourselves and our families healthier.”
12
Assembling the PMI Cohort
 One million or more U.S. volunteers
— Broadly reflect the diversity of America (including family
members of all ages, health statuses, areas)
— Strong focus on underrepresented groups
 Longitudinal cohort, with continuing interactions,
recontactable for secondary studies
— Collect EHR data, provide biospecimen(s) and survey,
and complete a baseline exam
 Two methods of enrollment
— Direct volunteers: anyone can sign up
— Healthcare provider organizations (incl. FQHCs): diverse
participants, robust EHRs, participant follow-up
 Substantial participant engagement in development,
implementation, governance
13
The Accelerating Medicines Partnership (AMP)
Public-private partnership: government, industry,
non-profit organizations, universities
Goal: facilitate identification of new targets for
diagnosis and therapy in selected disease areas
Approach: forge a new model for drug development
by working together to identify and validate promising
biological targets
Initial disease areas:
•
type 2 diabetes (T2D)
•
Alzheimer disease
•
autoimmune disorders lupus & rheumatoid
arthritis
14
Novel genetic variants associated with type 2 diabetes can be discovered
by studying different ancestry groups
Most risk variants are shared
across ancestry groups
Allele frequency varies
substantially across ancestry
groups
Studying genome wide
associations in multiple
ethnic/racial groups does yield
variants strongly associated with
diabetes only in certain
populations
Highlights need to aggregate
available genetic studies from
diabetes cohorts
NIDDK and pharmaceutical
partners have developed a new
resource to enable study of
genetics of diabetes and related
traits
Type 2 Diabetes Knowledge Portal
New tool to explore relationship
between genetic risk variants
and diabetes associated traits
across major ancestry groups
User friendly tools to query large
datasets from multiple cohorts
www.type2diabetesgenetics.org
Populations in Genetics Studies
Lek M et al- Analysis of protein-coding genetic variation in 60,706 humansExome Aggregation Consortium, Nature. 2016.
Proportion of Type 1 and Type 2 DM by
Race/Ethnicity in Youth aged 10-19 Years
NHW
NHB
Hispanic
ASPI
AIAN
4.4%
29.0%
27.2%
71.0%
31.8%
26.3%
72.8%
73.7%
68.2%
95.6%
Type 1
Type 2
NHW: non-Hispanic white; NHB: non-Hispanic black; API: Asian or Pacific Islander; AIAN:
American Indian or Alaska Native
Hamman et al. ADA 2012
SEARCH Glycemic Control Data for
Type 2 Diabetes by Race/Ethnicity
80
% HbA1c Distribution
70
60
50
Good
40
Intermediate
30
Poor
20
10
0
NHW
AA
H
A/PI
AI
“Good”: age specific HbA1c, < 6 yr, <8.5%; 6-12 yr, <8.0%; 13-18 yr, <7.5%; 19+ yr, <7.0%
“Intermediate”: HbA1c between “good” and “poor”
“Poor”: HbA1c ≥ 9.5%
J Peds 155: 668, 2009
Prevalence of Diabetes in Youth
By Age, Race/Ethnicity, and Clinical Type, 2001
3.0
3.0
NHW
Prevalence (per 1,000)
2.5
AA
2.5
H
A/PI
2.0
2.0
AI
1.5
1.5
1.0
1.0
0.5
0.5
0.0
0.0
T1
T2
Ages 0-9 years
T1
T2
Ages 10-19 years
Type 1 Diabetes TrialNet
P2P
Pathway to Prevention
Eligibility Requirements
• Anyone between age 1 and
45 with a sibling, child or
parent with type 1
• Anyone between age 1 and
20 with a sibling, child,
parent, cousin, uncle, aunt,
niece, nephew, grandparent
or half-sibling with T1D
• Those under 18 who do not
have autoantibodies can be
retested every year
www.diabetestrialnet.org
Tracy Rodriguez
TrialNet Coordinator, UCSF
21
Translational Research
T1 Translation
Basic science discoveries
used to develop new
treatments
Basic
Research
T2 Translation
Testing use of proven
therapies in clinical practice
& community settings
Clinical
Research
Efficacy Trials
Basic Research
Discovery
-Mechanisms
-Associations
Public
Health
Effectiveness
Trials
Dissemination &
Implementation Research
Translational Research Projects
Examples in Asian Americans/Pacific Islanders
 Role of stress and interaction of stress with
behavior/lifestyle factors in diabetes risk in
Chinese immigrants
 Use of smart phones and social media to
improve outcomes for Filipino Americans
with diabetes
 Ascertainment of diabetes prevalence and
risk factors in 10 Asian/PI subpopulations in
Hawaii using EHRs
Major T2D Clinical Research Needs






Management of diabetes in the elderly
Management of glycemia in hospitalized patients
CVD prevention
Foot ulcer prevention and therapy
Treatment of GDM
Improving diabetes care in primary care
setting/reducing disparities
 Defining heterogeneity for individualized care
NHANES Survey: Diabetes Prevalence in
U.S. Adults 2011-2012
Undiagnosed diabetes
as percent of total
24.6
diabetes cases:
32.8
39.7
36.8
35.2
40.2
26.9
15.5
25.0
Total diabetes
prevalence
20.0
Percent
Diagnosed
15.0
Undiagnosed
10.0
5.0
0.0
Race-ethnicity (age-adjusted)
Age (unadjusted)
Menke A, Casagrande S, Geiss L, and Cowie CC. Prevalence of and Trends in Diabetes Among Adults in the United
States, 1988-2012. JAMA 314: 1021-1029, 2015.; Table 2
NDEP Diabetes Prevention and Control Messages
Available to download
at www.ndep.nih.gov