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Volume 60, Issue 5
1 May 2011

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 * RESEARCH DESIGN AND METHODS
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Pathophysiology| April 23 2011


EFFECTS OF ROSIGLITAZONE, GLYBURIDE, AND METFORMIN ON Β-CELL FUNCTION AND
INSULIN SENSITIVITY IN ADOPT

Steven E. Kahn;
Steven E. Kahn
1Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, VA
Puget Sound Health Care System and University of Washington, Seattle, Washington
Corresponding author: Steven E. Kahn, skahn@u.washington.edu.
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John M. Lachin;
John M. Lachin
2Biostatistics Center, George Washington University, Rockville, Maryland
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Bernard Zinman;
Bernard Zinman
3Samuel Lunenfeld Research Institute, Mount Sinai Hospital and University of
Toronto, Ontario, Canada
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Steven M. Haffner;
Steven M. Haffner
4San Antonio Texas
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R. Paul Aftring;
R. Paul Aftring
5GlaxoSmithKline, King of Prussia, Pennsylvania
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Gitanjali Paul;
Gitanjali Paul
5GlaxoSmithKline, King of Prussia, Pennsylvania
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Barbara G. Kravitz;
Barbara G. Kravitz
5GlaxoSmithKline, King of Prussia, Pennsylvania
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William H. Herman;
William H. Herman
6Departments of Internal Medicine and Epidemiology, University of Michigan, Ann
Arbor, Michigan
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Giancarlo Viberti;
Giancarlo Viberti
7King’s College London School of Medicine, King’s College London, London, U.K.
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Rury R. Holman;
Rury R. Holman
8Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism,
Oxford University, Oxford, U.K.
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and the ADOPT Study Group
and the ADOPT Study Group
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Corresponding author: Steven E. Kahn, skahn@u.washington.edu.
1

*A complete list of the ADOPT Study Group can be found in N Engl J Med
2006;355:2427–2443.

Diabetes 2011;60(5):1552–1560
https://i646f69o6f7267z.oszar.com/10.2337/db10-1392
Article history
Received:
October 18 2010
Accepted:
February 08 2011
PubMed:
21415383

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Citation

Steven E. Kahn, John M. Lachin, Bernard Zinman, Steven M. Haffner, R. Paul
Aftring, Gitanjali Paul, Barbara G. Kravitz, William H. Herman, Giancarlo
Viberti, Rury R. Holman, and the ADOPT Study Group; Effects of Rosiglitazone,
Glyburide, and Metformin on β-Cell Function and Insulin Sensitivity in ADOPT.
Diabetes 1 May 2011; 60 (5): 1552–1560.
https://i646f69o6f7267z.oszar.com/10.2337/db10-1392

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OBJECTIVE

ADOPT (A Diabetes Outcome Progression Trial) demonstrated that initial
monotherapy with rosiglitazone provided superior durability of glycemic control
compared with metformin and glyburide in patients with recently diagnosed type 2
diabetes. Herein, we examine measures of β-cell function and insulin sensitivity
from an oral glucose tolerance test (OGTT) over a 4-year period among the three
treatments.

RESEARCH DESIGN AND METHODS

Recently diagnosed, drug-naïve patients with type 2 diabetes (4,360 total) were
treated for a median of 4.0 years with rosiglitazone, metformin, or glyburide
and were examined with periodic metabolic testing using an OGTT.

RESULTS

Measures of β-cell function and insulin sensitivity from an OGTT showed more
favorable changes over time with rosiglitazone versus metformin or glyburide.
Persistent improvements were seen in those who completed 4 years of monotherapy
and marked deterioration of β-cell function in those who failed to maintain
adequate glucose control with initial monotherapy.

CONCLUSIONS

The favorable combined changes in β-cell function and insulin sensitivity over
time with rosiglitazone appear to be responsible for its superior glycemic
durability over metformin and glyburide as initial monotherapy in type 2
diabetes.



In the UK Prospective Diabetes Study (UKPDS), a progressive decline in β-cell
function was the major determinant of loss of glycemic control over time in type
2 diabetes (1). However, differential effects of diet, sulfonylurea, and
metformin on insulin sensitivity and β-cell function did not yield substantive
differences in the rates of increase in glycated hemoglobin (1).

Subsequently, thiazolidinediones were introduced that primarily improve insulin
sensitivity in the peripheral tissues (2), while also affecting β-cell function
by reducing the demand to synthesize and release insulin. In contrast, the
biguanide metformin acts primarily to reduce hepatic glucose production, whereas
the sulfonylureas stimulate insulin release by binding to their receptor on the
β-cell (2).

Given these different mechanisms of action, A Diabetes Outcome Progression Trial
(ADOPT) was designed to assess whether initial monotherapy with the
thiazolidinedione rosiglitazone could slow the rate of decline of β-cell
function in type 2 diabetes and associated loss-of-glucose control, relative to
metformin or sulfonylurea (glyburide) (3). In ADOPT, rosiglitazone provided
lower rates of monotherapy failure and lower levels of fasting plasma glucose
and glycated hemoglobin, yielding superior durability of glycemic control than
metformin or glyburide (4).

Measures of insulin sensitivity and β-cell function determined from fasting and
30-min samples during an oral glucose tolerance test (OGTT) allowed examination
of mechanisms by which each agent affected glycemic outcomes. Herein, changes
over time for these measures are compared among the three treatment groups in
the full cohort and separately among those who either successfully completed or
failed initially assigned monotherapy over a period of 4 years. Joint vector
plots are used to display concomitant changes in secretory response and insulin
sensitivity over time with each therapy.


