Antidiabete suplements

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Systematic Review of Herbs and DietarySupplements for Glycemic Control inDiabetesGLORIA Y. YEH, MD, MPH1,2

DAVID M. EISENBERG, MD1TED J. KAPTCHUK, OMD1

RUSSELL S. PHILLIPS, MD1,2

OBJECTIVE To conduct a systematic review of the published literature on the efficacy andsafety of herbal therapies and vitamin/mineral supplements for glucose control in patients withdiabetes.

RESEARCH DESIGN AND METHODS We conducted an electronic literature searchof MEDLINE, OLDMEDLINE, Cochrane Library Database, and HealthSTAR, from databaseinception to May 2002, in addition to performing hand searches and consulting with experts in

the field. Available clinical studies published in the English language that used human partici-pants and examined glycemic control were included. Data were extracted in a standardizedmanner, and two independent investigators assessed methodological quality of randomizedcontrolled trials using the Jadad scale.

RESULTS Atotalof 108trials examining36 herbs (single or in combination)and 9 vitamin/mineral supplements, involving 4,565 patients with diabetes or impaired glucose tolerance, metthe inclusion criteria and wereanalyzed. There were58 controlled clinicaltrials involving individualswith diabetes or impaired glucose tolerance (42randomized and16 nonrandomized trials). Moststudies involved patients with type 2 diabetes.Heterogeneity andthe small numberof studies persupplement precluded formal meta-analyses. Of these 58 trials, the direction of the evidence forimproved glucose control waspositive in 76%(44 of 58). Very fewadverse effects were reported.

CONCLUSIONS There is still insufficient evidence to draw definitive conclusions aboutthe efficacy of individual herbs and supplements for diabetes; however, they appear to begenerally safe. The available data suggest that several supplements may warrant further study.The best evidence for efficacy from adequately designed randomized controlled trials (RCTs) isavailable for Coccinia indica and American ginseng. Chromium has been the most widely studiedsupplement. Other supplements with positive preliminary results include Gymnema sylvestre,Aloe vera, vanadium, Momordica charantia, and nopal.

Diabetes Care 26:12771294, 2003

Diabetes is a predominant publichealth concern, affecting 16 mil-lion persons in the U.S. The disease

causes substantial morbidity, mortality,

and long-term complications and remainsan important risk factor for cardiovascu-

lar disease. With increasing rates of child-hood and adult obesity, diabetes is likelyto become even more prevalent over thecoming decade (1).

In response to the increasing use ofcomplementary and alternative medicine

(CAM) among the general public (2,3),the American Diabetes Association issueda Position Statement in 2001 on Unprov-en Therapies that encouraged health careproviders to ask their patients about alter-native therapies and practices, evaluateeach therapys effectiveness, be cognizantof any potential harm to patients, and ac-knowledge circumstances in which newand innovative diagnostic or therapeuticmeasures might be provided to patients(4).

Recently, two national surveys haveexamined CAM use among those with di-abetes. One study, using 1996 MedicalExpenditure Panel Survey data, reportedthat 8% of respondents with diabetessaw a CAM professional for care (5). Anationally representative survey conductedin 19971998 reported that about one-third of respondents with diabetes useCAM to treat their condition (6). In othersurveys of specific diabetic populations,39% of Navajo, two-thirds of Vietnamese,and 49% of a largely Hispanic population

in South Texas used CAM (79).In general, the scientific literature on

the efficacy of CAM in the treatment ofdiabetes is relatively sparse and heteroge-neous. Studies have examined mind-bodytechniques, biofeedback,relaxation, qigong(1017), massage therapy, yoga, alterna-tive dietary/lifestyle modifications (18),aromatherapy, acupuncture, and othersystems of healing such as traditionalChinese medicine (TCM) (1930).

Most of the literature, however, hasfocused on herbs or other dietary supple-

ments. This finding parallels results fromprevalence surveys that report herbalremedies or other dietary supplementstaken by mouth to be consistently amongthe top CAM therapies used, regardless ofthe sample surveyed (5,6,8,9,31).

Plant derivatives with purported hy-poglycemic properties have been used infolk medicine and traditional healing sys-tems around the world (e.g., Native

American Indian, Jewish [32], Chinese[20], East Indian, Mexican). Many mod-ern pharmaceuticals used in conventional

From the 1Division for Research and Education in Complementary and Integrative Medical Therapies,Harvard Medical School, Boston, Massachusetts; and the 2Division of General Medicine and Primary Care,Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

Addresscorrespondence andreprintrequests to GloriaY. Yeh, MD,Harvard Osher Institute, 401ParkDr.,Ste. 22A, Boston, MA 02215. E-mail: [email protected].

Received for publication 30 October 2002 and accepted in revised form 13 January 2003. Additional information for this article can be found in an online appendix at http://care.

diabetesjournals.org.Abbreviations: CAM, complementary and alternative medicine; GTT, glucose tolerance test; RCT, ran-

domized controlled trial; TCM, Traditional Chinese medicine.A table elsewhere in this issue shows conventional and Systeme International (SI) units and conversion

factors for many substances.

R e v i e w s / C o m m e n t a r i e s / P o s i t i o n S t a t e m e n t s

DIABETES CARE, VOLUME 26, NUMBER 4, APRIL 2003 1277


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medicine today also have natural plant or-igins. Among them, metformin was de-rived from the flowering plant, Galegaofficinalis (Goats Rue or French Lilac),which was a common traditional remedyfor diabetes (33,34). Similarly, the use ofvitamin and mineral supplements for pri-mary or secondary disease prevention isof increasing interest (35).

However, there is relatively little knownregarding efficacy and safety of herb, vita-min, or other dietary supplements for di-abetes. Two prior reviews by Ernst et al.(36,37) examined plants with hypoglyce-mic activity in humans, including 22 clin-ical trials (5 randomized controlled trials[RCTs]). One recent systematic review on

Ayurvedic interventions was publishedunder the auspices of the Agency forHealthcare Research and Quality (AHRQ)

(38). Additionally, there have been sev-eral qualitative reviews reporting on se-lected supplements used in diabetes(33,35,39 45). To our knowledge, therehave been no comprehensive systematicreviews incorporating vitamin/mineralsupplements, in addition to herbal prod-ucts, for glucose control among patientswith diabetes.

Our objective was to review and sum-marize the literature on herbal remediesand dietary supplements for use in diabe-tes, to propose guidelines that may aidpractitioners in advising their patients,and to provide recommendations for fu-ture research.

RESEARCH DESIGN AND

METHODS

We searched MEDLINE, OLDMEDLINE,CAM-PubMed, HealthSTAR, and the Co-chrane Library Database from 1960 toMarch 2002 using the MeSH terms CAM,alternative therapies, hypoglycemic plants,and individual herb and supplementnames from popular sources, eachcrossed with the term diabetes mellitus. In

addition, we contacted experts in the fieldto identify studies, and we also hand-searched references of key articles. Wedid not include supplements made fromanimal components. Fish oil supplemen-tation, for example, has been examined inprior meta-analyses (46,47). We also didnot include soluble fiber supplements,which overlap considerably with dietaryfiber treatment and already play a role inconventional diabetes nutrition advice(48 51).

