ORIGINAL RESEARCH
Annals of Internal Medicine
Long-Term Weight Loss With Metformin or Lifestyle Intervention in the
Diabetes Prevention Program Outcomes Study
John W. Apolzan, PhD; Elizabeth M. Venditti, PhD; Sharon L. Edelstein, ScM; William C. Knowler, MD, DrPH;
Dana Dabelea, MD, PhD; Edward J. Boyko, MD; Xavier Pi-Sunyer, MD; Rita R. Kalyani, MD; Paul W. Franks, PhD;
Preethi Srikanthan, MD; and Kishore M. Gadde, MD; for the Diabetes Prevention Program Research Group*
Background: Identifying reliable predictors of long-term weight
loss (LTWL) could lead to improved weight management.
Objective: To identify some predictors of LTWL.
Design: The DPP (Diabetes Prevention Program) was a
randomized controlled trial that compared weight loss with metformin, intensive lifestyle intervention (ILS), or placebo. Its Outcomes Study (DPPOS) observed patients after the masked
treatment phase ended. (ClinicalTrials.gov: NCT00004992 and
NCT00038727)
Setting: 27 DPP and DPPOS clinics.
(95% CI, 5.2% to 7.2%) in the metformin group, 3.7% (CI, 3.1% to
4.4%) in the ILS group, and 2.8% (CI, 1.3% to 4.4%) in the placebo group. Independent predictors of LTWL included greater
weight loss in the first year in all groups, older age and continued metformin use in the metformin group, older age and absence of either diabetes or a family history of diabetes in the ILS
group, and higher fasting plasma glucose levels at baseline in
the placebo group.
Limitation: Post hoc analysis; examination of nonrandomized
subsets of randomized groups after year 1.
Participants: Of the 3234 randomly assigned participants, 1066
lost at least 5% of baseline weight in the first year and were
followed for 15 years.
Conclusion: Among persons with weight loss of at least 5% after 1 year, those originally randomly assigned to metformin had
the greatest loss during years 6 to 15. Older age and the amount
of weight initially lost were the most consistent predictors of
LTWL maintenance.
Measurements: Treatment assignment, personal characteristics, and weight.
Primary Funding Source: National Institutes of Health.
Results: After 1 year, 289 (28.5%) participants in the metformin
group, 640 (62.6%) in the ILS group, and 137 (13.4%) in the
placebo group had lost at least 5% of their weight. After the
masked treatment phase ended, the mean weight loss relative to
baseline that was maintained between years 6 and 15 was 6.2%
Ann Intern Med. 2019;170:682-690. doi:10.7326/M18-1605
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For author affiliations, see end of text.
This article was published at Annals.org on 23 April 2019.
* Members of the Diabetes Prevention Program Research Group are listed in
the Appendix (available at Annals.org).
O
ILS reduced risk for diabetes relative to placebo by
31% and 58%, respectively, over an average follow-up
of 2.8 years (2). Metformin and ILS were associated with
average weight losses at 2.8 years of 2.1 and 5.6 kg,
respectively, versus 0.1 kg with placebo (2), and weight
loss was the primary driver of diabetes prevention (4,
5). During long-term follow-up of DPP participants in its
Outcomes Study (DPPOS), weight changes differed
among treatment groups at 10 and 15 years (6, 7). After
achieving significantly greater initial weight loss than
participants in the other groups, those in the ILS group
regained about 3.5 kg over time, with a net loss of
about 2 kg relative to baseline at 10 years. However,
those in the metformin group achieved and maintained
an average loss of about 2.5 kg, and the average
weight of those in the placebo group changed by 1 kg
or less during the same period (6). The DPP and the
DPPOS make up the largest and longest clinical trial of
metformin for prevention of T2D. In the DPP, weight
loss explained 64% of the beneficial effect of metformin
on T2D risk (4).
The primary aims of the current study were to compare differences in LTWL maintenance by original intervention group among participants who achieved clinically significant weight loss of at least 5% at 1 year and
to examine baseline factors that predicted maintenance of weight loss for up to 15 years. We also evalu-
verweight and obesity are strong and potentially
modifiable risk factors for type 2 diabetes (T2D).
Prevention of T2D among persons with prediabetes is a
public health priority, and weight loss plays a central
role in efforts to prevent or delay the disease. Whereas
excess body weight is strongly associated with insulin
resistance and hyperglycemia, improved glycemia is
readily noticeable when persons with overweight or
obesity lose weight; however, the health benefits of
weight loss may last only when the initial weight loss
persists over the long term (1). There is clinical impetus
to examine whether baseline demographic, psychosocial, or physiologic factors can help to identify more
favorable long-term weight loss (LTWL) patterns, especially in the context of available treatments for diabetes
prevention.
Randomized controlled trials (RCTs) have shown efficacy of metformin, intensive lifestyle intervention (ILS),
or both in preventing or delaying onset of T2D among
high-risk persons with overweight and obesity (2, 3). In
the DPP (Diabetes Prevention Program), metformin and
See also:
Editorial comment . . . . . . . . . . . . . . . . . . . . . . . . . 724
Summary for Patients . . . . . . . . . . . . . . . . . . . . . . . I-24
682 © 2019 American College of Physicians
Long-Term Weight Loss With Metformin or Lifestyle Intervention
ated the effect of postbaseline factors, such as degree
of initial weight loss and adherence to the randomized
interventions.
METHODS
The DPP (July 1996 to July 2001) was an RCT that
compared the efficacy of ILS, metformin, and placebo
in prevention of T2D among 3234 participants with elevated glucose levels and overweight or obesity. The
1997 diagnostic criteria of the American Diabetes Association (8) were used to establish the primary outcome of diabetes, defined as a fasting plasma glucose
level of 7.0 mmol/L (126 mg/dL) or higher measured
semiannually or a 2-hour plasma glucose level of 11.1
mmol/L (200 mg/dL) or higher after a 75-g oral glucose
load measured annually, with confirmation within 6
weeks. The protocol, baseline characteristics of the
sample, and primary outcomes (including all clinical
and physiologic variables examined in these analyses)
have been described previously (2, 9, 10), along with
minor variations in eligibility criteria.
Participants were randomly assigned to receive an
individually administered ILS (a 16-session behavior
modification intervention implemented over approximately 6 to 8 months, with a goal of achieving 7%
weight loss through healthy dietary changes, reductions in intake of calories and fat, and 150 minutes of
moderate-intensity physical activity [mostly walking]
per week), metformin (850 mg twice daily), or placebo
(11). Both medication interventions were masked
(double-blind), but the ILS was not. After 6 months, participants in the ILS group continued to receive individual and group reinforcement of the behavioral intervention at least every 2 months, regardless of diabetes
status, but they were referred to their primary care provider (PCP) for diabetes management. Those in the
metformin and placebo groups continued to receive
the study drug until their plasma glucose level increased to 7.8 mmol/L (140 mg/dL) or higher, at which
time use of the study drug was discontinued and diabetes management was transferred to their PCP. The
DPP study protocol was modified in July 2001 after an
average follow-up of 3.2 years. Participants were informed of the main results, and there was a 1- to
2-week metformin and placebo washout period to
identify whether a short-term drug effect accounted for
the diabetes risk reduction with metformin (12).
The bridge protocol (1 August 2001 to 31 August
2002) was the 13-month period between the end of the
DPP and the start of long-term follow-up (DPPOS). Because efficacy was established for ILS compared with
metformin and placebo in the cumulative reduction in
diabetes incidence during the first 3.2 years, participants
in all 3 groups were offered a group-administered version
of the 16-session ILS. The group intervention, which
had similar content but did not include individualized
problem-solving and behavior change–support components, was implemented over a 6-month period and was
usually administered by the original staff. Rates of attendance at 1 or more sessions varied by group (58% in the
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ORIGINAL RESEARCH
metformin group, 40% in the ILS group, and 57% in the
placebo group) (13).