RESEARCH DESIGN AND METHODS




SUBJECTS.

ADOPT, a randomized, double-blind, parallel-group trial, enrolled 4,360
individuals with type 2 diabetes of up to 3 years’ duration who were drug-naïve
for glucose-lowering therapy (3). The protocol was approved by institutional
review boards for each center, and subjects gave written, informed consent to
participate in the study.

Subjects were randomly assigned to double-blind, twice-daily treatment with
rosiglitazone (n = 1,456), metformin (n = 1,454), or glyburide (n = 1,441) as
initial monotherapy; nine subjects never received study medication. Medications
were titrated, if fasting plasma glucose levels were 7.8 mmol/L or more, to a
maximum of 8 mg/day, 2 g/day, and 15 mg/day, respectively. Dose reductions were
permitted if adverse events occurred. The primary outcome was the time to
monotherapy failure on maximum-tolerated study drug dose, defined as a fasting
plasma glucose >10 mmol/L on two successive occasions or by independent
adjudication (3).

Analyses were performed in the full cohort and separately in those who completed
their metabolic assessments at 4 years (4-year completer cohort) and those who
failed monotherapy before 4 years (monotherapy failure cohort).


METHODS.

Assessments were performed using standardized procedures at baseline and then
every 6 months for the duration of the study (3). Fasting blood samples were
drawn for measurement of metabolic variables, including plasma glucose, HbA1c,
and immunoreactive insulin levels. An abbreviated 75-g OGTT measuring glucose
and immunoreactive insulin levels before and 30 min after glucose ingestion was
performed at baseline and then every 6 months for the duration of the study.


ASSAYS AND CALCULATIONS.

All assays were performed at a central laboratory (3).

Insulin sensitivity and the insulin response obtained from the OGTT were the
inverse of the fasting insulin concentration and the insulinogenic index,
respectively (5)—the latter a dynamic measure calculated as the ratio of the
incremental insulin and glucose responses over the first 30 min of the test
(insulin30 – insulin0/glucose30 – glucose0). Homeostasis model assessment (HOMA)
%S and HOMA %B were estimated using the HOMA2 model calculator
(http://i777777o647475o6f78o6163o756bz.oszar.com/homa) (6).

Metabolic assessments were not conducted after subjects reached monotherapy
failure or withdrew from study medication. Thus treatment group differences in
these measures over time may be influenced by the successive culling of subjects
reaching monotherapy failure. Thus sensitivity analyses assessed the potential
impact of bias.


STATISTICAL METHODS.

Of the 25,196 insulinogenic index values obtained through the 4-year visit, 768
(3.05%) were ≤0. Although mathematically possible, such values are currently
considered biologically implausible and were treated as missing values. These
implausible responses were observed in 637 subjects (average of 1.17 per such
subject), of which 156 had a response ≤0 at baseline necessitating their
exclusion from the longitudinal analyses. Of the 768 values, the median value
was −9.81, 25% were <−1.34, 5% were <−152, and 1% was <−1,021, and the minimum
was −5,880. Finally, no association was observed between the fasting glucose
concentration and values ≤0.

Wilcoxon rank sum test compared baseline variables between groups for
quantitative variables, and the contingency χ2 test for qualitative variables
(7). Normal errors longitudinal linear models (8) were used to estimate mean
levels of the parameters over time within groups up to 4 years of follow-up
using all available data. Mean change from baseline to 6 months described the
immediate impact of a therapy on outcomes. The average rate of change from 6
months to 4 years was estimated from a linear contrast of the model-estimated
means over time.

Analyses of the reciprocal fasting insulin and insulinogenic index used the
natural log transformation to better approximate a normal distribution for
errors and homoscedasticity of variances, with the results presented as
geometric means ± SE asymmetric limits, the latter obtained as exp(means ± SE of
the log values). For these variables, mean percent change over 6 months and mean
percent change per year from 6 months to 4 years are presented.

However, the longitudinal model results could be biased because subjects with
the most rapid decline in these metabolic measures (i.e., the steepest slopes)
have a shorter time to monotherapy failure and, therefore, contribute fewer
observations to estimation of the rate of change over time in the cohort. In
this setting, an unweighted average of the subject-specific slopes provides a
less biased estimate of the overall rate of change (9).

A two-sided P ≤ 0.05 was considered statistically significant.


RESULTS




DEMOGRAPHIC AND METABOLIC VARIABLES.

Table 1 presents the baseline values for all 4,351 patients, the 2,112 who
completed 4 years of follow-up, and the 526 who failed monotherapy before 4
years, of whom 11% were followed for less than 1 year, 25% for 1–2 years, 30%
for 2–3 years, 24% for 3–4 years, and 10% for 4 years or more. The monotherapy
failure cohort was younger, more obese, and initially had a greater waist
circumference, higher mean fasting plasma glucose and HbA1c levels, and a lower
systolic blood pressure than those completing 4 years on study medication. They
also had lower median β-cell function scores at baseline, determined as the
insulinogenic index and HOMA %B.

