Abstract
Objectives
Cherry concentrate has been suggested to reduce serum urate (SU) and gout flares. The aims of this study were to determine the magnitude of the effect of tart cherry concentrate on SU in people with gout, the most effective dose of tart cherry concentrate for lowering SU, and adverse effects.
Methods
Fifty people with gout and SU > 0.36 mmol/l were recruited. Half were on allopurinol and half were on no urate-lowering therapy. Participants were randomized to receive tart cherry juice concentrate: placebo, 7.5 ml, 15 ml, 22.5 ml or 30 ml twice daily for 28 days. Blood samples were taken at baseline, then at 1, 3 and 5 h post cherry and then on days 1, 3, 7, 14, 21 and 28. The area under the curve for SU was calculated over the 28-day study period.
Results
Cherry concentrate dose had no significant effect on reduction in SU area under the curve, urine urate excretion, change in urinary anthocyanin between day 0 and day 28, or frequency of gout flares over the 28-day study period (P = 0.76). There were 24 reported adverse events, with only one (hyperglycaemia) considered possibly to be related to cherry concentrate. Allopurinol use did not modify the effect of cherry on SU or urine urate excretion.
Conclusion
Tart cherry concentrate had no effect on SU or urine urate excretion. If there is an effect of cherry concentrate on gout flares over a longer time period, it is not likely to be mediated by reduction in SU.
Trial registration
Australian New Zealand Clinical Trials Registry (ANZCTR), https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368887, ANZCTR 12615000741583).
Keywords: gout, cherries, treatment, serum urate
Rheumatology key messages
Tart cherry concentrate had no effect on serum urate or urine urate excretion.
There were no significant adverse effects associated with tart cherry concentrate.
Any effect of cherry concentrate on flares over a longer period is unlikely to be mediated by serum urate reduction.
Introduction
Dietary supplementation with tart cherry concentrate has been suggested as an adjunct to urate-lowering therapy (ULT) in the management of gout. Small studies in healthy volunteers and animals have shown that cherry consumption lowers serum urate (SU). For example, a study of 10 healthy women aged 22–40 years examined the effects of two servings (280 g cherries) on plasma urate at 1.5, 3 and 5 h post ingestion. Plasma urate decreased by a mean of 0.5 mg/dl (31 µmol/l) (P < 0.05) at the 5-h time point. Urinary urate increased post cherry consumption, with a peak excretion at 3 h of 305 ± 33 µmol/mmol creatinine compared with 202 ± 13 at baseline (P< 0.01) [1]. In another study of 16 patients with crystal proven gout, one tablespoon of cherry juice concentrate (∼45–60 cherries) twice daily for 120 days resulted in a non-significant reduction in SU from the baseline urate of 8.37 ± 0.082 mg/dl to 8.17 ± 0.082 mg/dl at 120 days [2].
It has also been suggested that cherries may prevent gout flares because cherry concentrate contains anthocyanin, a naturally occurring anti-inflammatory molecule that inhibits cyclooxygenase activity and scavenges reactive nitric oxide radicals. In a study of 633 individuals, cherry intake over a 2-day period was associated with a 35% lower risk of gout attacks compared with no cherry intake [odds ratio (OR 0.65; 95% CI: 0.5, 0.85]. A similar association was observed with cherry extract. Furthermore, when cherry intake was combined with allopurinol use, the risk of gout was 75% lower than during periods without either (OR 0.25; 95% CI: 0.15, 0.42) [3].
To date, the optimal dose of tart cherry concentrate for either a SU effect or flare prevention is unknown. The aims of this study were to determine the magnitude of the effect of tart cherry concentrate, including its dose and duration of use, on SU in people with gout. In addition, we evaluated the effect of tart cherry concentrate on plasma oxypurinol concentration, its adverse effects, as well as patient acceptability and compliance.
Methods
A short-term dose ranging and time course study was undertaken in a single centre. Ethical approval was obtained from the New Zealand Health and Disability Ethics Committee (15/NTB/133), and all participants provided written informed consent. The study was prospectively registered with the Australian and New Zealand Clinical Trials Registry on 17 July 2015 (ANZCTR 12615000741583).
Participants
Fifty people with gout as defined by the ARA preliminary classification criteria for gout [4] with a SU of >0.36 mmol/l (6 mg/dl) were recruited. People with type 1 diabetes and those receiving diuretics were excluded. Recruitment was selective to ensure half the participants were receiving allopurinol and half were on no ULT. Participants in each of these two blocks were randomized into one of the five different cherry concentrations groups: i.e. placebo 2 drops, 7.5 ml twice daily, 15 ml twice daily, 22.5 ml twice daily and 30 ml twice daily in 250 ml water for 28 days. Participants were provided with Cherryvite® Tart Cherry Concentrate 946 ml bottles, which contain juice from ∼3000 Montmorency cherries (1 ml ∼ 3cherries) and ∼15 g sugar per 30 mls.
Baseline data collection included demographics (age, sex, ethnicity), comorbidities (e.g. hypertension, diabetes, hypercholesterolaemia, heart disease), alcohol consumption, current medications, height, weight, BMI, blood pressure, serum and urine creatinine, SU and urine urate, and for those on allopurinol plasma oxypurinol.
Participants were seen at baseline, 1, 3 and 5 h post the first dose of cherry and then on days 1, 3, 7, 14, 21 and 28. At all visits, blood was collected for SU measurement. At baseline, days 7, 14, 21 and 28, blood was collected for creatinine, HbA1c, and oxypurinol concentrations, and urine for levels of urate, creatinine and anthocyanins. Information about gout flares and adverse effects were collected at days 7, 14, 21 and 28 and coded according to the Common Terminology Criteria for Adverse Events. Adherence was assessed by the amount of tart cherry concentrate remaining at the end of the study period and comparing this with the estimated volume left depending on the dose and by measurement of urinary anthocyanins.
Statistical analyses
Baseline demographics and presenting features were summarized for each randomized group using means, standard deviations (s.d.) and frequencies and percentages as appropriate. The primary outcome (i.e. SU concentration) was compared between randomized doses using a general linear mixed model. This model included randomized dose, allopurinol stratum, and time as fixed factors and participant as a random effect. Pearson’s correlation coefficient was used to test the associations between decremental SU area under the curve, and changes from baseline to day 28 in SU, oxypurinol and urinary anthocyanins. A two-tailed P-value of <0.05 was taken to indicate statistical significance.
Results
Baseline demographics and adherence
Fifty people with gout were recruited, 25 on allopurinol and 25 on no urate-lowering therapy. Baseline demographics are shown in Table 1. One participant (no ULT/Cherry =7.5 ml) withdrew at day 7 after requiring surgery for a strangulated hernia, and one participant (no ULT/Cherry = 7.5 ml) withdrew at day 21 after being admitted with an exacerbation of heart failure. One participant (no ULT/Cherry = 22.5 ml) withdrew consent after day 1, and one participant (no ULT/Cherry = placebo) remained in the study, but did not take the placebo dose (Fig. 1). There were no indications for non-adherence as assessed from returning bottles.
Table 1.
Demographic and clinical features of participants
| Placebo (n = 10) | 7.5 ml (n = 10) | 15 ml (n = 10) | 22.5 ml (n = 10) | 30 ml (n = 10) | |
|---|---|---|---|---|---|
| Age (years) | 56.9 (12.9) | 63.3 (13.0) | 61.0 (9) | 56.2 (11.4) | 60.4 (11.6) |
| Male n (%) | 9 (90%) | 9 (90%) | 9 (90%) | 8 (80%) | 10 (100%) |
| Ethnicity | |||||
| NZ European | 4 (40%) | 9 (90%) | 7 (70%) | 7 (70%) | 8 (80%) |
| Maori/Pacific | 6 (60%) | 1 (10%) | 3 (30%) | 3 (30%) | 2 (20%) |
| Ideal body weight (kg) | 72.4 (9.9) | 74.3 (7.9) | 69.8 (8.4) | 69.7 (9.9) | 76.0 (3.6) |
| BMI (kg/m2) | 30.5 (9.2) | 31.2 (10.0) | 28.8 (3.7) | 28.9 (3.2) | 29.5 (4.5) |
| Type 2 diabetes | 2 | 1 | 1 | 0 | 1 |
| Chronic kidney disease | 2 | 0 | 0 | 0 | 1 |
| Hypertension | 3 | 3 | 5 | 3 | 3 |
| Hyperlipidaemia | 3 | 1 | 3 | 3 | 4 |
| Ischaemic heart disease | 1 | 5 | 2 | 3 | 2 |
| Current smoker | 3 | 0 | 0 | 1 | 0 |
| Allopurinol | 5 | 5 | 5 | 5 | 5 |
| eGFR (ml/min/1.73 m2) | 72 (13) | 73 (16) | 73 (10) | 75 (16) | 79 (13) |
| Urate (mmol/l) | 0.47 (0.08) | 0.43 (0.05) | 0.44 (0.05) | 0.45 (0.09) | 0.43 (0.08) |
| Oxypurinol (umol/l) | 50.58 (34.5) | 65.11 (35.9) | 41.36 (35.5) | 63.88 (27.5) | 59.96 (37.3) |
| HbA1c | 38 (9) | 36 (7) | 40 (13) | 34 (4) | 33 (5) |
GFR: glomerular filtration rate.
Fig. 1.
Consort flow chart
Effect of tart cherry concentrate on SU in people with gout
Cherry concentrate doses had no significant effect on SU over the 28-day study period (Fig. 2a, Table 2) in the group as a whole, in those receiving allopurinol and in those on no ULT (Fig. 2b and c). Cherry concentrate dose had no significant effect on reduction in SU area under the curve over the 28-day study period. There was no effect of cherry concentrate dose on change in urinary anthocyanins between day 0 and day 28. There was no correlation between change in anthocyanins and decrease in SU area under the curve (r = –0.10, P = 0.50). There was no statistically significant effect of cherry concentrate on oxypurinol concentration over the 28 day study period (P = 0.11) (Table 2).
Fig. 2.
Effect of tart cherry concentrate on serum urate
(A) The group as a whole by cherry concentrate dose, (B) those on allopurinol by cherry dose, and (C) those on no urate-lowering therapy by cherry dose.
Table 2.
Effect of tart cherry concentrate on clinical and laboratory variables over a 28-day period. Data are mean (s.d.)
| Placebo |
7.5 ml |
15 ml |
22.5 ml |
30 ml |
|||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Day 0 | Day 28 | Change | Day 0 | Day 28 | Change | Mean difference from placebo | Day 0 | Day 28 | Change | Mean difference from placebo | Day 0 | Day 28 | Change | Mean difference from placebo | Day 0 | Day 28 | Change | Mean difference from placebo | |
| Serum urate (mmol/l) | 0.47 | 0.47 | 0.00 | 0.43 | 0.40 | 0.01 | −0.01 | 0.44 | 0.44 | 0.00 | 0.00 | 0.45 | 0.44 | 0.01 | −0.02 | 0.43 | 0.42 | −0.02 | 0.02 |
| (0.08) | (0.12) | (0.06) | (0.05) | (0.08) | (0.08) | (0.08) | (0.05) | (0.10) | (0.06) | (0.08) | (0.09) | (0.12) | (0.05) | (0.08) | (0.08) | (0.08) | (0.02) | (0.08) | |
| Weight (kg) | 95.2 | 96.3 | 1.1 | 95 | 95.8 | 1.5 | −0.39 | 85.8 | 86.7 | 0.9 | 0.20 | 86.8 | 86.7 | −0.1 | 1.22 | 95.3 | 95.9 | 0.6 | 0.55 |
| (32.0) | (31.9) | (3.0) | (23.0) | (24.6 ) | (4.3) | (4.19) | (12.1) | (12.5) | (2.5) | (3.94) | (13.5) | (14.0) | (1.8) | (4.05) | (14.1) | (13.4) | (1.5) | (4.05) | |
| BMI (kg/m2) | 30.5 | 30.9 | 0.3 | 30.6 | 30.8 | 0.5 | −0.15 | 28.8 | 29.17 | 0.3 | 0.03 | 28.9 | 28.9 | 0.0 | 0.38 | 29.9 | 30.1 | 0.2 | 0.15 |
| (9.2) | (9.1) | (0.9) | (9.9) | (10.4) | (1.4) | (1.31) | (3.7) | (3.8) | (0.8) | (1.23) | (3.2) | (3.4) | (0.6) | (1.27) | (4.8) | (4.7) | (0.4) | (1.23) | |
| Systolic BP (mmhg) | 135.9 | 135.2 | 6.2 | 137.3 | 140.6 | 8.5 | −1.27 | 142.1 | 140.1 | −2.0 | 8.53 | 137.8 | 133.6 | −4.7 | 11.51 | 121.9 | 131.8 | 9.9 | −3.05 |
| (21.0) | (15.5) | (10.9) | (26.0) | (24.5) | (11.9) | (23.18) | (16.4) | (13.6) | (15.6) | (21.80) | (21.7) | (15.8) | (22.1) | (22.41) | (13.7) | (13.6) | (11.5) | (22.41) | |
| Diastolic BP (mmhg) | 84.9 | 85.8 | 1.2 | 78.3 | 77.5 | 1.25 | −0.24 | 87.2 | 84.9 | −2.3 | 3.46 | 82.3 | 78.5 | −4.2 | 5.32 | 73.7 | 77.4 | 4.4 | −3.35 |
| (12.7) | (10.6) | (6.2) | (8.4) | (8.7) | (8.3) | (13.40) | (11.5) | (9.0) | (12.6) | (12.60) | (13.1) | (8.3) | (8.0) | (12.95) | (12.2) | (10.9) | (5.3) | (12.95) | |
| Creatinine (μmol/l) | 99.3 | 103.5 | 4.2 | 93.8 | 97.1 | −0.8 | 5.23 | 94.7 | 98 | 3.3 | 0.90 | 94.5 | 93.2 | −1.4 | 5.77 | 91.8 | 94.5 | 2.7 | 1.50 |
| (15.7) | (21.1) | (11.1) | (13.2) | (16.5) | (8.1) | (13.27) | (7.8) | (9.7) | (4.7) | (12.47) | (8.7) | (8.7) | (10.9) | (12.82) | (9.2) | (9.1) | (7.8) | (12.47) | |
| eGFR (ml/ min/1.7m2) | 72.3 | 69.5 | −2.8 | 73.1 | 71.8 | 1.125 | −4.04 | 73.2 | 70.4 | −2.8 | 0.00 | 75 | 75.6 | 0.7 | −3.52 | 79 | 76.1 | −2.9 | 0.10 |
| (12.7) | (14.1) | (6.7) | (16.3) | (16.8) | (6.1) | (10.14) | (10.2) | (10.3) | (4.1) | (9.53) | (15.8) | (13.4) | (8.2) | (9.80) | (13.5) | (11.6) | (7.6) | (9.53) | |
| HbA1c | 37.6 | 36.5 | −1.1 | 36.1 | 36.5 | 0.5 | −1.36 | 40.3 | 39.7 | −0.6 | −0.50 | 33.6 | 34.2 | 0.7 | −1.66 | 33.3 | 34.5 | 1.2 | −2.30 |
| (9.1) | (8.2) | (4.0) | (7.3) | (9.4) | (4.0) | (5.74) | (13.5) | (12.4) | (5.0) | (5.40) | (4.4) | (5.3) | (3.3) | (5.55) | (4.6) | (4.5) | (2.9) | (5.40) | |
| Urine anthocyanins | 2482 | 100396 | 7557 | 3899 | 17018 | 12631 | −1943 | 1213 | 17509 | 16417 | −8860 | 1258 | 11266 | 10008 | −1059 | 2217 | 15619 | 13662 | −4715 |
| (2441) | (12662) | (11443) | (5085) | (20696) | (22431) | (19368) | (1866) | (26534) | (26254) | (18204) | (2723) | (10002) | (10916) | (18715) | (2445) | (15668) | (15303) | (18715) | |
| Gout flares | 0.5 | 0.4 | −0.1 | 0.4 | 0.6 | 0.1 | −0.21 | 0.2 | 0.4 | 0.2 | −0.30 | 0.4 | 0.6 | 0.1 | −0.21 | 0.0 | 0.4 | 0.4 | −0.50 |
| (0.5) | (0.5) | (0.6) | (0.5) | (0.5) | (0.8) | (0.87) | (0.4) | (0.5) | (0.6) | (0.89) | (0.5) | (0.5) | (0.6) | (0.87) | (0.0) | (0.5) | (0.5) | (0.89) | |
BP: blood pressure.
The effect of the cherry concentrate on SU over the first 24 h of the study is shown in Fig. 3. The dose of cherry concentrate had no significant effect (P = 0.32) on fractional excretion of urate (normalized to mmol of creatinine).
Fig. 3.
Effect of cherry concentrate on serum urate over the first 24 h of the study
(A) Those on allopurinol, and (B) those on no urate-lowering therapy.
As expected, participants receiving allopurinol had significantly lower SU concentrations at all time points compared with those not on ULT (Fig. 4a). There was no apparent influence of cherry concentrate on the urate-lowering effect of allopurinol (Fig. 4b). However, those receiving allopurinol had significantly greater increases in urinary anthocyanins (P < 001) (Fig. 4c).
Fig 4.
Effect of cherry concentrate dose
(A) Serum urate, (B) reduction in serum urate AUC, and (C) change in urinary anthocyanins. AUC: area under the curve.
Effect of tart cherry concentrate on other clinical variables
There was no significant effect of cherry concentrate on change in HbA1c (P = 0.68) or weight (P = 0.80) over the 28 days (Table 2). There was no effect of cherry concentrate on the frequency of gout flares in the month prior to enrolment to flares over the 28-day study period (P = 0.76) (Table 2).
Adverse and serious adverse events
There were 24 adverse events reported in 24 participants over the 28-day period. Eighteen of these occurred in participants taking cherry concentrate. Only 1 adverse event, hyperglycaemia, was considered possibly related to cherry concentrate. Adverse events occurred in all cherry concentrate groups, placebo (n = 6), 7.5 ml (n = 3), 15 ml (n = 11), 22.5 ml (n = 2) and 30 ml (n = 2). There were two serious adverse events, one admission with heart failure (no ULT/Cherry = 7.5 ml) and one admission for a strangulated hernia (no ULT/Cherry = 7.5 ml). Neither SAE was considered to be related to cherry concentrate.
Patient acceptance of tart cherry concentrate
In general, the tart cherry concentrate was well tolerated, with only 2/46 (4.3%) participants saying the taste was intolerable and that they would not take it long term if it was recommended by a medical practitioner. Of the 45 participants, 38 (84.4%) said they would recommend it to a friend for prevention of gout. The mean price that participants were prepared to pay per month for cherry concentrate was NZD$34.4 (range NZD $0–100).
Discussion
Dietary modification is recommended for people with gout [5–7], despite a paucity of robust clinical trial evidence to support a clinically meaningful effect on SU or gout flares [8]. People with gout also prefer complementary therapies and dietary modification in long-term management [9]. Given such therapies may be costly, it is important to obtain robust evidence for people about the beneficial and adverse effects of the complementary therapies that they can purchase over the counter.
Herein, we have shown that tart cherry concentrate has no clinically significant effect on SU at any dose over a 28-day period. This is in keeping with a previous study of 16 people with crystal proven gout who received one tablespoon (15 mls) of cherry juice concentrate (∼45–60 cherries) twice daily for 120 days, which resulted in non-significant reduction in SU (baseline urate 8.37 ± 0.082 mg/dl compared with 8.17 ± 0.082 mg/dl at 120 days) [2]. In contrast, a small study in 10 healthy participants aged 22–40 years reported two servings (280 g) of cherries resulted in a mean reduction in SU of 0.5 mg/dl (31 µmol/l) (P < 0.05) at 5 h post ingestion [1].
