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H/A: Hyperlipidemia (2009)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:

To evaluate the therapeutic potential, tolerability and adverse-effect profile, focusing on insulin resistance, of extended-release (ER)-niacin therapy.

Inclusion Criteria:
  • Age older than 18 years
  • HIV seropositivity
  • Receipt of HAART for at least six months with a stable regimen for at least four weeks prior to entry into the study
  • Willingness to adhere to a NCEP Step I diet.
Exclusion Criteria:
  • History of toxicity to niacin
  • Diagnosis of diabetes mellitus, gout, peptic ulcer diseases or currently receiving treatment for opportunistic infections or malignancy
  • History of cirrhosis, substance abuse or pregnancy or a present unwillingness to practice birth control.
Description of Study Protocol:

Recruitment

AIDS Clinical Trials Unit and Infectious Diseases Outpatient Clinic at Washington University School of Medicine.

Design

  • Nonrandomized trial
  • 14 HIV-infected individuals with dyslipidemia (eight-hour fasting TG of more than or equal to 200mg per dL and directly measured LDL of more than or equal to 130mg per dL) were consecutively enrolled.

Intervention

  • Four-week lead-in period (washout from lipid-lowering agents) and counseling on NCEP Step I diet
  • 14 weeks of study period (niacin therapy 500mg to 2,000mg per day), diet reinforcement and aspirin of 325mg as precaution against flushing
  • After 14 weeks, four weeks of wash-out period  
  • Outcomes were measured at weeks zero, four, 10, 14, 18 and 22; OGTT was measured baseline (week four) and after week 14 (week 18). 

Statistical Analysis

  • Wilcoxon signed rank used to compare lipid and glucose values at week four (baseline) and week 18
  • Median values were reported
  • P<0.05 used for statistical significance.

 

Data Collection Summary:

Timing of Measurements

  • Study weeks  zero, four, 10, 14, 18 and 22
  • OGTT was measured weeks four and 18.

Dependent Variables

  • Fasting lipid profile, a complete metabolic panel, uric acid level, CD4 cell count and HIV load; cholesterol levels, including direct LDL-C and TG levels, were measured using commercially available immunoassays
  • Glucose tolerance test (fasting) values for sensitivity and secretion parameters were derived from glucose, insulin and C-peptide levels measured during the five-hour OGTT/insulin sensitivity; insulin concentrations were determined using a double-antibody radioimmunoassay and C-peptide and glucagon concentrations were determined by radioimmunoassay
  • Plasma glucose concentrations were measured using a YSI 2300 glucose analyzer.

Independent Variables

  • Step I diet
  • Niacin dose.

 

 

Description of Actual Data Sample:
  • Initial N: N=14 (14 males, zero females)
  • Attrition (final N): Final N=12
  • Two patients discontinued prematurely
  • Age: Median age 48.9 years.

Ethnicity:

  • 13 Caucasian
  • One African American.

Other relevant demographics:

  • Median CD4 cell count: 421 at baseline, 398 at week 18
  • Time HIV seropositive: Median years, 5.2 years
  • Family history of diabetes: Three (21%)
  • Family history of CVD: Five (36%) 
  • Receiving lipid-lowering drugs: Four (29%)
  • Glucose tolerant: Seven. 

Anthropometrics

Mean BMI: 26.2 at baseline, 26.7 at week 18

Location

St Louis, MO: Washington University School of Medicine.

Summary of Results:
  • 43% (six of 14) of patients were glucose intolerant at baseline; after ER-niacin therapy, 64% (seven of 11) were glucose intolerant (new finding for three)
  • Calculated overall insulin sensitivity was not significantly reduced after 14 weeks of ER-niacin therapy, but Beta cell sensitivity to the basal glucose level and insulin secretion rate were increased significantly
  • On the basis of homeostasis model of insulin resistance (HOMA-IR) values, fasting insulin sensitivity was significantly reduced after ER-Niacin treatment
  • Subjects receiving protease inhibitor-based antiretroviral regimens tended to have higher HOMA-IR values at baseline compared to those not receiving protease inhibitor based regimens
  • All participants were men and all but one was Caucasian.