The DPPOS began in September 2002 and examined 2779 (88.5%) of the remaining DPP participants
for diabetes incidence and development of diabetesrelated complications. Although the DPPOS is ongoing,
the current analysis is based on average follow-up of 15
years from baseline of the DPP using data collected
annually through 2013 (Appendix Figure 1, available at
Annals.org). Similar proportions of the 3 randomized
DPP groups enrolled in the DPPOS (6). During the
DPPOS, metformin was provided to the group originally assigned to it, but without masking. In addition,
when hemoglobin A1c levels reached 7% or higher, use
of study metformin was discontinued and diabetes care
and medication management were transferred to the
participant's PCP (this often included prescription of
metformin by the PCP). In the ILS and placebo groups,
all diabetes care and medication management were
provided by the participant's PCP. Metformin use was
recorded at all visits for all participants during the DPP
and the DPPOS. During the DPPOS, all 3 groups were
offered educational lifestyle classes 4 times per year.
Twice a year, the original ILS group was offered 2 to 4
booster sessions designed to reinforce self-management
behaviors for weight and activity. Lifestyle class attendance among the groups did not exceed 20% for any of
the sessions offered during the DPPOS (data not shown).
In all trial phases, written informed consent was obtained
from all participants and studies were approved by each
center's institutional review board. An independent data
and safety monitoring board appointed by the study
sponsor (the National Institute of Diabetes and Digestive
and Kidney Diseases) oversaw the studies.
Statistical Analysis
Long-term weight loss was defined at each annual
examination after the first year as weight loss of at least
5% relative to baseline. We used fixed-effects models
with the assumption of normally distributed errors to
estimate the percentage of weight lost over time (SAS
Proc MIXED) and generalized estimating equation
(GEE) models to estimate the percentage of participants with LTWL (SAS Proc GENMOD) among those
who lost at least 5% in the first year (14). The fixedeffects models used a compound symmetry correlation, and the GEE models used a logit link with an exchangeable correlation structure.
The primary aim was to evaluate baseline and postrandomization predictors of maintenance of weight
loss among participants who achieved clinically significant weight loss of at least 5% at 1 year after randomization. Potential predictors of LTWL include the baseline variables listed in the Appendix Table (available at
Annals.org) as well as postrandomization measures of
percentage of weight lost in the first year, meeting the
ILS exercise goal at the end of the core 16-session curriculum, meeting the ILS weight loss goal of 7% at the
end of the core curriculum, total number of ILS sessions, use of PCP-prescribed metformin or study metAnnals of Internal Medicine • Vol. 170 No. 10 • 21 May 2019 683
ORIGINAL RESEARCH
formin at the annual visit, and diabetes status at the
annual visit.
Two statistical methods were used to examine predictors of LTWL. First, we used logistic regression models to evaluate potential predictors of medium-term (5
years), long-term (10 years), and very-long-term (15
years) weight loss (SAS Proc LOGISTIC). Second, we
used GEE models (15, 16) to examine potential predictors of LTWL across all follow-up years. The GEE models provided an average estimate of the effect of the
predictor on LTWL over the course of the study (SAS
Proc GENMOD) and used a logit link and an independent correlation to ensure proper parameter estimation
(17). For both approaches, univariate models were developed separately for each predictor variable. Multivariate models included variables that were significant
(P < 0.05) predictors of LTWL in the univariate analyses.
Final models included only measures that remained significant in the multivariate model. Given the wide variation
in the numbers of participants achieving and maintaining
weight loss of at least 5% among the intervention groups,
analyses were performed within groups.
The incidence of diabetes diagnosed at any time in
the DPP and the DPPOS was compared between participants who did and those who did not lose at least
5% of their weight in the first year by using Cox proportional hazards models within each intervention group
(SAS Proc PHREG). SAS, version 9.4 (SAS Institute), was
used for all statistical analyses.
Role of the Funding Source
The National Institutes of Health, the primary study
sponsor, was represented on the steering committee
and contributed to study design, implementation, and
publication. The funding agency was not represented
in the writing group, although all members of the steering committee had input on the article's contents. All
authors in the writing group had access to all data.
RESULTS
Participant Disposition
Appendix Figure 2 (available at Annals.org) shows
the total number of participants randomly assigned in
the DPP and those who lost at least 5% of their weight
in the first year. The numbers remaining in the DPP and
the DPPOS at years 5, 10, and 15 and the numbers
using study-provided metformin (original metformin
group only) or PCP-provided metformin among those
who met the weight loss threshold are also shown. Participants discontinued study visits for various reasons,
including loss to follow-up, illness, distance, and death.
Characteristics of Participants With at Least 5%
Weight Loss at Year 1
Participant characteristics in each of the 3 randomized groups are shown in the Appendix Table by the
amount of weight lost at year 1. A total of 289 (28.5%)
participants in the metformin group, 640 (62.6%) in the
ILS group, and 137 (13.4%) in the placebo group lost at
least 5% of their weight in the first year. Mean weight
losses at year 1 among these participants were 8.9%
684 Annals of Internal Medicine • Vol. 170 No. 10 • 21 May 2019
Long-Term Weight Loss With Metformin or Lifestyle Intervention
(95% CI, 8.5% to 9.3%), 11.0% (CI, 10.6% to 11.4%), and
9.2% (CI, 8.3% to 10.1%), respectively.
Weight Trajectories
Figure 1 (top) shows patterns of weight change by
group over the 15-year follow-up among all participants and stratified by weight loss (<5% vs. ≥5%) in the
first year. Among those who lost at least 5% in year 1,
mean losses relative to baseline at annual follow-up visits in years 2 to 15 ranged from 5.8% to 8.2% in the
metformin group, from 3.4% to 8.9% in the ILS group,
and from 1.6% to 5.8% in the placebo group. The mean
losses across years 6 to 15 (after the ILS was completed
and weight stabilized) relative to baseline were 6.2%
(CI, 5.2% to 7.2%) in the metformin group, 3.7% (CI,
3.1% to 4.4%) in the ILS group, and 2.8% (CI, 1.3% to
4.4%) in the placebo group. The ILS group had the
highest percentage (74%) of participants who lost at
least 5% by year 2, but this decreased to 51% to 62% in
years 3 to 5 and 41% to 47% in years 6 to 15 (Figure 1
[bottom]). In contrast, the percentage who lost at least
5% changed from 61% at year 2 to 54% to 57% in years
3 to 5 and 51% to 64% in years 6 to 15 in the metformin
group and from 49% at year 2 to 35% to 43% in years 3
to 5 and 35% to 50% in years 6 to 15 in the placebo
group. The mean percentages of participants with
LTWL across the 14-year follow-up among those who
lost at least 5% in the first year were 56.5% (CI, 55.5% to
57.5%), 48.9% (CI, 47.9% to 49.9%), and 41.7% (CI,
40.7% to 42.7%) in the metformin, ILS, and placebo
groups, respectively. The percentages for years 6 to 15
were 56.1% (CI, 55.1% to 57.1%), 43.1% (CI, 42.1% to
44.1%), and 41.9% (CI, 39.9% to 43.9%), respectively.
Predictors of LTWL
Metformin
In the metformin group, older age at baseline,
higher systolic blood pressure, higher 2-hour glucose
level, greater weight loss at year 1, and active use of
study metformin at the time of the visit were associated
with higher odds of LTWL in the univariate models. In
multiply adjusted logistic and GEE models, for years 5,
10, and 15 and overall, only older age at baseline (per
10 years; odds ratios [ORs], 1.74, 2.25, 2.37, and 1.74,
respectively; overall P < 0.001), greater weight loss at
year 1 (per 5% loss; ORs, 2.08, 1.97, 1.14, and 1.70,
respectively; overall P < 0.001), and active use of study
metformin (use vs. nonuse; ORs, 4.83, 4.02, 2.17, and
1.91, respectively; overall P < 0.001) independently
predicted LTWL (Figure 2 [top]).