TABLE 1

Baseline demographic and metabolic variables in the full cohort, those
completing 4 years, and those with monotherapy failure before 4 years

. All
subjects . 4-Year
completer cohort . 4-Year monotherapy
failure cohort . P
value
4-Year completers
vs. monotherapy
failures . n 4,351 2,112 526  Age
(years) 56.5 ± 10.0 58.0 ± 9.4 52.2 ± 9.7 <0.025 Males (n, %) 2,511 (57.7) 1,251
(59.2) 321 (61.0) N.S. Time since diagnosis of diabetes (years)      <1 1,961
(4.1) 929 (44.0) 237 (45.1) N.S.  1–2 2,233 (51.3) 1,100 (52.1) 274
(52.1) N.S.  >2 157 (3.6) 83 (3.9) 15 (2.9) N.S. GAD-positive 175 (4.0) 92
(4.4) 25 (4.8) N.S. BMI (kg/m2) 32.2 ± 6.3 31.8 ± 6.0 33.2 ± 6.4 <0.025 Waist
circumference (cm) 105.5 ± 14.7 104.8 ± 13.7 108.0 ± 16.1 <0.025 Waist-to-hip
ratio 0.95 ± 0.09 0.95 ± 0.09 0.96 ± 0.09 N.S. Blood pressure
(mmHg)      Systolic 132.9 ± 15.5 133.3 ± 15.4 131.1 ±
15.9 <0.025  Diastolic 79.6 ± 8.8 79.3 ± 8.6 79.7 ± 9.2 N.S. Fasting plasma
glucose (mmol/L) 8.4 ± 1.5 8.2 ± 1.3 9.1 ± 1.7 <0.025 HbA1c (%) 7.4 ± 0.9 7.2 ±
0.9 7.7 ± 1.0 <0.025 Fasting insulin (pmol/L) 150.7 ± 111.0
122.0 (84.0,
186.0) 147.9 ± 113.2
120.0 (84.0, 179.4) 148.5 ± 100.4
126.0 (84.0,
186.0) N.S. 1/Fasting insulin (pmol/L−1 × 10−3) 8.20 (5.38, 11.90) 8.33 (5.57,
11.90) 7.94 (5.38, 11.90) N.S. HOMA %S 33.4 (22.6–48.2) 34.6 (23.5–49.4) 31.5
(21.8–47.7) N.S. Insulinogenic index (pmol/L per mmol/L) 32.0 (17.9, 57.4) 33.2
(19.2, 58.9) 26.1 (12.5, 47.7) <0.025 HOMA %B 68.4 (52.0–88.3) 70.4
(53.4–90.4) 60.3 (44.5–79.7) <0.025 

. All
subjects . 4-Year
completer cohort . 4-Year monotherapy
failure cohort . P
value
4-Year completers
vs. monotherapy
failures . n 4,351 2,112 526  Age
(years) 56.5 ± 10.0 58.0 ± 9.4 52.2 ± 9.7 <0.025 Males (n, %) 2,511 (57.7) 1,251
(59.2) 321 (61.0) N.S. Time since diagnosis of diabetes (years)      <1 1,961
(4.1) 929 (44.0) 237 (45.1) N.S.  1–2 2,233 (51.3) 1,100 (52.1) 274
(52.1) N.S.  >2 157 (3.6) 83 (3.9) 15 (2.9) N.S. GAD-positive 175 (4.0) 92
(4.4) 25 (4.8) N.S. BMI (kg/m2) 32.2 ± 6.3 31.8 ± 6.0 33.2 ± 6.4 <0.025 Waist
circumference (cm) 105.5 ± 14.7 104.8 ± 13.7 108.0 ± 16.1 <0.025 Waist-to-hip
ratio 0.95 ± 0.09 0.95 ± 0.09 0.96 ± 0.09 N.S. Blood pressure
(mmHg)      Systolic 132.9 ± 15.5 133.3 ± 15.4 131.1 ±
15.9 <0.025  Diastolic 79.6 ± 8.8 79.3 ± 8.6 79.7 ± 9.2 N.S. Fasting plasma
glucose (mmol/L) 8.4 ± 1.5 8.2 ± 1.3 9.1 ± 1.7 <0.025 HbA1c (%) 7.4 ± 0.9 7.2 ±
0.9 7.7 ± 1.0 <0.025 Fasting insulin (pmol/L) 150.7 ± 111.0
122.0 (84.0,
186.0) 147.9 ± 113.2
120.0 (84.0, 179.4) 148.5 ± 100.4
126.0 (84.0,
186.0) N.S. 1/Fasting insulin (pmol/L−1 × 10−3) 8.20 (5.38, 11.90) 8.33 (5.57,
11.90) 7.94 (5.38, 11.90) N.S. HOMA %S 33.4 (22.6–48.2) 34.6 (23.5–49.4) 31.5
(21.8–47.7) N.S. Insulinogenic index (pmol/L per mmol/L) 32.0 (17.9, 57.4) 33.2
(19.2, 58.9) 26.1 (12.5, 47.7) <0.025 HOMA %B 68.4 (52.0–88.3) 70.4
(53.4–90.4) 60.3 (44.5–79.7) <0.025 

Continuous data are expressed as means ± SD and/or median (first, third
quartile). For time since diagnosis of diabetes and GAD-positive, data are n
(%). P values were adjusted for two comparisons using the Bonferroni method.
HOMA %S and HOMA %B were determined using the HOMA calculator
(www.dtu.ox.ac.uk/homa). N.S., nonsignificant.

View Large

Only patients with a baseline and follow-up evaluation of each outcome measure
(insulinogenic index and reciprocal fasting insulin) contributed data to the
longitudinal analyses of that measure described below. The longitudinal analyses
of the HOMA values are not presented because they have been published previously
(4).


EARLY INSULIN RESPONSE (INSULINOGENIC INDEX) FOR THE FULL COHORT.

The longitudinal model estimated mean insulinogenic index over up to 4 years of
follow-up within each treatment group for the full cohort is presented in Fig.
1A. Table 2 shows the short-term (acute) effect of therapy characterized as the
mean percent change from baseline to 0.5 years and the long-term (chronic)
effect characterized as the rate of change (percent per year) from 0.5 to 4
years. The longitudinal analysis of the log values provides estimates of the
percent change over time.

FIG. 1.
View largeDownload slide

Baseline adjusted geometric mean levels in the full cohort within each treatment
group over 4 years of follow-up for OGTT-derived dynamic measure of the early
insulin response (A; insulinogenic index; insulin30 − insulin0/glucose30 −
glucose0) and insulin sensitivity (B; 1/fasting insulin). Each was analyzed
using the log-transformed values, and the results presented are geometric means
(± SE asymmetric limits).

FIG. 1.
View largeDownload slide

Baseline adjusted geometric mean levels in the full cohort within each treatment
group over 4 years of follow-up for OGTT-derived dynamic measure of the early
insulin response (A; insulinogenic index; insulin30 − insulin0/glucose30 −
glucose0) and insulin sensitivity (B; 1/fasting insulin). Each was analyzed
using the log-transformed values, and the results presented are geometric means
(± SE asymmetric limits).

Close modal
TABLE 2

Changes in OGTT-derived measures of β-cell function (insulinogenic index) and
insulin sensitivity (1/fasting insulin) for the full cohort from baseline to 0.5
years and rates of change among means from 0.5 to 4 years based on a
longitudinal model adjusted for baseline factors

Variable . Rosiglitazone . Metformin . Glyburide . P value

--------------------------------------------------------------------------------

. Rosiglitazone vs. metformin . Rosiglitazone vs. glyburide . Insulinogenic
index (pmol/L per mmol/L)  n 1,125 1,124 1,060 — —  Mean %change from 0 to 0.5
years 0.0 (−3.9, 4.1) 2.5 (−1.5, 6.7) 6.6 (2.3, 11.1) 0.3826 0.0249  Rate of
change from 0.5 to 4 years (% per year) −6.0 (−7.2, −4.8) −7.4 (−8.5,
−6.2) −11.1 (−12.3, −9.8) 0.1133 <0.0001  Unweighted mean slope (% per
year) −8.0 (−9.5, −6.4) −8.8 (−10.3, −7.2) −13.2 (−15.0,
−11.4) 0.4798 <0.0001 1/Fasting insulin (pmol/L−1 ×
10−3)  n 1,255 1,256 1,187 — —  Mean %change from 0 to 0.5 years 25.7 (22.8,
28.7) 13.5 (10.9, 16.2) −9.2 (−11.4, −7.0) <0.0001 <0.0001  Rate of change from
0.5 to 4 years (% per year) 6.5 (5.8, 7.2) 5.9 (5.2, 6.7) 5.5 (4.7,
6.3) 0.2898 0.0822  Unweighted mean slope (% per year) 6.9 (6.1, 7.8) 5.3 (4.4,
6.3) 5.2 (4.1, 6.2) 0.0176 0.0128 

Variable . Rosiglitazone . Metformin . Glyburide . P value

--------------------------------------------------------------------------------

. Rosiglitazone vs. metformin . Rosiglitazone vs. glyburide . Insulinogenic
index (pmol/L per mmol/L)  n 1,125 1,124 1,060 — —  Mean %change from 0 to 0.5
years 0.0 (−3.9, 4.1) 2.5 (−1.5, 6.7) 6.6 (2.3, 11.1) 0.3826 0.0249  Rate of
change from 0.5 to 4 years (% per year) −6.0 (−7.2, −4.8) −7.4 (−8.5,
−6.2) −11.1 (−12.3, −9.8) 0.1133 <0.0001  Unweighted mean slope (% per
year) −8.0 (−9.5, −6.4) −8.8 (−10.3, −7.2) −13.2 (−15.0,
−11.4) 0.4798 <0.0001 1/Fasting insulin (pmol/L−1 ×
10−3)  n 1,255 1,256 1,187 — —  Mean %change from 0 to 0.5 years 25.7 (22.8,
28.7) 13.5 (10.9, 16.2) −9.2 (−11.4, −7.0) <0.0001 <0.0001  Rate of change from
0.5 to 4 years (% per year) 6.5 (5.8, 7.2) 5.9 (5.2, 6.7) 5.5 (4.7,
6.3) 0.2898 0.0822  Unweighted mean slope (% per year) 6.9 (6.1, 7.8) 5.3 (4.4,
6.3) 5.2 (4.1, 6.2) 0.0176 0.0128 

For the log-transformed insulinogenic index and reciprocal fasting insulin,
results are presented as a percentage change from baseline and mean rates of
change (percent per year) ± 95% confidence limits. The unweighted mean rate of
change (mean slopes) over 0.5 to 4 years are also listed. Changes from baseline,
or rates of change, for which the 95% confidence limits do not bracket zero are
statistically significantly different at the 0.05 level, without adjustment for
multiple tests of significance.

View Large

A significantly higher acute change in the insulinogenic index over the first 6
months was observed with glyburide versus rosiglitazone, with there being no
change with rosiglitazone and an intermediate change with metformin. Thereafter,
glyburide was associated with a significantly faster rate of decline (negative
slope) versus rosiglitazone (11.1 vs. 6.0% per year), with metformin as the
intermediate. The different rates of decline meant that, beyond 24 months, the
mean levels with glyburide were lower than those in the other groups. The
unweighted mean slope analysis demonstrated similar differences between groups.


INSULIN SENSITIVITY (1/FASTING INSULIN) FOR THE FULL COHORT.

