Cancer, CVD, Diabetes Mellitus
Conditions
Keywords
DPP, IGT, Prediabetes, Type 2 diabetes, Macrovascular disease, Microvascular disease, Lifestyle, Metformin, Obesity
Brief summary
The Diabetes Prevention Program (DPP) was a multi-center trial examining the ability of an intensive lifestyle or metformin to prevent or delay the development of diabetes in a high risk population due to the presence of impaired glucose tolerance (IGT, 2 hour glucose of 140-199 mg/dl). The DPP has ended early demonstrating that lifestyle reduced diabetes onset by 58% and metformin reduced diabetes onset by 31%. DPPOS (2002-2013) is designed to take advantage of the scientifically and clinically valuable DPP participants. This group of participants is nearly 50% minority and represents the largest at risk population ever studied. Clinically important research questions remain that focus on 1) durability of the prior DPP intervention, 2) determination of the clinical course of precisely known new onset diabetes, in particular regarding microvascular disease, CVD risk factors and atherosclerosis, 3) close examination of these topics in men vs women and in minority populations. The major aims of DPPOS-3 (2014-2025) take advantage of the long-term randomized exposure of the study cohort to metformin and the aging of the DPPOS cohort. The metformin exposure and high degree of study retention and adherence (\ 85% of the DPPOS cohort continues to attend annual and mid-year visits) allows DPPOS-3 to examine the long-term effects of metformin on cardiovascular disease (CVD) and cancer outcomes, outcomes of great clinical interest and import.
Detailed description
The current DPPOS Executive Summary and protocol, as well as DPPOS protocol and lifestyle manuals and publications are available at: http://www.dppos.org
Interventions
BEHAVIORALDPPOS Group Lifestyle
Quarterly group lifestyle sessions
DRUGMetformin
Administered as 850mg twice per day, masked in DPP and open label in DPPOS
BEHAVIORALDPPOS Boost Lifestyle
In addition to quarterly group, 2 additional classes per year and an annual 15 minute check-up.
BEHAVIORALIntensive Lifestyle Group Session
16 session curriculum in group format. In DPP delivered to ILS as individual sessions
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute on Aging (NIA)
National Institute on Minority Health and Health Disparities (NIMHD)
National Heart, Lung, and Blood Institute (NHLBI)
National Cancer Institute (NCI)
National Eye Institute (NEI)
National Center for Research Resources (NCRR)
Office of Research on Women's Health (ORWH)
Centers for Disease Control and Prevention
American Diabetes Association
Indian Health Service (IHS)
General Clinical Research Program
US Department of Veterans Affairs
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Masking description
Open label phase for metformin
Intervention model description
The study metformin was discontinued in January 31st, 2021. The current protocol is limited to long-term follow-up and does not involve any investigational product assignment.
