Does inhibition of iron absorption by coffee reduce the risk of gout?

To the Editor:Increased coffee consumption has been shownto be inversely associated with the risk ofgout both in men (1) and women (2). Aninverse association has also been foundbetween decaffeinated-coffee consumptionand the incidence of gout (1,2), thus suggest-ing that non-caffeine components of coffeealso contributed to the observed inverse asso-ciation. We suggest that some of the involvedmechanisms might be related to inhibition ofiron absorption by poliphenol compoundspresent in coffee, be it regular coffee or decaf-feinated coffee.

The main phenolic compound in coffee,chlorogenic acid, is a potent inhibitor of non-heme iron absorption (3,4). In particular, it hasbeen reported (3) that the polyphenolic contenttypical of a cup of instant coffee reduces ironabsorption from a test meal by 60–90%. Amongelderly participants in the Framingham HeartStudy (4), each 236 ml ⁄ week (1 cup ⁄ week) ofcoffee consumed was associated with 1% lowerserum ferritin.

On the other hand, mounting evidencesuggests that gout may be considered a dis-ease of iron overload. Uric acid accumulation,as both an antioxidant and an iron chelator(5), has been found in response to iron over-load (6,7). In fact, human tophi and thesynovial membrane contain iron (8). Further-more, it has been shown that some portion ofthe gouty inflammation after urate crystaldeposition could result from the incompletecomplexation of iron with subsequent cata-lytic generation of reactive oxygen species (6).Indeed, it was found that iron depletion pre-vented the relapse of the acute arthritis of pri-mary gout in 58% of gouty patients andmarkedly reduced its frequency and severityin the remaining 42% (9). Finally, it has beenshown that the association of coffee intake

with reduced insulin resistance may be par-tially explained by a decrease in body ironlevel (10); consequently, also the improvedinsulin sensitivity mediated by coffee-inducedinhibition of iron absorption could influenceserum uric acid concentrations thus reducingthe risk of gout. Moreover, it is well knownthat there is a strong positive relationshipbetween serum insulin resistance and hyper-uricemia (11), and gout forms part of thecore metabolic syndrome (12,13). In this set-ting, it has also been found that insulinreduces the renal excretion of urate (14).

Interestingly, tea intake, which is anotherrich source of polyphenols, was not associatedwith a reduced incidence of gout (1,2). How-ever, it has been speculated (2) that tea maycontain certain offending factors that counter-act the potential protective effect on the riskof gout of other beneficial compounds.

Therefore, increased intake of polyphenolcompounds present in coffee may maintain arelatively low iron status which in turn mayreduce the risk of gout.

L. Mascitelli,1 M. R. Goldstein2

1Medical Service, Comando Brigata alpina‘Julia’, Udine, Italy

2Fountain Medical Court, Bonita Springs, FL,USA

Email: lumasci@libero.it

References1 Choi HK, Willett W, Curhan G. Coffee consump-

tion and risk of incident gout in men: a prospective

study. Arthritis Rheum 2007; 56: 2049–55.

2 Choi HK, Curhan G. Coffee consumption and risk

of incident gout in women: the Nurses’ Health

Study. Am J Clin Nutr 2010; 92: 922–7.

3 Hurrell RF, Reddy M, Cook JD. Inhibition of non-

haem iron absorption in man by polyphenolic-

containing beverages. Br J Nutr 1999; 81: 289–95.

4 Fleming DJ, Jacques PF, Dallal GE, Tucker KL,

Wilson PW, Wood RJ. Dietary determinants of iron

stores in a free-living elderly population: the Fra-

mingham Heart Study. Am J Clin Nutr 1998; 67:

722–33.

5 Davies KJ, Sevanian A, Muakkassah-Kelly SF, Hoch-

stein P. Uric acid-iron ion complexes. A new aspect

of the antioxidant functions of uric acid. Biochem

J 1986; 235: 747–54.

6 Ghio AJ, Kennedy TP, Rao G, Cooke CL, Miller MJ,

Hoidal JR. Complexation of iron cation by sodium

urate crystals and gouty inflammation. Arch Biochem

Biophys 1994; 313: 215–21.

7 Ghio AJ, Ford ES, Kennedy TP, Hoidal JR. The

association between serum ferritin and uric acid in

humans. Free Radic Res 2005; 39: 337–42. [Erratum

in: Free Radic Res 2007; 41: 1385].

8 Muirden KD, Senator GB. Iron in the synovial

membrane in rheumatoid arthritis and other joint

diseases. Ann Rheum Dis 1968; 27: 38–48.

9 Facchini FS. Near-iron deficiency-induced remission

of gouty arthritis. Rheumatology 2003; 42: 1550–5.

10 Tuomainen TP, Lagundoye A, Voutilainen S. Coffee

intake and glucose homeostasis: is there a role for

body iron?. Arch Intern Med 2010; 170: 1400–1.

11 Fam AG. Gout, diet, and the insulin resistance syn-

drome. J Rheumatol 2002; 29: 1350–5.

12 Yoo HG, Lee SI, Chae HJ, Park SJ, Lee YC, Yoo

WH. Prevalence of insulin resistance and metabolic

syndrome in patients with gouty arthritis. Rheuma-

tol Int 2011; 31: 485–91.

13 Richette P, Bardin T. Gout. Lancet 2010; 375: 318–28.

14 Muscelli E, Natali A, Bianchi S et al. Effect of insulin

on renal sodium and uric acid handling in essential

hypertension. Am J Hypertens 1996; 9: 746–52.

Disclosure

None.

doi: 10.1111/j.1742-1241.2011.02640.x

LETTER

Rimonabant improves cholesterol, insulin resistance and markersof non-alcoholic fatty liver in morbidly obese patients: a retrospectivecohort study

To the Editor:Obesity is associated with co-morbiditiesincluding non-alcoholic fatty liver disease

(NAFLD), diabetes, obstructive sleep apnoeaand hypertension. This report describes clini-cal experience with the recently withdrawn

endocannabinoid CB-1 antagonist rimonabant(1,2) in morbidly obese patients presentingfor bariatric surgery.

LETTER

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, June 2011, 65, 6, 713–716 713

Clinical data were downloaded from theVector ⁄ Diabeta-3 database [Health Informa-tion Systems (UK) Limited, London, UK] forthe period 2006–2009 using the search terms:presentation- obesity and BMI > 40 kg ⁄ m2.This database includes records of patientdemography, ethnicity, anthropometry (includ-ing waist circumference), clinical diagnoses,metabolic and biochemical assessments andmedications at each clinic visit for nursing, die-tetic and medical visits. Patients had renal,liver, thyroid, lipid, insulin and glucose andHbA1c profiles measured. Insulin resistance wascalculated from the Homeostasis index(HOMA) (3). Data were analysed using Systat12 (Systat Corp; Hounslow, Middlesex, UK).Initial and final visits data were comparedusing parametric methods after log transforma-tion for non-Gaussian distributed variables. Ap-value of < 0.05 was considered significant.

Data were available for 222 patients for12.3 months (Figure S1). Patients were aged51 ± 11 years, 40% men and had a BMI of49.2 ± 8.8 kg ⁄ m2 (Table S1). Diabetes waspresent 36%, nocturnal hypoventilation in24%, hypertension in 66%, lymphoedema in10% and previous depression in 11%. Afterinitiation 35 patients discontinued rimonabantwithin 4 weeks because of side-effects or bypersonal choice leaving 187 patients in whom> 6 month compliance data were available(Table 1). Discontinuations occurred becauseof depression ⁄ mood change (18 patients; tworequiring psychiatric admission), nausea (fourpatients), and suicidal ideation (one patient)(Table S2). Continued follow-up of the 35patients receiving dietary counselling aloneshowed reductions in weight of 1.3 ± 12 kg,BMI 0.7 ± 4.1 kg ⁄ m2, blood pressure 0.7 ±14 ⁄ 0.5 ± 9 mmHg, glucose 0.5 ± 1.3 mmol ⁄ land an ALT increase 1 ± 6 IU ⁄ l at 12 months.The lipid profiles were essentially withunchanged: total cholesterol difference (0.0 ±

0.9 mmol ⁄ l), triglycerides (0, range )6.7 to1.3 mmol ⁄ l), HDL-C (0.03 ± 0.22 mmol ⁄ l)and LDL-C ()0.13 ± 0.70) mmol ⁄ l.