Figure 1B presents the longitudinal model estimated mean reciprocal fasting
insulin from the OGTT over time for 4 years of follow-up within each treatment
group for the full cohort. Table 2 shows the short- and long-term effects of
therapy on this measure.

Rosiglitazone produced a significantly greater increase over the first 6 months
in the reciprocal fasting insulin than did either comparator, with glyburide
initially decreasing by 9.2% over this period. This ratio then increased over
time in all groups with no significant differences between groups. However, the
unweighted analysis showed a significantly greater increase over time with
rosiglitazone than either comparator, suggesting that the lesser differences
between groups observed in the longitudinal model analysis could be attributed
to the effects of early termination of follow-up because of monotherapy failure.


OGTT MEASURES IN THE 4-YEAR COMPLETER COHORT.

Among those in the completer cohort, Fig. 2A and Table 3 indicate that the
insulinogenic index did not increase substantially over the first 6 months and
then declined at a significantly faster rate with glyburide than with
rosiglitazone.

FIG. 2.
View largeDownload slide

Baseline adjusted geometric mean levels in the 4-year completer cohort within
each treatment group over 4 years of follow-up for OGTT-derived dynamic measure
of the early insulin response (A; insulinogenic index; insulin30 −
insulin0/glucose30 − glucose0) and insulin sensitivity (B; 1/fasting insulin).
Each was analyzed using the log-transformed values, and the results presented
are geometric means (± SE asymmetric limits).

FIG. 2.
View largeDownload slide

Baseline adjusted geometric mean levels in the 4-year completer cohort within
each treatment group over 4 years of follow-up for OGTT-derived dynamic measure
of the early insulin response (A; insulinogenic index; insulin30 −
insulin0/glucose30 − glucose0) and insulin sensitivity (B; 1/fasting insulin).
Each was analyzed using the log-transformed values, and the results presented
are geometric means (± SE asymmetric limits).

Close modal
TABLE 3

Changes in OGTT-derived measures of β-cell function (insulinogenic index) and
insulin sensitivity (1/fasting insulin) for the 4-year completer and monotherapy
failure cohorts from baseline to 0.5 years and rates of change among means from
0.5 to 4 years based on a longitudinal model adjusted for baseline factors

Variable . 4-Year completer cohort

--------------------------------------------------------------------------------

. 4-Year monotherapy failure cohort

--------------------------------------------------------------------------------

. Rosiglitazone . Metformin . Glyburide . Rosiglitazone . Metformin . Glyburide
. Insulinogenic index (pmol/L per mmol/L)  n 691 671 512 93 128 215  Mean
%change from 0 to 0.5 years 0.2 (−4.5, 5.2) 5.2 (0.2, 10.5) 4.2 (−1.5,
10.1) −8.0 (−21.5, 7.9) 8.3 (−5.3, 24.0) 13.5* (2.2, 25.9)  Rate of change from
0.5 to 4 years   (% per year) −5.3 (−6.6, −4.0) −6.6 (−7.9, −5.4) −10.6* (−12.0,
−9.2) −20.0 (−27.2, −12.2) −16.9 (−22.9, −10.6) −19.9 (−25.1, −14.4) 1/Fasting
insulin (pmol/L−1 × 10−3)  n 756 730 555 108 153 244  Mean %change from 0 to 0.5
years 26.1 (22.5, 29.8) 14.5* (11.2, 17.9) −5.2* (−8.3, −1.9) 20.1 (11.3,
29.6) 3.6* (−2.8, 10.4) −13.5* (−17.8, −9.0)  Rate of change from 0.5 to 4 years
(% per year) 6.6 (5.8, 7.4) 6.0 (5.2, 6.8) 5.4* (4.4, 6.3) 4.5 (0.0, 9.3) 5.9
(2.8, 9.2) 4.6 (1.3, 8.0) 

Variable . 4-Year completer cohort

--------------------------------------------------------------------------------

. 4-Year monotherapy failure cohort

--------------------------------------------------------------------------------

. Rosiglitazone . Metformin . Glyburide . Rosiglitazone . Metformin . Glyburide
. Insulinogenic index (pmol/L per mmol/L)  n 691 671 512 93 128 215  Mean
%change from 0 to 0.5 years 0.2 (−4.5, 5.2) 5.2 (0.2, 10.5) 4.2 (−1.5,
10.1) −8.0 (−21.5, 7.9) 8.3 (−5.3, 24.0) 13.5* (2.2, 25.9)  Rate of change from
0.5 to 4 years   (% per year) −5.3 (−6.6, −4.0) −6.6 (−7.9, −5.4) −10.6* (−12.0,
−9.2) −20.0 (−27.2, −12.2) −16.9 (−22.9, −10.6) −19.9 (−25.1, −14.4) 1/Fasting
insulin (pmol/L−1 × 10−3)  n 756 730 555 108 153 244  Mean %change from 0 to 0.5
years 26.1 (22.5, 29.8) 14.5* (11.2, 17.9) −5.2* (−8.3, −1.9) 20.1 (11.3,
29.6) 3.6* (−2.8, 10.4) −13.5* (−17.8, −9.0)  Rate of change from 0.5 to 4 years
(% per year) 6.6 (5.8, 7.4) 6.0 (5.2, 6.8) 5.4* (4.4, 6.3) 4.5 (0.0, 9.3) 5.9
(2.8, 9.2) 4.6 (1.3, 8.0) 

For the log-transformed insulinogenic index and reciprocal fasting insulin,
results presented as a percent change from baseline and mean rates of change
(percent per year) ± 95% confidence limits. Changes from baseline, or rates of
change, for which the 95% confidence limits do not bracket zero are
statistically significantly different at the 0.05 level, without adjustment for
multiple tests of significance.

*P < 0.05 for metformin or glyburide vs. rosiglitazone.

View Large

The pattern of changes in insulin sensitivity is shown in Fig. 2B and Table 3.
The pattern in the completers was similar to that in the full cohort. There was
a significantly greater improvement at 6 months with rosiglitazone than with
either glyburide or metformin, and thereafter, there was also a significantly
greater rate of increase over time with rosiglitazone than with glyburide, with
those with metformin being intermediate.


OGTT MEASURES IN THE 4-YEAR MONOTHERAPY FAILURE COHORT.

Subjects who ultimately failed had lower levels of the insulinogenic index at
baseline (Fig. 3A) than those who completed (Fig. 2A). Glyburide produced a
small increase at 6 months, whereas rosiglitazone had little effect (Fig. 3A and
Table 3). Thereafter, the insulinogenic index declined, equally so in all
groups.

FIG. 3.
View largeDownload slide

Baseline adjusted geometric mean levels in the 4-year monotherapy failure cohort
within each treatment group over 4 years of follow-up for OGTT-derived dynamic
measure of the early insulin response (A; insulinogenic index; insulin30 −
insulin0/glucose30 − glucose0) and insulin sensitivity (B; 1/fasting insulin).
Each was analyzed using the log-transformed values, and the results presented
are geometric means (± SE asymmetric limits).

FIG. 3.
View largeDownload slide

Baseline adjusted geometric mean levels in the 4-year monotherapy failure cohort
within each treatment group over 4 years of follow-up for OGTT-derived dynamic
measure of the early insulin response (A; insulinogenic index; insulin30 −
insulin0/glucose30 − glucose0) and insulin sensitivity (B; 1/fasting insulin).
Each was analyzed using the log-transformed values, and the results presented
are geometric means (± SE asymmetric limits).

Close modal

Among failures, there was a much greater acute increase in 1/fasting insulin
with rosiglitazone than with either metformin or glyburide, but thereafter, the
rate of increase was similar among groups (Fig. 3B and Table 3). The failure
cohort started at approximately the same levels as the completer cohort, but the
increase with rosiglitazone was less. Thereafter, 1/fasting insulin increased
among failures at approximately the same rate as seen with completers.


VECTOR PLOTS OF OGTT MEASURES.

Figure 4A–C displays the concomitant changes over time in the relationship
between the insulinogenic index and 1/fasting insulin for the full, completer,
and monotherapy failure cohorts, respectively. This relationship depicts the
pattern of changes in glucose metabolism over time and is termed herein vector
plots.

FIG. 4.
View largeDownload slide

Vector plot of the joint changes in the baseline adjusted geometric mean levels
(± SE asymmetric limits) of the OGTT-derived dynamic measure of the early
insulin response (insulinogenic index; insulin30 − insulin0/glucose30 −
glucose0) and insulin sensitivity (1/fasting insulin) over time within each
treatment group over 4 years of follow-up in the full (A), 4-year completer (B),
and 4-year monotherapy failure (C) cohorts. The changes are plotted relative to
the regression line of the baseline levels (the concave line). The dots
represent the baseline measurements, that after 6 months and each annual
assessment thereafter, and the arrow the directional change with time. The 95%
confidence bands for the baseline relationship are illustrated. The SE limits
for the individual time points have been omitted for clarity.

FIG. 4.
View largeDownload slide

Vector plot of the joint changes in the baseline adjusted geometric mean levels
(± SE asymmetric limits) of the OGTT-derived dynamic measure of the early
insulin response (insulinogenic index; insulin30 − insulin0/glucose30 −
glucose0) and insulin sensitivity (1/fasting insulin) over time within each
treatment group over 4 years of follow-up in the full (A), 4-year completer (B),
and 4-year monotherapy failure (C) cohorts. The changes are plotted relative to
the regression line of the baseline levels (the concave line). The dots
represent the baseline measurements, that after 6 months and each annual
assessment thereafter, and the arrow the directional change with time. The 95%
confidence bands for the baseline relationship are illustrated. The SE limits
for the individual time points have been omitted for clarity.

Close modal

In each case, the concave line represents the known nonlinear relationship
between a measure of β-cell function and insulin sensitivity at baseline (10–12)
and is based on the linear regression between log-transformed insulinogenic
index and 1/fasting insulin values. The single dot on the line, which is the
origin for each vector, shows the common mean values for these two measures in
all three treatment groups, i.e., for the whole cohort, an insulinogenic index
of 33.1 pmol/L per mmol/L and a 1/fasting insulin of 8.2 pmol/l−1 × 10−3. This
point and each subsequent one is a measure of the joint action of insulin
sensitivity and β-cell function over time and is commonly known as the
disposition index (12). The overall mean is used because the baseline
covariate-adjusted longitudinal analyses presented in prior figures assume that
all groups start with a common baseline value.

Starting from this common point, joint geometric means for insulinogenic index
and 1/fasting insulin within each group are plotted for the first 6-month visit
and, thereafter, each annual anniversary visit. These are the same means as
presented separately in Figs. 1A and B, 2A and B, and 3A and B for the whole
4-year completer and 4-year monotherapy failure cohorts, respectively. Movement
of the joint mean values up or down represents changes in β-cell function, and
movement of the joint means left or right represents changes in insulin
sensitivity over time. Mean values remaining above the concave line represent
improvements in glucose metabolism from the level at baseline, whereas those
falling below the line represent deterioration in glucose metabolism.
Furthermore, the greater the movement away from the concave line, the larger the
difference in overall glucose metabolism.