Eligibility
Sex/Gender
ALL
Age
25 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Participation as a volunteer in the Diabetes Prevention Program (DPP).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Diabetes. | Outcomes were assessed from 1996-2020 for median follow-up of 21 years and a maximum follow-up of 23 years including a median of 3 years in DPP in all participants enrolled in DPPOS. | Primary outcome defined according to American Diabetes Association criteria (fasting plasma glucose level \>= 126 mg/dL \[7.0 mmol/L\] or 2-hour plasma glucose \>= 200 mg/dL \[11.1 mmol/L\], after a 75 gram oral glucose tolerance test (OGTT), and confirmed with a repeat test). |
| Prevalence of Aggregate Microvascular Complication | Outcomes were assessed from 2012-2013 (approximately 2 years). | Aggregate microvascular disease is defined as the average prevalence of 3 components: (1) retinopathy measured by photography (ETDRS of 20 or greater); (2) neuropathy detected by Semmes Weinstein 10 gram monofilament, and (3) nephropathy based on estimated glomerular filtration rate (eGFR by chronic kidney disease (CKD-Epi) equation ) (\<45 ml/min, confirmed) and albumin-to-creatinine ratio in spot urine (\> 30mg/gm, confirmed). |
| Number of Participants With Total Cancer Except Non-melanoma Skin Cancer | Outcomes were assessed from 1996-2020 (approximately 24 years). | All primary cancers except non-melanoma skin cancer that occurred after randomization in DPP |
| Number of Participants With Major Adverse Cardiovascular Events (MACE): Myocardial Infarction (MI), Stroke, or Cardiovascular Death (CVD) | Outcomes were assessed from 1996-2019 over a total median follow-up of 21 years since DPP randomization | MACE includes MI, stroke or CVD death that occurred after randomization and adjudicated by an outcomes committee who are blinded to treatment assignment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Subclinical Atherosclerosis | Outcomes were assessed from 2012-2013 (approximately 2 years). | Measured using coronary artery calcification (CAC). |
| Cognitive Function | Outcomes were assessed in visit year 8 starting in 2010 | Cognitive function was defined by tests of memory SEVLT (Spanish English Verbal Learning Test) and executive function, DSST (Digit Symbol Substitution Test). The measure of memory was the Spanish English Verbal Learning Test (SEVLT). The SEVLT consists of recalling a list of 15 words in three trials of immediate recall and one trial after a distractor list. The total number of correct words recalled after four trials is the outcome reported.The test of frontal-executive abilities was the total score in the Digit Symbol Substitution Test (DSST). The DSST is a test in which participants try to match numbers to symbols in 90 s. The total number of correct answers is reported. |
| Short Physical Performance Battery | Outcomes were assessed in visit years 8, 10 , and 15 which started in 2010, 2012, and 2017, respectively | Physical function is measured using the short physical performance battery (SPPB), which ranges from 0-12 and is comprised of measures of 1) time to walk 3-4 meters, 2) balance, i.e., side-by-side stand, semi-tandem stand, and tandem stand, and 3) repeated chair stands and derived as SPPB= (balance score + gait score + chair score). Each sub scale is 0, 1, 2, 3 or 4 depending on the gender specific quintiles with 0 being the lowest and 4 being the highest functional status as described in Guralnik JM, Simonsick EM, Ferrucci L, et al. A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission. J Gerontol. 1994 Mar 1;49(2):M85-94. |
| Frailty | Outcomes were assessed in DPPOS Visits years 8, 10 and 15 which started in 2010, 2012, and 2017 | Description: The Cardiovascular Health Study Frailty score is based on 5 frailty characteristics: slow walking speed, low energy expenditure, exhaustion, weak grip strength, and unintentional weight loss. |