 

Lipoprotein fraction
Value in mg per dL
Percentage Change in Value
(N=12)
P-value Week Four vs. Week 18
(N=11)
Value After End of Niacin Therapy Week 22
(N=11)
P-value
Week 18 vs. Week 22
(N=11)
Before NCEP Diet (Week Zero)
(N=14)
Before Start of Niacin therapy
(Week Four)
(N=14)
At end of Niacin Therapy
(Week 18)
(N=12)

Total Cholesterol

 Median (IQR)

   Mean ±SD
 
 
 

251 (197 to 313)

256±69
 
 
 

245 (205 to 339)

274±96
 
 
 

220 (183 to 265)

225±52
 
 
 

-14 (-9 to -25)

16±14
 
 
 

0.005
 
 
 

246 (232 to 311)

271±71
 
 
 

0.008

Triglycerides

Median (IQR)

   Mean ±SD
 

527 (311 to 677)

579±339
 

489 (341 to 715)

594±385
 

406 (263 to 471)

394±159
 

-34 (-17 to -42)

26±33
 

0.019
 

460 (320 to 621)

575±355
 

0.041

Non-HDL-C

Median (IQR)

   Mean ±SD
 

209 (164 to 274)

218±68
 

200 (172 to 300)

236±94
 

177 (143 to 215)

185±52
 

-19 (-10 to -31)

18±5
 

0.004
 

207 (186 to 262)

231±72
 

0.006

HDL-C

Median (IQR)

   Mean ±SD
 

37 (33 to 41)

38±6
 

39 (31 to 44)

38±8
 

39 (31 to 46)

40±9
 

+3 (0 to +13)

6±2
 

0.091
 

38 (35 to 42)

40±8
 

0.592

LDL-C

Median (IQR)

   Mean ±SD

 
 

121 (76 to 143)

116±48
 

114 (75 to 141)

107±40
 

123 (64 to 153)

117±45
 

-4 (-19 to +10)

14±33
 

1
 

121 (88 to 150)

128±54
 

0.505

 

 

 

 

 

Author Conclusion:
  • Findings indicate that ER-niacin may be a useful option for lipid-lowering therapy for HIV-infected people with normal glucose tolerance as dual or monotherapy
  • ER-niacin therapy significantly reduced serum TG, non-HDL-C, and total cholesterol
  • In contrast to other studies, this study did not find a significant change in LDL-C and HDL-C levels after niacin therapy
  • Continued increases in HDL-C level were observed after 16 weeks of full-dose niacin therapy
  • Voluntary changes in dietary intake may account for some of the favorable lipid profile changes; however, the lipid changes that were observed during ER-niacin therapy (weeks four to 18) were greater than the changes that might be expected for dietary intervention alone (decreases five to nine mg per dL for total cholesterol and increases of one to four mg per dL for TG)
  • Furthermore, total cholesterol non-HDL-C and TG values increased significantly after ER-niacin treatment was discontinued despite ongoing diet counseling; therefore, authors feel confident that the lipid profile changes observed during the study weeks four to 18 predominantly reflect the actions of niacin
  • ER formulation was well tolerated and should be evaluated in larger placebo-controlled trials that can define its role as a therapeutic agent for antiretroviral therapy-associated dyslipidemia
  • The use of ER-niacin in patients with glucose tolerance or diabetes may be limited
  • Findings show increased in basal insulin secretion rate cause by enhancement of the sensitivity of beta cells to stable basal glucose
  • The finding of this pilot study justify a larger, more extensive study of the use of this agent in the management of HIV-related dyslipidemia. 
Funding Source:
University/Hospital: Grants AI 25903, AI327 DK 59532 and RR00036
Not-for-profit
1
Other:
Reviewer Comments:
  • Strengths
    • It was a pilot study that was well executed and focus was on the effects niacin had on lipids
    • Overall good design
  • Concerns
    • Small sample; needs further investigation with much larger controlled study
    • Gender and ethnicity needs to be balanced
    • Diet assessment was not provided, especially for the expressed purpose of ruling it out as a confounder of outcomes. 
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? ???
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? No
3. Were study groups comparable? N/A
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? N/A
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) N/A
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? N/A
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? N/A
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? No
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? No
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) No
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? Yes
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? ???
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? No
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? N/A
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? No
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? No
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes