Evidence Analysis Project Write-Up Curcumin and Inflammation Bwilliams

In adults with type 2 diabetes, does curcumin supplementation, compared to a
placebo or no supplementation, decrease serum inflammatory markers?
Brittnee A. Williams
Dietetic Intern
2017
1
Table of Contents
Introduction…………………………………………………………………................……3-4
PICO Question……….………………………...……………….……………...…..........…..4-5
Search Strategy……….……………...………...……………….……………...…...……...….5
Table 1: Articles Considered but Excluded………………..………………...………..………6
Table 2: Primary Research Articles Included...……………..…………………………..…….7
Selected Citations for Review……………………...………………………………………….8
Literature Evaluation Worksheets and Quality Criteria Checklists……………………......9-31
Table 3: Quality Criteria Summary…………...………………………………………….31-33
Table 4: Overview....………………….…………………………………………...……..34-35
Summary of the Evidence……………………………….………………………………..36-39
Table 5: Summary of change in variables….……………………………………...…………37
Definitions…………………………………….………………..………………….…………40
Conclusion and Grading………………….………………………………….....…….……...41
Implications for Patient Care at JAHVH…………………………………….....………...41-42
References………………………………………………………………………..……....42-44
2
Introduction
According to the Centers for Disease Control and Prevention, one out of every eleven
people are currently living with diabetes1. Additionally, one out of every three adults is living
with prediabetes and at least one out of every three people will develop type 2 diabetes in their
lifetime1. The prevalence of diabetes has more than doubled since the year 2000 and associated
complications and death tolls are on the rise with it2. The causes are complex, however, chronic
elevated levels of inflammatory markers not only contribute to insulin resistance and diabetes but
also to associated diabetic complications and disease progression3.
Turmeric is the rhizome or underground root of the curcuma longa plant that, even
though it has been used in natural medicine for centuries, has more recently been the subject of
investigation in clinical trials for its ability to regulate numerous disorders4,5. One of the first
studies involving turmeric, or more specifically its bioactive component curcumin, and diabetes
was an article published in 1972 that focused on curcumin’s effect on blood sugar in a single
diabetic individual6. Since then, however, most of the trials that been conducted have been
preclinical animal or in vitro studies7.
These preclinical studies have identified curcumin’s many molecular targets including
transcription factors, inﬂammatory mediators, receptors, protein kinases, growth factors,
enzymes, adhesion molecules, and apoptotic regulators.5 Even with the role these many
molecular targets play in different cell-signaling pathways linked to chronic diseases, the lack of
published human trials to date, fails to validate turmeric, or curcumin’s effectiveness in reducing
serum inflammatory markers8.
Preliminary research focused on the possible glucose lowering effects of curcumin
supplementation in type 2 diabetes.7 Type 2 diabetes is primarily associated with insulin
3
secretory defects related to inflammation and metabolic stress9 therefore, the antioxidant capacity
of curcumin could potentially restore the balance of antioxidative systems and reactive oxygen
species allowing for better glucose control. The many signaling proteins involved in oxidative
stress pathways, however, have made the exact mechanisms of action particularly difficult to
identify4.
To complicate matters more, curcumin, has been found not only to be poorly absorbed in
the human gastrointestinal tract, but also rapidly metabolized and rapidly eliminated from the
system7,8. These bioavailability issues have given rise to higher dosing, and altered molecular
forms of curcumin supplementation for use in clinical human trials5.
The Standards of Medical Care in Diabetes- 2017 from the American Diabetic
Association involve a range of interventions to improve outcomes in diabetes including
pharmacologic and lifestyle management such as oral glucose lowering agents and nutrition11.
Assessment of glycemic control is recommended through patient self-monitoring of blood
glucose (SMBG) and A1C. The A1C goal may need to be individualized some but is likely
within the range of 6%-8%. To reduce disease progression and complication. In regards to
turmeric or curcumin supplementation however, “There is no clear evidence that dietary
supplementation with vitamins, minerals, herbs, or spices can improve outcomes in people with
diabetes who do not have underlying deficiencies11.”
The potential for curcumin to be effective against pro-inﬂammatory diseases has driven
researchers to continue to investigate the therapeutic potential of curcumin on various metabolic
parameters in human trials4,5,7,11-14. This paper attempt to review the current evidence in order to
investigate the question:
4
In adults with type 2 diabetes, does curcumin supplementation, compared to a
placebo or no supplementation, decrease serum inflammatory markers?
Search Strategy
In order to investigate literature currently available on the topic, the following
comprehensive search strategy was developed:
Date of Literature Review: 08/28/17
Inclusion Criteria
· Publication Dates: 10 years
· Article Types: Clinical Trials
· Species: Humans
Exclusion Criteria: None
Search terms: curcumin AND diabetes
Database: PUBMED
SEARCH DETAILS BOX: (("diabetes mellitus"[MeSH Terms] OR ("diabetes"[All
Fields] AND "mellitus"[All Fields]) OR "diabetes mellitus"[All Fields] OR
"diabetes"[All Fields] OR "diabetes insipidus"[MeSH Terms] OR ("diabetes"[All Fields]
AND "insipidus"[All Fields]) OR "diabetes insipidus"[All Fields]) AND
("curcumin"[MeSH Terms] OR "curcumin"[All Fields])) AND (Clinical Trial[ptyp]
AND "2007/09/01"[PDat] : "2017/08/28"[PDat] AND "humans"[MeSH Terms])
Summary of Articles Identified to Review:
· Total Number of Articles Considered : 11
· Number of Articles Considered but Excluded (Table 1): 7
· Number of Included Primary Research Articles Identified from all sources (Table 2): 4
5
Table 1: Articles Considered but Excluded
No. Article Title First Author’s Year Reason for Exclusion
Last Name
1 Potential role of curcumin Appendino 2011 Outcomes measure

phytosome (Meriva) in venoarteriolar response,
controlling the evolution of skin flux and peripheral
diabetic microangiopathy. A pilot edema
study.
2 Meriva®, a lecithinized curcumin Steigerwalt 2012 Outcomes measure

delivery system, in diabetic venoarteriolar response
microangiopathy and retinopathy. and peripheral edema
3 Curcumin extract for prevention Chuengsamarn 2012 Outcomes measure β-

of type 2 diabetes cell function, insulin
resistance, C-peptide,
and adiponectin
4 Reduction of atherogenic risk in Chuengsamarn 2014 Outcomes measure

patients with type 2 diabetes by atherosclerosis
curcuminoid extract: a parameters, adiponectin,
randomized controlled trial. & leptin
5 Curcuminoids exert glucose- Na 2013 Outcomes measure

lowering effect in type 2 diabetes insulin resistance,
by decreasing serum free fatty glucose and lipid levels
acids: a double-blind, placebo-
controlled trial.
6 Effects of curcumin on brain- 2014 Outcome measures

derived neurotrophic factor Franco-Robles focus on BDNF,
(BDNF) levels and oxidative involves mice & obese
damage in obesity and diabetes. humans
7 Evaluation of the effect of 2014 Outcomes focused on

curcumin capsules on glyburide Neerati glyburide concentration,
therapy in patients with type-2 glucose and lipid levels,
diabetes mellitus. not serum inflammatory
markers
6
Table 2: Primary Research Articles Included
No. Article Title First Author’s Year Reason for Inclusion
Last Name
1 Effect of NCB-02, Atorvastatin Usharani 2008 Outcomes measure

and Placebo on Endothelial oxidative stress markers
Function, Oxidative Stress and malondialdehyde
Inflammatory Markers in (MDA), tumour necrosis
Patients with Type 2 Diabetes factor-α (TNF-α),
Mellitus. interleukin-6(IL-6) and
low density lipoprotein
LDL-C
2 Oral supplementation of Khajehdehi 2011 Outcomes measure

turmeric attenuates proteinuria, oxidative stress markers
transforming growth factor-β TNF-α, interleukin-
and interleukin-8 levels in 8(IL-8) and LDL-C
patients with overt type 2
diabetic nephropathy: A
randomized, double-blind and
placebo-controlled study
3 Curcuminoids Target Na 2014 Outcomes measure

Decreasing Serum Adipocyte- oxidative stress markers
fattyAcid Binding Protein MDA, TNF-α, IL-6, c-
Levels in Their Glucose- reactive protein (CRP)
lowering Effect in Patients with and LDL-C
Type 2 Diabetes
4 Curcumin Attenuates Urinary Yang 2015 Outcomes measure

Excretion of Albumin in Type oxidative stress markers
II Diabetic Patients with MDA, LDL-C and
Enhancing Nuclear Factor lipopolysaccharide
Erythroid-Derived 2-Like 2 (LPS)
(Nrf2) System and Repressing
Inflammatory Signaling
Efficacies
7
Selected Citations for Review:
1. Usharani P, Mateen AA, Naidu MUR, Raju YSN, Chandra N. Effect of NCB-02,
Atorvastatin and Placebo on Endothelial Function, Oxidative Stress and Inflammatory
Markers in Patients with Type 2 Diabetes Mellitus. Drugs R D. 2008;9(4):243-250.
2. Khajehdehi P, Pakfetrat M, Javidnia K, et al. Oral supplementation of turmeric attenuates
proteinuria, transforming growth factor-β and interleukin-8 levels in patients with overt
type 2 diabetic nephropathy: A randomized, double-blind and placebo-controlled study.
Scand J Urol Nephrol. 2011;45(5):365-370.
3. Na L, Yan B, Jaing S, et al. Curcuminoids Target Decreasing Serum Adipocyte-fattyAcid
Binding Protein Levels in Their Glucose-lowering Effect in Patients with Type 2
Diabetes. Biomed Environ Sci. 2014; 27(11):902-906.
4. Yang H, Xu W, Zhou Z, et al. Curcumin Attenuates Urinary Excretion of Albumin in
Type II Diabetic Patients with Enhancing Nuclear Factor Erythroid-Derived 2-Like 2
(Nrf2) System and Repressing Inflammatory Signaling Efficacies. Exp Clin Endocrinol
Diabetes. 2015;123(06):360-367.
8
Literature Evaluation Worksheets and Quality Criteria Checklists for Selected Studies
Academy of Nutrition and Dietetics

