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DIABETES/METABOLISM RESEARCH AND REVIEWS RESEARCH ARTICLE
Diabetes Metab Res Rev 2008; 24: 41 –51.
Published online 16 May 2007 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/dmrr.755
Chromium picolinate and biotin combination
improves glucose metabolism in treated,
uncontrolled overweight to obese patients
with type 2 diabetes
Cesar A. Albarracin1
Burcham C. Fuqua2
Joseph L. Evans3
Ira D. Goldfine4*
1Alpha Therapy Center, 4626 Weber
Road, Suite 100, Corpus Christi, TX
78411; 361.852.0600 (voice), USA
2Global Medical Care, 5833 Spohn
Drive, Suite # 301, Corpus Christi, TX
78414; 361.880.4154 (voice), USA
3JERIKA Research Foundation,
Redwood City, CA 94061, USA
4University of California at San
Francisco, San Francisco, CA 94143,
USA
*Correspondence to: Ira D. Goldfine,
University of California, San
Francisco, Division of Diabetes and
Endocrine Research, Mt. Zion
Medical Center, 2200 Post Street;
Room 415C, San Francisco, CA
94115, USA.
E-mail: ira.goldfine@ucsf.edu
Received: 8 November 2006
Revised: 28 February 2007
Accepted: 1 April 2007
Abstract
Background Chromium and biotin play essential roles in regulating
carbohydrate metabolism. This randomized, double-blind, placebo-controlled
study evaluated the efficacy and safety of the combination of chromium
picolinate and biotin on glycaemic control.
Methods Four hundred and forty-seven subjects with poorly controlled
type 2 diabetes (HbA1c ≥7.0%) were enrolled and received either chromium
picolinate (600 µgCr
+3) with biotin (2 mg), or matching placebo, for 90 days
in combination with stable oral anti-diabetic agents (OADs). Major endpoints
were reductions in HbA1c, fasting glucose, and lipids. Safety and tolerability
were assessed.
Results Change in HbA1c was significantly different between treatment
groups (p=0.03). HbA1c in the chromium picolinate/biotin group decreased
0.54%. The decrease in HbA1c was most pronounced in chromium
picolinate/biotin subjects whose baseline HbA1c ≥10%, and highly significant
when compared with placebo (−1.76% vs −0.68%; p=0.005). Fasting
glucose levels were reduced in the entire chromium picolinate/biotin
group versus placebo (−9.8mg/dL vs 0.7 mg/dL; p=0.02). Reductions in
fasting glucose were also most marked in those subjects whose baseline
HbA1c ≥10.0%, and significant when compared to placebo (−35.8mg/dLvs.
16.2 mg/dL; p=0.01). Treatment was well tolerated with no adverse effects
dissimilar from placebo.
Conclusions These results suggest that the chromium picolinate/biotin
combination, administered as an adjuvant to current prescription anti-diabetic
medication, can improve glycaemic control in overweight to obese individuals
with type 2 diabetes; especially those patients with poor glycaemic control on
oral therapy. Copyright 2007 John Wiley & Sons, Ltd.
Keywords biotin; chromium; picolinate; diabetes; glucose; hemoglobin A1C
Introduction
Theprevalenceoftype2diabetes(type 2 DM) is increasing in the United
States and worldwide [1]. Insulin resistance, a major causative factor for
the early development of type 2 DM and cardiovascular disease (CVD), is
Copyright 2007 John Wiley & Sons, Ltd.
42 C. A. Albarracin et al.
even more widespread [2–4]. In addition, there is an
increasing prevalence of adult and childhood obesity
that markedly contributes to the development of type
2 DM [5–7]. Although pharmacological options for the
management of insulin resistance and type 2 DM in obese
individuals have been increasing [8,9], not all patients
have benefited, as the cost and adverse effects of new
pharmacologic agents preclude their use in many patients
[10,11]. Though a majority of diabetic patients are being
treated, many patients are unable to achieve the currently
recommended goal of HbA1c <7%, especially those who
are obese. Obese patients are likely to be the most insulin
resistant and, therefore, the most difficult to control with
currently available standard therapies. Thus, there is a
need to identify and evaluate adjunctive therapies that are
safe, efficacious, and cost-effective [10]. One adjunctive
therapy commonly used by patients to manage their type
2 DM is chromium, alone or in combination with biotin.
Chromium is an essential trace mineral required for
carbohydrate and lipid metabolism [12–14]. The link
between chromium and carbohydrate metabolism was
proposed more than 40 years ago, when it was identified
as a component of the biologically active ‘glucose
tolerance factor’ [15]. There is a growing body of evidence
from both animal [16–19] and human studies [12,20],
suggesting that dietary supplementation with trivalent
chromium, especially in the form of chromium picolinate,
is a safe [12,21– 24] and effective adjunctive therapy in
the management of insulin resistance and type 2 DM.
At present, chromium is widely used as a dietary
supplement in individuals with type 2 DM [12,24].
Most, but not all, studies report beneficial effects
of chromium on glycaemic control, lipid metabolism,
and insulin sensitivity [12,25–27]. Differences in study
design, subjects evaluated, dose administered, statistical
power, and the forms of chromium evaluated may
explain the difference in outcomes. A review of the
literature reveals that the form and dose of chromium
studied may predict treatment efficacy [12,24,28,29].
For instance, virtually all trials studying chromium,
using the chromium picolinate form, in subjects with
type 2 DM demonstrate a benefit on glycaemic control
[12,20,24,30–32]. Recent reports suggest that chromium
picolinate is more completely absorbed and has increased
bioavailability compared to other forms of chromium,
which helps explain the findings of the consistent
beneficial effect [12,24,33].