Intensive Lifestyle Intervention
Several measures were significant in univariate
models in the ILS group. However, in multiply adjusted
models, for years 5, 10, and 15 and overall, only older
age at baseline (per 10 years; ORs, 2.07, 2.17, 2.03, and
2.00, respectively; overall P < 0.001) and greater
weight loss at year 1 (per 5% loss; ORs, 1.83, 1.80, 1.40,
and 1.59, respectively; overall P < 0.001) independently increased the odds of LTWL. Conversely, a diagnosis of diabetes during follow-up (diabetes vs. no diaAnnals.org
ORIGINAL RESEARCH
Long-Term Weight Loss With Metformin or Lifestyle Intervention
Figure 1. Patterns of mean weight change over 15 years.
Intensive Lifestyle Intervention
Placebo
2
2
0
0
0
–2
–2
–2
–4
–6
Weight Change, %
2
Weight Change, %
Weight Change, %
Metformin
–4
–6
–4
–6
–8
–8
–8
–10
–10
–10
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Years Since Randomization
All participants
Intensive Lifestyle Intervention
Metformin
Placebo
100
100
90
90
90
80
80
80
70
70
70
60
50
40
30
Participants With LTWL, %
100
Participants With LTWL, %
Participants With LTWL, %
≥5% weight loss
<5% weight loss
60
50
40
30
60
50
40
30
20
20
20
10
10
10
0
0
0
2 3 4 5 6 7 8 9 10 11 12 13 14 15
2 3 4 5 6 7 8 9 10 11 12 13 14 15
2 3 4 5 6 7 8 9 10 11 12 13 14 15
Error bars represent 95% CIs. Sample sizes were 289 at year one, 247 at year five, 236 at year ten, and 172 at year fifteen in the metformin group; 640 at
year one, 540 at year five, 491 at year ten, and 373 at year fifteen in the intensive lifestyle intervention group; and 137 at year one, 110 at year five, 104
at year ten, and 92 at year fifteen in the placebo group. DPP = Diabetes Prevention Program; LTWL = long-term weight loss. Top. Observed weight loss
over 15 y among all participants and those who lost <5% vs. ≥5% of their weight in the first year, by treatment group. Bottom. Observed percentages of
participants with ≥5% weight loss each year in years 2 to 15 among those who lost ≥5% in the first year, by treatment group.
betes; ORs, 0.56, 0.86, 0.94, and 0.74, respectively;
overall P = 0.038) and family history of diabetes (history
vs. no history; ORs, 0.65, 0.66, 0.58, and 0.74, respectively; overall P = 0.051) independently decreased the
odds (Figure 2 [middle]).
Placebo
Age at baseline did not predict LTWL in the placebo group. In univariate and multivariate models, for
years 5, 10, and 15 and overall, only fasting glucose
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level (per 0.55 mmol/L [10 mg/dL]; ORs, 2.23, 2.08,
2.57, and 1.83, respectively; overall P = 0.002) and
weight loss at year 1 (per 5% loss; ORs, 1.09, 1.48, 1.32,
and 1.43, respectively; overall P = 0.001) were significant predictors (Figure 2 [bottom]).
Weight Loss and Diabetes Incidence
Among participants who had lost less than 5% versus at least 5% of their weight at year 1, diabetes incidence rates were 54% versus 41% for metformin
(P < 0.001), 61% versus 39% for ILS (P < 0.001), and
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ORIGINAL RESEARCH
Long-Term Weight Loss With Metformin or Lifestyle Intervention
Figure 2. Predictors of long-term weight loss.
Metformin
Percentage of Weight Loss at Year 1
Using Study Metformin
8
8
4
4
4
2
Odds Ratio
8
Odds Ratio
Odds Ratio
Age at Baseline
2
2
1
1
1
0.5
0.5
0.5
5
10
15
5
10
15
Overall
Years Since Randomization
Overall
5
15
10
Overall
Intensive Lifestyle Intervention
Family History of Diabetes
4
4
2
2
2
2
1
0.5
1
10
15
1
0.5
0.5
5
Odds Ratio
4
Odds Ratio
4
Odds Ratio
Odds Ratio
Diabetes Diagnosis During Follow-up
Percentage of Weight Loss at Year 1
Age at Baseline
5
Overall
10
15
0.5
5
Overall
1
10
15
5
Overall
10
15
Overall
Years Since Randomization
Placebo
Percentage of Weight Loss at Year 1
Fasting Glucose Level at Baseline
4
4
2
2
2
1
0.5
Odds Ratio
4
Odds Ratio
Odds Ratio
Age at Baseline
1
0.5
0.5
5
10
15
Overall
1
5
10
15
Overall
5
10
15
Overall
Years Since Randomization
Results are from generalized estimating equation and multiple logistic regression models predicting ≥5% weight loss overall and at 5, 10, and 15 y. Odds
ratios are displayed on a logarithmic scale. Error bars represent 95% CIs. Top. Metformin group. Older age at randomization (per 10 y), greater
weight loss at year 1 (per 5%), and active use of study metformin increased odds of long-term weight loss. Middle. Intensive lifestyle intervention
group. Older age at randomization (per 10 y) and greater weight loss at year 1 (per 5%) increased odds of long-term weight loss, whereas current
diabetes status and family history of diabetes decreased odds. Bottom. Placebo group. Greater weight loss at year 1 (per 5%) and higher fasting
glucose level (per 0.55 mmol/L [10 mg/dL]) were the only predictors of long-term weight loss.
686 Annals of Internal Medicine • Vol. 170 No. 10 • 21 May 2019
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Long-Term Weight Loss With Metformin or Lifestyle Intervention
57% versus 48% for placebo (P = 0.057) over the full
15-year follow-up.
DISCUSSION
We examined weight changes over 15 years among
persons who had overweight or obesity, were at risk for
T2D, were enrolled in the DPP, and continued in the
DPPOS and elucidated characteristics of those achieving
LTWL. Our key findings are 3-fold. First, although twice as
many participants in the ILS group versus the metformin
group lost at least 5% of their weight in the first year,
those who were originally assigned to metformin had
greater success in maintaining LTWL. Second, among the
many characteristics of participants examined in this exploratory analysis, greater 1-year weight loss predicted
LTWL in all groups. Other independent predictors of
LTWL were older age and current use of metformin in the
metformin group, older age and absence of either diabetes or a family history of diabetes in the ILS group, and
baseline fasting plasma glucose level in the placebo
group. Third, cumulative diabetes incidence rates over 15
years were lower among those who lost at least 5% of
their weight in the first year.
A recent systematic review and meta-analysis reported average weight loss of 1.1 kg with use of metformin for varying periods (18). In the DPP and the
DPPOS, participants in the metformin group lost an average of 2.1% after 2 years and maintained weight loss
of about 2% over the next 10 years (19). The current
investigation builds on this by showing that approximately 30% of persons with overweight or obesity at
baseline lost at least 5% over a year with metformin
therapy, and more than half of this subset maintained
this weight loss for as long as 15 years.
Among the drugs approved primarily for treatment
of obesity, only 2 have been studied for more than 2
years in RCTs. In the XENDOS (XENical in the prevention of Diabetes in Obese Subjects) trial (20) of 3305
patients with obesity and diabetes, orlistat was associated with weight loss of 9.6% versus 5.6% with placebo,
but this difference narrowed to 3.2% versus 1.3% at 4
years, at which point significant attrition in the study
sample hampered interpretation of weight changes
and diabetes results. In addition, long-term adherence
to orlistat is poor (21). Liraglutide (3.0 mg/d) led to
greater weight loss (6.1% vs. 1.9%) and lower cumulative diabetes incidence (2% vs. 6%) than placebo at 3
years in a large study of persons with obesity and prediabetes (22). However, the need for daily injections
and high cost are key limitations of liraglutide for longterm weight management and T2D prevention. Therefore, other interventions that could promote LTWL are
needed. Metformin is attractive because most professional guidelines, including those from the American
College of Physicians and the American Diabetes
Association (23, 24), recommend it as the first-line medication for patients with newly diagnosed T2D. It is inexpensive, is generally well tolerated, and is used extensively in primary care.
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ORIGINAL RESEARCH
Metformin has several mechanisms and sites of action in humans. Its beneficial effects include inhibition
of gluconeogenesis with a consequent decrease in hepatic glucose output and increased insulin sensitivity,
increased glucose utilization in the gut and enhanced
insulin sensitivity in skeletal muscle (25, 26), and effects
on the gut microbiota and the immune system (27).