Evidence Analysis Library® Worksheet Template
Primary Research
Usharani P, Mateen AA, Naidu MUR, Raju YSN, Chandra N. Effect of NCB-02, Atorvastatin and
Citation Placebo on Endothelial Function, Oxidative Stress and Inflammatory Markers in Patients with Type 2
Diabetes Mellitus. Drugs R D. 2008;9(4):243-250.
Study
RCT: Randomized, parallel-group, placebo controlled trial
Design
Class A
Quality
+ (Positive) - (Negative)  (Neutral) (choose one):  Neutral
Rating
Research Evaluate the effects of standardized preparation of curcuminoids supplementation on endothelial
Purpose function, oxidative stress and inflammatory markers in people with type 2 diabetes.
• Ages 21-80 years
Inclusion • Fasting plasma glucose ≥130mg/dL
Criteria • Glycosylated hemoglobin (HbA1c) 7% to 11%
• Stable antihyperglycemic medication (2-month period).
• Severe uncontrolled hyperglycemia (HbA1c >11%)
• Treatment with lipid-lowering drugs during the previous 3 months
• Smoking
• Chronic alcoholism
Exclusion • Uncontrolled hypertension
Criteria • Cardiac arrhythmia
• Congestive heart failure
• Hepatic and renal impairment
• Any other serious chronic disease requiring active treatment
• Treatment with other herbal supplements.
Recruitment: Current patients of Nizam’s Institute of Medical Sciences in Hyderabad, Andhra
Pradesh, India
Blinding used: No
Design: Randomized, parallel group, placebo-controlled 8-week study conducted between October
2005 and January 2007.
Intervention: Participants were randomized into three groups. The curcumin supplementation group
Description received two 150 mg capsules of NCB-02, a standardized preparation of C3 curcuminoids (curcumin
of Study
Protocol 72%, demethoxy curcumin 18.08%, bisdemethoxy curcumin 9.42%) twice a day (600mg/daily) for
eight weeks. The other two groups received either a statin (Atorvastatin 10 mg) once daily or a
placebo twice daily for eight weeks. Blood was drawn at baseline and post treatment for
determination of levels of oxidative stress marker (lipid peroxidation index) malondialdehyde
(MDA), and inflammatory cytokines tumour necrosis factor-α (TNF-α) and interleukin-6(IL-6),
along with HbA1c, fasting blood glucose (FBG) a lipid profile and other measures relevant to the
study (liver function, endothelial function etc).
9
Statistical Analysis: Graphpad Prism software version 4 (Graphpad Software Inc., San Diego, CA,
USA).
• Between group analysis: ANOVA, Tukey’s multiple comparison test
• Within group analysis: paired t-test.
• P-value <0.05 was considered statistically significant.
Timing of Measurements:
• Physical examination, laboratory evaluation and endothelial function assessment
• Baseline
• End of treatment (8 weeks post baseline)
• Assessment, laboratory evaluation (blood draws) taken in the morning after overnight fast,
12 hours since the last dose of medication
Dependent Variables:
• HbA1c %
• Fasting blood glucose (FBC)
Data • tumor necrosis factor- (TNF-)
Collection • interleukin-6 (IL-6)
Summary • malondialdehyde (MDA)
• low density lipoprotein- cholesterol (LDL-C)
• endothelin-1 (ET-1)
Plasma glucose, HbA1c, and lipid profile (HDL-C mentioned explicitly, but not LDL-C specifically)
were "measured using appropriate standard techniques”. MDA was estimated using
spectrophotometrically using using thiobarbituric acid reactive substancesmethod and ET-1, TNF-,
and IL-6 were measured in plasma by the ELISA method.
Independent Variables: NCB-02 curcumin supplementation
Control Variables: Placebo supplementation, baseline comparison for each group
Initial: Study Total 72
Attrition (final N):
• Study Total: 67 (35 Males, 32 Females)
• NCB-02 group total: 23 (12 Males, 11 Females)
Three subjects were lost to follow-up; two others relocated and could not complete study (group not
specified).
Description
of Actual
Age (mean±SD): Placebo group: 49.75±8.18, Atorvastatin group: 50.47±10.35, NCB-02 group:
Data 55.52±10.76
Sample
Ethnicity: No Data
Other relevant demographics: No significant difference between treatment groups in sex, age, body
mass index (BMI), blood pressure (BP), FBG, HbA1c, lipid profile or baseline serum levels of
inflammatory cytokines and malondialdehyde. Exact p-value not given.
Anthropometrics: No significant difference between treatment groups in BMI. Data and exact p-
value not provided.
10
Location: Hyderabad, Andhra Pradesh, India.
Key Findings:
NCB-02 600 mg curcumin daily
Parameter Placebo (n=21) (n=23) p-value
Pretreatment Post-treatment Pretreatment Post-treatment
Fasting glucose
(mg/dL) 161.2±20.0 158.1±17.4 155.0±17.9 150.2±18.8 ND*
HbA1c (%) 7.8±0.6 7.8±0.6 8.0±0.9 8.03±0.8 ND*
LDL-C (mg/dL) 125.3±34.9 122.2±35.6 120.4±42.1 111.3±37.7 ND*
Summary IL-6 (pg/mL) 4.3±2.4 3.6±2.2 4.5±0.9 1.8±0.7** <0.01
of Results
TNFα (pg/mL) 3.6±1.6 4.0±1.4 4.1±2.1 1.5±1.2** <0.01
MDA (nmol/mL) 3.89±1.5 4.0±1.2 4.1±0.7 2.5±0.3** <0.001
*ND No data given **Statistically significant (p<0.05) compared to baseline.
Other Findings:
• Adverse reports recorded on case report form
• Two participants experienced mild diarrhea
• No serious adverse events reported
Treatment with NCB-02 significantly improved endothelial function and reduced levels of
Author inflammatory cytokines and markers of oxidative stress in this study, but did not significantly reduce
Conclusion
LDL-C.
Strengths:
• One the few studies to test curcumin supplementation in humans/in vivo
• High dose/improved bioavailability of standard curcumin supplement used for intervention
• Placebo controlled
Weaknesses:
• Small number of participants
• Participant compliance/dropout rates not discussed
Reviewer
Comment • Method of randomization not identified
• Long term effects unknown
• Recruited from one institute in India
• Ethnic diversity not identified
• Baseline characteristics statistical significance not reported
• Blinding not addressed
• Study limitations not addressed in sufficient detail.
Funding Himalaya Healthcare Pvt Ltd, Bangalore, India
Source
11
Quality Criteria Checklist: Primary Research
Symbols Used Explanation
Positive – Indicates that the report has clearly addressed issues of
+
inclusion/exclusion, bias, generalizability, and data collection and analysis
-- Negative – Indicates that these issues have not been adequately addressed.
Neutral – indicates that the report is neither exceptionally strong nor exceptionally

weak
Relevance Questions
1. Would implementing the studied intervention or procedure (if found successful) result
in improved outcomes for the patients/clients/population group? (NA for some Epi 1 Yes
studies)
2. Did the authors study an outcome (dependent variable) or topic that the
2 Yes
patients/clients/population group would care about?
3. Is the focus of the intervention or procedure (independent variable) or topic of study a
3 Yes
common issue of concern to dietetics practice?
4. Is the intervention or procedure feasible? (NA for some epidemiological studies) 4 Yes
If the answers to all of the above relevance questions are “Yes,” the report is eligible for designation with a plus
(+) on the Evidence Quality Worksheet, depending on answers to the following validity questions.
Validity Questions
1. Was the research question clearly stated? 1 Yes

1.1. Was the specific intervention(s) or procedure (independent variable(s))
identified?
1.1 Yes
1.2. Was the outcome(s) (dependent variable(s)) clearly indicated? 1.2 Yes
1.3. Were the target population and setting specified? 1.3 Yes
2. Was the selection of study subjects/patients free from bias? 2 Yes
2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease
progression, diagnostic or prognosis criteria), and with sufficient detail and 2.1 Yes
without omitting criteria critical to the study?
2.2. Were criteria applied equally to all study groups? 2.2 Yes
2.3. Were health, demographics, and other characteristics of subjects described?
2.4. Were the subjects/patients a representative sample of the relevant population? 2.3 Yes
2.4 Unclear
3. Were study groups comparable?
3.1. Was the method of assigning subjects/patients to groups described and 3 No
unbiased? (Method of randomization identified if RCT)
3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., 3.1 No
demographics) similar across study groups at baseline?
3.3. Were concurrent controls used? (Concurrent preferred over historical controls.)
3.4. If cohort study or cross-sectional study, were groups comparable on important 3.2 Unclear
confounding factors and/or were preexisting differences accounted for by using
appropriate adjustments in statistical analysis? 3.3 Yes
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. Criterion may not be applicable in some cross-
3.4 N/A
sectional studies.)
3.6. If diagnostic test, was there an independent blind comparison with an 3.5 N/A
appropriate reference standard (e.g., “gold standard”)?
3.6 N/A
12
4. Was method of handling withdrawals described? 4 No
4.1. Were follow up methods described and the same for all groups?
4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, 4.1 Yes
attrition rate) and/or response rate (cross-sectional studies) described for each
group? (Follow up goal for a strong study is 80%.) 4.2 No
4.3. Were all enrolled subjects/patients (in the original sample) accounted for? 4.3 Unclear
4.4. Were reasons for withdrawals similar across groups
4.5. If diagnostic test, was decision to perform reference test not dependent on 4.4 Unclear
results of test under study?
4.5 N/A
5. Was blinding used to prevent introduction of bias?
5 Unclear
5.1. In intervention study, were subjects, clinicians/practitioners, and investigators
blinded to treatment group, as appropriate?
5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured 5.1 Unclear
using an objective test, such as a lab value, this criterion is assumed to be met.)
5.3. In cohort study or cross-sectional study, were measurements of outcomes and 5.2 Yes
risk factors blinded?
5.4. In case control study, was case definition explicit and case ascertainment not 5.3 N/A
influenced by exposure status?
5.5. In diagnostic study, were test results blinded to patient history and other test 5.4 N/A
results?
5.5 N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any 6 Yes
comparison(s) described in detail? Were intervening factors described?
6.1. In RCT or other intervention trial, were protocols described for all regimens 6.1 Yes
studied?
6.2. In observational study, were interventions, study settings, and 6.2 N/A
clinicians/provider described?
6.3. Was the intensity and duration of the intervention or exposure factor sufficient 6.3 Yes
to produce a meaningful effect?
6.4. Was the amount of exposure and, if relevant, subject/patient compliance 6.4 No
measured? 6.5 Yes
6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described?
6.6. Were extra or unplanned treatments described? 6.6 No
6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?
6.8. In diagnostic study, were details of test administration and replication sufficient? 6.7 Yes
6.8 N/A
7. Were outcomes clearly defined and the measurements valid and reliable? 7 Yes
7.1. Were primary and secondary endpoints described and relevant to the question?
7.2. Were nutrition measures appropriate to question and outcomes of concern? 7.1 Yes
7.3. Was the period of follow-up long enough for important outcome(s) to occur? 7.2 Yes
7.4. Were the observations and measurements based on standard, valid, and reliable
data collection instruments/tests/procedures? 7.3 Yes
7.5. Was the measurement of effect at an appropriate level of precision? 7.4 Yes
7.6. Were other factors accounted for (measured) that could affect outcomes?
7.5 Unclear
7.7. Were the measurements conducted consistently across groups?
7.6 Yes
7.7 Yes
13
8. Was the statistical analysis appropriate for the study design and type of outcome 8 No
indicators?
8.1. Were statistical analyses adequately described the results reported 8.1 Yes
appropriately?
8.2. Were correct statistical tests used and assumptions of test not violated? 8.2 Unclear
8.3. Were statistics reported with levels of significance and/or confidence intervals?
8.4. Was “intent to treat” analysis of outcomes done (and as appropriate, was there 8.3 Unclear
an analysis of outcomes for those maximally exposed or a dose-response
analysis)? 8.4 No
8.5. Were adequate adjustments made for effects of confounding factors that might 8.5 No
have affected the outcomes (e.g., multivariate analyses)?
8.6. Was clinical significance as well as statistical significance reported? 8.6 Unclear
8.7. If negative findings, was a power calculation reported to address type 2 error?
8.7 No
9. Are conclusions supported by results with biases and limitations taken into 9 Yes
consideration?
9.1. Is there a discussion of findings?
9.1 Yes
9.2. Are biases and study limitations identified and discussed? 9.2 No
10. Is bias due to study’s funding or sponsorship unlikely? 10 Yes
10.1. Were sources of funding and investigators’ affiliations described? 10.1 Yes
10.2. Was there no apparent conflict of interest?
10.2 Yes
MINUS/NEGATIVE (-)
If most (six or more) of the answers to the above validity questions are “No,” the report should be designated with
a minus (-) symbol on the Evidence Worksheet.
NEUTRAL ()
If the answers to validity criteria questions 2, 3, 6, and 7 do not indicate that the study is exceptionally strong, the
report should be designated with a neutral () symbol on the Evidence Worksheet.
PLUS/POSITIVE (+)
If most of the answers to the above validity questions are “Yes” (including criteria 2, 3, 6, 7 and at least one
additional “Yes”), the report should be designated with a plus symbol (+) on the Evidence Worksheet.