Several mechanisms have been suggested whereby cherry may affect SU concentrations. In healthy women, an increase in urinary urate excretion has been reported [1]. In a study in rats, 5 mg/kg of tart cherry juice inhibited hepatic xanthine oxidase activity, suggesting that cherries may be able to reduce uric acid production [10]. Cherries contain vitamin C, which has been suggested to reduce SU in healthy volunteers [11]. In the current study, there was no increase in urinary urate excretion, suggesting that while the uricosuric effects of cherry may be sufficient to lead to a reduction in SU in people with normal renal urate excretion, it may not be enough in the setting of decreased renal urate excretion such as occurs in people with gout. Similar differential effects of vitamin C on SU have been observed in healthy volunteers and people with gout, highlighting the importance of undertaking dietary studies in the target population for any complementary therapy [12].
It has also been suggested that cherries may prevent gout flares. In a study of 633 individuals, cherry intake over a 2-day period was associated with a 35% lower risk of gout attacks compared with no cherry intake (OR 0.65; 95% CI 0.5, 0.85). Furthermore, when cherry intake was combined with allopurinol use, the risk of gout was 75% lower than during periods without either (OR 0.25; 95% CI 0.15, 0.42) [3]. In another small retrospective study of 24 patients with crystal proven gout consuming one tablespoon of tart cherry juice per day for ≥4 months, there was a significant reduction in gout flares from 6.85 ± 1.34 flares/year to 2.0 ± 0.6 flares/year (P = 0.0086) [2].
The exact mechanism of action of cherries in reducing gout flares remains unclear and is likely multifactorial [13]. Cherries, especially tart cherries, contain high levels of anthocyanins [14–16], which possess anti-inflammatory properties, either through inhibiting cyclo-oxogenase activities [15] or via scavenging of nitric oxide radicals [17]. Tart cherry concentrate has also been shown to inhibit in vitro secretion of IL-1 by monocytes stimulated with MSU crystals [2]. In our study, there was no effect on gout flares over the 28-day study period compared with the month prior to study entry. However, this study was not designed to primarily assess effect on gout flare. From the current study, it would appear that if cherry is associated with a reduction in gout flares, it is not mediated by a reduction in SU. Furthermore, if there is an effect on gout flares, it may be more pronounced in people receiving allopurinol, who have higher levels of urinary anthocyanins than those not on allopurinol. The mechanism by which this occurs is unclear. It will require further study to determine the magnitude of the anti-inflammatory effect and whether tart cherry concentrate may be an alternative to gout flare prophylaxis in those commencing ULT with allopurinol.
In this study, we showed no negative effect of tart cherry concentrate on the urate-lowering effect of allopurinol. Thus, if an effect on prevention of gout flares can be confirmed, cherry concentrate may be an alternative to NSAIDs or colchicine for gout flare prophylaxis during the introduction of ULT. However, larger prospective randomized clinical trials are required to determine the effects of cherry concentrate on gout flares.
Importantly, there were no significant adverse effects associated with the tart cherry concentrate over the short duration of this study. There is often a view that ‘natural’ or complementary therapies are safe. However, serious adverse events may occur. For example, there are case reports of acute kidney injury occurring in people with chronic kidney disease taking cherry concentrate for gout [18, 19].
There are several limitations in this study. The placebo comprised 2 drops of tart cherry extract in 250 mls water. The placebo did not alter the taste or colour of the water. As participants had to prepare the doses daily at home, it was not possible to blind the study. There was no formal power calculation undertaken; however, as this was a dose-ranging study, the group size of 5 per dose is generally considered sufficient. Finally, we did not independently test the contents of the concentrate used.
In conclusion, tart cherry concentrate had no effect on SU concentration or urinary urate excretion. If there is an effect of cherry concentrate on gout flares over a longer time period, it is not likely to be mediated by reduction in SU.
Funding: This work was supported by the Heath Research Council of New Zealand.
Disclosure statement: The authors have declared no conflicts of interest.
Contributor Information
Lisa K Stamp, Department of Medicine, University of Otago, Christchurch.
Peter Chapman, Department of Rheumatology, Immunology and Allergy, Christchurch Hospital.
Christopher Frampton, Department of Medicine, University of Otago, Christchurch.
Stephen B Duffull, School of Pharmacy, University of Otago, Dunedin, New Zealand.
Jill Drake, Department of Medicine, University of Otago, Christchurch.
Yuqing Zhang, Boston University School of Medicine, Boston, USA.
Tuhina Neogi, Boston University School of Medicine, Boston, USA.
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