However, the mechanisms that contribute to its effects
on body weight are not well understood. Decreases in
appetite and food intake have been reported with metformin in several (22, 28 –30) but not all (31) studies.
Metformin is not known to significantly alter energy expenditure (25, 32). It is well recognized that the human
body adapts to weight loss with compensatory neuronal, hormonal, and metabolic changes that promote
weight regain (33–36). Whether metformin counters
some of these compensatory changes must be further
investigated.
Among participants who lost at least 5% of their
weight in the first year, the degree of weight loss at
year 1 predicted LTWL in each of the originally randomized groups. Several studies have reported that weight
loss in the first 3 to 6 months predicts weight loss at 1 to
2 years with lifestyle interventions as well as pharmacotherapy (1, 37– 40). Our findings that initial weight loss
and older age are predictive of LTWL and that weight
loss is largely associated with favorable diabetes and
other health outcomes are consistent with prior observations in the DPP, the DPPOS, and other studies (5,
41– 43). Findings of several physiologic, neurohormonal, and feeding studies that examined differences
between older and younger persons suggest that aging is associated with impaired ability to accurately regulate energy balance via adjustments in energy intake
(44 – 49). It is unclear whether LTWL over periods as
long as 15 years is associated with better or worse
health outcomes overall, especially among persons in
their seventh or eighth decade of life.
Of note, despite significant weight regain, participants in the ILS group who lost at least 5% of their
weight in the first year still maintained average weight
loss of 3.7% relative to baseline during years 6 to 15.
From a population health perspective, this finding
gains importance with increasing dissemination and
implementation of DPP-modeled lifestyle programs
(50) and reimbursement for such interventions (51, 52).
The decision by Medicare to reimburse for DPPmodeled lifestyle interventions when implemented by
recognized providers using standardized outcome
measures has strong potential to add to the research
on long-term treatment response.
The strengths of the current study include a long
follow-up of 15 years in the originally randomized
groups, high retention (7), and large sample sizes in the
metformin and ILS groups. However, this study has several limitations. Although the DPP was an RCT, our
subanalysis examining participants who lost at least 5%
of their weight in the first year was a secondary analysis.
Racial and ethnic minorities were well represented in
our sample, but it had few unemployed or low-income
participants (10) and thus may have limited generalizAnnals of Internal Medicine • Vol. 170 No. 10 • 21 May 2019 687
ORIGINAL RESEARCH
ability. Although retention was high, some participants
discontinued participation or died over the 15-year
follow-up. However, the observed effects at 5, 10, and
15 years and the average effects across the entire
follow-up were consistent. Other possible predictors of
LTWL were not measured in the DPP and the DPPOS.
We opted for the 5% threshold to define initial weight
loss as well as LTWL because this degree of weight loss
confers meaningful health benefits (1), but some researchers might apply a different threshold (53).
Whether the results of our analysis among persons at
high risk for diabetes would transfer to those beginning
T2D treatment with metformin is unknown. Finally, the
LTWL we report with metformin is only for the 28.5% of
participants who lost at least 5% of their weight in the
first year. However, this is a sizeable proportion given
that millions of persons worldwide are treated with
metformin as the first-line drug for T2D. It is also important to recognize that participants in the metformin
group continued use of the drug for up to 15 years,
whereas in the ILS group the intervention was administered at a high intensity in the first 3 years but at a much
lower intensity in later years, and although booster
therapy sessions were offered, attendance was poor,
reflecting the difficulty of implementing ILS beyond 1 to
3 years.
In conclusion, we found that older age and greater
1-year weight loss predicted LTWL over the next 14
years among DPP and DPPOS participants who lost at
least 5% of their weight in the first year. Many other
variables explored as potential predictors were not
consistently associated with LTWL. Also, among participants with significant initial weight loss, those who
were originally randomly assigned to metformin had
greater success in maintaining LTWL than those randomly assigned to ILS with longer follow-up, especially
during years 6 to 15. Future investigations should focus
on whether metformin could be a useful intervention
for LTWL after initial weight loss with lifestyle interventions, antiobesity drugs or devices, or bariatric surgery.
From Pennington Biomedical Research Center, Louisiana
State University System, Baton Rouge, Louisiana (J.W.A.,
K.M.G.); Western Psychiatric Institute and Clinic, University of
Pittsburgh Medical Center, Pittsburgh, Pennsylvania (E.M.V.);
George Washington University Biostatistics Center, Rockville,
Maryland (S.L.E.); National Institute of Diabetes and Digestive
and Kidney Diseases, Phoenix, Arizona (W.C.K.); Colorado
School of Public Health, Aurora, Colorado (D.D.); Seattle Epidemiologic Research and Information Center, VA Puget
Sound Health Care System, Seattle, Washington (E.J.B.); Columbia University College of Physicians and Surgeons, New
York, New York (X.P.); Johns Hopkins University School of
Medicine, Baltimore, Maryland (R.R.K.); Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden
(P.W.F.); and University of California, Los Angeles, Los Angeles, California (P.S.).
Long-Term Weight Loss With Metformin or Lifestyle Intervention
Acknowledgment: The members of the DPP Research Group
thank the participants in the DPP and the DPPOS for their
commitment and dedication.
Grant Support: Research reported in this article was sup-
ported by the National Institute of Diabetes and Digestive and
Kidney Diseases (NIDDK) of the National Institutes of Health
under award number U01 DK048489. During the DPP and the
DPPOS, the NIDDK provided funding to the clinical centers
and the Coordinating Center for the design and conduct of
the study and the collection, management, analysis, and interpretation of the data (U01 DK048489). The Southwestern
American Indian Centers were supported directly by the
NIDDK, including its Intramural Research Program, and the
Indian Health Service. The General Clinical Research Center
Program, the National Center for Research Resources, and the
Department of Veterans Affairs supported data collection at
many of the clinical centers. Funding was also provided by the
National Institute of Child Health and Human Development;
the National Institute on Aging; the National Eye Institute; the
National Heart, Lung, and Blood Institute; the National Cancer
Institute; the Office of Research on Women's Health; the National Institute on Minority Health and Health Disparities; the
Centers for Disease Control and Prevention; and the American Diabetes Association. Bristol-Myers Squibb and ParkeDavis provided additional funding and material support during the DPP. Lipha (Merck-Santé) provided medication, and
LifeScan donated materials during the DPP and the DPPOS.
This research was also supported in part by the intramural
research program of the NIDDK. LifeScan, Health o meter,
Hoechst Marion Roussel, Merck-Medco Managed Care, Merck
and Company, Nike Sports Marketing, SlimFast Foods, and
Quaker Oats donated materials, equipment, or medicines for
concomitant conditions. McKesson BioServices, Matthews
Media Group, and the Henry M. Jackson Foundation provided
support services under subcontract with the Coordinating
Center.
Disclosures: Dr. Pi-Sunyer reports personal fees from Novo
Nordisk and Zafgen outside the submitted work. Dr. Franks
reports grants from Boehringer Ingelheim, Eli Lilly, Janssen,
Novo Nordisk, Sanofi Aventis, and Servier and personal fees
from Zoe Global outside the submitted work. Dr. Gadde reports grants from AstraZeneca and BioKier and other support
from AstraZeneca and the American Diabetes Association
outside the submitted work. Authors not named here have
disclosed no conflicts of interest. Disclosures can also be
viewed at www.acponline.org/authors/icmje/ConflictOf
InterestForms.do?msNum=M18-1605.
Data Sharing Statement: The data set will be available via the
NIDDK Data Repository at https://repository.niddk.nih.gov
/studies/dpp and https://repository.niddk.nih.gov/studies
/dppos.
Corresponding Author: Kishore M. Gadde, MD, c/o DPPOS
Coordinating Center, The George Washington University Biostatistics Center, 6110 Executive Boulevard, Suite 750, Rockville, MD 20852; e-mail, Kishore.gadde@pbrc.edu.
Disclaimer: The opinions expressed are those of the investi-
Correction: This article was corrected on 3 August 2020 to
gators and do not necessarily reflect the views of the funding
agencies.
revise information in the data sharing statement about availability of the data set.
688 Annals of Internal Medicine • Vol. 170 No. 10 • 21 May 2019
Annals.org
Long-Term Weight Loss With Metformin or Lifestyle Intervention
Current author addresses and author contributions are available at Annals.org.
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Annals.org
Current Author Addresses: Drs. Apolzan and Gadde: Penning-
ton Biomedical Research Center, Louisiana State University
System, 6400 Perkins Road, Baton Rouge, LA 70810.
Dr. Venditti: Western Psychiatric Institute and Clinic, University
of Pittsburgh Medical Center, 3811 O’Hara Street, Pittsburgh,
PA 15213.
Ms. Edelstein: George Washington University Biostatistics
Center, 6110 Executive Boulevard, Suite 750, Rockville, MD
20852.
Dr. Knowler: National Institute of Diabetes and Digestive and
Kidney Diseases, 1550 East Indian School Road, Phoenix, AZ
85014.
Dr. Dabelea: Department of Epidemiology, Colorado School
of Public Health, 13001 East 17th Avenue, Aurora, CO 80045.
Dr. Boyko: Seattle Epidemiologic Research and Information
Center, VA Puget Sound Health Care System, 1660 South Columbian Way, Seattle, WA 98108.
Dr. Pi-Sunyer: Department of Medicine, Columbia University
College of Physicians and Surgeons, 1150 St. Nicholas Avenue, Suite 121, New York, NY 10032.
Dr. Kalyani: School of Medicine, Johns Hopkins University,
1830 East Monument Street, Suite 333, Baltimore, MD 21287.
Dr. Franks: Lund University Diabetes Centre, Skåne University
Hospital, Building 91, Jan Waldenströms gata 35, SE-205 02,
Malmö, Sweden.
Dr. Srikanthan: Department of Medicine, University of California, Los Angeles, 330 South Garfield Avenue, Suite 308, Alhambra, CA 91801.
Author Contributions: Conception and design: J.W. Apolzan,
E.M. Venditti, S.L. Edelstein, K.M. Gadde.
Analysis and interpretation of the data: J.W. Apolzan, E.M.
Venditti, S.L. Edelstein, W.C. Knowler, D. Dabelea, K.M.
Gadde.
Drafting of the article: J.W. Apolzan, E.M. Venditti, S.L.
Edelstein, K.M. Gadde.
Critical revision of the article for important intellectual content: J.W. Apolzan, E.M. Venditti, S.L. Edelstein, W.C. Knowler,
D. Dabelea, E.J. Boyko, X. Pi-Sunyer, R.R. Kalyani, P.W. Franks,
P. Srikanthan, K.M. Gadde.
Final approval of the article: J.W. Apolzan, E.M. Venditti, S.L.
Edelstein, W.C. Knowler, D. Dabelea, E.J. Boyko, X. Pi-Sunyer,
R.R. Kalyani, P.W. Franks, P. Srikanthan, K.M. Gadde.
Provision of study materials or patients: E.M. Venditti, S.L.
Edelstein, W.C. Knowler, X. Pi-Sunyer, K.M. Gadde.
Statistical expertise: S.L. Edelstein, W.C. Knowler.
Obtaining of funding: E.M. Venditti, S.L. Edelstein, W.C.
Knowler, D. Dabelea, X. Pi-Sunyer, K.M. Gadde.
Administrative, technical, or logistic support: S.L. Edelstein,
W.C. Knowler, K.M. Gadde.
Collection and assembly of data: S.L. Edelstein, W.C. Knowler,
D. Dabelea, X. Pi-Sunyer, K.M. Gadde.
APPENDIX: DIABETES PREVENTION PROGRAM
RESEARCH GROUP
Unless otherwise indicated, these investigators
contributed to this work but did not author the article.
Pennington Biomedical Research Center (Baton
Rouge, Louisiana)
George A. Bray, MD†; Kishore Gadde, MD*†;
Annie Chatellier, RN, CCRC‡; Jennifer Arceneaux, RN,
Annals.org
BSN‡; Amber Dragg, RD, LDN‡; Crystal Duncan, LPN;
Frank L. Greenway, MD; Erma Levy, RD; Monica
Lockett, LPN; and Donna H. Ryan, MD
University of Chicago (Chicago, Illinois)
David Ehrmann, MD†; Margaret J. Matulik, RN,
BSN‡; Kirsten Czech, MS; and Catherine DeSandre, BA
Jefferson Medical College (Philadelphia,
Pennsylvania)
Barry J. Goldstein, MD, PhD†; Kevin Furlong, DO†;
Kellie A. Smith, RN, MSN‡; Wendi Wildman, RN‡; and
Constance Pepe, MS, RD
University of Miami (Miami, Florida)
Ronald B. Goldberg, MD†; Jeanette Calles, MSEd‡;
Juliet Ojito, RN‡; Sumaya Castillo-Florez, MPH; Hermes
J. Florez, MD, PhD; Anna Giannella, RD, MS; Olga Lara;
and Beth Veciana
The University of Texas Health Science Center
(San Antonio, Texas)
Steven M. Haffner, MD, MPH†; Helen P. Hazuda,
PhD†; Maria G. Montez, RN, MSHP, CDE‡; Kathy
Hattaway, RD, MS; Carlos Lorenzo, MD, PhD; Arlene
Martinez, RN, BSN, CDE; and Tatiana Walker, RD, MS,
CDE
University of Colorado (Denver, Colorado)
Richard F. Hamman, MD, DrPH†; Dana Dabelea,
MD, PhD*†; Lisa Testaverde, MS‡; Denise Anderson,
RN, BSN; Alexis Bouffard, MA, RN, BSN; Tonya Jenkins,
RD, CDE; Dione Lenz, RN, BSN, CDE; Leigh Perreault,
MD; David W. Price, MD; and Sheila C. Steinke, MS
Joslin Diabetes Center (Boston, Massachusetts)
Edward S. Horton, MD†; Catherine S. Poirier, RN,
BSN‡; Kati Swift, RN, BSN‡; Enrique Caballero, MD;
Barbara Fargnoli, RD; Ashley Guidi, BS; Mathew Guido,
BA; Sharon D. Jackson, MS, RD, CDE; Lori Lambert, MS,
RD, LD; Kathleen E. Lawton, RN; Sarah Ledbury, MEd,
RD; Jessica Sansoucy, BS; and Jeanne Spellman, RD
VA Puget Sound Health Care System and
University of Washington (Seattle, Washington)
Steven E. Kahn, MB, ChB†; Brenda K. Montgomery,
RN, BSN, CDE‡; Wilfred Fujimoto, MD; Robert H.
Knopp, MD; Edward W. Lipkin, MD; Ivy MorganTaggart; Anne Murillo, BS; Lonnese Taylor, RN, BS;
April Thomas, RD, MPH, CDE; Elaine C. Tsai, MD, MPH;
and Dace Trence, MD
University of Tennessee (Memphis, Tennessee)
Abbas E. Kitabchi, PhD, MD, FACP†; Samuel
Dagogo-Jack, MD†; Mary E. Murphy, RN, MS, CDE,
MBA‡; Laura Taylor, RN, BSN, CDE‡; Jennifer Dolgoff,
RN, BSN‡; Debra Clark, LPN; Uzoma Ibebuogu, MD;
Helen Lambeth, RN, BSN; Harriet Ricks; Lily M.K.