Primary Research
Khajehdehi P, Pakfetrat M, Javidnia K, et al. Oral supplementation of turmeric attenuates proteinuria,
Citation transforming growth factor-β and interleukin-8 levels in patients with overt type 2 diabetic nephropathy:
A randomized, double-blind and placebo-controlled study. Scand J Urol Nephrol. 2011;45(5):365-370.
Study
RCT: Randomized, double blind, placebo controlled trial
Design
Class A
Quality
Rating
Research The effects of oral turmeric supplementation on biomarkers for decline in renal function in people with
Purpose overt type 2 diabetic nephropathy.
14
Inclusion • Overt type 2 diabetic nephropathy
Criteria • Normal kidney function
• Uncontrolled blood pressure
• Recurrent or relapsing urinary tract infection
Exclusion • Bacteriuria
Criteria • Pyuria
• Hematuria
• Failure to sign written informed consent
Recruitment: Diabetic patients of the Diabetes Clinic of Nader Kazemi Outpatient Department, Shiraz
University of Medical Sciences
Blinding used:
• Starch placebo of identical shape size and color for the same 2 months
• Supplementation was administered in separate room by nurse not affiliated with research team
Design: Randomized, double-blind, placebo-controlled 2 month study.
Intervention: Participants were randomized into two groups. The turmeric supplementation group
received a 500mg capsule of turmeric, containing 22.1mg active curcumin, with each meal (3 capsules
daily) for 2 months. Turmeric rhizomes were powdered, encapsulated and analyzed for curcumin content
by a separate department at the Shiraz University of Medical Sciences. The control group received an
identical placebo, three times daily, for the same duration. Participants were examined weekely by two
Description investigator of the study and by the physician treating them at the diabetes clinic. No changes were
of Study
Protocol
made to patients diet or drug regimen during the study. Levels of serum interleuin-8 (IL-8) and tumor
necrosis factor (TNF-), and urinary levels of IL-8, along with other parameters relevant to the interest
of the study (e.g. blood sugar, low density lipoprotein-cholesterol (LDL-C), transforming growth factor
(TGF-, urinary protein) were measured at baseline and post treatment.
Statistical Analysis: Data analyzed by Statistical Package for the Social Sciences software version 15.0
(SPSS, Chicago, IL,USA).
• Associations between categorical variables: chi-squared test
• Quantitative data (mean±standard deviation) comparison: non-parametric Mann–Whitney test
for two groups
• Pre-/post-test data variation analysis: Wilcoxon signed ranks test, non-parametric paired t test
• All tests two sided
• P-values <0.05 considered significant
Timing of Measurements: Laboratory urinary and serum evaluation at baseline and end of treatment (2
months post baseline).
Data Dependent Variables:
Collection
Summary
• fasting blood sugar (FBS)
• tumor necrosis factor- (TNF-)
• interleukin-8 (IL-8)
15
• low density lipoprotein- cholesterol (LDL-C)
• transforming growth factor- (TGF-)
Enzyme-linked immunoassay (ELISA) Reader Instrument Human GmbH, 15 BMS 254 Human TGF-,
Diamed EurogenTNF- and AviBionHuman IL-8 kits were used for the measurement of serum TGF-,
IL-8 and TNF-, and urinary TGF- and IL-8 using an ELISA method. Independent Variables:
Turmeric supplementation
Control Variables: Placebo supplementation group, Investigator blinding to type of supplementation
administered, baseline comparison for each group

• Turmeric group 20 (9 Males, 11 Females)
Age (mean ± standard deviation): Placebo group: 52.6±9.7, Turmeric group: 52.9±9.2
Description
Ethnicity: No data
of Actual Other relevant demographics: There was no significant difference between the two groups age or
Data
Sample gender and no significant difference between treatment groups in blood pressure, FBS, lipid profile or
baseline serum levels of inflammatory cytokines. All patients had history of diabetes for more than 7
years. Most did not follow low-carbohydrate diets and suffered from poorly controlled diabetes. No
information on dropout rate or rate of compliance.
Anthropometrics: No reported data
Location: Shiraz, Iran
Key Findings:
Parameter Turmeric 4.42% 1500mg/66.3mg
Placebo curcumin daily Btwn
(n=20) (n=20) groups
Pre- Post- P- Pre- Post- P- P-
treatment treatment value treatment treatment value value
Fasting
glucose
(mg/dL) 169.5±76.3 123.6±41.9 0.06 179.0±65.5 155.8±90.9 0.21 0.39
Summary LDL-C
of Results
(mg/dL) 108.3±39.9 84.4±12.2 0.14 114.1±34.6 110.3±41.9 0.71 0.4
TNFα
(pg/mL) 16.4±14.2 18.4±22.3 0.57 12.8±2.9 18.4±24.1 0.82 0.9
IL-8
(pg/mL) 80.8±102.7 88.4±116.3 0.1 41.4±50.3 30.6±75.2* 0.002* 0.76
IL-8 urinary
(pg/mL) 53.1±80.5 50.4±81.6 0.61 99.1±97.9 43.6±55.0* 0.002* 0.002*
*Statistically significant (p<0.05) compared to baseline.
Other Findings: No adverse effects were reported from this study.
16
Oral turmeric supplementation significantly decreased both serum and urinary IL-8 levels. Because IL-8
plays a major role in the pathogenesis of diabetic nephropathy and
Author inflammatory responses, and contribute to oxidative stress in ESRD, short-term oral turmeric
Conclusion
supplementation may prove to be a safe and effective alternative therapy for type 2 diabetic
nephropathy.
Strengths:
• One the few studies to test turmeric (curcumin) supplementation in humans/in vivo
• Intervention uses turmeric supplementation; curcumin in its natural state
• Double-blinded, Placebo-controlled (yet methods not entirely clear)
Weaknesses:
Reviewer • Low doses and bioavailability of turmeric (curcumin) questionable
Comment
• Participant compliance not discussed
• Recruited from one institute in Iran
• Method of randomization not identified
• Demographic, anthropometric data limited for baseline comparison and confounding factors
analysis
Funding Shiraz Nephro-Urology Research Center of Shiraz University of Medical Sciences, Shiraz, Iran
Source

+

weak
Relevance Questions
studies)
2 Yes
3 Yes
If the answers to all of the above relevance questions are “Yes,” the report is eligible for designation with a
plus (+) on the Evidence Quality Worksheet, depending on answers to the following validity questions.
17
Validity Questions

identified?
1.1 Yes
2.4 Unclear
3.1. Was the method of assigning subjects/patients to groups described and 3 Unclear
3.4. If cohort study or cross-sectional study, were groups comparable on important 3.2 Yes
3.4 N/A
sectional studies.)
3.6 N/A
4. Was method of handling withdrawals described? 4 Yes