Patients compliant with long-term rimona-bant therapy were aged 52 ± 12 years and40% men and weighed 141 ± 28 kg [50 ±9 kg ⁄ m2 (range 35–89)]; diabetes was presentin 38%, obstructive sleep apnoea in 25%;hypertension in 66%, lymphoedema in 12%and hepatic steatosis in 8%. Treatmentresulted in a non-significant 4.6 ± 11 kg(median 4.5; range )40 to 41 kg) weight lossequivalent to 1.7 ± 4 BMI points (p = 0.07).This was associated with a 6.6 ⁄ 3.8 mmHgreduction in blood pressure, 1.3 mmol ⁄ l(20%) in glucose; 0.5% absolute change inHbA1c and a 17% reduction in alanine trans-aminase (ALT). Lipid profiles improved witha 15% reduction in total cholesterol, 17% inLDL-C and 37% in triglycerides with a non-significant 7% increase in HDL-C. Insulinlevels decreased by 39% (p = 0.01) andhomeostasis index (HOMA-IR) by 55%(p = 0.005). No change was seen in beta cellindex, creatinine, estimated glomerular filtra-tion rate or creatine kinase (CK). Eightpatients discontinued rimonabant therapy asa result of side-effects. One patient had severedepression requiring psychiatric assessment.

Rimonabant, an endocannabinoid CB1antagonist (withdrawn in 2009), was licencedin 2006 based on the results of the rimona-bant in obesity (RIO) trials for reduction ofweight in patients with BMI 27–40 kg ⁄ m2.Weight was reduced by 10% in a populationof average BMI 34 kg ⁄ m2 (weight 98–100 kg) allied with beneficial metaboliceffects on blood pressure, triglyceride-richlipoproteins and glycaemia (absolute HbA1c

reduction 0.7%) (1,2). The ComprehensiveRimonabant Evaluation Study of Cardiovas-cular Endpoints and Outcomes (CRE-SCENDO) cardiovascular outcomes trial

showed an increased incidence of depressionand suicide with rimonabant and the drugwas withdrawn (4). No trial investigated theeffect of rimonabant on patients with BMI> 40 kg ⁄ m2. Presurgical management ofpatients due to undergo bariatric surgerytypically involves the prescription of a lowcalorie, low carbohydrate diet to reducehepatomegaly and fatty liver. In prebariatricpatients a trial of 19 patients showed anaverage 4.4 kg loss with this intervention asopposed to 2.6 kg with calorie restriction(5). In this audit rimonabant therapyresulted in a non-significant 3% weight loss(4.6 ± 11 kg; 1.7 ± 4 kg ⁄ m2) allied with pre-dictable reductions in blood pressure, glu-cose; and HbA1c, triglycerides and increasedHDL-C. Metabolic changes matched thosepredicted by the Framingham study ofapproximately 1.5 ⁄ 1 mmHg ⁄ kg and 0.1%HbA1c ⁄ kg (6) and those seen in the RIO tri-als (1). Novel findings included a 17%reduction in ALT, 15% in total cholesterol,and 17% in LDL-C. A study of sevenpatients with non-alcoholic steatohepatitisdiagnosed by biopsy who received rimona-bant therapy showed reductions of 5.9 kg inweight (BMI 2.4 kg ⁄ m2), 54% in ALT, 20%in LDL-C and 16% in triglycerides (7). Bothgamma-glutamyl transferase (not measuredhere) and ALT levels are associated withNAFLD and the metabolic syndrome (8).The reduction in insulin resistance, transam-inases and LDL-C seen in this study mayreflect a reduced net production of very lowdensity lipoprotein and a reduction in hepa-tic steatosis (8). The therapy was toleratedby 84% of patients initially reducing to 80%and was limited to the occurrence of rapidonset nausea, depression and mood changes.This study has a number of disadvantages. Itis a retrospective cohort study with all thedisadvantages of these studies. The untreatedgroup defined by early-onset of lack of toler-ance of rimonabant provides a small self-selected parallel comparison group but showsweight reductions similar to those seen in arandomised study of dietary therapy in aprebariatric population of 1.7 kg (5).

Rimonabant was withdrawn because of itsincreased rates of neuropsychiatric side-effects(2009). Endocannabinoid receptors exist inthe liver and adipose tissue as well as in thebrain and are involved in the progression ofNAFLD. Recently a hydrophilic derivative ofrimonabant (AM-6545) with only peripheralCB1 activity has been investigated in obesemouse models (9). AM-6545 produced themetabolic changes expected with rimonabantbut showed no evidence of anxio-genesis inmice. This implies that rimonabant may havea primary peripheral action and that centralactions are only responsible for its secondaryside-effects. It remains to be seen whetherthese effects can be confirmed in man.

Table 1 Effects of long-term treatment with rimonabant in morbidly obese patients

Parameter Continued (n = 187) Completed (n = 179) Change (%) p

Age (years) 51.4 ± 11.6 – –Gender (% male) 40 – –BMI (kg ⁄ m2) 49.7 ± 9.0 48.1 ± 8.8 1.7 ± 4.0 (3) 0.07Weight (kg) 140.7 ± 28.1 136.0 ± 28.2 4.7 ± 11.2 (3) 0.11Waist (cm) 141 ± 18 135 ± 20 7 ± 10 (5) 0.008Glucose (mmol ⁄ l) 6.77 ± 3.25 6.27 ± 2.82 1.35 ± 3.66 (20) 0.14Blood pressure (mmHg) 138 ± 18 ⁄ 84 ± 10 132 ± 14 ⁄ 80 ± 9 7 ± 17 ⁄ 4 ± 12 (5) < 0.001Total cholesterol (mmol ⁄ l) 5.20 ± 1.84 4.60 ± 1.13 0.77 ± 1.85 (15) < 0.001Triglycerides (mmol ⁄ l) 1.73 (0.54–47.2) 1.51 (0.55–15.5) 0.23 ()7.8 to 31.6) (37) 0.02HDL-C (mmol ⁄ l) 1.21 ± 0.32 1.27 ± 0.35 0.07 ± 0.27 (+7) 0.10LDL-C (mmol ⁄ l) 2.83 ± 1.40 2.44 ± 1.06 0.48 ± 1.33 (17) 0.002ALT (IU ⁄ l) 27 (6–116) 21 (7–80) 3 ()45 to 84) (17) 0.002Insulin (pmol ⁄ l) 138 (20–1350) 134 (20–1350) 38 ()196 to 1126) (39) 0.01HOMA 5.64 (0.71–153) 4.14 (0.82–72) )1.6 ()130 to 29) (55) 0.005ApoA1 (g ⁄ l) 1.47 ± 0.27 1.42 ± 0.28 0.04 ± 0.29 (3) 0.19ApoB (g ⁄ l) 1.08 ± 0.38 0.92 ± 0.29 0.15 ± 0.31 (15) 0.002Creatinine (lmol ⁄ l) 76 (41–734) 79 (42–947) 0 ()78 to 114) (0) 0.28

714 Letters

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, June 2011, 65, 6, 713–716

This study showed that when rimonabantwas available, medium term prescriptionresulted in a non-significant weight loss inmorbidly obese patients but was associatedwith metabolic benefits including improvedinsulin resistance and lipid profiles consistentwith an improvement in hepatic steatosis.

A. S. Wierzbicki,1 S. Pendleton,2

Z. McMahon,1 A. Dar,3 J. Oben,3

M. A. Crook,1 A. J. Botha4

1Departments of MetabolicMedicine ⁄ Chemical Pathology, Guy’s & StThomas’ NHS Trust, St Thomas Hospital,

London, UK2Departments of Nutrition & Dietetics, Guy’s

& St Thomas’ NHS Trust, St ThomasHospital, London, UK

3Departments of Gastroenterology, Guy’s &St Thomas’ NHS Trust, St Thomas Hospital,

London, UK4Departments of Bariatric & upper

gastrointestinal surgery, Guy’s & St Thomas’NHS Trust, St Thomas Hospital, London, UK

Email: anthony.wierzbicki@kcl.ac.uk

References1 Wierzbicki AS. Rimonabant: endocannabinoid inhibi-

tion for the metabolic syndrome. Int J Clin Pract

2006; 60: 1697–706.

2 National Institute for Health and Clinical Excellence.

Rimonabant for the treatment of overweight and

obese adults. 2008 Report No.: TA144.

3 Matthews DR, Hosker JP, Rudenski AS, Naylor BA,

Treacher DF, Turner RC. Homeostasis model assess-

ment: insulin resistance and beta-cell function from

fasting plasma glucose and insulin concentrations in

man. Diabetologia 1985; 28: 412–9.

4 Topol EJ, Bousser MG, Fox KA et al. Rimonabant for

prevention of cardiovascular events (CRESCENDO):

a randomised, multicentre, placebo-controlled trial.

Lancet 2010; 376: 517–23.

5 de Toledo Triffoni-Melo A, Dick-de-Paula I, Portari

GV, Jordao AA, Garcia CP, Diez-Garcia RW. Short-

term carbohydrate-restricted diet for weight loss in

severely obese women. Obes Surg 2010, in press

(PMID 20195788).

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J. Benefits and adverse effects of weight loss. Observa-

tions from the Framingham Study. Ann Intern Med

1993; 119(7 Pt 2): 758–63.

7 Barros F. Biopsy-proven NASH treatment with rimo-

nabant: a case series. J Hepatol 2009; 50(Suppl. 1):

S355.

8 Torres DM, Harrison SA. Diagnosis and therapy of

nonalcoholic steatohepatitis. Gastroenterology 2008;

134: 1682–98.

9 Tam J, Vemuri VK, Liu J et al. Peripheral CB1 can-

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Disclosures

Dr Wierzbicki was a member of National andInternational Advisory boards for Sanofi-

Aventis on rimonabant in 2005–2008, wasUK lead investigator on the ETERNAL trial(2007–2009) and an investigator on theCRESCENDO trial (2007–2009). He alsoreceived travel support and lecture honorariafrom this source.

Supporting Information

Additional Supporting Information may befound in the online version of this article:

Figure S1. Database characteristics of theretrospective cohort analysis of rimonabanttherapy.

Table S1. Baseline characteristics ofpatients adherent to treatment pathway andprescribed rimonabant therapy. Comparisonswere performed between the continued anddiscontinued therapy groups.

Table S2. Discontinuations associated withrimonabant therapy. Patients could have morethan one reason for discontinuing treatment.

Please note: Wiley-Blackwell are notresponsible for the content or functionality ofany supporting materials supplied by theauthors. Any queries (other than missingmaterial) should be directed to the corre-sponding author for the article.

doi: 10.1111/j.1742-1241.2011.02683.x

LETTER

Gender-based cardiometabolic risk evaluation in minority andnon-minority men grading the evidence of non-traditional determinantsof cardiovascular risk

To the Editor:We read with interest the review entitled‘Gender-based cardiometabolic risk evaluationin minority and non-minority men gradingthe evidence of non-traditional determinantsof cardiovascular risk’ (1). This review high-lights the relevance of surrogate markers forthe evaluation of vascular risk.

South Asians formed 4% of the UK popu-lation in 2001 and they are at a high risk ofvascular events (2,3). We screened 1027Gujrati Indians (both genders) in faith basedsettings. Our preliminary analysis (n = 434)shows that at least one modifiable risk factorwas present in 92% of those screened, 15% ofthe participants screened had a 10 year CVrisk score >20% using QRISK2. Central adi-posity (according to the 2009 consensus defi-

nition of metabolic syndrome) (4) waspresent in 75% of subjects. Therefore, thispopulation has a high prevalence of metabolicsyndrome and central obesity which are dis-cussed in the Billups et al. review (1).

In line with the review of Billups et al.(1), we will include some of the surrogatemarkers of vascular risk in our screeningprogramme. For example, we will measurearterial stiffness, ankle-brachial index andcarotid intima media thickness. We will alsobe using Point of Care Testing (5) to mea-sure glycated haemoglobin and microalbu-minuria.

Hopefully, increasing the number ofmarkers of vascular risk will help to estimaterisk better in primary prevention as well asto potentially monitor the success of treat-

ment in both primary and secondary preven-tion.

A. Jain, D. Harvey, L. Robertson,D. P. Mikhailidis, D. R. Nair

Department of Clinical Biochemistry, RoyalFree Hospital, London

Email: anjly.jain@nhs.net

References1 Billupus KK, Miner MM, Wierzbicki AS, Jackson G.

Gender-based cardiometabolic risk evaluation in

minority and non minority men grading the evidence

of non-traditional determinants of cardiovascular

risk. Int J Clin Pract 2011; 65: 134–47.

2 Office National Statistics. Population of United King-

dom: by ethnic group (2001) http://www.statistics.

gov.uk/cci/nugget_print.asp?ID=455 (accessed 24 Feb-

ruary 2011).

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ª 2011 Blackwell Publishing Ltd Int J Clin Pract, June 2011, 65, 6, 713–716