Biotin, a water-soluble B vitamin, plays an essential
role in carbohydrate and lipid metabolism [34]. Besides
its role as a carboxylase prosthetic group, biotin regulates
the expression of genes important for metabolism. Biotin
has stimulatory effects on genes whose actions favour
glycaemic control, including pancreatic and hepatic glu-
cokinases. It also suppresses the expression of hepatic
phosphoenolpyruvate carboxykinase, a key gluconeogenic
enzyme [34,35]. Biotin administration to diabetic rodents
has been reported to improve glycaemic control [36 –38].
A recent report indicated that biotin supplementation
alone reduced plasma triacylglycerol and very low den-
sity lipoprotein -cholesterol in subjects with type 2 DM
[39]. There is evidence that patients with type 2 DM
have reduced serum concentrations of biotin and that 30-
day supplementation with biotin improves fasting glucose
[40].
In cultured human skeletal muscle cells, the combi-
nation of chromium picolinate and biotin significantly
enhanced glycogen synthesis and glycogen synthase
mRNA to a greater extent than chromium picolinate or
biotin alone. (Wang, Z.Q, et al. Chromium picolinate and
biotin enhance glycogen synthesis and glycogen synthase
gene expression in human skeletal muscle culture. Pre-
sented at 17th International Diabetes Federation Congress
November 9, 2000. Mexico City, Mexico.) Pre-clinical
data suggest that biotin co-administration may enhance
chromium picolinate absorption and raise chromium tis-
sue levels in obese insulin-resistant rodents, as well as
decrease plasma glucose and plasma lipids to a greater
extent than chromium alone (Sahin, K, et al.Effectof
chromium picolinate/biotin on carbohydrate and lipid
metabolism in a rat model of type 2 diabetes. Diabetes
2006; 55 (Suppl 1):A387.). Thus, the administration
of chromium picolinate formulated with biotin warrants
evaluation as a useful adjunctive treatment for patients
with type 2 DM [35].
A recently reported 30-day pilot study [41] concluded
that the combination of chromium picolinate and biotin
improved short-term glycaemic control (oral glucose tol-
erance, fasting glucose, and fructosamine), and had a
favourable effect on lipid parameters in subjects with
type 2 DM. The study was a placebo-controlled 30-
day intervention in obese to overweight subjects with
poorly controlled type 2 DM, who were already receiv-
ing oral anti-diabetic medications (OADs). Treatment
with chromium picolinate/biotin (600 µgCrand2mg
biotin) once daily was well tolerated, and without any
adverse event profile dissimilar to placebo. A significant
decrease (∼6%) in plasma fructosamine was observed in
the active group compared to placebo. In subjects receiv-
ing chromium picolinate/biotin, the glucose excursion
following an oral glucose tolerance test was significantly
decreased by approximately 10%. The triglycerides/high
density lipoprotein (HDL)-cholesterol ratio, a proposed
metabolic marker of insulin resistance [42,43], was sig-
nificantly decreased in the chromium picolinate/biotin
group. These encouraging results provided the rationale
for conducting this 90-day trial to evaluate the effects of
chromium picolinate/biotin on glycaemic control.
Materials and methods
This randomized, double-blind, placebo-controlled study
was conducted at 17 geographically diverse sites in the
United States. The objective of this 90-day study was
to determine whether the combination of chromium
picolinate and biotin, as an adjunct to a stable regimen
Copyright 2007 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2008; 24: 41– 51.
DOI: 10.1002/dmrr
Chromium/Biotin Improve Glycaemic Control 43
of OADs, improves glycaemic control and blood lipids in
subjects with poorly controlled type 2 DM. In addition,
safety and tolerability were assessed. The study was
designed to reflect an actual clinical practice setting;
therefore, the length of type 2 DM diagnosis was set
at a 1-year minimum with no limit to duration defined,
and the type, class, or duration of OAD therapy was not
controlled for at entrance.
Obese to overweight men and women between
the ages of 18 and 70 years, with a documented
diagnosis of type 2 DM (according to American
Diabetes Association criteria) ≥12 months, who were
poorly controlled (HbA1c ≥7.0%) on OAD therapy were
eligible. A list of the major concurrent medications is
provided in Table 1. The inclusion criteria included the
following: (1) HbA1c ≥7.0%, (2) diagnosis of type 2 DM
≥12 months, (3) body mass index (BMI) ≥25 kg/m2
and <35 kg/m2, (4) currently taking OADs (stable for
≥60 days prior to entry), and (5) fasting triglycerides
<400 mg/dL.
The exclusion criteria were as follows: (1) diagnosis of
type I diabetes, (2) hypoglycemic event requiring emer-
gency transport ≤12 months, (3) supplementation with
chromium picolinate within 90 days and/or any form of
chromium ≥120 µg/d within 30 days, (4) daily insulin
usage or rescue insulin usage >1/week, (5) diabetic
ketoacidosis ≤12 months, (6) creatinine ≥2.0×upper
Table 1. Baseline concurrent medications
Concomitant
medication
Placebo
(
n
=
122
)%
Chromium/biotin
(
n
=
226
)%
Anti-diabetic medicationsa
,
b
Biguanide 97 (80.2) 174 (76.7)
Sulfonylurea 79 (65.3) 160 (70.5)
Thiazolidinediones 39 (32.2) 53 (23.3)
Non-sulfonylurea secretagogue 2 (1.7) 9 (4.0)
α
-Glucosidase inhibitor 0 3 (1.2)
Rescue insulin (freq
≤
1
week) 4 (3.3) 11 (4.8)
Other Rx medications (top 20)b
Aspirin 37 (24.3) 60 (20.3)
Lisinopril 16 (10.5) 44 (14.9)
Lipitor 21 (13.8) 36 (12.2)
Atenolol 5 (3.3) 15 (5.1)
Zocor 8 (5.3) 14 (4.7)
Lovastatin 5 (3.3) 13 (4.4)
Norvasc 6 (3.9) 11 (3.7)
Ibuprofen 3 (2.0) 10 (3.4)
Altace 9 (5.9) 8 (2.7)
Captopril 6 (3.9) 8 (2.7)
Prevacid 4 (2.6) 8 (2.7)
Avapro 0 (0.0) 7 (2.4)
Celebrex 4 (2.6) 7 (2.4)
Crestor 1 (0.7) ‘7 (2.4)
Diovan 1 (0.7) 7 (2.4)
HCTZ 5 (3.3) 7 (2.4)
Pravacol 5 (3.3) 7 (2.4)
Zetia 3 (2.0) 7 (2.4)
Bextra 3 (2.0) 7 (2.4)
Flomax 5 (3.3) 6 (2.0)
aStudy subjects enrolled were concomitantly using single, dual, and poly-
therapy. There were 105 active and 64 placebo subjects on dual or poly-
therapy. The most common combinations were, respectively, sulfonylurea
plus biguanide, TZD plus sulfonylurea, and TZD plus biguanide.
bSubjects’ concomitant OADs were not dissimilar between groups at
study entrance (
p
=
0
.
85
;Student’s
t
-test).
limit of normal (ULN); aspartate aminotransferase or
alanine transaminase ≥2.0×ULN; total bilirubin ≥1.5×
ULN, (7) cardiovascular conditions requiring hospitaliza-
tion ≤12 months, (8) history of cerebrovascular accident,
pulmonary embolism, or an unresolved deep vein throm-
bosis, (9) uncontrolled high blood pressure (seated: sys-
tolic ≥160 mmHg or diastolic ≥90 mm Hg), (10) serious
immunosuppressive disorder or current immunosuppres-
sive therapy, (11) hepatic disease, impaired thyroid,
impaired renal function, or diseases known to affect glu-
cose or lipid metabolism, (12) alcoholism or substance
abuse, (13) mental health issues that would prevent the
subject from completing the study, and (14) women who
were pregnant or nursing.
The study protocol was approved by a central Institu-
tional Review Board [New England Institutional Review
Board (IRB), Wellesley, MA]. Subjects were recruited
from the Principal Investigators’ database, referrals from
area physicians, and through advertisements. All con-
sent forms, advertisements, flyers, and posters were IRB
approved prior to use. Prior to enrollment, all subjects
were informed of the purpose and risks of the study and
gave voluntary written consent to participate. The study
was conducted in accordance with all federal, state, and
local requirements and in compliance with Good Clinical
Practice/International Conference on Harmonization of
Technical Requirements for Registration of Pharmaceuti-
cals for Human Use guidelines.
Patient contacts during the study included a pre-
screening phone contact, a Day-0 baseline visit, two
mid-study phone contacts, and a Day-90 final visit. At
the baseline visit, fasting blood and urine samples were
collected to determine: HbA1c, blood glucose, serum
insulin, serum lipid profile, blood chemistries, urinalysis
(via dipstick), and a urine pregnancy test on women
of childbearing potential. Subjects received a physical
examination including vital signs and measurements
of height and weight. Qualified subjects continued
on their existing medications and were randomized
blindly (2 : 1 ratio) to receive either chromium picolinate
(600 µgCr)+biotin (2 mg) (Diachrome, supplied by
Nutrition 21, Inc., Purchase, NY), or placebo, taken once
daily prior to the morning meal as an adjunct to their
stable OAD regimen. Treatment continued for 90 days.
Subjects were instructed not to change their diet or level
of physical activity. The office visit procedures outlined in
the preceding text were repeated during the final visit.
To facilitate compliance with study protocol, a central
call centre contacted the subjects twice (at Days 30 and
60) via telephone to reinforce subject-dosing compliance
by reminding the subjects to take their treatment daily,
along with their other prescription medications. The
subjects were also reminded to perform all diary-related
tasks (including recording date and time of each dose) and
to inform the study coordinator in case they experienced
an adverse event. The call also allowed the subjects an
opportunity to ask study-related questions. To assess
compliance, subjects were instructed to return at their
final visit with all unused capsules and bottles. The
Copyright 2007 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2008; 24: 41– 51.
DOI: 10.1002/dmrr
44 C. A. Albarracin et al.
subjects’ bottles were checked for capsule count at Day
90 (final visit) to calculate percent dosing compliance
and their diaries’ were checked for completeness of
dosing entries as an additional verification of dosing
compliance. Owing to logistical complexities, the subjects’
urine or blood samples were not screened for supplement
metabolites. Concomitant medication usage was also
assessed at the final visit and compared to baseline to
ensure that there were no medication changes.
Randomization
Subjects were randomized in a 2 : 1 ratio of active
treatment to placebo. The randomization schedule was
developed using standardized computer software with
block sizes of six subjects per unit. All subjects’ study
medication kits were pre-randomized by the provider
of the test product thereby assuring that all study site
personnel were blinded throughout the trial. Each site was
allocated study treatment kits by complete randomization
blocks. The randomization and blinding codes were
archived at the manufacturer’s facility by unblinded
personnel who were unaffiliated with the study.
Assays
Laboratory analyses (HbA1c, glucose, insulin, lipids,
chemistry panel, etc.) of fasting blood samples obtained at
the baseline and final visits were performed by Physician’s
Reference Lab (Overland Park, KS; www.prlnet.com);
these data were used for all statistical analyses. The
observed coefficient of variation for HbA1c analyses was
1.7% of the value reported.
Safety and tolerability
Safety parameters included a physical examination, vital
signs, and laboratory evaluation before entering the study.
Physical examinations and laboratory tests were repeated
at the final visit. Subjects were monitored on a regular
basis for adverse experiences. Subjects were contacted
at Days 30 and 60 by the call centre and reminded to
report all adverse events and serious adverse events to
the study coordinator. Patients were canvassed verbally
at their final visit as to whether they had experienced
an adverse event(s). The results of the clinical laboratory
assessments, vital signs, and detailed adverse event profile
are reported elsewhere.
Statistical analyses
The primary and secondary endpoints of this 90-day
study were the reduction in HbA1c and fasting glucose,
compared to placebo, respectively. HbA1c provides an
index of long-term glycaemic control and fasting plasma
glucose is an index of acute, short-term glycaemic control.
HbA1c is the biomarker that is recommended by
the American Diabetes Association as a measure of
overall glycaemic control. The intent to treat (ITT)
population was defined as any subject who took at
least one dose of study product and who had at least
one post-randomization HbA1c assessment. The modified
intent to treat (MITT) population included all ITT
subjects, regardless of the length of study participation or
dosing compliance, who were without significant protocol
entrance violations. Data analyses as stated were planned
for the overall MITT group (n=348), and for a subset of
subjects whose baseline HbA1c ≥10.0% (n=55).Forall
applicable efficacy outcome measures, a Student’s t-test
was used where appropriate. For analysis purposes, the
null hypothesis was defined as no overall treatment effect
when compared to placebo; statistical significance was
accepted at p≤0.05. All values were expressed as the
mean ±SE, unless otherwise indicated. Chi-square tests
were conducted for all categorical variables.
An analysis of covariance (ANCOVA) was also used
when evaluating change in HbA1c from baseline to control
for the potential effects of other variables in the overall
MITT analysis set. Results from previous intervention
studies [44] and guidelines recently published for
evaluating HbA1c data for diabetic interventions [45]
suggest using an ANCOVA model to assess baseline
HbA1c as a covariate, since baseline glycaemic control
appears to modulate treatment outcome [46]. Briefly,
the ANCOVA model was conducted by regression of the
response variable versus the covariate separately for each
treatment group. The slopes and intercepts of these two
models were compared statistically, with the difference in
intercepts being interpreted as the treatment difference,
and the difference in slopes being interpreted as the
difference in the amount of effect the covariate exerted
on the response.
The group sample size of subjects included in the final
data analyses (n=226 for the chromium/biotin group
and n=122 for placebo) had 30% power to detect
a 0.2% mean difference, 80% power to detect a 0.4%
mean difference, and 99% power to detect a 0.6% mean
difference in HbA1c change from baseline (treatment
vs placebo; p≤0.05; two-tailed). Data analyses were
performed using SAS(R) Version 8.2.
Results
The CONSORT flow diagram shows the progress of
subjects through the study (Figure 1). A total of 447
subjects were enrolled in the study (295 active; 152
placebo). Seventy-eight subjects did not return for further
assessments, and were therefore dropouts from the ITT
population and excluded from the data analysis. There
was no significant difference in the attrition rates between
the treatment and placebo groups. Further review of
the ITT group identified 21 subjects who had one
or more significant inclusion/exclusion violations; these
Copyright 2007 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2008; 24: 41– 51.
DOI: 10.1002/dmrr
Chromium/Biotin Improve Glycaemic Control 45
subjects were excluded from the data analyses. The study
entrance violations occurred due to human error during
the screening and enrollment process; subject entrance
violations discovered during the course of the trial were
allowed to continue unless there was a medical or ethical
reason to discontinue the patient. Of the 21 subjects
excluded, 7 had histories of significant CVD, coronary
heart disease, or hypertension, 4 subjects had significantly
abnormal lab values, 3 subjects failed BMI requirements, 2
subjects failed HbA1c requirements, 2 subjects’ OADs were
not stable for ≥60 days, 2 subjects were >70 years old,
and 1 subject’s diagnosis of type 2 DM was ≤1 year. There
was no significant difference in the attrition rates between
the treatment and placebo groups. The remaining 348
subjects were used for the final data analyses (MITT; n:
active 226; placebo 122).
Demographic data for the MITT population including
age, gender, ethnicity, weight, height, body mass index,
Figure 1. CONSORT study subject flow diagram. (See text for
details)
and blood pressure are shown in Table 2. Approximately
50% of the subjects were White, 30% were Hispanic,
and 10% were Black; there were no between-group
ethnic distribution differences noted. The groups were
similar and without significant differences in age, sex,
weight, height, BMI, blood pressure, or glycaemic control
(Tables 2 and 3).
Safety and tolerability
Treatment with chromium picolinate/biotin for 90 days
was well tolerated. The adverse effects and clinical safety
profile for the active group was not significantly different
from placebo. There were no changes in blood pressure
or blood chemistries, and no weight gain or sexual
dysfunction was noted (Table 4). There was no evidence
of fasting or episodic hypoglycemia in either treatment
group.
Glycemic control
Chromium picolinate/biotin treatment for 90 days pro-
duced modest but significant improvements in glycaemic
control compared to placebo, as judged by a reduction
in both fasting glucose and HbA1c. At baseline, HbA1c in
theactivegroupwas8.73 ±0.09% (mean ±SEM).After
90 days of treatment, HbA1c decreased to 8.19 ±0.09%;
an absolute decrease of 0.54%. In the placebo group,
HbA1c decreased by 0.34%. The difference between
the two groups was significant. (p=0.03 vs placebo;
Table 3).
At baseline, the mean fasting glucose level in
the chromium picolinate/biotin group was 169.7±
3.1mg/dL (mean ±SEM); declining after 90 days of
treatment to 159.9±3.1 mg/dL, a decrease of 9.8 mg/dL,
or approximately 6%. In contrast, subjects on placebo
experienced an increase of 0.7 mg/dL in glucose levels.
Table 2. Subject baseline demographics
MITT HbA1c
≥
10%
Placebo Chromium/Biotin
p
Placebo Chromium/Biotin
p
Subjects
n
=
122 n
=
226 n
=
16 n
=
39
Age (years)
59
.
6
±
0
.
857
.
6
±
0
.
7
0.06
59
.
4
±
1
.
955
.
4
±
1
.
1
0.06
Gender (
65%
=
M) (
56%
=
M) 0.08 (
75%
=
M) (
51%
=
M) 0.01
Ethnicity(%) – –0.38– –0.38
White 57.0% 52.4% – 31.3% 48.7% –
Hispanic 30.6% 28.6% – 50% 25.6% –
Black 6.6% 11.5% – 12.5% 20.5% –
Asian 3.3% 6.2% – 0% 5% –
Other 2.5% 1.3% – 6.3% 0% –
Weight (kg)
89
.
6
±
1
.
388
.
5
±
1
.
0
0.25
91
.
9
±
3
.
985
.
6
±
1
.
9
0.09
Height (cm)
171
.
5
±
0
.
9 170
.
0
±
0
.
7
0.10
172
.
7
±
3
.
1 167
.
6
±
1
.
5
0.08
Body mass index (kg/m2)
30
.
4
±
0
.
330
.
3
±
0
.
2
0.41
30
.
6
±
0
.
730
.
5
±
0
.
5
0.45
Blood pressure (mm Hg) – – – – – –
Systolic
131
.
9
±
1
.
2 129
.
7
±
0
.
9
0.07
136
.
3
±
3
.
9 127
.
4
±
2
.
6
0.04
Diastolic
78
.
7
±
0
.
978
.
8
±
0
.
6
0.53
80
.
9
±
2
.
578
.
7
±
1
.
6
0.22
Data are means
±
SEM and were analyzed by the Student’s
t
-test.
n
=
number of subjects.
Copyright 2007 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2008; 24: 41– 51.
DOI: 10.1002/dmrr
46 C. A. Albarracin et al.
Table 3. Effect of chromium/biotin on glycaemic control
Outcome variable Placebo (
n
=
122
) Chromium/biotin (
n
=
226
)
p
versus placebo
HbA1c (%)
Baseline
8
.
46
±
0
.
12 8
.
73
±
0
.
09
–
Final
8
.
12
±
0
.
12 8
.
19
±
0
.
09
–
Change
−
0
.
34
±
0
.
15
−
0
.
54
±
0
.
15
–
p
0.0001 0.0001 0.03
Fasting Glucose (mg/dL)
Baseline
171
.
7
±
4
.
5 169
.
7
±
3
.
1
–
Final
172
.
3
±
5
.
2 159
.
9
±
3
.
1
–
Change
0
.
7
±
5
.
9
−
9
.
8
±
8
.
5
–
p
0.84 0.002 0.02
Fasting insulin (
µ
U/mL)
Baseline
14
.
8
±
1
.
413
.
5
±
0
.
6
–
Final
13
.
5
±
1
.
014
.
0
±
0
.
7
–
Change
−
1
.
5
±
1
.
40
.
5
±
0
.
5
–
p
0.29 0.25 0.90
Subjects with baseline HbA1c
≥
10
.
0%
Outcome variable Placebo (
n
=
16
) Chromium/biotin (
n
=
39
)
p
versus placebo
Baseline HbA1c
≥
10
.
0%
Baseline
11
.
14
±
0
.
28 11
.
08
±
0
.
16
–
Final
10
.
46
±
0
.
46 9
.
32
±
0
.
27
–
Change
−
0
.
68
±
0
.
30
−
1
.
76
±
0
.
23
–
p
0.006 0.0001 0.005
Fasting glucose (mg/dL)
Baseline
230
.
3
±
13
.
8 222
.
0
±
9
.
0
–
Final
246
.
5
±
22
.
8 186
.
2
±
9
.
7
–
Change
16
.
2
±
18
.
4
−
35
.
8
±
9
.
1
–
p
0.63 0.017 0.01
Fasting insulin (
µ
U/mL)
Baseline
12
.
6
±
1
.
511
.
1
±
1
.
1
–
Final
11
.
6
±
1
.
312
.
3
±
1
.
3
–
Change
−
0
.
49
±
1
.
51
.
4
±
0
.
8
–
p
0.51 0.17 0.23
Data are means
±
SEM and were analysed by Student’s
t
-test.
n
=
the number of subjects.
This difference in response between the two groups was
significant (p=0.02 vs placebo; Table 3). No difference
between groups in fasting insulin was observed (Table 3).
As the study was designed not only to evaluate efficacy
but also to identify those subjects who responded the most
to chromium picolinate/biotin, an analysis was conducted
on those subjects whose HbA1c was ≥10.0% at baseline
(n=55; active 39; placebo 16). Reductions in HbA1c
and fasting glucose were significantly greater in subjects
receiving chromium picolinate/biotin in this set of subjects
than were seen in the overall study population. In subjects
whose baseline HbA1c ≥10%, the final HbA1c fell −1.8±
0.2% in those receiving chromium picolinate/biotin
compared to −0.7±0.3% in those receiving placebo
(p=0.005 vs placebo; Table 3). Fasting glucose also
fell significantly more in this set of patients in the
chromium picolinate/biotin group compared to placebo
(−35.8±9.1mg/dLvs 16.2±18.4mg/dL;p=0.01).
An ANCOVA was performed on the HbA1c change
from baseline data using the baseline HbA1c data as
the covariate. The fitted regression equations were as
follows: change from baseline in HbA1c=2.99 −0.40
(baseline HbA1c) for the chromium picolinate/biotin
group, and change from baseline in HbA1c=1.34 −0.20
Table 4. Prevalence of adverse events
Parameter
Placebo
n
=
122
%
Chromium/biotin
n
=
226
%
p
versus
placebo
Any AEa42 (34.7) 78 (34.4) 0.95
Any SAEb5 (4.1) 2 (0.9) 0.04
Potentially related AE 8 (6.6) 27 (11.9) 0.12
AE leading to drop-out 4 (3.3) 4 (1.8) 0.36
AE potentially related
Nervous system 1 (0.8) 10 (4.4) 0.07
Gastrointestinal 4 (3.3) 5 (2.2) 0.54
Skin and tissue 2 (1.8) 4 (1.7) 0.94
Musculoskeletal 0 (0.0) 3 (1.3) 0.20
General medicine 0 (0.0) 3 (1.3) 0.20
Metabolism 0 (0.0) 2 (0.9) 0.30
Immune 1 (0.8) 0 (0.0) 0.17
Hypoglycaemia 0 (0.0) 0 (0.0) NA
aAE, adverse event.
bSAE, serious adverse event.
n
=
number of subjects.
(baseline HbA1c)for the placebo group (Figure 2). The
slope coefficients were significantly different from zero
(p=0.002), and significantly different from each other
(p=0.008) as were the y-intercept coefficients (p=
0.01). The differences in the slope coefficients indicate
Copyright 2007 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2008; 24: 41– 51.
DOI: 10.1002/dmrr
Chromium/Biotin Improve Glycaemic Control 47
Figure 2. HbA1c ANCOVA regression model for treatment and
placebo groups. The fitted regression equations were as follows:
change from baseline in HbA1c=2.99 −0.40 (baseline HbA1c)for
the chromium picolinate/biotin group, and change from baseline
in HbA1c=1.34 −0.20 (baseline HbA1c)for the placebo group
that, for the chromium picolinate/biotin group, for every
unit increase in baseline HbA1c there was a 0.4-unit
decrease in the change from baseline HbA1c.
A review of covariates by demographic variables
revealed that being Black was predictive of modestly
better reductions in HbA1c (p=0.03).Ananalysisof
covariance using other baseline subject characteristics,
such as demography, weight, BMI, gender and age, did
not reveal any modulation of treatment effect on HbA1c
or fasting glucose.
Anti-diabetic medications
Concomitant OAD usage was similar between treatment
groups at baseline, as were other prescription medications
including statins and antihypertensive agents (p=
0.85). A preliminary comparison of the baseline OADs
versus treatment outcomes revealed that chromium
picolinate/biotin worked well with all subjects’ OAD
medications. However, it is interesting to note that a
subset analysis of metformin users demonstrated modestly
better treatment outcomes than the overall MITT results.
A total of 91 subjects met the criteria of taking only
abiguanide(n: active 56; placebo 35); HbA1c was
significantly reduced in the active group by 0.64% ±0.15,
while placebo was reduced by only 0.24% ±0.12 (p=
0.02 vs placebo). No additional differences or trends
were noted when performing similar analyses for other
OADs. Overall, the combination of chromium picolinate
and biotin worked well adjunctively with all concurrent
OADs.
Lipids
There was no significant difference in absolute values
of total cholesterol, low density lipoprotein cholesterol,
HDL cholesterol, and triglyceride levels between groups
in the MITT population (Table 5) or the subjects whose
baseline HbA1c was greater than 10%. A reduction in
lipids or lipid ratios would not be expected in this sample
as only a subset of subjects who entered the study was
Table 5. Effect of chromium/biotin on lipids and lipid ratios
Outcome
variable
Placebo
(
n
=
122
)
Chromium/biotin
(
n
=
226
)
p
versus
placebo
Total cholesterol (mg/dL)
Baseline
197
.
8
±
4
.
4 193
.
5
±
2
.
95
Final
195
.
8
±
5
.
0 187
.
6
±
4
.
2
Change
−
1
.
99
±
2
.
9
−
5
.
96
±
2
.
3
0.14
p
0.45 0.01
HDL-chol (mg/dL)
Baseline
46
.
2
±
1
.
044
.
8
±
0
.
7
Final
46
.
3
±
1
.
144
.
97
±
0
.
66
Change
0
.
12
±
0
.
57 0
.
16
±
0
.
46
0.48
p
0.71 0.86
LDL-chol (mg/dL)
Baseline
106
.
5
±
2
.
7 110
.
8
±
2
.
8
Final
103
.
2
±
3
.
0 104
.
4
±
2
.
7
Change
−
4
.
4
±
2
.
0
−
5
.
4
±
2
.
8
0.39
p
0.02 0.05
VLDL-chol (mg/dL)
Baseline
44
.
2
±
2
.
841
.
6
±
2
.
0
Final
47
.
9
±
3
.
642
.
1
±
2
.
7
Change
3
.
7
±
2
.
20
.
5
±
2
.
3
0.15
p
0.90 0.18
TG (mg/dL)
Baseline
220
.
7
±
13
.
9 207
.
9
±
10
.
2
Final
239
.
4
±
18
.
2 210
.
6
±
13
.
5
Change
18
.
7
±
10
.
82
.
7
±
11
.
4
0.15
p
0.09 0.81
TG/HDL-chol Ratio
Baseline
5
.
2
±
0
.
45
.
05
±
0
.
3
Final
5
.
7
±
0
.
05 4
.
9
±
0
.
3
Change
0
.
52
±
0
.
3
−
0
.
13
±
0
.
25
0.05
p
0.09 0.63
Data are means
±
SEM and were analysed by the Student’s
t
-test.
n
=
the number of subjects.
hypercholesterolemic. A more comprehensive analysis of
lipid data from subjects with elevated cholesterol levels at
baseline (>200 mg/dL) showed significant improvements
in lipids and lipid ratio results, as well as markers
of CVD disease risk, in the chromium picolinate/biotin
group; data are reported elsewhere (Juturu et al. 2007 J
Cardiometabolic Syndrome. In press). No change in body
mass index was observed in either group.
However, the triglycerides/HDL ratio was significantly
decreased in the chromium picolinate/biotin group.
The mean change in this ratio after treatment was
−0.13 ±0.25 in the chromium picolinate/biotin group
and 0.52 ±0.30 in the placebo group (p=0.05 versus
placebo). A review of covariates by demographic variables
revealed that being Hispanic was predictive of modestly
better reductions in the triglycerides/HDL ratio (p=
0.02). There were no other observations of demographic
predictors of treatment success for lipid parameters.
Discussion
This 90-day study was designed to determine whether
the combination of chromium picolinate and biotin, as an
adjunct to a stable regimen of OADs, reduced HbA1c and
fasting glucose in subjects with poorly controlled type 2
Copyright 2007 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2008; 24: 41– 51.
DOI: 10.1002/dmrr
48 C. A. Albarracin et al.
DM. In addition, safety and tolerability were assessed. This
study was designed to reflect an actual clinical practice
setting, therefore baseline class, type, and duration of
OAD were not controlled for and only two study visits,
90 days apart, were conducted.
Chromium picolinate/biotin significantly lowered
HbA1c and fasting plasma glucose when compared to
placebo. The greatest improvements were observed in
those individuals who had the poorest degree of control
at baseline, as defined by a HbA1c ≥10%. No safety or tol-
erability issues were identified in this study. Results from
an open-label patient experience program [44] evaluat-
ing the effects of chromium picolinate/biotin on subjects
with type 2 DM and HbA1c >7.0% reported significant
reductions in HbA1c from baseline (n=30; −1.0% HbA1c,
p=0.01). The results suggested that the reductions in
HbA1c observed were greatest in those subjects who had
the highest baseline HbA1c levels (n=18; −1.8% HbA1c,
p=0.001). On the basis of this information and accepted
guidelines for assessing the effect of baseline glycaemic
control on glycaemic outcome measures, we performed an
ANCOVA using baseline HbA1c as the covariate [44,45].
The results of the analysis suggest a positive relation-
ship between baseline HbA1c and the magnitude of HbA1c
reductions. The ANCOVA results reported here demon-
strate that the chromium picolinate/biotin combination
provides significant HbA1c reductions along the entire
range of entrance HbA1c values, but most profoundly
in those patients with the poorest control when com-
pared to placebo. Lowering HbA1c, especially in those
patients with poor control, results in significant reduc-
tions in diabetes-related deaths, all cause mortality, and
myocardial infarcts, and improve other diabetes-related
healthcare outcomes such as micro- and macro-vascular
complications [47,48]. However, the costs of these inter-
ventions may be prohibitively expensive [10]. A recent
report suggests that the improvements in HbA1c from
using the chromium picolinate/biotin combination as an
adjunct to current OADs may not only be inexpensive,
but result in substantial overall reductions in diabetes-
related costs, most especially in those patients with poor
glycaemic control [10].
Another recent report [41] from a well-controlled
acute 30-day intervention study indicated that the
combination of chromium picolinate and biotin resulted
in improvements in fasting glucose, post-prandial glucose
excursions, and fructosamine. This pilot study did not
include a measure of HbA1c since the duration of the
intervention was only 30 days; therefore, fructosamine
was selected as a measure of sustained glycaemic control.
Since the duration of the 90-day placebo-controlled
intervention study was of a more protracted length,
HbA1c was selected as the gold standard measure of
sustained glycaemic control. In both of these studies,
the two markers of sustained glycaemic control were
significantly reduced, implying similar and supporting
evidence of sustainable change.
It is well established that many patients with type 2
DM, especially obese individuals on multiple OADs, do
not achieve adequate diabetic control, as evidenced by
elevated HbA1c levels. These patients often present an
ongoing clinical challenge to physicians. Epidemiological
evidence exists that implies the risk of CVD begins
well below the current HbA1c target goal of 7.0% [49].
Therefore, additional reductions in HbA1c are desirable,
even when close to the target goal. Additional incremental
reductions are difficult to obtain, often require poly oral
therapy with the addition of insulin, and have an increased
risk of emergent hypoglycemic events. Bloomgarden
et al. reported that, for subjects whose HbA1c is ≤8.0%,
a modest reduction of ∼0.5% HbA1c was difficult to
achieve in controlled trials using OADs [46,49]. For
those subjects whose HbA1c was <8.0% (n=2030),the
reduction was only −0.1to−0.2% using OAD therapy
[46]. Although it is challenging to achieve additional
incremental reductions without side effects, by adding
chromium/biotin as an adjunctive therapy we report an
overall reduction of 0.5% HbA1c, without hypoglycaemic
events or other side effects dissimilar from placebo. In
fact, for subjects whose HbA1c was between 8.0 and 8.9%
(n=5269), the mean reduction amongst all OAD studies
analysed was −0.6% [46], confirming the importance of
the results reported here.
As noted in the preceding text, the lack of hypogly-
caemic side effects is not unexpected. In over 34 clinical
trials evaluating chromium picolinate, there has never
been any evidence of hypoglycemia whether adminis-
tered alone, or in combination with other prescription
medications including sulfonylureas [12,24].
In the meta-analysis by Bloomgarden et al.[46],the
group whose HbA1c was >10.0% (n=266)experienced
areductioninHbA
1c of ∼1.2%; whereas we report a
reduction in HbA1c of ∼1.76% in a similar sample without
an increase in deleterious effects. Findings from this trial
suggest that the chromium picolinate/biotin intervention,
when used as an adjuvant therapy, was as good as or better
than that reported on by Bloomgarden et al.[46],which
used OADs. Results of this trial indicate that chromium
picolinate/biotin supplementation had a beneficial effect
on HbA1c, especially in those subjects with the poorest
control on current OAD therapy.
In contrast to the results reported here and by
others [12,31], a recent study has found that chromium
picolinate (500 and 1000 µg daily for 6 months) was
ineffective in reducing HbA1c in obese, poorly controlled,
insulin-dependent individuals with type 2 diabetes [26].
Several possible explanations for these contrasting results
were the limited statistical power in the latter study to
detect a significant change due to the small number
of subjects (n=17 for placebo group; n=14 for
500 µggroup;n=15 for 1000 µggroup,vs n =226
for the chromium/biotin group and n=122 for placebo
group in this study), and the greater degree of obesity
and insulin resistance at baseline (BMI =33– 35 kg/m2
vs BMI =30 kg/m2in this study). Furthermore, these
subjects [26] were unable to achieve adequate glycaemic
control, even with OAD therapy and concomitant high
doses of insulin (>90 IU/day insulin).
Copyright 2007 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2008; 24: 41– 51.
DOI: 10.1002/dmrr
Chromium/Biotin Improve Glycaemic Control 49
Although the mechanism of chromium action has
not been definitively established, data from a recent
in vivo study suggest that chromium might exhibit its
insulin-sensitizing effect by reducing the content and
activity of the tyrosine phosphatase PTP-1B [19]. PTP-
1B has long been implicated in the regulation of insulin
receptor tyrosine phosphorylation and tyrosine kinase
activity [50], and has been validated as a bona fide
pharmacological target for increasing insulin sensitivity
[51–55]. In animals, small molecules that inhibit PTP-
1B increase insulin sensitivity and lower plasma glucose
[56–58]. Alternatively, chromium might act directly on
the insulin receptor, and increase its tyrosine kinase
activity [59], as has been observed with other small
molecules [60,61].
Reviews of the recent literature reveal additional
potential chromium mechanisms of action that may
be complementary to those discussed in the preceding
text. Researchers from the Elmendorf laboratory have
reported a novel potential mechanism of chromium
action [62]. Work from this laboratory has indicated
that chromium picolinate (and chromium chloride)
stimulated GLUT4 translocation to the plasma membrane
in cultured 3T3-L1 adipocytes. Concomitant with an
increase in GLUT4 at the plasma membrane, insulin-
stimulated glucose transport was enhanced by chromium
treatment. Chromium-stimulated GLUT4 translocation
did not involve known insulin signaling intermediates
such as the insulin receptor, insulin receptor substrate-
1, phosphatidylinositol 3-kinase, or Akt, but was
associated with decreased plasma membrane cholesterol.
Subsequent work from this group has found that the
GLUT4 redistribution in cultured adipocytes treated
with chromium picolinate occurred only in adipocytes
cultured in the presence of high glucose (25 mM), but
not in those cultured under normoglycemic (5.5 mM
glucose) conditions [63]. Examination of the effect of
chromium picolinate on proteins involved in cholesterol
homeostasis [62,63] revealed that the activity of
sterol regulatory element-binding protein, a membrane-
bound transcription factor ultimately responsible for
controlling cellular cholesterol balance, was up-regulated
by chromium picolinate. In addition, ABCA1, a major
player in mediating cholesterol efflux was decreased,
consistent with sterol regulatory element-binding protein
transcriptional repression of the ABCA1 gene.
Glucokinase, expressed in hepatocyte and pancreatic
βcells, has a central regulatory role in glucose metabolism
[64]. Efficient glucokinase activity is required for normal
glucose-stimulated insulin secretion, post-prandial hep-
atic glucose uptake, and the appropriate suppression of
hepatic glucose output and gluconeogenesis by elevated
plasma glucose. Hepatic glucokinase activity is subnor-
mal in diabetes, and glucokinase may also be decreased
in the βcells of individuals with type 2 DM [64]. In
supra-physiological concentrations, biotin promotes the
transcription and translation of the glucokinase gene in
hepatocytes; and more recent evidence indicates that
biotin increases glucokinase activity in pancreatic islet
cells [34,65].
Furthermore, researchers (Wang, Z.Q, et al.Chromium
picolinate and biotin enhance glycogen synthesis and
glycogen synthase gene expression in human skeletal
muscle culture. Presented at 17th International Diabetes
Federation Congress November 9, 2000. Mexico City,
Mexico.) using a human skeletal muscle cell line have
investigated whether chromium picolinate, biotin, or
the combination stimulate increased glycogen production
versus control. In this in vitro model, it was noted that
chromium picolinate alone and biotin alone stimulated
glycogen synthase mRNA production, as well as glycogen
production, to a greater extent than the control alone.
Interestingly, although the effect was more pronounced
in the chromium picolinate group than the biotin group,
the effect appeared to be synergistic using a combination
of chromium picolinate and biotin together versus control.
In conclusion, chromium picolinate was combined with
biotin in a 90-day double-blind placebo-controlled study
in overweight to obese subjects with poorly controlled
type 2 DM patients currently on OAD therapy. The results
of this study indicated that this combination provided a
significant improvement in a validated index of long-term
glycaemic control (HbA1c) with results similar to those
reported in the literature. Future studies are ongoing to
confirm the effectiveness of this supplement in patients
with other forms of metabolic dysfunction.
Acknowledgements
This study, and subsequent statistical analyses, was supported
by a grant from Nutrition 21, Inc. (Purchase, NY). Statistical
analyses of all data were independently performed by Dr
Dennis W. King (STATKING Consulting, Inc, Fairfield, OH;
www.statkingconsulting.com). Tables were reviewed by Joseph
Fuhr, Ph.D., Widener University, Chester, PA 19013-5792. All
authors (CAA, BCF, JLE, and IDG) had full access to all the data
in the study and take full responsibility for the integrity of the
data and the accuracy of the data analysis. Trial registered on
clinicaltrials.gov; registry # NCT00289354.
Conflict of interest
None declared.
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