In the full cohort (Fig. 4A), there was a small acute beneficial effect with
glyburide on the insulin response (shift upward) but a decrease in insulin
sensitivity (shift to the left), so that overall glucose metabolism was not
improved relative to the concave line. Thereafter, the insulinogenic index fell
(shift downward), whereas 1/fasting insulin increased (shift rightward), but at
a rate too slow to compensate for the loss in insulin response (hence, the
values remain below the baseline regression line). In contrast, with
rosiglitazone and metformin, there is a beneficial effect that continues over
time, more so with rosiglitazone. Although rosiglitazone had no acute effect on
the insulinogenic index over the first 6 months, it had a dramatic beneficial
effect on 1/fasting insulin, and thereafter, the rate of further increase in the
reciprocal insulin more than compensated for the decline in the insulinogenic
index. Thus, the joint means show the greatest distance from the baseline level
in keeping with the observation that rosiglitazone produced a more favorable
long-term improvement in glucose metabolism than either comparator.

The vector plot for the 4-year completer cohort (Fig. 4B), as in the full
cohort, shows that rosiglitazone produced a more favorable long-term improvement
in glucose metabolism than either of the comparators. These results are similar
both qualitatively and quantitatively to those observed in the full cohort.

The vector plot for the 4-year monotherapy failure cohort (Fig. 4C) shows an
initial improvement in glucose metabolism in all three groups that then rapidly
dissipates, with the subjects returning to their baseline status, on average, by
18–24 months, and then worsening further. The fall below the baseline regression
line with all treatments is in keeping with disease progression and these
subjects ultimately reaching the monotherapy failure end point. These results
are both qualitatively and quantitatively different from those of the 4-year
completer and full cohorts.


DISCUSSION

Type 2 diabetes is characterized by a progressive loss of β-cell function that
is represented by deteriorating measures of insulin response relative to the
prevailing insulin sensitivity (10–13), resulting in deteriorating glycemic
control (1,13). This is best demonstrated by the loss of β-cell function over
time in individuals who progress from states of impaired glucose metabolism to
diabetes (14,15). Thus, preserving the ability of the β-cell to secrete insulin
is thought to be critical to preventing the inexorable loss of glucose control.

ADOPT allowed the systematic, prospective evaluation of changes in glucose
metabolism over a period of 4 years in a large cohort of recently diagnosed type
2 diabetic subjects randomized to initial monotherapy using rosiglitazone,
metformin, or glyburide. In the first 6 months, as anticipated, glyburide
increased stimulated insulin release during the OGTT but did not change insulin
sensitivity. Metformin primarily improved insulin sensitivity, with a small
beneficial effect on β-cell function following glucose ingestion. Rosiglitazone
had similar effects to metformin, but of greater magnitude. Whether the
beneficial effects of rosiglitazone and/or metformin on the β-cell are indirect
as a result of their ability to improve insulin sensitivity or result from a
direct action on the β-cell, as suggested by some in vitro studies (16,17),
cannot be determined from these analyses.

Further differences emerged beyond the first 6 months. The insulinogenic index
fell at the greatest rate with glyburide but at the lowest rate with
rosiglitazone, whereas metformin was intermediate. Concurrently, insulin
sensitivity showed a long-term beneficial change with all three medications,
although the change with glyburide was less than with rosiglitazone. This change
with glyburide may be the result of alleviation of glucose toxicity (18).

This analysis represents the first longitudinal assessment of measures involved
in determining glucose metabolism in a cohort of individuals with type 2
diabetes followed for a prolonged period in a large, multicenter, clinical
trial. The effective evaluation of the time course of β-cell function and
insulin sensitivity was allowed by the selection of a glycemic level of 10
mmol/L to unequivocally represent monotherapy failure.

It is now well accepted that knowledge of the concomitant insulin sensitivity is
required to accurately evaluate β-cell function (10–13). Thus, vector plots of
the joint changes in OGTT measures of insulin response and insulin sensitivity
were used to describe changes in β-cell function over time. These highlight the
importance of this interplay between the insulin response and insulin
sensitivity and how the relationship between these two parameters changes over
time with all three treatments. These changes are different not only in
magnitude but also in nature, with the most favorable changes occurring with
rosiglitazone in keeping with improvements in both β-cell function and insulin
sensitivity.

These analyses used indirect measures of the β-cell and insulin sensitivity. The
dynamic measure of insulin release was computed from two glucose and insulin
pairs and the estimate of insulin sensitivity from the fasting insulin level.
Although both these measures include fasting insulin, they failed to show a
substantial correlation at baseline, R2 = 0.29, a level far below what would be
considered as collinearity (19). Thus, this OGTT measure of insulin release
alone is far from redundant with the measure of insulin sensitivity, and
examination of joint changes in the two measures provides a more complete
picture of disease progression over time than does examination of either in
isolation. Furthermore, joint changes in the OGTT measures are in keeping with
different responses to therapy and an overall preservation of β-cell function
that is greatest with rosiglitazone and least with glyburide.

Additional analyses were performed by examining the 526 subjects who failed
monotherapy and the 2,112 that did not during 4 years of follow-up. At baseline,
those who ultimately failed were younger and metabolically in a more advanced
state. The results among those who did not fail closely resemble those for the
full cohort, whereas among those who ultimately failed monotherapy, all three
medications demonstrated a short-term improvement in glucose metabolism manifest
as a change in the vector plot, such that it was above the concave line. In
those who failed monotherapy, the final point in each treatment group is
equidistant from the curve determined using the baseline data from the whole
cohort and is the position at which the pair of insulin release and insulin
sensitivity measures represent a deterioration in glucose metabolism associated
with a fasting glucose of 10 mmol/L.