Rutledge, RN, BSN; and Judith E. Soberman, MD
Annals of Internal Medicine • Vol. 170 No. 10 • 21 May 2019
Northwestern University Feinberg School of
Medicine (Chicago, Illinois)
Mark E. Molitch, MD†; Boyd E. Metzger, MD†;
Mariana K. Johnson, MS, RN‡; Mimi M. Giles, MS, RD;
Diane Larsen, BS; and Samsam C. Pen, BA
Massachusetts General Hospital (Boston,
Massachusetts)
David M. Nathan, MD†; Mary Larkin, MSN†; Charles
McKitrick, BSN‡; Heather Turgeon, BSN‡; Ellen
Anderson, MS, RD; Laurie Bissett, MS, RD; Kristy Bondi,
BS; Enrico Cagliero, MD; Kali D’Anna; Linda Delahanty,
MS, RD; Jose C. Florez, MD, PhD; Valerie Goldman, MS,
RD; Peter Lou, MD; Alexandra Poulos; Elyse Raymond,
BS; Christine Stevens; and Beverly Tseng
University of California, San Diego (San Diego,
California)
Elizabeth Barrett-Connor, MD†; Mary Lou CarrionPetersen, RN, BSN‡; Lauren N. Claravall, BS; Jonalle M.
Dowden, BS; Javiva Horne, RD; Diana Leos, RN, BSN;
Sundar Mudaliar, MD; Jean Smith, RN; Simona Szerdi
Janisch, BS; and Karen Vejvoda, RN, BSN, CDE, CCRC
Columbia University (New York, New York)
F. Xavier Pi-Sunyer, MD*†; Jane E. Lee, MS‡;
Sandra T. Foo, MD; and Susan Hagamen, MS, RN, CDE
Indiana University (Indianapolis, Indiana)
David G. Marrero, PhD†; Kieren J. Mather, MD†;
Susie M. Kelly, RN, CDE‡; Paula Putenney, RN‡; Marcia
A. Jackson‡; Gina McAtee‡; Ronald T. Ackermann, MD;
Carolyn M. Cantrell; Edwin S. Fineberg, MD; Angela
Hadden (deceased); Mario S. Kirkman; Erin O’Kelly
Phillips; and Paris J. Roach, MD
MedStar Health Research Institute (Washington,
DC)
Robert E. Ratner, MD†; Vanita Aroda, MD†; Sue
Shapiro, RN, BSN, CCRC‡; Catherine Bavido-Arrage,
MS, RD, LD; Peggy Gibbs; Gabriel Uwaifo, MD; and
Renee Wiggins, RD
University of Southern California/UCLA
Research Center (Alhambra, California)
Mohammed F. Saad, MD†; Karol Watson, MD†;
Medhat Botrous, MD‡; Sujata Jinagouda, MD‡; Maria
Budget; Claudia Conzues; Perpetua Magpuri; Kathy
Ngo; and Kathy Xapthalamous
Washington University (St. Louis, Missouri)
Neil H. White, MD, CDE†; Angela L. Brown, MD†;
Samia Das, MS, MBA, RD, LD‡; Prajakta Khare-Ranade,
MSc, RDN, LD‡; Tamara Stich, RN, MSN, CDE‡; Ana
Santiago, RN; and Cormarie Wernimont, RD, LD
Johns Hopkins School of Medicine (Baltimore,
Maryland)
Christopher D. Saudek, MD† (deceased); Sherita
Hill Golden, MD, MHS, FAHA†; Tracy Whittington, BS‡;
Frederick L. Brancati, MD, MHS (deceased); Jeanne M.
Annals of Internal Medicine • Vol. 170 No. 10 • 21 May 2019
Clark, MD; Alicia Greene; Dawn Jiggetts; Henry
Mosley; John Reusing; Richard R. Rubin, PhD (deceased); Shawne Stephens; and Evonne Utsey
University of New Mexico (Albuquerque, New
Mexico)
David S. Schade, MD†; Karwyn S. Adams, RN,
MSN‡; Claire Hemphill, RN, BSN‡; Penny Hyde, RN,
BSN‡; Janene L. Canady, RN, CDE‡; Kathleen Colleran,
MD; Ysela Gonzales, RN, MSN; Doris A. HernandezMcGinnis; and Carolyn King
Albert Einstein College of Medicine (Bronx, New
York)
Jill Crandall, MD†; Janet O. Brown, RN, MPH,
MSN‡; Gilda Trandafirescu, MD‡; Elsie Adorno, BS;
Helena Duffy, MS, C-ANP; Angela Goldstein, FNP-C,
NPP, CSW; Jennifer Lukin, BA; Helen Martinez, RN,
MSN, FNP-C; Dorothy Pompi, BA; Harry Shamoon, MD;
Jonathan Scheindlin, MD; Elizabeth A. Walker, RN,
DNSc, CDE; and Judith Wylie-Rosett, EdD, RD
University of Pittsburgh (Pittsburgh,
Pennsylvania)
Trevor Orchard, MD†; Andrea Kriska, PhD†; Susan
Jeffries, RN, MSN‡; M. Kaye Kramer, BSN, MPH‡;
Marie Smith, RN, BSN‡; Catherine Benchoff; Stephanie
Guimond, BS; Jessica Pettigrew, CMA; Debra Rubinstein,
MD; Linda Semler, MS, RD; Elizabeth Venditti, PhD*; and
Valarie Weinzierl, MPH
University of Hawaii (Honolulu, Hawaii)
Richard F. Arakaki, MD†; Narleen K. Baker-Ladao,
BS‡; Mae K. Isonaga, RD, MPH‡; Nina E. Bermudez,
MS; Marjorie K. Mau, MD; John S. Melish, MD; and
Robin E. Yamamoto, CDE, RD
Southwest American Indian Centers (Phoenix,
Arizona; Shiprock, New Mexico; and Zuni,
New Mexico)
William C. Knowler, MD, DrPH*†; Norman
Cooeyate‡; Alvera Enote‡; Mary A. Hoskin, RD, MS‡;
Camille Natewa‡; Carol A. Percy, RN, MS‡; Kelly J.
Acton, MD, MPH; Vickie L. Andre, RN, FNP; Roz Barber;
Shandiin Begay, MPH; Brian C. Bucca, OD, FAAO; Sherron
Cook; Jeff Curtis, MD; Charlotte Dodge; Matthew S.
Doughty, MD; Jason Kurland, MD; Justin Glass, MD;
Martia Glass, MD; Robert L. Hanson, MD, MPH; Louise
E. Ingraham, MS, RD, LN; Kathleen M. Kobus, RNCANP; Jonathan Krakoff, MD; Catherine Manus, LPN;
Cherie McCabe; Sara Michaels, MD; Tina Morgan; Julie
A. Nelson, RD; Christopher Piromalli, DO; Robert J.
Roy; Sandra Sangster, RD; Miranda Smart; Darryl P.
Tonemah, PhD; Rachel Williams, FNP; and Charlton
Wilson, MD
Annals.org
George Washington University Biostatistics
Center (DPP Coordinating Center, Rockville,
Maryland)
Sarah Fowler, PhD†; Marinella Temprosa, PhD†;
Michael Larsen, PhD†; Tina Brenneman‡; Hanna Sherif,
MS‡; Sharon L. Edelstein, ScM*‡; Solome Abebe, MS;
Julie Bamdad, MS; Melanie Barkalow; Joel Bethepu;
Tsedenia Bezabeh; Nicole Butler; Jackie Callaghan;
Caitlin E. Carter; Costas Christophi, PhD; Gregory M.
Dwyer; Mary Foulkes, PhD; Yuping Gao; Robert
Gooding; Adrienne Gottlieb; Nisha Grover; Heather
Hoffman, PhD; Ashley N. Hogan; Kathleen Jablonski,
PhD; Richard Katz, MD; Preethy Kolinjivadi, MS; John
M. Lachin, ScD; Yong Ma, PhD; Qing Pan, PhD; Susan
Reamer; and Alla Sapozhnikova
Lifestyle Resource Core
Elizabeth M. Venditti, PhD*†; Andrea M. Kriska, PhD;
Linda Semler, MS, RD, LDN; and Valerie Weinzierl, MPH
Central Biochemistry Laboratory (Seattle,
Washington)
Santica Marcovina, PhD, ScD†; Greg Strylewicz,
PhD‡; and John Albers, PhD
NIH/NIDDK (Bethesda, Maryland)
Judith Fradkin, MD; Sanford Garfield, PhD; and
Christine Lee, MD, MS
Centers for Disease Control and Prevention
(Atlanta, Georgia)
Edward Gregg, PhD, and Ping Zhang, PhD
University of Michigan (Ann Arbor, Michigan)
William H. Herman, MD, MPH; Michael Brändle,
MD, MS; and Morton B. Brown, PhD
* Authored the article.
† Principal investigator.
‡ Program coordinator.
Appendix Figure 1. DPP and DPPOS study design.
Bridge group
classes
(16 sessions)
in all groups
1996:
DPP
recruitment
began
1999:
DPP
enrollment
completed
2001: 2002:
DPP DPPOS
results began
2013:
End of data collection
for the current analysis
Intensive lifestyle
intervention
Group lifestyle education + semiannual refreshers
Metformin
Group lifestyle education + metformin
Placebo
Group lifestyle education only
DPP = Diabetes Prevention Program; DPPOS = Diabetes Prevention Program Outcomes Study.
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Annals of Internal Medicine • Vol. 170 No. 10 • 21 May 2019
Annals of Internal Medicine • Vol. 170 No. 10 • 21 May 2019
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168 (58.1)
54 (18.7)
40 (13.8)
20 (6.9)
7 (2.4)
72 (24.9)
133 (46.0)
84 (29.1)
395 (54.5)
157 (21.7)
116 (16)
32 (4.4)
25 (3.4)
183 (25.2)
354 (48.8)
188 (25.9)
95 (20.3)
34.1 (6.7)
105.7 (14.9)
113.7 (13.5)
0.93 (0.09)
Anthropometric characteristics
Mean weight (SD), kg
Mean BMI (SD), kg/m2
Mean waist circumference (SD), cm
Mean hip circumference (SD), cm
Mean waist-to-hip ratio (SD)
123.5 (15.0)
78.3 (9.6)
Mean blood pressure (SD), mm Hg
Systolic
Diastolic
180 (62.3)
16 (5.5)
93 (32.2)
37 (18.7)
18 (6.2)
4.2 (3.9)
3.81 (4.7)
0.80 (0.10)
417 (57.5)
51 (7.0)
257 (35.4)
63 (13.6)
43 (5.9)
4.6 (4.6)
3.9 (4.6)
0.80 (0.10)
125.5 (14.6)
77.7 (9.3)
106.2 (8.3)
166.5 (17.7)
5.9 (0.4)
25.8 (13.9)
6.8 (3.87)
163 (57.8)
57 (20.2)
43 (15.2)
19 (6.7)
384 (53.6)
137 (19.1)
162 (22.6)
33 (4.6)
106.6 (8.5)
164.6 (17.0)
5.9 (0.5)
27.6 (15.4)
7.3 (4.3)
204 (70.3)
497 (68.6)
Mean glucose and insulin levels (SD)
Fasting glucose, mg/dL
2-h glucose, mg/dL
Hemoglobin A1c, %
Fasting insulin, uU/mL
HOMA-IR
Baseline history
Family history of diabetes, n (%)†
Alcohol intake, n (%)†
None
<1 drink/wk
≥1 drink/wk to <1 drink/d
≥1 drink/d
Smoking, n (%)
Never
Current
Former
Gestational diabetes, n (%)‡
Antidepressant use, n (%)
Mean Beck Depression Inventory score (SD)
Mean Beck Anxiety Inventory score (SD)
Mean SF-6D score (SD)
90 (31)
199 (69)
261 (36)
464 (64)
92.2 (18.4)
33.1 (6.0)
102.6 (12.7)
112.1 (12.1)
0.92 (0.08)
52.1 (10.7)
289
>5%
Weight
Loss
50.8 (10.1)
725
<5%
Weight
Loss
Metformin
Demographic characteristics
Mean age at randomization (SD), y
Sex, n (%)
Men
Women
Race/ethnicity, n (%)
White
Black
Hispanic
American Indian
Asian
Education, n (%)
High school or less
College
Postgraduate
Participants, n
Variable
0.06
0.36
0.54
0.11
0.30
0.07
0.07
0.093
0.86
0.22
0.73
0.56
0.34
0.68
0.048
0.045
0.028
0.002
0.078
0.017
0.58
0.27
0.071
0.142
—
P Value*
122.7 (15.0)
78.4 (9.5)
106.0 (8.4)
164.8 (17.2)
5.9 (0.5)
27.7 (15.9)
7.3 (4.4)
242 (63.2)
26 (6.8)
115 (30.0)
59 (20.7)
26 (6.8)
4.8 (4.7)
4.7 (5.9)
0.79 (0.11)
227 (60.7)
66 (17.6)
66 (17.6)
51 (4.8)
283 (73.9)
95 (20.8)
34.5 (6.9)
106.0 (15.1)
115.6 (14.4)
0.92 (0.08)
105 (27.4)
178 (46.5)
100 (26.1)
179 (46.7)
97 (25.3)
58 (15.1)
29 (7.6)
20 (5.2)
98 (25.6)
285 (74.4)
48.2 (10.8)
383
<5%
Weight
Loss
124.0 (14.6)
78.6 (9.0)
106.4 (7.9)
163.9 (16.6)
5.9 (0.5)
25.8 (15.4)
6.8 (4.3)
357 (55.8)
36 (5.6)
247 (38.6)
52 (12.6)
25 (3.9)
4.4 (4.3)
3.8 (4.5)
0.81 (0.10)
333 (53.2)
131 (20.9)
127 (20.3)
35 (5.6)
426 (66.7)
93.2 (20.3)
33.4 (6.5)
104.4 (14.4)
112.8 (13.5)
0.93 (0.09)
162 (25.3)
309 (48.3)
169 (26.4)
380 (59.4)
90 (14.1)
107 (16.7)
28 (4.4)
35 (5.5)
228 (35.6)
412 (64.4)
52.3 (11.3)
640
>5%
Weight
Loss
Intensive Lifestyle
Intervention
Appendix Table. Baseline Characteristics of Participants With <5% Versus ≥5% Weight Loss in the First Year
0.185
0.74
0.44
0.40
0.39
0.062
0.090
0.006
0.057
0.136
0.005
0.015
0.021
0.019
0.130
0.174
0.013
0.097
0.002
0.112
0.75
<0.001
<0.001
0.001
—
P Value*
123.6 (14.5)
78.2 (9.0)
106.6 (8.4)
164.5 (17.2)
5.9 (0.5)
26.7 (15.4)
7.09 (4.29)
527 (59.3)
59 (6.6)
303 (34.1)
99 (16.3)
36 (4.0)
4.6 (4.7)
4.0 (5.2)
0.80 (0.10)
494 (56.5)
161 (18.4)
180 (20.6)
39 (4.5)
621 (69.9)
94.2 (20.2)
34.1 (6.8)
105.2 (14.2)
114.3 (14.8)
0.92 (0.08)
237 (26.7)
419 (47.1)
233 (26.2)
477 (53.7)
183 (20.6)
134 (15.1)
54 (6.1)
41 (4.6)
282 (31.7)
607 (68.3)
50.5 (10.4)
889
<5%
Weight
Loss
0.45
0.134
0.90
0.95
0.84
0.66
0.65
0.36
0.26
0.59
0.63
0.97
0.002
0.97
0.600
0.73
0.54
0.99
0.43
0.134
0.42
0.22
0.84
0.40
—
P Value*
Continued on following page
122.6 (14.4)
76.9 (10.2)
106.7 (8.2)
164.4 (16.9)
5.9 (0.5)
26.1 (13.9)
6.91 (3.73)
73 (53.3)
21 (15.3)
43 (31.4)
12 (12.1)
9 (6.6)
4.8 (4.6)
3.8 (4.3)
0.80 (0.10)
75 (55.6)
21 (15.6)
34 (25.2)
5 (3.7)
95 (69.3)
94.9 (20.2)
34.5 (6.0)
105.2 (14.1)
115.4 (12.2)
0.91 (0.08)
37 (27)
71 (51.8)
29 (21.2)
85 (62)
22 (16.1)
22 (16.1)
4 (2.9)
4 (2.9)
38 (27.7)
99 (72.3)
50.3 (9.8)
137
>5%
Weight
Loss
Placebo
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Annals of Internal Medicine • Vol. 170 No. 10 • 21 May 2019
31.5 (25.8)
2397 (1625)
911 (615)
778 (240)
553 (30–10 286)
55.7 (45.4)
54.7 (51.4–58.1)
25.9 (24.0–28.0)
Sex hormones
Mean FSH level (SD) in women, mIU/L
Mean DHEA level (SD), ng/mL
Mean DHEA-S level (SD), ng/mL