| Mortality | Outcomes were assessed throughout follow-up from 1996 to 2019. National Death Index search conducted in 2019 using early release data as of Dec 2018. | All cause-mortality through clinic reports and National Death Index search |
Countries
United States
Contacts
STUDY_CHAIRDavid M. Nathan, MD
Massachusetts General Hospital
PRINCIPAL_INVESTIGATORMarinella Temprosa, PhD
George Washington University Biostatistics Center
STUDY_DIRECTORBarbara Linder, MD, PhD
NIDDK Project Scientist
PRINCIPAL_INVESTIGATOROwen Carmichael, PhD
Pennington Biomedical Research Center
PRINCIPAL_INVESTIGATORCeleste Thomas, MD
University of Chicago
PRINCIPAL_INVESTIGATORIntekhab Ahmed, MD
Jefferson Medical College of Thomas Jefferson University
PRINCIPAL_INVESTIGATORKathleen Jablonski, PhD
George Washington University Biostatistics Center
PRINCIPAL_INVESTIGATORRonald B Goldberg, MD
University of Miami
PRINCIPAL_INVESTIGATORHelen P Hazuda, MD
The University of Texas Health Science Center at San Antonio
PRINCIPAL_INVESTIGATORDana Dabelea, MD, PhD
University of Colorado, Denver
PRINCIPAL_INVESTIGATORMedha Munshi, MD
Joslin Diabetes Center
PRINCIPAL_INVESTIGATORSteven Kahn, MB, ChB
University of Washington
PRINCIPAL_INVESTIGATORSamuel Dagogo-Jack, MD, MB
University of Tennessee
PRINCIPAL_INVESTIGATORAmisha Wallia, MD
Northwestern University
PRINCIPAL_INVESTIGATORHappy Araneta, PhD,MPH
University of California, San Diego
PRINCIPAL_INVESTIGATORBlandine Laferrere, MD
Columbia University
PRINCIPAL_INVESTIGATORMary de Groot, PhD
Indiana University
PRINCIPAL_INVESTIGATORSaurabh Sharma, MD
Medstar Health Research Institute
PRINCIPAL_INVESTIGATORKarol E Watson, MD
University of California, Los Angeles
PRINCIPAL_INVESTIGATORAngela Brown, MD
Washington University School of Medicine
PRINCIPAL_INVESTIGATORSherita Hill Golden, MD, MHS
Johns Hopkins School of Medicine
PRINCIPAL_INVESTIGATORDavid S Schade, MD
The University of New Mexico
PRINCIPAL_INVESTIGATORJill Crandall, MD
Albert Einstein College of Medicine
PRINCIPAL_INVESTIGATORElizabeth Venditti, PhD
University of Pittsburgh
PRINCIPAL_INVESTIGATORMarjerie Mau, MD
University of Hawaii
PRINCIPAL_INVESTIGATORRobert Hanson, MD
SW Indian Center - Phoenix
STUDY_DIRECTORChristine Lee, MD
NIDDK Project Scientist
PRINCIPAL_INVESTIGATORSunder Mudaliar, MD
University of California, San Diego
PRINCIPAL_INVESTIGATORLinda Delahanty, MD
Massachusetts General Hospital
PRINCIPAL_INVESTIGATORVallabh Shah, PhD
SW Indian Center - Zuni/Shiprock
Participant flow
Recruitment details
All surviving Diabetes Prevention Program (DPP) participants with consent were invited to enroll into DPPOS throughout the follow-up period. The majority of DPPOS participants were enrolled in 2002-2003.
Pre-assignment details
DPPOS covers 3 funding phases for the 3 study phases: DPPOS-1 (2002-2008), DPPOS-2 (2009-2014), DPPOS-3 (2015-2021). The groups are defined using the original randomized groups from DPP with recruitment period of 1996-1998.
Participants by arm
| Arm | Count |
|---|---|
| 1 Original Lifestyle randomized to unmasked Intensive Lifestyle (ILS) during the DPP and offered Intensive Lifestyle Group Session, DPPOS Group Lifestyle plus DPPOS Boost Lifestyle sessions in DPPOS Phase 1 and 2
DPPOS Group Lifestyle: Quarterly group lifestyle sessions
DPPOS Boost Lifestyle: In addition to quarterly group, 2 additional classes per year and an annual 15 minute check-up.
Intensive Lifestyle Group Session: 16 session curriculum in group format. In DPP delivered to ILS as individual sessions | 916 |
| 2 Original Metformin randomized to the masked metformin treatment group during DPP and continued open label in DPPOS. Participants were also offered Intensive Lifestyle Group Session, DPPOS Group Lifestyle in DPPOS Phase 1 and 2.