Analyses of the 4-year completer and 4-year monotherapy failure cohorts
demonstrated beneficial effects of rosiglitazone versus either comparator or the
lack of beneficial effects among those who failed. These outcomes are directly
explained by the presence or absence, respectively, of beneficial effects
jointly on both β-cell function and insulin sensitivity. Thus, the beneficial
effects of rosiglitazone on the durability of glycemic control are explained by
changes in determinants of glucose metabolism over time.

The longitudinal analyses within the full cohort may be biased because of the
truncation of follow-up assessments in those who failed monotherapy. Additional
sensitivity analyses conducted to allow for such bias showed little difference
from those in the longitudinal analyses. The analyses within the completer and
failure cohorts also suggest that had there been complete follow-up of all
subjects up to 4 years, regardless of monotherapy failure or not; the overall
beneficial effects observed with rosiglitazone would be expected to be diluted
by the lack of a sustained beneficial effect among those who failed. However,
given the smaller number of such subjects, the overall beneficial effects
observed in the full cohort would still apply.

In ADOPT, we chose to obtain measures of β-cell function and insulin sensitivity
that were the most practical to institute across the many clinics involved in
the study. This approach, of course, meant that we did not use more
sophisticated and precise measures of insulin sensitivity. However, we do not
believe that this severely limits our findings because, although glyburide
stimulates insulin release and we may have overestimated the decrease in insulin
sensitivity, the rate of change in the insulinogenic index over time was
greatest with the sulfonylurea. This change can be associated with the most
rapid decrease in β-cell function and thus more monotherapy failure.

In 3% of tests, the value for the insulinogenic index was ≤0, with a similar
percentage applicable to the values at each visit and with a minority of
subjects having only one such value (if any). However, it did not appear to be
occurring in subjects who had more severe diabetes because we failed to
demonstrate a relationship between the fasting glucose level and the magnitude
of this negative response. This is in line with a previous observation of ours
demonstrating that these negative responses occur not only in subjects with
diabetes but also in those with normal and impaired glucose tolerance (20). It
is noteworthy that a negative first-phase insulin response to intravenous
glucose has been observed in diabetic subjects with the greatest elevation in
glucose (21), suggesting that, in this instance, it may be a manifestation of
severely impaired β-cell function. Although further studies will be required to
better understand whether there is a physiological explanation for an
insulinogenic index ≤0, we believe that for the purpose of estimating insulin
release for large clinical studies, these responses are not likely to represent
a major limitation and that the measure should be used.

Although the study cohort was broadly representative of patients with type 2
diabetes diagnosed within 3 years, they were selected to have a fasting glucose
concentration between 7.0 and 10.0 mmol/L without medication. Thus, individuals
who were more hyperglycemic or already required oral therapy would have been
excluded. Furthermore, since ADOPT was initiated, there has been a move toward
tighter glucose control. Despite this, we believe that our findings regarding
β-cell function and insulin sensitivity would have been similar if a fasting
glucose <10 mmol/L was used and would, thus, be applicable to therapy today.
This belief is based on our observation that the monotherapy failure outcome was
similar if we restricted the analysis to an outcome of a fasting glucose >7.8
mmol/L in subjects who started below this threshold (4).

In summary, the different evolving relationships between β-cell function and
insulin sensitivity observed over time explain the propensity to either maintain
adequate glycemic control with the initial monotherapy or to fail. Differential
changes in β-cell function and insulin sensitivity, i.e., in glucose metabolism,
are responsible for the different degrees of glycemic durability observed with
rosiglitazone, metformin, and glyburide in ADOPT, with rosiglitazone providing
the most favorable changes in both parameters and greatest durability over time.

Clinical trial reg. no. NCT00279045, clinicaltrials.gov.


ACKNOWLEDGMENTS

The study was supported by GlaxoSmithKline. Academic members of the ADOPT
Steering Committee have received honoraria, consulting fees, and/or
grant/research support from GlaxoSmithKline. R.P.A., G.P., and B.G.K. are
employees of the company. No other potential conflicts of interest relevant to
this article were reported.

S.E.K. researched data, contributed to the discussion, and wrote the manuscript.
J.M.L. researched data, contributed to the discussion, and reviewed and edited
the manuscript. B.Z., S.M.H., and R.P.A. contributed to the discussion and
reviewed and edited the manuscript. G.P. researched data, contributed to the
discussion, and reviewed and edited the manuscript. B.G.K., W.H.H., G.V., and
R.R.H. contributed to the discussion and reviewed and edited the manuscript.

ADOPT was overseen by a steering committee (S.E.K., G.V. [co-chairs], S.M.H.,
W.H.H., R.R.H., Nigel Jones [GlaxoSmithKline], J.M.L., Colleen O’Neill
[GlaxoSmithKline], and B.Z.), and day-to-day operations were conducted under the
auspices of the ADOPT Study Team (B.G.K., Dahong Yu, Rosemary Fowler, Suzanne
Evans, Darlene Steele-Norwood, Mark Heise, G.P., Karen Huckel, Josephine
Koskinas, Andrea McClatchy, and Doreen Woodward). Without the effort of the
study participants and study staff, these analyses would not have been possible.




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© 2011 by the American Diabetes Association.
2011
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