group? (Follow up goal for a strong study is 80%.) 4.2 N/A
4.3. Were all enrolled subjects/patients (in the original sample) accounted for? 4.3 Yes
4.5 N/A
5 Unclear
5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured 5.1 Unclear
results?
5.5 N/A
18
studied?
measured? 6.5 Yes
6.6. Were extra or unplanned treatments described? 6.6 No
6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?
6.8. In diagnostic study, were details of test administration and replication sufficient? 6.7 Yes
6.8 N/A
7.5. Was the measurement of effect at an appropriate level of precision? 7.4 Yes
7.5 Unclear
7.6 Yes
7.7 Yes
8. Was the statistical analysis appropriate for the study design and type of outcome 8 Yes
indicators?
appropriately?
8.2. Were correct statistical tests used and assumptions of test not violated? 8.2 Yes
8.4. Was “intent to treat” analysis of outcomes done (and as appropriate, was there 8.3 Yes
analysis)? 8.4 Yes
8.5. Were adequate adjustments made for effects of confounding factors that might 8.5 No
8.6. Was clinical significance as well as statistical significance reported? 8.6 Yes
8.7 No
consideration?
9.1 Yes
9.2. Are biases and study limitations identified and discussed? 9.2 Yes
10.2 Yes
MINUS/NEGATIVE (-)
If six or more of the answers to the above validity questions are “No,” the report should be designated with a minus (-) symbol on Worksheet.
NEUTRAL ()
If the answers to validity criteria questions 2, 3, 6, and 7 do not indicate that the study is exceptionally strong, the report should be designated
with a neutral () symbol on the Evidence Worksheet.
PLUS/POSITIVE (+)
If most of the answers to the above validity questions are “Yes” (including criteria 2, 3, 6, 7 and at least one additional “Yes”), the report
should be designated with a plus symbol (+) on the Evidence Worksheet.
19
Primary Research
Na L, Yan B, Jaing S, et al. Curcuminoids Target Decreasing Serum Adipocyte-fatty Acid
Citation Binding Protein Levels in Their Glucose-lowering Effect in Patients with Type 2 Diabetes.
Biomed Environ Sci. 2014; 27(11):902-906.
Study Design RCT: Randomized, double blind, placebo controlled trial
Class A
Quality
Rating
Effect of curcuminoids on human type 2 diabetes and the adipocyte-fatty acid binding protein
Research
(A-FABP) promtion of curcumin regulation of lipid metabolism, oxidative stress and
Purpose
inflammation.
• Overweight/obese: body mass index (BMI) ≥ 24.0
Inclusion • Type 2 diabetes
Criteria • Fasting blood glucose ≥ 7.0 mmol/L or postprandial blood glucose ≥ 11.1 mmol/L
• On current optimal therapeutic regimens > 6 months.
• Type 1 diabetes
• Malignancies, thyroid, or any other endocrine diseases likely to interfere with the study
Exclusion • Diabetic ketoacidosis and infection in the previous 3 months
Criteria • Pregnancy or breastfeeding
• Incomplete information
• Unwilling to comply with intervention
Recruitment: Participants recruited from the 2nd Affiliated Hospital of Harbin Medical
University in 2009.
Blinding used:
• Starch placebo identical in appearance for the same duration
• Study participants and staff responsible for data collection, outcome measures were
blinded to allocation in groups
Design: Randomized, double-blind, placebo-controlled 3 month study from October 10, 2009
to January 10, 2010.
Intervention: Participants were sorted by blood glucose concentration and randomized into two
Description
of Study groups with random numbers generated by SPSS (version 13.01S, Beijing Stats Data Mining
Protocol
Co., Beijing, China). Differences in blood glucose, diabetes duration, current therapeutic
regimen, lipids, and gender between the two groups was tested when study subjects were first
recruited to ensure the homogeneity of outcome variables at baseline between the placebo and
curcuminoids groups. The trial group (n=50) received a 150mg capsule of 97.49% curcuminoids
(curcumin 36.6%, demethoxycurcumin 18.85%, bisdemethoxycurcumin 42.58%) twice daily
that were purchased in China and analyzed by high-performance liquid chromatography. The
control group (n=50) received a placebo twice daily for the same duration. Participants were
asked to maintain their diet, lifestyle and drug regimens during the intervention and to self-
20
monitor blood glucose. They were interviewed every 2 weeks via questionnaire for study
compliance.
Statistical Analysis:
• Means ± SD for continuous variables
• Percentage for categorical variables
• Comparison between groups baseline/follow-up: independent-samples t test/Analysis of
covariance (ANCOVA).
• ANCOVA adjusted for age, sex, smoking history, lipid-lowering drug use, physical
activity level, blood pressure, diabetes duration, drug treatment, and baseline values.
Correlations between A-FABP and other parameters analyzed using Pearson correlation
and Partial Pearson correlation analysis after adjustments for age, sex, BMI, and drug
treatment.
• Stepwise multi-linear regression analysis performed to identify A-FABP as a predictor
of selected serum markers.
• P<0.05 considered significant.
Timing of Measurements: Blood was collected after overnight fasting and before morning
medications. Laboratory evaluation at baseline and end of treatment (3 months post baseline).
• Low density lipoprotein (LDL-C)
• Fasting blood glucose
• HbA1c (%)
• Adipocyte-fatty acid binding protein (A-FABP)
• C-reactive protein (CRP)
• Interleukin-6 (IL-6)
• Tumor necrosis factor-α (TNF-α)
Data
Collection • Malondialdehyde (MDA)
Summary
• Serum superoxide dismutase (SOD)
• Glutathione peroxidase (SGH-Px)
Serum concentrations of LDL-C, glucose, and HbA1c measured using ROCHE Modular P800
Automatic Biochemical Analyzer (Roche Diagnostics).
Serum A-FABP level assessed by ELISA method (R&D System).
Serum CRP, TNF-α, and IL-6 determined using ELISA method with commercial kits (R&D
System).
Serum SOD, SGH-Px activity and MDA concentration measured with commercial kits using
enzymatic methods (Jiancheng Technology, Nanjing, China).
Independent Variables: Curcuminoid supplementation
21
Control Variables: Placebo supplementation group, investigator blinding

• Curcuminoid group 50 (24 Males, 26 Females)
Age (mean ± standard deviation): Placebo group: 54.72±8.34, Curcuminoid group: 55.42±6.40
Ethnicity: No data
Descriptionof
Actual Data Other relevant demographics: Baseline characteristics comparable between two groups with
Sample A-FABP showing positive correlations with participants’ blood pressure, HbA1c, blood glucose,
LDL-C, CRP, TNF-, and IL-6. All participants taking oral hypoglycemic agents, insulin or
both. Some participants also taking lipid-lowering drugs or antihypertensive medications.
Anthropometrics: Baseline characteristics between the two groups comparable, with A-FABP
showing positive correlations with participants BMI, waist circumference.
Location: China
Key Findings:
Parameter Placebo (n=50) C3 300mg/108mg curcumin
Between
daily (n=50)
Groups
Pre- Post- Pre- Post-
treatment treatment treatment treatment P-value
Fasting glucose
(mg/dL) 151.4±39.1 147.1±37.1 154.4±47.9 131.0±31.9* <0.01
HbA1c (%) 7.7±2.1 8.0±2.9 7.8±1.8 7.0 ± 2.0* 0.031
LDL-C (mg/dL) 77.8±20.7 74.7±21.1 77.4±21.6 68.4±18.5 0.115
Summary of A-FABP (ng/ml) No Data 34.5 ± 7.0 No Data 26.2±10.0* <0.001
Results CRP (mg/L) No Data 2.6 ± 1.1 No Data 2.1±1.0* <0.001
IL-6 (pg/ml) No Data 3.9 ± 2.0 No Data 2.7±1.6* <0.001
TNFα (pg/ml) No Data 2.1 ± 0.8 No Data 1.7±0.7* 0.047
MDA (pg/ml) No Data No Data No Data No Data NS/ND
*Statistically significant (p<0.05) compared to placebo group. Adjusted for baseline values, age,
sex, smoking history, physical activity level, diabetes duration, and drug treatment.
NS= Non Significant, ND=no data; mmol/L to mg/dL multiplier 18
Other Findings: No significant change in levels of MDA, SOD or SGH-Px. No adverse effects
were reported from this study.
These results collectively support the hypothesis that A-FABP probably links curcuminoids to
with their effect on oxidative stress and inflammation. The anti-diabetic effects of curcuminoids
Author
Conclusion may in part be due to the reduction in serum A-FABP level, which has been associated with
improved metabolic parameters in type 2 diabetes.
Reviewer Strengths:
Comments
22
• One the few studies to test curcumin supplementation in humans/in vivo
• Use of active curcuminoid extract in supplement used for intervention
• Double-blinded, placebo-controlled (yet methods not entirely clear)
Weaknesses:
• Curcumin content of curcuminoids questionably low
• Baseline comparison within groups not reported/discussed
• Recruited from one medical university in China
• Ethnic diversity not identified
• Study limitations not adequately addressed
Funding China Postdoctoral Science Foundation and Heilongjiang Postdoctoral Science Foundation.
Source

+

weak
Relevance Questions
studies)
2 Yes
3 Yes
If the answers to all of the above relevance questions are “Yes,” the report is eligible for designation with a
plus (+) on the Evidence Quality Worksheet, depending on answers to the following validity questions.
Validity Questions

identified?
1.1 Yes
1.3. Were the target population and setting specified?
1.3 Yes
23
2.4 Unclear
3.1. Was the method of assigning subjects/patients to groups described and 3 Yes
3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., 3.1 Yes
3.4. If cohort study or cross-sectional study, were groups comparable on important 3.2 Yes
3.4 N/A
sectional studies.)
3.6 N/A
4. Was method of handling withdrawals described? 4 Yes
group? (Follow up goal for a strong study is 80%.) 4.2 Yes
4.3. Were all enrolled subjects/patients (in the original sample) accounted for? 4.3 Yes
4.5. If diagnostic test, was decision to perform reference test not dependent on 4.4 Yes
4.5 N/A
5 Yes
5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured 5.1 Yes
results?
5.5 N/A
studied?
6.3 Yes
24
6.4. Was the amount of exposure and, if relevant, subject/patient compliance 6.5 Yes
measured?
6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? 6.6 No
6.6. Were extra or unplanned treatments described?
6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? 6.7 Yes
6.8. In diagnostic study, were details of test administration and replication sufficient?
6.8 N/A
7. Were outcomes clearly defined and the measurements valid and reliable? 7 Unclear
7.5. Was the measurement of effect at an appropriate level of precision? 7.4 Unclear
7.5 Unclear
7.6 Yes
7.7 Yes
8. Was the statistical analysis appropriate for the study design and type of outcome 8 Unclear
indicators?
8.1. Were statistical analyses adequately described the results reported 8.1 No
appropriately?
8.2. Were correct statistical tests used and assumptions of test not violated? 8.2 Unclear
analysis)? 8.4 No
8.5. Were adequate adjustments made for effects of confounding factors that might 8.5 Yes
8.6. Was clinical significance as well as statistical significance reported? 8.6 Yes
8.7 No
9. Are conclusions supported by results with biases and limitations taken into 9 Unclear
consideration?
9.1 Yes
9.2. Are biases and study limitations identified and discussed? 9.2 Unclear
10.2 Yes
MINUS/NEGATIVE (-)
If most (six or more) of the answers to the above validity questions are “No,” the report should be designated
with a minus (-) symbol on the Evidence Worksheet.
NEUTRAL ()
PLUS/POSITIVE (+)
25
Primary Research
Yang H, Xu W, Zhou Z, et al. Curcumin Attenuates Urinary Excretion of Albumin in Type II
Diabetic Patients with Enhancing Nuclear Factor Erythroid-Derived 2-Like 2 (Nrf2) System and
Citation
Repressing Inflammatory Signaling Efficacies. Exp Clin Endocrinol Diabetes. 2015;123(06):360-
367.
Study
Non controlled trial
Design
Class D
Quality
+ (Positive) - (Negative)  (Neutral) (choose one): - Negative
Rating
Research Effect of curcumin interventions on development of diabetic kidney disease and activation the
Purpose antioxidative master Nrf2 system in humans.
Inclusion
• Type 2 diabetes
Criteria
Exclusion
• None listed
Criteria
Recruitment: No information provided
Blinding used: No; Only single study group, laboratory values
Design: Non controlled 15 day trial.
Intervention: All participants of the study were given a dose of 500 mg curcumin/turmeric daily
for 15 days. “Curcumin” purchased from ORGANIKA Health Products, Canada. Those diagnosed
with overt DKD received curcumin supplementation for an extended 30 days total. Fasting blood
glucose (FBG), low-density lipoprotein (LDL-C), lipopolysaccharide (LPS), malondialdehyde
Description (MDA) and other measures relevant to the study (e.g. urinary microalbuminuria, blood lymphocyte
of Study inflammatory signaling, Nrf2 system regulated proteins, and fecal bacteria DNA analysis) were
Protocol
taken from samples before and after the 15 day treatment and again 30 days post baseline for those
treated for the additional 15 days. No changes were made to patients drug regimen during the
study.
Statistical Analysis:
• Data expressed as mean ± standard error of the mean
• Paired-sample T test or analysis of variance.
• P-values <0.05 considered significant.
Timing of Measurements: Overnight fasting blood samples were collected before and after the
15-day curcumin intervention. Overnight urine samples collected 8PM to 8AM.
Data • Fasting blood glucose (FBG)
Collection • Low-density lipoprotein (LDL-C)
Summary • Lipopolysaccharide (LPS)
• Malondialdehyde (MDA)
• Urinary microalbuminuria (U-mAlb)
• Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα)
26
• Caspase 3
• Nrf2
• Superoxide dismutase (SOD) 1 & 2
• NAD(P)H:quinone oxidoreductase-1 (NQO-1)
FBG and LDL-C analysis: clinical laboratories

LPS assay: LPS ELISA kit (CUSABIO, Wuhan, China)
Plasma MDA: MDA assay kit (Jiancheng Company, Nanjing, China)
U-mAlb assay: Quik Read U-mAlb kit (Orion Diagnostica Oy, Espoo, Finland) with enzyme
linked immunosorbent assay (ELISA) method.
Lymphocyte isolation: Lymphocyte isolation kit (Shanghai Kehua Bio-Engineering., Shanghai,
China)
Western blot analysis: BCA protein assay kit (Beyotime Institute of Biotechnology, Jiangsu,
China), Immunoreactive protein visualization enhanced chemiluminescence (Beijing ComWin
Biotech., Beijing, China), Intensities of bands phosphorimager analysis.
Antibodies: Nrf2 (Santa Cruz Biotechnology, Shanghai, China), IκBα (Proteintech Group,
Guangzhou, China), SOD 1 (Proteintech Group, Guangzhou, China), SOD 2 (Abgent, San
Diego, CA, USA), NQO-1 (Cell Signaling, Technology, Guangzhou, China), Caspase 3
(Sangon Biotech, Shanghai, China)
Independent Variables: Curcumin supplementation

Control Variables: Baseline comparison with each participant serving as their own control
Initial: 14 (8 Males, 6 Females)

Attrition (final N): 14
Age (mean ± standard deviation):
Males: 60.6 ± 4.2 (47–85 years)
Females: 69.1 ± 2.2 (62–82 years)
Ethnicity: No data
Other relevant demographics:
Description • Overt DKD (U-mAlb >200 mg/L): n=4

of Actual • Preclinical DKD (U-mAlb 20-200 mg/L): n=3
Data
Sample • Normal Range (U-mAlb <20 mg/L): n=7
• Average for study: U-mAlb 214.9 ± 104.5 mg/L, n=14
Twelve patients on current drug regimens. No information on dropout rate or rate of
compliance.
Anthropometrics: BMI
Males: 22.4 ± 1.0
Females: 23.7 ± 1.5
Location: Fuzhou, China
27
Key Findings:
Turmeric/Curcumin 500mg?/daily (n=14)

Parameter Pretreatment Post-treatment n P-value
Fasting glucose (mg/dL) 147.6±14.4 145.8±18.0 ** NS**
LDL-C (mg/dL) 64.8±5.4 50.4±3.6* ** <0.01
LPS (ng/mL) 38.1±4.3 28.8±5.0* 7 <0.01
MDA (nmol/L) 13.9±1.2 3.5±0.6* 7 <0.001
IκB (optical density) 0.6±0.0 1.24±0.1* 6 < 0.01
Summary Caspase 3 1.0±0.1 0.4±0.0* 6 <0.01
of Results
NQO-1 (Nrf2) 0.3±0.1 0.7±0.1* 6 < 0.01
SOD 1 & 2 (Nrf2) ** + ** **
? Curcumin content of supplement unclear
*Statistically significant (p<0.05) compared to baseline.
**Exact results not reported
+ Increase in activity
Note mmol/L to mg/dL multiplier 18
Other Findings: Noted more improvement in biomarkers for those with than without DKD but
not statistically significant. Adverse effects not addressed from this study.
Curcumin can prevent DKD by reducing U-mAlb excretion through anti-oxidative effect of Nrf2
Author
Conclusion upregulation and attenuate DKD by modulating gut microbiota, LPS, inflammatory pathway.
Strengths:
• One the few studies to test turmeric (curcumin) supplementation in humans/in vivo
• Examines gut interaction with turmeric
Weaknesses:
Reviewer • Lack of study protocols and control variables
Comments
• Study dosing levels questionable and at 33% of manufacturer recommendations
• Study participant recruiting methods unknown
• Ethnic diversity of participants not identified
• Study limitations not addressed
Funding Chinese National Science Foundation grant (No. 81270886) to ZY.
Source
28
+

weak
Relevance Questions
1. Would implementing the studied intervention or procedure (if found successful)
result in improved outcomes for the patients/clients/population group? (NA for 1 Yes
some Epi studies)
2 Yes
3 Yes
If the answers to all of the above relevance questions are “Yes,” the report is eligible for designation with a plus
(+) on the Evidence Quality Worksheet, depending on answers to the following validity questions.
Validity Questions

identified?
1.1 Yes
2. Was the selection of study subjects/patients free from bias? 2 Unclear
progression, diagnostic or prognosis criteria), and with sufficient detail and 2.1 No
2.2. Were criteria applied equally to all study groups? 2.2 N/A
2.4 Unclear
3.1. Was the method of assigning subjects/patients to groups described and 3 No
3.3. Were concurrent controls used? (Concurrent preferred over historical
controls.) 3.2 No
3.4. If cohort study or cross-sectional study, were groups comparable on important
confounding factors and/or were preexisting differences accounted for by 3.3 No
using appropriate adjustments in statistical analysis?
3.4 N/A
sectional studies.) 3.5 N/A
3.6. If diagnostic test, was there an independent blind comparison with an
appropriate reference standard (e.g., “gold standard”)? 3.6 N/A
29
4. Was method of handling withdrawals described? 4 Unclear
4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow 4.1 Yes
up, attrition rate) and/or response rate (cross-sectional studies) described for
each group? (Follow up goal for a strong study is 80%.) 4.2 Unclear
4.3. Were all enrolled subjects/patients (in the original sample) accounted for? 4.3 Unclear
4.5 N/A
5 Unclear
5.2. Were data collectors blinded for outcomes assessment? (If outcome is 5.1 Unclear
measured using an objective test, such as a lab value, this criterion is assumed
to be met.) 5.2 Yes
5.3. In cohort study or cross-sectional study, were measurements of outcomes and
risk factors blinded? 5.3 N/A
5.4. In case control study, was case definition explicit and case ascertainment not
influenced by exposure status? 5.4 N/A
5.5. In diagnostic study, were test results blinded to patient history and other test
results? 5.5 N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any 6 Unclear
6.1. In RCT or other intervention trial, were protocols described for all regimens 6.1 No
studied?
measured? 6.5 Yes
6.6. Were extra or unplanned treatments described? 6.6 Yes
6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all
groups? 6.7 Yes
6.8. In diagnostic study, were details of test administration and replication
sufficient? 6.8 N/A
7.1 Yes
7.2. Were nutrition measures appropriate to question and outcomes of concern?
7.4. Were the observations and measurements based on standard, valid, and 7.3 Yes
reliable data collection instruments/tests/procedures?
7.4 Yes
7.5. Was the measurement of effect at an appropriate level of precision?
7.6. Were other factors accounted for (measured) that could affect outcomes? 7.5 Unclear
7.7. Were the measurements conducted consistently across groups? 7.6 Unclear
7.7 Yes
8. Was the statistical analysis appropriate for the study design and type of outcome 8 Yes
indicators?
appropriately?
8.2. Were correct statistical tests used and assumptions of test not violated? 8.2 Yes
30
8.3. Were statistics reported with levels of significance and/or confidence 8.3 Yes
intervals?
analysis)? 8.5 Unclear
8.5. Were adequate adjustments made for effects of confounding factors that might
have affected the outcomes (e.g., multivariate analyses)? 8.6 Yes
8.6. Was clinical significance as well as statistical significance reported?
8.7. If negative findings, was a power calculation reported to address type 2 error? 8.7 No
consideration?
9.1 Yes
9.2. Are biases and study limitations identified and discussed? 9.2 Unclear
10.2 Yes
MINUS/NEGATIVE (-)
If most (six or more) of the answers to the above validity questions are “No,” the report should be designated with
a minus (-) symbol on the Evidence Worksheet.
NEUTRAL ()
PLUS/POSITIVE (+)
Table 3: Quality Criteria Summary

Khajehdehi et al
Overall Quality Rating

Usharani et al
Yang et al
Na et al
2008
2011
2014
2015
RELEVANCE QUESTIONS
1. Would implementing the studied intervention or procedure (if found
successful) result in improved outcomes for the patients/clients/population
group? (NA for some Epi studies) Yes Yes Yes Yes
patients/clients/population group would care about? Yes Yes Yes Yes
3. Is the focus of the intervention or procedure (independent variable) or
topic of study a common issue of concern to dietetics practice? Yes Yes Yes Yes
4. Is the intervention or procedure feasible? (NA for some epidemiological
studies) Yes Yes Yes Yes
If the answers to all of the above relevance questions are “Yes,” the
report is eligible for designation with a plus (+) on the Evidence Quality
Worksheet, depending on answers to the following validity questions.
31
VALIDITY QUESTIONS
1. Was the research question clearly stated? Yes Yes Yes Yes
1.1 Was the specific intervention(s) or procedure (independent variable(s))
identified? Yes Yes Yes Yes
1.2 Was the outcome(s) (dependent variable(s)) clearly indicated? Yes Yes Yes Yes
1.3 Were the target population and setting specified? Yes Yes Yes Yes
2. Was the selection of study subjects/patients free from bias? Yes Yes Yes Unclear
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 Yes Yes No
2.2 Were criteria applied equally to all study groups? Yes Yes Yes N/A
2.3 Were health, demographics, and other characteristics of subjects
described? Yes Yes Yes Yes
2.4 Were the subjects/patients a representative sample of the relevant
population? Unclear Unclear Unclear Unclear
3. Were study groups comparable? No Yes Yes No
3.1 Was the method of assigning subjects/patients to groups described and
unbiased? (Method of randomization identified if RCT) No Yes Yes No
3.2 Were distribution of disease status, prognostic factors, and other factors
(e.g., demographics) similar across study groups at baseline? Unclear Yes Yes No
3.3 Were concurrent controls used? (Concurrent preferred over historical
controls.) Yes Yes Yes No
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 N/A N/A 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. Criterion may not be applicable in
some cross-sectional studies.) N/A N/A N/A N/A
3.6 If diagnostic test, was there an independent blind comparison with an
appropriate reference standard (e.g., “gold standard”)? N/A N/A N/A N/A
4. Was method of handling withdrawals described? No Yes Yes Unclear
4.1 Were follow up methods described and the same for all groups? Yes Yes Yes Yes
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%.) No N/A Yes Unclear
4.3 Were all enrolled subjects/patients (in the original sample) accounted for?
Unclear Yes Yes Unclear
4.4 Were reasons for withdrawals similar across groups? Unclear Unclear Yes Unclear
4.5 If diagnostic test, was decision to perform reference test not dependent
on results of test under study? N/A N/A N/A N/A
5. Was blinding used to prevent introduction of bias? Unclear Yes Yes Unclear
5.1 In intervention study, were subjects, clinicians/practitioners, and
investigators blinded to treatment group, as appropriate? Unclear Yes Yes Unclear
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.) Yes Yes Yes Yes
5.3 In cohort study or cross-sectional study, were measurements of
outcomes and risk factors blinded? N/A N/A N/A N/A
5.4 In case control study, was case definition explicit and case ascertainment
not influenced by exposure status? N/A N/A N/A N/A
5.5 In diagnostic study, were test results blinded to patient history and other
test results?
N/A N/A N/A N/A
32
6. Were intervention/therapeutic regimens/exposure factor or
procedure and any comparison(s) described in detail? Were intervening
factors described? Yes Yes Yes Unclear
6.1 In RCT or other intervention trial, were protocols described for all
regimens studied? Yes Yes Yes No
6.2 n observational study, were interventions, study settings, and
clinicians/provider described? N/A N/A N/A N/A
6.3 Was the intensity and duration of the intervention or exposure factor
sufficient to produce a meaningful effect? Yes Yes Yes Yes
6.4 Was the amount of exposure and, if relevant, subject/patient compliance
measured? No No Yes No
6.5 Were co-interventions (e.g., ancillary treatments, other therapies)
described? Yes Yes Yes No
6.6 Were extra or unplanned treatments described? No No No No
6.7 Was the information for 6.4, 6.5, and 6.6 assessed the same way for all
groups? Yes Yes Yes Yes
6.8 In diagnostic study, were details of test administration and replication
sufficient? N/A N/A N/A N/A
7. Were outcomes clearly defined and the measurements valid and
reliable? Yes Yes Unclear Yes
7.1 Were primary and secondary endpoints described and relevant to the
question? Yes Yes Yes Yes
7.2 Were nutrition measures appropriate to question and outcomes of
concern? Yes Yes Yes Yes
7.3 Was the period of follow-up long enough for important outcome(s) to
occur? Yes Yes Yes Yes
7.4 Were the observations and measurements based on standard, valid, and
reliable data collection instruments/tests/procedures? Yes Yes Unclear Yes
7.5 Was the measurement of effect at an appropriate level of precision? Unclear Unclear Unclear Unclear
7.6 Were other factors accounted for (measured) that could affect outcomes?
Yes Yes Yes Unclear
7.7 Were the measurements conducted consistently across groups? Yes Yes Yes Yes
8. Was the statistical analysis appropriate for the study design and
type of outcome indicators? No Yes Unclear No
8.1 Were statistical analyses adequately described the results reported
appropriately? Yes Yes No No
8.2 Were correct statistical tests used and assumptions of test not violated? Unclear Yes Unclear Unclear
8.3 Were statistics reported with levels of significance and/or confidence
intervals? Unclear Yes Yes No
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 Yes No Unclear
8.5 Were adequate adjustments made for effects of confounding factors that
might have affected the outcomes (e.g., multivariate analyses)? No No Yes Unclear
8.6 Was clinical significance as well as statistical significance reported? Unclear Yes Yes Yes
8.7 If negative findings, was a power calculation reported to address type 2
error? No No No No
9. Are conclusions supported by results with biases and limitations
taken into consideration? Yes Yes Unclear Unclear
9.1 Is there a discussion of findings? Yes Yes Yes Yes
9.2 Are biases and study limitations identified and discussed? No Yes Unclear Unclear
10. Is bias due to study’s funding or sponsorship unlikely? Yes Yes Yes Yes
10.1 Were sources of funding and investigators’ affiliations described? Yes Yes Yes Yes
10.2 Was there no apparent conflict of interest? Yes Yes Yes Yes
Quality Rating    -
33
Table 4: Study Overview
Author Usharani P, Mateen AA, Naidu MUR, Raju YSN,
Khajehdehi P, Pakfetrat M, Javidnia K, et al.
Chandra N.
Year 2008 2011
Study Design Randomized, parallel-group placebo-controlled Randomized, double-blind and placebo-controlled
study study
Class A A
Rating  
Study Type/ Evaluate the effects of curcuminoid Evaluate the effects of turmeric supplementation,
Purpose supplementation, compared to placebo compared to placebo supplementation, after 2
supplementation, after 8 weeks compared to months compared to baseline, on biomarkers for
baseline on endothelial function, oxidative stress decline in renal function in people with overt type 2
and inflammatory markers in people with type 2 diabetic nephropathy.
diabetes.
Study Population: NCB-02: n=23 Turmeric: n=20
Intervention Group
Sex 12 Males, 11 Females 9 Males, 11 Females
Age yrs mean±SD 55.52 ± 10.76 52.9 ± 9.2
BMI 24.66 ± 2.42 No Data
FBG (mg/dL) 155.04 ± 17.94 179.0 ± 65.5
Study Population: n=21 n=20
Placebo group
Age yr mean±SD 49.75 ± 8.18 52.6 ± 9.7
BMI 23.98 ± 2.35 No Data
FBG (mg/dL) 161.19 ± 19.97 169.54 ± 76.3
Intervention Randomized into one of three groups: (1) The Randomized into one of two groups: (1) turmeric
curcumin supplementation group: two 150 mg supplementation group: 500mg capsule of turmeric,
capsules of NCB-02, a standardized preparation containing 22.1mg active curcumin, with each meal
of C3 curcuminoids (curcumin 72%, demethoxy (3 capsules daily) (2) control group: identical placebo:
curcumin 18.08%, bisdemethoxy curcumin three times daily, for the same duration
9.42%) twice a day (600mg/daily) (2) statin
group: Atorvastatin, 10 mg once daily. (3)
placebo group: starch placebo twice daily
Outcomes Significant reductions in levels of biomarkers Significantly decreased urinary IL-8 (99.1±97.9 vs.
from baseline vs after 8 week treatment in NCB- 43.6±55.0pg/mL, P=0.002) and serum IL-8 (41.4±50.3
02 Group: ET-1 1.4±0.5 vs 0.7±0.1, IL-6 4.5±0.9 vs vs. 30.6±75.2pg/mL, P=0.002). Serum level of TGF-
1.8±0.7 (P<0.01), TNF-α 4.1±2.1vs 1.45±1.2 and proteinuria also significant decrease. Increase
(P<0.01), MDA 4.1±0.7 vs 2.5±0.3 (P<0.001). TNF-; No other significant differences were found
between control and trial groups.
Conclusion Treatment with NCB-02 significantly improved Turmeric supplementation significantly decreased
endothelial function and reduced levels of serum and urinary IL-8 levels. Short-term oral
inflammatory cytokines and markers of oxidative turmeric supplementation may prove to be a safe
stress in this study, but did not significantly and effective alternative therapy for type 2 diabetic
reduce LDL-C. nephropathy.
Limitations Small number of participants, compliance/ Small number of participants, low doses and
dropout rates not discussed, method of bioavailability of turmeric (curcumin) questionable,
randomization not identified, long term effects participant compliance not discussed, long term
unknown, recruited from one institute in India, effects unknown, recruited from one institute in Iran,
ethnic diversity not identified, baseline method of randomization not identified,
characteristics statistical significance not demographic, anthropometric data limited for
reported, blinding not addressed, study baseline comparison and confounding factors
limitations not addressed in sufficient detail. analysis
Yrs=years, BMI=Body Mass Index, FBG=Fasting Blood Glucose
34
Table 4 (cont.): Study Overview
Author Na L, Yan B, Jaing S, et al. Yang H, Xu W, Zhou Z, et al.
Year 2014 2015
Study Design Randomized, double-blind, placebo-controlled Non-controlled trial
Class A D
Rating  -
Study Type/ Evaluate the effects of curcuminoid Evaluate the effects of curcumin supplementation,
Purpose supplementation, compared to placebo, after 3 compared to placebo, after 15 days or 30 days on
months compared to baseline, on T2DM and A- development of diabetic kidney disease and
FABP promotion of curcumin regulation of lipid activation of the antioxidative master Nrf2 system in
metabolism, oxidative stress and inflammation. humans
Study Population: C3: n=50 Curcumin: n=14
Intervention Group
Age yr mean±SD 55.42 ± 6.40 60.6 ± 4.2, 69.1 ± 2.2
BMI 27.12 ± 2.26 22.4 ± 1.0, 23.7 ± 1.5
FBG (mg/dL) 154.44 ± 47.88 147.6 ± 14.4
Placebo group n=50 N/A
Sex 25 males, 25 Females N/A
Age yr mean±SD 54.72 ± 8.34 N/A
BMI 27.42 ± 3.04 N/A
FBG (mg/dL) 151.38 ± 39.06 N/A
Intervention Participants sorted by FBG concentration and All participants given 500 mg curcumin/turmeric daily
randomized into two groups: C3 group: 150mg of for 15 days. Those diagnosed with overt DKD
97.49% curcuminoids (curcumin 36.6%, dimeth- received curcumin supplementation for an extended
oxycurcumin 18.85%, bisdemethoxycurcumin 30 days total.
42.58%) twice daily; control group: starch
placebo twice daily for the same duration.
Outcomes Significant decreases in FBG (147.1±37.1 vs. 15 day U-mAlb reduced to 69.7 ± 41.9 mg/L (~ 70 %
131.0±31.86mg/dL, P<0.01), HbA1c (%) (8±2.9 vs. reduction, n = 14, p < 0.05). No significant decrease
7.0±2.0, P=0.031)after curcuminoids in FBG (147.6±14.4 vs 145.8±18.0mg/dL), but did see
supplementation. Also significant decreases in decrease in LDL-C (64.8±5.4 vs. 50.4±3.6). MDA level
serum A-FABP (34.5±7.0 vs. 26.2±10.0ng/mL, significantly reduced (13.9nmol±1.2 vs.
P<0.001), CRP (2.6±1.1 vs.2.1±1.0mg/L, P<0.001), 3.5±0.6nmol/L, n = 7, p < 0.001. Increases in NQO-1
TNF-α (2.1±0.8 vs. 1.7±0.7pg/mL, P=0.047), and (optical density: 0.32±0.09 vs. 0.70±0.13, n = 6,
IL-6 (3.9±2.0 vs.2.7±1.6pg/mL, P<0.001), and p < 0.01); SOD1 (1.01±0.31 without DKD vs.
significant increases in SOD activity (81.9±22.6 2.38±0.54 fold increase in DKD); SOD2 (1.4± 0.1
vs. 94.7±23.8 U/mL, P=0.005). No significant without DKD vs. 1.8± 0.2 fold increase in DKD) and
effects on MDA (No data). IκB (optical density: 0.62±0.03 vs. 1.24±0.10,
n = 6, p < 0.01).
Conclusion The results collectively support the hypothesis Curcumin can prevent DKD by reducing U-mAlb
that A-FABP probably links curcuminoids with excretion through anti-oxidative effect of Nrf2
their effect on oxidative stress and inflammation. upregulation and attenuate DKD by modulating gut
The anti-diabetic effects of curcuminoids may in microbiota, LPS, inflammatory pathway.
part be due to reduction in serum A-FABP level.
Limitations Small number of participants, curcumin content Small number of participants, lack of study protocols
questionably low, baseline comparison within and control variables, dosing levels questionable and
groups not reported/discussed, long term effects at 33% of manufacturer recommendations, long term
unknown, recruited from one medical university effects unknown, study participant recruiting
in China, ethnic diversity not identified, study methods unknown, ethnic diversity of participants
limitations not adequately addressed not identified, study limitations not addressed
T2DM=Type 2 Diabetes Mellitus, A-FABP=Adipocyte Fatty AcidBinding Protein, Yrs=years, BMI=Body Mass Index,
FBG=Fasting Blood Glucose
35
Summary of the Evidence
Table 4 provides an overview of the following summary of the evidence. Usharani 2008
found the curcumin group showed significantly reduced levels of biomarkers MDA (4.1±0.7 to
2.5±0.3nmol/mL, P<0.001), TNF-α (4.1±2.1 to 1.5±1.2pg/mL,P<0.01), and IL-6 (4.5±0.89 to
1.8±0.7pg/mL,P<0.01) compared to baseline as well as non-significantly lower total cholesterol
(including LDL-C from 120.4±42.1 to 111.3±37.7mg/dL, p-value not given). The statin group
had comparable effects but the placebo group had no significant effect on parameters measured
(Table5).
Khajehdehi 2011 found reduced serum levels of IL-8 (41.4±50.3 vs 30.6±75.2pg/mL,
P=0.002) and urinary excretion of IL-8 (99.1±97.9 vs. 43.6±55.0pg/mL, P=0.002) in the turmeric
supplementation group compared to baseline. They did not however find any statistical
differences in LDL-C and although not significantly, TNF-α actually increased.
Na 2014 found supplementation of curcuminoids led to significant decreases in TNF-α
(2.1±0.8 vs. 1.7±0.7pg/mL, P=0.047), IL-6 (3.9± 2.0 vs. 2.7±1.6pg/mL, P<0.001), and c-reactive
protein (2.6±1.1 vs. 2.2±1.0mg/L, P<0.001) when compared to the placebo group. The study did
not find any significant effects of curcuminoid supplementation on MDA (no data given) or
LDL-C concentration, however, it is it not clear if any of these values were compared to
baselines or just between groups.
Yang 2015 found MDA level in the patients was slightly high, but dramatically reduced
(13.9±1.2 vs. 3.5±0.6nmol/mL, P<0.001) following curcumin therapy and that plasma LPS
content, an inducer of inflammation was decreased (38.1±4.3ng/ml vs. 28.8±5.0ng/ml,P<0.01)
along with LDL-C (64.8±5.4 vs. 50.4±3.6mg/dL,P<0.01) following the intervention.
36
Table 5: Summary of change in variables
MDA (nmol/mL) TNFα (pg/mL) IL-6 (pg/mL) LDL-C (mg/dL) Glucose (md/dL) Curcumin
Pre Post P-value Pre Post P-value Pre Post P-value Pre Post P-value Pre Post P-value mg/day
Usharani No No
4.1 2.5 <0.001 4.1 2.1 <0.01 4.5 1.8 <0.01 120 111 155 150 600
2008 Data Data
Khajehdehi
12.8 18.4 0.82 IL-8 IL-8 0.002 114 110 0.71 179 156 0.21 66.3
2011
Na No No No
2.1 1.7 0.047 3.9 2.7 <0.001 77 68 0.115 154 131 <0.01 108
2014 Data Data Data
Yang No
13.9 3.5 <0.001 65 50 <0.01 148 146 ~500
2015 Data
Table Key: Significant Decrease Non Significant Decrease Increase Not Measured
Usharani 2008, Khajehdehi 2011 and Na 2014 were randomized placebo controlled trials,
the latter two of which included blinding. Yang 2015 was a non-controlled trial. Although
randomized controlled trials are generally considered the more desirable study design, several
issues contributed to the failure of any of the four studies to earn a positive quality rating.
Trial group sizes ranged from 14 to 50, with the median two studies enrolling 20 and 23
participants in the intervention group. Therefore, none of these trial groups, or sample sizes for
that matter, were very large or very generalizable. The only information given on the ethnic
diversity of the participants comes from the knowledge of which country the trial was conducted
in. Moreover, the lack of information on controls for randomization, blinding, statistical
analyses or confounding factors was what earned three of these studies a neutral rating11 and the
fourth a negative rating14.
A 2013 review4 of the research for the previous ten years, suggested that higher levels, up
to 8,000 mg per day, of curcumin supplementation seems to be relatively safe, with no serious
adverse effects reported aside from some mild gastrointestinal discomfort. The highest
administration of curcumin from the articles for this review was approximately 600 mg of
curcumin with improved bioavailability from NCB-02 curcuminoid supplement form (full dose
37
or curcumin percentage not specified) from Usharani 2008. The intervention for Na 2014
consisted of 300 mg of 97.49% pure curcuminoids translating to a daily equivalent of 36.06%, or
approximately 108 mg, actual curcumin. Khajehdehi 2011 administered 1500 mg of whole
turmeric containing 66.3 mg curcumin daily and Yang 2015 administered 500 mg per day,
however the supplement’s turmeric/curcumin composition is unclear. The dose however, is only
one third of the manufacturers recommendations which further complicates values for
comparison.
Quantifying the amount of curcumin supplemented in these trials is a challenge.
Curcumin, only comprises about 2% of the turmeric rhizome and is therefore extracted for
benefits beyond the amounts which can reasonably be achieved through diet alone8.
Additionally, because bioavailability is a concern, the molecular form of curcumin must be
modified or complexed for better absorption but leaves in question the synergistic effects of
turmeric and the other curcuminoids, demethoxy curcumin and bis-demethoxy curcumin8.
Combined with the fact that each manufacturer’s preparation of curcumin and curcuminoids ratio
varies, these trials11-14 did not provide enough conclusive information for a clear determination of
levels of exposure to produce a meaningful effect on outcomes.
As a diagnostic criteria for diabetes9, and common outcome measured in curcumin
supplementation trials, fasting blood glucose levels were taken at baseline and post treatment for
all participants in all four studies. As Table 5 shows, Na 2014 was the only study to observe a
significant decrease in blood glucose levels following curcumin supplementation (154.4+47.9 vs.
131.0+31.9, P<0.01). Outside of fasting blood glucose, low density lipoprotein-cholesterol
(LDL-C), was the only other common dependent variable measured in all four of the studies.
Only Yang 2015 observed a significant decrease in this variable (64.8+5.4 vs. 50.4+3.6mg/dL,
38
P<0.01). Usharani 2008 and Na 2014 examined the changes in levels of inflammatory and
oxidative stress markers MDA, TNF-, and IL-6, while Khajehdehi 2011 examined levels of
TNF- and Yang 2015 only levels of MDA. Yang 2015 additionally studied other markers in
inflammatory pathways such as SOD and LPS as Khajehdehi 2011 measured IL-8. Na 2014 was
the only one to measure CRP and Usharani 2008 ET-1.
Populations selected for the four studies were limited in ethnic diversity. Usharani 2008
was conducted in India and Khajehdehi 2011 was conducted in Iran. Na 2014 and Yang 2015
were conducted in China, yet no other information was provided on participants being a
representative sample of all adults with type 2 diabetes. All study groups had equal distribution
between males and females and populations in each study group averaged in the mid-fifties age
range with the exception of Yang 2015 participants averaging at 61 for males and 69 for females.
BMI for Usharani 2008 and Na 2014 averaged out to 25 and 27 respectively, however, BMI >24
was inclusion criteria for Na 2014. Yang 2015 participants average a BMI of 22, which was
possibly reflective of their age. They also had lower fasting blood sugars of 147 mg/dL
compared to 155 mg/dL for Usharani 2008 and Na 2014 respectively, however, Khajehdehi 2011
averaged higher at 179 mg/dL.
Although Khajehdehi 2011 and Yang 2014 focused on type 2 diabetes and other
measures related to renal function, they differed in inflammatory marker selection. Usharani
2008 controlled for lipid and glucose lowering drugs and comorbidities, Khajehdehi 2011
controlled, or excluded for blood pressure and other abnormal urinary infection/excretion, but
made proteinuria an inclusion criteria and did not mention any other comorbidities. Na 2014
excluded for other endocrine disease, medications and infection but Yang 2015 did not exclude
or control or exclude for other interventions/comorbidities aside from range of proteinuria.
39
Definitions
A-FABP adipocyte-fatty acid binding protein
CRP c-reactive protein, acute phase reactant inflammatory marker
curcumin bioactive compound found in turmeric
curcuminoids refers to the bioactive compounds curcumin, demethoxycurcumin, and
bisdemethoxycurcumin found in turmeric
DKD diabetic kidney disease
ET-1 endothelin-1, a measure of endothelial function

FBG (FBS) fasting blood glucose
IκBα inhibitor of kappa 
IL-6 interleukin-6, Inflammatory cytokine
IL-8 interleukin-8, Inflammatory cytokine more specific to inflammation and the pathogenesis of
diabetic nephropathy
LDL-C low density lipoprotein-cholesterol
LPS lipopolysaccharide, inducer of inflammation
MDA malondialdehyde, lipid oxidation index
NF-κB protein that controls transcription of DNA, cytokine production and cell survival. Key
role in regulating the immune response to infection.
NQO-1 NAD(P)H quinone oxidoreductase 1, specifically regulated protein of Nrf2 system
Nrf2 system master antioxidative system
TNF- tumor necrosis factor- alpha, inflammatory cytokine
TGF- transforming growth factor, biomarker more specific to pathogenesis of diabetic
nephropathy
turmeric rhizome, or root, of the curcuma longa plant
40
Conclusion Statement and Grade
Question: In adults with type 2 diabetes, does curcumin supplementation, compared to
a placebo or no supplementation, decrease serum inflammatory markers?
Conclusion: There is no clear evidence that curcumin supplementation, compared to a placebo
or no supplementation, decreases serum inflammatory markers in adults with type 2 diabetes.
Combined, the studies show curcumin interventions reduced MDA levels by 39-75%11,14, TNF-
by 19-49%11,14, and IL-6 by 31-60%11,14 however, conflicting studies show no significant effect
on MDA13, and an increase in TNF-. Grade III: Limited. This conclusion is based on the
limited number of studies that were available to adequately address this question. Weaker study
design, small sample sizes, inconsistent variables and lack of generalizability in available studies
provided insufficient evidence to make any other conclusive decision at this time.
Implications for patient care at James A. Haley Veterans Hospital
One out of every four veterans is living with Diabetes15. Chronic elevated levels of
inflammatory markers not only contribute to the development of the disease, but also to disease
progression. Researchers continue to be hopeful in finding curcumin to be effective in reducing
inflammation, but the lack of human trails makes it is difficult to even begin to suggest a
threshold for dosing levels. Because curcumin seems to be well tolerated in high amounts4, if one
decides, of their own accord, that curcumin therapy is something they would like to explore,
there does not seem to be cause for concern aside from some mild gastrointestinal discomfort.
However, there is not nearly enough information to consider applying a recommendation at the
Veterans Administration. If future research begins to elucidate the mechanism and effect of
curcumin on inflammation in the human body, then supplementation could be a very practical
41
recommendation for patients with diabetes. Long term outcomes would need to be studied for
confidence in recommendations, but depending on the form and molecular composition, would it
still even be considered curcumin at that point? And how accessible would this formulation be?
Moreover, it would need to be determined how much of a reduction in inflammatory markers
would be considered biologically or clinically significant. These studies showed some statistical
significance but if TNF- or IL-6 is reduced by 1 or 2pg/mL, is this enough to provide a
meaningful effect? With the numerous molecular targets identified by preclinical studies,
curcumin’s influence in vivo is still far from being understood. The array of variables examined
by these studies only prove that for now, curcumin, or the turmeric root, should likely remain
within the recommendation to include more varied spices to the diet.
References
1. Diabetes Latest. Centers for Disease Control and Prevention.
https://www.cdc.gov/features/diabetesfactsheet/. Published June 17, 2014. Accessed
September 29, 2017.
2. Long-term Trends in Diabetes. Centers for Disease Control and Prevention.
https://www.cdc.gov/diabetes/statistics/slides/long_term_trends.pdf. Published April 2017.
Accessed September 30, 2017.
3. Rivero A, Mora C, Muros M, García J, Herrera H, Navarro-González JF. Pathogenic
perspectives for the role of inflammation in diabetic nephropathy. Clinical Science.
2009;116(6):479-492. doi:10.1042/cs20080394.
42
4. Meng B, Li J, Cao H. Antioxidant and Anti-inflammatory Activities of Curcumin on
Diabetes Mellitus and its Complications. Curr Pharm Des. 2013;19(11):2101-2113.
5. Kunnumakkara A, Bordoloi D, Padmavathi G, Monisha J, Roy N, Prasad S, Aggarwal B.
Curcumin, the golden nutraceutical: multitargeting for multiple chronic diseases. Br J
Pharmacol. 2017;174(11):1325-1348.
6. Srinivasan M. Effect of curcumin on blood sugar as seen in a diabetic subject. Indian J Med
Sci.1972;26(4):269-70.
7. Zhang D, Fu M, Gao S-H, Liu J-L. Curcumin and Diabetes: A Systematic Review. Evid
Based Complement Alternat Med: eCAM. 2013;2013:636053.
8. Nelson K, Dahlin J, Bisson J, Graham J, Pauli G, Walters M. The Essential Medicinal
Chemistry of Curcumin. J Med Chem. 2017;60(5):1620-1637.
9. Diabetes Care: Classification and Diagnosis of Diabetes. American Diabetes Association
Website. http://care.diabetesjournals.org/content/40/Supplement_1/S11. Published January 1,
2017. Accessed September 30, 2017.
10. Standards of Medical Care in Diabetes 2017. American Diabetes Association Website.
https://professional.diabetes.org/content/clinical-practice-recommendations. Accessed
September 30, 2017.
11. Usharani P, Mateen A, Naidu M, Raju Y, Chandra N. Effect of NCB-02, Atorvastatin and
Placebo on Endothelial Function, Oxidative Stress and Inflammatory Markers in Patients
with Type 2 Diabetes Mellitus. Drugs R D. August 2008;9(4):243-250.
43
12. Khajehdehi P, Pakfetrat M, Javidnia K, Azad F, Malekmakan L, Nasab MH, Dehghanzadeh
G. Oral supplementation of turmeric attenuates proteinuria, transforming growth factor-β and
interleukin-8 levels in patients with overt type 2 diabetic nephropathy: A randomized,
double-blind and placebo-controlled study. Scand J Urol Nephrol. 2011;45(5):365-370.
13. Na L, Yan B, Jiang S, Cui H, Li Y, Sun C. Curcuminoids Target Decreasing Serum
Adipocyte-fatty Acid Binding Protein Levels in Their Glucose-lowering Effect in Patients
with Type 2 Diabetes. Biomed Environ Sci. 2014; 27(11):902-6.
14. Yang H, Xu W, Zhou Z, Liu J, Li X, Chen L, Weng J, Yu Z. Curcumin attenuates urinary
excretion of albumin in type II diabetic patients with enhancing nuclear factor erythroid-
derived 2-like 2 (Nrf2) system and repressing inflammatory signaling efficacies. Exp Clin
Endocrinol Diabetes. 2015;123(6):360-7.
15. Close to 25 percent of VA Patients Have Diabetes. Veterans Health Administration Website.
https://www.va.gov/health/NewsFeatures/20111115a.asp. Published November 15, 2011.
Accessed September 29, 2017.
44