We limited studies to those publishedOpuntiastreptacantha

(Nopal)

FratiACetal

(1990)

Open-label;

Crossover;

Short-term

metabolictrial

14Type2;diet

and/orOHA

(dietalonedur-

ingstudy)

G

rillednopalstems;

500g;single

experimentaldose

400mlH2O

Decreaseglucose,

insulin

1

Notreported

Opuntiastreptacantha

(Nopal)

Frati-MunariAC

etal(1988)

Non-randomized;

Open-label;

Crossover;

Short-term

metabolictrial

32Type2;OHA

stoppedduring

study

Freshnopalstems,

broiled;500gcrude

weight;single

experimentaldose

Water;broiled

zucchinisquash

DecreaseFBG,

insulin

N/A

Notreported

Silymarin(Milk

Thistle)

VelussiMetal

(1997)

Open-label;2

parallelgroups

60Type2with

cirrhosis;diet

andinsulin

Silymarin;600mg/d

(Legalonformulation,

IBILorenzini,Milan);

for12mos

Notreatment

DecreaseFBG,

meanBG,urine

glucose,

HgbA1C,fasting

insulin,insulin

requirement,C

peptide

2

Nosideeffects

Trigonellafoenum

(Fenugreek)

SharmaRDetal

(1990)

Blindingunclear;

Crossover

15Type2;diet

andOHA(dose

decreased20%

duringstudy)

D

efattedfenugreekseed

powder;100g/dayin

unleavenedbread;for

10d

Notreatment

DecreaseFBG,PPG,

postprandial

insulin,urine

glucose

1

Notreported

Trigonellafoenum

(Fenugreek)

SharmaRDetal

(1990)

Blindingunclear;

Crossover

5Type2;dietand

OHA(dose

decreased20%

duringstudy)

D

efattedfenugreekseed

powder;100g/dayin

unleavenedbread;for

20d

Notreatment

DecreaseFBG,PPG,

urineglucose,

insulin

1

Notreported

Trigonellafoenum

(Fenugreek)

SharmaRDetal

(1990)

Blindingunclear;

Crossover

10Type1;diet

andinsulin

(dosedecreased

duringstudy)

D

efatteddebitterised

fenugreekseed

powder;100g/din

unleavenedbread;for

10d

Notreatment

DecreaseFBG,PPG,

urineglucose;no

changebody

weight,insulin

1

Notreported

Trigonellafoenum

(Fenugreek)

MadarZetal

(1988)

Non-randomized;

Open-label;

Crossover;

Short-term

metabolictrial

21Type2

Fenugreekseedpowder;

15ginwater;single

experimentaldosewith

mealtolerancetest

Notreatment

DecreasePPG;no

changeininsulin

N/A

Nosideeffects

*AlltrialsarerandomizedunlessotherwisespecifiedintheDesigncolumn.,nooutcom

emeasurespositive;,atleastoneoutcomemeasurepositive;,50%ofoutcomemeasurespositive.FBG,fasting

bloodglucose;PPG,postprandialglucose

;OHA,oralhypoglycemicagent.Fernando

MR,WickramasingheN,ThabrewMI,Ariya

nandaPL,KarunanayakeEH:EffectofArtocarpusheterophyllusand

Asteracanthalongifoliaonglucosetolerance

innormalhumansubjectsandinmaturity-on

setdiabeticpatients.JEthnopharmacol31:277277,1991

Review of herbs/vitamins in diabetes

1280 DIABETES CARE, VOLUME 26, NUMBER 4, APRIL 2003


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in the English language and restricted oursearch to herbs and supplements for gly-cemic control and symptoms of hypergly-cemia. We excluded trials that primarilyexamined diabetic complications such asneuropathy, nephropathy, or retinopa-thy. We included studies in subjects withimpaired glucose tolerance or those spe-cifically at risk for diabetes (e.g., older,sedentary, obese individuals with a familyhistory of diabetes). As supporting evi-dence, we also examined studies of glyce-mic control in healthy volunteers. Toassess quality of RCTs, we employed the

Jadad scale, a previously validated instru-ment that assesses trials based on appro-priate randomization, blinding, anddescription of study withdrawals or drop-outs (52,53). Quality of evidence for spe-cific herbs or supplements was assessed

using the U.S. Preventive Services TaskForce criteria (54) (online appendix A;http://care.diabetesjournals.org) and the

American Diabetes Association evidencegrading system for clinical practice rec-ommendations (55) (online appendix B).Clinical guidelines were based on the cri-teria developed by Weiger et al. (56) (on-line appendix C). These criteria placeindividual CAM therapies along a contin-uum that encompasses recommend(high-quality evidence supports both ef-ficacy and safety), accept/consider rec-ommending (evidence supports bothefficacy and safety), accept (evidence re-garding efficacy is inconclusive but sup-ports safety), and discourage (evidenceindicates either inefficacy or serious risk).

Data synthesisA total of 108 clinical studies were foundexamining 25 single herbs, 11 combina-tion herb formulas, and 9 vitamin/mineral supplements as potential therapyfor diabetes. Of these, 58 were controlledclinical trials in patients with diabetes orimpaired glucose tolerance (42 random-

ized, 16 nonrandomized). Only four ofthe controlled trials included patientswith type 1 diabetes (57 60). In addition,there were 12 trials examining glycemicparameters in healthy individuals. The re-maining studies were 36 uncontrolledprospective cohort trials and 2 case reports.

We present the available evidence for26 of the substances with either one ormore controlled clinical trials in patientswith diabetes or impaired glucose toler-ance. Methodological details and resultsof these trials are summarized in TablesT

able2Controlledclinicaltrialsofcombinationherbsforglycemiccontrol*

Herb/Supplement

Reference

Design

Sample

Intervention

Control

Outcomes

Evidence

Direction

Jadad

AdverseEffects/Events

TraditionalChinese

Medicine(TCM)

herbcombina-

tion

VrayMetal

(1995)

Do

uble-blind;4

parallelgroups

216Type2;on

dietalone

TraditionalChineseherbs;21

capsu

les/d(eachcontaining

150m

gCoptisChinensis,

30mg

Astragalus

membranaceus,120mg

Lonic

eraJaponica)/Oral

hypoglycemic(glibenclamide

7.5mg/d);for3mos

PlaceboTCM

capsule;

PlaceboOHA

tablet

DecreaseFBG,decrease

PPG,withsynergistic

effectofboth

treatments;no

changeininsulinor

HgbA1C

3

Diarrhea(1),drymouth

(1)TCMtreatment;

vertigo(1),

hypoglycemia(9)

OHAtreatment;

hypoglycemia(10)

OHATCM

Xiaoke(TCM)

HalePJetal

(1989)

Do

uble-blind;

Crossover

12Type2;ondiet

and/orOHA

Xiaoketea;uncharacterized

herbpreparationin2.72g

teabag(HomeandSutton,

London),4infusions/d;for4

wks

Ordinarytea

NochangeinHgbA1C,

FBG,PPG,orinsulin

3

Nosideeffects

SPDPA(TCM)

formula

XiongMetal

(1995)

No

n-randomized;

Open-label;2

parallelgroups

148Type2

SemenPersicalDecoctionfor

Purga

tionwithAddition

(Rhubarb,SemenPersical,

Ramu

lusCinnamomum,

Radix

Glycyrrhizae,Radix

Scrop

hularie,Radix

Rehm

anniae,Radix

Ophiopogonis,Radix

Astragalus);for2mos

OHA(glyburide)

DecreaseFBG,butno

differencefrom

control

N/A

Nosideeffects

NativeAmerican

herbcombina-

tion

RyanEAetal

(2000)

Sin

gle-blind;2

parallelgroups

40Type2;on

diet,OHA,and/

orinsulin

Herbaltea;Unspecifiedamount,

Populustremuloides

(trem

blingaspen)and

Heracleumlanatum(cow

parsn

ip)decoction;250mL/

d;for

10d

Placebodecoction

withChinese

greentea,

mint,fennel

seed

NochangeinPPG,

fructosamine,

HgbA1C

2

Minorgastrointestinal

discomfort(1)

TibetanMedicine

herbcombina-

tion

NamdulTetal

(2001)

Op

en-label;2

parallelgroups

200Type2;newly

diagnosedor

untreated;on

dietalone

Tibetanmedicineherbs;

individualizedpowder/pill

comb

ination(atleast2of

4:Kyu

ra-6,Aru-18,Yungwa-

4,Sugmel-19);for6mos

Noherb

treatment

DecreaseFPG,PPG,

andGHb;nochange

inweight

2

Notreported

*Alltrialsarerandomizedunlessotherwise

specifiedintheDesigncolumn.,nooutcom

emeasurespositive;,atleastoneoutcomemeasurepositive;,50%ofoutcomemeasur

espositive.FBG,fasting

bloodglucose;PPG,postprandialglucose;

OHA,oralhypoglycemicagent.

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13 (Single herbs, Multiple herb combi-nations, Vitamin and Mineral Supple-ments). These tables include supplementname, reference, study design, samplepopulation, intervention, control, out-comes, direction of evidence, Jadad score,and reported adverse effects. Other stud-ies, including some RCTs that examinedglycemic parameters in healthy individu-als, are not listed in the tables but are pre-sented as supporting evidence whenapplicable.

The most common outcomes mea-sures encountered in these trials includedthe following parameters of glycemic con-trol: fasting and postprandial plasma glu-cose, response to glucose tolerance tests(GTTs), insulin and C-peptide levels, pro-tein glycosylation (long-lived intracellu-lar glycated hemoglobin and shorter-lived

plasma fructosamine), and clinical insulinrequirements. Many of the vitamin stud-iesalso examined measures of insulin sen-sitivity, hepatic glucose production,glucose oxidation, and glucose uptake.Oftentimes, only a few of the above mea-sures were studied in any particular trial.

A significant positive change in at leastone of these important parameters was re-quired to categorize the trial as positive.

RESULTS

Single herbs/plant derivatives forglycemic controlTable 1 presents the controlled clinicaltrials of single herbs for glycemic controlin patients with diabetes. Of the singleherbs studied, the higher-quality RCTs(with Jadad scores of 3 or greater) areavailable for Coccinia indica, ginseng spe-cies, Bauhinia forficata, and Myrcia uni-

flora. One RCT forAllium sativum is also ofadequate quality but was conducted innondiabetic individuals. Other herbs, Al-lium cepa, Ocimum sanctum, Ficus carica,Silibum marianum, Opuntia streptacantha,

and Trigonella foenum, have been studiedin poorer-quality RCTs. Gymnema sylves-tre and Momordica charantia have beenstudied in only nonrandomized con-trolled trials.

Coccinia indicaCoccinia indica (ivy gourd) is a creepingplant that grows wildly in many parts ofthe India subcontinent, and is used totreat sugar urine (madhumeha) in

Ayurveda, a traditional East Indian heal-ing system. The mechanism of action ofV

anadium

BodenGetal

(1996)

Non-randomized;

Single-blind;

Crossover

8Type2;OHAand/or

insulin

Vanadylsulfate;100mg/d;for

4wks

Placebocapsule

DecreaseFBG,decrease

hepaticglucose

outputduringclamp

N

/A

4/8diarrhea;1/8

nausea;1/8

flatulence

VitE

ReavenPDetal

(1995)

Double-blind;2

parallelgroups

21Type2men;ondiet

and/orOHA

VitaminE;1600IU/ddl-

alpha-tocopherol

(Hoffman-LaRoche);for10

wks

Placebopill

NochangeinFBG,PPG,

postprandialinsulin,

glycatedHgb,

glycatedalbumin,

glycatedtotalplasma

proteins,fructos-

amine;decrease

susceptibilityofLDL

tooxidation

4

Nosideeffects

VitE

PaolissoGetal

(1993)

Double-blind;

Crossover

15Type2;wellcontrolled

ondietandOHA

VitaminE;900mg/ddl-

alpha-tocopherylacetate

(Ephynal,Roche,Italy);

for4mos

Sodiumcitrate

placebo

DecreaseHgbA1C,FPG,

PPG;nochangein

insulin,hepatic

glucoseoutput,

glucoseoxidation;

increasetotalbody

glucosedisposaland

non-oxidativeglucose

metabolism

3

Nosideeffects

VitE

Gomez-PerezFJet

al(1996)

Double-blind;

Crossover

53DM(39Type2,14Typ

e

1);poorlycontrolledon

diet,OHAand/orinsulin

VitaminE;1200mg/d(Searle

deMexicoSAdeCV):for2

mos

Placebocapsule

NochangeinFBG,

fructosamine,

HgbA1C

3

Notreported

VitE

PaolissoGetal

(1993)

Double-blind;

Crossover

25Type2;wellcontrolled

ondietandOHA

VitaminE;900mg/dd-alpha-

tocopherol(Ephynal,

Roche,Italy);for3mos

Placebopill

DecreaseFPG,HgbA1C,

PPG;nochangein

insulin

3

Nosideeffects;

noeffecton

liver/renal

functiontests

VitE

CerielloAetal

(1991)

Single-blind;3

parallelgroups

30insulin-requiringDM;

ondietandinsulin

VitaminE;1200mg/dvs.600

mg/d(unspecified

preparation);for2mos

Placebo

DecreaseHgbA1Cand

glycosylatedprotein

(doserelated);no

changeinFPGor

meandailyglucose

1

Notreported

VitE

JainSKetal

(1996)

Non-randomized;

Double-blind;2

parallelgroups

35Type1

VitaminE;100IU/d;for3

mos

Placebocapsule

DecreaseglycatedHgb;

nochangeFPG,

insulinrequirement

N

/A

Notreported

*Alltrialsarerandomizedunlessotherwise

specifiedintheDesigncolumn.,nooutcom

emeasurespositive;,atleastoneoutcomemeasurepositive;,50%ofoutcomemeasur

espositive.FBG,fasting

bloodglucose;FSIVGTT,frequentlysampledintravenousglucosetolerancetest;PPG,po

stprandialglucose;OHA,oralhypoglycemica

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Coccinia indica is not well understood, butthe herb appears to have insulin-mimeticproperties (61-63).

The one RCT of this herb (n 32),conducted in India, reported significantchanges in glycemic control following 6weeks use of powder from locally ob-tained crushed dried leaves in poorly con-trolled or otherwise untreated patientswith type 2 diabetes (64). Another three-arm controlled clinical trial (n 70) com-pared 12 weeks use of dried herb pelletsmade from fresh leaves with no treatmentand oral hypoglycemic agents (chloprop-amide) in patients with type 2 diabetes(61). The magnitude of change seen withthe herb was similar to that with a con-ventional drug. Two other open-labelprospective trials offer supporting evi-dence of a hypoglycemic effect (62,63).

No adverse events were reported in thesetrials. The preliminary evidence suggeststhat thepotential role for Coccinia indica indiabetes warrants further study. (U.S.Preventive Services Task Force Level I,

American Diabetes Association Guide-lines Level A)

Ginseng speciesSeveral different plant species are oftenreferred to as ginseng. These include Chi-nese or Korean ginseng (Panax ginseng),Siberian ginseng (Eleutherococcus sentico-sus), American ginseng (P. quiquefolius),andJapanese ginseng (P. japonicus). Panaxspecies (from the root panacea) are oftentouted for their cure-all adaptogenicproperties, immune-stimulant effects,and their ability to increase stamina, con-centration, longevity, and overall well-being (37). Preparations use the herbsroot; some sources report greater efficacywith roots that are greater than 3 yearsold. Principal components are believed tobe the triterpenoid saponin glycosides(ginsenosides or panaxosides). Hypogly-cemic effects have been shown in strepto-

zotocin rat models (65). Reported mech-anisms of action include decreased rate ofcarbohydrate absorption into the portalhepatic circulation, increased glucosetransport and uptake mediated by nitricoxide, increased glycogen storage, andmodulation of insulin secretion (39).

Most clinical trials we found utilizedAmerican ginseng, with many examiningthe herbs short-term effects on patientswith type 2 diabetes after a standard oralGTT (66,67). Two longer-term trials ad-ministered American ginseng for 8 weeks

(n 36 and n 24); both reported de-creases in fasting blood glucose andHbA

1c(68,69). Only one case of insomnia

was reported in these trials. Three othershort-term metabolic trials in healthy vol-unteers also found decreases in postpran-dial glucose (66,70,71). All but one of theclinical trials we examined were from thesame investigator group. The available ev-idence for American ginseng in diabetessuggests a possible hypoglycemic effect;however, the trials are small and longer-term studies are needed. (Level I, A)

Allium species: sativum and cepa Allium sativum (garlic), a member of thelily family, is most commonly used world-wide for flavorful cooking. Much of theclinical literature on garlic has focused on

its potential antioxidant activity and mi-crocirculatory effects (e.g., allicin andajoene for use in hypertension and hyper-lipidemia). Few studies have examined itseffects on insulin and glucose handling,although some attention has been given toallyl propyl disulfide, a volatile oil, andS-allyl-cysteine sulfoxide, a sulfur con-taining amino acid (39,72). Experimentsin animal models with alloxan-induceddiabetes have shown moderate reduc-tions in blood glucose; no effect is seen inpancreatectomized animals (72,72). Al-lium cepum (onion) also contains allyl pro-pyl disulphide and has similar purportedhypoglycemic properties. Reported mecha-nisms of allium species include increasedsecretion or slowed degradation of insu-lin, increased glutathione peroxidase ac-tivity, and improved liver glycogen storage(39,41).

The highest quality RCT ofAllium sa-tivum in humans was actually designed toexamine thrombocyte aggregation innondiabetic individuals (n 60). How-ever, the investigators found significantdecreases in fasting serum glucose (74).

The only availabletrialof garlicin patientswith type 2 diabetes (n 33) did not findconsistent glucose or insulin responses af-ter 1 month of supplementation (75). Theonly clinical trial available for Allium cepais a small RCT of allyl propyl disulphideextract capsules from onion in nondia-betic volunteers (n 6); investigatorsshowed an acute decrease in fasting bloodglucose and increase in insulin, support-ing an insulin-mediated effect (76). Noadverse events were reported in thesetrials. Thelimited data provide conflicting

evidence for allium species in glycemiccontrol. (Level I, C)

Ocimum sanctumOcimum sanctum (holy basil) is anothercommonly used herb in Ayurveda (relat-ed species include Ocimum album andOcimum basilicum). Studies in animalmodels suggest hypoglycemic effects(77), although the mechanism of actionremains unknown. Postulated effects in-clude enhanced -cell function and insu-lin secretion. The one available controlledclinical trial ofOcimum sanctum (n 40)showed positive effects on both fastingand postprandial glucose in patients withtype 2 diabetes using a local preparationof fresh leaf powder mixed in water for 4weeks (78). No adverse effects were re-ported. Further information is needed be-

fore the efficacy of Ocimum sanctum indiabetes can be fully assessed. (Level III,C)

Trigonella foenum graecumTrigonella foenum graecum (fenugreek) is alegume extensively cultivated in India,North Africa, and the Mediterranean. It isa common condiment used in Indiancooking and commonly used herb in

Ayurveda. Defatted seeds of fenugreek,which are rich in fiber, saponins, and pro-tein, have been described in early Greekand Latin pharmacopoeias for hypergly-cemia. Although the seed portion is oftenmentioned, other parts of the herb havealso been investigated. Purported mecha-nisms include delay of gastric emptying,slowing carbohydrate absorption, andinhibition of glucose transport from thefiber content, as well as increased eryth-rocyte insulin receptors and modulationof peripheral glucose utilization. Manystudies in alloxan-rat models have shownmodulated exocrine pancreatic secretion(79).

There are several trials available for

fenugreek in type 2 diabetes; however,most are noncontrolled (158). Of theavailable RCTs, they are generally poorer-quality studies with small numbers (n 515) and from a single investigatorgroup. Nonetheless, these trials, includ-ing a single trial in type 1 diabetes, havereported improved glycemic control us-ing seed powder incorporated into un-leavened bread (59,80). Another trial inhealthy volunteers (n 38) incorporatedseveral short-term randomized crossoverexperiments administering different

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preparations of fenugreek before oralGTT. In these series of trials, whole rawseeds, extracted seed powder, gum isolateof seeds, and cooked whole seeds seemedto decrease postprandial glucose levels,whereas degummed seeds and cookedleaves did not (79). Other open-label pro-spective cohort studies have followed pa-tients on fenugreek for up to 6 monthswith reported benefits in glycemic control(79,81 84). No adverse effects were re-ported in these trials. There is some pre-liminary evidence for the efficacy offenugreek that suggests further studiesmay be warranted. (Level II-2, C)

Bauhinia forficata and MyrciaunifloraIndigenous to rainforests and tropical ar-eas of South America, Bauhinia forficatahas been used in traditional treatment ofdiabetes in that area. In Brazilian herbalmedicine, Bauhinia species have been re-ferred to as vegetable insulin. Anothercommonly used South American herb isMyrcia uniflora. As part of a national effortto identify potential plant species usefulin glucose control, two small crossoverstudies (n 16 and n 18) by one in-vestigator administered each of theseherbs as tea infusions to separate groupsof patients three times daily for 8 weeks.No significant differences in glucose or

HbA1c were detected between study herbinfusion and a placebo tea using Imperatabrasiliensis. No adverse effects were re-ported (85). This limited preliminary evi-dence does not support the hypoglycemiceffect of these two plant species. (Level I,

American Diabetes Association level notapplicable if no studies show benefit)

Ficus caricaFicus carica (fig leaf) is a popular plantused for patients with diabetes in Spainand other areas in Southwestern Europe.

Its active component is unknown. Severalstudies in animal models with diabeteshave shown both short- and long-termhypoglycemic effects, although humantrials are lacking. Potential hypolipdemiceffects in diabetic rats have also beenshown (86 88). Its mechanism for glu-cose effect is unknown; however, somestudies suggest facilitation of glucose up-take peripherally. The one available clin-ical trial is a small crossover study of figleaf tea for 4 weeks in patients with type 1diabetes (n 10); investigators showed a

decrease in postprandial glucose and in-sulin requirements, but no change in fast-ing glucose when compared with thecontrol commercial tea (60). No effectwas seen in C-peptide levels, thereby sup-porting a noninsulin-mediated effect.No adverse effects were reported. Clearly,more information is needed before the ef-ficacy of Ficus carica can be properly as-sessed. (Level III, C)

Opuntia streptacanthaOpuntia streptacantha (nopal) or theprickly pear cactus can be found in aridregions throughout the Western hemi-sphere, including the southwestern U.S.,and is commonly used for glucose controlby those of Mexican descent. It has a high-soluble fiber and pectin content, whichmay affect intestinal glucose uptake, par-

tially accounting for its hypoglycemic ac-tions (65). Animal models have reporteddecreases in postprandial glucose andHbA

1cwith synergistic effects with insu-

lin. Studies in pancreatectomized animalsreport that hypoglycemic activity is notdependent on the presence of insulin(89). Most human studies of nopal havebeen published in Spanish and, thus, arenot included in this review. We foundonly two controlled short-term metabolictrials (n 14 and n 32) published inthe English language, both by the sameinvestigator (90,91). These reported im-provements in patients with type 2 diabe-tes with decreased fasting glucose anddecreased insulin levels, suggesting en-hanced insulin sensitivity. No side effectswere reported in these trials. The limiteddata suggests a possible hypoglycemic ef-fect of nopal; however, longer-term clini-cal trials are needed. (Level III, C)

Silibum marianumSilibum marianum (milk thistle), a mem-ber of the aster family, has been primarilystudied for its purported effects on alco-

holic and viral hepatitis, rather than forglycemic control. However, silymarin isrich in flavonoids, potent antioxidants,and some have postulated a potentialben-efit for those who have insulin resistancesecondary to hepatic damage (39). Mech-anisms are based on the herbs antioxi-dant activity and effects on hepatocytestabilization with decreased glutathioneoxidation, as well as on restoration of nor-mal malondialdehyde concentrations.

The one available clinical trial exam-ined cirrhotic patients with type 2 diabe-

t e s (n 60) using a commerciallyavailable preparation (Legalon 600 mg/day; IBI Lorenzini, Milan, Italy) for 12months, with significant improvementsin glycemic control when compared withno treatment (92). No adverse effectswere reported. Further information andhigher quality clinical trials are needed tofurther investigate milk thistle in glycemiccontrol. (Level III, C)

Gymnema sylvestreGymnema sylvestre is another commonlyused herb in Ayurveda. The plant is awoody climber that grows in tropical for-ests of central and southern India. Ac-cording to common folklore, chewing theleaves causes a loss of sweet taste, hencethe popular Hindi name of the plant gur-mar, meaning destroyer of sugar. Early

animal studies reported blood glucoselowering effects in animals with residualpancreatic function, but no effect in totalpancreatectomized animals. Studies of anethanol leaf extract, GS4, in diabetic ratand rabbit models have reported regener-ation of islets of Langerhans, decreases inblood glucose, and increases of serum in-sulin (58). Mechanism of action is un-known; postulated theories include anincrease in glucose uptake and utilization,increase in insulin release through cellpermeability, increase in -cell number,and stimulation of-cell function (39,93).

Two nonrandomized controlled clin-ical trials are available, both from thesame investigator group. Groups of pa-tients with type 1 diabetes (n 64) andtype 2 diabetes (n 47) showed im-proved glycemic control with chronic ad-

junctive use of GS4 extract comparedwith those who received conventionaltreatment alone (58,94). The evidence forthe beneficial effect ofGymnema sylvestrein diabetes is suggestive, although incon-clusive given the limited data. (Level II-1,C)

Momordica charantiaMomordica charantia is a vegetable indig-enous to tropical areas, including India,

Asia, South America, and Africa, alsoknown as balsam pear, karela (karolla),and bitter melon. Reported preparationsof the herb range from injectable extractsto fruit juice to fried melon bits (39,9597). Active components are thought to becharantin, vicine, and polypeptide-p (anunidentified insulin-like protein similarto bovine insulin). Theoretical mecha-




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nisms include increased insulin secretion,tissue glucose uptake, liver muscle glyco-gen synthesis, glucose oxidation, and de-creased hepatic gluconeogenesis. Studiesin alloxan-induced diabetic rabbits havesuggested hypoglycemic effects (98).

Two controlled short-term metabolictrials in patients with type 2 diabetes (n18 and n 9) have reported acute effectson blood glucose with Momordica charan-tia fruit juice, as well as subcutaneousvegetable insulin extract (95,99). Twoother small, uncontrolled open-label tri-als also reported positive effects on glyce-mic control after longer-term use (711weeks) (96,97). No adverse effects werereported in these trials. Some, albeit lim-ited, data suggest a potential effect ofMo-mordica charantia in diabetes. However,

further information in RCTs is needed.(Level III, C)

Aloe vera

Aloe vera is the most well-known speciesof aloe, a desert plant resembling the cac-tus in the Liliaceae family. It is popularlyused to treat burns and promote woundhealing. The dried sap of theAloe vera is atraditional remedy for diabetes in the Ara-bian peninsula (33), although aloe gel ispreferred over the sap as the latter con-tains the laxative anthraquinone (100).

Aloe gel, obtained from the inner portionof the leaves, contains glucomannan, ahydrosoluble fiber which may in part ac-count for its hypoglycemic effects (39).Reports in animal models have been in-consistent (100 103). Two nonrandom-ized clinical trials (n 40 and n 76) areavailable from the same investigatorgroup that reported improved fastingblood glucose with 6 weeks of juice madefrom aloe gel (100,104). Case reports offive type 2 diabetic individuals reporteddecreases in fasting blood glucose as wellas HbA

1c(101). No adverse effects were

reported in these trials. The preliminarydata suggest a potential effect ofAloe verain glycemic control; however, further in-formation is needed. (Level II-1, C)

Other herbs that have been studiedsolely in uncontrolled trials include ber-berine (105), Cinnamomym tamala (106),curry (107), Eugenia jambolana (108),gingko (109), Phyllanthus amarus (110),Pterocarpus marsupium (111), Solanumtorvum (112), and Vinca rosea (113).

Multiple herb combinations forglycemic controlTable 2 presents the controlled clinicaltrials of multiple herb combinations forglycemic control in patients with diabetes.

Combination formulas in TCMTCM encompasses a system of healingthat has origins over 2,000 years old. Itemphasizes the importance of a balancedand harmonious flow of qi, or lifeforce, and employs diverse modalitiessuch as acupuncture, massage, qigong,and an individualized approach to herbalmedicine (20). We found few trials ofTCM in the English language; most havebeen published in Chinese and were un-available for this review.

One controlled clinical trial of a mul-tiple herb combination examined a specific

formulation containing Coptis chinensis,Astragalus membranaceus, and Lonicera ja-ponica. Among a host of other plants usedin TCM for the treatment of diabetes,these plants were selected for study by theChinese Academy of Medical Sciencebased on experiential reports of efficacyand safety. Mechanisms of action are notwell reported, but may include decreasingdigestive carbohydrate absorption. Thisformula is not thought to influence actionof insulin. Using a 22 factorial design(n 216) with TCM verum pill or pla-cebo and glibenclamide verum pill or pla-cebo, investigators reported that the twotreatments together were more efficaciousthan either alone (114). Of 216 patients,there was one report of diarrhea and onereport of dry mouth. Also, one case ofhypoglycemia occurred in the combinedtreatment group.

A much smaller trial (n 12) of lowerquality examined another TCM prepara-tion,Xiaoke tea. Little is written about thisformulation in English literature. It ap-pears not to affect insulin concentrationsand was ineffective in rats that lack en-

dogenous insulin. The trial did not reportdetails about the constituents of the treat-ment tea, and investigators reported nodifference in glycemic parameters as com-pared with an ordinary tea infusion(115). Another controlled clinical trial(n 148) examined a formulation calledSemen Persical Decoction for Purgationwith Addition (SPDPA), a combination ofeight different herbs and reported de-creases in fasting blood glucose not signif-icantly different from changes seen withglyburide (116). No adverse effects were

reported with this formulation. The avail-able studies suggest that some TCM for-mulations, but not others, may havebeneficial effects. However, the data arecertainly limited and no formula has beenstudied in more than one trial. (Level I, C)

Combination formulas in NativeAmerican medicineNative American medicine refers to thehealing practices from the people indige-nous to North America; the approachcombines awareness of mind, body, andspirit and ritualistic observances withpractices of herbalism. One clinical trial(n 40) specifically examined an herbaltea preparation containing Populus tremu-loides (trembling aspen) and Heracleumlanatum (cow parsnip) prescribed by an

Alexis band Sioux healer (117). Investiga-

tors reported no glycemic benefit over acontrol tea containing mint and fennelseed. Little is known scientifically aboutthis formula, and it has not been studiedelsewhere. The limited evidence for thisNative American herb preparation doesnot support its use in glycemic control.(Level I, American Diabetes Associationlevel not applicable if studies show nobenefit)

Combination formulas in TibetanmedicineTibetan medicine is a traditional systemofhealing that has influences from China,Persia, India, and Greece, incorporatingconcepts from Ayurveda as well as psy-chological, philosophical, and spiritualaspects of Buddhism. Herbalism, espe-cially from the Himalayas, plays an im-portant role. Although of poorer quality,one large RCT (n 200) was availablethat examined individualized Tibetanherb prescription based on age, sex, per-sonality, pulse, and urine characteristicsin traditional diagnosis (118). Individualplant species and postulated mechanisms

were not reported. At 6 months, the studysuffered a large number of dropouts(44%); however, investigators analyzeddata by intention-to-treat, and improve-ments were nevertheless reported in fast-ing plasma glucose, postprandial glucose,and HbA

1cvalues. No adverse effects

were noted. These limited data are incon-clusive regarding use of individualTibetan herb prescriptions in type 2 dia-betes. (Level II-2, C)

We identified six other specific com-bination herb formulations that have

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been studied in patients with diabetes,three from Ayurveda (D-400, MA-471,and Ayush-82) (33,119 121) and threefrom Siddha (Chendooram, Sandan-apodi, and Kadal Azhinjil) (122125).None have been examined in RCTsonly open-label prospective cohort stud-ies or case reports.

Vitamins/trace elements/dietarysupplements for glycemic controlTable 3 presents the controlled clinicaltrials of vitamin/mineral supplements forglycemic control in patients with diabe-tes. Of the studies examining vitamin andmineral supplements for glycemic con-trol, the higher-quality RCTs (with Jadadscores of 3 or greater) are available forchromium, magnesium, vitamin E, and L-carnitine (126 137). Vanadium has been

studied in only nonrandomized con-trolled trials (138 140).

Chromium speciesChromium (Cr3), a trace element in itstrivalent form, is required for the mainte-nance of normal glucose metabolism. Ex-perimentally, chromium deficiency isassociated with impaired glucose toler-ance, which can be improved with sup-plementation (35). Most individuals withdiabetes, however, are not chromium de-ficient. In addition to glucose control, thesupplement has been studied for its ef-fects on weight control, lipids, and bonedensity. Its action is linked with glucosetolerance factor (GTF), and has beenshown to increase the number of insulinreceptors, to enhance receptor binding,and to potentiate insulin action. Somesuggest that chromium picolinate is thepreferred form because it is utilized moreefficiently (141).

Of the eight RCTs examining chro-mium in those with diabetes or impairedglucose tolerance, preparations differ andthe results are mixed. Among the larger

trials, one using organic chromium inbrewers yeast(n 78) and another usingchromium chloride (n 180) reporteddecreases in fasting and postprandial glu-cose (127,128). However, another trial by

Anderson (n 110) utilizing chromiumpidolate did not find changes in glycemiccontrol (142). One large noncontrolledopen-label trial of chromium picolinatefollowed 833 type 2 diabetic patients inChina for up to 10 months. Investigatorsreported a decrease in fasting and post-prandial glucose and a decrease in fatigue,

excessive thirst, and frequent urination(143). These studies all reported no ad-verse effects. A recent meta-analysis by

Althuis et al. (144) that included 15 RCTs(only 4 included diabetic individuals) re-ported that chromium had no effect onglucose or insulin concentrations in non-diabetic subjects; however, the dataamong patients with diabetes were incon-clusive. Althuis et al. also suggested thatmore trials should be performed in North

America, as the generalizabiltiy of trialsconducted in China is unknown given re-gional differences in diet and nutritionalstatus. (Level I, C)

MagnesiumHypomagnesemia is common in patientswith diabetes, especially those with glyco-suria, ketoacidosis, and excess urinary

magnesium losses. Deficiency of magne-sium can potentially cause states of insu-lin resistance. Studies have examinedmagnesiums potential role in the evolu-tion of such complications as neuropathy,retinopathy, thrombosis, and hyperten-sion. However, its role in glycemic controlis unknown. Magnesium is a cofactor invarious enzyme pathways involved in glu-cose oxidation, and it modulates glucosetransport across cell membranes. It mayincrease insulin secretion and/or improveinsulin sensitivity and peripheral glucoseuptake. It has been shown to have no ef-fect on hepatic glucose output and non-oxidative glucose disposal (35,40).Because it is an intracellular cation, it isdifficult to measure accurately, and totalbody stores are seldom measured.

Of the seven RCTs examining magne-sium supplementation for glycemic con-trol in diabetes, only two small lower-quality trials from one investigator group(n 8 and n 9) reported a decrease infasting plasma glucose and increase inpostprandial insulin (145,146). Of thethree highest-quality trials (Jadad score of

3), magnesium did not change blood glu-cose or HbA

1c(130 132). One trial (n

128) did find a decrease in serum fruc-tosamine, a short-term marker of glyce-mic control. Another study (n 40)reported one subject with an exanthemand one who had transient gastrointesti-nal pain with magnesium supplementa-tion. (Interestingly, the trial by Erikssonand Kohvakka [132] contained a studyarm that administered vitamin C supple-ments, which unlike magnesium, didshow improvements in glycemic control.

To our knowledge, this is the only reportof vitamin C for glucose control.) Theavailable data for magnesium are mixed,and thus the evidence for efficacy in dia-betes is inconclusive. (Level I, C)

Vitamin EDiabetes produces a state of increased freeradical activity. The purported effects ofvitamin E on glucose control relate to thevitamins potent lipophilic antioxidant ac-tivity, with possible influences on proteinglycation, lipid oxidation, and insulinsensitivity and secretion. Through un-known mechanisms, it may also affectnonoxida t ive gluc ose me t a b ol ism(35,40).

Of the controlled trials that examinedvitamin E for glucose control, the direc-

tion of the evidence for patients with type2 diabetes is positive in four of six, withdoses ranging from 100 to 1,600 mg/dayfor 2 4 months supplementation. Thelargest of these trials (n 53), however,was a double-blind placebo-controlledcrossover trial that found no change inserum glucose, fructosamine, or HbA

1c

(136). One clinical trial examined pa-tients with type 1 diabetes (n 35) andreported decreases in protein glycosyla-tion after 3 months of low-dose 100 IU/day vitamin E (57). Thus far, the available

evidence for vitamin E in glycemiccontrolis mixed and inconclusive. (Level I, C)

L-CarnitineSeveral in vitro studies have helped to elu-cidate L-carnitines role in metabolism,suggesting that it acts as a modulator offuel substrate utilization in cells, influenc-ing free fatty acid and glucose oxidation.Few have examined it clinically in pa-tients with diabetes. Three small con-trolled short-term metabolic trials

examined the acute effects in type 2 dia-betes (n 18, n 15, and n 9), show-ing that intravenous carnitine (or itsderivative acetyl-L-carnitine) administra-tion can possibly effect insulin sensitivityand enhance glucose uptake and storage(137,147,148). There are no longer-termclinical studies of L-carnitine for glucosecontrol and no studies of orally adminis-tered preparations. Thus, the availabledata are limited, and no conclusions canbe made regarding its possible use in dia-betes management. (Level I, A)




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VanadiumVanadium has been described as either anonessential nutrient or a nutrient that isrequired only in minute quantities, as nophysiological role of the trace element hasyet to be found (35,149). Human defi-ciency has not been documented. Thereare no accurate assays in clinical settings,and there is no recommended daily allow-ance. Vanadium exists in several valenceforms, with vanadyl (5) sulfate and so-dium metavanadate (4) being the mostcommon supplement forms. Its mecha-nism of action in glycemic control isthought to be primarily insulin-mimeticwith upregulation of insulin receptors. Inanimal models, it has been shown to fa-cilitate glucose uptake and metabolismand to enhance insulin sensitivity. Clini-cally, it may enhance glucose oxidation

and glycogen synthesis, and it may mod-ulate hepatic glucose output (35). Threevery small controlled clinical trials (n 6 8) have reported decreased fastingblood glucose (138 140); two of thesetrials also reported significant changes inHbA

1cand insulin sensitivity (138,139).

Two noncontrolled open-label studies,also with small sample sizes, nonethelessoffer supporting evidence (150,151).Goldfine et al. (151) included type 1 dia-betic patients (n 5) who decreased theirinsulin requirements after 2 weeks oftreatment. Gastrointestinal discomfort,including diarrhea, nausea, and flatu-lence, was reported by a large proportionof patients in all the vanadium trials. Or-ganically chelated compounds, however,are thought to cause less gastrointestinalirritation than vanadium salts (149). Theevidence for efficacy of vanadium in glu-cose control is suggestive, but as yet noRCTs are available. (Level II-1, C).

-Lipoic acidAlso known as thioctic acid, a disulfidecompound synthesized in the liver, -li-

poic acid is a potent lipophilic antioxi-dant. It is a cofactor in many multienzymecomplexes and may also play a role inglucose oxidation (152). Experimental invitro data have shown possible effects inenhancing glucose uptake in muscle andpreventing glucose-induced proteinmodifications. One multiple-dosage con-trolled trial is available in patients withtype 2 diabetes (n 74), and it reportedpositive effects on glucose uptake and in-sulin sensitivity with 600 1,800 mg/day-lipoic acid for 4 weeks; however, the

trial showed no changes in fasting bloodglucose (153). Another noncontrolledtrial offers supportive evidence for achange in insulin sensitivity (152). Theavailable data are limited and suggest thatfurther elucidation of -lipoic acids ac-tions is needed. (Level II-3, C)

DISCUSSION A total of 108 hu-man trials of herbs and vitamin/mineralsupplements for glycemic control wereobtained. Most trials examined supple-ments as an adjunct to conventional treat-ment with diet and/or medication. Of theavailable trials, 58 were controlled (42RCTs) and conducted specifically in indi-viduals with diabetes or impaired glucosetolerance. Among these controlled trials,statistically significant treatment effectswere reported in 88% (23 of 26) of those

examining single herbs, 60% (3 of 5) ofthose examining combination herbs, and67% (18 of 27) of those examining vita-min and mineral supplements. However,many trials were of poor quality. Morethan half of the RCTs (24 of 42, 57%)scored 2 or less on the Jadad scale. (NoRCT achieved a score of 5.) Thirteen trialshad sample sizes of 10 or fewer patients.In addition, there were generally few trialsper supplement, making it difficult todraw definitive conclusions regarding ef-ficacy. Nevertheless, no major safety con-cerns were reported in these trials. Fewmild adverse effects, mainly gastrointesti-nal irritation, were reported for ginseng,Native American herb tea, TCM pill, mag-nesium, and vanadium (see Tables). Forthe following supplements, 50% ofcontrolled clinical trials (at least two tri-als) suggested efficacy: Coccinia indica,Trigonella foenum, American ginseng, no-pal, Gymnema sylvestre, Aloe vera, Mo-mordica charantia, c hromium, a ndvanadium. Of these, the best evidence isavailable for Coccinia indica and Americanginseng. Supplements that appear effec-

tive but have only been studied in non-randomized trials include Gymnemasylvestre, Aloe vera, and vanadium. Sup-plements that appear to be effective inshort-term metabolic trials include Mo-mordica, nopal, and L-carnitine.