Mean androstenedione level (SD) in men, pg/mL
Geometric mean testosterone level (95% CI), pg/mL§
Mean SHBG level (SD), nmol/L
Geometric mean estrone level (95% CI), pg/mL§
Geometric mean estradiol level (95% CI), pg/mL§
35.9 (27.5)
2397 (1454)
911 (695)
815 (295)
473 (27–8123)
58.3 (44.0)
51.0 (45.6–56.9)
24.5 (21.7–27.7)
8.5 (3.4)
380.0 (81.3)
2.2 (1.7)
11.0 (4.1)
0.29 (0.04–2.31)
22.5 (13.4)
44.8 (16.2)
154.0 (102.8)
253.5 (82.5)
201.4 (34.3)
123.4 (31.6)
45.9 (11.1)
139.6 (51.7–377.2)
>5%
Weight
Loss
Metformin
0.090
0.99
0.99
0.27
0.172
0.44
0.28
0.45
0.018
0.83
0.029
0.38
0.009
0.105
0.180
0.88
0.36
0.50
0.53
0.68
0.89
P Value*
28.4 (25.8)
2543 (1558)
996 (683)
789 (283)
424 (29–6119)
54.7 (41.2)
63.3 (18.8–213)
28.7 (4.03–204)
7.7 (3.6)
385.7 (87.4)
2.6 (2.1)
11.6 (4.3)
0.41 (0.05–3.01)
26.7 (15)
45.8 (17.3)
148.6 (71.6)
253.3 (87.5)
203.3 (36.0)
124.7 (32.0)
46.5 (13.1)
138.7 (50.2–382.9)
<5%
Weight
Loss
32.9 (28.5)
2552 (1854)
919 (656)
773 (267)
556 (28–11 188)
55.2 (39.8)
51.29 (14.3–183)
22.9 (3.5–149.8)
8.2 (3.5)
385.7 (85.0)
2.4 (2.2)
11.2 (4.3)
0.32 (0.04–2.55)
21.8 (13.7)
44.7 (17.6)
145.2 (50.8)
246.4 (71.1)
204.6 (37.2)
125.5 (32.9)
45.9 (11.9)
142.5 (50.5–402.0)
>5%
Weight
Loss
Intensive Lifestyle
Intervention
0.068
0.94
0.094
0.65
0.010
0.87
<0.001
<0.001
0.056
0.99
0.100
0.25
<0.001
<0.001
0.36
0.37
0.167
0.59
0.71
0.46
0.42
P Value*
32.3 (28.8)
2480 (1665)
909 (599)
785 (265)
460 (27–7893)
55.1 (43.4)
54.1 (15.6–187)
24.6 (3.55–170)
7.7 (3.2)
385.4 (86.4)
2.5 (2.1)
11.5 (4.1)
0.35 (0.04–2.97)
24.5 (14.1)
47.3 (19.6)
148.5 (61.4)
247.6 (76.1)
203.1 (37.6)
124.6 (34.3)
44.9 (11.5)
147.0 (55.3–391.1)
<5%
Weight
Loss
36.5 (27.6)
2637 (2048)
998 (733)
851.8 (389)
359 (26–4920)
51.3 (36.2)
64.5 (18.3–226.8)
29.3 (3.6–238)
8.2 (4.0)
394.8 (81.7)
2.4 (1.5)
10.9 (3.4)
0.43 (0.06–3.33)
24.9 (13.4)
45.2 (18.3)
159.6 (172.0)
256.5 (77.9)
200.3 (32.5)
119.9 (29.3)
44.2 (11.5)
156.4 (55.1–443.8)
>5%
Weight
Loss
Placebo
0.25
0.38
0.136
0.20
0.082
0.35
0.132
0.081
0.112
0.234
0.66
0.132
0.034
0.72
0.25
0.161
0.21
0.41
0.130
0.49
0.182
P Value*
BMI = body mass index; CRP = C-reactive protein; DHEA = dehydroepiandrosterone; DHEA-S = dehydroepiandrosterone sulfate; FSH = follicle-stimulating hormone; HDL = high-density
lipoprotein; HOMA-IR = homeostasis model assessment of insulin resistance; IL-6 = interleukin-6; LDL = low-density lipoprotein; MCP-1 = monocyte chemoattractant protein; SF-6D = SixDimensional Health State Short Form; SHBG = sex hormone binding globulin; sICAM = soluble intercellular adhesion molecule; tPA = tissue plasminogen activator.
* Boldface values are statistically significant.
† Some participants were unable or declined to answer some questions at baseline; percentages are among respondents only.
‡ Among parous women only.
§ Nonnormally distributed data. P values are based on log-transformed values.
7.9 (3.5)
378.8 (86.6)
2.5 (2.4)
11.3 (4.4)
0.35 (0.04–3.07)
24.2 (15.4)
46.4 (17.8)
152.8 (112.7)
248.5 (75.8)
203.1 (35.7)
124.8 (32.3)
46.2 (11.7)
139.00 (50.6–381.9)
<5%
Weight
Loss
Adipocytokines/chemokines
Mean adiponectin level (SD), μg/mL
Mean fibrinogen level (SD), mg/dL
Mean IL-6 level (SD), pg/mL
Mean tPA level (SD), ng/mL
Geometric mean CRP level (95% CI), mg/dL§
Mean leptin level (SD), ng/mL
Mean e-selectin level (SD), ng/mL
Mean MCP-1 level (SD), pg/mL
Mean sICAM level (SD), ng/mL
Lipids
Mean total cholesterol level (SD), mg/dL
Mean LDL cholesterol level (SD), mg/dL
Mean HDL cholesterol level (SD), mg/dL
Geometric mean triglyceride level (95% CI), mg/dL§
Variable
Appendix Table—Continued
Appendix Figure 2. Study flow diagram.
Randomly assigned in
the DPP (n = 3234)
Metformin (n = 1073)
ILS (n = 1079)
Placebo (n = 1082)
Missing year-1 weight (n = 59)
Missing year-1 weight (n = 56)
Missing year-1 weight (n = 56)
Available
for analysis (n = 1014)
Available
for analysis (n = 1023)
Available
for analysis (n = 1026)
Lost <5% by year 1
(n = 725)
Lost ≥5% by year 1
(n = 289)
Lost <5% by year 1
(n = 383)
Year 1 (n = 289)
Receiving study metformin: 275
Receiving PCP metformin: 0
Year 5 (n = 247)
Receiving study metformin: 199
Receiving PCP metformin: 0
Year 10 (n = 236)
Receiving study metformin: 171
Receiving PCP metformin: 10
Year 15 (n = 172)
Receiving study metformin: 113
Receiving PCP metformin: 18
Lost ≥5% by year 1
(n = 640)
Year 1 (n = 640)
Receiving PCP metformin: 0
Year 5 (n = 540)
Receiving PCP metformin: 8
Year 10 (n = 491)
Receiving PCP metformin: 59
Year 15 (n = 373)
Receiving PCP metformin: 90
Lost <5% by year 1
(n = 889)
Lost ≥5% by year 1
(n = 137)
Year 1 (n = 137)
Receiving PCP metformin: 0
Year 5 (n = 110)
Receiving PCP metformin: 4
Year 10 (n = 104)
Receiving PCP metformin: 21
Year 15 (n = 92)
Receiving PCP metformin: 26
Participants discontinued DPP and DPPOS visits for various reasons, including loss to follow-up, health and mobility issues, and death. DPP =
Diabetes Prevention Program; DPPOS = Diabetes Prevention Program Outcomes Study; ILS = intensive lifestyle intervention; PCP = primary care
provider.
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