DPPOS Group Lifestyle: Quarterly group lifestyle sessions
Metformin: Administered as 850mg twice per day, masked in DPP and open label in DPPOS
Intensive Lifestyle Group Session: 16 session curriculum in group format. In DPP delivered to ILS as individual sessions | 927 |
| 3 Original Placebo randomized to masked placebo during DPP and offered Intensive Lifestyle Group Session, DPPOS Group Lifestyle in DPPOS Phase 1 and 2
DPPOS Group Lifestyle: Quarterly group lifestyle sessions
Intensive Lifestyle Group Session: 16 session curriculum in group format. In DPP delivered to ILS as individual sessions | 936 |
| Total | 2,779 |
Baseline characteristics
| Characteristic | Total | 1 Original Lifestyle | 2 Original Metformin | 3 Original Placebo |
|---|---|---|---|---|
| Age, Continuous All Participants at randomization | 51 years STANDARD_DEVIATION 11 | 51 years STANDARD_DEVIATION 11 | 51 years STANDARD_DEVIATION 10 | 50 years STANDARD_DEVIATION 10 |
| Age, Continuous DPPOS Participants at enrollment | 54 years STANDARD_DEVIATION 10 | 54 years STANDARD_DEVIATION 11 | 54 years STANDARD_DEVIATION 10 | 54 years STANDARD_DEVIATION 10 |
| BMI DPPOS participants at enrollment | 33.8 kg/m2 STANDARD_DEVIATION 6.5 | 33.7 kg/m2 STANDARD_DEVIATION 6.5 | 33.8 kg/m2 STANDARD_DEVIATION 6.5 | 34.0 kg/m2 STANDARD_DEVIATION 6.5 |
| BMI Overall participants at randomization | 34.0 kg/m2 STANDARD_DEVIATION 6.7 | 33.9 kg/m2 STANDARD_DEVIATION 6.8 | 33.9 kg/m2 STANDARD_DEVIATION 6.6 | 34.2 kg/m2 STANDARD_DEVIATION 6.7 |
| Race/Ethnicity, Customized American Indian | 171 Participants | 60 Participants | 52 Participants | 59 Participants |
| Race/Ethnicity, Customized Asian | 142 Participants | 57 Participants | 36 Participants | 49 Participants |
| Race/Ethnicity, Customized Black or African American | 645 Participants | 204 Participants | 221 Participants | 220 Participants |
| Race/Ethnicity, Customized Hispanic | 508 Participants | 178 Participants | 162 Participants | 168 Participants |
| Race/Ethnicity, Customized White | 1768 Participants | 580 Participants | 602 Participants | 586 Participants |
| Region of Enrollment United States | 3234 participants | 1079 participants | 1073 participants | 1082 participants |
| Sex: Female, Male All Participants at Randomization Female | 2191 Participants | 734 Participants | 710 Participants | 747 Participants |
| Sex: Female, Male All Participants at Randomization Male | 1043 Participants | 345 Participants | 363 Participants | 335 Participants |
| Sex: Female, Male DPPOS Participants Female | 1889 Participants | 624 Participants | 620 Participants | 645 Participants |
| Sex: Female, Male DPPOS Participants Male | 890 Participants | 292 Participants | 307 Participants | 291 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 129 / 916 | 122 / 927 | 143 / 936 | 158 / 1,079 | 152 / 1,073 | 143 / 1,082 |
| other Total, other adverse events | 302 / 916 | 347 / 927 | 338 / 936 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 649 / 916 | 657 / 927 | 646 / 936 | 235 / 1,079 | 251 / 1,073 | 238 / 1,082 |
Outcome results
Primary
Development of Diabetes.
Primary outcome for years 2002-2008 defined according to American Diabetes Association criteria (fasting plasma glucose level \>= 126 mg/dL \[7.0 mmol/L\] or 2-hour plasma glucose \>= 200 mg/dL \[11.1 mmol/L\], after a 75 gram oral glucose tolerance test (OGTT), and confirmed with a repeat test).
Time frame: Outcomes were assessed from 1996-2008 (approximately 12 years including 6 years of DPP).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1 Original Lifestyle | Development of Diabetes. | 5.3 diabetes incidence (cases per 100 person |
| 2 Original Metformin | Development of Diabetes. | 6.4 diabetes incidence (cases per 100 person |
| 3 Original Placebo | Development of Diabetes. | 7.8 diabetes incidence (cases per 100 person |
Primary
Major Adverse Cardiovascular Events (MACE): Myocardial Infarction (MI), Stroke, or Cardiovascular Death (CVD)
Defined as MI, stroke and CVD death. These outcomes were collected since randomization and adjudicated by an outcomes committee who are blinded to treatment assignment.
Time frame: Outcomes were assessed from 1996-2025 (approximately 29 years).
Primary
Prevalence of Aggregate Microvascular Complication
Aggregate microvascular disease is defined as the average prevalence of 3 components: (1) retinopathy measured by photography (ETDRS of 20 or greater); (2) neuropathy detected by Semmes Weinstein 10 gram monofilament, and (3) nephropathy based on estimated glomerular filtration rate (eGFR by chronic kidney disease (CKD-Epi) equation ) (\<45 ml/min, confirmed) and albumin-to-creatinine ratio in spot urine (\> 30mg/gm, confirmed).
Time frame: Outcomes were assessed from 2012-2013 (approximately 2 years).
Population: Number with microvascular outcome data and included in the primary outcome analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1 Original Lifestyle | Prevalence of Aggregate Microvascular Complication | 11.3 average percentage of participants |
| 2 Original Metformin | Prevalence of Aggregate Microvascular Complication | 13 average percentage of participants |
| 3 Original Placebo | Prevalence of Aggregate Microvascular Complication | 12.4 average percentage of participants |
Primary
Total Cancer Except Non-melanoma Skin Cancer
All primary incident cancers except non-melanoma skin cancer
Time frame: Outcomes were assessed from 1996-2020 (approximately 24 years).
Secondary
Cognitive Function
Cognitive function defined as a composite measure constructed from tests of memory (English Spanish Verbal Learning Test) and executive function (word fluency and Digit Symbol Substitution Test ).
Time frame: Outcomes were assessed in visit years starting in 2010, 2012, 2017, 2020.
Secondary
Frailty
Description: The Cardiovascular Health Study Frailty score is based on 5 frailty characteristics: slow walking speed, low energy expenditure, exhaustion, weak grip strength, and unintentional weight loss.
Time frame: Outcomes were assessed in visit years starting in 2010, 2012, 2017, 2020.
Secondary
Mortality
All cause-mortality through clinic reports and National Death Index search
Time frame: Outcomes were assessed throughout follow-up from 1996 to 2022. National Death Index search conducted in 2019 using early release data as of Dec 2018.
Population: All randomized to DPP were included
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 1 Original Lifestyle | Mortality | 158 Participants |
| 2 Original Metformin | Mortality | 152 Participants |
| 3 Original Placebo | Mortality | 143 Participants |
p-value: 0.8795% CI: [0.81, 1.28]Log Rank
p-value: 0.9595% CI: [0.79, 1.25]Log Rank
Secondary
Short Physical Performance Battery
Physical function is measured using the short physical performance battery (SPPB), which is comprised of measures of 1) time to walk 3-4 meters, 2) balance, i.e., side-by-side stand, semi-tandem stand, and tandem stand, and 3) repeated chair stands.
Time frame: Outcomes were assessed in visit years starting in 2010, 2012, 2017, 2020.
Secondary
Subclinical Atherosclerosis
Measured using coronary artery calcification (CAC).
Time frame: Outcomes were assessed from 2012-2013 (approximately 2 years).
Population: DPPOS Participants who met eligibility criteria and consented to have CAC measurements - by sex
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| 1 Original Lifestyle | Subclinical Atherosclerosis | Men | 70.1 CAC geometric mean in AU |
| 1 Original Lifestyle | Subclinical Atherosclerosis | Women | 6.0 CAC geometric mean in AU |
| 2 Original Metformin | Subclinical Atherosclerosis | Men | 40.2 CAC geometric mean in AU |
| 2 Original Metformin | Subclinical Atherosclerosis | Women | 6.1 CAC geometric mean in AU |
| 3 Original Placebo | Subclinical Atherosclerosis | Men | 63.7 CAC geometric mean in AU |
| 3 Original Placebo | Subclinical Atherosclerosis | Women | 5.3 CAC geometric mean in AU |