Guidelines for cliniciansIn assessing the quality of the evidence,we employed the American Diabetes As-sociation criteria for clinical guidelines(55). The evidence for the majority ofsupplements earned a C level rating,

mostly for supportive evidence fromRCTs with methodological flaws or un-controlled studies, or conflicting evidencewith weight supporting the recommenda-tion (online appendix B). Those supple-ments that earned an A rating includeCoccinia indica, American Ginseng, and L-carnitine, with supportive evidence fromat least one adequate RCT. However, ac-cording to the criteria described by

Weiger et al. (56), no herb or supplementhas sufficient evidence to actively recom-mend or discourage its use among pa-tients with diabetes. That is, evidenceregarding efficacy is inconclusive or notrigorous enough to meet the outlined re-quirements of efficacy, yet the herb orsupplement appears to be generally safe.Physicians should thus keep an openmind in advising patients who might al-

ready be using these supplements.The American Diabetes Association

and the American Dietetic Association donot have specific recommendations fortheuse of herb or vitamin/mineralsupple-ments in people with diabetes. Broad rec-ommendations for the general public arethat healthy people at low risk for nutri-tional deficiencies meet their require-ments with natural food sources. Those atincreased risk for deficiencies, such as theelderly, strict vegetarians, those followingvery low-calorie diets, and other special

populations, may benefit from multivita-min supplements (35).

Despite the lack of formal recommen-dations, the American Diabetes Associa-tion has acknowledged patient interestanduse of CAMsupplements for diabetes.In A Step-by-Step Approach to Complemen-tary Therapies and Guidelines for Using Vi-tamin, Mineral, and Herbal Supplements(154,155), safety is the main theme. Prac-tical information for patients on choosingsupplements is outlined (e.g., looking forproducts with recognized symbols of

quality: USP, NF, TruLabel, Consumer-Labs, etc.; looking for products with anexpiration date; avoiding foreign prod-ucts unless quality is known; and avoid-ing companies that make sensationalclaims or have misleading labels, etc). The

American Diabetes Association also warnsagainst combining supplements and pre-scription drugs without the physiciansknowledge and against stopping pre-scribed medication without the physiciansknowledge. They advise discontinuingsupplements before medical procedures

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(e.g., surgeries or anesthesia) and in theevent of an adverse effect.

Although the trials contained in thisreview reported very few adverse effects,other sources mentioned potential ortheoretical effects for six supplements.Theoretical cross-allergenicity was men-tioned with silymarin as a member of theaster family (daisy) and Trigonella as amember of the leguminosae family (pea-nuts), although no actual cases have beenreported. The most important potentialdrug-herb interaction was that of garlic orTrigonella with warfarin, as both herbsmay have limited anticoagulant proper-ties. Momordica may increase risk of po-tassium depletion, so caution might betaken with those on laxatives or diuretics.Ginseng used in conjunction with mono-amine oxidase inhibitors, phenelzine, or

stimulants may cause an enhanced eu-phoric effect. Other adverse effects havebeen reported with Panax ginseng (Asian)(e.g., hypertension, hypotension, mastal-gia, vaginal bleed, and insomnia), al-though the literature on diabetes haslargely involved Panax quiquefolius(American). Rare topical reactions havebeen reported with nopal,garlic, and-li-poic acid. Of note, one case of hypoglyce-mic c oma ha s b e e n re port e d wit hoverdosage of Momordica charantia(36,37,39, www.naturaldatabase.com).

Clinical research of CAMsupplements in diabetesCurrently, there is not yet sufficient eval-uation of herbs, vitamins, and mineralsupplements for glucose control in diabe-tes. Aside from relatively poor studymethodological quality, this area of sup-plement research has been fraught withseveral complications.

First, the multiple constituent natureof botanical products has made standard-ization a challenging task. Proponents ofherbal remedies caution that in standard-

izing to one constituent, resulting extractsmay have lost a proportion of benefit ascompared with the whole plant (156).Precise considerations of purity, chemicalcomposition, and potency of derivativesmay be grossly influenced by the age ofthe plant (especially of roots), the sourcelocation, the season of harvest, themethod of drying and crude preparation,etc. In the literature we examined, severalherb studies used homemade or other-wise unspecified preparations. Althoughindividual companies have begun to stan-

dardize supplements, there is a generallack of consistency across the market.

With vitamin and mineral supplements,these issues are less relevant.

In addition, the development ofproper supplement regulation and safetycodes has been slow. Currently, alldietarysupplements (including herbal products)are regulated under the Dietary Supple-ment Health and Education Act of 1994(DSHEA), which specifically differenti-ates supplements from drugs. Conse-quently, DSHEA does not require theextensive premarket approval that theFood and Drug Adminstration requiresfor a prescription drug, and although itcalls for good manufacturing practices[GMP], the burden of proof that a sup-plement is unsafe lies with the govern-ment, leaving manufacturers to operate

unchecked. This has contributed to skep-ticism among clinicians, and makes it es-pecially dif fic ult for physic ia ns t oresponsibly recommend supplements topatients. In the absence of external regu-lation, the industry has taken steps to po-lice itself. For example, the NationalNutritional Foods Association (NNFA),representing about one-third to one-halfof retailers and manufacturers of naturalproducts in the U.S., has encouraged theadoption of strict, self-imposed GMPstandards, as well as initiatives such as the

TruLabel program (in which products aresubjected to random laboratory testing byindependent third-party auditors to ver-ify contents) (42).

Research of vitamin and mineral sup-plements has also been hindered by a lackof accurate and meaningful assays that de-tect functional micronutrient deficiencies.In the case of chromium, for example, it ispostulated that supplementation of tar-geted individuals might be more benefi-cial. Some speculate that positive resultsseen in large studies in diabetic patients in

China may be due to the populations rel-ative chromium deficiency. However,without reliable assays, these theorieshave remained difficult to test (144).

Finally, the existing literature in thisarea includes a considerable amount ofstudy population heterogeneity. Futureresearch may need to more precisely de-fine targeted diabetic populations with re-gard to disease classification, severity,optimal adjunctive interventions, andperhaps nutrient deficiencies. It will alsobe important to further elucidate mecha-

nisms of action so that applicability totype 1 or type 2 diabetes can be clarified.

CONCLUSIONS As interest in thepotential benefit of herbs and supple-ments for diabetes grows, it will becomeincreasingly important to monitor theprogress of the clinical literature and tocommunicate these findings to patients.Based on this review, there is insufficientevidence to actively recommend or dis-courage use of any particular supplement,although most appeared to be generallysafe. Preliminary evidence of severalherbs and supplements suggest that fur-ther RCTs may be warranted. The sevenmost promising supplements includeCoccinia indica, American ginseng, Mo-mordica charantia, nopal, L-carnitine,Gymnema sylvestre, Aloe vera, and vana-

dium. Until more definitive studies helpto clarify our questions, clinicians shouldremain cautious, yet open-minded, re-garding adjunctive use of these supple-ments. They should be guided not only bysound clinical judgement, but also by pa-tients preferences, needs, and values. Aswe further our understanding of herbsand dietary supplements, we might beginto develop a framework for a medical sys-tem capable of incorporating those com-plementary therapies proven to bebeneficial.

Addendum Since our review of this topic,the report of a large multicenter trial (n 3,654), which examined the effects of vitaminE with and without ramipril in high-risk pa-tients with diabetes, has been published. Al-though this study was primarily concernedwith cardiovascular events and mortality, itdoes report that there were no differences inchange of HbA

1cbetween groups (157).

Acknowledgments The authors thank Dr. Alan Moses and Karen Chalmers for theirthoughtful review of the manuscript.

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