Evidence Analysis Project Write-Up Curcumin and Inflammation Bwilliams

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In adults with type 2 diabetes, does curcumin supplementation, compared to a

placebo or no supplementation, decrease serum inflammatory markers?

Table 1: Articles Considered but Excluded………………..………………...………..………6

Table 2: Primary Research Articles Included...……………..…………………………..…….7

Selected Citations for Review……………………...………………………………………….8

Literature Evaluation Worksheets and Quality Criteria Checklists……………………......9-31

Table 3: Quality Criteria Summary…………...………………………………………….31-33

Summary of the Evidence……………………………….………………………………..36-39

Table 5: Summary of change in variables….……………………………………...…………37

Conclusion and Grading………………….………………………………….....…….……...41

Implications for Patient Care at JAHVH…………………………………….....………...41-42

also to associated diabetic complications and disease progression3.

preclinical animal or in vitro studies7.

transcription factors, inﬂammatory mediators, receptors, protein kinases, growth factors,

serum inflammatory markers8.

Preliminary research focused on the possible glucose lowering effects of curcumin

supplementation in type 2 diabetes.7 Type 2 diabetes is primarily associated with insulin

forms of curcumin supplementation for use in clinical human trials5.

Association involve a range of interventions to improve outcomes in diabetes including

Assessment of glycemic control is recommended through patient self-monitoring of blood

turmeric or curcumin supplementation however, “There is no clear evidence that dietary

diabetes who do not have underlying deficiencies11.”

researchers to continue to investigate the therapeutic potential of curcumin on various metabolic

investigate the question:

placebo or no supplementation, decrease serum inflammatory markers?

In order to investigate literature currently available on the topic, the following

comprehensive search strategy was developed:

Date of Literature Review: 08/28/17

· Publication Dates: 10 years

· Article Types: Clinical Trials

Exclusion Criteria: None

Search terms: curcumin AND diabetes

SEARCH DETAILS BOX: (("diabetes mellitus"[MeSH Terms] OR ("diabetes"[All

Fields] AND "mellitus"[All Fields]) OR "diabetes mellitus"[All Fields] OR

"diabetes"[All Fields] OR "diabetes insipidus"[MeSH Terms] OR ("diabetes"[All Fields]

AND "insipidus"[All Fields]) OR "diabetes insipidus"[All Fields]) AND

("curcumin"[MeSH Terms] OR "curcumin"[All Fields])) AND (Clinical Trial[ptyp]

AND "2007/09/01"[PDat] : "2017/08/28"[PDat] AND "humans"[MeSH Terms])

Summary of Articles Identified to Review:

· Total Number of Articles Considered : 11

· Number of Articles Considered but Excluded (Table 1): 7

1 Potential role of curcumin Appendino 2011 Outcomes measure

2 Meriva®, a lecithinized curcumin Steigerwalt 2012 Outcomes measure

3 Curcumin extract for prevention Chuengsamarn 2012 Outcomes measure β-

4 Reduction of atherogenic risk in Chuengsamarn 2014 Outcomes measure

5 Curcuminoids exert glucose- Na 2013 Outcomes measure

6 Effects of curcumin on brain- 2014 Outcome measures

7 Evaluation of the effect of 2014 Outcomes focused on

1 Effect of NCB-02, Atorvastatin Usharani 2008 Outcomes measure

2 Oral supplementation of Khajehdehi 2011 Outcomes measure

3 Curcuminoids Target Na 2014 Outcomes measure

4 Curcumin Attenuates Urinary Yang 2015 Outcomes measure

Atorvastatin and Placebo on Endothelial Function, Oxidative Stress and Inflammatory

Markers in Patients with Type 2 Diabetes Mellitus. Drugs R D. 2008;9(4):243-250.

2. Khajehdehi P, Pakfetrat M, Javidnia K, et al. Oral supplementation of turmeric attenuates

type 2 diabetic nephropathy: A randomized, double-blind and placebo-controlled study.

Scand J Urol Nephrol. 2011;45(5):365-370.

3. Na L, Yan B, Jaing S, et al. Curcuminoids Target Decreasing Serum Adipocyte-fattyAcid

Binding Protein Levels in Their Glucose-lowering Effect in Patients with Type 2

Diabetes. Biomed Environ Sci. 2014; 27(11):902-906.

4. Yang H, Xu W, Zhou Z, et al. Curcumin Attenuates Urinary Excretion of Albumin in

Type II Diabetic Patients with Enhancing Nuclear Factor Erythroid-Derived 2-Like 2

Academy of Nutrition and Dietetics