Customize your JAMA Network experience by selecting one or more topics from the list below.
Elam MB, Hunninghake DB, Davis KB, et al. Effect of Niacin on Lipid and Lipoprotein Levels and Glycemic Control in Patients With Diabetes and Peripheral Arterial Disease: The ADMIT Study: A Randomized Trial. JAMA. 2000;284(10):1263–1270. doi:10.1001/jama.284.10.1263
Author Affiliations: University of Tennessee Health Science Center (Dr Elam), Memphis Veterans Affairs Medical Center (Dr Elam), Memphis, Tenn; University of Minnesota, Minneapolis (Dr Hunninghake); University of Washington (Dr Davis), Axio Research Corp (Dr Davis and Mr Johnson), Seattle, Wash; Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, Bethesda, Md (Dr Garg and Ms Egan); Robert Wood Johnson School of Medicine, Robert Wood Johnson University, New Brunswick, NJ (Dr Kostis); University of North Carolina, Chapel Hill (Dr Sheps); and Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC (Dr Brinton).Dr Garg is now with Eli Lilly Co; Dr Sheps is now with the University of Florida College of Medicine, Gainesville; and Dr Brinton is now with the University of Arizona College of Medicine, Tucson.
Context Although niacin increases low levels of high-density lipoprotein cholesterol
(HDL-C), which frequently accompany diabetes, current guidelines do not recommend
use of niacin in patients with diabetes because of concerns about adverse
effects on glycemic control; however, this is based on limited clinical data.
Objective To determine the efficacy and safety of lipid-modifying dosages of niacin
in patients with diabetes.
Design and Setting Prospective, randomized placebo-controlled clinical trial conducted
in 6 clinical centers from August 1993 to December 1995.
Participants A total of 468 participants, including 125 with diabetes, who had diagnosed
peripheral arterial disease.
Interventions After an active run-in period, participants were randomly assigned to
receive niacin (crystalline nicotinic acid), 3000 mg/d or maximum tolerated
dosage (n = 64 with diabetes; n = 173 without diabetes), or placebo (n = 61
with diabetes; n = 170 without diabetes) for up to 60 weeks (12-week active
run-in and 48-week double-blind).
Main Outcome Measures Plasma lipoprotein, glucose, hemoglobin A1c (HbA1c),
alanine aminotransferase, and uric acid levels; hypoglycemic drug use; compliance;
and adverse events, in patients with diabetes vs without who were receiving
niacin vs placebo.
Results Niacin use significantly increased HDL-C by 29% and 29% and decreased
triglycerides by 23% and 28% and low-density lipoprotein cholesterol (LDL-C)
by 8% and 9%, respectively, in participants with and without diabetes (P<.001 for niacin vs placebo for all). Corresponding
changes in participants receiving placebo were increases of 0% and 2% in HDL-C
and increases of 7% and 0% in triglycerides, and increases of 1% and 1% in
LDL-C. Glucose levels were modestly increased by niacin (8.7 and 6.3 mg/dL
[0.4 and 0.3 mmol/L]; P = .04 and P<.001) in participants with and without diabetes, respectively.
Levels of HbA1c were unchanged from baseline to follow-up in participants
with diabetes treated with niacin. In participants with diabetes treated with
placebo, HbA1c decreased by 0.3% (P =
.04 for difference). There were no significant differences in niacin discontinuation,
niacin dosage, or hypoglycemic therapy in participants with diabetes assigned
to niacin vs placebo.
Conclusions Our study suggests that lipid-modifying dosages of niacin can be safely
used in patients with diabetes and that niacin therapy may be considered as
an alternative to statin drugs or fibrates for patients with diabetes in whom
these agents are not tolerated or fail to sufficiently correct hypertriglyceridemia
or low HDL-C levels.
The Arterial Disease Muliple Intervention Trial (ADMIT) was a prospective,
placebo-controlled study. ADMIT evaluated the safety and efficacy of a combination
of high-density lipoprotein (HDL)–raising, antioxidant vitamin, and
low-dose warfarin therapy to modify multiple atherosclerotic vascular disease
risk factors in subjects with peripheral arterial disease. Niacin was selected
as the intervention in ADMIT to increase HDL levels because it is effective
in increasing HDL cholesterol (HDL-C) (and lowering triglycerides),1-4 and has
previously been shown to reduce cardiovascular morbidity and mortality.5-8 It was
anticipated that a substantial number of ADMIT participants would have diabetes
mellitus.9 Despite published guidelines discouraging
the use of niacin in the treatment of diabetes10-13;
the long-term use of lipid-modifying dosages of niacin in subjects with controlled,
stable diabetes has not been examined in a prospective, placebo-controlled,
double-blind study. We decided to include participants with diabetes in ADMIT
to provide useful information regarding the safety and efficacy of niacin
use in that patient population. Of 468 ADMIT participants, 125 patients with
diabetes were included. This article describes the effect of niacin treatment
on plasma lipoproteins and glycemic status in ADMIT participants with diabetes.
The design and rationale of ADMIT have been reported previously.14 ADMIT was a National Heart, Lung, and Blood Institute–sponsored
multicenter, randomized, placebo-controlled trial designed to evaluate the
feasibility of recruitment of subjects with peripheral arterial disease, and
their adherence and response to 3 interventions. These interventions included
niacin, antioxidant vitamins, and low-dose warfarin, or corresponding placebo
treatments, administered in a 2 ×2×2 factorial design.
Participants were enrolled at 6 clinical centers and the data were collected
and analyzed by the data coordinating center (Axio Research Corp, Seattle,
Wash). An independent data and safety monitoring board kept track of the progress
of the trial. The protocol and consent form were approved by the institutional
review board at each clinical center. Written informed consent was obtained
from all participants prior to enrollment into the study.
This article presents information on 125 ADMIT enrollees who met study
criteria for diabetes at the first study visit. Diabetes was defined as either
a history of diabetes treated by diet or medication or a hemoglobin A1c (HbA1c) level higher than 7% at the baseline visit. Inclusion
and exclusion criteria for ADMIT have been previously presented.14
ADMIT participants had either a reduced ankle brachial index of less than
0.85 or a history of prior lower-extremity revascularization. Subjects were
excluded from ADMIT for poorly controlled diabetes (HbA1c >9.0%),
a history of diabetic ketoacidosis or coma, renal disease, liver disease,
gout, hyperuricemia, peptic ulcer disease, history of myositis, or untreated
hypothyroidism. Participants with marked hypertriglyceridemia (>400 mg/dL)
for whom randomization to niacin placebo would not have been appropriate,
or whose low-density lipoprotein (LDL) level was not likely to be controlled
by niacin and/or pravastatin (baseline LDL cholesterol [LDL-C] >190 mg/dL
[4.9 mmol/L]) were also excluded from participation.
All participants underwent an active niacin run-in, during which crystalline
(immediate release) niacin tablets (Niacor, Upsher-Smith, Minneapolis, Minn)
were dispensed at 4-week intervals in increasing doses of 50, 250, and 500
mg twice daily.
Participants who successfully completed the active niacin run-in were
then randomly assigned to receive a combination of active niacin, antioxidant
vitamin cocktail, and warfarin or their respective placebo treatments. Randomization
into each of the 8 possible drug combinations (of the 2×2×2 factorial
design) was performed independently at each clinical center using block sizes
of 8, 16, or 24 selected at random. At randomization, the dosage of niacin
or its placebo was increased to 750 mg twice daily with subsequent increases
to 1000 mg and then 1500 mg twice daily at 6-week intervals, or until maximum
tolerated dose was reached. Participants were to receive 3000 mg/d or the
maximum tolerated dosage for the remainder of the 48-week double-blind treatment
Fasting blood glucose levels were monitored at 6-week intervals throughout
the follow-up period. If the fasting blood glucose level was higher than 189
mg/dL (10.5 mmol/L), the HbA1c level was then measured, and if
this was higher than 10.0%, the dosage of niacin (or its placebo) was down-titrated.
Niacin down-titration was also performed if any routine HbA1c level
(measured at study weeks 6, 24, and 48) was higher than 10.0%. The dosage
of niacin (or its placebo) was also down-titrated in any participant whose
uric acid level was higher than 595 µmol/L.
Among niacin placebo tablets, 15% contained 50 mg of active niacin.
This low dose of niacin was given to cause intermittent flushing in the participants
taking niacin placebo to minimize the risk of inadvertent subject unblinding.
The average daily dose of niacin in the placebo group was approximately 43
mg/d at maximum, a dosage not known to have a significant effect either on
lipids or on the other study parameters. Participants whose LDL-C levels remained
above 130 mg/dL (3.4 mmol/L) while taking the maximum dose of niacin or placebo
were provided with open-label pravastatin of 10 to 20 mg/d as needed to achieve
LDL-C levels of less than 115 mg/dL (3 mmol/L). Thus, pravastatin was given
in a nonrandom manner to participants in both the niacin and niacin-placebo
groups. To focus on the effects of niacin monotherapy, we only report lipid
results from the period prior to pravastatin therapy (first 30 weeks of the
study). In contrast, the other end points are reported herein for the full
60 weeks of the study to include all available safety data.
Lipoprotein profiles (total cholesterol, HDL-C, and total triglycerides)
were measured on plasma samples, obtained after an overnight fast, using the
Centers for Disease Control and Prevention's standardized methods and calibrator
standards at the Lipid Analytic Laboratory, Wake Forest University School
of Medicine, Winston-Salem, NC. LDL-C was calculated as described by Friedewald
et al.15 HbA1c level was measured
by high-pressure liquid chromatography (Laboratory Corporation of America,
Burlington, NC). Plasma or serum levels of glucose, uric acid, aspartate aminotransferase,
and alanine aminotransferase were measured by standard autoanalyzer methods
in the local clinical laboratories.
The effect of concurrent treatment with either warfarin or antioxidant
vitamins on the lipoprotein and glycemic response to niacin was examined by
longitudinal regression analysis. There was no interaction between the effect
of niacin and the other treatments on lipoproteins or glycemic control. This
report therefore presents data analyzed by niacin treatment assignment only
for participants both with and without diabetes. The overall study results,
including results of warfarin and antioxidant treatment on the variables of
interest for those interventions, will be reported elsewhere.
Descriptive statistics are reported as mean (SD) for continuous variables.
Univariate comparisons were made by 2-sided t tests, χ2 tests, and Fisher exact tests as appropriate. The follow-up effects
of niacin treatment on plasma lipids and lipoproteins, glycemic status, and
other safety parameters were each analyzed with a longitudinal regression
model using generalized estimating equations with random effects to take account
of the within-person correlation between visits. The baseline value of the
parameter, niacin treatment assignment, diabetes, obesity, follow-up visit
number, and the interaction of diabetes, niacin assignment, and obesity were
included as covariates. The initial screening value or, for lipoproteins,
the mean of the first 2 screening values was used as the baseline value. Follow-up
visit number was modeled both as a linear term and as an indicator variable
to examine nonlinear effects. Models were reduced by backward elimination
to the set of variables for which P<.05. Analyses
were performed and verified using STATA statistical software (release 5.0,
STATA Corp, College Station, Tex).
Of the 468 ADMIT participants, 125 (27%) met study criteria for diabetes
(Table 1 and Figure 1). ADMIT participants with diabetes were slightly older,
had slightly higher body mass indices, higher HbA1c levels, and
lower uric acid levels than those without diabetes. Participants with diabetes
were more likely to be black and were less likely to be current cigarette
smokers. Despite comparable ankle brachial index values, participants with
diabetes were less likely to have had prior vascular procedures or symptoms
of peripheral arterial disease. With the notable exception of HDL-C, which
was lower among participants with diabetes, plasma lipids and lipoproteins
at baseline were comparable in the 2 groups. When baseline characteristics
were compared by niacin treatment assignment, participants with diabetes who
were randomized to receive niacin placebo were older than those
who received niacin (68 vs 66 years; P = .04). There
were no other significant differences in baseline characteristics between
niacin and niacin placebo groups in participants either with or without diabetes.
During the 12-week active niacin run-in period, a small decrease in
total and LDL-C and triglycerides and increased HDL-C was detected in all
participants as niacin was increased from 100 mg/d to 1000 mg/d (Figure 2). After randomization, participants
both with and without diabetes who were receiving active niacin experienced
a progressive further decrease in total and LDL-C as niacin dosage was increased
to 3000 mg/d (Figure 2). Following
randomization, HDL-C levels continued to increase and triglycerides decreased
further in participants both with and without diabetes randomized to active
niacin. Table 2 summarizes the
baseline and treatment lipoprotein values by diabetes status and niacin treatment
assignment. Niacin treatment resulted in significant decreases in LDL-C and
triglycerides, and increased HDL-C compared with placebo control for participants
both with and without diabetes. The reduction in total cholesterol, LDL-C,
and triglycerides with niacin treatment were all significant (P<.001) in participants both with (−4%, −8%, −23%,
respectively) and without diabetes (−7%, −9%, −28%, respectively).
Levels of HDL-C were significantly increased by 29% and 29% in participants
with and without diabetes, respectively (P<.001).
Niacin therapy was equally effective in modifying lipoproteins in participants
both with and without diabetes (interaction, P =
.32-.66). The lipoprotein response to niacin was not affected by the presence
of obesity (defined as body mass index >27 kg/m2 for men and >25
kg/m2 for women).
Fasting glucose and HbA1c levels were monitored as indices
of glycemic status during niacin treatment. Table 3 presents the glucose, HbA1c, and uric acid levels
at baseline and the average of 6 postrandomization values. Niacin use resulted
in a small but statistically significant increase in average glucose levels
in participants both with (8.1 mg/dL [0.4 mmol/L]) and without diabetes (6.3
mg/dL [0.3 mmol/L]; P = .04 and P<.001, respectively). The effect of niacin on glucose was greater
in participants with diabetes than without (P = .04). Figure 3 depicts the course of glucose values
during the niacin treatment period. In subjects randomized to receive niacin,
there was a transient increase in glucose as the niacin dosage was increased
to 3000 mg/d; however, plasma glucose subsequently returned to baseline with
continued niacin therapy (Figure 3).
Niacin use also resulted in a small but statistically significant difference
in change in HbA1c levels (0.3%) in participants with diabetes
treated with niacin compared with those receiving niacin placebo (P = .04; Table 3). Niacin
use had no effect on HbA1c levels in participants without diabetes
(P = .38). The response of neither HbA1c
nor glucose levels to niacin was significantly affected by obesity.
Niacin increased uric acid levels over baseline values (P≤.001) similarly in both participants with and without diabetes
(interaction, P = .19; Table 3). During follow-up, uric acid levels were higher than 595
µmol/L (range, 613-684 µmol/L) for 3 of 61 participants with diabetes
assigned to niacin (5%) and for 1 of 59 participants with diabetes assigned
to placebo (2%). The dose was lowered for 1 participant with diabetes assigned
to niacin, but none had niacin discontinued. Among participants without diabetes,
4 had the niacin dosage reduced for uric acid levels exceeding the arbitrary
limit of 595 µmol/L and niacin was discontinued in 1 participant. One
participant with diabetes assigned to niacin and 1 without diabetes assigned
to placebo had niacin discontinued due to possible gout.
Mean plasma alanine aminotransferase level was not significantly changed
compared with baseline values (P = .09), nor was
it higher in niacin-treated subjects compared with niacin-placebo treatment
(P = .08). Further, plasma alanine aminotransferase
was not higher with niacin treatment in participants with diabetes compared
with those without (interaction, P = .38). The level
of alanine aminotransferase was more than 3 times above the normal range (0-35
U/L) during follow-up for 2 participants with diabetes and 3 without, all
of whom were taking niacin (P = .03) One participant
without diabetes had niacin therapy discontinued because of an elevated alanine
The effect of niacin on plasma glucose and HbA1c levels could
have been modified if hypoglycemic therapy was adjusted by primary caregivers
in response to receiving reports of abnormal laboratory results. We therefore
examined the frequency of insulin use and average dose of insulin used at
baseline and at the final follow-up visit for participants with diabetes randomized
to niacin vs those randomized to niacin placebo. Insulin use was increased
by 13% in participants with diabetes randomized to niacin vs 4% in those randomized
to niacin placebo (P = .09). For patients using insulin
at both first and final follow-up visits (n = 26), there was no effect of
niacin use on insulin dose (P = .68). There was also no significant change
in use of oral hypoglycemic agents as a result of niacin use (P = .94).
Niacin use might also have resulted in development of diabetes in patients
who did not have diabetes at entry into ADMIT. Therefore, we looked for new
users of insulin or oral hypoglycemic agents among ADMIT participants who
did not have diabetes at the baseline visit. Among the 173 participants randomized
to niacin treatment who did not have diabetes at baseline, only 1 reported
use of oral hypoglycemic therapy at subsequent follow-up visits. No niacin
users without diabetes reported insulin use during follow-up, nor did any
participants without diabetes who were randomized to niacin placebo report
subsequent use of either insulin or oral hypoglycemic therapy.
Adherence to niacin therapy was comparable in ADMIT participants with
and without diabetes, with niacin discontinuation rates of 23% and 16%, respectively
(P = .20). Niacin discontinuation was also comparable
in participants with diabetes randomized to receive active niacin and niacin
placebo (23% vs 18%, respectively; P = .46). Glucose
intolerance was listed as the reason for niacin discontinuation in 4 participants
with diabetes (6%) who were randomized to active niacin and in 2 participants
with diabetes (3%) randomized to niacin placebo (P
= .44). Other reasons for discontinuation of niacin in participants with diabetes
included comorbid vascular disease, patient request, and acanthosis nigricans.
The protocol specified down-titration of niacin if HbA1c level
exceeded 10%. This HbA1c limit was exceeded after randomization
in 18 participants with diabetes, 10 of whom were assigned to niacin and 8
assigned to placebo. The average dose of niacin at week 18 was 2553 mg in
participants with diabetes, and was 2626 mg in participants without diabetes
(P = .44).
Lipid-modifying therapy is recommended in both peripheral arterial disease
and diabetes to reduce the risk of atherosclerotic vascular disease.13,16 Although current guidelines focus
on LDL-C as a risk factor, hypertriglyceridemia and low HDL-C are common in
the dyslipidemia associated with type 2 diabetes mellitus,10,11,13
and contribute to the increased risk of arterial vascular disease in subjects
with diabetes. Despite its proven ability to increase HDL and lower triglycerides,
the use of niacin has been discouraged in patients with diabetes,10-13 largely
due to reports of deterioration of glycemic control in subjects both with
and without diabetes who were treated with niacin.3,17-19
The effect of niacin on glycemic status in patients with diabetes has, however,
not previously been assessed in the setting of a randomized, placebo-controlled
trial. We therefore decided to assess the safety and efficacy of niacin use
in ADMIT participants with diabetes.
This report demonstrates that immediate-release niacin is equally effective
in modifying lipid and lipoprotein levels in subjects with and without diabetes.
We also confirmed previous observations of increased plasma glucose levels
in patients both with and without diabetes and treated with lipid-modifying
doses of niacin; however, the effects observed over 60 weeks of follow-up
were relatively modest and did not result in significantly increased rates
of niacin discontinuation or alterations in hypoglycemic therapy. It is important
to note, however, that the results observed here might not reflect those obtained
with other niacin formulations, and that glycemic therapy may have been modified
in individual patients as a result of niacin treatment.
Previous reports of niacin-induced glucose intolerance are derived largely
from uncontrolled case reports involving small numbers of subjects.17-20 Many
of these earlier studies were performed on subjects without diabetes.18-20 Of studies conducted
on subjects with diabetes, some,3,17
but not all,21,22 reported worsened
glycemic control with niacin treatment. In addition, in these studies, glucose
tolerance was examined within 2 to 8 weeks following rapid institution of
lipid-lowering doses of niacin (3-6 g/d).3,18-20
The glucose intolerance following niacin therapy in these reports may reflect
short-term effects from rapid institution of lipid-lowering doses of niacin.
In the present study we, in fact, observed a transient increase in plasma
glucose as niacin was titrated to its maximum dose.
The only other report that includes a number of subjects comparable
with our own is a retrospective study of niacin use at a Department of Veterans
Affairs Medical Center.23 This study reported
higher niacin discontinuation rates overall and higher rates of discontinuation
due to poor glycemic status in patients with diabetes treated with a slow-release
niacin preparation. In that study, niacin was administered without blinding
or use of placebo controls. Given the current perception that niacin significantly
worsens glycemic status, it is possible that physician bias may have influenced
the niacin discontinuation rate. These findings may also reflect a difference
between sustained release and crystalline (immediate release) niacin and/or
the reliance on blood glucose rather than HbA1c level for clinical
Although the effect of niacin treatment on glycemic status overall was
modest in ADMIT, our findings do not preclude the possibility that its use,
particularly at doses higher than those used here, or using preparations other
than crystalline niacin, may significantly adversely affect glycemic control
in individual patients with diabetes. Therefore, glycemic status should be
carefully monitored during niacin therapy in patients with diabetes, and the
dose modified or discontinued if glycemic status clearly deteriorates. In
addition, plasma insulin was not measured nor was insulin resistance formally
assessed in this study. Several studies have shown decreased glucose tolerance
and increased plasma insulin levels in subjects without diabetes following
short-term niacin treatment.18,19,22,24
A more recent study,25 however, has shown minimal
effect of short-term niacin treatment on insulin levels and glucose use in
normal volunteers. It is also possible that the changes in glycemic indices
observed here, although relatively modest, might offset some of the cardiovascular
risk reduction with niacin.
Recently published guidelines for treatment of dyslipidemia in type
2 diabetes mellitus recommend aggressive lipid modification using statin drugs
or fibrates.12 Although LDL-C is recommended
as the primary target of therapy, it is recognized that hypertriglyceridemia
and decreased HDL-C are highly prevalent in type 2 diabetes mellitus, and
are associated with increased risk of atherosclerotic vascular disease.10,13 Niacin effectively reduces plasma
triglycerides by reducing hepatic production of very LDL, and increases HDL
cholesterol by up to 30%, possibly by reducing hepatic removal of apolipoprotein
A-1.26,27 Niacin also reduces
plasma LDL-C by 10% to 15% and normalizes LDL particle size distribution.28 Although the LDL-C lowering effect of niacin is modest
compared with that of statin drugs, niacin has a greater effect on HDL-C,
triglycerides, and lipoprotein (a).4 For patients
with diabetes who have hypertriglyceridemia or low HDL-C or both, gemfibrozil
has been shown to be effective and does not adversely affect glycemic status29; however, not all patients tolerate gemfibrozil therapy.
Furthermore, in cases of extreme hypertriglyceridemia, combination therapy
with gemfibrozil and niacin may be required to reduce triglycerides to acceptable
There is limited information about which of the currently available
lipid-modifying interventions offer the greatest benefit for patients with
diabetes in terms of reduced cardiovascular morbidity and mortality. A recent
post-hoc analysis of the Scandinavian Simvastatin Survival Study (4-S) indicates
that participants with diabetes experienced a significant reduction in coronary
heart disease events with simvastatin therapy.30
In the Helsinki Heart study, patients with diabetes experienced a 60% reduction
in coronary heart disease events with gemfibrozil therapy.31
This decrease was not statistically significant, however, because of the small
number of participants with diabetes in that study. Similarly, in the Veterans
Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT),
participants with diabetes experienced coronary heart disease event reduction
with gemfibrozil equivalent to that observed in the entire cohort.32 Although the effect of niacin on cardiovascular morbidity
and mortality has not been demonstrated specifically in diabetes, niacin therapy
has been shown to reduce vascular disease morbidity and mortality in general
populations of subjects with atherosclerotic vascular disease.5-8
Despite current recommendations against use of niacin in diabetes,10,12 the present study demonstrates that
lipid-modifying doses of immediate-release niacin can be used safely in patients
with stable, controlled, type 2 diabetes mellitus. Niacin therapy may be considered
as an alternative to statin drugs or fibrates in patients with diabetes in
whom these agents are not tolerated, or in whom they fail to sufficiently
correct hypertriglyceridemia or low HDL-C. Conversely, in view of the absence
of an effect on glycemic status of statin drugs or fibrates, these agents
should still be considered first-line therapy in diabetic dyslipidemia.
Create a personal account or sign in to: